(hetero)aryl-sulfonamide compounds as modulators of gpr35

Abstract

One aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, X-Y is -CONR6- or -NR6CO-; R6 and R7 are each independently H or alkyl; R8 is alkyl, cycloalkyl, (CH2)q-heterocycloalkyl or NR34R35; ring C is phenyl or a 6-membered heteroaryl group containing at least one N, each of which is optionally further substituted by one or more substituents selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, CN, NR9SO2-R10, NR9COR11, NR12R13, OH, SO2NR14R15, CONR16R17, cycloalkyl, O(CH2)qNR18R19, (CH2)q-heterocycloalkyl and CO2R20; 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; Ra and Rb are independently selected from alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR21COR22, NR21SO2R23, (CH2)qSR24, (CH2)qSOR25, (CH2)qSO2R26, SO2NR27R28, (CH2)qOH, (CH2)qOR29, NR30R31, CONR32R33, cycloalkyl and (CH2)q-heterocycloalkyl; L is a direct bond or is selected from, -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR36-SO2-, -NR36-SO2-alkylene, -SO2-NR36-, -SO2-NR36-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, wherein the alkylene moiety is optionally substituted. Further aspects of the invention relate to pharmaceutical compositions, and the use of said compounds in the treatment of various GPR35-related disorders.

Description

[0001] (HETERO)ARYL-SULFONAMIDE COMPOUNDS AS MODULATORS OF GPR35

[0002] The present invention relates to compounds that are capable of modulating GPR35 function. The compounds have potential therapeutic applications in the treatment of a variety of disorders, including proliferative, immune and inflammatory disorders.

[0003] BACKGROUND TO THE INVENTION

[0004] GPR35 is a class A, G protein-coupled receptor.1 2The human gene can be expressed as three variants: Variant 1 encodes a 309 amino acid polypeptide designated GPR35a (short form), while variants 2 and 3 encode a long form, GPR35b, which has a 31 amino acid extension at the N-terminus. Although several ligands have been suggested as endogenous agonists of GPR35, the GPCR officially remains an orphan receptor.3-11Several synthetic and exogenous modulators have also been reported, including agonists12-14and antagonists.15The synthetic chemical zaprinast, (5-(2-propoxyphenyl)- 1 H-[1 ,2,3]triazolo-[4,5-d]pyrimidin-7(4H)-one) is currently the standard GPR35 agonist used as a reference compound.18To date, however, the only GPR35 activator that has advanced into clinical trials is sodium cromoglycate (also known as RVT-1601 or PA101) which was investigated in the treatment of chronic cough in idiopathic pulmonary fibrosis1 37.

[0005] Both isoforms of GPR35 display similar pharmacology with respect to reported agonists13and any potential distinctive functions are unknown. GPR35 is primarily expressed throughout the epithelium of the gastrointestinal (Gl) tract, including the stomach, gall bladder, duodenum, small intestine and colon16 17, although expression is also prominent in certain macrophages and dendritic cells.2 18Evidence suggests possible links between GPR35 and a range of pathological conditions including inflammation, asthma, cardiovascular disorders, and diabetes.18Increased GPR35 expression is also associated with certain cancers.25High expression of GPR35 in gastric cancer is associated with poorer prognosis of patients. In vitro, GPR35 expression was associated with increased gastric cancer cell viability and proliferation, and reduced apoptosis.40siRNA knockdown of GPR35 in macrophages also reduced M2 markers ARG1 and PPARG, suggesting a role for GPR35 in supporting a pro-cancer macrophage M2 phenotype. GPR35 signalling, therefore, represents an attractive pathway for therapeutic intervention for the treatment of a range of diseases. Accordingly, there is an ongoing need to develop new small molecule GPR35 modulators. The present invention seeks to provide compounds that are capable of modulating GPR35. 5 As made clear from the above discussion, such compounds have potential therapeutic applications in the treatment of a variety of disorders, including proliferative disorders and immune disorders, as well as inflammatory disorders. STATEMENT OF INVENTION A first aspect of the invention relates to compounds of formula (I), or a pharmaceutically 10 acceptable salt or solvate thereof, wherein: X-Y is -CONR6- or -NR6CO-; 15 R6and R7are each independently selected from H and alkyl, more preferably H; R8is selected from alkyl, cycloalkyl, (CH2)q-heterocycloalkyl and NR34R35; ring C is a phenyl group or a 6-membered heteroaryl group containing at least one N, each of which is optionally further substituted by one or more substituents selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, CN, NR9SO2-R10, NR9COR11, NR12R13, OH, 20 SO2NR14R15, CONR16R17, cycloalkyl, O(CH2)qNR18R19, (CH2)q-heterocycloalkyl and CO2R20; each R9is independently selected from H and alkyl; R10-R19are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; or R12and R13together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; or R14and R15together with the nitrogen to which they are attached form a 4- to 7-membered 5 heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; or R16and R17together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; or 10 R18and R19together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2;R20is selected from alkyl, aralkyl, , alkoxyalkyl, hydroxyalkyl and cycloalkyl; ring A is a phenyl group or a 6-membered heteroaryl group; ring B is a phenyl group or a 6-membered heteroaryl group; 15 n and p are each independently an integer from 0 to 4; each q is independently an integer from 0 to 4; each Raand each Rbis independently selected from alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR21COR22, NR21SO2R23, (CH2)qSR24, (CH2)qSOR25, (CH2)qSO2R26, SO2NR27R28, (CH2)qOH, (CH2)qOR29, NR30R31, CONR32R33, cycloalkyl and 20 (CH2)q-heterocycloalkyl; each R21is independently selected from H and alkyl; R22-R35are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; or R27and R28together with the nitrogen to which they are attached form a 4- to 7-membered 25 heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; or R30and R31together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; or 30 R32and R33together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; L is a direct bond or is a group selected from, -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR36-SO2-, -NR36-SO2-alkylene, alkylene-SO2-NR36-, -SO2-NR36-, -SO2- NR36-alkylene, alkylene-NR36-SO2-, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, 5 -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, and cycloalkylene-heteroalkylene, wherein 10 the alkylene moiety in the above groups is optionally substituted by one or more substituents independently selected from halo, alkyl, haloalkyl and cycloalkyl; R36is independently selected from H and alkyl; and Z is a group selected from alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl, each of which is optionally further substituted by one or more groups each independently selected 15 from CN, halo, alkyl, OH, alkenyl, alkynyl, alkoxy, haloalkyl and haloalkoxy. Advantageously, the presently claimed compounds are capable of modulating GPR35, thereby rendering the compounds of therapeutic interest in the treatment of various disorders, including oncology applications, inflammatory disorders, and gastrointestinal disorders. 20 Another aspect of the invention relates to a pharmaceutical composition comprising a compound as described above and a pharmaceutically acceptable diluent, excipient, or carrier. Another aspect of the invention relates to a pharmaceutical composition as described above for use as a medicament. 25 Another aspect of the invention relates to a compound as described above for use in treating or preventing a disorder selected from a proliferative disorder, a gastrointestinal disorder, a fibrotic disorder, cardiovascular disease, and an inflammatory disorder. Another aspect of the invention relates to a pharmaceutical composition as described above for use in treating or preventing a disorder selected from a proliferative disorder, a gastrointestinal disorder, a fibrotic disorder, a cardiovascular disease, and an inflammatory disorder. Another aspect of the invention relates to a method of treating a disorder, comprising administering to a subject a compound or a pharmaceutical composition as described 5 above. Another aspect of the invention relates to a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in treating or preventing a GPR35-associated disease or disorder. Another aspect of the invention relates to the use of a compound as defined herein, or a 10 pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating or preventing a GPR35-associated disease or disorder in a subject. Another aspect of the invention relates to the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating or preventing a disorder selected from a proliferative disorder, a gastrointestinal 15 disorder, an inflammatory disorder, a fibrotic disorder and cardiovascular disease. DETAILED DESCRIPTION The present invention relates to compounds that are capable of modulating GPR35. “Alkyl” is defined herein as a straight-chain or branched alkyl radical, preferably C1-20alkyl, more preferably C1-12alkyl, even more preferably C1-10alkyl or C1-6alkyl, for example, 20 methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. More preferably, the alkyl is a C1-3alkyl. “Cycloalkyl” is defined herein as a cyclic alkyl ring, preferably, C3-7-cycloalkyl, more preferably C3-6-cycloalkyl. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or a fused bicyclic ring system such as norbornane. 25 As used herein, the term “aryl” or “aromatic” refers to a C6-12aromatic group, which may be benzocondensed, for example, phenyl or naphthyl. “Halogen” or “halo” is defined herein as chloro, fluoro, bromo or iodo. “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, that is substituted with one or more halogen atoms (that may be the same or different), such as fluorine, chlorine, bromine, and iodine. Preferably the haloalkyl group is a C1-20haloalkyl, 5 more preferably C1-12haloalkyl, even more preferably C1-10haloalkyl or C1-6haloalkyl. Preferred examples are CF3and CHF2, with CF3being particularly preferred. “Alkoxy” is defined herein as an oxygen atom bonded to an alkyl group as defined above. Preferably the alkoxy group is a C1-20alkoxy, more preferably C1-12alkoxy, even more preferably C1-10alkoxy or C1-6alkoxy, for example methoxy, ethoxy, propoxy, isopropoxy, 10 butoxy, isobutoxy, tert-butoxy, pentoxy and hexoxy. A particularly preferred example is methoxy (–OCH3). “Haloalkoxy” is defined herein as an alkoxy group as described above substituted with one or more halogen atoms (that may be the same or different), such as fluorine, chlorine, bromine, and iodine. Preferably the haloalkoxy group is a C1-20haloalkoxy, more 15 preferably C1-12haloalkoxy, even more preferably C1-10haloalkoxy or C1-6haloalkoxy. A particularly preferred example is OCF3. “Heteroaryl” is defined herein as a monocyclic aromatic ring comprising one or more heteroatoms (that may be the same or different), such as oxygen, nitrogen or sulphur. Examples of suitable 6-membered heteroaryl groups include pyridinyl, pyrazinyl, 20 pyrimidinyl, pyridazinyl and triazinyl. “Aralkyl’ is defined herein as an alkyl group as defined above substituted by one or more aryl groups as defined above. “Heterocycloalkyl” refers to a cyclic aliphatic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur, which is optionally interrupted by one or more 25 -(CO)- groups in the ring and / or which optionally contains one or more double bonds in the ring. Preferably, the heterocycloalkyl group is monocyclic or bicyclic. Preferably, the heterocycloalkyl group is a C3-7-heterocycloalkyl, more preferably a C3-6-heterocycloalkyl. Alternatively, the heterocycloalkyl group is a C4-7-heterocycloalkyl, more preferably a C4-6-heterocycloalkyl. Preferred heterocycloalkyl groups include, but are not limited to, 30 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 can be bonded to an adjacent group via a carbon atom or via a heteroatom (e.g. a nitrogen). 5 As used herein, the term “alkenyl” refers to both straight and branched carbon chains which have at least one carbon-carbon double bond. In some embodiments, alkenyl groups may include C2-C12alkenyl groups. In other embodiments, alkenyl includes C2-C10, C2-C8, C2-C6or C2-C4alkenyl groups. In one embodiment of alkenyl, the number of double bonds is 1-3; in another embodiment of alkenyl, the number of double bonds is one. Other 10 ranges of carbon-carbon double bonds and carbon numbers are also contemplated depending on the location of the alkenyl moiety on the molecule. “C2-C10-alkenyl” groups may include more than one double bond in the chain. As used herein, the term “alkynyl” refers to both straight and branched carbon chains which have at least one carbon-carbon triple bond. In some embodiments, alkynyl groups 15 may include C2-C12alkynyl groups. In other embodiments, alkynyl includes C2-C10, C2-C8, C2-C6or C2-C4alkynyl groups. In one embodiment of alkynyl, the number of triple bonds is 1-3; in another embodiment of alkenyl, the number of triple bonds is one. A particularly preferred alkynyl group is –C≡CH. As used herein, the term “alkylene” refers to a linear or branched saturated divalent 20 hydrocarbon radical. Preferably, the alkylene group is a linear saturated divalent hydrocarbon radical comprising one to six carbon atoms, or a branched saturated divalent hydrocarbon radical comprising three to six carbon atoms. As used herein, the term “heteroalkylene” refers to a divalent alkylene as defined above having one or more carbon atoms replaced with a heteroatom such as sulfur, oxygen, or 25 nitrogen (e.g. in the form of NR where R is H or alkyl). The heteroalkylene group can be linked to an adjacent group via a carbon or via the heteroatom. Preferably, the heteroalkylene group is a divalent alkylene having one or two carbon atoms, more preferably one carbon, replaced with a group selected from sulfur, oxygen and nitrogen. Preferably, the heteroalkylene group is a divalent alkylene having one or more carbon atoms replaced with an oxygen, more preferably one or two carbon atoms replaced with an oxygen, more preferably, one carbon atom replaced with an oxygen. Preferably, the heteroalkylene group is a linear saturated divalent hydrocarbon radical 5 comprising two to six carbon atoms in which one carbon is replaced by a heteroatom, or a branched saturated divalent hydrocarbon radical comprising three to six carbon atoms in which one carbon is replaced by a heteroatom. As used herein, the term “cycloalkylene” refers to a divalent cyclic saturated hydrocarbon radical, preferably comprising three to ten carbon atoms. Preferably, the cycloalkylene10 group is 3-, 4-, 5- or 6-membered cycloalkylene group, more preferably, a 3-, 4-, or 5- membered cycloalkylene group. As used herein, the term “heterocycloalkylene” refers to a divalent cycloalkylene group as defined above, having one or more carbon atoms replaced with a heteroatom, for example, sulfur, oxygen, or nitrogen. Where a carbon atom in a cycloalkylene group is replaced with 15 a nitrogen, the nitrogen can be in the form of NR where R is H or alkyl, or the nitrogen can link the heterocycloalkylene group to an adjacent group, for example, as illustrated below: Preferably, the heterocycloalkylene group is a 3-, 4-, 5- or 6-membered heterocycloalkylene group, more preferably, a 3-, 4-, or 5-membered heterocycloalkylene 20 group. As used herein, preferably alkyl is C1-C6alkyl, haloalkyl is C1-C6haloalkyl, haloalkoxy is C1-C6haloalkoxy and alkoxy is C1-C6alkoxy. Compounds according to the invention One aspect of the invention relates to a compound of formula (I'), or a pharmaceutically 25 acceptable salt or solvate thereof,

[0006] wherein: X-Y is -CONR6- or -NR6CO-; 5 R6and R7are each independently selected from H and alkyl, more preferably H; R8is selected from alkyl, cycloalkyl, (CH2)q-heterocycloalkyl and NR34R35; ring C is a phenyl group or a 6-membered heteroaryl group containing at least one N, each of which is optionally further substituted by one or more substituents selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, CN, NR9SO2-R10, NR9COR11, NR12R13, OH, 10 SO2NR14R15, CONR16R17, cycloalkyl, O(CH2)qNR18R19, (CH2)q-heterocycloalkyl and CO2R20; each R9is independently selected from H and alkyl; R10-R19are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; or R12and R13together with the nitrogen to which they are attached form a 4- to 7-membered 15 heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; or R14and R15together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; or 20 R16and R17together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; or R18and R19together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO 25 and SO2;R20is selected from alkyl, aralkyl, , alkoxyalkyl, hydroxyalkyl and cycloalkyl; ring A is a phenyl group or a 5- or 6-membered heteroaryl group; ring B is a phenyl group or a 6-membered heteroaryl group; n and p are each independently an integer from 0 to 4; each q is independently an integer from 0 to 4; each Raand each Rbis independently selected from alkyl, halo, haloalkyl, alkoxy, 5 cycloalkoxy, haloalkoxy, cyano, NR21COR22, NR21SO2R23, (CH2)qSR24, (CH2)qSOR25, (CH2)qSO2R26, SO2NR27R28, (CH2)qOH, (CH2)qOR29, NR30R31, CONR32R33, cycloalkyl and (CH2)q-heterocycloalkyl; each R21is independently selected from H and alkyl; R22-R35are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, 10 hydroxyalkyl and cycloalkyl; or R27and R28together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; or R30and R31together with the nitrogen to which they are attached form a 4- to 7-membered 15 heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; or R32and R33together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; 20 L is a direct bond or is a group selected from, -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR36-SO2-, -NR36-SO2-alkylene, -SO2-NR36-, -SO2-NR36-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-25 heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO-, CO2-heterocycloalkylene- alkylene, alkylene-heterocycloalkylene-CO2-, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene- heteroalkylene, wherein the alkylene moiety in the above groups is optionally substituted by one or more substituents independently selected from halo, alkyl, haloalkyl and 30 cycloalkyl; R36is independently selected from H and alkyl; and Z is a group selected from alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl, each of which is optionally further substituted by one or more groups each independently selected from CN, halo, alkyl, OH, alkenyl, alkynyl, alkoxy, haloalkyl and haloalkoxy. In one preferred embodiment, X-Y is NH-CO In one preferred embodiment, said compound is of formula (Ia'): 5 wherein X1, X2, X3, X4, X5, together with the carbon to which X1and X5are attached, form a phenyl group or a 6-membered heteroaryl group containing at least one N, and wherein said phenyl or heteroaryl group is optionally further substituted by one or more substituents selected from alkyl, CN, haloalkyl, alkoxy, haloalkoxy, halo, NR9SO2R10, NR9COR11, NR12R13, OH, SO2NR14R15, CONR16R17, cycloalkyl, O(CH2)qNR18R19, (CH2)q- 10 heterocycloalkyl and CO2R20; and A, B, Z, L, X, Y, Ra, Rb, R7, R8, n and p are as defined above. In one preferred embodiment, said compound is of formula (Ib'): wherein: X1is N or CR1; X3is N or CR3; X4is N or CR4; 5 X5is N or CR5; R1, R3, R4and R5are each independently selected from H, CN, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR12R13, OH, NR9SO2-alkyl, CONR16R17, cycloalkyl, O(CH2)qNR18R19and (CH2)q-heterocycloalkyl; and wherein Ra, Rb, R7, R8, n, p, L, A, B, X, Y and Z are as defined above. 10 In one preferred embodiment, X1, X2, X3, X4and X5, together with the carbon to which X1and X5are attached, form a 6-membered heteroaryl group comprising 1 or 2 nitrogens, preferably selected from pyridinyl, pyrimidinyl, pyradizinyl and pyrazinyl. In one preferred embodiment, ring A is: 15 wherein ring A is a phenyl group or 6-membered heteroaryl group; and B, C, Z, L, X, Y, Ra, Rb, n and p are as defined above. In another preferred embodiment, ring A is: wherein A is 5-membered heteroaryl group, and n is an integer from 0 to 3. In one preferred embodiment, A is selected from pyrrolyl, thiazolyl, oxazolyl, furanyl, thienyl and pyrazolyl, each of which is optionally substituted by one to three Ragroups as defined above. In one preferred embodiment, the compound is of formula (I), or a pharmaceutically 5 acceptable salt or solvate thereof, X-Y is -CONR6- or -NR6CO-; R6and R7are each independently selected from H and alkyl, more preferably H; 10 R8is selected from alkyl, cycloalkyl, (CH2)q-heterocycloalkyl and NR34R35; ring C is a phenyl group or a 6-membered heteroaryl group containing at least one N, each of which is optionally further substituted by one or more substituents selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, CN, NR9SO2-R10, NR9COR11, NR12R13, OH, SO2NR14R15, CONR16R17, cycloalkyl, O(CH2)qNR18R19, (CH2)q-heterocycloalkyl and CO2R20; 15 each R9is independently selected from H and alkyl; R10-R19are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; or R12and R13together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO 20 and SO2; R14and R15together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; R16and R17together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; R18and R19together with the nitrogen to which they are attached form a 4- to 7-membered 5 heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; R20is selected from alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl and cycloalkyl; ring A is a phenyl group or a 6-membered heteroaryl group; ring B is a phenyl group or a 6-membered heteroaryl group; 10 n and p are each independently an integer from 0 to 4; each q is independently an integer from 0 to 4; each Raand each Rbis independently selected from alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR21COR22, NR21SO2R23, (CH2)qSR24, (CH2)qSOR25, (CH2)qSO2R26, SO2NR27R28, (CH2)qOH, (CH2)qOR29, NR30R31, CONR32R33, cycloalkyl and 15 (CH2)q-heterocycloalkyl; each R21is independently selected from H and alkyl; R22-R35are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; or R27and R28together with the nitrogen to which they are attached form a 4- to 7-membered 20 heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; or R30and R31together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; or 25 R32and R33together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; L is a direct bond or is a group selected from, -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR36-SO2-, -NR36-SO2-alkylene, alkylene-SO2-NR36-, -SO2-NR36-, -SO2- 30 NR36-alkylene, alkylene-NR36-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- heterocycloalkylene-CO2-, heteroalkylene-heterocycloalkylene, heterocycloalkylene- heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, wherein the alkylene moiety in the above groups is optionally substituted by one or more 5 substituents independently selected from halo, alkyl, haloalkyl and cycloalkyl; R36is independently selected from H and alkyl; and Z is a group selected from alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl, each of which is optionally further substituted by one or more groups each independently selected from CN, halo, alkyl, OH, alkenyl, alkynyl, alkoxy, haloalkyl and haloalkoxy. 10 In one preferred embodiment, A is selected from phenyl, pyridinyl, pyrimidinyl and pyrazinyl, more preferably selected from phenyl and pyridinyl, each of which is optionally substituted by one to four Ragroups, more preferably one to three Ragroups. In one preferred embodiment, each Rais independently selected from C1-6-alkyl, halo, C1-6- haloalkyl, C1-6-alkoxy, C3-6-cycloalkoxy, C1-6-haloalkoxy, cyano, NHCO-C1-6-alkyl, NHSO2- 15 C1-6-alkyl, S-C1-6-alkyl, SO-C1-6-alkyl, CH2SO2-C1-6-alkyl, SO2-C1-6-alkyl, SO2N(C1-6-alkyl)2, CH2OH, CH2O-C1-6-alkyl, N(C1-6-alkyl)2, CON(C1-6-alkyl)2, cycloalkyl, heterocycloalkyl and CH2-heterocycloalkyl. In one preferred embodiment, each Rais independently selected from C1-6-alkyl, halo, C1-6- haloalkyl, C1-6-alkoxy, C3-6-cycloalkoxy and C1-6-haloalkoxy. 20 In one preferred embodiment, each Rais independently selected from halo, alkyl and alkoxy. In one preferred embodiment, each Rais independently selected from Me, halo, CF3, OMe, OCF3, amino, cyano, NHCOMe, NHSO2Me, S-Me, CH2SO2Me, SO2Me, SO2NMe2, CH2OH, CH2OMe, cycloalkyl, CH2-(morpholin-4-yl) and morpholin-4-yl. 25 In one preferred embodiment, each Rais independently selected from F, Me and OMe. In one preferred embodiment, n is 0. In one preferred embodiment, said compound is of formula (Ic):

[0007] wherein: X1is N or CR1; 5 X3is N or CR3; X4is N or CR4; X5is N or CR5; R1, R3, R4and R5are each independently selected from H, CN, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR12R13, OH, NR9SO2-alkyl, CONR16R17, cycloalkyl, O(CH2)qNR18R19and 10 (CH2)q-heterocycloalkyl; A is a phenyl or pyridinyl group, more preferably phenyl; and Ra, Rb, R7, R8, n, p, L, A, B, X, Y and Z are as defined above. In one preferred embodiment, R1, R3, R4and R5are each independently selected from H, C1-6-alkyl, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, Cl, F, NH2, NH-C1-6-alkyl, NH-C3-6-15 cycloalkyl, N(C1-6-alkyl)2,OH, NHSO2-C1-6-alkyl, CONR17R18, C3-6-cycloalkyl, NH-(hydroxy- C1-6-alkyl), NH-(C1-6-alkoxy), CH2-heterocycloalkyl and heterocycloalkyl. In one preferred embodiment, R1, R3, R4and R5are each independently selected from H, Me, MeO, CF3, Cl, F, NH2, NH-Me, NH-cyclopropyl, NMe2,OH, NHSO2Me, CONH2, cyclopropyl, NHCH2CH2OH, OCH2CH2NH2, NHCH2CH2OMe, CH2-( morpholin-4-yl) and 20 morpholin-4-yl. In one preferred embodiment: X1is CR1; X3is CR3; X4is N; and X5is CR5. In one preferred embodiment: X1is N; X3is CR3; X4is CR4; and X5is CR5.

[0008] In one preferred embodiment: X1is CR1; X3is N; X4is CR4; and X5is CR5. In one preferred embodiment: X1is CR1; X3is CR3; X4is CR4; and X5is N. In one preferred embodiment: X1is N; X3is CR3; X4is N; and X5is CR5. In one preferred embodiment: X1is N; X3is CR3; X4is CR4; and X5is N. 5 In one preferred embodiment: X1is N; X3is N; X4is CR4; and X5is CR5. In one preferred embodiment: X1is CR1; X3is N; X4is N; and X5is CR5. In one preferred embodiment: X1is CR1; X3is CR3; X4is N; and X5is N. In one preferred embodiment: X1is CR1; X3is N; X4is CR4; and X5is N. In one preferred embodiment, R1, R4and R5are H. 10 In one preferred embodiment, X3is CR3, and R3is selected from H, CN, C1-6-alkyl, C3-6- cycloalkyl, halo, C1-6-alkoxy, C1-6-haloalkyl, C1-6-haloalkoxy and O(CH2)qNR18R19, more preferably, H, CN, C1-6-alkyl, C1-6-alkoxy, C3-6-cycloalkyl, halo and O(CH2)qNR18R19. In one preferred embodiment, X3is CR3, and R3is selected from H, Me, CN, MeO, CF3, Cl, F, NH2, NH-Me, NH-cyclopropyl, NMe2,OH, NHSO2Me, CONH2, cyclopropyl, 15 NHCH2CH2OH, NHCH2CH2OMe, CH2-(morpholin-4-yl) and morpholin-4-yl, more preferably, H, Me, OMe, CN, cyclopropyl and OCH2CH2NH2. In one preferred embodiment, X3is CR3, and R3is selected from H, CN, C1-6-alkyl, C3-6- cycloalkyl, halo, C1-6-alkoxy, C1-6-haloalkyl, C1-6-haloalkoxy and O(CH2)qNR18R19, more preferably, H, CN, C1-6-alkyl, C1-6-alkoxy, C3-6-cycloalkyl, halo and O(CH2)qNR18R19; and R1, 20 R4and R5are H. In one preferred embodiment, X3is CR3, and R3is selected from H, Me, CN, MeO, CF3, Cl, F, NH2, NH-Me, NH-cyclopropyl, NMe2,OH, NHSO2Me, CONH2, cyclopropyl, NHCH2CH2OH, NHCH2CH2OMe, CH2-(morpholin-4-yl) and morpholin-4-yl, more 25 preferably, H, Me, OMe, CN, cyclopropyl and OCH2CH2NH2; and R1, R4and R5are H. In one preferred embodiment, said compound is of formula (Id):

[0009] 17

[0010] wherein: X1is N or CR1; 5 X2is N or CR2; X4is N or CR4; X5is N or CR5; R1, R2,R4and R5are each independently selected from H, CN, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR12R13, OH, NR9SO2-alkyl, CONR16R17, cycloalkyl, O(CH2)qNR18R19and 10 (CH2)q-heterocycloalkyl; A is a phenyl or pyridinyl group, more preferably phenyl; and Ra, Rb, R7, R8, n, p, L, A, B, X, Y and Z are as defined above. In one preferred embodiment: X1is N; X2is CR2; X4is N; and X5is CR5. In one preferred embodiment, R1, R4and R5are H. 15 In one preferred embodiment, X2is CR2, and R2is selected from H, CN, C1-6-alkyl, C3-6- cycloalkyl, halo, C1-6-alkoxy, C1-6-haloalkyl, C1-6-haloalkoxy and O(CH2)qNR18R19, more preferably, H, CN, C1-6-alkyl, C1-6-alkoxy, C3-6-cycloalkyl, halo and O(CH2)qNR18R19. In one preferred embodiment, X2is CR2, and R2is selected from H, CN, C1-6-alkyl, C3-6- cycloalkyl, halo, C1-6-alkoxy, C1-6-haloalkyl, C1-6-haloalkoxy and O(CH2)qNR18R19, more 20 preferably, H, CN, C1-6-alkyl, C1-6-alkoxy, C3-6-cycloalkyl, halo and O(CH2)qNR18R19; and R1, R4and R5are H. In one preferred embodiment, R7is H. In one preferred embodiment, R8is selected from alkyl, cycloalkyl, heterocycloalkyl and dialkylamino, more preferably, Me, cyclopropyl, morpholin-4-yl and N(Me)2. In one preferred embodiment, B is selected from phenyl, pyridinyl, pyradizinyl, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, and thiazolyl, each of which is 5 optionally substituted by one to four Rbgroups as defined above. In one preferred embodiment, B is selected from phenyl and pyridinyl, more preferably phenyl, optionally substituted by one to four Rbgroups as above. In one preferred embodiment, each Rbis independently selected from C1-6-alkyl, halo, C1-6- haloalkyl, C1-6-alkoxy, C3-6-cycloalkoxy and C1-6-haloalkoxy. 10 In one preferred embodiment, each Rbis independently selected from Me, halo, CF3, OMe, OCF3, amino, cyano, NHCOMe, NHSO2Me, S-Me, CH2SO2Me, SO2Me, SO2NMe2, CH2OH, CH2OMe, cycloalkyl, CH2-( morpholin-4-yl) and morpholin-4-yl. For all of the above embodiments described herein, B is preferably a phenyl or pyridinyl group, each of which is optionally substituted by one to four Rbgroups as defined above. 15 In one preferred embodiment, B is a phenyl group, optionally substituted by one or two groups selected from halo and alkoxy. In one preferred embodiment, B is a phenyl group, optionally substituted by one or two groups selected from F and MeO. In one preferred embodiment, B is a phenyl group, optionally substituted by one or two 20 halo groups. In one preferred embodiment, p is 0. In one preferred embodiment, Z is a group selected from C1-6-alkyl, phenyl, heteroaryl, C3-6-cycloalkyl and a 4-, 5- or 6-membered heterocycloalkyl group, each of which is optionally further substituted by one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, 25 haloalkyl, and alkoxy. In one preferred embodiment, Z is a group selected from phenyl, pyridinyl, methoxyphenyl, alkyl, tolyl, morpholinyl, pyrazolyl, oxetanyl, cyclohexyl, cyclopenyl, cyclobutyl, cyclopropyl, and tetrahydropyranyl, more preferably phenyl. In one preferred embodiment, Z is a group selected from phenyl, alkyl, tolyl, morpholinyl, 5 pyrazolyl, oxetanyl, cyclohexyl, cyclopenyl, cyclobutyl, cyclopropyl, and tetrahydropyranyl. In one preferred embodiment, Z is a group selected from phenyl, cyclopropyl and tetrahydropyranyl, more preferably phenyl. More preferably, Z is phenyl. In the compounds described herein, L is a direct bond or is a group selected from, -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR36-SO2-, -NR36-SO2-alkylene, 10 alkylene-SO2-NR36-, -SO2-NR36-, -SO2-NR36-alkylene, alkylene-NR36-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-, CO2-15 heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO2-, heteroalkylene- heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, wherein the alkylene moiety in the above groups is optionally substituted by one or more substituents independently selected from halo, alkyl and cycloalkyl; wherein the alkylene moiety in the above groups is optionally substituted by 20 one or more substituents selected from halo, haloalkyl, alkyl and cycloalkyl. Preferably, R36is H or Me, more preferably H. In one preferred embodiment, L is absent and the Z group is attached directly to the B ring. In one preferred embodiment L is present. In one preferred embodiment, L is -O- 25 In one preferred embodiment, L is a heteroalkylene group as defined hereinabove. In one preferred embodiment, L is an alkylene group having one or two carbon atoms, more preferably one carbon, replaced 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, replaced with an oxygen. In one preferred embodiment, the heteroalkylene is a group selected from -O-alkylene, alkylene-O- and alkylene-O-alkylene. 5 In one preferred embodiment, L is selected from -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- 10 (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-, 15 -(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-heterocycloalkylene-O-, wherein a and b are each independently an integer from 1 to 6, c is an integer from 1 to 3, and R' and R'' are each 20 independently selected from H, alkyl, halo and haloalkyl. In one preferred embodiment, L is selected from -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-, 25 -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- 30 heterocycloalkylene-O-, wherein a and b are each independently an integer from 1 to 6. In one preferred embodiment, L is selected from -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-, 5 -SO2-NH-, -SO2-NH-CH2-, -CH2CH2CH2CH2O-, -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-, 10

[0011] For all of the above embodiments, L is preferably selected from from -O-, -NH-SO2-, -NH- SO2-(CH2)a-, -SO2-NH-, -SO2-NH-(CH2)a-, -O-SO2-, -SO2-O-, -(CH2)a-, -(CH2)a-O-, O- 5 (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-heterocycloalkylene-O-, wherein a 10 and b are each independently an integer from 1 to 6. More preferably, L is selected from -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-O-heterocycloalkylene, wherein a and b are each independently an integer from 1 15 to 6. In one 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-, -CH2OCH2and -CH2SCH2O-. 5 In one preferred embodiment, L-Z is -OCH2CH2Ph, -OCH2Ph, -OCH2CH2CH(Me)2, -OCH2CH(Me)2, -OSO2-(4-methylphenyl), -CH2SO2CH2-Ph, -OCH2-cyclopropyl, -OCH2CH2CH2CH3, -CH2OCH2Ph, -OCH2SCH2Ph, -CH2OCH2Ph, 10 In one preferred embodiment, L-Z 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, 15 OCF3,tBu, 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, 20 SO2Ph, -CH2-O-CH(CF3)-Ph,

[0012] In one preferred embodiment, L-Z is -OCH2CH2Ph, -OCH2CH2CH2CH2Ph or -CH2OCH2Ph, more preferably -OCH2CH2Ph. In one preferred embodiment, the compound is selected from the following:

[0013]

[0014] and pharmaceutically acceptable salts and solvates thereof. In one preferred embodiment, the compound of formula (I) is selected from the following compounds as shown herein: 1-4, 6-10, 13, 14, 16-30, 33, 34, 36, 37 and 39-46, and pharmaceutically acceptable salts and solvates thereof. 5 In another preferred embodiment, the compound of formula (I) is selected from the following:

[0015] PROCESS A further aspect of the invention relates to processes for preparing a compound as defined herein. Further details of the synthetic processes are set forth in the accompanying examples section. 5 THERAPEUTIC APPLICATIONS A further aspect of the invention relates to compounds as described herein for use in medicine. The compounds have particular use in the field of oncology, gastrointestinal disorders, and inflammatory disorders as described in more detail below. In a preferred embodiment, the compound of the invention modulates GPR35 function. More preferably, 5 the compound is a GPR35 antagonist or inverse agonist. One aspect of the invention therefore relates to compounds as described herein for use as a medicament. Preferably, the compound of the invention is for use in treating or preventing a disorder selected from a proliferative disorder, a fibrotic disorder, a gastrointestinal disorder, a 10 cardiovascular disease, and an inflammatory disorder. In one preferred embodiment, the compounds have applications in the field of oncology. For example, in one preferred embodiment, the compounds are for use in treating a proliferative disorder, preferably a cancer or leukemia. GPR35 expression is known to be associated with cancer. More specifically, GPR35 expression is commonly upregulated in 15 cancers of the GI tract, relative to normal tissue.24GPR35 expression is capable of transforming NIH3T3 murine fibroblast cells and is expressed in gastric cancer cells.25GPR35b is expressed by colon cancer cell lines and primary colon tumours, while involved patient lymph nodes can express high levels of GPR35b.26High expression of GPR35b in lymph nodes of colon cancer patients is a marker for poor prognosis. Also, high 20 expression of GPR35 in primary gastric tumours is associated with poor prognosis.40Similarly, above median expression of GPR35 in primary tumours was seen as a poor prognostic marker in males with colorectal cancer, though the opposite effect was reported in females.27siRNA knockdown of GPR35 reduces viability and proliferation of human gastric cancer cells, while also reversing pro-tumour M2 macrophage phenotype.40Murine 25 Gpr35 was shown to promote glycolysis, proliferation and oncogenic signalling by engaging with the sodium potassium pump (Na / K-ATPase).21Deletion of Gpr35 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, with a specific anti-Gpr35 peptide (pepducin),28prevented inflammation- 30 associated and spontaneous intestinal tumorigenesis in mice. Furthermore, activation of human GPR35 in human inducible pluripotent stem cell (iPSC)-derived macrophages, by way of expression of T108M hypermorphic variant, has been shown to promote angiogenic tube formation by enhanced release of pro-angiogenic factors.28Finally, selective deletion of Gpr35 in macrophages profoundly reduced tumour growth in inflammation-associated and mutant (hypomorphic) tumour suppressor adenomatous polyposis coli (Apcmin), 5 spontaneous tumour models. In one preferred embodiment, the cancer is selected from cancers of the gastrointestinal tract (e.g. colon, rectum, stomach and oesophagus) and associated tissues (e.g. pancreas, gall bladder and bile duct, liver), and also lung, kidney, gynaecological, breast, testicular, skin, prostate, central nervous system and brain. 10 In one preferred embodiment, the compounds have applications in the field of immune- oncology and the treatment of immune disorders. Thus, in one preferred embodiment, the compound of the invention is for use in treating an immune disorder. In another preferred embodiment, the compound of the invention is for use in immunotherapy for the treatment of cancer. 15 In one preferred embodiment, the disorder is fibrosis or a fibrotic disorder. Fibrosis is defined by the 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 malfunction. In one preferred embodiment, the compounds have applications in treating or preventing 20 inflammatory disorders / diseases and / or inflammation. In one preferred embodiment, the disorder is a gastrointestinal disorder, preferably 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.18Six of these SNPs have been 25 associated with inflammatory diseases of the GI tract. Types of inflammatory bowel disease (IBD) include ulcerative colitis, Crohn’s disease and primary sclerosing cholangitis.19,20SNP rs3749171 is synonymous with a coding variant T108M (GPR35a amino acid sequence numbering) and has been associated with IBD. Research has shown that this variant is hypermorphic, leading to activation of GPR35 and increased 30 proliferation and metabolism in bone marrow-derived macrophages.21Furthermore, expression of T108M GPR35 leads to increased production of VEGF and CXCL8 by macrophages compared to the reference allele, with reduced production in GPR35- deficient cells.22It has also been suggested that the hypermorphic nature of T108M contributes to pathogenesis in IBD patients and could act as a biomarker for patients that 5 respond better to TNF blockers.2,23In one preferred embodiment, the disorder is a cardiovascular disease, preferably selected from hypertension, heart failure, atherosclerosis, peripheral vascular disease and stroke. A number of recent publications have suggested a role for GPR35 in hypertension and the pathology of both heart failure and atherosclerosis. For example, a S294R SNP within 10 GPR35 was shown to have significant association with coronary artery calcification in a patient cohort29. Further studies demonstrated a correlation between GPR35 upregulation and traditional heart failure biomarkers such as plasma brain natriuretic peptide, ejection fraction, and pulmonary arterial pressure, thereby implying that GPR35 plays a role in heart failure and hypertension30. 15 Another aspect relates to a compound as described herein for use in treating or preventing a disorder caused by, associated with or accompanied by abnormal activity of GPR35. Another aspect relates to a compound as described herein for use in treating or preventing a GPR35-associated disease or disorder. Another aspect of the invention relates to a method of treating a disorder as described 20 above comprising administering a compound as described herein to a subject. Another aspect of the invention relates to a method of treating a GPR35-associated disease or disorder in a subject. The method according to this aspect of the present invention is effected by administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, as described hereinabove, either 25 per se, or, more preferably, as a part of a pharmaceutical composition, mixed with, for example, a pharmaceutically acceptable carrier, as is detailed hereinafter. Yet another aspect of the invention relates to a method of treating a subject having a disease state alleviated by modulation of GPR35 wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to 30 the invention. Another aspect relates to a method of treating a disease state alleviated by modulation of GPR35, wherein the method comprises administering to a subject a therapeutically effective amount of a compound according to the invention. In one preferred embodiment, the compound inhibits GPR35 activity, for example, as 5 demonstrated in the functional GPR35 assay described in the accompanying examples section. In one preferred embodiment, the compound is a GPR35 antagonist, which reverses the agonist-driven function of a receptor. In another preferred embodiment, the compound is an inverse agonist of GPR35. Inverse 10 agonists are compounds that interact with receptor-signal transduction systems that have a constitutive level of activity, and, through interaction with the receptor, reduce the activity in the direction opposite of that of a pure agonist. Preferably, the subject is a mammal, more preferably a human. The term “method” refers to manners, means, techniques and procedures for 15 accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts. Herein, the term “treating” includes abrogating, substantially inhibiting, slowing or reversing 20 the progression of a disease or disorder, substantially ameliorating clinical symptoms of a disease or disorder or substantially preventing the appearance of clinical symptoms of a disease or disorder. Herein, the term “preventing” refers to a method for barring an organism from acquiring a disorder or disease in the first place. 25 The term “therapeutically effective amount” refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated. For any compound used in this invention, a therapeutically effective amount, also referred to herein as a therapeutically effective dose, can be estimated initially from cell culture assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50or the IC90as determined in cell culture. Such 5 information can be used to more accurately to determine useful doses in humans. Initial dosages can also be estimated from in vivo data. Using these initial guidelines one of ordinary skill in the art could determine an effective dosage in humans. Moreover, toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental 10 animals, e.g., by determining the LD50and the ED50. The dose ratio between toxic and therapeutic effect is the therapeutic index and can be expressed as the ratio between LD50and ED50. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell cultures assays and animal studies can be used in formulating a dosage range that is not toxic for use in human. The dosage of such compounds lies 15 preferably within a range of circulating concentrations that include the ED50with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see, e.g., Fingl et al, 1975, The Pharmacological Basis of 20 Therapeutics, chapter 1, page 1). Dosage amount and interval may be adjusted individually to provide plasma levels of the active compound which are sufficient to maintain therapeutic effect. Usual patient dosages for oral administration range from about 50-2000 mg / day, commonly from about 100-1000 mg / day, preferably from about 150-700 mg / day and most preferably from 50-150 mg / day. 25 Preferably, therapeutically effective serum levels will be achieved by administering multiple doses each day. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. One skilled in the art will be able to optimize therapeutically effective local dosages without undue experimentation. 30 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 enzyme or cellular assays, for example, compared to the activity in a healthy subject. Inappropriate activity could also be due to overexpression of GPR35 in diseased tissue compared with healthy adjacent tissue where GPR35 expression is lower. 5 Preferred diseases or disorders that the compounds described herein may be useful in preventing include those described hereinbefore. Thus, the present invention further provides use of compounds as defined herein in the preparation of a medicament for the treatment of a disease where it is desirable to modulate GPR35. Such diseases include proliferative disorders, gastrointestinal 10 disorders, fibrotic disorders, cardiovasular diseases, and inflammatory disorders. Proliferative disorders preferably include therapeutic applications in the field of oncology. As used herein the phrase “preparation of a medicament” includes the use of the components of the invention directly as the medicament in addition to their use in any stage of the preparation of such a medicament. 15 The functional GPR35 assay as described in the accompanying examples measures the ability of GPR35 modulators to inhibit a GPR35 agonist-induced phospho-ERK signal. This is expressed as the concentration of modulator required to reduce the phospho-ERK signal by 50 percent, i.e. the IC50; the signal window being defined as the difference between agonist plus modulator vehicle (no modulator) and agonist vehicle (no agonist) controls. 20 In one preferred embodiment, the compound exhibits an IC50value in the aforementioned GPR35 assay of less than about 50 µM. More preferably, the compound exhibits an IC50value in the GPR35 assay of less than about 10 µM, more preferably, less than about 1 µM. In one preferred embodiment, the compound according to the invention exhibits an IC50of 25 < 10 ^M in the aforementioned GPR35 assay. In one preferred embodiment, the compound is selected from those denoted “A” or “B” in Table 1. In one preferred embodiment, the compound according to the invention exhibits an IC50of > 1 ^M and < 10 ^M in the aforementioned GPR35 assay. In one preferred embodiment, the compound is selected from those denoted “B” in Table 1. In a more preferred embodiment, the compound according to the invention exhibits an IC50of < 1 ^M in the aforementioned assay. In one preferred embodiment, the compound is selected from those denoted “A” in Table 1. PHARMACEUTICAL COMPOSITIONS 5 For use according to the present invention, the compounds or physiologically acceptable salt, ester or other physiologically functional derivative thereof, described herein, may be presented as a pharmaceutical formulation, comprising the compounds or physiologically acceptable salt, ester or other physiologically functional derivative thereof, together with one or more pharmaceutically acceptable carriers, excipients or diluents therefor and 10 optionally other therapeutic and / or prophylactic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The pharmaceutical compositions may be for human or animal usage in human and veterinary medicine. Examples of such suitable excipients for the various different forms of pharmaceutical 15 compositions described herein may be found in the “Handbook of Pharmaceutical Excipients, 2ndEdition, (1994), Edited by A Wade and PJ Weller. The carrier, or, if more than one be present, each of the carriers, must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical 20 art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit.1985). Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like. Examples of suitable diluents include ethanol, glycerol and water. 25 The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s), buffer(s), flavouring agent(s), surface active agent(s), thickener(s), preservative(s) (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient. Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic 5 gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol. Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Preservatives, stabilizers, dyes and even flavoring agents may be provided in the 10 pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used. Pharmaceutical formulations include those suitable for oral, topical (including dermal, buccal and sublingual), rectal or parenteral (including subcutaneous, intradermal, 15 intramuscular and intravenous), nasal and pulmonary administration e.g., by inhalation. The formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product 20 into the desired formulation. Pharmaceutical formulations suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of active compound. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. 25 Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent. Moulded tablets may be made by moulding an active compound with an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored. Capsules 30 may be prepared by filling an active compound, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner. Cachets are analogous to capsules wherein an active compound together with any accessory ingredient(s) is sealed in a rice paper envelope. An active compound may also be formulated as dispersible granules, which may for example be suspended in water 5 before administration, or sprinkled on food. The granules may be packaged, e.g., in a sachet. Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil- in-water liquid emulsion. Formulations for oral administration include controlled release dosage forms, e.g., tablets 10 wherein an active compound is formulated in an appropriate release - controlling matrix, or is coated with a suitable release - controlling film. Such formulations may be particularly convenient for prophylactic use. Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa 15 butter and other materials commonly used in the art. The suppositories may be conveniently formed by admixture of an active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds. Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of an active compound in aqueous or oleaginous vehicles. 20 Injectable preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers which are sealed after introduction of the formulation until required for use. Alternatively, an active compound may be in powder form which is constituted with a suitable vehicle, such as sterile, pyrogen-free water, before use. 25 An active compound may also be formulated as long-acting depot preparations, which may be administered by intramuscular injection or by implantation, e.g., subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins. Such long-acting formulations are particularly convenient for prophylactic use. Formulations suitable for pulmonary administration via the buccal cavity are presented such that particles containing an active compound and desirably having a diameter in the range of 0.5 to 7 microns are delivered in the bronchial tree of the recipient. As one possibility such formulations are in the form of finely comminuted powders which 5 may conveniently be presented either in a pierceable capsule, suitably of, for example, gelatin, for use in an inhalation device, or alternatively as a self-propelling formulation comprising an active compound, a suitable liquid or gaseous propellant and optionally other ingredients such as a surfactant and / or a solid diluent. Suitable liquid propellants include propane and the chlorofluorocarbons, and suitable gaseous propellants include 10 carbon dioxide. Self-propelling formulations may also be employed wherein an active compound is dispensed in the form of droplets of solution or suspension. Such self-propelling formulations are analogous to those known in the art and may be prepared by established procedures. Suitably they are presented in a container provided with either a manually-operable or automatically functioning valve having the desired spray 15 characteristics; advantageously the valve is of a metered type delivering a fixed volume, for example, 25 to 100 microlitres, upon each operation thereof. As a further possibility an active compound may be in the form of a solution or suspension for use in an atomizer or nebuliser whereby an accelerated airstream or ultrasonic agitation is employed to produce a fine droplet mist for inhalation. 20 Formulations suitable for nasal administration include preparations generally similar to those described above for pulmonary administration. When dispensed such formulations should desirably have a particle diameter in the range 10 to 200 microns to enable retention in the nasal cavity; this may be achieved by, as appropriate, use of a powder of a suitable particle size or choice of an appropriate valve. Other suitable formulations include 25 coarse powders having a particle diameter in the range 20 to 500 microns, for administration by rapid inhalation through the nasal passage from a container held close up to the nose, and nasal drops comprising 0.2 to 5% w / v of an active compound in aqueous or oily solution or suspension. Pharmaceutically acceptable carriers are well known to those skilled in the art and include, 30 but are not limited to, 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Additionally, 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 such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, 5 emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. Formulations suitable for topical formulation may be provided for example as gels, creams 10 or ointments. Such preparations may be applied e.g. to a wound or ulcer either directly spread upon the surface of the wound or ulcer or carried on a suitable support such as a bandage, gauze, mesh or the like which may be applied to and over the area to be treated. Liquid or powder formulations may also be provided which can be sprayed or sprinkled directly onto the site to be treated, e.g. a wound or ulcer. Alternatively, a carrier such as a 15 bandage, gauze, mesh or the like can be sprayed or sprinkle with the formulation and then applied to the site to be treated. According to a further aspect of the invention, there is provided a process for the preparation of a pharmaceutical or veterinary composition as described above, the process comprising bringing the active compound(s) into association with the carrier, for example 20 by admixture. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. The invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound as described herein into 25 conjunction or association with a pharmaceutically or veterinarily acceptable carrier or vehicle. SALTS / ESTERS The compounds of the invention can be present as salts or esters, in particular pharmaceutically and veterinarily acceptable salts or esters. Pharmaceutically acceptable salts of the compounds of the invention include suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g. hydrohalic acids such as hydrochloride, 5 hydrobromide and hydroiodide, sulphuric acid, phosphoric acid sulphate, bisulphate, hemisulphate, thiocyanate, persulphate and sulphonic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or 10 tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C1-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid. Salts which are not pharmaceutically or veterinarily acceptable may still be 15 valuable as intermediates. Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, 20 pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2- hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesulphonate, benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, 25 hemisulphate, thiocyanate, persulphate, phosphoric and sulphonic acids. Esters are formed either using organic acids or alcohols / hydroxides, depending on the functional group being esterified. Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acid, for 30 example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C1-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide. Alcohols include alkanealcohols of 1- 5 12 carbon atoms which may be unsubstituted or substituted, e.g. by a halogen). ENANTIOMERS / TAUTOMERS In all aspects of the present invention previously discussed, the invention includes, where appropriate all enantiomers, diastereoisomers and tautomers of the compounds of the invention. The person skilled in the art will recognise compounds that possess optical 10 properties (one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and / or tautomers may be isolated / prepared by methods known in the art. Enantiomers are characterised by the absolute configuration of their chiral centres and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Such 15 conventions are well known in the art (e.g. see ‘Advanced Organic Chemistry’, 3rdedition, ed. March, J., John Wiley and Sons, New York, 1985). Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone. 20 STEREO AND GEOMETRIC ISOMERS Some of the compounds of the invention may exist as stereoisomers and / or geometric isomers – e.g. they may possess one or more asymmetric and / or geometric centres and so may exist in two or more stereoisomeric and / or geometric forms. The present invention contemplates the use of all the individual stereoisomers and geometric isomers of those 25 compounds, and mixtures thereof. The terms used in the claims encompass these forms, provided said forms retain the appropriate functional activity (though not necessarily to the same degree). The present invention also includes all suitable isotopic variations of the compound or a pharmaceutically acceptable salt thereof. An isotopic variation of a compound of the 30 present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine 5 such as2H,3H,11C,13C,14C,15N,17O,18O,31P,32P,35S,18F and36Cl, respectively. Certain isotopic variations of the agent and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as3H or14C is incorporated, are useful in drug and / or substrate tissue distribution studies. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, 10 substitution with isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half- life or reduced dosage requirements and hence may be preferred in some circumstances. For example, the invention includes compounds of general formula (I) where any hydrogen atom has been replaced by a deuterium atom. Isotopic variations of the agent of the 15 present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents. ATROPISOMERS Some of the compounds of the invention may exist as atropisomers. Atropisomers are 20 stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers. The invention encompasses all such atropisomers. PRODRUGS 25 The invention further includes the compounds of the present invention in prodrug form, i.e. covalently bonded compounds which release the active parent drug in vivo. Such prodrugs are generally compounds of the invention wherein one or more appropriate groups have been modified such that the modification may be reversed upon administration to a human or mammalian subject. Reversion is usually performed by an 30 enzyme naturally present in such subject, though it is possible for a second agent to be administered together with such a prodrug in order to perform the reversion in vivo. Examples of such modifications include ester (for example, any of those described above), wherein the reversion may be carried out by an esterase etc. Other such systems will be well known to those skilled in the art. SOLVATES 5 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. COMBINATIONS A further aspect of the invention relates to a combination comprising a compound as 10 described herein and one or more additional active agents. In a particularly preferred embodiment, the one or more compounds of the 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 invention may be administered consecutively, simultaneously or sequentially with the one or more other active agents. 15 Drugs in general can be more effective when used in combination. In particular, combination therapy is desirable in order to avoid an overlap of major toxicities, mechanism of action and resistance mechanism(s). Furthermore, it is also desirable to administer most drugs at their maximum tolerated doses with minimum time intervals between such doses. The major advantages of combining chemotherapeutic drugs are 20 that it may promote additive or possible synergistic effects through biochemical interactions and also may decrease the emergence of resistance. Beneficial combinations may be suggested by studying the activity of the test compounds with agents known or suspected of being valuable in the treatment of a particular disorder. This procedure can also be used to determine the order of administration of the agents, i.e. 25 before, simultaneously, or after delivery. Such scheduling may be a feature of all the active agents identified herein. In the context of cancer, compounds of the invention can be used in combination with immunotherapies such as cancer vaccines and / or with other immune-modulators. Thus, in one preferred embodiment, the additional active agent is an immunotherapy agent, more 30 preferably a cancer immunotherapy agent. An “immunotherapy agent“ refers to a

[0016] treatment that uses the subject’s own immune system to fight diseases such as cancer. For other disorders the compounds of the invention can be used in combination with agents that block or decrease inflammation such as antibodies that target pro-inflammatory cytokines. The compounds of the invention can also be used in combination with other 5 chemotherapy agents and / or in conjunction with radiotherapy. POLYMORPHS The invention further relates to the compounds of the present invention in their various crystalline forms, polymorphic forms and (an)hydrous forms. It is well established within the pharmaceutical industry that chemical compounds may be isolated in any of such 10 forms by slightly varying the method of purification and or isolation form the solvents used in the synthetic preparation of such compounds. ADMINISTRATION The pharmaceutical compositions of the present invention may be adapted for rectal, nasal, intrabronchial, topical (including buccal and sublingual), vaginal or parenteral 15 (including subcutaneous, intramuscular, intravenous, intraarterial and intradermal), intraperitoneal or intrathecal administration. Preferably the formulation is an orally administered formulation. The formulations may conveniently be presented in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose. By way of example, the formulations may be in the form of tablets and 20 sustained release capsules, and may be prepared by any method well known in the art of pharmacy. Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, gellules, drops, cachets, pills or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution, 25 emulsion or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; or as a bolus etc. Preferably, these compositions contain from 1 to 250 mg and more preferably from 10-100 mg, of active ingredient per dose. For compositions for oral administration (e.g. tablets and capsules), the term “acceptable 30 carrier” includes vehicles such as common excipients e.g. binding agents, for example

[0017] 48 syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl- methylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium 5 chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring and the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in 10 the art. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded 15 tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent. Other formulations suitable for oral administration include lozenges comprising the active 20 agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier. Other forms of administration comprise solutions or emulsions which may be injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally 25 or intramuscularly, and which are prepared from sterile or sterilisable solutions. Injectable forms typically contain between 10 - 1000 mg, preferably between 10 - 250 mg, of active ingredient per dose. The pharmaceutical compositions of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, 30 sprays, solutions or dusting powders. An alternative means of transdermal administration is by use of a skin patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. The active ingredient can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white 5 wax or white soft paraffin base together with such stabilisers and preservatives as may be required. DOSAGE A person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject without undue experimentation. Typically, a 10 physician will determine the actual dosage which will be most suitable for an individual patient, and it will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual 15 undergoing therapy. The dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. The dosage amount will further be modified according to the mode of administration of the compound. For example, to achieve an “effective amount” for acute therapy, parenteral 20 administration of a compound is typically preferred. An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful. Typically, the parenteral dose will be about 0.01 to about 100 mg; preferably between 0.1 and 20 mg, in a manner to maintain the concentration of drug in the plasma at a 25 concentration effective to modulate GPR35. The compounds may be administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg. The precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to 30 have a therapeutic effect. The compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to achieve one or more of the therapeutic indications disclosed herein. Typically, a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 5 500 mg or about 0.1 to about 50 mg in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0.5 to about 50 mg or about 0.5 to about 20 mg. No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention. The compounds of 10 this invention, which may have good bioavailability, may be tested in one of several biological assays to determine the concentration of a compound which is required to have a given pharmacological effect. The invention is further described by way of the following non-limiting examples. EXAMPLES 15 Where the preparation of starting materials is not described, these are commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. Where it is indicated that compounds were prepared analogously to earlier examples or intermediates, it will be appreciated by the skilled person that the reaction time, number of equivalents of reagents, solvent, concentration and temperature 20 can be modified for each specific reaction and that it may be necessary or desirable to employ different work-up or purification techniques. General Schemes Abbreviations: AcOH Acetic acid AIBN Azobisisobutyronitrile aq. Aqueous Ar Aryl B2Pin2Bis(pinacolato)diboron C18 Octadecyl carbon Celite®Diatomaceous earth d Days d Doublet (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 EtOAc Ethyl acetate EtOH Ethanol eq. Molar equivalents h Hour(s) HATU 1-[bis(Dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate het Heterocycle iPnONO Isopentyl / isoamyl nitrite LCMS Liquid chromatography mass spectrometry m multiplet MeCN Acetonitrile MeOH Methanol min Minute(s) mol. eq. Molar equivalent Ms Methanesulfonyl NBS N-Bromosuccinimide NEt3Triethylamine p Pentet 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 Reverse phase s Singlet Sat. Saturated SCX SiliaBond®Propylsulfonic Acid (SiliaBond SCX-2) t Triplet T3P 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide TBME tert-Butyl methyl ether THF Tetrahydrofuran Tr Trityl X Halogen atom (bromine or chlorine) Other abbreviations are intended to convey their generally accepted meaning. General experimental conditions All starting materials and solvents were obtained either from commercial sources or prepared according to literature methods. 5 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 irregular) or Silicycle, SiliaSep C18 (230-400 mesh, 40-63 µm irregular) pre-packed silica cartridges respectively. RP flash chromatography was performed using basic modifier (C18, 0 – 100% MeCN in 0.1% aq. 10 ammonia) except where acidic modifier (C18, 0 – 100% MeCN with 0.1% HCO2H in 0.1% aq. HCO2H) was used. Analytical LC-MS and UPLC-MS experiments were carried out as described in the tables below. 15 Method A – LCMS Acidic Method Method B – LCMS Basic Method 5 Method C – LCMS Acidic Method (10 min) Preparative HPLC purifications were performed as detailed below. Prep Method A – Preparative HPLC Acidic Method (x-y%) 5 Prep Method B – Preparative HPLC Basic Method (x-y%) NMR spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million (δ 5 ppm). NMR spectra were recorded using a Bruker 500 MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbeTMor 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. 10 Where reaction is likely at two or more atoms (e.g. N-alkylation of heterocycles containing two or more N to provide N-protection) and a mixture of two or more isomers was obtained as determined by LCMS, that mixture was carried through without further purification unless stated otherwise. Only one isomer is drawn although the term “+ isomers” is intended to convey a mixture of two or more isomers. Multiple peaks with the expected 15 mass ion may be listed as characterisation. Purification was achieved later in the synthesis following N-deprotection, multiple isomers leading to a single specified product. Where procedures are not given for intermediates identified in synthetic schemes these compounds were purchased. Intermediate 1 N-(6-Bromo-3-chloropyrazin-2-yl)methanesulfonamide (I-1) 5 N-(6-Bromo-3-chloropyrazin-2-yl)methanesulfonamide (I-1) A solution of 6-bromo-3-chloropyrazin-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 rt. The mixture was stirred for 30 min then a solution of methanesulfonyl chloride 10 (247 mg, 2.16 mmol) in DME (1 mL) was added over 10 min. The mixture was stirred at rt for 19 h and sat. aq. NH4Cl (5 mL) was added. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic phases were washed with water (2 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0 - 100% EtOAc in isohexane) afforded N-(6-bromo-3-chloropyrazin-2- 15 yl)methanesulfonamide (150 mg, 68%). LCMS: Method A, 1.03 min, MS ES+285.9 / 288.0. General procedure (sulfonylation) Following the procedure of Intermediate 1, substituting 6-bromo-3-chloropyrazin-2-amine and methanesulfonyl chloride with the appropriate starting materials, and with any minor20 modifications noted, the following Intermediates 2-17 were obtained as mono- or bis- sulfonylated derivatives, or a mixture of both: The mixture can be used directly in the next step, understanding that under the basic reaction conditions, any bis-sulfonylated derivative is rapidly hydrolysed to the required sulfonamide. For simplicity, only the major component is drawn. 5 Intermediate 2 N-(6-Bromo-3-chloropyrazin-2-yl)cyclopropanesulfonamide (I-2) Using cyclopropanesulfonyl chloride (CAS 139631-62-2, Apollo Scientific) in place of methanesulfonyl chloride was obtained N-(6-bromo-3-chloropyrazin-2- 10 yl)cyclopropanesulfonamide in 68% yield. LCMS: Method A,1.27 min, MS ES+311.9 / 313.9. Intermediate 3 N-(5-Bromo-3-chloropyrazin-2-yl)-N-(methylsulfonyl)methanesulfonamide (I-3) 15 Using 5-bromo-3-chloropyrazin-2-amine (CAS 21943-13-5, Fluorochem) in place of 6- bromo-3-chloropyrazin-2-amine was obtained N-(5-bromo-3-chloropyrazin-2-yl)-N- (methylsulfonyl)methanesulfonamide in 46% yield. LCMS: Method A, 1.19 min, MS ES+363.9 / 365.9. Intermediate 4 N-(6-Chloro-3-cyanopyrazin-2-yl)methanesulfonamide (I-4) Using 3-amino-5-chloropyrazine-2-carbonitrile (CAS 54632-11-0, Apollo Scientific) in place 5 of 6-bromo-3-chloropyrazin-2-amine, and without purification, was obtained N-(6-chloro-3- cyanopyrazin-2-yl)methanesulfonamide in 60% yield. LCMS: Method A, 0.97 min, MS ES+233.0. Intermediate 5 N-(6-Bromopyrazin-2-yl)-N-(methylsulfonyl)methanesulfonamide (I-5) 10 Using 6-bromopyrazin-2-amine (CAS 54237-53-5, Fluorochem) in place of 6-bromo-3- chloropyrazin-2-amine, and without purification, was obtained N-(6-bromopyrazin-2-yl)-N- (methylsulfonyl)methanesulfonamide in 37% yield. LCMS: Method A, 1.18 min, MS ES+329.9 / 331.9. 15 Intermediate 6 N-(2-Chloropyrimidin-4-yl)-N-(methylsulfonyl)methanesulfonamide (I-6) Using 2-chloropyrimidin-4-amine (CAS 7461-50-9, BLD) in place of 6-bromo-3- chloropyrazin-2-amine, and without purification, was obtained N-(2-chloropyrimidin-4-yl)-N- (methylsulfonyl)methanesulfonamide in 31% yield. LCMS: Method A, 1.13 min, MS ES+286.0. 5 Intermediate 7 N-(6-Bromopyridin-2-yl)-N-(methylsulfonyl)methanesulfonamide (I-7) Using 6-bromopyridin-2-amine (CAS 19798-81-3, Fluorochem) in place of 6-bromo-3- chloropyrazin-2-amine, and without purification, was obtained N-(6-bromopyridin-2-yl)-N- 10 (methylsulfonyl)methanesulfonamide in 17% yield. LCMS: Method A, 1.34 min, MS ES+329.0 / 331.0. Intermediate 8 N-(6-Bromopyrazin-2-yl)cyclopropanesulfonamide (I-8) 15 Using cyclopropanesulfonyl chloride (CAS 139631-62-2, Apollo Scientific) in place of methanesulfonyl chloride, and 6-bromopyrazin-2-amine (CAS 54237-53-5, Fluorochem) in place of 6-bromo-3-chloropyrazin-2-amine was obtained N-(6-bromopyrazin-2- yl)cyclopropanesulfonamide in 12% yield. LCMS: Method A, 1.10 min, MS ES+277.9 / 279.9. 20 Intermediate 9 N-(5-Bromopyrazin-2-yl)methanesulfonamide (I-9)

[0018] Using 5-bromopyrazin-2-amine (CAS 59489-71-3, BLD) in place of 6-bromo-3- chloropyrazin-2-amine was obtained N-(5-bromopyrazin-2-yl)methanesulfonamide in 45% yield. 5 LCMS: Method A, 0.63 min, MS ES+249.9 / 251.9. Intermediate 10 N-(5-Bromopyrazin-2-yl)morpholine-4-sulfonamide (I-10) Using morpholine-4-sulfonyl chloride (CAS 1828-66-6, BLD) in place of methanesulfonyl10 chloride, and 5-bromopyrazin-2-amine (CAS 59489-71-3, BLD) in place of 6-bromo-3- chloropyrazin-2-amine, and without purification, was obtained N-(5-bromopyrazin-2- yl)morpholine-4-sulfonamide in 41% yield. LCMS: Method A, 1.12 min, MS ES+323.0 / 325.0. Intermediate 11 15 N-(2-Chloro-5-methylpyrimidin-4-yl)-N-(methylsulfonyl)methanesulfonamide (I-11) Using 2-chloro-5-methylpyrimidin-4-amine (CAS 14394-70-8, BLD) in place of 6-bromo-3- chloropyrazin-2-amine, and without purification, was obtained N-(2-chloro-5- methylpyrimidin-4-yl)-N-(methylsulfonyl)methanesulfonamide in 49% yield.

[0019] 61 LCMS: Method A, 1.26 min, MS ES+300.0. Intermediate 12 N-(5-Bromo-2-methylpyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide (I-12) 5 Using 5-bromo-2-methylpyridin-3-amine (CAS 914358-73-9, BLD) in place of 6-bromo-3- chloropyrazin-2-amine, and stirring at 40 °C instead of rt, was obtained N-(5-bromo-2- methylpyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide in 20% yield. LCMS: Method A, 1.27 min, MS ES+343.0 / 345.0. Intermediate 13 10 N,N'-(5-Bromopyrazine-2,3-diyl)dimethanesulfonamide (I-13) Using 5-bromopyrazine-2,3-diamine (CAS 89123-58-0, Combi-Blocks) in place of 6-bromo- 3-chloropyrazin-2-amine was obtained N,N'-(5-bromopyrazine-2,3- diyl)dimethanesulfonamide in 46% yield. 15 LCMS: Method A, 1.18 min, MS ES+345.0 / 347.0. Intermediate 14 N-(6-Bromopyrazin-2-yl)morpholine-4-sulfonamide (I-14) Using 6-bromopyrazin-2-amine (CAS 54237-53-5, Fluorochem) in place of 6-bromo-3- chloropyrazin-2-amine, and morpholine-4-sulfonyl chloride (CAS 1828-66-6, BLD) in place of methanesulfonyl chloride was obtained N-(6-bromopyrazin-2-yl)morpholine-4- sulfonamide in 24% yield. 5 LCMS: Method A, 1.13 min, MS ES+323.0 / 325.0. Intermediate 15 N-(5-Bromo-3-methoxypyrazin-2-yl)methanesulfonamide (I-15) Using 5-bromo-3-methoxypyrazin-2-amine (CAS 5900-13-0, Apollo Scientific) in place of 6-10 bromo-3-chloropyrazin-2-amine, and without purification, was obtained N-(5-bromo-3- methoxypyrazin-2-yl)methanesulfonamide in 51% yield. LCMS: Method A, 1.07 min, MS ES+282.0 / 284.0. Intermediate 16 N′-(6-Bromo-2-pyrazinyl)-N,N-dimethylsulfamide (I-16) 15 Using 6-bromopyrazin-2-amine (CAS 54237-53-5, BLD) in place of 6-bromo-3- chloropyrazin-2-amine, dimethylsulfamoyl chloride (CAS 13360-57-1, Sigma Aldrich) in place of methanesulfonyl chloride, and without purification, was obtained N′-(6-Bromo-2- pyrazinyl)-N,N-dimethylsulfamide in 27% yield. 20 LCMS: Method A, 1.19 min, MS ES+281.0 / 283.0. Intermediate 17 N-(5-Bromo-3-methylpyrazin-2-yl)-N-(methylsulfonyl)methanesulfonamide (I-17) Using 5-bromo-3-methyl-pyrazin-2-amine (CAS 74290-67-8, BLD) in place of 6-bromo-3- 5 chloropyrazin-2-amine was obtained N-(5-bromo-3-methylpyrazin-2-yl)-N- (methylsulfonyl)methanesulfonamide in 86% yield. LCMS: Method A, 1.36 min, MS ES+343.9 / 345.9. Intermediates 18, 19 4-Phenethoxyaniline (I-18) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2- 10 dioxaborolan-2-yl)benzamide (I-19) 15 To a solution of 2-phenylethan-1-ol (CAS 60-12-8, Fluorochem, 3.38 g, 27.6 mmol) in DMF (20 mL) was added NaH (60% dispersion in mineral oil, 1.02 g, 25.5 mmol) and the mixture was stirred at rt for 30 min.1-Fluoro-4-nitrobenzene (CAS 350-46-9, Alfa Aesar,20 3.00 g, 21.3 mmol) was added. The mixture was stirred at rt for 18 h then poured into ice- water (400 mL) and the product was extracted with EtOAc (3 x 100 mL). The organic extracts were washed with brine (50 mL), dried over MgSO4and the filtrate adsorbed onto silica gel. Purification by flash chromatography (silica gel, 0 - 30% EtOAc in isohexane) afforded 1-nitro-4-phenethoxybenzene (4.80 g, 93%). 5 LCMS: Method A, 2.00 min, MS: ES+244.0. Step 2: 4-phenethoxyaniline (I-18) To a solution of 1-nitro-4-phenethoxybenzene (4.50 g, 18.5 mmol) in EtOH (55 mL) and 10 THF (30 mL), was added 10% Pd / C (wet with 50% water, 0.98 g, 9.3 mmol) and the mixture was stirred at rt under hydrogen (3 bar) for 18 h. The reaction mixture was filtered through Celite®and concentrated under reduced pressure to afford 4-phenethoxyaniline (3.50 g, 86%). LCMS: Method A, 0.99 min, MS: ES+214.2. 15 Step 3: N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) To a stirred solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 20 269409-73-6, BLD, 4.48 g, 18.1 mmol) and DIPEA (8.6 mL, 49.2 mmol) in DMF (40 mL) was added HATU (7.49 g, 20.0 mmol) and 4-phenethoxyaniline (I-18, 3.50 g, 16.4 mmol). The mixture was stirred at 40 °C for 18 h then cooled, poured into ice-water (500 mL), and extracted with EtOAc (3 x 120 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4and adsorbed onto silica gel, then purified by flash 25 chromatography (silica gel, 0 - 100% EtOAc in isohexane) to afford 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. 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) 5 10 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 h. The reaction was filtered through Celite®and the filtrate was adsorbed onto 15 silica gel then purified by flash chromatography (silica gel, 0 - 30% TBME in heptane) to afford 1-((benzyloxy)methyl)-4-nitrobenzene (6.33 g, 94%). LCMS: Method A, 1.96 min, MS: ES+244.1. 20 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 rt for 72 h. The mixture was filtered through Celite®and the crude concentrate was captured on SCX, washed with MeOH and eluted 5 with 10% of 0.7M ammonia / MeOH solution in DCM. Further purification by chromatography on (silica gel, 0 -10% (0.7M ammonia / MeOH) in DCM) afforded 4- ((benzyloxy)methyl)aniline (2.58 g, 79%). LCMS: Method A, 1.09 min, MS: ES+214.1. 10 Step 3: N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-21) Following the procedure of Intermediate 19 Step 3, using 4-((benzyloxy)methyl)aniline (I- 20) in place of 4-phenethoxyaniline (I-18), was obtained N-(4-((benzyloxy)methyl)phenyl)- 15 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. Intermediate 22 N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 20 yl)benzamide (I-22) Step 1: 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene 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) was 5 added (3-methoxy-4-nitrophenyl)methanol (CAS: 80866-88-2, BLD, 1.00 g, 5.46 mmol). The mixture was stirred at 45 °C for 16 h 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) afforded 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene (1.30 g, 85%). 10 LCMS: Method A, 1.94 min, MS ES+274.2. Step 2: 4-((benzyloxy)methyl)-2-methoxyaniline 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) was added iron 15 (2.39 g, 42.8 mmol). The mixture was stirred at 40 °C for 16 h. The mixture was diluted with sat. aq. NaHCO3(25 mL) and extracted with EtOAc (2 x 25 mL). The combined organics were dried over MgSO4and concentrated to afford 4-((benzyloxy)methyl)-2- methoxyaniline (1.14 g, 73%). LCMS: Method A, 1.27 min, MS ES+244.2. 20 Step 3: N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-22) Following the procedure of Intermediate 19 Step 3, using 4-((benzyloxy)methyl)-2- methoxyaniline in place of 4-phenethoxyaniline (I-18), and purification by flash chromatography (silica gel, 0-10% MeOH / DCM) was obtained N-(4-((benzyloxy)methyl)-2- methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 30% yield. 5 LCMS: Method A, 2.38 min, MS ES+474.2. Intermediate 23 N-(3-Fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-23) 10 Step 1: 2-(((2-fluoro-4-nitrobenzyl)oxy)methyl)pyridine Following the procedure of Intermediate 20 Step 1, using pyridin-2-ylmethanol (CAS 586- 98-1, BLD) in place of benzyl alcohol, 1-(bromomethyl)-2-fluoro-4-nitrobenzene (CAS 127349-56-8, Apollo Scientific) in place of 1-(bromomethyl)-4-nitrobenzene, and 15 purification by flash chromatography (silica gel, 0-100% EtOAc in isohexane) was obtained 2-(((2-fluoro-4-nitrobenzyl)oxy)methyl)pyridine in 53% yield. LCMS: Method A, 1.16 min, MS ES+263.1. Step 2: 3-fluoro-4-((pyridin-2-ylmethoxy)methyl)aniline Following the procedure of Intermediate 22 Step 2, using 2-(((2-fluoro-4- nitrobenzyl)oxy)methyl)pyridine in place of 4-((benzyloxy)methyl)-2-methoxy-1- nitrobenzene was obtained 3-fluoro-4-((pyridin-2-ylmethoxy)methyl)aniline in 80% yield. LCMS: Method A, 0.62 min, MS ES+m / z 233.2. 5 Step 3: N-(3-fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-23) Following the procedure of Intermediate 19 Step 3, using 3-fluoro-4-((pyridin-2- ylmethoxy)methyl)aniline in place of 4-phenethoxyaniline (I-18) was obtained N-(3-fluoro-4-10 ((pyridin-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, MS ES+463.2. Intermediate 24 (3-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid (I-24) 15 (3-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid (I-24) Following the procedure of Intermediate 19 Step 3, using 3-borono-2,6-difluorobenzoic acid (CAS 1451393-05-7, Combi-Blocks) in place of 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoic acid was obtained (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)- 2,4-difluorophenyl)boronic acid in 35% yield. 5 LCMS: Method A, 1.68 min, MS ES+398.1. Intermediate 25 N-(4-((Benzyloxy)methyl)phenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-25) 10 N-(4-((Benzyloxy)methyl)phenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-25) Following the procedure of Intermediate 19 Step 3, using 4-methyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 515131-35-8, BLD) in place of 3-(4,4,5,5-15 tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, was obtained 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. Intermediate 26 20 N-(3-Fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-26)

[0020] Step 1: 1-(bromomethyl)-2-fluoro-4-nitrobenzene To a stirred solution of 2-fluoro-1-methyl-4-nitrobenzene (CAS 455-88-9, Sigma Aldrich, 5 10.0 g, 64.46 mmol) in anhydrous DCE (100 mL) at rt was added 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). The mixture was stirred at reflux for 18 h then additional NBS (2.87 g, 16.1 mmol) and AIBN (212 mg, 1.29 mmol) were added. The mixture was stirred at reflux for 1 h, cooled to rt and diluted with water (20 mL). The mixture was extracted with DCM (50 10 mL), and the combined organic phases were dried over Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0-100% (3:1 EtOH / EtOAc) in heptane) afforded 1-(bromomethyl)-2-fluoro-4-nitrobenzene (5.40g, 34%). 1H NMR (400 MHz, DMSO) δ 8.16 (dd, J = 9.8, 2.3 Hz, 1H), 8.10 (ddd, J = 8.4, 2.3, 0.8 Hz, 1H), 7.85 (t, J = 8.1 Hz, 1H), 4.79 (d, J = 1.0 Hz, 2H). 15 Step 2: 2-fluoro-1-(((4-methoxybenzyl)oxy)methyl)-4-nitrobenzene Following the procedure of Intermediate 20 Step 1, using 4-methoxyphenyl)methanol (CAS 105-13-5, Apollo Scientific) in place of benzyl alcohol, 1-(bromomethyl)-2-fluoro-4- nitrobenzene in place of 1-(bromomethyl)-4-nitrobenzene, and purification by flash chromatography (silica gel, 0-100% EtOAc in isohexane) was obtained 2-fluoro-1-(((4- 5 methoxybenzyl)oxy)methyl)-4-nitrobenzene in 73% yield. LCMS Method A, 1.66 min, MS ES+NA (no ionisation). Step 3: 3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)aniline Following the procedure of Intermediate 22 step 2, using 2-fluoro-1-(((4-10 methoxybenzyl)oxy)methyl)-4-nitrobenzene in place of 4-((benzyloxy)methyl)-2-methoxy-1- nitrobenzene, at 45 °C for 24 h was obtained 3-fluoro-4-(((4- methoxybenzyl)oxy)methyl)aniline in 91% yield. Method A, 1.24 min, MS ES+262.2. Step 4: N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- 15 dioxaborolan-2-yl)benzamide (I-26) Following the procedure of Intermediate 19 Step 3, using 3-fluoro-4-(((4- methoxybenzyl)oxy)methyl)aniline in place of 4-phenethoxyaniline (I-18) was obtained N- (3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- 20 dioxaborolan-2-yl)benzamide in 49% yield. LCMS: Method A, 1.97 min, MS ES+492.2. Intermediate 27 N-(4-(Cyclopropylmethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-27) Step 1 Step 2 5 Step 1: 1-(cyclopropylmethoxy)-4-nitrobenzene Following the procedure of Intermediate 18 Step 1, using cyclopropylmethanol (CAS 2516- 33-8, Fluorochem) in place of 2-phenylethan-1-ol was obtained 1-(cyclopropylmethoxy)-4- nitrobenzene in 71% yield. 10 LCMS: Method A, 1.79 min, MS ES+194.2. Step 2: 4-(cyclopropylmethoxy)aniline Following the procedure of Intermediate 20 Step 2, using 1-(cyclopropylmethoxy)-4- nitrobenzene in place of 1-((benzyloxy)methyl)-4-nitrobenzene and without purification of 15 crude product, was obtained 4-(cyclopropylmethoxy)aniline in 60% yield. LCMS: Method A, 0.22 min, MS ES+164.2. Step 3: N-(4-(cyclopropylmethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-27) Following the procedure of Intermediate 19 Step 3, using 4-(cyclopropylmethoxy)aniline in 5 place of 4-phenethoxyaniline (I-18) was obtained N-(4-(cyclopropylmethoxy)phenyl)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 86% yield. LCMS: Method A, 2.09 min, MS ES+394.2. Intermediate 28 N-(3-Fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- 10 dioxaborolan-2-yl)benzamide (I-28) Step 1: 2-fluoro-1-(((3-methoxybenzyl)oxy)methyl)-4-nitrobenzene Following the procedure of Intermediate 20 Step 1, using (3-methoxyphenyl)methanol15 (CAS 105-13-5, Apollo Scientific) in place of benzyl alcohol, 1-(bromomethyl)-2-fluoro-4- nitrobenzene (CAS 127349-56-8, Apollo Scientific) in place of 1-(bromomethyl)-4- nitrobenzene, and purification by flash chromatography (silica gel, 0-100% EtOAc in isohexane) was obtained 2-fluoro-1-(((3-methoxybenzyl)oxy)methyl)-4-nitrobenzene in 81% yield. LCMS: Method A, 1.67 min, MS ES+309.1 (M+NH4)+. 5 Following the procedure of Intermediate 22 Step 2, using 2-fluoro-1-(((3- methoxybenzyl)oxy)methyl)-4-nitrobenzene in place of 4-((benzyloxy)methyl)-2-methoxy-1- nitrobenzene, stirring at 45 °C for 24 h, and with purification by flash chromatography (silica gel, 0-100% EtOAc in isohexane) was obtained 3-fluoro-4-(((3- 10 methoxybenzyl)oxy)methyl)aniline in 75% yield. Method A, 1.28 min, MS ES+262.1. 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) 15 Following the procedure of Intermediate 19 Step 3, using 3-fluoro-4-(((3- methoxybenzyl)oxy)methyl)aniline in place of 4-phenethoxyaniline (I-18) was obtained 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, MS ES+492.2. 20 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)

[0021] Step 1: 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene Following the procedure of Intermediate 20 Step 1 using (2-fluoro-4-nitrophenyl)methanol 5 (CAS 127349-56-8, Apollo Scientific) in place of benzyl alcohol, benzyl bromide (CAS 100- 39-0, Sigma Aldrich) in place of 1-(bromomethyl)-4-nitrobenzene, at 45 °C for 48 h, and without purification was obtained 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene in 43% yield. 1H NMR (500 MHz, DMSO) δ 8.15 – 8.09 (m, 2H), 7.80 (t, J = 7.9 Hz, 1H), 7.41 – 7.27 (m, 10 5H), 4.71 (s, 2H), 4.63 (s, 2H). Step 2: 4-((benzyloxy)methyl)-3-fluoroaniline Following the procedure of Intermediate 22 Step 2, using 1-((benzyloxy)methyl)-2-fluoro-4- nitrobenzene in place of 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene, stirring at 80 °C 15 for 16 h, and with purification by capturing the crude concentrate on SCX, washing with MeOH and eluting with 0.7M ammonia / MeOH, was obtained 4-((benzyloxy)methyl)-3- fluoroaniline in 55% yield. LCMS: Method A, 1.57 min, MS ES+232.2. 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) Following the procedure of Intermediate 19 Step 3, using 2-fluoro-5-(4,4,5,5-tetramethyl- 5 1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD) in place of 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)-3-fluoroaniline in place of 4-phenethoxyaniline (I-18) was obtained N-(4-((benzyloxy)methyl)-3- fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 44% yield. 101H NMR (500 MHz, DMSO) δ 10.68 (s, 1H), 7.93 (dd, J = 7.6, 1.7 Hz, 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, 2.6 Hz, 1H), 4.55 (d, J = 1.6 Hz, 4H), 1.32 (s, 12H). Intermediate 30 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)- 15 benzamide (I-30) 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)- benzamide (I-30) Following the procedure of Intermediate 19 Step 3, using 2-fluoro-5-(4,4,5,5-tetramethyl- 5 1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD) in place of 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, 4-(tosylmethyl)aniline (CAS 54306-15-9, Fluorochem) in place of 4-phenethoxyaniline (I-18), and isolation of the solid by filtration rather than extraction and chromatography, was obtained 2-fluoro-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)benzamide in 35% yield). 101H NMR (500 MHz, DMSO) δ 10.49 (s, 1H), 7.90 (dd, J = 7.6, 1.7 Hz, 1H), 7.88 – 7.81 (m, 1H), 7.61 (t, J = 8.4 Hz, 4H), 7.41 (d, J = 8.1 Hz, 2H), 7.37 (dd, J = 10.4, 8.3 Hz, 1H), 7.14 – 7.09 (m, 2H), 4.60 (s, 2H), 2.41 (s, 3H), 1.32 (s, 12H). Intermediate 31 (3-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid (I-31) 15 (3-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid (I-31) Following the procedure of Intermediate 19 Step 3, using 5-borono-2-methylbenzoic acid (CAS 1256346-18-5, Combi-Blocks) in place of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzoic acid, 4-((benzyloxy)methyl)aniline (I-20) in place of 4-phenethoxyaniline (I- 18), and purification by flash chromatography (silica gel, 0-10% MeOH in DCM) was 5 obtained (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid in 34% yield. LCMS: Method A, 1.71 min, MS ES+376.2. Intermediate 32 N-(4-((Benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 10 yl)benzamide (I-32) Step 1: 4-((benzyloxy)methyl)-2-fluoro-1-nitrobenzene Following the procedure of Intermediate 20 Step 1, using 4-(bromomethyl)-2-fluoro-1- 15 nitrobenzene (CAS 131858-37-2, Apollo) in place of 1-(bromomethyl)-4-nitrobenzene was obtained 4-((benzyloxy)methyl)-2-fluoro-1-nitrobenzene in 96% yield. LCMS: Method A, 1.94 min, MS: ES+261.1. Step 2: 4-((benzyloxy)methyl)-2-fluoroaniline Following the procedure of Intermediate 20 Step 2, using 4-((benzyloxy)methyl)-2-fluoro-1- nitrobenzene in place of 1-((benzyloxy)methyl)-4-nitrobenzene and with purification by flash chromatography (silica gel, 0 - 50% TBME in isohexane), was obtained 4- ((benzyloxy)methyl)-2-fluoroaniline in 75% yield. 5 LCMS: Method A, 1.64 min, MS ES+232.1. Step 3: N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-32) Following the procedure of Intermediate 19 Step 3, using 4-((benzyloxy)methyl)-2-10 fluoroaniline in place of 4-phenethoxyaniline (I-18), was obtained 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, MS ES+462.2. Intermediate 33 N-(4-((Benzyloxy)methyl)-2-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 15 yl)benzamide (I-33) N-(4-((Benzyloxy)methyl)-2-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-33) Following the procedure of Intermediate 19 Step 3, using 4-((benzyloxy)methyl)aniline (I- 20) in place 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) in place of 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, was obtained N-(4-((benzyloxy)methyl)- 5 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. Intermediate 34 (5-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-34) 10 (5-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-34) Following the procedure of Intermediate 19 Step 3, using 2-fluoro-5-15 carboxybenzeneboronic acid (CAS 874219-59-7, BLD) in place of 3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzoic acid and 4-((benzyloxy)methyl)aniline (I-20) in place of 4- phenethoxyaniline (I-18) and after RP chromatography (C18, 0 - 100% (0.1% HCO2H in MeCN) in (0.1% aq. HCO2H)), was obtained (5-((4-((benzyloxy)methyl)phenyl)carbamoyl)- 2-fluorophenyl)boronic acid in 55% yield. 20 LCMS: Method A, 1.68 min, MS ES+380.2. Intermediate 35 N-(4-((Benzyloxy)methyl)phenyl)-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-35) 5 N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-35) Following the procedure of Intermediate 19 Step 3, using 4-methoxy-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 269409-71-4, Manchester 10 Organics) in place of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4- ((benzyloxy)methyl)aniline (I-20) in place of 4-phenethoxyaniline (I-18), was obtained 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, MS ES+474.2. 15 Intermediate 36 (3-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid (I-36) (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid (I-36) Following the procedure of Intermediate 19 Step 3, using 5-borono-2-methoxybenzoic acid (CAS 913836-12-1, BLD) in place of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic 5 acid, and 4-((benzyloxy)methyl)aniline (I-20) in place of 4-phenethoxyaniline (I-18), was obtained (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid in 87% yield. LCMS: Method A, 1.74 min, MS ES+392.2. Intermediate 37 10 N-(4-((1-Phenylethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-37) Step 1: 1-nitro-4-((1-phenylethoxy)methyl)benzene Following the procedure of Intermediate 20 Step 1, using 1-phenylethan-1-ol (CAS 98-85- 1, Sigma Aldrich) in place of benzyl alcohol, at 45 °C and without purification, was obtained 1-nitro-4-((1-phenylethoxy)methyl)benzene in 54% yield. LCMS: Method A, 2.04 min, MS ES+258.1. 5 Step 2: 4-((1-phenylethoxy)methyl)aniline 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) was added AcOH (0.45 mL, 7.8 mmol). The mixture was stirred at 45 °C for 24 h, then diluted with sat. aq. 10 NaHCO3(150 mL) and extracted with EtOAc (3 x 60 mL). The combined organic phases were dried over Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0-10% (0.1% ammonia / MeOH) in DCM) afforded 4-((1- phenylethoxy)methyl)aniline (670 mg, 27%). LCMS: Method A, 1.22 min, MS ES+228.2. 15 Step 3: N-(4-((1-phenylethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-37) Following the procedure of Intermediate 19 Step 3, using 4-((1- phenylethoxy)methyl)aniline in place of 4-phenethoxyaniline (I-18) was obtained N-(4-((1- 20 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, MS ES+458.2. Intermediate 38 N-(6-Bromo-3-chloropyrazin-2-yl)methanesulfonamide (I-38) N-(6-Bromo-3-chloropyrazin-2-yl)methanesulfonamide (I-38) 5 Following the procedure of Intermediate 1, using morpholine-4-sulfonyl chloride (CAS 1828-66-6, BLD) in place of methanesulfonyl chloride was obtained N-(6-bromo-3- chloropyrazin-2-yl)methanesulfonamide in 27% yield. 10 LCMS: Method A, 1.07 min, MS ES+385.8 / 287.9. Intermediate 39 5-(6-Amino-5-methylpyrazin-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide (I- 39)

[0022] Step 1: 6-chloro-3-methylpyrazin-2-amine A mixture of 3-bromo-6-chloropyrazin-2-amine (CAS: 212779-21-0, BLD, 2.00 g, 9.60 5 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 N2then stirred 80 °C for 40 h. After cooling to rt, the mixture was filtered through Celite, washing with EtOAc (50 mL). The filtrate was diluted with brine (75 mL) and the aqueous was extracted with EtOAc (2 x 75 mL). The combined organics were washed 10 with brine (225 mL), dried over MgSO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0-100% (3:1 EtOAc / EtOH) / isohexane) afforded 6-chloro-3-methylpyrazin-2-amine (1.03 g, 73%). LCMS: Method A, 0.69 min, MS ES+144.0. Step 2: 5-(6-amino-5-methylpyrazin-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2- 15 fluorobenzamide (I-39) A mixture of 6-chloro-3-methylpyrazin-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 N2then stirred at 80 °C for 1.5 h. 5 After cooling to rt, the mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were dried over MgSO4and concentrated under reduced pressure. This was combined with a second batch, starting from 6-chloro-3- methylpyrazin-2-amine, 0.137 mmol scale, and purified by flash chromatography (silica gel, 0-100% (3:1 EtOAc / EtOH) / isohexane) to afford 5-(6-amino-5-methylpyrazin-2-yl)-N-(4- 10 ((benzyloxy)methyl)phenyl)-2-fluorobenzamide (255 mg, 48%). LCMS: Method A, 1.70 min, MS ES+443.1. Intermediate 40 5-(6-Amino-5-cyclopropylpyrazin-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide (I-40) 15 Step 1: 6-chloro-3-cyclopropylpyrazin-2-amine Following the procedure of Intermediate 39 Step 1, using cyclopropaneboronic acid (CAS: 411235-57-9, Fluorochem) in place of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane, and with stirring for 40 h (adding additional cyclopropaneboronic acid (0.4 eq) and Pd-118 (0.05 eq) after 22 h) afforded 6-chloro-3-cyclopropylpyrazin-2-amine in 62% yield. LCMS: Method A, 1.06 min, MS ES+ 170.0. Step 2: 5-(6-amino-5-cyclopropylpyrazin-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2- 5 fluorobenzamide (I-40) Following the procedure of Intermediate 39 Step 2, using 6-chloro-3-cyclopropylpyrazin-2- amine in place of 6-chloro-3-methylpyrazin-2-amine afforded 5-(6-amino-5- cyclopropylpyrazin-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide in 41% yield. 10 LCMS: Method A, 1.84 min, MS ES+ 469.1. Example 1 3-(5-Chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide 3-(5-Chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide 15 A mixture of N-(6-bromo-3-chloropyrazin-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 min, after which Pd(dppf)Cl2(43 mg, 0.077 5 mmol) was added and the mixture purged for a further 2 min. The mixture was stirred at 80 °C for 3 h. The mixture was cooled to rt, aq. HCl (1M, 5 mL) was added, and the mixture extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over Na2SO4and concentrated under reduced pressure. Purification by RP chromatography (C18, 0 - 100% (0.1 % HCO2H in MeCN) in 0.1% aq. HCO2H) afforded 3-(5-chloro-6- 10 (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (170 mg, 80%). LCMS: Method A, 1.98 min, MS ES+523.2. 1H NMR (500 MHz, DMSO) δ 10.98 (s, 1H), 10.27 (s, 1H), 8.90 (s, 1H), 8.61 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.41 – 7.29 (m, 4H), 7.24 (t, J = 6.6 Hz, 1H), 7.00 – 6.93 (m, 2H), 4.20 (t, J = 6.9 Hz, 15 2H), 3.50 (s, 3H), 3.05 (t, J = 6.9 Hz, 2H). Examples 2-9: The following Examples 2-9 were prepared analogously to Example 1, substituting N-(6- bromo-3-chloropyrazin-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 the appropriate starting 20 materials, using dioxane or acetonitrile at 80 °C for 1 h, and with any other minor modifications described. Examples 2, 3 and 4 were purified with basic modifier. Example 2 N-(4-((Benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)benzamide Using N-(6-bromo-3-chloropyrazin-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) afforded N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2- 5 yl)benzamide in 39% yield. LCMS: Method A, 1.96 min, MS ES+523.1. 1H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 10.40 (s, 1H), 8.56 (s, 1H), 8.51 (s, 1H), 8.26 (d, J = 7.7 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.69 (t, J = 7.7 Hz, 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 10 was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 3 3-(5-Chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(4- (cyclopropylmethoxy)phenyl)benzamide 15 Using N-(6-bromo-3-chloropyrazin-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 with trituration with CH3CN and Et2O, afforded 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(4-(cyclopropylmethoxy)phenyl)benzamide in 52% yield. 20 LCMS: Method A, 1.76 min, MS ES+473.1. 1H NMR (500 MHz, DMSO) δ 10.98 (s, 1H), 10.26 (s, 1H), 8.89 (s, 1H), 8.61 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.82 – 7.62 (m, 3H), 6.94 (d, J = 8.6 Hz, 2H), 3.81 (d, J = 7.0 Hz, 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 compound contained up to 1 mol. eq. of ammonia. Example 4 N-(4-((Benzyloxy)methyl)phenyl)-3-(5-chloro-6-(cyclopropanesulfonamido)pyrazin-2- 5 yl)benzamide Using N-(6-bromo-3-chloropyrazin-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) afforded N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6- 10 (cyclopropanesulfonamido)pyrazin-2-yl)benzamide in 50% yield. LCMS: Method A, 2.00 min, MS ES+549.1. 1H NMR (500 MHz, DMSO) δ 10.96 (s, 1H), 10.42 (s, 1H), 8.92 (s, 1H), 8.63 (d, J = 1.9 Hz, 1H), 8.34 – 8.29 (m, 1H), 8.10 – 8.05 (m, 1H), 7.82 – 7.77 (m, 2H), 7.74 (t, J = 7.8 Hz, 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), 15 1.15 – 1.08 (m, 2H).1H was obscured / not observed. The isolated compound contained up to 1 mol. eq. of ammonia. Example 5 N-(4-((Benzyloxy)methyl)-2-methoxyphenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2- yl)benzamide 20 Using N-(6-bromo-3-chloropyrazin-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) afforded N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)benzamide in 12% yield. LCMS: Method B, 1.34 min, MS ES+553.2 1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 9.63 (s, 1H), 8.92 (s, 1H), 8.64 (s, 1H), 8.29 5 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.43 – 7.34 (m, 4H), 7.34 – 7.27 (m, 1H), 7.10 (d, J = 1.8 Hz, 1H), 6.99 (dd, J = 8.1, 1.7 Hz, 1H), 4.56 (s, 2H), 4.55 (s, 2H), 3.85 (s, 3H), 3.50 (s, 3H). Example 6 3-(5-Chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(3-fluoro-4-(((4- 10 methoxybenzyl)oxy)methyl)phenyl)benzamide Using N-(6-bromo-3-chloropyrazin-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) afforded 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(3-fluoro-4- 15 (((4-methoxybenzyl)oxy)methyl)phenyl)benzamide in 43%yield. LCMS: Method A, 1.65 min, MS ES+572.1. 1H NMR (500 MHz, DMSO) δ 10.99 (s, 1H), 10.60 (s, 1H), 8.93 (s, 1H), 8.62 (t, J = 1.8 Hz, 1H), 8.31 (dt, J = 7.9, 1.4 Hz, 1H), 8.08 (dt, J = 7.8, 1.5 Hz, 1H), 7.81 – 7.72 (m, 2H), 7.57 (dd, J = 8.4, 2.0 Hz, 1H), 7.46 (t, J = 8.4 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 20 Hz, 2H), 4.52 (s, 2H), 4.48 (s, 2H), 3.76 (s, 3H), 3.52 (s, 3H). Example 7 3-(5-Chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(3-fluoro-4-(((3- methoxybenzyl)oxy)methyl)phenyl)benzamide Using N-(6-bromo-3-chloropyrazin-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 with purification by preparative HPLC (Prep Method A, x=20, 5 y=50), afforded 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(3-fluoro-4-(((3- methoxybenzyl)oxy)methyl)phenyl)benzamide in 6% yield. LCMS: Method A, 1.67 min, MS ES+571.2 1H NMR (500 MHz, DMSO) δ 10.99 (s, 1H), 10.61 (s, 1H), 8.92 (s, 1H), 8.62 (t, J = 1.9 Hz, 1H), 8.31 (d, J = 7.9 Hz, 1H), 8.08 (d, J = 6.6 Hz, 1H), 7.84 – 7.71 (m, 2H), 7.58 (dd, J = 10 8.4, 2.0 Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 6.97 – 6.90 (m, 2H), 6.87 (dd, J = 8.6, 2.5 Hz, 1H), 4.55 (s, 2H), 4.54 (s, 2H), 3.76 (s, 3H), 3.51 (s, 3H). Example 8 N-(4-((Benzyloxy)methyl)-3-fluorophenyl)-5-(6-chloro-5-(methylsulfonamido)pyrazin-2-yl)- 2-fluorobenzamide 15 Using N-(5-bromo-3-chloropyrazin-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) afforded N-(4-((benzyloxy)methyl)-3-fluorophenyl)-5- (6-chloro-5-(methylsulfonamido)pyrazin-2-yl)-2-fluorobenzamide in 14% yield. 20 LCMS: Method A, 1.72 min, MS ES+559.1. 1H NMR (500 MHz, DMSO) δ 10.94 (s, 1H), 10.79 (s, 1H), 9.07 (s, 1H), 8.32 (dd, J = 6.6, 2.4 Hz, 1H), 8.26 (m, 1H), 7.76 – 7.70 (m, 1H), 7.54 (t, J = 9.2 Hz, 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 5-(5-Chloro-6-(methylsulfonamido)pyrazin-2-yl)-2-fluoro-N-(4- 5 (tosylmethyl)phenyl)benzamide Using N-(6-bromo-3-chloropyrazin-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) afforded 5- (5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-2-fluoro-N-(4-(tosylmethyl)phenyl)benzamide 10 in 8% yield. LCMS: Method A, 1.45 min, MS ES+589.1 1H NMR (500 MHz, DMSO) δ 10.98 (s, 1H), 10.62 (s, 1H), 8.81 (s, 1H), 8.37 (dd, J = 6.8, 2.4 Hz, 1H), 8.27 (m, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.63 – 7.58 (m, 2H), 7.57 (t, J = 9.2 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 4.62 (s, 2H), 3.43 (s, 3H), 2.41 (s, 15 3H). Examples 10-21: The following Examples 10-21 were prepared analogously to Example 1, substituting N-(6- bromo-3-chloropyrazin-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 the appropriate starting 20 materials, using Pd-118 in place of Pd(dppf)Cl2, and either dioxane or acetonitrile at 80 °C for 9-18 h. Any other minor modifications are described. Examples 10-12, 14-15 and 18-21 were purified with basic modifier.

[0023] Example 10 3-(6-Chloro-5-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide Using N-(5-bromo-3-chloropyrazin-2-yl)methanesulfonamide (I-3) and N-(4- 5 phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(6-chloro-5-(methylsulfonamido)pyrazin-2-yl)-N-(4- phenethoxyphenyl)benzamide in 7% yield. LCMS: Method A, 1.97 min, MS ES+523.1. 1H NMR (500 MHz, DMSO) δ 10.96 (s, 1H), 10.24 (s, 1H), 8.96 (s, 1H), 8.50 (s, 1H), 8.18 10 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.66 (m, 3H), 7.37 – 7.30 (m, 3H), 7.23 (t, J = 6.8 Hz, 1H), 6.95 (d, J = 9.0 Hz, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.28 (s, 3H), 3.04 (t, J = 6.9 Hz, 2H).1H was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 11 15 3-(5-Cyano-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide Using N-(6-chloro-3-cyanopyrazin-2-yl)methanesulfonamide (I-4) and N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(5-cyano-6-(methylsulfonamido)pyrazin-2-yl)-N-(4- 20 phenethoxyphenyl)benzamide in 21% yield. LCMS: Method B, 1.95 min, MS ES+514.1. 1H NMR (500 MHz, DMSO) δ 12.04 (s, 1H), 10.29 (s, 1H), 8.44 (d, J = 1.9 Hz, 1H), 8.36 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.15 – 8.09 (m, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.71 – 7.64 (m,

[0024] 96 2H), 7.37 – 7.29 (m, 4H), 7.27 – 7.20 (m, 1H), 6.99 – 6.91 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.45 (s, 3H), 3.04 (t, J = 6.9 Hz, 2H). The isolated compound contains up to 1 mol. eq. of ammonia. Example 12 5 3-(5-Methyl-4-(methylsulfonamido)pyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide Using N-(2-chloro-5-methylpyrimidin-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) afforded 3-(5-methyl-4-(methylsulfonamido)pyrimidin-2-yl)-N-(4- 10 phenethoxyphenyl)benzamide in 23% yield. LCMS: Method A, 1.22 min, MS ES+503.2. 1H NMR (500 MHz, DMSO) δ 10.75 (s, 1H), 10.31 (s, 1H), 8.84 (s, 1H), 8.53 (s, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 7.7 Hz, 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 = 6.9 Hz, 2H), 3.54 (s, 3H), 3.05 (t, J = 6.9 Hz, 2H), 15 2.21 (s, 3H). The isolated compound contains up to 1 mol. eq. of ammonia. Example 13 3-(6-Methyl-5-(methylsulfonamido)pyridin-3-yl)-N-(4-phenethoxyphenyl)benzamide Using N-(5-bromo-2-methylpyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide (I-12) and 20 N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(6-methyl-5-(methylsulfonamido)pyridin-3-yl)-N-(4- phenethoxyphenyl)benzamide in 52% yield. LCMS: Method A, 1.81 min, MS ES+502.1.1H NMR (500 MHz, DMSO) δ 10.24 (s, 1H), 9.49 (s, 1H), 8.75 (d, J = 2.2 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.97 (q, J = 2.9 Hz, 2H), 7.90 (d, J = 7.7 Hz, 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 = 6.9 Hz, 2H), 3.11 (s, 3H), 3.04 (t, J = 6.9 Hz, 2H), 2.58 (s, 3H). 5 Example 14 3-(6-(Methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide Using N-(6-bromopyrazin-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) 10 afforded 3-(6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide in 43% yield. LCMS: Method A, 1.88 min, MS ES+489.2. 1H NMR (500 MHz, DMSO) δ 11.22 (s, 1H), 10.27 (s, 1H), 9.01 (s, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.29 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 7.7 Hz, 1H), 7.74 – 7.68 (m, 2H), 7.68 (d, J = 2.2 15 Hz, 1H), 7.38 – 7.29 (m, 4H), 7.27 – 7.20 (m, 1H), 7.00 – 6.93 (m, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.47 (s, 3H), 3.05 (t, J = 6.9 Hz, 2H). The isolated compound contains up to 1 mol. eq. of ammonia. Example 15 3-(4-(Methylsulfonamido)pyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide 20 Using N-(2-chloropyrimidin-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) afforded 3-(4-(methylsulfonamido)pyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide in 23% yield. LCMS: Method B, 1.85 min, MS ES+489.2. 1H NMR (500 MHz, DMSO) δ 11.41 (s, 1H), 10.32 (s, 1H), 8.88 (s, 1H), 8.68 (d, J = 5.7 Hz, 1H), 8.51 (d, J = 7.7 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.72 – 7.66 (m, 3H), 7.37 – 7.29 (m, 4H), 7.24 (t, J = 6.7 Hz, 1H), 6.95 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 5.6 Hz, 1H), 4.19 (t, J = 5 6.8 Hz, 2H), 3.49 (s, 3H), 3.05 (t, J = 6.9 Hz, 2H). The isolated compound contains up to 1 mol. eq. of ammonia. Example 16 3-(6-(Methylsulfonamido)pyridin-2-yl)-N-(4-phenethoxyphenyl)benzamide 10 Using N-(6-bromopyridin-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), with trituration with CH3CN and Et2O, afforded 3-(6-(methylsulfonamido)pyridin-2-yl)-N-(4- phenethoxyphenyl)benzamide in 19% yield. LCMS: Method A, 1.97 min, MS ES+488.1. 151H NMR (500 MHz, DMSO) δ 10.71 (s, 1H), 10.25 (s, 1H), 8.55 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.71 – 7.63 (m, 3H), 7.36 – 7.29 (m, 4H), 7.24 (d, J = 7.0 Hz, 1H), 6.95 (dd, J = 8.3, 5.6 Hz, 3H), 4.19 (t, J = 6.8 Hz, 2H), 3.44 (s, 3H), 3.05 (t, J = 6.9 Hz, 2H). Example 17 20 N-(4-((Benzyloxy)methyl)phenyl)-3-(6-(methylsulfonamido)pyrazin-2-yl)benzamide Using N-(6-bromopyrazin-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) afforded N-(4-((benzyloxy)methyl)phenyl)-3-(6-(methylsulfonamido)pyrazin-2- yl)benzamide in 14% yield. LCMS: Method B, 1.84 min, MS ES+489.1. 1H NMR (500 MHz, DMSO) δ 10.41 (s, 1H), 8.82 (s, 1H), 8.60 (s, 1H), 8.29 (d, J = 7.8 Hz, 5 1H), 8.15 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.40 – 7.27 (m, 7H), 4.54 (s, 2H), 4.52 (s, 2H), 3.27 (s, 3H).1H was obscured / not observed. Example 18 3-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide 10 Using N-(6-bromopyrazin-2-yl)cyclopropanesulfonamide (I-8) and N-(4-phenethoxyphenyl)- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(6- (cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide in 33% yield. LCMS: Method A, 1.92 min, MS ES+515.1. 151H NMR (500 MHz, DMSO) δ 11.18 (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 = 7.7 Hz, 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 = 6.9 Hz, 2H), 3.23 – 3.15 (m, 1H), 3.05 (t, J = 6.9 Hz, 2H), 1.19 – 1.12 (m, 2H), 1.12 – 1.06 (m, 2H). The isolated compound contains up to 1 mol. eq. of ammonia. 20 Example 19 N-(4-((Benzyloxy)methyl)phenyl)-3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)benzamide Using N-(6-bromopyrazin-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) afforded N-(4-((benzyloxy)methyl)phenyl)-3-(6-(cyclopropanesulfonamido)pyrazin-2- yl)benzamide in 44% yield. 5 LCMS: Method A, 1.87 min, MS ES+515.1. 1H NMR (500 MHz, DMSO) δ 11.19 (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 = 7.8 Hz, 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 up to 1 mol. eq. 10 of ammonia Example 20 3-(5-(Methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide Using N-(5-bromopyrazin-2-yl)methanesulfonamide (I-9) and N-(4-phenethoxyphenyl)-3-15 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(5- (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide in 25% yield. LCMS: Method A, 1.88 min, MS ES+489.1. 1H NMR (500 MHz, DMSO) δ 11.20 (s, 1H), 10.24 (s, 1H), 9.05 (d, J = 1.5 Hz, 1H), 8.61 – 8.57 (m, 1H), 8.44 – 8.40 (m, 1H), 8.24 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.71 – 20 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 = 6.9 Hz, 2H), 3.39 (s, 3H), 3.05 (t, J = 6.9 Hz, 2H). The isolated compound contains up to 1 mol. eq. of ammonia. Example 21 3-(5-(Morpholine-4-sulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide Using N-(5-bromopyrazin-2-yl)morpholine-4-sulfonamide (I-10) and N-(4- 5 phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(5-(morpholine-4-sulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide in 17% yield. LCMS: Method A, 1.95 min, MS ES+560.2. 1H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 8.97 (s, 1H), 8.57 (t, J = 1.8 Hz, 1H), 8.44 (d, J 10 = 1.6 Hz, 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 = 6.9 Hz, 2H), 3.66 – 3.60 (m, 4H), 3.20 (t, J = 4.8 Hz, 4H), 3.04 (t, J = 6.9 Hz, 2H).1H was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 22 15 N-(4-((Benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide N-(4-((Benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide 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-(methylsulfonamido)pyrazin-2-yl)benzamide 5 (Example 2, 40 mg, 0.077 mmol) in dioxane (4 mL) and water (1 mL) was purged with nitrogen for 5 min, after which Pd-118 (5 mg, 0.08 mmol) was added and the mixture purged for a further 2 min. The mixture was stirred at 80 °C for 9 h. The mixture was cooled to rt, aq. HCl (1M, 5 mL) was added, and the mixture extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over Na2SO4and concentrated under 10 reduced pressure. Purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH), followed by trituration with CH3CN and Et2O, afforded N-(4- ((benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(methylsulfonamido)pyrazin-2-yl)benzamide (18 mg, 42%). LCMS: Method A, 1.97 min, MS ES+529.1. 151H NMR (500 MHz, DMSO) δ 10.71 (s, 1H), 10.39 (s, 1H), 8.83 (s, 1H), 8.58 – 8.54 (m, 1H), 8.24 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.82 – 7.77 (m, 2H), 7.69 (t, J = 7.8 Hz, 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 = 7.7 Hz, 2H), 1.01 (dd, J = 5.4, 2.7 Hz, 2H).2H were obscured / not observed. 1H NMR (500 MHz, Acetone) δ 9.69 (s, 1H), 9.31 (br s, 1H), 8.84 (s, 1H), 8.67 (t, J = 1.8 20 Hz, 1H), 8.33 (dt, J = 7.9, 1.3 Hz, 1H), 8.08 (dt, J = 8.0, 1.3 Hz, 1H), 7.94 – 7.84 (m, 2H), 7.69 (t, J = 7.8 Hz, 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 up to 1 mol. eq. of ammonia. Example 23 25 N-(4-((Benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(morpholine-4-sulfonamido)pyrazin-2- yl)benzamide

[0025] Step 1: N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(morpholine-4-sulfonamido)pyrazin- 2-yl)benzamide 5 Following the procedure of Example 1, using N-(6-bromo-3-chloropyrazin-2-yl)morpholine- 4-sulfonamide (I-38) in place of N-(6-bromo-3-chloropyrazin-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) in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-19), with purification by flash chromatography (silica gel, 0-10 100% EtOAc in isohexane) afforded N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6- (morpholine-4-sulfonamido)pyrazin-2-yl)benzamide in 44% yield. LCMS: Method A, 1.33 min, MS ES+594.2. 1H NMR (500 MHz, DMSO) δ 10.75 (s, 1H), 10.41 (s, 1H), 8.88 (s, 1H), 8.63 (d, J = 1.9 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.81 – 7.75 (m, 2H), 7.72 (t, J = 7.8 15 Hz, 1H), 7.37 (t, J = 4.1 Hz, 6H), 7.31 (m, 1H), 4.53 (d, J = 9.0 Hz, 4H), 3.58 (t, J = 4.7 Hz, 4H), 3.37 (d, J = 9.4 Hz, 2H).2H were obscured / not observed. Step 2: N-(4-((benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(morpholine-4- sulfonamido)pyrazin-2-yl)benzamide Following the procedure of Example 22, using N-(4-((benzyloxy)methyl)phenyl)-3-(5- 5 chloro-6-(morpholine-4-sulfonamido)pyrazin-2-yl)benzamide in place of N-(4- ((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)benzamide (Example 2), at 80 °C for 9 h, and with purification by preparative HPLC (Prep Method A, x=20, y=50), afforded N-(4-((benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(morpholine-4- sulfonamido)pyrazin-2-yl)benzamide in 21% yield. 10 LCMS: Method A, 2.04 min, MS ES+600.2. 1H NMR (500 MHz, DMSO) δ 10.49 (s, 1H), 10.38 (s, 1H), 8.90 (s, 1H), 8.59 (s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.69 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 4.2 Hz, 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 were obscured / not observed. 15 1H NMR (500 MHz, Acetone) δ 9.67 (s, 1H), 9.15 (s, 1H), 8.84 (s, 1H), 8.72 (s, 1H), 8.30 (d, J = 7.7 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.68 (t, J = 7.8 Hz, 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).

[0026] Example 24 3-(5-Methyl-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide 3-(5-Methyl-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide 5 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-(methylsulfonamido)pyrazin-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 min, after which Pd-118 (7 mg, 0.012 mmol) 10 was added and the mixture purged for a further 2 min. The mixture was stirred at 80 °C for 9 h. The mixture was cooled to rt, aq. HCl (1M, 5 mL) was added, and the mixture extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over Na2SO4and concentrated under reduced pressure. Purification by RP chromatography (C18, 0- 100% (0.1 % HCO2H in MeCN) in 0.1% aq. HCO2H), followed by trituration with CH3CN15 and Et2O, afforded 3-(5-methyl-6-(methylsulfonamido)pyrazin-2-yl)-N-(4- phenethoxyphenyl)benzamide (15 mg, 25%). LCMS: Method A, 1.90 min, MS ES+503.1. 1H NMR (500 MHz, DMSO) δ 10.48 (s, 1H), 10.25 (s, 1H), 8.92 (s, 1H), 8.58 (s, 1H), 8.26 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.73 – 7.65 (m, 3H), 7.37 – 7.29 (m, 4H), 7.24 20 (t, J = 6.8 Hz, 1H), 6.96 (d, J = 9.0 Hz, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.50 (s, 3H), 3.05 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H). Examples 25-30: The following Examples 25-30 were prepared analogously to Example 24, substituting 3- (5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1) with the appropriate starting material, using dioxane or acetonitrile at 80 °C 5 for 16-18 h, and with any other minor modifications described. Examples 25-27 and 30 were purified with basic modifier. Example 25 N-(4-((Benzyloxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- 10 yl)benzamide Using N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2- yl)benzamide (Example 2) afforded N-(4-((benzyloxy)methyl)phenyl)-3-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide in 34% yield. 15 LCMS: Method A, 1.80 min, MS ES+503.2. 1H NMR (500 MHz, DMSO) δ 10.48 (s, 1H), 10.41 (s, 1H), 8.95 (s, 1H), 8.60 (s, 1H), 8.27 (d, J = 9.3 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.83 – 7.77 (m, 2H), 7.71 (t, J = 7.7 Hz, 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 up to 1 mol. eq. of ammonia. Example 26 N-(4-((Benzyloxy)methyl)phenyl)-3-(5-methyl-6-(morpholine-4-sulfonamido)pyrazin-2- yl)benzamide 5 Using N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(morpholine-4-sulfonamido)pyrazin-2- yl)benzamide (Example 57) afforded N-(4-((benzyloxy)methyl)phenyl)-3-(5-methyl-6- (morpholine-4-sulfonamido)pyrazin-2-yl)benzamide in 29% yield. LCMS: Method C, 4.53 min, MS ES+574.2. 1H NMR (500 MHz, DMSO) δ 10.39 (s, 1H), 8.82 (s, 1H), 8.62 – 8.58 (m, 1H), 8.27 (d, J = 10 7.8 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.68 (t, J = 7.8 Hz, 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 obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 27 15 N-(4-(Cyclopropylmethoxy)phenyl)-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide Using 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-(cyclopropylmethoxy)phenyl)- benzamide (Example 3) afforded N-(4-(cyclopropylmethoxy)phenyl)-3-(5-methyl-6- 20 (methylsulfonamido)pyrazin-2-yl)benzamide in 22% yield. LCMS: Method A, 1.67 min, MS ES+453.2.1H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 8.47 (s, 1H), 8.29 – 8.11 (m, 2H), 7.89 (d, J = 7.3 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 9.0 Hz, 2H), 3.81 (d, J = 7.0 Hz, 2H), 3.03 (d, J = 22.8 Hz, 3H), 2.28 (d, J = 11.1 Hz, 3H), 1.26 – 1.21 (m, 1H), 0.63 – 0.50 (m, 2H), 0.39 – 0.27 (m, 2H).1H was obscured / not observed. The 5 isolated compound contains up to 1 mol. eq. of ammonia. Example 28 N-(3-Fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamido)- pyrazin-2-yl)benzamide 10 Using 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(3-fluoro-4-(((3- methoxybenzyl)oxy)methyl)phenyl)benzamide (Example 7) afforded N-(3-fluoro-4-(((3- methoxybenzyl)oxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide in 22% yield. LCMS: Method A, 1.58 min, MS ES+551.2. 151H NMR (500 MHz, DMSO) δ 10.59 (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, 2.0 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.59 (dd, J = 8.3, 2.0 Hz, 1H), 7.47 (t, J = 8.4 Hz, 1H), 7.29 (t, J = 7.8 Hz, 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 20 N-(3-Fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide Using 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(3-fluoro-4-(((4- methoxybenzyl)oxy)methyl)phenyl)benzamide (Example 6) afforded N-(3-fluoro-4-(((4- methoxybenzyl)oxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide in 23% yield. 5 LCMS: Method A, 1.56 min, MS ES+551.1. 1H NMR (500 MHz, DMSO) δ 10.58 (s, 1H), 10.49 (s, 1H), 8.95 (s, 1H), 8.60 (s, 1H), 8.29 (d, J = 7.9 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.79 (dd, J = 12.5, 2.0 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.58 (dd, J = 8.3, 2.0 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 4.52 (s, 2H), 4.48 (s, 2H), 3.76 (s, 3H), 3.52 (s, 3H), 2.54 (s, 3H). 10 Example 30 N-(4-((Benzyloxy)methyl)phenyl)-3-(6-(cyclopropanesulfonamido)-5-methylpyrazin-2- yl)benzamide Using N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(cyclopropanesulfonamido)pyrazin-2-15 yl)benzamide (Example 4) afford N-(4-((benzyloxy)methyl)phenyl)-3-(6- (cyclopropanesulfonamido)-5-methylpyrazin-2-yl)benzamide in 25% yield. LCMS: Method C, 4.60 min, MS ES+529.2. 1H NMR (500 MHz, DMSO) δ 10.40 (s, 2H), 8.87 (s, 1H), 8.60 (d, J = 1.9 Hz, 1H), 8.29 (d, J = 7.7 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.81 – 7.76 (m, 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.37 20 (t, J = 4.4 Hz, 6H), 7.32 (m, 1H), 4.54 (s, 2H), 4.52 (s, 2H), 3.35 (dd, J = 8.6, 4.1 Hz, 1H), 1.15 (d, J = 4.1 Hz, 2H), 1.06 (d, J = 7.6 Hz, 2H).3H were obscured / 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 = 1.8 Hz, 1H), 8.36 (dt, J = 7.8, 1.4 Hz, 1H), 8.08 (dt, J = 7.8, 1.4 Hz, 1H), 7.93 – 7.85 (m, 2H), 7.69 (t, J = 7.8 Hz, 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 compound contains up to 1 mol. eq. of ammonia. Example 31 N-(4-((Benzyloxy)methyl)phenyl)-4-methoxy-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- 5 yl)benzamide Step 1: N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-4- methoxybenzamide 10 Following the procedure of Example 1, using N-(4-((benzyloxy)methyl)phenyl)-4-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-35) in place of N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), at 80 °C for 1 h and purification by chromatography on RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6- 15 (methylsulfonamido)pyrazin-2-yl)-4-methoxybenzamide in 42% yield. LCMS: Method A, 1.93 min, MS ES+553.1. Step 2: N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(5-methyl-6-(methylsulfonamido)- pyrazin-2-yl)benzamide Following the procedure of Example 24, using N-(4-((benzyloxy)methyl)phenyl)-3-(5- 5 chloro-6-(methylsulfonamido)pyrazin-2-yl)-4-methoxybenzamide in place of 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), at 80 °C for 16 h and with purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide in 28% yield. 10 LCMS: Method A, 1.80 min, MS ES+533.2. 1H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 10.22 (s, 1H), 8.72 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.10 (dd, J = 8.7, 2.4 Hz, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.45 – 7.18 (m, 8H), 4.52 (s, 2H), 4.50 (s, 2H), 3.95 (s, 3H), 3.47 (s, 3H).3H were obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. 15 Example 32 N-(4-((Benzyloxy)methyl)-2-fluorophenyl)-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide

[0027] Step 1: N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(5-chloro-6-(methylsulfonamido)- pyrazin-2-yl)benzamide 5 Following the procedure of Example 1, using N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-32) in place of N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), at 80 °C for 1 h and purification by chromatography on RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(5-chloro- 10 6-(methylsulfonamido)pyrazin-2-yl)benzamide in 40% yield. LCMS: Method A, 1.93 min, MS ES+541.1 Step 2: N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(5-methyl-6-(methylsulfonamido)- pyrazin-2-yl)benzamide Following the procedure of Example 24, using N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3- (5-chloro-6-(methylsulfonamido)pyrazin-2-yl)benzamide in place of 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), at 80 5 °C for 16 h and with purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide in 37% yield. LCMS: Method A, 1.84 min, MS ES+521.1. 1H NMR (500 MHz, DMSO) δ 10.48 (s, 1H), 10.27 (s, 1H), 8.93 (s, 1H), 8.65 (s, 1H), 8.29 10 (d, J = 7.8 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.46 – 7.34 (m, 4H), 7.35 – 7.29 (m, 2H), 7.25 (d, J = 8.3 Hz, 1H), 4.58 (s, 4H), 3.50 (s, 3H), 3.30 (s, 3H). The isolated compound contains up to 1 mol. eq. of ammonia. Example 33 N-(4-((Benzyloxy)methyl)phenyl)-2-methoxy-5-(5-methyl-6-(methylsulfonamido)pyrazin-2- 15 yl)benzamide Step 1: N-(4-((benzyloxy)methyl)phenyl)-5-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-2- methoxybenzamide Following the procedure of Example 1, using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)- 5 4-methoxyphenyl)boronic acid (I-36) in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), at 80 °C for 1 h and purification by chromatography on RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded N-(4-((benzyloxy)methyl)phenyl)-5-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)- 2-methoxybenzamide in 42% yield. 10 LCMS: Method A, 1.99 min, MS ES+553.1 Step 2: N-(4-((benzyloxy)methyl)phenyl)-2-methoxy-5-(5-methyl-6-(methylsulfonamido- )pyrazin-2-yl)benzamide Following the procedure of Example 24, using N-(4-((benzyloxy)methyl)phenyl)-5-(5-15 chloro-6-(methylsulfonamido)pyrazin-2-yl)-2-methoxybenzamide in place of 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), at 80 °C for 16 h and with purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded N-(4-((benzyloxy)methyl)phenyl)-2-methoxy-5-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide in 14% yield. 20 LCMS: Method A, 1.90 min, MS ES+533.2. 1H NMR (500 MHz, DMSO) δ 10.41 (s, 1H), 10.26 (s, 1H), 8.84 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.21 (dd, J = 8.8, 2.5 Hz, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.42 – 7.26 (m, 7H), 4.53 (s, 2H), 4.51 (s, 2H), 3.96 (s, 3H), 3.49 ( were obscured / not observed.

[0028] 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 up to 1 mol. eq. of ammonia. 5 Example 34 3-(5-Methyl-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-((1-phenylethoxy)methyl)phenyl)- benzamide Step 1: 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-((1-phenylethoxy)methyl)- 10 phenyl)benzamide Following the procedure of Example 1, using N-(4-((1-phenylethoxy)methyl)phenyl)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-37) in place of N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), at 8015 °C for 1 h and without purification afforded 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)- N-(4-((1-phenylethoxy)methyl)phenyl)benzamide in 51% yield.

[0029] 116 LCMS: Method A, 1.99 min, MS ES+537.1 Step 2: 3-(5-methyl-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-((1-phenylethoxy)methyl)- phenyl)benzamide 5 Following the procedure of Example 24, using 3-(5-chloro-6-(methylsulfonamido)pyrazin-2- yl)-N-(4-((1-phenylethoxy)methyl)phenyl)benzamide in place of 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), at 80 °C for 16 h and with purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded 3-(5-methyl-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-((1- 10 phenylethoxy)methyl)phenyl)benzamide in 16% yield. LCMS: Method A, 1.90 min, MS ES+517.2. 1H NMR (500 MHz, DMSO) δ 10.48 (s, 1H), 10.40 (s, 1H), 8.95 (s, 1H), 8.60 (s, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.71 (t, J = 7.8 Hz, 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), 15 3.52 (s, 3H), 2.53 (s, 3H), 1.41 (d, J = 6.6 Hz, 3H). The isolated compound contains up to 1 mol. eq. of ammonia.

[0030] Example 35 N-(4-((Benzyloxy)methyl)phenyl)-2-methyl-5-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide 5 Step 1: N-(4-((benzyloxy)methyl)phenyl)-5-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-2- methylbenzamide Following the procedure of Example 1, using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)- 4-methylphenyl)boronic acid (I-31) in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5- 10 tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), at 80 °C for 1 h and without purification afforded N-(4-((benzyloxy)methyl)phenyl)-5-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-2-methylbenzamide, which was used crude in the next step. LCMS: Method A, 1.95 min, MS ES+537.1 Step 2: N-(4-((benzyloxy)methyl)phenyl)-2-methyl-5-(5-methyl-6-(methylsulfonamido)- pyrazin-2-yl)benzamide Following the procedure of Example 24, using N-(4-((benzyloxy)methyl)phenyl)-5-(5- 5 chloro-6-(methylsulfonamido)pyrazin-2-yl)-2-methylbenzamide in place of 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), at 80 °C for 16 h and with purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded N-(4-((benzyloxy)methyl)phenyl)-2-methyl-5-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide in 2% yield. 10 LCMS: Method A, 1.87 min, MS ES+517.2. 1H NMR (500 MHz, DMSO) δ 10.46 (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 analogues above the pyrazine CH3is obscured by NMR solvent (DMSO) at 2.5 ppm and 2 x NH not observed. 15 The isolated compound contains up to 1 mol. eq. of ammonia.

[0031] Example 36 N-(4-((Benzyloxy)methyl)phenyl)-4-methyl-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide 5 Step 1: N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-4- methylbenzamide Following the procedure of Example 1, using N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-25) in place of N-(4- 10 phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), at 80 °C for 1 h and without purification afforded N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-4-methylbenzamide in 58% yield. LCMS: Method A, 1.97 min, MS ES+537.1. Step 2: N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3-(5-methyl-6-(methylsulfonamido)- 15 pyrazin-2-yl)benzamide Following the procedure of Example 24, using N-(4-((benzyloxy)methyl)phenyl)-3-(5- chloro-6-(methylsulfonamido)pyrazin-2-yl)-4-methylbenzamide in place of 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), at 80 5 °C for 16 h and with purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide in 32% yield. LCMS: Method A, 1.88 min, MS ES+517.2. 1H NMR (500 MHz, DMSO) δ 10.45 (s, 1H), 10.27 (s, 1H), 8.51 (s, 1H), 8.05 (s, 1H), 7.97 10 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.0 Hz, 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 N-(4-((Benzyloxy)methyl)phenyl)-2,6-difluoro-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide 15 Step 1: N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)- 2,6-difluorobenzamide Following the procedure of Example 1, using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)- 5 2,4-difluorophenyl)boronic acid (I-24) in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), at 80 °C for 1 h and without purification afforded N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-2,6-difluorobenzamide in 72% yield. LCMS: Method A, 1.96 min, MS ES+559.1. 10 Step 2: N-(4-((benzyloxy)methyl)phenyl)-2,6-difluoro-3-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide Following the procedure of Example 24, using N-(4-((benzyloxy)methyl)phenyl)-3-(5- chloro-6-(methylsulfonamido)pyrazin-2-yl)-2,6-difluorobenzamide in place of 3-(5-chloro-6- 15 (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), at 80 °C for 16 h and with purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded N-(4-((benzyloxy)methyl)phenyl)-2,6-difluoro-3-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide in 15% yield. LCMS: Method A, 1.87 min, MS ES+539.1. 201H NMR (500 MHz, DMSO) δ 10.94 (s, 1H), 10.56 (s, 1H), 8.62 (s, 1H), 8.07 (q, J = 8.1 Hz, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.49 (t, J = 8.6 Hz, 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 up to 1 mol. eq. of ammonia. Example 38 N-(3-Fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamido)- pyrazin-2-yl)benzamide 5 Step 1: 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(3-fluoro-4-((pyridin-2- ylmethoxy)methyl)phenyl)benzamide Following the procedure of Example 1, using N-(3-fluoro-4-((pyridin-2- ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-23)10 in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-19), at 80 °C for 1 h and without purification afforded 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(3-fluoro-4-((pyridin-2- ylmethoxy)methyl)phenyl)benzamide in 54% yield. LCMS: Method A, 1.08 min, MS ES+542.1 Step 2: N-(3-fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)-3-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide Following the procedure of Example 24, using 3-(5-chloro-6-(methylsulfonamido)pyrazin-2- 5 yl)-N-(3-fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)benzamide in place of 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), at 80 °C for 16 h and with purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded N-(3-fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)-3-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide in 10% yield. 10 LCMS: Method A, 1.00 min, MS ES+522.2. 1H NMR (500 MHz, DMSO) δ 10.59 (s, 1H), 8.79 (s, 1H), 8.58 (s, 1H), 8.55 – 8.50 (m, 1H), 8.28 (d, J = 7.7 Hz, 1H), 8.15 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.86 – 7.78 (m, 2H), 7.71 (d, J = 7.7 Hz, 1H), 7.60 (dd, J = 8.3, 2.0 Hz, 1H), 7.54 – 7.46 (m, 2H), 7.35 – 7.28 (m, 1H), 4.65 – 4.62 (m, 4H), 3.43 (s, 3H).3H were obscured / not observed. The isolated compound 15 contains up to 1 mol. eq. of ammonia. Example 39 N-(4-((Benzyloxy)methyl)phenyl)-4-fluoro-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide

[0032] Step 1: N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-4- fluorobenzamide 5 Following the procedure of Example 1, using (5-((4-((benzyloxy)methyl)phenyl)carbamoyl)- 2-fluorophenyl)boronic acid (I-34) in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), at 80 °C for 1 h and purification by chromatography on RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)- 10 4-fluorobenzamide in 48% yield. LCMS: Method A, 1.94 min, MS ES+541.1. Step 2: N-(4-((benzyloxy)methyl)phenyl)-4-fluoro-3-(5-methyl-6-(methylsulfonamido)- pyrazin-2-yl)benzamide Following the procedure of Example 24, using N-(4-((benzyloxy)methyl)phenyl)-3-(5- chloro-6-(methylsulfonamido)pyrazin-2-yl)-4-fluorobenzamide in place of 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), at 80 °C for 16 h and with purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. 5 NH4OH) afforded N-(4-((benzyloxy)methyl)phenyl)-4-fluoro-3-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide in 11% yield. LCMS: Method A, 1.86 min, MS ES+521.2. 1H NMR (500 MHz, DMSO) δ 10.55 (s, 1H), 10.39 (s, 1H), 8.56 (s, 1H), 8.48 (dd, J = 7.5, 2.4 Hz, 1H), 8.15 – 8.05 (m, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.56 (dd, J = 10.8, 8.6 Hz, 1H), 10 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 were obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 40 N-(4-((Benzyloxy)methyl)phenyl)-2-fluoro-5-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide 15 Step 1: N-(4-((benzyloxy)methyl)phenyl)-5-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-2- fluorobenzamide Following the procedure of Example 1, using N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-33) in place of N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), at 80 5 °C for 1 h and purification by chromatography on RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded N-(4-((benzyloxy)methyl)phenyl)-5-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-2-fluorobenzamide in 39% yield. LCMS: Method A, 1.94 min, MS ES+541.1. Step 2: N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(5-methyl-6-(methylsulfonamido)- 10 pyrazin-2-yl)benzamide Following the procedure of Example 24, using N-(4-((benzyloxy)methyl)phenyl)-5-(5- chloro-6-(methylsulfonamido)pyrazin-2-yl)-2-fluorobenzamide in place of 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), at 80 15 °C for 16 h and with purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide in 41% yield. LCMS: Method A, 1.86 min, MS ES+521.2. 1H NMR (500 MHz, DMSO) δ 10.59 (s, 1H), 10.48 (s, 1H), 8.91 (s, 1H), 8.35 (dd, J = 6.8, 20 2.4 Hz, 1H), 8.30 – 8.21 (m, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.55 (t, J = 9.1 Hz, 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 obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 41 3-(5-(2-Aminoethoxy)-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)- benzamide 5 3-(5-(2-Aminoethoxy)-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)- benzamide A mixture of 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)- benzamide (Example 1, 25 mg, 0.048 mmol), 2-aminoethan-1-ol (0.019 mL, 0.239 mmol) 10 and NEt3(0.020 mL, 0.143 mmol) in THF (2 mL) was stirred at 40 °C for 72 h. Purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded 3-(5-(2- aminoethoxy)-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (16 mg, 55%). LCMS: Method A, 1.54 min, MS ES+548.1. 15 1H NMR (500 MHz, DMSO) δ 10.19 (s, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.99 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 9.0 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.37 – 7.30 (m, 4H), 7.27 – 7.19 (m, 1H), 6.94 (d, J = 9.0 Hz, 2H), 4.53 – 4.43 (m, 2H), 4.18 (t, J = 6.9 Hz, 2H), 3.34 – 3.25 (m, 2H), 3.11 (s, 3H), 3.04 (t, J = 6.9 Hz, 2H).2H were obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. 20 Examples 42-46: The following Examples 42-46 were prepared analogously to Example 1, substituting N-(6- bromo-3-chloropyrazin-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 the appropriate starting materials, using Pd-118 in place of Pd(dppf)Cl2, at 80-90 °C for 9-18 h. Any other minor modifications are described. All examples were purified with basic modifier. 5 Example 42 3-(6-Amino-5-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide 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)10 afforded 3-(6-amino-5-(methylsulfonamido)pyrazin-2-yl)-N-(4- phenethoxyphenyl)benzamide in 13% yield. LCMS: Method A, 1.79 min, MS ES+504.2. 1H NMR (500 MHz, DMSO) δ 10.21 (s, 1H), 8.45 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.70 – 7.64 (m, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.38 – 7.29 (m, 4H), 7.27 – 15 7.20 (m, 1H), 6.98 – 6.92 (m, 2H), 6.58 (s, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H).5H were obscured / not observed. Regiochemistry confirmed by ROESY NMR. The isolated compound contains up to 1 mol. eq. of ammonia. Example 43 3-(6-(Morpholine-4-sulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide Using N-(6-bromopyrazin-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) afforded 3-(6-(morpholine-4-sulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide 5 in 17% yield. LCMS: Method A, 1.92 min, MS ES+560.2. 1H NMR (500 MHz, DMSO) δ 11.19 (s, 1H), 10.25 (s, 1H), 8.99 (s, 1H), 8.66 – 8.61 (m, 1H), 8.36 (s, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.7 Hz, 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 = 6.9 Hz, 2H), 3.59 10 (t, J = 4.8 Hz, 4H), 3.29 (t, J = 4.8 Hz, 4H), 3.05 (t, J = 6.9 Hz, 2H). The isolated compound contains up to 1 mol. eq. of ammonia. Example 44 N-(4-((Benzyloxy)methyl)phenyl)-3-(6-methyl-5-(methylsulfonamido)pyrazin-2- yl)benzamide 15 Using N-(5-bromo-3-methylpyrazin-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) afforded N-(4-((benzyloxy)methyl)phenyl)-3-(6-methyl-5-(methylsulfonamido)pyrazin- 2-yl)benzamide in 48% yield. 20 LCMS: Method A, 1.87 min, MS ES+503.1. 1H NMR (500 MHz, 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 = 7.7 Hz, 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 up to 1 mol. eq. of ammonia. Example 45 3-(6-Methoxy-5-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide 5 Using N-(5-bromo-3-methoxypyrazin-2-yl)methanesulfonamide (I-15) and N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(6-methoxy-5-(methylsulfonamido)pyrazin-2-yl)-N-(4- phenethoxyphenyl)benzamide in 45% yield. 10 LCMS: Method A, 1.97 min, MS ES+519.2. 1H NMR (500 MHz, DMSO) δ 10.21 (s, 1H), 8.52 (dd, J = 5.3, 3.4 Hz, 2H), 8.21 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.72 – 7.65 (m, 2H), 7.62 (t, J = 7.7 Hz, 1H), 7.35 – 7.29 (m, 4H), 7.23 (m, 1H), 6.99 – 6.92 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 4.04 (s, 3H), 3.29 (s, 3H), 3.04 (t, J = 6.9 Hz, 2H).1H was obscured / not observed. The isolated compound 15 contains up to 1 mol. eq. of ammonia. Example 46 3-(6-((N,N-Dimethylsulfamoyl)amino)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide Using N′-(6-Bromo-2-pyrazinyl)-N,N-dimethylsulfamide (I-16) and N-(4-phenethoxyphenyl)-20 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(6-((N,N- dimethylsulfamoyl)amino)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide in 20% yield. LCMS: Method A, 1.96 min, MS ES+518.2.1H NMR (500 MHz, DMSO) δ 10.94 (s, 1H), 10.16 (s, 1H), 8.82 (s, 1H), 8.54 (d, J = 1.9 Hz, 1H), 8.24 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 7.7 Hz, 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 = 6.9 Hz, 2H), 2.96 (t, J = 6.9 Hz, 2H), 2.78 (s, 6H). The isolated compound contains up to 1 mol. eq. of ammonia. 5 Example 58 N-(4-((Benzyloxy)methyl)phenyl)-5-(6-(cyclopropanesulfonamido)-5-methylpyrazin-2-yl)-2- fluorobenzamide To 5-(6-amino-5-methylpyrazin-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide 10 (I-39, 50 mg, 0.110 mmol) in pyridine (0.20 mL) was added DMAP (1.3 mg, 0.011 mmol) and cyclopropanesulfonyl chloride (56 μL, 0.548 mmol) and the mixture was stirred for 16 h at 80 °C. Additional cyclopropanesulfonyl chloride (56 μL, 0.548 mmol) was added and stirred at 80 °C for 6 h. This was combined with a second batch, starting from 5-(6-amino- 5-methylpyrazin-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide, 0.055 mmol 15 scale. The mixture was diluted with EtOAc (10 mL) and washed with water (2 x 10 mL), aq. HCl (2M, 2 x 10 mL) and brine (10 mL), dried over Na2SO4and concentrated under reduced pressure. Purification by RP chromatography (C18, 10-50% MeCN in 0.1% aq. NH4OH) afforded N-(4-((benzyloxy)methyl)phenyl)-5-(6-(cyclopropanesulfonamido)-5- methylpyrazin-2-yl)-2-fluorobenzamide (32 mg, 35%). 20 LCMS: Method A, 1.80 min, MS ES+547.0 1H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 10.42 (br s, 1H), 8.91 (s, 1H), 8.36 (dd, J = 6.8, 2.4 Hz, 1H), 8.31 – 8.23 (m, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.54 (t, J = 9.2 Hz, 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 up 25 to 1 mol. eq. of ammonia. Example 59 N-(4-((Benzyloxy)methyl)phenyl)-5-(5-cyclopropyl-6-(methylsulfonamido)pyrazin-2-yl)-2- fluorobenzamide 5 Following the procedure of Example 58, using 5-(6-amino-5-cyclopropylpyrazin-2-yl)-N-(4- ((benzyloxy)methyl)phenyl)-2-fluorobenzamide (I-40) in place of 5-(6-amino-5- methylpyrazin-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide (I-39) and methanesulfonyl chloride in place of cyclopropanesulfonyl chloride afforded N-(4- ((benzyloxy)methyl)phenyl)-5-(5-cyclopropyl-6-(methylsulfonamido)pyrazin-2-yl)-2- 10 fluorobenzamide in 13% yield. LCMS: Method A, 1.86 min, MS ES+547.0 1H NMR (400 MHz, DMSO) δ 10.72 (br s, 1H), 10.56 (s, 1H), 8.75 (s, 1H), 8.28 (dd, J = 6.8, 2.4 Hz, 1H), 8.24 – 8.15 (m, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.51 (t, J = 9.2 Hz, 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 – 15 0.99 (m, 2H), 0.99 – 0.91 (m, 2H).1H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. GPR35 assay The functional assay described measures the ability of GPR35 modulators to inhibit a GPR35 agonist-induced phospho-ERK signal. This is expressed as the concentration of 20 modulator required to reduce the phospho-ERK signal by 50 percent, i.e. the IC50; the signal window being defined as the difference between agonist plus modulator vehicle (no modulator) and agonist vehicle (no agonist) controls. This assay is a cellular GPR35 phospho-ERK homogeneous time resolved fluorescence (HTRF) assay using the GPR35-CHO-K1-mt aequorin-Gα16 cell line. Upon activation of 25 GPR35 with the agonist lodoxamide at EC80concentration, ERK 1 / 2 is phosphorylated, and after lysis of the cell membrane, phospho-ERK1 / 2 (Thr202 / Tyr204) is detected in a sandwich assay using two different specific antibodies, one labelled with Eu3+-cryptate (donor) and the second with d2 (acceptor). When the dyes are in proximity, the excitation of the donor with a light source (laser or flash lamp) triggers a Fluorescence Resonance Energy Transfer (FRET) towards the acceptor, resulting in specific acceptor fluorescence (at 665 nm). The specific signal is directly proportional to the amount of phospho-ERK1 / 2 5 (Thr202 / Tyr204) in the sample. Compounds that interfere with the levels of phospho- ERK1 / 2 (Thr202 / Tyr204) will result in a low HTRF signal. Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred 10 embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention which are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims. 15

[0033] Table 1: Activity of selected compounds according to the invention A = IC50< 1 μM; B = IC50> 1 μM and < 10 μM

[0034] REFERENCES1Quon et al, ACS Pharmacology and Translational Science 3, 801-812 (2020)2Kaya et al, Frontiers in Immunology 12: 717392 (2021)3Wang et al, J Biol Chem 281, 22021-22028 (2006)4Kapolka et al, PNAS 117, 13117-13126 (2020)5Giovanni et al, Cell 185, 815-830.e19 (2022)6Oka et al, Biochem & Biophys Res Comms 395, 232-237 (2010)7Deng et al. Scientific Reports 2, Article number: 373 (2012)8Maravillas-Montero et al, J Immunology 194, 29-33 (2015)9Lee et al Agricultural and Food Chem doi: 10.1021 / acs.jafc.2c01251. Online ahead of print (2022)10Jenkins et al, Biochem J 432, 451-419 (2010)11Yang et al, Pharmacology 86, 1-5. doi: 10.1159 / 000314164. Epub (2010)12Taniguchi et al. FEBS Letters 580, 5003-5008 (2006)13MacKenzie et al, Molecular Pharmacology 85, 91-104 (2014)14Wei et al, J Med Chem 64, 2634-2647 (2021)15Abdalhameed et al. Bioorg Med Chem Lett 27, 612-615 (2017)16https: / / www.ncbi.nlm.nih.gov / gene?Db=gene&Cmd=DetailsSearch&Term=285917https: / / www.proteinatlas.org / ENSG00000178623-GPR35 / tissue18MacKenzie et al, Frontiers in Endocrinology (Lausanne) 2, 68 , 1-10 (2011)19Imielinski et al, Nat Genet 41, 1335-1340 (2009)20Ellinghaus et al, Hepatology 58, 1074-1083 (2013)21Schneditz et al, Sci Signal 12:eaau9408 (2019)22Pagano et al, Gut gutjnl-2020-323363 (2021)23Kaya et al, Cell Rep 32:107979 (2020)24http: / / gepia.cancer-pku.cn / detail.php?gene=GPR3525Okumura et al, Cancer Sci 95, 131-135 (2004)26Ali et al, Tumor Biology 411-11 (2019)27Mackiewicz at al, Pharmacological Rep doi: 10.1007 / s43440-022-00371-2. Online ahead of print (2022)28Olson et al, Frontiers Chem, 9 article 671483 (2021)29Sun, Y.V. et al, Genet.Epi- demiol.32, 350–36030Min, K.D. et al (2010) Biochem. Biophys. Res. Commun.393, 55–6031Ohshiro, H. et al (2008) Biochem. Biophys. Res. Commun.365, 344–34832Cosi, C. et al (2010). Neuropharmacology 60, 1227–123133US20070077602; Leonard et al34Wang, J. et al (2006) J. Biol. Chem.281, 22021–2202835Fallarini, S. et al (2010) Biochem.Bio- phys.Res.Commun.398, 420–42536Barth,M.C. et al (2009) J. Biol.Chem.284, 19189–1919537Birring, S. S. et al (2017) Lancet Respir. Med.5 (10), 806−81538Yang, Y. et al (2010) Pharmacology; 86(1):1-539Smith J. A. (January 2015). Current Allergy and Asthma Reports.15 (1): 48940Shu C. et al (November 2022), Cell Death Disc, 444

Claims

CLAIMS 1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof,X-Y is -CONR6- or -NR6CO-; R6and R7are each independently selected from H and alkyl, more preferably H; R8is selected from alkyl, cycloalkyl, (CH2)q-heterocycloalkyl and NR34R35; ring C is a phenyl group or a 6-membered heteroaryl group containing at least one N, each of which is optionally further substituted by one or more substituents selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, CN, NR9SO2-R10, NR9COR11, NR12R13, OH, SO2NR14R15, CONR16R17, cycloalkyl, O(CH2)qNR18R19, (CH2)q-heterocycloalkyl and CO2R20; each R9is independently selected from H and alkyl; R10-R19are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; or R12and R13together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; R14and R15together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; R16and R17together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2;R18and R19together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; R20is selected from alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl and cycloalkyl; 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 independently an integer from 0 to 4; each q is independently an integer from 0 to 4; each Raand each Rbis independently selected from alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR21COR22, NR21SO2R23, (CH2)qSR24, (CH2)qSOR25, (CH2)qSO2R26, SO2NR27R28, (CH2)qOH, (CH2)qOR29, NR30R31, CONR32R33, cycloalkyl and (CH2)q-heterocycloalkyl; each R21is independently selected from H and alkyl; R22-R35are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; or R27and R28together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; or R30and R31together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; or R32and R33together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group which optionally comprises a further group selected from O, NH, S, SO and SO2; L is a direct bond or is a group selected from, -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR36-SO2-, -NR36-SO2-alkylene, alkylene-SO2-NR36-, -SO2-NR36-, -SO2- NR36-alkylene, alkylene-NR36-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- heterocycloalkylene-CO2-, heteroalkylene-heterocycloalkylene, heterocycloalkylene- heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, whereinthe alkylene moiety in the above groups is optionally substituted by one or more substituents independently selected from halo, alkyl, haloalkyl and cycloalkyl; R36is independently selected from H and alkyl; and Z is a group selected from alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl, each of which is optionally further substituted by one or more groups each independently selected from CN, halo, alkyl, OH, alkenyl, alkynyl, alkoxy, haloalkyl and haloalkoxy.

2. A compound according to claim 1 wherein said compound is of formula (Ia):wherein X1, X2, X3, X4, X5, together with the carbon to which X1and X5are attached, form a phenyl group or a 6-membered heteroaryl group containing at least one N, and wherein said phenyl or heteroaryl group is optionally further substituted by one or more substituents selected from alkyl, CN, haloalkyl, alkoxy, haloalkoxy, halo, NR9SO2R10, NR9COR11, NR12R13, OH, SO2NR14R15, CONR16R17, cycloalkyl, O(CH2)qNR18R19, (CH2)q- heterocycloalkyl and CO2R20; and A, B, Z, L, X, Y, Ra, Rb, R7, R8, n and p are as defined in claim 1.

3. A compound according to claim 1 or claim 2 wherein said compound is of formula (Ib):wherein: X1is N or CR1; X3is N or CR3; X4is N or CR4; X5is N or CR5; R1, R3, R4and R5are each independently selected from H, CN, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR12R13, OH, NR9SO2-alkyl, CONR16R17, cycloalkyl, O(CH2)qNR18R19and (CH2)q-heterocycloalkyl; and wherein Ra, Rb, R7, R8, n, p, L, A, B, X, Y and Z are as defined in claim 1.

4. A compound according to any preceding claim wherein A is selected from phenyl, pyridinyl, pyrimidinyl, pyradizinyl and pyrazinyl, each of which is optionally substituted by one to four Ragroups.

5. A compound according to any preceding claim wherein each Rais independently selected from halo, alkyl and alkoxy, and is more preferably selected from F, Me and OMe.

6. A compound according to any preceding claim wherein n is 0.

7. A compound according to any one of claims 2 to 6 wherein X1, X2, X3, X4and X5, together with the carbon to which X1and X5are attached, form a 6-membered heteroaryl group comprising 1 or 2 nitrogens, preferably selected from pyridinyl, pyrimidinyl, pyradizinyl and pyrazinyl.

8. A compound according to any preceding claim wherein X-Y is NH-CO.

9. A compound according to any preceding claim wherein said compound is of formula (Ic):wherein: X1is N or CR1; X3is N or CR3; X4is N or CR4; X5is N or CR5; R1, R3, R4and R5are each independently selected from H, CN, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR12R13, OH, NR9SO2-alkyl, CONR16R17, cycloalkyl, O(CH2)qNR18R19and (CH2)q-heterocycloalkyl; A is a phenyl or pyridinyl group, more preferably phenyl; and Ra, Rb, R7, R8, n, p, L, A, B, X, Y and Z are as defined in claim 1.

10. A compound according to claim 9 wherein R1, R3, R4and R5are each independently selected from H, C1-6-alkyl, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, Cl, F, NH2, NH-C1-6- alkyl, NH-C3-6-cycloalkyl, N(C1-6-alkyl)2,OH, NHSO2-C1-6-alkyl, CONR17R18, C3-6-cycloalkyl, NH-(hydroxy-C1-6-alkyl), NH-(C1-6-alkoxy), CH2-heterocycloalkyl and heterocycloalkyl.

11. A compound according to claim 9 or claim 10 wherein R1, R3, R4and R5are each independently selected from H, Me, MeO, CF3, Cl, F, NH2, NH-Me, NH-cyclopropyl, NMe2,OH, NHSO2Me, CONH2, cyclopropyl, NHCH2CH2OH, OCH2CH2NH2, NHCH2CH2OMe, CH2-(morpholin-4-yl) and morpholin-4-yl.

12. A compound according to any one of claims 9 to 11 wherein: X1is CR1; X3is CR3; X4is N; and X5is CR5.

13. A compound according to any one of claims 9 to 11 wherein: X1is N; X3is CR3; X4is CR4; and X5is CR5.

14. A compound according to any one of claims 9 to 11 wherein: X1is N; X3is CR3; X4is N; X5is CR5.

15. A compound according to any one of claims 9 to 11 wherein: X1is N; X3is CR3; X4is CR4; X5is N.

16. A compound according to any one of claims 9 to 15 wherein X3is CR3, and R3is selected from H, CN, C1-6-alkyl, C3-6-cycloalkyl, halo, C1-6-alkoxy, C1-6-haloalkyl, C1-6- haloalkoxy and O(CH2)qNR18R19, more preferably, H, CN, C1-6-alkyl, C1-6-alkoxy, C3-6- cycloalkyl, halo and O(CH2)qNR18R19; and R1, R4and R5are H.

17. A compound according to any one of claims 9 to 16 wherein X3is CR3, and R3is selected from H, Me, CN, MeO, CF3, Cl, F, NH2, NH-Me, NH-cyclopropyl, NMe2,OH, NHSO2Me, CONH2, cyclopropyl, NHCH2CH2OH, NHCH2CH2OMe, CH2-(morpholin-4-yl) and morpholin-4-yl, more preferably selected from, H, Me, OMe, CN, cyclopropyl and OCH2CH2NH2; and R1, R4and R5are H.

18. A compound according to any claim 1 or claim 2 wherein said compound is of formula (Id):wherein: X1is N or CR1; X2is N or CR2; X4is N or CR4; X5is N or CR5; R1, R2, R4and R5are each independently selected from H, CN, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR12R13, OH, NR9SO2-alkyl, CONR16R17, cycloalkyl, O(CH2)qNR18R19and (CH2)q-heterocycloalkyl; A is a phenyl or pyridinyl group, more preferably phenyl; and Ra, Rb, R7, R8, n, p, L, A, B, X, Y and Z are as defined in claim 1.

19. A compound according to claim 18 wherein: X1is N; X2is CR2; X4is N; and X5is CR5.

20. A compound according to claim 18 or claim 19 wherein X2is CR2, and R2is selected from H, CN, C1-6-alkyl, C3-6-cycloalkyl, halo, C1-6-alkoxy, C1-6-haloalkyl, C1-6- haloalkoxy and O(CH2)qNR18R19, more preferably selected from H, CN, C1-6-alkyl, C1-6- alkoxy, C3-6-cycloalkyl, halo and O(CH2)qNR18R19; and R1, R4and R5are H.

21. A compound according to any preceding claim wherein R7is H.

22. A compound according to any preceding claim wherein R8is selected from alkyl, cycloalkyl, heterocycloalkyl and dialkylamino, more preferably, Me, cyclopropyl, morpholin- 4-yl and N(Me)2.

23. A compound according to any preceding claim wherein B is a phenyl or pyridinyl group, each of which is optionally substituted by one to four Rbgroups.

24. A compound according to any preceding claim wherein B is a phenyl group, optionally substituted by one or two groups selected from halo and alkoxy, preferably selected from F and MeO.

25. A compound according to any preceding claim wherein Z is a group selected from C1-6-alkyl, phenyl, heteroaryl, C3-6-cycloalkyl and a 4-, 5- or 6-membered heterocycloalkyl group, each of which is optionally further substituted by one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, haloalkyl, and alkoxy.

26. A compound according to any preceding claim wherein Z is a group selected from phenyl, pyridinyl, methoxyphenyl, alkyl, tolyl, morpholinyl, pyrazolyl, oxetanyl, cyclohexyl, cyclopenyl, cyclobutyl, cyclopropyl, and tetrahydropyranyl, more preferably phenyl.

27. A compound according to any preceding claim wherein L is selected from -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-heterocycloalkylene-O-, wherein a and b are each independently an integer 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. A compound according to any preceding claim wherein L is selected from -O-, -O-CO-, -CO-O-, -O-CO-O-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2OCH(Me)-, -CH(Me)OCH2-, -CH2O-, -OCH2-, -CH2CH2O-, -OCH2CH2-, -CH2CH2S-, -SCH2CH2-, -CH2CH2CH2O-, -OCH2CH2CH2-, -OCH2CH2CH2O-, -CH2SO2CH2-, -CH2SOCH2-, -CH2SCH2-, -NH-SO2-, -NH-SO2-CH2-, -CH2-SO2-NH-, -CH2-NH-SO2-, -SO2-NH-CH2CH2-, - CH2CH2-NH-SO2-, -O-SO2-, -SO2-O-, -SO2-NH-, -SO2-NH-CH2-, -CH2CH2CH2CH2O-, -OCH2CH2CH2CH2-, -CH2SO2-, -SO2CH2-, -OCH2CO-, -COCH2O-, -CH2SO-, -SOCH2-, -CH2OCH2, -OCH2SCH2-,-CH2SCH2O-, -CH=CH-, -OCH(Me)-, -CH(Me)O-, -OCH(CF3)-, -CH(CF3)O-, -CH2CH(CF3)-, -CH(CF3)CH2-, -SO2N(Me)-, -N(Me)SO2-,29. A compound according to any preceding claim wherein L-Z 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,tBu, CF3, -OSO2Ph, -OCH2CH2CH2OPh, -OCH2-cyclopropyl, -CH2O-cyclopropyl, -OCH2CH2CH2CH3,-CH2OCH2Ph, -CH(Me)OCH2Ph, -CH2OCH(Me)Ph, -CH2OCH2(2-pyridinyl), -CH2OCH2(3- pyridinyl), -CH2OCH2(4-pyridinyl), -CH2OCH2(4-methoxyphenyl), -CH2OCH2(3- methoxyphenyl), CH2OCH2(2-methoxyphenyl), -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,30. A compound according to any preceding claim wherein L-Z is -OCH2CH2Ph, -OCH2CH2CH2CH2Ph or -CH2OCH2Ph, more preferably -OCH2CH2Ph.

31. A compound according to any preceding claim which is selected from the following:and pharmaceutically acceptable salts and solvates thereof.

32. A pharmaceutical composition comprising a compound according to any 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 medicament.

34. A compound according to any one of claims 1 to 31, or a pharmaceutical composition according to claim 32, for use in treating or preventing a disorder selected from a proliferative disorder, a fibrotic disorder, a gastrointestinal disorder, an inflammatory disorder, and a cardiovascular disease.

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

36. A compound or pharmaceutical composition for use according to claim 35, wherein the cancer is selected from colon, rectum, stomach, oesophagus, pancreas, gall bladder, bile duct, liver, lung, kidney, gynaecological, breast, testicular, skin, prostate, central nervous system and brain cancer.

37. A compound or pharmaceutical composition for use according to claim 34, wherein the disorder is a gastrointestinal disorder, preferably selected from inflammatory bowel disease, ulcerative colitis, primary sclerosing cholangitis and Crohn’s disease.

38. A compound or pharmaceutical composition for use according to claim 34, wherein the disorder is a cardiovascular disease, preferably 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, preferably wherein the use comprises inhibiting GPR35 signalling.

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

41. A compound as defined in any one of claims 1 to 31, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 32, for use in treating or preventing a GPR35-associated disease or disorder.

42. Use of a compound as defined in any one of claims 1 to 31, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating or preventing a GPR35-associated disease or disorder in a subject.

43. Use of a compound as defined in any one of claims 1 to 31, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating or preventing a disorder selected from a proliferative disorder, a gastrointestinal disorder, an inflammatory disorder, and cardiovascular disease.

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