Bicyclic heteroaryl compounds for use as gpr35 modulators

Abstract

One aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, Formula (I), wherein: ring A is a phenyl group or a 5- or 6-membered heteroaryl group; ring B is absent, or is phenyl, pyridinyl, pyradizinyl, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, isothiazolyl or thiazolyl; ring C is a fused bicyclic group of formula: (AA), wherein X1-X9 form an optionally substituted heteroaryl group containing at least one N and at least one NH; X-Y is -(CH2)mNR21CO; L is a direct bond or a linker group; Z is selected from alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl, each of which is optionally substituted; each Ra and each Rb is independently selected from alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR23COR25, NR24-SO2R26, (CH2)qSR27, (CH2)qSOR28, (CH2)qSO2R29, SO2NR30R31, (CH2)qOH, (CH2)qOR32, NR33R34, CONR35R36, cycloalkyl and (CH2)q-heterocycloalkyl; R10, R11, R21, R22, R23 and R24 are each independently selected from H and alkyl; R12-R20, and R25-R36 are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; m, n and p are each independently an integer from 0 to 4; and each q is independently an integer from 0 to 4. Further aspects of the invention relate to pharmaceutical compositions comprising compounds according to the invention, and the use of said compounds in the treatment of various GPR35-related disorders.

Description

[0001] BICYCLIC HETEROARYL COMPOUNDS FOR USE AS GPR35 MODULATORS.

[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. 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 a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: ring A is a phenyl group or a 5- or 6-membered heteroaryl group; ring B is absent, or is selected from phenyl, pyridinyl, pyradizinyl, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, isothiazolyl and thiazolyl; ring C is a fused bicyclic group of formula: wherein X1-X9form a heteroaryl group containing at least one N and at least one NH, wherein said heteroaryl group is optionally further substituted by one or more substituents each independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, NR10SO2-R12, NR11COR13, NR14R15, CO2R16, SO2NR17R18, CONR19R20, cycloalkyl and (CH2)q-heterocycloalkyl; X-Y is -(CH2)mNR21CO; L is a direct bond or is a group selected from, -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR22-SO2-, -NR22-SO2-alkylene, alkylene-SO2-NR22-, -SO2-NR22-, -SO2-NR22- alkylene, alkylene-NR22-SO2-, alkylene, alkenylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO2- alkylene, alkylene-SO-alkylene, -O-cycloalkylene, cycloalkylene-O-, -O-heterocycloalkylene, heterocycloalkylene-O-, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, -CO-heterocycloalkylene- alkylene, alkylene-heterocycloalkylene-CO-, CO2-heterocycloalkylene-alkylene, alkylene- heterocycloalkylene-CO2-, -CO2-heteroalkylene, heteroalkylene-CO2-, heteroalkylene- heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, wherein the alkylene, heteroalkylene, cycloalkylene and heterocycloalkylene moiety in each of the above groups is optionally substituted by one or more substituents independently selected from halo, alkyl, haloalkyl and cycloalkyl; 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; each Raand each Rbis independently selected from alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR23COR25, NR24-SO2R26, (CH2)qSR27, (CH2)qSOR28, (CH2)qSO2R29, SO2NR30R31, (CH2)qOH, (CH2)qOR32, NR33R34, CONR35R36, cycloalkyl and (CH2)q-heterocycloalkyl; R10, R11, R21, R22, R23and R24are each independently selected from H and alkyl; R12-R20, and R25-R36are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; m, n and p are each independently an integer from 0 to 4; and each q is independently an integer from 0 to 4. A second aspect of the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof,

[0006] wherein: ring A is a phenyl group or a 5- or 6-membered heteroaryl group; ring B is absent, or is a phenyl group or a 5- or 6-membered heteroaryl group; ring C is a fused bicyclic group of formula: wherein X1-X9form a heteroaryl group containing at least one N and at least one NH, wherein said heteroaryl group is optionally further substituted by one or more substituents each independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, NR10SO2-R12, NR11COR13, NR14R15, CO2R16, SO2NR17R18, CONR19R20, cycloalkyl and (CH2)q-heterocycloalkyl; X-Y is CONR21-(CH2)m-; L is a direct bond or is a group selected from, -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR22-SO2-, -NR22-SO2-alkylene, alkylene-SO2-NR22-, -SO2-NR22-, -SO2-NR22- alkylene, alkylene-NR22-SO2-, alkylene, alkenylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO2-alkylene, alkylene-SO-alkylene, -O-cycloalkylene, cycloalkylene-O-, -O-heterocycloalkylene, heterocycloalkylene-O-, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, -CO-heterocycloalkylene- alkylene, alkylene-heterocycloalkylene-CO-, CO2-heterocycloalkylene-alkylene, alkylene- heterocycloalkylene-CO2-,-CO2-heteroalkylene, heteroalkylene-CO2-, heteroalkylene- heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, wherein the alkylene, heteroalkylene, cycloalkylene and / or heterocycloalkylene moiety in the above groups is optionally substituted by one or more substituents independently selected from halo, alkyl, haloalkyl and cycloalkyl; Z is a group selected from 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; with the proviso that L cannot be a direct bond when Z is phenyl; each Raand each Rbis independently selected from alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR23COR25, NR24-SO2R26, (CH2)qSR27, (CH2)qSOR28, (CH2)qSO2R29, SO2NR30R31, (CH2)qOH, (CH2)qOR32, NR33R34, CONR35R36, cycloalkyl and (CH2)q-heterocycloalkyl; R10, R11, R21, R22, R23and R24are each independently selected from H and alkyl; R12-R20, and R25-R36are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; m, n and p are each independently an integer from 0 to 4; and each q is independently an integer from 0 to 4. 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. 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. 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 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 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 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, 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. 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, 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, 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 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, 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 - (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, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl and azetidinyl. Preferably the heterocycloalkyl group is monovalent. Preferably the heterocycloalkyl group is monocyclic. 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 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 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 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 “alkenylene” refers to a linear or branched divalent hydrocarbon radical comprising at least one carbon-carbon double bond. Preferably, the alkenylene group is a linear divalent hydrocarbon radical comprising two to six carbon atoms, or a branched divalent hydrocarbon radical comprising three to six carbon atoms. As used herein, the term “heteroalkylene” refers to a divalent alkylene having one or more carbon atoms replaced with a heteroatom, for example, sulfur, oxygen, or 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 a 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 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 cycloalkylene 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 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 group. As used herein, preferably alkyl is C1-C6alkyl, haloalkyl is C1-C6haloalkyl, haloalkoxy is C1-C6haloalkoxy and alkoxy is C1-C6alkoxy. Compounds of formula (I') One aspect of the invention relates to a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein: ring A is a phenyl group or a 5- or 6-membered heteroaryl group; ring B is absent, or is a phenyl group or a 5- or 6-membered heteroaryl group; ring C is a fused bicyclic group of formula: wherein X1-X9form a heteroaryl group containing at least one N and at least one NH, wherein said heteroaryl group is optionally further substituted by one or more substituents each independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, NR10SO2-R12, NR11COR13, NR14R15, CO2R16, SO2NR17R18, CONR19R20, cycloalkyl and (CH2)q-heterocycloalkyl; X-Y is selected from CONR21-(CH2)m- and -(CH2)mNR21CO; L is a direct bond or is a group selected from, -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR22-SO2-, -NR22-SO2-alkylene, -SO2-NR22-, -SO2-NR22-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, 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 cycloalkyl; 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; each Raand each Rbis independently selected from alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR23COR25, NR24-SO2R26, (CH2)qSR27, (CH2)qSOR28, (CH2)qSO2R29, SO2NR30R31, (CH2)qOH, (CH2)qOR32, NR33R34, CONR35R36, cycloalkyl and (CH2)q-heterocycloalkyl; R10, R11, R21, R22, R23and R24are each independently selected from H and alkyl; R12-R20, and R25-R36are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; m, n and p are each independently an integer from 0 to 4; and each q is independently an integer from 0 to 4. In one preferred embodiment, R10, R11, R23and R24are each independently selected from H and Me, more preferably H. In one preferred embodiment, R12-R20and R25-R36are each independently selected from alkyl. In one preferred embodiment, Ring B in formula (I') is selected from phenyl, pyridinyl, pyradizinyl, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, isothiazolyl and thiazolyl, each of which is optionally substituted by one to four Rbgroups as defined above. Preferred definitions for A, B, C, X, Y, L, Z, X1-X9, Ra, Rb, R10-R36, m, n, p, q, are as set out below for compounds of formula (I). Compounds of formula (I) One aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof as defined above, i.e.

[0007] where A, B, C, Z, L, Ra, Rb, R21, p, m, and n are as defined above. In one preferred embodiment, R21is H or Me, more preferably H. In one preferred embodiment, m is 0, 1 or 2, more preferably 0 or 1. In one preferred embodiment, m is 0. In one preferred embodiment, X-Y is selected from NH-CO, -CH2NH-CO and N(Me)CO. In one preferred embodiment, X-Y is NH-CO, i.e. the compound is of the formula: where A, B, C, Z, L, Ra, Rb, p and n are as defined above. In one preferred embodiment, ring A is meta-substituted: 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. Thus, in one preferred embodiment, the compound is of the formula: In one preferred embodiment, ring 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 three Ragroups. In one preferred embodiment, ring A is a phenyl group optionally substituted by one to three Ragroups, preferably optionally substituted by one or two Ragroups, more preferably, optionally substituted by one Ragroup. In one one preferred embodiment, the compound is of the formula: In another preferred embodiment, ring A is: wherein A is 5-membered heteroaryl group, and Z, L, B, X, Y, X1-X5, R2, Ra, Rb, n and p are as defined above. Thus, in one preferred embodiment, the compound is of the formula: In one preferred embodiment, ring A is selected from pyrrolyl, thiazolyl, oxazolyl, furanyl, thienyl and pyrazolyl, each of which is optionally substituted by 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-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. 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-N-morpholinyl and N-morpholinyl. In one preferred embodiment, each Rais independently selected from Me, Cl, F, CF3, OMe, OCF3, OCF3, amino, cyano, NHCOMe, NHSO2Me, S-Me, CH2SO2Me, SO2Me, SO2NMe2, CH2OH and CH2OMe. More preferably, each Rais independently selected from Me, Cl, F, CF3, OMe, OCF3, amino and cyano, more preferably halo, even more preferably F. In one preferred embodiment, n is 1 or 2, more preferably 1. In one preferred embodiment, n is 0. In the compounds of formula (I), ring B is selected from phenyl, pyridinyl, pyradizinyl, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, isothiazolyl and thiazolyl, each of which is optionally substituted by one to four Rbgroups as defined above. As used throughout, where B is a 6-membered group, preferably the L-Z group is in the para-position relative to the X-Y group. Thus, in one preferred embodiment, the compound is of the following formula (preferably where X is NH and Y is CO): In one preferred embodiment, ring 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. 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-N-morpholinyl and N-morpholinyl. For all of the above embodiments described herein, ring B is preferably a phenyl or pyridinyl group, each of which is optionally substituted by one to four Rbgroups as defined above. In one preferred embodiment, ring B is a phenyl group, optionally substituted by one or two groups selected from halo, CN and alkoxy, more preferably halo and alkoxy. In one preferred embodiment, ring B is a phenyl group, optionally substituted by one or two halo groups. In one preferred embodiment, p is 1. In one preferred embodiment, p is 0. In one preferred embodiment, B is absent, and the L-Z group is attached to X. In one preferred embodiment, X1, X3and X7in ring C are all sp2carbon atoms. In one preferred embodiment, R33and R34are each independently selected from H and alkyl. Preferably, R33and R34are both H. In the compounds according to the invention, ring C is a fused bicyclic group of formula: wherein X1-X9form a heteroaryl group containing at least one N and at least one NH, wherein said heteroaryl group is optionally further substituted. In one preferred embodiment, ring C is a group C-1: wherein: X2is N or CR2; X4is NH; X5and X6are both N; or X5is N and X6is CR6; or X5is CR5and X6is N; X8is N or CR8; X9is N or CR9; and R2, R5, R6, R8and R9are each independently selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR14R15, OH, NR10SO2-alkyl, CONR19R20, cycloalkyl and (CH2)q- heterocycloalkyl. In one preferred embodiment, X5and X6are both N. i.e. ring C is a fused triazole. As used herein, for compounds where X5and X6are both N, for example, the skilled person would understand that the fused bicyclic group may exist in a number of different tautomeric forms that can be represented as follows: The skilled person would understand that similar tautomeric forms may exist for compounds where X5is N and X6is CR6, or where X5is CR5and X6is N. For ease of reference throughout, only one tautomer representation is depicted (see, for example, formulae C-1a, C-1b, C-1c, C-1d and C-1e below). In one preferred embodiment, R2, R5,R6, R8and R9are 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, CONR18R19, C3-6-cycloalkyl, NH-(hydroxy- C1-6-alkyl), NH-(C1-6-alkoxy), CH2-C3-7-heterocycloalkyl and C3-7-heterocycloalkyl. In one preferred embodiment, R2, R5,R6, R8and R9are each independently selected from H, Me, MeO, CF3, Cl, F, NH2, NH-Me, NH-cyclopropyl, NMe2,OH, NHSO2Me, CONH2, cyclopropyl, NHCH2CH2OH, NHCH2CH2OMe, CH2-N-morpholinyl and N-morpholinyl. In one preferred embodiment, ring C is a group C-1a,

[0008] wherein R8and R9are each independently selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR14R15, OH, NR10SO2-alkyl, CONR19R20, cycloalkyl and (CH2)q- heterocycloalkyl. In one preferred embodiment, ring C is a group C-1b, wherein R9is selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR14R15, OH, NR10SO2-alkyl, CONR19R20, cycloalkyl and (CH2)q-heterocycloalkyl. Preferably R9 is H. In one preferred embodiment, ring C is a group C-1c, wherein R8is selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR14R15, OH, NR10SO2-alkyl, CONR19R20, cycloalkyl and (CH2)q-heterocycloalkyl. Preferably R8is H. In one preferred embodiment, ring C is a group C-1d,

[0009] wherein R2and R9are each independently selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR14R15, OH, NR10SO2-alkyl, CONR19R20, cycloalkyl and (CH2)q- heterocycloalkyl, preferably, wherein R2and R9are each independently selected from H and alkyl. Preferably R2and R9are H. In one preferred embodiment, ring C is a group C-1e, wherein R2, R8and R9are each independently selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR14R15, OH, NR10SO2-alkyl, CONR19R20, cycloalkyl and (CH2)q- heterocycloalkyl, preferably, wherein R2, R8and R9are each independently selected from H, alkyl and halo. Preferably R2, R8and R9are H. For each of the above embodiments, preferably, q is 0 or 1, more preferably 0. In one preferred embodiment, R10, R14, R15, R19and R20are each independently selected from H and Me. In one preferred embodiment, ring C is a group selected from the following:

[0010] 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, CN, haloalkyl, and alkoxy. In one preferred embodiment, Z is a group selected from 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, CN, haloalkyl, and alkoxy. In one preferred embodiment, Z is a group selected from C1-6-alkyl, phenyl, C3-6-cycloalkyl and a 5- or 6-membered heterocycloalkyl group, each of which is optionally further substituted by one or more groups selected from alkyl, halo, haloalkyl, CN, alkenyl, alkynyl and alkoxy. In one preferred embodiment, Z is a group selected from phenyl, pyridinyl, piperidinyl, cyclopropyl and tetrahydropyranyl, more preferably phenyl, each of which is optionally further substituted by one or more groups selected from alkyl, halo, haloalkyl, CN, alkenyl, alkynyl and alkoxy. In one preferred embodiment, Z is a group selected from phenyl and heteroaryl, each of which is optionally further substituted by one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, CN, haloalkyl, and alkoxy. In one preferred embodiment, Z is a phenyl group optionally substituted by one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, CN, haloalkyl, and alkoxy. In one preferred embodiment, Z is a group selected from phenyl, alkyl, tolyl, morpholinyl, pyrazolyl, oxetanyl, cyclohexyl, cyclopenyl, cyclobutyl, cyclopropyl, and tetrahydropyranyl. In one preferred embodiment, Z is a group selected from phenyl, tolyl, morpholinyl, pyridinyl, 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-, -NR22-SO2-, -NR22-SO2-alkylene, alkylene-SO2-NR22-, -SO2-NR22-, -SO2-NR22-alkylene, alkylene-NR22-SO2-, alkylene, alkenylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO2- alkylene, alkylene- SO-alkylene, -O-cycloalkylene, cycloalkylene-O-, -O-heterocycloalkylene, heterocycloalkylene-O-, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, -CO-heterocycloalkylene-alkylene, alkylene- heterocycloalkylene-CO-, CO2-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene- CO2-, -CO2-heteroalkylene, heteroalkylene-CO2-, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, cycloalkylene- heteroalkylene, wherein the alkylene, heteroalkylene, cycloalkylene and heterocycloalkylene moiety in each of the above groups is optionally substituted by one or more substituents independently selected from halo, alkyl, haloalkyl and cycloalkyl. In one preferred embodiment, L is a direct bond or is a group selected from, -O-CO-, -CO- O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR22-SO2-, -NR22-SO2-alkylene, -SO2-NR22-, -SO2-NR22-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 in the above groups is optionally substituted by one or more substituents independently selected from halo, alkyl, haloalkyl and cycloalkyl. Preferably, R22is 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- 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. In one preferred embodiment, L is selected from -(CR'R'')a-O-, -O-(CR'R'')a-, -(CR'R'')a-O- (CR'R'')b- and -O-, more preferably, -(CR'R'')a-O-, -O-(CR'R'')a- and -(CR'R'')a-O-(CR'R'')b-. In one preferred embodiment, L is selected from -(CH2)a-O-, -O-(CH2)a-, -(CH2)a-O-(CH2)b- and -O-, more preferably, -(CH2)a-O-, -O-(CH2)a- and -(CH2)a-O-(CH2)b-.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-(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 and wherein c is an integer from 1 to 3, and R' and R'' are each independently selected from H, alkyl, halo and haloalkyl, more preferably, H, Me, F and CF3, even more preferably H. Preferably, a and b are each independently an integer from 1 to 3, more preferably 1 or 2. Preferably, c is 1 or 2, more preferably 1. In one preferred embodiment, L is selected from -O-CO-, -CO-O-, -O-CO-O-, -O-, -NH-SO2-, -NH-SO2-(CH2)a-, -(CH2)a-SO2-NH-, -SO2-NH-, -SO2-NH-(CH2)a-, -(CH2)a-NH-SO2-, -O-SO2-, -SO2-O-, -(CH2)a-, -(CH=CH)c-, -(CH2)a-(CH=CH)c-, -(CH=CH)c-(CH2)a-, -(CH2)a-(CH=CH)c-(CH2)b-, -(CH2)a-O-, -O-(CH2)a-, -(CH2)a-O-(CH2)b-, -(CH2)a-S-(CH2)b-, -(CH2)a-SO2-, -SO2-(CH2)b-, -(CH2)a-SO-, -SO-(CH2)b-, -(CH2)a-SO-(CH2)b-, -(CH2)a-SO2-(CH2)b-, -(CH2)a-S-(CH2)b-O-, -O-(CH2)a-S-(CH2)b-, -(CH2)a-O-(CH2)b-S-, -S-(CH2)a-O-(CH2)b-, -(CH2)a-S-, -S-(CH2)a-, -O-(CH2)a-O-, heterocycloalkylene, cycloalkylene-O-, -O-cycloalkylene-, heterocycloalkylene-O-, -O-heterocycloalkylene-, heterocycloalkylene-(CH2)a, -(CH2)a-heterocycloalkylene-, 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-heterocycloalkylene-O-, wherein a and b are each independently an integer from 1 to 6 and wherein c is an integer from 1 to 3. Preferably, a and b are each independently an integer from 1 to 3, more preferably 1 or 2. Preferably, c is 1 or 2, even more preferably 1. 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-, -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-heterocycloalkylene-O-, wherein a and b are each independently an integer from 1 to 6. Preferably, a and b are each independently an integer from 1 to 3, more preferably 1 or 2. 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-, -CH2-SO2-NH-, -O-SO2-, -SO2-O-, -SO2-NH-, -SO2-NH-CH2-, -CH2-NH-SO2-, -SO2-NH-CH2CH2-, - CH2CH2-NH-SO2-, -CH2CH2CH2CH2O-, -OCH2CH2CH2CH2-, -CH2SO2-, -SO2CH2-, -OCH2CO-, -COCH2O-, -CH2SO-, -SOCH2-, -CH2OCH2, -OCH2SCH2-,-CH2SCH2O-, -CH=CH-, -OCH2CO2-, -CO2CH2O-, -OCH(Me)-, -CH(Me)O-, -OCH(CF3)-, -CH(CF3)O-, -CH2CH(CF3)-, -CH(CF3)CH2-, -SO2N(Me)-, -N(Me)SO2-,

[0011]

[0012] 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-(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 and b are each independently an integer from 1 to 6. Preferably, a and b are each independently an integer from 1 to 3, more preferably 1 or 2. 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 to 6. Preferably, a and b are each independently an integer from 1 to 3, more preferably 1 or 2. 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-. In one preferred embodiment, Z is a group selected from 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, CN, haloalkyl, and alkoxy; and L is a group -(CR'R'')a-O-(CR'R'')b- as defined above. In one preferred embodiment, Z is a group selected from phenyl and heteroaryl, each of which is optionally further substituted by one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, CN, haloalkyl, and alkoxy; and L is a group -(CR'R'')a-O-(CR'R'')b- as defined above. 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, 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, 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, SO2Ph, -CH2-O-CH(CF3)-Ph,

[0013] 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:

[0014]

[0015] 35

[0016]

[0017] 39

[0018] 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: 1-8, 16, 19-24, 26, 30, 35-47, 52-56, 61-65, 67, 69-77, 80-81, 83, 86-90, 94-111, 113-126, 128-143, 146-151, 155-157, 160-164, 166-173, 176-177, 182- 185, and 194-196, and pharmaceutically acceptable salts and solvates thereof. Compounds of formula (II) Another aspect of the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof,

[0019] wherein: ring A is a phenyl group or a 5- or 6-membered heteroaryl group; ring B is absent, or is a phenyl group or a 5- or 6-membered heteroaryl group; ring C is a fused bicyclic group of formula: wherein X1-X9form a heteroaryl group containing at least one N and at least one NH, wherein said heteroaryl group is optionally further substituted by one or more substituents each independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, NR10SO2-R12, NR11COR13, NR14R15, CO2R16, SO2NR17R18, CONR19R20, cycloalkyl and (CH2)q-heterocycloalkyl; X-Y is CONR21-(CH2)m-; L is a direct bond or is a group selected from, -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR22-SO2-, -NR22-SO2-alkylene, alkylene-SO2-NR22-, -SO2-NR22-, -SO2-NR22- alkylene, alkylene-NR22-SO2-, alkylene, alkenylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO2-alkylene, alkylene-SO-alkylene, -O-cycloalkylene, cycloalkylene-O-, -O-heterocycloalkylene, heterocycloalkylene-O-, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, -CO-heterocycloalkylene- alkylene, alkylene-heterocycloalkylene-CO-, CO2-heterocycloalkylene-alkylene, alkylene- heterocycloalkylene-CO2-, -CO2-heteroalkylene, heteroalkylene-CO2-, heteroalkylene- heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, wherein the alkylene, heteroalkylene, cycloalkylene and / or heterocycloalkylene moiety in the above groups is optionally substituted by one or more substituents independently selected from halo, alkyl, haloalkyl and cycloalkyl; Z is a group selected from 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; with the proviso that L cannot be a direct bond when Z is phenyl; each Raand each Rbis independently selected from alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR23COR25, NR24-SO2R26, (CH2)qSR27, (CH2)qSOR28, (CH2)qSO2R29, SO2NR30R31, (CH2)qOH, (CH2)qOR32, NR33R34, CONR35R36, cycloalkyl and (CH2)q-heterocycloalkyl; R10, R11, R21, R22, R23and R24are each independently selected from H and alkyl; R12-R20, and R25-R36are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; m, n and p are each independently an integer from 0 to 4; and each q is independently an integer from 0 to 4. In one embodiment, the compound is of the formula: where A, B, C, Z, L, Ra, Rb, R21, p, m, and n are as defined above. Preferably, R21is H or Me, more preferably H. Preferred definitions of A, B, C, Z, L, Ra, Rb, R21, p, m, n are as defined for formula (I). In one preferred embodiment, X-Y is selected from -CONH-, -CONHCH2- and -CON(Me)-. In one preferred embodiment, X-Y is -CONH-, i.e. the compound is of the formula:

[0020] In one preferred embodiment, ring A is as defined hereinabove for compounds of formula (I). In one preferred embodiment, ring B is absent, or is selected from phenyl, pyridinyl, pyradizinyl, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, isothiazolyl and thiazolyl, each of which is optionally substituted by one to four Rbgroups. In one preferred embodiment, ring B is as defined hereinabove for compounds of formula (I). Preferably, where B is a 6-membered group, the L-Z group is in the para-position relative to the CONH group. In one preferred embodiment, ring C is as defined hereinabove for compounds of formula (I). In one preferred embodiment, Z is a group selected from 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; with the proviso that L cannot be a direct bond when Z is phenyl, i.e. L-Z (together) cannot be phenyl. In one preferred embodiment, Z is a group selected from phenyl, tolyl, morpholinyl, pyrazolyl, oxetanyl, cyclohexyl, cyclopenyl, cyclobutyl, cyclopropyl, and tetrahydropyranyl; with the proviso that L cannot be a direct bond when Z is phenyl, i.e. L-Z (together) cannot be phenyl. In one preferred embodiment, L is defined hereinabove for compounds of formula (I). In one preferred embodiment, Z is defined hereinabove for compounds of formula (I). In one preferred embodiment, said compound of formula (II) is selected from the following:

[0021] and pharmaceutically acceptable salts and solvates thereof. In one preferred embodiment, the compound of formula (II) is selected from the following compounds as shown herein: 58, 112 and 113, and pharmaceutically acceptable salts and solvates thereof. In another preferred embodiment, the compound of formula (I) or (II) according to the invention is selected from the following:

[0022] 45

[0023] and pharmaceutically acceptable salts and solvates thereof. 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. 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, 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 according to the invention is for use in treating or preventing a disorder selected from a proliferative disorder, a fibrotic disorder, a gastrointestinal disorder, a cardiovascular disease, an immune disorder 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 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 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 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-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), spontaneous tumour models. In one preferred embodiment, the cancer is selected from cancers of the gastrointestinal tract (e.g. colon, colorectal, rectum, stomach, oesophagus, colorectal adenocarcinoma, oesophageal adenocarcinoma, gastric / stomach cancer / adenocarcinoma) and associated tissues (e.g. pancreas, gall bladder and bile duct, liver, intra- and extra-hepatic, perihilar bile duct cancer / adenocarcinoma, cholangiocarcinoma), and also lung, kidney, gynaecological, breast, testicular, skin, prostate, central nervous system and brain. 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 according to the invention is for use in treating an immune disorder. In another preferred embodiment, the compound according to the invention is for use in immunotherapy for the treatment of cancer. In one preferred embodiment, the immune disorder is an autoimmune disorder. Thus, in one preferred embodiment, the compounds of the invention have applications in treating or preventing multiple sclerosis (MS). Recent studies have implicated the gut microbiota in the pathogenesis of MS. In particular, gut microbiota-induced kynurenic acid recruits GPR35- positive macrophages to promote experimental autoimmune encephalitis, which is an established animal model for MS41. 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 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 disease42-45. Single nucleotide polymorphisms (SNPs) of human GPR35 have been investigated in genome wide association studies.18Six of these SNPs have been 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 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 respond better to TNF blockers.2,23 In 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 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. 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 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 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 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 demonstrated in the functional GPR35 assay described in the accompanying examples section. In one preferred embodiment, the compound is a GPR35 antagonist or inverse agonist. 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 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. In one preferred embodiment, the compound of the invention is an allosteric modulator of GPR35, more preferably a negative allosteric modulator. As used herein, a negative allosteric modulator antagonises the agonist activation of a receptor via binding to a different site to that of the agonist. Accordingly, a negative allosteric modulator reduces the affinity or efficacy of an agonist for a receptor. This is in contrast to an orthosteric antagonist that blocks the agonist activation of a receptor via binding at the same site as the agonist. Preferably, the subject is a mammal, more preferably a human. The term “method” refers to manners, means, techniques and procedures for 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 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. 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 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 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 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 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. 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. 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. 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 disorders, fibrotic disorders, cardiovasular diseases, immune disorders 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. 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. 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 < 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 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 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 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 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. 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 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 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, 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 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. 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 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 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 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 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. 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. 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 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 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 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. 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 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, 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, 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 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 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 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 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, 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 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 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, 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, 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 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- 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 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 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. 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 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 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 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, 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 according to the invention where any hydrogen atom has been replaced by a deuterium atom. Isotopic variations of the agent of the 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 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 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 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 be an esterase etc. Other such systems will be well known to those skilled in the art. SOLVATES 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 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. 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 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. 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

[0024] preferably a cancer immunotherapy agent. An “immunotherapy agent“ refers to a 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 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 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 (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 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, 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 carrier” includes vehicles such as common excipients e.g. binding agents, for example

[0025] 73 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 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 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 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 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 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, 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

[0026] 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 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 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 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 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 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 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

[0027] 75 compound is administered at an oral dose of between about 0.1 to about 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 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 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 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 aq. Aqueous Ar Aryl B2Pin2Bis(pinacolato)diboron C18 Octadecyl carbon Celite®Diatomaceous earth d Days d Doublet (context of NMR) 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 sulphoxide 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 2-methyl THF 2-Methyltetrahydrofuran min Minute(s) mol. eq. Molar equivalent Ms Methanesulfonyl NaSMe Sodium methanethiolate NEt3Triethylamine NMP 1-Methyl-2-pyrrolidone 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. 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. 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. Method A – LCMS Acidic Method

[0028] Method B – LCMS Basic Method Method Q – LCMS Acidic Method

[0029] 79 Method R – LCMS Basic Method Method S – UPLC Basic Method Preparative HPLC purifications were performed as detailed below. Prep Method A – Preparative HPLC Acidic Method (x-y%) Prep Method B – Preparative HPLC Basic Method (x-y%) Prep Method C – Preparative HPLC Basic Method (x-y%) Prep Method D – Preparative HPLC Acidic Method (x-y%) Prep Method E – Chiral SFC Method Prep Method F – Chiral SFC Method Prep Method G – Chiral SFC Method Prep Method H – Chiral SFC Method Prep Method I – Chiral SFC Method 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 ppm). NMR spectra were recorded using a Bruker 500 MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbeTM. Data were acquired using Bruker TopSpin software and processed using MestreNova software. Where reaction is likely at two or more atoms (eg. 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 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. For chiral separation, “enantiomer 1” = first eluting, and “enantiomer 2” = second eluting isomer under the chiral separation conditions described. Where procedures are not given for intermediates identified in synthetic schemes these compounds were purchased. Intermediates Intermediates 1-4 5-Bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1), 5-bromo-1-trityl-1H-[1,2,3]triazolo[4,5- b]pyridine (I-2), N-(4-hydroxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-3) and N-(4-hydroxyphenyl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)benzamide (I-4) Step 1: 5-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1) To iPnONO (1.71 mL, 12.8 mmol) and 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD, 1.50 g, 7.98 mmol) in THF (20 mL) was added AcOH (0.55 mL, 9.57 mmol) and the reaction was stirred at 65 °C for 16 h. The mixture was concentrated under reduced pressure to afford 5-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (1.60 g, 95%). LCMS: Method A, 0.55 min, MS: ES+199.0 / 201.0. Step 2: 5-bromo-1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine (I-2)

[0030] A solution of 5-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1, 1.59 g, 7.99 mmol) and NEt3(1.61 mL, 11.6 mmol) in THF (30 mL) was stirred for 10 min. The solution was cooled to 0 °C and trityl-Cl (1.77 g, 6.35 mmol) was added and stirred for 16 h at rt. The reaction mixture was cooled to 0 °C and diluted with water (140 mL). The mixture was extracted with EtOAc (3 x 60 mL), washed with brine (50 mL), dried over Na2SO4and concentrated under reduced pressure. Purification by chromatography (silica gel, 0 - 100% EtOAc in isohexane) afforded 5-bromo-1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine with a mixture of isomers (2.59 g, 70%). LCMS: Method A, 2.19 / 2.21 / 2.31 min, MS: ES+243.2 (Ph3C+). Step 3: N-(4-hydroxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-3) A solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 269409-73-6, BLD, 2.27 g, 9.16 mmol), 4-aminophenol (CAS 123-30-8, Fluorochem, 1.00 g, 9.16 mmol) and DIPEA (4.79 mL, 27.5 mmol) in DMF (5 mL) was stirred for 10 min at rt. HATU (3.48 g, 9.16 mmol) was added and the mixture was stirred for 16 h at rt. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 40 mL). The organic phase was washed with brine (40 mL), dried over Na2SO4and concentrated under reduced pressure. Purification by chromatography (silica gel, 0 - 10% MeOH in DCM) afforded N-(4- hydroxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (2.88 g, 81%) LCMS: Method A, 1.66^min, MS: ES+^340.2. Step 4: N-(4-hydroxyphenyl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide(I-4) To a stirred solution of 5-bromo-1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine (+ isomers, I-2, 2.96 g, 6.70 mmol) and N-(4-hydroxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-3, 2.50 g, 7.37 mmol) in dioxane (20 mL) and water (4 mL) was added Cs2CO3(8.73 g, 26.8 mmol). The mixture was purged with nitrogen for 5 min. Pd-118 (0.437 g, 0.67 mmol) was added and the mixture purged for a further 2 min. The mixture was stirred at 80 °C for 2 h then cooled and filtered through Celite®. The filtrate was diluted with water (150 mL) and extracted with EtOAc (3 x 60 mL). The combined organic phases were dried over Na2SO4and concentrated under reduced pressure. Purification by chromatography (silica gel, 0 - 100% EtOAc in isohexane) afforded N-(4-hydroxyphenyl)-3- (1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide with a mixture of isomers (2.60 g, 62%). LCMS: Method A, 2.07 / 2.20^min, MS: ES-^572.2. Intermediates 5, 6 4-Phenethoxyaniline (I-5) and N-(4-Phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-6) Step 1: 1-nitro-4-phenethoxybenzene 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, 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%). LCMS: Method A, 2.00 min, MS: ES+244.0. Step 2: 4-phenethoxyaniline (I-5) To a solution of 1-nitro-4-phenethoxybenzene (4.50 g, 18.5 mmol) in EtOH (55 mL) and 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. Step 3: N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6) To a stirred solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 269409-73-6, BLD, 4.48 g, 18.1 mmol) and DIPEA (8.6 mL, 49.2 mmol) in DMF (40 mL) was added HATU (7.49 g, 20.0 mmol) and 4-phenethoxyaniline (I-5, 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 chromatography (silica gel, 0 - 50% 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 7, 8 4-((Benzyloxy)methyl)aniline (I-7) and N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-8) Step 1: 1-((benzyloxy)methyl)-4-nitrobenzene 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 reaction stirred at 45 °C for 18 h. The reaction was filtered through Celite®and the filtrate was adsorbed onto 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 Step 2: 4-((benzyloxy)methyl)aniline (I-7) 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 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 Step 3: N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-8) Following the procedure of Intermediate 6, using 4-((benzyloxy)methyl)aniline (I-7) in place of 4-phenethoxyaniline (I-5), was obtained N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (2.75 g, 51%). LCMS: Method A, 2.27 min, MS: ES+444.2. Intermediate 9 3-(4,5-Diaminopyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide (I-9) 3-(4,5-Diaminopyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide (I-9) A mixture of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-6, 200 mg, 0.45 mmol), 2-chloropyrimidine-4,5-diamine (CAS 14631-08-4, BLD, 78 mg, 0.54 mmol) and Cs2CO3(441 mg, 1.35 mmol) in dioxane (4 mL) and water (1 mL) was purged with a flow of nitrogen for 5 min. Pd-118 (59 mg, 0.09 mmol) was added and the mixture purged for a further 2 min. The mixture was stirred at 90 °C for 5 h, cooled to rt, filtered and diluted with EtOAc (10 mL). The organics were washed with water (10 mL) and brine (5 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was stirred with EtOAc (5 mL), the solid collected by filtration and dried to give 3- (4,5-diaminopyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide (218 mg, 100%). LCMS: Method Q: 0.88 min, MS: ES+426.2. Intermediate 10 3-(5,6-Diaminopyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (I-10) 3-(5,6-Diaminopyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (I-10) A mixture of Cs2CO3(661 mg, 2.03 mmol), N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzamide (I-6, 300 mg, 0.68 mmol) and 5-bromopyrazine-2,3- diamine (CAS 89123-58-0, Combi-Blocks, 153 mg, 0.81 mmol) in dioxane (6.5 mL) and water (1.5 mL) was purged with a flow of nitrogen for 5 min, after which Pd-118 (88 mg, 0.14 mmol) was added and the mixture purged for a further 2 min. The mixture was stirred at 90 °C for 5 h, cooled to rt, filtered and diluted with EtOAc (10 mL). The organic phase was washed with water (10 mL) and brine (5 mL), dried over Na2SO4and concentrated under reduced pressure to afford 3-(5,6-diaminopyrazin-2-yl)-N-(4- phenethoxyphenyl)benzamide (180 mg, 56%). LCMS: Method Q: 0.94 min, MS: ES+426.2. Intermediate 11 3-(1H-[1,2,3]Triazolo[4,5-b]pyrazin-6-yl)benzoic acid (I-11) Step 1: methyl 3-(5,6-diaminopyrazin-2-yl)benzoate A mixture of 5-bromopyrazine-2,3-diamine (CAS 89123-58-0 / Combi-Blocks, 250 mg, 1.32 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (CAS 480425-35-2, BLD, 416 mg, 1.59 mmol) and Cs2CO3(1.72 g, 5.29 mmol) in dioxane (6 mL) and water (1 mL) was purged with nitrogen for 5 min, after which Pd-118 (172 mg, 0.27 mmol) was added. The mixture was purged with nitrogen for a further 2 min then stirred at 80 °C for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over Na2SO4and concentrated under reduced pressure. Purification by chromatography (silica gel, 0 - 10% (0.7M ammonia / MeOH) in DCM) afforded methyl 3-(5,6-diaminopyrazin-2-yl)benzoate (301 mg, 80%). LCMS: Method A: 0.92 min, MS: ES+245.2. Step 2: 3-(1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzoate To methyl 3-(5,6-diaminopyrazin-2-yl)benzoate (300 mg, 1.23 mmol) and AcOH (0.084 mL, 1.47 mmol) in THF (6 mL) was added iPnONO (0.26 mL, 1.97 mmol). The reaction mixture was heated to 65 °C for 72 h and concentrated under reduced pressure to give methyl 3- (1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzoate (310 mg, 99%). LCMS: Method A: 1.33 min, MS: ES+256.1. Step 3: 3-(1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzoic acid (I-11) To methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzoate (300 mg, 1.18 mmol) in THF (4 mL) was added aq. LiOH (3.5M, 2.0 mL, 7.05 mmol) and the mixture was stirred at 40 °C for 5 h. The mixture was concentrated under reduced pressure to give lithium 3-(1H- [1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzoate (350 mg, 96%). LCMS: Method A: 1.09 min, MS: ES+242.1. Intermediate 12 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)benzoic acid (I-12) Step 1: methyl 3-(5,6-diaminopyridin-2-yl)benzoate A mixture of 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD, 3.20 g, 17.0 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (CAS 480425-35-2, BLD, 4.91 g, 18.7 mmol) and Cs2CO3(13.3 g, 40.8 mmol) in dioxane (130 mL) and water (14.4 mL) was purged with nitrogen for 10 min, after which Pd-118 (1.1 g, 1.7 mmol) was added. The mixture was purged with nitrogen for a further 2 min and stirred at 75 °C for 18 h. The mixture was filtered through Celite®and adsorbed onto silica gel. Purification by chromatography (silica gel, 0 - 10% (0.7M ammonia / MeOH) in DCM) afforded methyl 3- (5,6-diaminopyridin-2-yl)benzoate (5.80 g, 100%). LCMS: Method A: 0.59 min, MS: ES+244.2. Step 2: methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate To methyl 3-(5,6-diaminopyridin-2-yl)benzoate (5.80 g, 16.7 mmol) and AcOH (2.20 mL, 36.7 mmol) in THF (100 mL) was added iPnONO (3.59 mL, 26.7 mmol). The mixture was stirred at 65 °C for 16 h then concentrated under reduced pressure and adsorbed onto silica gel. Purification by chromatography (silica gel, 0 - 100% (0.1% AcOH in MeOH) in DCM) afforded methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate (4.50 g, 100%). LCMS: Method A: 1.33 min, MS: ES+255.1. Step 3: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoic acid (I-12) To methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate (4.50 g, 17.7 mmol) in THF (40 mL) was added aq. LiOH (2.7M, 15 mL, 106 mmol) at rt and the mixture was stirred at 40 °C for 5 h. The mixture was concentrated under reduced pressure and diluted with water (50 mL). The mixture was acidified to ~pH 4 with aq. HCl (2M) at 0 °C and the resulting solid was collected by filtration to give 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoic acid (4.05 g, 95%). LCMS: Method A: 0.76 min, MS: ES+241.0. Intermediates 13, 14 Methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitrobenzoate (I-13) and 3-(1H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-aminobenzoate (I-14)

[0031] Step 1: methyl 3-(5,6-diaminopyridin-2-yl)-5-nitrobenzoate A mixture of 6-bromopyridine-2,3-diamine (CAS 129012-04-0 / BLD, 2.00 g, 10.6 mmol), (3- (methoxycarbonyl)-5-nitrophenyl)boronic acid (CAS 117342-20-8, Fluorochem, 3.11 g, 13.8 mmol) and Cs2CO3(13.3 g, 40.8 mmol) in dioxane (90 mL) and water (10 mL) was purged with nitrogen for 10 min, after which Pd-118 (0.693 g, 1.06 mmol) was added. The mixture was stirred at 75 °C for 3 h. The mixture was filtered through Celite®and adsorbed onto silica gel. Purification by chromatography (silica gel, 0 - 10% (0.7M ammonia / MeOH) in DCM) afforded methyl 3-(5,6-diaminopyridin-2-yl)-5-nitrobenzoate (3.03 g, 97%). LCMS: Method Q: 0.71 min, MS: ES+289.0. Step 2: methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitrobenzoate (I-13) To water (75 mL) and sulfuric acid (19.9 mL, 374 mmol) at 10 °C was added methyl 3-(5,6- diaminopyridin-2-yl)-5-nitrobenzoate (2.41 g, 8.36 mmol) and then aq. sodium nitrite (1M, 9.78 mL, 9.78 mmol). The mixture was stirred at 10 °C for 30 min. The solid was collected by filtration, washing with water, to give methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5- nitrobenzoate (2.50 g, 96%). LCMS: Method Q: 0.92 min, MS: ES+300.0. Step 3: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-aminobenzoate (I-14) To methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitrobenzoate (1.25 g, 4.18 mmol) in THF (90 mL) and water (30 mL) was added NH4Cl (2.24 g, 41.8 mmol) and zinc (2.73 g, 41.8 mmol). The mixture was stirred for 72 h. The procedure was repeated, starting with methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitrobenzoate (2.51 mmol). The two mixtures were combined and filtered through Celite®. The filtrate was diluted with EtOAc (300 mL) and washed with brine (2 x 100 mL). The solid was collected by filtration then stirred with water, filtered and dried under reduced pressure to give methyl 3-(1H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-aminobenzoate (1.50 g, 39%).1H NMR (500 MHz, DMSO) δ ppm: 8.39 – 8.28 (m, 1H), 7.87 (s, 1H), 7.79 – 7.66 (m, 1H), 7.60 (s, 1H), 7.26 (s, 1H), 5.54 (s, 2H), 3.86 (s, 3H).1 H obscured / not observed. Intermediate 15 N-(6-Phenethoxypyridin-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I- 15)

[0032] To a solution of 2-phenylethan-1-ol (CAS 60-12-8, Fluorochem, 0.55 mL, 4.7 mmol) in DMF (7 mL) were added 2-fluoro-5-nitropyridine (CAS 456-24-6, Activate Scientific, 0.50 g, 3.5 mmol) and Cs2CO3(2.29 g, 7.0 mmol). The mixture was stirred at 40 °C for 18 h then cooled to rt, diluted with brine (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic fractions were washed with brine (3 x 30 mL), dried over MgSO4, filtered, and adsorbed onto silica gel. Purification by flash chromatography (silica gel, 0 - 30% EtOAc in isohexane) afforded 5-nitro-2-phenethoxypyridine (0.70 g, 80%). LCMS: Method A, 1.96 min, MS: ES+245.0. A solution of methyl 5-nitro-2-phenethoxypyridine (700 mg, 2.9 mmol) in MeOH (25 mL) was passed through a 10% Pd / C cartridge under hydrogen at 30 °C at 1 bar (H-Cube®) for 1 h. The reaction mixture was concentrated under reduced pressure to give 6- phenethoxypyridin-3-amine (550 mg, 82%), used without purification in the next step. LCMS: Method A, 1.12 min, MS: ES+215.2. Step 3: N-(6-phenethoxypyridin-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-15) Following the procedure of Intermediate 6, using 6-phenethoxypyridin-3-amine in place of 4- phenethoxyaniline, was obtained N-(6-phenethoxypyridin-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide in 48% yield. LCMS: Method A, 2.18 min, MS ES+445.2. Intermediate 16 6-Bromo-3H-[1,2,3]triazolo[4,5-b]pyridine (I-16) 6-Bromo-3H-[1,2,3]triazolo[4,5-b]pyridine To a stirred solution at 0 °C of 5-bromopyridine-2,3-diamine (CAS 38875-53-5, Fluorochem, 300 mg, 1.28 mmol) in aq. HCl (6M, 10 mL) was added sodium nitrite (176 mg, 2.55 mmol) in portions. The mixture was stirred at rt for 24 h. The solid was collected by filtration, washed with water (3 x 20 mL) and dried to afford 6-bromo-3H-[1,2,3]triazolo[4,5-b]pyridine (120 mg, 45%). LCMS: Method A: 0.67 min, MS: ES+199.0 / 201.0. Intermediate 17 N-(4-((Benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-17) Step 1: 4-((benzyloxy)methyl)-2-fluoro-1-nitrobenzene Following the procedure of Intermediate 7 Step 1, using 4-(bromomethyl)-2-fluoro-1- 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 7 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 70% yield. 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-17) Following the procedure of Intermediate 6, using 4-((benzyloxy)methyl)-2-fluoroaniline in place of 4-phenethoxyaniline, 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 18 N-(4-((benzyloxy)methyl)-3-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-18) Step 1: 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene Following the procedure of Intermediate 7 Step 1, using 4-(bromomethyl)-2-fluoro-1- nitrobenzene (CAS 131858-37-2, Apollo) in place of 1-(bromomethyl)-4-nitrobenzene, was obtained 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene in 95% yield. LCMS: Method A, 1.98 min, MS: ES+no mass ion observed. Step 2: 4-((benzyloxy)methyl)-3-fluoroaniline Following the procedure of Intermediate 7 Step 2, using 1-((benzyloxy)methyl)-2-fluoro-4- nitrobenzene in place of 1-((benzyloxy)methyl)-4-nitrobenzene was obtained 4- ((benzyloxy)methyl)-3-fluoroaniline in 67% yield. LCMS: Method A, 1.56 min, MS ES+232.1. Step 3: N-(4-((benzyloxy)methyl)-3-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzamide (I-18) Following the procedure of Intermediate 6, using 4-((benzyloxy)methyl)-3-fluoroaniline in place of 4-phenethoxyaniline, was obtained N-(4-((benzyloxy)methyl)-3-fluorophenyl)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 34% yield. LCMS: Method A, 2.31 min, MS ES+462.2. Intermediate 19 (5-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-19) (5-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-19) Following the procedure of Intermediate 6, using 2-fluoro-5-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-7) in place of 4-phenethoxyaniline and after RP chromatography (C18, 0 - 100% (0.1 % HCO2H in MeCN) / (0.1% aq. HCO2H)), was obtained (5-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid in 55% yield. LCMS: Method A, 1.68 min, MS ES+380.2. Intermediate 20 (3-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-20) (3-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-20) Following the procedure of Intermediate 6, using 3-borono-2-fluorobenzoic acid (CAS 1072952-09-0, Combi-Blocks) in place of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoic acid and 4-((benzyloxy)methyl)aniline (I-7) in place of 4-phenethoxyaniline, was obtained (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid in 57% yield. LCMS: Method A, 1.67 min, MS ES+380.2. Intermediate 21 N-(4-((Benzyloxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-21) N-(4-((Benzyloxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-21) Following the procedure of Intermediate 6, using 2-fluoro-5-(4,4,5,5-tetramethyl-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)aniline (I-7) in place of 4- phenethoxyaniline, was obtained N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 35% yield. LCMS: Method A, 2.28 min, MS ES+462.2. Intermediate 22 4-(Cyclopropylmethoxy)aniline (I-22) Step 1: 1-(cyclopropoxymethyl)-4-nitrobenzene A mixture of cyclopropanol (4.03 g, 69.4 mmol), 1-(bromomethyl)-4-nitrobenzene (1.50 g, 6.94 mmol) and potassium hydroxide (468 mg, 1.2 eq, 8.33 mmol) was stirred for 18 h at rt and poured into ice water (400 mL). The mixture was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0 - 10% EtOAc in isohexane) afforded 1-(cyclopropoxymethyl)-4-nitrobenzene (1.25 g, 89 %). LCMS: Method A, 1.70 min, MS ES+194.2. Step 2: 4-(cyclopropylmethoxy)aniline (I-22) Following the procedure of Intermediate 7 Step 2, using 1-(cyclopropylmethoxy)-4- nitrobenzene in place of 1-((benzyloxy)methyl)-4-nitrobenzene, was obtained 4- (cyclopropylmethoxy)aniline in 60% yield. LCMS: Method A, 0.22 min, MS ES+164.2. Intermediate 23 4-(Cyclopropylmethoxy)aniline (I-23) Step 1: 1-(cyclopropylmethoxy)-4-nitrobenzene Following the procedure of Intermediate 5 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. LCMS: Method A, 1.79 min, MS ES+194.2. Step 2: 4-(cyclopropylmethoxy)aniline (I-23) Following the procedure of Intermediate 7 Step 2, using 1-(cyclopropylmethoxy)-4- nitrobenzene in place of 1-((benzyloxy)methyl)-4-nitrobenzene and without purification of crude product, was obtained 4-(cyclopropylmethoxy)aniline in 60% yield. LCMS: Method A, 0.22 min, MS ES+164.2. Intermediate 24 5-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-2-fluorobenzoic acid (I-24) Step 1: methyl 5-(5,6-diaminopyridin-2-yl)-2-fluorobenzoate Following the procedure of Intermediate 11 Step 1, using methyl 2-fluoro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (CAS 872459-87-5, Combi-Blocks) in place of methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate and MeCN in place of dioxane was obtained methyl 5-(5,6-diaminopyridin-2-yl)-2-fluorobenzoate in 83% yield. LCMS: Method Q: 0.68 min, MS: ES+262.1. Step 2: methyl 5-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-fluorobenzoate Following the procedure of Intermediate 11 Step 2, using methyl 5-(5,6-diaminopyridin-2-yl)- 2-fluorobenzoate in place of methyl 3-(5,6-diaminopyrazin-2-yl)benzoate and with isolation by dilution with water and collecting the solid, was obtained methyl 5-(3H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)-2-fluorobenzoate in 97% yield. LCMS: Method A: 1.23 min, MS: ES+273.1. Step 3: 5-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-fluorobenzoic acid (I-24) Following the procedure of Intermediate 12 Step 3, at 40 °C for 2 h, using methyl 5-(3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-fluorobenzoate in place of methyl 3-(1H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate was obtained 5-(3H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)-2-fluorobenzoic acid in 84% yield. LCMS: Method A: 1.01 min, MS: ES+259.1. Intermediate 25 Step 1: methyl 5-(4,5-diaminopyrimidin-2-yl)-2-fluorobenzoate Following the procedure of Intermediate 11 Step 1, using 2-chloropyrimidine-4,5-diamine (CAS 14631-08-4, BLD) in place 5-bromopyrazine-2,3-diamine and methyl 2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (CAS 872459-87-5, Combi-Blocks) in place of methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, and purification by chromatography (silica gel, 0 - 50% MeOH in DCM) was obtained methyl 5-(4,5- diaminopyrimidin-2-yl)-2-fluorobenzoate in 29% yield. LCMS: Method A: 0.69 min, MS: ES+363.0. Step 2: methyl 5-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-fluorobenzoate Following the procedure of Intermediate 11 Step 2, using methyl 5-(4,5-diaminopyrimidin-2- yl)-2-fluorobenzoate in place of methyl 3-(5,6-diaminopyrazin-2-yl)benzoate and with purification by flash chromatography (silica gel, 0 - 25% MeOH in DCM), was obtained methyl 5-(1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-2-fluorobenzoate in 95% yield. LCMS: Method A: 1.28 min, MS: ES+274.0. Step 3: 5-(3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-2-fluorobenzoic acid (I-25) Following the procedure of Intermediate 12 Step 3, using methyl 5-(3H-[1,2,3]triazolo[4,5- d]pyrimidin-5-yl)-2-fluorobenzoate in place of methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)benzoate, at rt for 1 h, and extraction with 2-methyl THF in place to filtration, was obtained 5-(3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-2-fluorobenzoic acid in 80% yield. LCMS: Method A: 1.04 min, MS: ES+260.0. Intermediate 26 5-(Trimethylstannyl)-1H-[1,2,3]triazolo[4,5-b]pyridine (I-26) 5-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1, 300 mg, 1.43 mmol) in dioxane (6 mL) was sparged with nitrogen then hexamethylditin (0.297 mL, 1.43 mmol) and Pd(PPh3)4(165 mg, 0.143 mmol) were added. The mixture was stirred at 100 °C for 18 hours and cooled to rt. The mixture was used directly in the next step (assuming 0.24 mmol / mL). LCMS: Method A: 1.20 min, MS: ES+281.0 / 283.0 / 285.0 Intermediate 27 6-Bromo-1H-[1,2,3]triazolo[4,5-c]pyridine (I-27) Following the procedure of Intermediate 1, using 6-bromopyridine-3,4-diamine (CAS 1033203-41-6, BLD) in place of 6-bromopyridine-2,3-diamine, at 60 °C for 1 h, was obtained 6-bromo-1H-[1,2,3]triazolo[4,5-c]pyridine in 100% yield. LCMS: Method Q: 0.33 min, MS: ES+199.0 / 201.0. Intermediate 28 6-Bromo-N-(4-phenethoxyphenyl)picolinamide (I-28) Following the procedure of Intermediate 6 Step 3, using T3P in place of HATU and 6- bromopicolinic acid (CAS 21190-87-4, Fluorochem) in place of 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoic acid was obtained 6-bromo-N-(4-phenethoxyphenyl)picolinamide in 88% yield. LCMS: Method A: 1.17 min, MS: ES+397.0 / 399.0. Intermediate 29 4-Bromo-N-(4-phenethoxyphenyl)picolinamide (I-29) Following the procedure of Intermediate 6 Step 3, using T3P in place of HATU and 4- bromopicolinic acid (CAS 30766-03-1, BLD) in place of 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoic acid was obtained 4-bromo-N-(4-phenethoxyphenyl)picolinamide in 74% yield. LCMS: Method A: 1.18 min, MS: ES+397.0 / 399.0. Intermediate 30 2-Bromo-N-(4-phenethoxyphenyl)isonicotinamide (I-30) Following the procedure of Intermediate 6 Step 3, using T3P in place of HATU and 2- bromopicolinic acid (CAS 66572-56-3, Fluorochem) in place of 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoic acid was obtained 2-bromo-N-(4- phenethoxyphenyl)isonicotinamide in 72% yield. LCMS: Method A: 1.10 min, MS: ES+397.0 / 399.0. Intermediate 31 (3-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid (I-31) Following the procedure of Intermediate 6 Step 3, using 3-borono-2,6-difluorobenzoic acid (1451393-05-7, Combi-Blocks) in place of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoic acid and 4-((benzyloxy)methyl)aniline (I-7) in place of 4-phenethoxyaniline (I-5), and with purification by flash chromatography (silica gel, 0 - 10% MeOH in DCM), was obtained (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid in 35% yield. LCMS: Method A: 1.68 min, MS: ES+398.1. Intermediate 32 (3-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-2-methoxyphenyl)boronic acid (I-32) Following the procedure of Intermediate 6 Step 3, using 3-borono-2-methoxybenzoic acid (CAS 913836-10-9, Combi-Blocks) in place of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoic acid and 4-((benzyloxy)methyl)aniline (I-7) in place of 4-phenethoxyaniline (I-5) and with purification by flash chromatography (silica gel, 0 - 10% MeOH in DCM) was obtained (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-methoxyphenyl)boronic acid in 63% yield. LCMS: Method A: 1.70 min, MS: ES+392.2. Intermediate 33 (3-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid (I-33) Following the procedure of Intermediate 6 Step 3, using 5-borono-2-methoxybenzoic acid (913836-12-1, BLD) in place of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and 4-((benzyloxy)methyl)aniline (I-7) in place of 4-phenethoxyaniline (I-5) 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 34 (3-((4-((Benzyloxy)methyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid (I-34) Following the procedure of Intermediate 6 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 and 4-((benzyloxy)methyl)aniline (I-7) in place of 4-phenethoxyaniline (I-5) and with purification by flash chromatography (silica gel, 0 - 10% MeOH in DCM) was 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 35 (Z)-N-(4-Styrylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-35)

[0033] To (Z)-1-nitro-4-styrylbenzene (CAS 6624-53-9, BLD, 100 mg, 0.391 mmol) and Fe (196 mg, 3.52 mmol) in EtOH / water (4:1, 5 mL) was added CaCl2(195 mg, 1.76 mmol). The mixture was stirred at 45 °C for 24 h, treated with sat. aq. NaHCO3(30 mL) and extracted with EtOAc (3 x 30 mL). The organics were dried over Na2SO4and concentrated under reduced pressure to afford (Z)-4-styrylaniline (76 mg, 86 %). LCMS: Method A: 1.12 min, MS: ES+196.1. Step 2: (Z)-N-(4-styrylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I- 35) Following the procedure of Intermediate 6 Step 3, using (Z)-4-styrylaniline in place of 4- phenethoxyaniline (I-5) was obtained (Z)-N-(4-styrylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide in 67% yield. LCMS: Method A: 2.03 min, MS: ES+426.2. Intermediate 36 N-(3-cyano-4-(1-cyclopropylethoxy)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-36) Step 1: 2-(1-cyclopropylethoxy)-5-nitrobenzonitrile To 1-cyclopropylethan-1-ol (CAS 765-42-4, Fluorochem, 0.59 mL, 6.02 mmol) in THF (150 mL) at 0 °C was added tBuOK (743 mg, 6.62 mmol) in one portion. After 15 minutes, 2- fluoro-5-nitrobenzonitrile (CAS 17417-09-3, Fluorochem, 1.00 g, 6.02 mmol) in THF (40 mL) was added over 10 min and the ice-bath was removed. The mixture was stirred at rt for 1h. Water (150 mL) was added and the mixture extracted with EtOAc (3 x 200 mL). The combined organics were washed with water (200 mL) and brine (200 mL), dried over Na2SO4and concentrated under reduced pressure to afford 2-(1-cyclopropylethoxy)-5- nitrobenzonitrile (1.15 g, 76 %). LCMS: Method A: 1.76 min, MS: ES+233.1 Step 2: 5-amino-2-(1-cyclopropylethoxy)benzonitrile Following the procedure of Intermediate 7 Step 2, using 2-(1-cyclopropylethoxy)-5- nitrobenzonitrile in place of 1-((benzyloxy)methyl)-4-nitrobenzene, CaCl2(4.5 eq) in place of AcOH, at 80 °C for 18 h, and without purification of crude product, was obtained 5-amino-2- (1-cyclopropylethoxy)benzonitrile in 25% yield. LCMS: Method A, 1.24 min, MS ES+203.2. Step 3: N-(3-cyano-4-(1-cyclopropylethoxy)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-36) Following the procedure of Intermediate 6 Step 3, using 2-fluoro-5-(4,4,5,5-tetramethyl- 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 5-amino-2-(1- cyclopropylethoxy)benzonitrile in place of 4-phenethoxyaniline (I-5), and at rt rather than 40 °C, was obtained N-(3-cyano-4-(1-cyclopropylethoxy)phenyl)-2-fluoro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 33% yield, which was used in the next step without purification or analysis. Intermediate 37 N-(3-fluoro-4-(((2-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-37) Step 1: 2-fluoro-1-(((2-methoxybenzyl)oxy)methyl)-4-nitrobenzene

[0034] 115 Following the procedure of Intermediate 7 Step 1, using (2-methoxyphenyl)methanol (CAS 612-16-8, Fluorochem) in place of phenylmethanol, and 1-(bromomethyl)-2-fluoro-4- nitrobenzene (CAS 127349-56-8, BLD) in place of 1-(bromomethyl)-4-nitrobenzene, and purification by flash chromatography (silica gel, 0 - 100% EtOAc in isohexane), was obtained 2-fluoro-1-(((2-methoxybenzyl)oxy)methyl)-4-nitrobenzene in 54% yield. LCMS: Method A: 1.72 min, MS: no mass ion observed. Step 2: 3-fluoro-4-(((2-methoxybenzyl)oxy)methyl)aniline Following the procedure of Intermediate 7 Step 2, using 2-fluoro-1-(((2- methoxybenzyl)oxy)methyl)-4-nitrobenzene in place of 1-((benzyloxy)methyl)-4- nitrobenzene, CaCl2(4.5 eq) in place of AcOH, at 45 °C for 18 h, and without purification of crude product, was obtained 3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)aniline in 75% yield. LCMS: Method A, 1.30 min, MS ES+284.1. Step 3: N-(3-fluoro-4-(((2-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-37) Following the procedure of Intermediate 6 Step 3, at rt, using 3-fluoro-4-(((2- methoxybenzyl)oxy)methyl)aniline in place of 4-phenethoxyaniline (I-5) was obtained N-(3- fluoro-4-(((2-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzamide in 59% yield. LCMS: Method A: 2.01 min, MS: ES+492.3. Intermediate 38 N-(3-Fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-38)

[0035] 116

[0036] Step 1: 2-fluoro-1-(((3-methoxybenzyl)oxy)methyl)-4-nitrobenzene Following the procedure of Intermediate 7 Step 1, using (3-methoxyphenyl)methanol (CAS 6971-51-3, Fluorochem) in place of phenylmethanol, and 1-(bromomethyl)-2-fluoro-4- nitrobenzene (CAS 127349-56-8, BLD) 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)+. Step 2: 3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)aniline Following the procedure of Intermediate 7 Step 2, using 2-fluoro-1-(((3- methoxybenzyl)oxy)methyl)-4-nitrobenzene in place of 1-((benzyloxy)methyl)-4- nitrobenzene, CaCl2(4.5 eq) in place of AcOH, at 45 °C for 18 h, and without purification of crude product, was obtained 3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)aniline in 75% yield. LCMS: 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-38)

[0037] 117 Following the procedure of Intermediate 6 Step 3, using 3-fluoro-4-(((3- methoxybenzyl)oxy)methyl)aniline in place of 4-phenethoxyaniline (I-5) 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. Intermediate 39 N-(3-Fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-39) Step 1: 2-fluoro-1-(((4-methoxybenzyl)oxy)methyl)-4-nitrobenzene Following the procedure of Intermediate 7 Step 1, using (4-methoxyphenyl)methanol (CAS 105-13-5, Apollo) in place of phenylmethanol, and 1-(bromomethyl)-2-fluoro-4-nitrobenzene (CAS 127349-56-8, BLD) 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-methoxybenzyl)oxy)methyl)-4-nitrobenzene in 73% yield. LCMS: Method A: 1.66 min, MS: no mass ion observed. Step 2: 3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)aniline Following the procedure of Intermediate 7 Step 2, using 2-fluoro-1-(((4- methoxybenzyl)oxy)methyl)-4-nitrobenzene in place of 1-((benzyloxy)methyl)-4- nitrobenzene, CaCl2(4.5 eq) in place of AcOH, at 45 °C for 18 h, and without purification of crude product, was obtained 3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)aniline in 91% yield. LCMS: Method A, 1.24 min, MS ES+262.2. Step 3: N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-39) Following the procedure of Intermediate 6 Step 3, using 3-fluoro-4-(((4- methoxybenzyl)oxy)methyl)aniline in place of 4-phenethoxyaniline (I-5) was obtained N-(3- fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzamide in 49% yield. LCMS: Method A: 1.97 min, MS: ES+492.2. Intermediate 40 N-(3-Fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-40) Step 1: 2-(((2-fluoro-4-nitrobenzyl)oxy)methyl)pyridine Following the procedure of Intermediate 7 Step 1, using pyridin-2-ylmethanol (CAS 586-98- 1, BLD) in place of phenylmethanol, and 1-(bromomethyl)-2-fluoro-4-nitrobenzene (CAS 127349-56-8, BLD) in place of 1-(bromomethyl)-4-nitrobenzene, and 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 7 Step 2, using 2-(((2-fluoro-4- nitrobenzyl)oxy)methyl)pyridine in place of 1-((benzyloxy)methyl)-4-nitrobenzene, CaCl2(4.5 eq) in place of AcOH, at 45 °C for 18 h, and without purification of crude product, was obtained 3-fluoro-4-((pyridin-2-ylmethoxy)methyl)aniline in 80% yield. LCMS: Method A, 0.62 min, MS ES+233.2. 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-22) Following the procedure of Intermediate 6 Step 3, using 3-fluoro-4-((pyridin-2- ylmethoxy)methyl)aniline in place of 4-phenethoxyaniline (I-5) was obtained N-(3-fluoro-4- ((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 41 N-(4-(((4-Chlorophenyl)sulfonyl)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-41)

[0038] Step 1: 1-chloro-4-((4-nitrobenzyl)sulfonyl)benzene To sodium 4-chlorobenzenesulfinate (CAS 14752-66-0, Fluorochem, 101 mg, 0.509 mmol) in DMF (2 mL) was added 1-(bromomethyl)-4-nitrobenzene (CAS 100-11-8, Apollo, 100 mg, 0.463 mmol). The mixture was stirred for 2 h at rt to give 1-chloro-4-((4- nitrobenzyl)sulfonyl)benzene, which was used directly in the subsequent step without workup. LCMS: Method A: 1.69 min, MS: ES- 310.0. Step 2: 4-(((4-chlorophenyl)sulfonyl)methyl)aniline To 1-chloro-4-((4-nitrobenzyl)sulfonyl)benzene (745 mg, 2.39 mmol) in DMF (2 mL) was added THF (15 mL), MeOH (5 mL) and Pd (10 wt% 254 mg, 2.39 mmol). The mixture was stirred under H2(5 bar) at rt for 18 h, then filtered through celite, washing with MeOH. The filtrate was concentrated to give 4-(((4-chlorophenyl)sulfonyl)methyl)aniline (520 mg, 77 % over 2 steps).1H NMR (500 MHz, DMSO) δ ppm: 7.72 – 7.65 (m, 4H), 6.82 (d, J = 8.1 Hz, 2H), 6.53 (d, J = 8.0 Hz, 2H), 4.48 (s, 2H). Step 3: N-(4-(((4-chlorophenyl)sulfonyl)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-41) Following the procedure of Intermediate 6 Step 3, using 2-fluoro-5-(4,4,5,5-tetramethyl- 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-(((4- chlorophenyl)sulfonyl)methyl)aniline in place of 4-phenethoxyaniline (I-5) was obtained N- (4-(((4-chlorophenyl)sulfonyl)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide in 29% yield. LCMS: Method A: 1.83 min, MS: ES+530.1. Intermediate 42 N-(4-(((4-Cyanobenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-42) Step 1: 4-(((4-nitrobenzyl)oxy)methyl)benzonitrile Following the procedure of Intermediate 7 Step 1, using 4-(hydroxymethyl)benzonitrile (CAS 874-89-5, Thermo Fisher) in place of phenylmethanol, with LiOH (1 eq) and purification by

[0039] 122 flash chromatography (silica gel, 0 - 100% EtOAc in isohexane), was obtained 4-(((4- nitrobenzyl)oxy)methyl)benzonitrile in 61% yield. LCMS: Method A: 0.76 min, MS: no mass ion observed. Step 2: 4-(((4-aminobenzyl)oxy)methyl)benzonitrile Following the procedure of Intermediate 7 Step 2, using 4-(((4- nitrobenzyl)oxy)methyl)benzonitrile in place of 1-((benzyloxy)methyl)-4-nitrobenzene, CaCl2(4.5 eq) in place of AcOH, at 45 °C for 24 h, and without purification of crude product, was obtained 4-(((4-aminobenzyl)oxy)methyl)benzonitrile in 93% yield. LCMS: Method A, 0.80 min, MS ES+239.1. Step 3: N-(4-(((4-cyanobenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-42) Following the procedure of Intermediate 6 Step 3, using 4-(((4- aminobenzyl)oxy)methyl)benzonitrile in place of 4-phenethoxyaniline (I-5) was obtained N- (4-(((4-cyanobenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide in 61% yield. LCMS: Method A: 1.84 min, MS: ES+469.2. Intermediate 43 N-(4-(Cyclopropylmethoxy)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-43) Following the procedure of Intermediate 6 Step 3, using 2-fluoro-5-(4,4,5,5-tetramethyl- 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-(cyclopropylmethoxy)aniline (I-23) in place of 4-phenethoxyaniline (I-5), and purification by flash chromatography (silica gel, 0 - 10% MeOH in DCM), was obtained N-(4-(cyclopropylmethoxy)phenyl)-2-fluoro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 42% yield. LCMS: Method A: 2.16 min, MS: ES+412.2. Intermediate 44 N-(4-((Benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-44) Step 1: 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene Following the procedure of Intermediate 7 Step 1, using (3-methoxy-4-nitrophenyl)methanol (CAS 80866-88-2, BLD) in place of phenylmethanol, and benzyl bromide (CAS 100-39-0, Merck) in place of 1-(bromomethyl)-4-nitrobenzene, with LiOH (1 eq) and purification by flash chromatography (silica gel, 0 - 10% (0.7M ammonia / MeOH) in DCM), was obtained 4- ((benzyloxy)methyl)-2-methoxy-1-nitrobenzene in 85% yield. LCMS: Method A: 1.94 min, MS: ES+274.2. Step 2: 4-((benzyloxy)methyl)-2-methoxyaniline Following the procedure of Intermediate 7 Step 2, using 4-((benzyloxy)methyl)-2-methoxy-1- nitrobenzene in place of 1-((benzyloxy)methyl)-4-nitrobenzene, CaCl2(4.5 eq) in place of

[0040] 124 AcOH, at 40 °C for 18 h, and without purification of crude product, was obtained 4- ((benzyloxy)methyl)-2-methoxyaniline in 73% yield. LCMS: Method A, 1.27 min, MS ES+244.2. Step 3: N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-44) Following the procedure of Intermediate 6 Step 3, using 4-((benzyloxy)methyl)-2- methoxyaniline in place of 4-phenethoxyaniline (I-5), and with purification by flash chromatography (silica gel, 0 - 10% MeOH in 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. LCMS: Method A: 2.38 min, MS: ES+474.2. Intermediate 45 N-(4-((Benzyloxy)methyl)-2-methylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-45) Step 1: 4-((benzyloxy)methyl)-2-methyl-1-nitrobenzene Following the procedure of Intermediate 7 Step 1, using 4-(bromomethyl)-2-methyl-1- nitrobenzene (CAS 127349-56-8, Apollo) in place of 1-(bromomethyl)-4-nitrobenzene was obtained 4-((benzyloxy)methyl)-2-methyl-1-nitrobenzene in 49% yield.

[0041] 125 LCMS: Method A: 2.02 min, MS: ES+258.2. Step 2: 4-((benzyloxy)methyl)-2-methylaniline Following the procedure of Intermediate 7 Step 2, using 4-((benzyloxy)methyl)-2-methyl-1- nitrobenzene in place of 1-((benzyloxy)methyl)-4-nitrobenzene, CaCl2(4.5 eq) in place of AcOH, at 80 °C for 18 h, and without purification of crude product, was obtained 4- ((benzyloxy)methyl)-2-methylaniline in 71% yield. LCMS: Method A, 1.28 min, MS ES+228.2. Step 3: N-(4-((benzyloxy)methyl)-2-methylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-45) Following the procedure of Intermediate 6 Step 3, using 4-((benzyloxy)methyl)-2- methylaniline in place of 4-phenethoxyaniline (I-5) was obtained N-(4-((benzyloxy)methyl)-2- methylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 47% yield. LCMS: Method A: 2.22 min, MS: ES+458.3. Intermediate 46 N-(4-((Benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzamide (I-46) Following the procedure of Intermediate 6 Step 3, using 2-fluoro-5-(4,4,5,5-tetramethyl- 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

[0042] 126 (Intermediate 18 Step 2) in place of 4-phenethoxyaniline (I-5), and at rt rather than 40 °C, was obtained N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide in 57% yield. LCMS: Method A: 2.34 min, MS: ES+480.2. Intermediate 47 N-(4-((Benzyloxy)methyl)phenyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-47) Step 1: lithium 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate A mixture of methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (CAS 955929-54-1, Fluorochem, 500 mg, 1.81 mmol) and LiOH (52 mg, 2.17 mmol) in MeOH (4 mL) was stirred at 40 °C for 4 h then concentrated under reduced pressure to afford lithium 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.47 g, 91 %). LCMS: Method A: 1.71 min, MS: ES+263.2. Step 2: N-(4-((benzyloxy)methyl)phenyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-47) Following the procedure of Intermediate 6 Step 3, using lithium 2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in place of 3-(4,4,5,5-tetramethyl-1,3,2-

[0043] 127 dioxaborolan-2-yl)benzoic acid and 4-((benzyloxy)methyl)aniline (I-7) in place of 4- phenethoxyaniline (I-5) was obtained N-(4-((benzyloxy)methyl)phenyl)-2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 48% yield. LCMS: Method A: 2.26 min, MS: ES+458.2. Intermediate 48 N-(4-((Benzyloxy)methyl)phenyl)-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-48) Following the procedure of Intermediate 6 Step 3, using 4-methoxy-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 269409-71-4, Manchester Organics) in place of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4- ((benzyloxy)methyl)aniline (I-7) in place of in place of 4-phenethoxyaniline (I-5) 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. Intermediate 49 N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-49) Following the procedure of Intermediate 6 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- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and 4-((benzyloxy)methyl)aniline (I-7) in place of 4-phenethoxyaniline (I-5) 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 50 N-(4-((Cyclopropylmethoxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-50) Step 1: 1-((cyclopropylmethoxy)methyl)-2-fluoro-4-nitrobenzene Following the procedure of Intermediate 7 Step 1, using cyclopropylmethanol (CAS 2516- 33-8, Fluorochem) in place of phenylmethanol, and 1-(bromomethyl)-2-fluoro-4- nitrobenzene (CAS 127349-56-8, Apollo) in place of 1-(bromomethyl)-4-nitrobenzene was obtained 1-((cyclopropylmethoxy)methyl)-2-fluoro-4-nitrobenzene in 82% yield. LCMS: Method A: 1.82 min, MS: ES+226.1. Step 2: 4-((cyclopropylmethoxy)methyl)-3-fluoroaniline Following the procedure of Intermediate 7 Step 2, using 1-((cyclopropylmethoxy)methyl)-2- fluoro-4-nitrobenzene in place of 1-((benzyloxy)methyl)-4-nitrobenzene, CaCl2(4.5 eq) in place of AcOH, at 80 °C for 18 h, and without purification of crude product, was obtained 4- ((cyclopropylmethoxy)methyl)-3-fluoroaniline in 67% yield. LCMS: Method A, 1.23 min, MS ES+196.2. Step 3: N-(4-((cyclopropylmethoxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzamide (I-50) Following the procedure of Intermediate 6 Step 3, using 2-fluoro-5-(4,4,5,5-tetramethyl- 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-((cyclopropylmethoxy)methyl)-3- fluoroaniline in place of 4-phenethoxyaniline (I-5), and at rt rather than 40 °C, was obtained N-(4-((cyclopropylmethoxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide in 60% yield. LCMS: Method A: 2.22 min, MS: ES+444.2. Intermediate 51 N-(4-(1-Cyclopropylethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-51) Step 1: 1-(1-cyclopropylethoxy)-2-fluoro-4-nitrobenzene To 1-cyclopropylethan-1-ol (CAS 765-42-4, Fluorochem, 0.62 mL, 6.29 mmol) in THF (150 mL) at 0 °C was added tBuOK (776 mg, 6.91 mmol) in one portion. After 15 min, 1,2- difluoro-4-nitrobenzene (CAS 369-34-6, Fluorochem, 1.00 g, 6.29 mmol) in THF (40 mL) was added over 10 min and the ice-bath was removed. The mixture was stirred at room temperature for 1 h. Water (150 mL) was added, and the mixture extracted with EtOAc (3 x 200 mL). The combined organics were washed with water (200 mL) and brine (200 mL), dried over Na2SO4and concentrated under reduced pressure to afford 1-(1- cyclopropylethoxy)-2-fluoro-4-nitrobenzene (1.20 g, 79 %). LCMS: Method A: 1.90 min, MS: ES+226.1. Step 2: 4-(1-cyclopropylethoxy)-3-fluoroaniline Following the procedure of Intermediate 7 Step 2, using 1-(1-cyclopropylethoxy)-2-fluoro-4- nitrobenzene in place of 1-((benzyloxy)methyl)-4-nitrobenzene, CaCl2(4.5 eq) in place of AcOH, at 80 °C for 18 h, and without purification of crude product, was obtained 4-(1- cyclopropylethoxy)-3-fluoroaniline in 37% yield. LCMS: Method A, 0.97 min, MS ES+196.2. Step 3: N-(4-(1-cyclopropylethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-51) Following the procedure of Intermediate 6 Step 3, at rt instead of 40 °C, using 2-fluoro-5- (4,4,5,5-tetramethyl-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-(1-cyclopropylethoxy)- 3-fluoroaniline in place of 4-phenethoxyaniline (I-5) was obtained N-(4-(1- cyclopropylethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide in 27% yield. LCMS: Method A: 2.33 min, MS: ES+444.2.

[0044] 131 Intermediate 52 N-(4-(1-Cyclopropylethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-52) Following the procedure of Intermediate 6 Step 3, using 4-(1-cyclopropylethoxy)aniline (CAS 2168664-20-6, Enamine) in place of 4-phenethoxyaniline (I-5), and with purification by flash chromatography (silica gel, 0 - 10% MeOH in DCM), was obtained N-(4-(1- cyclopropylethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 23% yield. LCMS: Method A: 2.17 min, MS: ES+408.2. Intermediate 53 N-(4-(Cyclopropylmethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-53) Following the procedure of Intermediate 6 Step 3, using 2-fluoro-5-(4,4,5,5-tetramethyl- 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-(cyclopropylmethoxy)-3- fluoroaniline (CAS 937598-42-0, Enamine) in place of 4-phenethoxyaniline (I-5), and at rt rather than 40 °C, was obtained N-(4-(cyclopropylmethoxy)-3-fluorophenyl)-2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 71% yield. LCMS: Method A: 2.2 min, MS: ES+430.2. Intermediate 54 N-(4-((4-Methylphenyl)sulfonamido)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-54)

[0045] Step 1: 3-bromo-N-(4-((4-methylphenyl)sulfonamido)phenyl)benzamide To 3-bromobenzoyl chloride (0.252 mL, 1.91 mmol) in THF (10 mL) and pyridine (0.46 mL, 5.72 mmol) was added N-(4-aminophenyl)-4-methylbenzenesulfonamide (CAS 6380-08-1, Fluorochem, 500 mg, 1.91 mmol) and DMAP (47 mg, 0.381 mmol). The mixture was stirred at rt for 18 h then water (30 mL) was added. The resulting solid was collected by filtration and triturated with ether (2 x 10 mL) to afford 3-bromo-N-(4-((4- methylphenyl)sulfonamido)phenyl)benzamide (660 mg, 76 %). LCMS: Method A: 1.87 min, MS: ES+445.0 / 447.0. Step 2: N-(4-((4-methylphenyl)sulfonamido)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-54) To 3-bromo-N-(4-((4-methylphenyl)sulfonamido)phenyl)benzamide (400 mg, 0.898 mmol) in dioxane (8 mL) was added bis(pinacolato)diboron (CAS 73183-34-3 , Fluorochem, 342 mg, 1.35 mmol) and KOAc (264 mg, 2.69 mmol). The mixture was sparged with nitrogen for 5 minutes and Pd-118 (117 mg, 0.180 mmol) was added. The mixture was sparged with nitrogen, stirred at 80 °C for 5 h and concentrated onto silica gel. Purification by flash chromatography (silica gel, 0 - 100% EtOAc in isohexane) afforded N-(4-((4-

[0046] 133 methylphenyl)sulfonamido)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (90 mg, 15 %). LCMS: Method Q: 1.11 min, MS: ES+493.2. Intermediate 55 N-(4-(N-Benzylsulfamoyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-55) Step 1: N-(4-(N-benzylsulfamoyl)phenyl)-3-bromobenzamide Following the procedure of Intermediate 54 Step 1, using 4-amino-N- benzylbenzenesulfonamide (CAS 1709-54-2, Enamine) in place of N-(4-aminophenyl)-4- methylbenzenesulfonamide was obtained N-(4-(N-benzylsulfamoyl)phenyl)-3- bromobenzamide in 83% yield. LCMS: Method A: 1.89 min, MS: ES+445.0 / 447.0. Step 2: N-(4-(N-benzylsulfamoyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-55) Following the procedure of Intermediate 54 Step 2, using N-(4-(N-benzylsulfamoyl)phenyl)- 3-bromobenzamide in place of 3-bromo-N-(4-((4-methylphenyl)sulfonamido)phenyl)- benzamide, except work-up was by addition of water, extraction into DCM and trituration of crude product with Et2O, was obtained N-(4-(N-benzylsulfamoyl)phenyl)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 81% yield. LCMS: Method A: 2.05 min, MS: ES+493.2. Intermediate 56 N-(4-(N-Phenethylsulfamoyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-56) Step 1: 3-bromo-N-(4-(N-phenethylsulfamoyl)phenyl)benzamide Following the procedure of Intermediate 54 Step 1, using 4-amino-N- phenethylbenzenesulfonamide (CAS 587850-67-7, Combi-Blocks) in place of N-(4- aminophenyl)-4-methylbenzenesulfonamide except work-up was by addition of water, extraction into DCM and trituration of crude product with Et2O, was obtained 3-bromo-N-(4- (N-phenethylsulfamoyl)phenyl)benzamide in 80% yield. LCMS: Method A: 1.96 min, MS: ES+459.0 / 461.0. Step 2: N-(4-(N-phenethylsulfamoyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-56) Following the procedure of Intermediate 54 Step 2, using 3-bromo-N-(4-(N- phenethylsulfamoyl)phenyl)benzamide in place of 3-bromo-N-(4-((4- methylphenyl)sulfonamido)phenyl)benzamide was obtained N-(4-(N- phenethylsulfamoyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 79% yield. LCMS: Method A: 2.10 min, MS: ES+507.2. Intermediate 57 N-(4-(Phenylsulfonyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I- 57) Step 1: 3-bromo-N-(4-(phenylsulfonyl)phenyl)benzamide Following the procedure of Intermediate 54 Step 1, using 4-(benzenesulfonyl)aniline (CAS 7019-01-4, Fluorochem) in place of N-(4-aminophenyl)-4-methylbenzenesulfonamide, except work-up was by addition of water, extraction into DCM and trituration of crude product with Et2O, was obtained 3-bromo-N-(4-(phenylsulfonyl)phenyl)benzamide in 80% yield. LCMS: Method A: 1.89 min, MS: ES+416.0 / 418.0. Step 2: N-(4-(Phenylsulfonyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-57) Following the procedure of Intermediate 54 Step 2, using 3-bromo-N-(4- (phenylsulfonyl)phenyl)benzamide in place of 3-bromo-N-(4-((4- methylphenyl)sulfonamido)phenyl)benzamide was obtained N-(4-(phenylsulfonyl)phenyl)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 100% yield. LCMS: Method A: 2.07 min, MS: ES+464.2. Intermediate 58 N-(4-((Benzyloxy)methyl)phenyl)-2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- A mixture of N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-21, 500 mg, 1.08 mmol) and NaSMe (91 mg, 1.30 mmol) in DMSO (6.00 mL) was stirred at 45 °C for 16 h. Water (40 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The organics were dried over Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0 - 100% EtOAc in isohexane) afforded N-(4-((benzyloxy)methyl)phenyl)-2-(methylthio)-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (220 mg, 34%). LCMS: Method A: 1.96 min, MS: ES+490.2. Intermediate 59 N-(4-(Cyclopropylmethoxy)phenyl)-5-(5,6-diaminopyridin-2-yl)-2-fluorobenzamide (I-59) Following the procedure of Intermediate 10, using 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD) in place of 5-bromopyrazine-2,3-diamine and N-(4- (cyclopropylmethoxy)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-43) in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-6), and purification by flash chromatography (silica gel, 0 – 100% (3:1 EtOH / EtOAc) in heptanes was obtained N-(4-(cyclopropylmethoxy)phenyl)-5- (5,6-diaminopyridin-2-yl)-2-fluorobenzamide in 58% yield. LCMS: Method A: 0.94 min, MS: ES+393.2. Intermediate 60 5-(5,6-Diaminopyridin-2-yl)-2-fluoro-N-(4-(tosylmethyl)phenyl)benzamide (I-60)

[0047] 138

[0048] Step 1: 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4- (tosylmethyl)phenyl)benzamide To 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD, 354 mg, 1.33 mmol) in DMF (2 mL) was added HATU (506 mg, 1.33 mmol), DIPEA (0.580 mL, 3.33 mmol) and, after 30 min, 4-(tosylmethyl)aniline (CAS 54306-15-9, Combi- Blocks, 290 mg, 1.11 mmol). The mixture was stirred for 18 h at 40 °C then poured into water (10 mL). The solid was collected by filtration, washing with water, to give 2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)benzamide (210 mg, 35 %).1H NMR (500 MHz, DMSO) δ ppm: 10.49 (s, 1H), 7.90 (dd, J = 7.6, 1.7 Hz, 1H), 7.85 (ddd, J = 7.6, 5.5, 1.8 Hz, 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). Step 2: 5-(5,6-diaminopyridin-2-yl)-2-fluoro-N-(4-(tosylmethyl)phenyl)benzamide (I-60) Following the procedure of Intermediate 10, using 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD) in place of 5-bromopyrazine-2,3-diamine and 2-fluoro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)benzamide in place of N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6), with K3PO4in place of Cs2CO3and purification by flash chromatography (silica gel, 0 – 100% (2% NH4OH in 3:1 EtOH / EtOAc) in hexanes) was obtained 5-(5,6-diaminopyridin-2-yl)-2- fluoro-N-(4-(tosylmethyl)phenyl)benzamide in 15% yield. LCMS: Method A: 1.3 min, MS: ES+491.2. Intermediate 61 N-(4-((Benzyloxy)methyl)-3-fluorophenyl)-5-(4,5-diaminopyrimidin-2-yl)-2-fluorobenzamide (I-61) Following the procedure of Intermediate 10, using 2-chloropyrimidine-4,5-diamine (CAS 14631-08-4, BLD) in place of 5-bromopyrazine-2,3-diamine and N-(4-((benzyloxy)methyl)-3- fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-46) in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6), and purification by flash chromatography (silica gel, 0 – 10% (0.7 M ammonia / MeOH) in DCM) was obtained N-(4-((benzyloxy)methyl)-3-fluorophenyl)-5-(4,5-diaminopyrimidin-2- yl)-2-fluorobenzamide in 38% yield. LCMS: Method A: 1.14 min, MS: ES+462.1. Intermediate 62 N-(4-((Benzyloxy)methyl)-3-fluorophenyl)-5-(4,5-diamino-6-methylpyrimidin-2-yl)-2- fluorobenzamide (I-62) Following the procedure of Intermediate 10, using 2-chloro-6-methylpyrimidine-4,5-diamine (CAS 63211-98-3, BLD) in place of 5-bromopyrazine-2,3-diamine and N-(4- ((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-46) in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-6), and purification by flash chromatography (silica gel, 0 – 10% (0.7 M ammonia / MeOH) in DCM) was obtained N-(4-((benzyloxy)methyl)-3- fluorophenyl)-5-(4,5-diamino-6-methylpyrimidin-2-yl)-2-fluorobenzamide in 36% yield. LCMS: Method A: 1.31 min, MS: ES+476.1. Intermediate 63 N-(4-((Benzyloxy)methyl)-3-fluorophenyl)-5-(4,5-diamino-6-(trifluoromethyl)pyrimidin-2-yl)-2- fluorobenzamide (I-63) Following the procedure of Intermediate 10, using 2-chloro-6-(trifluoromethyl)pyrimidine-4,5- diamine (CAS 708-46-3, Enamine) in place of 5-bromopyrazine-2,3-diamine and N-(4- ((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-46) in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-6), and purification by flash chromatography (silica gel, 0 – 10% (0.7 M ammonia / MeOH) in DCM) was obtained N-(4-((benzyloxy)methyl)-3- fluorophenyl)-5-(4,5-diamino-6-(trifluoromethyl)pyrimidin-2-yl)-2-fluorobenzamide in 37% yield. LCMS: Method A: 1.91 min, MS: ES+530.1. Intermediate 64 N-(4-((Benzyloxy)methyl)phenyl)-5-(4,5-diaminopyrimidin-2-yl)-2-fluorobenzamide (I-64) Following the procedure of Intermediate 10, using 2-chloropyrimidine-4,5-diamine (CAS 14631-08-4, BLD) in place of 5-bromopyrazine-2,3-diamine and N-(4- ((Benzyloxy)methyl)phenyl)-2-fluoro-5-(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-6), and purification by flash chromatography (silica gel, 0 – 10% (0.7 M ammonia / MeOH) in DCM) was obtained N-(4-((benzyloxy)methyl)phenyl)-5- (4,5-diaminopyrimidin-2-yl)-2-fluorobenzamide in 55% yield. LCMS: Method A: 1.26 min, MS: ES+444.1. Intermediate 65 5-(4,5-Diaminopyrimidin-2-yl)-2-fluoro-N-(4-phenethoxyphenyl)benzamide (I-65) Step 1: 2-fluoro-N-(4-phenethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide Following the procedure of Intermediate 6 Step 3, using 2-fluoro-5-(4,4,5,5-tetramethyl- 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, was obtained 2-fluoro-N-(4- phenethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 67% yield. LCMS: Method A, 2.10 min, MS: ES+462.2 Step 2: 5-(4,5-diaminopyrimidin-2-yl)-2-fluoro-N-(4-phenethoxyphenyl)benzamide (I-65) Following the procedure of Intermediate 10, using 2-chloropyrimidine-4,5-diamine (CAS 14631-08-4, BLD) in place of 5-bromopyrazine-2,3-diamine and 2-fluoro-N-(4- phenethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in place of N- (4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6), and purification by flash chromatography (silica gel, 0 – 10% (0.7 M ammonia / MeOH) in DCM) was obtained 5-(4,5-diaminopyrimidin-2-yl)-2-fluoro-N-(4-phenethoxyphenyl)benzamide in 38% yield. LCMS: Method A: 1.33 min, MS: ES+444.1 Intermediate 66 3-(4,5-diaminopyridin-2-yl)-N-(4-phenethoxyphenyl)benzamide Following the procedure of Intermediate 10, using 6-bromopyridine-3,4-diamine (CAS 1033203-41-6, BLD) in place of 5-bromopyrazine-2,3-diamine and purification by flash chromatography (silica gel, 0 – 10% (0.7 M ammonia / MeOH) in DCM) was obtained 3-(4,5- diaminopyridin-2-yl)-N-(4-phenethoxyphenyl)benzamide in 67% yield. LCMS: Method A: 1.25 min, MS: ES+425.1. Intermediate 67 N-(4-((Cyclopropylmethoxy)methyl)phenyl)-5-(5,6-diaminopyridin-2-yl)-2-fluorobenzamide (I- 67) Step 1: 1-((cyclopropylmethoxy)methyl)-4-nitrobenzene A solution of 1-(bromomethyl)-4-nitrobenzene (CAS 100-11-8, Thermo Scientific, 500 mg, 2.31 mmol) in cyclopropylmethanol (CAS 2516-33-8, Fluorochem, 1.9 mL, 23.1 mmol) was treated with KOH (156 mg, 2.78 mmol). The mixture was stirred at rt for 18 h. Further KOH (156 mg, 2.78 mmol) was added, and the mixture stirred for a further 3 h, then diluted with water (200 mL) and the product was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (3 x 50 mL), dried over Na2SO4, and the filtrate adsorbed onto silica gel. Purification by flash chromatography A (silica gel, 0 - 10% EtOAc in isohexane) afforded 1-((cyclopropylmethoxy)methyl)-4-nitrobenzene (400 mg, 83%). LCMS: Method A, 1.76 min, MS: ES+208.2 Step 2: 4-((cyclopropylmethoxy)methyl)aniline (I-67a) Following the procedure of Intermediate 7 Step 2, using 1-((benzyloxy)methyl)-3- nitrobenzene in place of 1-((benzyloxy)methyl)-4-nitrobenzene, was obtained 4- ((cyclopropylmethoxy)methyl)aniline in 58% yield. LCMS: Method A, 0.42 min, MS ES+178.2. Step 3: N-(4-((cyclopropylmethoxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide Following the procedure of Intermediate 6 Step 3, using T3P in place of HATU, 4- ((cyclopropylmethoxy)methyl)aniline (I-67a) in place of 4-phenethoxyaniline (I-5) and 2- fluoro-5-(4,4,5,5-tetramethyl-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 was obtained N-(4- ((cyclopropylmethoxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide in 32% yield. LCMS: Method A: 1.98 min, MS: ES+426.1 Step 4: N-(4-((cyclopropylmethoxy)methyl)phenyl)-5-(5,6-diaminopyridin-2-yl)-2- fluorobenzamide (I-67) Following the procedure of Intermediate 10, using 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD) in place of 5-bromopyrazine-2,3-diamine and N-(4-((cyclopropylmethoxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzamide (I-6), MeCN in place of dioxane, and purification by flash chromatography (silica gel, 0 – 100% (3:1 EtOH / EtOAc) in hexanes) was obtained N-(4- ((cyclopropylmethoxy)methyl)phenyl)-5-(5,6-diaminopyridin-2-yl)-2-fluorobenzamide in 66% yield.

[0049] LCMS: Method A: 1.16 min, MS: ES+407.1. Intermediate 68 N-(4-((Cyclopropylmethoxy)methyl)phenyl)-3-(5,6-diaminopyridin-2-yl)benzamide (I-68) Step 1: N-(4-((cyclopropylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide Following the procedure of Intermediate 6 Step 3, using T3P in place of HATU, and N-(4- ((cyclopropylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-67a) in place of 4-phenethoxyaniline (I-5) was obtained N-(4- ((cyclopropylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide in 37% yield. LCMS: Method A: 1.93 min, MS: ES+408.1 Step 2: N-(4-((cyclopropylmethoxy)methyl)phenyl)-3-(5,6-diaminopyridin-2-yl)benzamide (I- 68) Following the procedure of Intermediate 10, using 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD) in place of 5-bromopyrazine-2,3-diamine and N-(4-

[0050] 146 ((cyclopropylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzamide (I-6), MeCN in place of dioxane, and purification by flash chromatography (silica gel, 0 – 100% (3:1 EtOH / EtOAc) in hexanes) was obtained N-(4- ((cyclopropylmethoxy)methyl)phenyl)-3-(5,6-diaminopyridin-2-yl)benzamide in 70% yield. LCMS: Method A: 1.14 min, MS: ES+389.1. Intermediate 69 N-(4-((Benzyloxy)methyl)phenyl)-5-(5,6-diaminopyrazin-2-yl)-2-fluorobenzamide (I-69) Following the procedure of Intermediate 10, using N-(4-((Benzyloxy)methyl)phenyl)-2-fluoro- 5-(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-6), MeCN in place of dioxane, and purification by flash chromatography (silica gel, 0 – 100% (3:1 EtOH / EtOAc) in hexanes was obtained N-(4-((benzyloxy)methyl)phenyl)-5-(5,6- diaminopyrazin-2-yl)-2-fluorobenzamide in 51% yield. LCMS: Method A: 0.66 min, MS: ES+444.1. Intermediate 70 N-(4-((Benzyloxy)methyl)phenyl)-5-(4,5-diaminopyridin-2-yl)-2-fluorobenzamide (I-70) Following the procedure of Intermediate 10, using 6-bromopyridine-3,4-diamine (CAS 81033203-41-6, BLD) in place of 5-bromopyrazine-2,3-diamine and N-(4- ((Benzyloxy)methyl)phenyl)-2-fluoro-5-(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-6), MeCN in place of dioxane, and purification by flash chromatography (silica gel, 0 – 10% (0.7 M ammonia / MeOH) in DCM) was obtained N-(4- ((benzyloxy)methyl)phenyl)-5-(4,5-diaminopyridin-2-yl)-2-fluorobenzamide in 59% yield. LCMS: Method A: 1.25 min, MS: ES+443.1. Intermediate 71 4-((Benzyloxy)methyl)-N-(3-(5,6-diaminopyridin-2-yl)phenyl)benzamide (I-71) Step 1: methyl 4-((benzyloxy)methyl)benzoate Following the procedure of Intermediate 7 Step 1, using methyl 4-(bromomethyl)benzoate (CAS 2417-72-3, BLD) in place of 1-(bromomethyl)-4-nitrobenzene, was obtained methyl 4- ((benzyloxy)methyl)benzoate in 96% yield. LCMS: Method A, 1.94 min, MS: ES+261.1. Step 2: 4-((benzyloxy)methyl)benzoic acid (I-71a) A mixture of methyl 4-((benzyloxy)methyl)benzoate (922 mg, 3.36 mmol) and LiOH.H2O (706 mg, 16.8 mmol) in THF (13 mL) and water (4 mL) was stirred at rt for 18 h then 50 °C for 4 h. The mixture was cooled, acidified with aq. HCl (2 M), diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine (90 mL), dried over MgSO4and concentrated under reduced pressure to afford 4- ((benzyloxy)methyl)benzoic acid (709 mg, 85 %). LCMS: Method A: 1.50 min, MS: ES+243.0 Step 3: 4-((benzyloxy)methyl)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)benzamide Following the procedure of Intermediate 6 Step 3, using 4-((benzyloxy)methyl)benzoic acid (I-71a) in place of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, 3- aminobenzeneboronic acid pinacol ester (CAS 210907-84-9, Fluorochem) in place of 4- phenethoxyaniline (I-5) and at rt for 18 h was obtained 4-((benzyloxy)methyl)-N-(3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide in 83% yield. LCMS: Method A: 2.00 min, MS: ES+444.1. Step 4: 4-((benzyloxy)methyl)-N-(3-(5,6-diaminopyridin-2-yl)phenyl)benzamide (I-71) Following the procedure of Intermediate 10, using 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD) in place of 5-bromopyrazine-2,3-diamine and 4-((benzyloxy)methyl)-N- (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide in place of 4- ((benzyloxy)methyl)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide, MeCN in place of dioxane, and purification by flash chromatography (silica gel, 0 – 10% MeOH in DCM) was obtained 4-((benzyloxy)methyl)-N-(3-(5,6-diaminopyridin-2- yl)phenyl)benzamide in 66% yield. LCMS: Method A: 1.25 min, MS: ES+425.1 Intermediate 72 4-((Benzyloxy)methyl)-N-(5-(5,6-diaminopyridin-2-yl)-2-fluorophenyl)benzamide (I-72) Step 1: 4-((benzyloxy)methyl)-N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)benzamide Following the procedure of Intermediate 6 Step 3, using 4-((benzyloxy)methyl)benzoic acid (I-71a) in place of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, 2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (CAS 1003575-43-6, BLD) in place of 4-phenethoxyaniline (I-5) and with purification by flash chromatography (silica gel, 0 – 10% MeOH in DCM) was obtained 4-((benzyloxy)methyl)-N-(2-fluoro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide in 55% yield. LCMS: Method A: 2.04 min, MS: ES+462.1. Step 2: 4-((benzyloxy)methyl)-N-(5-(5,6-diaminopyridin-2-yl)-2-fluorophenyl)benzamide (I- 72) Following the procedure of Intermediate 10, using 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD) in place of 5-bromopyrazine-2,3-diamine and 4-((benzyloxy)methyl)-N- (2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide in place of N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6), MeCN in place of dioxane, and purification by flash chromatography (silica gel, 0 – 10% MeOH in DCM) was obtained 4-((benzyloxy)methyl)-N-(5-(5,6-diaminopyridin-2-yl)-2- fluorophenyl)benzamide in 72% yield. LCMS: Method A: 1.28 min, MS: ES+443.1 Intermediate 73 4',5'-Diamino-N-(4-((benzyloxy)methyl)phenyl)-2',4-difluoro-[1,1'-biphenyl]-3-carboxamide (I- 73) Following the procedure of Intermediate 10, using 4-bromo-5-fluorobenzene-1,2-diamine (CAS 153505-37-4, Apollo) in place of 5-bromopyrazine-2,3-diamine and N-(4- ((Benzyloxy)methyl)phenyl)-2-fluoro-5-(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-6), and purification by flash chromatography (silica gel, 0 – 100% (2% NH4OH in 3:1 EtOH / EtOAc) in hexanes was obtained 4',5'-diamino-N-(4- ((benzyloxy)methyl)phenyl)-2',4-difluoro-[1,1'-biphenyl]-3-carboxamide in 72% yield. LCMS: Method A: 0.71 min, MS: ES+460.1.

[0051] 151 Intermediate 74 3',4'-Diamino-N-(4-((benzyloxy)methyl)phenyl)-2',4-difluoro-[1,1'-biphenyl]-3-carboxamide (I- 74) Following the procedure of Intermediate 10, using 4-bromo-3-fluorobenzene-1,2-diamine (CAS 886762-86-3, Apollo) in place of 5-bromopyrazine-2,3-diamine and N-(4- ((benzyloxy)methyl)phenyl)-2-fluoro-5-(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-6), and purification by flash chromatography (silica gel, 0 – 100% (2% NH4OH in 3:1 EtOH / EtOAc) in hexanes was obtained 3',4'-diamino-N-(4- ((benzyloxy)methyl)phenyl)-2',4-difluoro-[1,1'-biphenyl]-3-carboxamide in 84% yield. LCMS: Method A: 0.74 min, MS: ES+460.1. Intermediate 75 3',4'-Diamino-N-(4-((benzyloxy)methyl)phenyl)-4-fluoro-[1,1'-biphenyl]-3-carboxamide (I-75) Following the procedure of Intermediate 10, using 4-bromobenzene-1,2-diamine (CAS 1575-37-7, BLD) in place of 5-bromopyrazine-2,3-diamine and N-(4- ((Benzyloxy)methyl)phenyl)-2-fluoro-5-(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-6), MeCN in place of dioxane, and purification by flash chromatography (silica gel, 0 – 10% MeOH in DCM) was obtained 3',4'-diamino-N-(4- ((benzyloxy)methyl)phenyl)-4-fluoro-[1,1'-biphenyl]-3-carboxamide in 85% yield. LCMS: Method A: 0.68 min, MS: ES+442.1. Intermediate 76 5-Chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-76) Following the procedure of Intermediate 1, using 2-chloropyrimidine-4,5-diamine (CAS 14631-08-4, BLD) in place of 6-bromopyridine-2,3-diamine, at 40 °C for 2 h, was obtained 5-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine in 88% yield. LCMS: Method A: 0.06 min, MS: ES+154.0. General methods (anilines) The following general methods were used for Intermediates 79 – 103 with any variations noted: Step 1: Method 1a: To KOtBu (358 mg, 3.19 mmol) in THF (3.4 mL) at 0 °C was added R’OH (1.5 eq). After 10 min, a solution of 1-fluoro-4-nitro-benzene (0.226 mL, 2.13 mmol) in THF (3.4 mL) was added and the mixture was warmed to rt. After 18 h, the mixture was diluted with sat. aq. NH4Cl (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine (90 mL), dried over MgSO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0 - 100% EtOAc in isohexane) gave the desired product. Method 1b: R’OH (1 Eq, 1.42 mmol) was added to NaH (142 mg, 3.54 mmol) in THF (2.4 mL) at 0 °C. After 10 min, a solution of 1-fluoro-4-nitro-benzene (0.150 mL, 1.417 mmol) in THF (2.4 mL) was added dropwise and the mixture was allowed to warm to rt. After stirring for 18 h, water (5 mL) was added. The mixture was extracted with EtOAc (3 x 10 mL). The combined organics were dried over Na2SO4and concentrated under reduce pressure. Purification by flash chromatography (silica gel, 0 - 100% EtOAc in isohexane) gave the desired product.  Method 1c: To cyclopropanol (0.812 mL, 12.8 mmol), was added 1-(bromomethyl)-2-fluoro- 4-nitrobenzene (300 mg, 1.28 mmol), KOH (86 mg, 1.54 mmol) in 2-methyl THF (5 mL) and the mixture stirred at 30 °C for 2 h. The mixture was cooled in ice and neutralised with aq. HCl (2 M, 0.64 mL, 1.28 mmol) and concentrated under reduced pressure. IPA (10 mL) was added, the mixture was filtered and the filtrate concentrated under reduced pressure to give desired product Method 1d: To R’2NH (1 Eq, 1.42 mmol) and potassium carbonate (588 mg, 4.25 mmol) in DMF (5.00 mL) was added 1-fluoro-4-nitrobenzene (200 mg, 1.42 mmol). The mixture was stirred at 65 °C for 16 h. Brine (20 mL) was added followed by EtOAc (30 mL). The aqueous phase was extracted with EtOAc (2 x 30 mL), the combined organics were washed with aq. LiCl (10%, 20 mL) and dried over MgSO4and filtered. Purification by flash chromatography (silica gel, 0 - 100% EtOAc in isohexane) gave the desired product. Method 1e: ArCH2Br (1.80 mmol) was added to a stirred suspension of Ar’CH2OH (1.50 mmol) and silver oxide (522 mg, 2.25 mmol) in DCM (2 mL). The mixture was stirred at 40 °C for 16 h then filtered through a plug of Celite®. The filtrate was concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0 - 100% (2% NH4OH in 3:1 EtOH / EtOAc) in isohexane) gave the desired product.   Step 2: Method 2a: A solution of appropriate starting material in MeOH or MeOH / THF was stirred under H2atmosphere (1 to 2 bar, 1 ml / min, 20 to 30 °C, Pd / C cartridge, H-Cube®) for 4 min to 4 h. The mixture was concentrated to give the desired product. Method 2b: The appropriate starting material and 10% Pd / C (0.1 eq) in EtOH was stirred under H2(2 bar, rt) for 20 h. The mixture was filtered through Celite®and concentrated under reduced pressure to give the desired product. Method 2c: A mixture of the appropriate starting material, Fe (5 eq) and NH4Cl (10 eq) in EtOH / H2O (6:1) was stirred at 85 °C for 2 h and the mixture was filtered through Celite®.The filtrate was washed with water and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0 - 100% EtOAc in hexanes) afforded the desired product. Method 2d: A mixture of appropriate starting material, Fe (13 eq) and CaCl2(4.5 eq) in EtOH / H2O (6:1) was stirred at 80 °C for 4 h. The mixture was filtered through Celite®. The filtrate was washed with water and concentrated under reduced pressure to give desired product. Intermediate 79 (R)-4-(1-Cyclopropylethoxy)aniline (I-79) Step 1: (R)-1-(1-cyclopropylethoxy)-4-nitrobenzene Using Method 1a with (R)-1-cyclopropylethan-1-ol (CAS 6516-09-2, Enamine) and without chromatography was obtained (R)-1-(1-cyclopropylethoxy)-4-nitrobenzene in 87% yield. LCMS: Method A: 1.69 min, MS: ES+208.1. Step 2: (R)-4-(1-cyclopropylethoxy)aniline Using Method 2a with (R)-1-(1-cyclopropylethoxy)-4-nitrobenzene was obtained (R)-4-(1- cyclopropylethoxy)aniline in 91% yield. LCMS: Method A: 0.68 min, MS: ES+178.1. Intermediate 80 (S)-4-(1-Cyclopropylethoxy)aniline (I-80) Step 1: (S)-1-(1-cyclopropylethoxy)-4-nitrobenzene Using Method 1a with (S)-1-cyclopropylethan-1-ol (CAS 55637-37-1, Enamine) and without chromatography was obtained (S)-1-(1-cyclopropylethoxy)-4-nitrobenzene in 87% yield. LCMS: Method A: 1.69 min, MS: ES+208.1 Step 2: (S)-4-(1-cyclopropylethoxy)aniline Using Method 2a with (S)-1-(1-cyclopropylethoxy)-4-nitrobenzene was obtained (S)-4-(1- cyclopropylethoxy)aniline in 89% yield. LCMS: Method A: 0.69 min, MS: ES+178.1 Intermediate 81 4-(((4-Aminobenzyl)oxy)methyl)benzonitrile (I-81) Using Method 1e with 4-(hydroxymethyl)benzonitrile (CAS 874-89-5, BLD) and 1- (bromomethyl)-4-nitrobenzene (CAS 100-11-8, Apollo) was obtained 4-(((4- nitrobenzyl)oxy)methyl)benzonitrile in 81% yield. LCMS: Method Q: 0.73 min, MS: ES+269.1. Using Method 2a with 4-(((4-nitrobenzyl)oxy)methyl)benzonitrile was obtained 4-(((4- aminobenzyl)oxy)methyl)benzonitrile in 90% yield. LCMS: Method A: 1.04 min, MS: ES+239.1. Intermediate 82 4-((2,2,2-Trifluoro-1-phenylethoxy)methyl)aniline (I-82) Using Method 1e with 2,2,2-trifluoro-1-phenylethan-1-ol (CAS 340-05-6, Apollo) and 1- (bromomethyl)-4-nitrobenzene (CAS 100-11-8, Apollo) was obtained 1-nitro-4-((2,2,2- trifluoro-1-phenylethoxy)methyl)benzene in 96% yield. LCMS: Method Q: 0.66 min, MS: no mass ion observed. Using Method 2a with 1-nitro-4-((2,2,2-trifluoro-1-phenylethoxy)methyl)benzene was obtained 4-((2,2,2-trifluoro-1-phenylethoxy)methyl)aniline in 90% yield. LCMS: Method Q: 0.67 min, MS: ES+282. Intermediate 83 4-((2-Chloro-4-fluorobenzyl)oxy)aniline (I-83) Using Method 1b with (2-chloro-4-fluorophenyl)methanol (CAS 208186-84-9, Apollo) and collection of solid in place of chromatography, was obtained 2-chloro-4-fluoro-1-((4- nitrophenoxy)methyl)benzene in 80% yield. LCMS: Method A: 1.87 min, MS: ES+282. Using Method 2c with 2-chloro-4-fluoro-1-((4-nitrophenoxy)methyl)benzene was obtained 4- ((2-chloro-4-fluorobenzyl)oxy)aniline in 89% yield. LCMS: Method A: 1.09 min, MS: ES+252. Intermediate 84 4-(3-Phenoxypiperidin-1-yl)aniline (I-84) Using Method 1d with 3-phenoxypiperidine (CAS 151666-08-9, Alfa Aesar) was obtained 1- (4-nitrophenyl)-3-phenoxypiperidine in 60% yield. LCMS: Method Q: 0.77 min, MS: ES+299.1. Using Method 2a with 1-(4-nitrophenyl)-3-phenoxypiperidine was obtained 4-(3- phenoxypiperidin-1-yl)aniline in 100% yield. LCMS: Method Q: 0.53 min, MS: ES+269.1. Intermediate 85 4-(3-Phenylpiperidin-1-yl)aniline (I-85) Using Method 1d with 3-phenylpiperidine (CAS 3973-62-4, BLD) was obtained 1-(4- nitrophenyl)-3-phenylpiperidine in 95% yield. LCMS: Method Q: 0.81 min, MS: ES+283.1. Step 2: 4-(3-phenylpiperidin-1-yl)aniline Using Method 2a with 1-(4-nitrophenyl)-3-phenylpiperidine was obtained 4-(3- phenylpiperidin-1-yl)aniline in 99% yield. LCMS: Method Q: 0.51 min, MS: ES+253.1. Intermediate 86 4-(3-Phenylpyrrolidin-1-yl)aniline (I-86) Using Method 1d with 3-phenylpyrrolidine (CAS 936-44-7, BLD) was obtained 1-(4- nitrophenyl)-3-phenylpyrrolidine in 78% yield. LCMS: Method Q: 0.78 min, MS: ES+269.1. Step 2: 4-(3-phenylpyrrolidin-1-yl)aniline Using Method 2a with 1-(4-nitrophenyl)-3-phenylpyrrolidine was obtained 4-(3- phenylpyrrolidin-1-yl)aniline in 100% yield. LCMS: Method Q: 0.56 min, MS: ES+239.2. Intermediate 87 4-(3-Phenylpyrrolidin-1-yl)aniline, enantiomer 1 (I-87) Step 1: Chiral SFC separation (Prep Method E) of 1-(4-nitrophenyl)-3-phenylpyrrolidine (I- 86 Step 1) afforded 1-(4-nitrophenyl)-3-phenylpyrrolidine, enantiomer 1 in 40% yield. LCMS: Method A: 1.90 min, MS: ES+269.2. Step 2: 4-(3-phenylpyrrolidin-1-yl)aniline, enantiomer 1 Using Method 2a with 1-(4-nitrophenyl)-3-phenylpyrrolidine, enantiomer 1 was obtained 4- (3-phenylpyrrolidin-1-yl)aniline, enantiomer 1 in 97% yield. LCMS: Method Q: 1.09 min, MS: ES+239.2. Intermediate 88 4-(3-Phenylpyrrolidin-1-yl)aniline, enantiomer 2 (I-88) Chiral SFC separation (Prep Method E) of 1-(4-nitrophenyl)-3-phenylpyrrolidine (I-86 Step 1) afforded 1-(4-nitrophenyl)-3-phenylpyrrolidine, enantiomer 2 in 40% yield. LCMS: Method A: 1.90 min, MS: ES+269.2. Using Method 2a with 1-(4-nitrophenyl)-3-phenylpyrrolidine, enantiomer 2 was obtained 4- (3-phenylpyrrolidin-1-yl)aniline, enantiomer 2 in 91% yield. LCMS: Method Q: 1.09 min, MS: ES+239.2. Intermediate 89 4-(Cyclopentyloxy)-3-fluoroaniline (I-89) Using Method 1b with cyclopentanol (CAS 96-41-3, Merck) and 1,2-difluoro-4-nitrobenzene (CAS 369-34-6, Fluorochem) in place of 1-fluoro-4-nitrobenzene and flash chromatography (silica gel, 0 - 50% DCM in heptane) was obtained 4-(cyclopentyloxy)-2-fluoro-1- nitrobenzene in 64% yield. LCMS: Method A: 1.79 min, MS: ES+226.0. Step 2: 4-(cyclopentyloxy)-3-fluoroaniline Using Method 2b with 4-(cyclopentyloxy)-2-fluoro-1-nitrobenzene was obtained 4- (cyclopentyloxy)-3-fluoroaniline in 98% yield. LCMS: Method A: 1.03 min, MS: ES+196.1. Intermediate 90 (R)-4-((2,2,2-Trifluoro-1-phenylethoxy)methyl)aniline (I-90) Using Method 1e with (R)-2,2,2-trifluoro-1-phenylethan-1-ol (CAS 10531-50-7, Enamine) and 1-(bromomethyl)-4-nitrobenzene (CAS 100-11-8, Apollo), and with purification by flash chromatography (silica gel, 0 - 20% EtOAc in isohexane), was obtained (R)-1-nitro-4- ((2,2,2-trifluoro-1-phenylethoxy)methyl)benzene in 43% yield. LCMS: Method Q: 0.64 min, MS: no mass ion observed. Using Method 2a with (R)-1-nitro-4-((2,2,2-trifluoro-1-phenylethoxy)methyl)benzene was obtained (R)-4-((2,2,2-trifluoro-1-phenylethoxy)methyl)aniline in 97% yield. LCMS: Method Q: 0.68 min, MS: ES+282.1. Intermediate 91 Step 1: 1-(cyclopropoxymethyl)-2-fluoro-4-nitrobenzene Using Method 1c was obtained 1-(cyclopropoxymethyl)-2-fluoro-4-nitrobenzene in 87% yield. LCMS: Method A: 1.59 min, MS: ES+212. Step 2: 4-(cyclopropoxymethyl)-3-fluoroaniline Using Method 2d with 1-(cyclopropoxymethyl)-2-fluoro-4-nitrobenzene was obtained 4- (cyclopropoxymethyl)-3-fluoroaniline in 41% yield. LCMS: Method A: 1.02 min, MS: ES+182. Intermediate 92 4-((Phenylmethoxy-d2)methyl-d2)aniline (I-92) Step 1: (4-nitrophenyl)methan-d2-ol A solution of 4-nitrobenzoyl chloride (1.00 g, 5.39 mmol) in THF (3.6 mL) was added dropwise to a suspension of NaBD4(226 mg, 5.39 mmol) in THF (3.6 mL) and DMF (3.6 mL) and the mixture was cooled with a water bath. After 1.5 h further NaBD4(68 mg, 1.617 mmol) was added. After 16 h the mixture was cooled to 0 °C, carefully diluted with sat. aq. NH4Cl (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were washed with sat. aq. NaHCO3(90 mL) and brine (3 x 90 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 0-100% EtOAc in isohexane) to afford (4-nitrophenyl)methan-d2- ol (529 mg, 60 %). LCMS: Method A: 0.78 min, MS: no mass ion observed. Step 2: 1-(bromomethyl-d2)-4-nitrobenzene A solution of (4-nitrophenyl)methan-d2-ol (100 mg, 0.612 mmol), triphenylphosphine (193mg, 0.735 mmol) and CBr4(244 mg, 0.735 mmol) in DCM (2 mL) was stirred at 0 °C for 10 mins, warmed to rt over 4 h then volatiles were removed under reduced pressure. The crude product was purified by flash chromatography (silica gel, 0-40% EtOAc in isohexane to afford 1-(bromomethyl-d2)-4-nitrobenzene (119 mg, 87%). LCMS: Method A: 1.45 min, MS: no mass ion observed. Step 3: 1-nitro-4-((phenylmethoxy-d2)methyl-d2)benzene Using Method 1e with benzenemethan-d2-ol (CAS 21175-64-4, SLS) and 1-(bromomethyl- d2)-4-nitrobenzene, and with purification by flash chromatography (silica gel, 0 - 30% TBME in isohexane), was obtained 1-nitro-4-((phenylmethoxy-d2)methyl-d2)benzene in 75% yield. LCMS: Method A: 1.76 min, MS: ES+248. Step 4: 4-((phenylmethoxy-d2)methyl-d2)aniline Using Method 2a with 1-nitro-4-((phenylmethoxy-d2)methyl-d2)benzene was obtained 4- ((phenylmethoxy-d2)methyl-d2)aniline in 77% yield. LCMS: Method A: 0.99 min, MS: ES+218.1. Intermediate 93 4-(3,3-Difluorocyclobutoxy)aniline (I-93) Using Method 1a with 3,3-difluorocyclobutan-1-ol (CAS 637031-88-0, BLD) was obtained 1- (3,3-difluorocyclobutoxy)-4-nitrobenzene in 60% yield. LCMS: Method A: 1.59 min, MS: ES+230. Using Method 2a with 1-(3,3-difluorocyclobutoxy)-4-nitrobenzene was obtained 4-(3,3- difluorocyclobutoxy)aniline in 89% yield. LCMS: Method A: 0.36 min, MS: ES+200.1 Intermediate 94 4-((1,1,1-Trifluoropropan-2-yl)oxy)aniline (I-94) Step 1: 1-nitro-4-((1,1,1-trifluoropropan-2-yl)oxy)benzene Using Method 1b with 1,1,1-trifluoropropan-2-ol (CAS 374-01-6, Fluorochem) was obtained 1-nitro-4-((1,1,1-trifluoropropan-2-yl)oxy)benzene in 54% yield. LCMS: Method A: 1.67 min, MS: ES+236. Step 2: 4-((1,1,1-trifluoropropan-2-yl)oxy)aniline Using Method 2a with 1-nitro-4-((1,1,1-trifluoropropan-2-yl)oxy)benzene was obtained 4- ((1,1,1-trifluoropropan-2-yl)oxy)aniline in 93% yield and was used without analysis. Intermediate 96 4-(3,3-Difluoropyrrolidin-1-yl)aniline (I-96) Using Method 1d with 3,3-difluoropyrrolidine (CAS 316131-01-8, Fluorochem) was obtained 3,3-difluoro-1-(4-nitrophenyl)pyrrolidine in 80% yield. LCMS: Method A: 1.51 min, MS: ES+229.1. Using Method 2a with 3,3-difluoro-1-(4-nitrophenyl)pyrrolidine was obtained 4-(3,3- difluoropyrrolidin-1-yl)aniline in 94% yield. LCMS: Method A: 0.27 min, MS: ES+199.1. Intermediate 98 6-((Benzyloxy)methyl)pyridin-3-amine (I-98) Step 1: 2-((benzyloxy)methyl)-5-nitropyridine Using Method 1e with (5-nitropyridin-2-yl)methanol (CAS 36625-57-7, Fluorochem) and benzyl bromide (CAS 100-39-0, Merck), and with purification by flash chromatography (silica gel, 0 - 60% EtOAc in isohexane), was obtained 2-((benzyloxy)methyl)-5-nitropyridine in 16% yield. LCMS: Method A: 1.56 min, MS: ES+245.2. Step 2: 6-((benzyloxy)methyl)pyridin-3-amine Using Method 2a with 2-((benzyloxy)methyl)-5-nitropyridine was obtained 6- ((benzyloxy)methyl)pyridin-3-amine in 93% yield. LCMS: Method A: 0.64 min, MS: ES+215.2. Intermediate 99 Step 1: 1-(4-nitrophenyl)-4-phenylpiperidine Using Method 1d with 4-phenylpiperidine (CAS 771-99-3, Merck) was obtained 1-(4- nitrophenyl)-4-phenylpiperidine in 76% yield. LCMS: Method Q: 0.79 min, MS: ES+283.1. Step 2: 4-(4-phenylpiperidin-1-yl)aniline Using Method 2a with 1-(4-nitrophenyl)-4-phenylpiperidine was obtained 4-(4- phenylpiperidin-1-yl)aniline in 100% yield. LCMS: Method Q: 0.49 min, MS: ES+253.1. Intermediate 100 Step 1: 1-(4-nitrophenyl)-4-phenoxypiperidine Using Method 1d with 4-phenoxypiperidine (CAS 3202-33-3, Combi-Blocks) was obtained 1-(4-nitrophenyl)-4-phenoxypiperidine in 81% yield. LCMS: Method Q: 0.78 min, MS: ES+299.1. Using Method 2a with 1-(4-nitrophenyl)-4-phenoxypiperidine was obtained 4-(4- phenoxypiperidin-1-yl)aniline in 99% yield. LCMS: Method Q: 0.51 min, MS: ES+269.1. Intermediate 101 Using Method 1d with 3-phenoxypyrrolidine hydrochloride (CAS 21767-15-7, BLD) was obtained 1-(4-nitrophenyl)-3-phenoxypyrrolidine in 31% yield. LCMS: Method Q: 0.76 min, MS: ES+285.1. Using Method 2a with 1-(4-nitrophenyl)-3-phenoxypyrrolidine was obtained 4-(3- phenoxypyrrolidin-1-yl)aniline in 94% yield. LCMS: Method Q: 0.55 min, MS: ES+255.1. Intermediate 102 Using Method 1d with 3-phenylazetidine hydrochloride (CAS 7606-30-6, Fluorochem) was obtained 1-(4-nitrophenyl)-3-phenylazetidine in 73% yield. LCMS: Method Q: 0.77 min, MS: ES+255.2. Using Method 2a with 1-(4-nitrophenyl)-3-phenylazetidine was obtained 4-(3-phenylazetidin- 1-yl)aniline in 96% yield. LCMS: Method Q: 0.52 min, MS: ES+225.2. Intermediate 103 Step 1: 1-(4-nitrophenyl)-3-phenoxyazetidine Using Method 1d with 3-phenoxyazetidine hydrochloride (CAS 301335-39-7, Fluorochem) was obtained 1-(4-nitrophenyl)-3-phenoxyazetidine in 92% yield. LCMS: Method Q: 0.76 min, MS: ES+271.2. Step 2: 4-(3-phenoxyazetidin-1-yl)aniline Using Method 2a with 1-(4-nitrophenyl)-3-phenoxyazetidine was obtained 4-(3- phenoxyazetidin-1-yl)aniline in 94% yield. LCMS: Method Q: 0.52 min, MS: ES+241.3. Examples Example 1 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-((1-phenylpiperidin-4- yl)methoxy)phenyl)benzamide Step 1: (1-phenylpiperidin-4-yl)methyl methanesulfonate To a stirred solution of (1-phenylpiperidin-4-yl)methanol (CAS 697306-45-9, Combi-Blocks, 100 mg, 0.52 mmol) and NEt3(0.18 mL, 1.3 mmol) in DCM (4 mL) at 0 °C was added MsCl (0.05 mL, 0.63 mmol). The reaction was warmed to rt and stirred for 1 h, then quenched with sat. aq. Na2CO3(20 mL) and extracted with DCM (2 x 10 mL). The organic phases were dried over Na2SO4and concentrated under reduced pressure to afford (1- phenylpiperidin-4-yl)methyl methanesulfonate (132 mg, 86%). LCMS: Method A, 1.52 min, MS ES+270.2 Step 2: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-((1-phenylpiperidin-4- yl)methoxy)phenyl)benzamide (Example 1) A mixture of N-(4-hydroxyphenyl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide (+ isomers; I-4, 50 mg, 0.07 mmol), (1-phenylpiperidin-4-yl)methyl methanesulfonate (19 mg, 0.07 mmol) and K2CO3(10 mg, 0.07 mmol) in THF (2 mL) was stirred at 50 °C for 16 h. NaI (1 mg, 0.07 mmol) and Cs2CO3(23 mg, 0.07 mmol) were added and stirring continued at 80 °C for 16 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over Na2SO4and concentrated under reduced pressure. The residue was dissolved in dioxane (1 mL) and HCl in dioxane (4M, 0.06 mL, 0.22 mmol) and stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure and purified by RP chromatography (C18, 0 - 100% (0.1 % HCO2H in MeCN) / (0.1% aq. HCO2H)) to afford 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-((1- phenylpiperidin-4-yl)methoxy)phenyl)benzamide (11 mg, 30%). LCMS: Method A, 2.05 min, MS: ES+505.3;1H NMR (500 MHz, DMSO) δ ppm: 10.33 (s, 1H), 8.74 (s, 1H), 8.59 (s, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.75 – 7.67 (m, 2H), 7.33 – 7.27 (m, 2H), 7.27 – 7.19 (m, 3H), 7.18 – 7.13 (m, 1H), 7.02 – 6.97 (m, 1H), 6.57 (t, J = 7.2 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 4.08 (t, J = 6.5 Hz, 2H), 3.51 – 3.42 (m, 1H), 3.28 – 3.19 (m, 1H), 2.95 (t, J = 8.6 Hz, 1H), 2.23 – 2.16 (m, 1H), 1.97 – 1.84 (m, 2H), 1.78 – 1.66 (m, 1H).2 H were obscured / not observed. Example 2 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(2-(tetrahydro-2H-pyran-4- yl)ethoxy)phenyl)benzamide 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(2-(tetrahydro-2H-pyran-4- yl)ethoxy)phenyl)benzamide A solution of N-(4-hydroxyphenyl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide (+ isomers; I-4, 70 mg, 0.11 mmol), 4-(2-bromoethyl)tetrahydro-2H-pyran (CAS 4677-20-7, Fluorochem, 0.02 mL, 0.11 mmol) and Cs2CO3(72 mg, 0.22 mmol) in DMF (2 mL) was stirred at 60 °C for 72 h. Water (30 mL) was added to the mixture and the product was extracted with EtOAc (3 x 20 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was dissolved in dioxane (1 mL) and HCl in dioxane (4M, 0.19 mL, 0.38 mmol) and stirred at rt for 16 h. The mixture was concentrated under reduced pressure and purified by RP chromatography (C18, 0 – 100% MeCN in 0.1% aq. HCO2H) to afford 3- (1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(2-(tetrahydro-2H-pyran-4- yl)ethoxy)phenyl)benzamide (15 mg, 30%). LCMS: Method A, 1.64 min, MS: ES+444.2;1H NMR (500 MHz, DMSO) δ ppm: 10.32 (s, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.75 – 7.66 (m, 2H), 6.96 (d, J = 8.9 Hz, 2H), 4.02 (t, J = 6.4 Hz, 2H), 3.91 – 3.78 (m, 2H), 1.80 – 1.54 (m, 5H), 1.32 – 1.17 (m, 2H).4 H were obscured / not observed. General procedure (alkylation, deprotection) Following the procedure of Example 2, substituting 4-(2-bromoethyl)tetrahydro-2H-pyran with the appropriate starting material and with any minor modifications noted, the following Examples 3-16 were obtained:

[0052] Example 3 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(cyclopropylmethoxy)phenyl)benzamide Using (bromomethyl)cyclopropane (CAS 7051-34-5, Apollo) in place of 4-(2- bromoethyl)tetrahydro-2H-pyran, and with NaI (0.1 eq.) in THF at 50 °C for 72 h. The intermediate residue was purified by chromatography (silica gel, 0 - 80% EtOAc in isohexane). After HCl treatment and purification by preparative HPLC (Prep Method A, x=30, y=60) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- (cyclopropylmethoxy)phenyl)benzamide in 17% yield. LCMS: Method A, 1.66 min, MS: ES+386.2;1H NMR (500 MHz, DMSO) δ ppm: 10.31 (s, 1H), 8.73 (s, 1H), 8.54 (d, J = 8.7 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.74 – 7.61 (m, 3H), 6.94 (d, J = 8.6 Hz, 2H), 3.82 (d, J = 6.9 Hz, 2H), 1.27 – 1.15 (m, 1H), 0.63 – 0.51 (m, 2H), 0.40 – 0.26 (m, 2H).1 H was obscured / not observed. Example 4 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(isopentyloxy)phenyl)benzamide Using 1-bromo-3-methylbutane (CAS 107-82-4, Acros, 1.2 eq.) in place of 4-(2- bromoethyl)tetrahydro-2H-pyran and with NaI (0.1 eq.) in THF at 60 °C for 16 h. Purification by chromatography (silica gel, 0 - 80% EtOAc in isohexane). After HCl treatment was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- (isopentyloxy)phenyl)benzamide in 22% yield. LCMS: Method A, 1.88 min, MS: ES+402.2;1H NMR (500 MHz, DMSO) δ ppm: 10.31 (s, 1H), 8.73 (s, 1H), 8.54 (s, 1H), 8.39 (d, J = 7.7 Hz, 1H), 8.15 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.70 (dd, J = 8.0, 5.4 Hz, 2H), 6.99 – 6.91 (m, 2H), 4.00 (t, J = 6.7 Hz, 2H), 1.82 – 1.76 (m, 1H), 1.66 – 1.59 (m, 2H), 1.05 – 0.87 (m, 6H).2 H was obscured / not observed. Example 5 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzylthio)methoxy)phenyl)benzamide Using benzyl(chloromethyl)sulfide (CAS 3970-13-6, Fluorochem, 1.2 eq.) in place of 4-(2- bromoethyl)tetrahydro-2H-pyran was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- ((benzylthio)methoxy)phenyl)benzamide in 12% yield. LCMS: Method A, 1.87 min, MS: ES+468.2;1H NMR (500 MHz, DMSO) δ ppm: 10.29 (s, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.33 (d, J = 7.8 Hz, 1H), 8.09 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.70 – 7.60 (m, 3H), 7.27 (d, J = 4.4 Hz, 4H), 7.23 – 7.17 (m, 1H), 6.96 (d, J = 8.9 Hz, 2H), 5.14 (s, 2H), 3.84 (s, 2H).1 H was obscured / not observed. Example 6 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamido)phenyl 4-methylbenzenesulfonate Using 4-methylbenzenesulfonyl chloride (CAS 98-59-9, Acros, 1.2 eq.) in place of 4-(2- bromoethyl)tetrahydro-2H-pyran was obtained 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)benzamido)phenyl 4-methylbenzenesulfonate in 61% yield. LCMS: Method A, 1.80 min, MS: ES+486.1;1H NMR (500 MHz, DMSO) δ ppm: 10.55 (s, 1H), 8.72 (s, 1H), 8.57 (d, J = 8.5 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.85 – 7.65 (m, 5H), 7.50 (d, J = 8.1 Hz, 2H), 7.09 – 6.97 (m, 2H), 2.44 (s, 3H).1 H was obscured / not observed. Example 7 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-butoxyphenyl)benzamide Using 1-bromobutane (CAS 109-65-9, Combi-Blocks, 1.2 eq.) in place of 4-(2- bromoethyl)tetrahydro-2H-pyran and with NaI (0.1 eq.). The intermediate residue was purified by chromatography (silica gel, 0 - 80% EtOAc in isohexane). After HCl treatment, was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- butoxyphenyl)benzamide in 31% yield. LCMS: Method A, 1.79 min, MS: ES+388.2;1H NMR (500 MHz, DMSO) δ ppm: 10.31 (s, 1H), 8.73 (s, 1H), 8.53 (d, J = 8.6 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.74 – 7.66 (m, 3H), 6.99 – 6.91 (m, 2H), 3.97 (t, J = 6.5 Hz, 2H), 1.77 – 1.66 (m, 2H), 1.52 – 1.40 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H).1 H was obscured / not observed. Example 8 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-isobutoxyphenyl)benzamide Using 1-bromo-2-methylpropane (CAS 78-77-3, Combi-Blocks) in place of 4-(2- bromoethyl)tetrahydro-2H-pyran and with K2CO3(1 eq.) in THF at 50 °C for 16 h. Then Cs2CO3(1 eq.) and NaI (0.1 eq.) at 50 °C for 16 h. The intermediate residue was purified by chromatography (silica gel, 0 - 80% EtOAc in isohexane). After HCl treatment, was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- isobutoxyphenyl)benzamide in 9% yield. LCMS: Method A, 1.84 min, MS: ES+388.2;1H NMR (500 MHz, DMSO) δ ppm: 10.31 (s, 1H), 8.72 (s, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.72 – 7.69 (m, 2H), 7.34 – 7.17 (m, 2H), 7.02 – 6.89 (m, 2H), 3.75 (d, J = 6.5 Hz, 2H), 2.08 – 1.95 (m, 1H), 1.00 (d, J = 6.6 Hz, 6H). Example 9 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)benzamide Using 4-(bromomethyl)tetrahydro-2H-pyran (CAS 125552-89-8, Fluorochem) in place of 4- (2-bromoethyl)tetrahydro-2H-pyran. After purification by preparative HPLC (Prep Method A, x=30, y=60) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-((tetrahydro-2H- pyran-4-yl)methoxy)phenyl)benzamide in 15% yield. LCMS: Method A, 1.57 min, MS: ES+430.2;1H NMR (500 MHz, DMSO) δ ppm: 10.32 (s, 1H), 8.73 (s, 1H), 8.54 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.76 – 7.67 (m, 2H), 7.00 – 6.88 (m, 2H), 3.92 – 3.79 (m, 3H), 2.07 – 1.95 (m, 2H), 1.75 – 1.63 (m, 2H), 1.41 – 1.27 (m, 2H).4 H were obscured / not observed. Example 10 4-(3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)benzamido)phenyl 3-methylbutanoate Using 3-methylbutanoyl chloride (CAS 108-12-3, Merck) in place of 4-(2- bromoethyl)tetrahydro-2H-pyran. After purification by preparative HPLC (Prep Method A, x=35, y=65) was obtained 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamido)phenyl 3- methylbutanoate in 15% yield. LCMS: Method A, 1.77 min, MS: ES+416.3;1H NMR (500 MHz, DMSO) δ ppm: 10.50 (s, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.87 – 7.81 (m, 2H), 7.67 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 8.9 Hz, 2H), 2.47 (d, J = 7.1 Hz, 2H), 2.20 – 2.07 (m, 1H), 1.02 (d, J = 6.7 Hz, 6H).1 H was obscured / not observed. Example 11 4-(3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)benzamido)phenyl morpholine-4-sulfonate Using morpholine-4-sulfonyl chloride (CAS 1828-66-6, BLD) in place of 4-(2- bromoethyl)tetrahydro-2H-pyran. After purification by preparative HPLC (Prep Method A, x=30, y=60) was obtained 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamido)phenyl morpholine-4-sulfonate in 29% yield. LCMS: Method A, 1.56 min, MS: ES+481.2;1H NMR (500 MHz, DMSO) δ ppm: 10.61 (s, 1H), 8.75 (s, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.29 – 8.20 (m, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.92 (d, J = 9.0 Hz, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 9.0 Hz, 2H), 3.77 – 3.59 (m, 4H).6 H were obscured / not observed. Example 12 4-(3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)benzamido)phenyl isobutyl carbonate Using isobutyl chloroformate (CAS 543-27-1, Merck) in place of 4-(2-bromoethyl)tetrahydro- 2H-pyran. After purification by preparative HPLC (Prep Method A, x=25, y=55) was obtained 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamido)phenyl isobutyl carbonate in 29% yield. LCMS: Method A, 1.79 min, MS: ES+432.2;1H NMR (500 MHz, DMSO) δ ppm: 10.53 (s, 1H), 8.74 (s, 1H), 8.58 (d, J = 8.7 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 9.0 Hz, 2H), 7.72 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 9.0 Hz, 2H), 4.01 (d, J = 6.6 Hz, 2H), 1.98 (dt, J = 13.4, 6.7 Hz, 1H), 0.95 (d, J = 6.8 Hz, 6H).1 H was obscured / not observed. Example 13 4-(3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)benzamido)phenyl benzenesulfonate Using benzenesulfonyl chloride (CAS 98-09-9, Merck) in place of 4-(2- bromoethyl)tetrahydro-2H-pyran. After purification by preparative HPLC (Prep Method A, x=35, y=65) was obtained 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamido)phenyl benzenesulfonate in 44% yield. LCMS: Method A, 1.73 min, MS: ES+472.1;1H NMR (500 MHz, DMSO) δ ppm: 10.56 (s, 1H), 8.72 (s, 1H), 8.59 (d, J = 8.7 Hz, 1H), 8.42 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.89 – 7.82 (m, 2H), 7.82 – 7.76 (m, 2H), 7.76 – 7.66 (m, 3H), 7.08 – 7.00 (m, 2H).2 H were obscured / not observed. Example 14 Isopropyl 2-(4-(3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)benzamido)phenoxy)acetate Using isopropyl 2-chloroacetate (CAS 105-48-6, Alfa) in place of 4-(2- bromoethyl)tetrahydro-2H-pyran. After purification by preparative HPLC (Prep Method A, x=30, y=60) was obtained isopropyl 2-(4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)benzamido)phenoxy)acetate in 46% yield. LCMS: Method A, 1.61 min, MS: ES+432.2;1H NMR (500 MHz, DMSO) δ ppm: 10.35 (s, 1H), 8.73 (d, J = 1.9 Hz, 1H), 8.59 (d, J = 8.7 Hz, 1H), 8.44 – 8.34 (m, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.76 – 7.64 (m, 3H), 7.00 – 6.90 (m, 2H), 5.09 – 4.95 (m, 1H), 4.74 (s, 2H), 1.23 (d, J = 6.3 Hz, 6H).1 H was obscured / not observed. Example 15 N-(4-(2-(1H-Pyrazol-4-yl)ethoxy)phenyl)-3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide Using 4-(2-chloroethyl)-1H-pyrazole (CAS 438475-37-7, BLD) in place of 4-(2- bromoethyl)tetrahydro-2H-pyran and with NaI (0.1 eq.). After purification by preparative HPLC (Prep Method A, x=25, y=55) was obtained N-(4-(2-(1H-pyrazol-4-yl)ethoxy)phenyl)- 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide in 16% yield. LCMS: Method A, 1.47 min, MS: ES+426.1;1H NMR (500 MHz, DMSO) δ ppm: 10.33 (s, 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.40 (d, J = 7.7 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.77 – 7.64 (m, 3H), 7.48 (s, 1H), 6.94 (d, J = 9.0 Hz, 2H), 6.26 (t, J = 2.1 Hz, 1H), 4.50 (t, J = 5.3 Hz, 2H), 4.34 (t, J = 5.3 Hz, 2H).1 H was obscured / not observed. Example 16 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-isopropoxyphenyl)benzamide Using 2-iodopropane (CAS 75-30-9, Merck) in place of 4-(2-bromoethyl)tetrahydro-2H- pyran and with NaI (0.1 eq.). After purification by preparative HPLC (Prep Method A, x=30, y=60) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- isopropoxyphenyl)benzamide in 43% yield. LCMS: Method A, 1.62 min, MS: ES+374.2;1H NMR (500 MHz, DMSO) δ ppm: 10.31 (s, 1H), 8.73 (s, 1H), 8.58 (d, J = 8.7 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.77 – 7.62 (m, 3H), 7.01 – 6.90 (m, 2H), 4.67 – 4.50 (m, 1H), 1.28 (d, J = 6.0 Hz, 6H).1 H was obscured / not observed. Example 17 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(4-chloro-3- (hydroxymethyl)butoxy)phenyl)benzamide Following the procedure of Example 1, using 2-(oxetan-3-yl)ethan-1-ol (CAS 251922-46-0, BLD) in place of (1-phenylpiperidin-4-yl)methanol. Intermediates were used without analysis. After purification by preparative HPLC (Prep Method A, x=25, y=55) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(4-chloro-3- (hydroxymethyl)butoxy)phenyl)benzamide in 15% yield. LCMS: Method A, 1.53 min, MS: ES+452.2 / 454.1;1H NMR (500 MHz, DMSO) δ ppm: 10.32 (s, 1H), 8.73 (d, J = 1.9 Hz, 1H), 8.55 (d, J = 8.7 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.74 – 7.67 (m, 3H), 6.97 (d, J = 9.0 Hz, 2H), 4.73 (t, J = 5.2 Hz, 1H), 4.06 (t, J = 6.6 Hz, 2H), 3.85 – 3.65 (m, 2H), 3.56 – 3.41 (m, 2H), 2.07 – 1.98 (m, 1H), 1.79 (q, J = 6.6 Hz, 2H).1 H was obscured / not observed. Example 18 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(2-(oxetan-3-yl)ethoxy)phenyl)benzamide The procedure of Example 1 was followed, using 2-(oxetan-3-yl)ethan-1-ol (CAS 251922- 46-0, BLD) in place of (1-phenylpiperidin-4-yl)methanol. Intermediates were used without analysis. After treatment with TFA (1 eq.) in place of HCl, and purification by preparative HPLC (Prep Method A, x=25, y=55) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N- (4-(2-(oxetan-3-yl)ethoxy)phenyl)benzamide in 16% yield. LCMS: Method A, 1.48 min, MS: ES+416.2;1H NMR (500 MHz, DMSO) δ ppm: 10.32 (s, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.60 (s, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.82 – 7.58 (m, 3H), 7.02 – 6.85 (m, 2H), 4.79 – 4.62 (m, 2H), 4.45 – 4.29 (m, 2H), 4.05 – 3.88 (m, 2H), 3.22 – 3.08 (m, 1H), 2.16 – 1.98 (m, 2H).1 H was obscured / not observed. Example 19 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(1-phenethyl-1H-pyrazol-4-yl)benzamide Step 1: N-(1H-pyrazol-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide A solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 269409-73-6, BLD, 1.49 g, 6.02 mmol), 1H-pyrazol-4-amine (CAS 69843-13-6, Fluorochem, 600 mg, 7.22 mmol) and DIPEA (4.19 mL, 24.1 mmol) in DMF (2 mL) was stirred for 10 min. HATU (2.29 g, 6.02 mmol) was added to the solution and stirred for 16 h at rt. Water (120 mL) was added and the product was extracted into EtOAc (3 x 60 mL), washed with brine (60 mL) dried over Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0 - 10% (0.7 M ammonia in MeOH in DCM) afforded N-(1H- pyrazol-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (280 mg, 15%). LCMS: Method B:^1.51 min, MS: ES+314.2. Step 2: N-(1H-pyrazol-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide A mixture of 5-bromo-1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine (+ isomers; I-2, 478 mg, 0.76 mmol), N-(1H-pyrazol-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (250 mg, 0.76 mmol) and Cs2CO3(988 mg, 3.03 mmol) in dioxane (4 mL) and water (1 mL), was purged with nitrogen for 5 min. Pd-118 (99 mg, 0.15 mmol) was added, the mixture purged for a further 2 min and then stirred at 80 °C for 2 h. The reaction mixture was filtered through Celite®(washing with EtOAc). The filtrate was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0 - 10% (0.7 M ammonia in MeOH in DCM) afforded N-(1H-pyrazol-4-yl)-3-(1-trityl-1H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide with a mixture of isomers (272 mg, 65%). LCMS: Method A: 1.97 / 1.99 / 2.10 min, MS: ES- 546.2. A solution of N-(1H-pyrazol-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide (+ isomers; 61 mg, 0.11 mmol), (2-bromoethyl)benzene (CAS 103-63-9 / Combi-Blocks, 0.017 mL, 0.12 mmol) and K2CO3(31 mg, 0.22 mmol) in THF (2 mL) was stirred at 50 °C for 6 d. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0 - 80% EtOAc in isohexane) afforded N-(1-phenethyl-1H-pyrazol-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)benzamide with a mixture of isomers (65 mg, 81%). LCMS: Method A: 1.99 / 2.32 / 2.45 min, MS: ES- 650.2. A solution of N-(1-phenethyl-1H-pyrazol-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)benzamide (+ isomers; 62 mg, 0.10 mmol) and aq. HCl (2M, 0.24 mL, 0.48 mmol) in dioxane (1 mL) was stirred for 16 h at rt. The reaction mixture was concentrated under reduced pressure and purified by RP chromatography (C18, 0 – 100% MeCN in 0.1% aq. HCO2H) to afford 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(1-phenethyl-1H-pyrazol-4- yl)benzamide (27 mg, 69%). LCMS: Method A: 1.55 min, MS: ES+410.2;1H NMR (500 MHz, DMSO) δ ppm: 10.60 (s, 1H), 8.73 (s, 1H), 8.65 – 8.53 (m, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.26 – 8.12 (m, 1H), 8.10 – 8.00 (m, 2H), 7.70 (t, J = 7.9 Hz, 1H), 7.66 (s, 1H), 7.33 – 7.25 (m, 2H), 7.27 – 7.16 (m, 3H), 4.36 (t, J = 7.3 Hz, 2H), 3.12 (t, J = 7.4 Hz, 2H).1 H was obscured / not observed. Example 20 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(1-(3-phenylpropyl)-1H-pyrazol-4-yl)benzamide A solution of 4-nitro-1H-pyrazole (CAS 2075-46-9, Fluorochem, 200 mg, 1.77 mmol), (3- bromopropyl)benzene (CAS 637-59-2, Fluorochem, 0.54 mL, 3.54 mmol) and Cs2CO3(1015 mg, 3.54 mmol) in DMF (2 mL) was stirred at 60 °C for 16 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0-80% EtOAc in isohexane) afforded 4-nitro-1-(3- phenylpropyl)-1H-pyrazole (387 mg, 94%). LCMS: Method A: 1.71 min, MS: ES+232.2. Step 2: 1-(3-phenylpropyl)-1H-pyrazol-4-amine A solution of 4-nitro-1-(3-phenylpropyl)-1H-pyrazole (200 mg, 0.87 mmol) in MeOH (25 mL) was passed 3 times through a 10% Pd / C cartridge under hydrogen at 30 °C, at 1 bar (H- Cube®) The mixture was concentrated under reduced pressure to give 1-(3-phenylpropyl)- 1H-pyrazol-4-amine (174 mg, 98%). LCMS: Method A: 0.45 min, MS: ES+202.2. Step 3: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(1-(3-phenylpropyl)-1H-pyrazol-4- yl)benzamide (Example 20) To 1-(3-phenylpropyl)-1H-pyrazol-4-amine (84 mg, 0.42 mmol), DIPEA (0.15 mL, 0.83 mmol) and 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoic acid (I-12, 50 mg, 0.21 mmol) in DMF (1 mL) was added HATU (119 mg, 0.31 mmol). The mixture was stirred for 16 h and purification by preparative HPLC (Prep Method A, x=30, y=60) afforded 3-(1H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(1-(3-phenylpropyl)-1H-pyrazol-4-yl)benzamide (47 mg, 53%). LCMS: Method A: 1.64 min, MS: ES+424.2;1H NMR (500 MHz, DMSO) δ ppm: 10.64 (s, 1H), 8.75 (s, 1H), 8.59 (d, J = 8.6 Hz, 1H), 8.44 – 8.33 (m, 1H), 8.20 (d, J = 8.6 Hz, 1H), 8.13 (s, 1H), 8.09 – 8.04 (m, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.34 – 7.26 (m, 2H), 7.26 – 7.16 (m, 3H), 4.13 (t, J = 6.9 Hz, 2H), 2.57 (t, J = 7.7 Hz, 2H), 2.16 – 2.02 (m, 2H).1 H was obscured / not observed. Example 21 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(2-cyclohexylethyl)benzamide To a solution of 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoic acid (I-12, 30 mg, 0.13 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF (0.40 mL) was added HATU (48 mg, 0.20 mmol) and the mixture was stirred for 30 min at rt.2-Cyclohexylethan-1-amine (CAS 4442- 85-7, BLD, 0.03 mL, 0.23 mmol) was added and the mixture stirred at rt for 18 h. Purification by preparative HPLC (Prep Method A, x=35, y=65) afforded 3-(1H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-cyclohexylethyl)benzamide (23 mg, 53%). LCMS: Method A: 1.74 min, MS: ES+350.2;1H NMR (500 MHz, DMSO) δ ppm: 8.65 – 8.59 (m, 2H), 8.57 (d, J = 8.7 Hz, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 3.36 – 3.32 (m, 2H), 1.79 – 1.71 (m, 2H), 1.70 – 1.64 (m, 2H), 1.64 – 1.58 (m, 1H), 1.47 (q, J = 7.1 Hz, 2H), 1.38 – 1.30 (m, 1H), 1.24 – 1.12 (m, 3H), 0.97 – 0.87 (m, 2H).1 H was obscured / not observed. Example 22 3-(1H-[1,2,3]Triazolo[4,5-b]pyrazin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)benzamide stirred at 50 °C for 16 h. Purification by preparative HPLC (Prep Method A, x=30, y=60) afforded 3-(1H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)benzamide (7 mg, 7%). LCMS: Method A: 1.82 min, MS: ES+437.2;1H NMR (500 MHz, DMSO) δ ppm: 10.48 (s, 1H), 9.51 (s, 1H), 8.81 (d, J = 1.8 Hz, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.92 – 7.70 (m, 3H), 7.49 – 7.26 (m, 7H), 4.55 (s, 2H), 4.53 (s, 2H).1 H was obscured / not observed. General procedure (T3P amide coupling) Following the procedure of Example 22, substituting 4-((benzyloxy)methyl)aniline with the appropriate starting material (1-2 eq) at rt - 50 °C for 16 - 72 h, and with any minor modifications noted, the following Examples 23-25 were obtained: Example 23 3-(1H-[1,2,3]Triazolo[4,5-b]pyrazin-5-yl)-N-(4-(cyclopropoxymethyl)phenyl)benzamide Using 4-(cyclopropoxymethyl)aniline (I-22) in place of 4-((benzyloxy)methyl)aniline and purification by preparative HPLC (Prep Method A, x=20, y=50) was obtained 3-(1H- [1,2,3]triazolo[4,5-b]pyrazin-5-yl)-N-(4-(cyclopropoxymethyl)phenyl)benzamide in 10% yield. LCMS: Method A: 1.61 min, MS: ES+387.2;1H NMR (500 MHz, DMSO) δ ppm: 10.47 (s, 1H), 9.51 (s, 1H), 8.81 (d, J = 1.8 Hz, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.84 – 7.67 (m, 3H), 7.34 (d, J = 8.2 Hz, 2H), 4.48 (s, 2H), 0.63 – 0.41 (m, 4H).2 H obscured / not observed. Example 24 3-(1H-[1,2,3]Triazolo[4,5-b]pyrazin-5-yl)-N-(4-(cyclopropylmethoxy)phenyl)benzamide Using 4-(cyclopropylmethoxy)aniline (I-23) in place of 4-((benzyloxy)methyl)aniline, purification by preparative HPLC (Prep Method A, x=20, y=50) was obtained 3-(1H- [1,2,3]triazolo[4,5-b]pyrazin-5-yl)-N-(4-(cyclopropylmethoxy)phenyl)benzamide in 6% yield. LCMS: Method A: 1.67 min, MS: ES+387.1; 1H NMR (500 MHz, DMSO) δ 10.31 (s, 1H), 9.37 (s, 1H), 8.77 (s, 1H), 8.42 (d, J = 7.7 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.76 – 7.64 (m, 3H), 6.95 (d, J = 8.6 Hz, 2H), 3.82 (d, J = 7.0 Hz, 2H), 1.26 – 1.20 (m, 1H), 0.62 – 0.51 (m, 2H), 0.37 – 0.28 (m, 2H).1 H obscured / not observed. Example 25 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-methoxyphenyl)benzamide Using 4-methoxyaniline (CAS 104-94-9, Acros Organics) in place of 4- ((benzyloxy)methyl)aniline, purification by preparative HPLC (Prep Method A, x=20, y=50) was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-methoxyphenyl)benzamide in 35% yield. LCMS: Method A: 1.43 min, MS: ES+346.2;1H NMR (500 MHz, DMSO) δ ppm: 10.32 (s, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.58 (d, J = 8.7 Hz, 1H), 8.41 – 8.37 (m, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.75 – 7.67 (m, 3H), 6.98 – 6.93 (m, 2H), 3.76 (s, 3H).1 H obscured / not observed. General procedure (HATU amide coupling) Following the procedure of Example 21, substituting the 2-cyclohexylethan-1-amine with the appropriate starting material (1.2 - 2 eq), and DIPEA (3 - 4 eq), stirring / shaking at rt - 40 °C for 5 - 24 h, and with any minor modifications noted, the following Examples 26-34 were obtained: Example 26 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(2-cyclopentylethyl)benzamide Using 2-cyclopentylethan-1-amine (CAS 5763-55-3, Combi-Blocks) in place of 2- cyclohexylethan-1-amine, purification by preparative HPLC (Prep Method A, x=30, y=60) was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-cyclopentylethyl)benzamide in 17% yield. LCMS: Method A: 1.64 min, MS: ES+336.2;1H NMR (500 MHz, DMSO) δ ppm: 8.66 – 8.62 (m, 2H), 8.58 (d, J = 8.7 Hz, 1H), 8.35 – 8.31 (m, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.98 – 7.93 (m, 1H), 7.64 (t, J = 7.7 Hz, 1H), 3.33 (d, J = 6.5 Hz, 2H), 1.85 – 1.76 (m, 3H), 1.58 (q, J = 7.2 Hz, 4H), 1.49 (m, 2H), 1.13 (q, J = 9.1 Hz, 2H).1 H obscured / not observed. Example 27 Tert-butyl 4-(2-(3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamido)ethyl)piperidine-1- carboxylate Using tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (CAS 146093-46-1, Fluorochem) in place of 2-cyclohexylethan-1-amine, purification by preparative HPLC (Prep Method A, x=30, y=60) was obtained tert-butyl 4-(2-(3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)benzamido)ethyl)piperidine-1-carboxylate in 24% yield. LCMS: Method A: 1.65 min, MS: ES+351.2 (M-Boc)+;1H NMR (500 MHz, DMSO) δ ppm: 8.66 – 8.60 (m, 2H), 8.55 (d, J = 8.7 Hz, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 3.92 (d, J = 12.8 Hz, 2H), 2.69 (s, 2H), 1.70 (d, J = 12.8 Hz, 2H), 1.51 (t, J = 5.6 Hz, 4H), 1.39 (s, 9H), 1.02 (t, J = 11.3 Hz, 2H).2 H obscured / not observed. Example 28 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-(p-tolyloxy)ethyl)benzamide Using 2-(p-tolyloxy)ethan-1-amine (CAS 26583-58-4, Apollo) in DMA in place of 2- cyclohexylethan-1-amine, purification by preparative HPLC (Prep Method C, x=10, y=40) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-(p-tolyloxy)ethyl)benzamide in 29% yield. LCMS: Method S, 0.79 min, MS: ES+374.3;1H NMR (500 MHz, DMSO) δ 8.90 (t, J = 5.5 Hz, 1H), 8.65 (s, 1H), 8.49 (d, J = 8.6 Hz, 1H), 8.33 (d, J = 7.9 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.08 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.1 Hz, 2H), 4.11 (t, J = 6.0 Hz, 2H), 3.71 – 3.62 (m, 2H), 2.22 (s, 3H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 29 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(2-((4-chlorophenyl)thio)ethyl)benzamide Using 2-((4-chlorophenyl)thio)ethan-1-amine (CAS 36155-35-8, Apollo) in DMA in place of 2-cyclohexylethan-1-amine, purification by preparative HPLC (Prep Method C, x=10, y=40) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-((4- chlorophenyl)thio)ethyl)benzamide in 26% yield. LCMS: Method S, 0.86 min, MS: ES+410.2;1H NMR (500 MHz, DMSO) δ 8.91 (t, J = 5.6 Hz, 1H), 8.61 (s, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.33 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 3.52 (q, J = 6.6 Hz, 2H), 3.21 (t, J = 7.1 Hz, 2H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 30 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzamide Using 5-phenyl-1,3,4-thiadiazol-2-amine (CAS 2002-03-1, Combi-Blocks) in DMA in place of 2-cyclohexylethan-1-amine, purification by preparative HPLC (Prep Method C, x=5, y=30) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(5-phenyl-1,3,4-thiadiazol-2- yl)benzamide in 6% yield. LCMS: Method S, 0.53 min, MS: ES+400.3.1H NMR (500 MHz, DMSO) δ 9.02 (s, 1H), 8.86 (s, 1H), 8.54 (d, J = 8.6 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 7.7 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.96 (d, J = 7.6 Hz, 2H), 7.69 (t, J = 7.8 Hz, 1H), 7.56 – 7.46 (m, 3H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 31 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-((3-phenylisoxazol-5-yl)methyl)benzamide Using (3-phenylisoxazol-5-yl)methanamine (CAS 54408-35-4, BLD) in DMA in place of 2- cyclohexylethan-1-amine, purification by preparative HPLC (Prep Method C, x=10, y=40) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-((3-phenylisoxazol-5- yl)methyl)benzamide in 24% yield. LCMS: Method S, 0.77 min, MS: ES+397.2;1H NMR (500 MHz, DMSO) δ 9.44 (t, J = 5.8 Hz, 1H), 8.72 (s, 1H), 8.53 (d, J = 8.7 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.92 – 7.86 (m, 2H), 7.68 (t, J = 7.9 Hz, 1H), 7.50 – 7.46 (m, 3H), 6.99 (s, 1H), 4.72 (d, J = 5.7 Hz, 2H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 32 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(2-methoxy-5- (trifluoromethoxy)phenyl)benzamide Using 2-methoxy-5-(trifluoromethoxy)aniline (CAS 660848-57-7, BLD) in DMA in place of 2- cyclohexylethan-1-amine, purification by preparative HPLC (Prep Method C, x=15, y=45) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-methoxy-5- (trifluoromethoxy)phenyl)benzamide in 4% yield. LCMS: Method S, 0.94 min, MS: ES+430.2. The isolated compound contains up to 1 mol. eq. of ammonia. Example 33 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-methyl-3-(trifluoromethyl)phenyl)benzamide Using 4-methyl-3-(trifluoromethyl)aniline (CAS 65934-74-9, BLD) in DMA in place of 2- cyclohexylethan-1-amine, purification by preparative HPLC (Prep Method C, x=15, y=45) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-methyl-3- (trifluoromethyl)phenyl)benzamide in 26% yield. LCMS: Method S, 0.94 min, MS: ES+398.2;1H NMR (500 MHz, DMSO) δ ppm: 10.65 (s, 1H), 8.76 (t, J = 1.9 Hz, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.45 – 8.39 (m, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.10 – 8.05 (m, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 2.43 (d, J = 2.0 Hz, 3H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 34 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(1-(2-fluorobenzyl)-1H-pyrazol-4-yl)benzamide Using 1-(2-fluorobenzyl)-1H-pyrazol-4-amine (CAS 925634-52-2, Manchester Organics) in DMA in place of 2-cyclohexylethan-1-amine, purification by preparative HPLC (Prep Method C, x=10, y=40) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(1-(2-fluorobenzyl)- 1H-pyrazol-4-yl)benzamide in 20% yield. LCMS: Method S, 0.76 min, MS: ES+414.3;1H NMR (500 MHz, DMSO) δ ppm: 10.66 (s, 1H), 8.73 (s, 1H), 8.54 (d, J = 8.7 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.19 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.72 – 7.67 (m, 1H), 7.39 (s, 1H), 7.39 – 7.32 (m, 1H), 7.28 – 7.10 (m, 3H), 5.40 (s, 2H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 35 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-5-(methylsulfonyl)-N-(4- phenethoxyphenyl)benzamide 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-5-(methylsulfonyl)-N-(4-phenethoxyphenyl- )benzamide To 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-(methylthio)-N-(4- phenethoxyphenyl)benzamide (E-46, 72 mg, 0.15 mmol) in DCM (5 mL) was added mCPBA (70%, 57 mg, 0.23 mmol). The mixture was stirred for 1 h then diluted with DCM (10 mL) and washed with aq. Na2S2O3(10%, 10 mL), sat. aq. NaHCO3(10 mL) and water (10 mL). The organic phase was dried over Na2SO4and concentrated under reduced pressure. Purification by chromatography (silica gel, 0-100% THF in DCM) and preparative HPLC (Prep Method A, x=35, y=65) afforded 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5- (methylsulfonyl)-N-(4-phenethoxyphenyl)benzamide (3 mg, 4%). LCMS: Method A, 1.30 min, MS: ES+514.0;1H NMR (500 MHz, DMSO) δ ppm: 10.57 (s, 1H), 9.04 (s, 1H), 8.89 (s, 1H), 8.77 (s, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 7.69 (d, J = 8.9 Hz, 2H), 7.41 – 7.29 (m, 4H), 7.29 – 7.14 (m, 1H), 6.99 (d, J = 9.1 Hz, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.39 (s, 3H), 3.05 (t, J = 6.9 Hz, 2H).1 H obscured / not observed. Example 36 3-(1H-[1,2,3]Triazolo[4,5-d]pyrimidin-5-yl)-N-(4-phenethoxyphenyl)benzamide 3-(1H-[1,2,3]Triazolo[4,5-d]pyrimidin-5-yl)-N-(4-phenethoxyphenyl)benzamide To a solution of 3-(4,5-diaminopyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide (I-9, 100 mg, 0.21 mmol) in THF (4 mL) was added AcOH (0.16 mL, 2.8 mmol) and iPnONO (0.05 mL, 0.34 mmol). The mixture was stirred at 65 °C for 2 h and concentrated under reduced pressure. Purification by chromatography (silica gel, 0-100% THF in DCM) followed by preparative HPLC (Prep Method A, x=40, y=70) afforded 3-(1H-[1,2,3]triazolo[4,5- d]pyrimidin-5-yl)-N-(4-phenethoxyphenyl)benzamide (15 mg, 16%). LCMS: Method A: 1.91 min, MS: ES+437.2; 1H NMR (500 MHz, DMSO) δ ppm: 10.37 (s, 1H), 9.83 (s, 1H), 9.06 (s, 1H), 8.69 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.76 – 7.68 (m, 3H), 7.38 – 7.30 (m, 4H), 7.28 – 7.21 (m, 1H), 6.96 (d, J = 9.0 Hz, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H).1 H was obscured / not observed. Example 37 3-(1H-[1,2,3]Triazolo[4,5-b]pyrazin-5-yl)-N-(4-phenethoxyphenyl)benzamide To 3-(5,6-diaminopyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (I-10, 177 mg, 0.37 mmol) in THF (5 mL) was added AcOH (0.03 mL, 0.49 mmol) and iPnONO (0.08 mL, 0.60 mmol). The mixture was stirred at 65 °C for 1 h and concentrated under reduced pressure. The residue was purified by RP chromatography (C18, 0 - 100% MeCN in 0.1% aq. NH4OH)), and trituration with EtOAc. Further purification by RP chromatography (C18, 0 - 100% MeCN then 0 – 100% THF in 0.1% aq. HCO2H) and trituration with EtOAc afforded 3- (1H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-N-(4-phenethoxyphenyl)benzamide (43 mg, 26%). LCMS: Method A: 1.87 min, MS: ES+437.2;1H NMR (500 MHz, DMSO) δ ppm: 10.33 (s, 1H), 9.56 (s, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.7 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.72 – 7.65 (m, 2H), 7.37 – 7.29 (m, 4H), 7.27 – 7.21 (m, 1H), 6.99 – 6.92 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H).1 H was obscured / not observed. Example 38 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-6-yl)-N-(4-phenethoxyphenyl)benzamide A mixture of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-6, 100 mg, 0.23 mol), 6-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-16, 36 mg, 0.18 mmol) and Cs2CO3(176 mg, 0.54 mmol) in dioxane (9 mL) and water (1 mL) was purged with nitrogen for 10 min. Pd-118 (23 mg, 0.04 mmol) was added, purged for a further 10 min and stirred at 80 °C for 3h. The mixture was cooled to rt, filtered through Celite®and concentrated under reduced pressure. Purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded 3- (1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(4-phenethoxyphenyl)benzamide (17 mg, 21%). LCMS: Method B: 1.27 min, MS: ES+436.2;1H NMR (500 MHz, DMSO) δ ppm: 10.23 (s, 1H), 8.98 – 8.94 (m, 1H), 8.64 – 8.60 (m, 1H), 8.36 (s, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.72 – 7.63 (m, 3H), 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), 3.05 (t, J = 6.9 Hz, 2H).1 H was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 39 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-6-yl)-N-(4-phenethoxyphenyl)benzamide A mixture of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-6, 100 mg, 0.23 mmol), 5-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1, 36 mg, 0.18 mmol) and Cs2CO3(176 mg, 0.54 mmol) in dioxane (9 mL) and water (1 mL) was purged with nitrogen for 10 min. Pd-118 (24 mg, 0.04 mmol) was added, then purged for a further 10 min before being heated to 80 °C for 3 h. The mixture was cooled to rt, filtered through Celite®and concentrated under reduced pressure. Purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded 3-(1H- [1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(4-phenethoxyphenyl)benzamide (17 mg, 21%). LCMS: Method B: 1.28 min, MS: ES+436.2;1H NMR (500 MHz, DMSO) δ ppm: 10.32 (s, 1H), 8.74 – 8.70 (m, 1H), 8.51 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 7.9 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.73 – 7.66 (m, 3H), 7.38 – 7.29 (m, 4H), 7.24 (t, J = 6.9 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 6.8 Hz, 2H).1 H was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 40 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(benzyloxy)phenyl)benzamide

[0053] Step 1: N-(4-(benzyloxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 269409-73-6, BLD, 324 mg, 1.30 mmol), DIPEA (0.7 mL, 4.02 mmol) and HATU (401 mg, 1.05 mmol) in DCM (5 mL) was stirred at rt for 30 min and then 4-(benzyloxy)aniline (CAS 6373-46- 2 / Fluorochem, 200 mg, 1.00 mmol) was added. The mixture was stirred at 35 °C for 18 h, cooled to rt and poured into ice-water (200 mL), and extracted with EtOAc (3 x 80 mL). The combined organic phases were combined, washed with brine (1 x 50 mL), dried (MgSO4) and the filtrate adsorbed onto silica gel. Purification by chromatography (silica gel, 0 - 30% EtOAc in isohexane) afforded N-(4-(benzyloxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (340 mg, 54%). LCMS: Method A: 2.21 min, MS: ES+430.2. Step 2: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(benzyloxy)phenyl)benzamide (Example 40) A mixture of 5-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1, 60 mg, 0.30 mmol), (3-((4- (benzyloxy)phenyl)carbamoyl)phenyl)boronic acid (113 mg, 0.30 mmol) and Cs2CO3(393 mg, 1.21 mmol) in dioxane (4 mL) and water (1.5 mL) was purged with nitrogen for 5 min, after which Pd-118 (39 mg, 0.06 mmol) was added. The mixture was stirred at 90 °C for 18 h and concentrated under reduced pressure, then diluted with EtOAc (30 mL) and washed with water (5 mL). The organic phase was dried over MgSO4and concentrated under reduced pressure. Purification by RP chromatography (C18, 0 - 100% MeCN in 0.1% aq. NH4OH afforded 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(benzyloxy)phenyl)benzamide (10 mg, 8%). LCMS: Method A: 1.79 min, MS: ES+422.2;1H NMR (500 MHz, DMSO) δ ppm: 10.33 (s, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 8.7 Hz, 1H), 8.41 – 8.37 (m, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.74 – 7.69 (m, 3H), 7.47 (d, J = 7.1 Hz, 2H), 7.43 – 7.38 (m, 2H), 7.37 – 7.33 (m, 1H), 7.07 – 7.01 (m, 2H), 5.11 (s, 2H).1 H was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 41 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)benzamide A mixture of 5-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1, 79 mg, 0.40 mmol), N-(4- ((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-8, 176 mg, 0.40 mmol) and Cs2CO3(517 mg, 1.59 mmol) in dioxane (4 mL) and water (1 mL) was purged with nitrogen for 5 min and Pd-118 (52 mg, 0.08 mmol) was added. The mixture was purged for a further 2 min then stirred at 90 °C for 18 h. The reaction was cooled to rt, acidified with aq. HCl (1M, 5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over Na2SO4,and concentrated under reduced pressure. Purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq. NH4OH) afforded 3- (1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)benzamide (35 mg, 19%). LCMS: Method B: 1.81 min, MS: ES+436.2;1H NMR (500 MHz, DMSO) δ ppm: 10.48 (s, 1H), 8.77 – 8.73 (m, 1H), 8.58 (d, J = 8.7 Hz, 1H), 8.44 – 8.38 (m, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.10 – 8.05 (m, 1H), 7.84 – 7.79 (m, 2H), 7.72 (t, J = 7.8 Hz, 1H), 7.42 – 7.35 (m, 6H), 7.38 – 7.27 (m, 1H), 4.55 (s, 2H), 4.53 (s, 2H).1 H was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 42 5-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-phenethoxyphenyl)nicotinamide Step 1: methyl 5,6-diamino-[2,3'-bipyridine]-5'-carboxylate

[0054] A mixture of 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD, 200 mg, 1.06 mmol), (5-(methoxycarbonyl)pyridin-3-yl)boronic acid (CAS 871329-53-2, BLD, 250 mg, 1.38 mmol) and Cs2CO3(866 mg, 2.66 mmol) in dioxane (9 mL) and water (1 mL) was purged with nitrogen, then Pd-118 (69 mg, 0.11 mmol) was added. The reaction mixture was stirred under nitrogen at 75 °C for 18 h. The mixture was filtered through Celite®and then adsorbed onto Celite®. Purification by chromatography (silica gel, 0-10% (0.7 M ammonia in MeOH) in DCM) afforded methyl 5,6-diamino-[2,3'-bipyridine]-5'-carboxylate (232 mg, 89%). LCMS: Method A: 0.26 min, MS: ES+245.2. Step 2: methyl 5-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)nicotinate To methyl 5,6-diamino-[2,3'-bipyridine]-5'-carboxylate (120 mg, 0.48 mmol) in THF (5 mL) was added AcOH (0.37 mL, 6.38 mmol) and iPnONO (0.10 mL, 0.76 mmol). The reaction mixture was stirred at 60 °C for 18 h and concentrated under reduced pressure to afford methyl 5-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)nicotinate, used without purification in the next step. LCMS: Method Q: 0.74 min, MS: ES+256.0. Step 3: lithium 5-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)nicotinate To methyl 5-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)nicotinate (160 mg, 0.48 mmol) in THF (8 mL) was added aq. LiOH (1M, 1.43 mL, 1.43 mmol) and MeOH (0.10 mL). The mixture was

[0055] 197 stirred at rt for 1 h and concentrated under reduced pressure to afford 5-(1H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)nicotinic acid, used without purification in the next step. LCMS: Method Q: 0.53 min, MS: ES+242.0. Step 4: 5-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-phenethoxyphenyl)nicotinamide (Example 42) To lithium 5-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)nicotinate (59 mg, 0.24 mmol) and 4- phenethoxyaniline (I-5, 87 mg, 0.29 mmol) in DMF (2 mL) was added DIPEA (0.17 mL, 0.95 mmol) and HATU (118 mg, 0.31 mmol). The mixture was stirred at rt for 18 h. Water (1 mL) was added and purification by preparative HPLC (Prep Method B, x=35, y=65) afforded 5- (1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-phenethoxyphenyl)nicotinamide (20 mg, 19% over 3 steps). LCMS: Method A: 1.73 min, MS: ES+437.2;1H NMR (500 MHz, DMSO) δ ppm: 10.49 (s, 1H), 9.53 (d, J = 2.2 Hz, 1H), 9.19 (d, J = 2.2 Hz, 1H), 9.02 (s, 1H), 8.63 (s, 1H), 8.29 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 9.0 Hz, 2H), 7.43 – 7.28 (m, 4H), 7.26 – 7.20 (m, 1H), 6.98 (d, J = 8.9 Hz, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H).1 H was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 43 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-5-(methylsulfonamido)-N-(4- phenethoxyphenyl)benzamide

[0056] Step 1: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-(methylsulfonamido)benzoic acid To methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-aminobenzoate (I-14, 100 mg, 0.18 mmol) in water (2 mL) was added MsCl (0.04 mL, 0.52 mmol). The mixture was stirred at rt for 18 h and then aq. LiOH (1 M, 0.35 mL, 0.35 mmol) was added. After 6 h, additional aq. LiOH (1M, 0.35 mL, 0.35 mmol) was added. After a further 18 h, the mixture was neutralised with aq. HCl (1M) and concentrated under reduced pressure to give 3-(1H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-(methylsulfonamido)benzoic acid, used without purification in the next step. LCMS: Method A: 0.72 min, MS: ES+334.0. Step 2: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-(methylsulfonamido)-N-(4- phenethoxyphenyl)benzamide (Example 43) To 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-(methylsulfonamido)benzoic acid (58 mg, 0.18 mmol) and 4-phenethoxyaniline (I-5, 69 mg, 0.23 mmol) in DMF (1 mL) was added DIPEA (0.12 mL, 0.70 mmol) and HATU (100 mg, 0.26 mmol). The mixture was stirred for 18 h at rt and diluted with water (0.1 mL). Purification by preparative HPLC (Prep Method A, x=35, y=65) afforded 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-(methylsulfonamido)-N-(4- phenethoxyphenyl)benzamide (2 mg, 2% over 2 steps). LCMS: Method A: 1.76 min, MS: ES+529.2;1H NMR (500 MHz, MeOD) δ ppm: 8.49 (d, J = 8.7 Hz, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.90 (s, 1H), 7.62 (d, J = 8.9 Hz, 2H), 7.37 – 7.29 (m, 5H), 7.26 – 7.20 (m, 1H), 6.97 (d, J = 8.9 Hz, 2H), 4.23 (t, J = 6.8 Hz, 2H), 3.12 (s, 3H), 3.09 – 3.05 (m, 2H).2 H were obscured / not observed. Example 44 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-5-acetamido-N-(4-phenethoxyphenyl)benzamide Step 1: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-acetamidobenzoic acid To methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-aminobenzoate (I-14, 318 mg, 0.51 mmol) in DCM (2 mL) at 0 °C was added acetic anhydride (0.19 mL, 2.03 mmol). The mixture was stirred at rt for 2 h then diluted with 9:1 DCM / MeOH (10 mL). The organic phase was washed with water (5 mL), sat. aq. NaHCO3(5 mL) and concentrated under reduced pressure. The residue was stirred in THF (3 mL) with aq. LiOH (1M, 0.51 mL, 0.51 mmol) for 1 h at rt. The mixture was acidified to pH 1-2 with aq. HCl (1M) and concentrated under reduced pressure to afford 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5- acetamidobenzoic acid, used without purification in the next step. LCMS: Method Q: 0.71 min, MS: ES+298.0. Step 2: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-acetamido-N-(4- phenethoxyphenyl)benzamide (Example 44) To 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-acetamidobenzoic acid (33 mg, 0.10 mmol) and 4-phenethoxyaniline (I-5, 34 mg, 0.13 mmol) in DMF (1 mL) was added DIPEA (0.07 mL, 0.40 mmol) and HATU (57 mg, 0.15 mmol). The mixture was stirred at rt for 18 h, then diluted with water (0.1 mL) and purified by preparative HPLC (Prep Method A, x=35, y=65) to afford 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-acetamido-N-(4- phenethoxyphenyl)benzamide (8 mg, 16% over 2 steps). LCMS: Method A: 1.74 min, MS: ES+493.2;1H NMR (500 MHz, MeOD) δ ppm: 8.57 (d, J = 3.7 Hz, 1H), 8.46 (dd, J = 8.6, 3.0 Hz, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 8.13 – 8.06 (m, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.38 – 7.29 (m, 4H), 7.26 – 7.20 (m, 1H), 6.97 (d, J = 8.9 Hz, 2H), 4.23 (t, J = 6.8 Hz, 2H), 3.10 (t, J = 6.8 Hz, 2H), 2.23 (s, 3H).3 H were obscured / not observed. Example 45 3-(7-Methyl-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-N-(4-phenethoxyphenyl)benzamide Step 1: 3-(4,5-diamino-6-methylpyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide A mixture of Cs2CO3(331 mg, 1.01 mmol), N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzamide (I-6, 150 mg, 0.34 mmol), and 2-chloro-6- methylpyrimidine-4,5-diamine (CAS 63211-98-3, BLD, 64 mg, 0.41 mmol) in dioxane (4 mL) and water (1 mL) was purged with nitrogen for 5 min and Pd-118 (44 mg, 0.07 mmol) was added. The mixture was purged for a further 2 min then stirred at 90 °C for 5 h. The reaction was cooled to rt, filtered and diluted with EtOAc (10 mL). The organic phase was washed with water (10 mL) and brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was triturated with ethyl acetate (5 mL) to give 3-(4,5-diamino-6- methylpyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide (18 mg, 86%). LCMS: Method A, 1.40 min, MS: ES+440.2. Step 2: 3-(7-methyl-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-N-(4- To 3-(4,5-diamino-6-methylpyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide (80 mg, 0.16 mmol) in THF (4 mL) was added AcOH (0.12 mL, 2.03 mmol) and iPnONO (0.033 mL, 0.25 mmol). The mixture was stirred at 65 °C for 1 h and concentrated under reduced pressure. The crude was purified by RP chromatography (C18, 0 - 100% MeCN in 0.1% aq. NH4OH)) to afford 3-(7-methyl-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-N-(4- phenethoxyphenyl)benzamide (18 mg, 24%). LCMS: Method A, 1.95 min, MS: ES+451.2;1H NMR (500 MHz, DMSO) δ ppm: 10.36 (s, 1H), 9.03 (d, J = 1.9 Hz, 1H), 8.68 (dt, J = 7.8, 1.5 Hz, 1H), 8.12 (dt, J = 7.8, 1.5 Hz, 1H), 7.75 – 7.67 (m, 3H), 7.38 – 7.30 (m, 4H), 7.29 – 7.20 (m, 1H), 7.00 – 6.93 (m, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H), 3.03 (s, 3H).1 H was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 46 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide

[0057] Step 1: 3-bromo-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide To 3-bromo-5-(methylthio)benzoic acid (CAS 453566-00-2, AChemBlock, 100 mg, 0.41 mmol) and 4-phenethoxyaniline (I-5, 116 mg, 0.45 mmol) in EtOAc (5 mL) was added DIPEA (0.21 mL, 1.21 mmol) and T3P (50% in EtOAc, 0.36 mL, 0.61 mmol). The reaction mixture was stirred at room temperature for 1 h and washed with sat. aq. NaHCO3. The organic phases were dried over Na2SO4and concentrated under reduced pressure. Purification by RP chromatography (C18, 0 - 100% (0.1 % HCO2H in MeCN) / (0.1% aq. HCO2H)) afforded 3-bromo-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide (157 mg, 88%). LCMS: Method Q, 1.22 min, MS: ES+442.0 / 444.0. Step 2: 3-(methylthio)-N-(4-phenethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide A mixture of 3-bromo-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide (100 mg, 0.22 mmol), bis(pinacolato)diboron (CAS 73183-34-3, Apollo, 62 mg, 0.24 mmol) and KOAc (65 mg, 0.67 mmol) in dioxane (5 mL) was purged with nitrogen, then Pd(dppf)Cl2(16 mg, 0.022 mmol) was added. The mixture was stirred at 95 °C for 18 h, cooled to rt, filtered and the filtrate was concentrated under reduced pressure to give 3-(methylthio)-N-(4- phenethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (167 mg, 100%). LCMS: Method R, 1.30 min, MS: ES+490.2 Step 3: 3-(5,6-diaminopyridin-2-yl)-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide

[0058] 204 A mixture of Cs2CO3(217 mg 0.67 mmol), 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD, 46.9 mg, 0.24 mmol), 3-(methylthio)-N-(4-phenethoxyphenyl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzamide (109 mg, 0.22 mmol) and Pd-118 (29 mg, 0.04 mmol) in dioxane (4 mL) and water (1 mL) was purged with nitrogen and stirred at 95 °C for 18 h. This was combined with a second batch, starting from 3-(methylthio)-N-(4- phenethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.11 mmol scale) and filtered. The filtrate was concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0-100% THF in DCM) afforded 3-(5,6-diaminopyridin-2-yl)- 5-(methylthio)-N-(4-phenethoxyphenyl)benzamide (159 mg, 99%). LCMS: Method Q, 0.93 min, MS: ES+471.2. Step 4: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-(methylthio)-N-(4- phenethoxyphenyl)benzamide (Example 46) To 3-(5,6-diaminopyridin-2-yl)-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide (158 mg, 0.33 mmol) in THF (4 mL) was added AcOH (0.25 mL, 4.28 mmol) and iPnONO (0.071 mL, 0.53 mmol). The mixture was stirred at 65 °C for 1 h and concentrated under reduced pressure to give 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-(methylthio)-N-(4- phenethoxyphenyl)benzamide (87 mg, 51%). LCMS: Method A, 2.01 min, MS: ES+482.2;1H NMR (500 MHz, DMSO, 70 °C) δ ppm: 10.17 (s, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 8.22 (s, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.92 (s, 1H), 7.67 (d, J = 9.0 Hz, 2H), 7.40 – 7.27 (m, 4H), 7.26 – 7.19 (m, 1H), 6.96 (d, J = 9.0 Hz, 2H), 4.23 (t, J = 6.8 Hz, 2H), 3.05 (t, J = 6.8 Hz, 2H), 2.66 (s, 3H).1 H was obscured / not observed. Example 47 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(tosylmethyl)phenyl)benzamide Step 1: 3-bromo-N-(4-(tosylmethyl)phenyl)benzamide To 3-bromobenzoyl chloride (CAS 1711-09-7, Apollo, 0.13 mL, 0.96 mmol) and pyridine (0.12 mL, 1.43 mmol) in THF (10 mL) was added 4-(tosylmethyl)aniline (CAS 54306-15-9, Combi-Blocks, 250 mg, 0.96 mmol) and DMAP (23 mg, 0.19 mmol). The mixture was stirred at 40 °C for 2 h then cooled to rt. Water (2 mL) and DCM (30 mL) were added, and the organic phase separated and concentrated under reduced pressure. The residue was triturated with diethyl ether to afford 3-bromo-N-(4-(tosylmethyl)phenyl)benzamide (360 mg, 85%). LCMS: Method A, 1.89 min, MS: ES- 442.0 / 444.0. Step 2: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)benzamide To a solution of 3-bromo-N-(4-(tosylmethyl)phenyl)benzamide (300 mg, 0.68 mmol) in dioxane (10 mL) was added B2Pin2(CAS 73183-34-3, Apollo, 257 mg, 1.01 mmol) and KOAc (199 mg, 2.03 mmol). The mixture was purged with nitrogen for 5 min and Pd-118 (44 mg, 0.07 mmol) was added, purged again for 2 min then stirred at 80 °C for 1.5 h. The mixture was cooled to rt, filtered through Celite®and concentrated under reduced pressure. Purification by chromatography (silica gel, 0-100% EtOAc in isohexane) afforded 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)benzamide (309 mg, 83%). LCMS: Method A, 2.05 min, MS: ES+492.3. Step 3: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(tosylmethyl)phenyl)benzamide (Example 47) A mixture of 5-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1, 60 mg, 0.30 mmol), 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)benzamide (195 mg, 0.30 mmol) and K3PO4(192 mg, 0.90 mmol) in dioxane (2.5 mL) and water (1.5 mL) was purged with nitrogen for 5 min. Pd-118 (39 mg, 0.060 mmol) was added and purged for 2 min. The mixture was stirred at 80 °C for 18 h and concentrated under reduced pressure. Purification by RP chromatography (C18, 0 - 100% MeCN in 0.1% aq. NH4OH)) and preparative HPLC (Prep Method B, x=30, y=60) afforded 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- (tosylmethyl)phenyl)benzamide (9 mg, 6%). LCMS: Method A, 1.63 min, MS: ES+484.1;1H NMR (500 MHz, DMSO) δ ppm: 10.48 (s, 1H), 8.73 (d, J = 1.9 Hz, 1H), 8.57 (d, J = 8.7 Hz, 1H), 8.43 – 8.38 (m, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.08 – 8.03 (m, 1H), 7.73 (d, J = 8.2 Hz, 3H), 7.64 – 7.58 (m, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.18 – 7.12 (m, 2H), 4.62 (s, 2H), 2.41 (s, 3H).1 H was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 48 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(5-(tert-butyl)isoxazol-3-yl)benzamide Step 1: 3-bromo-N-(5-(tert-butyl)isoxazol-3-yl)benzamide Following the procedure of Example 47 Step 1, using 5-(tert-Butyl)-1,2-oxazol-3-amine (CAS 55809-36-4, BLD) in place of 4-(tosylmethyl)aniline, was obtained 3-bromo-N-(5-(tert- butyl)isoxazol-3-yl)benzamide in 69% yield. LCMS: Method A, 1.93 min, MS: ES+323.0 / 325.1. Step 2: N-(5-(tert-butyl)isoxazol-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide Following the procedure of Example 47 Step 2, using 3-bromo-N-(5-(tert-butyl)isoxazol-3- yl)benzamide in place of 3-bromo-N-(4-(tosylmethyl)phenyl)benzamide, was obtained N-(5- (tert-butyl)isoxazol-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 75% yield. LCMS: Method A, 2.11 min, MS: ES+371.2. Following the procedure of Example 47 Step 3, using N-(5-(tert-butyl)isoxazol-3-yl)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in place of 3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)benzamide, was obtained 3-(1H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(5-(tert-butyl)isoxazol-3-yl)benzamide in 23% yield. LCMS: Method A, 1.63 min, MS: ES+363.1;1H NMR (500 MHz, DMSO) δ ppm: 11.52 (s, 1H), 8.75 (d, J = 2.0 Hz, 1H), 8.40 – 8.35 (m, 1H), 8.14 – 8.07 (m, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.70 – 7.64 (m, 1H), 7.61 (t, J = 7.7 Hz, 1H), 6.78 (s, 1H), 1.34 (s, 9H).1 H obscured / not observed. Example 49 3-(5-Methyl-1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(4-phenethoxyphenyl)benzamide Following the procedure of Example 46 Step 4, using 5-bromo-6-methylpyridine-2,3-diamine (CAS 59352-90-8, Combi-Blocks) in place of 3-(5,6-diaminopyridin-2-yl)-5-(methylthio)-N-(4- phenethoxyphenyl)benzamide, was obtained 6-bromo-5-methyl-1H-[1,2,3]triazolo[4,5- b]pyridine in 64% yield. LCMS: Method A, 1.01 min, MS: ES+213.0 / 215.0. Step 2: 3-(5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(4-phenethoxyphenyl)benzamide (Example 49) A mixture of 6-bromo-5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine (50 mg, 0.24 mmol), N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6, 125 mg, 0.28 mmol) and Cs2CO3(306 mg, 0.94 mmol) in dioxane (4 mL) and water (1 mL) was purged with nitrogen for 5 min, after which Pd-118 (31 mg, 0.047 mmol) was added and the mixture purged for a further 2 min. The mixture was stirred at 90 °C for 18 h. The mixture was cooled to rt, acidified with aq. HCl (1 M, 5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over Na2SO4and concentrated under reduced pressure. Purification by RP chromatography (C18, 0 - 100% MeCN in 0.1% aq. NH4OH)) afforded 3-(5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(4- phenethoxyphenyl)benzamide (30 mg, 27%). LCMS: Method A, 1.85 min, MS: ES+450.2;1H NMR (500 MHz, DMSO) δ ppm: 10.17 (s, 1H), 8.19 (s, 1H), 8.04 – 7.97 (m, 2H), 7.71 – 7.60 (m, 4H), 7.37 – 7.29 (m, 4H), 7.27 – 7.20 (m, 1H), 6.98 – 6.91 (m, 2H), 4.18 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H), 2.54 (s, 3H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 50 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(1-benzyl-1H-pyrazol-4-yl)benzamide

[0059] Step 1: N-(1-benzyl-1H-pyrazol-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)benzamide Following the procedure of Example 19 Step 3, using benzyl bromide (CAS 100-39-0, Aldrich) in place of (2-bromoethyl)benzene, and DMF in place of THF, was obtained N-(1- benzyl-1H-pyrazol-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide with another isomer in 76% yield. LCMS: Method A, 2.28 / 2.41 min, MS ES+436.2. Step 2: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(1-benzyl-1H-pyrazol-4-yl)benzamide (Example 50) Following the procedure of Example 19 Step 4, using N-(1-benzyl-1H-pyrazol-4-yl)-3-(1- trityl-1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide (+ isomers) in place of N-(1-phenethyl- 1H-pyrazol-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide, and purification by trituration in place of chromatography, was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)-N-(1-benzyl-1H-pyrazol-4-yl)benzamide in 20% yield. LCMS: Method A, 1.49 min, MS ES+396.2;1H NMR (500 MHz, DMSO) δ ppm: 10.65 (s, 1H), 8.73 (d, J = 1.8 Hz, 1H), 8.60 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 6.3 Hz, 2H), 8.06 (d, J = 7.7 Hz, 1H), 7.74 – 7.65 (m, 2H), 7.40 – 7.21 (m, 5H), 5.35 (s, 2H).1 H was obscured / not observed. Example 51 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-6-yl)-N-methyl-N-(4-phenethoxyphenyl)benzamide Step 1: N-methyl-N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide To N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6, 250 mg, 0.56 mmol) in DMF (1 mL) was added NaH (60% dispersion in mineral oil, 27 mg, 0.68 mmol) and the mixture was stirred for 30 min. To this was added MeI (0.042 mL, 0.68 mmol) and the mixture stirred for a further 2 h. Water (20 mL) was added, and the mixture extracted with ethyl acetate (3 x 20 mL). The combined organic phase was dried over Na2SO4and concentrated under reduced pressure to give N-methyl-N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (140 mg, 42%). LCMS: Method A, 2.68 min, MS: ES+458.2. Following the procedure of Example 45 Step 1, using 6-bromo-3H-[1,2,3]triazolo[4,5- b]pyridine (I-16) in place of 2-chloro-6-methylpyrimidine-4,5-diamine, and N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in place of N- (4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6) for 18 h, and with purification by RP chromatography (C18, 0 - 100% MeCN in 0.1% aq. NH4OH)) was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-methyl-N-(4- phenethoxyphenyl)benzamide in 6% yield. LCMS: Method A, 1.82 min, MS: ES+450.2;1H NMR (500 MHz, DMSO) δ ppm: 8.41 – 8.35 (m, 1H), 8.11 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.30 – 7.21 (m, 5H), 7.21 – 7.13 (m, 3H), 6.82 (d, J = 8.4 Hz, 2H), 4.09 (t, J = 6.8 Hz, 2H), 3.37 (s, 3H), 2.93 (t, J = 6.8 Hz, 2H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 52 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)-3-fluorophenyl)benzamide 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)-3-fluorophenyl)benzamide Following the procedure of Example 49 Step 2, using N-(4-((benzyloxy)methyl)-3- fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-18) in place of N- (4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, and 5- bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1) in place of 6-bromo-5-methyl-1H- [1,2,3]triazolo[4,5-b]pyridine was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- ((benzyloxy)methyl)-3-fluorophenyl)benzamide in 34% yield. LCMS: Method A, 1.88 min, MS: ES+454.2;1H NMR (500 MHz, DMSO) δ ppm: 10.65 (s, 1H), 8.75 – 8.71 (m, 1H), 8.47 (d, J = 8.6 Hz, 1H), 8.43 – 8.38 (m, 1H), 8.09 – 8.01 (m, 2H), 7.82 (dd, J = 12.5, 2.0 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.62 (dd, J = 8.4, 2.0 Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.42 – 7.35 (m, 4H), 7.35 – 7.27 (m, 1H), 4.58 – 4.55 (m, 4H).1H was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 53 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)-2-fluorophenyl)benzamide 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)-2-fluorophenyl)benzamide Following the procedure of Example 49 Step 2, using N-(4-((benzyloxy)methyl)-2- fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-17) in place of N- (4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, and 5- bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1) in place of 6-bromo-5-methyl-1H- [1,2,3]triazolo[4,5-b]pyridine was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- ((benzyloxy)methyl)-2-fluorophenyl)benzamide in 18% yield. LCMS: Method A, 1.78 min, MS: ES+454.2; 1H NMR (500 MHz, DMSO) δ ppm: 10.35 (s, 1H), 8.79 (s, 1H), 8.59 (d, J = 8.6 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.45 – 7.28 (m, 6H), 7.25 (d, J = 8.4 Hz, 1H), 4.58 (s, 4H).1H was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 54 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-4-fluorobenzamide 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-4-fluorobenzamide Following the procedure of Example 49 Step 2, using (5-((4-((benzyloxy)methyl)phenyl)- carbamoyl)-2-fluorophenyl)boronic acid (I-19) in place of N-(4-phenethoxyphenyl)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, and 5-bromo-1H-[1,2,3]triazolo[4,5- b]pyridine (I-1) in place of 6-bromo-5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-4-fluorobenzamide in 33% yield. LCMS: Method A, 1.82 min, MS: ES+454.2;1H NMR (500 MHz, DMSO) δ ppm: 10.46 (s, 1H), 8.59 (dd, J = 7.5, 2.5 Hz, 2H), 8.20 – 8.12 (m, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.59 (dd, J = 10.8, 8.6 Hz, 1H), 7.45 – 7.33 (m, 6H), 7.35 – 7.25 (m, 1H), 4.54 (s, 2H), 4.52 (s, 2H).1H was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 55 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide Following the procedure of Example 49 Step 2, using (3-((4-((benzyloxy)methyl)phenyl)- carbamoyl)-2-fluorophenyl)boronic acid (I-20) in place of N-(4-phenethoxyphenyl)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, and 5-bromo-1H-[1,2,3]triazolo[4,5- b]pyridine (I-1) in place of 6-bromo-5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- ((benzyloxy)methyl)phenyl)-2-fluorobenzamide in 17% yield. LCMS: Method A, 1.78 min, MS: ES+454.2;1H NMR (500 MHz, DMSO) δ ppm: 10.59 (s, 1H), 8.71 – 8.42 (m, 2H), 8.12 – 8.04 (m, 1H), 7.95 (s, 1H), 7.80 (t, J = 6.7 Hz, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.40 – 7.33 (m, 5H), 7.33 – 7.26 (m, 1H), 4.53 (s, 2H), 4.52 (s, 2H).1H was obscured / not observed. Example 56 5-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide 5-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide Following the procedure of Example 49 Step 2, using N-(4-((benzyloxy)methyl)phenyl)-2- fluoro-5-(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, and 5-bromo- 1H-[1,2,3]triazolo[4,5-b]pyridine (I-1) in place of 6-bromo-5-methyl-1H-[1,2,3]triazolo[4,5- b]pyridine and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 5-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- ((benzyloxy)methyl)phenyl)-2-fluorobenzamide in 21% yield. LCMS: Method A, 1.84 min, MS: ES+454.2;1H NMR (500 MHz, DMSO) δ ppm: 10.60 (s, 1H), 8.56 (d, J = 8.7 Hz, 1H), 8.50 (dd, J = 6.6, 2.5 Hz, 1H), 8.46 – 8.37 (m, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.55 (t, J = 9.2 Hz, 1H), 7.42 – 7.27 (m, 8H), 4.54 (s, 2H), 4.52 (s, 2H). Example 57 N-(3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)phenyl)-4-phenethoxybenzamide N-(3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)phenyl)-4-phenethoxybenzamide Following the procedure of Example 45 Step 1, using 5-bromo-3H-[1,2,3]triazolo[4,5- b]pyridine (I-1) in place of 2-chloro-6-methylpyrimidine-4,5-diamine at 80 °C for 3 h, and with purification by chromatography (silica gel, 0-10% (1% AcOH in MeOH) in DCM) and RP chromatography (C18, 0 - 100% MeCN in 0.1% aq. NH4OH)) was obtained N-(3-(3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)-4-phenethoxybenzamide in 13% yield. LCMS: Method B, 1.27 min, MS: ES+436.2;1H NMR (500 MHz, DMSO) δ ppm: 10.28 (s, 1H), 8.65 (s, 1H), 8.50 (d, J = 8.7 Hz, 1H), 8.05 – 7.97 (m, 3H), 7.97 – 7.91 (m, 1H), 7.91 – 7.86 (m, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.39 – 7.30 (m, 4H), 7.28 – 7.21 (m, 1H), 7.12 – 7.07 (m, 2H), 4.31 (t, J = 6.9 Hz, 2H), 3.09 (t, J = 6.9 Hz, 2H).1H was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 58 N-(3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-6-yl)phenyl)-4-phenethoxybenzamide N-(3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-6-yl)phenyl)-4-phenethoxybenzamide Following the procedure of Example 45 Step 1, using 5-bromo-3H-[1,2,3]triazolo[4,5- b]pyridine (I-16) in place of 2-chloro-6-methylpyrimidine-4,5-diamine at 80 °C for 3 h, and with purification by RP chromatography (C18, 0 - 100% MeCN in 0.1% aq. HCO2H)) and RP chromatography (C18, 0 - 100% MeCN in 0.1% aq. NH4OH)) was obtained N-(3-(1H- [1,2,3]triazolo[4,5-b]pyridin-6-yl)phenyl)-4-phenethoxybenzamide in 22% yield. LCMS: Method B, 1.26 min, MS: ES+436.2;1H NMR (500 MHz, DMSO) δ ppm: 10.23 (s, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 8.00 (d, J = 8.6 Hz, 2H), 7.90 (d, J = 7.8 Hz, 1H), 7.57 – 7.52 (m, 1H), 7.54 – 7.48 (m, 1H), 7.39 – 7.30 (m, 4H), 7.28 – 7.21 (m, 1H), 7.10 (d, J = 8.7 Hz, 2H), 4.31 (t, J = 6.9 Hz, 2H), 3.09 (t, J = 6.8 Hz, 2H).1H was obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 59 3-(1H-Benzo[d][1,2,3]triazol-5-yl)-N-(6-phenethoxypyridin-3-yl)benzamide 3-(1H-Benzo[d][1,2,3]triazol-5-yl)-N-(6-phenethoxypyridin-3-yl)benzamide Following the procedure of Example 45 Step 1, using 5-bromo-1H-benzotriazole (CAS 32046-62-1, BLD) in place of 2-chloro-6-methylpyrimidine-4,5-diamine and N-(6- phenethoxypyridin-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-15) in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6) at 90 °C for 18 h, and with purification by RP chromatography (C18, 0 - 100% MeCN in 0.1% aq. HCO2H)) was obtained 3-(1H-benzo[d][1,2,3]triazol-5-yl)-N-(6-phenethoxypyridin- 3-yl)benzamide in 11% yield. LCMS: Method A, 1.84 min, MS: ES+436.2;1H NMR (500 MHz, DMSO) δ ppm: 10.40 (s, 1H), 8.53 (d, J = 2.7 Hz, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.27 (s, 1H), 8.09 – 7.94 (m, 4H), 7.88 – 7.81 (m, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.32 (d, J = 4.3 Hz, 4H), 7.23 (h, J = 4.1 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 4.46 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H).1 H obscured / not observed. Example 60 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-5-amino-N-(4-phenethoxyphenyl)benzamide Step 1: lithium 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitrobenzoate To methyl 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitrobenzoate (I-13, 506 mg, 1.52 mmol) in THF (8 mL) was added aq. LiOH (1 M, 3.04 mL, 3.04 mmol) and MeOH (0.1 mL). The mixture was stirred at rt for 1 h and concentrated under reduced pressure to give lithium 3- (3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitrobenzoate, used without purification in the next step (assumed 1.52 mmol). LCMS: Method Q, 0.82 min, MS: ES+286.0. To lithium 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitrobenzoate (443 mg, 1.52 mmol) and 4-phenethoxyaniline (I-5, 556 mg, 1.82 mmol) in DMF (8 mL) was added DIPEA (1.06 mL, 6.08 mmol) and HATU (751 mg, 1.98 mmol). The mixture was stirred at rt for 18 h. The mixture was diluted with water (150 mL) and the solid collected by filtration to give 3-(1H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitro-N-(4-phenethoxyphenyl)benzamide (596 mg, 64% over 2 steps). LCMS: Method Q, 1.09 min, MS: ES+481.0. Step 5: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-amino-N-(4-phenethoxyphenyl)benzamide (Example 60) To 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitro-N-(4-phenethoxyphenyl)benzamide (100 mg, 0.083 mmol) in THF (2.5 mL) and water (0.5 mL) was added NH4Cl (22 mg, 0.42 mmol) and zinc (27 mg, 0.42 mmol). The mixture was stirred for 18 h at rt, then water (10 mL) and DCM (10 mL) were added. The mixture was filtered and purified by preparative HPLC (Prep Method A, x=30, y=60) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5- amino-N-(4-phenethoxyphenyl)benzamide (2 mg, 5%). LCMS: Method A, 1.70 min, MS: ES+451.2;1H NMR (500 MHz, MeOD) δ ppm: 8.28 (d, J = 8.6 Hz, 1H), 7.89 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.65 – 7.57 (m, 3H), 7.34 – 7.24 (m, 5H), 7.24 – 7.18 (m, 1H), 6.93 (d, J = 8.8 Hz, 2H), 4.21 (t, J = 6.9 Hz, 2H), 3.08 (t, J = 6.9 Hz, 2H).4 H obscured / not observed. Example 61 6-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-phenethoxyphenyl)picolinamide To a solution of 5-(trimethylstannyl)-1H-[1,2,3]triazolo[4,5-b]pyridine (I-26) in dioxane (1.4 mL, 0.34 mmol) was added 6-bromo-N-(4-phenethoxyphenyl)picolinamide (I-28, 0.14 g, 0.34 mmol) in dioxane (2 mL). The mixture was sparged with nitrogen and bis[tris(tert- butyl)phosphine]palladium (17 mg, 0.03 mmol) was added. The mixture was irradiated in a microwave at 150 °C for 3 h. The procedure was repeated using 5-(trimethylstannyl)-1H- [1,2,3]triazolo[4,5-b]pyridine in dioxane (0.6 mL, 0.14 mmol). To the combined mixtures was added KF (20 mg, 0.34 mmol), prior to stirring for 30 min. The mixture was filtered, concentrated and purified twice by RP chromatography (C18, 0 - 100% MeCN in 0.1% aq. NH4OH) to afford 6-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-phenethoxyphenyl)picolin- amide (21 mg, 10 %). LCMS: Method A: 1.92 min, MS: ES+437.2;1H NMR (400 MHz, DMSO) δ ppm: 10.55 (s, 1H), 9.15 – 8.98 (m, 1H), 8.72 (dd, J = 7.1, 1.9 Hz, 1H), 8.61 – 8.46 (m, 1H), 8.34 – 8.13 (m, 2H), 7.90 – 7.70 (m, 2H), 7.43 – 7.27 (m, 4H), 7.27 – 7.16 (m, 1H), 6.99 (d, J = 9.1 Hz, 2H), 4.21 (t, J = 6.8 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 62 4-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-phenethoxyphenyl)picolinamide Following the procedure of Example 61, using 4-bromo-N-(4- phenethoxyphenyl)picolinamide (I-29) in place of 6-bromo-N-(4- phenethoxyphenyl)picolinamide (I-28) was obtained 4-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)- N-(4-phenethoxyphenyl)picolinamide in 7% yield. LCMS: Method A: 1.83 min, MS: ES+437.2;1H NMR (400 MHz, DMSO, 90 °C) δ ppm: 10.28 (s, 1H), 8.70 (dd, J = 7.2, 1.9 Hz, 1H), 8.53 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.17 – 8.06 (m, 2H), 7.78 (d, J = 9.0 Hz, 2H), 7.46 – 7.26 (m, 4H), 7.26 – 7.16 (m, 1H), 6.99 (d, J = 9.0 Hz, 2H), 4.40 – 4.15 (m, 2H), 3.07 (t, J = 6.8 Hz, 2H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 63 2-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-phenethoxyphenyl)isonicotinamide Following the procedure of Example 61, using 2-bromo-N-(4-phenethoxyphenyl)- isonicotinamide (I-30) in place of 6-bromo-N-(4-phenethoxyphenyl)picolinamide (I-28) and with additional purification by preparative HPLC (Prep Method A, x=30, y=60) was obtained 2-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-phenethoxyphenyl)isonicotinamide in 0.2% yield. LCMS: Method A: 1.81 min, MS: ES 437.2;1H NMR (500 MHz, DMSO) δ ppm: 10.62 (s, 1H), 8.95 (s, 1H), 8.80 (d, J = 4.9 Hz, 1H), 8.13 (q, J = 8.3 Hz, 2H), 7.79 (d, J = 5.4 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.45 – 7.29 (m, 4H), 7.24 (s, 1H), 6.98 (d, J = 8.7 Hz, 2H), 4.21 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 6.8 Hz, 2H).1 H obscured / not observed. Example 64 2-(3H-[1,2,3]Triazolo[4,5-c]pyridin-6-yl)-N-(4-phenethoxyphenyl)isonicotinamide A mixture of 2-bromo-N-(4-phenethoxyphenyl)isonicotinamide (I-30, 50 mg, 0.116 mmol) and 6-bromo-3H-[1,2,3]triazolo[4,5-c]pyridine (I-27, 25 mg, 0.127 mmol) in NMP (2 mL) was sparged with nitrogen then Pd(PPh3)2Cl2(8.13 mg, 0.011.6 mmol) and Sn2Bu6(0.059 mL, 0.116 mmol) were added. The mixture was stirred at 120 °C for 18 h and 140 °C for 18 h. KF (20 mg, 0.347 μmol) was added and stirred at rt for 1h. The mixture was filtered and the filtrate was purified by RP chromatography (C18, 0 - 100% MeCN in 0.1% aq. NH4OH) and then preparative HPLC (Prep Method C, x=7.5, y=37.5) to give 2-(3H-[1,2,3]triazolo[4,5- c]pyridin-6-yl)-N-(4-phenethoxyphenyl)isonicotinamide in 2% yield. LCMS: Method A: 1.63 min, MS: ES 437.1;1H NMR (500 MHz, Acetone) δ ppm: 9.92 (s, 1H), 9.20 (s, 1H), 8.96 (s, 1H), 8.84 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.86 – 7.77 (m, 2H), 7.74 (d, J = 4.9 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.34 – 7.29 (m, 2H), 7.26 – 7.20 (m, 1H), 6.97 (d, J = 9.0 Hz, 2H), 4.24 (t, J = 6.9 Hz, 2H), 3.10 (t, J = 6.9 Hz, 2H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. General procedure (Suzuki coupling) Following the procedure of Example 49 Step 2, substituting the 6-bromo-5-methyl-1H- [1,2,3]triazolo[4,5-b]pyridine with 5-bromo-3H-[1,2,3]triazolo[4,5-b]pyridine (I-1), N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6) with appropriate starting materials, using MeCN or dioxane, and with any minor modifications noted, the following Examples 65-99 were obtained: Example 65 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2,6- difluorobenzamide Using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid (I-31) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- ((benzyloxy)methyl)phenyl)-2,6-difluorobenzamide in 10% yield. LCMS: Method A: 1.82 min, MS: ES+472.1;1H NMR (500 MHz, DMSO) δ ppm: 10.94 (s, 1H), 8.58 (s, 1H), 8.20 – 8.07 (m, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 8.6 Hz, 1H), 7.41 – 7.33 (m, 6H), 7.33 – 7.27 (m, 1H), 4.53 (s, 2H), 4.52 (s, 2H). 1 H obscured / not observed. Example 66 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2- methoxybenzamide Using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-methoxyphenyl)boronic acid (I-32) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- ((benzyloxy)methyl)phenyl)-2-methoxybenzamide in 8% yield. LCMS: Method A: 1.8 min, MS: ES+466.2;1H NMR (500 MHz, DMSO) δ ppm: 10.46 (s, 1H), 8.59 – 8.46 (m, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 9.7 Hz, 1H), 7.44 – 7.35 (m, 7H), 7.34 – 7.24 (m, 1H), 4.53 (s, 2H), 4.51 (s, 2H), 3.56 (s, 3H).1 H obscured / not observed. Example 67 5-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2- methoxybenzamide Using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid (I-33) was obtained 5-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2- methoxybenzamide in 9% yield. LCMS: Method A: 1.82 min, MS: ES+466.2;1H NMR (500 MHz, DMSO) δ ppm: 10.27 (s, 1H), 8.70 – 8.54 (m, 1H), 8.48 (s, 1H), 8.37 (d, J = 8.5 Hz, 1H), 8.26 – 8.04 (m, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.43 – 7.33 (m, 7H), 7.33 – 7.25 (m, 1H), 4.53 (s, 2H), 4.52 (s, 2H), 3.99 (s, 3H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 68 5-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2- methylbenzamide Using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid (I-34) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 5-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- ((benzyloxy)methyl)phenyl)-2-methylbenzamide in 6% yield. LCMS: Method A: 1.83 min, MS: ES+450.2;1H NMR (500 MHz, DMSO) δ ppm: 10.50 (s, 1H), 8.63 (d, J = 8.6 Hz, 1H), 8.41 – 8.37 (m, 1H), 8.30 (s, 1H), 8.29 – 8.20 (m, 1H), 8.19 – 8.11 (m, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.1 Hz, 1H), 7.40 – 7.36 (m, 5H), 7.34 – 7.29 (m, 1H), 4.53 (s, 2H), 4.52 (s, 2H), 2.47 (s, 3H).1 H obscured / not observed. Example 69 (Z)-3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-styrylphenyl)benzamide Using (Z)-N-(4-styrylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-35) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained (Z)-3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- styrylphenyl)benzamide in 11% yield. LCMS: Method A: 1.72 min, MS: ES+418.1;1H NMR (500 MHz, DMSO) δ ppm: 10.47 (s, 1H), 8.72 (s, 1H), 8.53 (d, J = 8.6 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.76 – 7.68 (m, 3H), 7.33 – 7.17 (m, 7H), 6.62 (s, 2H).1 H obscured / not observed. Example 70 5-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(3-cyano-4-(1-cyclopropylethoxy)phenyl)-2- fluorobenzamide Using N-(3-cyano-4-(1-cyclopropylethoxy)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-36) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 5-(1H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)-N-(3-cyano-4-(1-cyclopropylethoxy)phenyl)-2-fluorobenzamide in 14% yield. LCMS: Method A: 1.89 min, MS: ES+443.2;1H NMR (400 MHz, DMSO) δ ppm: 10.70 (s, 1H), 8.51 (dd, J = 6.8, 2.5 Hz, 1H), 8.45 – 8.36 (m, 1H), 8.25 – 8.15 (m, 1H), 8.08 (d, J = 2.7 Hz, 1H), 7.89 (dd, J = 9.2, 2.7 Hz, 1H), 7.59 – 7.51 (m, 1H), 7.32 (d, J = 9.3 Hz, 1H), 4.21 – 4.08 (m, 1H), 1.35 (d, J = 6.1 Hz, 3H), 1.18 – 1.07 (m, 1H), 0.58 – 0.49 (m, 2H), 0.43 – 0.26 (m, 2H).2 H obscured / not observed. Example 71 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(3-fluoro-4-(((2-methoxybenzyl)oxy)methyl)- phenyl)benzamide Using N-(3-fluoro-4-(((2-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-37) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 3-(3H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)-N-(3-fluoro-4-(((2-methoxybenzyl)oxy)methyl)phenyl)benzamide in 15% yield. LCMS: Method A: 1.58 min, MS: ES+484.2;1H NMR (500 MHz, DMSO) δ ppm: 10.65 (s, 1H), 8.75 (s, 1H), 8.61 (s, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 7.81 (dd, J = 12.5, 2.0 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.61 (dd, J = 8.3, 2.0 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.37 (dd, J = 7.5, 1.8 Hz, 1H), 7.29 (td, J = 7.8, 1.8 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 4.59 (s, 2H), 4.55 (s, 2H), 3.80 (s, 3H).1 H obscured / not observed. Example 72 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)- phenyl)benzamide Using N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-38) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 3-(3H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)-N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)benzamide in 16% yield. LCMS: Method A: 1.56 min, MS: ES+484.2;1H NMR (500 MHz, DMSO) δ ppm: 10.66 (s, 1H), 8.75 (s, 1H), 8.61 (s, 1H), 8.43 (d, J = 4.8 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.82 (dd, J = 12.6, 2.0 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.62 (dd, J = 8.4, 2.0 Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 6.98 – 6.90 (m, 2H), 6.91 – 6.85 (m, 1H), 4.56 (s, 2H), 4.54 (s, 2H), 3.77 (s, 3H).1 H obscured / not observed. Example 73 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)- phenyl)benzamide Using N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-39) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 3-(3H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)-N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)benzamide in 8% yield. LCMS: Method A: 1.53 min, MS: ES+484.2;1H NMR (500 MHz, DMSO) δ ppm: 10.65 (s, 1H), 8.75 (t, J = 1.8 Hz, 1H), 8.70 (d, J = 8.6 Hz, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H), 8.12 – 8.04 (m, 1H), 7.81 (dd, J = 12.6, 2.0 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.46 (t, J = 8.4 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 6.96 – 6.90 (m, 2H), 4.52 (s, 2H), 4.48 (s, 2H), 3.76 (s, 3H).1 H obscured / not observed. Example 74 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(3-fluoro-4-((pyridin-2-ylmethoxy)methyl)- phenyl)benzamide Using N-(3-fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-40) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 3-(3H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)-N-(3-fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)benzamide in 10% yield. LCMS: Method A: 0.98 min, MS: ES+455.1;1H NMR (500 MHz, DMSO) δ ppm: 10.66 (s, 1H), 8.74 (s, 1H), 8.58 – 8.50 (m, 2H), 8.42 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.87 – 7.78 (m, 2H), 7.73 (t, J = 7.7 Hz, 1H), 7.62 (dd, J = 8.3, 2.0 Hz, 1H), 7.55 – 7.45 (m, 2H), 7.36 – 7.29 (m, 1H), 4.65 (s, 4H).1 H obscured / not observed. Example 75 5-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(((4-chlorophenyl)sulfonyl)methyl)phenyl)-2- fluorobenzamide Using N-(4-(((4-chlorophenyl)sulfonyl)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-41) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 5-(3H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)-N-(4-(((4-chlorophenyl)sulfonyl)methyl)phenyl)-2-fluorobenzamide in 8% yield. LCMS: Method A: 1.39 min, MS: ES+522.1;1H NMR (500 MHz, DMSO) δ ppm: 10.63 (s, 1H), 8.53 (d, J = 8.6 Hz, 1H), 8.48 (dd, J = 6.8, 2.4 Hz, 1H), 8.41 (ddd, J = 8.6, 4.9, 2.5 Hz, 1H), 8.16 (dd, J = 8.4, 2.3 Hz, 1H), 7.79 – 7.65 (m, 6H), 7.54 (t, J = 9.2 Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 4.71 (s, 2H).1 H obscured / not observed. Example 76 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(((4- cyanobenzyl)oxy)methyl)phenyl)benzamide Using N-(4-(((4-cyanobenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzamide (I-42) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)- N-(4-(((4-cyanobenzyl)oxy)methyl)phenyl)benzamide in 16% yield. LCMS: Method A: 1.28 min, MS: ES+461.2;1H NMR (500 MHz, DMSO) δ ppm: 10.48 (s, 1H), 8.75 (t, J = 1.9 Hz, 1H), 8.57 (d, J = 8.7 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.10 – 8.03 (m, 1H), 7.90 – 7.78 (m, 4H), 7.72 (t, J = 7.7 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 4.65 (s, 2H), 4.57 (s, 2H).1 H obscured / not observed. Example 77 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((4-methylphenyl)sulfonamido)- phenyl)benzamide Using N-(4-((4-methylphenyl)sulfonamido)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-54) and with purification by preparative HPLC (Prep Method A, x=30, y=60) in place of RP chromatography was obtained 3-(1H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)-N-(4-((4-methylphenyl)sulfonamido)phenyl)benzamide in 9% yield. LCMS: Method A: 1.6 min, MS: ES+485.2;1H NMR (500 MHz, DMSO) δ ppm: 10.37 (s, 1H), 10.10 (s, 1H), 8.69 (s, 1H), 8.58 (d, J = 8.6 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.67 – 7.61 (m, 4H), 7.35 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 2.35 (s, 3H).1 H obscured / not observed. Example 78 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)-2- methoxyphenyl)benzamide Using N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-44) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 3-(3H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)-2-methoxyphenyl)benzamide in 19% yield. LCMS: Method A: 1.96 min, MS: ES+466.2;1H NMR (400 MHz, DMSO) δ ppm: 9.70 (s, 1H), 8.76 (t, J = 1.8 Hz, 1H), 8.61 (s, 1H), 8.41 (dt, J = 8.0, 1.4 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.78 – 7.65 (m, 2H), 7.45 – 7.36 (m, 4H), 7.35 – 7.26 (m, 1H), 7.10 (d, J = 1.7 Hz, 1H), 7.00 (dd, J = 8.0, 1.7 Hz, 1H), 4.57 (s, 2H), 4.56 (s, 2H), 3.86 (s, 3H).1 H obscured / not observed. Example 79 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)-2- methylphenyl)benzamide Using N-(4-((benzyloxy)methyl)-2-methylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzamide (I-45) was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- ((benzyloxy)methyl)-2-methylphenyl)benzamide in 36% yield. LCMS: Method A: 1.78 min, MS: ES+450.2;1H NMR (500 MHz, DMSO) δ ppm: 10.11 (s, 1H), 8.80 (s, 1H), 8.59 (d, J = 8.7 Hz, 1H), 8.42 (d, J = 7.7 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.41 – 7.35 (m, 5H), 7.35 – 7.28 (m, 2H), 7.27 – 7.21 (m, 1H), 4.56 (s, 2H), 4.54 (s, 2H), 2.29 (s, 3H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 80 5-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2- fluorobenzamide Using N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-46) was obtained 5-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N- (4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluorobenzamide in 9% yield. LCMS: Method A: 1.9 min, MS: ES+472.2;1H NMR (500 MHz, DMSO) δ ppm: 10.62 (s, 1H), 8.36 – 8.29 (m, 2H), 8.29 – 8.20 (m, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.60 – 7.54 (m, 1H), 7.40 – 7.24 (m, 3H), 7.21 – 7.16 (m, 4H), 7.16 – 7.09 (m, 1H), 4.38 (s, 2H), 4.37 (s, 2H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 81 3-(3H-[1,2,3]Triazolo[4,5-d]pyrimidin-5-yl)-N-(4-((benzyloxy)methyl)-3- fluorophenyl)benzamide Using N-(4-((benzyloxy)methyl)-3-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-18) and with 5-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-76) in place of 5- bromo-3H-[1,2,3]triazolo[4,5-b]pyridine (I-1) was obtained 3-(3H-[1,2,3]triazolo[4,5- d]pyrimidin-5-yl)-N-(4-((benzyloxy)methyl)-3-fluorophenyl)benzamide in 10% yield. LCMS: Method A: 1.9 min, MS: ES+455.2;1H NMR (500 MHz, DMSO) δ ppm: 10.71 (s, 1H), 9.70 (s, 1H), 9.07 (s, 1H), 8.71 (d, J = 7.7 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.86 – 7.79 (m, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.63 (dd, J = 8.2, 2.0 Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.38 (d, J = 4.5 Hz, 4H), 7.32 (q, J = 4.5 Hz, 1H), 4.57 (s, 4H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 82 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2- methylbenzamide Using N-(4-((benzyloxy)methyl)phenyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzamide (I-47) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)- N-(4-((benzyloxy)methyl)phenyl)-2-methylbenzamide in 9% yield. LCMS: Method A: 1.76 min, MS: ES+450.2;1H NMR (500 MHz, DMSO) δ ppm: 10.49 (s, 1H), 8.62 (s, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.63 (s, 1H), 7.56 (t, J = 6.8 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.41 – 7.25 (m, 8H), 4.52 (s, 2H), 4.51 (s, 2H), 2.33 (s, 3H). Example 83 3-(3H-[1,2,3]Triazolo[4,5-d]pyrimidin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)benzamide Using N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-8) and with 5-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-76) in place of 5- bromo-3H-[1,2,3]triazolo[4,5-b]pyridine (I-1) was obtained 3-(3H-[1,2,3]triazolo[4,5- d]pyrimidin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)benzamide in 19% yield. LCMS: Method A: 1.88 min, MS: ES+437.2;1H NMR (500 MHz, DMSO) δ ppm: 10.53 (s, 1H), 9.79 (s, 1H), 9.07 (t, J = 1.9 Hz, 1H), 8.70 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7.39 – 7.36 (m, 6H), 7.34 – 7.28 (m, 1H), 4.55 (s, 2H), 4.53 (s, 2H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 84 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-4- methoxybenzamide Using N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-48) was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N- (4-((benzyloxy)methyl)phenyl)-4-methoxybenzamide in 54% yield. LCMS: Method A: 1.78 min, MS: ES+466.2;1H NMR (400 MHz, DMSO) δ ppm: 10.26 (s, 1H), 8.65 – 8.50 (m, 1H), 8.40 (s, 1H), 8.14 (dd, J = 8.6, 2.4 Hz, 1H), 8.03 – 7.88 (m, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.40 – 7.29 (m, 8H), 4.53 (s, 2H), 4.50 (s, 2H), 3.95 (s, 3H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 85 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-4- methylbenzamide Using N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzamide (I-49) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)- N-(4-((benzyloxy)methyl)phenyl)-4-methylbenzamide in 16% yield. LCMS: Method A: 1.82 min, MS: ES+450.2;1H NMR (500 MHz, DMSO) δ ppm: 10.30 (s, 1H), 8.74 – 8.48 (m, 1H), 8.11 (s, 1H), 8.05 – 7.98 (m, 1H), 7.85 – 7.66 (m, 3H), 7.54 (d, J = 8.0 Hz, 1H), 7.44 – 7.24 (m, 7H), 4.53 (s, 2H), 4.51 (s, 2H), 2.45 (s, 3H).1 H obscured / not observed. Example 86 5-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((cyclopropylmethoxy)methyl)-3-fluorophenyl)- 2-fluorobenzamide Using N-(4-((cyclopropylmethoxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzamide (I-50) was obtained 5-(3H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)-N-(4-((cyclopropylmethoxy)methyl)-3-fluorophenyl)-2-fluorobenzamide in 55% yield. LCMS: Method A: 1.77 min, MS: ES+436.1;1H NMR (500 MHz, DMSO) δ ppm: 10.61 (s, 1H), 8.36 (d, J = 8.6 Hz, 1H), 8.34 – 8.29 (m, 1H), 8.28 – 8.21 (m, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 12.3 Hz, 1H), 7.38 (t, J = 9.2 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 8.3 Hz, 1H), 4.32 (s, 2H), 3.12 (d, J = 6.8 Hz, 2H), 0.88 – 0.84 (m, 1H), 0.34 – 0.26 (m, 2H), 0.03 – -0.03 (m, 2H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 87 5-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(1-cyclopropylethoxy)-3-fluorophenyl)-2- fluorobenzamide Using N-(4-(1-cyclopropylethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-51) and with purification by preparative HPLC (Prep Method A, x=45, y=80) in place of RP chromatography was obtained 5-(1H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)-N-(4-(1-cyclopropylethoxy)-3-fluorophenyl)-2-fluorobenzamide in 14% yield. LCMS: Method A: 1.94 min, MS: ES+436.2;1H NMR (400 MHz, DMSO) δ ppm: 16.32 (s, 1H), 10.60 (s, 1H), 8.56 (d, J = 8.7 Hz, 1H), 8.48 (dd, J = 6.8, 2.4 Hz, 1H), 8.41 (ddd, J = 8.9, 5.0, 2.5 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.71 (dd, J = 13.4, 2.5 Hz, 1H), 7.54 (t, J = 9.2 Hz, 1H), 7.40 (dd, J = 9.2, 1.9 Hz, 1H), 7.17 (t, J = 9.2 Hz, 1H), 3.89 – 3.77 (m, 1H), 1.31 (d, J = 6.1 Hz, 3H), 1.18 – 1.01 (m, 1H), 0.53 – 0.44 (m, 2H), 0.33 – 0.21 (m, 2H). Example 88 3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(1-cyclopropylethoxy)phenyl)benzamide Using N-(4-(1-cyclopropylethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-52) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- (1-cyclopropylethoxy)phenyl)benzamide in 25% yield. LCMS: Method A: 1.69 min, MS: ES+400.2;1H NMR (500 MHz, DMSO) δ ppm: 10.31 (s, 1H), 8.73 (s, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.22 (s, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.75 – 7.60 (m, 3H), 6.94 (d, J = 9.0 Hz, 2H), 3.98 – 3.84 (m, 1H), 1.29 (d, J = 6.1 Hz, 3H), 1.14 – 1.00 (m, 1H), 0.53 – 0.41 (m, 2H), 0.37 – 0.23 (m, 2H).2 H obscured / not observed. Example 89 5-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(cyclopropylmethoxy)-3-fluorophenyl)-2- fluorobenzamide Using N-(4-(cyclopropylmethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-53) was obtained 5-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N- (4-(cyclopropylmethoxy)-3-fluorophenyl)-2-fluorobenzamide in 16% yield. LCMS: Method A: 1.76 min, MS: ES+422.1;1H NMR (500 MHz, DMSO) δ ppm: 10.40 (s, 1H), 8.36 (d, J = 8.7 Hz, 1H), 8.34 – 8.28 (m, 1H), 8.26 – 8.20 (m, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.58 – 7.51 (m, 1H), 7.36 (t, J = 9.2 Hz, 1H), 7.28 – 7.22 (m, 1H), 6.98 (t, J = 9.2 Hz, 1H), 3.71 (d, J = 7.0 Hz, 2H), 1.11 – 1.01 (m, 1H), 0.44 – 0.37 (m, 2H), 0.19 – 0.13 (m, 2H). 1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 90 5-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(cyclopropylmethoxy)phenyl)-2- fluorobenzamide Using N-(4-(cyclopropylmethoxy)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzamide (I-43) and with purification by preparative HPLC (Prep Method A, x=20, y=50) in place of RP chromatography was obtained 5-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)- N-(4-(cyclopropylmethoxy)phenyl)-2-fluorobenzamide in 6% yield. LCMS: Method A: 1.69 min, MS: ES+404.2;1H NMR (500 MHz, DMSO) δ ppm: 10.41 (s, 1H), 8.55 (d, J = 8.8 Hz, 1H), 8.48 (dd, J = 6.7, 2.5 Hz, 1H), 8.40 (d, J = 8.3 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.53 (t, J = 9.2 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 3.81 (d, J = 7.0 Hz, 2H), 1.33 – 1.09 (m, 1H), 0.74 – 0.49 (m, 2H), 0.44 – 0.20 (m, 2H). 1 H obscured / not observed. Example 91 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(N-benzylsulfamoyl)phenyl)benzamide Using N-(4-(N-benzylsulfamoyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-55) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(N- benzylsulfamoyl)phenyl)benzamide in 2% yield. LCMS: Method A: 1.64 min, MS: ES+485.1;1H NMR (500 MHz, DMSO) δ ppm: 10.79 (s, 1H), 8.76 (s, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.11 – 7.99 (m, 4H), 7.83 (d, J = 8.4 Hz, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7.33 – 7.22 (m, 5H), 3.99 (d, J = 6.5 Hz, 2H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 92 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(N-phenethylsulfamoyl)phenyl)benzamide Using N-(4-(N-phenethylsulfamoyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-56) and with purification by preparative HPLC (Prep Method A, x=30, y=60) in place of RP chromatography was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- (N-phenethylsulfamoyl)phenyl)benzamide in 3% yield. LCMS: Method A: 1.67 min, MS: ES+499.2;1H NMR (500 MHz, DMSO) δ ppm: 10.78 (s, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7.63 (t, J = 5.8 Hz, 1H), 7.27 (t, J = 7.4 Hz, 2H), 7.22 – 7.14 (m, 3H), 2.97 (q, J = 7.0 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H).1 H obscured / not observed. Example 93 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(phenylsulfonyl)phenyl)benzamide Using N-(4-(phenylsulfonyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-57) was obtained 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4- (phenylsulfonyl)phenyl)benzamide in 7% yield. LCMS: Method A: 1.64 min, MS: ES+456.4;1H NMR (500 MHz, DMSO) δ ppm: 10.78 (s, 1H), 8.66 (s, 1H), 8.43 (d, J = 8.6 Hz, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.05 – 7.95 (m, 4H), 7.93 – 7.86 (m, 4H), 7.67 – 7.60 (m, 2H), 7.56 (t, J = 7.5 Hz, 2H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 94 5-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2- (methylthio)benzamide Using N-(4-((benzyloxy)methyl)phenyl)-2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-58) was obtained 5-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N- (4-((benzyloxy)methyl)phenyl)-2-(methylthio)benzamide in 19% yield. LCMS: Method A: 1.54 min, MS: ES+482.2;1H NMR (500 MHz, DMSO) δ ppm: 10.54 (s, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.21 (s, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.39 – 7.36 (m, 6H), 7.34 – 7.28 (m, 1H), 4.54 (s, 2H), 4.52 (s, 2H), 2.53 (s, 3H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 95 5-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2- (methylsulfonyl)benzamide 3-chlorobenzoperoxoic acid (~70% wt.) (15 mg, 70 wt%, 0.059 mmol) was added slowly to a stirred solution of 5-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2- (methylthio)benzamide (Example 94, 10 mg, 0.020 mmol) in DCM (4 mL) at 0 °C. The mixture was stirred at rt for 16 h, then treated with sat. aq. NaHCO3 and extracted with EtOAc (3 x 30 mL). The combined organics were washed with water (30 mL), and brine (30 mL), dried over Na2SO4and concentrated under reduced pressure to afford 5-(3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2- (methylsulfonyl)benzamide in 56% yield. LCMS: Method A: 1.26 min, MS: ES+514.2;1H NMR (500 MHz, DMSO) δ ppm: 10.79 (s, 1H), 8.49 (dd, J = 8.3, 1.9 Hz, 1H), 8.45 (d, J = 1.8 Hz, 1H), 8.14 – 8.05 (m, 2H), 7.79 – 7.71 (m, 3H), 7.42 – 7.34 (m, 6H), 7.34 – 7.25 (m, 1H), 4.54 (s, 2H), 4.53 (s, 2H), 3.44 (s, 3H).1 H obscured / not observed. Example 98 and Example 99 (S)-3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(1-cyclopropylethoxy)phenyl)benzamide and (R)-3-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(1- cyclopropylethoxy)phenyl)benzamide 3-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(1-cyclopropylethoxy)phenyl)benzamide (Example 88, 20 mg) was separated by chiral SFC (Prep Method G) to afford 3-(3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(1-cyclopropylethoxy)phenyl)benzamide, enantiomer 1 (6 mg, 29%, 97% ee). LCMS: Method A: 1.45 min, MS: ES+400.3;1H NMR (500 MHz, DMSO) δ ppm: 10.29 (s, 1H), 8.71 (s, 1H), 8.52 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.76 – 7.63 (m, 3H), 6.97 – 6.89 (m, 2H), 3.98 – 3.87 (m, 1H), 1.28 (d, J = 6.0 Hz, 3H), 1.11 – 1.04 (m, 1H), 0.53 – 0.45 (m, 2H), 0.38 – 0.24 (m, 2H).1 H obscured / not observed. And also 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(1-cyclopropylethoxy)phenyl)- benzamide, enantiomer 2 (12 mg, 58%, 71% ee). LCMS: Method A: 1.41 min, MS: ES+400.2;1H NMR (500 MHz, DMSO) δ ppm: 10.29 (s, 1H), 8.70 (s, 1H), 8.56 – 8.26 (m, 2H), 8.08 – 7.91 (m, 2H), 7.71 – 7.62 (m, 3H), 6.96 – 6.89 (m, 2H), 3.97 – 3.86 (m, 1H), 1.28 (d, J = 6.1 Hz, 3H), 1.10 – 1.01 (m, 1H), 0.54 – 0.44 (m, 2H), 0.38 – 0.24 (m, 2H).1 H obscured / not observed. Example 96 and Example 97 (R)-5-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(1-cyclopropylethoxy)-3-fluorophenyl)-2- fluorobenzamide and (S)-5-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(1-cyclopropylethoxy)- 3-fluorophenyl)-2-fluorobenzamide 5-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(1-cyclopropylethoxy)-3-fluorophenyl)-2- fluorobenzamide (Example 87, 14 mg) was separated by chiral SFC (Prep Method F) to afford 5-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(1-cyclopropylethoxy)-3-fluorophenyl)-2- fluorobenzamide, enantiomer 1 (5 mg, 30%, 99% ee). LCMS: Method A: 1.67 min, MS: ES+436.1;1H NMR (500 MHz, DMSO) δ ppm: 10.59 (s, 1H), 8.54 – 8.43 (m, 2H), 8.44 – 8.36 (m, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.71 (dd, J = 13.4, 2.5 Hz, 1H), 7.52 (t, J = 9.2 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.17 (t, J = 9.2 Hz, 1H), 3.91 – 3.77 (m, 1H), 1.31 (d, J = 6.1 Hz, 3H), 1.14 – 0.99 (m, 1H), 0.59 – 0.43 (m, 2H), 0.35 – 0.15 (m, 2H).1 H obscured / not observed. And also 5-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(1-cyclopropylethoxy)-3-fluorophenyl)- 2-fluorobenzamide, enantiomer 2 (5 mg, 30%, 95% ee). LCMS: Method A: 1.62 min, MS: ES+436.1;1H NMR (500 MHz, DMSO) δ ppm: 10.59 (s, 1H), 8.57 – 8.43 (m, 2H), 8.42 – 8.35 (m, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.71 (dd, J = 13.4, 2.5 Hz, 1H), 7.52 (t, J = 9.2 Hz, 1H), 7.40 (d, J = 9.5 Hz, 1H), 7.17 (t, J = 9.2 Hz, 1H), 3.91 – 3.75 (m, 1H), 1.31 (d, J = 6.1 Hz, 3H), 1.15 – 1.01 (m, 1H), 0.55 – 0.43 (m, 2H), 0.34 – 0.20 (m, 2H).1 H obscured / not observed.95% ee General procedure (Triazole formation) Following the procedure of Example 45 Step 2, with iPnONO (typically 1.5 - 2 eq) and AcOH (typically 1 - 2.2 eq) at 65 °C for 1 to 3 h, substituting 3-(4,5-diamino-6- methylpyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide with the appropriate starting material, and with any minor modifications noted, the following Examples 100-116 were obtained: Example 100 5-(3H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-N-(4-(cyclopropylmethoxy)phenyl)-2- fluorobenzamide Using N-(4-(cyclopropylmethoxy)phenyl)-5-(5,6-diaminopyridin-2-yl)-2-fluorobenzamide (I- 59) and with trituration with acetone in place of RP chromatography was obtained 5-(3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(cyclopropylmethoxy)phenyl)-2-fluorobenzamide in 13% yield. LCMS: Method A: 1.37 min, MS: ES+404.3;1H NMR (500 MHz, DMSO) δ ppm: 10.41 (s, 1H), 8.57 (d, J = 8.7 Hz, 1H), 8.48 (dd, J = 6.8, 2.5 Hz, 1H), 8.40 (ddd, J = 8.7, 4.9, 2.5 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.69 – 7.62 (m, 2H), 7.54 (t, J = 9.2 Hz, 1H), 6.97 – 6.91 (m, 2H), 3.81 (d, J = 6.9 Hz, 2H), 1.28 – 1.17 (m, 1H), 0.61 – 0.53 (m, 2H), 0.36 – 0.30 (m, 2H). 1 H obscured / not observed. Example 101 5-(1H-[1,2,3]Triazolo[4,5-b]pyridin-5-yl)-2-fluoro-N-(4-(tosylmethyl)phenyl)benzamide Using 5-(5,6-diaminopyridin-2-yl)-2-fluoro-N-(4-(tosylmethyl)phenyl)benzamide (I-60) with trituration with water and Et2O in place of RP chromatography was obtained 5-(1H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-fluoro-N-(4-(tosylmethyl)phenyl)benzamide in 66% yield. LCMS: Method A: 1.65 min, MS: ES+502.1;1H NMR (500 MHz, DMSO) δ ppm: 10.62 (s, 1H), 8.57 (s, 1H), 8.49 (dd, J = 6.7, 2.5 Hz, 1H), 8.42 (q, J = 5.1 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 9.2 Hz, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 4.62 (s, 2H), 2.41 (s, 3H).1 H obscured / not observed. Example 102 5-(3H-[1,2,3]Triazolo[4,5-d]pyrimidin-5-yl)-N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2- fluorobenzamide Using N-(4-((benzyloxy)methyl)-3-fluorophenyl)-5-(4,5-diaminopyrimidin-2-yl)-2- fluorobenzamide (I-61) was obtained 5-(3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-N-(4- ((benzyloxy)methyl)-3-fluorophenyl)-2-fluorobenzamide in 21% yield. LCMS: Method A: 1.66 min, MS: ES+473.1;1H NMR (500 MHz, DMSO) δ ppm: 10.82 (s, 1H), 9.76 (s, 1H), 8.79 – 8.74 (m, 1H), 8.70 – 8.65 (m, 1H), 7.77 – 7.72 (m, 1H), 7.57 (t, J = 9.2 Hz, 1H), 7.53 – 7.44 (m, 2H), 7.37 (d, J = 5.3 Hz, 4H), 7.33 – 7.27 (m, 1H), 4.56 (s, 2H), 4.55 (s, 2H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 103 N-(4-((Benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(7-methyl-3H-[1,2,3]triazolo[4,5- d]pyrimidin-5-yl)benzamide Using N-(4-((benzyloxy)methyl)-3-fluorophenyl)-5-(4,5-diamino-6-methylpyrimidin-2-yl)-2- fluorobenzamide (I-62) was obtained N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(7- methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)benzamide in 26% yield. LCMS: Method A: 1.84 min, MS: ES+487.1;1H NMR (500 MHz, DMSO) δ ppm: 10.82 (s, 1H), 8.79 – 8.72 (m, 1H), 8.71 – 8.65 (m, 1H), 7.77 – 7.71 (m, 1H), 7.56 (t, J = 9.2 Hz, 1H), 7.53 – 7.45 (m, 2H), 7.41 – 7.34 (m, 4H), 7.34 – 7.27 (m, 1H), 4.56 – 4.54 (m, 4H), 2.99 (s, 3H).1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 104 N-(4-((Benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(7-(trifluoromethyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-5-yl)benzamide Using N-(4-((benzyloxy)methyl)-3-fluorophenyl)-5-(4,5-diamino-6-(trifluoromethyl)pyrimidin- 2-yl)-2-fluorobenzamide (I-63) was obtained N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2- fluoro-5-(7-(trifluoromethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)benzamide in 36% yield. LCMS: Method A: 1.99 min, MS: ES+541.1;1H NMR (500 MHz, DMSO) δ ppm: 10.84 (s, 1H), 8.74 – 8.71 (m, 1H), 8.69 – 8.63 (m, 1H), 7.78 – 7.73 (m, 1H), 7.56 (t, J = 9.2 Hz, 1H), 7.53 – 7.44 (m, 2H), 7.37 (d, J = 5.0 Hz, 4H), 7.33 – 7.28 (m, 1H), 4.56 (s, 2H), 4.55 (s, 2H). 1 H obscured / not observed. The isolated compound contains up to 1 mol. eq. of ammonia. Example 105 5-(3H-[1,2,3]Triazolo[4,5-d]pyrimidin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2- fluorobenzamide Using N-(4-((benzyloxy)methyl)phenyl)-5-(4,5-diaminopyrimidin-2-yl)-2-fluorobenzamide (I- 64) and with trituration with water in place of RP chromatography was obtained 5-(3H- [1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide in 86% yield. LCMS: Method A: 1.71 min, MS: ES+455.1;1H NMR (500 MHz, DMSO) δ ppm: 10.62 (s, 1H), 9.84 (s, 1H), 8.76 (dd, J = 6.9, 2.3 Hz, 1H), 8.69 – 8.65 (m, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.57 (t, J = 9.2 Hz, 1H), 7.41 – 7.34 (m, 6H), 7.33 – 7.26 (m, 1H), 4.53 (s, 2H), 4.51 (s, 2H).1 H obscured / not observed. Example 106 5-(3H-[1,2,3]Triazolo[4,5-d]pyrimidin-5-yl)-2-fluoro-N-(4-phenethoxyphenyl)benzamide Using 5-(4,5-diaminopyrimidin-2-yl)-2-fluoro-N-(4-phenethoxyphenyl)benzamide (I-65) and with trituration with water and MeOH in place of RP chromatography was obtained 5-(3H- [1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-2-fluoro-N-(4-phenethoxyphenyl)ben...

Claims

CLAIMS 1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein: ring A is a phenyl group or a 5- or 6-membered heteroaryl group; ring B is absent, or is selected from phenyl, pyridinyl, pyradizinyl, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, isothiazolyl and thiazolyl; ring C is a fused bicyclic group of formula:wherein X1-X9form a heteroaryl group containing at least one N and at least one NH, wherein said heteroaryl group is optionally further substituted by one or more substituents each independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, NR10SO2-R12, NR11COR13, NR14R15, CO2R16, SO2NR17R18, CONR19R20, cycloalkyl and (CH2)q-heterocycloalkyl; X-Y is -(CH2)mNR21CO; L is a direct bond or is a group selected from, -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR22-SO2-, -NR22-SO2-alkylene, alkylene-SO2-NR22-, -SO2-NR22-, -SO2-NR22- alkylene, alkylene-NR22-SO2-, alkylene, alkenylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, - SO-alkylene, alkylene-SO2-alkylene, alkylene-SO-alkylene, -O-cycloalkylene, cycloalkylene-O-, -O-heterocycloalkylene, heterocycloalkylene-O-, cycloalkylene-alkylene, alkylene- heterocycloalkylene, heterocycloalkylene-alkylene, -CO-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO-, CO2-heterocycloalkylene-alkylene, alkylene- heterocycloalkylene-CO2-, -CO2-heteroalkylene, heteroalkylene-CO2-, heteroalkylene- heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, wherein the alkylene, heteroalkylene, cycloalkylene and heterocycloalkylene moiety in each of the above groups is optionally substituted by one or more substituents independently selected from halo, alkyl, haloalkyl and cycloalkyl; 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; each Raand each Rbis independently selected from alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR23COR25, NR24-SO2R26, (CH2)qSR27, (CH2)qSOR28, (CH2)qSO2R29, SO2NR30R31, (CH2)qOH, (CH2)qOR32, NR33R34, CONR35R36, cycloalkyl and (CH2)q-heterocycloalkyl; R10, R11, R21, R22, R23and R24are each independently selected from H and alkyl; R12-R20, and R25-R36are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; m, n and p are each independently an integer from 0 to 4; and each q is independently an integer from 0 to 4.

2. A compound according to claim 1 wherein X-Y is selected from NH-CO, -CH2NH-CO and N(Me)CO, more preferably NH-CO.

3. A compound according to claim 1 or claim 2 wherein ring A is: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 in claim 1.

4. A compound according to any preceding claim wherein ring 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 three Ragroups.

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

6. A compound according to any preceding claim wherein B is selected from phenyl and pyridinyl, more preferably phenyl, optionally substituted by one to four Rbgroups as defined in claim 1.

7. 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.

8. A compound according to any preceding claim wherein p is 0.

9. A compound according to any preceding claim wherein X1, X3and X7in ring C are all sp2carbon atoms.

10. A compound according to any preceding claim wherein ring C is a group C-1:wherein: X2is N or CR2; X4is NH; X5and X6are both N; or X5is N and X6is CR6; or X5is CR5and X6is N; X8is N or CR8; X9is N or CR9; andR2, R5, R6, R8and R9are each independently selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR14R15, OH, NR10SO2-alkyl, CONR19R20, cycloalkyl and (CH2)q- heterocycloalkyl.

11. A compound according to claim 10 wherein X5and X6are both N.

12. A compound according to any preceding claim wherein ring C is a group C-1a,wherein R8and R9are each independently selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR14R15, OH, NR10SO2-alkyl, CONR19R20, cycloalkyl and (CH2)q- heterocycloalkyl.

13. A compound according to claim 10 wherein ring C is a group C-1b,wherein R9is selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR14R15, OH, NR10SO2- alkyl, CONR19R20, cycloalkyl and (CH2)q-heterocycloalkyl.

14. A compound according to claim 10 wherein ring C is a group C-1c,wherein R8is selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR14R15, OH, NR10SO2- alkyl, CONR19R20, cycloalkyl and (CH2)q-heterocycloalkyl.

15. A compound according to claim 10 wherein ring C is a group C-1d,wherein R2and R9are each independently selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR14R15, OH, NR10SO2-alkyl, CONR19R20, cycloalkyl and (CH2)q-heterocycloalkyl, preferably wherein R2and R9are each independently selected from H and alkyl.

16. A compound according to claim 10 wherein ring C is a group C-1e,wherein R2, R8and R9are each independently selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR14R15, OH, NR10SO2-alkyl, CONR19R20, cycloalkyl and (CH2)q-heterocycloalkyl, preferably wherein R2, R8and R9are each independently selected from H, alkyl and halo.

17. A compound according to any preceding claim wherein ring C is a group selected from the following:

18. 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.

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

20. 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.

21. A compound according to any preceding claim wherein 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-, -CH2-SO2-NH-, -O-SO2-, -SO2-O-, -SO2-NH-, -SO2-NH-CH2-, -CH2-NH-SO2-, -SO2-NH- CH2CH2-, - CH2CH2-NH-SO2-, -CH2CH2CH2CH2O-, -OCH2CH2CH2CH2-, -CH2SO2-, - SO2CH2-, -OCH2CO-, -COCH2O-, -CH2SO-, -SOCH2-, -CH2OCH2, -OCH2SCH2-,- CH2SCH2O-, -CH=CH-, -OCH2CO2-, -CO2CH2O-, -OCH(Me)-, -CH(Me)O-, -OCH(CF3)-, - CH(CF3)O-, -CH2CH(CF3)-, -CH(CF3)CH2-, -SO2N(Me)-, -N(Me)SO2-,22. A compound according to any preceding claim wherein L-Z is selected from -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, -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,23. A compound according to any preceding claim wherein L-Z is -OCH2CH2Ph, -OCH2CH2CH2CH2Ph or -CH2OCH2Ph, more preferably -OCH2CH2Ph.

24. A compound according to any preceding claim which is selected from the following:312and pharmaceutically acceptable salts and solvates thereof.

25. A compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof,wherein: ring A is a phenyl group or a 5- or 6-membered heteroaryl group; ring B is absent, or is a phenyl group or a 5- or 6-membered heteroaryl group; ring C is a fused bicyclic group of formula:wherein X1-X9form a heteroaryl group containing at least one N and at least one NH, wherein said heteroaryl group is optionally further substituted by one or more substituents each independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, NR10SO2-R12, NR11COR13, NR14R15, CO2R16, SO2NR17R18, CONR19R20, cycloalkyl and (CH2)q-heterocycloalkyl; X-Y is CONR21-(CH2)m-; L is a direct bond or is a group selected from, -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR22-SO2-, -NR22-SO2-alkylene, alkylene-SO2-NR22-, -SO2-NR22-, -SO2-NR22- alkylene, alkylene-NR22-SO2-, alkylene, alkenylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO2-alkylene, alkylene-SO-alkylene, -O-cycloalkylene, cycloalkylene-O-, -O-heterocycloalkylene, heterocycloalkylene-O-, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, -CO-heterocycloalkylene- alkylene, alkylene-heterocycloalkylene-CO-, CO2-heterocycloalkylene-alkylene, alkylene- heterocycloalkylene-CO2-, -CO2-heteroalkylene, heteroalkylene-CO2-, heteroalkylene- heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, wherein the alkylene, heteroalkylene, cycloalkylene and / or heterocycloalkylene moiety in the above groups is optionally substituted by one or more substituents independently selected from halo, alkyl, haloalkyl and cycloalkyl; Z is a group selected from 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; with the proviso that L cannot be a direct bond when Z is phenyl; each Raand each Rbis independently selected from alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR23COR25, NR24-SO2R26, (CH2)qSR27, (CH2)qSOR28, (CH2)qSO2R29, SO2NR30R31, (CH2)qOH, (CH2)qOR32, NR33R34, CONR35R36, cycloalkyl and (CH2)q-heterocycloalkyl; R10, R11, R21, R22, R23and R24are each independently selected from H and alkyl;R12-R20, and R25-R36are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; m, n and p are each independently an integer from 0 to 4; and each q is independently an integer from 0 to 4.

26. A compound according to claim 25, wherein X-Y is selected from -CONH-, -CONHCH2- and -CON(Me)-, more preferably -CONH-.

27. A compound according to claim 25 or claim 26, wherein ring A is as defined in any one of claims 3 to 5.

28. A compound according to any one of claims 25 to 27, wherein ring B is absent, or is selected from phenyl, pyridinyl, pyradizinyl, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, isothiazolyl and thiazolyl, each of which is optionally substituted by one to four Rbgroups.

29. A compound according to any one of claims 25 to 28, wherein ring B is as defined in one of claims 6 to 8 above.

30. A compound according to any one of claims 25 to 29, wherein ring C is as defined in any one of claims 9 to 17 above.

31. A compound according to any one of claims 25 to 29, wherein, L and / or Z are as defined in any one of claims 18 to 23 above.

32. A compound according to any one of claims 25 to 30, which is selected from the following:and pharmaceutically acceptable salts and solvates thereof.

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

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

35. A compound according to any one of claims 1 to 32, or a pharmaceutical composition according to claim 33, for use in treating or preventing a disorder selected from a proliferative disorder, a fibrotic disorder, a gastrointestinal disorder, an inflammatory disorder, an immune disorder and a cardiovascular disease.

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

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

38. A compound or pharmaceutical composition for use according to claim 35, wherein the disorder is a gastrointestinal disorder, preferably selected from inflammatory bowel disease, ulcerative colitis, primary sclerosing cholangitis and Crohn’s disease.

39. A compound or pharmaceutical composition for use according to claim 35, wherein the disorder is a cardiovascular disease, preferably selected from hypertension, heart failure, atherosclerosis, peripheral vascular disease and stroke.

40. A compound or pharmaceutical composition for use according to any one of claims 35 to 39, wherein the use comprises modulating GPR35, preferably wherein the use comprises inhibiting GPR35 signalling.

41. A method of treating a disorder as defined in any of claims 35 to 39, comprising administering to a subject a compound as defined in any of claims 1 to 32, or a pharmaceutical composition as defined in claim 33.

42. A compound as defined in any one of claims 1 to 32, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 33, for use in treating or preventing a GPR35-associated disease or disorder.

43. Use of a compound as defined in any one of claims 1 to 32, 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.

44. Use of a compound as defined in any one of claims 1 to 32, 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, a fibrotic disorder, an immune disorder and a cardiovascular disease.

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