Bicyclic heteroaryl compounds for use as GPR35 modulators

Abstract

One aspect of the present 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 phenyl, pyridinyl, pyrazidinyl, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, isothiazolyl or thiazolyl; Ring C is a fused bicyclic group of formula: (AA), wherein X1 to X9 form a substituted heteroaryl group containing at least one N and at least one NH; X-Y is -(CH2) m NR 21 CO; L is a direct bond or a linker group; Z is selected from alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl, each of which may be substituted; each R a and each R b is independently selected from alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR 23 COR 25 、NR 24 -SO2R 26 、(CH2) q SR 27 、(CH2) q SOR 28 、(CH2) q SO2R 29 、SO2NR 30 R 31 、(CH2) q OH、(CH2) q OR 32 、NR 33 R 34 、CONR 35 R 36 、cycloalkyl and (CH q 2)-heterocycloalkyl; R 10 、R 11 、R 21 、R 22 、R 23 and R 24 are each independently selected from H and alkyl; R 12 ~R 20 、and R 25 ~R36 Each of the following is independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, and cycloalkyl; each of m, n, and p is independently an integer from 0 to 4; and each of q is independently an integer from 0 to 4. Further aspects of the present invention relate to pharmaceutical compositions comprising the compounds according to the present invention and the use of the compounds in the treatment of various GPR35-related disorders. [Formula 1] TIFF2026510355000540.tif56170

Description

[Technical Field]

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

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

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

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

[0005] [Non-Patent Document 1] Quon et al, ACS Pharmacology and Translational Science 3, 801-812 (2020) [Non-Patent Document 2] Kaya et al, Frontiers in Immunology 12: 717392 (2021) [Non-Patent Document 3] Wang et al, J Biol Chem 281, 22021-22028 (2006) [Non-licensed Document 4] Kapolka et al, PNAS 117, 13117-13126 (2020) [Non-licensed Document 5] Giovanni et al, Cell 185, 815-830.e19 (2022) [Non-licensed Document 6] Oka et al, Biochem & Biophys Res Comms 395, 232-237 (2010) [Non-licensed Document 7] Deng et al. Scientific Reports 2, Article number: 373 (2012) [Non-licensed Document 8] Maravillas-Montero et al, J Immunology 194, 29-33 (2015) [Non-licensed Document 9] Lee et al Journal of Agricultural and Food Chem 70, 27, 8365-8376 (2022) [Non-licensed Document 10] Jenkins et al, Biochem J 432, 451-419 (2010) [Non-licensed Document 11] Yang et al, Pharmacology 86, 1-5. doi: 10.1159 / 000314164. Epub (2010) [Non-licensed Document 12] Taniguchi et al. FEBS Letters 580, 5003-5008 (2006) [Non-licensed Document 13] MacKenzie et al, Molecular Pharmacology 85, 91-104 (2014) [Non-licensed Document 14] Wei et al, J Med Chem 64, 2634-2647 (2021) [Non-licensed Document 15] Abdalhameed et al. Bioorg Med Chem Lett 27, 612-615 (2017)

Non-licensed Document 16

Non-licensed Document 17

Non-licensed Document 18

Non-licensed Document 19

Non-licensed Document 20

Non-licensed Document 21

Non-licensed Document 22

Non-licensed Document 23

Non-licensed Document 24

Non-licensed Document 25

Non-licensed Document 26

Non-licensed Document 27

Non-licensed Document 28

Non-licensed Document 29

Non-licensed Document 30

Non-licensed Document 31

Non-licensed Document 32

Non-licensed Document 34

Non-licensed Document 35

Non-licensed Document 36

Non-licensed Document 37

Non-licensed Document 38

[0006] The present invention aims to provide compounds that can modulate GPR35. As has become clear from the above discussion, such compounds have potential therapeutic applications in the treatment of various disorders, including proliferative disorders, immune disorders, and inflammatory disorders. [Means for solving the problem]

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

Chemical formula

Chemical formula

[0008] A second aspect of the present invention relates to a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, [ka] During the ceremony: Ring A is a phenyl group or a 5-membered or 6-membered heteroaryl group; Ring B is either absent or is a phenyl group or a 5-membered or 6-membered heteroaryl group; Ring C is given by the formula: [ka] It is a condensed bicyclic group, In the formula, X1 to X9 form a heteroaryl group containing at least one N and at least one NH, wherein the heteroaryl group is alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, or NR. 10 SO2-R 12 , NR 11 COR 13 , NR 14 R 15 CO2R 16 SO2NR 17 R 18 CONR 19 R 20 , cycloalkyl and (CH2) q -These may be further substituted with one or more substituents independently selected from each heterocycloalkyl group; XY is CONR 21 -(CH2) m -and; L is a direct bond, or -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR 22 -SO2-, -NR 22 -SO2-alkylene, alkylene-SO2-NR 22 -, -SO2-NR 22 -, -SO2-NR 22 -Alkylene, Alkylene-NR 22-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- A group selected from CO-,CO2-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO2-,-CO2-heteroalkylene, heteroalkylene-CO2-,heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, where the alkylene, heteroalkylene, cycloalkylene and / or heterocycloalkylene portions of the above groups may be substituted with one or more substituents independently selected from halo, alkyl, haloalkyl and cycloalkyl; Z is a group selected from cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups, each of which may be further substituted with one or more groups independently selected from CN, halo, alkyl, OH, alkenyl, alkynyl, alkoxy, haloalkyl, and haloalkoxy groups; However, L cannot be directly bonded if Z is phenyl; Each R a and each R b These include alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, and NR. 23 COR 25 , NR 24 -SO2R 26 , (CH2) q SR 27 , (CH2) q SOR 28 , (CH2) qSO2R 29 、SO2NR 30 R 31 、(CH2) q OH、(CH2) q OR 32 、NR 33 R 34 、CONR 35 R 36 、 cycloalkyl and (CH2) q -heterocycloalkyl, independently selected; R 10 、R 11 、R 21 、R 22 、R 23 and R 24 are each independently selected from H and alkyl; R 12 ~R 20 、 and R 25 ~R 36 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; each q is independently an integer from 0 to 4.

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

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

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

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

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

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

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

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

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

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

[0019] "Alkyl" is defined herein as a linear or branched alkyl radical, preferably C 1-20 Alkyl, more preferably C 1-12 Alkyl, more preferably C 1-10 Alkyl or C 1-6 Alkyls include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. More preferably, the alkyl is C1-3 It is alkyl.

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

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

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

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

[0024] "Alkoxy" is defined herein as an oxygen atom bonded to the alkyl group defined above. Preferably, the alkoxy group is C 1-20 Alkoxy, comfort C 1-12 Alkoxy, more preferably C 1-10 Alkoxy or C1-6 Alkoxy compounds include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy. A particularly preferred example is methoxy(-OCH3).

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

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

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

[0028] "Hypercycloalkyl" refers to a cyclic aliphatic group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, which may be interrupted by one or more -(CO)- groups in the ring and / or may contain one or more double bonds in the ring. Preferably, the heterocycloalkyl group is monocyclic or bicyclic. Preferably, the heterocycloalkyl group is C 3-7 -heterocycloalkyl, more comfortably C 3-6 -It is a heterocycloalkyl group. Alternatively, a heterocycloalkyl group is C 4-7 -heterocycloalkyl, more comfortably C4-6 - It is a heterocycloalkyl group. Preferred heterocycloalkyl groups include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranil, tetrahydropyranil, oxetanil, and azetidinil. Preferably, the heterocycloalkyl group is monovalent. Preferably, the heterocycloalkyl group is monocyclic.

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

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

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

[0032] As used herein, the term "alkenylene" refers to a linear or branched divalent hydrocarbon radical containing at least one carbon-carbon double bond. Preferably, the alkenylene group is a linear divalent hydrocarbon radical containing 2 to 6 carbon atoms, or a branched divalent hydrocarbon radical containing 3 to 6 carbon atoms.

[0033] As used herein, the term "heteroalkylene" refers to a divalent alkylene having one or more carbon atoms substituted with a heteroatom, such as sulfur, oxygen, or nitrogen (for example, in the form NR where R is H or alkyl). Heteroalkylene groups can be linked to adjacent groups via carbon or heteroatoms.

[0034] Preferably, the heteroalkylene group is a divalent alkylene having one or two carbon atoms, more preferably one carbon atom, which are replaced by a group selected from sulfur, oxygen, and nitrogen.

[0035] Preferably, the heteroalkylene group is a divalent alkylene having one or more carbon atoms substituted with oxygen, more preferably one or two carbon atoms substituted with oxygen, and more preferably one carbon atom substituted with oxygen.

[0036] Preferably, the heteroalkylene group is a linear saturated divalent hydrocarbon radical containing 2 to 6 carbon atoms in which one carbon is replaced by a heteroatom, or a branched saturated divalent hydrocarbon radical containing 3 to 6 carbon atoms in which one carbon is replaced by a heteroatom.

[0037] As used herein, the term "cycloalkylene" refers to a divalent cyclic saturated hydrocarbon radical preferably containing 3 to 10 carbon atoms. Preferably, the cycloalkylene group is a 3-membered, 4-membered, 5-membered, or 6-membered cycloalkylene group, more preferably a 3-membered, 4-membered, or 5-membered cycloalkylene group.

[0038] As used herein, the term “heterocycloalkylene” refers to a divalent cycloalkylene group as defined above, having one or more carbon atoms replaced by heteroatoms, such as sulfur, oxygen, or nitrogen. When a carbon atom in a cycloalkylene group is replaced by nitrogen, the nitrogen may be in the form of NR, where R is H or alkyl, or the nitrogen may be linked to an adjacent group in the heterocycloalkylene group, as illustrated below, for example: [ka]

[0039] Preferably, the heterocycloalkylene group is a 3-membered, 4-membered, 5-membered, or 6-membered heterocycloalkylene group, more preferably a 3-membered, 4-membered, or 5-membered heterocycloalkylene group.

[0040] When used herein, alkyl is preferably C 1- It is a C6 alkyl, and haloalkyl is C 1- C6 haloalkyl, and haloalkoxy is C 1- It is a C6 haloalkoxy, where alkoxy is C 1- It is a C6 alkoxy.

[0041] Compound of formula (I') One aspect of the present invention relates to a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, [ka] During the ceremony: Ring A is a phenyl group or a 5-membered or 6-membered heteroaryl group; Ring B is either absent or is a phenyl group or a 5-membered or 6-membered heteroaryl group; Ring C is given by the formula: [ka] It is a condensed bicyclic group, In the formula, X1 to X9 form a heteroaryl group containing at least one N and at least one NH, wherein the heteroaryl group is alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, or NR. 10 SO2-R 12 , NR 11 COR 13 , NR 14 R 15 CO2R 16 SO2NR 17 R 18 CONR 19 R 20 , cycloalkyl and (CH2) q -These may be further substituted with one or more substituents independently selected from each heterocycloalkyl group; XY is CONR 21 -(CH2) m -and-(CH2) m NR 21 Selected from CO; L is a direct bond, or -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR 22 -SO2-, -NR 22 -SO2-alkylene, -SO2-NR 22 -, -SO2-NR 22-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 A group selected from -CO-, CO2-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO2-, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, where the alkylene portion of the above group may be substituted with one or more substituents independently selected from halo, alkyl, haloalkyl, and cycloalkyl; Z is a group selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups, each of which may be further substituted with one or more groups independently selected from CN, halo, alkyl, OH, alkenyl, alkynyl, alkoxy, haloalkyl, and haloalkoxy groups; Each R a and each R b These include alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, and NR. 23 COR 25 , NR 24 -SO2R 26 , (CH2) q SR 27 , (CH2) q SOR 28 , (CH2) q SO2R 29 SO2NR 30 R 31 , (CH2) q OH, (CH2) q Ure 32 , NR 33 R 34 CONR 35 R36 , cycloalkyl and (CH2) q -Selected independently from heterocycloalkyl groups; R 10 , R 11 , R 21 , R 22 , R 23 and R 24 is independently selected from H and alkyl; R 12 ~R 20 , and R 25 ~R 36 Each of these is independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, and cycloalkyl; m, n, and p are each independent integers between 0 and 4; Each q is an independent integer between 0 and 4.

[0042] In one preferred embodiment, R 10 , R 11 , R 23 and R 24 These are independently selected from H and Me, more preferably from H.

[0043] In one preferred embodiment, R 12 ~R 20 and R 25 ~R 36 Each of these is independently selected from alkyl groups.

[0044] In a preferred embodiment, ring B in formula (I') is selected from phenyl, pyridinyl, pyrazidinyl, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, isothiazolyl and thiazolyl, each of which has 1 to 4 R as defined above. b It may be substituted by a base.

[0045] A, B, C, X, Y, L, Z, X1~X9, R a , R b , R 10 ~R 36The preferred definitions for m, n, p, and q are as shown below for the compound of formula (I).

[0046] Compound of formula (I) One aspect of the present invention relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, i.e., [ka] Regarding In the formula, A, B, C, Z, L, R a , R b , R 21 p, m, and n are as defined above.

[0047] In one preferred embodiment, R 21 is H or Me, more preferably H.

[0048] In one preferred embodiment, m is 0, 1, or 2, more preferably 0 or 1. In one preferred embodiment, m is 0.

[0049] In one preferred embodiment, XY is selected from NH-CO, -CH2NH-CO, and N(Me)CO.

[0050] In a preferred embodiment, XY is NH-CO, i.e., the compound is of formula: [ka] And, In the formula, A, B, C, Z, L, R a , R b p and n are as defined above.

[0051] In one preferred embodiment, ring A is meta-substituted: [ka] (In the formula, ring A is a phenyl group or a 6-membered heteroaryl group.) B, C, Z, L, X, Y, R a , R b n and p are as defined above.

[0052] Therefore, in one preferred embodiment, the compound is of formula: [ka] That is the case.

[0053] In one preferred embodiment, ring A is selected from phenyl, pyridinyl, pyrimidinyl, and pyrazinyl, more preferably from phenyl and pyridinyl, each of which has 1 to 3 R a It may be substituted by a base.

[0054] In a preferred embodiment, ring A has 1 to 3 R a R may be substituted by a group, preferably one or two R groups. a More preferably, one R may be substituted by a group. a This is a phenyl group that may be substituted with another group.

[0055] In one preferred embodiment, the compound is of the formula: [ka] That is the case.

[0056] In another preferred embodiment, ring A is: [ka] (In the formula, A is a 5-membered heteroaryl group.) And Z, L, B, X, Y, X1-X5, R2, R a , R b n and p are as defined above.

[0057] Therefore, in one preferred embodiment, the compound is of formula: [ka] That is the case.

[0058] In a preferred embodiment, ring A is selected from pyrrolyl, thiazolyl, oxazolyl, furanyl, thienyl, and pyrazolyl, each of which has 1 to 3 R a It may be substituted by a base.

[0059] In one preferred embodiment, each R a C 1-6 -alkyl, halo, C 1-6 -Haloalkyl, C 1-6 -alkoxy, C 3-6 -Cycloalkoxy, C 1-6 - Haloalkoxy, cyano, NHCO-C 1-6 -alkyl, NHSO2-C 1-6 -alkyl, SC 1-6 -alkyl, SO-C 1-6 -alkyl, CH2SO2-C 1-6 -alkyl, SO2-C 1-6 -alkyl, SO2N(C 1-6 -alkyl)2,CH2OH,CH2O-C 1-6 -alkyl, N(C 1-6 -alkyl)2, CON(C 1-6 A CH2-heterocycloalkyl element is independently selected from CH2-alkyl, cycloalkyl, heterocycloalkyl, and CH2-heterocycloalkyl elements.

[0060] In one preferred embodiment, each R a C 1-6 -alkyl, halo, C 1-6 -Haloalkyl, C 1-6 -alkoxy, C 3-6 -Cycloalkoxy and C 1-6 - Selected independently of haloalkoxys.

[0061] In one preferred embodiment, each R aThe following are 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.

[0062] In one preferred embodiment, each R a R is 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 R a This is independently selected from Me, Cl, F, CF3, OMe, OCF3, amino and cyano, more preferably halo, and even more preferably F.

[0063] In one preferred embodiment, n is 1 or 2, more preferably 1.

[0064] In one preferred embodiment, n is 0.

[0065] In the compound of formula (I), ring B is selected from phenyl, pyridinyl, pyrazidinel, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, isothiazolyl, and thiazolyl, each of which has 1 to 4 R as defined above. b It may be substituted by a base.

[0066] When used throughout, if B is a 6-membered group, preferably the LZ group is in the para position relative to the XY group. Therefore, in one preferred embodiment, the compound has the following formula: [ka] (preferably, when X is NH and Y is CO).

[0067] In a preferred embodiment, ring B has 1 to 4 R as described above.b Phenyl and pyridinyl, which may be substituted with a group, are selected, more preferably from phenyl.

[0068] In one preferred embodiment, each R b C 1-6 -alkyl, halo, C 1-6 -Haloalkyl, C 1-6 -alkoxy, C 3-6 -Cycloalkoxy and C 1-6 - Selected independently of haloalkoxys.

[0069] In one preferred embodiment, each R b The following are independently selected from Me, halo, CF3, OMe, OCF3, amino, cyano, NHCOMe, NHSO2Me, S-Me, CH2SO2Me, SO2Me, SO2NMe2, CH2OH, CH2OMe, cycloalkyl, CH2-N-morpholinyl, and N-morpholinyl.

[0070] In all of the embodiments described herein, ring B is preferably a phenyl group or a pyridinyl group, each of which has 1 to 4 R groups as defined above. b It may be substituted by a base.

[0071] In a preferred embodiment, ring B is a phenyl group which may be substituted with one or two groups selected from halo, CN and alkoxy, more preferably halo and alkoxy.

[0072] In a preferred embodiment, ring B is a phenyl group which may be substituted with one or two halo groups.

[0073] In one preferred embodiment, p is 1.

[0074] In one preferred embodiment, p is 0.

[0075] In one preferred embodiment, B is absent, and the LZ group is bonded to X.

[0076] In one preferred embodiment, X1, X3, and X7 in ring C are all sp 2 It is a carbon atom.

[0077] In one preferred embodiment, R 33 and R 34 is independently selected from H and alkyl. Preferably, R 33 and R 34 Both are H.

[0078] In the compound according to the present invention, ring C is of formula: [ka] It is a condensed bicyclic group, In the formula, X1 to X9 form a heteroaryl group containing at least one N and at least one NH, and the heteroaryl group may be further substituted.

[0079] In one preferred embodiment, the ring C has a C-1 group: [ka] (In the formula: X2 is either N or CR2; X4 is NH; Both X5 and X6 are N; or X5 is N and X6 is CR6; or X5 is CR5 and X6 is N; X8 is either N or CR8; X9 is either N or CR9; R2, R5, R6, R8 and R9 are H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR 14 R 15 , OH, NR 10 SO2-alkyl, CONR 19 R 20 , cycloalkyl and (CH2) q(Each is independently selected from heterocycloalkyl groups.) That is the case.

[0080] In one preferred embodiment, both X5 and X6 are N. That is, ring C is a condensed triazole.

[0081] As used herein, for compounds in which both X5 and X6 are N, for example, those skilled in the art will know that the condensed bicyclic group is as follows: [ka] It should be understood that they can exist in a number of different tautomer forms that can be represented as shown.

[0082] Those skilled in the art will understand that similar tautomer forms may exist for compounds in which X5 is N and X6 is CR6, or in which X5 is CR5 and X6 is N.

[0083] For ease of reference throughout, only one tautomer representation is shown (see, for example, formulas C-1a, C-1b, C-1c, C-1d, and C-1e below).

[0084] In one preferred embodiment, R2, R5, R6, R8 and R9 are H, C 1-6 -alkyl, C 1-6 -Haloalkyl, C 1-6 -alkoxy, C 1-6 - Haloalkoxy, Cl, F, NH2, NH-C 1-6 -alkyl, NH-C 3-6 -Cycloalkyl, N(C) 1-6 -alkyl)2,OH,NHSO2-C 1-6 -alkyl, CONR 18 R 19 , C 3-6 -Cycloalkyl, NH-(hydroxy-C) 1-6 -alkyl), NH-(C 1-6 -alkoxy), CH2-C 3-7 -heterocycloalkyl and C 3-7-Each is independently selected from heterocycloalkyl groups.

[0085] In a preferred embodiment, R2, R5, R6, R8, and R9 are 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.

[0086] In one preferred embodiment, the ring C is a C-1a group, [ka] In the formula, R8 and R9 are H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR 14 R 15 , OH, NR 10 SO2-alkyl, CONR 19 R 20 , cycloalkyl and (CH2) q -Each is independently selected from heterocycloalkyl groups.

[0087] In one preferred embodiment, the ring C is a C-1b group, [ka] In the formula, R9 is H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR 14 R 15 , OH, NR 10 SO2-alkyl, CONR 19 R 20 , cycloalkyl and (CH2) q - Selected from heterocycloalkyl groups. Preferably, R9 is H.

[0088] In one preferred embodiment, the ring C is a C-1c group, [ka] In the formula, R8 is H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR 14 R 15 , OH, NR 10 SO2-alkyl, CONR 19 R 20 , cycloalkyl and (CH2) q - Selected from heterocycloalkyl groups. Preferably, R8 is H.

[0089] In one preferred embodiment, the ring C is a C-1d group, [ka] In the formula, R2 and R9 are H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR 14 R 15 , OH, NR 10 SO2-alkyl, CONR 19 R 20 , cycloalkyl and (CH2) q -Each is independently selected from heterocycloalkyl groups, and preferably, R2 and R9 are independently selected from H and alkyl groups, respectively. Preferably, R2 and R9 are H.

[0090] In one preferred embodiment, the ring C is a C-1e group, [ka] In the formula, R2, R8 and R9 are H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, and NR. 14 R 15 , OH, NR 10 SO2-alkyl, CONR 19 R 20 , cycloalkyl and (CH2) q -Each is independently selected from heterocycloalkyl groups, and preferably R2, R8, and R9 are independently selected from H, alkyl, and halo. Preferably, R2, R8, and R9 are H.

[0091] In each of the above embodiments, q is preferably 0 or 1, more preferably 0.

[0092] In one preferred embodiment, R 10 , R 14 , R 15 , R 19 and R 20 These are selected independently from H and Me, respectively.

[0093] In one preferred embodiment, ring C is: [ka] It is a base selected from among them.

[0094] In one preferred embodiment, Z is C 1-6 -alkyl, phenyl, heteroaryl, C 3-6 -A group selected from cycloalkyl and 4-membered, 5-membered, or 6-membered heterocycloalkyl groups, each of which may be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, CN, haloalkyl, and alkoxy.

[0095] In one preferred embodiment, Z is phenyl, heteroaryl, C 3-6 -A group selected from cycloalkyl and 4-membered, 5-membered, or 6-membered heterocycloalkyl groups, each of which may be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, CN, haloalkyl, and alkoxy.

[0096] In one preferred embodiment, Z is C 1-6 -Alkyl, phenyl, C 3-6 -A group selected from cycloalkyl and 5-membered or 6-membered heterocycloalkyl groups, each of which may be further substituted with one or more groups selected from alkyl, halo, haloalkyl, CN, alkenyl, alkynyl, and alkoxy.

[0097] In a preferred embodiment, Z is a group selected from phenyl, pyridinyl, piperidinyl, cyclopropyl, and tetrahydropyranyl, more preferably phenyl, each of which may be further substituted with one or more groups selected from alkyl, halo, haloalkyl, CN, alkenyl, alkynyl, and alkoxy.

[0098] In a preferred embodiment, Z is a group selected from phenyl and heteroaryl groups, each of which may be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, CN, haloalkyl, and alkoxy groups.

[0099] In a preferred embodiment, Z is a phenyl group which may be substituted with one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, CN, haloalkyl, and alkoxy.

[0100] In a preferred embodiment, Z is a group selected from phenyl, alkyl, tolyl, morpholinyl, pyrazolyl, oxetanyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, and tetrahydropyranyl.

[0101] In a preferred embodiment, Z is a group selected from phenyl, tolyl, morpholinyl, pyridinyl, pyrazolyl, oxetanyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, and tetrahydropyranyl.

[0102] In a preferred embodiment, Z is a group selected from phenyl, cyclopropyl, and tetrahydropyranyl, more preferably phenyl. More preferably, Z is phenyl.

[0103] In the compounds described herein, L is a direct bond, or -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR22 -SO2-, -NR 22 -SO2-alkylene, alkylene-SO2-NR 22 -, -SO2-NR 22 -, -SO2-NR 22 -Alkylene, Alkylene-NR 22 -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 The group is selected from -CO-, CO2-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO2-, -CO2-heteroalkylene, heteroalkylene-CO2-, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, where the alkylene, heteroalkylene, cycloalkylene, and heterocycloalkyl portions of each of the above groups may be substituted with one or more substituents independently selected from halo, alkyl, haloalkyl, and cycloalkyl.

[0104] In a preferred embodiment, L is a direct bond, or -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR 22 -SO2-, -NR 22 -SO2-alkylene, -SO2-NR 22 -, -SO2-NR 22-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 The group is selected from n-CO-, CO2-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO2-, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, where the alkylene portion of the above group may be substituted with one or more substituents independently selected from halo, alkyl, haloalkyl, and cycloalkyl.

[0105] Preferably, R 22 is H or Me, more preferably H.

[0106] In one preferred embodiment, L is absent, and the Z group is directly bonded to the B ring.

[0107] In one preferred embodiment, L is present.

[0108] In one preferred embodiment, L is -O-.

[0109] In one preferred embodiment, L is a heteroalkylene group as defined above.

[0110] In one preferred embodiment, L is an alkylene group having one or two carbon atoms, more preferably one carbon atom, substituted with a group selected from sulfur, oxygen, and nitrogen. In one preferred embodiment, L is an alkylene group having one or two carbon atoms, more preferably one carbon atom, substituted with oxygen. In one preferred embodiment, the heteroalkylene is a group selected from -O-alkylene, alkylene-O-, and alkylene-O-alkylene.

[0111] In one preferred embodiment, L is -(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 - Select from the options.

[0112] In one preferred embodiment, L is -(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 -Selected from. In one preferred embodiment, L is -O-CO-, -CO-O-, -O-CO-O-, -O-, -NH-SO2-, -NH-SO2-(CR'R) a -,-(CR'R) a -SO2-NH-, -SO2-NH-, -SO2-NH-(CR'R”) a -,-(CR'R) a -NH-SO2-, -O-SO2-, -SO2-O-, -(CR'R”) a -,-(CH=CH) c -,-(CR'R) a-(CH=CH) c -,-(CH=CH) c -(CR'R) a -,-(CR'R) a -(CH=CH) c -(CR'R) b -,-(CR'R) a -O-, -O-(CR'R) a -,-(CR'R) a -O-(CR'R) b -,-(CR'R) a -S-(CR'R) b -,-(CR'R) a -SO2-, -SO2-(CR'R)" b -,-(CR'R) a -SO-, -SO-(CR'R) b -,-(CR'R) a -SO-(CR'R) b -,-(CR'R) a -SO2-(CR'R) b -,-(CR'R) a -S-(CR'R) b -O-, -O-(CR'R) a -S-(CR'R) b -,-(CR'R) a -O-(CR'R) b -S-, -S-(CR'R) a -O-(CR'R) b -,-(CR'R) a -S-, -S-(CR'R) a -, -O-(CR'R) a -O, heterocycloalkylene, cycloalkylene-O-, -O-cycloalkylene-, heterocycloalkylene-O-, -O-heterocycloalkylene-, heterocycloalkylene-(CR'R) a ,-(CR'R) a -heterocycloalkylene-, heterocycloalkylene-(CR'R) a -O-, -O-(CR'R) a -heterocycloalkylene-, -(CR'R)" a-O-heterocycloalkylene-, heterocycloalkylene-O-(CR'R) a ,-O-heterocycloalkylene-(CR'R) a -,-CO-heterocycloalkylene-(CR'R) a ,-(CR'R) a -heterocycloalkylene-CO-,-CO2-heterocycloalkylene-(CR'R)") a ,-(CR'R) a -heterocycloalkylene-CO2- and -(CR'R)'' a Selected from -heterocycloalkylene-O-, where a and b are each independently integers from 1 to 6, c is an integer from 1 to 3, and R' and R'' are each independently selected from H, alkyl, halo and haloalkyl, more preferably H, Me, F and CF3, even more preferably H. Preferably a and b are each independently integers from 1 to 3, more preferably 1 or 2. Preferably c is 1 or 2, more preferably 1.

[0113] In one preferred embodiment, L is -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) aSelected from heterocycloalkylene-O-, where a and b are each independently integers from 1 to 6, and c is an integer from 1 to 3. Preferably, a and b are each independently integers from 1 to 3, more preferably 1 or 2. Preferably, c is 1 or 2, even more preferably 1.

[0114] In one preferred embodiment, L is -O-CO-, -CO-O-, -O-CO-O-, -O-, -NH-SO2-, -NH-SO2-(CH2) a -, -SO2-NH-, -SO2-NH-(CH2) a -, -O-SO2-, -SO2-O-, -(CH2) a -,-(CH2) a -O-, -O-(CH2) a -,-(CH2) a -O-(CH2) b -,-(CH2) a -S-(CH2) b -,-(CH2) a -SO2-, -SO2-(CH2) b -,-(CH2) a -SO-, -SO-(CH2) b -,-(CH2) a -SO-(CH2) b -,-(CH2) a -SO2-(CH2) b -,-(CH2) a -S-(CH2) b -O-, -O-(CH2) a -S-(CH2) b -,-(CH2) a -O-(CH2) b -S-, -S-(CH2) a -O-(CH2) b -,-(CH2) a -S-, -S-(CH2) a -, -O-(CH2) a -O-, heterocycloalkylene-(CH2) a -O-, -O-(CH2) a -heterocycloalkylene-, -(CH2) a-O-heterocycloalkylene-, heterocycloalkylene-O-(CH2) a -O-heterocycloalkylene-(CH2) a -,-CO-heterocycloalkylene-(CH2) a ,-(CH2) a -heterocycloalkylene-CO-, -CO2-heterocycloalkylene-(CH2) a ,-(CH2) a -heterocycloalkylene-CO2- and -(CH2) a Selected from -heterocycloalkylene-O-, where a and b are each an integer from 1 to 6. Preferably, a and b are each an integer from 1 to 3, more preferably 1 or 2.

[0115] In a preferred embodiment, L is -O-, -O-CO-, -CO-O-, -O-CO-O-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2O-, -OCH2-, -CH2CH2O-, -OCH2CH2-, -CH2CH2S-, -SCH2CH2-, -CH2CH2CH2O-, -OCH2CH2CH2-, -OCH2CH2CH2O-, -CH2SO2CH2-, -CH2SOCH2-, -CH2SCH2-, -NH-SO 2-, -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-, [ka] Selected from TIFF2026510355000027.tif113170.

[0116] In all of the above embodiments, L is preferably -O-, -NH-SO2-, -NH-SO2-(CH2) a -, -SO2-NH-, -SO2-NH-(CH2) a -, -O-SO2-, -SO2-O-, -(CH2) a -,-(CH2) a -O-, O-(CH2) a -,-(CH2) a -O-(CH2) b -,-(CH2) a -S-(CH2) b -,-(CH2) a -SO-(CH2) b -,-(CH2) a -SO2-, -SO2-(CH2) b -,-(CH2) a -SO-, -SO-(CH2) b -,-(CH2) a -SO2-(CH2) b -,-(CH2) a -S-(CH2) b -O-, -O-(CH2) a -S-(CH2) b -,-(CH2) a -O-(CH2) b -S-, -S-(CH2) a -O-(CH2) b -, heterocycloalkylene-(CH2) a -O-, -O-(CH2) a -heterocycloalkylene-, -(CH2) a -O-heterocycloalkylene, heterocycloalkylene-O-(CH2) a -,-O-heterocycloalkylene-(CH2) a -and-(CH2) aSelected from -heterocycloalkylene-O-, where a and b are each an integer from 1 to 6. Preferably, a and b are each an integer from 1 to 3, more preferably 1 or 2.

[0117] More preferably, L is -O-, -O-SO2-, -SO2-O-, -(CH2) a -,-(CH2) a -O-, O-(CH2) a -,-(CH2) a -O-(CH2) b -,-(CH2) a -S-(CH2) b -,-(CH2) a -S-(CH2) b -O-, -O-(CH2) a -S-(CH2) b -,-(CH2) a -O-(CH2) b -S-, -S-(CH2) a -O-(CH2) b -, heterocycloalkylene-(CH2) a -O- and -(CH2) a Selected from -O-heterocycloalkylenes, where a and b are each independently integers from 1 to 6. Preferably, a and b are each independently integers from 1 to 3, more preferably 1 or 2.

[0118] In a preferred embodiment, L is selected from -CH2-, -CH2CH2CH2-, -CH2CH2O-, -NH-SO2-, -NH-SO2-CH2-, -SO2-NH-, -SO2-NH-CH2-, -OCH2CH2-, -CH2CH2CH2O-, -OCH2CH2CH2-, -CH2SO2CH2-, -CH2SO2-, -SO2CH2-, -CH2SO-, -SOCH2-, -CH2SOCH2-, -CH2SCH2-, -CH2CH2CH2CH2O-, -OCH2CH2CH2CH2-, -CH2OCH2 and -CH2SCH2O-.

[0119] In one preferred embodiment, Z is phenyl, heteroaryl, C 3-6-A group selected from cycloalkyl and 4-membered, 5-membered, or 6-membered heterocycloalkyl groups, each of which may be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, CN, haloalkyl, and alkoxy; L is the -(CR'R) defined above. a -O-(CR'R) b - It is the basis.

[0120] In a preferred embodiment, Z is a group selected from phenyl and heteroaryl groups, each of which may be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, CN, haloalkyl, and alkoxy groups; L is the -(CR'R) defined above. a -O-(CR'R) b - It is the basis.

[0121] In a preferred embodiment, LZ is -OCH2CH2Ph, -OCH2Ph, -OCH2CH2CH(Me)2, -OCH2CH(Me)2, -OSO2-(4-methylphenyl), -CH2SO2CH2-Ph, -OCH2-cyclopropyl, -OCH2CH2CH2CH3, -CH2OCH2Ph, -OCH2SCH2Ph, -CH2OCH2Ph [ka] That is the case.

[0122] In a preferred embodiment, LZ is -OCH2CH2CH2CH2Ph, -OCH2CH2CH2Ph, -OCH2CH2Ph, -OCH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2Ph, -OCH2CH2-pyrazole, -CH2CH2Ph, -CH2Ph, -OCH2CH2CH(Me)2, -OCH2CH(Me)2, -OCOCH2CH(Me)2, -OCH(Me)2, -OCH2CO-O-CH(Me)2, -O(CO)OCH2CH(Me)2, -OSO2-(4-methylphenyl), -CH2SO2-(4-methylphenyl), -CH2CH2O-(4-methylphenyl), -CH2SO2CH2-Ph, OMe, Ph, OPh, OCF3, t Bu, CF3, -OSO2Ph, -OCH2CH2CH2OPh, -OCH2-cyclopropyl, -CH2O-cyclopropyl, -OCH2CH2CH2CH3, -CH2OCH2Ph, -OCH2SCH2Ph, -CH2OCH2Ph, -CH2CH2-cyclopentyl, CH2CH2-cyclohexyl, -CH2CH2S-(4-chlorophenyl), -CH2-(2-fluorophenyl), -CH=CH-phenyl, -SO2-NH-CH2-phenyl, -SO2-NH-CH2-CH2-phenyl, -CH2OCH2-cyclopropyl, -OCH(Me)-cyclopropyl, -CH(Me)-O-cyclopropyl, -OCH(CF3)-cyclopropyl, -CH(CF3)-O-cyclopropyl, SO2Ph, -CH2-O-CH(CF3)-Ph, [ka] That is the case.

[0123] In one preferred embodiment, LZ is -OCH2CH2Ph, -OCH2CH2CH2CH2Ph, or -CH2OCH2Ph, more preferably -OCH2CH2Ph.

[0124] In one preferred embodiment, the compound is as follows:

[0125] [Table 1-1]

[0126] Table 1-2

[0127] Table 1-3

[0128] Table 1-4

[0129] Table 1-5

[0130] Table 1-6

[0131] Table 1-7

[0132] Table 1-8

[0133] Table 1-9

[0134] Table 1-10

[0135] Table 1-11 The following are selected from pharmaceutically acceptable salts and solvates thereof.

[0136] In a preferred embodiment, the compound of formula (I) is selected from the following compounds 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, as well as their pharmaceutically acceptable salts and solvates.

[0137] Compound of formula (II) Another aspect of the present invention relates to a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, [ka] During the ceremony: Ring A is a phenyl group or a 5-membered or 6-membered heteroaryl group; Ring B is either absent or is a phenyl group or a 5-membered or 6-membered heteroaryl group; Ring C is given by the formula: [ka] It is a condensed bicyclic group, In the formula, X1 to X9 form a heteroaryl group containing at least one N and at least one NH, wherein the heteroaryl group is alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, or NR. 10 SO2-R 12 , NR 11 COR 13 , NR 14 R 15 CO2R 16 SO2NR 17 R 18 CONR 19 R 20 , cycloalkyl and (CH2) q-These may be further substituted with one or more substituents independently selected from each heterocycloalkyl group; XY is CONR 21 -(CH2) m -and; L is a direct bond, or -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR 22 -SO2-, -NR 22 -SO2-alkylene, alkylene-SO2-NR 22 -, -SO2-NR 22 -, -SO2-NR 22 -Alkylene, Alkylene-NR 22 -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- A group selected from CO-, CO2-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO2-, -CO2-heteroalkylene, heteroalkylene-CO2-, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, where the alkylene, heteroalkylene, cycloalkylene and / or heterocycloalkylene portions of the above groups may be substituted with one or more substituents independently selected from halo, alkyl, haloalkyl and cycloalkyl; Z is a group selected from cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups, each of which may be further substituted with one or more groups independently selected from CN, halo, alkyl, OH, alkenyl, alkynyl, alkoxy, haloalkyl, and haloalkoxy groups; However, L cannot be directly bonded if Z is phenyl; Each R a and each R b These include alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, and NR. 23 COR 25 , NR 24 -SO2R 26 , (CH2) q SR 27 , (CH2) q SOR 28 , (CH2) q SO2R 29 SO2NR 30 R 31 , (CH2) q OH, (CH2) q Ure 32 , NR 33 R 34 CONR 35 R 36 , cycloalkyl and (CH2) q -Selected independently from heterocycloalkyl groups; R 10 , R 11 , R 21 , R 22 , R 23 and R 24 is independently selected from H and alkyl; R 12 ~R 20 , and R 25 ~R 36 Each of these is independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, and cycloalkyl; m, n, and p are each independent integers between 0 and 4; Each q is an independent integer between 0 and 4.

[0138] In one embodiment, the compound is given by formula: [ka] And, In the formula, A, B, C, Z, L, R a , R b , R 21 p, m, and n are as defined above.

[0139] Preferably, R 21 is H or Me, more preferably H.

[0140] A, B, C, Z, L, R a , R b , R 21 The preferred definitions of p, m, and n are as defined for equation (I).

[0141] In a preferred embodiment, XY is selected from -CONH-, -CONHCH2-, and -CON(Me)-. In a preferred embodiment, XY is -CONH-, i.e., the compound is of formula: [ka] That is the case.

[0142] In a preferred embodiment, ring A is as defined above for the compound of formula (I).

[0143] In a preferred embodiment, ring B is absent or selected from phenyl, pyridinyl, pyrazidinel, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, isothiazolyl and thiazolyl, each of which has 1 to 4 R b It may be substituted by a base.

[0144] In a preferred embodiment, ring B is as defined above for the compound of formula (I). Preferably, when B is a 6-membered group, the LZ group is in the para position relative to the CONH group. In a preferred embodiment, ring C is as defined above for the compound of formula (I).

[0145] In one preferred embodiment, Z is phenyl, heteroaryl, C 3-6 -A group selected from cycloalkyl and 4-membered, 5-membered, or 6-membered heterocycloalkyl groups, each of which may be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, haloalkyl, and alkoxy; however, L cannot be directly bonded if Z is phenyl, i.e., LZ (together) cannot be phenyl.

[0146] In a preferred embodiment, Z is a group selected from phenyl, tolyl, morpholinyl, pyrazolyl, oxetanyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, and tetrahydropyranyl; however, L cannot be directly bonded if Z is phenyl, i.e., LZ (together) cannot be phenyl.

[0147] In a preferred embodiment, L is defined above for a compound of formula (I).

[0148] In a preferred embodiment, Z is defined above for the compound of formula (I).

[0149] In one preferred embodiment, the compound of formula (II) is as follows: [Table 2] The following are selected from pharmaceutically acceptable salts and solvates thereof.

[0150] In a preferred embodiment, the compound of formula (II) is selected from the following compounds shown herein: 58, 112, and 113, as well as their pharmaceutically acceptable salts and solvates.

[0151] In another preferred embodiment, the compound of formula (I) or (II) according to the present invention is as follows: [Table 3] TIFF2026510355000047.tif246170 TIFF2026510355000048.tif246170 TIFF2026510355000049.tif246170 TIFF2026510355000050.tif246170 TIFF2026510355000051.tif246170 TIFF2026510355000052.tif246170 TIFF2026510355000053.tif246170 TIFF2026510355000054.tif246170 TIFF2026510355000055.tif246170 TIFF2026510355000056.tif246170 TIFF2026510355000057.tif246170 Selected from TIFF2026510355000058.tif204170 and its pharmaceutically acceptable salts and solvates.

[0152] method Further aspects of the present invention relate to methods for preparing compounds as defined herein. Further details of the synthesis methods are described in the appended Examples section.

[0153] therapeutic use Further aspects of the present invention relate to compounds described herein for medical use. These compounds have special uses in the fields of oncology, gastrointestinal disorders, and inflammatory disorders, as described in more detail below. In preferred embodiments, the compounds of the present invention modulate GPR35 function. More preferably, the compounds are GPR35 antagonists or inverse agonists.

[0154] One aspect of the present invention relates, therefore, to compounds described herein for use as pharmaceuticals.

[0155] Preferably, the compounds according to the present invention are for use in the treatment or prevention of disorders selected from proliferative disorders, fibrotic disorders, gastrointestinal disorders, cardiovascular diseases, immune disorders, and inflammatory disorders.

[0156] In a preferred embodiment, the compound has applications in the field of oncology. For example, in a preferred embodiment, the compound is for use in the treatment of proliferative disorders, particularly cancer or leukemia. GPR35 expression is known to be associated with cancer. More specifically, GPR35 expression is commonly upregulated in GI duct cancers relative to normal tissue (Non-Patent Literature 24). GPR35 expression can be transformed into NIH3T3 mouse fibroblasts and expressed in gastric cancer cells (Non-Patent Literature 25). GPR35b is expressed in colon cancer cell lines and primary colon tumors, but the lymph nodes of patients involved may express high levels of GPR35b (Non-Patent Literature 26). High expression of GPR35b in the lymph nodes of colon cancer patients is a marker for poor prognosis. Furthermore, high expression of GPR35 in primary gastric tumors is associated with poor prognosis (Non-Patent Literature 40). Similarly, above-median GPR35 expression in primary tumors was observed as a poor prognostic marker in men with colorectal cancer, but the opposite effect was reported in women (Non-Patent Literature 27). siRNA knockdown of GPR35 reduced the viability and proliferation of human gastric cancer cells, and moreover, reversed the tumor-promoting M2 macrophage phenotype (Non-Patent Literature 40). Mouse Gpr35 has been shown to promote glycolysis, proliferation, and oncogenic signaling by interacting with the potassium-sodium pump (Na / K-ATPase) (Non-Patent Literature 21). Gpr35 deletion promoted Na / K-ATPase-mediated ion transport and reduced Src kinase activation and overall metabolic activity in both macrophages and intestinal epithelial cells. Gpr35 deletion or inhibition, along with a specific anti-Gpr35 peptide (peptucine) (Non-Patent Literature 28), prevented inflammation-related and spontaneous intestinal tumor formation in mice. Furthermore, it has been shown that activation of human GPR35 in human-induced pluripotent stem cell (iPSC)-derived macrophages promotes angiogenesis through enhanced release of pro-angiogenic factors, via the expression of T108M-enhanced variants (Non-Patent Literature 28). Ultimately, selective deletion of Gpr35 in macrophages is associated with inflammation-related and mutant (low-phenotype) tumor suppressors of adenomatous polyposis (APC). min), it significantly reduced tumor growth in spontaneously occurring tumor models.

[0157] In a preferred embodiment, the cancer is selected from the gastrointestinal tract (e.g., colon, colorectal, rectum, stomach, esophagus, colorectal adenocarcinoma, esophageal adenocarcinoma, gastric / stomach cancer / adenocarcinoma) and related tissues (e.g., pancreas, gallbladder and bile ducts, liver, intrahepatic and extrahepatic, perihilar bile duct cancer / adenocarcinoma, bile duct adenocarcinoma), as well as cancers of the lung, kidney, gynecology, breast, testis, skin, prostate, central nervous system, and brain tumors.

[0158] In one preferred embodiment, the compound has applications in the field of immuno-oncology and in the treatment of immune disorders. Therefore, in one preferred embodiment, the compound according to the present invention is for use in the treatment of immune disorders. In another preferred embodiment, the compound according to the present invention is for use in immunotherapy for the treatment of cancer.

[0159] In a preferred embodiment, the immune disorder is an autoimmune disorder. Therefore, in a preferred embodiment, the compounds of the present invention have applications in the treatment or prevention of multiple sclerosis (MS). Recent studies have shown the involvement of the gut microbiota in the pathogenesis of MS. In particular, gut microbiota-induced kynurenic acid promotes experimental autoimmune encephalitis, an established animal model for MS, by recruiting GPR35-positive macrophages (Non-Patent Literature 41).

[0160] In a preferred embodiment, the disorder is fibrosis or fibrous disorder. Fibrosis is defined by an excessive accumulation of fibrous connective tissue (components of the extracellular matrix (ECM), such as collagen and fibronectin) in and around inflamed or damaged tissue, which can lead to permanent scarring and organ failure.

[0161] In one preferred embodiment, the compound has applications in the treatment or prevention of inflammatory disorders / diseases and / or inflammation.

[0162] In a preferred embodiment, the disorder is a gastrointestinal disorder selected from inflammatory bowel disease, ulcerative colitis, primary sclerosing cholangitis, and Crohn's disease (Non-Patent Literature 42-45). Single nucleotide polymorphisms (SNPs) of human GPR35 have been investigated in genome-wide association studies (Non-Patent Literature 18). Six of these SNPs have been associated with inflammatory diseases of the GI duct. Types of inflammatory bowel disease (IBD) include ulcerative colitis, Crohn's disease, and primary sclerosing cholangitis (Non-Patent Literature 19, 20). SNP rs3749171 is synonymous with coding variant T108M (GPR35a amino acid sequence number) and has been associated with IBD. Research has shown that this variant is upexpression-dependent and leads to activation of GPR35 and increased proliferation and metabolism in myeloid-induced macrophages (Non-Patent Literature 21). Furthermore, T108M GPR35 expression leads to increased production of VEGF and CXCL8 by macrophages compared to the reference allele, which is reduced in GPR35-deficient cells (Non-Patent Literature 22). It has also been suggested that up-expression of T108M contributes to lesion formation in IBD patients and can act as a biomarker for patients who respond better to TNF inhibitors (Non-Patent Literature 2, 23).

[0163] In a preferred embodiment, the disorder is a cardiovascular disease selected from among hypertension, heart failure, atherosclerosis, peripheral vascular disease, and stroke. Many recent publications suggest a role for GPR35 in both hypertension and the pathophysiology of heart failure and atherosclerosis. For example, the S294R SNP within GPR35 has been shown to be significantly associated with coronary artery calcification in a patient cohort (Non-Patent Literature 29). Further studies have demonstrated a correlation between GPR35 upregulation and traditional heart failure biomarkers, such as plasma brain natriuretic peptide, ejection fraction, and pulmonary artery pressure, thereby indicating that GPR35 plays a role in heart failure and hypertension (Non-Patent Literature 30).

[0164] Another aspect relates to the compounds described herein for use in the treatment or prevention of disorders caused by, in connection with, or associated with the abnormal activity of GPR35.

[0165] Another aspect relates to the compounds described herein for use in the treatment or prevention of GPR35-related diseases or disorders.

[0166] Another aspect of the present invention relates to a method for treating the above-described disorders, comprising administering the compounds described herein to the subject.

[0167] Another aspect of the present invention relates to a method for treating GPR35-related diseases or disorders in a subject. The method according to this aspect of the present invention is achieved by administering a therapeutically effective amount of the compound of the present invention described above to a subject in need, either by itself or, more preferably, as part of a pharmaceutical composition mixed with a pharmaceutically acceptable carrier, for example, as detailed later.

[0168] Another aspect of the present invention relates to a method for treating a subject having a disease condition that is mitigated by modulation of GPR35, wherein the method includes administering a therapeutically effective dose of the compound according to the present invention to the subject.

[0169] Another aspect relates to a method for treating a disease condition mitigated by modulation of GPR35, wherein the method includes administering a therapeutically effective dose of the compound according to the present invention to the target.

[0170] In a preferred embodiment, the compound inhibits GPR35 activity, as demonstrated, for example, in the functional GPR35 assay described in the attached Examples section.

[0171] In one preferred embodiment, the compound is a GPR35 antagonist or inverse agonist.

[0172] In one preferred embodiment, the compound is a GPR35 antagonist that reverses the receptor's agonist-propelling function.

[0173] In another preferred embodiment, the compound is a reverse agonist of GPR35. A reverse agonist is a compound that interacts with a receptor signaling pathway having a constitutive level of activity and reduces its activity in the opposite direction to that of a pure agonist through interaction with the receptor.

[0174] In a preferred embodiment, the compound of the present invention is an allosteric modulator of GPR35, more preferably a negative allosteric modulator. As used herein, a negative allosteric modulator antagonizes receptor agonist activation by binding to a site different from that of the agonist. Thus, a negative allosteric modulator reduces the affinity or potency of the agonist to the receptor. This is in contrast to orthosteric antagonists, which block receptor agonist activation by binding to the same site as the agonist.

[0175] Preferably, the subject is a mammal, more preferably a human.

[0176] The term “method” means, means, techniques and procedures for accomplishing a given task, including, but not limited to, methods, means, techniques and procedures known to or readily developed from methods, means, techniques and procedures known to practitioners of chemical, pharmacological, biological, biochemical and medical technologies.

[0177] In this specification, the term “treating” includes inhibiting, substantially inhibiting, slowing or reversing the progression of a disease or disorder, substantially relieving the clinical symptoms of a disease or disorder, or substantially preventing the appearance of the clinical symptoms of a disease or disorder.

[0178] In this specification, the term “prevention” refers to methods for preventing an organism from first acquiring a disability or disease.

[0179] The term "therapeutic dose" refers to the amount of a compound administered that alleviates, to some extent, one or more symptoms of the disease or disorder being treated.

[0180] For any compound used in this invention, the therapeutically effective dose, also referred to herein as the therapeutically effective dose, can be initially estimated from a cell culture assay. For example, the dose is determined in the cell culture assay. 50 or IC 90 To achieve the circulating concentration range, including [specific concentration range], formulations can be developed in animal models. This information can be used to more accurately determine an effective dose in humans. Initial doses can also be estimated from in vivo data. Using these initial guidelines, those skilled in the art can determine an effective dose in humans.

[0181] Furthermore, the toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by LD (Low-Dose) testing. 50 and ED 50 This can be determined by determining the dose ratio between toxicity and therapeutic effect, which is the therapeutic index, LD50. 50 and ED 50 It can be expressed as a ratio between [a certain value] and [another value]. Compounds exhibiting a high therapeutic index are preferred. Data obtained from these cell culture assays and animal studies can be used when formulating a dosage range that is not toxic for use in humans. Doses of such compounds are preferably ED with little or no toxicity. 50The circulating concentration is within the range of [specific concentration]. The dosage may vary within this range depending on the dosage form used and the route of administration utilized. The exact prescription, route of administration, and dosage can be selected by the individual physician in consideration of the patient's condition (see, for example, Fingl et al, 1975, The Pharmacological Basis of Therapeutics, chapter 1, page 1).

[0182] The dosage and interval can be individually adjusted to provide plasma levels of the active compound sufficient to maintain the therapeutic effect. For oral administration, the usual patient dose ranges from approximately 50 to 2000 mg / day, commonly from approximately 100 to 1000 mg / day, preferably from approximately 150 to 700 mg / day, and most preferably from 50 to 150 mg / day. Preferably, therapeutically effective serum levels are achieved by administering multiple doses on each day. In the case of topical administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration. Those skilled in the art can optimize the therapeutically effective local dose without using excessive experimental methods.

[0183] As used herein, “GPR35-related disease or disorder” refers to a disease or disorder characterized by inappropriate GPR35 activity. Inappropriate GPR35 activity refers to either an increase or decrease in GPR35 activity, as measured by an enzymatic or cellular assay, compared to activity in a healthy subject, for example. Inappropriate activity may also be due to overexpression of GPR35 in affected tissue compared to healthy adjacent tissue with lower GPR35 expression.

[0184] Preferred diseases or disorders for which the compounds described herein may be useful in prevention include those described above.

[0185] Accordingly, the present invention further provides the use of the compounds defined herein in the preparation of pharmaceuticals for the treatment of diseases in which it is desirable to modulate GPR35. Such diseases include proliferative disorders, gastrointestinal disorders, fibrotic disorders, cardiovascular diseases, immunological disorders, and inflammatory disorders. Proliferative disorders preferably include therapeutic applications in the field of oncology.

[0186] As used herein, the phrase “preparation of a pharmaceutical product” includes the direct use of the components of the present invention as pharmaceutical products, in addition to their use at any stage of such preparation of a pharmaceutical product.

[0187] The functional GPR35 assay described in the attached examples measures the ability of a GPR35 modulator to inhibit GPR35 agonist-induced phosphoERK signaling. This determines the modulator concentration required to reduce the phosphoERK signal by 50 percent, i.e., IC50. 50 This is expressed as a signal window defined as the difference between an agonist-plus-modulator medium (without modulator) and an agonist medium (without agonist) control.

[0188] In one preferred embodiment, the compound has an IC50 of less than approximately 50 μM in the previously described GPR35 assay. 50 The compound exhibits a value of less than approximately 10 μM, more preferably less than approximately 1 μM, in the GPR35 assay. 50 It exhibits a value.

[0189] In a preferred embodiment, the compound according to the present invention exhibits an IC50 of less than 10 μM in the previously described GPR35 assay. 50 The compound exhibits the following characteristics. In a preferred embodiment, the compound is selected from those indicated as "A" or "B" in Table 1.

[0190] In a preferred embodiment, the compound according to the present invention exhibits an IC50 greater than 1 μM and less than 10 μM in the previously described GPR35 assay. 50It exhibits the following characteristics. In a preferred embodiment, the compound is selected from those indicated as "B" in Table 1.

[0191] In a more preferred embodiment, the compound according to the present invention exhibits an IC50 of less than 1 μM in the assay described above. 50 It exhibits the following characteristics. In a preferred embodiment, the compound is selected from those indicated as "A" in Table 1.

[0192] Pharmaceutical composition For use according to the present invention, the compounds or physiologically acceptable salts, esters, or other physiologically functional derivatives described herein may be presented as pharmaceutical formulations comprising the compound or physiologically acceptable salt, ester, or other physiologically functional derivative thereof together with one or more pharmaceutically acceptable carriers, excipients, or diluents and optionally other therapeutic and / or prophylactic components. The carrier(s) must be acceptable in the sense that they are compatible with the other components of the formulation and are not harmful to the recipient. The pharmaceutical compositions may be for human or animal use as pharmaceuticals for humans and animals.

[0193] Examples of such suitable excipients for various different forms of the pharmaceutical compositions described herein can be found in “Handbook of Pharmaceutical Excipients, 2 nd This can be found in Edition, (1994), Edited by A Wade and PJ Weller. If carriers exist, each carrier must be acceptable in the sense that it is compatible with the other components of the formulation and is not harmful to the recipient.

[0194] Acceptable carriers or diluents for therapeutic use are well known in pharmaceutical technology and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985).

[0195] Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, and sorbitol. Examples of suitable diluents include ethanol, glycerol, and water.

[0196] The choice of pharmaceutical carriers, excipients, or diluents may be made in relation to the intended route of administration and standard pharmaceutical practices. Pharmaceutical compositions may include, or in addition to, any suitable binders, lubricants, suspending agents, coatings, solubilizers, buffers, flavoring agents, surfactants, thickeners, preservatives (including antioxidants), and substances included for the purpose of making the formulation isotonic with the blood of the intended recipient.

[0197] Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural or synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, and polyethylene glycol.

[0198] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride.

[0199] Preservatives, stabilizers, dyes, and even flavorings may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0200] Examples of pharmaceutical formulations include those suitable for oral, topical (including cutaneous, buccal, and sublingual), rectal, or parenteral (including subcutaneous, intradermal, intramuscular, and intravenous), nasal, and, for example, pulmonary administration by inhalation. These formulations may, where appropriate and conveniently, be presented in individual dosage units and may be prepared by any method well known in the field of compounding. All methods involve associating the active compound with a liquid carrier or a micronized solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0201] Pharmaceutical formulations suitable for oral administration, where the carrier is solid, are most preferably presented as unit-dose formulations such as boluses, capsules, or tablets, each containing a predetermined amount of the active compound. Tablets can be prepared by compression or molding, optionally with one or more adjuncts. Tablets can be prepared by compressing the active compound in a suitable machine into a free-flowing form such as a powder or granules, which may be mixed with a binder, lubricant, inert diluent, lubricant, surfactant, or dispersant. Molded tablets can be prepared by molding the active compound with an inert liquid diluent. Tablets may be coated, or if uncoated, they may be notched. Capsules can be prepared by filling a capsule shell with the active compound, either alone or in a mixture with one or more adjuncts, and then sealing them in a conventional manner. Cachetes are similar to capsules in which the active compound, along with any adjuncts, is sealed in a rice paper envelope. The active compound can also be formulated, for example, as dispersible granules that can be suspended in water or sprinkled on food before administration. Granules can be packaged, for example, in sachets. Formulations suitable for oral administration, in which the carrier is liquid, can be presented as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.

[0202] Formulations for oral administration include controlled-release formulations, such as tablets in which the active compound is formulated in a suitable controlled-release matrix or coated with a suitable controlled-release film. Such formulations may be particularly convenient for prophylactic use.

[0203] Pharmaceutical formulations suitable for rectal administration, in which the carrier is solid, are most preferably presented as unit-dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can conveniently be formed by adding a mixture of the active compound with a softened or melted carrier(s), followed by cooling and shaping in a mold. Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of the active compound in an aqueous or oily medium.

[0204] Injectable preparations may be adapted for bolus injection or continuous infusion. Conveniently, these preparations are presented in sealed unit-dose or multi-dose containers after introduction of the formulation until required for use. Alternatively, the active compound may be in powder form, comprising a suitable medium such as sterile pyrogen-free water, before use.

[0205] The active compound can also be formulated as a long-acting Devo formulation that can be administered by intramuscular injection or, for example, by subcutaneous or intramuscular implantation. The Devo formulation may contain, for example, a suitable polymeric or hydrophobic material or an ion exchange resin. Such long-acting formulations are particularly suitable for prophylactic use.

[0206] Formulations suitable for pulmonary administration via the buccal oral cavity are presented so as to deliver particles containing the active compound, preferably having a diameter in the range of 0.5 to 7 microns, into the bronchial trees of the recipient.

[0207] One possibility is that such formulations may be presented in the form of a finely ground powder, preferably in a permeable capsule of gelatin for use in an inhalation device, or alternatively, as a self-propelled formulation comprising the active compound, a suitable liquid or gaseous spray, and optionally other components, such as a surfactant and / or a solid diluent. Suitable liquid sprays include propane and chlorofluorocarbons, and a suitable gaseous spray is carbon dioxide. Self-propelled formulations in which the active compound is dispensed in the form of droplets of solution or suspension may also be used.

[0208] Such self-propelled formulations are similar to those known in the art and can be prepared by established procedures. Preferably, they are presented in containers provided with either a manually operated or automatically functioning valve having the desired spray characteristics; advantageously, the valve is of a metering type that delivers a fixed volume, for example, 25 to 100 microliters, in each of its operations.

[0209] As a further possibility, the active compound may be in the form of a solution or suspension for use in an atomizer or nebulizer in which accelerated airflow or ultrasonic stirring is used to generate a fine droplet mist for inhalation.

[0210] Suitable formulations for nasal administration are generally the same as those described above for pulmonary administration. When dispensed, such formulations should preferably have a particle size in the range of 10 to 200 microns to allow retention in the nasal cavity; this can be achieved, where appropriate, by using a powder of appropriate particle size or by selecting an appropriate valve. Other suitable formulations include coarse powders with a particle size in the range of 20 to 500 microns for rapid inhalation via nasal passage from a container held close to the nose, and for administration by nasal sprays containing 0.2% to 5% w / v of the active compound in an aqueous or oily solution or suspension.

[0211] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1 M and preferably 0.05 M phosphate buffer or 0.8% physiological saline. In addition, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils, e.g., olive oil, and injectable organic esters, e.g., ethyl oleate. Aqueous carriers include water, alcohol solutions / aqueous solutions, emulsions, or suspensions containing physiological saline and a buffering medium. Parenteral media include sodium chloride solution, ringer's dextrose, dextrose and sodium chloride, ringer's lactate, or non-volatile oils. Preservatives and other additives may also be present, such as antimicrobial agents, antioxidants, chelating agents, and inert gases.

[0212] Suitable formulations for topical use can be provided, for example, as gels, creams, or ointments. Such preparations can be applied, for example, to wounds or ulcers, either by being sprayed directly onto the surface of a wound or ulcer, or by being supported on a suitable support such as a bandage, gauze, or mesh that can be applied to and over the area to be treated.

[0213] Liquid or powder formulations can also be provided that can be sprayed or scattered directly onto the area to be treated, such as a wound or ulcer. Alternatively, a carrier, such as a bandage, gauze, or mesh, can be used to spray or scatter the formulation and then apply it to the area to be treated.

[0214] A further aspect of the present invention provides a method for preparing the above-described pharmaceutical or veterinary compositions, the method comprising associating an active compound(s) with a carrier, for example, an additive mixture.

[0215] Generally, formulations are prepared by uniformly and closely associating an active agent with a liquid carrier, a micronized solid carrier, or both, and then, if necessary, shaping the product. The present invention relates to methods for preparing pharmaceutical compositions, comprising binding or associating the compounds described herein with pharmaceutically or veterinarily acceptable carriers or media.

[0216] Salt / Ester The compounds of the present invention can exist as salts or esters, particularly as pharmaceutically and veterinarily acceptable salts or esters.

[0217] pharmaceutically acceptable salts of the compounds of the present invention include suitable acid addition salts or base salts thereof. A general overview of suitable pharmaceutical salts can be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts include, for example, strong inorganic acids, such as mineral acids, such as hydrohalic acids, such as hydrochlorides, hydrobromids and hydroiodides, sulfuric acid, phosphoric acid, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate persulfate and sulfonic acid; strong organic carboxylic acids, such as alkane carboxylic acids with 1 to 4 carbon atoms that are unsubstituted or substituted (e.g. by halogens), such as acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; hydroxycarboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; amino acids, such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, such as unsubstituted or substituted (e.g. by halogens) (C 1- Formed from C4)-alkyl- or aryl-sulfonic acids, such as methane- or p-toluenesulfonic acid. Salts that are not pharmaceutically or veterinarily acceptable may also be valuable as intermediates.

[0218] Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipine, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentane, glucoheptane, glycerophosphate, oxalate, heptane, hexanoate, fumarate, nicotinate, palmate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobio This includes phosphates, pivotes, camphorates, undecanoates and succinates, organic sulfonic acids such as methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, camphorsulfonates, 2-naphthalenesulfonates, benzenesulfonates, p-chlorobenzenesulfonates and p-toluenesulfonates; and inorganic acids such as hydrochlorides, hydrobroms, hydroiodides, sulfates, bisulfates, hemisulfates, thiocyansates, persulfates, phosphoric acids and sulfonic acids.

[0219] Esters are formed using either an organic acid or an alcohol / hydroxide, depending on the functional group being esterified. Organic acids include carboxylic acids, e.g., alkanecarboxylic acids with 1 to 12 carbon atoms, unsubstituted or substituted (e.g., by halogens), e.g., acetic acid; saturated or unsaturated dicarboxylic acids, e.g., oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or tetraphthalic acid; hydroxycarboxylic acids, e.g., ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid; amino acids, e.g., aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, e.g., unsubstituted or substituted (e.g., by halogens) (C 1-This includes C4)-alkyl- or aryl-sulfonic acids, such as methane- or p-toluenesulfonic acid. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and aluminum hydroxide. Alcohols include alkane alcohols with 1 to 12 carbon atoms, which may be unsubstituted or substituted (e.g., by halogens).

[0220] Enantiomer / Tautomer In all embodiments of the present invention disclosed above, the present invention includes, where appropriate, all enantiomers, diastereoisomers, and tautomers of the compounds of the present invention. Those skilled in the art will recognize compounds possessing optical properties (one or more chiral carbon atoms) or tautomeristic features. The corresponding enantiomers and / or tautomers can be isolated / prepared by methods known in the art.

[0221] Enantiomers are characterized by the absolute stereochemistry of their chiral centers and described by the R and S sequencing rules of Cahn, Ingold, and Prelog. These conventions are well-known in the art (e.g., 'Advanced Organic Chemistry', 3) rd (See edition, ed. March, J., John Wiley and Sons, New York, 1985).

[0222] The compounds of the present invention containing chiral centers can be used as racemic mixtures, enantiomer-enriched mixtures, or the racemic mixtures can be separated using well-known techniques, and the individual enantiomers can be used individually.

[0223] Stereomorphs and geometric isomers Some of the compounds of the present invention can exist as stereoisomers and / or geometric isomers, for example, they may possess one or more chiral and / or geometric centers, and thus may exist in two or more stereoisomers and / or geometric forms. The present invention intends to utilize all of the individual stereoisomers and geometric isomers of these compounds, as well as mixtures thereof. The terms used in the claims encompass these forms, and the provided forms retain (but not necessarily, to the same extent) appropriate functional activity.

[0224] The present invention also includes all appropriate isotopic variations of compounds or their pharmaceutically acceptable salts. An isotopic variation of a compound or its pharmaceutically acceptable salt is defined as one in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass than that commonly found in nature. Examples of isotopes that can be incorporated into drugs and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl is one example. Certain isotopic variations in drugs and their pharmaceutically acceptable salts, for example, 3 H or 14 Those incorporating radioactive isotopes such as 13C are useful in drug and / or substrate tissue distribution studies. Tritiated, i.e. 3 H and carbon 14, that is 14 13C isotopes are particularly preferred due to their ease of preparation and detection. Furthermore, isotopes, such as deuterium, i.e. 2Substitution with H can result in certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and is therefore preferable in some situations. For example, the present invention includes compounds according to the present invention in which any hydrogen atom is replaced by a deuterium atom. The isotopic variations of the agents of the present invention and their pharmaceutically acceptable salts can generally be prepared by conventional procedures using appropriate isotopic variations of appropriate reagents.

[0225] Atropisomer Some of the compounds of the present invention can exist as atropisomers. Atropisomers are stereoisomers that arise due to rotational hindrance around a single bond, where the energy difference due to steric strain or other contributors creates a rotational barrier high enough to allow the isolation of individual conformational isomers. The present invention encompasses all such atropisomers.

[0226] Prodrug The present invention further includes compounds of the present invention in prodrug form, i.e., covalently bonded compounds that release an active parent drug in vivo. Such prodrugs are generally compounds of the present invention modified such that one or more suitable groups can be reversed upon administration to a human or mammalian subject. Reversal is usually carried out by enzymes naturally present in such subjects, but it is possible to carry out reversal in vivo by administering a second drug together with such prodrug. Examples of such modifications include esters (e.g., any of those described above), where reversal can be carried out by an esterase, etc. Other such systems are well known to those skilled in the art.

[0227] solvate The present invention also includes solvate forms of the compounds of the present invention. The terms used in the claims encompass these forms. Preferably, the solvate is a hydrate.

[0228] combination Further aspects of the present invention relate to combinations comprising the compounds described herein and one or more additional active agents. In particularly preferred embodiments, one or more compounds of the present invention are administered in combination with one or more additional active agents, for example, existing drugs available on the market. In such cases, the compounds of the present invention can be administered sequentially, simultaneously, or sequentially with one or more other active agents.

[0229] Drugs are generally more effective when used in combination. Combination therapy is particularly desirable to avoid overlapping primary toxicities, mechanisms of action, and resistance mechanisms. Furthermore, it is desirable to administer most drugs at their maximum tolerated doses, with minimal time intervals between these doses. The main advantage of combining chemotherapy drugs is that it can promote additional or possible synergistic effects through biochemical interactions and, moreover, reduce the development of resistance.

[0230] Beneficial combinations may be suggested by studying the activity of the test compound with drugs known or expected to be valuable in the treatment of specific disorders. This procedure can also be used to determine the order of drug administration, i.e., before, simultaneously with, or after delivery. Such dosing schedules may be characteristic of all active drugs identified herein.

[0231] In the context of cancer, the compounds of the present invention can be used in combination with immunotherapies such as cancer vaccines and / or other immune modulators. Therefore, in one preferred embodiment, the additional active agent is an immunotherapeutic agent, more preferably a cancer immunotherapeutic agent. "Immunotherapeutic agent" refers to a treatment that uses the subject's own immune system to fight a disease such as cancer. For other disorders, the compounds of the present invention can be used in combination with agents that block or reduce inflammation, such as antibodies that target pro-inflammatory cytokines. The compounds of the present invention can also be used in combination with other chemotherapeutic agents and / or in conjunction with radiotherapy.

[0232] polymorph The present invention further relates to the compounds of the present invention in their various crystalline, polymorphic, and (non-)hydrated forms. It is well established in the pharmaceutical industry that any of these forms of a chemical substance can be isolated by slightly varying the methods of purification and / or isolation from the solvents used in the synthesis and preparation of such compounds.

[0233] Administration The pharmaceutical compositions of the present invention may be adapted for administration rectally, nasally, intrabronchally, topically (including buccally and sublingually), vaginally, or parenterally (including subcutaneously, intramuscularly, intravenously, intraarterially, and intradermally), intraperitoneally, or subarachnoidally. Preferably, the formulation is an orally administered formulation. The formulation may conveniently be presented in unit dosage form, i.e., in the form of a unit dose, or individual portions containing multiple or subunits of a unit dose. For example, the formulation may be in the form of tablets and sustained-release capsules and may be prepared by any method well known in the field of pharmacy.

[0234] The oral formulations of the present invention can be presented as: individual units, each containing a predetermined amount of the active agent, such as capsules, gels, drops, cachets, pills, or tablets; as powders or granules; as solutions, emulsions, or suspensions of the active agent in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions; or as boluses, etc. Preferably, these compositions contain 1 mg to 250 mg and more preferably 10 to 100 mg of the active ingredient per dose.

[0235] For compositions for oral administration (e.g., tablets and capsules), the term "acceptable carrier" includes media, such as common excipients, such as binders, e.g., syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sucrose, and starch; fillers and carriers, e.g., corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid; and lubricants, e.g., magnesium stearate, sodium stearate, and other metal stearates, glycerol stearate, stearic acid, silicone fluids, talc wax, oils, and colloidal silica. Flavoring agents, e.g., peppermint, wintergreen oil, cherry flavoring, etc., may also be used. It may be desirable to add colorants to make the dosage form easily identifiable. Tablets may also be coated by methods well known in the art.

[0236] Tablets can be prepared by compression or molding with one or more optional adjuncts. Tablets can be prepared by compressing an active agent in a free-flowing form, such as a powder or granules, which may be mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. The tablets may be coated or notched and can be formulated to provide a slow or controlled release of the active agent.

[0237] Other formulations suitable for oral administration include medicinal candies containing the active agent in a flavoring base, usually sucrose and acacia or tragacanth; aromatic tablets containing the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active agent in a suitable liquid carrier.

[0238] Other forms of administration may be injected intravenously, intraarterially, subarachnoidally, subcutaneously, intradermally, intraperitoneally, or intramuscularly, and may include solutions or emulsions prepared from sterile or sterilizable solutions. Injectable forms typically contain between 10 and 1000 mg, preferably between 10 and 250 mg, of the active ingredient per dose.

[0239] The pharmaceutical composition of the present invention may be in the form of a suppository, pessary, suspension, emulsion, lotion, ointment, cream, gel, spray, solution, or powder.

[0240] An alternative to transdermal administration is the use of skin patches. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycol or liquid paraffin. The active ingredient can also be incorporated into an ointment consisting of a white wax or white soft paraffin base at a concentration between 1 and 10% by weight, together with stabilizers and preservatives as needed.

[0241] Dosage Those skilled in the art can easily determine an appropriate dose of one type of immediate composition for administration to a subject without excessive experimentation. Typically, a physician determines the actual dose that is most appropriate for an individual patient, and this depends on a variety of factors including the activity of the particular compound used, the metabolic stability and duration of action of that compound, age, weight, overall health, sex, diet, mode and time of administration, elimination rate, drug combination, severity of the particular condition, and the individual being treated. The doses disclosed herein are examples of average cases. Naturally, there are individual cases where higher or lower dose ranges are beneficial, and these are within the scope of this invention.

[0242] The dosage is further modified according to the mode of administration of the compound. For example, parenteral administration of the compound is typically preferred to achieve an "effective dose" for acute treatment. Intravenous infusion of the compound in 5% dextrose in water or standard saline or a similar formulation with appropriate excipients is most effective, but intramuscular bolus injection is also useful. Typically, the parenteral dose is between about 0.01 and about 100 mg; preferably between 0.1 and 20 mg, in a manner that maintains the concentration of the drug in plasma at a concentration effective in modulating GPR35. The compound can be administered 1 to 4 times daily at levels to achieve a total daily dose of about 0.4 to about 400 mg. The exact amount of the therapeutically effective compound of the invention, and the route of administration of such compounds, can be easily determined by those skilled in the art by comparing the blood level of the drug to the concentration required to have a therapeutic effect.

[0243] The compounds of this invention may also be administered orally to a patient in such a manner that the concentration of the drug is sufficient to achieve one or two or more of the therapeutic symptoms disclosed herein. Typically, a pharmaceutical composition containing the compound is administered in an oral dose between about 0.1 and about 500 mg or between about 0.1 and about 50 mg, in a manner consistent with the patient's condition. Preferably, the oral dose is between about 0.5 and about 50 mg or between about 0.5 and about 20 mg.

[0244] When the compounds of the present invention are administered in accordance with the present invention, no unacceptable toxicological effects are expected. The compounds of this invention, which may have good bioavailability, can be tested in one of several biological assays to determine the concentration of the compound required to have a given pharmacological effect.

[0245] The present invention is further described through the following non-limiting embodiments. [Examples]

[0246] If the preparation of starting materials is not described, they are commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. If it is indicated that a compound was prepared similarly to a previous example or intermediate, it will be recognized by those skilled in the art that reaction times, equivalent amounts of reagents, solvents, concentrations, and temperatures may be modified for each specific reaction, and that different workup or purification techniques may be necessary or desirable.

[0247] General scheme

[0248] Abbreviation: [Table 4] TIFF2026510355000060.tif179170

[0249] Other abbreviations are intended to convey their generally accepted meanings.

[0250] General experimental conditions All starting materials and solvents were either obtained from commercially available sources or prepared according to literature methods.

[0251] Normal-phase ("flash") chromatography and RP ("flash") chromatography were performed on a CombiFlash Companion automated flash chromatography system using either Redisep® Silver (230-400 mesh, 40-63 μm irregularity) or Silicycle, SiliaSep C18 (230-400 mesh, 40-63 μm irregularity) pre-packed silica cartridges, respectively. RP flash chromatography was performed using a basic modifier (C18, 0-100% MeCN in 0.1% ammonia aqueous solution), except when an acidic modifier (C18, 0-100% MeCN in 0.1% HCO2H aqueous solution) was used.

[0252] Analytical LC-MS and UPLC-MS experiments were performed as described in the table below. [Table 5] [Table 6] [Table 7] [Table 8] [Table 9]

[0253] Preparative HPLC purification was performed as detailed below. [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18]

[0254] NMR spectra were measured at 298 K unless otherwise indicated, and solvent resonance was used as reference. Chemical shifts are reported in parts per million (δ ppm).

[0255] NMR spectra were recorded using a Bruker 500 MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbe®. Data were acquired using Bruker TopSpin software and processed using MestreNova software.

[0256] If the reaction likely involves two or more atoms (e.g., N-alkylation of a heterocycle containing two or more N atoms to provide N-protection), and a mixture of two or more isomers is obtained as determined by LC-MS, the mixture was used without further purification unless otherwise specified. Although only one isomer is depicted, the term "+isomer" is intended to convey a mixture of two or more isomers. Multiple peaks may be listed as characterizations along with the expected mass ions. Purification was achieved later in the synthesis following N-deprotection, and multiple isomers led to a single specific product.

[0257] Regarding chiral separation, the first eluted isomer ("enantiomer 1") and the second eluted isomer ("enantiomer 2") under chiral separation conditions are described.

[0258] If the procedure for identified intermediates in the synthetic scheme was not provided, these compounds were purchased.

[0259] intermediate Intermediate 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]pyridine-5-yl)benzamide (I-4) [ka]

[0260] Step 1: 5-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1) [ka]

[0261] iPnONO (1.71 mL, 12.8 mmol) and 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD Co., 1.50 g, 7.98 mmol) were added to THF (20 mL), and the reaction mixture was stirred at 65°C for 16 hours. The mixture was concentrated under reduced pressure to obtain 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.

[0262] Step 2: 5-bromo-1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine(I-2) [ka]

[0263] 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 minutes. The solution was cooled to 0°C, trityl-Cl (1.77 g, 6.35 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0°C and diluted with water (140 mL). The mixture was extracted with toluene (3 × 60 mL), washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by chromatography (silica gel, isohexane, 0-100% toluene) yielded 5-bromo-1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine (2.59 g, 70%) along with a mixture of isomers. LCMS: Method A, 2.19 / 2.21 / 2.31 min, MS: ES + 243.2 (Ph3C) + ).

[0264] Step 3: N-(4-hydroxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-3) [ka]

[0265] 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 at room temperature for 10 minutes. HATU (3.48 g, 9.16 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (100 mL) and extracted with siRNA (3 × 40 mL). The organic phase was washed with brine (40 mL), dried over Na₂SO₄, and concentrated under reduced pressure. Purification by chromatography (silica gel, 0-10% MeOH in DCM) yielded 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.

[0266] Step 4: N-(4-hydroxyphenyl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide(I-4) [ka]

[0267] To a stirred solution of 5-bromo-1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine (+isomer, 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), Cs2CO3 (8.73 g, 26.8 mmol) was added. The mixture was purged with nitrogen for 5 minutes. Pd-118 (0.437 g, 0.67 mmol) was added, and the mixture was purged for a further 2 minutes. The mixture was stirred at 80°C for 2 hours, then cooled and filtered through Celite®. The filtrate was diluted with water (150 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. Purification by chromatography (silica gel, isohexane, 0-100% ethyl acetate) yielded N-(4-hydroxyphenyl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide (2.60 g, 62%) along with a mixture of isomers. LCMS: Method A, 2.07 / 2.20 min, MS: ES - 572.2.

[0268] 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) [ka]

[0269] Step 1: 1-Nitro-4-phenethoxybenzene [ka]

[0270] To a solution of 2-phenylethane-1-ol (CAS 60-12-8 / Fluorochem, 3.38 g, 27.6 mmol) in DMF (20 mL), NaH (60% dispersed in mineral oil, 1.02 g, 25.5 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. 1-fluoro-4-nitrobenzene (CAS 350-46-9, Alfa Aesar, 3.00 g, 21.3 mmol) was added. The mixture was stirred at room temperature for 18 hours, then poured into ice water (400 mL), and the product was extracted with siRNA (3 × 100 mL). The organic extract was washed with brine (50 mL), dried on MgSO4, and the filtrate was adsorbed onto silica gel. Purification by flash chromatography (silica gel, 0-30% siRNA in isohexane) yielded 1-nitro-4-phenethoxybenzene (4.80 g, 93%). LCMS: Method A, 2.00 min, MS: ES + 244.0.

[0271] Step 2: 4-Phenethoxyaniline (I-5) [ka]

[0272] To a solution of 1-nitro-4-phenethoxybenzene (4.50 g, 18.5 mmol) in EtOH (55 mL) and THF (30 mL), 10% Pd / C (wetted with 50% water, 0.98 g, 9.3 mmol) was added, and the mixture was stirred at room temperature under hydrogen (3 bar) for 18 hours. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to obtain 4-phenethoxyaniline (3.50 g, 86%). LCMS: Method A, 0.99 min, MS: ES + 214.2.

[0273] Step 3: N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-6) [ka]

[0274] 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), HATU (7.49 g, 20.0 mmol) and 4-phenethoxyaniline (I-5, 3.50 g, 16.4 mmol) were added. The mixture was stirred at 40°C for 18 hours, then cooled, poured into ice water (500 mL), and extracted with siRNA (3 × 120 mL). The combined organic phase was washed with brine (50 mL), dried on MgSO4, adsorbed onto silica gel, and then purified by flash chromatography (silica gel, isohexane with 0-50% ethyl phosphate) to obtain N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (7.10 g, 87%). LCMS: Method A, 2.27 min, MS: ES + 444.2.

[0275] 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) [ka]

[0276] Step 1: 1-((benzyloxy)methyl)-4-nitrobenzene [ka]

[0277] 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 mixture was stirred at 45°C for 18 hours. The reaction mixture was filtered through Celite®, and the filtrate was adsorbed onto silica gel. Subsequently, the filtrate was purified by flash chromatography (silica gel, heptane, 0-30% TBME) to obtain 1-((benzyloxy)methyl)-4-nitrobenzene (6.33 g, 94%). LCMS: Method A, 1.96 min, MS: ES + 244.1

[0278] Step 2: 4-((benzyloxy)methyl)aniline(I-7) [ka]

[0279] AcOH (1.65 mL, 28.8 mmol) was added to a mixture of 1-((benzyloxy)methyl)-4-nitrobenzene (3.50 g, 14.4 mmol) and iron (4.02 g, 71.9 mmol) in EtOH (25 mL) and water (25 mL), and the reaction mixture was stirred at room temperature for 72 hours. The mixture was filtered through Celite®, the crude concentrate was captured on SCX, washed with MeOH, and eluted with a 10% 0.7 M ammonia / MeOH solution in DCM. Further purification by chromatography on silica gel (0-10% (0.7 M ammonia / MeOH) in DCM) yielded 4-((benzyloxy)methyl)aniline (2.58 g, 79%). LCMS: Method A, 1.09 min, MS: ES + 214.1

[0280] Step 3: N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-8) [ka]

[0281] Following the procedure for intermediate 6, 4-((benzyloxy)methyl)aniline (I-7) was used instead of 4-phenethoxyaniline (I-5) to obtain 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.

[0282] Intermediate 9 3-(4,5-diaminopyrimidine-2-yl)-N-(4-phenethoxyphenyl)benzamide(I-9) [ka] 3-(4,5-diaminopyrimidine-2-yl)-N-(4-phenethoxyphenyl)benzamide(I-9) [ka]

[0283] 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 nitrogen stream for 5 minutes. Pd-118 (59 mg, 0.09 mmol) was added, and the mixture was purged for a further 2 minutes. The mixture was stirred at 90°C for 5 hours, cooled to room temperature, filtered, and diluted with ELISA (10 mL). The organic matter was washed with water (10 mL) and brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was stirred with SiO2 (5 mL), the solid was collected by filtration, and dried to obtain 3-(4,5-diaminopyrimidine-2-yl)-N-(4-phenethoxyphenyl)benzamide (218 mg, 100%). LCMS: Method Q: 0.88 min, MS: ES + 426.2.

[0284] Intermediate 10 3-(5,6-diaminopyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide(I-10) [ka] 3-(5,6-diaminopyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide(I-10) [ka]

[0285] 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 nitrogen stream for 5 minutes. Then, Pd-118 (88 mg, 0.14 mmol) was added, and the mixture was purged for a further 2 minutes. The mixture was stirred at 90°C for 5 hours, cooled to room temperature, filtered, and diluted with RINKAN (10 mL). The organic phase was washed with water (10 mL) and brine (5 mL), dried on Na2SO4, and concentrated under reduced pressure to obtain 3-(5,6-diaminopyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide (180 mg, 56%). LCMS: Method Q: 0.94 min, MS: ES + 426.2.

[0286] Intermediate 11 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-6-yl)benzoic acid (I-11) [ka]

[0287] Step 1: Methyl 3-(5,6-diaminopyrazine-2-yl)benzoate [ka]

[0288] 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 minutes, after which Pd-118 (172 mg, 0.27 mmol) was added. The mixture was further purged with nitrogen for 2 minutes and then stirred at 80°C for 2 hours. The mixture was diluted with water (20 mL) and extracted with siRNA (3 × 20 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography (silica gel, 0-10% in DCM (0.7M ammonia / MeOH)) yielded methyl 3-(5,6-diaminopyrazine-2-yl)benzoate (301 mg, 80%). LCMS: Method A: 0.92 min, MS: ES + 245.2.

[0289] Step 2: 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-6-yl)benzoate [ka]

[0290] 300 mg, 1.23 mmol of methyl 3-(5,6-diaminopyrazine-2-yl)benzoate and 0.084 mL, 1.47 mmol of AcOH were mixed with iPnONO (0.26 mL, 1.97 mmol) in THF (6 mL). The reaction mixture was heated at 65 °C for 72 hours and concentrated under reduced pressure to obtain 310 mg, 99% methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-6-yl)benzoate. LCMS: Method A: 1.33 min, MS: ES + 256.1.

[0291] Step 3: 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-6-yl)benzoic acid (I-11) [ka]

[0292] To methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-6-yl)benzoate (300 mg, 1.18 mmol) in THF (4 mL), an aqueous solution of LiOH (3.5 M, 2.0 mL, 7.05 mmol) was added, and the mixture was stirred at 40°C for 5 hours. By concentrating the mixture under reduced pressure, lithium 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-6-yl)benzoate (350 mg, 96%) was obtained. LCMS: Method A: 1.09 min, MS: ES + 242.1.

[0293] Intermediate 12 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzoic acid (I-12) [ka]

[0294] Step 1: Methyl 3-(5,6-diaminopyridine-2-yl)benzoate [ka]

[0295] 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 minutes, after which Pd-118 (1.1 g, 1.7 mmol) was added. The mixture was further purged with nitrogen for 2 minutes and stirred at 75°C for 18 hours. The mixture was filtered through Celite® and adsorbed onto silica gel. Purification by chromatography (silica gel, 0-10% in DCM (0.7M ammonia / MeOH)) yielded methyl 3-(5,6-diaminopyridine-2-yl)benzoate (5.80 g, 100%). LCMS: Method A: 0.59 min, MS: ES + 244.2.

[0296] Step 2: Methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzoate [ka]

[0297] 5.80 g, 16.7 mmol of methyl 3-(5,6-diaminopyridine-2-yl)benzoate and 2.20 mL, 36.7 mmol of AcOH were added to 100 mL of THF, to which iPnONO (3.59 mL, 26.7 mmol) was added. The mixture was stirred at 65°C for 16 hours, concentrated under reduced pressure, and adsorbed onto silica gel. Purification by chromatography (silica gel, 0-100% in DCM (0.1% AcOH in MeOH)) yielded 4.50 g, 100% of methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzoate. LCMS: Method A: 1.33 min, MS: ES + 255.1.

[0298] Step 3: 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzoic acid (I-12) [ka]

[0299] Methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate (4.50 g, 17.7 mmol) was added 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) at room temperature, and the mixture was stirred at 40 °C for 5 hours. The mixture was concentrated under reduced pressure and diluted with water (50 mL). The mixture was acidified to approximately pH 4 with aqueous HCl (2 M) at 0 °C, and the resulting solid was collected by filtration to obtain 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.

[0300] Intermediates 13, 14 Methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-nitrobenzoate (I-13) and 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-aminobenzoate (I-14) [ka]

[0301] Step 1: Methyl 3-(5,6-diaminopyridine-2-yl)-5-nitrobenzoate [ka]

[0302] 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 minutes, after which Pd-118 (0.693 g, 1.06 mmol) was added. The mixture was stirred at 75°C for 3 hours. The mixture was filtered through Celite® and adsorbed onto silica gel. Purification by chromatography (silica gel, 0-10% in DCM (0.7M ammonia / MeOH)) yielded methyl 3-(5,6-diaminopyridine-2-yl)-5-nitrobenzoate (3.03 g, 97%). LCMS: Method Q: 0.71 min, MS: ES + 289.0.

[0303] Step 2: Methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-nitrobenzoate (I-13) [ka]

[0304] Methyl 3-(5,6-diaminopyridine-2-yl)-5-nitrobenzoate (2.41 g, 8.36 mmol) and then aqueous sodium nitrite solution (1 M, 9.78 mL, 9.78 mmol) were added to water (75 mL) and sulfuric acid (19.9 mL, 374 mmol) at 10°C. The mixture was stirred at 10°C for 30 minutes. The solid was recovered by filtration and washed with water to obtain methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-nitrobenzoate (2.50 g, 96%). LCMS: Method Q: 0.92 min, MS: ES + 300.0.

[0305] Step 3: 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-aminobenzoate(I-14) [ka]

[0306] Methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitrobenzoate (1.25 g, 4.18 mmol) was added to THF (90 mL) and water (30 mL), to which NH4Cl (2.24 g, 41.8 mmol) and zinc (2.73 g, 41.8 mmol) were added. The mixture was stirred for 72 hours. This 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 ELISA (300 mL) and washed with brine (2 × 100 mL). The solid was recovered by filtration, then stirred with water, filtered, and dried under reduced pressure to obtain methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-aminobenzoate (1.50 g, 39%). 1 ¹H NMR (500MHz, DMSO) δppm: 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). ¹H was unclear / not observed.

[0307] Intermediate 15 N-(6-phenethoxypyridine-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-15) [ka]

[0308] Step 1: 5-Nitro-2-Phenethoxypyridine [ka]

[0309] To a solution of 2-phenylethane-1-ol (CAS 60-12-8, Fluorochem, 0.55 mL, 4.7 mmol) in DMF (7 mL), 2-fluoro-5-nitropyridine (CAS 456-24-6, Activate Scientific, 0.50 g, 3.5 mmol) and Cs2CO3 (2.29 g, 7.0 mmol) were added. The mixture was stirred at 40°C for 18 hours, then cooled to room temperature, diluted with brine (30 mL), and extracted with siRNA (3 × 30 mL). The combined organic fraction was washed with brine (3 × 30 mL), dried on MgSO4, filtered, and adsorbed onto silica gel. Purification by flash chromatography (silica gel, isohexane with 0-30% siRNA) yielded 5-nitro-2-phenethoxypyridine (0.70 g, 80%). LCMS: Method A, 1.96 min, MS: ES + 245.0.

[0310] Step 2: 6-Phenethoxypyridine-3-amine [ka]

[0311] 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 for 1 hour using an H-Cube®. The reaction mixture was concentrated under reduced pressure to obtain 6-phenethoxypyridine-3-amine (550 mg, 82%), which was used in the next step without purification. LCMS: Method A, 1.12 min, MS: ES + 215.2.

[0312] Step 3: N-(6-phenethoxypyridine-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-15) [ka]

[0313] Following the procedure for intermediate 6, 6-phenethoxypyridine-3-amine was used instead of 4-phenethoxyaniline to obtain N-(6-phenethoxypyridine-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.

[0314] Intermediate 16 6-bromo-3H-[1,2,3]triazolo[4,5-b]pyridine(I-16) [ka] 6-Bromo-3H-[1,2,3]triazolo[4,5-b]pyridine [ka]

[0315] Sodium nitrite (176 mg, 2.55 mmol) was added in small increments to a stirred solution of 5-bromopyridine-2,3-diamine (CAS 38875-53-5, Fluorochem, 300 mg, 1.28 mmol) in an aqueous HCl solution (6 M, 10 mL) at 0°C. The mixture was stirred at room temperature for 24 hours. The solid was collected by filtration, washed with water (3 × 20 mL), and dried to obtain 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.

[0316] Intermediate 17 N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-17) [ka]

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

[0318] Following the procedure of intermediate 7 step 1, 4-(bromomethyl)-2-fluoro-1-nitrobenzene (CAS 131858-37-2, Apollo) was used instead of 1-(bromomethyl)-4-nitrobenzene to obtain 4-((benzyloxy)methyl)-2-fluoro-1-nitrobenzene in 96% yield. LCMS: Method A, 1.94 min, MS: ES + 261.1.

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

[0320] Following the procedure of intermediate 7 step 2, 4-((benzyloxy)methyl)-2-fluoro-1-nitrobenzene was used instead of 1-((benzyloxy)methyl)-4-nitrobenzene, and 4-((benzyloxy)methyl)-2-fluoroaniline was obtained in 70% yield by flash chromatography (silica gel, isohexane, 0-50% TBME). LCMS: Method A, 1.64 min, MS ES + 232.1.

[0321] Step 3: N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-17) [ka]

[0322] Following the procedure of intermediate 6, 4-((benzyloxy)methyl)-2-fluoroaniline was used instead of 4-phenethoxyaniline to obtain N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 46% yield. LCMS: Method A, 2.26 min, MS ES + 462.2.

[0323] Intermediate 18 N-(4-((benzyloxy)methyl)-3-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-18) [ka]

[0324] Step 1: 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene [ka]

[0325] Following the procedure of intermediate 7 step 1, 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene was obtained in 95% yield by using 4-(bromomethyl)-2-fluoro-1-nitrobenzene (CAS 131858-37-2, Apollo) instead of 1-(bromomethyl)-4-nitrobenzene. LCMS: Method A, 1.98 min, MS: ES + No mass ions were observed.

[0326] Step 2: 4-((benzyloxy)methyl)-3-fluoroaniline [ka]

[0327] Following the procedure of intermediate 7 step 2, 4-((benzyloxy)methyl)-3-fluoroaniline was obtained in 67% yield by using 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene. LCMS: Method A, 1.56 min, MS ES + 232.1.

[0328] Step 3: N-(4-((benzyloxy)methyl)-3-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-18) [ka]

[0329] Following the procedure of intermediate 6, N-(4-((benzyloxy)methyl)-3-fluoroaniline was used instead of 4-phenethoxyaniline to obtain 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.

[0330] Intermediate 19 (5-((4-((benzyloxymethyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-19) [ka] (5-((4-((benzyloxymethyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-19) [ka]

[0331] Following the procedure of Intermediate 6, (5-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid was obtained in 55% yield by using 2-fluoro-5-carboxybenzeneboronic acid (CAS 874219-59-7, BLD) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)aniline (I-7) instead of 4-phenethoxyaniline, as well as by RP chromatography (C18, 0-100% (0.1% HCO2H in MeCN) / (0.1% HCO2H aqueous solution)). LCMS: Method A, 1.68 min, MS ES + 380.2.

[0332] Intermediate 20 (3-((4-((benzyloxymethyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-20) [ka] (3-((4-((benzyloxymethyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-20) [ka]

[0333] Following the procedure of intermediate 6, (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid was obtained in 57% yield by using 3-borono-2-fluorobenzoic acid (CAS 1072952-09-0, Combi-Blocks) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)aniline (I-7) instead of 4-phenethoxyaniline. LCMS: Method A, 1.67 min, MS ES + 380.2.

[0334] Intermediate 21 N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-21) [ka] N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-21) [ka]

[0335] Following the procedure of intermediate 6, 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD), and 4-((benzyloxy)methyl)aniline (I-7) was used instead of 4-phenethoxyaniline to obtain 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.

[0336] Intermediate 22 4-(Cyclopropylmethoxy)aniline(I-22) [ka]

[0337] Step 1: 1-(cyclopropoxymethyl)-4-nitrobenzene [ka]

[0338] 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 equivalents, 8.33 mmol) was stirred at room temperature for 18 hours and then poured into ice water (400 mL). The mixture was extracted with HCl (3 × 100 mL). The combined organic phase was washed with brine (50 mL), dried over MgSO4, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, isohexane with 0-10% HCl) yielded 1-(cyclopropoxymethyl)-4-nitrobenzene (1.25 g, 89%). LCMS: Method A, 1.70 min, MS ES + 194.2.

[0339] Step 2: 4-(cyclopropylmethoxy)aniline (I-22) [ka]

[0340] Following the procedure of intermediate 7 step 2, 4-(cyclopropylmethoxy)aniline was obtained in 60% yield by using 1-(cyclopropylmethoxy)-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene. LCMS: Method A, 0.22 min, MS ES + 164.2.

[0341] Intermediate 23 4-(Cyclopropylmethoxy)aniline(I-23) [ka]

[0342] Step 1: 1-(cyclopropylmethoxy)-4-nitrobenzene [ka]

[0343] Following the procedure of intermediate step 1, cyclopropyl methanol (CAS 2516-33-8, Fluorochem) was used instead of 2-phenylethane-1-ol to obtain 1-(cyclopropylmethoxy)-4-nitrobenzene in 71% yield. LCMS: Method A, 1.79 min, MS ES + 194.2.

[0344] Step 2: 4-(cyclopropylmethoxy)aniline (I-23) [ka]

[0345] Following the procedure of intermediate 7 step 2, 4-(cyclopropylmethoxy)aniline was obtained in 60% yield by using 1-(cyclopropylmethoxy)-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene, and without purifying the crude product. LCMS: Method A, 0.22 min, MS ES + 164.2.

[0346] Intermediate 24 5-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-2-fluorobenzoic acid (I-24) [ka]

[0347] Step 1: Methyl 5-(5,6-diaminopyridine-2-yl)-2-fluorobenzoate [ka]

[0348] Following the procedure of Step 1 of Intermediate 11, methyl 5-(5,6-diaminopyridine-2-yl)-2-fluorobenzoate was obtained in 83% yield by using methyl 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (CAS 872459-87-5, Combi-Blocks) instead of methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate and MeCN instead of dioxane. LCMS: Method Q: 0.68 min, MS: ES + 262.1.

[0349] Step 2: Methyl 5-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-2-fluorobenzoate [ka]

[0350] By following the procedure of step 2 of intermediate 11, methyl 5-(5,6-diaminopyridine-2-yl)-2-fluorobenzoate was used instead of methyl 3-(5,6-diaminopyrazine-2-yl)benzoate, and by isolation and recovery of the solid by dilution with water, methyl 5-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-2-fluorobenzoate was obtained in 97% yield. LCMS: Method A: 1.23 min, MS: ES + 273.1.

[0351] Step 3: 5-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-2-fluorobenzoic acid (I-24) [ka]

[0352] Following the procedure of intermediate 12 step 3, methyl 5-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-2-fluorobenzoate was used instead of methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzoate for 2 hours at 40°C to obtain 5-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-2-fluorobenzoic acid in 84% yield. LCMS: Method A: 1.01 min, MS: ES + 259.1.

[0353] Intermediate 25 [ka]

[0354] Step 1: Methyl 5-(4,5-diaminopyrimidine-2-yl)-2-fluorobenzoate [ka]

[0355] Following the procedure of intermediate 11 step 1, methyl 5-(4,5-diaminopyrimidine-2-yl)-2-fluorobenzoate was obtained in 29% yield by using 2-chloropyrimidine-4,5-diamine (CAS 14631-08-4, BLD) instead of 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) instead of methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, as well as by purification by chromatography (silica gel, DCM, 0-50% MeOH). LCMS: Method A: 0.69 min, MS: ES + 363.0.

[0356] Step 2: Methyl 5-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-2-fluorobenzoate [ka]

[0357] Following the procedure of step 2 of intermediate 11, methyl 5-(4,5-diaminopyrimidine-2-yl)-2-fluorobenzoate was used instead of methyl 3-(5,6-diaminopyrazine-2-yl)benzoate, and methyl 5-(1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-yl)-2-fluorobenzoate was obtained in 95% yield by flash chromatography (silica gel, DCM with 0-25% MeOH). LCMS: Method A: 1.28 min, MS: ES + 274.0.

[0358] Step 3: 5-(3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-yl)-2-fluorobenzoic acid (I-25) [ka]

[0359] Following the procedure of intermediate 12 step 3, methyl 5-(3H-[1,2,3]triazolo[4,5-b]pyrimidine-5-yl)-2-fluorobenzoate was used instead of methyl 3-(1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-yl)benzoate, and extraction was performed at room temperature for 1 hour and with 2-methyl THF instead of filtration to obtain 5-(3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-yl)-2-fluorobenzoic acid in 80% yield. LCMS: Method A: 1.04 min, MS: ES + 260.0.

[0360] Intermediate 26 5-(trimethylstannyl)-1H-[1,2,3]triazolo[4,5-b]pyridine(I-26) [ka]

[0361] 5-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1, 300 mg, 1.43 mmol) was sparged with nitrogen in dioxane (6 mL), and then hexamethylditine (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 then cooled to room temperature. The mixture was used directly in the next step (assuming a concentration of 0.24 mmol / mL). LCMS: Method A: 1.20 min, MS: ES + 281.0 / 283.0 / 285.0

[0362] Intermediate 27 6-Bromo-1H-[1,2,3]triazolo[4,5-c]pyridine(I-27) [ka]

[0363] Following the procedure for Intermediate 1, 6-bromopyridine-3,4-diamine (CAS 1033203-41-6, BLD) was used instead of 6-bromopyridine-2,3-diamine, and 6-bromo-1H-[1,2,3]triazolo[4,5-c]pyridine was obtained in 100% yield over 1 hour at 60°C. LCMS: Method Q: 0.33 min, MS: ES + 199.0 / 201.0.

[0364] Intermediate 28 6-Bromo-N-(4-phenethoxyphenyl)picolinamide (I-28) [ka]

[0365] Following the procedure of intermediate 6 step 3, 6-bromo-N-(4-phenethoxyphenyl)picolinamide was obtained in 88% yield by using T3P instead of HATU and 6-bromopicolinic acid (CAS 21190-87-4, Fluorochem) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. LCMS: Method A: 1.17 min, MS: ES + 397.0 / 399.0.

[0366] Intermediate 29 4-Bromo-N-(4-phenethoxyphenyl)picolinamide (I-29) [ka]

[0367] Following the procedure of intermediate 6 step 3, 4-bromo-N-(4-phenethoxyphenyl)picolinamide was obtained in 74% yield by using T3P instead of HATU and 4-bromopicolinic acid (CAS 30766-03-1, BLD) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. LCMS: Method A: 1.18 min, MS: ES + 397.0 / 399.0.

[0368] Intermediate 30 2-Bromo-N-(4-phenethoxyphenyl)isonicotinamide (I-30) [ka]

[0369] Following the procedure of intermediate 6 step 3, 2-bromo-N-(4-phenethoxyphenyl)isonicotinamide was obtained in 72% yield by using T3P instead of HATU and 2-bromopicolinic acid (CAS 66572-56-3, Fluorochem) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. LCMS: Method A: 1.10 min, MS: ES + 397.0 / 399.0.

[0370] Intermediate 31 (3-((4-((benzyloxymethyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid (I-31) [ka]

[0371] Following the procedure of intermediate 6 step 3, (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid was obtained in 35% yield by using 3-borono-2,6-difluorobenzoic acid (1451393-05-7, Combi-Blocks) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1451393-05-7, Combi-Blocks) and 4-((benzyloxy)methyl)aniline (I-7) instead of 4-phenethoxyaniline (I-5), and by purification by flash chromatography (silica gel, 0-10% MeOH in DCM). LCMS: Method A: 1.68 min, MS: ES + 398.1.

[0372] Intermediate 32 (3-((4-((benzyloxymethyl)phenyl)carbamoyl)-2-methoxyphenyl)boronic acid (I-32) [ka]

[0373] Following the procedure of intermediate 6 step 3, (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-methoxyphenyl)boronic acid was obtained in 63% yield by using 3-borono-2-methoxybenzoic acid (CAS 913836-10-9, Combi-Blocks) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid instead of 3-borono-2-methoxybenzoic acid (CAS 913836-10-9, Combi-Blocks) and 4-((benzyloxy)methyl)aniline (I-7) instead of 4-phenethoxyaniline (I-5), and by purification by flash chromatography (silica gel, 0-10% MeOH in DCM). LCMS: Method A: 1.70 min, MS: ES + 392.2.

[0374] Intermediate 33 (3-((4-((benzyloxymethyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid (I-33) [ka]

[0375] Following the procedure of intermediate 6 step 3, (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid was obtained in 87% yield by using 5-borono-2-methoxybenzoic acid (913836-12-1, BLD) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)aniline (I-7) instead of 4-phenethoxyaniline (I-5). LCMS: Method A: 1.74 min, MS: ES + 392.2.

[0376] Intermediate 34 (3-((4-((benzyloxymethyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid (I-34) [ka]

[0377] Following the procedure of intermediate 6 step 3, (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid was obtained in 34% yield by using 5-borono-2-methylbenzoic acid (CAS 1256346-18-5, Combi-Blocks) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)aniline (I-7) instead of 4-phenethoxyaniline (I-5), and by purification by flash chromatography (silica gel, 0-10% MeOH in DCM). LCMS: Method A: 1.71 min, MS: ES + 376.2.

[0378] Intermediate 35 (Z)-N-(4-styrylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-35) [ka]

[0379] Step 1: (Z)-4-Styrylaniline [ka]

[0380] (Z)-1-nitro-4-styrylbenzene (CAS 6624-53-9, BLD, 100 mg, 0.391 mmol) and Fe (196 mg, 3.52 mmol) were added to EtOH / water (4:1, 5 mL), to which CaCl2 (195 mg, 1.76 mmol) was added. The mixture was stirred at 45 °C for 24 hours, treated with saturated NaHCO3 aqueous solution (30 mL), and extracted with ethylethanol (3 × 30 mL). The organic matter was dried over Na2SO4 and concentrated under reduced pressure to obtain (Z)-4-styrylaniline (76 mg, 86%). LCMS: Method A: 1.12 min, MS: ES + 196.1.

[0381] Step 2: (Z)-N-(4-styrylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-35) [ka]

[0382] Following the procedure of intermediate 6 step 3, (Z)-4-styrylaniline was used instead of 4-phenethoxyaniline (I-5) to obtain (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.

[0383] 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) [ka]

[0384] Step 1: 2-(1-cyclopropylethoxy)-5-nitrobenzonitrile [ka]

[0385] 1-Cyclopropylethane-1-ol (CAS 765-42-4, Fluorochem, 0.59 mL, 6.02 mmol) was added in one dose to 150 mL of THF at 0°C, along with tBuOK (743 mg, 6.62 mmol). After 15 minutes, 2-Fluoro-5-nitrobenzonitrile (CAS 17417-09-3, Fluorochem, 1.00 g, 6.02 mmol) was added over 10 minutes to 40 mL of THF, and the ice bath was removed. The mixture was stirred at room temperature for 1 hour. 150 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic matter was washed with water (200 mL) and brine (200 mL), dried over Na₂SO₄, and concentrated under reduced pressure to obtain 2-(1-cyclopropylethoxy)-5-nitrobenzonitrile (1.15 g, 76%). LCMS: Method A: 1.76 min, MS: ES + 233.1

[0386] Step 2: 5-amino-2-(1-cyclopropylethoxy)benzonitrile [ka]

[0387] Following the procedure of intermediate 7 step 2, 5-amino-2-(1-cyclopropylethoxy)benzonitrile was obtained in 25% yield by using 2-(1-cyclopropylethoxy)-5-nitrobenzonitrile instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl2 (4.5 equivalents) instead of AcOH, and by fumigating at 80°C for 18 hours, without purifying the crude product. LCMS: Method A, 1.24 min, MS ES + 203.2.

[0388] 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) [ka]

[0389] Following the procedure of intermediate 6 step 3, 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 5-amino-2-(1-cyclopropylethoxy)benzonitrile was used instead of 4-phenethoxyaniline (I-5), and at room temperature instead of 40°C, N-(3-cyano-4-(1-cyclopropylethoxy)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 33% yield and used in the next step or analysis without purification.

[0390] 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) [ka]

[0391] Step 1: 2-Fluoro-1-(((2-methoxybenzyl)oxy)methyl)-4-nitrobenzene [ka]

[0392] Following the procedure of Intermediate 7 Step 1, 2-fluoro-1-(((2-methoxybenzyl)oxy)methyl)-4-nitrobenzene was obtained in 54% yield by using (2-methoxyphenyl)methanol (CAS 612-16-8, Fluorochem) instead of phenylmethanol, and 1-(bromomethyl)-2-fluoro-4-nitrobenzene (CAS 127349-56-8, BLD) instead of 1-(bromomethyl)-4-nitrobenzene, as well as by purification by flash chromatography (silica gel, isohexane, 0-100% ethyl phosphate). LCMS: Method A: 1.72 mins, MS: No mass ions were observed.

[0393] Step 2: 3-Fluoro-4-(((2-Methoxybenzyl)oxy)methyl)aniline [ka]

[0394] Following the procedure of intermediate 7 step 2, 3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)aniline was obtained in 75% yield by using 2-fluoro-1-(((2-methoxybenzyl)oxy)methyl)-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl2 (4.5 equivalents) instead of AcOH for 18 hours at 45°C, and without purifying the crude product. LCMS: Method A, 1.30 min, MS ES + 284.1.

[0395] 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) [ka]

[0396] Following the procedure of intermediate 6 step 3, N-(3-fluoro-4-(((2-methoxybenzyl)oxy)methyl)aniline was used instead of 4-phenethoxyaniline (I-5) at room temperature to obtain 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.

[0397] 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) [ka]

[0398] Step 1: 2-Fluoro-1-(((3-methoxybenzyl)oxy)methyl)-4-nitrobenzene [ka]

[0399] Following the procedure of Intermediate 7 Step 1, 2-fluoro-1-(((3-methoxybenzyl)oxy)methyl)-4-nitrobenzene was obtained in 81% yield by using (3-methoxyphenyl)methanol (CAS 6971-51-3, Fluorochem) instead of phenylmethanol, and 1-(bromomethyl)-2-fluoro-4-nitrobenzene (CAS 127349-56-8, BLD) instead of 1-(bromomethyl)-4-nitrobenzene, as well as by purification by flash chromatography (silica gel, isohexane, 0-100% ethyl phosphate). LCMS: Method A: 1.67 min, MS: ES + 309.1(M+NH4) + .

[0400] Step 2: 3-Fluoro-4-(((3-Methoxybenzyl)oxy)methyl)aniline [ka]

[0401] Following the procedure of intermediate 7 step 2, 3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)aniline was obtained in 75% yield by using 2-fluoro-1-(((3-methoxybenzyl)oxy)methyl)-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl2 (4.5 equivalents) instead of AcOH for 18 hours at 45°C, and without purifying the crude product. LCMS: Method A, 1.28 min, MS ES + 262.1.

[0402] 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) [ka]

[0403] Following the procedure of intermediate 6 step 3, 3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)aniline was used instead of 4-phenethoxyaniline (I-5) to obtain N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 56% yield. LCMS: Method A: 1.99 min, MS: ES + 492.2.

[0404] 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) [ka]

[0405] Step 1: 2-Fluoro-1-(((4-methoxybenzyl)oxy)methyl)-4-nitrobenzene [ka]

[0406] Following the procedure of Intermediate 7 Step 1, 2-fluoro-1-(((4-methoxybenzyl)oxy)methyl)-4-nitrobenzene was obtained in 73% yield by using (4-methoxyphenyl)methanol (CAS 105-13-5, Apollo) instead of phenylmethanol, and 1-(bromomethyl)-2-fluoro-4-nitrobenzene (CAS 127349-56-8, BLD) instead of 1-(bromomethyl)-4-nitrobenzene, as well as by purification by flash chromatography (silica gel, isohexane, 0-100% siRNA). LCMS: Method A: 1.66 min, MS: No mass ions were observed.

[0407] Step 2: 3-Fluoro-4-(((4-Methoxybenzyl)oxy)methyl)aniline [ka]

[0408] Following the procedure of intermediate 7 step 2, 3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)aniline was obtained in 91% yield by using 2-fluoro-1-(((4-methoxybenzyl)oxy)methyl)-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl2 (4.5 equivalents) instead of AcOH, and by fumigating at 45°C for 18 hours, without purifying the crude product. LCMS: Method A, 1.24 min, MS ES + 262.2.

[0409] 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) [ka]

[0410] Following the procedure of intermediate 6 step 3, 3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)aniline was used instead of 4-phenethoxyaniline (I-5) to obtain N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 49% yield. LCMS: Method A: 1.97 min, MS: ES + 492.2.

[0411] Intermediate 40 N-(3-fluoro-4-((pyridine-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-40) [ka]

[0412] Step 1: 2-(((2-fluoro-4-nitrobenzyl)oxy)methyl)pyridine [ka]

[0413] Following the procedure of Intermediate 7 Step 1, 2-(((2-fluoro-4-nitrobenzyl)oxy)methyl)pyridine was obtained in 53% yield by using pyridine-2-ylmethanol (CAS 586-98-1, BLD) instead of phenylmethanol and 1-(bromomethyl)-2-fluoro-4-nitrobenzene (CAS 127349-56-8, BLD) instead of 1-(bromomethyl)-4-nitrobenzene, and by purification by flash chromatography (silica gel, isohexane, 0-100% siRNA). LCMS: Method A: 1.16 min, MS: ES + 263.1.

[0414] Step 2: 3-Fluoro-4-((Pyridine-2-ylmethoxy)methyl)aniline [ka]

[0415] Following the procedure of intermediate 7 step 2, 3-fluoro-4-((pyridine-2-ylmethoxy)methyl)aniline was obtained in 80% yield by using 2-((2-fluoro-4-nitrobenzyl)oxy)methyl)pyridine instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl2 (4.5 equivalents) instead of AcOH, and by fumigating at 45°C for 18 hours, without purifying the crude product. LCMS: Method A, 0.62 min, MS ES + 233.2.

[0416] Step 3: N-(3-fluoro-4-((pyridine-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-22) [ka]

[0417] Following the procedure of intermediate 6 step 3, 3-fluoro-4-((pyridine-2-ylmethoxy)methyl)aniline was used instead of 4-phenethoxyaniline (I-5) to obtain N-(3-fluoro-4-((pyridine-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 72% yield. LCMS: Method A: 1.43 min, MS: ES + 463.2.

[0418] 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) [ka]

[0419] Step 1: 1-Chloro-4-((4-nitrobenzyl)sulfonyl)benzene [ka]

[0420] Sodium 4-chlorobenzene sulfinate (CAS 14752-66-0, Fluorochem, 101 mg, 0.509 mmol) was added to DMF (2 mL) with 1-(bromomethyl)-4-nitrobenzene (CAS 100-11-8, Apollo, 100 mg, 0.463 mmol). The mixture was stirred at room temperature for 2 hours to obtain 1-chloro-4-((4-nitrobenzyl)sulfonyl)benzene, which was used directly in subsequent steps without post-treatment. LCMS: Method A: 1.69 min, MS: ES - 310.0.

[0421] Step 2: 4-(((4-chlorophenyl)sulfonyl)methyl)aniline [ka]

[0422] 1-Chloro-4-((4-nitrobenzyl)sulfonyl)benzene (745 mg, 2.39 mmol) in DMF (2 mL) was mixed with THF (15 mL), MeOH (5 mL), and Pd (10 wt% 254 mg, 2.39 mmol). The mixture was stirred at room temperature under H2 (5 bar) for 18 hours, then filtered through Celite and washed with MeOH. By concentrating the filtrate, 4-(((4-chlorophenyl)sulfonyl)methyl)aniline (520 mg, 77% in two steps) was obtained. 1 H NMR (500MHz, DMSO) δppm: 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).

[0423] 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) [ka]

[0424] Following the procedure of intermediate 6 step 3, 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-(((4-chlorophenyl)sulfonyl)methyl)aniline was used instead of 4-phenethoxyaniline (I-5) to obtain 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.

[0425] Intermediate 42 N-(4-(((4-cyanobenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-42) [ka]

[0426] Step 1: 4-(((4-nitrobenzyl)oxy)methyl)benzonitrile [ka]

[0427] Following the procedure of Intermediate 7 Step 1, 4-(hydroxymethyl)benzonitrile (CAS 874-89-5, Thermo Fisher) was used instead of phenylmethanol, and 4-(((4-nitrobenzyl)oxy)methyl)benzonitrile was obtained in 61% yield by purification with LiOH (1 equivalent) and by flash chromatography (silica gel, isohexane, 0-100% SiO). LCMS: Method A: 0.76 min, MS: No mass ions were observed.

[0428] Step 2: 4-(((4-aminobenzyl)oxy)methyl)benzonitrile [ka]

[0429] Following the procedure of intermediate 7 step 2, 4-(((4-nitrobenzyl)oxy)methyl)benzonitrile was obtained in 93% yield by using 4-(((4-aminobenzyl)oxy)methyl)benzonitrile instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl2 (4.5 equivalents) instead of AcOH for 24 hours at 45°C, and without purifying the crude product. LCMS: Method A, 0.80 min, MS ES + 239.1.

[0430] Step 3: N-(4-(((4-cyanobenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-42) [ka]

[0431] Following the procedure of intermediate 6 step 3, 4-(((4-aminobenzyl)oxy)methyl)benzonitrile was used instead of 4-phenethoxyaniline (I-5) to obtain 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.

[0432] Intermediate 43 N-(4-(cyclopropylmethoxy)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-43) [ka]

[0433] Following the procedure of intermediate 6 step 3, N-(4-(cyclopropylmethoxy)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD), and 4-(cyclopropylmethoxy)aniline (I-23) was used instead of 4-phenethoxyaniline (I-5), and the mixture was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to obtain 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.

[0434] Intermediate 44 N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-44) [ka]

[0435] Step 1: 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene [ka]

[0436] Following the procedure of Intermediate 7 Step 1, 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene was obtained in 85% yield by purification using LiOH (1 equivalent) and flash chromatography (silica gel, DCM, 0-10% (0.7M ammonia / MeOH)), with (3-methoxy-4-nitrophenyl)methanol (CAS 80866-88-2, BLD) instead of phenylmethanol and benzyl bromide (CAS 100-39-0, Merck) instead of 1-(bromomethyl)-4-nitrobenzene. LCMS: Method A: 1.94 min, MS: ES + 274.2.

[0437] Step 2: 4-((benzyloxy)methyl)-2-methoxyaniline [ka]

[0438] Following the procedure of intermediate 7 step 2, 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene was used instead of 1-((benzyloxy)methyl)-4-nitrobenzene, and CaCl2 (4.5 equivalents) was used instead of AcOH, and 4-((benzyloxy)methyl)-2-methoxyaniline was obtained in 73% yield for 18 hours at 40°C, without purifying the crude product. LCMS: Method A, 1.27 min, MS ES + 244.2.

[0439] Step 3: N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-44) [ka]

[0440] Following the procedure of intermediate 6 step 3, using 4-((benzyloxy)methyl)-2-methoxyaniline instead of 4-phenethoxyaniline (I-5), and purified by flash chromatography (silica gel, 0-10% MeOH in DCM), N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 30% yield. LCMS: Method A: 2.38 min, MS: ES + 474.2.

[0441] Intermediate 45 N-(4-((benzyloxy)methyl)-2-methylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-45) [ka]

[0442] Step 1: 4-((benzyloxy)methyl)-2-methyl-1-nitrobenzene [ka]

[0443] Following the procedure of intermediate 7 step 1, 4-(bromomethyl)-2-methyl-1-nitrobenzene (CAS 127349-56-8, Apollo) was used instead of 1-(bromomethyl)-4-nitrobenzene to obtain 4-((benzyloxy)methyl)-2-methyl-1-nitrobenzene in 49% yield. LCMS: Method A: 2.02 min, MS: ES + 258.2.

[0444] Step 2: 4-((benzyloxy)methyl)-2-methylaniline [ka]

[0445] Following the procedure of intermediate 7 step 2, 4-((benzyloxy)methyl)-2-methyl-1-nitrobenzene was used instead of 1-((benzyloxy)methyl)-4-nitrobenzene, and CaCl2 (4.5 equivalents) was used instead of AcOH, and 4-((benzyloxy)methyl)-2-methylaniline was obtained in 71% yield for 18 hours at 80°C, without purifying the crude product. LCMS: Method A, 1.28 min, MS ES + 228.2.

[0446] Step 3: N-(4-((benzyloxy)methyl)-2-methylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-45) [ka]

[0447] Following the procedure of intermediate 6 step 3, 4-((benzyloxy)methyl)-2-methylaniline was used instead of 4-phenethoxyaniline (I-5) to obtain 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.

[0448] 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) [ka]

[0449] Following the procedure of intermediate 6 step 3, N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD), and 4-((benzyloxy)methyl)-3-fluoroaniline (intermediate 18 step 2) was used instead of 4-phenethoxyaniline (I-5), and at room temperature instead of 40°C, N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 57% yield. LCMS: Method A: 2.34 min, MS: ES + 480.2.

[0450] Intermediate 47 N-(4-((benzyloxy)methyl)phenyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-47) [ka]

[0451] Step 1: Lithium 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate [ka]

[0452] 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 hours, and then concentrated under reduced pressure to obtain 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.

[0453] Step 2: N-(4-((benzyloxy)methyl)phenyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-47) [ka]

[0454] Following the procedure of intermediate 6 step 3, lithium 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)aniline (I-7) was used instead of 4-phenethoxyaniline (I-5) to obtain 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.

[0455] Intermediate 48 N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-48) [ka]

[0456] Following the procedure of intermediate 6 step 3, N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 269409-71-4, Manchester Organics) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)aniline (I-7) was used instead of 4-phenethoxyaniline (I-5) to obtain N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 52% yield. LCMS: Method A: 2.12 min, MS: ES + 474.2.

[0457] Intermediate 49 N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-49) [ka]

[0458] Following the procedure of intermediate 6 step 3, 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 515131-35-8, BLD) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)aniline (I-7) was used instead of 4-phenethoxyaniline (I-5) to obtain N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 57% yield. LCMS: Method A: 2.34 min, MS: ES + 458.3.

[0459] 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) [ka]

[0460] Step 1: 1-((cyclopropylmethoxy)methyl)-2-fluoro-4-nitrobenzene [ka]

[0461] Following the procedure of intermediate 7 step 1, cyclopropyl methanol (CAS 2516-33-8, Fluorochem) was used instead of phenylmethanol, and 1-(bromomethyl)-2-fluoro-4-nitrobenzene (CAS 127349-56-8, Apollo) was used instead of 1-(bromomethyl)-4-nitrobenzene to obtain 1-((cyclopropylmethoxy)methyl)-2-fluoro-4-nitrobenzene in 82% yield. LCMS: Method A: 1.82 min, MS: ES + 226.1.

[0462] Step 2: 4-((cyclopropylmethoxy)methyl)-3-fluoroaniline [ka]

[0463] Following the procedure of intermediate 7 step 2, 4-((cyclopropylmethoxy)methyl)-3-fluoroaniline was obtained in 67% yield by using 1-((benzyloxy)methyl)-4-nitrobenzene instead of 1-((cyclopropylmethoxy)methyl)-2-fluoro-4-nitrobenzene and CaCl2 (4.5 equivalents) instead of AcOH for 18 hours at 80°C, and without purifying the crude product. LCMS: Method A, 1.23 min, MS ES + 196.2.

[0464] 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) [ka]

[0465] Following the procedure of intermediate 6 step 3, N-(4-((cyclopropylmethoxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD), and 4-((cyclopropylmethoxy)methyl)-3-fluoroaniline was used instead of 4-phenethoxyaniline (I-5), and at room temperature instead of 40°C, N-(4-((cyclopropylmethoxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 60% yield. LCMS: Method A: 2.22 min, MS: ES + 444.2.

[0466] 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) [ka]

[0467] Step 1: 1-(1-cyclopropylethoxy)-2-fluoro-4-nitrobenzene [ka]

[0468] 1-Cyclopropylethane-1-ol (CAS 765-42-4, Fluorochem, 0.62 mL, 6.29 mmol) was added in one batch to 150 mL of THF at 0°C with tBuOK (776 mg, 6.91 mmol). After 15 minutes, 1,2-Difluoro-4-nitrobenzene (CAS 369-34-6, Fluorochem, 1.00 g, 6.29 mmol) was added to 40 mL of THF over 10 minutes, and the ice bath was removed. The mixture was stirred at room temperature for 1 hour. 150 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic matter was washed with water (200 mL) and brine (200 mL), dried over Na₂SO₄, and concentrated under reduced pressure to obtain 1-(1-Cyclopropylethoxy)-2-Fluoro-4-nitrobenzene (1.20 g, 79%). LCMS: Method A: 1.90 min, MS: ES + 226.1.

[0469] Step 2: 4-(1-cyclopropylethoxy)-3-fluoroaniline [ka]

[0470] Following the procedure of intermediate 7 step 2, 4-(1-cyclopropylethoxy)-3-fluoroaniline was obtained in 37% yield by using 1-(1-cyclopropylethoxy)-2-fluoro-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl2 (4.5 equivalents) instead of AcOH, and by fumigating at 80°C for 18 hours, without purifying the crude product. LCMS: Method A, 0.97 min, MS ES + 196.2.

[0471] 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) [ka]

[0472] Following the procedure of intermediate 6 step 3, at room temperature instead of 40°C, N-(4-(1-cyclopropylethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 27% yield by using 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD) instead of 34-phenethoxyaniline (I-5). LCMS: Method A: 2.33 min, MS: ES + 444.2.

[0473] Intermediate 52 N-(4-(1-cyclopropylethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-52) [ka]

[0474] Following the procedure of intermediate 6 step 3, N-(4-(1-cyclopropylethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 23% yield by using 4-(1-cyclopropylethoxy)aniline (CAS 2168664-20-6, Enamine) instead of 4-phenethoxyaniline (I-5), and by purification by flash chromatography (silica gel, 0-10% MeOH in DCM). LCMS: Method A: 2.17 min, MS: ES + 408.2.

[0475] Intermediate 53 N-(4-(cyclopropylmethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-53) [ka]

[0476] Following the procedure of intermediate 6 step 3, N-(4-(cyclopropylmethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD), and 4-(cyclopropylmethoxy)-3-fluoroaniline (CAS 937598-42-0, Enamine) was used instead of 4-phenethoxyaniline (I-5), and at room temperature instead of 40°C, N-(4-(cyclopropylmethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 71% yield. LCMS: Method A: 2.2 min, MS: ES + 430.2.

[0477] Intermediate 54 N-(4-((4-methylphenyl)sulfonamide)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-54) [ka]

[0478] Step 1: 3-Bromo-N-(4-((4-methylphenyl)sulfonamide)phenyl)benzamide [ka]

[0479] 3-bromobenzoyl chloride (0.252 mL, 1.91 mmol) was added to THF (10 mL) and pyridine (0.46 mL, 5.72 mmol) with 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 room temperature for 18 hours, and then water (30 mL) was added. The resulting solid was recovered by filtration and triturated with ether (2 × 10 mL) to obtain 3-bromo-N-(4-((4-methylphenyl)sulfonamide)phenyl)benzamide (660 mg, 76%). LCMS: Method A: 1.87 min, MS: ES + 445.0 / 447.0.

[0480] Step 2: N-(4-((4-methylphenyl)sulfonamide)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-54) [ka]

[0481] 3-bromo-N-(4-((4-methylphenyl)sulfonamide)phenyl)benzamide (400 mg, 0.898 mmol) was added to dioxane (8 mL), to which bis(pinacolate)diborone (CAS 73183-34-3, Fluorochem, 342 mg, 1.35 mmol) and KOAc (264 mg, 2.69 mmol) were added. The mixture was sparged under nitrogen for 5 minutes, and Pd-118 (117 mg, 0.180 mmol) was added. The mixture was sparged under nitrogen, stirred at 80°C for 5 hours, and concentrated on silica gel. Purification by flash chromatography (silica gel, isohexane, 0-100% ethyl phosphate) yielded N-(4-((4-methylphenyl)sulfonamide)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.

[0482] Intermediate 55 N-(4-(N-benzylsulfamoyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-55) [ka]

[0483] Step 1: N-(4-(N-benzylsulfamoyl)phenyl)-3-bromobenzamide [ka]

[0484] Following the procedure of intermediate 54 step 1, 4-amino-N-benzylbenzenesulfonamide (CAS 1709-54-2, Enamine) was used instead of N-(4-aminophenyl)-4-methylbenzenesulfonamide to obtain N-(4-(N-benzylsulfamoyl)phenyl)-3-bromobenzamide in 83% yield. LCMS: Method A: 1.89 min, MS: ES + 445.0 / 447.0.

[0485] Step 2: N-(4-(N-benzylsulfamoyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-55) [ka]

[0486] Following the procedure of intermediate 54 step 2, N-(4-(N-benzylsulfamoyl)phenyl)-3-bromobenzamide was used instead of 3-bromo-N-(4-((4-methylphenyl)sulfonamide)phenyl)-benzamide, and N-(4-(N-benzylsulfamoyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 81% yield by extraction to DCM and trituration of the crude product with Et2O, except that the workup was by the addition of water. LCMS: Method A: 2.05 min, MS: ES + 493.2.

[0487] Intermediate 56 N-(4-(N-phenethylsulfamoyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-56) [ka]

[0488] Step 1: 3-Bromo-N-(4-(N-phenethylsulfamoyl)phenyl)benzamide [ka]

[0489] Following the procedure of intermediate 54 step 1, 3-bromo-N-(4-(N-phenethylsulfamoyl)phenyl)benzamide was obtained in 80% yield by extraction to DCM and trituration of the crude product in Et2O, except that 4-amino-N-phenethylbenzenesulfonamide (CAS 587850-67-7, Combi-Blocks) was used instead of N-(4-aminophenyl)-4-methylbenzenesulfonamide, and the workup was by the addition of water. LCMS: Method A: 1.96 min, MS: ES + 459.0 / 461.0.

[0490] Step 2: N-(4-(N-phenethylsulfamoyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-56) [ka]

[0491] Following the procedure of step 2 of intermediate 54, 3-bromo-N-(4-(N-phenethylsulfamoyl)phenyl)benzamide was used instead of 3-bromo-N-(4-(4-methylphenyl)sulfonamide)phenyl)benzamide to obtain 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.

[0492] Intermediate 57 N-(4-(phenylsulfonyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-57) [ka]

[0493] Step 1: 3-Bromo-N-(4-(phenylsulfonyl)phenyl)benzamide [ka]

[0494] Following the procedure of intermediate 54 step 1, 3-bromo-N-(4-(phenylsulfonyl)phenyl)benzamide was obtained in 80% yield by extraction into DCM and trituration of the crude product in Et2O, except that 4-(benzenesulfonyl)aniline (CAS 7019-01-4, Fluorochem) was used instead of N-(4-aminophenyl)-4-methylbenzenesulfonamide, and the workup was by the addition of water. LCMS: Method A: 1.89 min, MS: ES + 416.0 / 418.0.

[0495] Step 2: N-(4-(phenylsulfonyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-57) [ka]

[0496] Following the procedure of step 2 of intermediate 54, 3-bromo-N-(4-(phenylsulfonyl)phenyl)benzamide was used instead of 3-bromo-N-(4-(4-methylphenyl)sulfonamide)phenyl)benzamide to obtain 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.

[0497] Intermediate 58 N-(4-((benzyloxy)methyl)phenyl)-2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-58) [ka]

[0498] 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 hours. Water (40 mL) was added, and the mixture was extracted with ELISA (3 × 30 mL). The organic matter was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, isohexane, 0-100% ELISA) yielded 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.

[0499] Intermediate 59 N-(4-(cyclopropylmethoxy)phenyl)-5-(5,6-diaminopyridine-2-yl)-2-fluorobenzamide(I-59) [ka]

[0500] Following the procedure of intermediate 10, N-(4-(cyclopropylmethoxy)phenyl)-5-(5,6-diaminopyridine-2-yl)-2-fluorobenzamide was obtained in 58% yield by using 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD) instead 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) instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-43) instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-43), as well as by purification by flash chromatography (silica gel, heptane, 0-100% (3:1 EtOH / siRNA)). LCMS: Method A: 0.94 min, MS: ES + 393.2.

[0501] Intermediate 60 5-(5,6-diaminopyridine-2-yl)-2-fluoro-N-(4-(tosylmethyl)phenyl)benzamide(I-60) [ka]

[0502] Step 1: 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)benzamide [ka]

[0503] 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) was added to DMF (2 mL) with HATU (506 mg, 1.33 mmol), DIPEA (0.580 mL, 3.33 mmol), and after 30 minutes, 4-(tosylmethyl)aniline (CAS 54306-15-9, Combi-Blocks, 290 mg, 1.11 mmol). The mixture was stirred at 40°C for 18 hours and then poured into water (10 mL). The solid was recovered by filtration and washed with water to obtain 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)benzamide (210 mg, 35%). 1 H NMR(500MHz,DMSO)δppm:10.49(s,1H), 7.90(dd,J=7.6,1.7Hz,1H), 7.85(ddd,J=7.6,5.5,1.8Hz,1H), 7.61(t,J=8.4H) z,4H), 7.41(d,J=8.1Hz,2H), 7.37(dd,J=10.4,8.3Hz,1H), 7.14~7.09(m,2H), 4.60(s,2H), 2.41(s,3H), 1.32(s,12H).

[0504] Step 2: 5-(5,6-diaminopyridine-2-yl)-2-fluoro-N-(4-(tosylmethyl)phenyl)benzamide(I-60) [ka]

[0505] Following the procedure for intermediate 10, replace 5-bromopyrazine-2,3-diamine with 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD Corporation), and replace N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6) with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- Using 2-yl)-N-(4-(tosylmethyl)phenyl)benzamide, 5-(5,6-diaminopyridine-2-yl)-2-fluoro-N-(4-(tosylmethyl)phenyl)benzamide was obtained in 15% yield by purification using K3PO4 instead of Cs2CO3 and by flash chromatography (silica gel, hexane, 0-100% (2% NH4OH in 3:1 EtOH / siRNA)). LCMS: Method A: 1.3 min, MS: ES + 491.2.

[0506] Intermediate 61 N-(4-((benzyloxy)methyl)-3-fluorophenyl)-5-(4,5-diaminopyrimidine-2-yl)-2-fluorobenzamide(I-61) [ka]

[0507] Following the procedure for intermediate 10, replace 5-bromopyrazine-2,3-diamine with 2-chloropyrimidine-4,5-diamine (CAS 14631-08-4, BLD), and replace N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6) with N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5- N-(4-((benzyloxy)methyl)-3-fluorophenyl)-5-(4,5-diaminopyrimidine-2-yl)-2-fluorobenzamide was obtained in 38% yield by using (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-46) and by purification by flash chromatography (silica gel, DCM, 0-10% (0.7M ammonia / MeOH)). LCMS: Method A: 1.14 min, MS: ES + 462.1.

[0508] Intermediate 62 N-(4-((benzyloxy)methyl)-3-fluorophenyl)-5-(4,5-diamino-6-methylpyrimidine-2-yl)-2-fluorobenzamide(I-62) [ka]

[0509] Following the procedure for intermediate 10, replace 5-bromopyrazine-2,3-diamine with 2-chloro-6-methylpyrimidine-4,5-diamine (CAS 63211-98-3, BLD), and replace N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6) with N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5- N-(4-((benzyloxy)methyl)-3-fluorophenyl)-5-(4,5-diamino-6-methylpyrimidine-2-yl)-2-fluorobenzamide was obtained in 36% yield by purification using (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-46) and by flash chromatography (silica gel, DCM, 0-10% (0.7M ammonia / MeOH)). LCMS: Method A: 1.31 min, MS: ES + 476.1.

[0510] Intermediate 63 N-(4-((benzyloxy)methyl)-3-fluorophenyl)-5-(4,5-diamino-6-(trifluoromethyl)pyrimidine-2-yl)-2-fluorobenzamide(I-63) [ka]

[0511] Following the procedure for intermediate 10, replace 5-bromopyrazine-2,3-diamine with 2-chloro-6-(trifluoromethyl)pyrimidine-4,5-diamine (CAS 708-46-3, Enamine), and replace N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6) with N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5 N-(4-((benzyloxy)methyl)-3-fluorophenyl)-5-(4,5-diamino-6-(trifluoromethyl)pyrimidine-2-yl)-2-fluorobenzamide was obtained in 37% yield by purification using -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-46) and by flash chromatography (silica gel, DCM, 0-10% (0.7M ammonia / MeOH)). LCMS: Method A: 1.91 min, MS: ES + 530.1.

[0512] Intermediate 64 N-(4-((benzyloxy)methyl)phenyl)-5-(4,5-diaminopyrimidine-2-yl)-2-fluorobenzamide(I-64) [ka]

[0513] Following the procedure of intermediate 10, N-(4-((benzyloxymethyl)phenyl)-5-(4,5-diaminopyrimidine-2-yl)-2-fluorobenzamide was obtained in 55% yield by using 2-chloropyrimidine-4,5-diamine (CAS 14631-08-4, BLD) instead of 5-bromopyrazine-2,3-diamine, and N-(4-((benzyloxymethyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21) instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6), as well as by purification by flash chromatography (silica gel, 0-10% in DCM (0.7M ammonia / MeOH)). LCMS: Method A: 1.26 min, MS: ES + 444.1.

[0514] Intermediate 65 5-(4,5-diaminopyrimidine-2-yl)-2-fluoro-N-(4-phenethoxyphenyl)benzamide(I-65) [ka]

[0515] Step 1: 2-Fluoro-N-(4-phenethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka]

[0516] Following the procedure of intermediate 6 step 3, 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid to obtain 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

[0517] Step 2: 5-(4,5-diaminopyrimidine-2-yl)-2-fluoro-N-(4-phenethoxyphenyl)benzamide(I-65) [ka]

[0518] Following the procedure of intermediate 10, 5-(4,5-diaminopyrimidine-2-yl)-2-fluoro-N-(4-phenethoxyphenyl)benzamide was obtained in 38% yield by using 2-chloropyrimidine-4,5-diamine (CAS 14631-08-4, BLD) instead 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 instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6), as well as by purification by flash chromatography (silica gel, 0-10% in DCM (0.7M ammonia / MeOH)). LCMS: Method A: 1.33 min, MS: ES + 444.1

[0519] Intermediate 66 3-(4,5-diaminopyridine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0520] Following the procedure for intermediate 10, 3-(4,5-diaminopyridine-2-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 67% yield by using 6-bromopyridine-3,4-diamine (CAS 1033203-41-6, BLD) instead of 5-bromopyrazine-2,3-diamine, and by purification by flash chromatography (silica gel, DCM, 0-10% (0.7M ammonia / MeOH)). LCMS: Method A: 1.25 min, MS: ES + 425.1.

[0521] Intermediate 67 N-(4-((cyclopropylmethoxy)methyl)phenyl)-5-(5,6-diaminopyridine-2-yl)-2-fluorobenzamide(I-67) [ka]

[0522] Step 1: 1-((cyclopropylmethoxy)methyl)-4-nitrobenzene [ka]

[0523] A solution of 1-(bromomethyl)-4-nitrobenzene (CAS 100-11-8, Thermo Scientific, 500 mg, 2.31 mmol) in cyclopropyl methanol (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 room temperature for 18 hours. Further KOH (156 mg, 2.78 mmol) was added, and the mixture was stirred for a further 3 hours. Then, it was diluted with water (200 mL), and the product was extracted with siRNA (3 × 50 mL). The combined organic extract was washed with brine (3 × 50 mL), dried on Na₂SO₄, and the filtrate was adsorbed onto silica gel. Purification by flash chromatography A (silica gel, isohexane 0-10% siRNA) yielded 1-((cyclopropylmethoxy)methyl)-4-nitrobenzene (400 mg, 83%). LCMS: Method A, 1.76 min, MS: ES + 208.2

[0524] Step 2: 4-((cyclopropylmethoxy)methyl)aniline (I-67a) [ka]

[0525] Following the procedure of intermediate 7 step 2, 4-((cyclopropylmethoxy)methyl)aniline was obtained in 58% yield by using 1-((benzyloxy)methyl)-3-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene. LCMS: Method A, 0.42 min, MS ES + 178.2.

[0526] Step 3: N-(4-((cyclopropylmethoxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka]

[0527] Following the procedure of intermediate 6 step 3, N-(4-((cyclopropylmethoxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 32% yield by using T3P instead of HATU, 4-((cyclopropylmethoxy)methyl)aniline (I-67a) instead 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) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. LCMS: Method A: 1.98 min, MS: ES + 426.1

[0528] Step 4: N-(4-((cyclopropylmethoxy)methyl)phenyl)-5-(5,6-diaminopyridine-2-yl)-2-fluorobenzamide(I-67) [ka]

[0529] Following the procedure of intermediate 10, N-(4-((cyclopropylmethoxymethyl)phenyl)-5-(5,6-diaminopyridine-2-yl)-2-fluorobenzamide was obtained in 66% yield by using 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD) instead of 5-bromopyrazine-2,3-diamine, and N-(4-((cyclopropylmethoxymethyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6), MeCN instead of dioxane, and by purification by flash chromatography (silica gel, hexane 0-100% (3:1 EtOH / siRNA)). LCMS: Method A: 1.16 min, MS: ES + 407.1.

[0530] Intermediate 68 N-(4-((cyclopropylmethoxy)methyl)phenyl)-3-(5,6-diaminopyridine-2-yl)benzamide(I-68) [ka]

[0531] Step 1: N-(4-((cyclopropylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka]

[0532] Following the procedure of intermediate 6 step 3, N-(4-((cyclopropylmethoxymethyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-67a) was used instead of HATU and instead of 4-phenethoxyaniline (I-5) to obtain N-(4-((cyclopropylmethoxymethyl)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

[0533] Step 2: N-(4-((cyclopropylmethoxy)methyl)phenyl)-3-(5,6-diaminopyridine-2-yl)benzamide(I-68) [ka]

[0534] Following the procedure of intermediate 10, N-(4-((cyclopropylmethoxymethyl)phenyl)-3-(5,6-diaminopyridine-2-yl)benzamide was obtained in 70% yield by using 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD) instead of 5-bromopyrazine-2,3-diamine, and N-(4-((cyclopropylmethoxymethyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6), MeCN instead of dioxane, and by purification by flash chromatography (silica gel, hexane 0-100% (3:1 EtOH / siRNA)). LCMS: Method A: 1.14 min, MS: ES + 389.1.

[0535] Intermediate 69 N-(4-((benzyloxy)methyl)phenyl)-5-(5,6-diaminopyrazine-2-yl)-2-fluorobenzamide(I-69) [ka]

[0536] Following the procedure for intermediate 10, N-(4-((benzyloxymethyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21) was used instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6), and MeCN was used instead of dioxane. Purification by flash chromatography (silica gel, hexane 0-100% (3:1 EtOH / siRNA)) yielded N-(4-((benzyloxymethyl)phenyl)-5-(5,6-diaminopyrazine-2-yl)-2-fluorobenzamide in 51% yield. LCMS: Method A: 0.66 min, MS: ES+ 444.1.

[0537] Intermediate 70 N-(4-((benzyloxy)methyl)phenyl)-5-(4,5-diaminopyridine-2-yl)-2-fluorobenzamide(I-70) [ka]

[0538] Following the procedure for intermediate 10, replace 5-bromopyrazine-2,3-diamine with 6-bromopyridine-3,4-diamine (CAS 81033203-41-6, BLD), and replace N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(4,4,5) with N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6). ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21), using MeCN instead of dioxane, and purified by flash chromatography (silica gel, 0-10% in DCM (0.7M ammonia / MeOH)), N-(4-((benzyloxy)methyl)phenyl)-5-(4,5-diaminopyridine-2-yl)-2-fluorobenzamide was obtained in 59% yield. LCMS: Method A: 1.25 min, MS: ES + 443.1.

[0539] Intermediate 71 4-((benzyloxy)methyl)-N-(3-(5,6-diaminopyridine-2-yl)phenyl)benzamide(I-71) [ka]

[0540] Step 1: Methyl 4-((benzyloxy)methyl)benzoate [ka]

[0541] Following the procedure of intermediate step 1, methyl 4-(bromomethyl)benzoate (CAS 2417-72-3, BLD) was used instead of 1-(bromomethyl)-4-nitrobenzene to obtain methyl 4-((benzyloxy)methyl)benzoate in 96% yield. LCMS: Method A, 1.94 min, MS: ES + 261.1.

[0542] Step 2: 4-((benzyloxy)methyl)benzoic acid (I-71a) [ka]

[0543] 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 room temperature for 18 hours, and then at 50°C for 4 hours. The mixture was cooled, acidified with aqueous HCl (2 M), diluted with water (30 mL), and extracted with SiO2 (3 × 30 mL). The combined organic matter was washed with brine (90 mL), dried on MgSO4, and concentrated under reduced pressure to obtain 4-((benzyloxy)methyl)benzoic acid (709 mg, 85%). LCMS: Method A: 1.50 min, MS: ES + 243.0

[0544] Step 3: 4-((benzyloxy)methyl)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide [ka]

[0545] Following the procedure of intermediate 6 step 3, 4-((benzyloxy)methyl)benzoic acid (I-71a) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 3-aminobenzeneboronic acid pinacol ester (CAS 210907-84-9, Fluorochem) was used instead of 4-phenethoxyaniline (I-5), and after 18 hours at room temperature, 4-((benzyloxy)methyl)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide was obtained in 83% yield. LCMS: Method A: 2.00 min, MS: ES + 444.1.

[0546] Step 4: 4-((benzyloxy)methyl)-N-(3-(5,6-diaminopyridine-2-yl)phenyl)benzamide(I-71) [ka]

[0547] Following the procedure of intermediate 10, 4-((benzyloxy)methyl)-N-(3-(5,6-diaminopyridine-2-yl)phenyl)benzamide was obtained in 66% yield by using 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD) instead 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 instead of 4-((benzyloxy)methyl)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide instead of 4-((benzyloxy)methyl)-N-(3-(5,6-diaminopyridine LCMS: Method A: 1.25 min, MS: ES + 425.1

[0548] Intermediate 72 4-((benzyloxy)methyl)-N-(5-(5,6-diaminopyridine-2-yl)-2-fluorophenyl)benzamide(I-72) [ka]

[0549] Step 1: 4-((benzyloxy)methyl)-N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide [ka]

[0550] Following the procedure of intermediate 6 step 3, 4-((benzyloxy)methyl)benzoic acid (I-71a) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (CAS1003575-43-6, BLD) was used instead of 4-phenethoxyaniline (I-5), and 4-((benzyloxy)methyl)-N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide was obtained in 55% yield by flash chromatography (silica gel, 0-10% MeOH in DCM). LCMS: Method A: 2.04 min, MS: ES + 462.1.

[0551] Step 2: 4-((benzyloxy)methyl)-N-(5-(5,6-diaminopyridine-2-yl)-2-fluorophenyl)benzamide(I-72) [ka]

[0552] Following the procedure of intermediate 10, 4-((benzyloxy)methyl)-N-(5-(5,6-diaminopyridine-2-yl)-2-fluorophenyl)benzamide was obtained in 72% yield by using 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD) instead 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 instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6), MeCN instead of dioxane, and by purification by flash chromatography (silica gel, 0-10% MeOH in DCM). LCMS: Method A: 1.28 min, MS: ES + 443.1

[0553] Intermediate 73 4',5'-diamino-N-(4-((benzyloxy)methyl)phenyl)-2',4-difluoro-[1,1'-biphenyl]-3-carboxamide(I-73) [ka]

[0554] Following the procedure for intermediate 10, replace 5-bromopyrazine-2,3-diamine with 4-bromo-5-fluorobenzene-1,2-diamine (CAS 153505-37-4, Apollo), and replace N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6) with N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(4,4, 4',5'-diamino-N-(4-((benzyloxy)methyl)phenyl)-2',4-difluoro-[1,1'-biphenyl]-3-carboxamide was obtained in 72% yield by purification using 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21) and by flash chromatography (silica gel, hexane, 0-100% (2% NH4OH in 3:1 EtOH / siRNA)). LCMS: Method A: 0.71 min, MS: ES + 460.1.

[0555] Intermediate 74 3',4'-diamino-N-(4-((benzyloxy)methyl)phenyl)-2',4-difluoro-[1,1'-biphenyl]-3-carboxamide(I-74) [ka]

[0556] Following the procedure for intermediate 10, replace 5-bromopyrazine-2,3-diamine with 4-bromo-3-fluorobenzene-1,2-diamine (CAS 886762-86-3, Apollo), and replace N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(4,4, 3',4'-diamino-N-(4-((benzyloxy)methyl)phenyl)-2',4-difluoro-[1,1'-biphenyl]-3-carboxamide was obtained in 84% yield by purification using 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21) and by flash chromatography (silica gel, hexane, 0-100% (2% NH4OH in 3:1 EtOH / SiO)). LCMS: Method A: 0.74 min, MS: ES + 460.1.

[0557] Intermediate 75 3',4'-diamino-N-(4-((benzyloxy)methyl)phenyl)-4-fluoro-[1,1'-biphenyl]-3-carboxamide(I-75) [ka]

[0558] Following the procedure for intermediate 10, 3',4'-diamino-N-(4-((benzyloxymethyl)phenyl)-4-fluoro-[1,1'-biphenyl]-3-carboxamide was obtained in 85% yield by using 4-bromobenzene-1,2-diamine (CAS 1575-37-7, BLD) instead of 5-bromopyrazine-2,3-diamine, and N-(4-((benzyloxymethyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21) instead of N-(4-phenethoxyphenyl)-3ane) instead of N-(4,4,5,5-dioxane) instead of N-(4,4,5,5-dioxane) instead of N LCMS: Method A: 0.68 min, MS: ES + 442.1.

[0559] Intermediate 76 5-Chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-76) [ka]

[0560] Following the procedure for Intermediate 1, 5-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine was obtained in 88% yield by using 2-chloropyrimidine-4,5-diamine (CAS 14631-08-4, BLD) instead of 6-bromopyridine-2,3-diamine at 40°C for 2 hours. LCMS: Method A: 0.06 min, MS: ES + 154.0.

[0561] General method (aniline) With any noted changes, the following general method was used for intermediates 79–103: [ka]

[0562] Step 1: Method 1a: To KOtBu (358 mg, 3.19 mmol) in THF (3.4 mL), R'OH (1.5 equivalents) was added at 0°C. After 10 minutes, a solution of 1-fluoro-4-nitrobenzene (0.226 mL, 2.13 mmol) in THF (3.4 mL) was added, and the mixture was warmed to room temperature. After 18 hours, the mixture was diluted with saturated NH4Cl aqueous solution (30 mL) and extracted with HCl (3 × 30 mL). The combined organic matter was washed with brine (90 mL), dried on MgSO4, and concentrated under reduced pressure. The desired product was obtained by purification by flash chromatography (silica gel, isohexane, 0-100% HCl). Method 1b: R'OH (1 equivalent, 1.42 mmol) was added to NaH (142 mg, 3.54 mmol) in THF (2.4 mL) at 0°C. After 10 minutes, a solution of 1-fluoro-4-nitrobenzene (0.150 mL, 1.417 mmol) in THF (2.4 mL) was added dropwise, and the mixture was allowed to warm to room temperature. After stirring for 18 hours, water (5 mL) was added. The mixture was extracted with HCl (3 × 10 mL). The combined organic matter was dried over Na₂SO₄ and concentrated under reduced pressure. The desired product was obtained by purification by flash chromatography (silica gel, isohexane, 0-100% HCl). Method 1c: To cyclopropanol (0.812 mL, 12.8 mmol), 1-(bromomethyl)-2-fluoro-4-nitrobenzene (300 mg, 1.28 mmol) and KOH (86 mg, 1.54 mmol) in 2-methyl THF (5 mL) were added, and the mixture was stirred at 30°C for 2 hours. The mixture was cooled on ice, neutralized with aqueous 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 was concentrated under reduced pressure to obtain the desired product. Method 1d: 1-Fluoro-4-nitrobenzene (200 mg, 1.42 mmol) was added to R'2NH (1 equivalent, 1.42 mmol) and potassium carbonate (588 mg, 4.25 mmol) in DMF (5.00 mL). The mixture was stirred at 65°C for 16 hours. Brine (20 mL), followed by HCl (30 mL), was added. The aqueous phase was extracted with HCl (2 × 30 mL), the combined organic matter was washed with LiCl aqueous solution (10%, 20 mL), dried over MgSO4, and filtered. The desired product was obtained by purification by flash chromatography (silica gel, isohexane, 0-100% HCl). 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 hours and then filtered through a Celite® plug. The filtrate was concentrated under reduced pressure. The desired product was obtained by purification by flash chromatography (silica gel, isohexane, 0-100% (2% NH4OH in 3:1 EtOH / siRNA)).

[0563] Step 2: Method 2a: A solution of suitable starting material in MeOH or MeOH / THF was stirred under an H2 atmosphere (1-2 bar, 1 ml / min, 20°C-30°C, Pd / C cartridge, H-Cube®) for 4 minutes to 4 hours. The desired product was obtained by concentrating the mixture. Method 2b: Appropriate starting materials and 10% Pd / C (0.1 equivalent) in EtOH were stirred under H2 (2 bar, room temperature) for 20 hours. The mixture was filtered through Celite® and concentrated under reduced pressure to obtain the desired product. Method 2c: A mixture of suitable starting materials, Fe (5 equivalents), and NH4Cl (10 equivalents) in EtOH / H2O (6:1) was stirred at 85°C for 2 hours, and the mixture was filtered through Celite®. The filtrate was washed with water and concentrated under reduced pressure. The desired product was obtained by purification by flash chromatography (silica gel, hexane with 0-100% siRNA). Method 2d: A mixture of suitable starting materials, Fe (13 equivalents), and CaCl2 (4.5 equivalents) in EtOH / H2O (6:1) was stirred at 80°C for 4 hours. The mixture was filtered through Celite®. The filtrate was washed with water and concentrated under reduced pressure to obtain the desired product.

[0564] Intermediate 79 (R)-4-(1-Cyclopropylethoxy)aniline(I-79) [ka]

[0565] Step 1: (R)-1-(1-cyclopropylethoxy)-4-nitrobenzene Using Method 1a, (R)-1-(1-cyclopropylethoxy)-4-nitrobenzene was obtained in 87% yield using (R)-1-cyclopropylethane-1-ol (CAS 6516-09-2, Enamine) and without chromatography. LCMS: Method A: 1.69 min, MS: ES + 208.1.

[0566] Step 2: (R)-4-(1-cyclopropylethoxy)aniline Using Method 2a, (R)-1-(1-cyclopropylethoxy)-4-nitrobenzene was used to obtain (R)-4-(1-cyclopropylethoxy)aniline in 91% yield. LCMS: Method A: 0.68 min, MS: ES + 178.1.

[0567] Intermediate 80 (S)-4-(1-Cyclopropylethoxy)aniline (I-80) [ka]

[0568] Step 1: (S)-1-(1-cyclopropylethoxy)-4-nitrobenzene Using Method 1a, (S)-1-(1-cyclopropylethoxy)-4-nitrobenzene was obtained in 87% yield using (S)-1-cyclopropylethane-1-ol (CAS 55637-37-1, Enamine) and without chromatography. LCMS: Method A: 1.69 min, MS: ES + 208.1

[0569] Step 2: (S)-4-(1-cyclopropylethoxy)aniline Using Method 2a, (S)-1-(1-cyclopropylethoxy)-4-nitrobenzene was used to obtain (S)-4-(1-cyclopropylethoxy)aniline in 89% yield. LCMS: Method A: 0.69 min, MS: ES + 178.1

[0570] Intermediate 81 4-(((4-aminobenzyl)oxy)methyl)benzonitrile(I-81) [ka]

[0571] Step 1: 4-(((4-nitrobenzyl)oxy)methyl)benzonitrile Using Method 1e, 4-(((4-nitrobenzyl)oxy)methyl)benzonitrile was obtained in 81% yield using 4-(hydroxymethyl)benzonitrile (CAS 874-89-5, BLD) and 1-(bromomethyl)-4-nitrobenzene (CAS 100-11-8, Apollo). LCMS: Method Q: 0.73 min, MS: ES + 269.1.

[0572] Step 2: 4-(((4-aminobenzyl)oxy)methyl)benzonitrile Using Method 2a, 4-(((4-nitrobenzyl)oxy)methyl)benzonitrile was obtained in 90% yield using 4-(((4-aminobenzyl)oxy)methyl)benzonitrile. LCMS: Method A: 1.04 min, MS: ES + 239.1.

[0573] Intermediate 82 4-((2,2,2-trifluoro-1-phenylethoxy)methyl)aniline(I-82) [ka]

[0574] Step 1: 1-Nitro-4-((2,2,2-trifluoro-1-phenylethoxy)methyl)benzene Using Method 1e, 1-nitro-4-((2,2,2-trifluoro-1-phenylethoxy)methyl)benzene was obtained in 96% yield using 2,2,2-trifluoro-1-phenylethane-1-ol (CAS 340-05-6, Apollo) and 1-(bromomethyl)-4-nitrobenzene (CAS 100-11-8, Apollo). LCMS: Method Q: 0.66 min, MS: No mass ions were observed.

[0575] Step 2: 4-((2,2,2-trifluoro-1-phenylethoxy)methyl)aniline Using Method 2a, 4-((2,2,2-trifluoro-1-phenylethoxy)methyl)aniline was obtained in 90% yield using 1-nitro-4-((2,2,2-trifluoro-1-phenylethoxy)methyl)benzene. LCMS: Method Q: 0.67 min, MS: ES + 282.

[0576] Intermediate 83 4-((2-chloro-4-fluorobenzyl)oxy)aniline(I-83) [ka]

[0577] Step 1: 2-Chloro-4-fluoro-1-((4-nitrophenoxy)methyl)benzene Using Method 1b, 2-chloro-4-fluorophenyl)methanol (CAS 208186-84-9, Apollo) was used, and 2-chloro-4-fluoro-1-((4-nitrophenoxy)methyl)benzene was obtained in 80% yield by solid recovery instead of chromatography. LCMS: Method A: 1.87 min, MS: ES + 282.

[0578] Step 2: 4-((2-chloro-4-fluorobenzyl)oxy)aniline Using Method 2c, 4-((2-chloro-4-fluorobenzyl)oxy)aniline was obtained in 89% yield using 2-chloro-4-fluoro-1-((4-nitrophenoxy)methyl)benzene. LCMS: Method A: 1.09 min, MS: ES + 252.

[0579] Intermediate 84 4-(3-phenoxypiperidine-1-yl)aniline (I-84) [ka]

[0580] Step 1: 1-(4-nitrophenyl)-3-phenoxypiperidine Using Method 1d, 1-(4-nitrophenyl)-3-phenoxypiperidine was obtained in 60% yield using 3-phenoxypiperidine (CAS 151666-08-9, Alfa Aesar). LCMS: Method Q: 0.77 min, MS: ES + 299.1.

[0581] Step 2: 4-(3-phenoxypiperidine-1-yl)aniline Using Method 2a, 4-(3-phenoxypiperidine-1-yl)aniline was obtained in 100% yield using 1-(4-nitrophenyl)-3-phenoxypiperidine. LCMS: Method Q: 0.53 min, MS: ES + 269.1.

[0582] Intermediate 85 4-(3-phenylpiperidine-1-yl)aniline(I-85) [ka]

[0583] Step 1: 1-(4-nitrophenyl)-3-phenylpiperidine Using Method 1d, 1-(4-nitrophenyl)-3-phenylpiperidine was obtained in 95% yield using 3-phenylpiperidine (CAS 3973-62-4, BLD). LCMS: Method Q: 0.81 min, MS: ES + 283.1.

[0584] Step 2: 4-(3-phenylpiperidine-1-yl)aniline Using Method 2a, 4-(3-phenylpiperidine-1-yl)aniline was obtained in 99% yield using 1-(4-nitrophenyl)-3-phenylpiperidine. LCMS: Method Q: 0.51 min, MS: ES + 253.1.

[0585] Intermediate 86 4-(3-phenylpyrrolidine-1-yl)aniline(I-86) [ka]

[0586] Step 1: 1-(4-nitrophenyl)-3-phenylpyrrolidine Using Method 1d, 1-(4-nitrophenyl)-3-phenylpyrrolidine was obtained in 78% yield using 3-phenylpyrrolidine (CAS 936-44-7, BLD). LCMS: Method Q: 0.78 min, MS: ES + 269.1.

[0587] Step 2: 4-(3-phenylpyrrolidine-1-yl)aniline Using Method 2a, 4-(3-phenylpyrrolidine-1-yl)aniline was obtained in 100% yield using 1-(4-nitrophenyl)-3-phenylpyrrolidine. LCMS: Method Q: 0.56 min, MS: ES + 239.2.

[0588] Intermediate 87 4-(3-phenylpyrrolidine-1-yl)aniline, enantiomer 1(I-87) [ka]

[0589] Step 1: Chiral SFC separation of 1-(4-nitrophenyl)-3-phenylpyrrolidine (I-86 Step 1) (prep method E) yielded 1-(4-nitrophenyl)-3-phenylpyrrolidine, enantiomer 1 in 40% yield. LCMS: Method A: 1.90 min, MS: ES + 269.2.

[0590] Step 2: 4-(3-phenylpyrrolidine-1-yl)aniline, enantiomer 1 Using Method 2a, 4-(3-phenylpyrrolidine-1-yl)aniline, enantiomer 1 was obtained in 97% yield using 1-(4-nitrophenyl)-3-phenylpyrrolidine, enantiomer 1. LCMS: Method Q: 1.09 min, MS: ES + 239.2.

[0591] Intermediate 88 4-(3-phenylpyrrolidine-1-yl)aniline, enantiomer 2(I-88) [ka]

[0592] Step 1: 1-(4-nitrophenyl)-3-phenylpyrrolidine, enantiomer 2 Chiral SFC separation of 1-(4-nitrophenyl)-3-phenylpyrrolidine (I-86 Step 1) (Prep Method E) yielded 1-(4-nitrophenyl)-3-phenylpyrrolidine, enantiomer 2, in 40% yield. LCMS: Method A: 1.90 min, MS: ES + 269.2.

[0593] Step 2: 4-(3-phenylpyrrolidine-1-yl)aniline, enantiomer 2 Using Method 2a, 4-(3-phenylpyrrolidine-1-yl)aniline, enantiomer 2 was obtained in 91% yield using 1-(4-nitrophenyl)-3-phenylpyrrolidine, enantiomer 2. LCMS: Method Q: 1.09 min, MS: ES + 239.2.

[0594] Intermediate 89 4-(cyclopentyloxy)-3-fluoroaniline(I-89) [ka]

[0595] Step 1: 4-(cyclopentyloxy)-2-fluoro-1-nitrobenzene Using Method 1b, 4-(cyclopentyloxy)-2-fluoro-1-nitrobenzene was obtained in 64% yield by flash chromatography (silica gel, heptane, 0-50% DCM), using cyclopentanol (CAS 96-41-3, Merck) and 1,2-difluoro-4-nitrobenzene (CAS 369-34-6, Fluorochem) instead of 1-fluoro-4-nitrobenzene. LCMS: Method A: 1.79 min, MS: ES + 226.0.

[0596] Step 2: 4-(cyclopentyloxy)-3-fluoroaniline Using Method 2b, 4-(cyclopentyloxy)-2-fluoro-1-nitrobenzene was used to obtain 4-(cyclopentyloxy)-3-fluoroaniline in 98% yield. LCMS: Method A: 1.03 min, MS: ES + 196.1.

[0597] Intermediate 90 (R)-4-((2,2,2-trifluoro-1-phenylethoxy)methyl)aniline(I-90) [ka]

[0598] Step 1: (R)-1-Nitro-4-((2,2,2-trifluoro-1-phenylethoxy)methyl)benzene Using Method 1e, (R)-1-nitro-4-((2,2,2-trifluoro-1-phenylethoxy)methyl)benzene was obtained in 43% yield by purification using (R)-2,2,2-trifluoro-1-phenylethane-1-ol (CAS 10531-50-7, Enamine) and 1-(bromomethyl)-4-nitrobenzene (CAS 100-11-8, Apollo), as well as by flash chromatography (silica gel, isohexane, 0-20% ethyl acetate). LCMS: Method Q: 0.64 min, MS: No mass ions were observed.

[0599] Step 2: (R)-4-((2,2,2-trifluoro-1-phenylethoxy)methyl)aniline Using Method 2a, (R)-4-((2,2,2-trifluoro-1-phenylethoxy)methyl)aniline was obtained in 97% yield using (R)-1-nitro-4-((2,2,2-trifluoro-1-phenylethoxy)methyl)benzene. LCMS: Method Q: 0.68 min, MS: ES + 282.1.

[0600] Intermediate 91 4-(cyclopropoxymethyl)-3-fluoroaniline(I-91) [ka]

[0601] Step 1: 1-(cyclopropoxymethyl)-2-fluoro-4-nitrobenzene Using Method 1c, 1-(cyclopropoxymethyl)-2-fluoro-4-nitrobenzene was obtained in 87% yield. LCMS: Method A: 1.59 min, MS: ES + 212.

[0602] Step 2: 4-(cyclopropoxymethyl)-3-fluoroaniline Using method 2d, 4-(cyclopropoxymethyl)-3-fluoroaniline was obtained in 41% yield using 1-(cyclopropoxymethyl)-2-fluoro-4-nitrobenzene. LCMS: Method A: 1.02 min, MS: ES + 182.

[0603] Intermediate 92 4-((phenylmethoxy-d2)methyl-d2)aniline(I-92) [ka]

[0604] Step 1: (4-nitrophenyl)methane-d2-ol [ka]

[0605] 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 in a water bath. After 1.5 hours, an additional 68 mg, 1.617 mmol of NaBD4 was added. After 16 hours, the mixture was cooled to 0°C, carefully diluted with saturated NH4Cl aqueous solution (30 mL), and extracted with siRNA (3 × 30 mL). The combined organic matter was washed with saturated NaHCO3 aqueous solution (90 mL) and brine (3 × 90 mL), dried, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, isohexane, 0-100% siRNA) to obtain (4-nitrophenyl)methane-d2-ol (529 mg, 60%). LCMS: Method A: 0.78 min, MS: No mass ions were observed.

[0606] Step 2: 1-(bromomethyl-d2)-4-nitrobenzene [ka]

[0607] A solution of (4-nitrophenyl)methane-d2-ol (100 mg, 0.612 mmol), triphenylphosphine (193 mg, 0.735 mmol), and CBr4 (244 mg, 0.735 mmol) in DCM (2 mL) was stirred at 0°C for 10 minutes, then heated to room temperature for 4 hours, and volatiles were removed under reduced pressure. The crude product was purified by flash chromatography (silica gel, isohexane with 0-40% siRNA) to obtain 1-(bromomethyl-d2)-4-nitrobenzene (119 mg, 87%). LCMS: Method A: 1.45 min, MS: No mass ions were observed.

[0608] Step 3: 1-Nitro-4-((phenylmethoxy-d2)methyl-d2)benzene Using Method 1e, 1-nitro-4-((phenylmethoxy-d2)methyl-d2)benzene was obtained in 75% yield by purification using benzenemethane-d2-ol (CAS 21175-64-4, SLS) and 1-(bromomethyl-d2)-4-nitrobenzene, as well as by flash chromatography (silica gel, isohexane, 0-30% TBME). LCMS: Method A: 1.76 min, MS: ES + 248.

[0609] Step 4: 4-((phenylmethoxy-d2)methyl-d2)aniline Using Method 2a, 4-((phenylmethoxy-d2)methyl-d2)aniline was obtained in 77% yield using 1-nitro-4-((phenylmethoxy-d2)methyl-d2)benzene. LCMS: Method A: 0.99 min, MS: ES + 218.1.

[0610] Intermediate 93 4-(3,3-difluorocyclobutoxy)aniline (I-93) [ka]

[0611] Step 1: 1-(3,3-difluorocyclobutoxy)-4-nitrobenzene Using Method 1a, 1-(3,3-difluorocyclobutoxy)-4-nitrobenzene was obtained in 60% yield using 3,3-difluorocyclobutan-1-ol (CAS 637031-88-0, BLD). LCMS: Method A: 1.59 min, MS: ES + 230.

[0612] Step 2: 4-(3,3-difluorocyclobutoxy)aniline Using Method 2a, 4-(3,3-difluorocyclobutoxy)aniline was obtained in 89% yield using 1-(3,3-difluorocyclobutoxy)-4-nitrobenzene. LCMS: Method A: 0.36 min, MS: ES + 200.1

[0613] Intermediate 94 4-((1,1,1-trifluoropropan-2-yl)oxy)aniline(I-94) [ka]

[0614] Step 1: 1-Nitro-4-((1,1,1-trifluoropropan-2-yl)oxy)benzene Using Method 1b, 1-nitro-4-((1,1,1-trifluoropropan-2-yl)oxy)benzene was obtained in 54% yield using 1,1,1-trifluoropropan-2-ol (CAS 374-01-6, Fluorochem). LCMS: Method A: 1.67 min, MS: ES + 236.

[0615] Step 2: 4-((1,1,1-trifluoropropan-2-yl)oxy)aniline Using Method 2a, 4-((1,1,1-trifluoropropan-2-yl)oxy)aniline was obtained in 93% yield using 1-nitro-4-((1,1,1-trifluoropropan-2-yl)oxy)benzene and used without analysis.

[0616] Intermediate 96 4-(3,3-difluoropyrrolidine-1-yl)aniline(I-96) [ka]

[0617] Step 1: 3,3-difluoro-1-(4-nitrophenyl)pyrrolidine Using Method 1d, 3,3-difluoropyrrolidine (CAS 316131-01-8, Fluorochem) was used to obtain 3,3-difluoro-1-(4-nitrophenyl)pyrrolidine in 80% yield. LCMS: Method A: 1.51 min, MS: ES + 229.1.

[0618] Step 2: 4-(3,3-difluoropyrrolidine-1-yl)aniline Using Method 2a, 4-(3,3-difluoropyrrolidine-1-yl)aniline was obtained in 94% yield using 3,3-difluoro-1-(4-nitrophenyl)pyrrolidine. LCMS: Method A: 0.27 min, MS: ES + 199.1.

[0619] Intermediate 98 6-((benzyloxy)methyl)pyridine-3-amine(I-98) [ka]

[0620] Step 1: 2-((benzyloxy)methyl)-5-nitropyridine Using Method 1e, 2-((benzyloxy)methyl)-5-nitropyridine was obtained in 16% yield by purification using (5-nitropyridine-2-yl)methanol (CAS 36625-57-7, Fluorochem) and benzyl bromide (CAS 100-39-0, Merck), as well as by flash chromatography (silica gel, isohexane, 0-60% ethyl phosphate). LCMS: Method A: 1.56 min, MS: ES + 245.2.

[0621] Step 2: 6-((benzyloxy)methyl)pyridine-3-amine Using Method 2a, 6-((benzyloxy)methyl)pyridine-3-amine was obtained in 93% yield using 2-((benzyloxy)methyl)-5-nitropyridine. LCMS: Method A: 0.64 min, MS: ES + 215.2.

[0622] Intermediate 99 4-(4-phenylpiperidine-1-yl)aniline(I-99) [ka]

[0623] Step 1: 1-(4-nitrophenyl)-4-phenylpiperidine Using Method 1d, 1-(4-nitrophenyl)-4-phenylpiperidine was obtained in 76% yield using 4-phenylpiperidine (CAS 771-99-3, Merck). LCMS: Method Q: 0.79 min, MS: ES + 283.1.

[0624] Step 2: 4-(4-phenylpiperidine-1-yl)aniline Using Method 2a, 4-(4-phenylpiperidine-1-yl)aniline was obtained in 100% yield using 1-(4-nitrophenyl)-4-phenylpiperidine. LCMS: Method Q: 0.49 min, MS: ES + 253.1.

[0625] Intermediate 100 4-(4-phenoxypiperidine-1-yl)aniline (I-100) [ka]

[0626] Step 1: 1-(4-nitrophenyl)-4-phenoxypiperidine Using Method 1d, 1-(4-nitrophenyl)-4-phenoxypiperidine was obtained in 81% yield using 4-phenoxypiperidine (CAS 3202-33-3, Combi-Blocks). LCMS: Method Q: 0.78 min, MS: ES + 299.1.

[0627] Step 2: 4-(4-phenoxypiperidine-1-yl)aniline Using Method 2a, 4-(4-phenoxypiperidine-1-yl)aniline was obtained in 99% yield using 1-(4-nitrophenyl)-4-phenoxypiperidine. LCMS: Method Q: 0.51 min, MS: ES + 269.1.

[0628] Intermediate 101 4-(3-phenoxypyrrolidine-1-yl)aniline (I-101) [ka]

[0629] Step 1: 1-(4-nitrophenyl)-3-phenoxypyrrolidine Using Method 1d, 1-(4-nitrophenyl)-3-phenoxypyrrolidine was obtained in 31% yield using 3-phenoxypyrrolidine hydrochloride (CAS 21767-15-7, BLD). LCMS: Method Q: 0.76 min, MS: ES + 285.1.

[0630] Step 2: 4-(3-phenoxypyrrolidine-1-yl)aniline Using Method 2a, 4-(3-phenoxypyrrolidine-1-yl)aniline was obtained in 94% yield using 1-(4-nitrophenyl)-3-phenoxypyrrolidine. LCMS: Method Q: 0.55 min, MS: ES + 255.1.

[0631] Intermediate 102 4-(3-phenylazetidine-1-yl)aniline(I-102) [ka]

[0632] Step 1: 1-(4-nitrophenyl)-3-phenylazetidine Using Method 1d, 1-(4-nitrophenyl)-3-phenylazetidine was obtained in 73% yield using 3-phenylazetidine hydrochloride (CAS 7606-30-6, Fluorochem). LCMS: Method Q: 0.77 min, MS: ES + 255.2.

[0633] Step 2: 4-(3-phenylazetidine-1-yl)aniline Using Method 2a, 4-(3-phenylazetidine-1-yl)aniline was obtained in 96% yield using 1-(4-nitrophenyl)-3-phenylazetidine. LCMS: Method Q: 0.52 min, MS: ES + 225.2.

[0634] Intermediate 103 4-(3-phenoxyazetidine-1-yl)aniline (I-103) [ka]

[0635] Step 1: 1-(4-nitrophenyl)-3-phenoxyazetidine Using Method 1d, 1-(4-nitrophenyl)-3-phenoxyazetidine was obtained in 92% yield using 3-phenoxyazetidine hydrochloride (CAS 301335-39-7, Fluorochem). LCMS: Method Q: 0.76 min, MS: ES + 271.2.

[0636] Step 2: 4-(3-phenoxyazetidine-1-yl)aniline Using Method 2a, 4-(3-phenoxyazetidine-1-yl)aniline was obtained in 94% yield using 1-(4-nitrophenyl)-3-phenoxyazetidine. LCMS: Method Q: 0.52 min, MS: ES + 241.3. [Examples] [Example 1]

[0637] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((1-phenylpiperidine-4-yl)methoxy)phenyl)benzamide [ka]

[0638] Step 1: (1-phenylpiperidine-4-yl)methylmethanesulfonate A stirred solution of (1-phenylpiperidine-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) was mixed at 0°C and MsCl (0.05 mL, 0.63 mmol) was added. The reaction mixture was heated to room temperature and stirred for 1 hour, then quenched with saturated Na2CO3 aqueous solution (20 mL) and extracted with DCM (2 × 10 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure to obtain (1-phenylpiperidine-4-yl)methylmethanesulfonate (132 mg, 86%). LCMS: Method A, 1.52 min, MS ES + 270.2

[0639] Step 2: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-((1-phenylpiperidine-4-yl)methoxy)phenyl)benzamide (Example 1) [ka]

[0640] A mixture of N-(4-hydroxyphenyl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide (+isomer; I-4, 50 mg, 0.07 mmol), (1-phenylpiperidine-4-yl)methylmethanesulfonate (19 mg, 0.07 mmol), and K2CO3 (10 mg, 0.07 mmol) in THF (2 mL) was stirred at 50°C for 16 hours. NaI (1 mg, 0.07 mmol) and Cs2CO3 (23 mg, 0.07 mmol) were added, and stirring was continued at 80°C for 16 hours. The mixture was diluted with water (30 mL) and extracted with siRNA (3 × 20 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in dioxane (1 mL) and HCl (4 M, 0.06 mL, 0.22 mmol) in the dioxane, and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by RP chromatography (C18, 0-100% (0.1% HCO2H in MeCN) / (0.1% HCO2H aqueous solution)) to obtain 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((1-phenylpiperidine-4-yl)methoxy)phenyl)benzamide (11 mg, 30%). LCMS: Method A, 2.05 min, MS: ES + 505.3; 1 H NMR(500MHz,DMSO)δppm:10.33(s,1H), 8.74(s,1H), 8.59(s,1H), 8.40(d,J=7.8Hz,1H), 8.21(d,J=8.7H) z,1H), 8.07(d,J=7.8Hz,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=7.2Hz, 1H), 6.53 (d, J=8.0Hz, 1H), 4.08 (t, J=6.5Hz, 2H), 3.51~3.42 (m, 1H), 3.28~3.19 (m, 1H), 2.95 (t, J=8.6Hz, 1H), 2.23~2.16 (m, 1H), 1.97~1.84 (m, 2H), 1.78~1.66 (m, 1H). 2H was unclear / not observed. [Example 2]

[0641] 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)benzamide [ka] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)benzamide [ka]

[0642] A solution of N-(4-hydroxyphenyl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide (+isomer; 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 hours. Water (30 mL) was added to the mixture, the product was extracted with SiO (3 × 20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in dioxane (1 mL) and HCl (4 M, 0.19 mL, 0.38 mmol) in the dioxane and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and purified by RP chromatography (C18, 0-100% MeCN in 0.1% HCO2H aqueous solution) to obtain 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; 1¹H NMR (500MHz, DMSO) δppm: 10.32 (s, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 8.40 (d, J=7.8Hz, 1H), 8.21 (d, J=8.6Hz, 1H), 8.06 (d, J=7.8Hz, 1H), 7.75~7.66 (m, 2H), 6.96 (d, J=8.9Hz, 2H), 4.02 (t, J=6.4Hz, 2H), 3.91~3.78 (m, 2H), 1.80~1.54 (m, 5H), 1.32~1.17 (m, 2H). 4H was unclear / not observed.

[0643] General procedure (alkylation, deprotection) Examples 3 to 16 were obtained by following the procedure of Example 2, substituting 4-(2-bromoethyl)tetrahydro-2H-pyran with a suitable starting material, and using any of the minor modifications noted: [ka] [Example 3]

[0644] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-(cyclopropylmethoxy)phenyl)benzamide [ka]

[0645] (Bromomethyl)cyclopropane (CAS 7051-34-5, Apollo) was used instead of 4-(2-bromoethyl)tetrahydro-2H-pyran, and NaI (0.1 equivalent) in THF was used, at 50°C for 72 hours. The intermediate residue was purified by chromatography (silica gel, isohexane, 0-80% ethyl phosphate).

[0646] After treatment with HCl and purification by preparative HPLC (prep method A, x=30, y=60), 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-(cyclopropylmethoxy)phenyl)benzamide was obtained in 17% yield. LCMS: Method A, 1.66 min, MS: ES + 386.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.31 (s, 1H), 8.73 (s, 1H), 8.54 (d, J=8.7Hz, 1H), 8.39 (d, J=7.8Hz, 1H), 8.15 (d, J=8.7Hz, 1H), 8.05 (d, J=7.8Hz, 1H), 7.74~7.61 (m, 3H), 6.94 (d, J=8.6Hz, 2H), 3.82 (d, J=6.9Hz, 2H), 1.27~1.15 (m, 1H), 0.63~0.51 (m, 2H), 0.40~0.26 (m, 2H). 1H was unclear / not observed. [Example 4]

[0647] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-(isopentyloxy)phenyl)benzamide [ka]

[0648] Purification by chromatography (silica gel, isohexane, 0-80% SiO2) using 1-bromo-3-methylbutane (CAS 107-82-4, Acros, 1.2 equivalents) instead of 4-(2-bromoethyl)tetrahydro-2H-pyran, and with NaI (0.1 equivalents) in THF for 16 hours at 60°C.

[0649] After treatment with HCl, 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-(isopentyloxy)phenyl)benzamide was obtained in 22% yield. LCMS: Method A, 1.88 min, MS: ES + 402.2; 1¹H NMR (500MHz, DMSO) δppm: 10.31 (s, 1H), 8.73 (s, 1H), 8.54 (s, 1H), 8.39 (d, J=7.7Hz, 1H), 8.15 (s, 1H), 8.05 (d, J=8.1Hz, 1H), 7.70 (dd, J=8.0, 5.4Hz, 2H), 6.99~6.91 (m, 2H), 4.00 (t, J=6.7Hz, 2H), 1.82~1.76 (m, 1H), 1.66~1.59 (m, 2H), 1.05~0.87 (m, 6H). 2H was unclear / not observed. [Example 5]

[0650] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzylthio)methoxy)phenyl)benzamide [ka]

[0651] Using benzyl(chloromethyl) sulfide (CAS 3970-13-6, Fluorochem, 1.2 equivalents) instead of 4-(2-bromoethyl)tetrahydro-2H-pyran, 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzylthio)methoxy)phenyl)benzamide was obtained in 12% yield. LCMS: Method A, 1.87 min, MS: ES + 468.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.29 (s, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.33 (d, J=7.8Hz, 1H), 8.09 (s, 1H), 7.99 (d, J=7.8Hz, 1H), 7.70~7.60 (m, 3H), 7.27 (d, J=4.4Hz, 4H), 7.23~7.17 (m, 1H), 6.96 (d, J=8.9Hz, 2H), 5.14 (s, 2H), 3.84 (s, 2H). 1H was unclear / not observed. [Example 6]

[0652] 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide)phenyl 4-methylbenzene sulfonate [ka]

[0653] Using 4-methylbenzenesulfonyl chloride (CAS 98-59-9, Acros, 1.2 equivalents) instead of 4-(2-bromoethyl)tetrahydro-2H-pyran, 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide)phenyl 4-methylbenzenesulfonate was obtained in 61% yield. LCMS: Method A, 1.80 min, MS: ES + 486.1; 1 ¹H NMR (500MHz, DMSO) δppm: 10.55 (s, 1H), 8.72 (s, 1H), 8.57 (d, J=8.5Hz, 1H), 8.41 (d, J=7.8Hz, 1H), 8.18 (d, J=8.8Hz, 1H), 8.04 (d, J=7.8Hz, 1H), 7.85~7.65 (m, 5H), 7.50 (d, J=8.1Hz, 2H), 7.09~6.97 (m, 2H), 2.44 (s, 3H). ¹H was unclear / not observed. [Example 7]

[0654] 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-butoxyphenyl)benzamide [ka]

[0655] Instead of 4-(2-bromoethyl)tetrahydro-2H-pyran, 1-bromobutane (CAS 109-65-9, Combi-Blocks, 1.2 equivalents) and NaI (0.1 equivalents) were used. The intermediate residue was purified by chromatography (silica gel, isohexane, 0-80% ethyl phosphate).

[0656] After HCl treatment, 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-butoxyphenyl)benzamide was obtained in 31% yield. LCMS: Method A, 1.79 min, MS: ES + 388.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.31 (s, 1H), 8.73 (s, 1H), 8.53 (d, J=8.6Hz, 1H), 8.39 (d, J=7.8Hz, 1H), 8.15 (d, J=9.2Hz, 1H), 8.05 (d, J=7.8Hz, 1H), 7.74~7.66 (m, 3H), 6.99~6.91 (m, 2H), 3.97 (t, J=6.5Hz, 2H), 1.77~1.66 (m, 2H), 1.52~1.40 (m, 2H), 0.95 (t, J=7.4Hz, 3H). ¹H was unclear / not observed. [Example 8]

[0657] 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-isobutoxyphenyl)benzamide [ka]

[0658] The mixture was prepared using 1-bromo-2-methylpropane (CAS 78-77-3, Combi-Blocks) instead of 4-(2-bromoethyl)tetrahydro-2H-pyran, and with K2CO3 (1 equivalent) in THF for 16 hours at 50°C. Then, Cs2CO3 (1 equivalent) and NaI (0.1 equivalent) were prepared for 16 hours at 50°C. The intermediate residue was purified by chromatography (silica gel, isohexane, 0-80% SiO).

[0659] After treatment with HCl, 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-isobutoxyphenyl)benzamide was obtained in 9% yield. LCMS: Method A, 1.84 min, MS: ES + 388.2; 1H NMR(500MHz,DMSO)δppm:10.31(s,1H), 8.72(s,1H), 8.50(d,J=8.8Hz,1H), 8.38(d,J=7.8Hz,1H), 8.11(d,J=8.6Hz,1H), 8.04(d,J=7) .7Hz,1H), 7.72~7.69(m,2H), 7.34~7.17(m,2H), 7.02~6.89(m,2H), 3.75(d,J=6.5Hz,2H), 2.08~1.95(m,1H), 1.00(d,J=6.6Hz,6H). [Example 9]

[0660] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)benzamide [ka]

[0661] 4-(bromomethyl)tetrahydro-2H-pyran (CAS 125552-89-8, Fluorochem) was used instead of 4-(2-bromoethyl)tetrahydro-2H-pyran. After purification by preparative HPLC (prep method A, x=30, y=60), 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)benzamide was obtained in 15% yield. LCMS: Method A, 1.57 min, MS: ES + 430.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.32 (s, 1H), 8.73 (s, 1H), 8.54 (s, 1H), 8.39 (d, J=7.8Hz, 1H), 8.16 (d, J=8.5Hz, 1H), 8.05 (d, J=7.7Hz, 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). 4H was unclear / not observed. [Example 10]

[0662] 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide)phenyl 3-methylbutanoate [ka]

[0663] 3-methylbutanoyl chloride (CAS 108-12-3, Merck) was used instead of 4-(2-bromoethyl)tetrahydro-2H-pyran. After purification by preparative HPLC (prep method A, x=35, y=65), 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide)phenyl 3-methylbutanoate was obtained in 15% yield. LCMS: Method A, 1.77 min, MS: ES + 416.3; 1 ¹H NMR (500MHz, DMSO) δppm: 10.50 (s, 1H), 8.71 (d, J=2.1Hz, 1H), 8.37 (d, J=7.8Hz, 1H), 8.32 (d, J=8.5Hz, 1H), 7.99 (d, J=7.7Hz, 1H), 7.89 (d, J=8.5Hz, 1H), 7.87~7.81 (m, 2H), 7.67 (t, J=7.7Hz, 1H), 7.13 (d, J=8.9Hz, 2H), 2.47 (d, J=7.1Hz, 2H), 2.20~2.07 (m, 1H), 1.02 (d, J=6.7Hz, 6H). 1H was unclear / not observed. [Example 11]

[0664] 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide)phenylmorpholine-4-sulfonate [ka]

[0665] Morpholine-4-sulfonyl chloride (CAS 1828-66-6, BLD) was used instead of 4-(2-bromoethyl)tetrahydro-2H-pyran. After purification by preparative HPLC (prep method A, x=30, y=60), 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide)phenylmorpholine-4-sulfonate was obtained in 29% yield. LCMS: Method A, 1.56 min, MS: ES + 481.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.61 (s, 1H), 8.75 (s, 1H), 8.43 (d, J=7.8Hz, 1H), 8.29~8.20 (m, 1H), 8.08 (d, J=7.7Hz, 1H), 7.92 (d, J=9.0Hz, 2H), 7.74 (t, J=7.8Hz, 1H), 7.38 (d, J=9.0Hz, 2H), 3.77~3.59 (m, 4H). 6H was unclear / not observed. [Example 12]

[0666] 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide)phenylisobutyl carbonate [ka]

[0667] Isobutyl chloroformate (CAS 543-27-1, Merck) was used instead of 4-(2-bromoethyl)tetrahydro-2H-pyran. After purification by preparative HPLC (prep method A, x=25, y=55), 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide)phenylisobutyl carbonate was obtained in 29% yield. LCMS: Method A, 1.79 min, MS: ES + 432.2; 1¹H NMR (500MHz, DMSO) δppm: 10.53 (s, 1H), 8.74 (s, 1H), 8.58 (d, J=8.7Hz, 1H), 8.41 (d, J=7.8Hz, 1H), 8.20 (d, J=8.7Hz, 1H), 8.07 (d, J=7.7Hz, 1H), 7.84 (d, J=9.0Hz, 2H), 7.72 (t, J=7.8Hz, 1H), 7.25 (d, J=9.0Hz, 2H), 4.01 (d, J=6.6Hz, 2H), 1.98 (dt, J=13.4, 6.7Hz, 1H), 0.95 (d, J=6.8Hz, 6H). 1H was unclear / not observed. [Example 13]

[0668] 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide)phenylbenzenesulfonate [ka]

[0669] Instead of 4-(2-bromoethyl)tetrahydro-2H-pyran, benzenesulfonyl chloride (CAS 98-09-9, Merck) was used. After purification by preparative HPLC (prep method A, x=35, y=65), 4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide)phenylbenzenesulfonate was obtained in 44% yield. LCMS: Method A, 1.73 min, MS: ES + 472.1; 1 ¹H NMR (500MHz, DMSO) δppm: 10.56 (s, 1H), 8.72 (s, 1H), 8.59 (d, J=8.7Hz, 1H), 8.42 (d, J=7.8Hz, 1H), 8.20 (d, J=8.7Hz, 1H), 8.05 (d, J=7.8Hz, 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). 2H was unclear / not observed. [Example 14]

[0670] Isopropyl 2-(4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide)phenoxy)acetate [ka]

[0671] Isopropyl 2-chloroacetate (CAS 105-48-6, Alfa) was used instead of 4-(2-bromoethyl)tetrahydro-2H-pyran. After purification by preparative HPLC (prep method A, x=30, y=60), isopropyl 2-(4-(3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide)phenoxy)acetate was obtained in 46% yield. LCMS: Method A, 1.61 min, MS: ES + 432.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.35 (s, 1H), 8.73 (d, J=1.9Hz, 1H), 8.59 (d, J=8.7Hz, 1H), 8.44~8.34 (m, 1H), 8.21 (d, J=8.7Hz, 1H), 8.06 (d, J=8.0Hz, 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=6.3Hz, 6H). ¹H was unclear / not observed. [Example 15]

[0672] N-(4-(2-(1H-pyrazole-4-yl)ethoxy)phenyl)-3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide [ka]

[0673] Instead of 4-(2-bromoethyl)tetrahydro-2H-pyran, 4-(2-chloroethyl)-1H-pyrazole (CAS 438475-37-7, BLD) and NaI (0.1 equivalent) were used. After purification by preparative HPLC (prep method A, x=25, y=55), N-(4-(2-(1H-pyrazole-4-yl)ethoxy)phenyl)-3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide was obtained in 16% yield. LCMS: Method A, 1.47 min, MS: ES + 426.1; 1 ¹H NMR (500MHz, DMSO) δppm: 10.33 (s, 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.40 (d, J=7.7Hz, 1H), 8.21 (d, J=8.8Hz, 1H), 8.06 (d, J=7.7Hz, 1H), 7.80 (d, J=2.3Hz, 1H), 7.77~7.64 (m, 3H), 7.48 (s, 1H), 6.94 (d, J=9.0Hz, 2H), 6.26 (t, J=2.1Hz, 1H), 4.50 (t, J=5.3Hz, 2H), 4.34 (t, J=5.3Hz, 2H). 1H was unclear / not observed. [Example 16]

[0674] 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-isopropoxyphenyl)benzamide [ka]

[0675] 2-iodopropane (CAS 75-30-9, Merck) and NaI (0.1 equivalent) were used instead of 4-(2-bromoethyl)tetrahydro-2H-pyran. After purification by preparative HPLC (prep method A, x=30, y=60), 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-isopropoxyphenyl)benzamide was obtained in 43% yield. LCMS: Method A, 1.62 min, MS: ES + 374.2;1 ¹H NMR (500MHz, DMSO) δppm: 10.31 (s, 1H), 8.73 (s, 1H), 8.58 (d, J=8.7Hz, 1H), 8.40 (d, J=7.8Hz, 1H), 8.20 (d, J=8.7Hz, 1H), 8.06 (d, J=7.7Hz, 1H), 7.77~7.62 (m, 3H), 7.01~6.90 (m, 2H), 4.67~4.50 (m, 1H), 1.28 (d, J=6.0Hz, 6H). ¹H was unclear / not observed. [Example 17]

[0676] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-(4-chloro-3-(hydroxymethyl)butoxy)phenyl)benzamide [ka]

[0677] Following the procedure of Example 1, 2-(oxetan-3-yl)ethane-1-ol (CAS 251922-46-0, BLD) was used instead of (1-phenylpiperidine-4-yl)methanol. The intermediate was used without analysis. After purification by preparative HPLC (prep method A, x=25, y=55), 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-(4-chloro-3-(hydroxymethyl)butoxy)phenyl)benzamide was obtained in 15% yield. LCMS: Method A, 1.53 min, MS: ES + 452.2 / 454.1; 1H NMR(500MHz,DMSO)δppm:10.32(s,1H), 8.73(d,J=1.9Hz,1H), 8.55(d,J=8.7Hz, 1H), 8.39(d,J=7.8Hz,1H), 8.17(d,J=8.9Hz,1H), 8.05(d,J=7.7Hz,1H), 7.74~7 0.67 (m, 3H), 6.97 (d, J=9.0Hz, 2H), 4.73 (t, J=5.2Hz, 1H), 4.06 (t, J=6.6Hz, 2H), 3.85~3.65 (m, 2H), 3.56~3.41 (m, 2H), 2.07~1.98 (m, 1H), 1.79 (q, J=6.6Hz, 2H). 1H was unclear / not observed. [Example 18]

[0678] 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(2-(oxetan-3-yl)ethoxy)phenyl)benzamide [ka]

[0679] The procedure of Example 1 was followed, using 2-(oxetan-3-yl)ethane-1-ol (CAS 251922-46-0, BLD) instead of (1-phenylpiperidine-4-yl)methanol. The intermediate was used without analysis. After treatment with TFA (1 equivalent) instead of HCl and purification by preparative HPLC (prep method A, x=25, y=55), 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(2-(oxetan-3-yl)ethoxy)phenyl)benzamide was obtained in 16% yield. LCMS: Method A, 1.48 min, MS: ES + 416.2; 1¹H NMR (500MHz, DMSO) δppm: 10.32 (s, 1H), 8.74 (d, J=2.0Hz, 1H), 8.60 (s, 1H), 8.40 (d, J=7.8Hz, 1H), 8.23 ​​(d, J=8.8Hz, 1H), 8.07 (d, J=7.7Hz, 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). ¹H was unclear / not observed. [Example 19]

[0680] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(1-phenethyl-1H-pyrazole-4-yl)benzamide [ka]

[0681] Step 1: N-(1H-pyrazole-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka]

[0682] 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-pyrazole-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 minutes. HATU (2.29 g, 6.02 mmol) was added to the solution and stirred at room temperature for 16 hours. Water (120 mL) was added, the product was extracted in siRNA (3 × 60 mL), washed with brine (60 mL), dried over Na₂SO₄, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0-10% in DCM (0.7M ammonia in MeOH)) yielded N-(1H-pyrazole-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.

[0683] Step 2: N-(1H-pyrazole-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide [ka]

[0684] A mixture of 5-bromo-1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine (+isomer; I-2, 478 mg, 0.76 mmol), N-(1H-pyrazole-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 minutes. Pd-118 (99 mg, 0.15 mmol) was added, and the mixture was purged for a further 2 minutes, then stirred at 80°C for 2 hours. The reaction mixture was filtered through Celite® (washed with siRNA). The filtrate was diluted with water (20 mL) and extracted with siRNA (3 × 20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0-10% in DCM (0.7M ammonia in MeOH)) yielded N-(1H-pyrazole-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide (272 mg, 65%) along with a mixture of isomers. LCMS: Method A: 1.97 / 1.99 / 2.10 min, MS: ES - 546.2.

[0685] Step 3: N-(1-phenethyl-1H-pyrazole-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide [ka]

[0686] A solution of N-(1H-pyrazole-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide (+ isomer; 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 days. The reaction mixture was quenched with water (30 mL) and extracted with ELISA (3 × 20 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, isohexane, 0-80% Â) yielded N-(1-phenethyl-1H-pyrazole-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide (65 mg, 81%) along with a mixture of isomers. LCMS: Method A: 1.99 / 2.32 / 2.45 min, MS: ES - 650.2.

[0687] Step 4: 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(1-phenethyl-1H-pyrazole-4-yl)benzamide (Example 19) [ka]

[0688] A solution of N-(1-phenethyl-1H-pyrazole-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide (+ isomer; 62 mg, 0.10 mmol) and an aqueous HCl solution (2 M, 0.24 mL, 0.48 mmol) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by RP chromatography (C18, 0-100% MeCN in 0.1% HCO2H aqueous solution) to obtain 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(1-phenethyl-1H-pyrazole-4-yl)benzamide (27 mg, 69%). LCMS: Method A: 1.55 min, MS: ES + 410.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.60 (s, 1H), 8.73 (s, 1H), 8.65~8.53 (m, 1H), 8.38 (d, J=7.8Hz, 1H), 8.26~8.12 (m, 1H), 8.10~8.00 (m, 2H), 7.70 (t, J=7.9Hz, 1H), 7.66 (s, 1H), 7.33~7.25 (m, 2H), 7.27~7.16 (m, 3H), 4.36 (t, J=7.3Hz, 2H), 3.12 (t, J=7.4Hz, 2H). ¹H was unclear / not observed. [Example 20]

[0689] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(1-(3-phenylpropyl)-1H-pyrazole-4-yl)benzamide [ka]

[0690] Step 1: 4-Nitro-1-(3-phenylpropyl)-1H-pyrazole [ka]

[0691] 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 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, isohexane with 0-80% ethyl acetate) yielded 4-nitro-1-(3-phenylpropyl)-1H-pyrazole (387 mg, 94%). LCMS: Method A: 1.71 min, MS: ES + 232.2.

[0692] Step 2: 1-(3-phenylpropyl)-1H-pyrazole-4-amine [ka]

[0693] A solution of 4-nitro-1-(3-phenylpropyl)-1H-pyrazole (200 mg, 0.87 mmol) in MeOH (25 mL) was passed through a 10% Pd / C cartridge three times at 30°C under hydrogen pressure using a 1 bar (H-Cube®). The mixture was concentrated under reduced pressure to obtain 1-(3-phenylpropyl)-1H-pyrazole-4-amine (174 mg, 98%). LCMS: Method A: 0.45 min, MS: ES + 202.2.

[0694] Step 3: 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(1-(3-phenylpropyl)-1H-pyrazole-4-yl)benzamide (Example 20) [ka]

[0695] 1-(3-phenylpropyl)-1H-pyrazole-4-amine (84 mg, 0.42 mmol), DIPEA (0.15 mL, 0.83 mmol), and 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzoic acid (I-12, 50 mg, 0.21 mmol) in DMF (1 mL) were mixed with HATU (119 mg, 0.31 mmol). The mixture was stirred for 16 hours and purified by preparative HPLC (prep method A, x=30, y=60) to obtain 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(1-(3-phenylpropyl)-1H-pyrazole-4-yl)benzamide (47 mg, 53%). LCMS: Method A: 1.64 min, MS: ES + 424.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.64 (s, 1H), 8.75 (s, 1H), 8.59 (d, J=8.6Hz, 1H), 8.44~8.33 (m, 1H), 8.20 (d, J=8.6Hz, 1H), 8.13 (s, 1H), 8.09~8.04 (m, 1H), 7.71 (t, J=7.8Hz, 1H), 7.67 (s, 1H), 7.34~7.26 (m, 2H), 7.26~7.16 (m, 3H), 4.13 (t, J=6.9Hz, 2H), 2.57 (t, J=7.7Hz, 2H), 2.16~2.02 (m, 2H). ¹H was unclear / not observed. [Example 21]

[0696] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(2-cyclohexylethyl)benzamide [ka] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(2-cyclohexylethyl)benzamide [ka]

[0697] To a solution of 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzoic acid (I-12, 30 mg, 0.13 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF (0.40 mL), HATU (48 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. 2-cyclohexylethane-1-amine (CAS 4442-85-7, BLD, 0.03 mL, 0.23 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Purification by preparative HPLC (prep method A, x=35, y=65) yielded 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(2-cyclohexylethyl)benzamide (23 mg, 53%). LCMS: Method A: 1.74 min, MS: ES + 350.2; 1 H NMR(500MHz,DMSO)δppm:8.65~8.59(m,2H), 8.57(d,J=8.7Hz,1H), 8.32(d,J= 7.8Hz,1H), 8.16(d,J=8.7Hz,1H), 7.95(d,J=7.8Hz,1H), 7.64(t,J=7.7Hz,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=7.1Hz, 2H), 1.38~1.30 (m, 1H), 1.24~1.12 (m, 3H), 0.97~0.87 (m, 2H). 1H was unclear / not observed. [Example 22]

[0698] 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)benzamide [ka] 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)benzamide [ka]

[0699] A mixture of 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-5-yl)benzoic acid (I-11, 50 mg, 0.21 mmol), DIPEA (0.14 mL, 0.83 mol), and 4-((benzyloxy)methyl)aniline (I-7, 88 mg, 0.42 mmol) in DMF (8 mL) was mixed with T3P (50% in HCl, 0.16 mL, 0.27 mmol) at room temperature. The mixture was stirred at 50°C for 16 hours. Purification by preparative HPLC (prep method A, x=30, y=60) yielded 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)benzamide (7 mg, 7%). LCMS: Method A: 1.82 min, MS: ES + 437.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.48 (s, 1H), 9.51 (s, 1H), 8.81 (d, J=1.8Hz, 1H), 8.47 (d, J=7.8Hz, 1H), 8.13 (d, J=7.8Hz, 1H), 7.92~7.70 (m, 3H), 7.49~7.26 (m, 7H), 4.55 (s, 2H), 4.53 (s, 2H). ¹H was unclear / not observed.

[0700] General procedure (T3P amide coupling) Following the procedure of Example 22, 4-((benzyloxy)methyl)aniline was substituted with a suitable starting material (1-2 equivalents) and incubated at room temperature to 50°C for 16-72 hours, with any minor modifications noted, to obtain Examples 23-25 ​​below: [Example 23]

[0701] 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-5-yl)-N-(4-(cyclopropoxymethyl)phenyl)benzamide [ka]

[0702] Using 4-(cyclopropoxymethyl)aniline (I-22) instead of 4-((benzyloxy)methyl)aniline, and purified by preparative HPLC (prep method A, x=20, y=50), 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-5-yl)-N-(4-(cyclopropoxymethyl)phenyl)benzamide was obtained in 10% yield. LCMS: Method A: 1.61 min, MS: ES + 387.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.47 (s, 1H), 9.51 (s, 1H), 8.81 (d, J=1.8Hz, 1H), 8.47 (d, J=7.8Hz, 1H), 8.12 (d, J=8.0Hz, 1H), 7.84~7.67 (m, 3H), 7.34 (d, J=8.2Hz, 2H), 4.48 (s, 2H), 0.63~0.41 (m, 4H). 2H was unclear / not observed. [Example 24]

[0703] 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-5-yl)-N-(4-(cyclopropylmethoxy)phenyl)benzamide [ka]

[0704] Using 4-(cyclopropylmethoxy)aniline (I-23) instead of 4-((benzyloxy)methyl)aniline, 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-5-yl)-N-(4-(cyclopropylmethoxy)phenyl)benzamide was obtained in 6% yield by purification by preparative HPLC (prep method A, x=20, y=50). LCMS: Method A: 1.67 min, MS: ES +387.1; 1H NMR (500MHz, DMSO) δ 10.31 (s, 1H), 9.37 (s, 1H), 8.77 (s, 1H), 8.42 (d, J=7.7Hz, 1H), 8.07 (d, J=7.8Hz, 1H), 7.76~7.64 (m, 3H), 6.95 (d, J=8.6Hz, 2H), 3.82 (d, J=7.0Hz, 2H), 1.26~1.20 (m, 1H), 0.62~0.51 (m, 2H), 0.37~0.28 (m, 2H). 1H was unclear / not observed. [Example 25]

[0705] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-methoxyphenyl)benzamide [ka]

[0706] Using 4-methoxyaniline (CAS 104-94-9, Acros Organics) instead of 4-((benzyloxy)methyl)aniline, 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-methoxyphenyl)benzamide was obtained in 35% yield by preparative HPLC (prep method A, x=20, y=50). LCMS: Method A: 1.43 min, MS: ES + 346.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.32 (s, 1H), 8.73 (d, J=2.0Hz, 1H), 8.58 (d, J=8.7Hz, 1H), 8.41~8.37 (m, 1H), 8.20 (d, J=8.7Hz, 1H), 8.06 (d, J=7.7Hz, 1H), 7.75~7.67 (m, 3H), 6.98~6.93 (m, 2H), 3.76 (s, 3H). ¹H was unclear / not observed.

[0707] General procedure (HATU amide coupling) Following the procedure of Example 21, 2-cyclohexylethane-1-amine was replaced with appropriate starting material (1.2-2 equivalents) and DIPEA (3-4 equivalents), stirred / shaken at room temperature ~ 40°C for 5-24 hours, and with any minor modifications noted, Examples 26-34 were obtained: [Example 26]

[0708] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(2-cyclopentylethyl)benzamide [ka]

[0709] Using 2-cyclopentylethane-1-amine (CAS 5763-55-3, Combi-Blocks) instead of 2-cyclohexylethane-1-amine, 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(2-cyclopentylethyl)benzamide was obtained in 17% yield by preparative HPLC (prep method A, x=30, y=60). LCMS: Method A: 1.64 min, MS: ES + 336.2; 1 ¹H NMR (500MHz, DMSO) δppm: 8.66~8.62 (m, 2H), 8.58 (d, J=8.7Hz, 1H), 8.35~8.31 (m, 1H), 8.17 (d, J=8.7Hz, 1H), 7.98~7.93 (m, 1H), 7.64 (t, J=7.7Hz, 1H), 3.33 (d, J=6.5Hz, 2H), 1.85~1.76 (m, 3H), 1.58 (q, J=7.2Hz, 4H), 1.49 (m, 2H), 1.13 (q, J=9.1Hz, 2H). 1H was unclear / not observed. [Example 27]

[0710] Tert-butyl 4-(2(3(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide)ethyl)piperidine-1-carboxylate [ka]

[0711] Using tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (CAS 146093-46-1, Fluorochem) instead of 2-cyclohexylethane-1-amine, purification by preparative HPLC (prep method A, x=30, y=60) yielded tert-butyl 4-(2-(3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide)ethyl)piperidine-1-carboxylate in 24% yield. LCMS: Method A: 1.65 min, MS: ES + 351.2 (M-Boc) + ; 1 ¹H NMR (500MHz, DMSO) δppm: 8.66~8.60 (m, 2H), 8.55 (d, J=8.7Hz, 1H), 8.32 (d, J=7.8Hz, 1H), 8.14 (d, J=8.7Hz, 1H), 7.95 (d, J=7.7Hz, 1H), 7.64 (t, J=7.7Hz, 1H), 3.92 (d, J=12.8Hz, 2H), 2.69 (s, 2H), 1.70 (d, J=12.8Hz, 2H), 1.51 (t, J=5.6Hz, 4H), 1.39 (s, 9H), 1.02 (t, J=11.3Hz, 2H). 2H was unclear / not observed. [Example 28]

[0712] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(2-(p-tolyloxy)ethyl)benzamide [ka]

[0713] Using 2-(p-tolyloxy)ethane-1-amine in DMA (CAS 26583-58-4, Apollo) instead of 2-cyclohexylethane-1-amine, 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(2-(p-tolyloxy)ethyl)benzamide was obtained in 29% yield by preparative HPLC (prep method C, x=10, y=40). LCMS: Method S, 0.79 min, MS: ES + 374.3; 1 ¹H NMR (500MHz, DMSO) δ 8.90 (t, J=5.5Hz, 1H), 8.65 (s, 1H), 8.49 (d, J=8.6Hz, 1H), 8.33 (d, J=7.9Hz, 1H), 8.07 (d, J=8.6Hz, 1H), 7.96 (d, J=7.7Hz, 1H), 7.63 (t, J=7.7Hz, 1H), 7.08 (d, J=8.1Hz, 2H), 6.87 (d, J=8.1Hz, 2H), 4.11 (t, J=6.0Hz, 2H), 3.71~3.62 (m, 2H), 2.22 (s, 3H). 1H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 29]

[0714] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(2-((4-chlorophenyl)thio)ethyl)benzamide [ka]

[0715] Using 2-((4-chlorophenyl)thio)ethane-1-amine (CAS 36155-35-8, Apollo) in DMA instead of 2-cyclohexylethane-1-amine, 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(2-((4-chlorophenyl)thio)ethyl)benzamide was obtained in 26% yield by preparative HPLC (prep method C, x=10, y=40). LCMS: Method S, 0.86 min, MS: ES + 410.2; 1¹H NMR (500MHz, DMSO) δ 8.91 (t, J=5.6Hz, 1H), 8.61 (s, 1H), 8.48 (d, J=8.6Hz, 1H), 8.33 (d, J=7.8Hz, 1H), 8.04 (d, J=8.6Hz, 1H), 7.91 (d, J=7.7Hz, 1H), 7.63 (t, J=7.8Hz, 1H), 7.45 (d, J=8.6Hz, 2H), 7.38 (d, J=8.3Hz, 2H), 3.52 (q, J=6.6Hz, 2H), 3.21 (t, J=7.1Hz, 2H). 1H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 30]

[0716] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(5-phenyl-1,3,4-thiadiazole-2-yl)benzamide [ka]

[0717] Using 5-phenyl-1,3,4-thiadiazole-2-amine (CAS 2002-03-1, Combi-Blocks) in DMA instead of 2-cyclohexylethane-1-amine, 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(5-phenyl-1,3,4-thiadiazole-2-yl)benzamide was obtained in 6% yield by preparative HPLC (prep method C, x=5, y=30). LCMS: Method S, 0.53 min, MS: ES + 400.3. 1 ¹H NMR (500MHz, DMSO) δ 9.02 (s, 1H), 8.86 (s, 1H), 8.54 (d, J=8.6Hz, 1H), 8.40 (d, J=7.8Hz, 1H), 8.23 ​​(d, J=7.7Hz, 1H), 8.17 (d, J=8.7Hz, 1H), 7.96 (d, J=7.6Hz, 2H), 7.69 (t, J=7.8Hz, 1H), 7.56~7.46 (m, 3H). 1H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 31]

[0718] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-((3-phenylisoxazole-5-yl)methyl)benzamide [ka]

[0719] Using (3-phenylisoxazole-5-yl)methaneamine (CAS 54408-35-4, BLD) in DMA instead of 2-cyclohexylethane-1-amine, 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-((3-phenylisoxazole-5-yl)methyl)benzamide was obtained in 24% yield by preparative HPLC (prep method C, x=10, y=40). LCMS: Method S, 0.77 min, MS: ES + 397.2; 1 ¹H NMR (500MHz, DMSO) δ 9.44 (t, J=5.8Hz, 1H), 8.72 (s, 1H), 8.53 (d, J=8.7Hz, 1H), 8.38 (d, J=7.8Hz, 1H), 8.13 (d, J=8.7Hz, 1H), 8.03 (d, J=7.8Hz, 1H), 7.92~7.86 (m, 2H), 7.68 (t, J=7.9Hz, 1H), 7.50~7.46 (m, 3H), 6.99 (s, 1H), 4.72 (d, J=5.7Hz, 2H). 1H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 32]

[0720] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(2-methoxy-5-(trifluoromethoxy)phenyl)benzamide [ka]

[0721] Using 2-methoxy-5-(trifluoromethoxy)aniline (CAS 660848-57-7, BLD) in DMA instead of 2-cyclohexylethane-1-amine, 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(2-methoxy-5-(trifluoromethoxy)phenyl)benzamide was obtained in 4% yield by preparative HPLC (prep method C, x=15, y=45). LCMS: Method S, 0.94 min, MS: ES + 430.2. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 33]

[0722] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-methyl-3-(trifluoromethyl)phenyl)benzamide [ka]

[0723] Using 4-methyl-3-(trifluoromethyl)aniline (CAS 65934-74-9, BLD) in DMA instead of 2-cyclohexylethane-1-amine, 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-methyl-3-(trifluoromethyl)phenyl)benzamide was obtained in 26% yield by preparative HPLC (prep method C, x=15, y=45). LCMS: Method S, 0.94 min, MS: ES + 398.2; 1¹H NMR (500MHz, DMSO) δppm: 10.65 (s, 1H), 8.76 (t, J=1.9Hz, 1H), 8.56 (d, J=8.8Hz, 1H), 8.45~8.39 (m, 1H), 8.21 (d, J=2.2Hz, 1H), 8.18 (d, J=8.7Hz, 1H), 8.10~8.05 (m, 1H), 8.01 (d, J=8.4Hz, 1H), 7.73 (t, J=7.8Hz, 1H), 7.46 (d, J=8.3Hz, 1H), 2.43 (d, J=2.0Hz, 3H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 34]

[0724] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(1-(2-fluorobenzyl)-1H-pyrazole-4-yl)benzamide [ka]

[0725] Using 1-(2-fluorobenzyl)-1H-pyrazole-4-amine (CAS 925634-52-2, Manchester Organics) in DMA instead of 2-cyclohexylethane-1-amine, 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(1-(2-fluorobenzyl)-1H-pyrazole-4-yl)benzamide was obtained in 20% yield by preparative HPLC (prep method C, x=10, y=40). LCMS: Method S, 0.76 min, MS: ES + 414.3; 1¹H NMR (500MHz, DMSO) δppm: 10.66 (s, 1H), 8.73 (s, 1H), 8.54 (d, J=8.7Hz, 1H), 8.37 (d, J=7.8Hz, 1H), 8.19 (s, 1H), 8.13 (d, J=8.5Hz, 1H), 8.04 (d, J=7.7Hz, 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). 1H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 35]

[0726] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-(methylsulfonyl)-N-(4-phenethoxyphenyl)benzamide [ka] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-(methylsulfonyl)-N-(4-phenethoxyphenyl-)benzamide [ka]

[0727] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide (E-46, 72 mg, 0.15 mmol) in DCM (5 mL) was mixed with mCPBA (70%, 57 mg, 0.23 mmol). The mixture was stirred for 1 hour, then diluted with DCM (10 mL) and washed with aqueous Na2S2O3 (10%, 10 mL), saturated aqueous NaHCO3 (10 mL), and water (10 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography (silica gel, 0-100% THF in DCM) and preparative HPLC (prep method A, x=35, y=65) yielded 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-(methylsulfonyl)-N-(4-phenethoxyphenyl)benzamide (3 mg, 4%). LCMS: Method A, 1.30 min, MS: ES + 514.0; 1 ¹H NMR (500MHz, DMSO) δppm: 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=8.9Hz, 2H), 7.41~7.29 (m, 4H), 7.29~7.14 (m, 1H), 6.99 (d, J=9.1Hz, 2H), 4.20 (t, J=6.9Hz, 2H), 3.39 (s, 3H), 3.05 (t, J=6.9Hz, 2H). 1H is unclear / not observed. [Example 36]

[0728] 3-(1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-yl)-N-(4-phenethoxyphenyl)benzamide [ka] 3-(1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0729] To a solution of 3-(4,5-diaminopyrimidine-2-yl)-N-(4-phenethoxyphenyl)benzamide (I-9, 100 mg, 0.21 mmol) in THF (4 mL), AcOH (0.16 mL, 2.8 mmol) and iPnONO (0.05 mL, 0.34 mmol) were added. The mixture was stirred at 65°C for 2 hours 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), yielded 3-(1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-yl)-N-(4-phenethoxyphenyl)benzamide (15 mg, 16%). LCMS: Method A: 1.91 min, MS: ES + 437.2; 1H NMR (500MHz, DMSO) δppm: 10.37 (s, 1H), 9.83 (s, 1H), 9.06 (s, 1H), 8.69 (d, J=7.8Hz, 1H), 8.12 (d, J=7.8Hz, 1H), 7.76~7.68 (m, 3H), 7.38~7.30 (m, 4H), 7.28~7.21 (m, 1H), 6.96 (d, J=9.0Hz, 2H), 4.20 (t, J=6.9Hz, 2H), 3.05 (t, J=6.9Hz, 2H). 1H was unclear / not observed. [Example 37]

[0730] 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-5-yl)-N-(4-phenethoxyphenyl)benzamide [ka] 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-5-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0731] 3-(5,6-diaminopyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide (I-10, 177 mg, 0.37 mmol) in THF (5 mL) was mixed with AcOH (0.03 mL, 0.49 mmol) and iPnONO (0.08 mL, 0.60 mmol). The mixture was stirred at 65°C for 1 hour and concentrated under reduced pressure. The residue was purified by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution) and trituration with siRNA. Further purification by RP chromatography (C18, 0-100% MeCN followed by 0-100% THF in 0.1% HCO2H aqueous solution) and siRNA trituration yielded 3-(1H-[1,2,3]triazolo[4,5-b]pyrazine-5-yl)-N-(4-phenethoxyphenyl)benzamide (43 mg, 26%). LCMS: Method A: 1.87 min, MS: ES + 437.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.33 (s, 1H), 9.56 (s, 1H), 8.79 (d, J=2.0Hz, 1H), 8.46 (d, J=7.8Hz, 1H), 8.12 (d, J=7.7Hz, 1H), 7.75 (t, J=7.8Hz, 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=6.9Hz, 2H), 3.04 (t, J=6.9Hz, 2H). 1H was unclear / not observed. [Example 38]

[0732] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)-N-(4-phenethoxyphenyl)benzamide [ka] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0733] 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 minutes. Pd-118 (23 mg, 0.04 mmol) was added, and the mixture was purged for another 10 minutes and stirred at 80°C for 3 hours. The mixture was cooled to room temperature, filtered through Celite®, and concentrated under reduced pressure.

[0734] Purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution) yielded 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)-N-(4-phenethoxyphenyl)benzamide (17 mg, 21%). LCMS: Method B: 1.27 min, MS: ES + 436.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.23 (s, 1H), 8.98~8.94 (m, 1H), 8.64~8.60 (m, 1H), 8.36 (s, 1H), 8.02 (d, J=7.7Hz, 1H), 7.96 (d, J=7.7Hz, 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=6.9Hz, 2H), 3.05 (t, J=6.9Hz, 2H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 39]

[0735] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)-N-(4-phenethoxyphenyl)benzamide [ka] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0736] 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 minutes. Pd-118 (24 mg, 0.04 mmol) was added, followed by another 10 minutes of purging, and then the mixture was heated at 80°C for 3 hours. The mixture was cooled to room temperature, filtered through Celite®, and concentrated under reduced pressure. Purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution) yielded 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)-N-(4-phenethoxyphenyl)benzamide (17 mg, 21%). LCMS: Method B: 1.28 min, MS: ES + 436.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.32 (s, 1H), 8.74~8.70 (m, 1H), 8.51 (d, J=8.6Hz, 1H), 8.38 (d, J=7.9Hz, 1H), 8.12 (d, J=8.6Hz, 1H), 8.04 (d, J=7.8Hz, 1H), 7.73~7.66 (m, 3H), 7.38~7.29 (m, 4H), 7.24 (t, J=6.9Hz, 1H), 6.96 (d, J=8.7Hz, 2H), 4.20 (t, J=6.9Hz, 2H), 3.05 (t, J=6.8Hz, 2H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 40]

[0737] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-(benzyloxy)phenyl)benzamide [ka]

[0738] Step 1: N-(4-(benzyloxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka]

[0739] 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 room temperature for 30 minutes, 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 hours, cooled to room temperature, poured into cold water (200 mL), and extracted with siRNA (3 × 80 mL). The combined organic phases were washed with brine (1 × 50 mL), dried, and the filtrate was adsorbed onto silica gel. Purification by chromatography (silica gel, isohexane with 0-30% Â) yielded 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.

[0740] Step 2: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-(benzyloxy)phenyl)benzamide (Example 40) [ka]

[0741] 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 minutes, after which Pd-118 (39 mg, 0.06 mmol) was added. The mixture was stirred at 90°C for 18 hours, concentrated under reduced pressure, then diluted with RINKAN (30 mL) and washed with water (5 mL). The organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution) yielded 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-(benzyloxy)phenyl)benzamide (10 mg, 8%). LCMS: Method A: 1.79 min, MS: ES + 422.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.33 (s, 1H), 8.72 (d, J=2.0Hz, 1H), 8.55 (d, J=8.7Hz, 1H), 8.41~8.37 (m, 1H), 8.16 (d, J=8.7Hz, 1H), 8.05 (d, J=7.7Hz, 1H), 7.74~7.69 (m, 3H), 7.47 (d, J=7.1Hz, 2H), 7.43~7.38 (m, 2H), 7.37~7.33 (m, 1H), 7.07~7.01 (m, 2H), 5.11 (s, 2H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 41]

[0742] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)benzamide [ka] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)benzamide [ka]

[0743] 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 minutes, and Pd-118 (52 mg, 0.08 mmol) was added. The mixture was purged for a further 2 minutes and then stirred at 90°C for 18 hours. The reaction mixture was cooled to room temperature, acidified with aqueous HCl (1 M, 5 mL), and extracted with siRNA (3 × 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% NH4OH aqueous solution) yielded 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)benzamide (35 mg, 19%). LCMS: Method B: 1.81 min, MS: ES + 436.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.48 (s, 1H), 8.77~8.73 (m, 1H), 8.58 (d, J=8.7Hz, 1H), 8.44~8.38 (m, 1H), 8.20 (d, J=8.7Hz, 1H), 8.10~8.05 (m, 1H), 7.84~7.79 (m, 2H), 7.72 (t, J=7.8Hz, 1H), 7.42~7.35 (m, 6H), 7.38~7.27 (m, 1H), 4.55 (s, 2H), 4.53 (s, 2H). 1H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 42]

[0744] 5-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-phenethoxyphenyl)nicotinamide [ka]

[0745] Step 1: Methyl 5,6-diamino-[2,3'-bipyridine]-5'-carboxylate [ka]

[0746] A mixture of 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD, 200 mg, 1.06 mmol), (5-(methoxycarbonyl)pyridine-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, and then Pd-118 (69 mg, 0.11 mmol) was added. The reaction mixture was stirred under nitrogen at 75°C for 18 hours. The mixture was filtered through Celite® and then adsorbed onto Celite®. Purification by chromatography (silica gel, 0-10% in DCM (0.7M ammonia in MeOH)) yielded methyl 5,6-diamino-[2,3'-bipyridine]-5'-carboxylate (232 mg, 89%). LCMS: Method A: 0.26 min, MS: ES + 245.2.

[0747] Step 2: Methyl 5-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)nicotinate [ka]

[0748] Methyl 5,6-diamino-[2,3'-bipyridine]-5'-carboxylate (120 mg, 0.48 mmol) was added to THF (5 mL) with 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 hours and concentrated under reduced pressure to obtain methyl 5-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)nicotinate, which was used in the next step without purification. LCMS: Method Q: 0.74 min, MS: ES + 256.0.

[0749] Step 3: Lithium 5-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)nicotinate [ka]

[0750] Methyl 5-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)nicotinate (160 mg, 0.48 mmol) was added to THF (8 mL) with LiOH aqueous solution (1 M, 1.43 mL, 1.43 mmol) and MeOH (0.10 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to obtain 5-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)nicotinic acid, which was used in the next step without purification. LCMS: Method Q: 0.53 min, MS: ES + 242.0.

[0751] Step 4: 5-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-phenethoxyphenyl)nicotinamide (Example 42) [ka]

[0752] 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) were added with DIPEA (0.17 mL, 0.95 mmol) and HATU (118 mg, 0.31 mmol). The mixture was stirred at room temperature for 18 hours. Water (1 mL) was added and purification by preparative HPLC (prep method B, x = 35, y = 65) gave 5-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-phenethoxyphenyl)nicotinamide (20 mg, 19% in three steps). LCMS: Method A: 1.73 min, MS: ES + 437.2; 1 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). 1H was unclear / unobserved. The isolated compound contains up to 1 molar equivalent of ammonia. [Example 43]

[0753] 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-(methylsulfonamido)-N-(4-phenethoxyphenyl)benzamide

Chemical Structure

[0754] Step 1: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-(methylsulfonamido)benzoic acid

Chemical Structure

[0755] Methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-aminobenzoate (I-14, 100 mg, 0.18 mmol) was added to water (2 mL) with MsCl (0.04 mL, 0.52 mmol). The mixture was stirred at room temperature for 18 hours, and then an aqueous solution of LiOH (1 M, 0.35 mL, 0.35 mmol) was added. After 6 hours, an additional aqueous solution of LiOH (1 M, 0.35 mL, 0.35 mmol) was added. After a further 18 hours, the mixture was neutralized with an aqueous solution of HCl (1 M) and concentrated under reduced pressure to obtain 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-(methylsulfonamide)benzoic acid, which was used in the next step without purification. LCMS: Method A: 0.72 min, MS: ES + 334.0.

[0756] Step 2: 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-(methylsulfonamide)-N-(4-phenethoxyphenyl)benzamide (Example 43) [ka]

[0757] 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-(methylsulfonamide)benzoic acid (58 mg, 0.18 mmol) and 4-phenethoxyaniline (I-5, 69 mg, 0.23 mmol) were mixed in DMF (1 mL) with DIPEA (0.12 mL, 0.70 mmol) and HATU (100 mg, 0.26 mmol). The mixture was stirred at room temperature for 18 hours and diluted with water (0.1 mL). Purification by preparative HPLC (prep method A, x=35, y=65) yielded 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-(methylsulfonamide)-N-(4-phenethoxyphenyl)benzamide (2 mg, 2% in two steps). LCMS: Method A: 1.76 min, MS: ES+ 529.2; 1 ¹H NMR (500MHz, MeOD) δppm: 8.49 (d, J=8.7Hz, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 8.16 (d, J=8.7Hz, 1H), 7.90 (s, 1H), 7.62 (d, J=8.9Hz, 2H), 7.37~7.29 (m, 5H), 7.26~7.20 (m, 1H), 6.97 (d, J=8.9Hz, 2H), 4.23 (t, J=6.8Hz, 2H), 3.12 (s, 3H), 3.09~3.05 (m, 2H). 2H was unclear / not observed. [Example 44]

[0758] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-acetamide-N-(4-phenethoxyphenyl)benzamide [ka]

[0759] Step 1: 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-acetamidobenzoic acid [ka]

[0760] Methyl 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-aminobenzoate (I-14, 318 mg, 0.51 mmol) was added to DCM (2 mL) at 0°C with acetic anhydride (0.19 mL, 2.03 mmol). The mixture was stirred at room temperature for 2 hours and then diluted with 9:1 DCM / MeOH (10 mL). The organic phase was washed with water (5 mL) and saturated NaHCO3 aqueous solution (5 mL) and concentrated under reduced pressure. The residue was stirred at room temperature for 1 hour in THF (3 mL) with LiOH aqueous solution (1 M, 0.51 mL, 0.51 mmol). The mixture was acidified to pH 1-2 with an aqueous HCl solution (1M) and concentrated under reduced pressure to obtain 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-acetamidobenzoic acid, which was used in the next step without purification. LCMS: Method Q: 0.71 min, MS: ES + 298.0.

[0761] Step 2: 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-acetamide-N-(4-phenethoxyphenyl)benzamide (Example 44) [ka]

[0762] 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) were mixed in DMF (1 mL) with DIPEA (0.07 mL, 0.40 mmol) and HATU (57 mg, 0.15 mmol). The mixture was stirred at room temperature for 18 hours, then diluted with water (0.1 mL) and purified by preparative HPLC (prep method A, x=35, y=65) to obtain 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-acetamido-N-(4-phenethoxyphenyl)benzamide (8 mg, 16% in two steps). LCMS: Method A: 1.74 min, MS: ES+ 493.2; 1 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). 3H was unclear / unobserved. [Example 45]

[0763] 3-(7-Methyl-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-N-(4-phenethoxyphenyl)benzamide [Chemical formula]

[0764] Step 1: 3-(4,5-Diamino-6-methylpyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide [Chemical formula]

[0765] 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 (CAS63211-98-3, BLD, 64 mg, 0.41 mmol) in dioxane (4 mL) and water (1 mL) was purged with nitrogen for 5 minutes, and Pd-118 (44 mg, 0.07 mmol) was added. The mixture was purged for a further 2 minutes and then stirred at 90°C for 5 hours. The reaction product was cooled to room temperature, filtered, and diluted with SiO2 (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 obtain 3-(4,5-diamino-6-methylpyrimidine-2-yl)-N-(4-phenethoxyphenyl)benzamide (18 mg, 86%). LCMS: Method A, 1.40 min, MS: ES + 440.2.

[0766] Step 2: 3-(7-methyl-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-yl)-N-(4-phenethoxyphenyl)benzamide (Example 45) [ka]

[0767] 3-(4,5-diamino-6-methylpyrimidine-2-yl)-N-(4-phenethoxyphenyl)benzamide (80 mg, 0.16 mmol) in THF (4 mL) was mixed with AcOH (0.12 mL, 2.03 mmol) and iPnONO (0.033 mL, 0.25 mmol). The mixture was stirred at 65°C for 1 hour and concentrated under reduced pressure. The crude product was purified by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution) to obtain 3-(7-methyl-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-yl)-N-(4-phenethoxyphenyl)benzamide (18 mg, 24%). LCMS: Method A, 1.95 min, MS: ES + 451.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.36 (s, 1H), 9.03 (d, J=1.9Hz, 1H), 8.68 (dt, J=7.8, 1.5Hz, 1H), 8.12 (dt, J=7.8, 1.5Hz, 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=6.9Hz, 2H), 3.05 (t, J=6.9Hz, 2H), 3.03 (s, 3H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 46]

[0768] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide [ka]

[0769] Step 1: 3-Bromo-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide [ka]

[0770] 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 HCl (5 mL) were mixed with DIPEA (0.21 mL, 1.21 mmol) and T3P (50% in HCl, 0.36 mL, 0.61 mmol). The reaction mixture was stirred at room temperature for 1 hour and washed with saturated NaHCO3 aqueous solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification by RP chromatography (C18, 0-100% (0.1% HCO2H in MeCN) / (0.1% HCO2H aqueous solution)) yielded 3-bromo-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide (157 mg, 88%). LCMS: Method Q, 1.22 min, MS: ES + 442.0 / 444.0.

[0771] Step 2: 3-(methylthio)-N-(4-phenethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka]

[0772] A mixture of 3-bromo-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide (100 mg, 0.22 mmol), bis(pinacolate)diborone (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, and then Pd(dppf)Cl2 (16 mg, 0.022 mmol) was added. The mixture was stirred at 95°C for 18 hours, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain 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

[0773] Step 3: 3-(5,6-diaminopyridine-2-yl)-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide [ka]

[0774] A mixture of Cs2CO3 (217 mg, 0.67 mmol), 6-bromopyridine-2,3-diamine (CAS 129012-04-0, BLD Co., Ltd., 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 hours. 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) yielded 3-(5,6-diaminopyridine-2-yl)-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide (159 mg, 99%). LCMS: Method Q, 0.93 min, MS: ES + 471.2.

[0775] Step 4: 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide (Example 46) [ka]

[0776] 3-(5,6-diaminopyridine-2-yl)-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide (158 mg, 0.33 mmol) in THF (4 mL) was mixed with AcOH (0.25 mL, 4.28 mmol) and iPnONO (0.071 mL, 0.53 mmol). The mixture was stirred at 65°C for 1 hour and concentrated under reduced pressure to obtain 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide (87 mg, 51%). LCMS: Method A, 2.01 min, MS: ES + 482.2; 1 ¹H NMR (500MHz, DMSO, 70℃) δppm: 10.17 (s, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 8.22 (s, 1H), 8.20 (d, J=9.0Hz, 1H), 7.92 (s, 1H), 7.67 (d, J=9.0Hz, 2H), 7.40~7.27 (m, 4H), 7.26~7.19 (m, 1H), 6.96 (d, J=9.0Hz, 2H), 4.23 (t, J=6.8Hz, 2H), 3.05 (t, J=6.8Hz, 2H), 2.66 (s, 3H). 1H was unclear / not observed. [Example 47]

[0777] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-(tosylmethyl)phenyl)benzamide [ka]

[0778] Step 1: 3-Bromo-N-(4-(Tosylmethyl)phenyl)benzamide [ka]

[0779] 3-bromobenzoyl chloride (CAS 1711-09-7, Apollo, 0.13 mL, 0.96 mmol) and pyridine (0.12 mL, 1.43 mmol) were added to THF (10 mL), to which 4-(tosylmethyl)aniline (CAS 54306-15-9, Combi-Blocks, 250 mg, 0.96 mmol) and DMAP (23 mg, 0.19 mmol) were added. The mixture was stirred at 40°C for 2 hours and then cooled to room temperature. Water (2 mL) and DCM (30 mL) were added to separate the organic phase, which was concentrated under reduced pressure. The residue was triturated with diethyl ether to obtain 3-bromo-N-(4-(tosylmethyl)phenyl)benzamide (360 mg, 85%). LCMS: Method A, 1.89 min, MS: ES - 442.0 / 444.0.

[0780] Step 2: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)benzamide [ka]

[0781] To a solution of 3-bromo-N-(4-(tosylmethyl)phenyl)benzamide (300 mg, 0.68 mmol) in dioxane (10 mL), B2Pin2 (CAS 73183-34-3, Apollo, 257 mg, 1.01 mmol) and KOAc (199 mg, 2.03 mmol) were added. The mixture was purged with nitrogen for 5 minutes, Pd-118 (44 mg, 0.07 mmol) was added, and the mixture was purged again for 2 minutes, then stirred at 80°C for 1.5 hours. The mixture was cooled to room temperature, filtered through Celite®, and concentrated under reduced pressure. Purification by chromatography (silica gel, isohexane, 0-100% ethyl phosphate) yielded 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.

[0782] Step 3: 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-(tosylmethyl)phenyl)benzamide (Example 47) [ka]

[0783] 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 minutes. Pd-118 (39 mg, 0.060 mmol) was added and the mixture was purged for 2 minutes. The mixture was stirred at 80°C for 18 hours and concentrated under reduced pressure. Purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution) and preparative HPLC (prep method B, x=30, y=60) yielded 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-(tosylmethyl)phenyl)benzamide (9 mg, 6%). LCMS: Method A, 1.63 min, MS: ES + 484.1; 1 ¹H NMR (500MHz, DMSO) δppm: 10.48 (s, 1H), 8.73 (d, J=1.9Hz, 1H), 8.57 (d, J=8.7Hz, 1H), 8.43~8.38 (m, 1H), 8.19 (d, J=8.7Hz, 1H), 8.08~8.03 (m, 1H), 7.73 (d, J=8.2Hz, 3H), 7.64~7.58 (m, 2H), 7.42 (d, J=8.1Hz, 2H), 7.18~7.12 (m, 2H), 4.62 (s, 2H), 2.41 (s, 3H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 48]

[0784] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(5-(tert-butyl)isoxazole-3-yl)benzamide [ka]

[0785] Step 1: 3-Bromo-N-(5-(tert-butyl)isoxazole-3-yl)benzamide [ka]

[0786] In Example 47, following the procedure of Step 1, 3-bromo-N-(5-(tert-butyl)isoxazole-3-yl)benzamide was obtained in 69% yield by using 5-(tert-butyl)-1,2-oxazole-3-amine (CAS 55809-36-4, BLD) instead of 4-(tosylmethyl)aniline. LCMS: Method A, 1.93 min, MS: ES + 323.0 / 325.1.

[0787] Step 2: N-(5-(tert-butyl)isoxazol-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka]

[0788] In Example 47, following the procedure of Step 2, 3-bromo-N-(5-(tert-butyl)isoxazole-3-yl)benzamide was used instead of 3-bromo-N-(4-(tosylmethyl)phenyl)benzamide to obtain N-(5-(tert-butyl)isoxazole-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.

[0789] Step 3: 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(5-(tert-butyl)isoxazole-3-yl)benzamide (Example 48) [ka]

[0790] In Example 47, following the procedure of Step 3, N-(5-(tert-butyl)isoxazole-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)benzamide was used instead of 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(5-(tert-butyl)isoxazole-3-yl)benzamide was obtained in 23% yield. LCMS: Method A, 1.63 min, MS: ES + 363.1; 1 ¹H NMR (500MHz, DMSO) δppm: 11.52 (s, 1H), 8.75 (d, J=2.0Hz, 1H), 8.40~8.35 (m, 1H), 8.14~8.07 (m, 1H), 7.97 (d, J=7.8Hz, 1H), 7.70~7.64 (m, 1H), 7.61 (t, J=7.7Hz, 1H), 6.78 (s, 1H), 1.34 (s, 9H). 1H is unclear / not observed. [Example 49]

[0791] 3-(5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0792] Step 1: 6-bromo-5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine [ka]

[0793] In Example 46, following the procedure of Step 4, 6-bromo-5-methylpyridine-2,3-diamine (CAS 59352-90-8, Combi-Blocks) was used instead of 3-(5,6-diaminopyridine-2-yl)-5-(methylthio)-N-(4-phenethoxyphenyl)benzamide to obtain 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.

[0794] Step 2: 3-(5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)-N-(4-phenethoxyphenyl)benzamide (Example 49) [ka]

[0795] 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 minutes. Then, Pd-118 (31 mg, 0.047 mmol) was added, and the mixture was purged for a further 2 minutes. The mixture was stirred at 90°C for 18 hours. The mixture was cooled to room temperature, acidified with aqueous HCl (1 M, 5 mL), and extracted with dimethyl HCl (3 × 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% NH4OH aqueous solution) yielded 3-(5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)-N-(4-phenethoxyphenyl)benzamide (30 mg, 27%). LCMS: Method A, 1.85 min, MS: ES + 450.2; 1 ¹H NMR (500MHz, DMSO) δppm: 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=6.9Hz, 2H), 3.04 (t, J=6.9Hz, 2H), 2.54 (s, 3H). 1H is unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 50]

[0796] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(1-benzyl-1H-pyrazole-4-yl)benzamide [ka]

[0797] Step 1: N-(1-benzyl-1H-pyrazole-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide [ka]

[0798] In Example 19, following the procedure of Step 3, N-(1-benzyl-1H-pyrazole-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide was obtained in 76% yield along with other isomers, using benzyl bromide (CAS 100-39-0, Aldrich) instead of (2-bromoethyl)benzene and DMF instead of THF. LCMS: Method A, 2.28 / 2.41 min, MS ES + 436.2.

[0799] Step 2: 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(1-benzyl-1H-pyrazole-4-yl)benzamide (Example 50) [ka]

[0800] In Example 19, following the procedure of Step 4, 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(1-benzyl-1H-pyrazole-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamide (+ isomer) was obtained in 20% yield by using N-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(1-benzyl-1H-pyrazole-4-yl)benzamide instead of N-(1-phenethyl-1H-pyrazole-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(1-benzyl-1H-pyrazole-4-yl)benzamide instead of N-(1-phenethyl-1H-pyrazole-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(1-benzyl-1H-pyrazole-4-yl)benzamide instead of N-(1-phenethyl-1H-pyrazole-4-yl)-3-(1-trityl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-3-3-( LCMS: Method A, 1.49 min, MS ES + 396.2;1 ¹H NMR (500MHz, DMSO) δppm: 10.65 (s, 1H), 8.73 (d, J=1.8Hz, 1H), 8.60 (s, 1H), 8.38 (d, J=7.8Hz, 1H), 8.20 (d, J=6.3Hz, 2H), 8.06 (d, J=7.7Hz, 1H), 7.74~7.65 (m, 2H), 7.40~7.21 (m, 5H), 5.35 (s, 2H). 1H was unclear / not observed. [Example 51]

[0801] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)-N-methyl-N-(4-phenethoxyphenyl)benzamide [ka]

[0802] Step 1: N-methyl-N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka]

[0803] 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 mixed with NaH (60% dispersed in mineral oil, 27 mg, 0.68 mmol) and stirred for 30 minutes. MeI (0.042 mL, 0.68 mmol) was added and the mixture was stirred for a further 2 hours. Water (20 mL) was added and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phase was dried over Na₂SO₄ and concentrated under reduced pressure to obtain 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.

[0804] Step 2: 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-methyl-N-(4-phenethoxyphenyl)benzamide (Example 51) [ka]

[0805] Example 45 Following the procedure of Step 1, 6-bromo-3H-[1,2,3]triazolo[4,5-b]pyridine (I-16) was used instead 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 (I-6) was used instead of N-(4-phenethoxyphenyl)-3- Using (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-methyl-N-(4-phenethoxyphenyl)benzamide was obtained in 6% yield by filtration for 18 hours and purification by RP chromatography (C18, 0.1% NH4OH aqueous solution with 0-100% MeCN). LCMS: Method A, 1.82 min, MS: ES + 450.2; 1 ¹H NMR (500MHz, DMSO) δppm: 8.41~8.35 (m, 1H), 8.11 (s, 1H), 8.06 (d, J=7.9Hz, 1H), 7.79 (d, J=8.5Hz, 1H), 7.35 (t, J=7.5Hz, 1H), 7.30~7.21 (m, 5H), 7.21~7.13 (m, 3H), 6.82 (d, J=8.4Hz, 2H), 4.09 (t, J=6.8Hz, 2H), 3.37 (s, 3H), 2.93 (t, J=6.8Hz, 2H). 1H is unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 52]

[0806] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)-3-fluorophenyl)benzamide [ka] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)-3-fluorophenyl)benzamide [ka]

[0807] In Example 49, following the procedure of Step 2, 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)-3-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-18) was used instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-18), and 5-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1) was used instead of 6-bromo-5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)-3-fluorophenyl)benzamide was obtained in 34% yield. LCMS: Method A, 1.88 min, MS: ES + 454.2; 1¹H NMR (500MHz, DMSO) δppm: 10.65 (s, 1H), 8.75~8.71 (m, 1H), 8.47 (d, J=8.6Hz, 1H), 8.43~8.38 (m, 1H), 8.09~8.01 (m, 2H), 7.82 (dd, J=12.5, 2.0Hz, 1H), 7.71 (t, J=7.8Hz, 1H), 7.62 (dd, J=8.4, 2.0Hz, 1H), 7.48 (t, J=8.4Hz, 1H), 7.42~7.35 (m, 4H), 7.35~7.27 (m, 1H), 4.58~4.55 (m, 4H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 53]

[0808] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)-2-fluorophenyl)benzamide [ka] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)-2-fluorophenyl)benzamide [ka]

[0809] In Example 49, following the procedure of Step 2, 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-17) was used instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-17), and 5-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1) was used instead of 6-bromo-5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1), resulting in 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)-2-fluorophenyl)benzamide in 18% yield. LCMS: Method A, 1.78 min, MS: ES + 454.2; 1H NMR (500MHz, DMSO) δppm: 10.35 (s, 1H), 8.79 (s, 1H), 8.59 (d, J=8.6Hz, 1H), 8.43 (d, J=8.0Hz, 1H), 8.22 (d, J=8.7Hz, 1H), 8.10 (d, J=7.8Hz, 1H), 7.73 (t, J=7.7Hz, 1H), 7.63 (t, J=8.0Hz, 1H), 7.45~7.28 (m, 6H), 7.25 (d, J=8.4Hz, 1H), 4.58 (s, 4H). 1H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 54]

[0810] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-4-fluorobenzamide [ka] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-4-fluorobenzamide [ka]

[0811] In Example 49, following the procedure of Step 2, (5-((4-((benzyloxymethyl)phenyl)-carbamoyl)-2-fluorophenyl)boronic acid (I-19) was used instead 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) was used instead of 6-bromo-5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1), resulting in 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxymethyl)phenyl)-4-fluorobenzamide being obtained in 33% yield. LCMS: Method A, 1.82 min, MS: ES + 454.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.46 (s, 1H), 8.59 (dd, J=7.5, 2.5Hz, 2H), 8.20~8.12 (m, 1H), 7.96 (d, J=8.6Hz, 1H), 7.79 (d, J=8.4Hz, 2H), 7.59 (dd, J=10.8, 8.6Hz, 1H), 7.45~7.33 (m, 6H), 7.35~7.25 (m, 1H), 4.54 (s, 2H), 4.52 (s, 2H). 1H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 55]

[0812] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide [ka] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide [ka]

[0813] Example 49 Following the procedure of Step 2, replace N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide with (3-((4-((benzyloxymethyl)phenyl)-carbamoyl)-2-fluorophenyl)boronic acid (I-20) and 6-bromo-5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine Alternatively, 3-(3H-[1,2,3]triazolo[4,5-b]pyridine(I-1) was used, and purification by preparative HPLC (prep method A, x=20, y=50) instead of RP chromatography yielded 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide in 17% yield. LCMS: Method A, 1.78 min, MS: ES + 454.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.59 (s, 1H), 8.71~8.42 (m, 2H), 8.12~8.04 (m, 1H), 7.95 (s, 1H), 7.80 (t, J=6.7Hz, 1H), 7.74 (d, J=8.5Hz, 2H), 7.52 (t, J=7.6Hz, 1H), 7.40~7.33 (m, 5H), 7.33~7.26 (m, 1H), 4.53 (s, 2H), 4.52 (s, 2H). ¹H was unclear / not observed. [Example 56]

[0814] 5-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide [ka] 5-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide [ka]

[0815] Example 49 Following the procedure of Step 2, N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was replaced with N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21), and 6-bromo-5-methyl-1H-[1,2,3]triazolo By using 5-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (I-1) instead of [4,5-b]pyridine, and by purification by preparative HPLC (prep method A, x=20, y=50) instead of RP chromatography, 5-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide was obtained in 21% yield. LCMS: Method A, 1.84 min, MS: ES + 454.2; 1 H NMR(500MHz,DMSO)δppm:10.60(s,1H), 8.56(d,J=8.7Hz,1H), 8.50(dd,J=6.6,2.5Hz,1H), 8.46~8.37(m,1H), 8 .20(d,J=8.7Hz,1H), 7.76(d,J=8.2Hz,2H), 7.55(t,J=9.2Hz,1H), 7.42~7.27(m,8H), 4.54(s,2H), 4.52(s,2H). [Example 57]

[0816] N-(3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)phenyl)-4-phenethoxybenzamide [ka] N-(3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)phenyl)-4-phenethoxybenzamide [ka]

[0817] In Example 45, following the procedure of Step 1, N-(3-(3H-[1,2,3]triazolo[4,5-b]pyridine (I-1) was used instead of 2-chloro-6-methylpyrimidine-4,5-diamine, and N-(3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)phenyl)-4-phenethoxybenzamide was obtained in 13% yield by chromatography (silica gel, 0-10% in DCM (1% AcOH in MeOH)) and RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution). LCMS: Method B, 1.27 min, MS: ES + 436.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.28 (s, 1H), 8.65 (s, 1H), 8.50 (d, J=8.7Hz, 1H), 8.05~7.97 (m, 3H), 7.97~7.91 (m, 1H), 7.91~7.86 (m, 1H), 7.51 (t, J=8.0Hz, 1H), 7.39~7.30 (m, 4H), 7.28~7.21 (m, 1H), 7.12~7.07 (m, 2H), 4.31 (t, J=6.9Hz, 2H), 3.09 (t, J=6.9Hz, 2H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 58]

[0818] N-(3-(1H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)phenyl)-4-phenethoxybenzamide [ka] N-(3-(1H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)phenyl)-4-phenethoxybenzamide [ka]

[0819] In Example 45, following the procedure of Step 1, N-(3-(1H-[1,2,3]triazolo[4,5-b]pyridine (I-16) was used instead of 2-chloro-6-methylpyrimidine-4,5-diamine, and N-(3-(1H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)phenyl)-4-phenethoxybenzamide was obtained in 22% yield by RP chromatography (C18, 0.1% HCO2H aqueous solution, 0-100% MeCN) and RP chromatography (C18, 0.1% NH4OH aqueous solution, 0-100% MeCN). LCMS: Method B, 1.26 min, MS: ES + 436.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.23 (s, 1H), 8.95 (d, J=2.0Hz, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 8.00 (d, J=8.6Hz, 2H), 7.90 (d, J=7.8Hz, 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=8.7Hz, 2H), 4.31 (t, J=6.9Hz, 2H), 3.09 (t, J=6.8Hz, 2H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 59]

[0820] 3-(1H-benzo[d][1,2,3]triazole-5-yl)-N-(6-phenethoxypyridine-3-yl)benzamide [ka] 3-(1H-benzo[d][1,2,3]triazole-5-yl)-N-(6-phenethoxypyridine-3-yl)benzamide [ka]

[0821] Example 45 Following the procedure of Step 1, 5-bromo-1H-benzotriazole (CAS 32046-62-1, BLD) was used instead of 2-chloro-6-methylpyrimidine-4,5-diamine, and N-(6-phenethoxypyridine-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6) was used instead. Using 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-15), 3-(1H-benzo[d][1,2,3]triazole-5-yl)-N-(6-phenethoxypyridine-3-yl)benzamide was obtained in 11% yield by filtration at 90°C for 18 hours and purification by RP chromatography (C18, 0-100% MeCN in 0.1% HCO2H aqueous solution). LCMS: Method A, 1.84 min, MS: ES + 436.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.40 (s, 1H), 8.53 (d, J=2.7Hz, 1H), 8.34 (d, J=2.2Hz, 1H), 8.27 (s, 1H), 8.09~7.94 (m, 4H), 7.88~7.81 (m, 1H), 7.66 (t, J=7.7Hz, 1H), 7.32 (d, J=4.3Hz, 4H), 7.23 (h, J=4.1Hz, 1H), 6.84 (d, J=8.9Hz, 1H), 4.46 (t, J=6.9Hz, 2H), 3.04 (t, J=6.9Hz, 2H). 1H was unclear / not observed. [Example 60]

[0822] 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-amino-N-(4-phenethoxyphenyl)benzamide [ka]

[0823] Step 1: Lithium 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-nitrobenzoate [ka]

[0824] Methyl 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitrobenzoate (I-13, 506 mg, 1.52 mmol) was added to THF (8 mL) with aqueous LiOH (1 M, 3.04 mL, 3.04 mmol) and MeOH (0.1 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to obtain lithium 3-(3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitrobenzoate, which was used in the next step without purification (assuming 1.52 mmol). LCMS: Method Q, 0.82 min, MS: ES + 286.0.

[0825] Step 2: 3-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-5-nitro-N-(4-phenethoxyphenyl)benzamide [ka]

[0826] 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) were mixed with DIPEA (1.06 mL, 6.08 mmol) and HATU (751 mg, 1.98 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (150 mL), and the solid was recovered by filtration to obtain 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitro-N-(4-phenethoxyphenyl)benzamide (596 mg, 64% in two steps). LCMS: Method Q, 1.09 min, MS: ES + 481.0.

[0827] Step 5: 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-amino-N-(4-phenethoxyphenyl)benzamide (Example 60) [ka]

[0828] 3-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-5-nitro-N-(4-phenethoxyphenyl)benzamide (100 mg, 0.083 mmol) was mixed with NH4Cl (22 mg, 0.42 mmol) and zinc (27 mg, 0.42 mmol) in THF (2.5 mL) and water (0.5 mL). The mixture was stirred at room temperature for 18 hours, and 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) to obtain 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; 1 ¹H NMR (500MHz, MeOD) δppm: 8.28 (d, J=8.6Hz, 1H), 7.89 (s, 1H), 7.77 (d, J=8.7Hz, 1H), 7.65~7.57 (m, 3H), 7.34~7.24 (m, 5H), 7.24~7.18 (m, 1H), 6.93 (d, J=8.8Hz, 2H), 4.21 (t, J=6.9Hz, 2H), 3.08 (t, J=6.9Hz, 2H). 4H was unclear / not observed. [Example 61]

[0829] 6-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-phenethoxyphenyl)picolinamide [ka]

[0830] 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), 6-bromo-N-(4-phenethoxyphenyl)picolinamide (I-28, 0.14 g, 0.34 mmol) in dioxane (2 mL) was added. The mixture was sparged with nitrogen, and bis[tris(tert-butyl)phosphine]palladium (17 mg, 0.03 mmol) was added. The mixture was irradiated with microwaves at 150 °C for 3 hours. The procedure was repeated using 5-(trimethylstannyl)-1H-[1,2,3]triazolo[4,5-b]pyridine in dioxane (0.6 mL, 0.14 mmol). KF (20 mg, 0.34 mmol) was added to the combined mixture and stirred for 30 minutes. The mixture was filtered, concentrated, and purified twice by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution) to obtain 6-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-phenethoxyphenyl)picolineamide (21 mg, 10%). LCMS: Method A: 1.92 min, MS: ES + 437.2; 1 ¹H NMR (400MHz, DMSO) δppm: 10.55 (s, 1H), 9.15~8.98 (m, 1H), 8.72 (dd, J=7.1, 1.9Hz, 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=9.1Hz, 2H), 4.21 (t, J=6.8Hz, 2H), 3.05 (t, J=6.9Hz, 2H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 62]

[0831] 4-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-phenethoxyphenyl)picolinamide [ka]

[0832] Following the procedure of Example 61, 4-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-phenethoxyphenyl)picolinamide was obtained in 7% yield by using 4-bromo-N-(4-phenethoxyphenyl)picolinamide (I-29) instead of 6-bromo-N-(4-phenethoxyphenyl)picolinamide (I-28). LCMS: Method A: 1.83 min, MS: ES + 437.2; 1 ¹H NMR (400MHz, DMSO, 90℃) δppm: 10.28 (s, 1H), 8.70 (dd, J=7.2, 1.9Hz, 1H), 8.53 (d, J=8.5Hz, 1H), 8.24 (d, J=8.4Hz, 1H), 8.17~8.06 (m, 2H), 7.78 (d, J=9.0Hz, 2H), 7.46~7.26 (m, 4H), 7.26~7.16 (m, 1H), 6.99 (d, J=9.0Hz, 2H), 4.40~4.15 (m, 2H), 3.07 (t, J=6.8Hz, 2H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 63]

[0833] 2-(1H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-phenethoxyphenyl)isonicotinamide [ka]

[0834] Following the procedure of Example 61, 2-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(4-phenethoxyphenyl)isonicotinamide was obtained in 0.2% yield by using 2-bromo-N-(4-phenethoxyphenyl)isonicotinamide (I-30) instead of 6-bromo-N-(4-phenethoxyphenyl)picolinamide (I-28), and by additional purification by preparative HPLC (prep method A, x=30, y=60). LCMS: Method A: 1.81 min, MS: ES 437.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.62 (s, 1H), 8.95 (s, 1H), 8.80 (d, J=4.9Hz, 1H), 8.13 (q, J=8.3Hz, 2H), 7.79 (d, J=5.4Hz, 1H), 7.73 (d, J=8.7Hz, 2H), 7.45~7.29 (m, 4H), 7.24 (s, 1H), 6.98 (d, J=8.7Hz, 2H), 4.21 (t, J=6.9Hz, 2H), 3.05 (t, J=6.8Hz, 2H). ¹H was unclear / not observed. [Example 64]

[0835] 2-(3H-[1,2,3]triazolo[4,5-c]pyridine-6-yl)-N-(4-phenethoxyphenyl)isonicotinamide [ka]

[0836] 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, and 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 hours and at 140 °C for 18 hours. KF (20 mg, 0.347 μmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was purified by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution) and then by preparative HPLC (prep method C, x=7.5, y=37.5) to obtain 2-(3H-[1,2,3]triazolo[4,5-c]pyridine-6-yl)-N-(4-phenethoxyphenyl)isonicotinamide in 2% yield. LCMS: Method A: 1.63 min, MS: ES 437.1; 1¹H NMR (500MHz, acetone) δppm: 9.92 (s, 1H), 9.20 (s, 1H), 8.96 (s, 1H), 8.84 (s, 1H), 8.76 (d, J=4.8Hz, 1H), 7.86~7.77 (m, 2H), 7.74 (d, J=4.9Hz, 1H), 7.41~7.35 (m, 2H), 7.34~7.29 (m, 2H), 7.26~7.20 (m, 1H), 6.97 (d, J=9.0Hz, 2H), 4.24 (t, J=6.9Hz, 2H), 3.10 (t, J=6.9Hz, 2H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia.

[0837] General procedure (Suzuki coupling) Examples 49 and 65-99 were obtained by substituting 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) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-6) using appropriate starting materials, with MeCN or dioxane, and with any of the minor modifications noted below: [ka] [Example 65]

[0838] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2,6-difluorobenzamide [ka]

[0839] Using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid (I-31), and purified by preparative HPLC (prep method A, x=20, y=50) instead of RP chromatography, 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2,6-difluorobenzamide was obtained in 10% yield. LCMS: Method A: 1.82 min, MS: ES + 472.1; 1 ¹H NMR (500MHz, DMSO) δppm: 10.94 (s, 1H), 8.58 (s, 1H), 8.20~8.07 (m, 1H), 7.90 (d, J=8.6Hz, 1H), 7.71 (d, J=8.4Hz, 2H), 7.47 (t, J=8.6Hz, 1H), 7.41~7.33 (m, 6H), 7.33~7.27 (m, 1H), 4.53 (s, 2H), 4.52 (s, 2H). ¹H was unclear / not observed. [Example 66]

[0840] 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-methoxybenzamide [ka]

[0841] Using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-methoxyphenyl)boronic acid (I-32), and purified by preparative HPLC (prep method A, x=20, y=50) instead of RP chromatography, 3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-methoxybenzamide was obtained in 8% yield. LCMS: Method A: 1.8 min, MS: ES + 466.2; 1¹H NMR (500MHz, DMSO) δppm: 10.46 (s, 1H), 8.59~8.46 (m, 1H), 7.94 (d, J=8.6Hz, 1H), 7.87 (d, J=7.6Hz, 1H), 7.76 (d, J=8.2Hz, 2H), 7.67 (d, J=9.7Hz, 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). ¹H was unclear / not observed. [Example 67]

[0842] 5-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-methoxybenzamide [ka]

[0843] Using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid (I-33), 5-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-methoxybenzamide was obtained in 9% yield. LCMS: Method A: 1.82 min, MS: ES + 466.2; 1 ¹H NMR (500MHz, DMSO) δppm: 10.27 (s, 1H), 8.70~8.54 (m, 1H), 8.48 (s, 1H), 8.37 (d, J=8.5Hz, 1H), 8.26~8.04 (m, 1H), 7.77 (d, J=8.1Hz, 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). 1H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 68]

[0844] 5-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-methylbenzamide [ka]

[0845] Using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid (I-34), and purified by preparative HPLC (prep method A, x=20, y=50) instead of RP chromatography, 5-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-methylbenzamide was obtained in 6% yield. LCMS: Method A: 1.83 min, MS: ES + 450.2; 1 1H NMR (500MHz, DMSO) δppm: 10.50 (s, 1H), 8.63 (d, J=8.6Hz, 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=8.0Hz, 2H), 7.51 (d, J=8.1Hz, 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). 1H was unclear / not observed. [Example 69]

[0846] (Z)-3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-styrylphenyl)benzamide [ka]

[0847] (Z)-N-(4-styrylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-35) was used, and (Z)-3-(3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)-N-(4-styrylphenyl)benzamide was obtained in 11% yield by preparative HPLC (prep method A, x=20, y=50) instead of RP chromatography. LCMS:...

Claims

1. Compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof 【Chemistry 1】 [In the formula: Ring A is a phenyl group or a five-membered or six-membered heteroaryl group; Ring B is absent or selected from phenyl, pyridinyl, pyrazidinel, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, isothiazolyl and thiazolyl; Ring C is given by the formula: 【Chemistry 2】 It is a condensed bicyclic group, In the formula, X １ to X ９ form a heteroaryl group containing at least one N and at least one NH, and the heteroaryl group is alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, NR １０ SO ２ -R １２ NR １１ COR １３ NR １４ R １５ CO ２ R １６ SO ２ NR １７ R １８ CONR １９ R ２０ cycloalkyl and (CH ２ ) ｑ -heterocycloalkyl may each be further substituted by one or more substituents independently selected therefrom; X - Y is - (CH ２ ) ｍ NR ２１ CO is; L is a direct bond, or -O-CO-, -CO-O-, -O-CO-O-, -SO ２ -, -O-SO ２ -, -SO ２ -O-, -O-, -NR ２２ -SO ２ -, -NR ２２ -SO ２ -Alkylene, Alkylene-SO ２ -NR ２２ -, -SO ２ -NR ２２ -, -SO ２ -NR ２２ -Alkylene, Alkylene-NR ２２ -SO ２ -, alkylene, alkenylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-bu ２ -, -SO ２ -alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO ２ -alkylene, alkylene-bu-alkylene, -O-cycloalkylene, cycloalkylene-O-, -O-heterocycloalkylene, heterocycloalkylene-O-, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, -CO-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO-, CO ２ -heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO ２ -, -CO ２ - Heteroalkylene, Heteroalkylene-CO ２ - A group selected from heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, wherein the alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene portions of each of the above groups may be substituted with one or more substituents independently selected from halo, alkyl, haloalkyl, and cycloalkyl; Z is a group selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups, each of which may be further substituted with one or more groups independently selected from CN, halo, alkyl, OH, alkenyl, alkynyl, alkoxy, haloalkyl, and haloalkoxy groups; Each R ａ and each R ｂ Alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR ２３ COR ２５ , NR ２４ -SO ２ R ２６ , (CH ２ ) ｑ SR ２７ , (CH ２ ) ｑ SOR ２８ , (CH ２ ) ｑ SO ２ R ２９ SO ２ NR ３０ R ３１ , (CH ２ ) ｑ OH, (CH ２ ) ｑ OR ３２ , NR ３３ R ３４ CONR ３５ R ３６ , cycloalkyl and (CH ２ ) ｑ - Selected independently from heterocycloalkyl groups; R １０ , R １１ , R ２１ , R ２２ , R ２３ and R ２４ is independently selected from H and alkyl; R １２ ~R ２０ , and R ２５ ~R ３６ Each of these is independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, and cycloalkyl; m, n, and p are each independent integers between 0 and 4; Each q is an independent integer between 0 and 4.

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

3. Ring A is: 【Transformation 3】 (wherein ring A is a phenyl group or a six-membered heteroaryl group; B, C, Z, L, X, Y, R ａ , R ｂ (where n and p are as defined in claim 1) The compound according to claim 1 or 2.

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

5. The compound according to any one of claims 1 to 4, wherein n is 0.

6. B is selected from phenyl and pyridinyl, more preferably phenyl, and 1 to 4 R as defined in claim 1. ｂ The compound according to any one of claims 1 to 5, which may be substituted with a group.

7. The compound according to any one of claims 1 to 6, wherein B is a phenyl group and may be substituted with one or two groups selected from halo and alkoxy groups.

8. A compound according to any one of claims 1 to 7, wherein p is 0.

9. X in ring C １ , X ３ and X ７ are all sp ２ carbon atoms, the compound according to any one of claims 1 to 8.

10. Ring C has a C-1 group: 【Chemistry 4】 (In the formula: X ２ is N or CR ２ And; X ４ is NH; X ５ and X ６ are both N; or X ５ is N and X ６ is CR ６ ; or X ５ is CR ５ and X ６ is N; X ８ is N or CR ８ And; X ９ is N or CR ９ And; R ２ , R ５ , R ６ , R ８ and R ９ H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR １４ R １５ OH, NR １０ SO ２ - Alkyl, CONR １９ R ２０ , cycloalkyl and (CH ２ ) ｑ (Each element is independently selected from heterocycloalkyl groups.) The compound according to any one of claims 1 to 9.

11. X ５ and X ６ The compound according to claim 10, wherein both are N.

12. The ring C is a C-1a group, 【Transformation 5】 In the formula, R ８ and R ９ H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR １４ R １５ OH, NR １０ SO ２ - Alkyl, CONR １９ R ２０ , cycloalkyl and (CH ２ ) ｑ - A compound according to any one of claims 1 to 11, independently selected from heterocycloalkyl groups.

13. The ring C is a C-1b group, 【Transformation 6】 During the ceremony, R ９ H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR １４ R １５ OH, NR １０ SO ２ - Alkyl, CONR １９ R ２０ , cycloalkyl and (CH ２ ) ｑ - A compound according to claim 10, selected from heterocycloalkyl groups.

14. The ring C is a C-1c group, 【Transformation 7】 During the ceremony, R ８ H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR １４ R １５ OH, NR １０ SO ２ - Alkyl, CONR １９ R ２０ , cycloalkyl and (CH ２ ) ｑ - A compound according to claim 10, selected from heterocycloalkyl groups.

15. The ring C is a C-1d group, 【Transformation 8】 During the ceremony, R ２ and R ９ H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR １４ R １５ OH, NR １０ SO ２ - Alkyl, CONR １９ R ２０ , cycloalkyl and (CH ２ ) ｑ - Each is independently selected from heterocycloalkyls, preferably R ２ and R ９ The compound according to claim 10, wherein H and alkyl are independently selected.

16. The ring C is a C-1e group, 【Chemistry 9】 During the ceremony, R ２ , R ８ and R ９ H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR １４ R １５ OH, NR １０ SO ２ - Alkyl, CONR １９ R ２０ , cycloalkyl and (CH ２ ) ｑ - Each is independently selected from heterocycloalkyls, preferably R ２ , R ８ and R ９ The compound according to claim 10, wherein each of is independently selected from H, alkyl, and halo.

17. Ring C is as follows: 【Chemistry 10】 A compound according to any one of claims 1 to 16, wherein the group is selected from the following.

18. Z is C １－６ - Alkyl, phenyl, heteroaryl, C ３－６ - A compound according to any one of claims 1 to 17, wherein the group is selected from cycloalkyl and 4-membered, 5-membered, or 6-membered heterocycloalkyl groups, each of which may be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, haloalkyl, and alkoxy.

19. The compound according to any one of claims 1 to 18, wherein Z is a group selected from phenyl, alkyl, tolyl, morpholinyl, pyrazolyl, pyridinyl, oxetanyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, and tetrahydropyranyl, more preferably phenyl.

20. Lが、-O-CO-、-CO-O-、-O-CO-O-、-O-、-NH-SO ２ -、-NH-SO ２ -(CR’R”) ａ -、-(CR’R”) ａ -SO ２ -NH-、-SO ２ -NH-、-SO ２ -NH-(CR’R”) ａ -、-(CR’R”) ａ -NH-SO ２ -、-O-SO ２ -、-SO ２ -O-、-(CR’R”) ａ -、-(CH=CH) ｃ -、-(CR’R”) ａ -(CH=CH) ｃ -、-(CH=CH) ｃ -(CR’R”) ａ -、-(CR’R”) ａ -(CH=CH) ｃ -(CR’R”) ｂ -、-(CR’R”) ａ -O-、-O-(CR’R”) ａ -、-(CR’R”) ａ -O-(CR’R”) ｂ -、-(CR’R”) ａ -S-(CR’R”) ｂ -、-(CR’R”) ａ -SO ２ -、-SO ２ -(CR’R”) ｂ -、-(CR’R”) ａ -SO-、-SO-(CR’R”) ｂ -、-(CR’R”) ａ -SO-(CR’R”) ｂ -、-(CR’R”) ａ -SO ２ -(CR’R”) ｂ -、-(CR’R”) ａ -S-(CR’R”) ｂ -O-、-O-(CR’R”) ａ -S-(CR’R”) ｂ -、-(CR’R”) ａ -O-(CR’R”) ｂ -S-, -S-(CR'R") ａ -O-(CR'R") ｂ -, - (CR'R") ａ -S-, -S-(CR'R") ａ -, -O-(CR'R") ａ -O, heterocycloalkylene, cycloalkylene-O-, -O-cycloalkylene-, heterocycloalkylene-O-, -O-heterocycloalkylene-, heterocycloalkylene-(CR'R") ａ ,-(CR'R") ａ - Heterocycloalkylene -, Heterocycloalkylene - (CR'R'') ａ -O-, -O-(CR'R") ａ - Heterocycloalkylene -, - (CR'R'') ａ -O-heterocycloalkylene-, heterocycloalkylene-O-(CR'R'') ａ , -O-heterocycloalkylene-(CR'R'') ａ -,-CO-heterocycloalkylene-(CR'R'') ａ ,-(CR'R") ａ -heterocycloalkylene-CO-, -CO ２ - Heterocycloalkylene - (CR'R'') ａ ,-(CR'R") ａ - Heterocycloalkylene - CO ２ - and - (CR'R") ａ A compound according to any one of claims 1 to 19, selected from -heterocycloalkylene-O-, wherein a and b are each independently integers from 1 to 6, c is an integer from 1 to 3, and R' and R'' are each independently selected from H, alkyl, halo, and haloalkyl.

21. Lが、-O-、-O-CO-、-CO-O-、-O-CO-O-、-CH ２ -CH ２ CH ２ -CH ２ CH ２ CH ２ -CH ２ OCH ２ -CH ２ O-OCH ２ -CH ２ CH ２ O-OCH ２ CH ２ -CH ２ CH ２ S-,-SCH ２ CH ２ -CH ２ CH ２ CH ２ O-OCH ２ CH ２ CH ２ -、-OCH ２ CH ２ CH ２ O-CH ２ SO ２ CH ２ -CH ２ SOCHISM ２ -CH ２ SCH ２ -、-NH-SO ２ -、-NH-SO ２ -CH ２ -CH ２ -SO ２ -NHH-、-O-SO ２ -SO ２ -O-、-SO ２ -NHH-、-SO ２ -NH-CH ２ -CH ２ -NH-SO ２ -SO ２ -NH-CH ２ CH ２ -CH ２ CH ２ -NH-SO ２ -CH ２ CH ２ CH ２ CH ２ O-、-OCH ２ CH ２ CH ２ CH ２ -、-CH ２ SO ２ -、-S ２ CH ２ -、-OCH ２ -----EH ２ O-、-EH ２ SO-、-SOCH ２ -、-CH ２ OCH ２ ,-OCH ２ SCH ２ - 、 -CH ２ SCH ２ O-、-CH=E-、OCH ２ CO ２ -、-CC ２ CH ２ O-、-OCH(Me)-、-CH(Me)O-、-OCH(F ３ )-、-EH(EF ３ )O-、-EH ２ CH(CF) ３ )-、-EH(EF ３ )CH ２ -、-S ２ N(Me)-、-N(Me)SO ２ -、 【Chemistry 11】 【change】 A compound according to any one of claims 1 to 20, selected from the above.

22. L-Z is -OCH ２ CH ２ CH ２ CH ２ Ph, -OCH ２ CH ２ CH ２ Ph, -OCH ２ CH ２ Ph, -OCH ２ Ph, -CH ２ CH ２ CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ Ph, -OCH ２ CH ２ -pyrazole, -CH ２ CH ２ Ph, -CH ２ Ph, -OCH ２ CH ２ CH(Me) ２ , -OCH ２ CH(Me) ２ , -OCOCH ２ CH(Me) ２ , -OCH(Me) ２ , -OCH ２ CO-O-CH(Me) ２ , -O(CO)OCH ２ CH(Me) ２ , -OSO ２ -(4-methylphenyl), -CH ２ SO ２ -(4-methylphenyl), -CH ２ CH ２ O-(4-methylphenyl),-CH ２ SO ２ CH ２ -Ph, OMe, Ph, OPh, OCF ３ , ｔ Bu, CF ３ , -OSO ２ Ph, -OCH ２ CH ２ CH ２ OPh, -OCH ２ -Cyclopropyl, -CH ２ O-cyclopropyl, -OCH ２ CH ２ CH ２ CH ３ ien-CH ２ OCH ２ Ph, -OCH ２ SCH ２ Ph, -CH ２ OCH ２ Ph, -CH ２ CH ２ - Cyclopentyl, CH ２ CH ２ -Cyclohexyl, -CH ２ CH ２ S-(4-chlorophenyl),-CH ２ -(2-fluorophenyl), -CH=CH-phenyl, -SO ２ -NH-CH ２ -phenyl, -SO ２ -NH-CH ２ -CH ２ -phenyl, -CH ２ OCH ２ -Cyclopropyl, -OCH(Me)-Cyclopropyl, -CH(Me)-O-Cyclopropyl, -OCH(CF ３ )-Cyclopropyl,-CH(CF ３ )-O-cyclopropyl, SO ２ Ph, -CH ２ -O-CH(CF ３ )-Ph, 【Chemistry 12】 A compound according to any one of claims 1 to 21, selected from the above.

23. L-Z is -OCH ２ CH ２ Ph, -OCH ２ CH ２ CH ２ CH ２ Ph or -CH ２ OCH ２ Ph, more comfortably - OCH ２ CH ２ A compound according to any one of claims 1 to 22, wherein the pH is [value missing].

24. below: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 The compound according to any one of claims 1 to 23, as well as selected from pharmaceutically acceptable salts and solvates thereof.

25. Compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof 【Chemistry 13】 [In the formula: Ring A is a phenyl group or a five-membered or six-membered heteroaryl group; Ring B is either absent or is a phenyl group or a five- or six-membered heteroaryl group; Ring C is given by the formula: 【Chemistry 14】 It is a condensed bicyclic group, In the formula, X １ ~X ９ It forms a heteroaryl group containing at least one N and at least one NH, and the heteroaryl group is alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, NR １０ SO ２ -R １２ , NR １１ COR １３ , NR １４ R １５ CO ２ R １６ SO ２ NR １７ R １８ CONR １９ R ２０ , cycloalkyl and (CH ２ ) ｑ - They may be further substituted with one or more substituents independently selected from heterocycloalkyl groups; X-Y is CONR ２１ - (CH ２ ) ｍ - and; L is a direct bond, or -O-CO-, -CO-O-, -O-CO-O-, -SO ２ -, -O-SO ２ -, -SO ２ -O-, -O-, -NR ２２ -SO ２ -, -NR ２２ -SO ２ -Alkylene, Alkylene-SO ２ -NR ２２ -, -SO ２ -NR ２２ -, -SO ２ -NR ２２ -Alkylene, Alkylene-NR ２２ -SO ２ -, alkylene, alkenylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-bu ２ -, -SO ２ -alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO ２ -alkylene, alkylene-bu-alkylene, -O-cycloalkylene, cycloalkylene-O-, -O-heterocycloalkylene, heterocycloalkylene-O-, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, -CO-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO-, CO ２ -heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO ２ -, -CO ２ - Heteroalkylene, Heteroalkylene-CO ２ - A group selected from heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, wherein the alkylene, heteroalkylene, cycloalkylene and / or heterocycloalkylene portion of the above group may be substituted with one or more substituents independently selected from halo, alkyl, haloalkyl and cycloalkyl; Z is a group selected from cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups, each of which may be further substituted with one or more groups independently selected from CN, halo, alkyl, OH, alkenyl, alkynyl, alkoxy, haloalkyl, and haloalkoxy groups; However, L cannot be directly bonded if Z is phenyl; Each R ａ and each R ｂ Alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR ２３ COR ２５ , NR ２４ -SO ２ R ２６ , (CH ２ ) ｑ SR ２７ , (CH ２ ) ｑ SOR ２８ , (CH ２ ) ｑ SO ２ R ２９ SO ２ NR ３０ R ３１ , (CH ２ ) ｑ OH, (CH ２ ) ｑ OR ３２ , NR ３３ R ３４ CONR ３５ R ３６ , cycloalkyl and (CH ２ ) ｑ - Selected independently from heterocycloalkyl groups; R １０ , R １１ , R ２１ , R ２２ , R ２３ and R ２４ is independently selected from H and alkyl; R １２ ~R ２０ , and R ２５ ~R ３６ Each of these is independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, and cycloalkyl; m, n, and p are each independent integers between 0 and 4; Each q is an independent integer between 0 and 4.

26. X-Y is -CONH-, -CONHCH ２ The compound according to claim 25, selected from - and -CON(Me)-, preferably selected from -CONH-.

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

28. Ring B is absent, or selected from phenyl, pyridinyl, pyrazidinel, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, isothiazolyl and thiazolyl, each of which has 1 to 4 R ｂ The compound according to any one of claims 25 to 27, which may be substituted with a group.

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

30. The 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. The 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. below: Table 2 The compound according to any one of claims 25 to 30, as well as selected from pharmaceutically acceptable salts and solvates thereof.

33. A pharmaceutical composition comprising a compound according to any one 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 pharmaceutical.

35. A compound according to any one of claims 1 to 32, or a pharmaceutical composition according to claim 33, for use in the treatment or prevention of a disorder selected from proliferative disorders, fibrotic disorders, gastrointestinal disorders, inflammatory disorders, immune disorders, and cardiovascular diseases.

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

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

38. The compound or pharmaceutical composition for use according to claim 35, wherein the disorder is selected from gastrointestinal disorders, particularly inflammatory bowel disease, ulcerative colitis, primary sclerosing cholangitis, and Crohn's disease.

39. The compound or pharmaceutical composition for use according to claim 35, wherein the disorder is a cardiovascular disease 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, and preferably the use comprises inhibiting GPR35 signaling.

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

42. A compound as defined in any of claims 1 to 32, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 33, for use in the treatment or prevention of GPR35-related diseases or disorders.

43. Use of a compound defined in any of claims 1 to 32, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment or prevention of a GPR35-related disease or disorder in a subject.

44. Use of a compound defined in any of claims 1 to 32, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment or prevention of a disorder selected from proliferative disorders, gastrointestinal disorders, inflammatory disorders, fibrotic disorders, immune disorders, and cardiovascular diseases.

Images