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 X is NH, Y is CO, and ring C is a 6-membered heteroaryl or aryl group, or a 6-membered partially or fully unsaturated heterocyclic group containing at least one N and optionally at least one CO group, wherein said aryl, heteroaryl, or heterocyclic group is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, NRSO2R 11 , NR9COR 12 , N.R. 13 R 14 , OH, CO2R 15 , SO2NR 16 R 17 ,CONR 18 R 19 , cycloalkyl and (CH2) q -heterocycloalkyl; Ring A is a phenyl group or a 6-membered heteroaryl group, or Ring A is a 5-membered heteroaryl group; in each case, the wavy lines indicate the points of attachment to Y and Ring C, respectively; Ring B is a phenyl group or a 6-membered heteroaryl group; R2 is (CR 33 R 34 ) m COOH; each R6 is alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, NR 10 COR 20 , N.R. 10 SO2R 21 , (CH2) q SR 22 , (CH2) q SOR 23 , (CH2) q SO2R 24 , SO2NR 25 R 26 , (CH2) q OH, (CH2) q OR 27 , N.R. 28 R 29 ,CONR 30 R 31 , cycloalkyl and (CH2) q-heterocycloalkyl; each R is independently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, NR 10 COR 20 , N.R. 10 SO2R 21 , (CH2) q SR 22 , (CH2) q SOR 23 , (CH2) q SO2R 24 , SO2NR 25 R 26 , (CH2) q OH, (CH2) q OR 27 , N.R. 28 R 29 ,CONR 30 R 31 , cycloalkyl and (CH2) q -heterocycloalkyl; R7 is selected from H and alkyl; each R9 is independently selected from H and alkyl; and each R 10 is independently selected from H and alkyl; R 11 ~R 31 are each independently selected from H, alkyl, haloalkyl, 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; L is a direct bond or -SO2-, -O-SO2-, -SO2-O-, -O-, -NR 32 -SO2-, -NR 32 -SO2-alkylene, -SO2-NR 32 -, -SO2-NR 32-a group selected from alkylene, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO2-alkylene, alkylene-SO-alkylene, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, cycloalkylene-heteroalkylene, wherein the alkylene moiety in the group is optionally substituted by one or more substituents selected from halo, alkyl, haloalkyl, and cycloalkyl; R 32 , R 33 and R 34 are each independently selected from H and alkyl; Z is a group selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, each of which is optionally further substituted by one or more groups selected from CN, halo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, and haloalkoxy. Further aspects of the present invention relate to pharmaceutical compositions comprising compounds of formula (I) and the use of said compounds in the treatment of various GPR35-related disorders. [Formula 1] JPEG2026503167000340.jpg121170

Description

[Technical Field]

[0001] The present invention relates to compounds capable of modulating GPR35 function, which have potential therapeutic applications in the treatment of a variety of disorders, including proliferative, immune and inflammatory disorders. [Background technology]

[0002] GPR35 is a class A, G protein-coupled receptor (Quon et al, ACS Pharmacology and Translational Science 3, 801-812 (2020); Kaya et al, Frontiers in Immunology 12: 717392 (2021)). The human gene can be expressed as three variants: variant 1 encodes a 309 amino acid polypeptide designated GPR35a (short form), while variants 2 and 3 encode a long form, GPR35b, with a 31 amino acid extension at the N-terminus. Although several ligands have been suggested as endogenous agonists for GPR35, the GPCR remains officially an orphan receptor (Wang et al, J Biol Chem 281, 22021-22028 (2006); Kapolka et al, PNAS 117, 13117-13126 (2020); Giovanni et al, Cell 185, 815-830.e19 (2022); Oka et al, Biochem & Biophys Res Comms 395, 232-237 (2010); Deng et al. Scientific Reports 2, Article number: 373 (2012); Maravillas-Montero et al, J Immunology 194, 29-33 (2015); Lee et al. Agricultural and Food Chem doi: 10.1021 / acs.jafc.2c01251. Online ahead of print (2022), Jenkins et al, Biochem J 432, 451-419 (2010), Yang et al, Pharmacology 86, 1-5. doi: 10.1159 / 000314164. Epub (2010)).Several synthetic and exogenous modulators have also been reported, including agonists (Taniguchi et al. FEBS Letters 580, 5003-5008 (2006), MacKenzie et al, Molecular Pharmacology 85, 91-104 (2014), Wei et al, J Med Chem 64, 2634-2647 (2021)) and antagonists (Abdalhameed et al. Bioorg Med Chem Lett 27, 612-615 (2017)). The synthetic chemical zaprinast (5-(2-propoxyphenyl)-1H-[1,2,3]triazolo-[4,5-d]pyrimidin-7(4H)-one) is currently the standard GPR35 agonist used as a reference compound (MacKenzie et al., Frontiers in Endocrinology (Lausanne) 2, 68, 1-10 (2011)). 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 (Quon et al., ACS Pharmacology and Translational Science 3, 801-812 (2020); Birring, SS et al. (2017) Lancet Respir. Med. 5 (10), 806-815).

[0003] Both isoforms of GPR35 exhibit similar pharmacology with respect to reported agonists (MacKenzie et al, Molecular Pharmacology 85, 91-104 (2014)) and do not have any known potential unique functions. GPR35 is primarily expressed throughout the epithelium of the gastrointestinal (GI) tract, including the stomach, gallbladder, duodenum, small intestine, and colon (https: / / www.ncbi.nlm.nih.gov / gene?Db=gene&Cmd=DetailsSearch&Term=2859, https: / / www.proteinatlas.org / ENSG00000178623-GPR35 / tissue), but expression is also prominent in certain macrophages and dendritic cells (Kaya et al, Frontiers in Immunology 12: 717392 (2021), MacKenzie et al, Frontiers in Endocrinology (Lausanne) 2, 68, 1-10 (2011)). These evidences suggest a possible link between GPR35 and a range of pathologies, including inflammation, asthma, cardiovascular disorders, and diabetes (MacKenzie et al., Frontiers in Endocrinology (Lausanne) 2, 68, 1-10 (2011)). Increased GPR35 expression is also associated with certain cancers (Okumura et al., Cancer Sci 95, 131-135 (2004)). High expression of GPR35 in gastric cancer is associated with a poorer prognosis for patients. In vitro, GPR35 expression was associated with increased gastric cancer cell viability and proliferation, and reduced apoptosis (Shu C. et al. (November 2022), Cell Death Disc, 444). siRNA knockdown of GPR35 in macrophages also reduced the M2 markers ARG1 and PPARG, suggesting a role for GPR35 in supporting the cancer-promoting macrophage M2 phenotype.

[0004] GPR35 signaling therefore represents an attractive route of therapeutic intervention for the treatment of a range of diseases. Accordingly, there is a continuing 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-patent document 4] Kapolka et al, PNAS 117, 13117-13126 (2020) [Non-Patent Document 5] Giovanni et al, Cell 185, 815-830.e19 (2022) [Non-patent document 6] Oka et al, Biochem & Biophys Res Comms 395, 232-237 (2010) [Non-Patent Document 7] Deng et al. Scientific Reports 2, Article number: 373 (2012) [Non-patent document 8] Maravillas-Montero et al, J Immunology 194, 29-33 (2015) [Non-Patent Document 9] Lee et al Agricultural and Food Chem doi: 10.1021 / acs.jafc.2c01251. Online ahead of print (2022)

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[0006] The present invention seeks to provide compounds capable of modulating GPR35, and as is evident from the above discussion, such compounds have potential therapeutic applications in the treatment of a variety of disorders, including proliferative and immune disorders, as well as inflammatory disorders. [Means for solving the problem]

[0007] A first aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: [ka] [X is NR 7 and Y is CO; Ring C is a 6-membered heteroaryl or aryl group, or a 6-membered partially or fully unsaturated heterocyclic group containing at least one N and optionally at least one CO group, wherein the aryl, heteroaryl, or heterocyclic group is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, NR9SO2R 11 , NR9COR 12 , N.R. 13 R 14 , OH, CO2R 15 , SO2NR 16 R 17 ,CONR 18 R 19, cycloalkyl and (CH2) q -optionally further substituted by one or more substituents selected from heterocycloalkyl; Ring A is a group: [ka] (wherein A is a phenyl group or a 6-membered heteroaryl group). and; Or ring A is a group: [ka] wherein A is a 5-membered heteroaryl group. and; In each case, the wavy lines indicate the points of attachment to Y and ring C, respectively; Ring B is a phenyl group or a 6-membered heteroaryl group; R2 is (CR 33 R 34 ) m COOH; Each R6 is alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, NR 10 COR 20 , N.R. 10 SO2R 21 , (CH2) q SR 22 , (CH2) q SOR 23 , (CH2) q SO2R 24 , SO2NR 25 R 26 , (CH2) q OH, (CH2) q OR 27 , N.R. 28 R 29 ,CONR 30 R 31 , cycloalkyl and (CH2) q -independently selected from heterocycloalkyl; Each R8 is alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, NR 10 COR 20 , N.R. 10-SO2R 21 , (CH2) q SR 22 , (CH2) q SOR 23 , (CH2) q SO2R 24 , SO2NR 25 R 26 , (CH2) q OH, (CH2) q OR 27 , N.R. 28 R 29 ,CONR 30 R 31 , cycloalkyl and (CH2) q -independently selected from heterocycloalkyl; R7 is selected from H and alkyl; each R9 is independently selected from H and alkyl; Each R 10 is independently selected from H and alkyl; R 11 ~R 31 are each independently selected from H, alkyl, haloalkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, and cycloalkyl; m, n, and p each independently represent an integer of 0 to 4; each q is independently an integer from 0 to 4; L is a direct bond, or -SO2-, -O-SO2-, -SO2-O-, -O-, -NR 32 -SO2-, -NR 32 -SO2-alkylene, -SO2-NR 32 -, -SO2-NR 32-a group selected from alkylene, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO2-alkylene, alkylene-SO-alkylene, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, cycloalkylene-heteroalkylene, wherein the alkylene moiety in the group is optionally substituted by one or more substituents selected from halo, alkyl, haloalkyl, and cycloalkyl; R 32 , R 33 and R 34 are each independently selected from H and alkyl; Z is a group selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, each of which may be further substituted with one or more groups selected from cyano, halo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, and haloalkoxy.

[0008] Advantageously, the presently claimed compounds are capable of modulating GPR35, thereby making them of therapeutic interest in the treatment of a variety of disorders, including oncology applications, inflammatory disorders and gastrointestinal disorders.

[0009] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound described above and a pharmaceutically acceptable diluent, excipient, or carrier.

[0010] Another aspect of the invention relates to a pharmaceutical composition as described above for use as a medicament.

[0011] Another aspect of the present invention relates to a compound as described above for use in the treatment or prevention of a disorder selected from a proliferative disorder, a gastrointestinal disorder, a fibrotic disorder, a cardiovascular disease, an immune disorder, and an inflammatory disorder.

[0012] Another aspect of the present invention relates to a pharmaceutical composition as described above for use in the treatment or prevention of a disorder selected from a proliferative disorder, a gastrointestinal disorder, a fibrotic disorder, a cardiovascular disease, an immune disorder and an inflammatory disorder.

[0013] Another aspect of the present invention relates to a method of treating a disorder, comprising administering to a subject a compound or pharmaceutical composition described above.

[0014] Another aspect of the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a GPR35-related disease or disorder.

[0015] Another aspect of the invention relates to the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament in the treatment or prevention of a GPR35-related disease or disorder in a subject.

[0016] Another aspect of the invention relates to the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment or prevention of a disorder selected from a proliferative disorder, a gastrointestinal disorder, an inflammatory disorder, a fibrotic disorder, an immune disorder and a cardiovascular disorder. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention relates to compounds capable of modulating GPR35.

[0018] "Alkyl" refers to a straight or branched chain alkyl radical, preferably C 1-20 Alkyl, more preferably C 1-12 Alkyl, more preferably C 1-10 Alkyl or C1-6 Alkyl is defined herein as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. More preferably, alkyl is C 1-3 It is alkyl.

[0019] "Cycloalkyl" refers to a cyclic alkyl ring, preferably C 3-7 -cycloalkyl, more preferably C 3-6 -cycloalkyl, as defined herein. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or fused bicyclic ring systems such as norbornane.

[0020] As used herein, the term "aryl" or "aromatic" refers to an optionally benzo-fused C 6-12 It refers to an aromatic group, for example, phenyl or naphthyl.

[0021] "Halogen" or "halo" is defined herein as chloro, fluoro, bromo, or iodo.

[0022] "Haloalkyl" is defined herein as a straight or branched alkyl radical as defined above, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, 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 haloalkyl. Preferred examples are CF3 and CHF2, with CF3 being particularly preferred.

[0023] "Alkoxy" is defined herein as an oxygen atom attached to an alkyl group as defined above. Preferably, the alkoxy group is C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-10 Alkoxy or C 1-6 Alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy. A particularly preferred example is methoxy (-OCH3).

[0024] "Haloalkoxy" is defined herein as an alkoxy group, as described above, substituted with one or more halogen atoms (which may be the same or different), such as fluorine, chlorine, bromine, and iodine. Preferably, the haloalkoxy group is C 1-20 Haloalkoxy, more preferably C 1-12 haloalkoxy, more preferably C 1-10 Haloalkoxy or C 1-6 A particularly preferred example is OCF3.

[0025] "Heteroaryl" is defined herein as a monocyclic aromatic ring containing one or more heteroatoms (which may be the same or different), such as oxygen, nitrogen, or sulfur. Examples of suitable 6-membered heteroaryl groups include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.

[0026] "Aralkyl" is defined herein as an alkyl group, as defined above, substituted by one or more aryl groups, as defined above.

[0027] "Heterocycloalkyl" refers to a cyclic aliphatic group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, which may be interrupted by one or more -(CO)- groups in the ring, and / or 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 preferably C 3-6 Alternatively, the heterocycloalkyl group is C 4-7 -heterocycloalkyl, more preferably C 4-6 -heterocycloalkyl. Preferred heterocycloalkyl groups include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, and azetidinyl. Preferably, the heterocycloalkyl group is monovalent. Preferably, the heterocycloalkyl group is monocyclic.

[0028] As used herein, the term "alkenyl" refers to both straight and branched carbon chains having at least one carbon-carbon double bond. In some embodiments, an alkenyl group is a C-C 12 In other embodiments, the alkenyl group can be C-C 10 In one embodiment of alkenyl, the number of double bonds is 1 to 3; in another embodiment of alkenyl, the number of double bonds is 1. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated, depending on the location of the alkenyl moiety on the molecule. 10 An "-alkenyl" group can contain more than one double bond in the chain.

[0029] As used herein, the term "alkynyl" refers to both straight and branched carbon chains having at least one carbon-carbon triple bond. In some embodiments, an alkynyl group is a C-C 12In other embodiments, the alkynyl group can be C-C 10 The alkynyl group includes a C2-C8 group, a C2-C6 group, or a C2-C4 alkynyl group. In one embodiment of alkynyl, the number of triple bonds is 1 to 3; in another embodiment of alkenyl, the number of triple bonds is 1. A particularly preferred alkynyl group is -C≡CH.

[0030] As used herein, the term "alkylene" refers to a linear or branched saturated divalent hydrocarbon radical. Preferably, an 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.

[0031] As used herein, the term "heteroalkylene" refers to a divalent alkylene having one or more carbon atoms replaced by sulfur, oxygen, or NR', where R' is H or alkyl. Preferably, the heteroalkylene group is a divalent alkylene having one or more carbon atoms replaced by oxygen or sulfur, more preferably oxygen.

[0032] As used herein, the term "cycloalkylene" refers to a divalent cyclic saturated hydrocarbon radical preferably containing from 3 to 10 carbon atoms.

[0033] As used herein, the term "heterocycloalkylene" refers to a divalent cycloalkylene group, as defined above, with one or more carbon atoms replaced by sulfur, oxygen, or NR', where R' is H or alkyl.

[0034] As used herein, preferably, alkyl is C 1- C6 alkyl and haloalkyl is C 1- C6 haloalkyl and haloalkoxy are C 1- C6 haloalkoxy, alkoxy is C 1- It is a C6 alkoxy.

[0035] Compounds according to the present invention The preferred definitions of the various groups apply to all formulas and subformulas described herein.

[0036] One aspect of the present invention relates to a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof: [ka] (I') XY is -CONR7- or -NR7CO-; Ring C is a 6-membered aryl or heteroaryl group, or a 6-membered partially or fully unsaturated heterocyclic group containing at least one N and optionally at least one CO group, wherein the aryl, heteroaryl, or heterocyclic group is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, NR9SO2-R 11 , NR9COR 12 , N.R. 13 R 14 , OH, CO2R 15 , SO2NR 16 R 17 ,CONR 18 R 19 , cycloalkyl and (CH2) q -optionally further substituted by one or more substituents selected from heterocycloalkyl; Ring A is a phenyl group or a 5- or 6-membered heteroaryl group; Ring B is a phenyl group or a 6-membered heteroaryl group; R2 is (CR 33 R 34 ) m COOH; Each R6 is alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, NR 10 COR 20 , N.R. 10 SO2R 21 , (CH2) q SR 22 , (CH2) q SOR23 , (CH2) q SO2R 24 , SO2NR 25 R 26 , (CH2) q OH, (CH2) q OR 27 , N.R. 28 R 29 ,CONR 30 R 31 , cycloalkyl and (CH2) q -independently selected from heterocycloalkyl; Each R8 is alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, NR 10 COR 20 , N.R. 10 -SO2R 21 , (CH2) q SR 22 , (CH2) q SOR 23 , (CH2) q SO2R 24 , SO2NR 25 R 26 , (CH2) q OH, (CH2) q OR 27 , N.R. 28 R 29 ,CONR 30 R 31 , cycloalkyl and (CH2) q -independently selected from heterocycloalkyl; R7 is selected from H and alkyl; each R9 is independently selected from H and alkyl; Each R 10 is independently selected from H and alkyl; R 11 -R 31 are each independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, and cycloalkyl; m, n, and p each independently represent an integer of 0 to 4; each q is independently an integer from 0 to 4; L is a direct bond, or -SO2-, -O-SO2-, -SO2-O-, -O-, -NR 32 -SO2-, -NR 32 -SO2-alkylene, -SO2-NR 32 -, -SO2-NR 32 -a group selected from alkylene, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO2-alkylene, alkylene-SO-alkylene, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, cycloalkylene-heteroalkylene, wherein the alkylene portion of the group is optionally substituted by one or more substituents selected from halo, alkyl, and cycloalkyl; R 32 , R 33 and R 34 are each independently selected from H and alkyl; Z is a group selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, each of which may be further substituted with one or more groups selected from CN, halo, alkyl, alkenyl, alkynyl, alkoxy, and haloalkoxy.

[0037] In one preferred embodiment, XY is —NH—CO—.

[0038] In one preferred embodiment, R 2 The group is in the meta position on the C ring relative to the point of attachment to the A ring.

[0039] In one preferred embodiment, R 2 is ortho to the point of attachment to the A ring.

[0040] In one preferred embodiment, R2 is in the para position relative to the point of attachment to the A ring.

[0041] In one preferred embodiment, ring A is: [ka] wherein A is a phenyl or a 6-membered heteroaryl group. and Z, L, B, X, Y, X1 to X5, R2, R6, R8, n, and p are as defined above.

[0042] In one preferred embodiment, A is selected from phenyl, pyridinyl, pyrimidinyl, and pyrazinyl, each of which is optionally substituted with 1 to 4 R6 groups.

[0043] In another preferred embodiment, ring A is: [ka] wherein A is a 5-membered heteroaryl group. and Z, L, B, X, Y, X1-X5, R2, R6, R8, n, and p are as defined above.

[0044] In one preferred embodiment, A is selected from pyrrolyl, thiazolyl, oxazolyl, furanyl, thienyl, and pyrazolyl, each of which is optionally substituted with 1 to 3 R6 groups.

[0045] In one preferred embodiment, the compound has formula (Ia): [ka] (Ia) and wherein X1, X2, X3, X4 and X5 form a 6-membered aryl or heteroaryl group containing at least one N, and the aryl or heteroaryl group is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR9SO2R 11 , NR9COR12 , N.R. 13 R 14 , OH, CO2R 15 , SO2NR 16 R 17 ,CONR 18 R 19 , cycloalkyl and (CH2) q -optionally further substituted by one or more substituents selected from heterocycloalkyl; A, B, Z, L, X, Y, R2, R6, R8, n and p are as defined above.

[0046] In one preferred embodiment, the compound of the invention is of formula (I), or a pharmaceutically acceptable salt or solvate thereof: [ka] (I) X is NR 7 and Y is CO; Ring C is a 6-membered aryl or heteroaryl group, or a 6-membered partially or fully unsaturated heterocyclic group containing at least one N and optionally at least one CO group, wherein the aryl, heteroaryl, or heterocyclic group is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, NR9SO2R 11 , NR9COR 12 , N.R. 13 R 14 , OH, CO2R 15 , SO2NR 16 R 17 ,CONR 18 R 19 , cycloalkyl and (CH2) q -optionally further substituted by one or more substituents selected from heterocycloalkyl; Ring A is a group: [ka] (wherein A is a phenyl group or a 6-membered heteroaryl group). and; Or ring A is a group: [ka] wherein A is a 5-membered heteroaryl group. and; In each case, the wavy lines indicate the points of attachment to Y and ring C, respectively; Ring B is a phenyl group or a 6-membered heteroaryl group; R2 is (CR 33 R 34 ) m COOH; Each R6 is alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, NR 10 COR 20 , N.R. 10 -SO2R 21 , (CH2) q SR 22 , (CH2) q SOR 23 , (CH2) q SO2R 24 , SO2NR 25 R 26 , (CH2) q OH, (CH2) q OR 27 , N.R. 28 R 29 ,CONR 30 R 31 , cycloalkyl and (CH2) q -independently selected from heterocycloalkyl; Each R8 is alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, NR 10 COR 20 , N.R. 10 -SO2R 21 , (CH2) q SR 22 , (CH2) q SOR 23 , (CH2) q SO2R 24 , SO2NR 25 R 26 , (CH2) q OH, (CH2) q OR 27 , N.R. 28 R29 ,CONR 30 R 31 , cycloalkyl and (CH2) q -independently selected from heterocycloalkyl; R7 is selected from H and alkyl; each R9 is independently selected from H and alkyl; Each R 10 is independently selected from H and alkyl; R 11 ~R 31 are each independently selected from H, alkyl, haloalkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, and cycloalkyl; m, n, and p each independently represent an integer of 0 to 4; each q is independently an integer from 0 to 4; L is a direct bond, or -SO2-, -O-SO2-, -SO2-O-, -O-, -NR 32 -SO2-, -NR 32 -SO2-alkylene, -SO2-NR 32 -, -SO2-NR 32 -a group selected from alkylene, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO2-alkylene, alkylene-SO-alkylene, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, cycloalkylene-heteroalkylene, wherein the alkylene moiety in the group is optionally substituted by one or more substituents selected from halo, alkyl, haloalkyl, and cycloalkyl; R 32 , R 33 and R 34 are each independently selected from H and alkyl; Z is a group selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, each of which may be further substituted with one or more groups selected from CN, halo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, and haloalkoxy.

[0047] In one preferred embodiment of the invention, R7 is H, i.e., the XY group is -NH-CO-, and the compound has the formula (I-1): [ka] and wherein ring A, ring B, ring C, L, Z, R2, R6, R8, n, and p are as defined above.

[0048] In one preferred embodiment, the compound has formula (Ie): [ka] (Ie) and wherein A is phenyl or a 6-membered heteroaryl group, and R2, R6, R8, ring B, ring C, X, Y, Z, L, n, and p are as defined above.

[0049] In a preferred embodiment of formula (Ie), A is selected from phenyl, pyridinyl, pyrimidinyl, pyrazidinyl, and pyrazinyl, each of which is optionally substituted by 1 to 4 R groups. Preferably, A is an optionally substituted phenyl group. In a preferred embodiment, A is an unsubstituted phenyl group, i.e., n is 0.

[0050] In one preferred embodiment, the compound of claim 1 has the formula (If): [ka] (If) and In the formula, A is a 5-membered heteroaryl group, and R2, R6, R8, ring B, ring C, X, Y, Z, L, n, and p are as defined above. Preferably, n is an integer of 0 to 3.

[0051] In one preferred embodiment of formula (If), A is selected from pyrrolyl, thiazolyl, oxazolyl, furanyl, thienyl, and pyrazolyl, each of which is optionally substituted with 1 to 3 R groups. Preferably, A is a thiazolyl group optionally substituted with 1 to 3 R groups.

[0052] In one preferred embodiment, the compound has formula (Ig): [ka] and wherein X1, X2, X3, X4, and X5 form a 6-membered heteroaryl group containing at least one N, or a 6-membered aryl group, and the aryl or heteroaryl group is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR9SO2R 11 , NR9COR 12 , N.R. 13 R 14 , OH, CO2R 15 , SO2NR 16 R 17 ,CONR 18 R 19 , cycloalkyl and (CH2) q -optionally further substituted by one or more substituents selected from heterocycloalkyl; A, B, Z, L, X, Y, R2, R6, R8, n and p are as defined above.

[0053] In one preferred embodiment, A is a phenyl group or a 6-membered heteroaryl group and the compound has the formula (Ig-1): [ka] (Ig-1) and In the formula, B, Z, L, X, Y, X1, X2, X3, X4, X5, R2, R6, R8, n and p are as defined above.

[0054] In another preferred embodiment, A is a 5-membered heteroaryl group and the compound has the formula (Ig-2): [ka] (Ig-2) and In the formula, B, Z, L, X, Y, X1, X2, X3, X4, X5, R2, R6, R8, n and p are as defined above.

[0055] In one preferred embodiment, each R6 is C 1-6 -Alkyl, Halo, C 1-6 -haloalkyl, C 1-6 -alkoxy, 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 -alkyl), cycloalkyl, heterocycloalkyl, and CH-heterocycloalkyl.

[0056] In one preferred embodiment, each R6 is C 1-6 -Alkyl, Halo, C 1-6 -haloalkyl, C 1-6 -alkoxy, 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, CON(C 1-6 -alkyl), cycloalkyl, heterocycloalkyl, and CH-heterocycloalkyl.

[0057] In one preferred embodiment, each R6 is C 1-6 -Alkyl, Halo, C 1-6 -haloalkyl, C 1-6 -alkoxy and C 1-6 -haloalkoxy.

[0058] In one preferred embodiment, each R6 is independently selected from Me, halo, CF3, OMe, OCF3, amino, cyano, NHCOMe, NHSO2Me, S-Me, CH2SO2Me, SO2Me, SO2NMe2, CH2OH, CHOMe, cycloalkyl, CH2-N-morpholinyl, and N-morpholinyl.

[0059] In one preferred embodiment, each R is C 1-6 -Alkyl, Halo, C 1-6 -haloalkyl, C 1-6 -alkoxy, 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 -alkyl), cycloalkyl, heterocycloalkyl, and CH-heterocycloalkyl.

[0060] In one preferred embodiment, each R is C 1-6 -Alkyl, Halo, C 1-6 -haloalkyl, C 1-6 -alkoxy and C 1-6 -haloalkoxy.

[0061] In one preferred embodiment, each R8 is independently selected from Me, halo, CF3, OMe, OCF3, amino, cyano, NHCOMe, NHSO2Me, S-Me, CH2SO2Me, SO2Me, SO2NMe2, CH2OH, CHOMe, cycloalkyl, CH2-N-morpholinyl, and N-morpholinyl.

[0062] In one preferred embodiment, R7, each R9 and each R 10 is H and C 1-6 alkyl. More preferably, R, each R and each R are independently selected from the group consisting of alkyl, aryl ... 10 are each independently selected from H and Me. More preferably, R7, each R9 and each R 10 are all H.

[0063] In a preferred embodiment, R7 is H, i.e., the XY group is -NH-C(=O)- in the general formulae and subformulae described herein, where NH is linked to the B ring and CO is linked to the A ring.

[0064] In one preferred embodiment, R 11 ~R 31 is H, C 1-6 -Alkyl, C 1-6 -Haloalkyl, aralkyl, C 1-6 -Alkoxy, Hydroxyl-C 1-6 -alkyl and C 3-6 -cycloalkyl, more preferably H and C 1-6 -alkyl.

[0065] In one preferred embodiment, R 11 ~R 31are each independently selected from H, Me, CF3, cyclopropyl, -CH2CH2OH and -CH2CH2Me, more preferably H and Me.

[0066] In one preferred embodiment, R 33 and R 34 are each independently selected from H and alkyl. Preferably, R 33 and R 34 are both H.

[0067] In one preferred embodiment, m is 0 or 1, i.e., R2 is CH2COOH or COOH. More preferably, m is 0, i.e., R2 is COOH.

[0068] In one preferred embodiment, the compound has formula (Ib): [ka] and During the ceremony: X1 is N or CR1; X3 is N or CR3; X4 is N or CR4; X5 is N or CR5; R1, R3, R4 and R5 are H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR 13 R 14 , OH, NR9SO2-alkyl, CONR 18 R 19 , cycloalkyl and (CH2) q -heterocycloalkyl; where R2, R6, R8, n, p, L, A, B, X, Y and Z are as defined above.

[0069] For each of the above subformulas for ring A, each R6 is C 1-6 -Alkyl, Halo, C 1-6 -haloalkyl, C 1-6 -alkoxy and C 1-6-haloalkoxy.

[0070] In one preferred embodiment, n is 0.

[0071] In one preferred embodiment, X1, X2, X3, X4 and X5 form a phenyl group or a 6-membered heteroaryl group containing at least one nitrogen.

[0072] In a preferred embodiment, X1, X2, X3, X4, and X5 form a 6-membered heteroaryl group containing one, two, or three nitrogen atoms. In a preferred embodiment, the 6-membered heteroaryl group contains one or two nitrogen atoms. In another preferred embodiment, the 6-membered heteroaryl group contains one nitrogen atom.

[0073] In one preferred embodiment, X1, X2, X3, X4 and X5 form a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyridazinyl group or a pyrazinyl group.

[0074] In one preferred embodiment, X1, X2, X3, X4 and X5 form a pyridinyl or pyrazinyl group.

[0075] In one preferred embodiment, A is a phenyl group or a 6-membered heteroaryl group.

[0076] In one preferred embodiment, the compound has formula (Ic): [ka] and During the ceremony: X1 is N or CR1; X3 is N or CR3; X4 is N or CR4; X5 is N or CR5; R1, R3, R4 and R5 are H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR 13 R 14, OH, NR9SO2-alkyl, CONR 18 R 19 , cycloalkyl and (CH2) q -heterocycloalkyl; A is a phenyl or pyridinyl group, more preferably phenyl; R2, R6, R8, n, p, L, B and Z are as defined above.

[0077] Preferably, q is 0 or 1, more preferably 0.

[0078] In a preferred embodiment, R1, R3, R4 and R5 are selected from the group consisting of 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 -heterocycloalkyl,

[0079] In a preferred embodiment, R3 is H, C 1-6 -Alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, C 1-6 -Haloalkoxy, F, Cl, NH2, NH-C 3-6 -cycloalkyl, NH-C 1-6 -Alkyl, N(C 1-6 -alkyl)2, NH-C 1-6 -alkoxy, NH-(hydroxy-C 1-6 -alkyl), OH, NHSO2-C1-6 -Alkyl, CO2C 1-6 -Alkyl, C 3-6 -cycloalkyl and C 3-6 -heterocycloalkyl; R1, R4 and R5 are H.

[0080] In one preferred embodiment, R1, R3, R4 and R5 are each independently selected from H, Me, MeO, CF3, Cl, F, NH2, NH-Me, NH-cyclopropyl, NMe2, OH, NHSO2Me, CONH2, cyclopropyl, NHCH2CH2OH, NHCH2CHOMe, CH2-N-morpholinyl and N-morpholinyl.

[0081] In one preferred embodiment, R3 is 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; R1, R4 and R5 are H.

[0082] In one preferred embodiment: R2 is COOH; X1 is CR1; X3 is CR3; X4 is N; X5 is CR5.

[0083] Preferably, for this embodiment, X1 and X5 are CH and X3 is CR3, where R3 is selected from H, Me, MeO, CF3, Cl, F, NH2, NH-Me, NH-cyclopropyl, NMe2, OH, NHSO2Me, CONH2, cyclopropyl, NHCH2CH2OH, NHCH2CHOMe, CH2-N-morpholinyl and N-morpholinyl.

[0084] In one preferred embodiment: R2 is COOH; X1 is N; X3 is CR3; X4 is CR4; X5 is CR5.

[0085] Preferably, for this embodiment, X4 and X5 are CH and X3 is CR3, where R3 is selected from H, Me, MeO, CF3, Cl, F, NH2, NH-Me, NH-cyclopropyl, NMe2, OH, NHSO2Me, CONH2, cyclopropyl, NHCH2CH2OH, NHCH2CHOMe, CH2-N-morpholinyl and N-morpholinyl.

[0086] In one preferred embodiment: R2 is COOH; X1 is N; X3 is CR3; X4 is N; X5 is CR5.

[0087] Preferably, for this embodiment, X5 is CH and X3 is CR3, where R3 is 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.

[0088] In one preferred embodiment: R2 is COOH; X1 is CH or N, more preferably CH; X3 is C-alkyl, preferably Me; X4 is N; X5 is CH.

[0089] In one preferred embodiment, ring C is: [ka] and wherein the wavy line indicates the point of attachment to ring A.

[0090] In one preferred embodiment, A is a 5-membered heteroaryl group and the compound has the formula (Ic'): [ka] (I C') and wherein X1, X3, X4, X5, R2, R6, R8, n, p, L, B and Z are as defined above for formula (Ic).

[0091] In one preferred embodiment, ring C is a partially or fully unsaturated 6-membered heterocyclic group containing at least one N and optionally containing at least one CO group.

[0092] In one preferred embodiment, the compound has formula (Id) [ka] (Id) and wherein X1 is N or CR1, and X5 is N or CR5, where R1, R2, R5, R6, R8, A, B, X, Y, L, Z, n, and p are as defined above, and R4' is selected from H, alkyl, and cycloalkyl. Preferably, X1 and X5 are both CH. Preferably, R4' is H.

[0093] Those skilled in the art will recognize that when R4' is H, compounds of formula (Id) can exist as one of two possible tautomers shown below. For example, when X1 is CR1 and X5 is CR5: [ka] is.

[0094] The 2-pyridone tautomer is believed to be the predominant solid-state form. In solution, the energy difference between the two tautomeric forms is understood to be very small and is dependent on the polarity of the solvent. Those skilled in the art will recognize that other hydroxy-substituted N-containing heteroaromatic groups (e.g., pyrimidine, other pyridine positional isomers) can be similarly represented in the tautomeric forms shown above. The present invention encompasses all tautomeric forms of the compound.

[0095] In one preferred embodiment, A is a phenyl group or a 6-membered heteroaryl group and the compound has the formula (Id-1): [ka] (Id-1) and In the formula, X1 is N or CR1, and X5 is N or CR5, where R1, R2, R4', R5, R6, R8, B, X, Y, L, Z, n, and p are as defined above.

[0096] In one preferred embodiment, A is a 5-membered heteroaryl group and the compound has the formula (Id-2): [ka] (Id-2) and In the formula, X1 is N or CR1, and X5 is N or CR5, where R1, R2, R4', R5, R6, R8, B, X, Y, L, Z, n, and p are as defined above.

[0097] For all of the above embodiments described herein, B is preferably a phenyl or pyridinyl group, each of which is optionally substituted by 1 to 4 R groups as defined above. Preferably, each R is selected from the group consisting of C 1-6 -Alkyl, Halo, C 1-6 -haloalkyl, C 1-6 -alkoxy and C 1-6 -haloalkoxy.

[0098] In one preferred embodiment, B is a phenyl group optionally substituted by one or two halo groups.

[0099] In one preferred embodiment, p is 0.

[0100] For all of the above embodiments described herein, Z is preferably C 1-6 -Alkyl, phenyl, C 3-6 -a group selected from cycloalkyl and 5- or 6-membered heterocycloalkyl groups, each of which may be further substituted with one or more groups selected from alkyl, CN, halo, haloalkyl, alkenyl, alkynyl, and alkoxy.

[0101] For all of the above embodiments described herein, Z is preferably C 1-6 -Alkyl, phenyl, C 3-6 - a group selected from cycloalkyl and 5- or 6-membered heterocycloalkyl groups, each of which may be further substituted by one or more groups selected from alkyl, alkenyl, alkynyl, and alkoxy.

[0102] In one preferred embodiment, Z is a group selected from phenyl, pyridinyl, cyclopropyl, piperidinyl and tetrahydropyranyl, more preferably phenyl, each of which may be further substituted by one or more groups selected from alkyl, cyano, halo, haloalkyl, alkenyl, alkynyl and alkoxy.

[0103] In one preferred embodiment, Z is a group selected from phenyl, cyclopropyl and tetrahydropyranyl, more preferably phenyl.

[0104] In the compounds described herein, L is a direct bond or is -SO2-, -O-SO2-, -SO2-O-, -O-, -NR32 -SO2-, -NR 32 -SO2-alkylene, -SO2-NR 32 -, -SO2-NR 32 -alkylene, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-alkylene, alkylene-SO-alkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, -SO-alkylene, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, cycloalkylene-heteroalkylene, wherein the alkylene moiety in the above group is optionally substituted by one or more substituents selected from halo, alkyl, haloalkyl and cycloalkyl.

[0105] As used herein, substitution of an alkylene moiety refers to one or both of the hydrogens of one or more -CH2- groups in the alkylene (or heteroalkylene) group being replaced by a substituent selected from halo, haloalkyl, alkyl, and cycloalkyl.

[0106] In a preferred embodiment, the heteroalkylene group is a divalent alkylene group having one or more carbon atoms replaced with heteroatoms independently selected from O and S. More preferably, the heteroalkylene group is a divalent alkylene group having one or more carbon atoms replaced with oxygen.

[0107] In the compounds described herein, L is a direct bond or is selected from the group consisting of -SO2-, -O-SO2-, -SO2-O-, -O-, and -NR2-. 32 -SO2-, -NR 32 -SO2-alkylene, -SO2-NR 32 -, -SO2-NR 32-alkylene, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-alkylene, alkylene-SO-alkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, -SO2-alkylene, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylenealkylene, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, cycloalkylene-heteroalkylene, wherein the alkylene moiety in the above group is optionally substituted by one or more substituents selected from halo, alkyl and cycloalkyl.

[0108] Preferably, R 32 is H or Me, more preferably H.

[0109] For all of the above embodiments, L is preferably -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 -,-(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-(CR'R") b -,-(CR'R") a -SO2-, -SO2-(CR'R") b -,-(CR'R") a -SO-, -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 -, 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 -and-(CR'R") a -heterocycloalkylene-O-, where a and b are each independently an integer from 1 to 6, and each R' and each R" is independently selected from H, alkyl, and haloalkyl.

[0110] In a preferred embodiment, a and b are each independently an integer of 1 to 3.

[0111] In one preferred embodiment, each R' and each R" is independently selected from H, Me, and CF3.

[0112] For all of the above embodiments, L is preferably -O-, -NH-SO2-, -NH-SO2-(CH2) a -, -SO2-NH-, -SO2-NH-(CH2) a -, -(CH2) a -NH-SO2-, -O-SO2-, -SO2-O-, -(CH2) a -, -(CH2) a -O-, O-(CH2) a -, -(CH2) a -O-(CH2) b -, -(CH2) a -S-(CH2) b -, -(CH2) a-SO-(CH2) b -, -(CH2) a -SO2-, -SO2-(CH2) b -, -(CH2) a -SO-, -SO-(CH2) b -, -(CH2) a -SO2-(CH2) b -, -(CH2) a -S-(CH2) b -O-, -O-(CH2) a -S-(CH2) b -, -(CH2) a -O-(CH2) b -S-, -S-(CH2) a -O-(CH2) b -, heterocycloalkylene-(CH2) a -O-, -O-(CH2) a -Heterocycloalkylene-, -(CH2) a -O-heterocycloalkylene, heterocycloalkylene-O-(CH2) a -, -O-heterocycloalkylene-(CH2) a - and -(CH2) a -heterocycloalkylene-O-, wherein a and b are each independently an integer from 1 to 6.

[0113] In a preferred embodiment, L is -O-, -NH-SO2-, -NH-SO2-(CH2) a -, -SO2-NH-, -SO2-NH-(CH2) a -, -O-SO2-, -SO2-O-, -(CH2) a -, -(CH2) a -O-, O-(CH2) a -, -(CH2) a -O-(CH2) b -, -(CH2) a -S-(CH2) b -, -(CH2) a -SO-(CH2) b -, -(CH2) a -SO2-, -SO2-(CH2) b -, -(CH2) a-SO-, -SO-(CH2) b -, -(CH2) a -SO2-(CH2) b -, -(CH2) a -S-(CH2) b -O-, -O-(CH2) a -S-(CH2) b -, -(CH2) a -O-(CH2) b -S-, -S-(CH2) a -O-(CH2) b -, heterocycloalkylene-(CH2) a -O-, -O-(CH2) a -Heterocycloalkylene-, -(CH2) a -O-heterocycloalkylene, heterocycloalkylene-O-(CH2) a -, -O-heterocycloalkylene-(CH2) a - and -(CH2) a -heterocycloalkylene-O-, wherein a and b are each independently an integer from 1 to 6.

[0114] 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 -O-heterocycloalkylene, wherein a and b are each independently an integer from 1 to 6.

[0115] In a preferred embodiment, L is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2O-, -OCH2CH2-, -CHO-, -OCH2-, -CH(Me)OCH2, -CHOCH(Me)-, -CH(CF3)OCH2-, -CHOCH(CF3)-, -NH-SO2-, -NH-SO2-CH2-, -CH2-SON2NH-, -SO2-NH-, -SO2-NH-CH2-, -CH2-NH-SO2-, -CH 2CH2CH2O-, -OCH2CH2CH2-, -CH2SO2CH2-, -CH2SO2-, -SO2CH2-, -CH2SO-, -SOCH2-, -CH2SOCH2-, -CH2SCH2-, -CH2CH2CH2CH2O-, -OCH2CH2CH2CH2-, -CH2OCH2, -CH(Me)O-, -OCH(Me)-, -CH(CF3)O-, -OCH(CF3)-, -CH2SCH2O- and -O-CH2SCH2-.

[0116] In one preferred embodiment, L is selected from -CH2-, -CH2CH2CH2-, -CH2CH2O-, -NH-SO2-, -NH-SO2-CH2-, -SO2-NH-, -SO2-NH-CH2-, -OCH2CH2-, -CH2CH2CH2O-, -OCH2CH2CH2-, -CH2SO2-, -SO2CH2-, -CH2SO2-, -SO2CH2-, -CH2SO-, -SOCH2-, -CH2SOCH2-, -CH2SCH2-, -CH2CH2CH2CH2O-, -OCH2CH2CH2CH2-, -CH2OCH2 and -CH2SCH2O-.

[0117] In a preferred embodiment, LZ is -OCH2CH2Ph, -OCH2Ph, -OCH2CH2CH(Me)2, -OCH2CH(Me)2, -OSO2-(4-methylphenyl), -CH2SO2CH2-Ph, -CH2SO2C-Ph, -OCH2-cyclopropyl, -OCH2CH2CH2CH3, -OCH2CH2CH2CH2Ph, -CH2OCH2Ph, -OCH2SCH2Ph, -CH2OCH2Ph, -CH2CH2Ph, -CH2SO2-(4-methylphenyl), -CH2SO2-(4-methoxyphenyl), -CH2SO2-(4-chlorophenyl), -CH 2SO2-(3-chlorophenyl), -CH2SO2-(2-chlorophenyl), -CHOCH(Me)-Ph, -CHOCH(CF3)-Ph, -CHOCH2-cyclopropyl, -CHO-cyclopropyl, -OCH(Me)-cyclopropyl, -CH(Me)O-cyclopropyl, -OCH(CF3)-cyclopropyl, -CH(CF3)O-cyclopropyl, CHOCH2-(pyridin-2-yl), -CHOCH2(4-methoxyphenyl), CHOCH2(3-methoxyphenyl), -CHSO2-(4-methylpyridin-3-yl)-chlorophenyl), [ka] is.

[0118] In one preferred embodiment, LZ is -OCH2CH2Ph, -OCH2Ph, -OCH2CH2CH(Me)2, -OCH2CH(Me)2, -OSO2-(4-methylphenyl), -CH2SO2CH2-Ph, -OCH2-cyclopropyl, -OCH2CH2CH2CH3, -CH2OCH2Ph, [ka] is.

[0119] In one highly preferred embodiment, LZ is -OCH2CH2Ph, -OCH2CH2CH2CH2Ph ​​or -CH2OCH2Ph. More preferably, LZ is -OCH2CH2Ph.

[0120] In one preferred embodiment, the compound is: [Table 1] JPEG2026503167000029.jpg248170 JPEG2026503167000030.jpg238170 JPEG2026503167000031.jpg235170 JPEG2026503167000032.jpg232170 JPEG2026503167000033.jpg50170 and pharmaceutically acceptable salts and solvates thereof.

[0121] In a preferred embodiment, the compound of formula (I) is selected from the following compounds shown herein: 1-20, 22, 24, 28, 30, 33-39, 48, 52, 53, 56-60, 63-65, 67-70, 74-77, 80, 81, 83, 85, 88-90, 92, and 96, and pharmaceutically acceptable salts and solvates thereof.

[0122] In another preferred embodiment, the compound of formula (I) is: [Table 2] JPEG2026503167000035.jpg246170 JPEG2026503167000036.jpg252170 JPEG2026503167000037.jpg250170 JPEG2026503167000038.jpg250170 JPEG2026503167000039.jpg16170 and pharmaceutically acceptable salts and solvates thereof.

[0123] method A further aspect of the present invention relates to methods for preparing the compounds defined herein.

[0124] In one embodiment, the method comprises reacting a dioxaborolane intermediate with a halo intermediate (preferably a bromo intermediate) as shown below to produce a compound of formula (I): [ka] The method includes forming a compound of the formula:

[0125] In an alternative embodiment, the method comprises reacting a dioxaborolane intermediate with a halo intermediate (preferably a bromo intermediate) as shown below to produce a compound of formula (I): [ka] The method includes forming a compound of the formula:

[0126] In another embodiment, XY is NH—CO and the method comprises converting an amine intermediate to a carboxylic acid as shown below: [ka] This includes coupling.

[0127] Further details of the synthetic methods are set forth in the accompanying Examples section.

[0128] therapeutic use A further aspect of the present invention relates to the compounds described herein for use in medicine. The compounds have particular uses in the fields of oncology, gastrointestinal disorders and inflammatory disorders, as described in more detail below. In a preferred embodiment, the compounds of the present invention modulate GPR35 function.

[0129] One aspect of the present invention therefore pertains to the compounds described herein for use as pharmaceuticals.

[0130] Preferably, the compounds of formula (I) are for use in the treatment or prevention of a disorder selected from a proliferative disorder, a fibrotic disorder, a gastrointestinal disorder, a cardiovascular disease, an immune disorder and an inflammatory disorder.

[0131] In a preferred embodiment, the compound has application in the field of oncology. For example, in a preferred embodiment, the compound is for use in the treatment of proliferative disorders, preferably cancer or leukemia. GPR35 expression is known to be associated with cancer. More specifically, GPR35 expression is typically upregulated in GI tract cancers relative to normal tissues (http: / / gepia.cancer-pku.cn / detail.php?gene=GPR35). GPR35 expression can transform NIH3T3 murine fibroblasts and is expressed in gastric cancer cells (Okumura et al., Cancer Sci 95, 131-135 (2004)). GPR35b is expressed by colon cancer cell lines and primary colon tumors, while involved patient lymph nodes can express high levels of GPR35b (Ali et al., Tumor Biology 41, 1-11 (2019)). High expression of GPR35b in 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 (Shu C. et al. (November 2022), Cell Death Disc, 444). Similarly, above-median expression of GPR35 in primary tumors was observed as a poor prognostic marker in men with colorectal cancer, while the opposite effect was reported in women (Mackiewicz et al., Pharmacological Rep doi: 10.1007 / s43440-022-00371-2. Online ahead of print (2022)). siRNA knockdown of GPR35 reduced the viability and proliferation of human gastric cancer cells but also reversed the tumor-promoting M2 macrophage phenotype (Shu C. et al. (November 2022), Cell Death Disc, 444).Murine Gpr35 has been shown to promote glycolysis, proliferation, and oncogenic signaling by engaging the sodium / potassium pump (Na / K-ATPase) (Schneditz et al., Sci Signal 12:eaau9408 (2019) doi: 10.1126 / scisignal.aau9048). Deletion of Gpr35 promoted Na / K-ATPase-mediated ion transport and reduced Src kinase activation and overall metabolic activity in both macrophages and intestinal epithelial cells. Gpr35 deletion or inhibition, along with specific anti-Gpr35 peptides (pepducins) (Olson et al., Front. Chem., 9 article 671483 (2021)), prevented inflammation-associated and spontaneous intestinal tumorigenesis in mice. Furthermore, activation of human GPR35 in human induced pluripotent stem cell (iPSC)-derived macrophages, via expression of the T108M upregulatory variant, has been shown to promote angiogenic tube formation by enhancing the release of pro-angiogenic factors (Olson et al, Front. Chem., 9 article 671483 (2021)). Finally, selective deletion of GPR35 in macrophages inhibits the expression of the inflammation-associated and mutant (hypoplasmic) tumor suppressor adenomatous polyposis coli (APC). min ), which profoundly reduced tumor growth in spontaneous tumor models.

[0132] In a preferred embodiment, the cancer is also selected from cancers of the gastrointestinal tract (e.g., colon, rectum, colorectum, stomach, esophagus, colorectal adenocarcinoma, esophageal adenocarcinoma, gastric / stomach cancer / adenocarcinoma) and related tissues (e.g., pancreas, gallbladder and bile duct, liver, intrahepatic and extrahepatic, perihilar cholangiocarcinoma / adenocarcinoma, bile duct adenocarcinoma), as well as cancers of the lung, kidney, gynecological, breast, testis, skin, prostate, central nervous system, and brain.

[0133] In a preferred embodiment, the compounds have applications in the field of immuno-oncology and in the treatment of immune disorders. Thus, in a preferred embodiment, the compounds of formula (I) are used in the treatment of immune disorders. In another preferred embodiment, the compounds of formula (I) are used in immunotherapy for the treatment of cancer.

[0134] In a preferred embodiment, the immune disorder is an autoimmune disorder. Thus, in a preferred embodiment, the compounds of the present invention are useful in the treatment or prevention of multiple sclerosis (MS). Recent studies have shown the involvement of 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 (Miyamoto, K. et al. Cell Reports, (2023), 42, 113005).

[0135] In a preferred embodiment, the disorder is fibrosis or a fibrotic disorder. Fibrosis is defined by the excessive accumulation of fibrous connective tissue (components of the extracellular matrix (ECM) such as collagen and fibronectin) in and around inflamed or damaged tissue, which can lead to permanent scarring and organ dysfunction.

[0136] In a preferred embodiment, the compounds have use in the treatment or prevention of inflammatory disorders / diseases and / or inflammation.

[0137] In a preferred embodiment, the disorder is a gastrointestinal disorder, preferably selected from inflammatory bowel disease, ulcerative colitis, primary sclerosing cholangitis and Crohn's disease (Song, Z. et al. Bioorg. Med. Chem. (2023). https: / / doi.org / 10.1016 / j.bmc.2023.117511) (Otkur, W. et al. Eur. J. Pharmacol, (2023), 949, 175719) (Zheng, X. et al. Brain, Behavior and Immunity, (2019), 79, 244) (Boleij, A. et al. Communications Biology, (2021), 4:585). Single nucleotide polymorphisms (SNPs) in human GPR35 have been investigated in genome-wide association studies (MacKenzie et al., Frontiers in Endocrinology (Lausanne) 2, 68, 1-10 (2011)). Six of these SNPs have been associated with inflammatory diseases of the GI tract, including ulcerative colitis, Crohn's disease, and primary sclerosing cholangitis (Imielinski et al., Nat Genet 41, 1335-1340 (2009); Ellinghaus et al., Hepatology 58, 1074-1083 (2013)). SNP rs3749171, synonymous with the coding variant T108M (GPR35a amino acid sequence), has been associated with IBD. Research studies have shown that this variant is upregulated, leading to activation of GPR35 and increased proliferation and metabolism in bone marrow-derived macrophages (Schneditz et al, Sci Signal 12:eaau9408 (2019) doi: 10.1126 / scisignal.aau9048).Furthermore, expression of T108M GPR35 leads to increased production of VEGF and CXCL8 by macrophages compared to the reference allele, which is reduced in GPR35-deficient cells (Pagano et al., Gut (2021) Gut. 2022 Mar;71(3):509-520. doi: 10.1136 / gutjnl-2020-323363. Epub 2021 Mar 23). It has also been suggested that increased expression of T108M contributes to pathogenesis in IBD patients and can act as a biomarker for patients who respond better to TNF-blockers (Kaya et al., Frontiers in Immunology 12: 717392 (2021), Kaya et al., Cell Rep 32:107979 (2020)).

[0138] In a preferred embodiment, the disorder is cardiovascular disease, preferably selected from hypertension, heart failure, atherosclerosis, peripheral vascular disease and stroke.Many recent publications suggest the role of GPR35 in the pathology of both hypertension and heart failure and atherosclerosis.For example, S294R SNP in GPR35 has been shown to be significantly associated with coronary artery calcification in patient cohorts (Sun, YV et al., (2008) Genet. Epidemiol. 32, 350-360 doi: 10.1002 / gepi.20309). Further studies demonstrated a correlation between GPR35 upregulation and traditional heart failure biomarkers, such as plasma brain natriuretic peptide, ejection fraction, and pulmonary artery pressure, thereby implicating GPR35 in heart failure and hypertension (Min, KD et al (2010) Biochem. Biophys. Res. Commun. 393, 55-60).

[0139] Another aspect relates to a compound described herein for use in the treatment or prevention of a disorder caused by, associated with, or accompanied by abnormal activity of GPR35.

[0140] Another aspect relates to a compound described herein for use in the treatment or prevention of a GPR35-related disease or disorder.

[0141] Another aspect of the present invention relates to a method of treating the disorders described above, comprising administering to a subject a compound described herein.

[0142] Another aspect of the present invention relates to a method of treating a GPR35-related disease or disorder in a subject. The method according to this aspect of the invention is achieved by administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as hereinbefore described, either by itself or, more preferably, as part of a pharmaceutical composition in admixture with a pharmaceutically acceptable carrier, for example as detailed hereinafter.

[0143] Yet another aspect of the present invention relates to a method of treating a subject having a disease condition alleviated by modulation of GPR35, wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to the present invention.

[0144] Another aspect relates to a method of treating a disease state alleviated by modulation of GPR35, the method comprising administering to a subject a therapeutically effective amount of a compound according to the present invention.

[0145] In a preferred embodiment, the compound inhibits GPR35 activity, for example as demonstrated in the functional GPR35 assay described in the accompanying Examples section.

[0146] In a preferred embodiment, the compound is a GPR35 antagonist or inverse agonist.

[0147] In a preferred embodiment, the compound is a GPR35 antagonist that reverses the agonist-induced function of the receptor.

[0148] In another preferred embodiment, the compound is an inverse agonist of GPR35. An inverse agonist is a compound that interacts with a receptor signaling system that has a constitutive level of activity and, through interaction with the receptor, reduces activity in the opposite direction to that of a pure agonist.

[0149] 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 agonist activation of the receptor through binding to a site different from that of the agonist. Thus, a negative allosteric modulator reduces the affinity or potency of an agonist for the receptor. This is in contrast to an orthosteric antagonist, which blocks agonist activation of the receptor through binding to the same site as the agonist.

[0150] Preferably, the subject is a mammal, more preferably a human.

[0151] The term "method" refers to methods, 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 known methods, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0152] As used herein, the term "treating" includes arresting, substantially inhibiting, slowing or reversing the progression of a disease or disorder, substantially ameliorating clinical symptoms of a disease or disorder, or substantially preventing the appearance of clinical symptoms of a disease or disorder.

[0153] As used herein, the term "preventing" refers to a method for barring an organism from acquiring a disorder or disease in the first place.

[0154] The term "therapeutically effective amount" refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated.

[0155] For any compound used in this invention, the therapeutically effective amount, also referred to herein as the therapeutically effective dose, can be estimated initially from cell culture assays. For example, the dose can be determined based on the IC 50 or IC 90 The compound can be formulated in animal models to achieve a circulating concentration range including: (a) a concentration range of 0.01 to 0.1% of the active ingredient; (b) a concentration range of 0.01 to 0.1% of the active ingredient; (c) a concentration range of 0.01 to 0.1% of the active ingredient; (d) a concentration range of 0.01 to 0.1% of the active ingredient; (e) a concentration range of 0.01 to 0.1% of the active ingredient; (f) a concentration range of 0.01 to 0.1% of the active ingredient; (g ...

[0156] Furthermore, the toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., LD 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 Therapeutic indices can be expressed as a ratio between ED and ED. Compounds that exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used to formulate a non-toxic dosage range for use in humans. The dosage of such compounds is preferably within the ED range with little or no toxicity. 50 The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition (see, e.g., Fingl et al., 1975, The Pharmacological Basis of Therapeutics, chapter 1, page 1).

[0157] Dosage amount and interval can be adjusted individually to provide plasma levels of the active compound sufficient to maintain therapeutic efficacy. Typical patient dosages for oral administration range from about 50 to 2000 mg / day, generally about 100 to 1000 mg / day, preferably about 150 to 700 mg / day, and most preferably 50 to 150 mg / day. Preferably, therapeutically effective serum levels are achieved by administering multiple doses daily. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. One skilled in the art will be able to optimize a therapeutically effective local dosage without undue experimentation.

[0158] 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, for example, as measured by an enzyme or cellular assay, compared to activity in a healthy subject. Inappropriate activity may also be due to overexpression of GPR35 in affected tissue compared to adjacent healthy tissue in which GPR35 expression is lower.

[0159] Preferred diseases or disorders that the compounds described herein may be useful in preventing include those described hereinabove.

[0160] Therefore, the present invention further provides the use of the compounds defined herein in the preparation of a medicament for the treatment of diseases in which it is desirable to modulate GPR35. Such diseases include proliferative disorders, gastrointestinal disorders, fibrotic disorders, cardiovascular diseases, immune disorders and inflammatory disorders. Proliferative disorders preferably include therapeutic applications in the field of oncology.

[0161] As used herein, the reference to "preparation of a medicament" includes the direct use of the components of the invention as a medicament in addition to their use in any stage of the preparation of such a medicament.

[0162] The functional GPR35 assay described in the Examples measures the ability of a GPR35 modulator to inhibit GPR35 agonist-induced phospho-ERK signaling, which is the concentration of modulator required to reduce the phospho-ERK signaling by 50 percent, i.e., IC 50 expressed as a signal window defined as the difference between agonist plus modulator vehicle (no modulator) and agonist vehicle (no agonist) controls.

[0163] In one preferred embodiment, the compound has an IC of less than about 50 μM in the GPR35 assay described above. 50 More preferably, the compound exhibits an IC value of less than about 10 μM in the GPR35 assay, more preferably less than about 1 μM. 50 It presents value.

[0164] In one preferred embodiment, compounds according to the invention have an IC of less than 10 μM in the GPR35 assay described above. 50 In one preferred embodiment, the compound is selected from those designated "A" or "B" in Table 1.

[0165] In one preferred embodiment, compounds according to the invention have an IC of greater than 1 μM and less than 10 μM in the GPR35 assay described above. 50 In one preferred embodiment, the compound is selected from those designated "B" in Table 1.

[0166] In a more preferred embodiment, compounds according to the invention have an IC of less than 1 μM in the assay described above. 50 In one preferred embodiment, the compound is selected from those designated "A" in Table 1.

[0167] Pharmaceutical Composition For use according to the invention, the compounds described herein or physiologically acceptable salts, esters, or other physiologically functional derivatives thereof can be presented as pharmaceutical formulations comprising the compounds or physiologically acceptable salts, esters, or other physiologically functional derivatives thereof together with one or more pharmaceutically acceptable carriers, excipients, or diluents therefor and optionally other therapeutic and / or prophylactic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. The pharmaceutical compositions can be for human or animal use in human and veterinary medicine.

[0168] Examples of such suitable excipients for the various different forms of pharmaceutical compositions described herein can be found in "Handbook of Pharmaceutical Excipients, 2000." nd Edition, (1994), Edited by A Wade and PJ Weller. The carrier, or carriers, if more than one is present, must each be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0169] Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985).

[0170] Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, etc. Examples of suitable diluents include ethanol, glycerol and water.

[0171] The choice of pharmaceutical carrier, excipient, or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical composition can include as, or in addition to, the carrier, excipient, or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), buffer(s), flavoring agent(s), surface active agent(s), thickening agent(s), preservative(s) (including antioxidants), and the like, as well as substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.

[0172] Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flowing lactose, beta-lactose, corn sweeteners, natural or synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, and polyethylene glycol.

[0173] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.

[0174] Preservatives, stabilizers, dyes and even flavoring agents can be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents can also be used.

[0175] Pharmaceutical formulations include those suitable for oral, topical (including cutaneous, buccal and sublingual), rectal or parenteral (including subcutaneous, intradermal, intramuscular and intravenous), nasal, and pulmonary administration, for example, by inhalation.The formulations can be conveniently presented in individual dosage units, where appropriate, and can be prepared by any of the methods well known in the field of pharmacy.All methods include the step of bringing the active compound into association with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.

[0176] Pharmaceutical formulations suitable for oral administration in which 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 made by compression or molding, optionally with one or more accessory ingredients. Tablets can be prepared by compressing the active compound into a free-flowing form such as a powder or granules, which may be mixed with a binder, lubricant, inert diluent, glidant, surface-active agent, or dispersing agent, in a suitable machine. Molded tablets can be made by molding the active compound with an inert liquid diluent. Tablets can be coated or, if uncoated, can be scored. Capsules can be prepared by filling capsule shells with the active compound, either alone or in admixture with one or more accessory ingredients, and then sealing them in the usual manner. Cachets are similar to capsules in which the active compound, along with any accessory ingredient(s), is sealed in a rice paper envelope. The active compound can also be formulated as dispersible granules, which can be suspended in water or sprinkled on food before administration, for example. The granules may be packaged, for example, in a sachet.Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.

[0177] Formulations for oral administration include controlled-release dosage forms, such as tablets in which the active compound is formulated in a suitable release-controlling matrix or coated with a suitable release-controlling film. Such formulations may be particularly advantageous for prophylactic use.

[0178] The pharmaceutical preparation suitable for rectal administration, in which the carrier is solid, is most preferably presented as a unit-dose suppository.Suitable carriers include cocoa butter and other materials commonly used in the art.Suppositories can be conveniently formed by adding a mixture of the active compound with softened or melted carrier(s), followed by cooling and shaping in a mold.The pharmaceutical preparation suitable for parenteral administration includes a sterile solution or suspension of the active compound in an aqueous or oily medium.

[0179] Injectable preparations can be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in sealed unit-dose or multi-dose containers after introduction of the formulation until needed for use. Alternatively, the active compound can be in powder form, which is constituted with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0180] The active compounds can also be formulated as long-acting depot preparations, which can be administered by intramuscular injection or by implantation, for example, subcutaneously or intramuscularly. Depot preparations can include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins. Such long-acting preparations are particularly advantageous for prophylactic use.

[0181] Formulations suitable for pulmonary administration via the buccal cavity are presented so that particles containing the active compound and desirably having a diameter in the range of 0.5 to 7 microns are delivered into the recipient's bronchial tree.

[0182] One possibility is that this formulation is in the form of finely pulverized powder, which can be conveniently presented in a suitable capsule, such as gelatin, for use in inhalation device, or alternatively as a self-propelled formulation that includes active compound, suitable liquid or gaseous propellant, and optionally other components, such as surfactant and / or solid diluent.Suitable liquid propellants include propane and chlorofluorocarbons, and suitable gaseous propellants include carbon dioxide.Self-propelled formulations can also be used, in which active compound is dispensed in the form of droplets of solution or suspension.

[0183] Such self-propelling formulations are similar to those known in the art and can be prepared by established procedures. Suitably, they are presented in a container provided with either a manually operable or automatically functioning valve having the desired spray characteristics; advantageously, the valve is of the metered type that delivers a fixed volume, e.g., 25 to 100 microliters, with each actuation thereof.

[0184] 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 air or ultrasonic agitation is used to produce a fine droplet mist for inhalation.

[0185] Formulations suitable for nasal administration include preparations generally similar to those previously described for pulmonary administration. When dispensed, such formulations should desirably have a particle size in the range of 10-200 microns to allow retention in the nasal cavity; this can be achieved, where appropriate, by the use of powders of appropriate particle size or by the selection of an appropriate valve. Other suitable formulations include coarse powders having a particle size in the range of 20-500 microns for rapid inhalation via the nasal passage from a container held close to the nose, and nasal drops containing 0.2%-5% w / v of the active compound in an aqueous or oily solution or suspension.

[0186] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1M and preferably 0.05M phosphate buffer or 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Preservatives and other additives may also be present, such as, for example, antibacterial agents, antioxidants, chelating agents, inert gases, and the like.

[0187] Suitable formulations for topical use can be provided, for example, as gels, creams, or ointments. Such preparations can be applied to, for example, a wound or ulcer, either directly on the surface of the wound or ulcer, or carried on a suitable support such as a bandage, gauze, mesh, or the like, which can be applied to and over the area to be treated.

[0188] Liquid or powder formulations can also be provided that can be sprayed or sprinkled directly onto the area to be treated, e.g., a wound or ulcer. Alternatively, a carrier, e.g., a bandage, gauze, mesh, etc., can be sprayed or sprinkled with the formulation and then applied to the area to be treated.

[0189] According to a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical or veterinary composition as described above, the process comprising bringing into association the active compound(s) with the carrier, e.g. an additive mixture.

[0190] In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product. The present invention extends to a process for preparing a pharmaceutical composition which comprises combining or bringing into association a compound described herein with a pharmaceutically or veterinarily acceptable carrier or vehicle.

[0191] Salts / Esters The compounds of the present invention can exist as salts or esters, particularly pharmaceutically and veterinarily acceptable salts or esters.

[0192] Pharmaceutically acceptable salts of the compounds of the present invention include suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts can be found in Berge et al., J Pharm Sci, 66, 1-19 (1977). Salts may be prepared, for example, with strong inorganic acids, such as mineral acids, for example hydrohalic acids, for example hydrochlorides, hydrobromides and hydroiodides, sulfuric acid, phosphoric acid, sulfates, bisulfates, hemisulfates, thiocyanates, persulfates, persulfates and sulfonic acids; with strong organic carboxylic acids, for example alkanecarboxylic acids of 1 to 4 carbon atoms, which are unsubstituted or substituted (for example by a halogen), for example acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid; with hydroxycarboxylic acids, for example ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; with amino acids, for example aspartic acid or glutamic acid; with benzoic acid; or with organic sulfonic acids, for example unsubstituted or substituted (for example by a halogen) (C 1- C4)-Alkyl- or aryl-sulfonic acids, such as methane- or p-toluenesulfonic acid. Pharmaceutically or veterinarily unacceptable salts may also be valuable as intermediates.

[0193] Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanoate, glucoheptanoate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobiolate, and the like. phosphates, pivolates, 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, hydrobromides, hydroiodides, sulfates, bisulfates, hemisulfates, thiocyanates, persulfates, phosphoric and sulfonic acids.

[0194] Esters are formed using either organic acids or alcohols / hydroxides, depending on the functional group to be esterified. Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms, unsubstituted or substituted (e.g., by halogen), such as acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or terephthalic 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 halogen) (C 1-C4)-Alkyl- or aryl-sulfonic acids, such as methane- or p-toluenesulfonic acid, are included. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and aluminum hydroxide. Alcohols include alkane alcohols of 1 to 12 carbon atoms, which may be unsubstituted or substituted (e.g., by halogen).

[0195] Enantiomers / Tautomers In all aspects of the invention discussed above, the invention includes, where appropriate, all enantiomers, diastereoisomers, and tautomers of the compounds of the invention. Those skilled in the art will recognize compounds that possess optical properties (one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and / or tautomers can be isolated / prepared by methods known in the art.

[0196] Enantiomers are characterized by the absolute configuration 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 (see, for example, 'Advanced Organic Chemistry', 3 rd edition, ed. March, J., John Wiley and Sons, New York, 1985).

[0197] Compounds of the invention that contain chiral centers can be used as racemic mixtures, enantiomerically enriched mixtures, or racemic mixtures can be separated using well-known techniques and the individual enantiomers used alone.

[0198] Stereo and geometric isomers Some of the compounds of the present invention can exist as stereoisomers and / or geometric isomers; for example, they can possess one or more asymmetric and / or geometric centers and thus can exist in two or more stereoisomeric and / or geometric forms. The present invention contemplates the use of all individual stereoisomers and geometric isomers of these compounds, as well as mixtures thereof. The terms used in the claims encompass these forms, so long as the provided form retains the appropriate functional activity (to the same extent, although not necessarily).

[0199] The present invention also includes all suitable isotopic variations of the compound or its pharmaceutically acceptable salt. An isotopic variation of the compound of the present invention 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 an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into the drug and its pharmaceutically acceptable salt include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example, 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 Certain isotopic variations of the drug and its pharmaceutically acceptable salts, such as 3 H or 14 Those incorporating radioactive isotopes such as 13C are useful in drug and / or substrate tissue distribution studies. 3 H, and carbon 14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Further isotopes such as deuterium, i.e. 2Substitution with H can confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. For example, the present invention includes compounds of general formula (I) in which any hydrogen atom is replaced by a deuterium atom. Isotopic variants of the agents of the present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variants of suitable reagents.

[0200] Atropisomers Some of the compounds of the present invention can exist as atropisomers. Atropisomers are stereoisomers that arise due to hindrance of rotation about a single bond, where energy differences due to steric strain or other contributors create a rotational barrier high enough to allow isolation of individual conformers. The present invention encompasses all such atropisomers.

[0201] Prodrug The present invention further includes compounds of the invention in prodrug form, i.e., covalently bonded compounds that release the active parent drug in vivo. Such prodrugs are generally compounds of the invention in which one or more appropriate groups have been modified such that the modification can be reversed upon administration to a human or mammalian subject. Reversal is usually carried out by enzymes naturally occurring in such subjects, but a second agent can be administered along with such a prodrug to effect reversal in vivo. Examples of such modifications include esters (e.g., any of those described above), where reversal can be carried out by esterases, etc. Other such systems will be familiar to those skilled in the art.

[0202] solvate The present invention also includes solvated forms of the compounds of the present invention. The terms used in the claims encompass these forms. Preferably, the solvates are hydrates.

[0203] combination A further aspect of the present invention relates to a combination comprising a compound described herein and one or more additional active agents. In a particularly preferred embodiment, one or more compounds of the present invention are administered in combination with one or more additional active agents, such as existing drugs available on the market. In such cases, the compound of the present invention can be administered sequentially, simultaneously, or sequentially with one or more other active agents.

[0204] Drugs can generally be more effective when used in combination. In particular, combination therapy is desirable to avoid overlapping of major toxicities, mechanisms of action, and resistance mechanisms(s). Furthermore, it is also desirable to administer most drugs at their maximum tolerated doses with minimal time intervals between such doses. The main advantage of combining chemotherapy drugs is that it can promote additive or possible synergistic effects through biochemical interactions, and also reduce the occurrence of resistance.

[0205] Beneficial combinations may be suggested by studying the activity of a test compound with agents known or suspected to be valuable in treating a particular disorder. This procedure may also be used to determine the order of administration of the agents, i.e., before, simultaneously with, or after delivery. Such scheduling may be characteristic of all active agents identified herein.

[0206] In the context of cancer, the compounds of the present invention can be used in combination with immunotherapy, such as cancer vaccines, and / or with other immune modulators. Thus, in a 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 diseases 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 radiation therapy.

[0207] polymorph The present invention further relates to the compounds of the present invention in their various crystalline, polymorphic and (an)hydrous forms. It is well established within the pharmaceutical industry that chemical compounds can be isolated in any of these forms by slight variations in the methods of purification and / or isolation from solvents used in the synthetic preparation of such compounds.

[0208] Administration The pharmaceutical composition of the present invention can be adapted for rectal, nasal, intrabronchial, topical (including buccal and sublingual), intravaginal or parenteral (including subcutaneous, intramuscular, intravenous, intraarterial and intradermal), intraperitoneal or intrathecal administration.Preferably, the formulation is an orally administered formulation.The formulation can conveniently be presented in unit dosage form, i.e., in the form of individual portions containing a unit dose, or a multiple or subunit of a unit dose.For example, the formulation can be in the form of tablets and sustained-release capsules, and can be prepared by any method well known in the art of pharmacy.

[0209] Formulations for oral administration herein may be presented as: discrete units, such as capsules, gels, drops, cachets, pills, or tablets, each containing a predetermined amount of active agent; as a powder or granules; as a solution, emulsion, or suspension of the active agent in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as a bolus, etc. Preferably, these compositions contain 1 mg to 250 mg, and more preferably 10 to 100 mg, of the active ingredient per dose.

[0210] For compositions for oral administration (e.g., tablets and capsules), the term "acceptable carrier" includes vehicles, such as common excipients, e.g., 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, dibasic calcium phosphate, sodium chloride, and alginic acid; and lubricants, e.g., magnesium stearate, sodium stearate, and other metallic stearates, glycerol stearate, silicone fluid, talc wax, oils, and colloidal silica. Flavoring agents, e.g., peppermint, oil of wintergreen, cherry flavoring, and the like, may also be used. It may be desirable to add a coloring agent to facilitate easy identification of the dosage form. Tablets may also be coated by methods well known in the art.

[0211] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Tablets can be prepared by compressing the active agent in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent, in a suitable machine. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets can be coated or scored and can be formulated to provide slow or controlled release of the active agent.

[0212] Other formulations suitable for oral administration include lozenges containing the active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles 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.

[0213] Other modes of administration include solutions or emulsions prepared from sterile or sterilizable solutions, which can be injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally or intramuscularly. Injectable forms typically contain between 10 and 1000 mg, preferably between 10 and 250 mg, of the active ingredient per dose.

[0214] Pharmaceutical compositions of the present invention may be in the form of a suppository, pessary, suspension, emulsion, lotion, ointment, cream, gel, spray, solution or dustable powder.

[0215] An alternative means of transdermal administration is by use of a skin patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycol or liquid paraffin. The active ingredient can also be incorporated into an ointment consisting of a white wax or white soft paraffin base, together with any necessary stabilizers and preservatives, at a concentration of between 1 and 10% by weight.

[0216] Dosage Those skilled in the art can easily determine the appropriate dosage of a kind of instant composition for administering to a subject without undue experimentation.Typically, a doctor will determine the actual dosage that is most suitable for each patient, and it depends on various factors, including the activity of the specific compound used, the metabolic stability and duration of action of that compound, age, body weight, general health, sex, dietary therapy, mode and time of administration, excretion rate, drug combination, the severity of particular condition and the individual being treated.The dosage disclosed herein is an example of average case.Of course, there are individual cases where higher or lower dosage ranges are beneficial, and these are within the scope of this invention.

[0217] Dosages are 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 normal saline, or a similar formulation with appropriate excipients, is most effective, although intramuscular bolus injections are also useful. Typically, parenteral doses range from about 0.01 to about 100 mg; preferably 0.1 to 20 mg, in a manner to maintain a plasma concentration of drug at a concentration effective to modulate GPR35. The compound can be administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg. The precise amount of a compound of the invention that is therapeutically effective, and the route by which such a compound is best administered, can be readily determined by one of skill in the art by comparing the blood levels of the drug with the concentration required to have a therapeutic effect.

[0218] The compounds of this invention can also be administered orally to a patient in a manner that provides a drug concentration sufficient to achieve one or more of the therapeutic symptoms disclosed herein. Typically, pharmaceutical compositions containing the compounds are administered at oral doses of between about 0.1 and about 500 mg, or about 0.1 and about 50 mg, in a manner consistent with the patient's condition. Preferably, the oral dose is about 0.5 to about 50 mg, or about 0.5 to about 20 mg.

[0219] No unacceptable toxicological effects are expected when the compounds of the present invention are administered in accordance with the present invention. Compounds of the present invention that may have good bioavailability can be tested in one of several biological assays to determine the concentration of compound required to have a given pharmacological effect.

[0220] The present invention is further described through the following non-limiting examples. [Example]

[0221] Where 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. Where compounds are shown to have been prepared analogously to previous examples or intermediates, it will be recognized by those skilled in the art that reaction times, number of equivalents of reagents, solvents, concentrations, and temperatures may be modified for each particular reaction, and that it may be necessary or desirable to use different workup or purification techniques.

[0222] General Scheme

[0223] Abbreviation [Table 3] JPEG2026503167000044.jpg156170

[0224] Other abbreviations are intended to convey their generally accepted meaning.

[0225] General experimental conditions All starting materials and solvents were either obtained from commercial sources or prepared according to literature methods.

[0226] Normal phase ("flash") and RP ("flash") chromatography were performed on a CombiFlash Companion automated flash chromatography system using either Redisep® Silver (230-400 mesh, 40-63 μm irregular) or Silicycle, SiliaSep C18 (230-400 mesh, 40-63 μm irregular) prepacked silica cartridges, respectively. RP flash chromatography was performed using a basic modifier (C18, 0-100% MeCN in 0.1% aqueous NH4OH), except for Examples 15, 17, 39-42, and 49-51, which used an acidic modifier (C18, 0-100% MeCN in 0.1% aqueous HC0H).

[0227] Analytical UPLC-MS experiments to determine retention times and associated mass ions were performed using a Waters ACQUITY UPLC® H-Class system equipped with an ACQUITY PDA detector and an ACQUITY QDa mass spectrometer or a Waters SQD mass spectrometer, running the analytical method described below.

[0228] Analytical LC-MS experiments to determine retention times and associated mass ions were performed using an Agilent 1200 Series HPLC system coupled to an Agilent 1956, 6100, or 6120 Series single quadrupole mass spectrometer, running one of the analytical methods described below. [Table 4] [Table 5] [Table 6]

[0229] Preparative HPLC purification was performed using a Waters X-Bridge BEH C18 column performed as detailed below. [Table 7] [Table 8]

[0230] NMR spectra were recorded using a Bruker 500MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbe™. Spectra were measured at 298K and referenced to the solvent resonance unless otherwise indicated. Chemical shifts are reported in parts per million. Data were acquired using Bruker TopSpin software and processed using MestreNova software.

[0231] Reactions were carried out at ambient temperature (typically around 20° C.) unless otherwise stated.

[0232] All yields are adjusted for purity.

[0233] Intermediates Where no procedures are given for intermediates identified in the synthetic schemes, these compounds were purchased.

[0234] Intermediate 1 N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-1) [ka]

[0235] Step 1: 1-Nitro-4-phenethoxybenzene [ka]

[0236] To a solution of 2-phenylethan-1-ol (CAS 60-12-8, Fluorochem, 3.38 g, 27.6 mmol) in DMF (20 mL) was added NaH (60% dispersion in oil, 1.02 g, 25.5 mmol), and the mixture was stirred at room temperature for 30 min. 1-Fluoro-4-nitrobenzene (CAS 350-46-9, Alfa Aesar, 3.00 g, 21.3 mmol) was added, and the reaction was stirred at room temperature for 18 h. It was then poured into ice-water (400 mL), and the product was extracted with EtOAc (3 × 100 mL). The organic extract was washed with brine (50 mL), dried over MgSO4, and the filtrate was adsorbed onto silica gel. Purification by flash chromatography (silica gel, 0–30% EtOAc in isohexane) gave 1-nitro-4-phenethoxybenzene (4.80 g, 93%). LCMS: Method A, 2.00 min, MS: ES+ 244.0.

[0237] Step 2: 4-Phenethoxyaniline (I-1a) [ka]

[0238] To a solution of 1-nitro-4-phenethoxybenzene (4.50 g, 18.5 mmol) in EtOH (55 mL) and THF (30 mL) was added 10% Pd / C (50% water-wet, 0.984 g, 9.25 mmol), and the mixture was stirred at room temperature under hydrogen (3 bar) for 18 h. The mixture was filtered through Celite® and concentrated under reduced pressure to give 4-phenethoxyaniline (3.50 g, 86%). LCMS: Method A, 0.99 min, MS: ES + 214.2.

[0239] Step 3: N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-1) [ka]

[0240] 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 (8.60 mL, 49.2 mmol) in DMF (40 mL) was added HATU (7.49 g, 20 mmol). After 30 min, 4-phenethoxyaniline (3.50 g, 16.4 mmol) was added. The mixture was stirred at 40° C. for 18 h, then cooled, poured into ice-water (500 mL), and extracted with EtOAc (3×120 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO, adsorbed onto silica gel, and then purified by flash chromatography (silica gel, 0-50% EtOAc in isohexane) to give 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.

[0241] Intermediate 2 2-chloro-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate (I-2) [ka]

[0242] To a stirred solution of methyl 5-bromo-2-chloronicotinate (CAS 78686-79-0, Fluorochem, 237 mg, 0.95 mmol) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-1, 350 mg, 0.79 mmol) in dioxane (4 mL) and water (1 mL), CsCO (1000 mg, 3.16 mmol) was added, and the reaction mixture was degassed with a stream of nitrogen at room temperature for 5 minutes. Pd(dppf)Cl (87 mg, 0.12 mmol) was added, and the mixture was degassed for an additional 2 minutes. The reaction mixture was stirred at 80 °C for 18 hours, then cooled to room temperature, acidified with aqueous HCl (1 M, 5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over NaSO, adsorbed onto silica gel, and then purified by flash chromatography (silica gel, 0 to 100% EtOAc in isohexane) to give 2-chloro-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate (300 mg, 67%). LCMS: Method A, 2.14 min, MS: ES + 487.2.

[0243] Intermediate 3 4-((benzyloxy)methyl)aniline (I-3) [ka]

[0244] Step 1: 1-((benzyloxy)methyl)-4-nitrobenzene [ka]

[0245] Phenylmethanol (CAS100-51-6, Alfa Aesar, 3.60 g, 33.3 mmol) was added to a stirred suspension of 1-(bromomethyl)-4-nitrobenzene (CAS100-11-8, Combi-Blocks, 6.00 g, 27.8 mmol) and AgO (9.65 g, 41.7 mmol) in DCM (60 mL), and the reaction was stirred at 45° C. for 18 h. The mixture was filtered through Celite®, and the filtrate was adsorbed onto silica gel and purified by flash chromatography (silica gel, 0-30% TBME in heptane) to give 4-((benzyloxy)methyl)aniline (6.33 g, 94%). LCMS: Method A, 1.96 min, MS: ES + 244.1

[0246] Step 2: 4-((benzyloxy)methyl)aniline (I-3) [ka]

[0247] 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 h. The mixture was filtered through Celite®, and the crude concentrate was captured on SCX, washed with MeOH, and eluted with 10% 0.7 M ammonia / MeOH solution in DCM. Further purification by chromatography on silica gel (80 g cartridge, 0-10% (0.7 M ammonia / MeOH) in DCM) gave 4-((benzyloxy)methyl)aniline (2.58 g, 79%). LCMS: Method A, 1.09 min, MS: ES + 214.1

[0248] Intermediate 4 3-((benzyloxy)methyl)aniline (I-4) [ka]

[0249] Step 1: 1-((benzyloxy)methyl)-3-nitrobenzene [ka]

[0250] Following the procedure of Intermediate 3, Step 1, and using 1-(bromomethyl)-3-nitrobenzene (CAS 3958-57-4, Thermo Scientific) instead of 1-(bromomethyl)-4-nitrobenzene, 1-((benzyloxy)methyl)-3-nitrobenzene was obtained in 76% yield. 1 H NMR(500MHz,DMSO)δppm:8.21(s,1H), 8.19~8.14(m,1H), 7.83(d,J=7.6Hz,1H), 7.6 8(t,J=7.9Hz,1H), 7.41~7.35(m,4H), 7.35~7.28(m,1H), 4.69(s,2H), 4.61(s,2H).

[0251] Step 2: 3-((benzyloxy)methyl)aniline (I-4) [ka]

[0252] Following the procedure of Intermediate 3, Step 2, using 1-((benzyloxy)methyl)-3-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene, 3-((benzyloxy)methyl)aniline was obtained in 75% yield without purification of the crude product. LCMS: Method A, 1.14 min, MSES + 214.2.

[0253] Intermediate 5 N-(4-((cyclopropylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-5) [ka]

[0254] Step 1: 1-((cyclopropylmethoxy)methyl)-4-nitrobenzene [ka]

[0255] A solution of 1-(bromomethyl)-4-nitrobenzene (CAS 100-11-8, Thermo Scientific, 500 mg, 2.31 mmol) in cyclopropylmethanol (CAS 2516-33-8, Fluorochem, 1.9 mL, 23.1 mmol) was treated with KOH (156 mg, 2.78 mmol). The mixture was stirred at room temperature for 18 h. Additional KOH (156 mg, 2.78 mmol) was added, and the mixture was stirred for an additional 3 h. It was then diluted with water (200 mL), and the product was extracted with EtOAc (3 × 50 mL). The combined organic fractions were washed with brine (3 × 50 mL), dried over NaSO, and the filtrate was adsorbed onto silica gel. Purification by flash chromatography A (silica gel, 0–10% EtOAc in isohexane) gave 1-((cyclopropylmethoxy)methyl)-4-nitrobenzene (400 mg, 83%). LCMS: Method A, 1.76 min, MS: ES + 208.2

[0256] Step 2: 4-((cyclopropylmethoxy)methyl)aniline [ka]

[0257] Following the procedure of Intermediate 3, Step 2, using 1-((benzyloxy)methyl)-3-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene, 4-((cyclopropylmethoxy)methyl)aniline was obtained in 58% yield. LCMS: Method A, 0.42 min, MSES + 178.2.

[0258] Step 3: N-(4-((cyclopropylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-5) [ka]

[0259] Following the procedure of Intermediate 1, Step 3, using 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, N-(4-((cyclopropylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 52% yield without purification of the crude product. LCMS: Method A, 2.13 min, MSES + 408.2.

[0260] Intermediate 6 4-(Cyclopropylmethoxy)aniline (I-6) [ka]

[0261] Step 1: 1-(cyclopropylmethoxy)-4-nitrobenzene [ka]

[0262] Following the procedure of Intermediate 1, Step 1, using cyclopropylmethanol (CAS 2516-33-8, Fluorochem) instead of 2-phenylethan-1-ol, 1-(cyclopropylmethoxy)-4-nitrobenzene was obtained in 71% yield. LCMS: Method A, 1.79 min, MSES + 194.2.

[0263] Step 2: 4-(Cyclopropylmethoxy)aniline (I-6) [ka]

[0264] Following the procedure of Intermediate 3, Step 2, using 1-(cyclopropylmethoxy)-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene, 4-(cyclopropylmethoxy)aniline was obtained in 60% yield without purification of the crude product. LCMS: Method A, 0.22 min, MSES + 164.2.

[0265] Intermediate 7 4-(Cyclopropoxymethyl)aniline (I-7) [ka]

[0266] Step 1: 1-(cyclopropoxymethyl)-4-nitrobenzene [ka]

[0267] Following the procedure of Intermediate 5, Step 1, using cyclopropanol (CAS 16545-68-9, Combi-Blocks) instead of cyclopropylmethanol, 1-(cyclopropoxymethyl)-4-nitrobenzene was obtained in 89% yield. LCMS: Method A, 1.70 min, MSES+ 194.2.

[0268] Step 2: 4-(Cyclopropoxymethyl)aniline (I-7) [ka]

[0269] Following the procedure of Intermediate 3, Step 2, using 1-(cyclopropoxymethyl)-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene, 4-(cyclopropoxymethyl)aniline was obtained in 60% yield. LCMS: Method A, 0.22 min, MSES + 164.2.

[0270] Intermediate 8 N-(6-phenethoxypyridin-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-8) [ka]

[0271] Step 1: 5-Nitro-2-phenethoxypyridine [ka]

[0272] To a solution of 2-phenylethan-1-ol (CAS60-12-8, Fluorochem, 0.55 mL, 4.7 mmol) in DMF (7 mL) was added 2-fluoro-5-nitropyridine (CAS456-24-6, Activate Scientific, 0.50 g, 3.5 mmol) and CsCO (2.29 g, 7.0 mmol). The mixture was stirred at 40 °C for 18 h, then cooled to room temperature, diluted with brine (30 mL), and extracted with EtOAc (3 × 30 mL). The combined organic fractions were washed with brine (3 × 30 mL), dried over MgSO, filtered, and adsorbed onto silica gel. Purification by flash chromatography (silica gel, 0–30% EtOAc in isohexane) gave 5-nitro-2-phenethoxypyridine (0.70 g, 80%). LCMS: Method A, 1.96 min, MS: ES + 245.0.

[0273] Step 2: 6-Phenethoxypyridin-3-amine [ka]

[0274] 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. and 1 bar (H-Cube®) for 1 h. The reaction mixture was concentrated under reduced pressure to give 6-phenethoxypyridin-3-amine (550 mg, 82%), which was used without any purification. LCMS: Method A, 1.12 min, MS: ES + 215.2.

[0275] Step 3: N-(6-phenethoxypyridin-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-8) [ka]

[0276] Following the procedure of Intermediate 1, Step 3, using 6-phenethoxypyridin-3-amine instead of 4-phenethoxyaniline, N-(6-phenethoxypyridin-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 48% yield. LCMS: Method A, 2.18 min, MSES + 445.2.

[0277] Intermediate 9 4-((benzylsulfonyl)methyl)aniline (I-9) [ka]

[0278] Step 1: Benzyl (4-nitrobenzyl) sulfane [ka]

[0279] To a solution of phenylmethanethiol (CAS 100-53-8, Merck, 0.22 mL, 1.9 mmol) and triethylamine (0.26 mL, 1.9 mmol) in MeCN (5 mL) was added 1-(bromomethyl)-4-nitrobenzene (CAS 100-11-8, Apollo, 200 mg, 0.9 mmol) at 0 °C. The mixture was stirred at room temperature for 8 h, diluted with saturated aqueous Na2CO3 (20 mL), and extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0–50% EtOAc in isohexane) gave benzyl(4-nitrobenzyl)sulfane (150 mg, 62%). 1 H NMR (500MHz, DMSO) δppm: 8.23~8.15(d,J=8.5Hz,2H), 7.57(d,J=8.5Hz,2H), 7.35~7.22(m,5H), 3.81(s,2H), 3.69(s,2H).

[0280] Step 2: 1-((benzylsulfonyl)methyl)-4-nitrobenzene [ka]

[0281] To a solution of benzyl(4-nitrobenzyl)sulfane (150 mg, 0.58 mmol) in DCM (4 mL) was added mCPBA (314 mg, 70%, 1.3 mmol) slowly at 0 °C. The reaction was allowed to warm to room temperature for 4 h, then quenched with aqueous NaSO (10 wt%, 20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated aqueous NaHCO (20 mL), dried over NaSO, and concentrated under reduced pressure to give 1-((benzylsulfonyl)methyl)-4-nitrobenzene (157 mg, 89%). 1 H NMR (500MHz, DMSO) δppm: 8.27 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.46~7.36 (m, 5H), 4.70 (s, 2H), 4.55 (s, 2H).

[0282] Step 3: 4-((benzylsulfonyl)methyl)aniline (I-9) [ka]

[0283] Following the procedure of Intermediate 3, Step 2, using 1-((benzylsulfonyl)methyl)-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene, 4-((benzylsulfonyl)methyl)aniline was obtained in 64% yield without purification of the crude product. LCMS: Method A, 0.22 min, MSES + 164.2.

[0284] Intermediate 10 N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-10) [ka]

[0285] Step 1: 4-((benzyloxy)methyl)-2-fluoro-1-nitrobenzene [ka]

[0286] Following the procedure of Intermediate 3, Step 1, 4-(bromomethyl)-2-fluoro-1-nitrobenzene (CAS 131858-37-2, Apollo) was used instead of 1-(bromomethyl)-4-nitrobenzene, thus obtaining 4-((benzyloxy)methyl)-2-fluoro-1-nitrobenzene in 96% yield. LCMS: Method A, 1.94 min, MS: ES + 261.1.

[0287] Step 2: 4-((benzyloxy)methyl)-2-fluoroaniline [ka]

[0288] Following the procedure of Intermediate 3 Step 2, using 4-((benzyloxy)methyl)-2-fluoro-1-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene, and purification by flash chromatography (silica gel, 0 to 50% TBME in isohexane), 4-((benzyloxy)methyl)-2-fluoroaniline was thus obtained in 75% yield. LCMS: Method A, 1.64 min, MSES + 232.1.

[0289] Step 3: N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-10) [ka]

[0290] Following the procedure of Intermediate 1, Step 3, 4-((benzyloxy)methyl)-2-fluoroaniline was used instead of 4-phenethoxyaniline, thus obtaining N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 46% yield. LCMS: Method A, 2.26 min, MSES + 462.2.

[0291] Intermediate 11 3-(5-(Methoxycarbonyl)-6-methylpyridin-3-yl)benzoic acid (I-11) [ka]

[0292] Following the procedure of Intermediate 2, using methyl 5-bromo-2-methylnicotinate (CAS 1215916-40-7, BLD) instead of methyl 5-bromo-2-chloronicotinate and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 269409-73-6, BLD) instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, reaction at 80 °C for 2 h, and final trituration with EtO afforded 3-(5-(methoxycarbonyl)-6-methylpyridin-3-yl)benzoic acid in 98% yield. LCMS: Method A, 1.30 min, MS: ES + 272.1.

[0293] Intermediate 12 N-(4-((benzyloxy)methyl)-2-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-12) [ka]

[0294] Following the procedure of Intermediate 1, Step 3, using 4-((benzyloxy)methyl)aniline (I-3) instead of 4-phenethoxyaniline and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, Fluorochem) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 269409-73-6, BLD), N-(4-((benzyloxy)methyl)-2-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 46% yield. LCMS: Method A, 2.26 min, MS: ES + 462.2.

[0295] Intermediate 13 2-Bromo-N-(4-phenethoxyphenyl)isonicotinamide (I-13) [ka]

[0296] To a solution of 2-bromoisonicotinic acid (CAS 66572-56-3, Apollo, 417 mg, 2.06 mmol) and 4-phenethoxyaniline (I-1a, 500 mg, 1.88 mmol) in DMF (2.00 mL) was added DIPEA (0.98 mL, 5.63 mmol) and T3P (50 wt% in EtOAc, 1.22 mL, 2.06 mmol) at room temperature. The mixture was stirred for 18 h, then diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phases were dried over Na2SO4 and adsorbed onto silica gel. Purification by flash chromatography (silica gel, 0–100% EtOAc in isohexane) gave 2-bromo-N-(4-phenethoxyphenyl)isonicotinamide (705 mg, 87%). LCMS: Method C, 1.10 min, MS: ES + 397.0 and 399.0.

[0297] Intermediate 14 6-Chloro-N-(4-phenethoxyphenyl)pyrazine-2-carboxamide (I-14) [ka]

[0298] Following the procedure of Intermediate 13, 6-chloropyrazine-2-carboxylic acid (CAS 23688-89-3, Apollo) was used instead of 2-bromoisonicotinic acid (CAS 66572-56-3, Apollo) to give 6-chloro-N-(4-phenethoxyphenyl)pyrazine-2-carboxamide in 75% yield. LCMS: Method C, 1.11 min, MS: ES + 354.2.

[0299] Intermediate 15 2-Chloro-N-(4-phenethoxyphenyl)pyrimidine-4-carboxamide (I-15) [ka]

[0300] Following the procedure of Intermediate 13, 2-chloropyrimidine-4-carboxylic acid (CAS 149849-92-3, BLD) was used instead of 2-bromoisonicotinic acid (CAS 66572-56-3, Apollo) to give 2-chloro-N-(4-phenethoxyphenyl)pyrimidine-4-carboxamide in 84% yield. LCMS: Method C, 1.1 min, MS: ES + 354.0.

[0301] Intermediate 16 N-(4-((benzyloxy)methyl)-3-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-16)

[0302] [ka]

[0303] Step 1: 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene [ka]

[0304] Following the procedure of Intermediate 3, Step 1, and using 1-(bromomethyl)-2-fluoro-4-nitrobenzene [CAS 127349-56-8, Apollo] instead of 1-(bromomethyl)-4-nitrobenzene, 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene was obtained in 95% yield. LCMS: Method A: 1.98 min, MS: ES + No mass ions were observed

[0305] Step 2: 4-((benzyloxy)methyl)-3-fluoroaniline [ka]

[0306] Following the procedure of Intermediate 3, Step 2, using 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene at 45° C. for 18 hours, 4-((benzyloxy)methyl)-3-fluoroaniline was obtained in 67% yield without purification of the crude product. LCMS: Method A, 1.56 min, MSES + 232.1

[0307] Step 3: N-(4-((benzyloxy)methyl)-3-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-16) [ka]

[0308] To a mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 269409-73-6, BLD, 0.51 g, 2.1 mmol) and DIPEA (0.42 mL, 2.4 mmol) in DMF (2 mL) was added HATU (0.79 g, 2.1 mmol). After 10 min, 4-((benzyloxy)methyl)-3-fluoroaniline (0.40 g, 1.7 mmol) was added, and the mixture was stirred at 40 °C for 18 h. The mixture was cooled, poured into ice-water (30 mL), and extracted with EtOAc (2 × 50 mL). The combined organics were dried over Na SO and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0-100% EtOAc in isohexane) gave N-(4-((benzyloxy)methyl)-3-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (360 mg, 34%). LCMS: Method A: 2.31 min, MS: ES + 462.2

[0309] Intermediate 17 N-(4-(1-cyclopropylethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-17) [ka]

[0310] Step 1: 1-(1-cyclopropylethoxy)-2-fluoro-4-nitrobenzene [ka]

[0311] To 1-cyclopropylethan-1-ol (CAS 765-42-4, Fluorochem, 0.62 mL, 6.29 mmol) in THF (150 mL) was added tBuOK (776 mg, 6.91 mmol) in one portion at 0 °C. After 15 min, 1,2-difluoro-4-nitrobenzene (CAS 369-34-6, Fluorochem, 1.00 g, 6.29 mmol) in THF (40 mL) was added over 10 min, and the ice bath was removed. The mixture was stirred at room temperature for 1 h. Water (150 mL) was added, and the mixture was extracted with EtOAc (3 × 200 mL). The combined organics were washed with water (200 mL) and brine (200 mL), dried over NaSO, and concentrated under reduced pressure to give 1-(1-cyclopropylethoxy)-2-fluoro-4-nitrobenzene (1.20 g, 79%). LCMS: Method A: 1.90 min, MS: ES + 226.1

[0312] Step 2: 4-(1-cyclopropylethoxy)-3-fluoroaniline [ka]

[0313] Following the procedure of Intermediate 3, Step 2, using 1-(1-cyclopropylethoxy)-2-fluoro-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl (4.5 equivalents) instead of AcOH at 80 °C for 18 hours, 4-(1-cyclopropylethoxy)-3-fluoroaniline was obtained in 37% yield without purification of the crude product. LCMS: Method A, 0.97 min, MSES + 196.2

[0314] Step 3: N-(4-(1-cyclopropylethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-17) [ka]

[0315] Following the procedure of Step 3 of Intermediate 16, but using 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)benzoic acid and 4-(1-cyclopropylethoxy)-3-fluoroaniline instead of 4-((benzyloxy)methyl)-3-fluoroaniline 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. LCMS: Method A: 2.33 min, MS: ES + 444.2

[0316] Intermediate 18 N-(3-cyano-4-(1-cyclopropylethoxy)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-18) [ka]

[0317] Step 1: 2-(1-cyclopropylethoxy)-5-nitrobenzonitrile [ka]

[0318] To 1-cyclopropylethan-1-ol (CAS 765-42-4, Fluorochem, 0.59 mL, 6.02 mmol) in THF (150 mL) was added tBuOK (743 mg, 6.62 mmol) in one portion at 0 °C. After 15 min, 2-fluoro-5-nitrobenzonitrile (CAS 17417-09-3, Fluorochem, 1.00 g, 6.02 mmol) in THF (40 mL) was added over 10 min, and the ice bath was removed. The mixture was stirred at room temperature for 1 h. Water (150 mL) was added, and the mixture was extracted with EtOAc (3 × 200 mL). The combined organics were washed with water (200 mL) and brine (200 mL), dried over NaSO, and concentrated under reduced pressure to give 2-(1-cyclopropylethoxy)-5-nitrobenzonitrile (1.15 g, 76%). LCMS: Method A: 1.76 min, MS: ES + 233.1

[0319] Step 2: 5-Amino-2-(1-cyclopropylethoxy)benzonitrile [ka]

[0320] Following the procedure of Intermediate 3, Step 2, using 2-(1-cyclopropylethoxy)-5-nitrobenzonitrile instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl (4.5 equivalents) instead of AcOH at 80 °C for 18 hours, 5-amino-2-(1-cyclopropylethoxy)benzonitrile was obtained in 25% yield without purification of the crude product. LCMS: Method A, 1.24 min, MSES + 203.2

[0321] 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-18) [ka]

[0322] Following the procedure of Step 3 of Intermediate 16, using 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)benzoic acid and 5-amino-2-(1-cyclopropylethoxy)benzonitrile instead of 4-((benzyloxy)methyl)-3-fluoroaniline 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, which was used in the next step or analysis without purification.

[0323] Intermediate 19 N-(4-((1-phenylethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) [ka]

[0324] Following the procedure of Intermediate 16, Step 3, using 4-((1-phenylethoxy)methyl)aniline [CAS 2743-01-3, Fluorochem] instead of 4-((benzyloxy)methyl)-3-fluoroaniline, N-(4-((1-phenylethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 17% yield. LCMS: Method A: 2.3 min, MS: ES + 458.2

[0325] Intermediate 20 N-(4-(1-cyclopropylethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-20) [ka]

[0326] Following the procedure of Intermediate 16, Step 3, using 4-(1-cyclopropylethoxy)aniline [CAS 2168664-20-6, Enamine] instead of 4-((benzyloxy)methyl)-3-fluoroaniline, N-(4-(1-cyclopropylethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 23% yield. LCMS: Method A: 2.17 min, MS: ES + 408.2

[0327] Intermediate 21 N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21) [ka]

[0328] Step 1: 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene [ka]

[0329] Following the procedure of Intermediate 3, Step 1, using (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, 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene was obtained in 85% yield using LiOH (1 equiv.) and purification by flash chromatography (silica gel, 0-10% (0.7 M ammonia / MeOH) in DCM). LCMS: Method A: 1.94 min, MS: ES + 274.2

[0330] Step 2: 4-((benzyloxy)methyl)-2-methoxyaniline [ka]

[0331] Following the procedure of Intermediate 3, Step 2, using 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl (4.5 equivalents) instead of AcOH at 40 °C for 18 hours, 4-((benzyloxy)methyl)-2-methoxyaniline was obtained in 73% yield without purification of the crude product. LCMS: Method A, 1.27 min, MSES + 244.2

[0332] Step 3: N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21) [ka]

[0333] Following the procedure of Intermediate 16, Step 3, using 4-((benzyloxy)methyl)-2-methoxyaniline instead of 4-((benzyloxy)methyl)-3-fluoroaniline, 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

[0334] Intermediate 22 N-(3-fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-22) [ka]

[0335] Step 1: 2-(((2-fluoro-4-nitrobenzyl)oxy)methyl)pyridine [ka]

[0336] Following the procedure for Intermediate 3, Step 1, using pyridin-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, purification by flash chromatography (silica gel, 0 to 100% EtOAc in isohexane) gave 2-(((2-fluoro-4-nitrobenzyl)oxy)methyl)pyridine in 53% yield. LCMS: Method A: 1.16 min, MS: ES + 263.1

[0337] Step 2: 3-Fluoro-4-((pyridin-2-ylmethoxy)methyl)aniline [ka]

[0338] Following the procedure of Intermediate 3, Step 2, using 2-(((2-fluoro-4-nitrobenzyl)oxy)methyl)pyridine instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl (4.5 equivalents) instead of AcOH at 45 °C for 18 hours, 3-fluoro-4-((pyridin-2-ylmethoxy)methyl)aniline was obtained in 80% yield without purification of the crude product. LCMS: Method A, 0.62 min, MSES + 233.2

[0339] Step 3: N-(3-fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-22) [ka]

[0340] Following the procedure of Intermediate 16, Step 3, using 3-fluoro-4-((pyridin-2-ylmethoxy)methyl)aniline instead of 4-((benzyloxy)methyl)-3-fluoroaniline, N-(3-fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 72% yield. LCMS: Method A: 1.43 min, MS: ES + 463.2

[0341] Intermediate 23 N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-23) [ka]

[0342] Step 1: 2-Fluoro-1-(((4-methoxybenzyl)oxy)methyl)-4-nitrobenzene [ka]

[0343] Following the procedure for Intermediate 3, Step 1, 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, purification by flash chromatography (silica gel, 0 to 100% EtOAc in isohexane) gave 2-fluoro-1-(((4-methoxybenzyl)oxy)methyl)-4-nitrobenzene in 73% yield. LCMS: Method A: 1.66 min, MS: no mass ions observed

[0344] Step 2: 3-Fluoro-4-(((4-methoxybenzyl)oxy)methyl)aniline [ka]

[0345] Following the procedure of Intermediate 3, Step 2, using 2-fluoro-1-(((4-methoxybenzyl)oxy)methyl)-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl (4.5 equivalents) instead of AcOH at 45 °C for 18 hours, 3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)aniline was obtained in 91% yield without purification of the crude product. LCMS: Method A, 1.24 min, MSES + 262.2

[0346] 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-23) [ka]

[0347] Following the procedure of Intermediate 16, Step 3, using 3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)aniline instead of 4-((benzyloxy)methyl)-3-fluoroaniline, N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 49% yield. LCMS: Method A: 1.97 min, MS: ES + 492.2

[0348] Intermediate 24 N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-24) [ka]

[0349] Step 1: 2-Fluoro-1-(((3-methoxybenzyl)oxy)methyl)-4-nitrobenzene [ka]

[0350] Following the procedure for Intermediate 3, Step 1, 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, purification by flash chromatography (silica gel, 0 to 100% EtOAc in isohexane) gave 2-fluoro-1-(((3-methoxybenzyl)oxy)methyl)-4-nitrobenzene in 81% yield. LCMS: Method A: 1.67 min, MS: ES + 309.1(M+NH4)+

[0351] Step 2: 3-Fluoro-4-(((3-methoxybenzyl)oxy)methyl)aniline [ka]

[0352] Following the procedure of Intermediate 3, Step 2, using 2-fluoro-1-(((3-methoxybenzyl)oxy)methyl)-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl (4.5 equivalents) instead of AcOH at 45 °C for 18 hours, 3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)aniline was obtained in 75% yield without purification of the crude product. LCMS: Method A, 1.28 min, MSES + 262.1

[0353] 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-24) [ka]

[0354] Following the procedure of Intermediate 16, Step 3, using 3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)aniline instead of 4-((benzyloxy)methyl)-3-fluoroaniline, N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 56% yield. LCMS: Method A: 1.99 min, MS: ES + 492.2

[0355] Intermediate 25 N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-25) [ka]

[0356] Following the procedure of Intermediate 16, Step 3, using 4-((benzyloxy)methyl)aniline (I-3) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 70% yield. LCMS: Method A: 2.23 min, MS: ES + 444.2

[0357] Intermediate 26 6-Chloro-N-(4-phenethoxyphenyl)pyrimidine-4-carboxamide (I-26) [ka]

[0358] Following the procedure of Step 3 of Intermediate 16, using T3P (50% in EtOAc, 1.1 equivalents) instead of HATU, 6-chloro-4-pyrimidinecarboxylic acid [CAS 37131-91-2, BLD] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-phenethoxyaniline (I-1a) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, 6-chloro-N-(4-phenethoxyphenyl)pyrimidine-4-carboxamide was obtained in 46% yield. LCMS: Method C: 1.12 min, MS: ES + 354

[0359] Intermediate 27 4-Bromo-N-(4-phenethoxyphenyl)picolinamide (I-27) [ka]

[0360] Following the procedure of Step 3 of Intermediate 16, using T3P (50% in EtOAc, 1.1 equivalents) instead of HATU, 4-bromopicolinic acid [CAS 30766-03-1, BLD] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-phenethoxyaniline (I-1a) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, 4-bromo-N-(4-phenethoxyphenyl)picolinamide was obtained in 74% yield. LCMS: Method C: 1.18 min, MS: ES + 397.0 / 399.0

[0361] Intermediate 28 6-Chloro-N-(4-phenethoxyphenyl)pyridazine-4-carboxamide (I-28) [ka]

[0362] Following the procedure of Step 3 of Intermediate 16, using T3P (50% in EtOAc, 1.1 equiv.) instead of HATU, 3-chloropyridazine-5-carboxylic acid [CAS 1256794-24-7, BLD] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-phenethoxyaniline (I-1a) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, 6-chloro-N-(4-phenethoxyphenyl)pyridazine-4-carboxamide was obtained in 81% yield. LCMS: Method C: 1.04 min, MS: ES + 354

[0363] Intermediate 29 2-Bromo-N-(4-(cyclopropylmethoxy)phenyl)isonicotinamide (I-29) [ka]

[0364] Following the procedure of Step 3 of Intermediate 16, using T3P (50% in EtOAc, 1.1 equiv.) instead of HATU, 2-bromoisonicotinic acid [CAS 66572-56-3, Apollo] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-(cyclopropylmethoxy)aniline (I-6) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, 2-bromo-N-(4-(cyclopropylmethoxy)phenyl)isonicotinamide was obtained in 50% yield. LCMS: Method C: 1.02 min, MS: ES + 347.0 / 349.0

[0365] Intermediate 30 2-Bromo-N-(4-(cyclopropylmethoxy)phenyl)-5-fluoroisonicotinamide (I-30) [ka]

[0366] Following the procedure of Step 3 of Intermediate 16, using T3P (50% in EtOAc, 1.1 equiv.) instead of HATU, 2-bromo-5-fluoroisonicotinic acid [CAS 885588-12-5, BLD] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-(cyclopropylmethoxy)aniline (I-6) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, 2-bromo-N-(4-(cyclopropylmethoxy)phenyl)-5-fluoroisonicotinamide was obtained in 68% yield. LCMS: Method C: 1.04 min, MS: ES + 365.0 / 367.0

[0367] Intermediate 31 N-(4-((benzyloxy)methyl)phenyl)-2-bromoisonicotinamide (I-31) [ka]

[0368] Following the procedure of Step 3 of Intermediate 16, using T3P (50% in EtOAc, 1.1 equiv.) instead of HATU, 2-bromoisonicotinic acid [CAS 66572-56-3, Apollo] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)aniline (I-3) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, N-(4-((benzyloxy)methyl)phenyl)-2-bromoisonicotinamide was obtained in 53% yield. LCMS: Method A: 1.97 min, MS: ES + 397.0 / 399.0

[0369] Intermediate 32 N-(4-((benzyloxy)methyl)phenyl)-2-chloro-6-methylisonicotinamide (I-32) [ka]

[0370] Following the procedure of Step 3 of Intermediate 16, using T3P (50% in EtOAc, 1.1 equiv.) instead of HATU, 2-chloro-6-methylisonicotinic acid [CAS 25462-85-5, Fluorochem] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)aniline (I-3) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, N-(4-((benzyloxy)methyl)phenyl)-2-chloro-6-methylisonicotinamide was obtained in 52% yield. LCMS: Method C: 0.84 min, MS: ES + 367.2

[0371] Intermediate 33 N-(4-((benzyloxy)methyl)phenyl)-2-bromo-5-fluoroisonicotinamide (I-33) [ka]

[0372] Following the procedure of Step 3 of Intermediate 16, using T3P (50% in EtOAc, 1.1 equivalents) instead of HATU, 2-bromo-5-fluoroisonicotinic acid [CAS 885588-12-5, BLD] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)aniline (I-3) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, N-(4-((benzyloxy)methyl)phenyl)-2-bromo-5-fluoroisonicotinamide was obtained in 63% yield. LCMS: Method C: 1.1 min, MS: ES + 415.0 / 417.0

[0373] Intermediate 34 N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-bromoisonicotinamide (I-34) [ka]

[0374] Following the procedure of Intermediate 16, Step 3, using 2-bromoisonicotinic acid [CAS 66572-56-3, Apollo] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid at room temperature instead of 40 °C, N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-bromoisonicotinamide was obtained in 41% yield. LCMS: Method A: 2 min, MS: ES + 415.1 / 417.0

[0375] Intermediate 35 2-Bromo-N-(4-(cyclopropoxymethyl)-3-fluorophenyl)isonicotinamide (I-35) [ka]

[0376] Step 1: 1-(cyclopropoxymethyl)-2-fluoro-4-nitrobenzene [ka]

[0377] To a mixture of cyclopropanol (CAS 16545-68-9, BLD, 2.71 mL, 42.7 mmol) and 1-(bromomethyl)-2-fluoro-4-nitrobenzene (CAS 127349-56-8, BLD, 1.00 g, 4.27 mmol) was added KOH (288 mg, 5.13 mmol). The mixture was stirred at room temperature for 18 h, poured into ice-water (ca. 400 mL), and extracted with EtOAc (3 × 100 mL). The organics were washed with brine (50 mL), dried over MgSO4, and adsorbed onto silica gel. Purification by flash chromatography (silica gel, 0–10% EtOAc in isohexane) gave 1-(cyclopropoxymethyl)-2-fluoro-4-nitrobenzene (300 mg, 32%). LCMS: Method A: 1.71 min, MS: ES + 212.1

[0378] Step 2: 4-(cyclopropoxymethyl)-3-fluoroaniline [ka]

[0379] Following the procedure of Intermediate 3, Step 2, using 1-(cyclopropoxymethyl)-2-fluoro-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl (4.5 equivalents) instead of AcOH at 80 °C for 18 hours, 4-(cyclopropoxymethyl)-3-fluoroaniline was obtained in 58% yield without purification of the crude product. LCMS: Method A, 1.13 min, MS: ES + 182.2

[0380] Step 3: 2-Bromo-N-(4-(cyclopropoxymethyl)-3-fluorophenyl)isonicotinamide (I-35) [ka]

[0381] Following the procedure of Step 3 of Intermediate 16, using 2-bromoisonicotinic acid [CAS 66572-56-3, Apollo] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and 4-(cyclopropoxymethyl)-3-fluoroaniline instead of 4-((benzyloxy)methyl)-3-fluoroaniline, and at room temperature instead of 40° C., 2-bromo-N-(4-(cyclopropoxymethyl)-3-fluorophenyl)isonicotinamide was obtained in 65% yield. LCMS: Method A: 1.78 min, MS: ES + 365.0 / 367.0

[0382] Intermediate 36 2-Bromo-N-(4-(cyclopropylmethoxy)-3-fluorophenyl)isonicotinamide (I-36) [ka]

[0383] Following the procedure of Step 3 of Intermediate 16, using 2-bromoisonicotinic acid [CAS 66572-56-3, Apollo] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and 4-(cyclopropylmethoxy)-3-fluoroaniline [CAS 937598-42-0, Enamine] instead of 4-((benzyloxy)methyl)-3-fluoroaniline at room temperature instead of 40 °C, 2-bromo-N-(4-(cyclopropylmethoxy)-3-fluorophenyl)isonicotinamide was obtained in 74% yield. LCMS: Method A: 1.82 min, MS: ES + 365.0 / 367.0

[0384] Intermediate 37 (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid (I-37) [ka]

[0385] Following the procedure of Step 3 of Intermediate 16, using 5-borono-2-methoxybenzoic acid [CAS913836-12-1, BLD] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and 4-((benzyloxy)methyl)aniline (I-3) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid was obtained in 87% yield. LCMS: Method A: 1.74 min, MS: ES + 392.2

[0386] Intermediate 38 N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-38) [ka]

[0387] Following the procedure of Step 3 of Intermediate 16, using 4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid [CAS 269409-71-4, Manchester Organics] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and 4-((benzyloxy)methyl)aniline (I-3) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 52% yield. LCMS: Method A: 2.12 min, MS: ES + 474.2

[0388] Intermediate 39 (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid (I-39) [ka]

[0389] Following the procedure of Step 3 of Intermediate 16, 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-3) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid was obtained in 34% yield. LCMS: Method A: 1.71 min, MS: ES + 376.2

[0390] Intermediate 40 N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-40) [ka]

[0391] Following the procedure of Step 3 of Intermediate 16, using 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid [CAS 515131-35-8, BLD] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and 4-((benzyloxy)methyl)aniline (I-3) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3-(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 + 458.3

[0392] Intermediate 41 N-(4-(cyclopropylmethoxy)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-41) [ka]

[0393] Following the procedure of Step 3 of Intermediate 16, using 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)benzoic acid and 4-(cyclopropylmethoxy)aniline (I-6) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, purification by flash chromatography (silica gel, 0–10% MeOH in DCM) afforded 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

[0394] Intermediate 42 (5-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-42) [ka]

[0395] Following the procedure of Step 3 of Intermediate 16, using 3-borono-4-fluorobenzoic 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-3) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, (5-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid was obtained in 91% yield. LCMS: Method A: 1.67 min, MS: ES + 380.2

[0396] Intermediate 43 (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-43) [ka]

[0397] Following the procedure of Step 3 of Intermediate 16, 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-3) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid was obtained in 57% yield. LCMS: Method A: 1.67 min, MS: ES + 380.2

[0398] Intermediate 44 (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid (I-44) [ka]

[0399] Following the procedure of Step 3 of Intermediate 16, using 3-borono-2,6-difluorobenzoic acid [CAS 1451393-05-7, Combi-Blocks] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and 4-((benzyloxy)methyl)aniline (I-3) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, purification by flash chromatography (silica gel, 0–10% MeOH in DCM) afforded (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid in 35% yield. LCMS: Method A: 1.68 min, MS: ES + 398.1

[0400] Intermediate 45 N-(4-((cyclopropylmethoxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-45) [ka]

[0401] Step 1: 1-((cyclopropylmethoxy)methyl)-2-fluoro-4-nitrobenzene [ka]

[0402] Following the procedure of Intermediate 3, Step 1, using cyclopropylmethanol [CAS 2516-33-8, Fluorochem] instead of phenylmethanol and 1-(bromomethyl)-2-fluoro-4-nitrobenzene [CAS 127349-56-8, Apollo] instead of 1-(bromomethyl)-4-nitrobenzene, 1-((cyclopropylmethoxy)methyl)-2-fluoro-4-nitrobenzene was obtained in 82% yield. LCMS: Method A: 1.82 min, MS: ES+ 226.1

[0403] Step 2: 4-((cyclopropylmethoxy)methyl)-3-fluoroaniline [ka]

[0404] Following the procedure of Intermediate 3, Step 2, using 1-((cyclopropylmethoxy)methyl)-2-fluoro-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene and CaCl (4.5 equivalents) instead of AcOH at 80 °C for 18 hours, 4-((cyclopropylmethoxy)methyl)-3-fluoroaniline was obtained in 67% yield without purification of the crude product. LCMS: Method A, 1.23 min, MSES + 196.2

[0405] Step 3: N-(4-((cyclopropylmethoxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-45) [ka]

[0406] Following the procedure of Step 3 of Intermediate 16, using 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)benzoic acid and 4-((cyclopropylmethoxy)methyl)-3-fluoroaniline instead of 4-((benzyloxy)methyl)-3-fluoroaniline, 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

[0407] Intermediate 46 N-(4-(cyclopropylmethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-46) [ka]

[0408] Following the procedure of Step 3 of Intermediate 16, using 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)benzoic acid and 4-(cyclopropylmethoxy)-3-fluoroaniline [CAS 937598-42-0, Enamine] instead of 4-((benzyloxy)methyl)-3-fluoroaniline 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

[0409] Intermediate 47 N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-47) [ka]

[0410] Following the procedure of Step 3 of Intermediate 16, using 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)benzoic acid 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

[0411] Intermediate 48 N-(4-(cyclopropoxymethyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-48) [ka]

[0412] Following the procedure of Intermediate 16, Step 3, but using 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)benzoic acid and 4-(cyclopropoxymethyl)-3-fluoroaniline (Intermediate 35, Step 2) instead of 4-(benzyloxy)methyl)-3-fluoroaniline at room temperature instead of 40 °C, N-(4-(cyclopropoxymethyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 35% yield. LCMS: Method A: 2.19 min, MS: ES + 430.2

[0413] Intermediate 49 3-Bromo-N-(1-phenethyl-1H-pyrazol-4-yl)benzamide (I-49) [ka]

[0414] Step 1: 4-Nitro-1-phenethyl-1H-pyrazole [ka]

[0415] A mixture of 4-nitro-1H-pyrazole (CAS 2075-46-9, Fluorochem, 300 mg, 2.65 mmol), CsCO (1.73 g, 5.31 mmol), and (2-bromoethyl)benzene (CAS 103-63-9, Combi-Blocks, 0.722 mL, 5.31 mmol) in DMF (2 mL) was stirred at 60 °C for 16 h. Water (30 mL) was added, and the mixture was extracted with EtOAc (3 × 20 mL). The organics were dried over NaSO and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0–50% EtOAc in isohexane) gave 4-nitro-1-phenethyl-1H-pyrazole (620 mg, 100%). LCMS: Method A: 1.56 min, MS: ES + 218.1

[0416] Step 2: 1-phenethyl-1H-pyrazol-4-amine [ka]

[0417] A solution of 4-nitro-1-phenethyl-1H-pyrazole (300 mg, 1.30 mmol) in MeOH (15.0 mL) was passed through a Pd / C 10% cartridge under hydrogen at room temperature and 18 bar (H-Cube®). The mixture was concentrated under reduced pressure to give 1-phenethyl-1H-pyrazol-4-amine (238 mg, 89%). LCMS: Method A: 0.14 min, MS: ES + 188.2

[0418] Step 3: 3-Bromo-N-(1-phenethyl-1H-pyrazol-4-yl)benzamide (I-49) [ka]

[0419] To 3-bromobenzoyl chloride (1711-09-7, BLD, 254 mg, 1.16 mmol), pyridine (0.233 mL, 2.89 mmol) in THF (8 mL) was added 1-phenethyl-1H-pyrazol-4-amine (238 mg, 1.16 mmol) and then DMAP (28 mg, 0.231 mmol). The mixture was stirred at 40 °C for 2 h and cooled to room temperature. Water (2 mL) was added, and the mixture was extracted with DCM (30 mL). The organic phase was dried under reduced pressure, and the residue was triturated with EtO (2 × 10 mL) to give 3-bromo-N-(1-phenethyl-1H-pyrazol-4-yl)benzamide (400 mg, 93%). LCMS: Method A: 1.79 min, MS: ES + 370.0 / 372.0

[0420] Intermediate 50 3-Bromo-N-(4-(tosylmethyl)phenyl)benzamide (I-50) [ka]

[0421] Following the procedure of Step 3 of Intermediate 49, using (4-{[(4-methylphenyl)sulfonyl]methyl}phenyl)amine [54306-15-9, Combi-Blocks] instead of 1-phenethyl-1H-pyrazol-4-amine, 3-bromo-N-(4-(tosylmethyl)phenyl)benzamide was obtained in 85% yield. LCMS: Method A: 1.89 min, MS: ES +461.1 / 463.1(M+17)

[0422] Intermediate 51 Methyl 5-(3-(chlorocarbonyl)phenyl)-2-methylnicotinate, HCl (I-51) [ka]

[0423] To 3-(5-(methoxycarbonyl)-6-methylpyridin-3-yl)benzoic acid (I-11, 790 mg, 2.91 mmol) in DCM (12 mL) was added oxalyl chloride (2.55 mL, 29.1 mmol) and DMF (0.023 mL, 0.291 mmol) at 0° C. The mixture was stirred at room temperature for 18 h and concentrated under reduced pressure to give methyl 5-(3-(chlorocarbonyl)phenyl)-2-methylnicotinate, HCl (986 mg, 85%). LCMS: Method A: 1.28 min, MS: ES + 286.1 (in MeOH)

[0424] Intermediate 52 5-Bromo-6-chloro-N-(4-phenethoxyphenyl)nicotinamide (I-52) [ka]

[0425] Following the procedure of Step 3 of Intermediate 16, using T3P (50% in EtOAc, 1.1 equiv.) instead of HATU, 5-bromo-6-chloronicotinic acid [CAS 29241-62-1, Fluorochem] instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-phenethoxyaniline (I-1a) instead of 4-((benzyloxy)methyl)-3-fluoroaniline, 5-bromo-6-chloro-N-(4-phenethoxyphenyl)nicotinamide was obtained in 76% yield. LCMS: Method C: 1.16 min, MS: ES +431.0 / 433.0

[0426] Intermediate 53 Methyl 5-(3-((4-(((4-chlorophenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-53) [ka]

[0427] Step 1: 1-chloro-4-((4-nitrobenzyl)sulfonyl)benzene [ka]

[0428] To a vial containing sodium 4-chlorobenzenesulfinate (101 mg, 0.509 mmol) in DMF (2.00 mL) was added 1-(bromomethyl)-4-nitrobenzene (100 mg, 0.463 mmol), and the mixture was stirred at room temperature for 2 h to give 1-chloro-4-((4-nitrobenzyl)sulfonyl)benzene, which was used directly in the subsequent step and assumed 100% yield. LCMS: Method A: 1.69 min, MS: ES - 310.0

[0429] Step 2: 4-(((4-chlorophenyl)sulfonyl)methyl)aniline [ka]

[0430] The mixture from step 1 was diluted with MeOH (8 mL) and passed through a Pd / C 10% cartridge under hydrogen at room temperature at 1 bar for 1 h (H-Cube®). The mixture was concentrated under reduced pressure to give 4-(((4-chlorophenyl)sulfonyl)methyl)aniline (120 mg, 92% over two steps), which was used without purification. LCMS: Method A: 1.11 min, MS: ES + 282.1

[0431] Step 3: Methyl 5-(3-((4-(((4-chlorophenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-53) [ka]

[0432] Methyl 5-(3-(chlorocarbonyl)phenyl)-2-methylnicotinate. To HCl (I-51, 77 mg, 0.176 mmol) and pyridine (0.047 mL, 0.586 mmol) in THF (4 mL) was added 4-(((4-chlorophenyl)sulfonyl)methyl)aniline (55 mg, 0.195 mmol). The mixture was stirred at room temperature for 2 h, quenched with water (2 mL), and extracted with DCM (30 mL). The organics were dried under reduced pressure, and the residue was triturated with EtO (2 × 10 mL) to give methyl 5-(3-((4-(((4-chlorophenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (70 mg, 54%). LCMS: Method A: 1.87 min, MS: ES + 535.1

[0433] Intermediate 54 Methyl 5-(3-((4-(((3-chlorophenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-54) [ka]

[0434] Step 1: 1-chloro-3-((4-nitrobenzyl)sulfonyl)benzene [ka]

[0435] Following the procedure of Intermediate 53, Step 1, using sodium 3-chlorobenzenesulfinate [CAS 15946-37-9, Fluorochem] instead of sodium 4-chlorobenzenesulfinate, and isolating by addition of water and collecting the solid by filtration, 1-chloro-3-((4-nitrobenzyl)sulfonyl)benzene was obtained in 71% yield. LCMS: Method A: 1.28 min, MS: ES - 310

[0436] Step 2: 4-(((3-chlorophenyl)sulfonyl)methyl)aniline [ka]

[0437] Following the procedure of Intermediate 53, Step 2, using 1-chloro-3-((4-nitrobenzyl)sulfonyl)benzene instead of 1-chloro-4-((4-nitrobenzyl)sulfonyl)benzene, 4-(((3-chlorophenyl)sulfonyl)methyl)aniline was obtained in 93% yield. LCMS: Method A: 0.87 min, MS: ES + 282.1

[0438] Step 3: Methyl 5-(3-((4-(((3-chlorophenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-54) [ka]

[0439] Following the procedure of Intermediate 53, Step 3, using 4-(((3-chlorophenyl)sulfonyl)methyl)aniline instead of 4-(((4-chlorophenyl)sulfonyl)methyl)aniline, methyl 5-(3-((4-(((3-chlorophenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-54) was obtained in 67% yield. LCMS: Method A: 1.57 min, MS: ES + 535.1

[0440] Intermediate 55 Methyl 5-(3-((4-(((2-chlorophenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-55) [ka]

[0441] Step 1: 1-chloro-2-((4-nitrobenzyl)sulfonyl)benzene [ka]

[0442] Following the procedure of Intermediate 53, Step 1, using sodium 2-chlorobenzenesulfinate [CAS 15946-36-8, Fluorochem] instead of sodium 4-chlorobenzenesulfinate, with isolation by addition of water and collection of the solid by filtration, 1-chloro-2-((4-nitrobenzyl)sulfonyl)benzene was obtained in 82% yield. LCMS: Method A: 0.16 min, MS: ES + No mass ions were observed

[0443] Step 2: 4-(((2-chlorophenyl)sulfonyl)methyl)aniline [ka]

[0444] Following the procedure of Intermediate 53, Step 2, using 1-chloro-2-((4-nitrobenzyl)sulfonyl)benzene instead of 1-chloro-4-((4-nitrobenzyl)sulfonyl)benzene MeOH / THF (1:3), 4-(((2-chlorophenyl)sulfonyl)methyl)aniline was obtained in 79% yield. LCMS: Method A: 0.79 min, MS: ES+ 282.1

[0445] Step 3: Methyl 5-(3-((4-(((2-chlorophenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-55) [ka]

[0446] Following the procedure of Intermediate 53, Step 3, using 4-(((2-chlorophenyl)sulfonyl)methyl)aniline instead of 4-(((4-chlorophenyl)sulfonyl)methyl)aniline, methyl 5-(3-((4-(((2-chlorophenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate was obtained in 79% yield. LCMS: Method A: 0.79 min, MS: ES + 535

[0447] Intermediate 56 Methyl 5-(3-((4-(((4-methoxyphenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-56) [ka]

[0448] Step 1: 1-Methoxy-4-((4-nitrobenzyl)sulfonyl)benzene [ka]

[0449] Following the procedure of Intermediate 53, Step 1, using sodium 4-methoxybenzenesulfinate [CAS 6462-50-6, BLD] instead of sodium 4-chlorobenzenesulfinate, and isolating by addition of water and collecting the solid by filtration, 1-methoxy-4-((4-nitrobenzyl)sulfonyl)benzene was obtained in 31% yield. LCMS: Method A: 1.25 min, MS: ES + 308

[0450] Step 2: 4-(((4-methoxyphenyl)sulfonyl)methyl)aniline [ka]

[0451] A mixture of 1-methoxy-4-((4-nitrobenzyl)sulfonyl)benzene (250 mg, 0.496 mmol), zinc (195 mg, 2.98 mmol), and ammonium formate (188 mg, 2.98 mmol) in EtOH (8 mL) was stirred at 80° C. for 4 h. The mixture was diluted with DCM (40 mL), and the organics were decanted and dried under reduced pressure to give 4-(((4-methoxyphenyl)sulfonyl)methyl)aniline (95 mg, 43%). LCMS: Method A: 0.68 min, MS: ES + 278.1

[0452] Step 3: Methyl 5-(3-((4-(((4-methoxyphenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-56) [ka]

[0453] Following the procedure of Intermediate 53, Step 3, using 4-(((4-methoxyphenyl)sulfonyl)methyl)aniline instead of 4-(((4-chlorophenyl)sulfonyl)methyl)aniline, methyl 5-(3-((4-(((4-methoxyphenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate was obtained in 34% yield. LCMS: Method A: 1.47 min, MS: ES + 531.2

[0454] Intermediate 57 Methyl 5-(3-((4-(((3-methoxyphenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-57) [ka]

[0455] Step 1: 1-Methoxy-3-((4-nitrobenzyl)sulfonyl)benzene [ka]

[0456] Following the procedure of Intermediate 53, Step 1, using sodium 2-methoxybenzenesulfinate [CAS 15898-41-6, BLD] instead of sodium 4-chlorobenzenesulfinate, 1-methoxy-3-((4-nitrobenzyl)sulfonyl)benzene was obtained in 77% yield, with isolation by addition of water and collection of the solid by filtration. LCMS: Method A: 1.28 min, MS: ES + 325.1(M+NH4 + ) +

[0457] Step 2: 4-(((3-methoxyphenyl)sulfonyl)methyl)aniline [ka]

[0458] A mixture of 1-methoxy-3-((4-nitrobenzyl)sulfonyl)benzene (385 mg, 1.25 mmol), zinc (491 mg, 7.52 mmol), and ammonium formate (474 ​​mg, 7.52 mmol) in ethanol (8 mL) was stirred at 80° C. for 4 h. Additional Zn (200 mg) and ammonium formate (500 mg) were added, and the mixture was stirred at 80° C. for an additional 14 h. The mixture was diluted with THF / MeOH (30 mL, 3:1), and the solids were removed by filtration. Purification by capture on SCX, washing with MeOH, and elution with NH in MeOH (2 M) gave 4-(((3-methoxyphenyl)sulfonyl)methyl)aniline in 57% yield. LCMS: Method A: 0.72 min, MS: ES + 278.1

[0459] Step 3: Methyl 5-(3-((4-(((3-methoxyphenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-57) [ka]

[0460] Following the procedure of Intermediate 53, Step 3, using 4-(((3-methoxyphenyl)sulfonyl)methyl)aniline instead of 4-(((4-chlorophenyl)sulfonyl)methyl)aniline, methyl 5-(3-((4-(((3-methoxyphenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate was obtained in 43% yield. LCMS: Method A: 1.49 min, MS: ES + 531.2

[0461] Intermediate 58 Methyl 2-methyl-5-(3-((4-(((6-methylpyridin-3-yl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)nicotinate (I-58) [ka]

[0462] Step 1: 2-Methyl-5-((4-nitrobenzyl)sulfonyl)pyridine [ka]

[0463] Following the procedure of Intermediate 53, Step 1, using sodium 6-methylpyridine-3-sulfinate [CAS 1138034-14-6, Biosynth] instead of sodium 4-chlorobenzenesulfinate, with isolation by addition of water and collection of the solid by filtration, 2-methyl-5-((4-nitrobenzyl)sulfonyl)pyridine was obtained in 69% yield. LCMS: Method A: 1.01 min, MS: ES + 293.1

[0464] Step 2: 4-(((6-methylpyridin-3-yl)sulfonyl)methyl)aniline [ka]

[0465] A mixture of 2-methyl-5-((4-nitrobenzyl)sulfonyl)pyridine (510 mg, 1.74 mmol), zinc (1.14 g, 17.4 mmol), and ammonium formate (1.10 g, 17.4 mmol) in EtOH (8 mL) was stirred at 80° C. for 4 h. The mixture was concentrated under reduced pressure. THF / MeOH (30 mL, 3:1) was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure to give 4-(((6-methylpyridin-3-yl)sulfonyl)methyl)aniline (540 mg, 50%). LCMS: Method A: 0.38 min, MS: ES + 263.1

[0466] Step 3: Methyl 2-methyl-5-(3-((4-(((6-methylpyridin-3-yl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)nicotinate (I-58) [ka]

[0467] Following the procedure of Intermediate 53, Step 3, using 4-(((6-methylpyridin-3-yl)sulfonyl)methyl)aniline instead of 4-(((4-chlorophenyl)sulfonyl)methyl)aniline, methyl 2-methyl-5-(3-((4-(((6-methylpyridin-3-yl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)nicotinate was obtained in 23% yield. LCMS: Method A: 1.44 min, MS: ES + 516.1

[0468] Intermediate 59 5-Bromo-6-(methylthio)-N-(4-phenethoxyphenyl)nicotinamide (I-59) [ka]

[0469] To 5-bromo-6-chloro-N-(4-phenethoxyphenyl)nicotinamide (I-52, 319 mg, 0.724 mmol) in dry DMF (2 mL) was added NaSMe (51 mg, 0.724 mmol). The mixture was stirred at room temperature for 18 hours and diluted with water (10 mL). The solid was collected by filtration and washed with MeOH and acetone to give 5-bromo-6-(methylthio)-N-(4-phenethoxyphenyl)nicotinamide (213 mg, 66%). LCMS: Method A: 0.94 min, MS: ES + 443.0 / 445.0

[0470] Intermediate 60 5-Bromo-6-(2-methoxyethoxy)-N-(4-phenethoxyphenyl)nicotinamide (I-60) [ka]

[0471] A mixture of 2-methoxyethanol (0.627 mL, 7.95 mmol) and KOtBu (446 mg, 3.97 mmol) was stirred at room temperature for 10 minutes, and 5-bromo-6-chloro-N-(4-phenethoxyphenyl)nicotinamide (I-52, 350 mg, 0.795 mmol) was added. The mixture was stirred at room temperature for 1 hour and at 50° C. for 4 hours. The mixture was cooled to room temperature and diluted with water (10 mL). The solid was collected by filtration and washed with water to give 5-bromo-6-(2-methoxyethoxy)-N-(4-phenethoxyphenyl)nicotinamide (249 mg, 63%). LCMS: Method C: 0.88 min, MS: ES + 471.0 / 473.0 [Example] [Example 1]

[0472] 4-Hydroxy-3'-((4-phenethoxyphenyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid [ka]

[0473] To a stirred mixture of 5-bromo-2-hydroxybenzoic acid (CAS89-55-4, Acros, 50 mg, 0.23 mmol) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-1, 123 mg, 0.28 mmol) in dioxane (4 mL) and water (1 mL), CsCO (300 mg, 0.92 mmol) was added, and the reaction mixture was degassed with a stream of nitrogen at room temperature for 5 minutes. Pd-118 (0.03 g, 0.04 mmol) was added, and the mixture was degassed for another 2 minutes. The reaction mixture was stirred at 80 °C for 18 hours, then cooled to room temperature, acidified with aqueous HCl (1 M, 5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic phase was dried over NaSO and concentrated under reduced pressure. The crude product was purified by RP flash chromatography (C18, 0–100% MeCN in 0.1% aqueous NH4OH) to give 4-hydroxy-3′-((4-phenethoxyphenyl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid (40 mg, 36%). LCMS: Method A, 2.12 min, MS: ES + 454.2; 1 H NMR (500 MHz, DMSO) δ ppm: 10.23 (s, 1H), 8.14 (s, 1H), 8.12 (d, J = 2.6 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.83–7.78 (m, 2H), 7.68 (d, J = 9.0 Hz, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.38–7.29 (m, 4H), 7.27–7.20 (m, 1H), 6.95 (d, J = 9.0 Hz, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H). 3H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 2-29]

[0474] The following Examples 2-29 were prepared similarly to Example 1, substituting 5-bromo-2-hydroxybenzoic acid (CAS 89-55-4) for the appropriate starting material and with minor modifications as noted. In some cases, esters were used in place of the carboxylic acid, and partial or complete hydrolysis to the acid product occurred under the reaction conditions. Examples 15 and 17 were purified with an acidic modifier. [ka] [Example 2]

[0475] 2-Cyclopropyl-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0476] Starting from 5-bromo-2-cyclopropylnicotinic acid (CAS 1601026-05-4, Enamine), 2-cyclopropyl-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid was obtained in 62% yield after 18 hours of reaction at 90°C. LCMS: Method A, 2.05 min, MS: ES + 479.2; 1 H NMR(500MHz,DMSO)δppm:13.57(s,1H), 10.22(s,1H), 8.93(s,1H), 8.38(s, 1H), 8.26(d,J=1.9Hz,1H), 7.99~7.91(m,2H), 7.68~7.63(m,3H), 7.37~7.2 9(m,4H), 7.27~7.20(m,1H), 6.98~6.93(m,2H), 4.19(t,J=6.9Hz,2H), 3.12 ~3.07(m,1H), 3.04(t,J=6.9Hz,2H), 1.11~1.06(m,2H), 1.05~1.00(m,2H). The isolated compounds contained up to 1 molar equivalent of ammonia. [Example 3]

[0477] 2-Oxo-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)-1,2-dihydropyridine-3-carboxylic acid [ka]

[0478] Starting from methyl 5-bromo-2-hydroxynicotinate (CAS 120034-05-1, BLD), 2-oxo-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)-1,2-dihydropyridine-3-carboxylic acid was obtained in 10% yield after 18 hours of reaction at 90°C. LCMS: Method B, 1.23 min, MS: ES + 455.2; 1 H NMR(500MHz,DMSO)δppm:13.74(s,1H), 10.24(s,1H), 8.66(d,J=2.8Hz,1H), 8.44(d,J=2.8Hz,1H), 8.21~8.17(m,1H), 7.91(d,J=7.7Hz,1H), 7.88(d,J=7. 7Hz,1H), 7.70~7.63(m,2H), 7.60(t,J=7.7Hz,1H), 7.38~7.29(m,4H), 7.27~ 7.20(m,1H), 6.99~6.92(m,2H), 4.19(t,J=6.9Hz,2H), 3.05(t,J=6.9Hz,2H). 1H unclear / not observed. Isolated compounds contained up to 1 molar equivalent of ammonia. [Example 4]

[0479] 5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)-2-(trifluoromethyl)nicotinic acid [ka]

[0480] Starting from 5-bromo-2-(trifluoromethyl)nicotinic acid (CAS 436799-36-9, Combi-Blocks), 5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)-2-(trifluoromethyl)nicotinic acid was obtained in 46% yield after 18 hours of reaction at 90°C. LCMS: Method A, 2.03 min, MS: ES + 507.1; 1 H NMR (500 MHz, DMSO) δ ppm: 10.21 (s, 1H), 8.92 (s, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.19 (s, 1H), 7.97–7.92 (m, 2H), 7.61–7.58 (m, 2H), 7.29–7.23 (m, 4H), 7.17–7.12 (m, 2H), 6.90–6.87 (m, 2H), 4.12 (t, J = 6.9 Hz, 2H), 2.97 (t, J = 6.9 Hz, 2H). 1H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 5]

[0481] 5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0482] Starting from methyl 5-bromonicotinate (CAS 29681-44-5, Fluorochem), 5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid was obtained in 35% yield after 18 hours of reaction at 85°C. LCMS: Method A, 1.85 min, MS: ES + 439.2; 1H NMR (500 MHz, DMSO) δ ppm: 10.27 (s, 1H), 9.15–9.12 (m, 1H), 9.11–9.05 (m, 1H), 8.59–8.54 (m, 1H), 8.34–8.30 (m, 1H), 8.03–7.96 (m, 2H), 7.69–7.63 (m, 3H), 7.37–7.29 (m, 4H), 7.26–7.19 (m, 1H), 6.99–6.93 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H). 1H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 6]

[0483] 2-(5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)pyridin-3-yl)acetic acid [ka]

[0484] Starting from 2-(5-bromopyridin-3-yl)acetic acid (CAS 39891-12-839, Thermo Scientific), 2-(5-(3-((4-phenethoxyphenyl)carbamoyl)-phenyl)pyridin-3-yl)acetic acid was obtained in 45% yield after 18 hours of reaction at 80°C. LCMS: Method A, 1.66 min, MS: ES + 453.2; 1 H NMR(500MHz,DMSO)δppm:10.18(s,1H), 8.75(d,J=2.1Hz,1H), 8.39(d,J=2.1Hz,1H), 8.17(s,1H), 7.96(s,1H), 7.89(d,J=7.7Hz,1H), 7.83(d,J=7. 7Hz,1H), 7.64~7.55(m,3H), 7.30~7.22(m,4H), 7.20~7.13(m,1H), 6.88(d ,J=8.6Hz,2H), 4.11(t,J=6.9Hz,2H), 3.53(s,2H), 2.97(t,J=6.9Hz,2H). 1H is unclear / not observed. The isolated compounds contained up to 1 molar equivalent of ammonia. [Example 7]

[0485] 4-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)pyrimidine-2-carboxylic acid [ka]

[0486] Starting from methyl 4-bromopyrimidine-2-carboxylate (CAS 1206250-40-9, BLD), 4-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)pyrimidine-2-carboxylic acid was obtained in 30% yield after 18 hours of reaction at 90°C. LCMS: Method A, 1.24 min, MS: ES + 440.2; 1 H NMR (500 MHz, DMSO) δ ppm: 10.35 (s, 1H), 8.77 (d, J = 5.3 Hz, 1H), 8.68 (d, J = 5.3 Hz, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 5.3 Hz, 1H), 7.70–7.66 (m, 3H), 7.36–7.28 (m, 4H), 7.26–7.20 (m, 1H), 6.95 (d, J = 8.5 Hz, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H). 1H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 8]

[0487] 3-methyl-6-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)picolinic acid [ka]

[0488] Starting from 6-bromo-3-methylpyridine-2-carboxylic acid (CAS 1211516-18-5, BLD), 3-methyl-6-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)picolinic acid was obtained in 34% yield after 18 hours of reaction at 90°C. LCMS: Method A, 2.03 min, MS: ES + 453.2; 1 H NMR(500MHz,DMSO)δppm:10.29(s,1H), 8.64~8.59(m,1H), 8.29(d,J=7.8Hz, 1H), 8.03(d,J=8.1Hz,1H), 7.97(d,J=7.8Hz,1H), 7.81(d,J=8.1Hz,1H), 7.7 4~7.67(m,2H), 7.63(t,J=7.7Hz,1H), 7.37~7.29(m,4H), 7.27~7.21(m,1H), 7.04~6.91(m,2H), 4.19(t,J=6.9Hz,2H), 3.05(t,J=6.9Hz,2H), 2.42(s,3H). 1H unclear / not observed. Isolated compounds contained up to 1 molar equivalent of ammonia. [Example 9]

[0489] 3-Amino-6-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)pyrazine-2-carboxylic acid [ka]

[0490] Starting from methyl 3-amino-6-bromopyrazine-2-carboxylate (CAS 6966-01-4, Fluorochem), 3-amino-6-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)pyrazine-2-carboxylic acid was obtained in 8% yield after 18 hours of reaction at 80 °C. LCMS: Method A, 1.87 min, MS: ES + 455.2; 1H NMR (500 MHz, DMSO) δ ppm: 10.20 (s, 1H), 8.98 (s, 1H), 8.56 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.65–7.54 (m, 3H), 7.37–7.29 (m, 4H), 7.24 (d, J = 6.7 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H). 1H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 10]

[0491] 3-methyl-6-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)pyrazine-2-carboxylic acid [ka]

[0492] Starting from methyl 6-chloro-3-methylpyrazine-2-carboxylate (CAS 1166831-45-3, Combi-Blocks), 3-methyl-6-(3-((4-phenethoxy-phenyl)carbamoyl)phenyl)pyrazine-2-carboxylic acid was obtained in 55% yield after 18 hours of reaction at 90°C. LCMS: Method A, 1.92 min, MS: ES + 454.2; 1 H NMR (500 MHz, DMSO) δ ppm: 1 H NMR (500 MHz, DMSO) δ 13.81 (s, 1H), 10.27 (s, 1H), 9.25 (s, 1H), 8.64 (s, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.71–7.64 (m, 3H), 7.37–7.28 (m, 4H), 7.27–7.20 (m, 1H), 6.99–6.92 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H), 2.66 (s, 3H). The isolated compound contained up to 1 molar equivalent of ammonia. [Example 11]

[0493] 2-Fluoro-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0494] Starting from 5-bromo-2-fluoronicotinic acid (CAS 29241-66-5, Fluorochem), 2-cyclopropyl-5-(3-((4-phenethoxyphenyl)carbamoyl)-phenyl)nicotinic acid was obtained in 40% yield after 9 hours of reaction at 80°C. LCMS: Method A, 1.93 min, MS: ES + 457.2; 1 H NMR (500 MHz, DMSO) δ ppm: 10.27 (s, 1H), 8.46 (s, 1H), 8.40–8.35 (m, 1H), 8.25 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.70–7.59 (m, 3H), 7.38–7.29 (m, 3H), 7.24 (t, J = 6.9 Hz, 1H), 6.98–6.93 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H). 2H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 12]

[0495] 2-Amino-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0496] Starting from methyl 2-amino-5-bromonicotinate (CAS 50735-34-7, Fluorochem), 2-amino-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid was obtained in 29% yield after 18 hours of reaction at 90°C. LCMS: Method A, 1.63 min, MS: ES + 454.2; 1 H NMR(500MHz,DMSO)δppm:10.21(s,1H), 8.64(d,J=2.7Hz,1H), 8.40(d,J=2.6Hz,1H), 8.15(s,1H), 7.87(d,J=7.7Hz,1H), 7.83(d,J=7.7Hz,1H), 7.67( d,J=8.7Hz,2H), 7.58(t,J=7.7Hz,1H), 7.38~7.29(m,4H), 7.24(t,J=6.9H z,1H), 6.95(d,J=8.9Hz,2H), 4.19(t,J=6.9Hz,2H), 3.04(t,J=6.9Hz,2H). 3H is unclear / not observed. The isolated compounds contained up to 1 molar equivalent of ammonia. [Example 13]

[0497] 2-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)isonicotinic acid [ka]

[0498] Starting from methyl 2-bromoisonicotinate (CAS 26156-48-9, Fluorochem), 2-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)-isonicotinic acid was obtained in 11% yield after 18 hours of reaction at 80°C. LCMS: Method A, 1.91 min, MS: ES + 439.2; 1H NMR(500MHz,DMSO)δppm:10.32(s,1H), 8.83(d,J=4.9Hz,1H), 8.64(s,1H), 8.41(s,1H), 8.32(d,J=7.8Hz,1H), 8.02(d,J=7.8Hz,1H), 7.79(d, J=4.9Hz,1H), 7.71~7.64(m,3H), 7.36~7.30(m,4H), 7.22(t,J=6.8Hz,1H), 6.95(d,J=8.6Hz,2H), 4.19(t,J=6.9Hz,2H), 3.04(t,J=6.9Hz,2H). 1H is unclear / not observed. The isolated compounds contained up to 1 molar equivalent of ammonia. [Example 14]

[0499] 6-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)pyrazine-2-carboxylic acid [ka]

[0500] Starting from methyl 6-bromopyrazine-2-carboxylate (CAS 40155-34-8, BLD), 6-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)pyrazine-2-carboxylic acid was obtained in 17% yield after 18 hours of reaction at 90°C. LCMS: Method A, 1.86 min, MS: ES + 440.0; 1 H NMR (500 MHz, DMSO) δ ppm: 10.32 (s, 1H), 9.32 (s, 1H), 9.01 (s, 1H), 8.69 (t, J = 1.9 Hz, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.73–7.65 (m, 3H), 7.36–7.30 (m, 4H), 7.27–7.22 (m, 1H), 6.98–6.94 (m, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H). 1H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 15]

[0501] 2-methyl-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0502] Starting from methyl 5-bromo-2-methylnicotinate (CAS 1215916-40-7, BLD), 2-methyl-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)-nicotinic acid was obtained in 40% yield after 9 hours of reaction at 80°C. LCMS: Method A, 1.73 min, MS: ES + 453.2; 1 H NMR(500MHz,DMSO)δppm:13.44(s,1H), 10.24(s,1H), 9.01(d,J=2.4Hz,1H), 8.48(d,J=2.4Hz,1H), 8.27(s,1H), 7.97(t,J=7.5Hz,2H), 7.69~7.64(m,3H), 7.35~7.29(m,4H), 7.25~7.20(m,1H), 6.97~6.93(m,2H), 4.19(t,J=6.9Hz,2H), 3.04(t,J=6.9Hz,2H), 2.77(s,3H). [Example 16]

[0503] 4-Amino-3'-((4-phenethoxyphenyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid [ka]

[0504] Starting from methyl 2-amino-5-bromobenzoate (CAS 1215916-40-7, Combi-Blocks), 4-amino-3'-((4-phenethoxyphenyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid was obtained in 55% yield after 18 hours of reaction at 90 °C. LCMS: Method A, 1.97 min, MS: ES + 453.2; 1H NMR (500 MHz, DMSO) δ ppm: 10.20 (s, 1H), 8.11–8.07 (m, 2H), 7.81 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.71–7.65 (m, 3H), 7.54 (t, J = 7.7 Hz, 1H), 7.38–7.29 (m, 4H), 7.27–7.20 (m, 1H), 6.97–6.91 (m, 2H), 6.89 (d, J = 8.7 Hz, 1H), 4.19 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H). 3H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 17]

[0505] 2-Methoxy-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0506] Starting from methyl 5-bromo-2-methoxynicotinate (CAS 122433-41-4, BLD), 2-methoxy-5-(3-((4-phenethoxyphenyl)carbamoyl)-phenyl)nicotinic acid was obtained in 42% yield after 18 hours of reaction at 90°C. LCMS: Method A, 1.96 min, MS: ES + 469.2; 1 H NMR(500MHz,DMSO)δppm:13.18(s,1H), 10.22(s,1H), 8.76(d,J=2.6Hz,1H), 8.46(d,J=2.6Hz,1H), 8.24(d,J=2.0Hz,1H), 7.93(t,J=9.2Hz,2H), 7.70~ 7.64(m,2H), 7.63(t,J=7.7Hz,1H), 7.38~7.29(m,4H), 7.27~7.20(m,1H), 6 .98~6.92(m,2H), 4.19(t,J=6.9Hz,2H), 3.99(s,3H), 3.05(t,J=6.9Hz,2H). [Example 18]

[0507] 6-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)picolinic acid [ka]

[0508] Starting from methyl 6-bromopicolinate (CAS 26218-75-7, Fluorochem), 6-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)picolinic acid was obtained in 30% yield after 18 hours of reaction at 90°C. LCMS: Method A, 1.92 min, MS: ES + 439.2; 1 H NMR (500MHz, DMSO) δppm: 10.31 (s, 1H), 8.67 (d, J=1.9Hz, 1H), 8.38~8.34 (m, 1H) ), 8.23(d,J=7.8Hz,1H), 8.06(t,J=7.8Hz,1H), 8.01(d,J=7.7Hz,1H), 7.98(d, J = 7.7 Hz, 1H), 7.72–7.69 (m, 2H), 7.66 (d, J = 7.7 Hz, 1H), 7.37–7.30 (m, 4H), 7.26–7.21 (m, 1H), 6.97–6.94 (m, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H). 1H is unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 19]

[0509] 2-chloro-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0510] Starting from methyl 5-bromo-2-chloronicotinate (CAS 78686-79-0, Fluorochem), 2-chloro-5-(3-((4-phenethoxyphenyl)-carbamoyl)phenyl)nicotinic acid was obtained in 35% yield after 18 hours of reaction at 80°C. LCMS: Method A, 1.95 min, MS: ES+ 473.1; 1 H NMR (500 MHz, DMSO) δ ppm: 10.26 (s, 1H), 8.70 (d, J = 2.6 Hz, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.70–7.61 (m, 3H), 7.38–7.29 (m, 4H), 7.27–7.21 (m, 1H), 6.99–6.92 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H). 1H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 20]

[0511] 6-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0512] Starting from 6-bromonicotinic acid (CAS 6311-35-9, Fluorochem), 6-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid was obtained in 21% yield after 18 hours of reaction at 90°C. LCMS: Method B, 1.30 min, MS: ES + 439.2; 1 H NMR (500 MHz, DMSO) δ ppm: δ 13.49 (s, 1H), 10.29 (s, 1H), 9.18 (d, J = 1.9 Hz, 1H), 8.69 (d, J = 1.9 Hz, 1H), 8.40–8.33 (m, 2H), 8.22 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.71–7.65 (m, 3H), 7.36–7.29 (m, 4H), 7.26–7.21 (m, 1H), 6.98–6.92 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H). The isolated compound contained up to 1 molar equivalent of ammonia. [Example 21]

[0513] 4-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)picolinic acid [ka]

[0514] Starting from methyl 4-bromopicolinate (CAS 29681-42-3, Fluorochem), 4-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)picolinic acid was obtained in 9% yield after 18 hours of reaction at 90°C. LCMS: Method B, 1.22 min, MS: ES + 439.2; 1 H NMR (500 MHz, DMSO) δ ppm 10.31 (s, 1H), 8.64 (d, J = 4.9 Hz, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.04 to 7.97 (m, 2H), 7.81 to 7.76 (m, 1H), 7.70 to 7.64 (m, 3H), 7.36 to 7.28 (m, 4H), 7.25 to 7.20 (m, 1H), 6.98 to 6.92 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.05 (d, J = 6.9 Hz, 2H). 1H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 22]

[0515] 2-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)pyrimidine-4-carboxylic acid [ka]

[0516] Starting from methyl 2-bromopyrimidine-4-carboxylate (CAS 1209459-78-8, BLD), 2-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)-pyrimidine-4-carboxylic acid was obtained in 36% yield after 18 hours of reaction at 90°C. LCMS: Method B, 1.24 min, MS: ES + 440.0; 1H NMR (500 MHz, DMSO) δ ppm 10.34 (s, 1H), 9.11 (d, J = 4.9 Hz, 1H), 8.97–8.94 (m, 1H), 8.62 (d, J = 7.8 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 4.9 Hz, 1H), 7.72–7.67 (m, 3H), 7.36–7.29 (m, 4H), 7.26–7.21 (m, 1H), 6.97–6.92 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H). 1H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 23]

[0517] 5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)picolinic acid [ka]

[0518] Starting from methyl 5-bromopicolinate (CAS 29682-15-3, Fluorochem), 5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)picolinic acid was obtained in 36% yield after 18 hours of reaction at 90°C. LCMS: Method A, 1.79 min, MS: ES + 439.2; 1 H NMR (500 MHz, DMSO) δ ppm 10.36 (s, 1H), 8.94–8.90 (m, 1H), 8.33–8.29 (m, 1H), 8.18–8.12 (m, 1H), 7.99–7.92 (m, 3H), 7.73–7.61 (m, 3H), 7.37–7.29 (m, 4H), 7.23 (t, J = 6.8 Hz, 1H), 6.97–6.91 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H). 1H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 24]

[0519] 5-methyl-6-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)picolinic acid [ka]

[0520] Starting from methyl 6-chloro-5-methylpicolinate (CAS 178421-22-2, Fluorochem), 5-methyl-6-(3-((4-phenethoxyphenyl)-carbamoyl)phenyl)picolinic acid was obtained in 51% yield after 18 hours of reaction at 90°C. LCMS: Method A, 1.91 min, MS: ES + 453.2; 1 H NMR(500MHz,DMSO)δppm 10.20(s,1H), 8.11(s,1H), 8.00(d,J=7.8Hz,1H), 7.84(d,J=7.8Hz,1H), 7.79~7.71(m,2H), 7.68(d,J=8.9Hz,2H), 7.62(t,J=7 .8Hz,1H), 7.37~7.29(m,4H), 7.27~7.20(m,1H), 6.96~6.91(m,2H), 4.18(t,J=6.9Hz,2H), 3.04(t,J=6.9Hz,2H), 2.35(s,3H). 1H is unclear / not observed. The isolated compounds contained up to 1 molar equivalent of ammonia. [Example 25]

[0521] 6-methyl-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0522] Starting from 5-bromo-6-methylnicotinic acid (CAS 1190862-72-6, Apollo), 6-methyl-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)-nicotinic acid was obtained in 43% yield after 18 hours of reaction at 90°C. LCMS: Method A, 1.76 min, MS: ES + 453.2;1 H NMR (500 MHz, DMSO) δ ppm 13.53 (s, 1H), 10.18 (s, 1H), 8.99 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 8.04–7.98 (m, 2H), 7.71–7.61 (m, 4H), 7.37–7.29 (m, 4H), 7.27–7.20 (m, 1H), 6.98–6.91 (m, 2H), 4.18 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H), 2.53 (s, 3H). The isolated compound contained up to 1 molar equivalent of ammonia. [Example 26]

[0523] 4-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0524] Starting from 4-chloronicotinic acid (CAS 10177-29-4, Fluorochem), 4-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid was obtained in 24% yield after 18 hours of reaction at 90°C. LCMS: Method A, 1.66 min, MS: ES + 439.2; 1 H NMR(500MHz,DMSO)δppm 10.18(s,1H), 8.70(s,1H), 8.58(d,J=5.1Hz,1H), 8.03(d,J=1.9Hz,1H), 7.95(d,J=7.6Hz,1H), 7.71~7.64(m,3H), 7.55(t,J=7.7Hz) ,1H), 7.42(d,J=5.1Hz,1H), 7.37~7.29(m,4H), 7.27~7.20(m,1H), 6.97~6.90(m,2H), 4.18(t,J=6.9Hz,2H), 3.04(t,J=6.9Hz,2H). 1H is unclear / not observed. The isolated compounds contained up to 1 molar equivalent of ammonia. [Example 27]

[0525] 4-methyl-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0526] Starting from 5-bromo-4-methylnicotinic acid (CAS 677702-58-8, Combi-Blocks), 4-methyl-5-(3-((4-phenethoxyphenyl)-carbamoyl)phenyl)nicotinic acid was obtained in 63% yield after 18 hours of reaction at 90°C. LCMS: Method A, 1.75 min, MS: ES + 453.2; 1 H NMR (500 MHz, DMSO) δ ppm 13.46 (s, 1H), 10.15 (s, 1H), 8.89 (s, 1H), 8.56 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.97 (s, 1H), 7.69-7.60 (m, 4H), 7.37-7.29 (m, 4H), 7.27-7.20 (m, 1H), 6.98-6.91 (m, 2H), 4.18 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H), 2.43 (s, 3H). The isolated compound contained up to 1 molar equivalent of ammonia. [Example 28]

[0527] 5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)pyridazine-3-carboxylic acid [ka]

[0528] Starting from 5-chloropyridazine-3-carboxylic acid (CAS 1211587-01-7, BLD), 5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)-pyridazine-3-carboxylic acid was obtained in 19% yield after 18 hours of reaction at 90°C. LCMS: Method B, 1.25 min, MS: ES + 440.2; 1H NMR (500 MHz, DMSO) δ ppm 10.32 (s, 1H), 9.59 (s, 1H), 8.45 (s, 1H), 8.30–8.26 (m, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.74–7.65 (m, 3H), 7.37–7.29 (m, 4H), 7.24 (t, J = 7.0 Hz, 1H), 7.11–6.89 (m, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H). 1H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 29]

[0529] 2-Carbamoyl-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0530] Starting from 5-bromo-2-cyanonicotinic acid (CAS 914637-97-1, BLD), 2-carbamoyl-5-(3-((4-phenethoxyphenyl)carbamoyl)-phenyl)nicotinic acid was obtained in 5% yield after 18 hours of reaction at 90°C. LCMS: Method A, 1.78 min, MS: ES + 482.2; 1 H NMR (500 MHz, DMSO) δ ppm 13.40 (s, 1H), 10.26 (s, 1H), 9.03 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 8.02 (t, J = 8.6 Hz, 2H), 7.72–7.64 (m, 3H), 7.38–7.29 (m, 4H), 7.27–7.21 (m, 1H), 6.99–6.93 (m, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H). 2H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 30]

[0531] 2-(Methylsulfonamido)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0532] Step 1: Methyl 5-bromo-2-(methylsulfonamido)nicotinate [ka]

[0533] To an ice-cooled solution of methyl 2-amino-5-bromonicotinate (CAS 50735-34-7, Fluorochem, 50 mg, 0.22 mmol) and EtN (0.15 mL, 1.08 mmol) in DCM (4 mL) was added methanesulfonyl chloride (0.084 mL, 1.08 mmol) dropwise at 0 °C. The reaction mixture was stirred at 40 °C for 72 h, then cooled to room temperature, treated with saturated aqueous NH Cl (5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with water (2 mL), dried over Na SO , and concentrated under reduced pressure to give methyl 5-bromo-2-(methylsulfonamido)nicotinate (70 mg, 86%). LCMS: Method A, 1.43 min, MS: ES + 309.0 and 311.0.

[0534] Step 2: 2-(Methylsulfonamido)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid (Example 30) [ka]

[0535] Following the procedure of Example 1, using methyl 5-bromo-2-(methylsulfonamido)nicotinate instead of 5-bromo-2-hydroxybenzoic acid (CAS 89-55-4, Acros), and using a reaction time of 80° C. for 9 hours, 2-(methylsulfonamido)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid was obtained in 35% yield. LCMS: Method B, 1.24 min, MS: ES + 532.0; 1 H NMR (500 MHz, DMSO) δ ppm: 10.24 (s, 1H), 8.81 (s, 1H), 8.58 (s, 1H), 8.24 (s, 1H), 7.96–7.89 (m, 2H), 7.70–7.66 (m, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.37–7.29 (m, 4H), 7.27–7.22 (m, 1H), 6.98–6.93 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.39 (s, 3H), 3.05 (t, J = 6.9 Hz, 2H). 2H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 31]

[0536] 1-Methyl-2-oxo-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)-1,2-dihydropyridine-3-carboxylic acid [ka]

[0537] Step 1: Methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate [ka]

[0538] To a slurry of methyl 5-bromo-2-hydroxynicotinate (CAS120034-05-1, BLD, 100 mg, 0.43 mmol) and CsCO (280 mg, 0.86 mmol) in MeOH (3 mL) was added iodomethane (80 μL, 1.3 mmol), and the mixture was stirred under microwave irradiation at 80° C. for 2 h. The mixture was concentrated under reduced pressure, diluted with EtOAc (30 mL), and filtered through Celite® to give methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (60 mg, 56%). LCMS: Method A, 0.93 min, MS: ES + 246.0 and 248.0.

[0539] Step 2: 1-methyl-2-oxo-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)-1,2-dihydropyridine-3-carboxylic acid (Example 31) [ka]

[0540] Following the procedure of Example 1, using methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate instead of 5-bromo-2-hydroxybenzoic acid (CAS89-55-4, Acros), and using a reaction time of 80° C. for 9 hours, 1-methyl-2-oxo-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)-1,2-dihydropyridine-3-carboxylic acid was obtained in 35% yield. LCMS: Method B, 1.19 min, MS: ES + 469.2; 1H NMR (500 MHz, DMSO) δ ppm: 10.25 (s, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.18 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.70-7.65 (m, 2H), 7.62 (t, J = 7.8 Hz, 1H), 7.38-7.29 (m, 4H), 7.27-7.21 (m, 1H), 6.99-6.93 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.72 (s, 3H), 3.04 (t, J = 6.9 Hz, 2H). 1H is unclear / not observed. The isolated compounds contained up to 1 molar equivalent of ammonia. [Example 32]

[0541] 2-(morpholinomethyl)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0542] Step 1: 5-Bromo-2-(morpholinomethyl)nicotinic acid [ka]

[0543] To a solution of methyl 5-bromo-2-formylnicotinate (75 mg, 0.31 mmol) in DCM (0.75 mL) was added morpholine (0.27 mL, 3.1 mmol). The mixture was stirred for 3 h, and then NaBH(OAc) (195 mg, 0.92 mmol) was added. The mixture was stirred for an additional 20 h, then diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO (2 × 50 mL) and brine (2 × 50 mL). The organic phase was dried over NaSO and concentrated under reduced pressure to give 5-bromo-2-(morpholinomethyl)nicotinic acid (50 mg, 32%). LCMS: Method A, 0.23 min, MS: ES + 301.0 and 303.0.

[0544] Step 2: 2-(Morpholinomethyl)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid (Example 32) [ka]

[0545] Following the procedure of Example 1, using 5-bromo-2-(morpholinomethyl)nicotinic acid instead of 5-bromo-2-hydroxybenzoic acid (CAS89-55-4, Acros), 2-(morpholinomethyl)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid was obtained in 15% yield using a reaction time of 80° C. for 18 hours. LCMS: Method A, 1.62 min, MS: ES + 538.2; 1 H NMR(500MHz,DMSO)δppm:10.28(s,1H), 8.91~8.87(m,1H), 8.36~8.32(m,3H), 8 .31~8.26(m,1H), 7.98(d,J=7.9Hz,1H), 7.95(d,J=7.9Hz,1H), 7.71~7.62(m,2 HCl), 7.38–7.29 (m, 3H), 7.27–7.20 (m, 1H), 6.99–6.93 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 4.11 (s, 2H), 3.62–3.56 (m, 4H), 3.04 (d, J = 6.9 Hz, 2H), 2.63–2.57 (m, 4H). 1H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 33]

[0546] 2-Morpholino-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0547] Step 1: Methyl 2-morpholino-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate [ka]

[0548] Following the procedure of Example 1, using methyl 5-bromo-2-morpholinonicotinate (CAS 1017782-99-8, Key Organics) in place of 5-bromo-2-hydroxybenzoic acid (CAS 89-55-4, Acros), methyl 2-morpholino-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)-nicotinate was obtained in 76% yield. LCMS: Method A, 2.15 min, MS: ES + 538.2.

[0549] Step 2: 2-Morpholino-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid (Example 33) [ka]

[0550] To a solution of methyl 2-morpholino-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate (100 mg, 0.19 mmol) in THF (3 mL) was added LiOH (27 mg, 1.12 mmol) in water (2 mL) at room temperature. The mixture was stirred at 45 °C for 4 h, then cooled to room temperature, acidified with aqueous HCl (1 M, 5 mL), and extracted with EtOAc (3 × 20 mL). The combined organic phases were dried over NaSO and concentrated under reduced pressure. The crude product was purified by RP flash chromatography (C18, 0–100% MeCN in 0.1% aqueous NHOH) to give 2-morpholino-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid (28.0 mg, 27%). LCMS: Method B, 1.29 min, MS: ES + 524.2; 1H NMR (500 MHz, DMSO) δ ppm: 10.20 (s, 1H), 8.67 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.91–7.85 (m, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.38–7.30 (m, 4H), 7.24 (t, J = 6.8 Hz, 1H), 6.97–6.92 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.73–3.67 (m, 4H), 3.45–3.40 (m, 4H), 3.04 (t, J = 6.9 Hz, 2H). 1H was unclear / not observed. The isolated compounds contained up to 1 molar equivalent of ammonia. [Example 34]

[0551] 2-(Methylamino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0552] Step 1: Methyl 2-(methylamino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate [ka]

[0553] To a solution of methyl 2-chloro-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate (I-2) (50 mg, 0.10 μmol) in DMF (3 mL) was added methylamine (1 M in MeOH, 2.05 mL, 2.05 mmol). The mixture was stirred at 100° C. under microwave irradiation for 72 h, then cooled to room temperature, diluted with water (15 mL) and brine (15 mL), and extracted with EtOAc (3×30 mL). The combined organic phases were dried over NaSO and concentrated under reduced pressure to give methyl 2-(methylamino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate (40 mg, 64%). LCMS: Method A, 2.12 min, MS: ES + 482.2.

[0554] Step 2: 2-(methylamino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid Example 34 [ka]

[0555] Following the procedure of Example 33, Step 2, using methyl 2-(methylamino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate instead of methyl 2-morpholino-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate, 2-(methylamino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid was obtained in 61% yield. LCMS: Method A, 1.70 min, MS: ES + 468.2; 1 H NMR(500MHz,DMSO)δppm:10.20(s,1H), 8.71(d,J=2.6Hz,1H), 8.41(d,J=2.6Hz,1H), 8.15(s,1H), 7.86(d,J=7.7Hz,1H), 7.83(d,J=7.7Hz,1H), 7.71~7 .65(m,2H), 7.58(t,J=7.7Hz,1H), 7.38~7.29(m,4H), 7.27~7.20(m,1H), 6. 98~6.93(m,2H), 4.19(t,J=6.9Hz,2H), 3.04(t,J=6.9Hz,2H), 3.02(s,3H). 2H unclear / not observed. Isolated compounds contained up to 1 molar equivalent of ammonia. [Example 35]

[0556] 2-(Dimethylamino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0557] Step 1: Methyl 2-(dimethylamino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate [ka]

[0558] Following the procedure of Example 34, Step 1, using dimethylamine in methanol instead of methylamine in methanol, methyl 2-(dimethylamino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate was obtained in 61% yield. LCMS: Method A, 2.15 min, MS: ES+496.2.

[0559] Step 2: 2-(Dimethylamino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid (Example 35) [ka]

[0560] Following the procedure of Example 33, Step 2, using methyl 2-(dimethylamino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate instead of methyl 2-morpholino-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate, 2-(dimethylamino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid was obtained in 54% yield. LCMS: Method A, 1.76 min, MS: ES + 482.2; 1H NMR (500 MHz, DMSO) δ ppm: 10.20 (s, 1H), 8.61 (s, 1H), 8.22–8.15 (m, 2H), 7.89–7.82 (m, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.37–7.30 (m, 3H), 7.27–7.21 (m, 1H), 6.95 (d, J = 9.0 Hz, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.32 (s, 3H), 3.30 (s, 3H), 3.05 (t, J = 6.9 Hz, 2H). 2H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 36]

[0561] 2-((2-hydroxyethyl)amino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0562] Step 1: Methyl 2-((2-hydroxyethyl)amino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate [ka]

[0563] To a solution of 2-aminoethan-1-ol (CAS 141-43-5, Merck, 5.0 mg, 0.08 mmol) and methyl 2-chloro-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate (I-2, 20 mg, 0.04 mmol) in THF (2 mL), triethylamine (0.02 mL, 0.12 mmol) was added, and the mixture was then stirred at 40° C. for 72 h. The mixture was concentrated under reduced pressure to give methyl 2-((2-hydroxyethyl)amino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate (20 mg, 76%). LCMS: Method A, 1.96 min, MS: ES + 512.3.

[0564] Step 2: 2-((2-hydroxyethyl)amino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid (Example 36) [ka]

[0565] To a solution of methyl 2-((2-hydroxyethyl)amino)-5-(3-((4-phenethoxyphenyl)-carbamoyl)phenyl)nicotinate (20 mg, 0.04 mmol) in THF (1 mL) was added NaOH (78 mg, 0.98 mmol) in water (1 mL) at room temperature. The mixture was stirred at 45 °C for 4 h, then cooled to room temperature, acidified with aqueous HCl (2 M, 1 mL), and extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over NaSO and concentrated under reduced pressure. The crude product was purified by RP flash chromatography (C18, 0–100% MeCN in 0.1% aqueous NHOH) to give 2-((2-hydroxyethyl)amino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)-nicotinic acid (3 mg, 14%). LCMS: Method A, 1.66 min, MS: ES + 498.2; 1 H NMR(500MHz,DMSO)δppm:10.21(s,1H), 8.82~8.63(m,1H), 8.42(d,J=2.6Hz,1 H), 8.15(s,1H), 7.86(d,J=7.7Hz,1H), 7.82(d,J=7.7Hz,1H), 7.67(dd,J=9.5, 3.2 Hz, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.38-7.29 (m, 4H), 7.27-7.20 (m, 1H), 6.98-6.92 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.64-3.56 (m, 4H), 3.04 (t, J = 6.9 Hz, 2H). 3H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 37]

[0566] 2-((2-methoxyethyl)amino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0567] Step 1: Methyl 2-((2-hydroxyethyl)amino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate [ka]

[0568] Following the procedure of Example 36, Step 1, using 2-methoxyethan-1-amine (CAS 109-85-3, Fluorochem) instead of 2-aminoethan-1-ol, methyl 2-((2-methoxyethyl)amino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate was obtained in 65% yield. LCMS: Method A, 2.17 min, MS: ES + 526.2.

[0569] Step 2: 2-((2-methoxyethyl)amino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid (Example 37) [ka]

[0570] Following the procedure of Example 36, Step 2, using methyl 2-((2-methoxyethyl)amino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate instead of methyl 2-((2-hydroxyethyl)amino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate, 2-((2-methoxyethyl)amino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid was obtained in 78% yield. LCMS: Method A, 1.83 min, MS: ES + 512.3; 1 H NMR(500MHz,DMSO)δppm:10.21(s,1H), 9.19(s,1H), 8.55(s,1H), 8.40(d,J=2.4Hz,1H), 8.14(d,J=2.4Hz,1H), 7.84(d,J=7.7Hz,1H), 7.80(d,J=7.7Hz,1H), 7.70~7.64(m,2H), 7. 56 (t, J = 7.7 Hz, 1H), 7.38–7.29 (m, 4H), 7.27–7.20 (m, 1H), 6.98–6.91 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.68–3.61 (m, 2H), 3.53 (t, J = 5.6 Hz, 2H), 3.30 (s, 3H), 3.04 (t, J = 6.9 Hz, 2H). 1H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 38]

[0571] 2-(Cyclopropylamino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0572] To a stirred solution of cyclopropanamine (CAS765-30-0, Merck, 0.86 mL, 12.3 mmol) and methyl 2-chloro-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinate (I-2, 20 mg, 0.041 mmol) in DMF (2 mL) at 0 °C, CsF (13 mg, 0.082 mmol) was added, and the mixture was then stirred at 50 °C for 24 h, cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL). The organic phase was washed with brine (2 × 100 mL), dried over MgSO, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Prep method B, x = 30, y = 60, 0.1% aqueous NH4OH) to give 2-(cyclopropylamino)-5-(3-((4-phenethoxyphenyl)carbamoyl)phenyl)nicotinic acid (9 mg, 42%). LCMS: Method A, 1.72 min, MS: ES + 494.2; 1 H NMR(500MHz,DMSO)δppm:13.35(s,1H), 10.20(s,1H), 8.76(d,J=2.6Hz,1H), 8.42(d,J=2.6Hz) ,1H), 8.29(s,1H), 8.16(s,1H), 7.88(d,J=7.7Hz,1H), 7.85(d,J=7.8Hz,1H), 7.71~7.65(m,2 (m, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.38–7.29 (m, 4H), 7.27–7.20 (m, 1H), 6.99–6.92 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H), 2.98–2.89 (m, 1H), 0.84–0.76 (m, 2H), 0.56–0.49 (m, 2H). The isolated compounds contained up to 1 molar equivalent of ammonia. [Example 39]

[0573] 5-(3-((4-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid [ka]

[0574] Step 1: Methyl 5-(3-((4-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate [ka]

[0575] To a stirred solution of DIPEA (0.096 mL, 0.55 mmol) and 3-(5-(methoxycarbonyl)-6-methylpyridin-3-yl)benzoic acid (I-11, 30 mg, 0.11 mmol) in DMF (2 mL) was added HATU (84 mg, 0.22 mmol) at room temperature. After 10 min, 4-((benzyloxy)methyl)aniline (I-3, 24 mg, 0.11 mmol) was added. The mixture was stirred at 45 °C for 18 h, then cooled, poured into ice-water (30 mL), and extracted with EtOAc (2 × 15 mL). The combined organic phase was washed with brine (50 mL), dried over NaSO, and concentrated under reduced pressure to give methyl 5-(3-((4-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (45 mg, 45%). LCMS: Method A, 2.05 min, MS: ES + 467.2.

[0576] Step 2: 5-(3-((4-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid (Example 39) [ka]

[0577] To a solution of methyl 5-(3-((4-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (45 mg, 0.10 mmol) in MeOH (5 mL) and THF (5 mL) was added LiOH (23 mg, 0.97 mmol) in water (2 mL) at room temperature. The mixture was stirred at 45 °C for 4 h, then cooled to room temperature, acidified with aqueous HCl (2 M, 0.9 mL), and extracted with EtOAc (3 × 20 mL). The combined organic phases were dried over NaSO and concentrated under reduced pressure. The crude product was purified by RP flash chromatography (C18, 0-100% 0.1% HCOH / MeCN in 0.1% aqueous HCOH) to give 5-(3-((4-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid (35 mg, 76%). LCMS: Method A, 1.68 min, MS: ES + 453.2. 1 H NMR(500MHz,DMSO)δppm:13.45(s,1H), 10.39(s,1H), 9.01(d,J=2.4Hz,1H), 8.48(d,J=2.4Hz,1H), 8.29(s,1H), 7.99(t,J=8.2 Hz,2H), 7.81~7.76(m,2H), 7.67(t,J=7.7Hz,1H), 7.39~7.34(m,6H), 7.34~7.26(m,1H), 4.53(s,2H), 4.51(s,2H), 2.77(s,3H). [Example 40]

[0578] 5-(3-((3-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid [ka]

[0579] Step 1: Methyl 5-(3-((3-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate [ka]

[0580] Following the procedure of Example 39, Step 1, using 3-((benzyloxy)methyl)aniline (I-4) instead of 4-((benzyloxy)methyl)aniline (I-3), methyl 5-(3-((3-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate was obtained in 42% yield. LCMS: Method A, 2.06 min, MS: ES + 467.2.

[0581] Step 2: 5-(3-((3-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid (Example 40) [ka]

[0582] Following the procedure of Example 39, Step 2, using methyl 5-(3-((3-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate instead of methyl 5-(3-((4-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate, 5-(3-((3-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid was obtained in 61% yield. LCMS: Method A, 1.72 min, MS: ES + 453.1. 1 H NMR(500MHz,DMSO)δppm:13.67(s,1H), 10.45(s,1H), 9.15(s,1H), 8.68(s,1H), 8.39~8.34(m,1H), 8.07~8.01(m,2H), 7.85~7.81(m,1H) , 7.81~7.75(m,1H), 7.70(t,J=7.7Hz,1H), 7.42~7.34(m,5H), 7.34~7.27(m,1H), 7.11(d,J=7.7Hz,1H), 4.59~4.54(m,4H), 2.84(s,3H). [Example 41]

[0583] 5-(3-((4-(cyclopropylmethoxy)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid [ka]

[0584] Step 1: Methyl 5-(3-((4-(cyclopropylmethoxy)phenyl)carbamoyl)phenyl)-2-methylnicotinate [ka]

[0585] Following the procedure of Example 39, Step 1, using 4-(cyclopropylmethoxy)aniline (I-6) instead of 4-((benzyloxy)methyl)aniline (I-3), methyl 5-(3-((4-(cyclopropylmethoxy)phenyl)carbamoyl)phenyl)-2-methylnicotinate was obtained in 43% yield. LCMS: Method A, 1.90 min, MS: ES + 417.2.

[0586] Step 2: 5-(3-((4-(cyclopropylmethoxy)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid (Example 41) [ka]

[0587] Following the procedure of Example 39, Step 2, using methyl 5-(3-((4-(cyclopropylmethoxy)phenyl)carbamoyl)phenyl)-2-methylnicotinate instead of methyl 5-(3-((4-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate, 5-(3-((4-(cyclopropylmethoxy)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid was obtained in 35% yield. LCMS: Method A, 1.50 min, MS: ES + 403.2. 1 H NMR(500MHz,DMSO)δppm:13.45(s,1H), 10.24(s,1H), 9.02(d,J=2.4Hz,1H), 8.49(d,J=2.4Hz,1H), 8.31~8.26(m,1H), 8.01~7.95(m,2 H), 7.70~7.63(m,3H), 6.97~6.90(m,2H), 3.81(d,J=6.9Hz,2H), 2.78(s,3H), 1.27~1.18(m,1H), 0.61~0.53(m,2H), 0.36~0.30(m,2H). [Example 42]

[0588] 5-(3-((4-(cyclopropoxymethyl)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid [ka]

[0589] Step 1: Methyl 5-(3-((4-(cyclopropoxymethyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate [ka]

[0590] Following the procedure of Example 39, Step 1, using 4-(cyclopropoxymethyl)aniline (I-7) instead of 4-((benzyloxy)methyl)aniline (I-3), methyl 5-(3-((4-(cyclopropoxymethyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate was obtained in 41% yield. LCMS: Method A, 1.86 min, MS: ES + 417.2.

[0591] Step 2: 5-(3-((4-(cyclopropoxymethyl)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid (Example 42) [ka]

[0592] Following the procedure of Example 39, Step 2, using methyl 5-(3-((4-(cyclopropoxymethyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate instead of methyl 5-(3-((4-(benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate, 5-(3-((4-(cyclopropoxymethyl)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid was obtained in 39% yield. LCMS: Method A, 1.45 min, MS: ES + 403.2. 1H NMR(500MHz,DMSO)δppm:13.45~13.35(s,1H), 10.38(s,1H), 9.03(d,J=2.4Hz,1H), 8.50(d,J=2.4Hz,1H), 8.30(s,1H), 8.00(t,J=7.2Hz,2H), 7.7 (d,J=8.4Hz,2H), 7.68(t,J=7.7Hz,1H), 7.33(d,J=8.3Hz,2H), 4.48(s,2 H), 3.37~3.32(m,1H), 2.78(s,3H), 0.57~0.53(m,2H), 0.49~0.43(m,2H). [Example 43]

[0593] 5-(3-((4-((benzylsulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid [ka]

[0594] Step 1: Methyl 5-(3-((4-((benzylsulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate [ka]

[0595] Following the procedure of Example 39, Step 1, using 4-((benzylsulfonyl)methyl)aniline (I-9) instead of 4-((benzyloxy)methyl)aniline (I-3), methyl 5-(3-((4-((benzylsulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate was obtained in 61% yield. LCMS: Method A, 1.82 min, MS: ES + 515.1.

[0596] Step 2: 5-(3-((4-((benzylsulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid (Example 43) [ka]

[0597] Following the procedure of Example 39, Step 2, using methyl 5-(3-((4-((benzylsulfonyl)-methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate instead of methyl 5-(3-((4-((benzyloxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate and purifying with a basic modifier, 5-(3-((4-((benzylsulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid was obtained in 21% yield. LCMS: Method A, 1.45 min, MS: ES + 501.1. 1 H NMR (500 MHz, DMSO) δ ppm: 13.52–13.24 (m, 1H), 10.49 (s, 1H), 9.00 (d, J = 2.8 Hz, 1H), 8.47 (d, J = 2.8 Hz, 1H), 8.30 (s, 1H), 8.00 (t, J = 8.2 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.68 (t, J = 7.7 Hz, 1H), 7.45–7.34 (m, 7H), 4.54–4.39 (m, 4H), 2.77 (s, 3H). The isolated compound contained up to 1 molar equivalent of ammonia. [Example 44]

[0598] 5-(3-((4-((cyclopropylmethoxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid [ka]

[0599] Following the procedure of Example 1, using N-(4-((cyclopropylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-5) instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-1) and 5-bromo-2-methylnicotinate (CAS 1215916-40-7, BLD) instead of 5-bromo-2-hydroxybenzoic acid (CAS 89-55-4, Acros), 5-(3-((4-((cyclopropylmethoxy)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinic acid was obtained in 33% yield. LCMS: Method A, 1.47 min, MS: ES + 417.2. 1 H NMR(500MHz,DMSO)δppm 10.23(s,1H), 8.61(s,1H), 8.11~8.06(m,2H), 7.79(d,J=7.7Hz,1H), 7.74(d,J=7.7Hz,1H), 7.62~7.57(m,2H), 7.47(t,J=7.7Hz,1H) ), 7.15(d,J=8.3Hz,2H), 4.28(s,2H), 3.11(d,J=6.7Hz,2H), 2.52(s,3H), 0.92~0.81(m,1H), 0.34~0.27(m,2H), 0.11--0.06(m,2H). 1H was unclear / not observed. The isolated compounds contained up to 1 molar equivalent of ammonia. [Example 45]

[0600] 2-chloro-5-(3-((4-((cyclopropylmethoxy)methyl)phenyl)carbamoyl)phenyl)nicotinic acid [ka]

[0601] Following the procedure of Example 44, using methyl 5-bromo-2-chloronicotinate (CAS 78686-79-0, Fluorochem) instead of 5-bromo-2-methylnicotinate (CAS 1215916-40-7, BLD), 2-chloro-5-(3-((4-((cyclopropylmethoxy)methyl)phenyl)carbamoyl)-phenyl)nicotinic acid was obtained in 21% yield. LCMS: Method A, 1.75 min, MS: ES + 437.2. 1 H NMR(500MHz,DMSO)δppm 10.22(s,1H), 8.55(d,J=2.6Hz,1H), 8.14~8.09(m,1H), 8.07(d,J=2.6Hz,1H), 7.84~7.79(m,1H), 7.79~7.75(m,1H), 7.61~7.55(m,2H), 7 .47(t,J=7.7Hz,1H), 7.14(d,J=8.3Hz,2H), 4.27(s,2H), 3.10(d,J=6.7Hz,2H), 0.92~0.80(m,1H), 0.33~0.25(m,2H), 0.04--0.07(m,2H). 1H unclear / not observed. Isolated compounds contained up to 1 molar equivalent of ammonia. [Example 46]

[0602] 6-(3-((6-phenethoxypyridin-3-yl)carbamoyl)phenyl)picolinic acid [ka]

[0603] Following the procedure of Example 1, using N-(6-phenethoxypyridin-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-8) instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-1) and methyl 6-bromopicolinate instead of 5-bromo-2-hydroxybenzoic acid (CAS 89-55-4, Acros), 6-(3-((6-phenethoxypyridin-3-yl)carbamoyl)phenyl)picolinic acid was obtained in 17% yield. LCMS: Method A, 1.86 min, MS: ES + 440.2. 1 H NMR (500 MHz, DMSO) δ ppm 10.49(s,1H), 8.67(s,1H), 8.55(d,J=2.7Hz,1H), 8.34(d,J=7.8Hz,1H), 8 .12~8.05(m,2H), 8.01(d,J=7.7Hz,1H), 7.96(t,J=7.7Hz,1H), 7.88(d,J= 7.6Hz,1H), 7.67(t,J=7.7Hz,1H), 7.32(d,J=4.3Hz,4H), 7.24(h,J=4.2Hz ,1H), 6.84(d,J=8.9Hz,1H), 4.47(t,J=6.9Hz,2H), 3.05(t,J=6.9Hz,2H). 1H unclear / not observed. Isolated compounds contained up to 1 molar equivalent of ammonia. [Example 47]

[0604] 5-(3-((4-((benzyloxy)methyl)-2-fluorophenyl)carbamoyl)phenyl)-2-methylnicotinic acid [ka]

[0605] Following the procedure of Example 1, using N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-10) instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-1), and methyl 5-bromo-2-methylnicotinate (CAS 1215916-40-7, BLD) instead of 5-bromo-2-hydroxybenzoic acid (CAS 89-55-4, Acros), 5-(3-((4-((benzyloxy)methyl)-2-fluorophenyl)carbamoyl)phenyl)-2-methylnicotinic acid was obtained in 17% yield. LCMS: Method A, 1.66 min, MS: ES + 471.2. 1 H NMR (500 MHz, DMSO) δ ppm 13.50 (s, 1H), 10.30 (s, 1H), 9.00 (d, J = 2.5 Hz, 1H), 8.48 (d, J = 2.5 Hz, 1H), 8.35 (s, 1H), 8.04 to 7.97 (m, 2H), 7.68 (t, J = 7.7 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.41 to 7.36 (m, 4H), 7.34 to 7.28 (m, 2H), 7.26 to 7.22 (m, 1H), 4.60 to 4.54 (m, 4H), 2.77 (s, 3H). The isolated compound contained up to 1 molar equivalent of ammonia. [Example 48]

[0606] 6-(3-(4-(4-phenylbutoxy)benzamido)phenyl)picolinic acid [ka]

[0607] Step 1: Methyl 6-(3-aminophenyl)picolinate [ka]

[0608] A solution of methyl 6-(3-nitrophenyl)picolinate (CAS252921-23-6, Combi-Blocks, 200 mg, 0.78 mmol) in MeOH (15 mL) was passed through a 10% Pd / C cartridge once under hydrogen at 30° C. and 1 bar (H-Cube®). The reaction mixture was concentrated under reduced pressure to give methyl 6-(3-aminophenyl)picolinate (150 mg, 82%). LCMS: Method A, 0.85 min, MS: ES + 229.2.

[0609] Step 2: Methyl 6-(3-(4-(4-phenylbutoxy)benzamido)phenyl)picolinate [ka]

[0610] To a solution of methyl 6-(3-aminophenyl)picolinate (60 mg, 0.26 mmol) in DCM (5 mL) was added 4-(4-phenylbutoxy)benzoyl chloride (CAS 108807-05-2, SAGEM, 98.7 mg, 0.34 mmol), followed by dropwise addition of pyridine (0.03 mL, 0.37 mmol) at room temperature. The mixture was stirred at room temperature for 18 h, then diluted with saturated aqueous NH4Cl (10 mL) and extracted with DCM (3 × 20 mL). The combined organic phases were dried using a phase separator cartridge and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 0–100% EtOAc in isohexane) to give methyl 6-(3-(4-(4-phenylbutoxy)benzamido)phenyl)picolinate (60 mg, 47%). LCMS: Method A, 2.24 min, MS: ES + 481.2.

[0611] Step 3: 6-(3-(4-(4-phenylbutoxy)benzamido)phenyl)picolinic acid (Example 48) [ka]

[0612] To a solution of methyl 6-(3-(4-(4-phenylbutoxy)benzamido)phenyl)picolinate (25 mg, 0.05 mmol) in THF (1 mL) was added LiOH (4 mg, 0.16 mmol) in water (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 min, then acidified with HCl (1 M, 0.18 mL) diluted with water (5 mL) and extracted with DCM (3 × 5 mL). The combined organic phases were dried over NaSO and concentrated under reduced pressure. The crude product was triturated with acetonitrile followed by EtO to give 6-(3-(4-(4-phenylbutoxy)benzamido)phenyl)picolinic acid (18 mg, 73%). LCMS: Method A, 2.12 min, MS: ES + 467.2; 1 H NMR (500MHz, DMSO) δppm: 10.29 (s, 1H), 8.50~8.46 (m, 1H), 8.10~8.02 (m, 2H) ), 8.02~7.95(m,3H), 7.97~7.92(m,1H), 7.85(d,J=7.8Hz,1H), 7.49(t,J=7 .9Hz,1H), 7.30(t,J=7.5Hz,2H), 7.26~7.21(m,2H), 7.19(t,J=7.3Hz,1H), 7.09~7.04(m,2H), 4.12~4.06(m,2H), 2.70~2.64(m,2H), 1.79~1.70(m,4H). 1H unclear / not observed. Isolated compounds contained up to 1 molar equivalent of ammonia. [Example 49]

[0613] 5-(5-((4-((benzyloxy)methyl)phenyl)carbamoyl)thiazol-2-yl)-2-methylnicotinic acid [ka]

[0614] Step 1: N-(4-((benzyloxy)methyl)phenyl)-2-bromothiazole-5-carboxamide [ka]

[0615] Following the procedure of Example 39, Step 1, and using 2-bromothiazole-5-carboxylic acid (CAS 54045-76-0, BLD) instead of 3-(5-(methoxycarbonyl)-6-methylpyridin-3-yl)benzoic acid, N-(4-((benzyloxy)methyl)phenyl)-2-bromothiazole-5-carboxamide was obtained in 61% yield. LCMS: Method A, 2.00 min, MS: ES + 402.9 / 404.9.

[0616] Step 2: 5-(5-((4-((benzyloxy)methyl)phenyl)carbamoyl)thiazol-2-yl)-2-methylnicotinic acid (Example 49) [ka]

[0617] To a stirred solution of methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (89 mg, 0.32 mmol) and N-(4-((benzyloxy)methyl)phenyl)-2-bromothiazole-5-carboxamide (100 mg, 0.25 mmol) in 1,4-dioxane (4 mL) and water (1 mL), Cs2CO3 (323 mg, 0.99 mmol) was added, and the reaction mixture was degassed with a stream of nitrogen at room temperature for 5 minutes. Pd-118 (0.03 g, 0.05 mmol) was added, and the mixture was degassed for another 2 minutes. The reaction mixture was stirred at 80 °C for 18 hours, then cooled to room temperature, acidified with aqueous HCl (1 M, 5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by RP flash chromatography (C18, 0–100% 0.1% HCOH / MeCN in 0.1% aqueous HCOH) to give 5-(5-((4-((benzyloxy)methyl)phenyl)carbamoyl)thiazol-2-yl)-2-methylnicotinic acid (8 mg, 6% yield). LCMS: Method A, 1.81 min, MS: ES + 460.1; 1 H NMR (500 MHz, DMSO) δ ppm: 10.56 (s, 1H), 9.15 (s, 1H), 8.75 (s, 1H), 8.62 (s, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.41-7.32 (m, 6H), 7.34-7.28 (m, 1H), 4.54 (s, 2H), 4.52 (s, 2H), 2.78 (s, 3H). 1H was unclear / not observed. [Example 50]

[0618] 5-(4-((4-((benzyloxy)methyl)phenyl)carbamoyl)thiazol-2-yl)-2-methylnicotinic acid [ka]

[0619] Step 1: N-(4-((benzyloxy)methyl)phenyl)-2-bromothiazole-4-carboxamide [ka]

[0620] Following the procedure of Example 39, Step 1, 2-bromothiazole-4-carboxylic acid (CAS 5198-88-9, BLD) was used instead of 3-(5-(methoxycarbonyl)-6-methylpyridin-3-yl)benzoic acid, thus providing N-(4-((benzyloxy)methyl)phenyl)-2-bromothiazole-4-carboxamide in 71% yield. LCMS: Method A, 2.07 min, MS: ES + 402.9 / 404.9.

[0621] Step 2: 5-(4-((4-((benzyloxy)methyl)phenyl)carbamoyl)thiazol-2-yl)-2-methylnicotinic acid (Example 50) [ka]

[0622] Following the procedure of Example 49, Step 2, using N-(4-((benzyloxy)methyl)phenyl)-2-bromothiazole-4-carboxamide instead of N-(4-((benzyloxy)methyl)phenyl)-2-bromothiazole-5-carboxamide, 5-(4-((4-((benzyloxy)methyl)phenyl)carbamoyl)thiazol-2-yl)-2-methylnicotinic acid was obtained in 38% yield. LCMS: Method A, 1.87 min, MS: ES + 460.1; 1H NMR(500MHz,DMSO)δppm:13.62(s,1H), 10.38(s,1H), 9.36(d,J=2.4Hz,1H), 8.77(d,J=2.4Hz,1H), 8.57(s, 1H), 7.86(d,J=8.4Hz,2H), 7.38(d,J=4.6Hz,6H), 7.34~7.29(m,1H), 4.55(s,2H), 4.53(s,2H), 2.81(s,3H). [Example 51]

[0623] 6-methyl-5'-((4-phenethoxyphenyl)carbamoyl)-[3,3'-bipyridine]-5-carboxylic acid [ka]

[0624] Step 1: 5-Bromo-N-(4-phenethoxyphenyl)nicotinamide [ka]

[0625] To methyl 5-bromopyridine-3-carboxylate (CAS 29681-44-5, Fluorochem, 166 mg, 0.77 mmol) and 4-phenethoxyaniline (I-1a, 200 mg, 0.77 mmol) in THF (5.00 mL) was added tBuOK (173 mg, 1.54 mmol). The mixture was stirred at room temperature for 4 h, quenched with water (0.1 mL), and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 0 to 100% EtOAc in isohexane), followed by trituration with EtOAc to give 5-bromo-N-(4-phenethoxyphenyl)nicotinamide (50.0 mg, 12%). 1H NMR(500MHz,DMSO)δppm:10.38(s,1H), 9.06(d,J=2.0Hz,1H), 8.90(d,J=2.0Hz,1H), 8.53(s,1H), 7.65(d,J=8.9H) z,2H), 7.39~7.28(m,4H), 7.27~7.17(m,1H), 6.96(d,J=8.9Hz,2H), 4.19(t,J=6.9Hz,2H), 3.04(t,J=6.9Hz,2H).

[0626] Step 2: 6-methyl-5'-((4-phenethoxyphenyl)carbamoyl)-[3,3'-bipyridine]-5-carboxylic acid (Example 51) [ka]

[0627] Following the procedure of Example 49, Step 2, using 5-bromo-N-(4-phenethoxyphenyl)nicotinamide instead of N-(4-((benzyloxy)methyl)phenyl)-2-bromothiazole-5-carboxamide, 5'-((4-((benzyloxy)methyl)phenyl)carbamoyl)-6-methyl-[3,3'-bipyridine]-5-carboxylic acid was obtained in 29% yield. LCMS: Method A, 1.65 min, MS: ES + 454.2; 1 H NMR (500 MHz, DMSO) δ ppm: 10.33 (s, 1H), 9.08 (d, J = 2.2 Hz, 1H), 9.03 (d, J = 2.2 Hz, 1H), 9.00 (s, 1H), 8.56 (t, J = 2.2 Hz, 1H), 8.48 (s, 1H), 7.60 (d, J = 9.0 Hz, 2H), 7.31-7.22 (m, 4H), 7.19-7.13 (m, 1H), 6.90 (d, J = 9.0 Hz, 2H), 4.12 (t, J = 6.9 Hz, 2H), 2.97 (t, J = 6.9 Hz, 2H), 2.72 (s, 3H). 1H was unclear / not observed. [Example 52]

[0628] 5-(3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-fluorophenyl)-2-methylnicotinic acid [ka]

[0629] Following the procedure of Example 1, using N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-12) instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-1), and methyl 5-bromo-2-methylnicotinate (CAS 1215916-40-7, BLD) instead of 5-bromo-2-hydroxybenzoic acid (CAS 89-55-4, Acros), 5-(3-((4-((benzyloxy)methyl)-phenyl)carbamoyl)-4-fluorophenyl)-2-methylnicotinic acid was obtained in 46% yield. LCMS: Method A, 1.70 min, MS: ES + 471.2. 1 H NMR (500 MHz, DMSO) δ ppm 13.43 (s, 1H), 10.55 (s, 1H), 8.97 (d, J = 2.4 Hz, 1H), 8.44 (d, J = 2.5 Hz, 1H), 8.04 (dd, J = 6.6, 2.5 Hz, 1H), 8.01 to 7.92 (m, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.49 (t, J = 9.2 Hz, 1H), 7.45 to 7.22 (m, 7H), 4.53 (s, 2H), 4.52 (s, 2H), 2.76 (s, 3H). The isolated compound contained up to 1 molar equivalent of ammonia. [Example 53]

[0630] 6'-Methyl-4-((4-phenethoxyphenyl)carbamoyl)-[2,3'-bipyridine]-5'-carboxylic acid [ka]

[0631] Following the procedure of Example 49, Step 2, using 2-bromo-N-(4-phenethoxyphenyl)isonicotinamide (I-13) instead of N-(4-((benzyloxy)methyl)phenyl)-2-bromothiazole-5-carboxamide and purifying with a basic modifier, 6'-methyl-4-((4-phenethoxyphenyl)-carbamoyl)-[2,3'-bipyridine]-5'-carboxylic acid was obtained in 13% yield. LCMS: Method A, 1.70 min, MS: ES + 454.2. 1 H NMR(500MHz,DMSO)δppm 13.51(br s,1H), 10.48(s,1H), 9.35(d,J=2.4Hz,1H), 8.89(d,J=5.0Hz,1H), 8.87(d,J=2.4Hz,1H), 8.52(s,1H), 7.86(dd,J=5.0,1.6Hz,1H), 7.69 (d,J=8.8Hz,2H), 7.38~7.29(m,4H), 7.27~7.22(m,1H), 6.99(d,J=8.8Hz,2H), 4.20(t,J=6.9Hz,2H), 3.05(t,J=6.9Hz,2H), 2.80(s,3H). The isolated compounds contained up to 1 molar equivalent of ammonia. [Example 54]

[0632] 2-Methyl-5-(6-((4-phenethoxyphenyl)carbamoyl)pyrazin-2-yl)nicotinic acid [ka]

[0633] Following the procedure of Example 49, Step 2, using 6-chloro-N-(4-phenethoxyphenyl)-pyrazine-2-carboxamide (I-14) instead of N-(4-((benzyloxy)methyl)phenyl)-2-bromothiazole-5-carboxamide and purified with a basic modifier, 2-methyl-5-(6-((4-phenethoxyphenyl)-carbamoyl)pyrazin-2-yl)nicotinic acid was obtained in 13% yield. LCMS: Method A, 1.78 min, MS: ES + 455.2. 1 H NMR (500 MHz, DMSO) δ ppm 10.60 (s, 1H), 9.50 (s, 1H), 9.40 (s, 1H), 9.20 (s, 1H), 8.74 (s, 1H), 7.75 (d, J = 9.0 Hz, 2H), 7.42–7.29 (m, 4H), 7.28–7.19 (m, 1H), 6.98 (d, J = 9.0 Hz, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H), 2.71 (s, 3H). 1H was unclear / not observed. The isolated compound contained up to 1 molar equivalent of ammonia. [Example 55]

[0634] 2-Methyl-5-(4-((4-phenethoxyphenyl)carbamoyl)pyrimidin-2-yl)nicotinic acid [ka]

[0635] Following the procedure of Example 49, Step 2, using 2-chloro-N-(4-phenethoxyphenyl)pyrimidine-4-carboxamide (I-15) instead of N-(4-((benzyloxy)methyl)-phenyl)-2-bromothiazole-5-carboxamide and purified with a basic modifier, 2-methyl-5-(4-((4-phenethoxy-phenyl)carbamoyl)pyrimidin-2-yl)nicotinic acid was obtained in 13% yield. LCMS: Method A, 1.84 min, MS: ES + 455.2. 1H NMR (500 MHz, DMSO) δ ppm 13.48 (br s, 1H), 10.74 (s, 1H), 9.90 (d, J = 2.3 Hz, 1H), 9.34–9.11 (m, 2H), 8.07 (d, J = 5.0 Hz, 1H), 7.77 (d, J = 9.0 Hz, 2H), 7.40–7.30 (m, 4H), 7.26–7.21 (m, 1H), 7.00 (d, J = 9.0 Hz, 2H), 4.21 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H), 2.83 (s, 3H). The isolated compound contained up to 1 molar equivalent of ammonia. [Examples 56-95]

[0636] [ka]

[0637] Similar to Example 1, but substituting 5-bromo-2-hydroxybenzoic acid (CAS 89-55-4) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-1) for the appropriate starting materials, the following Examples 56-95 were prepared using Pd-118 (0.1-0.2 equivalents), MeCN, or dioxane at 75-90°C for 18-72 hours, with minor modifications as noted. In some cases, esters were used instead of carboxylic acids, and partial or complete hydrolysis to the acid products occurred under the reaction conditions. All compounds may contain up to 1 equivalent of ammonia. [Example 56]

[0638] 5-[3-[[4-(benzyloxymethyl)-3-fluoro-phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0639] Using N-(4-((benzyloxy)methyl)-3-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-16) and methyl 5-bromo-2-methylnicotinate (CAS 1215916-40-7, BLD), 5-[3-[[4-(benzyloxymethyl)-3-fluoro-phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 23% yield. LCMS: Method A: 1.75 min, MS: ES + 471.2; 1 H NMR (500 MHz, DMSO) δ ppm 10.58 (s, 1H), 8.93 (d, J = 2.5 Hz, 1H), 8.40 (d, J = 2.5 Hz, 1H), 8.30–8.26 (m, 1H), 8.01–7.95 (m, 2H), 7.80 (dd, J = 12.5 Hz, 2.0 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.62–7.56 (m, 1H), 7.47 (t, J = 8.4 Hz, 1H), 7.41–7.35 (m, 4H), 7.35–7.27 (m, 1H), 4.58–4.54 (m, 4H), 2.75 (s, 3H). 1H is unclear / not observed. [Example 57]

[0640] 2-Methyl-5-[3-[[1-(2-phenylethyl)pyrazol-4-yl]carbamoyl]phenyl]pyridine-3-carboxylic acid [ka]

[0641] Using 3-bromo-N-(1-phenethyl-1H-pyrazol-4-yl)benzamide (I-49) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks) and KPO (3 equiv.) instead of CsCO, 2-methyl-5-(3-((1-phenethyl-1H-pyrazol-4-yl)carbamoyl)phenyl)-nicotinic acid was obtained in 74% yield by stirring at 80 °C for 18 h followed by LiOH (2 equiv.) at 40 °C for 3 h. LCMS: Method A: 1.37 min, MS: ES + 427.2; 1 H NMR(400MHz,DMSO)δppm 10.58(s,1H), 8.72(d,J=2.5Hz,1H), 8.23(t,J=1.9Hz,1H), 8.20(d,J=2.5Hz,1H), 8.02(s,1H), 7.96~7.92(m,1H), 7.90~7.8 5(m,1H), 7.65~7.58(m,2H), 7.31~7.25(m,2H), 7.21(d,J=7.3Hz,3H), 4.37~4.31(m,2H), 3.11(t,J=7.3Hz,2H), 2.67(s,3H). 1H is unclear / not observed. [Example 58]

[0642] 2-Methyl-5-[3-[[4-(p-tolylsulfonylmethyl)phenyl]carbamoyl]phenyl]pyridine-3-carboxylic acid [ka]

[0643] Using 3-bromo-N-(4-(tosylmethyl)phenyl)benzamide (I-50) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks), and KPO (3 equiv.) instead of CsCO, and stirring at 80 °C for 18 h followed by LiOH (2 equiv.) at 40 °C for 3 h, 2-methyl-5-[3-[[4-(p-tolylsulfonylmethyl)phenyl]carbamoyl]phenyl]pyridine-3-carboxylic acid was obtained in 69% yield. LCMS: Method A: 1.48 min, MS: ES + 501.1; 1 H NMR (400 MHz, DMSO) δ ppm 10.47 (s, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.23 ​​(t, J = 1.9 Hz, 1H), 8.12 (d, J = 2.5 Hz, 1H), 7.95-7.90 (m, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.73-7.67 (m, 2H), 7.65-7.55 (m, 3H), 7.40 (d, J = 8.0 Hz, 2H), 7.14-7.08 (m, 2H), 4.60 (s, 2H), 2.64 (s, 3H), 2.40 (s, 3H). 1H is unclear / not observed. [Example 59]

[0644] 2-Methyl-5-[3-[[4-(1-phenylethoxymethyl)phenyl]carbamoyl]phenyl]pyridine-3-carboxylic acid [ka]

[0645] Using N-(4-((1-phenylethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) and methyl 5-bromo-2-methylnicotinate (CAS 1215916-40-7, BLD), 2-methyl-5-[3-[[4-(1-phenylethoxymethyl)phenyl]carbamoyl]phenyl]pyridine-3-carboxylic acid was obtained in 8% yield. LCMS: Method A: 1.76 min, MS: ES + 467.2; 1 H NMR (500 MHz, DMSO) δ ppm 10.39 (s, 1H), 8.98 (s, 1H), 8.45 (s, 1H), 8.29 (s, 1H), 8.04–7.92 (m, 2H), 7.76 (d, J = 8.5 Hz, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.41–7.36 (m, 4H), 7.33–7.28 (m, 3H), 4.59–4.51 (m, 1H), 4.37–4.25 (m, 2H), 2.77 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H). 1H is unclear / not observed. [Example 60]

[0646] 5-[3-[[4-(1-cyclopropylethoxy)phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0647] Using N-(4-(1-cyclopropylethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-20) and methyl 5-bromo-2-methylnicotinate (CAS 1215916-40-7, BLD), 5-[3-[[4-(1-cyclopropylethoxy)phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 52% yield. LCMS: Method A: 1.61 min, MS: ES + 417.2; 1H NMR(500MHz,DMSO)δppm 10.25(s,1H), 8.89(d,J=2.6Hz,1H), 8.36(s,1H), 8.26(s,1H), 7.95(dd,J=17.6,7.7Hz,2H), 7.65(d,J=8.3Hz,3H), 6.93(d,J=8.9 Hz,2H), 3.97~3.84(m,1H), 2.73(s,3H), 1.28(d,J=6.0Hz,3H), 1.13~0.99(m,1H), 0.49(dd,J=8.4,2.5Hz,2H), 0.39~0.23(m,2H). 1H is unclear / not observed. [Example 61]

[0648] 5-[3-[[4-(benzyloxymethyl)-2-methoxy-phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0649] Using N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[4-(benzyloxymethyl)-2-methoxy-phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 17% yield. LCMS: Method A: 1.83 min, MS: ES + 483.2; 1H NMR(400MHz,DMSO)δppm 9.70(s,1H), 9.03(d,J=2.5Hz,1H), 8.50(d,J=2.4Hz,1H), 8.33(s,1H), 7.99(dt,J=7.9,1.8Hz,2H), 7.71~7.62(m,2H), 7.42~7.34 (m,4H), 7.34~7.27(m,1H), 7.09(d,J=1.7Hz,1H), 6.98(dd,J=8.1,1.7Hz,1H), 4.56(s,2H), 4.55(s,2H), 3.84(s,3H), 2.78(s,3H). 1H is unclear / not observed. [Example 62]

[0650] 5-[3-[[3-fluoro-4-(2-pyridylmethoxymethyl)phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0651] Using N-(3-fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-22) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[3-fluoro-4-(2-pyridylmethoxymethyl)phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 15% yield. LCMS: Method A: 0.80 min, MS: ES + 472.2; 1H NMR (500 MHz, DMSO) δ ppm 10.60 (s, 1H), 8.86 (s, 1H), 8.59–8.51 (m, 1H), 8.33 (s, 1H), 8.27 (t, J = 1.9 Hz, 1H), 8.03–7.91 (m, 2H), 7.87–7.77 (m, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.60 (dd, J = 8.4, 2.1 Hz, 1H), 7.55–7.44 (m, 2H), 7.36–7.27 (m, 1H), 4.66–4.62 (m, 4H), 2.72 (s, 3H). 1H is unclear / not observed. [Example 63]

[0652] 5-[3-[[3-fluoro-4-[(4-methoxyphenyl)methoxymethyl]phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0653] Using N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-23) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[3-fluoro-4-[(4-methoxyphenyl)methoxymethyl]phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 40% yield. LCMS: Method A: 1.41 min, MS: ES + 501.2; 1H NMR(500MHz,DMSO)δppm 10.60(s,1H), 8.89(s,1H), 8.36(s,1H), 8.28(s,1H), 8.00~7.91(m,2H), 7.79(dd,J=12.5,2.0Hz,1H), 7.66(t,J=7.7Hz,1H), 7.58(dd,J= 8.3,2.0Hz,1H), 7.44(t,J=8.4Hz,1H), 7.29(d,J=8.6Hz,2H), 6.93(d,J=8.5Hz,2H), 4.51(s,2H), 4.47(s,2H), 3.76(s,3H), 2.73(s,3H). 1H unclear / not observed. [Example 64]

[0654] 5-[3-[[3-fluoro-4-[(3-methoxyphenyl)methoxymethyl]phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0655] Using N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-24) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[3-fluoro-4-[(3-methoxyphenyl)methoxymethyl]phenyl]-carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 22% yield. LCMS: Method A: 1.43 min, MS: ES + 501.2; 1H NMR(500MHz,DMSO)δppm 13.43(s,1H), 10.57(s,1H), 9.01(d,J=2.4Hz,1H), 8.47(d,J=2.4Hz,1H), 8.29(s,1H) ), 8.00(dd,J=7.8,1.8Hz,2H), 7.80(dd,J=12.5,2.1Hz,1H), 7.69(t,J=7.8Hz,1H),7. 59(dd,J=8.4,2.1Hz,1H), 7.47(t,J=8.4Hz,1H), 7.28(t,J=7.8Hz,1H), 6.97~6.89(m, 2H), 6.87(dd,J=8.0,2.8Hz,1H), 4.55(s,2H), 4.53(s,2H), 3.76(s,3H), 2.78(s,3H). [Examples 65-66]

[0656] 6-Fluoro-5-[3-[[4-(2-phenylethoxy)phenyl]carbamoyl]phenyl]pyridine-3-carboxylic acid and 6-hydroxy-5-[3-[[4-(2-phenylethoxy)phenyl]carbamoyl]-phenyl]pyridine-3-carboxylic acid [ka]

[0657] Using N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-1) and 5-bromo-6-fluoronicotinic acid (CAS 29241-63-2, Manchester Organics), 6-fluoro-5-[3-[[4-(2-phenylethoxy)phenyl]carbamoyl]phenyl]pyridine-3-carboxylic acid was obtained in 42% yield. LCMS: Method A: 1.96 min, MS: ES + 457.2; 1H NMR(500MHz,DMSO)δppm 10.19(s,1H), 8.21(s,1H), 8.09(d,J=2.5Hz,1H), 8.00(d,J=2.5Hz,1H), 7.94(d,J=7.7Hz,1H), 7.90(d,J=7.7Hz,1H), 7.69~7.64(m ,2H), 7.55(t,J=7.7Hz,1H), 7.38~7.29(m,4H), 7.27~7.20(m,1H), 6.98~6.91(m,2H), 4.19(t,J=6.9Hz,2H), 3.04(t,J=6.9Hz,2H). 1H is unclear / not observed.

[0658] [ka]

[0659] Additionally, 6-hydroxy-5-[3-[[4-(2-phenylethoxy)phenyl]carbamoyl]phenyl]pyridine-3-carboxylic acid was isolated in 20% yield. LCMS: Method A: 1.66 min, MS: ES + 455.1; 1 H NMR(500MHz,DMSO)δppm 10.19(s,1H), 8.21(s,1H), 8.09(d,J=2.5Hz,1H), 8.00(d,J=2.5Hz,1H), 7.94(d,J=7.7Hz,1H), 7.90(d,J=7.7Hz,1H), 7.69~7.64(m ,2H), 7.55(t,J=7.7Hz,1H), 7.38~7.29(m,4H), 7.27~7.20(m,1H), 6.98~6.91(m,2H), 4.19(t,J=6.9Hz,2H), 3.04(t,J=6.9Hz,2H). 2H is unclear / not observed. [Example 67]

[0660] 6-[3-[[4-(benzyloxymethyl)phenyl]carbamoyl]phenyl]pyridazine-4-carboxylic acid [ka]

[0661] Using N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-25) and 6-chloropyridazine-4-carboxylic acid (CAS 1256794-24-7, BLD), 6-[3-[[4-(benzyloxymethyl)phenyl]carbamoyl]phenyl]pyridazine-4-carboxylic acid was obtained in 14% yield. LCMS: Method A: 1.44 min, MS: ES + 440.2; 1 H NMR (500 MHz, DMSO) δ ppm 10.54 (s, 1H), 9.41 (d, J = 1.7 Hz, 1H), 8.71 (s, 1H), 8.42 (d, J = 1.8 Hz, 1H), 8.39 (d, J = 1.5 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.71 (t, J = 7.8 Hz, 1H), 7.40-7.33 (m, 6H), 7.33-7.26 (m, 1H), 4.53 (s, 2H), 4.52 (s, 2H). 1H unclear / not observed. [Example 68]

[0662] 6-[3-[[4-(benzyloxymethyl)phenyl]carbamoyl]phenyl]-3-methyl-pyrazine-2-carboxylic acid [ka]

[0663] Using N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-25) and methyl 6-chloro-3-methylpyrazine-2-carboxylate (CAS 1166831-45-3, Combi-Blocks), 6-[3-[[4-(benzyloxymethyl)phenyl]carbamoyl]phenyl]-3-methyl-pyrazine-2-carboxylic acid was obtained in 40% yield. LCMS: Method A: 1.53 min, MS: ES + 454.2; 1H NMR (500 MHz, DMSO) δ ppm 10.43 (s, 1H), 9.11 (s, 1H), 8.63 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 8.08-7.93 (m, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.67 (t, J = 7.7 Hz, 1H), 7.41-7.34 (m, 6H), 7.33-7.28 (m, 1H), 4.53 (s, 2H), 4.51 (s, 2H), 2.58 (s, 3H). 1H unclear / not observed. [Example 69]

[0664] 2-Methyl-5-[6-[[4-(2-phenylethoxy)phenyl]carbamoyl]pyrimidin-4-yl]pyridine-3-carboxylic acid [ka]

[0665] Using 6-chloro-N-(4-phenethoxyphenyl)pyrimidine-4-carboxamide (I-26) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks), 2-methyl-5-[6-[[4-(2-phenylethoxy)phenyl]carbamoyl]pyrimidin-4-yl]pyridine-3-carboxylic acid was obtained in 20% yield. LCMS: Method A: 1.89 min, MS: ES + 455.1; 1 H NMR(500MHz,DMSO)δppm 10.79(s,1H), 9.47(d,J=1.3Hz,1H), 9.37(d,J=2.4Hz,1H), 8.86(d,J=2.4Hz,1H), 8.66(d,J=1.3Hz,1H), 7.84(d,J=9.1Hz, 2H), 7.43~7.28(m,4H), 7.28~7.12(m,1H), 6.98(d,J=9.1Hz,2H), 4.21(t,J=6.9Hz,2H), 3.05(t,J=6.9Hz,2H), 2.80(s,3H). 1H is unclear / not observed. [Example 70]

[0666] 2-Methyl-5-[2-[[4-(2-phenylethoxy)phenyl]carbamoyl]-4-pyridyl]pyridine-3-carboxylic acid [ka]

[0667] Using 4-bromo-N-(4-phenethoxyphenyl)picolinamide (I-27) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks), 2-methyl-5-[2-[[4-(2-phenylethoxy)phenyl]carbamoyl]-4-pyridyl]pyridine-3-carboxylic acid was obtained in 45% yield. LCMS: Method A: 1.89 min, MS: ES + 454.2; 1 H NMR (500 MHz, DMSO) δ ppm 10.59 (s, 1H), 8.83–8.72 (m, 2H), 8.37 (s, 1H), 8.29–8.20 (m, 1H), 8.01 (dd, J = 5.1, 1.9 Hz, 1H), 7.83 (d, J = 9.0 Hz, 2H), 7.37–7.28 (m, 4H), 7.25–7.20 (m, 1H), 6.95 (d, J = 9.0 Hz, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H), 2.71 (s, 3H). 1H is unclear / not observed. [Example 71]

[0668] 2-Methyl-5-[5-[[4-(2-phenylethoxy)phenyl]carbamoyl]pyridazin-3-yl]pyridine-3-carboxylic acid [ka]

[0669] Using 6-chloro-N-(4-phenethoxyphenyl)pyridazine-4-carboxamide (I-28) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks), 2-methyl-5-[5-[[4-(2-phenylethoxy)phenyl]carbamoyl]pyridazin-3-yl]pyridine-3-carboxylic acid was obtained in 22% yield. LCMS: Method A: 1.68 min, MS: ES + 455.2; 1 H NMR (400 MHz, DMSO) δ ppm 11.04 (s, 1H), 9.54 (d, J = 2.0 Hz, 1H), 9.11 (d, J = 2.4 Hz, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.60 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 9.0 Hz, 2H), 7.42-7.27 (m, 4H), 7.27-7.13 (m, 1H), 6.98 (d, J = 9.1 Hz, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H), 2.69 (s, 3H). 1H is unclear / not observed. [Example 72]

[0670] 5-[4-[[4-(cyclopropylmethoxy)phenyl]carbamoyl]-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0671] Using 2-bromo-N-(4-(cyclopropylmethoxy)phenyl)isonicotinamide (I-29) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks), 5-[4-[[4-(cyclopropylmethoxy)phenyl]carbamoyl]-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 67% yield. LCMS: Method A: 1.45 min, MS: ES +404.2; 1 H NMR (500 MHz, DMSO) δ ppm 10.53 (s, 1H), 9.14 (s, 1H), 8.86 (d, J = 5.0 Hz, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.46 (s, 1H), 7.82 (d, J = 5.0 Hz, 1H), 7.68 (d, J = 8.9 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 3.82 (d, J = 6.9 Hz, 2H), 2.72 (s, 3H), 1.44-1.10 (m, 1H), 0.73-0.49 (m, 2H), 0.33 (d, J = 4.9 Hz, 2H). 1H is unclear / not observed. [Example 73]

[0672] 5-[4-[[4-(cyclopropylmethoxy)phenyl]carbamoyl]-5-fluoro-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0673] Using 2-bromo-N-(4-(cyclopropylmethoxy)phenyl)-5-fluoroisonicotinamide (I-30) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks), 5-[4-[[4-(cyclopropylmethoxy)phenyl]carbamoyl]-5-fluoro-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 31% yield. LCMS: Method A: 1.52 min, MS: ES + 422.1; 1H NMR(500MHz,DMSO)δppm 10.65(s,1H), 9.14(s,1H), 8.82(s,1H), 8.65(s,1H), 8.32(d,J=5.2Hz,1H), 7.63(d,J=8.7Hz,2H), 6.94(d, J=8.8Hz,2H), 3.81(d,J=6.9Hz,2H), 2.72(s,3H), 1.33~1.14(m,1H), 0.67~0.51(m,2H), 0.39~0.24(m,2H). 1H is unclear / not observed. [Example 74]

[0674] 5-[4-[[4-(benzyloxymethyl)phenyl]carbamoyl]-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0675] Using N-(4-((benzyloxy)methyl)phenyl)-2-bromoisonicotinamide (I-31) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks), 5-[4-[[4-(benzyloxymethyl)phenyl]carbamoyl]-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 41% yield. LCMS: Method A: 1.73 min, MS: ES + 454.2; 1 H NMR (500 MHz, DMSO) δ ppm 10.70 (s, 1H), 9.11 (d, J = 2.4 Hz, 1H), 8.86 (d, J = 5.0 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.47 (s, 1H), 7.82 (dd, J = 5.0, 1.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.41–7.35 (m, 6H), 7.30 (q, J = 4.3 Hz, 1H), 4.53 (s, 2H), 4.52 (s, 2H), 2.70 (s, 3H). 1H is unclear / not observed. [Example 75]

[0676] 5-[4-[[4-(benzyloxymethyl)phenyl]carbamoyl]-6-methyl-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0677] Using N-(4-((benzyloxy)methyl)phenyl)-2-chloro-6-methylisonicotinamide (I-32) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks), 5-[4-[[4-(benzyloxymethyl)phenyl]carbamoyl]-6-methyl-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 36% yield. LCMS: Method A: 1.40 min, MS: ES + 468.2; 1 H NMR (500 MHz, DMSO) δ ppm 10.61 (s, 1H), 9.12 (s, 1H), 8.63 (s, 1H), 8.27 (s, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.70 (s, 1H), 7.41-7.36 (m, 6H), 7.34-7.28 (m, 1H), 4.55 (s, 2H), 4.53 (s, 2H), 2.71 (s, 3H), 2.66 (s, 3H). 1H unclear / not observed. [Example 76]

[0678] 5-[4-[[4-(benzyloxymethyl)phenyl]carbamoyl]-5-fluoro-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0679] Using N-(4-((benzyloxy)methyl)phenyl)-2-bromo-5-fluoroisonicotinamide (I-33) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks), 5-[4-[[4-(benzyloxymethyl)phenyl]carbamoyl]-5-fluoro-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 26% yield. LCMS: Method A: 1.70 min, MS: ES + 472.2; 1 H NMR (500 MHz, DMSO) δ ppm 10.81 (s, 1H), 9.11 (s, 1H), 8.84 (s, 1H), 8.61 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.42-7.35 (m, 6H), 7.33-7.28 (m, 1H), 4.54 (s, 2H), 4.53 (s, 2H), 2.71 (s, 3H). 1H unclear / not observed. [Example 77]

[0680] 5-[4-[[4-(benzyloxymethyl)-3-fluoro-phenyl]carbamoyl]-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0681] Using N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-bromoisonicotinamide (I-34) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks), 5-[4-[[4-(benzyloxymethyl)-3-fluoro-phenyl]carbamoyl]-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 39% yield. LCMS: Method A: 1.67 min, MS: ES + 472.2; 1H NMR(500MHz,DMSO)δppm 10.90(s,1H), 9.20(d,J=2.4Hz,1H), 8.89(d,J=5.1Hz,1H), 8.71(d,J=2.5Hz,1H), 8.50(s,1H), 7.84(dd,J=5.0,1.5Hz,1H), 7.79(dd,J=1 2.3,2.0Hz,1H), 7.60(dd,J=8.2,2.1Hz,1H), 7.50(t,J=8.4Hz,1H), 7.41~7.35(m,4H), 7.35~7.27(m,1H), 4.58~4.54(m,4H), 2.73(s,3H). 1H unclear / not observed. [Example 78]

[0682] 5-[4-[[4-(cyclopropoxymethyl)-3-fluoro-phenyl]carbamoyl]-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0683] Using 2-bromo-N-(4-(cyclopropoxymethyl)-3-fluorophenyl)isonicotinamide (I-35) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks), 5-[4-[[4-(cyclopropoxymethyl)-3-fluoro-phenyl]carbamoyl]-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 36% yield. LCMS: Method A: 1.49 min, MS: ES + 422.2; 1H NMR (500 MHz, DMSO) δ ppm 10.78 (s, 1H), 9.36 (d, J = 2.4 Hz, 1H), 8.94-8.86 (m, 2H), 8.53 (s, 1H), 7.87 (d, J = 5.0 Hz, 1H), 7.77 (d, J = 12.3 Hz, 1H), 7.59-7.53 (m, 1H), 7.45 (t, J = 8.4 Hz, 1H), 4.53 (s, 2H), 3.36 (dt, J = 6.1, 3.2 Hz, 1H), 2.80 (s, 3H), 0.53 (q, J = 4.6 Hz, 2H), 0.48 (h, J = 5.3 Hz, 2H). 1H is unclear / not observed. [Example 79]

[0684] 5-[4-[[4-(cyclopropylmethoxy)-3-fluoro-phenyl]carbamoyl]-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0685] Using 2-bromo-N-(4-(cyclopropylmethoxy)-3-fluorophenyl)isonicotinamide (I-36) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks), 5-[4-[[4-(cyclopropylmethoxy)-3-fluoro-phenyl]carbamoyl]-2-pyridyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 37% yield. LCMS: Method A: 1.54 min, MS: ES + 422.2; 1H NMR(500MHz,DMSO)δppm 13.37(s,1H), 10.53(s,1H), 9.33~9.29(m,1H), 8.86~8.81(m,2H), 8.45(s,1H), 7.79(d,J=5.0Hz,1H), 7.71~7.64(m,1H), 7.41(d, J=8.8Hz,1H), 7.11(t,J=9.3Hz,1H), 3.83(d,J=7.0Hz,2H), 2.74(s,3H), 1.22~1.13(m,1H), 0.55~0.48(m,2H), 0.30~0.24(m,2H). [Example 80]

[0686] 5-[3-[[4-(benzyloxymethyl)phenyl]carbamoyl]-4-methoxy-phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0687] Using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid (I-37) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[4-(benzyloxymethyl)phenyl]carbamoyl]-4-methoxy-phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 20% yield. LCMS: Method A: 1.66 min, MS: ES + 483.2; 1 H NMR(500MHz,DMSO)δppm 13.36(s,1H), 10.24(s,1H), 8.94(d,J=2.5Hz,1H), 8.38(d,J=2.5Hz,1H), 7.96(d,J=2.6Hz,1H), 7.91(dd,J=8 .6,2.5Hz,1H), 7.75(d,J=8.3Hz,2H), 7.42~7.24(m,8H), 4.53(s,2H), 4.51(s,2H), 3.95(s,3H), 2.75(s,3H). [Example 81]

[0688] 5-[5-[[4-(benzyloxymethyl)phenyl]carbamoyl]-2-methoxy-phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0689] Using N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-38) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[5-[[4-(benzyloxymethyl)phenyl]carbamoyl]-2-methoxy-phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 31% yield. LCMS: Method A: 1.63 min, MS: ES + 483.2; 1 H NMR(400MHz,DMSO)δppm 13.29(s,1H), 10.18(s,1H), 8.79(d,J=2.3Hz,1H), 8.32(d,J=2.3Hz,1H), 8.12~7.99(m,2H) , 7.79~7.70(m,2H), 7.43~7.20(m,8H), 4.52(s,2H), 4.50(s,2H), 3.89(s,3H), 2.77(s,3H). [Example 82]

[0690] 5-[3-[[4-(benzyloxymethyl)phenyl]carbamoyl]-4-methyl-phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0691] Using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid (I-39) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[4-(benzyloxymethyl)phenyl]carbamoyl]-4-methyl-phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 39% yield. LCMS: Method A: 1.68 min, MS: ES + 467.2; 1 H NMR(500MHz,DMSO)δppm 13.38(s,1H), 10.42(s,1H), 8.98(d,J=2.5Hz,1H), 8.44(d,J=2.5Hz,1H), 7.85(d,J=2.1Hz,1H), 7.82~7.73(m,3H) , 7.45(d,J=8.0Hz,1H), 7.41~7.33(m,6H), 7.32~7.27(m,1H), 4.53(s,2H), 4.51(s,2H), 2.76(s,3H), 2.44(s,3H). [Example 83]

[0692] 5-[5-[[4-(benzyloxymethyl)phenyl]carbamoyl]-2-methyl-phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0693] Using N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-40) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[5-[[4-(benzyloxymethyl)phenyl]carbamoyl]-2-methyl-phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 15% yield. LCMS: Method A: 1.73 min, MS: ES + 467.2; 1H NMR(500MHz,DMSO)δppm 13.35(s,1H), 10.24(s,1H), 8.70(s,1H), 8.19(s,1H), 7.94(d,J=7.9Hz,1H), 7.90(s,1H), 7.76(d,J=8. 1Hz,2H), 7.52(d,J=7.9Hz,1H), 7.44~7.23(m,7H), 4.53(s,2H), 4.51(s,2H), 2.80(s,3H), 2.33(s,3H). [Example 84]

[0694] 5-[3-[[4-(cyclopropylmethoxy)phenyl]carbamoyl]-4-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0695] Using N-(4-(cyclopropylmethoxy)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-41) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[4-(cyclopropylmethoxy)phenyl]carbamoyl]-4-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 36% yield. LCMS: Method A: 1.53 min, MS: ES + 421.1; 1 H NMR(500MHz,DMSO)δppm 13.40(s,1H), 10.35(s,1H), 8.98(d,J=2.4Hz,1H), 8.44(d,J=2.5Hz,1H), 8.02(dd,J=6.6,2.5Hz,1H), 7.99~7.92(m,1H), 7.63(d,J=9.1Hz,2 H), 7.48(t,J=9.2Hz,1H), 6.93(d,J=9.0Hz,2H), 3.81(d,J=7.0Hz,2H), 2.77(s,3H), 1.33~1.06(m,1H), 0.65~0.46(m,2H), 0.41~0.14(m,2H). [Example 85]

[0696] 5-[5-[[4-(benzyloxymethyl)phenyl]carbamoyl]-2-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0697] Using (5-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-42) and methyl 5-bromo-2-methylnicotinate (CAS 1215916-40-7, BLD), 5-[5-[[4-(benzyloxymethyl)phenyl]carbamoyl]-2-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 12% yield. LCMS: Method A: 1.76 min, MS: ES + 471.2; 1 H NMR(500MHz,DMSO)δppm 13.49(s,1H), 10.37(s,1H), 8.88(s,1H), 8.40(s,1H), 8.24(dd,J=7.5,2.4Hz,1H), 8.10~8.05(m,1H), 7.77(d,J=8. 4Hz,2H), 7.55(dd,J=10.4,8.6Hz,1H), 7.39~7.34(m,6H), 7.33~7.28(m,1H), 4.54(s,2H), 4.52(s,2H), 2.79(s,3H). [Example 86]

[0698] 5-[3-[[4-(benzyloxymethyl)phenyl]carbamoyl]-2-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0699] Using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-43) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[4-(benzyloxymethyl)phenyl]carbamoyl]-2-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 40% yield. LCMS: Method A: 1.73 min, MS: ES + 471.2; 1 H NMR(500MHz,DMSO)δppm 13.45(s,1H), 10.54(s,1H), 8.84(d,J=2.1Hz,1H), 8.39(s,1H), 7.83~7.77(m,1H), 7.75~7.69(m,3H) , 7.47(t,J=7.6Hz,1H), 7.41~7.34(m,6H), 7.33~7.28(m,1H), 4.53(s,2H), 4.51(s,2H), 2.79(s,3H). [Example 87]

[0700] 5-[3-[[4-(benzyloxymethyl)phenyl]carbamoyl]-2,4-difluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0701] Using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid (I-44) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[4-(benzyloxymethyl)phenyl]carbamoyl]-2,4-difluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 30% yield. LCMS: Method A: 1.75 min, MS: ES + 489.1; 1H NMR (500 MHz, DMSO) δ ppm 10.91 (s, 1H), 8.63 (s, 1H), 8.15 (s, 1H), 7.78 (s, 1H), 7.73-7.62 (m, 2H), 7.47-7.24 (m, 8H), 4.54-4.49 (m, 4H), 2.72 (s, 3H). 1H unclear / not observed. [Example 88]

[0702] 5-[3-[[4-(cyclopropylmethoxymethyl)-3-fluoro-phenyl]carbamoyl]-4-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0703] Using N-(4-((cyclopropylmethoxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-45) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[4-(cyclopropylmethoxymethyl)-3-fluoro-phenyl]carbamoyl]-4-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 66% yield. LCMS: Method A: 1.61 min, MS: ES + 453.2; 1 H NMR(500MHz,DMSO)δppm 10.65(s,1H), 8.61(d,J=2.6Hz,1H), 8.06(d,J=2.6Hz,1H), 7.82(dd,J=6.7,2.6Hz,1H), 7.77~7.70(m,1H), 7.58~7.52(m,1H), 7. 35~7.26(m,2H), 7.28~7.21(m,1H), 4.32(s,2H), 3.12(d,J=6.8Hz,2H), 2.52(s,3H), 0.92~0.81(m,1H), 0.34~0.25(m,2H), 0.08- - 0.04 (m, 2H). 1H unclear / not observed. [Example 89]

[0704] 5-[3-[[4-(cyclopropylmethoxy)-3-fluoro-phenyl]carbamoyl]-4-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0705] Using N-(4-(cyclopropylmethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-46) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[4-(cyclopropylmethoxy)-3-fluoro-phenyl]carbamoyl]-4-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 50% yield. LCMS: Method A: 1.60 min, MS: ES + 439.1; 1 H NMR(500MHz,DMSO)δppm 10.36(s,1H), 8.45(d,J=2.6Hz,1H), 7.91(d,J=2.6Hz,1H), 7.69(dd,J=6.7,2.6Hz,1H), 7.66~7.59(m,1H), 7.47(dd,J=13.5,2.6Hz,1H) , 7.23~7.14(m,2H), 6.89(t,J=9.2Hz,1H), 3.63(d,J=7.0Hz,2H), 2.42(s,3H), 1.04~0.93(m,1H), 0.37~0.30(m,2H), 0.12~0.05(m,2H). 1H unclear / not observed. [Example 90]

[0706] 5-[3-[[4-(benzyloxymethyl)-3-fluoro-phenyl]carbamoyl]-4-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0707] Using N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-47) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[4-(benzyloxymethyl)-3-fluoro-phenyl]carbamoyl]-4-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 33% yield. LCMS: Method A: 1.79 min, MS: ES + 489.2; 1 H NMR (500 MHz, DMSO) δ ppm 10.77 (s, 1H), 8.85 (d, J = 2.5 Hz, 1H), 8.31 (d, J = 2.6 Hz, 1H), 8.02 (dd, J = 6.6, 2.6 Hz, 1H), 7.98-7.91 (m, 1H), 7.77-7.70 (m, 1H), 7.52-7.45 (m, 3H), 7.39-7.33 (m, 4H), 7.33-7.27 (m, 1H), 4.67-4.43 (m, 4H), 2.71 (s, 3H). 1H unclear / not observed. [Example 91]

[0708] 5-[3-[[4-(cyclopropoxymethyl)-3-fluoro-phenyl]carbamoyl]-4-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0709] Using N-(4-(cyclopropoxymethyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-48) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[4-(cyclopropoxymethyl)-3-fluoro-phenyl]carbamoyl]-4-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 16% yield. LCMS: Method A: 1.55 min, MS: ES + 439.2; 1 H NMR (500 MHz, DMSO) δ ppm 10.75 (s, 1H), 8.89–8.85 (m, 1H), 8.34 (d, J = 2.5 Hz, 1H), 8.05–8.00 (m, 1H), 7.98–7.92 (m, 1H), 7.75–7.68 (m, 1H), 7.52–7.45 (m, 2H), 7.41 (t, J = 8.3 Hz, 1H), 4.51 (s, 2H), 3.38–3.30 (m, 1H), 2.73 (s, 3H), 0.56–0.48 (m, 2H), 0.51–0.43 (m, 2H). 1H is unclear / not observed. [Example 92]

[0710] 5-[3-[[4-(1-cyclopropylethoxy)-3-fluoro-phenyl]carbamoyl]-4-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0711] Using N-(4-(1-cyclopropylethoxy)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-17) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[4-(1-cyclopropylethoxy)-3-fluoro-phenyl]carbamoyl]-4-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 37% yield. LCMS: Method A: 1.79 min, MS: ES + 453.2; 1H NMR(400MHz,DMSO)δppm 10.55(s,1H), 8.89(d,J=2.5Hz,1H), 8.35(d,J=2.5Hz,1H), 8.01(dd,J=6.6,2 .5Hz,1H), 7.98~7.90(m,1H), 7.70(dd,J=13.4,2.5Hz,1H), 7.52~7.43(m,1H) , 7.42-7.34 (m, 1H), 7.16 (t, J=9.2Hz, 1H), 3.87-3.76 (m, 1H), 2.73 (s, 3H), 1.30 (d, J=6.1Hz, 3H), 1.10-1.00 (m, 1H), 0.53-0.43 (m, 2H), 0.33-0.20 (m, 2H). 1H was unclear / not observed. [Example 93]

[0712] 5-[3-[[3-cyano-4-(1-cyclopropylethoxy)phenyl]carbamoyl]-4-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0713] Using N-(3-cyano-4-(1-cyclopropylethoxy)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-18) and 5-bromo-2-methylnicotinic acid (CAS 351003-02-6, Combi-Blocks), 5-[3-[[3-cyano-4-(1-cyclopropylethoxy)phenyl]carbamoyl]-4-fluoro-phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 51% yield. LCMS: Method A: 1.74 min, MS: ES + 460.2; 1H NMR(400MHz,DMSO)δppm 10.64(s,1H), 8.93(d,J=2.5Hz,1H), 8.39(d,J=2.4Hz,1H), 8.09~8.01(m,2H ), 8.01~7.93(m,1H), 7.87(dd,J=9.2,2.7Hz,1H), 7.49(dd,J=9.9,8.6Hz,1H) , 7.31 (d, J = 9.3 Hz, 1H), 4.19-4.08 (m, 1H), 2.74 (s, 3H), 1.34 (d, J = 6.1 Hz, 3H), 1.17-1.07 (m, 1H), 0.58-0.46 (m, 2H), 0.43-0.34 (m, 1H), 0.34-0.26 (m, 1H). 1H was unclear / not observed. [Example 94]

[0714] 2-Methyl-5-[2-methylsulfanyl-5-[[4-(2-phenylethoxy)phenyl]carbamoyl]-3-pyridyl]pyridine-3-carboxylic acid [ka]

[0715] Using 5-bromo-6-(methylthio)-N-(4-phenethoxyphenyl)nicotinamide (I-59) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks), 2-methyl-5-[2-methylsulfanyl-5-[[4-(2-phenylethoxy)phenyl]carbamoyl]-3-pyridyl]pyridine-3-carboxylic acid was obtained in 58% yield. LCMS: Method A: 1.58 min, MS: ES + 500.2; 1H NMR(500MHz,DMSO)δppm 10.24(s,1H), 8.99(d,J=2.3Hz,1H), 8.40(d,J=2.5Hz,1H), 8.07(d,J=2.3Hz,1H), 7.94(d,J=2.4Hz,1H), 7.64(d,J=9.1Hz,2H),7. 40~7.27(m,4H), 7.26~7.17(m,1H), 6.94(d,J=9.1Hz,2H), 4.18(t,J=6.9Hz,2H), 3.03(t,J=6.9Hz,2H), 2.68(s,3H), 2.52(s,3H). 1H is unclear / not observed. [Example 95]

[0716] 5-[2-(2-methoxyethoxy)-5-[[4-(2-phenylethoxy)phenyl]carbamoyl]-3-pyridyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0717] Using 5-bromo-6-(2-methoxyethoxy)-N-(4-phenethoxyphenyl)nicotinamide (I-60) and methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (CAS 2291165-13-2, Combi-Blocks), 5-[2-(2-methoxyethoxy)-5-[[4-(2-phenylethoxy)phenyl]carbamoyl]-3-pyridyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 16% yield. LCMS: Method A: 1.58 min, MS: ES + 528.1; 1H NMR(500MHz,DMSO)δppm 10.21(s,1H), 8.74(d,J=2.4Hz,1H), 8.70(s,1H), 8.37(d,J=2.4Hz,1H), 8.22(s,1H), 7.64(d,J=9.1Hz,2H), 7.40~7.28(m,4H), 7.26~7.20( m,1H), 6.95(d,J=9.1Hz,2H), 4.63~4.50(m,2H), 4.19(t,J=6.9Hz,2H), 3.81~3.58(m,2H), 3.28(s,3H), 3.04(t,J=6.9Hz,2H), 2.70(s,3H). 1H unclear / not observed.

[0718] General method [Examples 96-101]

[0719] [ka] Examples 96-101 were prepared as follows:

[0720] To the appropriate starting material in THF (2 mL) was added LiOH (6 equiv.) in water (2 mL). The mixture was stirred at 40° C. for 2 hours and then concentrated under reduced pressure to approximately 50% volume. The remaining mixture was diluted with water and acidified with aqueous HCl (1 M) to approximately pH 2. The solid was collected and triturated with acetonitrile (20 mL) and diethyl ether (15 mL) to give the desired product. [Example 96]

[0721] 5-[3-[[4-[(4-chlorophenyl)sulfonylmethyl]phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0722] Using methyl 5-(3-((4-(((4-chlorophenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-53), 5-[3-[[4-[(4-chlorophenyl)sulfonylmethyl]phenyl]-carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 71% yield. LCMS: Method A: 1.54 min, MS: ES + 521.1; 1 H NMR (500 MHz, DMSO) δ ppm 10.44 (s, 1H), 9.07 (d, J = 2.4 Hz, 1H), 8.56 (s, 1H), 8.31 (s, 1H), 8.00 (d, J = 7.6 Hz, 2H), 7.75-7.65 (m, 7H), 7.14 (d, J = 8.2 Hz, 2H), 4.70 (s, 2H), 2.80 (s, 3H). 1H unclear / not observed. [Example 97]

[0723] 5-[3-[[4-[(3-chlorophenyl)sulfonylmethyl]phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0724] Using methyl 5-(3-((4-(((3-chlorophenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-54), 5-[3-[[4-[(3-chlorophenyl)sulfonylmethyl]phenyl]-carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 81% yield. LCMS: Method A: 1.21 min, MS: ES + 521.1; 1H NMR(500MHz,DMSO)δppm 10.50(s,1H), 9.11(d,J=2.4Hz,1H), 8.60(d,J=2.4Hz,1H), 8.34(t,J=1.9Hz,1H), 8.01(dd,J=7.8,1.8Hz, 2H), 7.84~7.79(m,2H), 7.77~7.73(m,2H), 7.70~7.61(m,3H), 7.18~7.14(m,2H), 4.75(s,2H), 2.81(s,3H). 1H is unclear / not observed. [Example 98]

[0725] 5-[3-[[4-[(2-chlorophenyl)sulfonylmethyl]phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0726] Using methyl 5-(3-((4-(((2-chlorophenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-55), 5-[3-[[4-[(2-chlorophenyl)sulfonylmethyl]phenyl]-carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 60% yield. LCMS: Method A: 1.17 min, MS: ES + 521.1; 1 H NMR (500 MHz, DMSO) δ ppm 10.45 (s, 1H), 9.09 (d, J = 2.5 Hz, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.34-8.29 (m, 1H), 8.03-7.97 (m, 2H), 7.80-7.77 (m, 1H), 7.76-7.74 (m, 1H), 7.74-7.73 (m, 1H), 7.73-7.70 (m, 2H), 7.70-7.66 (m, 1H), 7.53-7.49 (m, 1H), 7.21-7.16 (m, 2H), 4.84 (s, 2H), 2.78 (s, 3H). 1H unclear / not observed. [Example 99]

[0727] 5-[3-[[4-[(4-methoxyphenyl)sulfonylmethyl]phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0728] Using methyl 5-(3-((4-(((4-methoxyphenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-56), 5-[3-[[4-[(4-methoxyphenyl)sulfonylmethyl]phenyl-]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 49% yield. LCMS: Method A: 1.11 min, MS: ES + 517.1; 1 H NMR (500 MHz, DMSO) δ ppm 10.47 (s, 1H), 9.10 (d, J = 2.4 Hz, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.00 (m, 2H), 7.75-7.65 (m, 3H), 7.64-7.59 (m, 2H), 7.14-7.06 (m, 4H), 4.58 (s, 2H), 3.84 (s, 3H), 2.81 (s, 3H). 1H unclear / not observed. [Example 100]

[0729] 5-[3-[[4-[(3-methoxyphenyl)sulfonylmethyl]phenyl]carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid [ka]

[0730] Using methyl 5-(3-((4-(((3-methoxyphenyl)sulfonyl)methyl)phenyl)carbamoyl)phenyl)-2-methylnicotinate (I-57), 5-[3-[[4-[(3-methoxyphenyl)sulfonylmethyl]phenyl]-carbamoyl]phenyl]-2-methyl-pyridine-3-carboxylic acid was obtained in 14% yield. LCMS: Method A: 1.28 min, MS: ES + 517.0; 1 H NMR (500 MHz, DMSO) δ ppm 10.40 (s, 1H), 9.01 (d, J = 2.4 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.28 (t, J = 1.9 Hz, 1H), 8.01 to 7.94 (m, 2H), 7.72 to 7.64 (m, 3H), 7.51 (t, J = 8.0 Hz, 1H), 7.31 to 7.25 (m, 2H), 7.24 to 7.20 (m, 1H), 7.18 to 7.13 (m, 2H), 4.66 (s, 2H), 3.80 (s, 3H), 2.77 (s, 3H). 1H is unclear / not observed. [Example 101]

[0731] 2-Methyl-5-[3-[[4-[(6-methyl-3-pyridyl)sulfonylmethyl]phenyl]carbamoyl]phenyl]pyridine-3-carboxylic acid [ka]

[0732] Using methyl 2-methyl-5-(3-((4-(((6-methylpyridin-3-yl)sulfonyl)methyl)phenyl)carbamoyl)-phenyl)nicotinate (I-58), 2-methyl-5-[3-[[4-[(6-methyl-3-pyridyl)sulfonylmethyl]-phenyl]carbamoyl]phenyl]pyridine-3-carboxylic acid was obtained in 9% yield. LCMS: Method A: 1.10 min, MS: ES + 502.1; 1H NMR(500MHz,DMSO)δppm 13.46(s,1H), 10.42(s,1H), 8.97(d,J=2.4Hz,1H), 8.64(d,J=2.4Hz,1H), 8.44(d,J=2.4Hz,1H), 8.27(t,J=1.9Hz,1H), 7.99~7.96 (m,2H), 7.74~7.69(m,2H), 7.66(t,J=7.8Hz,1H), 7.50(d,J=8.2Hz,1H), 7.19~7.12(m,2H), 4.74(s,2H), 2.76(s,3H), 2.57(s,3H). 1H is unclear / not observed.

[0733] GPR35 assay The described functional assay measures the ability of GPR35 modulators to inhibit GPR35 agonist-induced phospho-ERK signaling, which is the concentration of modulator required to reduce the phospho-ERK signal by 50 percent, i.e., IC 50 The signal window is defined as the difference between the agonist plus modulator vehicle (no modulator) and agonist vehicle (no agonist) controls.

[0734] This assay is a cellular GPR35 phospho-ERK homogeneous time-resolved fluorescence (HTRF) assay using the GPR35-CHO-K1-mtAequorin-Gα16 cell line. 80 Upon activation of GPR35 with the agonist trodoxamide at high concentrations, ERK1 / 2 was phosphorylated, and after lysis of the cell membrane, phospho-ERK1 / 2 (Thr202 / Tyr204) was converted to Eu 3+It is detected in a sandwich assay using two different specific antibodies, one labeled with cryptate (donor) and the other with d2 (acceptor). When the dyes are in close proximity, excitation of the donor with a light source (laser or flash lamp) triggers fluorescence resonance energy transfer (FRET) towards the acceptor, resulting in specific acceptor fluorescence (at 665 nm). The specific signal is directly proportional to the amount of phospho-ERK1 / 2 (Thr202 / Tyr204) in the sample. Compounds that interfere with the levels of phospho-ERK1 / 2 (Thr202 / Tyr204) result in a low HTRF signal.

[0735] Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention that are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.

[0736] [Table 9] JPEG2026503167000321.jpg255170 JPEG2026503167000322.jpg255170 JPEG2026503167000323.jpg56170

[0737] (References) 1 Quon et al, ACS Pharmacology and Translational Science 3, 801-812 (2020) 2 Kaya et al, Frontiers in Immunology 12: 717392 (2021) 3Wang et al, J Biol Chem 281, 22021-22028 (2006) 4 Kapolka et al, PNAS 117, 13117-13126 (2020) 5 Giovanni et al, Cell 185, 815-830.e19 (2022) 6 Oka et al, Biochem & Biophys Res Comms 395, 232-237 (2010) 7 Deng et al. Scientific Reports 2, Article number: 373 (2012) 8 Maravillas-Montero et al, J Immunology 194, 29-33 (2015) 9 Lee et al Agricultural and Food Chem doi: 10.1021 / acs.jafc.2c01251. Online ahead of print (2022) 10 Jenkins et al, Biochem J 432, 451-419 (2010) 11 Yang et al, Pharmacology 86, 1-5. doi: 10.1159 / 000314164. Epub (2010) 12 Taniguchi et al. FEBS Letters 580, 5003-5008 (2006) 13 MacKenzie et al, Molecular Pharmacology 85, 91-104 (2014) 14 Wei et al, J Med Chem 64, 2634-2647 (2021) 15According to Abdalhameed et al. Bioorg Med Chem Lett 27, 612–615 (2017) 16 https: / / www.ncbi.nlm.nih.gov / gene?Db=gene&Cmd=DetailsSearch&Term=2859 17 https: / / www.proteinatlas.org / ENSG00000178623-GPR35 / tissue 18 MacKenzie et al, Frontiers in Endocrinology (Lausanne) 2, 68, 1-10 (2011). 19 Imielinski et al, Nat Gene 41, 1335–1340 (2009) 20 Ellinghaus et al, Hepatology 58, 1074–1083 (2013). 21 Schneditz et al, Sci Signal 12:eaau9408 (2019). 22 Pagano et al, Gut (2021) Gut. 2022 Mar;71(3):509-520. doi: 10.1136 / gutjnl-2020-323363. Epub 2021 Mar 23 Kaya et al, Cell Rep 32:107979(2020) 24 http: / / gepia.cancer-pku.cn / detail.php?gene=GPR35 25 Okumura et al, Cancer Sci 95, 131–135 (2004). 26 Ali et al, Tumor Biology 411–11 (2019). 27 Mackiewicz at al, Pharmacological Rep doi: 10.1007 / s43440-022-00371-2. Online ahead of print (2022) 28 Olson et al, Front. Chem., 9 article 671483 (2021) 29 Sun, YV et al, (2008) Genet. Epidemiol. 32, 350-360 doi: 10.1002 / gepi.20309 30 Min, KD et al (2010) Biochem. Biophys. Res. Common. 393, 55-60 31 Ohshiro, H. et al (2008) Biochem. Biophys. Res. Common. 365, 344-348 32 Cosi, C. et al (2010). Neuropharmacology 60, 1227-1231 33 US20070077602; Leonard et al 34 Wang, J. et al (2006) J. Biol. Chem. 281, 22021-22028 35 Fallarini, S. et al (2010) Biochem. Bio-phys. Res. Commun. 398, 420-425 36 Barth, MC et al (2009) J. Biol.Chem. 284, 19189-19195 37 Birring, SS et al (2017) Lancet Respir. Med. 5 (10), 806-815 38Yang, Y. et al (2010) Pharmacology; 86(1):1-5 39 Smith J. A. (January 2015). Current Allergy and Asthma Reports. 15 (1): 489 40 Shu C. et al (November 2022), Cell Death Disc, 444 41 Miyamoto, K. et al. Cell Reports, (2023), 42, 113005. 42 Song, Z. et al. Bioorg. Med. Chem. (2023). https: / / doi.org / 10.1016 / j.bmc.2023.117511 43 Otkur, W. et al. Eur. J. Pharmacol, (2023), 949, 175719. 44 Zheng, X. et al. Brain, Behaviour and Immunity, (2019), 79, 244. 45 Boleij, A. et al. Communications Biology, (2021), 4:585.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof 【Chemistry 1】 [X is NR ７ and Y is CO; Ring C is a 6-membered heteroaryl or aryl group, or a 6-membered partially or fully unsaturated heterocyclic group containing at least one N and optionally at least one CO group, wherein the aryl, heteroaryl, or heterocyclic group is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, NR ９ SO ２ R １１ , N.R. ９ COR １２ , N.R. １３ R １４ , OH, CO ２ R １５ , S.O. ２ NR １６ R １７ , C.O.R. １８ R １９ , cycloalkyl and (CH ２ ) ｑ -heterocycloalkyl; Ring A is a group: 【Chemistry 2】 wherein A is a phenyl group or a 6-membered heteroaryl group. and Or ring A is a group: 【Transformation 3】 wherein A is a 5-membered heteroaryl group. and In each case, the wavy lines indicate the points of attachment to Y and ring C, respectively; Ring B is a phenyl group or a 6-membered heteroaryl group; R ２ (CR ３３ R ３４ ) ｍ COOH; Each R ６ is alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, NR １０ COR ２０ , N.R. １０ SO ２ R ２１ , (CH ２ ) ｑ SR ２２ , (CH ２ ) ｑ SOR ２３ , (CH ２ ) ｑ SO ２ R ２４ , S.O. ２ NR ２５ R ２６ , (CH ２ ) ｑ OH, (CH ２ ) ｑ OR ２７ , N.R. ２８ R ２９ , C.O.R. ３０ R ３１ , cycloalkyl and (CH ２ ) ｑ -heterocycloalkyl; Each R ８ is alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, NR １０ COR ２０ , N.R. １０ -SO ２ R ２１ , (CH ２ ) ｑ SR ２２ , (CH ２ ) ｑ SOR ２３ , (CH ２ ) ｑ SO ２ R ２４ , S.O. ２ NR ２５ R ２６ , (CH ２ ) ｑ OH, (CH ２ ) ｑ OR ２７ , N.R. ２８ R ２９ , C.O.R. ３０ R ３１ , cycloalkyl and (CH ２ ) ｑ -heterocycloalkyl; R ７ is selected from H and alkyl; Each R ９ is independently selected from H and alkyl; Each R １０ is independently selected from H and alkyl; R １１ ~R ３１ are each independently selected from H, alkyl, haloalkyl, 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; L is a direct bond or —SO ２ -, -O-SO ２ -, -SO ２ -O-, -O-, -NR ３２ -SO ２ -, -NR ３２ -SO ２ -Alkylene, -SO ２ -NR ３２ -, -SO ２ -NR ３２ -Alkylene, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO ２ -, -SO ２ -Alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO ２ -alkylene, alkylene-SO-alkylene, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, cycloalkylene-heteroalkylene, wherein the alkylene portion of the group is optionally substituted by one or more substituents selected from halo, alkyl, haloalkyl, and cycloalkyl; R ３２ , R ３３ and R ３４ are each independently selected from H and alkyl; Z is a group selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, each of which may be further substituted with one or more groups selected from CN, halo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, and haloalkoxy.

2. Formula (Ie): 【Chemistry 4】 (In the formula, ring A, ring B, ring C, X, Y, L, Z, R ２ , R ６ , R ８ , n and p are as defined in claim 1.

2. The compound of claim 1, wherein

3. A is selected from phenyl, pyridinyl, pyrazidinyl, pyrimidinyl, and pyrazinyl, each of which is selected from 1 to 4 R ６ The compound of claim 2, which is optionally substituted by a group.

4. Formula (If): 【Transformation 5】 (In the formula, ring A, ring B, ring C, X, Y, L, Z, R ２ , R ６ , R ８ , n and p are as defined in claim 1, and n is preferably an integer from 0 to 3.

2. The compound of claim 1, wherein

5. A is selected from pyrrolyl, thiazolyl, oxazolyl, furanyl, thienyl, and pyrazolyl, each of which is selected from 1 to 3 R ６ The compound according to claim 4, which is optionally substituted by a group.

6. Formula (Ig): 【Transformation 6】 (In the formula, X １ , X ２ , X ３ , X ４ , X ５ form a 6-membered heteroaryl or 6-membered aryl group containing at least one N, said heteroaryl or aryl group being selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR ９ SO ２ R １１ , N.R. ９ COR １２ , N.R. １３ R １４ , OH, CO ２ R １５ , S.O. ２ NR １６ R １７ , C.O.R. １８ R １９ , cycloalkyl and (CH ２ ) ｑ -heterocycloalkyl; A, B, Z, L, X, Y, R ２ , R ６ , R ８ , n and p are as defined in claim 1. The compound according to any one of claims 1 to 5, which is a compound of the formula:

7. Formula (Ib): 【Transformation 7】 (In the formula: X １ is N or CR １ and X ３ is N or CR ３ and X ４ is N or CR ４ and X ５ is N or CR ５ and R １ , R ３ , R ４ and R ５ is H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR １３ R １４ , O.H., N.R. ９ SO ２ -Alkyl, CONR １８ R １９ , cycloalkyl and (CH ２ ) ｑ -heterocycloalkyl; R ２ , R ６ , R ８ , n, p, L, A, B, X, Y and Z are as defined in claim 1. The compound according to any one of claims 1 to 6, which is a compound of the formula:

8. The compound according to any one of claims 1 to 7, wherein n is 0.

9. X １ , X ２ , X ３ , X ４ and X ５ The compound according to any one of claims 6 to 8, wherein forms a 6-membered heteroaryl group containing one or two nitrogen atoms, or a phenyl group.

10. X １ , X ２ , X ３ , X ４ and X ５ 10. The compound of claim 9, wherein: forms a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrazidinyl group, or a pyrazinyl group.

11. R ２ The compound according to any one of claims 1 to 10, wherein is COOH.

12. Formula (Ic): 【Transformation 8】 (In the formula: X １ is N or CR １ and X ３ is N or CR ３ and X ４ is N or CR ４ and X ５ is N or CR ５ and R １ , R ３ , R ４ and R ５ is H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR １３ R １４ , O.H., N.R. ９ SO ２ -Alkyl, CONR １８ R １９ , cycloalkyl and (CH ２ ) ｑ -heterocycloalkyl; A is a phenyl or pyridinyl group, more preferably phenyl; R ２ , R ６ , R ８ , n, p, L, B and Z are as defined in claim 1. The compound according to any one of claims 1 to 3 or 6 to 11,

13. R １ , R ３ , R ４ and R ５ But H, C １－６ -Alkyl, C １－６ -haloalkyl, C １－６ -alkoxy, C １－６ -haloalkoxy, Cl, F, NH ２ , NH-C １－６ -Alkyl, NH-C ３－６ -cycloalkyl, N(C １－６ -alkyl) ２ , OH, NHSO ２ -C １－６ -Alkyl, CONR １８ R １９ , C ３－６ -cycloalkyl, NH-(hydroxy-C １－６ -alkyl), NH—(C １－６ -alkoxy), CH ２ 13. The compound of claim 12, wherein each of the groups is independently selected from: -heterocycloalkyl and heterocycloalkyl.

14. R １ , R ３ , R ４ and R ５ But H, Me, MeO, CF ３ , Cl, F, NH ２ , NH-Me, NH-cyclopropyl, NMe ２ , OH, NHSO ２ Me, CONH ２ , cyclopropyl, NHCH ２ CH ２ OH,NHCH ２ CH ２ OMe, CH ２ 14. The compound of claim 12 or 13, wherein each of the groups is independently selected from N-morpholinyl and N-morpholinyl.

15. R ２ is COOH; X １ But, CR １ and X ３ But, CR ３ and X ４ is N; X ５ But, CR ５ That is, The compound according to any one of claims 12 to 14.

16. R ２ is COOH; X １ is N; X ３ But, CR ３ and X ４ But, CR ４ and X ５ But, CR ５ That is, The compound according to any one of claims 12 to 14.

17. R ２ is COOH; X １ is N; X ３ But, CR ３ and X ４ is N; X ５ But, CR ５ That is, The compound according to any one of claims 12 to 14.

18. R ３ But H, Me, MeO, CF ３ , Cl, F, NH ２ , NH-Me, NH-cyclopropyl, NMe ２ , OH, NHSO ２ Me, CONH ２ , cyclopropyl, NHCH ２ CH ２ OH,NHCH ２ CH ２ OMe, CH ２ -N-morpholinyl and N-morpholinyl; R １ , R ４ and R ５ The compound of any one of claims 12 to 17, wherein is H.

19. X １ is CH or N, more preferably CH; X ３ is C-alkyl, more preferably Me; X ４ is N; X ５ is CH, The compound of claim 12.

20. The compound according to any one of claims 1 to 5, wherein ring C is a partially or fully unsaturated 6-membered heterocyclic group containing at least one N and optionally containing at least one CO group.

21. Formula (Id) 【Chemistry 9】 (In the formula, X １ is N or CR １ and X ５ is N or CR ５ and R １ and R ５ is H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR １３ R １４ , O.H., N.R. ９ SO ２ -Alkyl, CONR １８ R １９ , cycloalkyl and (CH ２ ) ｑ -heterocycloalkyl; R ４ ' is selected from H, alkyl and cycloalkyl; A, B, L, Z, X, Y, R ２ , R ６ , R ８ , n and p are as defined in claim 1.

21. The compound of claim 20,

22. X １ and X ５ are both CH, and R ４ 22. The compound of claim 21, wherein ' is H or Me.

23. B is a phenyl or pyridinyl group, each of which is selected from 1 to 4 R as defined in claim 1 ８ The compound according to any one of claims 1 to 22, which is optionally substituted by a group.

24. The compound according to any one of claims 1 to 23, wherein B is a phenyl group optionally substituted by one or two halo groups.

25. Z is C １－６ - alkyl, phenyl, C ３－６ - a group selected from cycloalkyl and 5- or 6-membered heterocycloalkyl groups, each of which may be further substituted by one or more groups selected from alkyl, halo, haloalkyl, CN, alkenyl, alkynyl, and alkoxy.

26. 26. The compound of any one of claims 1 to 25, wherein Z is a group selected from phenyl, pyridinyl, piperidinyl, cyclopropyl and tetrahydropyranyl, more preferably phenyl, each of which may be further substituted by one or more groups selected from alkyl, halo, haloalkyl, CN, alkenyl, alkynyl and alkoxy.

27. L is -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 -, -(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-(CR'R") ｂ -, -(CR'R") ａ -SO ２ -, -SO ２ -(CR'R") ａ -, -(CR'R") ａ -SO-, -SO-(CR'R") ａ -, -(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 -, 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 -and-(CR'R") ａ -heterocycloalkylene-O-, a and b are each independently an integer from 1 to 6, and each R' and each R" is independently selected from H and alkyl, more preferably R' and R" are both H.

28. Lが、-CH ２ -、-CH ２ CH ２ CH ２ -、-CH ２ CH ２ -、-CH ２ O-、-OCH ２ -、-EH (Me)OEH ２ 、-CH ２ OCH(M%)-、-CH(CF ３ )OCH ２ 、-CH ２ OCH(CF) ３ )-、-H ２ CH ２ O-、-OCH ２ CH ２ -、-CH ２ CH ２ CH ２ O-、-OCH ２ CH ２ CH ２ -、-CH ２ SO ２ CH ２ -、-CH ２ SOCH ２ -、-CH ２ SCH ２ -、-NH-S ２ -、-NH-S ２ -CH ２ -、-CH ２ -ES ２ -NH-、-S ２ -NH-、-S ２ -NH-CH ２ -、-CH ２ -NH-S 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 -、-CH ２ SO-、-SOCH ２ -、-CH ２ OCH ２ , -CH(Me)O-, -OCH(Me)-, -CH(CF ３ )O-,-OCH(CF ３ ) -, -CH ２ SCH ２ O- and -OCH ２ SCH ２ The compound according to any one of claims 1 to 27, selected from:

29. L-Z is -OCH ２ CH ２ Ph, -OCH ２ Ph, -OCH ２ CH ２ CH(Me) ２ , -OCH ２ CH(Me) ２ , -OSO ２ -(4-methylphenyl), -CH ２ SO ２ CH ２ -Ph, -CH ２ SO ２ -Ph, -OCH ２ -cyclopropyl, -OCH ２ CH ２ CH ２ CH ３ , -OCH ２ CH ２ CH ２ CH ２ Ph, -CH ２ OCH ２ Ph, -OCH ２ SCH ２ Ph, -CH ２ OCH ２ Ph, -CH ２ CH ２ Ph, -CH ２ SO ２ -(4-methylphenyl), -CH ２ SO ２ -(4-methoxyphenyl), -CH ２ SO ２ -(4-chlorophenyl), -CH ２ SO ２ -(3-chlorophenyl), -CH ２ SO ２ -(2-chlorophenyl), -CH ２ OCH(Me)-Ph,-CH ２ OCH (CF ３ )-Ph, -CH ２ OCH ２ -cyclopropyl, -CH ２ O-cyclopropyl, —OCH(Me)-cyclopropyl, —CH(Me)O-cyclopropyl, —OCH(CF ３ )-cyclopropyl, —CH(CF ３ ) O-cyclopropyl, CH ２ OCH ２ -(pyridin-2-yl), -CH ２ OCH ２ (4-methoxyphenyl), CH ２ OCH ２ (3-methoxyphenyl), —CH ２ SO ２ -(4-methylpyridin-3-yl)-chlorophenyl), 【Chemistry 10】 The compound according to any one of claims 1 to 28,

30. L-Z is -OCH ２ CH ２ Ph, -OCH ２ CH ２ CH ２ CH ２ Ph or -CH ２ OCH ２ Ph, more preferably —OCH ２ CH ２ The compound according to any one of claims 1 to 29, wherein the compound is Ph.

31. below: Table 1 and pharmaceutically acceptable salts and solvates thereof.

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

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

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

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

36. 36. The compound or pharmaceutical composition for use according to claim 35, wherein the cancer is selected from colon, colorectal, rectal, gastric, esophageal, pancreatic, gallbladder, bile duct, liver, lung, kidney, gynecological, breast, testicular, skin, prostate, central nervous system and brain cancer.

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

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

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

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

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

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

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

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