Bicyclic heteroaryl derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors

Abstract

To provide certain bicyclic heteroaryl compounds that inhibit ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) enzymatic activity and are therefore useful for the treatment of diseases and conditions modulated at least in part by ENPP1.SOLUTION: In some embodiments, the bicyclic heteroaryl compounds includes those of Formula (I). Also provided herein are pharmaceutical compositions containing such compounds and processes for preparing such compounds.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 833,455, filed April 12, 2019, and U.S. Provisional Patent Application No. 62 / 881,111, filed July 31, 2019, the contents of each of which are incorporated herein by reference in their entirety for all purposes.

[0002] STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT Not applicable

[0003] Reference to a "Sequence Listing," a table, or a computer program listing appendix submitted on a compact disc Not applicable

[0004] The present disclosure provides certain bicyclic heteroaryl phosphonate and boronate compounds that inhibit ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) enzyme activity and are therefore useful in the treatment of diseases treatable by inhibition of ENPP1. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds. [Background technology]

[0005] The ENPP1 enzyme is present in a wide range of tissues and cell types, including lymphocytes, macrophages, liver, brain, heart, kidney, vascular smooth muscle cells, and chondrocytes. ENPP1 hydrolyzes ATP and other nucleoside triphosphates, releasing AMP or other nucleoside monophosphates and pyrophosphate (PPi) (Kato K et al. 2012 PNAS 109:16876-16881; Hessle L et al. 2002 PNAS 99:9445-9449). The enzyme can also hydrolyze other nucleoside monophosphates (Kato K et al. 2012 PNAS 109:16876-16881). ENPP1 has been identified as the predominant 2'-3'-cGAMP hydrolase in cultured cells, tissue extracts, and blood (Li L et al. 2014 Nat Chem Biol 10:1043-1048). Tissues and blood from ENPP1 knockout mice lack 2'-3'-cGAMP hydrolase activity. Elevated levels of ENPP1 are associated with calcific aortic valve disease (CAVD) and calcium pyrophosphate dihydrate (CPPD) disease, inflammatory disorders caused by CPPD crystal deposits in joints and surrounding tissues (Cote N et al. 2012 Eur J Pharmacol 689:139-146; Johnson K et al. 2001 Arthritis Rheum 44:1071). ENPP1 expression is upregulated in certain hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid, and breast cancers and is associated with resistance to chemotherapy (see Lau WM et al. 2013 PLoS One 8:5; Bageritz J et al. 2014 Mol Cell Oncology 1:3; Bageritz J et al. 2014 Cell Death, Differentiation 21:929-940; Umar A et al. 2009 Mol Cell Proteomics 8:1278-1294).ENPP1 upregulation and ENPP1 variants are also associated with insulin-resistant diabetes and type 2 diabetes (Meyre D et al. 2005 Nat Genet 37:863-867; Maddux BA et al. 1995 Nature 373:448-451; Rey D et al. 2012 Mol Biol Rep 39:7687-7693), and the enzymatic activity of ENPP1 has been reported to be required for the inhibition of insulin receptor signaling (Chin CN et al. 2009 Eur J Pharmacol 606:17-24).

[0006] Cyclic GMP-AMP synthase (cGAS) is a pattern recognition receptor that synthesizes the endogenous messenger molecule cGAMP from ATP and GTP in response to the presence of DNA from viruses, bacteria, damaged mitochondria, or cancer cells. The cGAMP molecule then binds to the stimulator of interferon genes (STING) protein, which initiates a signaling response that activates innate immunity and leads to the production of type I interferons, antiviral and immune-stimulating cytokines (Sun L et al. 2013 Science 339:786-791; Wu J et al. 2013 Science 339:826-830; Gao D et al. 2013 Science 341:903-906; Li X et al. 2013 Science 341:1390-1394; Schoggins JW et al. 2014 Nature 505:691-695; Wassermann R et al. 2015 Cell Host Microbe 17:799-810; Watson RO et al. 2015 Cell Host Microbe 17:811-819; Collins A et al. 2015 Cell Host Microbe 17:820-828; West A et al. 2015 Nature 520:533-557; Woo SR et al. 2014 Immunity 41:830-842; Deng L et al. 2014 Immunity 41:843-852; Chen Q et al. 2016 Nat Immunol 17:1142-1148). The cGAS enzyme, cGAMP messenger, and STING are also involved in host defense against RNA viruses and immune control of tumor development (Aguirre S et al. 2012 PLoS Pathog 8:e1002934; Barber GN 2015 Nat Rev Immunol 15:760-770). ENPP1 has been identified as an enzyme that naturally hydrolyzes cGAMP and thus counteracts the innate immune response against infectious pathogens, damaged cells, and cancer cells (Li L et al. 2014 Nat Chem Biol 10:1043-1048).The efficacy of non-hydrolyzable cGAMP analogs in inducing functional immune responses is higher than that of native hydrolyzable cGAMP (Li L et al. 2014 Nat Chem Biol 10:1043-1048; Corrales L et al. 2015 Cell Rep 11:1018-1030). Viral infection has been demonstrated to be enhanced by ENPP1 overexpression and attenuated by ENPP1 silencing (Wang J et al. 2018 Mol Immunol 95:56-63).

[0007] Therefore, inhibitors of cGAMP hydrolysis can be used to increase the effectiveness of immune responses against cancer cells and tumors, as well as infectious diseases caused by RNA or DNA viruses or bacteria. Inhibitors of ENPP1 and cGAMP or nucleoside triphosphate hydrolysis can also be used to treat inflammatory diseases associated with increased nucleotidase levels, decreased nucleoside triphosphates, reduced cGAMP, or decreased nucleoside monophosphate levels, or diseases associated with increased nucleoside or nucleoside monophosphate levels. For these reasons, ENPP1 is an attractive therapeutic target for the treatment of diseases.

[0008] The present disclosure addresses these needs and provides related advantages as well. Summary of the Invention [Means for solving the problem]

[0009] In a first aspect, a compound of formula (I): [ka] (In the formula, a, b, d, and e are CH; or one or two of a, b, d, and e are N, and the remaining a, b, d, and e are CH; One of y and z is N, and the other y and z is CR 7 or both y and z are CR 7 and each R7 are independently hydrogen, alkyl, hydroxy, or halo; alk is alkylene optionally substituted with 1, 2, or 3 halo; alk 1 is alkylene, wherein one carbon atom in the alkylene chain may be replaced by oxygen, and the alkylene chain is optionally substituted with 1, 2 or 3 halo; m and n are independently 0 or 1; provided that at least one of m and n is 1; Ar is aryl or heteroaryl; Q is -P(O)(R a )(R b ) or -B(R w )(R x ) and R a and R b are independently selected from hydroxy, alkoxy, -Oaryl (aryl optionally substituted with 1 to 3 substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCOR c (R c is alkyl), -O-(CH2)OCOOR c (R c is alkyl), -O-(alk 2 ) OR d (alk 2 is alkylene, and R d is alkyl), -S-(CH2)2SCOR e (R e is alkyl), or -NR g -(CHR)OCOR fR is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl, or phenylalkyl, wherein phenyl alone or as part of phenylalkyl is optionally substituted with 1 to 3 substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano, or nitro; and R f is alkyl or benzyl, and R g is hydrogen or together with R forms -(CH2)3-; or R a and R b together with the phosphorus atom to which they are attached to form a ring of formula (a): [ka] (In the formula, Ar 2 is phenyl or 6-membered heteroaryl optionally substituted with 1-3 halo; and R w and R x are independently selected from hydroxy, alkoxy, -Oaryl (aryl optionally substituted with 1 to 3 substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCOR c (R c is alkyl), -O-(alk 2 ) OR d (alk 2 is alkylene, and R d is alkyl), -S-(CH2)2SCOR e (R e is alkyl), or -NR g -(CHR)OCOR fR is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl, or phenylalkyl, where phenyl alone or as part of a phenylalkyl is optionally substituted with 1 to 3 substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano, or nitro; f is alkyl or benzyl, and R g is hydrogen or together with R forms —(CH)—; or R w and R x can be combined with the boron atom to which they are attached to form -O(CRR')2O- or -O(CRR')3O-, where each R and R' is independently hydrogen or methyl; R 2 and R 3 are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano; R 4 is hydrogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl; and R 5 and R 6R is independently hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, amino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, where either heterocyclyl alone or portions of heterocyclyloxy and heterocyclylamino are optionally independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl. h , R j , or R k substituted with), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl in phenyloxy and the heteroaryl in heteroaryloxy are optionally substituted with 1, 2, or 3 substituents, two of the optional substituents being independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano); or a pharmaceutically acceptable salt thereof; Subject to the following: 1. Formula (I) is the structure [ka] and: (i)R w and R x When each is -OH, [ka] 4-((6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)methyl)phenyl; 4-((5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 4-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 5-fluoro-2-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 3-fluoro-4-((2-methyl-1H-benzimidazol-1-yl) methyl)phenyl;3-((5,6-dimethyl-1H-benzimidazol-1-yl)methyl)phenyl;4-((5,6-dimethyl-1H-benzimidazol-1-yl)methyl)phenyl;2-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl;2-((5,6-dimethyl-1H-benzimidazol-1-yl)methyl)phenyl;2-fluoro-5-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 3-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl;3-(1H-benzimidazol-1-ylmethyl)phenyl;3-(1H-indazol-1-ylmethyl)phenyl;2-(1H-benzimidazol-1-ylmethyl)phenyl;4-(1H-benzimidazol-1-ylmethyl)phenyl;4-(1H-indol-1-ylmethyl)phenyl;4-((6-a 3-((6-amino-9H-purin-9-yl)methyl)phenyl; 2-((6-amino-9H-purin-9-yl)methyl)phenyl; 4-(1H-benzimidazol-1-ylmethyl)-3-fluorophenyl; 4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-fluorophenyl; 5 -(1H-Benzimidazol-1-ylmethyl)-2-fluorophenyl;4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-fluorophenyl;2-(1H-benzimidazol-1-ylmethyl)-5-fluorophenyl;5-(1H-benzimidazol-1-ylmethyl)-2-methoxyphenyl;3-(1H-benzimidazol- 1-ylmethyl)-4-methoxyphenyl; but not 2-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-pyrimidinyl, 6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-pyridinyl, or 4-(2-ethoxy-7-carboxy-1H-benzimidazol-1-ylmethyl)phenyl; (ii)-B(R w )(R x )but, [ka] When [ka] are 2-(1H-benzo[d]imidazol-1-ylmethyl)phenyl, 2-(1H-indol-1-ylmethyl)phenyl, 3-(1H-indazol-1-ylmethyl)phenyl, 4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methylphenyl, 4-(2-methyl-1H-benzimidazol-1-ylmethyl)phenyl; 4-(6-amino-8-methoxy-2-(tetrahydro-2H-pyran-4-yl)methoxy-9H-purin-9-ylmethyl)phenyl, 3-fluoro-4-(6-amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-9-ylmethyl)phenyl, 4-(6-amino-8-methoxy- is not 2-(2-methoxyethoxy)-9H-purin-9-ylmethyl)phenyl, 4-(6-amino-2-butoxy-8-methoxy-9H-purin-9-ylmethyl)phenyl, 4-(1H-indol-1-ylmethyl)phenyl, 4-(1H-benimidazol-1-ylmethyl)phenyl, 3-(7-methoxycarbonyl-1H-indol-1-ylmethyl)phenyl, 4-(7-methoxycarbonyl-1H-indol-1-ylmethyl)phenyl, 4-(2-ethoxy-7-methoxycarbonyl-1H-benzimidazol-1-ylmethyl)phenyl, or 4-(2-ethoxy-7-ethoxycarbonyl-1H-benzimidazol-1-ylmethyl)phenyl; and (iii)-B(R w )(R x )but, [ka] When [ka] is not 4-(2-ethoxy-7-ethoxycarbonyl-1H-benzimidazol-1-ylmethyl)phenyl; and 2.Q is -P(O)(R a )(R b ), then one of m and n is 1 and the other of m and n is 0; or a pharmaceutically acceptable salt thereof.

[0010] In a second aspect, a compound of formula (IA): [ka] (In the formula, a, b, d, and e are CH; or one or two of a, b, d, and e are N, and the remaining a, b, d, and e are CH; One of y and z is N, and the other y and z is CR 7 or both y and z are CR 7 and each R 7 are independently hydrogen, alkyl, hydroxy, or halo; alk is alkylene optionally substituted with 1, 2, or 3 halo; alk 1 is alkylene, wherein one carbon atom in the alkylene chain may be replaced by oxygen, and the alkylene chain is optionally substituted with 1, 2 or 3 halo; m and n are independently 0 or 1; provided that at least one of m and n is 1; Ar is aryl, heteroaryl, cycloalkyl, or heterocyclyl; Q is -P(O)(R a )(R b ) or -B(R w )(R x ) and R a , R b , R w and R x are independently selected from hydroxy, alkoxy, -Oaryl (aryl optionally substituted with 1 to 3 substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCOR c (R c is alkyl), -O-(alk 2 ) OR d (alk 2 is alkylene, and R dis alkyl), -S-(CH2)2SCOR e (R e is alkyl), or -NR g -(CHR)OCOR f R is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl, or phenylalkyl, where phenyl alone or as part of a phenylalkyl is optionally substituted with 1 to 3 substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano, or nitro; f is alkyl or benzyl, and R g is hydrogen or together with R forms -(CH2)3-; or R a and R b together with the phosphorus atom to which they are attached to form a ring of formula (a): [ka] (In the formula, Ar 2 is phenyl or 6-membered heteroaryl optionally substituted with 1-3 halo; or R w and R x can be combined with the boron atom to which they are attached to form -O(CRR')2O- or -O(CRR')3O-, where each R and R' is independently hydrogen or methyl; R 2 and R 3 are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano; R 4 is hydrogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl; and R 5 and R 6 R is independently hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, amino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, where either heterocyclyl alone or portions of heterocyclyloxy and heterocyclylamino are optionally independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl. h , R j , or R k substituted with), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl in phenyloxy and the heteroaryl in heteroaryloxy are optionally substituted with 1, 2, or 3 substituents, two of the optional substituents being independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano); or a pharmaceutically acceptable salt thereof; Subject to the following: 1. The compound of formula (IA) has the structure [ka] wherein Ar is aryl or heteroaryl, and (i)R w and R x When each is -OH, [ka] 4-((6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)methyl)phenyl; 4-((5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 4-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 5-fluoro-2-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 3-fluoro-4-((2-methyl-1H-benzimidazol-1-yl) methyl)phenyl;3-((5,6-dimethyl-1H-benzimidazol-1-yl)methyl)phenyl;4-((5,6-dimethyl-1H-benzimidazol-1-yl)methyl)phenyl;2-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl;2-((5,6-dimethyl-1H-benzimidazol-1-yl)methyl)phenyl;2-fluoro-5-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 3-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl;3-(1H-benzimidazol-1-ylmethyl)phenyl;3-(1H-indazol-1-ylmethyl)phenyl;2-(1H-benzimidazol-1-ylmethyl)phenyl;4-(1H-benzimidazol-1-ylmethyl)phenyl;4-(1H-indol-1-ylmethyl)phenyl;4-((6-a 3-((6-amino-9H-purin-9-yl)methyl)phenyl; 2-((6-amino-9H-purin-9-yl)methyl)phenyl; 4-(1H-benzimidazol-1-ylmethyl)-3-fluorophenyl; 4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-fluorophenyl; 5 -(1H-Benzimidazol-1-ylmethyl)-2-fluorophenyl;4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-fluorophenyl;2-(1H-benzimidazol-1-ylmethyl)-5-fluorophenyl;5-(1H-benzimidazol-1-ylmethyl)-2-methoxyphenyl;3-(1H-benzimidazol- 1-ylmethyl)-4-methoxyphenyl; but not 2-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-pyrimidinyl, 6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-pyridinyl, or 4-(2-ethoxy-7-carboxy-1H-benzimidazol-1-ylmethyl)phenyl; (ii)-B(R w )(R x )but, [ka] When [ka] are 2-(1H-benzo[d]imidazol-1-ylmethyl)phenyl, 2-(1H-indol-1-ylmethyl)phenyl, 3-(1H-indazol-1-ylmethyl)phenyl, 4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methylphenyl, 4-(2-methyl-1H-benzimidazol-1-ylmethyl)phenyl; 4-(6-amino-8-methoxy-2-(tetrahydro-2H-pyran-4-yl)methoxy-9H-purin-9-ylmethyl)phenyl, 3-fluoro-4-(6-amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-9-ylmethyl)phenyl, 4-(6-amino-8-methoxy- is not 2-(2-methoxyethoxy)-9H-purin-9-ylmethyl)phenyl, 4-(6-amino-2-butoxy-8-methoxy-9H-purin-9-ylmethyl)phenyl, 4-(1H-indol-1-ylmethyl)phenyl, 4-(1H-benimidazol-1-ylmethyl)phenyl, 3-(7-methoxycarbonyl-1H-indol-1-ylmethyl)phenyl, 4-(7-methoxycarbonyl-1H-indol-1-ylmethyl)phenyl, 4-(2-ethoxy-7-methoxycarbonyl-1H-benzimidazol-1-ylmethyl)phenyl, or 4-(2-ethoxy-7-ethoxycarbonyl-1H-benzimidazol-1-ylmethyl)phenyl; and (iii)-B(R w )(R x )but, [ka] When [ka] is not 4-(2-ethoxy-7-ethoxycarbonyl-1H-benzimidazol-1-ylmethyl)phenyl; and 2.Q is -P(O)(R a )(R b ), then one of m and n is 1 and the other of m and n is 0; or a pharmaceutically acceptable salt thereof.

[0011] In a second aspect, there is provided a pharmaceutical composition comprising a compound of the present disclosure, e.g., Formula (I) or (IA) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0012] In a third aspect, there is provided a method of treating a disease or a disease mediated by ENPP1 in a patient, preferably a patient identified as in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or (IA) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof. In one embodiment, the disease is cancer, such as hepatocellular carcinoma, glioblastoma, melanoma, testicular, pancreatic, thyroid, and breast cancer. In another embodiment, the disease is an inflammatory disease, such as aortic valve calcification disease and calcium pyrophosphate dihydrate. In yet another embodiment, the disease is a metabolic disease, such as type 2 diabetes or a viral infection.

[0013] In a fourth aspect, there is provided a compound of Formula (I) or (IA) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof for use as a medicament. In one embodiment, the medicament is for use in the treatment of cancer, such as hepatocellular carcinoma, glioblastoma, melanoma, testicular, pancreatic, thyroid, and breast cancer. In another embodiment, the medicament is for use in the treatment of inflammatory diseases, such as aortic valve calcification disease and calcium pyrophosphate dihydrate. In yet another embodiment, the medicament is for use in the treatment of metabolic diseases, such as type 2 diabetes or viral infections.

[0014] In a fifth aspect, there is provided the use of a compound of Formula (I) or (IA) or a pharmaceutically acceptable salt thereof (and any embodiment thereof disclosed herein) in the manufacture of a medicament for treating a disease in a patient in which ENPP1 activity contributes to the pathology and / or symptoms of the disease. In one embodiment, the disease is cancer, such as hepatocellular carcinoma, glioblastoma, melanoma, testicular, pancreatic, thyroid, and breast cancer. In another embodiment, the disease is an inflammatory disease, such as aortic valve calcification disease and calcium pyrophosphate dihydrate. In yet another embodiment, the disease is a metabolic disease, such as type 2 diabetes or a viral disease.

[0015] In any of the aforementioned aspects involving the treatment of cancer, there are further embodiments that include administering a compound of Formula (I) or (IA) or a pharmaceutically acceptable salt thereof (or any embodiment thereof disclosed herein) in combination with at least one additional anti-cancer agent. When combination therapy is used, the agents may be administered simultaneously or sequentially. DETAILED DESCRIPTION OF THE INVENTION

[0016] Definition: Unless otherwise stated, the following terms used in the specification and claims are defined for purposes of this application and have the following meanings:

[0017] "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.

[0018] "Alkylene," unless otherwise specified, means a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0019] "Alkenyl" means a linear or branched monovalent hydrocarbon radical of two to six carbon atoms containing a double bond, e.g., ethenyl, propenyl, 2-propenyl, and the like.

[0020] "Alkylthio" means an --SR group where R is alkyl as defined above, e.g., methylthio, ethylthio, and the like.

[0021] "Alkylsulfonyl" means a -SO2R group where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.

[0022] "Amino" means -NH2.

[0023] "Aminocarbonyl" means -CONH2.

[0024] "Alkylaminocarbonyl" means a -CONHR radical where R is alkyl as defined above, e.g., methylaminocarbonyl, ethylaminocarbonyl, and the like.

[0025] "Aminosulfonyl" means -SO2NH2.

[0026] "Alkylaminosulfonyl" means a -SO2NHR group where R is alkyl as defined above, e.g., methylaminosulfonyl, ethylaminosulfonyl, and the like.

[0027] "Alkylamino" means an --NHR group where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like.

[0028] "Aminoalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with --NR'R" where R' and R" are independently hydrogen or alkyl as defined above, e.g., aminomethyl, aminoethyl, methylaminomethyl, and the like.

[0029] "Aminoalkylamino" is R a is hydrogen or alkyl, and R b is aminoalkyl as defined above -NR a R b groups such as aminoethylamino, dimethylaminoethylamino, diethylaminoethylamino, dimethylaminopropylamino, diethylaminopropylamino, and the like.

[0030] "Aminoalkyloxy" is R a -OR is aminoalkyl as defined above a groups such as aminoethyloxy, dimethylaminoethyloxy, diethylaminoethyloxy, dimethylaminopropyloxy, diethylaminopropyloxy, and the like.

[0031] "Alkoxy" means an --OR group where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.

[0032] "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms substituted with at least one alkoxy group, such as one or two alkoxy groups, as defined above, e.g., 2-methoxyethoxy, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0033] "Alkoxyalkylamino" means an --NRR' group where R is hydrogen or alkyl and R' is alkoxyalkyl as defined above, eg, methoxyethylamino, ethoxyethylamino, propoxypropylamino, ethoxypropylamino, and the like.

[0034] "Alkoxyalkyloxy" or "alkoxyalkoxy" means an --(O)R group where R is alkoxyalkyl as defined above, e.g., methoxyethoxy, ethoxyethoxy, and the like.

[0035] "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.

[0036] "Phenyloxy" refers to the group --OR where R is phenyl.

[0037] "Cycloalkyl" means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0038] "Cycloalkyloxy" means an --OR group where R is cycloalkyl (including certain heterocyclyl rings) as defined above, e.g., cyclopropyloxy, and the like.

[0039] "Carboxy" means --COOH.

[0040] "Dialkylaminocarbonyl" means --CONHRR' where R and R' are independently alkyl as defined above, e.g., dimethylaminocarbonyl, methylethylaminocarbonyl, and the like.

[0041] "Dialkylaminosulfonyl" means -SO2NHRR' where R and R' are independently alkyl as defined above, e.g., dimethylaminosulfonyl, methylethylaminosulfonyl, and the like.

[0042] "Dialkylamino" means an --NRR' group where R and R' are alkyl as defined above, eg, dimethylamino, methylethylamino, and the like.

[0043] "Halo" means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

[0044] "Haloalkyl" means an alkyl group, as defined above, substituted with one or more halogen atoms, such as 1 to 5 halogen atoms such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When an alkyl is substituted with only fluoro, it may be referred to herein as fluoroalkyl.

[0045] "Haloalkoxy" means an -OR group where R is haloalkyl as defined above, e.g., -OCF, -OCHF, etc. When R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to herein as fluoroalkoxy.

[0046] "Hydroxyalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

[0047] "Hydroxyalkylamino" is R a is hydrogen or alkyl, and R b is hydroxyalkyl as defined above -NRa R b groups such as hydroxyethylamino, hydroxypropylamino, and the like.

[0048] "Hydroxyalkyloxy" is R a -OR is an aminohydroxyalkyl as defined above a groups such as hydroxyethyloxy, hydroxypropyloxy, and the like.

[0049] "Heterocyclyl" means a heterocyclic group in which one or two ring atoms are N, O, or S(O) n where n is an integer from 0 to 2, and the remaining ring atoms are C. Furthermore, one or two ring carbon atoms in the heterocyclyl ring can be optionally replaced by a -CO- group. More specifically, the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated, it can contain one or two double bonds, provided the ring is not aromatic. When a heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.

[0050] "Heterocyclylalkyl" or "heterocycloalkyl" means an -(alkylene)-R group where R is a heterocyclyl ring (including the specified heterocyclyl rings) as defined above, e.g., tetrahydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.

[0051] "Heterocyclylamino" means the group --NRR' where R is hydrogen or alkyl and R' is heterocyclyl (including specific heterocyclyl rings) as defined above.

[0052] "Heterocyclylalkylamino" or "heterocycloalkylamino" means the group -NRR' where R is hydrogen or alkyl and R' is a heterocyclylalkyl ring (including specific heterocyclyl rings) as defined above, e.g., tetrahydrofuranylmethylamino, piperazinylethylamino, morpholinylethylamino, piperidinylmethylamino, and the like.

[0053] "Heterocyclyloxy" means an -OR group where R is heterocyclyl (including specific heterocyclyl rings) as defined above.

[0054] "Heterocyclylalkyloxy" or "heterocycloalkyloxy" means an --OR group where R is a heterocyclylalkyl ring (including specific heterocyclyl rings) as defined above, e.g., tetrahydrofuranylmethyloxy, piperazinylethyloxy, morpholinylethyloxy, piperidinylmethyloxy, and the like.

[0055] "Heteroaryl," unless otherwise specified, refers to a monovalent monocyclic or bicyclic aromatic group of 5 to 10 ring atoms in which one or more (in one embodiment, 1, 2, or 3) ring atoms are heteroatoms selected from N, O, or S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. As defined herein, the terms "heteroaryl" and "aryl" are mutually exclusive. When a heteroaryl ring contains 5 or 6 ring atoms, it is also referred to herein as a 5- or 6-membered heteroaryl.

[0056] "Heteroaryloxy" means the group --OR where R is heteroaryl (including specific heteroaryl rings) as defined above.

[0057] The present disclosure also includes protected derivatives of the compounds of (I) of the present disclosure. For example, when the compounds of the present disclosure contain groups such as hydroxy, carboxy, thiol, or any group containing a nitrogen atom, these groups can be protected with suitable protecting groups. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999), the disclosure of which is incorporated herein by reference in its entirety. Protected derivatives of the compounds of the present disclosure can be prepared by methods well known in the art.

[0058] The present disclosure also includes polymorphic forms and deuterated forms of the disclosed compounds and / or pharmaceutically acceptable salts thereof.

[0059] A "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or with formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, and glucoheptonic acid. Acid addition salts formed with organic acids such as 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

[0060] The compounds of the present disclosure may have asymmetric centers. Compounds of the present disclosure containing asymmetrically substituted atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms, such as by resolution of materials, are well known in the art. All chiral, diastereomeric, and all mixtures of chiral or diastereomeric forms, as well as racemic forms, are within the scope of the present disclosure, unless a specific stereochemistry or isomer is specifically indicated. It will also be understood by those skilled in the art that when a compound is represented as the (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity, i.e., less than about 5%, preferably 2% by weight of the (S) stereoisomer; and when it is represented as a mixture of R and S isomers, the amount of R or S isomer in the mixture is greater than about 5%, preferably 2% w / w.

[0061] Certain compounds of the present disclosure may exist as tautomers and / or geometric isomers. All possible tautomers, as individual forms and mixtures thereof, and cis and trans isomers are within the scope of the present disclosure. For example, hydroxy-substituted compounds of formula (I) may exist as tautomers, as shown below: [ka]

[0062] Furthermore, as used herein, the term alkyl includes all possible isomers of said alkyl group. Furthermore, when cyclic groups such as aryl, heteroaryl, heterocyclyl, etc. are substituted, they also include all possible isomers. Furthermore, all hydrates of the compounds of the present disclosure are within the scope of the present disclosure.

[0063] Certain structures provided herein are drawn with one or more variable substituents. Unless otherwise specified or apparent from the context, the substituents may be present on any atom of the ring on which the substituent is drawn, provided that this is chemically feasible and valence rules permit. For example, the structure: [ka] In R 4 The substituent may replace any hydrogen on the six-membered aromatic ring portion of the bicyclic ring system, including the hydrogen of CH when a is CH.

[0064] Compounds of the present disclosure may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of isotopes may be defined as ranging from the amount found in nature to 100% of the amount of that atom, differing only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that may be incorporated into compounds of the present invention, such as compounds of Formula (I) (and any embodiment thereof disclosed herein, including specific compounds), include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 1. Isotopically labeled compounds (e.g., 3 H and 14 C) can be useful in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H, may provide certain therapeutic advantages resulting in greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in the compounds disclosed herein, including in Table 1 below, one or more hydrogen atoms are 2 H or 3H or one or more carbon atoms are replaced by 13 C- or 14 replaced by C-enriched carbon. 15 O. 13 N, 11 C, and 15 Positron-emitting isotopes such as F are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures similar to those disclosed in the schemes or examples herein, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0065] "Oxo" or "carbonyl" refers to the =(O) group.

[0066] "Optional" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl may, but need not, be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with an alkyl group.

[0067] A "pharmaceutically acceptable carrier or excipient" refers to a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes carriers or excipients that are acceptable for veterinary and human pharmaceutical use. As used in this specification and claims, "pharmaceutically acceptable carrier / excipient" includes both one and more than one such excipient.

[0068] The term "about," as used herein, is intended to qualify the numerical value it modifies and indicates that such value may vary within a margin of error. When a specific margin of error is not stated, such as a standard deviation for a given mean value in a chart or table of data, the term "about" should be understood to encompass and mean a range of ±10%, preferably ±5%, of the stated value.

[0069] As used herein, the term "disease" is generally intended to be synonymous with, and used interchangeably with, the terms "disorder," "syndrome," and "condition" (medical condition), in that all reflect an abnormal condition of the human or animal body or parts thereof that impairs normal function, is typically manifested by characteristic signs and symptoms, and reduces the duration or quality of the human or animal's life.

[0070] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, and horses. Preferably, the patient is a human.

[0071] The terms "inhibit" and "reduce," or variations of either of these terms in relation to EPPI, include any measurable decrease or complete inhibition that achieves the desired result. For example, there can be about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more reduction in EPPI activity compared to normal, or any range derivable therein.

[0072] "Treat" or "treatment" of a disease means (1) To prevent the disease, i.e., to prevent the development of clinical symptoms of the disease in a mammal that may be exposed to or susceptible to the disease but that has not yet experienced or exhibited symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) Relieving the disease, including causing regression of the disease or its clinical symptoms.

[0073] "Therapeutically effective amount" means the amount of a compound of the present disclosure and / or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal being treated.

[0074] Representative compounds of formula (I) are disclosed in Table 1 below.

[0075] [Table 1]

[0076] [Table 2]

[0077] [Table 3]

[0078] [Table 4]

[0079] [Table 5]

[0080] [Table 6]

[0081] [Table 7]

[0082]

Table 8

[0083]

Table 9

[0084]

Table 10

[0085]

Table 11

[0086]

Table 12

[0087]

Table 13

[0088]

Table 14

[0089]

Table 15

[0090] Table 16

[0091]

Table 17

[0092] [Table 18]

[0093] [Table 19]

[0094] Embodiments: Embodiment A In embodiment A, a compound of formula (I) or (IA) as defined in the summary above, or a pharmaceutically acceptable salt thereof.

[0095] In a first subembodiment A, the compound is of formula (I) as defined in the summary above or a pharmaceutically acceptable salt thereof. Within first subembodiment A, the compound of formula (I) or a pharmaceutically acceptable salt thereof is one in which Q is -P(O)(R a )(R b ) or -B(R w )(R x ) and R a , R b , R w and R x are independently selected from hydroxy, alkoxy, -Oaryl (aryl optionally substituted with 1 to 3 substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCOR c (R c is alkyl), -O-(alk 2 ) OR d (alk 2 is alkylene, and R d is alkyl), -S-(CH2)2SCOR e (R e is alkyl), or -NR g -(CHR)OCOR fR is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl, or phenylalkyl, where phenyl alone or as part of a phenylalkyl is optionally substituted with 1 to 3 substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano, or nitro; f is alkyl or benzyl, and R g is hydrogen or together with R forms -(CH2)3-; or R a and R b together with the phosphorus atom to which they are attached to form a ring of formula (a): [ka] (In the formula, Ar 2 is phenyl or 6-membered heteroaryl optionally substituted with 1-3 halo; and R w and R x can be combined with the boron atom to which they are attached to form -O(CRR')2O- or -O(CRR')3O-, where each R and R' is independently hydrogen or methyl.

[0096] In a second subembodiment A, the compound is of formula (IA) as defined in the summary above or a pharmaceutically acceptable salt thereof.

[0097] Embodiment B In embodiment B, the compound of embodiment A and any one of the subembodiments contained therein, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ia) or (Ib): [ka] It has.

[0098] (Bi) In a subembodiment (Bi) of embodiment B, the compound or a pharmaceutically acceptable salt thereof has the structure (Ia):

[0099] (Bii) In subembodiment (Bii) of embodiment B, the compound or a pharmaceutically acceptable salt thereof has the structure (Ib):

[0100] (Biii) In subembodiment (Biii) of embodiment B, the compounds of formula (Ia) and (Ib) or pharmaceutically acceptable salts thereof are those in which y is N and z is CR 7 It is what it is.

[0101] Embodiment C In embodiment C, the compound of embodiment A and any one of the subembodiments contained therein, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ic) or (Id): [ka] It has.

[0102] (Ci) In subembodiment (Ci) of embodiment C, the compound or a pharmaceutically acceptable salt thereof has the structure (Ic).

[0103] (Cii) In subembodiment (Cii) of embodiment C, the compound, or a pharmaceutically acceptable salt thereof, has the structure (Id):

[0104] Embodiment D In embodiment D, the compound of embodiment A and any one of the subembodiments contained therein, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ie) or (If): [ka] It has.

[0105] (Di) In a subembodiment (Di) of embodiment D, the compound or a pharmaceutically acceptable salt thereof has the structure (Ie).

[0106] (Dii) In subembodiment (Dii) of embodiment D, the compound or a pharmaceutically acceptable salt thereof has the structure (If):

[0107] Embodiment D1 In embodiment D, the compound of embodiment A and any one of the subembodiments contained therein, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ig) or (Ih): [ka] (In the formula, R 7 is alkyl, halo, or hydroxy).

[0108] (D1i) In a subembodiment (D1i) of embodiment D, the compound or a pharmaceutically acceptable salt thereof has the structure (Ig).

[0109] (D1ii) In a subembodiment (Dii) of embodiment D, the compound or a pharmaceutically acceptable salt thereof has the structure (Ih).

[0110] (D1iii) In subembodiment (Dii) of embodiment D, the compounds or pharmaceutically acceptable salts of structures (Ig) and (Ih) are 7 is alkyl.

[0111] Embodiment E In embodiment E, the compound of any one of embodiments A, B, C, D, and D1 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, comprises R 4 , R 5 , and R 6 and a, b, d, and e are CH or C when bound to any one of:

[0112] Embodiment F In embodiment F, the compound of any one of embodiments A, B, C, D, and D1 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, is 4, R 5 , and R 6 When a is N and b, d, and e are CH or C,

[0113] Embodiment G In embodiment G, the compound of any one of embodiments A, B, C, D, and D1 and the subembodiments contained therein, or a pharmaceutically acceptable salt thereof, comprises R 4 , R 5 , and R 6 When bonded to any one of the following, a and d are N, and b and e are CH or C.

[0114] Embodiment H In embodiment H, the compound of any one of embodiments A, B, C, D, and D1 and the subembodiments contained therein, or a pharmaceutically acceptable salt thereof, comprises R 4 , R 5 , and R 6 When b is N and a, c, and e are CH or C,

[0115] Embodiment I In embodiment I, the compound of any one of embodiments A, B, C, D, and D1 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, is 4 , R 5 , and R 6 When bonded to any one of the following, a and e are N, and a and d are CH or C.

[0116] In subembodiment Ii, the compound of any one of embodiments A, B, C, D, and D1 and the subembodiments contained therein, or a pharmaceutically acceptable salt thereof, is 5 and d is CR 6 and R 5 is hydroxyl. As mentioned above, R 5 Subembodiment Ii, in which is hydroxyl, includes the tautomeric form shown below: [ka] It can exist in

[0117] Embodiment J In embodiment J, the compound of any one of embodiments A, B, C, D, and D1 and the subembodiments contained therein, or a pharmaceutically acceptable salt thereof, comprises R 4 , R 5 , and R 6 When bonded to any one of the following, b and e are N, and a and d are CH or C.

[0118] Embodiment K In embodiment K, the compound of any one of embodiments A, B, C, D, and D1 and the subembodiments contained therein, or a pharmaceutically acceptable salt thereof, comprises R 4 , R 5 , and R 6 When d is N and a, b and e are CH or C,

[0119] Embodiment L (Li). In subembodiment Li, the compound or pharmaceutically acceptable salt thereof of any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, and K, and the subembodiments contained therein, is one in which Q is -P(O)(OH)2.

[0120] (Lii). Within subembodiment Lii, the compound or pharmaceutically acceptable salt thereof of any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, and K, and the subembodiments contained therein, is one in which Q is -B(OH)2.

[0121] (Liii). In subembodiment Liii, the compound of any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, and K, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is any one of the compounds of embodiments A, B, C, D, D1, E, F, G, H, I, J, and K, and subembodiments therein, wherein Q is —P(O)(R a)(R b Within subembodiment (Liii), in the first group of compounds, Q is R a and R b are independently selected from hydroxy, alkoxy, -Oaryl (aryl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, cyano, or nitro), -O-(CH2)OCOR c (R c is alkyl), -O-(CH2)OCOOR c (R c is alkyl), -O-(alk 2 ) OR d (alk 2 is alkylene, and R d is alkyl), and -S-(CH2)2SCOR e (R e is alkyl). Preferably, R a and R b are independently selected from alkoxy, -Oaryl (aryl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, cyano, or nitro), -O-(CH2)OCOR c (R c is alkyl), and -O-(alk 2 ) OR d (alk 2 is alkylene, and R d is alkyl, such as methyl, isopropyl, n-propyl, isobutyl, or n-butyl. a and R b are independently selected from hydroxy, alkoxy, -Ophenyl (wherein phenyl is optionally substituted with 1 to 3 substituents independently selected from alkoxy, halo, haloalkyl, cyano, or nitro), -O-(CH)OCOR c (R c is alkyl), or -NH-(CHR)OCOR f (R is alkyl, R fis alkyl, such as methyl, isopropyl, n-propyl, isobutyl, n-butyl or benzyl), preferably hydroxy or alkoxy.

[0122] Within subembodiment (Liii), in the second group of compounds, Q is R a is hydroxy, alkoxy, -Oaryl (aryl optionally substituted with 1 to 3 substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCOR c (R c is alkyl), -O-(alk 2 ) OR d (alk 2 is alkylene, and R d is alkyl), and -S-(CH2)2SCOR e (R e is alkyl), and R b But, -NR g -(CHR)OCOR f R is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl, or phenylalkyl, where phenyl alone or as part of a phenylalkyl is optionally substituted with 1 to 3 substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano, or nitro; f is alkyl or benzyl, and R g is hydrogen or together with R forms -(CH2)3-. Preferably, R a is selected from alkoxy and -Oaryl, where aryl is optionally substituted with 1 to 3 substituents independently selected from halo, cyano, or nitro; R b is -NR g -(CHR)OCOR fwherein R is alkyl, such as methyl, isopropyl, n-propyl, isobutyl, n-butyl, etc.

[0123] Within subembodiment (Liii), in the third group of compounds, Q is R a and R b together with the phosphorus atom to which they are attached to form a ring of formula (a): [ka] (In the formula, Ar 1 is phenyl or 6-membered heteroaryl optionally substituted with 1-3 halo. Preferably, Ar 1 is phenyl substituted with 1 to 3 halo or pyridinyl.

[0124] (Liv) In subembodiment Liv, the compound or pharmaceutically acceptable salt thereof of any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, and K, and subembodiments therein, is any one of the compounds or pharmaceutically acceptable salts thereof, wherein Q is -B(R w )(R x Within subembodiment (Liv), in the first group of compounds, R w and R x are independently selected from hydroxy, alkoxy, -Oaryl (aryl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, cyano, or nitro), -O-(CH)OCOR c (R c is alkyl), or -O-(alk 2 ) OR d (alk 2 is alkylene and R d is alkyl). Preferably, R w and R x are independently selected from alkoxy, -Oaryl (aryl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, cyano, or nitro), -O-(CH2)OCOR c (Rc is alkyl), and -O-(alk 2 ) OR d (alk 2 is alkylene, and R d is alkyl, such as methyl, isopropyl, n-propyl, isobutyl, or n-butyl. w and R x is independently hydroxy, alkoxy, or —Ophenyl (phenyl optionally substituted with 1 to 3 substituents independently selected from alkoxy, halo, haloalkyl, cyano, or nitro).

[0125] Within subembodiment (Liv), in the second group of compounds, R w and Rx are independently selected from hydroxy and alkoxy.

[0126] Within subembodiment (Liii), in the third group of compounds, R w and R x together with the boron atom to which they are attached to form a ring of formula (b) or (c): [ka] Form.

[0127] Embodiment M In embodiment M, the compound or a pharmaceutically acceptable salt thereof of any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, K, and L, and subembodiments contained therein, is one in which Ar is aryl or heteroaryl.

[0128] (Mi). In a subembodiment Mi of embodiment M, the compound of embodiment M, or a pharmaceutically acceptable salt thereof, is one in which Ar is phenyl. In one subembodiment of subembodiment Mi, the compound of subembodiment Mi, or a pharmaceutically acceptable salt thereof, is one in which Q is attached to a carbon on the phenyl ring that is meta to the carbon attaching the phenyl ring to the remainder of the compound of formula (I). In another subembodiment of subembodiment Mi, the compound of subembodiment Mi, or a pharmaceutically acceptable salt thereof, is one in which Q is attached to a carbon on the phenyl ring that is para to the carbon attaching the phenyl ring to the remainder of the compound of formula (I) and (Ia)-(Ih), respectively.

[0129] (Mii). In a subembodiment Mii of embodiment M, the compound of embodiment M is one where Ar is heteroaryl. In one subembodiment of subembodiment Mii, the compound of subembodiment Mii, or a pharmaceutically acceptable salt thereof, is one where Ar is pyridinyl, pyrimidinyl, pyridazinyl, thienyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, oxadiazolyl, or imidazolyl. In another subembodiment of embodiment Mii, the compound of subembodiment Mii, or a pharmaceutically acceptable salt thereof, is one where Ar is a six-membered ring, such as pyridinyl, pyrimidinyl, or pyridazinyl, and Q is attached to a carbon on the pyridinyl, pyrimidinyl, or pyridazinyl ring that is meta to the carbon attaching the pyridinyl, pyrimidinyl, or pyridazinyl ring to the rest of the compounds of formulae (I) and (Ia) through (Ih), respectively.

[0130] According to subembodiment Mii, in yet another group of compounds, Ar is benzofuranyl, quinolinyl, quinazolinyl, benzimidazolyl, indazolyl, benzotriazolyl, or benzoxazolyl.

[0131] Embodiment N In embodiment N, the compound or pharmaceutically acceptable salt thereof of any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, K, and L, and subembodiments contained therein, is one in which Ar is heterocyclyl.

[0132] (Ni). In a subembodiment Ni of embodiment N, the compound of subembodiment Ni, or a pharmaceutically acceptable salt thereof, is a compound wherein Ar is pyrrolidinyl, piperidinyl, or homopiperidinyl, preferably wherein Ar is piperidin-4-yl, and Q is alkoxy. 1 is bonded to the nitrogen atom of the piperidinyl ring via

[0133] Embodiment O In embodiment O, the compound of any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, K, L, M, and N, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of alk and alk 1 are independently methylene, ethylene, or propylene. In a first subembodiment, alk and alk 1 is methylene, and preferably, when Ar is a 6-membered ring, alk and alk 1 is methylene. In a second subembodiment, alk is methylene and alk 1 does not exist (i.e., m is 0).

[0134] Embodiment P In embodiment P, the compound or pharmaceutically acceptable salt thereof of any one of embodiments A, B, D, D1, E, F, G, H, J, K, L, M, and O, and subembodiments contained therein, is R 7 is hydrogen, methyl, isopropyl, or fluoro. In a first subembodiment of embodiment P, the compound is 7 is hydrogen, methyl, or fluoro. In a second subembodiment of embodiment P, the compound is 7 is hydrogen. In a second subembodiment of embodiment P, the compound is 7is methyl or isopropyl.

[0135] Embodiment Q In embodiment Q, the compound or pharmaceutically acceptable salt thereof of any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, K, L, M, N, O, and P, and subembodiments contained therein, is R 2 and R 3 is independently hydrogen, methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, or cyano. In a first subembodiment of embodiment Q, the compound is 2 and R 3 is hydrogen.

[0136] Embodiment R In embodiment R, the compound or pharmaceutically acceptable salt thereof of any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, K, L, M, N, O, P, and Q, and subembodiments contained therein, is R 4 is hydrogen, alkyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl.

[0137] (Ri) In a subembodiment (Ri) of embodiment R, the compound is R 4 is hydrogen, methyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, cyano, or trifluoromethyloxy. In a first subembodiment of (Ri), the compound is 4 is hydrogen, methoxy or ethoxy. In a second subembodiment of (Ri), the compound is 4 is hydrogen.

[0138] (Rii) In subembodiment (Rii) of embodiment R, R 4is cyano, carboxy, alkoxycarbonyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl. Within (Rii), in one group of the compound, R 4 is cyano, carboxy, methoxycarbonyl, methylsulfonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl. Within (Rii), in another group of the compound, R 4 is cyano, carboxy, methoxycarbonyl, aminocarbonyl, methylsulfonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl. Within (Rii), in further groups of compounds, R 4 is aminocarbonyl, methylaminocarbonyl, or dimethylaminocarbonyl. Within R(ii) and the groups they contain, in another group of the compound, R 4 is a six-membered ring comprising a, b, d, and e of formula (I) as shown below: [ka] (wherein the wavy line indicates the point of attachment to the remainder of the molecule. For clarity, the 6-membered ring comprising a, b, d, and e of Formula (I) is shown as an example. In embodiments encompassing one or more of the compounds of Formulas (Ia)-(Ih), R 4 It will be apparent to one skilled in the art that will be attached to the same carbon of the six-membered ring comprising a, b, d, and e as shown above).

[0139] (Riii) In a subembodiment (Riii) of embodiment R, the compound is R 4 is alkylsulfonyl, preferably methylsulfonyl, and R 4 is a six-membered ring comprising a, b, d, and e of formula I as shown below [ka] where the wavy line indicates the point of attachment to the rest of the molecule.

[0140] Embodiment S (Si) In embodiment Si, the compound or pharmaceutically acceptable salt thereof of any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, K, L, M, N, O, P, Q, and R, and subembodiments (or groups) contained therein, is R 5 and R 6 is independently hydrogen, alkyl, alkoxy, hydroxy, amino, halo, haloalkyl, or haloalkoxy. In a first subembodiment of embodiment (Si), the compound is 5 and R 6 is independently hydrogen, alkoxy, amino, or hydroxy. In a second subembodiment of embodiment (Si), the compound is 5 and R 6 is independently alkoxy, such as methoxy, ethoxy, or propoxy, and a six-membered ring comprising a, b, d, and e of formula I shown below: [ka] where the wavy line indicates the point of attachment to the rest of the molecule. In a third subembodiment of embodiment (Si), the compound is one that is bonded to R 5 and R 6 are independently hydrogen. In a fourth subembodiment of Formula (Si), the compound is 5 is a six-membered ring comprising a, b, d, and e of formula I as shown below [ka] wherein the wavy line indicates the point of attachment to the rest of the molecule. Within a fourth subembodiment, in one group of compounds, R 5 is hydroxy and R 4 and R 6 is hydrogen.

[0141] (Mii) In embodiment Mii, the compound of any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, K, L, M, N, O, P, Q, and R, and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, is R 5 is hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, or haloalkoxy; and R 6 is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein either heterocyclyl alone or the heterocyclyloxy and heterocyclylamino moieties are optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein and heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino, wherein the heterocyclyl ring is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl, cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl in phenyloxy and the heteroaryl in heteroaryloxy are optionally substituted with 1, 2, or 3 substituents, two of the optional substituents being independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano).

[0142] In a first subembodiment of embodiment Mii, R 5 is hydrogen, methoxy, ethoxy, or hydroxy, preferably R 5 is methoxy or ethoxy; and R 6are 2-hydroxyethyloxy, 3-hydroxypropyloxy, 2-methoxyethyloxy, 2-ethoxyethyloxy, 3-methoxypropyloxy, 3-ethoxypropyloxy, 2-aminoethyloxy, 2-methylaminoethyloxy, 2-dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3-aminopropyloxy, 3-methylaminopropyloxy, 3-dimethylaminopropyloxy, 3-diethylaminopropyloxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethyloxy, piperidinylmethyloxy, pyrrolidinylethyloxy, piperidinylethyloxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethyl propylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 2-aminoethylamino, 2-methylaminoethylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-aminopropylamino, 3-methylaminopropylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, pyrrolidinylamino, piperidinylamino, pyrrolidinylmethylamino, piperidinylmethylamino, pyrrolidinylethylamino, or piperidinylethylamino (wherein the pyrrolidinyl and piperidinyl in each of the aforementioned groups, alone or as part of another group, are optionally substituted with one or two substituents independently selected from methyl, fluoro, hydroxy, or methoxy). Preferably, R 5 and R 6 is a six-membered ring comprising a, b, d, and e of formula I as shown below: [ka] where the wavy line indicates the point of attachment to the rest of the molecule.

[0143] (Miii) In embodiment Mi, the compound or pharmaceutically acceptable salt thereof of any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, K, L, M, N, O, P, Q, and R, and subembodiments contained therein, is R 5 and R6 are independently hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein either heterocyclyl alone or the heterocyclyloxy and heterocyclylamino moieties are optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein The heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl of phenyloxy and the heteroaryl of heteroaryloxy are optionally substituted with 1, 2, or 3 substituents, two of the optional substituents being independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano).

[0144] In a first subembodiment of embodiment Miii, R 5 and R 6are independently 2-hydroxyethyloxy, 3-hydroxypropyloxy, 2-methoxyethyloxy, 2-ethoxyethyloxy, 3-methoxypropyloxy, 3-ethoxypropyloxy, 2-aminoethyloxy, 2-methylaminoethyloxy, 2-dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3-aminopropyloxy, 3-methylaminopropyloxy, 3-dimethylaminopropyloxy, 3-diethylaminopropyloxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethyloxy, piperidinylmethyloxy, pyrrolidinylethyloxy, piperidinylethyloxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxy ethylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 2-aminoethylamino, 2-methylaminoethylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-aminopropylamino, 3-methylaminopropylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, pyrrolidinylamino, piperidinylamino, pyrrolidinylmethylamino, piperidinylmethylamino, pyrrolidinylethylamino, or piperidinylethylamino (wherein the pyrrolidinyl and piperidinyl in each of the aforementioned groups, alone or as part of another group, are optionally substituted with one or two substituents independently selected from methyl, fluoro, hydroxy, or methoxy). Preferably, R 5 and R 6 is a six-membered ring comprising a, b, d, and e of formula I as shown below: [ka] where the wavy line indicates the point of attachment to the rest of the molecule.

[0145] Additional embodiments of the present disclosure include embodiments 1-58 below.

[0146] 1. In embodiment 1, a compound of formula (I): [ka] (In the formula, a, b, d, and e are CH; or one or two of a, b, d, and e are N, and the remaining a, b, d, and e are CH; One of y and z is N, and the other y and z is CR 7 or both y and z are CR 7 and each R 7 are independently hydrogen, alkyl, hydroxy, or halo; alk is alkylene optionally substituted with 1, 2, or 3 halo; alk 1 is alkylene, wherein one carbon atom in the alkylene chain may be replaced by oxygen, and the alkylene chain is optionally substituted with 1, 2 or 3 halo; m and n are independently 0 or 1; provided that at least one of m and n is 1; Ar is aryl or heteroaryl; Q is -B(R w )(R x ) and R w and R x are independently selected from hydroxy, alkoxy, -Oaryl (aryl optionally substituted with 1 to 3 substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCOR c (R c is alkyl), -O-(alk 2 ) OR d (alk 2 is alkylene, and R d is alkyl; or R w and R x can be combined with the boron atom to which they are attached to form -O(CRR')2O- or -O(CRR')3O-, where each R and R' is independently hydrogen or methyl; R 2 and R 3are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano; R 4 is hydrogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl; and R 5 and R 6 R is independently hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, amino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, where either heterocyclyl alone or portions of heterocyclyloxy and heterocyclylamino are optionally independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl. h , R j , or R k substituted with), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl in phenyloxy and the heteroaryl in heteroaryloxy are optionally substituted with 1, 2, or 3 substituents, two of the optional substituents being independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano); or Pharmaceutically acceptable salts thereof are provided; Formula (I) is the structure [ka] and: (i) When Q is -B(OH)2, [ka] 4-((6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)methyl)phenyl; 4-((5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 4-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 5-fluoro-2-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 3-fluoro-4-((2-methyl-1H-benzimidazol-1-yl) methyl)phenyl;3-((5,6-dimethyl-1H-benzimidazol-1-yl)methyl)phenyl;4-((5,6-dimethyl-1H-benzimidazol-1-yl)methyl)phenyl;2-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl;2-((5,6-dimethyl-1H-benzimidazol-1-yl)methyl)phenyl;2-fluoro-5-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 3-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl;3-(1H-benzimidazol-1-ylmethyl)phenyl;3-(1H-indazol-1-ylmethyl)phenyl;2-(1H-benzimidazol-1-ylmethyl)phenyl;4-(1H-benzimidazol-1-ylmethyl)phenyl;4-(1H-indol-1-ylmethyl)phenyl;4-((6-a 3-((6-amino-9H-purin-9-yl)methyl)phenyl; 2-((6-amino-9H-purin-9-yl)methyl)phenyl; 4-(1H-benzimidazol-1-ylmethyl)-3-fluorophenyl; 4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-fluorophenyl; 5 -(1H-Benzimidazol-1-ylmethyl)-2-fluorophenyl;4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-fluorophenyl;2-(1H-benzimidazol-1-ylmethyl)-5-fluorophenyl;5-(1H-benzimidazol-1-ylmethyl)-2-methoxyphenyl;3-(1H-benzimidazol- 1-ylmethyl)-4-methoxyphenyl; but not 2-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-pyrimidinyl, 6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-pyridinyl, or 4-(2-ethoxy-7-carboxy-1H-benzimidazol-1-ylmethyl)phenyl; (ii) Q is [ka] When [ka] are 2-(1H-benzo[d]imidazol-1-ylmethyl)phenyl, 2-(1H-indol-1-ylmethyl)phenyl, 3-(1H-indazol-1-ylmethyl)phenyl, 4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methylphenyl, 4-(2-methyl-1H-benzimidazol-1-ylmethyl)phenyl; 4-(6-amino-8-methoxy-2-(tetrahydro-2H-pyran-4-yl)methoxy-9H-purin-9-ylmethyl)phenyl, 3-fluoro-4-(6-amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-9-ylmethyl)phenyl, 4-(6-amino-8-methoxy- is not 2-(2-methoxyethoxy)-9H-purin-9-ylmethyl)phenyl, 4-(6-amino-2-butoxy-8-methoxy-9H-purin-9-ylmethyl)phenyl, 4-(1H-indol-1-ylmethyl)phenyl, 4-(1H-benimidazol-1-ylmethyl)phenyl, 3-(7-methoxycarbonyl-1H-indol-1-ylmethyl)phenyl, 4-(7-methoxycarbonyl-1H-indol-1-ylmethyl)phenyl, 4-(2-ethoxy-7-methoxycarbonyl-1H-benzimidazol-1-ylmethyl)phenyl, or 4-(2-ethoxy-7-ethoxycarbonyl-1H-benzimidazol-1-ylmethyl)phenyl; and (iii) Q is [ka] When [ka] is not 4-(2-ethoxy-7-ethoxycarbonyl-1H-benzimidazol-1-ylmethyl)phenyl.

[0147] 2. In embodiment 2, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ia) or (Ib): [ka] It has.

[0148] 3. In embodiment 3, the compound of embodiment 2, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ia):

[0149] 4. In embodiment 4, the compound of embodiment 2, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ib):

[0150] 5. In embodiment 5, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ic) or (Id): [ka] It has.

[0151] 6. In embodiment 6, the compound of embodiment 5, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ic):

[0152] 7. In embodiment 7, the compound of embodiment 5, or a pharmaceutically acceptable salt thereof, has the structure of formula (Id):

[0153] 8. In embodiment 8, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ie) or (If): [ka] It has.

[0154] 9. In embodiment 9, the compound of embodiment 8, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ie):

[0155] 10. In embodiment 18, the compound of embodiment 8, or a pharmaceutically acceptable salt thereof, has the structure of formula (If):

[0156] 11. In embodiment 11, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ig) or (Ih): [ka] (In the formula, R 7 is alkyl, halo, or hydroxy).

[0157] 12. In embodiment 12, the compound of embodiment 11, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ig):

[0158] 13. In embodiment 13, the compound of embodiment 11, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ih):

[0159] 14. In embodiment 14, the compound of embodiment 12 or 13, or a pharmaceutically acceptable salt thereof, is R 7 is alkyl.

[0160] 15. In embodiment 15, the compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, is one wherein a, b, d, and e are CH.

[0161] 16. In embodiment 16, the compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, is one wherein a is N and b, d, and e are CH.

[0162] 17. In embodiment 17, the compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, is one wherein a and d are N, and b and e are CH.

[0163] 18. In embodiment 18, the compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, is one wherein b is N and a, c, and e are CH.

[0164] 19. In embodiment 19, the compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, is one wherein b and e are N, and a and d are CH.

[0165] 20. In embodiment 20, the compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, is one wherein d is N, and a, b, and e are CH.

[0166] 21. In embodiment 21, the compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, is one of d and e is N, and the rest of a, b, d, and e are CH.

[0167] 21a. In embodiment 21a, the compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, is one wherein a and e are N, and b and d are CH.

[0168] 21b. In embodiment 21b, the compound of embodiment 21, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ii): [ka] It has.

[0169] 21c. In embodiment 21c, the compound of embodiment 21, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ij): [ka] (In the formula, R 7 is alkyl, halo, or hydroxy).

[0170] 21d. In embodiment 21d, the compounds of embodiments 21b and 21c, or pharmaceutically acceptable salts thereof, are 7 is alkyl.

[0171] 21e. In embodiment 21d, the compounds of embodiments 21b and 21c, or pharmaceutically acceptable salts thereof, are 7 is methyl or isopropyl.

[0172] 22. In embodiment 22, the compound of any one of embodiments 1-21e, or a pharmaceutically acceptable salt thereof, is one wherein Q is -B(OH)2.

[0173] 23. In embodiment 23, the compound of any one of embodiments 1-21e, or a pharmaceutically acceptable salt thereof, is any one of embodiments 1-21e, wherein Q is -B(R w )(R x ) and R w and R x is independently selected from hydroxy and alkoxy.

[0174] 24. In embodiment 24, the compound of any one of embodiments 1-21e, or a pharmaceutically acceptable salt thereof, is any one of embodiments 1-21e, wherein Q is -B(R w )(R x ) and R w and R x together with the boron atom to which they are attached to form a ring of formula (b) or (c): [ka] It forms the

[0175] 25. In embodiment 25, the compound of any one of embodiments 1-24, or a pharmaceutically acceptable salt thereof, is wherein Ar is phenyl.

[0176] 26. In embodiment 26, the compound of embodiment 25, or a pharmaceutically acceptable salt thereof, is one in which Q is attached to a carbon on the phenyl ring that is para to the carbon attaching the phenyl ring to the remainder of the compound of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (If), and (Ig).

[0177] 27. In embodiment 27, the compound of any one of embodiments 1-24, or a pharmaceutically acceptable salt thereof, is one wherein Ar is heteroaryl.

[0178] 28. In embodiment 28, the compound of embodiment 27, or a pharmaceutically acceptable salt thereof, is such that Ar is pyridinyl, pyrimidinyl, pyridazinyl, thienyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, oxadiazolyl, or imidazolyl.

[0179] 29. In embodiment 29, the compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of alk and alk 1 are independently methylene, ethylene, or propylene.

[0180] 30. In embodiment 30, the compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of alk and alk 1 is methylene.

[0181] 31. In embodiment 31, the compound of any one of embodiments 1-4, 8-20, 21a, and 22-30, or a pharmaceutically acceptable salt thereof, is R 7 is hydrogen, methyl, isopropyl, or fluoro.

[0182] 32. In embodiment 32, the compound of any one of embodiments 1-4, 8-20, 21a, and 22-30, or a pharmaceutically acceptable salt thereof, is R 7 is hydrogen, methyl, or fluoro.

[0183] 33. In embodiment 33, the compound of any one of embodiments 1 to 32, or a pharmaceutically acceptable salt thereof, is R 2 and R 3 are independently hydrogen, methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, or cyano.

[0184] 34. In embodiment 34, the compound of any one of embodiments 1 to 32, or a pharmaceutically acceptable salt thereof, is R 2 and R 3is hydrogen.

[0185] 35. In embodiment 35, the compound of any one of embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, is R 4 is hydrogen, alkyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl.

[0186] 36. In embodiment 36, the compound of embodiment 35, or a pharmaceutically acceptable salt thereof, is R 4 is hydrogen, methyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, cyano, or trifluoromethyloxy.

[0187] 37. In embodiment 27, the compound of any one of embodiments 1 to 35, or a pharmaceutically acceptable salt thereof, is R 4 is cyano, carboxy, alkoxycarbonyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl.

[0188] 38. In embodiment 38, the compound of embodiment 37, or a pharmaceutically acceptable salt thereof, is R 4 is cyano, carboxy, methoxycarbonyl, aminocarbonyl, methylsulfonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl.

[0189] 39. In embodiment 39, the compound of embodiment 37, or a pharmaceutically acceptable salt thereof, is R 4 is a six-membered ring comprising a, b, d, and e of formula I as shown below [ka] where the wavy line indicates the point of attachment to the rest of the molecule.

[0190] 40. In embodiment 40, the compound of any one of embodiments 1 to 39, or a pharmaceutically acceptable salt thereof, is R 5 and R 6 is hydrogen.

[0191] 41. In embodiment 41, the compound of any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, is R 5 and R 6 are independently hydrogen, alkyl, alkoxy, hydroxy, amino, halo, haloalkyl, or haloalkoxy.

[0192] 42. In embodiment 42, the compound of embodiment 41, or a pharmaceutically acceptable salt thereof, is R 5 is a six-membered ring comprising a, b, d, and e of formula I as shown below [ka] where the wavy line indicates the point of attachment to the rest of the molecule.

[0193] 43. In embodiment 43, the compound of embodiment 42, or a pharmaceutically acceptable salt thereof, is R 5 is hydroxy and R 4 and R 6 is hydrogen.

[0194] 44. In embodiment 44, the compound of embodiment 41, or a pharmaceutically acceptable salt thereof, is R 5 and R 6 is a six-membered ring comprising a, b, d, and e of formula I as shown below [ka] where the wavy line indicates the point of attachment to the rest of the molecule.

[0195] 45. In embodiment 45, the compound of any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, is R 5 is hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, or haloalkoxy; and R 6 is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein either heterocyclyl alone or the heterocyclyloxy and heterocyclylamino moieties are optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein and heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino, wherein the heterocyclyl ring is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl, cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl in phenyloxy and the heteroaryl in heteroaryloxy are optionally substituted with 1, 2, or 3 substituents, two of the optional substituents being independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano).

[0196] 46. ​​In embodiment 46, the compound of embodiment 45, or a pharmaceutically acceptable salt thereof, is R 5 is hydrogen, methoxy, ethoxy, or hydroxy, and R 6However, 2-hydroxyethyloxy, 3-hydroxypropyloxy, 2-methoxyethyloxy, 2-ethoxyethyloxy, 3-methoxypropyloxy, 3-ethoxypropyloxy, 2-aminoethyloxy, 2-methylaminoethyloxy, 2-dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3-aminopropyloxy, 3-methylaminopropyloxy, 3-dimethylaminopropyloxy, 3-diethylaminopropyloxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethyloxy, piperidinylmethyloxy, pyrrolidinylethyloxy, piperidinylethyloxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino and 3-methoxypropylamino, 3-ethoxypropylamino, 2-aminoethylamino, 2-methylaminoethylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-aminopropylamino, 3-methylaminopropylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, pyrrolidinylamino, piperidinylamino, pyrrolidinylmethylamino, piperidinylmethylamino, pyrrolidinylethylamino, or piperidinylethylamino (wherein the pyrrolidinyl and piperidinyl in each of the aforementioned groups, alone or as part of another group, are optionally substituted with 1 or 2 substituents independently selected from methyl, fluoro, hydroxy, or methoxy).

[0197] 47. In embodiment 47, the compound of embodiment 45 or 46, or a pharmaceutically acceptable salt thereof, is R 5 and R 6 is a six-membered ring comprising a, b, d, and e of formula I as shown below [ka] where the wavy line indicates the point of attachment to the rest of the molecule.

[0198] 48. In embodiment 48, the compound of any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, is R 5 and R 6 are independently hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein either heterocyclyl alone or the heterocyclyloxy and heterocyclylamino moieties are optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein The heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl of phenyloxy and the heteroaryl of heteroaryloxy are optionally substituted with 1, 2, or 3 substituents, two of the optional substituents being independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano).

[0199] 49. In embodiment 49, the compound of embodiment 48, or a pharmaceutically acceptable salt thereof, is R 5 and R 6are independently 2-hydroxyethyloxy, 3-hydroxypropyloxy, 2-methoxyethyloxy, 2-ethoxyethyloxy, 3-methoxypropyloxy, 3-ethoxypropyloxy, 2-aminoethyloxy, 2-methylaminoethyloxy, 2-dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3-aminopropyloxy, 3-methylaminopropyloxy, 3-dimethylaminopropyloxy, 3-diethylaminopropyloxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethyloxy, piperidinylmethyloxy, pyrrolidinylethyloxy, piperidinylethyloxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethyl and 2-aminoethylamino, 2-methylaminoethylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-aminopropylamino, 3-methylaminopropylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, pyrrolidinylamino, piperidinylamino, pyrrolidinylmethylamino, piperidinylmethylamino, pyrrolidinylethylamino, or piperidinylethylamino (wherein the pyrrolidinyl and piperidinyl in each of the aforementioned groups, alone or as part of another group, are optionally substituted with 1 or 2 substituents independently selected from methyl, fluoro, hydroxy, or methoxy).

[0200] 50. In embodiment 50, the compound of embodiment 48 or 49, or a pharmaceutically acceptable salt thereof, is R 5 and R 6 is a six-membered ring comprising a, b, d, and e of formula I as shown below [ka] where the wavy line indicates the point of attachment to the rest of the molecule.

[0201] 51. In embodiment 51, there is provided a pharmaceutical composition comprising a compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0202] 52. In embodiment 52, there is provided a method of treating a disease or condition mediated by ENPP1 in a patient, the method comprising administering to the patient a compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof.

[0203] 53. In embodiment 53, the method of embodiment 52 is one in which the disease or condition is cancer, an inflammatory disease, a metabolic disease, or a viral disease.

[0204] 54. In embodiment 54, the method of embodiment 52 is one in which the disease or condition is cancer.

[0205] 55. In embodiment 55, the method of embodiment 52 is one wherein the disease or condition is cancer, and the cancer is hepatocellular carcinoma, glioblastoma, melanoma, testicular, pancreatic, thyroid, or breast cancer.

[0206] 56. In embodiment 56, the method of claim 54 or 55 is wherein the compound of any one of claims 1-50 is administered in conjunction with an anti-cancer agent.

[0207] General synthetic scheme The compounds of the present disclosure can be made by the methods shown in the reaction schemes shown below.

[0208] The starting materials and reagents used in preparing these compounds are available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.), or are prepared by methods known to those skilled in the art according to procedures described in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some of the ways in which the compounds of the present disclosure may be synthesized, and various modifications to these schemes may be made and will be suggested to those of skill in the art upon reading this disclosure. The starting materials and intermediates, as well as the final products of the reactions, may be isolated and purified, if necessary, using conventional techniques, including, but not limited to, filtration, dialysis, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0209] Unless otherwise specified, reactions described herein are carried out at atmospheric pressure, at a temperature range of about −78° C. to about 150° C., such as about 0° C. to about 125° C., or even at about room (or ambient) temperature, such as about 20° C.

[0210] Compounds of formula (I), where Ar is aryl or heteroaryl, n is 1, m is 0, and other groups are as defined in the Summary, can be prepared as shown and described in Scheme 1 below. [ka]

[0211] a, b, d, e, y, and z are as defined in the Summary, and R 4 , R 5 , and R 6Arylation of a compound of Formula 1, where R is as defined in the Summary, or a precursor group thereof (e.g., hydroxy is a precursor group such as alkoxy), and a boronic acid of Formula 2, where Ar is aryl or heteroaryl, under Suzuki reaction conditions (Suzuki, A Journal of Organometallic Chemistry. 576:147-168, and references cited therein) provides an alcohol compound of Formula 3. The reaction is carried out under palladium or nickel catalysis using a base such as lithium carbonate, sodium carbonate, potassium carbonate, or cesium carbonate; lithium tert-butoxide, sodium tert-butoxide, or potassium tert-butoxide; lithium hydroxide, sodium hydroxide, or potassium hydroxide; a phosphate base such as tripotassium phosphate; or any other organic or inorganic base, in a solvent composed of a mixture of water and organic solvents such as 1,4-dioxane, tetrahydrofuran (THF), diethyl ether, toluene, ethanol, or methanol, dimethylformamide (DMF), either at room temperature or with heating. Compounds of formula 1, such as 5,6-dimethoxy-1H-benzo[d]imidazole, 6-methoxy-1H-benzo[d]imidazole, 6-chloro-9H-purin-2-amine, 6-chloro-9H-purine, 5-methoxy-1H-indole, 5,6-dimethoxy-1H-indole, 9H-purin-6-amine, 1H-benzo[d]imidazole-5-carbonitrile, methyl 1H-benzo[d]imidazole-5-carboxylate, 1H-benzo[d]imidazole-5-carboxamide, 1H-benzo[d]imidazole-5-carboxylic acid, 1H-pyrrolo[3,2-c]pyridin-4-ol, and 1H-imidazo[4,5-c]pyridine, are commercially available.

[0212] Conversion of the hydroxyl in the compound of formula 3 to a leaving group in the compound of formula 4, which is a halide, can be achieved by the Appel reaction (Appel, R. Angewandte Chemie International Edition in English. 14:801-811) by treating compound 3 with a halogenating agent such as N-bromosuccinimide, carbon tetrachloride, carbon tetrabromide, bromine, methyl iodide, or iodine in the presence of triphenylphosphine. The halo group in the compound of formula 4 can be displaced with various boronate or phosphinate nucleophiles to provide compounds of formula (I). For example, treatment of compound 4 with triethyl phosphite via heating in the absence or presence of an aprotic organic solvent such as DMF or THF, followed by hydrolysis of the resulting triethyl phosphonate, provides compounds of formula (I) where Q is -P(O)(OH). Triethyl phosphonate can be hydrolyzed in the presence of bromo- or chloro-trimethylsilane in dichloromethane, or hydrogen chloride in water, or trimethylsilyl iodide in dichloromethane, either at room temperature or with heat. Compounds of formula (I) where Q is -B(OH) can be prepared by treatment of compound 4 with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane, followed by hydrolysis of the resulting 4-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl group by methods well known in the art. Compounds of formula (I) can be converted to other compounds of formula (I) by methods well known in the art. For example, diethyl (4-((5-cyano-1H-benzo[d]imidazol-1-yl)methyl)phenyl)phosphonate is converted to (4-((5-cyano-1H-benzo[d]imidazol-1-yl)methyl)phenyl)phosphonic acid by treatment with bromotrimethylsilane in dichloromethane at room temperature.

[0213] Compounds of formula (I), where Ar is aryl or heteroaryl, n is 1, m is 0, and other groups are as defined in the Summary, can be prepared as shown and described in Scheme 2 below. [ka]

[0214] In the presence of a carbonate, hydroxide, or alkoxide (e.g., tert-butoxide) base, either with heating or at room temperature, Ar, alk are as defined in the overview, and R 2 and R 3 Treatment of a compound of formula 1 with a compound of formula 5 or 5', where L is as defined in the Summary or is a precursor group thereof, and LG is a suitable leaving group such as halo, results in a compound of formula 6 or 7, respectively. Compounds of formula 6 can be converted to compound 7, where LG is halo, by methods well known in the art. Compounds of formula 5 are commercially available or can be prepared by methods well known in the art. Compounds of formula 7 can then be converted to compounds of formula (I) as described in Scheme 1 above.

[0215] Alternatively, compounds of formula (I) where Q is a boronic acid can be prepared by displacement of the leaving group in a compound of formula 8 with a compound of formula 1. The reaction is carried out by treating a mixture of compounds of formula 1 and 8 with a carbonate, hydroxide, or alkoxide (e.g., tert-butoxide) base, or other organic or inorganic base, in a solvent such as acetonitrile, DMF, or THF at room temperature or with heating. Compounds of formula 8 are either commercially available or can be readily prepared by methods well known in the art. Compounds of formula 1 such as 5,6-dimethoxy-1H-benzo[d]imidazole, 6-methoxy-1H-benzo[d]imidazole, 6-chloro-9H-purin-2-amine, 6-chloro-9H-purine, 5-methoxy-1H-indole, 5,6-dimethoxy-1H-indole, 9H-purin-6-amine, 1H-benzo[d]imidazole-5-carbonitrile, methyl 1H-benzo[d]imidazole-5-carboxylate, 1H-benzo[d]imidazole-5-carboxamide, 1H-benzo[d]imidazole-5-carboxylic acid, 1H-pyrrolo[3,2-c]pyridin-4-ol, 1H-imidazo[4,5-c]pyridine, and 5-methanesulfonyl-1H-1,3-benzodiazole are commercially available. Compounds of formula 8, such as (4-(bromomethyl)phenyl)boronic acid, are commercially available. Compounds of formula 5, such as 1-bromo-4-(bromomethyl)benzene and 5-bromo-2-(bromomethyl)pyridine, are commercially available.

[0216] test The ENPP1 inhibitory activity of compounds of the present disclosure can be tested using the in vitro assays described in Biological Examples 1 and 2 below.

[0217] Administration and Pharmaceutical Compositions In general, compounds of the present disclosure will be administered in therapeutically effective amounts by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds of the present disclosure can range from about 0.01 to about 500 mg per kg of patient body weight per day, which can be administered in single or multiple doses. Suitable dosage levels can be about 0.1 to about 250 mg / kg per day; about 0.5 to about 100 mg / kg per day. Suitable dosage levels can be about 0.01 to about 250 mg / kg per day, about 0.05 to about 100 mg / kg per day, or about 0.1 to about 50 mg / kg per day. Within this range, dosages can be about 0.05 to about 0.5, about 0.5 to about 5, or about 5 to about 50 mg / kg per day. For oral administration, the composition may be provided in the form of a tablet containing about 1.0 to about 1000 milligrams of active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of active ingredient. The actual amount of a compound of the present disclosure, i.e., the active ingredient, will depend on numerous factors, such as the severity of the condition being treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.

[0218] Generally, the compounds of the present disclosure will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal, or suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred mode of administration is oral, using a conventional daily dosing regimen, which can be adjusted according to the severity of the affliction. The composition can take the form of a tablet, pill, capsule, semisolid, powder, sustained-release formulation, solution, suspension, elixir, aerosol, or any other appropriate composition.

[0219] The choice of formulation depends on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules, including enteric-coated or delayed-release tablets, pills, or capsules, are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed specifically for drugs exhibiting low bioavailability, based on the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing the particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles ranging in size from 10 to 1,000 nm in which the active ingredient is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which a drug substance is milled to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier, followed by dispersion in a liquid medium, resulting in a pharmaceutical formulation exhibiting significantly higher bioavailability.

[0220] The composition generally comprises a compound of the present disclosure combined with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, facilitate administration, and do not adversely affect the therapeutic effect of the compound of the present disclosure. Such excipients can be any solid, liquid, semi-solid, or, in the case of aerosol compositions, gaseous excipients generally available to those skilled in the art.

[0221] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, etc. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0222] Compressed gases can be used to disperse the compounds of the present disclosure in aerosol form. Suitable inert gases for this purpose include nitrogen, carbon dioxide, and the like.

[0223] Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by EW Martin (Mack Publishing Company, 20th ed., 2000).

[0224] The level of the compound in the formulation may vary within the full range utilized by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt.%) basis, about 0.01 to 99.99 wt.% of the compound of the present disclosure based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. For example, the compound may be present at a level of about 1 to 80 wt.%.

[0225] The compounds of the present disclosure can be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present disclosure or other drugs may be useful. Such other drugs may be administered by a route and in an amount commonly used, and thus may be administered simultaneously or sequentially with the compounds of the present disclosure. When the compounds of the present disclosure are used simultaneously with one or more other drugs, a pharmaceutical composition in a unit dosage form containing such other drugs and the compounds of the present disclosure is preferred. However, combination therapy can also include therapy in which the compounds of the present disclosure and one or more other drugs are administered on different overlapping schedules. It is also believed that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used alone. Thus, the pharmaceutical compositions of the present disclosure also include those containing one or more other drugs in addition to the compounds of the present disclosure.

[0226] The above combinations include not only combinations of the compounds of the present disclosure with one other drug, but also combinations with two or more other active drugs.Similarly, the compounds of the present disclosure can be used in combination with other drugs used in the prevention, treatment, control, amelioration, or reduction of risk of diseases or conditions for which the compounds of the present disclosure are useful.Such other drugs can be administered by commonly used routes and amounts, and thus can be administered simultaneously or sequentially with the compounds of the present disclosure.When the compounds of the present disclosure are used simultaneously with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the compounds of the present disclosure can be used.Thus, the pharmaceutical compositions of the present disclosure also include those that can contain one or more other active ingredients in addition to the compounds of the present disclosure.The weight ratio of the compounds of the present disclosure to the second active ingredient can vary and will depend on the effective dose of each ingredient.In general, an effective dose of each will be used.

[0227] If a subject in need thereof is suffering from or at risk of suffering from cancer, the subject may be treated with the compounds of the present disclosure in any combination with one or more other anti-cancer agents. In some embodiments, one or more of the anti-cancer agents is a pro-apoptotic agent. Examples of anti-cancer agents include gossypol, genasense, polyphenol E, chlorofusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec™), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY Examples of compounds that may be used in combination with the compounds described herein include, but are not limited to, 11-7082, PKC412, or PD184352, Taxol™, also known as "paclitaxel," a well-known anticancer drug that acts by promoting and stabilizing microtubule formation, and any of its analogs, such as Taxotere™. Compounds that share the basic taxane skeleton as a common structural feature have also been shown to have the ability to arrest cells in the G2-M phase by stabilizing microtubules and may be useful in treating cancer in combination with the compounds described herein.

[0228] Further examples of anti-cancer agents for use in combination with the compounds of the present disclosure include inhibitors of mitogen-activated protein kinase signaling, such as U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; antibodies (e.g., Rituxan); MET inhibitors such as foretinib, carbozantinib, or crizotinib; VEGFR inhibitors such as sunitinib, sorafenib, regorafinib, lenvatinib, vandetanib, carbozantinib, and axitinib; EGFR inhibitors such as afatinib, brivanib, carbozantinib, erlotinib, gefitinib, neratinib, and lapatinib; PI3K inhibitors such as XL147, XL765, BKM120 (buparisib), GDC-0941, BYL719, IPI145, and BAY80-6946. MTOR inhibitors such as BEX235 (dactolisib), CAL101 (idelalisib), GSK2636771, TG100-115; rapamycin (sirolimus), temsirolimus, everolimus, XL388, XL765, AZD2013, PF04691502, PKI-587, BEZ235, GDC0349; MEK inhibitors such as AZD6244, trametinib, PD184352, pimasetinib, GDC-0973, AZD8330; and proteasome inhibitors such as carfilzomib, MLN9708, delanzomib, or bortezomib.

[0229] Other anti-cancer agents that may be utilized in combination with the compounds of the present disclosure include adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, activin; aclarubicin; acodazole hydrochloride; acronine; adzelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; mesylate Visnafide; Biceresin; Bleomycin sulfate; Brequinar sodium; Bropirimine; Busulfan; Cactinomycin; Calsterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cilolemycin; Cladribine; Crisnatol mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin hydrochloride; Decitabine; Dexorumaplatin; Dezaguanine; Dezaguanine mesylate; Diazicon; Doxorubicin; Doxorubicin hydrochloride; Droloquinoline Cifen;Droloxifene citrate;Dromostanolone propionate;Zuazomycin;Edatrexate;Eflornithine hydrochloride;Elsamitrucin;Enloplatin;Enpromate;Epipropizine;Epirubicin hydrochloride;Elbrozole;Esorubicin hydrochloride;Estramustine;Estramustine phosphate sodium;Etanidazole;Etoposide;Etoposide phosphate;Etoprine;Fadrozole hydrochloride;Fazarabine;Fenretinide;Floxuridine;Fludarabine phosphate;Fluorouracil;Furocitabine;Fosquidone; Fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or Ril2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride;Lometrexol sodium; Lomustine; Losoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocalcin; Mitochromin; Mitogillin; Mitomarcin; Mitomycin; Mitospel; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Noco Dazol; Nogalamycin; Ormaplatin; Oxisuran; Pegaspargase; Periomycin; Pentamustine; Peplomycin sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone hydrochloride; Plicamycin; Promestane; Porfimer sodium; Porfiromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pirazofurin; Ribopurin; Rogletimide; Safingol; Safingol Hydrochloride; Semustine; Simtrazene; Sparfosate disodium; Sparsomycin; Spirogermanium hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Surofenur; Tallysomycin; Tecogalan sodium; Tegafur; Teloxantrone hydrochloride; Temoporfin; Teniposide; Teloxylon; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Toremifene citrate; Trestro acetate Examples of antihistamines include: triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tuburozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrocidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

[0230] Compounds of the present disclosure, such as 8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one, used to determine antitumor activity in HGS and RT4 tumor models (Example 4 below: in the HGS model, the vehicle-treated group reached a tumor size of 645 mm 42 days after inoculation, while for animals treated with 20 / kg compound, tumor size was 55 mm 3 , indicating significant antitumor activity and induction of tumor regression). Other anti-cancer agents that may be utilized in combination with the compounds include 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecipenol; adzelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic inhibitors. Growth protein-1; antiandrogens, prostate cancer; antiestrogens; antineoplastons; antisense oligonucleotides; aphidicolin glycinate; apoptotic gene regulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulaculin; atamestane; atlimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxins; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzoquinone Lorin; Benzoylstaurosporine; Beta-lactam derivatives; Beta-arretin; Betaclamycin B; Betulinic acid; Bfgf inhibitors; Bicalutamide; Bisantrene; Bisaziridinylspermine; Bisnafide; Bistraten A; Biceresin; Brefrate; Bropirimine; Budotitane; Buthionine sulfoximine; Calcipotriol; Calphostin C; Camptothecin derivatives; Canarypox IL-2; Capecitabine; Carboxamido-amino-triazole; Carboxamidotriazole; CaRest M3; CARN 700; Cartilage-derived inhibitors; Carzelesin;Casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorin; chloroquinoxaline sulfonamides; cicaprost; cis-porphyrins; cladribine; clomiphene analogs; clotrimazole; colismycin A; colismycin B; combretastatin A4; combretastatin analogs; conagenin; clambecidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanethraquinone; cycloplatam; sipemycin; cytarabine ocfosfate; cells Lytic factors; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexphosphamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine e); Elemene; Emitefur; Epirubicin; Epristeride; Estramustine analogues; Estrogen agonists; Estrogen antagonists; Etanidazole; Etoposide phosphate; Exemestane; Fadrozole; Fazarabine; Fenretinide; Filgrastim; Finasteride; Flavopiridol; Flezelastine; Fluasterone; Fludarabine; Fluorodornithin hydrochloride; Forfenimex; Formestane; Fostriecin; Fotemustine; Gadolinium texaphyrin; Gallium nitrate; Galocitabine; Ganirelix; Zela Anti-inflammatory drug inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridone; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; ilopract; irsogladine; isobengazole; isohomohalichondrin B;Itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; rissoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; loxoribine; lutotecan; lu Tethium texaphyrin; lisofylline; lytic peptides; maytansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; melbarone; meterelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosine; millimostim; mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogs; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofalotene; molgramostim ;Monoclonal antibodies, human chorionic gonadotropin;Monophosphoryl lipid A+-72 ethylstilbe cell wall sk;Mopidamol;Multidrug resistance gene inhibitors;Multiple tumor suppressor 1-based therapy;Mustard anticancer drugs;Mycaperoxide B;Mycobacterial cell wall extract;Miliaporone;N-acetyldinaline;N-substituted benzamides;Nafarelin;Nagressip;Naloxone + pentazocine;Napavine;Naphterpine;Nartograstim;Nedaplatin;Nemorubicin;Neridronic acid;Neutral endopeptidase;Nilutamide;Nisamycin;Monoxide Nitrogen regulators; Nitroxide antioxidants; Nitrulline; O6-benzylguanine; Octreotide; Oxenone; Oligonucleotides; Onapristone; Ondansetron; Ondansetron; Oracin; Oral cytokine inducers; Ormaplatin; Osateron; Oxaliplatin; Oxaunomycin; Palauamine; Palmitoylrhizoxin; Pamidronate; Panaxytriol; Panomyphen; Parabactin; Pazeliptin; Pegaspargase; Perdecin; Pentosan polysulfate sodium; Pentostatin; Pentrozole; Perflubron;Perfosfamide; Perillyl alcohol; Phenazinomycin; Phenyl acetate; Phosphatase inhibitors; Picibanil; Pilocarpine hydrochloride; Pirarubicin; Piritrexim; Prasetin A; Prasetin B; Plasminogen activator inhibitors; Platinum complexes; Platinum compounds; Platinum-triamine complexes; Porfimer sodium; Porfiromycin; Prednisone; Propylbisacridone; Prostaglandin J2; Proteasome inhibitors; Protein A-based immunomodulators; Microalgal protein kinase C inhibitors; Protein tyrosine phosphatase inhibitors; Purine nucleoside phosphorylase inhibitors; Purpurin; Pyrazoloacridines; Pyridoxylated hemoglobin polyoxyethylene conjugates; RAF antagonists; Raltitrexed; Ramosetron; Ras farnesyl protein transferase inhibitors; Ras inhibitors; Ras-GAP inhibitors; Demethylated reteriptin; Rhenium etidronate 186;rhizoxin;ribozyme;R.sub.11 retinamide;logletimide;rohitukin;romurtide;roquinimex;rubiginone B1;ruboxil;safingol;saintpin;SarCNU;sarcophytol A;sargramostim;Sdi1 mimetic;semustine;senescence-derived 1;sense oligonucleotide;signal transduction inhibitor;signal transduction modulator;single-chain antigen binding protein;sizofiran;sobzoxane;sodium borocaptate;sodium phenylacetate;sorberol;somatomedin binding protein;sonermin;sparfosic acid;spicamycin D;spiromustine;splenopentin;spongistatin 1;scu Alarmin; stem cell inhibitors; stem cell division inhibitors; stypiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonists; thradista; suramin; swainsonine; synthetic glycosaminoglycans; talimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetics; thymalfasin; thymopoietin receptor agonists; thymotrin; thyroid-stimulating hormone;These include tin ethyl etiopurpurin, tirapazamine, titanocene dichloride, topsentin, toremifene, totipotent stem cell factor, translation inhibitors, tretinoin, triacetyluridine, triciribine, trimetrexate, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, vector systems, erythrocyte gene therapy, veraresol, veramine, verudin, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoterone, zeniplatin, zilascorub, and zinostatin stimalamer.

[0231] Still other anti-cancer agents that may be utilized in combination with the compounds of the present disclosure include alkylating agents, antimetabolites, natural products, or hormones, such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, etc.), or triazenes (e.g., dacarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g., methotrexate, thioguanine, pentostatin).

[0232] Examples of natural products useful in combination with the compounds of the present disclosure include, but are not limited to, vinca alkaloids (e.g., vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).

[0233] Examples of alkylating agents that may be utilized in combination with the compounds of the present disclosure include, but are not limited to, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin, etc.), or triazenes (e.g., decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., methotrexate, thioguanine, pentostatin).

[0234] Examples of hormones and antagonists useful in combination with the compounds of the present disclosure include, but are not limited to, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), gonadotropin-releasing hormone analogs (e.g., leuprolide). Other agents that may be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboplatin), anthraquinones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoglutethimide).

[0235] Examples of anti-cancer agents that act by arresting cells in the G2-M phase through microtubule stabilization and that may be used in combination with irreversible Btk inhibitor compounds include, but are not limited to, the following marketed drugs and drugs in development: elbrozole (also known as R-55104), dolastatin 10 (also known as DLS-10 and NSC-376128), mivobulin isethionate (also known as CI-980), vincristine, NSC-639829, discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), altritol methyltransferase (ALT-10), and methyltransferase (ALT-10). steroids (such as altriltin A and altriltin C), spongistatins (such as spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), epothilones (epothilone A, epothilone B, epothilone C (also known as deoxyepothilone A or dEpoA), epothilone D (also referred to as KOS-862, dEpoB, and deoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as deoxyepothilone F and dEpoF), 26-fluoroepothilone, etc.), auristatin PE (also known as NSC-654663), sobridotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (HungarianAcademy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), vitilebumid, tubulysin A, canadensol, centaureydin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), physianolide B. laurimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), narcosine (also known as NSC-5366), nascapine, D-24851 (Asta Medica), A-105972 (Abbott), hemiasterin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University),University), vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-1AABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), eleutherobin (such as desmethyleleutherobin, desacetyleleutherobin, isoeutherobin A, and Z-eleutherobin), caribeoside, caribeolin, halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylahisteine ​​(also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0236] Further examples of anti-cancer agents for use in combination with the compounds of the present disclosure include immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors (flavoring molecules or biologics) of immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, HIF-2α, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137, and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT, and VISTA. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from a KIR inhibitor, a TIGIT inhibitor, a LAIR1 inhibitor, a CD160 inhibitor, a 2B4 inhibitor, and a TGFRbeta inhibitor.

[0237] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab.

[0238] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).

[0239] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN01876, or MK-1248. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, or INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600, or LAG 525. In some embodiments, the OX40L fusion protein is MEDI6383. [Example]

[0240] The following preparations of compounds of formula (I) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure, and they should not be construed as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.

[0241] All solvents used were commercially available and were used without further purification. Reactions were typically carried out under an inert atmosphere of nitrogen using anhydrous solvents.

[0242] 1 H spectra were recorded at 400 MHz or 300 MHz for proton on a Bruker 400 NMR spectrometer equipped with a Bruker 400 BBO probe or a Bruker BBFO ULTRASHIELD™ 300 AVANCE III, respectively. All deuterated solvents typically contained 0.03%-0.05% v / v tetramethylsilane, which was used as the reference signal ( 1 H and 13 C) were set at δ 0.00 for both.

[0243] LCMS analysis was performed on a SHIMADZU LCMS consisting of a UFLC 20-AD and an LCMS 2020 MS detector. The diode array detector scanned from 190 to 400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative mode. The mass spectrometer was scanned between m / z 90 and 900 with scan times of 0.5 to 3.0 seconds.

[0244] HPLC analysis was performed on a SHIMADZU UFLC with two LC20 AD pumps and an SPD-M20A photodiode array detector. The column used was an XBridge C18, 3.5 μm, 4.6 × 100 mm. A linear gradient was applied starting with 90% A (A: 0.05% TFA in water) and ending with 95% B (B: 0.05% TFA in MeCN) over 10 min with a total run time of 15 min. The column temperature was 40 °C with a flow rate of 1.5 mL / min. The diode array detector scanned from 200 to 400 nm.

[0245] Thin-layer chromatography (TLC) was performed on Alugram® (silica gel 60 F254) from Mancherey-Nagel, and UV was usually used to visualize spots. Additional visualization methods were also utilized in some cases. In these cases, TLC plates were stained with iodine (prepared by adding approximately 1 g of I2 to 10 g of silica gel and mixing thoroughly), ninhydrin (commercially available from Aldrich), or Magic Stain (25 g (NH4)6Mo7O in 450 mL of water and 50 mL of concentrated H2SO4). 24 The solution was developed with a 40-63 μm (230-400 mesh) silica gel from Silicycle, following a procedure similar to that disclosed in Still, W.C.; Kahn, M.; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923. Typical solvents used for flash or thin-layer chromatography were mixtures of chloroform / methanol, dichloromethane / methanol, ethyl acetate / methanol, and hexane / ethyl acetate.

[0246] Synthesis Examples Example 1 Synthesis of 4-((5,6-dimethoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid [ka] To a stirred solution of 5,6-dimethoxy-1H-1,3-benzodiazole (50 mg, 0.281 mmol, 1.00 equiv.) in N,N-dimethylformamide (3.00 mL) was added cesium carbonate (183 mg, 0.562 mmol, 2.00 equiv.). After stirring at room temperature for 1 hour, 4-(bromomethyl)phenylboronic acid (91 mg, 0.421 mmol, 1.50 equiv.) was added. The mixture was stirred overnight at room temperature, and the solid was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following column conditions: XBridge Prep C18 OBD column, 19 x 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 10% B to 25% B in 7 min, 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give 48.4 mg (54%) of the title compound as an off-white solid: MS (ESI, positive ion) m / z: 313.2 (M+1). 1 H-NMR:(300MHz,DMSO-d6,ppm)δ 8.18-8.14(m,1H),8.03(s,2H),7.75-7.72(m,2H),7.25-7.20(m,3H),7.11(s,1H),5.45(s,2H),3.74(s,3H),3.72(s,3H).

[0247] Example 2 Synthesis of 4-((6-oxo-1H-purin-7-yl)methyl)phenylboronic acid (2a) and 4-((6-oxo-1H-purin-9-yl)methyl)phenylboronic acid (2b) [ka] Step 1: 4-((6-chloro-7H-purin-7-yl)methyl)phenylboronic acid and 4-((6-chloropurin-9-yl)methyl)phenylboronic acid [ka] To a solution of 6-chloro-9H-purine (300 mg, 1.941 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL) was added 4-(bromomethyl)phenylboronic acid (625 mg, 2.909 mmol, 1.50 equiv) and potassium carbonate (537 mg, 3.882 mmol, 2.00 equiv) at room temperature. After stirring overnight, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol, and the solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was treated with dichloromethane. The precipitate was collected by filtration, washed with dichloromethane, and dried in vacuo to give 450 mg (80%) of a mixture of 4-((6-chloro-7H-purin-7-yl)methyl)phenylboronic acid and 4-((6-chloropurin-9-yl)methyl)phenylboronic acid as a yellow solid.

[0248] Step 2: 4-((6-oxo-1H-purin-7-yl)methyl)phenylboronic acid and 4-((6-oxo-1H-purin-9-yl)methyl)phenylboronic acid [ka] To a mixture of 4-((6-chloro-7H-purin-7-yl)methyl)phenylboronic acid and 4-((6-chloropurin-9-yl)methyl)phenylboronic acid (200 mg, 0.694 mmol, 1.00 equiv.) in tetrahydrofuran (5 mL) was added 6N hydrochloric acid (4 mL) dropwise at room temperature. After refluxing for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide and filtered. The filtrate was purified by preparative HPLC using the following column conditions: XBridge Prep Phenyl OBD column, 19 x 150 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 8% B to 15% B in 10 min, 220 and 254 nm. The fractions containing the desired product were combined and lyophilized to give two fractions.

[0249] Fraction 1: Rt: 8.02 min. 8.2 mg (4% yield) of 4-((6-oxo-1H-purin-7-yl)methyl)phenylboronic acid (2a) as a white solid. MS (ESI, positive ion) m / z: 271.2 (M+1). 1 H-NMR(300MHz,DMSO-d6,ppm)δ 12.14(brs,1H),8.39(s,1H),8.08(brs,2H),7.96(s,1H),7.74(d,J=7.8Hz,2H),7.27(d,J=8.1Hz,2H),5.57(s,2H).

[0250] Fraction 2: Rt: 9.35 min. 11.2 mg (6% yield) of 4-((6-oxo-1H-purin-9-yl)methyl)phenylboronic acid (2b) as a white solid. MS (ESI, positive ion) m / z: 271.2 (M+1). 1 H-NMR(300MHz,DMSO-d6,ppm)δ 11.98(brs,1H),8.25-8.02(m,4H),7.74(d,J=8.1Hz,2H),7.24(d,J=7.8Hz,2H),5.38(s,2H).

[0251] Example 3 Synthesis of 4-((2-amino-6-oxo-1H-purin-7-yl)methyl)phenylboronic acid (3a) and 4-((2-amino-6-oxo-1H-purin-9-yl)methyl)phenylboronic acid (3b) [ka] Step 1: 4-((2-amino-6-chloropurin-7-yl)methyl)phenylboronic acid and 4-((2-amino-6-chloropurin-9-yl)methyl)phenylboronic acid [ka] To a solution of 6-chloro-9H-purin-2-amine (100 mg, 0.590 mmol, 1.00 equiv) in N,N-dimethylformamide (3 mL) was added 4-(bromomethyl)phenylboronic acid (127 mg, 0.590 mmol, 1.00 equiv) and potassium carbonate (204 mg, 1.474 mmol, 2.50 equiv) at room temperature. After stirring overnight, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol, and the solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was treated with dichloromethane. The precipitate was collected by filtration, washed with dichloromethane, and dried in vacuo to give 200 mg (86% yield, 77% purity) of a mixture of 4-((2-amino-6-chloropurin-7-yl)methyl)phenylboronic acid and 4-((2-amino-6-chloropurin-9-yl)methyl)phenylboronic acid as a yellow solid.

[0252] Step 2: 4-((2-amino-6-oxo-1H-purin-7-yl)methyl)phenylboronic acid and 4-((2-amino-6-oxo-1H-purin-9-yl)methyl)phenylboronic acid [ka] To a mixture of 4-((6-chloro-7H-purin-7-yl)methyl)phenylboronic acid and 4-((6-chloropurin-9-yl)methyl)phenylboronic acid (200 mg, 0.507 mmol, 1.00 equiv., 77% purity) in tetrahydrofuran (2 mL) was added 6N hydrochloric acid (4 mL) dropwise at room temperature. After refluxing for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide and filtered to give 3.7 mL of a clear solution, which was purified by preparative HPLC using the following column conditions: XBridge Shield RP18 OBD column, 19 x 250 mm, 10 μm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10% B to 20% B in 7 min, 220 and 254 nm. The fractions containing the desired product were combined and lyophilized to give two fractions.

[0253] Fraction 1: Rt: 5.17 min. 17.5 mg (12% yield) of 4-((2-amino-6-oxo-1H-purin-7-yl)methyl)phenylboronic acid (3a) as an off-white solid. MS (ESI, positive ion) m / z: 286.2 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 10.73(brs,1H),8.15-8.04(m,3H),7.78-7.72(m,2H),7.25-7.18(m,2H),6.14(s,2H),5.42(s,2H).

[0254] Fraction 2: Rt: 6.45 min. 13.0 mg (9% yield) of 4-((2-amino-6-oxo-1H-purin-9-yl)methyl)phenylboronic acid (3b) as a white solid. MS (ESI, positive ion) m / z: 286.2 (M+1). 1 H-NMR(300MHz,DMSO-d6,ppm)δ 10.60(brs,1H),8.04(s,2H),7.76-7.72(m,3H),7.17-7.14(m,2H),6.46(s,2H),5.18(s,2H).

[0255] Example 4 Synthesis of 4-((6-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (4a) and 4-((5-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (4b) [ka] A mixture of 5-methoxybenzimidazole (100 mg, 0.675 mmol, 1.00 equiv.) and cesium carbonate (449 mg, 1.350 mmol, 2.00 equiv.) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 20 minutes. 4-(Bromomethyl)phenylboronic acid (174 mg, 0.810 mmol, 1.20 equiv.) was added. After stirring for 2 hours, the reaction mixture was filtered through Celite. The filtrate was purified by preparative HPLC using the following conditions: Column: XBridge Prep Phenyl OBD Column, 19 x 150 mm, 5 μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: Acetonitrile; Flow Rate: 25 mL / min; Gradient: 30% B to 35% B in 10 minutes, 220 and 254 nm. Two fractions were obtained.

[0256] Fraction 1: RT: 8.02 min. 47.8 mg (25%) of 4-((6-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid as a white solid (4a). MS (ESI, positive ion) m / z: 283.2 (M+1). 1 H-NMR (400 MHz, DMSO-d6, ppm): δ 9.31-9.17 (m, 1H), 8.18 (brs, 2H), 7.87-7.72 (m, 3H), 7.54-7.25 (m, 3H), 7.18-7.05 (m, 1H), 5.66-5.60 (m, 2H), 3.80-3.62 (m, 3H).

[0257] Fraction 2: RT: 9.35 min. 36.3 mg (17%) of 4-((5-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (4b) as a white solid. MS (ESI, positive ion) m / z: 283.2 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm):δ 9.44-9.31(m,1H),8.22(brs,2H),7.88-7.65(m,3H),7.39-7.22(m,3H),7.17-7.05(m,1H),5.68-5.60(m,2H),3.82-3.76(m,3H).

[0258] Example 5 Synthesis of 4-((5,6-dimethoxyindol-1-yl)methyl)phenylboronic acid [ka] To a stirred solution of 5,6-dimethoxy-1H-indole (150 mg, 0.847 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) was added sodium hydride (51 mg, 1.271 mmol, 60% in mineral oil, 1.50 equiv) at 0 °C. After stirring for 30 minutes, 4-(bromomethyl)phenylboronic acid (218 mg, 1.016 mmol, 1.20 equiv) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and filtered. The filtrate was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 19 x 250 μm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 45% B to 45% B in 7 minutes, 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give 63.7 mg (24%) of 4-((5,6-dimethoxyindol-1-yl)methyl)phenylboronic acid. MS (ESI, positive ion) m / z: 312.0 (M+1). 1 H-NMR (300MHz, DMSO-d6, ppm): δ 7.99(s,2H),7.71(d,J=5.7Hz,2H),7.42-7.03(m,5H),6.34(s,1H),5.36(s,2H),3.74(s,6H).

[0259] Example 6 Synthesis of 4-((6-aminopurin-7-yl)methyl)phenylboronic acid (6a) and 4-((6-aminopurin-9-yl)methyl)phenylboronic acid (6b) [ka] To a mixture of 9H-purin-6-amine (150 mg, 1.110 mmol, 1.00 equiv.) and cesium carbonate (724 mg, 2.222 mmol, 2.00 equiv.) in N,N-dimethylformamide (8 mL) was added 4-(bromomethyl)phenylboronic acid (286 mg, 1.333 mmol, 1.20 equiv.) at room temperature. After stirring at 80 °C for 3 h, the reaction mixture was treated with 2 N HCl (2 mL) and filtered. The filtrate was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 19 × 250 mm, 10 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: methanol; Flow rate: 25 mL / min; Gradient: 19% B to 27% B in 7 min, 220 and 254 nm. Two fractions were obtained.

[0260] Fraction 1: Rt = 4.22 min. 79.6 mg (23%) of 4-((6-aminopurin-7-yl)methyl)phenylboronic acid hydrochloride (6a) as a white solid. MS (ESI, positive ion) m / z: 270.3 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm):δ 14.52(brs,1H),9.38(s,1H),9.16(s,1H),9.02(s,1H),8.64(s,1H),8.21(brs,2H),7.77(d,J=7.6Hz,2H),7.41(d,J=7.6Hz,2H),5.63(s,2H).

[0261] Fraction 2: Rt = 5.53 min. 34.8 mg (11%) of 4-((6-aminopurin-9-yl)methyl)phenylboronic acid (76b) as a white solid. MS (ESI, positive ion) m / z: 270.2 (M+1). 1 H-NMR (400MHz, DMSO-d6, ppm): δ 8.71(brs,2H),8.52(s,1H),8.40(s,1H),8.14(brs,2H),7.76(d,J=8.0Hz,2H),7.28(d,J=8.0Hz,2H),5.45(s,2H).

[0262] Example 7 Synthesis of 4-((6-cyano-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (7a) and 4-((5-cyano-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (7b) [ka] To a suspension of sodium hydride (112 mg, 2.79 mmol, 60% in mineral oil, 2.00 equiv.) in N,N-dimethylformamide (4 mL) was added a solution of 1H-1,3-benzodiazole-5-carbonitrile (200 mg, 1.40 mmol, 1.00 equiv.) in N,N-dimethylformamide (1 mL) at 0° C. under a nitrogen atmosphere. After stirring at this temperature for 30 minutes, 4-(bromomethyl)phenylboronic acid (360 mg, 1.68 mmol, 1.20 equiv.) was added. The resulting mixture was stirred at room temperature for 2 hours, quenched with 1N hydrochloric acid (2 mL), and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following column conditions: XBridge Prep C18 OBD column, 19 x 250 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 21% B to 21% B in 10 min; 220 and 254 nm. Two fractions were obtained.

[0263] Fraction 1: Rt = 8.77 min. 42.4 mg (11% yield) of 4-((6-cyano-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (7a) as a white solid. MS (ESI, positive ion) m / z: 278.3 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm):δ 8.72(s,1H),8.21(s,1H),8.05(s,2H),7.85-7.82(m,1H),7.75(d,J=8.0Hz,2H),7.60-7.58(m,1H),7.32(d,J=8.0Hz,2H),5.57(s,2H).

[0264] Fraction 2: Rt = 10.18 min. 79.1 mg (20% yield) of 4-((5-cyano-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (7b) as a white solid. MS (ESI, positive ion) m / z: 278.3 (M+1). 1 H-NMR (400MHz, DMSO-d6, ppm): δ 8.68(s,1H),8.24(s,1H),8.05(s,2H),7.80-7.71(m,3H),7.63-7.59(m,1H),7.27(d,J=8.0Hz,2H),5.58(s,2H).

[0265] Example 8 Synthesis of (4-((5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid [ka] Step 1: 4-((4-chloro-5-fluoropyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl-boronic acid [ka] The title compound was synthesized by the same method described in Example 7, except that 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 1.75 mmol, 1.00 equiv.) was used instead of 1H-1,3-benzodiazole-5-carbonitrile. Yield: 0.45 g (69%). MS (ESI, positive ion) m / z: 306.2 (M+1).

[0266] Step 2: (4-((5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid [ka] 4-((4-Chloro-5-fluoropyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenylboronic acid (150 mg, 0.49 mmol, 82% purity, 1.00 equiv.) was dissolved in a mixture of hydrochloric acid (4 mL) and tetrahydrofuran (20 mL) at room temperature and stirred at 80°C for 48 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC using an XBridge Shield RP18 OBD column, 19 x 250 mm, 10 µm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 23% B to 23% B in 6 min; elution at 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give 6.1 mg (4%) of (4-((5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid as a white solid. MS (ESI, positive ion) m / z: 288.2 (M+1). 1 H-NMR:(400MHz,DMSO-d6,ppm)δ 12.03(s,1H),8.02(s,2H),7.90(d,J=4.0Hz,1H),7.72(d,J=8.0Hz,2H),7.19-7.13(m,3H),5.27(s,2H). 19 F-NMR:(376MHz,DMSO-d6,ppm)δ -166.3(1F).

[0267] Example 9 Synthesis of (4-((4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid [ka] To a sealed tube was added 150 mg of 4-((4-chloro-5-fluoropyrrolo[2,3-d]pyrimidin-7-yl)-methyl)phenylboronic acid (product of Step 1, Example 8), 0.49 mmol, 1.00 equiv.), ethanol (10 mL), and ammonia (4 mL) at room temperature. After stirring at 90 °C for 48 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following column conditions: XBridge Prep OBD C18 column, 19 × 250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 16% B to 16% B in 7 min; elution at 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give 41 mg (29%) of (4-((4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid as a white solid. MS (ESI, positive ion) m / z: 287.3 (M+1). 1 H-NMR:(400MHz,DMSO-d6,ppm)δ 8.07(s,1H),8.02(s,2H),7.71(d,J=8.0Hz,2H),7.20(d,J=2.0Hz,1H),7.14(d,J=8.0Hz,2H),6.97(s,2H),5.27(s,2H). 19 F-NMR:(376MHz,DMSO-d6,ppm)δ -168.2(1F).

[0268] Example 10 Synthesis of 4-((5-methoxyindol-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized as described in Example 7, except that 5-methoxyindole (100 mg, 0.679 mmol, 1.00 equiv) was used instead of 1H-1,3-benzodiazole-5-carbonitrile. Yield: 61.8 mg (32%). MS (ESI, positive ion) m / z: 282.3 (M+1). 1H-NMR(300MHz,DMSO-d6,ppm):δ 8.00(s,2H),7.75-7.68(m,2H),7.45-7.43(m,1H),7.29(d,J=8.7Hz,1H),7.15 -7.05(m,3H),6.74-6.70(m,1H),6.40-6.37(m,1H),5.37(s,2H),3.74(s,3H).

[0269] Example 11 Synthesis of (4-((4-hydroxy-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)phenyl)boronic acid [ka] Step 1: 4-Methoxy-1H-pyrrolo[3,2-c]pyridine [ka] To a solution of NaOMe (20 mL, 30%) in methanol was added 4-chloro-1H-pyrrolo[3,2-c]pyridine (1.00 g, 6.554 mmol, 1.00 equiv.). The resulting mixture was stirred in a sealed tube at 120° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (80 mL), washed with water, brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to give 0.7 g (58%) of 4-methoxy-1H-pyrrolo[3,2-c]pyridine as a pale yellow solid. 1 H-NMR:(400MHz,DMSO-d6,ppm)δ 11.48(s,1H),7.70(d,J=5.8Hz,1H),7.32-7.25(m,1H),7.02(dd,J=5.9,1.0Hz,1H),6.48-6.44(m,1H),3.94(s,3H)

[0270] Step 2: 4-((4-methoxypyrrolo[3,2-c]pyridin-1-yl)methyl)-phenylboronic acid [ka] To a solution of 4-methoxy-1H-pyrrolo[3,2-c]pyridine (400.0 mg, 2.16 mmol, 80% purity, 1.00 equiv.) in DMF (4 mL) was added NaH (207.3 mg, 8.64 mol, 4.00 equiv.) under an argon atmosphere at 0 °C. After stirring at this temperature for 30 min, a solution of 4-(bromomethyl)phenylboronic acid (640.4 mg, 2.98 mmol, 1.38 equiv.) in DMF (1 mL) was added. The reaction mixture was stirred at room temperature for 2 h, quenched with 2 N hydrochloric acid, and concentrated under reduced pressure. The residue was suspended in ACN and stirred for 30 min. The solid was removed by filtration, and the filtrate was evaporated to dryness to give 0.45 g (63%) of 4-((4-methoxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid as a pale yellow solid. 0.25 g of this material was further purified by preparative HPLC using the following column conditions: Sunfire prep C18 column, 30 x 150, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 7% B to 25% B in 7 min; 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give 88.7 mg of 4-((4-methoxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid as a white solid. MS (ESI, positive ion) m / z: 283.3 (M+1). 1 H-NMR:(400MHz,DMSO-d6,ppm)δ 8.00(s,2H),7.77-7.61(m,3H),7.44(d,J=3.2Hz,1H),7.20-7.04(m,3H),6.53(dd,J=3.2,0.9Hz,1H),5.41(s,2H),3.95(s,3H).

[0271] Step 3: (4-((4-hydroxy-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)phenyl)boronic acid [ka] To a suspension of 4-((4-methoxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid (0.20 g, 0.709 mmol, 1.00 equiv.) in DCM (10.00 mL) was added BBr3 (3.55 g, 14.18 mmol, 20.00 equiv.) at room temperature. After stirring overnight at room temperature, the mixture was quenched with methanol (10 mL) at -20 °C, warmed to room temperature, and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following column conditions: XBridge Shield RP18 OBD column, 19*250 mm, 10 μm; mobile phase A: water (10 mMol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 10 B to 30 B in 10 min; 254 / 220 nm. Fractions containing the desired product were combined and lyophilized to give 59.8 mg (31%) of 4-((4-hydroxypyrrolo[3,2-c]pyridin-1-yl)methyl)-phenylboronic acid as a white solid. MS (ESI, positive ion) m / z: 269.2 (M+1). 1 H NMR(400MHz,DMSO-d6,ppm)δ 10.78(d,J=5.6Hz,1H),8.01(s,2H),7.80-7.63(m,2H),7.20(d,J=3.1Hz,1H),7.12(d,J=7.7H z,2H),6.98(dd,J=7.2,5.8Hz,1H),6.53(d,J=3.0Hz,1H),6.48(d,J=7.2Hz,1H),5.32(s,2H).

[0272] Example 12 Synthesis of (4-((4-hydroxy-3H-imidazo[4,5-c]pyridin-3-yl)methyl)phenyl)boronic acid (12a) and 4-((4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (12b) [ka] Step 1: 4-((4-chloro-3H-imidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid and 4-((4-chloroimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid [ka] To a solution of 4-chloro-1H-imidazo[4,5-c]pyridine (150 mg, 0.977 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) was added 4-(bromomethyl)phenylboronic acid (252 mg, 1.172 mmol, 1.20 equiv) and cesium carbonate (636 mg, 1.954 mmol, 2.00 equiv) at room temperature. After stirring overnight, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (10 mL) and the solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was treated with dichloromethane (10 mL). The precipitate was collected by filtration, washed with dichloromethane (10 mL × 3), and dried in vacuo to give 200 mg (71%) of a mixture of 4-((4-chloro-3H-imidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid and 4-((4-chloroimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid as a yellow solid. MS (ESI, positive ion) m / z: 288.2 (M+1).

[0273] Step 2: 4-((4-hydroxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid and 4-((4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid [ka] To a mixture of 4-((4-chloro-3H-imidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid and 4-((4-chloroimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (180 mg, 0.62 mmol, 1.00 equiv.) in tetrahydrofuran (5 mL) was added 6N hydrochloric acid (5 mL) dropwise at room temperature. After refluxing overnight, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide and filtered. The filtrate was purified by preparative HPLC using the following column conditions: XBridge Prep Phenyl OBD column, 19 x 150 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 8% B to 15% B in 10 min, 220 and 254 nm. The fractions containing the desired product were combined and lyophilized to give two fractions.

[0274] Fraction 1: Rt: 8.02 min. 80.2 mg (44% yield) of 4-((4-hydroxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (13a) as a white solid. MS (ESI, positive ion) m / z: 270.3 (M+1). 1 H-NMR(300MHz,DMSO-d6,ppm)δ 11.26-11.24(m,1H),8.30(s,1H),8.00(s,2H),7.72(d,J=8.1Hz,2H),7.2 6(d,J=8.1Hz,2H),7.10-7.06(m,1H),6.54(d,J=7.2Hz,1H),5.65(s,2H).

[0275] Fraction 2: Rt: 9.35 min. 17.2 mg (10% yield) of 4-((4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (13b) as a white solid. MS (ESI, positive ion) m / z: 270.3 (M+1). 1 H-NMR(300MHz,DMSO-d6,ppm)δ 11.90(s,1H),9.21(s,1H),7.80-7.74(m,2H),7.47-7.10(m,5H),6.78-6.66(m,1H),5.58(s,2H).

[0276] Example 13 Synthesis of 4-((4-chloropyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid [ka] To a solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (150 mg, 0.98 mmol, 1.00 equiv) in N,N-dimethylformamide (8 mL) was added sodium hydride (47 mg, 1.97 mmol, 2.00 equiv, 60% purity) at 0°C. After stirring at 0°C for 30 minutes, 4-(bromomethyl)phenylboronic acid (253 mg, 1.18 mmol, 1.20 equiv) was added. The mixture was stirred at room temperature for 3 hours, and the mixture was quenched with 2N hydrogen chloride and concentrated under reduced pressure. The residue was dissolved in methanol, and the solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was treated with dichloromethane. The precipitate was collected by filtration, washed with dichloromethane, and dried in vacuo to give 250 mg (85% purity) of 4-((4-chloropyrrolo[3,2-c]pyridin-1-yl)methyl)-phenylboronic acid as a yellow solid. The crude product (50 mg) was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 19 × 250 mm, 10 μm; Mobile phase A: water (0.1% FA), Mobile phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 46% B to 46% B in 5 min, 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give 3.6 mg (6%) of 4-((4-chloropyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid as a white solid. MS (ESI, positive ion) m / z: 287.2 (M+1). 1 H-NMR(300MHz,DMSO-d6,ppm)δ 7.99(d,J=5.7Hz,1H),7.74-7.71(m,3H),7.60-7.57(m,1H),7.18(d,J=8.1Hz,2H),6.64-6.63(m,1H),5.50(s,2H).

[0277] Example 14 Synthesis of 4-((6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetate (14a), 4-((5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)-phenylboronic acid trifluoroacetate (14b), 3-((4-(dihydroxyboranyl)phenyl)methyl)-1,3-benzodiazole-5-carboxylic acid trifluoroacetate (14c), 1-((4-(dihydroxyboranyl)phenyl)methyl)-1,3-benzodiazole-6-carboxylic acid trifluoroacetate (14d), 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetate (14e), and 4-((6-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetate [ka] Step 1: 4-((6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetate (14a) and 4-((5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetate (14b) [ka] To a solution of methyl 1H-1,3-benzodiazole-5-carboxylate (500 mg, 2.838 mmol, 1.00 equiv.) in DMF (5 mL) was added sodium hydride (170 mg, 4.257 mmol, 1.50 equiv., 60% purity) at 0° C. After stirring for 20 minutes, 4-(bromomethyl)phenylboronic acid (732 mg, 3.406 mmol, 1.20 equiv.) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 500 mg of a mixture of 4-((6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetate (14a) and 4-((5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetate (14b). 250 mg of the mixture was purified by preparative HPLC using the following column conditions: XSelect CSH Prep C18 OBD column, 19 x 250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 12% B to 18% B in 17 min, 220 and 254 nm. The fractions containing the desired product were combined and lyophilized to give two fractions.

[0278] Fraction 1: Rt: 12.77 min. 70.3 mg (6% yield) of 4-((6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetate (14a) as a white solid. MS (ESI, positive ion) m / z: 311.2 (M+1). 1 H-NMR:(400MHz,DMSO-d6,ppm)δ 9.05-9.01(m,1H),8.43-8.10(m,3H),7.94-7.76(m,5H),7.29(d,J=7.6Hz,2H),5.71-5.69(m,2H),3.86-3.82(m,3H).

[0279] Fraction 2: Rt: 14.7 min. 80.8 mg (6% yield) of 4-((5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetate (14b) as a white solid. MS (ESI, positive ion) m / z: 311.2 (M+1). 1 H-NMR:(400MHz,DMSO-d6,ppm)δ 9.05-9.01(m,1H),8.34(s,1H),7.96-7.85(m,2H),7.77-7.50(m,5H),7.36-7.32(m,2H),5.60(s,2H),3.87(s,3H).

[0280] Step 2: 3-((4-(dihydroxyboranyl)phenyl)methyl)-1,3-benzodiazole-5-carboxylic acid trifluoroacetate (14c), 1-((4-(dihydroxyboranyl)phenyl)methyl)-1,3-benzodiazole-6-carboxylic acid trifluoroacetate (14d), 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetate (14e), and 4-((6-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetate (14f). [ka] A mixture of 4-((6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid) and 4-((5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetate (14a and 14b) (250 mg, 1 equiv.) was dissolved in aqueous ammonia (10 mL). After stirring in a sealed tube at 80° C. for 12 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following column conditions: XSelect CSH Prep C18 OBD column, 19×250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 5% B to 15% B in 14 minutes, 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give four fractions.

[0281] Fraction 1: Rt: 7.25 min. 16.8 mg (5% yield) of 3-((4-(dihydroxyboranyl)phenyl)methyl)-1,3-benzodiazole-5-carboxylic acid trifluoroacetate (14c) as a white solid. MS (ESI, positive ion) m / z: 297.2 (M+1). 1 H-NMR:(400MHz,DMSO-d6,ppm)δ 9.07(s,1H),8.20(s,1H),7.94-7.75(m,4H),7.30(d,J=8.0Hz,2H),5.65(s,2H).

[0282] Fraction 2: Rt: 8.92 min. 20.6 mg (6% yield) of 1-((4-(dihydroxyboranyl)phenyl)methyl)-1,3-benzodiazole-5-carboxylic acid trifluoroacetate (14d) as a white solid. MS (ESI, positive ion) m / z: 297.3 (M+1). 1 H-NMR:(400MHz,DMSO-d6,ppm)δ 12.81(brs,1H),8.68(s,1H),8.26-7.85(m,4H),7.76-7.61(m,3H),7.35-7.28(m,2H),5.57(s,2H).

[0283] Fraction 3: Rt: 10.22 min. 42.8 mg (13% yield) of 4-((6-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetate (14e) as a white solid. MS (ESI, positive ion) m / z: 296.2 (M+1). 1 H-NMR:(400MHz,DMSO-d6,ppm)δ 9.27(s,1H),8.28(s,1H),8.11(s,1H),7.97-7.73(m,5H),7.50-7.20(m,5H),5.68(s,2H).

[0284] Fraction 4: Rt: 11.84 min. 53.0 mg (16% yield) of 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetate (14f) as a white solid. MS (ESI, positive ion) m / z: 296.2 (M+1). 1H-NMR:(400MHz,DMSO-d6,ppm)δ 9.20(s,1H),8.31(s,1H),8.11(s,1H),7.94-7.88(m,1H),7.79-7.73(m,3H),7.43(s,1H),7.44-7.29(m,3H),5.66(s,2H).

[0285] Example 15 Synthesis of 4-((5-cyano-3-oxo-2H-indazol-1-yl)methyl)phenylboronic acid [ka] Step 1: 3-Oxo-1,2-dihydroindazole-5-carbonitrile [ka] Methyl 5-cyano-2-fluorobenzoate (500 mg, 2.79 mmol, 1.00 equiv.) was dissolved in hydrazine monohydrate (50 mL) and stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:2) to give 310 mg (68% yield) of 3-oxo-1,2-dihydroindazole-5-carbonitrile as a pale yellow solid.

[0286] Step 2: 4-((5-cyano-3-oxo-2H-indazol-1-yl)methyl)phenylboronic acid [ka] To a solution of 3-oxo-1,2-dihydroindazole-5-carbonitrile (100 mg, 0.63 mmol, 1.00 equiv.) in N,N-dimethylformamide (5 mL) was added potassium carbonate (127 mg, 1.26 mmol, 2.00 equiv.) and 4-(bromomethyl)phenylboronic acid (162 mg, 0.75 mmol, 1.20 equiv.). After stirring at 80 °C for 12 hours, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using a Sunfire prep C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 7% B to 52% B in 7 min; elution at 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give 50 mg (27%) of 4-((5-cyano-3-oxo-2H-indazol-1-yl)methyl)phenylboronic acid as a white solid. MS (ESI, positive ion) m / z: 294.3 (M+1). 1 H-NMR:(400MHz,DMSO-d6,ppm)δ 11.32(s,1H),8.19(s,1H),8.01(s,2H),7.77-7.62(m,4H),7.15(d,J=8.0Hz,2H),5.45(s,2H).

[0287] Example 16 Synthesis of 4-((5-carbamoyl-3-oxo-2H-indazol-1-yl)methyl)phenylboronic acid [ka] Step 1: 3-oxo-1,2-dihydroindazole-5-carboxamide [ka] 3-Oxo-1,2-dihydroindazole-5-carbonitrile (400 mg, 2.51 mmol, 1.00 equiv.) was dissolved in water (0.4 mL, 22.20 mmol) and concentrated sulfuric acid (2.4 mL, 45.03 mmol, 17.91 equiv.) at room temperature. After stirring at 100 °C for 1 h, the mixture was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with water (50 mL) and saturated aqueous sodium bicarbonate (50 mL × 2). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: petroleum ether / ethyl acetate 1:2) to afford 120 mg (22%) of 3-oxo-1,2-dihydroindazole-5-carboxamide as a pale yellow solid.

[0288] Step 2: 4-((5-carbamoyl-3-oxo-2H-indazol-1-yl)methyl)phenylboronic acid [ka] To a solution of 3-oxo-1,2-dihydroindazole-5-carboxamide (120 mg, 0.68 mmol, 80%, 1.00 equiv.) in N,N-dimethylformamide (5 mL) was added sodium hydride (24 mg, 1.02 mmol, 1.50 equiv.) at 0° C. under an argon atmosphere. After stirring at this temperature for 30 minutes, a solution of 4-(bromomethyl)phenylboronic acid (175 mg, 0.81 mmol, 1.20 equiv.) in N,N-dimethylformamide (2 mL) was added. After stirring at room temperature for 1 hour, the reaction mixture was quenched with 2 N hydrochloric acid (5 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following column conditions: Sunfire prep C18 column, 30 x 150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 5% B to 35% B in 7 min; 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to afford 33.5 mg (16%) of 4-((5-carbamoylno-3-oxo-2H-indazol-1-yl)methyl)phenylboronic acid as a white solid. MS (ESI, positive ion) m / z: 312.3 (M+1). 1H-NMR:(300MHz,DMSO-d6,ppm)δ 10.97(s,1H),8.23(s,1H),7.97(s,2H),7.96-7.78(m,2H),7.69(d,J=7.8Hz,2H),7.55(d,J=8.7Hz,1H),7.17-7.11(m,3H),5.39(s,2H).

[0289] Example 17 Synthesis of 1-(4-boronobenzyl)-3-chloro-1H-indole-5-carboxylic acid (17a) and 4-((5-carbamoyl-3-chloroindol-1-yl)methyl)phenylboronic acid (17b) [ka] Step 1: 3-chloro-1H-indole-5-carboxylate methyl [ka] Methyl 1H-indole-5-carboxylate (240 mg, 1.370 mmol, 1.00 equiv.) and N-chlorosuccinimide (366 mg, 2.740 mmol, 2.00 equiv.) were dissolved in methanol (5 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 99:1) to give 170 mg (57%) of methyl 3-chloro-1H-indole-5-carboxylate as a yellow solid. MS (ESI, positive ion) m / z: 210.1 (M+1).

[0290] Step 2: 4-((3-chloro-5-(methoxycarbonyl)indol-1-yl)methyl)phenylboronic acid [ka] To a stirred mixture of methyl 3-chloro-1H-indole-5-carboxylate (160 mg, 0.740 mmol, 1.00 equiv., 97% purity) and potassium carbonate (205 mg, 1.481 mmol, 2.00 equiv.) in N,N-dimethylformamide (5 mL) was added 4-(bromomethyl)phenylboronic acid (175 mg, 0.814 mmol, 1.10 equiv.) at room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 210 mg (81%) of 4-((3-chloro-5-(methoxycarbonyl)indol-1-yl)methyl)phenylboronic acid as a yellow solid. MS (ESI, positive ion) m / z: 344.2 (M+1).

[0291] Step 3: 1-(4-boronobenzyl)-3-chloro-1H-indole-5-carboxylic acid (17a) and 4-((5-carbamoyl-3-chloroindol-1-yl)methyl)phenylboronic acid (17b) [ka] 4-((3-Chloro-5-(methoxycarbonyl)indol-1-yl)methyl)phenylboronic acid (210 mg, 1.00 equiv., 98% purity) was dissolved in dioxane (3 mL) and aqueous ammonia (12 mL). After stirring at 80° C. for 48 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following column conditions: Sunfire prep C18 column, 30×150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 31% B to 48% B in 8 min; 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give two fractions.

[0292] Fraction 1: Rt: 4.5 min. 55.1 mg (27% yield) of 1-(4-boronobenzyl)-3-chloro-1H-indole-5-carboxylic acid (17a) as an off-white solid. MS (ESI, positive ion) m / z: 330.2 (M+1).1 H-NMR(300MHz,DMSO-d6,ppm)δ 12.70(s,1H),8.14(s,1H),8.02(s,2H),7.86(s,1H),7.81-7.61(m,4H),7.21-7.18(m,2H),5.46(s,2H).

[0293] Fraction 2: Rt: 6.62 min. 58.4 mg (29% yield) of 4-((5-carbamoyl-3-chloroindol-1-yl)methyl)phenylboronic acid (17b) as a pale yellow solid. MS (ESI, positive ion) m / z: 329.3 (M+1). 1 H-NMR(300MHz,DMSO-d6,ppm)δ 8.13(s,1H),8.01-7.90(m,3H),7.81-7.71(m,4H),7.58(d,J=8.7Hz,1H),7.21-7.18(m,3H),5.45(s,2H).

[0294] Example 18 Synthesis of 4-((5-carbamoyl-3-methylindol-1-yl)methyl)phenylboronic acid (18a), 4-((5-(ethoxycarbonyl)-3-methylindol-1-yl)methyl)phenylboronic acid (18b), and 1-((4-(dihydroxyboranyl)phenyl)methyl)-3-methylindole-5-carboxylic acid (18c) [ka] Step 1: 4-((5-(ethoxycarbonyl)-3-methylindol-1-yl)methyl)-phenylboronic acid (18b) and 1-((4-(dihydroxyboranyl)phenyl)methyl)-3-methylindole-5-carboxylic acid (18c) [ka] The title compound was synthesized by the method described in Example 7, except that ethyl 3-methyl-1H-indole-5-carboxylate (100 mg, 0.49 mmol, 1.00 equiv.) was used instead of 1H-1,3-benzodiazole-5-carbonitrile. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (20:1)) to give two fractions.

[0295] Fraction 1: 50 mg (26%) of 4-((5-(ethoxycarbonyl)-3-methylindol-1-yl)methyl)phenylboronic acid (18b) as an off-white solid. MS (ESI, positive ion) m / z: 338.3 (M+1).

[0296] Fraction 2: 100 mg (85% purity) of 1-((4-(dihydroxyboranyl)phenyl)methyl)-3-methylindole-5-carboxylic acid (18c) as an off-white solid was further purified by preparative HPLC using the following column conditions: XBridge Prep OBD C18 column, 19 x 250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 28% B to 64% B in 7 min; spectroscopy at 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to afford 43.2 mg (27%) of 1-((4-(dihydroxyboranyl)phenyl)methyl)-3-methylindole-5-carboxylic acid (18c) as a white solid. MS (ESI, positive ion) m / z: 310.3 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 12.42(s,1H),8.17(s,1H),7.99(s,2H),7.71-7.66(m,3H),7.46(d,J=8 .4Hz,1H),7.34(s,1H),7.14(d,J=8.0Hz,2H),5.38(s,2H),2.29(s,3H).

[0297] Step 2: 4-((5-carbamoyl-3-methylindol-1-yl)methyl)phenylboronic acid (18a) [ka] To a mixture of 4-((5-(ethoxycarbonyl)-3-methylindol-1-yl)methyl)phenylboronic acid (18b) (50 mg, 0.13 mmol, 1.00 equiv, 87% purity) in dioxane (3 mL) was added aqueous ammonia (3 mL). After stirring at 80 °C overnight, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following column conditions: XBridge Prep OBD C18 column, 19 × 250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 28% B to 64% B in 7 min; 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give 4.9 mg (12%) of 4-((5-carbamoyl-3-methylindol-1-yl)methyl)phenylboronic acid (18a) as a white solid. MS (ESI, positive ion) m / z: 309.2 (M+1). 1 H-NMR(300MHz,DMSO-d6,ppm)δ 9.18(s,1H),8.45(s,1H),8.13(s,1H),7.86(s,1H),7.68-7.62(m,3H),7.43- 7.39(m,1H),7.31-7.27(m,1H),7.14-7.10(m,3H),5.37(s,2H),2.30(s,3H).

[0298] Example 19 Synthesis of 4-((6-methoxy-5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenyl-boronic acid (19a), 4-((5-methoxy-6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)-phenyl-boronic acid (19b), 4-((6-carbamoyl-5-methoxy-1,3-benzodiazol-1-yl)methyl)-phenylboronic acid (19c), and 4-((5-carbamoyl-6-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (19d) [ka] Step 1: Methyl 4,5-diamino-2-methoxybenzoate [ka] To a solution of methyl 4-amino-2-methoxy-5-nitrobenzoate (1.00 g, 4.421 mmol, 1.00 equiv.) in methanol (10 mL) was added 10% Pd / C (200 mg, 0.20 equiv.). The resulting mixture was stirred at room temperature under a hydrogen atmosphere (2-3 atm) for 12 h. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give 760 mg (85%) of methyl 4,5-diamino-2-methoxybenzoate as a yellow oil.

[0299] Step 2: 6-Methoxy-1H-1,3-benzodiazole-5-carboxylate methyl [ka] Imidazole hydrochloride (37 mg, 0.354 mmol, 0.10 equiv) was dissolved in a solution of methyl 4,5-diamino-2-methoxybenzoate (710 mg, 3.535 mmol, 1.00 equiv, 97%) in DMF (10 mL). The resulting mixture was stirred at 150° C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give methyl 6-methoxy-1H-1,3-benzodiazole-5-carboxylate (510 mg, 59%) as a yellow oil.

[0300] Step 3: Mixture of 4-((6-methoxy-5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenyl-boronic acid (19a) and 4-((5-methoxy-6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)-phenyl-boronic acid (19b) [ka] The title compound was synthesized by the method described in Example 7, except that methyl 6-methoxy-1H-1,3-benzodiazole-5-carboxylate (480 mg, 1.979 mmol, 1.00 equiv, 85% purity) was used instead of 1H-1,3-benzodiazole-5-carbonitrile. Yield: 600 mg (86% purity) of a mixture of 4-((6-methoxy-5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenyl-boronic acid (19a) and 4-((5-methoxy-6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)-phenyl-boronic acid (19b). MS (ESI, positive ion) m / z: 341.3 (M+1).

[0301] Step 4: 4-((6-carbamoyl-5-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (19c) and 4-((5-carbamoyl-6-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (19d) [ka] The title compound was synthesized by the method described in Step 2 of Example 14, except that a mixture of 4-((6-methoxy-5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid and 4-((5-methoxy-6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (250 mg, 0.712 mmol, 1.00 equiv, 97% purity) was used as the starting material. The crude product was purified by preparative HPLC using the following column conditions: XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; Mobile phase A: water (10 mmol / L ammonium carbonate + 0.1% aqueous ammonia), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 10% B to 15% B in 10 min, 220 and 254 nm. The fractions containing the desired product were combined and lyophilized to give two fractions.

[0302] Fraction 1: Rt: 7.38 min. 24.4 mg (10%) of 4-((6-carbamoyl-5-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (19c) as a white solid. MS (ESI, positive ion) m / z: 326.3 (M+1). 1 H-NMR:(300MHz,DMSO-d6,ppm)δ 8.45(s,1H),7.96(s,1H),7.78-7.59(m,3H),7.50-7.35(m,2H),7.21-7.18(m,2H),5.51(s,2H),3.92(s,3H).

[0303] Fraction 2: Rt: 8.88 min. 23.9 mg (9% yield) of 4-((5-carbamoyl-6-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (19d) as an off-white solid. MS (ESI, positive ion) m / z: 326.3 (M+1). 1 H-NMR:(300MHz,DMSO-d6,ppm)δ 8.38(s,1H),8.15-8.06(m,3H),7.77-7.67(m,3H),7.46(s,1H),7.34-7.26(m,3H),5.52(s,2H),3.88(s,3H).

[0304] Example 20 Synthesis of (4-((6-carbamoyl-2-ethyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (20a) and 4-((5-carbamoyl-2-ethyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (20b) [ka] Step 1: 2-ethyl-1H-1,3-benzodiazole-5-carboxylate methyl [ka] To a solution of methyl 3,4-diaminobenzoate (500 mg, 3.01 mmol, 1.00 equiv.) in N,N-dimethylpropenamide (5 mL) was added 1H-imidazole hydrochloride (63 mg, 0.60 mmol, 0.20 equiv.) at room temperature. After stirring at 140 °C for 24 h, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate = 7:3) to give 0.36 g (51%) of methyl 2-ethyl-1H-1,3-benzodiazole-5-carboxylate as a brown solid. 1 H-NMR:(400MHz,DMSO-d6,ppm)δ 12.79-12.33(brs,1H),8.08(s,1H),7.78(dd,J=8.4,1.6Hz,1H),7.55(d,J=8.4Hz,1H),3.85(s,3H),2.87(q,J=8.0Hz,2H),1.33(t,J=7.6Hz,3H).

[0305] Step 2: 2-Ethyl-1H-1,3-benzodiazole-5-carboxylic acid [ka] To a solution of methyl 2-ethyl-1H-1,3-benzodiazole-5-carboxylate (300 mg, 1.47 mmol, 1.00 equiv.) in methanol (5 mL) was added sodium hydroxide (176 mg, 4.41 mmol, 3.00 equiv.) and water (2 mL) at room temperature. After stirring at room temperature for 1 hour, the mixture was adjusted to pH = 3 with 2N hydrogen chloride (3 mL), and a white precipitate formed. The solid was collected by filtration, washed with water, and dried under reduced pressure to give 0.25 g (89%) of 2-ethyl-1H-1,3-benzodiazole-5-carboxylic acid as an off-white solid.

[0306] Step 3: 2-Ethyl-1H-1,3-benzodiazole-5-carboxamide [ka] 2-Ethyl-1H-1,3-benzodiazole-5-carboxylic acid (250 mg, 1.31 mmol, 1.00 equiv.) was added to thionyl chloride (15 mL) to give a suspension that was stirred at 80° C. for 1 hour. The mixture was concentrated under reduced pressure to give the intermediate acid chloride as a brown solid, which was suspended in dichloromethane and slowly added to a stirred solution of ammonia in methanol (10 mL, 7 M, 70 mmol, 53.26 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give 0.23 g (92%) of 2-ethyl-1H-1,3-benzodiazole-5-carboxamide as a yellow solid.

[0307] Step 4: (4-((6-carbamoyl-2-ethyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (20a) and 4-((5-carbamoyl-2-ethyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (20b) [ka] To a suspension of sodium hydride (44 mg, 1.82 mmol, 1.50 equiv.) in N,N-dimethylformamide (5 mL) was added a solution of 2-ethyl-1H-1,3-benzodiazole-5-carboxamide (230 mg, 1.22 mmol, 1.00 equiv.) in N,N-dimethylformamide (5 mL) at 0° C. After stirring for 30 minutes at 0° C., a solution of 4-(bromomethyl)phenylboronic acid (313 mg, 1.46 mmol, 1.20 equiv.) in N,N-dimethylformamide (2 mL) was added at the same temperature. The resulting mixture was further stirred at room temperature for 2 hours. The reaction mixture was quenched with 2N hydrogen chloride (5 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following column conditions: XBridge C18 OBD column, 100 Å, 19×250, 5 μm; Mobile phase A: water (0.05% FA), Mobile phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 7% B to 14% B in 7 min; 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give two fractions.

[0308] Fraction 1: Rt = 5.35 min. 23.4 mg (5% yield) of (4-((6-carbamoyl-2-ethyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (20a) as a white solid. MS (ESI, positive ion) m / z: 323.8 (M+1). 1 H-NMR:(400MHz,DMSO-d6,ppm)δ 8.04(d,J=1.6Hz,1H),8.01(s,2H),7.90(s,1H),7.78-7.70(m,3H),7.62(d,J=8.4Hz,1H),7 .26(s,1H),7.04(d,J=7.9Hz,2H),5.52(s,2H),2.86(q,J=7.5Hz,2H),1.28(t,J=7.5Hz,3H).

[0309] Fraction 2: Rt = 7.13 min. 17.5 mg (4% yield) of 4-((5-carbamoyl-2-ethyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (20b) as a white solid. MS (ESI, positive ion) m / z: 324.4 (M+1). 1 H-NMR:(400MHz,DMSO-d6,ppm)δ 12.69(s,0.7HCOOH),8.16(d,J=1.6Hz,1H),8.13(s,0.7HCOOH),8.02(s,2H),7.92(s,1H),7.76-7.70(m,3H),7.5 0(d,J=8.4Hz,1H),7.23(s,1H),7.04(d,J=8.1Hz,2H),5.52(s,2H),2.86(q,J=7.5Hz,2H),1.28(t,J=7.5Hz,3H).

[0310] Example 21 Synthesis of 4-((5-(methoxycarbonyl)indazol-1-yl)methyl)phenylboronic acid (21a), 1-(4-boronobenzyl)-1H-indazole-5-carboxylic acid (21b), and 4-((5-carbamoylindazol-1-yl)methyl)phenylboronic acid (21c) [ka] Step 1: 4-((5-(methoxycarbonyl)indazol-1-yl)methyl)phenylboronic acid (21a) [ka] To a stirred solution of methyl 1H-indazole-5-carboxylate (300 mg, 1.70 mmol, 1.00 equiv.) in methanol (15 mL) was added 4-(bromomethyl)phenylboronic acid (439 mg, 2.04 mmol, 1.20 equiv.) and potassium carbonate (471 mg, 3.41 mmol, 2.00 equiv.) at room temperature. After stirring at 80 °C overnight, the resulting mixture was filtered. The filter cake was washed with methanol. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following column conditions: Sunfire prep C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 28% B to 36% B in 11 min; elution wavelengths at 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give the title compound. Fraction 1: Rt: 7.8 min. 220 mg (37% yield) of 4-((5-(methoxycarbonyl)indazol-1-yl)methyl)phenylboronic acid (21a) as a white solid. 1 H-NMR:(300MHz,DMSO-d6,ppm)δ 8.51(dd,J=1.6,0.8Hz,1H),8.32(d,J=0.9Hz,1H),8.01(s,2H),7.97-7.89(m,1H),7.8 1(m,1H),7.74-7.66(m,2H),7.18(d,J=8.0Hz,2H),5.71(s,2H),3.87(d,J=1.5Hz,3H).

[0311] Step 2: 1-((4-(dihydroxyboranyl)phenyl)methyl)indazole-5-carboxylic acid and 4-((5-carbamoylindazol-1-yl)methyl)phenylboronic acid [ka] A solution of 4-((5-(methoxycarbonyl)indazol-1-yl)methyl)phenylboronic acid (21a) (220 mg, 0.64 mmol, 1.00 equiv, 90% purity) in aqueous ammonia (10 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following column conditions: Sunfire prep C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 50% B in 7 min; elution at 220 and 254 nm. The fractions containing the desired product were combined and lyophilized to give two fractions.

[0312] Fraction 1: Rt: 5.42 min. 32.8 mg (17%) of 1-((4-(dihydroxyboranyl)phenyl)methyl)indazole-5-carboxylic acid (22c) as a white solid. MS (ESI, positive ion) m / z: 297.2 (M+1). 1 H-NMR:(300MHz,DMSO-d6,ppm)δ 12.79(s,1H),8.50-8.42(m,1H),8.33-8.25(m,1H),8.04-7.87(m,3H),7.82-7.67(m,3H),7.24-7.14(m,2H),5.71(s,2H).

[0313] Fraction 2: Rt: 6.50 min. 50.9 mg (27% yield) of 4-((5-carbamoylindazol-1-yl)methyl)phenylboronic acid (22d) as a white solid. MS (ESI, positive ion) m / z: 295.9 (M+1). 1 H-NMR:(300MHz,DMSO-d6,ppm)δ 8.37(d,J=1.3Hz,1H),8.25(d,J=0.9Hz,1H),8.01(s,3H),7.91(dd,J=8.8,1.6 Hz,1H),7.78-7.67(m,3H),7.33-7.27(m,1H),7.22-7.13(m,2H),5.70(s,2H).

[0314] Example 22 Synthesis of (4-((6-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (22a) and (4-((5-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (22b) [ka] Step 1: 2-methyl-1H-1,3-benzodiazole-5-carboxylate methyl [ka] To a stirred solution of methyl 3,4-diaminobenzoate (1.00 g, 6.02 mmol, 1.00 equiv.) in dimethylacetamide (15 mL) was added imidazole hydrochloride (307 mg, 3.01 mmol, 0.50 equiv.) at room temperature. After stirring at 150 °C for 8 h, the mixture was poured into water. The aqueous layer was extracted with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA 4:1) to give 0.95 g (71% yield) of methyl 2-methyl-1H-1,3-benzodiazole-5-carboxylate as a brown solid.

[0315] Step 2: 2-methyl-1H-1,3-benzodiazole-5-carboxylic acid [ka] To a stirred solution of methyl 2-methyl-1H-1,3-benzodiazole-5-carboxylate (500 mg, 2.63 mmol, 1.00 equiv, 86%) in MeOH (5.00 mL) and HO (5.00 mL) was added NaOH (210 mg, 5.23 mmol, 2 equiv) at room temperature. After stirring for 2 h at room temperature, the mixture was acidified with concentrated hydrochloric acid to pH 4-5 at 0 °C. The precipitated solid was collected by filtration, washed with water, and dried in vacuo to give 300 mg (74% yield) of 2-methyl-1H-1,3-benzodiazole-5-carboxylic acid.

[0316] Step 3: 2-methyl-1H-1,3-benzodiazole-5-carboxamide [ka] A suspension of 2-methyl-1H-1,3-benzodiazole-5-carboxylic acid (300 mg, 1.70 mmol, 1.00 equiv) in thionyl chloride (10 mL) was stirred at 80° C. for 1 h. After cooling to room temperature, the mixture was evaporated to dryness under reduced pressure. The residue was suspended in dichloromethane (10 mL) and slowly added to a stirred solution of ammonia in methanol (10 mL, 7 M, 70 mmol, 41.11 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give 180 mg (60% yield) of 2-methyl-1H-1,3-benzodiazole-5-carboxamide as an off-white solid. MS (ESI, positive ion) m / z: 176.25 (M+1).

[0317] Step 4: (4-((6-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-boronic acid 22a and (4-((5-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-phenyl)boronic acid 22b [ka] To a suspension of sodium hydride (43 mg, 1.78 mmol, 2.0 equiv) in N,N-dimethylformamide (8 mL) was added 1H-1,3-benzodiazole-5-carboxamide (180 mg, 0.89 mmol, 1.00 equiv, 80%) at 0 °C. After stirring at 0 °C for 30 min, 4-(bromomethyl)phenylboronic acid (230 mg, 1.07 mmol, 1.20 equiv) was added at room temperature, and the mixture was further stirred at room temperature for 2 h. The mixture was quenched with 2 N hydrogen chloride and concentrated under reduced pressure. The residue was purified by preparative HPLC using a column: Sunfire prep C18 column, 30*150, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2 B to 9 B in 10 min; 254 / 220 nm; RT1: 7.62; RT2: 9.32; injection volume: ml; run number:. The fractions containing the desired product were combined and lyophilized to obtain two fractions.

[0318] Fraction 1: Rt: 7.62 min. 84 mg (29% yield) of 4-((6-carbamoyl-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (22a) as a white solid. MS (ESI, positive ion) m / z: 310.3 (M+1). 1 H NMR(300MHz,DMSO-d6)δ 12.95-12.63(s,0.3HCOOH),δ 8.20-7.91(m,4H),7.73(d,J=7.8Hz,3H),7.50(d,J=8.5Hz,1H),7.24(s,1H),7.07(d,J=7.9Hz,2H),5.51(s,2H),2.53(s,3H).

[0319] Fraction 2: Rt: 9.32 min. 110 mg (37% yield) of 4-((5-carbamoyl-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (22b) as a white solid. MS (ESI, positive ion) m / z: 310.3 (M+1). 1H NMR(300MHz,DMSO-d6)δ 8.14(s,1H),8.05(s,2H),7.92(s,1H),7.74(d,J=7.7Hz,3H),7.58(d,J=8.4H z,1H),7.28(s,1H),7.07(d,J=7.7Hz,2H),5.51(s,2H),2.54(d,J=2.2Hz,3H).

[0320] Example 23 Synthesis of 4-((6-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (23a) and 4-((5-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (23b) [ka] Step 1: 2-isopropyl-1H-1,3-benzodiazole-5-carboxylate methyl [ka] The title compound was synthesized by the method described in Step 1 of Example 22, except that N,N-dimethylisobutyramide (5 mL) was used instead of dimethylacetamide.

[0321] Step 2: 2-Isopropyl-1H-1,3-benzodiazole-5-carboxylic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 22, except that methyl 2-isopropyl-1H-1,3-benzodiazole-5-carboxylate (220 mg) and sodium hydroxide (121 mg, 3.02 mmol, 3.00 equiv.) were used.

[0322] Step 3: 2-Isopropyl-1H-1,3-benzodiazole-5-carboxamide [ka] The title compound was synthesized by the method described in Step 3 of Example 22, except that 2-isopropyl-1H-1,3-benzodiazole-5-carboxylic acid (180 mg) was used.

[0323] Step 4: 4-((6-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (23a) and 4-((5-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (23b) [ka] The title compound was synthesized by the method described in Step 4 of Example 22, except that 2-isopropyl-1H-1,3-benzodiazole-5-carboxamide (160 mg) was used. The crude product was purified by preparative HPLC using the following conditions: column: XBridge C18 OBD column, 100 Å, 19×250, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 7% B to 15% B in 7 min; at 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give two fractions.

[0324] Fraction 1: Rt = 5.55 min. 43.4 mg (16% yield) of 4-((6-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (23a) as a white solid. MS (ESI, positive ion) m / z: 338.3 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 8.06-8.01(m,3H),7.90(s,1H),7.76-7.67(m,3H),7.62(d,J=8.3Hz,1H),7.59(s, 1H),7.00(d,J=8.0Hz,2H),5.56(s,2H),3.31-3.22(m,1H),1.24(d,J=6.8Hz,6H).

[0325] Fraction 2: Rt = 7.22 min. 37.6 mg (13% yield) of 4-((5-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (23b) as a white solid. MS (ESI, positive ion) m / z: 338.4 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 8.16(s,1H),8.03(s,2H),7.91(s,1H),7.74-7.70(m,3H),7.46(d,J=8.4Hz,1H),7.2 4(s,1H),7.00(d,J=8.0Hz,2H),5.55(s,2H),3.31-3.22(m,1H),1.24(d,J=6.8Hz,6H)

[0326] Example 24 Synthesis of 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylphosphonic acid [ka] Step 1: methyl 3-((4-bromophenyl)methyl)-1,3-benzodiazole-5-carboxylate and methyl 1-((4-bromophenyl)methyl)-1,3-benzodiazole-5-carboxylate [ka] Methyl 1H-1,3-benzodiazole-5-carboxylate (1.50 g, 8.51 mmol, 1.00 equiv.) was dissolved in MeOH (20.00 mL). 1-Bromo-4-(bromomethyl)benzene (2.56 g, 10.22 mmol, 1.20 equiv.) and CsCO (3.61 g, 11.07 mmol, 1.30 equiv.) were then added. After stirring at room temperature for 12 hours, the reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: DCM / MEOH 98:2) to give 2.3 g (77% yield) of a mixture of methyl 3-((4-bromophenyl)methyl)-1,3-benzodiazole-5-carboxylate and methyl 1-((4-bromophenyl)methyl)-1,3-benzodiazole-5-carboxylate as a yellow solid.

[0327] Step 2: 3-((4-(diethoxyphosphoryl)phenyl)methyl)-1,3-benzodiazole-5-carboxylate and methyl 1-((4-(diethoxyphosphoryl)phenyl)methyl)-1,3-benzodiazole-5-carboxylate [ka] To a mixture of methyl 3-((4-bromophenyl)methyl)-1,3-benzodiazole-5-carboxylate and methyl 1-((4-bromophenyl)methyl)-1,3-benzodiazole-5-carboxylate (1.20 g, 3.44 mmol, 1.00 equiv, 99%) in THF (15.00 mL) was added diethyl phosphite (0.62 g, 4.47 mmol, 1.30 equiv), CsCO (1.68 g, 5.16 mmol, 1.50 equiv), and Pd(PPh) (398 mg, 0.34 mmol, 0.10 equiv) at room temperature. The resulting mixture was irradiated in a microwave reactor at 100 °C for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: DCM / MeOH 96:4) to give 0.8 g (yield 56%) of a mixture of methyl 3-((4-(diethoxyphosphoryl)phenyl)methyl)-1,3-benzodiazole-5-carboxylate and methyl 1-((4-(diethoxyphosphoryl)phenyl)methyl)-1,3-benzodiazole-5-carboxylate (ratio=1:1) as a yellow solid.

[0328] Step 3: Diethyl 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylphosphonate [ka] A mixture of methyl 3-((4-(diethoxyphosphoryl)phenyl)methyl)-1,3-benzodiazole-5-carboxylate and methyl 1-((4-(diethoxyphosphoryl)phenyl)methyl)-1,3-benzodiazole-5-carboxylate (700 mg, 1.69 mmol, 1.00 equiv) was added to NH3-HO (15.00 mL). After stirring at 80 °C for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.05% NH3HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 13 B to 16 B in 7 min; 254 / 220 nm; RT 5.48; injection volume: ml; run number to give 80 mg (12% yield) of diethyl 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylphosphonate as a white solid. MS (ESI, positive ion) m / z: 388.00 (M+1). 1 H NMR(300MHz,Methanol-d4)δ 8.46(s,1H),8.30(dd,J=1.7,0.7Hz,1H),7.93-7.69(m,3H),7.56-7.35(m,3H),5.66(s,2H),4.10(m,4H),1.31(m,6H).

[0329] Step 4: 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylphosphonic acid [ka] To a stirred solution of diethyl 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylphosphonate (75.00 mg, 0.19 mmol, 1.00 equiv.) in DCM (5.00 mL) was added bromotrimethylsilane (296.40 mg, 1.97 mmol, 10.00 equiv.) dropwise at room temperature. The resulting mixture was stirred at room temperature for 12 hours. The reaction was quenched by the addition of MeOH (5 mL). After concentration under reduced pressure, the crude product was washed with hexane (5 mL) and MeOH / DCM = 1:1 (5 mL × 2) to give 25.3 mg (39% yield) of 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylphosphonic acid as a white solid. MS (ESI, positive ion) m / z: 332.25 (M+1). 1 H NMR(300MHz,DMSO-d6)δ 9.40(d,J=4.0Hz,1H),8.31(d,J=1.5Hz,1H),8.14(s,1H),7.97(dd,J=8.7,1.5Hz,1H ),7.79(d,J=8.6Hz,1H),7.74-7.61(m,2H),7.48(dd,J=8.1,3.2Hz,3H),5.76(s,2H).

[0330] Example 25 Synthesis of diethyl (4-((4-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)phenyl)phosphonate (25a) and 4-((4-hydroxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylphosphonic acid (25b) [ka] Step 1: 4-Methoxy-1H-pyrazolo[4,3-c]pyridine [ka] To 4-chloro-1H-pyrazolo[4,3-c]pyridine (1.00 g, 6.51 mmol, 1.00 equiv.) was added NaOMe (17.00 mL, 30% in MeOH) at room temperature. The resulting mixture was stirred in an oil bath at 120° C. for 12 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give 4-methoxy-1H-pyrazolo[4,3-c]pyridine (520 mg, 52.29% yield) as a white solid. MS (ESI, positive ion) m / z: 149.95 (M+1).

[0331] Step 2: Diethyl 4-((4-methoxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylphosphonate (96a) [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 4-methoxy-1H-pyrazolo[4,3-c]pyridine (250.00 mg, 1.68 mmol) and diethyl 4-(bromomethyl)phenylphosphonate (772 mg, 2.51 mmol) were used. The crude product was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18, 30*250, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN:MEOH=4:1; flow rate: 45 mL / min; gradient: 25 B to 40 B in 10 min; 254, 220 nm; RT1: 6.48 min; RT2: 7.75 min) to give the title compound.

[0332] Fraction 1: Rt: 6.48 min. 100 mg (15.9% yield) of diethyl 4-((4-methoxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylphosphonate (25a) as a white solid. MS (ESI, positive ion) m / z: 376.10 (M+1). 1H NMR(300MHz,DMSO-d6,ppm)δ 8.42(s,1H),7.86(d,J=5.8Hz,1H),7.76-7.62(m,2H),7.45-7.35(m,2H),7 .21(d,J=5.8Hz,1H),5.61(s,2H),4.05-3.91(m,7H),1.20(t,J=7.0Hz,6H).

[0333] Step 3: 4-((4-hydroxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylphosphonic acid (25b) [ka] The title compound was synthesized by Step 2 of Example 35, except that diethyl 4-((4-methoxypyrazolo[4,3-c]pyridin-1-yl)methyl)-phenylphosphonate (100.00 mg, 0.27 mmol) was used to give 4-((4-hydroxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylphosphonic acid (25b, 16.2 mg, 19.6%). MS (ESI, positive ion) m / z: 306.20 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm / D2O)δ 11.90(s,1H),9.22(s,1H),7.72-7.62(m,2H),7.48-7.37(m,3H),6.68(d,J=7.2Hz,1H),5.64(s,2H).

[0334] Example 26 Synthesis of diethyl (4-((5-carbamoyl-1H-indazol-1-yl)methyl)phenyl)phosphonate (26a) and 4-((5-carbamoylindazol-1-yl)methyl)phenylphosphonic acid (26b) [ka] Step 1: 1H-indazole-5-carboxamide [ka] Methyl 1H-indazole-5-carboxylate (500 mg, 2.84 mmol, 1.00 equiv.) in NH3.HO (10 mL) was stirred in an oil bath at 80 °C for 12 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: dichloromethane / methyl alcohol 93:7) to give 1H-indazole-5-carboxamide (122 mg, 23.3% yield) as an off-white solid. MS (ESI, positive ion) m / z: 162.20 (M+1).

[0335] Step 2: Diethyl 4-((5-carbamoylindazol-1-yl)methyl)phenylphosphonate (26a) [ka] The title compound was synthesized according to Step 2 of Example 55, except that 1H-indazole-5-carboxamide (122 mg, 0.76 mmol) and 4-(bromomethyl)phenylphosphonate (348.74 mg, 1.14 mmol) were used. The crude product was purified by preparative HPLC under the following conditions: Column: YMC-Actus Triart C18, 30*250, 5 μm; Mobile phase A: water (0.05% FA), Mobile phase B: ACN; Flow rate: 45 mL / min; Gradient: 25 B to 30 B in 7 min; 254 / 220 nm; RT1: 6.17 min; RT2: 8.20 min. The fractions containing the desired product were combined and lyophilized to give the title compound.

[0336] Fraction 1: Rt: 6.17 min. 89 mg (44.9% yield) of diethyl 4-((5-carbamoylindazol-1-yl)methyl)phenylphosphonate (26a) as a white solid. MS (ESI, positive ion) m / z: 388.25 (M+1). 1H NMR(300MHz,DMSO-d6,ppm)δ 8.38(s,1H),8.31-8.25(m,1H),8.00(s,1H),7.93(dd,J=8.9,1.5Hz,1H),7.77(d,J=8.9Hz,1H),7.67 (dd,J=12.9,7.9Hz,2H),7.34(dd,J=8.0,3.9Hz,3H),5.79(s,2H),3.98(m,4H),1.20(t,J=7.0Hz,6H).

[0337] Step 3: 4-((5-carbamoylindazol-1-yl)methyl)phenylphosphonic acid (26b) [ka] The title compound was synthesized by Step 2 of Example 85, except that diethyl 4-((5-carbamoylindazol-1-yl)methyl)phenyl-phosphonate (89 mg, 0.23 mmol) was used. (26b, 27.4 mg, 35.7%). MS (ESI, positive ion) m / z: 330.15 (M-1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.37(d,J=1.4Hz,1H),8.26(s,1H),7.98(s,1H),7.91(dd,J=8.7,1.6Hz,1H),7.7 4(d,J=8.8Hz,1H),7.59(dd,J=12.5,7.9Hz,2H),7.49-6.89(m,3H),5.72(s,2H).

[0338] Example 28 Synthesis of a mixture of (4-((5-(methylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-boronic acid (28a) and 4-((6-(methylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (28b) [ka] Step 1: 5-methanesulfonyl-1H-1,3-benzodiazole [ka] To a stirred solution of 4-methanesulfonylbenzene-1,2-diamine (150 mg, 0.81 mmol, 1.00 equiv) in N,N-dimethylformamide (4 mL) was added HMDS (130 mg, 0.805 mmol, 1.00 equiv). After stirring at 120 °C overnight, the resulting mixture was concentrated under reduced pressure. The residue was dissolved in methanol (10 mL), and the precipitated solid was collected by filtration, washed with methanol, and dried under vacuum to give 150 mg (84%) of 5-methanesulfonyl-1H-1,3-benzodiazole as a gray solid.

[0339] Step 2: Mixture of 4-((5-methanesulfonyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid and 4-((6-methanesulfonyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid [ka] To a stirred solution of 5-methanesulfonyl-1H-1,3-benzodiazole (150 mg, 0.68 mmol, 1.00 equiv, 89%) in N,N-dimethylformamide (5 mL) was added 4-(bromomethyl)phenylboronic acid (175 mg, 0.82 mmol, 1.20 equiv) and potassium carbonate (188 mg, 1.36 mmol, 2.00 equiv) at 0° C. After stirring overnight at room temperature, the resulting mixture was concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and the solid was filtered off. The filtrate was concentrated and purified by preparative HPLC using the following conditions: XBridge Shield RP18 OBD column, 19 x 250 mm, 10 μm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 20% B to 25% B in 7 min, 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give 44.5 mg (18%) of a mixture of 4-((5-methanesulfonyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (97a) and 4-((6-methanesulfonyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (97b) (1:1 ratio) as a white solid. MS (ESI, positive ion) m / z: 331.2 (M+1). 1 H-NMR:(300MHz,DMSO-d6,ppm)δ 8.71-8.67(m,1H),8.22-8.15(m,1H),8.05(s,2H),7.92-7.73(m,4H),7.28-7.25(m,2H),5.64-5.59(m,2H),3.20-3.18(m,3H).

[0340] Example 29 Synthesis of a mixture of (4-((5-cyano-1H-benzo[d]imidazol-1-yl)methyl)phenyl)phosphonic acid (29a) and (4-((6-cyano-1H-benzo[d]imidazol-1-yl)methyl)phenyl)phosphonic acid (29b) [ka] Step 1: 1-((4-bromophenyl)methyl)-1,3-benzodiazole-5-carbonitrile and 3-((4-bromophenyl)methyl)-1,3-benzodiazole-5-carbonitrile [ka] To a solution of 1H-1,3-benzodiazole-5-carbonitrile (400 mg, 2.794 mmol, 1.00 equiv.) in ethanol (10 mL) was added powdered potassium hydroxide (204 mg, 3.633 mmol, 1.30 equiv.) and 1-bromo-4-(bromomethyl)benzene (838 mg, 3.353 mmol, 1.20 equiv.). After stirring at room temperature for 12 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 97:3) to give 510 mg of a mixture of 1-((4-bromophenyl)methyl)-1,3-benzodiazole-5-carbonitrile and 3-((4-bromophenyl)methyl)-1,3-benzodiazole-5-carbonitrile as an off-white solid.

[0341] Step 2: Diethyl 4-((5-cyano-1,3-benzodiazol-1-yl)methyl)phenylphosphonate and diethyl 4-((6-cyano-1,3-benzodiazol-1-yl)methyl)phenylphosphonate [ka] To a mixture of 1-((4-bromophenyl)methyl)-1,3-benzodiazole-5-carbonitrile and 3-((4-bromophenyl)methyl)-1,3-benzodiazole-5-carbonitrile (210 mg, 0.666 mmol, 1.00 equiv., 99% purity) in tetrahydrofuran (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (77 mg, 0.067 mmol, 0.10 equiv.), cesium carbonate (282 mg, 0.866 mmol, 1.30 equiv.), and diethylphosphonate (110 mg, 0.799 mmol, 1.20 equiv.) at room temperature. The resulting mixture was irradiated in a microwave reactor at 100° C. for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 95:5) to give 225 mg (90%) of a mixture of diethyl 4-((5-cyano-1,3-benzodiazol-1-yl)methyl)phenylphosphonate and diethyl 4-((6-cyano-1,3-benzodiazol-1-yl)methyl)phenylphosphonate (ratio = 1:1) as a yellow solid. MS (ESI, positive ion) m / z: 370.35 (M+1).

[0342] Step 3: (4-((5-cyano-1H-benzo[d]imidazol-1-yl)methyl)phenyl)phosphonic acid (29a) and (4-((6-cyano-1H-benzo[d]imidazol-1-yl)methyl)phenyl)phosphonic acid (29b) [ka] To a mixture of diethyl 4-((5-cyano-1,3-benzodiazol-1-yl)methyl)phenylphosphonate and diethyl 4-((6-cyano-1,3-benzodiazol-1-yl)methyl)phenylphosphonate (210 mg, 0.563 mmol, 1.00 equiv., 99% purity) in dichloromethane (5 mL) was added bromotrimethylsilane (1.72 g, 11.257 mmol, 20 equiv.) at room temperature. The solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 19 x 250 mm, 10 μm; Mobile phase A: water (10 mmol / L ammonium bicarbonate), Mobile phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 4% B to 18% B in 7 min, 220 and 254 nm. Fractions containing the desired product were combined and lyophilized to give 119.5 mg (66%) of a mixture of (4-((5-cyano-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-phosphonic acid (29a) and (4-((6-cyano-1H-benzo[d]imidazol-1-yl)methyl)phenyl)phosphonic acid (29b) (ratio=1:1) as a white solid. MS (ESI, positive ion) m / z: 314.2 (M+1). 1 H-NMR:(300MHz,DMSO-d6,ppm)δ 8.69(d,J=10.7Hz,1H),8.22(s,1H),7.84(d,J=8.4Hz,1H),7.72-7.53(m,3H),7.36-6.80(m,4H),5.54(s,2H).

[0343] Example 30 Synthesis of 4-((5-carbamoyl-4-methoxyindol-1-yl)methyl)phenylboronic acid [ka] Step 1: 4-amino-5-chloro-2-methoxybenzoate [ka] To a stirred solution of methyl 4-amino-2-methoxybenzoate (5.00 g, 27.595 mmol, 1.00 equiv.) in DMF (50.00 mL) was added NCS (3.70 g, 27.709 mmol, 1.00 equiv.) at room temperature. The resulting mixture was stirred in an oil bath at 70 °C for 12 h and then quenched with water at room temperature. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluted with PE / EtOAc (30:70) to give methyl 4-amino-5-chloro-2-methoxybenzoate (4.9 g, 82.4% yield) as a yellow-green solid.

[0344] Step 2: 4-amino-5-chloro-3-iodo-2-methoxybenzoate [ka] To a solution of methyl 4-amino-5-chloro-2-methoxybenzoate (0.80 g, 3.71 mmol, 1.00 equiv.) in AcOH (20.00 mL) was added NIS (0.83 g, 3.71 mmol, 1.00 equiv.). After stirring at room temperature for 4 h, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to afford 1.0 g (79% yield) of methyl 4-amino-5-chloro-3-iodo-2-methoxybenzoate as a white solid.

[0345] Step 3: 7-chloro-4-methoxy-2-(trimethylsilyl)-1H-indole-5-carboxylate methyl [ka] To a mixture of methyl 4-amino-5-chloro-3-iodo-2-methoxybenzoate (1.00 g, 2.93 mmol, 1.00 equiv.) in THF (30.00 mL) was added ethynyltrimethylsilane (0.48 g, 5.85 mmol, 2.00 equiv.), K2CO3 (0.81 g, 5.86 mmol, 2.00 equiv.), X-Phos (0.28 g, 0.59 mmol, 0.20 equiv.), and Pd(PPh3)4 (0.34 g, 0.29 mmol, 0.10 equiv.). After stirring overnight at 80 °C under an argon atmosphere, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on 120 g of silica gel (eluent: petroleum ether-ethyl acetate 100%, 8:1) to give methyl 7-chloro-4-methoxy-2-(trimethylsilyl)-1H-indole-5-carboxylate (350 mg, 31% yield) as a brown solid.

[0346] Step 4: 7-chloro-4-methoxy-1H-indole-5-carboxylate methyl [ka] To a mixture of methyl 7-chloro-4-methoxy-2-(trimethylsilyl)-1H-indole-5-carboxylate (350.00 mg, 1.122 mmol, 1.00 equiv.) in DCM (10.00 mL) was added TFA (2 mL). After stirring at room temperature for 3 hours, the reaction mixture was poured into water. The aqueous layer was extracted with DCM, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether-ethyl acetate 100%, 8:1) to give methyl 7-chloro-4-methoxy-1H-indole-5-carboxylate (250 mg, 87% yield) as a brown solid.

[0347] Step 5: 4-Methoxy-1H-indole-5-carboxylate methyl [ka] To a mixture of methyl 7-chloro-4-methoxy-1H-indole-5-carboxylate (265 mg, 1.10 mmol, 1.00 equiv) in MeOH (5.00 mL) was added Pd / C (30 mg). After stirring for 24 h, the resulting mixture was filtered through Celite. The filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on 40 g of silica gel (eluent: petroleum ether-ethyl acetate 100%, 5:1) to give 4-methoxy-1H-indole-5-carboxamide (210 mg, 94.9% yield) as a light brown solid.

[0348] Step 6: 4-Methoxy-1H-indole-5-carboxamide [ka] A mixture of methyl 4-methoxy-1H-indole-5-carboxylate (210 mg, 1.02 mmol, 1.00 equiv) in aqueous ammonia (10 mL) was stirred at 80° C. for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on 100 g of silica gel (eluent: MeOH / DCM 100%, 5:95) to give 4-methoxy-1H-indole-5-carboxamide (150 mg, 77% yield) as a light brown solid.

[0349] Step 7: 4-((5-carbamoyl-4-methoxyindol-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by Step 4 of Example 22, except that 4-methoxy-1H-indole-5-carboxamide (150 mg, 0.79 mmol) was used. The crude product was purified by preparative HPLC under the following conditions: Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 9 B to 35 B in 7 min; 254 / 220 nm; RT: 2.95 min) to afford 8.8 mg (3.3% yield) of 4-((5-carbamoyl-4-methoxyindol-1-yl)methyl)phenylboronic acid as a white solid. MS (ESI, positive ion) m / z: 325.30 (M+1). 1 H-NMR(300MHz,DMSO-d6,ppm)δ 8.01(s,2H),7.79-7.46(m,5H),7.34(s,1H),7.18(dd,J=16.9,8.1Hz,3H),6.75(s,1H),5.43(s,2H),4.10(d,J=1.8Hz,3H).

[0350] Example 31 Synthesis of 4-((4-carbamoylindol-1-yl)methyl)phenylboronic acid [ka] Step 1: Indole-4-carboxamide [ka] To a solution of 1H-indole-4-carbonitrile (100 mg, 0.70 mmol, 1.00 equiv) in a mixture of EtOH (4.00 mL) and HO (1.00 mL) was added Parkins' catalyst (30.05 mg, 0.070 mmol, 0.10 equiv) at room temperature and stirred at 100° C. for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give indole-4-carboxamide (85 mg, 75%) as a pale yellow solid.

[0351] Step 2: 4-((4-carbamoylindol-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by Step 4 of Example 22, except that indole-4-carboxamide (85 mg, 0.53 mmol) was used. The residue was purified by preparative HPLC (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 18 B to 30 B in 7 min; 254 / 220 nm; RT: 6.93 min) to afford 53.4 mg (33.1% yield) of 4-((4-carbamoylindol-1-yl)methyl)phenylboronic acid as a white solid. MS (ESI, positive ion) m / z: 295.25 (M+1). 1 H-NMR(300MHz,DMSO-d6,ppm)δ 8.00(d,J=4.4Hz,2H),7.72(s,1H),7.70-7.67(m,2H),7.61-7.54(m,2H),7.47(d, J=7.3Hz,1H),7.22(s,1H),7.17-7.08(m,3H),6.95(d,J=3.1Hz,1H),5.47(s,2H).

[0352] Example 32 Synthesis of 4-(imidazo[4,5-c]pyridin-3-ylmethyl)phenylboronic acid (32a) and 4-(imidazo[4,5-c]pyridin-1-ylmethyl)phenylboronic acid (32b) [ka] A mixture of the title compounds was synthesized according to Example 13, except that 3,5-diazaindole (238 mg, 1.998 mmol, 1.00 equiv.) was used. Yield: 112.1 mg (21% purity) of 4-(imidazo[4,5-c]pyridin-3-ylmethyl)phenylboronic acid (32a) and 4-(imidazo[4,5-c]pyridin-1-ylmethyl)phenylboronic acid (32b). MS (ESI, positive ion) m / z: 254.3 (M+1). 1H-NMR(300MHz,DMSO-d6,ppm)δ 9.27-9.21(m,1H),8.49-8.40(m,1H),8.23-8.17(m,1H),7.84-7.78(m,3H),7.39-7.29(m,2H),5.68-5.62(m,2H).

[0353] Example 33 Synthesis of 4-((6-cyanoimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (33a) and 4-((6-cyanoimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (33b) [ka] Step 1: 3H-Imidazo[4,5-c]pyridine-6-carbonitrile [ka] A solution of 3H-imidazo[4,5-c]pyridine-6-carboxamide (80 mg, 0.493 mmol, 1.00 equiv) in POCl (8.00 mL) was stirred at 110 °C in an oil bath for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: EA / MEOH 85:15) to give 88 mg (55% yield) of 3H-imidazo[4,5-c]pyridine-6-carbonitrile as a white solid.

[0354] Step 2: Mixture of 4-((6-cyanoimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (33a) and 4-((6-cyanoimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (33b) [ka] The title compound was synthesized according to Step 4 of Example 22, except that 3H-imidazo[4,5-c]pyridine-6-carbonitrile (78 mg, 0.54 mmol) was used. The crude product was purified by preparative HPLC under the following conditions: (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5 B to 30 B in 10 min; 254:220 nm) to afford 26.2 mg (34% yield) of a mixture of 4-((6-cyanoimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (33a) and 4-((6-cyanoimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (33b) as a white solid. MS (ESI, positive ion) m / z: 279.20 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 9.10(d,J=8.7Hz,1H),8.88(dd,J=8.6,2.5Hz,1H),8.56-8.44(m,1H),8.08( s,2H),7.76(d,J=7.6Hz,2H),7.35(d,J=7.6Hz,2H),5.64(d,J=23.7Hz,2H).

[0355] Example 34 Synthesis of 4-((5-cyanoimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (34a) and 4-((5-cyanoimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (34b) [ka] Step 1: 1H-Imidazo[4,5-b]pyridine-5-carbonitrile [ka] The title compound was synthesized by Step 1 of Example 33, except that 1H-imidazo[4,5-b]pyridine-5-carboxamide (150 mg, 0.93 mmol) was used. Yield: 130 mg (91.0%) as an off-white solid.

[0356] Step 2: 4-((5-cyanoimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (34a) and 4-((5-cyanoimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (34b) [ka] The title compound was synthesized by the method described in Step 4 of Example 22, except that 1H-imidazo[4,5-b]pyridine-5-carbonitrile (150 mg, 1.04 mmol) was used. The crude product was purified by preparative HPLC under the following conditions (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5 B to 30 B in 10 min; 254 / 220 nm; RT1: 8.82 min; RT2: 9.12 min) to obtain two fractions.

[0357] Fraction 1: Rt: 8.82 min, 20.7 mg (7.07% yield) of 4-((5-cyanoimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (34b) as a white solid. MS (ESI, positive ion) m / z: 278.85 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.98(s,1H),8.23(d,J=8.2Hz,1H),8.07(s,2H),7.89(d,J=8.3Hz,1H),7.75(d,J=7.8Hz,2H),7.31(d,J=7.8Hz,2H),5.61(s,2H).

[0358] Fraction 2: Rt: 9.12 min. 16.4 mg (5.42% yield) of 4-((5-cyanoimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (34a) as a white solid. MS (ESI, positive ion) m / z: 279.20 (M+1). 1H-NMR(400MHz,DMSO-d6,ppm)δ 8.94(s,1H),8.36(d,J=8.2Hz,1H),8.07(s,2H),7.93(d,J=8.2Hz,1H),7.78-7.72(m,2H),7.29(d,J=7.7Hz,2H),5.56(s,2H).

[0359] Example 35 Synthesis of 4-((4-hydroxyindol-1-yl)methyl)phenylboronic acid [ka] Step 1: 4-((4-methoxyindol-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 4 of Example 22, except that 4-methoxy-1H-indole (200 mg, 1.36 mmol) was used. Yield: 200 mg (52.0%) as a light brown solid.

[0360] Step 2: 4-((4-hydroxyindol-1-yl)methyl)phenylboronic acid [ka] To a solution of 4-((4-methoxyindol-1-yl)methyl)phenylboronic acid (180 mg, 0.640 mmol, 1.00 equiv) in DCM (5.00 mL) was added BBr3 (1.00 mL). The resulting mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: Column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 41 B to 42 B in 7 min; 254 / 220 nm; RT: 6.3 min) to afford 17.8 mg (9.3% yield) of 4-((4-hydroxyindol-1-yl)methyl)phenylboronic acid as a white solid. MS (ESI, positive ion) m / z: 268.10 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 9.40(s,1H),8.01(s,2H),7.74-7.65(m,2H),7.31(d,J=3.2Hz,1H),7.11(d,J=7.8Hz,2H) ,6.92-6.78(m,2H),6.52(dd,J=3.2,0.6Hz,1H),6.37(dd,J=6.7,1.7Hz,1H),5.34(s,2H).

[0361] Example 36 Synthesis of 4-((4-hydroxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (36a) and 4-((7-hydroxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (36b) [ka] Step 1: 4-((4-methoxyindol-1-yl)methyl)phenylboronic acid and 4-((7-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 4 of Example 22, except that 4-methoxy-1H-1,3-benzodiazole (200 mg, 1.35 mmol) was used. Yield: 220 mg (57.2%) of a mixture of 4-((4-methoxyindol-1-yl)methyl)phenylboronic acid and 4-((7-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (ratio=1:1) as a light brown solid.

[0362] Step 2: 4-((4-hydroxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (36a) and 4-((7-hydroxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (36b) [ka] The title compound was synthesized by the method described in Step 2 of Example 35, except that 4-((4-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (150 mg, 0.532 mmol) was used. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge C18 OBD Prep Column, 19 mm × 250 μm; Mobile Phase A: Water (10 mmol / L, NH4HCO3 + 0.1% NH3.HO), Mobile Phase B: ACN; Flow Rate: 25 mL / min; Gradient: 10 B to 30 B in 7 min; 254 / 220 nm; RT1: 6.67 min; RT2: 6.99 min) to give two fractions.

[0363] Fraction 1: Rt: 6.67 min. 41.2 mg (28.0% yield) of 4-((7-hydroxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (36b) as a white solid. MS (ESI, positive ion) m / z: 269.25 (M+1). 1H NMR(300MHz,DMSO-d6,ppm)δ 9.97(s,1H),8.25(s,1H),8.01(s,2H),7.85-7.65(m,2H),7.26-7.06(m,3H),6.96(t,J=7.9Hz,1H),6.59(dd,J=7.7,1.0Hz,1H),5.63(s,2H).

[0364] Fraction 2: Rt: 6.99 min. 11.9 mg (8.1% yield) of 4-((4-hydroxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (36a) as a white solid. MS (ESI, positive ion) m / z: 269.30 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 9.77(s,1H),8.24(s,1H),8.03(s,2H),7.77-7.69(m,2H),7.22(d,J=8.0 Hz,2H),6.90(t,J=7.9Hz,2H),6.54(dd,J=7.6,1.1Hz,1H),5.43(s,2H).

[0365] Example 37 Synthesis of 4-((4-hydroxy-2-methylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (37a) and 4-((4-hydroxy-2-methylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (37b) [ka] Step 1: 4-Methoxy-2-methyl-1H-imidazo[4,5-c]pyridine [ka] To a stirred solution of 2-methoxypyridine-3,4-diamine (300 mg, 2.156 mmol, 1.00 equiv) in MeOH (5.00 mL) was added Pd / C (210 mg, 1.078 mmol, 0.5 equiv) and acetaldehyde (95 mg, 1.617 mmol, 1.50 equiv). After stirring in an oil bath at 120 °C for 12 h, the mixture was concentrated under reduced pressure. After stirring for 24 h, the resulting mixture was filtered through Celite, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, eluent: ethyl acetate / petroleum ether 3:2) to give 4-methoxy-2-methyl-1H-imidazo[4,5-c]pyridine (300 mg, 56.3% yield) as a white solid.

[0366] Step 2: 4-((4-hydroxy-2-methylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (37a) and 4-((4-hydroxy-2-methylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (37b) [ka] NaH (101 mg, 4.204 mmol, 2 equiv.) was placed in a nitrogen-purged three-neck flask at room temperature. A solution of 4-methoxy-2-methyl-1H-imidazo[4,5-c]pyridine (343 mg, 2.10 mmol, 1.00 equiv.) in DMF (6.00 mL) was added at 0° C. After stirring for 30 minutes, 4-(bromomethyl)phenylboronic acid (542 mg, 2.522 mmol, 1.20 equiv.) was added at 0° C. The mixture was stirred for an additional hour at room temperature, then quenched with hydrochloric acid (3N, 5.0 mL) and concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge C18 OBD Prep Column, 100 Å, 5 μm, 19 mm × 250 μm; Mobile phase A: Water (0.05% FA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 5 B to 12 B in 7 min; 254 / 220 nm; RT1: 7.13 min; RT2: 8.42 min) to obtain two fractions.

[0367] Fraction 1: Rt: 7.13 min. 32.7 mg (5.3% yield) of 4-((4-hydroxy-2-methylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (37b). MS (ESI, positive ion) m / z: 284.25 (M+1). 1 H NMR(400MHz,DMSO-d6,ppm)δ 11.27(d,J=5.8Hz,1H),8.06(s,2H),7.73(d,J=7.7Hz,2H),7.09(dd,J=11.1,7.1Hz,3H),6.51(d,J=7.0Hz,1H),5.73(s,2H),2.35(s,3H).

[0368] Fraction 2: Rt: 8.42 min. 3.7 mg (0.6% yield) of 4-((4-hydroxy-2-methylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (37a) as a white solid. MS (ESI, positive ion) m / z: 284.25 (M+1). 1 H NMR(400MHz,DMSO-d6,ppm)δ 11.12(s,1H),8.45(s,2H),7.73(d,J=7.6Hz,2H),7.05(d,J=7.6Hz,3H),6.52(d,J=7.0Hz,1H),5.38(s,2H),2.39(s,3H).

[0369] Example 38 Synthesis of 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (38a) and 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (38b) [ka] Step 1: 2-Ethyl-4-methoxy-1H-imidazo[4,5-c]pyridine [ka] The compound was synthesized by Step 1 of Example 37, except that 2-methoxypyridine-3,4-diamine (500 mg, 3.59 mmol) and propionaldehyde (208 mg, 3.59 mmol) were used. Yield: 200 mg (30.8%).

[0370] Step 2: 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (38a) and 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (38b) [ka] The title compound was synthesized by Step 2 of Example 37, except that 2-ethyl-4-methoxy-1H-imidazo[4,5-c]pyridine (350 mg, 1.975 mmol) was used. The crude product was purified by preparative HPLC under the following conditions (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 8 B to 25 B in 10 min; 254 / 220 nm; RT1: 5.08 min; RT2: 6.10 min) to obtain two fractions.

[0371] Fraction 1: Rt: 5.08 min. 12.7 mg (2.1% yield) of 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (38b). MS (ESI, positive ion) m / z: 298.25 (M+1). 1 H NMR(400MHz,DMSO-d6,ppm)δ 11.27(d,J=5.7Hz,1H),8.15(d,J=39.2Hz,2H),7.73(d,J=7.6Hz,2H),7.13-7.03(m, 3H),6.55(d,J=6.9Hz,1H),5.75(s,2H),2.67(q,J=7.5Hz,2H),1.16(t,J=7.5Hz,3H).

[0372] Fraction 2: Rt: 6.10 min. 13.8 mg (2.3% yield) of 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (38a) as a white solid. MS (ESI, positive ion) m / z: 298.20 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 11.11(d,J=5.5Hz,1H),8.10(s,2H),7.74(d,J=7.8Hz,2H),7.06(dd,J=29.5,7.0Hz, 3H),6.52(d,J=7.0Hz,1H),5.39(s,2H),2.71(q,J=7.5Hz,2H),1.21(t,J=7.4Hz,3H).

[0373] Example 39 Synthesis of 4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (39a) and 4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (39a) with formic acid [ka] Step 1: 2-Isopropyl-4-methoxy-1H-imidazo[4,5-c]pyridine [ka] The title compound was synthesized by the method described in Step 1 of Example 37, except that 2-methoxypyridine-3,4-diamine (500 mg, 3.59 mmol) and isobutyraldehyde (285 mg, 3.952 mmol) were used. Yield: 370 mg (46.2%). MS (ESI, positive ion) m / z: 192.25 (M+1).

[0374] Step 2: 4-((2-isopropyl-4-methoxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (39a) and 4-((2-isopropyl-4-methoxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (39b) [ka] The compound was synthesized according to Step 4 in Example 22, except that 2-isopropyl-4-methoxy-1H-imidazo[4,5-c]pyridine (370 mg, 1.935 mmol) was used. The residue was dissolved in methanol (5 mL) and filtered. The filtrate was concentrated under reduced pressure to give 420 mg (58.6% yield) of a mixture of 4-((2-isopropyl-4-methoxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid and 4-((2-isopropyl-4-methoxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (ratio = 1:1) as a brown solid. MS (ESI, positive ion) m / z: 325.90 (M+1).

[0375] Step 3: 4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (39a) and 4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid formate (39a) [ka] To a solution of a mixture of 4-((2-isopropyl-4-methoxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid and 4-((2-isopropyl-4-methoxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid) (420 mg, 1.033 mmol, 1.00 equiv, 80%) in ACN (10.00 mL) was added TMSI (1.29 g, 6.458 mmol, 5 equiv) at room temperature. The resulting mixture was stirred at 90° C. for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL / min; gradient: 9 B to 20 B in 10 min; 254 / 220nm; RT1: 8.12 min; RT2: 8.90 min) to obtain two fractions.

[0376] Fraction 1: Rt: 8.12 min. 74.2 mg (19.5% yield) of 4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (39b) as the formate salt (pale yellow solid). MS (ESI, positive ion) m / z: 312.25 (M+1). 1 H NMR(400MHz,DMSO-d6,ppm)δ11.27(d,J=5.8Hz,1H),8.14(s,1H),8.03(s,2H),7.73(d,J=7.9Hz,2H), 7.09(dd,J=16.9,7.1Hz,3H),6.56(d,J=6.9Hz,1H),5.80(s,2H),3.10(m,1H),1.12(d,J=6.7Hz,6H).

[0377] Fraction 2: Rt: 8.90 min. 108.3 mg (33.0% yield) of 4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (39a) as an off-white solid. MS (ESI, positive ion) m / z: 312.30 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ11.11(d,J=5.9Hz,1H),8.05(s,2H),7.74(d,J=7.8Hz,2H),7.10(t,J=6.5 Hz,1H),7.00(d,J=7.8Hz,2H),6.57-6.44(m,1H),5.44(s,2H),3.19-3.09(m,1H),1.18(d,J=6.8Hz,6H).

[0378] Example 40 Synthesis of 4-((4-hydroxy-2-methylpyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid [ka] Step 1: 4-Methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine [ka] To a stirred solution of 3-iodo-2-methoxypyridin-4-amine (500 mg, 2.00 mmol, 1.00 equiv) in THF (10 mL) was added KCO (552 mg, 4.0 mmol, 2.00 equiv), Pd(PPh) (231 mg, 0.200 mmol, 0.10 equiv), XPhos (191 mg, 0.400 mmol, 0.20 equiv), and propyne (1 M in THF) (6.00 mL, 6.000 mmol, 3.00 equiv) under an argon atmosphere. The reaction mixture was refluxed for 8 h. After removing THF by evaporation under reduced pressure, the residue was purified by flash chromatography on a silica gel column (PE / EtOAc, gradient 100:0 to 85:15) to give 4-methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine (150 mg, 35.6%) as a brown solid. MS (ESI, positive ion) m / z: 163.25 (M+1).

[0379] Step 2: 4-((4-methoxy-2-methylpyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid [ka] This compound was synthesized similarly to Step 4 in Example 22, except that 4-methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine (150 mg, 0.712 mmol) was used. Yield: 150 mg (66.2%) as a light brown solid. MS (ESI, positive ion) m / z: 297.30 (M+1).

[0380] Step 3: 4-((4-hydroxy-2-methylpyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid [ka] To a solution of 4-((4-methoxy-2-methylpyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid (150 mg, 0.52 mmol, 1.00 equiv) in ACN (5 mL) was added TMSI (0.5 mL). After stirring at 90° C. for 1 h, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 19*250 μm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 15 B to 70 B in 7 min; 254 / 220 nm; RT: 6.3 min) to give 4-((4-hydroxy-2-methylpyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid (25.8 mg, 17.6% yield) as a white solid. MS (ESI, positive ion) m / z: 283.25 (M+1). 1 H NMR (300 MHz, DMSO-d 6, ppm)δ 10.63(d,J=5.5Hz,1H),8.02(s,2H),7.77-7.68(m,2H),7.12(d,J=7.8Hz,2H) ,6.96-6.86(m,2H),6.42(d,J=7.1Hz,1H),5.23(s,2H),2.31(d,J=1.0Hz,3H).

[0381] Example 41 Synthesis of 4-((5-carbamoyl-2-methylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid [ka] Step 1: 2-Methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxamide [ka] To a solution of 5-chloro-2-methyl-1H-pyrrolo[3,2-b]pyridine (500.00 mg, 3.001 mmol, 1.00 equiv.) in 7 M NH3 (g) in MeOH (15.00 mL) was added Pd(dppf)Cl2CHCl2 (122.54 mg, 0.150 mmol, 0.05 equiv.). The resulting mixture was purged with carbon monoxide for 5 minutes and stirred at 120 °C under a carbon monoxide (20 atm.) atmosphere for 6 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate 1:1) to afford 400 mg (72.2% yield) of 2-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxamide as a pale yellow solid.

[0382] Step 2: 4-((5-carbamoyl-2-methylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by Step 4 of Example 22, except that 2-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxamide (150 mg, 0.856 mmol) was used. The residue was purified by preparative HPLC (Column: XBridge C18 OBD Prep Column, 100 mm x 5 um, 19 mm x 250 mm; Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN; Flow Rate: 25 mL / min; Gradient: 20 B to 30 B in 7 min; 254 / 220 nm) to afford 67.3 mg (25.1% yield) of 4-((5-carbamoyl-2-methylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid as a white solid. MS (ESI, positive ion) m / z: 310.25 (M+1). 1 H NMR(400MHz,DMSO-d6,ppm)δ 8.00(s,3H),7.92(d,J=8.5Hz,1H),7.80(d,J=8.5Hz,1H),7.71(d,J=7.8Hz,2H),7 .38(d,J=3.3Hz,1H),6.96(d,J=7.8Hz,2H),6.54(s,1H),5.50(s,2H),2.44(s,3H).

[0383] Example 42 Synthesis of 4-((5-cyano-2-methylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid [ka] Step 1: 2-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile [ka] The title compound was synthesized by Step 1 of Example 33, except that 2-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxamide (250 mg, 1.43 mmol) was used. Yield: 75 mg (78.0%) as a brown solid.

[0384] Step 2: 4-((5-cyano-2-methylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by Step 4 of Example 22, except that 2-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (175 mg, 1.113 mmol) was used. The residue was purified by preparative HPLC (Column: XBridge C18 OBD Prep Column, 100 mm x 5 um, 19 mm x 250 mm; Mobile Phase A: water (0.05% FA), Mobile Phase B: ACN; Flow Rate: 25 mL / min; Gradient: 30 B to 40 B in 7 min; 254 nm, 220 nm) to afford 4-((5-cyano-2-methylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid (74.5 mg, 22.5% yield) as a white solid. MS (ESI, positive ion) m / z: 292.25 (M+1). 1H NMR(400MHz,DMSO-d6,ppm)δ 8.07-7.99(m,3H),7.71(d,J=7.7Hz,2H),7.65(d,J=8.4Hz,1H),6.96(d,J=7.7Hz,2H),6.62(s,1H),5.54(s,2H),2.45(s,3H).

[0385] Example 43 Synthesis of 4-((5-carbamoyl-2-isopropylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid [ka] Step 1: 6-chloro-2-(3-methylbut-1-yn-1-yl)pyridin-3-amine [ka] To a solution of 6-chloro-2-iodopyridin-3-amine (900 mg, 3.537 mmol, 1.00 equiv) in ACN (10.00 mL), TEA (8 mL), CuI (33.68 mg, 0.177 mmol, 0.05 equiv), Pd(PPh3)4 (408.71 mg, 0.354 mmol, 0.10 equiv), and 1-butyne,3-methyl- (265 mg, 3.891 mmol, 1.1 equiv) were added at room temperature under an argon atmosphere. After stirring at room temperature for 20 h, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate 2:3) to give 6-chloro-2-(3-methylbut-1-yn-1-yl)pyridin-3-amine (620 mg, 90% yield) as a light brown solid.

[0386] Step 2: 5-chloro-2-isopropyl-1H-pyrrolo[3,2-b]pyridine [ka] To a solution of 6-chloro-2-(3-methylbut-1-yn-1-yl)pyridin-3-amine (580 mg, 2.980 mmol, 1.00 equiv.) in dry DMF (5.00 mL) was added t-BuOK (669 mg, 5.959 mmol, 2 equiv.) at room temperature. After stirring at room temperature for 4 hours, the reaction mixture was poured into cold water, and a brown precipitate formed. The solid was collected by filtration, washed with water, and dried in air to give 5-chloro-2-isopropyl-1H-pyrrolo[3,2-b]pyridine (440 mg, 75.9% yield) as a brown solid.

[0387] Step 3: 2-Isopropyl-1H-pyrrolo[3,2-b]pyridine-5-carboxamide [ka] The title compound was synthesized by Step 1 of Example 41, except that 5-chloro-2-isopropyl-1H-pyrrolo[3,2-b]pyridine (500 mg, 2.569 mmol) was used. Yield: 390 mg (63.7%) as a yellow solid.

[0388] Step 4: 4-((5-carbamoyl-2-isopropylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by Step 4 of Example 22, except that 2-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-carboxamide (150 mg, 0.74 mmol) was used. The crude product was purified by preparative HPLC under the following conditions (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20 B to 38 B in 7 min; 254 / 220 nm) to give 4-((5-carbamoyl-2-isopropylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid (76.1 mg, 29.5% yield) as a yellow solid. MS (ESI, positive ion) m / z: 338.30 (M+1). 1H NMR(400MHz,DMSO-d6,ppm)δ 7.98(d,J=15.7Hz,3H),7.89-7.74(m,2H),7.67(d,J=7.7Hz,2H),7.40(d,J=3.2Hz,1H),6.87 (d,J=7.7Hz,2H),6.54(s,1H),5.54(s,2H),3.09(sept,J=6.8Hz,1H),1.22(d,J=6.7Hz,6H).

[0389] Example 44 Synthesis of 4-((5-cyano-2-isopropylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid [ka] Step 1: 2-Isopropyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile [ka] The title compound was synthesized by Step 1 in Example 33, except that 2-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-carboxamide (150 mg, 0.74 mmol) was used. Yield: 35 mg (15.8%). MS (ESI, positive ion) m / z: 186.20 (M+1).

[0390] Step 2: 4-((5-cyano-2-isopropylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by Step 4 of Example 22, except that 2-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (35 mg, 0.19 mmol) was used. The crude product was purified by preparative HPLC under the following conditions: Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 15 B to 65 B in 7 min; 254 / 220 nm) to give 4-((5-cyano-2-isopropylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid (38.6 mg, 63.3% yield) as a white solid. MS (ESI, positive ion) m / z: 320.30 (M+1). 1 H NMR(400MHz,DMSO-d6,ppm)δ 8.06-7.87(m,3H),7.65(m,3H),6.88(d,J=7.9Hz,2H),6.64(s,1H),5.57(s,2H),3.11(sept,J=6.8Hz,1H),1.21(d,J=6.7Hz,6H).

[0391] Example 45 Synthesis of 4-((4-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (45a) and 4-((7-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (45b) [ka] Step 1: 4-chloro-1H-1,3-benzodiazole [ka] To a suspension of 3-chlorobenzene-1,2-diamine (200 mg, 1.403 mmol, 1.00 equiv) in HO (5.00 mL) was added HCOOH (129 mg, 2.805 mmol, 2.0 equiv). The resulting mixture was stirred at 100 °C for 3 h. After cooling to room temperature, the reaction mixture was adjusted to pH = 9 with 2 M sodium hydroxide and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to dryness to give 4-chloro-1H-1,3-benzodiazole (180 mg, 84.1% yield) as a tan solid.

[0392] Step 2: 4-((4-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (45a) and 4-((7-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (45b) [ka] The title compound was synthesized by Step 4 of Example 22, except that 4-chloro-1H-1,3-benzodiazole (180 mg, 1.18 mmol) was used. The residue was purified by preparative HPLC (Column: YMC-Actus Triart C18, 30*250, 5 μm; Mobile phase A: water (0.05% FA), Mobile phase B: ACN; Flow rate: 45 mL / min; Gradient: 20 B to 30 B in 7 min; 254, 220 nm; RT1: 6.45 min; RT2: 7.58 min) to give two fractions.

[0393] Fraction 1: Rt: 6.45 min. 30.0 mg (7.6% yield) of 4-((4-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (45a) as an off-white solid. MS (ESI, positive ion) m / z: 287.15 (M+1). 1 H NMR(400MHz,DMSO-d6,ppm)δ 8.50(s,1H),8.07(s,2H),7.75-7.63(m,2H),7.47(m,1H),7.30-7.12(m,4H),5.51(s,2H).

[0394] Fraction 2: Rt: 7.58 min. 33.3 mg (8.4% yield) of 4-((7-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (45b) as an off-white solid. MS (ESI, positive ion) m / z: 287.10 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 8.49(d,J=12.1Hz,1H),8.04(s,2H),7.75-7.63(m,3H),7.29-7.14(m,2H),7.00(d,J=7.8Hz,2H),5.75(s,2H).

[0395] Example 46 Synthesis of 4-((4,6-dichloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (46a) and 4-((5,7-dichloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (46a) [ka] Step 1: 4,6-Dichloro-1H-1,3-benzodiazole [ka] The title compound was synthesized by Step 1 of Example 45, except that 3,5-dichlorobenzene-1,2-diamine (300.00 mg, 1.70 mmol) was used. Yield: 280 mg (88.4%) as a pale yellow solid.

[0396] Step 2: 4-((4,6-dichloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid and 4-((5,7-dichloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 4 of Example 22, except that 4,6-dichloro-1H-1,3-benzodiazole (150 mg, 0.802 mmol) was used. The residue was purified by preparative HPLC (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 35 B to 40 B in 10 min; 254 / 220 nm; RT1: 7.03 min; RT2: 8.47 min) to give two fractions.

[0397] Fraction 1: Rt: 7.03 min. 27.9 mg (10.3% yield) of 4-((5,7-dichloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (46b) as a white solid. MS (ESI, positive ion) m / z: 321.20 (M+1). 1 H NMR(400MHz,DMSO-d6,ppm)δ 8.56(s,1H),8.02(s,2H),7.78(d,J=1.9Hz,1H),7.70(d,J=7.9Hz,2H),7.36(d,J=1.8Hz,1H),7.00(d,J=7.8Hz,2H),5.74(s,2H).

[0398] Fraction 2: Rt: 8.47 min. 17.4 mg (6.8% yield) of 4-((4,6-dichloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (46a) as a white solid. MS (ESI, positive ion) m / z: 321.15 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 8.56(s,1H),8.11(s,2H),7.76-7.65(m,3H),7.39(d,J=1.8Hz,1H),7.25(d,J=7.7Hz,2H),5.51(s,2H).

[0399] Example 47 Synthesis of 4-((4-fluoro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (47a) and 4-((7-fluoro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (47b) [ka] The title compound was synthesized by the method described in Step 4 of Example 22, except that 4-fluoro-1H-1,3-benzodiazole (150 mg, 1.102 mmol) was used. The residue was purified by preparative HPLC (column: Sunfire prep C18 column, 30*150, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10 B to 35 B in 10 min; 254 / 220 nm; RT1: 8.3 min; RT2: 8.98 min) to give two fractions.

[0400] Fraction 1: Rt: 8.30 min. 57.7 mg (18.8% yield) of 4-((4-fluoro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (47a) as a white solid. MS (ESI, positive ion) m / z: 271.20 (M+1). 1 H NMR(400MHz,DMSO-d6,ppm)δ 8.45(s,1H),8.03(s,2H),7.75-7.68(m,2H),7.33(m,1H),7.27-7.21(m,1H),7.17(m,2H),6.99(m,1H),5.51(s,2H).

[0401] Fraction 2: Rt: 8.98 min. 90.4 mg (29.5% yield) of 4-((7-fluoro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (47b) as a white solid. MS (ESI, positive ion) m / z: 271.25 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 8.45(s,1H),8.06(s,2H),7.74-7.68(m,2H),7.49(d,J=8.1Hz,1H),7.15(m,3H),7.01(dd,J=11.5,8.0Hz,1H),5.55(s,2H).

[0402] Example 48 Synthesis of 4-(imidazo[4,5-b]pyridin-1-ylmethyl)phenylboronic acid (48a) and 4-(imidazo[4,5-b]pyridin-3-ylmethyl)phenylboronic acid (48b) [ka] The title compound was synthesized by the method described in Step 4 of Example 22, except that 3H-imidazo[4,5-b]pyridine (150.00 mg, 1.259 mmol) was used. The residue was purified by preparative HPLC (Column: XBridge C18 OBD Prep Column, 100 Å, 5 μm, 19 mm × 250 μm; Mobile phase A: water (0.05% FA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 7 B to 17 B in 7 min; 254, 220 nm; RT1: 7.70 min; RT2: 9.88 min) to give two fractions.

[0403] Fraction 1: Rt: 7.70 min. 55.9 mg (16.3% yield) of 4-(imidazo[4,5-b]pyridin-1-ylmethyl)phenylboronic acid (48a) as a white solid. MS (ESI, positive ion) m / z: 254.25 (M+1). 1 H NMR(400MHz,DMSO-d6,ppm)δ 8.65(s,1H),8.38(dd,J=4.7,1.5Hz,1H),8.05(s,2H),7.93(dd,J=8.1,1.6Hz,1H),7.75-7.69(m,2H),7.39-7.10(m,3H),5.52(s,2H).

[0404] Fraction 2: Rt: 9.88 min. 73.3 mg (22.7% yield) of 4-(imidazo[4,5-b]pyridin-3-ylmethyl)phenylboronic acid (48b) as a white solid. MS (ESI, positive ion) m / z: 254.20 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 8.59(s,1H),8.35(dd,J=4.8,1.5Hz,1H),8.09(dd,J=8.1,1.5Hz,1H),8.02(d,J=4.5Hz,2H),7.74-7.67(m,2H),7.31-7.22(m,3H),5.49(s,2H).

[0405] Example 49 Synthesis of 4-((2-isopropylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (49a) and 4-((2-isopropylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (49b) [ka] Step 1: 2-Isopropyl-1H-imidazo[4,5-b]pyridine [ka] The title compound was synthesized by the method described in Step 1 of Example 37, except that pyridine-2,3-diamine (300 mg, 2.749 mmol) and isobutyraldehyde (198 mg, 2.749 mmol) were used. The crude product was purified by column chromatography (silica gel, eluent: ethyl acetate / petroleum ether 3:2) to afford 2-isopropyl-1H-imidazo[4,5-b]pyridine (210 mg, 26.1% yield) as a yellow solid.

[0406] Step 2: 4-((2-isopropylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid and 4-((2-isopropylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 4 of Example 22, except that 2-isopropyl-1H-imidazo[4,5-b]pyridine (210 mg, 1.30 mmol) was used. The residue was purified by preparative HPLC (Column: XBridge C18 OBD Prep Column, 100 Å, 5 μm, 19 mm × 250 μm; Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN; Flow Rate: 25 mL / min; Gradient: 10 B to 35 B in 8 min; 254, 220 nm; RT1: 3.60 min; RT2: 6.72 min) to give two fractions.

[0407] Fraction 1: Rt: 3.60 min. 8.0 mg (2.0% yield) of 4-((2-isopropylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (49a) as a white solid. MS (ESI, positive ion) m / z: 296.30 (M+1). 1 H NMR(400MHz,DMSO-d6,ppm)δ 8.28-7.93(m,4H),7.75-7.67(m,2H),7.39(d,J=7.9Hz,2H),7.12(dd,J=7.6,6.3Hz,1H),5.80(s,2H),3.20-3.08(m,1H),1.32(d,J=6.9Hz,6H).

[0408] Fraction 2: Rt: 6.72 min. 14.6 mg (3.6% yield) of 4-((2-isopropylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (49b) was obtained as a brown solid. MS (ESI, positive ion) m / z: 296.25 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 8.28(d,J=4.8Hz,1H),8.14-7.86(m,3H),7.69(d,J=7.6Hz,2H),7.25(dd,J=7.9,4.8Hz ,1H),7.06(d,J=7.7Hz,2H),5.54(s,2H),3.22(d,J=6.7Hz,1H),1.18(d,J=6.7Hz,6H).

[0409] Example 50 Synthesis of 4-((7-chloroimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (50a) and 4-((7-chloroimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (50b) [ka] The title compound was synthesized by the method described in Step 4 of Example 22, except that 7-chloro-3H-imidazo[4,5-c]pyridine (150 mg, 0.977 mmol) was used. The residue was purified by preparative HPLC (Column: XBridge C18 OBD Prep Column, 100 Å, 5 μm, 19 mm × 250 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile Phase B: ACN; Flow Rate: 25 mL / min; Gradient: 20 B to 30 B in 7 min; 254 / 220 nm; RT1: 6.58 min; RT2: 6.72 min) to give two fractions.

[0410] Fraction 1: Rt: 6.58 min. 12.6 mg (4.5% yield) of 4-((7-chloroimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (50a) as a white solid. MS (ESI, positive ion) m / z: 287.85 (M+1). 1 H NMR(400MHz,DMSO-d6,ppm)δ 9.25(d,J=1.3Hz,1H),8.56(d,J=1.3Hz,1H),8.37(s,2H),8.23(s,1H),7.80-7.73(m,2H),7.40(d,J=7.9Hz,2H),5.66(s,2H).

[0411] Fraction 2: Rt: 6.72 min. 29.6 mg (10.5% yield) of 4-((7-chloroimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (50b) as a white solid. MS (ESI, positive ion) m / z: 288.20 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 8.96(s,1H),8.66(s,1H),8.32(s,1H),8.05(s,2H),),7.74-7.72(d,J=7.9Hz,2H),7.08-7.06(d,J=7.9Hz,2H),5.77(s,2H).

[0412] Example 51 Synthesis of 4-((7-chloro-2-isopropylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid [ka] Step 1: 7-chloro-2-isopropyl-3H-imidazo[4,5-c]pyridine [ka] To a stirred solution of 5-chloropyridine-3,4-diamine (300 mg, 2.09 mmol, 1.00 equiv.) in N,N-dimethylisobutyramide (6.00 mL, 0.21 mmol, 0.02 equiv.) was added imidazole hydrochloride (328 mg, 3.13 mmol, 1.50 equiv.) at room temperature. After stirring at 140 °C for 24 h, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: ethyl acetate / petroleum ether 9:11) to give 7-chloro-2-isopropyl-3H-imidazo[4,5-c]pyridine (150 mg, 34.9% yield) as a yellow solid.

[0413] Step 2: 4-((7-chloro-2-isopropylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 4 of Example 22, except that 7-chloro-2-isopropyl-3H-imidazo[4,5-c]pyridine (150 mg, 0.77 mmol) was used. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30*250, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 45 mL / min; gradient: 5 B to 22 B in 7 min; 254, 220 nm) to give 4-((7-chloro-2-isopropylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (30.7 mg, 11.9% yield) as a white solid. MS (ESI, positive ion) m / z: 330.20 (M+1). 1H NMR(400MHz,DMSO-d6,ppm)δ 8.98(s,1H),8.46(s,1H),8.10(d,J=16.3Hz,2H),7.77(d,J=7.8Hz,2H), 7.37(d,J=7.8Hz,2H),5.61(s,2H),3.19-3.11(m,1H),1.42-1.18(m,6H).

[0414] Example 52 2.0 Synthesis of 4-((4-hydroxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (52a), 4-((7-methoxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (52b), and 4-((4-methoxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (52c) with formic acid [ka] Step 1: 4-Methoxy-2-methyl-1H-1,3-benzodiazole [ka] The title compound was synthesized by the method described in Step 4 of Example 37, except that 3-methoxybenzene-1,2-diamine (500 mg, 3.62 mmol) was used. Yield: 250 mg (27.5%) as a white solid. MS (ESI, positive ion) m / z: 163.25 (M+1).

[0415] Step 2: 4-((7-methoxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (52b) and 4-((4-methoxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (52c) [ka] The title compound was synthesized by the method described in Step 4 of Example 22, except that 4-methoxy-2-methyl-1H-1,3-benzodiazole (0.25 g, 1.54 mmol) was used. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30*250, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 45 mL / min; gradient: 20 B to 30 B in 7 min; 254, 220 nm; RT1: 9.05 min; RT2: 11.02 min) to give two fractions.

[0416] Fraction 1: Rt: 9.05 min. 22.2 mg (4.8% yield) of 4-((7-methoxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (52b) as a white solid. MS (ESI, positive ion) m / z: 296.90 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 7.99(s,2H),7.75-7.66(m,2H),7.13 -6.94(dd,J=8.1,0.9Hz,1H),7.04(t,J=8.0Hz,1H),7.00-6.94(m,2H),6.73(dd,J=7.9,0.9Hz,1H),5.60(s,2H),3.78(s,3H),2.39(s,3H).

[0417] Fraction 2: Rt: 11.02 min. 110 mg (23.7% yield) of 4-((4-methoxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (52c) as a white solid. MS (ESI, positive ion) m / z: 296.90 (M+1). 1 H NMR(400MHz,DMSO-d6,ppm)δ 8.01(s,2H),7.73-7.66(m,2H),7.08-6.96(m,4H),6.65(dd,J=7.3,1.5Hz,1H),5.41(s,2H),3.90(s,3H),2.45(s,3H).

[0418] Step 3: 4-((4-hydroxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (52a) with 2.0 formic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 35, except that 4-((4-methoxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (80 mg, 0.27 mmol) was used. The residue was purified by preparative HPLC (Column: YMC-Actus Triart C18, 30*250, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 45 mL / min; Gradient: 5 B to 30 B in 7 min; 254 / 220 nm; RT: 5.78 min) to give 4-((4-hydroxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid:formic acid (52a, 16.3 mg, 21.4% yield) as a white solid. MS (ESI, positive ion) m / z: 282.90 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 9.63(s,1H),8.15(s,2H),8.06(s,1H),7.72(d,J=7.8Hz,2H),7.06(d,J=7.8Hz ,2H),6.96-6.78(m,2H),6.51(dd,J=7.7,1.1Hz,1H),5.40(s,2H),2.48(s,3H)

[0419] Example 53 Synthesis of 4-((4-carbamoylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid [ka] Step 1: 1H-Imidazo[4,5-c]pyridine-4-carboxamide [ka] The title compound was synthesized by the method described in Step 1 of Example 41, except that 4-chloro-1H-imidazo[4,5-c]pyridine (220 mg, 1.43 mmol) was used. Yield: 160 mg (50.1%) as a purple solid. MS (ESI, positive ion) m / z: 162.99 (M+1).

[0420] Step 2: 4-((4-carbamoylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 4 of Example 22, except that 1H-imidazo[4,5-c]pyridine-4-carboxamide (82.00 mg, 0.506 mmol) was used. The residue was purified by preparative HPLC (YMC-Actus Triart C18, 30*250, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 45 mL / min; Gradient: 20 B to 30 B in 7 min; 254 / 220 nm; RT: 9.05 min) Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 4 B to 12 B in 7.5 min; 254 / 220 nm) to give 4-((4-carbamoylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (19.2 mg, 12.8% yield) as a white solid. MS (ESI, positive ion) m / z: 297.25 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 8.72(s,1H),8.58(s,1H),8.38(d,J=5.4Hz,1H),8.08(s,2H),7.80-7.67(m,4H),7.30-7.20(m,2H),5.58(s,2H).

[0421] Example 54 Synthesis of 4-((4-fluoropyrrolo[2,3-b]pyridin-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 4 of Example 22, except that 4-fluoro-1H-pyrrolo[2,3-b]pyridine (150 mg, 1.102 mmol) was used. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30*250, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN:MEOH=4:1; flow rate: 45 mL / min; gradient: 35 B to 55 B in 7 min; 254 / 220 nm; RT: 7.27 min) to give 4-((4-fluoropyrrolo[2,3-b]pyridin-1-yl)methyl)phenylboronic acid (157.9 mg, 50.8% yield) as a white solid. MS (ESI, positive ion) m / z: 271.10 (M+1). 1 H-NMR(400MHz,DMSO-d6,ppm)δ 8.33-8.22(m,1H),8.01(d,J=1.9Hz,2H),7.71(d,J=7.9Hz,3H),7.18(d,J=7 .5Hz,2H),7.02(dd,J=10.8,5.6Hz,1H),6.62(t,J=2.7Hz,1H),5.51(s,2H).

[0422] Example 55 Synthesis of 4-((4-methoxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid (55a) and 4-((4-hydroxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid (55b) [ka] Step 1: 4-Methoxy-1H-pyrazolo[4,3-c]pyridine [ka] To a solution of 30% NaOMe (10.00 mL) in MeOH was added 4-chloro-1H-pyrazolo[4,3-c]pyridine (500.00 mg, 1 equiv.). The resulting mixture was stirred at 140° C. for 2 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4-methoxy-1H-pyrazolo[4,3-c]pyridine (300 mg, 60.54% yield) as a yellow solid.

[0423] Step 2: 4-((4-methoxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid (55a) [ka] To a solution of 4-methoxy-1H-pyrazolo[4,3-c]pyridine (280 mg, 1.840 mmol, 1.00 equiv, 98%) in DMF (10.00 mL) was added 4-(bromomethyl)phenylboronic acid (474 ​​mg, 2.21 mmol, 1.2 equiv) and cesium carbonate (1.20 g, 3.68 mmol, 2 equiv). After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was purified using a Sunfire prep C18 column, 30*150, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20 B to 30 B in 10 min; 254 / 220 nm; RT1: 5.02 min; RT2: 9.17 min) to give 100 mg (18.4% yield) of 4-((4-methoxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid (55a) as a white solid. MS (ESI, positive ion) m / z: 284.25 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.18(s,1H),8.02(s,2H),7.90(d,J=6.1Hz,1H),7.72(d,J=7.7Hz,2H),7.32(d,J=6.1Hz,1H),7.16(d,J=7.5Hz,2H),5.64(s,2H),4.00(s,3H).

[0424] Step 3: 4-((4-hydroxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid [ka] To a solution of 4-((4-methoxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid (55a, 85.00 mg, 0.300 mmol, 1.00 equiv) in ACN (5 mL) was added TMSI (1.0 mL). After stirring at 90° C. for 1 h, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (Column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 10 B to 71 B in 7 min; 254 / 220 nm; RT: 5.83 min) to give 4-((4-hydroxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid (55c, 57.0 mg, 67.8% yield) as a white solid. MS (ESI, positive ion) m / z: 270.20 (M+1). 1 H-NMR (400MHz, DMSO-d6, ppm) 1 H NMR(300MHz,DMSO-d6)δ 11.05(d,J=5.7Hz,1H),8.06(d,J=0.8Hz,2H),7.82-7.69(m,2H),7.25-7.12(m,3H),6.70-6.61(m,1H),5.54(s,2H).

[0425] Example 56 Synthesis of 4-((5-(methylcarbamoyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (56a) and 4-((6-(methylcarbamoyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (56b) [ka] Step 1: N-methyl-1H-1,3-benzodiazole-5-carboxamide [ka] Methyl 1H-1,3-benzodiazole-5-carboxylate (500 mg, 1.00 equiv.) was dissolved in a solution of CHNH (10.00 mL, 30% in MeOH). After stirring at 80 °C overnight, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on 100 g of silica gel (eluent: petroleum ether-ethyl acetate 100%, 1:3) to give N-methyl-1H-1,3-benzodiazole-5-carboxamide (300 mg, 60.3% yield) as an off-white solid.

[0426] Step 2: 4-((5-(methylcarbamoyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (56a) and 4-((6-(methylcarbamoyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (56b) [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that N-methyl-1H-1,3-benzodiazole-5-carboxamide (200 mg, 1.142 mmol) was used. Two fractions were obtained.

[0427] Fraction 1: Rt: 5.02 min. 77.7 mg (21.8% yield) of 4-((6-(methylcarbamoyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (56b) as a white solid. MS (ESI, positive ion) m / z: 310.30 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.56(s,1H),8.43-8.34(m,1H),8.03(s,3H),7.79-7.68(m,4H),7.31-7.20(m,2H),5.55(s,2H),2.79(d,J=4.5Hz,3H).

[0428] Fraction 2: Rt: 6.65 min. 41.3 mg (11.5% yield) of 4-((5-(methylcarbamoyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (56a) as a white solid. MS (ESI, positive ion) m / z: 310.30 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.53(s,1H),8.38(t,J=4.5Hz,1H),8.20(d,J=1.5Hz,1H),8.03(s,2H),7.74(dd,J=8.3,1.5 Hz,3H),7.56(dd,J=8.5,0.7Hz,1H),7.31-7.22(m,2H),5.53(s,2H),2.80(d,J=4.5Hz,3H).

[0429] Example 57 Synthesis of diethyl 4-((4-methoxyindol-1-yl)methyl)phenylphosphonate (57a), 4-((4-methoxyindol-1-yl)methyl)phenylphosphonic acid (57b), and 4-((4-hydroxyindol-1-yl)methyl)phenylphosphonic acid (57c) [ka] Step 1: Diethyl 4-((4-methoxyindol-1-yl)methyl)phenylphosphonate (57a) [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 4-methoxy-1H-indole (250 mg, 1.70 mmol) and diethyl 4-(bromomethyl)phenylphosphonate (782 mg, 2.55 mmol) were used to afford diethyl 4-((4-methoxyindol-1-yl)methyl)phenylphosphonate (57a, 355 mg, 55.0%) as a yellow solid. MS (ESI, positive ion) m / z: 374.25 (M+1). 1H NMR(300MHz,DMSO-d6,ppm)δ 7.71-7.58(m,2H),7.40(d,J=3.1Hz,1H),7.27(dd,J=8.1,3.9Hz,2H),7.09-6.96(m,2H),6.60- 6.48(m,2H),5.49(s,2H),3.97(dqd,J=8.3,7.0,2.7Hz,4H),3.87(s,3H),1.20(t,J=7.0Hz,6H).

[0430] Step 2: 4-((4-methoxyindol-1-yl)methyl)phenylphosphonic acid (57b) [ka] The title compound was synthesized by the method described in Step 2 of Example 85, except that diethyl 4-((4-methoxyindol-1-yl)methyl)phenylphosphonate (170.00 mg, 0.46 mmol) was used to afford 4-((4-methoxyindol-1-yl)methyl)phenylphosphonic acid (57b, 85 mg, 50.0%) as an off-white solid. MS (ESI, positive ion) m / z: 318.05 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 7.59(dd,J=12.8,7.8Hz,2H),7.39(d,J=3.2Hz,1H),7.20(d,J=7.7Hz,2H) ,7.01(d,J=5.7Hz,2H),6.52(d,J=11.2Hz,2H),5.44(s,2H),3.87(s,3H).

[0431] Step 3: 4-((4-hydroxyindol-1-yl)methyl)phenylphosphonic acid (57c) [ka] The title compound was synthesized by the method described in Step 2 of Example 35, except that 4-((4-methoxyindol-1-yl)methyl)phenylphosphonic acid (70.00 mg, 0.22 mmol) was used to give 4-((4-methoxyindol-1-yl)methyl)phenylphosphonic acid (57c, 20.3 mg, 50.0%). MS (ESI, positive ion) m / z: 304.05 (M+1). 1 H NMR(300MHz,DMSO-d6 / D2O,ppm)δ 7.63-7.50(m,2H),7.29(d,J=3.5Hz,1H),7.19(d,J=7.8Hz,2H),6.98-6.70(m,2H),6.51(d,J=3.1Hz,1H),6.38(d,J=7.4Hz,1H),5.33(s,2H).

[0432] Example 58 Synthesis of 4-((6-carbamoylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (58a) and 4-((6-carbamoylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (58b) [ka] Step 1: 3H-Imidazo[4,5-c]pyridine-6-carboxamide [ka] Methyl 3H-imidazo[4,5-c]pyridine-6-carboxylate (200 mg, 1.13 mmol) was dissolved in NH—H O (10 mL) in a sealed tube. The resulting mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and evaporated to dryness to give 3H-imidazo[4,5-c]pyridine-6-carboxamide (180 mg, 98.3% yield) as a pale yellow solid.

[0433] Step 2: 4-((6-carbamoylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (58a) and 4-((6-carbamoylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (58b) [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except for 3H-imidazo[4,5-c]pyridine-6-carboxamide (80 mg, 0.493 mmol). Two fractions were obtained.

[0434] Fraction 1: Rt: 13.05 min. 28.9 mg (18.9% yield) of 4-((6-carbamoylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (58b) as a white solid. MS (ESI, positive ion) m / z: 297.30 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.98(d,J=1.0Hz,1H),8.72(s,1H),8.24(s,1H),8.14(d,J=2.7Hz,1H),8.08(d,J=4.4H z,2H),7.75(d,J=7.7Hz,2H),7.60(d,J=3.1Hz,1H),7.26(d,J=7.7Hz,2H),5.66(s,2H).

[0435] Fraction 2: Rt: 14.0 min. 21.2 mg (13.9% yield) of 4-((6-carbamoylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (58a) as a white solid. MS (ESI, positive ion) m / z: 297.30 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.88(s,1H),8.76(s,1H),8.28(s,1H),8.11-8.03(m,3H),7.76(d,J=7.8Hz,2H),7.56(s,1H),7.35(d,J=7.7Hz,2H),5.67(s,2H).

[0436] Example 59 Synthesis of 4-((6-(methylcarbamoyl)imidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (59a) and 4-((6-(methylcarbamoyl)imidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (59b) [ka] Step 1: N-methyl-3H-imidazo[4,5-c]pyridine-6-carboxamide [ka] To a solution of 3H-imidazo[4,5-c]pyridine-6-carboxylic acid (250 mg, 1.5 mmol, 1.00 equiv.) in DMF (5.00 mL) was added HATU (641 mg, 1.69 mmol, 1.1 equiv.), TEA (465 mg, 4.60 mmol, 3 equiv.), and methylamine (71 mg, 2.30 mmol, 1.5 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1.0 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, eluent: ethyl acetate / methanol 19:1) to give N-methyl-3H-imidazo[4,5-c]pyridine-6-carboxamide (120 mg, 44.5% yield) as a brown solid. MS (ESI, positive ion) m / z: 177.20 (M+1).

[0437] Step 2: 4-((6-(methylcarbamoyl)imidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (59a) and 4-((6-(methylcarbamoyl)imidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (59b) [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that N-methyl-3H-imidazo[4,5-c]pyridine-6-carboxamide (120 mg, 0.681 mmol) was used. Two fractions were obtained.

[0438] Fraction 1: Rt: 13.05 min. 27.9 mg (13.2% yield) of 4-((6-(methylcarbamoyl)imidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (59b) as a white solid. MS (ESI, positive ion) m / z: 311.05 (M+1). 1H NMR(300MHz,DMSO-d6,ppm)δ 8.98(s,1H),8.78(d,J=6.2Hz,1H),8.71(s,1H),8.21(s,1H),8.06(d,J=2.2Hz,2H ),7.75(d,J=7.6Hz,2H),7.26(d,J=7.3Hz,2H),5.66(s,2H),2.82(d,J=4.1Hz,3H).

[0439] Fraction 2: Rt: 14.0 min. 32.6 mg (15.0% yield) of 4-((6-(methylcarbamoyl)imidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (59a) as a white solid. MS (ESI, positive ion) m / z: 311.05 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.89(s,1H),8.75(s,1H),8.68(s,1H),8.26(s,1H),8.07(s,2H),7.76(d,J=7.4Hz,2H),7.34(d,J=7.6Hz,2H),5.67(s,2H),2.83(s,3H).

[0440] Example 60 Synthesis of 4-((4-amino-5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid [ka] Step 1: 5-methyl-4-nitro-1H-1,3-benzodiazole and 5-methyl-6-nitro-1H-1,3-benzodiazole [ka] 5-Methylbenzimidazole (6.0 g, 45.40 mmol) was dissolved in concentrated H2SO4 (20 mL) and cooled to 0 °C. KNO3 (1.68 g, 16.646 mmol, 1.10 equiv) was added dropwise. After stirring for 2 h, the reaction mixture was poured onto ice and Na2CO3 was added to adjust the pH to >8. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting yellow solid was recrystallized from 50% MeOH / water (80 mL) to give a mixture of 5-methyl-4-nitro-1H-1,3-benzodiazole and 5-methyl-6-nitro-1H-1,3-benzodiazole as a yellow solid (2.0 g, 74.6% yield).

[0441] Step 2: 4-nitro-1H-1,3-benzodiazole-5-carboxylic acid and 6-nitro-1H-1,3-benzodiazole-5-carboxylic acid [ka] A mixture of 5-methyl-4-nitro-1H-1,3-benzodiazole and 5-methyl-6-nitro-1H-1,3-benzodiazole (2.00 g, 11.289 mmol, 1.00 equiv.) was dissolved in water (30.00 mL) and t-BuOH (30.00 mL). KMnO4 (7.14 g, 45.156 mmol, 4 equiv.) was added, and the mixture was stirred at 90 °C for 24 hours. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The mixture was poured into water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: DCM / MEOH 90:10) to give a mixture of 4-nitro-1H-1,3-benzodiazole-5-carboxylic acid and 6-nitro-1H-1,3-benzodiazole-5-carboxylic acid (500 mg, yield 21.4%).

[0442] Step 3: 4-nitro-1H-benzo[d]imidazole-5-carboxamide and 6-nitro-1H-benzo[d]imidazole-5-carboxamide [ka] The title compound was synthesized by the method described in Step 3 of Example 23, except that a mixture of 4-nitro-1H-1,3-benzodiazole-5-carboxylic acid and 6-nitro-1H-1,3-benzodiazole-5-carboxylic acid (500 mg, 2.41 mmol) was used to give 150 mg (32.1% yield) of a mixture of 4-nitro-1H-benzo[d]imidazole-5-carboxamide and 6-nitro-1H-benzo[d]imidazole-5-carboxamide.

[0443] Step 4: (4-((5-carbamoyl-4-nitro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid and (4-((5-carbamoyl-6-nitro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that a mixture of 4-nitro-1H-benzo[d]imidazole-5-carboxamide and 6-nitro-1H-benzo[d]imidazole-5-carboxamide (150 mg 0.73 mmol) was used to give a mixture of (4-((5-carbamoyl-4-nitro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid and (4-((5-carbamoyl-6-nitro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (150 mg, 32.1% yield).

[0444] Step 5: 4-((4-amino-5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid [ka] To a solution of a mixture of (4-((5-carbamoyl-4-nitro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid and (4-((5-carbamoyl-6-nitro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (100 mg, 0.294 mmol, 1.00 equiv) in MeOH (5 mL) was added Pd / C (20 mg). After stirring at room temperature for 60 h, the resulting mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 19*250 μm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 8 B to 15 B in 12 min; 254 / 220 nm; RT: 7.8 min) to give 4-((4-amino-5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (3.2 mg, 3.1% yield) as a white solid. MS (ESI, positive ion) m / z: 311.30 (M+1). 1 H NMR(400MHz,DMSO-d6)δ 8.25(s,1H),8.04(d,J=4.2Hz,2H),7.79-7.69(m,4H),7.34(d,J=7.9Hz,2H),7.11(s,1H),6.84(s,1H),6.07(s,2H),5.33(s,2H).

[0445] Example 61 Synthesis of 4-((5-carbamoylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (61a) and 4-((5-carbamoylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (61b) [ka] Step 1: 1H-Imidazo[4,5-b]pyridine-5-carboxamide [ka] The title compound was synthesized by the method described in Step 1 of Example 58, except that methyl 1H-imidazo[4,5-b]pyridine-5-carboxylate (400 mg, 2.26 mmol) was used. Yield: 350 mg (83.1%) as a pale yellow solid.

[0446] Step 2: 4-((5-carbamoylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid 61a and 4-((5-carbamoylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid 61b [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 1H-imidazo[4,5-b]pyridine-5-carboxamide (100 mg, 0.62 mmol) was used. Two fractions were obtained.

[0447] Fraction 1: Rt: 13.05 min. 40.4 mg (21.3% yield) of 4-((5-carbamoylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (61a) as a white solid. MS (ESI, positive ion) m / z: 297.25 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm))δ 8.83(s,1H),8.17-8.05(m,4H),7.98(d,J=8.4Hz,1H),7.75(d,J=7.8Hz,2H),7.56-7.49(m,1H),7.30(d,J=7.7Hz,2H),5.58(s,2H).

[0448] Fraction 2: Rt: 14.0 min. 44.8 mg (23.6% yield) of 4-((5-carbamoylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (61b) as a white solid. MS (ESI, positive ion) m / z: 297.30 (M+1). 1H NMR(300MHz,DMSO-d6,ppm)δ 8.78(s,1H),8.26-8.18(m,2H),8.09(d,J=4.0Hz,2H),7.99(d,J=8.3Hz,1H),7 .74(d,J=7.7Hz,2H),7.66(d,J=2.8Hz,1H),7.42(d,J=7.7Hz,2H),5.60(s,2H).

[0449] Example 62 Synthesis of 4-((2-ethyl-4-hydroxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid [ka] Step 1: 2-Ethyl-4-methoxy-1H-pyrrolo[3,2-c]pyridine [ka] To a stirred solution of 3-iodo-2-methoxypyridin-4-amine (2.00 g, 7.999 mmol, 1.00 equiv) in THF (400 mL) under an atmosphere of 1-butyne (3.00 equiv) was added KCO (2.21 g, 15.998 mmol, 2.00 equiv), Pd(PPh) (0.92 g, 0.800 mmol, 0.10 equiv), and XPhos (0.76 g, 1.600 mmol, 0.20 equiv). The reaction mixture was refluxed for 24 h. After concentration under reduced pressure, the residue was purified by flash chromatography on a silica gel column (PE / EtOAc, gradient 100:0 to 85:15) to give 2-ethyl-4-methoxy-1H-pyrrolo[3,2-c]pyridine (350 mg, 23.1% yield) as a brown solid.

[0450] Step 2: 4-((2-ethyl-4-methoxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 2-ethyl-4-methoxy-1H-pyrrolo[3,2-c]pyridine (250.00 mg, 1.419 mmol) was used. Yield: 268 mg (58.2% yield) as a white solid.

[0451] Step 3: 4-((2-ethyl-4-hydroxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 3 of Example 55, except that 4-((2-ethyl-4-methoxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid (268 mg, 0.864 mmol) was used. Yield: 75.9 mg (29.3%) as a white solid. MS (ESI, positive ion) m / z: 297.10 (M+1); 1 H NMR (300 MHz, DMSO-d 6, ppm)δ 10.62(d,J=4.9Hz,1H),8.01(s,2H),7.73(d,J=7.7Hz,2H),7.12(d,J=7.7Hz,2H),6.93(d,J= 9.0Hz,2H),6.42(d,J=7.2Hz,1H),5.24(s,2H),2.76(q,J=7.4Hz,2H),1.19(t,J=7.4Hz,3H).

[0452] Example 63 Synthesis of 4-((4-hydroxy-2-isopropylpyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid [ka] Step 1: 2-Isopropyl-4-methoxy-1H-pyrrolo[3,2-c]pyridine [ka] The title compound was synthesized by the method described in Step 1 of Example 37, except that 3-iodo-2-methoxypyridin-4-amine (0.60 g, 2.40 mmol) and 3-methyl-1-butyne (0.33 g, 4.799 mmol) were used. Yield: 0.25 g (54.8%) as a brown solid.

[0453] Step 2: 4-((2-isopropyl-4-methoxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 2-isopropyl-4-methoxy-1H-pyrrolo[3,2-c]pyridine (250 mg, 1.314 mmol) was used. Yield: 230 mg (54.0%) as a light brown solid. MS (ESI, positive ion) m / z: 325.35 (M+1).

[0454] Step 3: 4-((4-hydroxy-2-isopropylpyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 3 of Example 55, except that 4-((2-isopropyl-4-methoxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid (130.00 mg, 0.30 mmol) was used. Yield: 75.9 mg (29.3%) as a white solid. MS (ESI, positive ion) m / z: 311.25 (M+1). 1 H NMR (300 MHz, DMSO-d 6, ppm)δ 10.75(d,J=5.2Hz,1H),8.00(s,2H),7.71(d,J=7.8Hz,2H),6.92(dd,J=17.2,7.1Hz,3H ),6.39(d,J=7.6Hz,2H),5.37(s,2H),2.92(sept,J=6.7Hz,1H),1.15(d,J=6.7Hz,6H).

[0455] Example 64 Synthesis of 4-((5-carbamoyl-4-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (64a) and 4-((5-carbamoyl-4-hydroxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (64b) with 0.5 para-toluenesulfonic acid [ka] Step 1: 4-Methoxy-1H-1,3-benzodiazole-5-carboxylate methyl [ka] To a solution of methyl 3,4-diamino-2-methoxybenzoate (0.50 g, 2.548 mmol, 1.00 equiv.) in DMF (10.00 mL) was added 1H-imidazole hydrochloride (0.35 g, 1 equiv.). After stirring at 140 °C for 24 h, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: EA:PE 1:3) to give methyl 4-methoxy-1H-1,3-benzodiazole-5-carboxylate (0.4 g, 76.1% yield).

[0456] Step 2: 4-Methoxy-1H-1,3-benzodiazole-5-carboxamide [ka] A mixture of methyl 4-methoxy-1H-1,3-benzodiazole-5-carboxylate (0.40 g, 1 equivalent) in NH3HO (10.00 mL) was stirred at 80 °C for 48 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on 40 g of silica gel (eluent: petroleum ether-ethyl acetate 100%, 2:1) to give 4-methoxy-1H-1,3-benzodiazole-5-carboxamide (0.25 g, 36.2% yield) as a light brown solid.

[0457] Step 3: 4-((5-carbamoyl-4-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 4-methoxy-1H-1,3-benzodiazole-5-carboxamide (250 mg, 1.31 mmol) was used to obtain a white solid (120 mg, 20% yield). MS (ESI, positive ion) m / z: 326.30 (M+1). 1 H NMR (300 MHz, DMSO-d 6, ppm)δ 8.45(t,J=1.8Hz,1H),8.05(d,J=2.5Hz,2H),7.78-7.64(m,4H),7.43(s,1H),7.22(dd,J=16.8,8.2Hz,3H),5.50(s,2H),4.43(t,J=1.8Hz,3H).

[0458] Step 4: 4-((5-carbamoyl-4-hydroxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; para-toluenesulfonic acid (64b) [ka] To a solution of 4-((5-carbamoyl-4-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (85 mg, 0.261 mmol, 1.00 equiv) in acetonitrile (5 mL) was added LiI (70.0 mg, 0.523 mmol, 2.00 equiv) and p-toluenesulfonic acid (90 mg, 0.523 mmol, 2.00 equiv). After stirring at 85° C. for 2 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5 B to 36 B in 7 min; 254 / 220 nm; RT: 6 min) to give 4-((5-carbamoyl-4-hydroxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (64b, 21.1 mg, 16.0% yield) with 0.5% para-toluenesulfonic acid as a white solid. MS (ESI, positive ion) m / z: 312.25 (M+1). 1 H NMR (300 MHz, DMSO-d / DO) , ppm)δ 8.75(s,1H),7.75-7.65(m,3H),7.49(d,J=7.7Hz,1H),7.27(d,J=7.6Hz,2 H),7.15(d,J=7.8Hz,1H),7.02(d,J=8.8Hz,1H),5.52(s,2H),2.27(s,2H).

[0459] Example 65 Synthesis of 4-(imidazo[4,5-b]pyrazin-1-ylmethyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 1H-imidazo[4,5-b]pyrazine (150 mg, 1.249 mmol) was used. Yield: 172.4 mg (42.6%) as an off-white solid. MS (ESI, positive ion) m / z: 255.20 (M+1). 1 H NMR (300 MHz, DMSO-d 6,ppm)δ 8.95(s,1H),8.52(d,J=2.7Hz,1H),8.40(d,J=2.7Hz,1H),8.03(s,2H),7.79-7.69(m,2H),7.31-7.25(m,2H),5.52(s,2H).

[0460] Example 66 Synthesis of 4-(pyrrolo[2,3-b]pyrazin-5-ylmethyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 5H-pyrrolo[2,3-b]pyrazine (200.00 mg, 1.679 mmol) was used. Yield: 190 mg (44.7%) as a white solid. MS (ESI, positive ion) m / z: 253.90 (M+1). 1 H NMR (300 MHz, DMSO-d 6, ppm)δ 8.42(m,1H),8.26(m,1H),8.05-7.98(m,2H),7.77-7.66(m,2H),7.23-7.15(m,2H),6.69(m,1H),5.48(d,J=3.4Hz,2H).

[0461] Example 67 Synthesis of 4-((2-carbamoylpyrrolo[2,3-b]pyrazin-5-yl)methyl)phenylboronic acid [ka] Step 1: 5H-pyrrolo[2,3-b]pyrazine-2-carboxamide [ka] The title compound was synthesized by the method described in Step 1 of Example 41, except that 2-bromo-5H-pyrrolo[2,3-b]pyrazine (500 mg, 2.525 mmol) was used. Yield: 500 mg (90.0%) as a brown solid.

[0462] Step 2: 4-((2-carbamoylpyrrolo[2,3-b]pyrazin-5-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 5H-pyrrolo[2,3-b]pyrazine-2-carboxamide (300 mg, 1.85 mmol) was used. Yield: 131.3 mg (23.0%) as an orange solid. MS (ESI, positive ion) m / z: 297.25 (M+1). 1 H NMR (300 MHz, DMSO-d 6, ppm)δ 8.94(s,1H),8.23-8.13(m,2H),8.03(s,2H),7.73(d,J=7.5Hz,2H),7.63(s,1H),7.22(d,J=7.5Hz,2H),6.81(d,J=3.2Hz,1H),5.55(s,2H).

[0463] Example 68 Synthesis of 4-((6-carbamoylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (68a) and 4-((6-carbamoylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (68b) [ka] Step 1: 3H-Imidazo[4,5-b]pyridine-6-carboxamide [ka] The title compound was synthesized by the method described in Step 1 of Example 41, except that 6-bromo-3H-imidazo[4,5-b]pyridine (500.00 mg, 2.525 mmol) was used. Yield: 480 mg (90.5%) as a brown solid. MS (ESI, positive ion) m / z: 163.10 (M+1).

[0464] Step 2: 4-((6-carbamoylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (68a) and 4-((6-carbamoylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (68b) [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 3H-imidazo[4,5-b]pyridine-6-carboxamide (490 mg, 3.022 mmol) was used. Two fractions were obtained.

[0465] Fraction 1: Rt: 3.53 min. 34.7 mg (3.9% yield) of 4-((6-carbamoylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (68a) as a white solid. MS (ESI, positive ion) m / z: 297.10 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.89(s,1H),8.72(d,J=1.9Hz,1H),8.57(d,J=2.2Hz,1H),8.14(s,1H),8.05(d,J= 1.9Hz,2H),7.74(d,J=7.6Hz,2H),7.52(s,1H),7.28(d,J=7.7Hz,2H),5.55(s,2H).

[0466] Fraction 2: Rt: 4.00 min. 4.2 mg (0.5% yield) of 4-((6-carbamoylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (68b) as a white solid. MS (ESI, positive ion) m / z: 297.10 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.95(s,1H),8.80(s,1H),8.38(s,1H),8.25(s,3H),7.79-7.67(m,3H),7.44(d,J=7.7Hz,2H),5.94(s,2H).

[0467] Example 69 Synthesis of (4-((1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that benzimidazole (234.00 mg, 1.981 mmol) was used. Yield: 221.4 mg (44.2%) as a white solid. MS (ESI, positive ion) m / z: 253.25 (M+1). 1 H NMR (300 MHz, DMSO-d 6, ppm)δ 8.53(d,J=11.8Hz,1H),8.05(d,J=1.8Hz,1H),7.83(d,J=7.4Hz,1H),7.73(t ,J=7.0Hz,2H),7.55-7.46(m,1H),7.30-7.15(m,4H),5.51(d,J=5.8Hz,2H).

[0468] Example 70 Synthesis of 4-((6-methoxypurin-9-yl)methyl)phenylboronic acid (70a) and 4-((6-methoxypurin-7-yl)methyl)phenylboronic acid (70b) [ka] Step 1: 4-((6-methoxypurin-9-yl)methyl)phenylboronic acid (70a) and 4-((6-methoxypurin-7-yl)methyl)phenylboronic acid (70b) [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 6-methoxy-9H-purine (200 mg, 1.332 mmol) was used. Two fractions were obtained.

[0469] Fraction 1: Rt: 8.5 min. 140 mg (35.9% yield) of 4-((6-methoxypurin-9-yl)methyl)phenylboronic acid (70a) as a white solid. MS (ESI, positive ion) m / z: 285.25 (M+1). 1H NMR(300MHz,DMSO-d6,ppm)δ 8.51(d,J=6.0Hz,2H),8.03(s,2H),7.76-7.68(m,2H),7.27-7.20(m,2H),5.46(s,2H),4.07(s,3H).

[0470] Fraction 2: Rt: 8.9 min. 72.2 mg (18.8% yield) of 4-((6-methoxypurin-7-yl)methyl)phenylboronic acid (70b) as a white solid. MS (ESI, positive ion) m / z: 285.25 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.67(s,1H),8.52(s,1H),8.03(s,2H),7.76-7.69(m,2H),7.24-7.17(m,2H),5.54(s,2H),4.02(s,3H).

[0471] Example 71 Synthesis of (4-((4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid [ka] Step 1: 4-((4-methoxypyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 1.341 mmol) was used. Yield: 270 mg (71.1%). MS (ESI, positive ion) m / z: 284.15 (M+1).

[0472] Step 2: (4-((4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 35, except that 4-((4-methoxypyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenylboronic acid (270.00 mg, 0.95 mmol) was used. Yield: 129.9 mg (50.2%) as a white solid. MS (ESI, positive ion) m / z: 270.30 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 11.90(s,1H),8.00(s,2H),7.88(d,J=3.6Hz,1H),7.73-7.66(m,2H),7.14(d,J=7.9Hz,3H),6.48(d,J=3.3Hz,1H),5.32(s,2H).

[0473] Example 72 Synthesis of 4-((4-hydroxypyrrolo[2,3-b]pyridin-1-yl)methyl)phenylboronic acid [ka] Step 1: 4-((4-methoxypyrrolo[2,3-b]pyridin-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 4-methoxy-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.35 mmol) was used. Yield: 270 mg (70.9%) as a white solid. MS (ESI, positive ion) m / z: 283.10 (M+1).

[0474] Step 2: 4-((4-hydroxypyrrolo[2,3-b]pyridin-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 35, except that 4-((4-methoxypyrrolo[2,3-b]pyridin-1-yl)methyl)phenylboronic acid (230.00 mg, 0.81 mmol) was used. Yield: 47.8 mg (21.4%) as a white solid. MS (ESI, positive ion) m / z: 267.05 (M-1). 1 H NMR (300 MHz, DMSO-d / DO, ppm) 1 H NMR(400MHz,DMSO-d6)δ 7.95(s,1H),7.69(d,J=7.8Hz,2H),7.31(d,J=13.6Hz,1H),7.14(d,J=7.6Hz,2H),6.49(d,J=13.9Hz,2H),6.05(s,1H),5.40(s,2H).

[0475] Example 73 Synthesis of 4-((2-carbamoylpyrrolo[3,2-d]pyrimidin-5-yl)methyl)phenylboronic acid [ka] Step 1: 5H-pyrrolo[3,2-d]pyrimidine-2-carboxamide [ka] The title compound was synthesized by the method described in Step 1 of Example 41, except that 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (300 mg, 1.95 mmol) was used. Yield: 227 mg (63.8%) as a brown solid. MS (ESI, positive ion) m / z: 162.9 (M+1).

[0476] Step 2: 4-((2-carbamoylpyrrolo[3,2-d]pyrimidin-5-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 5H-pyrrolo[3,2-d]pyrimidine-2-carboxamide (100.00 mg, 0.62 mmol) was used. Yield: 4.2 mg (2.3%) as a white solid. MS (ESI, positive ion) m / z: 297.30 (M+1). 1 H NMR(400MHz,DMSO-d6)δ 9.12(s,1H),8.38-7.99(m,4H),7.74(d,J=7.7Hz,2H),7.57(s,1H),7.26(d,J=7.7Hz,2H),6.78(d,J=3.2Hz,1H),5.61(s,2H).

[0477] Example 74 Synthesis of 4-((7-chloroimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (74a) and 4-((7-chloroimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (74b) [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 7-chloro-3H-imidazo[4,5-b]pyridine (300.00 mg, 1.954 mmol) was used. Two fractions were obtained.

[0478] Fraction 1: Rt: 4.92 min. 36.2 mg (6.1% yield) of 4-((7-chloroimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (74a) as a white solid. MS (ESI, positive ion) m / z: 288.20 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.72(s,1H),8.33(d,J=5.2Hz,1H),8.04(d,J=3.3Hz,2H),7.78-7.69(m,2H),7.46(d,J=5.2Hz,1H),7.32-7.23(m,2H),5.53(s,2H).

[0479] Fraction 2: Rt: 5.08 min. 23.3 mg (4.0% yield) of 4-((7-chloroimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (74) as a white solid. MS (ESI, positive ion) m / z: 288.20 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.78(s,1H),8.38(d,J=5.2Hz,1H),8.04(d,J=3.4Hz,2H),7.78-7.69(m,2H),7.37(d,J=5.2Hz,1H),7.07(d,J=7.9Hz,2H),5.75(s,2H).

[0480] Example 75 Synthesis of 4-((5-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (75a) and 4-((6-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (75b) [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 5-chloro-1H-benzo[d]imidazole (150 mg, 0.97 mmol) was used. Yield: 92.3 mg (32.0%) of a mixture of 4-((5-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid and 4-((6-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (ratio=1:1) as a white solid. MS (ESI, positive ion) m / z: 287.20 (M+1). 1H NMR(300MHz,DMSO-d6,ppm)δ 8.50(d,J=7.4Hz,1H),8.05(d,J=1.5Hz,2H),7.81-7.63(m,3H),7.54(d,J=8.6Hz,1H),7.32-7.18(m,3H),5.53(s,2H).

[0481] Example 76 Synthesis of 4-((4-cyano-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (76a) and 4-((7-cyano-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (76b) [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 1H-benzo[d]imidazole-4-carbonitrile (120 mg, 0.84 mmol) was used. The crude product was purified by preparative HPLC (column: C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 14 B to 20 B in 12 min; 254 / 220 nm; RT1: 7.32 min; RT2: 8.00 min) to give two fractions.

[0482] Fraction 1: Rt: 7.32 min. 48.6 mg (14.5% yield) of 4-((4-cyano-1,3-benzodiazol-1-yl)methyl)phenylboronic acid as an off-white solid. MS (ESI, positive ion) m / z: 278.20 (M+1). 1 H NMR(300MHz,DMSO-d6 / D2O,ppm)δ 8.63(s,1H),7.77(dd,J=42.8,7.6Hz,4H),7.50-6.92(m,3H),5.55(s,2H).

[0483] Fraction 2: Rt: 8.00 min. 7.6 mg (2.3% yield) of 4-((7-cyano-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (7.6 mg) as an off-white solid. MS (ESI, positive ion) m / z: 278.20 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)8.14-8.04(m,1H),8.06(s,3H),7.79-7.70(m,3H),7.45-7.26(m,1H),7.10(d,J=7.8Hz,2H),5.76(s,2H).

[0484] Example 77 Synthesis of 4-((4-aminoimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 1H-imidazo[4,5-c]pyridin-4-amine (300 mg, 2.24 mmol) was used. The crude product was purified by preparative HPLC under the following conditions: column: C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 1 B to 15 B in 8 min; 254 / 220 nm; to give 4-((4-aminoimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (160.9 mg, 26.7% yield) as a white solid. MS (ESI, positive ion) m / z: 269.20 (M+1). 1 H NMR(300MHz,DMSO-d6 / D2O,ppm)δ 8.34(s,1H),8.18(s,1H),7.73(d,J=7.8Hz,2H),7.61(d,J=6.1Hz,1H),7.24(d,J=8.0Hz,2H),6.84(d,J=6.1Hz,1H),5.44(s,2H).

[0485] Example 78 Synthesis of 4-((4-amino-1,3-benzodiazol-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 1H-1,3-benzodiazol-4-amine (100 mg, 0.75 mmol) was used. The crude product was purified by preparative HPLC under the following conditions: column: C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN; flow rate: 45 mL / min; gradient: 15 B to 35 B in 7 min; 254 nm, 220 nm) to give 4-((4-amino-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (37.2 mg, 19% yield) as a white solid. MS (ESI, positive ion) m / z: 268.25 (M+1). 1H NMR(300MHz,DMSO-d6,ppm)δ 8.16(s,1H),8.02(s,2H),7.73(d,J=7.8Hz,2H),7.21(d,J=7.8Hz,2H),6.86(t,J=7.8Hz ,1H),6.60(dd,J=8.1,1.0Hz,1H),6.35(dd,J=7.6,0.9Hz,1H),5.39(s,2H),5.26(s,2H).

[0486] Example 79 Synthesis of 4-((5-methoxyimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (79a), 4-((5-methoxyimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (79b), and (4-((5-hydroxy-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenyl)boronic acid (79c) [ka] Step 1: 6-Methoxypyridine-2,3-diamine [ka] The title compound was synthesized by the method described in Step 5 of Example 30, except that 6-methoxy-2-nitropyridin-3-amine (2.00 g, 11.83 mmol) was used. Yield: 910 mg (45.6%). MS (ESI, positive ion) m / z: 139.90 (M+1).

[0487] Step 2: 5-Methoxy-1H-imidazo[4,5-b]pyridine [ka] A solution of 6-methoxypyridine-2,3-diamine (910 mg, 6.54 mmol, 1.00 equiv) in formic acid (30 mL) was stirred in an oil bath at 105° C. for 8 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, eluent: ethyl acetate / petroleum ether 100:0) to give 5-methoxy-1H-imidazo[4,5-b]pyridine (810 mg, 78.6% yield) as a pink solid.

[0488] Step 3: 4-((5-methoxyimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (79a) and 4-((5-methoxyimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (79b) [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 5-methoxy-1H-imidazo[4,5-b]pyridine (810 mg, 5.43 mmol) was used. The crude product was purified by preparative HPLC using the following conditions: Column: C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 16 B to 20 B in 10 min; 254 / 220 nm; RT1: 7.8 min; RT2: 9.0 min. The fractions containing the desired product were combined and lyophilized to give two fractions.

[0489] Fraction 1: Rt: 7.8 min. 310 mg (17.2% yield) of 4-((5-methoxyimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (79a) as a white solid. MS (ESI, positive ion) m / z: 284.25 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.47(s,1H),8.04(d,J=3.3Hz,2H),7.86(d,J=8.7Hz,1H),7.79-7.70(m,2 H),7.25(d,J=7.8Hz,2H),6.68(d,J=8.7Hz,1H),5.49(s,2H),3.87(s,3H).

[0490] Fraction 2: Rt: 9.0 min. 254.2 mg (15.9% yield) of 4-((5-methoxyimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (79b) as a white solid. MS (ESI, positive ion) m / z: 284.20 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.39(s,1H),8.07-7.95(m,3H),7.75(d,J=7.9Hz,2H),7.37(dd,J=7.7,5.8Hz,2H),6.71(d,J=8.6Hz,1H),5.42(s,2H),3.90(d,J=4.4Hz,3H).

[0491] Step 4: (4-((5-hydroxy-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenyl)boronic acid (79c) [ka] To a stirred solution of 4-((5-methoxyimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (100 mg, 0.353 mmol, 1.00 equiv) in DCM (4.00 mL) was added BBr3 (3.00 mL) at room temperature. After stirring at room temperature for 3 days, the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 3 B to 30 B in 7 min; 254 / 220 nm) to give 4-((5-hydroxyimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (65.4 mg, 66.9% yield) as a white solid. MS (ESI, positive ion) m / z: 270.20 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 11.63(s,1H),8.21(s,1H),8.06(s,2H),7.75(d,J=7.6Hz,2H),7.69(d,J=9.1Hz,1H),7.25(d,J=7.5Hz,2H),6.20(d,J=9.2Hz,1H),5.41(s,2H).

[0492] Example 80 Synthesis of (4-((5-carbamoyl-1H-benzo[d]imidazol-1-yl)methyl)-3-methylphenyl)boronic acid (80a) and (4-((6-carbamoyl-1H-benzo[d]imidazol-1-yl)methyl)-3-methylphenyl)boronic acid (80b) [ka] Step 1: methyl 1-(4-bromo-2-methylbenzyl)-1H-benzo[d]imidazole-5-carboxylate and methyl 1-(4-bromo-2-methylbenzyl)-1H-benzo[d]imidazole-6-carboxylate [ka] Methyl 1H-benzo[d]imidazole-5-carboxylate (1.60 g, 9.082 mmol, 1.00 equiv.) was dissolved in MeOH (30.00 mL). 4-Bromo-1-(bromomethyl)-2-methylbenzene (2.88 g, 10.898 mmol, 1.20 equiv.) and CsCO (3.85 g, 11.806 mmol, 1.30 equiv.) were added. After stirring at room temperature for 12 hours, the reaction mixture was concentrated under reduced pressure. The residue was poured into water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: DCM / MEOH 97:3) to give 2.7 g (81.9% yield) of a mixture of 1-(4-bromo-2-methylbenzyl)-1H-benzo[d]imidazole-5-carboxylate and methyl 1-(4-bromo-2-methylbenzyl)-1H-benzo[d]imidazole-6-carboxylate as a yellow solid.

[0493] Step 2: methyl 1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazole-5-carboxylate and methyl 1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazole-6-carboxylate [ka] To a mixture of 1-(4-bromo-2-methylbenzyl)-1H-benzo[d]imidazole-5-carboxylate and methyl 1-(4-bromo-2-methylbenzyl)-1H-benzo[d]imidazole-6-carboxylate (1.50 g, 4.134 mmol, 1.00 equiv, 99%) in dioxane (20.00 mL), bis(pinacolato)diboron (2.14 g, 8.268 mmol, 2.00 equiv), KOAc (1.01 g, 10.335 mmol, 2.50 equiv), and Pd(dppf)Cl.CHCl (338 mg, 0.413 mmol, 0.10 equiv) were added at room temperature. After stirring at 90 °C for 6.5 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: EA:PE 1:2) to give 1.4 g (79% yield) of a mixture of methyl 1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazole-5-carboxylate and methyl 1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazole-6-carboxylate as a yellow oil.

[0494] Step 3: (4-((5-(methoxycarbonyl)-1H-benzo[d]imidazol-1-yl)methyl)-3-methylphenyl)boronic acid and (4-((6-(methoxycarbonyl)-1H-benzo[d]imidazol-1-yl)methyl)-3-methylphenyl)boronic acid [ka] To a solution of 1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazole-5-carboxylate and methyl 1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazole-6-carboxylate (1.40 g, 3.446 mmol, 1.00 equiv.) in THF (20 mL) and HO (5 mL) was added NaIO (2.21 g, 10.337 mmol, 3.00 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes, followed by the addition of 3N HCl (10.00 mL). After stirring at room temperature for 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: ethyl acetate / methanol 19:1) to afford 0.8 g (71% yield) of a mixture of (4-((5-(methoxycarbonyl)-1H-benzo[d]imidazol-1-yl)methyl)-3-methylphenyl)boronic acid and (4-((6-(methoxycarbonyl)-1H-benzo[d]imidazol-1-yl)methyl)-3-methylphenyl)boronic acid as a pale yellow solid.

[0495] Step 4: (4-((5-carbamoyl-1H-benzo[d]imidazol-1-yl)methyl)-3-methylphenyl)boronic acid (80a) and (4-((6-carbamoyl-1H-benzo[d]imidazol-1-yl)methyl)-3-methylphenyl)boronic acid 80b) [ka] A mixture of 4-((5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)-3-methyl-phenylboronic acid and 4-((6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)-3-methylphenylboronic acid) (120 mg, 0.370 mmol, 1.00 equiv) was dissolved in aqueous ammonia (10 mL). After stirring at 80° C. for 24 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 15 B to 25 B in 7 min; 254, 220 nm; RT1: 6.68 min; RT2: 7.22 min. The fractions containing the desired product were combined and lyophilized to give two fractions.

[0496] Fraction 1: Rt: 6.68 min. 9.4 mg (7.8% yield) of (4-((5-carbamoyl-1H-benzo[d]imidazol-1-yl)methyl)-3-methylphenyl)boronic acid (80a) as a white solid. MS (ESI, positive ion) m / z: 310.3 (M+1). 1 H NMR(300MHz,DMSO-d6,ppm)δ 8.42-8.25(m,2H),8.09-7.94(m,3H),7.77(d,J=8.2Hz,1H),7.63(s,1H),7.55-7. 40(m,2H),7.27(s,1H),6.68(d,J=7.8Hz,1H),5.56(s,2H),2.31(d,J=2.6Hz,3H).

[0497] Fraction 2: Rt: 7.22 min. 5.8 mg (5.1% yield) of (4-((6-carbamoyl-1H-benzo[d]imidazol-1-yl)methyl)-3-methylphenyl)boronic acid (80b) as a white solid. MS (ESI, positive ion) m / z: 310.3 (M+1). 1H-NMR(300MHz,DMSO-d6,ppm)δ 8.37(d,J=2.1Hz,1H),8.28(s,1H),8.09-7.94(m,3H),7.77(d,J=8.2Hz,1H),7.63(s,1H), 7.55-7.40(m,2H),7.27(s,1H),6.68(d,J=7.8Hz,1H),5.56(s,2H),2.31(d,J=2.6Hz,3H).

[0498] Example 81 Synthesis of 4-((4-(difluoromethyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid [ka] Step 1: 1H-1,3-benzodiazol-4-ylmethanol [ka] To a stirred solution of 1H-1,3-benzodiazole-4-carboxylic acid (2.00 g, 12.34 mmol, 1.00 equiv) in THF (30.00 mL) was added LiAlH (9 mL, 2.5 M in THF) in small portions at −70 °C under an argon atmosphere. After stirring at room temperature for 12 h, the reaction mixture was quenched with methanol at room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: ethyl acetate / petroleum ether 3:7) to give 1H-1,3-benzodiazol-4-ylmethanol (1.20 g, 66.0% yield) as an orange solid.

[0499] Step 2: 1H-1,3-benzodiazole-4-carbaldehyde [ka] To a stirred solution of 1H-1,3-benzodiazol-4-ylmethanol (1.20 g, 8.10 mmol, 1.00 equiv) in DCM (25.00 mL) was added Dess-Martin (6870.32 mg, 16.20 mmol, 2.00 equiv) at room temperature. After stirring at room temperature for 12 hours, saturated sodium thiosulfate solution (100 mL) was added. The mixture was extracted with DCM, and the combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate 42:58) to give 1H-1,3-benzodiazole-4-carbaldehyde (400 mg, 33.8%) as a white solid.

[0500] Step 3: 1-((4-bromophenyl)methyl)-1,3-benzodiazole-4-carbaldehyde [ka] The title compound was synthesized by the method described in Step 2 of Example 55, except that 1H-1,3-benzodiazole-4-carbaldehyde (400.00 mg, 2.74 mmol) and 1-bromo-4-(bromomethyl)benzene (1.03 g, 4.12 mmol) were used. The crude product was purified by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate 4:6) to afford 1-((4-bromophenyl)methyl)-1,3-benzodiazole-4-carbaldehyde (400 mg, 43.1% yield) as a white solid.

[0501] Step 4: 1-((4-bromophenyl)methyl)-4-(difluoromethyl)-1,3-benzodiazole [ka] To a stirred solution of 1-((4-bromophenyl)methyl)-1,3-benzodiazole-4-carbaldehyde (420 mg, 1.33 mmol, 1.00 equiv) in DCE (10 mL) was added BAST (bis(2-methoxyethyl)aminosulfur trifluoride, 0.5 mL) at room temperature. After stirring at room temperature for 12 h, the resulting mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate 32:68) to give the crude product, which was further purified by preparative HPLC under the following conditions (column: Sunfire prep C18, 30*250, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 45 mL / min; gradient: 54 B to 95 B in 8 min; 254 / 220 nm; RT: 7.3 min) to give 1-((4-bromophenyl)methyl)-4-(difluoromethyl)-1,3-benzodiazole (120 mg, 25.3% yield) as a white solid.

[0502] Step 5: 4-(Difluoromethyl)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-methyl)-1,3-benzodiazole [ka] To a stirred mixture of 1-((4-bromophenyl)methyl)-4-(difluoromethyl)-1,3-benzodiazole (120 mg, 0.36 mmol, 1.00 equiv.) in dioxane (10 mL), KOAc (70 mg, 0.71 mmol, 2.00 equiv.), bis(pinacolato)diboron (180 mg, 0.1 equiv.), and Pd(dppf)Cl (26 mg, 0.036 mmol, 0.10 equiv.) were added under an argon atmosphere at room temperature. After stirring in an oil bath at 100° C. for 12 hours, the resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate 3:7) to give 4-(difluoromethyl)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)-1,3-benzodiazole (130 mg, yield 86.41%) as a white solid.

[0503] Step 6: 4-((4-(difluoromethyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 3 of Example 80, except that 4-(difluoromethyl)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)-1,3-benzodiazole (110.00 mg, 0.29 mmol) was used. The crude product was purified by preparative HPLC under the following conditions (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10 B to 50 B in 7 min; 254, 220 nm) to give 4-((4-(difluoromethyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (10.8 mg, 12.3% yield) as an off-white solid. MS (ESI, positive ion) m / z: 303.05 (M+1). 1H NMR(300MHz,DMSO-d6,ppm)δ 8.55(s,1H),8.03(s,2H),7.72(m,3H),7.31(m,5H),5.56(s,2H).

[0504] Example 82 Synthesis of 3,5-difluoro-4-((4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid [ka] Step 1: 4-Methoxy-1H-imidazo[4,5-c]pyridine [ka] A solution of 4-chloro-1H-imidazo[4,5-c]pyridine (1.00 g, 6.51 mmol, 1.00 equiv) in sodium methanolate (17 mL, 30% in MeOH) was stirred at 120° C. for 12 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-methoxy-1H-imidazo[4,5-c]pyridine (520 mg, 50%) as a white solid.

[0505] Step 2: 1-((4-bromo-2,6-difluorophenyl)methyl)-4-methoxyimidazo[4,5-c]pyridine [ka] The title compound was synthesized by the method described in Step 1 of Example 80, except that 4-methoxy-1H-imidazo[4,5-c]pyridine (520 mg, 3.49 mmol) and 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.20 g, 4.18 mmol) were used. The crude product was purified by preparative HPLC under the following conditions (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10 B to 50 B in 7 min; 254 / 220 nm;) to give 1-((4-bromo-2,6-difluorophenyl)methyl)-4-methoxyimidazo[4,5-c]pyridine (420 mg, 33.4% yield) as a white solid.

[0506] Step 3: 1-((2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)-4-methoxyimidazo[4,5-c]pyridine [ka] The title compound was synthesized by the method described in Step 2 of Example 80, except that 1-((4-bromo-2,6-difluorophenyl)methyl)-4-methoxyimidazo[4,5-c]pyridine (370 mg, 1.05 mmol) was used. Yield: 400 mg (81.6%). MS (ESI, positive ion) m / z: 401.90 (M+1).

[0507] Step 4: 3,5-Difluoro-4-((4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid [ka] The title compound was synthesized by the method described in Step 3 of Example 80, except that 1-((4-bromo-2,6-difluorophenyl)methyl)-4-methoxyimidazo[4,5-c]pyridine (370 mg, 1.05 mmol) was used. Yield: 23.2 mg (16.0%). MS (ESI, positive ion) m / z: 306.00 (M+1). H NMR (300 MHz, DMSO-d6, ppm) δ 11.22 (s, 1H), 8.48 (s, 2H), 8.07 (s, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.20 (t, J = 5.8 Hz, 1H), 6.46 (d, J = 7.0 Hz, 1H), 5.50 (s, 2H).

[0508] Example 83 Synthesis of 3,5-difluoro-4-((4-hydroxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid [ka] Step 1: 4-Methoxy-1H-pyrrolo[3,2-c]pyridine [ka] The title compound was synthesized by the method described in Step 1 of Example 82, except that 4-chloro-1H-pyrrolo[3,2-c]pyridine (2.00 g, 13.11 mmol) was used. Yield: 840 mg (38.2%). MS (ESI, positive ion) m / z: 149.15 (M+1).

[0509] Step 2: 1-((4-bromo-2,6-difluorophenyl)methyl)-4-methoxypyrrolo[3,2-c]pyridine [ka] The title compound was synthesized by the method described in Step 1 of Example 80, except that 4-methoxy-1H-pyrrolo[3,2-c]pyridine (0.80 g, 5.40 mmol) and 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.70 g, 5.939 mmol) were used. The crude product was purified by column chromatography (silica gel, eluent: DCM / MEOH 98:2) to give 1-((4-bromo-2,6-...

Claims

1. Compounds of formula (I): 【Chemistry 1】 (In the formula, a, b, d, and e are CH; or one or two of a, b, d, and e are N and the remaining a, b, d, and e are CH; One of y and z is N, and the other y and z is CR 7 or both y and z are CR 7 and each R 7 is independently hydrogen, alkyl, hydroxy, or halo; alk is alkylene optionally substituted with 1, 2, or 3 halo; alk 1 is alkylene, wherein one carbon atom in the alkylene chain may be replaced by oxygen, and said alkylene chain is optionally substituted with 1, 2 or 3 halo; m and n are independently 0 or 1; provided that at least one of m and n is 1; Ar is aryl or heteroaryl; R w and R x are independently selected from hydroxy, alkoxy, -Oaryl (aryl is optionally substituted with 1 to 3 substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH 2 ) O.C.O.R. c (R c is alkyl), —O—(alk 2 ) OR d (alk 2 is alkylene, and R d is alkyl; or R w and R x together with the boron atom to which they are attached form -O(CRR') 2 O- or -O(CRR') 3 O-, where each R and R' is independently hydrogen or methyl; R 2 and R 3 is independently hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano; R 4 is hydrogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl; and R 5 and R 6 R is independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, amino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, where either heterocyclyl alone or the heterocyclyloxy and heterocyclylamino portions are optionally independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl. h , R j , or R k substituted with), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino, where the heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl, cycloalkyloxy, phenyloxy, or heteroaryloxy, where the phenyl in phenyloxy and the heteroaryl in heteroaryloxy are optionally substituted with 1, 2, or 3 substituents, two of the optional substituents being independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; or Pharmaceutically acceptable salts thereof (wherein formula (I) is the structure 【Chemistry 2】 and (i) R w and R x are each —OH, 【Chemistry 3】 is 4-((6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)methyl)phenyl; 4-((5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 4-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 5-fluoro-2-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 3-fluoro-4-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 3-((5,6-dimethyl-1H-benzimidazol-1-yl)methyl)phenyl; 4-((5,6-dimethyl-1H-benzimidazol-1-yl)methyl)phenyl; 2-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 2-((5,6-dimethyl-1H-benzimidazol-1-yl)methyl)phenyl; 2-fluoro-5-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 3-((2-methyl-1H-benzimidazol-1-yl)methyl)phenyl; 3-(1H-benzimidazol-1-ylmethyl)phenyl; 3-(1H-indazol-1-ylmethyl)phenyl; 2-(1H-benzimidazol-1-ylmethyl)phenyl; 4-(1H-benzimidazol-1-ylmethyl)phenyl; 4-(1H-indol-1-ylmethyl)phenyl; 4-((6-amino-9H-purin-9-yl)methyl)phenyl; 3-((6-amino-9H-purin-9-yl)methyl)phenyl; 2-((6-amino-9H-purin-9-yl)methyl)phenyl; 4-(1H-benzoimidazol-1-ylmethyl)-3-fluorophenyl; 4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-fluorophenyl; 5-(1H-benzoimidazol-1-ylmethyl)-2-fluorophenyl; 4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-fluorophenyl; not 2-(1H-benzimidazol-1-ylmethyl)-5-fluorophenyl; 5-(1H-benzimidazol-1-ylmethyl)-2-methoxyphenyl; 3-(1H-benzimidazol-1-ylmethyl)-4-methoxyphenyl; 2-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-pyrimidinyl, 6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-pyridinyl, or 4-(2-ethoxy-7-carboxy-1H-benzimidazol-1-ylmethyl)phenyl; (ii) -B(R w ) (R x )but, 【Chemistry 4】 When 【Chemistry 5】 are 2-(1H-benzo[d]imidazol-1-ylmethyl)phenyl, 2-(1H-indol-1-ylmethyl)phenyl, 3-(1H-indazol-1-ylmethyl)phenyl-, 4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methylphenyl, 4-(2-methyl-1H-benzimidazol-1-ylmethyl)phenyl; 4-(6-amino-8-methoxy-2-(tetrahydro-2H-pyran-4-yl)methoxy-9H-purin-9-ylmethyl)phenyl, 3-fluoro-4-(6-amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-9-ylmethyl)phenyl, 4-(6-amino-8-methoxy- is not 2-(2-methoxyethoxy)-9H-purin-9-ylmethyl)phenyl, 4-(6-amino-2-butoxy-8-methoxy-9H-purin-9-ylmethyl)phenyl, 4-(1H-indol-1-ylmethyl)phenyl, 4-(1H-benimidazol-1-ylmethyl)phenyl, 3-(7-methoxycarbonyl-1H-indol-1-ylmethyl)phenyl, 4-(7-methoxycarbonyl-1H-indol-1-ylmethyl)phenyl, 4-(2-ethoxy-7-methoxycarbonyl-1H-benzimidazol-1-ylmethyl)phenyl, or 4-(2-ethoxy-7-ethoxycarbonyl-1H-benzimidazol-1-ylmethyl)phenyl; and (iii)-B(2 w )(2 x )が、 【Chemistry 6】 When 【Chemistry 7】 is not 4-(2-ethoxy-7-ethoxycarbonyl-1H-benzimidazol-1-ylmethyl)phenyl).

2. Structure of Formula (Ia): 【Chemistry 8】 2. The compound of claim 1 having the formula: wherein one of d and e is N, and the remainder of a, b, c and d are CH; or a pharma- ceutically acceptable salt thereof.

3. Structure of formula (Ie): 【Chemistry 9】 2. The compound of claim 1 having the formula:

4. Structure of formula (Ii): 【Chemistry 10】 3. The compound of claim 2 having the formula: or a pharma- ceutically acceptable salt thereof.

5. Structure of formula (Ij): 【Chemistry 11】 (In the formula, R 7 is alkyl, halo, or hydroxy, or a pharma- ceutically acceptable salt thereof.

6. R 7 6. The compound of claim 4 or 5, or a pharma- ceutically acceptable salt thereof, wherein: is alkyl.

7. R 7 6. The compound according to claim 4 or 5, wherein is methyl or isopropyl, or a pharma- ceutically acceptable salt thereof.

8. Structure of Formula (Ia) or (Ib): 【Chemistry 12】 2. The compound of claim 1 having the formula:

9. 9. The compound of claim 8 having the structure of Formula (Ia): or a pharma- ceutically acceptable salt thereof.

10. 9. The compound of claim 8 having the structure of formula (Ib): or a pharma- ceutically acceptable salt thereof.

11. The compound according to any one of claims 8 to 10, or a pharma- ceutically acceptable salt thereof, wherein a, b, d, and e are CH.

12. 11. The compound according to any one of claims 8 to 10, wherein a is N, and b, d, and e are CH, or a pharma- ceutically acceptable salt thereof.

13. 11. The compound according to any one of claims 8 to 10, wherein a and d are N, and b and e are CH, or a pharma- ceutically acceptable salt thereof.

14. 11. The compound according to any one of claims 8 to 10, wherein b is N and a, c, and e are CH, or a pharma- ceutically acceptable salt thereof.

15. 11. The compound according to any one of claims 8 to 10, wherein b and e are N, and a and d are CH, or a pharma- ceutically acceptable salt thereof.

16. 11. The compound according to any one of claims 8 to 10, wherein d is N, and a, b and e are CH, or a pharma- ceutically acceptable salt thereof.

17. -B(R w ) (R x ) is -B(OH) 2 17. The compound according to any one of claims 1 to 16, wherein:

18. -B(R w ) (R x ) is R w and R x 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein is independently selected from hydroxy and alkoxy.

19. -B(R w ) (R x ) is R w and R x together with the boron atom to which they are attached to form a ring of formula (b) or (c): 【Chemistry 13】 17. The compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, which forms:

20. 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, wherein Ar is phenyl.

21. -B(R w ) (R x 21. The compound of claim 20, wherein: R is an integer from 1 to 10; and R is an integer from 1 to 10.

22. The compound of claim 20, wherein R is an integer from 1 to 10; and R is an integer from 1 to 10.

22. 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, wherein Ar is heteroaryl.

23. 23. The compound of claim 22, or a pharma- ceutically acceptable salt thereof, wherein Ar is pyridinyl, pyrimidinyl, pyridazinyl, thienyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, oxadiazolyl, or imidazolyl.

24. alk and alk 1 is independently methylene, ethylene, or propylene, or a pharma- ceutically acceptable salt thereof.

25. alk and alk 1 The compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, wherein is methylene.

26. R 7 26. The compound according to any one of claims 1 to 3 and 8 to 25, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen, methyl, isopropyl, or fluoro.

27. R 7 27. The compound of claim 26, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen, methyl, or fluoro.

28. R 2 and R 3 28. The compound of any one of claims 1 to 27, or a pharma- ceutically acceptable salt thereof, wherein is independently hydrogen, methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, or cyano.

29. R 2 and R 3 The compound according to any one of claims 1 to 27, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

30. R 4 30. The compound of any one of claims 1 to 29, wherein is hydrogen, alkyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl, or a pharma- ceutically acceptable salt thereof.

31. R 4 31. The compound of claim 30, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen, methyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, cyano, or trifluoromethyloxy.

32. R 4 30. The compound according to any one of claims 1 to 29, wherein is cyano, carboxy, alkoxycarbonyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl, or a pharma- ceutically acceptable salt thereof.

33. R 4 33. The compound of claim 32, wherein is cyano, carboxy, methoxycarbonyl, aminocarbonyl, methylsulfonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl, or a pharma- ceutically acceptable version thereof.

34. R 4 is a 6-membered ring comprising a, b, d, and e of formula I as shown below 【Chemistry 14】 33. The compound of claim 32, wherein the wavy line indicates the point of attachment to the remainder of the molecule, or a pharma- ceutically acceptable salt thereof.

35. R 5 and R 6 The compound according to any one of claims 1 to 34, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

36. R 5 and R 6 32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, wherein is independently hydrogen, alkyl, alkoxy, hydroxy, amino, halo, haloalkyl, or haloalkoxy.

37. R 5 is a 6-membered ring comprising a, b, d, and e of formula I as shown below 【Chemistry 15】 37. The compound of claim 36, wherein the wavy line indicates the point of attachment to the remainder of the molecule, or a pharma- ceutically acceptable salt thereof.

38. R 5 is hydroxy and R 4 and R 6 38. The compound of claim 37, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

39. R 5 and R 6 is a 6-membered ring comprising a, b, d, and e of formula I as shown below 【Chemistry 16】 37. The compound of claim 36, wherein the wavy line indicates the point of attachment to the remainder of the molecule, or a pharma- ceutically acceptable salt thereof.

40. R 5 is hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, or haloalkoxy; and R 6 is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein either heterocyclyl alone or the heterocyclyloxy and heterocyclylamino portions are optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein either heterocyclylalkyl, heterocyclylalkyi, 32. The compound of any one of claims 1 to 31, wherein the heterocyclyl ring in heterocyclylalkylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy, wherein the phenyl in phenyloxy and the heteroaryl in heteroaryloxy are optionally substituted with one, two, or three substituents, two of the optional substituents being independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano, or a pharma- ceutically acceptable salt thereof.

41. R 5 is hydrogen, methoxy, ethoxy, or hydroxy, and R 6 However, 2-hydroxyethyloxy, 3-hydroxypropyloxy, 2-methoxyethyloxy, 2-ethoxyethyloxy, 3-methoxypropyloxy, 3-ethoxypropyloxy, 2-aminoethyloxy, 2-methylaminoethyloxy, 2-dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3-aminopropyloxy, 3-methylaminopropyloxy, 3-dimethylaminopropyloxy, 3-diethylaminopropyloxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethyloxy, piperidinylmethyloxy, pyrrolidinylethyloxy, piperidinylethyloxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropyl 41. The compound of claim 40, wherein the arylamino group is arylamino, 3-ethoxypropylamino, 2-aminoethylamino, 2-methylaminoethylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-aminopropylamino, 3-methylaminopropylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, pyrrolidinylamino, piperidinylamino, pyrrolidinylmethylamino, piperidinylmethylamino, pyrrolidinylethylamino, or piperidinylethylamino, wherein pyrrolidinyl and piperidinyl, either alone or as part of another group, in each of the aforementioned groups, are optionally substituted with 1 or 2 substituents independently selected from methyl, fluoro, hydroxy, or methoxy, or a pharma- ceutically acceptable salt thereof.

42. R 5 and R 6 is a 6-membered ring comprising a, b, d, and e of formula I as shown below 【Chemistry 17】 42. The compound of claim 40 or 41, wherein the compound is attached to: or a pharma- ceutically acceptable salt thereof.

43. R 5 and R 6 are independently hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein either heterocyclyl alone or the heterocyclyloxy and heterocyclylamino portions are optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein either heterocyclylalkyl, heterocyclyloxy, 32. The compound of any one of claims 1 to 31, wherein the heterocyclyl ring in heterocyclylalkylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl, cycloalkyloxy, phenyloxy, or heteroaryloxy, wherein the phenyl of phenyloxy and the heteroaryl of heteroaryloxy are optionally substituted with one, two, or three substituents, two of the optional substituents being independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano, or a pharmaceutically acceptable salt thereof.

44. R 5 and R 6 are independently 2-hydroxyethyloxy, 3-hydroxypropyloxy, 2-methoxyethyloxy, 2-ethoxyethyloxy, 3-methoxypropyloxy, 3-ethoxypropyloxy, 2-aminoethyloxy, 2-methylaminoethyloxy, 2-dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3-aminopropyloxy, 3-methylaminopropyloxy, 3-dimethylaminopropyloxy, 3-diethylaminopropyloxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethyloxy, piperidinylmethyloxy, pyrrolidinylethyloxy, piperidinylethyloxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropyloxy, 44. The compound of claim 43, wherein the aryl group is propylamino, 3-ethoxypropylamino, 2-aminoethylamino, 2-methylaminoethylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-aminopropylamino, 3-methylaminopropylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, pyrrolidinylamino, piperidinylamino, pyrrolidinylmethylamino, piperidinylmethylamino, pyrrolidinylethylamino, or piperidinylethylamino, wherein pyrrolidinyl and piperidinyl, either alone or as part of another group, in each of the aforementioned groups, are optionally substituted with 1 or 2 substituents independently selected from methyl, fluoro, hydroxy, or methoxy, or a pharma- ceutically acceptable salt thereof.

45. R 5 and R 6 is a 6-membered ring comprising a, b, d, and e of formula I as shown below 【Chemistry 18】 45. The compound of claim 43 or 44, wherein the compound is attached to: or a pharma- ceutically acceptable salt thereof.

46. The compound is (4-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid; (4-((6-oxo-1,6-dihydro-7H-purin-7-yl)methyl)phenyl)boronic acid; (4-((6-oxo-1,6-dihydro-9H-purin-9-yl)methyl)phenyl)boronic acid; (4-((2-amino-6-oxo-1,6-dihydro-7H-purin-7-yl)methyl)phenyl)boronic acid; (4-((2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl)phenyl)boronic acid; (4-((6-methoxy-1H-benzo[]imidazol-1-yl)methyl)phenyl)boronic acid; (4-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid; (4-((4-hydroxy-1H-imidazo[4,5-c]pyridin-1-yl)methyl)phenyl)boronic acid; (4-((6-amino-9H-purin-9-yl)methyl)phenyl)boronic acid; (4-((6-amino-7H-purin-7-yl)methyl)phenyl)boronic acid; (4-((1H-imidazo[4,5-c]pyridin-1-yl)methyl)phenyl)boronic acid; (4-((5-(methylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid; (4-((5-cyano-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid; (4-((6-cyano-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid; 4-((5-carbamoyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid; 4-((6-carbamoyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid; (4-((5-(methoxycarbonyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid; 1-(4-boronobenzyl)-1H-benzo[d]imidazole-5-carboxylic acid; (4-((6-(methoxycarbonyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid; 4-((5-carbamoyl-6-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((5-carbamoyl-2-ethyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 1-(4-boronobenzyl)-1H-benzo[d]imidazole-6-carboxylic acid; (4-((5-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid; (4-((5-carbamoyl-2-isopropyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid; 1-(4-boronobenzyl)-1H-benzo[d]imidazole-6-carboxylic acid; 1-(4-boronobenzyl)-1H-benzo[d]imidazole-5-carboxylic acid; and 4-((6-(methoxycarbonyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid; (4-((5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid; 4-((5-carbamoyl-4-methoxyindol-1-yl)methyl)phenylboronic acid; 4-((4-carbamoylindol-1-yl)methyl)phenylboronic acid; 4-((6-cyanoimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid; 4-((5-cyanoimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid; 4-((5-cyanoimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid; 4-((4-hydroxy-2-methylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid; 4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((4-hydroxy-2-methylpyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((5-carbamoyl-2-methylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid; 4-((5-cyano-2-methylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid; 4-((5-carbamoyl-2-isopropylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid; 4-((5-cyano-2-isopropylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid; 4-((4-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((7-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((5,7-dichloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((4-fluoro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((7-fluoro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-(imidazo[4,5-b]pyridin-1-ylmethyl)phenylboronic acid; 4-((2-isopropylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid; 4-((2-isopropylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid; 4-((7-chloroimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid; 4-((7-chloroimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((7-chloro-2-isopropylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid; 4-((4-hydroxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((7-methoxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((4-methoxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((4-carbamoylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((4-fluoropyrrolo[2,3-b]pyridin-1-yl)methyl)phenylboronic acid; 4-((4-methoxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((4-hydroxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((5-(methylcarbamoyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((6-(methylcarbamoyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((6-carbamoylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid; 4-((6-carbamoylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((6-(methylcarbamoyl)imidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid; 4-((6-(methylcarbamoyl)imidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((4-amino-5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((5-carbamoylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid; 4-((5-carbamoylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid; 4-((2-ethyl-4-hydroxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((4-hydroxy-2-isopropylpyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((5-carbamoyl-4-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((5-carbamoyl-4-hydroxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-(imidazo[4,5-b]pyrazin-1-ylmethyl)phenylboronic acid; 4-(pyrrolo[2,3-b]pyrazin-5-ylmethyl)phenylboronic acid; 4-((2-carbamoylpyrrolo[2,3-b]pyrazin-5-yl)methyl)phenylboronic acid; 4-((6-carbamoylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid; (4-((1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid; (4-((6-oxo-1,6-dihydro-9H-purin-9-yl)methyl)phenyl)boronic acid; (4-((4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid; 4-((4-hydroxypyrrolo[2,3-b]pyridin-1-yl)methyl)phenylboronic acid; 4-((2-carbamoylpyrrolo[3,2-d]pyrimidin-5-yl)methyl)phenylboronic acid; 4-((7-chloroimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid; 4-((7-chloroimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid; 4-((5-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((6-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((4-cyano-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((7-cyano-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((4-aminoimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((4-amino-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 4-((5-methoxyimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid; 4-((5-methoxyimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid; (4-((5-hydroxy-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenyl)boronic acid; (4-((5-carbamoyl-1H-benzo[d]imidazol-1-yl)methyl)-3-methylphenyl)boronic acid; (4-((6-carbamoyl-1H-benzo[d]imidazol-1-yl)methyl)-3-methylphenyl)boronic acid; 4-((4-(difluoromethyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; 3,5-difluoro-4-((4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid; 3,5-difluoro-4-((4-hydroxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((4-(fluoromethyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; (4-((5-carbamoyl-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenyl)boronic acid; 4-((5-hydroxypyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid; 4-((5-carbamoyl-2-isopropylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid; (4-((5-hydroxy-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenyl)boronic acid; and 2. The compound of claim 1, selected from the group consisting of (4-((5-hydroxy-2-isopropyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenyl)boronic acid, or a pharma- ceutically acceptable salt thereof.

47. The compound is (4-((4-hydroxy-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)phenyl)boronic acid; (4-((5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid; (4-((4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid; 4-((5-methoxyindol-1-yl)methyl)phenylboronic acid; 4-((4-chloropyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid; 4-((5-carbamoyl-3-chloroindol-1-yl)methyl)phenylboronic acid; 4-((5-carbamoyl-3-methylindol-1-yl)methyl)phenylboronic acid; 4-((4-hydroxy-2-isopropylpyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid; (4-((5-carbamoyl-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenyl)boronic acid; or 47. The compound of claim 46 selected from pharma- ceutically acceptable salts thereof.

48. Compounds of formula (I): 【Chemistry 19】 (In the formula, a, b, d, and e are CH; or one or two of a, b, d, and e are N and the remaining a, b, d, and e are CH; One of y and z is N, and the other y and z is CR 7 or both y and z are CR 7 and each R 7 is independently hydrogen, alkyl, hydroxy, or halo; alk is alkylene optionally substituted with 1, 2, or 3 halo; alk 1 is alkylene, wherein one carbon atom in the alkylene chain may be replaced by oxygen, and said alkylene chain is optionally substituted with 1, 2 or 3 halo; m and n are independently 0 or 1; provided that one of m and n is 1 and the other of m and n is 0; Ar is aryl or heteroaryl; R a and R b are independently selected from hydroxy, alkoxy, -Oaryl (aryl is optionally substituted with 1 to 3 substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH 2 ) O.C.O.R. c (R c is alkyl), —O—(CH 2 ) OCOOR c (R c is alkyl), —O—(alk 2 ) OR d (alk 2 is alkylene, and R d is alkyl), —S—(CH 2 ) 2 SCOR e (R e is alkyl), or -NR g -(CHR)OCOR f R is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl, or phenylalkyl, where phenyl alone or as part of phenylalkyl is optionally substituted with 1 to 3 substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano, or nitro; f is alkyl or benzyl, and R g is hydrogen or, together with R, represents -(CH 2 ) 3 -forming; or R a and R b together with the phosphorus atom to which they are attached to form a ring of formula (a): 【Chemistry 20】 (In the formula, Ar 2 is phenyl or 6-membered heteroaryl optionally substituted with 1-3 halo; R 2 and R 3 is independently hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano; R 4 is hydrogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl; and R 5 and R 6 R is independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, amino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, where either heterocyclyl alone or the heterocyclyloxy and heterocyclylamino portions are optionally independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl. h , R j , or R k substituted with), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino, where the heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl, cycloalkyloxy, phenyloxy, or heteroaryloxy, where the phenyl in phenyloxy and the heteroaryl in heteroaryloxy are optionally substituted with 1, 2, or 3 substituents, two of the optional substituents being independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; or and pharma- ceutically acceptable salts thereof.

49. Structure of Formula (Ia): 【Chemistry 21】 49. The compound of claim 48 having the formula: wherein one of d and e is N, and the remainder of a, b, c and d are CH; or a pharma- ceutically acceptable salt thereof.

50. Structure of formula (Ie): 【Chemical 22】 49. The compound of claim 48, having the formula: or a pharma- ceutically acceptable salt thereof.

51. Structure of formula (Ii): 【Chemistry 23】 50. The compound of claim 49, having the formula: or a pharma- ceutically acceptable salt thereof.

52. Structure of formula (Ij): 【Chemistry 24】 (In the formula, R 7 or a pharma- ceutically acceptable salt thereof.

53. R 7 53. The compound of claim 51 or 52, or a pharma- ceutically acceptable salt thereof, wherein: is alkyl.

54. R 7 53. The compound of claim 51 or 52, or a pharma- ceutically acceptable salt thereof, wherein is methyl or isopropyl.

55. Structure of Formula (Ia) or (Ib): 【Chemistry 25】 49. The compound of claim 48, having the formula:

56. 56. The compound of claim 55 having the structure of Formula (Ia), or a pharma- ceutically acceptable salt thereof.

57. 56. The compound of claim 55 having the structure of formula (Ib): or a pharma- ceutically acceptable salt thereof.

58. 58. The compound of any one of claims 55 to 57, or a pharma- ceutically acceptable salt thereof, wherein a, b, d, and e are CH.

59. 58. The compound of any one of claims 55 to 57, or a pharma- ceutically acceptable salt thereof, wherein a is N, and b, d, and e are CH.

60. 58. The compound of any one of claims 55 to 57, or a pharma- ceutically acceptable salt thereof, wherein a and d are N, and b and e are CH.

61. 58. The compound of any one of claims 55 to 57, or a pharma- ceutically acceptable salt thereof, wherein b is N and a, c, and e are CH.

62. 58. The compound of any one of claims 55 to 57, wherein b and e are N, and a and d are CH, or a pharma- ceutically acceptable salt thereof.

63. 58. The compound according to any one of claims 55 to 57, or a pharma- ceutically acceptable salt thereof, wherein d is N, and a, b and e are CH.

64. R a and R b or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 48 to 63, wherein:

65. R a and R b 64. The compound of any one of claims 48 to 63, or a pharma- ceutically acceptable salt thereof, wherein is independently selected from hydroxy and alkoxy.

66. R a and R b together with the phosphorus atom to which they are attached to form a ring of formula (a) 【Chemistry 26】 64. The compound according to any one of claims 48 to 63, or a pharma- ceutically acceptable salt thereof, which forms:

67. 67. The compound of any one of claims 48 to 66, or a pharma- ceutically acceptable salt thereof, wherein Ar is phenyl.

68. -P(O((R a ) ( b 68. The compound of claim 67, wherein: R is attached to a carbon on the phenyl ring that is para to the carbon attaching the phenyl ring to the remainder of the compound of Formulas (I), (Ia), (Ib), (Ie), (Ii), and (Ij); or a pharma- ceutically acceptable salt thereof.

69. 67. The compound of any one of claims 48 to 66, or a pharma- ceutically acceptable salt thereof, wherein Ar is heteroaryl.

70. 70. The compound of claim 69, wherein Ar is pyridinyl, pyrimidinyl, pyridazinyl, thienyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, oxadiazolyl, or imidazolyl; or a pharma- ceutically acceptable salt thereof.

71. m is 0, n is 1, and alk is methylene, ethylene, or propylene, or n is 0, m is 1, and alk is 1 71. The compound of any one of claims 48 to 70, or a pharma- ceutically acceptable salt thereof, wherein is methylene, ethylene, or propylene.

72. m is 0, n is 1, and alk is methylene, or n is 0, m is 1, and alk is 1 The compound according to any one of claims 48 to 70, or a pharma- ceutically acceptable salt thereof, wherein is methylene.

73. R 7 73. The compound according to any one of claims 48 to 50 and 55 to 72, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen, methyl, isopropyl, or fluoro.

74. R 7 74. The compound of claim 73, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen, methyl, or fluoro.

75. R 2 and R 3 75. The compound of any one of claims 48 to 74, or a pharma- ceutically acceptable salt thereof, wherein is independently hydrogen, methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, or cyano.

76. R 2 and R 3 75. The compound according to any one of claims 48 to 74, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

77. R 4 77. The compound of any one of claims 48 to 76, wherein is hydrogen, alkyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl, or a pharma- ceutically acceptable salt thereof.

78. R 4 78. The compound of claim 77, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen, methyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, cyano, or trifluoromethyloxy.

79. R 4 77. The compound of any one of claims 48 to 76, wherein is cyano, carboxy, alkoxycarbonyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl, or a pharma- ceutically acceptable salt thereof.

80. R 4 80. The compound of claim 79, wherein is cyano, carboxy, methoxycarbonyl, aminocarbonyl, methylsulfonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl, or a pharma- ceutically acceptable version thereof.

81. R 4 is a 6-membered ring comprising a, b, d, and e of formula I as shown below 【Chemical 27】 80. The compound of claim 79, wherein the wavy line indicates the point of attachment to the remainder of the molecule, or a pharma- ceutically acceptable salt thereof.

82. R 5 and R 6 82. The compound according to any one of claims 48 to 81, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

83. R 5 and R 6 79. The compound of any one of claims 48-78, or a pharma- ceutically acceptable salt thereof, wherein is independently hydrogen, alkyl, alkoxy, hydroxy, amino, halo, haloalkyl, or haloalkoxy.

84. R 5 is a 6-membered ring comprising a, b, d, and e of formula I as shown below 【Chemistry 28】 84. The compound of claim 83, wherein the wavy line indicates the point of attachment to the remainder of the molecule, or a pharma- ceutically acceptable salt thereof.

85. R 5 is hydroxy and R 4 and R 6 85. The compound of claim 84, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

86. R 5 and R 6 is a 6-membered ring comprising a, b, d, and e of formula I as shown below 【Chemical 29】 84. The compound of claim 83, wherein the wavy line indicates the point of attachment to the remainder of the molecule, or a pharma- ceutically acceptable salt thereof.

87. R 5 is hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, or haloalkoxy; and R 6 is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein either heterocyclyl alone or the heterocyclyloxy and heterocyclylamino portions are optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein either heterocyclylalkyl, heterocyclylalkyi, 79. The compound of any one of claims 48 to 78, which is cycloalkyloxy, and the heterocyclyl ring in heterocyclylalkylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl, cycloalkyloxy, phenyloxy, or heteroaryloxy, where the phenyl in phenyloxy and the heteroaryl in heteroaryloxy are optionally substituted with one, two, or three substituents, two of the optional substituents being independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano, or a pharma- ceutically acceptable salt thereof.

88. R 5 is hydrogen, methoxy, ethoxy, or hydroxy, and R 6 However, 2-hydroxyethyloxy, 3-hydroxypropyloxy, 2-methoxyethyloxy, 2-ethoxyethyloxy, 3-methoxypropyloxy, 3-ethoxypropyloxy, 2-aminoethyloxy, 2-methylaminoethyloxy, 2-dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3-aminopropyloxy, 3-methylaminopropyloxy, 3-dimethylaminopropyloxy, 3-diethylaminopropyloxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethyloxy, piperidinylmethyloxy, pyrrolidinylethyloxy, piperidinylethyloxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropyl 88. The compound of claim 87, wherein the arylamino group is arylamino, 3-ethoxypropylamino, 2-aminoethylamino, 2-methylaminoethylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-aminopropylamino, 3-methylaminopropylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, pyrrolidinylamino, piperidinylamino, pyrrolidinylmethylamino, piperidinylmethylamino, pyrrolidinylethylamino, or piperidinylethylamino, wherein pyrrolidinyl and piperidinyl, either alone or as part of another group, in each of the aforementioned groups, are optionally substituted with 1 or 2 substituents independently selected from methyl, fluoro, hydroxy, or methoxy, or a pharma- ceutically acceptable salt thereof.

89. R 5 and R 6 is a 6-membered ring comprising a, b, d, and e of formula I as shown below 【Chemistry 30】 90. The compound of claim 87 or 88, wherein the compound is attached to: wherein the wavy line indicates the point of attachment to the remainder of the molecule; or a pharma- ceutically acceptable salt thereof.

90. R 5 and R 6 are independently hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein either heterocyclyl alone or the heterocyclyloxy and heterocyclylamino portions are optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein either heterocyclylalkyl, heterocyclyloxy, 79. The compound of any one of claims 48 to 78, wherein the heterocyclyl ring in heterocyclylalkylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl, cycloalkyloxy, phenyloxy, or heteroaryloxy, wherein the phenyl of phenyloxy and the heteroaryl of heteroaryloxy are optionally substituted with one, two, or three substituents, two of the optional substituents being independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano, or a pharmaceutically acceptable salt thereof.

91. R 5 and R 6 are independently 2-hydroxyethyloxy, 3-hydroxypropyloxy, 2-methoxyethyloxy, 2-ethoxyethyloxy, 3-methoxypropyloxy, 3-ethoxypropyloxy, 2-aminoethyloxy, 2-methylaminoethyloxy, 2-dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3-aminopropyloxy, 3-methylaminopropyloxy, 3-dimethylaminopropyloxy, 3-diethylaminopropyloxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethyloxy, piperidinylmethyloxy, pyrrolidinylethyloxy, piperidinylethyloxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropyloxy, 91. The compound of claim 90, wherein the aryl group is propylamino, 3-ethoxypropylamino, 2-aminoethylamino, 2-methylaminoethylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-aminopropylamino, 3-methylaminopropylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, pyrrolidinylamino, piperidinylamino, pyrrolidinylmethylamino, piperidinylmethylamino, pyrrolidinylethylamino, or piperidinylethylamino, wherein pyrrolidinyl and piperidinyl, alone or as part of another group, in each of the aforementioned groups, are optionally substituted with 1 or 2 substituents independently selected from methyl, fluoro, hydroxy, or methoxy, or a pharma- ceutically acceptable salt thereof.

92. R 5 and R 6 is a 6-membered ring comprising a, b, d, and e of formula I as shown below 【Chemistry 31】 92. The compound of claim 90 or 91, wherein the wavy line indicates the point of attachment to the remainder of the molecule, or a pharma- ceutically acceptable salt thereof.

93. A pharmaceutical composition comprising a compound according to any one of claims 1 to 92 and a pharma- ceutically acceptable excipient.

94. 93. A method of treating a disease or condition mediated by ENPP1 in a patient, comprising administering to said patient a compound according to any one of claims 1-92.

95. 95. The method of claim 94, wherein the disease or condition is cancer, an inflammatory disease, a metabolic disease, or a viral disease.

96. 96. The method of claim 95, wherein the disease or condition is cancer.

97. 97. The method of claim 96, wherein the disease or condition is cancer, wherein the cancer is hepatocellular carcinoma, glioblastoma, melanoma, testicular, pancreatic, thyroid or breast cancer.

98. The method of claim 97, wherein the compound of any one of claims 1 to 92 is administered together with an anti-cancer agent.

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