Bicyclic heteroaryl derivatives as inhibitors of ectonucleotide pyrophosphatase / phosphodiesterase 1

Abstract

The present invention provides certain bicyclic heteroaryl compounds that inhibit the enzyme activity of ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1), and are thus useful for treating diseases and disorders that are at least partially regulated by ENPP1. In some embodiments, the bicyclic heteroaryl compounds include those having formula (I): Also provided herein are pharmaceutical compositions containing such compounds and methods for preparing such compounds. #imgabs0#

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of priority under 35 U.S.C.§119(e) to U.S. Provisional Application No. 62 / 833,455, filed on April 12, 2019, and U.S. Provisional Application No. 62 / 881,111, filed on July 31, 2019. The entire content of each of these applications is hereby incorporated by reference in its entirety for all purposes.

[0003] Statement of Rights to Inventions Made Under Federally Sponsored Research and Development

[0004] Not applicable

[0005] Reference to a "Sequence Listing", Table, or Computer Program Listing Appendix Submitted on a Compact Disc

[0006] Not applicable Technical Field

[0007] Certain bicyclic heteroaryl phosphonates and boronic esters are provided herein that inhibit the activity of ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) enzyme and are thus useful for treating diseases that are treatable by inhibiting ENPP1. Pharmaceutical compositions containing such compounds and methods for preparing such compounds are also provided. Background Art

[0008] ENPP1 enzyme is present in a wide range of tissues and cell types, such as lymphocytes, macrophages, liver, brain, heart, kidney, vascular smooth muscle cells, and chondrocytes. ENPP1 hydrolyzes ATP and other nucleoside triphosphates and releases AMP or other monophosphonucleosides, as well as pyrophosphate nucleoside (PPi) (Kato K et al., 2012 PNAS 109:16876 - 16881; Hessle L et al., 2002 PNAS 99:9445 - 9449). This enzyme can also hydrolyze other nucleoside monophosphates (Kato K et al., 2012 PNAS 109:16876 - 16881). ENPP1 has been identified as the major 2'-3'-cGAMP hydrolase in cultured cells, tissue extracts, and blood (Li L et al., 2014 Nat Chem Biol [Nature Chemical Biology] 10:1043 - 1048). Tissues and blood from ENPP1 knockout mice lack 2'-3'-cGAMP hydrolase activity. Elevated ENPP1 levels are associated with calcific aortic valve disease (CAVD) and calcium pyrophosphate dihydrate (CPPD) disease (an inflammatory disease caused by CPPD crystal deposition in joints and surrounding tissues) (Cote N et al., 2012 Eur J Pharmacol [European Journal of Pharmacology] 689:139 - 146; Johnson K et al., 2001 Arthritis Rheum [Arthritis and Rheumatology] 44:1071). ENPP1 expression is upregulated in certain hepatocellular carcinomas, glioblastomas, melanomas, testicular cancers, pancreatic cancers, and thyroid and breast cancers and is associated with chemoresistance (see Lau WM et al., 2013 PLoS One [PLoS ONE] 8:5; Bageritz J et al., 2014 Mol Cell Oncology [Molecular and Cellular Oncology] 1:3; Bageritz J et al., 2014 Cell Death, Differentiation [Cell Death and Differentiation] 21:929 - 940; Umar A et al., 2009 Mol Cell Proteomics [Molecular and Cellular Proteomics] 8:1278 - 1294).Upregulation of ENPP1 and variants of ENPP1 are also associated with insulin tolerance and type 2 diabetes (Meyre D et al., Nat Genet 37:863-867, 2005; Maddux BA et al., Nature 373:448-451, 1995; Rey D et al., Mol Biol Rep 39:7687-7693, 2012), and it has been reported that inhibition of insulin receptor signaling requires the enzymatic activity of ENPP1 (Chin CN et al., Eur J Pharmacol 606:17-24, 2009).

[0009] 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 derived 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 immunostimulatory cytokines (Sun L et al., Science 2013;339:786-791; Wu J et al., Science 2013;339:826-830; Gao D et al., Science 2013;341:903-906; Li X et al., Science 2013;341:1390-1394; Schoggins JW et al., Nature 2014;505:691-695; Wassermann R et al., Cell Host Microbe 2015;17:799-810; Watson RO et al., Cell Host Microbe 2015;17:811-819; Collins A et al., Cell Host Microbe 2015;17:820-828; West A et al., Nature 2015;520:533-557; Woo SR et al., Immunity 2014;41:830-842; Deng L et al., Immunity 2014;41:843-852; Chen Q et al., Nat Immunol 2016;17:1142-1148). The cGAS enzyme, cGAMP messenger, and STING are also involved in host defense against RNA viruses and the immune control of tumor development (Aguirre S et al., PLoS Pathog 2012;8:e1002934; Barber GN, Nat Rev Immunol 2015;15:760-770). ENPP1 has been identified as the enzyme that naturally hydrolyzes cGAMP and thus counteracts the innate immune response to infectious agents, damaged cells, and cancer cells (Li L et al., Nat Chem Biol 2014;10:1043-1048).The efficacy of non-hydrolyzable cGAMP analogs in inducing functional immune responses is higher than that of natural hydrolyzable cGAMP (Li L et al., Nat Chem Biol 2014 [Nature Chemical Biology] 10:1043-1048; Corrales L et al., Cell Rep 2015 [Cell Reports] 11:1018-1030). It has been demonstrated that overexpression of ENPP1 promotes viral infection, and silencing of ENPP1 alleviates viral infection (Wang J et al., Mol Immunol 2018 [Molecular Immunology] 95:56-63).

[0010] Therefore, cGAMP hydrolysis inhibitors can be used to enhance the effectiveness of immune responses against cancer cells and tumors as well as infections by RNA or DNA viruses or bacteria. ENPP1 inhibitors and cGAMP or nucleoside triphosphate hydrolysis inhibitors can also be used to treat inflammatory diseases associated with elevated levels of nucleotide enzymes, reduced levels of nucleoside triphosphates, decreased levels of cGAMP or nucleoside monophosphates, or diseases associated with elevated levels of nucleosides or nucleoside monophosphates. For these reasons, ENPP1 is an attractive therapeutic target for treating diseases.

[0011] The present invention addresses these needs and also provides related advantages. SUMMARY OF THE INVENTION

[0012] In a first aspect, there is provided a compound having the formula (I):

[0013]

[0014] Wherein:

[0015] a, b, d, and e are CH; or one or two of a, b, d, and e are N, and the remainder of a, b, d, and e are CH;

[0016] One of y and z is N and the other of y and z is CR 7 ; or both y and z are CR 7 , where each R 7 is independently hydrogen, alkyl, hydroxy, or halo;

[0017] alk is an alkylene optionally substituted by one, two, or three halo groups;

[0018] alk 1 is an alkylene in which one carbon atom in the alkylene chain can be replaced by oxygen and the alkylene chain is optionally substituted by one, two, or three halo groups;

[0019] m and n are independently 0 or 1; provided that at least one of m and n is 1;

[0020] Ar is an aryl or heteroaryl;

[0021] Q is -P(O)(R a )(R b ) or -B(R w )(R x ), wherein R a and R b are independently selected from hydroxy, alkoxy, -O-aryl (wherein the aryl is optionally substituted by one to three substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, halogen, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCOR c (wherein R c is alkyl), -O-(CH2)OCOOR c (wherein R c is alkyl), -O-(alk 2 )OR d (wherein alk 2 is alkylene and R d is alkyl), -S-(CH2)2SCOR e (wherein R e is alkyl), or -NR g -(CHR)OCOR f (wherein R is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl or phenylalkyl (wherein the phenyl alone or as part of the phenylalkyl is optionally substituted by one to three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano or nitro), 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 form a ring having formula (a):

[0022]

[0023] wherein, Ar 2 is phenyl or a six-membered heteroaryl optionally substituted by one to three halogen atoms; and

[0024] R w and R xindependently selected from hydroxy, alkoxy, -Oaryl (wherein the aryl is optionally substituted by one to three substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCOR c (wherein R c is alkyl), -O-(alk 2 )OR d (wherein alk 2 is alkylene and R d is alkyl), -S-(CH2)2SCOR e (wherein R e is alkyl), or -NR g -(CHR)OCOR f (wherein R is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl or phenylalkyl (wherein the phenyl alone or as part of the phenylalkyl is optionally substituted by one to three substituents independently selected from the group consisting of alkyl, alkoxy, halo, hydroxy, cyano or nitro), R f is alkyl or benzyl and R g is hydrogen or together with R forms -(CH2)3-); or

[0025] R w and R x together with the bromine atom to which they are attached may form -O(CRR’)2O- or -O(CRR’)3O-, wherein each R and R’ is independently hydrogen or methyl;

[0026] R 2 and R 3 are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano;

[0027] R 4 is hydrogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl; and

[0028] R 5 and R 6Independently is hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, amino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein the heterocyclyl alone or a part of the heterocyclyloxy and heterocyclylamino is optionally independently selected from the group consisting of R h 、R j 、or R k substituted with: alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclic ring in the heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with one, two, or three substituents independently selected from the group consisting of: alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl in the phenyloxy and the heteroaryl in the heteroaryloxy are optionally substituted with one, two, or three substituents, and two of these optional substituents are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano); or

[0029] its pharmaceutically acceptable salts;

[0030] Provided that:

[0031] 1. When formula (I) has the structure

[0032] And:

[0033] (i) When R w and R x are each -OH, then not 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-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; 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;

[0034] (ii)-B(R w )(R x ) is when, then not 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-benzoimidazol-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-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-benzoimidazol-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-benzoimidazol-1-ylmethyl)phenyl, or 4-(2-ethoxy-7-ethoxycarbonyl-1H-benzoimidazol-1-ylmethyl)phenyl; and

[0035] (iii)-B(R w )(R x ) is when, then not 4-(2-ethoxy-7-ethoxycarbonyl-1H-benzoimidazol-1-ylmethyl)phenyl; and

[0036] 2. When 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;

[0037] or a pharmaceutically acceptable salt thereof.

[0038] In a second aspect, there is provided a compound having the formula (IA):

[0039]

[0040] wherein:

[0041] a, b, d and e are CH; or one or two of a, b, d and e are N and the remainder of a, b, d and e are CH;

[0042] one of y and z is N and the other of y and z is CR 7 ; or both y and z are CR 7, wherein each R 7 is independently hydrogen, alkyl, hydroxy, or halo;

[0043] alk is an alkylene optionally substituted by one, two, or three halo groups;

[0044] alk 1 is an alkylene in which one carbon atom in the alkylene chain may be replaced by oxygen and the alkylene chain is optionally substituted by one, two, or three halo groups;

[0045] m and n are independently 0 or 1; provided that at least one of m and n is 1;

[0046] Ar is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

[0047] Q is -P(O)(R a )(R b ) or -B(R w )(R x ), wherein, R a , R b , R w and R x are independently selected from hydroxy, alkoxy, -Oaryl (wherein the aryl is optionally substituted by one to three substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCOR c (wherein R c is alkyl), -O-(alk 2 )OR d (wherein alk 2 is alkylene and R d is alkyl), -S-(CH2)2SCOR e (wherein R e is alkyl), or -NR g -(CHR)OCOR f (wherein R is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl or phenylalkyl (wherein the phenyl alone or as part of the phenylalkyl is optionally substituted by one to three substituents independently selected from the group consisting of alkyl, alkoxy, halo, hydroxy, cyano or nitro), R f is alkyl or benzyl and R g is hydrogen or forms -(CH2)3- together with R); or R a and R b together with the phosphorus atom to which they are attached form a ring having formula (a):

[0048]

[0049] Wherein, Ar 2 is phenyl or a six-membered heteroaryl optionally substituted with one to three halogen groups; or

[0050] R w and R x together with the bromine atom to which they are attached may form -O(CRR’)2O- or -O(CRR’)3O-, wherein each R and R’ is independently hydrogen or methyl;

[0051] R 2 and R 3 are independently hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, or cyano;

[0052] R 4 is hydrogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl; and

[0053] R 5 and R 6 are independently hydrogen, alkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, amino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclic group, heterocyclic group oxy, heterocyclic group amino (wherein the heterocyclic group alone or a part of the heterocyclic group oxy and heterocyclic group amino is optionally substituted independently by R h selected from the group consisting of, R j or R k substituted: alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclic group alkyl, heterocyclic group alkyl oxy, heterocyclic group alkyl amino (wherein the heterocyclic group ring in the heterocyclic group alkyl, heterocyclic group alkyl oxy, and heterocyclic group alkyl amino is optionally substituted by one, two, or three substituents independently selected from the group consisting of: alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl in the phenyloxy and the heteroaryl in the heteroaryloxy are optionally substituted by one, two, or three substituents, and two of these optional substituents are independently selected from alkyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano); or

[0054] its pharmaceutically acceptable salts;

[0055] Provided that:

[0056] 1. When the compound of formula (IA) has the structure

[0057]

[0058] wherein Ar is aryl or heteroaryl and:

[0059] (i) When R w and R x are each -OH, then not 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-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; 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;

[0060] (ii)-B(R w )(R x ) is when, then not 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-benzoimid-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-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-benzoimid-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-benzoimid-1-ylmethyl)phenyl, or 4-(2-ethoxy-7-ethoxycarbonyl-1H-benzoimid-1-ylmethyl)phenyl; and

[0061] (iii)-B(R w )(R x ) is when, then not 4-(2-ethoxy-7-ethoxycarbonyl-1H-benzoimid-1-ylmethyl)phenyl; and

[0062] 2. When 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;

[0063] or a pharmaceutically acceptable salt thereof.

[0064] In a second aspect, there is provided a pharmaceutical composition comprising a compound of the invention, such as a compound of formula (I) or (IA) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0065] In a third aspect, there is provided a method of treating a disease or disorder mediated by ENPP1 in a patient, preferably in a patient considered in need of such treatment, the method comprising administering to the patient a compound of formula (I) or (IA) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof in a therapeutically effective amount. In one embodiment, the disease is cancer, such as hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, and breast cancer. In another embodiment, the disease is an inflammatory disease, such as calcific aortic valve disease and calcium pyrophosphate dihydrate. In yet another embodiment, the disease is a metabolic disease (such as type 2 diabetes) or a viral infection.

[0066] In a fourth aspect, there is provided a compound of formula (I) or (IA) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof for use as a medicament. In one embodiment, the medicament is for treating cancer, such as hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, and breast cancer. In another embodiment, the medicament is for treating an inflammatory disease, such as calcific aortic valve disease and calcium pyrophosphate dihydrate. In yet another embodiment, the medicament is for treating a metabolic disease (such as type 2 diabetes) or a viral infection.

[0067] 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 the pathology and / or symptoms of the disease are promoted by the activity of ENPP1. In one embodiment, the disease is cancer, such as hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, and breast cancer. In another embodiment, the disease is an inflammatory disease, such as calcific aortic valve disease and calcium pyrophosphate dihydrate. In yet another embodiment, the disease is a metabolic disease (such as type 2 diabetes) or a viral disease.

[0068] In any of the above aspects relating to the treatment of cancer, further embodiments 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 using combination therapy, these agents may be administered simultaneously or sequentially. Detailed Description

[0069] Definitions:

[0070] Unless otherwise indicated, the following terms used in this specification and claims are defined for the purposes of this application and have the following meanings:

[0071] "Alkyl" means a straight-chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc.

[0072] Unless otherwise specified, "alkylene" means a straight-chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated divalent hydrocarbon group having 3 to 6 carbon atoms, for example, methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, etc.

[0073] "Alkenyl" means a straight-chain or branched-chain monovalent hydrocarbon group having 2 to 6 carbon atoms containing a double bond, such as vinyl, propenyl, 2-propenyl, etc.

[0074] "Alkylthio" means an -SR group (wherein R is an alkyl as defined above), such as methylthio, ethylthio, etc.

[0075] "Alkylsulfonyl" means an -SO2R group (wherein R is an alkyl as defined above), such as methylsulfonyl, ethylsulfonyl, etc.

[0076] "Amino" means -NH2.

[0077] "Aminocarbonyl" means -CONH2.

[0078] "Alkylaminocarbonyl" means a -CONHR group (wherein R is an alkyl as defined above), such as methylaminocarbonyl, ethylaminocarbonyl, etc.

[0079] "Aminosulfonyl" means -SO2NH2.

[0080] "Alkylaminosulfonyl" means a -SO2NHR group (wherein R is an alkyl as defined above), such as methylaminosulfonyl, ethylaminosulfonyl, etc.

[0081] "Alkylamino" means an -NHR group, wherein R is an alkyl as defined above, such as methylamino, ethylamino, propylamino, or 2-propylamino, etc.

[0082] "Aminoalkyl" means a straight-chain monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched-chain monovalent hydrocarbon group having 3 to 6 carbon atoms substituted by -NR’R”, wherein R’ and R” are independently hydrogen or alkyl as defined above, such as aminomethyl, aminoethyl, methylaminomethyl, etc.

[0083] "Aminoalkylamino" means an -NR a R b group (wherein R a is hydrogen or alkyl and R bis an aminoalkyl as defined above), such as aminoethylamino, dimethylaminoethylamino, diethylaminopropylamino, dimethylaminopropylamino, diethylaminopropylamino, etc.

[0084] "Aminoalkyloxy" means -OR a group (wherein R a is an aminoalkyl as defined above), such as aminoethoxy, dimethylaminoethoxy, diethylaminoethoxy, dimethylaminopropoxy, diethylaminopropoxy, etc.

[0085] "Alkoxy" means an -OR group (wherein R is an alkyl as defined above), such as methoxy, ethoxy, propoxy, or 2-propoxy, n-butoxy, isobutoxy, or tert-butoxy, etc.

[0086] "Alkoxyalkyl" means a straight-chain monovalent hydrocarbon group having one to six carbon atoms or a branched-chain monovalent hydrocarbon group having three to six carbons substituted with at least one alkoxy as defined above (such as one or two alkoxy groups), such as 2-methoxyethyl, 1-methoxypropyl, 2-methoxypropyl, or 3-methoxypropyl, 2-ethoxyethyl, etc.

[0087] "Alkoxyalkylamino" means an -NRR' group (wherein R is hydrogen or alkyl and R' is an alkoxyalkyl as defined above), such as methoxyethylamino, ethoxyethylamino, propoxypropylamino, ethoxypropylamino, etc.

[0088] "Alkoxyalkyloxy" or "alkoxyalkoxy" means a -(O)R group (wherein R is an alkoxyalkyl as defined above), such as methoxyethoxy, ethoxyethoxy, etc.

[0089] "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms, such as phenyl or naphthyl.

[0090] "Phenyloxy" means an -OR group wherein R is phenyl.

[0091] "Cycloalkyl" means a cyclic saturated monovalent hydrocarbon group having three to ten carbon atoms, such as, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, etc.

[0092] "Cycloalkyloxy" means an -OR group wherein R is a cycloalkyl as defined above (including specific heterocyclic rings), such as, cyclopropoxy, etc.

[0093] "Carboxyl" means -COOH.

[0094] "Dialkylaminocarbonyl" means -CONHRR' (wherein R and R' are independently alkyls as defined above), such as dimethylaminocarbonyl, methylethylaminocarbonyl, etc.

[0095] "Dialkylaminosulfonyl" means -SO2NHRR' (wherein R and R' are independently alkyl as defined above), for example dimethylaminosulfonyl, methylethylaminosulfonyl, etc.

[0096] "Dialkylamino" means -NRR' group (wherein R and R' are alkyl as defined above), for example dimethylamino, methylethylamino, etc.

[0097] "Halogen" means fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

[0098] "Haloalkyl" means alkyl as defined above substituted by one or more halogen atoms (such as one to five halogen atoms, such as fluorine or chlorine), including those substituted by different halogens, for example -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When the alkyl is substituted only by fluorine, it may be referred to as fluoroalkyl in the present application.

[0099] "Haloalkoxy" means -OR group (wherein R is haloalkyl as defined above), for example -OCF3, -OCHF2, etc. When R is haloalkyl in which the alkyl is substituted only by fluorine, it may be referred to as fluoroalkoxy in the present application.

[0100] "Hydroxyalkyl" means a straight-chain monovalent hydrocarbon group having one to six carbon atoms or a branched-chain monovalent hydrocarbon group having three to six carbons substituted by one or two hydroxy groups, provided that if there are two hydroxy groups, they are not both on the same carbon atom. Representative examples include but are not limited to hydroxymethyl, 2-hydroxy-ethyl, 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.

[0101] "Hydroxyalkylamino" means -NR a R b group (wherein R a is hydrogen or alkyl and R b is hydroxyalkyl as defined above), for example hydroxyethylamino, hydroxypropylamino, etc.

[0102] "Hydroxyalkoxy" means -OR a group (wherein R ais an aminohydroxyoalkyl as defined above, such as hydroxyethoxy, hydroxypropoxy, etc.

[0103] "Heterocyclic group" means a saturated or unsaturated monovalent monocyclic group having 4 to 8 ring atoms, wherein one or two ring atoms are heteroatoms selected from N, O or S(O) n (where n is an integer from 0 to 2), and the remaining ring atoms are C. In addition, one or two ring carbon atoms in the heterocyclic group ring may optionally be replaced by a -CO- group. More specifically, the term heterocyclic group includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, etc. When the heterocyclic group ring is unsaturated, it may contain one or two ring double bonds, provided that the ring is not aromatic. When the heterocyclic group contains at least one nitrogen atom, it is also referred to herein as a heterocyclic amino group and is a subset of the heterocyclic group.

[0104] "Heterocyclic group alkyl" or "heterocyclic alkyl" means a -(alkylene)-R group wherein R is a heterocyclic group ring as defined above (including specific heterocyclic group rings), for example, tetrahydrofuranylmethyl, piperazinylmethyl, morpholinoethyl, etc.

[0105] "Heterocyclic group amino" means an -NRR' group, wherein R is hydrogen or alkyl and R' is a heterocyclic group as defined above (including specific heterocyclic group rings).

[0106] "Heterocyclic group alkyl amino" or "heterocyclic alkyl amino" means an -NRR' group wherein R is hydrogen or alkyl and R' is a heterocyclic group alkyl ring as defined above (including specific heterocyclic group rings), such as tetrahydrofuranylmethyl amino, piperazinylethyl amino, morpholinoethyl amino, piperidinylmethyl amino, etc.

[0107] "Heterocyclic group oxy" means an -OR group, wherein R is a heterocyclic group as defined above (including specific heterocyclic group rings).

[0108] "Heterocyclic group alkyl oxy" or "heterocyclic alkyl oxy" means an -OR group wherein R is a heterocyclic group alkyl ring as defined above (including specific heterocyclic group rings), for example, tetrahydrofuranylmethyl oxy, piperazinylethyl oxy, morpholinoethyl oxy, piperidinylmethyl oxy, etc.

[0109] Unless otherwise indicated, "heteroaryl" means a monovalent monocyclic or bicyclic aromatic group having 5 to 10 ring atoms, wherein one or more (in one embodiment, one, two, or three) of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc. 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-membered or 6-membered heteroaryl.

[0110] "Heteroaryloxy" means an -OR group, wherein R is a heteroaryl (including a specific heteroaryl ring) as defined above.

[0111] This document also includes protected derivatives of the compounds (I) herein. For example, when the compounds herein contain groups (such as hydroxyl, carboxyl, thiol, or any group containing one or more nitrogen atoms), these groups can be protected by 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. The protected derivatives of the compounds herein can be prepared by methods well known in the art.

[0112] This document also includes polymorphic forms and deuterated forms of the compounds herein and / or their pharmaceutically acceptable salts.

[0113] "Pharmaceutically acceptable salts" of a compound mean salts that are pharmaceutically acceptable and have the pharmacological activity of the desired parent compound. Such salts include: acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as 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, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-enoic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy-naphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or salts formed when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth metal ions or aluminum ions); or salts formed by coordination with organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Other information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, 1985, which is hereby incorporated by reference in its entirety.

[0114] The compounds of the present invention may have asymmetric centers. Compounds of the present invention containing asymmetrically substituted atoms may be isolated in enantiomeric or racemic forms. Methods for preparing enantiomeric forms are well known in the art, such as by resolution of the material. Unless specifically indicated as a particular stereochemistry or isomeric form, all chiral, diastereomeric, chiral or diastereomeric mixtures, and racemic forms are within the scope of the present invention. Those of ordinary skill in the art will also understand that when a compound is represented as the (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity, i.e., the (S) stereoisomer is less than about 5%, preferably 2% by weight, and it is then represented as a mixture of R and S isomers, wherein the amount of the R or S isomer in the mixture is greater than about 5%, preferably 2% w / w.

[0115] Certain compounds of the present invention may exist as tautomers and / or geometric isomers. All possible tautomers as well as cis and trans isomers, both as individual forms and mixtures thereof, are within the scope of the present invention. For example, a compound of formula (I) substituted with a hydroxyl group may exist as a tautomer as follows:

[0116]

[0117] In addition, as used herein, the term alkyl includes all possible isomeric forms of said alkyl. In addition, when cyclic groups such as aryl, heteroaryl, heterocyclic are substituted, they include all positional isomers. In addition, all hydrates of the compounds herein are within the scope hereof.

[0118] Certain structures provided herein are drawn with one or more floating substituents. Unless otherwise specified or otherwise clear from the context, the one or more substituents can be present on any atom in the ring through which the substituent is drawn, so long as it is chemically feasible and valence rules permit. For example, in the following structure: R 4 The substituent can replace any hydrogen on the six-membered aromatic ring portion of the bicyclic system, including the hydrogen of CH when a is CH.

[0119] The compounds herein can also contain unnatural amounts of isotopes at one or more atoms that make up such compounds. Unnatural amounts of isotopes can be defined as ranging from the amounts found in nature to 100% of the amounts of the atoms in question, which differ only in the presence of one or more isotope-enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the invention (such as compounds having formula (I) (and any embodiments thereof disclosed herein, including specific compounds)) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 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., those labeled with.sup.3H and.sup.14C) are useful in compound or substrate tissue distribution assays. Tritiated (i.e.,.sup.3H) and carbon-14 (i.e.,.sup.14C) isotopes are used because of their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e., 2H) Substitution can confer certain therapeutic advantages due to better metabolic stability (e.g., increased in vivo half-life or reduced dose requirements). In some embodiments, in the compounds disclosed herein, including those in Table 1 below, one or more hydrogen atoms are 2 replaced with H or 3 replaced with H, or one or more carbon atoms are 13 replaced with 13C- or 14 replaced with 14C-enriched carbon. Positron-emitting isotopes (such as 15 15O, 13 13N, 11 11C, and 15 18F) can be used 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 protocols or examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0120] "oxo" or "carbonyl" means the =(O) group.

[0121] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and means a description of a situation that includes where the event or circumstance occurs and where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl may but need not be present, and describes both the situation where the heterocyclyl is substituted with alkyl and the situation where the heterocyclyl is not substituted with alkyl.

[0122] "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and can be used in the preparation of pharmaceutical compositions, and includes carriers or excipients acceptable for veterinary use as well as for human pharmaceutical use. As used in this specification and the claims, "pharmaceutically acceptable carrier / excipient" includes one and more than one of such excipients.

[0123] As used herein, the term "about" is intended to qualify the value it modifies to indicate that this value can vary within the error bounds. When no specific error bounds are listed (such as the standard deviation of the mean given in a data graph or table), the term "about" should be understood to mean encompassing a range of ±10%, preferably ±5%, including the recited value and range.

[0124] As used herein, the term "disease" is intended to be generally synonymous with the terms "disorder", "symptom", and "condition" (as in a medical condition) and can be used interchangeably, as all of these reflect an abnormal condition of the human or animal body or one of its parts that impairs its normal function, typically manifested by distinguishable signs and symptoms, and results in a reduced life expectancy or quality of life for the person or animal.

[0125] Generally, the term "patient" is 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 pets (such as dogs, cats, and horses). Preferably, the patient is a human.

[0126] The terms "inhibit" and "reduce" with respect to EPPI, or any variants of these terms, include any measurable decrease or complete inhibition to achieve a desired result. For example, compared to normal conditions, there may be such a decrease: 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, or any range derivable therefrom, in the activity of EPPI.

[0127] "Treating" or "treatment" of a disease includes:

[0128] (1) Preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or is susceptible to the disease but has not yet experienced or shown symptoms of the disease;

[0129] (2) Inhibiting the disease, i.e., preventing or reducing the development of the disease or its clinical symptoms; or

[0130] (3) Relieving the disease, i.e., causing the disease or its clinical symptoms to subside.

[0131] "Therapeutically effective amount" means an amount of a compound and / or its pharmaceutically acceptable salt herein that is sufficient to produce such treatment of the disease when administered to a patient for treating 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 to be treated.

[0132] Representative compounds having formula (I) are disclosed in Table 1 below:

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150] Examples:

[0151] Example A

[0152] In Example A, the compound has the formula (I) or (IA) as defined in the above Summary of the Invention or a pharmaceutically acceptable salt thereof.

[0153] In the first sub - example A, the compound has the formula (I) as defined in the above Summary of the Invention or a pharmaceutically acceptable salt thereof. In the first sub - example A, the compound having the formula (I) or its pharmaceutically acceptable salt is one of the following, where Q is - P(O)(R a )(R b ) or - B(R w )(R x ), where R a , R b , R w and R x are independently selected from hydroxy, alkoxy, - O - aryl (wherein the aryl is optionally substituted by one to three substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), - O - (CH2)OCOR c (where R c is alkyl), - O - (alk 2 )OR d (where alk 2 is alkylene and R d is alkyl), - S - (CH2)2SCOR e (where Re is an alkyl group), or -NR g -(CHR)OCOR f (wherein R is hydrogen, an alkyl group, a hydroxymethyl group, a thiomethyl group, a methylthiomethyl group, an amidinopropyl group, an indol-3-ylmethyl group, an indol-4-ylmethyl group, a carboxymethyl group, a carboxyethyl group, an aminocarbonylmethyl group, an aminocarbonylethyl group, a phenyl group or a phenylalkyl group (wherein the phenyl group alone or as part of the phenylalkyl group is optionally substituted by one to three substituents independently selected from the group consisting of: an alkyl group, an alkoxy group, a halogen group, a hydroxyl group, a cyano group or a nitro group), R f is an alkyl group or a benzyl group 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 form a ring having formula (a):

[0154]

[0155] wherein, Ar 2 is a phenyl group or a six-membered heteroaryl group optionally substituted by one to three halogen groups; and

[0156] R w and R x together with the bromine atom to which they are attached may form -O(CRR’)2O- or -O(CRR’)3O-, wherein each R and R’ is independently hydrogen or methyl.

[0157] In the second sub-embodiment A, the compound has formula (IA) as defined in the above Summary of the Invention or is a pharmaceutically acceptable salt thereof.

[0158] Example B

[0159] In Example B, the compound as described in any one of Example A and the sub-embodiments contained therein, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ia) or (Ib):

[0160]

[0161] (Bi) In the sub-embodiment (Bi) of Example B, the compound or a pharmaceutically acceptable salt thereof has the structure (Ia).

[0162] (Bii) In the sub-embodiment (Bii) of Example B, the compound or a pharmaceutically acceptable salt thereof has the structure (Ib).

[0163] (Biii) In the sub-embodiment (Biii) of Example B, the compound having formula (Ia) and (Ib) or a pharmaceutically acceptable salt thereof is one wherein y is N and z is CR 7 .

[0164] Example C

[0165] In Example C, the compound as described in any one of Example A and its sub - examples, or a pharmaceutically acceptable salt thereof, has a structure of formula (Ic) or (Id):

[0166]

[0167] (Ci) In sub - example (Ci) of Example C, the compound or a pharmaceutically acceptable salt thereof has structure (Ic).

[0168] (Cii) In sub - example (Cii) of Example C, the compound or a pharmaceutically acceptable salt thereof has structure (Id).

[0169] Example D

[0170] In Example D, the compound as described in any one of Example A and its sub - examples, or a pharmaceutically acceptable salt thereof, has a structure of formula (Ie) or (If):

[0171]

[0172] (Di) In sub - example (Di) of Example D, the compound or a pharmaceutically acceptable salt thereof has structure (Ie).

[0173] (Dii) In sub - example (Dii) of Example D, the compound or a pharmaceutically acceptable salt thereof has structure (If).

[0174] Example D1

[0175] In Example D, the compound as described in any one of Example A and its sub - examples, or a pharmaceutically acceptable salt thereof, has a structure of formula (Ig) or (Ih):

[0176]

[0177] Wherein, R 7 is alkyl, halogen, or hydroxyl group.

[0178] (D1i) In sub - example (D1i) of Example D, the compound or a pharmaceutically acceptable salt thereof has structure (Ig).

[0179] (D1ii) In sub - example (Dii) of Example D, the compound or a pharmaceutically acceptable salt thereof has structure (Ih).

[0180] (D1iii) In sub - embodiment (Dii) of embodiment D, the compound having structures (Ig) and (Ih) or a pharmaceutically acceptable salt thereof is one in which R 7 is alkyl.

[0181] Embodiment E

[0182] In embodiment E, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments A, B, C, D, and D1 and the sub - embodiments contained therein is one in which when attached to R 4 、R 5 、and R 6 respectively, a, b, d, and e are CH or C.

[0183] Embodiment F

[0184] In embodiment F, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments A, B, C, D, and D1 and the sub - embodiments contained therein is one in which when attached to R 4 、R 5 、and R 6 respectively, a is N and b, d, and e are CH or C.

[0185] Embodiment G

[0186] In embodiment G, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments A, B, C, D, and D1 and the sub - embodiments contained therein is one in which when attached to R 4 、R 5 、and R 6 respectively, a and d are N and b and e are CH or C.

[0187] Embodiment H

[0188] In embodiment H, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments A, B, C, D, and D1 and the sub - embodiments contained therein is one in which when attached to R 4 、R 5 、and R 6 respectively, b is N and a, c, and e are CH or C.

[0189] Embodiment I

[0190] In embodiment I, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments A, B, C, D, and D1 and the sub - embodiments contained therein is one in which when attached to R 4 、R 5 、and R 6 respectively, b and e are N, and a and d are CH or C.

[0191] In sub - embodiment Ii, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments A, B, C, D, D1 and the sub - embodiments contained therein is one in which b and e are N, a is C - R 5 and d is C - R 6 , and R 5 is hydroxyl. As described above, sub - embodiment Ii in which R 5 is hydroxyl can exist in the following tautomeric forms:

[0192]

[0193] Embodiment J

[0194] In embodiment J, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments A, B, C, D, D1 and the sub - embodiments contained therein is one in which when attached to any one of R 4 , R 5 , and R 6 , b and e are N, and a and d are CH or C.

[0195] Embodiment K

[0196] In embodiment K, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments A, B, C, D, D1 and the sub - embodiments contained therein is one in which when attached to any one of R 4 , R 5 , and R 6 , d is N and a, b and e are CH or C.

[0197] Embodiment L

[0198] (Li). In sub - embodiment Li, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, and K and the sub - embodiments contained therein is one in which Q is - P(O)(OH)2.

[0199] (Lii). In sub - embodiment Lii, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, and K and the sub - embodiments contained therein is one in which Q is - B(OH)2.

[0200] (Liii). In sub - embodiment Liii, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, and K and the sub - embodiments contained therein is one in which Q is - P(O)(R a )(R b)。Within sub - embodiment (Liii), in the first group of compounds, Q is R a , and R b is independently selected from hydroxy, alkoxy, -O - aryl (wherein the aryl is optionally substituted by one to three substituents independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, or nitro), -O-(CH2)OCOR c (wherein is R c alkyl), -O-(CH2)OCOOR c (wherein R c is alkyl), -O-(alk 2 )OR d (wherein alk 2 is alkylene and R d is alkyl), and -S-(CH2)2SCOR e (wherein R e is alkyl). Preferably, R a and R b are independently selected from alkoxy, -O - aryl (wherein the aryl is optionally substituted by one to three substituents independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, or nitro), -O-(CH2)OCOR c (wherein R c is alkyl), and -O-(alk 2 )OR d (wherein alk 2 is alkylene and R d is alkyl, such as methyl, isopropyl, n - propyl, isobutyl, or n - butyl). Preferably, R a and R b are independently hydroxy, alkoxy, -O - phenyl (wherein the phenyl is optionally substituted by one to three substituents independently selected from the group consisting of alkoxy, halo, haloalkyl, cyano, or nitro), -O-(CH2)OCOR c (wherein R c is alkyl), and -NH-(CHR)OCOR f (wherein R is alkyl, R f is alkyl, such as methyl, isopropyl, n - propyl, isobutyl, n - butyl or benzyl), preferably hydroxy or alkoxy.

[0201] Within sub - embodiment (Liii), in the second group of compounds, Q is R a , which is selected from hydroxy, alkoxy, -O - aryl (wherein the aryl is optionally substituted by one to three substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCOR c (wherein R cis alkyl), -O-(alk 2 )OR d (where alk 2 is alkylene and R d is alkyl), and -S-(CH2)2SCOR e (where R e is alkyl), and R b is selected from -NR g -(CHR)OCOR f (where R is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl or phenylalkyl (where the phenyl is optionally substituted, alone or as part of the phenylalkyl, by one to three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano or nitro), R f is alkyl or benzyl and R g is hydrogen or forms -(CH2)3- together with R). Preferably, R a is selected from alkoxy and -Oaryl (where the aryl is optionally substituted by one to three substituents independently selected from halogen, cyano, or nitro), and R b is selected from -NR g -(CHR)OCOR f (where R is alkyl, such as methyl, isopropyl, n-propyl, isobutyl, n-butyl).

[0202] In sub - embodiment (Liii), within the third group of compounds, Q is where R a and R b together with the phosphorus atom to which they are attached form a ring having formula (a):

[0203]

[0204] wherein, Ar 1 is phenyl or a six - membered heteroaryl optionally substituted by one to three halogen atoms. Preferably, Ar 1 is phenyl substituted by one to three halogen atoms or pyridyl.

[0205] (Liv). In sub - embodiment Liv, as described in any one of Examples A, B, C, D, D1, E, F, G, H, I, J, and K and the sub - embodiments contained therein, the compound or its pharmaceutically acceptable salt is where Q is -B(R w )(R x ). In sub - embodiment (Liv), within the first group of compounds, R w and R xindependently selected from hydroxy, alkoxy, -Oaryl (wherein the aryl is optionally substituted with one to three substituents independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, or nitro), -O-(CH2)OCOR c (wherein R c is alkyl), or -O-(alk 2 )OR d (wherein alk 2 is alkylene and R d is alkyl). Preferably, R w and R x are independently selected from alkoxy, -Oaryl (wherein the aryl is optionally substituted with one to three substituents independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, or nitro), -O-(CH2)OCOR c (wherein R c is alkyl), and -O-(alk 2 )OR d (wherein alk 2 is alkylene and R d is alkyl, such as methyl, isopropyl, n-propyl, isobutyl, or n-butyl). Preferably, R w and R x are independently hydroxy, alkoxy, or -Ophenyl (wherein the phenyl is optionally substituted with one to three substituents independently selected from the group consisting of alkoxy, halo, haloalkyl, cyano, or nitro).

[0206] In sub-embodiment (Liv), within the second group of compounds, R w and Rx are independently selected from hydroxy and alkoxy.

[0207] In sub-embodiment (Liii), within the third group of compounds, R w and R x together with the boron atom to which they are attached form a ring having formula (b) or (c):

[0208]

[0209] Example M

[0210] In Example M, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, C, D, D1, E, F, G, H, I, J, K, and L and the sub-embodiments contained therein is one wherein Ar is aryl or heteroaryl.

[0211] (Mi). In sub - embodiment Mi of embodiment M, the compound or its pharmaceutically acceptable salt as described in embodiment M are those in which Ar is phenyl. In one sub - embodiment of sub - embodiment Mi, the compound or its pharmaceutically acceptable salt as described in sub - embodiment Mi are those in which Q is attached to a carbon of the phenyl ring, and this carbon is meta to the carbon that attaches the phenyl ring to the remaining compound having formula (I). In another sub - embodiment of sub - embodiment Mi, the compound or its pharmaceutically acceptable salt as described in sub - embodiment Mi are those in which Q is attached to a carbon of the phenyl ring, and this carbon is para to the carbon that attaches the phenyl ring to the remaining compounds having formula (I) and (Ia) to (Ih) respectively.

[0212] (Mii). In sub - embodiment Mii of embodiment M, the compounds as described in embodiment M are those in which Ar is a heteroaryl. In one sub - embodiment of sub - embodiment Mii, the compound or its pharmaceutically acceptable salt as described in sub - embodiment Mii are those in which Ar is pyridyl, pyrimidinyl, pyridazinyl, thienyl, furyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, oxadiazolyl or imidazolyl. In another sub - embodiment of embodiment Mii, the compound or its pharmaceutically acceptable salt as described in sub - embodiment Mii are those in which Ar is a six - membered ring, such as pyridyl, pyrimidinyl or pyridazinyl, and Q is attached to a carbon of the pyridyl, pyrimidinyl or pyridazinyl ring, and this carbon is meta to the carbon that attaches the pyridyl, pyrimidinyl or pyridazinyl ring to the remaining compounds having formula (I) and (Ia) to (Ih) respectively.

[0213] For sub - embodiment Mii, in yet another group of compounds, Ar is benzofuryl, quinolinyl, quinazolinyl, benzimidazolyl, indazolyl, benzotriazolyl, or benzoxazolyl.

[0214] Embodiment N

[0215] In embodiment N, the compound or its pharmaceutically acceptable salt as described in any one of embodiments A, B, C, D, D1, E, F, G, H, I, J, K, L and the sub - embodiments contained therein are those in which Ar is a heterocyclic group.

[0216] (Ni). In sub - embodiment Ni of embodiment N, the compound or its pharmaceutically acceptable salt as described in sub - embodiment Ni are those in which Ar is pyrrolidinyl, piperidinyl, or homopiperidinyl, preferably Ar is piperidin - 4 - yl, and Q is attached to the nitrogen atom of the piperidinyl ring through alk 1

[0217] Embodiment O

[0218] ​In Example O, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, C, D, D1, E, F, G, H, I, J, K, L, M, and N and the sub-examples contained therein is one in which alk and alk 1 are independently methylene, ethylene, or propylene. In a first sub-example, alk and alk 1 are methylene, and preferably when Ar is a six-membered ring, alk and alk 1 are methylene. In a second sub-example, alk is methylene and alk 1 is absent (i.e., m is 0).

[0219] Example P

[0220] In Example P, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, D, D1, E, F, G, H, J, K, L, M, and O and the sub-examples contained therein is one in which R 7 is hydrogen, methyl, isopropyl, or fluorine. In a first sub-example of Example P, these compounds are those in which R 7 is hydrogen, methyl, or fluorine. In a second sub-example of Example P, these compounds are those in which R 7 is hydrogen. In a second sub-example of Example P, these compounds are those in which R 7 is methyl or isopropyl.

[0221] Example Q

[0222] In Example Q, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, C, D, D1, E, F, G, H, I, J, K, L, M, N, O, and P and the sub-examples contained therein is one in which R 2 and R 3 are independently hydrogen, methyl, ethyl, methoxy, fluorine, trifluoromethyl, trifluoromethoxy, or cyano. In a first sub-example of Example Q, these compounds are those in which R 2 and R 3 are hydrogen.

[0223] Example R

[0224] In Example R, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, C, D, D1, E, F, G, H, I, J, K, L, M, N, O, P, and Q and the sub-examples contained therein is one in which R 4is hydrogen, alkyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl.

[0225] (Ri) In sub - embodiment (Ri) of embodiment R, these compounds are those in which R 4 is hydrogen, methyl, methoxy, ethoxy, fluorine, chlorine, trifluoromethyl, cyano, or trifluoromethoxy. In the first sub - embodiment of (Ri), these compounds are those in which R 4 is hydrogen, methoxy or ethoxy. In the second sub - embodiment of (Ri), these compounds are those in which R 4 is hydrogen.

[0226] (Rii) In sub - embodiment (Rii) of embodiment R, R 4 is cyano, carboxyl, alkoxycarbonyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl. Within (Rii), in one group of compounds, R 4 is cyano, carboxyl, methoxycarbonyl, methylsulfonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl. Within (Rii), in another group of compounds, R 4 is cyano, carboxyl, methoxycarbonyl, aminocarbonyl, methylsulfonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl. Within (Rii), in yet another group of compounds, R 4 is aminocarbonyl, methylaminocarbonyl, or dimethylaminocarbonyl. Within R(ii) and the groups contained therein, in another group of compounds, R 4 is attached to the six - membered ring containing a, b, d, and e of formula (I) as shown below

[0227]

[0228] where the wavy line represents the point of attachment to the remainder of the molecule (for clarity, the six - membered ring of formula (I) containing a, b, d, and e has been shown as an example. To those skilled in the art, it will be apparent that in embodiments encompassing one or more compounds of formula (Ia) through (Ih), R 4 will be attached to the same carbon of the six - membered ring containing a, b, d, and e as described above).

[0229] (Riii) In sub - embodiment (Riii) of embodiment R, these compounds are those in which R 4is an alkylsulfonyl group, preferably a methylsulfonyl group, and R 4 is attached to a six-membered ring containing a, b, d, and e of formula I as shown below

[0230]

[0231] where the wavy line represents the point of attachment to the remainder of the molecule.

[0232] Example S

[0233] (Si) In Example Si, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, C, D, D1, E, F, G, H, I, J, K, L, M, N, O, P, Q, and R and the sub-examples (or groups) contained therein is one in which R 5 and R 6 are independently hydrogen, alkyl, alkoxy, hydroxy, amino, halo, haloalkyl, or haloalkoxy. In the first sub-example of Example (Si), these compounds are those in which R 5 and R 6 are independently hydrogen, alkoxy, amino, or hydroxy. In the second sub-example of Example (Si), these compounds are those in which R 5 and R 6 are independently alkoxy, such as methoxy, ethoxy, or propoxy, and are attached to a six-membered ring containing a, b, d, and e of formula I as described below

[0234]

[0235] where the wavy line represents the point of attachment to the remainder of the molecule. In the third sub-example of Example (Si), these compounds are those in which R 5 and R 6 are independently hydrogen. In the fourth sub-example of Example (Si), these compounds are those in which R 5 is attached to a six-membered ring containing a, b, d, and e of formula I as shown below

[0236]

[0237] where the wavy line represents the point of attachment to the remainder of the molecule. Within the fourth sub-example, in one group of compounds, R 5 is hydroxy, and R 4 and R 6 are hydrogen.

[0238] (Mii) In Example Mii, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, C, D, D1, E, F, G, H, I, J, K, L, M, N, O, P, Q, and R and the sub-examples contained therein are those wherein:

[0239] R 5 is hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, or haloalkoxy; and

[0240] R 6 is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein the heterocyclyl alone or a part of the heterocyclyloxy and heterocyclylamino is optionally substituted by one, two, or three substituents independently selected from the group consisting of alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclic ring in the heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted by one, two, or three substituents independently selected from the group consisting of alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl in the phenyloxy and the heteroaryl in the heteroaryloxy are optionally substituted by one, two, or three substituents, and two of these optional substituents are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano).

[0241] In the first sub-example of Example Mii, R 5 is hydrogen, methoxy, ethoxy, or hydroxy, preferably R 5 is methoxy or ethoxy; and R 6is 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 2-methylaminoethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-aminopropoxy, 3-methylaminopropoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethoxy, piperidinylmethoxy, pyrrolidinylethoxy, piperidinylethoxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 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 above groups are optionally substituted, alone or as part of another group, by one or two substituents independently selected from methyl, fluorine, hydroxy or methoxy). Preferably, R 5 and R 6 are attached to the six-membered ring containing a, b, d, and e of formula I shown below

[0242]

[0243] wherein the wavy line represents the point of attachment to the remainder of the molecule.

[0244] (Miii) In Example Mi, the compound or its pharmaceutically acceptable salt as described in any one of Examples A, B, C, D, D1, E, F, G, H, I, J, K, L, M, N, O, P, Q, and R and the sub-examples contained therein are those wherein, R 5 and R 6Independently is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclic group, heterocyclic group oxy, heterocyclic group amino (wherein, the heterocyclic group alone or a part of the heterocyclic group oxy and the heterocyclic group amino is optionally substituted by one, two, or three substituents independently selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclic group alkyl, heterocyclic group alkyl oxy, heterocyclic group alkyl amino (wherein, the heterocyclic group ring in the heterocyclic group alkyl, the heterocyclic group alkyl oxy, and the heterocyclic group alkyl amino is optionally substituted by one, two, or three substituents independently selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein, the phenyl of the phenyloxy and the heteroaryl of the heteroaryloxy are optionally substituted by one, two, or three substituents, and two of these optional substituents are independently selected from alkyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano).

[0245] In the first sub - embodiment of Example Miii, R 5 and R 6 Independently are 2 - hydroxyethoxy, 3 - hydroxypropoxy, 2 - methoxyethoxy, 2 - ethoxyethoxy, 3 - methoxypropoxy, 3 - ethoxypropoxy, 2 - aminoethoxy, 2 - methylaminoethoxy, 2 - dimethylaminoethoxy, 2 - diethylaminoethoxy, 3 - aminopropoxy, 3 - methylaminopropoxy, 3 - dimethylaminopropoxy, 3 - diethylaminopropoxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethoxy, piperidinylmethoxy, pyrrolidinylethoxy, piperidinylethoxy, 2 - hydroxyethylamino, 3 - hydroxypropylamino, 2 - methoxyethylamino, 2 - ethoxyethylamino, 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 above groups alone or a part of the other group is optionally substituted by one or two substituents independently selected from methyl, fluorine, hydroxy, or methoxy). Preferably, R 5 and R 6 Are attached to the six - membered ring containing a, b, d, and e of formula I shown below

[0246]

[0247] Wherein the wavy line represents the attachment point to the rest of the molecule.

[0248] Additional embodiments of the present disclosure include the following Embodiments 1 to 58:

[0249] 1. In Embodiment 1, a compound having the formula (I) is provided:

[0250]

[0251] Wherein:

[0252] a, b, d, and e are CH; or one or two of a, b, d, and e are N, and the remainder of a, b, d, and e are CH;

[0253] One of y and z is N and the other of y and z is CR 7 ; or both y and z are CR 7 , where each R 7 is independently hydrogen, alkyl, hydroxy, or halo;

[0254] alk is an alkylene optionally substituted with one, two, or three halo groups;

[0255] alk 1 is an alkylene in which one carbon atom in the alkylene chain may be replaced by oxygen and the alkylene chain is optionally substituted with one, two, or three halo groups;

[0256] m and n are independently 0 or 1; provided that at least one of m and n is 1;

[0257] Ar is aryl or heteroaryl;

[0258] Q is -B(R w )(R x ), where R w and R x are independently selected from hydroxy, alkoxy, -Oaryl (wherein the aryl is optionally substituted with one to three substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCOR c (where R c is alkyl), -O-(alk 2 )OR d (where alk 2 is alkylene and R d is alkyl); or

[0259] R w and R xTogether with the bromine atoms to which they are attached, they can form -O(CRR’)2O- or -O(CRR’)3O-, where each R and R’ is independently hydrogen or methyl;

[0260] R 2 and R 3 are independently hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, or cyano;

[0261] R 4 is hydrogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl; and

[0262] R 5 and R 6 are independently hydrogen, alkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, amino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclic group, heterocyclic group oxy, heterocyclic group amino (wherein the heterocyclic group alone or a part of the heterocyclic group oxy and heterocyclic group amino is optionally substituted independently by an R selected from the group consisting of h R j or R k substituents: alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclic group alkyl, heterocyclic group alkyl oxy, heterocyclic group alkyl amino (wherein the heterocyclic group ring in the heterocyclic group alkyl, heterocyclic group alkyl oxy, and heterocyclic group alkyl amino is optionally substituted by one, two, or three substituents independently selected from the group consisting of: alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl in the phenyloxy and the heteroaryl in the heteroaryloxy are optionally substituted by one, two, or three substituents, and two of these optional substituents are independently selected from alkyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano); or

[0263] its pharmaceutically acceptable salts;

[0264] provided that when formula (I) has the structure

[0265] and:

[0266] (i) when Q is -B(OH)2, then not 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-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; 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;

[0267] (ii) Q is When, then not 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-benzoimidazol-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-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-benzoimidazol-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-benzoimidazol-1-ylmethyl)phenyl, or 4-(2-ethoxy-7-ethoxycarbonyl-1H-benzoimidazol-1-ylmethyl)phenyl; and

[0268] (iii) Q is when, then not 4-(2-ethoxy-7-ethoxycarbonyl-1H-benzoimidazol-1-ylmethyl)phenyl.

[0269] 2. In Example 2, the compound as described in Example 1, or a pharmaceutically acceptable salt thereof has the structure of formula (Ia) or (Ib):

[0270]

[0271] 3. In Example 3, the compound as described in Example 2, or a pharmaceutically acceptable salt thereof has the structure of formula (Ia).

[0272] 4. In Example 4, the compound as described in Example 2, or a pharmaceutically acceptable salt thereof has the structure of formula (Ib).

[0273] 5. In Example 5, the compound as described in Example 1, or a pharmaceutically acceptable salt thereof has the structure of formula (Ic) or (Id):

[0274]

[0275] 6. In Example 6, the compound as described in Example 5, or a pharmaceutically acceptable salt thereof has the structure of formula (Ic).

[0276] 7. In Example 7, the compound as described in Example 5, or a pharmaceutically acceptable salt thereof, has the structure of formula (Id).

[0277] 8. In Example 8, the compound as described in Example 1, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ie) or (If):

[0278]

[0279] 9. In Example 9, the compound as described in Example 8, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ie).

[0280] 10. In Example 18, the compound as described in Example 8, or a pharmaceutically acceptable salt thereof, has the structure of formula (If).

[0281] 11. In Example 11, the compound as described in Example 1, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ig) or (Ih):

[0282]

[0283] wherein, R 7 is alkyl, halo, or hydroxy.

[0284] 12. In Example 12, the compound as described in Example 11, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ig).

[0285] 13. In Example 13, the compound as described in Example 11, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ih).

[0286] 14. In Example 14, the compound as described in Example 12 or 13, or a pharmaceutically acceptable salt thereof, is one wherein R 7 is alkyl.

[0287] 15. In Example 15, the compound as described in any one of Examples 1 to 14, or a pharmaceutically acceptable salt thereof, is one wherein a, b, d, and e are CH.

[0288] 16. In Example 16, the compound as described in any one of Examples 1 to 14, or a pharmaceutically acceptable salt thereof, is one wherein a is N and b, d, and e are CH.

[0289] 17. In Example 17, the compound as described in any one of Examples 1 to 14, or a pharmaceutically acceptable salt thereof, is one wherein a and d are N and b and e are CH.

[0290] 18. In Example 18, the compound as described in any one of Examples 1 to 14, or a pharmaceutically acceptable salt thereof, is one in which b is N and a, c, and e are CH.

[0291] 19. In Example 19, the compound as described in any one of Examples 1 to 14, or a pharmaceutically acceptable salt thereof, is one in which b and e are N, and a and d are CH.

[0292] 20. In Example 20, the compound as described in any one of Examples 1 to 14, or a pharmaceutically acceptable salt thereof, is one in which d is N and a, b, and e are CH.

[0293] 21. In Example 21, the compound as described in any one of Examples 1 to 14, or a pharmaceutically acceptable salt thereof, is one in which one of d and e is N and the remainder of a, b, d, and e is CH.

[0294] 21a. In Example 21a, the compound as described in any one of Examples 1 to 14, or a pharmaceutically acceptable salt thereof, is one in which a and e are N, and b and d are CH.

[0295] 21b. In Example 21b, the compound as described in Example 21, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ii):

[0296]

[0297] 21c. In Example 21c, the compound as described in Example 21, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ij):

[0298]

[0299] wherein, R 7 is alkyl, halo, or hydroxy.

[0300] 21d. In Example 21d, the compound as described in Examples 21b and 21c, or a pharmaceutically acceptable salt thereof, is one in which R 7 is alkyl.

[0301] 21e. In Example 21d, the compound as described in Example 21b or 21c, or a pharmaceutically acceptable salt thereof, is one in which R 7 is methyl or isopropyl.

[0302] 22. In Example 22, the compound as described in any one of Examples 1 to 21e, or a pharmaceutically acceptable salt thereof, is one in which Q is -B(OH)2.

[0303] 23. In Example 23, the compound as described in any one of Examples 1 to 21e, or a pharmaceutically acceptable salt thereof, is one in which Q is -B(R w )(R x ), where R w and R x are independently selected from hydroxy and alkoxy.

[0304] 24. In Example 24, the compound as described in any one of Examples 1 to 21e, or a pharmaceutically acceptable salt thereof, is one in which Q is -B(R w )(R x ), where R w and R x together with the boron atom to which they are attached form a ring having formula (b) or (c):

[0305]

[0306] 25. In Example 25, the compound as described in any one of Examples 1 to 24, or a pharmaceutically acceptable salt thereof, is one in which Ar is phenyl.

[0307] 26. In Example 26, the compound as described in Example 25, or a pharmaceutically acceptable salt thereof, is one in which Q is attached to a carbon on the phenyl ring, and this carbon is para to the carbon attaching the phenyl ring to the remainder of the compound having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (If), and (Ig).

[0308] 27. In Example 27, the compound as described in any one of Examples 1 to 24, or a pharmaceutically acceptable salt thereof, wherein Ar is heteroaryl.

[0309] 28. In Example 28, the compound as described in Example 27, or a pharmaceutically acceptable salt thereof, is one in which Ar is pyridyl, pyrimidinyl, pyridazinyl, thienyl, furyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, oxadiazolyl or imidazolyl.

[0310] 29. In Example 29, the compound as described in any one of Examples 1 to 28, or a pharmaceutically acceptable salt thereof, is one in which alk and alk 1 are independently methylene, ethylene, or propylene.

[0311] 30. In Example 30, the compound as described in any one of Examples 1 to 28, or a pharmaceutically acceptable salt thereof, is one in which alk and alk 1 are methylene.

[0312] 31. In Example 31, the compound as described in any one of Examples 1 to 4 and 8 to 20, 21a, and 22 to 30, or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, methyl, isopropyl, or fluorine.

[0313] 32. In Example 32, the compound as described in any one of Examples 1 to 4 and 8 to 20, 21a, and 22 to 30, or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, methyl, or fluorine.

[0314] 33. In Example 33, the compound as described in any one of Examples 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are independently hydrogen, methyl, ethyl, methoxy, fluorine, trifluoromethyl, trifluoromethoxy, or cyano.

[0315] 34. In Example 34, the compound as described in any one of Examples 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are hydrogen.

[0316] 35. In Example 35, the compound as described in any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, alkyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl.

[0317] 36. In Example 36, the compound as described in Example 35, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, methyl, methoxy, ethoxy, fluorine, chlorine, trifluoromethyl, cyano, or trifluoromethyloxy.

[0318] 37. In Example 27, the compound as described in any one of Examples 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R 4 is cyano, carboxyl, alkoxycarbonyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl.

[0319] 38. In Example 38, the compound as described in Example 37, or a pharmaceutically acceptable salt thereof, wherein R 4 is cyano, carboxyl, methoxycarbonyl, aminocarbonyl, methylsulfonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl.

[0320] 39. In Example 39, the compound as described in Example 37, or a pharmaceutically acceptable salt thereof, is one in which R 4 is attached to a six-membered ring containing a, b, d, and e of Formula I as shown below

[0321]

[0322] where the wavy line represents the point of attachment to the remainder of the molecule.

[0323] 40. In Example 40, the compound as described in any one of Examples 1 to 39, or a pharmaceutically acceptable salt thereof, is one in which R 5 and R 6 are hydrogen.

[0324] 41. In Example 41, the compound as described in any one of Examples 1 to 36, or a pharmaceutically acceptable salt thereof, is one in which R 5 and R 6 are independently hydrogen, alkyl, alkoxy, hydroxy, amino, halo, haloalkyl, or haloalkoxy.

[0325] 42. In Example 42, the compound as described in Example 41, or a pharmaceutically acceptable salt thereof, is one in which R 5 is attached to a six-membered ring containing a, b, d, and e of Formula I as shown below

[0326]

[0327] where the wavy line represents the point of attachment to the remainder of the molecule.

[0328] 43. In Example 43, the compound as described in Example 42 or a pharmaceutically acceptable salt thereof, is one in which, R 5 is hydroxy, and R 4 and R 6 are hydrogen.

[0329] 44. In Example 44, the compound as described in Example 41, or a pharmaceutically acceptable salt thereof, is one in which R 5 and R 6 are attached to a six-membered ring containing a, b, d, and e of Formula I as shown below

[0330]

[0331] where the wavy line represents the point of attachment to the remainder of the molecule.

[0332] 45. In Example 45, the compound as described in any one of Examples 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, or haloalkoxy; and

[0333] R 6 is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein the heterocyclyl alone or a part of the heterocyclyloxy and heterocyclylamino is optionally substituted by one, two, or three substituents independently selected from the group consisting of alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclic ring in the heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted by one, two, or three substituents independently selected from the group consisting of alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl in the phenyloxy and the heteroaryl in the heteroaryloxy are optionally substituted by one, two, or three substituents, and two of these optional substituents are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano).

[0334] 46. In Example 46, the compound as described in Example 45, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, methoxy, ethoxy, or hydroxy, and R 6is 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 2-methylaminoethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-aminopropoxy, 3-methylaminopropoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethoxy, piperidinylmethoxy, pyrrolidinylethoxy, piperidinylethoxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 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 above groups are optionally substituted, alone or as part of another group, with one or two substituents independently selected from methyl, fluorine, hydroxy, or methoxy).

[0335] 47. In Example 47, the compound as described in Example 45 or 46, or a pharmaceutically acceptable salt thereof, is one wherein R 5 and R 6 are attached to the six-membered ring containing a, b, d, and e having Formula I as shown below

[0336]

[0337] wherein the wavy line represents the point of attachment to the remainder of the molecule.

[0338] 48. In Example 48, the compound as described in any one of Examples 1 to 36, or a pharmaceutically acceptable salt thereof, is one wherein R 5 and R 6Independently is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclic group, heterocyclic group oxy, heterocyclic group amino (wherein, the heterocyclic group alone or a part of the heterocyclic group oxy and the heterocyclic group amino is optionally substituted by one, two, or three substituents independently selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclic group alkyl, heterocyclic group alkyl oxy, heterocyclic group alkyl amino (wherein, the heterocyclic group ring in the heterocyclic group alkyl, the heterocyclic group alkyl oxy, and the heterocyclic group alkyl amino is optionally substituted by one, two, or three substituents independently selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein, the phenyl of the phenyloxy and the heteroaryl of the heteroaryloxy are optionally substituted by one, two, or three substituents, and two of these optional substituents are independently selected from alkyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano).

[0339] 49. In Example 49, the compound as described in Example 48, or a pharmaceutically acceptable salt thereof, is wherein R 5 and R 6 Independently are 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 2-methylaminoethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-amino-propoxy, 3-methylaminopropoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethoxy, piperidinylmethoxy, pyrrolidinyethoxy, piperidinyethoxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 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 above groups alone or a part of the other group is optionally substituted by one or two substituents independently selected from methyl, fluorine, hydroxy, or methoxy).

[0340] 50. In Example 50, the compound as described in Example 48 or 49, or a pharmaceutically acceptable salt thereof, is wherein R 5 and R 6 are attached to the six-membered ring containing a, b, d, and e of formula I as shown below

[0341]

[0342] Wherein the wavy line indicates the attachment point to the remainder of the molecule.

[0343] 51. In Example 51, there is provided a pharmaceutical composition comprising a compound as described in any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0344] 52. In Example 52, there is provided a method of treating a disease or disorder mediated by ENPP1 in a patient, the method comprising administering to the patient a compound as described in any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof.

[0345] 53. In Example 53, the method as described in Example 52 is one wherein the disease or disorder is cancer, an inflammatory disease, a metabolic disease, or a viral disease.

[0346] 54. In Example 54, the method as described in Example 52 is one wherein the disease or disorder is cancer.

[0347] 55. In Example 55, the method as described in Example 52 is one wherein the disease or disorder is cancer, wherein the cancer is hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, or breast cancer.

[0348] 56. In Example 56, the method as described in Example 54 or 55 is one wherein the compound as described in any one of claims 1 to 50 is administered together with an anti-cancer agent.

[0349] General synthetic scheme

[0350] The compounds herein can be prepared by the methods depicted in the reaction schemes shown below.

[0351] The starting materials and reagents used to prepare 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 the following 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 Supplements (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 illustrative only of some of the methods by which the compounds herein can be synthesized, and various modifications can be made to these schemes, and those skilled in the art will be inspired upon reading this text. If desired, the starting materials and intermediates of the reaction, as well as the final product, can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0352] Unless otherwise specified, the reactions described herein occur at atmospheric pressure in a temperature range from about -78 °C to about 150 °C, such as from about 0 °C to about 125 °C, and further such as at about room temperature (or ambient temperature), for example, about 20 °C.

[0353] Compounds having formula (I) wherein Ar is aryl or heteroaryl, n is 1, m is 0, and the other groups are as defined in the Summary of the Invention can be prepared as illustrated and described in Scheme 1 below.

[0354] Scheme 1

[0355]

[0356] Under the conditions of the Suzuki reaction (Suzuki, A, Journal of Organometallic Chemistry. 576: 147 - 168 and references cited therein), arylation of a compound of formula 1, wherein a, b, d, e, y and z are as defined in the Summary of the Invention and R 4 , R 5 and R 6 are as defined in the Summary of the Invention or precursor groups thereof (e.g., a hydroxyl group is a precursor group for an alkoxy group, etc.), with a boronic acid of formula 2, wherein Ar is an aryl or heteroaryl group, provides an alcohol compound of formula 3. The reaction is carried out under palladium- or nickel-catalyzed conditions, at room temperature or upon heating, 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 consisting of a mixture of water and an organic solvent such as 1,4-dioxane, tetrahydrofuran (THF), diethyl ether, toluene, ethanol or methanol, dimethylformamide (DMF), etc. 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, 1H-benzo[d]imidazole-5-carboxylic acid methyl ester, 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 are commercially available.

[0357] The conversion of the hydroxyl group in the compound of formula 3 to the 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 halogen group in the compound of formula 4 can be replaced by various borate or phosphite nucleophiles to provide the compound of formula (I). For example, treatment of compound 4 heated in the absence or presence of an aprotic organic solvent such as DMF or THF with triethyl phosphite, followed by hydrolysis of the resulting triethyl phosphonate provides the compound of formula (I) where Q is -P(O)(OH)2. The triethyl phosphonate can be hydrolyzed in dichloromethane in the presence of bromo - or chloro - trimethylsilane at room temperature or upon heating, or in water in the presence of hydrogen chloride, or in dichloromethane in the presence of trimethylsilyl iodide. The compound of formula (I) where Q is -B(OH)2 can be prepared by treating 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 - dioxaborolan - 2 - yl) by methods well known in the art. By methods well known in the art, the compound of formula (I) can be converted to other compounds of formula (I). For example, treatment of diethyl (4 - ((5 - cyano - 1H - benzo[d]imidazol - 1 - yl)methyl)phenyl)phosphonate with bromotrimethylsilane in dichloromethane at room temperature converts it to (4 - ((5 - cyano - 1H - benzo[d]imidazol - 1 - yl)methyl)phenyl)phosphonic acid.

[0358] The compound of formula (I) (where Ar is aryl or heteroaryl, n is 1, m is 0, and the other groups are as defined in the Summary of the Invention) can be prepared as illustrated and described in Scheme 2 below.

[0359] Scheme 2

[0360]

[0361] Treatment of the compound of formula 1 with the compound of formula 5 or 5’ (where Ar, alk are as defined in the Summary of the Invention, and R 2 and R 3is as defined in the Summary of the Invention or its precursor group, and LG is a suitable leaving group such as a halogen group) to provide a compound having Formula 6 or 7, respectively. By methods well known in the art, a compound having Formula 6 can be converted to a compound 7 in which LG is a halogen group. Compounds having Formula 5 are commercially available or can be prepared by methods well known in the art. Then, as described in Scheme 1 above, a compound having Formula 7 can be converted to a compound having Formula (I).

[0362] Alternatively, a compound having Formula (I) in which Q is boric acid can be prepared by replacing the leaving group in a compound having Formula 8 with a compound having Formula 1. The reaction is carried out by treating a mixture of compounds having Formulas 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, etc. at room temperature or with heating. Compounds having Formula 8 are commercially available or can be readily prepared by methods well known in the art. Compounds having 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, 1H - benzo[d]imidazole - 5 - methyl formate, 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, 5 - methanesulfonyl - 1H - 1,3 - benzodiazole are commercially available. Compounds having Formula 8 such as (4 - (bromomethyl)phenyl)boronic acid are commercially available. Compounds having Formula 5 such as 1 - bromo - 4 - (bromomethyl)benzene, 5 - bromo - 2 - (bromomethyl)pyridine are commercially available.

[0363] Testing

[0364] The ENPP1 inhibitory activity of the compounds herein can be tested using the in vitro assays described in Biological Examples 1 and 2 below.

[0365] Administration and Pharmaceutical Compositions

[0366] In general, the compounds of the present invention will be administered in a therapeutically effective amount by any acceptable mode of administration of a reagent for a similar utility. The therapeutically effective amount of the compounds of the present invention can range from about 0.01 to about 500 mg per kilogram of patient body weight per day, which can be administered in a single dose or multiple doses. Suitable dosage levels can be from 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, the dosage can be about 0.05 to about 0.5 mg / kg per day, about 0.5 to about 5 mg / kg per day or about 5 to about 50 mg / kg per day. For oral administration, these compositions can be provided in tablet form, which contain from about 1.0 to about 1000 milligrams of the 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 the active ingredient. The actual amount of the compound of the present invention (i.e., the active ingredient) will depend on a variety of factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound utilized, the route and form of administration and other factors.

[0367] In general, the compounds of the present invention will be administered as a pharmaceutical composition by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred mode of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of illness. The composition can take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or any other suitable composition.

[0368] The choice of formulation depends on a variety of 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 sustained release tablets, pills or capsules are preferred) and the bioavailability of the drug. Recently, based on the principle that bioavailability can be increased by increasing the surface area (i.e., reducing the particle size), drug formulations have been developed, particularly for drugs with poor bioavailability. For example, U.S. Patent No. 4,107,288 describes a drug formulation having particles in the size range from 10 nm to 1,000 nm, wherein the active material is loaded on a crosslinked matrix of a macromolecule. U.S. Patent No. 5,145,684 describes the production of a drug formulation, wherein the drug is ground into nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a drug formulation exhibiting very high bioavailability.

[0369] These compositions are generally composed of a combination of the compounds of the present invention with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefits of the compounds of the present invention. Such excipients can be any solid, liquid, semi-solid or, in the case of aerosol compositions, gaseous excipients commonly available to those skilled in the art.

[0370] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, skim milk powder, etc. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and a variety of oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, especially for injectable solutions, include water, saline, aqueous dextrose, and ethylene glycol.

[0371] Compressed gases can be used to disperse the compounds of the present invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

[0372] Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E.W. Martin (Mack Publishing Company, 20th edition, 2000).

[0373] The level of the compound in the formulation can vary over the full range used by those skilled in the art. Typically, based on the total formulation, the formulation will contain from about 0.01 - 99.99 wt.% of the compound of the present invention by weight percentage (wt.%), the balance being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1 - 80 wt%.

[0374] The compounds of the present invention can be used in combination with one or more other drugs for treating diseases or disorders for which the compounds of the present invention or the other drugs may have efficacy. Such one or more other drugs can be administered simultaneously or sequentially with the compounds of the present invention by their conventional routes and in their conventional amounts. When the compounds of the present invention are used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compounds of the present invention is preferred. However, combination therapy can also include regimens in which the compounds of the present invention and one or more other drugs are administered according to different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients can be used at lower doses than when used alone. Accordingly, the pharmaceutical compositions of the present invention also include those that contain one or more other drugs in addition to the compounds of the present invention.

[0375] The above combinations include not only combinations of the compounds of the present invention with one other drug, but also combinations with two or more other active drugs. Similarly, the compounds of the present invention can be used in combination with other drugs for preventing, treating, controlling, ameliorating diseases or disorders for which the compounds of the present invention are useful, or reducing the risk of diseases or disorders for which the compounds of the present invention are useful. Such one or more other drugs can be administered simultaneously or sequentially with the compounds of the present invention by their conventional routes and in their conventional amounts. When the compounds of the present invention are used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compounds of the present invention can be used. Accordingly, the pharmaceutical compositions of the present invention also include those that contain one or more other active ingredients in addition to the compounds of the present invention. The weight ratio of the compounds of the present invention to the second active ingredient can vary and will depend on the effective doses of each ingredient. Generally, the respective effective doses will be used.

[0376] When a subject in need suffers from cancer or is at risk of developing cancer, the subject can be treated with any combination of the compounds of the present invention and one or more other anti-cancer agents. In some embodiments, the one or more anti-cancer agents are apoptosis-promoting agents. Examples of anti-cancer agents include, but are not limited to, any one of the following: gossyphol, 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 TM) Geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), Flavopiridol, LY294002, Bortezomib, Trastuzumab, BAY 11-7082, PKC412, or PD184352, Taxol TM (also known as “Paclitaxel,” which is a well-known anti-cancer drug that acts by enhancing and stabilizing microtubule formation), and Taxol TM analogs such as Taxotere TM Compounds having a basic taxane skeleton as a common structural feature also exhibit the ability to arrest cells in the G2-M phase due to stabilized microtubules and can be used in combination with the compounds described herein for the treatment of cancer.

[0377] Additional examples of anti-cancer agents to be used in combination with the compounds herein 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, Cabozantinib, or Crizotinib; VEGFR inhibitors such as Sunitinib, Sorafenib, Regorafenib, Lenvatinib, Vandetanib, Cabozantinib, Axitinib; EGFR inhibitors such as Afatinib, Brivanib, Carbozatinib, Erlotinib, Gefitinib, Neratinib, Lapatinib; PI3K inhibitors such as XL147, XL765, BKM120 (Buparlisib), GDC-0941, BYL719, IPI145, BAY80-6946, BEX235 (Dactolisib), CAL101 (Idelalisib), GSK2636771, TG100-115; MTOR inhibitors such as Rapamycin (Sirolimus), Temsirolimus, Everolimus, XL388, XL765, AZD2013, PF04691502, PKI-587, BEZ235, GDC0349; MEK inhibitors such as AZD6244, Trametinib, PD184352, Pimasertinib, GDC-0973, AZD8330; and proteasome inhibitors such as Carfilzomib, MLN9708, Delanzomib, or Bortezomib.

[0378] Other anti-cancer agents that can be used in combination with the compounds of the present invention include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, Aciverine; Aclarubicin; Acodazole Hydrochloride; Aclacinomycin; Aclacinomycin A; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azatiprine; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Brostallicin; Busulfan; Actinomycin C; Calusterone; Caracemide; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin; Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate; Duazomycin; Edatrexate; Eflornithine Hydrochloride; Esafosfamide; Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estramustine; Estramustine Phosphate Sodium; Etanidazole; Etoposide; Etoposide Phosphate; Etoglucid; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil; Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine; Gemcitabine Hydrochloride; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Imofosine; Interleukin II (including recombinant interleukin II, or Ril2), Interferon α-2a; Interferon α-2b; Interferon α-n1; Interferon α-n3; Interferon β-1a; Interferon γ-1b; Iproplatin; Irinotecan Hydrochloride; Octreotide Acetate; Letrozole; Leuprolide Acetate; Liarozole Hydrochloride; Lomustine; Losoxantrone Hydrochloride; Masoprocol; Maytansine; Mechlorethamine Hydrochloride; Megestrol Acetate; Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium; Methopterin; Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin; Oxaliplatin; Oxybutynin; Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Pipobroman; Piposulfan; Pirarubicin Hydrochloride; Plicamycin; Promestriene; Porfimer Sodium;Bofedomycin; Pnimustine; Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol; Safingol Hydrochloride; Semustine; Sintetrin; Sodium Phosphoacetylaspartate; Sparsomycin; Geomycin Hydrochloride; Spirostatin; Spiroplatin; Streptonigrin; Streptozotocin; Sulfachlorophenamide; Telithromycin; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride; Timoporphin; Teniposide; Teloxirone; Testolactone; Thioguanine; Thiotepa; Thiazofurin; Tirapazamine; Toremifene Citrate; Trenbolone Acetate; Cilofarabine Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tobramycin Chloride; Uramustine; Uredepa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vindopinine Sulfate; Vinglycinate Sulfate; Vinflunine Sulfate; Vinorelbine Tartrate; Vindolidine Sulfate; Vinglydine Sulfate; Vorozole; Zeniplatin; Zinostatin; Zorubicin Hydrochloride;

[0379] Other anticancer agents that can be used in combination with the compounds of the present invention, 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, to determine the anti-tumor activity in HGS and RT4 tumor models (Example 4 below: In the HGS model, the vehicle dose group reached a tumor size of 645 doses on day 42 after inoculation, while for animals treated with 20 mg / kg of the compound, the tumor size was 55 mm3, showing significant anti-tumor activity and inducing tumor regression) include: 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adenocyclitol; adozelesin; aldesleukin; ALL-TK antagonist; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; ametantrone; anagrelide; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; anti-androgen, prostate cancer; anti-estrogen; antitumorone; antisense oligonucleotide; glycyl aphidicolin; apoptosis gene regulator; apoptosis regulator; apurinic acid; ara-CDP-DL-PTBA; arginine deiminase; asulacrine; atamestane; astemizole; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; diazo-tyrosine; baccatin III derivative; balanol; batimastat; BCR / ABL antagonist; benzoporphyrin; benzoylstaurosporine; beta-lactam derivative; beta-alethine; subarachnomycin B; betulinic acid; Bfgf inhibitor; bicalutamide; bisantrene; bisaziridinyl spermine; binifibrate; Bistratene A; bizelesin; breflate; brostallicin; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivative; canarypox IL-2; capecitabine; formamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogue; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin;Crambescidin 816; Clinatop; Cylindrospermopsin 8; Cylindrospermopsin A derivative; Curacin A; Cyclopentanthraquinone; Cycloplatam; Cypemycin; Cytarabine octadecylphosphate; Cytolytic factor; Hexestrol diphosphate; Daclizumab; Decitabine; Dehydrodidemnin B; Deslorelin; Dexamethasone; Ifosfamide; Dexrazoxane; Dextroverapamil; Diaziquone; Didemnin B; Didox; Diethylnorspermine; Dihydro-5-azacytidine; 9-Dioxamycin; BMS-247550; Behenyl alcohol; Dolasetron; Doxifluridine; Droloxifene; Dronabinol; Docamixin SA; Ebselen; Icotomustin; Edelfosine; Eculizumab; Eflornithine; Elemen; Emitefur; Epirubicin; Epristeride; Estramustine analogue; Estrogen agonist; Estrogen antagonist; Etazolate; Etoposide phosphate; Exemestane; Fadrozole; Fazarabine; Fenretinide; Filgrastim; fmasteride; Flavopiridol; Flutropium; Fluasterone; Fludarabine; Fluorodaunorunicin hydrochloride; Fosfolomycin; Formestane; Foroxymithine; Fotemustine; Gadolinium texaphyrin; Gallium nitrate; Galocitabine; Ganirelix; Gelatinase inhibitor; Gemcitabine; Glutathione inhibitor; Hepsulfam; Modulator protein; Hexamethylenebisacetamide; Hypericin; Ibandronic acid; Idarubicin; Idoxifene; Idomene; Ifomustin; Ilomastat; Imidazoacridone; Imiquimod; Immunostimulatory peptide; Insulin-like growth factor-1 receptor inhibitor; Interferon agonist; Interferon; Interleukin; Iobenguane; Iodoxorubicin; Ipomeanol, 4-; Iroplact; Irsogladine; Isobengazole; Isohomohalicondrin B; Itasetron; Jasplakinolide; Kahalalide F; Lamellarin-N triacetate; Lanreotide; Leinamycin; Lenograstim; Lentinan sulfate; Leptolstatin; Letrozole; Leukemia inhibitory factor; Leukocyte alpha interferon; Leuprorelin + estrogen + progesterone; Leuprorelin; Levamisole; Riluzole; Linear polyamine analogue; Lipophilic disaccharide peptide; Lipophilic platinum compound; Lissoclinamide 7; Lobaplatin; Lumbrokinase; Lomustine; Lovastatin; Losoxantrone; Letotecan; Lutetium texaphyrin; Lisofylline; Lytic peptide; Metansine;Mannostatin A; Marimastat; Masoprocol; Breast Secretory Proteinase Inhibitor; Stromelysin Inhibitor; Matrix Metalloproteinase Inhibitor; Menogaril; Mebaral; Metyrapone; Methioninase; Metoclopramide; MIF Inhibitor; Mifepristone; Miltefosine; Miltiromycin; Mismatched Double-Stranded RNA; Mitoguazone; Mitobronitol; Mitomycin Analogue; Mitonafide; Mytomycin; Fibroblast Growth Factor-Saponin; Mitoxantrone; Mofarotene; Molgramostim; Monoclonal Antibody, Human Chorionic Gonadotropin; Monophosphoryl Lipid A + -72-iethylstilbe Cell Wall Sk; Mopidamol; Multidrug Resistance Gene Inhibitor; Therapy Based on Multiple Tumor Suppressor 1; Mustard Anticancer Agent; Indian Ocean Sponge (Mycaperoxide) B; Mycobacterium Cell Wall Extract; Myriaporone; N-Acetyl Denaline; N-Substituted Benzamide; Nafarelin; Nareotide; Naloxone + Pentazocine; Napavin; Naphterpin; Nartograstim; Nedaplatin; Nemorubicin; Neridronic Acid; Neutral Endopeptidase; Nilutamide; Nisamycin; Nitric Oxide Modulator; Nitrogen Oxide Antioxidant; Nitrullyn; O6-Benzylguanine; Octreotide; Okicenone; Oligonucleotide; Onapristone; Ondansetron; Ondansetron; Oracin; Oral Cytokine Inducer; Ormaplatin; Oxasterone; Oxaliplatin; Oxaunomycin; Palauamine; Palmitoylrhizoxin; Pamidronic Acid; Panaxynol; Panomifene; Paracoccusin; Pexelizumab; Pegaspargase; Peldesine; Sodium Polyoxometalate; Pentostatin; Pentrozole; Perfluorobromooctane; Pipophosfamide; Perillyl Alcohol; Phenylazomycin; Phenylacetate; Phosphatase Inhibitor; Picibanil; Pilocarpine Hydrochloride; Pirarubicin; Pirroxantrone; Placetin A; Placetin B; Plasminogen Activator Inhibitor; Platinum Complex; Platinum Compound; Platinum-Triamine Complex; Porfimer Sodium; Methyl Mitomycin; Prednisone; Propyl Bis-Acridinone; Prostaglandin J2; Proteasome Inhibitor; Protein A-Based Immunomodulator; Protein Kinase C Inhibitor, Microalgae; Protein Tyrosine Phosphatase Inhibitor; Purine Nucleoside Phosphorylase Inhibitor; Purpurin; Pyrazoloacridine; Pyridoxylated Hemoglobin Polyoxyethylene Conjugate; Raf Antagonist; Raltitrexed; Ramosetron; Ras Farnesyl Protein Transferase Inhibitor; Ras Inhibitor; Ras-GAP Inhibitor; Demethyl Retiputide; Rhenium Etidronate Re 186; Rhizoxin; Ribozymes; R.sub.11 Retinamide; Rogletimide; Rohitukine; Romurtide; Raloxifene;rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; phytonadiene A; sargramostim; Sdi 1 mimetic; semustine; senescence-derived 1; sense oligonucleotide; signal transduction inhibitor; signal transduction modulator; single-chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin-binding protein; sonermin; phosphonasp; spicamycin D; spiro mustard; spinedine; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitor; stipiamide; matrix metalloproteinase inhibitor; sulfinosine; potent vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycan; tamoxastine; tamoxifen methiodide; tauromustine; tazarotene; ticagrelan sodium; tegafur; tellurapyrylium; telomerase inhibitor; temoporfin; temozolomide; teniposide; tetrachloro decoxide; tetrazomine; thaliblastine; thiazocor; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid-stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene dichloride; topsentin; toremifene; pluripotent stem cell factor; translation inhibitor; tretinoin; triacetyluridine; gemcitabine; trimetrexate; triptorelin; tropisetron; torasemide; tyrosine kinase inhibitor; tyrosine phosphorylation inhibitor; UBC inhibitor; bestatin; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonist; vapreotide; variolin B; vector system, erythrocyte gene therapy; veralresorcinol; veratramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zindostatin stimalamer.;

[0380] Another anti-cancer agent that can be used in combination with the compounds of the present invention includes alkylating agents, antimetabolites, natural products, or hormones, for example, nitrogen mustards (e.g., mechloroethamine, 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., mercaptopurine, thioguanine, pentostatin).

[0381] Examples of natural products useful in combination with the compounds of the present invention 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 α).

[0382] Examples of alkylating agents that can be used in combination with the compounds of the present invention include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethyleneimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin, 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., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0383] Examples of hormones and antagonists useful in combination with the compounds of the present invention include, but are not limited to, corticosteroids (e.g., prednisone), progesterones (e.g., hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol 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 for the treatment or prevention of cancer that can be used in the methods and compositions described herein include platinum coordination complexes (e.g., cisplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoglutethimide).

[0384] Examples of anti-cancer agents that act by arresting cells in the G2-M phase due to stabilized microtubules and can be used in combination with irreversible Btk inhibitor compounds include, but are not limited to, the following marketed and investigational drugs: erbulozole (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), altorhyrtin (such as altorhyrtin A and altorhyrtin C), spongistatin (such as spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), simadotin hydrochloride (also known as LU-103793 and NSC-D-669356), epothilone (such as epothilone A, epothilone B, epothilone C (also known as deoxyepothilone A or dEpoA), epothilone D (also known 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), auristatin PE (also known as NSC-654663), soblidotin (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 (Hungarian Academy of Sciences), BSF-223651 (BASF,Also known as ILX-651 and LU-223651), SAH-49960 (Eli Lilly and Company (Lilly) / Novartis AG), SDZ-268970 (Eli Lilly and Company / Novartis AG), AM-97 (Armad, Inc. / Kyowa Hakko Kogyo Co., Ltd.), AM-132 (Armad, Inc.), AM-138 (Armad, Inc. / Kyowa Hakko Kogyo Co., Ltd.), IDN-5005 (Indena S.p.A.), Nostocarboline 52 (also known as LY-355703), AC-7739 (Ajinomoto Co., Inc., also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto Co., Inc., also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, Inc., 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), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton, Inc. / Mount Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica AG), A-105972 (Abbott Laboratories), Hemiasterlin, 3-BAABU (Cytoskeleton, Inc. / Mount Sinai School of Medicine,Also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-1AABE (Cytoskeleton, Inc. / Mount Sinai School of Medicine), A-204197 (Abbott Laboratories), T-607 (Tularik, also known as T-900607), RPR-115781 (Aventis), Eleutherobin (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Astellas Pharma Inc.), D-68144 (Astellas Pharma Inc.), Diazonamide A, A-293620 (Abbott Laboratories), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott Laboratories), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (Astellas Pharma Inc.), D-68836 (Astellas Pharma Inc.), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott Laboratories), A-318315 (Abbott Laboratories), HTI-286 (also known as SPA-110, trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0385] Additional examples of anti-cancer agents for use in combination with the compounds of the present text include immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors (smack molecules or biologics) against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM kinases, 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 can be used in combination with one or more reagents selected from: KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFRβ inhibitors.

[0386] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, such as 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.

[0387] In some embodiments, the inhibitor of the 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).

[0388] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of OX40, such as 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 LAG525. In some embodiments, the OX40L fusion protein is MEDI6383.

[0389] Example

[0390] The preparation of the compounds having formula (I) below is provided so that those skilled in the art can more clearly understand and implement the present disclosure. They should not be considered as limiting the scope of the present disclosure, but merely illustrative and representative of the present disclosure.

[0391] All solvents used are commercially available and can be used without further purification. Reactions are typically carried out using anhydrous solvents under a nitrogen inert atmosphere.

[0392] Proton TM H spectra are recorded on a Bruker 400 NMR spectrometer equipped with a Bruker 400BBO probe or a Bruker BBFO ULTRASHIELD 1 300 AVANCE III at 400 MHz or 300 MHz, respectively. All deuterated solvents typically contain 0.03% to 0.05% v / v of tetramethylsilane, which is used as a reference signal ( 1 H and 13 C are both set to δ0.00).

[0393] LCMS analysis was performed on a Shimadzu LCMS, which consists of a UFLC 20-AD and an LCMS 2020 MS detector. The diode array detector scanned from 190 - 400 nm. The mass spectrometer was equipped with an electrospray ionization source (ESI) operating in positive or negative mode. The mass spectrometer scanned between m / z 90 - 900, and the scan time was from 0.5 to 3.0 s.

[0394] HPLC analysis of the Shimadzu UFLC was carried out using 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 and the flow rate was 1.5 mL / min. The diode array detector scanned from 200 - 400 nm.

[0395] Thin layer chromatography (TLC) was performed on (silica gel 60F254) from Manchery-Nagel, and the spots were typically visualized using UV. In some cases, additional visualization methods were also employed. In these cases, iodine (generated by adding approximately 1 g of I2 to 10 g of silica gel and mixing well), ninhydrin (commercially available from Aldrich), or Magic Stain (generated by mixing 25 g of (NH4)6Mo7O 24 .4H2O, 5 g of (NH4)2Ce(IV)(NO3)6 in 450 mL of water and 50 mL of concentrated H2SO4) were used to develop the TLC plates to visualize the compounds. Flash chromatography was carried out using 40 - 63 μm (230 - 400 mesh) silica gel from Silicycle, following similar techniques to those disclosed in Still, W.C.; Kahn, M.; and Mitra, M, Journal of Organic Chemistry, 1978, 43, 2923. Typical solvents for flash chromatography or thin layer chromatography were mixtures of chloroform / methanol, dichloromethane / methanol, ethyl acetate / methanol, and hexane / ethyl acetate.

[0396] Synthesis Examples

[0397] Example 1

[0398] Synthesis of 4-((5,6-dimethoxy-1,3-benzodioxol-1-yl)methyl)phenylboronic acid

[0399]

[0400] 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 for 1 h at room temperature, 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 prep-HPLC using the following conditions: column: XBridge Prep C18 OBD column, 19×150 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. The fractions containing the desired product were combined and lyophilized to afford 48.4 mg (54%) of the title compound as an off-white solid. MS (ESI, positive ion) m / z: 313.2 (M+1). 1 1H-NMR: (300 MHz, 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).

[0401] Example 2

[0402] 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)

[0403]

[0404] Step 1: 4-((6-chloro-7H-purin-7-yl)methyl)phenylboronic acid and 4-((6-chloropurin-9-yl)methyl)phenylboronic acid

[0405]

[0406] At room temperature, 4-(bromomethyl)phenylboronic acid (625 mg, 2.909 mmol, 1.50 equiv) and potassium carbonate (537 mg, 3.882 mmol, 2.00 equiv) were added to a solution of 6-chloro-9H-purine (300 mg, 1.941 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL). 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 afford 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.

[0407] Step 2: 4-((6-oxo-1H-purin-7-yl)methyl)phenylboronic acid and 4-((6-oxo-1H-purin-9-yl)methyl)phenylboronic acid

[0408]

[0409] 6N hydrochloric acid (4 mL) was added dropwise 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) at room temperature. After refluxing for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide and filtered. The filtrate was purified by prep-HPLC using the following conditions: column: XBridge Prep Phenyl OBD column, 19×150 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 components.

[0410] Component 1: Room temperature: 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 1H-NMR (300 MHz, DMSO-d6, ppm) δ 12.14 (brs, 1H), 8.39 (s, 1H), 8.08 (brs, 2H), 7.96 (s, 1H), 7.74 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 5.57 (s, 2H).

[0411] Component 2: At room temperature: 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 1H-NMR (300 MHz, DMSO-d6, ppm) δ 11.98 (brs, 1H), 8.25 - 8.02 (m, 4H), 7.74 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 7.8 Hz, 2H), 5.38 (s, 2H).

[0412] Example 3

[0413] 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)

[0414]

[0415] Step 1: 4-((2-Amino-6-chloropurin-7-yl)methyl)phenylboronic acid and 4-((2-amino-6-chloropurin-9-yl)methyl)phenylboronic acid

[0416]

[0417] To a solution of 6-chloro-9H-purin-2-amine (100 mg, 0.590 mmol, 1.00 equiv) in N,N-dimethylformamide (3 mL) at room temperature 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). 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 afford 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 (200 mg, 86% yield, 77% purity).

[0418] 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

[0419]

[0420] At room temperature, 6N hydrochloric acid (4 mL) was added dropwise 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 equivalent, 77% purity) in tetrahydrofuran (2 mL). After refluxing for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide and filtered to give a clear solution of 3.7 mL, which was purified by prep-HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 19×250 mm, 10 um; 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 components.

[0421] Component 1: Room temperature: 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 1H-NMR (400 MHz, 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).

[0422] Component 2: Room temperature: 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 1H-NMR (300 MHz, 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).

[0423] Example 4

[0424] 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)

[0425]

[0426] 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 min. 4-(Bromomethyl)phenylboronic acid (174 mg, 0.810 mmol, 1.20 equiv) was added. After stirring for 2 h, the reaction mixture was filtered through Celite. The filtrate was purified by prep-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 min, 220 and 254 nm. Two components were obtained.

[0427] Component 1: Room temperature: 8.02 min. 47.8 mg (25%) of 4-((6-methoxy-1,3-benzodioxol-1-yl)methyl)phenylboronic acid (4a) as a white solid. MS (ESI, positive ion) m / z: 283.2 (M+1). 1 1H-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).

[0428] Component 2: Room temperature: 9.35 min. 36.3 mg (17%) of 4-((5-methoxy-1,3-benzodioxol-1-yl)methyl)phenylboronic acid (4b) as a white solid. MS (ESI, positive ion) m / z: 283.2 (M+1). 1 1H-NMR (400 MHz, 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).

[0429] Example 5

[0430] Synthesis of 4-((5,6-dimethoxyindol-1-yl)methyl)phenylboronic acid

[0431]

[0432] At 0 °C, sodium hydride (51 mg, 1.271 mmol, 60% in mineral oil, 1.50 equiv) was added to a stirred solution of 5,6-dimethoxy-1H-indole (150 mg, 0.847 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL). 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 h. The reaction mixture was quenched with water and filtered. The filtrate was purified by prep-HPLC using the following conditions: column: XBridge Prep OBD C18 column, 19x250 mm, 5 um; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 45% B to 45% B in 7 min, 220 and 254 nm. The fractions containing the desired product were combined and lyophilized to afford 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 1H-NMR (300 MHz, DMSO-d6, ppm): δ 7.99 (s, 2H), 7.71 (d, J = 5.7 Hz, 2H), 7.42 - 7.03 (m, 5H), 6.34 (s, 1H), 5.36 (s, 2H), 3.74 (s, 6H).

[0433] Example 6

[0434] Synthesis of 4-((6-aminopurin-7-yl)methyl)phenylboronic acid (6a) and 4-((6-aminopurin-9-yl)methyl)phenylboronic acid (6b)

[0435]

[0436] At room temperature, 4-(bromomethyl)phenylboronic acid (286 mg, 1.333 mmol, 1.20 equiv) was added 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). 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 prep-HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 19x250 mm, 10 um; 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.

[0437] Component 1: At room temperature = 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 1H-NMR (400 MHz, 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 = 7.6 Hz, 2H), 7.41 (d, J = 7.6 Hz, 2H), 5.63 (s, 2H).

[0438] Component 2: At room temperature = 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 1H-NMR (400 MHz, DMSO-d6, ppm): δ 8.71 (brs, 2H), 8.52 (s, 1H), 8.40 (s, 1H), 8.14 (brs, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.45 (s, 2H).

[0439] Example 7

[0440] 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)

[0441]

[0442] At 0 °C under a nitrogen atmosphere, a solution of 1H-1,3-benzodiazole-5-carbonitrile (200 mg, 1.40 mmol, 1.00 eq) in N,N-dimethylformamide (1 mL) was added to a suspension of sodium hydride (112 mg, 2.79 mmol, 60% in mineral oil, 2.00 eq) in N,N-dimethylformamide (4 mL). After stirring for 30 minutes at this temperature, 4-(bromomethyl)phenylboronic acid (360 mg, 1.68 mmol, 1.20 eq) was added. The resulting mixture was stirred at room temperature for 2 h, quenched with 1 N hydrochloric acid (2 mL) and concentrated under reduced pressure. The residue was purified by prep-HPLC using the following conditions: column: XBridge Prep C18 OBD column, 19×250 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 components were obtained.

[0443] Component 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 1H-NMR (400 MHz, 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 = 8.0 Hz, 2H), 7.60 - 7.58 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 5.57 (s, 2H).

[0444] Component 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 1H-NMR (400 MHz, 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 = 8.0 Hz, 2H), 5.58 (s, 2H).

[0445] Example 8

[0446] Synthesis of (4-((5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid

[0447]

[0448] Step 1: 4-((4-Chloro-5-fluoropyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenylboronic acid

[0449]

[0450] 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 eq) was used in place of 1H-1,3-benzodiazole-5-carbonitrile. Yield: 0.45 g (69%). MS (ESI, positive ion) m / z: 306.2 (M+1).

[0451] Step 2: (4-((5-Fluoro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid

[0452]

[0453] 4-((4-Chloro-5-fluoropyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenylboronic acid (150 mg, 0.49 mmol, 82% purity, 1.00 eq) was dissolved in a mixed solvent of hydrochloric acid (4 mL) and tetrahydrofuran (20 mL) at room temperature and stirred at 80 °C for 48 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep-HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 19×250 mm, 10 um; 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; 220 and 254 nm. The 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 1H-NMR: (400 MHz, DMSO-d6, ppm) δ 12.03 (s, 1H), 8.02 (s, 2H), 7.90 (d, J = 4.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.19 - 7.13 (m, 3H), 5.27 (s, 2H). 19 19F-NMR: (376 MHz, DMSO-d6, ppm) δ -166.3 (1F).

[0454] Example 9

[0455] (4-((4-Amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid synthesis

[0456]

[0457] At room temperature, 4-((4-chloro-5-fluoropyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenylboronic acid (product of step 1 of Example 8) (150 mg, 0.49 mmol, 1.00 equivalent), ethanol (10 mL), and ammonia (4 mL) were added to a sealed tube respectively. After stirring at 90 °C for 48 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep-HPLC using the following conditions: column: 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; 220 and 254 nm. The 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 1H-NMR: (400 MHz, DMSO-d6, ppm) δ 8.07 (s, 1H), 8.02 (s, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 6.97 (s, 2H), 5.27 (s, 2H). 19 19F-NMR: (376 MHz, DMSO-d6, ppm) δ -168.2 (1F).

[0458] Example 10

[0459] 4-((5-Methoxyindol-1-yl)methyl)phenylboronic acid synthesis

[0460]

[0461] The title compound was synthesized as described in Example 7, except that 5-methoxyindole (100 mg, 0.679 mmol, 1.00 equivalent) 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 (300 MHz, DMSO-d6, ppm): δ 8.00 (s, 2H), 7.75 - 7.68 (m, 2H), 7.45 - 7.43 (m, 1H), 7.29 (d, J = 8.7 Hz, 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).

[0462] Example 11

[0463] Synthesis of (4 - ((4 - Hydroxy - 1H - pyrrolo[3,2 - c]pyridin - 1 - yl)methyl)phenyl)boronic acid

[0464] Step 1: 4 - Methoxy - 1H - pyrrolo[3,2 - c]pyridine

[0465]

[0466] To a solution of NaOMe in methanol (20 mL, 30%) was added 4 - chloro - 1H - pyrrolo[3,2 - c]pyridine (1.00 g, 6.554 mmol, 1.00 eq). 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 and filtered, and the solvent was evaporated to give 0.7 g (58%) of 4 - methoxy - 1H - pyrrolo[3,2 - c]pyridine as a pale yellow solid. 1 H - NMR: (400 MHz, DMSO - d6, ppm) δ 11.48 (s, 1H), 7.70 (d, J = 5.8 Hz, 1H), 7.32 - 7.25 (m, 1H), 7.02 (dd, J = 5.9, 1.0 Hz, 1H), 6.48 - 6.44 (m, 1H), 3.94 (s, 3H)

[0467] Step 2: 4 - ((4 - Methoxypyrrolo[3,2 - c]pyridin - 1 - yl)methyl)phenylboronic acid

[0468]

[0469] At 0 °C under a nitrogen atmosphere, NaH (207.3 mg, 8.64 mmol, 4.00 equivalents) was added to a solution of 4-methoxy-1H-pyrrolo[3,2-c]pyridine (400.0 mg, 2.16 mmol, 80% purity, 1.00 equivalent) in DMF (4 mL). After stirring for 30 minutes at this temperature, a solution of 4-(bromomethyl)phenylboronic acid (640.4 mg, 2.98 mmol, 1.38 equivalents) in DMF (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, quenched with 2N hydrochloric acid and concentrated under reduced pressure. The residue was suspended in ACN and stirred for 30 minutes. The solid was removed by filtration and the filtrate was evaporated to dryness to afford 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 prep-HPLC using the following conditions: column: Sunfire prep C18 column, 30×150, 5um; 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. The fractions containing the desired product were combined and lyophilized to afford 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 1H-NMR: (400 MHz, DMSO-d6, ppm) δ 8.00 (s, 2H), 7.77 - 7.61 (m, 3H), 7.44 (d, J = 3.2 Hz, 1H), 7.20 - 7.04 (m, 3H), 6.53 (dd, J = 3.2, 0.9 Hz, 1H), 5.41 (s, 2H), 3.95 (s, 3H).

[0470] Step 3: (4-((4-Hydroxy-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)phenyl)boronic acid

[0471]

[0472] At room temperature, BBr3 (3.55 g, 14.18 mmol, 20.00 equivalents) was added to a suspension of 4-((4-methoxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid (0.20 g, 0.709 mmol, 1.00 equivalent) in DCM (10.00 mL). After stirring overnight at room temperature, the mixture was quenched with methanol (10 mL) at -20 °C, allowed to warm to room temperature, and filtered under reduced pressure. The residue was purified by prep-HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 19*250 mm, 10 um; 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. The fractions containing the desired product were combined and lyophilized to yield 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 1H NMR (400 MHz, DMSO-d6, ppm) δ 10.78 (d, J = 5.6 Hz, 1H), 8.01 (s, 2H), 7.80 - 7.63 (m, 2H), 7.20 (d, J = 3.1 Hz, 1H), 7.12 (d, J = 7.7 Hz, 2H), 6.98 (dd, J = 7.2, 5.8 Hz, 1H), 6.53 (d, J = 3.0 Hz, 1H), 6.48 (d, J = 7.2 Hz, 1H), 5.32 (s, 2H).

[0473] Example 12

[0474] 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)

[0475]

[0476] 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

[0477]

[0478] At room temperature, 4-(bromomethyl)phenylboronic acid (252 mg, 1.172 mmol, 1.20 equiv) and cesium carbonate (636 mg, 1.954 mmol, 2.00 equiv) were added 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). 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 x 3), and dried under vacuum to afford 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).

[0479] 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

[0480]

[0481] 6N hydrochloric acid (5 mL) was added dropwise 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) 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 prep-HPLC using the following conditions: column: XBridge Prep Phenyl OBD column, 19×150 mm, 5um; 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 components.

[0482] Component 1: Room temperature: 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). 1H-NMR (300 MHz, DMSO-d6, ppm) δ 11.26 - 11.24 (m, 1H), 8.30 (s, 1H), 8.00 (s, 2H), 7.72 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 7.10 - 7.06 (m, 1H), 6.54 (d, J = 7.2 Hz, 1H), 5.65 (s, 2H).

[0483] Component 2: At room temperature: 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 (300 MHz, 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).

[0484] Example 13

[0485] Synthesis of 4-((4-chloropyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid

[0486]

[0487] At 0 °C, sodium hydride (47 mg, 1.97 mmol, 2.00 eq., 60% purity) was added to a solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (150 mg, 0.98 mmol, 1.00 eq.) in N,N-dimethylformamide (8 mL). After stirring for 30 minutes at 0 °C, 4-(bromomethyl)phenylboronic acid (253 mg, 1.18 mmol, 1.20 eq.) was added. The mixture was stirred at room temperature for 3 h, quenched with 2N hydrochloric acid 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 afford 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 prep-HPLC using the following conditions: column: XBridgeShield 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. The fractions containing the desired product were combined and lyophilized to yield 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 1H-NMR (300 MHz, DMSO-d6, ppm) δ 7.99 (d, J = 5.7 Hz, 1H), 7.74 - 7.71 (m, 3H), 7.60 - 7.57 (m, 1H), 7.18 (d, J = 8.1 Hz, 2H), 6.64 - 6.63 (m, 1H), 5.50 (s, 2H).

[0488] Example 14

[0489] 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

[0490]

[0491] 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)

[0492]

[0493] At 0 °C, sodium hydride (170 mg, 4.257 mmol, 1.50 equiv., 60% purity) was added to a solution of methyl 1H-1,3-benzodiazole-5-carboxylate (500 mg, 2.838 mmol, 1.00 equiv.) in DMF (5 mL). 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 h. 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 a mixture of 500 mg 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 prep-HPLC using the following conditions: column: 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: 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 components.

[0494] Component 1: Room temperature: 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 1H-NMR: (400 MHz, 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 = 7.6 Hz, 2H), 5.71 - 5.69 (m, 2H), 3.86 - 3.82 (m, 3H).

[0495] Component 2: At room temperature: 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 1H-NMR: (400 MHz, 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).

[0496] Step 2: Synthesis of 3-((4-(dihydroxyboranyl)phenyl)methyl)-1,3-benzodiazole-5-carboxylic acid trifluoroacetate (14c), 1-((4-(dihydroxy-boranyl)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).

[0497]

[0498] 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 equivalent) was dissolved in ammonia water (10 mL). After stirring in a sealed tube at 80 °C for 12 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC using the following conditions: column: 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 min, 220 and 254 nm. The fractions containing the desired products were combined and lyophilized to give four components.

[0499] Component 1: At room temperature: 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). 1H-NMR: (400 MHz, DMSO-d6, ppm) δ 9.07 (s, 1H), 8.20 (s, 1H), 7.94 - 7.75 (m, 4H), 7.30 (d, J = 8.0 Hz, 2H), 5.65 (s, 2H).

[0500] Component 2: At room temperature: 8.92 min. 20.6 mg (6% yield) of 1-((4-(dihydroxy-boranidyl)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: (400 MHz, 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).

[0501] Component 3: At room temperature: 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: (400 MHz, 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).

[0502] Component 4: At room temperature: 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). 1 H-NMR: (400 MHz, 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).

[0503] Example 15

[0504] Synthesis of 4-((5-cyano-3-oxo-2H-indazol-1-yl)methyl)phenylboronic acid

[0505]

[0506] Step 1: 3-oxo-1,2-dihydroindazole-5-carbonitrile

[0507]

[0508] Dissolve methyl 5-cyano-2-fluorobenzoate (500 mg, 2.79 mmol, 1.00 equiv) in hydrazine monohydrate (50 mL) and stir at room temperature for 24 h. Dilute the reaction mixture with ethyl acetate and wash with water and brine. Dry the organic layer over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:2) to afford 310 mg (68% yield) of 3-oxo-1,2-dihydroindazole-5-carbonitrile as a pale yellow solid.

[0509] Step 2: 4-((5-cyano-3-oxo-2H-indazol-1-yl)methyl)phenylboronic acid

[0510]

[0511] Add potassium carbonate (127 mg, 1.26 mmol, 2.00 equiv) and 4-(bromomethyl)phenylboronic acid (162 mg, 0.75 mmol, 1.20 equiv) 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) at room temperature. After stirring at 80 °C for 12 h, cool the reaction mixture to room temperature and filter. Concentrate the filtrate under reduced pressure. Purify the residue by prep-HPLC using the following conditions: column: Sunfire Prep C18 column, 30×150 mm, 5 um; 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; 220 and 254 nm. Combine the fractions containing the desired product and lyophilize to afford 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 1H-NMR: (400 MHz, 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 = 8.0 Hz, 2H), 5.45 (s, 2H).

[0512] Example 16

[0513] Synthesis of 4-((5-carbamoyl-3-oxo-2H-indazol-1-yl)methyl)phenylboronic acid

[0514]

[0515] Step 1: 3-oxo-1,2-dihydroindazole-5-carboxamide

[0516]

[0517] Dissolve 3-oxo-1,2-dihydroindazole-5-carbonitrile (400 mg, 2.51 mmol, 1.00 equivalent) in water (0.4 mL, 22.20 mmol) and concentrated sulfuric acid (2.4 mL, 45.03 mmol, 17.91 equivalents) at room temperature. After stirring at 100 °C for 1 h, cool the mixture to room temperature, dilute with ethyl acetate (150 mL), and wash with water (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL x 2). Dry the organic layer over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by prep-TLC (eluent: petroleum ether / ethyl acetate = 1:2) to give 120 mg (22%) of 3-oxo-1,2-dihydroindazole-5-carboxamide as a pale yellow solid.

[0518] Step 2: 4-((5-carbamoyl-3-oxo-2H-indazol-1-yl)methyl)phenylboronic acid

[0519]

[0520] At 0 °C under a nitrogen atmosphere, sodium hydride (24 mg, 1.02 mmol, 1.50 equiv) was added 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). The mixture was stirred at this temperature for 30 minutes, and then 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 h, the reaction mixture was quenched with 2N hydrochloric acid (5 mL) and concentrated under reduced pressure. The residue was purified by prep-HPLC using the following conditions: column: 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 35% B in 7 min; 220 and 254 nm. The fractions containing the desired product were combined and lyophilized to give 33.5 mg (16%) of 4-((5-carbamoyl-3-oxo-2H-indazol-1-yl)methyl)phenylboronic acid as a white solid. MS (ESI, positive ion) m / z: 312.3 (M+1). 1 1H-NMR: (300 MHz, 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 = 7.8 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H), 7.17 - 7.11 (m, 3H), 5.39 (s, 2H).

[0521] Example 17

[0522] 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)

[0523]

[0524] Step 1: Methyl 3-chloro-1H-indole-5-carboxylate

[0525]

[0526] 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 afford 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).

[0527] Step 2: 4-((3-chloro-5-(methoxycarbonyl)-1H-indol-1-yl)methyl)phenylboronic acid

[0528]

[0529] 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) at room temperature was added 4-(bromomethyl)phenylboronic acid (175 mg, 0.814 mmol, 1.10 equiv). 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 afford 210 mg (81%) of 4-((3-chloro-5-(methoxycarbonyl)-1H-indol-1-yl)methyl)phenylboronic acid as a yellow solid. MS (ESI, positive ion) m / z: 344.2 (M+1).

[0530] Synthesis of 1-(4-boronobenzyl)-3-chloro-1H-indole-5-carboxylic acid (17a) and 4-((5-carbamoyl-3-chloro-1H-indol-1-yl)methyl)phenylboronic acid (17b)

[0531]

[0532] 4-((3-chloro-5-(methoxycarbonyl)-1H-indol-1-yl)methyl)phenylboronic acid (210 mg, 1.00 eq., 98% purity) was dissolved in dioxane (3 mL) and ammonia water (12 mL). After stirring at 80 °C for 48 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep-HPLC using the following conditions: column: 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. The fractions containing the desired product were combined and lyophilized to give two fractions.

[0533] 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 1H-NMR (300 MHz, 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).

[0534] Fraction 2: RT: 6.62 min. 58.4 mg (29% yield) of 4-((5-carbamoyl-3-chloro-1H-indol-1-yl)methyl)phenylboronic acid (17b) as a pale yellow solid. MS (ESI, positive ion) m / z: 329.3 (M+1). 1 1H-NMR (300 MHz, DMSO-d6, ppm) δ 8.13 (s, 1H), 8.01 - 7.90 (m, 3H), 7.81 - 7.71 (m, 4H), 7.58 (d, J = 8.7 Hz, 1H), 7.21 - 7.18 (m, 3H), 5.45 (s, 2H).

[0535] Example 18

[0536] Synthesis of 4-((5-carbamoyl-3-methyl-1H-indol-1-yl)methyl)phenylboronic acid (18a), 4-((5-(ethoxycarbonyl)-3-methyl-1H-indol-1-yl)methyl)phenylboronic acid (18b), and 1-((4-(dihydroxyboranyl)phenyl)methyl)-3-methyl-1H-indole-5-carboxylic acid

[0537] (18c)

[0538]

[0539] Step 1: 4-((5-(Ethoxycarbonyl)-3-methyl-1H-indol-1-yl)methyl)phenylboronic acid (18b), and 1-((4-(dihydroxyboranyl)phenyl)methyl)-3-methyl-1H-indole-5-carboxylic acid (18c)

[0540]

[0541] The title compounds were 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 in place of 1H-1,3-benzodiazole-5-carbonitrile. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (20:1)) to afford two components:

[0542] Component 1: 50 mg (26%) of 4-((5-Ethoxycarbonyl)-3-methyl-1H-indol-1-yl)methyl)phenylboronic acid (18b) as an off-white solid. MS (ESI, positive ion) m / z: 338.3 (M+1).

[0543] Component 2: 100 mg (85% purity) of 1-((4-(dihydroxyboranyl)phenyl)methyl)-3-methyl-1H-indole-5-carboxylic acid (18c) as an off-white solid, which was further purified by prep-HPLC using the following conditions: column: XBridgePrep OBD C18 column, 19×250 mm, 5 um; 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. The fractions containing the desired product were combined and lyophilized to yield 43.2 mg (27%) of 1-((4-(dihydroxyboranyl)phenyl)methyl)-3-methyl-1H-indole-5-carboxylic acid (18c) as a white solid. MS (ESI, positive ion) m / z: 310.3 (M+1). 1 1H-NMR (400 MHz, 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 = 8.4 Hz, 1H), 7.34 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 5.38 (s, 2H), 2.29 (s, 3H).

[0544] Step 2: 4-((5-Carbamoyl-3-methyl-1H-indol-1-yl)methyl)phenylboronic acid (18a)

[0545]

[0546] To a mixture of 4-((5-(ethoxycarbonyl)-3-methyl-1H-indol-1-yl)methyl)phenylboronic acid (18b) (50 mg, 0.13 mmol, 1.00 eq., 87% purity) in dioxane (3 mL) was added aqueous ammonia (3 mL). After stirring overnight at 80 °C, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by prep-HPLC using the following conditions: column: 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. The fractions containing the desired product were combined and lyophilized to afford 4.9 mg (12%) of 4-((5-carbamoyl-3-methyl-1H-indol-1-yl)methyl)phenylboronic acid (18a) as a white solid. MS (ESI, positive ion) m / z: 309.2 (M+1). 1 1H-NMR (300 MHz, 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).

[0547] Example 19

[0548] Synthesis of 4-((6-methoxy-5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (19a), 4-((5-methoxy-6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic 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)

[0549]

[0550] Step 1: Methyl 4,5-diamino-2-methoxybenzoate

[0551]

[0552] To a solution of methyl 4-amino-2-methoxy-5-nitrobenzoate (1.00 g, 4.421 mmol, 1.00 eq) in methanol (10 mL) was added 10% Pd / C (200 mg, 0.20 eq). 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 afford 760 mg (85%) of methyl 4,5-diamino-2-methoxybenzoate as a yellow oil.

[0553] Step 2: Methyl 6-methoxy-1H-1,3-benzodiazole-5-carboxylate

[0554]

[0555] Imidazole hydrochloride (37 mg, 0.354 mmol, 0.10 eq) was dissolved in a solution of methyl 4,5-diamino-2-methoxybenzoate (710 mg, 3.535 mmol, 1.00 eq, 97%) in DMF (10 mL). The resulting mixture was stirred at 150 °C for 24 h. 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 afford methyl 6-methoxy-1H-1,3-benzodiazole-5-carboxylate (510 mg, 59%) as a yellow oil.

[0556] Step 3: 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)

[0557]

[0558] The title compounds were 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 eq, 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).

[0559] 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)

[0560]

[0561] The title compounds were 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 equivalent, 97% purity) was used as the starting material. The crude product was purified by prep-HPLC using the following conditions: column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), 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.

[0562] Fraction 1: At room temperature: 7.38 min. 24.4 mg (10% yield) 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 1H-NMR: (300 MHz, 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).

[0563] Fraction 2: At room temperature: 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 1H-NMR: (300 MHz, 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).

[0564] Example 20

[0565] (4 - ((6 - Carbamoyl - 2 - ethyl - 1H - benzo[d]imidazol - 1 - yl)methyl)phenyl)boronic acid (20a) Synthesis of 4 - ((5 - carbamoyl - 2 - ethyl - 1,3 - benzodiazol - 1 - yl)methyl)phenylboronic acid (20b)

[0566]

[0567] Step 1: Methyl 2 - ethyl - 1H - 1,3 - benzodiazole - 5 - carboxylate

[0568]

[0569] At room temperature, 1H - imidazole hydrochloride (63 mg, 0.60 mmol, 0.20 eq) was added to a solution of methyl 3,4 - diamino - benzoate (500 mg, 3.01 mmol, 1.00 eq) in N,N - dimethylacrylamide (5 mL). 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 1H - NMR: (400 MHz, DMSO - d6, ppm) δ 12.79 - 12.33 (brs, 1H), 8.08 (s, 1H), 7.78 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 2.87 (q, J = 8.0 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H).

[0570] Step 2: 2 - ethyl - 1H - 1,3 - benzodiazole - 5 - carboxylic acid

[0571]

[0572] 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 for 1 h at room temperature, the mixture was adjusted to pH = 3 with 2 N hydrochloric acid (3 mL), and a white precipitate formed. The solid was collected by filtration, washed with water and dried under reduced pressure to afford 0.25 g (89%) of 2-ethyl-1H-1,3-benzodiazole-5-carboxylic acid as an off-white solid.

[0573] Step 3: 2-Ethyl-1H-1,3-benzodiazole-5-carboxamide

[0574]

[0575] 2-Ethyl-1H-1,3-benzodiazole-5-carboxylic acid (250 mg, 1.31 mmol, 1.00 equiv) was added to thionyl chloride (15 mL), giving a suspension which was stirred at 80 °C for 1 h. The mixture was filtered under reduced pressure to afford the intermediate acyl 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 h and concentrated under reduced pressure to afford 0.23 g (92%) of 2-ethyl-1H-1,3-benzodiazole-5-carboxamide as a yellow solid.

[0576] 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)

[0577]

[0578] To a suspension of sodium hydride (44 mg, 1.82 mmol, 1.50 equiv) in N,N-dimethylformamide (5 mL) at 0 °C 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). After stirring at 0 °C for 30 minutes, 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 hydrochloric acid (5 mL) and concentrated under reduced pressure. The residue was purified by prep-HPLC using the following conditions: column: XBridge C18 OBD column, 19×250, 5um; 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. The fractions containing the desired product were combined and lyophilized to give two components.

[0579] Component 1: retention time at room temperature = 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 1H-NMR: (400 MHz, DMSO-d6, ppm) δ 8.04 (d, J = 1.6 Hz, 1H), 8.01 (s, 2H), 7.90 (s, 1H), 7.78 - 7.70 (m, 3H), 7.62 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 7.04 (d, J = 7.9 Hz, 2H), 5.52 (s, 2H), 2.86 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H).

[0580] Component 2: retention time at room temperature = 7.13 min. 17.5 mg (4% yield) of 4-((5-carbamoyl-2-ethyl-1,3-benzodiazol-1-yl)methyl)phenyl)boronic acid (20b) as a white solid. MS (ESI, positive ion) m / z: 324.4 (M+1). 11H-NMR: (400 MHz, DMSO-d6, ppm) δ 12.69 (s, 0.7 HCOOH), 8.16 (d, J = 1.6 Hz, 1H), 8.13 (s, 0.7 HCOOH), 8.02 (s, 2H), 7.92 (s, 1H), 7.76 - 7.70 (m, 3H), 7.50 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 7.04 (d, J = 8.1 Hz, 2H), 5.52 (s, 2H), 2.86 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H).

[0581] Example 21

[0582] 4 - ((5-(Methoxycarbonyl)indazol-1-yl)methyl)phenylboronic acid (21a), 1-(4-borobenzyl)-1H-indazole-5-carboxylic acid (21b)

[0583] and the synthesis of 4 - ((5-carbamoylindazol-1-yl)methyl)phenylboronic acid (21c)

[0584]

[0585] Step 1: 4 - ((5-(Methoxycarbonyl)indazol-1-yl)methyl)phenylboronic acid (21a)

[0586]

[0587] To a stirred solution of methyl 1H-indazole-5-carboxylate (300 mg, 1.70 mmol, 1.00 equiv) in methanol (15 mL) at room temperature 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). After stirring overnight at 80 °C, 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 prep-HPLC using the following conditions: column: Sunfire prep C18 column, 30 × 150 mm, 5 um; 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; 220 and 254 nm. The fractions containing the desired product were combined and lyophilized to afford the title compound. Fraction 1: room temperature: 7.8 min. 220 mg (37% yield) of 4 - ((5-(methoxycarbonyl)indazol-1-yl)methyl)phenylboronic acid (21a) as a white solid. 11H-NMR: (300 MHz, DMSO-d6, ppm) δ 8.51 (dd, J = 1.6, 0.8 Hz, 1H), 8.32 (d, J = 0.9 Hz, 1H), 8.01 (s, 2H), 7.97 - 7.89 (m, 1H), 7.81 (m, 1H), 7.74 - 7.66 (m, 2H), 7.18 (d, J = 8.0 Hz, 2H), 5.71 (s, 2H), 3.87 (d, J = 1.5 Hz, 3H).

[0588] Step 2: 1 - ((4-(Dihydroxyboranyl)phenyl)methyl)-1H-indazole-5-carboxylic acid and 4 - ((5-carbamoyl-1H-indazol-1-yl)methyl)phenylboronic acid

[0589]

[0590] A solution of 4 - ((5-(Methoxycarbonyl)-1H-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 h. Then, the reaction mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC using the following conditions: column: 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; 220 and 254 nm. The fractions containing the desired product were combined and lyophilized to give two fractions.

[0591] Fraction 1: RT: 5.42 min. 32.8 mg (17%) of 1 - ((4-(Dihydroxyboranyl)phenyl)methyl)-1H-indazole-5-carboxylic acid (22c) as a white solid. MS (ESI, positive ion) m / z: 297.2 (M+1). 1 1H-NMR: (300 MHz, 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).

[0592] Fraction 2: RT: 6.50 min. 50.9 mg (27% yield) of 4 - ((5-carbamoyl-1H-indazol-1-yl)methyl)phenylboronic acid (22d) as a white solid. MS (ESI, positive ion) m / z: 295.9 (M+1). 11H-NMR: (300 MHz, DMSO-d6, ppm) δ 8.37 (d, J = 1.3 Hz, 1H), 8.25 (d, J = 0.9 Hz, 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).

[0593] Example 22

[0594] 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)

[0595]

[0596] Step 1: Methyl 2 - methyl - 1H - 1,3 - benzodiazole - 5 - carboxylate

[0597]

[0598] To a stirred solution of methyl 3,4 - diamino - benzoate (1.00 g, 6.02 mmol, 1.00 equiv) in dimethylacetamide (15 mL) at room temperature was added imidazole hydrochloride (307 mg, 3.01 mmol, 0.50 equiv). After stirring at 150 °C for 8 h, the mixture was poured into water. The aqueous layer was extracted with dichloromethane. 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 afford 0.95 g (71% yield) of methyl 2 - methyl - 1H - 1,3 - benzodiazole - 5 - carboxylate as a brown solid.

[0599] Step 2: 2 - Methyl - 1H - 1,3 - benzodiazole - 5 - carboxylic acid

[0600]

[0601] At room temperature, NaOH (210 mg, 5.23 mmol, 2 equiv) was added 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 H2O (5.00 mL). After stirring for 2 h at room temperature, the mixture was acidified to pH 4 - 5 with concentrated hydrochloric acid at 0 °C. The precipitated solid was collected by filtration, washed with water and dried under vacuum to afford 300 mg (74% yield) of 2-methyl-1H-1,3-benzodiazole-5-carboxylic acid.

[0602] Step 3: 2-Methyl-1H-1,3-benzodiazole-5-carboxamide

[0603]

[0604] 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 afford 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).

[0605] 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)

[0606]

[0607] To a suspension of sodium hydride (43 mg, 1.78 mmol, 2.0 equiv) in N,N-dimethylformamide (8 mL) at 0 °C was added 1H-1,3-benzodiazole-5-carboxamide (180 mg, 0.89 mmol, 1.00 equiv, 80%). After stirring at 0 °C for 30 minutes, 4-(bromomethyl)phenylboronic acid (230 mg, 1.07 mmol, 1.20 equiv) was added at this temperature, and the mixture was further stirred at room temperature for 2 hours. The mixture was quenched with 2N hydrochloric acid and concentrated under reduced pressure. The residue was purified by prep-HPLC, where column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2B to 9B in 10 min; 254 / 220 nm; room temperature 1: 7.62; 9.32; room temperature 2: ; injection volume: ml; number of runs: ;. The fractions containing the desired product were combined and lyophilized to give two components.

[0608] Component 1: Room temperature: 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 (300 MHz, DMSO-d6) δ 12.95 - 12.63 (s, 0.3HCOOH), δ 8.20 - 7.91 (m, 4H), 7.73 (d, J = 7.8 Hz, 3H), 7.50 (d, J = 8.5 Hz, 1H), 7.24 (s, 1H), 7.07 (d, J = 7.9 Hz, 2H), 5.51 (s, 2H), 2.53 (s, 3H).

[0609] Component 2: Room temperature: 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). 1 H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.05 (s, 2H), 7.92 (s, 1H), 7.74 (d, J = 7.7 Hz, 3H), 7.58 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J = 7.7 Hz, 2H), 5.51 (s, 2H), 2.54 (d, J = 2.2 Hz, 3H).

[0610] Example 23

[0611] 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)

[0612]

[0613] Step 1: Methyl 2-isopropyl-1H-1,3-benzodiazole-5-carboxylate

[0614]

[0615] 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.

[0616] Step 2: 2-Isopropyl-1H-1,3-benzodiazole-5-carboxylic acid

[0617]

[0618] 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 eq.) were used.

[0619] Step 3: 2-Isopropyl-1H-1,3-benzodiazole-5-carboxamide

[0620]

[0621] 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.

[0622] 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)

[0623]

[0624] 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 prep-HPLC using the following conditions: Column: XBridge C18 OBD column, 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; 220 and 254 nm. The fractions containing the desired products were combined and lyophilized to give two fractions.

[0625] Fraction 1: RT = 5.55 min. 43.4 mg (16% yield) of 4-((6-carbamoyl-2-isopropyl-1,3-benzoxazol-1-yl)methyl)phenylboronic acid (23a) as a white solid. MS (ESI, positive ion) m / z: 338.3 (M+1). 1 H-NMR (400 MHz, DMSO-d6, ppm) δ 8.06 - 8.01 (m, 3H), 7.90 (s, 1H), 7.76 - 7.67 (m, 3H), 7.62 (d, J = 8.3 Hz, 1H), 7.59 (s, 1H), 7.00 (d, J = 8.0 Hz, 2H), 5.56 (s, 2H), 3.31 - 3.22 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H).

[0626] Fraction 2: RT = 7.22 min. 37.6 mg (13% yield) of 4-((5-carbamoyl-2-isopropyl-1,3-benzoxazol-1-yl)methyl)phenylboronic acid (23b) as a white solid. MS (ESI, positive ion) m / z: 338.4 (M+1). 1 H-NMR (400 MHz, 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 = 8.4 Hz, 1H), 7.24 (s, 1H), 7.00 (d, J = 8.0 Hz, 2H), 5.55 (s, 2H), 3.31 - 3.22 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H)

[0627] Example 24

[0628] Synthesis of 4-((5-carbamoyl-1,3-benzoxazol-1-yl)methyl)phenylphosphonic acid

[0629]

[0630] Step 1: Methyl 3-((4-bromophenyl)methyl)-1,3-benzoxazole-5-carboxylate and methyl 1-((4-bromophenyl)methyl)-1,3-benzoxazole-5-carboxylate

[0631]

[0632] Methyl 1H-1,3-benzodiazole-5-carboxylate (1.50 g, 8.51 mmol, 1.00 equiv) was dissolved in MeOH (20.00 mL). Then 1-bromo-4-(bromomethyl)benzene (2.56 g, 10.22 mmol, 1.20 equiv) and Cs2CO3 (3.61 g, 11.07 mmol, 1.30 equiv) were added. After stirring at room temperature for 12 h, the reaction mixture was concentrated under reduced pressure, diluted with water and extracted with dichloromethane. 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.

[0633] Step 2: Methyl 3-((4-(diethoxyphosphoryl)phenyl)methyl)-1,3-benzodiazole-5-carboxylate and methyl 1-((4-(diethoxyphosphoryl)phenyl)methyl)-1,3-benzodiazole-5-carboxylate

[0634]

[0635] Diethyl phosphite (0.62 g, 4.47 mmol, 1.30 equiv), Cs2CO3 (1.68 g, 5.16 mmol, 1.50 equiv) and Pd(PPh3)4 (398 mg, 0.34 mmol, 0.10 equiv) were added 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) 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 dichloromethane. 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 (56% yield) 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.

[0636] Step 3: Diethyl 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylphosphonate.

[0637]

[0638] 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 eq) was added to NH3-H2O (15.00 mL). After stirring at 80 °C for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by the following: column: XBridge Shield RP18 OBD column, 30*150 mm, 5 um; mobile phase A: water (0.05% NH3H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 13B to 16B in 7 min; 254 / 220 nm; room temperature 5.48:; injection volume: ml; number of runs 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 1H NMR (300 MHz, methanol-d4) δ 8.46 (s, 1H), 8.30 (dd, J = 1.7, 0.7 Hz, 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).

[0639] Step 4: 4-((5-Carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylphosphonic acid.

[0640]

[0641] Bromotrimethylsilane (296.40 g, 1.97 mmol, 10.00 eq) was added dropwise to a stirred solution of diethyl 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylphosphonate (75.00 mg, 0.19 mmol, 1.00 eq) in DCM (5.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 12 h. 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 x 2) to afford 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). 11H NMR (300 MHz, DMSO-d6) δ 9.40 (d, J = 4.0 Hz, 1H), 8.31 (d, J = 1.5 Hz, 1H), 8.14 (s, 1H), 7.97 (dd, J = 8.7, 1.5 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.74 - 7.61 (m, 2H), 7.48 (dd, J = 8.1, 3.2 Hz, 3H), 5.76 (s, 2H).

[0642] Example 25

[0643] 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)

[0644]

[0645] Step 1: 4-Methoxy-1H-pyrazolo[4,3-c]pyridine

[0646]

[0647] To 4-chloro-1H-pyrazolo[4,3-c]pyridine (1.00 g, 6.51 mmol, 1.00 equiv) at room temperature was added NaOMe (17.00 mL, 30% in MeOH). The resulting mixture was stirred in an oil bath at 120 °C for 12 h. 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. The organic layer was concentrated under reduced pressure to afford 4-methoxy-1H-pyrazolo[4,3-c]pyridine as a white solid (520 mg, 52.29% yield). MS (ESI, positive ion) m / z: 149.95 (M+1).

[0648] Step 2: Diethyl (4-((4-methoxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenyl)phosphonate (96a)

[0649]

[0650] 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 prep-HPLC using the following conditions (column: YMC-Actus Triart C18, 30*250, 5um; mobile phase A: water (0.05% FA), mobile phase B: ACN:MEOH = 4:1; flow rate: 45 mL / min; gradient: 25B to 40B in 10 min; 254, 220 nm; room temperature 1: 6.48 min; room temperature 2: 7.75 min), to give the title compound.

[0651] Component 1: Room temperature: 6.48 min. 100 mg (15.9% yield) of diethyl 4-((4-methoxyimidazo[4,3-c]pyridin-1-yl)methyl)phenylphosphonate (25a) as a white solid. MS (ESI, positive ion) m / z: 376.10 (M+1). 1 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.42 (s, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.76 - 7.62 (m, 2H), 7.45 - 7.35 (m, 2H), 7.21 (d, J = 5.8 Hz, 1H), 5.61 (s, 2H), 4.05 - 3.91 (m, 7H), 1.20 (t, J = 7.0 Hz, 6H).

[0652] Step 3: 4-((4-Hydroxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylphosphonic acid (25b)

[0653]

[0654] The title compound was synthesized by the method described in 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 1H NMR (300 MHz, 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 = 7.2 Hz, 1H), 5.64 (s, 2H).

[0655] Example 26

[0656] Synthesis of Diethyl (4-((5-carbamoyl-1H-indazol-1-yl)methyl)phenyl)phosphonate (26a) and 4-((5-carbamoylindazol-1-yl)methyl)phenylphosphonic Acid (26b)

[0657]

[0658] Step 1: 1H-Indazole-5-carboxamide

[0659]

[0660] Methyl 1H-indazole-5-carboxylate (500 mg, 2.84 mmol, 1.00 equiv) was stirred in NH3.H2O (10 mL) at 80 °C in an oil bath 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 / methanol 93:7) to afford 1H-indazole-5-carboxamide as an off-white solid (122 mg, 23.3% yield). MS (ESI, positive ion) m / z: 162.20 (M+1). Step 2: Diethyl 4-((5-carbamoylindazol-1-yl)methyl)phenylphosphonate (26a)

[0661]

[0662] The title compound was synthesized by the method in 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 prep-HPLC using the following conditions (column: YMC-Actus Triart C18, 30*250, 5um; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 45 mL / min; gradient: 25B to 30B in 7 min; 254 / 220 nm; room temperature 1: 6.17 min; room temperature 2: 8.20 min). The fractions containing the desired product were combined and lyophilized to afford the title compound.

[0663] Fraction 1: Room temperature: 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). 11H NMR (300 MHz, DMSO-d6, ppm) δ 8.38 (s, 1H), 8.31 - 8.25 (m, 1H), 8.00 (s, 1H), 7.93 (dd, J = 8.9, 1.5 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.67 (dd, J = 12.9, 7.9 Hz, 2H), 7.34 (dd, J = 8.0, 3.9 Hz, 3H), 5.79 (s, 2H), 3.98 (m, 4H), 1.20 (t, J = 7.0 Hz, 6H).

[0664] Step 3: 4-((5-Carbamoyl-1H-indazol-1-yl)methyl)phenylphosphonic acid (26b)

[0665]

[0666] The title compound was synthesized by the method in Step 2 of Example 85, except that diethyl 4-((5-carbamoyl-1H-indazol-1-yl)methyl)phenylphosphonate (89 mg, 0.23 mmol) was used. (26b, 27.4 mg, 35.7%). MS (ESI, positive ion) m / z: 330.15 (M - 1). 1 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.37 (d, J = 1.4 Hz, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.91 (dd, J = 8.7, 1.6 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.59 (dd, J = 12.5, 7.9 Hz, 2H), 7.49 - 6.89 (m, 3H), 5.72 (s, 2H).

[0667] Example 28

[0668] 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)

[0669]

[0670] Step 1: 5-Methylsulfonyl-1H-1,3-benzodiazole

[0671]

[0672] To a stirred solution of 4-(methylsulfonyl)benzene-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 overnight at 120 °C, 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 in vacuo to afford 150 mg (84%) of 5-(methylsulfonyl)-1H-1,3-benzodiazole as a grey solid.

[0673] Step 2: Mixture of 4-((5-(methylsulfonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid and 4-((6-(methylsulfonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid

[0674]

[0675] To a stirred solution of 5-(methylsulfonyl)-1H-1,3-benzodiazole (150 mg, 0.68 mmol, 1.00 equiv, 89%) in N,N-dimethylformamide (5 mL) at 0 °C 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). 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 prep-HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 19×250 mm, 10 um; 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. The fractions containing the desired product were combined and lyophilized to afford 44.5 mg (18%) of a mixture of 4-((5-(methylsulfonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (97a) and 4-((6-(methylsulfonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (97b) (ratio 1:1) as a white solid. MS (ESI, positive ion) m / z: 331.2 (M+1). 1 H-NMR: (300 MHz, 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).

[0676] Example 29

[0677] (4 - ((5 - Cyano - 1H - benzo[d]imidazol - 1 - yl)methyl)phenyl)phosphonic acid (29a) and (4 - ((6 - cyano - 1H - benzo[d]imidazol

[0678] - 1 - yl)methyl)phenyl)phosphonic acid (29b) mixture synthesis

[0679]

[0680] Step 1: 1 - ((4 - Bromophenyl)methyl)-1,3 - benzodiazole - 5 - carbonitrile and 3 - ((4 - bromophenyl)methyl)-1,3 - benzodiazole - 5 - carbonitrile

[0681]

[0682] To a solution of 1H - 1,3 - benzodiazole - 5 - carbonitrile (400 mg, 2.794 mmol, 1.00 equivalent) in ethanol (10 mL) was added potassium hydroxide powder (204 mg, 3.633 mmol, 1.30 equivalents) and 1 - bromo - 4 - (bromomethyl)benzene (838 mg, 3.353 mmol, 1.20 equivalents). After stirring at room temperature for 12 h, 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.

[0683] 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

[0684]

[0685] At room temperature, 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%) 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 triethyl phosphite (110 mg, 0.799 mmol, 1.20 equiv). 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 afford 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).

[0686] 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)

[0687]

[0688] At room temperature, bromotrimethylsilane (1.72 g, 11.257 mmol, 20 equiv) was added 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). The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC using the following conditions. Column: XBridge Shield RP18 OBD column, 19×250 mm, 10 um; 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. The 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 1H-NMR: (300 MHz, DMSO-d6, ppm) δ 8.69 (d, J = 10.7 Hz, 1H), 8.22 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.72 - 7.53 (m, 3H), 7.36 - 6.80 (m, 4H), 5.54 (s, 2H).

[0689] Example 30

[0690] Synthesis of 4-((5-carbamoyl-4-methoxyindol-1-yl)methyl)phenylboronic acid

[0691]

[0692] Step 1: 4-Amino-5-chloro-2-methoxybenzoate

[0693]

[0694] At room temperature, NCS (3.70 g, 27.709 mmol, 1.00 equiv) was added to a stirred solution of methyl 4-amino-2-methoxybenzoate (5.00 g, 27.595 mmol, 1.00 equiv) in DMF (50.00 mL). 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, eluting with PE / EtOAc (30:70), to afford methyl 4-amino-5-chloro-2-methoxybenzoate (4.9 g, 82.4% yield) as a yellowish-green solid.

[0695] Step 2: Methyl 4-amino-5-chloro-3-iodo-2-methoxybenzoate

[0696]

[0697] NIS (0.83 g, 3.71 mmol, 1.00 equiv) was added 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). 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 yield 1.0 g (79% yield) of methyl 4-amino-5-chloro-3-iodo-2-methoxybenzoate as a white solid.

[0698] Step 3: Methyl 7-chloro-4-methoxy-2-(trimethylsilyl)-1H-indole-5-carboxylate

[0699]

[0700] 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 afford methyl 7-chloro-4-methoxy-2-(trimethylsilyl)-1H-indole-5-carboxylate (350 mg, 31% yield) as a brown solid. Step 4: Methyl 7-chloro-4-methoxy-1H-indole-5-carboxylate

[0701]

[0702] 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 for 3 h at room temperature, 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 afford methyl 7-chloro-4-methoxy-1H-indole-5-carboxylate (250 mg, 87% yield) as a brown solid.

[0703] Step 5: Methyl 4-methoxy-1H-indole-5-carboxylate

[0704]

[0705] 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 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 afford 4-methoxy-1H-indole-5-carboxamide as a light brown solid (210 mg, 94.9% yield).

[0706] Step 6: 4-Methoxy-1H-indole-5-carboxamide

[0707]

[0708] A mixture of methyl 4-methoxy-1H-indole-5-carboxylate (210 mg, 1.02 mmol, 1.00 equiv) in ammonia water (10 mL) was stirred at 80 °C for 12 h. 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 afford 4-methoxy-1H-indole-5-carboxamide as a light brown solid (150 mg, 77% yield).

[0709] Step 7: 4-((5-Carbamoyl-4-methoxyindol-1-yl)methyl)phenylboronic acid

[0710]

[0711] The title compound was synthesized by the method in 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 Prep-HPLC using the following conditions (column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 9B to 35B in 7 min; 254 / 220 nm; room temperature: 2.95 min) to give 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). 1H-NMR (300 MHz, DMSO-d6, ppm) δ 8.01 (s, 2H), 7.79 - 7.46 (m, 5H), 7.34 (s, 1H), 7.18 (dd, J = 16.9, 8.1 Hz, 3H), 6.75 (s, 1H), 5.43 (s, 2H), 4.10 (d, J = 1.8 Hz, 3H).

[0712] Example 31

[0713] Synthesis of 4-((4-carbamoylindol-1-yl)methyl)phenylboronic acid

[0714]

[0715] Step 1: Indole-4-carboxamide

[0716]

[0717] To a solution of 1H-indole-4-carboxamide (100 mg, 0.70 mmol, 1.00 equiv) in a mixture of EtOH (4.00 mL) and H2O (1.00 mL) at room temperature was added Parkins catalyst (30.05 mg, 0.070 mmol, 0.10 equiv), and the mixture was stirred at 100 °C for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure to afford indole-4-carboxamide as a pale yellow solid (85 mg, 75%).

[0718] Step 2: 4-((4-carbamoylindol-1-yl)methyl)phenylboronic acid

[0719]

[0720] The title compound was synthesized by the method in Step 4 of Example 22, except that indole-4-carboxamide (85 mg, 0.53 mmol) was used. The residue was purified by Prep-HPLC (column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18B to 30B in 7 min; 254 / 220 nm; room temperature: 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). 1H-NMR (300 MHz, DMSO-d6, ppm) δ 8.00 (d, J = 4.4 Hz, 2H), 7.72 (s, 1H), 7.70 - 7.67 (m, 2H), 7.61 - 7.54 (m, 2H), 7.47 (d, J = 7.3 Hz, 1H), 7.22 (s, 1H), 7.17 - 7.08 (m, 3H), 6.95 (d, J = 3.1 Hz, 1H), 5.47 (s, 2H).

[0721] Example 32

[0722] 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)

[0723]

[0724] A mixture of the title compounds was synthesized by the method in Example 13, except that 3,5-diazaindole (238 mg, 1.998 mmol, 1.00 equivalent) was used. Yield: 112.1 mg (21% purity) of a mixture 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). 1 H-NMR (300 MHz, 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).

[0725] Example 33

[0726] 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)

[0727]

[0728] Step 1: 3H-Imidazo[4,5-c]pyridine-6-carbonitrile

[0729]

[0730] A solution of 3H-imidazo[4,5-c]pyridine-6-carboxamide (80 mg, 0.493 mmol, 1.00 eq) in POCl3 (8.00 mL) was stirred in an oil bath at 110 °C 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 afford 88 mg (55% yield) of 3H-imidazo[4,5-c]pyridine-6-carbonitrile as a white solid.

[0731] 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)

[0732]

[0733] The title compounds were synthesized by the method in 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 Prep-HPLC using 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: 5B to 30B in 10 min; 254 / 220 nm), giving 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 in 26.2 mg (34% yield). MS (ESI, positive ion) m / z: 279.20 (M+1). 1 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.10 (d, J = 8.7 Hz, 1H), 8.88 (dd, J = 8.6, 2.5 Hz, 1H), 8.56 - 8.44 (m, 1H), 8.08 (s, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.35 (d, J = 7.6 Hz, 2H), 5.64 (d, J = 23.7 Hz, 2H).

[0734] Example 34

[0735] 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)

[0736]

[0737] Step 1: 1H-Imidazo[4,5-b]pyridine-5-carbonitrile

[0738]

[0739] The title compound was synthesized by the method in 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%) of an off-white solid.

[0740] 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)

[0741]

[0742] 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 Prep-HPLC using the following conditions (column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5B to 30B in 10 min; 254 / 220 nm; room temperature 1: 8.82 min; room temperature 2: 9.12 min), to give two components:

[0743] Component 1: Room temperature: 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 HNMR (300 MHz, DMSO-d6, ppm) δ8.98 (s, 1H), 8.23 (d, J = 8.2 Hz, 1H), 8.07 (s, 2H), 7.89 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 5.61 (s, 2H).

[0744] Component 2: At room temperature: 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). 1 1H-NMR (400 MHz, DMSO-d6, ppm) δ 8.94 (s, 1H), 8.36 (d, J = 8.2 Hz, 1H), 8.07 (s, 2H), 7.93 (d, J = 8.2 Hz, 1H), 7.78 - 7.72 (m, 2H), 7.29 (d, J = 7.7 Hz, 2H), 5.56 (s, 2H).

[0745] Example 35

[0746] Synthesis of 4-((4-hydroxyindol-1-yl)methyl)phenylboronic acid

[0747]

[0748] Step 1: 4-((4-Methoxyindol-1-yl)methyl)phenylboronic acid

[0749]

[0750] 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%) of a light brown solid.

[0751] Step 2: 4-((4-Hydroxyindol-1-yl)methyl)phenylboronic acid

[0752]

[0753] 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 Prep-HPLC under the following conditions (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 41B to 42B in 7 min; 254 / 220 nm; room temperature: 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 (300 MHz, DMSO-d6, ppm) δ 9.40 (s, 1H), 8.01 (s, 2H), 7.74 - 7.65 (m, 2H), 7.31 (d, J = 3.2 Hz, 1H), 7.11 (d, J = 7.8 Hz, 2H), 6.92 - 6.78 (m, 2H), 6.52 (dd, J = 3.2, 0.6 Hz, 1H), 6.37 (dd, J = 6.7, 1.7 Hz, 1H), 5.34 (s, 2H).

[0754] Example 36

[0755] 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)

[0756]

[0757] Step 1: 4-((4-Methoxyindol-1-yl)methyl)phenylboronic acid and 4-((7-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid

[0758]

[0759] The title compounds were 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.

[0760] 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)

[0761]

[0762] 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 Prep-HPLC using the following conditions (column: XBridge C18 OBD Prep column, 19 mm X 250 mm; mobile phase A: water (10 mMOL / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 10% B to 30% B in 7 min; 254 / 220 nm; room temperature 1: 6.67 min; room temperature 2: 6.99 min), to afford two components:

[0763] Component 1: Room temperature: 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). 1 H NMR (300 MHz, 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 = 7.9 Hz, 1H), 6.59 (dd, J = 7.7, 1.0 Hz, 1H), 5.63 (s, 2H).

[0764] Component 2: Room temperature: 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 (400 MHz, 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 = 7.9 Hz, 2H), 6.54 (dd, J = 7.6, 1.1 Hz, 1H), 5.43 (s, 2H).

[0765] Example 37

[0766] 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)

[0767]

[0768] Step 1: 4-Methoxy-2-methyl-1H-imidazo[4,5-c]pyridine

[0769]

[0770] 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 for 12 h in an oil bath at 120 °C, the mixture was concentrated under reduced pressure. After stirring for 24 h, the resulting mixture was filtered through Celite and the 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 afford 4-methoxy-2-methyl-1H-imidazo[4,5-c]pyridine as a white solid (300 mg, 56.3% yield). 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)

[0771]

[0772] NaH (101 mg, 4.204 mmol, 2 equiv) was placed in a three-necked flask which was purged with nitrogen 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 min, 4-(bromomethyl)phenylboronic acid (542 mg, 2.522 mmol, 1.20 equiv) was added at 0 °C. The mixture was stirred for an additional 1 h at room temperature, then quenched with hydrochloric acid (3N, 5.0 mL) and concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following conditions (column: XBridge C18 OBD Prep column, 5 μm, 19 mm X 250 mm; Mobile phase A: water (0.05% FA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 5B to 12B in 7 min; 254 / 220 nm; Room temperature 1: 7.13 min; Room temperature 2: 8.42 min), to provide two components:

[0773] Component 1: Room temperature: 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 (400 MHz, DMSO-d6, ppm) δ 11.27 (d, J = 5.8 Hz, 1H), 8.06 (s, 2H), 7.73 (d, J = 7.7 Hz, 2H), 7.09 (dd, J = 11.1, 7.1 Hz, 3H), 6.51 (d, J = 7.0 Hz, 1H), 5.73 (s, 2H), 2.35 (s, 3H).

[0774] Component 2: Room temperature: 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 (400 MHz, DMSO-d6, ppm) δ 11.12 (s, 1H), 8.45 (s, 2H), 7.73 (d, J = 7.6 Hz, 2H), 7.05 (d, J = 7.6 Hz, 3H), 6.52 (d, J = 7.0 Hz, 1H), 5.38 (s, 2H), 2.39 (s, 3H).

[0775] Example 38

[0776] 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)

[0777]

[0778] Step 1: 2-Ethyl-4-methoxy-1H-imidazo[4,5-c]pyridine

[0779]

[0780] The compound was synthesized by the method in 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%).

[0781] 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)

[0782]

[0783] The title compound was synthesized by the method in 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 Prep-HPLC using the following conditions (column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 8B to 25B in 10 min; 254 / 220 nm; room temperature 1: 5.08 min; room temperature 2: 6.10 min), to provide two components:

[0784] Component 1: Room temperature: 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 (400 MHz, DMSO-d6, ppm) δ 11.27 (d, J = 5.7 Hz, 1H), 8.15 (d, J = 39.2 Hz, 2H), 7.73 (d, J = 7.6 Hz, 2H), 7.13 - 7.03 (m, 3H), 6.55 (d, J = 6.9 Hz, 1H), 5.75 (s, 2H), 2.67 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 7.5 Hz, 3H).

[0785] Component 2: Room temperature: 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). 11H-NMR (400 MHz, DMSO-d6, ppm) δ 11.11 (d, J = 5.5 Hz, 1H), 8.10 (s, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.06 (dd, J = 29.5, 7.0 Hz, 3H), 6.52 (d, J = 7.0 Hz, 1H), 5.39 (s, 2H), 2.71 (q, J = 7.5 Hz, 2H), 1.21 (t, J = 7.4 Hz, 3H).

[0786] Example 39

[0787] 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 and formic acid (39a)

[0788]

[0789] Step 1: 2-Isopropyl-4-methoxy-1H-imidazo[4,5-c]pyridine

[0790]

[0791] 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).

[0792] 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)

[0793]

[0794] These compounds were synthesized by the method in Step 4 of Example 22, except that 2-isopropyl-4-methoxy-1H-imidazo[4,5-c]pyridine (370 mg, 1.935 mmol) was used and the residue was dissolved in methanol (5 mL) and filtered. The filtrate was concentrated under reduced pressure to give a mixture (ratio = 1:1) 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 as a brown solid (420 mg, 58.6% yield). MS (ESI, positive ion) m / z: 325.90 (M+1).

[0795] 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)

[0796]

[0797] 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 equivalent, 80%) in ACN (10.00 mL) at room temperature was added TMSI (1.29 g, 6.458 mmol, 5 equivalents). The resulting mixture was stirred at 90 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 9B to 20B in 10 min; 254 / 220 nm; room temperature 1: 8.12 min; room temperature 2: 8.90 min) to give two components:

[0798] Component 1: Room temperature: 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 (light yellow solid). MS (ESI, positive ion) m / z: 312.25 (M+1). 11H NMR (400 MHz, DMSO-d6, ppm) δ 11.27 (d, J = 5.8 Hz, 1H), 8.14 (s, 1H), 8.03 (s, 2H), 7.73 (d, J = 7.9 Hz, 2H), 7.09 (dd, J = 16.9, 7.1 Hz, 3H), 6.56 (d, J = 6.9 Hz, 1H), 5.80 (s, 2H), 3.10 (m, 1H), 1.12 (d, J = 6.7 Hz, 6H).

[0799] Component 2: At room temperature: 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 1H-NMR (400 MHz, DMSO-d6, ppm) δ 11.11 (d, J = 5.9 Hz, 1H), 8.05 (s, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.10 (t, J = 6.5 Hz, 1H), 7.00 (d, J = 7.8 Hz, 2H), 6.57 - 6.44 (m, 1H), 5.44 (s, 2H), 3.19 - 3.09 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H).

[0800] Example 40

[0801] Synthesis of 4-((4-hydroxy-2-methylpyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid

[0802]

[0803] Step 1: 4-Methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine

[0804]

[0805] Under an argon atmosphere, K2CO3 (552 mg, 4.0 mmol, 2.00 equivalents), Pd(PPh3)4 (231 mg, 0.200 mmol, 0.10 equivalent), XPhos (191 mg, 0.400 mmol, 0.20 equivalent), and propyne (1 M in THF) (6.00 mL, 6.000 mmol, 3.00 equivalents) were added to a stirred solution of 3-iodo-2-methoxypyridin-4-amine (500 mg, 2.00 mmol, 1.00 equivalent) in THF (10 mL). The reaction mixture was refluxed for 8 h. After evaporation under reduced pressure to remove THF, the residue was purified by flash chromatography on a silica gel column (PE / EtOAc, gradient 100:0 to 85:15) to afford 4-methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine as a brown solid (150 mg, 35.6%). MS (ESI, positive ion) m / z: 163.25 (M+1).

[0806] Step 2: 4-((4-Methoxy-2-methylpyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid

[0807]

[0808] This compound was synthesized by the method in Step 4 of Example 22, except that 4-methoxy-2-methyl-1H-imidazo[3,2-c]pyridine (150 mg, 0.712 mmol) was used. Yield: 150 mg (66.2%) of a light brown solid. MS (ESI, positive ion) m / z: 297.30 (M+1).

[0809] Step 3: 4-((4-Hydroxy-2-methylpyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid

[0810]

[0811] 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 Prep-HPLC using the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm 5um; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 15B to 70B in 7 min; 254 / 220 nm; room temperature: 6.3 min), to afford 4-((4-hydroxy-2-methylpyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid as a white solid (25.8 mg, 17.6% yield). MS (ESI, positive ion) m / z: 283.25 (M+1). 1 H NMR (300 MHz, DMSO-d 6, ppm) δ 10.63 (d, J = 5.5 Hz, 1H), 8.02 (s, 2H), 7.77 - 7.68 (m, 2H), 7.12 (d, J = 7.8 Hz, 2H), 6.96 - 6.86 (m, 2H), 6.42 (d, J = 7.1 Hz, 1H), 5.23 (s, 2H), 2.31 (d, J = 1.0 Hz, 3H).

[0812] Example 41

[0813] Synthesis of 4-((5-carbamoyl-2-methylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid

[0814]

[0815] Step 1: 2-Methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxamide

[0816]

[0817] To a solution of 5-chloro-2-methyl-1H-pyrrolo[3,2-b]pyridine (500.00 mg, 3.001 mmol, 1.00 equiv) in 7M NH3(g) in MeOH (15.00 mL) was added Pd(dppf)Cl2 CH2Cl2 (122.54 mg, 0.150 mmol, 0.05 equiv). The resulting mixture was purged with carbon monoxide for 5 minutes and stirred for 6 hours at 120 °C under a carbon monoxide (20 atm.) atmosphere. 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.

[0818] Step 2: 4-((5-carbamoyl-2-methylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid

[0819]

[0820] The title compound was synthesized by the method in 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 prep-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: 20B to 30B 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 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.00 (s, 3H), 7.92 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 7.8 Hz, 2H), 7.38 (d, J = 3.3 Hz, 1H), 6.96 (d, J = 7.8 Hz, 2H), 6.54 (s, 1H), 5.50 (s, 2H), 2.44 (s, 3H).

[0821] Example 42

[0822] Synthesis of 4-((5-cyano-2-methylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid

[0823]

[0824] Step 1: 2-Methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile

[0825]

[0826] The title compound was synthesized by the method in 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%) of a brown solid.

[0827] Step 2: 4-((5-Cyano-2-methylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid

[0828]

[0829] The title compound was synthesized by the method in Step 4 of Example 22, except that 2-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (175 mg, 1.113 mmol) was used and the residue was purified by prep-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: 30B to 40B in 7 min; 254, 220 nm), to give 4-((5-cyano-2-methylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid as a white solid (74.5 mg, 22.5% yield). MS (ESI, positive ion) m / z: 292.25 (M+1). 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.07 - 7.99 (m, 3H), 7.71 (d, J = 7.7 Hz, 2H), 7.65 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 7.7 Hz, 2H), 6.62 (s, 1H), 5.54 (s, 2H), 2.45 (s, 3H).

[0830] Example 43

[0831] Synthesis of 4-((5-Carbamoyl-2-isopropylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid

[0832]

[0833] Step 1: 6-Chloro-2-(3-methylbut-1-yn-1-yl)pyridin-3-amine

[0834]

[0835] At room temperature under an argon atmosphere, 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 3-methylbut-1-yne (265 mg, 3.891 mmol, 1.1 equiv) were added to a solution of 6-chloro-2-iodopyridin-3-amine (900 mg, 3.537 mmol, 1.00 equiv) in ACN (10.00 mL). 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 afford 6-chloro-2-(3-methylbut-1-yn-1-yl)pyridin-3-amine as a light brown solid (620 mg, 90% yield).

[0836] Step 2: 5-Chloro-2-isopropyl-1H-pyrrolo[3,2-b]pyridine

[0837]

[0838] At room temperature, t-BuOK (669 mg, 5.959 mmol, 2 equiv) was added 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). After stirring at room temperature for 4 h, 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 afford 5-chloro-2-isopropyl-1H-pyrrolo[3,2-b]pyridine as a brown solid (440 mg, 75.9% yield).

[0839] Step 3: 2-Isopropyl-1H-pyrrolo[3,2-b]pyridine-5-carboxamide

[0840]

[0841] The title compound was synthesized by the method in 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%) of a yellow solid.

[0842] Step 4: 4-((5-carbamoyl-2-isopropylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid

[0843]

[0844] The title compound was synthesized by the method in 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 Prep-HPLC using the following conditions (column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20B to 38B in 7 min; 254 / 220 nm) to afford 4-((5-carbamoyl-2-isopropylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid as a yellow solid (76.1 mg, 29.5% yield). MS (ESI, positive ion) m / z: 338.30 (M+1). 1 1H NMR (400 MHz, DMSO-d6, ppm) δ 7.98 (d, J = 15.7 Hz, 3H), 7.89 - 7.74 (m, 2H), 7.67 (d, J = 7.7 Hz, 2H), 7.40 (d, J = 3.2 Hz, 1H), 6.87 (d, J = 7.7 Hz, 2H), 6.54 (s, 1H), 5.54 (s, 2H), 3.09 (sept, J = 6.8 Hz, 1H), 1.22 (d, J = 6.7 Hz, 6H).

[0845] Example 44

[0846] Synthesis of 4-((5-cyano-2-isopropylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid

[0847]

[0848] Step 1: 2-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile

[0849]

[0850] The title compound was synthesized by the method in Step 1 of 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).

[0851] Step 2: 4-((5-Cyano-2-isopropylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid

[0852]

[0853] The title compound was synthesized by the method in 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 Prep-HPLC using the following conditions (column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15B to 65B in 7 min; 254 / 220 nm) to afford 4-((5-cyano-2-isopropylpyrrolo[3,2-b]pyridin-1-yl)methyl)phenylboronic acid as a white solid (38.6 mg, 63.3% yield). MS (ESI, positive ion) m / z: 320.30 (M+1). 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.06 - 7.87 (m, 3H), 7.65 (m, 3H), 6.88 (d, J = 7.9 Hz, 2H), 6.64 (s, 1H), 5.57 (s, 2H), 3.11 (sept, J = 6.8 Hz, 1H), 1.21 (d, J = 6.7 Hz, 6H).

[0854] Example 45

[0855] 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).

[0856]

[0857] Step 1: 4-Chloro-1H-1,3-benzodiazole

[0858]

[0859] To a suspension of 3-chlorobenzene-1,2-diamine (200 mg, 1.403 mmol, 1.00 equiv) in H2O (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 afford 4-chloro-1H-1,3-benzodiazole as a pale yellow solid (180 mg, 84.1% yield).

[0860] 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)

[0861]

[0862] The title compounds were synthesized by the method in 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 prep-HPLC (column: YMC-Actus Triart C18, 30*250, 5um; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 45 mL / min; gradient: 20B to 30B in 7 min; 254, 220 nm; room temperature 1: 6.45 min; room temperature 2: 7.58 min), to afford two components:

[0863] Component 1: Room temperature: 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 (400 MHz, 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).

[0864] Component 2: Room temperature: 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). 1H-NMR (400 MHz, DMSO-d6, ppm) δ 8.49 (d, J = 12.1 Hz, 1H), 8.04 (s, 2H), 7.75 - 7.63 (m, 3H), 7.29 - 7.14 (m, 2H), 7.00 (d, J = 7.8 Hz, 2H), 5.75 (s, 2H).

[0865] Example 46

[0866] Synthesis of 4-((4,6-dichloro-1,3-benzodioxazol-1-yl)methyl)phenylboronic acid (46a) and 4-((5,7-dichloro-1,3-benzodioxazol-1-

[0867] yl)methyl)phenylboronic acid (46a).

[0868]

[0869] Step 1: 4,6-Dichloro-1H-1,3-benzodioxazole

[0870]

[0871] The title compound was synthesized by the method in 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%) of a pale yellow solid.

[0872] Step 2: 4-((4,6-Dichloro-1,3-benzodioxazol-1-yl)methyl)phenylboronic acid and 4-((5,7-dichloro-1,3-benzodioxazol-1-yl)methyl)phenylboronic acid

[0873]

[0874] The title compound was synthesized by the method described in Step 4 of Example 22, except that 4,6-dichloro-1H-1,3-benzodioxazole (150 mg, 0.802 mmol) was used. The residue was purified by Prep-HPLC (column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35B to 40B in 10 min; 254 / 220 nm; room temperature 1: 7.03 min; room temperature 2: 8.47 min), to afford two components:

[0875] Component 1: At room temperature: 7.03 min. 27.9 mg (10.3% yield) of 4-((5,7-dichloro-1,3-benzodioxazol-1-yl)methyl)phenylboronic acid (46b) as a white solid. MS (ESI, positive ion) m / z: 321.20 (M+1). 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.56 (s, 1H), 8.02 (s, 2H), 7.78 (d, J = 1.9 Hz, 1H), 7.70 (d, J = 7.9 Hz, 2H), 7.36 (d, J = 1.8 Hz, 1H), 7.00 (d, J = 7.8 Hz, 2H), 5.74 (s, 2H).

[0876] Component 2: At room temperature: 8.47 min. 17.4 mg (6.8% yield) of 4-((4,6-dichloro-1,3-benzodioxazol-1-yl)methyl)phenylboronic acid (46a) as a white solid. MS (ESI, positive ion) m / z: 321.15 (M+1). 1 H-NMR (400 MHz, DMSO-d6, ppm) δ 8.56 (s, 1H), 8.11 (s, 2H), 7.76 - 7.65 (m, 3H), 7.39 (d, J = 1.8 Hz, 1H), 7.25 (d, J = 7.7 Hz, 2H), 5.51 (s, 2H).

[0877] Example 47

[0878] Synthesis of 4-((4-fluoro-1,3-benzodioxazol-1-yl)methyl)phenylboronic acid (47a) and 4-((7-fluoro-1,3-benzodioxazol-1-yl)methyl)phenylboronic acid (47b)

[0879]

[0880] The title compounds were synthesized by the method described in Step 4 of Example 22, except that 4-fluoro-1H-1,3-benzodioxazole (150 mg, 1.102 mmol) was used. The residue was purified by Prep-HPLC (column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10B to 35B in 10 min; 254 / 220 nm; at room temperature 1: 8.3 min; at room temperature 2: 8.98 min), to afford two components:

[0881] Component 1: At room temperature: 8.30 min. 57.7 mg (18.8% yield) of 4-((4-fluoro-1,3-benzodioxol-1-yl)methyl)phenylboronic acid (47a) as a white solid. MS (ESI, positive ion) m / z: 271.20 (M+1). 1 H NMR (400 MHz, 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).

[0882] Component 2: At room temperature: 8.98 min. 90.4 mg (29.5% yield) of 4-((7-fluoro-1,3-benzodioxol-1-yl)methyl)phenylboronic acid (47b) as a white solid. MS (ESI, positive ion) m / z: 271.25 (M+1). 1 H-NMR (400 MHz, DMSO-d6, ppm) δ 8.45 (s, 1H), 8.06 (s, 2H), 7.74 - 7.68 (m, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.15 (m, 3H), 7.01 (dd, J = 11.5, 8.0 Hz, 1H), 5.55 (s, 2H).

[0883] Example 48

[0884] 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)

[0885]

[0886] The title compounds were 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 prep-HPLC (column: XBridge C18 OBD Prep column, 5 μm, 19 mm X 250 mm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 7B to 17B in 7 min; 254, 220 nm; at room temperature 1: 7.70 min; at room temperature 2: 9.88 min), to afford two components:

[0887] Component 1: At room temperature: 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 (400 MHz, DMSO-d6, ppm) δ 8.65 (s, 1H), 8.38 (dd, J = 4.7, 1.5 Hz, 1H), 8.05 (s, 2H), 7.93 (dd, J = 8.1, 1.6 Hz, 1H), 7.75 - 7.69 (m, 2H), 7.39 - 7.10 (m, 3H), 5.52 (s, 2H).

[0888] Component 2: At room temperature: 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 (400 MHz, DMSO-d6, ppm) δ 8.59 (s, 1H), 8.35 (dd, J = 4.8, 1.5 Hz, 1H), 8.09 (dd, J = 8.1, 1.5 Hz, 1H), 8.02 (d, J = 4.5 Hz, 2H), 7.74 - 7.67 (m, 2H), 7.31 - 7.22 (m, 3H), 5.49 (s, 2H).

[0889] Example 49

[0890] 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).

[0891]

[0892] Step 1: 2-Isopropyl-1H-imidazo[4,5-b]pyridine

[0893]

[0894] 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.

[0895] 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

[0896]

[0897] The title compounds were 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 prep-HPLC (column: XBridge C18 OBD Prep column, 5 μm, 19 mm X 250 mm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 10B to 35B in 8 min; 254, 220 nm; room temperature 1: 3.60 min; room temperature 2: 6.72 min), to afford two components:

[0898] Component 1: Room temperature: 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 (400 MHz, DMSO-d6, ppm) δ 8.28 - 7.93 (m, 4H), 7.75 - 7.67 (m, 2H), 7.39 (d, J = 7.9 Hz, 2H), 7.12 (dd, J = 7.6, 6.3 Hz, 1H), 5.80 (s, 2H), 3.20 - 3.08 (m, 1H), 1.32 (d, J = 6.9 Hz, 6H).

[0899] Component 2: Room temperature: 6.72 min. 14.6 mg (3.6% yield) of 4-((2-isopropylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (49b) as a brown solid. MS (ESI, positive ion) m / z: 296.25 (M+1). 1 H-NMR (400 MHz, DMSO-d6, ppm) δ 8.28 (d, J = 4.8 Hz, 1H), 8.14 - 7.86 (m, 3H), 7.69 (d, J = 7.6 Hz, 2H), 7.25 (dd, J = 7.9, 4.8 Hz, 1H), 7.06 (d, J = 7.7 Hz, 2H), 5.54 (s, 2H), 3.22 (d, J = 6.7 Hz, 1H), 1.18 (d, J = 6.7 Hz, 6H).

[0900] Example 50

[0901] 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)

[0902]

[0903] The title compounds were 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 prep-HPLC (column: XBridge C18 OBD Prep column, 5 μm, 19 mm X 250 mm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 20B to 30B in 7 min; 254 / 220 nm; room temperature 1: 6.58 min; room temperature 2: 6.72 min), to afford two components:

[0904] Component 1: Room temperature: 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 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.25 (d, J = 1.3 Hz, 1H), 8.56 (d, J = 1.3 Hz, 1H), 8.37 (s, 2H), 8.23 (s, 1H), 7.80 - 7.73 (m, 2H), 7.40 (d, J = 7.9 Hz, 2H), 5.66 (s, 2H).

[0905] Component 2: Room temperature: 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 1H-NMR (400 MHz, 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 = 7.9 Hz, 2H), 7.08 - 7.06 (d, J = 7.9 Hz, 2H), 5.77 (s, 2H).

[0906] Example 51

[0907] Synthesis of 4-((7-chloro-2-isopropylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid

[0908]

[0909] Step 1: 7-Chloro-2-isopropyl-3H-imidazo[4,5-c]pyridine

[0910]

[0911] 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) at room temperature was added imidazole hydrochloride (328 mg, 3.13 mmol, 1.50 equiv). 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 afford 7-chloro-2-isopropyl-3H-imidazo[4,5-c]pyridine as a yellow solid (150 mg, 34.9% yield).

[0912] Step 2: 4-((7-chloro-2-isopropylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid

[0913]

[0914] 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 prep-HPLC (column: YMC-Actus Triart C18, 30*250, 5um; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 45 mL / min; gradient: 5B to 22B in 7 min; 254, 220 nm) to give 4-((7-chloro-2-isopropylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid as a white solid (30.7 mg, 11.9% yield). MS (ESI, positive ion) m / z: 330.20 (M+1). 1HNMR (400 MHz, DMSO-d6, ppm) δ 8.98 (s, 1H), 8.46 (s, 1H), 8.10 (d, J = 16.3 Hz, 2H), 7.77 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 5.61 (s, 2H), 3.19 - 3.11 (m, 1H), 1.42 - 1.18 (m, 6H).

[0915] Example 52

[0916] Synthesis of 4-((4-Hydroxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid, 2.0 Formic 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)

[0917]

[0918] Step 1: 4-Methoxy-2-methyl-1H-1,3-benzodiazole

[0919]

[0920] 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%) of a white solid. MS (ESI, positive ion) m / z: 163.25 (M + 1).

[0921] 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)

[0922]

[0923] 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 prep-HPLC (column: YMC-Actus Triart C18, 30*250, 5um; mobile phase A: water (10 mMOL / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 45 mL / min; gradient: 20B to 30B in 7 min; 254, 220 nm; room temperature 1: 9.05 min; room temperature 2: 11.02 min), to afford two components:

[0924] Component 1: Room temperature: 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 1H-NMR (400 MHz, DMSO-d6, ppm) δ 7.99 (s, 2H), 7.75 - 7.66 (m, 2H), 7.13 - 6.94 (dd, J = 8.1, 0.9 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 7.00 - 6.94 (m, 2H), 6.73 (dd, J = 7.9, 0.9 Hz, 1H), 5.60 (s, 2H), 3.78 (s, 3H), 2.39 (s, 3H).

[0925] Component 2: Room temperature: 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 1H NMR (400 MHz, 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, 1.5 Hz, 1H), 5.41 (s, 2H), 3.90 (s, 3H), 2.45 (s, 3H).

[0926] Step 3: 4-((4-Hydroxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid formate with 2.0 formic acid (52a)

[0927]

[0928] 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)phenyl-boronic acid (80 mg, 0.27 mmol) was used. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 45 mL / min; gradient: 5B to 30B in 7 min; 254 / 220 nm; room temperature 1: 5.78 min) to afford 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 1H-NMR (400 MHz, DMSO-d6, ppm) δ 9.63 (s, 1H), 8.15 (s, 2H), 8.06 (s, 1H), 7.72 (d, J = 7.8 Hz, 2H), 7.06 (d, J = 7.8 Hz, 2H), 6.96 - 6.78 (m, 2H), 6.51 (dd, J = 7.7, 1.1 Hz, 1H), 5.40 (s, 2H), 2.48 (s, 3H)

[0929] Example 53

[0930] Synthesis of 4-((4-carbamoyl-imidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid

[0931]

[0932] Step 1: 1H-Imidazo[4,5-c]pyridine-4-carboxamide

[0933]

[0934] 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%) of a purple solid. MS (ESI, positive ion) m / z: 162.99 (M+1).

[0935] Step 2: 4-((4-carbamoyl-imidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid

[0936]

[0937] 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 prep-HPLC (column: YMC-Actus Triart C18, 30*250, 5um; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 45 mL / min; gradient: 20B to 30B in 7 min; 254 / 220 nm; room temperature: 9.05 min), column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 4B to 12B in 7.5 min; 254 / 220 nm), to afford 4-((4-carbamimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid as a white solid (19.2 mg, 12.8% yield). MS (ESI, positive ion) m / z: 297.25 (M+1). 1 1H-NMR (400 MHz, DMSO-d6, ppm) δ 8.72 (s, 1H), 8.58 (s, 1H), 8.38 (d, J = 5.4 Hz, 1H), 8.08 (s, 2H), 7.80 - 7.67 (m, 4H), 7.30 - 7.20 (m, 2H), 5.58 (s, 2H).

[0938] Example 54

[0939] Synthesis of 4-((4-fluoropyrrolo[2,3-b]pyridin-1-yl)methyl)phenylboronic acid

[0940]

[0941] 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 prep-HPLC (column: YMC-Actus Triart C18, 30*250, 5um; mobile phase A: water (0.05% FA), mobile phase B: ACN:MEOH = 4:1; flow rate: 45 mL / min; gradient: 35B to 55B in 7 min; 254 / 220 nm, room temperature: 7.27 min), to afford 4-((4-fluoropyrrolo[2,3-b]pyridin-1-yl)methyl)phenylboronic acid as a white solid (157.9 mg, 50.8% yield). MS (ESI, positive ion) m / z: 271.10 (M+1). 1H-NMR (400 MHz, DMSO-d6, ppm) δ 8.33 - 8.22 (m, 1H), 8.01 (d, J = 1.9 Hz, 2H), 7.71 (d, J = 7.9 Hz, 3H), 7.18 (d, J = 7.5 Hz, 2H), 7.02 (dd, J = 10.8, 5.6 Hz, 1H), 6.62 (t, J = 2.7 Hz, 1H), 5.51 (s, 2H).

[0942] Example 55

[0943] 4 - ((4 - Methoxypyrazolo[4,3 - c]pyridin - 1 - yl)methyl)phenylboronic acid (55a) and 4 - ((4 - hydroxypyrazolo[4,3 - c]

[0944] pyridin - 1 - yl)methyl)phenylboronic acid (55b) Synthesis

[0945]

[0946] Step 1: 4 - Methoxy - 1H - pyrazolo[4,3 - c]pyridine

[0947]

[0948] To a 30% solution of NaOMe in MeOH (10.00 mL) 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 h. 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 afford 4 - methoxy - 1H - pyrazolo[4,3 - c]pyridine as a yellow solid (300 mg, 60.54% yield).

[0949] Step 2: 4 - ((4 - Methoxypyrazolo[4,3 - c]pyridin - 1 - yl)methyl)phenylboronic acid (55a)

[0950]

[0951] 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 by: column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20B to 30B in 10 min; 254 / 220 nm; room temperature 1: 5.02 min; room temperature 2: 9.17 min), to afford 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 (300 MHz, DMSO-d6, ppm) δ 8.18 (s, 1H), 8.02 (s, 2H), 7.90 (d, J = 6.1 Hz, 1H), 7.72 (d, J = 7.7 Hz, 2H), 7.32 (d, J = 6.1 Hz, 1H), 7.16 (d, J = 7.5 Hz, 2H), 5.64 (s, 2H), 4.00 (s, 3H).

[0952] Step 3: 4-((4-hydroxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid

[0953]

[0954] 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 Prep-HPLC using the following conditions (column: XSelect CSH Prep C18 OBD column, 19 * 250 mm, 5 um; 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; retention time: 5.83 min) to afford 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 1H-NMR (400 MHz, DMSO-d6, ppm) 1 1H NMR (300 MHz, DMSO-d6) δ 11.05 (d, J = 5.7 Hz, 1H), 8.06 (d, J = 0.8 Hz, 2H), 7.82 - 7.69 (m, 2H), 7.25 - 7.12 (m, 3H), 6.70 - 6.61 (m, 1H), 5.54 (s, 2H).

[0955] Example 56

[0956] 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)

[0957]

[0958] Step 1: N-Methyl-1H-1,3-benzodiazole-5-carboxamide

[0959]

[0960] Methyl 1H-1,3-benzodiazole-5-carboxylate (500 mg, 1.00 eq) was dissolved in a solution of CH3NH2 (10.00 mL, 30% in MeOH). After stirring overnight at 80 °C, 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 as an off-white solid (300 mg, 60.3% yield).

[0961] 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)

[0962]

[0963] The title compounds were 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 components were obtained:

[0964] Component 1: At room temperature: 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 1H NMR (300 MHz, 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 = 4.5 Hz, 3H).

[0965] Component 2: At room temperature: 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). 1HNMR(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, 1.5Hz, 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).

[0966] Example 57

[0967] 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)

[0968]

[0969] Step 1: Diethyl 4-((4-methoxyindazol-1-yl)methyl)phenylphosphonate (57a)

[0970]

[0971] 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-methoxyindazol-1-yl)methyl)phenylphosphonate (57a, 355 mg, 55.0%) as a yellow solid. MS (ESI, positive ion) m / z: 374.25 (M+1). 1 H 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).

[0972] Step 2: 4-((4-methoxyindol-1-yl)methyl)phenylphosphonic Acid (57b)

[0973]

[0974] 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 give 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 (300 MHz, DMSO-d6, ppm) δ 7.59 (dd, J = 12.8, 7.8 Hz, 2H), 7.39 (d, J = 3.2 Hz, 1H), 7.20 (d, J = 7.7 Hz, 2H), 7.01 (d, J = 5.7 Hz, 2H), 6.52 (d, J = 11.2 Hz, 2H), 5.44 (s, 2H), 3.87 (s, 3H).

[0975] Step 3: 4-((4-Hydroxyindol-1-yl)methyl)phenylphosphonic acid (57c)

[0976]

[0977] 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-hydroxyindol-1-yl)methyl)phenylphosphonic acid (57c, 20.3 mg, 50.0%). MS (ESI, positive ion) m / z: 304.05 (M+1). 1 H NMR (300 MHz, DMSO-d6 / D2O, ppm) δ 7.63 - 7.50 (m, 2H), 7.29 (d, J = 3.5 Hz, 1H), 7.19 (d, J = 7.8 Hz, 2H), 6.98 - 6.70 (m, 2H), 6.51 (d, J = 3.1 Hz, 1H), 6.38 (d, J = 7.4 Hz, 1H), 5.33 (s, 2H).

[0978] Example 58

[0979] Synthesis of 4-((6-carbamoyl-imidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (58a) and 4-((6-carbamoyl-imidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (58b)

[0980]

[0981] Step 1: 3H-Imidazo[4,5-c]pyridine-6-carboxamide

[0982]

[0983] Methyl 3H-imidazo[4,5-c]pyridine-6-carboxylate (200 mg, 1.13 mmol) was dissolved in NH3-H2O (10 mL) in a sealed tube. The resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature and evaporated to dryness to afford 3H-imidazo[4,5-c]pyridine-6-carboxamide as a pale yellow solid (180 mg, 98.3% yield).

[0984] Step 2: 4-((6-Carbamimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (58a) and 4-((6-carbamimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (58b)

[0985]

[0986] The title compounds were synthesized by the method described in Step 2 of Example 55, except that 3H-imidazo[4,5-c]pyridine-6-carboxamide (80 mg, 0.493 mmol) was used. Two components were obtained:

[0987] Component 1: Room temperature: 13.05 min. 28.9 mg (18.9% yield) of 4-((6-carbamimidazo[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 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.98 (d, J = 1.0 Hz, 1H), 8.72 (s, 1H), 8.24 (s, 1H), 8.14 (d, J = 2.7 Hz, 1H), 8.08 (d, J = 4.4 Hz, 2H), 7.75 (d, J = 7.7 Hz, 2H), 7.60 (d, J = 3.1 Hz, 1H), 7.26 (d, J = 7.7 Hz, 2H), 5.66 (s, 2H).

[0988] Component 2: Room temperature: 14.0 min. 21.2 mg (13.9% yield) of 4-((6-carbamimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (58a) as a white solid. MS (ESI, positive ion) m / z: 297.30 (M+1). 11H NMR (300 MHz, 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 = 7.8 Hz, 2H), 7.56 (s, 1H), 7.35 (d, J = 7.7 Hz, 2H), 5.67 (s, 2H).

[0989] Example 59

[0990] 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)

[0991]

[0992] Step 1: N-Methyl-3H-imidazo[4,5-c]pyridine-6-carboxamide

[0993]

[0994] 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) at room temperature 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). 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 afford N-methyl-3H-imidazo[4,5-c]pyridine-6-carboxamide as a brown solid (120 mg, 44.5% yield). MS (ESI, positive ion) m / z: 177.20 (M + 1).

[0995] Step 2: 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)

[0996]

[0997] The title compounds were 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 components were obtained:

[0998] Component 1: At room temperature: 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). 1 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.98 (s, 1H), 8.78 (d, J = 6.2 Hz, 1H), 8.71 (s, 1H), 8.21 (s, 1H), 8.06 (d, J = 2.2 Hz, 2H), 7.75 (d, J = 7.6 Hz, 2H), 7.26 (d, J = 7.3 Hz, 2H), 5.66 (s, 2H), 2.82 (d, J = 4.1 Hz, 3H).

[0999] Component 2: At room temperature: 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 1H NMR (300 MHz, 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 = 7.4 Hz, 2H), 7.34 (d, J = 7.6 Hz, 2H), 5.67 (s, 2H), 2.83 (s, 3H).

[1000] Example 60

[1001] Synthesis of 4-((4-amino-5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid

[1002]

[1003] Step 1: 5-Methyl-4-nitro-1H-1,3-benzodiazole and 5-methyl-6-nitro-1H-1,3-benzodiazole

[1004]

[1005] 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 portionwise. After stirring for 2 h, the reaction mixture was poured above ice and Na2CO3 was added to adjust the pH > 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 afford 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).

[1006] Step 2: 4-Nitro-1H-1,3-benzodiazole-5-carboxylic acid and 6-nitro-1H-1,3-benzodiazole-5-carboxylic acid

[1007]

[1008] 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 after stirring at 90 °C for 24 h, 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 yield a mixture of 4-nitro-1H-1,3-benzodiazole-5-carboxylic acid and 6-nitro-1H-1,3-benzodiazole-5-carboxylic acid (500 mg, 21.4% yield).

[1009] Step 3: 4-Nitro-1H-benzo[d]imidazole-5-carboxamide and 6-nitro-1H-benzo[d]imidazole-5-carboxamide

[1010]

[1011] 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 produce a mixture of 4-nitro-1H-benzo[d]imidazole-5-carboxamide and 6-nitro-1H-benzo[d]imidazole-5-carboxamide (150 mg, 32.1% yield).

[1012] 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

[1013]

[1014] 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 produce 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).

[1015] Step 5: 4-((4-amino-5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid

[1016]

[1017] 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 Prep-HPLC using the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm 5 um; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 8B to 15B in 12 min; 254 / 220 nm; room temperature: 7.8 min) to afford 4-((4-amino-5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid as a white solid (3.2 mg, 3.1% yield). MS (ESI, positive ion) m / z: 311.30 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.04 (d, J = 4.2 Hz, 2H), 7.79 - 7.69 (m, 4H), 7.34 (d, J = 7.9 Hz, 2H), 7.11 (s, 1H), 6.84 (s, 1H), 6.07 (s, 2H), 5.33 (s, 2H).

[1018] Example 61

[1019] 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)

[1020]

[1021] Step 1: 1H-Imidazo[4,5-b]pyridine-5-carboxamide

[1022]

[1023] 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%) of a light yellow solid.

[1024] Step 2: 4-((5-carbamoyl-imidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (61a) and 4-((5-carbamoyl-imidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (61b)

[1025]

[1026] The title compounds were 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 components were obtained:

[1027] Component 1: Room temperature: 13.05 min. 40.4 mg (21.3% yield) of 4-((5-carbamoyl-imidazo[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 1H NMR (300 MHz, DMSO-d6, ppm)) δ 8.83 (s, 1H), 8.17 - 8.05 (m, 4H), 7.98 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.56 - 7.49 (m, 1H), 7.30 (d, J = 7.7 Hz, 2H), 5.58 (s, 2H).

[1028] Component 2: Room temperature: 14.0 min. 44.8 mg (23.6% yield) of 4-((5-carbamoyl-imidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (61b) as a white solid. MS (ESI, positive ion) m / z: 297.30 (M+1). 1 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.78 (s, 1H), 8.26 - 8.18 (m, 2H), 8.09 (d, J = 4.0 Hz, 2H), 7.99 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 7.7 Hz, 2H), 7.66 (d, J = 2.8 Hz, 1H), 7.42 (d, J = 7.7 Hz, 2H), 5.60 (s, 2H).

[1029] Example 62

[1030] Synthesis of 4-((2-ethyl-4-hydroxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid

[1031]

[1032] Step 1: 2-Ethyl-4-methoxy-1H-pyrrolo[3,2-c]pyridine

[1033]

[1034] To a stirred solution of 3-iodo-2-methoxypyridin-4-amine (2.00 g, 7.999 mmol, 1.00 equiv) in THF (400 mL) was added K2CO3 (2.21 g, 15.998 mmol, 2.00 equiv), Pd(PPh3)4 (0.92 g, 0.800 mmol, 0.10 equiv), and XPhos (0.76 g, 1.600 mmol, 0.20 equiv) under an atmosphere of 1-butyne (3.00 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 afford 2-ethyl-4-methoxy-1H-pyrrolo[3,2-c]pyridine as a brown solid (350 mg, 23.1% yield).

[1035] Step 2: 4-((2-Ethyl-4-methoxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid

[1036]

[1037] 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) of a white solid.

[1038] Step 3: 4-((2-Ethyl-4-hydroxypyrrolo[3,2-c]pyridin-1-yl)methyl)phenylboronic acid

[1039]

[1040] 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%) of 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 = 4.9 Hz, 1H), 8.01 (s, 2H), 7.73 (d, J = 7.7 Hz, 2H), 7.12 (d, J = 7.7 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 6.42 (d, J = 7.2 Hz, 1H), 5.24 (s, 2H), 2.76 (q, J = 7.4 Hz, 2H), 1.19 (t, J = 7.4 Hz, 3H).

[1041] Example 63

[1042] Synthesis of 4 - ((4 - hydroxy - 2 - isopropylpyrrolo[3,2 - c]pyridin - 1 - yl)methyl)phenylboronic acid

[1043]

[1044] Step 1: 2 - Isopropyl - 4 - methoxy - 1H - pyrrolo[3,2 - c]pyridine

[1045]

[1046] 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%) of a brown solid.

[1047] Step 2: 4 - ((2 - Isopropyl - 4 - methoxypyrrolo[3,2 - c]pyridin - 1 - yl)methyl)phenylboronic acid

[1048]

[1049] 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%) of a light brown solid. MS (ESI, positive ion) m / z: 325.35 (M + 1).

[1050] Step 3: 4 - ((4 - hydroxy - 2 - isopropylpyrrolo[3,2 - c]pyridin - 1 - yl)methyl)phenylboronic acid

[1051]

[1052] 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%) of 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 = 5.2 Hz, 1H), 8.00 (s, 2H), 7.71 (d, J = 7.8 Hz, 2H), 6.92 (dd, J = 17.2, 7.1 Hz, 3H), 6.39 (d, J = 7.6 Hz, 2H), 5.37 (s, 2H), 2.92 (sept, J = 6.7 Hz, 1H), 1.15 (d, J = 6.7 Hz, 6H).

[1053] Example 64

[1054] 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 with 0.5 p-toluenesulfonic acid (64b)

[1055]

[1056] Step 1: Methyl 4-methoxy-1H-1,3-benzodiazole-5-carboxylate

[1057]

[1058] 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 afford methyl 4-methoxy-1H-1,3-benzodiazole-5-carboxylate (0.4 g, 76.1% yield). Step 2: 4-Methoxy-1H-1,3-benzodiazole-5-carboxamide

[1059]

[1060] A mixture of methyl 4-methoxy-1H-1,3-benzodiazole-5-carboxylate (0.40 g, 1 equiv) in NH₃·H₂O (10.00 mL) was stirred at 80 °C for 48 h. After cooling the reaction mixture 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 afford 4-methoxy-1H-1,3-benzodiazole-5-carboxamide as a light brown solid (0.25 g, 36.2% yield).

[1061] Step 3: 4-((5-carbamoyl-4-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid

[1062]

[1063] 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 give a white solid (120 mg, 20% yield). MS (ESI, positive ion) m / z: 326.30 (M + 1). 1 ¹H NMR (300 MHz, DMSO-d 6, ppm) δ 8.45 (t, J = 1.8 Hz, 1H), 8.05 (d, J = 2.5 Hz, 2H), 7.78 - 7.64 (m, 4H), 7.43 (s, 1H), 7.22 (dd, J = 16.8, 8.2 Hz, 3H), 5.50 (s, 2H), 4.43 (t, J = 1.8 Hz, 3H).

[1064] Step 4: 4-((5-carbamoyl-4-hydroxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid; p-toluenesulfonate (64b)

[1065]

[1066] 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 Prep-HPLC under the following conditions (column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5B to 36B in 7 min; 254 / 220 nm; room temperature 1:6 min) to afford 4-((5-carbamoyl-4-hydroxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid 0.5 p-toluenesulfonate (64b, 21.1 mg, 16.0% yield) as a white solid. MS (ESI, positive ion) m / z: 312.25 (M+1). 1 H NMR (300 MHz, DMSO-d6 / D2O , ppm) δ 8.75 (s, 1H), 7.75 - 7.65 (m, 3H), 7.49 (d, J = 7.7 Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 7.15 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 5.52 (s, 2H), 2.27 (s, 2H).

[1067] Example 65

[1068] Synthesis of 4-(imidazo[4,5-b]pyrazin-1-ylmethyl)phenylboronic acid

[1069]

[1070] 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%) of 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 = 2.7 Hz, 1H), 8.40 (d, J = 2.7 Hz, 1H), 8.03 (s, 2H), 7.79 - 7.69 (m, 2H), 7.31 - 7.25 (m, 2H), 5.52 (s, 2H).

[1071] Example 66

[1072] Synthesis of 4-(pyrrolo[2,3-b]pyrazin-5-ylmethyl)phenylboronic acid

[1073]

[1074] 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%) of 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 = 3.4 Hz, 2H).

[1075] Example 67

[1076] Synthesis of 4-((2-carbamoylpyrrolo[2,3-b]pyrazin-5-yl)methyl)phenylboronic acid

[1077]

[1078] Step 1: 5H-Pyrrolo[2,3-b]pyrazine-2-carboxamide

[1079]

[1080] 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%) of a brown solid. Step 2: 4-((2-carbamoylpyrrolo[2,3-b]pyrazin-5-yl)methyl)phenylboronic acid

[1081]

[1082] 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%) of an orange solid. MS (ESI, positive ion) m / z: 297.25 (M+1). 11H 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 = 7.5 Hz, 2H), 7.63 (s, 1H), 7.22 (d, J = 7.5 Hz, 2H), 6.81 (d, J = 3.2 Hz, 1H), 5.55 (s, 2H).

[1083] Example 68

[1084] Synthesis of 4-((6-carbamoyl-imidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (68a) and 4-((6-carbamoyl-imidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (68b)

[1085]

[1086] Step 1: 3H-Imidazo[4,5-b]pyridine-6-carboxamide

[1087]

[1088] 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%) of a brown solid. MS (ESI, positive ion) m / z: 163.10 (M+1).

[1089] Step 2: 4-((6-carbamoyl-imidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (68a) and 4-((6-carbamoyl-imidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (68b)

[1090]

[1091] The title compounds were 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 components were obtained:

[1092] Component 1: At room temperature: 3.53 min. 34.7 mg (3.9% yield) of 4-((6-carbamoyl-imidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (68a) as a white solid. MS (ESI, positive ion) m / z: 297.10 (M+1). 11H NMR (300 MHz, DMSO-d6, ppm) δ 8.89 (s, 1H), 8.72 (d, J = 1.9 Hz, 1H), 8.57 (d, J = 2.2 Hz, 1H), 8.14 (s, 1H), 8.05 (d, J = 1.9 Hz, 2H), 7.74 (d, J = 7.6 Hz, 2H), 7.52 (s, 1H), 7.28 (d, J = 7.7 Hz, 2H), 5.55 (s, 2H).

[1093] Component 2: Room temperature: 4.00 min. 4.2 mg (0.5% yield) of 4-((6-carbamimidoyl-imidazo[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 1H NMR (300 MHz, 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 = 7.7 Hz, 2H), 5.94 (s, 2H).

[1094] Example 69

[1095] Synthesis of (4-((1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid

[1096]

[1097] 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%) of a white solid. MS (ESI, positive ion) m / z: 253.25 (M+1). 1 1H NMR (300 MHz, DMSO-d 6, ppm) δ 8.53 (d, J = 11.8 Hz, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 7.4 Hz, 1H), 7.73 (t, J = 7.0 Hz, 2H), 7.55 - 7.46 (m, 1H), 7.30 - 7.15 (m, 4H), 5.51 (d, J = 5.8 Hz, 2H).

[1098] Example 70

[1099] Synthesis of 4-((6-methoxypurin-9-yl)methyl)phenylboronic acid (70a) and 4-((6-methoxypurin-7-yl)methyl)phenylboronic acid (70b)

[1100]

[1101] Step 1: 4-((6-Methoxypurin-9-yl)methyl)phenylboronic acid (70a) and 4-((6-methoxypurin-7-yl)methyl)phenylboronic acid (70b)

[1102]

[1103] 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 components were obtained:

[1104] Component 1: At room temperature: 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). 1 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.51 (d, J = 6.0 Hz, 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).

[1105] Component 2: At room temperature: 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 1H NMR (300 MHz, 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).

[1106] Example 71

[1107] Synthesis of (4-((4-Oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid

[1108]

[1109] Step 1: 4-((4-Methoxypyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenylboronic acid

[1110]

[1111] 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).

[1112] Step 2: (4-((4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)boronic acid

[1113]

[1114] 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%) of a white solid. MS (ESI, positive ion) m / z: 270.30 (M+1). 1 H NMR (300 MHz, DMSO-d6, ppm) δ 11.90 (s, 1H), 8.00 (s, 2H), 7.88 (d, J = 3.6 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.14 (d, J = 7.9 Hz, 3H), 6.48 (d, J = 3.3 Hz, 1H), 5.32 (s, 2H).

[1115] Example 72

[1116] Synthesis of 4-((4-hydroxypyrrolo[2,3-b]pyridin-1-yl)methyl)phenylboronic acid

[1117]

[1118] Step 1: 4-((4-methoxypyrrolo[2,3-b]pyridin-1-yl)methyl)phenylboronic acid

[1119]

[1120] 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%) of a white solid. MS (ESI, positive ion) m / z: 283.10 (M+1).

[1121] Step 2: 4-((4-hydroxypyrrolo[2,3-b]pyridin-1-yl)methyl)phenylboronic acid

[1122]

[1123] 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%) of a white solid. MS (ESI, positive ion) m / z: 267.05 (M-1). 1 H NMR (300 MHz, DMSO-d6 / D2O, ppm) 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.31 (d, J = 13.6 Hz, 1H), 7.14 (d, J = 7.6 Hz, 2H), 6.49 (d, J = 13.9 Hz, 2H), 6.05 (s, 1H), 5.40 (s, 2H).

[1124] Example 73

[1125] Synthesis of 4-((2-carbamoylpyrrolo[3,2-d]pyrimidin-5-yl)methyl)phenylboronic acid

[1126]

[1127] Step 1: 5H-Pyrrolo[3,2-d]pyrimidine-2-carboxamide.

[1128]

[1129] 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%) of a brown solid. MS (ESI, positive ion) m / z: 162.9 (M+1).

[1130] Step 2: 4-((2-carbamoylpyrrolo[3,2-d]pyrimidin-5-yl)methyl)phenylboronic acid

[1131]

[1132] 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%) of a white solid. MS (ESI, positive ion) m / z: 297.30 (M+1). 11H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.38 - 7.99 (m, 4H), 7.74 (d, J = 7.7 Hz, 2H), 7.57 (s, 1H), 7.26 (d, J = 7.7 Hz, 2H), 6.78 (d, J = 3.2 Hz, 1H), 5.61 (s, 2H).

[1133] Example 74

[1134] Synthesis of 4-((7-chloroimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (74a) and 4-((7-chloroimidazo[4,5-b]pyridin-1-

[1135] yl)methyl)phenylboronic acid (74b)

[1136]

[1137] The title compounds were 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 components were obtained:

[1138] Component 1: At room temperature: 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 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.72 (s, 1H), 8.33 (d, J = 5.2 Hz, 1H), 8.04 (d, J = 3.3 Hz, 2H), 7.78 - 7.69 (m, 2H), 7.46 (d, J = 5.2 Hz, 1H), 7.32 - 7.23 (m, 2H), 5.53 (s, 2H).

[1139] Component 2: At room temperature: 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 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.78 (s, 1H), 8.38 (d, J = 5.2 Hz, 1H), 8.04 (d, J = 3.4 Hz, 2H), 7.78 - 7.69 (m, 2H), 7.37 (d, J = 5.2 Hz, 1H), 7.07 (d, J = 7.9 Hz, 2H), 5.75 (s, 2H).

[1140] Example 75

[1141] Synthesis of 4-((5-chloro-1,3-benzodioxazol-1-yl)methyl)phenylboronic acid (75a) and 4-((6-chloro-1,3-benzodioxazol-1-yl)methyl)phenylboronic acid. (75b)

[1142]

[1143] The title compounds were 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-benzodioxazol-1-yl)methyl)phenylboronic acid and 4-((6-chloro-1,3-benzodioxazol-1-yl)methyl)phenylboronic acid in the form of a white solid (ratio = 1:1). MS (ESI, positive ion) m / z: 287.20 (M+1). 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.50 (d, J = 7.4 Hz, 1H), 8.05 (d, J = 1.5 Hz, 2H), 7.81 - 7.63 (m, 3H), 7.54 (d, J = 8.6 Hz, 1H), 7.32 - 7.18 (m, 3H), 5.53 (s, 2H).

[1144] Example 76

[1145] Synthesis of 4-((4-cyano-1,3-benzodioxazol-1-yl)methyl)phenylboronic acid (76a) and 4-((7-cyano-1,3-benzodioxazol-1-yl)methyl)phenylboronic acid. (76b)

[1146]

[1147] The title compounds were 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 prep-HPLC (column: C18 column, 19 * 250 mm, 5 um; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 14B to 20B in 12 min; 254 / 220 nm; room temperature 1 = 7.32 min; room temperature 2 = 8.00 min), to give two components:

[1148] Component 1: At room temperature: 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 1H NMR (300 MHz, DMSO-d6 / D2O, ppm) δ 8.63 (s, 1H), 7.77 (dd, J = 42.8, 7.6 Hz, 4H), 7.50 - 6.92 (m, 3H), 5.55 (s, 2H).

[1149] Component 2: At room temperature: 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 1H NMR (300 MHz, 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 = 7.8 Hz, 2H), 5.76 (s, 2H).

[1150] Example 77

[1151] Synthesis of 4-((4-aminoimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid

[1152]

[1153] 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 prep-HPLC using the following conditions (column: C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 1B to 15B in 8 min; 254 / 220 nm;) to give 4-((4-aminoimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid as a white solid (160.9 mg, 26.7% yield). MS (ESI, positive ion) m / z: 269.20 (M+1). 11H NMR (300 MHz, DMSO-d6 / D2O, ppm) δ 8.34 (s, 1H), 8.18 (s, 1H), 7.73 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 6.1 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 6.1 Hz, 1H), 5.44 (s, 2H).

[1154] Example 78

[1155] Synthesis of 4-((4-Amino-1,3-benzodioxol-1-yl)methyl)phenylboronic acid

[1156]

[1157] The title compound was synthesized by the method described in Step 2 of Example 55, except that 1H-1,3-benzodioxol-4-amine (100 mg, 0.75 mmol) was used. The crude product was purified by prep-HPLC using the following conditions (column: C18 column, 30 * 150, 5 um; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 45 mL / min; gradient: 15B to 35B in 7 min; 254, 220 nm) to give 4-((4-Amino-1,3-benzodioxol-1-yl)methyl)phenylboronic acid as a white solid (37.2 mg, 19% yield). MS (ESI, positive ion) m / z: 268.25 (M + 1). 1 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.16 (s, 1H), 8.02 (s, 2H), 7.73 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 6.86 (t, J = 7.8 Hz, 1H), 6.60 (dd, J = 8.1, 1.0 Hz, 1H), 6.35 (dd, J = 7.6, 0.9 Hz, 1H), 5.39 (s, 2H), 5.26 (s, 2H).

[1158] Example 79

[1159] 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)

[1160]

[1161] Step 1: 6-Methoxypyridine-2,3-diamine

[1162]

[1163] 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).

[1164] Step 2: 5-Methoxy-1H-imidazo[4,5-b]pyridine

[1165]

[1166] 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 afford 5-methoxy-1H-imidazo[4,5-b]pyridine as a pink solid (810 mg, 78.6% yield).

[1167] 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)

[1168]

[1169] The title compounds were 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 prep-HPLC using the following conditions (column: C18 column, 30×150 mm, 5 um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 16B to 20B in 10 min; 254 / 220 nm; room temperature 1: 7.8 min; room temperature 2: 9.0 min;). The fractions containing the desired products were combined and lyophilized to afford two components:

[1170] Component 1: At room temperature: 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 (300 MHz, DMSO-d6, ppm) δ 8.47 (s, 1H), 8.04 (d, J = 3.3 Hz, 2H), 7.86 (d, J = 8.7 Hz, 1H), 7.79 - 7.70 (m, 2H), 7.25 (d, J = 7.8 Hz, 2H), 6.68 (d, J = 8.7 Hz, 1H), 5.49 (s, 2H), 3.87 (s, 3H).

[1171] Component 2: At room temperature: 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 (300 MHz, DMSO-d6, ppm) δ 8.39 (s, 1H), 8.07 - 7.95 (m, 3H), 7.75 (d, J = 7.9 Hz, 2H), 7.37 (dd, J = 7.7, 5.8 Hz, 2H), 6.71 (d, J = 8.6 Hz, 1H), 5.42 (s, 2H), 3.90 (d, J = 4.4 Hz, 3H).

[1172] Step 4: (4-((5-Hydroxy-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenyl)boronic acid (79c)

[1173]

[1174] 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 for 3 days at room temperature, the mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30×150 mm 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 3B to 30B in 7 min; 254 / 220 nm) to afford 4-((5-hydroxyimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid as a white solid (65.4 mg, 66.9% yield). MS (ESI, positive ion) m / z: 270.20 (M+1). 1 1H NMR (300 MHz, DMSO-d6, ppm) δ 11.63 (s, 1H), 8.21 (s, 1H), 8.06 (s, 2H), 7.75 (d, J = 7.6 Hz, 2H), 7.69 (d, J = 9.1 Hz, 1H), 7.25 (d, J = 7.5 Hz, 2H), 6.20 (d, J = 9.2 Hz, 1H), 5.4...

Claims

1. A compound having the formula (I): Wherein: When attached to any one of R 4 , R 5 , and R 6 , each of a, b, d, and e is independently CH or C; or one or two of a, b, d, and e are N, and when attached to R 4 , R 5 , and R 6 , the remainder of a, b, d, and e are each independently CH or C; One of y and z is N and the other of y and z is CR 7 ; or both y and z are CR 7 , wherein each R 7 is independently hydrogen, C1-C6 alkyl, hydroxy, or halo; alk is a C1-C6 alkylene group; alk 1 is a C1-C6 alkylene group; n is 1; m is 0; Ar is phenyl; R w and R x each independently represents a hydroxyl group; R 2 and R 3 each independently is hydrogen, a C1-C6 alkyl group, or a halogen group; R 4 is hydrogen, a C1-C6 alkoxy group, a halogen group, a cyano group, a C1-C6 alkoxycarbonyl group, an aminocarbonyl group or a C1-C6 alkylaminocarbonyl group; and R 5 and R 6 each independently is hydrogen, C1-C6 alkoxy, hydroxy, halogen, halo-C1-C6 alkyl, or amino; or its pharmaceutically acceptable salts; Provided that the compound mentioned is not and provided that when formula (I) has the structure Then is not 4-((5,6-dichloro-2-methyl-1H-benzoimidazol-1-yl)methyl)phenyl; 4-((2-methyl-1H-benzoimidazol-1-yl)methyl)phenyl; 5-fluoro-2-((2-methyl-1H-benzoimidazol-1-yl)methyl)phenyl; 3-fluoro-4-((2-methyl-1H-benzoimidazol-1-yl)methyl)phenyl; 2-((2-methyl-1H-benzoimidazol-1-yl)methyl)phenyl; 2-fluoro-5-((2-methyl-1H-benzoimidazol-1-yl)methyl)phenyl; 3-((2-methyl-1H-benzoimidazol-1-yl)methyl)phenyl; 3-(1H-benzoimidazol-1-ylmethyl)phenyl; 3-(1H-indazol-1-ylmethyl)phenyl; 2-(1H-benzoimidazol-1-ylmethyl)phenyl; 4-(1H-benzoimidazol-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; 5-(1H-benzoimidazol-1-ylmethyl)-2-fluorophenyl; or 2-(1H-benzoimidazol-1-ylmethyl)-5-fluorophenyl.

2. The compound according to claim 1, or its pharmaceutically acceptable salt, having the structure of formula (Ia): Among them, R 7 is a C1-C6 alkyl group.

3. The compound according to claim 1, or its pharmaceutically acceptable salt, having the structure of formula (Ij): Among them, R 7 is a C1-C6 alkyl group, a halogen group, or a hydroxyl group.

4. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R 7 is methyl or isopropyl.

5. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R 7 is isopropyl.

6. The compound according to claim 1, or its pharmaceutically acceptable salt, having the structure of formula (Ig): Among them, R 7 is a C1-C6 alkyl group, a halogen group, or a hydroxyl group.

7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein when attached to R 4 , R 5 , and R 6 , each of a, b, d, and e is independently CH or C.

8. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein, a and d are N, and when attached to R 4 , R 5 , and R 6 either, b and e are each independently CH or C.

9. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein, d is N, and when attached to R 4 、R 5 、and R 6 in any one of them, a, b and e are each independently CH or C.

10. The compound according to any one of claims 6-9, or a pharmaceutically acceptable salt thereof, wherein -B(R w )(R x ) is attached to a carbon of the phenyl ring, which carbon is para to the carbon attaching the phenyl ring to the remainder of the compound of formula (Ig).

11. The compound according to claim 10, or its pharmaceutically acceptable salt, wherein alk is methylene, ethylene, or propylene.

12. The compound according to claim 11, or its pharmaceutically acceptable salt, wherein alk is methylene.

13. The compound as claimed in claim 12, or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, methyl, isopropyl or fluorine.

14. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein R 7 is methyl or isopropyl.

15. The compound as claimed in claim 13, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently hydrogen, methyl, ethyl, or fluorine.

16. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each hydrogen.

17. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, methoxy, ethoxy, fluorine, chlorine, or cyano.

18. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R 4 is cyano, C1-C6 alkoxycarbonyl, aminocarbonyl, or C1-C6 alkylaminocarbonyl.

19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein R 4 is cyano, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl.

20. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein R 4 is attached to a six-membered ring containing a, b, d, and e of formula (Ig) as shown below Wherein the wavy line represents the point of attachment to the remainder of the molecule.

21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 are each hydrogen.

22. The compound as claimed in claim 15, or a pharmaceutically acceptable salt thereof, wherein R 5 is attached to a six-membered ring containing a, b, d, and e having the formula (Ig) as shown below Wherein the wavy line represents the point of attachment to the remainder of the molecule.

23. The compound according to claim 22, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydroxy and R 4 and R 6 are each hydrogen.

24. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 are attached to a six-membered ring containing a, b, d, and e of formula (I) as shown below Wherein the wavy line represents the point of attachment to the remainder of the molecule.

25. The compound according to claim 1, or its pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of:

26. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

27. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

28. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

29. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

30. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

31. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

32. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

33. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

34. The compound according to claim 25, characterized in that, The compound is: or its pharmaceutically acceptable salt.

35. The compound according to claim 25, wherein, The compound is:

36. The compound according to claim 25, characterized in that, The compound is: or its pharmaceutically acceptable salt.

37. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

38. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

39. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

40. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

41. The compound according to claim 25, characterized in that, The compound is: or its pharmaceutically acceptable salt.

42. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

43. The compound according to claim 25, wherein The compound is: or its pharmaceutically acceptable salt.

44. The compound according to claim 25, characterized in that, The compound is: or its pharmaceutically acceptable salt.

45. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

46. The compound according to claim 25, wherein, The compound is: or its pharmaceutically acceptable salt.

47. The compound according to claim 25, wherein The compound is:

48. The compound according to claim 25, wherein, The compound is:

49. The compound according to claim 25, wherein, The compound is:

50. The compound according to claim 25, wherein, The compound is:

51. The compound according to claim 25, wherein, The compound is:

52. The compound according to claim 25, wherein, The compound is:

53. The compound according to claim 25, characterized in that, The compound is:

54. The compound according to claim 25, wherein, The compound is:

55. The compound according to claim 25, wherein, The compound is:

56. The compound according to claim 25, wherein, The compound is:

57. The compound according to claim 25, wherein, The compound is:

58. The compound according to claim 25, wherein, The compound is:

59. The compound according to claim 25, wherein, The compound is:

60. The compound according to claim 25, wherein, The compound is:

61. The compound according to claim 25, wherein, The compound is:

62. The compound according to claim 25, wherein, The compound is:

63. The compound according to claim 25, wherein, The compound is:

64. The compound according to claim 25, characterized in that, The compound is:

65. The compound according to claim 25, wherein, The compound is:

66. A pharmaceutical composition comprising the compound according to any one of claims 1 to 65, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient. Use of a compound according to any one of claims 1 to 65, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 66, characterized in that, For the preparation of a pharmaceutical formulation for the treatment of a disease or disorder mediated by ENPP1 in a patient.

68. The use according to claim 67, wherein, The disease or disorder is a cancer, inflammatory disease, metabolic disease, or viral disease.

69. The use according to claim 68, wherein The disease or disorder is a cancer.

70. The use according to claim 69, wherein, The cancer is hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, or breast cancer.

71. The use according to claim 69, wherein, The pharmaceutical preparation is administered together with an anti-cancer agent.

72. The use according to claim 71, wherein The anti-cancer agent is an immune checkpoint inhibitor.

73. The use according to claim 72, wherein, The immune checkpoint inhibitor is an anti-PD-1 monoclonal antibody or an anti-PD-L1 monoclonal antibody.

74. The use according to claim 72, wherein The anti-cancer agent is an immune checkpoint inhibitor targeting an immune checkpoint molecule selected from the group consisting of: CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, 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.

75. The use according to claim 73, wherein, The immune checkpoint inhibitor is pembrolizumab, nivolumab, durvalumab (MEDI4736), atezolizumab (MPDL3280A), spartalizumab (PDR001), or camrelizumab (SHR-1210).

76. The use according to claim 73, wherein, The immune checkpoint inhibitor is pembrolizumab.

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