Boron heterocycle containing compounds as ENPP inhibitors and uses thereof

Abstract

Provided are compounds, compositions and methods are provided that are ENPP inhibitors, including specifically ENPP1 inhibitors, and have potential applications in treating various diseases, disorders and conditions mediated by ENPP, including specifically ENPP1.

Description

314352000740BORON HETEROCYCLE CONTAINING COMPOUNDS AS ENPP INHIBITORS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 694,487, filed September 13, 2024, and U.S. Provisional Patent Application No. 63 / 788,721, filed April 14, 2025, each which is hereby incorporated by reference in its entirety.FIELD

[0002] The present disclosure relates generally to boron heterocycle containing compounds, and more specifically to benzoxaboroles that inhibit ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) activity, including ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) activity, and are useful for treatment of diseases, disorders and conditions treatable by such inhibition.BACKGROUND

[0003] Ecto-nucleotide pyrophosphatase / phosphodiesterase (ENPP) family members (ENPP 1-7) have been implicated in key biological and pathophysiological processes, including nucleotide and phospholipid signaling, bone mineralization, fibrotic diseases, and tumor-associated immune cell infiltration. See Borza et al., J. Biol. Chem. (2022) 298(2) 101526.

[0004] In particular, ENPP1 has been identified as a type II transmembrane glycoprotein with nucleotide pyrophosphatase and phosphodiesterase enzymatic activities, critical for purinergic signaling. Recently, ENPP1 has emerged as a critical phosphodiesterase that degrades the stimulator of interferon genes (STING) ligand, cyclic GMP-AMP (cGAMP). cGAMP or analogs thereof have emerged as potent immunostimulatory agents, which have potential applications in immunotherapy. This emerging role of ENPP 1 has placed ENPP1 at the frontier of immunotherapy. See Onyedibe et al., Molecules 2019, 24, 4192; see also Ruiz- Fernandez de Cordoba, et al., Clin Cancer Res; 29(12) June 15, 2023, 2184-2193.

[0005] Thus, what is desired in the art are ENPP inhibitors, including ENPP1 inhibitors, that have potential applications in various disease states, including cancer.1MOFO-359177620.18314352000740BRIEF SUMMARY

[0006] Provided herein are compounds that inhibit ENPP, including ENPP1, and are suitable for use in treating diseases, disorders and conditions that are treatable by such inhibition.

[0007] In some aspects, provided is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is H or alkyl;R2and R3are each independently H or alkyl;R4is H or alkyl;R5a heteroaromatic ring system that is fused or unfused, optionally substituted with one or more groups independently selected from the group consisting of alkoxy, cyano, alkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, heteroaryl, or -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; alkyl, in each instance, is optionally substituted with halo or alkoxy; and each Raand Rbis independently H or alkyl; orR4and R5are taken together with the nitrogen atom to which they are attached to form: an optionally substituted heteroaromatic ring system that is fused or unfused, wherein the ring containing R4, N, and R5is aromatic; or an optionally substituted ring system of formula (DI) or (D2):each R6is independently alkyl, haloalkyl, halo, cyano, haloalkoxy, or alkoxy;2MOFO-359177620.18314352000740R7and R8are each independently H or alkyl; orR7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl;Z is -CH- or -N-; ring S is heteroaryl or phenyl; m is 0-3; n is 1-3; and q is O or l.

[0008] In some aspects, provided is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is H or alkyl;R2and R3are each independently H or alkyl;R4is H or alkyl;R5is a heteroaromatic ring system that is fused or unfused, optionally substituted with one or more groups independently selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, - C(=O)NRaRb, and -C(=O)ORa, wherein each Raand Rbis independently H or alkyl; orR4and R5are taken together with the nitrogen atom to which they are attached to form: an optionally substituted heteroaromatic ring system that is fused or unfused, wherein the point of attachment to -CR2R3- is a heteroaryl ring; or an optionally substituted ring system of formula (DI) or (D2):each R6is independently alkyl, haloalkyl, halo, cyano, or alkoxy;3MOFO-359177620.18314352000740R7and R8are each independently H or alkyl; orR7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl;Z is -CH- or -N-; ring S is heteroaryl or phenyl; m is 0-3; n is 1-3; and q is O or l.

[0009] In some aspects, provided is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is H or alkyl; n is 1-3; each of R2and R3is independently H or alkyl;R4is H or alkyl;R5is a heteroaromatic ring system that is fused or unfused, optionally substituted with alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, NRaRb, and -C(=O)NRaRb, wherein each Raand Rbis independently H or alkyl; orR4and R5are taken together with the nitrogen atom to which they are attached to form optionally substituted heteroaromatic ring system that is fused or unfused;R6is alkyl, haloalkyl, halo, or alkoxy; m is 0-3; q is 0 or 1; each of R7and R8is independently H or alkyl; or R7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl.

[0010] In one aspect, provided is a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, provided are pharmaceutical compositions, comprising any one of the compounds disclosed herein; and at least one pharmaceutically acceptable excipient.4MOFO-359177620.18314352000740

[0012] In other aspects, provided is a method of inhibiting ENPP (including inhibiting specifically ENPP1) in a subject in need thereof, comprising administering any one of the compounds or pharmaceutical compositions disclosed herein. In yet other aspects, provided is a method of treating a disease, disorder and condition mediated by inhibition of ENPP (including specifically, inhibition of ENPP1), comprising administering any one of the compounds or pharmaceutical compositions disclosed herein.DESCRIPTION OF THE FIGURES

[0013] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures.

[0014] FIG. 1 depicts results for a study with a compound of the present disclosure at two different doses in comparison to vehicle in the EMT6 syngeneic mouse model. The graph on the left-hand side shows tumor volume versus days of treatment while the graph on the righthand side shows body weight versus days of treatment. The tumor volume graph displays mean tumor volume with error bars representing the standard error mean (SEM) and the body weight graph displays mean body weight with error bars representing the SEM.DETAILED DESCRIPTION

[0015] The following description sets forth exemplary compounds, compositions, methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0016] In some aspects, provided is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is H or alkyl;R2and R3are each independently H or alkyl;R4is H or alkyl;5MOFO-359177620.18314352000740R5is a heteroaromatic ring system that is fused or unfused, optionally substituted with one or more groups independently selected from the group consisting of alkoxy, cyano, alkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, heteroaryl, or -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; alkyl, in each instance, is optionally substituted with halo or alkoxy; and each Raand Rbis independently H or alkyl; orR4and R5are taken together with the nitrogen atom to which they are attached to form: an optionally substituted heteroaromatic ring system that is fused or unfused, wherein the ring containing R4, N, and R5is aromatic;; or an optionally substituted ring system of formula (DI) or (D2):each R6is independently alkyl, haloalkyl, halo, haloalkoxy, or alkoxy;R7and R8are each independently H or alkyl; orR7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl;Z is -CH- or -N-; ring S is heteroaryl or phenyl; m is 0-3; n is 1-3; and q is O or l.

[0017] In some aspects, provided is a compound of Formula (I):6MOFO-359177620.18314352000740 or a pharmaceutically acceptable salt thereof, wherein:R1is H or alkyl;R2and R3are each independently H or alkyl;R4is H or alkyl;R5is a heteroaromatic ring system that is fused or unfused, optionally substituted with one or more groups independently selected from the group consisting of alkoxy, cyano, alkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, heteroaryl, or -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; alkyl, in each instance, is optionally substituted with halo or alkoxy; and each Raand Rbis independently H or alkyl; orR4and R5are taken together with the nitrogen atom to which they are attached to form: an optionally substituted heteroaromatic ring system that is fused or unfused, wherein the ring containing R4, N, and R5is aromatic; or an optionally substituted ring system of formula (DI) or (D2):each R6is independently alkyl, haloalkyl, halo, or alkoxy;R7and R8are each independently H or alkyl; orR7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl;Z is -CH- or -N-; ring S is heteroaryl or phenyl; m is 0-3; n is 1-3; and q is O or l.

[0018] In some embodiments:7MOFO-359177620.18314352000740R1is H or Ci-6 alkyl;R2and R3are each independently H or Ci-6 alkyl;R4is H or Ci-6 alkyl;R5is a 5-20 membered heteroaromatic ring system that is fused or unfused, optionally substituted with one or more groups independently selected from the group consisting of Ci-6 alkoxy, Ci-6 haloalkoxy, cyano, Ci-6 alkyl, Ci-6 haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, or -C(=O)ORa, wherein each Raand Rbis independently H or Ci-6 alkyl; orR4and R5are taken together with the nitrogen atom to which they are attached to form: an optionally substituted 5-20 membered heteroaromatic ring system that is fused or unfused, wherein the ring containing R4, N, and R5is aromatic; or an optionally substituted ring system of formula (DI) or (D2):each R6is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, or Ci-6 alkoxy;R7and R8are each independently H or Ci-6 alkyl; orR7and R8are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl;Z is -CH- or -N-; ring S is 5-6 membered heteroaryl or phenyl; m is 0-3; n is 1-3; and q is O or l.

[0019] In some embodiments, provided is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:8MOFO-359177620.18314352000740R1is H or alkyl; n is 1-3; each of R2and R3is independently H or alkyl;R4is H or alkyl;R5is a heteroaromatic ring system that is fused or unfused, optionally substituted with alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, NRaRb, and -C(=O)NRaRb, wherein each Raand Rbis independently H or alkyl; orR4and R5are taken together with the nitrogen atom to which they are attached to form optionally substituted heteroaromatic ring system that is fused or unfused;R6is alkyl, haloalkyl, halo, or alkoxy; m is 0-3; q is 0 or 1; each of R7and R8is independently H or alkyl; or R7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl.

[0020] As used herein, “alkyl” refers to a monoradical unbranched or branched saturated hydrocarbon chain. In some embodiments, alkyl has 1 to 20 carbon atoms (z.e., C1-20 alkyl), 1 to 8 carbon atoms (z.e., C1-8 alkyl), 1 to 6 carbon atoms (z.e., C1-6 alkyl), or 1 to 4 carbon atoms (z.e., C1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3 -methylpentyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed; thus, for example, “butyl” can include n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” can include n-propyl and isopropyl. In some embodiments, “Ci+alkyl” refers to alkyl having at least 1 carbon atom, and includes, for example, methyl, ethyl, propyl, etc. Similarly, “C2+alkyl” refers to alkyl having at least 2 carbon atoms, and includes, for example, ethyl, propyl, butyl, etc. In one variation, the alkyl is a C1-4 alkyl.

[0021] As used herein, “cycloalkyl” refers to a carbocyclic, non-aromatic group that is connected via a ring carbon atom, which contains only C and H when unsubstituted. The cycloalkyl may have one ring or multiple rings. In some variations, a cycloalkyl with more than one ring may be linked together by a C-C bond, fused, spiro or bridged, or combinations thereof. In some embodiments, cycloalkyl is a C3-10 cycloalkyl. In certain variations, the9MOFO-359177620.18314352000740 cycloalkyl is a C3-6 cycloalkyl. In one variation, cycloalkyl is cyclopropyl (C3) or cyclobutyl (C4).

[0022] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moi eties attached. Examples of a haloalkyl group include difluoromethyl (-CHF2) and trifluoromethyl (-CF3). It should be understood that trifluoromethyl (-CF3) may also be referred to as perfluoromethyl.

[0023] “Alkoxy” refers to the group “ — O- alkyl. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.

[0024] “Haloalkoxy” refers to an alkoxy group, as defined above, wherein one or more hydrogen atoms are replaced by a halogen. Examples of alkoxy groups include, e.g., — OCH2CF3, — OCF2H, and — OCF3.

[0025] “Heteroaromatic ring system” refers to (i) one heteroaromatic ring, or (ii) two or more rings forming a fused ring system, in which at least one of the rings has one or more ring heteroatoms and is aromatic. In some variations, the heteroaromatic ring system is a fused ring system with two or more rings, in which at least one of the rings is heteroaromatic. In some embodiments, the heteroatoms are selected from nitrogen, oxygen and sulfur. In certain embodiments, at least one heteroatom is nitrogen, and one or more of the remaining heteroatoms is selected from oxygen and sulfur. In some variations, the heteroaromatic ring system contains at least one nitrogen atom, or contains 1-4 nitrogen atoms.

[0026] It should be understood that a heteroaromatic ring system also includes a ring or a fused ring system that is not aromatic provided that its corresponding tautomeric form is aromatic. For example, exemplary moiety (A) below, having tautomeric form (B), is considered a heteroaromatic ring system. Examples of heteroaromatic rings systems having an aromatic tautomeric form include but are not limited to pyridin-2(lH)-one, pyrido[2,3- d]pyrimidin-7(8H)-one, 2,7-naphthyridin-l(2H)-one, l,6-naphthyridin-2(lH)-one, 1,8- naphthyridin-2(lH)-one, pyrido[3,4-b]pyrazin-5(6H)-one.10MOFO-359177620.18314352000740

[0027] Benzoxaborole and benzoxaborininols in the presence of water may be present as a neutral trigonal planar form or as an anionic tetrahedral form (generic, exemplary structures shown as A-l and B-l below; see also Tomsho, J.W. et al ACS Medicinal Chemistry Letters, 2012, 3 (1), pages 48- 52). This disclosure is intended to capture both forms, covalent variants thereof, and mixtures thereof that result from this equilibrium despite only displaying one.

[0028] Benzoxaborole and benzoxaborininols inhibitors may interact with a biological target, such as ENPP1, by forming a covalent bond via the boron atom. These boron heterocycles may also inhibit the biological target by non-covalent interactions, nonexclusive examples include electrostatic, Van der Waals, or hydrogen bonding interactions. In some embodiments, benzoxaborole and benzoxaborininols inhibitors may interact with the biological target resulting in inhibition by combinations of some or all of the different possible interactions.

[0029] In some variations, suitable examples of heteroaromatic ring systems may include11MOFO-359177620.18314352000740

[0030] A heteroaryl is a type of heteroaromatic ring system. As used herein, “heteroaryl,” refers to a fully aromatic group having a single ring or multiple fused rings with one or more ring heteroatoms. In some embodiments, the heteroatoms are selected from nitrogen, oxygen, and sulfur. Each ring in a heteroaryl — whether it be a single ring or two or more fused

[0031] It should be understood that a heteroaromatic ring system does not include heterocyclyl.12MOFO-359177620.18314352000740

[0032] The term, “heterocyclyl,” refers to any cyclic containing group containing at least one heteroatom ring member that is not a “heteroaromatic ring system.” For example, a heterocyclyl can be a single ring or multiple rings wherein the multiple rings are fused, bridged, or spiro. Further, a heterocyclyl is intended to encompass a ring or ring system comprising any non-aromatic ring containing at least one heteroatom, which may be fused to an aryl or cycloalkyl ring. In some variations, suitable examples of heterocyclyl s may include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, benzodi oxolyl, 1,4-benzodioxanyl, and dioxolanyl. In some other variations, suitable examples of heterocyclyl s may include

[0033] “Aryl” as used herein, refers to a fully aromatic group having a single ring or multiple fused rings, wherein none of the rings contain any heteroatoms. Each ring in an aryl — whether it be a single ring or two or more fused rings — is aromatic. In some variations, suitable examples of aryls may include phenyl and naphthyl.

[0034] The term “substituted”, in some variations, means that any one or more hydrogen atoms on the designated atom or group is replaced with a moiety other than hydrogen, provided that the designated atom’s normal valence is not exceeded.

[0035] The symbol whether as a bond or displayed perpendicular to a bond indicates the point at which the displayed moiety is attached to the remainder of the molecule. The symbol - indicates a single or double bond.

[0036] In some embodiments, provided is a compound of Formula (I-A):or a pharmaceutically acceptable salt thereof, wherein R1, n, R2, R3, R4, R5, R6, R7, R8, m and q are as defined for Formula (I) above.

[0037] In other embodiments, provided is a compound of Formula (I-B):13MOFO-359177620.18314352000740or a pharmaceutically acceptable salt thereof, wherein R1, n, R2, R3, R4, R5, R6, R7, R8, m and q are as defined for Formula (I) above.

[0038] In some embodiments, provided is a compound of Formula (I-C):or a pharmaceutically acceptable salt thereof, wherein R3, R5, R6, R8, and m are as defined for Formula (I) above.

[0039] In some embodiments, R1is H or alkyl. In some embodiments, R1is H. In some embodiments, R1is alkyl.

[0040] In some embodiments, R2and R3are each independently H or alkyl. In some embodiments, R2is H, and R3is H or alkyl. In some embodiments, R2is H, and R3is alkyl.In some embodiments, each of R2and R3is H.

[0041] In some embodiments, R4is H or alkyl. In some embodiments, R4is H. In some embodiments, R4is alkyl.

[0042] In some embodiments, R5is a heteroaromatic ring system that is fused or unfused, provided that whenthen either m is 1-3, n is 2-3, or q is 1.

[0043] In some variations of the foregoing, R5is a heteroaromatic ring system containing 1-4 nitrogen atoms. In other variations, R4and R5are taken together with the nitrogen atom to which they are attached to form a heteroaromatic ring system containing 1-4 nitrogen atoms.

[0044] In some variations, R5is a fused heteroaromatic ring system represented by the formula:14MOFO-359177620.18314352000740wherein:Xla, X2a, and X3aare each independently -CH- or -N-; and ring A is a 5-6 membered ring that is taken together with the ring bearing Xla, X2a, and X3ato form the fused heteroaromatic ring system; wherein the heteroaromatic ring system is optionally substituted with one or more substituents selected from the group consisting of alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, NRaRb, and -C(=O)NRaRb, wherein each Raand Rbis independently H or alkyl.

[0045] In other variations, R5is a fused heteroaromatic ring system represented by the formula:wherein:Xla, X2a, and X3aare each independently -CH- or -N-, wherein at least one of Xla, X2a, and X3ais -N-; and ring A is phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein the fused heteroaromatic ring system is optionally substituted with one or more substituents selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, -NRaRb, -C(=O)NRaRb, and -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; and each Raand Rbis independently H or alkyl.

[0046] In certain variations, R5is a fused heteroaromatic ring system optionally substituted with one or more substituents selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, -OCH2-(aryl), -OCH2-(5-membered heteroaryl), -NRaRb, -C(=O)NRaRb, and -C(=O)ORa, In certain other variations, -OCH2-(aryl) is -OCH2-(phenyl) and -OCH2-(5-membered heteroaryl) is -OCH2-(pyrazolyl).15MOFO-359177620.18314352000740

[0047] In other variations, R5is a fused heteroaromatic ring system represented by the formula:wherein:Xla, X2a, and X3aare each independently -CH- or -N-, wherein at least one of Xla, X2a, andX3ais -N-; and ring A is phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein the fused heteroaromatic ring system is optionally substituted with one or more substituents selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, NRaRb, -C(=O)NRaRb, and -C(=O)ORa, and wherein each Raand Rbis independently H or alkyl.each optionally substituted with one or more substituents selected from the group consisting of alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, NRaRb, and -C(=O)NRaRb, wherein each Raand Rbis independently H or alkyl. In one variation, each Raand Rbis independently H or Ci-4 alkyl.16MOFO-359177620.18314352000740selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, NRaRb, -C(=O)NRaRb, and -C(=O)ORa, wherein each Raand Rbis independently H or alkyl.17MOFO-359177620.18314352000740with one or more substituents selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, or -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; and each Raand Rbis independently H or alkyl.

[0051] In some variations, R5is a heteroaromatic ring system, substituted with 1 or 2 substituents.

[0053] In other variations, R5is a ring system of formula (Cl), (C2), or (C3):18MOFO-359177620.18314352000740wherein each of (Cl), (C2), and (C3) is optionally substituted with one or more alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, or - C(=O)ORa. In some embodiments, R9is methyl. In some embodiments, Z is -CH-. In some embodiments, ring R is 6-membered heteroaryl. In some embodiments, ring R is pyridyl or pyrazinyl. In certain variations,

[0054] In other variations, R4and R5are taken together with the nitrogen atom to which they are attached to form optionally substituted heteroaromatic ring system that is fused or unfused. In one variation, R4and R5are taken together with the nitrogen atom to which they are attached to form a heteroaromatic ring system represented by the formula:wherein: r is 0 or 1;Xlb, X2b, and X3bare each independently -CH- or -N-; and ring B is phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl.

[0055] In certain variations, R4and R5are taken together with the nitrogen atom to which they are attached to form a heteroaromatic ring system that is fused or unfused, and substituted with alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, NRaRb, or -C(=O)NRaRb. In some variations, the alkoxy, alkyl or haloalkyl is Ci-4 alkoxy, Ci-4 alkyl or Ci-4 haloalkyl.19MOFO-359177620.18314352000740

[0056] In one variation, R4and R5are taken together with the nitrogen atom to which, each of which is optionally substituted.

[0057] In one variation, R4and R5are taken together with the nitrogen atom to whicheach of which is optionally substituted.

[0058] In other variations, R4and R5are taken together with the nitrogen atom to which they are attached to form a 5-membered heteroaromatic ring system containing 1 to 3 nitrogen atoms, wherein the 5-membered heteroaromatic ring system is optionally substituted with Ci-4 alkyl, and is substituted with one or more: Rw; alkyl substituted with Rw; alkyl substituted with -O-Rw; or alkyl substituted with amino, -C(O)ORa, or both, wherein Rwis optionally substituted aryl, heteroaryl, heterocyclyl, or cycloalkyl, and Rais H or alkyl. In other variations, R4and R5are taken together with the nitrogen atom to which they are attached to form a 5-membered heteroaryl containing 1 to 3 nitrogen atoms, wherein the 5- membered heteroaryl is optionally substituted with Ci-4 alkyl, and is substituted with one or more: Rw; alkyl substituted with Rw; alkyl substituted with -O-Rw; or alkyl substituted with amino, -C(O)ORa, or both, wherein Rwis optionally substituted fused or unfused heteroaromatic ring system, aryl, heterocyclyl, or cycloalkyl, and Rais H or alkyl.

[0059] In other variations, R4and R5are taken together with the nitrogen atom to which they are attached to form a 5-membered heteroaryl containing 1 to 3 nitrogen atoms, wherein the 5-membered heteroaryl is substituted with an alkyl, wherein the alkyl is substituted with both amino and -C(O)ORa, and wherein Rais H or alkyl. In one variation, R4and R5are taken together with the nitrogen atom to which they are attached to form a triazolyl, wherein the20MOFO-359177620.18314352000740 triazolyl is substituted with ethyl, and wherein ethyl is substituted with both amino and -C(0)0CH3, as shown:

[0060] In some embodiments, R4and R5are taken together with the nitrogen atom to which they are attached to form thiazolyl, oxazolyl, pyrazolyl, imidazolyl, or triazolyl, which is substituted with: an Rw; alkyl substituted with Rw; or alkyl substituted with -O-Rw, wherein Rwis optionally substituted fused or unfused aryl, heteroaryl, heterocyclyl, or cycloalkyl. In other variations, R4and R5are taken together with the nitrogen atom to which they are attached to form triazolyl substituted with: Rw, alkyl substituted with Rw; alkyl substituted with -O-Rw; or alkyl substituted with amino and / or alkylnoate, wherein Rwis optionally substituted aryl, heteroaryl, heterocyclyl, or cycloalkyl. In other variations, R4and R5are taken together with the nitrogen atom to which they are attached to form triazolyl or pyrazolyl substituted with: Rw, alkyl substituted with Rw; alkyl substituted with -O-Rw; or alkyl substituted with amino and / or alkylnoate, wherein Rwis optionally substituted aryl, heteroaryl, heterocyclyl, or cycloalkyl. In some embodiments, R4and R5are taken together with the nitrogen atom to which they are attached to form triazolyl substituted with: Rw; alkyl substituted with Rw; or alkyl substituted with -O-Rw, wherein Rwis optionally substituted fused or unfused aryl, heteroaryl, heterocyclyl, or cycloalkyl. In some other embodiments, R4and R5are taken together with the nitrogen atom to which they are attached to form triazolyl or pyrazolyl substituted with: Rw; alkyl substituted with Rw; or alkyl substituted with -O-Rw, wherein Rwis optionally substituted fused or unfused aryl, heteroaryl, heterocyclyl, or cycloalkyl.

[0061] In one variation, the 5-membered heteroaromatic ring system is thiazolyl, oxazolyl, pyrazolyl, imidazolyl, or triazolyl. In one variation, the 5 -membered heteroaromatic ring system is triazolyl. In one variation, Rwis pyridyl, pyrimidinyl, pyrazolyl, phenyl, or cycloalkyl, wherein each is optionally substituted with alkyl, alkoxy, haloalkyl, halo, or cyano. In some embodiments, Rwis pyridyl, pyrazolyl, or phenyl, wherein each Rwis optionally substituted with one or more alkyl, alkoxy, halo. In some embodiments, Rwis pyridyl or phenyl, wherein each Rwis optionally substituted with one or more alkyl, alkoxy, halo. In some embodiments, Rwis pyridyl optionally substituted with one or more alkyl, alkoxy, or halo. In some embodiments, Rwis pyridyl optionally substituted with one or two21MOFO-359177620.18314352000740 substituents independently selected from the group consisting of alkyl, alkoxy, and halo. In some embodiments, Rwis phenyl optionally substituted with one or more alkyl, alkoxy, or halo. In some embodiments, Rwis phenyl optionally substituted with one or two alkyl, alkoxy, or halo. In some embodiments, Rwis pyrazolyl optionally substituted with one or more alkyl, alkoxy, or halo. In some embodiments, Rwis pyrazolyl optionally substituted with one or two alkyl, alkoxy, or halo. In one variation, Rwis pyridyl, pyrazolyl, phenyl, or cycloalkyl, wherein each is optionally substituted with alkyl, alkoxy, haloalkyl, or halo. In another variation, Rwis pyridyl, pyrimidinyl, phenyl, or cycloalkyl, wherein each is optionally substituted with alkyl, alkoxy, haloalkyl, hydroxyl, or halo. In a further variation, Rwis pyridyl, pyrimidinyl, or phenyl, wherein each Rwis optionally substituted with one or more alkyl, alkoxy, or halo. In another variation, Rwis pyrimidinyl optionally substituted with one or two substituents independently selected from the group consisting of: alkyl, alkoxy, and halo. In some variations, the alkyl, alkoxy or haloalkyl is C1-4 alkoxy, C1-4 alkyl or Ci-4 haloalkyl.

[0062] In other variations, R4and R5are taken together with the nitrogen atom to which they are attached to form an optionally substituted ring system of formula (DI) or (D2):

[0063] In some embodiments, Z is -N-. In some embodiments, ring S is 6-membered heteroaryl. In some embodiments, ring S is pyridyl or pyrazinyl. In other embodiments, ringS is phenyl. In certain variations R4and R5are taken together with the nitrogen atom to which they are attached to formsome embodiments,R4is H.

[0064] In some embodiments, R1is H.

[0065] In some embodiments, each of R2and R3is H. In other embodiments, R2is H, and R3is Ci-4 alkyl.22MOFO-359177620.18314352000740

[0066] In some embodiments, each R6is independently alkyl, haloalkyl, halo, or alkoxy. In some embodiments, each R6is independently Ci-ealkyl, Ci-ehaloalkyl, halo, or Ci-ealkoxy. In some embodiments, R6is halo. In some embodiments, R6is Ci-ealkoxy.

[0067] In some embodiments, R7and R8are each independently H or alkyl, or R7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl. In some embodiments, R7and R8are each independently H or Ci-ealkyl; or R7and R8are taken together with the carbon atom to which they are attached to form Cs-ecycloalkyl. In some embodiments, R7and R8are each H. In some embodiments, R7and R8are each alkyl. In some embodiments, R7and R8are each methyl. In some embodiments, one of R7and R8is H and the other of R7and R8is methyl.

[0068] In some embodiments, n is 1. In some embodiments, m is 0. In some embodiments, q is 0. In other embodiments, q is 1.

[0069] In some embodiments, each of R7and R8is independently H or alkyl. In certain embodiments, R7is H. In certain embodiments, R7is alkyl. In certain embodiments, R8is H. In certain embodiments, R8is alkyl. In other embodiments, R7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl. In some variations, the cycloalkyl formed is a C3-C6 cycloalkyl. In some variations, the cycloalkyl formed is cyclopropyl and cyclobutyl.

[0070] In some embodiments, provided is a compound of Formula (1-1):or a pharmaceutically acceptable salt thereof, wherein: each W is independently -N-, -CH-, or -C(Rw1)-, wherein at least one W is -N-; each Rwlis independently alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, -NRaRb, -C(=O)NRaRb, or -C(=O)ORa; and g is 0-4.

[0071] In some embodiments, provided is a compound of Formula (1-1):23MOFO-359177620.18314352000740or a pharmaceutically acceptable salt thereof, wherein: each W is independently -N-, -CH-, or -C(Rw1)-, wherein at least one W is -N-; each Rwlis independently alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, -NRaRb, - C(=O)NRaRb, or -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; and g is 0-4.

[0072] In certain embodiments of Formula (1-1), each Rwlis independently alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, haloalkoxy, -OCH2-(aryl), -OCH2-(5-membered heteroaryl), -NRaRb, -C(=O)NRaRb, or -C(=O)ORa. In certain variations, -OCH2-(aryl) is -OCH2-(phenyl) and -OCH2-(5-membered heteroaryl) is -OCH2-(pyrazolyl).

[0073] In some embodiments, provided is a compound of Formula (1-2):or a pharmaceutically acceptable salt thereof, wherein: each W is independently -N-, -CH-, or -C(Rw1)-, wherein at least one W is -N-; ring C is heteroaryl or a ring system of formula (C4), (C5), or (C6):whereinR9is alkyl, each * represents a point of attachment to the ring bearing W, and ring C is optionally substituted with one or more Rwl;24MOFO-359177620.18314352000740 each Rwlis independently alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, or -C(=O)ORa

[0074] In some embodiments, provided is a compound of Formula (1-3):or a pharmaceutically acceptable salt thereof, wherein: each W is independently -N-, -CH-, or -C(Rw1)-, wherein at least one W is -N-;X is -N-, -CH-, -C(RW1), or -S-; ring D is phenyl, heteroaryl, or a ring system of formula (C4), (C5), or (C6):wherein,R9is alkyl, each * represents a point of attachment to the ring bearing W, and ring D is optionally substituted with one or more Rwl; each Rwlis independently alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, or -C(=O)ORa; and r is 0 or 1.

[0075] In some embodiments, provided is a compound of Formula (1-4):or a pharmaceutically acceptable salt thereof, wherein:X is -N-, -CH-, -C(RW1), or -S-. ring E is phenyl or heteroaryl, wherein ring E is optionally substituted with one or more Rwl;25MOFO-359177620.18314352000740 each Rwlis independently alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, - NRaRb, -C(=O)NRaRb, or -C(=O)ORa; andRxis H, alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, -NRaRb, -C(=O)NRaRb, or -C(=O)ORa

[0076] In some embodiments, provided is a compound of Formula (1-5):or a pharmaceutically acceptable salt thereof, wherein:Y is a bond, alkyl, -alkyl-NRa-alkyl- or -O-alkyl-; ring F is 5-membered, unfused heteroaryl that is optionally substituted with one or more Rwl; ring G is phenyl, heterocyclyl, or heteroaryl, wherein ring G is optionally substituted with one or more Rwl; and each Rwlis alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, - C(=O)NRaRb, or -C(=O)ORa

[0077] In some embodiments, provided is a compound of Formula (1-5):or a pharmaceutically acceptable salt thereof, wherein:Y is a bond, alkyl, -alkyl-NRa-alkyl- or -O-alkyl-; ring F is 5-membered heteroaryl that is optionally substituted with one or more Rwl; ring G is phenyl, fused or unfused heterocyclyl, or fused or unfused heteroaromatic ring system, wherein ring G is optionally substituted with one or more Rwl; and each Rwlis alkoxy, cyano, alkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, or -C(=O)ORa, wherein alkyl and alkoxy, in each instance, are optionally independently substituted with hydroxyl, methoxy, or halo.26MOFO-359177620.18314352000740

[0078] In some embodiments, Y is a bond.

[0079] In some embodiments, ring G is phenyl, fused or unfused heterocyclyl, or fused or unfused heteroaryl, wherein ring G is optionally substituted with one or more Rwl. In someone or two Rwl, wherein each Rwlis selected from the group consisting of alkoxy, cyano, alkyl, halo and hydroxyl, wherein alkoxy and alkyl, in each instance, are optionally independently substituted with hydroxyl or halo. In some variations, each Rwlis selected from the group consisting of methoxy, ethoxy, -CH2CH2OH, -OCH2CH2OCH3, -OCHF2, F, methyl, or ethyl.

[0080] In some embodiments, ring F is triazolyl, pyrazolyl, or imidazolyl optionally substituted with one Rwl. Rwlis methyl. In some variations, Rwlis alkyl. In some variations, Rwlis methyl.

[0081] In some embodiments, provided is a compound of Formula (1-6):or a pharmaceutically acceptable salt thereof, wherein: ring J is a ring system of formula (DI) or (D2), wherein ring J is optionally substituted with one or more Rwl; each Rwlis alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, - C(=O)NRaRb, or -C(=O)ORa.

[0082] In some embodiments, provided is a compound of Formula (Al) or (A2):27MOFO-359177620.18314352000740or a pharmaceutically acceptable salt thereof, whereinYlais -N-, -CH- or -C(CN)-;Ylbis -N-, -CH-, or -C(ORlv)-, wherein Rlvis H, methyl, or ethyl;Rlwis H or methyl;Rlx, Rly, and Rlzare each independently -H, -OH or -OMe;R3is H, methyl or ethyl; each R6is independently methyl, F, Cl, or methoxy;R8is H or methyl; and m is 0-2.

[0083] In some embodiments, provided is a compound of Formula (Al) or (A2):or a pharmaceutically acceptable salt thereof, whereinYlais -N-, -CH- or -C(CN)-;Ylbis -N-, -CH-, or -C(ORlv)-, wherein Rlvis H, methyl, or ethyl;Rlwis H, -CF3, alkoxy, alkoxy substituted with phenyl or pyrazolyl, hydroxyl, - C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)OH, -C(=O)OCH3or methyl; Rlx, Rly, and Rlzare each independently -H, -OH or -OMe;R3is H, methyl or ethyl; each R6is independently methyl, F, Cl, or methoxy;R8is H or methyl; and m is 0-2.

[0084] In certain variations of Formula (Al) and (A2), Rlwis Ci-3alkoxy.

[0085] In some embodiments, provided is a compound of Formula (B):28MOFO-359177620.18314352000740or a pharmaceutically acceptable salt thereof, whereinY2ais -N- or -CH-;R3is H, methyl or ethyl; each R6is independently methyl, F, Cl, or methoxy;R8is H or methyl;R2Wis H, methoxy, or methyl;R2Xand R2yare each independently -H, F, Cl, methyl or methoxy; and m is 0-2.

[0086] In some embodiments, provided is a compound of Formula (B):or a pharmaceutically acceptable salt thereof, whereinY2ais -N- or -CH-;R3is H, methyl or ethyl; each R6is independently methyl, F, Cl, or methoxy;R8is H or methyl;R2Wis H or methyl;R2Xand R2yare each independently -H, F, Cl, methyl or methoxy; and m is 0-2.

[0087] In some embodiments, provided is a compound of Formula (C):29MOFO-359177620.18314352000740 or a pharmaceutically acceptable salt thereof, wherein ring X is a 5-membered heteroaryl;Y3aand Y3bare independently -N-, or -C(R3y)-;R2and R3are independently H or alkyl; each R6is independently methyl, F, Cl, or methoxy;R8is H or methyl;R3Xand R3yare each independently H, F, Cl, methyl, hydroxyl, or methoxy; and m is 0-2.

[0088] In some embodiments, Y3aand Y3bare independently -N-, -C(H)-, or -C(F)-.

[0089] In some embodiments, ring X is triazolyl. In some embodiments, ring X is triazolyl or pyrazolyl. In some embodiments, R3xis H, -OMe, or -OH. In some embodiments, R3X-OMe. In some embodiments, R3xis H. In some embodiments, m is 1, and R6is methyl or F. In some embodiments, R8is H. In certain embodiments, R2is H and R3is methyl. In certain embodiments, R6is F and m is 1. In certain variations, m is 0.

[0090] In some embodiments, provided is a compound of Formula (D) or (E):or a pharmaceutically acceptable salt thereof, wherein ring Y is phenyl, or heteroaryl, wherein each ring Y is optionally substituted with one or two R4X;Ydis selected from -N-, -CH-, and -C(R4y)-;R2and R3are independently H or methyl; each R4Xis independently selected from cyano, methyl, F, Cl, oxo, hydroxyl, and methoxy; andR4yis cyano, F or methyl.

[0091] In some embodiments, provided is a compound of Formula (Fl) or (F2):30MOFO-359177620.18314352000740or a pharmaceutically acceptable salt thereof, whereinY6ais -N- or -CH-;R6Wis H, hydroxyl, methoxy, or methyl;R6X, R6y, and R6zare each independently H, hydroxyl, or methoxy;R3is H or methyl; each R6is independently methyl, F, or methoxy;R8is H or methyl; and m is 0-2.

[0092] In some embodiments, provided is a compound of Formula (Gl) or (G2):or a pharmaceutically acceptable salt thereof, wherein Y5ais -N-, or -CH-; each Y5bis independently -O- or -CH2-, wherein at least one Y5bis -O-;Q is a bond or is -CH2-;R5Wis H, hydroxyl, or methoxy; each R5Xis independently H, F, or methyl;R3is H or methyl; each R6is independently methyl, F, or methoxy;R8is H or methyl; and m is 0-2.

[0093] In certain embodiments of Formula (Gl) or (G2), both R5xare H, both R5xare F, or both R5Xare methyl.31MOFO-359177620.18314352000740

[0094] In some embodiments, the moiety representedIn some embodiments, the moiety representedsome embodiments, the moiety represented

[0095] In some embodiments, the moiety represented byorIn some embodiments, the moiety represented byIn some embodiments, the moiety represented by

[0096] It should be understood that “haloalkoxy” includes “alkoxy substituted with halo.”

[0097] It should be understood that “haloalkyl” includes “alkyl substituted with halo.”

[0098] It should be understood that “alkyl substituted with hydroxyl” includes -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, and -CH2CH(CH3)OH.

[0099] It should be understood that “alkoxy substituted with hydroxy” includes -OCH2CH2OH.

[0100] It should be understood that “alkyl substituted with alkoxy” includes -CH2OCH3.

[0101] It should be understood that “alkoxy substituted with aryl” includes -O-CH2- phenyl.

[0102] It should be understood that “alkoxy substituted with alkoxy” includes -OCH2CH2OCH3.32MOFO-359177620.18314352000740

[0103] It should be understood that “alkoxy substituted with heteroaryl” includes -O- CH2-pyrazolyl.

[0104] In some embodiments, the compound of formula (I) is a compound of formula (I- A), (I-B), (I-C), (1-1), (1-2), (1-3), (1-4), (1-5), (1-6), (Al), (A2), (B), (C), (D), (E), (Fl), (F2), (Gl), or (G2), or a pharmaceutically acceptable salt thereof.

[0105] In some aspects, provided is a compound selected from a compound of Table 1 below, or a pharmaceutically acceptable salt thereof, including any isomers and tautomers thereof. In some variations of the foregoing compounds (e.g., in Table 1), the compounds are in salt form, such as hydrochloride (HC1) or trifluoroacetate salt.Table 1. Exemplary Compounds33MOFO-359177620.1831435200074034MOFO-359177620.1831435200074035MOFO-359177620.1831435200074036MOFO-359177620.18314352000740MOFO-359177620.1831435200074038MOFO-359177620.1831435200074039MOFO-359177620.1831435200074040MOFO-359177620.1831435200074041MOFO-359177620.1831435200074042MOFO-359177620.1831435200074043MOFO-359177620.1831435200074044MOFO-3591776204831435200074045MOFO-359177620.1831435200074046MOFO-359177620.1831435200074047MOFO-359177620.1831435200074048MOFO-359177620.1831435200074049MOFO-359177620.1831435200074050MOFO-359177620.1831435200074051MOFO-359177620.1831435200074052MOFO-359177620.1831435200074053MOFO-359177620.18314352000740

[0106] The term “pharmaceutically acceptable salts” includes salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. In some embodiments, the salt is a hydrochloride (HC1) or trifluoroacetate salt.Preparation of Compounds

[0107] The compounds described herein may be prepared in accordance with the general synthetic schemes set forth below.

[0108] Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith and March, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978).

[0109] Compounds as described herein can be purified by any purification protocol known in the art, including chromatography, such as HPLC, preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. In certain embodiments, the disclosed compounds are purified via silica gel and / or alumina chromatography. See, e.g., Introduction to Modem Liquid Chromatography, 2nd Edition, ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, ed E. Stahl, Springer-Verlag, New York, 1969.

[0110] During any of the processes for preparation of the subject compounds, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in “Methoden der organischen Chemie”, Houben-Weyl, 4th edition, Vol. 15 / 1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide, Proteine”, Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and / or in Jochen54MOFO-359177620.18314352000740Lehmann, “Chemie der Kohlenhydrate: Monosaccharide and Derivate”, Georg Thieme Verlag, Stuttgart 1974. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.[OHl] The subject compounds, including compounds that are not commercially available, can be synthesized via a variety of different synthetic routes using commercially available starting materials and / or starting materials prepared by conventional synthetic methods. A variety of examples of synthetic routes that can be used to synthesize the compounds disclosed herein are described in the schemes below.

[0112] The starting materials and reagents employed in the schemes below may be obtained commercially or through conventional techniques. Some examples of the Key Amine Intermediate in one or more of the schemes below can be purchased or alternatively generated as in literature, such as Y.-K. Zhang et al Bioorganic & Medicinal Chemistry Letters (2016), 26(13), 3182-3186; C.Z. Ding et al Bioorganic & Medicinal Chemistry Letters (2010), 20(24), 7317-7322; T. Akama et al ACS Infectious Diseases (2020), 6(2), 173-179, and Tomasz Glinka et al W02012109164. The schemes below provide examples of methods to generate the compounds of the present disclosure where the exact steps and materials will depend on the functional groups present. The selection of the starting materials, reagent, substrates, base, protecting group, solvent and leaving group are known to one of ordinary skilled in the art.55MOFO-359177620.18314352000740Scheme 1

[0113] It should be understood that for the formulae described in Scheme 1 above, P is a protecting group; X is OTf, Br or I; L is a suitable leaving group, such as X or OMs; and R1, R2, R3, R4, R5, R6, R7, R8, m, n, and q are as defined herein.56MOFO-359177620.18314352000740

[0114] One skilled in the art will understand that depending on n and the substituents, bromination, a non-limiting example is using bromine, or radial bromination, a non-limiting example with azobisisobutyronitrile and N-bromosuccinimide, can incorporate a bromine. The incorporated bromine can then be converted to a nitrile by nucleophilic displacement, a non-limiting example is using potassium cyanide, or by coupling, a non-limiting example is using palladium and iron cyanide or zinc cyanide. One can incorporate the boronic ester by using palladium coupling, with a non-limiting example using bis(pinacolato)diboron. The boron heterocycle, either a benzoxaborol-l-ol or benzoxaborinin-l-ol, can be formed with reduction of the ester, a methyl ester is shown as a non-limiting example and can be reduced with lithium borohydride for example. Alternatively, the ester can be alkylated with R7or R8, and then reduced to form the boron heterocycle or alkylation with both R7and R8can occur to form the boron heterocycle. The alkylation with R7or R8can use the corresponding Grignard reagent or the lithium anion, as two non-limiting examples. Reduction of the nitrile, with as a non-limiting example Raney Nickel under a hydrogen atmosphere, will generate the Key Amine Intermediate. Conversion of the Key Amine Intermediate to Formula (I) can be achieved with many different approaches that can be envisioned by one skilled in the art.Some examples of possible sequences of reactions is in Scheme 1. For example, when R4= H a direct reaction of the amine of the Key Amine Intermediate with R5bound to a leaving group (L) in the presence of a base, a non-limiting example of which is triethylamine. When R4is not H or the chemistry does not allow one step conversion to Formula I a protecting group (P) can be utilized. A non-limiting example of a protecting group for the nitrogen is tert-butyl carbonyl (Boc). After the nitrogen is protected the increased acidity of the proton on the nitrogen can be utilized for alternate chemistry. Such chemistry is coupling, such as Pd coupling, or substitution with R5-L. After deprotection using known chemistry for the nitrogen protection group the Formula I target with R4= H can be generated. Alternatively, when R4is alkyl the protecting group will allow introduction of the R4by alkylation using base, some non-limiting examples are sodium hydride or potassium tert-butoxide, followed by treatment with R4-L. To incorporate R5the protection group will require removal followed by a substitution reaction with R5-L in the presence of a base, such as triethylamine or N,N- diisopropylethylamine, to generate the compounds of Formula I.57MOFO-359177620.18314352000740Scheme 2For R4and R5together form a heteraromatic, subtituted or unsubstitutedKey Amine Intermediate Formula (I)

[0115] It should be understood that for the formulae described in Scheme 2 above, R1, R2, R3, R4, R5, R6, R7, R8, m, n, and q are as defined herein.

[0116] The present disclosure also includes R4, R5and the nitrogen to which they are attached being part of a heteroaromatic system, which is optionally substituted. One skilled in the art can anticipate multiple different synthetic sequences to generate such a system and Scheme 2 (above) and Scheme 3 (below) are non-limiting examples of methods to construct the heteroaromatic including R4, R5and N. Scheme 2 utilized the Key Amine Intermediate in Scheme 1 and an annulation reaction with an appropriate difunctional compound. One such non-limiting example is to react the Key Amine Intermediate with a 1,4-dicarbonyl system, such as (2 -methoxy carbonylphenyl)acetaldehyde as an non-exclusive example, to generate the heteroaromatic system after the annulation and any required additional reactions such as elimination. Depending on the substrate, after annulation other chemistry steps might be required if aromatization does not occur spontaneously. Two non-limiting examples of other chemistry that might be required are elimination and oxidation to form the heteroaromatic system. A non-limiting example to induce aromatization by elimination is to contact the compound with an acid like sulfuric acid. A non-limiting example to induce aromatization by oxidation is to contact the compound with a suitable reagent like 2,3-dichloro-5,6- dicyanobenzoquinone (DDQ).58MOFO-359177620.18314352000740Scheme 3R4and R5form a triazole, either substituted or unsubstitutedReduction or alkylation or combination thereof

[0117] It should be understood that for the formulae described in Scheme 3 above, Ac is an acetyl group; L is a suitable leaving group, such as MsO, Cl, Br, and I; and R1, R2, R3, R4, R5, R6, R7, R8, m, n, and q are as defined herein.

[0118] Scheme 3 provides an alternate method to generate a heteroaromatic system that includes R4, R5and the nitrogen to which they are attached. One skilled in the art can envision alternate sequences, reagent and chemistries depending on the precise compound being synthesized. A bromo intermediate, such as that generated in Scheme 1, can be converted to an acetate ester, such as by displacement with acetate, for example with potassium acetate. Palladium coupling will introduce the boronic ester, that can be R1as59MOFO-359177620.18314352000740 described herein or a pinacol ester or another variation. Boron heterocycle formation by reducing the ester or alkylation as described above for Scheme 1 will generate the desired 5- or 6-membered boron heterocycle with R7and R8as described herein. That chemistry will also cleave the acetate ester generating an alcohol. That alcohol can be converted to a leaving group, such as a methanesulfonate ester using methansulfonyl chloride and a suitable base such as triethylamine, and then displaced with an azide source, such as sodium azide. There are multiple other possible reagents and methods to convert an alcohol to an azide and another direct, non-limiting example is using diphenylphosphoryl azide with Mitsunobu conditions or with base depending on the alcohol reactivity. Formation of the heteroaromatic group with or without substitution proceeds with 'Click Chemistry' that is known to one skilled in the art. This chemistry uses copper catalysis that couples the azide to an alkyne to generate a triazole. For Scheme 3, R4, R5, and the nitrogen they are attached to are part of a substituted or unsubstituted triazole heteroaromatic system.

[0119] Schemes 1 to 3 are meant to be non-limiting examples only, and one of ordinary skill in the art will understand that alternate reagents, solvents, order of reactions or starting materials can be used to make compounds of the present disclosure and / or other intermediates or compounds contained herein.Pharmaceutical Compositions

[0120] In certain aspects, provided is a pharmaceutical composition comprising any of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient. Such compounds include the compounds of Formula (I), as well as the compounds of Table 1, or pharmaceutically acceptable salts thereof. Such compounds include the compounds of Formula (I), (I-A), (I-B), (I-C), (1-1), (1-2), (1-3), (1-4), (1-5), (1-6), (Al), (A2), (B), (C), (D), (E), (Fl), (F2), (Gl), or (G2) and any variations thereof, as well as the compounds of Table 1, or pharmaceutically acceptable salts thereof.

[0121] The term “pharmaceutically acceptable excipient” infers that the excipient is not biologically or otherwise undesirable; for example, the material may be added to a pharmaceutical composition and administered to a subject without causing significant undesirable effects.

[0122] The compounds or pharmaceutical compositions of the present disclosure may be administered by various methods including, for example, oral, rectal, buccal, intranasal, and60MOFO-359177620.18314352000740 transdermal routes. In certain embodiments, the pharmaceutical composition may be administered intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0123] Compounds and pharmaceutical compositions of the present disclosure may be administered to individuals in any form of generally accepted oral compositions (for example, tablets, coated tablets, gel capsules in a hard or in soft shell, emulsions or suspensions).Methods of Treatment

[0124] In certain aspects, provided is a method of treating a disease, disorder or condition in a subject in need thereof, comprising administering a therapeutically effective amount of any of the compounds, or pharmaceutically acceptable salts thereof, or compositions, including pharmaceutical compositions, described herein. In some variations, the method treats a disease, disorder or condition mediated by inhibition of ENPP1. Such compounds include the compounds of Formula (I), as well as the compounds of Table 1 and in the Examples, or pharmaceutically acceptable salts thereof. In some embodiments, the subject is a human. Such compounds include the compounds of Formula (I- A), (I-B), (I-C), (1-1), (1-2), (1-3), (1-4), (1-5), (1-6), (Al), (A2), (B), (C), (D), (E), (Fl), (F2), (Gl), or (G2) and any variations thereof, as well as the compounds of Table 1 and in the Examples, or pharmaceutically acceptable salts thereof.

[0125] In some variations of the foregoing, the disease, disorder or condition is cancer. In a certain variation, the cancer is a solid tumor. In other variations, the cancer is cervical cancer, colorectal cancer, lung cancer, prostate cancer, esophageal cancer, liver cancer, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, or breast cancer. In other variations of the foregoing, the disease, disorder or condition is an inflammatory disease, a metabolic disease, or a microbial infection, e.g., mediated by ENPP1. In other variations, the inflammatory disease is an autoimmune disease or an autoinflammatory disease. In certain embodiments, the autoimmune disease is systemic lupus erythematosus (SLE). In other variations of the foregoing, the disease, disorder or condition is hypophosphatasia (HPP). HPP is a rare inherited metabolic disorder that causes weak, soft bones and teeth due to a lack of the enzyme alkaline phosphatase (ALP). In one variation, the61MOFO-359177620.18314352000740 methods provided herein may treat any combinations of the diseases, disorders and condition described.

[0126] In some variations, the term “therapeutically effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation, such as those described elsewhere herein, that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof. It is to be understood that an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be needed to achieve the desired treatment endpoint.

[0127] The specific safe and effective amount or therapeutically effective amount will vary with such factors as the particular condition being treated, the physical condition of the subject, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives.

[0128] The terms “treating” or “treatment”, as used herein, refer to a method or procedure for obtaining beneficial or desired results — for example, clinical results. Beneficial or desired results may include: (1) alleviating one or more symptoms caused by or associated with a disease, disorder, or condition; (2) reducing the extent of the disease, disorder, or condition; (3) slowing or stopping the development or progression of one or more symptoms caused by or associated with the disease, disorder, or condition (for example, stabilizing the disease, disorder, or condition); and (4) relieving the disease, for example, by causing the regression of one or more clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying or stopping the progression of the disease, increasing the quality of life, and / or prolonging survival rates).

[0129] In some embodiments, provided herein is the use of a compound or a pharmaceutical composition, as described elsewhere herein, in any of the methods described elsewhere herein. In other embodiments, provided herein is a compound or a pharmaceutical composition, as described elsewhere herein, for use in the manufacture of a medicament for use in any of the methods described elsewhere herein. In other embodiments, provided herein is a compound or a pharmaceutical composition, as described elsewhere herein, for use in any of the methods described herein.

[0130] In certain aspects, articles of manufacture are also provided herein, wherein the article of manufacture comprises any of the compounds, or pharmaceutically acceptable salts62MOFO-359177620.18314352000740 thereof, or compositions, including pharmaceutical compositions, described herein, in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.

[0131] The present disclosure further provides kits for carrying out the methods of the invention. The kits may comprise any of the compounds, or pharmaceutically acceptable salts thereof, or compositions, including pharmaceutical compositions, described herein, and suitable packaging. The kits may comprise one or more containers comprising any compound described herein. In one aspect, a kit includes a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a label and / or instructions for use of the compound in the treatment of a disease or condition described herein. The kits may comprise a unit dosage form of the compound.

[0132] In certain aspects, provided herein are articles of manufacturing (such as kits), comprising: (i) an effective amount of any of the compounds, or pharmaceutically acceptable salts thereof, or compositions, including pharmaceutical compositions, described herein; and (ii) instructions for use in treating a disease or condition described herein.ENUMERATED EMBODIMENTS

[0133] The following Enumerated Embodiments are representative of some aspects of the invention.

[0134] Al. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is H or alkyl; n is 1-3; each of R2and R3is independently H or alkyl;R4is H or alkyl;R5is a heteroaromatic ring system that is fused or unfused, optionally substituted with alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, NRaRb, and -C(=O)NRaRb, wherein each Ra63MOFO-359177620.18314352000740 and Rbis independently H or alkyl; or R4and R5are taken together with the nitrogen atom to which they are attached to form optionally substituted heteroaromatic ring system that is fused or unfused;R6is alkyl, haloalkyl, halo, or alkoxy; m is 0-3; q is 0 or 1; and each of R7and R8is independently H or alkyl; or R7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl.

[0135] A2. The compound of Embodiment Al, wherein the compound is a compound ofFormula (I- A):or a pharmaceutically acceptable salt thereof, wherein R1, n, R2, R3, R4, R5, R6, R7, R8, m and q are as defined for Formula (I) above.

[0136] A3. The compound of Embodiment Al, wherein the compound is a compound ofFormula (I-B):or a pharmaceutically acceptable salt thereof, wherein R1, n, R2, R3, R4, R5, R6, R7, R8, m and q are as defined for Formula (I) above.

[0137] A4. The compound of any one of Embodiments Al to A3, or a pharmaceutically acceptable salt thereof, wherein R5is a heteroaromatic ring system containing 1-4 nitrogen atoms, or R4and R5are taken together with the nitrogen atom to which they are attached to form a heteroaromatic ring system containing 1-4 nitrogen atoms.64MOFO-359177620.18314352000740

[0138] A5. The compound of any of Embodiments Al to A4, or a pharmaceutically acceptable salt thereof, wherein R5is a fused heteroaromatic ring system represented by the formula:wherein:Xla, X2a, and X3aare each independently -CH- or -N-; and ring A is a 5-6 membered ring that is taken together with the ring bearing Xla, X2a, and X3ato form the fused heteroaromatic ring system; wherein the heteroaromatic ring system is optionally substituted with one or more substituents selected from the group consisting of alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, NRaRb, and -C(=O)NRaRb, wherein each Raand Rbis independently H or alkyl.

[0139] A6. The compound of Embodiment A4 or A5, or a pharmaceutically acceptable salt thereof, wherein R5is:each optionally substituted with one or more substituents selected from the group consisting of alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, NRaRb, and -C(=O)NRaRb, wherein each Raand Rbis independently H or alkyl.

[0140] A7. The compound of Embodiment A5 or A6, or a pharmaceutically acceptable salt thereof, wherein R5is a heteroaromatic ring system, substituted with 1 or 2 substituents.

[0141] A8. The compound of any one of Embodiments Al to A4, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form optionally substituted heteroaromatic ring system that is fused or unfused.65MOFO-359177620.18314352000740

[0142] A9. The compound of any one of Embodiments Al to A4, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form a heteroaromatic ring system that is fused or unfused, substituted with alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, NRaRb, and -C(=O)NRaRb, wherein each Raand Rbis independently H or alkyl.

[0143] A10. The compound of any one of Embodiments Al to A4, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form a heteroaromatic ring system represented by the formula:wherein: r is 0 or 1;Xlb, X2b, and X3bare each independently -CH- or -N-; and ring B is a 5-6 membered ring that is taken together with the ring bearing Xlb, X2b, and X3bto form an optionally substituted fused heteroaromatic ring system.

[0144] Al l. The compound of Embodiment A10, or a pharmaceutically acceptable salt thereof, wherein the fused heteroaromatic ring system is optionally substituted with one or more substituents selected from the group consisting of alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, NRaRb, and -C(=O)NRaRb, wherein each Raand Rbis independently H or alkyl.

[0145] A12. The compound of any one of Embodiments Al to A4, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to formwhich is optionally substituted.

[0146] A13. The compound of any of Embodiments Al to A3, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which66MOFO-359177620.18314352000740 they are attached to form triazolyl substituted with Rw, alkyl-Rw, alkyl-O-Rw, or alkyl substituted with amino and / or alkylnoate, wherein Rwis optionally substituted aryl, heteroaryl, heterocyclyl, or cycloalkyl .

[0147] A14. The compound of Embodiment A13, or a pharmaceutically acceptable salt thereof, wherein Rwis pyridyl, pyrazolyl, phenyl, or cycloalkyl, wherein each is optionally substituted with alkyl, alkoxy, haloalkyl, halo.

[0148] Al 5. The compound of any one of Embodiments Al to A7, or a pharmaceutically acceptable salt thereof, wherein R4is H.

[0149] A16. The compound of any one of Embodiments Al to A1519, or a pharmaceutically acceptable salt thereof, wherein R1is H.

[0150] Al 7. The compound of any one of Embodiments Al to Al 6, or a pharmaceutically acceptable salt thereof, wherein R2is H, and R3is H or Ci-4 alkyl.

[0151] A18. The compound of Embodiment 17, or a pharmaceutically acceptable salt thereof, wherein each of R2and R3is H.

[0152] Al 9. The compound of any one of Embodiments Al to Al 8, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0153] A20. The compound of any one of Embodiments Al to Al 9, wherein m is 1 andR6is methyl or F.

[0154] A21. The compound of any one of Embodiments Al to A19, or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0155] A22. The compound of any one of Embodiments Al to A21, or a pharmaceutically acceptable salt thereof, wherein q is 0.

[0156] A23. The compound of any one of Embodiments Al to A21, or a pharmaceutically acceptable salt thereof, wherein q is 1.

[0157] A24. The compound of any one of Embodiments Al to A23, or a pharmaceutically acceptable salt thereof, wherein each of R7and R8is independently H or alkyl.67MOFO-359177620.18314352000740

[0158] A25. The compound of Embodiment A24, or a pharmaceutically acceptable salt thereof, wherein each R7and R8is H.

[0159] A26. The compound of any one of Embodiments Al to A23, or a pharmaceutically acceptable salt thereof, wherein R7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl.

[0160] A27. The compound of Embodiment A26, wherein the cycloalkyl is cyclopropyl or cyclobutyl.

[0161] Bl. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is H or alkyl;R2and R3are each independently H or alkyl;R4is H or alkyl;R5is a heteroaromatic ring system that is fused or unfused, optionally substituted with one or more groups independently selected from the group consisting of alkoxy, cyano, alkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, heteroaryl, and -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; alkyl, in each instance, is optionally substituted with halo or alkoxy;each Raand Rbis independently H or alkyl; orR4and R5are taken together with the nitrogen atom to which they are attached to form: an optionally substituted heteroaromatic ring system that is fused or unfused, wherein the ring containing R4, N, and R5is aromatic; or an optionally substituted ring system of formula (DI) or (D2):68MOFO-359177620.18314352000740each R6is independently alkyl, haloalkyl, halo, cyano, haloalkoxy, or alkoxy;R7and R8are each independently H or alkyl; orR7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl;Z is -CH- or -N-; ring S is heteroaryl or phenyl; m is 0-3; n is 1-3; and q is O or l.

[0162] B2. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is H or alkyl;R2and R3are each independently H or alkyl;R4is H or alkyl;R5is a heteroaromatic ring system that is fused or unfused, optionally substituted with one or more groups independently selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, - C(=O)NRaRb, and -C(=O)ORa, wherein each Raand Rbis independently H or alkyl; orR4and R5are taken together with the nitrogen atom to which they are attached to form: an optionally substituted heteroaromatic ring system that is fused or unfused, wherein the point of attachment to -CR2R3- is a heteroaryl ring; or69MOFO-359177620.18314352000740 an optionally substituted ring system of formula (DI) or (D2):each R6is independently alkyl, haloalkyl, halo, cyano, or alkoxy;R7and R8are each independently H or alkyl; orR7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl;Z is -CH- or -N-; ring S is heteroaryl or phenyl; m is 0-3; n is 1-3; and q is O or l.

[0163] B3. The compound of Embodiment Bl or B2, or a pharmaceutically acceptable salt thereof, wherein:R4is H or alkyl; andR5is a heteroaromatic ring system that is fused or unfused, optionally substituted with alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, NRaRb, or - C(=O)NRaRb, wherein each Raand Rbis independently H or alkyl; orR4and R5are taken together with the nitrogen atom to which they are attached to form an optionally substituted heteroaromatic ring system that is fused or unfused, wherein the ring containing R4, N, and R5is aromatic; orR4is H or alkyl; andR5is a heteroaromatic ring system that is fused or unfused, optionally substituted with alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, NRaRb, or - C(=O)NRaRb, wherein each Raand Rbis independently H or alkyl; orR4and R5are taken together with the nitrogen atom to which they are attached to form an optionally substituted heteroaromatic ring system that is fused or unfused, wherein the point of attachment to -CR2R3- is a heteroaryl ring.70MOFO-359177620.18314352000740

[0164] B4. The compound of Embodiments B1-B3, wherein the compound is a compound of Formula (I-A) or (I-B):or a pharmaceutically acceptable salt thereof, wherein R1, n, R2, R3, R4, R5, R6, R7, R8, m and q are as defined for Formula (I) above.

[0165] B5. The compound of any one of Embodiments Bl to B4, or a pharmaceutically acceptable salt thereof, wherein R1is H.

[0166] B6. The compound of any one of Embodiments Bl to B5, or a pharmaceutically acceptable salt thereof, wherein R2is H, and R3is H or alkyl.

[0167] B7. The compound of Embodiment B6, or a pharmaceutically acceptable salt thereof, wherein R2and R3are hydrogen.

[0168] B8. The compound of any one of Embodiments Bl to B7, or a pharmaceutically acceptable salt thereof, wherein R4is H.

[0169] B9. The compound of any one of Embodiments Bl to B8, or a pharmaceutically acceptable salt thereof, wherein R5is a heteroaromatic ring system containing 1-4 nitrogen atoms, or R4and R5are taken together with the nitrogen atom to which they are attached to form a heteroaromatic ring system containing 1-4 nitrogen atoms.

[0170] B10. The compound of any one of Embodiments Bl to B9, or a pharmaceutically acceptable salt thereof, wherein R5is a fused heteroaromatic ring system represented by the formula:wherein:71MOFO-359177620.18314352000740Xla, X2a, and X3aare each independently -CH- or -N-, wherein at least one of Xla, X2a, and X3ais -N-; and ring A is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, or 6-membered heterocyclyl, wherein the fused heteroaromatic ring system is optionally substituted with one or more substituents selected from the group consisting of alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, and -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; and each Raand Rbis independently H or alkyl; or ring A is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, or 6-membered heterocyclyl, wherein the fused heteroaromatic ring system is optionally substituted with one or more substituents selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, and -C(=O)ORa, and wherein each Raand Rbis independently H or alkyl.

[0171] Embodiment B 11. The compound of any one of Embodiments Bl to B9, or a72MOFO-359177620.18314352000740each optionally substituted with one or more substituents selected from the group consisting of alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, or -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; and each Raand Rbis independently H or alkyl; or, wherein R5is:73MOFO-359177620.18314352000740optionally substituted with one or more substituents selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, or - C(=O)ORa, wherein each Raand Rbis independently H or alkyl.

[0172] B12. The compound of any one of Embodiments Bl to Bl 1, or a pharmaceutically acceptable salt thereof, wherein R5is a fused heteroaromatic ring system, substituted with 1 or 2 substituents.

[0173] B13. The compound of any one of Embodiments Bl to B7, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form an optionally substituted heteroaromatic ring system that is fused or unfused, wherein the ring containing R4, N, and R5is aromatic; or, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form an optionally substituted heteroaromatic ring system that is fused or unfused, wherein the point of attachment to -CR2R3- is a heteroaryl ring.

[0174] B14. The compound of any one of Embodiments Bl to B7 and B 13, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form a heteroaromatic ring system that is fused or unfused, optionally substituted with one or more substituents selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, NRaRb, - C(=O)NRaRb, and -COORa, wherein each Raand Rbis independently H or alkyl.

[0175] Bl 5. The compound of any one of Embodiments Bl to B7, B13 and Bl 4, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form an optionally substituted fused heteroaromatic ring system represented by the formula:74MOFO-359177620.18314352000740 wherein: r is 0 or 1;Xlb, X2b, and X3bare each independently -CH- or -N-; and ring B is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, or 6-membered heterocyclyl.

[0176] B16. The compound of Embodiment 15, or a pharmaceutically acceptable salt thereof, wherein the fused heteroaromatic ring system is optionally substituted with one or more substituents selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, and -COORa, wherein each Raand Rbis independently H or alkyl.

[0177] B17. The compound of any one of Embodiments Bl to B7 and B 13 to Bl 6, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the

[0178] Bl 8. The compound of any one of Embodiments Bl to B7 and Bl 3, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form a 5 -membered heteroaromatic ring system containing 1 to 3 nitrogen atoms, wherein the 5-membered heteroaromatic ring system is: optionally substituted with Ci-4 alkyl; and substituted with one or more:(i) Rw,(ii) alkyl substituted with Rw;(iii) alkyl substituted with -O-Rw; or(iv) alkyl substituted with amino, -C(O)ORa, or both, wherein Rwis optionally substituted fused or unfused aryl, heteroaryl, heterocyclyl, or cycloalkyl, and Rais H or alkyl; or75MOFO-359177620.18314352000740 wherein R4and R5are taken together with the nitrogen atom to which they are attached to form a 5-membered heteroaryl containing 1 to 3 nitrogen atoms, wherein the 5-membered heteroaryl is: optionally substituted with C1-4 alkyl, and substituted with one or more:(i) Rw;(ii) alkyl substituted with Rw;(iii) alkyl substituted with O-Rw; or(iv) alkyl substituted with amino, -C(O)ORa, or both, wherein Rwis optionally substituted fused or unfused heteroaromatic ring system, aryl, or cycloalkyl, and Rais H or alkyl.

[0179] B19. The compound of Embodiment Bl 8, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form: thiazolyl, oxazolyl, pyrazolyl, imidazolyl, or triazolyl, which is substituted with (i) an Rw; (ii) alkyl substituted with Rw; or (iii) alkyl substituted with -O-Rw, wherein Rwis optionally substituted fused or unfused aryl, heteroaromatic ring system, heterocyclyl, or cycloalkyl; or thiazolyl, oxazolyl, pyrazolyl, imidazolyl, or triazolyl, which is substituted with: (i) an Rw; (ii) alkyl substituted with Rw; or (iii) alkyl substituted with -O-Rw, wherein Rwis optionally substituted fused or unfused aryl, heteroaryl, heterocyclyl, or cycloalkyl.

[0180] B20. The compound of Embodiment B18 or Bl 9, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form: triazolyl substituted with: (i) Rw; (ii) alkyl substituted with Rw; or (iii) alkyl substituted with -O-Rw, wherein Rwis optionally substituted fused or unfused aryl, heteroaromatic ring system, heterocyclyl, or cycloalkyl; or triazolyl or pyrazolyl substituted with: (i) Rw; (ii) alkyl substituted with Rw; or (iii) alkyl substituted with -O-Rw, wherein Rwis optionally substituted fused or unfused aryl, heteroaryl, heterocyclyl, or cycloalkyl.

[0181] B21. The compound of any one of Embodiments B18 to B20, or a pharmaceutically acceptable salt thereof, wherein Rwis:76MOFO-359177620.18314352000740 pyridyl, thiazolyl, pyrimidinyl, pyrazolyl, phenyl, or cycloalkyl, wherein each is optionally substituted with alkyl, alkoxy, haloalkyl, halo, or cyano; or pyridyl, pyrimidinyl, pyrazolyl, phenyl, or cycloalkyl, wherein each is optionally substituted with alkyl, alkoxy, haloalkyl, halo, or cyano; or pyridyl, pyrimidinyl, phenyl, or cycloalkyl, wherein each is optionally substituted with alkyl, alkoxy, haloalkyl, halo, hydroxyl, or cyano.

[0182] B22. The compound of any one of Embodiments B18 to B21, or a pharmaceutically acceptable salt thereof, wherein Rwis: pyridyl, pyrazolyl, or phenyl, wherein each Rwis optionally substituted with one or more alkyl, alkoxy, or halo; or, pyridyl or phenyl, wherein each Rwis optionally substituted with one or more alkyl, alkoxy, or halo; or pyridyl, pyrimidinyl or phenyl, wherein each Rwis optionally substituted with one or more alkyl, alkoxy, or halo.

[0183] B23. The compound of any one of Embodiments B18 to B22, or a pharmaceutically acceptable salt thereof, wherein Rwis pyridyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, and halo.

[0184] B24. The compound of any one of Embodiments B18 to B22, or a pharmaceutically acceptable salt thereof, wherein Rwis: phenyl optionally substituted with one or two substituents independently selected from the group consisting of: alkyl, alkoxy, and halo; or pyrimidinyl optionally substituted with one or two substituents independently selected from the group consisting of: alkyl, alkoxy, and halo.

[0185] B25. The compound of any one of Embodiments Bl to B7, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form an optionally substituted ring system of formula (DI) or (D2):77MOFO-359177620.18314352000740

[0186] B26. The compound of any one of Embodiments Bl to B7 and B25, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form

[0187] B27. The compound of any one of Embodiments Bl to B4, wherein the compound is a compound of Formula (1-1):or a pharmaceutically acceptable salt thereof, wherein: each W is independently -N-, -CH-, or -C(Rw1)-, wherein at least one W is -N-; each Rwlis independently alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, -NRaRb, -C(=O)NRaRb, or -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; or wherein each Rwlis independently alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, - NRaRb, -C(=O)NRaRb, or -C(=O)ORa; and g is 0-4; or,

[0188] B28. The compound of any one of Embodiments Bl to B4, wherein the compound is a compound of Formula (1-2):78MOFO-359177620.18314352000740 or a pharmaceutically acceptable salt thereof, wherein: each W is independently -N-, -CH-, or -C(Rw1)-, wherein at least one W is -N-; ring C is heteroaryl or a ring system of formula (C4), (C5), or (C6):whereinR9is alkyl; each * represents a point of attachment to the ring bearing W, and ring C is optionally substituted with one or more Rwl; each Rwlis independently alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, - NRaRb, -C(=O)NRaRb, or -C(=O)ORa

[0189] B29. The compound of any one of Embodiments, Bl, B2, B3, and B4, wherein the compound is a compound of Formula (1-3):or a pharmaceutically acceptable salt thereof, wherein: each W is independently -N-, -CH-, or -C(Rw1)-, wherein at least one W is -N-;X is -N-, -CH-, -C(Rw1)-, or -S-; ring D is phenyl, heteroaryl, or a ring system of formula (C4), (C5), or (C6):wherein,R9is alkyl; each * represents a point of attachment to the ring bearing W, and ring D is optionally substituted with one or more Rwl;79MOFO-359177620.18314352000740 each Rwlis independently selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, -NRaRb, -C(=O)NRaRb, or -C(=O)ORa; and r is 0 or 1.

[0190] B30. The compound of any one of Embodiments Bl, B2, B3, and B4, wherein the compound is a compound of Formula (1-4):or a pharmaceutically acceptable salt thereof, wherein:X is -N-, -CH-, -C(Rwl), or -S-. ring E is phenyl, or heteroaryl, wherein ring E is optionally substituted with one or more Rwl; each Rwlis independently selected from the group consisting of: alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, or - C(=O)ORa; andRxis H, alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, -NRaRb, - C(=O)NRaRb, or -C(=O)ORa

[0191] B31. The compound of any one of Embodiments Bl, B3, and B4, wherein the compound is a compound of Formula (1-5):or a pharmaceutically acceptable salt thereof, wherein:Y is a bond, alkyl, -alkyl-NRa-alkyl- or -O-alkyl-; ring F is 5-membered heteroaryl that is optionally substituted with one or more Rwl; ring G is phenyl, fused or unfused heterocyclyl, or a fused or unfused heteroaromatic ring system, wherein ring G is optionally substituted with one or more Rwl;80MOFO-359177620.18314352000740 and each Rwlis independently selected from the group consisting of: alkoxy, cyano, alkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, and -C(=O)ORa, wherein alkyl and alkoxy, in each instance, are optionally independently substituted with hydroxyl, methoxy, or halo; or wherein the compound is a compound of Formula (1-5):or a pharmaceutically acceptable salt thereof, wherein:Y is a bond, alkyl, -alkyl-NRa-alkyl- or -O-alkyl-; ring F is 5-membered, unfused heteroaryl that is optionally substituted with one or more Rwl; ring G is phenyl, heterocyclyl, or a fused or unfused heteroaryl, wherein ring G is optionally substituted with one or more Rwl; and each Rwlis independently selected from the group consisting of: alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, and - C(=O)ORa.

[0192] B32. The compound of Embodiment B31, or a pharmaceutically acceptable salt thereof, wherein Y is a bond.

[0193] B33. The compound of Embodiment B31 or B32, or a pharmaceutically acceptable salt thereof, wherein ring G is phenyl, fused or unfused heterocyclyl, or fused or unfused heteroaryl, wherein ring G is optionally substituted with one or more Rwl.

[0194] B34. The compound of any one of Embodiments B31-B33, or a pharmaceutically acceptable salt thereof, wherein ring81MOFO-359177620.18314352000740each optionally substituted with one or two Rwl, wherein each Rwlis selected from the group consisting of alkoxy, cyano, alkyl, halo, and hydroxyl, wherein alkoxy and alkyl, in each instance, are optionally independently substituted with hydroxyl, methoxy, or halo.

[0195] B35. The compound of any one of Embodiments B31-B34, or a pharmaceutically acceptable salt thereof, wherein each Rwlis selected from the group consisting of methoxy, ethoxy, -CH2CH2OH, -OCH2CH2OCH3, -OCHF2, F, methyl, or ethyl.

[0196] B36. The compound of Embodiment B31, or a pharmaceutically acceptable salt thereof, wherein ring F is triazolyl, pyrazolyl, or imidazolyl optionally substituted with one Rwl.

[0197] B37. The compound of Embodiment B36, or a pharmaceutically acceptable salt thereof, wherein Rwlis methyl.

[0198] B38. The compound of any one of Embodiments Bl to B37, or a pharmaceutically acceptable salt thereof, wherein each R6is independently Ci-ealkyl, Ci-ehaloalkyl, halo, or Ci-ealkoxy.

[0199] B39. The compound of any one of Embodiments Bl to B38, or a pharmaceutically acceptable salt thereof, wherein R7and R8are each independently H or C1-6 alkyl; or R7and R8are taken together with the carbon atom to which they are attached to form Cs-ecycloalkyl.

[0200] B40. The compound of any one of Embodiments Bl to B39, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0201] B41. The compound of any one of Embodiments Bl to B39, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0202] B42. The compound of any one of Embodiments Bl to B41, or a pharmaceutically acceptable salt thereof, wherein m is 1 and R6is methyl, methoxy, or F.

[0203] B43. The compound of any one of Embodiments Bl to B41, or a pharmaceutically acceptable salt thereof, wherein m is 0.82MOFO-359177620.18314352000740

[0204] B44. The compound of any one of Embodiments Bl to B43, or a pharmaceutically acceptable salt thereof, wherein q is 0.

[0205] B45. The compound of any one of Embodiments Bl to B43, or a pharmaceutically acceptable salt thereof, wherein q is 1.

[0206] B46. The compound of any one of Embodiments Bl to B45, or a pharmaceutically acceptable salt thereof, wherein each of R7and R8is independently H or alkyl.

[0207] B47. The compound of Embodiment B46, or a pharmaceutically acceptable salt thereof, wherein R7and R8are H.

[0208] B48. The compound of any one of Embodiments Bl to B45, or a pharmaceutically acceptable salt thereof, wherein R7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl.

[0209] B49. The compound of Embodiment B48, wherein the cycloalkyl is cyclopropyl or cyclobutyl.

[0210] B50. The compound of any one of Embodiments Bl to B12, B27, B28, B29 andB38 to B49, or a pharmaceutically acceptable salt thereof, wherein the moiety represented by

[0211] B51. The compound of Embodiment Bl or B2, wherein the compound is a compound of Formula (I-C):or a pharmaceutically acceptable salt thereof; andR5is an optionally substituted heteroaromatic ring system that is fused.

[0212] B52. A compound Formula (Al) or (A2):83MOFO-359177620.18314352000740or a pharmaceutically acceptable salt thereof, whereinYlais -N-, -CH- or -C(CN)-;Ylbis -N-, -CH-, or -C(ORlv)-, wherein Rlvis H, methyl or ethyl;Rlwis H, -CF3, alkoxy, alkoxy substituted with phenyl or pyrazolyl, hydroxyl, - C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)OH, -C(=O)OCH3, or methyl;Rlx, Rly, and Rlzare each independently -H, -OH, or methoxy;R3is H, methyl or ethyl; each R6is independently methyl, F, Cl, or methoxy;R8is H or methyl; and m is 0-2; or, a compound Formula (Al) or (A2):or a pharmaceutically acceptable salt thereof, whereinYlais -N-, -CH- or -C(CN)-;Ylbis -N-, -CH-, or -C(ORlv)-, wherein Rlvis H, methyl or ethyl;Rlwis H, -CF3 or methyl;Rlx, Rly, and Rlzare each independently -H, -OH, or methoxy;R3is H, methyl or ethyl; each R6is independently methyl, F, Cl, or methoxy;R8is H or methyl; and m is 0-2.

[0213] B53. A compound of Formula (B):84MOFO-359177620.18314352000740or a pharmaceutically acceptable salt thereof, whereinY2ais -N- or -CH-;R3is H, methyl or ethyl; each R6is independently methyl, F, Cl, or methoxy;R8is H or methyl;R2Wis H or methyl; or R2wis H, methoxy, or methyl;R2Xand R2yare each independently -H, F, Cl, methyl or methoxy; and m is 0-2.

[0214] B54. A compound of Formula (C):or a pharmaceutically acceptable salt thereof, wherein ring X is a 5-membered heteroaromatic ring system that is unfused or 5-membered heteroaryl;Y3aand Y3bare independently -N-, or -C(R3y)-;R2and R3are independently H or alkyl; each R6is independently methyl, F, Cl, or methoxy;R8is H or methyl;R3Xand R3yare each independently H, F, Cl, methyl, hydroxyl or methoxy; and m is 0-2.

[0215] B55. The compound of Embodiment B54, or a pharmaceutically acceptable salt thereof, wherein, ring X is triazolyl; or wherein, ring X is triazolyl or pyrazolyl.

[0216] B56. The compound of Embodiment B54 or B55, or a pharmaceutically acceptable salt thereof, wherein R3xis H, -OMe, or -OH.85MOFO-359177620.18314352000740

[0217] B57. The compound of any one of Embodiments B54 to B56, or a pharmaceutically acceptable salt thereof, wherein R3xis -OMe.

[0218] B58. The compound of any one of Embodiments B54 to B57, or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0219] B59. The compound of any one of Embodiments B54 to B57, or a pharmaceutically acceptable salt thereof, wherein m is 1, and R6is methyl or F.

[0220] B60. The compound of any one of Embodiments B54 to B59, or a pharmaceutically acceptable salt thereof, wherein R8is H.

[0221] B61. A compound of Formula (D) or (E):or a pharmaceutically acceptable salt thereof, wherein ring Y is phenyl, heterocycle or a heteroaryl, and wherein each ring Y is optionally substituted with one or two R4x;Ydis selected from -N-, -CH- and -C(R4y)-;R2and R3are independently H or methyl; each R4Xis independently selected from cyano, methyl, F, Cl, oxo, hydroxyl and methoxy; andR4yis cyano, F or methyl.

[0222] B62. The compound of any one of Embodiments B54 to B61, or a pharmaceutically acceptable salt thereof, wherein the moiety represented by

[0223] B63. A compound of Formula (Fl) or (F2):86MOFO-359177620.18314352000740or a pharmaceutically acceptable salt thereof, whereinY6ais -N- or -CH-;R6Wis H, hydroxyl, methoxy, or methyl;R6X, R6y, and R6zare each independently H, hydroxyl, or methoxy;R3is H or methyl; each R6is independently methyl, F, or methoxy;R8is H or methyl; and m is 0-2.

[0224] B64. A compound of Formula (Gl) or (G2):or a pharmaceutically acceptable salt thereof, whereinY5ais -N-, or -CH-; each Y5bis independently -O- or -CEE-, wherein at least one Y5bis -O-;Q is a bond or is -CEE-;R5Wis H, hydroxyl, or methoxy; each R5Xis independently H, F, or methyl;R3is H or methyl; each R6is independently methyl, F, or methoxy;R8is H or methyl; and m is 0-2.

[0225] B65. The compound of Embodiment B64, or a pharmaceutically acceptable salt thereof, wherein both R5xare H, both R5xare F, or both R5xare methyl.87MOFO-359177620.18314352000740

[0226] B66. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0227] Cl. A pharmaceutical composition, comprising: a compound of any one of Embodiments Al to A27 and Bl to B66, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.

[0228] C2. A method of inhibiting ectonucleotide pyrophosphatase / phosphodiesterase 1(ENPP1) in a subject in need thereof, comprising: administering to the subject a compound of any one of Embodiments Al to A27 and B 1 to B66, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of Embodiment Cl.

[0229] C3. A method of treating a disorder, disease or condition mediated by ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) in a subject in need thereof, comprising: administering to the subject a compound of any one of Al to A27 and Bl to B66, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of Embodiment Cl.

[0230] C4. The method of Embodiment C3, wherein the disorder, disease or condition is cancer.

[0231] C5. The method of Embodiment C4, wherein the cancer is a solid tumor.

[0232] C6. The method of Embodiment C4, wherein the cancer is cervical cancer, colorectal cancer, lung cancer, prostate cancer, esophageal cancer, liver cancer, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, or breast cancer, or any combination thereof.

[0233] C7. The method of Embodiment C3, wherein the disorder, disease or condition is an inflammatory disease, a metabolic disease, or a microbial infection, or any combination thereof.88MOFO-359177620.18314352000740

[0234] C8. The method of Embodiment C7, wherein the inflammatory disease is an autoimmune disease or an autoinflammatory disease.

[0235] C9. The method of Embodiment C3, wherein the disorder, disease or condition is hypophosphatasia (HPP).

[0236] CIO. The method of any one of Embodiments C2 to C9, wherein the subject is a human.EXAMPLES

[0237] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.Synthesis and Characterization of Exemplary Compounds

[0238] All solvents used were commercially available and were used without further purification. Starting materials used were either available from commercial sources or prepared according to literature procedures. Reactions were typically run using anhydrous solvents under an inert atmosphere such as N2. Reactions commonly used oven-dried glassware, and were stirred at ambient temperatures unless otherwise indicated.

[0239] Nuclear Magnetic Resonance (NMR) spectroscopy was commonly performed at 400 MHz using a commercially available spectrometer.1H,13C and19F NMR were typically recorded at 400 MHz for proton, 100 MHz for carbon-13, and 376 MHz for fluorine-19.Deuterated solvents that contained 0.03% to 0.05% v / v tetramethylsilane set that reference signal to 0.00 ppm for both1H and13C or alternatively for1HNMR the residual H signal for the solvent was used as a secondary reference (for example, DMSO-ds signal in DMSO-de was set to 2.50 ppm or CHCI3 in CDCI3 set to 7.26 ppm for the1HNMR). The19FNMR chemical shifts are in relation to CFCI3 (0 ppm). In certain instances, automated NMR processing tools were used to extract spectral parameters including chemical shifts, coupling constants, and proton numbers from NMR spectra.89MOFO-359177620.18314352000740

[0240] Combined liquid chromatography - mass spectra (LC / MS) analyses were commonly performed on commercially available equipment under acidic or basic conditions, or using any other suitable methods and techniques known in the art.

[0241] Typical high-performance liquid chromatography (HPLC) analyses were performed on commercially available equipment under acidic or basic conditions, or using any other suitable methods and techniques known in the art.

[0242] Preparative chromatography was usually performed using commercially available purification system using acidic or basic conditions, or using any other suitable methods and techniques known in the art.

[0243] Compounds are named using ChemDraw 23.0, or IUPAC nomenclature or if commercially available their catalogue or common name. Abbreviations consistent with that found in the organic chemistry literature were used. Some non-exclusive examples are the following: Ac (acetyl), AcOH (acetic acid), ACN or MeCN (acetonitrile), ADMP (2-azido- 1,3-dimethylimidazolinium hexafluorophosphate), AIBN (azobisisobutyronitrile), Boc (tertButyloxycarbonyl), BOC2O (di -tert-butyl dicarbonate), B(OiPr)s, B2(Pin)2 (bis(pinacolato)diboron or 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane)), tBuOH (tert-butanol), nBuLi (n-butyllithium), Cp*Ru(COD)Cl (Chloro(pentamethylcyclopentadienyl)(cyclooctadiene) ruthenium(II)), DCM (dichloromethane), DIAD (diisopropyl azodicarboxylate), DIEA (N,N- diisopropylethylamine), dioxane (1,4-di oxane), DMF (N,N-dimethylforamide), DMP (1,1- bis(acetyloxy)-3-oxo-3H-lk5,2-benziodaoxol-l-yl acetate or Dess-Martin periodinane), DMSO (dimethylsulfoxide), EA or EtOAc (ethyl acetate), Et (ethyl), EtOH (ethanol), Et2O (diethyl ether), FA (formic acid), HPLC (high-performance liquid chromatography), [Ir(dtbbpy)(ppy)2]PFe ([4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine-Nl,Nl']bis[2-(2- pyridinyl-N)phenyl-C]iridium(III) hexafluorophosphate), KOAc or AcOK (potassium acetate), L-selectride (lithium tri-sec-butylhydroborate), Me (methyl), MeOH (methanol), MOMBr (bromo(methoxy)methane or bromomethyl methyl ether), MOM (methoxymethyl), Ms (methanesulfonyl), MsCl (methansulfonyl chloride), NBS (N-bromosuccinimide), NIS (N-iodosuccinimide), Pd / C (palladium on carbon), Pd(dppf)C12 ([1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium(II)), PE (petroleum ether), Ph (phenyl), Pd(OH)2 / C (palladium(II)hydroxide on carbon), prep-HPLC (preparative high-performance liquid chromatography), iPr (isopropyl), PPI13 (triphenyl phosphine), TBAF (tetra-n-90MOFO-359177620.18314352000740 butylammonium fluoride), TMSCN (trimethyl silyl cyanide), TEA (triethyl amine), TFA (trifluoroacetic acid), Tf (trifluoromethyl sulfonyl), TfzO (trifluoromethanesulfonic anhydride), THF (tetrahydrofuran), and THP (tetrahydropyranyl).EXAMPLE 1Synthesis of 5-(( 6-methoxy-9H-purin-9-yl)methyl) benzo [ c] [1,2 ]oxaborol-l( 3H)-ol

[0244] The compound above was synthesized using Scheme 4.Scheme 4( 4-Bromo-l, 3 -phenylene) dimethanol (C2)

[0245] A solution of 4-bromobenzene- 1,3 -dicarboxylic acid (Cl) (5.0 g, 20.4 mmol, 1.0 equiv.) in THF (80 mL) was treated with NaBH4 (2.7 g, 71.4 mmol, 3.5 equiv.) in THF (20 mL) at 0 °C under nitrogen atmosphere. To the above mixture was added BF3*Et2O (7.8 mL, 61.3 mmol, 3.0 equiv.) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature. Then NaOH aqueous solution (1 M in H2O, 40 mL) was added to the reaction mixture and the resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (1 x 300 mL), dried over anhydrous ISfeSC After91MOFO-359177620.18314352000740 filtration, the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluted with PEZEA = 1 / 1) to afford the desired intermediate (4-bromo-l,3-phenylene)dimethanol (C2) (3.78 g, 85.3% yield) as a white solid.1-Bromo-2, 4-bis((methoxymethoxy)methyl)benzene (C3)

[0246] To a stirred solution of (4-bromo- 1,3 -phenyl ene)dimethanol (C2) (2.0 g, 9.2 mmol, 1.0 equiv.) in DCM (20 mL) were added bromo(methoxy)methane (3.5 g, 28.0 mmol, 3.0 equiv.) and DIEA (8.0 mL, 46.1 mmol, 5.0 equiv.) at 0 °C. The resulting mixture was stirred for additional overnight at room temperature. Then the resulting mixture was diluted with water (100 mL) and extracted with DCM (3 * 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluted with PEZEA = 5 / 1) to afford the desired intermediate 1- bromo-2,4- bis((methoxymethoxy)methyl)benzene (C3) (2.3 g, 81.8% yield) as a light-yellow liquid.2-(2, 4-Bis( (methoxymethoxy)methyl)phenyl)-4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane (C4)

[0247] To a stirred solution of l-bromo-2,4-bis((methoxymethoxy)methyl)benzene (C3) (2.3 g, 7.5 mmol, 1.0 equiv. ) and bis(pinacolato) diboron (2.9 g, 11.3 mmol, 1.5 equiv.) in 1,4-dioxane (20 mL) were added KOAc (2.2 g, 22.6 mmol, 3.0 equiv.) and Pd(dppf)C12 (0.5 g, 0.7 mmol, 0.1 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional overnight at 80 °C. The resulting mixture was cooled down to room temperature and quenched with water (100 mL). Then the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The product was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 20% gradient in 20 min; detector, UV 220 nm.) to afford 2-(2,4- bis((methoxymethoxy)methyl)phenyl)-4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane (C4) (2.37 g, 89.3% yield) as a brown oil.5-(Bromomethyl)benzo[c] [ 1, 2 ]oxaborol-l(3H)-ol (C5)92MOFO-359177620.18314352000740

[0248] To a stirred solution of 2-(2,4-bis((methoxymethoxy)methyl)phenyl)-4, 4,5,5- tetramethyl-1, 3 ,2-dioxaborolane (1.1 g, 3.1 mmol, 1.0 equiv.) in THF (5 mL) was added HBr (40% aqueous, 5 mL) aqueous solution dropwise at room temperature. The resulting mixture was stirred for additional overnight at room temperature. The reaction mixture was concentrated in vacuo and the product was purified by reversed-phase flash chromatography with the following conditions (column, Cl 8 silica gel; mobile phase, MeCN in water, 0% to 50% gradient in 30 min; detector, UV 254 nm.) to afford 5- (bromomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C5) (118 mg, 16.6% yield) as a white solid.5-( 6-Methoxy-9H-purin-9-yl)methyl)benzo[c] [ 1, 2 ]oxaborol-l(3H)-ol (1)

[0249] To a stirred solution of 5-(bromomethyl)benzo[c][l,2]oxa borol-l(3H)-ol (C5) (98 mg, 0.4 mmol, 1.0 equiv. ) in DMF (1 mL) were added 6-methoxy-9H-purine (C6) (65 mg, 0.4 mmol, 1.0 equiv.) and potassium carbonate (180 mg, 1.3 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred for additional overnight at 60 °C. The mixture was cooled down to room temperature and filtered off. The filtrate was concentrated under reduced pressure. The product was purified by prep-HPLC with the following conditions (Column: Sunfire C18 5 pm, 30 mm * 150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 13% B to 30% B in 10 min; Wave Length: 254 / 220 nm) to afford 5-((6-methoxy-9H-purin-9-yl)methyl)benzo[c][l,2]oxaborol-l(3H)-ol (1) (16.1 mg, 12.1% yield) as a white solid.

[0250] LCMS (ESI): 297 [M+H]+

[0251] 1H NMR (400 MHz, DMSO-d6) 8 9.17 (s, 1H), 8.69 (s, 1H), 8.54 (s, 1H), 7.70 (d,J = 7.6 Hz, 1H), 7.40 - 7.10 (m, 2H), 5.63 (s, 2H), 4.94 (s, 2H), 4.04 (s, 3H).EXAMPLE 2Synthesis of 5-(( 6-methoxy- 7H-purin-7-yl)methyl) benzo [ c] [1,2 ]oxaborol-l( 3H)-ol93MOFO-359177620.18314352000740

[0252] The compound above was synthesized using Scheme 5.Scheme 55-(( 6-Methoxy- 7H-purin- 7-yl)methyl)benzo[ c] [1,2 ]oxaborol-l( 3H)-ol (2)

[0253] To a stirred solution of 5-(bromomethyl)-3H-2,l-benzoxaborol-l-ol (C5) (98 mg, 0.4 mmol, 1.0 equiv.) in DMF (1 mL) were added 6-methoxy-9H-purine (C6) (64.9 mg, 0.4 mmol, 1.0 equiv.) and potassium carbonate (180 mg, 1.3 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred for additional overnight at 60 °C. The mixture was cooled down to room temperature and filtered off. The filtrate was concentrated under reduced pressure. The product was purified by prep-HPLC with the following conditions (Column: Sunfire C18 5 pm, 30 mm * 150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 13% B to 30% B in 10 min; Wave Length: 254 / 220 nm) to afford 5-((6-methoxy-7H-purin-7- yl)methyl)benzo[c][l,2]oxaborol-l(3H)- ol (2) (17.5 mg, 11.7% yield) as a white solid.

[0254] LCMS (ESI): 297 [M+H]+

[0255] 1H NMR (400 MHz, DMSO-de) 5 9.17 (s, 1H), 8.54 (d, J = 5.4 Hz, 2H), 7.69 (d, J= 8.0 Hz, 1H), 7.30 (d, J = 5.4 Hz, 2H), 5.54 (s, 2H), 4.93 (s, 2H), 4.10 (s, 3H).EXAMPLE 3Synthesis of 2-amino-9-(2-( 1 -hydr oxy-1, 3 -dihydrobenzo [c] [ 1, 2 ]oxaborol-6-yl)ethyl)-l , 9- dihydro-6H-purin-6-one, hydrochloride salt94MOFO-359177620.18314352000740

[0256] The compound above was synthesized using Scheme 6.Scheme 6Methyl 2-(4-formyl-3-hydr oxyphenyl) acetate (C8)

[0257] To a stirred mixture of methyl 2-(3-hydroxyphenyl)acetate (C7) (20.0 g, 120.4 mmol, 1.0 equiv.), paraformaldehyde (24.0 g, 794.6 mmol, 6.6 equiv.) and TEA (35 mL, 251.8 mmol, 2.1 equiv.) in THF (150 mL) was added MgCh (17.2 g, 180.7 mmol, 1.5 equiv.) at room temperature. The resulting mixture was heated to reflux for 12 hours. The reaction mixture was cooled to room temperature and then quenched with 1 M HCI aqueous solution (200 mL). Then the mixture was evaporated to remove THF. The aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed by brine (3 x 200 mL), dried over anhydrous sodium sulfate, filtered off and concentrated under reduced pressure. The product was purified by column chromatography (silica gel, petroleum ether / ethyl95MOFO-359177620.18314352000740 acetate = 20 / 1 to 8 / 1) to afford methyl 2-(4-formyl-3-hydroxyphenyl)acetate (12.6 g, 53.9% yield) as a light brown oil.Methyl 2-(4-formyl-3-(((trifluoromethyl)sulfonyl)oxy)phenyl)acetate (C9)

[0258] To a stirred solution of methyl 2-(4-formyl-3-hydroxyphenyl)acetate (C8) (4.4 g, 22.7 mmol, 1.0 equiv.) and pyridine (5.5 mL, 68.1 mmol, 3.0 equiv.) in DCM (50 mL) was added TfzO (5.7 mL, 33.9 mmol, 1.5 equiv. ) dropwise at 0 °C. The mixture was allowed to warm to room temperature and stirred for overnight. The reaction mixture was diluted by 1 M HC1 aqueous solution (100 mL) and then extracted by DCM (3 x 100 mL). The combined organic layers were washed by brine (3 x 200 mL), dried over anhydrous sodium sulfate, filtered off and concentrated under reduced pressure. The product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to afford methyl 2- (4-formyl-3-(((trifluoromethyl)sulfonyl)oxy)phenyl)acetate (C9) (4.8 g, 64.9% yield) as a light-yellow oil.Methyl 2-(4-formyl-3-( 4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2-yl)phenyl)acetate (C 10)

[0259] To a stirred mixture of methyl 2-(4-formyl-3- (((trifluoromethyl)sulfonyl)oxy)phenyl)acetate (C9) (4.5 g, 13.8 mmol, 1.0 equiv.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (4.5 g, 17.7 mmol, 1.3 equiv. ) and KOAc (3.9 g, 39.7 mmol, 2.9 equiv.) in 1,4-dioxane (45 mL) was added Pd^ppfJCh’CLLCh (220 mg, 0.3 mmol, 0.02 equiv.) under nitrogen atmosphere. The resulting mixture was heated to 80 °C and stirred at 80 °C for 3 hours. The reaction mixture was cooled to room temperature and filtered off by Celite. The filtrate was concentrated under reduced pressure. The product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 25 / 1 to 5 / 1) to afford methyl 2-(4-formyl-3-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)phenyl)acetate (CIO) (1.4 g, 33.4% yield) as a colorless oil.6-(2-Hydroxyethyl)benzo [c] [ 1 ,2] oxaborol- 1 (3H)-ol (Cl 1)

[0260] To a stirred solution of methyl 2-(4-formyl-3-(4, 4, 5, 5-tetramethyl-l, 3,2- dioxaborolan-2-yl)phenyl)acetate (CIO) (1.4 g, 4.6 mmol, 1.0 equiv.) in THF / MeOH (30 mL / 3 mL) was added NaBFL (1.4 g, 37.0 mmol, 8.0 equiv.) in portions at 0 °C. The reaction mixture was allowed to warm to 25 °C and stirred at 25 °C for 14 hours. The reaction mixture was quenched by the addition of 2 M HC1 aqueous solution (100 mL) and extracted by96MOFO-359177620.18314352000740EtOAc (3 x 100 mL). The combined organic layers were washed by brine (3 * 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by reverse phase flash with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 220 nm.) to afford 6-(2-hydroxyethyl)benzo[c][l,2]oxaborol-l(3H)-ol (700 mg, 85.4% yield) as a white solid.6-(2-(2-Ammo-6-chloro-9H-purin-9-yl)ethyl)benzo[c] [ 1, 2 Joxaborol-1 (3H)-ol (C 13)

[0261] To a stirred mixture of 6-(2-hydroxyethyl)benzo[c][l,2]oxaborol-l(3H)-ol (Cl l) (700 mg, 3.9 mmol, 1.0 equiv.), 6-chloro-9H-purin-2-amine (C12) (735 mg, 4.3 mmol, 1.1 equiv.) and PPh3 (1.6 g, 6.1 mmol, 1.6 equiv.) in DMF (5 mL) was added DIAD (1.8 mL, 8.8 mmol, 2.3 equiv.) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was allowed to warm to 75 °C and stirred at 75 °C for overnight. The reaction mixture was concentrated in vacuo. The product was purified by prep-HPLC (Column: SunFire Cl 8 5 pm, 30 mm x 150 mm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 20% B in 8 min; Wave Length: 254 nm / 220 nm), which afforded 6-(2-(2-amino-6-chloro-9H-purin-9-yl)ethyl)benzo[c] [ 1 ,2]oxaborol- 1 (3H)-ol (C 13) (38 mg, crude) as a white solid.2-Amino-9-(2-( 1 -hydr oxy-1, 3-dihydrobenzo[c] [ 1, 2 ]oxaborol-6-yl)ethyl)-l, 9-dihydro-6H- purin-6-one, hydrochloride salt (3)

[0262] A mixture of 6-(2-(2-amino-6-chloro-9H-purin-9-yl)ethyl)benzo[c][l,2]oxa borol- l(3H)-ol (Cl 3) (38 mg, crude) in 1 M HC1 aqueous solution (3 mL) was stirred at 80 °C for 3 hours. The mixture was concentrated in vacuo. The resulting residue was triturated by EtOH (3 x 10 mL) and filtered off. The filter cake was diluted with water (20 mL) and lyophilized to afford 2-amino-9-(2-( 1 -hydroxy- 1 ,3 -di hydrobenzo[c] [ 1 ,2]oxaborol-6-yl)ethyl)- 1,9- dihydro-6H-purin-6-one, hydrochloride salt (3) (17.4 mg, 42.7% yield) as an off-white solid.

[0263] LCMS (ESI): 312 [M+H]+

[0264] 1H NMR (400 MHz, DMSO-d6) 8 11.18 (s, 1H), 9.15 (brs, 1H), 8.34 (s, 1H), 7.52 - 7.46 (m, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.29 (dd, J = 7.9, 1.7 Hz, 1H), 6.90 (brs, 2H), 4.96 (s, 2H), 4.29 (t, J = 7.2 Hz, 2H), 3.17 (t, J = 7.2 Hz, 2H).97MOFO-359177620.18314352000740EXAMPLE 4Synthesis of 6-(4-phenyl-[ 1, 2, 3 ] triazol- l-ylmethyl)-3H-benzo[ c] [1,2 ]oxaborol-l-ol

[0265] The compound above was synthesized using Scheme 7.Scheme 7(2-Bromo-l, 4-phenylene)dimethanol (C 15)

[0266] To a solution of dimethyl 2-bromoterephthalate (C14) (5.0 g, 18.31 mmol) in THF (40 mL) was added LiBTL (918 mg, 42.12 mmol) slowly at 0 °C. Then 1.3 mL MeOH was added to the mixture. The reaction mixture was stirred at room temperature overnight, quenched with 1 M HC1 to pH = 6~7. The product was extracted with ethyl acetate (3x40 mL), dried over ISfeSCU and evaporated to obtain C15 (3.83 g) as a white powder. The crude material was carried to next step without further purification.98MOFO-359177620.183143520007402, 2 '-(((2-Bromo-l, 4-phenylene)bis(methylene))bis(oxy))bis(tetrahydro-2H-pyran) (C 16)

[0267] 2-Bromo-l,4-phenylene)dimethanol (C15) (3.83 g, 17.64 mmol, 1.0 equiv.) and p- toluenesulfonic acid monohydrate (168 mg, 0.88 mmol, 0.05 equiv.) were dissolved in DMF (26 mL), and DHP (6.45 mL, 70.58 mmol) was added. The reaction mixture was stirred at room temperature for 1 day and was quenched with saturated NaHCCL, extracted with ethyl ether (3 x 40 mL), washed with brine, dried over Na2SO4 and evaporated to obtain C16 (7.0 g) as a light-yellow oil. The material was carried to next step without further purification.6-(Hydroxymethyl)benzo[c] [ 1, 2 ]oxaborol-l ( 3H)-ol (C 17)

[0268] 2,2'-(((2-Bromo-l,4-phenylene)bis(methylene))bis(oxy))bis(tetrahydro-2H-pyran) (C16) (7.20 g, 18.68 mmol) was dissolved in THF (130 mL) and n-BuLi (2.5 M in hexane, 8.44 mL, 21.11 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 20 min and then triisopropyl borate (4.33 mL, 18.68 mmol) was added to the reaction flask. The reaction mixture was allowed to warm to room temperature and stirred overnight. Then it was quenched with 6 M HC1 (100 mL) and stirred at room temperature for 6 h. The THF was removed by evaporation and product was extracted with ethyl acetate (3 x 50 mL), dried over Na2SO4 and evaporated to obtain 5.0 g of crude, which was washed with 0 to 50% EtOAc in n-hexanes to give 330 mg of pure product. Another 1.10 g of product was obtained from the crude after purification by prep-HPLC using a gradient of 0 to 100% ACN with 0.1% TFA. Altogether 1.43 g, 48% yield (over 3 steps) of C17 was obtained as a white solid.( 1 -Hydr oxy-1, 3-dihydrobenzo [ c] [1,2 ]oxaborol-6-yl)methyl methane sulfonate (C 18)

[0269] To a solution of 6-(hydroxymethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C17) (310 mg, 1.89 mmol, 1.0 equiv.) in DCM (10 mL) was added EtsN (319 pL, 2.26 mmol, 1.2 equiv.) and methanesulfonyl chloride (170 pL, 2.17 mmol) at 0 °C. The reaction mixture was warmed to rt and stirred overnight. The reaction mixture was diluted with DCM (3x10 mL), washed with 2 N aqueous HC1 (5 mL), brine (10 mL), dried over anhydrous Na2SO4, concentrated under vacuum to give C18 (302 mg) as brown oil, which was carried to next step without further purification.6-(Azidomethyl) benzo [ c] [1,2 ]oxaborol-l ( 3H)-ol (C 19)99MOFO-359177620.18314352000740

[0270] To a solution of (l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)methyl methanesulfonate (C18) (302 mg, 1.24 mmol, 1.0 equiv.) in DMF (15 mL) was added Nal (38 mg, 0.24 mmol, 0.2 equiv.) and NaNs (98 mg, 1.49 mmol, 1.2 equiv.). The reaction mixture was stirred at 60 °C overnight. The reaction mixture was diluted with EtOAc (30 mL), washed with 10% aqueous Na2S20s (10 mL), brine (10 mL), dried over anhydrous ISfeSCU, concentrated under vacuum to generate C19 (220 mg) as a red oil, which was used in the next step without further purification.6-(4-Phenyl-[ 1, 2, 3 ]triazol-l-ylmethyl)-3H-benzo[ c] [1,2 ]oxaborol-l-ol (4)

[0271] A 50 mL round-bottom flask was charged with 6- (azidomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C19) (171 mg, 0.90 mmol, 1.0 equiv.) and dissolved in solvent mixture of tBuOH : water = 1 : 1 (2 mL). To this was added the phenyl acetylene (C20) (200 pL, 1.80 mmol, 2.0 equiv.) followed by sodium ascorbate (90 mg, 0.45 mmol, 0.5 equiv.) and CuSCLSLEO (23 mg, 0.09 mmol, 0.1 equiv.) at rt. Then a mixture of sodium ascorbate (90 mg, 0.45 mmol, 0.5 equiv.) and CuSCL SLEO (23 mg, 0.09 mmol, 0.1 equiv.) in minimum amount of water (1.0 mL) was also added to the reaction mixture and it was stirred at 35 °C for 12 h. The product was purified by prep-HPLC using a gradient of 0 to 60% ACN with 0.1% TFA. After lyophilization, 4 was obtained (55 mg, 10% yield over 3 steps) as a yellow solid.

[0272] LCMS: 292 [M+H]+, 583 [2M+H]+

[0273] 'H NMR (400 MHz, DMSO-d6) 8 8.64 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.66 (s, 1H), 7.54-7.47 (m, 1H), 7.45-7.41 (m, 3H), 7.34-7.30 (m, 1H), 5.70 (s, 2H), 4.97 (s, 2H).EXAMPLE 5Synthesis of 6-(4-phenoxymethyl-[ 1, 2, 3 ]triazol-l-ylmethyl)-3H-benzo [ c] [1,2 ]oxaborol-l-ol5

[0274] The compound above was synthesized using Scheme 8.100MOFO-359177620.18314352000740Scheme 8tBuOH, H2O6-(4-Phenoxymethyl-[ 1, 2, 3 ] triazol- 1 -ylmethyl)-3H-benzo [c] [ 1, 2 ]oxaborol-l-ol (5)

[0275] A 50 mL round-bottom flask was charged the 6- (azidomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C19) (150 mg, 0.79 mmol, 1.0 equiv.) and dissolved in solvent mixture of tBuOH : water = 1 : 1 (2 mL). To this was added the prop-2 - ynyloxy-benzene (C21) (107 pL, 0.83 mmol, 1.05 equiv.) followed by sodium ascorbate (79 mg, 0.39 mmol, 0.5 equiv.) and CuSCU 5H2O (20 mg, 0.07 mmol, 0.1 equiv.) at rt. Then a mixture of sodium ascorbate (79 mg, 0.39 mmol, 0.5 equiv.) and CuSCh 5H2O (20 mg, 0.07 mmol, 0.1 equiv.) in minimum amount of water (1.0 mL) was also added to the reaction mixture and it was stirred at 35 °C for 12 h. The product was purified by prep-HPLC using a gradient of 0 to 60% ACN in water with 0.1% TFA. After lyophilization, 5 (71 mg, 24% yield) was obtained as a white solid.

[0276] LCMS: 322 [M+H]+, 643 [2M+H]+

[0277] 'H NMR (400 MHz, DMSO-d6) 8 9.24 (br.s, 1H), 8.27 (s, 1H), 7.66 (s, 1H), 7.47 (dd, J = 8.0, 1.7 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.31 - 7.27 (m, 2H), 7.02 (d, J = 8.1 Hz, 2H), 6.96 - 6.92 (m, 1H), 5.66 (s, 2H), 5.12 (s, 2H), 4.97 (s, 2H).EXAMPLE 6Synthesis of 6-(( 4-(4-jluorophenyl)-lH-l , 2, 3-triazol-l-yl)methyl)benzo[ c] [1,2 ]oxaborol- l(3H)-ol101MOFO-359177620.18314352000740

[0278] The compound above was synthesized using Scheme 9.Scheme 919 tBuOH, H2O6-(( 4-(4-Fluorophenyl)-lH-l , 2, 3-triazol-l-yl)methyl) benzo [ c] [1,2 ]oxaborol-l( 3H)-ol (6)

[0279] A 50 mL round-bottom flask was charged with 6- (azidomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C19) (150 mg, 0.79 mmol, 1.0 equiv.) and dissolved in solvent mixture of tBuOH : water = 1 : 1 (2 mL). To this was added the 1- ethynyl-4-fluoro-benzene (C22) (96 pL, 0.83 mmol, 1.05 equiv.) followed by sodium ascorbate (79 mg, 0.39 mmol, 0.5 equiv.) and CuSCLSJLO (20 mg, 0.07 mmol, 0.1 equiv.) at rt. Then a mixture of sodium ascorbate (79 mg, 0.39 mmol, 0.5 equiv.) and CuSCh 5H2O (20 mg, 0.07 mmol, 0.1 equiv.) in minimum amount of water (1.0 mL) was also added to the reaction mixture and then stirred at 35 °C for 12 h. The product was purified by prep-HPLC using a gradient of 0 to 60% ACN with 0.1% TFA. After lyophilization, 6 (81 mg, 29% yield) was obtained as a white solid.

[0280] LCMS : 310 [M+H]+, 619 [2M+H]+

[0281] 'H NMR (400 MHz, DMSO-d6) 8 8.62 (s, 1H), 7.91 - 7.87 (m, 2H), 7.65 (s, 1H), 7.49 (dd, J = 7.9, 1.7 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.30 - 7.25 (m, 2H), 5.69 (s, 2H), 4.97 (s, 2H).EXAMPLE 7Synthesis of 6-(( 4-benzyl-lH-l, 2, 3-triazol-l-yl)methyl)benzo[ c] [1,2 ]oxaborol-l ( 3H)-ol102MOFO-359177620.18314352000740

[0282] The compound above was synthesized using Scheme 10.tBuOH, H2O6-(( 4-Benzyl-lH-l, 2, 3-lriazol-l-y I) methyl) benzo / c] [1,2 ]oxaborol-l( 3H)-ol (7)

[0283] A 50 mL round-bottomed flask was charged with 6- (azidomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C19) (150 mg, 0.79 mmol, 1.0 equiv.) and dissolved in solvent mixture of tBuOH : water = 1 : 1 (2 mL). To this was added the prop-2 - ynyl-benzene (C23) (100 pL, 0.83 mmol, 1.05 equiv.) followed by sodium ascorbate (79 mg, 0.39 mmol, 0.5 equiv.) and CuSCU 5H2O (20 mg, 0.07 mmol, 0.1 equiv.) at rt. Then a mixture of sodium ascorbate (79 mg, 0.39 mmol, 0.5 equiv.) and CuSCU 5H2O (20 mg, 0.07 mmol, 0.1 equiv.) in minimum amount of water (1.0 mL) was also added to the reaction mixture and then stirred at 35 °C for 12 h. The product was purified by prep-HPLC using a gradient of 0 to 60% ACN with 0.1% TFA. After lyophilization, 7 (35 mg, 13% yield over 3 steps) was obtained as a yellow solid.

[0284] LCMS: 306 [M+H]+, 611 [2M+H]+

[0285] 'H NMR (400 MHz, DMSO-d6) 8 7.87 (s, 1H), 7.63 (s, 1H), 7.44 - 7.38 (m, 2H), 7.30 - 7.17 (m, 5H), 5.58 (s, 2H), 4.96 (s, 2H), 3.97 (s, 2H).EXAMPLE 8Synthesis of 6-(( 4-(pyridin-3-yl)-lH-l , 2, 3-triazol-l-yl)methyl)benzo[ c] [1,2 ]oxaborol-l ( 3H)~ ol8103MOFO-359177620.18314352000740

[0286] The compound above was synthesized using Scheme 11.Scheme 11tBuOH, H2O6-(( 4-(Pyridin-3-yl)-lH-l, 2, 3-triazol-l-yl)methyl) benzo [ c] [1,2 ]oxaborol-l ( 3H)-ol (8)

[0287] A 50 mL round-bottom flask was charged the 6- (azidomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C19) (120 mg, 0.63 mmol, 1.0 equiv.) and dissolved in solvent mixture of tBuOH : water = 1 : 1 (2 mL). To this was added the 3- ethynyl-pyridine (C24) (86 mg, 0.82 mmol, 1.3 equiv.) followed by sodium ascorbate (63 mg, 0.31 mmol, 0.5 equiv.) and CuSCU 5H2O (16 mg, 0.06 mmol, 0.1 equiv.) at rt. Then a mixture of sodium ascorbate (63 mg, 0.31 mmol, 0.5 equiv.) and CuSCLSJLO (16 mg, 0.06 mmol, 0.1 equiv.) in minimum amount of water (1.0 mL) was also added to the reaction mixture and then stirred at 35 °C for 12 h. The product was purified by prep-HPLC using a gradient of 0 to 60% ACN with 0.1% TFA. After lyophilization, 8 (52 mg, 28% yield over 3 steps) was obtained in as a yellow solid.

[0288] LCMS: 293 [M+H]+

[0289] 1H NMR (400 MHz, DMSO-d6) 8 9.17 (s, 1H), 8.83 (s, 1H), 8.65 (s, 1H), 8.49 (d,J = 8.0 Hz, 1H), 7.72 (dd, J = 8.1, 5.1 Hz, 1H), 7.68 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 5.75 (s, 2H), 4.98 (s, 2H).EXAMPLE 9Synthesis of 6-(( 4-(morpholinomethyl)-lH-l, 2, 3-triazol-l-yl)methyl) benzo [ c] [1,2 ]oxaborol- l(3H)-ol104MOFO-359177620.18314352000740

[0290] The compound above was synthesized using Scheme 12.Scheme 12C 9 tBuOH, H2O6-(( 4-(morpholinomethyl)-lH-l, 2, 3-lriazol-l-y I) methyl) benzo / c] [1,2 ]oxaborol-l( 3H)-ol, trifluoroacetate salt (9)

[0291] A 50 mL round-bottomed flask was charged with 6- (azidomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C19) (120 mg, 0.63 mmol, 1.0 equiv.) and dissolved in solvent mixture of tBuOH : water = 1 : 1 (2 mL). To this was added the 4-(prop- 2-yn-l-yl)morpholine (C25) (104 mg, 0.82 mmol, 1.3 equiv.) followed by sodium ascorbate (63 mg, 0.31 mmol, 0.5 equiv.) and CuSCU 5H2O (16 mg, 0.06 mmol, 0.1 equiv.) at rt. Then a mixture of sodium ascorbate (63 mg, 0.31 mmol, 0.5 equiv.) and CuSC STBO (16 mg, 0.06 mmol, 0.1 equiv.) in minimum amount of water (1.0 mL) was also added to the reaction mixture and then stirred at 35 °C for 12 h. The product was purified by prep-HPLC using a gradient of 0 to 60% ACN with 0.1% TFA. After lyophilization, 9 (50 mg, 19% yield over 3 steps) was obtained as a yellow solid.

[0292] LCMS : 315 [M+H]+, 629 [2M+H]+

[0293] 'H NMR (400 MHz, DMSO-d6) 8 10.24 (brs, 1H), 9.26 (brs, 1H), 8.30 (s, 1H), 7.69 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 5.71 (s, 2H), 4.98 (s, 2H), 4.45 (s, 2H), 4.02-3.84 (m, 2H), 3.36-3.28 (m, 4H), 3.20-3.08 (m, 2H).EXAMPLE 10105MOFO-359177620.18314352000740Synthesis of 6-(( 4-cyclopropyl-lH-l , 2, 3-triazol-l-yl)methyl) benzo [ c] [1,2 ]oxaborol-l ( 3H)-ol

[0294] The compound above was synthesized using Scheme 13.Scheme 13tBuOH, H2O6-(( 4-Cyclopropyl-lH-l , 2, 3-triazol-l-yl)methyl) benzo [ c] [1,2 ]oxaborol-l( 3H)-ol (10)

[0295] A 50 mL round-bottom flask was charged the 6- (azidomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C19) (150 mg, 0.79 mmol, 1.0 equiv.) and dissolved in solvent mixture of tBuOH : water = 1 : 1 (2 mL). To this was added the ethynylcyclopropane (C26) (69 mg, 1.03 mmol, 1.3 equiv.) followed by sodium ascorbate (79 mg, 0.39 mmol, 0.5 equiv.) and CuSCLSJLO (20 mg, 0.07 mmol, 0.1 equiv.) at the rt. Then a mixture of sodium ascorbate (79 mg, 0.39 mmol, 0.5 equiv.) and CuSCU 5H2O (20 mg, 0.07 mmol, 0.1 equiv.) in minimum amount of water (1.0 mL) was also added to the reaction mixture and stirred at 35 °C for 12 h. The product was purified by prep-HPLC using a gradient of 0 to 60% ACN with 0.1% TFA. After lyophilization 10 (48 mg, 24% yield over 3 steps) was obtained as a yellow solid.

[0296] LCMS: 256 [M+H]+, 511 [2M+H]+

[0297] 'H NMR (400 MHz, DMSO-d6) 8 7.85 (s, 1H), 7.59 (s, 1H), 7.44-7.39 (m, 2H), 5.54 (s, 2H), 4.96 (s, 2H), 1.94-1.88 (m, 1H), 0.89-0.85 (m, 2H), 0.71-0.67 (m, 2H).EXAMPLE 11106MOFO-359177620.18314352000740Synthesis of 6-( 4-( (benzyl(methyl)amino)methyl)-lH-l, 2, 3-triazol-l- yl)methyl)benzo [c] [ 1 ,2] oxaborol-1 (3H)-ol, trifluoroacetic acid salt

[0298] The compound above was synthesized using Scheme 14.tBuOH, H2O6-( 4-( f3enzyl(methyl)amino)methyl)-lH-l, 2, 3-triazol-l-yl)methyl)benzo[c] [ 1, 2 ]oxaborol- l(3H)-ol, trifluoroacetic acid salt (11)

[0299] A 50 mL round-bottom flask was charged the 6- (azidomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C19) (150 mg, 0.63 mmol, 1.0 equiv.) and dissolved in solvent mixture of tBuOH : water = 1 : 1 (2 mL). To this was added the N- benzyl-N-methylprop-2-yn-l -amine (C27) (131 mg, 0.81 mmol, 1.3 equiv.) followed by sodium ascorbate (79 mg, 0.39 mmol, 0.5 equiv.) and CuSCLSJLO (20 mg, 0.07 mmol, 0.1 equiv.) at rt. Then a mixture of sodium ascorbate (79 mg, 0.39 mmol, 0.5 equiv.) and CUSO45H2O (20 mg, 0.07 mmol, 0.1 equiv.) in minimum amount of water (1.0 mL) was also added to the reaction mixture and then stirred at 35 °C for 12 h. The product was purified by prep-HPLC using a gradient of 0 to 60% ACN with 0.1% TFA. After lyophilization 11 (75 mg) was obtained as a yellow solid.

[0300] LCMS: 349 [M+H]+, 697 [2M+H]+

[0301] 'H NMR (400 MHz, DMSO-d6) 8 10.30 (s, 1H), 8.34 (s, 1H), 7.68 (s, 1H), 7.55- 7.51 (m, 2H), 7.50-7.42 (m, 5H), 5.72 (s, 2H), 4.98 (s, 2H), 4.44-4.25 (m, 4H), 2.62 (s, 3H).107MOFO-359177620.18314352000740EXAMPLE 12Synthesis of methyl 2-amino-3-( l-((l -hydr oxy-1, 3-dihydrobenzo[ c] [1,2 ]oxaborol-6- yl)methyl)-lH-l,2,3-triazol-4-yl)propanoate, trifluoroacetate salt (12)

[0302] The compound above was synthesized using Scheme 15.Scheme 15Methyl 2-(( tert-butoxycarbonyl)amino)-3-( 1-((1 -hydroxy- 1, 3-dihydrobenzo [ c] [1,2 ]oxaborol- 6-yl)methyl)-lH-l ,2, 3-triazol-4-yl)propanoate (C29)

[0303] A 50 mL round-bottom flask was charged the 6- (azidomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C19) (150 mg, 0.63 mmol, 1.0 equiv.) and dissolved in solvent mixture of tBuOH : water = 1 : 1 (2 mL). To this was added the methyl 2-(( / c / 7-butoxycarbonyl)amino)pent-4-ynoate (C28) (143 mg, 0.63 mmol, 1.0 equiv.) followed by sodium ascorbate (79 mg, 0.39 mmol, 0.5 equiv.) and CuSC 5H2O (20 mg, 0.07 mmol, 0.1 equiv.) at rt. Then a mixture of sodium ascorbate (79 mg, 0.39 mmol, 0.5 equiv.) and CuSO45H2O (20 mg, 0.07 mmol, 0.1 equiv.) in minimum amount of water (1.0 mL) was also added to the reaction mixture and then stirred at 35 °C for 12 h. The reaction mixture was purified by prep-HPLC using a gradient of 0 to 60% ACN with 0.1% TFA. After lyophilization, C29 (50 mg, 13% over 3 steps) was obtained as a yellow solid.Methyl 2-amino-3-( 1-((1 -hydroxy- 1, 3-dihydrobenzo [c] [ 1, 2 ]oxaborol-6-yl)methyl)-lH-l , 2, 3- triazol-4-yl)propanoate, trifluoroacetate salt (12)108MOFO-359177620.18314352000740

[0304] A 50 mL round-bottom was charged the methyl 2-((tert-butoxycarbonyl)amino)-3- (l-((l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)methyl)-lH-l,2,3-triazol-4- yl)propanoate (C29) (50 mg, 0.12 mmol, 1.0 equiv.) and dissolved in dry 1,4-dioxane (2 mL). To this was added the 4.0 M HC1 in 1,4-dioxane (0.6 mL, 2.40 mmol, 20 equiv.) and stirred at rt for 12 h. The reaction mixture was purified by reverse phase prep-HPLC in 0 to 60% ACN in water with 0.1% TFA. After lyophilization, 12 (13 mg, 31% yield) was obtained as a white solid as its trifluoroacetate salt.

[0305] LCMS: 317 [M+H]+, 633 [2M+H]+

[0306] 1H NMR (400 MHz, DMSO-d6) 8 8.44 (s, 3H), 8.00 (s, 1H), 7.64 (s, 1H), 7.50 -7.39 (m, 2H), 5.62 (s, 2H), 4.97 (s, 2H), 4.38 (t, J = 5.9 Hz, 1H), 3.68 (s, 3H), 3.19 (dd, J = 6.1, 2.8 Hz, 2H).EXAMPLE 13Synthesis of 6-((4-((lH-pyrazol-l-yl)methyl)-lH-l,2,3-triazol-l- yl)methyl)benzo [ c] [1,2 ]oxaborol-l ( 3H)-ol

[0307] The compound above was synthesized using Scheme 16.Scheme 16C19 tBuOH, H2O6-((4-(( lH-Pyrazol-l-yl)methyl)-lH-l, 2, 3-triazol-l-yl)methyl)benzo[ c] [1,2 ]oxaborol-l ( 3H)~ ol (13)109MOFO-359177620.18314352000740

[0308] A 50 mL round-bottom flask was charged with 6- (azidomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C19) (80 mg, 0.42 mmol, 1.0 equiv.) and dissolved in solvent mixture of tBuOH : water = 1 : 1 (2 mL). To this was added the l-(prop- 2-yn-l-yl)-lH-pyrazole (C30) (59 mg, 0.55 mmol, 1.0 equiv.) followed by sodium ascorbate (42 mg, 0.21 mmol, 0.5 equiv.) and CuSCU 5H2O (11 mg, 0.04 mmol, 0.1 equiv.) at rt. Then a mixture of sodium ascorbate (42 mg, 0.21 mmol, 0.5 equiv.) and CuSCLSJLO (11 mg, 0.04 mmol, 0.1 equiv.) in minimum amount of water (1.0 mL) was also added to the reaction mixture and then stirred at 35 °C for 12 h. The reaction mixture was purified by prep-HPLC using a gradient of 0 to 60% ACN with 0.1% TFA. After lyophilization 13 (40 mg, 23% yield) was obtained as a white solid.

[0309] LCMS: 296 [M+H]+, 591 [2M+H]+

[0310] 1H NMR (400 MHz, DMSO-d6) 6 8.13 (s, 1H), 7.90 (br.s, 1H), 7.66 (s, 1H), 7.55(br.s, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 6.31 (br.s, 1H), 5.59 (s, 2H), 5.39 (s, 2H), 4.91 (s, 2H).EXAMPLE 14Synthesis of 4-(((l -hydr oxy-1, 3-dihydrobenzo [ c] [1,2 ]oxaborol-5-yl)methyl)amino)-8- methoxyquinoline-3-carbonitrile14

[0311] The compound above was synthesized using Scheme 17.110MOFO-359177620.18314352000740Scheme 173-Formyl-4-( 4, 4, 5, 5 -tetr ame thy l-l , 3, 2-dioxaborolan-2-yl)benzonitrile (C32)

[0312] Into a 100 mL Schlenk tube were added bis(pinacolato)diboron (5.1 g, 20.0 mmol, 1.5 equiv.), KOAc (3.9 g, 40.0 mmol, 3.0 equiv.) and Pd(dppf)C12*CH2C12 (540 mg, 0.7 mmol, 0.05 equiv.) at room temperature. To the above mixture was added the solution of 4- bromo-3 -formylbenzonitrile (C31) (2.50 g, 11.9 mmol, 1.0 equiv.) in 1,4-dioxane (30 mL) at room temperature. The resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 x 20 mL) and methanol (3 x 20 mL). The filtrate was concentrated under reduced pressure. The product was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 10% gradient in 20 min; detector, UV 254 nm. This resulted in 3-formyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzonitrile (C32) (3.3 g, 96.3% yield) as a white solid.1-Hydr oxy-1, 3-dihydrobenzo[ c] [1,2 ] oxaborole-5-carbonitrile (C33 )

[0313] To a stirred solution of 3-formyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzonitrile (C32) (3.3 g, 12.8 mmol, 1.0 equiv.) in the mixture solution of THF (30 mL) and methanol (3 mL) was added NaBFL (1.5 g, 38.5 mmol, 3.0 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was acidified to pH 3 with 1 M HC1 (aq.). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers111MOFO-359177620.18314352000740 were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The product was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborole-5-carbonitrile (C33) (2.0 g, 98.0% yield) as a white solid.5 -(Aminomethyl) benzo [ c] [1,2 ]oxaborol-l( 3H)-ol (C34)

[0314] To a solution of l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborole-5-carbonitrile (C33) (1.0 g, 6.3 mmol, 1.0 equiv.) in the mixture solution of MeOH (10 mL) and EA (10 mL) was added Raney nickel (37 mg, 0.63 mmol, 0.1 equiv.) and NEL’FEO (1.1 g, 31.4 mmol, 5.0 equiv.) in a pressure tank. The mixture was hydrogenated at room temperature under 5 atm of hydrogen pressure overnight. There's a parallel reaction going on. The combined reaction mixtures were filtered through a Celite pad. The filter cake was washed with water (2 ^ 30 mL). The filtrate was concentrated under reduced pressure. The product was purified by trituration with acetone (3 x 3 mL). This resulted 5- (aminomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C34) (1.2 g, crude) as an off-white solid.

[0315] A portion of C34 (200 mg) was further purified by Prep-HPLC with the following conditions (Column: YMC Triart C18 ExRs 5 pm, 30 mm x 150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3«H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 5% B in 8 min; Wave Length: 254 / 220 nm) to afford 5- (aminomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C34) (58.2 mg, 14.4% yield) as a white solid.

[0316] LCMS (ESI): 164 [M+H]+

[0317] 1H NMR (400 MHz, DMSO-d6) 6 9.11 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.36 (s,1H), 7.29 (d, J = 7.6 Hz, 1H), 4.96 (s, 2H), 3.77 (s, 2H).

[0318] 1H NMR (400 MHz, deuterium oxide) 6 7.43 (d, J = 7.3 Hz, 1H), 7.16 (dd, J =7.4, 1.6 Hz, 1H), 7.11 (s, 1H), 4.69 (s, 2H) 4.04 (s, 2H).4-(((l -Hydr oxy-1, 3-dihydrobenzo[ c] [1,2 ]oxaborol-5-yl)methyl)amino)-8-methoxyquinoline- 3-carbonitrile (14)112MOFO-359177620.18314352000740

[0319] Into a 10 mL pressure tank reactor were added 5- (aminomethyl)benzo[c][l,2]oxaborol-l(3H)-ol C34 (200 mg, 1.2 mmol, 1.0 equiv.), 4- chloro-8-methoxyquinoline-3-carbonitrile (C35) (161 mg, 0.74 mmol, 0.6 equiv.) and TEA (340 pL, 2.4 mmol, 2.0 equiv.) at room temperature. The residue was dissolved in DMF (5 mL). The final reaction mixture was irradiated with microwave radiation at 50 °C for 6 hours. The resulting mixture was filtered, the filter cake was washed with DMF (3 x 1 mL). The product was purified by Prep-HPLC with the following conditions (Column: XBridge BEH C18 5 pm, 30 x 150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3«H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 12% B to 29% B in 8 min; Wave Length: 254 / 220 nm) to afford 4-(((l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-5- yl)methyl)amino)-8-methoxyquinoline-3-carbonitrile (14) (56.3 mg, 13.3% yield) as a white solid.

[0320] LCMS (ESI): 346 [M+H]+

[0321] 1H NMR (400 MHz, DMSO-d6) 8 9.14 (s, 1H), 8.63 (t, J = 6.9 Hz, 1H), 8.38 (s,1H), 7.98 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.36 - 7.27 (m, 3H), 5.11 (d, J = 6.7 Hz, 2H), 4.94 (s, 2H), 3.93 (s, 3H).EXAMPLE 15Synthesis of 6-(( 6-methoxy-9H-purin-9-yl)methyl) benzo [ c] [1,2 ]oxaborol-l( 3H)-ol15

[0322] The compound above was synthesized using Scheme 18.113MOFO-359177620.18314352000740Scheme 18Methyl 2-bromo-4-(bromomethyl)benzoate (C37)

[0323] To a stirred solution of methyl 2 -brom o-4-m ethylbenzoate (C36) (1.0 g, 4.3 mmol, 1.0 equiv.) and NBS (1.1 g, 6.5 mmol, 1.5 equiv.) in CCh (10 mL) was added 2-[(E)- 2-(l -cyano- l-methylethyl)diazen-l-yl]-2-m ethylpropanenitrile (0.1 g, 0.8 mmol, 0.2 equiv.) at room temperature. The reaction mixture was stirred at 80 °C for 2 hours. The resulting mixture was diluted with water (100 mL) and then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 ml), dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The product was purified by reverse phase flash with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water, 10 % to 50 % gradient in 10 min; detector, UV 254 nm. This resulted in methyl 2-bromo-4-(bromomethyl)benzoate (C37) (500 mg, 37.19% yield) as a white solid.Methyl 2-bromo-4-((6-methoxy-9H-purin-9-yl)methyl)benzoate & Methyl 2-bromo-4-((6- methoxy-7Hpurin-7-yl)methyl)benzoate (C38a and C38b)

[0324] To a stirred solution of methyl 2-bromo-4-(bromomethyl)benzoate (C37) (500 mg, 1.6 mmol, 1.0 equiv.) and 6-methoxy-9H-purine (C6) (365 mg, 2.4 mmol, 1.5 equiv.) in DMF (10 mL) was added K2CO3 (224 mg, 1.6 mmol, 1.0 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was114MOFO-359177620.18314352000740 diluted with water (100 mL) and then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 ml), dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The product was purified by reverse phase flash with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10 % to 50 % gradient in 10 min; detector, UV 254 nm. This resulted in a mixture of methyl 2-bromo-4-((6-methoxy-9H-purin-9-yl)methyl)benzoate (C38a) and methyl 2-bromo-4-((6-methoxy-7H-purin-7-yl)methyl)benzoate (C38b) (460 mg, 75% yield) as a white solid.(5-((6-Methoxy-9H-purin-9-yl)methyl)-2-(methoxycarbonyl)phenyl)boronic acid & (5-((6- Methoxy-7Hpurin-7-yl)methyl)-2-(methoxycarbonyl)phenyl)boronic acid (C39a and C39b)

[0325] To a stirred solution of methyl 2-bromo-4-((6-methoxy-9H-purin-9- yl)methyl)benzoate and methyl 2-bromo-4-((6-methoxy-7H-purin-7-yl)methyl)benzoate (C38a and C38b) (450 mg, 1.1 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (454 mg, 1.7 mmol, 1.5 equiv.), and KO Ac (292 mg, 2.9 mmol, 2.5 equiv.) in 1,4-dioxane (10 mL) was added Pd PPhs^Ch (83 mg, 0.1 mmol, 0.1 equiv.) at room temperature. The resulting mixture was stirred at 80 °C overnight under N2 atmosphere. The resulting mixture was diluted with water (100 mL) and then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The product was purified by reverse phase flash with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10 % to 50 % gradient in 10 min; detector, UV 254 nm. This resulted in a mixture of (5-((6-methoxy-9H-purin-9-yl)methyl)-2- (methoxycarbonyl)phenyl)boronic acid (C39a) and (5-((6-methoxy-7H-purin-7-yl)methyl)-2- (m ethoxy carbonyl)phenyl)boronic acid (C39b) (300 mg, 73.5% yield) as a white solid.6-(( 6-Methoxy-9H-purin-9-yl)methyl)benzo[ c] [1,2 ]oxaborol-l( 3H)-ol (15)

[0326] To a stirred solution of (5-((6-methoxy-9H-purin-9-yl)methyl)-2- (methoxycarbonyl)phenyl)boronic acid (C39a) and (5-((6-methoxy-7H-purin-7-yl)methyl)-2- (methoxycarbonyl)phenyl)boronic acid (C39b) (300 mg, 0.8 mmol, 1.0 equiv.) in methanol (10 mL) was added NaBEL (99 mg, 2.6 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of saturated NH4CI aqueous solution (30 mL) at room temperature. The resulting115MOFO-359177620.18314352000740 mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Cl 85 pm, 19 mm X 250 mm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: MeCN; Flow rate: 25 mL / min; Gradient: 20% B to 25%B in 10 min; Wave Length: 254nm / 220nm nm) to afford 6-((6-methoxy-9H-purin-9- yl)methyl)benzo[c][l,2]oxaborol-l(3H)-ol (15) (123.5 mg, 47.6% yield) as a white solid.

[0327] LCMS (ESI): 297 [M+H]+

[0328] 1H NMR (400 MHz, DMSO-d6) 8 9.18 (s, 1H), 8.54 (s, 2H), 7.58 (d, J = 1.7 Hz, 1H), 7.49 (dd, J = 7.8, 1.8 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 5.53 (s, 2H), 4.95 (s, 2H), 4.10 (s, 3H).EXAMPLE 16

[0329] The compound above was synthesized using Scheme 19.Scheme 19

[0330] 6-(( 6-Methoxy- 7H-purin- 7-yl)methyl)benzo[ c] [1,2 ]oxaborol-l ( 3H)-ol (16)116MOFO-359177620.18314352000740

[0331] To a stirred solution of (5-((6-methoxy-9H-purin-9-yl)methyl)-2- (methoxycarbonyl)phenyl)boronic acid and (5-((6-methoxy-7H-purin-7-yl)methyl)-2- (methoxycarbonyl)phenyl)boronic acid mixture (C39a and C39b from Example 15) (300 mg, 0.8 mmol, 1.0 equiv.) in methanol (10 mL) was added NaBH4 (99 mg, 2.6 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of saturated NH4C1 aqueous solution (30 ml) at room temperature. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C185 pm, 19 mm X 250 mm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: MeCN; Flow rate: 25 mL / min; Gradient: 20% B to 25%B in 10 min; Wave Length: 254nm / 220nm nm) to afford 6-((6- methoxy-7H-purin-7-yl)methyl)benzo[c][l,2]oxaborol-l(3H)-ol (65.3 mg, 25.2% yield) as a white solid.

[0332] LCMS (ESI): 297 [M+H]+

[0333] 1H NMR (400 MHz, DMSO-d6) 5 9.19 (s, 1H), 8.70 (s, 1H), 8.54 (s, 1H), 7.57 - 7.52 (m, 1H), 7.45 (dd, J = 7.9, 1.8 Hz, 1H), 7.40 (dd, J = 7.8, 0.9 Hz, 1H), 5.62 (s, 2H), 4.95 (s, 2H), 4.04 (s, 3H).EXAMPLE 17Synthesis of 5-(((6, 7-dimethoxyquinazolin-4-yl)amino)methyl)benzo[c] [l,2]oxaborol-l(3H)~ ol

[0334] This compound was synthesized using Scheme 20.Scheme 20117MOFO-359177620.183143520007405-(((6, 7 -Di methoxy quinazolin-4-y I) ami no) methyl) benzo [ c] [1,2 ]oxaborol-l ( 3H)-ol (17)

[0335] Into a 10 mL pressure tank reactor were added 5- (aminomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C34) (200 mg, 1.2 mmol, 1.0 equiv.), 4- chloro-6,7-dimethoxyquinazoline (C40) (220 mg, 0.98 mmol, 0.8 equiv.) and TEA (340 pL, 2.4 mmol, 2.0 equiv.). The residue was dissolved in DMF (5 mL). The final reaction mixture was irradiated with microwave radiation at 50 °C for 6 hours. The resulting mixture was filtered, the filter cake was washed with DMF (3 ^ 1 mL). The product was purified by Prep- HPLC with the following conditions (Column: XBridge BEH Cl 8 OBD Prep Column, 5 pm, 30 mm x 150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3«H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 25% B in 8 min; Wave Length: 254 / 220 nm) to afford 5-(((6,7-dimethoxyquinazolin-4- yl)amino)methyl)benzo[c][l,2]oxaborol-l(3H)-ol (17) (59.8 mg, 13.9 % yield) as a white solid.

[0336] LCMS (ESI): 352 [M+H]+

[0337] 1H NMR (400 MHz, DMSO-d6) 6 9.11 (s, 1H), 8.50 (t, J = 6.0 Hz, 1H), 8.32 (s,1H), 7.71 - 7.65 (m, 2H), 7.40 - 7.32 (m, 2H), 7.11 (s, 1H), 4.95 (s, 2H), 4.85 (d, J = 5.8 Hz, 2H), 3.93 - 3.87 (m, 6H).EXAMPLE 18Synthesis of 5-( (8-methoxyquinazolin-4-yl)amino)methyl)benzo[ c][l,2 ]oxaborol-l(3H)-ol118MOFO-359177620.18314352000740

[0338] This compound was synthesized using Scheme 21.Scheme 215-(( (8-Methoxyquinazolin-4-yl)amino)methyl) benzo [ c] [1,2 ]oxaborol-l( 3H)-ol (18)

[0339] A mixture of 5-(aminomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C34) (200 mg, 1.2 mmol, 1.0 equiv.) , 4-chloro-8-methoxyquinazoline (C41) (239 mg, 1.227 mmol, 1.0 equiv.) and TEA (340 pL, 2.4 mmol, 2.0 equiv.) in DMF (5 mL) was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DMF (3 ^ 1 mL) and filtrate concentrated under reduced pressure. The product was purified by Prep-HPLC with the following conditions (Column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3»H2O), Mobile Phase B: MeOH; Flow rate: 60 mL / min; Gradient: 5% B to 20% B in 8 min; Wave Length: 254 / 220 nm) to afford 5-(((8-methoxyquinazolin-4- yl)amino)methyl)benzo[c][l,2]oxaborol-l(3H)-ol (18) (61.5 mg, 15.6% yield) as a white solid.

[0340] LCMS (ESI): 322 [M+H]+

[0341] 1H NMR (400 MHz, DMSO-d6) 6 9.11 (s, 1H), 8.76 (t, J = 6.0 Hz, 1H), 8.41 (s,1H), 7.82 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.26 (d, J = 7.9 Hz, 1H), 4.94 (s, 2H), 4.84 (d, J = 5.9 Hz, 2H), 3.90 (s, 3H).EXAMPLE 19Synthesis of 5-(( iiinazolin-4-ylamino) methyl) benzo [ c] [1,2 ]oxaborol-l ( 3H)-ol119MOFO-359177620.18314352000740

[0342] This compound was synthesized using Scheme 22.5- Quinazolin-4-ylamino)methyl) benzo [ c] [1,2 ]oxaborol-l( 3H) -ol (19)

[0343] A mixture of 5-(aminomethyl)benzo[c][l,2]oxaborol-l(3H)-ol (C34) (200 mg, 1.227 mmol, 1.0 equiv.), 4-chloroquinazoline (C42) (202 mg, 1.2 mmol, 1.0 equiv.) and TEA (340 pL, 2.4 mmol, 2.0 equiv.) in DMF (5 mL) was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DMF (3 x 1 mL) and the filtrate concentrated under reduced pressure. The product was purified by Prep-HPLC with the following conditions (Column: XB ridge BEH C18 OBD Prep Column, 5 pm, 30 mm x 150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3«H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 20% B in 8 min; Wave Length: 254 / 220 nm) to afford 5-((quinazolin-4-ylamino)methyl) benzofc] [l,2]oxaborol-l(3H)-ol (19) (61.0 mg, 17.1% yield) as a white solid.

[0344] LCMS (ESI): 292 [M+H]+

[0345] 1H NMR (400 MHz, DMSO-d6) 8 9.11 (s, 1H), 8.89 (t, J = 5.9 Hz, 1H), 8.45 (s,1H), 8.32 (dd, J = 8.4, 1.3 Hz, 1H), 7.79 (ddd, 8.3, 6.8, 1.3 Hz, 1H), 7.74 - 7.64 (m, 2H), 7.56 - 7.52 (m, 1H), 7.40 - 7.31 (m, 2H), 4.94 (s, 2H), 4.86 (d, J = 5.9 Hz, 2H).120MOFO-359177620.18314352000740EXAMPLE 20Synthesis of 4-{[(l -hydroxy-3H-2, l-benzoxaborol-6-yl)methyl ]amino}-8-methoxyquinoline-3- carbonitrile, hydrochloride salt

[0346] This compound was synthesized using Scheme 23.Scheme 235-Cyano-2-formylphenylboronic acid (C44)

[0347] To a stirred mixture of 3-bromo-4-formylbenzonitrile (C43) (15.0 g, 71.4 mmol, 1.0 equiv.) and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (27.2 g, 107.1 mmol, 1.5 equiv.) in 1,4-di oxane (250 mL) were added KOAc (17.5 g, 178.5 mmol, 2.5 equiv.) and Pd(dppf)C12 (5.2 g, 7.1 mmol, 0.1 equiv.) in portions at room temperature. The resulting mixture was stirred at 80 °C for overnight under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and then extracted with EtOAc (3 x 70 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The product was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 15% to 20%121MOFO-359177620.18314352000740 gradient in 10 min; detector, UV 220 nm. This resulted in 5-cyano-2-formylphenylboronic acid (C44) (9.1 g, 72.5% yield) as a white solid. l-Hydroxy-3H-2, l-benzoxaborole-6-carbonitrile (C45)

[0348] To a stirred solution of 5-cyano-2-formylphenylboronic acid (C44) (9.0 g, 51.4 mmol, 1.0 equiv.) in THF (250 mL) was added lithium borohydride (4.0M in THF, 25.7 mL, 102.9 mmol, 2.0 equiv.) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 2 hours at 0 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. This resulted l-hydroxy-3H-2,l-benzoxaborole-6- carbonitrile (C45) (10.0 g) as a light brown oil, which was directly used in the next step without further purification.6-(Aminomethyl)-3H-2,l-benzoxaborol-l-ol, hydrochloride salt (C46)

[0349] To a stirred solution of l-hydroxy-3H-2,l-benzoxaborole-6-carbonitrile (C45) (200 mg, 1.3 mmol, 1.0 equiv.) in MeOH (20 mL) were added AcOH (20 mg, 0.3 mmol, 0.3 equiv.) and palladium hydroxide, Pd 5% on carbon powder, nominally 50% water, 100 mg, 0.7 mmol, 0.6 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for 4 hours under hydrogen atmosphere. The resulting mixture was filtered off and the filter cake was washed with MeOH (2 x 10 mL). The filtrate was concentrated under reduced pressure. The product was purified by reverse phase flash with the following conditions (Column: SunFire C185 pm, 19 mm X 250 mm; Mobile Phase A: Water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 1% B to 10% B in 7 min; Wave Length: 254 / 220 nm) to afford 6-(aminomethyl)-3H-2,l-benzoxaborol-l-ol, hydrochloride salt (C46) (60.7 mg, 4.8% yield) as a white solid.

[0350] LCMS (ESI): 164 [M+H]+

[0351] 1H NMR (400 MHz, DMSO-d6) 8 9.29 (s, 1H), 8.30 (s, 3H), 7.77 (d, J = 1.7 Hz,1H), 7.59 (dd, J = 7.9, 1.7 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 5.01 (s, 2H), 4.06 (s, 2H).4-{[(l-Hydroxy-3H-2,l-benzoxaborol-6-yl)methyl]amino}-8-methoxyquinoline-3-carbonitrile hydrochloride salt (20)

[0352] To a stirred mixture of 6-(aminomethyl)-3H-2,l-benzoxaborol-l-ol, hydrochloride salt (C46) (800 mg, 4.9 mmol, 1.0 equiv.) and 4-chloro-8-methoxyquinoline-3-carbonitrile122MOFO-359177620.18314352000740(C35) (322 mg, 1.5 mmol, 0.3 equiv.) in DMF (8 mL) was added TEA (1.5 g, 14.7 mmol, 3.0 equiv.) dropwise at room temperature. The resulting mixture was stirred at room temperature for 4 hours under nitrogen atmosphere. The resulting mixture was filtered off and the filter cake was washed with water (2 x 10 mL). The filtrate was concentrated under reduced pressure. The product (800 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C185 pm, 30 mm X 150 mm; Mobile Phase A: Water (0.1% HCL), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 22% B in 8 min; Wave Length: 254 / 220 nm) to afford 4-{[(l-hydroxy-3H-2,l-benzoxaborol-6-yl)methyl]amino}-8- methoxyquinoline-3-carbonitrile, hydrochloride salt (20) (52.7 mg, 2.8% yield) as a lightyellow solid.

[0353] LCMS (ESI): 346 [M+H]+

[0354] XH NMR (400 MHz, DMSO-d6) 8 10.12 (s, 1H), 9.16 (s, 1H), 8.78 (s, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 9.5, 7.1 Hz, 1H), 7.69 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.51 - 7.40 (m, 2H), 5.28 (d, J = 6.4 Hz, 2H), 4.99 (s, 2H), 4.07 (d, J = 2.1 Hz, 3H).EXAMPLE 21Synthesis of 6-{[(6, 7-dimethoxyquinazolin-4-yl)amino]methyl}-3H-2,l-benzoxaborol-l-ol

[0355] This compound was synthesized using Scheme 24.Scheme 24123MOFO-359177620.183143520007406-{[(6, 7-Dimethoxyquinazolin-4-yl)amino]methyl}-3H-2,l-benzoxaborol-l-ol (21)

[0356] To a stirred solution of 6-(aminomethyl)-3H-2,l-benzoxaborol-l-ol hydrochloride (C46) (400 mg, 2.5 mmol, 1.0 equiv.) in DMF (10 mL) were added 4-chloro-6,7- dimethoxyquinazoline (C40) (165 mg, 0.7 mmol, 0.3 equiv.) and TEA (248 mg, 2.5 mmol, 1.0 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse phase flash with the following conditions (Column: Xselect CSH C185 pm, 30 mm X 150 mm; Mobile Phase A: Water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 20% B in 8 min; Wave Length: 254 / 220 nm) to afford 6-{[(6,7-dimethoxyquinazolin-4-yl)amino]methyl}-3H-2,l-benzoxaborol-l-ol (21) (133.1 mg, 15.4% yield) as a white solid.

[0357] LCMS (ESI): 352 [M+H]+

[0358] 'H NMR (400 MHz, DMSO-d6) 8 14.66 (s, 1H), 10.67 (t, J = 6.0 Hz, 1H), 8.82 (s, 1H), 8.15 (s, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.56 (dd, J = 7.9, 1.7 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.31 (s, 1H), 4.98 (d, J = 5.0 Hz, 4H), 3.97 (d, J = 3.4 Hz, 6H).EXAMPLE 22Synthesis of 6-[(quinazolin-4-ylamino)methyl]-3H-2, 1-benzoxaborol-l-ol

[0359] This compound was synthesized using Scheme 25.124MOFO-359177620.183143520007406-[ ( Quinazolin-4-ylamino)methyl J-3H-2, 1-benzoxaborol-l-ol (22)

[0360] To a stirred solution of 6-(aminomethyl)-3H-2, 1-benzoxaborol-l-ol hydrochloride (C46) (500 mg, 3.3 mmol, 1.0 equiv.) in DMF (10 mL) were added 4-chloroquinazoline (C42) (161 mg, 1.0 mmol, 0.3 equiv.) and TEA (330 mg, 3.3 mmol, 1.0 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: Xselect CSH C185 pm, 30 mm X 150 mm; Mobile Phase A: Water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 15%B in 8 min; Wave Length: 254 nm / 220 nm) to afford the desired product 6-[(quinazolin-4-ylamino)methyl]-3H-2, 1-benzoxaborol-l-ol (22) (177.0 mg, 18.6% yield) as a white solid.

[0361] LCMS (ESI): 292 [M+H]+

[0362] 1H NMR (400 MHz, DMSO-d6) 5 14.88 (s, 1H), 11.07 (t, J = 6.0 Hz, 1H), 8.94 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.08 (t, J = 7.8 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.83 (t, J = 7.7 Hz, 1H), 7.75 (s, 1H), 7.56 (dd, J = 8.0, 1.7 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 5.11 - 4.90 (m, 4H).EXAMPLE 23Synthesis of 4-((2-(l -hydr oxy-1, 3-dihydrobenzo[ c] [1,2 ]oxaborol-5-yl)ethyl)amino)-8- methoxyquinoline-3-carbonitrile125MOFO-359177620.1831435200074023

[0363] This compound was synthesized using Scheme 26.Scheme 265-(Hydroxymethyl)benzo[c] [ 1, 2 ]oxaborol-l ( 3H)-ol (C47)

[0364] To a stirred solution 2-{2,4-bis[(methoxymethoxy)methyl]phenyl}-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (C4) (3.5 g, 9.9 mmol, 1.0 equiv.) in THF (15 mL) was added hydrobromic acid (48% solution in water) (15 mL) dropwise at 0 °C .The resulting mixture was stirred at room temperature for overnight. The resulting mixture was concentrated under vacuum. The product was purified by reverse phase flash with the following conditions (water / ACN) to afford 5-(hydroxymethyl)benzo[c][l,2]oxaborol-l(3H)- ol (C47) (1.5 g, 92.1% yield) as a white solid.5-(Bromomethyl)benzo[c] [ 1, 2 ]oxaborol-l(3H)-ol (C5):

[0365] To a stirred solution of 5-(hydroxymethyl)-3H-2,l-benzoxaborol-l-ol (C4) (1.5 g, 9.1 mmol, 1.0 equiv.) in DCM (30 mL) was added BBn (2.2 g, 9.1 mmol, 1.0 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of MeOH (10 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse phase flash with126MOFO-359177620.18314352000740 the following conditions (water / ACN) to afford 5 -(bromomethyl) benzofc] [1,2] oxaborol- l(3H)-ol (C5) (1.8 g, 86.7% yield, 95% purity) as a white solid.2-( 1 -Hydr oxy-1, 3-dihydrobenzo[ c][l,2 ]oxaborol-5-yl)acetonitri\Q (C48)

[0366] To a stirred solution of 5-(bromomethyl)-3H-2,l-benzoxaborol-l-ol (1.8 g, 7.9 mmol, 1.0. equiv.) in DMF (20 mL) was added KCN (620 mg, 9.5 mmol, 1.2 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The product was purified by reverse phase flash with the following conditions (water / ACN) to afford 2-(l-hydroxy-3H-2,l-benzoxaborol-5-yl) acetonitrile (C48) (1.1 g, 80.15% yield, 95% purity) as a white solid.5-(2-Aminoethyl)benzo [c] [ 1 ,2]oxaborol-l (3H)-ol, hydrochloride salt (C49)

[0367] To a stirred solution of 2-(l-hydroxy-3H-2,l-benzoxaborol-5-yl)acetonitrile (300 mg, 1.7 mmol, 1.0 equiv.) in methanol (100 mL) was added Raney -Ni (101 mg, 1.7 mmol, 1.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 3 hours under H2 atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The product was purified by Prep-HPLC with the following conditions (Column: XB ridge BEH Shield RP18 5 pm, 30 mm *150 mm; Mobile Phase A: Water(10mmol / L NH4HCO3+0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 5% B in 8min; Wave Length: 254 / 220 nm) to afford crude product (100 mg). The product (100 mg) was further purified by Prep-HPLC with the following conditions (Column: SunFire Cl 85 pm, 19 mm X 250 mm; Mobile Phase A: Water(0.1%HCL), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 2% B to 10%B in 7 min; Wave Length: 254nm / 220nm nm) to afford 5-(2-aminoethyl)-3H- 2,1-benzoxaborol-l-ol, hydrochloride salt (C49) (64.1 mg, 17.3% yield) as a white solid.

[0368] LCMS (ESI): 178 [M+H]+

[0369] XH NMR (400 MHz, DMSO-d6) 8 9.18 (s, 1H), 8.09 (s, 3H), 7.71 (d, J = 7.5 Hz, 1H), 7.30 (s, 1H), 7.24 (d, J = 7.5, 1.4 Hz, 1H), 4.97 (s, 2H), 3.10 - 3.00 (m, 2H), 2.99 - 2.91 (m, 2H).127MOFO-359177620.183143520007404-((2-(l -Hydroxy- 1, 3-dihydrobenzo [ c] [1,2 ]oxaborol-5-yl)ethyl)amino)-8-methoxyquinoline- 3-carbonitrile (23)

[0370] To a stirred solution of 5-(2-aminoethyl)benzo[c][l,2]oxaborol-l(3H)-ol, hydrochloride salt (C49) (242 mg, 1.3 mmol) and 4-chloro-8-methoxyquinoline-3- carbonitrile (C35) (200 mg, 0.9 mmol, 1.0 equiv.) in DMF (2 mL) was added EtsN (277 mg, 2.7 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred at 40 °C overnight. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl5 pm, 30*150 mm; Mobile Phase A: Water (0.1% HCL), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 7% B to 17% B in 8 min; Wave Length: 254 nm / 220 nm) to afford 4-((2-(l -hydroxy- 1,3- dihydrobenzo[c][l,2]oxaborol-5-yl)ethyl)amino)-8-methoxyquinoline-3-carbonitrile (23) (55.8 mg, 16.9% yield) as a white solid.

[0371] LCMS (ESI): 360 [M+H]+

[0372] 1H NMR (400 MHz, DMSO-d6) 8 10.33 (d, J = 7.1 Hz, 1H), 8.87 (s, 1H), 8.37 - 8.28 (m, 1H), 7.75 (t, J = 8.3 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.33 - 7.27 (m, 1H), 4.94 (s, 2H), 4.26 - 4.18 (m, 2H), 4.08 (s, 3H), 3.23 - 3.15 (m, 2H).EXAMPLE 24Synthesis of 5-(2-((6, 7-dimethoxyquinazolin-4-yl)amino)ethyl)benzo[c] [l,2]oxaborol-l(3H)~ ol, hydrochloride salt

[0373] This compound was synthesized using Scheme 27.128MOFO-359177620.183143520007405-(2-((6, 7-Dimethoxyquinazolin-4-yl)amino)ethyl) benzo [ c] [1,2 ]oxaborol-l ( 3H)-o[ hydrochloride salt (24)

[0374] To a stirred solution of 5-(2-aminoethyl)benzo[c][l,2]oxaborol-l(3H)-ol, hydrochloride salt (C49) (236 mg, 1.3 mmol, 1.5 equiv.) and 4-chloro-6,7- dimethoxyquinazoline (C40) (200 mg, 0.9 mmol, 1.0 equiv.) in DMF (2 mL) was added EtsN (270 mg, 2.6 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred at 40 °C overnight. The product was purified by prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl5 pm, 30*150 mm; Mobile Phase A: Water (0.1%HCL), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 8% B to 15%B in 8 min; Wave Length: 254 nm / 220 nm) to afford 5-(2-((6,7-dimethoxyquinazolin-4- yl)amino)ethyl)benzo[c][l,2]oxaborol-l(3H)-ol, hydrochloride salt (24) (59.6 mg, 16.67% yield) as a white solid.

[0375] LCMS (ESI): 366 [M+H]+

[0376] 'H NMR (400 MHz, DMSO-d6) 8 14.53 (s, 1H), 10.19 (t, J = 5.7 Hz, 1H), 9.15 (s, 1H), 8.81 (s, 1H), 8.04 (s, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.34 (s, 1H), 7.27 (d, J = 7.0 Hz, 2H), 4.95 (s, 2H), 3.97-3.96 (s, 3H), 3.96-3.94 (s, 3H), 3.94-3.90 (m, 2H), 3.08 (t, J = 8.7, 6.4 Hz, 2H).129MOFO-359177620.18314352000740EXAMPLE 25Synthesis of 5-(2-((8-methoxyquinazolin-4-yl)amino)ethyl)benzo[c] [l,2]oxaborol-l(3H)-ol, hydrochloride salt

[0377] This compound was synthesized using Scheme 28.5-(2-((8-Methoxyquinazolin-4-yl)amino)ethyl)benzo[c] [l,2]oxaborol-l(3H)-ol, hydrochloride salt (25)

[0378] To a stirred solution of 5-(2-aminoethyl)benzo[c][l,2]oxaborol-l(3H)-ol, hydrochloride salt (C49) (409 mg, 2.3 mmol, 1.5 equiv.) and 4-chloro-8-methoxyquinazoline (C41) (300 mg, 1.5 mmol, 1.0 equiv.) in DMF (3 mL) was added EtsN (467 mg, 4.6 mmol, 3.0 equiv.) at room temperature. The product was purified by prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl5 pm, 30*150 mm; Mobile Phase A: Water (0.1% HCI), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 18% B in 8 min; Wave Length: 254 nm / 220 nm) to afford 5-(2-((8-methoxyquinazolin-4- yl)amino)ethyl)benzo[c][l,2]oxaborol-l(3H)-ol, hydrochloride salt (25) (66.8 mg, 12.9% yield) as a white solid.

[0379] LCMS (ESI): 336 [M+H]+

[0380] 'H NMR (400 MHz, DMSO-d6) 8 14.14 (s, 1H), 10.59 (t, J = 5.7 Hz, 1H), 9.15 (s, 1H), 8.75 (s, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.73 (t, J = 8.2 Hz, 1H), 7.68-7.61 (m, 2H), 7.33130MOFO-359177620.18314352000740(s, 1H), 7.26 (d, J = 7.5, 1.4 Hz, 1H), 4.94 (s, 2H), 4.06 (s, 3H), 4.00-3.92 (m, 2H), 3.09 (t, J = 7.4 Hz, 2H).EXAMPLE 26Synthesis of 5-(2-(quinazolin-4-ylamino)ethyl)benzo[c] [l,2]oxaborol-l(3H)-ol, hydrochloride salt

[0381] This compound was synthesized using Scheme 29.5-(2-(Quinazolin-4-ylamino)ethyl)benzo[c] [l,2]oxaborol-l(3H)-ol, hydrochloride salt (26)

[0382] To a stirred solution of 5-(2-aminoethyl)benzo[c][l,2]oxaborol-l(3H)-ol, hydrochloride salt (C49) (322 mg, 1.8 mmol, 1.5 equiv.) and 4-chloroquinazoline (C42) (200 mg, 1.2 mmol, 1.0 equiv.) in DMF (5 mL) was added EtsN (368 mg, 3.6 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The product was purified by prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl5 pm, 30*150 mm; Mobile Phase A: Water (0.1% HCI), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 12% B in 8 min; Wave Length: 254 nm / 220 nm) to afford 5-(2-(quinazolin-4-ylamino)ethyl)benzo[c][l,2]oxaborol-l(3H)-ol, hydrochloride salt (26) (67.4 mg, 16.2% yield) as a white solid.

[0383] LCMS (ESI): 306 [M+H]131MOFO-359177620.18314352000740

[0384] 1H NMR (400 MHz, DMSO-d6) 8 14.95 (s, 1H), 10.70 (t, J = 6.1 Hz, 1H), 9.16 (s, 1H), 8.91 (s, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.06 - 8.01 (m, 1H), 7.92 - 7.88 (m, 1H), 7.80 - 7.74 (m, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.33 (s, 1H), 7.26 (d, J = 7.5, 1.4 Hz, 1H), 4.94 (s, 2H), 4.00 - 3.92 (m, 2H), 3.13 - 3.03 (m, 2H).EXAMPLE 27Synthesis of 6-{[(8-methoxyquinazolin-4-yl)amino]methyl}-3H-2, 1-benzoxaborol-l-ol

[0385] This compound was synthesized using Scheme 30.6-{[(8-Methoxyquinazolin-4-yl)amino]methyl}-3H-2, 1-benzoxaborol-l-ol (27)

[0386] To a stirred solution of 6-(aminomethyl)-3H-2, 1-benzoxaborol-l-ol hydrochloride (C46) (900 mg, 5.5 mmol, 1.0 equiv.) in DMF (15 mL) were added 4-chloro-8- methoxyquinazoline (C41) (322 mg, 1. 7 mmol, 0.3 equiv.) and TEA (559 mg, 5.5 mmol, 1.0 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse phase flash with the following conditions (Column: Xselect CSH C185 pm, 30 mm X 150 mm; Mobile Phase A: Water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 17%B in 8 min; Wave Length: 254 / 220 nm) to afford 6- {[(8-m ethoxy quinazolin-4-yl)amino]methyl}-3H-2, 1-benzoxaborol-l-ol (27) (46.7 mg, 2.6% yield) as a white solid.132MOFO-359177620.18314352000740

[0387] LCMS (ESI): 322 [M+H]+

[0388] 1H NMR (400 MHz, DMSO-d6) 14.24 (s, 1H), 10.89 (d, J = 6.9 Hz, 1H), 9.17 (s,1H), 8.78 (s, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.77 (t, J = 8.2 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.55 (dd, J = 7.9, 1.7 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 5.11 - 4.88 (m, 4H), 4.07 (s, 3H).EXAMPLE 28Synthesis of 4-((2-(l -hydr oxy-1, 3-dihydrobenzo[ c] [1,2 ]oxaborol-6-yl) ethyl) amino) -8- methoxyquinoline-3-carbonitrile

[0389] This compound was synthesized using Scheme 31.Scheme 31Methyl 2-bromo-4-(cyanomethyl)benzoate (C51)

[0390] To a stirred mixture of TBAF (19.3 g, 74.03 mmol, 3.0 equiv.) and TMSCN (7.3 g, 74.03 mmol, 3.0 equiv.) in MeCN (150 mL) was added methyl 2-bromo-4- (bromomethyl)benzoate (C50) (7.6 g, 24.68 mmol, 1.0 equiv.) in portions at 25 °C under air133MOFO-359177620.18314352000740 atmosphere. The resulting mixture was stirred at 25 °C for 20 minutes. The resulting mixture was diluted with H2O (300 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography, eluted with PE / EA (3 / 2) to afford methyl 2-bromo-4- (cyanomethyl)benzoate (C51) (5.0 g, 79.7% yield) as a white oil.Methyl 4-(cyanomethyl)-2-( 4, 4, 5, 5 -tetramethyl- 1 , 3, 2-dioxaborolan-2-yl) benzoate (C 52) :

[0391] A solution of methyl 2-bromo-4-(cyanomethyl)benzoate (C51) (5.0 g, 19.68 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (7.5 g, 29.52 mmol, 1.5 equiv.), KO Ac (4.8 g, 49.20 mmol, 2.5 equiv.) and Pd(PPh3)2Cl2(1.4 g, 1.97 mmol, 0.1 equiv.) in 1,4-dioxane (100 mL) was stirred at 80 °C for 4 hours under nitrogen atmosphere. The resulting mixture was filtered off and the filter cake was washed with EtOAc (3 x 30 mL). The filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography, eluted with PE / EA (1.5 / 1) to afford methyl 4-(cyanomethyl)-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (C52) (3.7 g, 62.75% yield, 94 % purity) as a white solid.2-(l -Hydr oxy-1, 3-dihydrobenzo[ c] [1,2 ]oxaborol-6-yl)acetonitrile (C53 )

[0392] To a stirred solution of 5-(cyanomethyl)-2-(methoxycarbonyl)phenylboronic acid (C52) (3.7 g, 16.90 mmol, 1.0 equiv.) in methanol (60 mL) was added NaBEL (5.1 g, 135.16 mmol, 8.0 equiv.) in portions at 0 °C under air atmosphere. The resulting mixture was stirred at 25 °C for 2 hours under air atmosphere. The reaction was quenched with ice water (50 mL). The mixture was acidified to pH 6 with HC1 (4 M aqueous solution) and the resulting mixture was concentrated under vacuum. The product was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 20 min; detector, UV 254 nm to afford 2-(l-hydroxy-3H- 2,l-benzoxaborol-6-yl)acetonitrile (C53) (1.5 g, 51.3% yield) as a light-yellow oil.6-(2-Aminoethyl)benzo [c] [ 1 ,2]oxaborol-l (3H)-ol, hydrochloride salt (C54)

[0393] A solution of 2-(l-hydroxy-3H-2,l-benzoxaborol-6-yl)acetonitrile (C53) (100 mg, 0.58 mmol, 1.0 equiv.) and Raney-Ni (51 mg, 0.87 mmol, 1.5 equiv.) in methanol (3 mL) was stirred at 25 °C for 2 hours under hydrogen atmosphere. The resulting mixture was filtered134MOFO-359177620.18314352000740 off over the celite and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The product was purified by Prep-HPLC with the following conditions (Column: SunFire Cl 85 pm, 19 mm X 250 mm; Mobile Phase A: Water (0.2%HCl), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 2% B to 12%B in 7 min; Wave Length: 254nm / 220nm nm) to afford 6-(2-aminoethyl)benzo[c][l,2]oxaborol- l(3H)-ol, hydrochloride salt (C54) (58.1 mg, 56.8% yield) as an off-white solid.

[0394] LCMS (ESI): 178 [M+H]+

[0395] 1H NMR (400 MHz, DMSO-d6) 9.21 (d, J = 4.1 Hz, 1H), 8.16 (s, 3H), 7.63 (s, 1H), 7.37 (s, 2H), 4.97 (s, 2H), 2.99 - 2.95 (m, 4H).4-((2-(l -Hydr oxy-1, 3-dihydrobenzo [ c] [1,2 ]oxaborol-6-yl)ethyl)amino)-8-methoxyquinoline- 3-carbonitrile (28):

[0396] A solution of 6-(2-aminoethyl)-3H-2,l-benzoxaborol-l-ol, hydrochloride salt (C54) (80 mg, 0.45 mmol, 1.0 equiv.), 4-chloro-8-methoxyquinoline-3-carbonitrile (C35) (90 mg, 0.45 mmol, 1.0 equiv.) and EtsN (137 mg, 1.36 mmol, 3.0 equiv.) in DMF (3 mL) was stirred at 25 °C for 2 hours under air atmosphere. The product was purified by Prep-HPLC with the following conditions (Column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 33% B in 8 min; Wave Length: 254 / 220 nm) to afford 4-((2-(l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)ethyl)amino)-8- methoxyquinoline-3 -carbonitrile (28) (57.2 mg, 35.2% yield) as a white solid.

[0397] LCMS (ESI): 360 [M+H]+

[0398] 1H NMR (400 MHz, DMSO-d6) 8 9.14 (s, 1H), 8.46 (s, 1H), 8.11 (t, J = 6.3 Hz,1H), 7.83 (dd, J = 8.7, 1.0 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.53-7.42 (m, 2H), 7.35 (d, . / = 7.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 4.96 (s, 2H), 4.05-3.95 (m, 2H), 3.92 (s, 3H), 3.09 (dd, J = 9.1, 6.4 Hz, 2H).EXAMPLE 29Synthesis of 6-(2-((6, 7-dimethoxyquinazolin-4-yl)amino)ethyl)benzo[c] [l,2]oxaborol-l(3H)~ ol, hydrochloride salt135MOFO-359177620.18314352000740

[0399] This compound was synthesized using Scheme 32.Scheme 326-12-116, 7-Dimethoxyquinazolin-4-yl)amino)ethyl) benzo [ c] [1,2 ]oxaborol-l ( 3H)-ol, hydrochloride salt (29)

[0400] A solution of 6-(2-aminoethyl)-3H-2,l-benzoxaborol-l-ol, hydrochloride salt (C54) (80 mg, 0.45 mmol, 1.0 equiv.), 4-chloro-6,7-dimethoxyquinazoline (101 mg, 0.45 mmol, 1.0 equiv.) and EtsN (137 mg, 1.36 mmol, 3.0 equiv.) in DMF (3 mL) was stirred at 40 °C for overnight. The product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl5 pm, 30*150 mm; Mobile Phase A: Water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 8% B to 15%B in 8 min; Wave Length: 254nm / 220nm nm) to afford 6-(2-((6,7-dimethoxyquinazolin-4- yl)amino)ethyl)benzo[c][l,2]oxaborol-l(3H)-ol, hydrochloride salt (29) (55.5 mg, 30.6% yield) as an off-white solid.

[0401] LCMS (ESI): 366 [M+H]+

[0402] 'H NMR (400 MHz, DMSO-d6) 14.49 (s, 1H), 10.15 (t, J = 5.7 Hz, 1H), 9.15 (s, 1H), 8.82 (s, 1H), 8.02 (s, 1H), 7.65 (s, 1H), 7.44 - 7.33 (m, 2H), 7.27 (s, 1H), 4.96 (s, 2H), 3.99 - 3.88 (m, 8H), 3.07 (t, J = 7.5 Hz, 2H).136MOFO-359177620.18314352000740EXAMPLE 30Synthesis of 6-(2-( (8-methoxyquinazolin-4-yl)amino)ethyl) benzo [ c] [1,2 ]oxaborol-l ( 3H)-ol

[0403] This compound was synthesized using Scheme 33.6-(2-((8-Methoxyquinazolin-4-yl)amino)ethyl)benzo[c] [l,2]oxaborol-l(3H)-ol (30)

[0404] A solution of 6-(2-aminoethyl)-3H-2,l-benzoxaborol-l-ol, hydrochloride salt (C54) (80 mg, 0.45 mmol, 1.0 equiv.), 4-chloro-8-methoxyquinazoline (C41) (88 mg, 0.45 mmol, 1.0 equiv.) and EtsN (137 mg, 1.36 mmol, 3.0 equiv.) in DMF (3 mL) was stirred at 25 °C for 3 hours under air atmosphere. The product was purified by Prep-HPLC with the following conditions (Column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: Water(10 mmol / L NH4HCO3+0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 27% B in 8min; Wave Length: 254 / 220 nm) to afford 6-(2-((8-m ethoxy quinazolin-4-yl)amino)ethyl)benzo[c] [ 1 ,2]oxaborol- 1 (3H)-ol (30) (56.9 mg, 37.6% yield) as a white solid.

[0405] LCMS (ESI): 336 [M+H]+

[0406] 1H NMR (400 MHz, DMSO-d6) 9.12 (s, 1H), 8.49 (s, 1H), 8.40 (s, 1H), 7.73 (d, J= 8.4 Hz, 1H), 7.64 (s, 1H), 7.48-7.32 (m, 3H), 7.27 (dd, J = 8.0, 1.1 Hz, 1H), 4.96 (s, 2H), 3.91 (s, 3H), 3.77 (dt, J = 8.2, 6.0 Hz, 2H), 3.01 (t, J = 7.5 Hz, 2H).137MOFO-359177620.18314352000740EXAMPLE 31Synthesis of 6-(2-(quinazolin-4-ylamino)ethyl)benzo[c] [l,2]oxaborol-l(3H)-ol31

[0407] This compound was synthesized using Scheme 34.6-(2-(Quinazolin-4-ylamino)ethyl) benzo [ c] [1,2 ]oxaborol-l( 3H)-ol (31)

[0408] A solution of 6-(2-aminoethyl)-3H-2,l-benzoxaborol-l-ol, hydrochloride salt (C54) (80 mg, 0.45 mmol, 1.0 equiv.), 4-chloroquinazoline (C42) (74 mg, 0.45 mmol, 1.0 equiv.) and EtsN (137 mg, 1.36 mmol, 3.0 equiv.) in DMF (3 mL) was stirred at 25 °C for 3 hours under air atmosphere. The product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Cl 85 pm, 19 mm X 250 mm; Mobile Phase A: Water (0.2% HC1), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 10% B to 20% B in 10 min; Wave Length: 254 / 220 nm) to afford 6-(2-(quinazolin-4- ylamino)ethyl)benzo[c][l,2]oxaborol-l(3H)-ol (31) (58.0 mg, 42.0% yield) as a white solid.

[0409] LCMS (ESI): 306 [M+H]+

[0410] XH NMR (400 MHz, DMSO-d6) 9.12 (s, 1H), 8.50 (s, 1H), 8.39 (t, J = 5.6 Hz, 1H), 8.20 (dd, J = 8.4, 1.3 Hz, 1H), 7.80-7.61 (m, 3H), 7.52 - 7.46 (m, 1H), 7.42-7.31 (m, 2H), 4.96 (s, 2H), 3.77 (dt, J = 8.3, 6.0 Hz, 2H), 3.02 (t, J = 7.5 Hz, 2H).EXAMPLE 32138MOFO-359177620.18314352000740Synthesis of 3-((l -hydr oxy-1, 3-dihydrobenzo[ c] [1,2 ]oxaborol-5-yl)methyl)-2-methyl-3H- imidazo[4,5-c]pyridin-4-ol, hydrochloride salt

[0411] This compound was synthesized using Scheme 35.Scheme 355-({4-Methoxy-2-methylimidazo[4,5-c]pyridin-3-yl}methyl)-3H-2,l-benzoxaborol-l-ol (C56) and 5-({4-methoxy-2-methylimidazo[4,5-c]pyridin-l-yl}methyl)-3H-2,l-benzoxaborol-l-ol (C57)

[0412] A solution of 4-methoxy-2-methyl-lH-imidazo[4,5-c]pyridine (C55) (518 mg, 3.2 mmol, 0.9 equiv.) in DMF (8 mL) was treated with NaH (353 mg, 8.8 mmol, 2.5 equiv., 60%) at 0 °C for 15 minutes, followed by the addition of 5-(bromomethyl)-3H-2,l- benzoxaborol-l-ol (C5) (800 mg, 3.5 mmol, 1.0 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of ice water (4 mL) at 0 °C. The product was purified by Prep-HPLC with the139MOFO-359177620.18314352000740 following conditions (Column: Ultimate p XB-C18, 50*250 mm, 10 pm; Flow rate: 100 mL / min; Gradient: isocratic; Wave Length: 254 nm; Injection Volume: 1 mL) to afford 5- ({4-methoxy-2-methylimidazo[4,5-c]pyridin-3-yl}methyl)-3H- 2,1-benzoxaborol-l-ol (56) (370 mg, 33.9% yield) as a colorless semi-solid and 5-({4-methoxy- 2-methylimidazo[4,5- c]pyridin-l-yl}methyl)-3H-2,l-benzoxaborol-l-ol (57) (470 mg, 43.1% yield) as a white solid.3-((l -Hydr oxy-1, 3-dihydrobenzo[ c] [1,2 ] oxaborol-5-yl)methyl)-2-methyl-3H-imidazo [ 4, 5- c]pyridin-4-ol, hydrochloride salt (32)

[0413] A solution of 5-({4-methoxy-2-methylimidazo[4,5-c]pyridin-3-yl}methyl)-3H- 2,1-benzoxaborol-l-ol (C56) (300 mg, 1.0 mmol, 1.0 equiv.) in HC1 (20 mL, 3 M in H2O) was stirred at room temperature for overnight under air atmosphere. The resulting mixture was filtered off and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The product (200 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C185 pm, 30 mm X 150 mm; Mobile Phase A: Water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 10%B in 7 min; Wave Length: 254 nm / 220 nm) to afford the desired product 3 -((1 -hydroxy - l,3-dihydrobenzo[c][l,2]oxaborol-5-yl)methyl)-2-methyl-3H-imidazo[4,5-c]pyridin-4-ol, hydrochloride salt (32) (146.3 mg, 45.4% yield) as a white solid.

[0414] LCMS (ESI): 296 [M+H]+

[0415] 'H NMR (400 MHz, DMSO-d6) 8 12.06 (d, J = 5.7 Hz, 1H), 8.88 (s, 1H), 7.82 - 7.73 (m, 1H), 7.53 - 7.41 (m, 1H), 7.26 (d, J = 6.5 Hz, 2H), 6.73 (d, J = 7.1 Hz, 1H), 5.66 (s, 2H), 4.94 (s, 2H), 2.68 (s, 3H).EXAMPLE 33Synthesis of 1-((1 -hydr oxy-1, 3-dihydrobenzo[ c] [1,2 ]oxaborol-5-yl)methyl)-2-methyl-lH- imidazo[ 4, 5-c ]pyridin-4-ol

[0416] This compound was synthesized using Scheme 36.140MOFO-359177620.18314352000740Scheme 361-((1 -Hydroxy-1, 3-dihydrobenzo[ c] [1,2 ] oxaborol-5-yl)methyl) -2 -methyl- lH-imidazo[ 4, 5- c]pyridin-4-ol (33):

[0417] A solution of 5-({4-methoxy-2-methylimidazo[4,5-c]pyridin-l-yl}methyl)-3H- 2,1-benzoxaborol-l-ol (C57 in Example 32) (470 mg, 1.5 mmol, 1.0 equiv.) in HC1 (6 M in H2O, 50 mL) was stirred at 50 °C for overnight under air atmosphere. The resulting mixture was concentrated under vacuum. The product was purified by trituration with MeCN (10 mL) twice and trituration with DCMZEA (1 / 1) (10 mL) twice. This resulted in the intermediate 1- ((l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-5-yl)methyl)-2-methyl-lH-imidazo[4,5- c]pyridin-4-ol, hydrochloride salt (319.9 mg, 63.4% yield) as a white solid. The material was dissolved in DMSO (6 mL), MeOH (2 mL) and H2O (2 mL). The mixture was basified to pH 10 with TEA. The product was purified by Prep-HPLC with the following conditions (Column: YMC Triart C18 ExRs 5 pm, 30 mm * 150 mm; Mobile Phase A: Water(10 mmol / L NH4HCO3+0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 3% B to 15% B in 14min; Wave Length: 254 / 220 nm) to afford l-((l-hydroxy-l,3- dihydrobenzo[c][l,2]oxaborol-5-yl)methyl)-2-methyl-lH-imidazo[4,5-c]pyridin-4-ol hydrochloride salt (60 mg). The product was dissolved in DMSO (6 mL) and further purified by Prep-HPLC with the following conditions (Column: XB ridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: Water(100% H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 1% B to 20% B in lOmin; Wave Length: 254 / 220 nm) to afford l-((l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-5-yl)methyl)-2-methyl-lH- imidazo[4,5-c]pyridin-4-ol (33) (32.5 mg, 24.3% yield) as a white solid.

[0418] LCMS (ESI): 296 [M+H]+

[0419] 'H NMR (400 MHz, DMSO-d6) 8 11.11 (d, J= 5.1 Hz, 1H), 9.18 (s, 1H), 7.73 - 7.67 (m, 1H), 7.13 - 7.07 (m, 3H), 6.53 (d, J = 7.0 Hz, 1H), 2.40 (s, 3H).141MOFO-359177620.18314352000740EXAMPLE 34Synthesis of 1-((1 -hydr oxy-1, 3-dihydrobenzo[ c] [1,2 ]oxaborol-6-yl)methyl)-2-methyl-lH- imidazo[ 4, 5-c ]pyridin-4-ol

[0420] This compound was synthesized using Scheme 37.Scheme 37Methyl 2-bromo-4-( 4-methoxy-2-methyl-lH-imidazo[ 4, 5-c ]pyridin-l-yl)methyl)benzoate (C59) & methyl 2-bromo-4-((4-methoxy-2-methyl-3H-imidazo[4,5-c]pyridin-3- yl)methyl)benzoate (C58)

[0421] To a stirred solution of 4-methoxy-2-methyl-17 / -imidazo[4,5-c]pyridine (C55) (1.6 g, 9.8 mmol, 1.0 equiv.) in DMF (20 mL) was added NaH (588 mg, 14.7 mmol, 1.5 equiv., 60%) at 0 °C. The reaction mixture was stirred for another 30 minutes at 0 °C. To the above mixture was added methyl 2-bromo-4-(bromomethyl)benzoate (C50) (3.6 g, 11.8 mmol, 1.2 equiv.). The resulting mixture was warmed to room temperature and stirred at room temperature overnight. The reaction was quenched by the addition of water (60 mL) at142MOFO-359177620.183143520007400 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with H2O (3 x 30 mL) and dried over anhydrous ISfeSC After filtration, the mixture was concentrated under reduced pressure. The product was purified by reversephase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in a mixture of C59 & C58 (3.1 g, 81.0% yield) as a yellow solid.(5-((4-Methoxy-2-methyl-lH-imidazo[4,5-c]pyridin-l-yl)methyl)-2- (methoxycarbonyl)phenyl)boronic acid (C61) & (5-((4-methoxy-2-methyl-3H-imidazo[4,5- c]pyridin-3-yl)methyl)-2-(methoxycarbonyl)phenyl)boronic acid (C60)

[0422] To a stirred solution of a mixture of methyl 2-bromo-4-((4-methoxy-2-methyl-UT- imidazo[4,5-c]pyridin-l-yl)methyl)benzoate (C59) & methyl 2-bromo-4-((4-methoxy-2- methyl-3J / -imidazo[4,5-c]pyridin-3-yl)methyl)benzoate (C58) (2.9 g, 7.4 mmol, 1.0 equiv.) in 1,4-dioxane (30 mL) was added Pin2B2 (9.4 g, 36.9 mmol, 5.0 equiv.), CsF (2.8 g, 18.5 mmol, 2.5 equiv.) and Pd(PPh3)2C12 (518 mg, 0.7 mmol, 0.1 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was heated to 80 °C overnight under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in a mixture of C61 & C60 (1.0 g, 38.1% yield) as a light-yellow solid.6-(( 4-Methoxy-2 -methyl- lH-imidazo[ 4, 5-c ]pyridin-l-yl)methyl) benzo [ c] [1,2 ]oxaborol- l(3H)-ol (C57) & 6-((4-methoxy-2-methyl-3H-imidazo[4,5-c]pyridin-3- yl)methyl)benzo[ c] [1,2 ]oxaborol-l ( 3H) -0 / (C 56)

[0423] To a stirred solution of the mixture of (5-((4-methoxy-2-methyl-lH-imidazo[4,5- c]pyridin-l-yl)methyl)-2-(methoxycarbonyl)phenyl)boronic acid (C61) & (5-((4-methoxy-2- methyl-3H-imidazo[4,5-c]pyridin-3-yl)methyl)-2-(methoxycarbonyl)phenyl)boronic acid (C60) (1.0 g, 2.8 mmol, 1.0 equiv.) in methanol (10 mL) was added NaBFL (106 mg, 2.8 mmol, 1.0 equiv.) at 0 °C. The mixture was stirred for 2 hours at room temperature. The reaction was quenched with saturated NH4CI aqueous solution (100 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, Cl 8 silica gel; mobile143MOFO-359177620.18314352000740 phase, MeCN in Water (0.1% FA), 0 to 30% gradient in 20 min; detector, UV 220 nm. This resulted in a mixture of C57 & C56 (250 mg, 28.7% yield) as a light-yellow solid.1-((1 -Hydr oxy-1, 3-dihydrobenzo[ c] [1,2 ] oxaborol-6-yl)methyl) -2 -methyl- lH-imidazo[ 4, 5- c]pyridin-4-ol (34)

[0424] A solution of the mixture of 6-((4-methoxy-2-methyl-U / -imidazo[4,5-c]pyridin-l- yl)methyl)benzo[c][l,2]oxaborol-l(3J7)-ol (C57) & 6-((4-methoxy-2-methyl-3JT- imidazo[4,5-c]pyridin-3-yl)methyl)benzo[c][l,2]oxaborol-l(3J7)-ol (C56) (250 mg, 0.8 mmol, 1.0 equiv.) in 1,4-dioxane (2 mL) was added HC1 in 1,4-dioxane (4.0 M, 4 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The collected residue was dissolved in MeOH (2 mL) and TEA (0.5 mL) and the product purified by prep-HPLC with following conditions: Column: XBridge BEH Shield RP18 5 pm, 30 mm *150 mm; Mobile Phase A: water (10 mmol / L NH-tHCCh+O. E / o NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 0% B to 10% B in 12min; Wave Length: 220 nm. This resulted in 34 (48.9 mg, 20.49% yield, 98.9% purity) as a white solid.

[0425] LCMS (ESI): 296 [M+H]+

[0426] XH NMR (400 MHz, DMSO-de) 6 11.11 (s, 1H), 9.19 (s, 1H), 7.46 - 7.35 (m, 2H), 7.32 (dd, J = 7.9, 1.8 Hz, 1H), 7.11 (d, J= 6.3 Hz, 1H), 6.52 (d, J= 7.0 Hz, 1H), 5.44 (s, 2H), 4.96 (s, 2H), 2.41 (s, 3H).EXAMPLE 35Synthesis of l-[2-(l -Hydroxy-3H-2, l-benzoxaborol-6-yl) ethyl ]-2-methylimidazo[ 4, 5- c]pyridin-4-ol

[0427] This compound was synthesized using Scheme 38.144MOFO-359177620.18314352000740Scheme 386-{2-[(2-Methoxy-3-nitropyridin-4-yl)amino]ethyl}-3H-2,l-benzoxaborol-l-ol (C63)

[0428] To a stirred solution of 4-chloro-2-methoxy-3-nitropyridine (C62) (1.0 g, 5.3 mmol, 1.0 equiv.) and 6-(2-aminoethyl)-3J / -2,l-benzoxaborol-l-ol (C54) (1.1 g, 6.3 mmol, 1.2 equiv.) in DMF (20 mL) was added K2CO3 (1.5 g, 10.6 mmol, 2.0 equiv.) at room temperature under nitrogen atmosphere The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse-phase combi- chromatography with the following conditions: column, Cl 8; mobile phase, MeCN in Water, 30% to 40% gradient in 10 min; detector, UV 254 nm to afford (C63) (1.0 g, 57.3% yield) as a yellow solid.6-{2-[(3-Amino-2-methoxypyridin-4-yl)amino]ethyl}-3H-2,l-benzoxaborol-l-ol (C64)

[0429] To a stirred solution of 6-{2-[(2-methoxy-3-nitropyridin-4-yl)amino]ethyl}-3JT- 2,1-benzoxaborol-l-ol (C63) (1.0 g, 3.0 mmol, 1.0 equiv.) and B2(OH)4 (817 mg, 9.1 mmol, 3.0 equiv.) in DMF (10 mL) was added 4-(pyridin-4-yl)pyridine (95 mg, 0.6 mmol, 0.2145MOFO-359177620.18314352000740 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse-phase combi- chromatography with the following conditions: column, Cl 8; mobile phase, MeCN in Water, 10% to 30% gradient in 10 min; detector, UV 254 nm to afford C64 (690 mg, 75.9% yield) as a light-yellow solid.(E)-(ethyl N-(4-{[2-(l-hydroxy-3H-2, l-benzoxaborol-6-yl)ethyl]amino}-2-methoxypyridin-3- yl)ethanimidate) (C65)

[0430] To a stirred solution of 6-{2-[(3-amino-2-methoxypyridin-4-yl)amino]ethyl}-3JT- 2,1-benzoxaborol-l-ol (C64) (360 mg, 1.2 mmol, 1.0 equiv.) and 1,1,1 -tri ethoxy ethane (585 mg, 3.6 mmol, 3.0 equiv.) in toluene (10 mL) was added pyridine hydrochloride (28 mg, 0.2 mmol, 0.2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was heated to 110 °C overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse-phase combi- chromatography with the following conditions: column, Cl 8; mobile phase, MeCN in water, 40% to 50% gradient in 10 min; detector, UV 254 nm to afford C65 (150 mg, 33.8% yield) as a yellow solid.6-(2-{4-Methoxy-2-methylimidazo[4,5-c]pyridin-l-yl}ethyl)-3H-2,l-benzoxaborol-l-ol (C66)

[0431] A solution of intermediate (E)-(ethyl 7V-(4-{[2-(l -hydroxy-3 JT-2,1 -benzoxaborol- 6-yl)ethyl]amino}-2-methoxypyridin-3-yl)ethanimidate) (C65) (200 mg, 0.5 mmol, 1.0 equiv.) in AcOH (8 mL) was heated to 80 °C overnight under nitrogen atmosphere. The resulting mixture was concentrated under vacuum to afford C66 (180 mg) as a brown oil, which was used directly in the next step without further purification. l-[2-(l -Hydroxy-3H-2, l-benzoxaborol-6-yl) ethyl ]-2-methylimidazo[ 4, 5-c ]pyridin-4-ol (35)

[0432] A solution of 6-(2-{4-methoxy-2-methylimidazo[4,5-c]pyridin-l-yl}ethyl)-3JT- 2,1-benzoxaborol-l-ol (C66) (220 mg, 0.6 mmol, 1.0 equiv.) in HC1 (4.0 M in 1,4-dioxane, 3 mL) was heated to 50 °C overnight under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The product was purified by Prep-HPLC with the following conditions: Column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate:146MOFO-359177620.1831435200074060 mL / min; Gradient (B%): 3% B to 12% B in 8 min; Wave Length: 254 / 220 nm. This resulted in 35 (76.9 mg, 36.5% yield) as a pink solid.

[0433] LCMS (ESI): 310 [M+H]+

[0434] 1H NMR (400 MHz, DMSO-t / 6) 5 11.04 (s, 1H), 9.11 (s, 1H), 7.47 - 7.44 (m, 1H),7.30 (d, J= 7.8 Hz, 1H), 7.21 (dd, J= 7.8, 1.7 Hz, 1H), 7.08 (d, J= 7.0 Hz, 1H), 6.49 (d, J= 7.0 Hz, 1H), 4.95 (s, 2H), 4.30 (t, J= 7.0 Hz, 2H), 3.01 (t, J= 7.0 Hz, 2H), 2.15 (s, 3H).EXAMPLE 37Synthesis of 6-( (8-Methoxyquinazolin-4-yl)amino)methyl)-3-methylbenzo[ c][l,2 ]oxaborol-l (3H)-ol dihydrochloride

[0435] This compound was synthesized using Scheme 39.147MOFO-359177620.18314352000740Scheme 394-Acetyl-3-bromobenzonitrile (C68)

[0436] To a stirred solution of 3-bromo-4-iodobenzonitrile (C67) (5.0 g, 16.2 mmol, 1.0 equiv.) and Pd(PPh3)2Ch (570 mg, 0.8 mmol, 0.05 equiv.) in 1,4-dioxane (80 mL) was added tributyl(l -ethoxy ethenyl)stannane (6.5 g, 17.9 mmol, 1.1 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight under nitrogen atmosphere. The mixture was acidified to pH 2 with an aqueous HC1 solution. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 90% gradient in 30 min; detector, UV 254 nm. This resulted in C68 (2.9 g, 79.7% yield) as a yellow solid.

[0437] XH NMR (400 MHz, DMSO-t / e) 5 8.33 - 8.29 (m, 1H), 8.00 (dd, J= 7.9, 1.5 Hz, 1H), 7.81 (d, J= 7.9 Hz, 1H), 2.59 (s, 3H).3-Bromo-4-(2-methyl-l , 3-dioxolan-2-yl)benzonitrile (C69)148MOFO-359177620.18314352000740

[0438] To a stirred solution of 4-acetyl-3 -bromobenzonitrile (C68) (1.4 g, 6.3 mmol, 1.0 equiv.) and ethylene glycol (1.5 g, 24.9 mmol, 4.0 equiv.) in DCM (20 mL) was added trimethoxymethane (1.3 g, 12.5 mmol, 2.0 equiv.) and concentrated H2SO4 (61 mg, 0.6 mmol, 0.1 equiv.) dropwise at room temperature. The resulting mixture was stirred at45 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 90% gradient in 30 min; detector, UV 254 nm. This resulted in C69 (1.4 g, 83.6% yield) as a white solid.

[0439] 'HNMR (400 MHz, DMSO-t / 6) 8 8.27 (s, 1H), 8.20 (d, J= 1.6 Hz, 1H), 7.88 (dd, J= 8.1, 1.7 Hz, 1H), 7.77 (d, J= 8.1 Hz, 1H), 4.06 - 4.00 (m, 2H), 3.70 - 3.63 (m, 2H), 1.69 (s, 3H).(5-Cyano-2-(2-methyl-l, 3-dioxolan-2-yl)phenyl)boronic acid (C70)

[0440] To a stirred solution of 3-bromo-4-(2-methyl-l,3-dioxolan-2-yl)benzonitrile (C69) (500 mg, 1.9 mmol, 1.0 equiv.) and Pin2B2 (2.4 g, 9.3 mmol, 5.0 equiv.) in 1,4-dioxane (15 mL) were added Pd(dppf)C12 CH2CI2 (152 mg, 0.2 mmol, 0.1 equiv.) and KOAc (549 mg, 5.6 mmol, 3.0 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 90% gradient in 30 min; detector, UV 254 nm. This resulted in C70 (300 mg, 69.0% yield) as a brown oil.(2-Acetyl-5-cyanophenyl)boronic acid (C71)

[0441] A solution of 5-cyano-2-(2-methyl-l,3-dioxolan-2-yl)phenylboronic acid (C70) (1.0 g, 4.3 mmol, 1.0 equiv.) in HC1 in 1,4-dioxane (4.0 M, 20 mL) was stirred at room temperature for 5 hours. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 90% gradient in 30 min; detector, UV 254 nm. This resulted in C71 (700 mg, 86.3% yield) as a yellow solid.

[0442] XH NMR (400 MHz, DMSO-t / e) 6 8.20 - 8.13 (m, 1H), 8.06 (dd, J= 8.0, 1.8 Hz, 1H), 7.91 (d, J= 1.7 Hz, 1H), 2.66 (s, 3H).149MOFO-359177620.183143520007406-(Aminomethyl)-3-methylbenzo [ c][l,2 ]oxaborol-l(3H)-ol (C72)

[0443] To a stirred solution of 2-acetyl-5-cyanophenylboronic acid (C71) (400 mg, 2.2 mmol, 1.0 equiv.) in THF (40 mL) was added lithium aluminum hydride (1.0 M in THF, 4 mL, 4.0 mmol, 2.0 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The mixture was acidified to pH 6 with an aqueous HC1 solution. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% HC1), 0% to 10% gradient in 10 min; detector, UV 254 nm. This resulted in C72 (200 mg) as a colorless oil, which was used directly without further purification.6-( (8-Methoxyquinazolin-4-yl)amino)methyl)-3-methylbenzo [c] [ 1, 2 ]oxaborol-l(3H)-ol dihy drochloride (37)

[0444] To a stirred solution of 6-(aminomethyl)-3-methyl-3J / -2,l-benzoxaborol-l-ol (C72) (400 mg, 2.3 mmol, 1 .0 equiv.) and 4-chloro-8-methoxyquinazoline (C41) (528 mg, 2.7 mmol, 1.2 equiv.) in DMF (30 mL) was added EtsN (457 mg, 4.5 mmol, 2.0 equiv.) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% HC1), 10% to 17% gradient in 9 min; detector, UV 254 nm. This resulted in 37 (118.6 mg, 15.7% yield) as a white solid.

[0445] LCMS (ESI): 336 [M+H]+

[0446] 'H NMR (400 MHz, Methanol-^) 8 8.72 (s, 1H), 7.90 (dt, J= 8.5, 1.4 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.77 - 7.70 (m,lH), 7.64 - 7.57 (m, 1H), 7.38 (dd, J= 7.9, 0.9 Hz, 1H), 5.31 (q, J= 6.6 Hz, 1H), 5.09 (s, 2H), 4.15 (s, 3H), 1.47 (d, J= 6.6 Hz, 3H).EXAMPLE 38Synthesis of 6-(((8-methoxyquinazolin-4-yl)amino)methyl)-3,3- dimethylbenzo[ c] [1,2 ]oxaborol-l( 3H)-ol hydrochloride150MOFO-359177620.18314352000740

[0447] This compound was synthesized using Scheme 40.Scheme 406-( (8-Methoxyquinazolin-4-yl)amino)methyl)-3, 3 -dimethylbenzo [c] [ 1, 2 ]oxaborol-l(3H)-ol hydrochloride (38)

[0448] To a stirred solution of 6-(aminomethyl)-3,3-dimethyl-2,l-benzoxaborol-l-ol (C73 [preparation similar to Y.-K. Zhang et al Bioorganic & Medicinal Chemistry Letters, 26 (2016), page 3182-3186]) (70 mg, 0.37 mmol, 1.0 equiv.) in DMF (5 mL) were added 4- chloro-8-methoxyquinazoline (C41) (86 mg, 0.4 mmol, 1.2 equiv.) and K2CO3 (76 mg, 0.5 mmol, 1.5 equiv.) in portions at room temperature. The reaction mixture was stirred at 80 °C for 1.5 hours. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse phase with the following conditions (Column:Xselect CSH Cl 85 pm, 30 mm X 150 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; flow rate: 60 mL / min; Gradient (B%): 10% B to 25%B in 8 min; Wave Length: 254 / 220 nm to afford 38 (67.2 mg, 47.5% yield) as a white solid.

[0449] LCMS (ESI): 350 [M+H]+

[0450] 'H NMR (400 MHz, DMSO-t / 6) 8 14.24 (br.s, 1H), 10.95 (t, J= 6.0 Hz, 1H), 9.03 (s, 1H), 8.77 (s, 1H), 8.22 (d, J= 8.2 Hz, 1H), 7.75 (t, J= 8.2 Hz, 1H), 7.70 - 7.62 (m, 2H),151MOFO-359177620.183143520007407.54 (dd, J= 7.9, 1.7 Hz, 1H), 7.40 (d, J= 7.8 Hz, 1H), 4.98 (d, J= 5.8 Hz, 2H), 4.07 (s, 3H), 1.43 (s, 6H).EXAMPLE 40Synthesis of 4-{[(l -hydroxy-3H-2, l-benzoxaborol-5-yl)methyl amino}-8H -pyrido[ 2,3- d]pyrimidin- 7 -one

[0451] This compound was synthesized using Scheme 41.Scheme 41Methyl (E)-3-(4,6-dichloropyrimidin-5-yl)acrylate (C75)

[0452] A solution of 4,6-dichloropyrimidine-5-carbaldehyde (C74) (2.0 g, 11.3 mmol, 1.0 equiv.) and methyl 2-(triphenyl-15-phosphaneylidene)acetate (4.5 g, 13.6 mmol, 1.2 equiv.) in tetrahydrofuran (50 mL) was stirred at room temperature for 24 hours under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The product was purified by silica gel column chromatography, eluted with PEZEA (5 / 1) to afford C75 (1.5 g, 57.0% yield) as a white solid.152MOFO-359177620.18314352000740Methyl (E)-3-(4-amino-6-chloropyrimidin-5-yl)acrylate (C76)

[0453] A solution of methyl (£)-3-(4,6-dichloropyrimidin-5-yl)acrylate (C75) (1.1 g, 4.7 mmol, 1.0 equiv.) in ammonia solution (0.4 M in THF, 100 mL) was stirred at 60 °C overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. This resulted in C76 (1.1 g) as a yellow solid, which was used directly in the next step without further purification.Methyl (2E)-3-( 4-amino-6-{[ ( I -hydroxy-3H-2, l-benzoxaborol-5-yl)methyl ]amino}pyrimidin- 5 -yl)pr op-2 -enoate (C77)

[0454] To a stirred mixture of 5-(aminomethyl)-3J / -2,l-benzoxaborol-l-ol (C34) (230 mg, 1.4 mmol, 1.5 equiv.) and methyl (2£)-3-(4-amino-6-chloropyrimidin-5-yl)prop-2-enoate (C76) (201 mg, 0.9 mmol, 1.0 equiv.) in DMSO (1 mL) was added DIEA (365 mg, 2.8 mmol, 3.0 equiv.) dropwise at room temperature. The resulting mixture was stirred at 80 °C overnight. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in C77 (170 mg, 53.1% yield) as a light-yellow solid.4-{[(l-Hydroxy-3H-2,l-benzoxaborol-5-yl)methyl]amino}-8H-pyrido[2, 3-d]pyrimidin-7-one (40)

[0455] A mixture of methyl (2E)-3-(4-amino-6-{[(l-hydroxy-3J / -2,l-benzoxaborol-5- yl)methyl]amino}pyrimidin-5-yl)prop-2-enoate (C77) (120 mg, 0.4 mmol, 1.0 equiv.) and sodium thiomethoxide (99 mg, 1.4 mmol, 4.0 equiv.) in DMSO (2 mL) was stirred at 80 °C for 2 hours under nitrogen atmosphere. The resulting mixture was filtered off and the filter cake was washed with MeOH (1 mL). The filtrate was concentrated under reduced pressure. The product was purified by prep-HPLC with the following conditions (Column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3+0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 3% B to 13% B in 8 min; Wave Length: 254 / 220 nm) to afford 40 (12.0 mg, 11.0% yield) as a white solid.

[0456] LCMS (ESI): 309 [M+H]+153MOFO-359177620.18314352000740

[0457] 1H NMR (400 MHz, DMSO-t / 6) 5 11.92 (s, 1H), 9.12 (s, 1H), 8.61 (t, J= 5.9 Hz, 1H), 8.27 (s, 1H), 8.19 (d, J= 9.8 Hz, 1H), 7.67 (d, J= 7.5 Hz, 1H), 7.40 - 7.25 (m, 2H), 6.42 (d, J= 9.7 Hz, 1H), 4.95 (s, 2H), 4.78 (d, J= 5.9 Hz, 2H).EXAMPLE 41Synthesis of 4-(((l -hydr oxy-1, 3-dihydrobenzo [ c] [1,2 ]oxaborol-5-yl)methyl) amino) -N,N, 5- trimethyl-5H-pyrrolo[ 3, 2-d]pyrimidine- 7 -carboxamide41

[0458] This compound was synthesized using Scheme 42.Scheme 424-Chloro-N,N, 5-trimethyl-5H-pyrrolo [ 3, 2-d]pyrimidine- 7 -carboxamide (C79)

[0459] A mixture of 4-chloro-5-methylpyrrolo[3,2- ]pyrimidine-7-carboxylic acid (C78) (600 mg, 2.8 mmol, 1.0 equiv.) and SOCh (4.1 mL, 56.7 mmol, 20.0 equiv.) was stirred at 90 °C for 3 hours under air atmosphere. The resulting mixture was concentrated under vacuum. The resulting mixture was dissolved into dimethylamine (40% in water, 479 mg, 4.3 mmol, 1.5 equiv.) and DCM (5 mL). The reaction mixture was stirred at room temperature for 1 hour under air atmosphere. The resulting mixture was concentrated under vacuum. The154MOFO-359177620.18314352000740 product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 20% gradient in 15 min; detector, UV 254 nm to afford C79 (400 mg, 59.1% yield) as an off-white solid.4-( ((1 -Hydr oxy-1, 3-dihydrobenzo[c] [ 1, 2 ]oxaborol-5-yl)methyl)amino)-N,N, 5-trimethyl-5H- pyrrolo[ 3, 2-d]pyrimidine- 7 -carboxamide (41)

[0460] A solution of 4-chloro-A,A,5-trimethylpyrrolo[3,2-t ]pyrimidine-7-carboxamide (C79) (100 mg, 0.4 mmol, 1.0 equiv.), 5-(aminomethyl)-3J / -2,l-benzoxaborol-l-ol (C34) (136 mg, 0.8 mmol, 2.0 equiv.), and EtsN (85 mg, 0.8 mmol, 2.0 equiv.) in DMSO (2 mL) was stirred at 60 °C overnight under air atmosphere. The product was firstly purified by prep- HPLC with the following conditions (Column: Xselect CSH Cl 85 pm, 30 mm X 150 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 4% B to 14% B in 8 min; Wave Length: 254 nm / 220 nm; RT(min): 7.68) and the resulting material (52 mg) was dissolved in DMSO (6 mL) and the second prep-HPLC used the following conditions (Column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3+0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 3% B to 20% B in 8 min; Wave Length: 254 / 220 nm), which afforded 41 (23.1 mg, 97.9% purity) as an off-white solid.

[0461] LCMS (ESI): 366 [M+H]+

[0462] 'HNMR (400 MHz, DMSO-t / 6) 9.09 (s, 1H), 8.15 (s, 1H), 7.71 (s, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.44 (t, J= 5.9 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J= 7.7 Hz, 1H), 4.95 (s, 2H), 4.80 (d, J= 5.8 Hz, 2H), 4.13 (s, 3H), 3.00 (br.s, 6H).EXAMPLE 42Synthesis of 4-(((l -hydr oxy-1, 3-dihydrobenzo [ c] [1,2 ]oxaborol-5-yl)methyl)amino)-N, 5- dimethyl-5H-pyrrolo[ 3, 2 -d] pyrimidine- 7 -carboxamide hydrochloride

[0463] This compound was synthesized using Scheme 43.155MOFO-359177620.18314352000740Scheme 43C78C83 42Ethyl 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (C81)

[0464] A solution of ethyl 4-oxo-37 / ,57 / -pyrrolo[3,2-d]pyrimidine-7-carboxylate (C80) (5.0 g, 24.1 mmol, 1.0 equiv.) and phosphoryl trichloride (68 mL, 723.9mmol, 30.0 equiv.) was stirred at 100 °C overnight. The resulting mixture was concentrated under vacuum. The reaction was quenched with ice water (50 mL) at room temperature and the resulting mixture was basified to pH 7 with saturated Na2COs aqueous solution. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford C81 (2.8 g, 51.4% yield) as a yellow solid.Ethyl 4-chloro-5-methyl-5H-pyrrolo[ 3, 2-d]pyrimidine- 7 -carboxylate (C82)

[0465] A solution of ethyl 4-chloro-5J / -pyrrolo[3,2-d]pyrimidine-7-carboxylate (C81) (2.5 g, 11.0 mmol, 1.0 equiv.), Mel (1.6 g, 11.1 mmol, 1.0 equiv.) and K2CO3 (2.3 g, 16.6 mmol, 1.5 equiv.) in DMF (30 mL) was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (80 mL) and then extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN156MOFO-359177620.18314352000740 in Water, 10% to 50% gradient in 25 min; detector, UV 254 nm to afford C82 (2.4 g, 90.4% yield) as a white solid.4-Chloro-5-methyl-5H-pyrrolo[ 3, 2-d]pyrimidine- 7 -carboxylic acid (C78)

[0466] A solution of ethyl 4-chloro-5-methylpyrrolo[3,2-d]pyrimidine-7-carboxylate (C82) (2.4 g, 10.0 mmol, 1.0 equiv.) and LiOH.EEO (500 mg, 12.0 mmol, 1.2 equiv.) in THF (20 mL) and H2O (10 mL) was stirred at room temperature for 1 hour. The precipitated solids were collected by filtration and washed with EtOAc (3 x 20 mL). The resulting mixture was concentrated under vacuum to afford C78 (1.4 g) as a white solid. This material was used in the next step directly without further purification.4-Chloro-N, 5-dimethyl-5H-pyrrolo[ 3, 2-d]pyrimidine- 7 -carboxamide (C 83 )

[0467] A mixture of 4-chloro-5-methylpyrrolo[3,2-J]pyrimidine-7-carboxylic acid (C78) (500 mg, 2.4 mmol, 1.0 equiv.) and SOCh (3.4 mL, 47.2 mmol, 20.0 equiv.) was stirred at 90 °C for 3 hours. The resulting mixture was concentrated under vacuum. The resulting mixture was dissolved into methylamine (40% in water, 275 mg, 3.5 mmol, 1.5 equiv.) in DCM (5 mL) stirred at room temperature for 1 hour under air atmosphere. The resulting mixture was concentrated under vacuum. The product was purified by reverse-phase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm to afford C83 (300 mg, 56.5% yield) as a white solid.4-(((l -Hydr oxy-1, 3-dihydrobenzo[ c] [1,2 ] oxaborol-5-yl)methyl)amino)-N, 5-dimethyl-5H- pyrrolo [3, 2-d]pyrimidine-7 -carboxamide hydrochloride (42)

[0468] A solution of 4-chloro-7V,5-dimethylpyrrolo[3,2- ]pyrimidine-7-carboxamide (C83) (100 mg, 0.4 mmol, 1.0 equiv.), 5-(aminomethyl)-3J / -2,l-benzoxaborol-l-ol (145 mg, 0.9 mmol, 2.0 equiv.) and EtsN (90 mg, 0.9 mmol, 2.0 equiv.) in DMSO (2 mL) was stirred at 60 °C overnight under air atmosphere. The product was purified by prep-HPLC with the following conditions (Column: Xselect CSH C185 pm, 30 mm X 150 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 5% B to 13% B in 8 min; Wave Length: 254 / 220 nm) to afford 42 (38.4 mg, 22.3% yield) as a grey white solid.157MOFO-359177620.18314352000740

[0469] LCMS (ESI): 352 [M+H]+

[0470] 'H NMR (400 MHz, DMSO-t / 6) 13.98 (br.s, 1H), 9.05 (br.s, 2H), 8.61 (s, 1H), 8.45 (s, 1H), 8.33-8.27 (m, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.46-7.35 (m, 2H), 4.95 (s, 4H), 4.22 (s, 3H), 2.81 (d, J = 4.6 Hz, 3H).EXAMPLE 43Synthesis of 5-[ ( {5-methylpyrrolo[ 3, 2-d]pyrimidin-4-yl }amino)methyl J-3H-2, 1-

[0471] This compound was synthesized using Scheme 44.Scheme 444-Chloro-5-methylpyrrolo[3,2-d]pyrimidine (C85)

[0472] To the stirred solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (C84) (5.0 g, 32.6 mmol, 1.0 equiv.) in DMF (20 mL) was added NaH (1.6 g, 39.1 mmol, 1.2 equiv., 60% purity) at 0 °C. The mixture was stirred for another 30 minutes at 0 °C. Then Mel (6.9 g, 48.8 mmol, 1.5 equiv.) was added to the reaction mixture. The reaction mixture was heated to 50 °C for 2 hours. The reaction was quenched with saturated NH4CI aqueous solution (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The product158MOFO-359177620.18314352000740 was purified by trituration with heptane, which produced C85 (4.2 g), which was used directly in the next step.5-[ ( {5-Methylpyrrolo[ 3, 2-d]pyrimidin-4-yl}amino)methyl -3H-2, 1-benzoxaborol-l-ol hydrochloride (43)

[0473] To a stirred mixture of 5-(aminomethyl)-3J / -2, 1-benzoxaborol-l-ol (C34) (340 mg, 2.1 mmol) and 4-chloro-5-methylpyrrolo[3,2-t ]pyrimidine (C85) (420 mg, 2.5 mmol, 1.2 equiv.) in DMF (4 mL) was added TEA (633 mg, 6.3 mmol, 3.0 equiv.) dropwise at room temperature. The resulting mixture was stirred at 80 °C overnight. After concentration, the product was purified by prep-HPLC with the following conditions (Column: Xselect CSH C185 pm, 30 mm X 150 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 5%B to 15%B in 7 min; Wave Length: 254 nm / 220 nm) to afford 43 (52.0 mg, 7.5% yield) as a light-yellow solid.

[0474] LCMS (ESI): 295 [M+H]+

[0475] XH NMR (400 MHz, DMSO- e) 6 14.63 (s, 1H), 9.15 (s, 1H), 8.92 (t, J = 6.0 Hz, 1H), 8.60 (s, 1H), 7.82 (d, J= 3.0 Hz, 1H), 7.70 (d, J= 7.5 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J= 7.6 Hz, 1H), 6.53 (d, J= 3.0 Hz, 1H), 4.96 (s, 4H), 4.21 (s, 3H).EXAMPLE 44Synthesis of 5-[ ( {2-isopropyl-5-methylpyrrolo[ 3, 2-d]pyrimidin-4-yl}amino)methyl J-3H-2, 1- benzoxaborol-l-ol hydrochloride

[0476] This compound was synthesized using Scheme 45.159MOFO-359177620.18314352000740Scheme 454-Chloro-2-isopropyl-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (C86) & 4-chloro-6-isopropyl-5-methyl-5H-pyrrolo [ 3, 2 -d] pyrimidine (C87)

[0477] To a stirred solution of 4-chloro-5-methylpyrrolo[3,2-d]pyrimidine (C85) (1.0 g, 6.0 mmol, 1.0 equiv.), 2-iodopropane (3.0 g, 17.9 mmol, 3.0 equiv.) and 2, 2,6,6- tetramethylpiperidine (2.5 g, 17.9 mmol, 3.0 equiv.) in methanol (30 mL) was added [Ir(dtbbpy)(ppy)2]PFe (0.27 g, 0.3 mmol, 0.05 equiv.) at room temperature. The reaction solution was stirred for another 72 hours at 50 °C with the irradiation by 50 W, 450 nm blue LED. The resulting mixture was filtered off and the filter cake was washed with methanol (2 x 5 mL). The filtrate was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 10 min; detector, UV 220 nm and further purified with following conditions: Column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3+0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 28% B to 38% B in 8min; Wave Length: 254 / 220 nm. This resulted in C86 (30 mg, 2.4% yield) as a white solid and C87 (80 mg, 6.4% yield) as a white solid.5-[ ( {2-Isopropyl-5-methylpyrrolo [ 3, 2-d]pyrimidin-4-yl }amino)methyl J-3H-2, 1- benzoxaborol-l-ol hydrochloride (44)160MOFO-359177620.18314352000740

[0478] To a stirred mixture of 5-(aminomethyl)-3H-2,l-benzoxaborol-l-ol (C34) (100 mg, 0.6 mmol, 1.0 equiv.) and 4-chloro-2-isopropyl-5-methylpyrrolo[3,2-d]pyrimidine (C86) (154 mg, 0.7 mmol, 1.2 equiv.) in DMSO (5 mL) was added EtsN (310 mg, 3.0 mmol, 5.0 equiv.) dropwise at room temperature. The resulting mixture was stirred at 80 °C overnight under air atmosphere. After concentration in vacuo, the product was purified by prep-HPLC with the following conditions (Column: Xselect CSH C185 pm, 19 mm X 250 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 13% B to 25%B in 8 min; Wave Length: 254 / 220 nm) to afford 44 (25.2 mg, 11.0% yield) as a white solid.

[0479] LCMS (ESI): 337 [M+H]+

[0480] 'HNMR (400 MHz, DMSO-d6) 8 14.48 (s, 1H), 9.16 (s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.75 (d, J = 3.0 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.47 (s, 1H), 7.42 (dd, J = 7.6, 1.3 Hz, 1H), 6.45 (d, J = 3.0 Hz, 1H), 4.94 (s, 2H), 4.91 (d, J = 5.8 Hz, 2H), 4.17 (s, 3H), 3.10 (septet, J = 6.8 Hz, 1H), 1.19 (d, J = 6.8 Hz, 6H).EXAMPLE 45Synthesis of 4-{[( 1R)-1~( 1 -hydroxy-3H-2, 1 -benzoxaborol-5-yl)ethyl ]amino}-8- methoxyquinoline-3-carbonitrile

[0481] This compound was synthesized using Scheme 46.161MOFO-359177620.18314352000740Methyl 2-hydroxy-5-(2-methyl-l,3-dioxolan-2-yl)benzoate (C89)

[0482] Into a 500 mL 3-necked round-bottom flask were added methyl 5-acetyl-2- hydroxybenzoate (C88) (5.0 g, 25.7 mmol, 1.0 equiv.), toluene (150 mL), TsOH (133 mg, 0.8 mmol, 0.03 equiv.) and ethylene glycol (2.9 mL, 51.5 mmol, 2.0 equiv.) at room temperature. The resulting mixture was stirred at 135 °C for 16 hours under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The product was purified by silica gel column chromatography, eluted with PEZEA (20 / 1) to afford C89 (4.4 g, 71.7% yield) as a white oil.Methyl 5-(2-methyl-l,3-dioxolan-2-yl)-2-(trifluoromethanesulfonyloxy)benzoate (C90)162MOFO-359177620.18314352000740

[0483] A solution of methyl 2-hydroxy-5-(2-methyl-l,3-dioxolan-2-yl)benzoate (C89) (13.0 g, 54.6 mmol, 1.0 equiv.) in DCM (100 mL) was treated with pyridine (17.6 mL, 218.3 mmol, 4.0 equiv.) at 0 °C for 5 minutes under nitrogen atmosphere, followed by the addition of Tf2O (11.1 mL, 65.5 mmol, 1.2 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The product was purified by silica gel column chromatography, eluted with PE / EA (12 / 1) to afford C90 (18.0 g, 89.1% yield) as a white solid.Methyl 5-(2-methyl-l, 3-dioxolan-2-yl)-2-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)benzoate (C91)

[0484] A solution of methyl 5-(2-methyl-l,3-dioxolan-2-yl)-2- (trifluoromethanesulfonyloxy)benzoate (C90) (18.5 g, 49.9 mmol, 1.0 equiv.), Pd(dppf)C12 (3.7 g, 5.0 mmol, 0.1 equiv.), Pin2B2 (19.0 g, 74.9 mmol, 1.5 equiv.), and KOAc (9.8 g, 99.9 mmol, 2.0 equiv.) in 1,4-dioxane (150 mL) was stirred at 100 °C for 2 hours under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The product was purified by silica gel column chromatography, eluted with PEZEA (12 / 1) to afford C91 (15.8 g, 90.8% yield) as a white solid.5-(2-Methyl-l, 3-dioxolan-2-yl)-3H-2, 1-benzoxaborol-l-ol (C92)

[0485] A solution of methyl 5-(2-methyl-l,3-dioxolan-2-yl)-2-(4, 4, 5, 5-tetramethyl-l, 3,2- dioxaborolan-2-yl)benzoate (C91) (5.0 g, 14.4 mmol, 1.0 equiv.) in MeOH (50 mL) was treated with NaBEL (2.2 g, 57.4 mmol, 4.0 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water (5 mL) at 0 °C. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm to afford C92 (1.5 g, 47.5% yield) as a white solid.1-(1 -Hydr oxy-1, 3-dihydrobenzo[ c] [1,2 ]oxaborol-5-yl)ethan-l-one (C93 )

[0486] A solution of 5-(2-methyl-l,3-dioxolan-2-yl)-3J / -2, 1-benzoxaborol-l-ol (C92) (2.4 g, 10.9 mmol, 1.0 equiv.) and HC1 in 1,4-dioxane (4.0 M, 28 mL) in 1,4-dioxane (24 mL) was stirred at room temperature for 1 hour under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The product was purified by silica gel column163MOFO-359177620.18314352000740 chromatography and eluted with PEZEA (5 / 1) to afford C93 (1.1 g, 57.3% yield) as a white solid.(S)-N-[ 1-(1 -hydroxy-3H-2, l-benzoxaborol-5-yl)ethylidene ]-2-methylpropane-2-sulfinamide (C94)

[0487] A solution of l-(l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-5-yl)ethan-l-one (C93) (200 mg, 1.1 mmol, 1.0 equiv.) in THF (4 mL) was treated with tetraethoxytitanium (714.8 uL, 3.4 mmol, 3.0 equiv.) at room temperature for 5 minutes under nitrogen atmosphere, followed by the addition of (5)-2-methylpropane-2-sulfinamide (207 mg, 1.7 mmol, 1.5 equiv.) at room temperature. The resulting mixture was stirred at 65 °C for 2 hours under nitrogen atmosphere. The resulting mixture was concentrated under vacuum to afford C94 (250 mg) as an off-white oil, which was used directly without further purification.(S)-N-[ ( 1R)-1~( 1 -hydroxy-3H-2, l-benzoxaborol-5-yl)ethyl ]-2-methylpropane-2-sulfinamide (C95)

[0488] A solution of (5)-A-[l-(l -hydroxy-3 JT-2,1 -benzoxaborol-5-yl)ethylidene]-2- methylpropane-2-sulfmamide (C94) (200 mg, 0.7 mmol, 1.0 equiv.) in THF (2 mL) was treated with lithium tri-sec-butylhydroborate (L- sei ectride) (2.2 mL, 2.1 mmol, 3.0 equiv.) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The reaction was quenched with saturated NH4CI aqueous solution (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 8 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography, eluted with C LCh / MeOH (12 / 1) to afford C95 (70 mg, 34.8% yield) as a colorless oil.5-[ ( 1R)-1-Aminoethyl -3H-2, 1-benzoxaborol-l-ol (C96)

[0489] A solution of intermediate (5 -A-[(lA)-l-(l-hydroxy-3J / -2,l-benzoxaborol-5- yl)ethyl]-2-methylpropane-2-sulfinamide (C95) (180 mg, 0.6 mmol, 1.0 equiv.) and HC1 in 1,4-dioxane (4.0 M, 1.6 mL) in 1,4-dioxane (10 mL) was stirred at room temperature for 1 hour under nitrogen atmosphere. The resulting mixture was concentrated under vacuum to afford C96 (210 mg) as a white solid, which was used directly in the next step without further purification.164MOFO-359177620.183143520007404-{[ (1R)-1-(1 -Hydroxy-3H-2, l-benzoxaborol-5-yl)ethyl ]amino}-8-methoxyquinoline-3- carbonitrile (45)

[0490] A solution of 5-[(lA)-l-aminoethyl]-3J / -2,l-benzoxaborol-l-ol (C96) (151 mg, 0.9 mmol, 1.0 equiv.) and 4-chloro-8-methoxyquinoline-3-carbonitrile (C35) (224 mg, 1.0 mmol, 1.2 equiv.), and K2CO3 (354 mg, 2.6 mmol, 3.0 equiv.) in ACN (10 mL) was stirred at 80 °C overnight under nitrogen atmosphere. The product was purified by reverse-phase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in water (0.05% HC1), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 45 (53.3 mg, 17.4% yield) as a white solid.

[0491] LCMS (ESI): 360 [M+H]+

[0492] 1H NMR (400 MHz, DMSO-t / 6) 8 9.18 (br.s, 2H), 8.73 (s, 1H), 8.36 (d, J= 8.7 Hz, 1H), 7.80 - 7.69 (m, 2H), 7.58 (d, J= 8.1 Hz, 1H), 7.47 (s, 1H), 7.42 (d, J= 7.9 Hz, 1H), 6.09 - 5.97 (m, 1H), 4.95 (s, 2H), 4.04 (s, 3H), 1.78 (d, J= 6.7 Hz, 3H).EXAMPLE 47Synthesis of 4-{[(l S)-l-( 1 -hydroxy-3H-2, l-benzoxaborol-5-yl)ethyl ]amino}-8- methoxyquinoline-3-carbonitrile

[0493] This compound was synthesized using Scheme 47.165MOFO-359177620.18314352000740Scheme 47(R)-N-[ 1-(1 -Hydroxy-3H-2, l-benzoxaborol-5-yl)ethylidene ]-2-methylpropane-2-sulfinamide(C97)

[0494] A solution of l-(l-hydroxy-3H-2,l-benzoxaborol-5-yl)ethanone (C93) (200 mg, 1.1 mmol, 1.0 equiv.), (R)-2-methylpropane-2-sulfinamide (206 mg, 1.7 mmol, 1.5 equiv.), and tetraethoxytitanium (714.8 uL, 3.4 mmol, 3.0 equiv.) in THF (3 mL) was stirred at 65 °C for 2 hours under nitrogen atmosphere. The reaction was quenched by the addition of saturated NH4CI aqueous solution (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure to afford C97 (240 mg) as a yellow oil, which was used directly in the next step without further purification.(S)-N-[ ( 1R)-1~( 1 -hydroxy-3H-2, l-benzoxaborol-5-yl)ethyl ]-2-methylpropane-2-sulfinamide (C98)

[0495] A solution of (R)-N-[l-(l-hydroxy-3H-2,l-benzoxaborol-5-yl)ethylidene]-2- methylpropane-2-sulfmamide (C97) (450 mg, 1.6 mmol, 1.0 equiv.) in THF (2 mL) was treated with lithium tri-sec-butylhydroborate (L- sei ectride) (919 mg, 4.8 mmol, 3.0 equiv.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The reaction was quenched by the166MOFO-359177620.18314352000740 addition of saturated NH4CI aqueous solution (5mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography, eluted with CH2C12 / MeOH (12 / 1) to afford C98 (100 mg, 22.1% yield) as a white oil.5-[ ( 1 S)-l -Aminoethyl -3H-2, 1-benzoxaborol-l-ol (C99)

[0496] A solution of (R)-N-[(lS)-l-(l-hydroxy-3H-2,l-benzoxaborol-5-yl)ethyl]-2- methylpropane-2-sulfmamide (C98) (50 mg, 0.2 mmol, 1.0 equiv.) and HC1 in 1,4-dioxane (4.0 M, 2 mL) in 1,4-dioxane (2 mL) was stirred at room temperature for 1 hour under nitrogen atmosphere. The resulting mixture was concentrated under vacuum to afford C99 (60 mg) as a white solid, which was used directly without further purification.4-{[(l S)-l-( I -Hydroxy-3H-2, l-benzoxaborol-5-yl)ethyl ]amino}-8-methoxyquinoline-3- carbonitrile (47)

[0497] A solution of 5-[(15)-l-aminoethyl]-3H-2, 1-benzoxaborol-l-ol (C99) (80 mg, 0.5 mmol, 1.0 equiv.) in DMSO (2 mL) was treated with TEA (188.5 uL, 1.4 mmol, 3.0 equiv.) at room temperature for 5 minutes under nitrogen atmosphere, followed by the addition of 4- chloro-8-methoxyquinoline-3-carbonitrile (C35) (109 mg, 0.5 mmol, 1.1 equiv.) in portions at room temperature. The resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% HC1), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 47 (47.5 mg, 29.3% yield) as a yellow solid.

[0498] LCMS (ESI): 360 [M+H]+

[0499] 1H NMR (400 MHz, DMSO-d6) 8 9.39 (s, 1H), 9.17 (s, 1H), 8.78 (s, 1H), 8.41 (d,J = 8.7 Hz, 1H), 7.82 - 7.71 (m, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.43 (d, J = 7.7 Hz, 1H), 6.11 - 6.01 (m, 1H), 4.96 (s, 2H), 4.06 (s, 3H), 1.79 (d, J = 6.6 Hz, 3H).EXAMPLE 49Synthesis of 4-{[(l-hydr oxy-3, 4-dihydro-2, l-benzoxaborinin-6-yl)methyl]amino}-8- methoxyquinoline-3-carbonitrile167MOFO-359177620.18314352000740

[0500] This compound was synthesized using Scheme 48.Scheme 48Methyl 4-bromo-3-(bromomethyl)benzoate (Cl 01)

[0501] To a stirred solution of methyl 4-bromo-3 -methylbenzoate (C100) (5.0 g, 21.8 mmol, 1.0 equiv.) and NBS (4.7 g, 26.2 mmol, 1.2 equiv.) in ACN (100 m ) was added AIBN (358 mg, 2.2 mmol, 0.1 equiv.) at room temperature. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was concentrated under reduced pressure.The product was purified by silica gel column chromatography, eluted with PEZEA (20 / 1) to afford C101 (5.2 g, 77.6% yield) as a white solid.168MOFO-359177620.18314352000740Methyl 4-bromo-3-(cyanomethyl)benzoate (Cl 02)

[0502] To a stirred solution of TMSCN (10.2 g, 102.3 mmol, 3.0 equiv.) and tetra-w- butylammonium fluoride (1.0 M in THF, 10 mL, 102.3 mmol, 3.0 equiv.) in ACN (200 mL) was added methyl 4-bromo-3-(bromomethyl)benzoate (C101) (10.5 g, 34.1 mmol, 1. equiv.) at 0 °C in portions. The reaction mixture was stirred at room temperature for 20 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (4 / 1) to afford C102 (8.0 g, 95.2% yield) as a white solid.

[0503] 'H NMR (400 MHz, DMSO-t / 6) 8 8.15 (d, J= 2.0 Hz, 1H), 7.91 - 7.83 (m, 2H), 4.20 (s, 2H), 3.89 (s, 3H).4-Bromo-3-(carboxymethyl)benzoic acid (Cl 03)

[0504] To a stirred solution of methyl 4-bromo-3-(cyanomethyl)benzoate (C102) (1.0 g,3.9 mmol, 1.0 equiv.) in H2O (10 mL) and MeOH (10 mL) was added NaOH (787 mg, 19.7 mmol, 5.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The mixture was acidified to pH 2 with HC1 (12 M in H2O) aqueous solution at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in water, 0% to 5% gradient in 10 min; detector, UV 254 nm. This resulted in C103 (980 mg, 98.0% yield) as a light-yellow solid.2-[ 2-Bromo-5-(hydroxymethyl)phenyl ethanol (C 104)

[0505] To a stirred solution of 4-bromo-3-(carboxymethyl)benzoic acid (C103) (2.3 g,8.9 mmol, 1.0 equiv.) in THF (23 mL) was added borane-tetrahydrofuran complex (1.0 M in THF, 88.8 mL, 88.8 mmol, 10.0 equiv.) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred overnight at 70 °C under nitrogen atmosphere. The reaction was quenched with MeOH (50 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 15% to 20% gradient in 10 min; detector, UV 220 nm. This resulted in C104 (1.3 g, 65.0% yield) as a light-yellow solid.169MOFO-359177620.18314352000740

[0506] JH NMR (400 MHz, DMSO-t / 6) 5 7.51 (d, J= 8.1 Hz, 1H), 7.28 (d, J= 2.2 Hz, 1H), 7.09 (dd, J= 8.2, 2.2 Hz, 1H), 5.25 (t, J= 5.7 Hz, 1H), 4.75 (t, J= 5.3 Hz, 1H), 4.44 (d, J= 4.9 Hz, 2H), 3.59 (td, J= 7.1, 4.8 Hz, 2H), 2.85 (t, J= 7.2 Hz, 2H).6-(Hydroxymethyl)-3, 4-dihydro-2, 1-benzoxaborinin-l-ol (C 105)

[0507] To a stirred solution of 2-[2-bromo-5-(hydroxymethyl)phenyl]ethanol (C104) (3.2 g, 13.8 mmol, 1.0 equiv.) and Pin2B2 (5.3 g, 20.7 mmol, 1.5 equiv.) in 1,4-dioxane (50 mL) were added AcOK (3.4 g, 34.6 mmol, 2.5 equiv.) and Pd(dppf)C12 CH2CI2 (1.1 g, 1.4 mmol, 0.1 equiv.) in portions at room temperature. The resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 5% gradient in 10 min; detector, UV 254 nm. This resulted in C105 (2.2 g, 89.1% yield) as a yellow oil.1 -Hydroxy-3, 4-dihydro-2, l-benzoxaborinine-6-carbaldehyde (C 106)

[0508] To a stirred mixture of 6-(hydroxymethyl)-3,4-dihydro-2, 1-benzoxaborinin-l-ol (C105) (2.0 g, 11.2 mmol, 1.0 equiv.) in DCM (20 mL) was added l,l-bis(acetyloxy)-3-oxo- 3H-lX5,2-benziodaoxol-l-yl acetate (Dess-Martin periodinane) (7.2 g, 16.8 mmol, 1.5 equiv.) at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered and the filter cake was washed with DCM (1 x 10 mL). The filtrate was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in water, 0% to 5% gradient in 10 min; detector, UV 254 nm. This resulted in C106 (1.6 g, 81.2% yield) as a yellow solid.6-[ (Hydroxyimino)methyl -3, 4-dihydro-2, 1-benzoxaborinin-l-ol (C 107)

[0509] To a stirred solution of 1 -hydroxy-3, 4-dihydro-2, 1 -benzoxaborinine-6- carbaldehyde (C106) (1.5 g, 8.5 mmol, 1.0 equiv.) in THF (20 mL) and H2O (4 mL) were added hydroxylamine hydrochloride (0.7 g, 10.2 mmol, 1.2 equiv.) and NaOAc (1.0 g, 11.9 mmol, 1.4 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was extracted with EtOAc (10 x 30 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over170MOFO-359177620.18314352000740 anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in Cl 07 (2.1 g) as a brown solid. This material was used in the next step directly without further purification.6-(Aminomethyl)-3, 4-dihydro-2, 1-benzoxaborinin-l-ol (C 108)

[0510] To a stirred solution of 6-[(hydroxyimino)methyl]-3,4-dihydro-2,l- benzoxaborinin-l-ol (C107) (1.0 g, 5.2 mmol, 1.0 equiv.) in AcOH (20 mL) was added Zn (1.0 g, 15.7 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred at 40 °C overnight. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 5% gradient in 10 min; detector, UV 254 nm. This resulted in Cl 08 (460 mg, 49.7% yield) as a light-yellow oil.4-{[(l -Hydroxy-3, 4-dihydro-2, l-benzoxaborinin-6-yl)methyl ]amino}-8-methoxyquinoline-3- carbonitrile (49)

[0511] To a stirred solution of 6-(aminomethyl)-3,4-dihydro-2, 1-benzoxaborinin-l-ol (C108) (150 mg, 0.85 mmol, 1.0 equiv.) and 4-chloro-8-methoxyquinoline-3-carbonitrile (C35) (222 mg, l.O mmol, 1.2 equiv.) in DMF (3.0 mL) was added TEA (112 mg, 1.1 mmol, 1.3 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse-phase with the following conditions (Column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3+0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 18% B to 35% B in 8min; Wave Length: 254 / 220 nm) to afford 49 (44.5 mg, 14.6% yield) as a white solid.

[0512] LCMS (ESI): 360 [M+H]+

[0513] 'H NMR (400 MHz, DMSO-t / 6) 8 8.58 (br.s, 1H), 8.45 - 8.33 (m, 2H), 7.98 (d, J = 8.6 Hz, 1H), 7.64 (d, J= 7.5 Hz, 1H), 7.54 (t, J= 8.2 Hz, 1H), 7.30 (d, J= 7.9 Hz, 1H), 7.23 - 7.14 (m, 2H), 5.05 (d, J= 6.5 Hz, 2H), 4.04 (t, J= 5.8 Hz, 2H), 3.93 (s, 3H), 2.82 (t, J = 6.0 Hz, 2H).171MOFO-359177620.18314352000740EXAMPLE 50Synthesis of 6-{[(8-methoxyquinazolin-4-yl)amino]methyl}-3,4-dihydro-2, 1-benzoxaborinin- l-ol hydrochloride

[0514] This compound was synthesized using Scheme 49.Scheme 496-{[ ( 8-Methoxyquinazolin-4-yl)amino ]methyl}-3, 4-dihydro-2, 1-benzoxaborinin-l-ol hydrochloride (50)

[0515] To a stirred solution of 6-(aminomethyl)-3,4-dihydro-2, 1-benzoxaborinin-l-ol (C108) (150 mg, 0.85 mmol, 1.0 equiv.) and 4-chloro-8-methoxyquinazoline (C41) (198 mg, 1.0 mmol, 1.2 equiv.) in DMF (5 mL) was added K2CO3 (176 mg, 1.3 mmol, 1.5 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse phase with the following conditions (Column:Xselect CSH Cl 85 pm, 30 mm X 150 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 8% B to 18% B in 8 min; Wave Length: 254 nm / 220 nm) to afford 50 (124.1 mg, 39.4% yield) as a white solid.

[0516] LCMS (ESI): 336 [M+H]+

[0517] 'H NMR (400 MHz, DMSO-t / 6) 8 14.22 (s, 1H), 10.98 (s, 1H), 8.76 (s, 1H), 8.44 (br.s, 1H), 8.23 (d, J= 8.3 Hz, 1H), 7.75 (t, J= 8.2 Hz, 1H), 7.66 (d, J= 7.7 Hz, 2H), 7.32 - 7.21 (m, 2H), 4.96 (d, J= 5.9 Hz, 2H), 4.07 (s, 3H), 4.04 (d, J= 5.9 Hz, 2H), 2.84 (t, J= 5.9 Hz, 2H).172MOFO-359177620.18314352000740EXAMPLE 51Synthesis of 4-{[(l -hydroxy-3H-2, l-benzoxaborol-6-yl)methyl ]amino}-8H-pyrido[2, 3- d]pyrimidin- 7 -one

[0518] This compound was synthesized using Scheme 50.Scheme 50Methyl (2E)-3-( 4-amino-6-{[ ( I -hydroxy-3H-2, l-benzoxaborol-6-yl)methyl ]amino}pyrimidin- 5 -yl)pr op-2 -enoate (Cl 09)

[0519] To a stirred solution of methyl 6-(aminomethyl)-3H-2,l-benzoxaborol-l-ol hydrochloride (C46) (200 mg, 1.2 mmol, 1.3 equiv.) and methyl (2£)-3-(4-amino-6- chloropyrimidin-5-yl)prop-2-enoate (C76) (200 mg, 0.9 mmol, 1.0 equiv.) in DMSO (5 mL) was added DIEA (363 mg, 2.8 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred at 80 °C for 4 hours. The resulting mixture was diluted with water (10 mL) and then extracted with EtOAc (3 x 5mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in C109 (130 mg) as a colorless oil.4-{[(l-Hydroxy-3H-2,l-benzoxaborol-6-yl)methyl]amino}-8H-pyrido[2, 3-d]pyrimidin-7-one (51)173MOFO-359177620.18314352000740

[0520] To a stirred mixture of methyl (2£)-3 -(4-amino-6-{[(l -hydroxy-3 JT-2,1- benzoxaborol-6-yl)methyl]amino}pyrimidin-5-yl)prop-2-enoate (Cl 09) (120 mg, 0.4 mmol, 1.0 equiv.) in MeOH (3 mL) was added sodium thiomethoxide (99 mg, 1.4 mmol, 4.0 equiv.) at room temperature. The resulting mixture was stirred at 80 °C for 4 hours. The precipitated solids were collected by filtration and washed with MeOH (1 x 3 mL). The resulting mixture was concentrated under reduced pressure. The product was purified by reverse-phase with the following conditions (Column: XBridge BEH Cl 8 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3+0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 7% B to 20% B in 8min; Wave Length: 254 / 220 nm) to afford 51 (43.9 mg, 40.4% yield) as a white solid.

[0521] LCMS (ESI): 309 [M+H]+

[0522] XH NMR (400 MHz, DMSO-t / e) 5 11.64 (s, 1H), 9.13 (s, 1H), 8.61 (t, J= 5.9 Hz, 1H), 8.27 (s, 1H), 8.19 (d, J= 9.7 Hz, 1H), 7.71 - 7.64 (m, 1H), 7.46 (dd, J= 7.9, 1.7 Hz, 1H), 7.36 (d, J= 7.9 Hz, 1H), 6.42 (d, J= 9.6 Hz, 1H), 4.96 (s, 2H), 4.76 (d, J= 5.8 Hz, 2H).EXAMPLE 52Synthesis of 4-(((l -hydr oxy-1, 3-dihydrobenzo [ c] [1,2 ]oxaborol-6-yl)methyl)amino)-N,N, 5- trimethyl-5H-pyrrolo[ 3, 2-d]pyrimidine- 7 -carboxamide hydrochloride52

[0523] This compound was synthesized using Scheme 51.174MOFO-359177620.18314352000740Scheme 514-( ((1 -Hydroxy- 1, 3-dihydrobenzo[c] [ 1, 2 ]oxaborol-6-yl)methyl)amino)-N,N, 5-trimethyl-5H- pyrrolo [3, 2-d]pyrimidine-7 -carboxamide hydrochloride (52)

[0524] A solution of 4-chloro-A,A,5-trimethylpyrrolo[3,2-d]pyrimidine-7-carboxamide (C79) (100 mg, 0.4 mmol, 1.0 equiv.), 6-(aminomethyl)-3J / -2,l-benzoxaborol-l-ol hydrochloride (C46) (136 mg, 0.8 mmol, 2.0 equiv.), and EtsN (85 mg, 0.8 mmol, 2.0 equiv.) in DMSO (2 mL) was stirred at 60 °C overnight under air atmosphere. The product was purified by prep-HPLC with the following conditions (Column: Xselect CSH Cl 85 pm, 30 mm X 150 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B %): 5% B to 18% B in 8 min; Wave Length: 254 / 220 nm) to afford 52 (87.1 mg, 51.8% yield) as an off-white solid.

[0525] LCMS (ESI): 366 [M+H]+

[0526] 1H NMR (400 MHz, DMSO-t / 6) 14.07 (s, 1H), 9.22 (t, J= 6.0 Hz, 1H), 8.51 (s,1H), 8.33 (s, 1H), 7.77 (d, J= 1.7 Hz, 1H), 7.55 (dd, J= 7.9, 1.7 Hz, 1H), 7.37 (d, J= 7.9 Hz, 1H), 4.97 (s, 2H), 4.96 (s, 2H), 4.26 (s, 3H), 3.22 - 3.08 (m, 6H).EXAMPLE 53Synthesis of 4-(((l -hydr oxy-1, 3-dihydrobenzo [ c] [1,2 ]oxaborol-6-yl)methyl)amino)-N, 5- dimethyl-5H-pyrrolo[ 3, 2 -d] pyrimidine- 7 -carboxamide hydrochloride175MOFO-359177620.18314352000740

[0527] This compound was synthesized using Scheme 52.Scheme 524-(((l -Hydroxy- 1, 3-dihydrobenzo[ c] [1,2 ]oxaborol-6-yl)methyl) amino) -N, 5-dimethyl-5H- pyrrolo [3, 2-d]pyrimidine-7 -carboxamide hydrochloride (53)

[0528] A solution of 4-chloro-A,5-dimethylpyrrolo[3,2-d]pyrimidine-7-carboxamide (C83) (100 mg, 0.4 mmol, 1.0 equiv.), 6-(aminomethyl)-3J / -2,l-benzoxaborol-l-ol hydrochloride (C46) (145 mg, 0.9 mmol, 2.0 equiv.) and EtsN (123 mg, 0.9 mmol, 2.0 equiv.) in DMSO (2 mL) was stirred at 60 °C overnight under air atmosphere. The product was purified by prep-HPLC with the following conditions (Column: Xselect CSH Cl 85 pm, 19 mm X 250 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 8% B to 18% B in 8 min; Wave Length: 254 / 220 nm) to afford 53 (113.8 mg, 66.0% yield) as an off-white solid.

[0529] LCMS (ESI): 352 [M+H]+

[0530] 'H NMR (400 MHz, DMSO-d6) 13.97 (s, 1H), 9.28 (t, J= 6.0 Hz, 1H), 8.75 (q, J = 4.4 Hz, 1H), 8.49 - 8.43 (m, 2H), 7.80 (d, J= 1.7 Hz, 1H), 7.55 (dd, J= 7.9, 1.7 Hz, 1H), 7.36 (d, J= 7.9 Hz, 1H), 4.96 (s, 2H), 4.94 (s, 2H), 4.24 (s, 3H), 2.79 (d, J= 4.3 Hz, 3H).EXAMPLE 54Synthesis of 6-[ ( {5-methylpyrrolo[ 3, 2-d]pyrimidin-4-yl }amino)methyl -3H-2, 1- benzoxaborol-l-ol hydrochloride176MOFO-359177620.18314352000740

[0531] This compound was synthesized using Scheme 53.Scheme 536-[ ( {5-Methylpyrrolo[ 3, 2-d]pyrimidin-4-yl}amino)methyl J-3H-2, 1-benzoxaborol-l-ol hydrochloride (54)

[0532] To a stirred solution of 6-(aminomethyl)-3J / -2,l-benzoxaborol-l-ol hydrochloride (C46) (100 mg, 0.6 mmol, 1.0 equiv.) and 4-chloro-5-methylpyrrolo[3,2-d]pyrimidine (C85) (104 mg, 0.6 mmol, 1.0 equiv) in DMF (4 mL) was added TEA (186 mg, 1.8 mmol, 3.0 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was heated to 80 °C and stirred overnight under nitrogen atmosphere. The product was initially purified by reverse-phase combi- chromatography with the following conditions: column, C18; mobile phase, MeCN in water, 10% to 30% gradient in 10 min; detector, UV 254 nm and then purified by prep-HPLC with the following conditions: Column: Xselect CSH Cl 85 pm, 30 mm X 150 mm; Mobile Phase A: water (0.1%HCl), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 5% B to 15% B in 8 min; Wave Length: 254 nm / 220 nm. This resulted in 54 (81.7 mg, 40.3% yield) as a light pink solid.

[0533] LCMS (ESI): 295 [M+H]+

[0534] XH NMR (400 MHz, DMSO- e) 6 14.78 (br.s, 1H), 9.17 (brt.s, 1H), 9.01 (t, J= 6.0 Hz, 1H), 8.61 (s, 1H), 7.82 (d, J= 3.0 Hz, 1H), 7.76 (d, J= 1.7 Hz, 1H), 7.54 (dd, J= 7.8,177MOFO-359177620.183143520007401.7 Hz, 1H), 7.37 (d, J= 7.9 Hz, 1H), 6.53 (d, J= 3.1 Hz, 1H), 4.97 - 4.93 (m, 4H), 4.22 (s, 3H).EXAMPLE 55Synthesis of 6-[ ( {2-isopropyl-5-methylpyrrolo[ 3, 2-d]pyrimidin-4-yl}amino)methyl J-3H-2, 1- benzoxaborol-l-ol hydrochloride

[0535] This compound was synthesized using Scheme 54.Scheme 546-[ ( {2-Isopropyl-5-methylpyrrolo [ 3, 2-d]pyrimidin-4-yl }amino)methyl J-3H-2, 1- benzoxaborol-l-ol hydrochloride (55)

[0536] To a stirred solution of 6-(aminomethyl)-3J / -2,l-benzoxaborol-l-ol hydrochloride (C46) (200 mg, 1.2 mmol, 1.0 equiv.) and 4-chloro-2-isopropyl-5-methylpyrrolo[3,2- d]pyrimidine (C86) (308 mg, 1.4 mmol, 1.2 equiv.) in DMSO (6 mL) were added TEA (620 mg, 6.1 mmol, 5.0 equiv.) and KF (142 mg, 2.4 mmol, 2.0 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was heated to 50 °C and stirred overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The product was initially purified by reverse-phase combi- chromatography with the following conditions: column, C18; mobile phase, MeCN in water, 40% to 60% gradient in 10 min; detector, UV 254 nm and then was further purified by prep-HPLC with the following conditions: Column: Xselect CSH C185 pm, 30 mm X 150 mm; Mobile Phase178MOFO-359177620.18314352000740A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 12% B to 26%B in 8 min; Wave Length: 254 nm / 220 nm. This resulted in 55 (59.5 mg, 14.4% yield) as a light-yellow solid.

[0537] LCMS (ESI): 337 [M+H]+

[0538] 1H NMR (400 MHz, DMSO-t / 6) 8 14.40 (s, 1H), 9.13 (s, 1H), 8.95 (t, J= 5.9 Hz, 1H), 7.78 - 7.74 (m, 2H), 7.57 (dd, J= 7.9, 1.7 Hz, 1H), 7.37 (d, J= 7.9 Hz, 1H), 6.45 (d, J= 3.0 Hz, 1H), 4.96 (s, 2H), 4.91 (d, J= 5.8 Hz, 2H), 4.17 (s, 3H), 3.12 (heptet, J= 6.8 Hz, 1H), 1.21 (d, J= 6.8 Hz, 6H).EXAMPLE 56Synthesis of (R)-4-( (1-(1 -hydroxy- 1, 3-dihydrobenzo [c] [ 1, 2 ]oxaborol-6-yl)ethyl)amino)-8- methoxyquinoline-3-carbonitrile

[0539] This compound was synthesized using Scheme 55.179MOFO-359177620.18314352000740Scheme 55Methyl 4-acetyl-2-hydroxybenzoate (Cl 11)

[0540] To a stirred solution of methyl 4-bromo-2-hydroxybenzoate (Cl 10) (5.0 g, 21.6 mmol, 1.0 equiv.) and tributyl(l-ethoxyvinyl)stannane (9.4 g, 26.0 mmol, 1.2 equiv.) in 1,4- dioxane (100 mL) was added Pd PPhs^Ch (1.5 g, 2.2 mmol, 0.1 equiv.) at room temperature under N2 atmosphere. The reaction mixture was heated to 90 °C overnight under N2 atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with the following conditions: mobile phase, EA in PE, 0% to 10% gradient in 20 min; detector, UV 254 nm. The resulting material was dissolved in 1 M HCI aqueous solution (50 mL) and THF (50 mL) and the solution was stirred for 2 hours. The resulting mixture was concentrated under vacuum. This resulted in Cl 11 (5.0 g) as a yellow solid, which was used directly without further purification.180MOFO-359177620.18314352000740Methyl 2-hydroxy-4-(2-methyl-l,3-dioxolan-2-yl)benzoate (Cl 12)

[0541] To a stirred solution of methyl 4-acetyl-2 -hydroxybenzoate (Cl 11) (5.0 g, 25.7 mmol, 1.0 equiv.) and ethylene glycol (8.0 g, 128.7 mmol, 5.0 equiv.) in toluene (100 mL) was added TsOH (0.44 g, 2.6 mmol, 0.1 equiv.) at room temperature. The resulting mixture was heated to 130 °C for 4 hours. The resulting mixture was concentrated under vacuum. The product was purified by silica gel column chromatography with the following conditions: mobile phase, EA in PE, 0% to 10% gradient in 20 min; detector, UV 300 nm. This resulted in Cl 12 (2.9 g, 47.3% yield) as a brown oil.Methyl 4-(2-methyl-l,3-dioxolan-2-yl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (Cl 13)

[0542] To a stirred solution of methyl 2-hydroxy-4-(2-methyl-l,3-dioxolan-2-yl)benzoate (Cl 12) (6.4 g, 26.9 mmol, 1.0 equiv.) in THF (100 mL) was added NaH (1.61 g, 40.3 mmol, 1.5 equiv., 60% in oil) at 0 °C. The resulting mixture was warmed to room temperature and stirred at room temperature for an additional 30 minutes. To the above mixture was added 1 , 1 , 1 -trifluoro-A-phenyl-A-trifluorom ethanesulfonylmethanesulfonamide (11.5 g, 32.2 mmol, 1.2 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight and then quenched with MeOH (20 mL) at 0 °C. Then the mixture was concentrated under vacuum. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in Cl 13 (8.6 g, 86.5% yield) as a light-yellow solid.Methyl 4-(2 -methyl- 1, 3-dioxolan-2-yl)-2-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)benzoate (Cl 14)

[0543] To a stirred mixture of methyl 4-(2-methyl-l,3-dioxolan-2-yl)-2- (trifhioromethanesulfonyloxy)benzoate (Cl 13) (8.0 g, 21.6 mmol, 1.0 equiv.), Pin2B2 (8.2 g, 32.4 mmol, 1.5 equiv.), and KOAc (4.2 g, 43.2 mmol, 2.0 equiv.) in 1,4-dioxane (150 mL) was added Pd(dppf)C12 (1.6 g, 2.2 mmol, 0.1 equiv.) at room temperature under N2 atmosphere. The resulting mixture was heated to 80 °C overnight. The resulting mixture was concentrated under vacuum. The product was purified by silica gel column chromatography with the following conditions: mobile phase, EA in PE, 0% to 20% gradient in 30 min; detector, UV 254 nm. This resulted in Cl 14 (7.5 g) as a light-yellow solid, which was used directly without further purification.181MOFO-359177620.183143520007406-(2-Methyl-l, 3-dioxolan-2-yl)benzo[ c][l,2 ]oxaborol-l(3H)-ol (C 115)

[0544] To a stirred solution of methyl 4-(2-methyl-l,3-dioxolan-2-yl)-2-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (Cl 14) (7.0 g, 26.3 mmol, 1.0 equiv.) in methanol (70 mL) was added NaBT (5.0 g, 131.5 mmol, 5.0 equiv.) in portions at 0 °C. The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated NH4CI aqueous solution (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in Cl 15 (5.5 g, 95.0% yield) as a white solid.1-(1 -Hydr oxy-1, 3-dihydrobenzo[ c] [1,2 ]oxaborol-6-yl)ethan-l-one (C 116)

[0545] To a solution of 6-(2-methyl-l,3-dioxolan-2-yl)benzo[c][l,2]oxaborol-l(3H)-ol (Cl 15) (5.5 g, 25.0 mmol, 1.0 equiv.) in THF (50 mL) was added 1 M HC1 aqueous solution (50 mL) and the mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in Cl 16 (5.0 g) as a yellow oil, which was used directly without further purification.(S)-N-( l-(l -hydroxy-1, 3-dihydrobenzo[c] [ 1, 2 ]oxaborol-6-yl)ethylidene)-2-methylpropane-2- sulfmamide (Cl 17)

[0546] To a stirred solution of l-(l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6- yl)ethan-l-one (Cl 16) (500 mg, 2.8 mmol, 1.0 equiv.) and (5)-2-methylpropane-2- sulfinamide (1.0 g, 8.5 mmol, 3.0 equiv.) in THF (25 mL) was added tetraethoxytitanium (3.2 g, 14.2 mmol, 5.0 equiv.) at room temperature under N2 atmosphere. The resulting mixture was heated to 80 °C for 4 hours under N2 atmosphere. The reaction was quenched with water (20 mL) at 0 °C. The resulting mixture was filtered off and the filter cake was washed with EA (3 x 10 mL). The filtrate was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water, 0% to 30% gradient in 20 min; detector, UV 220 nm. This resulted in Cl 17 (220 mg, 27.7% yield) as a light-yellow solid.182MOFO-359177620.18314352000740(S)-N-( (R)-l-( 1 -hydr oxy-1, 3-dihydrobenzo [c] [ 1, 2 ]oxaborol-6-yl)ethyl)-2-methylpropane-2- sulfmamide (C 118)

[0547] To a stirred solution of (5)-A-(l-(l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6- yl)ethylidene)-2-methylpropane-2-sulfinamide (Cl 17) (200 mg, 0.7 mmol, 1.0 equiv.) in THF (5 mL) was added lithium tri-sec-butylhydroborate (L-selectride) (2.1 mL, 2.1 mmol, 3.0 equiv.) dropwise at 0 °C. The resulting mixture was warmed to room temperature and stirred for another 2 hours at room temperature. The reaction was quenched with 1 M HC1 aqueous solution at 0 °C. The resulting mixture was concentrated under vacuum. This resulted in Cl 18 (230 mg), which was used in the next step directly without further purification.(R)-6-(l-Aminoethyl)benzo[c] [l,2]oxaborol-l(3H)-ol hydrochloride (Cl 19)

[0548] To a stirred solution of intermediate (5)-N-((A)-l-(l-hydroxy-l,3- dihydrobenzo[c][l,2]oxaborol-6-yl)ethyl)-2-methylpropane-2-sulfinamide (Cl 18) (230 mg, 0.8 mmol, 1.0 equiv.) in 1,4-dioxane (2 mL) was added 4 M HC1 in 1,4-dioxane (2 mL). The resulting mixture was stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 0% to 20% gradient in 20 min; detector, UV 220 nm. This resulted in Cl 19 (100 mg, 96.0% yield) as a colorless oil.(R)-4-( (1-(1 -hydr oxy-1, 3-dihydrobenzo [c] [ 1, 2 ] oxaborol-6-yl)ethyl)amino)-8- methoxyquinoline-3-carbonitrile (56)

[0549] To the stirred solution of (R)-6-(l-aminoethyl)benzo[c][l,2]oxaborol-l(3H)-ol hydrochloride (Cl 19) (130 mg, 0.7 mmol, 1.0 equiv.) and 4-chl oro-8-m ethoxy quinoline-3- carbonitrile (C35) (321 mg, 1.5 mmol, 2 equiv.) in MeCN (3 mL) was added K2CO3 (203 mg, 1.5 mmol, 2.0 equiv.) at room temperature. The resulting mixture was heated to 80 °C overnight. The resulting mixture was concentrated under reduced pressure. The product was purified by prep-HPLC with following conditions : Column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 18% B to 30% B in 8min; Wave Length: 254 / 220 nm. This resulted in 56 (20.3 mg, 7.7% yield) as a white solid.183MOFO-359177620.18314352000740

[0550] LCMS (ESI): 360 [M+H]+

[0551] XH NMR (400 MHz, DMSO-t / 6) 6 9.13 (s, 1H), 8.36 (s, 1H), 8.22 (dd, J= 8.8, 1.0 Hz, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.74 (d, J= 1.8 Hz, 1H), 7.59 - 7.49 (m, 2H), 7.37 (d, J= 8.0 Hz, 1H), 7.30 (d, J= 7.7 Hz, 1H), 5.84 (quintet, J= 6.9 Hz, 1H), 4.95 (s, 2H), 3.92 (s, 3H), 1.70 (d, J = 6.7 Hz, 3H).EXAMPLE 57Synthesis of (R)-6-( 1 -((8-methoxyquinazolin-4-yl)amino)ethyl)benzo [c] [ 1, 2 ]oxaborol-l(3H)~

[0552] This compound was synthesized using Scheme 56.(R)-6-( 1 -((8-Methoxyquinazolin-4-yl)amino)ethyl)benzo [c] [ 1, 2 ]oxaborol-l(3H)-ol (57)

[0553] To the solution of (7?)-6-(l-aminoethyl)benzo[c][l,2]oxaborol-l(3J7)-ol hydrochloride (Cl 19) (120 mg, 0.7 mmol, 1.0 equiv.) and 4-chloro-8-methoxyquinazoline (C41) (263 mg, 1.4 mmol, 2.0 equiv.) in MeCN (5 mL) was added K2CO3 (281 mg, 2.0 mmol, 3.0 equiv.) at room temperature. The resulting mixture was heated to 50 °C overnight. The resulting mixture was concentrated under reduced pressure. The product was purified by prep-HPLC with following conditions: Column: XBridge BEH Cl 8 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH),184MOFO-359177620.18314352000740Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 8% B to 26% B in 8min;Wave Length: 254 / 220 nm. This resulted in 57 (34.6 mg, 15.2% yield) as a white solid.

[0554] LCMS (ESI): 336 [M+H]+

[0555] 1H NMR (400 MHz, DMSO-t / 6) 8 9.11 (s, 1H), 8.38 - 8.35 (m, 2H), 8.00 (dd, J=8.5, 1.1 Hz, 1H), 7.80 - 7.75 (m, 1H), 7.56 (dd, J= 7.9, 1.7 Hz, 1H), 7.45 (t, J= 8.1 Hz, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.26 (dd, J= 8.0, 1.0 Hz, 1H), 5.62 (quintet, J= 7.1 Hz, 1H), 4.94 (s, 2H), 3.89 (s, 3H), 1.60 (d, J= 7.1 Hz, 3H).EXAMPLE 58Synthesis of (S)-4-( (1-(1 -hydr oxy-1, 3-dihydrobenzo[c] [ 1, 2 ]oxaborol-6-yl)ethyl)amino)-8- methoxyquinoline-3-carbonitrile5

[0556] This compound was synthesized using Scheme 57.Scheme 57(R)-N-( 1-(1 -Hydroxy- 1, 3-dihydrobenzo [c] [ 1, 2 ]oxaborol-6-yl)ethylidene)-2-methylpropane-2- sulfmamide (Cl 20)185MOFO-359177620.18314352000740

[0557] To a stirred solution of l-(l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6- yl)ethan-l-one (Cl 16) (500 mg, 2.8 mmol, 1.0 equiv.) and (R)-2-methylpropane-2- sulfinamide (1.0 g, 8.5 mmol, 3.0 equiv.) in THF (25 mL) was added tetraethoxytitanium (3.2 g, 14.2 mmol, 5.0 equiv.) at room temperature under N2 atmosphere. The resulting mixture was heated to 80 °C for 4 hours under N2 atmosphere. The reaction was quenched with water at 0 °C. The resulting mixture was filtered off and the filter cake was washed with EA (3 x 10 mL). The filtrate was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 30% gradient in 20 min; detector, UV 220 nm. This resulted in C120 (220 mg, 27.7% yield) as a light-yellow solid.(R)-N-( (S)-l-( I -Hydr oxy-1, 3-dihydrobenzo [c] [ 1, 2 ]oxaborol-6-yl)ethyl)-2-methylpropane-2- sulfmamide (C121)

[0558] To a stirred solution of (A)-7V-(l-(l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6- yl)ethylidene)-2-methylpropane-2-sulfinamide (C120) (200 mg, 0.7 mmol, 1.0 equiv.) in THF (5 mL) was added lithium tri-sec-butylhydroborate (L-selectride) (2.1 mL, 2.1 mmol, 3.0 equiv.) dropwise at 0 °C. The resulting mixture was warmed to room temperature and stirred for 2 hours at room temperature. The reaction was quenched with 1 M HC1 aqueous solution at 0 °C. The resulting mixture was concentrated under vacuum. This resulted in C121 (230 mg), which was used in the next step directly without further purification.(S)-6-( I -Aminoethyl)benzo[c] [ 1, 2 ]oxaborol-l ( 3H)-ol hydrochloride (C 122)

[0559] To a stirred solution of (A)-W((5)-l-(l -hydroxy- 1,3- dihydrobenzo[c][l,2]oxaborol-6-yl)ethyl)-2-methylpropane-2-sulfinamide (C 121) (230 mg, 0.8 mmol, 1.0 equiv.) in 1,4-dioxane (2 mL) was added 4 M HC1 in 1,4-dioxane (2 mL). The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 0% to 20% gradient in 20 min; detector, UV 220 nm. This resulted in C122 (100 mg, 96.0% yield) as a colorless oil.(S)-4-( (1-(1 -Hydroxy-1, 3-dihydrobenzo [c] [ 1, 2 ]oxaborol-6-yl)ethyl)amino)-8- methoxyquinoline-3-carbonitrile (58)186MOFO-359177620.18314352000740

[0560] To the stirred solution of (5)-6-(l-aminoethyl)benzo[c][l,2]oxaborol-l(3J7)-ol hydochloride (C122) (160 mg, 0.9 mmol) and 4-chloro-8-methoxyquinoline-3-carbonitrile (C35) (296 mg, 1.4 mmol, 1.5 equiv.) in MeCN (6 mL) was added K2CO3 (375 mg, 2.7 mmol, 3.0 equiv.) at room temperature. The resulting mixture was heated to 80°C overnight. The resulting mixture was concentrated under reduced pressure and the residue collected. The product was purified by prep-HPLC with following conditionsColumn: XB ridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 20% B to 33% B in 8min; Wave Length: 254 / 220 nm. This resulted in 58 (14.6 mg, 4.2% yield) as a white solid.

[0561] LCMS (ESI): 360 [M+H]+

[0562] 1H NMR (400 MHz, DMSO-t / 6) 8 9.13 (s, 1H), 8.36 (s, 1H), 8.22 (dd, J= 8.8, 1.1 Hz, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.74 (d, J= 1.7 Hz, 1H), 7.59 - 7.49 (m, 2H), 7.37 (d, J= 7.9 Hz, 1H), 7.30 (dd, J= 8.0, 0.9 Hz, 1H), 5.84 (quintet, J= 6.9 Hz, 1H), 4.95 (s, 2H), 3.92 (s, 3H), 1.70 (d, J= 6.8 Hz, 3H).EXAMPLE 59Synthesis of (S)-6-( 1 -((8-methoxyquinazolin-4-yl) amino) ethyl)benzo[ c][l,2 ]oxaborol-l(3H)~ ol

[0563] This compound was synthesized using Scheme 58.Scheme 58187MOFO-359177620.18314352000740(S)-6-(l-(( 8-methoxyquinazolin-4-yl)amino)ethyl ) benzo [ c] [1,2 ]oxaborol-l ( 3H)-ol (59)

[0564] To the stirred solution of (5)-6-(l-aminoethyl)benzo[c][l,2]oxaborol-l(3J7)-ol hydrochloride (C122) (120 mg, 0.7 mmol, 1.0 equiv.) and 4-chloro-8-methoxyquinazoline (C41) (263 mg, 1.4 mmol, 2.0 equiv.) in MeCN (5 mL) was added K2CO3 (281 mg, 2.0 mmol, 3.0 equiv.) at room temperature. The resulting mixture was heated to 50 °C overnight. The resulting mixture was concentrated under reduced pressure and the residue collected. The product was purified by prep-HPLC with following conditions: Column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 8% B to 26% B in 8 min; Wave Length: 254 / 220 nm. This resulted in 59 (34.6 mg, 15.2% yield) as a white solid.

[0565] LCMS (ESI): 336 [M+H]+

[0566] 1H NMR (400 MHz, DMSO-t / 6) 8 9.10 (s, 1H), 8.38 - 8.35 (m, 2H), 8.00 (dd, J=8.5, 1.1 Hz, 1H), 7.79 - 7.76 (m, 1H), 7.56 (dd, J= 7.9, 1.7 Hz, 1H), 7.45 (t, J= 8.1 Hz, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.26 (dd, J= 8.0, 1.1 Hz, 1H), 5.62 (quintet, J= 7.1 Hz, 1H), 4.94 (s, 2H), 3.89 (s, 3H), 1.61 (d, J= 7.1 Hz, 3H).

[0567] Alternative method for synthesizing Compound 59:

[0568] To the stirred solution of (5)-6-(l-aminoethyl)benzo[c][l,2]oxaborol-l(3J7)-ol hydrochloride (C122) (4.5 g, 23.1 mmol, 1.0 equiv.) and 4-chloro-8-methoxyquinazoline (C41) (6.4 g, 30.1 mmol, 1.3 equiv.) in DMSO (60 mL) was added CsF (17.6 g, 115.6 mmol, 5.0 equiv.) at room temperature. The resulting mixture was heated to 50 °C for 2 hours. The product was initially purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, MeCN in water, 0% to 35% gradient in 20 min; detector, UV 220 nm. The product was further purified by prep-HPLC with following conditions: Column: X Bridge BEH Cis OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient (B%): 8% B to 30% B in 30 min; Wave Length: 220 nm. This resulted in 59 (3.75 g, 48.4% yield, 99.0% purity) as a white solid.

[0569] LCMS (ESI): 336 [M+H]+188MOFO-359177620.18314352000740

[0570] 1H NMR (400 MHz, DMSO-t / 6) 8 9.11 (s, 1H), 8.37 (d, J= 5.7 Hz, 2H), 8.00 (dd,J= 8.5, 1.1 Hz, 1H), 7.80 - 7.75 (m, 1H), 7.56 (dd, J= 8.0, 1.8 Hz, 1H), 7.45 (t, J= 8.1 Hz, 1H), 7.35 (d, J= 7.9 Hz, 1H), 7.26 (dd, J= 8.0, 1.0 Hz, 1H), 5.62 (quintet, J= 7.2 Hz, 1H), 4.94 (s, 2H), 3.89 (s, 3H), 1.60 (d, J= 7.0 Hz, 3H)EXAMPLE 60Synthesis of 4-{[(l-hydr oxy-3, 4-dihydro-2, l-benzoxaborinin-7-yl)methyl]amino}-8- methoxyquinoline-3-carbonitrile hydrochloride

[0571] This compound was synthesized using Scheme 59.Scheme 59Methyl 3-bromo-4-(bromomethyl)benzoate (C50)189MOFO-359177620.18314352000740

[0572] To a stirred solution of methyl 3 -brom o-4-m ethylbenzoate (C123) (10.0 g, 43.7 mmol, 1.0 equiv.) and NBS (9.3 g, 52.4 mmol, 1.2 equiv.) in ACN (100 mL) was added AIBN (717 mg, 4.4 mmol, 0.1 equiv.) in portions at room temperature. The resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere. The product was purified by silica gel column chromatography, eluted with PE / EA (15 / 1) to afford C50 (10.0 g, 74.4% yield) as a white solid.

[0573] 'H NMR (400 MHz, DMSO-t / 6) 8 8.12 (dq, J= 5.2, 3.4, 2.5 Hz, 1H), 7.95 (ddt, J = 8.0, 3.2, 1.5 Hz, 1H), 7.78 (dt, J= 8.0, 1.6 Hz, 1H), 4.79 (d, J= 2.0 Hz, 2H), 3.88 (d, J= 0.9 Hz, 3H).Methyl 3-bromo-4-(cyanomethyl)benzoate (C51)

[0574] To a stirred solution of TMSCN (4.8 g, 48.7 mmol, 1.5 equiv.) and TBAF (1.3 g,48.7 mmol, 1.5 equiv.) in ACN (200 mL) was added methyl 3-bromo-4- (bromomethyl)benzoate (C50) (10.0 g, 32.5 mmol, 1.0 equiv.) in portions at 0 °C. The resulting mixture was stirred at room temperature for 4 hours under nitrogen atmosphere. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in C51 (5.4 g, 65.5% yield) as a colorless oil.

[0575] XH NMR (400 MHz, DMSO-t / 6) 6 8.14 (d, J= 1.7 Hz, 1H), 8.00 (dd, J= 8.0, 1.8 Hz, 1H), 7.71 (d, J= 8.0 Hz, 1H), 4.19 (s, 2H), 3.88 (s, 3H).3-Bromo-4-(carboxymethyl)benzoic acid (Cl 24)

[0576] To a stirred solution of methyl 3-bromo-4-(cyanomethyl)benzoate (C51) (4.5 g,17.7 mmol, 1.0 equiv.) and H2O (20 mL) in MeOH (20 mL) was added NaOH (2.5 g, 62.0 mmol, 3.5 equiv.) in portions at 0 °C under air atmosphere. The resulting mixture was stirred at 80 °C overnight under air atmosphere. The reaction residue was acidified to pH 2 with HC1 aqueous solution. The resulting mixture was extracted with EtOAc (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in C124 (3.9 g) as a white solid, which was used directly in the next step without further purification.2- [2-Bromo-4-(hydroxymethyl)phenyl] ethanol (C 125)190MOFO-359177620.18314352000740

[0577] To a stirred solution of 3-bromo-4-(carboxymethyl)benzoic acid (C124) (3.9 g, 15.1 mmol, 1.0 equiv.) in THF (40 mL) was added borane-tetrahydrofuran complex (1.0 M in THF, 151 mL, 150.6 mmol, 10.0 equiv.) dropwise at 0 °C under air atmosphere. The resulting mixture was stirred at 70 °C overnight under nitrogen atmosphere. The reaction was quenched with ice water (100 mL) at 0°C. The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The product was purified by reversephase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water, 0% to 90% gradient in 10 min; detector, UV 254 nm. This resulted in C125 (3.1 g, 89.1% yield) as a colorless oil.7-(Hydroxymethyl)-3, 4-dihydro-2, 1-benzoxaborinin-l-ol (C 126)

[0578] To a stirred mixture of 2-[2-bromo-4-(hydroxymethyl)phenyl]ethanol (C125) (3.1 g, 13.4 mmol, 1.0 equiv.) and Pd(dppf)C12 (982 mg, 1.3 mmol, 0.1 equiv.) in 1,4-dioxane (31 mL) were added Pin2B2 (5.1 g, 20.1 mmol, 1.5 equiv.) and AcOK (3.3 g, 33.5 mmol, 2.5 equiv.) in portions at room temperature under air atmosphere. The resulting mixture was stirred at 80 °C for 4 hours under nitrogen atmosphere. The resulting mixture was filtered off and the filter cake was washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in C126 (2.2 g, 92.1% yield) as a light brown solid.1 -Hydroxy-3, 4-dihydro-2, 1-benzoxaborinine- 7-carbaldehyde (C 127)

[0579] To a stirred solution of 7-(hydroxymethyl)-3,4-dihydro-2, 1-benzoxaborinin-l-ol (C126) (2.2 g, 12.4 mmol, 1.0 equiv.) in DCM (20 mL) was added DMP (l,l-bis(acetyloxy)- 3-oxo-3H-lk5,2-benziodaoxol-l-yl acetate or Dess-Martin periodinane) (7.9 g, 18.5 mmol, 1.5 equiv.) in portions at 0 °C under air atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was filtered off and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in C127 (1.1 g, 50.6% yield) as a light brown solid.191MOFO-359177620.183143520007407-[ (Hydroxyimino)methyl J-3, 4-dihydro-2, 1-benzoxaborinin-l-ol (C 128)

[0580] To a stirred solution of 1 -hydroxy-3, 4-dihydro-2,l-benzoxaborinine-7- carbaldehyde (C127) (2.3 g, 13.1 mmol, 1.0 equiv.) and H2O (5 mL) in THF (20 mL) were added AcONa (1.5 g, 18.3 mmol, 1.4 equiv.) and hydroxylamine hydrochloride (1.1 g, 15.7 mmol, 1.2 equiv.) in portions at room temperature under air atmosphere. The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. This resulted in C128 (2.3 g) as a light brown solid, which was used directly in the next step without further purification.7 -(Aminomethyl) -3, 4-dihydro-2, 1-benzoxaborinin-l-ol (C 129)

[0581] A mixture of 7-[(hydroxyimino)methyl]-3,4-dihydro-2, 1-benzoxaborinin-l-ol(C128) (2.0 g, 10.5 mmol, 1.0 equiv.) and Zn (2.1 g, 31.4 mmol, 3.0 equiv.) in AcOH (20 mL) was stirred at 80 °C overnight under nitrogen atmosphere. The resulting mixture was filtered off and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in C129 (1.8 g) as a light brown solid.4-{[(l -Hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl ]amino}-8-methoxyquinoline-3- carbonitrile hydrochloride (60)

[0582] To a stirred solution of 7-(aminomethyl)-3,4-dihydro-2, 1-benzoxaborinin-l-ol (C129) (600 mg, 3.4 mmol, 1.0 equiv.) and 4-chloro-8-methoxyquinoline-3-carbonitrile (C35) (371 mg, 1.7 mmol, 0.5 equiv.) in DMF (4 mL) was added TEA (686 mg, 6.8 mmol, 2.0 equiv.) dropwise at room temperature under air atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The product was purified by prep-HPLC with the following conditions (Column: Xselect CSH Cl 85 pm, 30 mm X 150 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 8% B to 22%B in 8 min; Wave Length: 254 nm / 220 nm) to afford 60 (78.1 mg, 5.8% yield) as a white solid.192MOFO-359177620.18314352000740

[0583] LCMS (ESI): 360 [M+H]+

[0584] XH NMR (400 MHz, DMSO- e) 8 10.38 - 10.18 (m, 1H), 8.79 (s, 1H), 8.48 - 8.26 (m, 2H), 7.77 (t, J= 8.3 Hz, 1H), 7.70 - 7.58 (m, 2H), 7.39 (dd, J= 7.9, 2.1 Hz, 1H), 7.22 (d, J= 7.8 Hz, 1H), 5.22 (d, J= 6.4 Hz, 2H), 4.07 (s, 5H), 2.86 (t, J= 5.9 Hz, 2H).EXAMPLE 61Synthesis of 7-{[(8-methoxyquinazolin-4-yl)amino]methyl}-3,4-dihydro-2,l-benzoxaborinin- l-ol

[0585] This compound was synthesized using Scheme 60.Scheme 607-{[(8-Methoxyquinazolin-4-yl)amino]methyl}-3,4-dihydro-2,l-benzoxaborinin-l-ol (61)

[0586] To a stirred solution of 7-(aminomethyl)-3,4-dihydro-2,l-benzoxaborinin-l-ol (C129) (300 mg, 1.7 mmol, 1.0 equiv.) and 4-chloro-8-methoxyquinoline-3-carbonitrile (C41) (371 mg, 1.7 mmol, 1.0 equiv.) in DMF (4 mL) was added TEA (257 mg, 2.5 mmol, 1.5 equiv.) dropwise at room temperature under air atmosphere. The resulting mixture was stirred at room temperature overnight. The product was purified by prep-HPLC with the following conditions (Column: YMC Triart C18 ExRs 5 pm, 30 mm * 150 mm; Mobile Phase A: water (lOmmol / L NH4HCO3+0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 14% B to 42% B in 8min; Wave Length: 254 / 220 nm) to afford 61 (49.8 mg, 8.8% yield) as a white solid.193MOFO-359177620.18314352000740

[0587] LCMS (ESI): 336 [M+H]+

[0588] 'H NMR (400 MHz, DMSO-t / 6) 6 8.77 (s, 1H), 8.82 - 8.43 (m, 2H), 7.82 (d, J=8.3 Hz, 1H), 7.67 (d, J= 2.0 Hz, 1H), 7.45 (t, J= 8.1 Hz, 1H), 7.38 (dd, J= 7.8, 2.0 Hz, 1H), 7.27 (d, J= 7.8 Hz, 1H), 7.15 (d, J= 7.8 Hz, 1H), 4.76 (d, J= 5.8 Hz, 2H), 4.04 (t, J= 5.9 Hz, 2H), 3.91 (s, 3H), 2.83 (t, J= 5.9 Hz, 2H).EXAMPLE 62Synthesis of 4-{[2-(l-hydroxy-3H-2,l-benzoxaborol-6-yl)ethyl]amino}-8H-pyrido[2,3- d]pyrimidin- 7 -one trihydrochloride

[0589] This compound was synthesized using Scheme 61.Methyl (E)-3-( 4-amino-6-( (2-( I -hydr oxy-1, 3 -dihydrobenzo [c] [ 1, 2 ]oxaborol-6- yl)ethyl)amino)pyrimidin-5-yl)acrylate (C 130)

[0590] To a stirred solution of 6-(2-aminoethyl)-3J / -2,l-benzoxaborol-l-ol (C54) (828 mg, 4.6 mmol, 2.0 equiv.) and methyl (2E)-3-(4-amino-6-chloropyrimidin-5-yl)prop-2-enoate (C76) (200 mg, 0.9 mmol, 1.0 equiv.) in DMSO (1 mL) was added EtsN (473 mg, 4.6 mmol, 2.0 equiv.) at room temperature. The resulting mixture was stirred at 80 °C overnight. The product was purified by reverse-phase with the following conditions (water / ACN) to afford methyl C130 (400 mg, 48.3% yield) as a white solid.4-{[2-(l-Hydroxy-3H-2,l-benzoxaborol-6-yl)ethyl]amino}-8H-pyrido[2,3-d]pyrimidin-7-one194MOFO-359177620.18314352000740 trihydrochloride (62)

[0591] To a stirred solution of methyl (2£)-3 -(4-amino-6-{[2-( 1 -hydroxy-3 JT-2,1- benzoxaborol-6-yl)ethyl]amino}pyrimidin-5-yl)prop-2-enoate (C130) (250 mg, 0.7 mmol, 1.0 equiv.) in DMSO (10 mL) was added sodium thiomethoxide (494 mg, 7.0 mmol, 10.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The product was purified by prep-HPLC with the following conditions (Column: Xselect CSH C185 pm, 19 mm X 250 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 7% B to 15%B in 9 min; Wave Length: 254 nm / 220 nm) to afford 62 (76.4 mg, 25.1% yield) as a white solid.

[0592] LCMS (ESI): 323 [M+H]+

[0593] XH NMR (400 MHz, DMSO- e) 6 13.39 (br.s, 1H), 12.54 (br.s, 1H), 9.14 (s, 1H), 8.34 (d, J= 5.3 Hz, 1H), 8.22 - 8.18 (m, 1H), 7.84 - 7.80 (m, 2H), 7.58 (s, 1H), 7.36 - 7.25 (m, 3H), 6.26 - 6.17 (m, 1H), 4.95 (s, 2H), 3.71 - 3.61 (m, 2H), 2.93-2.86 (m, 6.4 Hz, 2H).EXAMPLE 63Synthesis of 4-{[2-( I -hydroxy-3H-2, l-benzoxaborol-6-yl) ethyl ]amino}-N,N, 5- trimethylpyrrolo[ 3, 2-d]pyrimidine- 7 -carboxamide63

[0594] This compound was synthesized using Scheme 62.Scheme 62195MOFO-359177620.183143520007404-{[2-( 1 -Hydroxy-3H-2, l-benzoxaborol-6-yl)ethyl ]amino}-N,N, 5-trimethylpyrrolo[ 3, 2- d] pyrimidine- 7 -carboxamide (63)

[0595] To a stirred solution of 6-(2-aminoethyl)-3J / -2,l-benzoxaborol-l-ol (C54) (110 mg, 0.6 mmol, 1.5 equiv.) and 4-chloro-A,A,5-trimethylpyrrolo[3,2-d]pyrimidine-7- carboxamide (C79) (100 mg, 0.4 mmol, 1.0 equiv.) in DMSO (5 mL) was added EtsN (84 mg, 0.8 mmol, 2.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The product was purified by prep-HPLC with the following conditions (Column: XBridge BEH Shield RP18 5 pm, 30 mm *150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3+0.1% NH4OH), Mobile Phase B: MeOH; Flow rate: 60 mL / min; Gradient (B%): 30% B to 42% B in 8min; Wave Length: 254 / 220 nm) to afford 63 (43.9 mg, 27.9% yield) as a white solid.

[0596] LCMS (ESI): 380 [M+H]+

[0597] 1H NMR (400 MHz, DMSO-t / 6) 8 9.14 (s, 1H), 8.25 (s, 1H), 7.67 (s, 1H), 7.65 (s,1H), 7.43 - 7.32 (m, 2H), 6.87 (t, J= 5.7 Hz, 1H), 4.96 (s, 2H), 4.01 (s, 3H), 3.76 - 3.67 (m, 2H), 3.03 - 2.97 (m, 8H).EXAMPLE 64Synthesis of 4-{[2-( 1 -hydroxy-3H-2, l-benzoxaborol-6-yl) ethyl ]amino}-N, 5- dimethylpyrrolo[ 3, 2-d]pyrimidine- 7 -carboxamide64

[0598] This compound was synthesized using Scheme 63.196MOFO-359177620.18314352000740Scheme 634-{[2-( 1 -Hydroxy-3H-2, l-benzoxaborol-6-yl)ethyl ]amino}-N, 5-dimethylpyrrolo[ 3, 2- d] pyrimidine- 7 -carboxamide (64)

[0599] To a stirred solution of 6-(2-aminoethyl)-3J / -2,l-benzoxaborol-l-ol (C54) (100 mg, 0.5 mmol, 1.0 equiv.) and 4-chloro-A,5-dimethylpyrrolo[3,2-d]pyrimidine-7- carboxamide (C83) (128 mg, 0.5 mmol, 1.0 equiv.) in DMSO (5 mL) at room temperature was added EtsN (156 mg, 1.1 mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature overnight. The product was purified by prep-HPLC with the following conditions (Column: XBridge BEH Shield RP18 5 pm, 30 mm *150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3+0.1% NH4OH), Mobile Phase B: MEOH; Flow rate: 60 mL / min; Gradient (B%): 30% B to 42% B in 8 min; Wave Length: 254 / 220 nm) to afford 64 (37.5 mg, 18.2% yield) as a white solid.

[0600] LCMS (ESI): 366 [M+H]+

[0601] 1H NMR (400 MHz, DMSO-t / 6) 8 9.14 (s, 1H), 8.45 (q, J= 4.7 Hz, 1H), 8.34 (s,1H), 7.93 (s, 1H), 7.65 (s, 1H), 7.43 - 7.32 (m, 2H), 7.04 (t, J= 5.7 Hz, 1H), 4.96 (s, 2H), 4.03 (s, 3H), 3.76 - 3.67 (m, 2H), 2.99 (q, J= 8.6, 6.3 Hz, 2H), 2.87 (d, J= 4.8 Hz, 3H).EXAMPLE 65Synthesis of 6-(2-((5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4- yl) amino) ethyl) benzo [ c] [1,2 ]oxaborol-l( 3H)-ol hydrochloride197MOFO-359177620.18314352000740

[0602] This compound was synthesized using Scheme 64.Scheme 646-(2-((5-Methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)ethyl)benzo[c] [l,2]oxaborol-l(3H)~ ol hydrochloride (65)

[0603] To the stirred solution of 6-(2-aminoethyl)benzo[c][l,2]oxaborol-l(3J7)-ol hydrochloride (C54) (162 mg, 0.9 mmol, 1.1 equiv.) and 4-chloro-5-methyl-5J / -pyrrolo[3,2- t ]pyrimidine (C85) (140 mg, 0.8 mmol, 1.0 equiv.) in DMSO (10 mL) was added TEA (127 mg, 1.3 mmol, 1.5 equiv.) at 25 °C. The mixture was heated to 100 °C overnight. The resulting mixture was concentrated under reduced pressure. The product was purified by prep-HPLC with following conditions: Column: Xselect CSH C185 pm, 19 mm X 250 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 10% B to 23% B in 8 min; Wave Length: 254 / 220 nm. This resulted in 65 (55.4 mg, 18.9% yield) as a white solid.

[0604] LCMS (ESI): 309 [M+H]+

[0605] XH NMR (400 MHz, DMSO-t / 6) 8 14.69 (br.s, 1H), 9.18 (s, 1H), 8.65 (s, 1H), 8.48 (t, J= 5.8 Hz, 1H), 7.77 (d, J= 3.0 Hz, 1H), 7.65 (d, J= 1.5 Hz, 1H), 7.44 - 7.33 (m, 2H), 6.51 (d, J= 3.0 Hz, 1H), 4.96 (s, 2H), 4.12 (s, 3H), 3.88 (dt, J= 8.4, 6.1 Hz, 2H), 3.03 (dd, J = 8.6, 6.4 Hz, 2H).198MOFO-359177620.18314352000740EXAMPLE 66Synthesis of 6-(2-( (2-Isopropyl-5-methyl-5H-pyrrolo[ 3, 2-d]pyrimidin-4- yl) amino) ethyl) benzo [ c] [1,2 ]oxaborol-l( 3H)-ol hydrochloride

[0606] This compound was synthesized using Scheme 65.Scheme 656-(2-( (2-Isopropyl-5-methyl-5H-pyrrolo[ 3, 2-d]pyrimidin-4- yl)amino)ethyl)benzo[c] [l,2]oxaborol-l(3H)-ol hydrochloride (66)

[0607] To a stirred solution of 6-(2-aminoethyl)-3J / -2,l-benzoxaborol-l-ol (C54) (100 mg, 0.5 mmol, 1.2 equiv.) and 4-chloro-2-isopropyl-5-methylpyrrolo[3,2-d]pyrimidine (C86) (100 mg, 0.4 mmol, 1.0 equiv.) in DMSO (1 mL) was added EtsN (239 mg, 2.3 mmol, 5.0 equiv.) at room temperature. The resulting mixture was stirred at 50 °C overnight. The product was purified by prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl5 pm, 30*150 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 13% B to 20%B in 9 min; Wave Length: 254 nm / 220 nm to afford 66 (48.1 mg, 26.3% yield) as a white solid.

[0608] LCMS (ESI): 351 [M+H]+

[0609] XH NMR (400 MHz, DMSO- e) 6 14.34 (s, 1H), 9.16 (s, 1H), 8.44 (t, J= 5.8 Hz, 1H), 7.72 (d, J= 3.0 Hz, 1H), 7.63 (s, 1H), 7.42 - 7.32 (m, 2H), 6.44 (d, J= 2.9 Hz, 1H),199MOFO-359177620.183143520007404.96 (s, 2H), 4.09 (s, 3H), 3.92 - 3.83 (m, 2H), 3.16 (septet, J= 6.8 Hz, 1H), 3.03 (dd, J = 8.7, 6.3 Hz, 2H), 1.33 (d, J= 6.8 Hz, 6H).EXAMPLE 67Synthesis of 4-amino-8-[ ( 1 -hydroxy-3, 4-dihydro-2, l-benzoxaborinin-6-yl)methyl ]pyrido[ 2,3- d]pyrimidin- 7 -one

[0610] This compound was synthesized using Scheme 66.Scheme 66Methyl ( 2E)-3-( 4-amino-6-{[ ( I -hydroxy-3, 4-dihydro-2, l-benzoxaborinin-6- yl)methyl]amino}pyrimidin-5-yl)prop-2-enoate (Cl 31)

[0611] To a stirred solution of 6-(aminomethyl)-3,4-dihydro-2,l-benzoxaborinin-l-ol (C108) (350 mg, 2.0 mmol, 1.0 equiv.) and methyl (2£)-3-(4-amino-6-chloropyrimidin-5-yl) prop-2-enoate (C76) (507 mg, 2.4 mmol, 1.2 equiv.) in DMF (10 mL) was added K2CO3 (410 mg, 3.0 mmol, 1.5 equiv.) at room temperature. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 40% gradient in 10 min; detector, UV 254 nm. This resulted in C131 (200 mg) as a colorless oil, which was used directly in the next step without further purification.200MOFO-359177620.183143520007404-Amino-8-[ ( 1 -hydroxy- 3, 4-dihydro-2, l-benzoxaborinin-6-yl)methyl ]pyrido[ 2, 3-d Jpyrimidin- 7-one (67)

[0612] To a stirred mixture of methyl (2E)-3 -(4-amino-6-{[(l -hydroxy-3, 4-dihydro-2,l- benzoxaborinin-6-yl)methyl]amino}pyrimidin-5-yl)prop-2-enoate (C131) (170 mg, 0.5 mmol, 1.0 equiv.) in DMSO (3 mL) was added sodium thiomethoxide (135 mg, 1.9 mmol, 4.0 equiv.) at room temperature. The resulting mixture was stirred at 100 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse phase with the following conditions (Column: XSelect CSH Phenyl-Hexyl OBD Prep Column, 5 pm, 30 mm X 150 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 10% B to 20%B in 9 min; Wave Length: 254 nm / 220 nm) to afford 67 (24.3 mg, 15.7% yield) as a white solid.

[0613] LCMS (ESI): 323 [M+H]+

[0614] 1H NMR (400 MHz, DMSO-t / 6) 8 8.36 (s, 1H), 8.29 (s, 1H), 8.19 (d, J= 9.7 Hz, 1H), 7.76 (s, 2H), 7.57 (d, J= 7.5 Hz, 1H), 7.08 - 6.98 (m, 2H), 6.56 (d, J= 9.6 Hz, 1H), 5.48 (s, 2H), 4.02 (t, J= 5.9 Hz, 2H), 2.79 (t, J= 5.9 Hz, 2H).EXAMPLE 68Synthesis of 4-{[(l-hydr oxy-3, 4-dihydro-2, l-benzoxaborinin-6-yl)methyl]amino}-8H- pyrido[ 2, 3-d]pyrimidin- 7 -one

[0615] This compound was synthesized using Scheme 67.Scheme 67201MOFO-359177620.183143520007404-{[(l -Hydroxy-3, 4-dihydro-2, l-benzoxaborinin-6-y I) methyl ]amino}-8H-pyrido[2, 3- d]pyrimidin-7-one (68)

[0616] To a stirred mixture of methyl (2E)-3 -(4-amino-6-{[(l -hydroxy-3, 4-dihydro-2,l- benzoxaborinin-6-yl)methyl]amino}pyrimidin-5-yl)prop-2-enoate (C131) (260 mg, 0.7 mmol, 1.0 equiv.) in DMSO (3 mL) was added MeONa (159 mg, 2.9 mmol, 4.0 equiv.) at room temperature. The resulting mixture was stirred at 80 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse phase with the following conditions (Column: XBridge BEH Shield RP18 5 pm, 30 mm *150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 5% B to 23% B in 8 min; Wave Length: 254 / 220 nm; RT(min): 7.35; 8.35) to afford 68 (36.5 mg, 15.4% yield) as a white solid.

[0617] LCMS (ESI): 323 [M+H]+

[0618] XH NMR (400 MHz, DMSO- e) 6 11.81 (br.s, 1H), 8.57 (t, J= 5.9 Hz, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.19 (d, J= 9.7 Hz, 1H), 7.63 (d, J= 7.5 Hz, 1H), 7.22 - 7.12 (m, 2H), 6.42 (d, J= 9.7 Hz, 1H), 4.71 (d, J= 5.8 Hz, 2H), 4.04 (t, J= 5.9 Hz, 2H), 2.84 (t, J= 5.9 Hz, 2H).EXAMPLE 69Synthesis of 4-{[(l-hydr oxy-3, 4-dihydro-2, l-benzoxaborinin-7-yl)methyl]amino}-8H- pyrido[ 2, 3-d]pyrimidin- 7 -one

[0619] This compound was synthesized using Scheme 68.202MOFO-359177620.18314352000740Scheme 68Methyl ( 2E)-3-( 4-amino-6-{[ ( I -hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7- yl)methyl ]amino}pyrimidin-5-yl)prop-2-enoate (C 132)

[0620] To a stirred solution of 7-(aminomethyl)-3,4-dihydro-2,l-benzoxaborinin-l-ol (C129) (700 mg, 4.0 mmol, 1.0 equiv.) and methyl (2E)-3-(4-amino-6-chloropyrimidin-5- yl)prop-2-enoate (C76) (840 mg, 4.0 mmol, 1.0 equiv.) in DMSO (8 mL) was added EtsN (2.0 g, 2.0 mmol, 5.0 equiv.) dropwise at room temperature. The resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere. The product was directly purified by reversephase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Cl 32 (210 mg, 15.0 % yield) as a colorless oil.4-{[(l -Hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl ]amino}-8H-pyrido[2, 3- d]pyrimidin-7-one (69)

[0621] A solution of methyl (2£)-3 -(4-amino-6-{[(l -hydroxy-3, 4-dihydro-2,l- benzoxaborinin-7-yl)methyl]amino}pyrimidin-5-yl)prop-2-enoate (C132) (200 mg, 0.6 mmol, 1.0 equiv.) and MeONa (122 mg, 2.3 mmol, 4.0 equiv.) in DMSO (3 mL) was stirred at 80 °C for 4 hours under nitrogen atmosphere. The product was purified by prep-HPLC with the following conditions (Column: YMC Triart C18 ExRs 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN;Flow rate: 60 mL / min; Gradient (B%): 8% B to 25% B in 9 min; Wave Length: 254 / 220 nm) to afford 69 (51.1 mg, 28.1% yield) as a white solid.

[0622] LCMS (ESI): 323 [M+H]+203MOFO-359177620.18314352000740

[0623] XH NMR (400 MHz, DMSO- e) 8 11.94 (s, 1H), 8.55 (t, = 5.9 Hz, 1H), 8.41 (s, 1H), 8.27 (s, 1H), 8.18 (d, J= 9.8 Hz, 1H), 7.64 (d, J= 1.9 Hz, 1H), 7.35 (dd, J= 1.1, 2.0 Hz, 1H), 7.16 (d, J= 1.1 Hz, 1H), 6.40 (d, J= 9.7 Hz, 1H), 4.69 (d, J= 5.8 Hz, 2H), 4.05 (t, J= 5.9 Hz, 2H), 2.83 (t, J= 5.9 Hz, 2H).EXAMPLE 70Synthesis of 4-amino-8-[ ( 1 -hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl ]pyrido[ 2,3- d]pyrimidin- 7 -one

[0624] This compound was synthesized using Scheme 69.Scheme 694-Amino-8-[ ( 1 -hydroxy- 3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl ]pyrido[ 2, 3-d Jpyrimidin- 7 -one (70)

[0625] A solution of methyl (2E)-3 -(4-amino-6-{[(l -hydroxy-3, 4-dihydro-2,l- benzoxaborinin-7-yl)methyl]amino}pyrimidin-5-yl)prop-2-enoate (C132) (200 mg, 0.6 mmol, 1.0 equiv.) and MeSNa (122 mg, 2.3 mmol, 4.0 equiv.) in DMSO (3 mL) was stirred at 80 °C for 4 hours under nitrogen atmosphere. The product was purified by prep-HPLC with the following conditions (Column: YMC Triart C18 ExRs 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 8% B to 25% B in 9min; Wave Length: 254 / 220 nm) to afford 70 (37.4 mg, 20.6% yield) as a white solid.

[0626] LCMS (ESI): 323 [M+H]+204MOFO-359177620.18314352000740

[0627] XH NMR (400 MHz, DMSO-t / e) 6 8.38 (s, 1H), 8.30 (s, 1H), 8.18 (d, J= 9.7 Hz, 1H), 7.74 (s, 2H), 7.52 (d, J= 2.0 Hz, 1H), 7.26 (dd, J= 7.8, 2.0 Hz, 1H), 7.10 (d, J= 7.8 Hz, 1H), 6.55 (d, J= 9.6 Hz, 1H), 5.46 (s, 2H), 4.02 (t, J= 5.9 Hz, 2H), 2.80 (t, J= 5.9 Hz, 2H).EXAMPLE 71Synthesis of 1-[(1 -hydroxy-3, 4-dihydro-2, l-benzoxaborinin-6-yl)methyl -l, 3-benzodiazole-5- carboxamide

[0628] This compound was synthesized using Scheme 70.Scheme 706-(Bromomethyl)-3, 4-dihydro-2, 1-benzoxaborinin-l-ol (C 133 )

[0629] To a stirred mixture of 6-(hydroxymethyl)-3,4-dihydro-2, 1-benzoxaborinin-l-ol (C105) (100 mg, 0.56 mmol, 1.0 equiv.) in DCM (10 mL) was added BBr3 (53.1 pL, 0.56 mmol, 1.0 equiv.) at 0 °C. The reaction was stirred for 2 hours at 0 °C. The reaction was quenched with H2O (10 mL) at 0 °C. The resulting mixture was concentrated under reduced205MOFO-359177620.18314352000740 pressure. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 0% to 45% gradient in 20 min; detector, UV 220 nm. This resulted in C133 (50 mg, 36.9% yield) as a light-yellow oil.Methyl l-[ ( I -hydroxy-3, 4-dihydro-2, l-benzoxaborinin-6-yl)methyl -l, 3-benzodiazole-5- carboxylate (Cl 35) and methyl 3- [(1 -hydroxy-3, 4-dihydro-2,l -benzoxaborinin-6-yl)methyl]- 1, 3-benzodiazole-5-carboxylate (C 136)

[0630] To the stirred solution of methyl 1 / 7-1, 3-benzodiazole-5-carboxylate (C134) (350 mg, 2.0 mmol, 1.0 equiv.) and 6-(bromomethyl)-3,4-dihydro-2,l-benzoxaborinin-l-ol (C133) (718 mg, 3.0 mmol, 1.5 equiv.) in DMF (10 mL) was added K2CO3 (550 mg, 4.0 mmol, 2.0 equiv.) at 25 °C under N2 atmosphere. The resulting mixture was stirred at 25 °C for 4 hours. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, Cis silica gel; mobile phase, MeCN in Water, 0% to 30% gradient in 15 min; detector, UV 220 nm. This resulted in a mixture of C135 and C136 (600 mg, 89.8% yield) as a yellow solid. l-[ ( I -Hydroxy-3, 4-dihydro-2, l-benzoxaborinin-6-yl)methyl ]-l, 3-benzodiazole-5- carboxamide (71)

[0631] To a solution of methyl l-[(l-hydroxy-3,4-dihydro-2,l-benzoxaborinin-6- yl)methyl]-l,3-benzodiazole-5-carboxylate (C135) and methyl 3-[(l-hydroxy-3,4-dihydro- 2,l-benzoxaborinin-6-yl)methyl]-l,3-benzodiazole-5-carboxylate (C136) (400 mg, 1.2 mmol, 1.0 equiv.) in NH3 H2O (45 mL) was added methanol (15 mL) at room temperature under N2 atmosphere. The mixture was heated to 80 °C overnight under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The product was purified by prep-HPLC with following conditions: Column: XBridge BEH Cis OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 6% B to 23% B in 8min; Wave Length: 220 nm This resulted in 71 (65.0 mg, 17.0% yield) as a white solid.

[0632] LCMS (ESI): 322 [M+H]+

[0633] 'H NMR (400 MHz, DMSO-t / 6) 8 8.51 (s, 1H), 8.43 (s, 1H), 8.25 (d, J= 1.5 Hz, 1H), 7.95 (s, 1H), 7.79 (dd, J= 8.5, 1.6 Hz, 1H), 7.64 (d, J= 7.5 Hz, 1H), 7.57 (d, J= 8.5 Hz,206MOFO-359177620.183143520007401H), 7.25 (s, 1H), 7.20 - 7.11 (m, 2H), 5.53 (s, 2H), 4.03 (t, J= 5.9 Hz, 2H), 2.81 (t, J= 5.9 Hz, 2H).EXAMPLE 72Synthesis of 3- [(1 -hydroxy-3, 4-dihydro-2, l-benzoxaborinin-6-yl)methyl -l, 3-benzodiazole-5- carboxamide

[0634] This compound was synthesized using Scheme 71.Scheme 713-[ ( 1 -Hydroxy-3, 4-dihydro-2, l-benzoxaborinin-6-yl)methyl ]-l, 3-benzodiazole-5- carboxamide (72)

[0635] To the stirred solution of methyl l-[(l-hydroxy-3,4-dihydro-2,l-benzoxaborinin- 6-yl)methyl]-l,3-benzodiazole-5-carboxylate (C135) and 3-[(l-hydroxy-3,4-dihydro-2,l- benzoxaborinin-6-yl)methyl]-l,3-benzodiazole-5-carboxylate (C136) (400 mg, 1.2 mmol, 1.0 equiv.) in NH3 H2O (45 mL) was added methanol (20 mL) at room temperature under N2 atmosphere. The mixture was heated to 80 °C overnight under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The product was purified by prep-HPLC with following conditions: Column: XBridge BEH Cis OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 6% B to 23% B in 8min; Wave Length: 220 nm. This resulted in 72 (55.9 mg, 14.6% yield) as a white solid.207MOFO-359177620.18314352000740

[0636] LCMS (ESI): 322 [M+H]+

[0637] 'HNMR (400 MHz, DMSO-t / 6) 6 8.51 (s, 1H), 8.43 (s, 1H), 8.25 (d, J= 1.5 Hz, 1H), 7.95 (s, 1H), 7.79 (dd, J= 8.5, 1.6 Hz, 1H), 7.64 (d, J= 7.5 Hz, 1H), 7.57 (d, J= 8.5 Hz, 1H), 7.25 (s, 1H), 7.20 - 7.11 (m, 2H), 5.53 (s, 2H), 4.03 (t, J= 5.9 Hz, 2H), 2.81 (t, J= 5.9 Hz, 2H).EXAMPLE 73Synthesis of 3- [(1 -hydroxy-3, 4-dihydro-2, l-benzoxaborinin-6-yl)methyl ]-l, 3-benzodiazole-5- carboxylic acid

[0638] This compound was synthesized using Scheme 72.Scheme 723-[ ( 1 -Hydroxy-3, 4-dihydro-2, l-benzoxaborinin-6-yl)methyl ]-l, 3-benzodiazole-5-carboxylic acid (73)

[0639] To the stirred solution of methyl l-[(l-hydroxy-3,4-dihydro-2,l-benzoxaborinin- 6-yl)methyl]-l,3-benzodiazole-5-carboxylate (C135) and 3-[(l-hydroxy-3,4-dihydro-2,l- benzoxaborinin-6-yl)methyl]-l,3-benzodiazole-5-carboxylate (C136) (400 mg, 1.2 mmol, 1.0 equiv.) in NH3.H2O (45 mL) was added methanol (20 mL) at room temperature under N2 atmosphere. The mixture was heated to 80 °C overnight under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The product was purified by prep-HPLC with following conditions: Column: XBridge BEH Cis OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B:208MOFO-359177620.18314352000740ACN; Flow rate: 60 mL / min; Gradient (B%): 6% B to 23% B in 8 min; Wave Length: 220 nm. This resulted in 73 (16.6 mg, 4.3% yield) as a white solid.

[0640] LCMS (ESI): 323 [M+H]+

[0641] 1H NMR (400 MHz, DMSO-t / 6) 8 8.55 (s, 1H), 8.43 (br.s, 1H), 8.08 (d, J= 1.5 Hz, 1H), 7.82 (dd, J= 8.5, 1.5 Hz, 1H), 7.68 - 7.63 (m, 2H), 7.21 - 7.07 (m, 2H), 5.58 (s, 2H), 4.03 (t, J= 5.9 Hz, 2H), 2.81 (t, J= 5.9 Hz, 2H).EXAMPLE 74Synthesis of 1-[(1 -hydroxy-3, 4-dihydro-2, l-benzoxaborinin-6-yl)methyl ]-l, 3-benzodiazole-5- carboxylic acid

[0642] This compound was synthesized using Scheme 73.Scheme 73l-[ ( 1 -Hydroxy-3, 4-dihydro-2, l-benzoxaborinin-6-y I) methyl ]-l, 3-benzodiazole-5-carboxylic acid (74)

[0643] To the stirred solution of methyl l-[(l-hydroxy-3,4-dihydro-2,l-benzoxaborinin- 6-yl)methyl]-l,3-benzodiazole-5-carboxylate (C135) and 3-[(l-hydroxy-3,4-dihydro-2,l- benzoxaborinin-6-yl)methyl]-l,3-benzodiazole-5-carboxylate (C136) (400 mg, 1.2 mmol, 1.0 equiv.) in NH3.H2O (45 mL) was added methanol (20 mL) at room temperature under N2 atmosphere. The mixture was heated to 80 °C overnight under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The product was purified by prep-HPLC with following conditions: Column: XBridge BEH Cis OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B:209MOFO-359177620.18314352000740ACN; Flow rate: 60 mL / min; Gradient (B%): 6% B to 23% B in 8min; Wave Length: 220 nm. This resulted in 74 (20.5 mg, 5.4% yield) as a white solid.

[0644] LCMS (ESI): 323 [M+H]+

[0645] 'H NMR (400 MHz, DMSO-t / 6) 8 8.48 (s, 1H), 8.23 (s, 1H), 7.85 (d, J= 8.4 Hz, 1H), 7.64 (dd, J= 7.5, 2.8 Hz, 1H), 7.52 (d, J= 8.5 Hz, 1H), 7.21 - 7.11 (m, 3H), 5.52 (s, 2H), 4.06 - 4.02 (m, 2H), 2.85 - 2.81 (m, 2H).EXAMPLE 75Synthesis of 1-[(1 -hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl -l, 3-benzodiazole-5- carboxamide

[0646] This compound was synthesized using Scheme 74.Scheme 74C1397-(Bromomethyl)-3, 4-dihydro-2, 1-benzoxaborinin-l-ol (C 137)

[0647] To a stirred solution of 7-(hydroxymethyl)-3,4-dihydro-2, 1-benzoxaborinin-l-ol (C126) (700 mg, 3.9 mmol, 1.0 equiv.) in DCM (10 mL) was added BB (492 mg, 1.9 mmol,210MOFO-359177620.183143520007400.5 equiv.) in portions at 0 °C. The resulting mixture was stirred at room temperature for an additional 3 hours. The reaction was quenched by the addition of MeOH (50 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (10 mM NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in C137 (400 mg, 42.2% yield) as a white solid.Methyl l-[ ( I -hydroxy-3, 4-dihydro-2, l-benzoxaborinin-7-yl)methyl]-l, 3-benzodiazole-5- carboxylate (Cl 38) and methyl 3- [(1 -hydroxy-3, 4-dihydro-2,l -benzoxabor inin-7 -yl)methyl]- 1, 3-benzodiazole-5-carboxylate (C 139)

[0648] To a stirred solution of 7-(bromomethyl)-3,4-dihydro-2,l-benzoxaborinin-l-ol (C137) (400 mg, 1.6 mmol, 1.0 equiv.) and methyl lH-l,3-benzodiazole-5-carboxylate (C134) (438 mg, 2.4 mmol, 1.5 equiv.) in DMF (1 mL) was added K2CO3 (688 mg, 4.9 mmol, 3.0 equiv.) in portions at room temperature under air atmosphere. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. This resulted in a mixture of C138 and C139 (400 mg) as a brownyellow solid, which was used directly without further purification.1-[(1 -Hydroxy-3, 4-dihydro-2, 1 -benzoxabor inin- 7-yl)methyl ]-l, 3-benzodiazole-5- carboxamide (75)

[0649] To a stirred solution of methyl l-[(l-hydroxy-3,4-dihydro-2,l-benzoxaborinin-7- yl)methyl]-l,3-benzodiazole-5-carboxylate (C138) and methyl 3-[(l-hydroxy-3,4-dihydro- 2,l-benzoxaborinin-7-yl)methyl]-l,3-benzodiazole-5-carboxylate (C139) (400 mg, 1.1 mmol, 1.0 equiv.) in MeOH (5 mL) was added NH3 H2O (5 mL) dropwise at room temperature. The resulting mixture was stirred at 50 °C overnight. The reaction residue was purified by reverse-phase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, Column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 3% B to 29% B in 8min; Wave Length: 254 / 220 nm. This resulted in 75 (53.1 mg, 13.9% yield) as a white solid.

[0650] LCMS (ESI): 322 [M+H]+211MOFO-359177620.18314352000740

[0651] JH NMR (400 MHz, DMSO-tZe) 5 8.50 (s, 1H), 8.46 (s, 1H), 8.24 (d, J= 1.5 Hz, 1H), 7.94 (s, 1H), 7.77 (dd, J= 8.5, 1.6 Hz, 1H), 7.63 (d, J= 2.0 Hz, 1H), 7.56 (d, J= 8.5 Hz, 1H), 7.37 (dd, J= 7.8, 2.1 Hz, 1H), 7.24 (s, 1H), 7.18 (d, J= 7.8 Hz, 1H), 5.50 (s, 2H), 4.03 (t, J= 5.9 Hz, 2H), 2.82 (t, J= 5.9 Hz, 2H).EXAMPLE 76Synthesis of 3- [(1 -hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl -l, 3-benzodiazole-5- carboxamide

[0652] This compound was synthesized using Scheme 75.Scheme 753-[(l -Hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl ]-l, 3-benzodiazole-5- carboxamide (76)

[0653] To a stirred solution of methyl l-[(l-hydroxy-3,4-dihydro-2,l-benzoxaborinin-7- yl)methyl]-l,3-benzodiazole-5-carboxylate (C138) and methyl 3-[(l-hydroxy-3,4-dihydro- 2,l-benzoxaborinin-7-yl)methyl]-l,3-benzodiazole-5-carboxylate (C139) (400 mg, 1.1 mmol, 1.0 equiv.) in MeOH (5 mL) was added NH3 H2O (5 mL) dropwise at room temperature. The resulting mixture was stirred at 50 °C overnight. The product was purified by reverse-phase chromatography with the following conditions: XBridge BEH Cl 8 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 3% B to 29% B in 8min; Wave Length: 254 / 220 nm. This resulted in 76 (60.1 mg, 15.7% yield) as a white solid.

[0654] LCMS (ESI): 322 [M+H]+212MOFO-359177620.18314352000740

[0655] JH NMR (400 MHz, DMSO-tZe) 5 8.53 (s, 1H), 8.45 (s, 1H), 8.09 (d, J= 1.5 Hz, 1H), 7.95 (s, 1H), 7.76 (dd, J= 8.5, 1.6 Hz, 1H), 7.68 (d, J= 8.5 Hz, 1H), 7.60 (d, J= 2.0 Hz, 1H), 7.35 (dd, J= 7.8, 2.0 Hz, 1H), 7.31 (s, 1H), 7.19 (d, J= 7.8 Hz, 1H), 5.52 (s, 2H), 4.03 (t, J= 5.9 Hz, 2H), 2.82 (t, J= 5.9 Hz, 2H).EXAMPLE 77Synthesis of 3- [(1 -hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl ]-l, 3-benzodiazole-5- carboxylic acid

[0656] This compound was synthesized using Scheme 76.Scheme 763-[(l -Hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl ]-l, 3-benzodiazole-5-carboxylic acid (77)

[0657] To a stirred solution of methyl l-[(l-hydroxy-3,4-dihydro-2,l-benzoxaborinin-7- yl)methyl]-l,3-benzodiazole-5-carboxylate (C138) and methyl 3-[(l-hydroxy-3,4-dihydro- 2,l-benzoxaborinin-7-yl)methyl]-l,3-benzodiazole-5-carboxylate (C139) (400 mg, 1.1 mmol, 1.0 equiv.) in MeOH (5 mL) was added NH3 H2O (5 mL) dropwise at room temperature. The resulting mixture was stirred at 50 °C overnight. The product was purified by reverse-phase chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, Column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 3% B to 29% B in 8min; Wave Length: 254 / 220 nm. This resulted in 77 (20.9 mg, 5.5% yield) as a white solid.213MOFO-359177620.18314352000740

[0658] LCMS (ESI): 323 [M+H]+

[0659] 'H NMR (400 MHz, DMSO-t / 6) 6 8.52 (s, 1H), 8.45 (s, 1H), 8.06 (s, 1H), 7.82 (d, J= 8.5 Hz, 1H), 7.65 (d, J= 8.5 Hz, 1H), 7.58 (d, J= 2.0 Hz, 1H), 7.33 (dd, J= 7.8, 2.1 Hz, 1H), 7.18 (d, J= 7.8 Hz, 1H), 5.54 (s, 2H), 4.03 (t, J= 5.9 Hz, 2H), 2.82 (t, J= 5.9 Hz, 2H).EXAMPLE 78Synthesis of 1-[(1 -hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl ]-l, 3-benzodiazole-5- carboxylic acid

[0660] This compound was synthesized using Scheme 77.Scheme 771-[(1 -Hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl ]-l, 3-benzodiazole-5-carboxylic acid (78)

[0661] To a stirred solution of methyl l-[(l-hydroxy-3,4-dihydro-2,l-benzoxaborinin-7- yl)methyl]-l,3-benzodiazole-5-carboxylate (C138) and methyl 3-[(l-hydroxy-3,4-dihydro- 2,l-benzoxaborinin-7-yl)methyl]-l,3-benzodiazole-5-carboxylate (C139) (400 mg, 1.1 mmol, 1.0 equiv.) in MeOH (5 mL) was added NH3 H2O (5 mL) dropwise at room temperature. The resulting mixture was stirred at 50 °C overnight. The product was purified by reverse-phase chromatography with the following conditions: Column: XB ridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 3% B to 29% B in 8min; Wave Length: 254 / 220 nm. This resulted in 78 (20.2 mg, 5.3% yield) as a white solid.

[0662] LCMS (ESI): 323 [M+H]214MOFO-359177620.18314352000740

[0663] 1H NMR (400 MHz, DMSO-t / 6) 5 8.49 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 7.84 (d,J= 8.6 Hz, 1H), 7.63 (d, J= 2.0 Hz, 1H), 7.53 (d, J= 8.5 Hz, 1H), 7.37 (dd, J= 7.8, 2.0 Hz, 1H), 7.18 (d, J= 7.8 Hz, 1H), 5.50 (s, 2H), 4.03 (t, J= 5.9 Hz, 2H), 2.82 (t, J= 6.0 Hz, 2H).EXAMPLE 79Synthesis of 1-((1 -Hydroxy-3, 4-dihydro-lH-benzo [ c] [1,2 ]oxaborinin- 7 -yl) methyl) -2 -me thy l- lH-imidazo[ 4, 5-c ]pyridin-4-ol hydrochloride

[0664] This compound was synthesized using Scheme 78.Scheme 78

[0665] To a stirred solution of 2-methoxypyridine-3,4-diamine (C140) (3.0 g, 21.6 mmol, 1.0 equiv.) and acetaldehyde (5.0 M in THF, 5.2 mL, 25.9 mmol, 1.2 equiv.) in methanol (100 mL) was added Pd / C (2.1 g, 70% w / w) in a pressure tank at 25 °C. The mixture was heated to 120 °C overnight. The resulting mixture was filtered off over the celite and the filter cake was washed with methanol (3 x 20 mL). The filtrate was concentrated under215MOFO-359177620.18314352000740 reduced pressure. The product was purified by silica gel column chromatography with the following conditions: mobile phase, EtOH in DCM, 0% to 5% gradient in 10 min; detector, UV 254 nm. This resulted in C55 (1.3 g, 36.9% yield) as a yellow solid.7-({4-Methoxy-2-methylimidazo[4,5-c]pyridin-l-yl}methyl)-3,4-dihydro-2,l-benzoxaborinin- l-ol (C141) and 7-({4-methoxy-2-methylimidazo[4,5-c]pyridin-3-yl}methyl)-3,4-dihydro-2,l- benzoxaborinin-l-ol (Cl 42)

[0666] To a stirred solution of 7-(bromomethyl)-3,4-dihydro-2,l-benzoxaborinin-l-ol (C137) (400 mg, 1.6 mmol, 1.0 equiv.) and 4-methoxy-2-methyl-U / -imidazo[4,5-c]pyridine (C55) (298 mg, 1.8mmol, 1.1 equiv.) in DMF (5 mL) was added K2CO3 (688 mg, 4.9 mmol, 3.0 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature overnight. The product was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mM NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in C141 and C142 (170 mg) as a yellow solid.1-((1 -Hydroxy-3, 4-dihydro-lH-benzo[ c] [1,2 ]oxaborinin- 7-yl)methyl) -2-methyl-lH- imidazo [4,5-c]pyridin-4-ol hydrochloride (79)

[0667] To a stirred solution of 7-({4-methoxy-2-methylimidazo[4,5-c]pyridin-l- yl}methyl)-3,4-dihydro-2,l-benzoxaborinin-l-ol (C141) and 7-({4-methoxy-2- methylimidazo[4,5-c]pyridin-3-yl}methyl)-3,4-dihydro-2,l-benzoxaborinin-l-ol (C142) (150 mg, 0.4 mmol, 1.0 equiv.) in THF (5 mL) was added HC1 (6 M in H2O, 5 mL) in portions at room temperature. The resulting mixture was stirred at 50 °C overnight. The resulting mixture was concentrated under reduced pressure. The product was purified with Column: XSelect CSH Phenyl-Hexyl OBD Prep Column, 5 pm, 30 mm X 150 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 3% B to 13%B in 8 min; Wave Length: 254 nm / 220 nm. This resulted in 79 (32.5 mg, 22.7% yield) as a white solid.

[0668] LCMS (ESI): 310 [M+H]+

[0669] 1H NMR (400 MHz, DMSO-t / 6) 8 11.93 (br.s, 1H), 8.50 (br.s, 1H), 7.54 (d, J= 2.0 Hz, 1H), 7.42 (t, J= 6.6 Hz, 1H), 7.30 (dd, J= 7.8, 2.1 Hz, 1H), 7.22 (d, J= 7.8 Hz, 1H),216MOFO-359177620.183143520007406.72 (d, J= 7.2 Hz, 1H), 5.55 (s, 2H), 4.05 (t, J= 5.9 Hz, 2H), 2.85 (t, J= 5.9 Hz, 2H), 2.66 (s, 3H).EXAMPLE 80Synthesis of 3-((l -hydroxy-3, 4-dihydro-lH-benzo[ c] [1,2 ]oxaborinin- 7-yl)methyl)-2-methyl- 3H-imidazo[ 4, 5-c ]pyridin-4-ol hydrochloride

[0670] This compound was synthesized using Scheme 79.3-((l -Hydroxy-3, 4-dihydro-lH-benzo[ c] [1,2 ]oxaborinin- 7-yl)methyl) -2-methyl-3H- imidazo [4,5-c]pyridin-4-ol hydrochloride (80)

[0671] To a stirred solution of 7-({4-methoxy-2-methylimidazo[4,5-c]pyridin-l- yl}methyl)-3,4-dihydro-2,l-benzoxaborinin-l-ol (C141) and 7-({4-methoxy-2- methylimidazo[4,5-c]pyridin-3-yl}methyl)-3,4-dihydro-2,l-benzoxaborinin-l-ol (C142) (150 mg, 0.4 mmol, 1.0 equiv.) in THF (5 mL) was added HC1 (6 M in H2O, 5 mL) in portions at room temperature. The resulting mixture was concentrated under reduced pressure. The product was directly purified by reverse-phase chromatography with the following conditions: Column: XSelect CSH Phenyl-Hexyl OBD Prep Column, 5 pm, 30 mm X 150 mm; Mobile Phase A: water (0.1% HC1), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 3% B to 13%B in 8 min; Wave Length: 254 nm / 220 nm. This resulted in 80 (59.5 mg, 41.5% yield) as a white solid.

[0672] LCMS (ESI): 310 [M+H]+217MOFO-359177620.18314352000740

[0673] XH NMR (400 MHz, DMSO- e) 8 11.80 (br.s, 1H), 8.45 (br.s, 1H), 7.55 (d, J= 2.0 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.20 (d, J= 7.8 Hz, 1H), 6.66 - 6.60 (m, 1H), 5.79 (s, 2H), 4.04 (t, J= 5.9 Hz, 2H), 2.84 (t, J= 5.9 Hz, 2H), 2.68 (s, 3H).EXAMPLE 81Synthesis of l-[ ( I -hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl ]-2-methyl-l, 3- benzodiazole-5-carboxamide

[0674] This compound was synthesized using Scheme 80.Scheme 802-Methyl-lH-l, 3-benzodiazole-5-carboxamide (C 144)

[0675] A solution of 2-methyl-U / -benzo[J]imidazole-5-carboxylic acid (C143) (2.0 g, 10.5 mmol, 1.0 equiv.) in SOCh (30 mL) was stirred at 80 °C for 1 hour. The resulting mixture was concentrated under reduced pressure. To the above mixture was added ammonia (0.4 M in 1,4-di oxane, 30 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The product was partially purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 5% gradient in 10 min; detector, UV 254 nm. This resulted in C144 (2.0 g) as a brown solid, which was used directly in the next step without further purification.1-[(1 -Hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl / -2 -methyl- 1, 3-benzodiazole-5- carboxamide (81)218MOFO-359177620.18314352000740

[0676] To a stirred solution of 7-(bromomethyl)-3,4-dihydro-2,l-benzoxaborinin-l-ol (C137) (200 mg, 0.8 mmol, 1.0 equiv.) and 2-methyl-U / -l,3-benzodiazole-5-carboxamide (C144) (160 mg, 0.9 mmol, 1.1 equiv.) in DMF (5 mL) was added CS2CO3 (541 mg, 1.6 mmol, 2.0 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature overnight. The product was purified by reverse-phase chromatography with the following conditions: Column: YMC Triart C18 ExRs 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 15% B to 20% B in 8min; Wave Length: 254 / 220 nm; which afforded 81 (35.2 mg, 12.7% yield) as a white solid.

[0677] LCMS (ESI): 336 [M+H]+

[0678] 'HNMR (400 MHz, DMSO-t / 6) 8 8.45 (s, 1H), 8.13 (d, J= 1.5 Hz, 1H), 7.92 (s, 1H), 7.73 (dd, J= 8.5, 1.6 Hz, 1H), 7.50 (d, J= 8.5 Hz, 1H), 7.46 (d, J= 1.6 Hz, 1H), 7.22 - 7.14 (m, 3H), 5.47 (s, 2H), 4.04 (t, J= 5.9 Hz, 2H), 2.82 (t, J= 6.0 Hz, 2H), 2.54 (s, 3H).EXAMPLE 82Synthesis of 3-[ ( 1 -hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl ]-2-methyl-l, 3- benzodiazole-5-carboxamide

[0679] This compound was synthesized using Scheme 81.219MOFO-359177620.183143520007403-[(l -Hydroxy-3, 4-dihydro-2, 1-benzoxaborinin- 7-yl)methyl ] -2 -methyl- 1, 3-benzodiazole-5- carboxamide (82)

[0680] To a stirred solution of 7-(bromomethyl)-3,4-dihydro-2,l-benzoxaborinin-l-ol (C137) (200 mg, 0.8 mmol, 1.0 equiv.) and 2-methyl-U / -l,3-benzodiazole-5-carboxamide (C144) (160 mg, 0.9 mmol, 1.1 equiv.) in DMF (5 mL) was added CS2CO3 (541 mg, 1.6 mmol, 2.0 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature overnight. The product was purified by reverse-phase chromatography with the following conditions: Column: YMC Triart C18 ExRs 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 15% B to 20% B in 8 min; Wave Length: 254 / 220 nm. This afforded 82 (40.6 mg, 14.6% yield) as a white solid.

[0681] LCMS (ESI): 336 [M+H]+

[0682] 'H NMR (400 MHz, DMSO-t / 6) 8 8.45 (s, 1H), 8.03 (d, J= 1.5 Hz, 1H), 7.92 (s, 1H), 7.73 (dd, J= 8.5, 1.6 Hz, 1H), 7.56 (d, J= 8.5 Hz, 1H), 7.43 (d, J= 1.6 Hz, 1H), 7.21 - 7.14 (m, 3H), 5.49 (s, 2H), 4.04 (t, J= 5.9 Hz, 2H), 2.82 (t, J= 6.0 Hz, 2H), 2.54 (s, 3H).EXAMPLE 83Synthesis of 4-amino-8-[ ( I -hydroxy-3H-2, l-benzoxaborol-5-yl)methyl]pyrido[2, 3- d]pyrimidin- 7 -one

[0683] This compound was synthesized using Scheme 82.Scheme 824-Amino-8-[ ( I -hydroxy-3H-2, l-benzoxaborol-5-yl)methyl ]pyrido[ 2, 3-d]pyrimidin- 7 -one (83)220MOFO-359177620.18314352000740

[0684] A mixture of methyl (2£)-3-(4-amino-6-{[(l-hydroxy-3J / -2,l-benzoxaborol-5- yl)methyl]amino}pyrimidin-5-yl)prop-2-enoate (C77) (120 mg, 0.4 mmol, 1.0 equiv.) and sodium thiomethoxide (99 mg, 1.4 mmol, 4.0 equiv.) in DMSO (2 mL) was stirred at 80 °C for 2 hours under nitrogen atmosphere. The resulting mixture was filtered off and the filter cake was washed with MeOH (1 mL). The filtrate was concentrated under reduced pressure. The product was purified by prep-HPLC with the following conditions (Column: XBridge BEH C18 OBD Prep Column, 5 pm, 30 mm * 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3+0.1% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 3% B to 13% B in 8min; Wave Length: 254 / 220 nm) to afford 83 (34.3 mg, 31.6% yield) as a white solid.

[0685] LCMS (ESI): 309 [M+H]+

[0686] 1H NMR (400 MHz, DMSO-t / 6) 8 9.10 (s, 1H), 8.29 (s, 1H), 8.19 (d, J= 9.7 Hz, 1H), 7.76 (s, 2H), 7.63 (d, J= 7.8 Hz, 1H), 7.26 - 7.15 (m, 2H), 6.57 (...

Claims

314352000740CLAIMSWhat is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is H or alkyl;R2and R3are each independently H or alkyl;R4is H or alkyl;R5is a heteroaromatic ring system that is fused or unfused, optionally substituted with one or more groups independently selected from the group consisting of alkoxy, cyano, alkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, heteroaryl, and -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; alkyl, in each instance, is optionally substituted with halo or alkoxy; and each Raand Rbis independently H or alkyl; orR4and R5are taken together with the nitrogen atom to which they are attached to form: an optionally substituted heteroaromatic ring system that is fused or unfused, wherein the ring containing R4, N, and R5is aromatic; or an optionally substituted ring system of formula (DI) or (D2):each R6is independently alkyl, haloalkyl, halo, cyano, haloalkoxy, or alkoxy;R7and R8are each independently H or alkyl; or494MOFO-359177620.18314352000740R7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl;Z is -CH- or -N-; ring S is heteroaryl or phenyl; m is 0-3; n is 1-3; and q is O or l.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:R4is H or alkyl; andR5is a heteroaromatic ring system that is fused or unfused, optionally substituted with alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, NRaRb, - C(=O)NRaRb, or -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; and wherein each Raand Rbis independently H or alkyl; orR4and R5are taken together with the nitrogen atom to which they are attached to form an optionally substituted heteroaromatic ring system that is fused or unfused, wherein the ring containing R4, N, and R5is aromatic.

3. The compound of claim 1 or 2, wherein the compound is a compound of Formula (I-or a pharmaceutically acceptable salt thereof, wherein R1, n, R2, R3, R4, R5, R6, R7, R8, m and q are as defined for Formula (I) above.

4. The compound of claim 1 or 2, wherein the compound is a compound of Formula (I-B):495MOFO-359177620.18314352000740 or a pharmaceutically acceptable salt thereof, wherein R1, n, R2, R3, R4, R5, R6, R7, R8, m and q are as defined for Formula (I) above.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R1is H.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R2is H, and R3is H or alkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R2and R3are hydrogen.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R4is H.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R5is a heteroaromatic ring system containing 1-4 nitrogen atoms, or R4and R5are taken together with the nitrogen atom to which they are attached to form a heteroaromatic ring system containing 1-4 nitrogen atoms.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R5is a fused heteroaromatic ring system represented by the formula:wherein:Xla, X2a, and X3aare each independently -CH- or -N-, wherein at least one of Xla, X2a, and X3ais -N-; and ring A is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, or 6-membered heterocyclyl, wherein the fused heteroaromatic ring system is optionally substituted with one or more substituents selected from the group consisting of alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, and -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; and496MOFO-359177620.18314352000740 each Raand Rbis independently H or alkyl.

11. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R5is:selected from the group consisting of alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -497MOFO-359177620.18314352000740NRaRb, -C(=O)NRaRb, or -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; and each Raand Rbis independently H or alkyl.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R5is a fused heteroaromatic ring system, substituted with 1 or 2 substituents.

13. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form an optionally substituted heteroaromatic ring system that is fused or unfused, wherein the ring containing R4, N, and R5is aromatic.

14. The compound of any one of claims 1 to 7 and 13, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form a heteroaromatic ring system that is fused or unfused, optionally substituted with one or more substituents selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, NRaRb, -C(=O)NRaRb, and -COORa, wherein each Raand Rbis independently H or alkyl.

15. The compound of any one of claims 1 to 7, 13 and 14, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form an optionally substituted fused heteroaromatic ring system represented by the formula:wherein: r is 0 or 1;Xlb, X2b, and X3bare each independently -CH- or -N-; and ring B is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, or 6-membered heterocyclyl.498MOFO-359177620.1831435200074016. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein the fused heteroaromatic ring system is optionally substituted with one or more substituents selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, and -COORa, wherein each Raand Rbis independently H or alkyl.

17. The compound of any one of claims 1 to 7 and 13 to 16, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which18. The compound of any one of claims 1 to 7 and 13, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form a 5-membered heteroaryl containing 1 to 3 nitrogen atoms, wherein the 5- membered heteroaryl is: optionally substituted with Ci-4 alkyl; and substituted with one or more:(i) Rw;(ii) alkyl substituted with Rw;(iii) alkyl substituted with -O-Rw; or(iv) alkyl substituted with amino, -C(O)ORa, or both, whereinRwis optionally substituted fused or unfused heteroaromatic ring system, aryl, heterocyclyl, or cycloalkyl, and Rais H or alkyl.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form thiazolyl, oxazolyl, pyrazolyl, imidazolyl, or triazolyl, which is substituted with: (i) an Rw, (ii) alkyl substituted with Rw; or (iii) alkyl substituted with -O-Rw, wherein Rwis optionally substituted fused or unfused aryl, heteroaryl, heterocyclyl, or cycloalkyl.499MOFO-359177620.1831435200074020. The compound of claim 18 or 19, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form triazolyl or pyrazolyl substituted with: (i) Rw; (ii) alkyl substituted with Rw; or (iii) alkyl substituted with -O-Rw, wherein Rwis optionally substituted fused or unfused aryl, heteroaryl, heterocyclyl, or cycloalkyl.

21. The compound of any one of claims 18 to 20, or a pharmaceutically acceptable salt thereof, wherein Rwis pyridyl, thiazolyl, pyrimidinyl, phenyl, or cycloalkyl, wherein each is optionally substituted with alkyl, alkoxy, haloalkyl, halo, hydroxyl, or cyano.

22. The compound of any one of claims 18 to 21, or a pharmaceutically acceptable salt thereof, wherein Rwis pyridyl, pyrimidinyl or phenyl, wherein each Rwis optionally substituted with one or more alkyl, alkoxy, or halo.

23. The compound of any one of claims 18 to 22, or a pharmaceutically acceptable salt thereof, wherein Rwis pyridyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, and halo.

24. The compound of any one of claims 18 to 22, or a pharmaceutically acceptable salt thereof, wherein Rwis pyrimidinyl optionally substituted with one or two substituents independently selected from the group consisting of: alkyl, alkoxy, and halo.

25. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form an optionally substituted ring system of formula (DI) or (D2):

26. The compound of any one of claims 1 to 7 and 25, or a pharmaceutically acceptable salt thereof, wherein R4and R5are taken together with the nitrogen atom to which they are attached to form500MOFO-359177620.1831435200074027. The compound of any one of claims 1 to 4, wherein the compound is a compound of Formula (1-1):or a pharmaceutically acceptable salt thereof, wherein: each W is independently -N-, -CH-, or -C(Rw1)-, wherein at least one W is -N-; each Rwlis independently alkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, -NRaRb, -C(=O)NRaRb, or -C(=O)ORa, wherein alkoxy, in each instance, is optionally substituted with halo, aryl, or heteroaryl; and g is 0-4.

28. The compound of any one of claims 1 to 4, wherein the compound is a compound of Formula (1-2):or a pharmaceutically acceptable salt thereof, wherein: each W is independently -N-, -CH-, or -C(Rw1)-, wherein at least one W is -N-; ring C is heteroaryl or a ring system of formula (C4), (C5), or (C6):whereinR9is alkyl; each * represents a point of attachment to the ring bearing W, and ring C is optionally substituted with one or more Rwl; each Rwlis independently alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, - NRaRb, -C(=O)NRaRb, or -C(=O)ORa.501MOFO-359177620.1831435200074029. The compound of any one of claims 1, 3, and 4, wherein the compound is a compound of Formula (1-3):or a pharmaceutically acceptable salt thereof, wherein: each W is independently -N-, -CH-, or -C(Rw1)-, wherein at least one W is -N-;X is -N-, -CH-, -C(Rw1)-, or -S-; ring D is phenyl, heteroaryl, or a ring system of formula (C4), (C5), or (C6):wherein,R9is alkyl; each * represents a point of attachment to the ring bearing W, and ring D is optionally substituted with one or more Rwl; each Rwlis independently selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, -NRaRb, -C(=O)NRaRb, or -C(=O)ORa; and r is 0 or 1.

30. The compound of any one of claims 1, 3, and 4, wherein the compound is a compound of Formula (1-4):or a pharmaceutically acceptable salt thereof, wherein:X is -N-, -CH-, -C(Rwl), or -S-. ring E is phenyl or heteroaryl, wherein ring E is optionally substituted with one or more Rwl;502MOFO-359177620.18314352000740 each Rwlis independently selected from the group consisting of alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, or - C(=O)ORa; andRxis H, alkoxy, haloalkoxy, cyano, alkyl, haloalkyl, halo, hydroxyl, -NRaRb, -C(=O)NRaRb, or -C(=O)ORa31. The compound of any one of claims 1, 3, and 4, wherein the compound is a compound of Formula (1-5):or a pharmaceutically acceptable salt thereof, wherein:Y is a bond, alkyl, -alkyl-NRa-alkyl- or -O-alkyl-; ring F is 5-membered heteroaryl that is optionally substituted with one or more Rwl; ring G is phenyl, fused or unfused heterocyclyl, or a fused or unfused heteroaromatic ring system, wherein ring G is optionally substituted with one or more Rwl; and each Rwlis independently selected from the group consisting of: alkoxy, cyano, alkyl, halo, hydroxyl, oxo, -NRaRb, -C(=O)NRaRb, and -C(=O)ORa, wherein alkyl and alkoxy, in each instance, are optionally independently substituted with hydroxyl, methoxy, or halo.

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein Y is a bond.

33. The compound of claim 31 or 32, or a pharmaceutically acceptable salt thereof, wherein ring G is phenyl, fused or unfused heterocyclyl, or fused or unfused heteroaryl, wherein ring G is optionally substituted with one or more Rwl.

34. The compound of any one of claims 31-33, or a pharmaceutically acceptable salt503MOFO-359177620.18314352000740each optionally substituted with one or two Rwl, wherein each Rwlis selected from the group consisting of alkoxy, cyano, alkyl, halo, and hydroxyl, wherein alkoxy and alkyl, in each instance, are optionally independently substituted with hydroxyl, methoxy, or halo.

35. The compound of any one of claims 31-34, or a pharmaceutically acceptable salt thereof, wherein each Rwlis selected from the group consisting of methoxy, ethoxy, -CH2CH2OH,-OCH2CH2OCH3, -OCHF2, F, methyl, or ethyl.

36. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein ring F is triazolyl, pyrazolyl, or imidazolyl optionally substituted with one Rwl.

37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein Rwlis methyl.

38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein each R6is independently Ci-ealkyl, Ci-ehaloalkyl, halo, or Ci-ealkoxy.

39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R7and R8are each independently H or C1-6 alkyl; or R7and R8are taken together with the carbon atom to which they are attached to form Cs-ecycloalkyl.

40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein n is 1.

41. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein n is 2.

42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein m is 1 and R6is methyl, methoxy, or F.

43. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein m is 0.504MOFO-359177620.1831435200074044. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein q is 0.

45. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein q is 1.

46. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein each of R7and R8is independently H or alkyl.

47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein R7and R8are H.

48. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein R7and R8are taken together with the carbon atom to which they are attached to form cycloalkyl.

49. The compound of claim 48, wherein the cycloalkyl is cyclopropyl or cyclobutyl.

50. The compound of any one of claims 1 to 12, 27, 28, 29 and 38 to 49, or a pharmaceutically acceptable salt thereof, wherein the moiety represented by51. The compound of claim 1, wherein the compound is a compound of Formula (I-C):or a pharmaceutically acceptable salt thereof; andR5is an optionally substituted heteroaromatic ring system that is fused.

52. A compound Formula (Al) or (A2):505MOFO-359177620.18314352000740or a pharmaceutically acceptable salt thereof, whereinYlais -N-, -CH- or -C(CN)-;Ylbis -N-, -CH-, or -C(ORlv)-, wherein Rlvis H, methyl or ethyl;Rlwis H, -CF3, alkoxy, alkoxy substituted with phenyl or pyrazolyl, hydroxyl, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)OH, -C(=O)OCH3, or methyl;Rlx, Rly, and Rlzare each independently -H, -OH, or methoxy;R3is H, methyl, or ethyl; each R6is independently methyl, F, Cl, or methoxy;R8is H or methyl; and m is 0-2.

53. A compound of Formula (B):or a pharmaceutically acceptable salt thereof, whereinY2ais -N- or -CH-;R3is H, methyl or ethyl; each R6is independently methyl, F, Cl, or methoxy;R8is H or methyl;R2Wis H, methoxy, or methyl;R2Xand R2yare each independently -H, F, Cl, methyl, or methoxy; and m is 0-2.

54. A compound of Formula (C):506MOFO-359177620.18314352000740or a pharmaceutically acceptable salt thereof, wherein ring X is a 5-membered heteroaryl;Y3aand Y3bare independently -N-, or -C(R3y)-;R2and R3are independently H or alkyl; each R6is independently methyl, F, Cl, or methoxy;R8is H or methyl;R3Xand R3yare each independently H, F, Cl, methyl, hydroxyl or methoxy; and m is 0-2.

55. The compound of claim 54, or a pharmaceutically acceptable salt thereof, wherein, ring X is triazolyl or pyrazolyl.

56. The compound of claim 54 or 55, or a pharmaceutically acceptable salt thereof, wherein R3xis H, -OMe, or -OH.

57. The compound of any one of claims 54 to 56, or a pharmaceutically acceptable salt thereof, wherein R3xis -OMe.

58. The compound of any one of claims 54 to 57, or a pharmaceutically acceptable salt thereof, wherein m is 0.

59. The compound of any one of claims 54 to 57, or a pharmaceutically acceptable salt thereof, wherein m is 1, and R6is methyl or F.

60. The compound of any one of claims 54 to 59, or a pharmaceutically acceptable salt thereof, wherein R8is H.

61. A compound of Formula (D) or (E):507MOFO-359177620.18314352000740or a pharmaceutically acceptable salt thereof, wherein ring Y is phenyl, heterocycle, or a heteroaryl, and wherein ring Y is optionally substituted with one or two R4x;Ydis selected from -N-, -CH- and -C(R4y)-;R2and R3are independently H or methyl; each R4Xis independently selected from cyano, methyl, F, Cl, oxo, hydroxyl, and methoxy; andR4yis cyano, F, or methyl.

62. The compound of any one of claims 54 to 61, or a pharmaceutically acceptable salt thereof, wherein the moiety represented63. A compound of Formula (Fl) or (F2):or a pharmaceutically acceptable salt thereof, whereinY6ais -N- or -CH-;R6Wis H, hydroxyl, methoxy, or methyl;R6X, R6y, and R6zare each independently H, hydroxyl, or methoxy;R3is H or methyl; each R6is independently methyl, F, or methoxy;R8is H or methyl; and m is 0-2.

64. A compound of Formula (Gl) or (G2):508MOFO-359177620.18314352000740or a pharmaceutically acceptable salt thereof, whereinY5ais -N- or -CH-; each Y5bis independently -O- or -CH2-, wherein at least one Y5bis -O-;Q is a bond or is -CH2-;R5Wis H, hydroxyl, or methoxy; each R5Xis independently H, F, or methyl;R3is H or methyl; each R6is independently methyl, F, or methoxy;R8is H or methyl; and m is 0-2.

65. The compound of claim 64, or a pharmaceutically acceptable salt thereof, wherein both R5Xare H, both R5xare F, or both R5xare methyl.

66. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

67. A pharmaceutical composition, comprising: a compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.

68. A method of inhibiting ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) in a subject in need thereof, comprising: administering to the subject a compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of claim 67.

69. A method of treating a disorder, disease or condition mediated by ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) in a subject in need thereof, comprising:509MOFO-359177620.18314352000740 administering to the subject a compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of claim 67.

70. The method of claim 69, wherein the disorder, disease or condition is cancer.

71. The method of claim 70, wherein the cancer is a solid tumor.

72. The method of claim 70, wherein the cancer is cervical cancer, colorectal cancer, lung cancer, prostate cancer, esophageal cancer, liver cancer, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, or breast cancer, or any combination thereof.

73. The method of claim 69, wherein the disorder, disease or condition is an inflammatory disease, a metabolic disease, or a microbial infection, or any combination thereof.

74. The method of claim 73, wherein the inflammatory disease is an autoimmune disease or an autoinflammatory disease.

75. The method of claim 69, wherein the disorder, disease or condition is hypophosphatasia (HPP).

76. The method of any one of claims 68 to 75, wherein the subject is a human.510MOFO-359177620.18

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