Bicyclic heteroaryl phosphonate derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors

A compound of Formula (I):

• wherein:
• dashed line is a bond between x and y or y and z;
• b, d, and e are CH;
• or one or two of b, d, and e are N and remaining of b, d, and e are CH;
• one of x and z is NH, O, or S and the other of x and z is CH or N;
• and y is CH or N;
• provided that, at least one of y and the x or z that is CH or N, is CH;
• G is a bond, NR (where R is hydrogen or alkyl), O, S, or SO2;
• alk is alkylene optionally substituted with one, two, or three halo, or alkynylene, provided that when alk is alkynylene G is a bond and n is 1;
• alk1 is alkylene optionally substituted with one, two, or three halo;
• m and n are independently 0 or 1;
• provided that at least one of m and n is 1;
• Ar is aryl, heteroaryl, or heterocyclyl;
• Ra and Rb are independently selected from hydroxy, alkoxy, —Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, and nitro), —O—(CH2)OCORc (where Rc is alkyl), —O—(CH2)OCOORc1 (where Rc1 is alkyl), —O-(alk2)ORd (where alk2 is alkylene and Rd is alkyl), —S—(CH2)2SCORc(where Rc is alkyl), and —NRg—(CHRh)OCORf (where Rh is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl or phenylalkyl (wherein phenyl, either alone or as part of phenylalkyl, is optionally substituted with one to three substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano, and nitro), Rf is alkyl or benzyl and Rg is hydrogen or Rg together with Rh forms —(CH2)3—);
• or
• Ra and Rb together with the phosphorus atom to which they are attached form a ring of formula (a):
• wherein Ar2 is phenyl or six membered heteroaryl wherein the phenyl and six membered heteroaryl aryl optionally substituted with one to three halo;
• R1 and R2 are independently absent, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano;
• R3 and R4 are independently absent, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, alkylsulfonyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, amino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein heterocyclyl, either alone or part of heterocyclyloxy, and heterocyclylamino is optionally substituted with Ri, Rj, and/or Rk independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyl, heteroaryl, phenylalkenyl, heteroarylalkenyl, phenyloxy, and heteroaryloxy (where phenyl, by itself or as part of phenylalkenyl and phenyloxy and heteroaryl, by itself or as part of heteroarylalkenyl and heteroaryloxy are optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano);
• provided that when two of b, d, and e are N, then at least one of R3 and R4 is absent;
• R5 is absent, alkyl, hydroxy, alkoxy, alkoxycarbonyl, halo, acylamino, hydroxyalkylamino, alkoxyalkylamino, cyano, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminoalkyloxycarbonyl, alkoxyalkyloxycarbonyl, or hydroxyalkylaminocarbonyl;
• and
• R6 is absent or alkyl;
• provided that one of R3 and R6 is absent when two of x, y, and z are other than CH;
• or
• a pharmaceutically acceptable salt thereof.