Quinazoline derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors

A compound of Formula (IA):

• wherein:
• X is N or CH;
• Z is NH, O, S, SO, or SO2;
• alk is alkylene optionally substituted with one, two, or three halo;
• m and n are independently 0 or 1;
• (i) -Ar-(alk1)m-Q is wherein Ar is aryl, heteroaryl, cycloalkyl, or heterocyclyl;
• alk1 is alkylene wherein one carbon atom in the alkylene chain is optionally replaced by oxyen and further wherein alkylene is optionally substituted with one, two, or three halo;
• and
• Q is —B(OH)2 or —P(O)(Ra)(Rb) wherein 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, or nitro), —O—(CH2)OCORc(where Rc is alkyl), —O-(alk2)ORd (where alk2 is alkylene and Rd is alkyl), —S—(CH2)2SCORe (where Re is alkyl), or —NRg—(CHR)OCORf (where R 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 or nitro), Rf is alkyl or benzyl, and Rg is hydrogen or Rg together with R forms —(CH2)3—);
• or Ra and R together with the phosphorus atom to which they are attached form a ring of formula (c):
• wherein Ar1 is phenyl or six membered heteroaryl optionally substituted with one to three halo;
• provided that, when Q is —P(O)(Ra)(Rb) or —B(OH)2, then at least one of n and m is 1;
• or
• (ii) -Ar-(alk1)m-Q is a ring of formula (a):
• R1 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, diaminoalkyl, diaminoalkoxy, diaminoalkylamino, or cyano;
• R2, R3, R9, and R10 are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy, or cyano;
• R7 and R8 are independently hydrogen or alkyl;
• and
• one of R4, R5, and R6 is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, alkylamino, or dialkylamino;
• and the remaining two of R4, R5, and R6 are independently hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein heterocyclyl either alone or part of heterocyclyloxy and heterocyclylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (where phenyl in phenyloxy and heteroaryl in heteroaryloxy are optionally substituted with one, two, or three substituents where two of the optional substituents are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano);
• or
• a pharmaceutically acceptable salt thereof.