Inhibitors of the hedgehog pathway

A Compound of Formula I

• or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof, where
• R1 is alkyl, cycloalkyl, phenyl, or heteroaryl where the cycloalkyl, phenyl, and heteroaryl are optionally substituted with 1, 2, or 3 R6;
• R2 and R3 together with the pyrimidinyl to which they are attached form a quinazolinyl optionally substituted at the 5-, 6-, 7-, and 8-positions with one or two groups independently selected from alkyl, alkoxy, halo, hydroxy, heterocycloalkylalkyloxy, heterocycloalkyl, and heterocycloalkyl substituted with alkyl;
• or
• each R6, when R6 is present, is independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, halophenyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoalkylamino, alkylaminoalkylamino, dialkylaminoalkylamino, alkyloxyalkylamino, heterocycloalkyl, and heterocycloalkylalkyl;
• where the heterocycloalkyl, either alone or as part of heterocycloalkylalkyl, is optionally substituted with alkyl or alkoxycarbonyl;
• R40 is hydrogen or alkyl;
• R50 is selected from
• n1 is 0, 1, or 2;
• each R5, when R5 is present, is independently alkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, halo, nitro, heterocycloalkyl, heterocycloalkylamino, or heterocycloalkylalkyloxy;
• where each heterocycloalkyl, either alone or as part of another group in R5, is independently optionally substituted with alkyl or alkoxycarbonyl;
• R4a is hydrogen or alkyl;
• R4 is heteroaryl substituted with one R8 and additionally substituted with 1 or 2 R8a, wherein heteroaryl is selected from 1,2,3,4-tetrahydroisoquinolinyl or 2,3,4,5-tetrahydro-1,4-benzoxazepinyl;
• or R4 is phenyl substituted with one R29 and additionally substituted with 1 or 2 R9a;
• each R8 is independently alkyl, cycloalkyl, phenylalkyloxyalkyl, or R9b;
• each R8a is independently hydrogen, halo, or R8;
• each R9a is independently hydrogen, R9b, or R9a;
• R29 is alkyl substituted with —NR15R15a;
• or alkyl substituted with optionally substituted heterocycloalkyl;
• each R9b, when R9b is present, is independently amino, alkylamino, dialkylamino, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyloxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, optionally substituted heteroaryl, cyano, —C(O)R14, —CR14a(NR14b), —C(═NR24)R24a, —S(O)2NR13R13a,
• —NR23C(O)R23a—C(O)NR12R12a, or alkyl substituted with one or two R11;
• each R9c, when R9c is present, is independently alkyl, haloalkyl, hydroxyalkyl, halo, hydroxy, alkoxy, cyano, nitro, or phenylcarbonyl;
• each R11 is independently selected from hydroxy, —NR15R15a, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and optionally substituted cycloalkyl;
• R12 is hydrogen or alkyl and R12a is hydrogen, hydroxy, alkoxy, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, or optionally substituted heteroaryl;
• or R12 and R12a together with the nitrogen to which they are attached form a heterocycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from alkyl, hydroxyalkyl, haloalkyl, alkylcarbonyl, alkoxycarbonyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted phenyl, and optionally substituted phenylalkyl;
• R13 is hydrogen or alkyl;
• R13a is alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
• each R14 is independently hydrogen, alkyl, hydroxy, alkoxy, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkylalkyl;
• each R14a is hydrogen or alkyl;
• R14b is alkoxy, amino, alkylamino, dialkylamino, or optionally substituted heterocycloalkyl;
• R15 is hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, or haloalkyl;
• R15a is hydrogen, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, optionally substituted cycloalkyl, or optionally substituted phenylalkyl;
• R23 is hydrogen or alkyl;
• R23a is hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or optionally substituted heterocycloalkylalkyl;
• R24 is hydrogen or alkyl, hydroxy, or alkoxy;
• and
• R24a is hydroxy, alkoxy, amino, alkylamino, or dialkylamino.