Inhibitors of the hedgehog pathway

1. A Compound of Formula I

or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof, where

R 1 is alkyl, cycloalkyl, phenyl, or heteroaryl where the cycloalkyl, phenyl, and heteroaryl are optionally substituted with 1, 2, or 3 R 6 ;

R 2 and R 3 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 R 6 , when R 6 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;

R 40 is hydrogen or alkyl;

R 50 is selected from

n1 is 0, 1, or 2;

each R 5 , when R 5 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 R 5 , is independently optionally substituted with alkyl or alkoxycarbonyl;

R 4a is hydrogen or alkyl;

R 4 is heteroaryl substituted with one R 8 and additionally substituted with 1 or 2 R 8a , wherein heteroaryl is selected from 1,2,3,4-tetrahydroisoquinolinyl or 2,3,4,5-tetrahydro-1,4-benzoxazepinyl; or R 4 is phenyl substituted with one R 29 and additionally substituted with 1 or 2 R 9a ;

each R 8 is independently alkyl, cycloalkyl, phenylalkyloxyalkyl, or R 9b ;

each R 8a is independently hydrogen, halo, or R 8 ;

each R 9a is independently hydrogen, R 9b , or R 9a ;

R 29 is alkyl substituted with —NR 15 R 15a ; or alkyl substituted with optionally substituted heterocycloalkyl;

each R 9b , when R 9b is present, is independently amino, alkylamino, dialkylamino, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyloxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, optionally substituted heteroaryl, cyano, —C(O)R 14 , —CR 14a (NR 14b ), —C(═NR 24 )R 24a , —S(O) 2 NR 13 R 13a ,

—NR 23 C(O)R 23a —C(O)NR 12 R 12a , or alkyl substituted with one or two R 11 ;

each R 9c , when R 9c is present, is independently alkyl, haloalkyl, hydroxyalkyl, halo, hydroxy, alkoxy, cyano, nitro, or phenylcarbonyl;

each R 11 is independently selected from hydroxy, —NR 15 R 15a , optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and optionally substituted cycloalkyl;

R 12 is hydrogen or alkyl and R 12a is hydrogen, hydroxy, alkoxy, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, or optionally substituted heteroaryl; or R 12 and R 12a 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;

R 13 is hydrogen or alkyl;

R 13a is alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;

each R 14 is independently hydrogen, alkyl, hydroxy, alkoxy, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkylalkyl;

each R 14a is hydrogen or alkyl;

R 14b is alkoxy, amino, alkylamino, dialkylamino, or optionally substituted heterocycloalkyl;

R 15 is hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, or haloalkyl;

R 15a is hydrogen, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, optionally substituted cycloalkyl, or optionally substituted phenylalkyl;

R 23 is hydrogen or alkyl;

R 23a is hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or optionally substituted heterocycloalkylalkyl;

R 24 is hydrogen or alkyl, hydroxy, or alkoxy; and

R 24a is hydroxy, alkoxy, amino, alkylamino, or dialkylamino.

2. The Compound of claim 1 where R 40 is hydrogen and R 2 and R 3 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, and hydroxy; or a single isomer thereof and optionally as a pharmaceutically acceptable salt-thereof.

3. The Compound of claim 2 where R 2 and R 3 together with the pyrimidinyl to which they are attached form a quinazolinyl that is not substituted at the 5-, 6-, 7-, or 8-position; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

4. The Compound of claim 3 where R 1 is alkyl; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

5. The Compound of claim 3 where R 1 is heteroaryl optionally substituted with 1, 2, or 3 R 6 ; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

6. The Compound of claim 3 where R 1 is cycloalkyl optionally substituted with 1, 2, or 3 R 6 ; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

7. The Compound of claim 3 where R 1 is phenyl substituted with one or two R 6 where each R 6 is independently amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocycloalkylalkyl (optionally substituted with alkyl or alkoxycarbonyl), aminoalkylamino, alkylaminoalkylamino, or dialkylaminoalkylamino; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

8. The Compound of claim 3 where R 1 is unsubstituted phenyl; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

9. The Compound of claim 1 according to Formula Ib

or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

10. The Compound of claim 9 where R 4 is heteroaryl substituted with one R 8 , wherein heteroaryl is selected from 1,2,3,4-tetrahydroisoquinolinyl or 2,3,4,5-tetrahydro-1,4-benzoxazepinyl; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

11. The Compound of claim 9 where R 4 is phenyl substituted with R 29 and additionally substituted with 1 or 2 R 9a ; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

12. The Compound of claim 3 where R 1 is alkyl, cycloalkyl, or heteroaryl, where the cycloalkyl and heteroaryl are optionally substituted with 1, 2, or 3 R 6 ; R 50 is

R 4 is phenyl substituted with one R 29 and additionally substituted with 1 or 2 R 9a and each R 9a is independently hydrogen or R 9c ; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

13. A method of preparing a compound of claim 1 which method comprises

reacting an intermediate of formula 8, or a salt, hydrate, solvate, or combination thereof:

where A is CH or N, and D is N; with an intermediate of formula 9:

to yield a Compound of Formula XI:

and optionally separating individual isomers; and optionally modifying any of the R 6 , R 29 , and R 9a groups; and optionally forming a pharmaceutically acceptable salt thereof; or

reacting an intermediate of formula II, or a salt, hydrate, solvate, or combination thereof:

where A is CH or N, and D is N; with an intermediate of formula NHR 12 R 12a to yield a Compound of formula 8f

and optionally separating individual isomers; and optionally modifying any of the R 6 , R 9a , and R 12a groups; and optionally forming a pharmaceutically acceptable salt thereof; or

reacting an intermediate of formula 13, or a salt, hydrate, solvate, or combination thereof:

where A is CH or N, and D is N; with an intermediate of formula NHR 15 R 15a to yield a Compound of Formula XII:

and optionally separating individual isomers; and optionally modifying any of the R 6 , R 9a , and R 15a groups; and optionally forming a pharmaceutically acceptable salt thereof; or

reacting an intermediate of formula 15a, or a salt, hydrate, solvate, or combination thereof:

where A is CH or N, and D is N; with an intermediate of formula NH 2 R 15 to yield a Compound of Formula XIII:

and optionally separating individual isomers; and optionally modifying any of the R 6 , R 9a , and R 15 groups; and optionally forming a pharmaceutically acceptable salt thereof; or

reacting an intermediate of formula 23, or a salt, hydrate, solvate, or combination thereof:

where A is CH or N, and D is N; with an intermediate of formula R 23a C(O)OH or R 23a C(O)Cl to yield a Compound of Formula XIV

and optionally separating individual isomers; and optionally modifying any of the R 6 , R 9a , and R 23a groups; and optionally forming a pharmaceutically acceptable salt thereof; or

reacting an intermediate of formula 26, or a salt, hydrate, solvate, or combination thereof:

where A is CH or N, and D is N; with an intermediate of formula R″B(OH) 2 where R″ is optionally substituted heteroaryl to yield a Compound of Formula XV:

and optionally separating individual isomers; and optionally modifying any of the R 6 , R 9a , and R″ groups; and optionally forming a pharmaceutically acceptable salt thereof;

reacting an intermediate of formula 31, or a salt, hydrate, solvate, or combination thereof:

where R 1 is cycloalkyl, and D is N; with an intermediate of formula 9 as defined above to yield a Compound of the Invention of Formula XVI

where R 29 and R 9a are as defined in the Summary of the Invention for a Compound of Formula I; and optionally separating individual isomers; and optionally modifying any of the R 1 , R 9a , and R 29 groups; and optionally forming a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound according to claim 1 or a single isomer thereof, optionally as a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.