Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas

1. A compound of formula I or a pharmaceutically acceptable salt thereof

wherein A is

wherein R 1 is C 3 -C 10 alkyl, C 3 -C 10 cycloalkyl, up to per-halosubstituted C 1 -C 10 alkyl or up to per-halosubstituted C 3 -C 10 cycloalkyl;

B is phenyl, pyridinyl, or naphthyl, substituted by —M—L 1 ; and is optionally substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and X n ,

wherein n is 0-2 and each X is independently selected from the group consisting of —CN, —CO 2 R 5 , —C(O)NR 5 R 5′ , —C(O)R 5 , —NO 2 , —OR 5 , —SR 5 , —NR 5 R 5′ , —NR 5 C(O)OR 5′ , —NR 5 C(O)R 5′ , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 7 -C 24 alkaryl, C 3 -C 13 heteroaryl, C 4 -C 23 alkheteroaryl, substituted C 1 -C 10 alkyl, substituted C 2 -C 10 alkenyl, substituted C 1 -C 10 alkoxyl, substituted C 3 -C 10 cycloalkyl, up to per-halosubstituted C 6 -C 14 aryl, up to per-halosubstituted C 3 -C 13 heteroaryl and substituted C 4 -C 23 alkheteroaryl and —M—L 1 ;

where X is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 5 , —C(O)R 5 , —C(O)NR 5 R 5′ , —OR 5 , —SR 5 , —NR 5 R 5′ , —NO 2 , —NR 5 C(O)R 5′ , —NR 5 C(O)OR 5′ and halogen up to per-halosubstitution;

wherein R 5 and R 5′ are independently selected from H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl, up to per-halosubstituted C 1 -C 10 alkyl, up to per-halosubstituted C 2 -C 10 alkenyl, up to per-halosubstituted C 3 -C 10 cycloalkyl, up to per-halosubstituted C 6 -C 14 aryl and up to per-halosubstituted C 3 -C 13 heteroaryl,

wherein M is —O—, —S—, or —(CH 2 )— m

m=1-3, and X a is halogen; and

L 1 is pyridinyl, quinolinyl or isoquinolinyl, optionally substituted by halogen up to per-halosubstitution and optionally substituted by Z n1 ,

wherein n1 is 0 to 3 and each Z is independently —CN, —CO 2 R 5 , —C(O)NR 5 R 5′ , —C(O)NR 5 , —NO 2 , —OR 5 , —SR 5 , —NR 5 R 5′ , —NR 5 C(O)OR 5′ , —C(O)R 5 , NR 5 C(O)R 5′ , C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl, substituted C 1 -C 10 alkyl, substituted C 3 -C 10 cycloalkyl, substituted C 7 -C 24 alkaryl or substituted C 4 -C 23 alkheteroaryl;

wherein if Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of —CN, —CO 2 R 5 , —C(O)NR 5 R 5′ , —OR 5 , —SR 5 , —NO 2 , —NR 5 R 5′ , —NR 5 C(O)R 5′ and —NR 5 C(O)OR 5′ , and

wherein R 2 is unsubstituted phenyl, unsubstituted pyridinyl, substituted phenyl or substituted pyridinyl

wherein if R 2 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and V n ,

wherein n=0-3 and each V is independently selected from the group consisting of —CN, —CO 2 R 5 , —C(O)NR 5 R 5′ , —OR 5 , —SR 5 , —NR 5 R 5′ , —C(O)R 5 , —OC(O)NR 5 R 5′ , —NR 5 C(O)OR 5′ , —SO 2 R 5 , —SOR 5 , —NR 5 C(O)R 5′ , —NO 2 , C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 24 alkheteroaryl, substituted C 1 -C 10 alkyl, substituted C 3 -C 10 cycloalkyl, substituted C 6 -C 14 aryl, substituted C 3 -C 13 heteroaryl, substituted C 7 -C 24 alkaryl and substituted C 4 -C 24 alkheteroaryl,

where if V is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, —CN, —CO 2 R 5 , —C(O)R 5 , —C(O)NR 5 R 5 , —NR 5 R 5′ , —OR 5 , —SR 5 , —NR 5 C(O)R 5′ , —NR 5 C(O)OR 5′ and —NO 2 ;

wherein R 5 and R 5′ are each independently as defined above.

2. A compound of claim 1 , wherein R1 is t-butyl and R2 is unsubstituted or substituted phenyl.

3. A compound of claim 1 of the formula

wherein B and R 2 are as defined in claim 1 .

4. A compound of claim 1 wherein one of the following combinations is satisfied:

R 2 =unsubstituted phenyl, B=phenyl and L 1 is pyridinyl, quinolinyl or isoquinolinyl,

R 2 =unsubstituted phenyl, B=pyridinyl and L 1 is pyridinyl, quinolinyl or isoquinolinyl,

R 2 =unsubstituted phenyl, B=naphthyl and L 1 is pyridinyl, quinolinyl or isoquinolinyl,

R 2 =unsubstituted pyridinyl, B=phenyl and L 1 is pyridinyl, quinolinyl or isoquinolinyl,

R 2 =unsubstituted pyridinyl, B=pyridinyl and L 1 is pyridinyl, quinolinyl or isoquinolinyl,

R 2 =unsubstituted pyridinyl, B=naphthyl and L 1 is pyridinyl, quinolinyl or isoquinolinyl,

R 2 =substituted phenyl, B=phenyl and L 1 is pyridinyl, quinolinyl or isoquinolinyl,

R 2 =substituted phenyl, B=pyridinyl and L 1 is pyridinyl, quinolinyl or isoquinolinyl,

R 2 =substituted phenyl, B=naphthyl and L 1 is pyridinyl, quinolinyl or isoquinolinyl,

R 2 =substituted pyridinyl, B=phenyl and L 1 is pyridinyl, quinolinyl or isoquinolinyl,

R 2 =substituted pyridinyl, B=pyridinyl and L 1 is pyridinyl, quinolinyl or isoquinolinyl, or

R 2 =substituted pyridinyl, B=naphthyl and L 1 is pyridinyl, quinolinyl isoquinolinyl.

5. A compound of Formula I or a pharmaceutically acceptable salt thereof

wherein A is

wherein R 1 is C 3 -C 10 alkyl, C 3 -C 10 cycloalkyl, up to per-halosubstituted C 1 -C 10 alkyl or up to per-halosubstituted C 3 -C 10 cycloalkyl;

wherein n is 0-2 and each X is independently selected from the group consisting of —CN, —CO 2 R 5 , —C(O)NR 5 R 5′ , —C(O)R 5 , —NO 2 , —OR 5 , —SR 5 , —NR 5 R 5′ , NR 5 C(O)OR 5′ , —NR 5 C(O)R 5′ , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 7 -C 24 alkaryl, C 3 -C 13 heteroaryl, C 4 -C 23 alkheteroaryl, substituted C 1 -C 10 alkyl, substituted C 2 -C 10 alkenyl, substituted C 1 -C 10 alkoxyl, substituted C 3 -C 10 cycloalkyl, up to per-halosubstituted C 6 -C 14 aryl, up to per-halosubstituted C 3 -C 13 heteroaryl and substituted C 4 -C 23 alkheteroaryl and —M—L 1 ;

where X is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 5 , —C(O)R 5 , —C(O)NR 5 R 5′ , —OR 5 , —SR 5 , —NR 5 R 5′ , —NO 2 , —NR 5 C(O)R 5′ , —NR 5 C(O)OR 5′ and halogen up to per-halosubstitution;

wherein R 5 and R 5′ are independently selected from H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl, up to per-halosubstituted C 1 -C 10 alkyl, up to per-halosubstituted C 2 -C 10 alkenyl, up to per-halosubstituted C 3 -C 10 cycloalkyl, up to per-halosubstituted C 6 -C 14 aryl and up to per-halosubstituted C 3 -C 13 heteroaryl,

wherein M is —O—, —S—, —N(R 5 )—, —(CH 2 )— m , —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —NR 5 C(O)—, —C(O)NR 5 , —O(CH 2 ) m —, —(CH 2 ) m S—, —(CH 2 ) m N(R 5 )—, —CHX a —, —CX a 2 —, —S—(CH 2 ) m — or —N(R 5 )(CH 2 ) m —, m=1-3, and X a is halogen; and

L 1 is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, optionally substituted by halogen up to per-halosubstitution and optionally substituted by Z n1 ,

wherein n1 is 0 to 3 and each Z is independently —CN, —CO 2 R 5 , —C(O)NR 5 R 5′ , —C(O)NR 5 , —NO 2 , —OR 5 , —SR 5 , —NR 5 R 5′ , —NR 5 C(O)OR 5′ , —C(O)R 5 , NR 5 C(O)R 5′ , C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl, substituted C 1 -C 10 alkyl, substituted C 3 -C 10 cycloalkyl, substituted C 7 -C 24 alkaryl or substituted C 4 -C 23 alkheteroaryl;

wherein if Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of —CN, —CO 2 R 5 , —C(O)NR 5 R 5′ , —OR 5 , —SR 5 , —NO 2 , —NR 5 R 5′ , —NR 5 C(O)R 5′ and —NR 5 C(O)OR 5′ .

6. A compound as in claim 5 wherein B is optionally substituted pyridinyloxyphenyl, benzothiazolyloxyphenyl, benzothiazolylthiophenyl, pyrimidinyloxyphenyl, quinolinylthiophenyl, and phthalimidylmethylphenyl and R 2 is phenyl, substituted phenyl, pyridinyl or substituted pyridinyl.

7. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.