Arylmethyl triazolo- and imidazopyrazines as c-Met inhibitors

1. A compound of the formula I:

wherein:

X is N;

each Y is N;

R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, —CN, —COR 7 , —COOR 7 , —CONR 7 R 8 , —CF 3 , lower alkyl, cycloalkyl, heteroalicyclic, alkenyl and alkynyl;

R 3 is a substituent selected from the group consisting of F, Cl, —OH, —OR 7 , —COR 9 , —NR 7 R 8 , —CN, —SO 2 R 7 , —S(O)R 7 , SO 2 NR 7 R 8 , —CF 3 , and lower alkyl;

wherein if p is greater than 1, then each R 3 is independently F, Cl, —OH, —OR 7 , —COR 9 , —NR 7 R 8 , —CN, —SO 2 R 7 , —S(O)R 7 , SO 2 NR 7 R 8 , —CF 3 , or lower alkyl;

R 4 is selected from the group consisting of substituted or unsubstituted heteroaryl, and substituted aryl;

R 5 is selected from the group consisting of hydrogen, halogen, —OH, —COR 7 , —COOR 7 , —CONR 7 R 8 , —NR 7 R 8 , —CN, —NO 2 , —S(O) 2 R 7 , —S(O)R 7 , —SO 2 NR 6 R 7 , —CF 3 , —NR 6 C(O)NR 7 R 8 , —NR 6 C(O)R 7 , —NR 6 SO 2 R 7 substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalicyclic, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl;

R 6 , R 7 and R 8 are independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, heteroalicyclic, alkenyl, alkynyl, aryl, heteroaryl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl and heteroaryl; or

R 7 and R 8 or R 6 and R 7 , together with the atom to which they are attached, form a heteroalicyclic ring optionally substituted with a group selected from the group consisting of alkyl, —OH, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylamino, or dialkylamino;

R 9 is a substituent selected from the group consisting of H, lower alkyl, cycloalkyl, heteroalicyclic, alkenyl, alkynyl, aryl, dialkylaminoalkyl, heteroaryl and alkylaminoalkyl;

n is 1, 2 or 3, it being understood that when n is greater than 1, the R 1 and R 2 groups on each carbon atom may be the same as or different from the R 1 and R 2 groups on any adjacent carbon atom; and

p is 0, 1, 2 or 3; or

a pharmaceutically acceptable salt thereof.

2. A compound of the formula II:

wherein:

X is CH or N;

each Y is independently CH or N;

R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, —CN, —COR 7 , —COOR 7 , —CONR 7 R 8 , —CF 3 , lower alkyl, cycloalkyl, heteroalicyclic, alkenyl and alkynyl;

R 3 is a substituent selected from the group consisting of F, Cl, —OH, —OR 7 , —COR 9 , —NR 7 R 8 , —CN, —SO 2 R 7 , —S(O)R 7 , SO 2 NR 7 R 8 , —CF 3 , and lower alkyl;

wherein if p is greater than 1, then each R 3 is independently F, Cl, —OH, —OR 7 , —COR 9 , —NR 7 R 8 , —CN, —SO 2 R 7 , —S(O)R 7 , SO 2 NR 7 R 8 , —CF 3 , or lower alkyl;

R 4 and R 5 are selected from the group consisting of hydrogen, halogen, —OH, —COR 7 , —COOR 7 , —CONR 7 R 8 , —NR 7 R 8 , —CN, —NO 2 , —S(O) 2 R 7 , —S(O)R 7 , —SO 2 NR 6 R 7 , —CF 3 , —NR 6 C(O)NR 7 R 8 , —NR 6 C(O)R 7 , —NR 6 SO 2 R 7 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalicyclic, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl;

R 6 , R 7 and R 8 are independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, heteroalicyclic, alkenyl, alkynyl, aryl, heteroaryl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl and heteroaryl; or

R 7 and R 8 or R 6 and R 7 , together with the atom to which they are attached, form a heteroalicyclic ring substituted with a group selected from the group consisting of alkyl, —OH, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylamino, dialkylamino;

R 9 is a substituent selected from the group consisting of H, lower alkyl, cycloalkyl, heteroalicyclic, alkenyl, alkynyl, aryl, heteroaryl, dialkylaminoalkyl, heteroaryl and alkylaminoalkyl;

n is 1, 2, or 3, it being understood that when n is greater than 1, the R 1 and R 2 groups on each carbon atom may be the same as or different from the R 1 and R 2 groups on any adjacent carbon atom; and

p is 0, 1, 2, or 3; or

a pharmaceutically acceptable salt thereof.

3. A compound of the formula III:

wherein:

X is CH or N;

each Y is independently CH or N;

R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, —CN, —COR 7 , —COOR 7 , —CONR 7 R 8 , —CF 3 , lower alkyl, cycloalkyl, heteroalicyclic, alkenyl and alkynyl;

R 3 is a substituent selected from the group consisting of F, Cl, —OH, —OR 7 , —COR 9 , —NR 7 R 8 , —CN, —SO 2 R 7 , —S(O)R 7 , SO 2 NR 7 R 8 , —CF 3 , and lower alkyl;

wherein if p is greater than 1, then each R 3 is independently F, Cl, —OH, —OR 7 , —COR 9 , —NR 7 R 8 , —CN, —SO 2 R 7 , —S(O)R 7 , —SO 2 NR 7 R 8 , —CF 3 , or lower alkyl;

R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, —OH, —COR 7 , —COOR 7 , —CONR 7 R 8 , —NR 7 R 8 , —CN, —NO 2 , —S(O) 2 R 7 , —S(O)R 7 , —SO 2 NR 6 R 7 , —CF 3 , —NR 6 C(O)NR 7 R 8 , —NR 6 C(O)R 7 , —NR 6 SO 2 R 7 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalicyclic, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl;

R 6 , R 7 and R 8 are selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, heteroalicyclic, alkenyl, alkynyl, aryl, heteroaryl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl and heteroaryl; or

R 7 and R 8 or R 6 and R 7 , together with the atom to which they are attached, form a heteroalicyclic ring optionally substituted with a group selected from the group consisting of alkyl, —OH, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylamino, dialkylamino;

R 9 is a substituent selected from the group consisting of H, lower alkyl, cycloalkyl, heteroalicyclic, alkenyl, alkynyl, aryl, heteroaryl, dialkylaminoalkyl, heteroaryl and alkylaminoalkyl;

n is 1, 2, or 3, it being understood that when n is greater than 1, the R 1 and R 2 groups on each carbon atom may be the same as or different from the R 1 and R 2 groups on any adjacent carbon atom; and

p is 0, 1, 2, or 3; or

a pharmaceutically acceptable salt thereof.

4. A compound of the formula IV:

wherein:

p is 0, 1, 2, or 3;

Y is N;

R 1 and R 2 is a substituent selected from the group consisting of hydrogen, halogen, —CN, —COR 7 , —COOR 7 , —CONR 7 R 8 , —CF 3 , lower alkyl, cycloalkyl, heteroalicyclic, alkenyl and alkynyl;

each R 11 is independently selected from the group consisting of halogen, —OH, —OR 7 , —COR 7 , —COOR 7 , —CONR 7 R 8 , —NR 7 R 8 , —CN, —NO 2 , —S(O) 2 R 7 , —S(O)R 7 , —SO 2 NR 7 R 8 , —CF 3 , lower alkyl, cycloalkyl, heteroalicyclic, alkenyl, alkynyl and aryl;

R 12 is

wherein R 10 is selected from the group consisting of —OH, halogen, —O(CH 2 ) m NR 7 R 8 , —NHC(O)NH(CH 2 ) m NR 7 R 8 , —C(O)NR 7 R 8 , —(CH 2 ) m aryl, —NR 6 C(O)R 7 , —NR 6 SO 2 R 7 , —S(CH 2 ) m NR 7 R 8 , —SO 2 R 7 , —S(O)R 7 , and —SO 2 NR 7 R 8 ;

wherein m is 0, 1, 2, or 3;

R 13 is selected from the group consisting of hydrogen, halogen, —OR 7 , —COR 7 , —COOR 7 , —CONR 7 R 8 , —NR 7 R 8 , —CN, —NO 2 , —S(O) 2 R7, —S(O)R 7 , —SO 2 NR 6 R 7 , —CF 3 , lower alkyl, cycloalkyl, heteroalicyclic, heteroaryl, alkenyl, alkynyl, and aryl;

R 6 , R 7 and R 8 are independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, heteroalicyclic, alkenyl, alkynyl, aryl, heteroaryl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl; or

R 7 and R 8 together with the atom to which they are attached form a heteroalicyclic ring optionally substituted with a group selected from the group consisting of alkyl, —OH, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; and

n is 1, 2, or 3, it being understood that when n is an integer greater than 1, the R 1 and R 2 groups on each carbon atom may be the same as or different from the R 1 and R 2 groups on any adjacent carbon atom; or

a pharmaceutically acceptable salt thereof.

5. A compound of the formula IV:

wherein:

p is 0, 1, 2, or 3;

Y is N;

R 1 and R 2 is a substituent selected from the group consisting of hydrogen, halogen, —CN, —COR 7 , —COOR 7 , —CONR 7 R 8 , —CF 3 , lower alkyl, cycloalkyl, heteroalicyclic, alkenyl and alkynyl;

each R 11 is independently selected from the group consisting of halogen, —OH, —OR 7 , —COR 7 , —COOR 7 , —CONR 7 R 8 , —NR 7 R 8 , —CN, —NO 2 , —S(O) 2 R 7 , —S(O)R 7 , SO 2 NR 7 R 8 , —CF 3 , lower alkyl, cycloalkyl, heteroalicyclic, alkenyl, alkynyl and aryl;

R 12 is a substituent selected from the group consisting of:

wherein R 10 is selected from the group consisting of hydrogen, —OH, halogen, —O(CH 2 ) m NR 7 R 8 , —NHC(O)NH(CH 2 ) m NR 7 R 8 , —C(O)NR 7 R 8 , —(CH 2 ) m aryl, —NR 6 C(O)R 7 , —NR 6 SO 2 R 7 , —S(CH 2 ) m NR 7 R 8 , —SO 2 R 7 , —S(O)R 7 and —SO 2 NR 7 R 8 ;

wherein m is 0, 1, 2, or 3;

R 13 is selected from the group consisting of hydrogen, halogen, —OR 7 , —COR 7 , —COOR 7 , —CONR 7 R 8 , —NR 7 R 8 , —CN, —NO 2 , —S(O) 2 R 7 , —S(O)R 7 , —SO 2 NR 6 R 7 , —CF 3 , lower alkyl, cycloalkyl, heteroalicyclic, heteroaryl, alkenyl, alkynyl, and aryl;

R 6 , R 7 and R 8 are independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, heteroalicyclic, alkenyl, alkynyl, aryl, heteroaryl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl; or

R 7 and R 8 together with the atom to which they are attached form a heteroalicyclic ring optionally substituted with a group selected from the group consisting of alkyl, —OH, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; and

n is 1, 2, or 3, it being understood that when n is an integer greater than 1, the R 1 and R 2 groups on each carbon atom may be the same as or different from the R 1 and R 2 groups on any adjacent carbon atom; or

a pharmaceutically acceptable salt thereof.

6. A compound selected from the group consisting of:

a pharmaceutically acceptable salt thereof.

7. A method of treating cancer, wherein said cancer is selected from the group consisting of lung cancer, and renal cancer, comprising administering a compound of claim 1 to a patient in need thereof.

8. A pharmaceutical composition comprising a compound of any one of claims 1, 2 or 3, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.