Substituted acetylenic pyrazolo[1,5-a]pyrimidines as kinase inhibitors
This invention relates to compounds of the general formula: in which the variable groups are as defined herein, and to their preparation and use.
1. A compound of the formula:
or a tautomer, or an individual stereoisomer or a mixture of stereoisomers thereof wherein:
Ring A is a 5- or 6-membered aryl or heteroaryl ring;
Ring B is a 5- or 6-membered aryl or heteroaryl ring;
L 1 is selected from NR 1 C(O), C(O)NR 1 , NR 1 C(O)O, NR 1 C(O)NR 1 , and OC(O)NR 1 ;
each occurrence of R a and R b is independently halo, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —SC(O)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NR 2 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 2 R 3 and —NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, —O—, —S— or —NR 3 —;
R e , at each occurrence, is independently halo, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —SC(O)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NR 2 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 2 R 3 or —NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, —O—, —S— or —NR 3 —;
R 1 , R 2 and R 3 are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, or heteroaryl;
or R 2 and R 3 , taken together with the atom to which they are attached, form a 5- or 6-membered saturated, partially saturated or unsaturated ring, which contains 0-2 heteroatoms selected from N, O and S(O) r ;
each occurrence of R 4 is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, or heteroaryl;
each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl, moieties is optionally substituted with one or more groups selected from halo, —CN, —R 4 , —OR 2 , —S(O)—R 2 , —SO 2 NR 2 R 3 , —NR 2 R 3 , —(CO)YR 2 , —O(CO)YR 2 , —NR 2 (CO)YR 2 , —S(CO)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )Y′R 2 , —COCOR 2 , —COMCOR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NO 2 , —NR 2 SO 2 R 2 , —NR 2 SO 2 NR 2 R 3 , ═O, ═S, ═NH, ═NNR 2 R 3 , ═NNHC(O)R 2 , ═NNHCO 2 R 2 , and ═NNHSO 2 R 2 , wherein M is a 1-6 carbon alkyl group;
each of the aryl and heteroaryl moieties is optionally substituted on an unsaturated carbon atom with one or more groups selected from halo, —CN, —R 4 , —OR 2 , —S(O) r R 2 , —SO 7 NR 2 R 3 , —NR 2 R 3 , —(CO)YR 2 , —O(CO)YR 2 , —NR 2 (CO)YR 2 , —S(CO)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )Y′R 2 , —COCOR 2 , —COMCOR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NO 2 , —NR 2 SO 2 R 2 , and —NR 2 SO 2 NR 2 R 3 ;
m is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3, 4 or 5;
r is 0, 1 or 2; and
s is 0, 1, 2, 3 or 4,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 of the formula:
wherein:
Ring C is a 5- or 6-membered heterocyclyl, or heteroaryl ring, comprising carbon atoms and 1-3 heteroatoms independently selected from O, N and S(O) r ;
R c , at each occurrence, is independently selected from halo, ═O, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —Si(R 2 ) 3 , —SC(O)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —NR 2 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 2 R 3 and —NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, —O—, —S— or —NR 3 —; and,
v is 0, 1, 2, 3, 4 or 5.
3. The compound of claim 2 wherein Ring A and Ring B are independently a 5- or 6-membered aryl.
4. The compound of claim 3 wherein Ring C is imidazolyl.
5. The compound of claim 1 having the formula:
wherein:
Ring D represents a 5- or 6-membered heterocyclyl or heteroaryl ring comprising carbon atoms and 1-3 heteroatoms independently selected from O, N and S(O) r ;
L 2 is (CH 2 ) z , O(CH 2 ) x , NR 3 (CH 2 ) x , S(CH 2 ) x or (CH 2 ) x NR 3 C(O)(CH 2 ) x in either direction;
R d , at each occurrence, is H, halo, ═O, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —SC(O)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NR 2 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 2 R 3 or —NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, —O—, —S— or —NR 3 —;
R 2 and R 3 are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, or heteroaryl;
or R 2 and R 3 , taken together with the atom to which they are attached, form a 5- or 6-membered saturated, partially saturated or unsaturated ring, which contains 0-2 heteroatoms selected from N, O and S(O) r ;
each occurrence of R 4 is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, or heteroaryl;
each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is optionally substituted with one or more groups selected from halo, —CN, —R 4 , —OR 2 , —S(O) r —R 2 , —SO 2 NR 2 R 3 , —NR 2 R 3 , —(CO)YR 2 , —O(CO)YR 2 , —NR 2 (CO)YR 2 , —S(CO)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )Y′R 2 , —COCOR 2 , —COMCOR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NO 2 , —NR 2 SO 2 R 2 , —NR 2 SO 2 NR 2 R 3 , ═O, ═S, ═NH, ═NNR 2 R 3 , ═NNHC(O)R 2 , ═NNHCO 2 R 2 , and ═NNHSO 2 R 2 , wherein M is a 1-6 carbon alkyl group;
each of the aryl and heteroaryl moieties is optionally substituted on an unsaturated carbon atom with one or more groups selected from halo, —CN, —R 4 , —OR 2 , —S(O) r R 2 , —SO 2 NR 2 R 3 , —NR 2 R 3 , —(CO)YR 2 , —O(CO)YR 2 , —NR 2 (CO)YR 2 , —S(CO)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )Y′R 2 , —COCOR 2 , —COMCOR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NO 2 , —NR 2 SO 2 R 2 , and —NR 2 SO 2 NR 2 R 3 ;
w is 0, 1, 2, 3, 4 or 5;
x is 0, 1, 2 or 3; and,
z is 1, 2, 3 or 4.
6. The compound of claim 5 , wherein Ring A and Ring B are independently a 5- or 6-membered aryl.
7. The compound of claim 6 , wherein Ring D is piperazinyl and L 2 is CH 2 .
8. The compound of claim 5 wherein s is 0, m is 1, p is 1, R a is —CH 3 , R b is —CF 3 , and R d is —CH 3 or —CH 2 CH 2 OH.
9. A composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or vehicle.
10. A compound selected from:
or a pharmaceutically acceptable salt thereof.
11. A composition comprising a compound selected from:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or vehicle.