Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors
The present disclosure provides compounds of Formula (I)and pharmaceutically acceptable salts that are tyrosine kinase inhibitors,in particular BLK, BMX, EGFR, HER2, HER4, ITK, Jak3, TEC, Btk, and TXK and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer and inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts and processes for preparing such compounds and pharmaceutically acceptable salts.
1. A compound of Formula (I):
wherein:
the dashed lines are independently an optional bond;
Z 1 , Z 2 , and Z 3 are —N— or CH, provided that at least one and not more than two of Z 1 , Z 2 , and Z 3 are simultaneously N;
L is O, CO, CH 2 , S, SO, SO 2 , NR, NRCO, CONR, NR′SO 2 , SO 2 NR′, or NRCONR′, where each R and R′ is independently hydrogen, alkyl, or cycloalkyl;
Ar is aryl, heteroaryl, cycloalkyl or heterocyclyl;
one of R 1 and R 5 is hydrogen, alkyl, hydroxy, cyano, alkoxy, halo, haloalkyl, or haloalkoxy and the other of R 1 and R 5 is:
formula (a) or (b);
where P is a bond, NR a (where R a is hydrogen or alkyl), —O—, S, SO, SO 2 , alkylene or heteroalkylene;
Q is a bond, aryl or heteroaryl wherein aryl or heteroaryl is optionally substituted with one or two substituents independently selected from hydrogen, halo, alkyl, alkoxy, alkylhio, haloalkyl, or haloalkoxy;
X a is O, S, N(H), or N(alkyl);
R c′ is hydrogen, alkyl, substituted alkyl, haloalkoxy, cycloalkyl, or cycloalkyleneNR d R e where R d and R e are independently hydrogen, alkyl, or cycloalkyl;
R 2 is hydrogen, alkyl, hydroxy, alkoxy, cyano, halo or haloalkyl;
R 3 and R 4 are independently hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl or haloalkoxy; and
R 6 and R 7 are independently hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl, cyano, —CONH 2 , amino, monosubstituted or disubstituted amino;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein:
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein:
4. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein L is O, S, NH, N(methyl), NHCO, CONH, or NHCONH.
5. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein L is O, S, NH, N(methyl), NHCO, CONH, or NHCONH.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 and R 4 are independently hydrogen, methyl, fluoro, methoxy, chloro, trifluoromethyl, or trifluoromethoxy.
7. The compound of claim 4 or a pharmaceutically acceptable salt thereof wherein R 3 and R 4 are independently hydrogen, methyl, fluoro, methoxy, chloro, trifluoromethyl, or trifluoromethoxy.
8. The compound of claim 5 or a pharmaceutically acceptable salt thereof wherein R 3 and R 4 are independently hydrogen, methyl, fluoro, methoxy, chloro, trifluoromethyl, or trifluoromethoxy.
9. The compound of claim 6 or a pharmaceutically acceptable salt thereof wherein R 6 and R 7 are independently hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, or cyano.
10. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein R 5 is hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy or cyano;
R 1 is formula (a)
where X a is O, S, N(H) or N(alkyl);
R c′ is hydrogen, alkyl, cycloalkyl, substituted alkyl or cycloalkyleneNR d R e ;
R 6 and R 7 are independently hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, or cyano; and
L is O.
11. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein R 5 is hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, or cyano;
R 1 is formula (a)
where X a is O, S, N(H) or N(alkyl);
R c′ is hydrogen, alkyl, cycloalkyl, substituted alkyl or cycloalkyleneNR d R e ;
R 6 and R 7 are independently hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, or cyano; and
L is O.
12. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein R 5 is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, or haloalkoxy;
R 1 is formula (b)
R 6 and R 7 are independently hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, or trifluoromethoxy; and
L is O.
13. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein R 5 is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, or haloalkoxy;
R 1 is formula (b);
R 6 and R 7 are independently hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, or trifluoromethoxy; and
L is O.
14. The compound of claim 12 or a pharmaceutically acceptable salt thereof wherein X a is O;
R c′ is ethyl, propyl, cyclopropyl, or alkyl substituted with hydroxyl, alkoxy, alkylamino or dialkylamino;
P is alkylene; and
Q is a bond.
15. The compound of claim 13 or a pharmaceutically acceptable salt thereof wherein X a is O;
R c′ is ethyl, propyl, cyclopropyl, or alkyl substituted with hydroxyl, alkoxy, alkylamino or dialkylamino;
P is alkylene; and
Q is a bond.
16. The compound of claim 9 or a pharmaceutically acceptable salt thereof wherein the
group is attached at the 4-position of the phenyl ring,
the carbon atom of the phenyl ring attached to
being carbon 1; and
is selected from
where R 3 is hydrogen or fluoro.
17. The compound of claim 14 or a pharmaceutically acceptable salt thereof wherein the
group is attached at the 4-position of the phenyl ring,
the carbon atom of the phenyl ring attached to
being carbon 1; and
is selected from
where R 3 is hydrogen or fluoro.
18. The compound of claim 15 or a pharmaceutically acceptable salt thereof wherein the
group is attached at the 4-position of the phenyl ring,
the carbon atom of the phenyl ring attached to
being carbon 1; and
is selected from
where R 3 is hydrogen or fluoro.
19. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
20. A method of treating chronic lymphocytic leukemia or mantle cell lymphoma in a patient which method comprises administering to the patient in need thereof, a pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable exciplent.