Substituted pyrazolo[3,4-d]pyrimidines as kinase inhibitors
The present disclosure provides compounds of Formula (II) as disclosed herein, and/or pharmaceutically acceptable salts thereof that are tyrosine kinase inhibitors, in particular BTK inhibitors, and are potentially useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer, inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and/or pharmaceutically acceptable salts thereof and processes for preparing such compounds and pharmaceutically acceptable salts thereof.
1. A compound of Formula (II):
where:
—Z— is:
R 1 and R 2 are independently hydrogen, alkyl, halo, or alkoxy;
R 3 is hydrogen or halo; and
R c is:
(a) —C(CH 3 ) 2 -(4-R 5 -piperazin-1-yl), wherein R 5 is hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, acyl, or oxetan-3-yl, and the piperazinyl ring is additionally optionally substituted with one or two alkyl;
(b) —C(CH 3 ) 2 -(2-oxo-4-R a -piperazin-1-yl) or —C(CH 3 ) 2 -(3-oxo-4-R a -piperazin-1-yl), wherein R a is hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, or oxetan-3-yl and the piperazinyl ring is additionally optionally substituted with one or two alkyl;
(c) —C(CH 3 ) 2 —NR b -oxetan-3-yl, wherein R b is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or cycloalkyl;
(d) —C(CH 3 ) 2 —R d , wherein R d is
wherein one or two of X 1 , X 2 , and X 3 are nitrogen and the rest are carbon and the ring is optionally substituted with one or two substituents independently chosen from alkyl, haloalkyl, or halo; or
(e) —C(CH 3 ) 2 -2-oxa-6-azaspiro[3.3]heptan-6-yl or —C(CH 3 ) 2 —CH 2 -morpholin-4-yl,
and/or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 2 is alkyl, halo, or alkoxy.
3. The compound of claim 2 , and/or a pharmaceutically acceptable salt thereof, wherein R 3 is fluoro.
4. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein:
R 2 is alkyl, halo, or alkoxy; and
R c is —C(CH 3 ) 2 -(4-R 5 -piperazin-1-yl), wherein R 5 is hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, acyl, or oxetan-3-yl.
5. The compound of claim 4 , and/or a pharmaceutically acceptable salt thereof, wherein the piperazinyl ring of R c is substituted with one or two alkyl.
6. The compound of claim 4 , and/or a pharmaceutically acceptable salt thereof, wherein R 3 is fluoro.
7. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein
R 1 is hydrogen;
R 2 is hydrogen; and
R c is —C(CH 3 ) 2 -(4-R 5 -piperazin-1-yl), wherein R 5 is hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, acyl, or oxetan-3-yl.
8. The compound of claim 7 , and/or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen; and R c is —C(CH 3 ) 2 -(4-R 5 -piperazin-1-yl), wherein R 5 is hydrogen, alkyl, or oxetan-3-yl.
9. The compound of claim 7 , and/or a pharmaceutically acceptable salt thereof, wherein R 3 is fluoro.
10. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 , and/or a pharmaceutically acceptable salt thereof.
11. The pharmaceutical composition of claim 10 , wherein said pharmaceutical composition is in the form of a parenteral composition.
12. The pharmaceutical composition of claim 10 , wherein said pharmaceutical composition is in the form of an oral composition.
13. A method of inhibiting Bruton's tyrosine kinase activity in a patient suffering from a disease chosen from an autoimmune disease, an inflammatory disease, and cancer, wherein the method comprises the step of administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 1 , and/or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein the patient suffers from a disease chosen from rheumatoid arthritis, psoriatic arthritis, lupus, uveitis, myasthenia gravis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, Sjogren's disease, Sjogren's dry eye, non-Sjogren's dry eye disease, psoriasis, idiopathic thrombocytopenic purpura, and asthma.
15. A compound chosen from:
2-[[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl]-piperidin-1-yl]carbonyl]-4-methyl-4-(piperazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(S)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-ethyl-3-oxopiperazin-1-yl)-4-methylpent-2-enenitrile;
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-ethyl-3-oxopiperazin-1-yl)-4-methylpent-2-enenitrile; and
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(3-oxopiperazin-1-yl)pent-2-enenitrile, or
a pharmaceutically acceptable salt thereof, or
an (E) stereoisomer or (Z) stereoisomer of any of the above compounds.
16. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and compound of claim 15 , and/or a pharmaceutically acceptable salt thereof.
17. A method of inhibiting Bruton's tyrosine kinase activity in a patient suffering from a disease chosen from an autoimmune disease, an inflammatory disease, and cancer, wherein the method comprises the step of administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 15 , and/or a pharmaceutically acceptable salt thereof.
18. The method of claim 17 , wherein the patient suffers from a disease chosen from rheumatoid arthritis, psoriatic arthritis, lupus, uveitis, myasthenia gravis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, Sjogren's disease, Sjogren's dry eye, non-Sjogren's dry eye disease, psoriasis, idiopathic thrombocytopenic purpura, and asthma.
19. An (E) stereoisomer of a compound chosen from:
2-[[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl]piperidin-1-yl]carbonyl]-4-methyl-4-(piperazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(S)-2-(3-(4-amino-3-(4-phenoxyphenyI)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyI)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyI)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-ethyl-3-oxopiperazin-1-yl)-4-methylpent-2-enenitrile;
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-ethyl-3-oxopiperazin-1-yl)-4-methylpent-2-enenitrile; and
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl piperidine-1-carbonyl)-4-methyl-4-(3-oxopiperazin-1-yl)pent-2-enenitrile,
and/or a pharmaceutically acceptable salt thereof.
20. A (Z) stereoisomer of a compound chosen from:
2-[[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl]-piperidin-1-yl]carbonyl]-4-methyl-4-(piperazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(S)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyI)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyI)-4-(4-ethyl-3-oxopiperazin-1-yl)-4-methylpent-2-enenitrile;
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-ethyl-3-oxopiperazin-1-yl)-4-methylpent-2-enenitrile; and
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyriidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(3-oxopiperazin-1-yl)pent-2-enenitrile,
and/or a pharmaceutically acceptable salt thereof.
21. A method of treating idiopathic thrombocytopenic purpura in a patient in recognized need thereof, wherein the method comprises the step of administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of:
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-y)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; or
a mixture of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile and (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile, or
an individual (E) or (Z) stereoisomer of any of the above compounds, and/or
a pharmaceutically acceptable salt of any of the above compounds.
22. A method of treating idiopathic thrombocytopenic purpura in a patient in recognized need thereof, wherein the method comprises the step of administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a mixture of (E) and (Z) stereoisomers of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile, and/or a pharmaceutically acceptable salt thereof.