Pyrrolo[2,1-F[1,2,4]triazine compounds, preparation methods and applications thereof
The present invention relates to a pyrrolo[2,1-f][1,2,4]triazine compound, an isomer thereof or a pharmaceutically acceptable salt, ester or hydrate thereof, and a preparation method and application thereof. The pyrrolo[2,1-f][1,2,4]triazine compound has a structure expressed in general formula (I). The pyrrolo[2,1-f][1,2,4]triazine compound expressed in general formula (I) can inhibit a phosphatidylinositol-3 kinase (PI3K) signal pathway, thereby being used to prepare medicine for treating phosphatidylinositol-3 kinase related diseases such as cancer.
1. A method for treating cancer, comprises:
administrating to a subject in need thereof an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pyrrolo[2,1-f][1,2,4]triazine compound of formula I,
wherein,
X═CH or N;
R 1 is —NR 5 R 6 ;
R 2 is
R 3 is —NH 2 , —NHC(O)NHR 11 , —NHC(O)OR 11 , —NHC(O)R 11 , —CH 2 OH, —CH 2 S(O) 2 R 12 or —CH 2 NHS(O) 2 R 12 ;
R 4 is H or CF 3 ;
R 5 and R 6 are each independently a C1-C4 alkyl, or combined with the nitrogen atom to which they are attached to form an unsubstituted 5-8 membered saturated heterocycle or a 5-8 membered saturated heterocycle substituted by a substituent, the substituent is —S(O) 2 R 12 ;
R 7 , R 8 , R 9 and R 10 are each independently H or a C1-C3 alkyl, alternatively, R 7 and R 8 , or R 9 and R 10 , with the carbon atoms to which they are attached as bridge carbon atoms, form bridged bicylco-heterocycle with morpholine ring;
R 11 is a C1-C4 alkyl, an unsubstituted C3-C6 cycloalkyl or a C3-C6 cycloalkyl substituted by one or more substituents, an unsubstituted benzyl or a benzyl substituted by one or more substituents, an unsubstituted phenyl or a phenyl substituted by one or more substituents, an unsubstituted isoxazolyl or an isoxazolyl substituted by one or more substituents, or an unsubstituted pyridyl or a pyridyl substituted by one or more substituents, and the one or more substituents are selected from halogen, a C1-C3 alkyl, or a C1-C3 alkoxyl, —CF 3 , —C(O)OR 12 , —C(O)NR 12 R 15 ,
R 12 and R 15 are each independently a C1-C3 alkyl;
or a pharmaceutically acceptable salt, or hydrate thereof;
wherein the subject is a human patient having esophageal cancer.
2. The method of claim 1 , wherein the compound is of formula A or formula B:
3. The method of claim 1 , wherein,
R 2 is
in which R 7 , R 8 , R 9 , and R 10 are as defined in claim 1 ;
R 5 and R 6 are combined with the nitrogen atom to which they are attached to form an unsubstituted saturated heterocycle or a saturated heterocycle substituted by a substituent, wherein the saturated heterocycle is pyrrolidyl, piperidinyl or piperazinyl, and the substituent is —S(O) 2 R 12 , in which R 12 is defined as in claim 1 .
4. The method of claim 3 , wherein,
R 1 is dimethylamino or 1-methylsulfonyl piperazinyl;
R 2 is
R 11 is a methyl, an ethyl, a propyl, a cyclopropyl, a tert-butyl, an iso-butyl, a 4-fluorobenzyl, an unsubstituted phenyl or a phenyl substituted by one or more substituents, an unsubstituted isoxazolyl or an isoxazolyl substituted by one or more substituents, or an unsubstituted pyridine ring or a pyridine ring substituted by one or more substituents, and the substituent is selected from a fluorine, a chlorine, a trifluoromethyl, a methyl, a methoxy, an ethoxycarbonyl, a dimethylaminocarbonyl, a 4-methyl-piperazine-1-carbonyl, a piperidine-1-carbonyl and a 4-dimethylamino-piperidine-1-carbonyl.
5. The method of claim 1 , wherein the compound is selected from the group consisting of:
wherein, R 1 , R 2 , R 11 and R 12 are as defined in claim 1 ,
R 16 and R 17 are identical or different, and each is independently a C1-C4 alkyl, or R 16 and R 17 are combined with the nitrogen atom to which they are attached to form a 4-methyl-piperazinyl, a 4-dimethylamino-piperidinyl, or piperidin-1-yl.
6. The method of claim 1 , wherein the compound is selected from the group consisting of:
7. The method of claim 1 , wherein the pharmaceutical composition has a dose of the compound ranging from 1 to 1000 mg.
8. The method of claim 7 , wherein the dose of the compound in the pharmaceutical composition ranges from 10 to 500 mg.
9. The method of claim 1 , wherein the pharmaceutical composition is in a form of capsule, tablet, pill, powder, granule, emulsion, solution, suspension, syrup or tincture.
10. The method of claim 1 , wherein the pharmaceutically acceptable carrier is cellulose, gelatin, talc, solid lubricant, calcium sulfate, vegetable oil, polyol, emulsifier, wetting agent, coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, suspending agent, sweetener, perfume, or a combinations thereof.
11. The method of claim 1 , wherein the subject is administered with 1-1000 mg of the compound daily.
12. The method of claim 11 , wherein the subject is administered with 30-500 mg of the compound daily.
13. A pharmaceutical composition, comprising a pyrrolo[2,1-f][1,2,4]triazine compound of formula I, a pharmaceutically acceptable salt, or hydrate thereof,
and a pharmaceutically acceptable carrier,
wherein in formula I,
X═CH or N;
R 1 is —NR 5 R 6 ;
R 2 is
R 3 is —NH 2 , —NHC(O)NHR 11 , —NHC(O)OR 11 , —NHC(O)R 11 , —CH 2 OH, —CH 2 S(O) 2 R 12 or —CH 2 NHS(O) 2 R 12 ;
R 4 is H or CF 3 ;
R 5 and R 6 are each independently a C1-C4 alkyl, or combined with the nitrogen atom to which they are attached to form an unsubstituted 5-8 membered saturated heterocycle or a 5-8membered saturated heterocycle substituted by a substituent, the substituent is —S(O) 2 R 12 ;
R 7 , R 8 , R 9 and R 10 are each independently H or a C1-C3 alkyl, alternatively, R 7 and R 8 , or R 9 and R 10 , with the carbon atoms to which they are attached as bridge carbon atoms, form bridged bicylco-heterocycle with morpholine ring;
R 11 is a C1-C4 alkyl, an unsubstituted C3-C6 cycloalkyl or a C3-C6 cycloalkyl substituted by one or more substituents, an unsubstituted benzyl or a benzyl substituted by one or more substituents, an unsubstituted phenyl or a phenyl substituted by one or more substituents, an unsubstituted isoxazolyl or an isoxazolyl substituted by one or more substituents, or an unsubstituted pyridyl or a pyridyl substituted by one or more substituents, and the one or more substituents are selected from halogen, a C1-C3 alkyl, or a C1-C3 alkoxyl, —CF 3 , —C(O)OR 12 , —C(O)NR 12 R 15 ,
and
R 12 and R 15 are each independently a C1-C3 alkyl.
14. The pharmaceutical composition of claim 13 , wherein the compound is selected from the group consisting of:
15. The pharmaceutical composition of claim 13 , wherein the amount of the compound in the pharmaceutical composition is 1-1000 mg.
16. The pharmaceutical composition of claim 15 , wherein the amount of the compound in the pharmaceutical composition is 10-500 mg.
17. The pharmaceutical composition of claim 13 , wherein the pharmaceutical composition is in a form of a capsule, tablet, pill, powder, granule, emulsion, solution, suspension, syrup or tincture.
18. The pharmaceutical composition of claim 13 , wherein the pharmaceutically acceptable carrier is cellulose, gelatin, talc, solid lubricant, calcium sulfate, vegetable oil, polyol, emulsifier, wetting agent, coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, suspending agent, sweetener, flavoring agent, perfume, or a combination thereof.