Methods for cancer therapy

Abstract

The present invention relates to methods for treating patients with cancer, including patients with hematological malignancy, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are as defined herein.

We claim: 
     
         1 . A method of treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R 1  is hydrogen, C 1-4  alkyl, C 3-6  cycloalkyl, C 1-4  alkyloxy, or phenyl; and R 2  is hydrogen, C 1-4  alkyl, C 3-6  cycloalkyl, or halogen. 
       
     
     
         2 . The method of  claim 1 , wherein the cancer is hematological malignancy. 
     
     
         3 . The method of  claim 2 , wherein the hematological malignancy is leukemia or chronic myeloid leukemia. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 3 , wherein the method is in the treatment of the patient with chronic myeloid leukemia resistant to current tyrosine kinase inhibitor therapies. 
     
     
         6 . The method of  claim 5 , wherein the patient with chronic myeloid leukemia resistant to the current tyrosine kinase inhibitor therapies is caused by BCR-ABL mutations, where the BCR-ABL mutation is T315I, E255K/V, G250E, H396P, M351T, Q252H, Y253F/H, or BCR-ABL WT  mutations. 
     
     
         7 .- 8 . (canceled) 
     
     
         9 . The method of  claim 5 , wherein the patient with chronic myeloid leukemia resistant to the current tyrosine kinase inhibitor therapies is caused by BCR-ABL complex mutation, preferably, wherein the BCR-ABL complex mutation is BCR-ABL E255V/T315I , BCR-ABL Y253H/E255V , BCR-ABL T315M , BCR-ABL Y253H/T315I , BCR-ABL Y253H/F359V , or BCR-ABL T315I/F317L , or one or more of the above-said types of mutations, and the tyrosine kinase inhibitor is Ponatinib. 
     
     
         10 .- 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the compound of formula (I), or pharmaceutically acceptable salt thereof is administered orally every one, two, or three days during a treatment cycle, wherein said treatment cycle is 20-40 days, 25-35 days, or 28-day treatment cycle. 
     
     
         13 . The method of  claim 1 , wherein the therapeutically effective amount is from 0.5 mg to 100 mg, from 1 mg to 80 mg, or from 1 mg to 60 mg. 
     
     
         14 . The method of  claim 13 , wherein the therapeutically effective amount is about 1 mg, about 2 mg, about 4 mg, about 8 mg, about 12 mg, about 20 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg or about 60 mg. 
     
     
         15 . The method of  claim 1 , wherein R 1  is selected from the group consisting of hydrogen, methyl, cyclopropyl, phenyl, and methoxy; and R 2  is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, fluorine, chlorine, or bromine. 
     
     
         16 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (I-A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . (canceled) 
     
     
         18 . A method of inhibiting BCR-ABL mutants, comprising contacting a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof with BCR-ABL mutants, 
         wherein R 1  is hydrogen, C 1-4  alkyl, C 3-6  cycloalkyl, C 1-4  alkyloxy, or phenyl; and R 2  is hydrogen, C 1-4  alkyl, C 3-6  cycloalkyl, or halogen. 
       
     
     
         19 . The method of  claim 18 , wherein the BCR-ABL mutants is T315I, E255K/V, G250E, H396P, M351T, Q252H, Y253F/H, or BCR-ABL WT    
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 18 , wherein the compound of formula (I) is a compound of formula (I-A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 18 , wherein the inhibition is in a patient with chronic myeloid leukemia resistant to current tyrosine kinase inhibitor therapies. 
     
     
         24 . The method of  claim 23 , wherein the patient with chronic myeloid leukemia resistant to the current tyrosine kinase inhibitor therapies is caused by BCR-ABL mutations, wherein the BCR-ABL mutation is T315I, E255K/V, G250E, H396P, M351T, Q252H, Y253F/H, or BCR-ABL WT  mutations. 
     
     
         25 .- 26 . (canceled) 
     
     
         27 . The method of  claim 23 , wherein the patient with chronic myeloid leukemia resistant to the current tyrosine kinase inhibitor therapies is caused by BCR-ABL complex mutation, wherein the BCR-ABL complex mutation is BCR-ABL E255V/T315I , BCR-ABL Y253H/E255V , BCR-ABL T315M , BCR-ABL Y253H/T315I , BCR-ABL Y253H/F359V , or BCR-ABL T315I/F317L , or one or more of the above-said types of mutations, and the tyrosine kinase inhibitor is Ponatinib. 
     
     
         28 . (canceled) 
     
     
         29 . The method of  claim 23 , wherein the method comprising orally administering to the patient a therapeutically effective amount of a compound of formula (I-A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         30 . The method of  claim 29 , wherein the compound of formula (I), or pharmaceutically acceptable salt thereof is administered every one, two, or three days during a treatment cycle, wherein said treatment cycle is 20-40 days, 25-35 days, or 28-day treatment cycle. 
     
     
         31 . The method of  claim 29 , wherein the therapeutically effective amount is from 0.5 mg to 100 mg, from 1 mg to 80 mg, or from 1 mg to 60 mg. 
     
     
         32 . The method of  claim 31 , wherein the therapeutically effective amount is about 1 mg, about 2 mg, about 4 mg, about 8 mg, about 12 mg, about 20 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, or about 60 mg. 
     
     
         33 . A pharmaceutical composition for inhibiting BCR-ABL mutants or for treating hematological malignancy, including chronic myelogenous leukemia, comprising the compound of formula (I) or formula (I-A) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R 1  is hydrogen, C 1-4  alkyl, C 3-6  cycloalkyl, C 1-4  alkyloxy, or phenyl; and R 2  is hydrogen, C 1-4  alkyl, C 3-6  cycloalkyl, or halogen. 
       
     
     
         34 .- 35 . (canceled) 
     
     
         36 . The method of  claim 16 , wherein the compound of formula (I-A), or pharmaceutically acceptable salt thereof is administered once every other day (QOD) during a 28-day treatment cycle in an amount at about 1 mg, about 2 mg, about 4 mg, about 8 mg, about 12 mg or about 20 mg. 
     
     
         37 . (canceled)