Dasatinib and another 5-thiazolecarboxamide kinase inhibitor, and uses thereof

Abstract

The invention relates to a kinase inhibitor, in particular an inhibitor of protein kinases including the protein-tyrosine kinases LCK, ABL, SRC, KIT, SIK-family and/or their mutants. Although structurally similar to dasatinib, the kinase inhibitor of the invention displays, eg functional and ADMET properties distinct to dasatinib. Also, the invention relates to pharmaceutical compositions that comprise the kinase inhibitor, including those formulated for oral administration, such as in unit dose form that comprise particular ranges or amounts of the kinase inhibitor. The kinase inhibitor or pharmaceutical composition may be used in the treatment of a proliferative disorder, such as a leukaemia or solid tumour. The kinase inhibitor or pharmaceutical composition may be used in a treatment regimen that corresponds to, is similar to or is distinct from that used with dasatinib for a corresponding disorder, and in particular may be used in a combination treatment regimen together with one or more additional therapeutic agents, such as immune-checkpoint inhibitors.

1 . A method for the treatment of a proliferative disorder in a subject, comprising:
 (X) administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition; and   (Y) further administrating to the subject an additional therapeutic agent being:
 (i) an immune checkpoint inhibitor being an inhibitor of PD1 or PDL1; or 
 (ii) chimeric antigen receptors T (CAR T) cells directed against a tumor antigen, 
   wherein, the compound is:   (B)   
       
         
           
           
               
               
           
         
         
           or the mono-hydrate thereof, and the pharmaceutical composition comprises said compound or the mono-hydrate thereof and optionally further comprises a pharmaceutically acceptable excipient, or 
         
         (A) 
       
       
         
           
           
               
               
           
         
         
           wherein:
 each of R 2  and R 3  is H; and 
 R 1  is: 
 
         
       
       
         
           
           
               
               
           
         
         
           and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, conformers, tautomers, isotopically labelled forms, prodrugs, and combinations thereof, and the pharmaceutical composition comprises said compound, solvate, salt, N-oxide, complex, polymorph, crystalline form, conformer, tautomer, isotopically labelled form, prodrug, and combinations thereof and optionally further comprises a pharmaceutically acceptable excipient. 
         
       
     
     
         2 . A compound or a pharmaceutical composition for use in a treatment of a proliferative disorder in a subject, the treatment comprising administering the compound or the pharmaceutical composition recited in (X) of  claim 1  to the subject to the subject,
 wherein, the treatment further comprises administration to the subject of the additional therapeutic agent recited in (Y) of  claim 1 . 
 
     
     
         3 . A compound or a pharmaceutical composition for use in a treatment of a proliferative disorder in a subject, the treatment comprising administering the additional therapeutic agent recited in (Y) of claim to the subject to the subject,
 wherein, the treatment further comprises administration to the subject the compound or the pharmaceutical composition recited in (X) of  claim 1 .   
     
     
         4 . The method of  claim 1 , or the compound or pharmaceutical composition for use of  claim 2  or  3 , wherein the additional therapeutic agent is an inhibitor of PD1. 
     
     
         5 . The method of  claim 1 , or the compound or pharmaceutical composition for use of  claim 2  or  3 , wherein the additional therapeutic agent is an antibody selected from the group consisting of: nivolumab, pembrolizumab, atezolizumab, avelumab and durvaluma. 
     
     
         6 . The method of  claim 1 , or the compound or pharmaceutical composition for use of  claim 2  or  3 , wherein the additional therapeutic agent is nivolumab. 
     
     
         7 . The method of  claim 1 , or the compound or pharmaceutical composition for use of  claim 2  or  3 , wherein the additional therapeutic agent is CAR T cells. 
     
     
         8 . The method of any one of  claims 1  and  4  to  7 , or compound or pharmaceutical composition for use of any one of  claims 2  to  7 , wherein the subject treated is an adult human; suitably the adult human is a young adult having an age between about 18 and 45, is a middle aged adult having an age between about 45 and 65, or is an elderly adult having an age between about 65 and 85. 
     
     
         9 . The method of any one of  claims 1  and  4  to  7 , or compound or pharmaceutical composition for use of any one of  claims 2  to  7 , wherein the subject treated is a paediatric human; suitably the paediatric human has an age between about 3 and 18, or is an infant between about two months of age to about 2 years of age. 
     
     
         10 . The method or the compound or pharmaceutical composition for use of  claim 8 , wherein the treatment comprises administering to the adult human subject an amount of the compound recited in (X) of  claim 1  of less than about 140 mg daily; suitably, wherein the proliferative disorder is not chronic phase Ph+ CML. 
     
     
         11 . The method or the compound or pharmaceutical composition for use of  claim 10 , wherein the treatment comprises administering to the adult human subject an amount of the compound recited in (X) of  claim 1  of less than about 100 mg daily; suitably, wherein the proliferative disorder is not chronic phase Ph+ CML. 
     
     
         12 . The method or the compound or pharmaceutical composition for use of  claim 9 , wherein the treatment comprises administering to the paediatric human subject in need thereof an amount of the compound of:
 less than about 40 mg daily for paediatric patients with a body weight of 10 kg to less than 20 kg;   less than about 60 mg daily for paediatric patients with a body weight of 20 kg to less than 30 kg;   less than about 70 mg daily for paediatric patients with a body weight of 30 kg to less than 45 kg; or   less than about 100 mg daily for paediatric patients with a body weight of at least 45 kg.   
     
     
         13 . The method or the compound or pharmaceutical composition for use of any one of  claims 10  to  12 , wherein the subject treated is administered the amount of the compound less frequently than once daily. 
     
     
         14 . The method of any one of  claims 1  and  4  to  13 , or compound or pharmaceutical composition for use of any one of  claims 2  to  13 , wherein, the treatment involves inhibiting one or more of the key-kinases listed in  FIG. 3 . 
     
     
         15 . The method or the compound or pharmaceutical composition for use of  claim 14 , wherein a key-kinase listed in  FIG. 3  is one having a residual activity of less than about 25%. 
     
     
         16 . The method or the compound or pharmaceutical composition for use of  claim 14  or  15 , wherein a key-kinase is selected from the list consisting of: ABL1, ABL2, ACK1, ACV-R1, ACV-R1B, ACV-R2A, ACV-R2B, ACV-RL1, BLK, BMX, B-RAF, BRK, BTK, CSF1-R, CSK, EGF-R, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, ERBB4, FGR, FRK, FYN, HCK, KIT, LCK, LYN, MAP4K5, NLK, p38-alpha, p38-beta, PDGFR-alpha, PDGFR-beta, RAF1, RIPK2, SIK1, SIK2, SIK3, SRC, SRMS, TEC, TGFB-R1, TXK, YES, ZAK and DDR2; suitably, wherein the key-kinase is DDR2 and/or SIK2. 
     
     
         17 . The method or the compound or pharmaceutical composition for use of any one of  claims 14  to  16 , wherein a key-kinase is DDR2. 
     
     
         18 . The method or the compound for use of any one of  claims 14  to  17 , wherein the treatment involves inhibiting DDR2. 
     
     
         19 . The method or the compound or pharmaceutical composition for use of any one of  claims 14  to  17 , wherein the treatment comprises inhibiting the key kinase and enhancing tumour response to anti-PD-1 immunotherapy. 
     
     
         20 . The method of any one of  claims 1  and  4  to  19 , or compound or pharmaceutical composition for use of any one of  claims 2  to  19 , wherein the proliferative disorder is a solid tumour; preferably wherein the solid tumour is selected from the group consisting of pancreatic cancer, breast cancer, lung, prostate, melanoma, ovarian cancer, oesophageal cancer, sarcomoa and colorectal cancer; and suitably is a lung tumour, in particular non-small cell lung cancer. 
     
     
         21 . The method or the compound or pharmaceutical composition for use of  claim 20 , wherein the proliferative disorder is lung cancer, in particular non-small cell lung cancer. 
     
     
         22 . The method or the compound or pharmaceutical composition for use of  claim 21 , wherein:
 the additional therapeutic agent is an inhibitor of PD1;   the subject treated is an adult human; and   the treatment comprises administering to the adult human subject an amount of the compound recited in (X) of  claim 1  of less than about 140 mg daily.   
     
     
         23 . The method or the compound or pharmaceutical composition for use of  claim 22 , wherein the compound or pharmaceutical composition is in unit dose form and comprising between 1 and 950 mg of the compound per unit does form. 
     
     
         24 . The method or the compound or pharmaceutical composition for use of  claim 23 , wherein the unit dose form is a tablet, caplet or capsule. 
     
     
         25 . The method or the compound or pharmaceutical composition for use of any one of  claims 22  to  24 , wherein the inhibitor of PD1 is nivolumab. 
     
     
         26 . The method of any one of  claims 1  and  4  to  25 , or compound or pharmaceutical composition for use of any one of  claims 2  to  25 , wherein the treatment involves sensitising cells involved with the proliferative disorder to a cell-mediated immune response. 
     
     
         27 . The method of any one of  claims 1  and  4  to  26 , or compound or pharmaceutical composition for use of any one of  claims 2  to  26 , wherein the treatment comprises that the cell-mediated immune response induces killing of cells involved with the proliferative disorder. 
     
     
         28 . The method of any one of  claims 1  and  4  to  27 , or compound or pharmaceutical composition for use of any one of  claims 2  to  27 , wherein the compound or pharmaceutical composition is administered to the subject to sensitise cells involved with the proliferative disorder to killing induced by TNF. 
     
     
         29 . The method or the compound or pharmaceutical composition for use of any one of  claims 26  to  28 , wherein cells involved with the proliferative disorder are exposed to TNF, a TNF variant and/or an agonist of TNFR1- or TNFR2-signalling. 
     
     
         30 . The method or the compound or pharmaceutical composition for use of any one of  claims 26  to  29 , wherein:
 (x) the subject is distinguished by having a plasma concentration of TNF greater than about 5 pg/mL; and/or 
 (y) the proliferative disorder is a solid tumour that, in the subject, by having an intratumoural concentration of TNF greater than about 1 pg/mL. 
 
     
     
         31 . The method of any one of  claims 1  and  4  to  30 , or compound or pharmaceutical composition for use of any one of  claims 2  to  30 , the treatment comprising exposing cells involved with the proliferative disorder in the subject to: (i) TNF, a TNF variant and/or an agonist of TNFR1- or TNFR2-signalling; and (ii) the compound or pharmaceutical composition recited in (X) of  claim 1 . 
     
     
         32 . The method or the compound or pharmaceutical composition for use of  claim 31 , wherein the amount of TNF exposed to cells involved with the proliferative disorder in the subject is increased. 
     
     
         33 . The method or the compound or pharmaceutical composition for use of  claim 31  or  32 , wherein: (i) TNF, a TNF variant or an agonist of TNFR1- or TNFR2-signalling is administered to the subject; (ii) an agent that is capable of inducing or induces the exposure of the cells involved with the proliferative disorder to TNF a TNF variant or an agonist of TNFR1- or TNFR2-signalling, is administered to the subject; or (iii) the exposure of the cells involved with the proliferative disorder to TNF is induced by a pharmaceutical, therapeutic or other procedure that increases the amount of TNF in the plasma of the subject and/or in the environment of such cells. 
     
     
         34 . The method of any one of  claims 1  and  4  to  33 , or compound or pharmaceutical composition for use of any one of  claims 2  to  33 , wherein the compound recited in in (X) of  claim 1  is in greater than about 98% or 99% pure form. 
     
     
         35 . The method of any one of  claims 1  and  4  to  34 , or compound or pharmaceutical composition for use of any one of  claims 2  to  34 , wherein the compound recited in in (X) of  claim 1  is as a hydrate. 
     
     
         36 . The method of any one of  claims 1  and  4  to  35 , or compound or pharmaceutical composition for use of any one of  claims 2  to  35 , wherein the compound or pharmaceutical composition is formulated for oral administration. 
     
     
         37 . The method or the compound or pharmaceutical composition for use of  claim 36 , wherein the compound or pharmaceutical composition is in unit dose form. 
     
     
         38 . The method or the compound or pharmaceutical composition for use of 37, wherein the compound or pharmaceutical composition is comprising between 1 and 950 mg of the compound per unit dose form. 
     
     
         39 . The method or the compound or pharmaceutical composition for use of 38, wherein the compound or pharmaceutical composition is comprising about an amount of the compound per unit dose form selected from the list of amounts consisting of: 2 mg, 5 mg, 15 mg, 20 mg, 50 mg, 70 mg, 80 mg, 100 mg and 140 mg. 
     
     
         40 . The method or the compound or pharmaceutical composition for use of any one of  claims 37  to  39 , wherein the unit dose form is a tablet, caplet or capsule. 
     
     
         41 . The method or the compound or pharmaceutical composition for use of any one of  claims 37  to  40 , wherein the unit dose form is a film-coated tablet or a film-coated caplet. 
     
     
         42 . The method or the compound or pharmaceutical composition for use of  claim 41 , wherein the film-coating comprises one or more, preferably all, of the excipients selected from the list consisting of: hypromellose, titanium dioxide and macrogol 400. 
     
     
         43 . The method of any one of  claims 1  and  4  to  42 , or compound or pharmaceutical composition for use of any one of  claims 2  to  42 , wherein the treatment involves inhibiting SIK3. 
     
     
         44 . The method of any one of  claims 1  and  4  to  43 , or compound or pharmaceutical composition for use of any one of  claims 2  to  43 , wherein the subject is an adult human. 
     
     
         45 . The method or the compound or pharmaceutical composition for use of  claim 44 , wherein the subject is an adult human over about 30 years of age, and wherein the treatment comprises administering to the adult human subject an amount of the compound recited in (X) of  claim 1  of less than about 140 mg daily. 
     
     
         46 . The method or the compound or pharmaceutical composition for use of  claim 45 , wherein the compound or pharmaceutical composition is in unit dose form and comprising between 1 and 950 mg of the compound per unit does form. 
     
     
         47 . The method or the compound or pharmaceutical composition for use of  claim 46 , wherein the unit dose form is a tablet, caplet or capsule. 
     
     
         48 . A compound or a pharmaceutical composition for use in a treatment of lung cancer in a subject, the treatment comprising administering the compound the pharmaceutical composition to the subject,
 wherein, the compound is as recited in (A) of  claim 1 , and the pharmaceutical composition comprises said compound and further comprises a pharmaceutically acceptable excipient; and   wherein, the treatment further comprises administration of a PD1 inhibitor to the subject.   
     
     
         49 . The compound or pharmaceutical composition for use of  claim 48 , wherein the treatment involves inhibiting DDR2 and/or involves inhibiting SIK3. 
     
     
         50 . The method of any one of  claims 1  and  4  to  45 , or compound or pharmaceutical composition for use of any one of  claims 2  to  49 , wherein the administrations are sequential.