Kinase modulators for the treatment of cancer

Abstract

A method of treating cancer in which a compound that inhibits the expression, production or release of IL-10 by immune cells is combined with a compound that stimulates the production of IL-12 when given in combination with, or in the presence of TNFa. Said method is effective when provided in addition to standard therapies, notably chemotherapy using cytotoxic drugs and other forms of immune therapy including therapeutic vaccines.

1 . A method of treating cancer in a subject in need thereof, the method comprising administering one or more compounds to the subject to enhance IL-12 production or inhibit IL-10 production. 
     
     
         2 .- 6 . (canceled) 
     
     
         7 . The method of  claim 1  wherein the compound inhibiting IL-10 is represented by the following structure: 
       
         
           
           
               
               
           
         
         wherein x=0, 1, or 2; 
         R 1 =2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, 2-hydroxy-3-aminopropyl, 2-hydroxy-3-aminobutyl, 3,4-dihydroxybutyl, 2,3,4-trihydroxybutyl, —(CH 2 ) n —COR with R=OH, O-alkyl (C 1 -C 4 ), O-alkylaryl, NH 2 , NHMe, NHOH, and n=1, 2, 3, 4, 5; —CH 2 —P═O(OR) 2  with R=H, CH 3 , CH 2 CH 3 , —CH 2 —(CH 2 ) m —S(═O) n —R with R=alkyl (C 1 -C 5 ), OH, NH 2 , and m=1, 2, 3 and n=0, 1, 2; glycidyl, 3-methylglycidyl, —CH 2 —CHOH—COR with R=OH, OMe, OEt, NH 2 , NHOH; —CH(CH 2 OH)—COR with R=OH, OMe, OEt, NH 2 , NHOH, —CH 2 —CHOH—CN, —CH(CH 2 OH)—CN, methyl, phenyl, or benzyl; 
         R 2 =hydrogen, methyl, ethyl, n-propyl, isopropyl, sec-butyl, isobutyl, tert-butyl, 2-(3-methyl)butyl, cyclopropyl, cyclobutyl, cyclopentyl, 3-pentyl, cyclohexyl, morpholinyl, methylcyclohexyl, methylcyclopentyl, methylmorpholinyl, hydroxycyclohexyl, hydroxycyclopentyl, benzyl, 1-phenylethyl, tetrahydropyran-4-yl, (4-hydroxy)cyclohexyl, 1-(1 phenyl)propyl, 1-indanyl, 1-(1,2,3,4-tetrahydro)naphthyl, 1-(2-phenyl)propyl, 1-(1-methyl-3-phenyl)propyl, 1,2-diphenylethyl, 1,3-diphenyl-2-propyl, (4-tert-butyl)benzyl, 4-fluorobenzyl, 2-(2-para-xylyl)ethyl, (1-naphthyl)methyl, (2-thiophenyl)methyl, 2-(2-thiophenyl)ethyl, (2-benzo[b]thiophenyl)methyl, (2-furyl)methyl, [(5-methyl)furan-2-yl]-methyl, (2-pyridyl)methyl, (3-pyridyl)methyl, (4-pyridyl)methyl, —(C═O)—R 2 ′, R 2 ′=H, C1-C10 alkyl, hydroxyalkyl, aryl, heteroaryl, or arylalkyl, with alkyl chains being branched or linear; 1,5-dihydroxy-3-pentyl, 1,3-dihydroxy-2-propyl, 2,3-dihydroxy-1-propyl, 3-pentyl, 3-methoxy-1-propyl, 2-methylsulfonylethyl, 3-methyoxypropyl, or 2-diethylaminocarbonyl-1-ethyl; 
         R 3 =H, halogen, CF 3 , or; OCF 3 ; 
         R 4 =H, halogen, CF 3 , or OCF 3 ; 
         R 5 =H, halogen, or CF 3 ; or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The method of  claim 1  wherein the compound inhibiting IL-10 is represented by the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         x=0, 1, 2; 
         R 1 =methyl, —(CH 2 ) 2 —OCH 3 , 2-hydroxyethyl, 2,3-dihydroxypropyl, 1,3-dihydroxy-2-propyl, 1,5-dihydroxy-3-pentyl, cyclohexyl, trans-4-hydroxy-cyclohexyl, 3-hydroxypropyl, 4-tetrahydropyranyl, cyclopropyl, 4-hydroxyethyl, 3-oxo-3-pyrrolidin-1-yl-propyl, 3-pentyl, 2-ethoxycarbonyl-1-ethyl, 2-diethylaminocarbonyl-1-ethyl, 3-bromo-1-propyl, 2-methoxycarbonyl-1-ethyl, 3-oxo-3-piperidin-1-yl-propyl, 2-chloroethyl, 2-carboxy-1-ethyl, 3-oxo-3-morpholin-4-yl-propyl, 3-chloro-1-propyl, 3-carboxypropyl, diethylaminocarbonylmethyl, 4-chlorobutyl, 4-carboxybutyl, 2-oxo-2-morpholin-4-yl-ethyl, 3-fluoropropyl, 2-methylsulfonylethyl, or 3-iodopropyl; and 
         R 2 =phenyl, 1-phenylethyl, 1-cyclohexylethyl, cyclohexyl, (2 hydroxycyclohexyl)methyl, 4-tetrahydropyranyl, 2-hydroxycyclohexyl, (1-hydroxy)-2-propyl, or (2-hydroxy)-1-propyl; or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The method of  claim 1 , wherein the compound inhibiting IL-10 is represented by the following structure: 
       
         
           
           
               
               
           
         
       
       Wherein
 X=0, 1, or 2; 
 R 1 =—(NH)—(C═O)—R 1 ′, R 1 ′=H, C 1 -C 10  alkyl, hydroxyalkyl, aryl, heteroaryl, or arylalkyl; with alkyl chains being branched or linear —(NH)—R 1 ′; 
 R 1 ′=H, C 1 -C 10  alkyl, hydroxyalkyl, aryl, heteroaryl, or arylalkyl; with alkyl chains being branched or linear; or a pharmaceutically acceptable salt thereof. 
 
     
     
         10 . The method of  claim 1  wherein the compound enhancing production of IL-12 is represented by the following structure: 
       
         
           
           
               
               
           
         
       
       Wherein
 R 1 =hydrogen or acyl; 
 R 2 =hydrogen or alkyl; A=aryl or heteroaryl ring; B=aryl ring; 
 R 3 =selected from the group consisting of: 
 (a) amino, alkylamino or dialkylamino; 
 (b) acylamino; 
 (c) optionally substituted heterocyclyl; 
 (d) optionally substituted aryl or heteroaryl; 
 (e) heteroalkyl; 
 (f) heteroalkenyl; 
 (g) heteroalkynyl; 
 (h) heteroalkoxy; 
 (i) heteroalkylamino; 
 (j) optionally substituted heterocyclylalkyl; 
 (k) optionally substituted heterocyclylalkenyl; 
 (l) optionally substituted heterocyclylalkynyl; 
 (m) optionally substituted cycloalkoxy, cycloalkylalkyloxy, heterocyclylalkoxy, or heterocyclyloxy; 
 (n) optionally substituted heterocyclylalkylamino; 
 (o) optionally substituted heterocyclylalkylcarbonyl; 
 (p) heteroalkylcarbonyl; 
 (q) optionally substituted cycloalkylamino; 
 (r) —NHSO 2  R 6  where R 6  is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl; 
 (s) —NHSO2 NR 7  R 8  where R 7  and R 8  are, independently of each other, hydrogen, alkyl or heteroalkyl; 
 (t) —Y-(alkylene)-R 9  where: Y is a single bond, —O— —NH— or —S(O)n- (where n is an integer from 0 to 2); and R 9  is cyano, optionally substituted heteroaryl, —COOH, —COR 10 , —COOR 11 , —CONR 12  R 13 , —SO 2 —R 14 , —SO 2 —NR 15 R 16 , —NHSO 2 R 17  or NHSO 2 NR 18 R 19 , where R 10  is alkyl or optionally substituted heterocycle, R 11  is alkyl, and R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18  and R 19  are, independent of each other, hydrogen, alkyl or heteroalkyl; 
 (u) —C(NR 20 )(NR 21 R 22 ) where R 20 , R 21  and R 22  independently represent hydrogen, alkyl or hydroxy, or R 20  and R 21  together are —(CH 2 ) n — where n is 2 or 3 and R 22  is hydrogen or alkyl; 
 (v) —NHC(X)NR 23 R 24  where X is —O— or —S— and R 23  and R 24  are, independent of each other, hydrogen, alkyl or heteroalkyl; 
 (w) —CONR 25 R 26  where R 25  and R 26  independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R 25  and R 26  together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring; 
 (x) —S(O) n R 27  where n is an integer from 0 to 2, and R 27  is alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, or —NR 28  R 29  where R 28  and R 29  are, independent of each other, hydrogen, alkyl or heteroalkyl; 
 (y) cycloalkyl alkyl, cycloalkyl alkynyl and cycloalkyl alkynyl, all optionally substituted with alkyl, halo, hydroxy or amino; (z) arylamino alkylene or heteroaryl aminoalkylene; 
 (aa) Z-alkylene-NR 30 R 31  or Z-alkylene-OR 32  where Z is —NH—, —N(alkyl)- or —O—, and R 30 , R 31  and R 32  are independently of each other, hydrogen, alkyl or heteroalkyl; 
 (bb) —OC(O)-alkylene-CO 2  H or —OC(O)—NR′R″ (where R′ and R″ are independently hydrogen or alkyl); 
 (cc) heteroarylalkenylene or heteroarylalkynylene; 
 (dd) X-(alkylene)CH[(CR′R″)m OR 40 ][(CR′R″)n OR 40 ] where: X is —O—, —NH—, —NR— (where R is alkyl), —S(O) p — (where p is an integer from 0 to 2); R 40  is acyl, C(O)OR 41  (where R 41  is hydrogen, alkyl, or cycloalkyl); C(O)ONR 41  R 42  (where R 41  is as defined above and R 42  is hydrogen or alkyl); or C(O)NR 41  R 42  (where R 41  and R 42  are as defined above); R′ and R″, independently, are hydrogen or alkyl; and m and n, independently, are an integer from 0 to 3 provided that m and n are not both zero; 
 (ee) X-(alkylene)-CH(OH)CH 2  NHR 50  where: X is —O—, —NH—, —NR— (where R is alkyl), or —S(O) n — (where n is an integer from 0 to 2); and R 50  is C(O)OR 51  and C(O)NR 51 R 52  (where R 52  is hydrogen, alkyl, or cycloalkyl and R 52  is hydrogen or alkyl); and 
 (ff) X-(alkylene)-CH(NR50)-CH2 OH where: X is —O—, —NH—, —NR— (where R is alkyl), or —S(O) n — (where n is an integer from 0 to 2); and R 50  is C(O)OR 51  and C(O)NR 51  R 52  (where R 51  is hydrogen, alkyl, or cycloalkyl and R 52  is hydrogen or alkyl); 
 R 4  is selected from the group consisting of: 
 (a) hydrogen; (b) halo; (c) alkyl; (d) alkoxy; and (e) hydroxy; 
 R 5  is selected from the group consisting of: 
 (a) hydrogen; (b) halo; (c) alkyl; (d) haloalkyl; (e) thioalkyl; (f) hydroxy; (g) amino; (h) alkylamino; (i) dialkylamino; (j) heteroalkyl; (k) optionally substituted heterocycle; (l) optionally substituted heterocyclylalkyl; (m) optionally substituted heterocyclylalkoxy; (n) alkylsulfonyl; (o) aminosulfonyl, mono-alkylaminosulfonyl or dialkylaininosul fonyl; (p) heteroalkoxy; and (q) carboxy; and 
 R 6  is selected from a group consisting of: 
 (a) hydrogen; (b) halo; (c) alkyl; and (d) alkoxy; 
 or a pro-drug, individual isomer, mixture of isomers and pharmaceutically acceptable salt thereof. 
 
     
     
         11 . The method of  claim 1  wherein the compound enhancing production of IL-12 is represented by the following structure: 
       
         
           
           
               
               
           
         
         wherein:
 R is selected from: (a) alkyl optionally-substituted with one to three of R 17 ; (b) cycloalkyl optionally substituted with one, two or three groups selected from R 18 ; and (c) optionally-substituted aryl; 
 Q is selected from alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, and alkyl substituted with one, two or three of halogen, cyano, —OR 8 , —SR 8 , —C(═O)R 8 , —C(O)2R 8 , —C(═O)NR 8 R 9 , —S(O) p R 10 , —C(O) 2 NR 8 R 9 , —S(O) 2 NR 8 R 9 , —NR 8 R 9 , cycloalkyl, substituted cycloalkyl, heterocyclyl, and/or substituted heterocyclyl; 
 R 6  is hydrogen or lower alkyl; 
 R 7  is selected from hydrogen, alkyl, substituted alkyl, halogen, cyano, nitro, hydroxy, alkoxy, haloalkoxy, amino, alkylamino, and optionally-substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; 
 R 8  and R 9  are (i) independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; or (ii) when R 8  and R 9  are attached to the same nitrogen atom (as in —C(O) 2 NR 8 R 9 , —S(O) 2 NR 8 R 9 , and —NR 8 R 9 ), R 8  and R 9  may be taken together to form an optionally-substituted heterocyclyl ring; 
 R 10  is alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl; 
 R 17  is at each occurrence independently selected from halogen, haloalkoxy, haloalkyl, alkoxy, or optionally-substituted phenyl, benzyl, phenyloxy, benzyloxy, or cycloalkyl; and 
 R 18  is at each occurrence independently selected from alkyl, substituted alkyl, halogen, haloalkyl, haloalkoxy, cyano, alkoxy, acyl, alkoxycarbonyl, alkylsulfonyl, or optionally-substituted phenyl, phenyloxy, benzyloxy, cycloalkyl, heterocyclyl, or heteroaryl; and p is 1 or 2; 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         12 .- 13 . (canceled) 
     
     
         14 . The method of  claim 1  wherein the one or both of the inhibitors are covalently bound to a macrolide as represented in Formula 6: 
       
         
           
           
               
               
           
         
         Wherein 
         R 1 =H and R 2 =OH or O-cladinosyl or 
         R 1 , R 2 =(═O); 
         X=(C═O) or (C═N—OH) or —[N(CH 3 )—CH 2 ]— or —[CH 2 —N(CH 3 )]—; 
         R 3 , R 4 =H or binding site; 
         R 5 =R 6 —(NCH 3 ) or binding site; 
         R 6 =CH 3  or binding site; and 
         wherein a p38 kinase inhibitory moiety (such as a molecule as defined in formulas 1, 2, 3, 4, 5, 7, 8, or 9) is covalently bound to the moiety of Formula 6 at any binding site such that the macrolide, an optional spacer, and a functional complex in a linear arrangement are representing R 1 , R 2 , R 3 , R 4 , or R 5  in formula 1 or R 1  or R 2  in formula 2 or R 1  in formula 3 or R 1 , R 2 , R 3 , R 4 , R 5 , or R 6  in formula 4 or R, R 6 , R 7  or Q in formula 5 or R 1 , R 2 , R 3 , R 4 , or R 5  in formula 7 or R 1 , R 2 , R 3 , R 4 , or R 5  in formula 8 or R 1 , R 2 , R 3 , R 4 , or R 5  in formula 9; or a pharmaceutically acceptable salt thereof. 
       
     
     
         15 .- 22 . (canceled) 
     
     
         23 . The method of  claim 1  wherein the compound is represented by the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         x=CH 2 , O, S, S(═O), S(═O) 2 , 
         R 1 =2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, 2-hydroxy-3-aminopropyl, 2-hydroxy-3-aminobutyl, 3,4-dihydroxybutyl, 2,3,4-trihydroxybutyl, —(CH 2 ) n —COR with R=OH, O-alkyl (C 1 -C 4 ), O-alkylaryl, NH 2 , NHMe, NHOH, and n=1, 2, 3, 4, or 5; —CH 2 —P═O(OR) 2  with R=H, CH 3 , CH 2 CH 3 , —CH 2 —(CH 2 ) m —S(═O) n —R with R=alkyl (C 1 -C 5 ), OH, NH 2 , and m=1, 2, 3 and n=0, 1, or 2; glycidyl, 3-methylglycidyl, —CH 2 —CHOH—COR with R=OH, OMe, OEt, NH 2 , NHOH, —CH(CH 2 OH)—COR with R=OH, OMe, OEt, NH2, NHOH, —CH 2 —CHOH—CN, —CH(CH 2 OH)—CN, methyl, ethyl, 1-propyl, 2-propyl, phenyl, benzyl, R 2 =hydrogen, alkyl, aryl, or arylalkyl with 1-10 carbon atoms, or acyl with 1-11 carbon atoms, 
         R 3 =H, halogen, CH 3 , CF 3 , or OCF 3 ; 
         R 4 =H, halogen, CH 3 , CF 3 , or OCF 3 ; and 
         R 5 =H, halogen, or CF 3 ; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         24 . The method of  claim 23  wherein the compound inhibiting IL-10 is represented by the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         x=CH 2 , S, S(═O), S(═O) 2    
         R 1 =2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, 2-hydroxy-3-aminopropyl, 2-hydroxy-3-aminobutyl, 3,4-dihydroxybutyl, 2,3,4-trihydroxybutyl, glycidyl, 3-methylglycidyl, methyl, ethyl, 1-propyl, or 2-propyl; 
         R 2 =hydrogen, alkyl, aryl, or arylalkyl with 1-10 carbon atoms, or acyl with 1-11 carbon atoms, 
         R 3 =H, halogen, CH 3 , CF 3 , or OCF 3 ; 
         R 4 =H, halogen, CH 3 , CF 3 , or OCF 3 ; and 
         R 5 =H, halogen, or CF 3 ; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         25 . The method of  claim 24  wherein the compound inhibiting IL-10 is represented by the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         x=CH 2 ; 
         R 1 =methyl; 
         R 2 =benzoyl; 
         R 3 =CH 3 ; 
         R 4 =H; and 
         R 5 =H; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 . A pharmaceutical composition for treating cancer in a subject in need thereof, the pharmaceutical composition comprising one or more compounds to enhance IL-12 production or inhibit IL-10 production, together with a pharmaceutically acceptable carrier. 
     
     
         27 .- 31 . (canceled) 
     
     
         32 . The method of  claim 1 , wherein the cancer is selected from the group consisting of breast cancer, pancreas cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer of the larynx, gallbladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma, fibrosarcoma, multiple myeloma, reticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, hyperplastic corneal nerve tumor, marfanoid habitus tumor, Wilm's tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia and in situ carcinoma, neuroblastoma, glioblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosis fungoide, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic and other sarcoma, malignant hypercalcemia, renal cell tumor, polycythemia vera, adenocarcinoma, glioblastoma multiforma, leukemias, lymphomas, malignant melanomas, epidermoid carcinomas, and other carcinomas and sarcomas. 
     
     
         33 .- 37 . (canceled) 
     
     
         38 . A method of treating cancer, neoplasm, growth or tumour in a human in need of treatment, comprising the step of administering to the human the compound according to Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, or Formula 9, or a pharmaceutically acceptable salt thereof in a therapeutically effective dose to treat said cancer, neoplasm, growth or tumour. 
     
     
         39 . The method of  claim 38  wherein the compound is the compound with the generic name RO3201195, pamapimod, or TAK-715. 
     
     
         40 . The method of  claim 39  wherein the compound is the R isomer of RO3201195 
     
     
         41 .- 49 . (canceled) 
     
     
         50 . A method for enhancing a vaccination response in a patient in need of same using the compound of Formula 1, Formula 4, Formula 5, Formula 6, or Formula 7, or a pharmaceutically acceptable salt thereof. 
     
     
         51 .- 54 . (canceled) 
     
     
         55 . A compound disclosed herein for the treatment of cancer, or a pharmaceutically acceptable salt thereof. 
     
     
         56 . (canceled) 
     
     
         57 . (canceled) 
     
     
         58 . The compound of  claim 55  represented by any of the structures of Formula 10: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         59 . (canceled)