Compounds and compositions for treating egfr expressing tumors

Abstract

The present invention relates to compounds for targeted immunotherapy, as well as compositions comprising the same. Further, the present invention relates to the use of the compounds in the treatment of EGFR expressing tumors/cancers.

1 - 22 . (canceled) 
     
     
         23 . A method of treating cancer in a subject with an EGFR-expressing tumor, comprising administering to the subject, a compound having the structure of Formula (Ia):
   TM-L-AM  (Ia),
   wherein TM is an antibody or a functional fragment thereof that specifically binds to EGFR, L is a linker, and AM is an activating moiety that is represented by structure of formula (I):   
       
         
           
           
               
               
           
         
         wherein dashed line represents bond or absence of bond,   is the point to be connected to the linker; 
         X is S or —NR 1 , R 1  is —W 0 —W 1 —W 2 —W 3 —W 4 , 
         W 0  is a bond, alkyl, alkenyl, alkynyl, alkoxy, or -alkyl-S-alkyl-, 
         W 1  is a bond, —O—, or —NR 2 —, wherein R 2  is hydrogen, alkyl or alkenyl, 
         W 2  is a bond, —O—, —C(O)—, —C(S)—, or —S(O) 2 —, 
         W 3  is a bond, —NR 3 —, wherein R 3  is hydrogen, alkyl or alkenyl, 
         W 4  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aryloxy, heteroaryl, or heterocyclyl, each of which is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , nitro, -alkyl-hydroxyl, -alkyl-aryl, -alkyl-heteroaryl, -alkyl-heterocyclyl, —O—R 4 , —O-alkyl-R 4 , -alkyl-O—R 4 , —C(O)—R 4 , -alkyl-C(O)—R 4 , -alkyl-C(O)—O—R 4 , —C(O)—O—R 4 , —S—R 4 , —S(O) 2 —R 4 , —NH—S(O) 2 —R 4 , -alkyl-S—R 4 , -alkyl-S(O) 2 —R 4 , —NHR 4 , —NR 4 R 4 , —NH-alkyl-R 4 , halogen, —CN, —NO 2 , and —SH, wherein R 4  is independently hydrogen, alkyl, alkenyl, -alkyl-hydroxyl, aryl, heteroaryl, heterocyclyl, or haloalkyl; 
         Z is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, haloalkyl, heteroaryl, heterocyclyl, each of which can be optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, nitro, —N(R 5 ) 2 , -alkoxy-alkyl, -alkoxy-alkenyl, —C(O)-alkyl, —C(O)—O-alkyl, —O—C(O)— alkyl, —C(O)—N(R 5 ) 2 , aryl, heteroaryl, —CO-aryl, and —CO-heteroaryl, wherein each R 5  is independently hydrogen, alkyl, haloalkyl, -alkyl-aryl, or -alkyl-heteroaryl; 
         R is hydrogen, alkyl, alkoxy, haloalkyl, halogen, aryl, heteroaryl, heterocyclyl, each of which is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , nitro, -alkyl-hydroxyl, -alkyl-aryl, -alkyl-heteroaryl, -alkyl-heterocyclyl, —O—R 4 , —O-alkyl-R 4 , -alkyl-O—R 4 , —C(O)—R 4 , —C(O)—NH—R 4 , —C(O)—NR 4 R 4 , -alkyl-C(O)—R 4 , -alkyl-C(O)—O—R 4 , —C(O)—O—R 4 , —O—C(O)—R 4 , —S—R 4 , —C(O)—S—R 4 , —S—C(O)—R 4 , —S(O) 2 —R 4 , —NH—S(O) 2 —R 4 , -alkyl-S—R 4 , -alkyl-S(O) 2 —R 4 , —NHR 4 , —NR 4 R 4 , —NH-alkyl-R 4 , halogen, —CN, and —SH, wherein R 4  is independently hydrogen, alkyl, alkenyl, alkoxy, -alkyl-hydroxyl, aryl, heteroaryl, heterocyclyl, or haloalkyl; 
         n is 0, 1, 2, 3, or 4; 
         Y is —NR 6 R 7 , —CR 6 R 7 R 8 , or -alkyl-NH 2 , each of which can be optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, —NH 2 , halogen, —N(R 5 ) 2 , -alkoxy-alkyl, -alkoxy-alkenyl, —C(O)-alkyl, —C(O)—O-alkyl, —C(O)—N(R 5 ) 2 , aryl, heteroaryl, —CO-aryl, and —CO-heteroaryl, 
         wherein R 6 , R 7  and R 8  are independently hydrogen, alkyl, alkenyl, alkoxy, alkylamino, dialkylamino, alkylthio, arylthio, -alkyl-hydroxyl, -alkyl-C(O)—O—R 9 , -alkyl-C(O)—R 9 , or -alkyl-O—C(O)—R 9 , wherein each R 5  is independently hydrogen, alkyl, haloalkyl, -alkyl-aryl, or -alkyl-heteroaryl, wherein R 9  is hydrogen, alkyl, alkenyl, halogen, or haloalkyl; 
         X and Z taken together may optionally form a (5-9)-membered ring; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         24 . The method of  claim 23 , wherein AM is a compound of formula (I) selected from:
 2-propylthiazolo[4,5-c]quinolin-4-amine,   1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine,   4-amino-2-(ethoxymethyl)-aa-di-methyl-1H-imidazo[4,5-c]quinoline-1-ethanol,   1-(4-amino-2-ethylaminomethylimidazo-[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol,   N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl-]methanesulfonamide,   4-amino-2-ethoxymethyl-aa-dimethyl-6,7,8,9-tetrahydro-1 h-imidazo[4,5-c]quinoline-1-ethanol,   4-amino-aa-dimethyl-2-methoxyethyl-1 h-imidazo[4,5-c]quinoline-1-ethanol,   1-{2-[3-(benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,   1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,   1-{4-[(3,5-dichlorophenyl)sulfonyl]butyl}-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine,   N-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-n′-(3-cyanophenyl)thiourea,   N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropyl]benzamide,   2-butyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine,   N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-2-ethoxyacetamide,   1-[4-amino-2-ethoxymethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol,   1-[4-amino-2-(ethoxymethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol,   N-{3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}methanesulfonamide,   1-[4-amino-7-(5-hydroxymethylpyridin-3-yl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol,   3-[4-amino-2-(ethoxymethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol,   1-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-3-propylurea,   1-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-3-cyclopentylurea,   1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-7-(4-hydroxymethylphenyl)-1H-imidazo[4,5-c]quinolin-4-amine,   4-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N-methoxy-N-methylbenzamide,   2-ethoxymethyl-N1-isopropyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1,4-diamine,   1-[4-amino-2-ethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol, and   N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide, wherein the amine group on the quinoline ring is the point of connection with the linker.   
     
     
         25 . The method of  claim 23 , wherein L is represented by a structure of formula (II): 
       
         
           
           
               
               
           
         
         m is 1, 2, 3, 4, 5, or 6, each b independently is 0 or 1, and D is independently represented by a structure of formula (III): 
       
       
         
           
           
               
               
           
         
         wherein each i independently is 0 or 1; 
         each j independently is 0, 1, 2, 3, 4, 5, or 6; 
         each A independently is S, O, or N—Ra, wherein Ra is hydrogen, alkyl, alkenyl, or alkoxy; 
         each B independently is alkyl, alkenyl, —O-alkyl-, -alkyl-O—, —S-alkyl-, -alkyl-S—, aryl, heteroaryl, heterocyclyl, or peptide, each of which is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-aryl, -alkyl-heteroaryl, -alkyl-heterocyclyl, —O—R 4 , —O-alkyl-R 4 , —C(O)—R 4 , —C(O)—O—R 4 , —S—R 4 , —S(O) 2 —R 4 , —NHR 4 , —NH-alkyl-R 4 , halogen, —CN, —NO 2 , and —SH, wherein R 4  is alkyl, alkenyl, -alkyl-hydroxyl, aryl, heteroaryl, heterocyclyl, or haloalkyl. 
       
     
     
         26 . The method of  claim 25 , wherein the linker is represented by any one of the following structures of formula (V)-(VII): 
       
         
           
           
               
               
           
         
         wherein A, B, i and j are defined above. 
       
     
     
         27 . The method of  claim 26 , wherein the linker is selected from S1, S2, S3, S4, S5, S6, S7, -Gly-Phe-Leu-Gly-, -Ala-Leu-Ala-Leu-, -Phe-Arg-, -Phe-Lys-, -Val-Lys-, -Val-Ala-, and Val-Cit-, wherein S1-S7 are represented by the following structures: 
       
         
           
           
               
               
           
         
         wherein each m is independently 1 to 20. 
       
     
     
         28 . The method of  claim 23 , wherein the antibody is Cetuximab, Panitumumab, necitumumab, Matuzumab Nimotuzumab, Zalutumumab, RO5083945, MDX447, or MEHD7945. 
     
     
         29 . The method of  claim 27 , wherein AM is a compound of formula (I) selected from:
 2-propylthiazolo[4,5-c]quinolin-4-amine,   1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine,   4-amino-2-(ethoxymethyl)-aa-di-methyl-1H-imidazo[4,5-c]quinoline-1-ethanol,   1-(4-amino-2-ethylaminomethylimidazo-[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol,   N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl-]methanesulfonamide,   4-amino-2-ethoxymethyl-aa-dimethyl-6,7,8,9-tetrahydro-1 h-imidazo[4,5-c]quinoline-1-ethanol,   4-amino-aa-dimethyl-2-methoxyethyl-1 h-imidazo[4,5-c]quinoline-1-ethanol,   1-{2-[3-(benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,   1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,   1-{4-[(3,5-dichlorophenyl)sulfonyl]butyl}-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine,   N-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-n′-(3-cyanophenyl)thiourea,   N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropyl]benzamide,   2-butyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine,   N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-2-ethoxyacetamide,   1-[4-amino-2-ethoxymethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol,   1-[4-amino-2-(ethoxymethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol,   N-{3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}methanesulfonamide,   1-[4-amino-7-(5-hydroxymethylpyridin-3-yl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol,   3-[4-amino-2-(ethoxymethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol,   1-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-3-propylurea,   1-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-3-cyclopentylurea,   1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-7-(4-hydroxymethylphenyl)-1H-imidazo[4,5-c]quinolin-4-amine,   4-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N-methoxy-N-methylbenzamide,   2-ethoxymethyl-N1-isopropyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1,4-diamine,   1-[4-amino-2-ethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol, and   N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide, wherein the amine group on the quinoline ring is the point of connection with the linker.   
     
     
         30 . The method of  claim 29 , wherein the anti-EGFR antibody is Cetuximab, Panitumumab, necitumumab, Matuzumab Nimotuzumab, Zalutumumab, RO5083945, MDX447, or MEHD7945; and L is S1, S2 or S3. 
     
     
         31 . The method of  claim 30 , wherein the antibody is cetuximab; and AM is Resiquimod or Imiquimod. 
     
     
         32 . The compound of  claim 23 , wherein the compound has a structure of Formula A, B, or C: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         33 . The method of  claim 32 , wherein the antibody is Cetuximab, Panitumumab, necitumumab, Matuzumab Nimotuzumab, Zalutumumab, RO5083945, MDX447, or MEHD7945; and the compound of formula (I) is selected from:
 2-propylthiazolo[4,5-c]quinolin-4-amine,   1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine,   4-amino-2-(ethoxymethyl)-aa-di-methyl-1H-imidazo[4,5-c]quinoline-1-ethanol,   1-(4-amino-2-ethylaminomethylimidazo-[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol,   N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl-]methanesulfonamide,   4-amino-2-ethoxymethyl-aa-dimethyl-6,7,8,9-tetrahydro-1 h-imidazo[4,5-c]quinoline-1-ethanol,   4-amino-aa-dimethyl-2-methoxyethyl-1 h-imidazo[4,5-c]quinoline-1-ethanol,   1-{2-[3-(benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,   1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,   1-{4-[(3,5-dichlorophenyl)sulfonyl]butyl}-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine,   N-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-n′-(3-cyanophenyl)thiourea,   N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropyl]benzamide,   2-butyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine,   N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-2-ethoxyacetamide,   1-[4-amino-2-ethoxymethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol,   1-[4-amino-2-(ethoxymethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol,   N-{3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}methanesulfonamide,   1-[4-amino-7-(5-hydroxymethylpyridin-3-yl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol,   3-[4-amino-2-(ethoxymethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol,   1-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-3-propylurea,   1-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-3-cyclopentylurea,   1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-7-(4-hydroxymethylphenyl)-1H-imidazo[4,5-c]quinolin-4-amine,   4-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N-methoxy-N-methylbenzamide,   2-ethoxymethyl-N1-isopropyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1,4-diamine,   1-[4-amino-2-ethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol, and   N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide, wherein the amine group on the quinoline ring is the point of connection with the linker.   
     
     
         34 . The method of  claim 33 , wherein the compound of formula (I) is Resiquimod or Imiquimod, wherein the amine group on the quinoline ring is the point of connection with the linker. 
     
     
         35 . The method of  claim 23 , wherein the antibody is cetuximab. 
     
     
         36 . The method of  claim 23 , further comprising administering an effective amount of an additional therapeutic agent. 
     
     
         37 . The method of  claim 36 , wherein the additional therapeutic agent is an anticancer agent selected from an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor, an antiandrogen agent, a GNRh modulator, and mixtures thereof. 
     
     
         38 . The method of  claim 23 , wherein the cancer is selected from esophageal cancer, stomach cancer, colon cancer, rectal cancer, pancreatic cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, gynecologic cancer, cervical cancer, uterine cancer, cancer of the corpus uteri ovarian cancer, bladder cancer, head and neck cancer, squamous cell cancer of the head and neck, endometrial cancer, osteosarcoma, prostate cancer, neuroblastoma, renal cancer, glioma, glioblastoma multiforme, skin cancer, and epithelioid carcinoma.