Compounds and compositions for immunotherapy

1. A compound having the structure of Formula (Ib):

TM-L-AM  (Ib),

wherein TM is a targeting moiety that comprises an immunoglobulin that specifically binds to a tumor antigen on a tumor cell, wherein the tumor antigen is selected from the group consisting of CD2, CD19, CD20, CD22, CD37, CD38, CD44, CD47, CD52, CD56, CD79, 5T4, AGS-5, AGS-16, Angiopoietin 2, BT-062, BTLA, CAIX, Carcinoembryonic antigen, CTLA4, Cripto, ErbB1, ErbB2, ErbB3, ErbB4, EGFL7, EGFR, EpCAM, EphA2, EphA3, EphB2, FAP, Folate Receptor, Ganglioside GM3, GD2, gp100, gpA33, GPNMB, Her2, ICOS, IGF1R, KIR, LAG-3, Lewis Y, Mesothelin, c-MET, MN Carbonic anhydrase IX, MUC1, MUC16, Nectin-4, NOTCH, OX40, OX40L, PD-1, PD-L1, PSCA, PSMA, RANKL, ROR1, ROR2, SLC44A4, Syndecan-1, TACI, TAG-72, Tenascin, and TIM3;

L is a linker, -T a -W w -Y y -, wherein TM-T a is

wherein T forms a bond with a sulfur atom of the immunoglobulin, or T is linked to the immunoglobulin via a disulfide bond;

a is 0 or 1;

R 1 is —C 1 -C 10 alkylene-, —C 3 -C 8 carbocyclo-, —O—(C 1 -C 8 alkyl)-, -arylene-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-, —(CH 2 CH 2 O) r —, or —(CH 2 CH 2 O) r —CH 2 —;

each W is, independently, an amino acid;

w is an integer ranging from 2 to 12;

Y is 2-aminoimidazol-5-methanol, 4-aminobutyric acid amide, 2-aminophenylpropionic acid amide, a branched bis(hydroxymethyl)styrene (BHMS), -glycine-, -glycine-glycine-, or a p-aminobenzyl alcohol (PAB) group that is linked to -W w - via the nitrogen atom of the PAB unit, and connected directly to -AM via a carbonate, carbamate, or ether group;

y is 0, 1, or 2;

and AM is a radical of 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—R4, -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.

2. The compound of claim 1 , wherein W w is a dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, or decapeptide.

3. The compound of claim 1 , wherein X is —NR 1 , R 1 is alkyl, -alkyl-W 4 , -alkyl-O-W 4 , -alkyl-NH—C(O)-W 4 , -alkoxy-NH—C(O)-W 4 , -alkyl-NH—C(O)—NH-W 4 , -alkoxy-NH—C(O)—NH-W 4 , -alkyl-S(O) 2 -W 4 , or -alkyl-NH—C(S)-W 4 .

4. The compound of claim 1 , wherein X is S.

5. The compound of claim 1 , wherein Z is hydrogen, alkyl, alkoxy, aryl, heteroaryl, haloalkyl, each of which is optionally substituted by one to three substituents selected from the group consisting of hydroxyl, alkyl, aryl, heteroaryl, heterocyclyl, cyano, -alkoxy-alkyl, nitro, and —N(R 5 ) 2 , wherein each R 5 is independently hydrogen, alkyl, haloalkyl, -alkyl-aryl, or -alkyl-heteroaryl.

6. The compound of claim 1 , wherein n is 1 or 2, R is aryl or heteroaryl each of which is optionally substituted by one to three substituents selected from the group consisting of hydroxyl, alkoxy, -alkyl-hydroxyl, —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.

7. The compound of claim 1 , wherein Y is —NH 2 , -alkyl-NH 2 , each of which is optionally substituted by one to three substituents selected from the group consisting of alkyl, alkoxy, alkenyl, and alkynyl.

8. The compound of claim 1 , wherein AM is a compound selected from the group consisting of: 2-propylthiazolo[4,5-c]quinolin-4-amine, 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, 4-amino-2-(ethoxymethyl)-a,a-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-1h-imidazo[4,5-c]quinoline-1-ethanol, 4-amino-aa-dimethyl-2-methoxyethyl-1h-imidazo[4,5-c]quinoline-1-ethanol, 1-{2-[3-(benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine, N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-n′-butylurea, N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-amino-4-methylpentanamide, N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-n′-phenylurea, 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-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-n′-cyclohexylurea, 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, N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide, and N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-n′-cyclohexylurea.

9. The compound of claim 1 , wherein TM binds to a tumor cell specifically or preferably in comparison to a non-tumor cell.

10. The compound of claim 1 , wherein the immunoglobulin comprises an antibody or a functional fragment thereof.

11. The compound of claim 1 , wherein the immunoglobulin comprises Rituxan® (rituximab), Herceptin® (trastuzumab), Erbitux® (cetuximab), Vectibix® (Panitumumab), Arzerra® (Ofatumumab), Benlysta® (belimumab), Yervoy® (ipilimumab), Perjeta® (Pertuzumab), Tremelimumab, Nivolumab, Dacetuzumab, Urelumab, MPDL3280A, Lambrolizumab, Blinatumomab, a functional fragment thereof; or a mixture thereof.

12. A pharmaceutical composition comprising an effective amount of the compound according to claim 1 and one or more pharmaceutically acceptable carriers.

13. The pharmaceutical composition of claim 12 , further comprising an effective amount of an additional therapeutic agent.

14. The pharmaceutical composition of claim 13 , 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 a mixture thereof.

15. The compound of claim 8 , wherein the AM is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine.

16. The compound of claim 8 , wherein the AM is 4-amino-2-(ethoxymethyl)-a,a-di-methyl-1H-imidazo[4,5-c]quinoline-1-ethanol.

17. The compound of claim 8 , wherein the AM is 1-(4-amino-2-ethylaminomethylimidazo-[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol.

18. The compound of claim 1 , wherein the tumor antigen is PD-L1.

19. The compound of claim 1 , wherein the tumor antigen is CD20.

20. The compound of claim 1 , wherein the tumor antigen is Her2.

21. The compound of claim 1 , wherein the tumor antigen is EGFR.

22. The compound of claim 1 , wherein W w is

wherein R 2 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CH 2 SCH 3 , —CH 2 CONH 2 , —CH 2 COOH, —CH 2 CH 2 CONH 2 , —CH 2 CH 2 COOH, —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 3 NH 2 , —(CH 2 ) 3 NHCOCH 3 , —(CH 2 ) 3 NHCHO, —(CH 2 ) 4 NHC(═NH)NH 2 , —(CH 2 ) 4 NH 2 , —(CH 2 ) 4 NHCOCH 3 , —(CH 2 ) 4 NHCHO, —(CH 2 ) 3 NHCONH 2 , —(CH 2 ) 4 NHCONH 2 , —CH 2 CH 2 CH(OH)CH 2 NH 2 , 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, phenyl, cyclohexyl,

23. The compound of claim 1 , wherein W w is

wherein

R 3 is benzyl, methyl, isopropyl, isobutyl, sec-butyl, or

 and

R 4 is (CH 2 ) 4 NH 2 , (CH 2 ) 3 NHCONH 2 , methyl, or (CH 2 ) 3 NHC(═NH)NH 2 .

24. The compound of claim 1 , wherein W w is

wherein

R 3 is benzyl and R 4 is (CH 2 ) 4 NH 2 ,

R 3 is methyl and R 4 is (CH 2 ) 4 NH 2 ,

R 3 is isopropyl and R 4 is (CH 2 ) 4 NH 2 ,

R 3 is isopropyl and R 4 is (CH 2 ) 3 NHCONH 2 ,

R 3 is benzyl and R 4 is (CH 2 ) 3 NHCONH 2 ,

R 3 is isobutyl and R 4 is (CH 2 ) 3 NHCONH 2 ,

R 3 is sec-butyl and R 4 is (CH 2 ) 3 NHCONH 2 ,

R 4 is (CH 2 ) 3 NHCONH 2 and R 3 is

R 3 is benzyl and R 4 is methyl, or

R 3 is benzyl and R 4 is (CH 2 ) 3 NHC(═NH)NH 2 .

25. The compound of claim 1 , wherein

Y y is

m is 0; and

W w is

wherein

R 3 is benzyl and R 4 is (CH 2 ) 4 NH 2 ,

R 3 is methyl and R 4 is (CH 2 ) 4 NH 2 ,

R 3 is isopropyl and R 4 is (CH 2 ) 4 NH 2 ,

R 3 is isopropyl and R 4 is (CH 2 ) 3 NHCONH 2 ,

R 3 is benzyl and R 4 is (CH 2 ) 3 NHCONH 2 ,

R 3 is isobutyl and R 4 is (CH 2 ) 3 NHCONH 2 ,

R 3 is sec-butyl and R 4 is (CH 2 ) 3 NHCONH 2 ,

R 4 is (CH 2 ) 3 NHCONH 2 and R 3 is

R 3 is benzyl and R 4 is methyl, or

R 3 is benzyl and R 4 is (CH 2 ) 3 NHC(═NH)NH 2 .

26. The compound of claim 1 , wherein TM-T a is

27. The compound of claim 1 , wherein TM-T a is

28. The compound of claim 1 , wherein TM-T a is

29. The compound of claim 1 , wherein Y y is

Q is —C 1 -C 8 alkyl, —C 1 -C 8 alkoxy, halogen, nitro, or cyano;

m is an integer ranging from 0 to 4.

30. The compound of claim 1 , wherein -T a -W w -Y y - is

31. The compound of claim 1 , wherein R 1 is —(CH 2 ) 5 —.

32. The compound of claim 1 , wherein R 1 is —(CH 2 CH 2 O) r —CH 2 —, and r is 2.

33. The compound of claim 1 , wherein AM is a radical of

34. The compound of claim 1 , wherein AM is a radical of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine.

35. The compound of claim 8 , wherein AM is a radical of 4-amino-2-(ethoxymethyl)-a,a-di-methyl-1H-imidazo[4,5-c]quinoline-1-ethanol.

36. The compound of claim 8 , wherein AM is a radical of 1-(4-amino-2-ethylaminomethylimidazo-[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol.

37. The compound of claim 1 , wherein AM is a radical of

38. The compound of claim 1 , wherein the activating moiety is capable of activating a dendritic cell, a macrophage, a monocyte, a myeloid-derived suppressor cell, an NK cell, a B cell, a T cell, a tumor cell, or a combination thereof.