NOVEL TRICYCLIC PROTEIN KINASE MODULATORS

1 . A compound having a structure of Formula I:

wherein:

A is a saturated or partially saturated optionally substituted 5, 6 or 7 membered ring;

represents a single bond or a double bond;

Z 1 and Z 2 are independently N or C when represents a single bond, provided Z 1 and Z 2 are not both N; and

Z 1 and Z 2 are C when represents a double bond;

L is a linker selected from a bond, NR 3 , O, S, CR 4 R 5 , CR 4 R 5 —NR 3 , CR 4 R 5 —O—, and CR 4 R 5 —S;

each R 1 , R 2 , R 3 , R 4 and R 5 is independently H, or an optionally substituted member selected from the group consisting of C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, and C6-C12 heteroarylalkyl group,

or halo, OR, NR 2 , NROR, NRNR 2 , SR, SOR, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRCONR 2 , NRCSNR 2 , NRC(═NR)NR 2 , NRCOOR, NRCOR, CN, COOR, CONR 2 , OOCR, COR, or NO 2 ,

wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl,

and wherein two R on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or more N, O or S;

and each R group, and each ring formed by linking two R groups together, is optionally substituted with one or more substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′ 2 , SR′, SO 2 R′, SO 2 NR′ 2 , NR′SO 2 R′, NR′CONR′ 2 , NR′CSNR′ 2 , NR′C(═NR′)NR′ 2 , NR′COOR′, NR′COR′, CN, COOR′, CONR′ 2 , OOCR′, COR′, and NO 2 ,

wherein each R′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and ═O;

 and wherein two R′ on the same atom or on adjacent atoms can be linked to form a 3-7 membered ring optionally containing up to three heteroatoms selected from N, O and S;

and R 1 can be ═O, or two R 1 groups on the same atom or on adjacent connected atoms, can optionally be linked together to form a 3-8 membered cycloalkyl or heterocycloalkyl, which is optionally substituted;

and R 4 and R 5 , when on the same atom or on adjacent connected atoms, can optionally be linked together to form a 3 to 8 membered cycloalkyl or heterocycloalkyl, which is optionally substituted;

W is alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl or heteroarylalkyl, each of which can be optionally substituted;

X is a polar substituent;

and each m is independently 0, 1, 2, or 3;

or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof.

2 . The compound of claim 1 , wherein L is NH or NMe.

3 . The compound of claim 1 , wherein W is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl.

4 . The compound of claim 1 , wherein Z 1 and Z 2 are C and represents a double bond.

5 . The compound of claim 1 , 2 or 3 , wherein Z 1 is N, Z 2 is C and represents a single bond.

6 . The compound of claim 1 , wherein Z 1 is C, Z 2 is N and represents a single bond.

7 . The compound of claim 1 , wherein W is optionally substituted phenyl, optionally substituted heterocyclyl, or C1-C4 alkyl substituted with at least one member selected from the group consisting of optionally substituted phenyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, halo, hydroxy and —NR″ 2 ,

where each R″ is independently H or optionally substituted C1-C6 alkyl;

and two R″ taken together with the N to which they are attached can be linked together to form an optionally substituted 3 to 8 membered ring, which can contain another heteroatom selected from N, O and S as a ring member, and can be saturated, unsaturated or aromatic.

8 . The compound of claim 7 , wherein L is NH or NMe.

9 . The compound of claim 7 , wherein W comprises at least one group of the formula —(CH 2 ) p —NR x 2 ,

where p is 1, 2, 3, or 4,

R x is independently at each occurrence H or optionally substituted alkyl;

and two R x taken together with the N to which they are attached can be linked together to form an optionally substituted 3 to 8 membered ring, which can contain another heteroatom selected from N, O and S as a ring member, and can be saturated, unsaturated or aromatic.

10 . The compound of claim 1 , wherein A is selected from the group consisting of:

wherein Z 3 is CR 1 2 , NR 1 , S(═O) p , or O;

n is 1, 2, or 3; and

p is 0, 1, or 2.

11 . The compound of claim 1 , wherein X is selected from the group consisting of COOR S , C(O)NR 9 —OR 9 , triazole, tetrazole, CN, imidazole, carboxylate, a carboxylate bioisostere,

wherein each R 9 is independently H or an optionally substituted member selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, and heteroarylalkyl,

and two R 9 on the same or adjacent atoms can optionally be linked together to form an optionally substituted ring that can also contain an additional heteroatom selected from N, O and S as a ring member;

R 10 is halo, CF 3 , CN, SR, OR, NR 2 , or R, where each R is independently H or optionally substituted C1-C6 alkyl, and two R on the same or adjacent atoms can optionally be linked together to form an optionally substituted ring that can also contain an additional heteroatom selected from N, O and S as a ring member;

and B is N or CR 10 .

12 . The compound of claim 11 , wherein the polar substituent X is located at position 3 on the phenyl ring.

13 . The compound of claim 11 , wherein the polar substituent X is located at position 4 on the phenyl ring.

14 . The compound of claim 1 , wherein -L-W is selected from:

wherein each R a is independently H, Cl or F;

each R b is independently Me, F, or Cl;

each R is independently selected from H, halo, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl,

and two R groups on the same or adjacent connected atoms can optionally be linked together to form a 3 to 8 membered ring;

each B is N or CR;

and each Solgroup is a solubility-enhancing group.

15 . The compound of claim 1 , having the Formula I-A, I-B, I-C, I-D or I-E:

or a pharmaceutically acceptable salt thereof.

16 . A compound having a structure of Formula II:

wherein:

A is a saturated or partially saturated optionally substituted 5, 6 or 7 membered ring;

represents a single bond or a double bond;

Z 1 and Z 2 are independently N or C when represents a single bond, provided Z 1 and Z 2 are not both N; and

Z 1 and Z 2 are C when represents a double bond;

each of R 1 and R 2 is independently H, or an optionally substituted member selected from the group consisting of C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, and C6-C12 heteroarylalkyl group,

or halo, OR, NR 2 , NROR, NRNR 2 , SR, SOR, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRCONR 2 , NRCSNR 2 , NRC(═NR)NR 2 , NRCOOR, NRCOR, CN, COOR, CONR 2 , OOCR, COR, or NO 2 ,

wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl,

and wherein two R on the same atom or on adjacent atoms can be linked to form a 3 to 8 membered ring, optionally containing one or more N, O or S;

and each R group, and each ring formed by linking two R groups together, is optionally substituted with one or more substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′ 2 , SR′, SO 2 R′, SO 2 NR′ 2 , NR′SO 2 R′, NR′CONR′ 2 , NR′CSNR′ 2 , NR′C(═NR′)NR′ 2 , NR′COOR′, NR′COR′, CN, COOR′, CONR′ 2 , OOCR′, COR′, and NO 2 ,

wherein each R′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and ═O;

 and wherein two R′ on the same atom or on adjacent atoms can be linked to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O and S;

and R 1 can be ═O, or two R 1 groups on the same atom or on adjacent connected atoms, can optionally be linked together to form a 3 to 8 membered cycloalkyl or heterocycloalkyl, which is optionally substituted;

W is alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl or heteroarylalkyl, each of which can be optionally substituted;

X is a polar substituent;

and each m is independently 0, 1, 2, or 3;

or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof.

17 . The compound of claim 16 , wherein W is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl.

18 . The compound of claim 16 , wherein Z 1 and Z 2 are C and represents a double bond.

19 . The compound of claim 16 , wherein Z 1 is N, Z 2 is C and represents a single bond.

20 . The compound of claim 16 , wherein Z 1 is C, Z 2 is N and represents a single bond.

21 . The compound of claim 16 , wherein W is optionally substituted phenyl, optionally substituted heterocyclyl, or C1-C4 alkyl substituted with at least one member selected from the group consisting of optionally substituted phenyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, halo, hydroxy and —NR″ 2 ,

where each R″ is independently H or optionally substituted C1-C6 alkyl;

and two R″ taken together with the N to which they are attached can be linked together to form an optionally substituted 3 to 8 membered ring, which can contain another heteroatom selected from N, O and S as a ring member, and can be saturated, unsaturated or aromatic.

22 . The compound of claim 21 , wherein W comprises at least one group of the formula —(CH 2 ) p —NR x 2 ,

where p is 1, 2, 3, or 4,

R x is independently at each occurrence H or optionally substituted alkyl;

and two R x taken together with the N to which they are attached can be linked together to form an optionally substituted 3 to 8 membered ring, which can contain another heteroatom selected from N, O and S as a ring member, and can be saturated, unsaturated or aromatic.

23 . The compound of claim 16 , wherein A is selected from the group consisting of:

wherein Z 3 is CR 1 2 , NR 1 , S(═O) p , or O;

n is 1, 2, or 3; and

p is 0, 1, or 2.

24 . The compound of claim 16 , wherein X is selected from the group consisting of COOR 9 , C(O)NR 9 —OR 9 , triazole, tetrazole, CN, imidazole, carboxylate, a carboxylate bioisostere,

wherein each R 9 is independently H or an optionally substituted member selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, and heteroarylalkyl,

and two R 9 on the same or adjacent atoms can optionally be linked together to form an optionally substituted ring that can also contain an additional heteroatom selected from N, O and S as a ring member;

R 10 is halo, CF 3 , CN, SR, OR, NR 2 , or R, where each R is independently H or optionally substituted C1-C6 alkyl, and two R on the same or adjacent atoms can optionally be linked together to form an optionally substituted ring that can also contain an additional heteroatom selected from N, O and S as a ring member;

and B is N or CR 10 .

25 . The compound of claim 24 , wherein the polar substituent X is located at position 3 on the phenyl ring.

26 . The compound of claim 24 , wherein the polar substituent X is located at position 4 on the phenyl ring.

27 . The compound of claim 1 , having the Formula II-A, II-B, II-C, II-D or II-E:

or a pharmaceutically acceptable salt thereof.

28 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof; and a pharmaceutically acceptable excipient.

29 . A method of inhibiting cell proliferation, which comprises contacting cells with a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof in an amount effective to inhibit proliferation of the cells.

30 . The method of claim 29 , wherein the cells are in a cancer cell line.

31 . The method of claim 29 , wherein the cells are in a tumor in a subject, or from an eye of a subject having macular degeneration, or in a subject having macular degeneration.

32 . A method of treating a condition related to aberrant cell proliferation, which comprises administering a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof, to a subject in need thereof in an amount effective to treat the cell proliferative condition.

33 . The method of claim 32 , wherein the cell proliferative condition is a tumor-associated cancer, a non-tumor cancer, or macular degeneration.

34 . The method of claim 33 , wherein the non-tumor cancer is a hematopoietic cancer.

35 . A method of treating a condition or disease associated with casein kinase 2 activity, Pim kinase activity, and/or Fms-like tyrosine kinase activity comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof, to a subject in need thereof in a therapeutically effective amount.

36 . The method of claim 35 , wherein the condition or disease is a cancer of colorectum, breast, lung, liver, pancreas, lymph node, colon, prostate, brain, head and neck, skin, liver, kidney, blood and heart.

37 . A method of treating pain or inflammation in a subject, which comprises administering a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof, to a subject in need thereof in an amount effective to treat the pain or the inflammation.

38 . A method of inhibiting angiogenesis in a subject, which comprises administering a compound claim 1 , or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof, to a subject in need thereof in an amount effective to inhibit the angiogenesis.

39 . A method of treating an infection in a subject, which comprises administering a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof to a subject in need thereof, in an amount effective to treat the infection.

40 . The method of claim 39 , wherein the infection is selected from Theileria parva, Trypanosoma cruzi, Leishmania donovani, Herpetomonas muscarum muscarum, Plasmodium falciparum, Trypanosoma brucei, Toxoplasma gondii and Schistosoma mansoni , human immunodeficiency virus type 1 (HIV-1), human papilloma virus, herpes simplex virus, human cytomegalovirus, hepatitis C and B viruses, Epstein-Barr virus, Borna disease virus, adenovirus, coxsackievirus, coronavirus, influenza, and varicella zoster virus.

41 . A method of modulating casein kinase 2 activity, Pim kinase activity, and/or Fms-like tyrosine kinase activity in a cell comprising contacting the cell with a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof.

42 - 43 . (canceled)