MX2008007740A - Dibenzonaphthyridine derivatives and methods of use thereof - Google Patents

Abstract

The present invention relates to Dibenzonaphthyridine Derivatives , compositions comprising an ef fective amount of a Dibenzonaphthyridine Derivative and methods for treating or preventing a proliferative disorder, comprising administering to a subj ect in need thereof an ef f ective amount of a Dibenzonaphthyridine Derivative of formula ( I ):or a pharmaceutically acceptable salt thereof, wherein R1is -H, -OH, -O-C1,-C6alkyl, -halo, -C2-C6alkenyl, -C2-C6alkynyl, -N(RI8)2, -NH-OR18or-C(0)N(Rl8)2;R2is -H, -0-C1-C6alkyl, -halo, -C2-C6alkenyl, -C2-C6alkynyl, -NHR17. -N(RI7)2, -NH-OR18or -C(O)N(RI8)2, such that when R1is -OH or -0-C1-C6alkyl, R2is hydrogen;R3, R4, R5, R6, R7, R8. R9and R10are each independently -H, -halo, -OH, -SH, -N(RI2)2, -NHOR12, -CN, -NO2, -CF3, -OCF3, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6 alkynyl, -C3-C8cycloalkyl, -C3-C8cycloalkenyl, -phenyl, -benzyl, -(CH2)n-O-C1-C6alkyl, -0-C2-C6alkenyl, -0-C2-C6alkynyl, -O-phenyl, -S-phenyl, -NH-C1-C6alkyl, -(CH2)n-C(O)-R11, -(CH2)n-O)-R11, -(CH2)n-NHC(O)-R11, -S-C1-C6alkyl, -S(O)-C1-C6alkyl, -SO2-C1-C6alkyl, -SO2NH-C1-C6alkyl, -SO2NH-C2-C6alkenyl, -SO2NH-C2-C6alkynyl, -Y-(CH2)K-M- CH(R14)R15, -Y-(CH2)g-R16, -Y-(CH2)k-M-(CH2)p-R16, -Y-(CH2)k-(W)a-(CH2)q-Z, -Y-(CH2)P- (Z)_-(CH2)q-Z, or such that R3, R4, R5, R6, R7, R8, R9and R10are not simultaneously hydrogen.

Description

DERIVATIVES OF DIBENZONAFTIRIDINA AND METHODS FOR ITS USE This application claims the priority of U.S. Provisional Application No. 60 / 857,411, filed on November 7, 2006, and of U.S. Provisional Application No. 60 / 750,145, filed on December 13, 2005, whose description of each one is incorporated here as a reference in its entirety.

FIELD OF THE INVENTION The present invention relates to Dibenzonaphthyridine derivatives, compositions comprising an effective amount of a Dibenzonaphthyridine derivative and methods for treating or preventing a proliferative disorder, comprising administering to a subject in need thereof an effective amount of a Dibenzonaphthyridine derivative.

BACKGROUND OF THE INVENTION Cancer is only the second leading cause of death cardiovascular disease in the United States. The American Cancer Society estimates that in 2004, there were 1.6 million new cases and 655,000 cancer-related deaths. There are currently more than ten million living Americans who have been diagnosed with cancer and the NIH estimates the direct medical cost of cancer at more than $ 100,000,000 per year with an additional $ 100,000,000 in indirect costs due to the loss of cancer. productivity - the highest cost of any major disease.

Cancer is a process by which the control of the mechanisms that regulate cell growth and differentiation is deteriorated, resulting in a failure in the control of cell growth and change. This lack of control causes a tumor to grow progressively, enlarge and occupy space in vital areas of the body. If the tumor invades the surrounding tissue and is transported to distant sites, it can result in the death of the individual.

Selective killing of cancer cells, while minimizing detrimental effects, in normal cells, is a desired goal in cancer therapy.

The modalities commonly used in the treatment of cancer include chemotherapy, radiation therapy, surgery and biological therapy (a broad category that includes treatments based on genes, proteins or cells and immunotherapy). Despite the availability of a variety of anticancer agents, traditional chemotherapy has disadvantages. Many anticancer agents are toxic, and chemotherapy can cause significant, and often dangerous, side effects, including severe nausea, bone marrow depression, liver, heart and kidney damage, and immunosuppression. Additionally, many tumor cells eventually develop resistance to multiple drugs after being exposed to one or more anticancer agents. As such, single agent chemotherapy is effective only for a very limited number of cancers. Many chemotherapeutic drugs are antiproliferative agents, which act in different stages of the cell cycle. Because it is difficult to predict the sensitivity pattern of a neoplastic cell population for anticancer drugs, or the current stage of the cell cycle that happens to a cell, it is common to use multidrug regimens in the treatment of cancer.

Despite significant efforts in research and resources that have been directed toward the development of new anticancer agents and improved methods for treating cancer, there remains a need in the art for novel compounds, compositions, and methods that are useful for treating cancer with indices. improved therapeutic BRIEF DESCRIPTION OF THE INVENTION In one aspect the invention provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, where R1 is -H, -OH, -O-alkyl d-C6, -halo, -C2-C6 alkenyl, alkynyl -C2-C6, -N (R18) 2, -NH-OR18 or-C (O) N (R18) 2; R2 is-H, -O- dC6 alkyl, -halo, -C2-C6 alkenyl, -C2-C6 alkynyl, -NHR17, -N (R17) 2, -NH-OR18 or -C (O) N ( R18) 2, such that when R1 is -OH or -O-C6 alkyl, R2 is hydrogen; R3, R4, R5, R6, R7, R8, R9 and R10 are each independently -H, -halo, -OH, -SH, -N (R12) 2, -NHOR12, -CN, -NO2, -CF3, -OCF3, -alkyl C? -C6, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -phenyl, -benzyl, - (CH2) nO-C? -C6 alkyl, - O C 2 -C 6 alkenyl, C 2 -C 6 -O-alkynyl, -O-phenyl, -S-phenyl, -NH-C 6 alkyl, - (CH 2) n -C (O) -R 11, - (CH 2) n-OC (O) -R11, - (CH2) n-NHC (O) -R11, -S-alkyl d-C6, -S (O) -alkyl d-C6, - SO2-alkyl d-C6, - SO2NH-C6 alkyl, -SO2NH-C2-C6 alkenyl, -SO2NH-C2-C6 alkynyl, -Y- (CH2) kM-CH (R14) R15, -Y- (CH2) g-R16, -Y- ( CH2) kM- (CH2) pR16, -Y- (CH2) k- (W) a- (CH2) qZ, -Y- (CH2) p- (Z) a- (CH2) qZ, or such that R3, R4, R5, R6, R7, R8, R9 and R10 are not simultaneously hydrogen; R11 is-H, -alkyl d-C6, C2-C6 alkenyl, C2-C6 alkynyl, -phenyl, -O-alkyl d-C6, -O-alkenyl C2-C6, -O-alkynyl C2-C6, -O phenyl, -S-phenyl, -S-C-C6 alkyl or -N (R12) 2; each occurrence of R12 is independently -H, -alkyl d-C6, C2-C6 alkenyl, C2-C6 alkynyl, -phenyl or -benzyl; each occurrence of G is independently -O-, -S-, - (CH2) -, ~~ N, or -N (R13) -; M is -O-, -N (R13) -, -N ((C (R13) 2) PN (R13) 2) - or -N ((C (R13) 2) p-OR13) - W is -O- or -N (R13) -, Y is -O-, -S-, - (CH2) a- or -N (R?, Z is a 3-7 membered non-aromatic monocyclic heterocycle, a 5- or 6-membered aromatic monocyclic heterocycle, or an 8- or 12-membered bicyclic heterocycle, wherein a 3-7 membered non-aromatic monocyclic heterocycle may or may not be substituted independently replacing one carbon of the ring or nitrogen atom of the ring with one or more of -R13, -N (R13) 2, -OH, -OR13, - (C (R13) 2) sOR13 or - (C (R13) 2) SN (R13) 2, each occurrence of R13 is independently -H, -alkyl C? -C6, -CH2-alkenyl or C2-C6, -CH2-alk? n C2-C6, cycloalkyl C3-C8, cycloalkenyl C3-C8, -phenyl , -C (O) -alkyl d-C6 or -C (O) -O-alkyl d-C6, such that when R13 is -phenyl, the phenyl group can be substituted or not independently substituted with one or more than -OH, -CN, -NO2, -CF3, -alkyl C C6, -NH (Alkyl D-C3), -N (Alkyl C1-C3) 2, - (CH2) a-halo, - (CH2) aO-alkyl C C6, - (CH2) aOC (O) Alkyl C C6, -S-alkyl d-C6, -C (O) OH, -C (O) O-alk? d-C6, -S-phenyl, -O-phenol, -phenyl, -benzyl, -NH- (CH2) a-phenol or -NHC (O) Alqu? lo C C6, R14 is -H, - (C (R13) 2) rN (R3) 2 or - (C (R13) 2) rOR13, R > 115b e? "S-? H_l, R16 is -H, -halo, -N (R13) 2, -OR13, -N (R13) 3 + or -N (R13) -OR13, each occurrence of R17 is independently -C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -phenyl or benzyl, each occurrence of R18 is independently -H, -C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -phenyl or benzyl, a is 0 or 1, g is an integer in the range of 1 to 6; k is an integer in the range of 1 to 4; n is an integer in the range of 0 to 6; p is an integer in the range of 1 to 4; q is an integer in the range of 0 to 4; r is an integer in the range of 1 to 4; s is an integer in the range of 1 to 6; Y each occurrence of t is independently an integer in the range of 1 to 3.

The compounds of Formula (I) or a pharmaceutically acceptable salt thereof (a "Dibenzonaphthyridine Derivative") are useful for treating or preventing a proliferative disorder.

The invention provides methods for treating or preventing a proliferative disorder, comprising administering to a subject in need of such treatment or prevention an effective amount of a Dibenzonaphthyridine derivative.

The invention further provides compositions comprising an effective amount of a Dibenzonaphthyridine derivative and a physiologically acceptable carrier or vehicle.

The details of the invention are set forth in the description that follows. All references cited in this specification are incorporated herein by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION Definitions and Abbreviations The following definitions are used in connection with derivatives of Dibenzonaphttinine "C? -C6 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1-6 carbon atoms Representative d6-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl and neohexyl In one embodiment, the group Alkyl d-C6 is substituted with one or more of the following groups -halo, -O- (Alqu? lo d-C6), -OH, -CN, -COOR ', -OC (O) R', -N (R ') 2, -NHC (O) R 'or -C (O) NHR' wherein each R 'is independently -H or -alkyl d-C6 unsubstituted Unless otherwise indicated, the group Alkyl d-C6 is not substituted "C2-C6 alkenyl" refers to a straight or branched chain saturated hydrocarbon containing 2-6 carbon atoms and at least one double bond Representative C2-C6 alkenyl groups include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene and isohexene. In one embodiment, the alkenyl group C2-C6 is substituted with one or more of the following groups -halo, -O- (Alqu? Lo d-C6), -OH, -CN, -COOR ', -OC (O) R', -N ( R ') 2, -NHC (O) R' or -C (O) NHR 'wherein each R' is independently -H or-unsubstituted C? -C6 alkyl Unless otherwise indicated, the C2-C6 alkenyl group it is not replaced "Alkyl C2-C6" refers to a straight or branched chain unsaturated hydrocarbon containing 2-6 carbon atoms and at least one triple bond Representative alkynyl groups include, but are not limited to, acetylene, propyne, 1- butyne, 2-butyl, isobutyne, sec-butyne, 1-pentene, 2-pentene, isopentine, 1-hexano, 2 -hexine, 3-hexanoy and isohexine In one embodiment, the C2-C6 alkenyl group is substituted with one or more of the following groups -halo, -O- (Alqu? lo d-C6), -OH, -CN, -COOR ', -OC (O) R', - N (R ') 2, -NHC (O) R' or -C (O) NHR 'wherein each R' is independently -H or -alkyl d-C6 unsubstituted Unless otherwise indicated, the group C2-C6 alkenyl is not replaced "Halo" refers to -F, -Cl, -Br or -I A "monocyclic C3-C8 cycloalkyl" is a saturated non-aromatic hydrocarbon ring containing 3-8 carbon atoms. Monocyclic C3-C8 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In one embodiment, the monocyclic C3-C8 cycloalkyl group is substituted with one or more of the following groups -alkyl d-C6, -halo, -O- (Alkyl C C6), -OH, -CN, - COOR ', -OC (O) R', -N (R ') 2, -NHC (O) R' or -C (O) NHR 'wherein each R' is independently -H or -alkyl d-C6 not replaced Unless otherwise indicated, the monocyclic C3-C8 cycloalkyl group is not replaced A "monocyclic C3-C8 cycloalkenyl" is a non-aromatic hydrocarbon ring containing 3-8 carbon atoms and having at least one endocyclic double bond. Representative C3-C8 cycloalkenyl monocyclic groups include, but are not limited to, cyclopropenyl , cyclobuteral, 1,3-c? clobutad? en, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,3-c? clohexadiene, cycloheptenyl, 1,3-c? cloheptad? , 1, 4-c? Cloheptad? In? 1,?, 3,5-c? Cloheptatr? In? Lo, cyclooctenyl, 1,3-c? Clooctad? In? 1, 4-cyclooctadienyl, -1 , 3,5-c? Clooctatr? En? In one embodiment, the monocyclic C3-C8 cycloalkenyl group is substituted with one or more of the following groups -alkyl d-C6, -halo, -O- (Alkyl) groups ? d-C6), -OH, -CN, -COOR ', -OC (O) R', -N (R ') 2, -NHC (O) R' or -C (O) NHR 'wherein each R 'is independently -H or - unsubstituted d6C6 alkyl Unless indicated, the monocyclic C3-C8 cycloalkenyl group is not substituted The term "3- to 7-membered non-aromatic monocyclic heterocycle" refers to (1) a 3- or 4-membered non-aromatic monocyclic cycloalkyl wherein one of the ring carbon atoms has been replaced with an N, O or S, or (2) a non-aromatic monocyclic cycloalkyl of 5, 6 or 7 members in which 1 to 3 of the ring carbon atoms have been independently replaced with an N, O or S atom. In one embodiment, an carbon of a 3 to 7 membered heterocycle is replaced with a carbonyl group A non-aromatic monocyclic 3 to 7 membered heterocycle can be attached via a ring nitrogen or ring carbon atom Representative examples of a non-aromatic monocyclic heterocyclic group of 3 to 7 members include, but are not limited to azepanyl, aziridinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl,? / - methylpiperazinyl, piperidinyl,? / - methylpiperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinonyl, pyrrolidinyl,? / - methylpyrrolidinyl,? / - benzylpyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl and trityanil. In one embodiment, the 3- to 7-membered non-aromatic monocyclic heterocycle group is independently substituted on one or more ring nitrogens or ring carbon atoms with one or more of the following groups: -R13, -N (R13) 2, -OH, -OR13, - (C (R13) 2) sOR13 or - (C (R13) 2) SN (R13) 2, wherein R13 and s are as defined above for the compounds of Formula (I). In another embodiment, the non-aromatic monocyclic 3 to 7 membered heterocyclic group is not substituted.

The term "5- or 6-membered aromatic monocyclic heterocycle" refers to a 5- or 6-membered aromatic monocyclic cycloalkyl in which 1 to 4 of the ring carbon atoms have been replaced with a N, O or S atom. The 5- or 6-membered aromatic monocyclic heterocycle is attached via a ring carbon atom. Representative examples of a 5- or 6-membered aromatic monocyclic heterocycle group include, but are not limited to furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrimidinyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrrolyl, thiazolyl, thiadiazolyl, thiophenyl, triazinyl, and triazolyl. In one embodiment, the 5- or 6-membered aromatic monocyclic heterocycle group is independently substituted with one or more of the following groups: -R13, -N (R13) 2, -OH, -OR13, - (C (R13) 2) sOR13 or - (C (R13) 2) SN (R13) 2, wherein R13 and s are as defined above for the compounds of Formula (I). Unless indicated, the 5- or 6-membered aromatic monocyclic heterocycle group is not substituted.

The term "8 to 12 membered bicyclic heterocycle" refers to an aromatic or non-aromatic bicyclic cycloalkyl of 8 to 12 members in which one or both rings of the bicyclic ring system have 1-4 of their ring carbon atoms. they independently replace with an N, O or S atom. Included in this class are the 3- to 7-membered monocyclic heterocycles that bind to a benzene ring. A non-aromatic ring of an 8 to 12 membered monocyclic heterocycle is attached via a ring nitrogen or a ring carbon atom. An aromatic 8 to 12 membered monocyclic heterocycle is attached via a ring carbon atom. Examples of bicyclic heterocycle from 8 to 12 members include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazole, benzthiazole, benztpazole, benztetrazole, benzisoxazole, benzisothiazole, benzimidazolenyl, cinolmyl, decahydroquinolinyl, 1H-βdazolyl, indolenyl, indolyl. , indohzinyl, indole, isobenzofuranyl, isoindazole, isoindolyl, isoindolinyl, isoquinolyl, naphthipdinyl, octahydroisoquinolyl, phthalazinyl, ptepdinyl, punnyl, quinoxahnyl, tetrahydroisoquinolyl, tetrahydroquinolyl, and xanthenyl In one embodiment, each ring of the 8 to 12 membered bicyclic heterocycle group is can be substituted with one or more of the following groups -R13, -N (R13) 2, -OH, -OR13, - (C (R13) 2) sOR13 or - (C (R13) 2) SN (R13) 2, wherein R13 and s are as defined above for the compounds of Formula (I) Unless otherwise indicated, the 8 to 12 membered bicyclic heterocycle group is not substituted A "subject" is a mammal, for example, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon. In a modality, the monkey is a rhesus monkey In one modality, a subject is a human The phrase "pharmaceutically acceptable salt," as used herein, is a salt that is formed from an acid and a basic nitrogen group of one of the Dibenzonaphttinine derivatives. Illustrative salts include, but are not limited to, sulfate salts, citrate , acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, sahcylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succmate, maleate, gentisinate, fumarate, gluconate , glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, besylate, mesylate, camphorsulfonate, and pamoate (i.e. 1,1 '-met? leno-b? s- (2-OH -3-naphthoate)) The term "pharmaceutically acceptable salt" also refers to a salt prepared from a Dibenzonaphthipine derivative having an acidic functional group, and a pharmaceutically acceptable organic or inorganic base. Suitable bases include, but are not limited to, alkali metal hydroxides such as sodium, potassium, and lithium, hydroxides of alkaline earth metals such as calcium and magnesium, hydroxides of other metals, such as aluminum and zinc, ammonia, and organic amines, such as hydroxy substituted or unsubstituted mono-, di-, or tp -alkylamines, dicyclohexyl amine, t-butyl amine, pindine, N-methyl, N-ethylamine, diethylamine, tetylamine, mono-, bis-, or tr? s- (2-OH-lower alkylamines), such as mono-, bis-, or tr? s- (2- h? drox? et? l) am? na, tps- (hydrox? met?) met? lam? na, or 2-hydroxy? -terc-but? lam? na, or N, Nd? -alqu? lo? nfer? or-N- (hydroxy? alkyl? nfer? or) -am? nas, such as N, Nd? met? lN- (2-h? drox? et? l) am? na or tr? - (2-hydroxy et? l) amine, N-methyl-D-glucamine, and amino acids such as arginine, hsin, and the like A hydrate is another example of a pharmaceutically acceptable salt An "effective amount" when used in connection with a derivative of Dibenzonaftipdine is an amount effective to treat or prevent a pro-inflammatory disorder.

An "effective amount" when used in connection with another anticancer agent is an amount that is effective to treat or prevent cancer alone or in combination with a derivative of Dibenzonaphttinine.

"In combination with" includes administration within the same composition and within separate compositions In the above case, the anticancer agent is administered for a time when the derivative Dibenzonaphthipine exerts its therapeutic or prophylactic effect, or vice versa Some chemical structures are described here using dotted and bold lines to represent chemical bonds. These dotted and bold lines describe the absolute stereochemistry. Illustrative examples of the Derivatives of Dibenzonaftipdine are described here using both chemical structures and chemical names The following abbreviations are used herein and have the indicated definitions BOC is tert-butyl carbamate, BSA is bovine serum albumin, DIBAL is diisobutylaluminum hydride, DME is dimethoxyethane, DMF is? /,? / - d? Met? Lformamide, DMSO is dimethyl sulfoxide, Et is ethyl, EtOAc is ethyl acetate, EtOH is ethanol, HPLC is high performance liquid chromatography, Me is methyl, MS is mass spectrometry, NMP is? / - met? Lp? Rrol? Dona, NMR it is nuclear magnetic resonance, PBS is buffered saline with phosphate (pH 7 4), and Ph is phenyl 4. 2 The Dibenzonaphthyridine Derivatives of the Formula (I) The present invention provides Dibenzonaphthyridine derivatives according to Formula (I), below: (I) and pharmaceutically acceptable salts thereof, where R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as defined above for the compounds of Formula (I).

In one embodiment, R1 is -NH2.

In another embodiment, R 1 is -NH (C 6 C alkyl).

In another modality, R is -H In one embodiment, R1 is -NH2 and R2 is -H.

In another embodiment, R1 is -NH (Alkyl d-C6) and R2 is -H.

In a specific embodiment, R1 is -NHCH3.

In another specific embodiment, R1 is -NHEt. In another specific embodiment, R1 is -OH and R2 is -H. In one embodiment, R1 is -O-alkyl d-C6. In a specific embodiment, R1 is -OCH3. In another embodiment, R3 is -C6-C6 alkyl. In a specific embodiment, R3 is -CH3. In another modality, R3 is -H. In yet another specific modality, R3 is -halo. In a specific modality, R3 is -Cl. In yet another specific embodiment, R3 is -O-alkyl d-C6.

In yet another specific embodiment, R3 is -OCH3. In one embodiment, R4 is -H. In a specific embodiment, R4 is -NH2. In another specific embodiment, R 4 is -phthalimid-1-yl. In one embodiment, R8 is -O-C6 alkyl. In a specific embodiment, R8 is -OCH3. In one embodiment, R 9 is -O-C 1 -C 6 alkyl.

In another embodiment, R9 is -OCH3 or -OEt In another modality, R9 is -halo In a specific modality, R9 is -F In one embodiment, at least one of R3, R4, R5, R6, R7, R8, R9 and R10 is -Y-CH2-Z-CH2-Z, wherein Z is non-aromatic monocyclic 3 to 7 membered heterocyclic substituted or unsubstituted, a 5- or 6-membered aromatic monocyclic heterocycle, or a 8- or 12-membered bicyclic heterocycle In one embodiment, at least one of R3, R4, R5, R6, R7, R8, R9 and R10 is ,, R 11 - > wherein R1, R2, G, k, p and t are as defined above for the compounds of Formula (I) 0 In one embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 do not they are simultaneously hydrogen In another embodiment, R9 is -OCH2- (monocyclic non-aromatic heterocyclic of 3 to 7 members), -O (CH2) 2- (non-aromatic monocyclic heterocyclic of 3 to 7 members), -O (CH2) 2 (C3-C8 cycloalkyl), or -O (CH2) 3- (non-aromatic monocyclic heterocyclic 3-7 membered) In another embodiment, R9 is -NHCH2- (non-aromatic monocyclic heterocyclic 3-7-30 members), -NH (CH2) 2- (non-aromatic monocyclic heterocyclic 3-7 membered) or -NH (CH2) 3- (non-aromatic monocyclic heterocyclic 3-7 membered) In another embodiment, R9 is -N (CH3) CH2- (non-aromatic monocyclic heterocyclic 3-7 membered), -N (CH3) (CH2) 2- (monocyclic non-aromatic heterocyclic 3-7 membered) or -N (CH3) (CH2) 3- (non-aromatic monocyclic heterocyclic 3-7 membered) In one modality, R °, R °, R 'and R1u are each -H In another mode, R2, R5, R6, R7 and R10 are each -H In another embodiment, R, R, R, R 'and R1u are each -H and R3 is -alkyl d-C6 In yet another specific embodiment, R2, R5, R6, R7 and R10 are each -H and R3 is -CH3 In one embodiment, R2, R5, R6, R7 and R10 are each -H, R3 is -alkyl C C6, and R4 is -NH2 In a specific embodiment, R2, R5, R6, R7 and R10 are each -H, R3 is -CH3, and R4 is-NH2 In one embodiment, R ', Rs, Rb, R' and R1U each -H, R is -alkyl d-C6, R * is -NH2, and R8 is -O-C6alkyl In a specific embodiment, R, R, R °, R 'and R1U are each -H, RJ is -CH3, R4 is -NH2, and R8 is -OCH3 Illustrative examples of the Dibenzonaphttinine derivatives of Formula (I) include the compounds set forth below and pharmaceutically acceptable salts thereof.

In one embodiment, the compounds of Formula (I) have Formula (la): (the) wherein R3, R4, R5, R6, R7, R8, R9 and R10 are as defined above for the compounds of Formula (I).

In another embodiment, for the compounds of Formula (la), R3 is -alkyl dC6.

In a specific embodiment, for the compounds of Formula (la), R3 is -CH3.

In another embodiment, for the compounds of Formula (la), R3 is -H.

In still another specific embodiment, for the compounds of Formula (Ia), R3 is -halo.

In a specific embodiment, for the compounds of Formula (la), R3 is -Cl.

In yet another specific embodiment, for the compounds of Formula (la), R3 is -O-alkyl d-C6.

In yet another specific embodiment, for the compounds of Formula (la), R3 is -OCH3.

In one embodiment, for the compounds of Formula (la), R 4 is -H.

In a specific embodiment, for the compounds of Formula (la), R 4 is -NH 2.

In another specific embodiment, for the compounds of Formula (la), R 4 is -phthalimid-1-ylo.

In another embodiment, for the compounds of Formula (la), R 4 is -OH.

In yet another specific embodiment, for the compounds of Formula (la), R 4 is -O-C C 6 alkyl.

In a specific embodiment, for the compounds of Formula (la), R 4 is -OCH 3.

In one embodiment, for the compounds of Formula (la), R8 is -O-Ci-Cß alkyl.

In a specific embodiment, for the compounds of Formula (la), R8 is -OCH3.

In one embodiment, for the compounds of Formula (la), R 9 is -O-C 6 -C 6 alkyl In another embodiment, for the compounds of Formula (la), R9 is -OCH3 or -OEt.

In another embodiment, for the compounds of Formula (la), R9 is -halo.

In a specific embodiment, for the compounds of Formula (la), R9 is -F.

In another embodiment, for the compounds of Formula (Ia), R9 is -OCH2- (3- to 7-membered monocyclic non-aromatic heterocycle), -O (CH2) 2- (3- to 7-membered monocyclic non-aromatic heterocycle), -O (CH2) 2 (C3-C8 cycloalkyl), or -O (CH2) 3- (monocyclic non-aromatic heterocycle of 3 to 7 members).

In another embodiment, for compounds of Formula (Ia), R9 is -NHCH2- (3- to 7-membered monocyclic non-aromatic heterocycle), -NH (CH2) 2- (non-aromatic monocyclic heterocyclic 3-7 membered) or -NH (CH2) 3- (3 to 7 membered monocyclic non-aromatic heterocycle).

In another embodiment, for the compounds of Formula (Ia), R9 is -N (CH3) CH2- (3- to 7-membered monocyclic non-aromatic heterocycle), -N (CH3) (CH2) 2- (monocyclic non-aromatic heterocycle) 3 to 7 members) or -N (CH 3) (CH 2) 3- (3 to 7 membered monocyclic non-aromatic heterocycle).

In one embodiment, for the compounds of Formula (la), R5, R6, R7 and R10 are each -H.

In another embodiment, for the compounds of Formula (Ia), R5, R6, R7 and R10 are each -H.

In another embodiment, for compounds of Formula (Ia), R5, R6, R7 and R10 are each -H and R3 is -alkyl d-C6.

In still another specific embodiment, for the compounds of Formula (Ia), R5, R6, R7 and R10 are each -H and R3 is -CH3.

In one embodiment, for compounds of Formula (Ia), R5, R6, R7 and R0 are each -H, R3 is -alkyl d-C6, and R4 is -NH2 In a specific embodiment, for the compounds of Formula (Ia), R5, R6, R7 and R10 are each -H, R3 is -CH3, and R4 is -NH2 In one embodiment, for the compounds of Formula (Ia), R5, R6, R7 and R10 each -H, R3 is -alkyl C C6, R4 is -NH2, and R8 is -O-alk? Lo C? -C6 In a specific embodiment, for the compounds of Formula (la), R5, R6, R7 and R10 is each -H, R3 is -CH3, R4 is -NH2, and R8 is -OCH3 In one embodiment, for the compounds of Formula (Ia), R5, R6, R7 and R10 each -H, R3 is-C6 alkyl, R4 is -OH, and R8 is -O-alkyl d-C6 In another embodiment, for the compounds of Formula (Ia), R5, R6, R7 and R0 each -H, R3 is-C6 alkyl, R4 is -OCH3, and R8 is -O-alkyl d-C6 In still another specific embodiment, for the compounds of Formula (Ia), R5, R6, R7 and R10 each -H, R3 is -alkyl d-C6, R4 is -NH2, R8 is -O-alk? Lo d- C6 and R9 is -O-alkyl d-C6 In another embodiment, the compounds of Formula (I) have the Formula (Ib) (Ib) wherein R3, R4, R8 and R9 are as defined above for the compounds of Formula (I).

Further illustrative examples of the Dibenzonaphthyridine derivatives of the Formula (I) include the compounds of the Formula (Ib) as set forth below: and pharmaceutically acceptable salts of these An additional illustrative Dibenzonaftipdine Derivative of Formula (Ib) is the compound set forth below lb-53 and pharmaceutically acceptable salts of this In another embodiment, the compounds of Formula (I) have the Formula (le) wherein R3, R4, R8, R9 and R17 are as defined above for the compounds of Formula (I). a further illustrative example of a Dibenzonaphthyridine derivative of Formula (I) is the compound of Formula (le) as set forth below: lc-1 and pharmaceutically acceptable salts thereof.

Illustrative derivatives of Dibenzonaphthyridine can also be described using the chemical nomenclature, as stated below: and pharmaceutically acceptable salts or hydrates thereof Another illustrative compound of Formula (I) is I-4, Which can alternatively be described as 2,3-dimethoxydibenzo [c, r] -2,7-naphthine. 4. 3 Methods for making Dibenzonaphthyridine Derivatives Examples of synthetic routes that are useful for making Dibenzonaphthyridine Derivatives are set forth in the examples below and are generalized in Schemes 1-4.

Scheme 1 illustrates a useful method for making the Dibenzonaphthyridine Derivatives of Formula (I) wherein R 1 is -NH 2, R 2 is -H, and P 3, R 4, R 5, R 6, R 7, R 8, R 9 and R 10 are as defined above for the compounds of Formula (I). Scheme 1 Derivatives of Dibenzonaphthyridine of the Formula (I), wherein R 1 is -NH 2 and R 2 is -H wherein R3, R4, R5, R6, R7, R8, R9 and R10 are as defined above for the compounds of Formula (I), R1 is -NH2 and R2 is -H. A corresponds to method A, which is described below, and B corresponds to method B, which is also described below.

An aniline compound of Formula 1 can be reacted with ethyl- (ethoxymethylene) -cyanoacetate to provide a nitrile compound of Formula 2. A compound of Formula 2 can then undergo thermal cyclization to provide a substituted quinolinone compound of the Formula 3. The compound of Formula 3 can then be chlorinated, for example using phosphorus oxychloride or oxalyl chloride, with or without heat, to provide a chloro compound of Formula 4, which can be further reacted with an aniline compound of Formula 5 with heating not under microwave conditions (method A) or using microwave radiation (method B), in a high boiling solvent such as ethoxyethanol, or the like, to provide the compounds of Formula (I) wherein R 1 is -NH 2 and R 2 is -H. the solvents and reagents, which include the starting and intermediate materials, used in all schemes are intended to be illustrative.

In one embodiment, the invention provides methods for synthesizing the compounds of Formula I, which include heating the high-boiling solvent chemical reagents, optionally by applying microwave radiation.

In a method B method, the reactions are carried out using microwave radiation with an energy of less than 500 Watts and pressure of less than 40 psi. In another embodiment, the reactions are carried out using microwave radiation with an energy of less than 300 Watts and a pressure of less than 20 psi.

In one embodiment, high-boiling solvents are used in the synthesis of the compounds of Formula (I). The intermediates can be dissolved or suspended in such solvents. The solvents can have a boiling point, at standard temperature and pressure, of 100 ° C or higher, for example up to 200 ° C or 300 ° C, such as nitrobenzene, ortho dichlorobenzene, diphenyl ether, polyethylene glycol, or etioxyethanol.

In one embodiment, method A and method B additionally include the use of a proton catalyst, such as pyridine hydrochloride, para-toluenesulfonic acid, PPTS, a combination of these, or similar Scheme 2 illustrates useful methods for making the compounds of Formula (I), wherein one or more of R3, R4, R5, R6, R7, R8, R9 and R10 is -OH, -OY or -NHY, wherein And is-C6-alkyl, C2-C6 alkenyl, C2-C6 alkynyl or -phenyl Scheme 2 wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8 and R 10 are as defined above for the compounds of Formula (I), and Y is -C 6 alkyl, C 2 -C 6 alkenyl, C 2 alkyl -C6 or -phenyl A fluoro substituted compound of Formula 6 can be reacted with (i) NaOH in DMSO to provide the corresponding hydroxy substituted compounds of Formula 7, (n) a compound of Formula YOH in the presence of a suitable base, such as NaH, to provide the corresponding alkoxy-substituted compounds of Formula 8; or (m) a compound of Formula NH2Y under microwave conditions in NMP to provide the corresponding amino substituted compounds of Formula 9 although the methods described in Scheme 2 specifically illustrates the chemical transformations for the R9 group of the Dibenzonaphthyridine derivatives, it should be understood that the methods described in Scheme 2 are general methods that are useful for making the Dibenzonaphthyridine Derivatives of the Formula (I) wherein one or more than any of the groups R3, R4, R5, R6, R7, R8, R9 and R10 can be substituted with a group -OH, -OY or -NHY, wherein Y is -alkyl d-C6, C2-C6 alkenyl , C2-C6 alkynyl or -phenyl.

In addition, a compound of Formula 6 can be reacted: (i) with a compound of the formula NaSH in the presence of base to provide Dibenzonaphthyridine derivatives of Formula (I) wherein one or more of any of the groups R3, R4, R5, R6, R7, R8, R9 and R10 are substituted with a -SH group, or (ii) with a compound of the formula HSY in the presence of a base to provide Dibenzonaphthyridine derivatives of the Formula ( I) wherein one or more of any of the groups R3, R4, R5, R6, R7, R8, R9 and R10 is substituted with a -SY group, wherein Y is -alkyl d-C6, C2-C6alkenyl, C2-C6 alkynyl or -phenyl.

Scheme 3 illustrates a useful method for making the Dibenzonaphthyridine Derivatives of Formula (I) wherein R 1 is -NH 2, R 2 is -H, and R 3, R 4, R 5, R 6, R 7, R 8, R 9 and R 0 are as was defined above for the compounds of Formula (I).

Scheme 3 The derivatives of Formula (I) wherein R is -NH2 and R2 is -H. wherein R3, R4, R5, R6, R7, R8, R9 and R10 are as defined above for the compounds of Formula (I).

A nitrile compound of Formula 4 can be crosslinked with a phenyl boronic acid compound of Formula 10 using Suzuki coupling conditions as described, for example, in Miyaura er al., Chem. Rev., 95: 2457 (1995), to provide the Dibenzonaphthyridine Derivatives of Formula (I) wherein R 1 is -NH 2, R 2 is -H, and R 3, R 4, R 5, R 6, R 7, R 8, R 9 and R 10 are as defined above for the compounds of Formula (I). Alternatively, the cesium salts may be used in place of sodium carbonate, such as cesium carbonate or cesium fluoride.

Scheme 4 illustrates a useful method for making a Dibenzonaphthyridine derivative of Formula (I), wherein one or more of R3, R4, R5, R6, R7, R8, R9 and R10 is -halo, -CN, -SO2Cl, -CH3, vinyl, or -C (O) -Y, and Y is -C6-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or -phenyl. Scheme 4 Derivatives of dibenzonaftipyridine of Formula (I), wherein G 'is -halo, -CN, -S jCl, -CH3 > vinyl, or -C (0) -Y wherein R1, R2, R3, R5, R6, R7, R8, R9 and R10 are as defined above for the compounds of Formula (I), G 'is -halo, -CN, -SO2CI, -CH3, vinyl , or -C (O) -Y, and Y is C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or -phenyl.

A substituted amino compound of Formula 11 (which can be prepared using the methods described in Scheme 1) can be diazotized using, for example, NaNO2 to provide a diazo intermediate of Formula 12. See March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, Fourth Edition, John Wiley and Sons, p. 635-637 (1992). The diazonium salt of Formula 12 can then be placed with numerous functional groups as described in March, p. 723-725, to provide a Dibenzonaphthyridine derivative of the Formula (I) wherein one or more of the groups R3, R4, R5, R6, R7, R8, R9 and R10 are substituted with -halo, -CN, -SO2CI , -methyl, -vinyl, or -C (O) (Alkyl C? -C6). Although the methods described in Scheme 2 specifically illustrate chemical transformations for the R4 group of the Dibenzonaphthyridine derivatives, it should be understood that the methods described in Scheme 4 are general methods which are useful for making the Dibenzonaphthyridine derivatives of the Formula (I) wherein one or more of R3, R4, R5, R6, R7, R8, R9 and R10 is -halo, -CN, -SO2CI, -CH3, vinyl, or -C (O) -Y, and Y is -C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or -phenyl.

Compounds that can be made using the methods provided above in Schemes 1-4 can be derived using methods known to one skilled in the art of organic synthesis in order to provide the entire scope of the Dibenzonaphthyridine derivatives of the Formula (I ). 4. 4 Methods for using Dibenzonaphthyridine Derivatives According to the invention, the Dibenzonaphthyridine derivatives are administered to a subject in need of treatment or prevention of a proliferative disorder. 4. 4.1 Methods to treat or prevent a proliferative disorder A proliferative disorder can be treated or prevented by administering an effective amount of a Dibenzonaphthyridine derivative.

Prophylactic disorders that can be treated or prevented by administering an effective amount of a Dibenzonaftipdine derivative include, but are not limited to, cancer, uterine fibroids, benign prostatic hyperplasia, familial adenomatous pohposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis. , sopasis, glomerulonephritis, restenosis followed by angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplant rejection, endotoxic shock, a fungal infection, a condition associated with defective apoptosis, or a prophylactic disease that depends on the PDK-1 activity In one modality, the pro-inflammatory disorder is cancer In another modality, the prophylactic disorder is a prophylactic disorder that depends on PDK-1 activity 4. 4.2 Methods to treat or prevent cancer Dibenzonaftipdine Derivatives can be used to treat or prevent cancer The invention provides methods for treating or preventing cancer, which comprises administering to a subject in need of such treatment or prevention an effective amount of a Dibenzonaphthipine derivative.

Examples of treatable or preventable cancers using the Derivatives of Dibenzonaftipdine include, but are not limited to, a cancer expressing PDK-1, the cancers described later in Table 1, and metastasis thereof.

TABLE 1 Solid tumors, include but are not limited to fibrosarcoma mixosarcoma liposarcoma chondrosarcoma osteogenic sarcoma chordoma angiosarcoma endotheliosarcoma limfangiosarcoma limfangioendoteliosarcoma sinovioma mesothelioma tumor Swing leiomyosarcoma rhabdomyosarcoma colon cancer colorectal cancer kidney cancer pancreatic cancer bone cancer breast cancer ovarian cancer prostate cancer esophagus cancer stomach cancer oral cancer nasal cancer throat cancer squamous cell carcinoma basal cell carcinoma adenocarcinoma sweat gland carcinoma sebaceous gland carcinoma papillary carcinoma papillary adenocarcinomas cystadenocarcinoma medullary carcinoma bronchogenic carcinoma renal cell carcinoma hepatoma bile duct carcinoma choriocarcinoma semimoma embryonal carcinoma Wilms tumor cervical cancer uterine cancer testicular cancer small cell carcinoma of the lung bladder carcinoma lung cancer epithelial carcinoma skin cancer melanoma neuroblastoma retinoblastoma Bone marrow cancers, include but are not limited to: acute lymphoblastic leukemia ("ALL") acute B-cell lymphoblastic leukemia acute T-cell lymphoblastic leukemia acute myeloblastic leukemia ("AML") acute promyelocytic leukemia ("APL") acute monoblastic leukemia acute erythroleukemic leukemia acute megakaryoblastic leukemia acute myelomonocytic leukemia leukemia no acute lymphocytic acute undifferentiated leukemia Chronic myelocytic leukemia ("CML") chronic lymphocytic leukemia ("CLL") tpcoleukemia multiple myeloma Lymphomas Hodgkm's disease Non-Hodgkm lymphoma Multiple myeloma Macroglobuhnemia Waldenstrom Heavy chain disease Pohcythemia vera cancers of the brain and the CNS ghoma pilocytic astrocytoma astrocytoma anaplastic astrocytoma ghoblastoma multiforme medulloblastoma craniofapngioma ependymoma pinealoma hemangioblastoma acoustic neuroma oligodendroglioma meningioma vestibular schwannoma adenoma metastatic brain tumor meningioma spinal tumor medulloblastoma In one modality the cancer is lung cancer, breast cancer, colorectal cancer, prostate cancer, a leukemia, a lymphoma, a skin cancer, a brain cancer, a central nervous system cancer, ovarian cancer, uterine cancer, stomach cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver cancer, or cancer of the head and neck.

In another modality cancer is metastatic cancer.

In yet another specific modality, cancer is a cancer that expresses PDK-1.

In yet another specific embodiment, the subject has previously experienced or is currently undergoing cancer treatment. Such prior treatments include, but are not limited to, prior chemotherapy, radiation therapy, surgery or immunotherapy, such as cancer vaccines.

The Dibenzonaphthyridine Derivatives are also useful for the treatment or prevention of a cancer caused by a virus. Such viruses include human papilloma virus, which can lead to cervical cancer (see, for example, Hernandez-Avila et al., Archives of Medical Research (1997) 28: 265-271); Epstein-Barr virus (EBV), which can lead to lymphoma (see, for example, Herrmann ef al., J Pathol (2003) 199 (2): 140-5); hepatitis B or C virus, which can lead to liver carcinoma (see, for example, El-Serag, J Clin Gastroenterol (2002) 35 (5 Suppl 2): S72-8); human T cell leukemia virus (HTLV) -I, which can lead to T-cell leukemia (see for example Mortreux et al., Leukemia (2003) 17 (1): 26-38); infection with human herpes virus 8, which can lead to a Kaposi sarcoma (see, for example, Kadow et al., Curr Opin Investig Drugs (2002) 3 (1): 1574-9); and infection by Human Immunodeficiency Virus (HIV), which can lead to cancer as a consequence of immunodeficiency (see, for example, Dal Maso et al., Lancet Oncol (2003) 4 (2): 110-9).

The Dibenzonaphthyridine derivatives can also be administered to prevent the progression of a cancer, which includes but is not limited to the cancers listed in Table 1 Such prophylactic use includes that in non-neoplastic cell growth of hyperplasia, metaplasia, or more particularly, dysplasia has occurred.

Alternatively or in addition to the presence of abnormal cell growth is characterized as hyperplasia, metaplasia, or dysplasia, the presence of one or more characteristics of a transformed phenotype, or of a malignant phenotype, is exhibited m vivo or exhibited m vitro by a cellular sample from a subject, may indicate the desirable prophylactic / therapeutic administration of the dibenzonaphthipdine derivatives. Such characteristics of a transformed phenotype include morphological changes, loose adhesion of substrate, loss of contact inhibition, loss of fixation dependence, protease release. , increase in sugar transport, reduction of serum requirement, expression of fetal antigens, disappearance of cell surface protein of 250,000 dalton, etc (see also id, at pp 84-90 for characteristics associated with a malignant or transformed phenotype) ) In a specific modality, leukoplakia, a dysplastic or hyperplastic lesion that appears benign from the epithelium, or Bowen's disease, a carcinoma in situ, are also treatable or preventable according to current methods In another modality, the fibrocystic disease (cystic hyperplasia, mammary dysplasia, particularly adenosis (benign epithelial hyperplasia)) is treatable or preventable according to the present methods In other embodiments, a subject who exhibits one or more of the following predisposing factors for malignancy may administer an amount of a Dibenzonaftipdine derivative which is effective to treat or prevent the cancer a chromosomal translocation associated with a malignancy (e.g., the chromosome Philadelphia for chronic myelogenous leukemia, t (14,18) for follicular hnfoma), familial polyposis or Gardner syndrome, benign monoclonal gammopathy, a first degree kinship with people who have a cancer or precancerous disease shows a Mendehano inheritance pattern (genetic ) (for example, familial polyposis of the colon, Gardner syndrome, hereditary exostosis, polyendocpna adenomatosis, medullary thyroid carcinoma with amyloid and pheochromocytoma production, Peutz-Jeghers syndrome, von Reckhnghausen neurofibromatosis, retinoblastoma, carotid body tumor, cutaneous melanocarcinoma, infraocular melanocarcinoma, xeroderma pigmentosum, ataxia telangiectasia, Chediak-Higashi syndrome, albinism, Fanconi aplastic anemia, and Bloom syndrome, and exposure by carcinogens (eg, smoking, secondhand exposure to smoking, and inhalation or in contact with certain chemicals) . 3.2 Combination of chemotherapy for the treatment of cancer In one embodiment, methods present to treat cancer or prevent cancer additionally comprise administering another anticancer agent In one embodiment, the present invention provides methods for treating or preventing cancer in a subject, the method comprising administering an effective amount of (i) a derivative of Dibenzonaphthipine and (n) another anti-cancer agent.

In one embodiment, (i) a derivative of Dibenzonaftipdine and (n) another anticancer agent are administered in doses commonly employed when such agents are used as monotherapy for the treatment of cancer In another embodiment, (i) a derivative of Dibenzonaftipdine and (II) another anticancer agent acts synergistically and is administered in doses that are less than the doses commonly employed when such agents are used as monotherapy for the treatment of cancer The dosage of (i) a Dibenzonaftipdine derivative, and (n) another anticancer agent administered as well as the dosing schedule may depend on a number of parameters, including, but not limited to, the cancer to be treated, the general health of the subject, and the discretion of the doctor who administers A derivative of Dibenzonaftipdine can be administered before (for example 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours , 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or after (for example 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of another anticancer agent to a subject in need of this In vain modalities, i) a derivative of Dibenzonaftipdine, and (n) another anticancer agent is administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart , 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart In one embodiment, i) a derivative of Dibenzonaftipdine, and (n) another anticancer agent is administered within 3 hours of each In another embodiment, i) a derivative of Dibenzonaftipdine, and (n) another anticancer agent are administered 1 minute to 24 hours apart In one embodiment, an effective amount of a Dibenzonaphttin derivative and an effective amount of another anticancer agent are present in the same composition. In one embodiment, this composition is useful for oral administration. In another embodiment, this composition is useful for intravenous administration.

Cancers that can be treated or prevented by administering a Dibenzonaftipdine derivative and another anticancer agent include, but are not limited to, the list of cancers set forth in Table 1 In one modality the cancer is lung cancer, breast cancer, colorectal cancer, prostate cancer, a leukemia, a hnfoma, a skin cancer, a brain cancer, a central nervous system cancer, ovarian cancer, uterine cancer stomach cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver cancer, or head and neck cancer The Dibenzonaftipdine Derivative and the other anticancer agent may act additively or synergistically. A synergistic combination of a Dibenzonaftipdine derivative and another anticancer agent may allow the use of lower dosages of one or both of these agents and / or less frequent dosages of one or both of Derivatives of Dibenzonaftipdine and other anticancer agents and / or to administer less frequent agents can reduce any associated toxicity with the administration of the agents to a subject without reducing the efficacy of the agents in the treatment of cancer In addition, a synergistic effect may result in the improved efficacy of these agents in the treatment of cancer and / or the reduction of any side effects unwanted adverse effects associated with the use of the agent alone In one embodiment, a Dibenzonaftipdine derivative and another anticancer agent act synergistically when administered in doses typically employed when such agents are used as monotherapy for the treatment of cancer. In another embodiment, a Dibenzonaphttinine derivative and another anticancer agent act smergistically when administered. in doses that are less than the doses typically used when such agents are used as monotherapy for the treatment of cancer In one embodiment, administration of an effective amount of a Dibenzonaphthipine derivative and an effective amount of another anti-cancer agent inhibits a cancer's resistance to the Dibenzonaphthipine derivative and / or the other anti-cancer agent. In one embodiment, the cancer is a solid tumor.

In one embodiment, other anticancer agents useful in the methods and compositions of the present invention include, but are not limited to, a drug listed in Table 2 or a pharmaceutically acceptable salt thereof.

TABLE 2 Alkylating agents Nitrogen mustards Cyclophosphamide Ifosfamide Trofosfamide Chorambucil Nitrosoureas Carmustine (BCNU) Lomustine (CCNU) Alkylsulfonates Busulfan Treosulfan Tnazenas Dacarbazine Procarbazine Temozolomide Complexes of Platins Cisplatin Carboplatin Aroplatin Oxahplatin Plants Alkaloids Alkaloids Vinca Vincnstin Vmblastma Vindesma Vinorelbine Taxans Paclitaxel Docetaxel Inhibitors of Topoisomerase DNA Epipodophyllins Etoposide Teniposide Topotecan Ipnotecan 9-am? Nocamptotec? Na Camptothecin Cpsnatol Mitomycin Mitomycin C Anti-folate Inhibitors DHFR Methotrexate Tpmetrexate Inhibitors dehydrogenase IMP acid Mycophenol Tiazofupn Ribavinn CAR Reductase inhibitors Ribonuclotide Deferoxamma Analogs Pipmidine Analogs Uracil 5-Fluorouracol Fluoxuridine Doxifluridine Ralitrexed Analogs Cytosine: Cytarabine Cytosine arabinoside Fludarabine Gemcitabine Capecitabine Analogs Purine: Mercaptopurine Thioguanine O-6-benzylguanine Antimetabolites DNA: 3-HP 2'-deoxy-5-fluorouridine 5-HP alpha-TGDR afidicolin glycinate ara-C 5-aza-2'-deoxycytidine beta-TGDR cyclocytidine Guanazol nosine glycolodialdehyde macebecin II Pyrazoloimidazole Hormone Therapies: Receptor Antagonists : Anti-estrogens: Tamoxifen Raloxifene Megestrol LHRH agonists: Goserelin Leuprolide acetate Anti-androgens: Flutamide Bicalutamide Retinoids / Deltoids Cis-retinoic acid Vitamin A derivative: All trans-retinoic acids (ATRA-IV) Vitamin D3 analogues: EB 1089 CB 1093 KH 1060 Photodynamic therapies: Vertoporfin (BPD-MA) Phthalocyanine Photosensitizer Pc4 Demetoxy-hypocrelin A (2BA-2) -DMHA) Cytokines: Interferon-a Interferon-ß Interferon-? Necrosis Factor Tumor Interleukin-2 Inhibitors of Angiogenesis: Angiostatin (plasminogen fragment) Antiangromic Antithrombin III Angiozyme ABT-627 Bay 12-9566 Benefin Bevacizumab BMS-275291 Cartilage-Derived Inhibitor (CDI) CAI Complement Fragment CD59 CEP-7055 Col 3 Combretastatin A-4 Endostatin (fragment of Collagen XVIII) Fragment of Fibronectin Gro-beta Halofuginone 5 Heparinases Fragment of Heparin hexasacaride HMV833 Chorionic gonadotropin human (hCG) IM-862 Interleukins Kringle 5 (fragment of plasminogen) 15 Marimastat Inhibitors of Metalloproteinase 2-Methoxyestradiol MMI 270 (CGS 27023A) MoAb lMC-1 C1 1 Neovastat NM-3 Panzem PI-88 25 Placental ribonuclease inhibitor Plasminogen activator-4 activator of platelet (PF4) Prinomastat Fragment Prolactin 16kD Proliferin-related protein (PRP) PTK 787 / ZK 222594 Retinoids Sohmastat Squalamin SS 3304 SU 5416 SU6668 SU11248 Tetrahydrocortisol-S Tetrathiomolybdate Thalidomide Thrombospond? N-1 (TSP-1) TNP-470 Growth factor Beta transformer (TGF-ß) Vasculostatin Vasostatin (fragment calreticulm) ZD6126 ZD 6474 Inhibitors of famesyl transferase (FTI) Bisphosphonates Antimitotic Agents Alocolcicin Halichondn B Colchicine Colchicine Derivative Dolastatin 10 Maitansin Rhizoxin Thiocolcicin Cysteine tptilo Other Isoprenylation Inhibitors Dopaminergic Neurotoxins Ion 1 -met? L-4-phen? Lp? R? D? N? Cell cycle inhibitors Staurospopna Actinomycins Actinomycin D Dactmomycin Bleomycins Bleomycin A2 Bleomycin B2 Peplomycin Anthracicums Daunorubicma Doxorubicin Idarubicin Epirubicin Pirarubicma Zorubicin Mitoxantrone MDR Inhibitors Verapamil Ca2 + Inhibitors Tapsigargina ATPase Other suitable additional anticancer agents useful in the methods and compositions of the present invention include, but are not limited to, abiraterone, acivicin, aclarubicin, acodazole, acronine, acylfulvene, adecypenol, adozelesin, aldesleukin, an ALL-TK antagonist, altretamine, ambamustma, ambomicma, ametantrone, amidox, amifostma, aminoglutethimide, aminolevulinic acid, amrubicin, amsacnna, anagrelide, anastrozole, andrograph, an inhibitor of angiogenesis, antarelix, anthramic, a modulator of gene apoptosis, apurinic acid, ara-CDP-DL-PTBA , deaminase arginine, L-asparaginase, aspergillum, asulacpna, atamestane, atpmustine, axinastatin 1, axinastatin 2, axmastatin 3, azacitidma, azasetron, azatoxin, azetepa, azatyrosine, azotomycin, batimastat, benzodepa, bisantrene, bisnafide, bizelesin, brequinar, bropipmin, balanol, a BCR / ABL antagonist, beta-aletine, betaclamycin B, betulinic acid, bisazipdinilspermine, bisnafide, bistratene A, bizelesin, calcipotpol, calfostin C, calusterone, canappox IL-2, carubicin, carboxamidotpazole, CaRest M3, CARN 700, carzelesma, castanospermine, cecropm B, cetrorelix, chloroqumoxaline, cicaprost, cirolemycin, cladpbina, clotpmazol, colismicma A, colismicma B, conagenina, crambescidin 816, cpsnatol, cryptophycm 8, derivatives of cpptoficina A, curacina A, cyclopentantraqumonas, cicloplatam, cipemycin, cytostatin, dachximab, decitabine, dehydrodidemnin B, deslorehna, dexiphosphamide, dexormaplatin, dexrazoxane, dexdiaziquone, didemnin B, didox, diethylnorspermam, d? h? dro-5-ac? t? d? na, dihydrotaxol, dioxamycin, diphenyl spiromustine, docosanol, dolasetron, droloxifene, dronabinol, duazomycin, duocarmycin SA, ecomustine, edatrexate, eflornithine , ammonitrucin, enloplatin, enpromato, epipropidina, erbulozol, esorubicina, estramustina, estramustina, an estrogen antognista, etanidazol, etoppna, exemestano, fadrozol, fazarabina, fenretinida, finastepda, flavopindol, flezelastina, fluasterona, fluorodaunorunicina, floxupdina, flurocitabina, forfenimex, formestane, fostnecin, fotemustine, gadolinium texafipna, galocitabine, ganirex, a gelatinase inhibitor, a glutathione inhibitor, hepsulfam, herbimycin A, hereguan, hexamethylene bisacetamide, hypepin, ibandronic acid, idoxifen, idramantone, ilmofosin, ilomastat, imatinib mesylate, imidazoacpdones, imiquimod, an inhibitor IGF-1, lobenguan, iodoipomeanol, iproplatin, irsogladine, isobengazol, isohomohahcondpn B, itasetron, jaspla kinohda, leucovopna, levamisole, leuprorehna, harozol, hssoclinamide 7, lobaplatin, lombpcina, lometrexol, lonidamine, losoxantrone, lovastatin, loxopin, lurtotecan, lutetio texafinna, lisofihna, manostatin A, masoprocol, maspina, a matrix metalloproteinase inhibitor, mechlorethamine, acetate of melphalan megestrol, metoclopramide, mifeppstone, miltefosine, mipmostim, mitoguazone, mitolactol, mitonafide, mofarotene, molgramostim, mopidamol, a multi-drug resistant gene inhibitor, mipaporone, N-acetyldmahna, nafarehna, nagrestip, napavine, nafterpina, nartograstim, nedaplatin , nemorubicin, nepdronic acid, nilutamide, nisamycin, a nitrogen mustard, a nitric oxide modulator, a nitrosourea, nitruhna, nocodazole, octreotide, okicenone, onappstone, oracin, ormaplatin, osaterone, oxaunomicma, palauamine, palmitoylpamidronic acid, panaxitpol, panomiphene , parabactin, pazehptin, pegaspargase, peldesin, pehomycin, pentamustine, pentosan, pentostati na, pentrozole, peplomycin, perfosfamide, perflubrona, perfosfamide, phenazinomycin, a phosphatase inhibitor, picibanil, pilocarpine, pipobroman, piposulfan, piptrexim, placetin A, placetin B, phcamycin, porphyromycin, pentamethasone, sodium porfimer, porphyromycin, prednimustine, prednisone, prostaglandin J2, microalgal, puromycin, pyrazoloacpdine, pyrazofupn, a raf antagonist, raltitrexed, ramosetron, a farnesyl ras proteinase inhibitor, a ras-GAP inhibitor, demethylated retehptin, rellinamide Rll, pboppna, rogletimide, rohitucin, romurtide, roquinimex, rubiginone B1 , ruboxilo, safingol, saintopin, SarCNU, sarcophytol A, sargramostim, semustine, a signal transduction modulator, simtrazeno, sizofiran, sobuzoxane, solverol, sonermm, sparfósicod acid, esparfosato, sparsomycin, espicamycin D, spiromustine, espiroplatin, splenopentin, spongistatin 1, a inhibitor of division of cellular stem, stimiamide, streptonigpna, inhibitor estromehsina, sulfinosina, suradista, suramm, swainsonina, tahsomicina, talimustina, tauromustina, tazaroteno, tecogalan, tegafur, telurapipho, an inhibitor telomerasa, teloxantrona, temoporfina, teroxirona, testolactona, tetraclorodecaxido , tetrazomine, tahblastine, tiamippna, thiocorahna, thrombopoietin, thymlophatine, thymotropin, tirapazamine, titanocene, topsentin, toremifene, trestolone, tretmoin, tpacetilupdine, tpcipbina, tpmetrexate, tpptorehna, tropisetron, tubulozol, turostepda, a tyrosine kinase inhibitor, ubenimex, mustard of uracil, uredepa, vaprethide, vapohna B, velaresol, veramina, verteporfin, vinxaltina, vinepidina, vinghcinato, vinleurosina, vmrosidina, vinzohdina, vitaxina, vorozol, zanoterona, zeniplatina, zilascorb, zinostatin, and zorubicina In vain embodiments, the other anticancer agent is an alkylating agent, an agent containing platinum, an anthracycline, a vinca alkaloid, a taxane, a topoisomerase inhibitor or an angiogenesis inhibitor.

In one embodiment, the other anticancer agent is administered orally In another embodiment, the other anticancer agent is administered intravenously . 3.3 Multi-Therapy for Cancer The Dibenzonaftipdine derivatives can be administered to a subject who has experienced or is undergoing one or more additional anti-cancer therapies including, but not limited to, surgery, radiation therapy, or immunotherapy, such as cancer vaccines.

In one embodiment, the invention provides methods of treating or preventing cancer comprising administering to a subject in need thereof (a) an amount of an effective Dibenzonaftipdine derivative to treat or prevent cancer, and (b) other anti-cancer therapy including but is not limited to, surgery, radiation therapy, or immunotherapy, such as a vaccine for cancer In one modality, the other anticancer therapy is radiation therapy In another modality, the other anticancer therapy is surgery In yet another specific modality, the other anticancer therapy is immunotherapy In a specific embodiment, methods present for treating or preventing cancer comprise administering a Dibenzonaphthipine derivative and radiation therapy. Radiation therapy may be administered concurrently with, before, or after the Dibenzonaphthipine derivative, in one embodiment, at least one hour, 5 hours, 12 hours, one day, one week, one month, or several months (for example, up to three months), before or after the administration of Dibenzonaftipdine derivatives When the other anticancer therapy is radiation therapy, any radiation therapy protocol may be used depending on the type of cancer to be treated. For example, but not as a limiting route, X-ray radiation, in particular, megavoltage, may be administered. High energy (radiation is greater than 1 MeV of energy) can be used for tumor death, and electron beam and X-ray radiation orthovoltage can be used for skin cancers. Gamma rays emit radioisotopes, such as radioactive isotopes radio, cobalt and other elements, can also be administered Additionally, in one embodiment The invention provides methods for the treatment of cancer using a derivative of Dibenzonaphthipine as an alternative chemotherapy or radiation therapy wherein the chemotherapy or radiation therapy results in negative effects on the subject to be treated. The subject to be treated can, optionally, be treated with another anticancer therapy such as surgery, radiation therapy, or immunotherapy The Dibenzonaftipdine derivatives can also be used in vitro or ex vivo, such as for the treatment of certain types of cancers, including but not limited to leukemias and hnfomas, wherein such treatment involves autologous stem cell transplants. This may involve a process wherein the subject hematopoietic stem cells are harvested and purged from all cancer cells, then the remaining bone marrow cell population of the subject is eradicated via the administration of a Dibenzonaftipdine derivative and / or radiation, and the Resulting stem cells are infused back into the subject, then supportive care is provided while the bone marrow function is restored and recovered to the subject. 4. 5 Therapeutic / Prophylactic Administration In one embodiment, the invention provides compositions useful for treating or preventing a proliferative disorder. The compositions are suitable for internal use and comprise an effective amount of a Dibenzonaphthyridine derivative and a physiologically acceptable carrier or vehicle.

The Dibenzonaphthyridine derivatives can be administered in amounts that are effective to treat or prevent a proliferative disorder in a subject.

The administration of the Dibenzonaphthyridine Derivatives can be carried out via any mode of administration for the therapeutic agents. These modes include local or systemic administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical modes of administration. In some cases, administration will result in the release of a Dibenzonaphthyridine derivative in the bloodstream.

In one embodiment, the Dibenzonaphthyridine Derivatives are administered orally.

Depending on the mode of administration, the compositions may be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures. , emulsions, syrups, powders, liquids, suspensions, or the like, preferably in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered intravenously (bolus and infusion), intraperitoneally, subcutaneously or intramuscularly, using forms well known to those skilled in the pharmaceutical art.

Illustrative pharmaceutical compositions include tablets and gelatin capsules comprising a Dibenzonaphthyridine derivative and a physiologically carrier acceptable or vehicle Illustrative carriers or vehicles include a) a diluent, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine, b) a lubricant, eg, silica, talc , stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or poethylene glycol, also for tablets, c) a burner, for example , aluminum magnesium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or alginate sodium, waxes and / or polyvinylpyrrohdone, if desired, d) a disintegrant, for example, starches, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures, and / or e) absorbents, coloring es, sabopzantes and sweeteners The liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the derivative Dibenzonaphthipine is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, dextrose aqueous, ghcerol, ethanol, and the like, such a form of an isotonic injectable solution or suspension The Dibenzonaftipdine derivatives can also be formulated as a suppository that can be prepared from fat emulsions or suspensions, using polyalkylene glycols such as propylene glycol, as the carrier The Dibenzonaftipdine derivatives can also be administered in the form of hposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, esteaplamine or phosphatidylcohnes. embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a lipid in the form of a capsule encapsulating the drug, as described in U.S. Patent No. 5,262,564 The Dibenzonaftipdine derivatives can also be supplied for the use of monoclonal antibodies as individual carriers for which the molecules of the Dibenzonaftipdine derivative are coupled Dibenzonaftipdine Derivatives as well they can be coupled with soluble polymers as carriers of the target drug. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidaphenol, or polyethylene-oxidepolylysine substituted with palmitoyl residues. Additionally, Dibenzonaphthyridine Derivatives can be coupled to a class of biodegradable polymers useful in achieving controlled release of drug, for example, polylactic acid, caprolactone polyepsilon, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and amphiphatic block copolymers or cross-linked hydrogels.

Parenteral injectable administration can be used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, such as solutions or solid suspensions or solid forms suitable for dissolving in liquid before injection.

One embodiment, for parenteral administration employs the implantation of a sustained release or slow release system, according to U.S. Pat. No. 3,710,795, incorporated herein by reference.

The compositions can be sterilized or contain non-toxic amounts of adjuvants, such as preservatives, stabilizers, emulsifying or wetting agents, solution promoters, exits to regulate the osmotic pressure of pH-buffering agents, and other substances, which include but are not limited to, sodium acetate or triethanolamine oleate. In addition, they may also contain other therapeutically valuable substances.

The compositions may be prepared according to a conventional mixture, granulation or coating methods, respectively, and the pharmaceutical compositions present may contain from about 0.1% to about 99%, preferably from about 1% to about 70% of the derivative Dibenzonaphthyridine by weight or volume.

The dosage regimen using the Dibenzonaphthyridine derivative can be selected according to a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration: the renal or hepatic function of the subject; and the particular Dibenzonaphthyridine derivative employed. A person skilled in the art can easily determine and prescribe the effective amount of the drug useful for treating or preventing a proliferative disorder.

The effective dosage amounts of the Dibenzonaphthyridine derivatives, when administered to a subject, are in the range of about 0.05 to about 1000 mg of the Dibenzonaphthyridine derivative per day. Compositions for in vivo or in vitro use may contain approximately 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100.0, 250.0, 500.0 or 1000.0 mg of the Dibenzonaphthyridine Derivative. In one embodiment, the compositions are in the form of a tablet that can be classified. The effective plasma levels of the Dibenzonaphthyridine derivatives may be in the range of about 0.002 mg to about 50 mg per kg of body weight per day. The amount of a Dibenzonaphthyridine derivative that is effective in the treatment or prevention of cancer can be determined by clinical techniques that are known to those skilled in the art. In addition, the in vitro and in vivo assays can be optionally employed to help identify the optimal dosage ranges. The precise dose to be employed may also depend on the route of administration, and the seriousness of the proliferative disorder to be treated and may be decided according to the practitioner's judgment and due to the subject's circumstances, for example, published clinical studies. Suitable effective dosage amounts, however, may be in the range of about 10 micrograms to about 5 grams approximately every 4 hours, although they are typically about 500 mg or less per 4 hours. In one embodiment the effective dosage is about 0.01 mg, 0.5 mg, about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, approximately 3.2 g, approximately 3.4 g, about 3.6 g, about 3.8 g, about 4.0 g, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 4 hours. Equivalent dosages may be administered glove several periods of time including, but not limited to, approximately every 2 hours, approximately every 6 hours, approximately every 8 hours, approximately every 12 hours, approximately every 24 hours, approximately every 36 hours, approximately every 48 hours, approximately every 72 hours, approximately every week, approximately every two weeks, approximately every three weeks, approximately every month, and approximately every two months. The effective dosage amounts described herein refer to a total of amounts administered; that is, if more than one Dibenzonaphthyridine derivative is administered, the effective dosage amounts correspond to the total amount administered.

The dosage regimen using the Dibenzonaphthyridine derivative can be selected according to a variety of factors including the type, species, age, weight, sex and medical condition of the subject; the severity of the proliferative disorder to be treated; the administration route; the renal or hepatic function of the subject; and the particular Dibenzonaphthyridine derivative employed. A person skilled in the art can easily determine and prescribe the effective amount of the drug required to prevent, control or arrest the progress of the proliferative disorder.

The Dibenzonaphthyridine derivatives can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Additionally, the Dibenzonaphthyridine derivatives can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those skilled in the art. To administer in the form of a transdermal delivery system, the dosing of the administration may be continuous, something is allowed through the dosage regimen. Other illustrative topical preparations include creams, ointments, lotions, aerosols and gels, wherein the concentration of the Dibenzonaphthyridine derivative ranges from about 0.1% to about 15%, w / w or w / v.

In one embodiment, the compositions comprise an amount of each of a derivative of Dibenzonaphthipine and another anticancer agent which together are effective to treat or prevent cancer. In another embodiment, the amount of the derivative Dibenzonaphthipine and another anticancer agent is at least about 0. 01% Combination Chemotherapy Agents Combined by Weight of the Composition When intended for oral administration, this amount may vary from about 0 1% to about 80% by weight of the composition. Some oral compositions may comprise about 4% by weight. about 50% of a dibenzonaphthipine derivative and another to anti-cancer people. Other compositions of the present invention are prepared as such at parenteral dosage units containing from about 0.01% to about 2% by weight of the composition The Dibenzonaftipdine derivatives can be tested in vitro or m vivo for the desired therapeutic or prophylactic activity before use in humans. Animal model systems can be used to demonstrate safety and efficacy The present methods for treating or preventing cancer in a subject may further comprise administering another therapeutic or prophylactic agent to the subject by administering a Dibenzonaphttinine derivative. In one embodiment the other therapeutic or prophylactic agent is administered in an effective amount. The other therapeutic or prophylactic agent includes , but is not limited to, an anti-inflammatory agent, an anti-renal failure agent, an anti-diabetic agent, and an anti cardiovascular disease agent, an antiemetic agent, a hematopoietic colony stimulating factor, an anxiolytic agent, and an agent analgesic In a further embodiment, the derivative Dibenzonaftipdine can be administered before, concurrent with, or after an antiemetic agent, or on the same day, or Within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other In another embodiment, the Dibenzonaftipdine derivative can be administered before, concurrent with, or after a hematopoietic colony stimulating factor, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours, 72 hours, 1 week, 2 weeks, 3 weeks or 4 weeks of each other In yet one embodiment, the Dibenzonaftipdine derivative can be administered before, concurrent with, or after an opioid or non-opioid analgesic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other In yet another specific embodiment, the Dibenzonaftipdine derivative can be administered before, concurrent with, or after an anxiolytic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours, or 72 hours. hours of each other Effective amounts of other therapeutic agents are well known to those skilled in the art. However, this is within the scope of one skilled in the art to determine the other optimal therapeutic agent from the range of the effective amount. In one embodiment of the invention, wherein , another therapeutic agent is administered to a subject, the effective amount of the derivative Dibenzonaftipdine is less than its effective amount which would be where the other therapeutic agent is not administered. In this case, without being limited by theory, it is believed that the derivative Dibenzonaftipdine and the other therapeutic agent act smergistically to treat or prevent cancer Antiemetic agents useful in the methods of the present invention include, but are not limited to, metoclopromide, dompendone, prochlorperazine, promethazine, chlorpromazine, tnmetobenzamide, ondansetron, granisetron, hydroxyzine, acetyleucine monoethanolamm, alizappda, azasetron, benzquinamide, bietanautin, bromoppda, buclizine, cleboppda, cichin, dimenhydpnate, diphenidol, dolasetron, mechzine, metalatal, metopimazine, nabilone, oxyperdyl, pipamazine, scopolamine, sulpipda, tetrahydrocannabinol, thiethylperazine, thioproperazine, and tropisetron Hematopoietic colony stimulating factors useful in the methods of the present invention include, but are not limited to, filgrastima, sargramostima, molgramostima and epoetin alfa Opioid analgesic agents useful in the methods of the present invention include, but are not limited to, morphine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopona, apomorphine, normorphma, etorphine, buprenorphine, mepepdine, lopermide, anilepdine, ethoheptazine, piminidine, betaprodine, diphenoxylate, fentanyl, sufentanil, alfentanil, remifentanil, levorphanol, dextromethorphan, phenazocine, pentazocine, cyclazocine, methadone, isomethadone and propoxyphene.

Non-opioid analgesic agents useful in the methods of the present invention include, but are not limited to, aspirin, celecoxib, rofecoxib, diclofinac, diflusinal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac, meclofenamate, mefanamic acid, nabumetone, naproxen, piroxicam and sulindac.

The anxiolytic agents useful in the methods of the present invention include, but are not limited to, buspirone, and benzodiazepines such as diazepam, lorazepam, oxazapam, clorazepate, clonazepam, chlordiazepoxide and alprazolam. 4. 6 Kits The invention encompasses kits that can simplify the administration of a Dibenzonaphthyridine derivative to a subject.

A typical kit of the invention comprises a unit dosage form of a Dibenzonaphthyridine derivative. In one embodiment the unit dosage form is a container, which may be sterile, which contains an effective amount of a derivative of Dibenzonaphthyridine and a physiologically acceptable carrier or vehicle. The kit may additionally comprise a label or printed instructions that instruct the use of the derivative Dibenzonaphthyridine to treat or prevent cancer. The kit may also additionally comprise a unit dosage form of another therapeutic or prophylactic agent, for example, a container containing an effective amount of another therapeutic or prophylactic agent or another to anti-cancer people. In one modality the kit comprises a container that contains an effective amount of a derivative of Dibenzonaphthyridine and an effective amount of another therapeutic or prophylactic agent. Examples of another therapeutic or prophylactic agent and other anti-cancer agents include, but are not limited to, those listed above.

The kits of the invention may additionally comprise a device that is useful for administering the unit dosage forms. Examples of such a device include, but are not limited to, a syringe, a drip bag, a patch, an inhaler, and an enema bag. The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

The following examples illustrate the synthesis of Dibenzonaftipdine derivatives and demonstrate their utilities to treat or prevent a pro-inflammatory disorder EXAMPLES General Methods The synthetic intermediates selected and illustrative Dibenzonaftipipdine Derivatives are characterized on the basis of their melting point, 1 H NMR and / or MS data. The 1 H NMR spectrum is obtained using a Bruker AM-400 spectrometer (400 MHz) and change values are reported. chemicals (d) in parts per million (ppm) Mass spectrometry data are obtained using an Agilent MSD LC / MS instrument using an API ionization mode equipped with a reverse phase Aquasil C18 column (column temperature 40 ° C) ), is eluted at a flow rate of 0 800 mL / min using the following gradient of a mobile phase consisting of a mixture of 0 1% Formic Acid in water (by volume) and 0 1% Formic Acid in acetonitplo (by volume) Table of Gradients Time (min)% of formic acid in acetonitplo 0 0 2 5 100 4 0 100 4 1 0 5 5 0 The column output is monitored using UV detection at 215 nm, 230 nm, 254 nm, 280 nm, and 300 nm HPLC retention times are calculated for illustrative Dibenzonaftipipdine Derivatives using this procedure and the purity is determined of the compounds at 254 nm Example 1 Synthesis of Compound lb-38 Step A Preparation of ethyl ester of 2-c? Ano-3- (3,4-d? Methox? Phen? Lam?) Acrylic acid 3,4-D? -methoxannone (30.6 g, 200 mmol) is diluted with toluene (80 mL) and the resulting solution is added with et? L (ethoxy? Methylene) cyanoacetate (33). 8 g, 200 mmol) The resulting reaction is heated to 100 ° C and allowed to stir for 1 hour, then heated to 125 ° C and allowed to stir for 15 minutes. The reaction mixture is cooled to room temperature and Concentrate in vacuo to provide a crude residue, which is recrystallized from EtOAc to give ethyl 2-c? ano-3- (3,4-d? methox? phen? lam?) acrylic acid ester as a tan solid (40 0 g, 72%) mp 166-170 ° C, MS (ES +) miz 277 2 [M + H] Step B: Preparation of 6, 7-d? Methox? -4-oxo-1,4-d? H? Droqu? Nol? Na-3-carbon? Tplo A mixture of ethyl ester of 2-c? Ano-3- (3,4-d? Metox? Phen? Lam?) Acrylic acid (from Step A, 40 g, 145 mmol) and Dowtherm A ( 1 2 L) is heated to reflux and allowed to stir under a nitrogen atmosphere for 10 hours. The resulting reaction mixture is then allowed to cool to 50 ° C and diluted with hexane. The resulting suspension is filtered and the collected solid is washed sequentially with hexane and methylene chloride, then m vacuo is dried to provide 6,7-d? methox? -4-oxo-1,4-d? -hydroquinol-na-3-carbonityl as a brown solid ( 21 1 g, 63%) mp 330-350 ° C dec, 1 H NMR (DMSO-c / βJ d 12 57 (s, 1 H), 8 59 (s, 1 H), 7 44 (s, 1 H) , 7 03 (s, 1H), 3 89 (s, 3H), 3 87 (s, 3H), MS (ES +) m / z 231 0 [M + H] Step C: Preparation of 4-chloro-6,7-d? Methox? Qu? Nol? Na-3-carbon? Tr? Lo A mixture of 6,7-d? Methox? -4-oxo-1,4-d? -hydroquinol? Na-3-carbon? Tplo (from Step B, 20 g, 87 mmol) and POCI3 ( 87 mL) is heated to reflux and allowed to stir for 2 hours. The reaction mixture is cooled to 70 ° C and concentrated m vacuo to give a crude residue. The crude residue is diluted with methylene chloride and the The resulting solution is cooled to 0 ° C and the resulting solution is added aqueous K2CO3 until the solution is at pH 8-9. The resulting solution is allowed to stir for 30 minutes at 25 ° C, then transferred to a separation funnel. The organic layer is collected, washed with water, dried over sodium sulfate, filtered through celite, and concentrated in vacuo to provide 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile as an off-white solid ( 19.8 g, 92%). A sample recrystallized from methylene chloride is characterized as follows: mp 220-223 ° C; 1 H NMR (DMSO-d 6 J d 8.98 (s, 1 H), 7.54 (s, 1 H), 7.42 (s, 1 H), 4.02 (s, 3 H), 4.01 (s, 3 H).

Step D: Preparation of Compound lb-38 (using Method A): A mixture of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile (from Step C, 2.5 g, 10 mmol), 1,3-diaminobenzene (2.4 g, 20 mmol), and 2-ethoxyethanol (50 mL) is heated to reflux and allowed to stir for about 15 hours. The resulting reaction mixture is concentrated in vacuo to give a crude residue, which is diluted with ethyl acetate (300 mL) and the resulting solution transferred to a separatory funnel. The organic layer is collected and washed sequentially with saturated sodium bicarbonate (200 mL) and saline (200 mL). The organic layer is then collected, dried over sodium sulfate, filtered, then concentrated in vacuo to provide a crude residue. The crude residue is purified using flash column chromatography (120 g column silica gel, eluted with 12.5% 0.2 N ammonia in methanol / methylene chloride) to provide Compound lb-38 as a yellow solid (2.6 g, 79% yield). MS 335 [M + H]; MS (ES +) miz 335.1 [M + H]; 1 H NMR (DMSO-d 6): d 9.4 (1 H, s); 8.4 (1 H, d); 8.2 (1 H, s); 7.5 (1 H, s); 6.9 (1 H, br); 6.8 (1 H, d); 5.4 (2H, br); 4.0 (3H, s); 3.9 (1 H, s); 2.4 (3H, s), HPLC: Rt = 2.08 minutes.

Example 2 Synthesis of Compound lb-2 Using Method A A stirred mixture of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile (25 mg, 0.10 mmol), 2,6-diaminotoluene (49 mg, 0.40 mmol) and pyridine hydrochloride (58 mg, 0.50 mmol) in 2 mL of 2-ethoxyethanol is heated at 130 ° for 8 h. 10,11-dimethoxy- is formed 4-methyldibenzo [c, /] - 2,7-naphthyridine-3,6-diamine lb-2 in 65% yield based on the LC / MS integration.

Using Method B A stirred mixture of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile (25 mg, 0.10 mmol), 2,6-diaminotoluene (24 mg, 0.20 mmol) and pyridine hydrochloride (12 mg , 0.10 mmol) in 2 mL of 2-ethoxyethanol is heated to 210 ° in a microwave oven for 1 h using an energy limit of 300 Watts and an internal pressure in the reaction vessel of less than 20 psi. 10,11-Dimethoxy-4-methyldibenzo [c, /] -2,7-naphthyridine-3,6-diamine lb-2 is formed in 80% yield based on LC / MS integration. The reaction mixture is concentrated in vacuo to give a crude residue, which is diluted with ethyl acetate and the resulting solution is transferred to a separatory funnel. The organic layer is collected and washed sequentially with saturated sodium bicarbonate and saline. The organic layer is then collected, dried over sodium sulfate, filtered, then concentrated in vacuo to provide a crude residue. The crude residue is purified using flash column chromatography using a gradient from 5% to 10% 0.2 N ammonia in methanol / methylene chloride. Isolated yield: 72%. Compound lb-2: HPLC: R t = 2.13 min; MS (ES +) miz 335.1; [M + H] HRMS: 335.15122 [M + H]; 335.15026 [calculated]; 1 H NMR (DMSO-d 6): d 9.4 (1 H, s); 8.4 (1 H, d); 8.2 (1 H, s); 7.5 (1 H, s); 6.9 (1 H, br); 6.8 (1 H, d); 5.4 (2H, br); 4.0 (3H, s); 3.9 (1 H, s); 2.4 (3H, s); IR (cm'1). Absorption of the cyano groups is not observed at approximately 2200 cm "1.

Example 3 Synthesis of Compounds lb-3, lb-4, lb-17, lb-18 and lb-53 Using the procedure described in Example 1 and replacing 3,4-diethoxyaniline with 3,4-dimethoxyaniline in Step A, and 2,6-diaminotoluene with 1,3-diaminobenzene in Step C, Compound lb-3 is prepared . MS 363 [M + H], HPLC: R t = 2.40 minutes Using the procedure described in Example 1 and substituting 3-fluoro-4-methoxyaniline for 3,4-dimethoxyaniline in Step A, and 2,6-diaminotoluene for 1,3-diaminobenzene in Step C, Compound Ib is prepared -4. MS 323 [M + H], HPLC: R t = 1.75 minutes Using the procedure described in Example 1 and substituting 3,4-d? (2-methoxy-ethoxy) aniline for 3,4-d? Methoxy? In Stage A, and 2,6-d? am? Notoluene for 1,3-diaminobenzene in Step C, Compound lb-17 MS 423 [M + H], HPLC Rt = 1 74 minutes is prepared Using the procedure described in Example 1 and substituting 3- (2-chloroethoxy?) -4-methoxyamino for 3,4-d? Methoxyanine in Step A, and 2, 6-d? Am? Notoluene by 1, 3-d? Am? Nobenzene in Step C, Compound lb-18 MS 383 [M + H], HPLC Rt = 78 minutes is prepared Using the procedure described in Example 1 and substituting 3-/ /?? / - dimethylanilma for 1,3-dαaminobenzene in Step C, Compound lb-53 MS 349 [M + H], HPLC is prepared Rt = 2 48 minutes Example 4 Synthesis of Compound lb-9 A mixture of 10-fluoro-1 1-methox? -4-meth? Ld? Benzo [c, /] -2,7-naphth? Pd? Na-3,6-d? Amine (32 mg, 10 mmol), 2- (morpholine-4-? L) -et? Lam? Na (26 mg, 0 20 mmol) and 1 -met? Lp? Rrol? D? N-2-one (3 mL) is heated at 200 ° C in a microwave oven for 3 hours The resulting reaction mixture is purified using HPLC to give Compound lb-9 (15 mg, 35%) MS 433 [M + H], HPLC Rt = 1 31 min Example 5 Synthesis of Compounds lb-5 to lb-8 and lb-12 to lb-15 Using the procedure described in Example 4 and substituting? / - met? L-3 - (? /,? / - d? Met? Lam? No) -prop? Lam? Na for 2- (morph? N-4-) l) -et? lam? na, prepare Compound lb-5 MS 419 [M + H] HPLC Rt = 1 40 minutes Using the procedure described in Example 4 and substituting? / - met? L-2 - (? /,? / - d? Met? Lam? No) -et? Lam? Na for 2- (morph? N-4-) ?) -et? lam? na, Compound Ib-6 MS 405 [M + H], HPLC Rt = 1 39 minutes is prepared Using the procedure described in Example 4 and substituting 3- (1-met? Lp? Peraz? N-4-? L) -prop? Lam? Na for 2- (morpholin? 4-? L) -et? Lam? na, Compound lb-7 MS 460 [M + H], HPLC Rt = 1 31 minutes is prepared Using the procedure described in Example 4 and substituting 3- (morpholin-4-yl) -prop? Lamna for 2- (morpholin-4? L) -et? Lam? Na, it is prepared Compound lb-8 MS 447 [M + H], HPLC Rt = 1 32 minutes Using the procedure described in Example 4 and substituting 3- (p? Rrold? N-1-? L) -prop? Lam? Na for 2- (morpholin? 4-? L) -et? Lam? Na, Compound lb-12 MS 431 [M + H], HPLC Rt = 1 35 minutes is prepared Using the procedure described in Example 4 and substituting 2- (p? Rrold? N-1-? L) -et? Lam? Na for 2- (morpholin? 4-? L) -et? Lam? Na, Compound lb-13 MS 417 [M + H], HPLC Rt = 1 35 minutes is prepared Using the procedure described in Example 4 and substituting 2- (N, Nd? Met? Lam? No) -et? Lam? Na for 2- (morpholin? 4-? L) -et? Lam? Na, prepare Compound lb-14 MS 391 [M + H], HPLC Rt = 1 30 minutes Using the procedure described in Example 4 and substituting 3 - (? /,? / - d? Met? Lam? No) -prop? Lam? Na for 2- (morph? N-4-? L) -et? Lam Na, prepare Compound lb-15 MS 405 [M + H], HPLC Rt = 1 31 minutes Example 6 Synthesis of Compound lb-10 Dilute 2- (Morpholin-4-? L) -ethanol (26 mg, 0 20 mmol) with DMF (2 mL) and to the resulting solution add sodium hydride (8 mg, 0 2 mmol) The resulting reaction it is allowed to stir at room temperature for 20 minutes, then 10-fluoro-11-methox-4-meth? ld? benzo [c, /] - 2,7-naft? r? d? na-3 is added, 6-dimamine (32 mg, 0-10 mmol) to the reaction mixture The resulting reaction is heated to 70 ° C and allowed to stir for 2 hours, then concentrated in vacuo to provide a crude residue, which HE purify using HPLC to give Compound lb-10 (14 mg, 33%) MS 434 [M + H], HPLC Rt = 1 36 minutes Example 7 Synthesis of Compounds lb-11, lb-16, lb-19 to lb-35, lb-42 to lb-48, and lb-50 Using the procedure described in Example 6 and substituting 3- (morpholine-4-yl) -propanol for 2- (morpholine-4-yl) -ethanol, Compound lb-11 MS 448 is prepared [ M + H], HPLC Rt = 1 40 minutes Using the procedure described in Example 6 and substituting? / -methyl-4-hydroxymethyl-pipepdine for 2- (morpholine-4?) -ethanol, Compound lb-16 MS 432 [M + H], HPLC Rt = 1 44 minutes Using the procedure described in Example 6 and substituting 2- (azet? D? N-1-? L) -ethanol for 2- (morpholine? 4-? L) -ethanol, Compound lb-19 MS is prepared 390 [M + H], HPLC Rt = 1 47 minutes Using the procedure described in Example 6 and substituting 2- (N, Nd? Met? L) -ethanol for 2- (morpholine? 4-? L) -ethanol, Compound lb-20 MS 392 [M + H], HPLC Rt = 1 40 minutes Using the procedure described in Example 6 and substituting 3 - (? /, / -d? Met? L) -propanol for 2- (morpholine? 4-? L) -ethanol, Compound lb-21 MS is prepared 406 [M + H], HPLC Rt = 1 44 minutes Using the procedure described in Example 6 and substituting 2- (pyridold-1-? L) -ethanol for 2- (morpholine-4-? L) -ethanol, Compound lb-22 MS is prepared 418 [M + H], HPLC Rt = 1 44 minutes Using the procedure described in Example 6 and substituting 2 - (? /,? / - d? Et? L) -ethanol for 2- (morpholine-4? L) -ethanol, Compound lb-23 is prepared MS 420 [M + H], HPLC Rt = 1 47 minutes Using the procedure described in Example 6 and substituting 2- (p? Pd? N-2-? L) -ethanol for 2- (morpholine-4? L) -ethanol, Compound lb-24 MS is prepared 426 [M + H], HPLC Rt = 1 60 minutes Using the procedure described in Example 6 and substituting 2 - (? / - met? Lp? Rrold? N-2-? L) -ethanol for 2- (morpholine-4-? L) -ethanol, the Compound lb-25 MS 432 [M + H], HPLC Rt = 1 49 minutes Using the procedure described in Example 6 and substituting 2- (p? Per? D? N-1-? L) -ethanol for 2- (morpholine? 4-? L) -ethanol, Compound lb- is prepared. 26 MS 432 [M + H], HPLC Rt = 1 48 minutes Using the procedure described in Example 6 and substituting 3 - (? /,? / - d? Et? L) -propanol for 2- (morpholine-4? L) -ethanol, Compound lb-27 is prepared MS 434 [M + H] HPLC Rt = 1 50 minutes Using the procedure described in Example 6 and substituting 2- (az? R? D? N-1-? L) -ethanol for 2- (morpholine-4? L) -ethanol, Compound lb- is prepared. 28 MS 446 [M + H], HPLC Rt = 1 53 minutes Using the procedure described in Example 6 and substituting 3- (p? Pepd? N-1-? L) -propanol for 2- (morpholine-4? L) -ethanol, Compound lb-29 MS is prepared 446 [M + H], HPLC Rt = 1 51 minutes Using the procedure described in Example 6 and substituting 3 - (? /,? / - d? Met? Lam? No) -prop? Lam? Na for 2- (morpholine-4-? L) -ethanol, prepare Compound lb-30 MS 449 [M + H], HPLC Rt = 1 33 minutes Using the procedure described in Example 6 and substituting 2 - (? Ndol-3? L) -ethanol for 2- (morpholine-4? 1) -ethanol, Compound lb-31 MS 464 [M + H], HPLC Rt = 2 04 minutes Using the procedure described in Example 6 and substituting 2- (4 -? /,? / - d? Met? Lfen? L) -ethanol for 2- (morpholin? 4-? L) -ethanol, the Compound lb-32 MS 468 [M + H], HPLC: Rt = 1.67 minutes Using the procedure described in Example 6 and substituting 2 - (? / - methylpiperidin-4-yl) -ethanol for 2- (morpholin-4-yl) -ethanol, Compound lb-33 is prepared. MS 446 [M + H], HPLC: R t = 1.52 minutes Using the procedure described in Example 6 and substituting 3-hydroxymethyl-γ-methylpiperidine for 2- (morpholin-4-yl) -ethanol, Compound lb-34 is prepared. MS 432 [M + H], HPLC: Rt = 1.49 minutes Using the procedure described in Example 6 and substituting 3- (pyrrolidin-1-yl-2-one) -propanol for 2- (morpholin-4-yl) -ethanol, Compound lb-35 is prepared. MS 446 [M + H], HPLC: Rt = 1.75 minutes Using the procedure described in Example 6 and substituting 3-methyl-1-butanol for 2- (morpholin-4-yl) -ethanol, Compound lb-40 is prepared. MS 391 [M + H], HPLC: R t = 2.66 minutes Using the procedure described in Example 6 and substituting neopentyl alcohol for 2- (morpholin-4-yl) -ethanol, Compound lb-41 is prepared. MS 405 [M + H], HPLC: R t = 2.72 minutes Using the procedure described in Example 6 and substituting 2-benzyloxy-ethanol for 2- (morpholin-4-yl) -ethanol, Compound lb-42 is prepared. MS 469 [M + H], HPLC: R t = 2.59 minutes Using the procedure described in Example 6 and substituting 1- (benzyl-pyrrolidin-2-yl) -methanol for 2- (morpholin-4-yl) -ethanol, Compound lb-43 MS 494 [M + H] is prepared HPLC: Rt = 1.65 minutes Using the procedure described in Example 6 and substituting [1- (1-methyl-pyrroline-2-ylmethyl) -pyrroldin-2-yl] -methanol for 2- (morpholin-4-yl) -ethanol, the Compound is prepared lb-44. MS 501 [M + H], HPLC: R t = 1.36 minutes Using the procedure described in Example 6 and substituting 2-c? Clohex? -ethanol for 2- (morpholine? 4-? L) -ethanol, Compound lb-45 MS 417 [M + H] is prepared, HPLC Rt = 2 21 minutes Using the procedure described in Example 6 and substituting 2-c? Clopropyl-ethanol for 2- (morpholine-4?) -ethanol, Compound lb-46 MS 389 [M + H] is prepared, HPLC Rt = 1 96 minutes Using the procedure described in Example 6 and substituting 2-ethoxyethanol for 2- (morpholine-4-yl) -ethanol, Compound lb-47 MS 393 [M + H], HPLC Rt = 2 is prepared 22 minutes Example 8 Synthesis of Compound lb-36 A mixture of 10.1 1-d? Methox? -4-meth? Ld? Benzo [c, id] -2,7-naphth? Pd? Na-3,6-d? Am? Na (1.0 g, 3.0 mmol), phthalic anhydride (0 46 g, 3 1 mmol) and acetic acid (10 mL) is heated at 1 15 ° C and the resulting reaction is allowed to stir for 48 hours, then cooled to room temperature. The resulting reaction is concentrated m vacuo and the resulting residue is diluted with ethyl acetate (250 mL) The resulting solution is washed with aqueous sodium hydroxide (1 N), then saline The organic layer is collected, dried over sodium sulfate, Sodium and concentrated in vacuo The resulting residue is purified using flash column chromatography (silica gel with 3% methanol / methylene chloride eluent) to provide Compound lb-36 as a yellow solid (1.0 g, 72%). ) MS 465 [M + H], HPLC Rt = 2 34 minutes Example 9 Synthesis of Compound I-3 A mixture of Compound lb-36 (from Example 8, 33 mg, 0 070 mmol), p-toluenesulfonyl chloride (22 mg, 0 1 1 mmol) and pipdin (1 mL) is heated to 60 ° C and the resulting reaction it is allowed to stir for 1 hour. The resulting reaction mixture is cooled to room temperature and concentrated in vacuo. The resulting residue is treated with hydrazine (0 5 mL in 1 mL ethanol) and the resulting reaction is allowed to stir for 15 hours. hours at room temperature The resulting reaction mixture is then purified using HPLC to provide Compound 1-3 (10 mg, 44%) MS 320 [M + H], 1 H NMR (DMSO-d 6) d 9 34 (1 H, s), 9 26 (1 H, s), 8 79 (1 H, d), 8 35 (1 H, s), 7 63 (1 H, s), 7 29 (1 H, d), 5 86 (2H, br), 4 08 (3H, s), 4 01 (3H, s), 2 58 (3H, s) HPLC Rt = 1 82 minutes Example 10 Synthesis of Compound lc-1 Compound lb-36 (from Example 8, 46 mg, 0-10 mmol) is diluted with DMF (2 mL) and iodomethane (21 mg, 0 15 mmol) is added to the resulting reaction. The resulting reaction is heated to 60 ° C. and allowed to stir for 15 hours. The resulting reaction mixture is concentrated in vacuo to give a crude residue which is treated with hydrazine (0 5 mL in 1 mL of ethanol) and the resulting reaction is allowed to stir at room temperature for 15 hours. hours The reaction mixture is then purified using HPLC to give Compound lc-1 (14 mg, 40%) MS 349 [M + H], HPLC Rt = 2 26 minutes Example 11 Synthesis of Compound lb-1 Dilute 4-chloro-6,7-d? Methox? -quinol? Na-3-carbonyl (from Example 1, Step C, 25 mg, 0-10 mmol) with DME (2 mL) and to the resulting solution is added (2-boc-aminophenyl) boronic acid (26 mg, 11 mmol), iodine / / s-tr? phen? lfosf? napalad? o (0) (2 mg, 2 mol%), and aqueous sodium carbonate (2.0 M, 0 2 mL) The resulting reaction is heated to 80 ° C and allowed to stir for 16 hours. The reaction mixture is then cooled to room temperature and purified using HPLC to provide Compound lb. -1 (15 mg, 53% yield) MS 306 [M + H], HPLC Rt = 2 96 minutes Example 12 Synthesis of Compound lb-39 A mixture of 10,11-d? Methox? -4-meth? Ld? Benzo [c,? -2,7-naft? Pd? Na-3,6-d? Am? Na (0 17 g, 0 50 mmol. ), 2 mL of acetic acid (2 mL), 0 8 mL of water (0 8 mL) and HCl Concentrate (0.22 mL) is cooled to 0 ° C and an aqueous solution of sodium nitrite (76 mg, 1.1 mmol, in 0.3 mL of water) is added to the resulting solution in dropwise fashion. The resulting reaction is allowed to stir at 0 ° C for 30 minutes, then hypophosphorous acid (2.4 mL, 50% by weight of solution in water) is added. The resulting reaction is allowed to stir at 0 ° C for 8 hours then allowed to warm to room temperature. The reaction mixture is neutralized using aqueous sodium bicarbonate and the neutralized solution is extracted with ethyl acetate. The organic layer is collected, concentrated in vacuo and the resulting crude residue is purified using HPLC to provide lb-39 as a solid (44 mg, 28%). MS 320 [M + H]; 1 H NMR (DMSO-d 6): d 9.44 (1 H, s); 8.61 (1 H, d); 8.14 (1 H, s); 7.61 (1 H, s); 7.50 (1 H, d); 7.31 (1 H, m); 4.03 (3H, s); 4.02 (3H, s); 2.53 (3H, s). HPLC: Rt = 2.42 minutes.

Example 13 Synthesis of Compound lb-48 -Fluoro-1-methoxy-4-methyldibenzo [c, 1] -2,7-naphthyridine-3,6-diamine (16 mg, 0.050 mmol) is diluted with DMSO (1 mL) and the resulting solution is added sodium hydroxide (10 mg, 0.25 mmol). The resulting reaction is heated to 80 ° C and allowed to stir for 15 hours. The reaction is cooled to room temperature and the resulting reaction mixture is purified using HPLC to give Compound lb-48 (5.4 mg, 34% yield). MS 321 [M + H], HPLC: R t = 1.87 minutes.

Example 14 Synthesis of Compound lb-49 A mixture of 10,1-dimethoxy-4-methyldibenzo [c, 2,7-naphthyridine-3,6-diamine (40 mg, 0.12 mmol), acetic acid (0.5 mL), water (0.2 mL) and Concentrated HCl (0.06 mL) is cooled to 0 ° C. To the resulting solution, an aqueous solution of sodium nitrite (19 mg, 0.28 mmol, in 1 mL of water) is added dropwise and the resulting reaction is allowed to take place. stir for 30 minutes at 0 ° C. To the resulting reaction mixture is added copper (I) chloride (15 mg, 0.15 mmol), then water (1.0 mL) and the resulting reaction is heated to 100 ° C and Allow to stir for 1 hour. The reaction is then allowed to cool to room temperature, the reaction mixture is filtered, and the filtrate is concentrated in vacuo to provide a crude residue which is purified using HPLC to provide Compound lb-49 (5.0 mg, 12%). MS 354 [M + H], HPLC: R t = 2.71 minutes.

Example 15 Synthesis of Compound lb-50 Using the method described in Example 14, and substituting 20% aqueous sulfuric acid (2 mL) and toluene (4 mL) for copper (I) chloride and water, Compound lb-50 is prepared. MS 336 [M + H], HPLC: R t = 2.02 minutes.

Example 16 Synthesis of Compound lb-51 Dilute 6-Amino-10,11-dimethoxy-4-methyldibenzo [c, /] -2,7-naphthyridin-3-ol (10 mg, 0.03 mmol) with DMSO (1 mL) and add to the resulting solution dimethyl sulfate (6.0 mg, 0.047 mmol), then potassium carbonate (6 mg, 0.1 mmol). The resulting reaction is allowed to stir at room temperature for 15 hours, then the reaction mixture is purified using HPLC to provide Compound lb-51 (2.4 mg, 22%). MS 350 [M + H], HPLC: R t = 2.39 minutes.

Example 17 Synthesis of Compound 1-1 Using the method described in Example 16 and substituting 6-methoxy-10,11-dimethoxy-4-methyldibenzo [c, i] -2,7-naphthyridin-3-ol for 6-amino-10,11-dimethoxy-4 -metidibenzofc, i] -2,7-naphthyridn-3-ol, Compound 1-1 is prepared. MS 365 [M + H], HPLC: R t = 2.95 minutes Example 18 The PDK-1 Inhibitory Activity in vitro for Illustrative Dibenzonaftipyridine Derivatives The ability of the illustrative Dibenzonaftipyridine Derivatives to inhibit PDK-1 in vitro can be determined using the ELISA assay as described in Kobayashi went to., Biochem. J. 339: 319-328 (1999) and Park et al., EMBO J. 18: 3024-3033 (1999).

In this in vitro assay, the PDK-1 kinase phosphorylates SGK1 in Threonine 256. After 17 minutes, the reaction is quenched via the addition of urea. The 6xHIS labeled SGK1 then binds to a well of 96 Ni-NTA HisSorb plates and the phosphorylated SGK1 is detected using anti-rabbit SGK antibody derived from rabbit as the primary antibody and HRP coupled to anti-rabbit antibody as the secondary antibody. The HRP is then detected using a Chemiluminescent Substrate.

Table 3 shows PDK-1 inhibition data for illustrative Dibenzonaftipyridine Derivatives which are obtained using the assay described above in Example 18.

Table 3 PDK-1 Inhibition Data for Illustrative Dibenzonaftipyridine Derivatives 15 20 25 The results in Table 3 show that Dibenzonaftipindin Derivatives are non-effective in inhibiting PDK-1. Accordingly, Applicants consider that Dibenzonaftipipdine Derivatives are useful in treating or preventing a proliferative disorder, such as cancer.

The present invention is not limited in scope by the specific embodiments described in the examples or schemes, which are intended as illustrations of a few aspects of the invention and any modalities that are equivalent are within the scope of this invention. In fact, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

A number of references have been cited, the full descriptions of which are incorporated herein by reference in their entirety.

Claims (13)

1. A compound that has the formula (I) or a pharmaceutically acceptable salt thereof, where R1 is -H, -OH, -O-alkyl, d-C6, -halo, C2-C6 alkenyl, C2-C6 alkynyl, -N (R8) 2, NH-OR18 or -C (O) N ( R18) 2, R2 is-H, -O-alkyl, d-C6, -halo, C2-C6 alkenyl, C2-C6 alkynyl, -NHR17, -N (R17) 2, -NH-OR18 or -C (O) N ( R18) 2, such that when R1 is -OH or -O-alkyl C6, R2 is hydrogen, R3, R4, R5, R6, R7, R8, R9 and R10 are each independently -H, -halo, -OH, -SH, -N (R12) 2, -NHOR12, -CN, -NO2, -CF3, -OCF3, -alkyl d-C6, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -phenyl, -benzyl, - (CH2) n- O-alkyl d-C6, -O-alkenyl, C2-C6, -O-C2-C6 alkynyl, -O-phenol, -S-phenyl, -NH- dC6 alkyl, - (CH2) nC (O) -R11, - (CH2) n-OC (O) -R11, - (CH2) n -NHC (O) -R11, -S- alkyl d-C6, -S (O) -alkyl d-C6, -SO2-alqu ? d-C6, -SO2NH-alkyl C C6, - SO2NH-alkenyl or C2-C6, -SO2NH-alkyl? C2-C6, -Y- (CH2) kM-CH (R14) R15 , -Y- (CH2) g-Rlb, -Y- (CH2) kM- (CH2) p-Rld, -Y- (CH2) k- (W) a- (CH2) qZ, -Y- (CH2) p- (Z) a (CH2) qZ, or such that R3, R4, R5, R6, R7, R8, R9 and R10 are not simultaneously hydrogen; R11 is-H, -alkyl d-C6, C2-C6 alkenyl, C2-C6 alkynyl, -phenyl, -O-C6 alkyl, -O-C2-C6 alkenyl, -O-C2-C6 alkynyl, -O-phenyl, -S-phenyl, -S-C6-alkyl or -N (R12) 2; each occurrence of R12 is independently -H, -alkyl d-C6, C2-C6 alkenyl, C2-C6 alkynyl, -phenyl or -benzyl; each occurrence of G is independently -O-, -S-, - (CH 2) -, N 0 -N (R 13) -; M is -O-, -N (R13) -, -N ((C (R13) 2) pN (R13) 2) - or -N ((C (R13) 2) p-OR13) -; W is -O- or -N (R13) -; Y is -O-, -S-, - (CH2) a- or -N (R13) -; Z is a 3- to 7-membered non-aromatic monocyclic heterocycle, a 5- or 6-membered aromatic monocyclic heterocycle, or an 8- or 12-membered bicyclic heterocycle, wherein a 3 to 7 membered non-aromatic monocyclic heterocycle may or may not be substituted independently replacing one carbon of the ring or nitrogen atom of the ring with one or more of -R13, -N (R13) 2, -OH, -OR13, - (C (R13) 2) sOR13 or - (C (R13) 2) SN (R13) 2; each occurrence of R13 is independently -H, -alkyl d-C6, -CH2.C2-C6aikonyl, -C2-C6-aikinyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -phenyl, -C (O )-I rent d-C6 or -C (O) -O-C? -C6 alkyl, such that when R13 is -phenyl, the phenyl group can be substituted or not independently substituted with one or more of -OH, -CN, -NO2, -CF3, -alkyl d-C6, -NH (C3 alkyl), -N (C3) alkyl, - (CH2) a-halo, - (CH2) aO-C6 alkyl, - (CH2) aOC (O) Alkyl d-C6, -S-alkyl d-C6, -C (O) OH, - C (O) O-C6 alkyl, -S-phenyl, -O-phenyl, -phenyl, -benzyl, -NH- (CH2) a-phenyl or -NHC (O) Alkyl C C6; R14 is-H, - (C (R13) 2) rN (R13) 2 or - (C (R13) 2) rOR13; R15 is-H, - (C (R13) 2) rN (R13) 2 or - (C (R3) 2) rOR13; R16 is -H, -halo, -N (R13) 2, -OR13, -N (R13) 3 + or -N (R13) -OR13; each occurrence of R 7 is independently -alkyl d-C6, C2-C6 alkenyl, C2-C6 alkynyl, -phenyl or benzyl; each occurrence of R18 is independently -H, -alkyl d-C6, C2-C6 alkenyl, C2-C6 alkynyl, -phenyl or benzyl; a is 0 or 1; g is an integer in the range of 1 to 6; k is an integer in the range of 1 to 4; n is an integer in the range of 0 to 6; p is an integer in the range of 1 to 4; q is an integer in the range of 0 to 4; r is an integer in the range of 1 to 4; s is an integer in the range of 1 to 6; Y each occurrence of t is independently an integer in the range of 1 to 3.
2. 2. The compound of claim 1, wherein R1 is -NH2 and R2 is -H.
3. 3. The compound of claim 2, wherein R3 is-d-C6 alkyl.
4. 4. The compound of claim 2, wherein R 4 is-NH 2.
5. 5. The compound of claim 2, wherein R4 is -O-C6 alkyl.
6. 6. The compound of claim 2, wherein R 4 is -OH.
7. 7. The compound of claim 2, wherein R8 and R9 are each -O-Cr C6 alkyl.
8. 8. The compound of claim 2, wherein R2, R5, R6, R7 and R10 are each - H.
9. 9. The compound of claim 8, wherein R2, R5, R6, R7 and R10 are each -H, R3 is -alkyl d-C6, and R4 is -NH2.
10. 10. The compound of claim 9, wherein R2, R5, R6, R7 and R10 are each-H, RJ is-C6 alkyl, R is -NH2, and R ° is -O-C6 alkyl.
11. 11. The compound of claim 10, wherein R2, R5, R6, R7 and R10 are each-H, R3 is-C6 alkyl, R4 is -NH2, R8 is -O-alkyl d-C6 and R9 is -O -Cr C6 alkyl.
12. 12. The compound of claim 8, wherein R2, R5, R6, R7 and R10 are each -H, R3 is -alkyl d-C6, R4 is -OH, and R8 is -O-alkyl d-C6.
13. 13. The compound of claim 12, wherein R2, R5, R6, R7 and R10 are each -H, R3 is -alkyl d-C6, R4 is -OH, R8 is -O-alkyl dC6 and R9 is - O-alkyl C The compound of claim 8, wherein R2, R5, R6, R7 and R10 are each - H, R3 is - C6 alkyl, R4 is -OCH3, and R8 is -O-alkyl C6 The compound of claim 14, wherein R2, R5, R6, R7 and R10 are each-H, R3 is -alkyl d-C6, R4 is -OCH3, R8 is -O-alkyl or d-C6 and R9 is- O-alkyl d- C6 The compound of claim 1 wherein at least one of R3, R4, R5, R6, R7, R8, R9 and R10 is A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1 and a physiologically acceptable carrier A method for treating a proliferative disorder, the method comprises administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1 The method of claim 18, wherein the proliferative disorder is cancer The method of claim 19, wherein the cancer is lung cancer, breast cancer, colorectal cancer, prostate cancer, a leukemia, a hnfoma, a skin cancer, a brain cancer, a central nervous system cancer , ovarian cancer, uterine cancer, stomach cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver cancer, or cancer of the head and neck The method of claim 19, further comprising the administration of another anticancer agent The compound of claim 1, wherein the compound is 10,11 -d? Methox? D? Benzo [c, f] -2,7-naft? Pd? N-6-am? Na, 10,11 -d? Methox? -4-met? Ld? Benzo [ c, f] -2,7-naft? pd? na-3,6-d? am? na, 10,11 -d? ethoxy? -4-met? ld? benzo [c, t] -2.7 -naft? r? d? na-3,6-d? am? na, 10-fluoro-11-methox? -4-met? ld? benzo [c, /] - 2,7-naft? r? d ? na-3,6-d? am? na,? / 10- [3- (d? met? lam? no) prop? l] -11-methox? -? / 10,4-d? met? ld benzo [c, y] -2,7-naphthr? na? na-3,6,10-tpam? na,? / 10- [2- (d? met? lam? no) et? l] -11-methox? -? / 10,4-d? Met? Ld? Benzo [c, r] -2,7-naft? Pd? Na-3,6,10-tpamine, 11-methox? -4- met? l -? / 10- [3- (4-met? l? peraz? n-1-? l) prop? l] d? benzo [c, /] - 2,7-naft? r? d? na- 3,6,10-tpam? na, 11-methox? -4-met? l -? / 10- (3-morpholin? 4-? lprop? l) d? benzo [c, í] - 2,7-naphthyrna-3,6,10-tnamine, 11-methox-4-methyl-1? -? / 10- (2-morpholine-4? Let? L) d? Benzo [c, i] -2,7-naphthyrne-3,6,10-tpamine, 11-methox-4-methyl-10- (2-morpholine-4-? letox ?) d? benzo [c, /] - 2,7-naphthr? na? na-3,6-d? am? na, 11-methox? -4-met? l-10- (3-morph ? n-4-? lpropox?) d? benzo [c, /] - 2,7-naphthr? na? na-3,6-diamine, 11-methox? -4-met? l -? / 10 - (3-pyrrolidone-1-? Lpropyl) d? Benzo [c, /] - 2,7-naft? R? D? Na-3,6,10-tpami na, 11-methox? -4-met? l -? / 0- (2-p? rrol? d? n-1-? let? l) d? benzo [c, í] -2,7-naft? pd? na-3,6,10-tpamine,? / 10- [2- (d? met? lam? no) et? l] -11-methox? -4-met? ld? benzo [c, /] -2,7-naft? R? D? Na-3,6,10-tpamine,? / 10- [3- (d? Met? Lam? No) prop? L] -11-methox? -4-met ? ld? benzo [c, y] -2,7-naphth? pd? na-3,6,10-tnamine, 11-methox? -4-met? l-10 - [(1-met? lp? pepd ? n-4-? l) methox?] d? benzo [c, id] -2,7-naft? pd? na-3,6-diamine, 10,11-b? s (2-methox? ethoxy? ) -4-met? Ld? Benzo [c, í] -2,7-naft? Pd? Na-3,6-d? Am? Na, 10- (2-chloroethoxy?) - 11-methox? -4 -met? ld? benzo [c, í] -2,7-naft? pd? na-3,6-d? am? na, 10- (2-az? R? D? N-1-? Letox?) - 11-methox? -4-met? Ldtbenzo [c, r] -2,7-naft? R? D? Na-3, 6-d? Am? Na, 10- [2- (d? Met? Lam? No) ethox?] - 11-methox? -4-met? Ld? Benzo [c, id] -2,7-naft? R? D? Na-3, 6-diamine, 10- [3- (d? Met? Lam? No) propox?] - 11-methox? -4-met? Ld? Benzo [c, id] -2,7-naft? Pd? Na- 3,6-diamine, 11-methox? -4-met? L-10- (2-p? Rrol? D? N-1-? Letox?) D? Benzo [c, í] -2,7-naft ? r? d? na-3,6-d? am? na, 10- [2- (d? Et? Lam? No) ethoxy?] - 11-methox? -4-met? Ld? Benzo [c, id] -2,7-naft? R? D? Na-3, 6-d? Am? Na, 11-methox? -4-met? L-10- (2-p? Pd? N-2-? Letox?) D? Benzo [c, r] -2,7-naft? Pd? Na-3.6 -d? am? na, 11-methox? -4-met? L-10- [2- (1-met? Lp? Rrol? D? N-2-? L) ethoxy?] D? Benzo [c, /] - 2,7- naphthyrna-3,6-diamine, 11-methoxy? -4-met? l-10- (2-p? per? d? n-1-? letox?) d? benzo [c, /] -2,7-naft? Pd? Na-3,6-d? Am? Na, 10- [3- (d? Et? Lam? No) propox?] - 11-methox? -4-met? Ld? Benzo [c,] -2,7-naft? R? D? Na-3,6 -diamine, 10- (2-azepan-1-? letox?) - 11-methox? -4-met? ld? benzo [c, í] -2,7-naft? pd? na-3,6-d ? am? na, 11-methox? -4-met? L-10- (3-p? Pepd? N-1-? Lpropox?) D? Benzo [c,] -2,7-naft? R? D? Na-3, 6-diamma, 10-. { 2 - [[2- (d? Met? Lam? No) et? L] (met? L) am? No] ethox ?} -11-methox? -4-meth? Ld? Benzo [c, /] - 2,7-naphth? Pd? Na-3,6-d? Am? Na, 10- [2- (1H-? Ndol- 3-?) Etox?] - 11-methox? -4-met? Ld? Benzo [c, id] -2,7-naphthr? D? Na-3,6-diamine, 10-. { 2- [4- (d? Met? Lam? No) fen? L] etox ?} -11-methox? -4-meth? Ld? Benzo [c, l] -2,7-naphth? Pd? Na-3,6-diamine, 11-methox? -4-met? L-10- [2 - (1-met? Lp? Pepd? N-4-? L) ethoxy?] D? Benzo [c, r] -2,7-naft? Pd? Na-3,6-diamma, 11-methoxy? 4-met? L-10 - [(1-met? Lp? Per? D? N-3-? L) methox?] D? Benzo [c, /] - 2,7-naphthyridine -3,6-diamine, 1-. { 3 - [(7,10-d? Am? No-2-methox? -9-met? Ld? Benzo [c, /] -2,7-naphthyrid? 3-? L) ox ?] prop? l} pyrrolidone-2-one, 2- (6-am? no-10,11-d? methox? -4-met? ld? benzo [c, id] -2,7-naft? pd ? n-3-? l) -1 / -? so? ndol- 1,3 (2 / - /) - d? ona, 10,11-d? methox? -4-met? ld? benzo [c , /] - 2,7-naft? R? D? N-3-am? Na, 10,11-d? Methox? -? / 1,? / 1-d? Met? Ld? Benzo [c, r ] -2,7-naft? R? D? Na-1,6-d? Am? Na, 10,11-d? Methox? D? Benzo [c, /] - 2,7-naft? R? D ? na-3,6-d? am? na, 2,3-d? methox? d? benzo [c, /] - 2,7-naphthyridine, 10,11 -d? methox? -4-met? Ld? Benzo [c, /] - 2,7-naft? Pd? N-6-am? Na, 11-methox? -4-met? L-10- (3-met? Lbutox?) D? Benzo [c, id] -2,7-naft? Pd? Na-3,6-d? Am? Na, 10- (3,3-d? Met? Lbutox?) - 11-methox? -4-met? Ld? Benzo [c, í] -2,7-naft? Pd? Na-3,6-d? Am ? na, 10- [3- (benz? lox?) propox?] - 1 1-methox? -4-met? ld? benzo [c, /] - 2,7-naft? pd? na-3,6 -d? am? na, 10-. { [(2S) -1-benz? Lp? Rrol? D? N-2-? L] methox ?} -11-methox? -4-met? Ld? Benzo [c, r 2,7- naft? Pd? Na-3,6-d? Am? Na, 11-methox? -4-met? L-10- [((2S) -1- { [(2S) -1-met? Lp? Rrol? D? N-2-? L] met? L.}. P? Rrol? D? N-2-? l) methox?] d? benzo [c, r] -2,7-naft? pd? na-3,6-d? am? na, 10- (2-c? clopent? letox?) - 11-methox ? -4-met? Ld? Benzo [c, í] -2,7-naft? R? D? Na-3,6-d? Am? Na, 10- (2-c? Cloprop? Letox?) - 11-methox? -4-met? Ld? Benzo [c, /] - 2,7-naphthr? Na? Na-3,6-d? Am? Na, 10.1 1 -d? Methox? - ? / 6,4-d? Met? Ld? Benzo [c, f] -2,7-naft? R? D? Na-3,6-d? Am? Na, 10- (2-ethoxy? Ethoxy? ) -11-methox? -4-meth? Ld? Benzo [c, f] -2,7-naft? Pd? Na-3,6-d? Am? Na, 7,10-d? Am? No- 2-methox? -9-meth? Ld? Benzo [c, /] -2,7-naphth? Pd? N-3-ol, 3-chloro-10,1 1 -d? Methox? -4-met? ld? benzo [c, y] -2,7-naft? pd? n-6-am? na, 6-am? no-10,11-d? methox? -4-met? ld? benzo [c, ]] -2,7-naft? pd? n-3-ol, 3,10,11 -tr? methox? -4-met? ld? benzo [c, /] - 2,7-naft? pd? n 6-amin, 2,3,7, 10-tetramethoxy? -9-meth? Ld? Benzo [c, l] -2,7-naft? Pd? Na, 10, 11 -d? Methox? - 4-met? Ld? Benzo [c, y] -2,7-naphthr? Na? -3,6-d? Ol, 10-am? No-3-methox? -9-met? Ld? benzo [c, i] -2,7-naphthr? d? n-2-ol, or 11-methoxy? -10- (2-methox? ethoxy?) - 4- met? ld? benzo [c, f] -2,7-naft? pd? na-3,6-d? am? na, or a pharmaceutically acceptable salt thereof A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 22 and a physiologically acceptable carrier A method for treating a prophylactic disorder, the method comprises administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 22 The method of claim 24, wherein the proliferative disorder is cancer The method of claim 18, wherein the subject is a human A method for making a compound of claim 1, which comprises heating chemical reagents in a solvent having a boiling point greater than 100 ° C, the reactants are therefore reacted to form a compound of claim 1 The method of claim 27, wherein the solvent is ortho dichlorobenzene, diphenyl ether, polyethylene glycol, nitrobenzene, or ethoxyethanol The method of claim 27, wherein the solvent is ethoxyethanol The method of claim 27, further comprising using a proton catalyst The method of claim 30, wherein the catalyst comprises pipdin hydrochloride, para-toluenesulfonic acid, or PPTS, or a combination of these A method for making a compound of claim 1, comprising applying microwave radiation to the chemical reagents, which react to form a compound of claim 1