Fused quinoline compounds as pi3k / mtor inhibitors

Abstract

The present invention relates to compounds of Formula I, processes for their preparation, pharmaceutical compositions containing them as active ingredients, methods of treating disease conditions associated with protein kinase related cancers, their use as medicaments for producing an inhibitory effect on the reduction of mTor, pi3k in warm-blooded animals such as humans.

Description

TECHNICAL FIELD

[0001] The present invention relates to compounds, methods for their preparation, pharmaceutical compositions containing them as active ingredients, methods of treating disease conditions associated with protein kinase related cancers, their use as medicaments for producing an inhibitory effect on mTor, pi3k in warm-blooded animals such as humans. BACKGROUND

[0002] The phosphatidylinositol 3-kinase (PI3K) signaling axis influences cancer cell growth, survival, motility, and metabolism, J Clin Oncol 28: 1075-1083. The serine-threonine kinase mammalian target of rapamycin (mTor) also plays an important role in regulating protein translation, cell growth, and metabolism, J Clin Oncol 27: 2278-2287. In addition to their physiological roles, several isoforms of the PI3K family are involved in pathological processes and diseases. Alterations in the mTor signaling pathway are common in cancer and therefore mTor is being actively sought as a therapeutic target.

[0003] The present invention is based on the discovery that compounds of Formula I surprisingly inhibit the effect of mTor or pi3k / mTor. These compounds are a new class of compounds that have advantageous pharmacological properties that are valuable for treating disease conditions associated with various cancers such as but not limited to tumors of the colon, liver, lung, prostate, brain, breast; chronic myelogenous leukemia; Waldenstrom's macroglobulinemia; myelofibrosis; polycythemia vera; acute lymphoblastic leukemia; and other diseases such as but not limited to arthritis; autoimmune diseases; bacterial infections; macular degeneration; multiple sclerosis; neurodegeneration.

[0004] Examples of compounds similar in structure or kinase inhibition to the compounds of the present invention are disclosed in WO2006122806, WO2008103636, WO2004048365, WO07044698, WO07044729, and WO2009155527. SUMMARY

[0005] The present invention relates to compounds of Formula I:

[0006]

[0007] wherein

[0008] Q1and Q2are independently selected from aryl, 5-6 membered heterocyclyl, or 9-11 membered bicyclic heterocyclyl; Q1is halogen when R and R1are not present.

[0009] Z is N or C-R;

[0010] R and R1are independently selected from H, halogen, halogen C1-C6alkyl, -C1-C6alkyl, -OR7, or -NR7R8;

[0011] R2and R3are independently selected from H, halogen, -OH, -C1-C6alkyl, -C1-C6alkoxy, -C1-C6alkenyl, or -C1-C6alkynyl; R2is not -CF3;

[0012] R4and R5are independently selected from H, halogen, halogen C1-C6alkyl, -C1-C6alkyl, -OH, -C1-C6alkoxy, cycloalkyl; or R4and R5may combine together to form a 3-8 membered saturated or unsaturated ring, which can be an aliphatic ring group or a heterocyclic ring group;

[0013] R6is selected from H, -CH3, or -CN;

[0014] R7and R8are independently selected from H, halogen, -C1-C6alkyl, -C1-C6alkylOH, -C1-C6alkoxy, -C1-C6alkylNR4R5, -C(=O)C1-C6alkyl, -C(=O)C1-C6alkyl-R4R5, -C(=O)C1-C6alkylOH, -C(=O)C1-C6alkoxy, -C(=O)C1-C6alkylNR4R5, -C(=O)OC1-C6alkyl, -C(=O)OC1-C6alkylOH, -C(=O)OC1-C6alkoxy, -C(=O)OC1-C6alkylNR4R5, -C(=O)NR4C1-C6alkyl, -C(=O)NR4C1-C6alkyl-OH, -C(=O)-NR4C1-C6alkoxy, -C(=O)NR4C1-C6alkylNR4R5; or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION

[0015] The present invention relates to novel compounds of Formula I:

[0016] Q1and Q2are independently selected from aryl, 5-6 membered heterocyclyl, or 9-11 membered bicyclic heterocyclyl; preferably, Q1is independently selected from pyridyl, pyrimidinyl, quinolinyl, or quinazolinyl, and Q2is phenyl;

[0017] When R and R1are not present, Q1is halogen; preferably Br or I;

[0018] Z is N or C-R; preferably N;

[0019] R and R1are independently selected from H, halogen, halogen C1-C6alkyl, -C1-C6alkyl, -OR7, or -NR7R8; preferably H or -NR7R8

[0020] R2and R3are independently selected from H, -OH, -C1-C6alkyl, -C1-C6alkoxy, -C1-C6alkenyl, or -C1-C6alkynyl; R2is not -CF3; preferably independently selected from H, halogen, or -C1-C6alkyl, and R2is not -CF3;

[0021] R4and R5are independently selected from H, halogen, halogen C1-C6alkyl, -C1-C6alkyl, -OH, -C1-C6alkoxy, cycloalkyl; or R4and R5may be combined together to form a 3-8 membered saturated or unsaturated ring, which can be an aliphatic ring group or a heterocyclic ring group; preferably H, halogen C1-C6alkyl, -C1-C6alkyl, or both combined together to form a saturated aliphatic ring group or a heterocyclic ring group ring;

[0022] R6is selected from H, -CH3, or -CN; preferably -CH3or -CN;

[0023] R7and R8are independently selected from H, halogen, -C1-C6alkyl, -C1-C6alkylOH, -C1-C6alkoxy, -C1-C6alkylNR4R5, -C(=O)C1-C6alkyl, -C(=O)C1-C6alkyl-R4R5, -C(=O)C1-C6alkylOH, -C(=O)C1-C6alkoxy, -C(=O)C1-C6alkylNR4R5, -C(=O)OC1-C6alkyl, -C(=O)OC1-C6alkylOH, -C(=O)OC1-C6alkoxy, -C(=O)OC1-C6alkylNR4R5, -C(=O)NR4C1-C6alkyl, -C(=O)NR4C1-C6alkylOH, -C(=O)N-R4C1-C6alkoxy, -C(=O)NR4C1-C6alkylNR4R5; preferably independently selected from H, -C(=O)C1-C6alkyl, -C1-C6alkylNR4R5, or -C(=O)C1-C6alkylNR4R5;

[0024] or a pharmaceutically acceptable salt thereof.

[0025] The present invention relates to a compound of Formula I, which is useful in the treatment of neoplastic or proliferative or inflammatory diseases, or transplant disorders, especially those caused by excess or inappropriate protein kinases such as, but not limited to, mTor or pi3k / mTor.

[0026] The present invention relates to the use of a compound of Formula I for the manufacture of a medicament for the treatment of a neoplastic or proliferative or inflammatory disease, or a transplantation disorder, especially those caused by an excess or inappropriate activity of a protein kinase such as, but not limited to, mTor or pi3k / mTor.

[0027] The term "halogen" as used herein, unless otherwise indicated, includes fluorine, chlorine, bromine or iodine. Examples include fluorine and chlorine.

[0028] The term "haloCi-C6alkyl" as used herein, unless otherwise indicated, includes an alkyl group of 1 to 6 carbons substituted with a halogen, such as -CF3.

[0029] The term "-Ci-C6alkyl" as used herein, unless otherwise indicated, includes a saturated monovalent hydrocarbon group of 1 to 6 carbons having a straight or branched chain, including but not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, and the like.

[0030] The term "-Ci-C6alkenyl" as used herein, unless otherwise indicated, includes a -Ci-C6alkyl group as defined above having at least one carbon-carbon double bond, such as -CH2-CH=CH2.

[0031] The term "-Ci-C6alkynyl" as used herein, unless otherwise indicated, includes a -Ci-C6alkyl group as defined above having at least one C-C triple bond, such as -CH2-C≡CH.

[0032] The term "-Ci-C6alkoxy" as used herein, unless otherwise indicated, includes -OCi-C6alkyl, wherein the lower alkyl group is as defined above, such as methoxy and ethoxy.

[0033] The term "cycloalkyl" as used herein, unless otherwise indicated, includes cyclic groups having three to eight ring carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group can be optionally substituted one or more times with a substituent selected from the group of substituents defined above for aryl, preferably halogen, -Ci-C6alkyl.

[0034] The term "aryl" as used herein, unless otherwise indicated, includes organic radicals derived by removal of a hydrogen from an aromatic hydrocarbon, such as phenyl or naphthyl, preferably phenyl, and which is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, halogen-lower alkyl, lower alkyl, lower alkenyl, lower alkynyl, cyano, lower alkylcyano, hydroxy, lower alkoxy, carboxy, carboxyalkyl, amino, carbamoyl, carbamate, ureido, mercapto, sulfo, lower alkylsulfinyl, lower alkylsulfonyl, sulfonamide; aryl includes one aromatic ring fused to an aliphatic ring, such as a saturated or partially saturated ring, such as tetrahydronaphthyl.

[0035] The term "heterocyclyl" as used herein, unless otherwise indicated, includes non-aromatic saturated or partially saturated monocyclic and fused rings, each ring suitably containing up to four heteroatoms, each of which is independently selected from O, N and S, and which rings can be unsubstituted or independently substituted by, for example, up to three substituents. Each heterocycle suitably has 4 to 7, preferably 5 or 6 ring atoms. Fused heterocyclic systems can include carbocyclic rings and need include only one heterocyclic ring which can be partially saturated or saturated. Heterocyclyl includes monocyclic, bicyclic and tricyclic heteroaromatic ring systems containing up to four, preferably 1 or 2 heteroatoms, each selected from O, N and S. Each ring can have 4 to 7, preferably 5 or 6 ring atoms. Bicyclic or tricyclic systems can include carbocyclic rings. Carbocyclic rings include cycloalkyl, cycloalkenyl or aryl rings. Examples of heterocyclyl include, but are not limited to: azetidine, pyrrolidine, pyrrolidinone, piperidine, piperidone, piperazine, morpholine, oxetane, tetrahydrofuran, tetrahydropyran, imidazolidine, pyrazolidine and hydantoin, pyrrole, indole, pyrazole, indazole, triazole, benzotriazole, imidazole, benzimidazole, thiophene, benzothiophene, thiazole, benzothiazole, furan, benzofuran, oxazole, benzoxazole, isoxazole, tetrazole, pyridine, pyrimidine, trizine, quinoline, isoquinoline, quinazoline, indoline, indolinone, benzotetrahydrofuran, tetrahydroquinoline, tetrahydroisoquinoline, methylene-dioxyphenyl. Heterocycles can be substituted and the substituents are selected from the group of substituents as defined above for aryl.

[0036] The term "aliphatic ring" as used herein, unless otherwise indicated, includes cyclic saturated or unsaturated carbon compounds, not including aromatic compounds, such as cyclopropyl or cyclopropene, and the like.

[0037] In vitro kinase inhibitory activity including Pi3k and mTor activity can be tested by Millipore / Merck KGA of Europe with their kinase panel screen. Animal antitumor activity testing of compounds of Formula I can be performed by various cancer xenograft models.

[0038] The compounds of Formula I can be administered alone or in combination with one or more other therapeutic agents, including (but not limited to) 17a-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, megestrol acetate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, zoladex, matrix metalloproteinase inhibitors, suitable EGFR inhibitors include gefitinib, erlotinib and cetuximab. Pan Her inhibitors include canertinib, EKB-569 and GW-572016. VEGF inhibitors such as Avastin, ZD6474 and BAY-43-9006, SU11248, CP-547632 and CEP-7055. Also included are Src inhibitors and Casodex® (bicalutamide, AstraZeneca), tamoxifen, MEK-1 kinase inhibitors, MAPK kinase inhibitors and PDGF inhibitors such as imatinib. Also included are IGF1R inhibitors, inhibitors of non-receptor and receptor tyrosine kinases and inhibitors of integrin signaling. Also included are anti-angiogenic and anti-vascular agents, which cause cancer cells to go dormant by depriving them of nutrients by interrupting blood flow to solid tumors. Other cytotoxic agents include melphalan, hexamethylmelamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, topotecan, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.Other anticancer agents include microtubule-stabilizing agents such as paclitaxel, docetaxel, 09 / 712,352 filed November 14, 2000), C-4 methyl carbate paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D, desoxyepothilone A, desoxyepothilone and microtubule disassembly agents. Also suitable are CDK inhibitors, antiproliferative cell cycle inhibitors, epidophyllotoxins, antineoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; anti-hormone therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors. Castration can also be utilized which also renders androgen-related carcinomas non-proliferative. Possible combination therapies take the form of fixed combinations or administration of the compounds of the application and one or more other therapeutic agents given in sequence or independently of each other, or the combined administration of a fixed combination and one or more other therapeutic agents.

[0039] In addition or in the alternative, the compounds of formula I can be administered in particular for tumor therapy in combination with chemotherapy, radiotherapy, surgical intervention or a combination of these therapies. As mentioned above, long-term therapy is likewise possible as is generally the case with adjuvant therapy as part of other therapeutic strategies. Other possible treatments are therapy to maintain the status of the patient after tumor regression or even chemopreventive therapy (for example in patients at risk). The compounds of formula I are suitable for the treatment of a variety of cancers, including but not limited to the following: (a) carcinomas, including bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (including small-cell lung cancer), cancer of the esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); (b) hematopoietic tumors of lymphoid lineage: including leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma; (c) hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (d) tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannoma; and (f) other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer and Kaposi's sarcoma.

[0040] The compounds of the present application are useful not only for the management of humans, but also for the treatment of other warm-blooded animals, such as commercially useful animals. Such compounds can also be used as reference standards in the test systems described above to allow comparison with other compounds.

[0041] Salts are especially pharmaceutically acceptable salts of the compounds of Formula I. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art, and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids e.g. succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthalenesulfonic acid. Other salts can be useful, e.g. in the isolation or purification of a compound of Formula I, and are included within the scope of the application.

[0042] The compounds of the present application can be in crystalline or non-crystalline form and, if in crystalline form, can optionally be hydrated or solvated. The present application includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water.

[0043] The present application extends to all isomeric forms, including stereoisomers and geometric isomers of the compounds of Formula I, including enantiomers, and mixtures thereof, such as racemates. The different isomeric forms can be separated or resolved from each other by conventional methods or any given isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0044] One skilled in the art will recognize various synthetic methodologies that can be used to prepare nontoxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I. One skilled in the art will recognize a variety of nontoxic pharmaceutically acceptable solvents that can be used to prepare solvates of the compounds of the present application, such as water, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide.

[0045] The compounds of Formula I can be administered in dosages units formulations containing conventional non-toxic pharmaceutically-acceptable vehicles, adjuvants, and vehicles. Oral administration, topical administration, parenteral administration by injection or infusion, or rectal administration are preferred. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit formulations for injection or infusion can be presented in unit dosage form, e.g., in ampules or in multidose containers containing a preservative. Formulations for parenteral administration include aqueous solutions of the active compounds in water- soluble form. These preparations for injections or infusions can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood. Compositions containing a compound of Formula I can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0046] Compositions intended to be administered orally can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients that are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.

[0047] Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil for example peanut oil, liquid paraffin or olive oil.

[0048] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally occurring phosphatide, for example, lecithin, or an ester or partial ester of a fatty acid, for example, polyoxyethylene sorbitan monooleate, or a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, or a condensation product of an alkylene oxide with long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol, or a condensation product of an alkylene oxide with a partial ester derived from a fatty acid and a hexitol, for example, polyoxyethylene sorbitol monooleate, or a condensation product of an alkylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example, polyoxyethylene sorbitan monooleate. The aqueous suspensions can also contain one or more preservatives, for example, ethyl, or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents, such as sucrose or saccharin.

[0049] Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. The oily suspensions can contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant, for example, ascorbic acid.

[0050] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

[0051] The pharmaceutical compositions of this application can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of these. Suitable emulsifying agents can be naturally occurring gums, for example, acacia or gum tragacanth; naturally occurring phosphatide, for example, soya bean, lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate; and condensation products of these partial esters with alkylene oxides, for example, polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents.

[0052] Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose, if desired, can contain a demulcent, preservative, flavoring and coloring agent.

[0053] The compounds can also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal or vaginal temperature and therefore will melt in the rectum or vaginal cavity to release the drug. Such materials include cocoa butter and polyethylene glycols.

[0054] The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0055] The compounds of the present application can also be administered transdermally using methods known to those skilled in the art (see for example: Chien; "Transdermal Controlled Systemic Medications"; Marcel Dekker, Inc.; 1987. Lipp et al. WO 94 / 04157).

[0056] The compounds of Formula I can be administered parenterally by injection, including intravenous, subcutaneous, intravenous, intramuscular, or intrasternal injection. The compounds can be administered in a form suitable for injection, for example, as a sterile solution or suspension in a sterile vehicle. Suitable vehicles include, but are not limited to, water, saline, dextrose solution, and the like. The solution can be filtered sterile and packaged in unit or multi-dose containers. The injectable form can include additives such as preservatives, buffers, and agents for bulking the formulation. The injectable form can also include additives such as local anesthetics, preservatives and buffers, as would be known to one of skill in the art.

[0057] For administration to non-human animals, the compositions can also be added to the animal's feed or drinking water. These animal feed and drinking water compositions are desirably formulated so that the animal ingests an appropriate amount of the composition with its diet. The compositions are also desirably presented in pre-mix form for addition to the feed or drinking water.

[0058] For all dosage regimens contemplated herein for the compounds of Formula I, the oral daily dosage regimen will preferably be from 0.01 to 200 mg per kilogram of body weight. The daily dosage regimen by injection (including intravenous, intramuscular, subcutaneous, and parenteral injections) and using infusion techniques will preferably be from 0.01 to 200 mg per kilogram of body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg per kilogram of body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg per kilogram of body weight. The daily topical dosage regimen will preferably be from 0.01 to 200 mg, given between one and four times daily. The transdermal concentration will preferably be that concentration necessary to maintain a daily dosage of from 0.01 to 200 mg per kilogram. The daily inhalation dosage regimen will preferably be from 0.01 to 200 mg per kilogram of body weight.

[0059] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

[0060] Preferred compounds of the application will have certain pharmacological properties. Such properties include, but are not limited to, oral bioavailability, low toxicity, low degree of serum protein binding, and desired in vitro and in vivo half-lives. Assays to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Cultured hepatocyte toxicity can be used to predict compound toxicity. Degree of serum protein binding can be predicted from albumin binding assays. Compound half-life is inversely related to the frequency of dosing of the compound. In vitro half-life of a compound can be predicted from microsomal half-life assays.

[0061] Representative examples of the preparation of the application are given in Scheme I - Scheme II. One skilled in the art will recognize that the starting materials can vary and that other procedures can be used to produce the compounds encompassed by the application.

[0062] Scheme I

[0063]

[0064] Hal is halogen, preferably Br and I;

[0065] Q1, Q2, R, R1, R2, R3, R4, R5, R6 are as defined above.

[0066] Scheme II

[0067]

[0068] R1is selected from:

[0069] -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -NHCO(CH2)nCH3, -NHCO(CH2)nNH2, -NHCO(CH2)nNHCH3, -NHCO(CH2)nN(CH3)2, -NHCO(CH2)n-pyrrolidine, -NHCO(CH2)n-piperazine, -NHCO(CH2)n-morpholine, -NH(CH2)nNHCH3, -NH(CH2)nN(CH3)2, -NH(CH2)n-pyrrolidine, -NH(CH2)n-piperazine, -NH(CH2)n-morpholine;

[0070] n = 1, 2, 3 or 4;

[0071] R3 is H or -Ci-C6alkyl;

[0072] Q1 is independently selected from pyridine, pyrimidine, quinoline or quinazoline;

[0073] The following examples of Formula II (but not limited thereto) can also be prepared analogously according to the methods described in Scheme I - Scheme II.

[0074]

[0075] wherein

[0076] Q1 is independently selected from aryl, 5-6 membered heterocyclyl or 9-11 membered bicyclic heterocyclyl; preferably, Q1 is independently selected from pyridyl, pyrimidyl, quinolinyl or quinazolinyl;

[0077] When R and R1 are not present, Q1 is halogen; preferably Br or I;

[0078] Z is N or C-R; preferably N;

[0079] R and R1 are independently selected from H, halogen, halogen Ci-C6alkyl, -Ci-C6alkyl, -OR7 or -NR7R8; preferably H or -NR7R8

[0080] R2 and R3 are independently selected from H, -OH, -Ci-C6alkyl, -Ci-C6alkoxy, -Ci-C6alkenyl or -Ci-C6alkynyl; R2 is not -CF3; preferably, independently selected from H, halogen or -Ci-C6alkyl, and R2 is not -CF3;

[0081] R4 and R5 are independently selected from H, halogen Ci-C6alkyl, -Ci-C6alkyl or two are combined together to form a saturated aliphatic or heterocyclyl ring;

[0082] R7and R8are independently selected from H, halogen, -Ci-C6alkyl, -Ci-C6alkylOH, -Ci-C6alkoxy, -Ci-C6alkylNR4R5, -C(=O)Ci-C6alkyl, -C(=O)Ci-C6alkyl-R4R5, -C(=O)Ci-C6alkylOH, -C(=O)Ci-C6alkoxy, -C(=O)Ci-C6alkylNR4R5, -C(=O)OCi-C6alkyl, -C(=O)OCi-C6alkylOH, -C(=O)OCi-C6alkoxy, -C(=O)OCi-C6alkylNR4R5, -C(=O)NR4Ci-C6alkyl, -C(=O)NR4Ci-C6alkylOH, -C(=O)NR4Ci-C6alkoxy, -C(=O)NR4Ci-C6alkylNR4R5; preferably independently from H, -C(=O)Ci-C6alkyl, -Ci-C6alkylNR4R5or -C(=O)Ci-C6alkylNR4R5;

[0083] or a pharmaceutically acceptable salt thereof.

[0084] The following compounds or pharmaceutically acceptable salts thereof (but not limited thereto) can also be similarly prepared according to the methods described in Scheme I - Scheme II. Their inhibitory effects on mTor or pi3k kinases or tumor cell lines were also tested.

[0085]

[0086] wherein

[0087]

[0088]

[0089]

[0090] In some cases, it can be necessary to protect certain reactive functional groups to obtain some of the above transformations. Generally, the need for such protecting groups will be recognized by one skilled in the art, as will the necessity and manner for effecting cleavage or removal of such groups. One skilled in the art will recognize the need for utilizing different solvents or reagents in order to obtain some of the above transformations.

[0091] The disclosures of all articles and references cited herein (including patents) are expressly incorporated herein by reference in their entireties.

[0092] The present application is further illustrated by the following examples which are not to be considered as limiting the scope or spirit of the application to the specific procedures described therein.

[0093] Starting materials and various intermediates can be obtained from commercial sources, prepared from commercially available organic compounds or prepared using well known synthetic methods. Representative methods for preparing the intermediates of the present application are set forth in the examples below. The following abbreviations have been used and others are standard chemical notation.

[0094] DCM: dichloromethane, DMF: N,N-dimethylformamide, HOBt: 1-hydroxy- benzotriazole hydrate, EDC: l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, DPPA: diphenylphosphoryl azide, (dppf)2PdCl2: [l,l'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll), g: gram, mg: milligram, ml: milliliter.

[0095] Example 1

[0096] Preparation of 2-methyl-2-{4-[12-methyl-4-(quinolin-3-yl)-8,11,13,14,16- pentaazatetracyclo-[8.6.0.0 2,7 ,.0 11,15 ]hexadeca-l(10),2,4,6,8,12,14-heptaen-16-yl]phenyl}propionitrile

[0097] A mixture of 4-bromoaniline (17.2 g, 0.1 mol) and diethyl ethoxymethylene malonate (21.6 g, 0.1 mol) was heated at 130 °C for 2 h (monitored by TLC for the consumption of starting material). After cooling to room temperature, the reaction was concentrated under reduced pressure to give diethyl 2-((4-bromo- phenylamino)methylene)malonate (Compound 1, 30.5 g, 89%) as a light yellow solid.

[0098] Compound 1 (30.5 g, 0.0892 mol) was added to preheated refluxing diphenyl ether (50 ml) over ~ 15 min. The resulting mixture was heated under reflux for ~ 1 to 2 h until the bubbling ceased. After cooling to room temperature, the solid was collected and dried to give ethyl 6-bromo-4-oxo-l,4-dihydroquinoline-3-carboxylate (Compound 2, 25.4 g, 88%) as an off-white solid.

[0099] Compound 2 (19.4 g, 0.06 mol) was suspended in POCl3(45 ml) and heated under reflux for 1 h. The excess solvent was evaporated under reduced pressure and the dark brown residue was dissolved in dichloromethane (150 ml) and washed sequentially with water (100 ml), saturated sodium bicarbonate (100 ml) and brine (100 ml). The organic phase was dried over sodium sulfate, the solids were filtered off and the filtrate was concentrated to give ethyl 6-bromo-4-chloroquinoline-3-carboxylate (Compound 3, 17.67 g, 93.8%) as a light yellow solid.

[0100] A mixture of compound 3 (6.75 g, 0.0215 mol) and 2-(4-aminophenyl)-2- methylpropanenitrile (compound 4, 3.72 g, 0.0233 mol) in 2-propanol (25 ml) was heated under reflux for 30 minutes. The precipitated solid was collected and dried to give ethyl 6-bromo-4-(4-(2-cyanopropan-2-yl)phenylamino)quinoline-3-carboxylate (compound 5, 8.35 g, 88.9%) as a bright yellow solid.

[0101] Compound 5 (8.35 g, 0.0191 mol) was suspended in ethanol (60 ml) and 2N sodium hydroxide (12 ml) was added at room temperature. The resulting mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was dissolved in water (100 ml) and methanol (10 ml). The solution was acidified to pH 3 by acetic acid and the precipitated solid was collected and washed thoroughly with water before drying to give 6-bromo-4-(4-(2-cyanopropan-2-yl)phenylamino)quinoline-3-carboxylic acid (compound 6, 7.25 g, 92.8%) as a bright yellow solid.

[0102] To a suspension of compound 6 (3.4 g, 8.31 mmol) in toluene (100 ml) was added DMF (5 ml), triethylamine (2.5 ml, 18.28 mmol) and DPPA (5.1 g, 18.55 mmol). The resulting mixture was heated at 85-95 °C for 4 hours before cooling to room temperature. The solid was collected, washed with hexane and dried to give 2-(4-(8-bromo-2-oxo-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l- yl)phenyl)-2-methylpropanenitrile (compound 7, 2.42 g, 71.7%) as a light yellow solid.

[0103] To a suspension of compound 7 (5.68 g, 13.99 mmol) in phosphorous oxychloride (80 ml) was added N,N-diisopropylethylamine (24 ml) and the mixture was heated under reflux for 40 hours. After cooling to room temperature, the excess solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane (150 ml) before washing the organic phase sequentially with water (100 ml), saturated sodium bicarbonate (100 ml) and brine (100 ml). The organic phase was dried over sodium sulfate, the solid was filtered off and the filtrate was concentrated to give 2-(4-(8-bromo-2-chloro-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)-2- methylpropanenitrile (compound 8, 5.67 g, 95.8%) as a brown solid.

[0104] To a suspension of compound 8 (1.82 g, 4.29 mmol) in ethanol (80 ml) was added hydrazine monohydrate (2 ml) and the resulting mixture was heated at reflux for 3 h (reaction monitored by TLC). After cooling to room temperature, the reaction solution was concentrated under reduced pressure, then the residue was dissolved in dichloromethane (50 ml) and washed sequentially with water (50 ml) and brine (50 ml). The organic phase was dried over sodium sulfate, the solids were filtered off, and the filtrate was concentrated to give 2-(4-(8-bromo-2-hydrazinyl- lH-imidazo[4,5-c]quinolin-l-yl)phenyl)-2-methylpropanenitrile (compound 9, 1.32 g, 73.4%) as a dark brown solid. A 38 ml sealed tube was charged with compound 9 (383 mg, 0.913 mmol), triethyl orthoacetate (5 ml), and hydrogen chloride (37%, 5 drops). The sealed tube was sealed and heated at reflux for 10 h. After cooling to room temperature, the precipitated solid was collected and dried to give 2-(4-{4-bromo-12-methyl-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2，7 .0 11，15 ]hexadeca-l(10),2,4,6,8,12,14-heptaen-16-yl}phenyl)-2-methylpropanenitrile (compound 10, 196 mg, 48.4%) as a gray solid.

[0105] A 50 ml round flask was charged with compound 10 (64 mg, 0.144 mmol), 3- quinolineboronic acid (35 mg, 0.20 mmol), chlorobis(triphenylphosphine)palladium(II) (2.5 mg, 0.0036 mmol), sodium carbonate monohydrate (18 mg, 0.145 mmol), DMF (5 ml), and water (0.5 ml). The mixture was degassed three times, filled with nitrogen, and heated at 110 °C for 24 h. The reaction mixture was dissolved in dichloromethane (50 ml), washed with water (30 ml) and brine (30 ml), then dried over sodium sulfate, the solids were filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC to give the title compound (40 mg, 62.5%) as a light brown solid.

[0106] Example 2

[0107] Preparation of 2-methyl-2-{4-[4-(quinolin-3-yl)-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11 ,15 hexadeca-l(10),2,4,6,8,12,14-heptaen-16-yl]phenyl}propanenitrile

[0108] A 50 ml round bottom flask was charged with compound 9 (86 mg, 0.205 mmol), triethyl orthoformate (2 ml) and hydrogen chloride (37%, 1 drop). The mixture was heated at 130 °C for 24 hours. After cooling to room temperature, the precipitated solid was collected and dried to give 2-(4-{4-bromo-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaen-16-yl}phenyl)-2-methylpropanenitrile (compound 12, 31 mg, 35%).

[0109] A 50 ml round bottom flask was charged with compound 12 (29 mg, 0.067 mmol), 3- quinolineboronic acid (17.5 mg, 0.1 mmol), bis(triphenylphosphine)palladium(II) chloride (1.1 mg, 0.0016 mmol), sodium carbonate monohydrate (7.1 mg, 0.067 mmol), DMF (2.5 ml) and water (0.25 ml). The mixture was degassed three times, filled with nitrogen and heated at 100 °C for 1 hour. The reaction mixture was dissolved in dichloromethane (50 ml), washed with water (30 ml) and brine (30 ml), then dried over sodium sulfate, the solid was filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by flash column using 4% methanol / ethyl acetate to give the title compound as a light brown solid (14 mg, 46.3%).

[0110] Example 3

[0111] Preparation of 2-{4-[12-methyl-4-(pyridin-3-yl)-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2, 7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaen-16-yl]phenyl}-2-methylpropanenitrile

[0112] A 50 ml round bottom flask was charged with compound 12 (29 mg, 0.067 mmol), 3- quinolineboronic acid (17.5 mg, 0.1 mmol), bis(triphenylphosphine)palladium(II) chloride (1.1 mg, 0.0016 mmol), sodium carbonate monohydrate (7.1 mg, 0.067 mmol), DMF (2.5 ml) and water (0.25 ml). The mixture was degassed three times, filled with nitrogen and heated at 100 °C for 1 hour. The reaction mixture was dissolved in dichloromethane (50 ml), washed with water (30 ml) and brine (30 ml), then dried over sodium sulfate, the solid was filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by flash column using 4% methanol / ethyl acetate to give the title compound as a light brown solid (14 mg, 46.3%). 2,7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaen-16-yl}phenyl)-2-methylpropanenitrile (compound 12, 31 mg, 35%).

[0113] A 50 ml round flask was charged with methyl triazole bromide (compound 15, 57 mg, 0.124 mmol), 3-pyridineboronic acid (23 mg, 0.19 mmol), palladium (II) bis(triphenylphosphine)chloride (2.2 mg, 0.0031 mmol), sodium carbonate monohydrate (16 mg, 0.124 mmol), DMF (4 ml) and water (0.4 ml). The mixture was degassed three times, filled with nitrogen and heated at 100 °C for 24 hours. The reaction mixture was dissolved in dichloromethane (50 ml), washed with water (30 ml) and brine (30 ml), then dried over sodium sulfate, the solid was filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (1.5:1 ethyl acetate:methanol) to give the title compound as a light brown solid (52 mg, 91.8%).

[0114] The following compound examples were similarly prepared according to the methods described in Examples 1-4 by using 4-tert-butylaniline and different boronic acids.

[0115] 16-(4-tert-Butylphenyl)-4-(bromo-3-yl)-8,11,13,14,16-pentaazatetracyclo-[8.6.0.0 2, 7 .0 11,15 ]-hexadeca-1(10),2,4,6,8,12,14-heptaene;

[0116] 2-(4-{4-bromo-8,11,13,14,16-pentaazatetracyclo-[8.6.0.0 2,7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaen-16-yl}phenyl)-2-methylpropanenitrile;

[0117] 16-(4-tert-Butylphenyl)-4-(bromo-3-yl)-12-methyl-8,11,13,14,16-pentaazatetracyclo-[8.6.0.0 2,7 .0 11,15 ]-hexadeca-1(10),2,4,6,8,12,14-heptaene;

[0118] 2-(4-{4-bromo-12-ethyl-8,11,13,14,16-pentaazatetracyclo-[8.6.0.0 2,7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaen-16-yl}phenyl)-2-methylpropanenitrile;

[0119] 16-(4-tert-Butylphenyl)-4-(bromo-3-yl)-12-ethyl-8,11,13,14,16-pentaazatetracyclo- [8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaene;

[0120] 2-Methyl-2-{4-[4-(pyridin-3-yl)-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]-hexadeca- 1 (10),2,4,6,8,12,14-heptaen-16-yl]phenyl}propanenitrile;

[0121] 2-Methyl-2-{4-[12-methyl-4-(pyridin-3-yl)-8,11,13,14,16-pentaazatetracyclo- [8.6.0.0 2 ,7 .0 11,15 ]-hexadeca- 1 (10),2,4,6,8,12,14-heptaen-16-yl]phenyl}propanenitrile;

[0122] 1-{4-[4-(quinolin-3-yl)-8,11,13,14,16-pentaazatetracyclo-[8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaen-16-yl]phenyl}cyclopentan- 1 -carbonitrile;

[0123] 1-{4-[12-methyl-4-(pyridin-3-yl)-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaen-16-yl]phenyl}cyclopentan- 1 -carbonitrile;

[0124] 1-{4-[12-methyl-4-(pyridin-3-yl)-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaen-16-yl]phenyl}cyclopropan- 1 -carbonitrile;

[0125] 2-Methyl-2-{4-[12-methyl-4-(pyridin-4-yl)-8,11,13,14,16-pentaazatetracyclo- [8.6.0.0 2 ,7 .0 11,15] -hexadecan- 1 (10), 2, 4, 6, 8, 12, 14-hepten- 16-yl] phenyl} propionitrile;

[0126] 4-(4-Fluorophenyl)-12-methyl-16-[4-(2-methylbut-3-yn-2-yl)phenyl]-8,11,13,14,16- pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadecan- 1 (10), 2, 4, 6, 8, 12, 14-heptene;

[0127] 4-(3-Fluorophenyl)-12-methyl-16-[4-(2-methylbut-3-yn-2-yl)phenyl]-8,11,13,14,16- pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadecan- 1 (10), 2, 4, 6, 8, 12, 14-heptene;

[0128] 4-(3,4-Difluorophenyl)-12-methyl-16-[4-(2-methylbut-3-yn-2-yl)phenyl]-8,11,13,14,16- pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadecan- 1 (10), 2, 4, 6, 8, 12, 14-heptene;

[0129] 4-(2-Fluorophenyl)-12-methyl-16-[4-(2-methylbut-3-yn-2-yl)phenyl]-8,11,13,14,16- pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadecan- 1 (10), 2, 4, 6, 8, 12, 14-heptene;

[0130] 16-(4-tert-Butylphenyl)-12-methyl-4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-8,11,13,14,16- pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadecan- 1 (10), 2, 4, 6, 8, 12, 14-heptene;

[0131] N-{5-[16-(4-tert-Butylphenyl)-12-methyl-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2, 7 .0 11,15 ]hexadecan- 1 (10), 2, 4, 6, 8, 12, 14-heptene-4-yl]pyridin-2-yl}acetamide;

[0132] 16-(4-tert-Butylphenyl)-4-(6-methoxypyridin-3-yl)-12-methyl-8,11,13,14,16- pentazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaene;

[0133] 16-(4-tert-Butylphenyl)-12-methyl-4-(pyrimidin-5-yl)-8,11,13,14,16-pentazatetracyclo- [8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaene;

[0134] 16-(4-tert-Butylphenyl)-12-methyl-4-(pyridin-3-yl)-8,11,13,14,16-pentazatetracyclo- [8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaene;

[0135] 2-{4-[4-(6-Aminopyridin-3-yl)-8,11,13,14,16-pentazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaen-16-yl]phenyl}-2-methylpropanenitrile;

[0136] 2-Methyl-2-{4-[4-(pyrimidin-5-yl)-8,11,13,14,16-pentazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaen-16-yl]phenyl}propanenitrile;

[0137] N-{5-[16-(4-tert-Butylphenyl)-8,11,13,14,16-pentazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaen-4-yl]pyridin-2-yl}acetamide;

[0138] 16-(4-tert-Butylphenyl)-4-{ 1 H-pyrrolo[2,3-b]pyridin-5-yl}-8,11,13,14,16- pentazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaene;

[0139] 5-[16-(4-tert-Butylphenyl)-8,11,13,14,16-pentazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaen-4-yl]pyridin-2-amine;

[0140] 5-[16-(4-tert-Butylphenyl)-12-methyl-8,11,13,14,16-pentazatetracyclo[8.6.0.0 2,7 .0 11 ,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaen-4-yl]pyridin-2-amine;

[0141] 16-(4-tert-Butylphenyl)-4-(6-methoxypyridin-3-yl)-8,11,13,14,16-pentazatetracyclo- [8.6.0.0 2,7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaene;

[0142] 16-(4-tert-Butylphenyl)-4-(pyrimidin-5-yl)-8,11,13,14,16-pentazatetracyclo[8.6.0.0 2, 7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaene;

[0143] 16-(4-tert-Butylphenyl)-4-(pyridin-3-yl)-8,11,13,14,16-pentazatetracyclo[8.6.0.0 2, 7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaene;

[0144] 2-[4-(12-Ethyl-4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-8,11,13,14,16-pentazatetracyclo- [8.6.0.0 2,7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaen-16-yl)phenyl]-2-methylpropanenitrile;

[0145] N-(5-{16-[4-(1-Cyano-1-methylethyl)phenyl]-12-ethyl-8,11,13,14,16-pentazatetracyclo- [8.6.0.0 2,7 .0 11,15[Hexadecyl-1(10),2,4,6,8,12,14-heptaen-4-ylpyridin-2-yl)acetamide;

[0146] 5-{12-ethyl-16-[4-(2-methylbut-3-yn-2-yl)phenyl]-8,11,13,14,16-pentazatetracyclo-[8.6.0.0] 2,7 .0 11,15 [Hexadecyl-1(10),2,4,6,8,12,14-heptaen-4-ylpyridin-2-amine;]

[0147] 2-{4-[12-ethyl-4-(pyrimidin-5-yl)-8,11,13,14,16-pentazatetracyclo[8.6.0.0]} 2,7 .0 11,15 [-Hexadecyl-1(10),2,4,6,8,12,14-heptaen-16-yl]phenyl}-2-methylpropionitrile;

[0148] 12-Ethyl-4-(6-methoxypyridin-3-yl)-16-[4-(2-methylbut-3-yn-2-yl)phenyl]-8,11,13,14,16-pentazatetracyclo[8.6.0.0] 2,7 .0 11,15 Hexadec-1(10),2,4,6,8,12,14-heptaene;

[0149] 2-Methyl-2-[4-(4-{1H-pyrrolo[2,3-b]pyridin-4-yl}-8,11,13,14,16-pentazatetracyclo-[8.6.0.0] 2,7 .0 11,15 [hexadecyl-1(10),2,4,6,8,12,14-heptaen-16-yl)phenyl]propionitrile;

[0150] N-(5-{16-[4-(1-cyano-1-methylethyl)phenyl]-12-methyl-8,11,13,14,16-pentazatetracyclo-[8.6.0.0] 2,7 .0 11,15 [Hexadecyl-1(10),2,4,6,8,12,14-heptaen-4-ylpyridin-2-yl)acetamide;

[0151] N-(5-{16-[4-(1-cyano-1-methylethyl)phenyl]-8,11,13,14,16-pentazatetracyclo-[8.6.0.0] 2,7 .0 11,15 [Hexadecyl-1(10),2,4,6,8,12,14-heptaen-4-ylpyridin-2-yl)acetamide;

[0152] 2-methyl-2-{4-[12-methyl-4-(pyrimidin-5-yl)-8,11,13,14,16-pentaazatetracyclo- [8.6.0.0 2 ,7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaen-16-yl]phenyl}propanenitrile;

[0153] 4-(6-methoxypyridin-3-yl)-12-methyl-16-[4-(2-methylbut-3-yn-2-yl)phenyl]- 8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaene;

[0154] 2-methyl-2-[4-(12-methyl-4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-8,11,13,14,16- pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaen-16-yl]phenyl}propanenitrile;

[0155] 2-{4-[4-(6-aminopyridin-3-yl)-12-methyl-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2, 7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaen-16-yl]phenyl}-2-methylpropanenitrile;

[0156] 5-[16-(4-tert-butylphenyl)-12-methyl-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11 ,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaen-4-yl]-4-(trifluoromethyl)pyridin-2-amine;

[0157] 5-[16-(4-tert-butylphenyl)-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca-1(10),2,4,6,8,12,14-heptaen-4-yl]-4-(trifluoromethyl)pyridin-2-amine;

[0158] 16-(4-tert-Butylphenyl)-12-ethyl-4-(pyridin-3-yl)-8,11,13,14,16-pentaazatetracyclo- [8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaene;

[0159] 5-[16-(4-tert-Butylphenyl)-12-ethyl-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11 ,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaen-4-yl]pyridin-2-amine;

[0160] 2-(4-{4-[6-amino-4-(trifluoromethyl)pyridin-3-yl]-8,11,13,14,16-pentaazatetracyclo- [8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaen-16-yl}phenyl)-2-methylpropanenitrile;

[0161] 2-{4-[4-(6-aminopyridin-3-yl)-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaen-16-yl]phenyl}-2-methylpropanenitrile;

[0162] 5-[16-(4-tert-Butylphenyl)-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaen-4-yl]pyridin-2-amine;

[0163] Example 4

[0164] Preparation of 2-amino-N-(5-{16-[4-(l-cyano-l-methylethyl)phenyl]-8,11,13,14,16- pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadeca- 1 (10),2,4,6,8,12,14-heptaen-4-yl}pyridin-2-yl)acetamide

[0165] To a mixture of 2-amino-5-bromopyridine (4 g, 22.86 mmol) and boc-glycine (4 g, 22.86 mmol) in DCM (200 ml) was added EDC (4.4 g, 22.86 mmol) and HOBt (3.5 g, 22.86 mmol), the reaction was stirred and heated at 40 °C for 18 h. The reaction was allowed to cool and washed with 0.25 N HC1 (100 ml) followed by saturated NaHC03(100 ml). The organic layer was further washed with brine and dried over sodium sulfate, then evaporated under reduced pressure to give tert-butyl 2-(5-bromopyridin-2-ylamino)-2-oxoethylcarbamate 1.4 g.

[0166] A mixture of the above amide (660 mg, 2 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bis(l,3,2-dioxaborolane) (1 g, 4 mmol), KOAc (1 g, 10 mmol) and (dppf)2PdCl2(100 mg) in dioxane (20 ml) was heated at 110 °C for 2 h. To the above cooled reaction was added compound 12 (430 mg, 1 mmol), chloro(bis-triphenylphosphine) palladium (II) (85 mg), 2 N Na2C03(1.3 ml) and dioxane (15 ml), the reaction was heated to 110 °C for 10 h. The reaction mixture was dissolved in dichloromethane (50 ml), washed with water (30 ml) and brine (30 ml), then dried over sodium sulfate, the solid was filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by column to give the boc protected title compound (140 mg), which was mixed with 4 N HC1 dioxane (10 ml) and stirred for 1 h. The reaction was then basified with Na2C03and extracted with ethyl acetate (25 ml) twice, washed with brine (30 ml), then dried over sodium sulfate, the solid was filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC to give the title product (75 mg).

[0167] The following compound example was similarly prepared according to the method described in Example 4 by using 4-tert-butylaniline and boronate esters of different side chains.

[0168] N-(5-{16-[4-(l-cyano-l-methylethyl)phenyl]-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 .0

[0169] N-(5-{16-[4-(1-cyano-1-methylethyl)phenyl]-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]-hexadec-1(10),2,4,6,8,12,14-heptaen-4-yl}pyridin-2-yl)-2-(cyclohexylamino)acetamide;

[0170] N-(5-{16-[4-(1-cyano-1-methylethyl)phenyl]-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]-hexadec-1(10),2,4,6,8,12,14-heptaen-4-yl}pyridin-2-yl)-2-(oxan-4-ylamino)acetamide;

[0171] N-(5-{16-[4-(1-cyano-1-methylethyl)phenyl]-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]-hexadec-1(10),2,4,6,8,12,14-heptaen-4-yl}pyridin-2-yl)-2-(thian-4-ylamino)acetamide;

[0172] N-(5-{16-[4-(1-cyano-1-methylethyl)phenyl]-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]-hexadec-1(10),2,4,6,8,12,14-heptaen-4-yl}pyridin-2-yl)-2-(dimethylamino)acetamide;

[0173] N-(5-{16-[4-(1-cyano-1-methylethyl)phenyl]-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]-hexadec-1(10),2,4,6,8,12,14-heptaen-4-yl}pyridin-2-yl)-2-(methylamino)acetamide

[0174] 16-(4-tert-butylphenyl)-4-(quinolin-3-yl)-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2, 7 .0 11,15 ]-hexadec-1(10),2,4,6,8,12,14-heptaene;

[0175] N-(5-{16-[4-(1-cyano-1-methylethyl)phenyl]-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]-hexadecan-1(10),2,4,6,8,12,14-heptaen-4-yl}pyridin-2-yl)-2-(4-oxopiperidin-1-yl)acetamide;

[0176] N-(5-{16-[4-(1-cyano-1-methylethyl)phenyl]-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]-hexadecan-1(10),2,4,6,8,12,14-heptaen-4-yl}pyridin-2-yl)-2-(4-hydroxypiperidin-1-yl)acetamide;

[0177] N-(5-{16-[4-(1-cyano-1-methylethyl)phenyl]-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]-hexadecan-1(10),2,4,6,8,12,14-heptaen-4-yl}pyridin-2-yl)-2-(4-methylpiperazin-1-yl)acetamide

[0178] N-(5-{16-[4-(1-cyano-1-methylethyl)phenyl]-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]-hexadecan-1(10),2,4,6,8,12,14-heptaen-4-yl}pyridin-2-yl)-2-(morpholin-4-yl)acetamide;

[0179] N-(5-{16-[4-(1-cyano-1-methylethyl)phenyl]-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]-hexadecan-1(10),2,4,6,8,12,14-heptaen-4-yl}pyridin-2-yl)-2-(pyrrolidin-1-yl)acetamide;

[0180] N-{5-[16-(4-tert-butylphenyl)-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]hexadecan-1(10),2,4,6,8,12,14-heptaen-4-yl]pyridin-2-yl}-2-(pyrrolidin-1-yl)acetamide;

[0181] N-{5-[16-(4-tert-Butylphenyl)-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11,15 ]-hexadec-1(10),2,4,6,8,12,14-heptaen-4-yl]pyridin-2-yl}-2-(methylamino)acetamide;

[0182] N-{5-[16-(4-tert-Butylphenyl)-12-ethyl-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2, 7 .0 11,15 ]-hexadec-1(10),2,4,6,8,12,14-heptaen-4-yl]pyridin-2-yl}-2-(methylamino)acetamide;

[0183] N-{5-[16-(4-tert-Butylphenyl)-12-ethyl-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2, 7 .0 11,15 ]-hexadec-1(10),2,4,6,8,12,14-heptaen-4-yl]pyridin-2-yl}-2-(methylamino)acetamide;

[0184] 5-[16-(4-tert-Butylphenyl)-12-ethyl-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11 ,15 ]hexadec-1(10),2,4,6,8,12,14-heptaen-4-yl]-N-methylpyridin-2-amine;

[0185] 5-[16-(4-tert-Butylphenyl)-12-ethyl-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11 ,15 ]hexadec-1(10),2,4,6,8,12,14-heptaen-4-yl]-N-(2-methoxyethyl)pyridin-2-amine;

[0186] 5-[16-(4-tert-Butylphenyl)-12-ethyl-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11 ,15 ]hexadec-1(10),2,4,6,8,12,14-heptaen-4-yl]-N-[2-(pyrrolidin-1-yl)ethyl]pyridin-2-amine;

[0187] 5-[16-(4-tert-Butylphenyl)-12-ethyl-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2,7 .0 11 ,15 ]Hexadecan-1 (10), 2, 4, 6, 8, 12, 14-heptaen-4-yl]-N-[2-(morpholin-4- yl)ethyl]pyridin-2-amine;

[0188] N-{5-[16-(4-tert-Butylphenyl)-12-ethyl-8,11,13,14,16-pentaazatetracyclo[8.6.0.0 2, 7 .0 11,15 ]Hexadecan-1 (10), 2, 4, 6, 8, 12, 14-heptaen-4-yl]-N-[2-(morpholin-4- yl)ethyl]pyridin-2-amine;

[0189] Example 5

[0190] Preparation of 2-methyl-2-{4-[4-(quinolin-3-yl)-8,11,14,16-tetraazatetracyclo[8.6.0.0 2,7 .0 11,15 ]Hexadecan-1 (10), 2, 4, 6, 8, 12, 14-heptaen-4-yl]-N-[2-(morpholin-4- yl)ethyl]pyridin-2-amine;

[0191] To a suspension of compound 8 (200 mg) in ethanol (10 ml) was added ammonium hydroxide (0.5 ml) and the resulting mixture was heated at 90 °C in a sealed tube for 10 h. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, then the residue was dissolved in dichloromethane (20 ml) and washed sequentially with water (20 ml) and brine (20 ml). The organic phase was dried over sodium sulfate, the solid was filtered off and the filtrate was concentrated and further purified on a silica gel column to give 2-(4-(8-bromo-2-amino-1 H-imidazo[4,5-c]quinolin-1 -yl)phenyl)-2- methylpropanenitrile (35 mg) which was mixed with 2-bromomethyl-1,3-dioxolane (100 mg) and one drop of TFA in toluene (1 ml). The reaction was heated at 110 °C in a sealed tube for 16 h and evaporated for further purification on a silica gel column to give 2-(4-{4-bromo-8,11,14,16-tetraazatetracyclo[8.6.0.0 2,7 .0 11,15 ]Hexadecan-1 (10), 2, 4, 6, 8, 12, 14-heptaen-4-yl]-N-[2-(morpholin-4- yl)ethyl]pyridin-2-amine;

[0192] The following compound examples were similarly prepared according to the method described in Example 5 by using boronic esters of different side chains or 4-tert-butylaniline or 3-tert-butylaniline.

[0193] 2-methyl-2-{4-[4-(pyridin-3-yl)-8,11,14,16-tetraazatetracyclo[8.6.0.0 2 ,7.0 11,1 5]hexadecan-1(10),2,4,6,8,12,14-hepten-16-yl]benzene

[0194] 4-bromo-16-(4-tert-butylphenyl)-8,11,14,16-tetraazatetracyclo[8.6.0.0 2 ,7.0 11,1 5]hexadecan-1(10),2,4,6,8,12,14-heptene

[0195] 16-(4-tert-butylphenyl)-4-(pyridin-3-yl)-8,11,14,16-tetraazatetracyclo[8.6.0.0 2 ,7.0 11,1 5]hexadecan-1(10),2,4,6,8,12,14-heptene

[0196] 16-(4-tert-butylphenyl)-4-(quinolin-3-yl)-8,11,14,16-tetraazatetracyclo[8.6.0.0 2 ,7.0 11,1 5]hexadecan-1(10),2,4,6,8,12,14-heptene

[0197] 16-(3-tert-butylphenyl)-4-(quinolin-3-yl)-8,11,14,16-tetraazatetracyclo[8.6.0.0 2 ,7.0 11,1 5]hexadecan-1(10),2,4,6,8,12,14-heptene

[0198] Formulation Example:

[0199] The following are examples of formulations and these formulations are merely exemplary and are in no way to be construed as being limiting. Formulation Example 1:

[0200] Each capsule contains:

[0201]

[0202] Formulation Example 2:

[0203] The solution contains:

[0204]

[0205] Formulation Example 3:

[0206] The powder for admixture with feed contains:

[0207] Compound 1 to 10 g from the above compounds

[0208] Corn starch 98.5 to 89.5 g

[0209] Light anhydrous silicic acid 0.5g

[0210] 100.0 g

Claims

1. A compound selected from any one of the following: ； wherein: or a pharmaceutically acceptable salt thereof. 。

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