WO2008106168A1 - Combination of imidazo [1,5-a] pyrazinyl derivatives with an agent that inhibits serine phosphorylation of irs1 for use in the treatment of cancer - Google Patents

Combination of imidazo [1,5-a] pyrazinyl derivatives with an agent that inhibits serine phosphorylation of irs1 for use in the treatment of cancer Download PDF

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WO2008106168A1
WO2008106168A1 PCT/US2008/002593 US2008002593W WO2008106168A1 WO 2008106168 A1 WO2008106168 A1 WO 2008106168A1 US 2008002593 W US2008002593 W US 2008002593W WO 2008106168 A1 WO2008106168 A1 WO 2008106168A1
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agent
irs1
cancer
serine phosphorylation
inhibitor
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PCT/US2008/002593
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French (fr)
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Osi Pharmaceuticals, Inc.
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Priority to EP08726171A priority Critical patent/EP2131836A1/en
Publication of WO2008106168A1 publication Critical patent/WO2008106168A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Cancer is a generic name for a wide range of cellular malignancies characterized by unregulated growth, lack of differentiation, and the ability to invade local tissues and metastasize. These neoplastic malignancies affect, with various degrees of prevalence, every tissue and organ in the body.
  • DNA-alkylating agents e.g., cyclophosphamide, ifosfamide
  • anti-metabolites e.g., methotrexate, a folate antagonist, and 5-fluorouracil, a pyrimidine antagonist
  • microtubule disrupters e.g., vincristine, vinblastine, paclitaxel
  • DNA intercalators e.g., doxorubicin, daunomycin, cisplatin
  • hormone therapy e.g., tamoxifen, flutamide
  • Colorectal cancer is among the leading causes of cancer-related morbidity and mortality in the U.S. Treatment of this cancer depends largely on the size, location and stage of the tumor, whether the malignancy has spread to other parts of the body (metastasis), and on the patient's general state of health. Options include surgical removal of tumors for early stage localized disease, chemotherapy and radiotherapy. However, chemotherapy is currently the only treatment for metastatic disease. 5-fluorouracil is currently the most effective single-agent treatment for advanced colorectal cancer, with response rates of about 10 %. Additionally, new agents such as the topoisomerase I inhibitor irinotecan (CPT11), the platinum-based cytotoxic agent oxaliplatin (e.g.
  • ELOXATINTM ELOXATINTM
  • erlotinib [6,7-bis(2- methoxyethoxy)-4-quinazolin-4-yl]-(3-ethynylphenyl)amine
  • erlotinib HCI, TARCEVA ® OSI Pharmaceuticals, Inc. Melville, NY
  • EGFR epidermal growth factor receptor
  • EGFR stimulated signaling pathways promote multiple processes that are potentially cancer-promoting, e.g. proliferation, angiogenesis, cell motility and invasion, decreased apoptosis and induction of drug resistance.
  • Activation of EGFR stimulated signaling pathways promote multiple processes that are potentially cancer-promoting, e.g. proliferation, angiogenesis, cell motility and invasion, decreased apoptosis and induction of drug resistance.
  • the development for use as anti-tumor agents of compounds that directly inhibit the kinase activity of the EGFR, as well as antibodies that reduce EGFR kinase activity by blocking EGFR activation, are areas of intense research effort (de Bono J. S. and Rowinsky, E. K. (2002) Trends in MoI. Medicine 8:S19-S26; Dancey, J. and Sausville, E.A. (2003) Nature Rev. Drug Discovery 2:92-313).
  • EGFR kinase inhibitors can improve tumor cell or neoplasia killing when used in combination with certain other anti-cancer or chemotherapeutic agents or treatments (e.g. Raben, D. et al. (2002) Semin. Oncol. 29:37-46; Herbst, R.S. et al. (2001 ) Expert Opin. Biol. Ther. 1 :719-732; Magne, N et al. (2003) Clin. Can. Res. 9:4735-4732; Magne, N. et al. (2002) British Journal of Cancer 86:819-827; Torrance, CJ. et al. (2000) Nature Med.
  • cancerous cells exposed to slightly sub-lethal concentrations of a chemotherapeutic agent will very often develop resistance to such an agent, and quite often cross-resistance to several other antineoplastic agents as well.
  • oxaliplatin when combined with 5-FU and leucovorin, oxaliplatin exhibits response rates of 25-40% as first- line treatment for colorectal cancer (Raymond, E. et al.(1998) Semin Oncol. 25(2 Suppl. 5):4- 12).
  • RTKs receptor tyrosine kinases
  • EGF epidermal growth factor
  • IGF insulin-like growth factor
  • NSCLC non-small cell lung cancer
  • ErbB receptors directing key signaling networks throughout life.
  • Tumor cells can exhibit redundancy surrounding RTKs that contributes to de novo resistance to a single RTK inhibitor, and crosstalk between RTKs can confer acquired resistance whereby the inhibition of one RTK is compensated by enhanced activity through an alternative RTK.
  • IGF-1 R signaling is associated with acquired resistance of cancer cells to chemo or radiation therapies, and molecular targeted therapies including epidermal growth factor receptor (EGFR) inhibition
  • EGFR epidermal growth factor receptor
  • IGF-I Insulin-like growth factor-I rescues breast cancer cells from chemotherapy-induced cell death-proliferative and anti-apoptotic effects.
  • Insulin-like growth factor-l receptor signaling in tamoxifen-resistant breast cancer a supporting role to the epidermal growth factor receptor.
  • Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer research 62, 200-207; Jones, H. E., Goddard, L., Gee, J. M., Hiscox, S., Rubini, M., Barrow, D., Knowlden, J. M., Williams, S., Wakeling, A. E., and Nicholson, R. I. (2004). Insulin-like growth factor-l receptor signaling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells.
  • IGF-1 R activation correlates with acquired resistance of breast and prostate cancer cells to EGFR inhibition (Jones et al., 2004).
  • IGF-IR has also been shown to mediate resistance to anti-EGFR therapies in glioblastoma, colorectal, and NSCLC tumor cells (Chakravarti et al., 2002; Liu et al., 2001; Jones et al., 2004; Morgillo et al., 2006; Hurbin et al., 2003; Knowlden et al., 2005).
  • US2006/0235031 refers to 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors as IFG1 R inhibitors and uses thereof, including for treating cancer.
  • Valeriote et al., Cancer Chemotherapy Reports, 59(5), 895-900 (1975) states that "extensive literature describing additivity and synergism in anticancer agents exists.”
  • US2003/0114467; US2003/0153752; and US2005/0037999 refer to pyrazolo- and pyrrolo- pyrimidines and uses thereof, including for cancer treatment, and generally refer to various combinations with other anticancer agents.
  • US2005/0153966 refers to heterocyclic compounds said to be kinase inhibitors and uses thereof, including for cancer treatment.
  • U S2004/0180911 refers to pyrimidine derivatives and uses thereof, including for tumors and proliferative diseases, and states that the compounds can be used in combination with other chemotherapy drugs.
  • WO2004/056830 refers to pyrrolopyrimidine derivatives and uses thereof, including for cancer treatment, and states that the compounds can be used in combination with other anticancer agents.
  • US2004/0106605 is entitled “Synergistic Methods and Compositions for Treating Cancer," and generally refers to combinations of IGF1 R inhibitors with EGFR inhibitors.
  • the present invention is directed to methods for treating cancer patients.
  • the present invention is directed to combined treatment of patients with novel substituted heterobicyclic IGF1 R protein kinase inhibitors and anti-cancer agents.
  • the present invention provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent which inhibits serine phosphorylation of IRS1 and IGF1 R inhibitor combination, with or without additional agents or treatments, such as other anti-cancer drugs or radiation therapy, wherein the IGF1 R inhibitor relates to compounds of Formula I:
  • This invention provides anti-cancer combination therapies that reduce the dosages for individual components required for efficacy, thereby decreasing side effects associated with each agent, while maintaining or increasing therapeutic value.
  • an agent which inhibits serine phosphorylation of IRSIthat can be used in practicing this invention is an EGFR kinase inhibitor.
  • an agent which inhibits serine phosphorylation of IRSI is erlotinib HCI (TARCEVA®, OSI Pharmaceuticals, Inc. Melville, NY).
  • the agent which inhibits serine phosphorylation of IRSIthat can be used in practicing this invention is a pAkt/MAPK/IRS-1 serine phosphorylation/pS-IRS-1 inhibitor.
  • the agent which inhibits serine phosphorylation of IRSIthat can be used in practicing this invention is a MEK inhibitor.
  • the agent which inhibits serine phosphorylation of IRS1 that can be used in practicing this invention is an inhibitor of the MAPK pathway.
  • the agent which inhibits serine phosphorylation of IRSIthat can be used in practicing this invention is a Raf inhibitor.
  • the agent which inhibits serine phosphorylation of IRSIthat can be used in practicing this invention is a Ras inhibitor.
  • the agent which inhibits serine phosphorylation of IRSIthat can be used in practicing this invention is a PKC inhibitor.
  • Figures 1A and 1 B Plots depicting synergistic effect of IGF-1 R inhibitor Compound A (c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1-methyl-cyclobutanol) in combination with Erlotinib (TARCEVA) on inhibiting cell proliferation (1A) and promoting apoptosis (1 B) in the epithelial pancreatic cancer cell line BxPC3.
  • IGF-1 R inhibitor Compound A c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1-methyl-cyclobutanol
  • TARCEVA Erlotinib
  • Figures 2A and 2B Plots depicting anti-tumor efficacy of oral co-administration of Compound A (c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1-methyl- cyclobutanol) with Erlotinib (TARCEVA) in BxPC3 human pancreatic cancer xenograft model.
  • Compound A c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1-methyl- cyclobutanol
  • TARCEVA Erlotinib
  • Figures 3A and 3B Plots depicting synergistic effect of IGF-1 R inhibitor Compound A (c/s-3-[8-Amino-1 -(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1 -methyl-cyclobutanol) in combination with Erlotinib (TARCEVA) on inhibiting cell proliferation in the epithelial breast tumor cell line MDA-MB-468 (A), and additive effect of the combination in the breast tumor cell line BT20 (B).
  • IGF-1 R inhibitor Compound A c/s-3-[8-Amino-1 -(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1 -methyl-cyclobutanol
  • TARCEVA Erlotinib
  • Figures 4A and 4B Plots depicting effect of IGF-1 R inhibitor Compound A (c/s-3-[8- Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1 -methyl-cyclobutanol) in combination with Erlotinib (TARCEVA) on inhibiting cell proliferation in two mesenchymal breast tumor cell lines DU4475 and MDA-MB-435. Synergistic effect achieves in DU4475 cell line (A), and additive effect is observed in MDA-MB-435 cell line (B).
  • IGF-1 R inhibitor Compound A c/s-3-[8- Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1 -methyl-cyclobutanol
  • TARCEVA Erlotinib
  • Figure 5 Table representing anti-tumor efficacy of oral co-administration of Compound A (c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1 -methyl-cyclobutanol) with Erlotinib (TARCEVA) in GEO human colorectal cancer xenograft model.
  • Compound A c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1 -methyl-cyclobutanol
  • Erlotinib TARCEVA
  • Figures 6A and 6B Plots depicting synergistic effect of IGF-1 R inhibitor Compound A (c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1 -methyl-cyclobutanol) in combination with MEK1 (6A) and with PD-98059 (6B) on inhibiting cell proliferation in the non- small cell lung carcinoma cell line H292.
  • Compound A c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1 -methyl-cyclobutanol
  • agents that prevent serine phosphorylation of the IGF-1 R adaptor protein IRS1 potentiate IGF-driven Akt, thereby enhancing sensitivity to IGF-1 R inhibition.
  • the present invention is directed to methods for treating cancer patients comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an a IGF1 R protein kinase inhibitor compound of Formula I in combination with an agent which inhibits serine phosphorylation of IRS1 , with or without additional agents or treatments such as other anti-cancer drugs or radiation therapy.
  • agents that inhibit serine phosphorylation of IRS1 include inhibitors of the MAPK pathway, including for example EGFR inhibitors, MEK inhibitors, Ras inhibitors, Raf inhibitors, and PKC inhibitors.
  • EGFR and IGF-IR can cooperate to regulate tumor growth and survival.
  • the present inventors have found that for epithelial tumor cells, but not for mesenchymal-like tumor cells, Akt is controlled synergistically by EGFR and IGF-IR.
  • Two molecular aspects contributing to synergy were identified: 1 ) inhibition of EGFR or IGF-1 R individually promotes activation of the reciprocal receptor, and 2) inhibition of EGFR-directed MAPK shifts regulation of Akt from EGFR towards IGF-1 R.
  • inhibition of the MAPK pathway by EGFR blockade circumvents a negative feedback loop imposed on the IGF-1 R- IRS-1 signaling complex.
  • the synergistic inhibition of Akt achieved by co-targeting EGFR and IGF-1 R in epithelial tumor cells conferred synergistic apoptosis and growth inhibition in vitro and growth regression in vivo.
  • the present inventors find that the ability of an agent which inhibits serine phosphorylation of IRS1 , such as erlotinib, to inhibit the MAPK pathway is responsible for the potentiation of IGF-driven Akt, and this is likely mediated by augmented coupling of IGF-1 R to Akt through IRS-1.
  • the ability of IRS-1 phosphorylation at select serine sites to tightly regulate activity has been observed.
  • Serine phosphorylation of IRS-1 promotes a decrease in the ability of IGF-1R to couple to downstream effectors including PI3K by affecting either the stability of IRS-1 or by affecting protein-protein interactions between receptor and effector.
  • the ability of the MAPK pathway to affect the serine- phosphorylation of IRS-1 could be mediated either directly through Erk, or indirectly through Erk's ability to transactivate p70S6K. Therefore, inhibition of the MAPK pathway, such as by EGFR inhibition or MEK inhibition, primes signaling through the IGF-1 R to sustain Akt activity and cell survival.
  • a first aspect of the present invention is directed to methods for treating cancer patients comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent which inhibits serine phosphorylation of IRSIand a IGF1 R protein kinase inhibitor compound of Formula I combination, with or without additional agents or treatments, such as other anti-cancer drugs or radiation therapy.
  • This aspect of the present invention is also directed to combined treatment of patients with the IGF1 R protein kinase inhibitors of Formula I, and their salts, and epidermal growth factor receptor (EGFR) kinase inhibitors, and their salts.
  • EGFR epidermal growth factor receptor
  • a second aspect of the present invention includes methods for treating cancer patients comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R inhibitor combination, with or without additional agents or treatments, such as other anti-cancer drugs or radiation therapy, wherein the IGF1 R inhibitor is a compound of Formula I:
  • X 11 , X 12 , Xi 3 , Xi 4 , and Xi 5 are C; [37] X 16 is N;
  • R 1 is cycloC 3-10 alkyl substituted by one or more independent G 11 substituents;
  • G 1 optionally is -(W 1 ) n -(Y 1 ) m -R 4 ;
  • G 11 is aryl-C o- ioalkyl, aryl-C 2 .
  • R 2 , R 2a , R 3 , R 3a , R 222 , R 222a , R 333 , R 333a , R 21 , R 2a1 , R 31 , R 3a1 , R 2221 , R 222a1 , R 3331 , and R 333a1 are each independently C o .ioalkyl, C 2- i 0 alkenyl, C 2- i 0 alkynyl, C 1-10 alkoxyCi.i 0 alkyl, Ci.
  • R 2 and R 3 , or R 222 and R 333 , or R 2221 and R 3331 are optionally taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted by one or more independent G 1111 substituents and wherein said ring optionally includes one or more heteroatoms other than the nitrogen to which R 2 and R 3 , or R 222 and R 333 , or R 2221 and R 3331 are attached;
  • R 5 , R 6 , G 111 , and G 1111 are each independently C o- ioalkyl, C 2 -i O alkenyl, C 2 .i O alkynyl, d-ioalkoxyd.ioalkyl, C 1-10 alkoxyC 2 .ioalkenyl, C 1-10 alkoxyC 2- ioalkynyl, C 1-10 alkylthioC 1-10 alkyl, C 1 .
  • R 5 with R 6 are optionally taken together with the carbon atom to which they are attached to form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted with one or more independent R 69 substituents and wherein said ring optionally includes one or more heteroatoms;
  • R 7 , R 7a , and R 8 are each independently acyl, C O -i O alkyl, C 2 . 10 alkenyl, aryl, heteroaryl, heterocyclyl or cycloC 3-10 alkyl, any of which is optionally substituted by one or more independent G 111 substituents;
  • R 4 is C o- ioalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, cyclo ⁇ a ⁇ y!, heterocyclyl, cycloC 3-8 alkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more independent G 41 substituents;
  • R 69 is aryl-C o- i O alkyl, aryl-C 2- i 0 alkenyl, aryl-C 2-10 alkynyl, hetaryl-C 0 .ioalkyl, hetaryl-C 2- 10 alkenyl, hetaryl-C 2- i O alkynyl, monoCC ⁇ alkylJaminoC ⁇ alkyl, diCd- ⁇ alkyOaminod-ealkyl, mono(aryl)aminoC 1-6 alkyl, di(aryl)aminoC 1-6 alkyl, or -N(C 1-6 alkyl)-d- 6 alkyl-aryl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 778 , C 1-10 alkyl, C 2- i O alkenyl, C 2- ioalkynyl, haloC 1-10 alkyl,
  • alkylaminocarbonyl diC 1-6 alkylaminocarbonyl, mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or C 1-10 alkyl(aryl)aminocarbonyl, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, d. 10 alkoxy, -SO ⁇ CCo ⁇ alkyOCCo ⁇ alkyl), or -NCCo ⁇ alkyOCCo ⁇ alkyl) substituents;
  • R 77 , R 78 , R 87 , R 88 , R 778 , and R 888 are each independently aryl-C o- i O alkyl, aryl-C 2- 10 alkenyl, aryl-C 2- i 0 alkynyl, hetaryl-C o- i O alkyl, hetaryl-C 2- i 0 alkenyl, hetaryl-C 2 . 10 alkynyl, mono(C 1 .
  • n, m, j1 , j1a, j2a, j4, j4a, j5a, j7, and j8 are each independently O, 1 , or 2.
  • the IGF1 R inhibitor is represented by Formula I, or a salt thereof, wherein X 3 and X 5 are N; X 1 , X 2 , X 4 , X 6 , and X 7 are C; and the other variables are described as above for Formula I.
  • the IGF1 R inhibitor is represented by Formula I, or a salt thereof, wherein X 3 and X 5 are N; X 1 , X 2 , X 4 , X 6 , and X 7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor.
  • the IGF1 R inhibitor is represented by Formula I, or a salt thereof, wherein X 3 and X 5 are N; X 1 , X 2 , X 4 , X 6 , and X 7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib, cetuximab, gefitinib, or a salt thereof.
  • the IGF1 R inhibitor is represented by
  • the IGF1 R inhibitor is represented by
  • Formula I 1 or a salt thereof wherein X 3 and X 5 are N; X 1 , X 2 , X 4 , X 6 , and X 7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is an inhibitor of the MAPK pathway or a salt thereof.
  • the IGF1 R inhibitor is represented by
  • Formula I or a salt thereof, wherein X 3 and X 5 are N; X 1 , X 2 , X 4 , X 6 , and X 7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a Ras, Raf, MEK or PKC inhibitor; or a salt thereof.
  • the IGF1 R inhibitor is represented by
  • Formula I or a salt thereof, wherein X 3 and X 5 are N; X 1 , X 2 , X 4 , X 6 , and X 7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRSIis a MEK inhibitor or a salt thereof.
  • the IGF1 R inhibitor is represented by
  • Formula I or a salt thereof, wherein X 3 and X 5 are N; X 1 , X 2 , X 4 , X 6 , and X 7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a MEK inhibitor wherein the MEK inhibitor is ARRY-142886, PD-
  • the IGF1 R inhibitor is represented by
  • Formula I or a salt thereof, wherein X 3 and X 5 are N; X 1 , X 2 , X 4 , X 6 , and X 7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a Ras inhibitor; or a salt thereof.
  • the IGF1 R inhibitor is represented by
  • Formula I or a salt thereof, wherein X 3 and X 5 are N; X 1 , X 2 , X 4 , X 6 , and X 7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a Ras inhibitor; or a salt thereof, wherein the Ras inhibitor is BMS-
  • the IGF1 R inhibitor is represented by
  • Formula I or a salt thereof, wherein X 3 and X 5 are N; X 1 , X 2 , X 4 , X 6 , and X 7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a Raf inhibitor; or a salt thereof.
  • the IGF1 R inhibitor is represented by
  • Formula I or a salt thereof, wherein X 3 and X 5 are N; X 1 , X 2 , X 4 , X 6 , and X 7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a Raf inhibitor; or a salt thereof, wherein the Raf inhibitor is sorafenib; or a salt thereof.
  • the IGF1 R inhibitor is represented by
  • Formula I or a salt thereof, wherein X 3 and X 5 are N; X 1 , X 2 , X 4 , X 6 , and X 7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a PKC inhibitor; or a salt thereof.
  • the IGF1 R inhibitor is represented by Formula I, or a salt thereof, wherein X 3 and X 5 are N; X 1 , X 2 , X 4 , X 6 , and X 7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a PKC inhibitor; or a salt thereof, wherein the PKC inhibitor is byrostatin, staurosporine, staurosporine analog including UCN-01 or CGP41251 , safingol; or a salt thereof.
  • the IGF1 R inhibitor is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi 6 is N; Xn, X 12 , X 13 , X 14 , and X 15 are C; and the other variables are as described in each of the above aspects.
  • the IGF1 R inhibitor is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 16 is N; X 11 , X 12 , X i3 , Xi 4 , and X 15 are C; Gi is aryl-C o- ioalkyl; and the other variables are as described in each of the above aspects.
  • the IGF1 R inhibitor is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 16 is N; X 11 , X 12 , X 13 , X M , and Xi 5 are C; G 1 is aryl; R 1 is cycloC 3-10 alkyl substituted by one or more independent G 11 substituents; and the other variables are as described in each of the above aspects.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor wherein the IGFR inhibitor is c/s-3-[8-Amino-1 -(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1 -methyl-cyclobutanol.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor wherein the IGFR inhibitor is wherein the IGFR inhibitor is
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib, cetuximab, gefitinib, panitumumab, or a salt thereof.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the IGFR inhibitor is c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3- yl]-1-methyl-cyclobutanol and wherein the agent that inhibits serine phosphorylation of IRS1 is erlotinib or a salt thereof.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, wherein the patient is a human that is being treated for cancer, and wherein the cancer is colorectal cancer, non-small cell lung carcinoma, pancreatic cancer, head and neck cancer, breast cancer, or neuroblastoma.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, wherein the patient is a human that is being treated for cancer, and wherein the cancer is colorectal cancer or non-small cell lung carcinoma.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, wherein the patient is a human that is being treated for cancer, and wherein the cancer is colorectal cancer or non-small cell lung carcinoma.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, and wherein erlotinib and the IGFR inhibitor are coadministered to the patient in the same formulation.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, and wherein erlotinib and the IGFR inhibitor are coadministered to the patient in different formulations.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, wherein erlotinib and the IGFR inhibitor are coadministered to the patient by the same route.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, and wherein erlotinib and the IGFR inhibitor are coadministered to the patient by different routes.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, and wherein erlotinib is administered to the patient by parenteral or oral administration.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, and wherein the IGFR inhibitor is administered to the patient by parenteral administration.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 agent is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, and additionally comprising one or more other anticancer agents.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, and additionally comprising one or more other anticancer agents wherein the other anti-cancer agents are selected from an alkylating agent, cyclophosphamide, chlorambucil, cisplatin, busulfan, melphalan, carmustine, streptozotocin, triethylenemelamine, mitomycin C, an anti-metabolite, methotrexate, etoposide, 6- mer
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRS1 is an inhibitor of the MAPK pathway.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I 1 wherein the agent that inhibits serine phosphorylation of IRS1 is an inhibitor of the MAPK pathway, wherein the MAPK pathway inhibitor is selected from Ras inhibitors, Raf inhibitors, MEK inhibitors or PKC inhibitors.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRS1 is a MEK inhibitor.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRS1 is a MEK inhibitor, wherein the MEK inhibitor is ARRY-142886, PD-184352, PD-98059, PD-0325901 , XL518, or MEK1.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRSIis a Raf protein kinase family inhibitor.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRSIis a Raf protein kinase family inhibitor, wherein the Raf protein kinase family inhibitor is sorafenib.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRSIis a Ras inhibitor.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRSI is a Ras inhibitor is BMS-214662 , SCH 66336, R115777, or 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4- (3-ethynyl-phenyl)-1 -methyl-1 H-quinolin-2-one.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRSIis a PKC inhibitor.
  • the present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRSIis a PKC inhibitor, wherein the
  • PKC inhibitor is byrostatin, staurosporine, a staurosporine analog, UCN-01 , CGP41251 , or safingol.
  • connection of compound name moieties are at the rightmost recited moiety. That is, the substituent name starts with a terminal moiety, continues with any bridging moieties, and ends with the connecting moiety. For example, hetarylthioCi.
  • alkyl has a heteroaryl group connected through a thio sulfur to a C 1-4 alkyl that connects to the chemical species bearing the substituent.
  • Co- 4 alkyl is used to mean an alkyl having 0-4 carbons - that is, 0, 1 , 2, 3, or 4 carbons in a straight or branched configuration.
  • An alkyl having no carbon is hydrogen when the alkyl is a terminal group.
  • An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group.
  • C o alkyl includes being a substituted bond - that is, for example, -X-Y-Z is -C(O)-C 2 - 4 alkyl when X is C o alkyl, Y is C o alkyl, and Z is -C(O)-C 2-4 alkyl.
  • alkyl includes both branched and straight chain alkyl groups. Typical alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, te/if-butyl, ⁇ -pentyl, isopentyl, n-hexyl, n-heptyl, isooctyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl, and the like.
  • halo refers to fluoro, chloro, bromo, or iodo.
  • haloalkyl refers to an alkyl group substituted with one or more halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl, trifluoromethyl, perfluoropropyl, 8- chlorononyl, and the like.
  • cycloalkyl refers to a 3-8 carbon cyclic aliphatic ring structure, optionally substituted with for example, alkyl, hydroxy, oxo, and halo, such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyl, cyclohexyl, 4- chlorocyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • bicycloalkyl refers to a structure consisting of two cycloalkyl moieties that have two or more atoms in common. If the cycloalkyl moieties have exactly two atoms in common they are said to be “fused”. Examples include, but are not limited to, bicyclo[3.1.0]hexyl, perhydronaphthyl, and the like. If the cycloalkyl moieties have more than two atoms in common they are said to be "bridged”. Examples include, but are not limited to, bicyclo[2.2.1]heptyl ("norbomyl”), bicyclo[2.2.2]octyl, and the like.
  • spiroalkyl refers to a structure consisting of two cycloalkyl moieties that have exactly one atom in common. Examples include, but are not limited to, spiro[4.5]decyl, spiro[2.3]hexyl, and the like.
  • heterocycloalkyl refers to a bicycloalkyl structure in which at least one carbon atom is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur.
  • heterospiroalkyl refers to a spiroalkyl structure in which at least one carbon atom is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur.
  • alkylcarbonyloxyalkyl refers to an ester moiety, for example acetoxymethyl, n-butyryloxyethyl, and the like.
  • alkynylcarbonyl refers to an alkynylketo functionality, for example propynoyl and the like.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, for example hydroxymethyl, 2,3-dihydroxybutyl, and the like.
  • alkylsulfonylalkyl refers to an alkyl group substituted with an alkylsulfonyl moiety, for example mesylmethyl, isopropylsulfonylethyl, and the like.
  • alkylsulfonyl refers to a sulfonyl moiety substituted with an alkyl group, for example mesyl, n-propylsulfonyl, and the like.
  • acetylaminoalkyl refers to an alkyl group substituted with an amide moiety, for example acetylaminomethyl and the like.
  • acetylaminoalkenyl refers to an alkenyl group substituted with an amide moiety, for example 2-(acetylamino)vinyl and the like.
  • alkenyl refers to an ethylenically unsaturated hydrocarbon group, straight or branched chain, having 1 or 2 ethylenic bonds, for example vinyl, allyl, 1-butenyl, 2-butenyl, isopropenyl, 2-pentenyl, and the like.
  • haloalkenyl refers to an alkenyl group substituted with one or more halo groups.
  • cycloalkenyl refers to a cyclic aliphatic 3 to 8 ring structure, optionally substituted with alkyl, hydroxy and halo, having 1 or 2 ethylenic bonds such as methylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl, cyclohexenyl, 1 ,4- cyclohexadienyl, and the like.
  • alkynyl refers to an unsaturated hydrocarbon group, straight or branched, having at least one acetylenic bond, for example ethynyl, propargyl, and the like.
  • haloalkynyl refers to an alkynyl group substituted with one or more independent halo groups.
  • alkylcarbonyl refers to an alkylketo functionality, for example acetyl, n- butyryl, and the like.
  • alkenylcarbonyl refers to an alkenylketo functionality, for example, propenoyl and the like.
  • aryl refers to phenyl or naphthyl which may be optionally substituted.
  • aryl examples include, but are not limited to, phenyl, 4-chlorophenyl, 4-fluorophenyl, A- bromophenyl, 3-nitrophenyl, 2-methoxyphenyl, 2-methylphenyl, 3-methyphenyl, A- methylphenyl, 4-ethylphenyl, 2-methyl-3-methoxyphenyl, 2,4-dibromophenyl, 3,5- difluorophenyl, 3,5-dimethylphenyl, 2,4,6-trichlorophenyl, 4-methoxyphenyl, naphthyl, 2- chloronaphthyl, 2,4-dimethoxyphenyl, 4-(trifluoromethyl)phenyl, and 2-iodo-4-methylphenyl.
  • heteroaryl or “hetaryl” or “heteroar-” or “hetar-” refer to a substituted or unsubstituted 5- or 6-membered unsaturated ring containing one, two, three, or four independently selected heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur or to a bicyclic unsaturated ring system containing up to 10 atoms including at least one heteroatom selected from oxygen, nitrogen, and sulfur.
  • hetaryls include, but are not limited to, 2-, 3- or 4-pyridinyl, pyrazinyl, 2-, A-, or 5- pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, imidazolyl, 2- or 3-thienyl, 2- or 3-furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, and benzothienyl.
  • the heterocyclic ring may be optionally substituted with one or more substituents.
  • aryl— alkyl or “arylalkyl” or “aralkyl” are used to describe a group wherein the alkyl chain can be branched or straight chain forming a bridging portion with the terminal aryl, as defined above, of the aryl— alkyl moiety.
  • aryl— alkyl groups include, but are not limited to, optionally substituted benzyl, phenethyl, phenpropyl and phenbutyl such as A- chlorobenzyl, 2,4-dibromobenzyl, 2-methylbenzyl, 2-(3-fluorophenyl)ethyl, 2-(4- methylphenyl)ethyl, 2-(4-(trifluoromethyl)phenyl)ethyl, 2-(2-methoxyphenyl)ethyl, 2-(3- nitrophenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl, 3-phenylpropyl, 3-
  • aryl-cycloalkyl or "arylcycloalkyl” are used to describe a group wherein the terminal aryl group is attached to a cycloalkyl group, for example phenylcyclopentyl and the like.
  • aryl-alkenyl or "arylalkenyl” or “aralkenyl” are used to describe a group wherein the alkenyl chain can be branched or straight chain forming a bridging portion of the aralkenyl moiety with the terminal aryl portion, as defined above, for example styryl (2- phenylvinyl), phenpropenyl, and the like.
  • aryl-alkynyl or “arylalkynyl” or “aralkynyl” are used to describe a group wherein the alkynyl chain can be branched or straight chain forming a bridging portion of the aryl-alkynyl moiety with the terminal aryl portion, as defined above, for example 3-phenyl-1- propynyl, and the like.
  • aryl-oxy or "aryloxy” or “aroxy” are used to describe a terminal aryl group attached to a bridging oxygen atom.
  • Typical aryl-oxy groups include phenoxy, 3,4- dichlorophenoxy, and the like.
  • aryl-oxyalkyl or "aryloxyalkyl” or “aroxyalkyl” are used to describe a group wherein an alkyl group is substituted with a terminal aryl-oxy group, for example pentafluorophenoxymethyl and the like.
  • heterocycloalkenyl refers to a cycloalkenyl structure in which at least one carbon atom is replaced with a heteroatom selected from oxygen, nitrogen, and sulfur.
  • hetaroxy or "heteroaroxy” are used to describe a terminal hetaryl group attached to a bridging oxygen atom.
  • Typical hetaryl-oxy groups include 4,6-dimethoxypyrimidin-2-yloxy and the like.
  • heteroarylalkyl or “heteroarylalkyl” or “hetaryl-alkyl” or “heteroaryl-alkyl” or “heteroaryl-alkyl” or
  • heteroalkyl or “heteroaralkyl” are used to describe a group wherein the alkyl chain can be branched or straight chain forming a bridging portion of the heteroaralkyl moiety with the terminal heteroaryl portion, as defined above, for example 3-furylmethyl, thenyl, furfuryl, and the like.
  • heteroaryl-alkenyl or “hetaralkenyl” or heteroaralkenyl” are used to describe a group wherein the alkenyl chain can be branched or straight chain forming a bridging portion of the heteroaralkenyl moiety with the terminal heteroaryl portion, as defined above, for example 3-(4- pyridyl)-1-propenyl.
  • heteroarylalkynyl or “heteroarylalkynyl” or “hetaryl-alkynyl” or “hetaryl-alkynyl” or
  • heteroaryl-alkynyl or “hetaralkynyl” or “heteroaralkynyl” are used to describe a group wherein the alkynyl chain can be branched or straight chain forming a bridging portion of the heteroaralkynyl moiety with the heteroaryl portion, as defined above, for example 4-(2-thienyl)-
  • heterocyclyl or “hetcyclyl” refers to a substituted or unsubstituted 4-, 5-, or
  • 6-membered saturated or partially unsaturated ring containing one, two, or three heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen and sulfur; or to a bicyclic ring system containing up to 10 atoms including at least one heteroatom independently selected from oxygen, nitrogen, and sulfur wherein the ring containing the heteroatom is saturated.
  • heterocyclyls include, but are not limited to, tetrahydrofuranyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, 4-pyranyl, tetrahydropyranyl, thiolanyl, morpholinyl, piperazinyl, dioxolanyl, dioxanyl, indolinyl, and 5-methyl-6-chromanyl.
  • heterocyclylalkyl or “heterocyclyl-alkyl” or “hetcyclylalkyl” or “hetcyclyl- alkyl” are used to describe a group wherein the alkyl chain can be branched or straight chain forming a bridging portion of the heterocyclylalkyl moiety with the terminal heterocyclyl portion, as defined above, for example 3-piperidinylmethyl and the like.
  • heterocyclylalkenyl or “heterocyclyl-alkenyl” or “hetcyclylalkenyl” or
  • heterocyclyl-alkenyl are used to describe a group wherein the alkenyl chain can be branched or straight chain forming a bridging portion of the heterocyclylalkenyl moiety with the terminal heterocyclyl portion, as defined above, for example 2-morpholinyl-1-propenyl and the like.
  • heterocyclylalkynyl or “heterocyclyl-alkynyl” or “hetcyclylalkynyl” or
  • heterocyclyl-alkynyl are used to describe a group wherein the alkynyl chain can be branched or straight chain forming a bridging portion of the heterocyclylalkynyl moiety with the terminal heterocyclyl portion, as defined above, for example 2-pyrrolidinyl-1 -butynyl and the like.
  • carboxylalkyl refers to a terminal carboxyl (-COOH) group attached to branched or straight chain alkyl groups as defined above.
  • carboxylalkenyl refers to a terminal carboxyl (-COOH) group attached to branched or straight chain alkenyl groups as defined above.
  • carboxylalkynyl refers to a terminal carboxyl (-COOH) group attached to branched or straight chain alkynyl groups as defined above.
  • carboxylcycloalkyl refers to a terminal carboxyl (-COOH) group attached to a cyclic aliphatic ring structure as defined above.
  • carboxylcycloalkenyl refers to a terminal carboxyl (-COOH) group attached to a cyclic aliphatic ring structure having ethylenic bonds as defined above.
  • cycloalkylalkyl or “cycloalkyl— alkyl” refer to a terminal cycloalkyl group as defined above attached to an alkyl group, for example cyclopropylmethyl, cyclohexylethyl, and the like.
  • cycloalkylalkenyl or “cycloalkyl-alkenyl” refer to a terminal cycloalkyl group as defined above attached to an alkenyl group, for example cyclohexylvinyl, cycloheptylallyl, and the like.
  • cycloalkylalkynyl or “cycloalkyl-alkynyl” refer to a terminal cycloalkyl group as defined above attached to an alkynyl group, for example cyclopropylpropargyl, A- cyclopentyl-2-butynyl, and the like.
  • cycloalkenylalkyl or "cycloalkenyl-alkyl” refer to a terminal cycloalkenyl group as defined above attached to an alkyl group, for example 2-(cyclopenten-1-yl)ethyl and the like.
  • cycloalkenylalkenyl or "cycloalkenyl-alkenyl” refer to terminal a cycloalkenyl group as defined above attached to an alkenyl group, for example 1 -(cyclohexen-
  • cycloalkenylalkynyl or “cycloalkenyl-alkynyl” refer to terminal a cycloalkenyl group as defined above attached to an alkynyl group, for example 1-(cyclohexen-
  • carboxylcycloalkylalkyl refers to a terminal carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkyl group as defined above.
  • carboxylcycloalkylalkenyl refers to a terminal carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkenyl group as defined above.
  • carboxylcycloalkylalkynyl refers to a terminal carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkynyl group as defined above.
  • carboxylcycloalkenylalkyl refers to a terminal carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkyl group as defined above.
  • carboxylcycloalkenylalkenyl refers to a terminal carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkenyl group as defined above.
  • carboxylcycloalkenylalkynyl refers to a terminal carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkynyl group as defined above.
  • alkoxy includes both branched and straight chain terminal alkyl groups attached to a bridging oxygen atom. Typical alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy, tert-butoxy and the like.
  • haloalkoxy refers to an alkoxy group substituted with one or more halo groups, for example chloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroisobutoxy, and the like.
  • alkoxyalkoxyalkyl refers to an alkyl group substituted with an alkoxy moiety which is in turn is substituted with a second alkoxy moiety, for example methoxymethoxymethyl, isopropoxymethoxyethyl, and the like.
  • alkylthio includes both branched and straight chain alkyl groups attached to a bridging sulfur atom, for example methylthio and the like.
  • haloalkylthio refers to an alkylthio group substituted with one or more halo groups, for example trifluoromethylthio and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group, for example isopropoxymethyl and the like.
  • alkoxyalkenyl refers to an alkenyl group substituted with an alkoxy group, for example 3-methoxyallyl and the like.
  • alkoxyalkynyl refers to an alkynyl group substituted with an alkoxy group, for example 3-methoxypropargyl.
  • alkoxycarbonylalkyl refers to a straight chain or branched alkyl substituted with an alkoxycarbonyl, for example ethoxycarbonylmethyl, 2-(methoxycarbonyl)propyl and the like.
  • alkoxycarbonylalkenyl refers to a straight chain or branched alkenyl as defined above substituted with an alkoxycarbonyl, for example 4-(ethoxycarbonyl)-2-butenyl and the like.
  • alkoxycarbonylalkynyl refers to a straight chain or branched alkynyl as defined above substituted with an alkoxycarbonyl, for example 4-(ethoxycarbonyl)-2-butynyl and the like.
  • haloalkoxyalkyl refers to a straight chain or branched alkyl as defined above substituted with a haloalkoxy, for example 2-chloroethoxymethyl, trifluoromethoxymethyl and the like.
  • haloalkoxyalkenyl refers to a straight chain or branched alkenyl as defined above substituted with a haloalkoxy, for example 4-(chloromethoxy)-2-butenyl and the like.
  • haloalkoxyalkynyl refers to a straight chain or branched alkynyl as defined above substituted with a haloalkoxy, for example 4-(2-fluoroethoxy)-2-butynyl and the like.
  • alkylthioalkyl refers to a straight chain or branched alkyl as defined above substituted with an alkylthio group, for example methylthiomethyl, 3-(isobutylthio)heptyl, and the like.
  • alkylthioalkenyl refers to a straight chain or branched alkenyl as defined above substituted with an alkylthio group, for example 4-(methylthio)-2-butenyl and the like.
  • alkylthioalkynyl refers to a straight chain or branched alkynyl as defined above substituted with an alkylthio group, for example 4-(ethylthio)-2-butynyl and the like.
  • haloalkylthioalkyl refers to a straight chain or branched alkyl as defined above substituted with an haloalkylthio group, for example 2-chloroethylthiomethyl, trifluoromethylthiomethyl and the like.
  • haloalkylthioalkenyl refers to a straight chain or branched alkenyl as defined above substituted with an haloalkylthio group, for example 4-(chloromethylthio)-2- butenyl and the like.
  • haloalkylthioalkynyl refers to a straight chain or branched alkynyl as defined above substituted with a haloalkylthio group, for example 4-(2-fluoroethylthio)-2-butynyl and the like.
  • dialkoxyphosphorylalkyl refers to two straight chain or branched alkoxy groups as defined above attached to a pentavalent phosphorous atom, containing an oxo substituent, which is in turn attached to an alkyl, for example diethoxyphosphorylmethyl and the like.
  • oligomer refers to a low-molecular weight polymer, whose number average molecular weight is typically less than about 5000 g/mol, and whose degree of polymerization (average number of monomer units per chain) is greater than one and typically equal to or less than about 50.
  • Compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the above Formula I is shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium slats.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
  • Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethyl
  • the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids Particularly preferred are formic and hydrochloric acid.
  • the compounds represented by Formula I, or a prodrug, or a metabolite, or a pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • dosage levels on the order of from about 0.01 mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient per day.
  • inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
  • cancer in an animal refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. Often, cancer cells will be in the form of a tumor, but such cells may exist alone within an animal, or may circulate in the blood stream as independent cells, such as leukemic cells.
  • tumor cells tumor cells that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (4) any tumors that proliferate by receptor tyrosine kinases; (5) any tumors that proliferate by aberrant serine/threonine kinase activation; and (6) benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing, either partially or completely, the growth of tumors, tumor metastases, or other cancer-causing or neoplastic cells in a patient.
  • treatment refers to the act of treating.
  • a method of treating or its equivalent, when applied to, for example, cancer refers to a procedure or course of action that is designed to reduce or eliminate the number of cancer cells in an animal, or to alleviate the symptoms of a cancer.
  • a method of treating" cancer or another proliferative disorder does not necessarily mean that the cancer cells or other disorder will, in fact, be eliminated, that the number of cells or disorder will, in fact, be reduced, or that the symptoms of a cancer or other disorder will, in fact, be alleviated. Often, a method of treating cancer will be performed even with a low likelihood of success, but which, given the medical history and estimated survival expectancy of an animal, is nevertheless deemed an overall beneficial course of action.
  • terapéuticaally effective agent means a composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • terapéuticaally effective amount or “effective amount” means the amount of the subject compound or combination that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the present invention provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor combination.
  • the tumors or tumor metastases to be treated are colorectal tumors or tumor metastases.
  • the tumors or tumor metastases to be treated are non small cell lung (NSCL) tumors or tumor metastases.
  • the present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition, one or more other cytotoxic, chemotherapeutic or anti-cancer agents, or compounds that enhance the effects of such agents.
  • additional other cytotoxic, chemotherapeutic or anticancer agents include, for example: alkylating agents or agents with an alkylating action, such as cyclophosphamide (CTX; e.g. CYTOXAN®), chlorambucil (CHL; e.g. LEUKERAN®), cisplatin (CisP; e.g. PLATINOL®), oxaliplatin (e.g. ELOXATINTM), busulfan (e.g.
  • alkylating agents or agents with an alkylating action such as cyclophosphamide (CTX; e.g. CYTOXAN®), chlorambucil (CHL; e.g. LEUKERAN®), cisplatin (CisP; e.g. PLATINOL®), oxaliplatin (e.g. ELOXATINTM), busulfan (e.g.
  • CX cyclophosphamide
  • CHL chloram
  • MYLERAN® melphalan
  • BCNU carmustine
  • streptozotocin triethylenemelamine
  • TEM mitomycin C
  • anti-metabolites such as methotrexate (MTX), etoposide (VP16; e.g. VEPESID®), 6-mercaptopurine (6MP), 6- thiocguanine (6TG), cytarabine (Ara-C), 5-fluorouracil (5-FU), capecitabine (e.g. XELODA®), dacarbazine (DTIC), and the like
  • antibiotics such as actinomycin D, doxorubicin (DXR; e.g.
  • ADRIAMYCIN® daunorubicin (daunomycin), bleomycin, mithramycin and the like
  • alkaloids such as vinca alkaloids such as vincristine (VCR), vinblastine, and the like
  • antitumor agents such as paclitaxel (e.g. TAXOL®) and paclitaxel derivatives, the cytostatic agents, glucocorticoids such as dexamethasone (DEX; e.g.
  • DECADRON® corticosteroids
  • corticosteroids such as prednisone, nucleoside enzyme inhibitors such as hydroxyurea, amino acid depleting enzymes such as asparaginase, leucovorin, folinic acid, raltitrexed, and other folic acid derivatives, and similar, diverse antitumor agents.
  • the following agents may also be used as additional agents: amifostine (e.g. ETHYOL®), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, lornustine (CCNU), doxorubicin lipo (e.g. DOXIL®), gemcitabine (e.g.
  • GEMZAR® daunorubicin lipo
  • DAUNOXOME® daunorubicin lipo
  • procarbazine mitomycin
  • docetaxel e.g. TAXOTERE®
  • aldesleukin carboplatin, cladribine, camptothecin, 10-hydroxy 7-ethyl- camptothecin (SN38), floxuridine, fludarabine, ifosfamide, idarubicin, mesna, interferon alpha, interferon beta, mitoxantrone, topotecan, leuprolide, megestrol, melphalan, mercaptopurine, plicamycin, mitotane, pegaspargase, pentostatin, pipobroman, plicamycin, tamoxifen, teniposide, testolactone, thioguanine, thiotepa, uracil mustard, or vinorelbine, chlor
  • the present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition, one or more anti-hormonal agents.
  • an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination and in addition, one or more anti-hormonal agents.
  • anti-hormonal agent includes natural or synthetic organic or peptidic compounds that act to regulate or inhibit hormone action on tumors.
  • Anti-hormonal agents include, for example: steroid receptor antagonists, anti- estrogens such as tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, other aromatase inhibitors, 42-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (e.g.
  • FARESTON® anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above; agonists and/or antagonists of glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH) and LHRH (leuteinizing hormone-releasing hormone); the LHRH agonist goserelin acetate, commercially available as ZOLADEX® (AstraZeneca); the LHRH antagonist D-alaninamide N-acetyl-3-(2- naphthalenyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-N6-( 3- pyridinylcarbonyl)-L-lysyl-N6-(3-pyridinyl
  • ANTIDE® Ares-Serono
  • the LHRH antagonist ganirelix acetate the steroidal anti-androgens cyproterone acetate (CPA) and megestrol acetate, commercially available as MEGACE® (Bristol-Myers Oncology); the nonsteroidal anti-androgen flutamide (2-methyl-N-[4, 20-nitro-3-(trifluoromethyl) phenylpropanamide), commercially available as EULEXIN® (Schering Corp.); the non-steroidal anti-androgen nilutamide, (5,5-dimethyl-3-[4-nitro-3- (trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazolidine-dione); and antagonists for other non- permissive receptors, such as antagonists for RAR, RXR, TR, VDR, and the like.
  • CPA steroidal anti-androgens cyproterone acetate
  • cytotoxic and other anticancer agents described above in chemotherapeutic regimens is generally well characterized in the cancer therapy arts, and their use herein falls under the same considerations for monitoring tolerance and effectiveness and for controlling administration routes and dosages, with some adjustments.
  • the actual dosages of the cytotoxic agents may vary depending upon the patient's cultured cell response determined by using histoculture methods. Generally, the dosage will be reduced compared to the amount used in the absence of additional other agents.
  • Typical dosages of an effective cytotoxic agent can be in the ranges recommended by the manufacturer, and where indicated by in vitro responses or responses in animal models, can be reduced by up to about one order of magnitude concentration or amount.
  • the actual dosage will depend upon the judgment of the physician, the condition of the patient, and the effectiveness of the therapeutic method based on the in vitro responsiveness of the primary cultured malignant cells or histocultured tissue sample, or the responses observed in the appropriate animal models.
  • the compounds 5-fluorouracil and raltitrexed are preferred.
  • a combination of 5-fluorouracil with leucovoran or folinic acid can be used with the agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination of this invention.
  • the compounds etoposide and cisplatin are also preferred.
  • the present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition one or more angiogenesis inhibitors.
  • Anti-angiogenic agents include, for example: VEGFR inhibitors, such as SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, Calif., USA), or as described in, for example International Application Nos. WO 99/24440, WO 99/62890, WO 95/21613, WO 99/61422, WO 98/50356, WO 99/10349, WO 97/32856, WO 97/22596, WO 98/54093, WO 98/02438, WO 99/16755, and WO 98/02437, and U.S. Patent Nos.
  • VEGF inhibitors such as VEGF Trap (Regeneron Pharmaceuticals Inc. of Tarrytown, NY), or as described in, for example, U.S. Pat. App. Pub. US 2006/0058234 or U.S. Pat. No. 7,087,411 ; IM862 (Cytran Inc. of Kirkland, Wash., USA); angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.); and antibodies to VEGF, such as bevacizumab (e.g.
  • AVASTINTM Genentech, South San Francisco, CA
  • integrin receptor antagonists and integrin antagonists such as to ⁇ v ⁇ 3, ⁇ v ⁇ 5 and ⁇ v ⁇ 6 integrins, and subtypes thereof, e.g. cilengitide (EMD 121974), or the anti-integrin antibodies, such as for example ⁇ v ⁇ 3 specific humanized antibodies (e.g. VITAXIN®); factors such as IFN-alpha (U.S. Patent Nos. 41530,901 , 4,503,035, and 5,231 ,176); angiostatin and plasminogen fragments (e.g.
  • PF4 platelet factor 4
  • plasminogen activator/urokinase inhibitors plasminogen activator/urokinase inhibitors
  • urokinase receptor antagonists heparinases
  • fumagillin analogs such as TNP-4701 ; suramin and suramin analogs; angiostatic steroids; bFGF antagonists; flk-1 and flt-1 antagonists
  • anti-angiogenesis agents such as MMP-2 (matrix-metalloproteinase 2) inhibitors and MMP-9 (matrix-metalloproteinase 9) inhibitors. Examples of useful matrix metalloproteinase inhibitors are described in International Patent Publication Nos.
  • MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1 , MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11 , MMP-12, and MMP-13).
  • MMP-1 , MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11 , MMP-12, and MMP-13 matrix-metalloproteinases
  • the present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition one or more tumor cell pro-apoptotic or apoptosis-stimulating agents.
  • the present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition one or more signal transduction inhibitors.
  • Signal transduction inhibitors include, for example: erbB2 receptor inhibitors, such as organic molecules, or antibodies that bind to the erbB2 receptor, for example, trastuzumab (e.g. HERCEPTIN®); inhibitors of other protein tyrosine-kinases, e.g. imitinib (e.g. GLEEVEC®); ras inhibitors; raf inhibitors; MEK inhibitors; mTOR inhibitors; cyclin dependent kinase inhibitors; protein kinase C inhibitors; and PDK-1 inhibitors (see Dancey, J. and Sausville, E.A. (2003) Nature Rev. Drug Discovery 2:92-313, for a description of several examples of such inhibitors, and their use in clinical trials for the treatment of cancer).
  • trastuzumab e.g. HERCEPTIN®
  • imitinib e.g. GLEEVEC®
  • ras inhibitors e.g. raf inhibitors
  • ErbB2 receptor inhibitors include, for example: ErbB2 receptor inhibitors, such as GW- 282974 (Glaxo Wellcome pic), monoclonal antibodies such as AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Tex., USA) and 2B-1 (Chiron), and erbB2 inhibitors such as those described in International Publication Nos. WO 98/02434, WO 99/35146, WO 99/35132, WO 98/02437, WO 97/13760, and WO 95/19970, and U.S. Patent Nos. 5,587,458, 5,877,305, 6,465,449 and 6,541 ,481.
  • the present invention further thus provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition an anti- HER2 antibody or an immunotherapeutically active fragment thereof.
  • the present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition one or more additional anti-proliferative agents.
  • Additional antiproliferative agents include, for example: Inhibitors of the enzyme famesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFR, including the compounds disclosed and claimed in U.S. Patent Nos.
  • the present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition a COX Il (cyclooxygenase Il ) inhibitor.
  • COX Il cyclooxygenase Il
  • useful COX-II inhibitors include alecoxib (e.g. CELEBREXTM), valdecoxib, and rofecoxib.
  • the present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition treatment with radiation or a radiopharmaceutical.
  • the source of radiation can be either external or internal to the patient being treated.
  • the therapy is known as external beam radiation therapy (EBRT).
  • EBRT external beam radiation therapy
  • BT brachytherapy
  • Radioactive atoms for use in the context of this invention can be selected from the group including, but not limited to, radium, cesium-137, iridium-192, americium-241 , gold-198, cobalt-57, copper-67, technetium-99, iodine-123, iodine-131 , and indium-1 1 1.
  • the agent that inhibits serine phosphorylation of IRS1 according to this invention is an antibody, it is also possible to label the antibody with such radioactive isotopes.
  • Radiation therapy is a standard treatment for controlling unresectable or inoperable tumors and/or tumor metastases. Improved results have been seen when radiation therapy has been combined with chemotherapy. Radiation therapy is based on the principle that high-dose radiation delivered to a target area will result in the death of reproductive cells in both tumor and normal tissues.
  • the radiation dosage regimen is generally defined in terms of radiation absorbed dose (Gy), time and fractionation, and must be carefully defined by the oncologist.
  • the amount of radiation a patient receives will depend on various considerations, but the two most important are the location of the tumor in relation to other critical structures or organs of the body, and the extent to which the tumor has spread.
  • a typical course of treatment for a patient undergoing radiation therapy will be a treatment schedule over a 1 to 6 week period, with a total dose of between 10 and 80 Gy administered to the patient in a single daily fraction of about 1.8 to 2.0 Gy, 5 days a week.
  • the inhibition of tumor growth by means of the agents comprising the combination of the invention is enhanced when combined with radiation, optionally with additional chemotherapeutic or anticancer agents.
  • Parameters of adjuvant radiation therapies are, for example, contained in International Patent Publication WO 99/60023.
  • the present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition treatment with one or more agents capable of enhancing antitumor immune responses.
  • Agents capable of enhancing antitumor immune responses include, for example: CTLA4 (cytotoxic lymphocyte antigen 4) antibodies (e.g. MDX-CTLA4), and other agents capable of blocking CTLA4.
  • CTLA4 cytotoxic lymphocyte antigen 4
  • Specific CTLA4 antibodies that can be used in the present invention include those described in U.S. Patent No. 6,682,736.
  • the present invention further provides a method for reducing the side effects caused by the treatment of tumors or tumor metastases in a patient with an agent that inhibits serine phosphorylation of IRS1 or an IGF1 R protein kinase inhibitor compound of Formula I, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and irinotecan combination, in amounts that are effective to produce an additive, or a superadditive or synergistic antitumor effect, and that are effective at inhibiting the growth of the tumor.
  • the present invention further provides a method for the treatment of cancer, comprising administering to a subject in need of such treatment (i) an effective first amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically acceptable salt thereof; and (ii) an effective second amount of an IGF1 R protein kinase inhibitor compound of Formula I.
  • the present invention also provides a method for the treatment of cancer, comprising administering to a subject in need of such treatment (i) a sub-therapeutic first amount of the EGFR kinase inhibitor erlotinib, or a pharmaceutically acceptable salt thereof; and (ii) a subtherapeutic second amount of an IGF1 R protein kinase inhibitor compound of Formula I.
  • the term "patient” preferably refers to a human in need of treatment with an agent that inhibits serine phosphorylation of IRS1 for any purpose, and more preferably a human in need of such a treatment to treat cancer, or a precancerous condition or lesion.
  • the term "patient” can also refer to non-human animals, preferably mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others, that are in need of treatment with an agent that inhibits serine phosphorylation of IRS1.
  • the patient is a human in need of treatment for cancer, or a precancerous condition or lesion.
  • the cancer is preferably any cancer treatable, either partially or completely, by administration of an agent that inhibits serine phosphorylation of IRS1.
  • the cancer may be, for example, lung cancer, non small cell lung (NSCL) cancer, bronchioloalviolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesot
  • the precancerous condition or lesion includes, for example, the group consisting of oral leukoplakia, actinic keratosis (solar keratosis), precancerous polyps of the colon or rectum, gastric epithelial dysplasia, adenomatous dysplasia, hereditary nonpolyposis colon cancer syndrome (HNPCC), Barrett's esophagus, bladder dysplasia, and precancerous cervical conditions.
  • oral leukoplakia actinic keratosis (solar keratosis)
  • precancerous polyps of the colon or rectum gastric epithelial dysplasia
  • adenomatous dysplasia adenomatous dysplasia
  • HNPCC hereditary nonpolyposis colon cancer syndrome
  • Barrett's esophagus bladder dysplasia
  • precancerous cervical conditions for example, the group consisting of oral leukoplakia, actin
  • co-administration of and “co-administering" of an IGF1 R protein kinase inhibitor compound of Formula I with an agent that inhibits serine phosphorylation of IRS1 refer to any administration of the two active agents, either separately or together, where the two active agents are administered as part of an appropriate dose regimen designed to obtain the benefit of the combination therapy.
  • the two active agents can be administered either as part of the same pharmaceutical composition or in separate pharmaceutical compositions.
  • An IGF1 R protein kinase inhibitor compound of Formula I can be administered prior to, at the same time as, or subsequent to administration of the agent that inhibits serine phosphorylation of IRS1 , or in some combination thereof.
  • an IGF1 R protein kinase inhibitor compound of Formula I can be administered prior to, at the same time as, or subsequent to, each administration of the agent that inhibits serine phosphorylation of IRS1 , or some combination thereof, or at different intervals in relation to the agent that inhibits serine phosphorylation of IRS1 treatment, or in a single dose prior to, at any time during, or subsequent to the course of treatment with the agent that inhibits serine phosphorylation of IRS1.
  • the agent that inhibits serine phosphorylation of IRS1 will typically be administered to the patient in a dose regimen that provides for the most effective treatment of the cancer (from both efficacy and safety perspectives) for which the patient is being treated, as known in the art, and as disclosed, e.g. in International Patent Publication No. WO 01/34574.
  • the agent that inhibits serine phosphorylation of IRS1 can be administered in any effective manner known in the art, such as by oral, topical, intravenous, intra-peritoneal, intramuscular, intra-articular, subcutaneous, intranasal, intraocular, vaginal, rectal, or intradermal routes, depending upon the type of cancer being treated, the type of agent that inhibits serine phosphorylation of IRS1 being used (e.g., small molecule, antibody, RNAi or antisense construct), and the medical judgment of the prescribing physician as based, e.g., on the results of published clinical studies.
  • any effective manner known in the art such as by oral, topical, intravenous, intra-peritoneal, intramuscular, intra-articular, subcutaneous, intranasal, intraocular, vaginal, rectal, or intradermal routes, depending upon the type of cancer being treated, the type of agent that inhibits serine phosphorylation of IRS1 being used (e.g., small molecule,
  • agent that inhibits serine phosphorylation of IRS1 administered and the timing of agent that inhibits serine phosphorylation of IRS1 administration will depend on the type (species, gender, age, weight, etc.) and condition of the patient being treated, the severity of the disease or condition being treated, and on the route of administration.
  • small molecule agents that inhibits serine phosphorylation of IRS1 can be administered to a patient in doses ranging from 0.001 to 100 mg/kg of body weight per day or per week in single or divided doses, or by continuous infusion (see for example, International Patent Publication No. WO 01/34574).
  • erlotinib HCI can be administered to a patient in doses ranging from 5- 200 mg per day, or 100-1600 mg per week, in single or divided doses, or by continuous infusion.
  • a preferred dose is 150 mg/day.
  • Antibody-based agents that inhibits serine phosphorylation of IRS1 , or antisense, RNAi or ribozyme constructs can be administered to a patient in doses ranging from 0.1 to 100 mg/kg of body weight per day or per week in single or divided doses, or by continuous infusion.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • the agents that inhibits serine phosphorylation of IRS1 and IGF1 R protein kinase inhibitors can be administered either separately or together by the same or different routes, and in a wide variety of different dosage forms.
  • the agent that inhibits serine phosphorylation of IRS1 is preferably administered orally or parenterally, whereas the IGF1 R protein kinase inhibitor compound of Formula I is preferably administered parenterally.
  • the agent that inhibits serine phosphorylation of IRS1 is erlotinib HCI (TARCEVA) 1 oral administration is preferable.
  • the agent that inhibits serine phosphorylation of IRS1 can be administered with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, elixirs, syrups, and the like. Administration of such dosage forms can be carried out in single or multiple doses. Carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the agent that inhibits serine phosphorylation of IRS1 and IGF1 R protein kinase inhibitor compound of Formula I can be combined together with various pharmaceutically acceptable inert carriers in the form of sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, and the like. Administration of such dosage forms can be carried out in single or multiple doses.
  • Carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents, etc.
  • tablets containing one or both of the active agents are combined with any of various excipients such as, for example, micro-crystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinyl pyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinyl pyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting purposes.
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the agent that inhibits serine phosphorylation of IRS1 may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions in either sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions comprising the active agent or a corresponding water-soluble salt thereof.
  • sterile aqueous solutions are preferably suitably buffered, and are also preferably rendered isotonic, e.g., with sufficient saline or glucose.
  • These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
  • the oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes.
  • Any parenteral formulation selected for administration of proteinaceous agents that inhibits serine phosphorylation of IRS1 should be selected so as to avoid denaturation and loss of biological activity of the inhibitor.
  • a topical formulation comprising either an agent that inhibits serine phosphorylation of IRS1 or an IGF1 R protein kinase inhibitor compound of Formula I in about 0.1% (w/v) to about 5% (w/v) concentration can be prepared.
  • the active agents can be administered separately or together to animals using any of the forms and by any of the routes described above.
  • the agent that inhibits serine phosphorylation of IRS1 is administered in the form of a capsule, bolus, tablet, liquid drench, by injection or as an implant.
  • the agent that inhibits serine phosphorylation of IRS1 can be administered with the animal feedstuff, and for this purpose a concentrated feed additive or premix may be prepared for a normal animal feed.
  • the IGF1 R protein kinase inhibitor compound of Formula I is preferably administered in the form of liquid drench, by injection or as an implant. Such formulations are prepared in a conventional manner in accordance with standard veterinary practice.
  • the present invention further provides a kit comprising a single container comprising both an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I.
  • the present invention further provides a kit comprising a first container comprising an agent that inhibits serine phosphorylation of IRS1 and a second container comprising an IGF1 R protein kinase inhibitor compound of Formula I.
  • the kit containers may further include a pharmaceutically acceptable carrier.
  • the kit may further include a sterile diluent, which is preferably stored in a separate additional container.
  • the kit may further include a package insert comprising printed instructions directing the use of the combined treatment as a method for treating cancer.
  • the term "agent which inhibits serine phosphorylation of IRS1” refers to any agent which inhibits serine phosphorylation of IRS1 that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of IRS1 in the patient, other than agents that block the mTORCI signaling pathway.
  • IRS1 inhibitors include any agent that can block IRS1 activation or any of the downstream biological effects of IRS1 activation that are relevant to treating cancer in a patient. Such an inhibitor can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity.
  • IRS1 inhibitors include but are not limited to low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, small inhibitory RNAs (i.e. RNA interference by dsRNA; RNAi), and ribozymes.
  • Agents which inhibit serine phosphorylation of IRS1 include, for example, EGFR kinase inhibitors, MAPK inhibitors, MEK inhibitors, Ras inhibitors, Raf inhibitors, and PKC inhibitors.
  • MAPK inhibitor refers to any MAPK inhibitor that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of the MAPK receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to MAPK of its natural ligand.
  • Such MAPK kinase inhibitors include any agent that can block MAPK activation or any of the downstream biological effects of MAPK activation that are relevant to treating cancer in a patient. Such an inhibitor can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity.
  • such an inhibitor can act by occupying the ligand binding site or a portion thereof of the MAPK receptor, thereby making the receptor inaccessible to its natural ligand so that its normal biological activity is prevented or reduced.
  • such an inhibitor can act by modulating the dimerization of MAPK polypeptides, or interaction of MAPK polypeptide with other proteins, or enhance ubiquitination and endocytotic degradation of MAPK.
  • MAPK kinase inhibitors include but are not limited to low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, small inhibitory RNAs (i.e. RNA interference by dsRNA; RNAi), and ribozymes.
  • the MAPK kinase inhibitor is a small organic molecule or an antibody that binds specifically to the human MAPK.
  • MAPK kinase inhibitors include, for example, Ras inhibitors, Raf inhibitors, MEK inhibitors or PKC inhibitors.
  • MEK inhibitor refers to any MEK inhibitor that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of the MEK receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to MEK of its natural ligand.
  • MEK kinase inhibitors include any agent that can block MEK activation or any of the downstream biological effects of MEK activation that are relevant to treating cancer in a patient.
  • Such an inhibitor can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity.
  • such an inhibitor can act by occupying the ligand binding site or a portion thereof of the MEK receptor, thereby making the receptor inaccessible to its natural ligand so that its normal biological activity is prevented or reduced.
  • such an inhibitor can act by modulating the dimerization of MEK polypeptides, or interaction of MEK polypeptide with other proteins, or enhance ubiquitination and endocytotic degradation of MEK.
  • MEK kinase inhibitors include but are not limited to low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, small inhibitory RNAs (i.e. RNA interference by dsRNA; RNAi), and ribozymes.
  • the MEK kinase inhibitor is a small organic molecule or an antibody that binds specifically to the human MEK.
  • a MEK inhibitor is a compound that shows MEK inhibition when tested in the assays titled, "Enzyme Assays" in U.S. Pat. No. 5,525,625, column 6, beginning at line 35.
  • the complete disclosure of U.S. Pat. No. 5,525,625 is hereby incorporated by reference.
  • a compound is an MEK inhibitor if a compound shows activity in the assay titled, "Cascade Assay for Inhibitors of the MAP Kinase Pathway," column 6, line 36 to column 7, line 4 of the U.S. Pat. No. 5,525,625 and/or shows activity in the assay titled, "In Vitro MEK Assay” at column 7, lines 4 to 27 of the above-referenced patent.
  • MEK inhibition can be measured in the assay described in WO 02/06213 A1 , the complete disclosure of which is hereby incorporated by reference.
  • MEK kinase inhibitors include, for example, ARRY-142886 (also known as AZD6244; Array BioPharma/Astrazeneca), PD-184352 (also known as CI-1040; Pfizer), XL518 (Exelixis), PD0325901 (Pfizer), PD-98059 (Pfizer), MEK1 (EMD), or 2-(2-amino-3-methoxyphenyl)-4-oxo- 4H-[1]benzopyran and 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide.
  • MEK inhibitors that can be used according to the present invention include ARRY-142886, PD-184352, PD-98059, PD-0325901 , XL518, or MEK1.
  • Ras inhibitor refers to any Ras inhibitor that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of the Ras receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to Ras of its natural ligand.
  • Ras kinase inhibitors include any agent that can block Ras activation or any of the downstream biological effects of Ras activation that are relevant to treating cancer in a patient. Such an inhibitor can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity.
  • Ras kinase inhibitors include but are not limited to low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, small inhibitory RNAs (i.e. RNA interference by dsRNA; RNAi), and ribozymes.
  • the Ras kinase inhibitor is a small organic molecule or an antibody that binds specifically to the human Ras.
  • Ras kinase inhibitors include, for example, BMS-214662 (Bristol-Myers Squibb), SCH 66336 (also known as lonafarnib; Schering-Plough), L-778,123 (Merck), R115777 (also known as Zarnestra or Tipifamib; Johnson and Johnson), and 6-[(4-chloro-phenyl)-hydroxy-(3-methyl- 3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1 H-quinolin-2-one (OSI)
  • a specific preferred example of a Ras inhibitors that can be used according to the present invention includes 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4- (3-ethynyl-phenyl)-1-methyl-1 H-quinolin-2-one.
  • Raf inhibitor refers to any Raf inhibitor that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of the Raf receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to Raf of its natural ligand.
  • Raf kinase inhibitors include any agent that can block Raf activation or any of the downstream biological effects of Raf activation that are relevant to treating cancer in a patient.
  • Such an inhibitor can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity.
  • Raf kinase inhibitors include but are not limited to low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, small inhibitory RNAs (i.e. RNA interference by dsRNA; RNAi), and ribozymes.
  • the Raf kinase inhibitor is a small organic molecule or an antibody that binds specifically to the human Raf.
  • Raf kinase inhibitors include, for example, sorafenib (also known as BAY 43-9006; Bayer).
  • PKC inhibitor refers to any PKC inhibitor that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of the PKC receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to PKC of its natural ligand.
  • PKC kinase inhibitors include any agent that can block PKC activation or any of the downstream biological effects of Raf activation that are relevant to treating cancer in a patient.
  • Such an inhibitor can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity.
  • such an inhibitor can act by occupying the ligand binding site or a portion thereof of the PKC receptor, thereby making the receptor inaccessible to its natural ligand so that its normal biological activity is prevented or reduced.
  • such an inhibitor can act by modulating the dimerization of PKC polypeptides, or interaction of PKC polypeptide with other proteins, or enhance ubiquitination and endocytotic degradation of PKC.
  • PKC kinase inhibitors include but are not limited to low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, small inhibitory RNAs (i.e. RNA interference by dsRNA; RNAi), and ribozymes.
  • the PKC kinase inhibitor is a small organic molecule or an antibody that binds specifically to the human PKC.
  • PKC kinase inhibitors include, for example, byrostatin, staurosporine, staurosporine analogs including UCN-01 or CGP41251 , or safingol.
  • EGFR kinase inhibitor refers to any EGFR kinase inhibitor that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of the EGF receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to EGFR of its natural ligand.
  • Such EGFR kinase inhibitors include any agent that can block EGFR activation or any of the downstream biological effects of EGFR activation that are relevant to treating cancer in a patient. Such an inhibitor can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity.
  • such an inhibitor can act by occupying the ligand binding site or a portion thereof of the EGFR receptor, thereby making the receptor inaccessible to its natural ligand so that its normal biological activity is prevented or reduced.
  • such an inhibitor can act by modulating the dimerization of EGFR polypeptides, or interaction of EGFR polypeptide with other proteins, or enhance ubiquitination and endocytotic degradation of EGFR.
  • EGFR kinase inhibitors include but are not limited to low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, small inhibitory RNAs (i.e. RNA interference by dsRNA; RNAi), and ribozymes.
  • the EGFR kinase inhibitor is a small organic molecule or an antibody that binds specifically to the human EGFR.
  • EGFR kinase inhibitors that include, for example quinazoline EGFR kinase inhibitors, pyrido-pyrimidine EGFR kinase inhibitors, pyrimido-pyrimidine EGFR kinase inhibitors, pyrrolo- pyrimidine EGFR kinase inhibitors, pyrazolo-pyrimidine EGFR kinase inhibitors, phenylamino- pyrimidine EGFR kinase inhibitors, oxindole EGFR kinase inhibitors, indolocarbazole EGFR kinase inhibitors, phthalazine EGFR kinase inhibitors, isoflavone EGFR kinase inhibitors, quinalone EGFR kinase inhibitors, and
  • Additional non-limiting examples of low molecular weight EGFR kinase inhibitors include any of the EGFR kinase inhibitors described in Traxler, P., 1998, Exp. Opin. Ther. Patents 8(12):1599-1625.
  • low molecular weight EGFR kinase inhibitors that can be used according to the present invention include [6,7-bis(2-methoxyethoxy)-4-quinazolin-4- yl]-(3-ethynylphenyl) amine (also known as OSI-774, erlotinib, or TARCEVA (erlotinib HCI); OSI Pharmaceuticals/Genentech/Roche) (U.S. Pat. No. 5,747,498; International Patent Publication No. WO 01/34574, and Moyer, J.D. et al. (1997) Cancer Res.
  • CI-1033 (formerly known as PD183805; Pfizer) (Sherwood et al., 1999, Proc. Am. Assoc. Cancer Res. 40:723); PD-158780 (Pfizer); AG-1478 (University of California); CGP-59326 (Novartis); PKI-166 (Novartis); EKB-569 (Wyeth); GW-2016 (also known as GW-572016 or lapatinib ditosylate ; GSK); and gefitinib (also known as ZD1839 or IRESSATM; Astrazeneca) (Woodbum et al., 1997, Proc. Am. Assoc. Cancer Res.
  • a particularly preferred low molecular weight EGFR kinase inhibitor that can be used according to the present invention is [6,7-bis(2- methoxyethoxy)-4-quinazolin-4-yl]-(3-ethynylphenyl) amine (i.e. erlotinib), its hydrochloride salt (i.e. erlotinib HCI, TARCEVA), or other salt forms (e.g. erlotinib mesylate).
  • Antibody-based EGFR kinase inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand.
  • Non- limiting examples of antibody-based EGFR kinase inhibitors include VECTIBIXTM (panitumumab; Amgen, Thousand Oaks, CA); those described in Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al., 1995, Clin. Cancer Res. 1 :1311-1318; Huang, S. M., et al., 1999, Cancer Res. 15:59(8):1935- 40; and Yang, X., et al., 1999, Cancer Res. 59:1236-1243.
  • the EGFR kinase inhibitor can be monoclonal antibody Mab E7.6.3 (Yang, X.D. et al. (1999) Cancer Res. 59:1236-43), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.
  • Suitable monoclonal antibody EGFR kinase inhibitors include, but are not limited to, IMC-C225 (also known as cetuximab or ERBITUXTM; lmclone Systems), ABX-EGF (Abgenix), EMD 72000 (Merck KgaA, Darmstadt), RH3 (York Medical Bioscience Inc.), and MDX-447 (Medarex/Merck KgaA).
  • Additional antibody-based EGFR kinase inhibitors can be raised according to known methods by administering the appropriate antigen or epitope to a host animal selected, e.g., from pigs, cows, horses, rabbits, goats, sheep, and mice, among others.
  • a host animal selected, e.g., from pigs, cows, horses, rabbits, goats, sheep, and mice, among others.
  • Various adjuvants known in the art can be used to enhance antibody production.
  • Monoclonal antibodies against EGFR can be prepared and isolated using any technique that provides for the production of antibody molecules by continuous cell lines in culture. Techniques for production and isolation include but are not limited to the hybridoma technique originally described by Kohler and Milstein (Nature, 1975, 256: 495-497); the human B-cell hybridoma technique (Kosbor et al., 1983, Immunology Today 4:72; Cote et al., 1983, Proc. Natl. Acad. Sci.
  • Antibody-based EGFR kinase inhibitors useful in practicing the present invention also include anti-EGFR antibody fragments including but not limited to F(ab') 2 fragments, which can be generated by pepsin digestion of an intact antibody molecule, and Fab fragments, which can be generated by reducing the disulfide bridges of the F(ab') 2 fragments.
  • Fab and/or scFv expression libraries can be constructed (see, e.g., Huse et al., 1989, Science 246: 1275- 1281 ) to allow rapid identification of fragments having the desired specificity to EGFR.
  • EGFR kinase inhibitors for use in the present invention can alternatively be based on antisense oligonucleotide constructs.
  • Anti-sense oligonucleotides including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of EGFR mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of EGFR kinase protein, and thus activity, in a cell.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding EGFR can be synthesized, e.g., by conventional phosphodiester techniques and administered by e.g., intravenous injection or infusion.
  • Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Patent Nos. 6,566,135; 6,566,131 ; 6,365,354; 6,410,323; 6,107,091 ; 6,046,321 ; and 5,981 ,732).
  • Small inhibitory RNAs can also function as EGFR kinase inhibitors for use in the present invention.
  • EGFR gene expression can be reduced by contacting the tumor, subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that expression of EGFR is specifically inhibited (i.e. RNA interference or RNAi).
  • dsRNA small double stranded RNA
  • RNAi RNA interference
  • Methods for selecting an appropriate dsRNA or dsRNA-encoding vector are well known in the art for genes whose sequence is known (e.g. see Tuschi, T., et al. (1999) Genes Dev. 13(24):3191-3197; Elbashir, S.M.
  • Ribozymes can also function as EGFR kinase inhibitors for use in the present invention.
  • Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA.
  • the mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage.
  • Engineered hammerhead motif ribozyme molecules that specifically and efficiently catalyze endonucleolytic cleavage of EGFR mRNA sequences are thereby useful within the scope of the present invention.
  • ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, which typically include the following sequences, GUA, GUU, and GUC. Once identified, short RNA sequences of between about 15 and 20 ribonucleotides corresponding to the region of the target gene containing the cleavage site can be evaluated for predicted structural features, such as secondary structure, that can render the oligonucleotide sequence unsuitable. The suitability of candidate targets can also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using, e.g., ribonuclease protection assays.
  • Both antisense oligonucleotides and ribozymes useful as EGFR kinase inhibitors can be prepared by known methods. These include techniques for chemical synthesis such as, e.g., by solid phase phosphoramadite chemical synthesis. Alternatively, anti-sense RNA molecules can be generated by in vitro or in vivo transcription of DNA sequences encoding the RNA molecule. Such DNA sequences can be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters. Various modifications to the oligonucleotides of the invention can be introduced as a means of increasing intracellular stability and half-life.
  • Possible modifications include but are not limited to the addition of flanking sequences of ribonucleotides or deoxyribonucleotides to the 5' and/or 3' ends of the molecule, or the use of phosphorothioate or 2'-O-methyl rather than phosphodiesterase linkages within the oligonucleotide backbone.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • a compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (cupric and cuprous), ferric, ferrous, lithium, magnesium, manganese (manganic and manganous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium slats.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
  • Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N',N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine,
  • a compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • the present invention provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor combination.
  • the tumors or tumor metastases to be treated is non small cell lung (NSCL) cancer.
  • MEK inhibitors include ARRY-142886 (also known as AZD6244; Array
  • PD0325901 Pfizer
  • PD-98059 Pfizer
  • EMD Mek1
  • Particularly preferred MEK inhibitors that can be used according to the present invention are MEK1 or PD-98059.
  • IGF-1 R inhibitors potentiate TARCEVA (erlotinib) effects on cell survival in the presence of IGF-1 , and the ability of IGF-1 R inhibitors in combination with TARCEVA (erlotinib)
  • MAPK and PI3K-AKT were assessed for their effects on tumor growth in mouse xenograft models.
  • CRC colorectal cancer
  • pancreatic cancer cells were assessed for their tumor growth in mouse xenograft models.
  • Ebliss EA + EB - EA * EB, where EA and EB are the fractional inhibitions obtained by drug A alone and drug B alone at specific concentrations.
  • Ebliss is the fractional inhibition that would be expected if the combination of the two drugs was exactly additive. If the experimentally measured fractional inhibition is less than Ebliss the combination was said to be synergistic. If the experimentally measured fractional inhibition is greater than Ebliss the combination was said to be antagonistic.
  • TGI tumor growth inhibition
  • T t median tumor volume of treated at time t
  • T 0 median tumor volume of treated at time 0
  • C t median tumor volume of control at time t
  • C 0 median tumor volume of control at time 0
  • the combination of Compound A and Erlotinib by coadministration leads to much greater anti-tumor effect than either drug alone in vivo, and only the combination achieves early growth regression of the tumor during the treatment period. Approximately 26% of tumor regression is achieved on day 4 of dosing (maximum regression). The average tumor regression for the treatment period is approximately 13.2%.
  • the combination of Compound A and Erlotinib has synergist effect on inhibiting cell proliferation in the epithelial breast tumor cell line MDA-MB-468. The additive effect of the combination treatment on growth inhibition is observed in the breast tumor cell line BT20.
  • Ce// lines The cell lines NCI-H292, GEO, BxPC3, MDA-MB-435, DU4475, and MDA- MB-468, and BT-20 were routinely cultured in media as prescribed by the ATCC containing 10% FCS. With the exception of GEO tumor cells (obtained from RPCI, Roswell Park Cancer Institute), all tumor cells were obtained from the ATCC. Measurement of Cell Proliferation:
  • Cell proliferation was determined using the Cell Titer GIo assay (Promega), and apoptosis was determined by measuring caspase 3/7 activity with Caspase GIo (Promega).
  • Cell lines were seeded at a density of 3000 cells per well in a 96-well plate. 24 hours after plating cells were dosed with varying concentrations of drug, either as a single agent or in combination.
  • the signal for Cell Titer GIo was determined 72 hours after dosing, and the signal for Caspase GIo was determined 48 hours after dosing. Analysis of Additivity and Synergy:
  • %TGI Tumor growth inhibition
  • T-C Growth delay is calculated as T-C where T and C are the times in days for mean tumor size in the treated (T) and control (C) groups to reach 400% of the initial tumor volume. Cures are excluded from this calculation. Percent regression is measured by the following formula: 100 x (T o -T t )/To, where T 0 is the median tumor volume of a treatment group on day 0, and T, is the median tumor volume of the same group on day t.
  • Durable cures were determined by the absence of palpable tumor 60 days post final dose of drug. Tarceva was dosed in a 6% Captisol (CyDex, Inc) in WFI (Water for Injection) solution and all control animals were dosed with an equal volume of the vehicle. Compd A was dosed in 25 mM tartaric acid at the appropriate concentration in 20 ml/kg dose volume. All mice were dosed daily by oral gavage for the indicated time periods.
  • 98059 is more efficacious than either drug alone in both in vitro and in vivo.

Abstract

Compositions and methods for treating tumors or tumor metastases in a patient, comprising administering to a patient simultaneously or sequentially a therapeutically effective amount of an agent which inhibits serine phosphorylation of IRS1 and an IGF1 R inhibitor compound of Formula I, such as c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5- a]pyrazin-3-yl]-1-methyl-cyclobutanol, or a pharmaceutically acceptable salt thereof.

Description

COMBINATION OF IMIDAZO [1 , 5 -A] PYRAZINYL DERIVATIVES WITH AN AGENT THAT INHIBITS SERINE PHOSPHORYLATION OF IRSl FOR USE IN THE TREATMENT OF CANCER
BACKGROUND
[1] Cancer is a generic name for a wide range of cellular malignancies characterized by unregulated growth, lack of differentiation, and the ability to invade local tissues and metastasize. These neoplastic malignancies affect, with various degrees of prevalence, every tissue and organ in the body.
[2] A multitude of therapeutic agents have been developed over the past few decades for the treatment of various types of cancer. The most commonly used types of anticancer agents include: DNA-alkylating agents (e.g., cyclophosphamide, ifosfamide), anti-metabolites (e.g., methotrexate, a folate antagonist, and 5-fluorouracil, a pyrimidine antagonist), microtubule disrupters (e.g., vincristine, vinblastine, paclitaxel), DNA intercalators (e.g., doxorubicin, daunomycin, cisplatin), and hormone therapy (e.g., tamoxifen, flutamide). [3] Colorectal cancer is among the leading causes of cancer-related morbidity and mortality in the U.S. Treatment of this cancer depends largely on the size, location and stage of the tumor, whether the malignancy has spread to other parts of the body (metastasis), and on the patient's general state of health. Options include surgical removal of tumors for early stage localized disease, chemotherapy and radiotherapy. However, chemotherapy is currently the only treatment for metastatic disease. 5-fluorouracil is currently the most effective single-agent treatment for advanced colorectal cancer, with response rates of about 10 %. Additionally, new agents such as the topoisomerase I inhibitor irinotecan (CPT11), the platinum-based cytotoxic agent oxaliplatin (e.g. ELOXATIN™), and the EGFR kinase inhibitor erlotinib ([6,7-bis(2- methoxyethoxy)-4-quinazolin-4-yl]-(3-ethynylphenyl)amine, e.g. erlotinib HCI, TARCEVA ® (OSI Pharmaceuticals, Inc. Melville, NY)) have shown promise in treatment.
[4] Over-expression of the epidermal growth factor receptor (EGFR) kinase, or its ligand TGF-alpha, is frequently associated with many cancers, including breast, lung, colorectal and head and neck cancers (Salomon D. S., et al. (1995) Crit. Rev. Oncol. Hematol. 19:183-232; Wells, A. (2000) Signal, 1 :4-1 1 ), and is believed to contribute to the malignant growth of these tumors. A specific deletion-mutation in the EGFR gene has also been found to increase cellular tumorigenicity (Halatsch, M-E. et al. (2000) J. Neurosurg. 92:297-305; Archer, G.E. et al. (1999) Clin. Cancer Res. 5:2646-2652). Activation of EGFR stimulated signaling pathways promote multiple processes that are potentially cancer-promoting, e.g. proliferation, angiogenesis, cell motility and invasion, decreased apoptosis and induction of drug resistance. The development for use as anti-tumor agents of compounds that directly inhibit the kinase activity of the EGFR, as well as antibodies that reduce EGFR kinase activity by blocking EGFR activation, are areas of intense research effort (de Bono J. S. and Rowinsky, E. K. (2002) Trends in MoI. Medicine 8:S19-S26; Dancey, J. and Sausville, E.A. (2003) Nature Rev. Drug Discovery 2:92-313). Several studies have demonstrated or disclosed that some EGFR kinase inhibitors can improve tumor cell or neoplasia killing when used in combination with certain other anti-cancer or chemotherapeutic agents or treatments (e.g. Raben, D. et al. (2002) Semin. Oncol. 29:37-46; Herbst, R.S. et al. (2001 ) Expert Opin. Biol. Ther. 1 :719-732; Magne, N et al. (2003) Clin. Can. Res. 9:4735-4732; Magne, N. et al. (2002) British Journal of Cancer 86:819-827; Torrance, CJ. et al. (2000) Nature Med. 6:1024-1028; Gupta, R.A. and DuBois, R.N. (2000) Nature Med. 6:974-975; Tortora, et al. (2003) Clin. Cancer Res. 9:1566-1572; Solomon, B. et al (2003) Int. J. Radiat. Oncol. Biol. Phys. 55:713-723; Krishnan, S. et al. (2003) Frontiers in Bioscience 8, e1- 13; Huang, S et al. (1999) Cancer Res. 59:1935-1940; Contessa, J. N. et al. (1999) Clin. Cancer Res. 5:405-41 1 ; Li, M. et al. Clin. (2002) Cancer Res. 8:3570-3578; Ciardiello, F. et al. (2003) Clin. Cancer Res. 9:1546-1556; Ciardiello, F. et al. (2000) Clin. Cancer Res. 6:3739- 3747; Grunwald, V. and Hidalgo, M. (2003) J. Nat. Cancer Inst. 95:851-867; Seymour L. (2003) Current Opin. Investig. Drugs 4(6):658-666; Khalil, M.Y. et al. (2003) Expert Rev. Anticancer Ther.3:367-380; Bulgaru, A.M. et al. (2003) Expert Rev. Anticancer Ther.3:269-279; Dancey, J. and Sausville, E.A. (2003) Nature Rev. Drug Discovery 2:92-313; Kim, E. S. et al. (2001 ) Current Opinion Oncol. 13:506-513; Arteaga, CL. and Johnson, D.H. (2001 ) Current Opinion Oncol. 13:491-498; Ciardiello, F. et al. (2000) Clin. Cancer Res. 6:2053-2063; Patent Publication Nos: US 2003/0108545; US 2002/0076408; US 2004/0209930; and US 2003/0157104; and International Patent Publication Nos: WO 99/60023; WO 01/12227; WO 02/055106; WO 03/088971 ; WO 01/34574; WO 01/76586; WO 02/05791 ; and WO 02/089842). [5] An anti-neoplastic drug would ideally kill cancer cells selectively, with a wide therapeutic index relative to its toxicity towards non-malignant cells. It would also retain its efficacy against malignant cells, even after prolonged exposure to the drug. Unfortunately, none of the current chemotherapies possess such an ideal profile. Instead, most possess very narrow therapeutic indexes. Furthermore, cancerous cells exposed to slightly sub-lethal concentrations of a chemotherapeutic agent will very often develop resistance to such an agent, and quite often cross-resistance to several other antineoplastic agents as well.
[6] Thus, there is a need for more efficacious treatment for neoplasia and other proliferative disorders. Strategies for enhancing the therapeutic efficacy of existing drugs have involved changes in the schedule for their administration, and also their use in combination with other anticancer or biochemical modulating agents. Combination therapy is well known as a method that can result in greater efficacy and diminished side effects relative to the use of the therapeutically relevant dose of each agent alone. In some cases, the efficacy of the drug combination is additive (the efficacy of the combination is approximately equal to the sum of the effects of each drug alone), but in other cases the effect is synergistic (the efficacy of the combination is greater than the sum of the effects of each drug given alone). For example, when combined with 5-FU and leucovorin, oxaliplatin exhibits response rates of 25-40% as first- line treatment for colorectal cancer (Raymond, E. et al.(1998) Semin Oncol. 25(2 Suppl. 5):4- 12).
[7] Growth factors acting through receptor tyrosine kinases (RTKs) drive tumor initiation and progression by accelerating cell proliferation and promoting cell survival. The RTKs for epidermal growth factor (EGF) and insulin-like growth factor (IGF) contribute to tumorigenesis for a multitude of tumor types including non-small cell lung cancer (NSCLC), colorectal, pancreatic, and breast tumors (Holbro, T., and Hynes, N. E. (2004). ErbB receptors: directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol 44, 195-217; Kurmasheva, R. T., and Houghton, P. J. (2006). IGF-I mediated survival pathways in normal and malignant cells. Biochim Biophys Acta 1766, 1-22; Levitzki, A. (2003). EGF receptor as a therapeutic target. Lung Cancer 41 Suppl 1, S9-14; Roskoski, R., Jr. (2004). The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem Biophys Res Commun 319, 1-11.) Tumor cells can exhibit redundancy surrounding RTKs that contributes to de novo resistance to a single RTK inhibitor, and crosstalk between RTKs can confer acquired resistance whereby the inhibition of one RTK is compensated by enhanced activity through an alternative RTK. It has been shown that IGF-1 R signaling is associated with acquired resistance of cancer cells to chemo or radiation therapies, and molecular targeted therapies including epidermal growth factor receptor (EGFR) inhibition (Chakravarti et al., 2002; Gooch, J. L., Van Den Berg, C. L., and Yee, D. (1999). Insulin-like growth factor (IGF)-I rescues breast cancer cells from chemotherapy-induced cell death-proliferative and anti-apoptotic effects. Breast Cancer Res Treat 56, 1-10.; Jones et al., 2004; Knowlden, J. M., Hutcheson, I. R., Barrow, D., Gee, J. M., and Nicholson, R. I. (2005). Insulin-like growth factor-l receptor signaling in tamoxifen-resistant breast cancer: a supporting role to the epidermal growth factor receptor. Endocrinology 146, 4609-4618.; Lu, Y., Zi, X., Zhao, Y., Mascarenhas, D., and Pollak, M. (2001 ). Insulin-like growth factor-l receptor signaling and resistance to trastuzumab (Herceptin). Journal of the National Cancer Institute 93, 1852-1857.; Nahta et al., 2005; Turner, B. C, Haffty, B. G., Narayanan, L., Yuan, J., Havre, P. A., Gumbs, A. A., Kaplan, L., Burgaud, J. L., Carter, D., Baserga, R., and Glazer, P. M. (1997). Insulin-like growth factor-l receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation. Cancer research 57, 3079-3083.). Indeed, it has recently been shown that in several different cancer types the efficacy of EGFR and ErbB2 signal transduction inhibitors could be acutely attenuated by IGF-1 R activation of the PI3-kinase/Akt pathway (Chakravarti, A., Loeffler, J. S., and Dyson, N. J. (2002). Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer research 62, 200-207; Jones, H. E., Goddard, L., Gee, J. M., Hiscox, S., Rubini, M., Barrow, D., Knowlden, J. M., Williams, S., Wakeling, A. E., and Nicholson, R. I. (2004). Insulin-like growth factor-l receptor signaling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer 11, 793-814; Lu, Y., Zi, X., Zhao, Y., Mascarenhas, D., and Pollak, M. (2001 ). Insulin-like growth factor-l receptor signaling and resistance to trastuzumab (Herceptin). Journal of the National Cancer Institute 93, 1852-1857; Nahta, R., Yuan, L. X., Zhang, B., Kobayashi, R., and Esteva, F. J. (2005). Insulin-like growth factor-l receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer research 65, 11118-11128) . For instance, IGF-1 R activation correlates with acquired resistance of breast and prostate cancer cells to EGFR inhibition (Jones et al., 2004). IGF-IR has also been shown to mediate resistance to anti-EGFR therapies in glioblastoma, colorectal, and NSCLC tumor cells (Chakravarti et al., 2002; Liu et al., 2001; Jones et al., 2004; Morgillo et al., 2006; Hurbin et al., 2003; Knowlden et al., 2005).
[8] US2006/0235031 refers to 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors as IFG1 R inhibitors and uses thereof, including for treating cancer. Valeriote et al., Cancer Chemotherapy Reports, 59(5), 895-900 (1975), states that "extensive literature describing additivity and synergism in anticancer agents exists." US2003/0114467; US2003/0153752; and US2005/0037999 refer to pyrazolo- and pyrrolo- pyrimidines and uses thereof, including for cancer treatment, and generally refer to various combinations with other anticancer agents. US2005/0153966 refers to heterocyclic compounds said to be kinase inhibitors and uses thereof, including for cancer treatment. U S2004/0180911 refers to pyrimidine derivatives and uses thereof, including for tumors and proliferative diseases, and states that the compounds can be used in combination with other chemotherapy drugs. WO2004/056830 refers to pyrrolopyrimidine derivatives and uses thereof, including for cancer treatment, and states that the compounds can be used in combination with other anticancer agents. US2004/0106605 is entitled "Synergistic Methods and Compositions for Treating Cancer," and generally refers to combinations of IGF1 R inhibitors with EGFR inhibitors.
SUMMARY
[9] The present invention is directed to methods for treating cancer patients. In particular, the present invention is directed to combined treatment of patients with novel substituted heterobicyclic IGF1 R protein kinase inhibitors and anti-cancer agents.
[10] The invention described herein provides new drug combinations, and methods for using drug combinations in the treatment of cancer.
[1 1] The present invention provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent which inhibits serine phosphorylation of IRS1 and IGF1 R inhibitor combination, with or without additional agents or treatments, such as other anti-cancer drugs or radiation therapy, wherein the IGF1 R inhibitor relates to compounds of Formula I:
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof.
[12] This invention provides anti-cancer combination therapies that reduce the dosages for individual components required for efficacy, thereby decreasing side effects associated with each agent, while maintaining or increasing therapeutic value.
[13] According to one aspect of the invention, an agent which inhibits serine phosphorylation of IRSIthat can be used in practicing this invention is an EGFR kinase inhibitor.
[14] According to a second aspect of the present invention, an agent which inhibits serine phosphorylation of IRSI is erlotinib HCI (TARCEVA®, OSI Pharmaceuticals, Inc. Melville, NY).
[15] According to another aspect of the present invention, the agent which inhibits serine phosphorylation of IRSIthat can be used in practicing this invention is a pAkt/MAPK/IRS-1 serine phosphorylation/pS-IRS-1 inhibitor.
[16] According to another aspect of the present invention, the agent which inhibits serine phosphorylation of IRSIthat can be used in practicing this invention is a MEK inhibitor.
[17] According to another aspect of the present invention, the agent which inhibits serine phosphorylation of IRS1 that can be used in practicing this invention is an inhibitor of the MAPK pathway.
[18] According to another aspect of the present invention, the agent which inhibits serine phosphorylation of IRSIthat can be used in practicing this invention is a Raf inhibitor.
[19] According to another aspect of the present invention, the agent which inhibits serine phosphorylation of IRSIthat can be used in practicing this invention is a Ras inhibitor.
[20] According to another aspect of the present invention, the agent which inhibits serine phosphorylation of IRSIthat can be used in practicing this invention is a PKC inhibitor.
FIGURES
[21] Figures 1A and 1 B: Plots depicting synergistic effect of IGF-1 R inhibitor Compound A (c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1-methyl-cyclobutanol) in combination with Erlotinib (TARCEVA) on inhibiting cell proliferation (1A) and promoting apoptosis (1 B) in the epithelial pancreatic cancer cell line BxPC3.
[22] Figures 2A and 2B: Plots depicting anti-tumor efficacy of oral co-administration of Compound A (c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1-methyl- cyclobutanol) with Erlotinib (TARCEVA) in BxPC3 human pancreatic cancer xenograft model. [23] Figures 3A and 3B: Plots depicting synergistic effect of IGF-1 R inhibitor Compound A (c/s-3-[8-Amino-1 -(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1 -methyl-cyclobutanol) in combination with Erlotinib (TARCEVA) on inhibiting cell proliferation in the epithelial breast tumor cell line MDA-MB-468 (A), and additive effect of the combination in the breast tumor cell line BT20 (B).
[24] Figures 4A and 4B: Plots depicting effect of IGF-1 R inhibitor Compound A (c/s-3-[8- Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1 -methyl-cyclobutanol) in combination with Erlotinib (TARCEVA) on inhibiting cell proliferation in two mesenchymal breast tumor cell lines DU4475 and MDA-MB-435. Synergistic effect achieves in DU4475 cell line (A), and additive effect is observed in MDA-MB-435 cell line (B).
[25] Figure 5: Table representing anti-tumor efficacy of oral co-administration of Compound A (c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1 -methyl-cyclobutanol) with Erlotinib (TARCEVA) in GEO human colorectal cancer xenograft model. The combination of Compound A and Erlotinib is more efficacious than either drug alone in vivo, and only the combination achieves growth regression of the tumor during the treatment period. [26] Figures 6A and 6B: Plots depicting synergistic effect of IGF-1 R inhibitor Compound A (c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1 -methyl-cyclobutanol) in combination with MEK1 (6A) and with PD-98059 (6B) on inhibiting cell proliferation in the non- small cell lung carcinoma cell line H292.
DETAILED DESCRIPTION
[27] It has been discovered by the present inventors that agents that prevent serine phosphorylation of the IGF-1 R adaptor protein IRS1 potentiate IGF-driven Akt, thereby enhancing sensitivity to IGF-1 R inhibition. As a result, the present invention is directed to methods for treating cancer patients comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an a IGF1 R protein kinase inhibitor compound of Formula I in combination with an agent which inhibits serine phosphorylation of IRS1 , with or without additional agents or treatments such as other anti-cancer drugs or radiation therapy. According to the invention, agents that inhibit serine phosphorylation of IRS1 include inhibitors of the MAPK pathway, including for example EGFR inhibitors, MEK inhibitors, Ras inhibitors, Raf inhibitors, and PKC inhibitors.
[28] As further described below, EGFR and IGF-IR can cooperate to regulate tumor growth and survival. The present inventors have found that for epithelial tumor cells, but not for mesenchymal-like tumor cells, Akt is controlled synergistically by EGFR and IGF-IR. Two molecular aspects contributing to synergy were identified: 1 ) inhibition of EGFR or IGF-1 R individually promotes activation of the reciprocal receptor, and 2) inhibition of EGFR-directed MAPK shifts regulation of Akt from EGFR towards IGF-1 R. Specifically, inhibition of the MAPK pathway by EGFR blockade circumvents a negative feedback loop imposed on the IGF-1 R- IRS-1 signaling complex. The synergistic inhibition of Akt achieved by co-targeting EGFR and IGF-1 R in epithelial tumor cells conferred synergistic apoptosis and growth inhibition in vitro and growth regression in vivo.
[29] Without being bound by a particular theory, the present inventors find that the ability of an agent which inhibits serine phosphorylation of IRS1 , such as erlotinib, to inhibit the MAPK pathway is responsible for the potentiation of IGF-driven Akt, and this is likely mediated by augmented coupling of IGF-1 R to Akt through IRS-1. The ability of IRS-1 phosphorylation at select serine sites to tightly regulate activity has been observed. Serine phosphorylation of IRS-1 promotes a decrease in the ability of IGF-1R to couple to downstream effectors including PI3K by affecting either the stability of IRS-1 or by affecting protein-protein interactions between receptor and effector. It was found by the present inventors that inhibition of EGFR conferred a decrease in IRS-1 serine phosphorylation only in tumor cells for which Erk activity was inhibited by erlotinib, and a specific inhibitor of the MAPK pathway evoked an increase in Akt phosphorylation that was associated with a decrease in IRS-1 serine phosphorylation. According to an aspect of the present invention, this increase in Akt phosphorylation could be blocked by the combination of an IGF-1 R inhibitor, and synergistic growth inhibition for the combination of IGFR inhibitors with inhibitors of the MAPK pathway, such as EGFR inhibitors and MEK inhibitors, was observed. The ability of the MAPK pathway to affect the serine- phosphorylation of IRS-1 could be mediated either directly through Erk, or indirectly through Erk's ability to transactivate p70S6K. Therefore, inhibition of the MAPK pathway, such as by EGFR inhibition or MEK inhibition, primes signaling through the IGF-1 R to sustain Akt activity and cell survival.
[30] A first aspect of the present invention is directed to methods for treating cancer patients comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent which inhibits serine phosphorylation of IRSIand a IGF1 R protein kinase inhibitor compound of Formula I combination, with or without additional agents or treatments, such as other anti-cancer drugs or radiation therapy. This aspect of the present invention is also directed to combined treatment of patients with the IGF1 R protein kinase inhibitors of Formula I, and their salts, and epidermal growth factor receptor (EGFR) kinase inhibitors, and their salts.
[31] A second aspect of the present invention includes methods for treating cancer patients comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R inhibitor combination, with or without additional agents or treatments, such as other anti-cancer drugs or radiation therapy, wherein the IGF1 R inhibitor is a compound of Formula I:
Figure imgf000009_0001
I
[32] or a pharmaceutically acceptable salt thereof, wherein: [33] X1 , X2, X4, X6, and X7 are C; [34] X3and X5 are N;
Figure imgf000009_0002
[36] X11, X12, Xi3, Xi4, and Xi5 are C; [37] X16 is N;
[38] R1 is cycloC3-10alkyl substituted by one or more independent G11 substituents; [39] G1 and G41 are each independently halo, -CF3, -OCF3, -OR2, -NR2R3^)11 , -C(=0)R2, -CO2R2, -CONR2R3, -NO2, -CN, -S(O)J1R2, -SO2NR2R3, -NR2C(=O)R3, -NR2C(=O)OR3, -NR2C(=O)NR3R2a, -NR2S(O)11R3, -C(=S)OR2, -C(=O)SR2, -NR2C(=NR3)NR2aR3a, -NR2C(=NR3)OR2a, -NR2C(=NR3)SR2a, -OC(=O)OR2, -OC(=O)NR2R3, -OC(=O)SR2, -SC(=O)OR2, -SC(=O)NR2R3, C0-1oalkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxyC1-10alkyl, C1- 10alkoxyC2-10alkenyl, C1-10alkoxyC2-10alkynyl, C^oalkylthioC^oalkyl, C1-10alkylthioC2-10alkenyl, C1-10alkylthioC2-10alkynyl, cycloC3-8alkyl, cycloC3-8alkenyl, cycloC3-8alkylC1-10alkyl, cycloC3-
Figure imgf000009_0003
cycloC3-8alkylC2. 10alkynyl, cycloC3-8alkenylC2-10alkynyl, heterocyclyl-C0-10alkyl, heterocyclyl-C2-10alkenyl, or heterocyclyl-C2-10alkynyl, any of which is optionally substituted with one or more independent halo, oxo, -CF3, -OCF3, -OR222, -NR222R333(R222a))1a, -C(=O)R222, -CO2R222, -C(=O)NR222R333, -NO2, -CN, -S(=O)J1aR222, -SO2NR222R333, -NR222C(=O)R333, -NR222C(=O)OR333, -NR222C(=O)NR333R222a, -NR222S(O)J1aR333, -C(=S)OR222, -C(=O)SR222,
-NR222C(=NR333)NR222aR333a, -NR222C(=NR333)OR222a, -NR222C(=NR333)SR222a, -OC(=O)OR222, -OC(=O)NR222R333, -OC(=O)SR222, -SC(=O)OR222, or -SC(=O)N R222R333 substituents; [40] or G1 optionally is -(W1)n-(Y1)m-R4;
[41] or G1 or G41 optionally independently is aryl-Co-1oalkyl, aryl-C2-10alkenyl, aryl-C2- 10alkynyl, hetaryl-C0-10alkyl, hetaryl-C2-10alkenyl, or hetaryl-C2-10alkynyl, any of which is optionally substituted with one or more independent halo, -CF3, -OCF3, -OR222, -NR222R333(R222a)j2a, -C(O)R222, -CO2R222, -C(=O)N R222R333, -NO2, -CN, -S(O)j2aR222, -SO2NR222R333, -NR222C(=O)R333, -NR222C(=O)OR333, -NR222C(=O)NR333R222a,
-NR222S(O)123R333, -C(=S)OR222, -C(=O)SR222, -NR222C(=NR333)NR222aR333a,
-NR222C(=NR333)OR222a, -NR222C(=NR333)SR222a, -OC(=O)OR222, -OC(=O)NR222R333, -OC(=O)SR222, -SC(=O)OR222, or -SC(=O)N R222R333 substituents;
[42] G11 is halo, oxo, -CF3, -OCF3, -OR21, -NR21R31(R2a1)j4, -C(O)R21, -CO2R21, -C(=O)NR21R31, -NO2, -CN, -S(O)14R21 , -SO2NR21R31, NR21(C=O)R31, NR21C(=O)OR31, NR21C(=O)NR31R2a1, NR21S(O)J4R31, -C(=S)OR21, -C(=O)SR21, -NR21C(=NR31)NR2a1R3a1, -NR21C(=NR31)OR2a1, -NR21C(=NR31)SR2a1, -OC(=O)OR21, -OC(=O)NR21R31 , -OC(=O)SR21, -SC(=O)OR21, -SC(=O)NR21R31, -P(O)OR21OR31, C1-10alkylidene, C0-10alkyl, C2-10alkenyl, C2- iOalkynyl, Ci.i0alkoxyC1-10alkyl,
Figure imgf000010_0001
iOalkyl, Ci.i0alkylthioC2.10alkenyl, CMoalkylthioC^oalkynyl, cycloC3-8alkyl, cycloC3-8alkenyl,
Figure imgf000010_0002
cycloC3-8alkenylC1-10alkyl, cycloC3-8alkylC2-10alkenyl, cycloC3-8alkenylC2. iOalkenyl, cycloC3-8alkylC2-10alkynyl, cycloC3-8alkenylC2-i0alkynyl, heterocyclyl-Co-ioalkyl,
Figure imgf000010_0003
or heterocyclyl-C2-10alkynyl, any of which is optionally substituted with one or more independent halo, oxo, -CF3, -OCF3, -OR2221, -NR2221R3331(R222a1))4a, -C(O)R2221, -CO2R2221, -C(=O)NR2221R3331, -NO2, -CN, -S(O)j4aR2221, -SO2NR2221R3331, -NR2221C(=O)R3331, -NR2221C(=O)OR3331, -NR2221C(=O)NR3331R222a1, -NR2221S(O)j4aR3331, -C(=S)OR2221, -C(=O)SR2221, -NR2221C(=NR3331)NR222a1R333a1, -NR2221C(=NR3331)OR222a1,
-NR2221C(=NR3331)SR222a1, -OC(=O)OR2221, -OC(=O)NR2221R3331, -OC(=O)SR2221, -SC(=O)OR2221, -P(O)OR2221OR3331, or -SC(=O)NR2221R3331 substituents; [43] or G11 is aryl-Co-ioalkyl, aryl-C2.10alkenyl, aryl-C2-ioalkynyl, hetaryl-Co.ioalkyl, hetaryl-C2-10alkenyl, or hetaryl-C2-10alkynyl, any of which is optionally substituted with one or more independent halo, -CF3, -OCF3, -OR2221, -NR2221R3331(R222a1))5a, -C(O)R2221, -CO2R2221, -C(=O)NR2221R3331, -NO2, -CN, -S(O)j5aR2221, -SO2NR2221R3331 , -NR2221C(=O)R3331, -NR2221C(=O)OR3331, -NR2221C(=O)NR3331R222a1, -NR2221S(O)j5aR3331, -C(=S)OR2221, -C(=O)SR2221, -NR2221C(=NR3331)NR222a1R333a1, -NR2221C(=NR3331)OR222a1,
-NR2221C(=NR3331)SR222a1, -OC(=O)OR2221, -OC(=O)NR2221R3331, -OC(=O)SR2221, -SC(=O)OR2221, -P(O)OR2221OR3331, or -SC(=O)NR2221R3331 substituents; [44] or G11 is C, taken together with the carbon to which it is attached forms a C=C double bond which is substituted with R5 and G111;
[45] R2, R2a, R3, R3a, R222, R222a, R333, R333a, R21, R2a1, R31, R3a1, R2221, R222a1, R3331, and R333a1 are each independently Co.ioalkyl, C2-i0alkenyl, C2-i0alkynyl, C1-10alkoxyCi.i0alkyl, Ci.10alkoxyC2- 10alkenyl, C1-10alkoxyC2-10alkynyl, CMoalkylthioC^^alkyl, C1-10alkylthioC2.i0alkenyl, C1- 10alkylthioC2.10alkynyl, cycloC3-8alkyl, cycloCs-βalkenyl, cycloC3-8alkylCi.i0alkyl, cycloC3- 8alkenylC1-10alkyl,
Figure imgf000010_0004
cycloC3-8alkylC2. 10alkynyl, cycloC3-8alkenylC2-i0alkynyl, heterocyclyl-Co-ioalkyl, heterocyclyl-C2-i0alkenyl, heterocyclyl-C2-10alkynyl, aryl-CO-iOalkyl, aryl-C2-ioalkenyl, aryl-C2.ioalkynyl, hetaryl-Co.iOalkyl, hetaryl-C2.ioalkenyl, or hetaryl-C2.i0alkynyl, any of which is optionally substituted by one or more independent G111 substituents;
[46] or in the case of -NR2R3CR2^1 or -NR222R333(R222a)J1a or -NR222R333(R222a)j2a or -NR21R31(R2a1))4 or -NR2221R3331(R222a1)j4a or -NR2221R3331(R222a1)j5a, then R2 and R3, or R222 and R333, or R2221 and R3331, respectfully, are optionally taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted by one or more independent G1111 substituents and wherein said ring optionally includes one or more heteroatoms other than the nitrogen to which R2 and R3, or R222 and R333, or R2221 and R3331 are attached;
[47] W1 and Y1 are each independently -O-, -NR7-, -S(O)j7-, -CR5R6-, -N(C(O)OR7)-, -N(C(O)R7)-, -N(SO2R7)-, -CH2O-, -CH2S-, -CH2N(R7)-, -CH(NR7)-, -CH2N(C(O)R7)-, -CH2N(C(O)OR7)-, -CH2N(SO2R7)-, -CH(NHR7)-, -CH(NHC(O)R7)-, -CH(NHSO2R7)-, -CH(NHC(O)OR7)-, -CH(OC(O)R7)-, -CH(OC(O)NHR7)-, -CH=CH-, -C≡C-, -C(=NOR7)-, -C(O)-, -CH(OR7)-, -C(O)N(R7)-, -N(R7)C(O)-, -N(R7)S(O)-, -N(R7)S(O)2- -OC(O)N(R7)-, -N(R7)C(O)N(R8)-. -NR7C(O)O-, -S(O)N(R7)-, -S(O)2N(R7)-, -N(C(0)R7)S(0)-, -N(C(O)R7JS(O)2-, -N(R7)S(O)N(R8)-, -N(R7)S(O)2N(R8)-, -C(O)N(R7)C(O)-,
-S(O)N(R7)C(O)-, -S(O)2N(R7)C(O)-, -OS(O)N(R7)-, -OS(O)2N(R7)-, -N(R7JS(O)O-, -N(R7JS(O)2O-, -N(R7)S(O)C(O)-, -N(R7JS(O)2C(O)-, -SON(C(O)R7)-, -SO2N(C(O)R7)-, -N(R7)SON(R8)-, -N(R7)SO2N(R8)-, -C(O)O-, -N(R7)P(OR8)O-, -N(R7)P(OR8)-, -N(R7)P(O)(OR8)O- -N(R7)P(O)(OR8)-, -N(C(O)R7)P(OR8)O-, -N(C(O)R7)P(OR8)-, -N(C(O)R7)P(O)(OR8)O- -N(C(O)R7)P(OR8)-, -CH(R7)S(O)-, -CH(R7JS(O)2-,
-CH(R7)N(C(O)OR8)-, -CH(R7JN(C(O)R8J-, -CH(R7JN(SO2R8J-, -CH(R7JO-, -CH(R7JS-, -CH(R7JN(R8J-, -CH(R7JN(C(O)R8J-, -CH(R7JN(C(O)OR8J-, -CH(R7)N(SO2R8)-, -CH(R7)C(=NOR8)-, -CH(R7)C(0)-, -CH(R7)CH(OR8)-, -CH(R7)C(O)N(R8)-,
-CH(R7)N(R8)C(O)-, -CH(R7JN(R8JS(OJ-, -CH(R7JN(R8JS(O)2-, -CH(R7)OC(O)N(R8)-, -CH(R7)N(R8)C(O)N(R7a)-, -CH(R7)NR8C(O)O- -CH(R7)S(O)N(R8)-, -CH(R7)S(O)2N(R8)-, -CH(R7)N(C(O)R8)S(O)-, -CH(R7)N(C(O)R8)S(O)-, -CH(R7)N(R8)S(O)N(R7a)-,
-CH(R7)N(R8)S(O)2N(R7a)-, -CH(R7)C(O)N(R8)C(O)-, -CH(R7)S(O)N(R8)C(O)-,
-CH(R7)S(O)2N(R8)C(O)-, -CH(R7)OS(O)N(R8)-, -CH(R7JOS(O)2N(R8J-,
-CH(R7)N(R8)S(O)O-, -CH(R7JN(R8JS(O)2O-, -CH(R7)N(R8)S(O)C(O)-,
-CH(R7JN(R8JS(O)2C(OJ-, -CH(R7JSON(C(O)R8J-, -CH(R7JSO2N(C(O)R8J-,
-CH(R7JN(R8JSON(R73J-, -CH(R7JN(R8JSO2N(R73J-, -CH(R7JC(O)O-,
-CH(R7JN(R8JP(OR73JO-, -CH(R7JN(R8JP(OR73J-, -CH(R7JN(R8JP(O)(OR73JO-, -CH(R7)N(R8)P(O)(OR7a)-, -CH(R7)N(C(O)R8)P(OR7a)O-, -CH(R7)N(C(O)R8)P(OR7a)-, -CH(R7)N(C(O)R8)P(O)(OR7a)O-, or -CH(R7)N(C(O)R8)P(OR7a)-;
[48] R5, R6, G111, and G1111 are each independently Co-ioalkyl, C2-iOalkenyl, C2.iOalkynyl, d-ioalkoxyd.ioalkyl, C1-10alkoxyC2.ioalkenyl, C1-10alkoxyC2-ioalkynyl, C1-10alkylthioC1-10alkyl, C1. 10alkylthioC2-ioalkenyl, Ci-10alkylthioC2-ioalkynyl, cycloC3^alkyl, cycloC3-8alkenyl, cycloC3- βalkyld.ioalkyl, cycloCs-βalkenyld-ioalkyl, cycloC3-8alkylC2-ioalkenyl, cycloC3-8alkenylC2- 10alkenyl, cycloC3-8alkylC2-1oalkynyl, cycloC3-8alkenylC2-1oalkynyl, heterocyclyl-Co-ioalkyl,
Figure imgf000012_0001
heterocyclyl-C2-10alkynyl, aryl-Co-iOalkyl, aryl-C2-10alkenyl, aryl-C2- 10alkynyl, hetaryl-CO-ioalkyl, hetaryl-C2-i0alkenyl, or hetaryl-C2-10alkynyl, any of which is optionally substituted with one or more independent halo, -CF3, -OCF3, -OR77, -NR77R87, -C(O)R77, -CO2R77, -CONR77R87, -NO2, -CN, -S(O)j5aR77, -SO2NR77R87, -NR77C(=O)R87, -NR77C(=O)OR87, -NR77C(=O)NR78R87, -NR77S(O)j5aR87, -C(=S)OR77, -C(=O)SR77, -NR77C(=NR87)NR78R88, -NR77C(=NR87)OR78, -NR77C(=NR87)SR78, -OC(=O)OR77, -OC(=O)NR77R87, -OC(=O)SR77, -SC(=O)OR77, -P(O)OR77OR87, or -SC(=O)NR77R87 substituents;
[49] or R5 with R6 are optionally taken together with the carbon atom to which they are attached to form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted with one or more independent R69 substituents and wherein said ring optionally includes one or more heteroatoms;
[50] R7, R7a, and R8 are each independently acyl, CO-iOalkyl, C2.10alkenyl, aryl, heteroaryl, heterocyclyl or cycloC3-10alkyl, any of which is optionally substituted by one or more independent G111 substituents;
[51] R4 is Co-ioalkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, cyclo^^a^y!, heterocyclyl, cycloC3-8alkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more independent G41 substituents;
[52] R69 is halo, -OR78, -SH, -NR78R88, -CO2R78, -CC=O)NR78R88, -NO2, -CN, -S(O)j8R78, -SO2NR78R88, Co-iOalkyl, C2-iOalkenyl, C2-10alkynyl, Ci.10alkoxyC1-10alkyl, C1-10alkoxyC2-10alkenyl, C1-10alkoxyC2-ioalkynyl, C1-10alkylthiod-ioalkyl, C1-10alkylthioC2-10alkenyl, C1-10alkylthioC2. 10alkynyl, cycloC3-8alkyl, cycloC3-8alkenyl, cycloC3-8alkylCi-10alkyl,
Figure imgf000012_0002
cycloC3-8alkylC2-10alkenyl, cycloC3-8alkenylC2-10alkenyl, cycloC3-8alkylC2.i0alkynyl, cycloC3- 8alkenylC2-10alkynyl, heterocyclyl-Co-ioalkyl, heterocyclyl-C2-10alkenyl, or heterocyclyl-C2- 10alkynyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, -SO2NR778R888, Or -NR778R888 substituents;
[53] or R69 is aryl-Co-iOalkyl, aryl-C2-i0alkenyl, aryl-C2-10alkynyl, hetaryl-C0.ioalkyl, hetaryl-C2- 10alkenyl, hetaryl-C2-iOalkynyl, monoCC^alkylJaminoC^alkyl, diCd-βalkyOaminod-ealkyl, mono(aryl)aminoC1-6alkyl, di(aryl)aminoC1-6alkyl, or -N(C1-6alkyl)-d-6alkyl-aryl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, C1-10alkyl, C2- iOalkenyl, C2-ioalkynyl, haloC1-10alkyl, haloC2-10alkenyl, haloC2-10alkynyl, -COOH, C1. 4alkoxycarbonyl, -C(=O)NR778R888, -SO2NR778R888, Or -NR778R888 substituents; [54] or in the case of -NR78R88, R78 and R88 are optionally taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C1-10alkoxy, -SO2NR778R888, or -NR778R888 substituents, and wherein said ring optionally includes one or more heteroatoms other than the nitrogen to which R78 and R88 are attached; [55] R77, R78, R87, R88, R778, and R888 are each independently C0-10alkyl, C2.i0alkenyl, C2- 10alkynyl, C1-10alkoxyC1-10alkyl, C1-10alkoxyC2-1oalkenyl, C1-10alkoxyC2-10alkynyl, d.^alkylthiod. iOalkyl, C1-1oalkylthioC2-1oalkenyl, C1-10alkylthioC2-ioalkynyl, cycloC3-8alkyl, cycloC3-8alkenyl, cycloC3-8alkylCi-10alkyl, cycloCs-salkenyld.^alkyl, cycloC3-8alkylC2-1oalkenyl, cycloC3-8alkenylC2- 10alkenyl, cycloC3-8alkylC2-10alkynyl, cycloC3-8alkenylC2-i0alkynyl, heterocyclyl-Co-ioalkyl, heterocyclyl-C2-i0alkenyl, heterocyclyl-C2-10alkynyl, C1-10alkylcarbonyl, C2-ioalkenylcarbonyl, C2- 10alkynylcarbonyl, Ci.i0alkoxycarbonyl, C1-10alkoxycarbonylC1-10alkyl, monod.
6alkylaminocarbonyl, diC1-6alkylaminocarbonyl, mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or C1-10alkyl(aryl)aminocarbonyl, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, d.10alkoxy, -SO^CCo^alkyOCCo^alkyl), or -NCCo^alkyOCCo^alkyl) substituents;
[56] or R77, R78, R87, R88, R778, and R888 are each independently aryl-Co-iOalkyl, aryl-C2- 10alkenyl, aryl-C2-i0alkynyl, hetaryl-Co-iOalkyl, hetaryl-C2-i0alkenyl, hetaryl-C2.10alkynyl, mono(C1.6alkyl)aminoC1-6alkyl, dKd-ealkyOaminod-ealkyl, mono(aryl)aminoCi-6alkyl, di(aryl)aminoC1-6alkyl, or -N(C1-6alkyl)-C1-6alkyl-aryl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(C0-4alkyl), d.ioalkyl, C2-10alkenyl, C2-10alkynyl, haloC1-10alkyl, haloC2-10alkenyl, haloC2-i0alkynyl, -COOH, C1-4alkoxycarbonyl, -CON(C0- 4alkyl)(C0.10alkyl), -SO2N(C0^alkyl)(C0-4alkyl), or -N(C0^alkyl)(C0-4alkyl) substituents; and [57] n, m, j1 , j1a, j2a, j4, j4a, j5a, j7, and j8 are each independently O, 1 , or 2. [58] In an aspect of the present invention, the IGF1 R inhibitor is represented by Formula I, or a salt thereof, wherein X3 and X5 are N; X1, X2, X4, X6, and X7 are C; and the other variables are described as above for Formula I.
[59] In another aspect of the present invention, the IGF1 R inhibitor is represented by Formula I, or a salt thereof, wherein X3 and X5 are N; X1, X2, X4, X6, and X7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor.
[60] In another aspect of the present invention, the IGF1 R inhibitor is represented by Formula I, or a salt thereof, wherein X3 and X5 are N; X1, X2, X4, X6, and X7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib, cetuximab, gefitinib, or a salt thereof.
[61] In another aspect of the present invention, the IGF1 R inhibitor is represented by
Formula I1 or a salt thereof, wherein X3 and X5 are N; X1, X2, X4, X6, and X7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof.
[62] In another aspect of the present invention, the IGF1 R inhibitor is represented by
Formula I1 or a salt thereof, wherein X3 and X5 are N; X1, X2, X4, X6, and X7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is an inhibitor of the MAPK pathway or a salt thereof.
[63] In another aspect of the present invention, the IGF1 R inhibitor is represented by
Formula I, or a salt thereof, wherein X3 and X5 are N; X1, X2, X4, X6, and X7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a Ras, Raf, MEK or PKC inhibitor; or a salt thereof.
[64] In another aspect of the present invention, the IGF1 R inhibitor is represented by
Formula I, or a salt thereof, wherein X3 and X5 are N; X1, X2, X4, X6, and X7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRSIis a MEK inhibitor or a salt thereof.
[65] In another aspect of the present invention, the IGF1 R inhibitor is represented by
Formula I, or a salt thereof, wherein X3 and X5 are N; X1, X2, X4, X6, and X7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a MEK inhibitor wherein the MEK inhibitor is ARRY-142886, PD-
184352, PD-98059, PD-0325901 , XL518, or MEK1 ; or a salt thereof.
[66] In another aspect of the present invention, the IGF1 R inhibitor is represented by
Formula I, or a salt thereof, wherein X3 and X5 are N; X1, X2, X4, X6, and X7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a Ras inhibitor; or a salt thereof.
[67] In another aspect of the present invention, the IGF1 R inhibitor is represented by
Formula I, or a salt thereof, wherein X3 and X5 are N; X1, X2, X4, X6, and X7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a Ras inhibitor; or a salt thereof, wherein the Ras inhibitor is BMS-
214662, SCH 66336, L-778,123, R115777, 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-
4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1 H-quinolin-2-one; or a salt thereof.
[68] In another aspect of the present invention, the IGF1 R inhibitor is represented by
Formula I, or a salt thereof, wherein X3 and X5 are N; X1, X2, X4, X6, and X7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a Raf inhibitor; or a salt thereof.
[69] In another aspect of the present invention, the IGF1 R inhibitor is represented by
Formula I, or a salt thereof, wherein X3 and X5 are N; X1, X2, X4, X6, and X7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a Raf inhibitor; or a salt thereof, wherein the Raf inhibitor is sorafenib; or a salt thereof.
[70] In another aspect of the present invention, the IGF1 R inhibitor is represented by
Formula I, or a salt thereof, wherein X3 and X5 are N; X1, X2, X4, X6, and X7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a PKC inhibitor; or a salt thereof.
In another aspect of the present invention, the IGF1 R inhibitor is represented by Formula I, or a salt thereof, wherein X3 and X5 are N; X1, X2, X4, X6, and X7 are C; and the other variables are described as above for Formula I; and the agent that inhibits serine phosphorylation of IRS1 is a PKC inhibitor; or a salt thereof, wherein the PKC inhibitor is byrostatin, staurosporine, staurosporine analog including UCN-01 or CGP41251 , safingol; or a salt thereof.
[71] In further embodiments according to the above aspects of the invention, the IGF1 R inhibitor is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi6 is N; Xn, X12, X13, X14, and X15 are C; and the other variables are as described in each of the above aspects.
[72] In further embodiments according to the above aspects of the invention, the IGF1 R inhibitor is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X16 is N; X11, X12, Xi3, Xi4, and X15 are C; Gi is aryl-Co-ioalkyl; and the other variables are as described in each of the above aspects.
[73] In further embodiments according to the above aspects of the invention, the IGF1 R inhibitor is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X16 is N; X11, X12, X13, XM, and Xi5 are C; G1 is aryl; R1 is cycloC3-10 alkyl substituted by one or more independent G11 substituents; and the other variables are as described in each of the above aspects.
[74] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor wherein the IGFR inhibitor is c/s-3-[8-Amino-1 -(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1 -methyl-cyclobutanol.
[75] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor wherein the IGFR inhibitor is wherein the IGFR inhibitor is
Figure imgf000016_0001
[76] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor.
[77] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib, cetuximab, gefitinib, panitumumab, or a salt thereof.
[78] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof.
[79] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the IGFR inhibitor is c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3- yl]-1-methyl-cyclobutanol and wherein the agent that inhibits serine phosphorylation of IRS1 is erlotinib or a salt thereof.
[80] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer.
[81] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, wherein the patient is a human that is being treated for cancer, and wherein the cancer is colorectal cancer, non-small cell lung carcinoma, pancreatic cancer, head and neck cancer, breast cancer, or neuroblastoma. [82] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, wherein the patient is a human that is being treated for cancer, and wherein the cancer is colorectal cancer or non-small cell lung carcinoma.
[83] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, wherein the patient is a human that is being treated for cancer, and wherein the cancer is colorectal cancer or non-small cell lung carcinoma.
[84] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, and wherein erlotinib and the IGFR inhibitor are coadministered to the patient in the same formulation. [85] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, and wherein erlotinib and the IGFR inhibitor are coadministered to the patient in different formulations.
[86] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, wherein erlotinib and the IGFR inhibitor are coadministered to the patient by the same route.
[87] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, and wherein erlotinib and the IGFR inhibitor are coadministered to the patient by different routes.
[88] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, and wherein erlotinib is administered to the patient by parenteral or oral administration.
[89] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, and wherein the IGFR inhibitor is administered to the patient by parenteral administration.
[90] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 agent is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, and additionally comprising one or more other anticancer agents.
[91] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib or a salt thereof, and wherein the patient is a human that is being treated for cancer, and additionally comprising one or more other anticancer agents wherein the other anti-cancer agents are selected from an alkylating agent, cyclophosphamide, chlorambucil, cisplatin, busulfan, melphalan, carmustine, streptozotocin, triethylenemelamine, mitomycin C, an anti-metabolite, methotrexate, etoposide, 6- mercaptopurine, 6-thiocguanine, cytarabine, 5-fluorouracil, raltitrexed, capecitabine, dacarbazine, an antibiotic, actinomycin D, doxorubicin, daunorubicin, bleomycin, mithramycin, an alkaloid, vinblastine, paclitaxel, a glucocorticoid, dexamethasone, a corticosteroid, prednisone, a nucleoside enzyme inhibitors, hydroxyurea, an amino acid depleting enzyme, asparaginase, folinic acid, leucovorin, and a folic acid derivative.
[92] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRS1 is an inhibitor of the MAPK pathway.
[93] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I1 wherein the agent that inhibits serine phosphorylation of IRS1 is an inhibitor of the MAPK pathway, wherein the MAPK pathway inhibitor is selected from Ras inhibitors, Raf inhibitors, MEK inhibitors or PKC inhibitors.
[94] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRS1 is a MEK inhibitor. [95] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRS1 is a MEK inhibitor, wherein the MEK inhibitor is ARRY-142886, PD-184352, PD-98059, PD-0325901 , XL518, or MEK1. [96] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRSIis a Raf protein kinase family inhibitor.
[97] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRSIis a Raf protein kinase family inhibitor, wherein the Raf protein kinase family inhibitor is sorafenib.
[98] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRSIis a Ras inhibitor. [99] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRSI is a Ras inhibitor is BMS-214662 , SCH 66336, R115777, or 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4- (3-ethynyl-phenyl)-1 -methyl-1 H-quinolin-2-one. [100] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRSIis a PKC inhibitor.
[101] The present invention includes a method for treating cancer in a patient, comprising administering to said patient simultaneously or sequentially (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically salt thereof; and (ii) a therapeutically effective amount an IGFR inhibitor represented by Formula I, wherein the agent that inhibits serine phosphorylation of IRSIis a PKC inhibitor, wherein the
PKC inhibitor is byrostatin, staurosporine, a staurosporine analog, UCN-01 , CGP41251 , or safingol.
[102] Unless otherwise stated, the connections of compound name moieties are at the rightmost recited moiety. That is, the substituent name starts with a terminal moiety, continues with any bridging moieties, and ends with the connecting moiety. For example, hetarylthioCi.
4alkyl has a heteroaryl group connected through a thio sulfur to a C1-4 alkyl that connects to the chemical species bearing the substituent.
[103] As used herein, for example, "Co-4alkyl" is used to mean an alkyl having 0-4 carbons - that is, 0, 1 , 2, 3, or 4 carbons in a straight or branched configuration. An alkyl having no carbon is hydrogen when the alkyl is a terminal group. An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group. Further, Coalkyl includes being a substituted bond - that is, for example, -X-Y-Z is -C(O)-C2-4alkyl when X is Coalkyl, Y is Coalkyl, and Z is -C(O)-C2-4alkyl.
[104] In all embodiments of this invention, the term "alkyl" includes both branched and straight chain alkyl groups. Typical alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, te/if-butyl, π-pentyl, isopentyl, n-hexyl, n-heptyl, isooctyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl, and the like.
[105] The term "halo" refers to fluoro, chloro, bromo, or iodo.
[106] The term "haloalkyl" refers to an alkyl group substituted with one or more halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl, trifluoromethyl, perfluoropropyl, 8- chlorononyl, and the like.
[107] The term "acyl" refers to the structure -C(=O)-R, in which R is a general substituent variable such as, for example R1 described above. Examples include, but are not limited to,
(bi)(cyclo)alkylketo, (cyclo)alkenylketo, alkynylketo, arylketo, hetarylketo, heterocyclylketo, heterobicycloalkylketo, spiroalkylketo.
[108] Unless otherwise specified, the term "cycloalkyl" refers to a 3-8 carbon cyclic aliphatic ring structure, optionally substituted with for example, alkyl, hydroxy, oxo, and halo, such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyl, cyclohexyl, 4- chlorocyclohexyl, cycloheptyl, cyclooctyl, and the like.
[109] The term "bicycloalkyl" refers to a structure consisting of two cycloalkyl moieties that have two or more atoms in common. If the cycloalkyl moieties have exactly two atoms in common they are said to be "fused". Examples include, but are not limited to, bicyclo[3.1.0]hexyl, perhydronaphthyl, and the like. If the cycloalkyl moieties have more than two atoms in common they are said to be "bridged". Examples include, but are not limited to, bicyclo[2.2.1]heptyl ("norbomyl"), bicyclo[2.2.2]octyl, and the like.
[1 10] The term "spiroalkyl" refers to a structure consisting of two cycloalkyl moieties that have exactly one atom in common. Examples include, but are not limited to, spiro[4.5]decyl, spiro[2.3]hexyl, and the like.
[1 1 1] The term "heterobicycloalkyl" refers to a bicycloalkyl structure in which at least one carbon atom is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur.
[1 12] The term "heterospiroalkyl" refers to a spiroalkyl structure in which at least one carbon atom is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur.
[1 13] The term "alkylcarbonyloxyalkyl" refers to an ester moiety, for example acetoxymethyl, n-butyryloxyethyl, and the like.
[1 14] The term "alkynylcarbonyl" refers to an alkynylketo functionality, for example propynoyl and the like.
[1 15] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, for example hydroxymethyl, 2,3-dihydroxybutyl, and the like.
[1 16] The term "alkylsulfonylalkyl" refers to an alkyl group substituted with an alkylsulfonyl moiety, for example mesylmethyl, isopropylsulfonylethyl, and the like.
[1 17] The term "alkylsulfonyl" refers to a sulfonyl moiety substituted with an alkyl group, for example mesyl, n-propylsulfonyl, and the like.
[1 18] The term "acetylaminoalkyl" refers to an alkyl group substituted with an amide moiety, for example acetylaminomethyl and the like.
[1 19] The term "acetylaminoalkenyl" refers to an alkenyl group substituted with an amide moiety, for example 2-(acetylamino)vinyl and the like.
[120] The term "alkenyl" refers to an ethylenically unsaturated hydrocarbon group, straight or branched chain, having 1 or 2 ethylenic bonds, for example vinyl, allyl, 1-butenyl, 2-butenyl, isopropenyl, 2-pentenyl, and the like.
[121] The term "haloalkenyl" refers to an alkenyl group substituted with one or more halo groups. [122] Unless otherwise specified, the term "cycloalkenyl" refers to a cyclic aliphatic 3 to 8 ring structure, optionally substituted with alkyl, hydroxy and halo, having 1 or 2 ethylenic bonds such as methylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl, cyclohexenyl, 1 ,4- cyclohexadienyl, and the like.
[123] The term "alkynyl" refers to an unsaturated hydrocarbon group, straight or branched, having at least one acetylenic bond, for example ethynyl, propargyl, and the like.
[124] The term, "haloalkynyl" refers to an alkynyl group substituted with one or more independent halo groups.
[125] The term "alkylcarbonyl" refers to an alkylketo functionality, for example acetyl, n- butyryl, and the like.
[126] The term "alkenylcarbonyl" refers to an alkenylketo functionality, for example, propenoyl and the like.
[127] The term "aryl" refers to phenyl or naphthyl which may be optionally substituted.
Examples of aryl include, but are not limited to, phenyl, 4-chlorophenyl, 4-fluorophenyl, A- bromophenyl, 3-nitrophenyl, 2-methoxyphenyl, 2-methylphenyl, 3-methyphenyl, A- methylphenyl, 4-ethylphenyl, 2-methyl-3-methoxyphenyl, 2,4-dibromophenyl, 3,5- difluorophenyl, 3,5-dimethylphenyl, 2,4,6-trichlorophenyl, 4-methoxyphenyl, naphthyl, 2- chloronaphthyl, 2,4-dimethoxyphenyl, 4-(trifluoromethyl)phenyl, and 2-iodo-4-methylphenyl.
[128] The terms "heteroaryl" or "hetaryl" or "heteroar-" or "hetar-" refer to a substituted or unsubstituted 5- or 6-membered unsaturated ring containing one, two, three, or four independently selected heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur or to a bicyclic unsaturated ring system containing up to 10 atoms including at least one heteroatom selected from oxygen, nitrogen, and sulfur.
Examples of hetaryls include, but are not limited to, 2-, 3- or 4-pyridinyl, pyrazinyl, 2-, A-, or 5- pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, imidazolyl, 2- or 3-thienyl, 2- or 3-furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, and benzothienyl. The heterocyclic ring may be optionally substituted with one or more substituents.
[129] The terms "aryl— alkyl" or "arylalkyl" or "aralkyl" are used to describe a group wherein the alkyl chain can be branched or straight chain forming a bridging portion with the terminal aryl, as defined above, of the aryl— alkyl moiety. Examples of aryl— alkyl groups include, but are not limited to, optionally substituted benzyl, phenethyl, phenpropyl and phenbutyl such as A- chlorobenzyl, 2,4-dibromobenzyl, 2-methylbenzyl, 2-(3-fluorophenyl)ethyl, 2-(4- methylphenyl)ethyl, 2-(4-(trifluoromethyl)phenyl)ethyl, 2-(2-methoxyphenyl)ethyl, 2-(3- nitrophenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl, 3-phenylpropyl, 3-
(3-chlorophenyl)propyl, 3-(2-methylphenyl)propyl, 3-(4-methoxyphenyl)propyl, 3-(4-
(trifluoromethyl)phenyl)propyl, 3-(2,4-dichlorophenyl)propyl, 4-phenylbutyl, 4-(4- chlorophenyl)butyl, 4-(2-methylphenyl)butyl, 4-(2,4-dichlorophenyl)butyl, 4-(2- methoxphenyl)butyl, and 10-phenyldecyl.
[130] The terms "aryl-cycloalkyl" or "arylcycloalkyl" are used to describe a group wherein the terminal aryl group is attached to a cycloalkyl group, for example phenylcyclopentyl and the like.
[131] The terms "aryl-alkenyl" or "arylalkenyl" or "aralkenyl" are used to describe a group wherein the alkenyl chain can be branched or straight chain forming a bridging portion of the aralkenyl moiety with the terminal aryl portion, as defined above, for example styryl (2- phenylvinyl), phenpropenyl, and the like.
[132] The terms "aryl-alkynyl" or "arylalkynyl" or "aralkynyl" are used to describe a group wherein the alkynyl chain can be branched or straight chain forming a bridging portion of the aryl-alkynyl moiety with the terminal aryl portion, as defined above, for example 3-phenyl-1- propynyl, and the like.
[133] The terms "aryl-oxy" or "aryloxy" or "aroxy" are used to describe a terminal aryl group attached to a bridging oxygen atom. Typical aryl-oxy groups include phenoxy, 3,4- dichlorophenoxy, and the like.
[134] The terms "aryl-oxyalkyl" or "aryloxyalkyl" or "aroxyalkyl" are used to describe a group wherein an alkyl group is substituted with a terminal aryl-oxy group, for example pentafluorophenoxymethyl and the like.
[135] The term "heterocycloalkenyl" refers to a cycloalkenyl structure in which at least one carbon atom is replaced with a heteroatom selected from oxygen, nitrogen, and sulfur.
[136] The terms "hetaryl-oxy" or "heteroaryl-oxy" or "hetaryloxy" or "heteroaryloxy" or
"hetaroxy" or "heteroaroxy" are used to describe a terminal hetaryl group attached to a bridging oxygen atom. Typical hetaryl-oxy groups include 4,6-dimethoxypyrimidin-2-yloxy and the like.
[137] The terms "hetarylalkyl" or "heteroarylalkyl" or "hetaryl-alkyl" or "heteroaryl-alkyl" or
"hetaralkyl" or "heteroaralkyl" are used to describe a group wherein the alkyl chain can be branched or straight chain forming a bridging portion of the heteroaralkyl moiety with the terminal heteroaryl portion, as defined above, for example 3-furylmethyl, thenyl, furfuryl, and the like.
[138] The terms "hetarylalkenyl" or "heteroarylalkenyl" or "hetaryl-alkenyl" or
"heteroaryl-alkenyl" or "hetaralkenyl" or heteroaralkenyl" are used to describe a group wherein the alkenyl chain can be branched or straight chain forming a bridging portion of the heteroaralkenyl moiety with the terminal heteroaryl portion, as defined above, for example 3-(4- pyridyl)-1-propenyl.
[139] The terms "hetarylalkynyl" or "heteroarylalkynyl" or "hetaryl-alkynyl" or
"heteroaryl-alkynyl" or "hetaralkynyl" or "heteroaralkynyl" are used to describe a group wherein the alkynyl chain can be branched or straight chain forming a bridging portion of the heteroaralkynyl moiety with the heteroaryl portion, as defined above, for example 4-(2-thienyl)-
1-butynyl.
[140] The term "heterocyclyl" or "hetcyclyl" refers to a substituted or unsubstituted 4-, 5-, or
6-membered saturated or partially unsaturated ring containing one, two, or three heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen and sulfur; or to a bicyclic ring system containing up to 10 atoms including at least one heteroatom independently selected from oxygen, nitrogen, and sulfur wherein the ring containing the heteroatom is saturated. Examples of heterocyclyls include, but are not limited to, tetrahydrofuranyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, 4-pyranyl, tetrahydropyranyl, thiolanyl, morpholinyl, piperazinyl, dioxolanyl, dioxanyl, indolinyl, and 5-methyl-6-chromanyl.
[141] The terms "heterocyclylalkyl" or "heterocyclyl-alkyl" or "hetcyclylalkyl" or "hetcyclyl- alkyl" are used to describe a group wherein the alkyl chain can be branched or straight chain forming a bridging portion of the heterocyclylalkyl moiety with the terminal heterocyclyl portion, as defined above, for example 3-piperidinylmethyl and the like.
[142] The terms "heterocyclylalkenyl" or "heterocyclyl-alkenyl" or "hetcyclylalkenyl" or
"hetcyclyl-alkenyl" are used to describe a group wherein the alkenyl chain can be branched or straight chain forming a bridging portion of the heterocyclylalkenyl moiety with the terminal heterocyclyl portion, as defined above, for example 2-morpholinyl-1-propenyl and the like.
[143] The terms "heterocyclylalkynyl" or "heterocyclyl-alkynyl" or "hetcyclylalkynyl" or
"hetcyclyl-alkynyl" are used to describe a group wherein the alkynyl chain can be branched or straight chain forming a bridging portion of the heterocyclylalkynyl moiety with the terminal heterocyclyl portion, as defined above, for example 2-pyrrolidinyl-1 -butynyl and the like.
[144] The term "carboxylalkyl" refers to a terminal carboxyl (-COOH) group attached to branched or straight chain alkyl groups as defined above.
[145] The term "carboxylalkenyl" refers to a terminal carboxyl (-COOH) group attached to branched or straight chain alkenyl groups as defined above.
[146] The term "carboxylalkynyl" refers to a terminal carboxyl (-COOH) group attached to branched or straight chain alkynyl groups as defined above.
[147] The term "carboxylcycloalkyl" refers to a terminal carboxyl (-COOH) group attached to a cyclic aliphatic ring structure as defined above.
[148] The term "carboxylcycloalkenyl" refers to a terminal carboxyl (-COOH) group attached to a cyclic aliphatic ring structure having ethylenic bonds as defined above.
[149] The terms "cycloalkylalkyl" or "cycloalkyl— alkyl" refer to a terminal cycloalkyl group as defined above attached to an alkyl group, for example cyclopropylmethyl, cyclohexylethyl, and the like. [150] The terms "cycloalkylalkenyl" or "cycloalkyl-alkenyl" refer to a terminal cycloalkyl group as defined above attached to an alkenyl group, for example cyclohexylvinyl, cycloheptylallyl, and the like.
[151] The terms "cycloalkylalkynyl" or "cycloalkyl-alkynyl" refer to a terminal cycloalkyl group as defined above attached to an alkynyl group, for example cyclopropylpropargyl, A- cyclopentyl-2-butynyl, and the like.
[152] The terms "cycloalkenylalkyl" or "cycloalkenyl-alkyl" refer to a terminal cycloalkenyl group as defined above attached to an alkyl group, for example 2-(cyclopenten-1-yl)ethyl and the like.
[153] The terms "cycloalkenylalkenyl" or "cycloalkenyl-alkenyl" refer to terminal a cycloalkenyl group as defined above attached to an alkenyl group, for example 1 -(cyclohexen-
3-yl)allyl and the like.
[154] The terms "cycloalkenylalkynyl" or "cycloalkenyl-alkynyl" refer to terminal a cycloalkenyl group as defined above attached to an alkynyl group, for example 1-(cyclohexen-
3-yl)propargyl and the like.
[155] The term "carboxylcycloalkylalkyl" refers to a terminal carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkyl group as defined above.
[156] The term "carboxylcycloalkylalkenyl" refers to a terminal carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkenyl group as defined above.
[157] The term "carboxylcycloalkylalkynyl" refers to a terminal carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkynyl group as defined above.
[158] The term "carboxylcycloalkenylalkyl" refers to a terminal carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkyl group as defined above.
[159] The term "carboxylcycloalkenylalkenyl" refers to a terminal carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkenyl group as defined above.
[160] The term "carboxylcycloalkenylalkynyl" refers to a terminal carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkynyl group as defined above.
[161] The term "alkoxy" includes both branched and straight chain terminal alkyl groups attached to a bridging oxygen atom. Typical alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy, tert-butoxy and the like.
[162] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halo groups, for example chloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroisobutoxy, and the like.
[163] The term "alkoxyalkoxyalkyl" refers to an alkyl group substituted with an alkoxy moiety which is in turn is substituted with a second alkoxy moiety, for example methoxymethoxymethyl, isopropoxymethoxyethyl, and the like. [164] The term "alkylthio" includes both branched and straight chain alkyl groups attached to a bridging sulfur atom, for example methylthio and the like.
[165] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halo groups, for example trifluoromethylthio and the like.
[166] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, for example isopropoxymethyl and the like.
[167] The term "alkoxyalkenyl" refers to an alkenyl group substituted with an alkoxy group, for example 3-methoxyallyl and the like.
[168] The term "alkoxyalkynyl" refers to an alkynyl group substituted with an alkoxy group, for example 3-methoxypropargyl.
[169] The term "alkoxycarbonylalkyl" refers to a straight chain or branched alkyl substituted with an alkoxycarbonyl, for example ethoxycarbonylmethyl, 2-(methoxycarbonyl)propyl and the like.
[170] The term "alkoxycarbonylalkenyl" refers to a straight chain or branched alkenyl as defined above substituted with an alkoxycarbonyl, for example 4-(ethoxycarbonyl)-2-butenyl and the like.
[171] The term "alkoxycarbonylalkynyl" refers to a straight chain or branched alkynyl as defined above substituted with an alkoxycarbonyl, for example 4-(ethoxycarbonyl)-2-butynyl and the like.
[172] The term "haloalkoxyalkyl" refers to a straight chain or branched alkyl as defined above substituted with a haloalkoxy, for example 2-chloroethoxymethyl, trifluoromethoxymethyl and the like.
[173] The term "haloalkoxyalkenyl" refers to a straight chain or branched alkenyl as defined above substituted with a haloalkoxy, for example 4-(chloromethoxy)-2-butenyl and the like.
[174] The term "haloalkoxyalkynyl" refers to a straight chain or branched alkynyl as defined above substituted with a haloalkoxy, for example 4-(2-fluoroethoxy)-2-butynyl and the like.
[175] The term "alkylthioalkyl" refers to a straight chain or branched alkyl as defined above substituted with an alkylthio group, for example methylthiomethyl, 3-(isobutylthio)heptyl, and the like.
[176] The term "alkylthioalkenyl" refers to a straight chain or branched alkenyl as defined above substituted with an alkylthio group, for example 4-(methylthio)-2-butenyl and the like.
[177] The term "alkylthioalkynyl" refers to a straight chain or branched alkynyl as defined above substituted with an alkylthio group, for example 4-(ethylthio)-2-butynyl and the like.
[178] The term "haloalkylthioalkyl" refers to a straight chain or branched alkyl as defined above substituted with an haloalkylthio group, for example 2-chloroethylthiomethyl, trifluoromethylthiomethyl and the like. [179] The term "haloalkylthioalkenyl" refers to a straight chain or branched alkenyl as defined above substituted with an haloalkylthio group, for example 4-(chloromethylthio)-2- butenyl and the like.
[180] The term "haloalkylthioalkynyl" refers to a straight chain or branched alkynyl as defined above substituted with a haloalkylthio group, for example 4-(2-fluoroethylthio)-2-butynyl and the like.
[181] The term "dialkoxyphosphorylalkyl" refers to two straight chain or branched alkoxy groups as defined above attached to a pentavalent phosphorous atom, containing an oxo substituent, which is in turn attached to an alkyl, for example diethoxyphosphorylmethyl and the like.
[182] One in the art understands that an "oxo" requires a second bond from the atom to which the oxo is attached. Accordingly, it is understood that oxo cannot be subststituted onto an aryl or heteroaryl ring.
[183] The term "oligomer" refers to a low-molecular weight polymer, whose number average molecular weight is typically less than about 5000 g/mol, and whose degree of polymerization (average number of monomer units per chain) is greater than one and typically equal to or less than about 50.
[184] Compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above Formula I is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
[185] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium slats. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
[186] When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. Particularly preferred are formic and hydrochloric acid.
[187] In practice, the compounds represented by Formula I, or a prodrug, or a metabolite, or a pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
[188] Generally, dosage levels on the order of from about 0.01 mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS), may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
[189] It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
[190] The term "cancer" in an animal refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. Often, cancer cells will be in the form of a tumor, but such cells may exist alone within an animal, or may circulate in the blood stream as independent cells, such as leukemic cells. [191] "Abnormal cell growth", as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1 ) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (4) any tumors that proliferate by receptor tyrosine kinases; (5) any tumors that proliferate by aberrant serine/threonine kinase activation; and (6) benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs. [192] The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing, either partially or completely, the growth of tumors, tumor metastases, or other cancer-causing or neoplastic cells in a patient. The term "treatment" as used herein, unless otherwise indicated, refers to the act of treating. [193] The phrase "a method of treating" or its equivalent, when applied to, for example, cancer refers to a procedure or course of action that is designed to reduce or eliminate the number of cancer cells in an animal, or to alleviate the symptoms of a cancer. "A method of treating" cancer or another proliferative disorder does not necessarily mean that the cancer cells or other disorder will, in fact, be eliminated, that the number of cells or disorder will, in fact, be reduced, or that the symptoms of a cancer or other disorder will, in fact, be alleviated. Often, a method of treating cancer will be performed even with a low likelihood of success, but which, given the medical history and estimated survival expectancy of an animal, is nevertheless deemed an overall beneficial course of action.
[194] The term "therapeutically effective agent" means a composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
[195] The term "therapeutically effective amount" or "effective amount" means the amount of the subject compound or combination that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
[196] The data presented below demonstrate that co-administration of an IGF1 R protein kinase inhibitor compound of Formula I with an agent that inhibits serine phosphorylation of IRS1 is effective for treatment of cancers, such as colorectal and non small cell lung (NSCL) cancer. Accordingly, the present invention provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor combination. In one embodiment the tumors or tumor metastases to be treated are colorectal tumors or tumor metastases. In another embodiment the tumors or tumor metastases to be treated are non small cell lung (NSCL) tumors or tumor metastases.
[197] The present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition, one or more other cytotoxic, chemotherapeutic or anti-cancer agents, or compounds that enhance the effects of such agents.
[198] In the context of this invention, additional other cytotoxic, chemotherapeutic or anticancer agents, or compounds that enhance the effects of such agents, include, for example: alkylating agents or agents with an alkylating action, such as cyclophosphamide (CTX; e.g. CYTOXAN®), chlorambucil (CHL; e.g. LEUKERAN®), cisplatin (CisP; e.g. PLATINOL®), oxaliplatin (e.g. ELOXATIN™), busulfan (e.g. MYLERAN®), melphalan, carmustine (BCNU), streptozotocin, triethylenemelamine (TEM), mitomycin C, and the like; anti-metabolites, such as methotrexate (MTX), etoposide (VP16; e.g. VEPESID®), 6-mercaptopurine (6MP), 6- thiocguanine (6TG), cytarabine (Ara-C), 5-fluorouracil (5-FU), capecitabine (e.g. XELODA®), dacarbazine (DTIC), and the like; antibiotics, such as actinomycin D, doxorubicin (DXR; e.g. ADRIAMYCIN®), daunorubicin (daunomycin), bleomycin, mithramycin and the like; alkaloids, such as vinca alkaloids such as vincristine (VCR), vinblastine, and the like; and other antitumor agents, such as paclitaxel (e.g. TAXOL®) and paclitaxel derivatives, the cytostatic agents, glucocorticoids such as dexamethasone (DEX; e.g. DECADRON®) and corticosteroids such as prednisone, nucleoside enzyme inhibitors such as hydroxyurea, amino acid depleting enzymes such as asparaginase, leucovorin, folinic acid, raltitrexed, and other folic acid derivatives, and similar, diverse antitumor agents. The following agents may also be used as additional agents: amifostine (e.g. ETHYOL®), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, lornustine (CCNU), doxorubicin lipo (e.g. DOXIL®), gemcitabine (e.g. GEMZAR®), daunorubicin lipo (e.g. DAUNOXOME®), procarbazine, mitomycin, docetaxel (e.g. TAXOTERE®), aldesleukin, carboplatin, cladribine, camptothecin, 10-hydroxy 7-ethyl- camptothecin (SN38), floxuridine, fludarabine, ifosfamide, idarubicin, mesna, interferon alpha, interferon beta, mitoxantrone, topotecan, leuprolide, megestrol, melphalan, mercaptopurine, plicamycin, mitotane, pegaspargase, pentostatin, pipobroman, plicamycin, tamoxifen, teniposide, testolactone, thioguanine, thiotepa, uracil mustard, or vinorelbine, chlorambucil. [199] The present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition, one or more anti-hormonal agents. As used herein, the term "anti-hormonal agent" includes natural or synthetic organic or peptidic compounds that act to regulate or inhibit hormone action on tumors.
[200] Anti-hormonal agents include, for example: steroid receptor antagonists, anti- estrogens such as tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, other aromatase inhibitors, 42-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (e.g. FARESTON®); anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above; agonists and/or antagonists of glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH) and LHRH (leuteinizing hormone-releasing hormone); the LHRH agonist goserelin acetate, commercially available as ZOLADEX® (AstraZeneca); the LHRH antagonist D-alaninamide N-acetyl-3-(2- naphthalenyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-N6-( 3- pyridinylcarbonyl)-L-lysyl-N6-(3-pyridinylcarbonyl)-D-lysyl-L-leucyl-N6- (i-methylethyl)-L-lysyl - L-proline (e.g. ANTIDE®, Ares-Serono); the LHRH antagonist ganirelix acetate; the steroidal anti-androgens cyproterone acetate (CPA) and megestrol acetate, commercially available as MEGACE® (Bristol-Myers Oncology); the nonsteroidal anti-androgen flutamide (2-methyl-N-[4, 20-nitro-3-(trifluoromethyl) phenylpropanamide), commercially available as EULEXIN® (Schering Corp.); the non-steroidal anti-androgen nilutamide, (5,5-dimethyl-3-[4-nitro-3- (trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazolidine-dione); and antagonists for other non- permissive receptors, such as antagonists for RAR, RXR, TR, VDR, and the like. [201] The use of the cytotoxic and other anticancer agents described above in chemotherapeutic regimens is generally well characterized in the cancer therapy arts, and their use herein falls under the same considerations for monitoring tolerance and effectiveness and for controlling administration routes and dosages, with some adjustments. For example, the actual dosages of the cytotoxic agents may vary depending upon the patient's cultured cell response determined by using histoculture methods. Generally, the dosage will be reduced compared to the amount used in the absence of additional other agents. [202] Typical dosages of an effective cytotoxic agent can be in the ranges recommended by the manufacturer, and where indicated by in vitro responses or responses in animal models, can be reduced by up to about one order of magnitude concentration or amount. Thus, the actual dosage will depend upon the judgment of the physician, the condition of the patient, and the effectiveness of the therapeutic method based on the in vitro responsiveness of the primary cultured malignant cells or histocultured tissue sample, or the responses observed in the appropriate animal models.
[203] In the context of this invention, of the above additional other cytotoxic, chemotherapeutic or anticancer agents the compounds 5-fluorouracil and raltitrexed are preferred. Conveniently, a combination of 5-fluorouracil with leucovoran or folinic acid can be used with the agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination of this invention. Additionally, of the above additional other cytotoxic, chemotherapeutic or anticancer agents the compounds etoposide and cisplatin are also preferred.
[204] The present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition one or more angiogenesis inhibitors.
[205] Anti-angiogenic agents include, for example: VEGFR inhibitors, such as SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, Calif., USA), or as described in, for example International Application Nos. WO 99/24440, WO 99/62890, WO 95/21613, WO 99/61422, WO 98/50356, WO 99/10349, WO 97/32856, WO 97/22596, WO 98/54093, WO 98/02438, WO 99/16755, and WO 98/02437, and U.S. Patent Nos. 5,883,113, 5,886,020, 5,792,783, 5,834,504 and 6,235,764; VEGF inhibitors such as VEGF Trap (Regeneron Pharmaceuticals Inc. of Tarrytown, NY), or as described in, for example, U.S. Pat. App. Pub. US 2006/0058234 or U.S. Pat. No. 7,087,411 ; IM862 (Cytran Inc. of Kirkland, Wash., USA); angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.); and antibodies to VEGF, such as bevacizumab (e.g. AVASTIN™, Genentech, South San Francisco, CA), a recombinant humanized antibody to VEGF; integrin receptor antagonists and integrin antagonists, such as to αvβ3, αvβ5 and αvβ6 integrins, and subtypes thereof, e.g. cilengitide (EMD 121974), or the anti-integrin antibodies, such as for example αvβ3 specific humanized antibodies (e.g. VITAXIN®); factors such as IFN-alpha (U.S. Patent Nos. 41530,901 , 4,503,035, and 5,231 ,176); angiostatin and plasminogen fragments (e.g. kringle 1-4, kringle 5, kringle 1-3 (O'Reilly, M. S. et al. (1994) Cell 79:315-328; Cao et al. (1996) J. Biol. Chem. 271 : 29461-29467; Cao et al. (1997) J. Biol. Chem. 272:22924-22928); endostatin (O'Reilly, M. S. et al. (1997) Cell 88:277; and International Patent Publication No. WO 97/15666); thrombospondin (TSP-1 ; Frazier, (1991 ) Curr. Opin. Cell Biol. 3:792); platelet factor 4 (PF4); plasminogen activator/urokinase inhibitors; urokinase receptor antagonists; heparinases; fumagillin analogs such as TNP-4701 ; suramin and suramin analogs; angiostatic steroids; bFGF antagonists; flk-1 and flt-1 antagonists; anti-angiogenesis agents such as MMP-2 (matrix-metalloproteinase 2) inhibitors and MMP-9 (matrix-metalloproteinase 9) inhibitors. Examples of useful matrix metalloproteinase inhibitors are described in International Patent Publication Nos. WO 96/33172, WO 96/27583, WO 98/07697, WO 98/03516, WO 98/34918, WO 98/34915, WO 98/33768, WO 98/30566, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667, and WO 99/07675, European Patent Publication Nos. 818,442, 780,386, 1 ,004,578, 606,046, and 931 ,788; Great Britain Patent Publication No. 9912961 , and U.S. Patent Nos. 5,863,949 and 5,861 ,510. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1 , MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11 , MMP-12, and MMP-13).
[206] The present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition one or more tumor cell pro-apoptotic or apoptosis-stimulating agents.
[207] The present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition one or more signal transduction inhibitors.
[208] Signal transduction inhibitors include, for example: erbB2 receptor inhibitors, such as organic molecules, or antibodies that bind to the erbB2 receptor, for example, trastuzumab (e.g. HERCEPTIN®); inhibitors of other protein tyrosine-kinases, e.g. imitinib (e.g. GLEEVEC®); ras inhibitors; raf inhibitors; MEK inhibitors; mTOR inhibitors; cyclin dependent kinase inhibitors; protein kinase C inhibitors; and PDK-1 inhibitors (see Dancey, J. and Sausville, E.A. (2003) Nature Rev. Drug Discovery 2:92-313, for a description of several examples of such inhibitors, and their use in clinical trials for the treatment of cancer).
[209] ErbB2 receptor inhibitors include, for example: ErbB2 receptor inhibitors, such as GW- 282974 (Glaxo Wellcome pic), monoclonal antibodies such as AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Tex., USA) and 2B-1 (Chiron), and erbB2 inhibitors such as those described in International Publication Nos. WO 98/02434, WO 99/35146, WO 99/35132, WO 98/02437, WO 97/13760, and WO 95/19970, and U.S. Patent Nos. 5,587,458, 5,877,305, 6,465,449 and 6,541 ,481.
[210] The present invention further thus provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition an anti- HER2 antibody or an immunotherapeutically active fragment thereof.
[21 1] The present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition one or more additional anti-proliferative agents. [212] Additional antiproliferative agents include, for example: Inhibitors of the enzyme famesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFR, including the compounds disclosed and claimed in U.S. Patent Nos. 6,080,769, 6,194,438, 6,258,824, 6,586,447, 6,071 ,935, 6,495,564, 6,150,377, 6,596,735 and 6,479,513, and International Patent Publication WO 01/40217.
[213] The present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition a COX Il (cyclooxygenase Il ) inhibitor. Examples of useful COX-II inhibitors include alecoxib (e.g. CELEBREX™), valdecoxib, and rofecoxib.
[214] The present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition treatment with radiation or a radiopharmaceutical.
[215] The source of radiation can be either external or internal to the patient being treated. When the source is external to the patient, the therapy is known as external beam radiation therapy (EBRT). When the source of radiation is internal to the patient, the treatment is called brachytherapy (BT). Radioactive atoms for use in the context of this invention can be selected from the group including, but not limited to, radium, cesium-137, iridium-192, americium-241 , gold-198, cobalt-57, copper-67, technetium-99, iodine-123, iodine-131 , and indium-1 1 1. Where the agent that inhibits serine phosphorylation of IRS1 according to this invention is an antibody, it is also possible to label the antibody with such radioactive isotopes.
[216] Radiation therapy is a standard treatment for controlling unresectable or inoperable tumors and/or tumor metastases. Improved results have been seen when radiation therapy has been combined with chemotherapy. Radiation therapy is based on the principle that high-dose radiation delivered to a target area will result in the death of reproductive cells in both tumor and normal tissues. The radiation dosage regimen is generally defined in terms of radiation absorbed dose (Gy), time and fractionation, and must be carefully defined by the oncologist. The amount of radiation a patient receives will depend on various considerations, but the two most important are the location of the tumor in relation to other critical structures or organs of the body, and the extent to which the tumor has spread. A typical course of treatment for a patient undergoing radiation therapy will be a treatment schedule over a 1 to 6 week period, with a total dose of between 10 and 80 Gy administered to the patient in a single daily fraction of about 1.8 to 2.0 Gy, 5 days a week. In a preferred embodiment of this invention there is synergy when tumors in human patients are treated with the combination treatment of the invention and radiation. In other words, the inhibition of tumor growth by means of the agents comprising the combination of the invention is enhanced when combined with radiation, optionally with additional chemotherapeutic or anticancer agents. Parameters of adjuvant radiation therapies are, for example, contained in International Patent Publication WO 99/60023.
[217] The present invention further provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I combination, and in addition treatment with one or more agents capable of enhancing antitumor immune responses. [218] Agents capable of enhancing antitumor immune responses include, for example: CTLA4 (cytotoxic lymphocyte antigen 4) antibodies (e.g. MDX-CTLA4), and other agents capable of blocking CTLA4. Specific CTLA4 antibodies that can be used in the present invention include those described in U.S. Patent No. 6,682,736.
[219] The present invention further provides a method for reducing the side effects caused by the treatment of tumors or tumor metastases in a patient with an agent that inhibits serine phosphorylation of IRS1 or an IGF1 R protein kinase inhibitor compound of Formula I, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and irinotecan combination, in amounts that are effective to produce an additive, or a superadditive or synergistic antitumor effect, and that are effective at inhibiting the growth of the tumor.
[220] The present invention further provides a method for the treatment of cancer, comprising administering to a subject in need of such treatment (i) an effective first amount of an agent that inhibits serine phosphorylation of IRS1 , or a pharmaceutically acceptable salt thereof; and (ii) an effective second amount of an IGF1 R protein kinase inhibitor compound of Formula I.
[221] The present invention also provides a method for the treatment of cancer, comprising administering to a subject in need of such treatment (i) a sub-therapeutic first amount of the EGFR kinase inhibitor erlotinib, or a pharmaceutically acceptable salt thereof; and (ii) a subtherapeutic second amount of an IGF1 R protein kinase inhibitor compound of Formula I. [222] As used herein, the term "patient" preferably refers to a human in need of treatment with an agent that inhibits serine phosphorylation of IRS1 for any purpose, and more preferably a human in need of such a treatment to treat cancer, or a precancerous condition or lesion. However, the term "patient" can also refer to non-human animals, preferably mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others, that are in need of treatment with an agent that inhibits serine phosphorylation of IRS1. [223] In a preferred embodiment, the patient is a human in need of treatment for cancer, or a precancerous condition or lesion. The cancer is preferably any cancer treatable, either partially or completely, by administration of an agent that inhibits serine phosphorylation of IRS1. The cancer may be, for example, lung cancer, non small cell lung (NSCL) cancer, bronchioloalviolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma, hepatocellular cancer, biliary cancer, chronic or acute leukemia, lymphocytic lymphomas, neoplasms of the central nervous system (CNS), spinal axis tumors, brain stem glioma, glioblastoma multiforme, astrocytomas, schwanomas, ependymonas, medulloblastomas, meningiomas, squamous cell carcinomas, pituitary adenoma, including refractory versions of any of the above cancers, or a combination of one or more of the above cancers. The precancerous condition or lesion includes, for example, the group consisting of oral leukoplakia, actinic keratosis (solar keratosis), precancerous polyps of the colon or rectum, gastric epithelial dysplasia, adenomatous dysplasia, hereditary nonpolyposis colon cancer syndrome (HNPCC), Barrett's esophagus, bladder dysplasia, and precancerous cervical conditions.
[224] For purposes of the present invention, "co-administration of and "co-administering" of an IGF1 R protein kinase inhibitor compound of Formula I with an agent that inhibits serine phosphorylation of IRS1 (both components referred to hereinafter as the "two active agents") refer to any administration of the two active agents, either separately or together, where the two active agents are administered as part of an appropriate dose regimen designed to obtain the benefit of the combination therapy. Thus, the two active agents can be administered either as part of the same pharmaceutical composition or in separate pharmaceutical compositions. An IGF1 R protein kinase inhibitor compound of Formula I can be administered prior to, at the same time as, or subsequent to administration of the agent that inhibits serine phosphorylation of IRS1 , or in some combination thereof. Where the agent that inhibits serine phosphorylation of IRS1 is administered to the patient at repeated intervals, e.g., during a standard course of treatment, an IGF1 R protein kinase inhibitor compound of Formula I can be administered prior to, at the same time as, or subsequent to, each administration of the agent that inhibits serine phosphorylation of IRS1 , or some combination thereof, or at different intervals in relation to the agent that inhibits serine phosphorylation of IRS1 treatment, or in a single dose prior to, at any time during, or subsequent to the course of treatment with the agent that inhibits serine phosphorylation of IRS1.
[225] The agent that inhibits serine phosphorylation of IRS1 will typically be administered to the patient in a dose regimen that provides for the most effective treatment of the cancer (from both efficacy and safety perspectives) for which the patient is being treated, as known in the art, and as disclosed, e.g. in International Patent Publication No. WO 01/34574. In conducting the treatment method of the present invention, the agent that inhibits serine phosphorylation of IRS1 can be administered in any effective manner known in the art, such as by oral, topical, intravenous, intra-peritoneal, intramuscular, intra-articular, subcutaneous, intranasal, intraocular, vaginal, rectal, or intradermal routes, depending upon the type of cancer being treated, the type of agent that inhibits serine phosphorylation of IRS1 being used (e.g., small molecule, antibody, RNAi or antisense construct), and the medical judgment of the prescribing physician as based, e.g., on the results of published clinical studies.
[226] The amount of agent that inhibits serine phosphorylation of IRS1 administered and the timing of agent that inhibits serine phosphorylation of IRS1 administration will depend on the type (species, gender, age, weight, etc.) and condition of the patient being treated, the severity of the disease or condition being treated, and on the route of administration. For example, small molecule agents that inhibits serine phosphorylation of IRS1 can be administered to a patient in doses ranging from 0.001 to 100 mg/kg of body weight per day or per week in single or divided doses, or by continuous infusion (see for example, International Patent Publication No. WO 01/34574). In particular, erlotinib HCI can be administered to a patient in doses ranging from 5- 200 mg per day, or 100-1600 mg per week, in single or divided doses, or by continuous infusion. A preferred dose is 150 mg/day. Antibody-based agents that inhibits serine phosphorylation of IRS1 , or antisense, RNAi or ribozyme constructs, can be administered to a patient in doses ranging from 0.1 to 100 mg/kg of body weight per day or per week in single or divided doses, or by continuous infusion. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
[227] The agents that inhibits serine phosphorylation of IRS1 and IGF1 R protein kinase inhibitors can be administered either separately or together by the same or different routes, and in a wide variety of different dosage forms. For example, the agent that inhibits serine phosphorylation of IRS1 is preferably administered orally or parenterally, whereas the IGF1 R protein kinase inhibitor compound of Formula I is preferably administered parenterally. Where the agent that inhibits serine phosphorylation of IRS1 is erlotinib HCI (TARCEVA)1 oral administration is preferable. [228] The agent that inhibits serine phosphorylation of IRS1 can be administered with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, elixirs, syrups, and the like. Administration of such dosage forms can be carried out in single or multiple doses. Carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Oral pharmaceutical compositions can be suitably sweetened and/or flavored.
[229] The agent that inhibits serine phosphorylation of IRS1 and IGF1 R protein kinase inhibitor compound of Formula I can be combined together with various pharmaceutically acceptable inert carriers in the form of sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, and the like. Administration of such dosage forms can be carried out in single or multiple doses. Carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents, etc.
[230] All formulations comprising proteinaceous agents that inhibits serine phosphorylation of IRS1 should be selected so as to avoid denaturation and/or degradation and loss of biological activity of the inhibitor.
[231] For oral administration of agents that inhibits serine phosphorylation of IRS1 , tablets containing one or both of the active agents are combined with any of various excipients such as, for example, micro-crystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinyl pyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the agent that inhibits serine phosphorylation of IRS1 may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. [232] For parenteral administration of either or both of the active agents, solutions in either sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions comprising the active agent or a corresponding water-soluble salt thereof. Such sterile aqueous solutions are preferably suitably buffered, and are also preferably rendered isotonic, e.g., with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Any parenteral formulation selected for administration of proteinaceous agents that inhibits serine phosphorylation of IRS1 should be selected so as to avoid denaturation and loss of biological activity of the inhibitor.
[233] Additionally, it is possible to topically administer either or both of the active agents, by way of, for example, creams, lotions, jellies, gels, pastes, ointments, salves and the like, in accordance with standard pharmaceutical practice. For example, a topical formulation comprising either an agent that inhibits serine phosphorylation of IRS1 or an IGF1 R protein kinase inhibitor compound of Formula I in about 0.1% (w/v) to about 5% (w/v) concentration can be prepared.
[234] For veterinary purposes, the active agents can be administered separately or together to animals using any of the forms and by any of the routes described above. In a preferred embodiment, the agent that inhibits serine phosphorylation of IRS1 is administered in the form of a capsule, bolus, tablet, liquid drench, by injection or as an implant. As an alternative, the agent that inhibits serine phosphorylation of IRS1 can be administered with the animal feedstuff, and for this purpose a concentrated feed additive or premix may be prepared for a normal animal feed. The IGF1 R protein kinase inhibitor compound of Formula I is preferably administered in the form of liquid drench, by injection or as an implant. Such formulations are prepared in a conventional manner in accordance with standard veterinary practice. [235] The present invention further provides a kit comprising a single container comprising both an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor compound of Formula I. The present invention further provides a kit comprising a first container comprising an agent that inhibits serine phosphorylation of IRS1 and a second container comprising an IGF1 R protein kinase inhibitor compound of Formula I. In a preferred embodiment, the kit containers may further include a pharmaceutically acceptable carrier. The kit may further include a sterile diluent, which is preferably stored in a separate additional container. The kit may further include a package insert comprising printed instructions directing the use of the combined treatment as a method for treating cancer.
[236] As used herein, the term "agent which inhibits serine phosphorylation of IRS1" refers to any agent which inhibits serine phosphorylation of IRS1 that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of IRS1 in the patient, other than agents that block the mTORCI signaling pathway. Such IRS1 inhibitors include any agent that can block IRS1 activation or any of the downstream biological effects of IRS1 activation that are relevant to treating cancer in a patient. Such an inhibitor can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity. Alternatively, such an inhibitor can act by occupying the ligand binding site or a portion thereof of the IRS1 receptor, thereby making the receptor inaccessible to its natural ligand so that its normal biological activity is prevented or reduced. Alternatively, such an inhibitor can act by modulating the dimerization of IRS1 polypeptides, or interaction of IRS1 polypeptide with other proteins, or enhance ubiquitination and endocytotic degradation of IRS1. IRS1 inhibitors include but are not limited to low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, small inhibitory RNAs (i.e. RNA interference by dsRNA; RNAi), and ribozymes.
[237] Agents which inhibit serine phosphorylation of IRS1 include, for example, EGFR kinase inhibitors, MAPK inhibitors, MEK inhibitors, Ras inhibitors, Raf inhibitors, and PKC inhibitors.
[238] The term "MAPK inhibitor" refers to any MAPK inhibitor that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of the MAPK receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to MAPK of its natural ligand. Such MAPK kinase inhibitors include any agent that can block MAPK activation or any of the downstream biological effects of MAPK activation that are relevant to treating cancer in a patient. Such an inhibitor can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity. Alternatively, such an inhibitor can act by occupying the ligand binding site or a portion thereof of the MAPK receptor, thereby making the receptor inaccessible to its natural ligand so that its normal biological activity is prevented or reduced. Alternatively, such an inhibitor can act by modulating the dimerization of MAPK polypeptides, or interaction of MAPK polypeptide with other proteins, or enhance ubiquitination and endocytotic degradation of MAPK. MAPK kinase inhibitors include but are not limited to low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, small inhibitory RNAs (i.e. RNA interference by dsRNA; RNAi), and ribozymes. In a preferred embodiment, the MAPK kinase inhibitor is a small organic molecule or an antibody that binds specifically to the human MAPK.
[239] MAPK kinase inhibitors include, for example, Ras inhibitors, Raf inhibitors, MEK inhibitors or PKC inhibitors.
[240] The term "MEK inhibitor" refers to any MEK inhibitor that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of the MEK receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to MEK of its natural ligand. Such MEK kinase inhibitors include any agent that can block MEK activation or any of the downstream biological effects of MEK activation that are relevant to treating cancer in a patient. Such an inhibitor can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity. Alternatively, such an inhibitor can act by occupying the ligand binding site or a portion thereof of the MEK receptor, thereby making the receptor inaccessible to its natural ligand so that its normal biological activity is prevented or reduced. Alternatively, such an inhibitor can act by modulating the dimerization of MEK polypeptides, or interaction of MEK polypeptide with other proteins, or enhance ubiquitination and endocytotic degradation of MEK. MEK kinase inhibitors include but are not limited to low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, small inhibitory RNAs (i.e. RNA interference by dsRNA; RNAi), and ribozymes. In a preferred embodiment, the MEK kinase inhibitor is a small organic molecule or an antibody that binds specifically to the human MEK.
[241] A MEK inhibitor is a compound that shows MEK inhibition when tested in the assays titled, "Enzyme Assays" in U.S. Pat. No. 5,525,625, column 6, beginning at line 35. The complete disclosure of U.S. Pat. No. 5,525,625 is hereby incorporated by reference. Specifically, a compound is an MEK inhibitor if a compound shows activity in the assay titled, "Cascade Assay for Inhibitors of the MAP Kinase Pathway," column 6, line 36 to column 7, line 4 of the U.S. Pat. No. 5,525,625 and/or shows activity in the assay titled, "In Vitro MEK Assay" at column 7, lines 4 to 27 of the above-referenced patent. Alternatively, MEK inhibition can be measured in the assay described in WO 02/06213 A1 , the complete disclosure of which is hereby incorporated by reference.
[242] MEK kinase inhibitors include, for example, ARRY-142886 (also known as AZD6244; Array BioPharma/Astrazeneca), PD-184352 (also known as CI-1040; Pfizer), XL518 (Exelixis), PD0325901 (Pfizer), PD-98059 (Pfizer), MEK1 (EMD), or 2-(2-amino-3-methoxyphenyl)-4-oxo- 4H-[1]benzopyran and 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide.
[243] Specific preferred examples of MEK inhibitors that can be used according to the present invention include ARRY-142886, PD-184352, PD-98059, PD-0325901 , XL518, or MEK1.
[244] The term "Ras inhibitor" refers to any Ras inhibitor that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of the Ras receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to Ras of its natural ligand. Such Ras kinase inhibitors include any agent that can block Ras activation or any of the downstream biological effects of Ras activation that are relevant to treating cancer in a patient. Such an inhibitor can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity. Alternatively, such an inhibitor can act by occupying the ligand binding site or a portion thereof of the Ras receptor, thereby making the receptor inaccessible to its natural ligand so that its normal biological activity is prevented or reduced. Alternatively, such an inhibitor can act by modulating the dimerization of Ras polypeptides, or interaction of Ras polypeptide with other proteins, or enhance ubiquitination and endocytotic degradation of Ras. Ras kinase inhibitors include but are not limited to low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, small inhibitory RNAs (i.e. RNA interference by dsRNA; RNAi), and ribozymes. In a preferred embodiment, the Ras kinase inhibitor is a small organic molecule or an antibody that binds specifically to the human Ras.
[245] Ras kinase inhibitors include, for example, BMS-214662 (Bristol-Myers Squibb), SCH 66336 (also known as lonafarnib; Schering-Plough), L-778,123 (Merck), R115777 (also known as Zarnestra or Tipifamib; Johnson and Johnson), and 6-[(4-chloro-phenyl)-hydroxy-(3-methyl- 3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1 H-quinolin-2-one (OSI
Pharmaceuticals, Inc.). Ras inhibitors disclosed in U.S. Pat. Nos. 6,150,377 and 6,645,982 are included. The complete disclosures of U.S. Pat. Nos. 6,150,377 and 6,645,982 are incorporated by reference.
[246] A specific preferred example of a Ras inhibitors that can be used according to the present invention includes 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4- (3-ethynyl-phenyl)-1-methyl-1 H-quinolin-2-one.
[247] The term "Raf inhibitor" refers to any Raf inhibitor that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of the Raf receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to Raf of its natural ligand. Such Raf kinase inhibitors include any agent that can block Raf activation or any of the downstream biological effects of Raf activation that are relevant to treating cancer in a patient. Such an inhibitor can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity. Alternatively, such an inhibitor can act by occupying the ligand binding site or a portion thereof of the Raf receptor, thereby making the receptor inaccessible to its natural ligand so that its normal biological activity is prevented or reduced. Alternatively, such an inhibitor can act by modulating the dimerization of Raf polypeptides, or interaction of Raf polypeptide with other proteins, or enhance ubiquitination and endocytotic degradation of Raf. Raf kinase inhibitors include but are not limited to low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, small inhibitory RNAs (i.e. RNA interference by dsRNA; RNAi), and ribozymes. In a preferred embodiment, the Raf kinase inhibitor is a small organic molecule or an antibody that binds specifically to the human Raf.
[248] Raf kinase inhibitors include, for example, sorafenib (also known as BAY 43-9006; Bayer). [249] The term "PKC inhibitor" refers to any PKC inhibitor that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of the PKC receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to PKC of its natural ligand. Such PKC kinase inhibitors include any agent that can block PKC activation or any of the downstream biological effects of Raf activation that are relevant to treating cancer in a patient. Such an inhibitor can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity. Alternatively, such an inhibitor can act by occupying the ligand binding site or a portion thereof of the PKC receptor, thereby making the receptor inaccessible to its natural ligand so that its normal biological activity is prevented or reduced. Alternatively, such an inhibitor can act by modulating the dimerization of PKC polypeptides, or interaction of PKC polypeptide with other proteins, or enhance ubiquitination and endocytotic degradation of PKC. PKC kinase inhibitors include but are not limited to low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, small inhibitory RNAs (i.e. RNA interference by dsRNA; RNAi), and ribozymes. In a preferred embodiment, the PKC kinase inhibitor is a small organic molecule or an antibody that binds specifically to the human PKC.
[250] PKC kinase inhibitors include, for example, byrostatin, staurosporine, staurosporine analogs including UCN-01 or CGP41251 , or safingol.
[251] As used herein, the term "EGFR kinase inhibitor" refers to any EGFR kinase inhibitor that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of the EGF receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to EGFR of its natural ligand. Such EGFR kinase inhibitors include any agent that can block EGFR activation or any of the downstream biological effects of EGFR activation that are relevant to treating cancer in a patient. Such an inhibitor can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity. Alternatively, such an inhibitor can act by occupying the ligand binding site or a portion thereof of the EGFR receptor, thereby making the receptor inaccessible to its natural ligand so that its normal biological activity is prevented or reduced. Alternatively, such an inhibitor can act by modulating the dimerization of EGFR polypeptides, or interaction of EGFR polypeptide with other proteins, or enhance ubiquitination and endocytotic degradation of EGFR. EGFR kinase inhibitors include but are not limited to low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, small inhibitory RNAs (i.e. RNA interference by dsRNA; RNAi), and ribozymes. In a preferred embodiment, the EGFR kinase inhibitor is a small organic molecule or an antibody that binds specifically to the human EGFR. [252] EGFR kinase inhibitors that include, for example quinazoline EGFR kinase inhibitors, pyrido-pyrimidine EGFR kinase inhibitors, pyrimido-pyrimidine EGFR kinase inhibitors, pyrrolo- pyrimidine EGFR kinase inhibitors, pyrazolo-pyrimidine EGFR kinase inhibitors, phenylamino- pyrimidine EGFR kinase inhibitors, oxindole EGFR kinase inhibitors, indolocarbazole EGFR kinase inhibitors, phthalazine EGFR kinase inhibitors, isoflavone EGFR kinase inhibitors, quinalone EGFR kinase inhibitors, and tyrphostin EGFR kinase inhibitors, such as those described in the following patent publications, and all pharmaceutically acceptable salts and solvates of said EGFR kinase inhibitors: International Patent Publication Nos. WO 96/33980, WO 96/30347, WO 97/30034, WO 97/30044, WO 97/38994, WO 97/49688, WO 98/02434, WO 97/38983, WO 95/19774, WO 95/19970, WO 97/13771 , WO 98/02437, WO 98/02438, WO 97/32881 , WO 98/33798, WO 97/32880, WO 97/3288, WO 97/02266, WO 97/27199, WO 98/07726, WO 97/34895, WO 96/31510, WO 98/14449, WO 98/14450, WO 98/14451 , WO 95/09847, WO 97/19065, WO 98/17662, WO 99/35146, WO 99/35132, WO 99/07701 , and WO 92/20642; European Patent Application Nos. EP 520722, EP 566226, EP 787772, EP 837063, and EP 682027; U.S. Patent Nos. 5,747,498, 5,789,427, 5,650,415, and 5,656,643; and German Patent Application No. DE 19629652. Additional non-limiting examples of low molecular weight EGFR kinase inhibitors include any of the EGFR kinase inhibitors described in Traxler, P., 1998, Exp. Opin. Ther. Patents 8(12):1599-1625.
[253] Specific preferred examples of low molecular weight EGFR kinase inhibitors that can be used according to the present invention include [6,7-bis(2-methoxyethoxy)-4-quinazolin-4- yl]-(3-ethynylphenyl) amine (also known as OSI-774, erlotinib, or TARCEVA (erlotinib HCI); OSI Pharmaceuticals/Genentech/Roche) (U.S. Pat. No. 5,747,498; International Patent Publication No. WO 01/34574, and Moyer, J.D. et al. (1997) Cancer Res. 57:4838-4848); CI-1033 (formerly known as PD183805; Pfizer) (Sherwood et al., 1999, Proc. Am. Assoc. Cancer Res. 40:723); PD-158780 (Pfizer); AG-1478 (University of California); CGP-59326 (Novartis); PKI-166 (Novartis); EKB-569 (Wyeth); GW-2016 (also known as GW-572016 or lapatinib ditosylate ; GSK); and gefitinib (also known as ZD1839 or IRESSA™; Astrazeneca) (Woodbum et al., 1997, Proc. Am. Assoc. Cancer Res. 38:633). A particularly preferred low molecular weight EGFR kinase inhibitor that can be used according to the present invention is [6,7-bis(2- methoxyethoxy)-4-quinazolin-4-yl]-(3-ethynylphenyl) amine (i.e. erlotinib), its hydrochloride salt (i.e. erlotinib HCI, TARCEVA), or other salt forms (e.g. erlotinib mesylate). [254] Antibody-based EGFR kinase inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Non- limiting examples of antibody-based EGFR kinase inhibitors include VECTIBIX™ (panitumumab; Amgen, Thousand Oaks, CA); those described in Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al., 1995, Clin. Cancer Res. 1 :1311-1318; Huang, S. M., et al., 1999, Cancer Res. 15:59(8):1935- 40; and Yang, X., et al., 1999, Cancer Res. 59:1236-1243. Thus, the EGFR kinase inhibitor can be monoclonal antibody Mab E7.6.3 (Yang, X.D. et al. (1999) Cancer Res. 59:1236-43), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof. Suitable monoclonal antibody EGFR kinase inhibitors include, but are not limited to, IMC-C225 (also known as cetuximab or ERBITUX™; lmclone Systems), ABX-EGF (Abgenix), EMD 72000 (Merck KgaA, Darmstadt), RH3 (York Medical Bioscience Inc.), and MDX-447 (Medarex/Merck KgaA).
[255] Additional antibody-based EGFR kinase inhibitors can be raised according to known methods by administering the appropriate antigen or epitope to a host animal selected, e.g., from pigs, cows, horses, rabbits, goats, sheep, and mice, among others. Various adjuvants known in the art can be used to enhance antibody production.
[256] Although antibodies useful in practicing the invention can be polyclonal, monoclonal antibodies are preferred. Monoclonal antibodies against EGFR can be prepared and isolated using any technique that provides for the production of antibody molecules by continuous cell lines in culture. Techniques for production and isolation include but are not limited to the hybridoma technique originally described by Kohler and Milstein (Nature, 1975, 256: 495-497); the human B-cell hybridoma technique (Kosbor et al., 1983, Immunology Today 4:72; Cote et al., 1983, Proc. Natl. Acad. Sci. USA 80: 2026-2030); and the EBV-hybridoma technique (Cole et al, 1985, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). [257] Alternatively, techniques described for the production of single chain antibodies (see, e.g., U.S. Patent No. 4,946,778) can be adapted to produce anti-EGFR single chain antibodies. Antibody-based EGFR kinase inhibitors useful in practicing the present invention also include anti-EGFR antibody fragments including but not limited to F(ab')2 fragments, which can be generated by pepsin digestion of an intact antibody molecule, and Fab fragments, which can be generated by reducing the disulfide bridges of the F(ab')2 fragments. Alternatively, Fab and/or scFv expression libraries can be constructed (see, e.g., Huse et al., 1989, Science 246: 1275- 1281 ) to allow rapid identification of fragments having the desired specificity to EGFR. [258] Techniques for the production and isolation of monoclonal antibodies and antibody fragments are well-known in the art, and are described in Harlow and Lane, 1988, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, and in J. W. Goding, 1986, Monoclonal Antibodies: Principles and Practice, Academic Press, London. Humanized anti-EGFR antibodies and antibody fragments can also be prepared according to known techniques such as those described in Vaughn, T. J. et al., 1998, Nature Biotech. 16:535-539 and references cited therein, and such antibodies or fragments thereof are also useful in practicing the present invention.
[259] EGFR kinase inhibitors for use in the present invention can alternatively be based on antisense oligonucleotide constructs. Anti-sense oligonucleotides, including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of EGFR mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of EGFR kinase protein, and thus activity, in a cell. For example, antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding EGFR can be synthesized, e.g., by conventional phosphodiester techniques and administered by e.g., intravenous injection or infusion. Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Patent Nos. 6,566,135; 6,566,131 ; 6,365,354; 6,410,323; 6,107,091 ; 6,046,321 ; and 5,981 ,732). [260] Small inhibitory RNAs (siRNAs) can also function as EGFR kinase inhibitors for use in the present invention. EGFR gene expression can be reduced by contacting the tumor, subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that expression of EGFR is specifically inhibited (i.e. RNA interference or RNAi). Methods for selecting an appropriate dsRNA or dsRNA-encoding vector are well known in the art for genes whose sequence is known (e.g. see Tuschi, T., et al. (1999) Genes Dev. 13(24):3191-3197; Elbashir, S.M. et al. (2001 ) Nature 411 :494-498; Hannon, GJ. (2002) Nature 418:244-251 ; McManus, MT. and Sharp, P. A. (2002) Nature Reviews Genetics 3:737-747; Bremmelkamp, T.R. et al. (2002) Science 296:550-553; U.S. Patent Nos. 6,573,099 and 6,506,559; and International Patent Publication Nos. WO 01/36646, WO 99/32619, and WO 01/68836).
[261] Ribozymes can also function as EGFR kinase inhibitors for use in the present invention. Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. The mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage. Engineered hammerhead motif ribozyme molecules that specifically and efficiently catalyze endonucleolytic cleavage of EGFR mRNA sequences are thereby useful within the scope of the present invention. Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, which typically include the following sequences, GUA, GUU, and GUC. Once identified, short RNA sequences of between about 15 and 20 ribonucleotides corresponding to the region of the target gene containing the cleavage site can be evaluated for predicted structural features, such as secondary structure, that can render the oligonucleotide sequence unsuitable. The suitability of candidate targets can also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using, e.g., ribonuclease protection assays. [262] Both antisense oligonucleotides and ribozymes useful as EGFR kinase inhibitors can be prepared by known methods. These include techniques for chemical synthesis such as, e.g., by solid phase phosphoramadite chemical synthesis. Alternatively, anti-sense RNA molecules can be generated by in vitro or in vivo transcription of DNA sequences encoding the RNA molecule. Such DNA sequences can be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters. Various modifications to the oligonucleotides of the invention can be introduced as a means of increasing intracellular stability and half-life. Possible modifications include but are not limited to the addition of flanking sequences of ribonucleotides or deoxyribonucleotides to the 5' and/or 3' ends of the molecule, or the use of phosphorothioate or 2'-O-methyl rather than phosphodiesterase linkages within the oligonucleotide backbone.
[263] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When a compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (cupric and cuprous), ferric, ferrous, lithium, magnesium, manganese (manganic and manganous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium slats. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N',N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
[264] When a compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. [265] The data presented below demonstrate that co-administration of an IGF1 R protein kinase inhibitor compound of Formula I with an agent that inhibits serine phosphorylation of IRS1 is effective for treatment of cancers, such as colorectal cancer, non-small cell lung (NSCL) cancer, pancreatic cancer, head and neck cancer, breast cancer, neuroblastoma, or ovarian cancer. Accordingly, the present invention provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 and an IGF1 R protein kinase inhibitor combination. In one embodiment the tumors or tumor metastases to be treated is non small cell lung (NSCL) cancer.
[266] In addition to the above EGFR inhibitors, specific agent that inhibits serine phosphorylation of IRS1 include MEK inhibitors. Examples of MEK inhibitors that can be used according to the present invention include ARRY-142886 (also known as AZD6244; Array
BioPharma/Astrazeneca), PD-184352 (also known as CI-1040; Pfizer), XL518 (Exelixis),
PD0325901 (Pfizer), PD-98059 (Pfizer), and Mek1 (EMD). Particularly preferred MEK inhibitors that can be used according to the present invention are MEK1 or PD-98059.
[267] This invention will be better understood from the Experimental Details that follow.
However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter, and are not to be considered in any way limited thereto.
[268] Experiment Details: Effect of Pharmacological Combination of TARCEVA, an EGF-1R inhibitor, and IGF-1R inhibitor, Compound-A, on cell survival and viability of cancer cells in vitro and tumor growth in vivo.
[269] Compound A: c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1- methyl-cyclobutanol is represented by the following structure and can be prepared according to
US2006/0235031 in conjunction with the ordinary skill in the art:
Figure imgf000049_0001
[270] The ability of IGF-1 R inhibitors to potentiate TARCEVA (erlotinib) effects on cell survival in the presence of IGF-1 , and the ability of IGF-1 R inhibitors in combination with
TARCEVA to reduce cell viability and modulate downstream signaling pathways, namely Ras-
MAPK and PI3K-AKT, and to promote apoptosis in colorectal cancer (CRC), breast, and pancreatic cancer cells in vitro, as well as to inhibit the tumor growth in mouse xenograft models was assessed.
[271] Measurement of Cell Proliferation and apoptosis:
[272] The models identified in experiments are for all the cell lines. Cell proliferation was determined using the Cell Titer GIo assay (Promega), and apoptosis was determined using the Caspase GIo assay (Promega). Cell lines were seeded at a density of 3000 cells per well in a 96-well plate. 24 hours after plating cells were dosed with varying concentrations of drug, either as a single agent or in combination. The signal for Cell Titer GIo was determined 72 hours after dosing, and fold induction for apoptosis was measured 48 hours after dosing. [273] Analysis ofAdditivity and Synergy.
[274] The Bliss additivism model was used to classify the effect of combining Compound A and erlotinib as additive, synergistic, or antagonistic. A theoretical curve was calculated for combined inhibition using the equation: Ebliss = EA + EB - EA*EB, where EA and EB are the fractional inhibitions obtained by drug A alone and drug B alone at specific concentrations. Here, Ebliss is the fractional inhibition that would be expected if the combination of the two drugs was exactly additive. If the experimentally measured fractional inhibition is less than Ebliss the combination was said to be synergistic. If the experimentally measured fractional inhibition is greater than Ebliss the combination was said to be antagonistic. For dose response curves, the bliss additivity value was calculated for varying doses of drug A when combined with a constant dose of drug B. This allowed an assessment as to whether drug B affected the potency of drug A or shifted its intrinsic activity. All plots were generated using Prism Graphpad software. [275] Xenograft studies in nude mice:
[276] Female CD-1 nu/nu mice (Charles River Laboratories) were implanted with harvested BxPC3 (pancreatic) or GEO (colorectal) tumor cells in a single subcutaneous site on the flank of the mice in the axillary region. Tumors were allowed to grow to 200 + 50 mm3, at which time the animals were sorted into treatment groups of 8 animals per group based on weight (+/- 1 g body weight) and tattooed on the tail for permanent identification. Tumor volumes and body weights were determined twice weekly. The tumor volume was determined by measuring in two directions with vernier calipers and calculated using the formula: Tumor volume = (length x width2)/2. The data were plotted as the % change in mean values of tumor volume and body weight for each group. The tumor growth inhibition (%TGI) was determined as %TGI = (1- {Tt/TO / Ct/CO} / 1-{C0/Ct}) X 100 where Tt = median tumor volume of treated at time t, TO = median tumor volume of treated at time 0, Ct = median tumor volume of control at time t and CO = median tumor volume of control at time 0. Mean %TGI was determined for the dosing period of each study. Erlotinib was dosed in a 6% Captisol (CyDex, Inc) in WFI (Water for Injection) solution, Compound A was dosed in 25 mM Tartaric acid solution, combination treated mice were dosed with 2X concentrated erlotinib in 6% captisol and 2X concentrated Compound A in 25 mM Tartaric Acid mixed 50:50 just prior to dosing and control animals were dosed with a 50:50 mix of both vehicles. All mice were dosed by oral gavage once a day for 14 days, unless otherwise noted. [277] % tumor growth inhibition (TGI) as calculated by the following formula : (1-{Tt/T0 / Ct/C0} / 1-{C0/Ct}) X 100
Tt = median tumor volume of treated at time t
T0 = median tumor volume of treated at time 0
Ct = median tumor volume of control at time t
C0 = median tumor volume of control at time 0
Mean %TGI determined for the dosing period of each study.
[278] As seen in Figures 1-5, the combination of Compound A with erlotinib is more efficacious than either drug alone in both in vitro and in vivo.
[279] In Figures 1 , the combination of Compound A and Erlotinib produces synergist effect on inhibiting cell proliferation and promoting apoptosis in the epithelial pancreatic cancer cell line BxPC3.
[280] As seen in Figures 2A and 2B, the combination of Compound A and Erlotinib by coadministration leads to much greater anti-tumor effect than either drug alone in vivo, and only the combination achieves early growth regression of the tumor during the treatment period. Approximately 26% of tumor regression is achieved on day 4 of dosing (maximum regression). The average tumor regression for the treatment period is approximately 13.2%. [281] In Figures 3, the combination of Compound A and Erlotinib has synergist effect on inhibiting cell proliferation in the epithelial breast tumor cell line MDA-MB-468. The additive effect of the combination treatment on growth inhibition is observed in the breast tumor cell line BT20.
[282] In Figures 4, the combination of Compound A and Erlotinib produces synergistic effect on inhibiting cell proliferation in mesenchymal breast tumor cell lines DU4475. The combination treatment has additive effect on cell growth inhibition of mesenchymal breast cancer cell line MDA-MB-435.
[283] In Figure 5, the combination of Compound A and Erlotinib by co-administration achieves much greater anti-tumor effect than either drug alone in GEO human colorectal cancer xenograft model, and only the combination leads growth regression of the tumor during the treatment period. Approximately 18%, 5% and 20% of maximum tumor regression are seen with Erlotinib at 100 mg/kg in combination with doses of Compound A at 7.5 mg/kg, 15 mg/kg and 30 mg/kg, respectively. The average tumor regression is approximately 10%, 4% and 13% at the three doses of Compound A in combination with Erlotinib, respectively. [284] Experimental Procedures: Effect of Pharmacological Combination of a MEK inhibitor, and IGF-1R inhibitor, Compound-A, on cell survival and viability of cancer cells in vitro and tumor growth in vivo.
[285] Ce// lines: The cell lines NCI-H292, GEO, BxPC3, MDA-MB-435, DU4475, and MDA- MB-468, and BT-20 were routinely cultured in media as prescribed by the ATCC containing 10% FCS. With the exception of GEO tumor cells (obtained from RPCI, Roswell Park Cancer Institute), all tumor cells were obtained from the ATCC. Measurement of Cell Proliferation:
[286] Cell proliferation was determined using the Cell Titer GIo assay (Promega), and apoptosis was determined by measuring caspase 3/7 activity with Caspase GIo (Promega). Cell lines were seeded at a density of 3000 cells per well in a 96-well plate. 24 hours after plating cells were dosed with varying concentrations of drug, either as a single agent or in combination. The signal for Cell Titer GIo was determined 72 hours after dosing, and the signal for Caspase GIo was determined 48 hours after dosing. Analysis of Additivity and Synergy:
[287] The Bliss additivism model was used to classify the effect of combining Compd A or PD98059 or MEK1 and erlotinib as additive, synergistic, or antagonistic. A theoretical curve was calculated for combined inhibition using the equation: Eb|iss = EA + EB - EA *EB, where EA and E8 are the fractional inhibitions obtained by drug A alone and drug B alone at specific concentrations, wherein drug A is Compd A and drug B is a MEK inhibitor PD98059 or MEK1. Here, Ebhss is the fractional inhibition that would be expected if the combination of the two drugs was exactly additive. If the experimentally measured fractional inhibition is less than Eb|iss the combination was said to be synergistic. If the experimentally measured fractional inhibition is greater than Ebι,ss the combination was said to be antagonistic. For dose response curves, the bliss additivity value was calculated for varying doses of drug A when combined with a constant dose of drug B. This allowed an assessment as to whether drug B affected the potency of drug A or shifted its intrinsic activity. All plots were generated using Prism Graphpad software. [288] Animals: Female athymic nude nu/nu CD-1 mice (6-8 wks, 22-29 g) were obtained from Charles River Laboratories (Wilmington, MA). Animals were allowed to acclimate for a minimum of one week prior to initiation of a study. Throughout the studies, animals were allowed sterile rodent chow and water ad libitum, and animals were maintained under specific pathogen free conditions. All animal studies were conducted at OSI facilities with the approval of the Institutional Animal Care and Use Committee in an American Association for Accreditation of Laboratory Animal Care (AAALAC)-accredited vivarium and in accordance with the Institute of Laboratory Animal Research (Guide for the Care and Use of Laboratory Animals, NIH1 Bethesda, MD). [289] In vivo anti-tumor efficacy study:
[290] Cells were harvested from cell culture flasks during exponential cell growth, washed twice with sterile PBS, counted and resuspended in PBS to a suitable concentration before s.c. implantation on the right flank of female nu/nu CD-1 mice. Tumors were established to 200 +/- 50 mm3 in size before randomization into treatment groups of 8 mice each. Compd A or vehicle was administered orally as indicated. Body weights were determined twice weekly along with tumor volume {V=[length x (width )2]/2} measurements using Vernier calipers during the study.
Tumor growth inhibition (%TGI) was determined twice weekly during the dosing period by the following formula: %TGI = (1-{Tt/T0 / Ct/C0} / 1-{Co/Ct}) X 100 where T4 = median tumor volume of treated at time t, T0 = median tumor volume of treated at time 0, Ct = median tumor volume of control at time t and C0 = median tumor volume of control at time 0. Tumor growth inhibition of
>50% is considered meaningful. Growth delay is calculated as T-C where T and C are the times in days for mean tumor size in the treated (T) and control (C) groups to reach 400% of the initial tumor volume. Cures are excluded from this calculation. Percent regression is measured by the following formula: 100 x (To-Tt)/To, where T0 is the median tumor volume of a treatment group on day 0, and T, is the median tumor volume of the same group on day t.
Durable cures were determined by the absence of palpable tumor 60 days post final dose of drug. Tarceva was dosed in a 6% Captisol (CyDex, Inc) in WFI (Water for Injection) solution and all control animals were dosed with an equal volume of the vehicle. Compd A was dosed in 25 mM tartaric acid at the appropriate concentration in 20 ml/kg dose volume. All mice were dosed daily by oral gavage for the indicated time periods.
[291] As seen in Figures 6A and 6B, the combination of Compound A with MEK1 and PD-
98059 is more efficacious than either drug alone in both in vitro and in vivo.
[292] In Figure 6A, the combination of Compound A and MEK1 produces synergist effect on inhibiting cell proliferation and promoting apoptosis in the non-small cell lung carcinoma cell line
H292.
[293] In Figure 6B, the combination of Compound A and PD-98059 produces synergist effect on inhibiting cell proliferation and promoting apoptosis in the non-small cell lung carcinoma cell line H292.
Incorporation by Reference
[294] All priority documents, and all patents, published patent applications and other references disclosed herein are hereby expressly incorporated herein by reference.

Claims

WHAT IS CLAIMED IS:
1. A method for treating cancer comprising administering to a patient, simultaneously or sequentially, (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 ; and (ii) a therapeutically effective amount of c/s-3-[8-Amino-1-(2- phenyl-quinolin-Z-yO-imidazoti .δ-alpyrazin-S-yll-i-methyl-cyclobutanol, or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the agent that inhibits serine phosphorylation of IRS1 is an EGFR kinase inhibitor.
3. The method of claim 1 , wherein the agent that inhibits serine phosphorylation of IRS1 is selected from erlotinib, cetuximab, gefitinib, or panitumumab, or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the agent that inhibits serine phosphorylation of IRS1 is erlotinib or a pharmaceutically acceptable salt thereof.
5. The method of claim 1 , wherein the agent that inhibits serine phosphorylation of IRS1 is an inhibitor of the MAPK pathway.
6. The method of claim 1 , wherein the agent that inhibits serine phosphorylation of IRS1 is selected from Ras inhibitors, Raf inhibitors, MEK inhibitors, or PKC inhibitors.
7. The method of claim 1 , wherein the agent that inhibits serine phosphorylation of IRS1 is an MEK inhibitor.
8. The method of claim 1 , wherein the agent that inhibits serine phosphorylation of IRS1 is selected from ARRY-142886, PD-184352, PD-98059, PD-0325901 , XL518, or MEK1.
9. The method of claim 1 , wherein the agent that inhibits serine phosphorylation of IRS1 is a Raf protein kinase family inhibitor.
10. The method of claim 1 , wherein the agent that inhibits serine phosphorylation of IRS1 is sorafenib.
11. The method of claim 1 , wherein the agent that inhibits serine phosphorylation of IRS1 is a Ras inhibitor.
12. The method of claim 1 , wherein the agent that inhibits serine phosphorylation of IRS1 is selected from BMS-214662, SCH 66336, R115777, or 6-[(4-chloro-phenyl)-hydroxy-(3- methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1 H-quinolin-2-one.
13. The method of claim 1 , wherein the agent that inhibits serine phosphorylation of IRS1 is a PKC inhibitor.
14. The method of claim 1 , wherein the agent that inhibits serine phosphorylation of IRS1 is selected from byrostatin, staurosporine, a staurosporine analog, UCN-01 , CGP41251 , or safingol.
15. The method of any one of claims 1-14, wherein the cancer is selected from colorectal cancer, non-small cell lung carcinoma, pancreatic cancer, head and neck cancer, breast cancer, neuroblastoma, or ovarian cancer.
16. The method of any one of claims 1-14, wherein the cancer is colorectal cancer or non-small cell lung carcinoma.
17. A pharmaceutical composition comprising (i) a therapeutically effective amount of an agent that inhibits serine phosphorylation of IRS1 ; and (ii) a therapeutically effective amount of c/s-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1-methyl-cyclobutanol, or a pharmaceutically acceptable salt thereof.
18. The composition of claim 17, wherein the agent that inhibits serine phosphorylation of IRS1 is erlotinib or a pharmaceutically acceptable salt thereof.
PCT/US2008/002593 2007-02-27 2008-02-27 Combination of imidazo [1,5-a] pyrazinyl derivatives with an agent that inhibits serine phosphorylation of irs1 for use in the treatment of cancer WO2008106168A1 (en)

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