WO2008008539A2 - Fused heterocyclic derivatives useful as inhibitors of the hepatocyte growth factor receptor - Google Patents

Fused heterocyclic derivatives useful as inhibitors of the hepatocyte growth factor receptor Download PDF

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Publication number
WO2008008539A2
WO2008008539A2 PCT/US2007/016068 US2007016068W WO2008008539A2 WO 2008008539 A2 WO2008008539 A2 WO 2008008539A2 US 2007016068 W US2007016068 W US 2007016068W WO 2008008539 A2 WO2008008539 A2 WO 2008008539A2
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Prior art keywords
alkylene
mmol
allowed
heterocyclo
alkyl
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Ceased
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PCT/US2007/016068
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French (fr)
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WO2008008539A3 (en
Inventor
Brian Albrecht
David Bauer
Steven Bellon
Christiane Bode
Shon Booker
Alessandro Boezio
Deborah Choquette
Derin D'amico
Jean-Christophe Harmange
Satoko Hirai
Randall Hungate
Tae-Seong Kim
Richard Lewis
Longbin Liu
Julia Lohman
Mark Norman
Michele Potashman
Aaron Siegmund
Stephanie Springer
Markian Stec
Ning Xi
Kevin Yang
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Amgen Inc
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Amgen Inc
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Priority to EA200900178A priority Critical patent/EA016028B1/en
Priority to NZ574002A priority patent/NZ574002A/en
Priority to CN200780034205XA priority patent/CN101528743B/en
Application filed by Amgen Inc filed Critical Amgen Inc
Priority to CA002657327A priority patent/CA2657327A1/en
Priority to KR1020097003060A priority patent/KR101140474B1/en
Priority to EP07810473.4A priority patent/EP2081931B1/en
Priority to ES07810473.4T priority patent/ES2592888T3/en
Priority to AU2007272783A priority patent/AU2007272783B2/en
Priority to JP2009519563A priority patent/JP5532398B2/en
Priority to BRPI0714387-7A priority patent/BRPI0714387A2/en
Priority to MX2009000531A priority patent/MX2009000531A/en
Priority to DK07810473.4T priority patent/DK2081931T3/en
Publication of WO2008008539A2 publication Critical patent/WO2008008539A2/en
Priority to IL196243A priority patent/IL196243A/en
Anticipated expiration legal-status Critical
Publication of WO2008008539A3 publication Critical patent/WO2008008539A3/en
Priority to NO20090723A priority patent/NO20090723L/en
Ceased legal-status Critical Current

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    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention is in the field of pharmaceutical agents and specifically relates to compounds, compositions, uses and methods for treating cancer.
  • Protein kinases represent a large family of proteins, which play a central role in the regulation of a wide variety of cellular processes, maintaining control over cellular function.
  • a partial list of such kinases includes abl, Akt, bcr-abl, BIk, Brk, Btk, c-kit, c-Met, c-src, c-fms, CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDKlO, cRafl, CSFlR, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-IR, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR,
  • c-Met The hepatocyte growth factor receptor
  • c-Met is a unique receptor tyrosine kinase shown to be overexpressed in a variety of malignancies.
  • c-Met typically comprises, in its native form, a 190-kDa heterodimeric (a disulfide-linked 50-kDa ⁇ -chain and a 145-kDa ⁇ - chain) membrane-spanning tyrosine kinase protein (Proc. Natl. Acad. Sci. USA, 84:6379-6383 (1987)).
  • c-Met is mainly expressed in epithelial cells and stimulation of c-Met leads to scattering, angiogenesis, proliferation and metastasis. (See Cytokine and Growth Factor Reviews, 13:41-59 (2002)).
  • HGF hepatocyte growth factor
  • SF scatter factor
  • HGF-SF Hepatocyte Growth Factor- Scatter Factor
  • c-Met Receptor Goldberg and Rosen, eds., Birkhauser Verlag-Basel, 67-79 (1993).
  • HGF/SF Hepatocyte Growth Factor- Scatter Factor
  • the biological effect of HGF/SF may depend in part on the target cell.
  • HGF induces a spectrum of biological activities in epithelial cells, including mitogenesis, stimulation of cell motility and promotion of matrix invasion (Biochem. Biophys. Res. Comm., 122:1450-1459 (1984); Proc. Natl. Acad. Sci. U.S.A., 88:415-419 (1991)).
  • HGF can also act as a "scatter factor", an activity that promotes the dissociation of epithelial and vascular endothelial cells (Nature, 327:239-242 (1987); J. Cell Biol., 111:2097-2108 (1990); EMBO J., 10:2867- 2878 (1991); Proc. Natl. Acad. Sci. USA, 90:649-653 (1993)).
  • HGF Hepatocyte Growth Factor-Scatter Factor
  • C-Met Receptor Goldberg and Rosen, eds., Birkhauser Verlag-Basel, 131-165 (1993)
  • HGF and c-Met are expressed at abnormally high levels in a large variety of solid tumors.
  • High levels of HGF and/or c-Met have been observed in liver, breast, pancreas, lung, kidney, bladder, ovary, brain, prostate, gallbladder and myeloma tumors in addition to many others.
  • the role of HGF/c-Met in metastasis has been investigated in mice using cell lines transformed with HGF/c-Met (J. MoI. Med., 74:505-513 (1996)).
  • Overexpression of the c-Met oncogene has also been suggested to play a role in the pathogenesis and progression of thyroid tumors derived from follicular epithelium (Oncogene, 7:2549-2553 (1992)).
  • HGF is a morphogen (Development, 110:1271-1284 (1990); Cell, 66:697-711 (1991)) and a potent angiogenic factor (J. Cell Biol., 1 19:629-641 (1992)).
  • Angiogenesis can be stimulated by HGF, as well as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).
  • HGF vascular endothelial growth factor
  • bFGF basic fibroblast growth factor
  • Angiogenesis the process of sprouting new blood vessels from existing vasculature and arteriogenesis, the remodeling of small vessels into larger conduit vessels are both physiologically important aspects of vascular growth in adult tissues. These processes of vascular growth are required for beneficial processes such as tissue repair, wound healing, recovery from tissue ischemia and menstrual cycling. They are also required for the development of pathological conditions such as the growth of neoplasias, diabetic retinopathy, rheumatoid arthritis, psoriasis, certain forms of macular degeneration, and certain inflammatory pathologies. The inhibition of vascular growth in these contexts has also shown beneficial effects in preclinical animal models.
  • angiogenesis For example, inhibition of angiogenesis by blocking vascular endothelial growth factor or its receptor has resulted in inhibition of tumor growth and in retinopathy. Also, the development of pathological pannus tissue in rheumatoid arthritis involves angiogenesis and might be blocked by inhibitors of angiogenesis.
  • the ability to stimulate vascular growth has potential utility for treatment of ischemia- induced pathologies such as myocardial infarction, coronary artery disease, peripheral vascular disease, and stroke.
  • ischemia- induced pathologies such as myocardial infarction, coronary artery disease, peripheral vascular disease, and stroke.
  • the sprouting of new vessels and/or the expansion of small vessels in ischemic tissues prevents ischemic tissue death and induces tissue repair.
  • Certain diseases are known to be associated with deregulated angiogenesis, for example ocular neovascularization, such as retinopathies (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, such as a rheumatoid or rheumatic inflammatory disease, especially arthritis (including rheumatoid arthritis), or other chronic inflammatory disorders, such as chronic asthma, arterial or post- transplantational atherosclerosis, endometriosis, and neoplastic diseases, for example so-called solid tumors and liquid tumors (such as leukemias). Treatment of malaria and related viral diseases may also be mediated by HGF and cMet.
  • HGF HGF-like growth factor
  • c-Met Elevated levels of HGF and c-Met have also been observed in non-oncological settings, such as hypertension, myocardial infarction and rheumatoid arthritis. It has been observed that levels of HGF increase in the plasma of patients with hepatic failure (Gohda et al., supra) and in the plasma (Hepatol., 13:734-750 (1991)) or serum (J. Biochem., 109:8-13 (1991)) of animals with experimentally induced liver damage. HGF has also been shown to be a mitogen for certain cell types, including melanocytes, renal tubular cells, keratinocytes, certain endothelial cells and cells of epithelial origin (Biochem. Biophys. Res.
  • Metastatic SCC cells overexpress c-Met and have enhanced tumoregenesis and metastasis in vivo [G. Gong et al., Oncogene, 23:6199-6208 (2004)].
  • C-Met is required for tumor cell survival [N. Shinomiya et al., Cancer Research, 64:7962-7970 (2004)].
  • C. Birchmeier et al. Nature Reviews/Molecular Biology 4:915-925 (2003).
  • HGF and/or c-Met in potentiating or promoting such diseases or pathological conditions, it would be useful to have a means of substantially reducing or inhibiting one or more of the biological effects of HGF and its receptor.
  • a compound that reduces the effect of HGF would be a useful compound.
  • Compounds of the current invention have not been previously described as inhibitors of angiogenesis such as for the treatment of cancer.
  • a class of compounds useful in treating cancer and angiogenesis is defined by Formulae, IV, V, VI and VII
  • J is N or CR 3 ;
  • W is N or CR 2b ;
  • W* is N or CR 2b ;
  • X is O or S
  • Z and Z* are independently -O-, -S(O) V -, or -NR 5 -;
  • R 5 and R 5a are independently H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl; and
  • G 1 and G 2 are independently alkyl, cycloalkyl, or G 1 and G 2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring;
  • R 4 is independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally independently substituted as allowed by valance with one or more R 10 groups;
  • R s and R 5a are independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally substituted as allowed by valance with one or more R 10 ; or R 5 and R 5a may combine to form a heterocyclo ring optionally substituted with one or more R 10 ;
  • Preferred compounds include compounds wherein R 1 is phenyl, naphthyl, benzodioxolyl, benzooxazolyl, benzoisoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrimidinyl, pyrazidinyl, isoquinolinyl, quinolinyl, quinazolinyl, quinazolinonyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolop
  • Preferred R 1 groups include
  • R 1 groups include
  • R 2 groups include
  • m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
  • Preferred compounds of the present invention include compounds having either or both of preferred R 1 groups and preferred R 2 groups either alone or in any combination thereof.
  • Preferred compounds of the present invention include compounds wherein R a , R b , R c and R d groups are independently hydrogen, alkyl (especially methyl), and halogen (especially fluorine).
  • Preferred compounds within the scope of formula I and II include compounds of the following formualae IA, IB, IC, ID and HA
  • R 2a , R 2b , R 3 , Z, Z*, n, q and t are as previously defined above.
  • Preferred compounds of formulae IA, IB, IC, ID and IIA include compounds having any of the preferred R 1 groups and R 2 groups, either alone or in any combination thereof.
  • Preferred compounds within the scope of formula I and II also include compounds having the following formula IE, IF, HB and HC
  • G 1 and G 2 are independently alkyl, cycloalkyl, or G 1 and G 2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring; and further wherein q is O, 1, 2 or 3; n* is 0, 1 or 2; t* is 0 or 1
  • U 1 , U 2 , U 3 and U 4 are each independently C, or N;
  • R IOc at each occurence is independently selected from the groups listed in the definition of R 10 previously described above.
  • Preferred compounds of formulae IE, IF, IIB and HC include compounds having any of the preferred R 2 groups described above.
  • Preferred compounds within the scope of formulae IE and IF include compounds of the following formula IEi, IEii, IEiii, IEiv, IFi, IFii, IFiii and IFiv
  • Preferred compounds within the scope of formula I further include compounds of the following formula IEA and IFA
  • G 1 and G 2 are independently alkyl, cycloalkyl, or G 1 and G 2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring.
  • Preferred compounds of formulae IEA and IFA include compounds having any of the preferred R 2 groups described above.
  • Preferred compounds of formulae IEA and IFA include compounds of formulae IEAi, IEAii, IEAiii, IFAi, IFAii and IFAiii
  • Preferred compounds within the scope of formula I further include compounds of the following formula IG or IH
  • U is CR 1Oc or N
  • variables ⁇ Rr» a a , r R ⁇ b b , ⁇ R r>2 2 , T Rv 2 2 a a , T R- ,2 2 b b , n Rl l O O a a , R IOb , R lOc , and Z* are as previously defined above, provided that in compounds of formula IG R 2 is not phenyl substituted with a group
  • G 1 and G 2 are independently alkyl, cycloalkyl, or G 1 and G 2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring.
  • Preferred compounds of formulae IG and IH include compounds having any of the preferred R 2 groups described above.
  • Preferred compounds of the present invention include the compounds exemplified herein.
  • the invention also relates to pharmaceutical compositions containing the above compounds, together with a pharmaceutically acceptable vehicle or carrier.
  • the invention also relates to a method of treating cancer in a subject using the above compounds.
  • the invention also relates to a method of reducing tumor size in a subject using the above compounds.
  • the invention also relates to a method of reducing metastasis in a tumor in a subject, using the above compounds.
  • the invention also relates to a method of treating HGF-mediated disorders in a subject using the above compounds.
  • Compounds of the present invention would be useful for, but not limited to, the prevention or treatment of angiogenesis related diseases.
  • the compounds of the invention have c-Met inhibitory activity.
  • the compounds of the invention are useful in therapy as antineoplasia agents or to minimize deleterious effects of HGF.
  • neoplasia including cancer and metastasis, including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including small cell lung cancer), esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia); tumors of me
  • tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma and schwannomas); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma).
  • the compounds are useful for the treatment of neoplasia selected from lung cancer, colon cancer and breast cancer.
  • the compounds also would be useful for treatment of ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemangiomas, including infantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; and disorders of the female reproductive system such as endometriosis.
  • the compounds are also useful for the treatment of edema, and conditions of vascular hyperpermeability.
  • the compounds of the invention are useful in therapy of proliferative diseases. These compounds can be used for the treatment of an inflammatory rheumatoid or rheumatic disease, especially of manifestations at the locomotor apparatus, such as various inflammatory rheumatoid diseases, especially chronic polyarthritis including rheumatoid arthritis, juvenile arthritis or psoriasis arthropathy; paraneoplastic syndrome or tumor-induced inflammatory diseases, turbid effusions, collagenosis, such as systemic Lupus erythematosus, poly-myositis, dermato-myositis, systemic sclerodermia or mixed collagenosis; postinfectious arthritis (where no living pathogenic organism can be found at or in the affected part of the body), seronegative spondylarthritis, such as spondylitis ankylosans; vasculitis, sarcoidosis, or arthrosis; or further any combinations thereof.
  • synovial inflammation for example, synovitis, including any of the particular forms of synovitis, in particular bursal synovitis and purulent synovitis, as far as it is not crystal-induced.
  • synovial inflammation may for example, be consequential to or associated with disease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis or arthritis deformans.
  • the present invention is further applicable to the systemic treatment of inflammation, e.g. inflammatory diseases or conditions, of the joints or locomotor apparatus in the region of the tendon insertions and tendon sheaths.
  • Such inflammation may be, for example, consequential to or associated with disease or further (in a broader sense of the invention) with surgical intervention, including, in particular conditions such as insertion endopathy, myofasciale syndrome and tendomyosis.
  • the present invention is further especially applicable to the treatment of inflammation, e.g. inflammatory disease or condition, of connective tissues including dermatomyositis and myositis.
  • These compounds can be used as active agents against such disease states as arthritis, atherosclerosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacter related diseases, fractures, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy or macular degeneration.
  • some of these compounds can be used as active agents against solid tumors, malignant ascites, hematopoietic cancers and hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome)) since such diseases require a proliferation of blood vessel cells for growth and/or metastasis.
  • thyroid hyperplasia especially Grave's disease
  • cysts such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome)
  • some of these compounds can be used as active agents against burns, chronic lung disease, stroke, polyps, anaphylaxis, chronic and allergic inflammation, ovarian hyperstimulation syndrome, brain tumor-associated cerebral edema, high-altitude, trauma or hypoxia induced cerebral or pulmonary edema, ocular and macular edema, ascites, and other diseases where vascular hyperpermeability, effusions, exudates, protein extravasation, or edema is a manifestation of the disease.
  • the compounds will also be useful in treating disorders in which protein extravasation leads to the deposition of fibrin and extracellular matrix, promoting stromal proliferation (e.g. fibrosis, cirrhosis and carpal tunnel syndrome).
  • the compounds of the present invention are also useful in the treatment of ulcers including bacterial, fungal, Mooren ulcers and ulcerative colitis.
  • the compounds of the present invention are also useful in the treatment of conditions wherein undesired angiogenesis, edema, or stromal deposition occurs in viral infections such as Herpes simplex, Herpes Zoster, AIDS, Kaposi's sarcoma, protozoan infections and toxoplasmosis, following trauma, radiation, stroke, endometriosis, ovarian hyperstimulation syndrome, systemic lupus, sarcoidosis, synovitis, Crohn's disease, sickle cell anemia, Lyme disease, pemphigoid, Paget's disease, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic inflammation, chronic occlusive pulmonary disease, asthma, and inflammatory rheumatoid or rheumatic disease.
  • the compounds are also useful in the reduction of subcutaneous fat and for the treatment of obesity.
  • the compounds of the present invention are also useful in the treatment of ocular conditions such as ocular and macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser complications, glaucoma, conjunctivitis, Stargardt's disease and Eales disease in addition to retinopathy and macular degeneration.
  • ocular conditions such as ocular and macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser complications, glaucoma, conjunctivitis, Stargardt's disease and Eales disease in addition to retinopathy and macular degeneration.
  • the compounds of the present invention are also useful in the treatment of cardiovascular conditions such as atherosclerosis, restenosis, arteriosclerosis, vascular occlusion and carotid obstructive disease.
  • the compounds of the present invention are also useful in the treatment of cancer related indications such as solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, including leukemia and lymphoma, tumor-induced pleural or pericardial effusions, and malignant ascites.
  • cancer related indications such as solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, including leukemia and lymphoma, tumor-induced pleural or pericardial effusions, and malignant ascites.
  • the compounds of the present invention are also useful in the treatment of diabetic conditions such as diabetic retinopathy and microangiopathy.
  • the compounds of the present invention are also useful in the reduction of blood flow in a tumor in a subject.
  • the compounds of the present invention are also useful in the reduction of metastasis of a tumor in a subject.
  • the compounds of this invention may also act as inhibitors of other protein kinases, e.g. tie-2, lck, src, fgf, c-Met, ron, ckit and ret, and thus be effective in the treatment of diseases associated with other protein kinases.
  • other protein kinases e.g. tie-2, lck, src, fgf, c-Met, ron, ckit and ret.
  • these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • the compounds of the present invention include the pharmaceutically acceptable derivatives thereof. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt and the like.
  • Angiogenesis is defined as any alteration of an existing vascular bed or the formation of new vasculature, which benefits tissue perfasion. This includes the formation of new vessels by sprouting of endothelial cells from existing blood vessels or the remodeling of existing vessels to alter size, maturity, direction or flow properties to improve blood perfusion of tissue.
  • HGF refers to hepatocyte growth factor/scatter factor. This includes purified hepatocyte growth factor/scatter factor, fragments of hepatocyte growth factor/scatter factor, chemically synthesized fragments of hepatocyte growth factor/scatter factor, derivatives or mutated versions of hepatocyte growth factor/scatter factor, and fusion proteins comprising hepatocyte growth factor/scatter factor and another protein. "HGF” as used herein also includes hepatocyte growth factor/scatter factor isolated from species other than humans.
  • c-Met refers to the receptor for HGF. This includes purified receptor, fragments of receptor, chemically synthesized fragments of receptor, derivatives or mutated versions of receptor, and fusion proteins comprising the receptor and another protein. “c-Met” as used herein also includes the HGF receptor isolated from a species other than humans.
  • HGF refers to hepatocyte growth factor/scatter factor. This includes purified hepatocyte growth factor/scatter factor, fragments of hepatocyte growth factor/scatter factor, chemically synthesized fragments of hepatocyte growth factor/scatter factor, derivatives or mutated versions of hepatocyte growth factor/scatter factor, and fusion proteins comprising hepatocyte growth factor/scatter factor and another protein. "HGF” as used herein also includes hepatocyte growth factor/scatter factor isolated from species other than humans.
  • c-Met refers to the receptor for HGF. This includes purified receptor, fragments of receptor, chemically synthesized fragments of receptor, derivatives or mutated versions of receptor, and fusion proteins comprising the receptor and another protein. “c-Met” as used herein also includes the HGF receptor isolated from a species other than humans.
  • hepatocyte growth factor and "HGF” refer to a growth factor typically having a structure with six domains (finger, Kringle 1 , Kringle 2, Kringle 3, Kringle 4 and serine protease domains). Fragments of HGF constitute HGF with fewer domains and variants of HGF may have some of the domains of HGF repeated; both are included if they still retain their respective ability to bind a HGF receptor.
  • the terms "hepatocyte growth factor” and “HGF” include hepatocyte growth factor from humans (“huHGF”) and any non-human mammalian species, and in particular rat HGF.
  • Human HGF is encoded by the cDNA sequence published by Miyazawa et al. (1989), supra, or Nakamura et al. (1989), supra.
  • the sequences reported by Miyazawa et al. and Nakamura et al. differ in 14 amino acids. The reason for the differences is not entirely clear; polymorphism or cloning artifacts are among the possibilities. Both sequences are specifically encompassed by the foregoing terms.
  • hepatocyte growth factor and "HGF” specifically include the delta 5 huHGF as disclosed by Seki et al., supra.
  • HGF receptor and "c-Met” when used herein refer to a cellular receptor for HGF, which typically includes an extracellular domain, a transmembrane domain and an intracellular domain, as well as variants and fragments thereof which retain the ability to bind HGF.
  • HGF receptor and "c-Met” include the polypeptide molecule that comprises the full-length, native amino acid sequence encoded by the gene variously known as pl90.sup.MET. The present definition specifically encompasses soluble forms of HGF receptor, and HGF receptor from natural sources, synthetically produced in vitro or obtained by genetic manipulation including methods of recombinant DNA technology.
  • the HGF receptor variants or fragments preferably share at least about 65% sequence homology, and more preferably at least about 75% sequence homology with any domain of the human c-Met amino acid sequence published in Rodrigues et al., MoI. Cell. Biol., 11 :2962-2970 (1991); Park et al., Proc. Natl. Acad. Sci., 84:6379-6383 (1987); or Ponzetto et al., Oncogene, 6:553- 559 (1991).
  • agonist and “agonistic” when used herein refer to or describe a molecule which is capable of, directly or indirectly, substantially inducing, promoting or enhancing HGF biological activity or HGF receptor activation.
  • cancer refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • examples of cancer include but are not limited to, carcinoma, lymphoma, sarcoma, blastoma and leukemia. More particular examples of such cancers include squamous cell carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer. While the term “cancer” as used herein is not limited to any one specific form of the disease, it is believed that the methods of the invention will be particularly effective for cancers which are found to be accompanied by increased levels of HGF or expression of c-Met in the mammal.
  • treating refers to curative therapy, prophylactic therapy, and preventative therapy.
  • mammal refers to any mammal classified as a mammal, including humans, cows, horses, dogs and cats. In a preferred embodiment of the invention, the mammal is a human.
  • nucleic acid ligands Given that elevated levels of c-Met and HGF are observed in hypertension, arteriosclerosis, myocardial infarction, and rheumatoid arthritis, nucleic acid ligands will serve as useful therapeutic agents for these diseases.
  • treatment includes therapeutic treatment as well as prophylactic treatment (either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals).
  • a “pharmaceutically-acceptable derivative” denotes any salt, ester of a compound of this invention, or any other compound which upon administration to a patient is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to inhibit angiogenesis.
  • neoplastic therapeutic agents prolong the survivability of the patient, inhibit the rapidly proliferating cell growth associated with the neoplasm, or effect a regression of the neoplasm.
  • H denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
  • alkyl is used, either alone or within other terms such as “haloalkyl” and “alkylamino", it embraces linear or branched radicals having one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, /er/-butyl, pentyl, isoamyl, hexyl and the like. Even more preferred are lower alkyl radicals having one or two carbon atoms.
  • alkylenyl embraces bridging divalent alkyl radicals such as methylenyl and ethylenyl.
  • the term "lower alkyl substituted with R 2 " does not include an acetal moiety.
  • alkenyl embraces linear or branched radicals having at least one carbon- carbon double bond of two to about twelve carbon atoms. More preferred alkenyl radicals are “lower alkenyl” radicals having two to about six carbon atoms. Most preferred lower alkenyl radicals are radicals having two to about four carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkenyl and “lower alkenyl” embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • alkynyl denotes linear or branched radicals having at least one carbon- carbon triple bond and having two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl” radicals having two to about six carbon atoms. Most preferred are lower alkynyl radicals having two to about four carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.
  • Alkyl, alkylenyl, alkenyl, and alkynyl radicals may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclo and the like.
  • halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals including perhaloalkyl.
  • a monohaloalkyl radical for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • “Lower haloalkyl” embraces radicals having 1-6 carbon atoms.
  • haloalkyl radicals having one to three carbon atoms.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Perfluoroalkyl means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
  • hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having one to three carbon atoms.
  • alkoxy embraces linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms.
  • More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a fused manner.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is phenyl.
  • Said "aryl” group may have 1 or more substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino, and the like. Phenyl substituted with -0-CH 2 -O- forms the aryl benzodioxolyl substituent.
  • heterocyclyl (or “heterocyclo”) embraces saturated, and partially saturated and heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. It does not include rings containing -O-O-.-O-S- or -S-S- portions.
  • Said “heterocyclyl” group may have 1 to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino, lower alkylamino, and the like.
  • saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6- membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl].
  • partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl, dihydrothiazolyl, and the like.
  • Particular examples of partially saturated and saturated heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2- dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4 ,4a,9,9a- hexahydro-1 H-3-aza-fluorenyl, 5,6,7-trihydro-l,2,4-triazolo[3,4-a]isoquinolyl
  • heterocyclyl also embraces radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5- b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
  • benzoxazolyl, benzoxadiazolyl unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms
  • benzothiazolyl, benzothiadiazolyl unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms
  • saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[l,4]dioxinyl and dihydrobenzofuryl].
  • heteroaryl denotes aryl ring systems that contain one or more heteroatoms selected from the group O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized.
  • Examples include unsaturated S to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl]; unsaturated 5- to 6- membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1
  • sulfonyl whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO 2 -.
  • sulfamyl denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-SO 2 NH 2 ).
  • alkylaminosulfonyl includes "N-alkylaminosulfonyl” where sulfamyl radicals are independently substituted with one or two alkyl radical(s). More preferred alkylaminosulfonyl radicals are “lower alkylaminosulfonyl” radicals having one to six carbon atoms. Even more preferred are lower alkylaminosulfonyl radicals having one to three carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl, and N-ethylaminosulfonyl.
  • N-alkylaminocarbonyl and N,N-dialkylaminocarbonyl denote aminocarbonyl radicals independently substituted with one or two alkyl radicals, respectively. More preferred are “lower alkylaminocarbonyl” having lower alkyl radicals as described above attached to an aminocarbonyl radical.
  • N-arylaminocarbonyl and "N-alkyl-N-arylaminocarbonyl” denote aminocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical.
  • heterocyclylalkylenyl and “heterocyclylalkyl” embrace heterocyclic- substituted alkyl radicals. More preferred heterocyclylalkyl radicals are "5- or 6-membered heteroarylalkyl” radicals having alkyl portions of one to six carbon atoms and a 5- or 6- membered heteroaryl radical. Even more preferred are lower heteroarylalkyl enyl radicals having alkyl portions of one to three carbon atoms. Examples include such radicals as pyridylmethyl and thienylmethyl.
  • aralkyl embraces aryl-substituted alkyl radicals.
  • Preferable aralkyl radicals are "lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are “phenylalkylenyl” attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl.
  • the aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower alkylthio radicals having one to three carbon atoms.
  • An example of “alkylthio” is methylthio, (CH 3 S-).
  • haloalkylthio embraces radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower haloalkylthio radicals having one to three carbon atoms. An example of “haloalkylthio” is trifluor ⁇ methylthio.
  • alkylamino embraces "N-alkylamino” and “N,N-dialkylamino" where amino groups are independently substituted with one alkyl radical and with two alkyl radicals, respectively.
  • alkylamino radicals are "lower alkylamino" radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N- dimethylamino, N,N-diethylamino and the like.
  • arylamino denotes amino groups, which have been substituted with one or two aryl radicals, such as N-phenylamino.
  • the arylamino radicals may be further substituted on the aryl ring portion of the radical.
  • heteroarylamino denotes amino groups, which have been substituted with one or two heteroaryl radicals, such as N-thienylamino.
  • heteroarylamino radicals may be further substituted on the heteroaryl ring portion of the radical.
  • aralkylamino denotes amino groups, which have been substituted with one or two aralkyl radicals. More preferred are phenyl-Ci-C 3 -alkylamino radicals, such as N- benzylamino. The aralkylamino radicals may be further substituted on the aryl ring portion.
  • N-alkyl-N-arylamino and “N-aralkyl-N-alkylamino” denote amino groups, which have been independently substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively, to an amino group.
  • aminoalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl” radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferred are lower aminoalkyl radicals having one to three carbon atoms.
  • alkylaminoalkyl embraces alkyl radicals substituted with alkylamino radicals. More preferred alkylaminoalkyl radicals are "lower alkylaminoalkyl” radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl radicals may be mono or dialkyl substituted, such as N-methylaminomethyl, N.N-dimethyl-aminoethyl, N,N-diethylaminomethyl and the like.
  • alkylaminoalkoxy embraces alkoxy radicals substituted with alkylamino radicals. More preferred alkylaminoalkoxy radicals are "lower alkylaminoalkoxy” radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxy radicals may be mono or dialkyl substituted, such as N-methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy and the like.
  • alkylaminoalkoxyalkoxy embraces alkoxy radicals substituted with alkylaminoalkoxy radicals. More preferred alkylaminoalkoxyalkoxy radicals are "lower alkylaminoalkoxyalkoxy" radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxyalkoxy radicals having alkyl radicals of one to three carbon atoms.
  • Suitable alkylaminoalkoxyalkoxy radicals may be mono or dialkyl substituted, such as N-methylaminomethoxyethoxy, N-methylaminoethoxyethoxy, N 5 N- dimethylaminoethoxyethoxy, N,N-diethylaminomethoxymethoxy and the like.
  • carboxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more carboxy radicals. More preferred carboxyalkyl radicals are "lower carboxyalkyl” radicals having one to six carbon atoms and one carboxy radical. Examples of such radicals include carboxymethyl, carboxypropyl, and the like. Even more preferred are lower carboxyalkyl radicals having one to three CH 2 groups.
  • halosulfonyl embraces sulfonyl radicals substituted with a halogen radical. Examples of such halosulfonyl radicals include chlorosulfonyl and fluorosulfonyl.
  • arylthio embraces aryl radicals of six to ten carbon atoms, attached to a divalent sulfur atom.
  • An example of “arylthio” is phenylthio.
  • aralkylthio embraces aralkyl radicals as described above, attached to a divalent sulfur atom. More preferred are phenyl-C
  • aryloxy embraces optionally substituted aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy.
  • aralkoxy embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy” radicals having optionally substituted phenyl radicals attached to lower alkoxy radical as described above.
  • heteroaryloxy embraces optionally substituted heteroaryl radicals, as defined above, attached to an oxygen atom.
  • heteroarylalkoxy embraces oxy-containing heteroarylalkyl radicals attached through an oxygen atom to other radicals. More preferred heteroarylalkoxy radicals are "lower heteroarylalkoxy” radicals having optionally substituted heteroaryl radicals attached to lower alkoxy radical as described above.
  • cycloalkyl includes saturated carbocyclic groups.
  • Preferred cycloalkyl groups include C 3 -C 6 rings. More preferred compounds include, cyclopentyl, cyclopropyl, and cyclohexyl.
  • cycloalkylalkyl embraces cycloalkyl-substituted alkyl radicals.
  • Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl” radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are “5-6- membered cycloalkylalkyl” attached to alkyl portions having one to three carbon atoms. Examples of such radicals include cyclohexylmethyl.
  • the cycloalkyl in said radicals may be additionally substituted with halo, alkyl, alkoxy and hydroxy.
  • cycloalkenyl includes carbocyclic groups having one or more carbon- carbon double bonds including “cycloalkyldienyl” compounds.
  • Preferred cycloalkenyl groups include C 3 -C 6 rings. More preferred compounds include, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl.
  • the compounds of the invention are endowed with c-Met inhibitory activity.
  • the present invention also comprises the use of a compound of the invention, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment either acutely or chronically of an angiogenesis mediated disease state, including those described previously.
  • the compounds of the present invention are useful in the manufacture of an anti-cancer medicament.
  • the compounds of the present invention are also useful in the manufacture of a medicament to attenuate or prevent disorders through inhibition of c-Met.
  • the present invention comprises a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the current invention in association with a least one pharmaceutically acceptable carrier, adjuvant or diluent.
  • the present invention also comprises a method of treating angiogenesis related disorders in a subject having or susceptible to such disorder, the method comprising treating the subject with a therapeutically effective amount of a compound of the current invention.
  • the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents.
  • the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition.
  • co-therapy in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.
  • the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of neoplasia, such as with radiation therapy or with cytostatic or cytotoxic agents.
  • Such combination products employ the compounds of this invention within the accepted dosage ranges.
  • Compounds of the current invention may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate.
  • the invention is not limited in the sequence of administration; compounds of the invention may be administered either prior to, simultaneous with or after administration of the known anticancer or cytotoxic agent.
  • the typical chemotherapy regime consists of either DNA alkylating agents, DNA intercalating agents, CDK inhibitors, or microtubule poisons.
  • the chemotherapy doses used are just below the maximal tolerated dose and therefore dose limiting toxicities typically include, nausea, vomiting, diarrhea, hair loss, neutropenia and the like.
  • antineoplastic agents there are large numbers of antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which would be selected for treatment of neoplasia by combination drug chemotherapy. Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and a category of miscellaneous agents.
  • a first family of antineoplastic agents which may be used in combination with compounds of the present invention, consists of antimetabolite-type/thymidilate synthase inhibitor antineoplastic agents.
  • Suitable antimetabolite antineoplastic agents may be selected from but not limited to the group consisting of 5-FU-f ⁇ brinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co.
  • EX-Ol 5 isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC- 127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, Taiho UFT and uricytin.
  • a second family of antineoplastic agents which may be used in combination with compounds of the present invention, consists of alkylating-type antineoplastic agents.
  • Suitable alkylating-type antineoplastic agents may be selected from but not limited to the group consisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA- 102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA- 2114R,
  • a third family of antineoplastic agents which may be used in combination with compounds of the present invention consists of antibiotic-type antineoplastic agents.
  • Suitable antibiotic-type antineoplastic agents may be selected from but not limited to the group consisting of Taiho 4181 -A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY- 25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin, chrom
  • a fourth family of antineoplastic agents which may be used in combination with compounds of the present invention consists of a miscellaneous family of antineoplastic agents, including tubulin interacting agents, topoisomerase II inhibitors, topoisomerase I inhibitors and hormonal agents, selected from but not limited to the group consisting of ⁇ - carotene, ⁇ -difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonaf ⁇ de, amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston AlO, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen- Beaufour BIM-23015, bisant
  • the present compounds may also be used in co-therapies with other antineoplastic agents, such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, dox
  • the present compounds may also be used in co-therapies with VEGFR inhibitors including
  • the combination comprises a composition of the present invention in combination with at least one anti-angiogenic agent.
  • Agents are inclusive of, but not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof.
  • An agent can be an agonist, antagonist, allosteric modulator, toxin or, more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or arrest cell growth.
  • anti-tumor agents include HERCEPTINTM (trastuzumab), which may be used to treat breast cancer and other forms of cancer, and RITUXANTM (rituximab), ZEVALINTM (ibritumomab tiuxetan), and LYMPHOCIDETM (epratuzumab), which may be used to treat non-Hodgkin's lymphoma and other forms of cancer, GLEEV ACTM which may be used to treat chronic myeloid leukemia and gastrointestinal stromal tumors, and BEXXARTM (iodine 131 tositumomab) which may be used for treatment of non-Hodgkins's lymphoma.
  • anti-angiogenic agents include ERBITUXTM (IMC-C225), KDR (kinase domain receptor) inhibitory agents (e.g., antibodies and antigen binding regions that specifically bind to the kinase domain receptor), anti-VEGF agents (e.g., antibodies or antigen binding regions that specifically bind VEGF, or soluble VEGF receptors or a ligand binding region thereof) such as AVASTINTM or VEGF-TRAPTM, and anti-VEGF receptor agents (e.g., antibodies or antigen binding regions that specifically bind thereto), EGFR inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto) such as ABX-EGF (panitumumab), IRESS ATM (gefitinib), TARCE V ATM (erlotinib), anti-Angl and anti-Ang2 agents (e.g., antibodies or antigen binding regions specifically binding thereto or to their receptors, e.g., Tie2/Tek), and anti-
  • compositions of the present invention can also include one or more agents (e.g., antibodies, antigen binding regions, or soluble receptors) that specifically bind and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as Scatter Factor), and antibodies or antigen binding regions that specifically bind its receptor "c-met".
  • agents e.g., antibodies, antigen binding regions, or soluble receptors
  • HGF hepatocyte growth factor
  • c-met antibodies or antigen binding regions that specifically bind its receptor "c-met”.
  • anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (Ceretti et al., US Publication No. 2003/0162712; US Patent No. 6,413,932), anti-TWEAK agents (e.g., specifically binding antibodies or antigen binding regions, or soluble TWEAK receptor antagonists; see, Wiley, US Patent No. 6,727,225), ADAM distintegrin domain to antagonize the binding of integrin to its ligands (Fanslow et al., US Publication No. 2002/0042368), specifically binding anti-eph receptor and/or anti-ephrin antibodies or antigen binding regions (US Patent Nos.
  • anti-PDGF-BB antagonists e.g., specifically binding antibodies or antigen binding regions
  • antibodies or antigen binding regions specifically binding to PDGF-BB ligands
  • PDGFR kinase inhibitory agents e.g., antibodies or antigen binding regions that specifically bind thereto
  • Additional anti-angiogenic/anti-tumor agents include: SD-7784 (Pfizer, USA); cilengitide.(Merck KGaA, Germany, EPO 770622); pegaptanib octasodium, (Gilead Sciences, USA); Alphastatin, (BioActa, UK); M-PGA, (Celgene, USA, US 5712291); ilomastat, (Arriva, USA, US 58921 12); emaxanib, (Pfizer, USA, US 5792783); vatalanib, (Novartis, Switzerland); 2-methoxyestradiol, (EntreMed, USA); TLC ELL- 12, (Elan, Ireland); anecortave acetate, (Alcon, USA); alpha-D148 Mab, (Amgen, USA); CEP-7055,(Cephalon, USA); anti- Vn Mab, (Crucell, Netherlands) DACrantiangiogenic, (ConjuChem
  • the present compounds may also be used in co-therapies with other antineoplastic agents, such as VEGF antagonists, other kinase inhibitors including p38 inhibitors, KDR inhibitors, EGF inhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP), COX-2 inhibitors including celecoxib, NSAID' s, or ⁇ v ⁇ 3 inhibitors.
  • VEGF antagonists such as VEGF antagonists, other kinase inhibitors including p38 inhibitors, KDR inhibitors, EGF inhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP), COX-2 inhibitors including celecoxib, NSAID' s, or ⁇ v ⁇ 3 inhibitors.
  • the present invention comprises processes for the preparation of a compound of Formula I, II, III, IV, V, VI and VII.
  • pharmaceutically acceptable salts and solvates thereof are also included in the family of compounds of the current.
  • pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable.
  • Suitable pharmaceutically acceptable acid addition salts of compounds of the current invention may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,
  • Suitable pharmaceutically-acceptable base addition salts of compounds of the current invention include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine.
  • metallic salts such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc
  • organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine
  • All of these salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of the current invention.
  • a compound of the current invention may also form internal salts.
  • the compounds of the invention can be synthesized according to the following procedures.
  • HBTA 0-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HATU O-CT-azabenzotriazoM-yO-N ⁇ N'.N'-tetramethyluroniurn hexafluorophosphate
  • PyBop benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium hexafluorophosphate
  • N'-(6-chloroDyridazin-3-ylV2-(7-methoxyquinolin-4-yloxy)aeetohvdrazide A mixture of l-(6-chloropyridazin-3-yl)hydrazine (0.372 g, 2.57 mmol), l-hydroxy-7-aza- benzotriazole (0.350 g, 2.57 mmol), EDC (0.641 g, 3.34 mmol), 2-(7-methoxyquinolin-4- yloxy)acetic acid (0.600 g, 2.57 mmol) and diisopropylethylamine (1.34 ml, 7.72 mmol) in DMF (20 mL) was allowed to stir at 50 0 C for 2h.
  • N'-(6-chloropyridazin-3-yl)-2-(7-methoxyquinolin-4-yloxy)acetohydrazide (2.53 g, 7.0 mmol) was suspended in tetrahydrofuran (50 mL) then added triphenylphosphine (2.8 g, 11 mmol) and trimethylsilyl azide (1.4 ml, 11 mmol). To this suspension, was added diethylazodicarboxylate (2.0 ml, 13 mmol) in rapid drops with a syringe.
  • the reaction mixture was heated at 50 0 C for 30 minutes.
  • the reaction mixture was concentrated in vacuo.
  • the remaining oil was triturated with diethyl ether.
  • a gel-like solid formed which was collected on a glass frit, washing with diethyl ether.
  • the solid was then triturated with ethyl acetate, and finally acetonitrile.
  • An amorphous solid formed which was collected on a glass frit, washing with acetonitrile.
  • the solid was further dried under high vacuum.
  • the ethyl acetate filtrate was concentrated in vacuo.
  • the remaining oil was then triturated with acetonitrile.
  • Step 1 4- ( (6-phenyl-[1,2,4] triazolo [4,3-b] pyridazin-3-yl)methoxy)pyridin-2- amine.
  • Butyllithium (1.6M in hexanes, 18.9 ml, 30.3 mmol) was added to a stirred solution of 3- ⁇ nethylisothiazole (2.73 g, 27.5 mmol) in THF (80 mL) at -78°C.
  • the reaction mixture was stirred at - 78°C for 30 min and chlorotrimethylstannane (IM in THF, 27.5 ml, 27.5 mmol) was added dropwise. After Ih at -78°C for Ih, the reaction mixture was quenched with a saturated aqueous solution of NaHCO 3 . The water layer was extracted with Et 2 ⁇ .
  • a pressure vessel was purged with Ar and charged with tert- butyl (6-chloro- [1,2,4] triazolo [4 , 3-b] pyridazin-3- yl) methylcarbamate (5.00 g, 17.6 mraol) , tris (dibenzylideneacetone) dipalladium (0) (0.807 g, 0.881 mmol) , 2-dicyclohexylphosphinobiphenyl (0.618 g, 1.76 mmol) .
  • DMF 50 mL
  • 3-methyl-5- (trimethylstannyl) isothiazole (6.46 g, 24.7 mmol).
  • Trifluoroacetic acid (2889 ⁇ l, 37505 ⁇ mol) was added to a stirred suspension of tert-butyl (6- (3-methylisothiazol-5-yl) -
  • Ethyl 3- (7-meth ⁇ 3cyquinolin-4-yl)propanoate 4-chloro-7-methoxyquinoline (0.35 g, 2 mmol) , tri-t- butylphosphonium tetrafluoroborate (0.05 g, 0.2 mmol), and tris (dibenzylideneacetone)dipalladium (0) (0.08 g, 0.09 mmol) were combined.
  • the reaction vessel was purged and flushed with nitrogen three times, followed by addition of 3-ethoxy-3- oxopropylzinc bromide in THF (10 mL, 5 mmol, 0.5 M). The reaction mixture was microwaved at 150 0 C for 60 minutes.
  • Example 18 7-meth ⁇ 3cy-4- ( (6- (1-methyl-IH-I, 2, 3-triazol-4-yl) - [1,2,4] triazolo [4, 3-a] pyridin-3-yl)methoxy) quinoline. Step 1.
  • Tri-t-butylphosphonium tetrafluoroborate (0.0377 g, 0.130 mmol) , tris (dibenzylideneacetone) dipalladium (0.0594 g, 0.0649 mmol) , trimethylsilyl acetylene (1.82 ml, 13.0 mmol), 4-((6- bromo- [1,2,4] triazolo [4, 3-a]pyridin-3-yl)methoxy) -7- methoxyquinoline (0.500 g, 1.30 mmol) were taken up in dioxane (10 mL) and triethylamine (3 mL) . Added CuI.
  • a sealable tube was charged with PdCl 2 (dppf) -CH 2 Cl 2 Adduct (0.064 g, 0.078 mmol), N- ( (6-bromo- [1, 2, 4] triazolo [4 , 3-a] pyridin-3- yDmethyl) -7-methoxy-l, 5-naphthyridin-4 -amine (0.120 g, 0.31 mmol), 3-chloro-4-fluorophenylboronic acid (0.057 g, 0.33 mmol), sat NaHCO 3 (0.75 ml, >0.69 mmol) and dioxane (2 mL) .
  • the vessel was sealed and the mixture heated at 80 for 2.5 h.
  • Example 25 N- ( (6- (3 -Fluorophenyl) - [1,2,4] triazolo [4, 3-a] pyridin-3- yDmethyl) -7-methoxy-l, 5-naphthyridin-4-amine .
  • M/Z 401.2 [M+H] , calC 401.4153 for C 22 H 17 FN 6 O.
  • tert-butyl (6- (2- (triethylailyl) ethynyl) - [1, 2 , 4] triazolo [4, 3- b] pyridazin-3-yl)methylcarba ⁇ tate : A IL-round-bottomed flask flushed with argon was charged with tert-butyl (6-chloro-
  • tert-butyl (6-ethynyl- [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) methylcarbamate Potassium fluoride (2M in water, 27.6 ml, 55.3 mmol) was added to a stirred suspension of tert-butyl6- (2- (triethylsilyl)ethynyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) methylcarbamate (3.57 g, 9.21 mmol) in acetonitrile (56 mL) at room temperature. The reaction mixture turned dark immediately, and was stirred at room temp for twenty minutes until complete.
  • tert-butyl (6- (3-methyliBoxazol-5-yl) - [1, 2, 4] triazolo [4, 3- b] pyridazin-3-yl) methylcarbamate : To a solution of nitroethane (1.02 ml, 14.3 mmol) in benzene (50 mL) was added phenyl isocyanate (3.12 ml, 28.5 mmol) .
  • the compound was dissolved partially in DCM/MeOH, however, fully dissolved after addition of hot DMSO.
  • the compound was purified via flash chromatograph, eluting with 0-10% MeOH/NH 4 OH in DCM.
  • the compound was sonicated in DCM and filtered to remove the triethylamine-hydrochloride salt, and yielded 6- (3- ( (7-methoxyquinolin-4-yloxy) ⁇ nethyl) - [1,2,4] triazolo [4,3- a] pyridin-6-yl)pyridin-2 (IH) -one.
  • the filtrate was concentrated and triturated with EtOAc/DCM.
  • the solid was dissolved in a small amount of hot MeOH and DCM and purified by chromatography using a 40 g ISCO column, eluting with a gradient of 1-7% MeOH (with 10% NH 4 OH) /DCM over 40 minutes.
  • a 16 mm test tube was charged with 4- ( (6-bromoH-imidazo [1, 2- a] pyridin-3-yl) methoxy) -7-methoxyquinoline (0.0607 g, 0.16 mmol), phenylboronic acid (0.039 g, 0.32 mmol), SPhos (0.0065 g, 0.016 mmol), Potassium phosphate (0.10 g, 0.47 mmol), Pd2 (dba) 3 (0.0036 g, 0.0039 mmol), and 1-butanol (0.014 ml, 0.16 mmol), then stirred at 100 0 C for 16 hours.
  • the reaction mixture was diluted with chloroform (15 mL) and washed with water (15 mL) , sat. aq. NaHCO 3 (15 mL) , and brine (15 mL) ; the organic layer was dried with MgSO 4 , filtered, and concentrated. This was purified using the prep HPLC machine using a gradient of 10% MeCN/water to 95% MeCN/water over 20 min. The fractions were combined and the product free based by diluting with 10% MeOH/HCCl 3 (30 tnL) and washing with sat. aq. NaHCO 3 (30 mL) .
  • the mixture was diluted with DCM (60 mL) , resulting in an emulsion.
  • the emulsion was filtered to give a brown solid..
  • the solid was triturated with a combination of DCM/MeOH/MeCN and filtered to give 7-methoxy-4- ( (6- (6- (piperazin-1- yl)pyridin-3-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) methoxy) quinoline .
  • the solid was collected and purified by MPLC using a 40 g RediSep column, eluting with a gradient of 3 - 6% MeOH/DCM over 40 minutes.
  • the solid was triturated with MeCN and filtered; the mother liquor was concentrated to give tert-butyl 3- (5- (3- ( (7-methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6-yl) pyridin- ⁇ - ylamino) pyrrolidine-1-carboxylate .
  • Example 50 4- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) -2-methylbut-3-yn-2-ol.
  • the reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL) , sat. NaHCO 3 (100 mL) , and brine (100 mL) , dried with MgSO 4 , filtered, and concentrated. This was purified by MPLC uisng a 40 g RediSep column, eluting with 1-5% MeOH/DCM over 40 minutes. The fractions were concentrated to give 1- (2- fluoro-4- (4,4,5, 5-tetramethyl-l, 3 , 2-dioxaborolan-2- yl) phenyl) pyrrolidin-2-one, -85% pure, as an orange oil that solidified upon standing.
  • a 500 mL RB flask was charged with aluminum (III) chloride (4.1 g, 31 mmol) and 10 mL of 1, 2-dichloroethane (90 ml, 1142 mmol) , then cooled to 0 0 C.
  • a separate 250 mL flask was charged with 90 mL of 1, 2-dichloroethane (90 ml, 1142 mmol) and cooled to 0 0 C; methylamine (gas) (1.8 g, 59 mmol) was bubbled through the solution for 10 minutes.
  • the dichloroethane solution was slowly poured into the aluminum chloride solution, resulting in the formation of a thick white slush. This was warmed to room temperature.
  • the tube was placed in a 150°C oil bath for 1 hour. The mixture was then diluted with EtOAc (100 mL) , then washed with IM aqueous HCl . The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and then the combined organics were washed with water (100 mL) and brine (100 mL) , dried with MgSO 4 , filtered, then concentrated to give a yellow oil . This was purified by column chromatography, eluting with 1 - 4% MeOH/DCM to give 5-bromo-2-methylisoindolin-l-one (1.774 g, 57.3% yield) as a yellow solid.
  • reaction mixture was concentrated to give a thick brown oil, which was purified by column chromatography using an 80 g ISCO column, eluting with a gradient of 5% MeOH (containing NH 4 OH) /DCM to 10% MeOH (containing NH 4 OH) /DCM over 40 minutes.
  • 6 -phenyl- [1, 2,4] triazolo [4, 3-b] [1, 2, 4] triazin-3-yl) methanamine was isolated as a yellow solid.
  • a sealable tube was charged with Pd 2 dba 3 (0.20 g, 0.22 mmol), racemic-2- (di-t-butylphosphino) -1, 1 ' -binaphthyl (0.18 g, 0.44 tnmol) , (6-phenyl- [1, 2 , 4] triazolo [4 , 3 -b] pyridazin-3-yl) methanol ( 0.100 g, 0.44 mmol), 4-chloro-3-fluoro-7-methoxyquinoline ( 0.14 g, 0.66 mmol), cesium carbonate (0.29 g, 0.88 mmol), and toluene and sealed. The mixture was heated at 100 C for 12 h.
  • N-2-Phenyl-N-4- (6-phenyl-[1,2,4] triazolo [4,3-b] pyridazin-3- yl) methyl) pyrimidine-2,4 -diamine hydrochloride .
  • 6- (4,4,5, 5-tetramethyl-l, 3 , 2-dioxaborolan-2- yl) benzo [d] thiazole .
  • 6-bro ⁇ nobenzo [d] thiazole according to the above procedures .
  • l-Cyclobutyl-4- (4,4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) - lH-pyrazole
  • l-Iaopropyl-4- (4,4, 5, 5-tetramethyl-l, 3 , 2-dioxaborolan-2-yl) -IH- pyrazole
  • a sealable vessel was charged with potassium carbonate (3.76 g, 27.2 mmol), 4-bromo- lH-pyrazole (4.00 g, 27.2 mmol), and 10 mL DMF.
  • 2-iodopropane (3.27 ml, 32.7 mmol) was added and the vessel sealed. The mixture was heated at 80 C for 16 h and allowed to cool to rt .
  • Step 1 6-Dichloro-4-methylpyridazine (1.00 g, 6.1 mmol) was mostly dissolved in dioxane (22.5 mL) then added phenylboronic acid (0.82 g, 6.7 mmol), PdCl 2 (dppf) -CH 2 Cl 2 Adduct (0.25 g, 0.31 mmol) and a solution of cesium carbonate (6.0 g, 18 mmol) in water (7.5 mL) . The reaction mixture was heated at 80 0 C for 6 hours. The reaction mixture was concentrated under vacuum and the remaining solid was triturated with water. The solid was collected on a glass frit, washing well with water.
  • Step 1 5-Bromopyridin-2 (IH) -one (0.250 g, 1.44 mmol) was dissolved in DMF (3 mL) then added iodomethane (0.0943 ml, 1,51 mmol) and potassium carbonate (0.218 g, 1.58 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The remaining residue was dissolved in ethyl acetate then washed with water and brine. The aqueous layer was back-extracted with ethyl acetate (3x) .
  • Example 75 To a solution of 5- ( 3- ( (7-methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo[4,3-a]pyridin-6-yl) thiophene-2-carbonyl chloride (0.150 g, 0.33 mmol) and Hunig • s Base (0.17 ml, 1.00 mmol) in DCM (2.5 mL) was added methanamine (0.17 ml, 0.33 mmol) in THF dropwise. The solution was stirred at room temperature for 3 hours, at which point an additional 1.5 equivalents of amine were added.
  • Methyl 2- (quinolin-6-yl) propanoate To a 250 ml round-bottomed flask was added lithium bis (trimethylsilyl) amide (2.0 g, 12 mmol) and tetrahydrofuran (75 ml) . The mixture was cooled to - 78 0 C and methyl 2- (quinolin-6-yl) acetate (2.O g, 9.9 mmol) was added as a solution in 1 ml THF. This was stirred at -78 0 C for 30 min and then methyl iodide (0.75 ml, 12 mmol) was added. This was stirred for 30 min at -78 0 C and then allowed to warm to rt.
  • Example 78 (S) -6- (1- (6-phenyl- [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) ethyl) quinoline . Isolated from chiral separation of 6- (1- (6-phenyl- [1,2,4] triazolo [4 , 3-b] pyridazin-3-yl) ethyl) quinoline. Column: Chiralpak AS-H (250 x 21 mm) . Mobile Phase: A: Liquid CO 2 . B: Methanol (0.1% DEA). Isocratic: 75:25 (A:B) . Flow rate: 70.0 mL/min. Outlet Pressure: 100 bar. Retention time: 4.38 min. Enantiomeric purity: >99% ee . MS (ESI, pos . ion) m/z: 352 (M+l) .
  • Methyl 2-£luoro-2- (quinolin-6-yl) acetate To a 250 ml round- bottomed flask was added lithium bis (trimethylsilyl) amide (2.0 g, 12 mmol) and tetrahydrofuran (75 ml) . The mixture was cooled to -78 0 C and methyl 2- (quinolin-6-yl) acetate (2.0 g, 9.9 mmol) was added as a solution in 1 ml THF. After stirring at -78 0 C for 30 min, n-fluorobenzenesulfonimide (3.8 g, 12 ⁇ wnol) was added as a 1 M solution in THF.
  • Step Ii 4-amino-3-bromo-2-chloropyridine .
  • 4 -amino-2- chloropyridine 50 g, 388 mmol was dissolved in glacial acetic acid (500 tnL) .
  • N-bromosuccinamide 75 g, 426 mmol,
  • the reaction mixture was stirred at RT for 1 h at which point the reaction was found complete (as monitored by TLC) .
  • Solvent was removed under reduced pressure followed by azeotropic distillation with ethanol.
  • the crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.
  • Step 2 4-amino-3-bromo-2- ⁇ iethoxypyridine.
  • Methanol 350 mL was charged in a two-neck round bottom flask equipped with a guard tube and septum and cooled to 0 0 C.
  • Sodium metal 23 g was added to it slowly in pieces. After all sodium metal had dissolved, 4-amino-3-bromo-2-chloro pyridine (23 g, 178 mmol) was added and the solution was heated at 180 0 C in a pressure vessel for 5-6 h. The reaction mixture was then cooled to 0 0 C and adjusted to pH 8 by addition of cone. HCl.
  • Step 3 5- [ (3-Bromo-2-methoxy-pyridin-4-ylamino) -methylene] - 2, 2-dimethyl- [1, 3] dioxane-4, 6-dione.
  • a two necked round bottomed flask equipped with a reflux condenser was charged with Meldrum's acid (15.6 g, 108 mmol) and trimethyl orthoformate (143 mL) .
  • the reaction mixture was heated 100 0 C for 2 h.
  • Step 4 8-Bromo-7-meth ⁇ 3cy-lH- [1, 6] naphthyridin-4-one.
  • a two neck round bottomed flask equipped with an air condenser was charged with 5- [ (3-Bromo-2-methoxy-pyridin-4-ylamino) - methylene] -2, 2-dimethyl- [1, 3] dioxane-4, 6-dione (23g, 64 mmol) and diphenyl ether (230 mL) .
  • the reaction mixture was heated at 250 0 C for 30 min under nitrogen atmosphere after which it was cooled to RT, diluted with hexane and filtered to obtain a dark solid.
  • the crude product was refluxed in hexane for 30 min and filtered to obtained 8-Bromo-7-methoxy-lH- [1, 6] naphthyridin-4- one as a brown solid.
  • Step 5 7-Methoxy-lH- [1, 6] naphthyridin-4-one.
  • 8-Bromo-7- methoxy-lH- [1, 6] naphthyridin-4-one (12 g, 33.5 mmol) was dissolved in anhydrous methanol (240 mL) and 10 % Dry Pd/C (2.4 g) was added carefully in portions. This was followed by portionwise addition of ammonium formate (24 g) which caused an exotherm.
  • the reaction mixture was heated to reflux for 1 h.
  • the reaction mixture was cooled to room temperature, filtered through Celite, and washed with hot methanol.
  • Step 6 4-Chloro-7-methoxy- [l, 6]naphthyridine.
  • a two neck round bottomed flask equipped with CaCl 2 guard tube was charged with 7-Methoxy-lH- [1, 6] naphthyridin-4-one (28 g, 159 mmol) and POCl 3 (280 mL) .
  • the reaction mixture was stirred at RT for 3 h.
  • the reaction mixture was poured into ice water and the pH was carefully adjusted to 8 with solid sodium carbonate (highly exothermic reaction) .
  • the product was extracted with EtOAc .
  • the combined organic layer was washed with water, dried over Na 2 SO 4 and concentrated.
  • the crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture .
  • Step 2 It 3-Bromo-5-methoxypyridine.
  • Sodium (12 g) was dissolved in methanol (150 mL) while cooling, and excess MeOH was removed under reduced pressure to obtain NaOMe, which was azeotroped with toluene (2 x 100 mL) .
  • a solution of 3,5- dibromopyridine (100 g) in DMSO (500 mL) was added to sodium methoxide and the mixture was stirred at 90 0 C for 2 h.
  • aqueous NaOH solution (3 M, 300 mL) was added and the mixture was extracted with Et 2 O.
  • the ethereal layer was washed with brine and dried over Na 2 SO 4 .
  • concentration the crude product obtained was purified by flash column chromatography (Hexane: EtOAc 85:15) to afford pure product 3- bromo-5-methoxy pyidine .
  • Step 2 3-amino-5-methoxypyridine.
  • 3-Bromo-5-methoxypyridine ) (15 g) was added to a pressure vessel, and CuSO 4 (3.9 g) and 251 aq. ammonia (150 mL) were added.
  • the reaction mixture was stirred for 4 h at 135 0 C, then cooled to RT, basified with aqeous NaOH solution, and extracted with CH 2 Cl 2 . After evaporation of volatiles, 3-amino-5-methoxypyridine was obtained as yellow solid.
  • Step 3 5- [ (5-Methoxy-pyridin-3-ylamino) -methylene] -2,2- dimethyl- [1, 3] dioxane-4, 6-dione.
  • a two-necked round bottomed flask equipped with a reflux condenser was charged with Meldrum' s acid (14.4 g, 100 mmol) and trimethylorthoformate (100 mL) .
  • the reaction mixture was heated at 100-105 0 C for 2 h.
  • 5-amino-3-methoxy pyridine (12.5 g, 100 mmol) was added to the reaction mixture and heating was continued for an additional 4 h at the same temperature.
  • the reaction mixture was allowed to cool to RT, diluted with hexane and filtered to obtain the product as light yellow solid.
  • Step 4 -Methoxy-1H- [1, 5] naphthyridin-4-one .
  • a two-necked round bottomed flask equipped with an air condenser was charged with 5- [ (5-Methoxy-pyridin-3-ylamino) -methylene] -2, 2-dimethyl- [1,3] dioxane-4, 6-dione (18 g) and diphenyl ether (180 mL) .
  • the reaction mixture was heated at 240-250 0 C for 5 min under N 2 atmosphere after which it was cooled to RT, diluted with hexane and filtered to obtain a dark solid.
  • the crude product was refluxed in hexane for 30 min and filtered to obtain product as a brown solid.
  • Step 5 8-chloro-3-methoxy-l, 5-naphthyridine.
  • a two-necked round bottomed flask equipped with an air condenser (protected with CaCl 2 guard tube) was charged with 7-Methoxy-lH- [1, 5] naphthyridin-4-one (13 g) and POCl 3 (65 mL) .
  • the reaction mixture was allowed to reflux at 120 0 C for 12 h.
  • the POCl 3 was removed In vacuo and azeotroped twice with toluene.
  • EtOAc 75 mL was added and the reaction mixture was stirred at 50-60 0 C for 15-20 min. EtOAc removed separated by decantation.
  • the organic layers were combined and concentrated.
  • Tetrakis (triphenylphosphine) palladium (0) (14.4 mg, 12.5 ⁇ mol) was added to a suspension of 3- ( ⁇ 3-iodopyridin-4-yloxy) methyl) - 6-phenyl- [1, 2,4] triazolo [4 , 3-b] pyridazine (107 mg, 249 ⁇ mol) and l-dimethylamino-2-propyne (80.4 ⁇ l, 748 ⁇ mol) in THF (0.6 mL) and triethylamine (591 ⁇ l, 4238 ⁇ mol) at RT.
  • the reaction mixture was heated at 100 0 C for 8 hours. Additional zinc cyanide (0.012 g, 0.095 mmol), 1,1'- bis (diphenylphosphino) ferrocene (0.004 g, 0.0065 mmol) and tris (dibenzylideneacetone)dipalladium(O) (0.003 g, 0.0032 mmol) were added and heating was continued at 100 0 C for 6 hours. The reaction mixture was concentrated under vacuum.
  • N-Ethyldiisopropylamine (0.070 ml, 0.40 mmol) was added to the reaction mixture. The clear reaction mixture was stirred at 20 0 C overnight.. The reaction mixture was concentrated under vacuum then triturated with water. The solid was collected on a glass frit, washing with water. The sample was purified by preparative TLC eluting with 8% 7N ammonia in methanol/ dichloromethane to afford N-cyclopropyl-3- ( (7- methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4 , 3 -a] pyridine- 6-carboxamide (0.023 g, 44% yield) as a tan solid. MS (ESI pos. ion) m/z: 390.2 (MH + ).
  • N-Ethyl-3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1, 2, 4] triazolo [4 , 3-a] pyridine-6-carboxamide was prepared as previously described for N-cyclopropyl-3- ( (7-methoxyquinolin-4 yloxy) methyl) - [1,2,4] triazolo [4 , 3-a] pyridine-6-carboxamide.
  • N- (4 -Fluorophenyl) -3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1, 2, 4] triazolo [4 , 3-a] pyridine-6-carboxamide was prepared as described for 3- ( (7-methoxyquinolin-4-yloxy)methyl) -N- (2- (methylamino) ethyl) - [1,2,4] triazolo [A 1 3-a] pyridine-6- carboxamide .
  • N- (3-Fluorophenyl) -3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1, 2, 4] triazolo [4 , 3-a]pyridine-6-carboxamide was prepared as described for 3- ( (7-metho ⁇ yquinolin-4-yloxy) methyl) -N- (2- (methylamino) ethyl) - [1,2,4] triazolo [4, 3 -a] pyridine-6- carboxamide .
  • tert-butyl 2-chloro-4 ⁇ (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan- 2-yl) benzylcarbamate .
  • reaction partitioned between DCM (5OmL) and 5% NaHCO3 (25mL) .

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Abstract

Selected compounds are effective for prophylaxis and treatment of diseases, such as HGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

Description

FUSED HETEROCYCLIC DERIVATIVES AND METHODS OF USE
This application claims priority to U.S. Provisional Application Serial No. 60/830,882 filed July 14, 2006 the entirety of which is incorportated herein by reference.
FIELD OF THE INVENTION
This invention is in the field of pharmaceutical agents and specifically relates to compounds, compositions, uses and methods for treating cancer.
BACKGROUND OF THE INVENTION
Protein kinases represent a large family of proteins, which play a central role in the regulation of a wide variety of cellular processes, maintaining control over cellular function. A partial list of such kinases includes abl, Akt, bcr-abl, BIk, Brk, Btk, c-kit, c-Met, c-src, c-fms, CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDKlO, cRafl, CSFlR, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-IR, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes, and Zap70. Inhibition of such kinases has become an important therapeutic target.
The hepatocyte growth factor receptor ("c-Met") is a unique receptor tyrosine kinase shown to be overexpressed in a variety of malignancies. c-Met typically comprises, in its native form, a 190-kDa heterodimeric (a disulfide-linked 50-kDa α-chain and a 145-kDa β- chain) membrane-spanning tyrosine kinase protein (Proc. Natl. Acad. Sci. USA, 84:6379-6383 (1987)). c-Met is mainly expressed in epithelial cells and stimulation of c-Met leads to scattering, angiogenesis, proliferation and metastasis. (See Cytokine and Growth Factor Reviews, 13:41-59 (2002)).
The ligand for c-Met is hepatocyte growth factor (also known as scatter factor, HGF and SF). HGF is a heterodimeric protein secreted by cells of mesodermal origin (Nature, 327:239-242 (1987); J. Cell Biol., 11 1 :2097-2108 (1990)).
Various biological activities have been described for HGF through interaction with c- met (Hepatocyte Growth Factor- Scatter Factor (HGF-SF) and the c-Met Receptor, Goldberg and Rosen, eds., Birkhauser Verlag-Basel, 67-79 (1993). The biological effect of HGF/SF may depend in part on the target cell. HGF induces a spectrum of biological activities in epithelial cells, including mitogenesis, stimulation of cell motility and promotion of matrix invasion (Biochem. Biophys. Res. Comm., 122:1450-1459 (1984); Proc. Natl. Acad. Sci. U.S.A., 88:415-419 (1991)). It stimulates the motility and invasiveness of carcinoma cells, the former having been implicated in the migration of cells required for metastasis. HGF can also act as a "scatter factor", an activity that promotes the dissociation of epithelial and vascular endothelial cells (Nature, 327:239-242 (1987); J. Cell Biol., 111:2097-2108 (1990); EMBO J., 10:2867- 2878 (1991); Proc. Natl. Acad. Sci. USA, 90:649-653 (1993)). Therefore, HGF is thought to be important in tumor invasion (Hepatocyte Growth Factor-Scatter Factor (HGF-SF) and the C-Met Receptor, Goldberg and Rosen, eds., Birkhauser Verlag-Basel, 131-165 (1993)).
HGF and c-Met are expressed at abnormally high levels in a large variety of solid tumors. High levels of HGF and/or c-Met have been observed in liver, breast, pancreas, lung, kidney, bladder, ovary, brain, prostate, gallbladder and myeloma tumors in addition to many others. The role of HGF/c-Met in metastasis has been investigated in mice using cell lines transformed with HGF/c-Met (J. MoI. Med., 74:505-513 (1996)). Overexpression of the c-Met oncogene has also been suggested to play a role in the pathogenesis and progression of thyroid tumors derived from follicular epithelium (Oncogene, 7:2549-2553 (1992)). HGF is a morphogen (Development, 110:1271-1284 (1990); Cell, 66:697-711 (1991)) and a potent angiogenic factor (J. Cell Biol., 1 19:629-641 (1992)).
Recent work on the relationship between inhibition of angiogenesis and the suppression or reversion of tumor progression shows great promise in the treatment of cancer (Nature, 390:404-407 (1997)), especially the use of multiple angiogenesis inhibitors compared to the effect of a single inhibitor. Angiogenesis can be stimulated by HGF, as well as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).
Angiogenesis, the process of sprouting new blood vessels from existing vasculature and arteriogenesis, the remodeling of small vessels into larger conduit vessels are both physiologically important aspects of vascular growth in adult tissues. These processes of vascular growth are required for beneficial processes such as tissue repair, wound healing, recovery from tissue ischemia and menstrual cycling. They are also required for the development of pathological conditions such as the growth of neoplasias, diabetic retinopathy, rheumatoid arthritis, psoriasis, certain forms of macular degeneration, and certain inflammatory pathologies. The inhibition of vascular growth in these contexts has also shown beneficial effects in preclinical animal models. For example, inhibition of angiogenesis by blocking vascular endothelial growth factor or its receptor has resulted in inhibition of tumor growth and in retinopathy. Also, the development of pathological pannus tissue in rheumatoid arthritis involves angiogenesis and might be blocked by inhibitors of angiogenesis.
The ability to stimulate vascular growth has potential utility for treatment of ischemia- induced pathologies such as myocardial infarction, coronary artery disease, peripheral vascular disease, and stroke. The sprouting of new vessels and/or the expansion of small vessels in ischemic tissues prevents ischemic tissue death and induces tissue repair. Certain diseases are known to be associated with deregulated angiogenesis, for example ocular neovascularization, such as retinopathies (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, such as a rheumatoid or rheumatic inflammatory disease, especially arthritis (including rheumatoid arthritis), or other chronic inflammatory disorders, such as chronic asthma, arterial or post- transplantational atherosclerosis, endometriosis, and neoplastic diseases, for example so-called solid tumors and liquid tumors (such as leukemias). Treatment of malaria and related viral diseases may also be mediated by HGF and cMet.
Elevated levels of HGF and c-Met have also been observed in non-oncological settings, such as hypertension, myocardial infarction and rheumatoid arthritis. It has been observed that levels of HGF increase in the plasma of patients with hepatic failure (Gohda et al., supra) and in the plasma (Hepatol., 13:734-750 (1991)) or serum (J. Biochem., 109:8-13 (1991)) of animals with experimentally induced liver damage. HGF has also been shown to be a mitogen for certain cell types, including melanocytes, renal tubular cells, keratinocytes, certain endothelial cells and cells of epithelial origin (Biochem. Biophys. Res. Commun., 176:45-51 (1991); Biochem. Biophys. Res. Commun., 174:831-838 (1991); Biochem., 30:9768-9780 (1991); Proc. Natl. Acad. Sci. USA, 88:415-419 (1991)). Both HGF and the c-Met proto- oncogene have been postulated to play a role in microglial reactions to CNS injuries (Oncogene, 8:219-222 (1993)).
Metastatic SCC cells overexpress c-Met and have enhanced tumoregenesis and metastasis in vivo [G. Gong et al., Oncogene, 23:6199-6208 (2004)]. C-Met is required for tumor cell survival [N. Shinomiya et al., Cancer Research, 64:7962-7970 (2004)]. For a general review see C. Birchmeier et al., Nature Reviews/Molecular Biology 4:915-925 (2003).
In view of the role of HGF and/or c-Met in potentiating or promoting such diseases or pathological conditions, it would be useful to have a means of substantially reducing or inhibiting one or more of the biological effects of HGF and its receptor. Thus a compound that reduces the effect of HGF would be a useful compound. Compounds of the current invention have not been previously described as inhibitors of angiogenesis such as for the treatment of cancer.
Sugen application WO 05/010005 describes certain Triazolotriazine compounds that , are c-met inhibitors. Diamon Shamrock Corp. application WO 83/00864 discloses certain Triazolotriazine compounds that are useful as anti-inflammatory agents. Yamanouchi applications EP 1481955 and US 2005/0261297 disclose certain nitrogen-containing heterocyclic compounds that are therapeutic agents having a bone formation-stimulating effect. Compounds of the current invention are inhibitors of c-Met. DESCRIPTION OF THE INVENTION
A class of compounds useful in treating cancer and angiogenesis is defined by Formulae, IV, V, VI and VII
Figure imgf000005_0001
II
Figure imgf000005_0002
III
Figure imgf000005_0003
IV
Figure imgf000006_0001
VI
Figure imgf000006_0002
VII enantiomers, diastereomers, salts and solvates thereof wherein
J is N or CR3;
W is N or CR2b;
W* is N or CR2b;
X is O or S;
Z and Z* are independently -O-, -S(O)V-, or -NR5-;
Ra, Rb, Rc and Rd are each independently H, halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, -NO2, -CN, -NR5R5a, -OR4, -C(=O)R4, -C(=O)OR4; -C(=O)NR5RSa, -N(R5)C(=O)NR5R5a, -OC(=O)NR5R5a, -S(O)VR4, -S(O)2NR5R53, -N(R5)SO2R4 any of which may be optionally independently substituted with one or more R10 groups as allowed by valance; or Ra and Rb together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R10 groups as allowed by valance.; or Rc and Rd together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R10 groups as allowed by valance; or R° and/or Rb may combine with any Rc or Rd to form a partially or fully saturated 3-8 membered cycloalkyl ring or heterocyclo ring, either of which may be optionally substituted with one or more R10 groups as allowed by valance; or Ra and Rb may combine to form a carbonyl group; or Rc and Rd attached to the same carbon atom may combine to form a carbonyl group; R1 is aryl, heteroaryl or heterocyclo any of which may be optionally independently substituted with one or more R10 groups as allowed by valance; R2 is
(i) H, halo, cyano, nitro, or
(ii) alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -OR4, -S(O)VR4, -NR5R50, -C(=O)R4, -C(=S)R4, -C(=O)OR4, -C(=S)OR4, -C(=O)NR5R5a, -C(=S)NR5R5β, -N(R5)C(=O)NR5R5a, -N(R5)C(=S)NR5R5a, -N(R5)C(=O)R4, -N(R5)C(=S)R4, -OC(=O)NR5R5a, -OC(=S)NR5R5a, -SO2NR5R53, -N(R5)SO2R4, -N(R5)SO2NR5R5a, -N(R5)C(=O)OR4, -N(R5)C(=S)OR4, -N(R5)Sθ2R4, any of which may be optionally independently substituted with one or more R10 as allowed by valance, provided that in compounds of formula I when W and J are both N, R2 is other than
(a) -NR5R5a where R5 and R5a are independently H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl; and
(b) phenyl substituted with a group
Figure imgf000007_0001
where G1 and G2 are independently alkyl, cycloalkyl, or G1 and G2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring; R2a, R2b and R3 are independently selected at each occurrence from H, halo, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -OR4, -S(O)VR4, -NR5R5a, -C(=O)R4, -CO=S)R4, -C(=O)OR4, -C(=S)OR4, -C(=O)NR5R5a, -C(=S)NR5R5a, -N(R5)C(=O)NR5R5a, -N(R5)C(=S)NR5R5a, -N(RS)C(=O)R4, -N(R5)C(=S)R4, -OC(=O)NR5RSa, -OC(=S)NR5RSa, -SO2NR5R58, -N(R5)SO2R4, -N(R5)SO2NR5R5a, -N(R5)C(=O)OR4, -N(R5)C(=S)OR4, -N(R5)SO2R4, any of which may be optionally independently substituted with one or more R10 groups as allowed by valance;
R4 is independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally independently substituted as allowed by valance with one or more R10 groups;
Rs and R5a are independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally substituted as allowed by valance with one or more R10; or R5 and R5a may combine to form a heterocyclo ring optionally substituted with one or more R10;
R10 at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)m-OR4, -(alkylene)m-S(O)vR4, -(alkylene)m-NR5R5a, -(alkylene)m-C(=O)R4, -(alkylene)m-C(=S)R4, -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4, -(alkylene)m-C(=S)OR4, -(alkylene)m-C(=O)NR5R5a, -(alkylene)m-C(=S)NR5R5a, -(alkylene)m-N(R5)C(=O)NR5R5a, -(alkylene)m-N(R5)C(=S)NR5R5a, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-N(R5)C(=S)R4,
-(alkylene)m-OC(=O)NR5R5a, -(alkylene)m-OC(=S)NR5R5a, -(alkylene)m-SO2NR5R5a, -(alkylene)m-N(R5)SO2R4, -(alkylene)m-N(R5)SO2NR5R5a, -(alkylene)m-N(R5)C(=O)OR4, -(alkylene)m-N(R5)C(=S)OR4, or -(alkylene)m-N(R5)SO2R4; wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene)m-OR4, -(alkylene)m-S(O)vR4, -(alkylene)m-NR5R5\ -(alkylene)m-C(=O)R4, -(alkylene)m-C(=S)R4, -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4, -(alkylene)m-C(=S)OR4, -(alkylene)m-C(=O)NR5R5a, -(alkylene)m-C(=S)NR5R5a, -(alkylene)m-N(R5)C(=O)NRsRSa, -(alkylene)m-N(Rs)C(=S)NRsRSa > -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-N(Rs)C(=S)R4,
-(alkylene)m-OC(=O)NR5R5a, -(alkylene)m-OC(=S)NR5R5a, -(alkylene)m-SO2NR5R5a, -(alkylene)m-N(R5)SO2R4, -(alkylene)m-N(R5)SO2NR5R5a, -(alkylene)m-N(R5)C(=O)OR4, -(alkylene)m-N(R5)C(=S)OR4, or -(alkylene)m-N(R5)SO2R4; and further wherein any two R10 groups attached to the same atom or attached to adjacent atoms may combine to form an optionally substituted 3- to 8 membered ring system; m is 0 or 1; n is 0, 1 or 2; q and t are each independently 0 or 1 ; v is 0, 1 or 2.
Preferred compounds include compounds wherein R1 is phenyl, naphthyl, benzodioxolyl, benzooxazolyl, benzoisoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrimidinyl, pyrazidinyl, isoquinolinyl, quinolinyl, quinazolinyl, quinazolinonyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl, thienopyridinyl, thienopyrimidinyl, thienopyridazinyl, furopyridinyl, furopyrimidinyl, furopyrazidinyl, benzofuranyl, benzoimidazolyl, indolyl, benzoisoxazolyl, benzothiazolyl, or benzoisothiazolyl any of which may be optionally independently substituted with one or more R10 groups as allowed by valance.
Preferred R1 groups include
Figure imgf000010_0001
Figure imgf000011_0001
where m* is 0, 1 , 2, 3, 4, 5 or 6, as allowed by valence. Especially preferred R1 groups include
Figure imgf000012_0001
where R1Oa, RIOb. RIOy and RIOz are independently absent, halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene)m-OR4, -(alkylene)m-NR5RSa, -(alkylene)m-C(=O)R4, -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4 > -Calkylene)m-C(=O)NR5RSa, -(alkylene)m-N(R5)C(=O)NR5R5a, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-OC(=O)NR5RSa, or -(alkylene)m-N(R5)C(=O)OR4; or where RIOa and RIOb combine to form an optionally substituted 3- to 8-membered ring system.
Most preferred R1 groups include moieties that are either unsubstituted or independently substituted as allowed by valance with one or more halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene)m-OR4, -(alkylene)m-NR5R5a, -(alkylene)m-C(=O)R4, -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4, -(alkylene)m-C(=O)NR5R5a, * -(alkylene)m-N(R5)C(=O)NR5R5a, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-OC(=O)NR5R5a, or -(alkylene)m-N(R5)C(=O)OR4.
Preferred compounds of the present invention further include compounds wherein R2 is H, halo, cyano, alkynyl, -C(=O)NR5R5a, -N(R5)C(=O)R4, -N(R5)C(=O)OR4, phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, tetrahydropyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, indolinonyl, isoidolinyl, isoindolinonyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, benzofuranyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, quinoxalinyl, tetrahydroquinoxalinyl, benzomorpholinyl, dihydrobenzodioxinyl, imidazopyridinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl, thienopyrrolyl, tetrahydrothienopyrrolyl, dihydrothienopyrrolonyl, thienopyridinyl, thienopyrimidinyl, thienopyridazinyl, furopyridinyl, furopyrimidinyl, furopyrazidinyl, benzofuranyl, benzoimidazolyl, benzoisoxazolyl, benzothiazolyl, or benzoisothiazolyl any of which may be optionally independently substituted with one or more R10 groups as allowed by valance.
Preferred R2 groups include
(a) halo, alkynyl, -C(=O)NR5R5a, -N(R5)C(=O)R4 or -N(R5)C(=O)OR4 any of which may be optionally independently substituted with one or more R10 groups as allowed by valance; and
(b) an aryl, heteroaryl or heterocyclo ring system selected from
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
Preferred compounds of the present invention include compounds having either or both of preferred R1 groups and preferred R2 groups either alone or in any combination thereof.
Preferred compounds of the present invention include compounds wherein Ra, Rb, Rc and Rd groups are independently hydrogen, alkyl (especially methyl), and halogen (especially fluorine).
Preferred compounds within the scope of formula I and II include compounds of the following formualae IA, IB, IC, ID and HA
Figure imgf000016_0002
IA
Figure imgf000017_0001
enantiomers, diastereomers, salts and solvates thereof, wherein variables Ra, Rb, Rc, Rd, R1, R2,
R2a, R2b, R3, Z, Z*, n, q and t are as previously defined above. Preferred compounds of formulae IA, IB, IC, ID and IIA include compounds having any of the preferred R1 groups and R2 groups, either alone or in any combination thereof.
Preferred compounds within the scope of formula I and II also include compounds having the following formula IE, IF, HB and HC
Figure imgf000018_0001
Figure imgf000019_0001
enantiomers, diasterεomers, salts and solvates thereof wherein variables Ra, Rb, Rc, Rd, R2, R2a, R2b, and Z*, are as previously defined above, provided that in compounds of formula IE R2 is not phenyl substituted with a group
Figure imgf000019_0002
where G1 and G2 are independently alkyl, cycloalkyl, or G1 and G2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring; and further wherein q is O, 1, 2 or 3; n* is 0, 1 or 2; t* is 0 or 1
U1, U2, U3 and U4 are each independently C, or N; and
RIOc at each occurence is independently selected from the groups listed in the definition of R10 previously described above.
Preferred compounds of formulae IE, IF, IIB and HC include compounds having any of the preferred R2 groups described above.
Preferred compounds within the scope of formulae IE and IF include compounds of the following formula IEi, IEii, IEiii, IEiv, IFi, IFii, IFiii and IFiv
Figure imgf000020_0001
Figure imgf000021_0001
enantiomers, diastereomers, salts and solvates thereof.
Preferred compounds within the scope of formula I further include compounds of the following formula IEA and IFA
Figure imgf000021_0002
Figure imgf000022_0001
enantiomers, diastereomers, salts and solvates thereof wherein variables Ra, R , Rc, R , R2, R2a, R2b, RIOc, U1, U2, U3, Z*, n*. q, and t*are as previously defined above provided that in compounds of formula IEA R2 is not phenyl substituted with a group
Figure imgf000022_0002
where G1 and G2 are independently alkyl, cycloalkyl, or G1 and G2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring. . Preferred compounds of formulae IEA and IFA include compounds having any of the preferred R2 groups described above.
Preferred compounds of formulae IEA and IFA include compounds of formulae IEAi, IEAii, IEAiii, IFAi, IFAii and IFAiii
Figure imgf000023_0001
enantiomers, diastereomers, salts and solvates thereof.
Preferred compounds within the scope of formula I further include compounds of the following formula IG or IH
Figure imgf000024_0001
Wherein U is CR1Oc or N, and variables ■ Rr» aa, r R^ bb, ■ R r>22, T Rv 22aa, T R- ,22bb, n RllOOaa, RIOb, RlOc, and Z*, are as previously defined above, provided that in compounds of formula IG R2 is not phenyl substituted with a group
Figure imgf000024_0002
where G1 and G2 are independently alkyl, cycloalkyl, or G1 and G2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring. Preferred compounds of formulae IG and IH include compounds having any of the preferred R2 groups described above.
Preferred compounds of the present invention include the compounds exemplified herein.
The invention also relates to pharmaceutical compositions containing the above compounds, together with a pharmaceutically acceptable vehicle or carrier.
The invention also relates to a method of treating cancer in a subject using the above compounds.
The invention also relates to a method of reducing tumor size in a subject using the above compounds.
The invention also relates to a method of reducing metastasis in a tumor in a subject, using the above compounds.
The invention also relates to a method of treating HGF-mediated disorders in a subject using the above compounds.
INDICATIONS
Compounds of the present invention would be useful for, but not limited to, the prevention or treatment of angiogenesis related diseases. The compounds of the invention have c-Met inhibitory activity. The compounds of the invention are useful in therapy as antineoplasia agents or to minimize deleterious effects of HGF. Compounds of the invention would be useful for the treatment of neoplasia including cancer and metastasis, including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including small cell lung cancer), esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma and schwannomas); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma).
Preferably, the compounds are useful for the treatment of neoplasia selected from lung cancer, colon cancer and breast cancer.
The compounds also would be useful for treatment of ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemangiomas, including infantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; and disorders of the female reproductive system such as endometriosis. The compounds are also useful for the treatment of edema, and conditions of vascular hyperpermeability.
The compounds of the invention are useful in therapy of proliferative diseases. These compounds can be used for the treatment of an inflammatory rheumatoid or rheumatic disease, especially of manifestations at the locomotor apparatus, such as various inflammatory rheumatoid diseases, especially chronic polyarthritis including rheumatoid arthritis, juvenile arthritis or psoriasis arthropathy; paraneoplastic syndrome or tumor-induced inflammatory diseases, turbid effusions, collagenosis, such as systemic Lupus erythematosus, poly-myositis, dermato-myositis, systemic sclerodermia or mixed collagenosis; postinfectious arthritis (where no living pathogenic organism can be found at or in the affected part of the body), seronegative spondylarthritis, such as spondylitis ankylosans; vasculitis, sarcoidosis, or arthrosis; or further any combinations thereof. An example of an inflammation related disorder is (a) synovial inflammation, for example, synovitis, including any of the particular forms of synovitis, in particular bursal synovitis and purulent synovitis, as far as it is not crystal-induced. Such synovial inflammation may for example, be consequential to or associated with disease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis or arthritis deformans. The present invention is further applicable to the systemic treatment of inflammation, e.g. inflammatory diseases or conditions, of the joints or locomotor apparatus in the region of the tendon insertions and tendon sheaths. Such inflammation may be, for example, consequential to or associated with disease or further (in a broader sense of the invention) with surgical intervention, including, in particular conditions such as insertion endopathy, myofasciale syndrome and tendomyosis. The present invention is further especially applicable to the treatment of inflammation, e.g. inflammatory disease or condition, of connective tissues including dermatomyositis and myositis.
These compounds can be used as active agents against such disease states as arthritis, atherosclerosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacter related diseases, fractures, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy or macular degeneration. In addition, some of these compounds can be used as active agents against solid tumors, malignant ascites, hematopoietic cancers and hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome)) since such diseases require a proliferation of blood vessel cells for growth and/or metastasis.
Further, some of these compounds can be used as active agents against burns, chronic lung disease, stroke, polyps, anaphylaxis, chronic and allergic inflammation, ovarian hyperstimulation syndrome, brain tumor-associated cerebral edema, high-altitude, trauma or hypoxia induced cerebral or pulmonary edema, ocular and macular edema, ascites, and other diseases where vascular hyperpermeability, effusions, exudates, protein extravasation, or edema is a manifestation of the disease. The compounds will also be useful in treating disorders in which protein extravasation leads to the deposition of fibrin and extracellular matrix, promoting stromal proliferation (e.g. fibrosis, cirrhosis and carpal tunnel syndrome).
The compounds of the present invention are also useful in the treatment of ulcers including bacterial, fungal, Mooren ulcers and ulcerative colitis.
The compounds of the present invention are also useful in the treatment of conditions wherein undesired angiogenesis, edema, or stromal deposition occurs in viral infections such as Herpes simplex, Herpes Zoster, AIDS, Kaposi's sarcoma, protozoan infections and toxoplasmosis, following trauma, radiation, stroke, endometriosis, ovarian hyperstimulation syndrome, systemic lupus, sarcoidosis, synovitis, Crohn's disease, sickle cell anemia, Lyme disease, pemphigoid, Paget's disease, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic inflammation, chronic occlusive pulmonary disease, asthma, and inflammatory rheumatoid or rheumatic disease. The compounds are also useful in the reduction of subcutaneous fat and for the treatment of obesity.
The compounds of the present invention are also useful in the treatment of ocular conditions such as ocular and macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser complications, glaucoma, conjunctivitis, Stargardt's disease and Eales disease in addition to retinopathy and macular degeneration.
The compounds of the present invention are also useful in the treatment of cardiovascular conditions such as atherosclerosis, restenosis, arteriosclerosis, vascular occlusion and carotid obstructive disease.
The compounds of the present invention are also useful in the treatment of cancer related indications such as solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, including leukemia and lymphoma, tumor-induced pleural or pericardial effusions, and malignant ascites.
The compounds of the present invention are also useful in the treatment of diabetic conditions such as diabetic retinopathy and microangiopathy.
The compounds of the present invention are also useful in the reduction of blood flow in a tumor in a subject.
The compounds of the present invention are also useful in the reduction of metastasis of a tumor in a subject.
The compounds of this invention may also act as inhibitors of other protein kinases, e.g. tie-2, lck, src, fgf, c-Met, ron, ckit and ret, and thus be effective in the treatment of diseases associated with other protein kinases.
Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
As used herein, the compounds of the present invention include the pharmaceutically acceptable derivatives thereof. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt and the like.
DEFINITIONS
" Angiogenesis" is defined as any alteration of an existing vascular bed or the formation of new vasculature, which benefits tissue perfasion. This includes the formation of new vessels by sprouting of endothelial cells from existing blood vessels or the remodeling of existing vessels to alter size, maturity, direction or flow properties to improve blood perfusion of tissue.
As used herein, "HGF" refers to hepatocyte growth factor/scatter factor. This includes purified hepatocyte growth factor/scatter factor, fragments of hepatocyte growth factor/scatter factor, chemically synthesized fragments of hepatocyte growth factor/scatter factor, derivatives or mutated versions of hepatocyte growth factor/scatter factor, and fusion proteins comprising hepatocyte growth factor/scatter factor and another protein. "HGF" as used herein also includes hepatocyte growth factor/scatter factor isolated from species other than humans.
As used herein "c-Met" refers to the receptor for HGF. This includes purified receptor, fragments of receptor, chemically synthesized fragments of receptor, derivatives or mutated versions of receptor, and fusion proteins comprising the receptor and another protein. "c-Met" as used herein also includes the HGF receptor isolated from a species other than humans.
As used herein, "HGF" refers to hepatocyte growth factor/scatter factor. This includes purified hepatocyte growth factor/scatter factor, fragments of hepatocyte growth factor/scatter factor, chemically synthesized fragments of hepatocyte growth factor/scatter factor, derivatives or mutated versions of hepatocyte growth factor/scatter factor, and fusion proteins comprising hepatocyte growth factor/scatter factor and another protein. "HGF" as used herein also includes hepatocyte growth factor/scatter factor isolated from species other than humans.
As used herein "c-Met" refers to the receptor for HGF. This includes purified receptor, fragments of receptor, chemically synthesized fragments of receptor, derivatives or mutated versions of receptor, and fusion proteins comprising the receptor and another protein. "c-Met" as used herein also includes the HGF receptor isolated from a species other than humans.
As used herein, the terms "hepatocyte growth factor" and "HGF" refer to a growth factor typically having a structure with six domains (finger, Kringle 1 , Kringle 2, Kringle 3, Kringle 4 and serine protease domains). Fragments of HGF constitute HGF with fewer domains and variants of HGF may have some of the domains of HGF repeated; both are included if they still retain their respective ability to bind a HGF receptor. The terms "hepatocyte growth factor" and "HGF" include hepatocyte growth factor from humans ("huHGF") and any non-human mammalian species, and in particular rat HGF. The terms as used herein include mature, pre, pre-pro, and pro forms, purified from a natural source, chemically synthesized or recombinantly produced. Human HGF is encoded by the cDNA sequence published by Miyazawa et al. (1989), supra, or Nakamura et al. (1989), supra. The sequences reported by Miyazawa et al. and Nakamura et al. differ in 14 amino acids. The reason for the differences is not entirely clear; polymorphism or cloning artifacts are among the possibilities. Both sequences are specifically encompassed by the foregoing terms. It will be understood that natural allelic variations exist and can occur among individuals, as demonstrated by one or more amino acid differences in the amino acid sequence of each individual. The terms "hepatocyte growth factor" and "HGF" specifically include the delta 5 huHGF as disclosed by Seki et al., supra.
The terms "HGF receptor" and "c-Met" when used herein refer to a cellular receptor for HGF, which typically includes an extracellular domain, a transmembrane domain and an intracellular domain, as well as variants and fragments thereof which retain the ability to bind HGF. The terms "HGF receptor" and "c-Met" include the polypeptide molecule that comprises the full-length, native amino acid sequence encoded by the gene variously known as pl90.sup.MET. The present definition specifically encompasses soluble forms of HGF receptor, and HGF receptor from natural sources, synthetically produced in vitro or obtained by genetic manipulation including methods of recombinant DNA technology. The HGF receptor variants or fragments preferably share at least about 65% sequence homology, and more preferably at least about 75% sequence homology with any domain of the human c-Met amino acid sequence published in Rodrigues et al., MoI. Cell. Biol., 11 :2962-2970 (1991); Park et al., Proc. Natl. Acad. Sci., 84:6379-6383 (1987); or Ponzetto et al., Oncogene, 6:553- 559 (1991).
The terms "agonist" and "agonistic" when used herein refer to or describe a molecule which is capable of, directly or indirectly, substantially inducing, promoting or enhancing HGF biological activity or HGF receptor activation.
The terms "cancer" and "cancerous" when used herein refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include but are not limited to, carcinoma, lymphoma, sarcoma, blastoma and leukemia. More particular examples of such cancers include squamous cell carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer. While the term "cancer" as used herein is not limited to any one specific form of the disease, it is believed that the methods of the invention will be particularly effective for cancers which are found to be accompanied by increased levels of HGF or expression of c-Met in the mammal.
The terms "treating," "treatment," and "therapy" as used herein refer to curative therapy, prophylactic therapy, and preventative therapy.
The term "mammal" as used herein refers to any mammal classified as a mammal, including humans, cows, horses, dogs and cats. In a preferred embodiment of the invention, the mammal is a human.
Given that elevated levels of c-Met and HGF are observed in hypertension, arteriosclerosis, myocardial infarction, and rheumatoid arthritis, nucleic acid ligands will serve as useful therapeutic agents for these diseases.
The term "treatment" includes therapeutic treatment as well as prophylactic treatment (either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals).
A "pharmaceutically-acceptable derivative " denotes any salt, ester of a compound of this invention, or any other compound which upon administration to a patient is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to inhibit angiogenesis.
The phrase "therapeutically-effective" is intended to qualify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. For example, effective neoplastic therapeutic agents prolong the survivability of the patient, inhibit the rapidly proliferating cell growth associated with the neoplasm, or effect a regression of the neoplasm.
The term "H" denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
Where the term "alkyl" is used, either alone or within other terms such as "haloalkyl" and "alkylamino", it embraces linear or branched radicals having one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, /er/-butyl, pentyl, isoamyl, hexyl and the like. Even more preferred are lower alkyl radicals having one or two carbon atoms. The term "alkylenyl" embraces bridging divalent alkyl radicals such as methylenyl and ethylenyl. The term "lower alkyl substituted with R2" does not include an acetal moiety. The term "alkenyl" embraces linear or branched radicals having at least one carbon- carbon double bond of two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about six carbon atoms. Most preferred lower alkenyl radicals are radicals having two to about four carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.
The term "alkynyl" denotes linear or branched radicals having at least one carbon- carbon triple bond and having two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having two to about six carbon atoms. Most preferred are lower alkynyl radicals having two to about four carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.
Alkyl, alkylenyl, alkenyl, and alkynyl radicals may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclo and the like.
The term "halo" means halogens such as fluorine, chlorine, bromine or iodine atoms.
The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals including perhaloalkyl. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. "Lower haloalkyl" embraces radicals having 1-6 carbon atoms. Even more preferred are lower haloalkyl radicals having one to three carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Perfluoroalkyl" means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
The term "hydroxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having one to three carbon atoms. The term "alkoxy" embraces linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a fused manner. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is phenyl. Said "aryl" group may have 1 or more substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino, and the like. Phenyl substituted with -0-CH2-O- forms the aryl benzodioxolyl substituent.
The term "heterocyclyl" (or "heterocyclo") embraces saturated, and partially saturated and heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. It does not include rings containing -O-O-.-O-S- or -S-S- portions. Said "heterocyclyl" group may have 1 to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino, lower alkylamino, and the like.
Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6- membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl, dihydrothiazolyl, and the like.
Particular examples of partially saturated and saturated heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2- dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4 ,4a,9,9a- hexahydro-1 H-3-aza-fluorenyl, 5,6,7-trihydro-l,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro- 2H-benzo[ 1 ,4]oxazinyl, benzo[ 1 ,4]dioxanyl, 2,3-dihydro- 1 H- lλ'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl, and the like.
The term heterocyclyl, (or heterocyclo) also embraces radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5- b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms [e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[l,4]dioxinyl and dihydrobenzofuryl].
The term "heteroaryl" denotes aryl ring systems that contain one or more heteroatoms selected from the group O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized. Examples include unsaturated S to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl]; unsaturated 5- to 6- membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1 ,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6- membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5- thiadiazolyl].
The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO2-.
The terms "sulfamyl," "aminosulfonyl" and "sulfonamidyl," denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-SO2NH2).
The term "alkylaminosulfonyl" includes "N-alkylaminosulfonyl" where sulfamyl radicals are independently substituted with one or two alkyl radical(s). More preferred alkylaminosulfonyl radicals are "lower alkylaminosulfonyl" radicals having one to six carbon atoms. Even more preferred are lower alkylaminosulfonyl radicals having one to three carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl, and N-ethylaminosulfonyl.
The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes -CO2H.
The term "carbonyl", whether used alone or with other terms, such as "aminocarbonyl", denotes -(C=O)-.
The term "aminocarbonyl" denotes an amide group of the formula -C(=0)NH2.
The terms "N-alkylaminocarbonyl" and "N,N-dialkylaminocarbonyl" denote aminocarbonyl radicals independently substituted with one or two alkyl radicals, respectively. More preferred are "lower alkylaminocarbonyl" having lower alkyl radicals as described above attached to an aminocarbonyl radical.
The terms "N-arylaminocarbonyl" and "N-alkyl-N-arylaminocarbonyl" denote aminocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical.
The terms "heterocyclylalkylenyl" and "heterocyclylalkyl" embrace heterocyclic- substituted alkyl radicals. More preferred heterocyclylalkyl radicals are "5- or 6-membered heteroarylalkyl" radicals having alkyl portions of one to six carbon atoms and a 5- or 6- membered heteroaryl radical. Even more preferred are lower heteroarylalkyl enyl radicals having alkyl portions of one to three carbon atoms. Examples include such radicals as pyridylmethyl and thienylmethyl.
The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are "phenylalkylenyl" attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower alkylthio radicals having one to three carbon atoms. An example of "alkylthio" is methylthio, (CH3S-).
The term "haloalkylthio" embraces radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower haloalkylthio radicals having one to three carbon atoms. An example of "haloalkylthio" is trifluorόmethylthio. The term "alkylamino" embraces "N-alkylamino" and "N,N-dialkylamino" where amino groups are independently substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred alkylamino radicals are "lower alkylamino" radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N- dimethylamino, N,N-diethylamino and the like.
The term "arylamino" denotes amino groups, which have been substituted with one or two aryl radicals, such as N-phenylamino. The arylamino radicals may be further substituted on the aryl ring portion of the radical.
The term "heteroarylamino" denotes amino groups, which have been substituted with one or two heteroaryl radicals, such as N-thienylamino. The "heteroarylamino" radicals may be further substituted on the heteroaryl ring portion of the radical.
The term "aralkylamino" denotes amino groups, which have been substituted with one or two aralkyl radicals. More preferred are phenyl-Ci-C3-alkylamino radicals, such as N- benzylamino. The aralkylamino radicals may be further substituted on the aryl ring portion.
The terms "N-alkyl-N-arylamino" and "N-aralkyl-N-alkylamino" denote amino groups, which have been independently substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively, to an amino group.
The term "aminoalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl" radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferred are lower aminoalkyl radicals having one to three carbon atoms.
The term "alkylaminoalkyl" embraces alkyl radicals substituted with alkylamino radicals. More preferred alkylaminoalkyl radicals are "lower alkylaminoalkyl" radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl radicals may be mono or dialkyl substituted, such as N-methylaminomethyl, N.N-dimethyl-aminoethyl, N,N-diethylaminomethyl and the like.
The term "alkylaminoalkoxy" embraces alkoxy radicals substituted with alkylamino radicals. More preferred alkylaminoalkoxy radicals are "lower alkylaminoalkoxy" radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxy radicals may be mono or dialkyl substituted, such as N-methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy and the like.
The term "alkylaminoalkoxyalkoxy" embraces alkoxy radicals substituted with alkylaminoalkoxy radicals. More preferred alkylaminoalkoxyalkoxy radicals are "lower alkylaminoalkoxyalkoxy" radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxyalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxyalkoxy radicals may be mono or dialkyl substituted, such as N-methylaminomethoxyethoxy, N-methylaminoethoxyethoxy, N5N- dimethylaminoethoxyethoxy, N,N-diethylaminomethoxymethoxy and the like.
The term "carboxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more carboxy radicals. More preferred carboxyalkyl radicals are "lower carboxyalkyl" radicals having one to six carbon atoms and one carboxy radical. Examples of such radicals include carboxymethyl, carboxypropyl, and the like. Even more preferred are lower carboxyalkyl radicals having one to three CH2 groups.
The term "halosulfonyl" embraces sulfonyl radicals substituted with a halogen radical. Examples of such halosulfonyl radicals include chlorosulfonyl and fluorosulfonyl.
The term "arylthio" embraces aryl radicals of six to ten carbon atoms, attached to a divalent sulfur atom. An example of "arylthio" is phenylthio.
The term "aralkylthio" embraces aralkyl radicals as described above, attached to a divalent sulfur atom. More preferred are phenyl-C|-C3-alkylthio radicals. An example of "aralkylthio" is benzylthio.
The term "aryloxy" embraces optionally substituted aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy.
The term "aralkoxy" embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy" radicals having optionally substituted phenyl radicals attached to lower alkoxy radical as described above.
The term "heteroaryloxy" embraces optionally substituted heteroaryl radicals, as defined above, attached to an oxygen atom.
The term "heteroarylalkoxy" embraces oxy-containing heteroarylalkyl radicals attached through an oxygen atom to other radicals. More preferred heteroarylalkoxy radicals are "lower heteroarylalkoxy" radicals having optionally substituted heteroaryl radicals attached to lower alkoxy radical as described above.
The term "cycloalkyl" includes saturated carbocyclic groups. Preferred cycloalkyl groups include C3-C6 rings. More preferred compounds include, cyclopentyl, cyclopropyl, and cyclohexyl.
The term "cycloalkylalkyl" embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl" radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are "5-6- membered cycloalkylalkyl" attached to alkyl portions having one to three carbon atoms. Examples of such radicals include cyclohexylmethyl. The cycloalkyl in said radicals may be additionally substituted with halo, alkyl, alkoxy and hydroxy.
The term "cycloalkenyl" includes carbocyclic groups having one or more carbon- carbon double bonds including "cycloalkyldienyl" compounds. Preferred cycloalkenyl groups include C3-C6 rings. More preferred compounds include, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl.
The term "comprising" is meant to be open ended, including the indicated component but not excluding other elements.
The term(s) "Formulas I, II, III, IV, V, VI and VH" either alone or in combination includes any sub formulas.
The compounds of the invention are endowed with c-Met inhibitory activity.
The present invention also comprises the use of a compound of the invention, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment either acutely or chronically of an angiogenesis mediated disease state, including those described previously. The compounds of the present invention are useful in the manufacture of an anti-cancer medicament. The compounds of the present invention are also useful in the manufacture of a medicament to attenuate or prevent disorders through inhibition of c-Met.
The present invention comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of the current invention in association with a least one pharmaceutically acceptable carrier, adjuvant or diluent.
The present invention also comprises a method of treating angiogenesis related disorders in a subject having or susceptible to such disorder, the method comprising treating the subject with a therapeutically effective amount of a compound of the current invention. COMBINATIONS
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition.
The phrase "co-therapy" (or "combination-therapy"), in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.
Specifically, the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of neoplasia, such as with radiation therapy or with cytostatic or cytotoxic agents.
If formulated as a fixed dose, such combination products employ the compounds of this invention within the accepted dosage ranges. Compounds of the current invention may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of the invention may be administered either prior to, simultaneous with or after administration of the known anticancer or cytotoxic agent.
Currently, standard treatment of primary tumors consists of surgical excision followed by either radiation or IV administered chemotherapy. The typical chemotherapy regime consists of either DNA alkylating agents, DNA intercalating agents, CDK inhibitors, or microtubule poisons. The chemotherapy doses used are just below the maximal tolerated dose and therefore dose limiting toxicities typically include, nausea, vomiting, diarrhea, hair loss, neutropenia and the like.
There are large numbers of antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which would be selected for treatment of neoplasia by combination drug chemotherapy. Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and a category of miscellaneous agents. A first family of antineoplastic agents, which may be used in combination with compounds of the present invention, consists of antimetabolite-type/thymidilate synthase inhibitor antineoplastic agents. Suitable antimetabolite antineoplastic agents may be selected from but not limited to the group consisting of 5-FU-fϊbrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-Ol 5, fazarabine, floxuridine, fludarabine phosphate, 5- fluorouracil, N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC- 127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, Taiho UFT and uricytin.
A second family of antineoplastic agents, which may be used in combination with compounds of the present invention, consists of alkylating-type antineoplastic agents. Suitable alkylating-type antineoplastic agents may be selected from but not limited to the group consisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA- 102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA- 2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI- 17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC- 342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-1 19, ranimustine, semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.
A third family of antineoplastic agents which may be used in combination with compounds of the present invention consists of antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from but not limited to the group consisting of Taiho 4181 -A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY- 25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC- 102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindanycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.
A fourth family of antineoplastic agents which may be used in combination with compounds of the present invention consists of a miscellaneous family of antineoplastic agents, including tubulin interacting agents, topoisomerase II inhibitors, topoisomerase I inhibitors and hormonal agents, selected from but not limited to the group consisting of α- carotene, α-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafϊde, amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston AlO, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen- Beaufour BIM-23015, bisantrene, Bristol-Myers BMY-40481, Vestar boron- 10, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX- 100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner- Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel elliprabin, elliptinium acetate, Tsumura EPMTC, the epothilones, ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K- 76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanlne derivatives, methylanilinoacridine, Molecular Genetics MGI- 136, minactivin, mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021, N-acylated-dehydroalanines, nafazatrom, Taisho NCU- 190, nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC- 95580, ocreotide, Ono ONO-1 12, oquizanocine, Akzo Org-10172, paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD- 131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, SmithKline SK&F- 104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN- 1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides and Yamanouchi YM-534.
Alternatively, the present compounds may also be used in co-therapies with other antineoplastic agents, such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisυlind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil/oteracil/tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa, interferon alfa, natural, interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-Nl, interferon alfa-n3, interferon alfacon-1 , interferon alpha, natural, interferon beta, interferon beta- Ia, interferon beta- Ib, interferon gamma, natural interferon gamma- Ia, interferon gamma- Ib, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis stimulating protein, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburicase, rhenium Re 186 etidronate, RII retinamide, rituximab, romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfϊn, vinorelbine, VIRULIZIN, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941 (Aetema), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SDOl (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Trilex), LYM-I -iodine 131 MAb (Techniclone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenyl acetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolysate vaccine (New York Medical College), viral melanoma cell lysates vaccine (Royal Newcastle Hospital), or valspodar.
Alternatively, the present compounds may also be used in co-therapies with VEGFR inhibitors including
N-(4-chlorophenyl)-4-(4-pyridinylmethyl)- 1 -phthalazinamine; 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2- pyridinecarboxamide; N-[2-(diethylamino)ethyl]-5-[(5-fluoro-l,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4- dimethyl-l H-pyrrole-3-carboxamide; 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-[[[[4-(l- pyrrolidinyl)butyl]amino]carbonyl]amino]-4-isothiazolecarboxamide; N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(l-methyl-4-piperidinyl)methoxy]-4- quinazolinamine; 3-[5>6,7,13-tetrahydro-9-[(l-methylethoxy)methyl]-5-oxo-12H-indeno[2,l-a]pyrrolo[3,4- c]carbazol-12-yl]propyl ester N,N-dimethyl-glycine;
N-[5-[[[5-(l,l-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thia2θlyl]-4-piperidinecarboxamide; N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[[[2-
(methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine
4-[(4-Methyl-l-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]- phenyl]benzamide
Λ^-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4-quinazolinamine
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine
N-(3-((((2R)- 1 -methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-2-((3-( 1 ,3- oxazol-5-yl)phenyl)amino)-3-pyridinecarboxamide; 2-(((4-fluorophenyl)methyl)amino)-N-(3-((((2R)-l-methyl-2-pyrrolidinyl)methyl)oxy)-5-
(trifluoromethyl)phenyl)-3-pyridinecarboxamide; N-[3-(Azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-(4-fluoro-benzylamino)- nicotinamide. 6-fluoro-N-(4-( 1 -methylethyl)phenyl)-2-((4-pyridinylmethyl)amino)-3 -pyridinecarboxamide; 2-((4-pyridinylmethyl)amino)-N-(3-(((2S)-2-py.τolidinylmethyl)oxy)-5-
(trifluoromethyl)phenyl)-3-pyridinecarboxamide; N-CS-Cl-l-dimethylethyO-lH-pyrazol-S-yO^-^-pyridinylmethy^amino)^- pyridinecarboxamide; N-CS^-dimethyl^^-dihydro-l-benzofuran-ό-yO^-^-pyridinylmethyOamino^S- pyridinecarboxamide; N-(3-((((2S)-l-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-2-((4- pyridinylmethyl)amino)-3-pyridinecarboxamide; 2-((4-pyridinylmethyl)amino)-N-(3-((2-(l-pyrrolidinyl)ethyl)oxy)-4-(trifluoromethyl)phenyl)-
3-pyridinecarboxamide; N-(3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-2-((4-pyridinylmethyl)amino)-3- pyridinecarboxamide; N-(4-(pentafluoroethyl)-3-(((2S)-2-pyrrolidinylmethyl)oxy)phenyl)-2-((4- pyridinylmethyl)amino)-3-pyridinecarboxamide; N-(3-((3-azetidinylmethyl)oxy)-5-(trifluoromethyl)phenyl)-2-((4-pyridinylmethyl)amino)-3- pyridinecarboxamide; N-(3-(4-piperidinyloxy)-5-(trifluoromethyl)phenyl)-2-((2-(3-pyridinyl)ethyl)amino)-3- pyridinecarboxamide;
N-(4,4-dimethyl-l,2,3,4-tetrahydro-isoquinolin-7-yl)-2-(lH-indazol-6-ylamino)-nicotinamide; 2-(lH-indazol-6-ylamino)-N-[3-(l-methylpyrrolidin-2-ylmethoxy)-5-trifluoroπiethyl-phenyI]- nicotinamide; N-[I -(2-dimethylamino-acetyl)-3 ,3 -dimethyl-2,3 -dihydro- 1 H-indol-6-yl]-2-( 1 H-indazol-6- ylamino)-nicotinamide; 2-(lH-indazol-6-ylamino)-N-[3-(pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]- nicotinamide;
N-(l-acetyl-3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-2-(lH-indazol-6-ylamino)-nicotinamide; N-(4,4-dimethyl- 1 -oxo- 1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-(l H-indazoI-6-y lamino)- nicotinamide; N-[4-(tert-butyl)-3-(3-piperidylpropyl)phenyl][2-(lH-indazol-6-ylamino)(3- pyridyl)]carboxamide;
N-[5-(tert-butyl)i soxazol-3-yl] [2-( 1 H-indazol-6-ylamino)(3 -pyridyl)]carboxamide; and N-^-ζtert-buty^phenylJP-ClH-indazol-β-ylaminoXS-pyridyl^carboxamide.
Other compounds described in the following patents and patent applications can be used in combination therapy: US 6,258,812, US 2003/0105091, WO 01/37820, US 6,235,764, WO 01/32651, US 6,630,500, US 6,515,004, US 6,713,485, US 5,521,184, US 5,770,599, US 5,747,498, WO 02/68406, WO 02/66470, WO 02/55501, WO 04/05279, WO 04/07481, WO 04/07458, WO 04/09784, WO 02/59110, WO 99/45009, WO 00/59509, WO 99/61422, US 5,990,141, WO 00/12089 and WO 00/02871.
In some embodiments, the combination comprises a composition of the present invention in combination with at least one anti-angiogenic agent. Agents are inclusive of, but not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof. An agent can be an agonist, antagonist, allosteric modulator, toxin or, more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or arrest cell growth.
Exemplary anti-tumor agents include HERCEPTIN™ (trastuzumab), which may be used to treat breast cancer and other forms of cancer, and RITUXAN™ (rituximab), ZEVALIN™ (ibritumomab tiuxetan), and LYMPHOCIDE™ (epratuzumab), which may be used to treat non-Hodgkin's lymphoma and other forms of cancer, GLEEV AC™ which may be used to treat chronic myeloid leukemia and gastrointestinal stromal tumors, and BEXXAR™ (iodine 131 tositumomab) which may be used for treatment of non-Hodgkins's lymphoma.
Exemplary anti-angiogenic agents include ERBITUX™ (IMC-C225), KDR (kinase domain receptor) inhibitory agents (e.g., antibodies and antigen binding regions that specifically bind to the kinase domain receptor), anti-VEGF agents (e.g., antibodies or antigen binding regions that specifically bind VEGF, or soluble VEGF receptors or a ligand binding region thereof) such as AVASTIN™ or VEGF-TRAP™, and anti-VEGF receptor agents (e.g., antibodies or antigen binding regions that specifically bind thereto), EGFR inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto) such as ABX-EGF (panitumumab), IRESS A™ (gefitinib), TARCE V A™ (erlotinib), anti-Angl and anti-Ang2 agents (e.g., antibodies or antigen binding regions specifically binding thereto or to their receptors, e.g., Tie2/Tek), and anti-Tie2 kinase inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto). The pharmaceutical compositions of the present invention can also include one or more agents (e.g., antibodies, antigen binding regions, or soluble receptors) that specifically bind and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as Scatter Factor), and antibodies or antigen binding regions that specifically bind its receptor "c-met".
Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (Ceretti et al., US Publication No. 2003/0162712; US Patent No. 6,413,932), anti-TWEAK agents (e.g., specifically binding antibodies or antigen binding regions, or soluble TWEAK receptor antagonists; see, Wiley, US Patent No. 6,727,225), ADAM distintegrin domain to antagonize the binding of integrin to its ligands (Fanslow et al., US Publication No. 2002/0042368), specifically binding anti-eph receptor and/or anti-ephrin antibodies or antigen binding regions (US Patent Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and patent family members thereof), and anti-PDGF-BB antagonists (e.g., specifically binding antibodies or antigen binding regions) as well as antibodies or antigen binding regions specifically binding to PDGF-BB ligands, and PDGFR kinase inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto).
Additional anti-angiogenic/anti-tumor agents include: SD-7784 (Pfizer, USA); cilengitide.(Merck KGaA, Germany, EPO 770622); pegaptanib octasodium, (Gilead Sciences, USA); Alphastatin, (BioActa, UK); M-PGA, (Celgene, USA, US 5712291); ilomastat, (Arriva, USA, US 58921 12); emaxanib, (Pfizer, USA, US 5792783); vatalanib, (Novartis, Switzerland); 2-methoxyestradiol, (EntreMed, USA); TLC ELL- 12, (Elan, Ireland); anecortave acetate, (Alcon, USA); alpha-D148 Mab, (Amgen, USA); CEP-7055,(Cephalon, USA); anti- Vn Mab, (Crucell, Netherlands) DACrantiangiogenic, (ConjuChem, Canada); Angiocidin, (InKine Pharmaceutical, USA); KM-2550, (Kyowa Hakko, Japan); SU-0879, (Pfizer, USA); CGP-79787, (Novartis, Switzerland, EP 970070); ARGENT technology, (Ariad, USA); YIGSR-Stealth, (Johnson & Johnson, USA); fibrinogen-E fragment, (BioActa, UK); angiogenesis inhibitor, (Trigen, UK); TBC-1635, (Encysive Pharmaceuticals, USA); SC-236, (Pfizer, USA); ABT-567, (Abbott, USA); Metastatin, (EntreMed, USA); angiogenesis inhibitor, (Tripep, Sweden); maspin, (Sosei, Japan); 2-methoxyestradiol, (Oncology Sciences Corporation, USA); ER-68203-00, (IVAX, USA); Benefin, (Lane Labs, USA); Tz-93, (Tsumura, Japan); TAN-1120, (Takeda, Japan); FR-1 11142, (Fujisawa, Japan, JP 02233610); platelet factor 4, (RepliGen, USA, EP 407122); vascular endothelial growth factor antagonist, (Borean, Denmark); cancer therapy, (University of South Carolina, USA); bevacizumab (plNN), (Genentech, USA); angiogenesis inhibitors, (SUGEN, USA); XL 784, (Exelixis, USA); XL 647, (Exelixis, USA); MAb, alpha5beta3 integrin, second generation, (Applied Molecular Evolution, USA and Medlmmune, USA); gene therapy, retinopathy, (Oxford BioMedica, UK); enzastaurin hydrochloride (USAN), (Lilly, USA); CEP 7055, (Cephalon, USA and Sanofi-Synthelabo, France); BC 1, (Genoa Institute of Cancer Research, Italy); angiogenesis inhibitor, (Alchemia, Australia); VEGF antagonist, (Regeneron, USA); rBPI 21 and BPI-derived antiangiogenic, (XOMA, USA); PI 88, (Progen, Australia); cilengitide (plNN), (Merck KGaA, German; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); cetuximab (INN), (Aventis, France); AVE 8062, (Ajinomoto, Japan); AS 1404, (Cancer Research Laboratory, New Zealand); SG 292, (Telios, USA); Endostatin, (Boston Childrens Hospital, USA); ATN 161, (Attention, USA); ANGIOST ATIN, (Boston Childrens Hospital, USA); 2-methoxyestradiol, (Boston Childrens Hospital, USA); ZD 6474, (AstraZeneca, UK); ZD 6126, (Angiogene Pharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD 9935, (AstraZeneca, UK); AZD 2171, (AstraZeneca, UK); vatalanib (pINN), (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitors, (EntreMed, USA); pegaptanib (Pinn), (Gilead Sciences, USA); xanthorrhizol, (Yonsei University, South Korea); vaccine, gene-based, VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2, (Supratek, Canada); SDX 103, (University of California at San Diego, USA); PX 478, (ProlX, USA); METAST ATIN, (EntreMed, USA); troponin I, (Harvard University, USA); SU 6668, (SUGEN, USA); OXI 4503, (OXiGENE, USA); o-guanidines, ( Dimensional Pharmaceuticals, USA); motuporamine C, (British Columbia University, Canada); CDP 791, (Celltech Group, UK); atiprimod (pINN), (GlaxoSmithKline, UK); E 7820, (Eisai, Japan); CYC 381, (Harvard University, USA); AE 941, (Aeterna, Canada); vaccine, angiogenesis, (EntreMed, USA); urokinase plasminogen activator inhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte, USA); HIF-lalfa inhibitors, (Xenova, UK); CEP 5214, (Cephalon, USA); BAY RES 2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6, (Angstrom, USA); KR 31372, (Korea Research Institute of Chemical Technology, South Korea); GW 2286, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP 868596, (Pfizer, USA); CP 564959, (OSI, USA); CP 547632, (Pfizer, USA); 786034, (GlaxoSmithKline, UK); KRN 633, (Kirin Brewery, Japan); drug delivery system, intraocular, 2-methoxyestradiol, (EntreMed, USA); anginex, (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510, (Abbott, USA); AAL 993, (Novartis, Switzerland); VEGI, (ProteomTech, USA); tumor necrosis factor-alpha inhibitors, (National Institute on Aging, USA); SU 11248, (Pfizer, USA and SUGEN USA); ABT 518, (Abbott, USA); YHl 6, (Yantai Rongchang, China); S-3APG , (Boston Childrens Hospital, USA and EntreMed, USA); MAb, KDR, (ImClone Systems, USA); MAb, alpha5 betal, (Protein Design, USA); KDR kinase inhibitor, (Celltech Group, UK, and Johnson & Johnson, USA); GFB 116, (South Florida University, USA and Yale University, USA); CS 706, (Sankyo, Japan); combretastatin A4 prodrug, (Arizona State University, USA); chondroitinase AC, (IBEX, Canada); BAY RES 2690, (Bayer, Germany); AGM 1470, (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925, (Agouron, USA); Tetrathiomolybdate, (University of Michigan, USA); GCS 100, (Wayne State University, USA) CV 247, (Ivy Medical, UK); CKD 732, (Chong Kun Dang, South Korea); MAb, vascular endothelium growth factor, (Xenova, UK); irsogladine (INN), (Nippon Shinyaku, Japan); RG 13577, (Aventis, France); WX 360, (Wilex, Germany); squalamine (pINN), (Genaera, USA); RPI 4610, (Sirna, USA); cancer therapy, (Marinova, Australia); heparanase inhibitors, (InSight, Israel); KL 3106, (Kolon, South Korea); Honokiol, (Emory University, USA); ZK CDK, (Schering AG, Germany); ZK Angio, (Schering AG, Germany); ZK 229561, (Novartis, Switzerland, and Schering AG, Germany); XMP 300, (XOMA, USA); VGA 1 102, (Taisho, Japan); VEGF receptor modulators, (Pharmacopeia, USA); VE-cadherin-2 antagonists , (ImClone Systems, USA); Vasostatin, (National Institutes of Health, USA);vaccine, FIk-I, (ImClone Systems, USA); TZ 93, (Tsumura, Japan); TumStatin, (Beth Israel Hospital, USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1), (Merck & Co, USA); Tie-2 ligands, (Regeneron, USA); and, thrombospondin 1 inhibitor, (Allegheny Health, Education and Research Foundation, USA).
Alternatively, the present compounds may also be used in co-therapies with other antineoplastic agents, such as VEGF antagonists, other kinase inhibitors including p38 inhibitors, KDR inhibitors, EGF inhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP), COX-2 inhibitors including celecoxib, NSAID' s, or αvβ3 inhibitors.
The present invention comprises processes for the preparation of a compound of Formula I, II, III, IV, V, VI and VII.
Also included in the family of compounds of the current are the pharmaceutically acceptable salts and solvates thereof. The term "pharmaceutically-acceptable salts" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds of the current invention may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic, nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic, persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic, tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of the current invention include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine. All of these salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of the current invention. When a basic group and an acid group are present in the same molecule, a compound of the current invention may also form internal salts.
GENERAL SYNTHETIC PROCEDURES
The compounds of the invention can be synthesized according to the following procedures.
The following abbreviations are used throughout the specification: HOAc - acetic acid
MeCN, CH3CN - acetonitrile
NH3 - ammonia
NH4Cl - ammonium chloride
Ar - argon
HBTA - 0-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU - O-CT-azabenzotriazoM-yO-N^N'.N'-tetramethyluroniurn hexafluorophosphate PyBop - benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium hexafluorophosphate
Pd2(dba)3 - bis(dibenzylideneacetone) palladium
BINAP - 2,2'-bis(diphenylphosphino)-l,r-binaphthyl
TEAC - bis(tetra-ethylammonium)carbonate
BBr3 - boron tribromide
BSA - bovine serum albumin
Br2 - bromine
BOC - butyloxycarbonyl Cs2CO3 cesium carbonate
CHCl3 chloroform
CDCl3 chloroform deuterated
Cu copper
CuI copper(I) iodide
Et2O diethyl ether
DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
DIBAL diisobutylaluminum hydride
DIAD diisopropyl azodicarboxylate
DIEA diisopropylethylamine
DMF dimethylformamide
DMAP 4-dimethylaminopyridine
DMSO dimethylsulfoxide
EDC5 EDCI 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride dppa diphenylphosphoryl azide
EtOAc ethyl acetate
FBS fetal bovine serum g gram h hour
HBr hydrobromic acid
HCl hydrochloric acid
HOBt 1-hydroxybenzotriazole hydrate
H2 hydrogen
H2O2 hydrogen peroxide
Fe iron
LiHMDS lithium bis(trimethylsilyl)-amide
LDA Lithium diisopropylamide
MCPBA me/a-chloroperbenzoic acid
MgSO4 magnesium sulfate
MeOH, CH3OH - methanol
MeI methyl iodide
CH2Cl2, DCM methylene chloride
NMP N-methylpyrrolidinone
ML, ml milliliter N2 nitrogen
Pd/C palladium on carbon
Pd(OAc)2 palladium acetate
Pd(OH)2 palladium hydroxide
Pd(PPh3)4 palladium tetrakis triphenylphosphine
Pd(dppf)Cl2 l,l-bis(diphenylphosphino)ferrocene palladium chloride
PBS phosphate buffered saline
POCl3 phosphorous oxychloride
K2CO3 potassium carbonate
KOH potassium hydroxide
RT room temperature
NaHCO3 sodium bicarbonate
NaBH4 sodium borohydride
NaBH3CN sodium cyanoborohydride
NaOtBu sodium tert-butoxide
NaOH sodium hydroxide
NaClO2 sodium chlorite
NaCl sodium chloride
NaHPO4 sodium biphospate
NaH sodium hydride
NaI sodium iodide
Na2SO4 sodium sulfate
TBTU O-benzotriazol- 1 -y 1-N,N,N ' ,N ' -tetramethyluronium tetrafluoroborate
THF tetrahydrofuran
Et3N, TEA triethylamine
TFA trifluoroacetic acid
P(/-bu)3 tri(tert-butyl)phosphine
H2O water General Method A
Figure imgf000052_0001
DEAD. TMSN3 Pd catalysis
Figure imgf000052_0003
Figure imgf000052_0002
Figure imgf000052_0004
Example 1
4-((6-(3-fluorophenylH1.2.41triazolof4<3-blpyridazin-3-yl)methoxy)-7-methoxyquinoline.
Step 1.
2-(7-methoxyquinolin-4-yloxy)acetic acid.
A 250-mL, 3-neck, rb flask equipped with a magnetic stirbar, a reflux condenser and a powder funnel was charged with potassium hydroxide (6.0 g, 90 mmol) then 2-hydroxyacetic acid (5.0 g, 65 mmol) with stirring. The solid reactants gradually reacted and liquified as significant heat was generated. Upon dissolution of all the reagents, flask containing the hot syrupy liquid was immersed in a 170 0C oil bath, then a solution of 4-chloro-7-methoxyquinoline (5.0 g, 26 mmol) in anhydrous DMSO (20 mL, 4 vol wrt quinoline) was added dropwise over 20-30 min via addition funnel. The resulting brown solution was maintained in the oil bath with stirring. After 2.5 h, the flask was removed from the oil bath, then quenched by the addition of water (100 mL, 5 vol wrt DMSO). The resulting brown solution was immersed in an ice bath, and the mixture was neutralized by the dropwise addition of 6 N HCl (15 mL, 1 equiv to KOH), which resulted in the formation of a thick yellow ppt and brought the mixture to pH 3. The mixture was filtered and washed with water and ACN. The solid products were dried under vacuum to yield 2-(7-methoxyquinolin-4-yloxy)acetic acid (2.16 g, 36% yield) as a yellow solid. (ESI, pos. ion) m/z: 234.1 (M+H). Step 2.
N'-(6-chloroDyridazin-3-ylV2-(7-methoxyquinolin-4-yloxy)aeetohvdrazide. A mixture of l-(6-chloropyridazin-3-yl)hydrazine (0.372 g, 2.57 mmol), l-hydroxy-7-aza- benzotriazole (0.350 g, 2.57 mmol), EDC (0.641 g, 3.34 mmol), 2-(7-methoxyquinolin-4- yloxy)acetic acid (0.600 g, 2.57 mmol) and diisopropylethylamine (1.34 ml, 7.72 mmol) in DMF (20 mL) was allowed to stir at 500C for 2h. Concentrated. Reconstitued in MeCN (30 mL). Concentrated with cooling. Product crashed out of solution and was isolated by filtration. Used without further purification. (ESI, pos. ion) m/z: 234.1 (M+H). Step 3.
4-((6-ehloro-π.2.41triazolof43-blpyridazin-3-vDmethoxy)-7-methoxyquinoline. N'-(6-chloropyridazin-3-yl)-2-(7-methoxyquinolin-4-yloxy)acetohydrazide (2.53 g, 7.0 mmol) was suspended in tetrahydrofuran (50 mL) then added triphenylphosphine (2.8 g, 11 mmol) and trimethylsilyl azide (1.4 ml, 11 mmol). To this suspension, was added diethylazodicarboxylate (2.0 ml, 13 mmol) in rapid drops with a syringe. The mixture became clear and hot to the touch. The reaction mixture was heated at 50 0C for 30 minutes. The reaction mixture was concentrated in vacuo. The remaining oil was triturated with diethyl ether. A gel-like solid formed which was collected on a glass frit, washing with diethyl ether. The solid was then triturated with ethyl acetate, and finally acetonitrile. An amorphous solid formed which was collected on a glass frit, washing with acetonitrile. The solid was further dried under high vacuum. In addition, the ethyl acetate filtrate was concentrated in vacuo. The remaining oil was then triturated with acetonitrile. An amorphous solid formed and was collected on a glass frit, washing with acetonitrile. The solid was further dried under high vacuum affording 4-((6-chloro-[l ,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7- methoxyquinoline as a tan solid. MS (ESI, pos. ion) m/z: 342.1 (M+l). Step 4.
4-((6-f3-fluorophcnvπ-H>2,41triazoIo|4<3-blpyridazin-3-yl)niethoxyV7-ιnethoxyquinoline. 3-fluorophenylboronic acid (0.092 g, 0.66 mmol) was added to a suspension of 4-((6-chloro- [l ,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.150 g, 0.44 mmol) in 2.5 mL dimethyl formamide, followed by the addition of potassium carbonate (0.18 g, 1.3 mmol) in 0.6 mL water. PdCl2(dppf)-CH2Cl2 adduct (0.018 g, 0.022 mmol) was added and the flask was purged with argon, sealed and heated at 80 0C for four hours. Purification by MPLC (eluted with 5 then 10 % MeOH in CH2Cl2) afforded the product as an off-white solid (78 mg, 44%). (ESI, pos. ion) m/z: 402.1 (M+H).
General Method B.
Figure imgf000054_0001
Example 2
4- ( (6-phenyl- [1, 2, 4] triazolo [4, 3-b]pyridazin-3- yDmethoxy) opαinoline . Step 1.
(6-phenyl- [1,2,4] triazolo [4, 3-b] pyridazin-3 -yl) methanol . A mixture of 1- (6-phenylpyridazin-3-yl) hydrazine (2.00 g, 10.7 mmol), glycolic acid (0.825 g, 10.8 mmol), p-TsOHH2O (2.55 g, 13.4 mmol) in PhMe (50 mL) was refluxed for 14 h. PhMe was removed in vacuo. The resulting solids were diluted with water
(30 mL) . The mixture was brought to pH~l0 with 2N NaOH. The solids were isolated solid by filtration, washed with water and dried under vacuum to give an off white solid which was used without further purification. (ESI, pos. ion) m/z: 227.0
(M+H) . Step 2 .
4- ( (6-phenyl- [1, 2,4] triazolo [4, 3-b]pyridazin-3- yl) methoxy) quinoline .
Cesium carbonate (335 mg, 1027 μmol) was added to a mixture of 4-chloroquinoline (465 mg, 2054 μmol) and above alcohol (112 mg, 685 μmol) in DMSO (1.8 mL) at RT. The reaction mixture was stirred at 1200C under microwave irradiation for 2h. The reaction mixture was diluted with EtOAc and washed with water. The water layer was extracted with EtOAC. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by MPLC (CH2Cl2/MeOH+l%NH4OH: 100/0 to 95/5) afforded the title compound. (ESI, pos . ion) m/z: 354.1 (M+H) . In addition to the above reaction, potassium hydride in DME can also be utilized in a similar manner.
General Method C.
Figure imgf000055_0001
Figure imgf000055_0002
Example 3
N- (4- ( (6-phenyl- [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) methoxy) pyridin-2-yl) pyrrolidine-1-carboxamide.
Step 1. 4- ( (6-phenyl-[1,2,4] triazolo [4,3-b] pyridazin-3-yl)methoxy)pyridin-2- amine.
To an argon purged flask was added cesium carbonate (0.24 g, 0.73 mmol) , 3- ( (2-chloropyridin-4-yloxy) methyl) -5-phenyl-3aH- pyrazolo [4,3 -b] pyridine (0.0820 g, 0.24 mmol), tris (dibenzylideneacetone) dipalladium (o) (0.0056 g, 0.0061 mmol), rac-2 , 2 ' -bis (diphenylphosphino) -1, 1 ' -binaphthyl (0.0091 g, 0.015 mmol) . The mixture was taken up in dioxane (8 mL) followed by the addition of benzophenone imine (0.049 ml, 0.29 mmol) . The mixture was heated to reflux for 6h. The mixture was cooled to room temperature and filtered through a plug of silica gel which was washed with a large amount of 10% MeOH in CH2Cl2. The resulting mixture was concentrated. The mixture was reconstitued in THF (5 mL) and IM HCl (5 mL) and allowed to stir for 3h then concentrated under reduced pressure. The resulting residue was triturated with ether (3 x 20 mL) and suspended in 9% sodium carbonate. The solid was isolated by filtration and utilized without further purification. (ESI, pos. ion) m/z: 319.1 (M+H) .
Step 2.
N- (4- ( (6-phenyl- [1, 2 , 4] triazolo [4, 3-b] pyridazin-3- yl)methoxy) pyridin-2 -yl) pyrrolidine-1-carboxamide .
To the resulting solid in THF (5 mL) was added TRIETHYLAMINE (0.17 ml, 1.2 mmol) followed by phenyl chloroformate (0.15 ml, 1.2 mmol) . The mixture was allowed to stir for 2h. Added pyrrolidine (0.14 ml, 1.7 mmol) and stirred for an additional 2h. The reaction mixture was concentrated, reconstituted in DMSO and purified via HPLC. (ESI, pos. ion) m/z: 416.2 (M+H).
General Method D.
Figure imgf000057_0001
Figure imgf000057_0002
Example 4
7-methoxy-N- ( (6- (3-methylisothiazol-5-yl) - [1,2,4] triazolo [4#3 b]pyridazin-3 -yl) methyl) -1, 5-naphthyridin-4-amine
1) Preparation of 3-methyl-5-trimethylstannyl) iβothiazole
Figure imgf000057_0003
Butyllithium (1.6M in hexanes, 18.9 ml, 30.3 mmol) was added to a stirred solution of 3-τnethylisothiazole (2.73 g, 27.5 mmol) in THF (80 mL) at -78°C. The reaction mixture was stirred at - 78°C for 30 min and chlorotrimethylstannane (IM in THF, 27.5 ml, 27.5 mmol) was added dropwise. After Ih at -78°C for Ih, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The water layer was extracted with Et2θ. The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo. The material (6.97g) was taken forward without further purification MS m/z = 264.1 . Calc'd for C7H13NSSn: 261.94
2) Preparation of tert-butyl (6- (3-methylisothiazol-5-yl) - [I72, 4] triazolo [4, 3-b] pyridazin-3-yl)methylcarbamate
Figure imgf000058_0001
A pressure vessel was purged with Ar and charged with tert- butyl (6-chloro- [1,2,4] triazolo [4 , 3-b] pyridazin-3- yl) methylcarbamate (5.00 g, 17.6 mraol) , tris (dibenzylideneacetone) dipalladium (0) (0.807 g, 0.881 mmol) , 2-dicyclohexylphosphinobiphenyl (0.618 g, 1.76 mmol) . DMF (50 mL) was added, immediately followed by 3-methyl-5- (trimethylstannyl) isothiazole (6.46 g, 24.7 mmol). The reaction mixture was stirred at 1000C for Ih. Two more portions of tris (dibenzylideneacetone) dipalladium (0) (0.807 g, 0.881 mmol) and 2-dicyclohexylphosphinobiphenyl (0.618 g, 1.76 mmol) were added every hour for the first two hours of stirring. Reaction was then stirred was at 1000C overnight, cooled to room temperature and concentrated in vacuo. Purification by MPLC (EtOAC/MeOH: 100/0 to 90/10) afforded the title compound (1.8Og, 30% yield). MS m/z = 347.1 [M+H]+. Calc'd for
C15H18N6O2S: 346.41
3) Preparation of (6- (3-methylisothiazol-5-yl) -
[1,2,4] triazolo [4.3-b] pyridazin-3-yl)methanamine
Figure imgf000058_0002
Trifluoroacetic acid (2889 μl, 37505 μmol) was added to a stirred suspension of tert-butyl (6- (3-methylisothiazol-5-yl) -
[1, 2,4] triazolo [4, 3-b] pyridazin-3-yl)methylcarbamate (464 mg, 1339 μmol) in DCM (10 mL) at RT. The reaction mixture was stirred at RT for 45 min. and then concentrated in vacuo. 2M NH3 in MeOH was added. Purification by MPLC (DCM/MeOH+l%NH4OH) afforded the title compound (226 mg, 69% yield). MS m/z = 247.1
[M+H]+. CaIc 'd for C10H10N6S: 246.30.
4) 7 -methoxy-N- ( (6- (3-methylisothiazol-5-yl) -
[1,2,4] triazolo [4, 3-b] pyridazin-3-yl)methyl) -1,5- naphthyridin-4 -amine
Figure imgf000059_0001
(6- (3-methylisothiazol-5-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3- yDmethanamine (548 mg, 2225 μmol) and 8-chloro-3-methoxy-l, 5- naphthyridine (576 mg, 2959 μmol) were charged in a microwave vial. 2-butanol (7 mL) was added and the reaction mixture was stirred at 1200C under micro-waves irradiation for 8h. 2M NH3 in MeOH was added. Purification by MPLC (DCM/MeOH+l%NH4OH: 100/0 to 90/10) afforded the title compound (720 mg, 80% yield). MS m/z = 405.1 [M+H]+. Calc'd for C19H16N8OS: 404.46
General Method E.
Figure imgf000060_0001
Example 5
7-methoxy-4- (2- (6-phenyl- [1, 2, 4] triazolo [4, 3-b]pyridazin-3- yl) ethyl) quinoline. Step 1.
Ethyl 3- (7-methθ3cyquinolin-4-yl)propanoate. 4-chloro-7-methoxyquinoline (0.35 g, 2 mmol) , tri-t- butylphosphonium tetrafluoroborate (0.05 g, 0.2 mmol), and tris (dibenzylideneacetone)dipalladium (0) (0.08 g, 0.09 mmol) were combined. The reaction vessel was purged and flushed with nitrogen three times, followed by addition of 3-ethoxy-3- oxopropylzinc bromide in THF (10 mL, 5 mmol, 0.5 M). The reaction mixture was microwaved at 150 0C for 60 minutes. Upon completion, ammonium hydroxide (10 mL) was added. After 30 minutes the mixture was filtered and the filtrate was partitioned between water and ethyl acetate. Extracted with ethyl acetate (3 x 20 mL) . The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated. Purified by MPLC with a gradient of 20 to 50% EtOAc in CH2Cl2- (ESI, pos . ion) m/z: 354.1 (M+H) . Step 2. 7-methoxy-4- (2- (6-phenyl- [1,2,4] triazolo [4, 3-b]pyridazin-3- yl) ethyl) quinoline.
Ethyl 3- (7-methoxyquinolin-4-yl)propanoate (156 mg, 0.60 mmol) was combined with 1- (6-phenylpyridazin-3-yl) hydrazine (115 mg, 0.62 mmol) and pTsOH'H2O(140 mg, 0.72 mmol). The mixture was microwaved at 150 0C for 60 minutes. The residue was taken up in DMSO and purified by HPLC and neutralized to yield the desired product as an off-white solid. (ESI, pos. ion) m/z: 382.1 (M+H) .
Figure imgf000061_0001
Example 6
(4- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) phenyl) -N,N-dimethylmethanamine. A mixture of 4- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) benzaldehyde (prepared according to General Method A) (0.150 g, 0.36 mmol) and dimethylamine, 2.0m solution in thf (0.36 ml, 0.73 mmol) in THF (5 mL) was allowed to stir for 20 min. Added sodium triacetoxyborohydride (0.15 g, 0.73 mmol) and stirred for 4h. Concentrated. Suspended in DMSO, filtered through a 0.45 uM acrodisc. Purified on RPHPLC. Took fractions that contained product and made basic with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z = 441.2 [M+l]+. CaIc'd for C25H24N6O2: 440.2.
Figure imgf000062_0001
Example 7
7-methoxy-4- ( (6- (4- (pyrrolidin-1-ylmethyl) phenyl) - [1,2,4] triazolo [4f 3-b] pyridazin-3-yl)methoxy) quinoline. Prepared in a similar manner as (4- (3- ( (7-methoxyquinolin-4- ~ yloxy) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin- 6 -yl) phenyl) -U1N- dimethylmethanamine .
Figure imgf000062_0002
Example 8
4- ( (6- (3-fluoro-4- (morpholinomethyl) phenyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-3-yl) methoxy) -7 - methoxyquinoline . Prepared in a similar manner as above (4- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4 , 3- b] pyridazin-6-yl) phenyl) -N, N-dimethylmethanamine .
Figure imgf000062_0003
Example 9
2-fluoro-N- (2-methoxyeth.yl) -4- (3- ( (7-methoxyquinolin-4- yloxy) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6-yl)benzamide.
A mixture of methyl 2-fluoro-4- (3- ( (7-methoxyquinolin-4- yloxy) methyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-6-yl) benzoate
(.488 g, 1.06 mmol) (prepared according to General Method A) and lithium hydroxide hydrate (0.223 g, 5.31 mmol) in THF (20 mL) , water (5 mL) and MeOH (5 mL) was heated to 400C for 3h. Brought to near neutral pH with IM HCl. Concentrated. Azeotroped with MeCN (20 mL) and PhMe (20 mL) . Used without futher purification. A mixture of 2-methoxyethylamine (0.033 ml, 0.38 mmol), HATU (0.24 g, 0.62 mmol), Hunig ' sBase (0.24 ml, 1.4 mmol) , 2-fluoro-4- (3- ( (7-methoxyquinolin-4-yloxy) methyl) -
[1, 2,4] triazolo [4, 3-b] pyridazin-6-yl) benzoic acid (0.153 g, 0.34 mmol) in DMF was allowed to stir at room temperature for Ih. Concentrated. Purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate. The volatiles were removed in vacuo and the product was isolated by filtration. Dried under vacuum. MS m/z = 503.2
[M+l] + . CaIc ' d for C2SH23FN6O4 : 502 . 5 .
Figure imgf000063_0001
Example 10
2 - f luoro- 4 - ( 3 - ( (7 -metho3cyquinolin- 4 -yloxy) methyl) -
[1,2,43 triazolo [4, 3-b] pyridazin-6-yl) -N,N-dimethylbenzamide.
Prepared in a similar manner as 2-fluoro-N- (2-methoxyethyl) -4 (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl)benzamide .
Figure imgf000064_0001
Example 11
2-fluoro-4- (3- ( (7 -methoxyquinolin-4-ylθ3cy) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6-yl) benzamide. Prepared in a similar manner as 2-fluoro-N- (2-methoxyethyl) -4- (3- ( (7- methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) benzamide .
Figure imgf000064_0002
4- ( (6 -phenyl- U, 2, 4] triazolo [4, 3-b] pyridazin-3- yDmethoxy) quinoline-7-carboxamide. A mixture of 4- ( (6-phenyl- [1,2,4] triazolo [4 , 3-b] pyridazin-3-yl)methoxy) quinoline-7- carbonitrile (0.300 g, 0.793 mmol) and SULFURIC ACID (3.00 ml, 56.3 mmol) was heated at 900C for 30 rain. Quenched onto ice and sodium bicarbonate. Isolated solid by filtration and purified on RPHPLC. Fractions containing product were treated with 9% sodium carbonate. Removed volatiles . Product crashed out and was isolated by filtraton. MS m/z = 397.1 [M+l]+. CaIc 'd for C22Hi6N6O2: 396.4.
Figure imgf000065_0001
Example 13
1- { (6-phenyl- [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl)methyl) -IH- [1, 2,3] triazolo [4, 5-c] pyridine. Step 1. To a solution of ethyl 2- (3-nitropyridin-4-ylamino) acetate (1.41 g, 6.26 mmol) (prepared according to J. Med. Chem. (1991), 34, 2993.) in THF (10 mL) , MeOH (10 inL) and water (5 mL) at 00C was added lithium hydroxide, monohydrate (0.522 ml, 18.8 mmol) . Stirred at 00C for 30 min. Acidified to pH~4 with cone. HCl. Concentrated. Azeotroped with MeCN (40 mL) followed by PhMe (30 mL) . Took up in DMF (30 mL) . Added 1- (6-phenylpyridazin-3-yl) hydrazine (1.17 g, 6.26 mmol), diisopropylethylamine (3.27 ml, 18.8 mmol) followed by HATU (3.57 g, 9.39 mmol). Stirred for 30 min. Concentrated. Partitioned between DCM (30 mL) and water (30 mL) . Filtered and isolated solid material. Washed with water (10 mL) and DCM (10 mL) . Dried under vacuum. MS m/z = 366.1 [M+l]+. CaIc 'd for Ci7H15N7O3: 365.4.
Step 2. To a mixture of 2- (3-nitropyridin-4-ylamino) -N' - (6- phenylpyridazin-3-yl)acetohydrazide (0.663 g, 1.81 mmol), triphenylphosphine (0.952 g, 3.63 mmol) and trimethylsilyl azide (0.482 ml, 3.63 mmol) in THF (10 mL) at room temperature was added diisopropyl azodicarboxylate (0.715 ml, 3.63 mmol). Heated to ~70°C for 30 min. Reaction is complete. Concentrated. Purified on silica gel. 0 to 7% MeOH in CH2Cl2 with 1% NH4OH. MS m/z = 348.1 [M+l]+. CaIc 'd for Ci7H13N7O2: 347.3.
Step 3. To a mixture of 3-nitro-N- ( (6-phenyl- [1,2,4] triazolo [4, 3-b] pyridazin-3 -yl) methyl) pyridin-4-amine (0.373 g, 1.07 mmol) in THF (10 mL) , MeOH (5 mL) , EtOH (10 mL) was added Raney Nickel (wet, washed, ~lg wet) . Stirred for 20 min. Reaction is complete. Filtered through a 0.45 μm acrodisc. Concentrated. Used without further purification. MS m/z = 318.1 [M+l]+. Calc'd for C17H15N7: 317.4. Step 3. To a solution of N4- ( (6 -phenyl- [1, 2 , 4] triazolo [4 , 3- b] pyridazin-3-yl)methyl)pyridine-3, 4-diamine (0.0640 g, 0.202 mmol) in HOAc (5 mL) was added sodium nitrite (0.0153 g, 0.222 mmol) in water (2 mL) . Stirred for Ih. Concentrated. Took up in DMSO and purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate and removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z = 329.2[M+1] + . Calc'd for C17H12N8: 328.3.
Figure imgf000066_0001
Example 14
3- ( (lH-imidazo [4, 5-c] pyridin-1-yl) methyl) -6-phenyl- [1,2,4] triazolo [4, 3-b] pyridazine. A mixture of N4- ( (6-phenyl- [1,2,4] triazolo [4, 3-b] pyridazin-3-yl) methyl) pyridine-3 , 4- diamine (0.0650 g, 0.20 mmol), triethyl orthoformate (5.0 ml, 30 mmol), and p-TsOH (0.0039 g, 0.020 mmol) was heated at 600C. After 2h reaction is complete. Reaction was concentrated. Took up in DMSO and purified on RPHPLC. Fractions containing product were treated with 9% sodium carbonate and volatiles removed. Collected product by filtration. MS m/z = 328.1 [M+l]+. Calc'd for C18H13N7: 327.3.
Figure imgf000067_0001
Example 15
4- ( (6- (3-flυ.oro-4- (2 -morpholinoethoxy) phenyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-3-yl) methoxy) -7- methoxyquinoline . To a mixture of 4- (2-hydroxyethyl) morpholine (0.0964 ml, 0.788 mmol) , triphenylphosphine (0.238 g, 0.909 mmol) , 2-fluoro-4- (3- ( (7-methoxyquinolin-4-yloxy) methyl) - [1, 2,4] triazolo [4, 3-b] pyridazin-6-yl) phenol (.253 g, 0.606 mmol) (prepared according to General Method A) in THF (10 raL) was added DEAD (0.144 ml, 0.909 mmol) . Stirred at room temperature for Ih. Concentrated. Purifed on RPHPLC. Fractions containing product were treated with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z = 531.2 [M+l]+. CaIc'd for C28H27FN6O4: 530.5.
Figure imgf000067_0002
Example 16
2-chloro-N- (2-methoxyethyl) -4- (3- ( (7-methoxyquinolin-4- yloxy) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6-yl)benzainide.
Prepared in a similar manner as 2-fluoro-N- (2-methoxyethyl) -4- (3- ( (7-methoxyquinolin-4-yloxy)methyl) -[1,2,4] triazolo [4,3- b] pyridazin-6-yl) benzamide . MS m/z = 519.1 [M+l] + . CaIc'd for C26H23ClN6O4: 518.9.
Figure imgf000068_0001
Example 17
4- ( (6- (3-chloro-4- (3-methyl-l, 2,4-oxadiazol-5-yl) phenyl) - [1,2,4] triazolo[4,3-b]pyridazin-3-yl)methoxy) -7- methoxyquinoline . HATU (0.370 g, 0.974 mmol) and 2-chloro-4- (3- ( ( 7-methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) benzoic acid (0.300 g, 0.650 mmol) were taken up in DMF (5 mL) . Added Hunig'sBase (0.339 ml, 1.95 mmol) . Stirred for 10 min. Added (Z) -N1 -hydroxyacetamidine (0.289 g, 3.90 mmol). Stirred for an additional 30 min. Removed DMF in vacuo. Suspended in water. Isolated product by filtration. The resulting solid was allowed to try under vacuum. Split into 3 portions and separately took up in dioxane (4 mL) in a microwave tube and heated for 12 min at 1500C. Combined all 3 reactions. Concentrated. Purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z = 500.0 [M+l]+. CaIc 'd for C25H18ClN7O3: 499.1.
Figure imgf000068_0002
Example 18 7-methθ3cy-4- ( (6- (1-methyl-IH-I, 2, 3-triazol-4-yl) - [1,2,4] triazolo [4, 3-a] pyridin-3-yl)methoxy) quinoline. Step 1. Tri-t-butylphosphonium tetrafluoroborate (0.0377 g, 0.130 mmol) , tris (dibenzylideneacetone) dipalladium (0.0594 g, 0.0649 mmol) , trimethylsilyl acetylene (1.82 ml, 13.0 mmol), 4-((6- bromo- [1,2,4] triazolo [4, 3-a]pyridin-3-yl)methoxy) -7- methoxyquinoline (0.500 g, 1.30 mmol) were taken up in dioxane (10 mL) and triethylamine (3 mL) . Added CuI. Sealed in a tube and heated at 800C for 3h. Concentrated. Took up in MeOH and added solid potassium carbonate (large excess) . Allowed to stir for 30 min. Filtered through a plug of Celite and concentrated. Took up in 10% MeOH in DCM and filtered through a plug of silica gel to afford 4- ( (6-ethynyl-
[1,2,4] triazolo [4 , 3 -a] pyridin-3-yl)methoxy) -7-methoxyquinoline. MS m/z = 331.0 [M+l]+. CaIc' d for C19H14N4O2: 330.3. Step 2. To a mixture of 4- ( (6-ethynyl- [1, 2 , 4] triazolo [4 , 3- a]pyridin-3-yl)methoxy) -7-methoxyquinoline (.200 g, 0.605 mmol), trimethylsilylmethyl azide (0.156 g, 1.21 mmol), sodium ascorbate (0.240 g, 1.21 mmol) in THF (4 mL) and water (1 mL) was added 1 drop of a copper sulfate (0.00966 g, 0.0605 mmol) solution. Stirred for Ih. Concentrated. Suspended in water and extracted with CH2Cl2 (3 x 5 mL) . Dried over sodium sulfate and concentrated. Took up crude mixture in DMF (4 mL) . Added cesium fluoride (0.368 g, 2.42 mmol) and heated to 60° for Ih. Concentrated. Purified on RPHPLC. Fractions containing product were treated with 9% sodium carbonate and volatiles were removed in vacuo. Product crashed out of solution and was isolated by filtration. MS m/z = 388.1 [M+l]+. CaIc 'd for C20H17N7O2: 387.4.
Figure imgf000069_0001
Example 19
(R/S) -7-methoxy-4- ( (6-phenyl- [1, 2 , 4] triazolo [4, 3-b]pyridazin-3- yl) methylaulfinyl) quinoline . In a 50 mL round bottom flask under N2 were dissolved 7-methoxy-4- ( (6-phenyl- [1,2,4] triazolo [4 , 3-b] pyridazin-3-yl)methylthio) quinoline (prepared according to General Method B) (220 mg, 551 μmol) in 5.5 mL of DCM then cooled down at -78 0C and treated with solid m-CPBA (77%) (124 mg, 716 μmol) then warmed slowly to rt over 3h. The reaction mixture was diluted with DCM then neutralized with NaHCO3 (sat.). The aqueous phase was extracted 3X with DCM then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO) with DCM / DCM :MeOH :NH4OH (90:10:1)100:0 to 90:10 to afforded 7-methoxy-4- ( (6-phenyl-
[1,2,4] triazolo [4, 3-b] pyridazin-3 -yl) methylsulfinyl) quinoline (109 mg, 47.6% yield) as a white solid. MS m/z = 415.1 [MH-I]+. CaIc 'd for C22H17N5O2S: 416.0.
Figure imgf000070_0001
Example 20
3- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) -Jf,N-dimethylprop-2-yn-l-amine. In a 10 mL sealed tube under N2 were dissolved dichlorobis (triphenylphosphine) palladium (41 mg, 59 μmol) , N1N- dimethylprop-2-yn-l-amine (97 mg, 1170 μmol) , 4- ( (6-chloro- [1,2,4] triazolo [4 , 3-b] pyridazin-3-yl)methoxy) -7- methoxyquinoline (prepared according to General Method A) (200 mg, 585 μmol) , TRIETHYLAMINE (1631 μl, 11704 μmol) and COPPER(I) IODIDE (11 mg, 59 μmol) in 3 mL of MeCN then stirred and heated at 80 0C for 1Oh. The crude reaction mixture was directly purified by MPLC (ISCO) with DCM / DCM :MeOH: NH4OH (90:10:1) 95:5 to afforded 3- (3- ( (7-methoxyquinolin-4- yloxy) methyl) - [1,2,4] triazolo[4, 3-b] pyridazin-6-yl) -N, N- dimethylprop-2-yn-l-amine (26 mg, 11% yield) as a yellow solid. MS m/z = 388.2 [M+l]+. CaIc' d for C2IH20N6O2: 389.2.
Figure imgf000071_0001
Example 21
S- ( (6-phenyl- [1,2,4] triazolo [4, 3-b]pyridazin-3-yl)methylamino) - 1, 5-naphthyridin-3-ol. In a 25 mL sealed tube was dissolved 7- methoxy-N- ( (6-phenyl- [1,2,4] triazolo [4 , 3-b] pyridazin-3- yDmethyl) -1, 5-naphthyridin-4-amine (prepared according to General Method D) (300 mg, 782 μmol) in 5 mL of concentrated HBr then stirred and heated at 100 0C for 48h. The reaction mixture was diluted with DCM and H2O then neutralized with NaOH
(IN) to neutral pH. The aqueous phase was extracted 3X with DCM then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO) with DCM: MeOH: NH4OH (90:10:1) and then triturated with hot EtOH to afforded 8- ( (6-phenyl-
[1,2,4] triazolo [4 , 3-b] pyridazin-3-yl)τnethylamino) -1,5- naphthyridin-3-ol (230 mg, 79.6% yield) as a tan solid. MS m/z = 369.1 [M+l]+. CaIc 'd for C20H15N7O: 370.0.
Figure imgf000072_0001
Example 22
N- ( (6-phenyl- [1,2,4] triazolo [4, 3-b] pyridazin-3-yl)methyl) -7- (2- (pyrrolidin-1-yl) ethoxy) -1, 5-naphthyridin-4-amine« In a 10 mL sealed tube under N2 were dissolved CESIUM CARBONATE (221 mg, 677 μmol) , 8- ( (6-phenyl- [1, 2 , 4] triazolo [4 , 3-b] pyridazin-3- yDmethylamino) -1, 5-naphthyridin-3-ol (50 mg, 135 μmol), 1- (2- chloroethyl) pyrrolidine hydrochloride (46 mg, 271 μmol) and SODIUM IODIDE (41 mg, 271 μmol) in 1 mL of DMSO then stirred and heated at 75 0C for 3h. The reaction mixture was diluted with H2O and the aqueous phase was extracted 3X with DCM then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure . The crude mixture was purified by MPLC (ISCO) with DCM / DCM:MeOH : NH4OH (90:10:1)100:0 to 90:10 to afforded N- ( (6-phenyl- [1, 2, 4] triazolo [4 , 3- b] pyridazin-3 -yl) methyl) -7- (2- (pyrrolidin-1-yl) ethoxy) -1,5- naphthyridin-4-amine (7 mg, 11% yield) as a yellow solid. MS m/z = 466.2 [M+l]+. CaIc'd for C26H26N8O: 467.0.
Figure imgf000072_0002
Example 23
7-Methoxy-4- ( (5-phenyl- [1, 2, 3] triazolo [1, 5-a]pyridin-3- yDmethoxy) quinoline a) 5-Phenyl- [1,2,3] triazolo [1, 5-a] pyridine-3 -carboxylate. To a solution of methyl 2- (4-phenylpyridin-2-yl) acetate (see Lohse, O. ; Thevenin, P.; Waldvogel, E. Synlett 1999, 1, 45-48) (0.504 g, 2.22 mmol) in 12 mL CH3CN was added DBU (0.501 ml, 3.33 mmol) and the mixture cooled in an ice bath. To the solution, 4-acetamidobenzenesulfonyl azide (0.533 g, 2.22 mmol) was added and the mixture allowed to warm to rt . The mixture was stirred at rt for 5 h then evaporated. The residue was diluted with CH2Cl2, washed with water, brine, dried over Na2SO4, and filtered. The title compound was obtained after purification via flash chromatography. b) (5-Phenyl- [1, 2,3] triazolo [1, 5-a] pyridin-3-yl)methanol . To a cooled (ice bath) suspension of lithium tetrahydroaluminate (0.0929 g, 2.45 mmol) in 2 mL THF (anhy) was added slowly a solution of methyl 5-phenyl-
[1, 2, 3] triazolo [1, 5-a] pyridine-3 -carboxylate (0.310 g, 1.22 mmol) in 20 mL THF (internal temp remained <20 C) . The mixture was allowed to stir in the ice bath 10 minutes. The mixture was diluted with EtOAc, washed with water, sat. NaHCO3, the organic layer dried over Na2SO4, and filtered. The aqueous layer still had uv activity so a solution of Rochelle ' s salt and EA were added and the mixture stirred 30 min. The organic layer was washed with sat NaHCO3, dried over Na2SO4, filtered, combined with main portion and evaporated. The title compound was isolated as a yellow solid. c) 7-Methoxy-4- ( (5-phenyl- [1,2,3] triazolo [1, 5-a] pyridin-3- yDmethoxy) quinoline . A sealable tube was charged with Pd2dba3
(0.219 g, 0.239 mmol), di-tert-butyl (1- (naphthalen-1- yl) naphthalen-2-yl)phosphine (0.190 g, 0.477 mmol), (5-phenyl-
[1, 2, 3] triazolo [1, 5-a] pyridin-3-yl) methanol (0.215 g, 0.955 mmol), 4-chloro-7-methoxyquinoline (0.222 g, 1.15 mmol), Cs2CO3
(0.622 g, 1.91 mmol) and dioxane (3 mL) . The tube was blanketed with N2, sealed and heated at 100 C for 45 min. The mixture was allowed to cool to rt and evaporated. The residue was purified via flash chromatography using a 1% NH4OH in MeOH in CH2Cl2 gradient. The title compound was collected as a tan solid. M/Z = 405.1 [M+Na] , calC 382.415 for C23Hi8N4O2.
Figure imgf000074_0001
Example 24
N- ( (6- (3-Chloro-4-fluorophenyl) - [1,2,4] triazolo [4, 3-a]pyridin- 3 -yl) methyl) -7-methoxy-l, 5-naphthyridin-4-amine. a) N1 - (5-bromopyridin-2-yl) -2- (tert- butoxycarbonylamino) acetohydrazide. A suspension of l-(5- bromopyridin-2-yl) hydrazine (4.00 g, 21 mmol) , 2-(tert- butoxycarbonyl) acetic acid (3.7 g, 21 mmol), and HATU (12 g, 32 mmol) in 50 mL CH3CN was cooled to -78 (solid precipitates to prevent stirring) . The flask was removed from bath gradually allow to warm. When stirring resumed, triethylamine (8.9 ml, 64 mmol) was added and the mixture stirred for 1 h, then evaporated. The residue was dissolved with CH2Cl2/ washed with water, brine, and the organic layer dried over Na2SO4, filtered and evaporated. The mixture was purified via flash chromatography using a EtOAc in hexanes gradient. The title compound was collected as a yellow oil. b) tert-Butyl (6-bromo- [1, 2, 4] triazolo [4 , 3-a] pyridin-3- yl) methylcarbamate . To a solution of N1 - (5-bromopyridin-2-yl) - 2- (tert-butoxycarbonylamino) acetohydrazide (2.2 g, 6.4 mmol) in THF (30 mL) was added triphenylphosphine (2.5 g, 9.6 mmol) and TMS azide (1.3 ml, 9.6 mmol) . DEAD (1.8 ml, 11 mmol) was added dropwise rapidly and the mixture heated at 55 C 1 h. The solvent was evaporated and the residue dissolved in CH2Cl2, washed with water, brine, dried over Na2SO4, and filtered. The mixture was purified via flash chromatography using a EtOAc in CH2Cl2 gradient. The title compound obtained as a tan solid (664 mg, 32%) . c) N- ( (6-Bromo- [1,2,4] triazolo [4, 3-a] pyridin-3-yl) methyl) -7- methoxy-1, 5-naphthyridin-4-amine . To a suspension of tert- butyl (6-bromo- [1,2,4] triazolo [4 , 3 -a] pyridin-3- yUmethylcarbamate (0.900 g, 2.75 mmol) in CH2Cl2 (10 mL) was added TFA (0.848 ml, 11.0 mmol) and the mixture stirred at rt. After 30 minutes additional TFA (0.848 ml, 11.0 mmol) was added, and the mixture stirred at rt 2 h more then concentrated. The residue was taken up into 2-butanol (5 mL) and combined with 8-chloro-3-methoxy-l, 5-naphthyridine (0.535 g, 2.75 mmol) in a 5 mL microwave vessel. The vessel was sealed and the mixture heated in the microwave for 10 min at 120 C with a 60 sec prestir. The mixture was concentrated, diluted with DCM and stirred with 2N NaOH (pH 14) for 30 minutes. The solid was filtered to afford the title compound as a beige solid. d) N- ( (6- ( 3-Chloro-4 -fluorophenyl) - [1,2,4] triazolo [4 , 3- a] pyridin-3-yl) methyl) -7-methoxy-l, 5-naphthyridin-4-amine . A sealable tube was charged with PdCl2 (dppf) -CH2Cl2 Adduct (0.064 g, 0.078 mmol), N- ( (6-bromo- [1, 2, 4] triazolo [4 , 3-a] pyridin-3- yDmethyl) -7-methoxy-l, 5-naphthyridin-4 -amine (0.120 g, 0.31 mmol), 3-chloro-4-fluorophenylboronic acid (0.057 g, 0.33 mmol), sat NaHCO3 (0.75 ml, >0.69 mmol) and dioxane (2 mL) . The vessel was sealed and the mixture heated at 80 for 2.5 h. The mixture was allowed to cool to rt and diluted with water, causing a tan solid to precipitate. CH2Cl2 (1 mL) was added and the solid filtered. The title compound was obtained after purification via flash chromatography (using a MeOH in CH2Cl2 gradient) as a tan solid. M/Z = 435.1 [M+H] , calc 434.8604 for C22H16ClFN6O.
The following compounds were prepared using the same method as desribed for N- ( (6- (3 -chloro-4-fluorophenyl) - [1,2,4] triazolo [4 , 3-a] pyridin-3 -yl) methyl) -7-methoxy-l, 5- naphthyridin-4 -amine :
Figure imgf000075_0001
Example 25 N- ( (6- (3 -Fluorophenyl) - [1,2,4] triazolo [4, 3-a] pyridin-3- yDmethyl) -7-methoxy-l, 5-naphthyridin-4-amine . M/Z = 401.2 [M+H] , calC 401.4153 for C22H17FN6O.
Figure imgf000076_0001
Example 26
7-Methoxy-N- ( (6-phenyl- [1,2,4] triazolo [4, 3-a] pyridin-3- yl) methyl) -1, 5-naphthyridin-4 -amine . M/Z = 383.2 [M+H], calc
382.4252 for C22Hi8N6O.
Figure imgf000076_0002
5- (3- ( (7 -methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) thiophene-2 -carbonyl chloride: To a suspension of 5- (3- ( ( 7-τnethoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6-yl) thiophene-2 -carboxylic acid (prepared according to general method A) (0.500 g, 1.15 mraol) in dichloromethane at 0 0C was added thionyl chloride (1.26 ml, 17.3 mmol) dropwise. Three drops DMF were added and the solution was stirred at room temp for three hours. The solution was concentrated to a brown residue and taken forward without further purification.
Figure imgf000077_0001
Example 27
(5- (3- ( (7-methoxyquinolln-4-yloxy)-nethyl) - [1,2,4] triazolo [4,3- b]pyridazin-6-yl) thiophen-2-yl) (morpholino)methanone : To a solution of 5- (3- ( (7-methoxyquinolin-4-yloxy) methyl) -
[1,2,4] triazolo [4 , 3-b] pyridazin-6-yl) thiophene-2-carbonyl chloride (0.260 g, 0.58 mmol) in dichlorotnethane (5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.15 ml, 0.86 mmol) and morpholine (0.15 ml, 1.7 mmol). The solution was stirred at room temperature for two hours then was concentrated in vacuo. The brown residue was purified via MPLC chromatography (eluted with 0-5% methanol in dichloromethane) to yield the product as a tan solid. MS m/z = 503.0 [M+l]+. CaIc 'd for C25H22N6O4S: 502.1.
Figure imgf000077_0002
Example 28
(5- (3- ( (7-methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) thiophen-2-yl) (pyrrolidin-1-yl) methanone : Prepared by a method similar to (5- (3- ( (7-methoxyquinolin-4- yloxy) methyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-6-yl) thiophen-2- yl) (morpholino) methanone . MS m/z = 487.1 [M+l]+. CaIc 'd for C25H22N6O3S: 486.2
Figure imgf000078_0001
Example 29
5- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4,3- b]pyridazin-6-yl) -N,N-dimethylthiophene-2-carboxamide : T o a solution of 5- (3- { (7-methoxyquinolin-4-yloxy) methyl) - [1, 2,4] triazolo [4 , 3-b] pyridazin-6-yl) thiophene-2-carbonyl chloride (0.260 g, 0.58 mraol) in dichloromethane was added N- ethyl-N-isopropylpropan-2-amine (0.20 ml, 1.2 mmol) and ditnethylamine (1.4 ml, 2.9 mmol). The solution was stirred at room temperature for one hour then was concentrated in vacuo. The residue was triturated with water and filtered; the resulting precipitate was triturated with acetonitrile and filtered to yield the product as an off-white solid. MS tn/z = 461.0 [M+l]+. CaIc 'd for C23H20NeO3S: 460.1.
Figure imgf000078_0002
Example 30
5- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) -N-methylthiopb.ene-2-carboxamide : Prepared by a method similar to (5- (3- ( (7-methoxyquinolin-4-yloxy) methyl) - [1, 2,4] triazolo [4 , 3-b] pyridazin-6-yl) thiophen-2- yl) (morpholino)methanone . MS m/z = 447.0 [M+l]+. CaIc 'd for C22Hi8N6O3S: 446.1
Figure imgf000079_0001
Example 31
5- (3- ( (7 -methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4, 3- b] pyridazin-6-yl) thiophene-2 -carboxamide : Prepared by a method similar to (5- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-6-yl) thiophen-2- yl) (morpholino)methanone. MS m/z = 433.0 [M+l]+. CaIc'd for C2IH16N6O3S: 432.1.
Figure imgf000079_0002
5- (3- ( (7 -methoxyquinolin-4-yloxy) methyl) - [1, 2,4] triazolo [4, 3- b] pyridazin-6-yl) -3-methylthiophene-2-carbonyl chloride: To a suspension of 5- (3- ( (7-methoxyquinolin-4-yloxy)πιethyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-6-yl) -3 -methylthiophene-2- carboxylic acid (prepared by General Method A) (0.150 g, 0.335 mmol) in dichloromethane (2 mL) was added thionyl chloride (0.734 ml, 10.1 mmol and DMF (1 drop). The solution was stirred at room temp for three hours then concentrated and taken forward without further purification.
Figure imgf000080_0001
(5- (3- ( (7 -methoxyguinolin-4-yloxy)methyl) - [1,2,4] triazolo [4, 3- b] pyridazln-6-yl) -3-methylthiophen-2-yl) (morpholino)methanone : To a solution of 5- (3- ( (7-methoxyquinolin-4-yloxy) methyl) -
[1,2,4] triazolo [4 , 3-b] pyridazin-6-yl) -3-methylthiophene-2- carbonyl chloride (0.100 g, 0.21 mmol) in dichloromethane (2 tnL) at 00C was added morpholine (0.19 g, 2.1 mmol). The solution was stirred at room temperature twenty minutes, then was concentrated and purified by MPLC chromatography (eluted with 3% methanol in dichloromethane) to yield a yellow solid. Trituration in acetonitrile and filtration afforded the product as a white solid. MS m/z = 517.2 [M+l]+. CaIc' d for C26H24N6O4S: 516.2.
Figure imgf000080_0002
7-methoxy-N- ( (6- (2- (triethylsilyl) ethynyl) - [1, 2 , 4] triazolo [4, 3- blpyridazin-3 -yl) methyl) -1, 5-naphthyridin-4-amine: To an argon flushed pressure vial (15 mL) was added copper (I) iodide (0.0070 g, 0.037 mmol), PdCl2 (dppf) -CH2Cl2Adduct (0.012 g, 0.015 mmol) , N- ( (6-chloro- [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) methyl) -7-tnethoxy-l, 5-naphthyridin-4-amine (0.050 g, 0.15 mmol), and triethyl (ethynyl) silane (0.13 ml, 0.73 mmol) in acetonitrile (2 mL) followed by triethylamine (0.61 ml, 4.4 mmol) . The vial was sealed and stirred at room temperature overnight The solution was concentrated and purified by MPLC (eluted with 0-10% (90:10:1 DCM : MeOH:NH4OH)) to yield the product as a light yellow solid. MS m/z = 446.1 [M+l]+. CaIc'd for C23H27N7OSi: 445.2.
Figure imgf000081_0001
N- ( (6-ethynyl- [1, 2, 4] triazolo [4, 3 -b]pyridazin-3-yl)methyl) -7- methoxy-1, 5-naphthyridin-4-amine : To a solution of 7-methoxy-N- ( (6- (2- (triethylsilyl)ethynyl) - [1, 2, 4] triazolo [4 , 3-b] pyridazin- 3-yl) methyl) -1, 5-naphthyridin-4-amine (0.360 g, 0.808 ramol) in acetic acid (8 raL) was added TBAF (1.21 ml, 1.21 mmol) . The mixture was stirred at room temperature overnight, additional TBAF (1.21 ml, 1.21 mmol) was added and the mixture was heated to 50 0C for five hours. The mixture was concentrated and purified via MPLC (eluted with 0-10% (1:10:90 NH4OH: MeOH:DCM) in dichloromethane) to yield the product as an off-white solid. MS m/z = 332.0 [M+l]+. CaIc' d for Ci7Hi3N7O: 331.1.
Figure imgf000081_0002
tert-butyl (6- (2- (triethylailyl) ethynyl) - [1, 2 , 4] triazolo [4, 3- b] pyridazin-3-yl)methylcarbaπtate : A IL-round-bottomed flask flushed with argon was charged with tert-butyl (6-chloro-
[1, 2, 4] triazolo [4 , 3-b}pyridazin-3 -yl)methylcarbamate (12.00 g, 42.3 mmol), Pd (dppf) Cl2-CH2Cl2 adduct (3.45 g, 4.23 mmol), copper iodide (2.01 g, 10.6 mmol) at room temperature. Acetonitrile
(400 mL) was added followed by triethy1 (ethynyl) silane (37.9 ml, 211 mmol) . Upon stirring the reaction mixture turned dark red. Triethylamine (177 ml, 1269 mmol) was added via cannula over five minutes. The first drops resulted in a change of color to light yeHow/orange . At the end of the addition, the reaction mixture was dark red again. After stirring at 500C for one hour, the mixture was cooled to room temperature and concentrated in vacuo. Purification by MPLC (ISCO, EtOAc/MeOH: 100/0 to 90/10) afforded the desired product. The material was taken forward without further purification. MS m/z = 388.3 [M+l]+. CaIC d for Ci9H29NSO2Si: 387.2.
Figure imgf000082_0001
tert-butyl (6-ethynyl- [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) methylcarbamate : Potassium fluoride (2M in water, 27.6 ml, 55.3 mmol) was added to a stirred suspension of tert-butyl6- (2- (triethylsilyl)ethynyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) methylcarbamate (3.57 g, 9.21 mmol) in acetonitrile (56 mL) at room temperature. The reaction mixture turned dark immediately, and was stirred at room temp for twenty minutes until complete. The mixture was concentrated in vacuo, triturated with water and filtered to yield the product as a brown solid (2.46 g) . MS m/z = 274.1 [M+l]+. Calc'd for C13H15N5O2: 273.1.
Figure imgf000082_0002
tert-butyl (6- (3-methyliBoxazol-5-yl) - [1, 2, 4] triazolo [4, 3- b] pyridazin-3-yl) methylcarbamate : To a solution of nitroethane (1.02 ml, 14.3 mmol) in benzene (50 mL) was added phenyl isocyanate (3.12 ml, 28.5 mmol) . The mixture was stirred at 50 0C for twenty minutes followed by the addition of tert-butyl (6-ethynyl- [1,2,4] triazolo [4 , 3-b] pyridazin-3-yl) methylcarbamate (3.00 g, 11.0 mmol) and triethylamine (0.0765 ml, 0.549 mmol). The mixture was stirred at 50 0C for six hours then at room temperature overnight . The mixture was cooled to room temperature, filtered and the resulting brown precipitate was washed with additional benzene. The filtrate was concentrated to yield the product as a black solid. MS m/z = 331.1 [M+l]+. CaIc 'd for C15H18N6O3: 330.1.
Figure imgf000083_0001
(6- (3-methyliaoxazol-5-yl) - [1, 2,4] triazolo [4, 3-b] pyridazin-3- yl) methanamine : To a solution of tert-butyl (6- (3- methylisoxazol-5-yl) - [1,2,4] triazolo [4 , 3-b] pyridazin-3- yUmethylcarbamate (3.63 g, 11.0 raraol) in dichloromethane (50 mli) was added trifluoroacetic acid (16.9 ml, 220 mmol) and the mixture was stirred at room temperature for one hour. The mixture was concentrated, taken up in a solution of ammonia in methanol (2.0 M) and purified by MPLC chromatography (eluted with 0-10% (1:10:90 NH4OH:MeOH: DCM) in DCM) to yield the product as a brown solid. MS m/z = 230.8 [M+l]+. CaIc 'd for Ci0H10N6O: 230.1.
Figure imgf000083_0002
Example 34
7-methoxy-N- ( (6- (3-methylisoxazol-5-yl) - [1,2,4] triazolo [4,3- b] pyridazin-3-yl)methyl) -1, 5-naph.thyridin-4-amine: To a microwave vial (10-20 mL) was added (6- (3-methylisoxazol-5-yl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 -yl) methanamine (1.00 g, 4.34 mmol) and 8-chloro-3-methoxy-l, 5-naphthyridine (1.10 g, 5.65 mmol) in 2-butanol (12 mL) . The suspension was stirred at 1200C under microwave irradiation for four hours . The mixture was concentrated and taken up in ammonia in methanol (2.0 M) then purified by MPLC chromatography (eluted with 0-10% methanol in dichloromethane) to yield the product as a tan solid. MS m/z = 389.0 [M+l] + . CaIc 'd for Ci9Hi6N8O2: 388.1
Figure imgf000084_0001
Example 35
Ethyl-5- (3- ( (7-methoxy-1, 5-naphthyridin-4-ylamino)methyl) - [1,2,4] triazolo 14, 3 -b] pyridazin-6-yl) isoxazole-3-carboxylate
Prepared by a method similar to 7-methoxy-N- ( (6- (3- methylisoxazol-5-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) methyl) -1, 5 -naphthyridin-4 -amine . MS m/z = 446.6 [M+l]+. CaIc 'd for C2IHi8N8O4: 446.2.
Figure imgf000084_0002
Example 36
5- (3- ( (7 -methoxy-1, 5-naphthyridin,-4-ylamino)methyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-6-yl) isoxazole-3-carboxylic acid: To a solution of ethyl 5- (3- ( (7-methoxy-l, 5-naphthyridin- 4-ylamino) methyl) - [1,2,4] triazolo [4, 3-b]pyridazin-6- yl) isoxazole-3-carboxylate (0.045 g, 0.10 mmol) in methanol (1 mL) and water (0.5 mL) was added sodium hydroxide (6M, 0.050 ml, 0.30 mmol) . The mixture was stirred at 50 0C for two hours, then was concentrated and diluted with water (2 mL) . 2M HCL was added dropwise until precipitation was observed, the tan solid was collected by filtration. The solid was taken up in isopropanol and heated to 100 0C. The resulting suspension was cooled to room temperature and filtered to yield the product as a tan solid. MS m/z = 418.6 [M+l]+. CaIc 'd for Ci9H14N8O4: 418.1.
Figure imgf000085_0001
tert-butyl- (6- (3- ( (tetrahydro-2H-pyran-2-yloxy) methyl) isoxazol- 5-yl) - [1,2,4] triazolo[4,3-b]pyridazin-3-yl)methylcarbamate:
Prepared by a method similar to tert-butyl- (6- (3- methylisoxazol-5-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3- yDmethylcarbamate. MS m/z = 430.7 [M+l]+. CaIc' d for C20H26NGO5: 430.2.
Figure imgf000085_0002
(5- (3- (aminomethyl) - [1,2,4] triazolo [4 , 3 -b] pyridazin-β- yl) iaoxazol-3-yl)methanol : To a solution of tert-butyl (6- (3-
( (tetrahydro-2H-pyran-2-yloxy) methyl) isoxazol-5-yl) -
[1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl)methylcarbamate (4.73 g, 11.0 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (16.9 ml, 220 mmol) . The mixture was stirred at room temperature for one hour, then was concentrated, taken up in 2.0 M ammonia in methanol and purified by MPLC chromatography
(eluted with 0-10% (1:10:90 NH4OH:MeOH:DCM) in DCM) to yield the product as a tan solid. MS m/z = 246.9 [M+l]+. Calc'd for
Ci0H10N6O2: 246.1.
Figure imgf000086_0001
Example 37
(5- (3- ( (7 -meth.oxy-l,5-naphthyridin-4-ylamino) methyl) -
[1, 2,4] triazolo [4, 3-b] pyridazin-6-yl) iBoxazol - 3 -yl) methanol :
Prepared by a method similar to 7-τnethoxy-N- ( (6- (3- methylisoxazol-5-yl) - [1,2,4] triazolo [4 , 3-b] pyridazin-3- yl) methyl) -1, 5 -naphthyridin- 4 -amine. MS m/z = 404.6 [M+l]+, CaIc 'd for Ci9Hi6N8O3: 404.1.
Figure imgf000086_0002
5- (tributylstannyl) -2- (trimethylsilyl) thiazole : To a stirred solution of butyllithium (0.763 ml, 1.91 mraol) in diethyl ether (10 mL) at -78 0C was added dropwise over 30 minutes a solution of 2- ( trimethylsilyl) thiazole (0.300 ml, 1.91 mtnol) in ether (5 mL) . The solution was stirred at -78 0C for one hour, followed by the addition of chlorotrimethylstannane (1.59 ml, 1.59 mmol) in THF over 15 minutes. After an additional hour at -78 0C, the solution was washed with saturated bicarbonate and extracted with diethyl ether. Organic extracts were dried over magnesium sulfate and filtered then concentrated in vacuo to yield the product as a colorless oil.
Figure imgf000086_0003
5- (tributylstannyl) thiazole : To a solution of 2-
(trimethylsilyl) -5- (trimethylstannyl) thiazole (0.509 g, 1.6 mmol) in 5 mL THF was added 2 N HCl (1.0 mL) . The solution was stirred at room temperature for one hour. The solution was diluted with diethyl ether and washed with sodium bicarbonate. Organic extracts were dried over magnesium sulfate and filtered then concentrated to yield the product as a colorless oil.
Figure imgf000087_0001
3-methyl-5- (tributylstannyl) isoxazole: To a solution of nitroethane (0.0952 ml, 1.33 mmol) in benzene (2 mL) was added phenyl isocyanate (0.291 ml, 2.66 mmol). The solution was stirred at 50 0C for ten minutes followed by the addition of triethylamine (0.00925 ml, 0.0666 mmol) and tributyl (ethynyl) stannane (0.365 ml, 1.27 mmol). The mixture was left to stir at 50 0C overnight. The solution was diluted with water and filtered though a celite plug, the resulting filtrate was extracted with toluene. Organic extracts were dried over magnesium sulfate and filtered then concentrated to yield the product as a yellow oil.
Figure imgf000087_0002
In a pressure vessel, 3N HCl (1.2 ml, 3.5 mmol) was added to 4- ( (6- (6-fluoropyridin-2-yl) -[1,2,4] triazolo [4 , 3-a] pyridin-3- yDmethoxy) -7-methoxyquinoline (0.071 g, 0.18 mmol) in dioxane (0.60 mL) . The reaction mixture was then heated at 100 0C for 3.5 h. Concentrated HCl (0.300 mL, 9.9 mmol) was added and the reaction was heated at 100 0C for 2 h. The reaction mixture was concentrated in vacuo, and then dried on high vacuum. Triethylamine (0.74 ml, 5.3 mmol) was added to the compound. and it was allowed to stir for one hour until the free base crashed out of solution.
The compound was dissolved partially in DCM/MeOH, however, fully dissolved after addition of hot DMSO. The compound was purified via flash chromatograph, eluting with 0-10% MeOH/NH4OH in DCM. The compound was sonicated in DCM and filtered to remove the triethylamine-hydrochloride salt, and yielded 6- (3- ( (7-methoxyquinolin-4-yloxy)τnethyl) - [1,2,4] triazolo [4,3- a] pyridin-6-yl)pyridin-2 (IH) -one.
Figure imgf000088_0001
Example 39
6- ( (6-Chloro- [1/2,4] triazolo [4, 3-b]pyridazin-3- yl) methyl) quinoline .
A mixture of 1- (6 -chloropyridazin-3-yl) hydrazine (1.67 g, 12 mmol) , 2- (quinolin-6-yl) acetic acid (1.65 g, 8.8 mraol) , and HCl (2000 μl, 24 mmol) was heated in an oil bath at 110 0C for 20 min before it was heated in a microwave (Personal Chemistry) at 180 °C&15 tnin. The mixture was quenched with a solution of NaOH (1.2 g, 5 mL) slowly until the suspension is -neutral in pH. The mixture was filtered and washed with H2O (2x 5 mL) . A brown solid was obtained (2.2 g) . The solid was treated with aqueous Na2CO3 (3 g, 20 mL, pH -11) and heated at 50 0C for 30 min. The blue mixture was cooled to room temperature, and filtered. The black solid was wahsed with H2O and lyophilized to give the product . LCMS: calc'd for Ci5Hi0ClN5: 295.1; found 296.1 (M+l) .
Figure imgf000089_0001
Example 40
3-Methoxy-6- ( (6-phenyl- [1, 2,4] triazolo [4, 3-b]pyridazin-3- yl) methyl) quinoline.
A mixture of tert-butyl 2- (3-methoxyquinolin-6-yl) acetate (148 mg) and 1- (6 -phenylpyridazin-3-yl) hydrazine (126 mg) in HCl
(cone, 0.3 mL) was heated at 100 0C for 5 min and was subject to microwave heating (180 0C, 15 min) . The yellow sludge was quenched with NaOH (5N, 1 mL) . The pink mixture was filtered and washed with NaOH (1 N, 1 mL) , H2O (2 mL) . The solid was suspended in DMF (2 mL) -DCM (2 mL) . MeI (0.2 mL) was added followed by the addition of NaOH (2N, 1 mL) . After 2 h, the mixture was partitioned between DCM (10 mL) and aqueous Na2SO3
(5 mL) . The organic was dried over MgSO4, concentrated, and purified in silica (1-15% MeOH in DCM) to give the product as a yellow powder. LCMS: calc'd for C22H17N5O: 367.1; found 368.2 (M+l) .
Figure imgf000089_0002
Example 41
4- (3- ( (7 -methoxyquinolin-4-yloxy)methyl) -[1,2,4] triazolo [4, 3- b]pyridazin-6-yl) -2-methylbut-3-yn-2-ol . 1 ) 6 -bromoH- imidazo [1 , 2 -a] pyridine- 3 -carbaldehyde
Figure imgf000090_0001
A 250 mL RB flask was charged with DMF (21.3 ml, 274 mmol) and cooled to 00C; phosphorus oxychloride (2.46 ml, 26.4 mmol) was added dropwise . This was stirred for 1 hour, then 6-bromoH- imidazo [1, 2-a] pyridine (2.00 g, 10.2 mmol) was added in one portion. This was stirred at 1000C for 5 hours and at room temperature for 16 hours. The flask was cooled to 00C and slowly neutralized with 6N aq. NaOH and sat. aq. NaHCO3, resulting in the formation of a precipitate which was collected by filtration to give 6-bromoH-imidazo [1, 2-a] pyridine-3- carbaldehyde as a yeHow-orange solid.
2) (6-bromoH-imidazo [1, 2-a] pyridin-3-yl) methanol
Figure imgf000090_0002
A 50 mL RB flask was charged with sodium borohydride (0.074 g, 2.0 mmol) and water (0.84 ml, 47 mmol), then cooled to 00C. A solution of 6-bromoH-imidazo [1, 2-a] pyridine-3-carbaldehyde (0.8792 g, 3.9 mmol), methanol (6.3 ml, 156 mmol), and DCM was added slowly. This was allowed to warm to room temperature. The mixture was concentrated, then the yellow residue was triturated with water and filtered to give (6-bromoH- imidazo [1, 2-a] pyridin-3-yl) methanol as a yellow solid.
3) 4- ( (6-bromoH-imidazo [1, 2-a] pyridin-3-yl) methoxy) -7- methoxyquinoline
Figure imgf000091_0001
A 10 - 20 mL microwave vial was charged with (6-bromoH- imidazo [1, 2-a] pyridin-3-yl)methanol (0.756 g, 3.3 mmol) , 4- chloro-7-methoxyquinoline (0.81 g, 4.2 mmol), cesium carbonate (2.2 g, 6.7 mmol), and DMSO (8.00 ml, 113 mmol), sealed, and placed in a Personal Chemistry microwave at 1000C for 2 hours. The reaction mixture was added dropwise to a flask containing water, resulting in the formation of a precipitate which was collected by filtration. The solid was dissolved in a combination of MeOH/DCM and filtered. The filtrate was concentrated and triturated with EtOAc/DCM. The solid was dissolved in a small amount of hot MeOH and DCM and purified by chromatography using a 40 g ISCO column, eluting with a gradient of 1-7% MeOH (with 10% NH4OH) /DCM over 40 minutes.
4) 4- (3- ( (7-methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-6-yl) -2-methylbut-3-yn-2-ol . A 16 mm test tube was charged with 4- ( (6-bromoH-imidazo [1, 2- a] pyridin-3-yl) methoxy) -7-methoxyquinoline (0.0607 g, 0.16 mmol), phenylboronic acid (0.039 g, 0.32 mmol), SPhos (0.0065 g, 0.016 mmol), Potassium phosphate (0.10 g, 0.47 mmol), Pd2 (dba) 3 (0.0036 g, 0.0039 mmol), and 1-butanol (0.014 ml, 0.16 mmol), then stirred at 1000C for 16 hours. The reaction mixture was diluted with chloroform (15 mL) and washed with water (15 mL) , sat. aq. NaHCO3 (15 mL) , and brine (15 mL) ; the organic layer was dried with MgSO4, filtered, and concentrated. This was purified using the prep HPLC machine using a gradient of 10% MeCN/water to 95% MeCN/water over 20 min. The fractions were combined and the product free based by diluting with 10% MeOH/HCCl3 (30 tnL) and washing with sat. aq. NaHCO3 (30 mL) . The organic layer was dried with MgSO4, filtered, and concentrated, then the resulting yellow solid was submitted to the Analytical Chemistry group for purification. This was returned as the formic acid salt in water, which was concentrated, free based with sat. NaHCO3 (5 mL) , diluted with water (15 mL) , and extracted with 10% MeOH/HCCl3 (3 x 25 mL) . The combined organics were dried with MgSO4, filtered, and concentrated to yield 7-τnethoxy-4- ( (6-phenylH-imidazo [1, 2- a] pyridin-3-yl) methoxy) quinoline .
MS (ESI pos . ion) m/z: 382 (MH+) . CaIc' d exact mass for C24H19N3O2: 381.
Figure imgf000092_0001
Example 42
N- ( (6-phenyl- [1, 2,43 triazolo [4, 3 -b] pyrldazin-3-yl) methyl) -7H- purin-6-amine.
A 15 mL tube was charged with (6-phenyl- [1, 2 , 4] triazolo [4 , 3- b] pyridazin-3-yl)methanamine (0.100 g, 0.444 mmol) , 6- chloropurine (0.103 g, 0.666 mmol), and sec-butanol (3.00 ml, 32.4 mmol), sealed, then heated in a 1000C oil bath for 5 hours. The reaction mixture was concentrated and the yellow residue was purified by MPLC using a 40 g RediSep column, eluting with a gradient of 3-8% MeOH/DCM over 80 minutes. N- ( (6-phenyl- [1,2,4] triazolo [4 , 3-b] pyridazin-3-yl) methyl) -7H- purin-6-amine (0.0500 g, 32.8% yield) was isolated as the hydrochloride salt.
MS (ESI pos. ion) m/z: 344 (MH+) . CaIc 'd exact mass for C23Hi8FN5O2: 343.
Figure imgf000093_0001
Example 43
5- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4, 3- b] pyridazin-6-yl) -N,N-dimethylpyridin-2-amine.
A 48 mL tube was charged with 6- (dimethylamino) pyridin-3- ylboronic acid (0.109 g, 0.658 mmol) , 4- ( (6-chloro- [1,2,4] triazolo [4, 3-b]pyridazin-3-yl)methoxy) -7- methoxyquinoline (0.150 g, 0.439 mmol), and DMF (3.00 ml, 38.6 mmol) , and stirred for 10 minutes. A solution of potassium carbonate (0.182 g, 1.32 mmol) and water (0.696 ml, 38.6 mmol) was added, followed by PdC12 (dppf) -CH2C12Adduct (0.0358 g, 0.0439 mmol) . The tube was flushed with argon, sealed, and heated in a 800C oil bath for 5 hours. The mixture was concentrated, and the residue was triturated with water to give a brown solid which was purified by MPLC using a 40 g column, eluting with 1-5% MeOH/DCM over 40 minutes to give 5-(3-((7- τnethoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) -N, N-dimethylpyridin-2-amine as a dark green solid.
MS (ESI pos. ion) m/z: 428 (MH+). Calc'd exact mass for C23Hi8FN5O2: 427.
Figure imgf000093_0002
Example 44
7-methoxy-4- ( (6- (6-morpholin.opyridin-3-yl) - [1,2,4] triazolo [4,3- b] pyridazin-3-yl)met.hoxy) quinoline.
Prepared in a similar manner as 5- (3- ( (7-methoxyquinolin-4- yloxy) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6-yl) -N,N- dimethylpyridin-2-amine .
MS (ESI pos. ion) m/z: 470 (MH+). Calc'd exact mass for
C23H18FN5O2: 469.
Figure imgf000094_0001
Example 45
4- ( (6- (H-imidazo[l,2-a]pyridin-6-yl) - [1, 2 , 4] triazolo [4, 3- b] pyridazin-3-yl)methoxy) -7-methoxyquinoline .
Prepared in a similar manner as 5- (3- ( (7-tnethoxyquinolin-4 yloxy) methyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-6-yl) -N, N- dimethylpyridin-2-amine .
MS (ESI pos. ion) m/z: 424 (MH+) . Calc'd exact mass for
C23H17N7O2 : 423 .
Figure imgf000094_0002
Example 46 tert-butyl 4-(5-(3-((7 -methoxyquinolin-4-yloxy)methyl) -
[1,2,4] triazolo [4, 3-b] pyridazin-6-yl)pyridin-2-yl)piperazine-l- carboxylate .
Prepared in a similar manner as 5- (3- ( (7-methoxyquinolin-4- yloxy) methyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-6-yl) -N,N- dimethylpyridin-2-amine .
MS (ESI pos . ion) m/z: 569 (MH+) . CaIc' d exact mass for C30H32N8O4: 568.
Figure imgf000095_0001
Example 47
7-methoxy-4- ( (6- (6- (piperazin-l-yl)pyridin-3-yl) - [1, 2,4] triazolo [4, 3-b] pyridazin-3 -yl) methoxy) quinoline. A 50 mL recovery flask was charged with tert-butyl 4- (5- (3- '( (7- methoxyquinolin-4 -yloxy) methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl)pyridin-2-yl)piperazine-l-carboxylate (0.250 g, 0.44 mmol) , TFA (0.75 ml, 9.6 mmol) , and DCM (1.50 ml, 23 mmol) , then stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, then quenched with sat. aq. NaHCO3. The mixture was diluted with DCM (60 mL) , resulting in an emulsion. The emulsion was filtered to give a brown solid.. The solid was triturated with a combination of DCM/MeOH/MeCN and filtered to give 7-methoxy-4- ( (6- (6- (piperazin-1- yl)pyridin-3-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) methoxy) quinoline .
MS (ESI pos. ion) m/z: 469 (MH+). Calc'd exact mass for C25H24N8O2: 468.
Figure imgf000096_0001
Example 48
tert-butyl 3- (5- (3- ( (7-methoxyquinolin-4-yloxy)methyl) ■ [1,2,4] triazolo [4, 3-b] pyridazin-6-yl) pyridin-2- ylamino) pyrrolidine-1-carboxylate.
1) 4- ( (6- (6-fluoropyridin-3-yl) - [1,2,4] triazolo [4,3- b] pyridazin-3-yl)methoxy) -7-methoxyquinoline
Figure imgf000096_0002
Prepared in a similar manner as 5- (3- ( (7-methoxyquinolin-4- yloxy) methyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-6-yl) -N, N- dimethylpyridin-2-amine.
2) tert-butyl 3- (5- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-6-yl)pyridin-2- ylamino) pyrrolidine-1-carboxylate
A 0.5 - 2 τnli microwave vial was charged with 4- ( (6- (6- fluoropyridin-3-yl) - [1,2,4] triazolo [4 , 3-b] pyridazin-3- yl) methoxy) -7-methoxyquinoline (0.100 g, 0.249 mmol) , tert- butyl 3 -aminopyrrolidine-1-carboxylate (0.116 g, 0.622 mmol), and DMSO (4.00 ml, 56.4 mmol), sealed and placed in a Personal Chemistry microwave for 1 hour at 1000C and then 30 minutes at 1200C. Water was added slowly to the reaction mixture until a precipitate formed. The solid was collected and purified by MPLC using a 40 g RediSep column, eluting with a gradient of 3 - 6% MeOH/DCM over 40 minutes. The solid was triturated with MeCN and filtered; the mother liquor was concentrated to give tert-butyl 3- (5- (3- ( (7-methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6-yl) pyridin-^- ylamino) pyrrolidine-1-carboxylate .
MS ( ESI pos . ion) m/ z : 569 (MH+ ) . Calc ' d exact mass for C30H32N8O4 : 568 .
Figure imgf000097_0001
Example 49
5- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4,3- b]pyridazin-6-yl) -N- (pyrrolidin-3-yl)pyridin-2-amine.
Prepared in a similar manner as 7-methoxy-4- ( (6- (6- (piperazin- 1-yl) pyridin-3-yl) - [1,2,4] triazolo [4 , 3-b] pyridazin-3- yDmethoxy) quinoline.
MS (ESI pos. ion) m/z: 469 (MH+) . Calc'd exact mass for C25H24N8O2: 468.
Figure imgf000097_0002
Example 50 4- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) -2-methylbut-3-yn-2-ol.
A 25 x 200 mm test tube was charged with 4- ( (6-chloro-
[1,2,4] triazolo [4 , 3-b] pyridazin-3-yl)methoxy) -7- methoxyquinoline (0.150 g, 0.439 mmol) , 2-methylbut-3-yn-2-ol
(0.213 ml, 2.19 mmol), copper (I) iodide (0.0209 g, 0.110 mmol), triethylamine (1.83 ml, 13.2 mmol), and acetonitrile
(5.00 ml, 96.2 mmol), flushed with argon, sealed, and placed in a 900C oil bath for 30 minutes. PdCl2 (dppf) -CH2C12Adduct
(0.0358 g, 0.0439 mmol) was added in one portion, the tube flushed with argon, sealed, then heated in a 90°C oil bath for 4 hours . The reaction mixture was filtered thru a pad of silica gel (eluting with EtOAc/DCM/MeOH) , then concentrated to yield a dark brown oil. This was purified by MPLC, using a 4Og RediSep column, eluting with 1 - 7% MeOH/DCM over 40 minutes. The appropriate fractions were collected to give 4- (3- ((7- methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) -2-methylbut-3-yn-2-ol (0.0877 g, 51.3% yield) .
MS (ESI pos. ion) m/z: 390 (MH+). Calc'd exact mass for
Figure imgf000098_0001
Figure imgf000098_0002
Example 51
1- (2-fluoro-4- (3- ( (7 -methoxy-1, 5-naphthyridln-4 - ylamino) methyl) -[1,2,4] triazolo [4, 3-b] pyridazin-6- yl) phenyl) pyrrolidin-2-one 1) 1- (4-chloro-2-fluorophenyl) pyrrolidin-2-one
Figure imgf000099_0001
A 100 mL sealed tube was charged with 4-chloro-2-fluoro-1- iodobenzene (0.498 ml, 3.90 mmol) , pyrrolidin-2-one (0.598 ml, 7.80 mmol), (IR, 2R) -cyclohexane-1, 2-diamine (0.0703 ml, 0.585 mmol), potassium phosphate (1.66 g, 7.80 mmol), copper (I) iodide (0.0223 g, 0.117 mmol), and 1,4-dioxane (4.00 ml, 46.8 mmol) , then flushed with argon, sealed, and placed in a 1100C oil bath for 17 hours. The reaction mixture was filtered through a pad of silica gel, eluting with EtOAc and DCM, then the filtrate was concentrated to yield a brown oil This was purified by column chromatography using a 40 g ISCO column, eluting with a gradient of 3-5% MeOH/DCM over 30 minutes to give 1- (4-chloro-2-fluorophenyl) pyrrolidin-2-one (0.903 g, 108% yield) as a yellow solid.
2) 1- (2-fluoro-4- (4,4,5, 5-tetramethyl-l , 3, 2-dioxaborolan-2- yl) phenyl) pyrrolidin-2-one
Figure imgf000099_0002
A 48 mL sealed tube was charged with 1- (4-chloro-2- fluorophenyl) pyrrolidin-2-one (0.444 g, 2.08 mmol), pinacol diborane (1.06 g, 4.16 mmol), X-Phos (0.0991 g, 0.208 mmol), Pd2dba3 (0.0571 g, 0.0623 mmol), potassium acetate (0.408 g, 4.16 mmol), and 1,4-dioxane (4.62 ml, 54.0 mmol), flushed with argon, sealed, then placed in a 900C oil bath for 5 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL) , sat. NaHCO3 (100 mL) , and brine (100 mL) , dried with MgSO4, filtered, and concentrated. This was purified by MPLC uisng a 40 g RediSep column, eluting with 1-5% MeOH/DCM over 40 minutes. The fractions were concentrated to give 1- (2- fluoro-4- (4,4,5, 5-tetramethyl-l, 3 , 2-dioxaborolan-2- yl) phenyl) pyrrolidin-2-one, -85% pure, as an orange oil that solidified upon standing.
3) tert-butyl (6- (3-fluoro-4- (2-oxopyrrolidin-l-yl) phenyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-3-yl)methylcarbamate
Figure imgf000100_0001
A 48 mL sealed tube was charged with tert-butyl (6-chloro- [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl)methylcarbamate (0.150 g, 0.529 mmol) , 1- (2-fluoro-4- (4 , 4 , 5, 5-tetramethyl-l, 3 , 2- dioxaborolan-2-yl) phenyl) pyrrolidin-2-one (0.242 g, 0.793 mmol), PdCl2 (dppf) -CH2C12Adduct (0.0432 g, 0.0529 mmol), cesium carbonate (0.689 g, 2.11 mmol), 1,4-dioxane (3.62 ml, 42.3 mmol), and water (0.905 ml, 50.2 mmol), flushed with argon, sealed, then placed in a 800C oil bath for 5 hours. The contents were transferred to a flask and concentrated. The solid was triturated with water to give a red residue, which was purified by MPLC using a 40 g RediSep column, eluting with 2-6% MeOH/DCM over 40 minutes. tert-butyl (6- (3-fluoro-4- (2- oxopyrrolidin-1-yl)phenyl) -[1,2,4] triazolo [4 , 3-b] pyridazin-3- yl)methylcarbamate (0.117 g, 51.9% yield) was isolated as a tan solid.
4) 1- (4- (3- (aminomethyl) - [1, 2,4] triazolo [4, 3-b]pyridazin-6-yl) - 2-fluorophenyl)pyrrolidin-2-one
Figure imgf000101_0001
A 50 mL recovery flask was charged with tert-butyl (6- (3- fluoro-4- (2-oxopyrrolidin-1-yl)phenyl) - [1,2,4] triazolo [4 , 3- b]pyridazin-3-yl)methylcarbamate (0.117 g, 0.274 mmol) , TFA (0.0211 ml, 0.274 mraol) , and DCM (0.0177 ml, 0.274 mmol), then stirred open to air at room temperature for 2 hours. The mixture was concentrated, then taken up in MeOH. K2CO3 was added, and this was stirred for 1 hour. The mixture was concentrated, then the residue was taken up in MeOH/CHCl3 then filtered. The filtrate was evaporated, taken up in water, then passed through a reverse phase Ci8 column, eluting with MeOH/DCM, then concentrated.
5) 1- (2-fluoro-4- (3- ( (7-methoxy-l, 5-naphthyridin-4- ylamino) methyl) - [1,2,4] triazolo [4, 3-b]pyridazin-6- yl) phenyl) pyrrolidin-2-one
A 0.5 - 2 mL microwave vial was charged with 1- (4- (3- (aminomethyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6-yl) -2- fluorophenyl)pyrrolidin-2-one (0.0792 g, 0.243 mmol), 8-chloro- 3-methoxy-l, 5-naphthyridine (0.0590 g, 0.303 mmol), and butan- 2-ol (1.00 ml, 0.243 mmol), sealed, then placed in a Personal Chemistry Microwave for 4 hours at 1200C. The mixture was concentrated, then triturated with MeOH to give 1- (2-fluoro-4- (3- ( (7-methoxy-l, 5-naphthyridin-4-ylamino) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6-yl) phenyl)pyrrolidin-2-one as the hydrochloric salt .
MS (ESI pos. ion) m/z: 485 (MH+). Calc'd exact mass for C25H2IFN8O2: 484.
Figure imgf000102_0001
Example 52
5 - (3 - ( ( 7 -methoxy- l # 5 -naphthyridin-4 -ylamino) methyl) - [1 , 2 / 4 ] triazolo [4 / 3 -b] pyridazin- 6 -yl ) -2 -methyl isoindolin-1- one 1) 4 -bromo-2- (hydroxymethyl) -N-methylbenzamide
Figure imgf000102_0002
A 500 mL RB flask was charged with aluminum (III) chloride (4.1 g, 31 mmol) and 10 mL of 1, 2-dichloroethane (90 ml, 1142 mmol) , then cooled to 00C. A separate 250 mL flask was charged with 90 mL of 1, 2-dichloroethane (90 ml, 1142 mmol) and cooled to 00C; methylamine (gas) (1.8 g, 59 mmol) was bubbled through the solution for 10 minutes. The dichloroethane solution was slowly poured into the aluminum chloride solution, resulting in the formation of a thick white slush. This was warmed to room temperature. 5-bromoisobenzofuran-1 (3H) -one (5.00 g, 23 mmol) was added in one portion and the reaction mixture was stirred for 2.5 hours and quenched with water. The mixture was filtered to remove the solid impurities, then the filtrate was washed with 0.5N aqueous HCl (100 mL) and brine (200 mL) . The organic layer was dried with MgSO4, filtered, and concentrated to give a white solid. This was triturated with EtOAc and filtered to give 4-bromo-2- (hydroxymethyl) -N-methylbenzamide (3.34 g, 58% yield) as a white solid.
2) 5-bromo-2-methylisoindolin-l-one
Figure imgf000103_0001
A 150 mL sealed tube was charged with 4-bromo-2- (hydroxymethyl) -N-tnethylbenzamide (3.34 g, 13.7 mmol) and 1,3- dimethylimidazolidin-2-one (40.4 ml, 369 mmol). The solution was cooled to 00C and Isopropylmagnesium chloride (15.3 ml, 30.5 mmol) was added slowly. The tube was capped and the reaction mixture was stirred at room temperature for 30 minutes. This was recooled to 00C and N,N,N,N- tetramethylphosphorodiamidoyl chloride (2.64 ml, 17.8 mmol) was added in one portion; this mixture was stirred at room temperature for 4 hours. The tube was placed in a 150°C oil bath for 1 hour. The mixture was then diluted with EtOAc (100 mL) , then washed with IM aqueous HCl . The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and then the combined organics were washed with water (100 mL) and brine (100 mL) , dried with MgSO4, filtered, then concentrated to give a yellow oil . This was purified by column chromatography, eluting with 1 - 4% MeOH/DCM to give 5-bromo-2-methylisoindolin-l-one (1.774 g, 57.3% yield) as a yellow solid.
3) 2-methyl-5- (4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) isoindolin-1-one
Figure imgf000103_0002
Prepared in a similar manner as 1- (2-fluoro-4- (4 , 4 , 5, 5- tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl)pyrrolidin-2-one ,
4) tert-butyl (6- (2-methyl-l-oxoisoindolin-5-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3-yl)methylcarbamate
Figure imgf000104_0001
Prepared in a similar manner as tert-butyl (6- (3-fluoro-4- (2- oxopyrrolidin-l-yl) phenyl) - [1,2,4] triazolo [4 , 3-b]pyridazin-3- yl) methylcarbamate .
5) 5- (3 - (aminomethyl) - [1,2,4] triazolo [4 , 3 -b] pyridazin-6-yl) -2 methylisoindolin-1-one
Figure imgf000104_0002
Prepared in a similar manner as 1- (4- (3- (aminomethyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6-yl) -2- fluorophenyl) pyrrolidin-2-one.
6) 5- (3- { (7-methoxy-l, 5-naphthyridin-4-ylamino) methyl) -
[1,2,4] triazolo [4, 3-b]pyridazin-6-yl) -2-methylisoindolin-l-one
Prepared in a similar manner as 1- (2-fluoro-4- (3- ( (7-methoxy-
1, 5-naphthyridin-4-ylamino)methyl) - [1,2,4] triazolo [4 , 3- b] pyridazin- 6 -yl) phenyl) pyrrolidine2-one .
MS (ESI pos. ion) m/z: 453 (MH+). Calc'd exact mass for
C24H20N8O2: 452.
Figure imgf000104_0003
Example 53 N- ( (6- (l-isopropyl-lH-pyrazol-4-yl) - [1/ 2, 4] triazolo [4, 3- blpyridazin-3 -yl)methyl) -7-methoxy-1, 5-naphthyridin-4-amine
1) tert-butyl (6- (l-isopropyl-lH-pyrazol-4-yl) -
[1, 2 ,4] triazolo [4 , 3-b] pyridazin-3-yl)methylcarbamate
Figure imgf000105_0001
Prepared in a similar manner as tert-butyl (6- (3-fluoro-4- (2- oxopyrrolidin-l-yl) phenyl) -[1,2,4] triazolo [4, 3-b] pyridazin-3- y1) methylcarbamate .
2) (6- (l-isopropyl-lH-pyrazol-4-yl) - [1,2,4] triazolo [4 ,3- b] pyridazin-3 -yl) methanamine hydrochloride
Figure imgf000105_0002
Prepared in a similar manner as 1- (4- (3- (aminomethyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6 -yl) -2- fluorophenyl) pyrrolidin-2-one.
3) N- ( (6- (l-isopropyl-lH-pyrazol-4-yl) - [1, 2 , 4] triazolo [4 , 3- b] pyridazin-3 -yl) methyl) -7-methoxy-1, 5-naphthyridin-4 -amine
Prepared in a similar manner as 1- (2-fluoro-4- (3- ( (7-methoxy-
1, 5-naphthyridin-4-ylamino) methyl) - [1,2,4] triazolo [4 , 3- b] pyridazin-6-yl) phenyl) pyrrolidin-2-one .
MS (ESI pos. ion) m/z: 416 (MH+) . CaIc 'd exact mass for
C21H21N9O2 : 415.
Figure imgf000105_0003
Example 54
N- ( (6- (lH-pyrazol-4-yl) - [1,2,4] triazolo [4, 3-b]pyridazin-3- yl) methyl) -7-methoxy-l, 5-naphthyrldln-4-amine
A 48 mL sealed tube was charged with N- ( (6-chloro- [1,2,4] triazolo [4, 3-b] pyridazin-3-yl)methyl) -7-methoxy-l, 5- naphthyridin-4-amine (0.150 g, 0.439 mmol) , lH-pyrazol-4- ylboronic acid (0.0737 g, 0.658 mmol), and DMF (3.00 ml, 38.6 mmol). A solution of potassium carbonate (0.182 g, 1.32 mmol) and water (0.696 ml, 38.6 mmol) was added, followed by PdCl2 (dppf) -CH2C12Adduct (0.0358 g, 0.0439 mmol). The tube was flushed with argon, sealed, then placed in a 900C oil bath for 5 hours . The mixture was concentrated and the black solid was triturated with water to remove K2CO3, then purified by column chromatography using a 40 g RediSep column, eluting with 30-70% (90:10:1 DCM: MeOH :NH4OH solution) in DCM over 40 minutes. Pure fractions were collected to give N- ( (6- (lH-pyrazol-4-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3-yl) methyl) -7-methoxy-l, 5- naphthyridin-4-amine as a white solid.
MS (ESI pos. ion) m/z: 374 (MH+) . Calc'd exact mass for Ci8H15N9O: 373.
Figure imgf000106_0001
Example 55
7-methoxy-N- ((6-phenyl- [1, 2, 4] triazolo [4, 3-b] [l,2,4]triazin-3- yl)methyl) -1, 5-naphthyridin-4-amine.
1) 3- (azidomethyl) -6-phenyl- [1,2,4] triazolo [4,3- b] [1, 2, 4] triazine
Figure imgf000107_0001
A 16 mm test tube was charged with (6-phenyl- [1,2,4] triazolo [4, 3 -b] [1,2,4] triazin-3-yl) methanol (0.500 g, 2.20 mmol) , Reactant 2 (0.951 ml, 4.40 mmol) , DBU (0.663 ml, 4.40 mmol), and toluene (8.16 ml, 77.0 mmol), flushed with argon, sealed, then stirred at room temperature for 3 hours. The dark maroon mixture was concentrated and the resulting dark purple/black oil was purified by column chromatography using a gradient of 3-5% MeOH/DCM over 20 minutes. 3- (azidomethyl) -6- phenyl- [1, 2,4] triazolo [4,3 -b] [1, 2, 4] triazine was isolated as a brown solid.
2) (6-phenyl- [1,2,4] triazolo [4, 3-b] [1, 2 , 4] triazin-3- yl) methanamine
Figure imgf000107_0002
A 50 mL RB flask was charged with 3- (azidomethyl) -6 -phenyl- [1, 2,4] triazolo [4, 3-b] [1,2,4] triazine (0.3492 g, 1.38 mmol) and THF (14.0 ml, 171 mmol), resulting in a dark brown solution. Triphenylphosphine (0.545 g, 2.08 mmol) and water (0.0998 ml, 5.54 mmol) were added, and the flask was placed in a 650C oil bath for 2 hours. The reaction mixture was concentrated to give a thick brown oil, which was purified by column chromatography using an 80 g ISCO column, eluting with a gradient of 5% MeOH (containing NH4OH) /DCM to 10% MeOH (containing NH4OH) /DCM over 40 minutes. (6 -phenyl- [1, 2,4] triazolo [4, 3-b] [1, 2, 4] triazin-3-yl) methanamine was isolated as a yellow solid.
3) 7-methoxy-N- ( (6-phenyl- [1,2,4] triazolo [4 , 3-b] [1, 2,4] triazin- 3-yl) methyl) -1, 5-naphthyridin-4-amine Prepared in a similar manner as 1- (2-fluoro-4- (3- ( (7-methoxy-
1, 5 -naphthyridin-4-ylamino) methyl) - [1,2,4] triazolo [4, 3- b] pyridazin-6-yl) phenyl) pyrrolidin-2-one .
MS (ESI pos. ion) m/z: 385 (MH+). Calc'd exact mass for
C20H16N8O: 384.
Figure imgf000108_0001
(6-Phenylimidazo [1, 2 -b] pyridazin-3-yl) methanol
To a mixture of (6-chloroimidazo [1, 2-b] pyridazin-3 -yl) methanol (see Galtier, C. et al, Antiviral Chemistry & Chemotherapy, 2003, 14, 177-182) (0.200 g, 1.09 mmol) , phenylboronic acid (0.133 g, 1.09 mmol), PdCl2 (dppf) -CH2Cl2 (0.0445 g, 0.0545 mmol) in dioxane was added sat NaHCO3 (1.20 ml, >2.40 mmol) . The mixture was blanketed with N2, the vessel sealed and heated at 80 C for 1 h. The mixture was allowed to cool to rt and diluted with EtOAc. The organic phase was washed with water, then sat. NaHCO3, dried over Na2SO4, filtered and evaporated. The mixture was purified via flash chromatography using a gradient of 0 % to 10 % MeOH in EtOAc. The title compound was collected as a white solid.
The following compounds were prepared according to the method described for (6-phenylimidazo [1, 2-b] pyridazin-3-yl) methanol : (6- (3 -Fluorophenyl) imidazo[l, 2-b] pyridazin-3-yl) methanol (6- (3 , 4-Difluorophenyl) imidazo [1, 2-b] pyridazin-3-yl) methanol (6- (3,4, 5-Trifluorophenyl) imidazo [1, 2-b] pyridazin-3-yl) methanol 7-Methoxy-4- ( (6 -phenylimidazo [1, 2-b] pyridazin-3- yl) methoxy) quinoline . In a microwave vessel, (6- phenylimidazo.l, 2-b] pyridazin-3-yl) methanol (0.075 g, 0.33 mmol), 4-chloro-7-methoxyquinoline (0.19 g, 1.00 mmol), Cs2CO3 {0.22 g, 0.67 mmol) and 0.7 mL DMSO were combined and the vessel sealed. The mixture was pre-stired for 2 min, followed by microwave heating for 2 h at 120 C, then 1 h at 130 C. The mixture was allowed to cool to rt, diluted with water to precipitate a cream solid. The solid was collected and rinsed with water. The solid was purified via flash chromatography using a 0 % to 5 % MeOH in EtOAc gradient to afford the title compound as a yellow solid. M/Z = 383.2 [M+H] , calc 382.4212 for C23H18N4O2.
The following compounds were prepared using the method desribed for 7-methoxy-4- ( (6-phenylimidazo [1, 2-b] pyridazin-3- yl) methoxy) quinoline :
Figure imgf000109_0001
Example 57
4- ( (6- (3 -Fluorophenyl) imidazo [1, 2-b] pyridazin-3-yl) methoxy) -7 methoxyquinoline . M/Z = 401.2 [M+H] , calc 400.4113 for C23Hi7FN4O2.
Figure imgf000109_0002
Example 58
4- ( (β- (3, 4 -Di fluorophenyl) imidazo [1, 2-b] pyridaz in- 3- yl) methoxy) -7-methoxyquinoline. M/Z = 419.2 [M+H] , calc 418.4014 for C23H16F2N4O2.
Figure imgf000110_0001
Example 59
7-Methoxy-4- ( (6- (1- (piperiάin-4-yl) -lH-pyrazol-4-yl) - [1/2,4] triazolo [4, 3-b]pyridazin-3-yl)πtethoxy) quinoline. In a
50 mL sealable flask was charged with PdCl2 (dppf) -CH2Cl2 adduct (0.011 g, 0.013 tnmol) , 4- ( (6-chloro- [1, 2, 4] triazolo [4, 3- b] pyridazin-3-yl) methoxy) -7-methoxyquinoline (0.150 g, 0.44 mmol) , tert-butyl 4- (4- (4, 4, 5, 5-tetramethyl-l, 3 , 2-dioxaborolan- 2-yl) -lH-pyrazol-1-yUpiperidine-l-carboxylate (0.18 g, 0.48 mmol), sat NaHCO3 (0.75 ml, >0.97 mmol) and 4 mL dioxane . The vessel was sealed and the mixture heated at 80 C for 22 h. The mixture was allowed to cool to rt and diluted with EtOAc, the organic layer washed with water, sat. NaHCO3, dried over Na2SO4, filtered and evaporated. The residue was dissolved in 5 mL CH2Cl2 and TFA (1.20 ml, 16 mmol) was added. The mixture was stirred at rt forlO min and evaporated. The residue was taken up into CH2Cl2 and stirred with minimal 2N NaOH for 1 h (ph basic) . The mixture was evaporated and purified by prep hplc . The title compound was obtained as an off-white solid. M/Z = 457.3 [M+H] , calc 456.5076 for C24H24N8O2.
Figure imgf000110_0002
Example 60
> 3-Fluoro-7-methoxy-4- ( (6-phenyl- [1, 2, 4] triazolo [4,3- b] pyridazin-3-yl)methoxy) quinoline .
A sealable tube was charged with Pd2dba3 (0.20 g, 0.22 mmol), racemic-2- (di-t-butylphosphino) -1, 1 ' -binaphthyl (0.18 g, 0.44 tnmol) , (6-phenyl- [1, 2 , 4] triazolo [4 , 3 -b] pyridazin-3-yl) methanol (0.100 g, 0.44 mmol), 4-chloro-3-fluoro-7-methoxyquinoline (0.14 g, 0.66 mmol), cesium carbonate (0.29 g, 0.88 mmol), and toluene and sealed. The mixture was heated at 100 C for 12 h. The mixture was allowed to cool to rt and the solid filtered, and rinsed with toluene. The solid was stirred with a mixture of EA, MeOH, CH2Cl2 and filtered. The filtrate was purified via flash chromatographyuseing a MeOH in CH2Cl2 gradient. The resulting solid was triturated with CH2Cl2/Hexanes then purified by prep hplc. The title compound was collected as a white solid. M/Z = 402.1 [M+H] , calc 401.3994 for C22H16FN5O2.
Figure imgf000111_0001
Example 61
N-2-Phenyl-N-4- ( (6-phenyl-[1,2,4] triazolo [4,3-b] pyridazin-3- yl) methyl) pyrimidine-2,4 -diamine hydrochloride . 2-Chloro-N- ( (6-phenyl- [1,2,4] triazolo [4 , 3-b] pyridazin-3- yl) methyl)pyrimidin-4 -amine (0.036 g, 0.11 mmol) was combined with 500 mL aniline and heated at 70 C for 2 h, at which point 300 mL aniline more was added and stirred an additional 30 minutes. The mixure was allowed to cool to rt . Ether (5 mL) was added and the mixture stirred. The title compound was collected as a white solid. M/Z = 395.2 [M+H], calc 394.4402 for C22H18N8.
Figure imgf000111_0002
Example 62
7-Methoxy-N- ( (6- (3, 4, 5-trifluorophenyl) imidazo [1# 2-b]pyridazin- 3 -yl) methyl) -1, 5-naphthyridin-4 -amine . a) (6- (3, 4, 5-Trifluorophenyl) im±dazo [1, 2-Jb/pyridaz±n-3 - yDmethanamine. To a suspension of (6- (3,4,5- trifluorophenyl) imidazo [1, 2-b] pyridazin-3 -yl) methanol (0.442 g, 1.6 mmol) in CH2Cl2 (5 mL) was added Mesyl-Cl (0.37 ml, 4.7 mmol) and triethylamine (0.66 ml, 4.7 mmol) -slight exotherm, place flask in water bath- and the mixture stirred at rt 1 h. The mixture was concentrated in vacuo (without heating the flask) and the residue dissolved in DMF (2 mL) and azidosodium (0.23 g, 3.5 mmol) was added in one portion. After 45 minutes, additional azidosodium (0.40 g, 6.0 mmol) was added and the mixture stirred 1 h longer. The mixture was diluted with EtOAc, washed with water, brine, (back extract aq layer) and dry organic layer over Na2SO4, filter and evaporate. The azide intermediate was dissolved in THF (4 mL) and trimethylphosphine IM in THF (2.4 ml, 2.4 mmol) was added. The reaction mixture was stir at rt until the bubbling stops, plus an additional 2 minutes, then water (1 mL) was added. The mixture was diluted with EtOAc, washed with NaHCO3 solution, sat. NaHCO3 , (back extract aq layer) , then dry organic layer over Na2SO4, filter and evaporate. The residue was purified via flash chromatography using al% NH4OH in MeOH in CH2Cl2 gradient to afford the title compound as a tan solid. b) 7-Methoxy-N- ( (6- (3,4, 5-trifluorophenyl) imidazo [1, 2- b]pyridazin-3 -yl)methyl) -1, 5-naphthyridin-4-amine . The title compound was prepared according to Method D, with the addition of 1 equivalent TFA. M/Z = 437.1 [M+H] , calc 436.3955 for C22H15F3N6O .
2-Methyl-5- (4,4,5, 5-tetramethyl-l, 3, 2 -dioxaborolan-2- yl) isoindolin-1-one. In a sealable tube was combined Pd2dba3 (0.0270 g, 0.0295 mmol), 2- (dicyclohexylphosphino) -2' , 4', 6'- tri-i-propyl-1, 1' -biphenyl (0.0563 g, 0.118 mmol) , 4 , 4, 5, 5- tetramethyl-2- (4,4, 5 , 5-tetramethyl-l, 3 , 2-dioxaborolan-2-yl) - 1, 3, 2-dioxaborolane (0.450 g, 1.77 mmol), 5-bromo-2- methylisoindolin-1-one (see Tsuritani, T., et al Synlett 2006, 5 801-803} (0.267 g, 1.18 mmol) , potassium acetate (0.232 g, 2.36 mmol) and 2 mL dioxane . The mixture was blanketed with N2, sealed and heated at 80 C for 22 h. The mixture was allowed to cool to rt then diluted with EtOAc, and the organic layer washed with water, sat. NaHCO3, then dried over Na2SO4, filtered and evaporated. The residue was purified via flash chromatography using a EtOAc in CH2Cl2 gradient. The title compound was collected as a tan solid.
tert-Butyl 4- (4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) - IH-pyrazol-1-y1) piperidine-1-carboxylate . The title compound was prepared according procedures known in the art .
l-Ethyl-4- (4, 4, 5, 5-tetramethyl-l, 3 , 2-dioxaborolan-2-yl) -IH- pyrazole. A 150 mL sealable tube was charged with Pd2dba3 (0.216 g, 0.235 mmol), 2- (dicyclohexylphosphino) -2' , 4', 6'- tri-i-propyl-1, 1' -biphenyl (0.224 g, 0.471 mmol), 4,4,5,5- tetramethyl-2- (4,4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) - 1, 3, 2-dioxaborolane (7.47 g, 29.4 mmol), 4-bromo-l-ethyl-lH- pyrazole (see Ivachtchenko, A. V., et al J". Het. Chem. 2004, 41, 931-939) (4.12 g, 23.5 mmol), potassium acetate (4.62 g, 47.1 mmol) and dioxane (10 mL) . The mixture was blanketed with N2, the vessel sealed and heated at 85 C for 22 h. Allow the mixture to cool to rt and dilute with EtOAc, wash with water, sat. NaHCO3, then dry organic layer over Na2SO4, filter and evaporate. The mixture was purified via flash chromatography using an EtOAc in CH2Cl2 gradient. Use I2 stain to develop tic (compound not uv active at 254) . The title compound was collected as a mixture with pinacol diborane.
1- (2-Methoxyethyl) -4- (4,4, 5, 5-tetramethyl-l, 3,2-dioxaborolan-2- yl) -lH-pyrazole. The title compound was prepared in the same manner as l-ethyl-4- (4, 4 , 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) -lH-pyrazole, using 1- (2-methoxyethyl) -4-bromo-lH-pyrazole (see Ivachtchenko, A. V., et al J. Het. Chem. 2004, 41, 931- 939) .
Figure imgf000114_0001
6- (4,4,5, 5-tetramethyl-l, 3 , 2-dioxaborolan-2- yl) benzo [d] thiazole . Prepared from 6-broτnobenzo [d] thiazole according to the above procedures . l-Cyclobutyl-4- (4,4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) - lH-pyrazole a) 4-Bromo-l-cyclobutyl-lH-pyrazole. To a cooled (0 C) stirred solution of 4-bromo-lH-pyrazole (5.360 g, 36.47 mmol) in DMF (50 mL) was added sodium hydride (1.925 g, 80.23 mmol) slowly. The mixture was allowed to stir in the ice bath 30 min and bromocyclobutane (3.433 ml, 36.47 mmol) was added. The vessel was sealed and the reaction mixture heated at 95 C for 23 h. The mixture was allowed to cool to rt and diluted with 200 mL EtOAc, washed with 500 mL water, then 2x 100 mL water, sat NaHCO3, then the organic layer dried over Na2SO4, filtered and evaporated. The mixture was purified via flash chromatography using a CH2Cl2 in hexanes gradient. (12 stain for visualization) . The title compound was collected as a colorless liquid. b) l-Cyclobutyl-4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) -lH-pyrazole. The title compound was prepared in the same manner as described for i-ethyl-4- (4, 4 , 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) -lH-pyrazole.
l-Iaopropyl-4- (4,4, 5, 5-tetramethyl-l, 3 , 2-dioxaborolan-2-yl) -IH- pyrazole a) 4-bromo-l-isopropyl-lH-pyrazole. A sealable vessel was charged with potassium carbonate (3.76 g, 27.2 mmol), 4-bromo- lH-pyrazole (4.00 g, 27.2 mmol), and 10 mL DMF. To this mixture, 2-iodopropane (3.27 ml, 32.7 mmol) was added and the vessel sealed. The mixture was heated at 80 C for 16 h and allowed to cool to rt . The mixture was diluted with EtOAc, extracted with water, water, sat NaHCO3, and the organic layer dried over Na2SO4, filtered and evaporated. The mixture was purified via flash chromatography using a EtOAc in CH2C12 gradient. The desired compound (as determined by TLC, 12 stain) was collected as a colorless liquid. b) l-isopropyl-4- (4,4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) - lH-pyrazole. The title compound was prepared in the same manner as described for l-ethyl-4- (4 , 4 , 5, 5-tetramethyl-l, 3 , 2- dioxaborolan-2-yl) -lH-pyrazole.
Figure imgf000115_0001
Example 63
Intermediate 4- ( (6- (6-fluoropyridin-3-yl) - [1, 2,4] triazolo [4, 3- b] pyridazin-3-yl)methoxy) -7-methoxyquinoline was prepared as described in general Method A.
5- (3- ( (7 -Methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4 , 3- b]pyridazin-6-yl)pyridin-2 (IH) -one.
4- ( (6- (6-Fluoropyridin-3-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3- yDmethoxy) -7-methoxyquinoline (0.121 g, 0.30 mmol) was suspended in dioxane (1 mL) then added 3M aqueous hydrochloric acid (2.0 ml, 6.0 mmol) . The reaction mixture was then heated at 100 0C for 1 hour. The mixture was concentrated under vacuum and the remaining solid was dissolved in methanol (4 mL) then added triethylamine (0.42 ml, 3.0 mmol). The mixture was stirred at room temperature for 1 hour then concentrated under vacuum. The sample was purified by flash chromatography eluting with 15% 7N NH3 in methanol/ dichloromethane to afford 5- (3- ( (7 methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4, 3- b]pyridazin-6-yl)pyridin-2 (IH) -one as a pale orange solid.
Figure imgf000116_0001
Example 64
4- (3- ( (7-Methoxyquinolin-4-yloxy)τnethyl) - [1,2,4] triazolo [4 , 3- b] pyridazin-6-yl)pyridin-2 (IH) -one was prepared as previously described for 5- (3- ( (7-methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-6-yl)pyridin-2 (IH) -one.
Figure imgf000116_0002
Example 65
Synthesis of the Hydrazine Intermediate
Figure imgf000117_0001
Step 1. 3 , 6-Dichloro-4-methylpyridazine (1.00 g, 6.1 mmol) was mostly dissolved in dioxane (22.5 mL) then added phenylboronic acid (0.82 g, 6.7 mmol), PdCl2 (dppf) -CH2Cl2Adduct (0.25 g, 0.31 mmol) and a solution of cesium carbonate (6.0 g, 18 mmol) in water (7.5 mL) . The reaction mixture was heated at 80 0C for 6 hours. The reaction mixture was concentrated under vacuum and the remaining solid was triturated with water. The solid was collected on a glass frit, washing well with water. The sample was purified by flash chromatography eluting with 1:4 ethyl acetate/ hexane to afford 3-chloro-4-methyl-6- phenylpyridazine as an off-white solid. MS (ESI pos. ion) m/z: 205.2 (MH+).
Step 2. 3-Chloro-4-methyl-6-phenylpyridazine (0.510 g, 2.49 mmol) was dissolved in hydrazine (1.56 ml, 49.8 mmol) then the reaction mixture was heated at 100 0C for 1.5 hours. The precipitate that had formed in the mixture was collected and washed with 1PrOH. The solid was dried under high vacuum to afford 1- (4 -methyl-6-phenylpyridazin-3 -yl) hydrazine as a pale yellow solid. MS (ESI pos. ion) m/z: 201.1 (MH+).
The remaining synthesis of 7-methoxy-N- ( (8-methyl-6-phenyl- [1,2,4] triazolo [4 , 3-b] pyridazin-3 -yl) methyl) -1, 5-naphthyridin- 4 -amine was conducted as described in general Method B. Synthesis of the 1-Methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2- dioxaborolan-2-yl) pyrldin-2 (IH) -one Intermediate.
Figure imgf000118_0001
Step 1. 5-Bromopyridin-2 (IH) -one (0.250 g, 1.44 mmol) was dissolved in DMF (3 mL) then added iodomethane (0.0943 ml, 1,51 mmol) and potassium carbonate (0.218 g, 1.58 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The remaining residue was dissolved in ethyl acetate then washed with water and brine. The aqueous layer was back-extracted with ethyl acetate (3x) . The organic layers were combined and dried over sodium sulfate then concentrated under vacuum to afford 5- bromo-l-methylpyridin-2 (IH) -one as an orange waxy solid. MS (ESI pos. ion) m/z: 188.0 and 190.0 (MH+).
Step 2. 5-Bromo-l-methylpyridin-2 (IH) -one (0.100 g, 0.532 mmol) was suspended in dioxane (2 mL) then added 4,4,5,5- tetramethyl-2- (4,4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) - 1, 3, 2-dioxaborolane (0.203 g, 0.798 mmol), PdC12 (dppf) - CH2C12Adduct (0.0217 g, 0.0266 mmol) and sodium acetate (0.109 g, 1.33 mmol) . The reaction mixture was heated at 120 0C for 5.5 hours then at 130 0C for 3 hours. The reaction mixture was filtered through a pad of Celite, washing with MeOH. The filtrate was concentrated under vacuum. The remaining black residue was then dissolved in dichloromethane and filtered through another pad of Celite, washing well with dichloromethane. The filtrate was concentrated under vacuum and the remaining black residue was further dried under high vacuum to afford l-methyl-5- (4,4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)pyridin-2 (IH) -one as a black solid. MS (ESI pos. ion) m/z: 236.1 (MH+).
Figure imgf000119_0001
Example 66
Intermediate 3- (4-methoxybenzyl) -6-phenyl- [1,2,4] triazolo [4,3- a] pyridine was prepared as described in general Method A.
4- ( (6-phenyl- 11,2,4] triazolo [4, 3-a] pyridin-3-yl)methyl) phenol.
3- (4-Methoxybenzyl) -6-phenyl- [1,2,4] triazolo [4, 3 -a] pyridine (0.057 g, 0.18 mmol) was dissolved in dichloromethane (2.5 raL) then cooled to 0 0C. A IM solution of boron tribromide (0.72 ml, 0.72 mmol) in dichloromethane was added slowly. The reaction mixture was stirred at 0 0C for 2 hours. A precipitate was present in the reaction mixture . The reaction was quenched with ice chips and stirred overnight at room temperature. A solid remained in the mixture . The reaction mixture was diluted with dichloromethane/methanol to give a clear mixture then washed with saturated aqueous sodium bicarbonate and brine . The organic layer was dried over sodium sulfate and concentrated under vacuum. The sample was purified by preparative TLC eluting with 7% methanol in dichloromethane which afforded 4- ( (6-phenyl- [1,2,4] triazolo [4 , 3-a] pyridin-3 -yl) methyl) phenol as an off-white solid
Figure imgf000120_0001
Example 67
4- ( (6- (Pyridin-2-yl) - [1,2,4] triazolo [4, 3 -a] pyridin-3- yl) methyl) phenol was prepared as previously described for 4- ( (6-phenyl- [1,2,4] triazolo [4, 3-a] pyridin-3-yl) methyl) phenol
Figure imgf000120_0002
Example 68
4- ( (6- (Pyrazin-2-yl) - [1, 2, 4] triazolo [4 , 3-a] pyridin-3- yl) methyl) phenol was prepared as previously described for 4- ( (6-phenyl- [1,2,4] triazolo [4, 3-a] pyridin-3 -yl) methyl) phenol,
Figure imgf000120_0003
Example 69
4- ( (6- (IH-Pyrrol-2-yl) - [1,2,4] triazolo [4 , 3 -a] pyridin-3 - yl) methyl) phenol was prepared as previously described for 4- ( (6-phenyl- [1,2,4] triazolo [4, 3-a] pyridin-3-yl)methyl) phenol
6 -bromoquinoxaline. To a solution of 4-bromobenzene-1, 2-diaτnine (4.0 g, 21 mtnol) in 60 mL of EtOH was added 40% glyoxal aldehyde (4.1 ml, 32 mmol) soultion in water. The resulting mixture was refluxed for 10 hours. The mixture was concentrated in vacuo and the residue was diluted in 100 mLof EtOAc. The organic soultion was washed with 40 mL of satd. NaHCO3 and 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silca gel column chromatography (5% EtOAc/hex to EtOAC) to give light yellow solid 6-bromoquinoxaline. MS (ESI, pos . ion) m/z: 208.9 (M+l) . tert-butyl 2- (quinoxalin-6-yl) acetate. To a solution of 6-bromoquinoxaline (1.40 g, 7 mmol), tris (dibenzylideneacetone) dipalladium (o) (0.6 g, 0.7 mmol) and Q-phos (1.0 g) in 25 mL of THF was added Reactant 2 (27 ml, 27 mmol) three time in 3 hours. The reaction was heated at 50 oC for 16 hours and was quenched with 50 mL of satd. NH4C1. The mixture was diluted with 60 mL of EtOAc. The organic phase was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give red oil. The residue was purified by a silica gel column chromatography (5% EtOAc/hex to EtOAC) twice to give red solid tert-butyl 2- (quinoxalin-6- yDacetate. MS (ESI, pos. ion) ra/zi 245.1 (M+l).
6- ( (6-phenyl- [1, 2 , 4] triazolo [4, 3-b]pyridazin-3- yl)methyl) quinoxaline.
A mixture of tert-butyl 2- {quinoxalin-6-yl) acetate (0.15 g, 0.6 mmol), 1- (6 -phenylpyridazin-3-yl) hydrazine (0.1 g, 0.7 mmol) and p-toluenesulfonic acid monohydrate (0.1 g, 0.6 mmol) in 3 mL of dioxane was heated with microwave at 150 0C for 1 hour in a microwave tube. The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO3 solution. The organic phase was separated and was washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc) to give light yellow solid as desired product 6- { (6-phenyl- [1,2,4] triazolo[4, 3-b] pyridazin-3-yl)methyl)quinoxaline.
6-bromoquinazolin-4 (3H) -one.
A solution of 5-bromoisatoic anhydride (5.0 g, 21 mmol) and formamidinium acetate (2.2 g, 21 mmol) in 60 tnL of i-PrOH was heated at reflux for 10 hours. The reaction mixture was cooled to rt and the white solid was collected by filtration. The white solid was washed with small amount of i-PrOH and dried in air to give desired product 6-bromoquinazolin-4 (3H) -one . MS (ESI, pos. ion) m/z: 224.9 (M+l) .
tert-butyl 2- (4-oxo-3,4-dihydroquinazolin-6-yl) acetate.
To a solution of 6-bromoquinazolin-4 (3H) -one (1.00 g, 4 mmol), tris (dibenzylideneacetone) dipalladium (o) (0.4 g, 0.4 mmol) and Q-phos (0.8 g) in 25 mL of THF was added Reactant 2 (27 ml, 13 mmol) three time in 5 hours. The reaction was heated at 50 0C for 16 hours and was quenched with 50 mL of satd. NH4Cl. The mixture was diluted with 60 mL of EtOAc. The organic phase was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give red oil. The residue was purified by a silica gel column chromatography (5% EtOAc/hex to EtOAC) twice to give orange solid tert-butyl 2- (4-oxo-3 , 4- dihydroquinazolin-6-yl) acetate . MS (ESI, pos. ion) m/z: 261.1 (M+l) .
2- (4-oxo-3,4-dihydroquiiiazolin-6-yl) acetic acid. A solution of tert-butyl 2- (4-oxo-3 , 4-dihydroquinazolin-6- yl) acetate (0.25 g, 0.96 mmol) in 10 mL of satd. HCl in EtOAc was stirred at rt for 4 hours . The mixture was concentrated in vacuo at rt, and the residue was used in the next reaction without further purification. MS (ESI, pos. ion) m/z: 205.1 (M+l) .
Figure imgf000123_0001
6- ( (6-phenyl- [1,2,4] trlazσlo [4, 3-b] pyridazin-3- yl)methyl) quinazolin-4 (3H) -one.
A mixture of 2- (4-oxo-3, 4-dihydroquinazolin-6-yl) acetic acid (0.10 g, 0.5 mmol) , 1- (6-phenylpyridazin-3-yl) hydrazine (0.1 g, 0.6 mmol) and p-toluenesulfonic acid monohydrate (0.09 g, 0.5 mmol) in 3 mL of dioxane was heated with microwave at 150 °C for l hour in a microwave tube . The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHC03 solution. The organic phase was separated and was washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc) to give light yellow. solid as desired product 6- ( (6-phenyl- [1,2,4] triazolo[4, 3-b] pyridazin-3- yl) methyl) quinazolin-4 (3H) -one. MS (ESI, pos . ion) m/z: 355.1 (M+l) .
Figure imgf000123_0002
6- (1- (6- (3-methylisothiazol-5-yl) -[1,2,4] triazolo [4,3- bl pyridazin-3-yl) ethyl) quinoline .
To a solution of 5-bromo-3-methylisothiazole (1.00 g, 5.6 mmol) in 10 mL of THF at -45 0C (CH3CN/dry ice) was added isopropylmagnesium chloride LiCl complex (7.9 ml, 7.9 mmol)
(LiCl complex, IM in THF) . The mixture was stirred at -45 0C for 20 minutes and was added zinc chloride, 0.5m in thf (17 ml, 8.4 mmol) slowly via a syringe. The mixture was then warmed up to rt and continued to stir for additional 30 minutes. 6- (1- (6-chloro- [1, 2,4] triazolo [4, 3-b] pyridazin-3-yl) ethyl) quinoline (0.5787 g, 1.9 mmol), tris (dibenzylideneacetone) dipalladium (o) (0.51 g, 0.56 mmol) and Q-Phos (0.65 g) in 15 mL of N, N- dimethyl acetamide was added to the reaction mixture. The reaction was warmed up to 50 0C for 6h and was quenched with 50 mL of satd. NH4Cl aq. solution. The mixture was extracted with 150 mL of EtOAc and the organic phase was washed with 60 mL of brine. The aqueous phases were extracted with 100 mL EtOAc again. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH in EtOAc) to give red solid as desired product 6- (1- (6- (3-methylisothiazol-5-yl) - [1, 2,4] triazolo [4, 3-b] pyridazin-3-yl) ethyl) quinoline. MS (ESI, pos. ion) m/z: 373.2 (M+l) .
Figure imgf000124_0001
Methyl 2-fluoro-4- (3- ( (7-methoxyquinolin-4-yloxy) methyl) - [1, 2,4] triazolo[4, 3-a] pyridin-6-yl) benzoate (0.368 g, 0.803 mmol) was diluted with dioxane (17 mL) and to the solution was added lithium hydroxide (0.0384 g, 1.61 mmol) in water (8 mL) . The reaction mixture was heated at 40 0C for 4.5 hours. The reaction mixture was concentrated in vacuo to remove most of the dioxane and water (not concentrated to dryness) . To the crude mixture, water (8 mL) was added. Dropwise, IN HCl was added to pH = 7. The neutral solution was then filtered through a frit and the crude solid product was washed with MeCN and a small amount of MeOH. The final acid product was concentrated, and carried on to the acid chloride.
Figure imgf000125_0001
To a suspension of 2-fluoro-4- (3- ( (7-methoxyquinolin-4- yloxy) methyl) - [1,2,4] triazolo [4 , 3-a] pyridin-6-yl) benzoic acid (0.150 g, 0.338 mmol) in DCM (1.5 mL) at 0 0C was added dropwise thionyl chloride (0.370 ml, 5.06 mmol). DMF (1 drop) was added and the solution was allowed to stir at room temperature for 5 h. The reaction mixture was concentrated in vacuo to a light brown solid. The material was taken on crude for synthesis of the following amide.
Figure imgf000125_0002
Example 72
2-fluoro-N- (2-methoxyethyl) -4- (3- ( (7-methoxyquinolin-4- yloxy) methyl) - [1,2,4] triazolo [4, 3-a] pyridin-6-yl)benzamide.
To a solution of N-ethyl-N-isopropylpropan-2-aτnine (0.077 ml, 0.44 mmol) and 2-fluoro-4- (3- ( (7-methoxyquinolin-4- yloxy) methyl) - [1,2,4] triazolo [4, 3-a] pyridin-6-yl) benzoyl chloride-HCl (0.088 g, 0.18 mmol) in DCM (1.25 mL) was added 2- methoxyethanamine (0.023 ml, 0.26 mmol) dropwise. The solution was stirred at room temperature for 5h. The crude material was concentrated and then triturated with sodium bicarbonate and washed with water. The resultant solid was dissolved in DCM/MeOH and concentrated.
The crude material was dissolved in DCM/MeOH and was purified via flash chromatography, eluting with 0-10% MeOH/NH4OH in DCM to yield 2-fluoro-N- (2-methoxyethyl) -4- (3- ( (7-methoxyquinolin- 4-yloxy) methyl) - [1,2,4] triazolo [4 , 3 -a] pyridin-6-yl) benzamide .
Figure imgf000126_0001
Example 73
tert-butyl 4- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4, 3-a] pyridin-6-yl) phenyl (methyl) carbamate (0.067 g, 0.13 mmol) was dissolved in MeOH (1.7 mL) and to the solution was added concentrated HCl (0.50 ml, 6.0 mmol). The reaction mixture was stirred at room temperature overnight.
Upon completion, the crude mixture was concentrated in vacuo.
The solid that remained after concentration was dissolved in MeOH and to the solution was added triethylamine (0.23 ml, 1.6 mmol) . The reaction was allowed to stir for Ih. The crude mixture was concentrated in vacuo.
The compound was purified using via flash chromatography, eluting with 5-8% MeOH/NH4OH in DCM to yield 4- (3- ( (7- methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4, 3 -a] pyridin- 6-yl) -N-methylbenzenamine as a yellow solid.
Figure imgf000127_0001
Example 74
A solution of 2-fluoro-4- (3- ( (7-methoxyquinolin-4- yloxy) methyl) - [1,2,4] triazolo [4, 3 -a] pyridin-6-yl) benzoic acid (0.192 g, 0.43 mmol) , HATU (0.26 g, 0.69 mmol) , and Hunig • sBase (0.30 ml, 1.7 mmol) in DMF (10.75 mL) was allowed to stir for
30 minutes. Ammonia (0.0093 ml, 0.43 mmol) was then bubbled through the mixture for another 30 minutes.
The solution was concentrated in vacuo and purified using via flash chromatography, eluting with 5-10% MeOH/NH4OH in DCM. There remained an unidentified peak in the NMR, so the solid was triturated in MeCN, filtered, and quickly washed with DCM to wash through the impurities. Concentration in vacuo yielded 2-fluoro-4- (3- { (7-methoxyquinolin-4-yloxy)methyl) - [1, 2,4] triazolo [4, 3-a]pyridin-6-yl)benzamide as an off-white solid.
Figure imgf000127_0002
Example 75 To a solution of 5- (3- ( (7-methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo[4,3-a]pyridin-6-yl) thiophene-2-carbonyl chloride (0.150 g, 0.33 mmol) and Hunig • s Base (0.17 ml, 1.00 mmol) in DCM (2.5 mL) was added methanamine (0.17 ml, 0.33 mmol) in THF dropwise. The solution was stirred at room temperature for 3 hours, at which point an additional 1.5 equivalents of amine were added.
The solution was concentrated in vacuo and purified via flash chromatography eluting with 3-8% MeOH -.NH4OH in DCM. There remained an impurity, so the product was triturated with MeCN, filtered and washed with DCM to yield 5- (3- ( (7-methoxyquinolin- 4-yloxy) methyl) - [1,2,4] triazolo [4, 3 -a] pyridin-6-yl) -N- methylthiophene-2-carboxamide (0.0276 g, 19% yield) as an amorphous tan solid.
Figure imgf000128_0001
Example 76
6- ( (6-Phenyl- [1,2,41 triazolo [4, 3-b] pyridazin-3- yl) methyl) quinoline ♦ To a 50 ml round-bottomed flask was added 2- (quinolin-6-yl) acetic acid (0.6O g, 3.2 mmol), CH2Cl2 (20 ml) and oxalyl chloride (4.0 ml, 8.0 mmol, 2 M in CH2Cl2) and DMF (0.2 mL of a solution of 1 drop DMF in 1 mL CH2Cl2) . After 3 d, an additional 2.5 eq. of oxalyl chloride was added. After 4 h, toluene (1 mL) was added and the mixture was concentrated. Toluene (3 mL) was added and again concentrated. The residue was taken up in CH2Cl2 (20 mL) and 1- (6-phenylpyridazin-3- yl) hydrazine (0.60 g, 3.2 mmol) was added. The mixture was stirred for 17 h and then concentrated. The mixture was then taken up in phosphorous oxychloride (20 ml, 220 mmol) and heated at 100 0C for 15 h. Toluene (5 mL) was added and the solution was concentrated. Another 5 mL toluene was added to the residue and once again it was concentrated. The brown solid residue was taken up in sat. NaHCO3 and extracted with EtOAc (4 x 150 mL) and 25% iPrOH/CHCl3 (3 x 150 mL) . The combined extracts were washed with brine, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0 to 5% MeOH (2M in NH3) /CH2Cl2) afforded the title compound as a tan solid. MS (ESI, pos. ion) m/z-. 338 (M+l) .
Figure imgf000129_0001
Methyl 2- (quinolin-6-yl) propanoate. To a 250 ml round-bottomed flask was added lithium bis (trimethylsilyl) amide (2.0 g, 12 mmol) and tetrahydrofuran (75 ml) . The mixture was cooled to - 78 0C and methyl 2- (quinolin-6-yl) acetate (2.O g, 9.9 mmol) was added as a solution in 1 ml THF. This was stirred at -78 0C for 30 min and then methyl iodide (0.75 ml, 12 mmol) was added. This was stirred for 30 min at -78 0C and then allowed to warm to rt. The mixture was quenched with sat NH4Cl (40 mL) and diluted with water (200 mL) . The mixture was concentrated in vacuo to remove the THF and then was extracted with EtOAc (2 x 100 ml) . The combined extracts were washed with brine (50 ml) , dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (20 to 60% EtOAc/hexane) afforded the title compound as a brown oil (1.8 g, 85%). MS (ESI, pos. ion) m/z: 216 (M+l) .
Figure imgf000129_0002
2- (Quinolin-6-yl) propanoic acid. To a 15 ml round-bottomed flask was added methyl 2- (quinolin-6-yl) propanoate (1.0 g, 4.7 mmol) , methanol (5.0 ml, 12 tnmol) and aq. sodium hydroxide (5 M, 2.3 ml, 12 mmol) . The mixture was stirred at 25 0C for 24 h. The mixture was neutralized with ag. HCl (5 M, 2.3 mL, 12 mmol) . After sitting overnight a white precipitate had formed. The mixture was filtered and the filtercake was washed with water and then dried in vacuo to afford the title compound as a white solid (0.72 g, 77%). MS (ESI, pos . ion) m/zi 202 (M+l) .
Figure imgf000130_0001
Example 77
6- (1- (6 -Phenyl- [1, 2#4] triazolo [4, 3-b] pyridazin-3- yl) ethyl) quinoline. To a 2-5 ml Personal Chemistry microwave vial was added 2- (quinolin- 6-yl) propanoic acid (0.25 g, 1.2 mmol), 1- (6-phenylpyridazin-3-yl) hydrazine (0.42 g, 2.2 mmol) and cone. HCl (2 mL) . The mixture was heated in the microwave at 160 0C for 8 h. After cooling to rt, the mixture was poured into sat. NaHCO3 (100 mL) and then extracted with EtOAc (4 x 75 mL) . The combined extracts were washed with brine, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (1.0 to 4.5% MeOH (2 M in NH3) /CH2Cl2) afforded the title compound as an off-white solid (0.23 g, 53% yield). MS (ESI, pos. ion) m/zι 352 (M+l).
Figure imgf000130_0002
Example 78 (S) -6- (1- (6-phenyl- [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) ethyl) quinoline . Isolated from chiral separation of 6- (1- (6-phenyl- [1,2,4] triazolo [4 , 3-b] pyridazin-3-yl) ethyl) quinoline. Column: Chiralpak AS-H (250 x 21 mm) . Mobile Phase: A: Liquid CO2 . B: Methanol (0.1% DEA). Isocratic: 75:25 (A:B) . Flow rate: 70.0 mL/min. Outlet Pressure: 100 bar. Retention time: 4.38 min. Enantiomeric purity: >99% ee . MS (ESI, pos . ion) m/z: 352 (M+l) .
Figure imgf000131_0001
(R) -6- (1- (6-phenyl- [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) ethyl) quinoline (AMG 2121451). Isolated from chiral separation of 6- (1- (6-phenyl- [1, 2, 4] triazolo [4 , 3-b] pyridazin-3- yl) ethyl) quinoline. Column: Chiralpak AS-H (250 x 21 mm). Mobile Phase: A: Liquid CO2 . B: Methanol (0.1% DEA). Isocratic: 75:25 (A:B). Flow rate: 70.0 mL/min. Outlet Pressure: 100 bar. Retention time: 4.90 min. Enantiomeric purity: 96.8% ee . MS (ESI, pos. ion) m/z: 352 (M+l).
Figure imgf000131_0002
Methyl 2-£luoro-2- (quinolin-6-yl) acetate. To a 250 ml round- bottomed flask was added lithium bis (trimethylsilyl) amide (2.0 g, 12 mmol) and tetrahydrofuran (75 ml) . The mixture was cooled to -78 0C and methyl 2- (quinolin-6-yl) acetate (2.0 g, 9.9 mmol) was added as a solution in 1 ml THF. After stirring at -78 0C for 30 min, n-fluorobenzenesulfonimide (3.8 g, 12 πwnol) was added as a 1 M solution in THF. This was stirred for 30 min at -78 0C and then allowed to warm to rt. The mixture was quenched with sat NH4Cl (50 raL) and diluted with water (200 mL) . The mixture was concentrated in vacuo to remove the THF and then was extracted with EtOAc (2 x 100 ml) . The combined extracts were washed with brine (100 ml) , dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (20 to 60% EtOAc/hexane) afforded the title compound as a tan solid. MS (ESI, pos. ion) m/z: 220 (M+l) .
Figure imgf000132_0001
2-Fluoro-2- (quinolin-6-yl) acetic acid. To a solution containing methyl 2-fluoro-2- (quinolin-6-yl) acetate (0.49 g, 2.2 mmol) in methanol (3.0 ml) was added sodium hydroxide (5 M, 1.0 ml, 5.0 mmol) . The mixture was stirred at rt for 48 h and then neutralized with 5 N HCl (1.0 mL) . The solution was allowed to sit overnight during which time a precipitate formed. The solution was filtered and the filtercake washed with cold water then dried under vacuum to afford the title compound as a tan solid. MS (ESI, pos. ion) m/z: 206 (M+l) .
Figure imgf000132_0002
(6-Phenyl- [1,2,4] triazolo [4, 3-b] pyridazin-3-yl) (quinolin-6- yl) methanol TFA salt. To a 2-5ml Personal Chemistry microwave vial was added 2-fluoro-2- (quinolin-6-yl) acetic acid (0.20 g, 0.98 mmol), 1- (6 -phenylpyridazin-3-yl) hydrazine (0.27 g, 1.5 mmol) and cone, hydrochloric acid (2.0 ml, 66 mmol). The mixture was heated at 160 0C for 6 h in the microwave. After cooling to rt, the mixture was poured into sat. NaHCO3 (100 mL) and extracted with 25% iPrOH/CHCl3 (4 x 50 mL) . The combined extracts were dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (2.0 to 6.5% MeOH (2 M in NH3) /CH2Cl2) followed by further purification by Prep-HPLC (Phenomenex Synergi 4u MAX-RP 8OA 150 x 21.20 mm, 10 to 65% CH3CN (0.1% TFA) /H2O (0.1% TFA) over 15 min then 65%CH3CN for 5 minutes at 20 ml/τnin) with the fractions containing product concentrated to afford the title compound as a tan solid (0.10 g, 22% yield) . MS (ESI, pos . ion) m/z: 354 (M+l) .
Figure imgf000133_0001
Example 81
(R) - (6-Phenyl- [1,2,41 triazolo [4, 3-b] pyridazin-3-yl) (quinolin-6- yl) methanol . Isolated from chiral separation of racemic (6- phenyl- [1,2,4] triazolo [4, 3-b]pyridazin-3-yl) (quinolin-6 - yDmethanol TFA salt (AMG 2120533). Column: Chirotechnology AS-H column, 4.6 mm x 15 cm. Mobile phase: 70/30 Carbon dioxide/0.2% diethylamine in ethanol. Flow rate: 4.0 mL/min. Temperature: 40 0C. Back pressure: 100 bar. Retention time: 1.65 min. Enantiomeric purity: >99% ee . MS (ESI, pos. ion) m/z: 354 (M+l) .
Figure imgf000133_0002
(S) - (6-Phenyl- [1, 2 , 4} triazolo [4 , 3-b] pyridazin-3-yl) (quinolin-6 y1) methanol . Isolated from chiral separation of racemic (6- phenyl- [1,2,4] triazolo [4 , 3-b] pyridazin-3-yl) (quinolin-6- yl) methanol TFA salt (AMG 2120533) . Column: Chirotechnology AS-H column, 4.6 mm x 15 cm. Mobile phase: 70/30 Carbon dioxide/0.2% diethylamine in ethanol. Flow rate: 4.0 mL/rain. Temperature: 40 0C. Back pressure: 100 bar. Retention time: 2.22 min. Enantiomeric purity: >99% ee . MS (ESI, pos . ion) m/z: 354 (M+l) .
Figure imgf000134_0001
Step Ii 4-amino-3-bromo-2-chloropyridine . 4 -amino-2- chloropyridine (50 g, 388 mmol) was dissolved in glacial acetic acid (500 tnL) . To this solution was added N-bromosuccinamide (75 g, 426 mmol,) portionwise at room temperature (water bath cooling was provided to control the exothermicity) . The reaction mixture was stirred at RT for 1 h at which point the reaction was found complete (as monitored by TLC) . Solvent was removed under reduced pressure followed by azeotropic distillation with ethanol. The crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.
Step 2: 4-amino-3-bromo-2-πiethoxypyridine. Methanol (350 mL) was charged in a two-neck round bottom flask equipped with a guard tube and septum and cooled to 0 0C. Sodium metal (23 g) was added to it slowly in pieces. After all sodium metal had dissolved, 4-amino-3-bromo-2-chloro pyridine (23 g, 178 mmol) was added and the solution was heated at 180 0C in a pressure vessel for 5-6 h. The reaction mixture was then cooled to 0 0C and adjusted to pH 8 by addition of cone. HCl. Solvent was removed under reduced pressure and the residue was suspended in ethyl acetate, ϋndissolved impurities were removed by filtration and the filtrate was concentrated under reduced pressure to obtain pure product . Step 3 ; 5- [ (3-Bromo-2-methoxy-pyridin-4-ylamino) -methylene] - 2, 2-dimethyl- [1, 3] dioxane-4, 6-dione. A two necked round bottomed flask equipped with a reflux condenser was charged with Meldrum's acid (15.6 g, 108 mmol) and trimethyl orthoformate (143 mL) . The reaction mixture was heated 100 0C for 2 h. 4-amino-3-bromo-2-methoxypyridine (22 g, 108 mmol) was added and heating was continued for an additional 4 h at 100 0C. The reaction mixture was allowed to cool to RT, diluted with hexane and filtered to obtain the product as a yellow solid.
Step 4; 8-Bromo-7-methθ3cy-lH- [1, 6] naphthyridin-4-one. A two neck round bottomed flask equipped with an air condenser was charged with 5- [ (3-Bromo-2-methoxy-pyridin-4-ylamino) - methylene] -2, 2-dimethyl- [1, 3] dioxane-4, 6-dione (23g, 64 mmol) and diphenyl ether (230 mL) . The reaction mixture was heated at 250 0C for 30 min under nitrogen atmosphere after which it was cooled to RT, diluted with hexane and filtered to obtain a dark solid. The crude product was refluxed in hexane for 30 min and filtered to obtained 8-Bromo-7-methoxy-lH- [1, 6] naphthyridin-4- one as a brown solid.
Step 5; 7-Methoxy-lH- [1, 6] naphthyridin-4-one. 8-Bromo-7- methoxy-lH- [1, 6] naphthyridin-4-one (12 g, 33.5 mmol) was dissolved in anhydrous methanol (240 mL) and 10 % Dry Pd/C (2.4 g) was added carefully in portions. This was followed by portionwise addition of ammonium formate (24 g) which caused an exotherm. The reaction mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with hot methanol. The filtrate was concentrated and the residue purified by column chromatography on silica gel (230 -400 mesh) eluting with ethyl acetate- methanol. Step 6: 4-Chloro-7-methoxy- [l, 6]naphthyridine. A two neck round bottomed flask equipped with CaCl2 guard tube was charged with 7-Methoxy-lH- [1, 6] naphthyridin-4-one (28 g, 159 mmol) and POCl3 (280 mL) . The reaction mixture was stirred at RT for 3 h. The reaction mixture was poured into ice water and the pH was carefully adjusted to 8 with solid sodium carbonate (highly exothermic reaction) . The product was extracted with EtOAc . The combined organic layer was washed with water, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture .
Figure imgf000136_0001
Step It 3-Bromo-5-methoxypyridine. Sodium (12 g) was dissolved in methanol (150 mL) while cooling, and excess MeOH was removed under reduced pressure to obtain NaOMe, which was azeotroped with toluene (2 x 100 mL) . A solution of 3,5- dibromopyridine (100 g) in DMSO (500 mL) was added to sodium methoxide and the mixture was stirred at 90 0C for 2 h. After cooling to RT, aqueous NaOH solution (3 M, 300 mL) was added and the mixture was extracted with Et2O. The ethereal layer was washed with brine and dried over Na2SO4. After concentration the crude product obtained was purified by flash column chromatography (Hexane: EtOAc 85:15) to afford pure product 3- bromo-5-methoxy pyidine .
Step 2: 3-amino-5-methoxypyridine. 3-Bromo-5-methoxypyridine ) (15 g) was added to a pressure vessel, and CuSO4 (3.9 g) and 251 aq. ammonia (150 mL) were added. The reaction mixture was stirred for 4 h at 135 0C, then cooled to RT, basified with aqeous NaOH solution, and extracted with CH2Cl2. After evaporation of volatiles, 3-amino-5-methoxypyridine was obtained as yellow solid.
Step 3 ; 5- [ (5-Methoxy-pyridin-3-ylamino) -methylene] -2,2- dimethyl- [1, 3] dioxane-4, 6-dione. A two-necked round bottomed flask equipped with a reflux condenser was charged with Meldrum' s acid (14.4 g, 100 mmol) and trimethylorthoformate (100 mL) . The reaction mixture was heated at 100-105 0C for 2 h. 5-amino-3-methoxy pyridine (12.5 g, 100 mmol) was added to the reaction mixture and heating was continued for an additional 4 h at the same temperature. The reaction mixture was allowed to cool to RT, diluted with hexane and filtered to obtain the product as light yellow solid.
Step 4: -Methoxy-1H- [1, 5] naphthyridin-4-one . A two-necked round bottomed flask equipped with an air condenser was charged with 5- [ (5-Methoxy-pyridin-3-ylamino) -methylene] -2, 2-dimethyl- [1,3] dioxane-4, 6-dione (18 g) and diphenyl ether (180 mL) . The reaction mixture was heated at 240-250 0C for 5 min under N2 atmosphere after which it was cooled to RT, diluted with hexane and filtered to obtain a dark solid. The crude product was refluxed in hexane for 30 min and filtered to obtain product as a brown solid.
Step 5: 8-chloro-3-methoxy-l, 5-naphthyridine. A two-necked round bottomed flask equipped with an air condenser (protected with CaCl2 guard tube) was charged with 7-Methoxy-lH- [1, 5] naphthyridin-4-one (13 g) and POCl3 (65 mL) . The reaction mixture was allowed to reflux at 120 0C for 12 h. The POCl3 was removed In vacuo and azeotroped twice with toluene. EtOAc (75 mL) was added and the reaction mixture was stirred at 50-600C for 15-20 min. EtOAc removed separated by decantation. The organic layers were combined and concentrated. The obtained crude was dissolved in EtOAc (50ml) and a washed with satd. aqueous sodium bicarbonate . The organic layer was dried over Na2SO4 and concentrated. The resulting solids were suspended in hexane, stirred for 15 min, filtered and dried under vacuum.
Figure imgf000138_0001
Example 83
7- (difluoromethoxy) -N- ( (6-phenyl- [1, 2,4] triazolo [4, 3- b] pyridazin-3-yl) methyl) -1, 5-naphthyridin-4-amine
DMF (0.5 mL) and water (0.1 mL) were added to a pressure vessel containing 8- ( (6-phenyl- [1,2,4] triazolo [4 , 3 -b] pyridazin-3- yl) methylamino) -1, 5-naphthyridin-3-ol (50 mg, 135 μmol) , sodium
2-chloro-2, 2-difluoroacetate (47 mg, 311 μmol), cesium carbonate (62 mg, 190 μmol) . The reaction mixture was stirred at 1000C for 18h, cooled to RT and concentrated in vacuo.
Purification by MPLC (DCM/MeOH+l%NH4OH : 100/0 to 90/10) afforded the title compound (10 mg, 17% yield). MS m/z = 420.1 [M+H]+.
CaIc' d for C21H15F2N7O: 419.40.
Figure imgf000138_0002
Example 84
N- ( (6- (3H-l,2,3-triazol-4-yl) - [1, 2, 41 triazolo [4, 3-b3pyridazin- 3 -yl) methyl) -7 -methoxy-l# 5-naphthyridin-4-amine 1) Preparation of tert-butyl (6- (3H-1, 2, 3-trlazol-4-yl) ■ [1,2,4] triazolo [4,3-b] pyridazin-3-yl) methylcarbamate
Figure imgf000139_0001
tert-Butyl (6-ethynyl- [1,2,4] triazolo [4 , 3-b] pyridazin-3- yDraethylcarbamate (0.109 g, 0.399 mmol) and sodium azide (0.0285 g, 0.439 mmol) were dissolved DMF (2mL) at RT. The reaction mixture was stirred overnight at RT then at 700C for 3h. Water was added at RT and the aqueous layer was extracted with EtOAc and l-butanol. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Used without further purification.
2) Preparation of N- ( (6- (3H-1, 2, 3-triazol-4-yl) -
[1,2,4] triazolo [4,3-b]pyridazin-3-yl)methyl) -7-methoxy- 1, 5-naphthyridin-4-amine
Figure imgf000139_0002
Prepared by a method similar to 7-methoxy-N- ( (6- (3- τnethylisothiazol-5-yl) -[1,2,4] triazolo [4 , 3-b] pyridazin-3- yDmethyl) -1, 5-naphthyridin-4-aτnine. MS m/z = 375.1 [M+H] + . CaIC d for C17H14N10O: 374.37
Figure imgf000140_0001
4- ( (8-fluoro-6- <3-methyliaothiazol-5-yl) - [1,2,4] triazolo [4, 3- a] pyridin-3-yl)methoxy) -7-methoxyquinoline Dioxane (3.6 mL) was added to 4- ( (6-chloro-8-fluoro- [1,2,4] triazolo [4, 3 -a] pyridin-3 -yl) methoxy) -7-methoxyquinoline (175 mg, 488 μmol) , X-Phos (32.6 mg, 68.3 μmol) , 3-methyl-5- (trimethylstannyl) isothiazole (153 ing, 585 μmol), palladium acetate (7.67 mg, 34.1 μmol) . The flask was purged with argon and sealed. The reaction mixture was stirred at 800C for 2d. . More X-Phos (32.6 mg, 68.3 μmol), palladium acetate (7.67 mg, 34.1 μmol) and 3-methyl-5- (trimethylstannyl) isothiazole (153 mg, 585 μmol) were added and stirring was continued at 800C overnight. The reaction mixture was cooled at RT, concentrated in vacuo and urified by MPLC (CH2Cl2/MeOH: 100/0 to 90/10) . Further purification by MPLC (ISCO, EtOAc/MeOH: 9/1, isocratic) afforded the title compound (105 mg, 51% yield). MS m/z = 422.0 [M+H]+. CaIc 'd for C2IH16FN5O2S: 421.46
Figure imgf000140_0002
4- ( (8-fluoro-6- (2-methylthiazol-5-yl) - [1,2,4] triazolo [4, 3- a] pyridin-3 -yl) methoxy) -7 -methoxyquinoline
1) Preparation of 2-methyl-5- (trimethylstannyl) thiazole
Figure imgf000141_0001
Butyllithium (1.6M in THF, 3.5 ml, 5.5 mmol) was added to a stirred solution of 2 -methylthiazole (0.45 ml, 5.0 mmol) in THF (15 tnL) at -78°C. The reaction mixture was stirred at -78°C for 40min. Chlorotrimethylstannane (IM in THF, 5.0 ml, 5.0 mmol) was added. Stirring was continued at -78°C for 45min. The reaction mixture was quenched with a satured aqueous solution of NaHCO3. The aqueous layer was extracted with Et2O. The organic extracts were dried over MgSO4, filtered and concentrated in vacuo. Used in the next step without purification (obtained 1.29g). MS m/z = 264.1. Calc'd for C7H13NSSn: 261.94.
2) Preparation of 4- ( (8-fluoro-6- (2-methylthiazol-5-yl) - [1,2,4] triazolo [4 , 3-a] pyridin-3-yl) methoxy) -7- methoxycpiino1ine
Prepared by a method similar to 4- ( (8-fluoro-6- (3- methylisothiazol-5-yl) - [1, 2 , 4] triazolo [4 , 3 -a] pyridin-3 - yl) methoxy) -7-methoxyquinoline . MS m/z = 422.1 [M+H]+. Calc'd for C21H16FN5O2S: 421.46
Figure imgf000141_0002
Example 87 N,N-dimethyl-3-(4- ( (6-phenyl- [1.2,4] triazolo [4, 3-b]pyridazin-3- yl)methoxy)pyridin-3-yl)prop-2-yn-l-amine
1) Preparation of 3- ( (3 -iodopyridin-4-yloxy) methyl) -6-phenyl- [1,2,4] triazolo [4, 3-b] pyridazine
Figure imgf000142_0001
Cesium carbonate (354 mg, 1087 μmol) was added to a mixture of (6-phenyl- [1,2,4] triazolo [4, 3-b] pyridazin-3 -yl) methanol (123 mg, 544 μmol) (named 77289-19-99) and (6-phenyl- [1, 2,4] triazolo [4, 3-b] pyridazin-3-yl) methanol (123 mg, 544 μmol) in DMSO (1.8 mL) . The reaction mixture was stirred at 1200C for 2h under micro-waves irradiation. The reaction mixture was diluted with EtOAc. The organic layer was washed with water. The water layer extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by MPLC afforded the title compound (161 mg, 69% yield) .
2) Preparation of N,N-dimethyl-3- (4- ( (6-phenyl-
[1,2,4] triazolo [4, 3-b] pyridazin-3-yl) methoxy) pyridin-3 -yl) prop- 2 -yn-l~amine
Figure imgf000143_0001
Tetrakis (triphenylphosphine) palladium (0) (14.4 mg, 12.5 μmol) was added to a suspension of 3- ( {3-iodopyridin-4-yloxy) methyl) - 6-phenyl- [1, 2,4] triazolo [4 , 3-b] pyridazine (107 mg, 249 μmol) and l-dimethylamino-2-propyne (80.4 μl, 748 μmol) in THF (0.6 mL) and triethylamine (591 μl, 4238 μmol) at RT. Copper (i) iodide, 99.999% (4.75 mg, 24.9 μmol) was added and the reaction mixture was stirred at 75°C (oil bath) for -75min. The reaction mixture was cooled at RT, concentrated in vacuo. Purification by MPLC (ISCO, CH2Cl2/MeOH: 100/0 to 90/10) afforded the title compound. MS m/z = 385.1 [M+H]+. CaIc' d for C22H20N6O: 384.44
Figure imgf000143_0002
Example 88
DMF
Figure imgf000143_0003
Figure imgf000143_0004
Preparation of 3- ( (7-metho3cyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4, 3-a] pyridine- 6-carbonitrile .
4- ( (6-Bromo- [1,2,4] triazolo [4 , 3 -a] pyridin-3-yl)methoxy) -7- methoxyquinoline was prepared as previously described in general Method A. 4- ( (6-Bromo- [1,2,4] triazolo[4, 3-a] pyridin-3-yl)methoxy) -7- methoxyquinoline (0.050 g, 0.13 mmol) was dissolved in DMF (1 mL) then added zinc cyanide (0.023 g, 0.19 mmol), 1,1'- bis (diphenylphosphino) ferrocene (0.0072 g, 0.013 mmol) and tris (dibenzylideneacetone)dipalladium(O) (0.0059 g, 0.0065 mmol). The reaction mixture was heated at 100 0C for 8 hours. Additional zinc cyanide (0.012 g, 0.095 mmol), 1,1'- bis (diphenylphosphino) ferrocene (0.004 g, 0.0065 mmol) and tris (dibenzylideneacetone)dipalladium(O) (0.003 g, 0.0032 mmol) were added and heating was continued at 100 0C for 6 hours. The reaction mixture was concentrated under vacuum. The sample was purified by preparative TLC eluting with 10% 7N ammonia in methanol/ dichloromethane to afford 3- ( (7-τnethoxyquinolin-4- yloxy) methyl) - [1,2,4] triazolo [4 , 3 -a] pyridine-6-carbonitrile (23 mg, 53% yield) as a white solid. MS (ESI pos. ion) m/z: 332.1 (MH+) .
Figure imgf000144_0001
Figure imgf000144_0002
Preparation of 3- ( (7-πtethoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4, 3-a] pyridine-6-carboxamide .
3- ( (7-Methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4,3- a] pyridine-6-carbonitrile was prepared as previously described. 3- ( (7-Methoxyquinolin-4-yloxy)methyl) - .1,2,4] triazolo [4 , 3- a] pyridine-6-carbonitrile (0.050 g, 0.15 mraol) was dissolved in concentrated sulfuric acid (0.5 mL) . The reaction mixture was heated at 50 0C for 30 minutes. The reaction mixture was slowly poured in to cold saturated aqueous sodium bicarbonate. A precipitate formed which was collected on a glass frit, washing with water. The solid was transferred with dichloromethane/methanol to a flask and dried under high vacuum to afford 3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1, 2,4] triazolo [4, 3-a] pyridine-6-carboxamide (0.050 g, 95% yield) as a tan solid. MS (ESI pos. ion) m/z: 350.2 (MH+).
Figure imgf000145_0001
Example 90
Figure imgf000145_0002
Preparation of 3- ( (7 -methoxyquinolin-4-yloxy) methyl) - 11.2.4] triazolo [4, 3-a]pyridine-6-carboxylic acid.
3- ( (7-Methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4, 3- a] pyridine-6-carbonitrile was prepared as previously described.
3- ( (7-Methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4 , 3- a] pyridine-6 -carbonitrile (0.050 g, 0.15 mmol) was dissolved in concentrated sulfuric acid (0.375 mL) and water (0.125 mL) . The reaction mixture was heated at 100 0C for 3.5 hours then slowly- poured in to ice. The mixture was adjusted to approx. pH 7 with saturated aqueous sodium carbonate. A precipitate formed which was collected on a glass frit, washing with water. The solid was dried under high vacuum to afford 3- ( (7- methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4 , 3 -a] pyridine- 6-carboxylic acid (0.047 g, 89% yield) as a tan solid. MS (ESI pos. ion) m/z: 351.1 (MH+).
Figure imgf000146_0001
Preparation of N-cyclopropyl-3- ( (7-methoxyquinolin-4- yloxy)methy1) - [1,2,4] triazolo [4, 3-a] pyridine-6 -carboxamide.
3- ( (7-Methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4,3- a] pyridine- 6-carboxylic acid (0.047 g, 0.13 ramol) , cyclopropanamine (0.011 ml, 0.16 mmol) , l-hydroxy-7- azabenzotriazole (0.018 g, 0.13 mmol), and N-ethyl-N1 - (3- dimethylaminopropyl) carbodiimide hydrochloride, (0.039 g, 0.20 mmol) were added to a reaction flask then suspended in DMF (1 mL) . N-Ethyldiisopropylamine (0.070 ml, 0.40 mmol) was added to the reaction mixture. The clear reaction mixture was stirred at 20 0C overnight.. The reaction mixture was concentrated under vacuum then triturated with water. The solid was collected on a glass frit, washing with water. The sample was purified by preparative TLC eluting with 8% 7N ammonia in methanol/ dichloromethane to afford N-cyclopropyl-3- ( (7- methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4 , 3 -a] pyridine- 6-carboxamide (0.023 g, 44% yield) as a tan solid. MS (ESI pos. ion) m/z: 390.2 (MH+).
Figure imgf000147_0001
Example 91
Figure imgf000147_0002
Preparation of 7-methoxy-4- ( (6- (1, 2, 3, 6-tetrahydropyridin-4- yl) - [1,2,4] triazolo [4, 3-a] pyridin-3-yl)methθ3cy) quinoline.
tert-Butyl 4- (3- ( ( 7-methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-6-yl) -5, 6-dihydropyridine- 1 (2H) -carboxylate was prepared as described in general Method A.
tert-Butyl 4- (3- ( (7-methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4 , 3-a] pyridin-6-yl) -5, 6-dihydropyridine-l (2H) - carboxylate (0.113 g, 0.23 mmol) was dissolved in methanol (3 mL) then added concentrated hydrochloric acid (0.500 ml, 6.0 mmol) . The reaction mixture was stirred at room temperature overnight then concentrated under vacuum. The remaining solid was suspended in methanol (1 mL) then added triethylamine (0.40 ml, 2.9 mmol) . The clear solution was stirred at room temperature for 2 hours then concentrated under vacuum. The sample was purified by flash chromatography eluting with 8% 7N ammonia in methanol/ dichloromethane to afford 7-methoxy-4- ( (6- (1,2,3, 6-tetrahydropyridin-4-yl) - [1,2,4] triazolo [4 , 3-a]pyridin- 3-yl)methoxy) quinoline (0.038 g, 42% yield) as a tan solid. MS ( ESI pos . ion) tn/ z : 388 . 1 (MH+)
Figure imgf000148_0001
Preparation of (S) -3- ( (7-methoxyquinolin-4-yloxy)methyl) -N- (pyrrolidin-3-yl) - [1,2,4] triazolo [4, 3-a] pyridine-6-carboxamide.
(S) -tert-Butyl 3- (3- ( (7-methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4 , 3-a] pyridine-6-carboxamido) pyrrolidine-1- carboxylate was prepared as previously described for N- cyclopropyl-3- ( (7-methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4 , 3-a] pyridine-6-carboxamide.
(S) -tert-Butyl 3- (3- ( (7-methoxyquinolin-4-yloxy) methyl) -
[1,2,4] triazolo [4 , 3 -a] pyridine-β-carboxamido) pyrrolidine-1- carboxylate (0.050 g, 0.096 mmol) was dissolved in methanol
(1.5 mL) then added concentrated hydrochloric acid (0.400 ml, 4.8 mmol) . The reaction mixture was stirred at room temperature for 5 hours then concentrated under vacuum. The remaining solid was dissolved in methanol (1 mL) then added potassium carbonate
(0.062 g, 0.45 mmol) . The reaction mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The sample was purified by flash chromatography eluting with 10%- 15% 7N ammonia in methanol/ dichloromethane to afford (S) -3-
( (7-methoxyquinolin-4-yloxy) methyl) -N- (pyrrolidin-3-yl) - [1, 2, 4] triazolo[4, 3-a]pyridine-6-carboxamide (0.039 g, 97% yield) as a pale yellow solid. MS (ESI pos. ion) m/z: 419.2 (MH+).
Figure imgf000149_0001
Example 93
(R) -3- ( ( 7-Methoxyquinolin-4-yloxy) methyl) -N- (pyrrolidin-3- yl) - [1,2, 4] triazolo [4, 3-a] pyridine-6-carboxamide was prepared as previously described for (S) -3- ( (7-methoxyquinolin-4- yloxy) methyl) -N- (pyrrolidin-3-yl) - [1,2,4] triazolo [4,3- a] pyridine-6-carboxamide.
Figure imgf000149_0002
Example 94
N-Ethyl-3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1, 2, 4] triazolo [4 , 3-a] pyridine-6-carboxamide was prepared as previously described for N-cyclopropyl-3- ( (7-methoxyquinolin-4 yloxy) methyl) - [1,2,4] triazolo [4 , 3-a] pyridine-6-carboxamide.
Figure imgf000149_0003
Example 95
Figure imgf000150_0001
Preparation of tert-butyl 2- (3- ( (7-methoxyc[uinolin-4- yloxy) methyl) - [1, 2, 4] triazolo [4, 3-a] pyridine-6- carboxamido) ethyl (methyl) carbamate «
3- ( (7-Methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4,3- a] pyridine- 6 -carboxylic acid was prepared as previously described.
3- ( (7-Methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4,3- a] pyridine-6-carboxylic acid (0.072 g, 0.21 ramol) was dissolved in DMF (1.5 mL) then added N- (2-aminoethyl) -N-methyl carbamic acid tert-butyl ester (0.054 ml, 0.31 mmol) , 2-(7-aza-lH- benzotriazole-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (0.12 g, 0.31 mmol) and triethylamine
(0.043 ml, 0.31 mmol) . The reaction mixture was stirred at room temperature overnight then concentrated under vacuum. The sample was purified by flash chromatography eluting with 6% 7N ammonia in methanol/ dichloromethane to afford tert-butyl 2- (3-
{ (7 -methoxyquinolin-4-yloxy) methyl) - [1,2,4] triazolo [4 , 3- a] pyridine-6-carboxamido) ethyl (methyl) carbamate (0.097 g, 93% yield) as a pale yellow solid.
MS (ESI pos. ion) m/z: 507.3 (MH+).
Preparation of 3- ( (7-methoxyquinolin-4-yloxy)methyl) -N- (2- (methylamino) ethyl) - [1,2,4] triazolo [4, 3 -a] pyridine-6- carboxamide .
tert-Butyl 2- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4, 3-a] pyridine-6- carboxamido) ethyl (methyl) carbamate was deprotected as previously described for 7-methoxy-4- ( (6- (1, 2 , 3 , 6- tetrahydropyridin-4-yl) - [1, 2,4] triazolo [4 , 3-a] pyridin-3- yl) methoxy) quinoline .
Figure imgf000151_0001
Example 96
3- ( (7-Methoxyquinolin-4-yloxy) methyl) -N-phenyl- [1,2,4] triazolo [4, 3-a] pyridine- 6-carboxamide was prepared as described for 3- ( (7-methoxyquinolin-4-yloxy)methyl) -N- (2- (raethylamino) ethyl) - [1,2,4] triazolo [4, 3-a] pyridine-6- carboxamide .
Figure imgf000151_0002
Example 97
N- (4 -Fluorophenyl) -3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1, 2, 4] triazolo [4 , 3-a] pyridine-6-carboxamide was prepared as described for 3- ( (7-methoxyquinolin-4-yloxy)methyl) -N- (2- (methylamino) ethyl) - [1,2,4] triazolo [A13-a] pyridine-6- carboxamide .
Figure imgf000152_0001
Example 98
N- (3-Fluorophenyl) -3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1, 2, 4] triazolo [4 , 3-a]pyridine-6-carboxamide was prepared as described for 3- ( (7-methoχyquinolin-4-yloxy) methyl) -N- (2- (methylamino) ethyl) - [1,2,4] triazolo [4, 3 -a] pyridine-6- carboxamide .
Figure imgf000152_0002
(4-bromo-2-chlorophenyl) methanamine . To a solution of 4-bromo- 2-chlorobenzonitrile (2500 mg, 11549 μmol) in THF (2OmL) at 00C was added borane-methyl sulfide complex, 2.0 m sol in THF (28873 μl, 57747 μmol) . Ice bath removed and reaction stirred overnight warming to 230C. Reaction cooled to 00C and quenched with MeOH (15mL) . Reaction then partitioned between CHCl3 (10OmL) and IM NaOH (10OmL) . Organic dried with brine and MgSO4. Organic then concentrated to an oil under reduced pressure and purified on silica (8Og) eluting with 0>6% 2M NH3 in MeOH/DCM and product isolated as a colorless oil. MS (ESI pos. ion) m/z: 220/222 (MH+). Calc'd exact mass for C7H7BrClN: 219/221
Figure imgf000152_0003
tert-butyl 4 -bromo-2 -chlorobenzylcarbamate . To a stirring solution of (4 -bromo-2-chlorophenyl) methanamine (2200 mg, 9978 μmol) in DCM (1OmL) was added BOC-Anhydride (9978 μl, 9978 μmol) [IM in THF] and stirred for Ih at 230C after which ethylenediatnine (ImL) added . Solvents removed under reduce pressure and residue purified on 8Og silica eluting product with 0>50% Hex/EtOAc.
Figure imgf000153_0001
tert-butyl 2-chloro-4~ (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan- 2-yl) benzylcarbamate . A suspension of tert-butyl 4-bromo-2- chlorobenzylcarbamate (1670 mg, 5209 μmol) , bis (pinacolato) diboron (1455 mg, 5730 μmol), dichloro [1, 1 'bis (diphenylphoshino) ferrocene] palladium (ii)dichlo romethane adduct (190.6 mg, 260.4 μmol), and potassium acetate (1022 mg, 10418 μmol) in dioxane (8mL) was sparged with argon for 5min then heated to 1200C in an appropiately sealed vial with stirring. After Ih, reaction partitioned between DCM (5OmL) and 5% NaHCO3 (25mL) . Organic dried over MgSO4 , concentrated, then purified on 8Og silica eluting with 0>40% EtOAc/hexanes and product isolated as a viscous amber oil.
Figure imgf000153_0002
(4 -bromo-2 -chlorophenyl) methanol . To a stirring solution of 4- bromo-2-chlorobenzoic acid (11.1 g, 47 mmol) in THF (10OmL) at 00C under nitrogen was added borane-methyl sulfide complex (9.4 ml, 94 mmol) via syringe over lOmin. Gas evolution quite evident. Ice bath removed, and once gas evolution subsided reaction gently heated to reflux for Ih. Reaction slowly quenched with MeOH (5OmL) and 2M HCl (2OmL) . Aqueous extracted with 9:1 CHCl3/IPA (15OmL) . Organic dried with sat NH4Cl, MgSO4, then concentrated to a colorless oil under reduced pressure. Product crystalized after 1 week sitting neat.
Figure imgf000154_0001
(2-chloro-4 - (4,4,5, S-tetramethyl-1,3, 2 -dioxaborolan-2- yl)phenyl) . A suspension of (4-bromo-2-chlorophenyl) methanol
(1000 mg, 4515 μmol) , bis (pinacolato) diboron (1261 mg, 4967 μmol) , dichloro [1, 1 'bis (diphenylphoshino) ferrocene] palladium (ii) dichlo romethane adduct (165.2 mg, 225.8 μtnol) , and potassium acetate
(886.2 mg, 9030 μmol) in dioxane (5mL) was sparged with argon for lOmin then heated to 1200C with stirring in an appropiately sealed vial . After Ih, reaction then partioned between DCM
(5OmL) and 5% NaHCO3 (2OmL) . Organic dried over MgSO4, concentrated, then purified on 8Og silica eluting with 0>70% EtOAc/Hex. Product isolated as a light amber oil.
Figure imgf000154_0002
To a stirring solution of 4-bromo-2-chlorobenzoic acid (3.45 g, 15 mmol) and DIEA (7.7 ml, 44 mmol) in DMF (3OmL) was added HATU (6.1 g, 16 mmol) at 23°C under nitrogen. Darkened suspension stirred for Ih, then added n, o-dimethylhydroxylamine hydrochloride (2.1 g, 22 mmol). Solution stirred overnight at 23°C. Reaction then partitioned between 2.5% NaHCO3 (25OmL) and diethyl ether (10OmL) . Aqueous further extracted with ether (2x50mL) . Combined ethereal extracts dried over MgSO4, then concentrated an amber oil under reduced pressure. 4-bromo-2- chloro-N-methoxy-N-methylbenzamide isolated as a light amber oil.
Figure imgf000154_0003
1- (4-bromo-2-chlorophenyl) ethanone . To a stirring solution of 4-broτno-2-chloro-N-methoxy-N-methylbenzamide (890 mg, 3195 μmol) in THF (1OmL) at -5°C under nitrogen was slowly added methylmagnesium bromide 3.0m in diethyl ether (1278 μl, 3834 μmol). After 30min another 1.3mL (3.8mmol; 1.2eq) of MeMgBr added at 230C. After an additional hour, LCMS suggests 95% conversion. Reaction quenched with sat NH4Cl (1OmL) and resulting white cake washed repeatedly with diethyl ether. Combined organics washed with water and sat NaCl then pushed through a plug of silica (1Og) . 1- (4-bromo-2- chlorophenyl) ethanone isolated as a colorless oil.
Figure imgf000155_0001
1- (4 -bronto-2-chlorophenyl) ethanol . To a stirring solution of 1- (4 -bromo-2-chlorophenyl) ethanone (700 mg, 2998 μmol) in THF
(2OmL) was added sodium borohydride (340 mg, 8994 μmol) and methanol (5mL) . Reaction suspension stirred overnight at 300C. Reaction then partioned between EtOAc (5OmL) and sat NH4Cl
(25mL) . Aqueous further extracted with EtOAc (2x25mL) . Combined organics dried over MgSO4, concentrated, then purified on silica (4Og) eluting with 10>40% EtOAc/hexanes . Product isolated as a colorless oil.
Figure imgf000155_0002
1- (2-chloro-4- (4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) phenyl) ethanol . A suspension of 1- (4-bromo-2- chlorophenyl) ethanol (600 mg, 2548 μmol), bis (pinacolato)diboron (712 mg, 2802 μmol), dichloro [1,1 "bis (diphenylphoshino) ferrocene] palladium (ii) dichlo romethane adduct (93.2 mg, 127 μmol), potassium acetate (319 μl, 5095 μmol) in dioxane (5mL) was sparged with argon for 5min then heated to 1200C in an appropiately sealed vial. Reaction then partitioned between EtOAc (25mL) and 5% NaHCO3 (25mL) . Aqueous further washed with EtOAc (2x2OmL) . Combined organics dried with sat NH4Cl, MgSO4, concentrated, then purified on silica (8Og) eluting with 10>35% EtOAc/Hex. Product isolated as a colorless oil.
Figure imgf000156_0001
4 -bromo-2-chlorobenzaldehyde . To a stirring solution of (4- bromo-2-chlorophenyl) methanol (4.5 g, 20 mmol) in DCM (5OmL) was added Dess-Martin periodinane (9.3g) at 230C. Reaction refluxed after addition. After 20min, TLC (1:4 EtOAc/Hex) suggests full conversion of alcohol. Suspension then washed with 5% NaHCO3 (10OmL plus 15g dry NaHCO3) . Organic dried over MgSO4, concentrated onto dry silica (15g) , then purified on silica (12Og) eluting with 0>10% EtOAc/hex. 4 -bromo-2- chlorobenzaldehyde isolated as a white solid.
Figure imgf000156_0002
1- (4 -bromo-2-chlorophenyl) ethanamine. A solution of l-(4- bromo-2-chlorophenyl) ethanone (2.430 g, 10 mmol), ammonia, 2.0m solution in methanol (26 ml, 52 mmol) and titanium (iv) isopropoxide (6 ml, 21 mmol) was stirred for 16h in a sealed vessel. Reaction then added to a freshly made suspension of sodium borohydride powder, 98% (4 g, 104 mmol) in MeOH (2OmL) . Exothermic reaction started at 9:45am, then continued to stir with a 450C external heating bath for 45min. Water (1OmL ) then added to reaction and stirred for an additional lOmin. Resulting white solid removed via filtration through Celite, and filtrated reduced in volume under reduced pressure. This suspension then partioned between 9:1 CHC13/IPA (3OmL) and IM NaOH (1OmL). Aqueous further extracted with 9:1 CHC13/IPA (2xl0mL) . Combined organics dried over MgSO4, concentrated, then purified on silica (8Og) eluting with 0>5% 2M NH3 in MeOH/DCM. MS (ESI pos . ion) m/z: 234/236 (MH+). CaIc ' d exact mass for C8H9BrClN: 233/235. 1- (4 -bromo-2- chlorophenyl) ethanamine isolated as a colorless oil.
Figure imgf000157_0001
tert-butyl 1- (2-chloro-4- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2 -yl) phenyl) ethylcarbamate . To a stirring solution of 1- (4-bromo-2-chlorophenyl) ethanamine (950 mg, 4051 μmol) in DCM (5mL) was added BOC-anhydride (4861 μl, 4861 μmol) [IM in THF] . Reaction stirred for 18h at 230C. Ethanolamine (0.25mL) added and stirred for 5min. Reaction then partitioned between diethyl ether (5OmL) and 5% NaHCO3 (25mL) . Organic dried over MgSO4, concentrated, then purified on silica (8Og) eluting with 0>20% EtOAc/hexanes . BOC-I.1Og. A suspension of the Bromo-BOC intermediate, bis (pinacolato) diboron (1132 mg, 4456 μmol) , dichloro [1,1 'bis (diphenylphoshino) ferrocene] palladium (ii) dichlo romethane adduct (148 mg, 203 μmol) , and potassium acetate (795 mg, 8102 μmol) in dioxane (8mL) was sparged with argon for 5min then heated to 1200C in an appropiately sealed vessel for 2h. Reaction then partitioned between 9:1 CHC13/IPA (5OmL) and sat. NH4Cl (2OmL). Organic dried over MgSO4, concentrated, and product purified on silica (8Og) eluting with 1O>15% of EtOAc/Hex. tert-butyl 1- (2-chloro-4- (4 , 4 , 5, 5-tetramethyl- 1, 3 , 2-dioxaborolan-2-yl) phenyl) ethylcarbamate isolated as a white foam.
Figure imgf000158_0001
(R, Z) -N- (4-bromo-2-chlorobenzylidene) -2-methylpropane-2- sulfinamide. A suspension of 4-bromo-2-chloroben2aldehyde (1150 mg, 5240 μmol), (r) -(+) -2-methyl-2-propanesulfinamide (1588 mg, 13100 μmol), copper(ii) sulfate (696.4 μl, 15720 μmol) in DCM (1OmL) was stirred at 37°C for 78h. Reaction filtered through Celite, and solid washed repeatedly with DCM. Filtrate concentrated then purified on silica (8Og) eluting product with 0>30% of EtOAc/Hex. MS (ESI pos . ion) m/z: 322/324 (MH+). Calc'd exact mass for CnH13BrClNOS: 321/323.
Figure imgf000158_0002
(R) -N- ( (S) -1- (4-bromo-2-chlorophenyl) -2, 2, 2-trifluoroethyl) -2- methylpropane-2-gulfinamide . To a stirring solution of (R, Z)- N- (4-bromo-2-chlorobenzylidene) -2-methylpropane-2-sulfinamide
(1370 mg, 4246 μmol) and ( trifluoromethyl) trimethylsilane (943 μl, 6369 μmol) in DMF (5mL) was added l,3-bis(l- adamantyl) imidazol-2-ylidene (143 mg, 425 μmol). Reaction stirred at 35°C for 18h then quenched with sat NH4Cl (1OmL) . Reaction partitioned between EtOAc (4OmL) and 5% NaHCO3 (1OmL) . Organic dried over MgSO4 , concentrated to and oil from toluene, then purified on silica (8Og) eluting with 20>30% EtOAc/Hex. Product isolated as a white solid.
Figure imgf000159_0001
(R) -N- < (S) -1- (2-chloro-4- (4, 4, 5, 5-tetramethyl-l, 3 , 2- dioxaborolan-2-yl) phenyl) -2,2, 2-trifluoroethyl) -2- methylpropane-2-sulfinamide . A suspension of (R) -N- ( (S) -1- (4- bromo-2-chlorophenyl) -2, 2, 2-trifluoroethyl) -2-methylρropane-2- sulfinamide (950 mg, 2419 μmol) , bis (pinacolato) diboron (676 mg, 2661 μmol) , dichloro [1, I1 bis (diphenylphoshino) ferrocene] palladium (ii) dichlo rotnethane adduct (88.5 mg, 121 μmol), and potassium acetate
(475 mg, 4839 μmol) in dioxane (6mL) was sparged with argon for 5min. Reaction then appropiately sealed and heated to 1200C with stirring for Ih. Reaction then partitioned between EtOAc
(25mL) and 5% NaHCO3 (1OmL) . Organic dried over MgSO4, concentrated, then purified on silica (12Og) eluting product with 10>20% of EtOAc/hexanes . Product isolated as a waxy white solid. MS (ESI pos. ion) m/z: 440 (MH+). CaICd exact mass for C18H26BClF3NO3S: 439.
Figure imgf000159_0002
Example 99
(2-chloro-4- (3- (qulnolin-6-ylmethyl) - [1, 2, 4] triazolo [4, 3- bl pyridazin-6-yl) phenyl)methanol. A suspension of 6- ( (6- chloro- [1,2,4] triazolo [4 , 3-b] pyridazin-3-yl) methyl) quinoline (170 mg, 575 μmol) , (2-chloro-4- (4 , 4 , 5 , 5-tetramethyl-l, 3 , 2- dioxaborolan-2-yl) phenyl) methanol (309 mg, 1150 μmol) , dichloro [1, 1 ■ bis (diphenylphoshino) ferrocene] palladium (ii) dichlo romethane adduct (126 mg, 172 μmol) , cesium carbonate (749 mg, 2299 μtnol) in Dioxane (0.3mL) and water (0.3mL) was sparged with argon for 5min then heated to 1000C with stirring. 1:30am. After 90min, LCMS suggests 95% conversion. Reaction then partitioned between 9:1 CHC13/IPA (25mL) and 5% NaHCO3 (15mL) . Aqueous further extracted with 9:1 CHC13/IPA (2xl0mL) . Combined organics dried with MgSO4, concentrated onto dry silica (1Og) , and then purified on silica (12g) eluting with 0>10% 2M NH3 in MeOH/DCM. Resulting solid triturated with methanol (2mL) and collected by filtration. MS (ESI pos. ion) m/z: 402 (MH+) . CaIc 'd exact mass for C22H16ClN5O: 401.
Figure imgf000160_0001
Example 100
(2-chloro-4- (3- ( (7 -methoxyqυinolin-4-ylθ3cy) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6-yl) phenyl) methanol . A suspension of 4- ( (6-chloro- [1, 2, 4] triazolo [4, 3-b] pyridazin-3- yl) methoxy) -7-methoxyquinoline (200 mg, 585 μmol), (3-chloro-4- (4,4,5, 5-tetramethyl-l, 3 , 2-dioxaborolan-2-yl) phenyl) methanol (173 mg, 644 μmol) , dichloro [1, 1 ' bis (diphenylphoshino) ferrocene] palladium (ii) dichlo romethane adduct (21 mg, 29 μmol), and sodium carbonate (2M; 1170 μl, 2341 μmol) in DME (2mL) was sparged with argon for lOmin then heated to 850C for 6h. Reaction then partitioned between 9:1 CHCI3/IPA (25mL) and 5% NaHCO3 (1OmL) and aqueous further extracted with 9:1 CHC13/IPA (2xl0mL) . Combined organics dried with MgSO4 then concentrated onto dry silica under reduced pressure. Product purified on 4Og silica eluting with 0>12% of 2M NH3 in MeOH/DCM and isolated as an off white powder. MS (ESI pos . ion) tn/z: 448 (MH+). CaIc 'd exact mass for C23Hi8ClN5O3: 447.
Figure imgf000161_0001
Example 101
1- (2-cliloro-4- (3- ( (7-methoxy-l, 5-naphthyridin-4- ylamino) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6- yl)phenyl) ethanol . A suspension of 1- (2-chloro-4- (4, 4, 5, 5- tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethanol (228 mg, 807 μmol) , N- ( (6-chloro- [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) methyl) -7-methoxy-l, 5-naphthyridin-4-amine (197 mg, 576 μmol) , dichloro [1, 1 'bis (diphenylphoshino) ferrocene] palladium (ii) dichlo romethane adduct (127 mg, 173 μmol) , cesium carbonate (751 mg,
2306 μmol) in dioxane (3mL) and water (0.6mL) was sparged with argon for 5min then heated to 1000C for 6h. Reaction cooled then partitioned between 9:1 CHC13/IPA (2OmL) and IM NaOH
(15mL) . Aqueous further extracted with 9:1 CHC13/IPA (2x1OmL) . The combined organics dried over MgSO4. concentrated, then purified on 4Og silica eluting with an isocratic 7% 2M NH3 in MeOH/DCM. Product further purified prep HPLC eluting with water/ACN (0.1% TFA). After collected fractions were reduced to a clear the residue was dissolved in 1:1 ACN/water and pH adjusted to 9 with IM NaOH (3-4 drops) . Resulting solid collected by filteration and solid washed with water (2mL) . MS
(ESI pos. ion) m/z: 462 (MH+). CaIc ' d exact mass for C23H20ClN7O2: 461.
Figure imgf000162_0001
Example 102
tert-butyl (2-chloro-4- (3- ( (7-methoxyquinolin-4-yloxy) methyl) - [1, 2,4] triazolo [4, 3-b] pyridazin-6-yl) phenyl)methylcarbamate . A suspension of 4- ( (6-chloro- [1, 2, 4] triazolo [4, 3-b] pyridazin-3- yl)methoxy) -7-methoxyquinoline (200 mg, 585 μmol) , tert-butyl 2-chloro-4- (4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yDbenzylcarbamate (323 mg, 878 μmol) , dichloro.l, l'bis (diphenylphoshino) ferrocene] palladium (ii) dichlo roraethane adduct (86 mg, 117 μmol) , cesium carbonate (763 mg, 2341 μmol) in dioxane (3mL) and water (0.3mL) was sparged with argon for 10 min then heated to 1000C for 18h. Reaction then partitioned between 9:1 CHC13/IPA (5OmL) and 5% NaHCO3 (25mL) . Aqueous further extracted with 9:1 CHC13/IPA (2xl0mL) . Combined organics then dried over MgSO4, concentrated, and purified on silica (4Og) eluting with 0>6% 2M NH3 in MeOH/DCM. Product isolated as an off white solid. 84024-19-2 MS (ESI pos . ion) m/z: 547 (MH+). CaIc ' d exact mass for C28H27CIN6O4 : 546.
Figure imgf000162_0002
Example 103
2-chloro-4- (3- ( (7 -methoxyquinolin-4-yloxy)methyl) -
[1,2,4] triazolo [4 , 3-b] pyridazin-6-yl) phenyl) methanamine . A solution of tert-butyl (2-chloro-4- (3- ( (7-methoxyquinolin-4- yloxy) methyl) -[1,2,4] triazolo [4 , 3-b] pyridazin-6- yl) phenyl) methylcarbamate (85 mg, 155 μmol) in DCM (2mL) and TFA (2mL) stirred for 30min at 23°C. Solvents removed under reduced pressure, then residue partitioned between 9:1 DCM/IPA (1OmL) and IM NaOH (5mli) . Aqueous further extracted with DCM (2x5mL) . Combined organics dried over MgSO4, then reduced to an off white solid under reduced pressure. MS (ESI pos. ion) m/z: 447 (MH+) . CaIc 'd exact mass for C23Hi9ClNeO2: 446.
Figure imgf000163_0001
Example 104
(S) -1- (2-chloro-4- (3- ( (7-methoxyquinolin-4-yloxy)methyl) - [1,2,4] triazolo [4,3 -b] pyridazin-6-yl) phenyl) -2 , 2 , 2- trifluoroethanamine .
A solution of (R) -N- ( (S) -1- (2-chloro-4- (3- ( (7-methoxyquinolin- 4-yloxy) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6-yl) phenyl) - 2, 2, 2-trifluoroethyl) -2-methylpropane-2-sulfinamide (135 mg, 218 μmol) in MeOH (2mL) and 4M HCl (2mL) was stirred for 30min at 350C. LCMS suggests full conversion. Solvents removed under reduced pressure with azeotroping from toluene. Residue dissolved in MeOH (1OmL) and Si-Carbonate (2g; 1.4mmol) added. Suspension stirred for 30min, then filtrated collected by filtration. Solvents removed under reduced pressure and residue purified on silica (I2g) eluting product with 0>5% MeOH/DCM. MS (ESI pos. ion) m/z: 515 (MH+). Calc ' d exact mass for C24H18ClF3N6O2: 514.
Figure imgf000164_0001
Example 105
(R) -1- (2-chloro-4- (3- ( (7-methoxyquiiiolin-4-yloxy)methyl) - [l,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl) -2,2,2- trifluoroethanamine.
A solution of (S) -N- ( (R) -1- (2-chloro-4- (3- ( (7-methoxyquinolin- 4 -yloxy) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin-6-yl) phenyl) - 2, 2, 2-trifluoroethyl) -2-methylpropane-2-sulfinamide (62 mg, 100 μmol) in MeOH (2mL) and 5M HCl (2mL) was stirred at 35°C for 18h. LCMS suggests full conversion. Solvents removed under reduced pressure and residue dissolved in MeOH (2OmL) . Si- Carbonate (1.3g,- 0.9mτnol) added to solution and stirred for 2h. Filtrated isolated by filtration and reduced to a film under reduced pressure. Product purified on silica (4g) eluting with 7% 2M NH3 in MeOH/DCM. MS (ESI pos . ion) m/z: 515 (MH+). Calc'd exact mass for
Figure imgf000164_0002
Example 106
tert-butyl 1- (2-chloro-4- (3- ( (7-methoxyquinolin-4- yloxy)methyl) - [1, 2, 4] triazolo [4, 3-b]pyridazin-6- yl) phenyl) ethylcarbamate . A suspension of 4- ( (6-chloro- [1,2,4] triazolo [4, 3-b] pyridazin-3-yl) methoxy) -7- methoxyquinoline (180 mg, 527 μmol) , tert-butyl 1- (2-chloro-4- (4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) phenyl) ethylcarbamate (302 mg, 790 μmol), dichloro [1, 1 'bis (diphenylphoshino) ferrocene] palladium (ii) dichlo romethane adduct (77.1 mg, 105 μmol), cesium carbonate (686 mg, 2107 μmol) in DMF (2mL) and water (0.4mL) was first sparged with argon for 5min then heated to 1000C with stirring. 2:20pm After lOmin, LCMS suggests >95% conversion. Reaction then partitioned between 9:1 CHC13/IPA (2OmL) and IM NaOH (5mL) . Organic then dried over MgSO4 , concentrated, and purified on silica (4Og) eluting with isocratic 4% of 2M NH3 in MeOH/DCM. MS (ESI pos. ion) m/z: 561 (MH+). Calc'd exact mass for C29H29ClN6O4: 560.
Figure imgf000165_0001
Example 107
1- (2-chloro-4- (3- ( (7 -methoxyquinolin-4-ylO3cy) methyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-6-yl) phenyl) ethanamine . A solution of tert-butyl 1- (2-chloro-4- (3- { (7-methoxyquinolin-4- yloxy) methyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-6- yl) phenyl) ethylcarbamate (100 mg, 178 μmol) in DCM (2mL) and TFA (2mL) was stirred for 30min at 23°C. Solvents removed under reduced pressure (not- toluene azeotroping is suggested!) and residue dissolved in CHCl3/IPA (1OmL) . Solution stirred as a suspension with Si-Carbonate (1.3g,- lmmol) for 30min. Suspension filtered and filtrate reduced to an amber film (150mg) . Product purified on silica (12g) eluting with 4-7% of 2M NH3 in MeOH/DCM. MS (ESI pos. ion) m/z: 461 (MH+) . Calc'd exact mass for C24H2IClN6O2 : 460.
Figure imgf000166_0001
Example 108
N- ((6- (4- (aminomethyl) -3-chlorophenyl) - [1, 2, 4] triazolo [4, 3- b] pyridazin-3-yl) methyl) -7 -methoxy-1,5-naphthyridin-4 -amine . To a sitrring solution of tert-butyl (2-chloro-4- (3- ( (7- methoxy-1, 5-naphthyridin-4-ylamino) methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) phenyl) methylcarbamate (70 mg, 128 μmol) in DCM (2mL) was added TFA (2mL) . Reaction solution stirred for 30min at 230C. Solvents then removed under reduced pressure and residue purified on prep-HPLC using a water/ACN (0.1% TFA) gradient. Resulting solid was dissolved in 1:1 ACN/water (ImL) and pH adjusted to 10 with IM NaOH (approx 10 drops) . Resulting solid collected by filtraton and washed with water (5mL) . MS (ESI pos . ion) m/z: 447 (MH+). CaIc ' d exact mass for C22H19ClN8O: 446.
Figure imgf000166_0002
methyl 2- Q-methoxyquinolin-β-yl) -2-meth.ylpropanoate. To a stirring solution of methyl 2- (3-methoxyquinolin-6-yl) acetate (450 mg, 1946 μmol) in THF (5mL) at -700C under nitrogen was added lithium bis (trimethylsilyl) amide, 1.0m solution in tetrahydrofuran (5838 μl, 5838 μmol) . Dark red solution stirred for lOmin, then added iodomethane (364 μl, 5838 μmol) in THF (ImL) . Reaction removed from cooling bath, and monitored by LCMS after 45min. LCMS suggests very clean conversion. Reaction quenched with sat NH4Cl (5mL) and NaHCO3 (5mL) . Aqueous extracted with EtOAc (3x4OmL) . Combined organics dried over MgSO4, concentrated, then purified on silica (4Og) eluting with 10>30% of EtOAc/Hex. MS (ESI pos, ion) m/z: 260 (MH+). Calc'd exact mass for C15Hi7NO3: 259.
Figure imgf000167_0001
2- (3-methoxyquinolin-6-yl) -2-methylpropanoic acid . A solution of methyl 2- (3-methoxyquinolin-6-yl) -2-methylpropanoate (400 mg, 1543 μmol) , LiOH (1928 μl, 7713 μmol) [4M], MeOH (2mL) , and THF (2mL) was stirred at 500C overnight. LCMS suggests full conversion. Solution cooled, acidified to pH 1 with 5M HCl, and precipitate collected by filtration. White cake washed with water (2mL) and EtOH (ImL) . Product air dried for 3h and isolated as a white solid. MS (ESI pos. ion) m/z: 246 (MH+). Calc'd exact mass for Ci4Hi5NO3: 245.
Figure imgf000167_0002
2- (3-methoxyquinolin-6-yl) -2-methyl -N' - (6-phenylpyridazin-3- yl)propanehydrazide. A suspension of 2- (3-methoxyquinolin-6- yl) -2-methylpropanoic acid (92 mg, 375 μmol), DIEA (66 μl, 375 μmol), and o- (7-azabenzotriazol-l-yl) -n, n,n' ,n-tetramethyl uronium hexafluorophosphate (143 mg, 375 μmol) in DMF was stirred for 2h at 230C. To the solution was added 1- (6- phenylpyridazin-3-yl) hydrazine (70 mg, 375 μmol) and stirred for 72h at 23°C. Reaction partitioned between 9:1 CHC13/IPA (25mL) and IM NaOH (5mL) . Organic dried over MgSO4 the concentrated to a solid from toluene under reduced pressure. Solid triturated with ACN (2mL) and collected by filtration. 2- (3-methoxyquinolin-6-yl) -2-methyl-N1 - (6-phenylpyridazin-3- yD propanehydrazide isolated as a white solid . MS (ESI pos ion) m/z : 414 (MH+ ) . CaIc ' d exact mass for C24H2SN5O2 : 413 .
Figure imgf000168_0001
Example 109
3-methoxy-6- (2- (6-phenyl- [1, 2,4] triazolo [4, 3-b] pyridazin-3- yl> propan-2-yl) quinoline .
A solution of 2- (3-methoxyquinolin-6-yl) -2-methyl-N' - (6- phenylpyridazin-3 -yDpropanehydrazide (270 mg, 653 μraol) in TFA
(2mL) was heated to 1500C in microwave (6bar; 20W) for 2h. IJCMS suggests very good conversion: 89425-17-1. Reaction concentrated under reduced pressure then partitioned between CHCI3/IPA (5OmL) and IM NaOH (5OmL) . Aqueous further extracted with CHCI3/IPA (15mL) and combined organics dried over MgSO4, concentrated, then dissolved in ACN (2mL) . Crystalized solid washed with ACN (ImL) and dried under reduced pressure. MS
(ESI pos. ion) m/z: 396 (MH+). Calc'd exact mass for C24H2IN5O: 395.
Figure imgf000168_0002
Example 110
6- (1- (6-chloro- [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) ethyl) quinoline . A solution of N1 - (6-chloropyridazin-3-yl) - 2- (quinolin-6-yDpropanehydrazide (4300 mg, 13119 μmol) in TFA (4OmL) was heated to 1200C with microwaves for 40min. LCMS suggests very good converson. Solvents removed under reduced pressure and residue partitioned between 9:1 CHC13/IPA (75mL) and IM NaOH (10OmL). Aqueous further extracted with 9:1 CHCI3/IPA (2x25mL) . Combined organics dried over MgSO4 , concentrated, and oily residue dissolved in ACN/MeOH (2mL) . Resulting solid after 2h was isolated by filtration and washed with ACN (5mL) . 6- (1- (6-chloro- [1, 2, 4] triazolo [4, 3- b]pyridazin-3-yl)ethyl)quinoline isolated as a white solid. MS (ESI pos. ion) m/z: 310 (MH+) . CaIc 'd exact mass for Ci6H12ClN5: 309.
Figure imgf000169_0001
Example 111
6- (1- (6- (l-methyl-lH-pyrazol-4-yl) - [1, 2, 4] triazolo [4, 3- b]pyridazin-3-yl) ethyl) quinoline. A suspension of 6- (1- (6- chloro- [1,2,4] triazolo [4, 3 -b] pyridazin-3 -yl) ethyl) quinoline
(106 mg, 342 μmol) , l-methyl-4- (4 , 4 , 5, 5-tetramethyl-l, 3 , 2- dioxaborolan-2-yl) -lH-pyrazole (142 mg, 684 μmol) , dichloro [1,1 'bis (diphenylphoshino) ferrocene] palladium (ii) dichlo romethane adduct (25 mg, 34 μmol) , and cesium carbonate (446 mg, 1369 μmol) in DMF (ImL) and water (0.5mL) was sparged for 5min with argon then heated to 1000C in an appropiately sealed vial for 30min. Reaction then partitioned between 9:1 CHCI3/IPA
(2OmL) and IM NaOH (5mL) . Aqueous futher extracted with 9:1 CHCI3/IPA (5mL) and combined organics dried over MgSO4 , concentrated to a solid from toluene, then purified on silica
(12g) eluting with 30>50% of 10% 2M NH3 in MeOH/DCM. 6- (1- (6-
(l-methyl-lH-pyrazol-4-yl) - [1,2,4] triazolo [4, 3 -b] pyridazin-3- yl) ethyl) quinoline isolated as off white crystals from ACN ( ImL) . MS (ESI pos . ion) m/ z : 356 (MH+) . Calc ' d exact mass for C20H17N7 : 355 .
Figure imgf000170_0001
Example 112
3- (6- (3, 5-difluorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3- yl) methoxy) quinoline . To a mixture of quinolin-3-ol (0.058 g, 0.40 mmol) , (6- (3 , 5-difluorophenyl) - [1, 2 , 4] triazolo [4 , 3- b] pyridazin-3 -yl) methanol (0.104 g, 0.4 mmol), and triphenylphosphine (0.11 g, 0.44 mmol) in dry tetrahydrofuran (2 ml) and dry dichloromethane (2 ml) under argon, was added dropwise with stirring, diethyl azodicarboxylate (0.069 ml, 0.44 mmol) . The resulting mixture was stirred at room temperature for 18 hours . The solvent was then stripped at reduced pressure, and the residue subjected to chromatography on Silica gel, eluent 5% methanol in dichloromethane to afford the title compound, which was recrystallised from hot toluene to give a colourless solid. M/e 390 (MH+)
Figure imgf000170_0002
Example 113
N- ( (6- (4- (1-aminoethyl) -3 -chlorophenyl) - [1,2,4] triazolo [4, 3- b] pyridazin-3-yl)methyl) -7-methoxy) -1,5-naphthyridin-4 -amine. A suspension of N- ( (6-chloro- [1, 2 , 4] triazolo [4 , 3-b] pyridazin-3- yUmethyl) -7-methoxy-l, 5-naphthyridin-4-amine (300 mg, 878 μtnol) , tert-butyl 1- (2-chloro-4- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) phenyl) ethylcarbamate (419 mg, 1097 μmol) , dichloro [1, 1 'bis (diphenylphoshino) ferrocene] palladium (ii) dichlo romethane adduct (193 mg, 263 μmol) , cesium carbonate (1144 mg, 3511 μmol) in dioxane (6mL) and water (ImL) was sparged with argon for lOmin then heated to 1000C for 2Oh with stirring. Reaction then partitioned between 9:1 CHC13/IPA (5OmL) and IM NaOH (25mL) . Aqueous further extracted with 9:1 CHC13/IPA
(2OmL) . Combined organics then dried over MgSO4, concentrated, and purified on 4Og silica eluting with 7>8% of 2M NH3 in MeOH/DCM. Product then further purified on prep HPLC eluting with water/ACN (0.1% TFA) . BOC intermediate then stirred as a solution in DCM (ImL) and TFA (3mL) for 30min. Solvents removed under reduced pressure and residue dissolved in MeOH
(8mL) and DCM (8mL) . Solution then stirred with Si-Carbonate from Silicycle (Ig/ with a labeled loading of 0.77mmol/g) for Ih at 230C. Suspension filtered and filtrate reduced to a film under reduced pressure. Product was lyophilized from 1:1 ACN/water (1.5mL) to provide N- ( (6- (4- (1-aminoethyl) -3- chlorophenyl ) - [1,2,4] triazolo [4 , 3-b] pyridazin-3 -yl) methyl) -7- methoxy) -1, 5-naphthyridin-4-amine as an off white fluffy solid. MS (ESI pos . ion) m/z: 461 (MH+) . CaIc ' d exact mass for C23H21ClN8O: 460.
Figure imgf000171_0001
Example 114
6- ( (6-phenyl- [1.2, 4] triazolo [4, 3-b]pyridazin-3 yl)methyl) isoquinoline. Step 1. tert-Butyl 2- (iaoquinolin-6-yl) acetate. A dry, 25 mL, 1 neck round bottom flask was charged with a 0.5 M Et2O solution of Zincate 2 (10.00 ml, 5.0 mmol, Reike Metals), and concentrated in vacuo. The vacuum was released with nitrogen, and the flask was charged with a stirbar, 5 mL dry THF, fitted with a reflux condenser and an Ar inlet. Upon dissolution of the solids, 6-bromoisoquinoline (0.516 g, 2.5 mmol) and tetrakis (triphenylphosphine) palladium (0.24 g, 0.21 mmol) was added. The solution was heated with an 80 0C oil bath for 5 h, and cooled. The solution was treated with 30 mL of 10% aqueous EDTA (pH adjusted to 6.1 with NaOH), and stirred for I h. A precipitate had formed that was removed by filtration of the biphasic solution through a sintered glass funnel and discarded. The filtrate was concentrated to ~35 mL, and extracted with DCM (4 x 30 mL) . The combined extracts were washed with water (1 x 30 mL) , and the water was was back- extracted with DCM (1 x 10 mL) . The DCM layers were dried over MgSO4, and the resultant slurry filtered through a sintered glass funnel. The filtrate was concentrated in vacuo. The residue was dissolved in 10 mL DCM and treated with Si- carbonate (Silicycle, 5.5 g, 3.7 mmol). The slurry was swirled occasionally for 1 h, and filtered through a 0.22 uM PTPE membrane. The silica was washed with DCM (4 x 20 mL) , and the combined filtrates were concentrated in vacuo. The residue was purified in three injections using a Waters Spherisorb S5 column (PN PSS830195, 20 X 250 mm, 60 A pore, 5 μm particle size) ; flow = 20 mL/min; A = DCE, B = EtOH; isocratic at 5% B. A band that eluted from 3.9 to 5.9 minutes was isolated. The solvent was removed in vacuo to afford tert-butyl 2-
(isoquinolin-6-yl) acetate .
Step 2. 6- ( (6-phenyl- [1,2,4] triazolo [4, 3-bl pyridazin-3- yl) methyl) isoquinoline hydrochloride. A 10 mL, CEM microwave vessel was charged with 3 (0.1040 g, 0.427 mmol), 1- (5- phenylpyridin-2-yl) hydrazine (4, 0.119 g, 0.641 mmol), a stirbar and 1 mL concentrated HCl. The vessel was sealed, and fitted with an 18-guage needle and an Argon inlet. The slurry- was placed in a heating block at 115 0C for 15 minutes with stirring. A volatile substance evolved during this time. The vessel was briefly cooled, and the seal was replaced. The vessel was irradiated on a CEM Explorer using the following parameters: ramp time 20 s, hold time 10 min, hold temperature 150 0C, powermax = on, 75 W max. The resultant turbid aqueous solution was filtered and concentrated in vacuo. The solids were suspended in 3 mL hot EtOH, and cooled. The precipitate was isolated by filtration and washed with EtOH (3 x 3 mL) . The solids were taken up in 2 ττ»L H2O, and filtered through a 0.1 μm PVDF Ultra-free-CL centrifugal filter (Millipore Corp, PN UFC40W00, 200Og for 5 minutes) . The aqueous filtrate was lyophilized to afford 6- ( (6-phenyl- [1, 2, 4] triazolo [4 , 3- b] pyridazin-3 -yl) methyl) isoquinoline hydrochloride. Anal. Calcd for C2IH15N5 .HCl.1.7 H2O: C, 62.36; H, 4.83; N, 17.31. Found: C, 62.39 ±0.08; H, 4.48 ±0.02; N, 17.28 ± 0.03.
Figure imgf000173_0001
Example 115
8- ( (6- (3, 4 , 5-trlfluorophenyl) - [1, 2, 43 triazolo [4 , 3-b] pyridazin- 3 -yDmethylamino) -1, 5-naphfchyridin-3-ol . A sealed tube was charged with 7 -methoxy-N- ( (6- (3 , 4 , 5-trifluorophenyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-3-yl) methyl) -1 , 5-naphthyridin- 4-amine hydrochloride (238 mg, 502 μmol) and HBr (5966 μl, 52740 μmol) , sealed, then placed in a 1200C oil bath for 48 h. Cooled to room temperature and brought to pH~14 with NaOH (6N) Isolated solid by filtration which was purified by RPHPLC to afford 8- ( (6- (3,4, 5-trifluorophenyl) - [1,2,4] triazolo [4 , 3- b] pyridazin-3 -yDmethylamino) -1, 5-naphthyridin-3 -ol as its formate salt . MS (ESI pos . ion) m/z : 424 (MH+) . CaIc ' d exact mass for C20H12F3N7O : 423 .
Figure imgf000174_0001
3 -hydroxy-6-iodoquinoline-4 -carboxylic acid. 5-iodoindoline- 2,3-dione (50 g, 183 mmol) was dissolved in a hot solution containing potassium hydroxide (82 g, 1465 mmol) and water (250 mL) . The reaction mixture was in homogeneous solution for 5 min then was precipitated out completely. Enough ethanol (30 ml) was added to redissolve the reaction mixture. After cooled to rt and mechanically stirred, 3-bromo-2-oxopropanoic acid hydrate (47 g, 256 mmol) was added portionwise - tremendous heat was generated (> 80 0C) . After the addition, the reaction mixture was cooled to rt and continued to stir for 3 days. The reaction mixture was treated with sat. solution of NaHSO3 (sodium bisulfite, 12 g, 115.32 mmol) in order to prevent the development of color in the product. The resulting mixture was then acidified to pH=2 using concentrated HCl. After stirred for Ih, the yellow ppt . that was formed in the solution mixture was collected by filtration. The solid was washed with water and suspended in water with SO2 bubbling in the solution. After 30 minutes the solid again was separated by filtration. This wet solid was suspended in water, stirred, and dissolved by gradual addition of solid Na2CO3. The solution was treated with a saturated solution of NaHSO3 and filtered. The filtrate was acidified to pH=2 using concentrated HCl. The solid that was formed in the solution mixture was collected by filtration. The solid was washed with water, then resuspended in water, and again filtered. The solid was suspended in EtOH, separated by filtration, and airdried to afford the desired product as a brown solid. MS m/zι 316.2 (M+H) . Calc'd. for Ci0H6INO3 - 315.06.
Figure imgf000175_0001
β-iodoquinolin-3-ol . 3-hydroxy-6-iodoquinoline-4-carboxylic acid (22 g, 70 mmol) was suspended in 1-nitrobenzene (143 ml, 1397 mmol) followed by adding Hunig's base (25 mL) - the suspension was completely dissolved. The resulting mixture was heated to reflux (210 0C) under N2. After 3 h, LC/MS showed no sign of starting material mass . The reaction mixture was cooled to rt; solvent was removed as much as possible in vacuo. The crude product was redissolved in DCM/MeOH and the solid was collected by filtration. The solid was rinsed with hexane and either and dried as brownish solid. The filtrate was removed excess solvent and purified using SiO2 chromatography (Teledyne Isco RediSep*, P/N 68-2203-058, 330 g SiO2, solvent system: hexanes :acetone=80%: 20%, Flow = 100 mL/min) to afford the desired product as brown solid. MS m/z: 272.3 (M+H) . Calc'd. for C9H6INO - 271.05.
Figure imgf000175_0002
tert-butyl 2- (3-hydroxyquinolin-6-yl) acetate. A stirred solution of 6-iodoquinolin-3 -ol (1.76 g, 6 mmol) in THF (10 mL) was treated with 2-tert-butoxy-2-oxoethylzinc chloride
(39 ml, 19 mmol) followed by tetrakis (triphenylphosphine) palladium (0) (0.8 g, 0.6 mmol). After the addition, it was heated to reflux ( 75 0C) under N2. After 3 h, TLC 89368-3-1 showed no sign of starting material. Reaction was stop. The reaction was cooled to rt. Solvent was removed. The residue was stirred in EtOAc/10% EDTA (50 mL/50 mL) solution mixture. After 1 h, the organic layer was separated. The aqueous layer was extracted with more EtOAc (2 x 25 mL) . The combined organic layers were washed with water, brine, dried over MgSO4, and removed solvent. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep , P/N 68-2203-026, 12 g SiO2, hex: acetone=80% : 20%, Flow = 30 mli/min) . to afford the desired product as brownish liquid. MS m/z- 260.3 (M+H) . Calc'd. for C15H17NO3 - 259.2.
Figure imgf000176_0001
tert-butyl 2- (3-methoxyquinolin-6-yl) acetate. To a suspension of tert-butyl 2- (3-hydroxyquinolin-6-yl) acetate (0.1 g, 0.4 mmol) in benzene (5 mL) was added methanol (0.05 ml, 1 mmol) and tributylphosphine (0.1 ml, 0.6 mmol). The resulting mixture was cooled to 0 0C followed by adding l.l1- (azodicarbonyl)dipiperidine (0.1 g, 0.6 mmol) . After 10 min, ice bath was removed; the reaction mixture was warmed up to rt. The reaction mixture was contiuned to stir for 20 h. TLC showed about 80% conversion. More MeOH (1 ml) , tibutylphosphine (0.05 mL) , and ADDP (50 mg) were added and allowed to stir for 3 h. Hexane was added to the reaction mixture and dihydro-ADDP separated out and was filtered off. The filtrate was concentrated. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep*, P/N 68-2203- 027, 40 g Siθ2) to afford the desired product as colorless liquid. MS m/z: 274.3 (M+H). Calc'd. for C16H19NO3 - 273.2.
Figure imgf000176_0002
6- ( (6-phenyl- [1,2,41 triazolo [4, 3-b]pyridazin-3- yl)methyl) quinolin-3-ol . To a 5 ml CEM microwave tube was added tert-butyl 2- (3-methoxyquinolin-6-yl) acetate (0.3 g, 1 mmol), 1- (6 -phenylpyridazin-3-yl) hydrazine (0.3 g, 2 mmol), and HYDROCHLORIC ACID (0.3 ml, 11 mmol) as solvent. The vial was sealed and first heated at 100 0C for 20 min then placed into CEM microwave for 20 min. at 180 0C, with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH. The ppt . was collected by filtration. The ppt. was washed with water and dried. The solid was purified using SiO2 chromatography (Teledyne Isco RediSep*, P/N 68-2203- 027, 40 g SiO2, DCM:MeOH=95%:5%, Flow = 40 mL/min) to afford the desired product as gray solid. MS m/z: 354.2 (M+H) . Calc'd.
Figure imgf000177_0001
Example 116
N,N-dimethyl-2- (6- ( (6-phenyl- [1,2,4] trlazolo [4,3-b]pyridazin-3- yl) methyl) quinolin-3-yloxy) ethanamine. 6- ( (6-phenyl-
[1,2,4] triazolo [4 , 3-b] pyridazin-3-yl) methyl) quinolin-3-ol (0.05 g, 0.1 mmol) was dissolved in DMF (8 mL) . SODIUM HYDRIDE (0.01 g, 0.3 mmol) was added and allowed to stir for 1 h at rt. 2- chloro-N,N-dimethylethanamine hydrochloride (0.06 g, 0.4 mmol), which was free-based using 5 N NaOH then extracted with ether, was added. The resulting mixture was continued to stir for 20 h at rt. Solvent was removed in vacuo. The crude material was purified using SiO2 chromatography (Teledyne Isco RediSep , P/N 68-2203-026, 12 g SiO2, solvent system: DCM:MeOH(2M NH3)=95%:5%, Flow = 30 mL/min) to afford the title compound MS m/zι 425.3
(M+H) . Calc ' d . for C25H24N6O - 424 . 49 .
Figure imgf000177_0002
tert-butyl 2- (3-methoxyquinolin-6-yl)propanoate. To a flame- dry 100 ml 3 -neck round-bottomed flask was added lithium bis (trimethylsilyl) amide, 1.0m solution in tetrahydrofuran (5 ml, 5 mmol) and THF (20 mL) . The mixture was cooled to -78 0C followed by adding tert-butyl 2- (3-methoxyquinolin-6-yl) acetate (0.88 g, 3 mmol) in THF (10 mL) dropwise via addition funnel. After stirring at -78 0C for 30 min, iodomethane (0.4 ml, 6 mmol) was added. The reaction mixture was stirred for 30 min at -78 0C then allowed to warm to rt and stir for Ih. The mixture was then quenched with sat. NH4Cl (3 mL) . Solvent was removed. The residue was partitioned between EtOAc/water. The organic layer was washed with brine, dried over MgSO4 and removed solvent. The crude material was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO2, solvent system: hexane:acetone=90%: 10%, Flow = 30 mL/min) to afford a final product as yellowish liquid. MS m/z: 288.4 (M+H) . CaIc 'd. for Ci7H21NO3 - 287.3.
Figure imgf000178_0001
Example 117
3-methoxy-6- (1- (6-phenyl- [1, 2,4] triazolo [4, 3-b]pyridazin-3- yl) ethyl) quinoline To a 5 ml CEM microwave tube was added tert- butyl 2- (3-methoxyquinolin-6-yl)propanoate (0.130 g, 0.45 mmol), 1- (6-phenylpyridazin-3-yl) hydrazine (0.17 g, 0.90 mmol), HYDROCHLORIC ACID (0.11 ml, 1.4 mmol), and water (0.2 mL) as solvent. The vial was sealed and first heated at 90 0C for 30 min then placed into CEM microwave for 15 min. at 140 0C, with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH and the solid was collected by filtration. The brown ppt . was dissolved in DCM. The organic was washed with water, dried over MgSO4, and removec solvent in vacuo. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep*, P/N 68-2203-027, 40 g SiO2, DCM:MeOH=97%:3%, Flow = 40 mL/min) to afford the desired product as light yellowish solid. MS m/z-. 382.3 (M+H) CaIc' d. for C23H19N5O - 381.43.
Figure imgf000179_0001
Example 118
(S) -3-methoxy~6- (1- (6 -phenyl- [1,2,4] triazolo [4, 3-b]pyridazln-3- yl) ethyl) quinoline. Chiral separation. MS m/z: 382.3 (M+H) . CaIc' d. for C23Hi9N5O - 381.43.
Figure imgf000179_0002
Example 119
(R) -3-methoxy-β- (1- (6 -phenyl- [1, 2,4] triazolo [4, 3-b]pyridazin-3 yl) ethyl ) quinoline . Chiral separation. MS m/z: 382.3 (M+H) . CaIc' d. for C23H19N5O - 381.43.
Figure imgf000179_0003
tert-butyl 2- (3- (2-methoxyethoxy) quinolln-6-yl) acetate. To a suspension of tert-butyl 2- (3-hydroxyquinolin-6-yl) acetate (0.1 g, 0.4 mmol) in benzene (5 mL) was added 2-τnethoxyethanol (0.09 ml, 1 mmol) and tri-n-butylphosphine (0.1 ml, 0.6 mmol). The resulting mixture was cooled to 0 0C followed by adding 1.1 ' - (azodicarbonyl)dipiperidine (0.1 g, 0.6 mmol). After 10 πiin, ice bath was removed; the reaction mixture was warmed up to rt. After 2 h, TLC showed there still existed 50% starting material. More methoxymethanol (2eq, 0.06 mL) was added. The reaction mixture was contiuned to stir for 20 h. Hexane was added to the reaction mixture and dihydro-ADDP separated out was filtered off. The filtrate was concentrated. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep0", P/N 68-2203-027, 40 g SiO2, hexane : acetone=85% : 15%, Flow = 40 mL/min) to afford the desired product as colorless liquid. MS m/z: 318.4 (M+H) . Calc'd. for Ci8H23NO4 - 317.38.
Figure imgf000180_0001
Example 120
3- (2-methoxyethoxy) -6- ( (6-phenyl- [1, 2 , 43 triazolo [4, 3- b]pyridazin-3-yl)π^etIlyl) quinoline . To a 5 ml CEM microwave tube was added tert-butyl 2- (3- (2-methoxyethoxy) quinolin-6- yl) acetate (0.080 g, 0.25 mmol) , 1- (6-phenylpyridazin-3- yl) hydrazine (0.094 g, 0.50 mmol) , HYDROCHLORIC ACID (0.063 ml, 0.76 mmol), and water (0.2 mL) as solvent. The vial was sealed and first heated at 90 0C for 30 min then placed into CEM microwave for 15 min. at 140 0C, with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH and the precipitate was collected via filtration. The brown ppt. was dissolved in DCM. The organic was washed with water, dried over MgSO4, and removed solvent in vacuo. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep*, P/N 68-2203-026, 12 g SiO2, DCM:EtOAc:MeOH=60%:37%:3%, Flow = 30 mL/min) to afford the desired product as light yellowish solid. MS m/z: 412.3 (M+H) . Calc'd. for C24H2IN5O2 - 411.45.
Figure imgf000181_0001
methyl 2, 2-difluoro-2- (quinolin-6 -yl) acetate. To a stirring solution of methyl 2- (quinolin- 6-yl) acetate (450 mg, 2236 μxnol) in THF (2mL) at -700C under nitrogen was added lithium bis (trimethylsilyl) amide, 1.0m solution in tetrahydrofuran (5144 μl, 5144 μmol) and stirred for lOmin. To this solution was added n-fluorobis (phenylsulfonyl) amine (1481 mg, 4696 μmol) in THF (5mL) and slowly warmed to 00C over the course of Ih. Reaction stirred for an additional Ih at 230C, and resulting solid (sulfonamide) removed by filtration. The filtrate was concentrated to a solid under reduced pressure. The resulting solid was then partitioned between EtOAc (2OmL) and sat NH4Cl (1OmL) . The organic layer was dried over MgSO4 then concentrated to a solid under reduced pressure and used without further purification.
Figure imgf000181_0002
Example 121
6- (difluoro (6-phenyl- [1,2,4] triazolo [4, 3-b]pyridazin,-3- yl) methyl) quinollne . A mixture of methyl 2, 2-difluoro-2- (quinolin-6-yl) acetate (0.5O g, 2.1 mmol) , l-(6- phenylpyridazin-3-yl) hydrazine (0.39 g, 2.1 mmol) and p- toluenesulfonic acid monohydrate (0.2O g, 1.1 mmol) in 5 mL of dioxane was heated at 150 0C for 1 hour in a microwave tube in the microwave. The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO3 solution. The organic phase was separated and washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc) to give yellow solid as desired product 6- (difluoro (6-phenyl- [1,2,4] triazolo [4 , 3 -b] pyridazin-3 -yl) methyl) quinoline . MS (ESI pos. ion) m/z: 374.1 (M+H) . Calc'd Exact Mass for C2iHi3P2Ns: 373.1.
Figure imgf000182_0001
tert-butyl 2- (4 -aminoquinazolin-β-yl) acetate. To a solution of 6-bromoquinazolin-4-amine (0.400 g, 1.79 mmol) , tris (dibenzylideneacetone) dipalladium (o) (0.163 g, 0.179 mmol) and Q-phos (0.20 g) in 10 mL of THF was added 2- tert-butoxy-2-oxoethylzinc chloride 0.5 m in diethyl ether (10.7 ml, 5.36 mmol). The reaction was heated at 50 0C for 16 hours and was quenched with 50 mL of satd. NH4Cl. The mixture was diluted with 60 mL of EtOAc. The organic phase was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give red solid. The residue was purified by a silica gel column chromatography (5% EtOAc/hex to EtOAC) to give red solid tert-butyl 2- (4-aminoquinazolin-6-yl) acetate which was used without further purification. MS (ESI pos. ion) m/z: 260.1 (M+H) . Calc'd Exact Mass for Ci4Hi7N3O2: 259.1.
Figure imgf000182_0002
Example 122
6- ((6-phenyl- [1, 2 , 4] triazolo [4 , 3 -b] pyridazin-3 - yl) methyl) quinazolin-4 -amine . Prepared according to example 121 from tert-butyl 2- (4-aminoquinazolin-6-yl) acetate . MS (ESI pos. ion) m/z: 354 (M+H). Calc'd Exact Mass for C20Hi5N7: 353.
Figure imgf000182_0003
Figure imgf000183_0001
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Figure imgf000240_0001
Although the pharmacological properties of the compounds of the current invention vary with structural change, in general, activity possessed by these compounds may be demonstrated in vivo. The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological in vitro assays. The exemplified pharmacological assays, which follow, have been carried out with the compounds according to the invention. The exemplified compounds of the present invention demonstrated a Ki between 20 μM and 0.3 nM. Illustrative activity values are provided in the following table.
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
BIOLOGICAL TESTING
The efficacy of the compounds of the invention as inhibitors of HGF related activity is demonstrated as follows. c-Met receptor assay Cloning, Expression and Purification of c-Met Kinase Domain
A PCR product covering residues 1058-1365 of c-Met (c-Met kinase domain) is generated from Human Liver QuickClone™ cDNA (Invitrogen) using forward primer 5'- ATTGACGGATCCATGCTAAATCC AGAGCTGGTCCAGGCA-S' (SEQ ID NO. 1) and reverse primer 5'-ACAACAGAATTCAATACGGAGCGACACATTTTACGTT-S' (SEQ ID NO. 2). The PCR product is cloned into a modified pFastBacl expression vector (harboring the gene for S.japonicum glutathione S-transferase immediately upstream of the multiple cloning site) using standard molecular biological techniques. The GST-c-Met kinase domain fusion (GST-Met) gene is transposed into full-length baculovirus DNA using the BacToBac™ system (Invitrogen). High5 cells are infected with the recombinant baculovirus for 72 h at 27°C. The infected cells are harvested by centrifugation and the pellet is stored at -800C. The pellet is resuspended in buffer A (50 mM HEPES, pH 8.0, 0.25 M NaCl, 10 mM 2- mercaptoethanol, 10% (w/v) glycerol, 0.5 % (v/v) protease inhibitor cocktail (Sigma P8340), stirred at 4°C to homogeneity, and the cells are disrupted by microfluidization (Microfluidics) at 105OOO psi. The resulting lysate is centrifuged at 50,000 x g for 90 min at 4 0C, and the supernatant is adsorbed onto 10 mL of glutathione sepharose™ 4B (Amersham) by batch method. The slurry is rocked gently overnight at 4°C. The glutathione resin is harvested by centrifugation and washed three times with 40 mL buffer A by batch method. The resin is washed three times with buffer B (buffer A adjusted to 0.1 M NaCl, less protease inhibitors). The protein is eluted with buffer B containing 25 mM reduced glutathione. Eluted fractions are analyzed by SDS-PAGE and concentrated to <10 mL (-10 mg/mL total protein). The concentrated protein is separated by Superdex™ 200 (Amersham) size exclusion chromatography in buffer C (25 mM Tris, pH 7.5, 0.1 M NaCl, 10 mM 2-mercaptoethanol, 10% glycerol). The fractions are analyzed by SDS-PAGE and the appropriate fractions are pooled and concentrated to ~1 mg/mL. The protein is aliquotted and stored at -800C. Alternative purification of human GST-cMET from Baculovirus cells Baculovirus cells are broken in 5x (volume/weight) of Lysis Buffer (50 mM HEPES, pH 8.0, 0.25 M NaCl, 5 mM mercaptoethanol, 10% glycerol plus Complete Protease Inhibitors (Roche (#10019600), 1 tablet per 50 mL buffer). The lysed cell suspension is centrifuged at 100,000 x g (29,300 rpm) in a Beckman ultracentrifuge Ti45 rotor for 1 h. The supernatant is incubated with 10 ml of Glutathione Sepharose 4B from Amersham Biosciences (#27-4574- 01). Incubation is carried out overnight in a cold room (approximately 8°C). The resin and supernatant is poured into an appropriately sized disposable column and the flow through supernatant was collected. The resin is washed with 10 column volumes (100 mL) of Lysis Buffer. The GST-cMET is eluted with 45 mL of 10 mM Glutathione (Sigma #G-4251) in Lysis Buffer. The elution is collected as 15 mL fractions. Aliquots of the elution fractions are run on SDS PAGE (12% Tris Glycine gel, Invitrogen, #EC6005BOX). The gel is stained with 0.25% Coomassie Blue stain. Fractions with GST-cMET are concentrated with a Vivaspin 20 mL Concentrator (#VS2002; 10,00 MW cutoff) to a final volume less than 2.0 ml. The concentrated GST-cMET solution is applied to a Superdex 75 16/60 column (Amersham Biosciences #17-1068-01) equilibrated with 25 mM Tris, pH 7.5, 100 mM NaCl, 10 mM mercaptoethanol, 10% glycerol. The GST-cMET is eluted with an isocratic run of the above buffer, with the eluent collected in 1.0 mL fractions. Fractions with significant OD∑βo readings are run on another 12% Tris Glycine gel. The peak tubes with GST-cMET are pooled and the OD280 is read with the column buffer listed above as the blank buffer.
Phosphorylation of the purified GST-cMET is performed by incubating the protein for 3 h at RT with the following:
Final concentration a) 10O mM ATP (Sigma #A7699) 25 mM b) 1.0 M MgCl2 (Sigma #M-0250) 10O mM c) 200 mM Sodium Orthovanadate (Sigma #S-6508) 15 mM d) 1.0 M Tris-HCl, pH 7.00 (in house) 5O mM e) H2O f) GST-cMET 0.2 - 0.5 mg/mL
After incubation, the solution is concentrated in a Vivaspin 20 ml Concentrator to a volume less than 2.00 ml. The solution is applied to the same Superdex 75 16/60 column used above after re-equilibration. The GST-cMET is eluted as described above. The elution fractions corresponding to the first eluted peak on the chromatogram are run on a 12% Tris Glycine gel, as above, to identify the fractions with GST-cMET. Fractions are pooled and the OD∑βo is read with the column buffer used as the blank.
A Kinase reaction Buffer is prepared as follows:
Per l L
60 mM HEPES PH 7.4 1 M stock 16.7 X 6O mL
50 mM NaCI 5 M stock 100 X 1O mL
20 mM MgCl2 1 M stock 50 X 2O mL
5 mM MnCl2 1 M stock 200 X 5 mL
When the assay is carried out, freshly add:
2 mM DTT 1 M stock 500 X
0.05 % BSA 5 % stock 100 X
0.I mM Na3OV4 0.1 M stock 1000 X
The HTRF buffer contains:
50 mM Tris-HCl (PH 7.5), 100 mM NaCl, 0.1 % BSA, 0.05 % Tween 20,5mM EDTA Fresh add SA-APC (PJ25S Phycolink Streptavidin-Allophycocyanin Conjugate, Prozyme Inc.) and Eu-PT66 ( Eu-W 1024 labeled anti-phosphorotyrosine antibody PT66, AD0069, Lot 168465, Perkin-Elmer Inc.) to reach the final concentration:
0.1 nM final Eu-PT66
11 nM final SA-APC
Methods:
1. Dilute GST-cMet (P) enzyme in kinase buffer as follows:
Prepare 8 nM GST-cMet (P) working solution (7.32 μM to 8 nM, 915 X, 10 μL to 9.15 mL). In a 96 well clear plate [Costar # 3365] add 100 μL in eleven columns, in one column add 100 μL kinase reaction buffer alone.
2. Assay plate preparation:
Use Biomek FX to transfer 10 μL 8 nM GST-cMet (P) enzyme, 48.4 μL kinase reaction buffer, 1.6 μL compound (in DMSO) (Start concentration at 10 mM, 1 mM and 0.1 mM, sequential dilution 1 :3 to reach 10 test points) in a 96 well costar clear plate [Costar # 3365], mix several times. Then incubate the plate at RT for 30 min.
3. Prepare Gastrin and ATP working solution in kinase reaction buffer as follows: Prepare 4 μM Gastrin and 16 μM ATP working solution
Per 1O mL
Gastrin 4 μM stock (500 μM to 4 μM, 125 X) 80 μL
ATP 16 μM stock (1000 μM to 16 μM, 62.5 X) 160 μL
Use Biomek FX to add 20 μl ATP and Gastrin working solution to the assay plate to start reaction, incubate the plate at RT for 1 h.
4. Transfer 5 μL reaction product at the end of 1 h into 80 μL HTRF buffer in black plate [Costar # 3356], read on Discover after 30 min incubation.
Assay condition summary:
KM ATP * - 6 μM
[ATP] - 4 μM
KM Gastrin/p(EY) - 3.8 μM
[gastrin] - 1 μM [enzyme] - 1 nM
KM ATP, KM gastrin for various enzymes were determined by HTRFV33P labeling and HTRF methods.
Examples 1-28, 30, 33-34, 36-37, and 39-48 exhibited activity with IC50 values less than 0.5 μM. c-Met cell-based autophosphorylation assay
Human PC3 and mouse CT26 cells are available obtained from ATCC. The cells were cultured in a growth medium containing RPMI 1640, penicillin/streptomycin/glutamine (IX) and 5% FBS. 2 x 104 cells in medium were plated per well in a 96 well plate and incubated at 37 0C overnight. The cells were serum-starved by replacing the growth media with basic medium (DMEM low glucose + 0.1 BSA, 120 μL per well) at 37 0C for 16 h. Compounds (either 1 mM and 0.2 mM) in 100% DMSO were serially diluted (1:3) 3333 fold on a 96 well plate, diluting 1 :3 with DMSO from column 1 to 11 (columns 6 and 12 receive no compound). Compound samples (2.4 μL per well) were diluted with basic medium (240 μL) in a 96 well plate. The cells were washed once with basic medium (GIBCO, DMEM 11885-076) then compound solution was added (100 μL). The cells were incubated at 37 0C for 1 h. A (2 mg/mL) solution of CHO-HGF (7.5 μL) was diluted with 30 mL basic medium to provide a final concentration of 500 ng/mL. This HGF-containing media (120 μL) was transferred to a 96 well plate. Compounds (1.2 μL) was added to the HGF-containing media and mixed well. The mixture of media/HGF/compound (100 μL) was added to the cells (final HGF concentration - 250 ng/mL) then incubated at 37 0C for 10 min. A cell lysate buffer (20 mL) was prepared containing 1% Triton X-100, 50 mM Tris pH 8.0, 100 mM NaCl, Protease inhibitor (Sigma, #P-8340) 200 μL, Roche Protease inhibitor (Complete, # 1-697-498) 2 tablets, Phosphatase Inhibitor II (Sigma, #P-5726) 200 μL, and a sodium vanadate solution (containing 900 μL PBS, 100 μL 300 mM NaVO3, 6 μL H2O2 (30% stock) and stirred at RT for 15 min) (90 μL). The cells were washed once with ice cold IX PBS (GIBCO, #14190- 136), then lysis buffer (60 μL) was added and the cells were incubated on ice for 20 min.
The IGEN assay was performed as follows: Dynabeads M-280 streptavidin beads were pre-incubated with biotinylated anti-human HGFR (240 μL anti-human-HGFR (R&D system, BAF527 or BAF328) @ 100 μg/mL + 360 μL Beads (IGEN #10029 + 5.4 μL buffer - PBS/l°/t BSA/0.1% Tween20) by rotating for 30 min at RT. Antibody beads (25 μL) were transferred to a 96 well plate. Cell lysate solution (25 μL) was transferred added and the plate was shaken at RT for 1 h. Anti-phosphotyrosine 4G10 (Upstate 05-321) (19.7 μL antibody + 6 mL IX PBS) (12.5 μL) was added to each well, then incubated for 1 h at RT. Anti-mouse IgG ORI- Tag (ORIGEN #1 10087) (24 μL Antibody + 6 mL buffer) (12.5 μL) was added to each well, then incubated at RT for 30 min. IX PBS (175 μL) was added to each well and the electrochemiluminescence was read by an IGEN M8. Raw data was analyzed using a 4- parameter fit equation in XLFit. IC50 values are then determined using Grafit software. Examples 2, 4, 6-8, 11, 13, 15-21, 23-26, 36-37, 39, 41, and 43-44 exhibited activity in PC3 cells with IC50 values less than 1.0 μM. Examples 2, 4, 6-8, 11-13, 15-21, 23-26, 36-37, 41, and 43-44 exhibited activity in CT26 cells with IC50 values less than 1.0 μM.
rHu-bFGF: Stock concentration of 180 ng/μL: R&D rHu- bFGF: Added 139 μL of the appropriate vehicle above to the 25 μg vial lyophilized vial. 13.3 μL of the [180 ng/μL] stock vial and added 26.6 μL of vehicle to yield a final concentration of 3.75 μM concentration. Nitro-cellulose disk preparation: The tip of a 20-gauge needle was cut off square and beveled with emery paper to create a punch. This tip was then used to cut out = 0.5 mm diameter disks from a nitrocellulose filter paper sheet (Gelman Sciences). Prepared disks were then placed into Eppendorf microfuge tubes containing solutions of either 0.1% BSA in PBS vehicle, 10 μM rHu- VEGF (R&D Systems, Minneapolis, MN), or 3.75 μM rHu-bFGF (R&D Systems, Minneapolis, MN) and allowed to soak for 45-60 min before use. Each nitrocellulose filter disk absorbs approximately 0.1 μL of solution.
In the rat micropocket assay, compounds of the present invention will inhibit angiogenesis at a dose of less than 50 mg/kg/day.
Tumor model
A431 cells (ATCC) are expanded in culture, harvested and injected subcutaneously into 5-8 week old female nude mice (CDl nu/nu, Charles River Labs) (n = 5-15). Subsequent administration of compound by oral gavage (10 - 200 mpk/dose) begins anywhere from day 0 to day 29 post tumor cell challenge and generally continues either once or twice a day for the duration of the experiment. Progression of tumor growth is followed by three dimensional caliper measurements and recorded as a function of time. Initial statistical analysis is done by repeated measures analysis of variance (RMANOVA), followed by Scheffe post hoc testing foi multiple comparisons. Vehicle alone (Ora-Plus, pH 2.0) is the negative control. Compounds o the present invention will be active at doses less than 150 mpk.
Tumor models
Human glioma tumor cells (U87MG cells, ATCC) are expanded in culture, harvested and injected subcutaneously into 5-8 week old female nude mice (CDl nu/nu, Charles River Labs) (n=10). Subsequent administration of compound by oral gavage or by IP (10-100 mpk/dose) begins anywhere from day 0 to day 29 post tumor cell challenge and generally continues either once or twice a day for the duration of the experiment. Progression of tumor growth is followed by three dimensional caliper measurements and recorded as a function of time. Initial statistical analysis is done by repeated measures analysis of variance (RMANOVA), followed by Scheffe post hoc testing for multiple comparisons. Vehicle alone (captisol, or the like) is the negative control. Compounds of the present invention will be active at 150 mpk.
Human gastric adenocarcinoma tumor cells (MKN45 cells, ATCC) are expanded in culture, harvested and injected subcutaneously into 5-8 week old female nude mice (CDl nu/nu, Charles River Labs) (n=l 0). Subsequent administration of compound by oral gavage or by IP (10-100 mpk/dose) begins anywhere from day 0 to day 29 post tumor cell challenge and generally continues either once or twice a day for the duration of the experiment. Progression of tumor growth is followed by three dimensional caliper measurements and recorded as a function of time. Initial statistical analysis is done by repeated measures analysis of variance (RMANOVA), followed by Scheffe post hoc testing for multiple comparisons. Vehicle alone (captisol, or the like) is the negative control. Compounds of the present invention will be active at 150 mpk.
FORMULATIONS
Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of the current invention in association with one or more nontoxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds and compositions of the present invention may, for example, be administered orally, mucosally, topically, rectally, pulmonarily such as by inhalation spray, or parentally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly intrasternally and infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.
The pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. For example, these may contain an amount of active ingredient from about 1 to 2000 mg, preferably from about 1 to 500 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods.
The amount of compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. A daily dose of about 0.01 to 500 mg/kg, preferably between about 0.01 and about 50 mg/kg, and more preferably about 0.01 and about 30 mg/kg body weight may be appropriate. The daily dose can be administered in one to four doses per day.
For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled- release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
In the case of psoriasis and other skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day.
Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (e.g., liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose. A suitable topical dose of active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, preferably one or two times daily. For topical administration, the active ingredient may comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, but preferably not more than 5% w/w, and more preferably from 0.1% to 1% of the formulation.
When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane- 1, 3 -diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound, which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include DMSO and related analogs.
The compounds of this invention can also be administered by a transdermal device. Preferably transdermal administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di- isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.
Formulations for parenteral administration may be in the form of aqueous or nonaqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie. propylene glycol) or micellar solubilization (ie. Tween 80).
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
For pulmonary administration, the pharmaceutical composition may be administered in the form of an aerosol or with an inhaler including dry powder aerosol.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes, which are obvious to one skilled in the art are intended to be within the scope and nature of the invention, which are defined, in the appended claims.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
No unacceptable toxological effects are expected when compounds of the present invention are administered in accordance with the present invention.
All mentioned references, patents, applications and publications, are hereby incorporated by reference in their entirety, as if here written.

Claims

WE CLAIM:
1. A compound of formula I , II, III, IV, V, VI or VII
Figure imgf000255_0001
II
Figure imgf000255_0002
III
Figure imgf000255_0003
IV
Figure imgf000256_0001
VI
Figure imgf000256_0002
VII enantiomers, diastereomers, salts and solvates thereof wherein
J is N or CR3;
W is N or CR2b;
W* is N or CR2b;
X is O or S;
Z and Z* are independently -O-, -S(O)V-, or -NR5-;
Ra, Rb, Rc and Rd are each independently H, halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, -NO2, -CN, -NR5R5a, -OR4, -C(=O)R4, -C(=O)OR4; -C(=O)NR5R5a, -N(R5)C(=O)NR5R5a, -OC(=O)NR5R5a, -S(O)VR4, -S(O)2NR5R58, -N(R5)SO2R4 any of which may be optionally independently substituted with one or more R10 groups as allowed by valance; or Ra and Rb together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R10 groups as allowed by valance.; or Rc and Rd together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R10 groups as allowed by valance; or Ra and/or Rb may combine with any Rc or Rd to form a partially or fully saturated 3-8 membered cycloalkyl ring or heterocyclo ring, either of which may be optionally substituted with one or more R10 groups as allowed by valance; or Ra and Rb may combine to form a carbonyl group; or Rc and Rd attached to the same carbon atom may combine to form a carbonyl group; R1 is aryl, heteroaryl or heterocyclo any of which may be optionally independently substituted with one or more R10 groups as allowed by valance; R2 is
(i) H, halo, cyano, nitro, or
(ii) alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -OR4, -S(O)vR4, -NR5R58, -C(=O)R4, -C(=S)R4, -C(=O)OR4, -C(=S)OR4, -C(=O)NR5R5\ -C(=S)NR5R5a, -N(R5)C(=O)NRsR5a, -N(R5)C(=S)NR5R5a, -N(R5)C(=O)R4, -N(R5)C(=S)R4, -OC(=O)NR5R5a, -OC(=S)NR5R5a, -SO2NR5R58, -N(R5)SO2R4, -N(R5)SO2NR5R5a, -N(R5)C(=O)OR4, -N(R5)C(=S)OR4, -N(R5)SO2R4, any of which may be optionally independently substituted with one or more R10 as allowed by valance, provided that in compounds of formula I when W and J are both N, R is other than
(c) -NR5R58 where Rs and R5a are independently H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl; and
(d) phenyl substituted with a group
Figure imgf000257_0001
where G1 and G2 are independently alkyl, cycloalkyl, or G .1 a ™nd-4 / G-_2 ■ together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring;
R2a, R2b and R3 are independently selected at each occurrence from H, halo, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -OR4, -S(O)VR4, -NR5R5a, -C(=O)R4, -C(=S)R4, -C(=O)OR4, -C(=S)OR4, -C(=O)NR5R5a, -C(=S)NR5R5a, -N(R5)C(=O)NR5R5a, -N(Rs)C(=S)NR5R5a, -N(R5)C(=O)R4, -N(R5)C(=S)R4, -OC(=O)NR5R5a, -OC(=S)NR5R5a, -SO2NR5R5", -N(R5)SO2R4, -N(R5)SO2NR5R5a, -N(R5)C(=O)OR\ -N(R5)C(=S)OR4, -N(RS)SO2R4, any of which may be optionally independently substituted with one or more R10 groups as allowed by valance;
R4 is independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally independently substituted as allowed by valance with one or more R10 groups;
R5 and R5a are independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally substituted as allowed by valance with one or more R10; or R5 and R5a may combine to form a heterocyclo ring optionally substituted with one or more R10;
R10 at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)m-OR4, -(alkylene)m-S(O)vR4, -(alkylene)m-NR5R5a, -(alkylene)m-C(=O)R4, -(alkylene)m-C(=S)R4, -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4, -(alkylene)m-C(=S)OR4, -(alkylene)m-C(=O)NR5R5a, -(alkylene)m-C(=S)NR5R5a, -(alkylene)m-N(R5)C(=O)NRsR5a, -(alkylene)m-N(R5)C(=S)NR5R5a, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-N(R5)C(=S)R4,
-(alkylene)m-OC(=0)NR5R5a, -(alkylene)m-OC(=S)NR5R5a, -(alkylene)m-SO2NR5R5a, -(alkylene)m-N(R5)SO2R4, -(alkylene)m-N(R5)SO2NR5R5\ -(alkylene)m-N(R5)C(=O)OR4, -(alkylene)m-N(R5)C(=S)OR4, or -(alkylene)m-N(R5)SO2R4; wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene)m-OR4, -(alkylene)m-S(O)vR4, -(alkylene)m-NR5R5a, -(alkylene)m-C(=O)R4, -(alkylene)m-C(=S)R\ -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=0)R4, -(alkylene)m-C(=S)OR4, -(alkylene)m-C(=O)NR5R5a, -(alkylene)m-C(=S)NR5RSa, -(alkylene)m-N(R5)C(K))NR5R5a, -(alkylene)m-N(R5)C(=S)NR5R5a,
-(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-N(R5)C(=S)R4,
-(alkylene)m-OC(=O)NR5R5a, -(alkylene)m-OC(=S)NRsR5a, -(alkylene)m-SO2NR5R5a,
-(alkylene)m-N(R5)SO2R4, -(alkylene)m-N(R5)SO2NR5RSa,
-(alkylene)m-N(R5)C(=O)OR4, -(alkylene)m-N(Rs)C(=S)OR4, or
-(alkylene)m-N(R5)SO2R4; and further wherein any two R10 groups attached to the same atom or attached to adjacent atoms may combine to form an optionally substituted 3- to 8 membered ring system; m is O or 1; n is 0, 1 or 2; q and t are each independently 0 or 1 ; v is 0, 1 or 2.
2. A compound of claim 1 wherein R1 is phenyl, naphthyl, benzodioxolyl, benzooxazolyl, benzoisoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrimidinyl, pyrazidinyl, isoquinolinyl, quinolinyl, quinazolinyl, quinazolinonyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl, thienopyridinyl, thienopyrimidinyl, thienopyridazinyl, furopyridinyl, furopyrimidinyl, furopyrazidinyl, benzofuranyl, benzoimidazolyl, indolyl, benzoisoxazolyl, benzothiazolyl, or benzoisothiazolyl any of which may be optionally independently substituted with one or more R10 groups as allowed by valance.
3. A compound of claim 1 wherein R2 is H, halo, cyano, alkynyl, -C(=O)NR5R5a, -N(R5)C(=O)R4, -N(R^C(O)OR4, phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, tetrahydropyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, indolinonyl, isoidolinyl, isoindolinonyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, benzofuranyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, quinoxalinyl, tetrahydroquinoxalinyl, benzomorpholinyl, dihydrobenzodioxinyl, imidazopyridinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl, thienopyrrolyl, tetrahydrothienopyrrolyl, dihydrothienopyrrolonyl, thienopyridinyl, thienopyrimidinyl, thienopyridazinyl, furopyridinyl, furopyrimidinyl, furopyrazidinyl, benzofuranyl, benzoimidazolyl, benzoisoxazolyl, benzothiazolyl, or benzoisothiazolyl any of which may be optionally independently substituted with one or more R10 groups as allowed by valance.
4. A compound of claim 2 wherein R2 is H, halo, cyano, alkynyl, -C(=O)NR5R5a, -N(R5)C(=O)R4, -N(R5)C(=O)OR4, phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, tetrahydropyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, indolinonyl, isoidolinyl, isoindolinonyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, benzofuranyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, quinoxalinyl, tetrahydroquinoxalinyl, benzomorpholinyl, dihydrobenzodioxinyl, imidazopyridinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl, thienopyrrolyl, tetrahydrothienopyrrolyl, dihydrothienopyrrolonyl, thienopyridinyl, thienopyrimidinyl, thienopyridazinyl, furopyridinyl, furopyrimidinyl, furopyrazidinyl, benzofuranyl, benzoimidazolyl, benzoisoxazolyl, benzothiazolyl, or benzoisothiazolyl any of which may be optionally independently substituted with one or more R10 groups as allowed by valance.
5. A compound of claim 2 wherein R1 is selected from
Figure imgf000261_0001
Figure imgf000262_0001
where m* is 0, 1 , 2, 3, 4, 5 or 6, as allowed by valence.
6. A compound of claim 3 wherein R2 is
(a) halo, alkynyl, -C(=O)NR5R5a, -N(R5)C(=O)R4 or -N(R5)C(=O)OR4 any of which may be optionally independently substituted with one or more R10 groups as allowed by valance; or
(b) an aryl, heteroaryl or heterocyclo ring system selected from
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
7. A compound of claim 5 wherein R is
(a) halo, alkynyl, -C(=O)NR5R5a, -N(R5)C(=O)R4 or -N(R5)C(=O)OR4 any of which may be optionally independently substituted with one or more R10 groups as allowed by valance; or
(b) an aryl, heteroaryl or heterocyclo ring system selected from
Figure imgf000265_0002
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
8. A compound of any of claims 1, 2, 3, 4, 5, 6 or 7 having a formula IA, IB, IC, ID, or
HA
Figure imgf000268_0002
Figure imgf000269_0001
enantiomers, diastereomers, salts and solvates thereof.
9. A compound of claim 8 wherein R1 groups are either unsubstituted or independently substituted as allowed by valance with one or more halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene)m-OR4, -(alkylene)m-NR5R5a, -(alkylene)m-C(=O)R4, -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4, -<alkylene)m-C(=O)NR5R5a, -(alkylene)m-N(R5)C(=O)NRsR5a, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-OC(=O)NR5R5a, or -(alkylene)m-N(R5)C(=O)OR4.
10. A compound of claim 9 wherein R1 groups are selected from
Figure imgf000269_0002
Figure imgf000270_0001
and
where Rl0\ R1Ob. RIOy and R1Oz are independently absent, halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene)m-OR\ -(aIkylene)m-NR S3RnS3aa,
Figure imgf000270_0002
-(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4, -(alkylene)m-C(=O)NR5R5a,
-(alkylene)m-N(Rs)C(=O)NR5R5a, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-OC(=O)NR5R5a, or -(alkylene)m-N(R5)C(=O)OR4; or where RlOa and RIOb combine to form an optionally substituted 3- to 8-membered ring system.
11. A compound of claim 10 wherein R1 is
Figure imgf000271_0001
12. A compound having the following formula IE, IF, HB or HC
Figure imgf000271_0002
enantiomers, diastereomers, salts and solvates thereof wherein q is O, 1, 2 or 3; n* is 0, 1 or 2; t* is 0 or 1
U1, U2, U3 and U4 are each independently C, or N;
Z* is -O -, -S(O)v, or -NH;
RB, Rb, Rc and Rd are each independently H, halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, -NO2, -CN, -NR5R5a, -OR4, -C(=O)R4, -C(O)OR4; -C(=O)NR5R5a, -N(R5)C(=O)NR5R5a, -OC(=O)NR5R5a, -S(O)VR4, -S(O)2NR5R58, -N(RS)SO2R4 any of which may be optionally independently substituted with one or more R10 groups as allowed by valance; or Ra and Rb together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R10 groups as allowed by valance.; or Rc and Rd together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R10 groups as allowed by valance; or Ra and/or Rb may combine with any Rc or Rd to form a partially or fully saturated 3-8 membered cycloalkyl ring or heterocyclo ring, either of which may be optionally substituted with one or more R10 groups as allowed by valance; or Ra and Rb may combine to form a carbonyl group; or Rc and Rd attached to the same carbon atom may combine to form a carbonyl group;
R2 is
(i) H, halo, cyano, nitro, or
(ii) alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -OR4, -S(O)vR4, -C(=O)R\ -C(=S)R4, -C(=O)OR4, -CC=S)OR4, -C(=O)NR5R5a, -C(=S)NR5R5a, -N(R5)C(=O)NR5R5β, -N(R5)C(=S)NR5R5a, -N(R5)C(=O)R4, -N(R5)C(=S)R\ -OC(=O)NR5R5a, -OC(=S)NR5R5a, -SO2NR5R5", -N(R5)SO2R4, -N(R5)SO2NR5R5a, -N(R5)C(=O)OR4, -N(RS)C(=S)OR4, -N(R5)SO2R4, any of which may be optionally independently substituted with one or more R10 as allowed by valance, provided that in compounds of formula IE5 R2 is not a phenyl substituted with a group
Figure imgf000273_0001
where G1 and G2 are independently alkyl, cycloalkyl, or G1 and G2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring;
R2a and R2b are independently selected from H, halo, alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino and alkoxy;
R4 is independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally independently substituted as allowed by valance with one or more R10 groups;
R5 and R5a are independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally substituted as allowed by valance with one or more R10; or R5 and RSa may combine to form a heterocyclo ring optionally substituted with one or more R10;
R10 and RIOc at each occurrence are independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)m-OR4, -(alkylene)m-S(O)vR4, -(alkylene)m-NR5R5a, -(alkylene)m-C(=O)R4, -(alkylene)m-C(=S)R\ -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4, -(alkylene)m-C(=S)OR4, -(alkylene)m-C(=O)NR5R5a, -(alkylene)m-C(=S)NR5R5a, -(alkylene)m-N(R5)C(=O)NRsR5a, -(alkylene)m-N(R5)C(=S)NR5R5a, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-N(R5)C(=S)R4,
-(alkylene)m-OC(=O)NR5R5a, -(alkylene)m-OC(=S)NR5R5a, -(alkylene)m-SO2NR5R5a, -(alkylene)m-N(R5)S02R4, -(alkylene)m-N(R5)SO2NR5R5a, -(alkylene)m-N(Rs)C(=O)OR4, -(alkylene)m-N(R5)C(=S)OR4, or -(alkylene)m-N(R5)SO2R4; wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene)m-OR4, -(alkylene)m-S(O)vR4, -(alkylene)m-NR5R5a, -(alkylene)m-C(=O)R4, -(alkylene)m-C(=S)R4, -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4, -(alkylene)m-C(=S)OR4, -(alkylene)m-C(=O)NR5R5a, -(alkylene)m-C(=S)NRsR5a, -(alkylene)m-N(R5)C(=O)NR5R5a, -(alkylene)m-N(R5)C(=S)NR5R5a, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-N(R5)C(=S)R4,
-(alkylene)m-OC(=O)NRsR5a, -(alkylene)m-OC(=S)NR5R5a, -(alkylene)m-SO2NR5R5a, -(alkylene)m-N(R5)SO2R4, -(alkylene)m-N(R5)Sθ2NR5R5a, -(alkylene)m-N(R5)C(=O)OR4, -(alkylene)m-N(R5)C(=S)OR4, or -(alkylene)m-N(R5)SO2R4; v is 0, 1 or 2.
13. A compound of claim 12 having formula IEi, IEii, IEiii, IEiv, IFi, IFii, IFiii or IFiv
Figure imgf000275_0001
Figure imgf000276_0001
eπantiomers, diastereomers, salts and solvates thereof.
14. A compound of claim 13 wherein R2 is H, halo, cyano, alkynyl, -C(=O)NR5R5a, -N(R5)C(=O)R4, -N(R5)C(=O)OR4, phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, tetrahydropyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, indolinonyl, isoidolinyl, isoindolinonyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, benzofuranyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, quinoxalinyl, tetrahydroquinoxalinyl, benzomoφholinyl, dihydrobenzodioxinyl, imidazopyridinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl, thienopyrrolyl, tetrahydrothieπopyrrolyl, dihydrothienopyrrolonyl, thienopyridinyl, thienopyrimidinyl, thienopyridazinyl, furopyridinyl, furopyrimidinyl, furopyrazidinyl, benzofuranyl, benzoimidazolyl, benzoisoxazolyl, benzothiazolyl, or benzoisothiazolyl any of which may be optionally independently substituted with one or more R10 groups as allowed by valance.
15. A compound of claim 14 wherein R2 is
(a) halo, alkynyl, -C(=O)NR5R5a, -N(R5)C(=O)R4 or -N(R5)C(=O)OR4 any of which may be optionally independently substituted with one or more R10 groups as allowed by valance; or
(b) an aryl, heteroaryl or heterocyclo ring system selected from
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
277
Figure imgf000280_0001
where m* is O, 1 , 2, 3, 4, 5 or 6, as allowed by valence.
16. A compound of claim 15 wherein R1Oc at each occurrence is independently absent, halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene)m-OR4, -(alkylene)m-NR5R5a, -(alkylene)m-C(=O)R\ -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4, -(alkylene)m-C(=O)NRsR5a, -(alkylene)m-N(R5)C(=O)NR5R5a, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-OC(=O)NR5R5a, or -(alkylene)m-N(R5)C(=O)OR4.
17. A compound of claim 12 wherein n* is 0 or 1, and t* is 1 ;
18. A compound of claim 12 wherein n* is 1 and t* is 0.
19. A compound of claim 12 selected from
Figure imgf000281_0001
Figure imgf000281_0002
Figure imgf000281_0004
Figure imgf000281_0003
Figure imgf000282_0001
280
Figure imgf000283_0001
281
Figure imgf000284_0001
282
Figure imgf000285_0001
Figure imgf000286_0001
284
Figure imgf000287_0001
285
Figure imgf000288_0001
Figure imgf000289_0001
287
Figure imgf000290_0001
Figure imgf000291_0001
salts and solvates thereof.
20. A compound of claim 12 selected from
Figure imgf000291_0002
289
Figure imgf000292_0001
290
Figure imgf000293_0001
291
Figure imgf000294_0001
292
Figure imgf000295_0001
Figure imgf000296_0001
salts and solvates thereof.
21. A compound having the following formula IEA or IFA
Figure imgf000296_0002
enantiomers, diastereomers, salts and solvates thereof wherein
294 q is O, 1, 2 or 3; n* is 0, 1 or 2; t* is 0 or 1
U1, U2, U3 and U4 are each independently C, or N;
Z* is -O -, -S(O)V, or -NH;
Ra, Rb, Rc and Rd are each independently H, halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, -NO2, -CN, -NR5R5", -OR4, -C(=O)R4, -C(=O)OR4; -C(=O)NR3R5a, -N(R^C(O)NR5R*3, -OC(=O)NR5R5a, -S(O)VR4, -S(O)2NR5R53, -N(R5)SO2R4 any of which may be optionally independently substituted with one or more R10 groups as allowed by valance; or Ra and R together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R10 groups as allowed by valance.; or Rc and Rd together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R10 groups as allowed by valance; or Ra and/or Rb may combine with any Rc or Rd to form a partially or fully saturated 3-8 membered cycloalkyl ring or heterocyclo ring, either of which may be optionally substituted with one or more R10 groups as allowed by valance; or Ra and Rb may combine to form a carbonyl group; or Rc and Rd attached to the same carbon atom may combine to form a carbonyl group; R2 is
(i) H, halo, cyano, nitro, or
(ii) alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -OR4, -S(O)vR4, -C(=O)R4, -C(=S)R4, -C(=O)OR4, -C(=S)OR4, -C(=O)NR5R5a, -C(=S)NR5R5a, -N(Rs)C(=O)NR5R5a, -N(R5)C(=S)NR5R5a, -N(R5)C(=O)R4, -N(R5)C(=S)R4, -OC(=O)NR5R5\ -OC(=S)NR5R5a, -SO2NR5R5"1, -N(R5)SO2R4, -N(R5)SO2NR5R5a, -N(RS)C(=O)OR4, -N(R5)C(=S)OR4, -N(R5)SO2R4, any of which may be optionally independently substituted with one or more R10 as allowed by valance, provided that in compounds of formula IEA, R2 is not a phenyl substituted with a group
295
Figure imgf000298_0001
where G1 and G2 are independently alkyl, cycloalkyl, or G1 and G2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring;
R2a and R2b are independently selected from H, halo, alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino and alkoxy;
R4 is independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally independently substituted as allowed by valance with one or more R10 groups;
R5 and R5a are independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally substituted as allowed by valance with one or more R10; or R5 and R5a may combine to form a heterocyclo ring optionally substituted with one or more R10;
R10 and R1Oc at each occurrence are independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)m-OR4, -(alkylene)m-S(O)vR\ -(alkylene)m-NR5R5a, -(alkylene)m-C(=O)R4, -(alkylene)m-C(=S)R4, -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4, -(alkylene)m-C(=S)OR4, -(alkylene)m-C(=O)NR5R5a, -(alkylene)m-C(=S)NR5R5a, -(alkylene)m-N(R5)C(=O)NR5R5a, -(alkylene)m-N(Rs)C(=S)NR5RSa, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-N(R5)C(=S)R4,
-(alkylene)m-OC(=O)NR5R5a, -(alkyl ene)m-OC(=S)NR5R5a, -(a.kylene)m-SO2NR5R5a, -(alkylene)m-N(R5)SO2R4, -(alkylene)m-N(R5)SO2NR5R5a, -(alkylene)m-N(R5)C(=O)OR4, -(alkylene)m-N(R5)C(=S)OR4, or -(alkylene)m-N(R5)SO2R4; wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene)m-OR4, -(alkylene)m-S(O)vR4, -(alkylene)m-NR5R5a, -(alkylene)m-C(=O)R4,
296 -(alkylene)m-C(=S)R4, -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=0)R4, -(alkylene)m-C(=S)OR4, -(alkylene)m-C(=O)NR5R5a, -(alkylene)m-C(=S)NR5R5a, -(alkylene)m-N(R5)C(=O)NR5R5a, -(alkylene)m-N(R5)C(=S)NR5R5a, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-N(R5)C(=S)R4,
-(alkylene)m-OC(=O)NR5R5a, -(alkylene)m-OC(=S)NR5R5a, -(alkylene)m-SO2NR5R5a, -(alkylene)m-N(R5)SO2R4, -(alkylene)m-N(R5)SO2NR5R5a, -(alkylene)m-N(R5)C(=O)OR4, -(alkylene)m-N(R5)C(=S)OR4, or -(alkylene)m-N(R5)SO2R4; v is 0, 1 or 2.
22. A compound of claim 21 having formula IEAi, IEAii, IEAiii, IFAi, IFAii or IFAiii
Figure imgf000300_0001
enantiomers, diastereomers, salts and solvates thereof.
23. A compound of claim 22 wherein R2 is H, halo, cyano, alkynyl, -C(=O)NR5R5\ -N(R5)C(=O)R4, -N(R5)C(=O)OR4, phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, tetrahydropyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, indolinonyl, isoidolinyl, isoindolinonyl, dihydrobenzofυranyl,
298 dihydroisobenzofuranyl, benzofuranyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, quinoxalinyl, tetrahydroquinoxalinyl, benzomoφholinyl, dihydrobenzodioxinyl, imidazopyridinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl, thienopyrrolyl, tetrahydrothienopyrrolyl, dihydrothienopyrrolonyl, thienopyridinyl, thienopyrimidinyl, thienopyridazinyl, furopyridinyl, furopyrimidinyl, furopyrazidinyl, benzofuranyl, benzoimidazolyl, benzoisoxazolyl, benzothiazolyl, or benzoisothiazolyl any of which may be optionally independently substituted with one or more R10 groups as allowed by valance.
24. A compound of claim 23 wherein R2 is
(a) halo, alkynyl, -C(=O)NR5R5\ -N(R5)C(=O)R4 or -N(R5)C(=O)OR4 any of which may be optionally independently substituted with one or more R10 groups as allowed by valance; or
(b) an aryl, heteroaryl or heterocyclo ring system selected from
Figure imgf000301_0001
299
Figure imgf000302_0001
300
Figure imgf000303_0001
} where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
25. A compound of claim 24 wherein RIOc at each occurrence is independently H, halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene)m-OR4, -(alkylene)m-NR5R5a, -(alkylene)m-C(=O)R4, -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4, -(alkylene)m-C(=O)NR5R5\ -(alkylene)m-N(R5)C(=O)NR5R5a, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-OC(=O)NR5R5a, or -(alkylene)m-N(R5)C(=O)OR4.
26. A compound of claim 21 wherein n* is 0 or 1, and t* is 1;
27. A compound of claim 21 wherein n* is 1 and t* is 0.
28. A compound of claim 21 selected from
Figure imgf000304_0001
Figure imgf000305_0001
salts and solvates thereof.
29. A compound of formula IG or IH
Figure imgf000305_0002
wherein
U is CR10c or N;
Z* is absent, CH2, -O -, -S(O)V, or -, -NH
Ra, Rb, Rc and Rd are each independently H, halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, -NO2, -CN, -NR5R5a, -OR4, -C(=O)R4, -C(=O)OR4; -C(=O)NR5R5a, -N(R5)C(=O)NRsR5a, -OC(=O)NR5R5a, -S(O)vR4, -S(O)2NR5R58, -N(RS)SO2R4 any of which may be optionally independently substituted with one or more R10 groups as allowed by valance; or Ra and Rb together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R10 groups as allowed by valance.; or Rc and Rd together with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring,
303 any of which may be optionally substituted with one or more R10 groups as allowed by valance; or R" and/or Rb may combine with any Rc or Rd to form a partially or fully saturated 3-8 membered cycloalkyl ring or heterocyclo ring, either of which may be optionally substituted with one or more R10 groups as allowed by valance; or Ra and Rb may combine to form a carbonyl group; or Rc and Rd attached to the same carbon atom may combine to form a carbonyl group; R2 is
(i) H, halo, cyano, nitro, or
(ii) alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -OR4, -S(O)vR4, -C(=O)R4, -C(=S)R4, -C(O)OR4, -C(=S)OR4, -C(=O)NR5R5a, -C(=S)NR5R5a, -N(R5)C(=O)NR5R5a, -N(R5)C(=S)NR5R5a, -N(R5)C(=O)R4, -N(RS)C(=S)R4, -OC(=O)NR5R5a, -OC(=S)NR5R5a, -SO2NR5R5", -N(R5)SO2R4, -N(R5)SO2NR5R5a, -N(R5)C(=O)OR4, -N(R5)C(=S)OR4, -N(R5)SO2R4, any of which may be optionally independently substituted with one or more R10 as allowed by valance, provided that in compounds of formula IG R2 is not phenyl substituted with a group
Figure imgf000306_0001
where G1 and G2 are independently alkyl, cycloalkyl, or G1 and G2 together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring; R2a and R2b are independently selected from H, halo, alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino and alkoxy; R4 is independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally independently substituted as allowed by valance with one or more R10 groups; R5 and R5a are independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally substituted as allowed by valance with one or more R10;
304 or R5 and R5a may combine to form a heterocyclo ring optionally substituted with one or more R10;
R1 at each occurrence are independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)m-OR4, -(alkylene)m-S(O)vR4, -(alkylene)m-NR5R5a, -(alkylene)m-C(=O)R4 J -(alkylene)m-C(=S)R4, -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4, -(alkylene)m-C(=S)OR4, -(alkylene)m-C(=O)NR5R5a, -(alkylene)m-C(=S)NR5R5a, -(alkylene)m-N(R5)C(=O)NR5R5a, -(alkylene)m-N(R5)C(=S)NR5R5β, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-N(R5)C(=S)R4,
-(alkylene)m-OC(=O)NRsR5a, -(alkylene)m-OC(=S)NR5R5a, -(alkylene)m-SO2NR5R5a, -(alkylene)m-N(R5)SO2R\ -(alkylene)m-N(R5)SO2NR5R5a, -(alkylene)m-N(R5)C(=O)OR4, -(alkylene)m-N(R5)C(=S)OR4, or -(alkylene)m-N(R5)SO2R4; wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycioalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene)m-OR4, -(alkylene)m-S(O)vR4, -(alkylene)m-NR5R5a, -(alkylene)m-C(=O)R4, -(alkylene)m-C(=S)R4, -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4, -(alkylene)m-C(=S)OR4, -(alkylene)m-C(=O)NR5RSa, -(alkylene)m-C(=S)NR5R5a, -(alkylene)m-N(R5)C(=O)NR5R5a, -(alkylene)m-N(R5)C(=S)NR5R5a, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)m-N(R5)C(=S)R4,
-(alkylene)m-OC(=O)NR5R5a, -(alkylene)m-OC(=S)NR5R5a, -(alkylene)m-SO2NR5R5a, -(alkylene)m-N(R5)SO2R4, -(alkylene)m-N(R5)SO2NR5R5a, -(alkylene)m-N(Rs)C(=O)OR4, -(alkylene)m-N(R5)C(=S)OR4, or -(alkylene)m-N(R5)SO2R4;
RIOa, R1Ob and RIOc are each independently H, halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene)m-OR4, -(alkylene)m-NR5R5a, -(alkylene)m-C(=O)R4, -(alkylene)m-C(=O)OR4, -(alkylene)m-OC(=O)R4, -(alkylene)m-C(=O)NR5R5a, -(alkylene)m-N(R5)C(=O)NR5RSa, -(alkylene)m-N(R5)C(=O)R4, -(alkylene)rn-OC(=O)NR5R5a, or -(alkylene)m-N(Rs)C(=O)OR4; and v is O, 1 or 2.
30. A compound of claim 29 selected from
Figure imgf000308_0001
salts and solvates thereof.
306
31. A compound of claim 29 selected from
Figure imgf000309_0001
salts and solvates thereof.
32. A compound of claim 8 selected from
Figure imgf000309_0002
307
Figure imgf000310_0001
[salts and solvates thereof.
33. A pharmaceutical composition comprising a compound of claim 1 together with a pharmaceutically acceptable vehicle or carrier.
34. A method of treating cancer in a subject, said method comprising administering an effective amount of a compound as in claim 1.
35. The method of claim 34 wherein said compound of claim 1 is administered in combination with at least one compound selected from antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and miscellaneous agents.
36. A method of reducing tumor size in a subject, said method comprising administering an effective amount of a compound as in claim 1.
37. A method of treating HGF mediated disorders in a subject, said method comprising administering an effective amount of a compound as in claim 1.
38. A method of reducing metastasis in a tumor in a subject, said method comprising administering an effective amount of a compound as in claim 1.
308
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