WO2007095188A2 - Dihydrodiazepines useful as inhibitors of protein kinases - Google Patents

Dihydrodiazepines useful as inhibitors of protein kinases Download PDF

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Publication number
WO2007095188A2
WO2007095188A2 PCT/US2007/003699 US2007003699W WO2007095188A2 WO 2007095188 A2 WO2007095188 A2 WO 2007095188A2 US 2007003699 W US2007003699 W US 2007003699W WO 2007095188 A2 WO2007095188 A2 WO 2007095188A2
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Prior art keywords
compound
aliphatic
pyrimido
cyclopentyl
hplc
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PCT/US2007/003699
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French (fr)
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WO2007095188A3 (en
Inventor
Jean Damien-Charrier
David Kay
Ronald Knegtel
Heather Twin
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Vertex Pharmaceuticals Incorporated
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Priority to JP2008555299A priority Critical patent/JP5243970B2/en
Priority to AU2007215221A priority patent/AU2007215221C1/en
Application filed by Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated
Priority to DE602007008837T priority patent/DE602007008837D1/en
Priority to RU2008136854/04A priority patent/RU2475488C2/en
Priority to CA2652648A priority patent/CA2652648C/en
Priority to EP07750530A priority patent/EP1983987B1/en
Priority to NZ570530A priority patent/NZ570530A/en
Priority to AT07750530T priority patent/ATE479434T1/en
Priority to CN200780013031.9A priority patent/CN101420955B/en
Publication of WO2007095188A2 publication Critical patent/WO2007095188A2/en
Publication of WO2007095188A3 publication Critical patent/WO2007095188A3/en
Priority to IL193240A priority patent/IL193240A0/en
Priority to NO20083918A priority patent/NO20083918L/en
Priority to HK09106822.2A priority patent/HK1129298A1/en
Priority to US13/206,638 priority patent/US8394952B2/en
Priority to US13/745,968 priority patent/US20140038935A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the present invention relates to compounds useful as inhibitors of protein kinases.
  • the invention also relates to pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
  • the invention also relates to processes for preparing the compounds of the invention.
  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell (see Hardie, G and Hanks, S. The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA: 1995) . Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250- 300 amino acid catalytic domain.
  • the kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/ threonine, lipids etc) . Sequence motifs have been identified that generally correspond to each of these kinase families (See, for example, Hanks, S. K., Hunter, T., FASEB J. 1995, 9, 576-596; Knighton et al., Science 1991, 253, 407-414; Hiles et al , Cell 1992, 70, 419-429; Kunz et al , Cell 1993, 73, 585-596; Garcia-Bustos et al, EMBO J 1994, 13, 2352-2361) .
  • protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli .
  • Examples of such stimuli include environmental and chemical stress signals (e.g., shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H 2 O 2 ), cytokines (e.g., interleukin-1 (IL-I) and tumor necrosis factor alpha (TNF-a) , and growth factors (e.g., granulocyte macrophage-colony stimulating factor (GM-CSF), and fibroblast growth factor (FGF)) .
  • IL-I interleukin-1
  • TNF-a tumor necrosis factor alpha
  • growth factors e.g., granulocyte macrophage-colony stimulating factor (GM-CSF), and fibroblast growth factor (FGF)
  • An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthes ' is, survival and regulation of the cell cycle.
  • the Polo-like kinases belong to a family of serine / threonine kinases that are highly conserved across the species, ranging from yeast to man (reviewed in Lowery DM et al., Oncogene 2005, 24; 248-259 ).
  • the Plk kinases have multiple roles in. cell cycle, including control of entry into and progression through mitosis.
  • Plkl is the best characterized of the Plk family members. Plkl is widely expressed and is most abundant in tissues with a high mitotic index. Protein levels of Plkl rise and peak in mitosis (Hamanaka, R et al . , J Biol Chem 1995, 270, 21086-21091) . The reported substrates of Plkl are all molecules that are known to regulate entry and progression through mitosis, and include CDC25C, cyclin B, p53 , APC, BRCA2 and the proteasome. Plkl is upregulated in multiple cancer types and the expression levels correlate with severity of disease (Macmillan, JC et al . , Ann Surg Oncol 2001, 8, 729- 740) .
  • Plkl is an oncogene and can transform NIH-3T3 cells (Smith, MR et al . , Biochem Biophys Res Commun 1997, 234, 397- 405). Depletion or inhibition of Plkl by siRNA, antisense, microinjection of antibodies, or transfection of a dominant negative construct of Plkl into cells, reduces proliferation and viability of tumour cells in vitro (Guan, R et al . , Cancer Res 2005, 65, 2698-2704; Liu, X et al . , Proc Natl Acad Sci U S A 2003, 100, 5789-5794, Fan, Y et al .
  • Plk2 is mainly expressed during the Gl phase of the cell cycle and is localized to the centrosome in interphase cells.
  • Plk2 knockout mice develop normally, are fertile and have normal survival rates, but are around 20% smaller than wild type mice. Cells from knockout animals progress through the cell cycle more slowly than in normal mice (Ma, S et al . , MoI Cell Biol 2003, 23, 6936-6943) . Depletion of Plk2 by siRNA or transfection of kinase inactive mutants into cells blocks centriole duplication.
  • Plk3 Downregulation of Plk2 also sensitizes tumour cells to taxol and promotes mitotic catastrophe, in part by suppression of the p53 response (Burns TF et al., MoI Cell Biol 2003, 23, 5556-5571). [0009] Plk3 is expressed throughout the cell cycle and increases from Gl to mitosis . Expression is upregulated in highly proliferating ovarian tumours and breast cancer and is associated with a worse prognosis (Weichert, W et al . , Br J Cancer 2004, 90, 815-821; Weichert, W et al . , Virchows Arch 2005, 446, 442-450).
  • Plk3 In addition to regulation of mitosis, Plk3 is believed to be involved in Golgi fragmentation during the cell cycle and in the DNA-damage response. Inhibition of Plk3 by dominant negative expression is reported to promote p53-independent apoptosis after DNA damage and suppresses colony formation by tumour cells (Li, Z et al . , J Biol Chem 2005, 280, 16843-16850.
  • Plk4 is structurally more diverse from the other PIk family members . Depletion of this kinase causes apoptosis in cancer cells (Li, J et al . , Neoplasia 2005, 7, 312-323). Plk4 knockout mice arrest at E7.5 with a high fraction of cells in mitosis and partly segregated chromosomes (Hudson, JW et al . , Current Biology 2001, 11, 441-446) .
  • Molecules of the protein kinase family have been implicated in tumour cell growth, proliferation and survival. Accordingly, there is a great need to develop compounds useful as inhibitors of protein kinases.
  • the evidence implicating the PIk kinases as essential for cell division is strong. Blockade of the cell cycle is a clinically validated approach to inhibiting tumour cell proliferation and viability. It would therefore be desirable to develop compounds that are useful as inhibitors of the Plk family of protein kinases (e.g., Plkl, Plk2 , Plk3 and Plk4), that would inhibit proliferation and reduce viability of tumour cells, particularly as there is a strong medical need to develop new treatments for cancer, including treatments that would be administered orally.
  • Compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as inhibitors of protein kinases.
  • these compounds are useful as inhibitors of PLK protein kinases; in some embodiments, as inhibitors of PLKl protein kinases.
  • These compounds have the formula I, as defined herein, or a pharmaceutically acceptable salt thereof.
  • These compounds and pharmaceutically acceptable compositions thereof are useful for treating or preventing a variety of diseases, disorders or conditions, including, but not limited to, an autoimmune, inflammatory, proliferative, or hyperproliferative disease, a neurodegenerative disease, or an immunologically-mediated disease.
  • the compounds provided by this invention are also useful for the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors .
  • X 1 is a bond, O, NR 8 , S, SO, or SO 2 ;
  • Y 1 is O or NR 9 ;
  • R 1 is H, Ci-ioaliphatic, C 3 _ioc ⁇ cloaliphatic, C 6 -ioaryl, 5-10 membered heteroaryl , or 3-10 membered heterocyclyl ; wherein said R 1 is optionally substituted with 0-5 J 1 ; provided that when X 1 is a bond, R 1 is not H,- R 2 is H, Ci-ioaliphatic, - (Ci-i O aliphatic) - (Cs-iocycloaliphatic) ,
  • each R 3 , R 4 , R 5 , and R 6 is independently H, Ci-i O aliphatic,
  • R 3 -iocycloaliphatic C ⁇ -ioaryl, or 5-10 membered heteroaryl; wherein each R 3 , R 4 , R 5 , and R 6 is optionally and independently substituted with 0-5 J 3 , J 4 , J 5 , and J 6 respectively; and R 7 is H, C(O)R, C(O)OR, or C(O)NRR', Ci_i O aliphatic ,
  • R 7 is optionally substituted with 0-5 J 7 ; or R 3 and R 4 , together with the carbon atom to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from 0, N, and S; said monocyclic ring formed by R 3 and R 4 is optionally substituted with 0-4 J 34 ;
  • R 5 and R 6 together with the carbon atom to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R 5 and R 6 is optionally substituted with 0-4 J 56 ;
  • R 3 and R 5 together with the carbon atoms to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R 3 and R 5 is optionally substituted with 0-4 J 35 ;
  • R 3 and R 7 together with the atoms to which they are attached, optionally form a 4-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from 0, N, and S; said monocyclic ring formed by R 3 and R 7 is optionally substituted with 0-4 J 37 ;
  • R 5 and R 7 together with the atoms to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from 0, N, and S; said monocyclic ring formed by R 5 and R 7 is optionally substituted with 0-4 J 57 ;
  • R 8 is H, Ci- ⁇ aliphatic, C 3 - 8 cycloaliphatic , C(O)R, C(O)OR, or C (O)NRR' ;
  • R 9 is H or unsubstituted Ci- ⁇ aliphatic
  • V 1 is halo(Ci- 4 aliphatic), -O(haloCi- 4 aliphatic), halo, NO 2 , CN, OH, OR", SH, SR", NH 2 , NHR", N (R") 2 , COH, COR", CO 2 H, CO 2 R", CONH 2 , CONHR", CONR” 2 , OCOR", OCONH 2 , OCONHR", OCON(R") 2 , NHCOR", NR"COR", NHCO 2 R", NR"CO 2 R” , NHCO 2 H, NR"CO 2 H, NHCONH 2 , NHCONHR", NHCON (R") 2 , SO 2 NH 2 , SO 2 NHR” , SO 2 N (R” ) 2 , NHSO 2 R" , NR"SO 2 R” ; or V 1 is a cyclic group selected from
  • R' is unsubstituted Ci- ⁇ aliphatic,- or two R' groups, together with the atom to which they are bound, form an unsubstituted 3-8 membered saturated or partially unsaturated monocyclic ring having 0-1 heteroatoms independently selected from O, N, and S.
  • R 1 is H, Ci-ioaliphatic , C 3 -iocycloaliphatic, C ⁇ -ioaryl , 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; wherein said R 1 is optionally substituted with 0-5 J 1 ; provided that when X 1 is a bond, R 1 is not H,- and the other variables are as defined herein.
  • R 7 is H, C(O)R, C(O)OR, or C(O)NRR', Ci-ioaliphatic, C 3 -i 0 cycloaliphatic, C ⁇ -ioaryl , 5-10 membered heteroaryl, 3-10 membered heterocyclyl,
  • Q is H; C 1 . 6 aliphatic; a 3-8- membered aromatic or nonaromatic monocyclic ring having 0-3 heteroatoms independently selected from O, N, and S; or a 7-12 membered aromatic or nonaromatic bicyclic ring system having 0-5 heteroatoms independently selected from O, N, and S; each Q is optionally substituted with 0-5 J Q ; and the other variables are as defined herein.
  • each M is independently H, C ⁇ - 6 aliphatic, C 3 -6Cycloaliphatic, halo(Ci- 4 aliphatic), -0(haloCi- 4 aliphatic), 3-6 membered heterocycIyI , C ⁇ -ioaryl, halo, NO 2 , CN, OH, OR', SH, SR', NH 2 , NHR', N(R' ) 2 , COH, COR', CO 2 H, CO 2 R', CONH 2 , CONHR', CONR' 2 , OCOR', OCONH 2 , OCONHR', OCON(R' ) 2 , NHCOR', NR' COR', NHCO 2 R', NR' CO 2 R' , NHCO 2 H, NR' CO 2 H, NHCONH 2 , NHCONHR', NHCON(R') 2, SO 2 NH 2 , SO 2 NHR
  • a specified number range of atoms includes any integer therein.
  • a group having from 1-4 atoms could have 1, 2, 3, or 4 atoms.
  • compounds of the invention may optionally be substituted with one or more substituents , such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted. " In general, the term "substituted”, whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent .
  • an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 0 C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • aliphatic or "aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1- 20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups.
  • Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl , sec-butyl, vinyl, n-butenyl, ethynyl , and tert-butyl .
  • cycloaliphatic refers to a monocyclic C3-C8 hydrocarbon or bicyclic C8-C12 hydrocarbon or bicyclic C7-C12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members.
  • Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups. Specific examples include, but are not limited to, cyclohexyl, cyclopropenyl , and cyclobutyl .
  • heterocycle means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members are an independently selected heteroatom.
  • the "heterocycle”, “heterocyclyl”, or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.
  • Suitable heterocycles include, but are not limited to, 3-lH-benzimidazol-2-one, 3- (1-alkyl ) -benzimidazol-2-one, 2- tetrahydrofuranyl, 3-tetrahydrofuranyl , 2- tetrahydrothiophenyl , 3-tetrahydrothiophenyl , 2-morpholino, 3- morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl , 3- pyrrolidinyl , 1-tetrahydropiperazinyl , 2- tetrahydropiperazinyl, 3-tetrahydropiperazinyl , 1-piperidinyl , 2-piperidinyl , 3-piperidinyl , 1-pyrazolinyl , 3-pyrazolinyl , 4- pyrazolinyl, 5-pyra
  • Cyclic groups can be linearly fused, bridged, or spirocyclic.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon,- the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4- dihydro-2 ⁇ -pyrrolyl) , NH (as in pyrrolidinyl) or NR + (as in N- substituted pyrrolidinyl) ) .
  • nonaromatic as used herein, describes rings that are either saturated or partially unsaturated.
  • alkoxy or “thioalkyl”, as used herein, refers to an alkyl group, as previously defined, attached through an oxygen (“alkoxy") or sulfur (“thioalkyl") atom.
  • haloalkyl means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyaIky1” , refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring”.
  • heteroaryl used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy” , refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members . In some embodiments, there are 1-4 heteroatoms in a ring system.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic” .
  • Suitable heteroaryl rings include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl , 2-imidazolyl, 4-imidazolyl, 5- imidazolyl, benzimidazolyl , 3-isoxazolyl , 4-isoxazolyl , 5- isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidinyl, 4-pyrimidinyl , 5-pyrimidinyl , pyridazinyl (e.g., 3-pyridazinyl) , 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl) , triazolyl (e.g., 2-triazo
  • a protecting group and "protective group” as used herein, are interchangeable and refer to an agent used to temporarily block one or more desired functional groups in a compound with multiple reactive sites.
  • a protecting group has one or more, or preferably all, of the following characteristics: a) is added selectively to a functional group in good yield to give a protected substrate that is b) stable to reactions occurring at one or more of the other reactive sites; and c) is selectively removable in good yield by reagents that do not attack the regenerated, deprotected functional group. As would be understood by one skilled in the art, in some cases, the reagents do not attack other reactive groups in the compound.
  • the reagents may also react with other reactive groups in the compound.
  • Exemplary protecting groups are detailed in Greene, T. W. , Wuts , P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999 (and other editions of the book), the entire contents of which are hereby incorporated by reference.
  • the term "nitrogen protecting group”, as used herein, refers to an agents used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen protecting groups also possess the characteristics exemplified above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T. W., Wuts, P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
  • an alkyl or aliphatic chain can be optionally replaced with another atom or group.
  • a methylene unit of the alkyl or the aliphatic chain is optionally replaced with said other atom or group.
  • the optional replacements form a chemically stable compound.
  • Optional replacements can occur both within the chain and at either end of the chain,- i.e., both at the point of attachment and/or also at the terminal end.
  • Two optional replacements can also be adjacent to each other within a chain so long as it results in a chemically stable compound.
  • the optional replacements can also completely replace all of the carbon atoms in a chain.
  • a C 3 aliphatic can be optionally replaced by -NR-, -C(O)-, and -NR- to form -NRC(O)NR- (a urea).
  • the replacement atom is bound to an H on the terminal end.
  • the replacement atom could be -OCH 2 CH 3 , -CH 2 OCH 3 , or -CH 2 CH 2 OH.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, geometric, conformational, and rotational forms of the structure) .
  • isomeric e.g., enantiomeric, diastereomeric, geometric, conformational, and rotational forms of the structure
  • R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this invention.
  • a substituent can freely rotate around any other substituent.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C- enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • the compounds of this invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable salt.
  • the term "pharmaceutically acceptable salt” refers to salts of a compound which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et a.1. , describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1971, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds. Acid addition salts can be prepared by 1) reacting the purified compound in its free- based form with a suitable organic or inorganic acid and 2) isolating the salt thus formed.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci_ 4 alkyl) 4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil- soluble or dispersible products may be obtained by such quaternization.
  • Base addition salts can be prepared by 1) reacting the purified compound in its acid form with a suitable organic or inorganic base and 2) isolating the salt thus formed.
  • Base addition salts include alkali or alkaline earth metal salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • Other acids and bases while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid or base addition salts.
  • the following abbreviations are used: LG leaving group
  • X 1 is O, NR 8 , or S. In some embodiments, X 1 is NR 8 . In other aspects, Y 1 is 0. [0051] In another aspect of this invention, R 1 is optionally- substituted C ⁇ -ioaryl or optionally substituted 5-10 membered heteroaryl .
  • R 1 is optionally substituted C 6 -i 0 aryl , such as phenyl .
  • R 1 is optionally substituted with J 1 , wherein J 1 is -H, -O-Ci_ 6 alkyl , halo, or -C(O)N(R)(Q), wherein the R is -H.
  • R 1 is optionally substituted with J 1 , wherein J 1 is -H, -OCH 3 , halo, or -C(O)N(R) (Q), wherein the R is -H.
  • J 1 is -OCH 3 or -C(O)N(R)ZQ, wherein Z is Ci- ⁇ aliphatic and Q is a 3-8-membered aromatic or nonaromatic monocyclic ring having 1-3 heteroatoms independently selected from 0, N, and S; or an 8-12 membered aromatic or nonaromatic bicyclic ring system having 1-5 heteroatoms independently selected from O, N, and S; and Q is optionally substituted with 0-5 J Q .
  • Z is Ci_ 6 alkyl and in more specific embodiments, Z is -CH 2 -.
  • J 1 is -OCH 3 or -C(O)N(R)ZQ, wherein Z is Ci_ 6 aliphatic and Q is a 5-6-membered aromatic having 1 heteroatom selected from 0 and N (e.g., pyridine) ; wherein Q is optionally substituted with 0-5 J Q .
  • Z is Ci- 6 alkyl and in more specific embodiments, Z is -CH 2 -.
  • Z is and in more specific embodiments, Z is -CH 2 -.
  • J 1 is -OCH 3 or -C(O)N(R)(Q), wherein the R is -H and the Q is Ci_ 6 alkyl, 3-6-membered cycloalkyl, a 7-12 nonaromatic bicyclic ring system, or a 8-12 nonaromatic bicyclic ring system, wherein each Q is substituted with 0-5 J Q .
  • J 1 is -OCH 3 or -C(O)N(R)(Q), wherein the R is -H and the Q is 3-6-membered cycloalkyl, wherein each Q is substituted with 0-5 J Q .
  • J 1 is -OCH 3 or -C(O)N(R) (Q), wherein the R is -H and the Q is cyclohexyl, wherein each Q is substituted with 0-5 J Q .
  • J 1 is -OCH 3 or -C(O)N(R)(Q), wherein the R is -H and the Q is C 6 _ 10 aryl or 5-10 membered heteroaryl having 0-5 heteroatoms independently selected from O, N, and S; wherein each Q is substituted with 0-5 J Q .
  • J 1 is -OCH 3 or -C(O)N(R) (Q), wherein the R is -H and the Q is a 3-8-membered heterocyclic ring having 1 or 2 heteroatoms independently selected from O, N, and S; wherein each Q is substituted with 0-5 J Q .
  • J 1 is Q and Q is:
  • Q is substituted with 0, 1, or 2 J Q .
  • each J Q is independently F, -OH, - OR' , or -OC(O)R' .
  • each R' is independently Ci- ⁇ aliphatic, wherein the aliphatic is straight-chained.
  • each R' is independently Ci- ⁇ alkyl, wherein the alkyl is straight-chained.
  • R' is CH 3 .
  • R 2 is optionally substituted Ci-ioaliphatic or optionally substituted C 3 _i 0 cycloaliphatic .
  • R 3 and R 4 together with the carbon atom to which they are attached, form an optionally substituted 3-6 membered monocyclic ring.
  • R 3 and R 5 together with the carbon atoms to which they are attached, form an optionally substituted 3-6 membered monocyclic ring.
  • R 3 , R 4 , R 5 , and R 6 is independently an optionally substituted group selected from H, Ci- 10 aliphatic, C 3 _iocycloaliphatic, C 6 -ioaryl, or 5-10 membered heteroaryl .
  • each R 3 and R 4 is independently H, Ci- 6 aliphatic, or C 3 - 8 cycloaliphatic.
  • one of R 3 and R 4 is H and the other is Ci- ⁇ aliphatic or C 3 _8Cycloaliphatic .
  • each R 3 and R 4 is independently H or Ci_ 3 alkyl or R 3 and R 4 , together with the carbon atoms to which they are attached, form an optionally substituted 3-4 membered monocyclic ring.
  • one of R 3 and R 4 is H and the other is ethyl or (S) -methyl.
  • one of R 3 and R 4 is H and the other is (R) -methyl .
  • each R 3 and R 4 is methyl. [0077] In one embodiment, R 3 and R 4 , together with the carbon atoms to which they are attached, form an unsubstituted 3-4 membered monocyclic ring.
  • R 3 and R 4 together with the carbon atoms to which they are attached, form an unsubstituted 3 membered monocyclic ring.
  • R 5 is H.
  • R 6 is H.
  • J 3 and J 4 is independently halo.
  • R 5 and R 7 together with the atoms to which they are attached, form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring.
  • R 7 is an optionally substituted group selected from Ci-ioaliphatic, C 3 -i 0 cycloaliphatic, C 6 -ioaryl , 5-10 membered heteroaryl, and 3-10 membered heterocyclyl .
  • R 7 is an optionally substituted group selected from Ci-ioaliphatic, C 3 - ⁇ cycloaliphatic , phenyl, a 5-membered heteroaryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 , 5-pyridazinyl , 3 , 5-pyrimidyl , and a 3-8 membered heterocyclyl .
  • R 7 is not
  • R 8 is H.
  • One aspect of this invention provides a compound of formula II :
  • R 1 is optionally substituted C ⁇ -ioaryl or optionally substituted 5-10 membered heteroaryl ;
  • R 2 is H or an optionally substituted group selected from
  • each R 3 , R 4 , R 5 , and R 6 is independently H, Cx-xoaliphatic, or C 3 -i 0 cycloaliphatic ; wherein each R 3 , R 4 , R 5 , and R 6 is optionally substituted with 0-5 J 3 , J 4 , J 5 , and J 6 respectively; or R 3 and R 4 , together with the carbon atom to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R 3 and R 5 , together with the carbon atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R 5 and R 7 , together with the atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated . monocyclic ring; R 2 and R 9 , together with the
  • Another aspect of this invention provides a compound of formula III:
  • R 1 is optionally substituted C 6 -ioaryl or optionally substituted 5-10 membered heteroaryl;
  • R 2 is H or an optionally substituted group selected from
  • each R 3 , R 4 , R 5 , and R 6 is independently H, Ci-ioaliphatic, or C 3 -i 0 cycloaliphatic; wherein each R 3 , R 4 , R 5 , and R 6 is optionally substituted with 0-5 J 3 , J 4 , J 5 , and J 6 respectively; or R 3 and R 4 , together with the carbon atom to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R 3 and R 5 , together with the carbon atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R 5 and R 7 , together with the atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R 2 and R 9 , together with the atoms to which they are
  • each J 3 , J 4 , J 5 , and J 6 is independently Ci-e aliphatic, C 3 - 6 cycloaliphatic, or - wherein n is 0 or 1;
  • V 1 is halo(Ci_ 4 aliphatic), -0(haloCi- 4 aliphatic), halo, NO 2 , CN, OH, OR", SH, SR", NH 2 , NHR", N (R") 2, COH, COR", CO 2 H, CO 2 R", CONH 2 , CONHR", CONR” 2 , OCOR", OCONH 2 , OCONHR", OCON(R") 2 , NHCOR", NR"COR", NHCO 2 R", NR"CO 2 R” , NHCO 2 H, NR"CO 2 H, NHCONH 2 , NHCONHR", NHCON (R” ) 2 , SO 2 NH 2 , SO 2 NHR", SO 2 N(R") 2 , NHSO 2 R", NR"SO 2 R”; R" is unsubstituted C 1 - 4 aliphatic; or two of the same J 3 , J 4 , J 5 , or J 6 , bonded to
  • the variables are as depicted in the species disclosed herein.
  • the compounds of this invention are represented in Table 1.
  • Starting material I ⁇ (wherein LGi and LG2 can be, but not restricted to, chlorine atoms) reacts with ⁇ -aminoester 1"_ to give adduct 3 ⁇ Reduction of the nitro group, followed by cyclo-condensation gives bicyclic compound 4.
  • the amide N-H can be functionalized at this stage to give 5 ⁇ .
  • LG 2 can finally be used as a handle for preparation of the compounds of formula I.
  • LG 2 can, for example, be displaced with amines or be engaged in palladium assisted coupling reactions known to one skilled in the art (e.g., Suzuki, Stille) .
  • the compound of formula 3 ⁇ after reduction of the nitro group can be first functionalized to form a compound of formula 3-b;
  • R 0 LG 2 5
  • R 0 LG 2 5-a
  • R 0 R 1 X 1 I
  • R 0 R 1 X 1 I-a
  • Scheme 2 above shows a general synthetic route for preparing compounds of this invention where Y x is NR 9 .
  • the lactam functional group in 5 ⁇ or I can be engaged into a functional group transformation to form an amidine group (either 5-a where LG 2 is still present or I-a if it has already been derivatised as R 1 X 1 ) .
  • lactam functional group in 5_ or I can be engaged in a multi-step cyclisation sequence to form ring A ( ei ther 5-b where LG 2 is still present or I-b i f it has already been derivatised as R 1 X 1 ) .
  • Scheme 3 above shows a general synthetic route for preparing compounds of this invention where Y 1 is NR 9 and R 2 and R 9 are taken together to form a triazole ring. Activation of the lactam functional group in 4 ⁇ followed by displacement with hydrazine lead to intermediates of- formula 1_. Compoun'ds of formula I-b were finally obtain by cyclisation of derivatives 1_ and subsequent displacement with HX 1 -Ri.
  • Scheme 4 above shows another general synthetic route for preparing compounds ⁇ > of this invention.
  • Compounds of formula 5a containing a protecting group on the amine, can be prepared like previously shown (see compound j> scheme 1) .
  • Deprotection of amines 5a, followed by substitution of the free amines of 9 ⁇ with the desired R 7 -halides can be achieved by methods well known in the art.
  • this invention also provides a process for preparing a compound of this invention.
  • One embodiment of this invention provides a process for preparing a compound of formula I:
  • Y 1 is O and X 1 , R 1 , R 2 , R 3 , R 4 R 5 , R 6 , and R 7 are as defined herein; comprising reacting a compound of formula 5;
  • R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined herein; and LG2 is a suitable leaving group, such as halo, with XlRl under suitable conditions to form the compound of formula I.
  • XlRl can displace LG 2 in a variety of ways known to one skilled in the art. For example, if X 1 is NHR 8 , O, or S, then X 1 R 1 can displace LG 2 in the presence of suitable base or acid, solvent, and conditions. Suitable displacement reactions are known to one skilled in the art and can be found in a variety of resources, including "March's Advanced Organic Chemistry".
  • a sulfur linker (wherein X 1 is S) can be oxidized under suitable oxidation conditions to form compounds wherein X 1 is SO or SO2.
  • Compounds of formula I, wherein X 1 is a bond and R 1 is bonded to X 1 via a carbon atom, can be formed under suitable cross- coupling conditions.
  • one of the starting materials is R 1 bonded to a cross-coupling group. This starting material can react with the compound of formula 5 ⁇ under cross coupling conditions to form compounds of formula I, wherein X 1 is a bond and R 1 is bonded to X 1 via a carbon atom.
  • cross-coupling reaction refers to a reaction in which a carbon-carbon bond is formed with the aid of a metal catalyst. Usually, one of the carbon atoms is bonded to a functional group (a "cross- coupling group") while the other carbon atom is bonded to a halogen. Examples of cross coupling reactions include, but are not limited to, Suzuki couplings, Stille couplings, and Negishi couplings.
  • cross-coupling group refers to a functional group capable of- reacting with another functional group (e.g., halo) in a cross coupling reaction to form a carbon-carbon (“C-C") bond.
  • C-C carbon-carbon
  • cross coupling condition refers to the chemical conditions (e.g., temperature, length of time of reaction, volume of solvent required) required in order to enable the cross coupling reaction to occur .
  • cross-coupling groups and their respective cross-coupling conditions include, but are not limited to, boronic acids and boronic esters with Suzuki coupling conditions, SnBu 3 with Stille coupling conditions, and ZnX with Negishi coupling conditions.
  • All three of these coupling conditions typically involve the use of a catalyst, a suitable solvent, and optionally a base.
  • Suzuki coupling conditions involve the use of a palladium catalyst and a suitable solvent.
  • suitable palladium catalysts include, but are not limited to,
  • PdCl 2 (PPh 3 J 2 , Pd(Ph 3 J 4 , and PdCl 2 (dppf).
  • Suitable bases include, but are not limited to, K 2 CO 3 and Na 2 CO 3 .
  • Suitable solvents include, but are not limited to, tetrahydrofuran, toluene, and ethanol .
  • Stille coupling conditions involve the use of a catalyst (usually palladium, but sometimes nickel), a suitable solvent, and other optional reagents.
  • a catalyst usually palladium, but sometimes nickel
  • suitable solvent usually a solvent
  • other optional reagents include, but are not limited to, PdCl 2 (PPh 3 ) 2 ,
  • Suitable solvents include, but are not limited to, tetrahydrofuran, toluene, and dimethylformamide .
  • Negishi coupling conditions involve the use of a catalyst (palladium or nickel) and a suitable solvent.
  • Suitable catalysts include, but are not limited to
  • Suitable solvents include, but are not limited to, tetrahydrofuran, toluene, and dimethylformamide .
  • cross coupling groups are formed from coupling groups precursors.
  • a "coupling group precursor is a reagent or group of reagents used to form a cross-coupling group.
  • Examples include, but are not limited to, bis (pinacolato) diborane for the formation of boronate esters, trimethylborates for the formation of boronic acids, Bu 3 SnCl for the formation of stannanes, and ZnCl 2 for the formation zincates in Negishi coupling reactions.
  • suitable coupling group formation conditions include, but are not limited to, making boronic esters via palladium-mediated catalysis; making boronic acids by hydrolyzing boronic esters; making stannaries via a two step process: 1) halogen metal exchange followed by 2) transmetallation with Bu3SnCl; and making zincates via a two step process: 1) halogen metal exchange followed by 2) addition of ZnCl 2 .
  • Another embodiment provides a process for forming a compound of formula 5 comprising reacting a compound of formula 4 ;
  • R 3 , R 4 , R 5 , R 6 , and R 7 are as defined herein; and LG 2 is a suitable leaving group, such as halo; with R 2 -LG 3 , wherein LG3 is a leaving group capable of being displaced by an NH-amide.
  • leaving groups include, but are not limited to, halo, tosylate, and mesylate.
  • the first step involves reduction of the nitro group under suitable reduction conditions, such as iron powder, SnCl2, zinc powder, indium/HCl, or H 2 ZPd to form a compound of formula 3-a:
  • the second step involves cyclocondensation of the amine with the carboxyl ic es ter of formula 3 -a , resul ting in the compound of formula £. Cyclocondensations typically occur in the presence of an acid or a base. In some embodiments, this two- step process occurs in situ.
  • One example of an in situ condition involves treating the nitro-compound with iron powder in glacial acetic acid.
  • Another aspect of this invention provides an alternative way of forming the compounds of formula Ek Instead of directly cyclizing the compound of formula 3-a to form the compound of formula 4 ⁇ the amino intermediate can be functionalized first to form the compound of formula 3-b
  • the amino group can react with R 2 -LG 3 , wherein LG 3 is a leaving group capable of being displaced by an amine.
  • leaving groups include, but are not limited to, halo, tosylate, and mesylate.
  • This compound can then be cyclized under suitable cyclocondensation conditions to form the compound of formula 5.
  • Another embodiment of this invention provides a process for forming the compound of formula 3_; comprising reacting the compound of formula 2 ⁇ ;
  • Suitable displacement conditions typically comprise of a suitable solvent and a suitable base or acid.
  • suitable displacement conditions include, but are not limited to, K 2 CO3 and acetone, Hunig' s base/THF.
  • Another aspect of this invention provides a process for making compounds of formula I wherein Y 1 is NR 9 .
  • One embodiment involves reacting the compound of formula I wherein Y 1 is O and X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined herein; under suitable conditions known in the art for converting amides into amidines , to form a compound of formula I wherein Y 1 is NR 9 (shown in Scheme II as l-a) .
  • suitable conditions typically involve an amine (R ⁇ NHR 9 ) , a suitable solvent, and an activated intermediate deriving from an amide (e.g., a thioamide prepared from an amide and Lawesson's Reagent) .
  • the compound of formula 5_ can be subject to similar amide-converting conditions to form a compound of formula 5-a.
  • the LG 2 group in 5-a or 5-b can be used as a handle for preparation of the compounds of this invention.
  • LG2 can, for example, be displaced with amines or be engaged in palladium assisted coupling reactions (e.g., Suzuki, Stille) .
  • the compounds of formula I or 5 ⁇ can be converted into cyclic amidines, wherein R 2 and R 9 are taken together to form ring A.
  • cyclic amidines shown in Scheme II as I-b
  • Ring A can vary in size (e.g. 5-8 membered ring) and in degree of unsaturation .
  • formation of ring A can be carried out using methods similar to the ones reported in: J. Am. Chem.
  • LG 2 group in 5-a or 5-b can be used as a handle for preparation of the compounds of this invention.
  • LG 2 can, for example, be displaced with amines or be engaged in palladium assisted coupling reactions (e.g., Suzuki, Stille) .
  • compositions that are inhibitors of protein kinases, and thus are useful for the treatment of the diseases, disorders, and conditions, along with other uses described herein.
  • pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents .
  • the present invention provides compounds and compositions that are useful as inhibitors of protein kinases.
  • the protein kinases are PLK.
  • PLKl are PLK.
  • the compounds and compositions of this invention are particularly useful for treating or lessening the severity of a disease, condition, or disorder where a protein kinase is implicated in the disease, condition, or disorder.
  • the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where a protein kinase is implicated in the disease state.
  • the present invention provides a method for treating or lessening the severity of a kinase disease, condition, or disorder where inhibition of enzymatic activity is implicated in the treatment of the disease.
  • this invention provides a method for treating or lessening the severity of a disease, condition, or disorder with compounds that inhibit enzymatic activity by binding to the protein kinase.
  • Another aspect provides a method for treating or lessening the severity of a kinase disease, condition, or disorder by inhibiting enzymatic activity of the kinase with a protein kinase inhibitor.
  • said protein kinase inhibitor is a PLK inhibitor.
  • One aspect of the invention relates to a method of inhibiting protein kinase activity in a patient, which method comprises administering to the patient a compound of formula I, or a composition comprising said compound.
  • said method is used to treat or prevent a condition selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immunologically-mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone related diseases, allergies, asthma, and Alzheimer's disease.
  • said protein kinase in PLK is selected from a proliferative disorder and a neurodegenerative disorder.
  • additional drugs which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention.
  • chemotherapeutic agents or other anti-proliferative agents may be combined with the protein kinase inhibitors of this invention to treat proliferative diseases.
  • those additional agents may be administered separately, as part of a multiple dosage regimen, from the protein kinase inhibitor-containing compound or composition.
  • those agents may be part of a single dosage form, mixed together with the protein kinase inhibitor in a single composition.
  • the compounds and compositions of this invention are also useful in biological samples.
  • One aspect of the invention relates to inhibiting protein kinase activity in a biological sample, which method comprises contacting said biological sample with a compound of formula I or a composition comprising said compound.
  • biological sample means an in vitro or an ex vivo sample, including, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Inhibition of protein kinase activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ- transplantation, and biological specimen storage. [00125] Another aspect of this invention relates to the study of protein kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such protein kinases; and the comparative evaluation of new protein kinase inhibitors. Examples of such uses include, but are not limited to, biological assays such as enzyme assays and cell-based assays .
  • the activity of the compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of either the kinase activity or ATPase activity of the activated kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and may be measured either by radiolabelling the inhibitor prior to binding, isolating the inhibitor/kinase complex and determining the amount of radiolabel bound, or by running a competition experiment where new inhibitors are incubated with the kinase bound to known radioligands.
  • Detailed conditions for assaying a compound utilized in this invention as an inhibitor of PLKl, PLK2 , PLK3 , and PLK4 are set forth in the Examples below.
  • One aspect of this invention provides compounds that are useful for the treatment of diseases, disorders, and conditions characterized by excessive or abonormal cell proliferation.
  • diseases include, a proliferative or hyperproliferative disease, and a neurodegenerative disease.
  • proliferative and hyperproliferative diseases include, without limitation, cancer.
  • cancer includes, but is not limited to, the following cancers: breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus; larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone; colon; colorectal; adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine; colon-rectum, large intestine,
  • cancer includes, but is not limited to, the following cancers: myeloma, lymphoma, or a cancer selected from gastric, renal, or and the following cancers: head and neck, oropharangeal , non-small cell lung cancer (NSCLC), endometrial, hepatocarcinoma, Non-Hodgkins lymphoma, and pulmonary.
  • NSCLC non-small cell lung cancer
  • cancer also includes, but is not limited to, the following cancers: epidermoid Oral : buccal cavity, lip, tongue, mouth, pharynx; Cardiac : sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma) , myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal : esophagus (squamous cell carcinoma, larynx, adenocar
  • the compounds of this invention are useful for treating cancer, such as colorectal, thyroid, breast, and lung cancer; and myeloproliferative disorders, such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mast cell disease.
  • cancer such as colorectal, thyroid, breast, and lung cancer
  • myeloproliferative disorders such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mast cell disease.
  • the compounds of this invention are useful for treating hematopoietic disorders, in particular, acute-myelogenous leukemia (AMLi) , chronic- myelogenous leukemia (CML) , acute-prornyelocytic leukemia
  • AMLi acute-myelogenous leukemia
  • CML chronic- myelogenous leukemia
  • APL acute lymphocytic leukemia
  • ALL acute lymphocytic leukemia
  • neurodegenerative diseases include, without limitation, Alzheimer's disease.
  • Another aspect of this invention provides a method for the treatment or lessening the severity of a disease selected from a proliferative or hyperproliterative disease, or a neurodegenerative disease, comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound, to a subject in need thereof .
  • an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective in order to treat said disease.
  • the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of said disease.
  • said disease is a protein-kinase mediated condition. In some embodiments, said disease is a PLK-mediated disease.
  • protein kinase-mediated condition means any disease or other deleterious condition in which a protein kinase plays a role.
  • Such conditions include, without limitation, autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immunologically-mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone related diseases, allergies, asthma, and Alzheimer's disease.
  • PLK-mediated condition means any disease or other deleterious condition in which PLK plays a role. Such conditions include, without limitation, a proliferative or hyperproliterative disease, or a neurodegenerative disease.
  • compositions comprising any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • compositions optionally further comprise one or more additional therapeutic agents .
  • chemotherapeutic agents or other antiproliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer.
  • chemotherapeutic agents include, but are not limited to, GleevecTM, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil , topotecan, taxol , interferons, and platinum derivatives.
  • agents the inhibitors of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as Aricept 18 and Excelon ® ; treatments for Parkinson's Disease such as L- DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl , and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex ® and Rebif ® ) , Copaxone ® , and mitoxantrone; treatments for asthma such as albuterol and Singulair ® ; agents for treating schizophrenia such as zyprexa, risperdal, seroquel , and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-I RA, azathioprine, cyclophosphamide, and sulfasalazin
  • the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, ' Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable
  • any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component (s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
  • Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates , waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; ge
  • the protein kinase inhibitors or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to animals or humans .
  • These pharmaceutical compositions which comprise an amount of the protein inhibitor effective to treat or prevent a protein kinase- mediated condition and a pharmaceutically acceptable carrier, are another embodiment of the present invention.
  • said protein kinase-mediated condition is a PLK- mediated condition.
  • the exact amount of compound required for treatment will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • compounds of this invention are administered orally.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adj
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol .
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U. S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides .
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle.
  • injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide . Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides) . Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues .
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound .
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia/ c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
  • the dosage form may also comprise buffering agents .
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using, such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in microencapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents . They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s ) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes .
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions , ⁇ sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel .
  • compositions to treat or prevent the above-identified disorders .
  • the compounds of this invention can also exist as pharmaceutically acceptable derivatives .
  • a "pharmaceutically acceptable derivative” is an adduct or derivative which, upon administration to a patient in need, is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters.
  • a "pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof .
  • Particularly favoured derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species .
  • compositions of this invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.
  • Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates , waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorb
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial , intrasternal , intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously .
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, for example as a solution in 1 , 3-butanediol .
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides .
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens , Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions .
  • carriers commonly used include, but are not limited to, lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • the pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers .
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol , benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of inhibitor will also depend upon the particular compound in the composition.
  • the invention provides methods for treating or preventing a protein kinase- mediated condition (in some embodiments, a PLK-mediated condition) comprising the step of administering to a patient one of the above-described pharmaceutical compositions.
  • a protein kinase- mediated condition in some embodiments, a PLK-mediated condition
  • patient means an animal, preferably a human.
  • said method is used to treat or prevent a condition selected from a proliferative disorder, such as cancer, a neurodegenerative disorder, an autoimmune disorder, an inflammatory disorder, and an immunologicalIy- mediated disorder.
  • a proliferative disorder such as cancer, a neurodegenerative disorder, an autoimmune disorder, an inflammatory disorder, and an immunologicalIy- mediated disorder.
  • said method is used to treat or prevent a condition selected from cancers such as cancers of the breast, colon, prostate, skin, pancreas, brain, genitourinary tract, lymphatic system, stomach, larynx and lung, including lung adenocarcinoma and small cell lung cancer; stroke, diabetes, myeloma, hepatomegaly, cardiomegaly, Alzheimer's disease, cystic fibrosis, and viral disease, or any specific disease described above.
  • the compounds of this invention may be prepared in general by methods known to those skilled in the art. Those compounds may be analyzed by known methods, including but not limited to LCMS (liquid chromatography mass spectrometry) and NMR (nuclear magnetic resonance) . Compounds of this invention may be also tested according to these examples. It should be understood that the specific conditions shown below are only examples, and are not meant to limit the scope of the conditions that can be used for making, analyzing, or testing the compounds of this invention. Instead, this invention also includes conditions known to those skilled in that art for making, analyzing, and testing the compounds of this invention .
  • Rt (min) refers to the HPLC retention time, in minutes, associated with the compound. Unless otherwise indicated, the HPLC method utilized to obtain the reported retention time is as follows: Column: ACE C8 column, 4.6 x 150 mm
  • Mass spec, samples were analyzed on a MicroMass Quattro Micro mass spectrometer operated in single MS mode with electrospray ionization. Samples were introduced into the mass spectrometer using chromatography.

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Abstract

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

Description

DIHYDRODIAZEPINES USEFUL AS INHIBITORS OF PROTEIN KINASES
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to compounds useful as inhibitors of protein kinases. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders. The invention also relates to processes for preparing the compounds of the invention.
BACKGROUND OF THE INVENTION
[0002] The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of intensive study is protein kinases. [0003] Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell (see Hardie, G and Hanks, S. The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA: 1995) . Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250- 300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/ threonine, lipids etc) . Sequence motifs have been identified that generally correspond to each of these kinase families (See, for example, Hanks, S. K., Hunter, T., FASEB J. 1995, 9, 576-596; Knighton et al., Science 1991, 253, 407-414; Hiles et al , Cell 1992, 70, 419-429; Kunz et al , Cell 1993, 73, 585-596; Garcia-Bustos et al, EMBO J 1994, 13, 2352-2361) .
[0004] In general, protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli . Examples of such stimuli include environmental and chemical stress signals (e.g., shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (e.g., interleukin-1 (IL-I) and tumor necrosis factor alpha (TNF-a) , and growth factors (e.g., granulocyte macrophage-colony stimulating factor (GM-CSF), and fibroblast growth factor (FGF)) . An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthes'is, survival and regulation of the cell cycle.
[0005] Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events as described above. These diseases include, but are not limited to, cancer, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents .
[0006] The Polo-like kinases (Plk) belong to a family of serine / threonine kinases that are highly conserved across the species, ranging from yeast to man (reviewed in Lowery DM et al., Oncogene 2005, 24; 248-259 ). The Plk kinases have multiple roles in. cell cycle, including control of entry into and progression through mitosis.
[0007] Plkl is the best characterized of the Plk family members. Plkl is widely expressed and is most abundant in tissues with a high mitotic index. Protein levels of Plkl rise and peak in mitosis (Hamanaka, R et al . , J Biol Chem 1995, 270, 21086-21091) . The reported substrates of Plkl are all molecules that are known to regulate entry and progression through mitosis, and include CDC25C, cyclin B, p53 , APC, BRCA2 and the proteasome. Plkl is upregulated in multiple cancer types and the expression levels correlate with severity of disease (Macmillan, JC et al . , Ann Surg Oncol 2001, 8, 729- 740) . Plkl is an oncogene and can transform NIH-3T3 cells (Smith, MR et al . , Biochem Biophys Res Commun 1997, 234, 397- 405). Depletion or inhibition of Plkl by siRNA, antisense, microinjection of antibodies, or transfection of a dominant negative construct of Plkl into cells, reduces proliferation and viability of tumour cells in vitro (Guan, R et al . , Cancer Res 2005, 65, 2698-2704; Liu, X et al . , Proc Natl Acad Sci U S A 2003, 100, 5789-5794, Fan, Y et al . , World J Gastroenterol 2005, 11, 4596-4599; Lane, HA et al . , J Cell Biol 1996, 135, 1701-1713) . Tumour cells that have been depleted of Plkl have activated spindle checkpoints and defects in spindle formation, chromosome alignment and separation and cytokinesis. Loss in viability has been reported to be the result of an induction of apoptosis. In contrast, normal cells have been reported to maintain viability on depletion of Plkl . In vivo knock down of Plkl by siRNA or the use of dominant negative constructs leads to growth inhibition or regression of tumours in xenograft models .
[0008] Plk2 is mainly expressed during the Gl phase of the cell cycle and is localized to the centrosome in interphase cells. Plk2 knockout mice develop normally, are fertile and have normal survival rates, but are around 20% smaller than wild type mice. Cells from knockout animals progress through the cell cycle more slowly than in normal mice (Ma, S et al . , MoI Cell Biol 2003, 23, 6936-6943) . Depletion of Plk2 by siRNA or transfection of kinase inactive mutants into cells blocks centriole duplication. Downregulation of Plk2 also sensitizes tumour cells to taxol and promotes mitotic catastrophe, in part by suppression of the p53 response (Burns TF et al., MoI Cell Biol 2003, 23, 5556-5571). [0009] Plk3 is expressed throughout the cell cycle and increases from Gl to mitosis . Expression is upregulated in highly proliferating ovarian tumours and breast cancer and is associated with a worse prognosis (Weichert, W et al . , Br J Cancer 2004, 90, 815-821; Weichert, W et al . , Virchows Arch 2005, 446, 442-450). In addition to regulation of mitosis, Plk3 is believed to be involved in Golgi fragmentation during the cell cycle and in the DNA-damage response. Inhibition of Plk3 by dominant negative expression is reported to promote p53-independent apoptosis after DNA damage and suppresses colony formation by tumour cells (Li, Z et al . , J Biol Chem 2005, 280, 16843-16850.
[0010] Plk4 is structurally more diverse from the other PIk family members . Depletion of this kinase causes apoptosis in cancer cells (Li, J et al . , Neoplasia 2005, 7, 312-323). Plk4 knockout mice arrest at E7.5 with a high fraction of cells in mitosis and partly segregated chromosomes (Hudson, JW et al . , Current Biology 2001, 11, 441-446) .
[0011] Molecules of the protein kinase family have been implicated in tumour cell growth, proliferation and survival. Accordingly, there is a great need to develop compounds useful as inhibitors of protein kinases. The evidence implicating the PIk kinases as essential for cell division is strong. Blockade of the cell cycle is a clinically validated approach to inhibiting tumour cell proliferation and viability. It would therefore be desirable to develop compounds that are useful as inhibitors of the Plk family of protein kinases (e.g., Plkl, Plk2 , Plk3 and Plk4), that would inhibit proliferation and reduce viability of tumour cells, particularly as there is a strong medical need to develop new treatments for cancer, including treatments that would be administered orally.
SUMMARY OF THE INVENTION
[0012] Compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as inhibitors of protein kinases. In some embodiments, these compounds are useful as inhibitors of PLK protein kinases; in some embodiments, as inhibitors of PLKl protein kinases. These compounds have the formula I, as defined herein, or a pharmaceutically acceptable salt thereof. [0013] These compounds and pharmaceutically acceptable compositions thereof are useful for treating or preventing a variety of diseases, disorders or conditions, including, but not limited to, an autoimmune, inflammatory, proliferative, or hyperproliferative disease, a neurodegenerative disease, or an immunologically-mediated disease. The compounds provided by this invention are also useful for the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors .
DETAILED DESCRIPTION OF THE INVENTION [0014] This invention provides compounds of Formula I:
Figure imgf000007_0001
I wherein
X1 is a bond, O, NR8, S, SO, or SO2;
Y1 is O or NR9;
R1 is H, Ci-ioaliphatic, C3_iocγcloaliphatic, C6-ioaryl, 5-10 membered heteroaryl , or 3-10 membered heterocyclyl ; wherein said R1 is optionally substituted with 0-5 J1; provided that when X1 is a bond, R1 is not H,- R2 is H, Ci-ioaliphatic, - (Ci-iOaliphatic) - (Cs-iocycloaliphatic) ,
C3-8cycloaliphatic, haloCi-4 aliphatic; wherein said R2 is optionally substituted with 0-4 J2; each R3, R4, R5, and R6 is independently H, Ci-iOaliphatic,
C3-iocycloaliphatic , Cβ-ioaryl, or 5-10 membered heteroaryl; wherein each R3, R4, R5, and R6 is optionally and independently substituted with 0-5 J3, J4, J5, and J6 respectively; and R7 is H, C(O)R, C(O)OR, or C(O)NRR', Ci_iOaliphatic ,
C3-i0cycloaliphatic, Cβ-ioaryl , 5-10 membered heteroaryl, 3-
10 membered heterocyclyl, - (Ci-βaliphatic) - (C3-iocycloaliphatic) , - (Ci_6aliphatic) - (C6-ioaryl ) , or
- (Ci-βaliphatic) - (5-10 membered heteroaryl); wherein said R7 is optionally substituted with 0-5 J7; or R3 and R4, together with the carbon atom to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from 0, N, and S; said monocyclic ring formed by R3 and R4 is optionally substituted with 0-4 J34 ;
R5 and R6, together with the carbon atom to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R5 and R6 is optionally substituted with 0-4 J56;
R3 and R5, together with the carbon atoms to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R3 and R5 is optionally substituted with 0-4 J35;
R3 and R7, together with the atoms to which they are attached, optionally form a 4-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from 0, N, and S; said monocyclic ring formed by R3 and R7 is optionally substituted with 0-4 J37;
R5 and R7, together with the atoms to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from 0, N, and S; said monocyclic ring formed by R5 and R7 is optionally substituted with 0-4 J57;
R8 is H, Ci-βaliphatic, C3-8cycloaliphatic , C(O)R, C(O)OR, or C (O)NRR' ;
R9 is H or unsubstituted Ci-βaliphatic; or
R2 and R9, together with the atoms to which they are attached, optionally form a 5-8 membered aromatic or nonaromatic monocyclic ring containing 2-4 heteroatoms independently selected from 0, N, and S; said monocyclic ring formed by R2 and R9 is optionally substituted with 0-4 J29; each J1 is independently Ci-6haloalkyl , halo, NO2, CN, Q, or -Z-Q; or, two J1 taken together can optionally form -O; Z is Ci-6aliphatic optionally replaced with 0-3 occurrences of -NR-, -0-, -S-, -C(O)-, -C(=NR)-, -C(=N0R)-, -SO-, or -SO2- ; each Z is optionally substituted with 0-2 jz; Q is H; Ci-6 aliphatic; a 3-8-membered aromatic or nonaromatic monocyclic ring having 0-3 heteroatoms independently selected from O, N, and S; or an 8-12 membered aromatic or nonaromatic bicyclic ring system having 0-5 heteroatoms independently selected from O, N, and S; each Q is optionally substituted with 0-5 JQ; each J2 is halo or haloCi-4 aliphatic; each J3, J4, J5, and J6 is independently Ci_6 aliphatic, C3-6Cycloaliphatic, or - (Ci-4alkyl ) n-V1; wherein n is 0 or 1 ;
V1 is halo(Ci-4 aliphatic), -O(haloCi-4 aliphatic), halo, NO2, CN, OH, OR", SH, SR", NH2, NHR", N (R") 2, COH, COR", CO2H, CO2R", CONH2, CONHR", CONR"2, OCOR", OCONH2, OCONHR", OCON(R") 2, NHCOR", NR"COR", NHCO2R", NR"CO2R" , NHCO2H, NR"CO2H, NHCONH2, NHCONHR", NHCON (R") 2, SO2NH2, SO2NHR" , SO2N (R" ) 2 , NHSO2R" , NR"SO2R" ; or V1 is a cyclic group selected from
C3-6cycloaliphatic, phenyl, 5-6 membered heteroaryl , or 3-6 membered heterocyclyl ; wherein said cyclic group is optionally substituted with 0-3 Jv; R" is unsubstituted Ci_4 aliphatic; or two of the same J3, J4, J5, or J6, bonded to the same atom, together can optionally form =O; each Jz and Jv is independently halo, Ci-6 aliphatic,
C3-6cycloaliphatic, NO2, CN, -NH2, -NH(Ci-4 aliphatic), -N(Ci-4 aliphatic)2, -OH, -O(Ci-4 aliphatic), -CO2H, -CO2(Ci- 4 aliphatic), -O (haloCi-4 aliphatic), or halo(Ci_4 aliphatic) ; each JQ, J7, J29, J34, J56, J35, J37, and J57 is independently M or
-Y-M; each Y is independently an unsubstituted Ci-βaliphatic optionally replaced with 0-3 occurrences of -NR-, -O- , -S-, -C(O)-, -SO-, or -SO2-; each M is independently H, Ci_6 aliphatic, C3-6cycloaliphatic, halo(Ci_4 aliphatic), -0(haloCi-4 aliphatic), 3-6 membered heterocyclyl, halo, NO2, CN, OH, OR', SH, SR', NH2, NHR', N(R' )2, COH, COR', CO2H, CO2R', CONH2, CONHR', CONR' 2 , OCOR', OCONH2, OCONHR', OCON(R' )2/ NHCOR', NR'COR' , NHCO2R', NR' CO2R', NHCO2H, NR' CO2H, NHCONH2, NHCONHR', NHCON(R' )2, SO2NH2, SO2NHR', SO2N(R' )2, NHSO2R', or NR' SO2R' ; R is H or unsubstituted C1^aIiphatic;
R' is unsubstituted Ci-βaliphatic,- or two R' groups, together with the atom to which they are bound, form an unsubstituted 3-8 membered saturated or partially unsaturated monocyclic ring having 0-1 heteroatoms independently selected from O, N, and S. [0015] In one embodiment, R1 is H, Ci-ioaliphatic , C3-iocycloaliphatic, Cβ-ioaryl , 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; wherein said R1 is optionally substituted with 0-5 J1; provided that when X1 is a bond, R1 is not H,- and the other variables are as defined herein. [0016] In another embodiment, R7 is H, C(O)R, C(O)OR, or C(O)NRR', Ci-ioaliphatic, C3-i0cycloaliphatic, Cβ-ioaryl , 5-10 membered heteroaryl, 3-10 membered heterocyclyl,
- (Ci-βaliphatic) - (C3-iocycloaliphatic) , - (Ci-βaliphatic) - (Cβ-ioaryl), - (Ci-βaliphatic) - (5-10 membered heteroaryl), or
- (Ci-βaliphatic) - (3-6 membered heterocyclyl ); wherein said R7 is optionally substituted with 0-5 J7; and the other variables are as defined herein. [0017] In another embodiment, Q is H; C1.6 aliphatic; a 3-8- membered aromatic or nonaromatic monocyclic ring having 0-3 heteroatoms independently selected from O, N, and S; or a 7-12 membered aromatic or nonaromatic bicyclic ring system having 0-5 heteroatoms independently selected from O, N, and S; each Q is optionally substituted with 0-5 JQ; and the other variables are as defined herein.
[0018] In another embodiment, each M is independently H, Cχ-6 aliphatic, C3-6Cycloaliphatic, halo(Ci-4 aliphatic), -0(haloCi-4 aliphatic), 3-6 membered heterocycIyI , Cβ-ioaryl, halo, NO2, CN, OH, OR', SH, SR', NH2, NHR', N(R' )2, COH, COR', CO2H, CO2R', CONH2, CONHR', CONR' 2, OCOR', OCONH2, OCONHR', OCON(R' )2, NHCOR', NR' COR', NHCO2R', NR' CO2R' , NHCO2H, NR' CO2H, NHCONH2, NHCONHR', NHCON(R') 2, SO2NH2, SO2NHR', SO2N(R' )2, NHSO2R', or NR' SO2R' , or two M taken together can optionally form =O; and the other variables are as defined herein.
[0019] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[0020] As described herein, a specified number range of atoms includes any integer therein. For example, a group having from 1-4 atoms could have 1, 2, 3, or 4 atoms. [0021] As described herein, compounds of the invention may optionally be substituted with one or more substituents , such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted. " In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent . Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. [0022] The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 400C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
[0023] The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation that has a single point of attachment to the rest of the molecule.
[0024] Unless otherwise specified, aliphatic groups contain 1- 20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl , sec-butyl, vinyl, n-butenyl, ethynyl , and tert-butyl . [0025] The term "cycloaliphatic" (or "carbocycle" or "carbocyclyl" or "cycloalkyl" ) refers to a monocyclic C3-C8 hydrocarbon or bicyclic C8-C12 hydrocarbon or bicyclic C7-C12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups. Specific examples include, but are not limited to, cyclohexyl, cyclopropenyl , and cyclobutyl .
[0026] The term "heterocycle", "heterocyclyl" , or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members are an independently selected heteroatom. In some embodiments, the "heterocycle", "heterocyclyl", or "heterocyclic" group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members. In some embodiments, there are 1-4 heteroatoms in a ring system. [0027] Suitable heterocycles include, but are not limited to, 3-lH-benzimidazol-2-one, 3- (1-alkyl ) -benzimidazol-2-one, 2- tetrahydrofuranyl, 3-tetrahydrofuranyl , 2- tetrahydrothiophenyl , 3-tetrahydrothiophenyl , 2-morpholino, 3- morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl , 3- pyrrolidinyl , 1-tetrahydropiperazinyl , 2- tetrahydropiperazinyl, 3-tetrahydropiperazinyl , 1-piperidinyl , 2-piperidinyl , 3-piperidinyl , 1-pyrazolinyl , 3-pyrazolinyl , 4- pyrazolinyl, 5-pyrazolinyl , 1 -piperidinyl , 2-piperidinyl, 3- piperidinyl, 4-piperidinyl , 2-thiazolidinyl, 3-thiazolidinyl , 4-thiazolidinyl , 1-imidazolidinyl , 2-imidazolidinyl , 4- imidazolidinyl , 5-imidazolidinyl , indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and 1, 3-dihydro-imidazol-2-one.
[0028] Cyclic groups, (e.g., cycloaliphatic and heterocycles) , can be linearly fused, bridged, or spirocyclic. [0029] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon,- the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4- dihydro-2ϋ-pyrrolyl) , NH (as in pyrrolidinyl) or NR+ (as in N- substituted pyrrolidinyl) ) .
[0030] The term "unsaturated", as used herein, means that a moiety has one or more units of unsaturation.
[0031] The term "nonaromatic", as used herein, describes rings that are either saturated or partially unsaturated. [0032] The term "alkoxy", or "thioalkyl", as used herein, refers to an alkyl group, as previously defined, attached through an oxygen ("alkoxy") or sulfur ("thioalkyl") atom. [0033] The terms "haloalkyl", "haloalkenyl" , "haloaliphatic" , and "haloalkoxy" mean alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The terms "halogen", "halo", and "hal" mean F, Cl, Br, or I. [0034] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyaIky1" , refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". [0035] The term "heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy" , refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members . In some embodiments, there are 1-4 heteroatoms in a ring system. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic" . Suitable heteroaryl rings include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl , 2-imidazolyl, 4-imidazolyl, 5- imidazolyl, benzimidazolyl , 3-isoxazolyl , 4-isoxazolyl , 5- isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidinyl, 4-pyrimidinyl , 5-pyrimidinyl , pyridazinyl (e.g., 3-pyridazinyl) , 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl) , triazolyl (e.g., 2-triazolyl and 5-triazolyl ), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl , indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl) , isothiazolyl , 1 , 2 , 3-oxadiazolyl , 1,2,5- oxadiazolyl, 1 , 2 , 4-oxadiazolyl , 1 , 2 , 3 -triazolyl , 1,2,3- thiadiazolyl , 1 , 3 , 4-thiadiazolyl , 1 , 2 , 5-thiadiazolyl , purinyl, pyrazinyl, 1 , 3 , 5-triazinyl , quinolinyl (e.g., 2-quinolinyl , 3- quinolinyl, 4-quinolinyl ) , and isoquinolinyl (e.g., 1- isoquinolinyl , 3-isoquinolinyl , or 4-isoquinolinyl ) . [0036] The term "protecting group" and "protective group" as used herein, are interchangeable and refer to an agent used to temporarily block one or more desired functional groups in a compound with multiple reactive sites. In certain embodiments, a protecting group has one or more, or preferably all, of the following characteristics: a) is added selectively to a functional group in good yield to give a protected substrate that is b) stable to reactions occurring at one or more of the other reactive sites; and c) is selectively removable in good yield by reagents that do not attack the regenerated, deprotected functional group. As would be understood by one skilled in the art, in some cases, the reagents do not attack other reactive groups in the compound. In other cases, the reagents may also react with other reactive groups in the compound. Exemplary protecting groups are detailed in Greene, T. W. , Wuts , P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999 (and other editions of the book), the entire contents of which are hereby incorporated by reference. The term "nitrogen protecting group", as used herein, refers to an agents used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen protecting groups also possess the characteristics exemplified above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T. W., Wuts, P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
[0037] in some embodiments, an alkyl or aliphatic chain can be optionally replaced with another atom or group. This means that a methylene unit of the alkyl or the aliphatic chain is optionally replaced with said other atom or group. Examples of such atoms or groups would include, but are not limited to, -NR-, -O- , -C(O)-, -C(=N-CN)-, -C(=NR)-, -C(=NOR)-, -S-, -SO-, or -SO2-. These atoms or groups can be combined to form larger groups. Examples of such groups include, but are not limited to, -OC(O)-, -C(O)CO-, -CO2-, -C(O)NR-, -C(=N-CN), -NRCO-, -NRC(O)O-, -SO2NR-, -NRSO2-, -NRC(O)NR-, -OC(O)NR-, and -NRSO2NR-, wherein R is defined herein.
[0038] Unless otherwise specified, the optional replacements form a chemically stable compound. Optional replacements can occur both within the chain and at either end of the chain,- i.e., both at the point of attachment and/or also at the terminal end. Two optional replacements can also be adjacent to each other within a chain so long as it results in a chemically stable compound. The optional replacements can also completely replace all of the carbon atoms in a chain. For example, a C3 aliphatic can be optionally replaced by -NR-, -C(O)-, and -NR- to form -NRC(O)NR- (a urea).
[0039] Unless otherwise specified, if the replacement occurs at the terminal end, the replacement atom is bound to an H on the terminal end. For example, if -CH2CH2CH3 were optionally replaced with -0- , the resulting compound could be -OCH2CH3, -CH2OCH3, or -CH2CH2OH.
[0040] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, geometric, conformational, and rotational forms of the structure) . For example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this invention. As would be understood to one skilled in the art, a substituent can freely rotate around any
Figure imgf000017_0001
also represents
Figure imgf000017_0002
[0041] Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, geometric, conformational, or rotational mixtures of the present compounds are within the scope of the invention.
[0042] Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
[0043] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C- enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.
[0044] The compounds of this invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable salt.
[0045] As used herein, the term "pharmaceutically acceptable salt" refers to salts of a compound which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. [0046] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et a.1. , describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1971, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds. Acid addition salts can be prepared by 1) reacting the purified compound in its free- based form with a suitable organic or inorganic acid and 2) isolating the salt thus formed.
[0047] Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+ (Ci_4alkyl) 4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil- soluble or dispersible products may be obtained by such quaternization.
[0048] Base addition salts can be prepared by 1) reacting the purified compound in its acid form with a suitable organic or inorganic base and 2) isolating the salt thus formed. Base addition salts include alkali or alkaline earth metal salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. Other acids and bases, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid or base addition salts. [0049] The following abbreviations are used: LG leaving group
TBTU O- (Benzotriazol-1-yl ) -N, N, N' , N ' -tetramethyluronium tetrafluoroborate DMSO dimethyl sulfoxide DMA dimethyl acetamide TCA trichloroacetic acid ATP adenosine triphosphate DEAD diethylazodicarboxylate HEPES 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid
BSA bovine serum albumin DTT dithiothreitol
MOPS 4-morpholinepropanesulfonic acid NMR nuclear magnetic resonance HPLC high performance liquid chromatography LCMS liquid chromatography-mass spectrometry TLC thin layer chromatography Rt retention time
[0050] In one aspect of this invention, X1 is O, NR8, or S. In some embodiments, X1 is NR8. In other aspects, Y1 is 0. [0051] In another aspect of this invention, R1 is optionally- substituted Cβ-ioaryl or optionally substituted 5-10 membered heteroaryl .
[0052] In one embodiment, R1 is optionally substituted C6-i0aryl , such as phenyl .
[0053] In one embodiment, R1 is optionally substituted with J1, wherein J1 is -H, -O-Ci_6 alkyl , halo, or -C(O)N(R)(Q), wherein the R is -H.
[0054] In one embodiment, R1 is optionally substituted with J1, wherein J1 is -H, -OCH3, halo, or -C(O)N(R) (Q), wherein the R is -H.
[0055] In one embodiment, J1 is -OCH3 or -C(O)N(R)ZQ, wherein Z is Ci-βaliphatic and Q is a 3-8-membered aromatic or nonaromatic monocyclic ring having 1-3 heteroatoms independently selected from 0, N, and S; or an 8-12 membered aromatic or nonaromatic bicyclic ring system having 1-5 heteroatoms independently selected from O, N, and S; and Q is optionally substituted with 0-5 JQ. In certain embodiments, Z is Ci_6alkyl and in more specific embodiments, Z is -CH2-. [0056] In one embodiment, J1 is -OCH3 or -C(O)N(R)ZQ, wherein Z is Ci_6aliphatic and Q is a 5-6-membered aromatic having 1 heteroatom selected from 0 and N (e.g., pyridine) ; wherein Q is optionally substituted with 0-5 JQ. In certain embodiments, Z is Ci-6alkyl and in more specific embodiments, Z is -CH2-. [0057] In certain embodiments, Z is
Figure imgf000021_0001
and in more specific embodiments, Z is -CH2-.
[0058] In one embodiment, J1 is -OCH3 or -C(O)N(R)(Q), wherein the R is -H and the Q is Ci_6 alkyl, 3-6-membered cycloalkyl, a 7-12 nonaromatic bicyclic ring system, or a 8-12 nonaromatic bicyclic ring system, wherein each Q is substituted with 0-5 JQ.
[0059] In one embodiment, J1 is -OCH3 or -C(O)N(R)(Q), wherein the R is -H and the Q is 3-6-membered cycloalkyl, wherein each Q is substituted with 0-5 JQ. [0060] In one embodiment, J1 is -OCH3 or -C(O)N(R) (Q), wherein the R is -H and the Q is cyclohexyl, wherein each Q is substituted with 0-5 JQ .
[0061] In one embodiment, J1 is -OCH3 or -C(O)N(R)(Q), wherein the R is -H and the Q is C6_10aryl or 5-10 membered heteroaryl having 0-5 heteroatoms independently selected from O, N, and S; wherein each Q is substituted with 0-5 JQ.
[0062] In one embodiment, J1 is -OCH3 or -C(O)N(R) (Q), wherein the R is -H and the Q is a 3-8-membered heterocyclic ring having 1 or 2 heteroatoms independently selected from O, N, and S; wherein each Q is substituted with 0-5 JQ. [0063] In one embodiment, J1 is Q and Q is:
Figure imgf000022_0001
, wherein Q is substituted with 0-5 JQ.
[0064] In one embodiment, Q is substituted with 0, 1, or 2 JQ. [0065] In one embodiment, each JQ is independently F, -OH, - OR' , or -OC(O)R' .
[0066] In one embodiment, each R' is independently Ci- βaliphatic, wherein the aliphatic is straight-chained. [0067] In one embodiment, each R' is independently Ci-βalkyl, wherein the alkyl is straight-chained. [0068] In one embodiment, R' is CH3.
[0069] In another aspect, R2 is optionally substituted Ci-ioaliphatic or optionally substituted C3_i0cycloaliphatic . [0070] in some embodiments, R3 and R4, together with the carbon atom to which they are attached, form an optionally substituted 3-6 membered monocyclic ring.
[0071] In other embodiments, R3 and R5, together with the carbon atoms to which they are attached, form an optionally substituted 3-6 membered monocyclic ring. [0072] In yet other embodiments, R3, R4, R5, and R6 is independently an optionally substituted group selected from H, Ci-10aliphatic, C3_iocycloaliphatic, C6-ioaryl, or 5-10 membered heteroaryl . In some embodiments, each R3 and R4 is independently H, Ci-6aliphatic, or C3-8cycloaliphatic. In some embodiments, one of R3 and R4 is H and the other is Ci-βaliphatic or C3_8Cycloaliphatic .
[0073] In one embodiment, each R3 and R4 is independently H or Ci_3alkyl or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 3-4 membered monocyclic ring.
[0074] In one embodiment, one of R3 and R4 is H and the other is ethyl or (S) -methyl.
[0075] In one embodiment, one of R3 and R4 is H and the other is (R) -methyl .
[0076] In one embodiment, each R3 and R4 is methyl. [0077] In one embodiment, R3 and R4, together with the carbon atoms to which they are attached, form an unsubstituted 3-4 membered monocyclic ring.
[0078] In one embodiment, R3 and R4, together with the carbon atoms to which they are attached, form an unsubstituted 3 membered monocyclic ring. [0079] In one embodiment, R5 is H. [0080] In one embodiment, R6 is H.
[0081] In some embodiments, J3 and J4 is independently halo. [0082] In other embodiments, R5 and R7, together with the atoms to which they are attached, form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring.
[0083] In one aspect of this invention, R7 is an optionally substituted group selected from Ci-ioaliphatic, C3-i0cycloaliphatic, C6-ioaryl , 5-10 membered heteroaryl, and 3-10 membered heterocyclyl . In some aspects, R7 is an optionally substituted group selected from Ci-ioaliphatic, C3-βcycloaliphatic , phenyl, a 5-membered heteroaryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 , 5-pyridazinyl , 3 , 5-pyrimidyl , and a 3-8 membered heterocyclyl . in other aspects, R7 is not
3-amino-2, 4-pyrimidine.
[0084] In one embodiment, R8 is H.
[0085] One aspect of this invention provides a compound of formula II :
Figure imgf000024_0001
II wherein
R1 is optionally substituted Cβ-ioaryl or optionally substituted 5-10 membered heteroaryl ; R2 is H or an optionally substituted group selected from
Ci-ioaliphatic and C3-i0cycloaliphatic; each R3, R4, R5, and R6 is independently H, Cx-xoaliphatic, or C3-i0cycloaliphatic ; wherein each R3, R4, R5, and R6 is optionally substituted with 0-5 J3, J4, J5, and J6 respectively; or R3 and R4, together with the carbon atom to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R3 and R5, together with the carbon atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R5 and R7, together with the atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated . monocyclic ring; R2 and R9, together with the atoms to which they are attached, can form an optionally substituted 5-8 membered saturated or partially unsaturated monocyclic ring.
[0086] Another aspect of this invention provides a compound of formula III:
Figure imgf000025_0001
III wherein
R1 is optionally substituted C6-ioaryl or optionally substituted 5-10 membered heteroaryl; R2 is H or an optionally substituted group selected from
Ci-iOaliphatic and C3-iocycloaliphatic; each R3, R4, R5, and R6 is independently H, Ci-ioaliphatic, or C3-i0cycloaliphatic; wherein each R3, R4, R5, and R6 is optionally substituted with 0-5 J3, J4, J5, and J6 respectively; or R3 and R4, together with the carbon atom to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R3 and R5, together with the carbon atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R5 and R7, together with the atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R2 and R9, together with the atoms to which they are attached, can form an optionally substituted 5-8 membered saturated or partially unsaturated monocyclic ring.
[0087 J In some embodiments, each J3, J4, J5, and J6 is independently Ci-e aliphatic, C3-6cycloaliphatic, or -
Figure imgf000026_0001
wherein n is 0 or 1;
V1 is halo(Ci_4 aliphatic), -0(haloCi-4 aliphatic), halo, NO2, CN, OH, OR", SH, SR", NH2, NHR", N (R") 2, COH, COR", CO2H, CO2R", CONH2, CONHR", CONR"2, OCOR", OCONH2, OCONHR", OCON(R") 2, NHCOR", NR"COR", NHCO2R", NR"CO2R" , NHCO2H, NR"CO2H, NHCONH2, NHCONHR", NHCON (R" )2, SO2NH2, SO2NHR", SO2N(R") 2, NHSO2R", NR"SO2R"; R" is unsubstituted C1-4 aliphatic; or two of the same J3, J4, J5, or J6, bonded to the same atom, together can optionally form =O .
[0088] In some embodiments, the variables are as depicted in the species disclosed herein.
[0089] In some embodiments, the compounds of this invention are represented in Table 1.
Table 1
Figure imgf000026_0002
Figure imgf000027_0001
1-4 1-5 1-6
Figure imgf000027_0002
1-7 1-8 1-9
Figure imgf000027_0003
1-14 1-15
Figure imgf000027_0004
1-16 1-17 1-18
Figure imgf000028_0001
1-19 1-20 1-21
Figure imgf000028_0002
-L-21 1-23 1-24
Figure imgf000028_0003
1-25 1-26 1-27
Figure imgf000028_0004
1-28 1-29 1-30
Figure imgf000028_0005
1-31 1-32 1-33
Figure imgf000029_0001
1-34 1-35 1-36
Figure imgf000029_0002
1-37 1-38 1-39
Figure imgf000029_0003
1-40 1-41 1-42
Figure imgf000029_0004
1-43 1-44 1-45
Figure imgf000029_0005
1-46 1-47 1-48
Figure imgf000030_0001
1-49 1-50 1-51
Figure imgf000030_0002
1-52 1-53 1-54
Figure imgf000030_0003
1-55 1-56 1-57
Figure imgf000030_0004
1-58 1-59 1-60
Figure imgf000030_0005
1-61 1-62 1-63
Figure imgf000031_0001
1-64 1-65 1-66
Figure imgf000031_0002
1-67 1-68 1-69
Figure imgf000031_0003
1-70 1-71 1-72
Figure imgf000031_0004
1-73 1-74 1-75
Figure imgf000031_0005
1-76 1-77 1-78
Figure imgf000032_0001
1-79 1-80 1-81
Figure imgf000032_0002
1-82 1-83 1-84
Figure imgf000032_0003
1-85 1-86 1-87
Figure imgf000032_0004
1-88 1-89 1-90
Figure imgf000032_0005
1-91 1-92 1-93
Figure imgf000033_0001
1-94 1-95 1-96
Figure imgf000033_0002
1-97 1-98 1-99
Figure imgf000033_0003
1-100 1-101 1-102
Figure imgf000033_0004
1-103 1-104 1-105
Figure imgf000033_0005
1-106 1-108
Figure imgf000034_0001
1-109 1-110 1-111
Figure imgf000034_0002
1-112 1-113 1-114
Figure imgf000034_0003
1-115 1-116 1-117
Figure imgf000034_0004
1-118 1-119 1-120
Figure imgf000034_0005
1-121 1-122 1-123
Figure imgf000035_0001
1-124 1-125 1-126
Figure imgf000035_0002
1-127 1-128 1-129
Figure imgf000035_0003
1-130 1-131 1-132
Figure imgf000035_0004
1-133 1-134 1-135
Figure imgf000035_0005
1-136 1-137 1-138
Figure imgf000036_0001
1-139 1-140 1-141
Figure imgf000036_0002
1-142 1-143 1-144
Figure imgf000036_0003
1-145 1-146 1-147
Figure imgf000036_0004
1-148 1-149 1-150
Figure imgf000036_0005
1-151 1-152 1-153
Figure imgf000037_0001
1-154 1-155 1-156
Figure imgf000037_0002
1-157 1-158 1-159
Figure imgf000037_0003
1-160 1-161 1-162
Figure imgf000037_0004
1-163 1-164 1-165
Figure imgf000037_0005
1-166 1-167 1-168
Figure imgf000038_0001
1-169 1-170 1-171
Figure imgf000038_0002
1-172 1-173 1-174
Figure imgf000038_0003
1-175 1-176 1-177
Figure imgf000038_0004
1-178 1-179 1-180
Figure imgf000039_0001
1-181 1-182 1-183
Figure imgf000039_0002
1-184 1-185 1-186
Figure imgf000039_0003
1-187 1-188 1-189
Figure imgf000039_0004
1-190 1-191 1-192
Figure imgf000039_0005
1-193 1-194 1-195
Figure imgf000040_0001
1-196 1-197 1-198
Figure imgf000040_0002
1-199 1-200 1-201
Figure imgf000040_0003
1-202 1-203 1-204
Figure imgf000040_0004
1-205 1-206 1-207
Figure imgf000040_0005
1-208 1-209 1-210
Figure imgf000041_0001
1-211 1-212 1-213
Figure imgf000041_0002
1-217 1-218 1-219
Figure imgf000041_0003
1-220 1-221 1-222
Figure imgf000042_0001
1-223 1-224 1-225
Figure imgf000042_0002
1-226 1-227 1-228
Figure imgf000042_0003
1-229 1-230 1-231
Figure imgf000042_0004
1-232 1-233 1-234
Figure imgf000043_0001
1-235 1-236 1-237
Figure imgf000043_0002
1-238 1-239 1-240
Figure imgf000043_0003
1-241 1-242 1-243
Figure imgf000043_0004
1-244 1-245 1-246
Figure imgf000044_0001
1-247 1-248 1-249
Figure imgf000044_0002
1-250 1-251 1-252
Figure imgf000044_0003
1-253 1-254 1-255
Figure imgf000044_0004
1-256 1-257 1-258
Figure imgf000045_0001
1-259 1-260 1-261
Figure imgf000045_0002
1-262 1-263 1-264
Figure imgf000045_0003
1-265 1-266 1-267
Figure imgf000045_0004
1-268 1-269 1-270
Figure imgf000045_0005
1-271 1-272 1-273
Figure imgf000046_0001
1-274 1-275 1-276
Figure imgf000046_0002
1-277 1-278 1-279
Figure imgf000046_0003
1-280 1-281 1-282
Figure imgf000046_0004
1-283 1-284 1-285
Figure imgf000046_0005
1-286 1-287 General synthetic methodology
[0090] The compounds of this invention may be prepared in general by methods such as those depicted in the general schemes below, and the preparative examples that follow. Unless otherwise indicated, all variables in the following schemes are as defined herein.
Scheme 1
Figure imgf000047_0001
N-funclionalisation use of handle LG2
Figure imgf000047_0003
Figure imgf000047_0002
[0091] Scheme 1 above shows a general synthetic route for preparing compounds of formula I where Y1 = 0. Starting material I^ (wherein LGi and LG2 can be, but not restricted to, chlorine atoms) reacts with β-aminoester 1"_ to give adduct 3^ Reduction of the nitro group, followed by cyclo-condensation gives bicyclic compound 4. The amide N-H can be functionalized at this stage to give 5^. LG2 can finally be used as a handle for preparation of the compounds of formula I. In this last step LG2 can, for example, be displaced with amines or be engaged in palladium assisted coupling reactions known to one skilled in the art (e.g., Suzuki, Stille) . [0092] Alternatively, the compound of formula 3^ after reduction of the nitro group, can be first functionalized to form a compound of formula 3-b;
Figure imgf000048_0001
3-b
[0093] which can subsequently be cyclized to form the compound of formula 5_. Scheme 2
Figure imgf000048_0002
5 or I I-a
R0 = LG2 5 R0 = LG2 5-a R0 = R1X1 I R0 = R1X1 I-a
ring A formation
Figure imgf000048_0003
I-b
R0 = LG2 i 5-b
R0 = R1X1 I-b
[0094] Scheme 2 above shows a general synthetic route for preparing compounds of this invention where Yx is NR9. The lactam functional group in 5^ or I (either in 5^ where LG2 is still present or in I if it has already been derivatised as R1X1) can be engaged into a functional group transformation to form an amidine group (either 5-a where LG2 is still present or I-a if it has already been derivatised as R1X1) . [0095] Alternatively, Scheme 2 above also shows a general synthetic route for preparing compounds of this invention where Y1 = N and R2 and R9 are taken together to form ring A. The lactam functional group in 5_ or I (either in 5_ where LG2 is still present or in I if it has already been derivatised as R1X1) can be engaged in a multi-step cyclisation sequence to form ring A ( ei ther 5-b where LG2 is still present or I-b i f it has already been derivatised as R1X1 ) .
Scheme 3
Figure imgf000049_0001
[0096] Scheme 3 above shows a general synthetic route for preparing compounds of this invention where Y1 is NR9 and R2 and R9 are taken together to form a triazole ring. Activation of the lactam functional group in 4^ followed by displacement with hydrazine lead to intermediates of- formula 1_. Compoun'ds of formula I-b were finally obtain by cyclisation of derivatives 1_ and subsequent displacement with HX1-Ri.
Scheme 4
amine deprotection
Figure imgf000049_0003
Figure imgf000049_0002
5a 9 5
[0097] Scheme 4 above shows another general synthetic route for preparing compounds ϊ> of this invention. Compounds of formula 5a, containing a protecting group on the amine, can be prepared like previously shown (see compound j> scheme 1) . Deprotection of amines 5a, followed by substitution of the free amines of 9^ with the desired R7-halides can be achieved by methods well known in the art.
[0098] Accordingly, this invention also provides a process for preparing a compound of this invention.
[0099] One embodiment of this invention provides a process for preparing a compound of formula I:
Figure imgf000050_0001
wherein
Y1 is O and X1, R1, R2, R3, R4 R5, R6, and R7 are as defined herein; comprising reacting a compound of formula 5;
Figure imgf000050_0002
wherein
R2, R3, R4, R5, R6, and R7 are as defined herein; and LG2 is a suitable leaving group, such as halo, with XlRl under suitable conditions to form the compound of formula I. XlRl can displace LG2 in a variety of ways known to one skilled in the art. For example, if X1 is NHR8, O, or S, then X1R1 can displace LG2 in the presence of suitable base or acid, solvent, and conditions. Suitable displacement reactions are known to one skilled in the art and can be found in a variety of resources, including "March's Advanced Organic Chemistry". A sulfur linker (wherein X1 is S) can be oxidized under suitable oxidation conditions to form compounds wherein X1 is SO or SO2. Compounds of formula I, wherein X1 is a bond and R1 is bonded to X1 via a carbon atom, can be formed under suitable cross- coupling conditions. In these cross coupling reactions, one of the starting materials is R1 bonded to a cross-coupling group. This starting material can react with the compound of formula 5^ under cross coupling conditions to form compounds of formula I, wherein X1 is a bond and R1 is bonded to X1 via a carbon atom.
[00100] The term "cross-coupling reaction", as used herein, refers to a reaction in which a carbon-carbon bond is formed with the aid of a metal catalyst. Usually, one of the carbon atoms is bonded to a functional group (a "cross- coupling group") while the other carbon atom is bonded to a halogen. Examples of cross coupling reactions include, but are not limited to, Suzuki couplings, Stille couplings, and Negishi couplings.
[00101] The term "cross-coupling group", as used herein, refers to a functional group capable of- reacting with another functional group (e.g., halo) in a cross coupling reaction to form a carbon-carbon ("C-C") bond. In some embodiments, the C-C bond is formed between two aromatic groups . [00102] The term "cross coupling condition", as used herein, refers to the chemical conditions (e.g., temperature, length of time of reaction, volume of solvent required) required in order to enable the cross coupling reaction to occur .
[00103] Examples of cross-coupling groups and their respective cross-coupling conditions include, but are not limited to, boronic acids and boronic esters with Suzuki coupling conditions, SnBu3 with Stille coupling conditions, and ZnX with Negishi coupling conditions.
[00104] All three of these coupling conditions typically involve the use of a catalyst, a suitable solvent, and optionally a base. Suzuki coupling conditions involve the use of a palladium catalyst and a suitable solvent. Examples of suitable palladium catalysts include, but are not limited to,
PdCl2(PPh3J2, Pd(Ph3J4, and PdCl2(dppf). Suitable bases include, but are not limited to, K2CO3 and Na2CO3. Suitable solvents include, but are not limited to, tetrahydrofuran, toluene, and ethanol .
[00105] Stille coupling conditions involve the use of a catalyst (usually palladium, but sometimes nickel), a suitable solvent, and other optional reagents. Examples of suitable catalysts include, but are not limited to, PdCl2 (PPh3) 2 ,
Pd(Ph3J4, and PdCl2(dppf). Suitable solvents include, but are not limited to, tetrahydrofuran, toluene, and dimethylformamide .
[00106] Negishi coupling conditions involve the use of a catalyst (palladium or nickel) and a suitable solvent.
Examples of suitable catalysts include, but are not limited to
Pd2(dba)3, Ni (PPh3J2Cl2, PdCl2 (PPh3) 2, and Pd(Ph3J4. Suitable solvents include, but are not limited to, tetrahydrofuran, toluene, and dimethylformamide .
Suzuki, Stille, and Negishi conditions are known to one skilled in the art and are described in more detail in a variety of references, including "March's Advanced Organic
Chemistry" .
[00107] As would be understood by one skilled in the art, cross coupling groups are formed from coupling groups precursors. A "coupling group precursor is a reagent or group of reagents used to form a cross-coupling group.
Examples include, but are not limited to, bis (pinacolato) diborane for the formation of boronate esters, trimethylborates for the formation of boronic acids, Bu3SnCl for the formation of stannanes, and ZnCl2 for the formation zincates in Negishi coupling reactions. Examples of suitable coupling group formation conditions include, but are not limited to, making boronic esters via palladium-mediated catalysis; making boronic acids by hydrolyzing boronic esters; making stannaries via a two step process: 1) halogen metal exchange followed by 2) transmetallation with Bu3SnCl; and making zincates via a two step process: 1) halogen metal exchange followed by 2) addition of ZnCl2.
[00108] Another embodiment provides a process for forming a compound of formula 5 comprising reacting a compound of formula 4 ;
Figure imgf000053_0001
4 wherein R3, R4, R5, R6, and R7 are as defined herein; and LG2 is a suitable leaving group, such as halo; with R2-LG3, wherein LG3 is a leaving group capable of being displaced by an NH-amide. Examples of leaving groups include, but are not limited to, halo, tosylate, and mesylate. [00109] Another embodiment provides a process for forming a compound of formula 4 comprising reacting a compound of formula 3_;
Figure imgf000053_0002
3 under a two step process. The first step involves reduction of the nitro group under suitable reduction conditions, such as iron powder, SnCl2, zinc powder, indium/HCl, or H2ZPd to form a compound of formula 3-a:
Figure imgf000053_0003
The second step involves cyclocondensation of the amine with the carboxyl ic es ter of formula 3 -a , resul ting in the compound of formula £. Cyclocondensations typically occur in the presence of an acid or a base. In some embodiments, this two- step process occurs in situ. One example of an in situ condition involves treating the nitro-compound with iron powder in glacial acetic acid.
[00110] Another aspect of this invention provides an alternative way of forming the compounds of formula Ek Instead of directly cyclizing the compound of formula 3-a to form the compound of formula 4^ the amino intermediate can be functionalized first to form the compound of formula 3-b
Figure imgf000054_0001
3-b under suitable conditions known to one skilled in the art. For example, the amino group can react with R2-LG3, wherein LG3 is a leaving group capable of being displaced by an amine. Examples of leaving groups include, but are not limited to, halo, tosylate, and mesylate.
This compound can then be cyclized under suitable cyclocondensation conditions to form the compound of formula 5.
[00111] Another embodiment of this invention provides a process for forming the compound of formula 3_; comprising reacting the compound of formula 2^;
Figure imgf000054_0002
with a compound of formula 1 ;
Figure imgf000054_0003
under suitable displacement conditions to form the compound of formula 3_. Suitable displacement conditions typically comprise of a suitable solvent and a suitable base or acid. Examples of suitable displacement conditions include, but are not limited to, K2CO3 and acetone, Hunig' s base/THF. [00112] Another aspect of this invention provides a process for making compounds of formula I wherein Y1 is NR9. One embodiment involves reacting the compound of formula I wherein Y1 is O and X1, R1, R2, R3, R4, R5, R6, and R7 are as defined herein; under suitable conditions known in the art for converting amides into amidines , to form a compound of formula I wherein Y1 is NR9 (shown in Scheme II as l-a) . Suitable conditions typically involve an amine (R^NHR9) , a suitable solvent, and an activated intermediate deriving from an amide (e.g., a thioamide prepared from an amide and Lawesson's Reagent) .
[00113] In another aspect, the compound of formula 5_ can be subject to similar amide-converting conditions to form a compound of formula 5-a. The LG2 group in 5-a or 5-b can be used as a handle for preparation of the compounds of this invention. In this last step LG2 can, for example, be displaced with amines or be engaged in palladium assisted coupling reactions (e.g., Suzuki, Stille) .
[00114] In some embodiments, the compounds of formula I or 5^, wherein Y1 is O and X1, R1, R2, R3, R4, R5, R6, and R7 are as defined herein, can be converted into cyclic amidines, wherein R2 and R9 are taken together to form ring A. These cyclic amidines (shown in Scheme II as I-b) can be made via a multi- step cyclisation sequence. Ring A can vary in size (e.g. 5-8 membered ring) and in degree of unsaturation . For example, formation of ring A can be carried out using methods similar to the ones reported in: J. Am. Chem. Soc, 103 (14), 4186- 4194, 1981; J. Het . Chem., 19(1), 193-200, 1982; Angew. Chem., 43(4), 478-482, 2004; Scientia Pharm. , 57(1), 27-38, 1989; Tetrahedron Lett., 16(2), 449-469, 2005; J. Org. Chem. , 59 (17), 5084-5087, 1994. The LG2 group in 5-a or 5-b can be used as a handle for preparation of the compounds of this invention. In this last step LG2 can, for example, be displaced with amines or be engaged in palladium assisted coupling reactions (e.g., Suzuki, Stille) .
[00115] Another aspect of this invention provides compounds that are inhibitors of protein kinases, and thus are useful for the treatment of the diseases, disorders, and conditions, along with other uses described herein. In another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents .
[00116] The present invention provides compounds and compositions that are useful as inhibitors of protein kinases. In some embodiments, the protein kinases are PLK. In some embodiments , PLKl .
[00117] As inhibitors of protein kinases, the compounds and compositions of this invention are particularly useful for treating or lessening the severity of a disease, condition, or disorder where a protein kinase is implicated in the disease, condition, or disorder. In one aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where a protein kinase is implicated in the disease state. In another aspect, the present invention provides a method for treating or lessening the severity of a kinase disease, condition, or disorder where inhibition of enzymatic activity is implicated in the treatment of the disease. In another aspect, this invention provides a method for treating or lessening the severity of a disease, condition, or disorder with compounds that inhibit enzymatic activity by binding to the protein kinase. Another aspect provides a method for treating or lessening the severity of a kinase disease, condition, or disorder by inhibiting enzymatic activity of the kinase with a protein kinase inhibitor.
[00118] In some embodiments, said protein kinase inhibitor is a PLK inhibitor.
[00119] One aspect of the invention relates to a method of inhibiting protein kinase activity in a patient, which method comprises administering to the patient a compound of formula I, or a composition comprising said compound.
[00120] In some embodiments, said method is used to treat or prevent a condition selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immunologically-mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone related diseases, allergies, asthma, and Alzheimer's disease. In some embodiments, said protein kinase in PLK. In other embodiments, said condition is selected from a proliferative disorder and a neurodegenerative disorder. [00121] Depending upon the particular protein kinase- mediated conditions to be treated or prevented, additional drugs, which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention. For example, chemotherapeutic agents or other anti-proliferative agents may be combined with the protein kinase inhibitors of this invention to treat proliferative diseases.
[00122] Those additional agents may be administered separately, as part of a multiple dosage regimen, from the protein kinase inhibitor-containing compound or composition. Alternatively, those agents may be part of a single dosage form, mixed together with the protein kinase inhibitor in a single composition.
[00123] As inhibitors of protein kinases, the compounds and compositions of this invention are also useful in biological samples. One aspect of the invention relates to inhibiting protein kinase activity in a biological sample, which method comprises contacting said biological sample with a compound of formula I or a composition comprising said compound. The term "biological sample", as used herein, means an in vitro or an ex vivo sample, including, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. [00124] Inhibition of protein kinase activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ- transplantation, and biological specimen storage. [00125] Another aspect of this invention relates to the study of protein kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such protein kinases; and the comparative evaluation of new protein kinase inhibitors. Examples of such uses include, but are not limited to, biological assays such as enzyme assays and cell-based assays .
[00126] The activity of the compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the kinase activity or ATPase activity of the activated kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and may be measured either by radiolabelling the inhibitor prior to binding, isolating the inhibitor/kinase complex and determining the amount of radiolabel bound, or by running a competition experiment where new inhibitors are incubated with the kinase bound to known radioligands. Detailed conditions for assaying a compound utilized in this invention as an inhibitor of PLKl, PLK2 , PLK3 , and PLK4 are set forth in the Examples below.
[00127] One aspect of this invention provides compounds that are useful for the treatment of diseases, disorders, and conditions characterized by excessive or abonormal cell proliferation. Such diseases include, a proliferative or hyperproliferative disease, and a neurodegenerative disease. [00128] Examples of proliferative and hyperproliferative diseases include, without limitation, cancer. [00129] The term "cancer" includes, but is not limited to, the following cancers: breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus; larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone; colon; colorectal; adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine; colon-rectum, large intestine, rectum,- brain and central nervous system; chronic myeloid leukemia (CML) , and leukemia. The term "cancer" includes, but is not limited to, the following cancers: myeloma, lymphoma, or a cancer selected from gastric, renal, or and the following cancers: head and neck, oropharangeal , non-small cell lung cancer (NSCLC), endometrial, hepatocarcinoma, Non-Hodgkins lymphoma, and pulmonary.
[00130] For the avoidance of doubt, the term "cancer" also includes, but is not limited to, the following cancers: epidermoid Oral : buccal cavity, lip, tongue, mouth, pharynx; Cardiac : sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma) , myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal : esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small ■ bowel or small intestines (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , large bowel or large intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal; rectum, Genitourinary tract: kidney (adenocarcinoma, WiIm 's tumor [nephroblastoma] , lymphoma, leukemia) , bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma) , cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages; Bone : osteogenic sarcoma (osteosarcoma) , fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing ' s sarcoma, malignant lymphoma (reticulum cell sarcoma) , multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses) , benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) , meninges (meningioma, meningiosarcoma, gliomatosis) , brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma] , glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma) ; Gynecological : uterus (endometrial carcinoma) , cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma] , granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) , vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Hematologic : blood (myeloid leukemia [acute and chronic] , acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin ' s lymphoma [malignant lymphoma] hairy cell; lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, moles dysplastic nevi , lipoma, angioma, dermatofibroma, keloids, psoriasis, Thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma , paraganglioma; and Adrenal glands : neuroblastoma. Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of the above-identified conditions.
[00131] In some embodiments, the compounds of this invention are useful for treating cancer, such as colorectal, thyroid, breast, and lung cancer; and myeloproliferative disorders, such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mast cell disease.
[00132] In some embodiments, the compounds of this invention are useful for treating hematopoietic disorders, in particular, acute-myelogenous leukemia (AMLi) , chronic- myelogenous leukemia (CML) , acute-prornyelocytic leukemia
(APL) , and acute lymphocytic leukemia (ALL) .
[00133] Examples of neurodegenerative diseases include, without limitation, Alzheimer's disease.
[00134] Another aspect of this invention provides a method for the treatment or lessening the severity of a disease selected from a proliferative or hyperproliterative disease, or a neurodegenerative disease, comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound, to a subject in need thereof .
[00135] In certain embodiments, an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective in order to treat said disease. The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of said disease.
[00136] In some embodiments, said disease is a protein-kinase mediated condition. In some embodiments, said disease is a PLK-mediated disease.
[00137] The term "protein kinase-mediated condition", as used herein, means any disease or other deleterious condition in which a protein kinase plays a role. Such conditions include, without limitation, autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immunologically-mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone related diseases, allergies, asthma, and Alzheimer's disease.
[00138] The term "PLK-mediated condition", as used herein means any disease or other deleterious condition in which PLK plays a role. Such conditions include, without limitation, a proliferative or hyperproliterative disease, or a neurodegenerative disease.
[00139] In another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
[00140] In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents . [00141] For example, chemotherapeutic agents or other antiproliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer. [00142] Examples of known chemotherapeutic agents include, but are not limited to, Gleevec™, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil , topotecan, taxol , interferons, and platinum derivatives.
[00143] Other examples of agents the inhibitors of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as Aricept18 and Excelon®; treatments for Parkinson's Disease such as L- DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl , and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®) , Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel , and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-I RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and antiparkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, antileukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin. [00144] As described herein, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences,' Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof . Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component (s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. [00145] Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates , waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes,- oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate,- agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water,- isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. [00146] The protein kinase inhibitors or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to animals or humans . These pharmaceutical compositions, which comprise an amount of the protein inhibitor effective to treat or prevent a protein kinase- mediated condition and a pharmaceutically acceptable carrier, are another embodiment of the present invention. In some embodiments, said protein kinase-mediated condition is a PLK- mediated condition.
[00147] The exact amount of compound required for treatment will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human. [00148] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. In a preferred embodiment, compounds of this invention are administered orally.
[00149] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[00150] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic 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, U. S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides . In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[00151] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00152] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide . Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides) . Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues .
[00153] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound .
[00154] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia/ c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents . [00155] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using, such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
[00156] The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents . They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s ) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes . [00157] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions ,\ sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel .
[00158] In addition to the compounds of this invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of this invention may also be employed in compositions to treat or prevent the above-identified disorders .
[00159] The compounds of this invention can also exist as pharmaceutically acceptable derivatives .
[00160] A "pharmaceutically acceptable derivative" is an adduct or derivative which, upon administration to a patient in need, is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof. Examples of pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters.
[00161] A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof . Particularly favoured derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species .
[00162] Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.
[00163] Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates , waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
[00164] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial , intrasternal , intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously .
[00165] Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic 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 di-glycerides . Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens , Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
[00166] The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions . In the case of tablets for oral use, carriers commonly used include, but are not limited to, lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. [00167] Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols. [00168] The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. [00169] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
[00170] For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers . Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol , benzyl alcohol and water. [00171] For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
[00172] The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
[00173] The amount of protein kinase inhibitor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
[00174] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of inhibitor will also depend upon the particular compound in the composition.
[00175] According to another embodiment, the invention provides methods for treating or preventing a protein kinase- mediated condition (in some embodiments, a PLK-mediated condition) comprising the step of administering to a patient one of the above-described pharmaceutical compositions. The term "patient", as used herein, means an animal, preferably a human.
[00176] In some embodiments, said method is used to treat or prevent a condition selected from a proliferative disorder, such as cancer, a neurodegenerative disorder, an autoimmune disorder, an inflammatory disorder, and an immunologicalIy- mediated disorder. In some embodiments, said method is used to treat or prevent a condition selected from cancers such as cancers of the breast, colon, prostate, skin, pancreas, brain, genitourinary tract, lymphatic system, stomach, larynx and lung, including lung adenocarcinoma and small cell lung cancer; stroke, diabetes, myeloma, hepatomegaly, cardiomegaly, Alzheimer's disease, cystic fibrosis, and viral disease, or any specific disease described above.
[00177] The compounds of this invention may be prepared in general by methods known to those skilled in the art. Those compounds may be analyzed by known methods, including but not limited to LCMS (liquid chromatography mass spectrometry) and NMR (nuclear magnetic resonance) . Compounds of this invention may be also tested according to these examples. It should be understood that the specific conditions shown below are only examples, and are not meant to limit the scope of the conditions that can be used for making, analyzing, or testing the compounds of this invention. Instead, this invention also includes conditions known to those skilled in that art for making, analyzing, and testing the compounds of this invention .
EXAMPLES [00178] As used herein, the term "Rt (min) " refers to the HPLC retention time, in minutes, associated with the compound. Unless otherwise indicated, the HPLC method utilized to obtain the reported retention time is as follows: Column: ACE C8 column, 4.6 x 150 mm
Gradient: 0-100% acetonitrile+methanol 50:50 (2OmM Tris phosphate)
Flow rate: 1.5 mL/minute
Detection: 225 nm.
[00179] Mass spec, samples were analyzed on a MicroMass Quattro Micro mass spectrometer operated in single MS mode with electrospray ionization. Samples were introduced into the mass spectrometer using chromatography.
[00180] 1H-NMR spectra were recorded at 400 MHz using a Bruker DPX 400 instrument. The following compounds of formula I were prepared and analyzed as follows .
[00181] Compounds 1-1 to 1-273 and 1-278 to 1-282 were prepared and characterized as follows in the Examples below. Example 1 :
4- (9-Cyclopentyl-6,7,8, 9-tetrahydro-5-methyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-methoxybenzoic acid
(1-1)
Figure imgf000077_0001
Method A: Methyl 3- (N-cyclopentyl-N- (2-chloro-5- nitropyrimidin-4-yl ) amino ) propionate
Figure imgf000077_0002
[00182] Methyl 3- (cyclopentylamino)propanoate (1.78g, 10.4 m mole) and potassium carbonate (1.52 g, 11.0 m mol) in acetone (25 ml) was stirred at 00C during the addition of a solution of 2 , 4-dichloro-5-nitropyrimidine (2.04 g, 10.4 m mol) in acetone (15ml). The mixture was stirred at ambient temperature overnight, concentrated and diluted with ethyl acetate/water. The mixture was extracted x3 with ethyl acetate, dried over magnesium sulphate and concentrated to an amber oil which solidified on standing. Flash chromatography on silica gel eluting with 30% ethyl acetate / petrol gave methyl 3- (N- cyclopentyl-N- (2-methyl-5-nitropyrimidin-4-yl) amino) propionate as a pale yellow solid (2.24 g, 65%). NMR CDCl3 1.50-2.07 (8H, m) , 2.70-2.82 (2H, m) , 3.65-3.90 (6H, m) , 8.72 (IH, s). Method B: 2-Chloro-9-cyclopentyl-8, 9-dihydro-5H-pyrimido [4.5- b] [1 , 4] diazepin-6 (7H) -one
Figure imgf000078_0001
[00183] Methyl 3- (N-cyclop -N- (2-chloro-5-nitropyrimidin- 4-yl) amino) propionate (2.Og, 6. lmmol ) in glacial acetic acid at 700C was treated in portions with iron powder (0.7g, 12.4mmol) over 6 hours. The mixture was concentrated and triturated with dichloromethane and filtered. The filtrate was absorbed onto silica gel and soxhlet extracted over 7 hours with ethyl acetate. The extract was concentrated to a black oil and triturated with methanol to give pale brown crystals of 2-chloro-9-cyclopentyl-8 , 9-dihydro-5H- pyrimido[4.5-b] [l,4]diazepin-6 (7H) -one (499mg, 31%). NMR 1.46-1.58 (4H, m) , 1.60-1.72 (2H, m) , 1.75-1.85 (2H, m) , 2.64
(2H, d) , 3.55 (2H, d) , 4.92-5.03 (IH, m) , 7.83 (IH, s), 9.72
(IH, s) .
Method C: 2-Chloro-9-cyclopentyl-8 , 9-dihydro-5-methyl-5H- pyrimido [4 , 5-b] [1,4] diazepin-6 (7H) -one
Figure imgf000078_0002
[00184] 2-Chloro-9-cyclopentyl-8 , 9-dihydro-5H-pyrimido [4.5- b] [1, 4]diazepin-6 (7H) -one (474.7mg, 1.78mmol) and methyl iodide (0.122ml, 1.96mmol) in DMA (4.5 ml) stirred at -100C and treated with sodium hydride 60% oil dispersion (75mg, 1.87 πunol) . The mixture was warmed to 00C for 20 min and then to 200C for 40 min. A further 0.12 ml methyl iodide and 8 mg sodium hydride were added and the mixture stirred at ambient overnight . Ice was added and the mixture concentrated under reduced pressure. The residual oil was treated dropwise with water (6ml), filtered and the buff solid dried under high vacuum at 60°C (486mg, 98%). NMR DMSO D61.45-1.72 (6H, m) , 1.76-1.91 (2H, m) , 2.61 (2H, d) , 3.18 (3H, s) , 3.64 (2H, d) , 4.65-4.74 (IH, m) , 8.15 (IH, s).
Method D: 4- (9-Cyclopentyl-6,7, 8# 9-tetrahydro-5-methyl-6-oxo- 5H-pyrimido [4, 5-b] [1, 4] diazepin-2-ylamino) -3-methoxybenzoic acid (1-1)
Figure imgf000079_0001
[00185] 2-Chloro-9-cyclopentyl-8, 9-dihydro-5-methyl-5H- pyrimido [4 , 5-b] [1 , 4]diazepin-6 (7H) -one (150 mg, 0.536 mmol) in ethanol (2.25 ml) and water (9 ml) was treated with cone. HCl
(0.088 ml) and 4-amino-3-methoxy benzoic acid (134 mg, 0-804 mmol). The mixture was stirred at 90°C 24 hours, concentrated and the residue triturated with methanol/ether , filtered and the solid washed with ethanol then ether to give 4- (9- cyclopentyl-6 ,7,8, 9-tetrahydro-5-methyl-6-oxo-5H-pyrimido [4,5- b] [1 , 4] diazepin-2-ylamino) -3-methoxybenzoic acid as a buff powder (185.5 mg, 84%). NMR DMSO D6 1.51-1.79 (6H, m) , 1.82- 1.93 (2H, m) , 2.70-2.75 (2H m), 3.18 (3H, s), 3.72-3.78 (2H, m) , 3.98 (3H, s), 4.81-4.93 (IH, m) , 7.57-7.64 (2H, m) , 8.15- 8.22 (2H, m) , 9.46 (IH, br s) ; HPLC rt (min) : 6.57. Example 2 ;
Method E: 4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo- 5H-pyrimido [4,5-b] [1,4] diazepin-2-ylamino) -3-methoxy-N- (1- methylpiperidin-4-yl)benzamide (1-2)
Figure imgf000080_0001
[00186] Cyclopentyl-6, 7,8, 9-tetrahydro-5-methyl-6-oxo-5H- pyrimido [4 , 5-b] [1 , 4] diazepin-2-ylamino) -3-methoxybenzoic acid
(150 mg, 0.365 mmol) in dichloromethane (5 ml) was treated with diisopropylethylamine (0.127 ml, 0.73 mmol) and TBTU (127 mg, 0.394 mmol) . The mixture was stirred for 25 min then treated with 4-amino-l-methylpiperidine (52 mg, 0.453 mmol) and stirred overnight. The mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate, x2 with 0.02 M sodium hydroxide solution, brine, dried over magnesium sulphate and concentrated. Trituration with ethyl acetate/ether gave 4- (9-cyclopentyl-6 , 7, 8 , 9-tetrahydro-5- methyl-6-oxo-5H-pyrimido [4,5-b] [1,4] diazepin-2-ylamino) -3- methoxy-N- (l-methylpiperidin-4-yl) benzamide as a colourless solid (132 mg, 71%). IH NMR DMSO D6 1.50-2.08 (14H, m) , 2.21
(3H, s), 2.55-2.65 (2H, m) , 2.77-2.87 (2H, m) , 3.21 (3H, s), 3.60-3.70 (2H, m) , 3.70-3.82 (IH, m) , 3.98 (3H, s), 4.80-4.90
(IH, m) , 7.42-7.52 (2H, m) , 7.75 (IH, s) , 8.10-8.18 (2H, m) , 8.40 (IH, d) ; HPLC rt(rain) : 9.60. Example 3 :
4- (9-Cyclopentyl-6,7# 8, 9-tetrahydro-5-methyl-6-oxo-5H- pyrimido[4, 5-b] [l#4]diazepin-2-ylamino) -benzoic acid(1-3)
Figure imgf000081_0001
[00187] Prepared from 2-chloro-9-cyclopentyl-8 , 9-dihydro-S1 methyl-5H-pyrimido[4, 5-b] [1, 4] diazepin-6 (7H) -one and 4- aminobenzoic acid using method D. NMR DMSO D6 1.59-1.80 (6H, m) , 1.90-1.98 <2H, m) , 2.70-2.75 (2H m), 3.18 (3H, s), 3.71- 3.75 (2H, m) , 4.91 (IH, m) , 7.77 (2H, d) , 7.94 (2H, d) , 8.17
(IH, s), 10.65 (IH, br S). HPLC rt(min): 6.39. Example 4 ;
4- (9-cyclopentyl-6,7, 8, 9-tetrahydro-5-methyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -N- (1-methylpiperidin- 4-yl)benzamide (1-4)
Figure imgf000081_0002
[00188] Prepared from compound 1-3 and 4-amino-l- methylpiperidine using method E. IH NMR DMSO D6 1.62-2.05 (14H, m) , 2.23 (3H, s), 2.60-2.68 (2H, m) , 2.77-2.86 (2H, m) , 3.23 (3H, s), 3.65-3.70 (2H, m) , 3.78 (IH, m) , 4.91 (IH, m) , 7.76-7.85 (4H, m) , 8.00 (IH, d) , 8.11 (IH, s), 9.50 (IH, s ) ; HPLC rt (min) : 7.50. Example 5 ;
4-(9-cyclopentyl-6,7#8,9-tetrahydro-5-methyl-6-oxo-5H- pyrimido [4, 5-b] [l,4]diazepin-2-ylamino) -3-methoxy-N- [1- ( tert- butoxycarbony1 )piperidin-4-yl]benzamide (I-5)
Figure imgf000082_0001
[00189] Prepared from compound 1-1 and 4-amino-l- ( tejrt- butoxycarbonyl )piperidine using method E. NMR DMSO D6 1.41 (9H, s), 1.37-1.98 (14H, m) , 2.57-2.63 (2H, m) , 2.80 (2H, m) , 3.17 (3H, s), 3.61-3.69 (2H, m) , 3.91 (3H, s), 3.97 (IH, m) , 4.83 (IH, m) , 7.47-7.52 (2H, m) , 8.07-8.15 (3H, m) , 8.27 (IH, m) ; HPLC rt(πύn) : 10.07. Example 6 :
Method F: 4- (9-cyclopentyl-6, 7, 8, 9-tetrahydiO-5-methyl-6-oxo- 5H-pyrimido[4# 5-b] [1,4] diazepin-2-ylamino) -3-methoxy-N- (pipe-ridin-4-yl)benzamide (1-6)
Figure imgf000082_0002
[00190] To a solution of 4- (9-cyclopentyl-6 , 7 , 8 , 9- tetrahydro-5-methyl-6-oxo-5H-pyrimido [4, 5-b] [1 , 4]diazepin-2- ylamino) -3-methoxy-N- [1- ( tert-butoxycarbonyl ) piperidin-4- yl]benzamide (1-5) (72 mg, 0.12 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid at 00C. The reaction mixture was stirred for 30 minutes at 00C, 60 minutes at room temperature and then solvents were evaporated. The residue was triturated in diethyl ether and the solid filtered to give the TFA salt of the title compound as an off-white solid
(70mg, 95%). IH NMR DMSO D6 1.55-2.04 (14H, m) , 2.62-2.70 (2H, m) , 2.98-3.08 (2H, m) , 3.19 (3H, s), 3.40-3.48 (2H, m) , 3.65-
3.71 (2H, m) , 3.97 (3H, s), 4.09 (IH, m) , 4.89 (IH, m) , 7.49- 7.56 (2H, m) , 8.10 (IH, s) , 8.19 (IH, d) , 8.30-8.40 (2H, d) ,
8.60-8.69 (2H, m) ; HPLC rt (min) : 7.53.
Example 7 :
4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-methoxyphenyl- (4- tert-butoxycarbonypiperazin-1-yl)methanone (1-7)
Figure imgf000083_0001
[00191] Prepared from compound 1-1 and N- tert- butoxycarbonylpiperazine using method E. NMR DMSO D6 1.41 (9H, S), 1.55-1.95 (1OH, m) , 2.57-2.62 (2H, m) , 3.18 (3H, s), 3.27- 3.63 (8H, m) , 3.90 (3H, s), 4.80 (IH, m) , 6.96 (IH, d) , 7.05
(IH, s), 7.72 (IH, s), 8.07 (IH, s), 8.30 (IH, d) ; HPLC rt (min) : 9.98. Example 8 ;
4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino)-3- metlioxyph.en.yl (piperazin-1-yl)methanone (I-8 )
Figure imgf000083_0002
[00192] Prepared from compound 1-7 using method F. NMR DMSO D6 1.50-1.91 (8H, m) , 2.65-2.73 (2H, m) , 3.15-3.22 (7H, m) , 7.63-7.70 (6H, m) , 3.94 (3H, s), 4.80 (IH, m) , 7.12 (IH, d) , 7.20 (IH, s), 8.04 (IH, d) , 8.10 (IH, s), 9.02-9.11 (2H, m) . HPLC rt (min) : 7.81. Example 9 ;
4 - ( 9 - eye 1 open tyl- 6 , 7 , 8 , 9 - tetrahydro- 5-methyl - 6 -oxo-5H- pyrimido [4 , 5-b] [ l, 4 ] diazepin-2-ylamino> -3-methoxy-N- xnethylbenzamide ( 1-9 )
Figure imgf000084_0001
[00193] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.62-1.73 (6H, m) , 1.92-1.97 (2H, m) , 2.58-2.60 (2H, m) , 2.78-2.80 (3H, m) , 3.17 (3H, s), 3.62-3.64 (2H, m) , 3.94 (3H, s), 4.82 (IH, m) , 7.46-7.50 (2H, m) , 7.73 (IH, s), 8.08 (IH, s), 8.35 (IH, m) , 8.38 (IH, m) ; HPLC rt(min): 8.45; MS (ES+) 425, (ES") 423. Example 10 :
4- ( 9-cyclopentyl-6,7,8,9-tetrahydro-5, 7-dimethyl-6-oxo-5H- pyrimido [4, 5-b] [1, 4]diazepin-2-ylamino) -3-methoxybenzoic acid(l-lθ)
Figure imgf000084_0002
[00194] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.08 (3H, d) , 1.48-1.86 (7H, m) , 1.98- 2.10 (IH, m) , 2.90-3.00 (IH, m) , 3.20 (3H, s), 3.37 (IH, d) , 3.56 (IH, t) , 3.95 (3H, s), 4.72-4.85 (IH, m) , 7.56 (IH, s), 7.60 (IH, d) , 8.13 (IH, s), 8.31 (IH, d) , 8.66 (IH, br s); HPLC rt(min): 7.47; MS (ES+) 426, (ES") 424. Example 11 :
4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-methoxy-N- (2- methoxyethyl)benzamide (I-11)
Figure imgf000085_0001
[00195] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.62-1.73 (6H, m) , 1.90-2.0 (2H, m) , 2.54-2.60 (2H, m) , 3.17 (3H, s), 3.25 (3H, s), 3.42-3.46 (4H, m) , 3.62-3.64 (2H, m) , 3.95 (3H, s), 4.82 (IH, m) , 7.49-7.52 (2H, m), 7.74 (IH, s), 8.09 (IH, s), 8.41 (2H, m) ; HPLC rt(min) : 8.65; MS (ES+) 469, (ES") 467. Example 12 ;
4- (9-cyclopentyl-6,7, 8, 9-tetrahydro-5, 7-dimethyl-6-oxo-5H- pyrimido [4# 5-b] [1, 4]diazepin-2-ylamino) -3-methoxy-N- (1- methylpiperidin-4-yl)benzaπιide (1-12 )
Figure imgf000085_0002
[00196] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.03 (3H, d) , 1.50-2.15 (14H, m) , 2.18 (3H, s), 2.76-2.90 (3H, m) , 3.20 (3H, s), 3.28-3.48 (2H, m) , 3.70-3.80 (IH, m) , 3.98 (3H, s), 7.49-7.52 (2H, m) , 7.74 (IH, S), 8.05-8.12 (2H, m) , 8.40 (IH, d) ; HPLC rt(min): 8.95; MS (ES+) 522, (ES") 520. Example 13 :
Method G: Ethyl 4- ( 9-cyclopentyl-6, 7, 8, 9-tetrahydro-5-methyl- 6-oxo-5H-pyrimido[4, 5-b] [l,4]diazepin-2-ylamino)piperidin-l- carboxylate (Z-13)
Figure imgf000085_0003
[00197] 2-Chloro-9-cyclopentyl-8, 9-dihydro-5-methyl-5H- pyrimido[4,5-b] [1 , 4] diazepin-6 (7H) -one (100 mg, 0.357 mmol) and ethyl 4-aminopiperidine-l-carboxylate (129 μl, 0.714 mmol) in isopropylalcohol (2 ml) were heated at 900C for 24 hours. Diisopropylethylamine (125 μl , 0.714 mmol) was added and the reaction mixture was heated at 1050C for another 24 hours. The crude mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, lOuM, 100 A column, gradient 10% - 95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] to afford the title compound (18 mg) as an off-white powder. NMR DMSO D6 1.20 (3H, t) , 1.28-1.91 (14H, m) , 2.80-2.96 (2H, m) , 3.11 <3H," s), 3.50-3.58 (2H, m) , 3.70-3.85 (IH, m) , 3.90-3.98 (2H, m) , 4.03 (2H, q) , 4.60-4.70 (IH, m) , 6.65 (IH, br s) , 7.88 (IH, S); HPLC rt(min) : 8.09; MS (ES+) 417, (ES") 415. Example 14 ;
4-(6,7,8, 9-tetrahydro-5, 9-dimethyl-6-oxo-5H-pyrimido [4,5- b] [l,4]diazepin.-2-ylamino) -3-methoxy-N- (l-methylpiperidin-4- yl)benzamide(l-14) -•"*-
Figure imgf000086_0001
[00198] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.65-1.67 (2H, m) , 1.83-1.85 (2H, m) , 2.33-2.36 (3H, m) , 2.50-2.53 (2H, m) , 2.60-2.63 (2H, m) , 3.07 (3H, s), 3.18 (3H, s), 3.29 (3H, s), 3.69-3.71 (2H, m) , 3.94 (3H, s), 7.48-7.53 (2H, m) , 7.75 (IH, s), 8.11 (2H, m) , 8.46 (IH, m) ; HPLC rt(min): 6.75; MS (ES+) 454, (ES") 452. Example 15 :
4-( (3aR,10aS) -4-cyclopentyl-9-methyl-10-oxo-
1,2,3, 3a, 4,9,10, lOa-octahydro-4,5,7, 9-tetraaza-benzo [f] azulen- 6-ylamino) -3-methoxy-N-methylbenzamide (1-15)
Figure imgf000087_0001
[00199] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.40-1.60 (9H, m) , 1.66-1.69 (2H, m) ,
1.79 (IH, m) , 1.86-1.87 (2H, m) , 2.04 (IH, m) , 2.15 (IH, m) ,
2.80 (3H, d) , 3.20 (3H, s), 3.92 (3H, s), 4.14 (IH, m) , 7.55 (IH, d) , 7.57 (IH, s), 7.95 (IH, d) , 8.22 (IH, s), 8.44 (IH, d) , 8.95 (IH, br s); HPLC rt(min): 9.45; MS (ES+) 465, (ES")
463.
Example 16 ;
4- (9-cyclopentyl-6,7, 8, 9-tetrahydro-5,7, 7-fcrimethyl-6-oxo-5H- pyrimido [4,5-b] [1,4] diazepin-2-ylamino) -3-methoxy-N- methylbenzamide (X-16)
Figure imgf000087_0002
[00200] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.10 (6H, s), 1.62-1.65 (4H, m) , 1.74 (2H, m) , 1.88 (2H, m) , 2.79 (3H, d) , 3.19 (3H, s), 3.36-3.40 (2H, m) , 3.94 (3H, s), 5.18 (IH, m) , 7.45-7.50 (2H, m) , 7.68 (IH, s), 7.99 (IH, s), 8.30 (IH, m) , 8.37 (IH, d) ; HPLC rt(min): 9.23; MS (ES+) 453, (ES") 451. Example 17 ;
4- ( (S) -9-cyclopentyl-6, 7,8, 9-tetrahydro-5, 7-dimethyl-6-oxo-5H- pyrimido [4,5-b] [1,4] diazepin-2-ylamino) -3-methoxy-N- methylbenzamide (1-17)
Figure imgf000088_0001
[00201] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.03-1.07 (3H, m) , 1.55-1.61 (4H, m) , 1.70-1.78 (4H, m) , 1.99 (IH, m) , 2.80 (3H, m) , 3.18 (3H, s) , 3.56-3.61 (2H, m) , 3.94 (3H, s), 4.80 (IH, m) , 7.50-7.52 (IH, m) , 7.58 (IH, m) , 8.07-8.10 (IH, m) , 8.13 (IH, br s), 8.47
(IH, m) , 9.25 (IH, br s) ;. HPLC rt (min) : 8.92; MS (ES+) 439,
(ES") 437.
Example 18 :
4- ( (R) -9-cyclopβntyl-6,7,8, 9-tθtrahydro-5, 7-dimethyl-6-oxo-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -3-methoxy-N- methylbenzamide N(I-18)
Figure imgf000088_0002
[00202] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.03-1.07 (3H, m) , 1.56-1.60 (4H, m) , 1.72-1.78 (4H, m) , 1.98 (IH, m) , 2.80 (3H, m) , 3.19 (3H, m) , 3.57-3.63 (2H, m) , 3.94 (3H, s), 4.81 (IH, m) , 7.50-7.53 (IH, m) , 7.60 (IH, m) , 8.06 (IH, d) , 8.15 (IH, m) , 8.50 (IH, d) , 9.49 (IH, br s); HPLC rt(min): 8.92; MS (ES+) 439, (ES") 437. Example 19 ;
4- (6, 7 , 8, 9-tetrahydro-5, 7,7-trimethyl-6-oxo-9- ((R) -pyrrolidin- 3-yl ) -5H-pyrimido [4,5-b] [1,4] diazepin-2-ylamino) -3-methoxy-N- methylbenzamide (1-19)
Figure imgf000089_0001
[00203] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.118 (3H, s), 1.124 (3H, s) , 2.04 (IH m) , 2.27 (IH, m) , 2.80 <3H, d) , 3.11-3.28 (5H, m) , 3.40-3.56
(4H, m) , 3.93 (3H, s), 5.42 (IH, quint.), 7.53-7.57 (2H, m) , 8.10 (IH, s), 8.17 (IH, d) , 8.39 (IH, q) , 8.55 (IH, br s), 9.05 (IH, br s), 9.12 (IH, br s); HPLC rt(min): 6.14; MS (ES+) 454, (ES7) 452. Example 20;
4-(6,7,8,9-tetraΛydro-5,7,7-trimethyl-9-( (R)-I- methylpyrrolidin-3-yl) -6-oxo-5H-pyrimido[4, 5-b] [l,4]diazepin- 2-ylamino) -3-methoxy-N-methylbenzamide (1-20)
Figure imgf000089_0002
[00204] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.11-1.15 (6H, m) , 2.00-2.41 (2H m) , 2.80 (3H, d) , 2.85-2.95 (3H, m) , 3.10-3.40 (5H, m) , 3.51-3.80
(4H, m) , 3.93 (3H, s), 5.36-5.60 (IH, m) , 7.56-7.59 (2H, m) ,
8.04-8.13 (2H, m) , 8.46 (IH, m) , 8.93-9.13 (IH, br s), 10.38-
10.77 (IH, br s ) ; HPLC rt(min): 7.25; MS (ES+) 468, (ES") 466.
Example 21.
4- ( (S) -9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7-dimethyl-6-oxo-5H- pyrimido [4, 5-b] [1,4] diazepin-2-ylamino) -3-methoxy-N- ( 1- methylpiperidin-4-y1)benzamide (1-21)
Figure imgf000090_0001
[00205] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.06-1.07 (3H, d) , 1.56-2.03 (14H, m) , 2.70 (3H, d) , 3.09 (3H, m) , 3.19 (3H, s) , 3.58-3.64 (2H, m) , 3.95 (3H, S), 4.04 (IH, m) , 4.84 (IH, m) , 7.56-7.64 (2H, m) , 8.08 (IH, d) , 8.22 (IH, s), 8.59 (IH, d) , 9.61 (IH, br s ), 10.77 (IH, br s ) ; HPLC rt (min) : 9.00; MS (ES+) 522, (ES") 520. Example 22 ;
4- ( (R) -θ-cyclopentyl-β,?, 8, 9-tetrahydrO-5,7-dimeth.yl-6-oxo-5H- pyrimido[4# 5-b] [l,4]diazepin-2-ylamino) -3-meth.oxy-N- (1- methylpiperidin-4-yl)benzamide (1-22)
Figure imgf000090_0002
[00206] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.06-1.07 (3H, d) , 1.56-1.98 (14H, m) , 2.71 (3H, d) , 3.02-3.08 (3H,m), 3.19 (3H, s), 3.58-3.64 (2H, m) , 3.95 (3H, s), 4.05 (IH, m) , 4.83 (IH, m) , 7.57-7.64 (2H, m) , 8.09 (IH, m) , 8.23 (IH, s), 8.60 (IH, d) , 9.64 (IH, br s) , 10.81 (IH, br s ) ; HPLC rt (min) : 9.11; MS (ES+) 522, (ES') 520. Example 23:
4- ( 9-cyclopentyl-6,7,8, 9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido[4,5-b] [1, 4]diazepin-2-ylamino) -3-methoxy-N- (1- methylpiperidin-4-yl)benzamide (1-23)
Figure imgf000090_0003
[00207] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.20 (6H, s), 1.55-2.08 (12H, m) , 2.70
(3H, s), 3.00-3.14 (2H, m) , 3.52 (3H, s), 3.50-3.85 (4H, m) , 3.96 (3H, s), 3.98-4.08 (IH, m) , 5.07-5.18 (IH, m) , 7.56 (IH, d) , 7.65 (IH, s), 8.07 (IH, d) , 8.10 (IH, s), 8.57 (IH, d) , 9.50 (IH, br s), 10.60 (IH, br s); HPLC rt(min): 9.55; MS (ES+) 536, (ES") 534. Example 24 :
4- (9-cyclopentyl-6,7, 8, 9-tetrah.yc.ro-5, 7, 7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamin.o) -3-methoxy-N- (pyridin- 4-yl)benzamlde (1-24)
Figure imgf000091_0001
[00208] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.20 (6H, s), 1.55-1.90 (8H, m) , 3.19
(3H, s), 3.50-3,60 (2H, m) , 4.04 (3H, s), 5.13-5.22 (IH, m) , 7.85 (IH, d) , 7.90 (IH,. s), 8.11 (IH, s), 8.31 (IH, d) , 8.45
(2H, d) , 8.77 (2H, d) , 9.18 (IH, br s), 11.78 (IH, S ) ; HPLC rt(min): 9.94; MS (ES+) 516, (ES") 514.
Example 25;
Method H: 4- ( 9-cyclopentyl-6,7, 8, 9-tetrahydro-5, 7 , 7-trimethyl-
6-oxo-5H-pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -3-methoxy-N-
(l-methylazetidin-3-yl)benzamide (1-25)
Figure imgf000091_0002
[00209] 4- (9-cyclopentyl-6, 7,8, 9-tetrahydro-5 , 7 , 7-trimethyl- 6-oxo-5H-pyrimido [4 , 5-b] [1,4] diazepin-2-ylamino) -N- (azetidin- 3-yl) -3-methoxybenzamide (69 mg, 0.14 mmol) was dissolved in methanol (1.5 ml). 37% aqueous formaldehyde (66 μl , 0.84 mmol) and sodium cyanoborohydride (26 mg, 0.42 iranol) were successively added. The reaction mixture was stirred at room temperature for 2 hours. The crude mixture was diluted with 2N HCl then, basified with a saturated solution of NaHCO3. The mixture was extracted twice with ethyl acetate. The combined organic phases were dried (MgSU4 and concentrated in vacuo. The title compound (33 mg) was obtained as a white solid after crystallization from ethyl acetate. NMR DMSO D6 1.10 (6H, s), 1.55-1.69 (4H, m) , 1.69-1.80 (2H, m) , 1.82-1.95 (2H, m) , 2.28 (3H, s), 3.01(2H, t) , 3.38 (2H, s), 3.57 (2H, t), 3.95 (3H, s), 4.39-4.50 (IH, m) , 5.12-5.25 (IH, m) , 7.43-7.52 (2H, m) , 7.71 (IH, S), 8.00 (IH, s), 8.38 (IH, d) , 8.63 (IH, d) ; HPLC rt(min): 9.60; MS (ES+) 508, (ES") 506. Example 26;
4- (9-cyclopenfcyl-6, 7,8, 9-tetrahydro-5,7, 7-trimethyl-6-oxo-5H- pyrimido [4, 5-b] [l,4]diazepin-2-ylamino) -3-methoxy-N-( (R)-I- methylpyrrolidin-3-yl)benzamide (1-26)
Figure imgf000092_0001
[00210] Prepared using the appropriate reagents according to method H. NMR DMSO D5 1.01 (6H, s), 1.52-1.94 (9H, m) , 2.12- 2.20 (IH, m) , 2.27 (3H, s), 2.35-2.42 (IH, m) , 2.8-2.68 (2H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.95 (3H, s), 4.36-4.47 5.13- 5.26 (IH, m) , 7.46-7,56 (2H, m) , 7.69 (IH, s) , 7.99 (IH, s) , 8.33-8.41 (2H, m) ; HPLC rt (min) : 9.71; MS (ES+) 522, (ES") 520. Example 27 :
4-(9-cyclopentyl-6,7,8,9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -3-methoxy-N- (2- (1- methyl-lH-imidazo-5-yl)ethyl )benzamide (1-27 )
Figure imgf000093_0001
[00211] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.01 (6H, s), 1.55-1.94 (8H, m) , 2.77- 2.85 (2H, m) , 3.20 <3H, s), 3.38 (2H, s), 3.45-3.50 (2H, m) , 3.58 (3H, s), 5.15-5.25 (IH, m) , 6.73 (IH, s), 7.45-7.55 (2H, m) , 7.70 (IH, s), 7.99 (IH, s), 8.49 (IH, d) , 8.55-8.59 (IH, m) ; HPLC rt(min): 9.10; MS (ES+) 547, (ES") 545. Example 28:
4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-meth.oxy-N- (3- (4- methylpiperazin-1-yl)propyl )benzamide (1-28 )
Figure imgf000093_0002
[00212] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.53-1.95 (12H, m) , 2.15
(3H, s), 2.20-2.45 (8H, m) , 3.19 (3H, s), 3.22-3.30 (2H, m) , 3.38 (2H, s), 3.94 (3H, s), 5.10-5.21 (IH, m) , 7.48 (IH, d) , 7.49 (IH, S), 7.69 (IH, s), 7.99 (IH, s), 8.30-8.40 (2H, m) ; HPLC rt(min): 9.37; MS (ES+) 579, (ES') 577. Example 29:
4- (9-cyclopentyl-6,7, 8, 9-tetrahydro-7, 7-dimethyl-6-oxo-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -3-metlioxy-N- methylbenzamide (1-29)
Figure imgf000094_0001
[00213] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.15(6H, s), 1.59-1.60 (4H, m) , 1.75- 1.82 (4H, m) , 2.80 (3H, d) , 3.45 (2H, m) , 3.93 (3H, s), 5.21
(IH, m) , 7.48 (IH, m) , 7.56 (IH, s), 7.79 (IH, s), 8.05 (IH, m) , 8.44 (IH, m) , 9.00 (IH, v br s ) , 9.76 (IH, s ) ; HPLC rt (min) : 8.97; MS (ES+) 439, (ES") 437. Example 30;
4- ( 9-cyclopropyl-6, 7, 8, 9-tetrahydro-5 , 7 , 7-trimβthyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylaπιino) -3-methoxy-N- methylbenzamide (1-30)
Figure imgf000094_0002
[00214] Prepared using the appropriate reagents according to method D. NMR DMSO D6 0.83 (2H, m) , 0.96 (2H, q) , 1.16 (6H, s), 2.79 (3H, d) , 3.09 (IH, m) , 3.17 (3H, S), 3.71 (2H, s), 3.96 (3H, s), 7.52-7.56 (2H, m) , 8.12 (IH, s), 8.38 (IH, q) , 8.53 (IH, d) , 9.12 (IH, br s); HPLC rt (min) : 8.26; MS (ES+) 425, (ES") 423. Example 31:
4- (9-cyclopentyl-6,7,8, 9-tetrahydro-5, 7 , 7-trimethyl-6-oxo-5H- pyrimido[4,5-b] [1, 4]diazepin-2-ylaitιino) -3-methoxy-N- (2- (1- methyl-lH-imidazo-4-yl)ethyl )benzamide (1-31)
Figure imgf000094_0003
[00215] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.55-1.68 (4H, m) , 1.70- 1.78 (2H, m) , 1.83-1.93 (2H, m) , 2.70 (2H, t) , 3.19 (3H, s), 3.39 (2H, s), 3.93-3.51 (2H, m) , 3.60 (3H, s), 3.95 (3H, s), 5.14-5.25 (IH, m) , 6.91 (IH, s), 7.43-7.52 (3H, m) , 7.65 (IH, s), 7.99 (IH, s), 8.37 (IH, d) , 8.41-8.46 (IH, m) ; HPLC rt(min): 9.16; MS (ES+) 547, (ES") 545. Example 32:
9-Cyclopentyl-2- [4- ( (S) -3-fluoro-pyrrolidine-1-carbonyl) -2- mβthoxyphenylamino] -5,7, 7-trimethyl-5, 7,8,9- tetrahydropyrimido[4, 5-b] [l,4]diazepin-6-one (1-32)
Figure imgf000095_0001
[00216] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.15 (6H, s), 1.60-2.27 (10H, m) , 3.25 (3H, s), 3.43 (2H, s), 3.65-3.90 (4H, m) , 3.98 (3H, s), 5.18- 5.29 (IH, m) , 5.30-5.53 (IH, m) , 7.15-7.25 (2H, m) , 7.73 (IH, s), 8.03 (IH, s), 8.39 (IH, d) ; HPLC rt(min): 9.67; MS (ES+) 411, (ES") 409. Example 33:
4- (9-cyclopentyl-6,7,8,9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido [4, 5-b] [1, 4]diazepin-2-ylamlno) -3-methoxy-N- (2- morpholinoethyl )benzamide (1-33)
Figure imgf000095_0002
[00217] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.55-1.92 (8H, m) , 2.38- 2.52 (6H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.36-3.44 (2H, m) , 3.54-3.63 (4H, m) , 3.94 (3H, s), 5.12-5.22 (IH, m) , 7.45 (IH, d) , 7.49 (IH, s), 7.69 (IH, s), 7.99 (IH, s), 8.26 (IH, br s) , 8.37 (IH, d) ; HPLC rt (min) : 9.26; MS (ES+) 552, (ES") 550. Example 34 :
4- (9-cyclopentyl-6,7, 8, 9-tefcrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-methoxy-N- (2- (pyrrolidin-1-yl)ethyl )benzamide (1-34)
Figure imgf000096_0001
[00218] Prepared using t e reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.55-1.93 (12H, m) , 2.52- 2.73 (6H, m) , 3.19 (3H, s), 3.39 (2H, s), 2.28-2.46 (2H, m) , 3.95 (3H, s), 5.13-5.22 (IH, m) , 7.43-7.50 (2H, m) , 7.69 (IH, s), 7.99 (IH, s), 8.34-8.42 (2H, m) ; HPLC rt(min): 9.17; MS
(ES+) 536, (ES") 534. Example 35;
4- ( 6 , 7 # 8 , 9 - tet rahydro- 9 - isopropyl -5 , 7 , 7 - trimethyl- 6-oxo- 5H- pyrimido [4 , 5-b] El, 4] diazepin-2 -ylamino) -3-methoxy-N- me thy lbenz amide ( 1-35 )
Figure imgf000096_0002
[00219] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.11 (6H, s), 1.23 (6H, d) , 2.80 (3H, d) , 3.18 (3H, s), 3.50 (2H, s), 3.95 (3H, s), 5.09 (IH, hept) , 7.53 (IH, dd) , 7.57 (IH, d) , 8.01 (IH, s), 8.07 (IH, d) , 8.41
(IH, q) , 9.15 (IH, br s ) ; HPLC rt(min): 8.63; MS (ES+) 527,
(ES") 525. Example 36;
4- (6-Cyclopentyl-4, 4-dimethyl-5, 6-dihydro-4H-2, 3 , 6, 7, 9, 10b- hexaazabenzo [e] azulen-8-ylamino) -3-meth.oxy-N-methylbenzamide
(1-36)
Figure imgf000097_0001
Method I : 8-Chloro-6-Cyclopentyl-4 , 4-dimethyl-5 , 6-dihydro-4H- 2,3,6,7,9, lOb-hexaazabenzo [e] azulene
Figure imgf000097_0002
[00220] 2-Chloro-9-cyclopentyl O-8, 9-dihydro-7 , 7-dimethyl-5H- pyrimido[4, 5-b] (1, 4]diazepin-6 (7H) -one (0.21 g, 0.73 mmol) in phosphorus oxychloride (6 ml) was heated at 1100C for 4 hours. The reaction mixture was concentrated in vacuo and redissolved in dichloromethane (4 ml). This latest solution was then added dropwise to a IM solution of hydrazine in tetrahydrofuran (7.27.ml, 7.27 mmol) . The reaction mixture was stirred overnight at room temperature. A saturated solution of NaHCO3 was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The resulting mixture was dissolved in trimethylorthoformate (4 ml) and heated to 1100C for 90 minutes. The reactionnel mixture was evaporated in vacuo and purified by silica gel chromatography eluting with ethyl acetate to give the title compound as an off-white solid
(0.16 g, 69% yield). NMR DMSO D6 1.37 (6H, s), 1.52-1.88 (8H, m) , 3.44 (2H, s), 5.23 (IH, quint.), 8.56 (IH, s), 9.02 (IH, S) ; MS (ES+) 319. 4- (6-Cyclopentyl-4/4-dimethyl-5, β-dihydro-4H-2,3, 6,7, 9, IQb- hexaazabenzo [e] azulen-8-ylamino) -S-methoxy-N-methylbenzamide (1-36)
Figure imgf000098_0001
[00221] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.41 (6H, s), 1.55-1.90 (8H, m) , 2.80 (3H, d) , 3.50 (2H, s), 3.94 (3H, s), 5.27 (IH, quint.), 7.51 (IH, dd) , 7.57 (IH, d) , 8.08 (IH, d) , 8.47 (IH, q) , 8.51 (IH, S), 8.97 (IH, br S), 9.12 (IH, s) ; HPLC rt(min): 8.54; MS (ES+) 463, (ES") 461. Example 37 ;
4- (9-cyclopenfcyl-6, 7, 8, 9-.tetrahydro-5,7, 7-trimethyl-6-oxo-5H- pyrimido[4,5-b] [1, 4]diazepi->-2-ylamino) - N-(2-((S)-3- fluoropyr-rolidin-1-yl)ethyl) -3-methoxybenzamide (1-37)
Figure imgf000098_0002
[00222] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.16 (6H, s), 1.62-2.04 (9H, m) , 2.08- 2.50 (2H, m) , 2.60-3.00 (5H, m) , 3.25 (3H, s), 3.43-3.48 (2H, m) , 3.44 (2H, s), 4.00 (3H, s), 5.17-5.38 (2H, m) , 7.51 (IH, d) , 7.56 (IH, s), 7.74 (IH, s), 8.05 (IH, s), 8.35-8.48 (IH, m) , 8.43 (IH, d) ; HPLC rt(min): 9.57; MS (ES+) 554, (ES") 552. Example 38:
4-(9-cyclopentyl-6,7#8,9-tetrahydro-5,7,7-trimeth.yl-6-oxo-5H- pyrimido[4,5-b] [l,4]diazepin-2-ylamino) - N- (2azetidin-l- yl)ethyl) -3-methoxybenzamide (1-38)
Figure imgf000099_0001
[00223] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.55-2.04 (1OH. m) , 2.35- 2.55 (2H, ra) , 3.08-3.25 (6H, m) , 3.20 (3H, s) , 3.38 (2H, s), 3.75-3.95 (IH, m) , 3.94 (3H, s) , 5.15-5.25 (IH, m) , 7.46 (IH, s), 7.50 (IH, s), 7.68 (IH, s), 7.80 (IH, s), 8.24-8.30 (IH, m) , 8.36 (IH, d) ; HPLC rt(min): 9.31; MS (ES+) 522, (ES") 520. Example 39;
(R) -S-Fluoro-pyrrolidine-l-carboxylic acid 2-[4-(9- cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7,8, 9-tetrahydro-5H- pyrim±do[4, 5-b] [1, 4] diazepin-2-ylamino) -3- methoxybenzoylamino] -ethyl ester (1-39)
Figure imgf000099_0002
[00224] Prepared using the appropriate reagents according to method E. IMMR DMSO D6 1.10 (6H, s), 1.55-1.96 (8H, m) , 2.05- 2.15 (2H, m) , 3.19 (3H, s), 3.88 (2H1 s), 3.45-3.58 (6H, m) , 3.94 (3H, s), 4.09-4.20 (2H, m) , 7.46 (IH, d) , 7.50 (IH, s), 7.72 (IH, s), 7.99 (IH, s), 8.37 (IH, d) , 8.43-8.47 (IH, m) ; HPLC rt(min) : 9.49; MS (ES+) 598, (ES") 596. Example 40;
4- (6, 7, 8, 9-tetrahydro-5, 7 , 7-trimethyl-6-oxo-9-phenyl-5H- pyrimido[4, 5-b] [1, 4] diazepin-2-ylamino) -3-meth.oxy-N- methylbenzamide (1-40)
Figure imgf000100_0001
[00225] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.29 (6H, s), 2.78 (3H, d) , 3.29 (3H, s), 3.89 (3H, s), 3.93 (2H, s) , 6.86 (IH, dd) , 7.08 (IH, d) , 7.38-7.42 (3H, m) , 7.52-7.57 (IH, in), 7.61 (2H, t) , 8.26-8.30 (2H, m) , 8.86 (IH, br s) ; HPLC rt(min): 8.59; MS (ES+) 461, (ES") 459. Example 41;
4- (9-cyclopentyl-5-ethyl-6,7, 8, 9-tefcrahydrO-6-oxo-5H- pyrimido[4, 5-b] [1, 4] diazepin-2-ylamino) -3-mefch.oxy-N- methylbenzand.de (X-41)
Figure imgf000100_0002
[00226] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.00 (3H, t), 1.56-1.76 (6H, m) , 1.88- 2.02 (2H, m) , 2.50-2.56 (2H, m) , 2.79 (3H, d) , 3.61-3.64 (2H, m) , 3.70 (2H, q) , 3.94 (3H, s), 4.74 (IH, dt) , 7.47 (IH, dd) , 7.51 (IH, d) , 7.86 (IH, br s), 8.13 (IH, s), 8.28-8.33 (IH, m) , 8.36 (IH, d) ; HPLC rt(min): 8.76; MS (ES+) 439, (ES") 437. Example 42 ;
4- (6-Cyclopentyl-5# 6-dihydro-4H-2, 3,6,7,9, 10b-hexaaza- benzo [e] azulβn-8-ylamino) -3-methoxy-N-methylbenzamidθ (1-42)
Figure imgf000100_0003
Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.63-1.71 (4H, m) , 1.73-1.85 (2H, m) , 1.88-2.00 (2H, m) , 2.85 (3H, d) , 3.26-3.31 (2H, m) , 3.62-3.67 (2H, m) , 3.99 (3H, s), 5.26 (IH, dt), 7.53 (IH, dd) , 7.57 (IH, d) , 8.02 (IH, s), 8.34 (IH, d) , 8.34-8.39 (IH, m) , 8.45 (IH, s), 9.01 (IH, s); HPLC rt (min) : 7.88; MS (ES+) 435, (ES") 433. Example 43 ;
2- (lH-benzo[d] imidazol-6-ylamino) -9-cyclopentyl-β, 9-dihydro- 5,7,7-trimethyl-5H-pyrimido[4,5-b] [1, 4]diazepin-6 (7H) -one (I- 43)
Figure imgf000101_0001
[00227] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.12 (6H, s), 1.52-1.65 (4H, m) , 1.66- 1.76 (2H1 m) , 1.82-1.93 (2H, m) , 3.20 (3H, s) , 3.40 (2H, s), 5.25 (IH, dt), 7.69-7.76 (2H, m) , 7.97 (IH, s), 8.26 (IH, br s), 9.31 (IH, br s) , 9.67 (IH, br s); HPLC rt(min): 8.52; MS (ES+) 406, (ES") 404. Example 44 t
2- (benzotd] thiazol-6-ylamino) -9-cyclopentyl-8,9-dihydro-5,7,7- trimetliyl-5H-pyrimido[4#5-b] [1, 4]diazepin-6 (7H) -one (1-44)
Figure imgf000101_0002
[00228] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s), 1.57-1.68 (4H, m) , 1.69- 1.79 (2H, m) , 1.82-1.94 (2H, m) , 3.20 (3H, s), 3.43 (2H, s) , 5.22 (IH, dt) , 7.62 (IH, dd) , 7.97 (IH, s) , 7.99 (IH, d) , 8.65 (IH, br S), 9.21 (IH, s), 9.70 (IH, br s) ; HPLC rt (min) : 9.99; MS (ES+) 423, (ES") 421. Example 45 ;
2 - ( 2-oxoindolin-5-ylamino) -9-cyclopentyl-8 # 9-dihydro-5 , 7 , 7- trimethyl-5H-pyriiαido [4 , 5-b] [ l# 4 ] diazepin-6 ( 7H) -one ( 1-45 )
Figure imgf000102_0001
[00229] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s), 1.47-1.63 (4H, m) , 1.64- 1.78 (2H, m) , 1.79-1.90 (2H, m) , 3.17 (3H, s), 3.45 (2H, s) , 3.47 (2H, s), 5.13 (IH, dt), .6.79 (IH, d) , 7.29 (IH, d) , 7.49
(IH, Ξ) , 7.83 (IH, s), 9.60 (lH, br s) , 10.33 (IH, s); HPLC rt(min): 8.59; MS (ES+) 421, (ES") 419. Example 46;
3-(9-cyclopentyl-6,7,8,9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido[4/ 5-b] [l,,4]diazepin-2-ylamino) -N-methylbenzamide (I- 46)
Figure imgf000102_0002
[00230] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s), 1.50-1.62 (4H, m) , 1.62- 1.75 (2H, m) , 1.78-1.90 (2H, m) , 2.77 (3H, d) , 3.19 (3H, s), 3.44 (2H, s), 7.39 (IH, dd) , 7.47 (IH, d) , 7.59 (IH, d) , 7.94
(IH, s), 8.19 (IH, dd) , 8.34-8.39 (IH, m) , 9.85 (IH, br s ) ; HPLC rt(min): 8.80; MS (ES+) 423, (ES") 421. Example 47 ;
2- ( IH-indazo-6-ylamino) -9-cyclopentyl-8 , 9-dihydro-5, 7,7- trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin-6 (7H) -one (1-47)
Figure imgf000102_0003
[00231] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.14 (6H, s), 1.51-1.77 (6H, m) , 1.81- 1.90 (2H, m) , 3.19 (3H, s), 3.46 (2H, s), 5.21 (IH, dt) , 7.25
(IH, dd) , 7.69 (IH, d) , 7.85 (IH, s), 7.93 (IH, s), 8.01 (IH, s), 9.98 (IH, br s), 12.97 (IH, br s); HPLC rt(min): 9.25; MS
(ES+) 406, (ES") 404. Example 48;
2- (4- (lH-imidazol-l-yDphenylamino) -9-cyclopentyl-8, 9-dihydro- 5,7,7-trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin-6 (7H) -one (I- 48)
Figure imgf000103_0001
[00232] Prepared using t appropriate reagents according to method D. NMR DMSO D6 1.12 (6H, s), 1.56-1.69 (4H, m) , 1.70- 1.77 (2H, m) , 1.83-1.94 (2H, m) , 3.19 (3H, s), 3.42 (2H, s), 5.23 (IH, dt) , 7.69 (IH, s), 7.72 (IH, s), 7.87-7.93 (2H, m) , 7.93 (IH, s), 8.01 (IH, s), 8.23 (IH, dd) , 9.58 (IH, s), 9.79
(IH, br S); HPLC rt(min): 9.75; MS (ES+) 432, (ES") 430. Example 49:
2- (4- (lH-l,2,4-triazol-l-yl)phenylamino) -9-cyclopentyl-8, 9- dihydro-5, 7 , 7-trimethyl-5H-pyrimido [4, 5-b] [1, 4] diazepin-6 (7H) - one (1-49)
Figure imgf000103_0002
[00233] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s), 1.57-1.68 (4H, m) , 1.69- 1.79 (2H, m) , 1.82-1.95 (2H, m) , 3.19 (3H, s), 3.45 (2H, s), 5.19 (IH, dt) , 7.75-7.83 (4H, m) , 7.96 (IH, s), 8.22 (IH, s), 9.23 (IH, s), 9.88 (IH, br s); HPLC rt (min) : 9.45; MS (ES+)
433, (ES') 431.
Example 50 :
4- ( 9-cyclopentyl-6, 7,8, 9-tetrahydro-5, 7 , 7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-isopropoxy-N- methylbenzamide (1-50)
Figure imgf000104_0001
[00234] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.10 (6H, s), 1.36 (6H, d) , 1.57-1.70
(4H, m) , 1.70-1.81 (2H, m) , 1.85-1.94 (2H, m) , 2.78 (3H,d), 3.19 (3H, s), 3.39 (2H, Ξ), 4.68-4.78 (IH, m) , 5.08-5.18 (IH, m) , 7.44 (IH, d) , 7.50 (IH, s), 7.62 (IH, s), 7.98 (IH, s), 8.30-8.35 (IH, m) , 8.38 (IH, d) ; HPLC rt(min): 9.84; MS (ES+) 481, (ES") 479. Example 51;
4- (9-cyclopentyl-.6,7, 8#9-tetrahydro-5, 7, 7-trimeth.yl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-isopropoxy-N- (1- methylpiperidin-4-yl)benzamide (1-51)
Figure imgf000104_0002
[00235] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.10 (6H, s), 1.35 (6H, d) , 1.55-2.05
(14H, m) , 2.19 (3H, s), 2.78-2.87 (2H, m) , 3.19 (3H, s), 3.39
(2H, s), 3.22-3.30 (IH, m) , 4.73-4.82 (IH, m) , 5.09-5.20 (IH, m) , 7.47 (IH, d) , 7.52 (IH, s), 7.34 (IH, s), 7.98 (IH, s), 8.09 (IH, d) , 8.38 (IH, d) ; HPLC rt (min) : 10.05; MS (ES+) 564,
(ES") 562. Example 52 t
4-(9-cyclopentyl-6,7r8,9-tetrahydro-5,7/7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -N- (1- isopropylazetidin-3-yl) -3-methoxybenzamide (1-52)
Figure imgf000105_0001
[00236] Prepared using the appropriate reagents according to method H. NMR DMSO D6 0.89 (6H, d) , 1.10 (6H, s), 1.55-1.93 (8H, m) , 2.32-2.42 (IH, m) , 2.90-3.06 (2H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.48-3.61 (2H, m) , 3.95 (3H, s), 4.35-4.47 (IH, m) , 5.17-5.26 (Ih, m) , 7.49 (IH, d) , 7.50 (IH, s), 7.71 (IH, Ξ) , 7.99 (IH, s), 8.38 (IH, d) , 8.63 (IH, br s); HPLC rt(min): 9.60; MS (ES+) 536, (ES") 534. Example 53 ;
4- (9-cyclopentyl-6, 7, 8, 9-tetrah.ydro-5,7,7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -N- (1- (cyclopropylmethyl)azetidin-3-yl) -3-methoxybenzamide (1-53)
Figure imgf000105_0002
[00237] Prepared using the appropriate reagents according to method H. MMR DMSO Ds 0.00-0.05 (2H, m) , 0.30-0.35 (2H, m) , 0.50-0.71 (IH, m) , 1.00 (6H, s), 1.47-1.85 (8H, m) , 2.17-2.26
(2H, m) , 2.88-3.00 (2H m), 3.09 (3H, s), 3.29 (2H, s), 3.48- 3.57 (2H, m) , 3.85 (3H, s), 4.32-4.42 (IH, m) , 5.04-5.14 (IH, m) , 7.38 (IH, d) , 4.41 (IH, s), 7.61 (IH, s), 7.90 (IH, s), 8.28 (IH, d) , 8.53 (IH, d) ; HPLC rt(min): 9.68; MS (ES+) 548,
(ES") 546. Example 54 :
Method J: 2- (benzylamino) -9-cyclopentyl-8,9-dihydro-5,7,7- trimβthyl-5H-pyrimido[4,5-b] [1, 4]diazepin-6 (7H) -one (1-54)
Figure imgf000106_0001
[00238] To 2-Chloro-9-cyclopentyl-8,9-dihydro-5,7,7- trimethyl-5H-pyrimido [4 , 5-b] [1 , 4] diazepin-6 (7H) -one (50 mg, 0.162 irtmol) in "butanol (2 ml), was added benzylamine (71 μl , 0.648 πunol) and diisopropylethylamine (113 μl , 0.648 mmol ) . The reaction mixture was heated to 140 0C in a microwave for 90 minutes. The crude mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, lOuM, 100 A column, gradient 10% - 95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] to afford the title compound (33 mg) as an off-white powder. NMR DMSO D6 1.10 (6H, s), 1.46-1.58 (4H, m) , 1.60-1.74 (4H, m) , 3.13 (3H, s), 3.42 (2H, s), 4.52 (2H, d) , 4.95-5.04 (IH, m) , 7.24-7.30 (IH, m) , 7.31-7.39 (4H, m) , 7.83 (IH, s), 8.64 (IH, br s ) ; HPLC rt(min): 10.36; MS (ES+) 380, (ES") 378. Example 55:
9-cyclopentyl-8 , 9-dihydro-5, 7 , 7-trimethyl-2- (phenethylami.no) - 5H-pyrimido[4/5-b] [l,4]diazepin-6(7H) -one (1-55)
Figure imgf000106_0002
[00239] Prepared using the appropriate reagents according to method J. NMR DMSO D6 1.07 (6H, s), 1.51-1.60 (4H, m) , 1.62- 1.72 (2H, m) , 1.77-1.89 (2H, m) , 2.78-2.84 (2H, m) , 3.13 (3H, s), 3.31 (2H, d) , 3.36-3.45 (2H, m) , 5.18-5.28 (IH, m) , 7.17- 7.24 (3H, m) , 7.26-7.32 (2H, m) , 7.78 (IH, s ) ; HPLC rt(min): 10.64; MS (ES+) 394, (ES") 392. Example 56;
4- ( 6, 7, 8 , 9-tθtrahydro-9- (tetrahydro-2H-pyran-4-yl ) -5, 7 , 7- trimethyl-6-oxo-5H-pyrimido[4, 5-b] [l,4]diazβpin-2-ylamino) -3- methoxy-N-methylbenzamide (1-56)
Figure imgf000107_0001
[00240] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.15 (6H, s), 1.63 (2H, br d) , 1.91 (2H, dq) , 2.82 (3H, d) , 3.18 (3H, s), 3.37 (2H, t), 3.57 (2H, s), 3.94 (3H, s), 4.01 (2H, dd) , 4.92 (IH, tt) , 7.57 (IH, dd) , 7.60 (IH, d) , 8.06 (IH, d) , 8.09 (IH, s), 8.51 (IH, q) , 9.32 (IH, br S); HPLC rt (min) : 7.94; MS (ES+) 469, (ES") 467. Example 57 ;
2- ( (R) -2, 3-dihydro-lH-inden-l-ylamino) -9-cyclopentyl-8,9- dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin-6 (7H) - one (1-57)
Figure imgf000107_0002
[00241] Prepared using the appropriate reagents according to method J. NMR DMSO D5 1.08 (6H, s), 1.41-1.57 (4H, m) , 1.59- 1.82 (4H, m) , 1.91-2.04 (IH, m) , 2.36-2.45 (IH, m) , 2.74-2.84
(IH, m) , 2.90-2.98 (IH, m) , 3.15 (3H, s) , 3.29 (2H1 d) , 5.01- 5.16 (IH, m) , 5.32-5.44 (IH, m) , 6.94 (IH, br s), 7.11-7.24
(4H, m) , 7.81 (IH, s); HPLC rt (min) : 10.83; MS (ES+) 406, (ES") 404.
Example 58 :
4- (9- (cyclopropylmethyl) -6,7, 8,9-tetrahydro-5,7#7-trimethyl-6- oxo-5H-pyrimido[4, 5-b] [1, 4] diazepin-2-ylamino) -3-methoxy-N- methylbenzamide (1-58)
Figure imgf000108_0001
[00242] Prepared using the appropriate reagents according to method D. NMR DMSO D6 0.27-0.35 (2H, m) , 0.47-0.53 (2H, m) , 1.15-1.25 (7H1 m) , 2.80 (3H, d) , 3.19 (3H, s), 3.66 (2H, d) , 3.72 (2H, S), 3.94 (3H, s) , 7.51 (IH, dd) , 7.57 (IH, d) , 8.03 (IH, s), 8.07 (IH, d) , 8.46 (IH, q) , 9.15 (IH, br s); HPLC rt(min): 8.72; MS (ES+) 439, (ES") 437. Example 59 ; . •
4- (9-cyclopentyl-6,7, 8, 9-tetrahydro-5,7, 7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -N- (1-
(cyclopropylmethyl)pipβridin-4-yl) -3-methoxybenzamide (1-59)
Figure imgf000108_0002
[00243] Prepared using the appropriate reagents according to method H. NMR DMSO D6 0.00-0.05 (2H, m) , 0.30-0.35 (2H, m) , 0.50-0.71 (IH, m) , 1.00 (6H, s), 1.47-1.85 (8H, m) , 2.17-2.26
(2H, m) , 2.88-3.00 (2H m)., 3.09 (3H, s), 3.29 (2H, s), 3.48- 3.57 (2H, m) , 3.85 (3H, s), 4.32-4.42 (IH, m) , 5.04-5.14 (IH, m) , 7.38 (IH, d) , 4.41 (IH, s), 7,61 (IH, s), 7.90 (IH, s), 8.28 (IH, d) , 8.53 (IH, d) ; HPLC rt (min) : 9.68; MS (ES+) 548,
(ES") 546. Example 60 ;
4- ( 9 ' -cyclopentyl-5 • -methyl-6 • -oxo-5 ' , 6 ' , 8 • , 9 • - tetrahydrospiro [cyclobutane-1,7' -pyrimido [4, 5- b] [1, 4]diazepine] -2 • -ylamino) -3-methoxy-N-methylbθnzamidθ (I- 60)
Figure imgf000109_0001
[00244] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.67-1.89 (9H, m) , 2.08-2.10 (2H, m) , 2.30-2.40 (3H, m) , 2.85 (3H, d) , 3.27 (3H, s), 3.70 (2H, s), 3.99 (3H, s), 4.88 (IH, quint.), 7.52 (IH, d) , 7.56 (IH, s), 7.79 (IH, S), 8.11 (IH, s), 8.40 (IH, d) , 8.44 (IH, d) ; HPLC rt(min): 9.30; MS (ES+) 465, (ES") 463. Example 61;
4- ( (R) -S-cyclopentyl-δrT/βj-i-tetraLhydro-S, 8-dimethyl-6-oxo-5H- pyrimido [4, 5-b] [1,4] diazepin-2-ylamino) -3-methoxy-N- methylbenzamide (1-61)
Figure imgf000109_0002
[00245] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.18 (3H, d) , 1.31-1.49 (IH, m) , 1.60- 1.81 (5H, m) , 1.90-1.96 (IH, m) , 1.97-2.02 (IH, m) , 2.33-2.40
(2H, m) , 2.78 (3H, d) , 3.19 (3H, s), 3.96 (3H, s), 4.03 (IH, t) , 4.66 (IH, quint.), 7.46 (IH, d) , 7.50 (IH, s), 7.78 (IH, m) , 8.10 (IH, s), 8.30-8.34 (2H, m) ; HPLC rt(min): 8.70; MS
(ES+) 439, (ES") 437. Example 62 :
4- (9 • -cyclopentyl-5 ■ -methyl-6 ' -oxo-5 • , 6 • , 8 • , 9 • - tetrahydrospiro [cyclopropane-1,7" -pyrimido [4, 5- b] [l,4]diazepine] -2 ■ -ylamino) -3-methoxy-N-methylbenzamide (l- 62)
Figure imgf000110_0001
[00246] Prepared using the appropriate reagents according to method D. NMR DMSO D6 0.66-0.69 (2H, m) , 0.88-0.92 (2H, m) , 1.48-1.72 (6H, m) , 1.85-1.91 (2H, m) , 2.78 (3H, d) , 3.17 (3H, S), 3.48 {2H, S), 3.94 (3H, s), 4.85 (IH, quint.), 7.46 (IH, d) , 7.49 (IH, s), 7.69 (IH, s), 7.90 (IH, s), 8.33 (IH, m) , 8.40 (IH, d) ; HPLC rt (min) : 8.80; MS (ES+) 451, (ES") 449. Example 63 :
2- (4-morpholinophenylami.no) -9-cyclopentyl-8, 9-dihydrO-5, 7, 7- trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin-6 (7H) -one (1-63)
Figure imgf000110_0002
[00247] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.14 (6H, s), 1.48-1.85 (8H, m) , 3.10
(4H, t) , 3.16 (3H, s), 3.48 (2H, s), 3.75 (4H, t) , 5.11 (lH, dt) , 6.98 (2H, d) , 7.38 (2H, d) , 7.84 (IH, s), 10.01 (IH, br S); HPLC rt(min): 9.47; MS (ES+) 451, (ES") 449. Example 64 ;
4- (9 ' -cyclopentyl-5 • -methyl-6 • -oxo-5 ■ , 6 ' ,8 • , 9 ' - tetrahydrospiro [cyclobutane-1, 7 • -pyrimido [4 , 5- b] [1, 4] diazepine] -2 • -ylamino) -3-methoxy-N- (1-methylpiperidin- 4-yl )benzaπιide (1-64)
Figure imgf000110_0003
[00248] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.53-1.71 (9H, m) , 1.78-1.99 (6H, m) , 2.08-2.12 (2H, m) , 2.20-2.33 (6H, m) , 2.77-2.96 (2H, m) , 3.19 (3H, s), 3.65 (2H, s), 3.75-3.84 (IH, m) , 3.95 (3H, s), 4.83 (IH, quint.), 7.48 (IH, d) , 7.50 (IH, s), 7.73 (IH, s), 8.06 (IH, s), 8.13 (IH, br d) , 8.37 (IH, d) ; HPLC rt(min) : 9.50; MS (ES+) 548, (ES") 546. Example 65 ;
4- ( (R) -9-cyclopentyl-β, 7, 8, 9-tetrahydro-5# 8-dimethyl-6-oxo-5H- pyrimido [4, 5-b] [l,4]diazepin-2-ylamino) -3-xnethoxy-N- (1- methylpiperidin-4-yl)benzamide (1-65)
Figure imgf000111_0001
[00249] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.27 (3H, d) , 1.33-1.42 (IH, m) , 1.56- 1.79 (9H), 1.91-2.02 (4H, m) , 2.20 (3H, s), 2.41-2.54 (IH, m) , 2.66-2.75 (IH, m) , 2.76-2.86 (2H, m) , 3.21 (3H, s), 3.71-3.79
(IH, m) , 3.94 (3H, s), 4.00-4.05 (IH, m) , 4.64 (IH, quint.), 7.48 (IH, d) , 7.49 (IH, s), 7.74 (IH, s), 8.11 (IH, s), 8.13
(IH, s), 8.32 (IH, d) ; HPLC rt (min) : 8.50; MS (ES+) 522, (ES") 520.
Example 66 ;
4- (9- ( (R) -l-cyclopropylmethyl)pyrrolidin-3-yl) -6,7,8,9- tetrahydro-5, 7 , 7-trimethyl-6-oxo-5H-pyrimido[4, 5- b] [1,4] diazepin-2-ylamino) -3-mβthoxy-N-methylbenzamide (1-66)
Figure imgf000111_0002
[00250] Prepared using the appropriate reagents according to method D. NMR DMSO D6 0.27-0.35 (2H, m) , 0.47-0.53 (2H, m) , 1.15-1.25 (7H, m) , 2.80 (3H, d) , 3.19 (3H, s) , 3.66 (2H, d) , 3.72 (2H, s), 3.94 (3H, s) , 7.51 (IH, dd) , 7.57 (IH, d) , 8.03
(IH, s), 8.07 (IH, d) , 8.46 (IH, q) , 9.15 (IH, br s); HPLC rt(min): 7.93; MS (ES+) 508, (ES") 507.
Example 67 ;
4- ( 9-cyclopentyl-6, 7 , 8, 9-tetrahydro-5, 7 , 7-trixnethyl-6-oxo-5H- pyrimido[4/5-b] [l,4]diazepin-2-ylaminό) -N- (1-
(isopropylpiperidin-4-yl) -3-methoxybenzamide (1-67)
Figure imgf000112_0001
[00251] Prepared using the appropriate reagents according to method H. NMR CDCl3 1.05 (6H, d) , 1.13 (6H, s) , 1.40-2.41
(13H, m) , 2.78-2.95 (3H, m) , 3.20 <3H, s), 3.30 (2H, s), 3.90
(3H, s), 3.90-4.01 (IH, m) , 5.18-5.30 (IH, m) , 5.96-6.01 (IH, m) , 7.17 (IH, d) , 7.19 (IH, s) , 7.34 (IH, s), 7.55 (IH, s), 7.78 (IH, s), 8.41 (IH, d) ; HPLC rt(min): 9.06; MS (ES+) 564,
(ES") 562. Example 68 :
4- (9-cyclopentyl-6, 7 , 8, 9-tetrahydro-5, 7 , 7-trimeth.yl-6-oxo-5H- pyximido [4, 5-b] [1, 4]diazepin-2-ylamino) -3-methoxy-N-
(1,2,2,6, 6-pentamethylpiperidin-4-yl) -benzamide (1-68)
Figure imgf000112_0002
[00252] Prepared using the appropriate reagents according to method E. NMR CDCl3 1.07 (12H, s), 1.20 (6H, s), 1.40-1.95
(HH, in), 2.28 (3H, S) , 3.22 (3H, s), 3.30 (2H, s), 3.90 (3H, s), 4.30-4.40 (IH, m) , 5.20-5.29 (IH, m) , 5.33-5.43 (IH, m) , 7.16 (IH, d) , 7.19 (IH, s), 7.36 (IH, s), 7.56 (IH, S), 7.78 (IH, s), 8.41 (IH, d) ; HPLC rt(min) : 9.07; MS (ES+) 591, (ES") 590.
Example 69 ;
4-(9-cyclopentyl-6,7,8,9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido[4,5-b] [l/4]diazepin-2-ylamino) -3-metlxoxy-N- (1-
(propylpiperidin-4-yl)benzamide (1-69)
Figure imgf000113_0001
[00253] Prepared using the appropriate reagents according to method H. NMR CDCl3 0.85 (3H, t) , 1.13 (6H, s), 1.17-1.21 (2H, m) , 1.47-2.40 (19H, m) , 2.90-2.99 <2H, m) , 3.22 (3H, s), 3.30
(2H, s), 3.90 (3H, s), 3.91-4.02 (IH, m) , 5.18-5.28 (IH, m) ,
5.95-6.00 (IH, m) , 7.16 (IH, d) , 7.18 (IH, s), 7.34 (IH, s),
7.55 (IH, s), 7.78 (IH, s), 8.41 (IH, d) ; HPLC rt(min): 9.45;
MS (ES+) 564, (ES") 562.
Example 70;
4- (9-cyclopentyl-6, 7 , 8 , 9-tetrahydro-5,7 , 7-trimethyl-6-oxo-5H- pyrimido [4, 5-b] [l,4]diazepin-2-ylamino) -N-(I-
(isobutylpiperidin-4-yl) -3-methoxybenzamide (1-70)
Figure imgf000113_0002
[00254] Prepared using the appropriate reagents according to method H. NMR CDCl3 0.85 (6H, d) , 1.13 (6H, s), 1.41-2.15
(16H, m) , 2.75-2.85 (2H, m) , 3.23 (3H, s), 3.30 (2H, s), 3.90
(3H, s), 3.90-3.97 (IH, m) , 5.20-5.29 (IH, m) , 5.91-5.97 (IH, m) , 7.14 (IH, s), 7.20 (IH, s), 7.34 (IH, s), 7.55 (IH, s), 7.78 (IH, s), 8.41 (IH, d) ; HPLC rt(min): 9.83; MS (ES+) 578,
(ES") 576. Example 71:
4-(9-cyclopentyl-6,7,8,9-tetrahydrx>-5,7,7-trimethyl-6-oxo-5H- pyrimido[4,5-b] [l,4]diazepin-2-ylamino) -N- (1-tert- butylpipβridin-4-yl) -3-methoxybenzamide (1-71)
Figure imgf000114_0001
[00255] Prepared using the appropriate reagents according to method E. NMR CDCl3 1.10 (9H, s), 1.13 (6H, s), 1.40-2.09
(12H, m) , 2.26-2.36 (2H, m) , 2.97-3.10 (2H, m) , 3.23 (3H, s), 3.30 (2H, s), 3.90 (3H1 s), 3.30-3.10 (IH, m) , 5.18-5.28 (IH, m) , 5.95-6.01 (IH, m) , 7.15 (IH, d) , 7.20 (IH, s), 7.35 (IH, s), 7.55 (IH, s), 7.78 (IH, s) , 8.41 (IH, d) ; HPLC rt (min) : 8.83; MS (ES+) 578, (ES") 576. Example 72 :
4- ( 9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 1, 7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -N- (1- (ethylpiperidin- 4-yl) -3-methoxybenzamide (1-72)
Figure imgf000114_0002
[00256] Prepared using the appropriate reagents according to method H. NMR CDCl3 1.22 (3H, t), 1.26 (6H, s), 1.50-2.18
(HH, m) , 2.20-2.34 (2H, m) , 2.58 (2H, g) , 3.06-3.13 (2H, m) , 3.32 (3H, s) , 3.39 (2H, s), 4.00 (3H, s), 4.02-4.15 (IH, m) , 5.27-5.37 (IH, m) , 6.00-6.07 (IH, m) , 7.25 (IH, d) , 7.28 (IH, S), 7.43 (IH, s), 7.65 (IH, s), 7.87 (IH, s), 8.50 (IH, s); HPLC rt(min): 9.12; MS (ES+) 550, (ES") 548. Example 73 ;
4- (9-cyclopentyl-6,7, 8, 9-tetrahydro-5, 7,7-trimethyl-6-oxo-5H- pyrimido[4,5-b] [l,4]diazepin-2-ylamino) -N- ( (S)-I- isoipropylpyrrolidin-3-yl) -3-methoxybenzamide (1-73)
Figure imgf000115_0001
[00257] Prepared using the appropriate reagents according to method H. NMR DMSO D6 1.02-1.14 (12H, m) , 1.53-2.23 (10H, m) , 2.08-2.15 (IH, m) , 2.45-3.00 <4H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.95 (3H, s), 4.40 (IH, m) , 5.19 (IH, m) , 7.47-7,53 (2H, m) , 7.70 (IH, s), 7.99 (IH, s), 8.33-8.40 (2H, m) ; HPLC rt(min): 9.42; MS (ES+) 551, (ES") 549. Example 74 ;
4-(9-cyclopentyl-6,7,8,9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -3-ethoxy-N- (1- methylpiperidin-4-yl)benzamide (1-74)
Figure imgf000115_0002
[00258] Prepared using the appropriate reagents according to method D. NMR CDCl3 1.18 (6H, s), 1.43 (3H, t), 1.50 (2H, br m) , 1.69 (6H, br m) , 1.97 (4H, br m) , 2.22 (2H, br m) , 2.32 (3H, s), 2.89 (2H, br m) , 3.21 (3H, s) , 3.31 (2H, s), 4.05 (IH, br m) , 4.15 (2H, q) , 5.22 (IH, m) , 6.10 (NH), 7.17 (IH, m) , 7.31 (IH, s), 7.60 (NH), 7.78 (IH, s), 8.41 (IH, m) ; HPLC rt(min): 9.93; MS (ES+) 550, (ES') 548. Example 75;
4- ( 9-cyclopentyl-6, 7 , 8, 9-tβtrahydro-5 , 7, 7-trimethyl-6-oxo-5H- pyrimido [4 , 5-b] [1,4] diazepin-2-ylamino) -N- ((S)-I- (eyelopropylmethy1)pyrrolidin-3-yl) -3-mβthoxybβnzamidβ (1-75)
Figure imgf000116_0001
[00259] Prepared using the appropriate reagents according to method H. NMR DMSO D6 -0.01 (2H, q) , 0.35 (2H, m) , 0.76 (IH, hept) , 1.00 (6H, s), 1.45-1.85 (9H, m) , 2.07 (IH, m) , 2.18
(2H, d) , 2.35-2.47 (2H, m) , 2.60-2.75 (2H, m) , 3. OS (3H, s),
3.28 (2H, s), 3.85 (3H, s), 4.31 (IH, hex), 5.09 (IH, quint),
7.40-7,47 (2H, m) , 7.60 (IH, s), 7.90 (IH, s), 8.24-8.29 (2H, m) ; HPLC rt(min): 9.67; MS (ES+) 562, (ES") 561.
Example 76:
4- ( 9 ' -cyclopentyl-5 • -methyl-6 • -oxo-5 * , 6 • , 8 ■ , 9 • - tetrahydrospiro [cyclopropane-1, 7 • -pyrimido [4, 5- b] [l,4]diazepine] -2 • -ylamino) -3-methoxy-N- (1-methylpiperidin-
4-yl)benzamide (1-76)
Figure imgf000116_0002
[00260] Prepared using the appropriate reagents according to method D. NMR DMSO D6 0.73-0.75 (2H, m) , 0.91-0.98 (2H, m) , 1.51-1.79 (8H, m) , 1.84-2.00 (5H, m) , 2.31-2.42 (4H, m) , 2.95- 3.05 (2H7 m) , 3.23 (3H, s), 3.54 (2H, s), 3.81-3.94 (IH, m) , 4.01 (3H, s), 4.91 (IH, quin) , 7.54 (IH, d) , 7.55 (IH, s), 7.58 (IH, s), 8.05 (IH, s), 8.20 (IH, d) , 8.45 (IH, d) ; HPLC rt(min): 8.90; MS (ES+) 532, (ES") 534. Example 77 ;
4- ( -9-cyclopentyl-6 , 7 , 8 , 9-tetrahydro-5 , 7 , 7 -trimethyl-6-oxo-
5H-pyrimido [4 , 5-b] [l# 4 ] diazepin-2-ylamino) -N- ( l- ( 2- f luoroethyl )piperidin-4-yl ) -3-methoxybenzamidβ ( 1-77 )
Figure imgf000117_0001
[00261] Prepared using the appropriate reagents according to method H. MMR CDCl3 1.13 (6H, s), 1.40-1.80 (7H, m) , 1.85-1.95
(2H, m) , 1.97-2.05 {2H, m) , 2.23-2.34 (2H, m) , 2.66-2.78 (2H, m) , 2.93-3.02 (2H, m) , 3.23 (3H, s), 3.30 (2H, s), 3.91 (3H, s), 3.90-4.04 (IH, m) , 1.45-1.64 (2H, m) , 5.16-5.28 (IH, m) , 5.85-5.95 (IH, m) , 7.15 (IH, d) , 7.20 (IH, s), 7.34 (IH, s), 7.56 (IH, s), 7.78 (IH, s), 8.42 (IH, d) ; HPLC rt(min): 9.58; MS (ES+) 568, (ES") 566. Example 78;
N- (4- (9-cyclopentyl-6,7, 8, 9-tetrahydro-5,7,7-trimethyl-6-oxo- 5H-pyrimido [4, 5-b] [l,4]diazepin-2-ylamino)phenyl) -2,2,2- trifluoroacetamide (1-78)
Figure imgf000117_0002
[00262] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.15 (6H, s), 1.52-1.68 (4H, m) , 1.69- 1.78 (2H, m) , 1.79-1.94 (2H, m) , 3.17 (3H, s), 3.43 (2H, s), 5.16 (IH, dt), 7.60 (2H, d) , 7.65 (2H1 d) , 7.92 (IH, s), 9.64
(IH, br S), 11.19 (IH, s); HPLC rt (min) : 9.90; MS (ES+) 477,
(ES") 475. Example 79;
2-(l-acetylindolin-5-ylamino)-9-cyclopentyl-8,9-dihydro-5,7,7- trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin-6 (7H) -one (1-79)
Figure imgf000118_0001
[00263] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.12 (6H, s) , 1.50-1.68 (4H, m) , 1.69- 1.77 (2H, m) , 1.78-1.88 (2H, m) , 2.14 (3H, s), 3.12 (2H, t) , 3.16 (3H, s), 3.44 (2H, s), 4.10 (2H, t) , 5.15 (IH, dt) , 7.26 (IH, d) , 7.54 (IH, s), 7.86 (IH, s), 7.97 (IH, d) , 9.65 (IH, br s); HPLC rt (min) : 9.37; MS (ES+) 449, (ES") 447. Example 80:
4- (9-cyclopentyl-6,7,8,9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido [4 , 5-b] [1, 4] diazepin-2-ylamino) -N-methylbenzamide (I- 80)
Figure imgf000118_0002
[00264] Prepared using the appropriate reagents according to method D. NMR DMSO Dδ 1.13 (6H, s), 1.55-1.69 (4H, m) , 1.70- 1.80 (2H, m) , 1.82-1.93 (2H, m) , 2.78 (3H, d) , 3.18 (3H, s), 3.45 (2H, S), 5.20 (IH, dt), 7.71 (2H, d) , 7.79 (2H, d) , 7.97 (IH, s), 8.27-8.34 (IH, m) , 9.86 (IH, br s); HPLC rt(min): 8.73; MS (ES+) 423, (ES") 421. Example 81;
2- (lH-indazol-4-ylamino)-9-cyclopentyl-8,9-dihydro-5/7,7- trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin-6 (7H) -one (1-81)
Figure imgf000118_0003
[00265] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s), 1.41-1.79 (8H, m) , 3.20
(3H, s), 3.44 (2H, s), 5.10 (IH, dt) , 7.22-7.34 (2H, m) , 7.51- 7.59 (IH, m) , 7.95 (IH, s) , 8.27 (IH, s), 9.91 (IH, br s), 13.10 (IH, br S); HPLC rt (min) : 9.32; MS (ES+) 406, (ES") 404. Example 82 ;
2- (1, 6-dihydro-6-oxopyridin-3-ylamino) -9-cyclopentyl-e, 9- dihydro-5, 7 , 7-trimethyl-5H-pyrimido [4, 5-b] [1,4] diazepin-6 (7H) - one (X-82)
Figure imgf000119_0001
[00266] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.12 (6H, s), 1.48-1.84 (8H, m) , 3.16 (3H, s), 3.45 (2H, s), 5.00-5.09 (IH, m) , 6.39 (IH, d) , 7.54 (IH, d) , 7.61 (IH, s), 7.81 (IH, s), 9.45 (IH, br s ) ; HPLC rt(min): 7.77,- MS' (ES+) 383, (ES") 381. Example 83;
2- (1, 6-dih.ydro-4-methyl-6-oxopyridin-3-ylamino) -9-cyclopentyl- 8,9-dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin- 6(7H)-one (1-83)
Figure imgf000119_0002
[00267] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s), 1.39-1.78 (8H, m) , 2.04
(3H, s), 3.16 (3H, s), 3.48 (2H, s), 6.30 (IH, s), 7.49 (IH, S), 7.75 (IH, br s) , 9.39 (IH, br s) ; HPLC rt(min): 7.86; MS
(ES+) 397, (ES") 395. Example 84;
2- (3-methoxy-5-nitrophenylamino) -9-cyclopentyl-8, 9-dihydro- 5,7,7-trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin-6(7H) -one (l- 84)
Figure imgf000120_0001
[00268] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.11 (6H, s), 1.56-1.77 (6H, m) , 1.83- 1.96 (2H, m) , 3.19 (3H, s) , 3.42 (2H, s), 3.86 (3H, s) , 5.29 (IH, dt), 7.33 (IH, t), 7.60 (IH, t) , 8.01 (IH, S), 8.41 (IH, t) , 9.88 (IH, br s); HPLC rt (min) : 10.48; MS (ES+) 441, (ES') 439.
Example 85:
2- (4- (4-methylpiperazin-l-yl)phenylamino) -9-cyclopentyl-β, 9- dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b] [1, 4] diazepin-6 (7H) ■ one (1-85)
Figure imgf000120_0002
[00269] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s), 1.51-1.65 (4H, m) , 1.66- 1.75 (2H, m) , 1.76-1.86 (2H, m) , 2.88 (3H, s), 2.86-2.94 (2H, m) , 3.17 (3H, s), 3.12-3.24 (2H, m) , 3.45 (2H, s), 3.53 (2H, d) , 3.79 (2H, d) , 5.13 (IH, dt) , 7.00 (2H, d) , 7.46 (2H, d) , 7.90 (IH, s), 9.75 (IH, br s), 9.86 (IH, br s ) ; HPLC rt(min): 9.66; MS (ES+) 464, (ES") 462. Example 86;
2- (4morpholinomethy1)phenylamino) -9-cyclopentyl-8# 9-dihydro- 5#7,7-trimethyl-5H-pyrimido[4,5-b] [1,4] diazepin-6 (7H) -one (I- 86)
Figure imgf000121_0001
[00270] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.11 (6H, s), 1.53-1.67 (4H, m) , 1.69- 1.78 (2H, m) , 1.80-1.94 (2H, m) , 3.02-3.17 (2H, m) , 3.19 (3H, s), 3.26 (2H, d) , 3.40 <2H, s), 3.62 (2H, t) , 3.97 (2H, d) , 4.28 (2H, d) , 5.21 (IH, dt), 7.39 (2H, d) , 7.79 (2H, d) , 7.97
(IH, s), 9.62 (IH, br s), 9.75 (IH, br s ) ; HPLC rt (min) : 9.82; MS • (ES+) 465, (ES") 463. Example 87 t
4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylam±no) -N- (2- hydroxyethyl)benzamide (1-87)
Figure imgf000121_0002
[00271] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.11 (6H, s), 1.56-1.66 (4H, m) , 1.68- 1.81 (2H, m) , 1.83-1.95 (2H, m) , 3.20 (3H, s), 3.20-3.28 (2H, m) , 3.41 (2H, s), 4.40 (2H, t), 5.23 (IH, dt) , 7.86 (2H, d) , 7.92-7.99 (4H, m) , 8.01 (IH, s), 9.80 (IH, br s); HPLC rt(min): 8.74; MS (ES+) 453, (ES") 451. Example 88;
N- (4- (9-cyclopentyl-6# 7, B, 9-tetrahydro-5,7, 7-trimethyl-6-oxo- 5H-pyrimido[4, 5-b] [1, 4] diazepin-2-ylamino)phenyl) -N- methylacetamide (1-88)
Figure imgf000122_0001
[00272] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.11 (6H, s), 1.52-1.65 (4H, m) , 1.66- 1.73 (2H, m) , 1.77 (3H, s), 1.77-1.86 (2H, m) , 3.13 (3H, s), 3.18 (3H, s), 3.44 (2H, s), 5.13 (IH, dt), 7.29 (2H, d) , 7.65
(2H, d) , 7.93 (IH, s), 9.80 (IH, br s ) ; HPLC rt (min) : 9.38; MS
(ES+) 437, (ES") 435. Example 89 :
2- ( lH-indazo-7-ylamino) -9-cyclopentyl-β , 9-dihydro-5, 7,7- trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin—6 (7H)-one (1-89)
Figure imgf000122_0002
[00273] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s), 1.40-1.79 (8H, m) , 3.20 (3H, s), 3.45 (2H, s), 5.09 (IH, dt), 7.25-7.34 (2H, m) , 7.53 (IH, d) , 7.94 (IH, s), 8.26 (IH, s), 9.95 (IH, br s), 13.11 (IH, br s); HPLC rt (min) : 9.33; MS (ES+) 406, (ES') 404.
Example 90;
9-cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-2- (phenylamino) -5H- pyrimido[4,5-b] [1, 4] diazepin-6 (7H) -one (1-90)
Figure imgf000122_0003
[00274] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s), 1.51-1.89 (8H, m) , 3.18 (3H, s), 3.45 (2H, s), 5.16 (IH, dt), 7.07 (IH, t), 7.34 (2H, t), 7.59 (2H, d) , 7.91 (IH, s), 9.77 (IH, br s); HPLC rt(min) 10.38; MS (ES+) 366, (ES") 364. Example 91 ;
2- (2-mefchyl-2H-indazol-7-ylami.no) -9-cyclopentyl-8, 9-dihydro-
5,7,7-trimethyl-5H-pyrimido[4,5-b] [1, 4]diazepin-6 (7H) -one (I-
91)
Figure imgf000123_0001
[00275] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.15 (6H, s), 1.53-1.78 (6H, m) , 1.81- 1.93 (2H, m) , 3.19 (3H, s), 3.53 (2H, s), 4.22 (3H, s), 5.18
(IH, dt) , 7.05 (IH, t) , 7.47 (IH, d) , 7.80 (IH, d) , 8.02 (IH, s), 8.43 (IH, s), 9.60 (IH, br s) ; HPLC rt (min) : 10.19; MS
(ES+) 420. Example 92 :
Method K: 2-( [1, 2, 4] triazolo [1, 5-a]pyridin-8-ylamino) -9- cyclopentyl-8,9-dih.ydro-5, 7, 7-trimethyl-5H-pyrimido[4, 5- b] [l,4]diazepin-6(7H)-one (1-92)
Figure imgf000123_0002
[00276] To 2-Chloro-9-cγclopentyl-8, 9-dihydro-5 , 7 , 7- trimethyl-5H-pyrimido[4 , 5-b] [1 , 4]diazepin-6 (7H) -one (50 mg, 0.16 mmol) and triazolopyridinamine (22 mg, 0.16 mmol) in dioxane (1.5 mL) was added xantphos (2.8 mg, 0.005 mmol) , palladium (II) acetate (0.7 mg, 0.003 mmol) and cesium carbonate (106 mg, 0.32 mmol). The reaction mixture was heated to 1600C in a microwave for 40 minutes. The crude mixture was filtered through a path of celite and washed with methanol. The resulting mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, lOuM, 100 A column, gradient 10% - 95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] to afford the title compound as a TFA salt (6.2 mg) . NMR DMSO D6 1.13 (6H, s), 1.53-1.66 (4H, m) , 1.68-1.77 (2H, m) , 1.81-1.90 (2H, m) , 3.20 (3H, s), 3.46 (2H, s) , 5.15 (IH, dt) , 7.21 (IH, t) , 8.05 (IH, s), 8.23 (IH, d) , 8.53 (IH, s), 8.64
(IH, d) , 9.05 (IH, br s) ; HPLC rt(min): 9.71; MS (ES+) 407,
(ES") 405. Example 93;
4- ( 9-cyclopβntyl-6,7,8, 9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido[4,5-b] [1, 4] diazepin—2-ylamino) -N-cyclopropyl-3- methoxybenzamide (I-93 )
Figure imgf000124_0001
[00277] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.55-0.59 (2H, m) , 0.68-0.73 (2H, m) , 1.09 (6H, s), 1.54-1.68 (4H, m) , 1.70-1.78 (2H, m) , 1.83-1.95
(2H, m) , 2.79-2.84 (IH, m) , 3.19 (3H, s), 3.38 (2H, s), 4.03
(3H, s), 5.16-5.22 (IH, m) , 7.43-7.47 (2H, m) , 7.70 (IH, br s), 7.99 (IH, s)', 8.32-8.35 (2H, m) ; HPLC rt(min): 9.60; MS
(ES+) 479, (ES') 477. Example 94 ;
4- (9-cyclopentyl-6,7,8, 9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [1, 4] diazepin—2-ylamino) -N-cyclobutyl-3- methoxybenzamide (1-94)
Figure imgf000124_0002
[00278] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.58-1.78 (8H, m) , 1.84- 1.91 (2H, m) , 2.03-2.13 (2H, m) , 2.18-2.23 (2H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.95 (3H, s), 4.37-4.46 (IH, m) , 5.15-5.23
(IH, m) , 7.46-7.49 (2H, m) , 7.69 (IH, s), 7.99 (IH, s), 8.36 (IH, d) , 8.46 (IH, d) ; HPLC rt (min) : 10.10; MS (ES+) 493, (ES') 491.
Example 95:
4- [4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro- 5H-pyrimido[4,5-b] [l,4]diazepin-2-ylπιethyl) -3- methoxybβnzoylamino] -piperidine-l-carboxylic acid tert-butyl ester (1-95)
Figure imgf000125_0001
[00279] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.15 (6H, s), 1.45 (3H, s), 1.48 (9H, s), 1.64-1.97 (1OH, m) , 2.90 (2H, br s), 3.25 (3H, s), 3.44
(2H, s), 4.01 (3H, s), 4.02-4.10 (2H, br s), 5.21-5.32 (IH, m) , 7.51-7.54 (2H, m) , 7.76 (IH, s), 8.06 (IH, s), 8.18 (IH, d) , 8.43 (IH, s); HPLC rt (min) : 10.50; MS (ES+) 622, (ES") 620 Example 96:
4- ( 6, 7, 8 , 9-tetrah.ydro-5, 7 , 7-trimethyl-9- ( (R) -1- methylpiperidine-3-yl) -6-oxo-5H-pyrimido[4, 5-b] [l#4]diazepin— 2-ylamino) -3-methoxy-N-methylbβnzamide (1-96)
Figure imgf000125_0002
[00280] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.08 (3H, s), 1.10 (3H, s), 1.5-1.92 (5H, m) , 2.00-2.10 (2H, m) , 2.23 (3H, s), 2.79 (3H, d) , 2.87 (IH, br d) , 3.18 (3H, s), 3.42 (2H, s), 3.94 (3H, s), 4.86 (IH, tt) , 7.45 (IH, dd) , 7.49 (IH, d) , 7.66 (IH, S), 7.99 (IH, S), 8.30 (IH, q) , 8.38 (IH, d) ; HPLC rt(min): 7.64; MS (ES+) 482, (ES") 480. Example 97 ;
4-(6,7,8,9-tθtrahydro-5,7,7-trimethyl-9-( (R)-I- methylpiperidine-4-yl) -6-oxo-5H-pyrimido[4, 5-b] [1, 4]diazepin- 2-ylamino) -3-methoxy-N-methylbenzaπιide (1-97)
Figure imgf000126_0001
[00281] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.09 (6H, s), 1.66 (2H, br d) , 1.83 (2H, dq) , 2.00-2.15 (2H, m) , 2.24 (3H, s), 2.79 (3H, d) , 2.92 (2H, br d) , 3.18 (3H, s) , 3.38 (2H, s), 3.94 (3H, s), 4.71 (IH, tt), 7.47 (IH, dd) , 7.50 (IH, d) , 7.68 (IH, s), 7.98 (IH, s), 8.25-8.34 (2H, m) ; HPLC rt(min): 7.28; MS (ES+) 482, (ES') 480. Example 98 ;
2- (4- (5-hydroxy-3-methyl-lH-pyrazol-1-yl )phenylamino) -9- cyclopentyl-8, 9-dihydro-5, 7, 7-trimethyl-5H-pyrimido[4, 5- b] [l,4]diazepin—6(7H)-one (1-98)
Figure imgf000126_0002
[00282] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.14 (6H, s), 1.51-1.77 (6H, m) , 1.81- 1.92 (2H, m) , 2.12 (3H, s) , 3.19 (3H, s), 3.46 (2H, s) , 5.17 (IH, dt) , 5.36 (IH, s), 7.56-7.68 (4H, m) , 7.90 (IH, s), 9.79 (IH, br s); HPLC rt(min): 8.75; MS (ES+) 462, (ES") 460. Example 99:
2- (4- (lH-pyrazol-3-yl)phenylamino) -9-cyclopentyl-8, 9-dihydro- 5,7,7-trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin-6 (7H) -one (I- 99)
Figure imgf000127_0001
[00283] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.15 (6H, s), 1.55-1.78 (6H, m) , 1.82- 1.93 (2H, m) , 3.19 (3H, s) , 3.48 (2H, s) , 5.19 (IH, dt) , 6.67
(IH, d) , 7.62 (2H, d) , 7.70 (IH, d) , 7.78 (2H, d) , 7.92 (IH, s) , 9.93 (IH, br s) ; HPLC rt(min) : 8.45; MS (ES+) 432, (ES") 430.
Example 100 ;
4- ( 9-cyclopentyl-6, 1 , 8# 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin— 2-ylthio) -N-methylbenzamide (I- 100)
Figure imgf000127_0002
Method L: 4- ( 9-cyclopentyl-6 , 7 , 8 , 9-tetrahydro-5 , 7 , 7-trimethyl- 6-oxo-5H-pyrimido [4 , 5-b] [1 , 4] diazepin—2-ylthio) -benzoic acid
Figure imgf000127_0003
[00284] A solution of 2-Chloro-9-cyclopentyl-8 , 9-dihydro- 5, 7, 7-trimethyl-5H-pyrimido[4, 5-b] [ 1 , 4] diazepin-6 (7H) -one (100 mg, 0.324 mmol) and 4-mercaptobenzoic acid (50 mg, 0.324 mtnol) in acetonitrile (5 mL) was heated under reflux for 4 hours. Additional 4-mercaptobenzoic acid (50 mg, 0.324 mmol) was added and the reaction mixture was heated under reflux for 16 hours. After cooling, the crude reaction mixture was filtered through Celite and washed with acetonitrile. The crude product was purified by column chromatography (0%-10% MeOH 1 CH2C12) and triturated with MeOH to give the title compound
(37 mg, 27% yield) as a white solid. NMR DMSO D61.03 (6H, s), 1.20-1.38 (6H, m) , 1.42-1.53 (2H, m) , 3.17 (3H, s), 3.27 (2H, s), 4.47 (IH, dt), 7.72 (2H, dd) , 7.99 (2H, dd) , 8.02 (IH, s); MS (ES+) 427, (ES") 425.
[00285] 4- (9-cyclopentyl-6,7, 8, 9-tetrahydro-5 , 7, 7-trimethyl- 6-oxo-5H-pyrimido [4 , 5-b] [1,4] diazepin—2-ylthio) -N- methylbenzamide (1-100) has been Prepared using the appropriate reagents according to method D.
NMR DMSO D6 1.03 (6H, s), 1.22-1.44 (6H, m) , 1.46-1.58 (2H, m) , 2.80 (3H, d) , 3.17 (3H, s), 3.28 <2H, s), 4.51 (IH, dt), 7.68
(2H, d)., 7.91- (2H7 d) , 8.02 (IH, s), 8.47-8.53 (IH, m) ; HPLC rt(min): 8.86; MS (ES+) 440, (ES") 438. Example 101;
2- (9-cyclopentyl-6,7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H- pyrimido [4 , 5-b] [1,4] diazepin—2-ylamino) -3-methoxy-N-
(piperidin-4-yl)benzamide (1-101)
Figure imgf000128_0001
[00286] Prepared using the appropriate reagents according to method F. NMR MeOD 1.21 (6H, s), 1.61-1.85 (8H, m) , 2.02-2.15 (4H, m) , 2.85 (2H, br t) , 3.23 (2H, br d) , 3.39 (3H, s), 3.48 (2H, s), 4.02 (3H, s), 4.03-4.10 (IH, m) , 5.36 (IH, quint), 7.50-7.54 (2H, m) , 7.94 (IH, s), 8.48 (IH, d) ; HPLC rt (min) : 9.00; MS (ES+) 522, (ES") 520. Example 102 :
2- (2-methoxyphenylamino)-9-cyclopentyl-8, 9-dihydro-5,7,7- trimethyl-5H-pyrimido[4,5-b] [1,4] diazepin—6(7H) -one (1-102)
Figure imgf000128_0002
[00287] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.14 (6H, s), 1.48-1.84 <8H, m) , 3.18
(3H, S), 3.49 (2H, s), 3.87 (3H, S), 5.07 (IH, dt), 6.99 (IH, dt), 7.14 (IH, dt), 7.19 (IH, dt) , 7.83 (IH, d) , 7.94 (IH, s) , 9.13 (IH, br s); HPLC rt(min): 10.65; MS (ES+) 396, (ES") 394. Example 103 ;
Methyl 4- O-cyclopentyl-S^^-trimethyl-β-oxo-β,?, 8,9- tetrahydro-5H-pyrimido[4,5-b] [l,4Jdiazepin—2-ylamino) -3- methoxyphenylcarbamate (1-103 )
Figure imgf000129_0001
[00288] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.10(6H, s), 1.56 (4H, br m) , 1.71(2H, br m) , 1.82(2H, br m) , 3.17(3H, s), 3.35(2H, s), 3.66(3H, s), 3.8K3H, s), 5.11(1H, br m) , 6.96(1H, dd) , 7.23(1H, s) , 7.44(1H, s), 7.90UH, s), 7.98(1H, d) , 9.46(lH br s) ; HPLC rt(min): 9.60; MS (ES+) 469, (ES") 467. Example 104 :
N- (4- (9-cyclopenfcyl-5, 7,7-fcrimethyl-6-oxo-6,7, 8, 9-tetrahydro- 5H-pyrimido [4, 5-b] [1, 4] diazepin—2-ylamino) -3-methoxypheny1) -2- raethoxyacetamide (1-104)
Figure imgf000129_0002
[00289] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.09 (6H, s), 1.57 (4H, br m) , 1.71(2H, br m) , 1.84(2H, br m) , 3.18(3H, s), 3.35(2H, s), 3.39(3H, s), 3.83(3H, s), 3.98(2H, s), 5.13(1H, br m) , 7.23(1H, dd) , 7.46(2H, s), 7.92(1H, s), 8.06(lH, d) , 9.6O(1H, br ε); HPLC rt(min): 9.50; MS (ES+) 483, (ES") 481. Example 105;
[4- (9-cyclopentyl-6, 7, 8, 9-tetraliydro-5, 7,7-trimethyl-6-oxo-5H- pyrimido[4,5-b] [1, 4] diazepin—2-ylamino) -N- (2,2,2- trifluoroethyl) -3-methoxybenzamide (1-105)
Figure imgf000130_0001
[00290] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.10 (6H, S), 1.63 (4H, br m) , 1.75 (2H, br m) , 1.89 (2H, br m) , 3.19 (3H, s), 3.38 (2H, s), 3.95 (3H, s), 4.10 (2H, m) , 5.20 (IH, m) , 7.54 (2H, m) , 7.73 (NH), 8.00
(IH, s), 8.43 (IH, m) , 8.41 (IH, s); HPLC rt(min): 9.94; MS
(ES+) 521, (ES") 519. Example 106 t
9-cyclopentyl-5, 7, 7-trimethyl-2- [3- (4-methylpiperazine-l- carbonyl) -phenylamino] -5,7,8, 9-tetrahydropyrimido [4 , 5- b] [1,4] diazepin—6-one (1-106)
Figure imgf000130_0002
[00291] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.10 (6H, S), 1.57 (4H, br m) , 1.71 (2H, br m) , 1.85 (2H, br m) , 2.82 - 3.34 (8H, br m) , 3.19 (3H, s), 3.36 (3H, s), 5.23 (IH, m) , 6.97 (IH, m) , 7.31 (IH, m) , 7.69
(IH, m) , 7.96 (2H, m) , 9.33 (IH, s) ; HPLC rt(min): 9.12; MS
(ES+) 492, (ES") 490. Example 107 :
Method M: 4- (9-cyclopentyl-6, 7,8, 9-tetrahydro-5,7,7-trimetliyl- 6-oxo-5H-pyrimido [4, 5-b] [l,4]diazepin—2-yloxy) -3- methoxybenzoic acid (1-107)
Figure imgf000131_0001
[00292] To 2-Chloro-9-cyclopentyl-8, 9-dihydro-5, I17- trimethyl-5H-pyrimido [4 , 5-b] [1, 4] diazepin-6 (7H) -one (100 mg, 0324 itnnol) in DMF (5 inL) was added vanillic acid (55 mg, 0.324 irtmol) and potassium carbonate (90 mg, 0.648 mmol) . The reaction mixture was heated at 800C for 48 hours. After cooling, the solvent was removed in vacuo and the residue taken up in methanol and purified by reverse phase preparative HPLC [Waters Sunfire C18, lOuM, 100 A column, gradient 10% - 95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] to afford the title compound as a TFA salt (12 mg, 7% yield). NMR DMSO D6 1.06 (6H, s), 1.23-1.37
(2H, m) , 1.38-1.50 (2H, m) , 1.51-1.62 (4H, m) , 3.18 (3H, s), 3.34 (2H, s), 3.76 (3H, s), 4.58 (IH, dt), 7.26 (IH, d) , 7.56- 7.62 (2H, m) , 7.99 (IH, S ) ; HPLC rt(min): 7.18; MS (ES+) 441,
(ES') 439. Example 108:
2- (2, 3-dihydro-2-oxo-lH-benzo[d] ixnidazol-6-ylamino) -9- cyclopentyl-8, 9-dihydro-5,7,7-trimefchyl-5H-pyrimido[4, 5- b] [l,4]diazepin—6(7H) -one (1-108)
Figure imgf000131_0002
[00293] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.14 (6H, s), 1.44-1.76 (6H, m) , 1.78-
1.92 (2H, m) , 3.17 (3H, s), 3.46 (2H, s), 5.13 (IH, dt) , 6.89 (IH, d) , 7.05 (IH, d) , 7.13 (IH, s), 7.81 (IH, S), 9.75 (IH, br s), 10.57 (IH, s), 10.67 (IH, s ) ; HPLC rt(min): 8.21; MS
(ES+) 422, (ES") 420. Example 109 ;
2- (2 , 3-dihydro-3-oxo-IH-indazol-5-ylamino) -9-cyclopentyl-8, 9- dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b] [1, 4] diazepin-6 (7H) - one (1-109)
Figure imgf000132_0001
[00294] Prepared using the appropriate reagents according to • method D. NMR DMSO D6 1.14 (6H, s), 1.50-1.74 (6H, m) , 1.79- 1.90 (2H, m) , 3.18 (3H, s), 3.46 (2H, s), 5.18 (IH, dt ) , 7.27 (IH, d) , 7.37 (IH, dd) , 7.85 (IH, s) , 7.88 (IH, s), 9.76 (IH, br s), 11.28 (IH, br s); HPLC rt(min): 8.01; MS (ES+) 422, (ES" ) 420.
Example 110 ;
2- (l-methyl-lH-indazol-5-ylamino) -9-cyclopentyl-8,9-dihydro- 5,7,7-trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin—6(7H) -one (I- 110)
Figure imgf000132_0002
[00295] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.15 (6H, s), 1.43-1.77 (6H, m) , 1.78- 1.88 (2H, m) , 3.18 (3H, s), 3.48 (2H, s) , 4.05 (3H, s), 5.14
(IH, dt), 7.48 (IH, dd) , 7.66 (IH, d) , 7.87 (IH, s), 7.96 (IH, s), 7.99 (IH, s), 10.01 (IH, br s); HPLC rt (min) : 9.65; MS
(ES+) 420, (ES') 418. Example 111 ;
N- ( 3 - ( 9 -cyclopentyl - 6 , 7 , 8 , 9 -tetrahydro- 5 , 7 , 7 - trimethyl - 6 -oxo-
5H-pyrimido [4 , 5-b] [l , 4 ] diazepin— 2-ylamino)phenyl ) acetamide ( I-
111)
Figure imgf000133_0001
[00296] Prepared using the appropriate reagents according to method D. HPLC rt(min): 8.95; MS (ES+) 423, (ES") 421. Example 112 :
N- (4- (9-cyclopentyl-6, 7,8,9-tetrahydro-5, 7, 7-trimethyl-6-oxo- 5H-pyrimido[4,5-b] [1, 4]diazepin—2-ylamino)phenyl )acetamide (I- 112)
Figure imgf000133_0002
[00297] Prepared using the appropriate reagents according to method D. HPLC rt(min) : 8.74; MS (ES+) 423, (ES") 421.
Example 113 :
4-( (S)-9-cyclopentyl-7-ethyl-6,7,8,9-tetrahydro-5-methyl-6- oxo-5H-pyrimido [4, 5-b] [1, 4] diazepin—2-ylamino) -3-methoxy-N- (1- methylpiperidin-4-yl)benzamide (1-113 )
Figure imgf000133_0003
[00298] Prepared using the appropriate reagents according to method D. NMR DMSO D6 0.88 (3H, t), 1.04 (IH, d) , 1.25-1.36 (IH, m) , 1.52-1.85 (HH, m) , 1.95-2.12 (3H, m) , 2.20 (3H, s), 2.57-2.64 (IH, m) , 2.78-2.83 (2H, m) , 3.20 (3H, s), 3.41-3.45 (2H, m) , 3.75-3.80 (IH, m) , 3.95 (3H, s) , 4.78 (IH, quint), 7.48 (IH, d) , 7.49 (IH, s), 7.75 (IH, s), 8.07 (IH, d) , 8.10
(IH, s) , 8.39 (IH, d) ; HPLC rt (min) : 9.70; MS (ES+) 536, (ES") 534.
Example 114 t
2- (lH-indazo-5-ylamino) -9-cyclopentyl-8, 9-dihydro-5,7, 7- triiαethyl-5H-pyrimido[4,5-b] [l,4]diazepin— 6 (7H) -one (1-114)
Figure imgf000134_0001
[00299] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.14 (6H, s), 1.44-1.93 (8H, m) , 3.18
(3H, S), 3.47 (2H, s), 5.14 (IH, dt), 7.43 (IH, dd) , 7.55 (IH, d) , 7.86 (IH, Ξ), 7.98 (IH, s), 8.02 (IH, s), 9.92 (IH, br s) , 13.06 (IH, br s); HPLC rt (min) : 8.99; MS (ES+) 406, (ES") 404. Example 115 :
2- (lH-benzo[d] imidazol-4-ylamino) -9-cyclopentyl-8#9-dihydro- 5,7,7-trimethyl-5H-pyrimido[4,5-b] [l,4]diazβpin—6 (7H) -one (I- 115)
Figure imgf000134_0002
[00300] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s), 1.38-1.73 (8H, m) , 3.20
(3H, s), 3.42 (2H, s), 4.96 (IH, dt) , 7.42 (IH, t) , 7.50 (IH, d) , 7.70 (IH, d) , 8.01 (IH, s), 9.09 (IH, br s), 9.85 (IH, br s); HPLC rt(min) : 9.37; MS (ES+) 406, (ES") 404. Example 116 :
2- (3-aminophθnylam±no) -9-cyclopentyl-8# 9-dihydro-5#7,7- trimethyl-5H-pyrimido[4,5-b] [1, 4] diazepin—6 (7H) -one (1-116)
Figure imgf000134_0003
[00301] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.12 (6H, s), 1.53-1.73 (6H, m) , 1.80- 1.92 (2H, m) , 3.18 (3H, s) , 3.43 (2H, s) , 5.19 (IH, dt) , 6.61
(IH, d) , 7.14-7.24 (3H, m) , 7.89 (IH, s) , 9.67 (IH, br s) ; HPLC rt(min): 9.16; MS (ES+) 381, (ES") 379. Example 117 ;
2- (4-aminophenylamino) -9-cyclopentyl-8, 9-dihydro-5# 7,7- trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin—6(7H) -one (1-117)
Figure imgf000135_0001
[00302] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.12 (6H, s), 1.50-1.92 (8H, m) , 3.18
(3H, S), 3.43 (2H, s), 5.16 (IH, dt), 7.01-7.10 (2H, m) , 7.50-
7.63 (2H, m) , 7.89 (IH, s), 9.67 (IH, br s); HPLC rt (min) :
8.76; MS (ES+) 381, (ES") 379.
Example 118 ;
4-(9-cyclopentyl-6,7/ 8, 9-tetrahydro-5# 7,7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin—2-ylamino) -3-ethyl-N- methylbenzamide (1-118)
Figure imgf000135_0002
[00303] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s), 1.18 (3H, t), 1.44 (2H, br m) , 1.57 - 1.69 (6H, br m) , 2.51 (2H, q) , 2.64 (3H, m) , 2.79 (3H, s), 3.45 <3H, s), 4.95 (IH, m) , 7.69 (2H, m) , 7.78 (IH, m) , 7.87 (IH, s), 8.38 (IH, s ) ; HPLC rt(min): 9.24; MS (ES+) 451, (ES") 449. Example 119;
4-( (S)-9-cyclopentyl-7-ethyl-6,7,8,9-tetrahydro-5-met;hyl-6- oxo-5H-pyrimido[4#5-b] [1,4] diazepin—2-ylamino) -N-cyclobutyl-3- methoxybenzamide (1-119)
Figure imgf000136_0001
[00304] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s), 1.18 (3H, t) , 1.44 (2H, br m) , 1.57 - 1.69 <6H, br m) , 2.51 (2H, q) , 2.64 (3H, m) , 2.79 (3H, s), 3.45 (3H, s), 4.95 (IH, m) , 7.69 (2H, m) , 7.78 (IH, m) , 7.87 (IH, s), 8.38 (IH, s); HPLC rt (min) : 10.10; MS (ES+) 493, (ES") 491. Example 120:
4- ( 9-cyclopentyl-6, 7 , 8, 9-tetrahydro-5, 7 , 7-trimethyl-6-oxo-5H- pyrimido [4 , 5-b] [1, 4] diazepin—2-ylamino) -3-methoxybenzoic acid (1-120)
Figure imgf000136_0002
[00305] Prepared using the appropriate reagents according to method D. HPLC rt (min) : 7.81; MS (ES+) 440, (ES") 438. Example 121;
3- (2- (pyrrolidin-1-yl ) ethoxy) -4- (9-cyclopentyl-6,7,8,9- tetrahydro-5, 7, 7-trimethyl-6-oxo-5H-pyrimido[4, 5- b] [1,4] diazepin—2-ylamino) -N-methylbenzamide (1-121)
Figure imgf000136_0003
[00306] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.11 (6H, s), 1.61 (4H, br m) , 1.74 (2H, br m) , 1.84 (2H, br m) , 1.91 (2H, br m) , 2.06 (2H, br m) , 2.79 (3H, m) , 3.19 (5H, m) , 3.43 (2H, s), 3.68 (4H, br m) , 4.42 (2H, m) , 5.14 (IH, ra) , 7.50 - 7.55 (2H, m) , 8.02 (IH, s), 8.24 (IH, m) , 8.38 (IH, s); HPLC rt(min): 8.87; MS (ES+) 536, (ES") 534.
Example 122 ;
4- ( 9-benzyl-6 , 7 , 8 , 9-tetrahydro-5 , 7 , 7 -trimethyl-6-oxo-5H- pyrimido [4 , 5-b] [l, 4 ] diazepin— 2 -yl ami no) -3-meth.oxy-N- methylbenzamide ( 1-122 )
Figure imgf000137_0001
Method N: 2-Chloro-8 , 9-dihydro-5 , 7 , 7-trimethyl-5H- pyrimido[4, 5-b] [1 , 4]diazepin-6 (7H) -one
Figure imgf000137_0002
[00307] 9-allyl-2-chloro-8, 9-dihydro-5, 7 , 7-trimethyl-5H- pyrimido[4, 5-b] [1, 4]diazepin-6 (7H) -one (1.21 g, 4.34 mmol , prepared by method C) and dichloro (2 , 7-dimethyl-octa-2 , 6- diene-1 , 8-yl) ruthenium (IV) (0.26 g, 0.43 mmol, prepared following Tetrahedron Letters, 1965, 47, 4187) were suspended in dioxane (10 mL) and water (30 mL) in a pressure tube. The resultant suspension was stirred at 1000C over two nights. The reaction was allowed to cool to room temperature and filtered through celite. The celite was washed copiously with water and DCM. The combined filtrates were concentrated under reduced pressure and partitioned between brine and DCM. The aqueous layer was extracted with dichloromethane (5 x 20 mL) and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown gum. This gum was purified by column chromatography (50% EtOAc in hexanes, loaded on silica, -100 mL silica) to give a white solid, which was triturated with diethyl ether.
The solid was collected by filtration and washed with diethyl ether (1 x 2 mL) and pentane (3 x 2 mL) to give a cream powder (351 mg, 34% yield). NMR DMSO D6 l.O9(6H, s), 3.22(3H, s),
3.25(2H, d) , 8.08(1H, s), 8.48(1H, br d) ; MS (ES+) 241.
Method O: 9-Benzyl-2-chloro-8 , 9-dihydro-5 , 7 , 7-trimethyl-5H- pyrimido [4 , 5-b] [1,4] diazepin-6 (7H) -one
Figure imgf000138_0001
[00308] 2-Chloro-8, 9-dihydro-5, 7 , 7-trimethyl-5H-pyrimido [4, 5- b] [1 , 4] diazepin-6 (7H) -one (50 mg, 0.21 mmol ) and benzylbromide
(30 μl, 0.25 mmol) in DMA (0.5 ml) was treated with sodium hydride 60% oil dispersion (9 mg, 0.23 mmol) at room temperature. The mixture was stirred at room temperature for 5 hours . The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography
(50% EtOAc in hexanes, loaded on silica, ~50 mL silica) to give the title compound as a white solid (63 mg, 91%) . MMR DMSO D6 LOO (6H, s), 3.22 (3H, s), 3.53 (2H, s), 4.91 (2H, s), 7.28-7.39 (5H, m) , 8.12 (lH, s ) ; MS (ES+) 331. 4- (9-benzyl-6, 7, 8, 9-tetrahydro-5 , 7, 7-trimethyl-6-oxo-5H- pyrimido [4, 5-b] [1,4] diazepin—2-ylamino) -3-methoxy-N- methylbenzamide (1-122)
Figure imgf000138_0002
[00309] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.03 (6H, s), 2.75(3H, d) , 3.23(3H, s), 3.47(2H, s), 3.90(3H, s), 4.98(2H, br s), 7.2-7.4(6H, m) , 7.45(1H, s), 7.72(1H, s), 8.07(lH, s), 8.19(1H1 d) , 8.27(lH, br d) ; HPLC rt (min) : 9.00; MS (ES+) 475, (ES") 473. Example 123 :
4- ( 9- (cyclobutylmβthyl ) -6, 7, 8, 9-tetrahydro-5 , 7 , 7-trimethyl-6- oxo-5H-pyrimido[4, 5-b] [l,4]diazepin—2-ylamino) -3-methoxy-N- methylbenzamide (1-123 )
Figure imgf000139_0001
[00310] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.09 (6H, s), 1.84 (4H, br m) , 2.05(2H, br m) , 2.78(4H, br m) , 3.18(3H, s), 3.50(2H, s), 3.78(2H, d) , 3.94(3H, s), 7.47(2H, m) , 7.67(1H, s), 7.97(1H, s), 8.34(2H, br m) ; HPLC rt (min) : 9.20; MS (ES+) 453, (ES") 451. Example 124 :
2- (l-oxoisoindolin-4-ylamino) -9-cyclopentyl-8, 9-dihydro-5, 7,7- trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin—6 (7H) -one (1-124)
Figure imgf000139_0002
[00311] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.09 (6H, s), 1.52 (4H, br m) , 1.69 (2H, br m) , 1.76 (2H, br m) , 3.18 (3H, s), 3.34 (2H, s) , 4.40 (2H, s), 5.15 (IH, m) , 7.31 (IH, d) , 7.40 (IH, t), 7.96 (IH, s), 8.08 (IH, d) , 8.52 (IH, s), 8.86 (IH, s); HPLC rt(min): 8.90; MS (ES+) 421, (ES") 419. Example 125 t
2- (l-methyl-2-oxoindolin-5-ylainino) -9-cyclopentyl-β, 9-dihydro-
5,7,7-trimethyl-5H-pyrimido[4,5-b] [l,4]diazβpin—6 (7H) -one (I-
125)
Figure imgf000140_0001
[00312] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s), 1.54 (4H, br m) , 1.62 (2H, br m) , 1.82 (2H, br m) , 3.12 (3H, s), 3.17 (3H, s), 3.46 (2H, s), 3.55 (2H, s), 5.13 (IH, m) , 6.96 (IH, m) , 7.39 (IH, m) , 7.54 (IH, s) , 7.86 (IH, s), 9.89 (IH, s); HPLC rt(min): 9.24; MS (ES+) 435, (ES") 433. Example 126:
6- (9-cyclopentyl-6#7,8,9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [1, 4] diazepin—2-ylamino) -N-methylpyridine-3- carboxazni.de (1-126)
Figure imgf000140_0002
[00313] Prepared using the appropriate reagents according to method J. NMR DMSO D6 1.09 (6H, s), 1.61 (4H, br m) , 1.74 (2H, br m) , 1.90 (2H, br m) , 2.79 (3H, m) , 3.20 (3H, s), 3.38 (2H, S), 5.20 (IH, m) , 8.02 (IH, s) , 8.15 (IH, m) , 8.24 (IH, m) , 8.42 (IH, s), 8.70 (IH, s), 9.71 (IH, s); HPLC rt (min) : 8.63; MS (ES+) 424, (ES") 422. Example 127;
2- (3-amino-lH-indazol-l-ylamino) -9-cyclopentyl-8# 9-dihydro- 5,7,7-trimethyl-5H-pyrimido[4,5-b] [1, 4] diazepin—6 (7H) -one (I- 127)
Figure imgf000141_0001
[00314] Prepared using the appropriate reagents according to method K. NMR DMSO D6 1.12 (6H, s), 1.61-1.84 (6H, m) , 1.89- 1.96 (2H, m) , 3.24 (3H, s), 3.43 (2H, s), 5.39 (IH, dt) , 6.04 (2H, s, NH2), 7.18 (lH, t), 7.46 (IH, t) , 7.85 (IH, d) , 8.14 (IH, s), 8.44 (IH, d) ; HPLC rt (min) : 9.84; MS (ES+) 406. Example 128;
2- (3-nitrophenylami.no) -9-cyclopentyl-8,9-dihydro-5, 7,7- trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin—6 (7H) -one (1-128)
Figure imgf000141_0002
[00315] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.10 (6H, s), 1.52-1.65 (4H, m) , 1.69- 1.75 (2H, m) , 1.84-1.96 (2H, m) , 3.20 <3H, s), 3.39 (2H, s), 5.34 (IH, quint), 7.52 (IH, t), 7.73 (IH, dd) , 7.88 (IH, d) , 8.02 (IH, s) , 8.92 (IH, d) , 9.74 (IH, s ) ; HPLC rt (min) : 10.50; MS (ES+) 411, (ES") 409. Example 129;
4-(9-cyclopentyl-6,7,8,9-tetrahydro-5,7,7-triinethyl-6-oxo-5H- pyrimido [4, 5-b] [1, 4]diazepin-2-ylamino) -N-cyclopentyl-3- methoxybenzamide (1-129)
Figure imgf000141_0003
[00316] Prepared using the appropriate reagents according to method D. NMR CDCl3 1.13 (6H, m) , 1.36-1.78 (12H, m) , 1.88- 1.98 (2H, m) , 2.00-2.10 (2H, m) , 3.22 <3H, s), 3.31 (2H, s), 3.91 (3H, S) , 4.28-4.37 (IH, m) , 5.18-5.30 (IH, m) , 5.93 (IH, d) , 7.14 (IH, d) , 7.35 (IH, s), 7.64 (IH, br s), 7.77 (IH, s), 8.38 (IH, d) ; HPLC rt(min): 10.33; MS (ES+) 507, (ES") 505. Example 130:
4- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-5H- pyrimido[4,5-b] [1, 4] diazepin-2-ylamino) -N-tert-butyl-3- methoxybenzamide (X-130)
Figure imgf000142_0001
[00317] Prepared using the appropriate reagents according to method E. NMR CDCl3 1-22 (6H, s), 1.51 (9H, s), 1.50-1.87 (6H, m) , 1.96-2.06 (2H, m) , 3.32 (3H, s) , 3.99 (2H, s), 5.26-5.38
(IH, m) , 5.95 (IH, S), 7.19 (IH, d) , 7.43- (IH, s), 7.22 (IH, br s), 7.86 (IH, s), 8.45 (IH, d) ; HPLC rt(min): 10.36; MS
(ES+) 495, (ES") 493. Example 131:
4- (9-cyclopentyl-6, 1, 8, 9-tetrahydro-5,7, 7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [1,4] diazepin-2-ylamino) -N- (cyclopropylmethyl) - 3-methoxybenzamide (1-131)
Figure imgf000142_0002
[00318] Prepared using the appropriate reagents according to method E. NMR CDCl3 0.08-0.13 (2H, m) , 0.35-0.41 (2H, m) , 0.75-0.84 (IH, m) , 1.01 (6H, s), 1.27-1.65 (6H, m) , 1.76-1.85 (2H, m) , 3.08-3.18 (2H, m) , 3.11 (3H, s), 3.19 (2H, s), 3.79 (3H, s), 5.08-5.18 (IH, m) , 6.00 (IH, t), 7.09 (IH, d) , 7.25 (IH, s), 7.57 (IH, br s), 7.64 (IH, s), 8.26 (IH, d) ; HPLC rt(min): 10.00; MS (ES+) 493, (ES") 491. Example 132 ;
4- (9-cyclopentyl-6,7, 8, 9-tetrahydro-5,7, 7-trimethyl-6-oxo-5H- pyrimido[4,5-b] [l,4]diazepin-2-ylamino) -N- (3,3,3- trifluoropropyl) -3-methoxybenzamide (1-132)
Figure imgf000143_0001
[00319] Prepared using the appropriate reagents according to method E. NMR CDCl3 1.13 (6H, s), 1.45-1.80 (6H# m) , 1.88-1.97
(2H, m) , 2.35-2,49 (2H, m) , 3.22 (3H, s), 3.31 (2H, s), 3.64- 3.70 (2H, m) , 3.91 (3H, s), 5.18-5.28 (2H, m) , 6.28 (IH, t), 7.17 (IH, d) , 7.34 (IH, s), 7.68 (IH, br S), 7.77 (IH, s), 8.41 (IH, d) ; HPLC rt(min): 10.03; MS (ES+) 535, (ES") 533. Example 133 t
4- (9-cyclopentyl-6,7, 8, 9-tetrah.yd.-O-5, 7, 7-trimethyl-6-oxo-5H- pyrimido [4 , 5-b] [1,4] diazepin-2-ylamino) -N-cyclohexyl-3- methoxybenzamide (I-133 )
[00320] Prepared using the appropriate reagents according to method E. NMR CDCl3 1.13 (6H, s), 1.10-1.74 (14H, m) , 1.88- 2.05 (4H, m) , 3.22 (3H, s), 3.31 (2H, s ) ., 3.95-4.00 (IH, m) , 3.91 (3H, s), 5.18-5.29 (IH, m) , 5.85 (IH, d) , 7.14 (IH, d) , 7.35 (IH, s), 7.68 (IH, br s), 7.76 (IH, s), 8.37 (IH, d) ; HPLC rt(min): 10.56; MS (ES+) 521, (ES') 519. Example 134 ;
4- (9-cyclopentyl-6,7,8, 9-tetrahydro-5,7, 7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [1,4] diazepin-2-ylamino) -N- (tetrahydro-2H- pyran-4-yl) -3-methoxybenzamide (1-134)
Figure imgf000144_0001
[00321] Prepared using the appropriate reagents according to method E. NMR CDCl3 1.22 (6H, s), 1.48-1.85 (12H, m) , 1.97- 2.08 (4H, m) , 3.32 (3H, s), 3.40 (2H, s), 3.53-3.61 <2H, m) , 3.97-4.07 (2H, m) , 4.00 (3H, s), 5.29-5.40 (IH, m) , 5.97 (IH, d) , 7.24 (IH, d) , 7.43 (IH, s), 7.77 (IH, br s), 7.86 (IH, s), 8.48 (IH, d) ; HPLC rt(min): 9.52; MS (ES+) 523, (ES") 521. Example 135;
4- (9-cyclopentyl-6#7,8,9-tetrahydro-5,7#7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [1,4] diazepin-2-ylamino) -3-ethoxy-N- (1- isopropylpiperidin-4-yl)benzamide (1-135)
Figure imgf000144_0002
[00322] Prepared using the appropriate reagents according to method E. NMR CDCl3 1.10 (6H, d) , 1.22 (6H, s), 1.52 (3H, t), 1.54-1.86 (8H, m) , 1.97-2.16 (4H, m) , 2.35-2.43 (2H, m) , 2.77- 2.89 (IH, m) , 2.90-3.00 (2H, m) , 3.32 (3H, s), 3.40 (2H, s), 3.98-4.07 (IH, m) , 4.22 (2H, q) , 5.25-5.36 (IH, m) , 6.00 (IH, d) , 7.23 (IH, d) , 7.41 (IH, s), 7.66 (IH, s), 7.87 (IH, s), 8.49 (IH, d) ; HPLC rt (min) : 9.47; MS (ES+) 578, (ES") 576. Example 136 t
4- (9-cyclopentyl-6, 7,8, 9-tetrahydro-5,7, 7-trimethyl-6-oxo-5H- pyrimido [4, 5-b] [1,4] diazepin-2-ylamino) -N-(I, 3-dihydroxy-2- methylpropan-2-yl) -3-methoxybenzamide (1-136)
Figure imgf000145_0001
[00323] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.05 (3H, s), 1.14 (6H, s), 1.55-1.94 (8H, m) , 3.13-3.26 (2H, m) , 3.18 (3H, s) , 3.28-3.37 (2H, m) , 3.49 (2Hf s), 3.96 (3H, s), 5.10-5.20 (IH, m) , 7.54 (IH, d) , 7.60 (IH, s), 8.01 (IH, s), 8.15 (IH, d) , 8.40-8.47 (IH, m) , 8.85 (IH, br s); HPLC rt(min): 9.47; MS (ES+) 527, (ES") 526. Example 137 ;
2- (3- (lH-pyra2ol-3-yl)phenylamino) -9-cyclopentyl-8,9-dihydro- 5,7,7-trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin-6(7H)-one (I- 137)
Figure imgf000145_0002
[00324] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s), 1.24-1.36 (2H, m) , 1.50- 1.63 (4H, m) , 1.71-1.86 (2H, m) , 3.19 (3H, s), 3.47 (2H, s), 5.21 (IH, dt), 6.67 (IH, d) , 7.38 (2H, d) , 7.48-7.56 (IH, m) , 7.75 (IH, s), 7.93 (IH, d) , 8.12 (IH, s), 10.01 (IH, br s ) ; HPLC rt(min): 9.58; MS (ES+) 432, (ES") 430. Example 138:
9-Cyclopentyl-2- (l-mefchanesulfonyl-2, 3-dihydro-lH-indol-5- ylamino) -5,7, 7-trimethyl-5, 7, 8,9-tetrahydro-pyrimido[4, 5- b] [l,4]diazepiix-6-one (1-138)
Figure imgf000145_0003
[00325] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.13 (6H, s) , 1.52-1.85 (8H, m) , 2.97 (3H, s), 3.11 (2H, t), 3.17 (3H1 s), 3.45 (3H, s), 3.95 (2H, t) , 5.14 (IH, dt) , 7.20 (IH, d) , 7.31 (IH, d) , 7.62 (IH, s), 7.88 (IH, s), 9.75 (IH, br s); HPLC rt (min) : 9.42; MS (ES+) 485, (ES") 484. Example 139;
5- (9-Cyclopentyl-6, 7, 8 , 9-tβtrahydro-5 , 7 , 7-trimethyl-6-oxo-5H- pyrimido [4, 5-b] [1, 4]diazepin-2-ylaitιino) indoline-2# 3-dionβ (1-139)
[00326] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.12 (6H, s), 1.56-1.76 (6H, m) , 1.81- 1.90 (2H, m) , 3.18 (3H1 s), 3.42 (2H, s), 5.15 (IH, dt) , 6.88
(IH, d) , 7.63 (IH, d) , 7.92 (IH, s), 7.99 (IH, s), 9.63 (IH, br S), 10.96 (IH, s) ; HPLC rt (min) : 8.75; MS (ES+) 435, (ES") 433.
Example 140;
3-(9-Cyclopentyl-6,7#8,9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [1, 4]diazβpin-2-ylamino) -5- (trifluoromethyl) -N- methylbenzamide (1-140)
Figure imgf000146_0002
[00327] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.10 (6H, s), 1.48-1.70 (6H, m) , 1.80- 1.89 (2H, m) , 2.78 (3H, d) , 3.19 (3H, s), 3.40 (2H, s), 5.25 (IH, dt) , 7.70 (IH, s), 7.99 (IH, s), 8.23 (IH, s), 8.34 (IH, s), 8.58-8.65 (IH, m) , 9.87 (IH, br s); HPLC rt(min): 9.99; MS (ES+) 491, (ES") 490. Example 141;
3-(9-C^clopentyl-6,7,8,9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido [4, 5-b] [1, 4] diazepin-2-ylamino) -N- (tetrahydro-2H- pyran-4-yl)benzamide (1-141)
Figure imgf000147_0001
[00328] Prepared using the appropriate reagents according to method E. NMR DMSO D5 1.12 (6H, s), 1.53-1.80 (12H, m) , 3.18
(3H1 s), 3.36-3.43 <5H, m) , 3.90 (2H, m) , 3.98 (IH, m) , 5.18
(IH, m) , 7.39 (IH, m) , 7.48 (IH, m) , 7.63 (IH, m) , 7.93 (IH, s) , 8.27 (IH, m) , 9.75 (IH, s); HPLC rt (min) : 9.07; MS (ES+) 493, (ES") 492. Example 142 :
4- (9-Cyclopentyl-6, 7, 8, 9-tetrahydro-5,7, 7-trimethyl-6-oxo-5H- pyrimido [4, 5-b] [1, 4] diazepin-2-ylamino) -N-meth.yl-3-
(trifluoromethoxy)benzamide (1-142)
Figure imgf000147_0002
[00329] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.09 (6H, s), 1.55 (4H, br m) , 1.69 - 1.81 (4H, br m) , 2.79 (3H, m) , 3.18 (3H, s), 3.36 (2H, s), 5.11 (IH, m) , 7.83 (2H, m) , 7.98 (IH, s), 8.28 (IH, m) , 8.50
(IH, s), 8.64 (IH, s); HPLC rt (min) : 9.78; MS (ES+) 507, (ES")
505.
Example 143 ;
3- [3- (9-Cyclopentyl-5, 7 , 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-
5H-pyrimido[4, 5-b] [1,4] diazepin-2-ylamino) -benzoylamino] - azetidine-1-carboxylic acid tert-butyl ester (1-143)
Figure imgf000148_0001
[00330] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.39 (9H, s), 1.53 (4H, m) , 1.66 (2H, m) , 1.83 (2H, m) , 3.19 (3H, s), 3.31 (2H, s), 3.85 (2H, m) , 4.10 (2H, m) , 4.61 (IH, m) , 5.25 (IH, m) , 7.30- 7.37 (2H, m) , 7.68 (IH, m) , 7.96 (IH, s), 8.27 (IH, s), 8.89
(IH, m) , 9.29 (IH, s ) ; HPLC rt (min) : 9.98; MS (ES+) 565, (ES")
563.
Example 144 :
3-(9-Cyclopentyl-6,7,8,9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -N- (2- methoxyethyl )benzamide (1-144)
Figure imgf000148_0002
[00331] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.11 (6H, s), 1.54 (4H, m) , 1.67 (2H, m) , 1.82 (2H, m) , 3.19 (3H, s), 3.27 (2H, m) , 3.85 masked signal, 4.10 (2H, m) , 5.22 (IH, m) , 7.35 (IH, m) , 7.46 (IH, m) , 7.65 (IH, m) , 7.93 (IH, s), 8.20 (IH, s), 8.46 (IH, m) , 9.68 (IH, s); HPLC rt (min) : 9.04; MS (ES+) 467, (ES") 466. Example 145:
N- (3- (9-Cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7,7-trimethyl-6-oxo- 5H-pyrimido [4,5-b] [1,4] diazepin-2-ylamino)phenyl-3,3,3- trifluoropropanaxnide (X-145)
Figure imgf000149_0001
[00332] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.12 (6H, s), 1.50 - 1.67 (6H, br m) , 1.8K2H, br m) , 3.18 (3H, s), 3.44 (2H, s), 3.50 (2H, m) , 5.21
(IH, m) , 7.14 (IH, m) , 7.28 (2H7 m) , 7.92 (2H, m) , 9.87 (NH), 10.34 (IH, s); HPLC rt (min) : 9.63; MS (ES+) 491, (ES") 489. Example 146 t
N- (3- (9-Cyclopentyl-6# 1, 8, 9-tetrahydro-5, 7 , 7-trimethyl-6-oxo- 5H-pyrimido [4, 5-b] [1, 4]diazepin-2-ylamino)phenyl) -N- methylacetamide (1-146)
Figure imgf000149_0002
[00333] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.09 (6H, s), 1.52-1.63 (4H, m) , 1.67- 1.73 (2H, m) , 1.78 (3H, s), 1.81-1.88 (2H, m) , 3.14 (3H, s), 3.18 (3H, s), 3.36 (2H, s), 5.23 (IH, quint), 6.84 (IH, d) , 7.29 (IH, t) , 7.49 (IH, d) , 7.93 (IH, s), 7.98 (IH, s), 9.38
(IH, s); HPLC rt(min): 9.40; MS (ES+) 437, (ES") 435. Example 147;
N- (3- (9-Cyclopentyl-6, 7, 8 , 9-tetrahydro-5, 7 , 7-trimethyl-6-oxo- 5H-pyrimido[4, 5-b] [1, 4] diazepin-2-ylamino)phenyl) -2- methoxyacetamide (1-147)
Figure imgf000149_0003
[00334] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s) , 1.51-1.57 (4H, m) , 1.65- 1.71 (2H, m) , 1.81-1.87 (2H, m) , 3.18 (3H, s), 3.32 (2H, s), 3.37 (3H, s), 3.97 (2H, s), 5.26 (IH, quint), 7.10-7.17 (2H, in), 7.34 (IH, d) , 7.94 (IH, s), 8.00 (IH, s), 9.14 (IH, s), 9.59 (IH, s); HPLC rt(min): 9.30; MS (ES+) 453, (ES") 451. Example 148;
3- (9-Cyclopentyl-6, 7, 8, 9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido [4, 5-b] [1, 4] diazepin-2-ylamino) -N,N-dimethylbenzamide (1-148)
Figure imgf000150_0001
[00335] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.12 (6H, s), 1.56 (4H, m) , 1.70 (2H, m) , 1.81 (2H, m) , 2.91 (3H, s), 2.98 (3H, s), 3.18 (3H, s), 3.42 (2H, s), 5.19 (IH, m) , 7.00 (IH, m) , 7.34 (IH, m) , 7.53
(IH, m) , 7.86 (IH, s), 7.95 (IH, s), 9.70 (IH, s); HPLC rt(min): 9.21; MS (ES+) 437, (ES") 435. Example 149;
2- (3- (2-oxopyrrolidin-l-yl)phenylam.ino) -9-cyclopentyl-β, 9- dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b] [l,4]diazepin-6 (7H) - one (1-149)
Figure imgf000150_0002
[00336] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.15 (6H, s), 1.60 (4H, m) , 1.77 (2H, m) , 1.91 (2H, m) , 2.12 (2H, m) , 2.51 masked signal, 3.24 (3H, s), 3.37 (2H, s), 3.87 (2H, m) , 5.32 (IH, m) , 7.19 (IH, m) , 7.27 (IH, m) , 7.52 (IH, m) , 8.01 (IH, s), 8.04 (IH, m) , 9.22
(IH, s); HPLC rt (min) : 9.52; MS (ES+) 449, (ES") 447. Example 150:
N- [3- ( 9-cyclopentyl-5,7, 7-trimethyl-6-oxo-6, 7,8, 9-tetrahydro-
5H-pyrimido[4, 5-b] [1, 4] diazepin-2-ylamino) -phenyl] - methanesulfonamide (1-150)
Figure imgf000151_0001
[00337] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.55-1.65 (4H, s), 1.68- 1.73 (2H, m) , 1.80-1.89 (2H, m) , 2.94 (3H, s) , 3.18 (3H, s) , 3.32 (2H, S) , 5.25 (IH, quint), 6.71 (IH, d) , 7.15 (IH, t) , 7.47 (IH, d) , 7.59 (IH, s), 7.93 (IH, s), 9.16 (IH, s), 9.56 (IH, br s); HPLC rt(min): 9.10; MS (ES+) 459, (ES") 457. Example 151:
N- (3- (9-cyclopentyl-6, 7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo- 5H-pyrimido[4,5-b] [1, 4]diazepin-2- ylamino)phenyl)cyclobutanecarboxamide (1-151)
Figure imgf000151_0002
[00338] Prepared using appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.48-1.59 (4H, m) , 1.63- 1.73 (2H, m) , 1.76-1.89 (3H, m) , 1.90-1.98 (IH, m) , 2.04-2.14 (2H, m) , 2.16-2.27 (2H, m) , 3.19 (3H, s), 3.18-3.26 (IH, m) , 3.34 (2H, s), 5.27 (IH, quint), 7.03-7.12 (2H, m) , 7.27 (IH, d) , 7.93 (IH, s), 7.99 (IH, S), 9.08 (IH, s) , 9.59 (IH, s); HPLC rt(min): 9.80; MS (ES+) 463, (ES') 461. Example 152 :
9-Cyclopentyl-2- [3- (3-cyclopropyl-3-fluoro-azetidine-1- carbonyl) -phenylamino] -5,7,7-trimethyl-5, 7,8,9-tetrahydro- pyrimido [4, 5-b] [l,4]diazepin-6-one (1-152)
Figure imgf000152_0001
[00339] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.20 (2H, m) , 0.36 (2H, m) , 0.86 (6H, s), 1.16 (IH, m) , 1.34 (4H, m) , 1.46 (2H, m) , 1.63 (2H, m) , 2.95 <3H, s), 3.08 masked signal, 3.79 (2H, m) , 3.96-4.08 (2H, m) , 5.01 (IH, m) , 6.89 (IH, m) , 7.07 (IH, m) , 7.73 (IH, s), 7.83 (IH, s), 9.09 (IH, s ) ; HPLC rt(min): 10.03; MS (ES+) 507,
(ES") 505. Example 153 :
2- (3- (pyridin-3-yl)phenylamino) -9-cyclopentyl-8,9-dihydro- 5,7,7-trimethyl-5H-pyrimido[4,5-b] [1, 4Jdiazepin-6 (7H) -one (I- 153)
Figure imgf000152_0002
[00340] Prepared using the appropriate reagents according to method. D. NMR DMSO D6 1.06 (6H, s), 1.19-1.28 (2H, m) , 1.47- 1.58 (4H, m) , 1.70-1.83 (2H, m) , 3.19 (3H, s), 3.33 (2H, s), 5.16-5.24 (IH, m) , 7.20 (IH, d) , 7.37 (IH, t) , 7.49 (IH, dd) , 7.62 (IH, d) , 7.98 (IH, s), 8.00-8.02 (IH, m) , 8.14-8.15 (IH, m) , 8.58 (IH, dd) , 8.82 (IH, d) , 9.30 (IH, s); HPLC rt(min): 10.10; MS (ES+) 443, (ES") 441. Example 154:
N- (3- (9-cyclopentyl-6,7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo- 5H-pyrimido[4, 5-b] [1, 4] diazepin-2-ylamino)phenyl )benzamide (I- 154)
Figure imgf000153_0001
[00341] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.08 (6H, s), 1.34-1.42 (2H, m) , 1.49- 1.56 (4H, m) , 1.78-1.86 (2H, m) , 3.19 (3H, s), 3.33 (2H, s), 5.28 (IH, quint), 7.15-7.22 (2H, m) , 7.30-7.32 (IH, m) , 7.51- 7.61 (3H, m), 7.94-8.00 (3H, m) , 8.26 (IH, s), 9.20 (IH, s), 10.17 (IH, S); HPLC rt (min) : 9.70; MS (ES+) 485, (ES") 483. Example 155:
Methyl 3- (9-cyclopentyl-6,7, 8, 9-tetrahydro-5# 7, 7-trimethyl-6- oxo-5H-pyrimido[4, 5-b] [1,4] diazepin-2-ylam±no)phenyl)carbamate (1-155)
Figure imgf000153_0002
[00342] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.08 (6H, s), 1.48-1.57 (4H, m) , 1.64- 1.73 (2H, m) , 1.79-1.88 (2H, m) , 3.18 (3H, s), 3.29 (2H, s), 3.64 (3H, s), 5.26 (IH, quint), 6.88 (IH, d) , 7.11 (IH, t) , 7.26 (IH, d) , 7.90 (IH, s), 7.93 (IH, s), 9.11 (lH, s), 9.50 (IH, s); HPLC rt (min) : 9.40; MS (ES+) 439, (ES") 437. Example 156;
3- (9-cyclopentyl-6,7, 8, 9-tetrahydro-5,7,7-trimethyl-6-oxo-5H- pyrimido [4, 5-b] [l,4]diazepin-2-ylamino) -N- (azetidin-3- yDbenzamide (1-156)
Figure imgf000153_0003
[00343] Prepared using the appropriate reagents according to method F. NMR DMSO D6 1.11 (6H, s), 1.53 (4H, m) , 1.67 (2H, m) , 1.81 (2H, m) , 3.18 (3H, s) 4.07 (4H, m) , 4.81 (IH, m) , 5.24 (IH, m) 7.41 (2H, m) , 7.70 (IH, m) , 7.97 (IH, s) , 8.24
(IH, m) , 8.72 (2H, br s ) , 9.05 (IH, m) , 9.72 (IH, m) ; HPLC rt(min): 8.38; MS (ES+) 464, (ES") 463.
Example 157 :
N- (3- (9-cyclopentyl-6,7, 8, 9-tefcraliydro-5,7,7-triineth.yl-6-oxo-
5H-pyrimido[4, 5-b] [l,4]diazepin-2-ylamino)phen.yl) -1- meth.ylpiperidine-4-carboxamide (1-157)
Figure imgf000154_0001
[00344] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.35 (2H, br m) , 1.50 - 1.81 (8H, br m) , 1.96 (2H, br m) , 2.51 (IH, br m) , 2.72 (3H, s), 2.91 (2H, m) , 3.12 (3H, s) , 3.43 (2H, m) , 3.44 (2H, s), 5.07 (IH, m) , 7.10 <2H, m) , 7.31 (IH, m) , 7.73 (IH, s), 7.96
(IH, s) , 10.20 (IH, s) ; HPLC rt (min) : 8.96; MS (ES+) 506, (ES"")
504.
Example 158 ;
N- (3- O-cyclopentyl-6,7, 8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo-
5H-pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -4- methoxyphenyl ) acetamide ( I-158 )
Figure imgf000154_0002
[00345] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.12 (6H, s), 1.45-1.70 (6H, m) , 1.76- 1.88 (2H, m) , 2.00 (3H1 s), 3.17 (3H, s) , 3.46 (2H, s), 3.83 (3H, s), 5.21 (IH, dt), 7.01-7.11 (2H, m) , 7.93-7.96 (IH, m) , 8.26-8.34 (IH, m) , 9.84 (IH, s) ; HPLC rt (min) : 8.85; MS (ES+)
453, (ES") 452.
Example 159:
3- ( 9-cyclopentyl-6,7,8, 9-tβtrahydro-5, 7,7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -N-cyclopropylbenzamide
(1-159)
Figure imgf000155_0001
[00346] Prepared using appropriate reagents according to method E. NMR DMSO D6 0.56 (2H, m) , 0.68 (2H, m) , 1.12 (6H, s), 1.55 (4H, m) , 1.67 (2H, m) , 1.91 (2H, m) , 2.83 (IH, m) , 3.18 (3H, s), 3.43 (2H, s), 5.20 (IH, m) , 7.36-7.44 (2H, m) , 7.60 (IH, m) , 7.93 (IH, s), 8.16 (IH, s), 8.38 (IH, m) , 9.70
(IH, s); HPLC rt (min) : 9.19; MS (ES+) 449, (ES") 448. Example 160;
4-(9-(2,2,3,3r3-pentafluoropropyl) -6, 7 , 8, 9-tetrahydro-5,7,7- trimethyl-6-oxo-5H-pyrimido[4, 5-b] [1, 4] diazepin-2-ylamiiio) -3- methoxy-N-methylbenzamide (1-160)
Figure imgf000155_0002
[00347] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.11 (6H, s), 2.79 (3H, d) , 3.22 (3H, s), 3.66 (2H, s), 3.92 (3H, s), 4.83 (2H, t), 7.42 (IH, dd) , 7.50 (IH, d) , 7.89 (IH, s), 8.14 (IH, d) , 8.15 (IH, s) , 8.35
(IH, q) ; HPLC rt (min) : 9.00; MS (ES+) 517, (ES") 515. Example 161:
4- (9- ( 3-chlorophenyl) -6, 7 , 8 , 9-tetrahydro-5, 7 , 7-trimeth.yl-6- oxo-5H-pyrimido[4, 5-b] [1, 4] diazepin-2-ylamino) -3-methoxy-N- methylbenzamide (1-161)
Figure imgf000156_0001
[00348] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.23 (6H, s), 2.77 (3H, d) , 3.29 (3H, s), 3.82 (2H, s), 3.87 <3H, s), 6.96 (IH, dd) , 7.32 (IH, d) , 7.34-7.38 (2H, m) , 7.49-7.54 (2H, m) , 7.57 (IH, d) , 7.60 (IH, s), 8.17 (IH, s), 8.23 (IH, q) ; HPLC rt (min) : 8.99; MS (ES+) 495, (ES") 493. Example 162 ;
N- (5- (9-cyclopentyl-6,7#8#9-tetrahydro-5# 7, 7-trimethyl-6-oxo- 5H-pyrimido [4,5-b] [1,4] diazepin-2-ylamino) -2- methylphenyl)acetamide (1-162)
Figure imgf000156_0002
[00349] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.08 (6H, s), 1.57 (4H, br m) , 1.70 (2H1 br m) , 1.84 (2H, br m) , 2.02 (3H, s), 2.11 (3H, s), 3.17 (3H, s), 3.34 (2H, s), 5.24 (IH, m) , 7.02 (IH, m) , 7.28 (IH, m) , 7.83 (IH, S), 7.92 (IH, s), 9.09 (IH, s), 9.27 (IH, s ) ; HPLC rt(min): 8.91; MS (ES+) 437, (ES') 435. Example 163 :
N- (3- ( 9-cyclopentyl-6,7, 8, 9-tβtrahydro-5, 7, 7-trimethyl-6-oxo- 5H-pyrimido [4, 5-b] [1, 4] diazepin-2-ylamino) -4- methylphenyl) acetamide (1-163)
Figure imgf000156_0003
[00350] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.07 (6H, s), 1.41 (4H, br m) , 1.45 - 1.70 (4H, br m) , 1.99 (3H, s) , 2.17 (3H, s), 3.17 (3H, s) , 3.30 (2H, s), 5.07 (IH, m) , 7.04 - 7.13 (2H, m) , 7.89 (2H, m) , 8.21 (IH ,s), 9.77 (IH, s) ; HPLC rt(min): 9.01; MS (ES+) 437, (ES") 435. Example 164 ;
N- (3- (9-cyclopentyl-6, 7,8, 9-tetrahydro-5, 7, 7-trimethyl-6-oxo- 5H-pyr-imido[4, 5-b] [1, 4]diazepin-2-ylamino)phenyl )piperidine-l- carboxamide (1-164)
Figure imgf000157_0001
[00351] Prepared using the appropriate reagents according to method E- NMR DMSO D6 1.09 (6H, s), 1.46-1.61 (10H, m) , 1.64- 1.69 (2H, m) , 1.81-1.89 (2H1 m) , 3.18 (3H, s), 3.32 (2H, s), 3.38-3.41 (4H, m) , 5.26 (IH, quint), 6.89 (IH, d) , 7.06 (IH, t) , 7.16 (IH, d) , 7.88-7.90 (IH, m) , 7.92 (IH, s), 8.31 (IH, s) , 9.03 (IH, s) ; HPLC rt(min): 9.70; MS (ES+) 492, (ES") 490. Example 165:
N- (3- (9-cyclopenfcyl-6,7, 8, 9-tetrahydro-5, 7, 7-fcrimethyl-6-oxo- 5H-pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -2,6- difluorophenyl) acetamide (1-165)
Figure imgf000157_0002
[00352] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.17 (6H, s), 1.53 (4H, br m) , 1.60 - 1.76 (4H, br m) , 2.13 (3H, s), 3.23 (3H, s), 3.48 (2H, s), 5.03 (IH, m) , 7.23 (IH, m) , 7.64 (IH, m) , 7.95 (IH, s), 9.57 (IH, s), 9.83 (IH, s); HPLC rt(min): 8.90; MS (ES+) 459, (ES") 457. Example 166 t
4- ( 9-cyclopentyl-6,7,8, 9-tetrahydro-5, 7 , 7-trimethyl-6-oxo-5H- pyrimido [4, 5-b] [1,4] diazepin-2-ylamino) -N- (3,3- difluorocyclobutyl) -3-methoxybenzamide (I-166 )
Figure imgf000158_0001
[00353] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.53-1.68 (4H, m) , 1.69- 1.80 (2H, m) , 1.82-1.94 (2H, m) , 2.69-2.86 (2H, m) , 2.90-3.04
(2H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.95 (3H, s), 4.28 (IH, dt), 5.19 (IH, dt), 7.48 (IH, d) , 7.49 (IH, s), 7.72 (IH, s), 8.00 (IH, s), 8.40 (IH, d) , 8.66 (IH, d) ; HPLC rt(min): 10.04; MS (ES+) 529, (ES") 528. Example 167 :
4- (9-cyclobutyl-6, 7, 8, 9-tetrahydro-5, 7 , 7-trimethyl-6-oxo-5H- pyrimido[4, 5-b] [1, 4] diazepin-2-ylamino) -3-methoxy-N- methylbenzamide (1-167)
Figure imgf000158_0002
[00354] Prepared using the appropriate reagents according to method D. NMR CDCl3 1.22 (6H, s), 1.76-1.85 (2H, m) , 2.14 (2H, dquint), 2.30-2.33 (2H, m) , 3.05 (3H, d) , 3.32 <3H, s), 3.51 (2H, s), 4.00 (3H, s), 5.09 (IH, quint), 6.14 (IH, q) , 7.30 (IH, dd) , 7.47 (IH, d) , 7.64 (IH, s), 7.90 (IH, s), 8.58 (IH, d) ; HPLC rt(min): 8.98; MS (ES+) 439, (ES") 437. Example 168 :
4- ( 6 , 7 , 8 , 9-tetraliydro-5 , 7 , 7-trimethyl-9-neopentyl-6-oxo-5H- pyr±mido [4 , 5-b] [ 1, 4] diazepin-2-ylamino) -3-methoxy-N- methylbenz amide ( 1-168 )
Figure imgf000159_0001
[00355] Prepared using the appropriate reagents according to method D. NMR DMSO D6 0.96 (9H, s), 1.10 (6H, s), 2.78 (3H, s), 3.21 (3H, s), 3.60 (2H, s), 3.79 (2H, s), 3.93 (3H, s), 7.49 (2H, m) , 7.71 (IH7 s), 8.00 (IH, s), 8.35 (2H, m) ; HPLC rt(min): 9.30; MS (ES+) 455, (ES") 453. Example 169 ;
4-(9-((2,2-difluorocyclopropyl)methyl )-6,7,8,9-tetrahydro- 5,7,7-trimethyl-6-oxo-5H-pyrimido[4, 5-b] [l,4]diazepin-2- ylamino) -3-methoxy-N-methylbenzamide (1-169)
Figure imgf000159_0002
[00356] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.11 (6H, d) , 1.44 (IH, br m) , 1.67 (IH, br m) , 2.17(1H, br m) , 2.78(3H, d) , 3.20(3H, s) , 3.46(2H, br m) , 3.63(1H, d) , 3.93(3H, s), 4.14(lH, br m) , 7.46(2H, br m) , 7.76(1H, s), 8.04(1H, s), 8.32(2H, br d) ; HPLC rt(min): 8.70; MS (ES+) 475, (ES") 473. Example 170;
4- ( 9- ( 3 , 3-difluorocyclobutyl) -6, 7, 8 , 9-tetrahydro-5, 7, 7- trimethyl-6-oxo-5H-pyrimido[4,5-b] [1, 4] diazepin-2-ylamino) -3- methoxy-N-methylbenzamide (1-170)
Figure imgf000160_0001
[00357] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.10 (6H, s), 2.76-2.95 (4H, m) , 2.78 (3H, d) , 3.21 (3H, s), 3.48 (2H, s), 3.93 (3H, s) , 4.58-4.64 (IH, m) , 7.43-7.54 (2H, m) , 7.87 (IH, s), 8.09 (IH, s), 8.30- 8.38 (2H, m) ; HPLC rt(min): 8.35; MS (ES+) 475, (ES") 473. Example 171;
4-(9-(3,3-difluorocyclobutyl)-6,7,8,9-tetrahydro-5,7,7- trimethyl-6-oxo-5H-pyr-imido[4, 5-b] [l,4]diazepin-2-ylamino) -N- (tβtrahydro-2H-pyran-4-yl) -3-methoxybenzamide (1-171)
Figure imgf000160_0002
[00358] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.10 (6H, s), 1.54-1.65 (2H, m) , 1.75- 1.79 (2H, m) , 2.78-2.98 (4H, m) , 3.21 (3H, s), 3.34-3.43 (2H, m) , 3.48 (2H, s), 3.85-3.89 (IH, m) , 3.90-3.93 (IH, m) , 3.95
(3H, s), 3.98-4.05 (IH, m) , 4.56-4.63 (IH, m) , 7.48-7.51 (2H, m) , 7.88 (IH, s), 8.10 (IH, s), 8.19 (IH, d) , 8.33 (IH, d) ; HPLC rt(min): 8.86; MS (ES+) 545, (ES") 544. Example 172 ;
4- ( 9-eye1opentyl-6,7,8, 9-tetrab.ydro-5, 7, 7-trimethyl-6-oxo-5H- pyrimido[4,5-b] [1, 4]diazepin-2-ylamino) -N- ( (S) - tetrahydrofuran-3-yl) -3-methoxybenzamide (1-172)
Figure imgf000161_0001
[00359] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.10 (6H, m) , 1.55-1.68 (4H, m) , 1.69- 1.77 (2H, m) , 1.84-1.95 (4H, m) , 2.12-2.21 (IH, m) , 3.19 (3H, s), 3.38 (2H, s), 3.59 (IH, dd) , 3.68-3.76 (IH, m) , 3.83-3.91 (2H, m) , 3.95 (3H, s), 4.45-4.49 (IH, m) , 5.19 (IH, dt) , 7.47- 7.52 (2H, m) , 7.70 (IH, s), 7.99 (IH, s), 8.35-8.41 (2H, m) ; HPLC rt(min): 9.37; MS (ES+) 509, (ES") 507. Example 173:
4-((S)-9-cyclopentyl-6,7,8, 9-tetrahydro-5, 7-dimethyl-6-oxo-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -N-cyclopentyl-3- methoxybenzamide (1-173)
Figure imgf000161_0002
[00360] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.02 (3H, d) , 1.50-1.83 (14H, m) , 1.89- 1.94 (2H, m) , 2.08-2.11 (IH, m) , 2.83-2.88 (IH, m) , 3.19 (3H, s), 3.37-3.45 (IH, m) , 3.95 (3H, s), 4.20-4.26 (IH, m) , 4.71- 4.76 (IH, m) , 7.47 (IH, d) , 7.49 (IH, s), 7.75 (IH, s), 8.10 (IH, s), 8.14 (IH, d) , 8.38 (IH, d) ; HPLC rt (min) : 10.10; MS (ES+) 493, (ES") 491. Example 174 ;
4-((S)-9-cyclopentyl-6,7,8,9-tetrahydro-5,7-dimethyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylaminoj -N- (tetrahydro-2H- pyran-4-yl) -3-methoxybenzamide (1-174)
Figure imgf000162_0001
[00361] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.02 (3H, s) , 1.52-1.78 (HH, m) , 2.04- 2.12 (IH, m) , 2.84-2.90 (IH, m) , 3.19 (3H, s), 3.39-3.46 (4H, m) , 3.89 (2H, br dd) , 3.95 (3H, s), 3.96-4.06 (IH, m) , 4.74
(IH, quint), 7.49 (IH, d) , 7.50 (IH, s), 7.76 (IH, s), 8.10
(IH, S), 8.17 (IH, d) , 8.40 (IH, d) ; HPLC rt(min): 9.20; MS
(ES+) 509, (ES") 507. Example 175 ;
4- ( (S) -9-cyclopentyl-6,7, 8, 9-tetrahydro-5, 7-dimethyl-6-oxo-5H- pyrimido[4, 5-b] [l,4]d±azepin-2-ylam±no) -N-cyclopropyl-3- methoxybenzamide (1-175)
Figure imgf000162_0002
Prepared using the appropriate reagents according to method D. NMR DMSO D6 0.55-0.59 (2H, m) , 0.68-0.73 (2H, m) , 1.02 (3H, d) , 1.47-1.85 (7H, m) , 2.04-2.12 (IH, m) , 2.79-2.88 (2H, m) , 3.19
(3H, s), 3.36-3.46 (2H, m) , 3.94 (3H, s), 4.69-4.75 (IH, m) , 7.45 (IH, d) , 7.47 (IH, s), 7.75 (IH, s), 8.10 (IH, s), 8.34
(IH, d) , 8.38 (IH, d) ; HPLC rt (min) : 9.10; MS (ES+) 465, (ES")
463.
Example 176 i
N-cyclopentyl-4- (9 • -cyclopentyl-5 ■ -methyl-6 ' -oxo-5 • , 6 ' , 8 • , 9 ' - tetrahydrospiro [cyclopropane-1# 7 ' -pyrimido [4,5- b] [1, 4]diazepine] -2 • -ylamino) -3-meth.oxybenzamide (1-176)
Figure imgf000163_0001
[00362] Prepared using the appropriate reagents according to method D. NMR DMSO D6 0.66-0.69 (2H, in), 0.89-0.91 (2H, m) ,
1.46-1.71 (12H, m) , 1.85-1.95 (4H, m) , 3.17 (3H, s), 3.48 (2H, s), 3.95 (3H, S), 4.23 (IH, quint), 4.85 (IH, quint), 7.47
(IH, d) , 7.49 (IH, s), 7.66 (IH, s), 7.99 (IH, s), 8.13 (IH, d) , 8.38 (IH, d) ; HPLC rt (min) : 10.00; MS (ES+) 505, (ES") 503.
Example 177;
4- (9 ' -cyclopentyl-5 • -methyl-6 • -oxo-5 • , 6 ■ , 8 • , 9 ■ - tetrahydrospiro [cyclopropane-1, 7 • -pyrimido [4, 5- b] [l,4]diazepine] -2 • -ylamino) -3-methoxy-N- (tetrahydro-2H- pyran-4-yl)benzaiiιide (1-177)
Figure imgf000163_0002
[00363] Prepared using the appropriate reagents according to method D. NMR DMSO D6 0.67 (2H, br t) , 0.90 (2H, br t), 1.51- 1.78 (HH, m) , 1.75-1.85 (2H, m) , 3.17 (3H, s), 3.36-3.42 (2H, m) , 3.48 (2H, s), 3.89 (2H, br d) , 3.99 (3H, s), 3.99-4.03
(IH, m) , 4.85 (IH, quint), 7.93 (IH, d) , 7.94 (IH, S), 7.70
(IH, s), 7.99 (IH, s), 8.16 (IH, d) , 8.40 (IH, d) ; HPLC rt(min): 9.10; MS (ES+) 521, (ES") 519.
Example 178:
4- (9 • -cyclopentyl-5 • -methyl-6 • -oxo-5 ' , 6 ' , 8 ' , 9 ' - tetrahydrospiro [cyclopropane-1, 7 ■ -pyrimido [4, 5- b] [1, 4] diazepine] -2 ' -ylamino) -N-cyclopropyl-S-methoxybenzamide
(1-178)
Figure imgf000164_0001
[00364] Prepared using the appropriate reagents according to method D. MMR DMSO D6 0.56-0.59 (2H, m) , 0.66-0.73 (4H, m) , 0.84-0.91 (2H, m) , 1.50-1.76 (6H, m) , 1.85-1.95 (2H, m) , 2.79- 2.83 (IH, m) , 3.10 (3H, s), 3.49 (2-H, s),* 3'.94 (3H, s), 4.85 (IH, quint), 7.45 (IH, " d) , 7.47 (IH, s), 7.69 (IH, s), 7.99 (IH, s), 8.33 (IH, d) , 8.38 (IH, d) ; HPLC rt(min): 9.00; MS (ES+) 477, (ES") 475. Example 179:
(S)-4-(91-cyclopentyl-51-methyl-6'-oxo-5t ,6' ,8' ,9'- tβtrahydrospiro [cyclopropane-l, 7 • -pyrimido [4,5- b] [l,4]diazepine]-2 • -ylamino) -3-methoxy-N- (tθtrahydrofuran-3- yl )benzamide (1-179)
Figure imgf000164_0002
[00365] Prepared using the appropriate reagents according to method D. NMR DMSO D6 0.67 (2H, br m) , 0.90 (2H, br m) , 1.50
1.69 (6H, br m) , 1.88 - 1.91 (3H, m) , 2.16 (IH, m) , 3.17 (3H, Ξ), 3.48 (2H, s), 3.60 (IH, m) , 3.61 (IH, m) , 3.84 (2H, m) , 3.95 (3H, s), 4.46 (IH, m) , 4.85 (IH, m) , 7.50 (2H, m) , 7.70 (IH, s), 7.99 (IH, s), 8.38 (IH, m) , 8.41 (IH, s); HPLC rt(min): 7.39; MS (ES+) 507, (ES") 505. Example 180;
4- (6,7,8,9-tetrahydro-9-( (S) -tetrahydrofuran-3-yl) -5,7,7- trimethyl-6-oxo-5H-pyrimido [4, 5-b] [1, 4]diazepin-2-ylamino) -3- methoxy-N-methylbenzamide (1-180)
Figure imgf000165_0001
[00366] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.09 (6H, d) , 1.92 (IH, m) , 2.31 (IH, m) , 2.78 (3H, d) , 3.19 (3H, s), 3.47 (2H, m) , 3.63 (IH, q) , 3.80 (2H, m) , 3.93 (3H, s) , 3.98 (IH, m) , 5.44 (IH, m) , 7.48 (2H, m) , 7.77 (IH, s), 8.03 (IH, s), 8.35 (2H, m) ; HPLC rt(min): 7.80; MS (ES+) 455, (ES') 453. Example 181t
4- ( 6, 7 , 8 , 9-tβtrahydro-9- ( (R) -tβtrahydrofuran-3-yl) -5, 7, 7- trimethyl-6-oxo-5H-pyrimido[4, 5-b] [1/ 4]diazepin-2-ylamiiio) -3- methoxy-N-methylbenzamide (1-181)
Figure imgf000165_0002
[00367] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.09 (6H, d) , 1.92 (IH, m) , 2.31 (IH, m) , 2.78 (3H, d) , 3.19 (3H, s), 3.47 (2H, m) , 3.63 (IH, q) , 3.80 (2H, m) , 3.93 (3H, s), 3.98 (IH, m) , 5.44 (IH, m) , 7.48 (2H, m) , 7.77 (IH, s), 8.03 (IH, s), 8.35 (2H, m) ; HPLC rt(min): 7.80; MS (ES+) 455, (ES") 453. Example 182;
(R) -4- ( 9-cyclopentyl-5, 7-dimethyl-6-oxo-6,7, 8, 9-tetrahydro-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -3-methoxy-N- (tetrahydro-2H-pyran-4-yl)benzamide (I-182 )
Figure imgf000165_0003
[00368] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.09 (3H, d) , 1.58-1.91 (11H, m) , 2.10- 2.20 (IH, m) , 2.88-2.96 (IH, m) , 3.25 (3H, s), 3.36-3.54 (4H, m) , 3.90-3.97 (2H, m),.4.02 (3H, s), 4.03-4.12 (IH, m) , 4.75- 4.85 (IH, m) , 7.54-7.57 (2H, m) , 7.83 (IH, s), 8.17 (IH, s) , 8.24 (IH, d) , 8.46 (IH, d) ; HPLC rt (min) : 9.24. Example 183 :
4-( (R)-9-cyclopentyl-5/7-dimethyl-6-oxo-6,7,8/9-tetrahydro-5H- pyrimido[4, 5-b] ^'l,4]diazepin-2-ylaiftino)-3-metlxoxy-N- ( (S) - tetrahydrofuran-3-yL)benzamide (1-183 )
Figure imgf000166_0001
[00369] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.09 (3H, d) , 1.48-1.63 (3H, m) , 1.65- 1.85 (4H, m) , 1.85-2.022.10-2.23 (IH, m) , 2.30 (3H, s), 2.95- 3.05 (IH, m) , 3.19 (3H, s), 3.35-3.42 (IH, m) , 3.54-3.65 (2H, m) , 3.66-3.75 (IH, m) , 3.80-3.90 (2H, m) , 3.97 (3H, s), 4.42- 4.52 (IH, m) , 4.76-4.87 (IH, m) , 7.52-7.62 (2H, m) , 8.04-8.15 (2H, m) , 8.52 (IH, d) , 9.27 (IH, br s); HPLC rt (min) : 9.11. Example 184 ;
(R) -4- (9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8, 9-tetrahydro-5H- pyrimido[4, 5-b] [1, 4] diazepin-2-ylamin.o) -N-cyclopropyl-3- methoxybenzamide (1-184)
Figure imgf000166_0002
[00370] Prepared using the appropriate reagents according to method D. NMR DMSO D6 0.55-0.59 (2H, m) , 0.67-0.73 (2H, m) , 1.02 (3H, d) , 1.52-1.83 (7H, m) , 2.05-2.10 (IH, m) , 2.79-2.88
(2H, m) , 3.19 (3H, s) , 3.59-3.45 (2H, m) , 3.94 (3H, s), 4.73 (IH, quint), 7.45 (IH, d) , 7.47 (IH, s), 7.78 (IH, s), 8.09
(IH, s), 8.33 (IH, d) , 8.83 (IH, d) ; HPLC rt(min): 9.40; MS
(ES+) 465, (ES") 463. Example 185;
(R) -N-cyclopentyl-4-(9-cyclopentyl-5, 7-dimethyl-6-oxo-6, 7,8,9• tθtrahydro-5H-pyrimido[4/5-b] [l,4]diazepin-2-ylamino> -3- methoxybenzamide (X-185)
Figure imgf000167_0001
[00371] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.02 (3H, d) , 1.50-1.61 (6H, m) , 1.63- 1.83 <8H, m) , 1.86-1.96 (2H, m) , 2.04-2.11 (IH, m) , 2.83-2.88 (IH, m) , 3.19 (3H, s), 3.36-3.46 (IH, m) , 3.95 (3H, s), 4.18- 4.28 (IH, m) , 4.74 (IH, quint), 7.47 (IH, d) , 7.48 (IH, s) , 7.75 (IH, s), 8.10 (IH, s), 8.15 (IH, s), 8.38 (IH, d) ; HPLC rt(min) : 10.10; MS (ES+) 493, (ES") 491. Example 186;
(R)-N-cyclobutyl-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9- tetrahydro-5H-pyrimido[4, 5-b] [l#4]diazepin-2-ylamino) -3- methoxybenzamide (1-186)
Figure imgf000167_0002
[00372] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.02 (3H, d) , 1.50-1.83 (9H, m) , 2.03- 2.12 (3H, m) , 2.19-2.23 (2H, m) , 2.81-2.90 (IH, m) , 3.19 (3H, s), 3.30-3.33 (IH, m) , 3.43 (IH, t) , 3.65 (3H, s), 4.43 (IH, q) , 4.73 (IH, quint), 7.48 (IH, dd) , 7.49 (IH, s), 7.76 (IH, s), 8.10 (IH, s), 8.39 (IH, d) , 8.47 (IH, d) ; HPLC rt (min) : 9.90; MS (ES+) 479. Example 187 :
(R)-4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro- 5H-pyrimido [4, 5-b] [1, 4] diazepin-2-ylamino) -3-methoxy-N- (tetrahydrofuran-3-yl)benzamide (1-187 )
Figure imgf000168_0001
[00373] Prepared using the appropriate reagents according to method D- NMR DMSO D6 1.10 (6H, s), 1.62 (4H, br m) , 1.74 (2H, br m) , 1.89 (3H, br m) , 2.16 (IH, br m) , 3.19 (3H, s) , 3.38
(2H, s), 3.60 (IH, m) , 3.71 (IH, m) , 3.86 (2H, m) , 3.95 (3H, s), 4.45 (IH, m) , 5.20 (IH, m) , 7.51 (2H, m) , 7.70 (IH, s), 7.99 (IH, s), 8.39 (2H, m) ; HPLC rt(min): 9.40; MS (ES+) 509. Example 188:
9-cyclopentyl-2- (2-methoxyphenylamino) -5-methyl-8 , 9-dihydro- 5H-pyrimido[4,5-b] [1, 4]diazepin-6 (7H)-one (1-188)
Figure imgf000168_0002
[00374] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.52-1.75 (6H, m) , 1.85-1.95 (2H, m) , 2.52-2.58 (2H, m) , 3.16 (3H, s), 3.58-3.62 (2H, m) , 3.86 (3H, s), 4.75 (IH, quint), 6.93 (2H, dt) 7.02 (IH, dd) , 7.61 (IH, s), 8.04 (IH, s), 8.21 (IH, dd) ; HPLC rt (min) : 10.07; MS (ES+) 368.
Example 189 ;
2- (2-methoxyphenylamino) -5, 9-dimethyl-8, 9-dihydro-5H- pyrimido[4,5-b] [1, 4] diazepin-6 (7H) -one (1-189)
Figure imgf000168_0003
[00375] Prepared using the appropriate reagents according to method D. NMR DMSO D6 2.58-2.61 (2H, m) , 3.03 (3H, s), 3.17
(3H, s), 3.65-3.69 (2H, m) , 3.87 (3H, s) , 6.90-6.97 (2H, m)
7.01-7.03 (IH, m) , 7.62 (IH, s) , 8.07 (IH, s), 8.30-8.33 (IH, m) ; HPLC rt(min) : 8.61; MS (ES+) 314.
Example 190;
4- O-cyclopentyl-V-ethyl-S-methyl-β-oxo-β, 7, 8, 9-tetrahydro-5H- pyrimido [4, 5-b] [1,4] diazepin-2-ylamino) -3-methoxy-N- methylbenzamide (1-190)
Figure imgf000169_0001
[00376] Prepared using the appropriate reagents according to method D. NMR DMSO D6 0.87 (3H, t) , 1.09 (IH, t) , 1.28 (IH, m) , 1.69 (8H, br m) , 2.07 (IH, br m) , 2.60 (IH, m) , 2.78 (3H, d) , 3.19 (3H, s), 3.40 (2H, m) , 3.94 (3H, s), 4.77 (IH, br m) , 7.48 (2H, m) , 7.76 (IH, s), 8.11 (IH, s), 8.33 (IH, br d) , 8.38 (IH, d) ; HPLC rt (min) : 9.40; MS (ES+) 453. Example 191;
4-(9-(bicyclo[2.2.1]heptan-2-yl)-5,7,7-trimethyl-6-oxo- 6,7, 8, 9-tetrahydro-5H-pyrimido[4, 5-b] [1, 4] diazepin-2-ylamino) - 3-methoxy-N-methylbenzamide (1-191)
Figure imgf000169_0002
[00377] Prepared using the appropriate reagents according to method D. NMR DMSO D6 0.95-1.08 (2H, m) , 1.06 (3H, s), 1.08 (3H, Ξ) , 1.16-1.58 (6H, m) , 1.95-2.06 (IH, m) , 2.18-2.23 (IH, m) , 2.58-2.65 (IH, m) , 2.79 (3H, d) , 3.22 (3H, s), 3.30 (IH, d) , 3.52 (IH, d) , 3.94 (3H, s) , 4.24-4.31 (IH, m) , 7.44-7.51 (2H, m) , 7.77 (IH, s), 8.12 (IH, s) , 8.30-8.36 (IH, m) , 8.39
(IH, d) ; HPLC rt (min) : 9.78; MS (ES+) 479. Example 192;
3-methoxy-N-methyl-4- ( 5, 7, 7-trd.metl-.yl-9- (morpholin-2- ylmethyl) -6-oxo-6, 7 , 8 , 9-tetrahydro-5H-pyrimido [4,5- b] [1/ 4]diazepin-2-ylamino)benzamide (1-192)
Figure imgf000170_0001
[00378] Prepared, using the appropriate reagents according to method O. NMR DMSO D6 1.10 (6H, s), 2.40-2.48 (IH, m) , 2.60- 2.69 (2H, m) , 2.78 (3H, d) , 2.78-2.85 (IH, m) , 3.19 (3H, s), 3.34 (2H, s), 3.34-3.44 (IH, m) , 3.52-3.60 <2H, m) , 3.68-3.78
(2H, m) , 3.85-3.95 (IH, m) , 3.93 (3H1 s), 7.45 (IH, d) , 7.48
(IH, d) , 7.69 (IH, s), 7.99 (IH, s), 8.30-8.35 (IH, m) , 8.31
(IH, d) ; HPLC rt(min): 6.88; MS (ES+) 484. Example 193 :
4- (9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7, 8, 9-tetraliydχ-o-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -N- (furan-2-ylmethyl) - 3-methoxybenzamidθ (1-193)
Figure imgf000170_0002
[00379] Prepared using the appropriate reagents according to method E. HPLC rt (min) : 9.90; MS (ES+) 519. Example 194 ;
4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido [4, 5-b] [l,4]diazepin-2-ylamino) -3-methoxy-N-
( (tetrahydrofuran-2-yl)methyl)benzamide (1-194)
Figure imgf000171_0001
[00380] Prepared using the appropriate reagents according to method E. HPLC rt (min) : 9.70; MS (ES+) 523. Example 195;
4- (9-cyclopentγl-5,7,7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-methoxy-N-
( (tetrahydrofuran-2H-pyran-4-yl)πιethyl)benzainide (1-195)
Figure imgf000171_0002
[00381] Prepared using the appropriate reagents according to method E. HPLC rt (min) : 9.60; MS (ES+) 537. Example 196:
N- (cyclohβxylmethyl) -4- (9-cyclopentyl-5,7,7-trimeth.yl-6-oxo- 6,7, 8,9-tetrahydro-5H-pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) - 3-methoxybenzamide (1-196)
Figure imgf000171_0003
[00382] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.90-0.96 (2H, m) , 1.10 (6H, s), 1.15- 1.14 (3H1 m) , 1.54-1.73 (12 H, m) , 1.84-1.91 (2H, m) , 3.11 (2H, t), 3.19 (3H, s), 3.38 (2H, s), 3.94 (3H, s), 5.18 (IH, Quint), 7.47 (IH, d) , 7.50 (IH, s) , 7.69 (IH, s), 7.99 (IH, s) , 8.32-8.37 (2H, m) ; HPLC rt (min) : 10.90; MS (ES+) 535. Example 197 ;
4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-methoxy-N- (2- methoxyethyl)benzamide (1-197)
Figure imgf000172_0001
[00383] Prepared using the appropriate reagents according to method E. HPLC rt (min) : 9.40; MS (ES+) 497.
Example 198 :
4- <9-cyclopentyl-5 , 7 , 7-trimethyl-6-oxo-6, 7 ,8, 9-tetrahydro-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-methoxy-N- (3- methoxypropyl)benzamide (1-198)
Figure imgf000172_0002
[00384] Prepared using the appropriate reagents according to method E. HPLC rt (min) : 9.60; MS (ES+) 511. Example 199 :
9-cyclopentyl-2- (2-methoxy-4- (morph.oline-4- carbonyl )phenylamino)-5,7,7-tximethyl-8,9-dihydro-5H- pyrimido[4,5-b] [l,4]diazepin-6(7H) -one (1-199)
Figure imgf000172_0003
[00385] Prepared using the appropriate reagents according to method E. HPLC rt(min): 9.50; MS (ES+) 509. Example 200:
4- (9-cyclopentyl-5,7, 7-trimethyl-6-oxo-6, 7, 8 , 9-tβtrahydro-5H- pyrimido[4 , 5-b] [1, 4]diazepin-2-ylamino) -3-methoxy-N- phenylbenzamide (1-200)
Figure imgf000173_0001
[00386] Prepared using the appropriate reagents according to method E. HPLC rt(min) : 10.30; MS (ES+) 515. Example 201;
4- (9-cyclopentyl-5/7,7-trimethyl-6-oxo-6,7, 8, 9-tetrahydro-5H- pyrimido [4, 5-b] [1, 4]diazepin-2-ylamino) -3-methoxy-N- ( (tetrahydrofuran-2-yl)methyl)benzamide (1-201)
Figure imgf000173_0002
[00387] Prepared using the appropriate reagents according to method E. HPLC rt(min): 10.20; MS (ES+) 529. Example 202;
4- (9-cyclopentyl-5, 7,7-fcrimethyl-6-oxo-6,7# 8, 9-tetrahydro-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-methoxy-N- (pyridin- 3-ylmethyl)benzamide (1-202)
Figure imgf000173_0003
[00388] Prepared using the appropriate reagents according to method E. HPLC rt(min): 9.50; MS (ES+) 530. Example 203 :
4- ( 9-cyclopentyl-5 , 7 , 7-trimethyl-6-oxo-6 , 7 , 8 , 9-tetrahydro-5H- pyrimido [4 , 5-b] [ l, 4 ] diazepin-2-ylamino) -3 -methoxy-N- phenethylbenzamide ( 1-203 )
Figure imgf000174_0001
[00389] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.58-1.66 (4H, m) , 1.70- 1.78 (2H, m) , 1.84-1.92 (2H, m) , 2.85 (2H, t), 3.19 (3H, s), 3.38 (2H, s), 3.48 (2H, q) , 3.94 (3H1 s), 5.18 (IH, quint), 7.19-7.33 (5H, m) , 7.45 (IH, d) , 7.49 (IH, s), 7.70 (IH, s), 7.99 (IH, s), 8.37 (IH, d) , 8.47 (IH, br t); HPLC rt (min) : 10.40; MS (ES+) 543. Example 204;
4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -N- ( (IR, 4R) -4- hydroxycyclohexyl) -3-methoxybenzamide ( 1-204)
Figure imgf000174_0002
[00390] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.19-1.43 (4H, m) , 1.55- 1.93 (12H, m) , 3.19 (3H, s) , 3.34-3.45 (IH, m) , 3.38 (2H, s), 3.68-3.79 (IH, m) , 3.94 (3H, s), 4.57 (IH, d) , 5.19 (IH, dt) , 7.46 (IH, d) , 7.47 (IH, s), 7.68 (IH, s), 7.99 (IH, s), 8.02 (IH, S), 8.36 (IH, d) ; HPLC rt(min): 9.21; MS (ES+) 537. Example 205:
4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -N- ( (1- hydroxycyclohexyl)methyl) -3-methoxy-benzamide (1-205)
Figure imgf000175_0001
[00391] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.16-1.26 (IH, m) , 1.29- 1.80 (15H, m) , 1.82-1.92 (2H, m) , 3.19 (3H, S)7 3.28 (2H, d) , 3.38 (2H, s), 3.95 (3H, s), 4.43 (IH, s), 5.19 (IH, dt) , 7.51 (IH, d) , 7.53 (IH, s), 7.70 (IH, s), 7.99 (IH, s), 8.16 (IH, t) , 8.38 (IH, d) ; HPLC rt(min): 10.06; MS (ES+) 551. Example 206;
4- (9-cyclopentyl-5,7#7-trimethyl-6-oxo-6, 7,8, 9-tetrahydro-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylaπιino) -3-methoxy-N- (pyrrolidin-l-yl)benzamidβ (1-206)
Figure imgf000175_0002
[00392] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.57-1.92 (12H, m) , 2.90- 2.99 (4H, m) , 3.19 (3H, s), 3.38 (2H, S), 3.94 (3H, s), 5.18 (IH, dt), 7.41 (IH, d) , 7.43 (IH, s), 7.69 (IH, s), 7.99 (IH, S), 8.37 (IH, d) , 9.27 (IH, s); HPLC rt (min) : 9.57; MS (ES+) 508.
Example 207;
4- (9-cyclopentyl-5,7#7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-methoxy-N- (pyridin- 3-yl)benzamide (1-207)
Figure imgf000175_0003
[00393] Prepared using the appropriate reagents according to method E. HPLC rt (min) : 9.85,- MS (ES+) 516.
Example 208:
9-cyclopentyl-2- (4- (3-cyclopropyl-3-fluoroazetidine-1- carbonyl) -2-methoxyphenylamiiio) -5, 7, 7-trimethyl-8, 9-dihydro-
5H-pyrimido[4,5-b] [1, 4]diazepin-6 (7) -one (1-208)
Figure imgf000176_0001
[00394] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.44 (2H, br s), 0.61 (2H, d) , 1.09 (6H, s), 1.35-1.45 (IH, m) , 1.53-1.80 (6H, m) , 1.82-1.92 (2H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.94 (3H, s), 3.96-4.13 (2H, m) , 4.20-4.51 (2H, m) , 5.19 (IH, dt) , 7.24 (IH, s) , 7.25 (IH, d) , 7.73 (IH, s), 7.99 (IH, s), 8.37 (IH, d) ; HPLC rt (min) : 10.37; MS (ES+) 537. Example 209:
(R) -4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrah.ydro- 5H-pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -N- (2, 3-dihydro-lH- inden-lyl) -3-methoxy-benzamide (1-209)
Figure imgf000176_0002
[00395] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, m) , 1.55-1.79 (6H, m) , 1.82- 1.95 (2H, m) , 1.96-2.06 (IH, m) , 2.43-2.51 (IH, m) , 2.82-2.93 (IH, m) , 2.96-3.07 (IH, m) , 3.19 (3H, s), 3.38 (2H, s), 3.94 (3H, s), 5.19 (IH, dt) , 5.61 (IH, q) , 7.18-7.31 (4H, m) , 7.55- 7.60 (2H, m) , 7.71 (IH, s), 8.00 (IH, s), 8.39 (IH, d) , 8.67
(IH, d) ; HPLC rt (min) : 10.60; MS (ES+) 555. Example 210:
N- (bicyclo[2.2.l]heptan-2-yl) -4- (9-cyclopentyl-5,7,7- trimeth.yl-6-oxo-6,7, 8, 9-tetrahydro-5H-pyrimido[4, 5- b] [l,4]diazepin-2-ylamino)-3-methoxybenzamide (1-210)
Figure imgf000177_0001
[00396] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.12-1.23 (3H, m) , 1.48- 1.75 (HH, m) , 1.84-1.92 (2H, m) , 2.18-2.28 (2H, m) , 3.18 (3H, S), 3.37 (2H, s), 3.67-3.75 (IH, m) , 3.94 (3H, s), 5.18 (IH, quint), 7.46 (IH, d) , 7.47 (IH, s), 7.68 (IH, s), 7.91 (IH, d) , 7.98 (IH, s), 8.34 (IH, d) ; HPLC rt(min): 10.70; MS (ES+) 533.
Example 211;
4- ( 9-cyclopentyl-5 , 7 , 7 -trimethyl-6-oxo-6 , 7 , 8 , 9-tetrahydro-5H- pyrimido [ 4 , 5-b] [l , 4 ] diazepin-2-ylamino) -N- ( 3-hydroxy-2 , 2- dimethylpropyl ) -3-meth.oxybenzamide ( 1-211)
Figure imgf000177_0002
[00397] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.84 (6H, s), 1.09 (6H, s), 1.55-1.65 (4H, m) , 1.70-1.77 (2H, m) , 1.84-1.92 (2H, m) , 3.10 (2H, d) , 3.15 (2H, d) , 3.19 (3H, s), 3.38 (2H, s), 3.95 (3H, s), 4.69 (IH, t) , 5.18 (IH, quint), 7.48 (IH, d) , 7.50 (IH, s), 7.71 (IH, s) , 7.99 (IH, s), 8.33-8.39 (2H, m) ; HPLC rt(min): 9.80; MS (ES+) 525. Example 212;
4- (9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7, 8, 9-tetrahydro-5H- pyrimido[4, 5-b] [1, 4] diazθpin-2-γlamino) -3-methoxy-N-(pyridin- 4-ylmethyl)benzamide (1-212)
Figure imgf000178_0001
[00398] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s) , 1.56-1.67 (4H, m) , 1.69- 1.75 (2H, m) , 1.84-1.93 (2H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.95 (3H, s), 4.51 (2H, d) , 5.19 (IH, quint), 7.31 (2H, d) , 7.55 (IH, d) , 7.56 (IH, s), 7.73 (IH, s), 8.00 (IH, s) , 8.41
(IH, d) , 8.51 (2H, d) , 9.02 (IH, t); HPLC rt(min) : 9.40; MS
(ES+) 530. Example 213;
4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -3-methoxy-N- (4- methoxybenzyl)benzamide (1-213)
Figure imgf000178_0002
[00399] Prepared using the appropriate reagents according to method E. HPLC rt(min): 10.20; MS (ES+) 559. Example 214;
4- (9-cyclopentyl-5,7, 7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido[4, 5-b] [1, 4] diazepin-2-ylamino) -3-methoxy-N- (4- (methylsulfonyl )benzyl)benzamide (1-214)
Figure imgf000179_0001
[00400] Prepared using the appropriate reagents according to method E. HPLC rt(min): 9.40; MS (ES+) 607. Example 215;
4- (9-cyclopentyl-5,7,7-trimethyl-6-oxo-6# 7, 8,9-tetrahydro-5H- pyrimido[4#5-b] [l,4]diazepin-2-ylamino) -3-meth.oxy-N,N- dimethylbenzamide (Z-215)
Figure imgf000179_0002
[00401] Prepared using the appropriate reagents according to method E. HPLC rt(min) : 9.70; MS (ES+) 467. Example 216;
4- (9-cyclopentyl-5, 7 , 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H- pyrimido[4,5-b] [l,4]diazepin-2-ylamino) -N- ( ( ( IS,2S) -2- hydroxycyclohexyl)methyl ) -3-methoxybenzamide (1-216)
Figure imgf000179_0003
[00402] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.14-1.25 (lH, m) , 1.28- 1.40 (4H, m) , 1.51-1.67 (10H, m) , 1.84-1.92 (2H, m) , 3.09-3.19 (IH, m) , 3.19 (3H, s), 3.24-3.31 (IH, m) , 3.38 (2H, s), 3.73 (IH, br s), 3.94 (3H, s), 4.42 (IH, d) , 5.18 (IH, quint), 7.47 (IH, d) , 7.50 (IH, s), 7.70 (IH, s), 7.99 (IH, s) , 8.36-8.38 (2H, m) ; HPLC rt (min) : 10.20; MS (ES+) 551. Example 217;
(S)-4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro- 5H-pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-meth.oxy-N- (1- methoxypropan-2-yl)benzamide (1-217)
Figure imgf000180_0001
[00403] Prepared using the appropriate reagents according to method E. HPLC rt(min): 9.80; MS (ES+) 511. Example 218:
4- (9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7, 8, 9-tetrahydro-5H- pyrimido [4, 5-b] [1, 4]diazepin-2-ylamino) -3-meth.oxy-N- propylbenzamide (1-218)
Figure imgf000180_0002
[00404] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.89 (3H, t) , 1.09 (6H, s), 1.53 (2H, dt) , 1.53-1.77 (6H, m) , 1.82-1.92 (2H, m) , 3.19 (3H, s), 3.18- 3.25 (2H, m) , 3.38 (2H, ε), 3.94 (3H, s), 5.18 (IH, dt), 7.47 (IH, d) , 7.50 (IH, s), 7.69 (IH, s), 7.99 (IH, s), 8.32-8.39 (2H, m) ; HPLC rt (min) : 9.97; MS (ES+) 481. Example 219:
4- ( 9-cyclopentyl-5,7, 7-trimethyl-6-oxo-6, 7,8, 9-tetrahydro-5H- pyrimido [4, 5-b] [1, 4]diazepin-2-ylamino) -N-ethyl-3- methoxybenzamide (1-219)
Figure imgf000181_0001
[00405] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.13 (3H, t) , 1.57-1.78 <6H, m) , 1.82-1.92 (2H, m) , 3.18 (3H, s), 3.24-3.34 (2H, m) , 3.38 (2H, s), 3.94 (3H, s) , 5.18 (IH, dt) , 7.47 (IH, d) , 7.49 (IH, s), 7.69 (IH, s), 7.99 (IH, s), 8.35-8.39 (2H, m) ; HPLC rt(min): 9.65,- MS (ES+) 467. Example 220;
9-cyclopentyl-2- (2-methoxy-4- (3-methoxyazefcidine-l- carbonyl)phenylamino) -5,7 , 7-trimethy1-8, 9-dihydro-5H- pyrimido[4,5-b] [1, 4] diazepin-6 (7H) -one (1-220)
Figure imgf000181_0002
[00406] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.53-1.77 (6H, m) , 1.82- 1.92 (2H, m) , 3.18 (3H, s), 3.22 (3H, s), 3.37 (2H, s), 3.79- 3.89 (IH, m) , 3.92 (3H, s), 4.13-4.27 (3H, m) , 4.43-4.53 (IH, m) , 5.17 (IH, dt) , 7.21 (IH, d) , 7.23 (IH, s), 7.71 (IH, s), 7.98 (IH, s) , 8.35 (IH, d) ; HPLC rt(min) : 9.69; MS (ES+) 509. Example 221:
4- (9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7, 8, 9-tetrahydro-5H- pyrimido [4, 5-b] [1, 4] diazepin-2-ylamino) -3-methoxy-N- (pyridin- 2-yl)benzaxnide (1-221)
Figure imgf000181_0003
[00407] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.56-1.77 (6H, m) , 1.86- 1.94 (2H, m) , 3.20 (3H, s), 3.42 (2H, s), 4.00 (3H, S), 5.21 (IH, quint), 7.16 (IH, dd) , 7.72-7.77 (3H, m) , 7.82-7.86 (IH, m) , 8.01 (IH, s), 8.21 (IH, d) , 8.38 (IH, dd) , 8.46 (IH, d) , 10.69 (IH, s); HPLC rt(min): 10.30; MS (ES+) 516. Example 222:
4- (9-cyclopentyl-5,7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H- pyrimido [4, 5-b] [l,4]diazepin-2-ylamino) -3-methoxy-N- (pyrimidin-4-yl)benzamlde (1-222)
Figure imgf000182_0001
[00408] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.03 (6H, s), 1.51-1.70 (6H, m) , 1.79- 1.86 (2H, m) , 3.13 (3H, s), 3.32 (2H, s), 3.93 (3H, ε), 5.13 (IH, quint), 7.66-7.69 (2H, m) , 7.74 (IH, s), 7.95 (IH, s), 8.16 (IH, d) , 8.40-8.43 (IH, m) , 8.64 (IH, d) , 8.88 (IH, s) , 11.07 (IH, s); HPLC rt(min): 10.10,- MS (ES+) 517. Example 223:
4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-met.hoxy-N- (thiazol- 2-yl )benzamide (1-223)
Figure imgf000182_0002
[00409] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.03 (6H, s), 1.52-1.73 (6H, m) , 1.78- 1.84 (2H, m) , 3.13 (3H, ε), 3.32 (2H, s), 3.93 (3H, s), 5.13
(IH, quint), 7.19 (IH, d) , 7.49 (IH, d) , 7.71-7.74 (3H, m) , 7.95 (IH, s), 8.44 (IH, d) , 12.42 (IH br s ) ; HPLC rt(min): 10.30; MS (ES+) 522. Example 224 :
4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -3-methoxy-N-(pyrazin- 2-yl)benzamide (1-224)
Figure imgf000183_0001
[00410] P-repared using the appropriate reagents according to method E. NMR DMSO D5 1.14 (6H, s), 1.58-1.80 (6H, m) , 1.82- 1.92 (2H, m) , 3.19 (3H, s), 3.50 (2H, s), 4.01 (3H, s), 5.17 (IH, dt) , 7.79 (IH, d) , 7.83 (IH, s), 8.05 (IH, s), 8.29 (IH, t) , 8.43 (IH, d) , 8.50 (IH, s), 9.46 (IH, s), 11.12 (IH, s); HPLC rt(min): 9.99; MS (ES+) 517. Example 225;
4- (9-cyclopentyl-5,7, 7-trimethyl-6-oxo-6,7,8 , 9-tetrahydro-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -3-methoxy-N- ( (IR, 2S)- 2-phenylcyclopropyl)benzamide (1-225)
Figure imgf000183_0002
[00411] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.21-1.27 (IH, m) , 1.32- 1.39 (IH, m) , 1.56-1.79 (6H, m) , 1.82-1.92 (2H, m) , 2.03-2.11 (IH, m) , 2.86-3.04 (IH, m) , 3.19 (3H1 s), 3.38 (2H, s), 3.94 (3H, s), 5.19 (IH, dt), 7.15-7.20 (3H, m) , 7.24-7.32 (2H, m) , 7.45-7.51 (2H, m) , 7.70 (IH, s), 7.99 (IH, s), 8.38 (IH, d) , 8.57 (IH, d) ; HPLC rt (min) : 10.50; MS (ES+) 555. Example 226;
(R)-4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro- SH-pyr-imido [4, 5-b] [1, 4] diazepin-2-ylamino) -3-methoxy-N- (1- phenylethyl)benzamide (1-226)
Figure imgf000184_0001
[00412] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s) , 1.50 (3H, d) , 1.53-1.78 (6H1 m) , 1.82-1.92 (2H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.95 (3H, s), 5.16-5.23 (2H, m) , 7.23 (IH, t) , 7.33 (2H, t). , 7.39 (2H, d) , 7.53 (2H, d) , 7.71 (IH, s), 7.99 (IH, s), 8.38 (IH, d) , 8.66 (IH, d) ; HPLC rt(min): 10.39; MS (ES+) 543. Example 227 :
N- (2-chloropyridin-4-yl)4- (9-cyclopentyl-5, 7, 7-trimethyl-6- oxo-6,7,8, 9-tetrahydro-5H-pyrimido [4, 5-b] [1,4] diazepin-2- ylamino) -3-methoxybenzamide (1-227)
Figure imgf000184_0002
[00413] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.14 (6H, s), 1.58-1.80 (6H, m) , 1.82- 1.92 (2H, m) , 3.19 (3H, s), 3.51 (2H, s), 4.01 (3H, s), 5.17
(IH, dt), 7.66 (IH, s), 7.67 (IH, d) , 7.77 (IH, dd) , 7.95 (IH, s), 8.05 (IH, d) , 8.27 (IH, t) , 8.33 (IH, d) , 10.69 (IH, s);
HPLC rt(min): 10.46; MS (ES+) 550.
Example 228:
4- ( 9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8 , 9-tθtrahydro-5H- pyrimido[4, 5-b] [1,4] diazepin-2-ylamino) -3-methoxy-N- (2- methoxypyridin-3-yl)benzamide (1-228 )
Figure imgf000185_0001
[00414] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.14 (6H, s), 1.58-1.80 (6H, m) , 1.82- 1.92 (2H, m) , 3.19 (3H, s), 3.50 (2H, s), 3.93 (3H, s), 3.99 (3H, s), 5.15 (IH, dt), 7.06 (IH, dd) , 7.66 (IH, d) , 7.69 (IH, s), 7.98-8.05 (3H, m) , 8.23 (IH, t) , 8.88 (IH, bs) , 9.64 (IH, s); HPLC rt(min) : 10.51; MS (ES+) 546. Example 229;
4- (9-cyclopentyl-5 , 7 , 7-trimethyl-6-oxo-6,7,8, 9-tetrahydro-5H- pyrimido[4,5-b] [1, 4]diazepin-2-ylamino) -N- ( ( (IS, 2R) -2- hydroxycyclohexyl )methyl ) -3-methoxybenzamide (1-229 )
Figure imgf000185_0002
[00415] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.93-0.99 (IH, m) , 1.09 (6H, s), 1.10- 1.20 (2H, m) , 1.36-1.46 (IH, m) , 1.52-1.91 (12H, m) , 3.07-3.13 (IH, m) , 3.19 (3H, s), 3.35-3.45 (2H, m) , 3.38 (2H, s), 3.94 (3H, s), 4.82 (IH, d) , 5.18 (IH, dt) , 7.48 (IH, d) , 7.50 (IH, S), 7.70 (IH, s), 7.99 (IH, s), 8.32 (IH, t), 8.36 (IH, d) ; HPLC rt(min): 10.17; MS (ES+) 551. Example 230:
4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -N- (cyclopentylmethyl) - 3-methoxybenzamide (1-230)
Figure imgf000186_0001
[00416] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.21-1.30 (2H, m) , 1.43- 1.79 (12H, m) , 1.83-1.96 (2H, m) , 2.11-2.19 (IH, m) , 3.15-3.22 (2H, m) , 3.19 (3H, s), 3.38 (2H1 s), 3.94 (3H, s), 5.18 (IH, dt), 7.47 (IH1 d) , 7.50 (IH, s), 7.69 (IH, s), 7.99 (IH, S), 8.36 (IH, d) ; HPLC rt(inin): 10.65; MS (ES+) 521. Example 231:
4- (9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7, 8, 9-tetrah.ydro-5H- pyirimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-mettioxy-N- (5-methyl- lH-pyrazol-3-yl)benzamide (1-231)
Figure imgf000186_0002
[00417] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.14 (6H, s) , 1.59-1.90 (8H, m) , 2.23
(3H, s) , 3.18 (3H, s) , 3.50 (2H, s) , 3.99 (3H, s) , 5.15 (IH, dt) , 6.41 (IH, br s) , 7.70 (IH, d) , 7.76 (IH, s) , 8.03 (IH, s) , 8.19 (IH, d) , 10.69 (IH, s ) ; HPLC rt(min) : 9.57; MS (ES+) 519.
Example 232 ;
4- (9-cyclopentyl-5, 7,7-trimethyl-6-oxo-6,7, 8, 9-tetrah.ydro-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3-methoxy-N- (3- methylisothiazol-5-yl)benzamide (1-232)
Figure imgf000186_0003
[00418] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.14 <6H, s), 1.59-1.82 (6H, m) , 1.84- 1.98 (2H, m) , 2.36 (3H, s), 3.19 (3H, s), 3.51 (2H, s), 4.01 (3H, S), 5.16 (IH, dt) , 6.93 (IH, s), 7.74 (IH, d) , 7.75 (IH, s), 8.05 (IH, s), 8.27 (IH, d) , 9.01 (IH, br s) , 12.19 (IH, s); HPLC rt(min): 10.15; MS (ES+) 536. Example 233;
N- (cyanomethyl) -4- ( 9-cyclopentyl-5, 7 , 7-trimethyl-6-oxo- 6,7,8, 9-tetrahydro-5H-pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) - 3-methoxybenzamide (1-233)
Figure imgf000187_0001
[00419] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.56-1.80 (6H, m) , 1.82- 1.88 (2H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.95 (3H, s), 4.31 (2H, d) , 5.18 (IH, dt) , 7.50 (IH, d) , 7.52 (IH, s) , 7.75 (lH, S), 8.00 (IH, s), 8.43 (IH, d) , 9.07 (IH, t); HPLC rt (min) : 9.34; MS (ES+) 478. Example 234:
4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H- pyrimido [4, 5-b] [1,4] diazepin-2-ylamino) -3-methoxy-N- (3- trifluoromethyl)pyridin-4-yl) )benzamide (1-234)
Figure imgf000187_0002
[00420] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.15 (6H, s), 1.58-1.78 (6H, m) , 1.82-
1.92 (2H, m) , 3.19 (3H, s) , 3.52 (2H, s), 3.99 (3H, s), 5.14
(IH, quint), 7.64-7.69 (2H, m) , 7.75-7.79 (IH, m) , 8.05 (IH, d) , 8.20-8.24 (IH, m) , 8.89 (IH, d) , 9.00 (IH, s), 9.15 (IH, br s), 10.23 (IH, br s) ; HPLC rt (min) : 10.70; MS (ES+) 584. Example 235;
4- ( 9-cyclopentyl-5, 7 , 7-trimethyl-6-oxo-6# 7 , 8, 9-tetrahydro-5H- pyrimido[4, 5-b] [1, 4] diazepin-2-ylamino) -3-methoxy-N-( (5- methylisoxazol-3-yl)methyl )benzamide (1-235)
Figure imgf000188_0001
[00421] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.54-1.67 (4H, m) , 1.69- 1.76 (2H, m) , 1.82-1.93 <2H, m) , 2.37 (3H, s), 3.19 (3H, s), 3.38 (2H, s), 3.94 (3H, s), 4.46 (2H, d) , 5.18 (IH, quint), 6.15 (IH, s), 7.52 (IH, d) , 7.53 (IH, s), 7.72 (IH, s), 7.99
(IH, S), 8.40 (IH, d) , 8.96 (IH, t); HPLC rt(min): 9.70; MS
(ES+) 534. Example 236:
4- (9-cyclopentyl-5,7, 7-fcrimethyl-6-oxo-6# 7, 8, 9-tetrahydro-5H- pyrimido[4, 5-b] [1,4] diazepin-2-ylamino) -3-methoxy-N- (5- methylthiazol-2-yl)benzamide (1-236)
Figure imgf000188_0002
[00422] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.12 (6H, s), 1.58-1.82 (6H, s), 1.83- 1.91 (2H, m) , 2.38 (3H, s), 3.19 (3H, s), 3.50 (2H, s), 4.00
(3H, S), 5.16 (IH, quint), 7.24 (IH, s), 7.79 (IH, d) , 7.85
(IH, s), 8.05 (IH, S), 8.27 (IH, d) , 8.78 (IH, br s), 12.44
(IH, br s); HPLC rt (min) : 10.50; MS (ES+) 536. Example 237:
4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H- pyrimido[4,5-b] [l,4]diazepin-2-ylamino) -N- (2- (2- hydroxyethoxy) ethyl ) -3-methoxybenzamide (1-237 )
Figure imgf000189_0001
[00423] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.54-1.69 (4H, s), 1.70- 1.81 (2H, m) , 1.84-1.93 (2H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.40-3.47 (4H, m) , 3.49-3.55 (4H, m) , 3.94 (3H, s) , 4.62 (IH, t) , 5.18 (IH, quint), 7.48 (IH, d) , 7.51 (IH, s), 7.70 (IH, S), 7.99 (IH, s), 8.38 (IH, d) , 8.42 (IH, t); HPLC rt (min) : 9.00; MS (ES+) 527. Example 238;
4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7 , 8 , 9-tetrahydro-5H- pyrimido [4, 5-b] [1, 4]diazepin-2-ylamino) -N-isopropyl-3- methoxybenzamide (1-238)
Figure imgf000189_0002
[00424] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.17 (6H, s), 1.54-1.69 (4H, m) , 1.72-1.79 (2H, m) , 1.82-1.93 (2H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.94 (3H, s), 4.11 (IH, dt), 5.19 (IH, quint), 7.48 (IH, d) , 7.49 (IH, s), 7.68 (IH, s), 7.99 (IH, s) , 8.08 (IH, d) , 8.36 (IH, d) ; HPLC rt (min) : 10.10; MS (ES+) 481. Example 239:
(S) -4- (9-cyclopentyl-5,7, 7-trimethyl-6-oxo-6,7,8, 9-tetrahydro- 5H-pyrimido [4 , 5-b] [1, 4] diazepin-2-ylamino) -N- ( 1-hydroxy-3- methylbutan-2-yl) -3-methoxybenzamide (1-239)
Figure imgf000190_0001
[00425] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.89 (3H, d) , 0.91 (3H, d) , 1.09 (6H, S), 1.58-1.77 (6H, m) , 1.83-1.97 (3H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.53 (2H, t), 3.76-3.85 (IH, m) , 3.95 (3H, s) , 4.60 (IH, t), 5.19 (IH, dt), 7.51 (IH, d) , 7.52 (IH, s), 7.69 (IH, s), 7.86 (IH, d) , 7.99 (IH, s), 8.36 (IH, d) ; HPLC rt(min): 9.75; MS (ES+) 525. Example 240:
4- ( 9-cyclopβntyl-5 , 7 , 7-fcrimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -N- (l-hydroxy-2- methylpropan-2-yl) -3-meth.oxybenzamide (1-240)
Figure imgf000190_0002
[00426] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.32 (6H, s), 1.57-1.90 (8H, m) , 3.18 (3H, s), 3.38 (2H, s), 3.52 (2H, d) , 3.94 (3H, s), 4.96 (IH, t), 5.19 (IH, dt), 7.40-7.44 (3H, m) , 7.68 (IH, S), 7.99 (IH, s), 8.36 (IH, d) ; HPLC rt(min): 9.61; MS (ES+) 511.
Example 241:
4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H- pyrimido [4, 5-b] [1, 4]diazepin-2-ylamino) -N- (3-hydroxypropy1 ) -3- methoxy-N- (thiazol-2-yl)benzamide (1-241)
Figure imgf000191_0001
[00427] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.54-1.79 <8H, m) , 1.82- 1.93 (2H, m) , 3.18 (3H, s) , 3.28-3.36 (2H, m) , 3.38 (2H, s) , 3.46 (2H, dd) , 3.94 (3H, s) , 4.50 (IH, t) , 5.18 (IH, dt), 7.47
(IH, d) , 7.50 (IH, s), 7.69 (IH, s), 7.99 (IH, s), 8.34-8.39
(2H, m) ; HPLC rt(min): 9.02; MS (ES+) 497. Example 242 ;
(S) -4- (9-cyclopentyl-5, 7,7-trimethyl-6-oxo-6#7, 8, 9-tetrahydro- 5H-pyrimido [4,5-b] [1,4] diazepin-2-ylamino) -N- (2,3- dihydroxypropyl) -3-methoxybenzamide (1-242 )
Figure imgf000191_0002
[00428] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.53-1.77 (6H, m) , 1.82- 1.94 (2H, m) , 3.19 (3H, s), 3.18-3.24 (IH, m) , 3.38 (2H, s), 3.30-3.43 (3H, m) , 3.60-3.66 (IH, m) , 3.94 (3H, s), 4.61 (IH, t) , 4.85 (IH, d) , 5.19 (IH, dt) , 7.50 (IH, d) , 7.53 (IH, s), 7.70 (IH, s), 7.99 (IH, s), 8.34-8.41 (2H, m) ; HPLC rt(min): 8.62; MS (ES+) 513. Example 243;
4- (9-cyclopentyl-5, 7 , 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H- pyrimido [4,5-b] [1,4] diazepin-2-ylamino) -N- (3-hydroxybutyl) -3- methoxybenzamide (1-243)
Figure imgf000192_0001
[00429] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.07-1.10 (3H, m) , 1.09 (6H, s), 1.51- 1.89 (1OH, m) , 3.18 (3H, s), 3.28-3.38 (2H, m) , 3.39 (2H, s), 3.63-3.70 (IH, m) , 3.93 (3H, s) , 4.54 (IH, d) , 5.18 (IH, dt) , 7.46 (IH, d) , 7.49 (IH, s), 7.69 (IH, s), 7.99 (IH, s), 8.32- 8.39 (2H, m) ,- HPLC rt(min): 9.31; MS (ES+) 511. Example 244:
4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H- pyrimido[4,5-b] [l,4]diazepin-2-ylamino) -N- ( (lR,2R)-2- hydroxycyclopentyl) -3-methoxybenzamide (1-244)
Figure imgf000192_0002
[00430] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.44-1.52 (2H, m) , 1.53- 1.78 (8H, m) , 1.81-1.96 (3H, m) , 1.97-2.04 (IH, m) , 3.18 (3H, S), 3.38 (2H, s), 3.94 (3H, s), 3.94-4.03 (2H, m) , 4.80 (IH, d) , 5.19 (IH, dt) , 7.48 (IH, d) , 7.49 (IH, s), 7.69 (IH, s), 7.99 (IH, s), 8.11 (IH, d) , 8.36 (IH, d) ; HPLC rt(min): 9.55; MS (ES+) 523. Example 245;
4- (9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7,8, 9-tetrahydrO-5H- pyrimido[4,5-b] [l,4]diazβpin-2-ylamino)-N- ( (2,2- difluorocyclopropyl)methyl) -3-methoxybenzamide (1-245)
Figure imgf000193_0001
[00431] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.26-1.36 (IH, m) , 1.55- 1.70 (5H, m) , 1.70-1.79 (2H, m) , 1.82-1.94 (2H, m) , 1.95-2.09 (IH, m) , 3.19 (3H, s), 3.31-3.39 (2H, m) , 3.39 (2H, s), 3.95 (3H, s) , 5.18 (IH, dt), 7.50 (IH, d) , 7.52 (IH, s), 7.76 (IH, bs), 7.99 (IH, s), 8.38 (IH, d) , 8.65 (IH, t); HPLC rt (min) : 10.00; MS (ES+) 529. Example 246;
N- (cyclobutylmethyl) -4- (9-cyclopentyl-5, 7 , 7-trimethyl-6-oxo- 6,7, 8,9-tetrahydro-5H-pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) - 3-methoxybenzamide (1-246)
Figure imgf000193_0002
[00432] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.58-2.04 (14H, m) , 2.50- 2.56 (IH, m) , 3.18 (3H, s), 3.30 (2H, t), 3.38 (2H, s), 3.94
(3H, s), 5.18 (IH, dt), 7.47 (IH, d) , 7.49 (IH, s), 7.69 (IH, s), 7.99 (IH, s), 8.32-8.38 (2H, m) ; HPLC rt (min) : 10.42; MS
(ES+) 507. Example 247 ;
4- (9' -cyclopentyl-5' -methyl-6' -oxo-5' ,6' ,8' ,9' - tetrahydrospiro [cyclopropane-1, 7 ' -pyrimido [4,5- b] [1, 4]diazepine] -2' -ylamino) -3-methoxy-N- (pyridin-4- ylxnethyDbenzamidθ ( 1-247 )
Figure imgf000194_0001
[00433] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.66-0.69 <2H, m) , 0.89-0.91 (2H, m) , 1.51-1.55 (2H, m) , 1.60-1.64 (2H, m) , 1.69 (2H, m) , 1.89 (2H, m) , 3.17 (3H, s), 3.44 (2H, m) , 3.95 (3H, s), 4.50-4.52 (2H, m) , 4.85 (IH, m) , 7.30-7.31 (2H, m) , 7.55-7.57 (2H, m) , 7.73
(IH, s), 8.00 (IH, s), 8.44 (IH, s), 8.50-8.51 (2H, m) , 9.03
(IH, m) ; HPLC rt(min): 9.08; MS (ES1") 528. Example 248 ;
4- (9' -cyclopentyl-5' -methyl-6' -oxo-5' ,6' ,8' ,9' - tetrahydrospiro [cyclopropane-1, 7' -pyrimido [4, 5- b] [l,4]diazep±ne] -2' -ylamino) -N- (furan-2-ylmethyl) -3- methoxybenzamide (1-248)
Figure imgf000194_0002
[00434] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.72 (2H, m) , 0.90 (2H, m) , 1.50-1.54 (2H, m) , 1.60-1.64 (2H, m) , 1.69 (2H# m) , 1.89 (2H, m) , 3.17 (3H, s), 3.48 (2H, br s) , 3.94 (3H, s), 4.47-4.48 (2H, m) , 4.85 (IH, m) , 6.27 (IH, m) , 6.41 (IH, m) , 7.53 (2H, m) , 7.59 (IH, br s), 7.70 (IH, br s), 7.99 (IH, br s), 8.41 (IH, d) ; HPLC rt(min): 9.58; MS (ES+) 517. Example 249 :
4- (9' -cyclopentyl-5' -methyl-6' -oxo-5' .6' ,8' ,9' - tetrahydrospiro [cyclopropane-1, 7' -pyrimido [4, 5- b] [ l, 4] diazepine] -2 ' -ylamino) -3-methoxy-N- (pyridin-3- ylmethyl ) benzamide (1-249 )
Figure imgf000195_0001
[00435] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.67-0.68 (2H, m) , 0.90-0.91 (2H, m) , 1.50-1.54 (2H, in), 1.59-1.64 (2H, m) , 1.69 (2H, m) , 1.89 (2H, m) , 3.17 (3H, s), 3.45-3.48 (2H, m> , 3.94 (3H, s), 4.50-4.51
(2H, m) , 4.58 (IH, m) , 7.37 (IH, m) , 7.52-7.55 (2H, m) , 7.71-
7.73 (2H, m) , 7.99 (IH, s) , 8.42-8.47 (2H, m) , 8.56 (IH, s),
9.00 (IH, m) ; HPLC rt(min): 9.12; MS (ES+) 528.
Example 250;
2- (4- (lH-imldazole-2-yl) -2-methoxyphenylamino)-9-cyclopentyl-
5# 7 , 7-tri.meth.yl-8, 9-dihydro-5H-pyrimido [4 , 5-b] [1, 4] d±azepin-
6 (7H) -one (1-250)
Figure imgf000195_0002
[00436] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.09 (6H, s), 1.56-1.81 (6H, m) , 1.82- 1.97 (2H, m) , 3.19 (3H, S), 3.30-3.40 (2H, m) , 3.94 (3H, s), 5.14-5.25 (IH, m) , 7.1 (2H, br s), 7.49-7.54 (IH, m) , 7.59- 7.65 (2H, m) , 7.97 (IH, s), 8.30-8.36 (IH, m) , 12.40 (IH, s ) ; HPLC rt(min): 9.50; MS (ES+) 462. Example 251:
4- (9' -cyclopentyl-5' -methyl-6' -oxo-5' ,6' ,8' ,9'- tetrahydrospiro [cyclopropane-1, 7 ' -pyrimido [4, 5- b] [l,4]diazepine] -2' -ylamino) -N- ( (IR, 4R) -4-hydroxycyclohexyl) ■ 3-methoxybenzamide (1-251)
Figure imgf000196_0001
[00437] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.67 (2H, m) , 0.90 (2H, m) , 1.20-1.28 (2H, m) , 1.34-1.43 (2H, m) , 1.50-1.54 (2H, m) , 1.59-1.87 (10H, m) , 3.16 (3H, s), 3.47 (2H, m) , 3.73 (IH, m) , 3.94 (3H, s) , 4.58 (IH, m) , 4.86 (IH, m) , 7.45-7.47 (2H, m) , 7.68 (IH, m) , 7.98-8.04 (2H, m) , 8.38 (IH, m) ; HPLC rt(min): 8.84; MS (ES+) 535.
Example 252;
4- (9' -cyclopentyl-5' -methyl-6' -oxo-5' , 6' ,8' ,9' - tetrahydrospiro [cyclopropane-1, 7' -pyrimido [4, 5- b] [l#4]diazβpinβ] -2' -ylamino) -N- ( ( (lS,2S)-2- hydroxycyclohexyl)methyl) -3-methoxybenzamide (1-252 )
Figure imgf000196_0002
[00438] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.66-0.67 (2H, m) , 0.90-0.91 (2H, m) , 1.15-1.18 (2H, m) , 1.23-1.35 (4H, m) , 1.501-1.69 (1OH, m) , 1.88 (2H, m) , 3.17 (3H, s), 3.48 (2H, m) , 3.73 (IH, m) , 3.94 (3H, s), 4.42 (IH, m) , 4.84 (IH, m) , 7.46-7.50 (2H, m) , 7.70 (IH, br s), 7.99 (IH, br s), 8.36-8.41 (2H, m) ; HPLC rt(min): 9.85; MS (ES+) 549. Example 253;
4- (9' -cyclopentyl-5' -methyl-6' -oxo-5' , 6' ,8' ,9' - tetrahydrospiro [cyclopropane-1, 7' -pyrimido [4, 5- b] [1, 4] diazepine] -2' -ylamino) -3-methoxy-N- (pyrrolidin-1- yDbenzamide (1-253)
Figure imgf000197_0001
[00439] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.66-0.68 (2H, m) , 0.90-0.91 (2H, m) , 1.49 (2H, m) , 1.50-1.54 (2H, m) , 1.60-1.61 (2H, m) , 1.64-1.78 (4H, m) , 1.88 (2H, m) , 2.95 (4H, m) , 3.17 (3H, s), 3.48 (2H, m) , 3.94 (3H, s), 4.84 (IH, m) , 7.41 (2H, m) , 7.69 (IH, s), 7.99 (IH, s), 8.40 (IH, m) , 9.28 (IH, s); HPLC rt(min): 9.20; MS (ES+) 506. Example 254 :
4- (9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7, 8, 9-tetrahydro-5H- pyrimido[4, 5-b] [l#4]diazepin-2-ylamino) -N- (1- (hydroxymethyl) cyclopentyl ) -3-methoxybenzamide (1-254)
Figure imgf000197_0002
[00440] Prepared using the appropriate reagents according to method E. NMR DMSO Ds 1.09 (6H, s), 1.52-1.78 (12H, m) , 1.83- 1.92 (2H, m) , 1.95-2.05 (2H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.58 (2H, d) , 3.94 <3H, s), 4.89 (IH, t) , 5.19 (IH, quint), 7.44-7.46 (2H, m) , 7.63 (IH, s), 7.68 (IH, s), 7.99 (IH, s) , 8.36 (IH, d) ; HPLC rt (min) : 10.10; MS (ES+) 537. Example 255:
4- (9-cyclopentyl-5, 7,7-trimethyl-6-oxo-6#7,8,9-tetrahydro-5H- pyrimido[4, 5-b] [1, 4]diazepin-2-ylamino) -3-methoxy-N- (pyridin- 2-ylmetlayl)ben.zamide (1-255)
Figure imgf000198_0001
[00441] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.08 (6H, s), 1.54-1.67. (4H, m) , 1.68- 1.78 (2H, m) , 1.85-1.93 (2H, m) , 3.16 (3H, s), 3.38 (2H, s), 3.95 (3H, S), 4.57 (2H, d) , 5.19 (IH, quint), 7.25-7.28 (IH, m) , 7.32 (IH, d) , 7.57 (IH, d) , 7.58 (IH, s), 7.74 (IH, s), 7.76 (IH, t), 8.00 (IH, s), 8.41 (IH, d) , 8.51 (IH, d) , 9.04
(IH, t) ; HPLC rt(min): 9.60; MS (ES+) 530. Example 256:
9-cyclopentyl-2-(4-(4,5-dihydro-lH-imidazol-2-yl)-2- methoxyphenylamino) -5, 7 , 7-trimethyl-8,9-dihydro-5H- pyrimido[4,5-b] [l,4]diazepin-6(7H) -one (1-256)
Figure imgf000198_0002
[00442] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.09 (6H, s), 1.55-1.95 (8H, m) , 3.19
(3H, s), 3.38 (2H, s), 3.65 (4H, s), 3.92 (3H, s), 5.20 (IH, quint), 7.42 (IH, d) 7.50 (IH, s), 7.71 (IH, s), 7.99 (IH, s), 8.38 (IH, d) ; HPLC rt (min) : 9.06; MS (ES+) 464. Example 257 :
9-cyclopentyl-2- (4- (5, 5-dimethyl-4, 5-dihydro-lH-imidazol-2- yl) -2-methoxyplienylamino) -5, 7,7-trimethyl-8# 9-dihydro-5H- pyrimido[4,5-b] [l,4]diazepin-6(7H) -one (1-257)
Figure imgf000199_0001
[00443] Prepared using the appropriate reagents according to method D. NMR DMSO D6 1.09 (6H, s), 1.24 (6H, s), 1.55-1.95 (8H, m) , 3.18 (3H, s), 3.32 (2H, s), 3.38 (2H, s), 3.92 (3H, s), 5.18 (IH, quint), 7.38 (IH, dd) 7.46 (IH, s), 7.67 (IH, s), 7.99 (IH, s), 8.36(1H, d) ; HPLC rt (min) : 9.43; MS (ES+) 492.
Example 258;
4-(9-cyclopentyl-5,7,7-triπιethyl-6-oxo-6,7,8,9-tetrahydrO-5H- pyrimido [4 , 5-b] [1,4] diazepin-2-ylamino) -N- ( ( IR, 3R) -3- (hydroxycyclopentyl) -3-methoxybenzamide (1-258)
Figure imgf000199_0002
[00444] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.87 (6H, s), 1.21-1.31 (2H, m) , 1.37- 1.53 (7H, m) , 1.60-1.74 (4H, m) , 1.80-1.87 (IH, m) , 2.96 (3H, s), 3.16 (2H, s), 3.72 (3H, s), 4.00 (IH, br s), 4.23 (IH, dd) , 4.31 (IH, d) , 4.96 (IH, quint), 7.23 (IH, d) , 7.25 (IH, Ξ), 7.46 (IH, s), 7.77 (IH, s), 7.91 (IH, d) , 8.13 (IH, d) ; HPLC rt(min): 9.20; MS (ES+) 523. Example 259;
4- (9-cyclopentyl-5, 7 , 7-trimethyl-6-oxo-6, 7,8,9-tetrahydro-5H- pyrimido[4,5-b] [1, 4] diazepin-2-ylamino) -N- ( ( IR, 3R) -3- (hydroxycyclopentyl)methyl ) -3-methoxybenzamide (1-259 )
Figure imgf000200_0001
[00445] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.18-1.27 (IH, m) , 1.34- 1.47 (2H, m) , 1.57-1.69 (5H, m) , 1.72-.93 (6H, m) , 2.33-2.41 (IH, m) , 3.19 (3H, s), 3.34 (2H, s), 3.39 (2H, s), 3.94 (3H, s), 4.14 (IH, br d) , 4.38 (IH, d) , 5.18 (IH, quint), 7.47 (IH, d) , 7.50 (IH, s), 7.69 (IH, s) , 7.99 (IH, s), 8.35-8.37 (2H, m) ; HPLC rt(min): 9.30; MS (ES+) 537. Example 260:
4- ( 9-cyclopβntyl-5, 7, 7-trimethyl-6-oxo-6,7,8, 9-tetrahydro-5H- pyrimido [4, 5-b] [1, 4] diazepin-2-ylamino) -N- ( ( IR, 3R) -3- (hydroxymefch.yl)cyclopentyl) -3-meth.oxybenzamide (1-260)
Figure imgf000200_0002
[00446] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.08 (6H, s), 1.23-1.29 (IH, m) , 1.50- 1.68 (6H, m) , 1.70-1.76 (2H, m) , 1.78-1.98 (5H, m) , 2.16-2.24 (IH, m) , 3.19 (3H, s), 3.30 (2H, t), 3.38 (2H, s), 3.94 (3H, s), 4.22-4.28 (IH, m) , 4.55 (IH, t), 5.18 (IH, quint), 7.46 (IH, d) , 7.47 (IH, s), 7.68 (IH, s), 7.99 (IH, s), 8.13 (IH, d) , 8.35 (IH, d) ; HPLC rt (min) : 9.40; MS (ES+) 537. Example 261:
4- (9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7, 8, 9-tetrahydro-5H- pyrimido[4, 5-b] [1,4]diazepin-2-ylamino) -3-methoxy-N- (4- methoxyphenyl )benzamide (1-261)
Figure imgf000201_0001
[00447] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.56-1.69 (4H, m) , 1.70- 1.79 (2H, m) , 1.83-1.93 (2H, m) , 3.19 (3H, s) , 3.39 (2H, s), 3.75 (3H, s), 3.98 (3H, s), 5.21 (IH, quint), 6.93 (2H, d) , 7.59-7.66 (4H, m) , 7.76 (IH, s), 8.01 (IH, s), 8.44 (IH, d) , 9.98 (IH, s); HPLC rt (min) : 10.19,- MS (ES+) 545. Example 262;
4-(9'-cyclopentyl-5'-methyl-6' -oxo-5' ,6' ,8' ,9' - tetrahydrospiro [cyclopropane-1, 7' -pyrimido [4,5- b] [l,4]diazepine] -2' -ylamino) -N- (3-hydroxypropyl ) -3- methoxybenzamide (1-262)
Figure imgf000201_0002
[00448] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.67 (2H, m) , 0.90 (2H, m) , 1.50-1.71 (6H, m) , 1.89-1.91 (2H, m) , 3.17 (3H1 s), 3.29-3.34 (4H, m) , 3.44-3.47 (4H, m) , 3.94 (3H, s), 4.50 (IH, m) , 4.84 (IH, m) , 7.46-7.50 (2H, m) , 7.69 (IH, ε), 7.99 (IH, s), 8.35-8.41 (2H, m) ; HPLC rt (min) : 8.58; MS (ES+) 495. Example 263;
4- (9' -cyclopentyl-5'-methyl-6' -oxo-5' , 6' ,8' ,9' - tetrahydrospiro[cyclopropane-1, 7' -pyrimido[4, 5- b] [1, 4]diazepine] -2' -ylamino) -N-isopropyl-3-methoxybenzamide
(1-263)
Figure imgf000202_0001
[00449] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.67 (2H, m) , 0.90 (2H, m) , 1.17 (3H, s), 1.18 (3H, s), 1.50-1.70 (6H, m) , 1.80 (2H, m) , 3.17 (3H, S), 3.48 (2H, s), 3.95 <3H, s),, 4.10 (IH, m) , 4.85 <1H, m) , 7.49 (2H, m) , 7.69 (IH, s) , 7.99 (IH, s), 8.10 (IH, d) , 8.40
(IH, d) ,- HPLC rt (min) : 9.58; MS (ES+) 479. Example 264;
4- (9-cyclopentyl-5,7,7-trimeth.yl-6-oxo-6,7, 8, 9-tetrahydro-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -N- (2-hydroxyethyl) -3- methoxybenzamide (I-264)
Figure imgf000202_0002
[00450] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.19 (6H, s), 1.52-1.67 (4H, m) , 1.69- 1.81 (2H, m) , 1.82-1.94 (2H, m) , 3.19 <3H, s), 3.30-3.34 (2H, br m) , 3.38 <2H, s), 3.48-3.53 (2H, m) , 3.94 (3H, s), 4.75 (IH, t) , 5.18 (IH, quint), 7.49 (IH, d) , 7.51 (IH, s), 7.69 (IH, s), 7.99 (IH, s), 8.35 (IH, s), 8.37 (IH, d) . ; HPLC rt(min): 8.87; MS (ES+) 483. Example 265:
(S) -4- (9-cyclopentyl-5,7,7-trimethyl-6-oxo-6, 7,8, 9-tetrahydro- 5H-pyrimido[4,5-b] [1, 4] diazepin-2-ylamino) -N- (1- (hydroxypropan-2-yl) -3-methoxybθnzamide (1-265)
Figure imgf000203_0001
[00451] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.10 (6H, s), 1.14 (3H, d) , 1.52-1.67 (4H, m) , 1.69-1.81 (2H, m) , 1.82-1.94 (2H, m) , 3.19 (3H, s) , 3.31-3.34 (IH, m) , 3.38 <2H, s), 3.44-3.50 (IH, m) , 3.95 (3H, s), 3.99-4.06 (IH, m) , 4.74 (IH, t) , 5.19 (IH, quint), 7.49 (IH, d) , 7.50 (IH, s), 7.69 (IH, s), 7.96 (IH, s), 7.99 (IH, S), 8.37 (IH, d) ; HPLC rt(min): 9.15; MS (ES+) 497. Example 266;
4- (9-cyclopentyl-5, 7 , 7-trimethyl-6-oxo-6, 7 , 8, 9-tetrahydro-5H- pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -N- (1- (hydroxymethyl)eyelopentyl) -3-methoxybenzamide (1-266)
Figure imgf000203_0002
[00452] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.65-0.72 (2H, m) , 0.75-0.80 (2H, m) , 1.09 <6H, s), 1.57-1.94 (8H, m) , 3.18 (3H, s), 3.38 (2H, s), 3.53 (2H, d) , 3.93 (3H, s), 4.80 (IH, t) , 5.18 (IH, dt ) , 7.50 (IH, d) , 7.52 (IH, S), 7.68 (IH, s), 7.99 (IH, s), 8.37 (IH, d) , 8.61 (IH, S); HPLC rt (min) : 9.26; MS (ES+) 510, (ES") 508. Example 267:
4- (9-eyelopentyl-5, 7 , 7-trimethyl-6-oxo-6, 7 , 8 , 9-tetrahydro-5H- pyrimido[4,5-b] [l,4]diazepin-2-ylamino)-N- ( ( IS, 4S) -4- fluorocylohexyl) -3-methoxybenzamide ( 1-267 )
Figure imgf000204_0001
[00453] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.55-1.79 (12H, m) , 1.85- 2.02 (4H, m) , 3.19 (3H, s), 3.38 (2H, s) , 3.85-3.94 (IH, m) , 3.94 (3H, s), 4.85 (IH, d) , 5.19 (IH, dt) , 7.49 (IH, d) , 7.50 (IH, s), 7.69 (IH, s), 7.99 (IH, s), 8.13 (IH, d) , 8.37 (IH, d) ; HPLC rt(min): 10.17; MS (ES+) 540, (ES") 538. Example 268;
4- (9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8, 9-tetrahydro-5H- pyrimido[4,5-b] [l,4]diazepin-2-ylamino) -N- ( (IR, 2R) -2- hydroxycyclohexyl) -3-mβthoxybenzamide (1-268)
Figure imgf000204_0002
[00454] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.19-1.30 (4H, m) , 1.55- 1.79 (8H, m) , 1.81-1.96 (4H, m) , 3.19 (3H, s), 3.38 (2H, m) , 3.38-3.48 (IH, m) , 3.56-3.67 (IH, m) , 3.95 (3H, s), 4.62 (IH, d) , 5.19 (IH, dt), 7.49 (IH, d) , 7.51 (IH, s), 7.69 (IH, s), 7.98 (IH, d) , 7.99 (IH, s), 8.37 (IH, d) ; HPLC rt(min): 9.74; MS (ES+) 538, (ES") 536. Example 269;
4-(9'-cyclopentyl-5' -methyl-6' -oxo-5' ,6' ,8' ,9' - tetrahydrospiro [cyclopropane-1, 7 ' -pyrimido [4,5- b] [l,4]diazepine] -2' -ylamino) -N- (3, 3-difluorocyclobutyl) -3- methoxybenzamide (1-269)
Figure imgf000205_0001
[00455] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.63-0.71 (2H, m) , 0.87-0.93 (2H, m) , 1.44-1.76 (6H, m) , 1.84-1.94 (2H, m) , 2.70-2.82 (2H, m) , 2.90- 3.02 (2H, m) , 3.17 (3H, s) , 3.48 (2H, s), 3.95 (3H, s), 4.23- 4.31 (IH, m) , 4.85 (IH, dt), 7.48 (IH, d) , 7.49 (IH, s), 7.72 (IH, s), 7.99 (IH, S), 8.43 (IH, d) , 8.66 (IH, d) ; HPLC rt(min): 9.75; MS (ES+) 528, (ES") 526. Example 270;
(S) -4- ( 9-cyclopentyl-5, 7, 7-trimethyl-6-oxo-6,7,8, 9-tetrahydro- 5H-pyrimido[4,5-b] [1, 4]diazepin-2-ylamino) -N- (2- hydroxypropy1) -3-methoxybenzamide (1-270)
Figure imgf000205_0002
[00456] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.06 (3H, d) , 1.14 (6H, s), 1.54-1.78 (6H, m) , 1.82-1.94 (2H, m) , 3.13-3.24 (2H, m) , 3.16 (3H, s), 3.38 (2H, s), 3.73-3.82 (IH, m) , 3.95 (3H, s), 4.77 (IH, d) , 5.18 (IH, dt), 7.50 (IH, d) , 7.52 (IH, s), 7.69 (IH, s), 7.99 (IH, s), 8.30-8.40 (2H, m) ; HPLC rt(min): 9.10; MS (ES+) 498, (ES") 496. Example 271;
4- (9' -cyclopentyl-5' -methyl-6' -oxo-5' , 6' ,8' ,9' - tetrahydrospiro [cyclopropane-1,7' -pyrimido [4 , 5- b] [l,4]diazepine] -2' -ylamino) -N- (l-hydroxy-2-methylpropan-2- yl) -3-methoxybenzamide (1-271)
Figure imgf000206_0001
[00457] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.66-0.69 (2H, m) , 0.89-0.92 (2H, m) , 1.32 (6H, s), 1.48-1.69 (6H, m) , 1.89 (2H, m) , 3.17 (3H, s), 3.44-3.48 (2H, m) , 3.51-3.52 (2H, m) , 3.95 <3H, s), 4.85 (IH, m) , 4.96 (IH, m) , 7.42-7.43 (3H, m) , 7.68 (IH, s), 7.99 (IH, s), 8.38 (IH, d) ; HPLC rt(min): 9.23; MS (ES+) 510, (ES") 508. Example 272:
4- (9' -cyclopentyl-5' -mβthyl-6' -oxo-5' ,6' ,8' ,9' - tetrahydrospiro [cyclopropane-1, 7' -pyrimido [4,5- b] [l,4]diazepine]-2' -ylamino) -N- ( <lR,2R)-2- hydroxycyc1openty1 ) -3-methoxybenzamide (1-272)
Figure imgf000206_0002
[00458] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.67 (2H, m) , 0.90 (2H, m) , 1.49-1.50 (2H, m) , 1.55-1.68 (8H, m) , 1.86-1.89 (3H, m) , 2.00 - 2.01 (IH, m) , 3.17 (3H, s), 3.48 (2H, m) , 3.95 (3H, s), 3.97-4.00 (2H, m) , 4.80 (IH, m) , 4.85 (IH, m) , 7.47-7.49 (2H, m) , 7.69 (IH, s), 7.99 (IH, s), 8.11 (IH, m) , 8.39 (IH, d) ; HPLC rt(min): 9.16; MS (ES+) 522, (ES") 520. Example 273;
4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido [4,5-b] [1,4] diazepin-2-ylamino) -3-methoxy-N- (3,3,3- trifluoro-2-hydroxypropyl)benzamide (1-278)
Figure imgf000207_0001
[00459] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.57-1.94 (8H, m) , 3.19
(3H, s), 3.21-3.28 (IH, m) , 3.38 (2H, s), 3.59-3.68 (IH, m) , 3.94 (3H, s), 4.12-4.24 (IH, m) , 5.18 (IH, dt) , 6.54 (IH, d) , 7.52 (IH, d) , 7.53 (IH, s), 7.72 (IH, s), 7.99 (IH, s), 8.39
(IH, d) , 8.65 (IH, t); HPLC rt(min): 9.67; MS (ES+) 552, (ES")
550.
Example 274;
4- (9-cyclopentyl-5, 7,7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5H- pyrimido[4,5-b] [1,4] diazepin-2-ylamino) -N- (2-fluoroethyl) -3- methoxybenzamide (1-279)
Figure imgf000207_0002
[00460] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.09 (6H, s), 1.55-1.80 (6H, m) , 1.82- 1.93 (2H, m) , 3.19 (3H, s), 3.38 (2H, s), 3.53 (IH, q) , 3.60 (IH, q) , 3.94 (3H, s), 4.48 (IH, t) , 4.60 (IH, t) , 5.18 (IH, dt) , 7.52 (IH, d) , 7.53 (IH, s), 7.71 (IH, s), 7.99 (lH, s), 8.39 (IH, d) , 8.61 (IH, t); HPLC rt(min): 9.54; MS (ES+) 486, (ES") 484. Example 275:
3- (4- ( 9-cyclopentyl-5, 7 , 7-trimethyl-6-oxo-6,7,8, 9-tetrahydro- 5H-pyrimido[4,5-b] [1,4] diazepin-2-ylamino) -3- methoxybenzamido)propyl acetate (1-273)
Figure imgf000208_0001
[00461] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.15 (6H, s), 1.58-1.70 (8H, m) , 1.83- 1.87 (2H, m) , 2.01 (3H, s), 3.18 (3H, s), 3.33-3.37 (2H, m) , 3.47-3.52 (2H, m) , 3.94 (3H, s), 4.04-4.08 (2H, m) , 5.11 (IH, m) , 7.52 (IH, d) , 7.59 (IH, s), 8.03 (2H, m) , 8.54 (IH, m) , 9.28 (IH, br s ) ; HPLC rt(min): 9.64; MS (ES+) 540, (ES") 538. Example 276.
(lr,4rr)-4-(4-(9-cyclopentyl-5,7,7-triinethyl-6-oxo-6,7,8,9- tetrahydro-5H-pyrimido[4, 5-b] [l,4]diazepin-2-ylamino) -3- meth.oxybenzamido)cycloh.exyl acetate (1-280)
Figure imgf000208_0002
[00462] Prepared using the appropriate reagents according to method E. NMR DMSO D6 1.14 (6H, s), 1.44-1.96 (15 H, m) , 2.00 (3H, s), 3.17 (3H, s), 3.50 (3H, s), 3.82 (IH, m) , 3.95 (3H, s), 4.59 (IH, m) , 5.13 (IH, m) , 7.50-7.55 (2H, m) , 8.01 (IH, s), 8.08 (IH, d) , 8.20 (IH, d) , 9.00 (IH, br s); HPLC rt(min): 10.04; MS (ES+) 580, (ES") 578. Example 277;
4- (9 ■ -cyclopentyl-5 • -methyl-6 ' -oxo-5 ■ , 6 • , 8 ' , 9 • - tetrahydrospiro [cyclopropane-1, 7 ' -pyrimido [4,5- b] [l,4]diazepine] -2 • -ylamino) -N- ( (Is, 4s) -4-fluorocyclohexyl) - 3-methoxybenzamide (1-281)
Figure imgf000209_0001
[00463] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.63-0.71 (2H, m) , 0.86-0.94 (2H, m) , 1.47-1.99 (16H, m) , 3.17 (3H, s), 3.47 (2H, s), 3.83-3.91 (IH, m) , 3.95 (3H, S), 4.78-4.89 (2H, m) , 7.49 (IH, d) , 7.50 (IH, s), 7.69 (IH, s), 7.99 (IH, s), 8.13 (IH, d) , 8.39 (IH, d) ; HPLC rt(min): 9.88; MS (ES+) 538, (ES") 536. Example 278;
4- (9 • -cyclopentyl-5 • -methyl-6 • -oxo-5 ' , 6 • , 8 ' , 9 • - tetrahydrospiro [cyclopropane-1, 7 • -pyrimido [4, 5- b] [l,4]diazepine]-2'-ylamino)-N-( (IR, 3R) -3- hydroxycyclopentyl) -3-methoxybenzamide ( 1-282)
Figure imgf000209_0002
[00464] Prepared using the appropriate reagents according to method E. NMR DMSO D6 0.63-0.69 (2H, m) , 0.86-0.93 (2H, m) , 1.43-1.75 (9H, m) , 1.83-2.09 (5H, m) , 3.17 (3H, s), 3.48 (2H, S), 3.94 (3H, s), 4.19-4.26 (IH, m) , 4.46 (IH, dt), 4.53 (IH, d) , 4.85 (IH, dt) , 7.46 (IH, d) , 7.48 (IH, s), 7.69 (IH, s), 7.99 (IH, s), 8.14 (IH, d) , 8.39 (IH, d) ; HPLC rt(min): 8.83; MS (ES+) 522, (ES") 520. Example 279: PLKl Assay
[00465] The compounds of the present invention are evaluated as inhibitors of human PLK kinase using the following assays. Plkl Inhibition Assay:
[00466] Compounds were screened for their ability to inhibit Plkl using a radioactive-phosphate incorporation assay. Assays were carried out in a mixture of 25mM HEPES (pH 7.5), 1OmM MgCl2, and ImM DTT. Final substrate concentrations were 5OuM [γ-33P]ATP (136mCi 33P ATP/ mmol ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and lOμM peptide (SAM68 protein Δ332-443) . Assays were carried out at 25 °C in the presence of 15nM Plkl (A20-K338) . An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 30μL of the stock solution was placed in a 96 well plate followed by addition of 2μL of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of lOμM with 2-fold serial dilutions) in duplicate (final DMSO concentration 5%) . The plate was pre- incubated for 10 minutes at 25°C and the reaction initiated by addition of 8μL [γ-33P]ATP (final concentration 5OuM) . [00467] The reaction was stopped after 60 minutes . by the addition of lOOμL 0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no. MAPHN0B50) was pretreated with lOOμL 0.2M phosphoric acid prior to the addition of 125μL of the stopped assay mixture. The plate was washed with 4 x 200μL 0.2M phosphoric acid. After drying, lOOμL Optiphase λSuperMix' liquid scintillation cocktail (Perkin Elmer) was added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac) .
[00468] After removing mean background values for all of the data points, Ki(app) data were calculated from non-linear regression analysis of the initial rate data using the Prism software package (GraphPad Prism version 3.0cχ for Macintosh, GraphPad Software, San Diego California, USA) . Plkl Inhibition Assay:
[00469] Compounds were screened for their ability to inhibit Plkl using a radioactive-phosphate incorporation assay. Assays were carried out in a mixture of 25mM HEPES (pH 7.5), 1OmM MgCl2, 0.1% BSA, and 2mM DTT. Final substrate concentrations were 150μM (350μM for determining values of < InM) [γ-33P]ATP (115mCi 33P ATP/ mmol ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and 30OuM (450μM for determining values of < InM) peptide (KKKISDELMDATFADQEAK) . Assays were carried out at 25 'C in the presence of 4nM (InM for determining values of < InM) Plkl . An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 30μL of the stock solution was placed in a 96 well plate followed by addition of 2μL of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of lOμM with 2-fold serial dilutions) in duplicate (final DMSO concentration 5%). The plate was pre- incubated for 10 minutes at 25°C and the reaction initiated by addition of 8μL [γ-33P]ATP (final concentration 150μM (35OuM for determining values of < InM) ) ) .
[00470] The reaction was stopped after 90 minutes (240 minutes for determining values of < InM) by the addition of lOOμL 0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no. MAPHN0B50) was pretreated with lOOμL 0.2M phosphoric acid prior to the addition of 125μL of the stopped assay mixture. The plate was washed with 4 x 200μL 0.2M phosphoric acid. After drying, 100μL Optiphase 'SuperMix' liquid scintillation cocktail (Perkin Elmer) was added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac) .
[00471] After removing mean background values for all of the data points, Ki(app) data were calculated from non-linear regression analysis of the initial rate data using the Prism software package (GraphPad Prism version 3. Ocx for Macintosh, GraphPad Software, San Diego California, USA) . [00472] In general, compounds of the invention are effective for the inhibition of Plkl . The following compounds showed Ki below 10 nM in the radioactive incorporation assay: 1-2, 1-5, 1-4, 1-6, 1-9, 1-11, 1-12, 1-16, 1-17, 1-18, 1-21, 1-22, 1-23, 1-24, 1-25, 1-26, 1-27, 1-28, 1-31, 1-32, 1-33, 1-34, 1-36, I- 37, 1-38, 1-39, 1-47, 1-48, 1-51, 1-52, 1-53, 1-58, 1-59, I- 60, 1-62, 1-64, 1-67, 1-68, 1-69, 1-70, 1-71, 1-72, 1-73, I- 74, 1-75, 1-76, 1-77, 1-80, 1-85, 1-87, 1-93, 1-94, 1-95, I- 96, 1-99, 1-101, 1-103, 1-104, 1-105, 1-108, 1-113, 1-118, I- 119, 1-123, 1-129, 1-130, 1-131, 1-132, 1-133, 1-134, 1-135, 1-136, 1-157, 1-158, 1-163, 1-166, 1-167, 1-169, 1-170, 1-171,
1-172, 1-173, 1-174, 1-175 1-176, 1-177, 1-178, 1-179, 1-180,
1-181, 1-182, 1-183, 1-184 1-185, 1-186, 1-187, 1-190, 1-191,
1-192, 1-193, 1-194, 1-195 1-196, 1-197, 1-198, 1-199, 1-200,
1-201, 1-202, 1-203, 1-204 1-205, 1-206, 1-207, 1-208, 1-209,
1-210, 1-211, 1-212, 1-213 1-214, 1-216, 1-217, 1-218, 1-219,
1-220, 1-221, 1-222, 1-223 1-224, 1-225, 1-226, 1-227, 1-228,
1-229, 1-230, 1-231, 1-232 1-233, 1-234, 1-235, 1-236, 1-237,
1-238, 1-239, 1-240, 1-241 1-242, 1-243, 1-244, 1-245, 1-246,
1-247, 1-248, 1-249, 1-250 1-251, 1-252, 1-253, 1-254, 1-255,
1-256, 1-257, 1-258, 1-259 1-260, 1-261, 1-262, 1-263, 1-264,
1-265, 1-266, 1-267, 1-268 1-269, 1-270, 1-271, 1-272, 1-273, 1-278, 1-279, 1-280, 1-282. The following compounds showed Ki between 10 nM and 100 nM in the radioactive incorporation assay: 1-1, 1-3, 1-7, 1-8, 1-10, 1-14, 1-15, 1-19, 1-20, I- 30, 1-35, 1-40, 1-42, 1-43, 1-44, 1-45, 1-46, 1-49, 1-50, I- 56, 1-63, 1-65, 1-66, 1-78, 1-79, 1-81, 1-86, 1-89, 1-90, I- 91, 1-92, 1-97, 1-98, 1-102, 1-109, 1-110, 1-111, 1-112, I- 114, 1-116, 1-117, 1-120, 1-122, 1-124, 1-125, 1-137, 1-138, 1-139, 1-141, 1-143, 1-144, 1-145, 1-147, 1-149, 1-150, 1-151, 1-152, 1-153, 1-154, 1-155, 1-156, 1-159, 1-160, 1-161, 1-162, 1-164, 1-165, 1-168, 1-188, 1-192, 1-215. The following compounds showed Ki between 100 nM and 4 uM in the radioactive incorporation assay: 1-29, 1-41, 1-54, 1-55, 1-57, 1-61, I- 82, 1-83, 1-84, 1-88, 1-100, 1-106, 1-115, 1-121, 1-127, I- 128, 1-140, 1-146, 1-148, 1-189. The following compounds were not soluble under the assay conditions: 1-126 and 1-142. The following compounds were not active within the limits of the assay: 1-13 and 1-107. Plk2 Inhibition Assay;
[00473] Compounds were screened for their ability to inhibit Plk2 using a radioactive-phosphate incorporation assay. Assays were carried out in a mixture of 25mM HEPES (pH 7.5), 1OmM MgCl2, 0.1% BSA, and 2mM DTT. Final substrate concentrations were 200μM [γ-33P]ATP (57mCi 33P ATP/ mmol ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and 30OuM peptide (KKKISDELMDATFADQEAK) . Assays were carried out at 25 "C in the presence of 25nM Plk2. An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 30μL of the stock solution was placed in a 96 well plate followed by addition of 2μL of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of lOμM with 2-fold serial dilutions) in duplicate (final DMSO concentration 5%) . The plate was pre- incubated for 10 minutes at 25°C and the reaction initiated by addition of 8μL [γ-33P]ATP (final concentration 20OuM) . [00474] The reaction was stopped after 90 minutes by the addition of lOOμL 0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no. MAPHNOB50) was pretreated with lOOμL 0.2M phosphoric acid prior to the addition of 125μL of the stopped assay mixture. The plate was washed with 4 x 200μL 0.2M phosphoric acid. After drying, lOOμL Optiphase λSuperMix' liquid scintillation cocktail (Perkin Elmer) was added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac) . [00475] After removing mean background values for all of the data points, Ki(app) data were calculated from non-linear regression analysis of the initial rate data using the Prism software package (GraphPad Prism version 3. Ocx for Macintosh, GraphPad Software, San Diego California, USA) . Plk3 Inhibition Assay;
[00476] Compounds were screened for their ability to inhibit Plk3 using a radioactive-phosphate incorporation assay. Assays were carried out in a mixture of 25mM HEPES (pH 7.5), 1OmM MgCl2, and ImM DTT. Final substrate concentrations were 75μM [γ-33P]ATP (6OmCi 33P ATP/ mmol ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and lOμM peptide (SAM68 protein Δ332-443). Assays were carried out at 25°C in the presence of 5nM Plk3 (S38-A340) . An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 30μL of the stock solution was placed in a 96 well plate followed by addition of 2μL of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of lOμM with 2-fold serial dilutions) in duplicate (final DMSO concentration 5%) . The plate was pre- incubated for 10 minutes at 250C and the reaction initiated by addition of 8μL [γ-33P]ATP (final concentration 75μM) . [00477] The reaction was stopped after 60 minutes by the addition of 100μL 0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no. MAPHN0B50) was pretreated with lOOμL 0.2M phosphoric acid prior to the addition of 125μL of the stopped assay mixture. The plate was washed with 4 x 200μL 0.2M phosphoric acid. After drying, lOOμL Optiphase vSuperMix' liquid scintillation cocktail (Perkin Elmer) was added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, WaIlac) . [00478] After removing mean background values for all of the data points, Ki (app) data were calculated from non-linear regression analysis of the initial rate data using the Prism software package (GraphPad Prism version 3. Ocx for Macintosh, GraphPad Software, San Diego California, USA) . Plk4 Inhibition Assay:
[00479] Compounds were screened for their ability to inhibit Plk4 using a radioactive-phosphate incorporation assay. Assays were carried out in a mixture of 8mM MOPS (pH 7.5) , 1OmM MgCl2, 0.1% BSA and 2mM DTT. Final substrate concentrations were 15μM [γ-33P]ATP (227mCi 33P ATP/ mmol ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and 30OuM peptide (KKKMDATFADQ) . Assays were carried out at 25 °C in the presence of 25nM Plk4. An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 30μL of the stock solution was placed in a 96 well plate followed by addition of 2μL of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of lOμM with 2-fold serial dilutions) in duplicate (final DMSO concentration 5%) . The plate was pre- incubated for 10 minutes at 25°C and the reaction initiated by addition of 8μL [γ-33P]ATP (final concentration 15uM) . [00480] The reaction was stopped after 180 minutes by the addition of lOOμL 0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no. MAPHN0B50) was pretreated with lOOμL 0.2M phosphoric acid prior to the addition of 125μL of the stopped assay mixture. The plate was washed with 4 x 200μL 0.2M phosphoric acid. After drying, lOOμL Optiphase 'SuperMix' liquid scintillation cocktail (Perkin Elmer) was added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac) . [00481] After removing mean background values for all of the data points, Ki (app) data were calculated from non-linear regression analysis of the initial rate data using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA) . [00482] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize or encompass the compounds, methods, and processes of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims .

Claims

We claim :
1. A compound of formula I
Figure imgf000217_0001
wherein
X1 is a bond, O, NR8, S, SO, or SO2;
Y1 is O or NR9;
R1 is H, Ci-ioaliphatic, C3-iocycloaliphatic, C6-ioarγl , 5-10 membered heteroaryl , or 3-10 membered heterocyclyl; wherein said R1 is optionally substituted with 0-5 J1 ; provided that when X1 is a bond, R1 is not H; R2 is H, Ci-ioaliphatic, - (Ci-iOaliphatic) - (C3-i0cycloaliphatic) ,
C3-8cycloaliphatic, haloCi_4 aliphatic; wherein said R2 is optionally substituted with 0-4 J2; each R3, R4, R5, and R6 is independently H, Ci-iOaliphatic,
C3-iocycloaliphatic,
Figure imgf000217_0002
or 5-10 membered heteroaryl; wherein each R3, R4, Rs, and R6 is optionally and independently substituted with 0-5 J3, J4, JB, and J6 respectively; and R7 is H, C(O)R, C(O)OR, or C(O)NRR', Ci-ioaliphatic ,
C3-iocycloaliphatic, C6-ioaryl, 5-10 membered heteroaryl,
3-10 membered heterocyclyl, - (Ci-βaliphatic) - (C3-iocycloaliphatic) , - (Ci_6aliphatic) - (C6-ioaryl ) , or
- (Ci-6aliphatic) - (5-10 membered heteroaryl), or
- (Ci-6aliphatic) - (3-6 membered heterocyclyl ; wherein said R7 is optionally substituted with 0-5 J7; or
R3 and R4, together with the carbon atom to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R3 and R4 is optionally substituted with 0-4 J34;
R5 and R6, together with the carbon atom to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R5 and R6 is optionally substituted with 0-4 J56,-
R3 and R5, together with the carbon atoms to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from 0, N, and S,- said monocyclic ring formed by R3 and R5 is optionally substituted with 0-4 J35;
R3 and R7, together with the atoms to which they are attached, optionally form a 4-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R3 and R7 is optionally substituted with 0-4
R5 and R7, together with the atoms to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R5 and R7 is optionally substituted with 0-4 v TJ 57 ;- R8 is H , Ci-6al iphatic , C3_8cycloal iphatic , C ( O ) R , C ( O ) OR, or
C ( O ) NRR' ;
R9 is H or unsubstituted Ci-εaliphatic; or R2 and R9, together with the atoms to which they are attached, optionally form a 5-8 membered aromatic or nonaromatic monocyclic ring containing 2-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R2 and R9 is optionally substituted with 0-4 J29; each J1 is independently Ci_6haloalkyl, halo, NO2, CN, Q, or -Z-Q; or, two J1 taken together can optionally form =0; Z is Ci-εaliphatic optionally replaced with 0-3 occurrences of -NR-, -O-, -S-, -C(O)-, -C(=NR)-, -C(=NOR)-, -SO-, or -SO2- ; each Z is optionally substituted with 0-2 Jz; Q is H; Ci-6 aliphatic; a 3-8-membered aromatic or nonaromatic monocyclic ring having 0-3 heteroatoms independently selected from 0, N, and S; or an 7-12 membered aromatic or nonaromatic bicyclic ring system having 0-5 heteroatoms independently selected from 0, N, and S; each Q is optionally substituted with 0-5 JQ; each J2 is halo or haloCi-4 aliphatic; each J3, J4, J5, and J6 is independently Ci-β aliphatic, C3-6cycloaliphatic, or - (Ci-4alkyl)n-V1; wherein n is 0 or 1 ;
V1 is halo(Ci-4 aliphatic), -0(haloCi-4 aliphatic), halo, NO2, CN, OH, OR", SH, SR", NH2, NHR", N (R") 2. COH, COR", CO2H, CO2R", CONH2, CONHR", CONR"2 , OCOR" , OCONH2 , OCONHR" , OCON (R" ) 2 , NHCOR", NR"COR", NHCO2R", NR"C02R" , NHCO2H, NR"C02H, NHCONH2, NHCONHR", NHCON (R") 2, SO2NH2, SO2NHR", SO2N (R" )2, NHSO2R", NR"SO2R"; or V1 is a cyclic group selected from
C3-6cycloaliphatic, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl ; wherein said cyclic group is optionally substituted with 0-3 Jv; R" is unsubstituted Cχ-4 aliphatic; or two of the same J3, J4, J5, or J6, bonded to the same atom, together can optionally form =0; each Jz and Jv is independently halo, Ci_6 aliphatic,
C3-6cycloaliphatic, NO2, CN, -NH2, -NH(Ci-4 aliphatic), -N(Ci-4 aliphatic) 2, -OH, -O(Ci_4 aliphatic), -CO2H, -CO2(Ci- 4 aliphatic), -O (haloC!-4 aliphatic), or halo(Cχ-4 aliphatic) ; each JQ, J7, J29, J34, J56, J35, J37, and J57 is independently M or -Y-M; each Y is independently an unsubstituted Ci-βaliphatic optionally replaced with 0-3 occurrences of -NR-, -O- , -S-, -C(O)-, -SO-, or -SO2-; each M is independently H, Ci-6 aliphatic, C3_6cycloaliphatic, halo(Ci_4 aliphatic), -0(haloCi_4 aliphatic), 3-6 membered heterocyclyl, C6-i0aryl, halo, NO2, CN, OH, OR', SH, SR', NH2, NHR', N(R' )2, COH, COR', CO2H, CO2R', CONH2, CONHR', CONR' 2, OCOR', OCONH2, OCONHR', OCON(R' )2, NHCOR', NR' COR', NHCO2R', NR' CO2R', NHCO2H, NR' CO2H, NHCONH2, NHCONHR', NHCON(R' )2, SO2NH2, SO2NHR', SO2N(R' )2, NHSO2R', Or NR7SO2R', or two M taken together can optionally form =0;
R is H or unsubstituted Ci_6aliphatic;
R' is unsubstituted C!-6aliphatic; or two R' groups, together with the atom to which they are bound, form an unsubstituted 3-8 membered saturated or partially unsaturated monocyclic ring having 0-1 heteroatoms independently selected from O, N, and S.
2. The compound of claim 1, wherein:
R1 is H, Ci-ioaliphatic, Cε-ioaryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; wherein said R1 is optionally substituted with 0-5 J1; provided that when X1 is a bond, R1 is not H;
R7 is H, C(O)R, C(O)OR, or C(O)NRR', Ci-iOaliphatic,
C3-i0cycloaliphatic, C6-ioaryl , 5-10 membered heteroaryl, 3- 10 membered heterocyclyl, - (Ci-εaliphatic) - (C3_iocycloaliphatic) , - (Ci-6aliphatic) - (C6-ioaryl) , or - (Ci-βaliphatic) - ( 5-10 membered heteroaryl); wherein said R7 is optionally substituted with 0-5 J7; Q is H; Ci-6 aliphatic; a 3 -8-membered aromatic or nonaromatic monocyclic ring having 0-3 heteroatoms independently selected from 0, N, and S; or an 8-12 membered aromatic or nonaromatic bicyclic ring system having 0-5 heteroatoms independently selected from O, N, and S; each Q is optionally substituted with 0-5 JQ; and each M is independently H, Ci_6 aliphatic, C3-6cycloaliphatic , halo(Ci_4 aliphatic), -0(haloCi_4 aliphatic), 3-6 membered heterocyclyl, halo, NO2, CN, OH, OR', SH, SR', NH2, NHR', N(R' ) 2, COH, COR', CO2H, CO2R', CONH2, CONHR', CONR' 2, OCOR', OCONH2, OCONHR', OCON(R' )2, NHCOR', NR' COR' , NHCO2R', NR' CO2R', NHCO2H, NR' CO2H, NHCONH2, NHCONHR' , NHCON(R' )2, SO2NH2, SO2NHR', SO2N(RM2, NHSO2R', or NR' SO2R' .
3. The compound of claim 1 or claim 2, wherein X1 is NR8.
4. The compound of any one of claims 1-3, wherein Y1 is 0.
5. The compound of any one of claims 1-4, wherein R1 is C6-ioaryl or 5-10 membered heteroaryl , wherein R1 is substituted with 0-5 J1.
6. The compound of any one of claims 1-5, wherein R2 is Ci- ioaliphatic or C3-iocycloaliphatic, wherein R2 is substituted with 0-4 J2.
7. The compound of any one of claims 1-6, wherein R2 -CH3.
8. The compound of any one of claims 1-7, wherein R3 and R4, together with the carbon atom to which they are attached, form a 3-6 membered monocyclic ring substituted with 0-5 R3 or R4.
9. The compound of any one of claim 1-7, wherein R3 and R5, together with the carbon atoms to which they are attached, form a 3-6 membered monocyclic ring substituted with 0-5 R3 or
R3
10. The compound of any one of claim 1-7, wherein each R3, R4, R5, and R6 is independently a group selected from H, Ci-10aliphatic, C3-i0cycloaliphatic, Cβ-ioaryl , or 5-10 membered heteroaryl , wherein each R3, R4, R5, and R6 is independetly substituted with 0-5 J3, J4, J5, and J6, respectively.
11. The compound of any one of claims 1-7, wherein each R3 and R4 is independently H, Ci-εaliphatic, or C3-acycloaliphatic, wherein each R3 and R4 is independetly substituted with 0-5 J3 and J4, respectively.
12. The compound of any one of claims 1-7, wherein one of R3 and R4 is H and the other is Ci-saliphatic or C3-8cycloaliphatic wherein the R3 and R4 that is not H is independetly substituted with 0-5 J3 and J4, respectively.
13. The compound any one of claims 1-12, wherein each J3 and J4 is independently halo.
14. The compound of any one of claims 1-8 and 11-13, wherein R5 and R7, together with the atoms to which they are attached, form a 3-6 membered saturated or partially unsaturated monocyclic ring substituted with 0-5 J5 or J7
15. The compound of any one of claims 1-13, wherein R7 is a group selected from Ci-10aliphatic, C3-iocycloaliphatic, Cβ- loaryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl , wherein R7 is substituted with 0-5 J7.
16. The compound of any one of claims 1-13, wherein R7 is a group selected from Ci-ioaliphatic, C3-acycloaliphatic, phenyl, a 5-membered heteroaryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,5- pyridazinyl, 3 , 5-pyrimidyl , and a 3-8 membered heterocyclyl, wherein R7 is substituted with 0-5 J7.
17. The compound of any one of claims 1-13, wherein R7 is not 3-amino-2 , 4-pyrimidine.
18. The compound of any one of claims 1-13, wherein R7 is a group selected from C3-6alkyl, C3-6cycloalkyl , phenyl, or 5-6 membered heterocyclyl , wherein the heterocyclyl contains 1 oxygen heteroatom and wherein R7 is substituted with 0-5 J7.
19. The compound of any one of claims 1-13, wherein R7 is a C4-5cycloalkyl , wherein R7 is substituted with 0-5 J7.
20. The compound of any one of claims 1-13, wherein R7 is Cj-scycloalkyl substituted with 1 or 2 -F.
21. The compound of any one of claims 1-13, wherein R7 is an unsubstituted C4_5cycloalkyl .
22. The compound of any one of claims 1-13, wherein R7 is cyclopentyl substituted with 0-5 J7.
23. The compound of any one of claims 1-13, wherein R7 is cyclopentyl substituted with 1 or 2 -F.
24. The compound of any one of claims 1-13, wherein R7 is an unsubstituted cyclopentyl.
25. The compound of any one of claims 1-24, wherein R8 is H.
26. The compound of claim 1 or claim 2, represented by formula II;
Figure imgf000224_0001
II wherein
R1 is optionally substituted Cβ-ioaryl or optionally substituted 5-10 membered heteroaryl; R2 is H or an optionally substituted group selected from
Ci-ioaliphatic and C3-χocycloaliphatic; each R3, R4, R5, and R6 is independently H, Ci-iOaliphatic, or C3_iocycloaliphatic; wherein each R3, R4, R5, and R6 is optionally substituted with 0-5 J3, J4, J5, and J6 respectively; or R3 and R4, together with the carbon atom to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R3 and R5, together with the carbon atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R5 and R7, together with the atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R2 and R9, together with the atoms to which they are attached, can form an optionally substituted 5-8 membered saturated or partially unsaturated monocyclic ring.
27. The compound of claim 1 or claim 2, represented by formula III;
Figure imgf000225_0001
III wherein
R1 is optionally substituted Cβ-ioaryl or optionally substituted 5-10 membered heteroaryl; R2 is H or an optionally substituted group selected from
Ci-iOaliphatic and C3.10cycloaliph.atic; each R3, R4, R5, and R6 is independently H, Ci-ioaliphatic, or C3-iocycloaliphatic; wherein each R3, R4, R5, and R5 is optionally substituted with 0-5 J3, J4, J5, and J6 respectively; or R3 and R4, together with the carbon atom to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R3 and R5, together with the carbon atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring; R5 and R7, together with the atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring,- R2 and R9, together with the atoms to which they are attached, can form an optionally substituted 5-8 membered saturated or partially unsaturated monocyclic ring.
28. The compound according to any one of claims 1-27, wherein each J3, J4, J5, and J6 is independently Ci-6 aliphatic, C3-6cycloaliphatic, or - (Ci-4alkyl Jn-V1; wherein n is 0 or 1 ;
V1 is halo(Ci-4 aliphatic), -0(haloCi_4 aliphatic), halo, NO2, CN, OH, OR", SH, SR", NH2, NHR", N (R") 2, COH, COR", CO2H, CO2R", CONH2, CONHR", C0NR"2, OCOR", OCONH2, OCONHR", OCON(R") 2, NHCOR", NR"COR", NHCO2R", NR"C02R" , NHCO2H, NR"C02H, NHCONH2, NHCONHR", NHCON (R") 2, SO2NH2, SO2NHR", SO2N(R") 2, NHSO2R", NR"S02R" ; R" is unsubstituted C3.-4 aliphatic; or two of the same J3, J4, J5, or J6, bonded to the same atom, together can optionally form =O.
29. A compound selected from the following:
Figure imgf000226_0001
1 - 1 1 - 2 1 - 3
Figure imgf000226_0002
1 -4 1 - 5 1 - 6
Figure imgf000227_0001
1-7 1-8.
30. A compound selected from the following:
Figure imgf000227_0002
1-11 1-12
Figure imgf000227_0003
1-14 1-15
Figure imgf000227_0004
1-16 1-17 1-18
Figure imgf000228_0001
1-19 1-20 1-21
Figure imgf000228_0002
1-22 1-23 1-24
Figure imgf000228_0003
1-25 1-26 1-27
Figure imgf000228_0004
1-28 1-29 1-30
Figure imgf000228_0005
1-31 1-32 1-33
Figure imgf000229_0001
1-34 1-35 1-36
Figure imgf000229_0002
1-37 1-38 1-39
Figure imgf000229_0003
1-43 1-44 1-45
Figure imgf000229_0004
1-46 1-47 1-48
Figure imgf000230_0001
1-49 1-50 1-51
Figure imgf000230_0002
1-52 1-53 1-54
Figure imgf000230_0003
1-55 1-56 1-57
Figure imgf000230_0004
1-58 1-59 1-60
Figure imgf000230_0005
1-61 1-62 1-63
Figure imgf000231_0001
1-64 1-65 1-66
Figure imgf000231_0002
1-67 1-68 1-69
Figure imgf000231_0003
1-70 1-71 1-72
Figure imgf000231_0004
1-73 1-74 1-75
Figure imgf000231_0005
1-76 1-77 1-78
Figure imgf000232_0001
1-79 1-80 1-81
Figure imgf000232_0002
1-82 1-83 1-84
Figure imgf000232_0003
1-85 1-86 1-87
Figure imgf000232_0004
1-88 1-89 1-90
Figure imgf000232_0005
1-91 1-92 1-93
Figure imgf000233_0001
1-94 1-95 1-96
Figure imgf000233_0002
1-97 1-98 1-99
Figure imgf000233_0003
1-100 1-101 1-102
Figure imgf000233_0004
1-103 1-104 1-105
Figure imgf000233_0005
1-106 1-108
Figure imgf000234_0001
1-109 1-110 1-111
Figure imgf000234_0002
1-112 1-113 1-114
Figure imgf000234_0003
1-115 1-116 1-117
Figure imgf000234_0004
1-118 1-119 1-120
Figure imgf000234_0005
1-121 1-122 1-123
Figure imgf000235_0001
1-124 1-125 1-126
Figure imgf000235_0002
1-127 1-128 1-129
Figure imgf000235_0003
1-130 1-131 1-132
Figure imgf000235_0004
1-133 1-134 1-135
Figure imgf000235_0005
1-136 1-137 1-138
Figure imgf000236_0001
1-139 1-140 1-141
Figure imgf000236_0002
1-142 1-143 1-144
Figure imgf000236_0003
1-145 1-146 1-147
Figure imgf000236_0004
1-148 1-149 1-150
Figure imgf000236_0005
1-151 1-152 1-153
Figure imgf000237_0001
1-154 1-155 1-156
Figure imgf000237_0002
1-157 1-158 1-159
Figure imgf000237_0003
1-160 1-161 1-162
Figure imgf000237_0004
1-163 1-164 1-165
Figure imgf000237_0005
1-166 1-167 1-168
Figure imgf000238_0001
1-169 1-170 1-171
Figure imgf000238_0002
1-172 1-173 1-174
Figure imgf000238_0003
1-175 1-176 1-177
Figure imgf000238_0004
1-178 1-179 1-180
Figure imgf000239_0001
1-181 1-182 1-183
Figure imgf000239_0002
1-184 1-185 1-186
Figure imgf000239_0003
1-187 1-188 1-189
Figure imgf000239_0004
1-190 1-191 1-192
Figure imgf000239_0005
1-193 1-194 1-195
Figure imgf000240_0001
1-196 1-197 1-198
Figure imgf000240_0002
1-199 1-200 1-201
Figure imgf000240_0003
1-202 1-203 1-204
Figure imgf000240_0004
1-205 1-206 1-207
Figure imgf000240_0005
1-208 1-209 1-210
Figure imgf000241_0001
1-211 1-212 1-213
Figure imgf000241_0002
1-214 1-215 1-216
Figure imgf000241_0003
1-217 1-218 1-219
1-220 1-221 1-222
Figure imgf000242_0001
1-223 1-224 1-225
Figure imgf000242_0002
1-226 1-227 1-228
Figure imgf000242_0003
1-229 1-230 1-231
Figure imgf000242_0004
1-232 1-233 1-234
Figure imgf000243_0001
1-235 1-236 1-237
Figure imgf000243_0002
1-238 1-239 1-240
Figure imgf000243_0003
1-241 1-242 1-243
Figure imgf000243_0004
1-244 1-245 1-246
Figure imgf000243_0005
1-247 1-248 1-249
Figure imgf000244_0001
1-250 1-251 1-252
Figure imgf000244_0002
1-253 1-254 1-255
Figure imgf000244_0003
1-256 1-257 1-258
Figure imgf000244_0004
1-259 1-260 1-261
Figure imgf000245_0001
1-262 1-263 1-264
Figure imgf000245_0002
1-265 1-266 1-267
Figure imgf000245_0003
1-268 1-269 1-270
Figure imgf000245_0004
1-271 1-272 1-273
Figure imgf000245_0005
1-274 1-275 1-276
Figure imgf000246_0001
1-277 1-278 1-279
Figure imgf000246_0002
1-280 1-281 1-282
Figure imgf000246_0003
1-283 1-284 1-285
Figure imgf000246_0004
1-286 1-287
31. A composition comprising a compound of any one of claims 1-30, and a pharmaceutically acceptable carrier, adjuvant, or vehicle .
32. A method of inhibiting protein kinase activity in a patient comprising administering to said patient a) a composition of claim 31; or b) a compound of any one of claims 1-30.
33. A method of inhibiting protein kinase activity in a biological sample comprising contacting said biological sample with: a) a composition of claim 31,- or b) a compound of any one of claims 1-30.
34. The method of claim 32 or claim 33, wherein said protein kinase is PLK.
35. The method of claim 34, wherein said protein kinase is PLKl.
36. A method of treating a proliferative disorder, a neurodegenerative disorder, an autoimmune disorder, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising the step of administering to a patient: a) a composition of claim 31; or b) a compound of any one of claims 1-30.
37. The method according to claim 36, comprising administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an antiinflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein: a) said additional therapeutic agent is appropriate for the disease being treated; and b) said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
38. A method of treating melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from colon, breast, gastric, ovarian, cervical, lung, central nervous system (CNS), renal, prostate, bladder, or pancreatic, in a patient wherein said method comprises administering to said patient a) a composition of claim 31; or b) a compound of any one of claims 1-30.
39. A method of treating cancer in a patient wherein said method comprises administering to said patient a) a composition of claim 31; or b) a compound of any one of claims 1-30.
40. The method of claim 39, wherein said method comprises the step of disrupting mitosis of the cancer cells by inhibiting PLK with: a) a composition of claim 31; or b) a compound of any one of claims 1-30.
41. A process for preparing a compound of formula I :
Figure imgf000248_0001
wherein Y1 is O and X1, R1, R2, R3, R4, R5, R6, and R7 are as defined according to any one of claims 1-30; comprising reacting a compound of formula 5;
Figure imgf000249_0001
5 wherein
R2, R3, R4, R5, R6, and R7 are as defined according to any¬ one of claims 1-29; and LG2 is a suitable leaving group; with X1R1 under suitable conditions to form the compound of formula I .
42. The process of claim 41, further comprising the step of reacting a compound of formula 4;
Figure imgf000249_0002
wherein R3, R4, R5, R6, and R7 are as defined according to any one of claims 1-29; and LG2 is a suitable leaving group,- with R2-LG3, wherein LG3 is a leaving group capable of being displaced by an NH-amide; to form the compound of formula 5.
43. The process of claim 42, further comprising cyclizing a compound of formula 3-a;
Figure imgf000249_0003
wherein LG2 is a suitable leaving group and R3, R4, R5, R6, and R7 are as defined according to any one of claims 1-29; under cyclo-condensation conditions to form a compound of formula 4.
44. The process of claim 43 , further comprising the step reacting a compound of formula 3;
Figure imgf000250_0001
3 wherein LG2 is a suitable leaving group and R3, R4, R5, R6, and R7 are as defined according to any one of claims 1-29; under suitable reduction conditions to form a compound of formula 3-a.
45. The process of claim 43, further comprising a) functionalizing the amino group in the compound of formula 3-a under suitable conditions to form a compound of formula 3-b;
Figure imgf000250_0002
3-b wherein LG2 is a suitable leaving group and R3, R4, R5, R6, and R7 are as defined according to any one of claims 1-29; b) cyclizing the compound of formula 3-b under suitable cyclo-condensation conditions to form a compound of formula 4.
46. The process of claim 44, further comprising reacting a compound of formula 2 ;
Figure imgf000251_0001
2 wherein R3, R4, R5, R6, and R7 are as defined according to any one of claims 1-29; with a compound of formula 1;
Figure imgf000251_0002
1 wherein LGi and LG2 are each independently suitable leaving groups ; under suitable displacement conditions to form the compound of formula 3.
47. A process for preparing a compound of formula I:
Figure imgf000251_0003
I wherein Y1 is NR9 and X1, R1, R2, R3, R4, R5, R6, and R7 are as defined herein; comprising reacting the compound of formula I wherein Y1 is 0 and X1, R1, R2, R3, R4, R5, R6, and R7 are as defined herein,- under suitable conditions known in the art for converting amides into amidines, to form a compound of formula I wherein Y1 is NR9.
48. A process for preparing a compound of formula 5-a:
Figure imgf000252_0001
5-a wherein LG2 is a suitable leaving group and R2, R3, R4, R5, R6, R7, and R9 are as defined according to any one of claims 1-29; comprising reacting a compound of formula 5
Figure imgf000252_0002
j> wherein LG2 is a suitable leaving group and R2, R3, R4, R5, R6 and R7 are as defined according to any one of claims 1- 29; under suitable conditions known in the art for converting amides into amidines, to form a compound of formula 5-a.
49. The process of claim 48, further comprising displacing LG2 with X1R1 to form a compound of formula I wherein Y1 is NR9 and X1, R1, R2, R3, R4, R5, R6, and R7 are as defined herein.
50. The process of any one of claims 47-48, wherein R2 and R9 are taken together to form Ring A, and wherein suitable conditions known in the art for converting amides into amidines comprise a multi-step cyclisation secpαence to form ring A.
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