US20090304692A1 - Triazine compounds as pi3 kinase and mtor inhibitors - Google Patents

Triazine compounds as pi3 kinase and mtor inhibitors Download PDF

Info

Publication number
US20090304692A1
US20090304692A1 US12/470,525 US47052509A US2009304692A1 US 20090304692 A1 US20090304692 A1 US 20090304692A1 US 47052509 A US47052509 A US 47052509A US 2009304692 A1 US2009304692 A1 US 2009304692A1
Authority
US
United States
Prior art keywords
phenyl
triazin
azabicyclo
oxa
urea
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/470,525
Inventor
Aranapakam Mudumbai Venkatesan
Zecheng Chen
Christoph Martin Dehnhardt
Osvaldo Dos Santos
Efren Guillermo Delos Santos
Arie Zask
Jeroen Cunera Verheijen
Joshua Aaron Kaplan
David James Richard
Semiramis Ayral-Kaloustian
Tarek Suhayl Mansour
Ariamala Gopalsamy
Kevin Joseph Curran
Mengxiao Shi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Original Assignee
Wyeth LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=40911929&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20090304692(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Wyeth LLC filed Critical Wyeth LLC
Priority to US12/470,525 priority Critical patent/US20090304692A1/en
Assigned to WYETH reassignment WYETH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GOPALSAMY, ARIAMALA, SHI, MENGXIAO, DEHNHARDT, CHRISTOPH MARTIN, DOS SANTOS, OSVALDO, MANSOUR, TAREK SUHAYL, CURRAN, KEVIN JOSEPH, KAPLAN, JOSHUA AARON, CHEN, ZECHENG, DELOS SANTOS, EFREN GUILLERMO, AYRAL-KALOUSTIAN, SEMIRAMIS, RICHARD, DAVID JAMES, VERHEIJEN, JEROEN CUNERA, ZASK, ARIE, VENKATESAN, ARANAPAKAM MUDUMBAI
Publication of US20090304692A1 publication Critical patent/US20090304692A1/en
Assigned to WYETH LLC reassignment WYETH LLC CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: WYETH
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • This invention relates to 2,4,6-substituted [1,3,5]triazine compounds in which one substituent is an optionally substituted morpholino, tetrahydropyranyl or dihydropyranyl group, which inhibit PI3 kinase and mTOR, to processes for preparing them, to methods of treatment using them and to pharmaceutical compositions containing them.
  • Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of the phospholipids in cell membranes.
  • PI Phosphatidylinositol
  • PIP2 Phosphatidylinositol
  • Phosphatidylinositol-3 kinase is an enzyme that phosphorylates the 3-position of the inositol ring of phosphatidylinositol [D. Whitman et al., Nature, 332, 664 (1988)].
  • Pluralities of PI3K subtypes exist. Three major subtypes of PI3Ks have now been identified on the basis of their in vitro substrate specificity, and these three are designated class I (a & b), class 11, and class III [B. Vanhaesebroeck, Trend in Biol. Sci., 22, 267 (1997)].
  • the class Ia PI3K subtype has been most extensively investigated to date. Within the class Ia subtype there are three isoforms (a, b, & d) that exist as hetero dimers of a catalytic 110-kDa subunit and regulatory subunits of 50-85 kDa.
  • the regulatory subunits contain SH2 domains that bind to phosphorylated tyrosine residues within growth factor receptors or adaptor molecules and thereby localize PI3K to the inner cell membrane.
  • PI3K converts PIP2 to PIP3 (phosphatidylinositol-3,4,5-trisphosphate) that serves to localize the downstream effectors PDK1 and Akt to the inner cell membrane where Akt activation occurs.
  • Akt Activated Akt mediates a diverse array of effects including inhibition of apoptosis, cell cycle progression, response to insulin signaling, and cell proliferation.
  • Class Ia PI3K subtypes also contain Ras binding domains (RBD) that allow association with activated Ras providing another mechanism for PI3K membrane localization.
  • RBD Ras binding domains
  • Activated, oncogenic forms of growth factor receptors, Ras, and even PI3K kinase have been shown to aberrantly elevate signaling in the PI3K/Akt/mTOR pathway resulting in cell transformation.
  • PI3K As a central component of the PI3K/Akt/mTOR signaling pathway PI3K (particularly the class Ia a isoform) has become a major therapeutic target in cancer drug discovery.
  • Class I PI3Ks are PI, PI(4)P and PI(4,5)P2, with PI(4,5)P2 being the most favored.
  • Class I PI3Ks are further divided into two groups, class Ia and class Ib, because of their activation mechanism and associated regulatory subunits.
  • the class Ib PI3K is p110 ⁇ that is activated by interaction with G protein-coupled receptors. Interaction between p110 ⁇ and G protein-coupled receptors is mediated by regulatory subunits of 110, 87, and 84 kDa.
  • PI and PI(4)P are the known substrates for class II PI3Ks; PI(4,5)P2 is not a substrate for the enzymes of this class.
  • Class II PI3Ks include PI3K C2 ⁇ , C2 ⁇ and C2 ⁇ isoforms, which contain C2 domains at the C terminus, implying that their activity is regulated by calcium ions.
  • the substrate for class III PI3Ks is PI only. A mechanism for activation of the class III PI3Ks has not been clarified. Because each subtype has its own mechanism for regulating activity, it is likely that activation mechanism(s) depend on stimuli specific to each respective class of PI3K.
  • the compound PI103 (3-(4-(4-morpholinyl)pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)phenol) inhibits PI3K ⁇ and PI3Kg as well as the mTOR enzymes with IC 50 values of 2, 3, and 50-80 nM respectively.
  • PI103 3-(4-(4-morpholinyl)pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)phenol
  • mice of this compound in human tumor xenograft models of cancer demonstrated activity against a number of human tumor models, including the glioblastoma (PTEN null U87MG), prostate (PC3), breast (MDA-MB-468 and MDA-MB-435) colon carcinoma (HCT 116); and ovarian carcinoma (SKOV3 and IGROV-1); (Raynaud et al, Pharmacologic Characterization of a Potent Inhibitor of Class I Phosphatidylinositide 3-Kinases, Cancer Res. 2007 67: 5840-5850).
  • ZSTK474 (2-(2-difluoromethylbenzoimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine) inhibits PI3K ⁇ and PI3Kg but not the mTOR enzymes with an IC 50 values of 16, 4.6 and >10,000 nM respectively (Dexin Kong and Takao Yamori, ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms, Cancer Science, 2007, 98:10 1638-1642).
  • NVP-BEZ-235 (2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)propanenitrile) inhibits both PI3K ⁇ and PI3Kg as well as the mTOR enzymes with IC 50 values 4, 5, and “nanomolar”.
  • Testing in human tumor xenograft models of cancer demonstrated activity against human tumor models of prostrate (PC-3) and glioblastoma (U-87) cancer. It entered clinical trials in December of 2006 (Verheijen, J. C. and Zask, A., Phosphatidylinositol 3-kinase (PI3K) inhibitors as anticancer drugs, Drugs Fut. 2007, 32(6): 537-547).
  • the compound SF-1126 (a prodrug form of LY-294002, which is 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) is “a pan-PI3K inhibitor”. It is active in preclinical mouse cancer models of prostrate, breast, ovarian, lung, multiple myeloma, and brain cancers. (Verheijen, J. C. and Zask, A., Phosphatidylinositol 3-kinase (PI3K) inhibitors as anticancer drugs, Drugs Fut. 2007, 32(6): 537-547).
  • PI3K Phosphatidylinositol 3-kinase
  • PI3K inhibitors Selectivity versus other related kinases is also an important consideration for the development of PI3K inhibitors. While selective inhibitors may be preferred in order to avoid unwanted side effects, there have been reports that inhibition of multiple targets in the PI3K/Akt pathway (e.g., PI3K ⁇ and mTOR [mammalian target of rapamycin]) may lead to greater efficacy. It is possible that lipid kinase inhibitors may parallel protein kinase inhibitors in that nonselective inhibitors may also be brought forward to the clinic.
  • targets in the PI3K/Akt pathway e.g., PI3K ⁇ and mTOR [mammalian target of rapamycin]
  • lipid kinase inhibitors may parallel protein kinase inhibitors in that nonselective inhibitors may also be brought forward to the clinic.
  • Mammalian Target of Rapamycin is a cell-signaling protein that regulates the response of tumor cells to nutrients and growth factors, as well as controlling tumor blood supply through effects on Vascular Endothelial Growth Factor, VEGF.
  • Inhibitors of mTOR starve cancer cells and shrink tumors by inhibiting the effect of mTOR. All mTOR inhibitors bind to the mTOR kinase. This has at least two important effects. First, mTOR is a downstream mediator of the PI3K/Akt pathway. The PI3K/Akt pathway is thought to be over activated in numerous cancers and may account for the widespread response from various cancers to mTOR inhibitors.
  • mTOR kinase over-activation of the upstream pathway would normally cause mTOR kinase to be over activated as well. However, in the presence of mTOR inhibitors, this process is blocked. The blocking effect prevents mTOR from signaling to downstream pathways that control cell growth. Over-activation of the PI3K/Akt kinase pathway is frequently associated with mutations in the PTEN gene, which is common in many cancers and may help predict what tumors will respond to mTOR inhibitors. The second major effect of mTOR inhibition is anti-angiogenesis, via the lowering of VEGF levels.
  • mTOR inhibitors There are three mTOR inhibitors, which have progressed into clinical trials. These compounds are Wyeth's Torisel, also known as 42-(3-hydroxy-2-(hydroxymethyl)-rapamycin 2-methylpropanoate, CCI-779 or Temsirolimus; Novartis' Everolimus, also known as 42-O-(2-hydroxyethyl)-rapamycin, or RAD 001; and Ariad's AP23573 also known as 42-(dimethylphopsinoyl)-rapamycin.
  • the FDA has approved Torisel for the treatment of advanced renal cell carcinoma.
  • Torisel is active in a NOS/SCID xenograft mouse model of acute lymphoblastic leukemia [Teachey et al, Blood, 107(3), 1149-1155, 2006].
  • FDA U.S. Food and Drug Administration
  • Everolimus AFINITORTM
  • AP23573 has been given orphan drug and fast-track status by the FDA for treatment of soft-tissue and bone sarcomas.
  • the three mTOR inhibitors have non-linear, although reproducible pharmacokinetic profiles. Mean area under the curve (AUC) values for these drugs increase at a less than dose related way.
  • the three compounds are all semi-synthetic derivatives of the natural macrolide antibiotic rapamycin. It would be desirable to find fully synthetic compounds, which inhibit mTOR that are more potent and exhibit improved pharmacokinetic behaviors.
  • R 2 , R 4 , and R 6-9 are defined below, and pharmaceutically acceptable salts and esters thereof. These compounds are useful as inhibitors of mTOR and PI3 kinases.
  • compositions containing one or more of the aforementioned compounds which compositions may contain a pharmaceutically acceptable carrier.
  • the present invention provides methods for making the compounds of the invention, as described below. Methods of using the invention are also provided, for example: a method for inhibiting mTOR, a method for inhibiting a PI3 kinase, and methods for treating various forms of cancer.
  • the present invention provides compounds of formula I
  • R 6 , R 7 , R 8 , R 9 are each independently selected from the group consisting of a hydrogen atom, and a C 1 -C 6 alkyl optionally substituted with C 2 -C 6 alkenyl, C 4 -C 6 alkadienyl, C 2 -C 6 alkynyl or C 4 -C 6 alkadiynyl;
  • R 6 and R 9 , R 6 and R 8 , or R 7 and R 8 are attached by a (CH 2 ) y , (CH 2 —X—), or (CH 2 —X—CH 2 ) linking group wherein one or two hydrogen atoms in the linking group may be independently replaced by C 1 -C 6 alkyl, (C 1 -C 6 alkyl)NH—, (C 1 -C 6 alkyl) 2 N—, (C 6 -C 14 aryl)alkyl-O—, halo, 3-10 membered C 1 -C 9 heterocyclyl optionally substituted with C 1 -C 6 alkyl-, HO—, or H 2 N—;
  • any two hydrogen atoms on the same carbon atom of the linking group can be replaced by an oxygen atom to form an oxo ( ⁇ O) substituent
  • y is 1, 2 or 3;
  • X is O, S(O) n , or NR 10 ;
  • n 0, 1 or 2;
  • R 10 is selected from the group consisting of H, C 1 -C 6 alkyl, —SO 2 (C 1 -C 6 alkyl), —COO(C 1 -C 6 alkyl), —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CO(C 1 -C 6 alkyl), and —SO 2 NHR 11 ;
  • R 11 is selected from the group consisting of H, C 1 -C 6 alkyl optionally substituted with OH, NR 11 R 11 or a 3-7 membered C 1 -C 6 heterocyclyl, —CO(C 1 -C 6 alkyl), optionally substituted C 6 -C 10 aryl, and optionally substituted C 1 -C 9 heteroaryl;
  • R 2 is optionally substituted C 6 -C 14 aryl-NH—COR 3 , optionally substituted C 1 -C 9 heteroaryl-NH—COR 3 , —CH ⁇ CH—C 6 -C 10 aryl-NH—COR 3 or —CH ⁇ CH—C 1 -C 9 heteroaryl-NH—COR 3 ;
  • R 3 is OR 5 , NR 5 R 5 or NHR 5 ;
  • R 5 is independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, optionally substituted C 6 -C 10 aryl, C 1 -C 6 haloalkyl, optionally substituted C 1 -C 9 heteroaryl, C 1 -C 6 hydroxylalkyl-, C 3 -C 10 saturated or unsaturated mono or bicyclic C 3 -C 10 cycloalkyl optionally substituted with OH, NR 11 R 11 or 3-7 membered C 1 -C 6 heterocyclyl, and 3-10 membered saturated or unsaturated mono or bicyclic C 1 -C 9 heterocyclyl, with the proviso that three-membered cycloalkyl and heterocyclyl rings are saturated;
  • R 5 groups taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with C 1 -C 6 alkyl, which ring system is saturated or unsaturated and has, in addition to said nitrogen atom, 0 to 2 heteroatom ring members selected from O, S, S(O), S(O) 2 and NR 10 ;
  • R 4 is selected from the group consisting of: a) C 1 -C 6 alkyl optionally substituted with: i) 3-10 membered C 1 -C 9 heterocyclyl optionally substituted with C 1 -C 6 alkyl-, ii) H 2 N—, iii) (C 1 -C 6 alkyl)NH—, iv) (C 1 -C 6 alkyl) 2 N—, v) NH(CH 2 ) a N(C 1 -C 6 alkyl) 2 wherein a is 2, 3 or 4, and yl) CHO, b) C 3 -C 6 alkenyl, c) C 3 -C 6 alkynyl, d) —O—C 1 -C 8 alkyl optionally substituted with —O—C 1 -C 8 alkyl, e) —O—C 3 -C 8 alkenyl, f) —O—C 3 -C 8 alkynyl,
  • Z is CH 2 , O, S(O), or NR 10 ; ee) halogen, ff) C 6 -C 14 aryl-S(O) 2 —NH—, gg) R 11 NHC(O)NH—O—, and hh) optionally substituted 5-membered monocyclic C 1 -C 4 heteroaryl attached to the triazine moiety via a nitrogen atom;
  • R 12 and R 13 are each independently selected from H, optionally mono or disubstituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 alkenyl, and optionally substituted C 3 -C 8 alkynyl, the optional substituents being selected from C 1 -C 6 alkoxy, OH, NR 11 R 11 , and 3-7 membered C 1 -C 6 heterocyclyl, provided that an OH or NR 11 R 11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom;
  • R 12 and R 13 taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with C 1 -C 6 alkyl, which ring system is saturated or
  • C 1 -C 9 heteroaryl refers to a 5-10 membered aromatic ring system having one or more rings and 1, 2, 3 or 4 ring members independently selected from O, NR 10 , and S(O) n ;
  • C 1 -C 9 heterocyclyl refers to a 3-10 membered ring system having one or more rings and 1, 2, 3 or 4 ring members independently selected from O, NR 10 , and S(O) n ;
  • optionally substituted aryl and heteroaryl groups are unsubstituted or are substituted with 1 or 2 moieties selected from the group consisting of: a) C 1 -C 6 alkyl optionally substituted with OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , —NH(CH 2 ) w N(C 1 -C 6 alkyl) 2 wherein w is 2, 3 or 4, or 3-10 membered C 1 -C 9 heterocyclyl optionally substituted with from 1 to 3 independently selected C 1 -C 6 alkyl- substituents; b) halogen; c) hydroxy; d) NH 2 ; e) NO 2 ; f) SO 2 NH 2 ; g) COOH; h) COO(C 1 -C 6 alkyl); i) NHCOO(C 1 -C 6 alkyl); j) NH(C 1 -C 6 al
  • R 1 and/or R 4 is
  • R 1 and/or R 4 is
  • R 1 and/or R 4 is
  • R 1 and/or R 4 is independently selected from
  • R 4 is
  • R 4 is
  • R 4 is
  • R 2 is optionally substituted C 6 -C 14 aryl-NH—COR 3 ; in others R 2 is optionally substituted phenyl-NH—COR 3 .
  • R 3 is NHR 5 or OR 5 .
  • R 5 is optionally substituted C 6 -C 10 aryl or C 1 -C 9 heteroaryl, such as pyridyl.
  • the C 1 -C 9 heteroaryl is 4-pyridyl.
  • the invention also includes the following compounds, not of Formula I, made by the process illustrated in Scheme 13, which have mTOR inhibiting activity:
  • the invention also includes pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier.
  • the invention includes a compound of formula I when provided as a pharmaceutically acceptable prodrug, hydrated salt, such as pharmaceutically acceptable salt, or mixtures thereof.
  • the invention provides that the pharmaceutically acceptable carrier suitable for oral administration and the composition comprises an oral dosage form.
  • the invention provides a composition comprising a compound of Formula I, a second compound selected from the group consisting of a topoisomerase I inhibitor, a MEK 1/2 inhibitor, a HSP90 inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouraci
  • the second compound is Avastin.
  • the invention provides a method of treating a PI3K-related disorder, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat a PI3K-related disorder.
  • the PI3K-related disorder is selected from restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, and cancer.
  • the PI3K-related disorder is cancer.
  • the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer.
  • the invention provides a method of treating an mTOR-related disorder, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat an mTOR-related disorder.
  • the mTOR-related disorder is selected from restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, and cancer.
  • the mTOR-related disorder is cancer.
  • the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer.
  • the invention provides a method of treating a hSMG-1-related disorder, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat a hSMG-1-related disorder.
  • the hSMG-1-related disorder is selected from restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, and cancer.
  • the hSMG-1-related disorder is cancer.
  • the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer.
  • the invention provides a method of treating advanced renal cell carcinoma, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat advanced renal cell carcinoma.
  • the invention provides a method of treating acute lymphoblastic leukemia, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat acute lymphoblastic leukemia.
  • the invention provides a method of treating acute malignant melanoma, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat malignant melanoma.
  • the invention provides a method of treating soft-tissue or bone sarcoma, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat soft-tissue or bone sarcoma.
  • the invention provides a method of treating a cancer selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer comprising administering to a mammal in need thereof a composition comprising a compound of Formula I; a second compound selected from the group consisting of a topoisomerase I inhibitor, a MEK 1/2 inhibitor, a HSP90 inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide
  • the invention provides a method of inhibiting mTOR in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit mTOR.
  • the invention provides a method of inhibiting PI3K in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit PI3K.
  • the invention provides a method of inhibiting hSMG-1 in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit hSMG-1.
  • the invention provides a method of inhibiting mTOR, PI3K, and hSMG-1 together in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit mTOR, PI3K, and hSMG-1.
  • the invention provides a method of synthesizing compounds of the Formula I, which are:
  • said method comprising reacting 2,4,6-trichloro[1,3,5]triazine with
  • R 6 , R 7 , R 8 and R 9 is independently selected and defined according to formula I.
  • the third chlorine atom in intermediates 3 and 5 was replaced with 4-aminoaryl and aminoheteroaryl boronic acid in the presence of (Ph 3 ) 4 P(Pd)/Na 2 CO 3 /DME/Reflux or microwave condition to yield 4 and 8 respectively.
  • the amino group was converted to the urea derivatives by different two procedures depending upon the availability of the starting material. Some of the examples reported here were transformed into the urea derivative by reacting 4 or 8 with an appropriately substituted isocyanate derivative. Many of the urea derivatives reported here were prepared by reacting intermediates 4 or 8 with triphosgene/Et 3 N and an appropriately substituted primary amine derivative.
  • the corresponding carbamate derivatives were prepared by reacting intermediates 4 or 8 with an appropriately substituted chloroformate reagents.
  • the intermediates 2 were also used to prepare derivatives of 6, where in R is a alkyl, alkene, alkyne, aryl or heteroaryl. Reacting 6 with the appropriately substituted alkyl introduced alkyl or cycloalkyl groups in intermediate 6 or cycloalkyl magnesium bromide or the corresponding appropriately substituted organo-zinc reagent.
  • Alkenes can be introduced in compound 6 by a Pd catalyzed appropriately substituted vinyl tin derivatives.
  • aryl or heteroaryl substituents can be introduced either by reacting 6 with the corresponding boronic acid (Suzuki coupling) or aryl or heteroaryl magnesium bromide.
  • Alkynes can be introduced by reacting compound 6 with an appropriately substitute alkyne and Pd(0).
  • the alkyne and the alkene introduced can also be functionally converted into other derivatives such as alkyl, alcohol and amine moieties. Detailed procedures are described in the experimental section for each derivative prepared.
  • thiomorpholine and bis morpholine compounds were prepared from 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine and the appropriate morpholine and thiomorpholine reagents as shown in Scheme 6.
  • dihydropyran and tetrahydropyran compounds were prepared from 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine, tributyl(3,6-dihydro-2H-pyran-4-yl)stannane, and the appropriate morpholine as shown in Scheme 7.
  • (6-(1H-benzo[d]imidazol-1-yl)-1,3,5-triazine compounds can be prepared from cyanuric chloride as shown in Scheme 13. Cyanuric chloride is treated with one or two equivalents of bridged morpholine in aprotic solvent in the presence of base to give dichlorotriazine or chlorotriazine, respectively. The chlorotriazine is treated with benzoimidazole in aprotic solvent in the presence of base to give the benzoimidazole triazine. The dichlorotriazine is treated with a morpholine in aprotic solvent in the presence of base followed by benzoimidazole in aprotic solvent in the presence of base to give the benzoimidazole triazine.
  • the number of carbon atoms present in a given group is designated “C x -C y ” where x and y are the lower and upper limits, respectively.
  • a group designated as “C 1 -C 6 ” contains from 1 to 6 carbon atoms.
  • the carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
  • the nomenclature of substituents that are not explicitly defined herein are arrived at by naming from left to right the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • arylalkyloxycabonyl refers to the group (C 6 -C 14 aryl)-(C 1 -C 6 alkyl)-O—C(O)—.
  • Terms not defined herein have the meaning commonly attributed to them by those skilled in the art.
  • “Acyl-” refers to a group having a straight, branched, or cyclic configuration or a combination thereof, attached to the parent structure through a carbonyl functionality. Such groups may be saturated or unsaturated, aliphatic or aromatic, and carbocyclic or heterocyclic. Examples of a C 1 -C 8 acyl- group include acetyl-, benzoyl-, nicotinoyl-, propionyl-, isobutyryl-, oxalyl-, and the like. Lower-acyl refers to acyl groups containing one to four carbons.
  • An acyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N—, (C 1 -C 6 alkyl)amino-, di(C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (C 1 -C 6 alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (C 1 -C 6 alkyl)NHC(O)—, di(C 1 -C 6 alkyl)NC(O)—, —CN, hydroxyl, C 1 -C 6 alkoxy-, C 1 -C 6 alkyl-, HO 2 C—, (C 1 -C 6 alkoxy)carbonyl-, (C 1 -C 6 alkyl)C(O)—, C 6 -C 14 aryl-, C 1 -C 9 hetero
  • Alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a C 1 -C 12 alkyl group may have from 1 to 12 (inclusive) carbon atoms in it.
  • Examples of C 1 -C 6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • C 1 -C 8 alkyl groups include, but are not limited to, methyl, propyl, pentyl, hexyl, heptyl, 3-methylhex-1-yl, 2,3-dimethylpent-2-yl, 3-ethylpent-1-yl, octyl, 2-methylhept-2-yl, 2,3-dimethylhex-1-yl, and 2,3,3-trimethylpent-1-yl.
  • An alkyl group can be unsubstituted or substituted with one or more groups, including: halogen, —NH 2 , (C 1 -C 6 alkyl)N—, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—, —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 al
  • Alkadienyl refer to a straight or branched chain unsaturated hydrocarbon containing at least two double bonds, and either may exist in the E or Z conformation.
  • Examples of a C 4 -C 6 alkadienyl group include, but are not limited to, buta-1,3-dienyl, buta-2,3-dienyl, isoprenyl, penta-1,3-dienyl, and penta-2,4-dien-2-yl.
  • Alkadiynyl refer to a straight or branched chain unsaturated hydrocarbon containing at least two triple bonds. Examples of a C 4 -C 6 alkadiynyl group include, but are not limited to, buta-1,3-diynyl, buta-2,3-diynyl, penta-1,3-diynyl, and penta-2,4-diynyl.
  • Alkenyl refer to a straight or branched chain unsaturated hydrocarbon containing at least one double bond, and may exist in the E or Z conformation.
  • Examples of a C 2 -C 8 alkenyl group include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, 1-octene, 2-octene, 3-octene, and 4-octene.
  • Examples of a C 2 -C 6 alkenyl group include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene, and isohexene.
  • Examples of a C 3 -C 8 alkenyl group include, but are not limited to, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, 1-octene, 2-octene, 3-octene, and 4-octene.
  • Examples of a C 3 -C 6 alkenyl group include, but are not limited to, prop-2-enyl, but-3-enyl, but-2-enyl, 2-methylallyl, pent-4-enyl, and hex-5-enyl.
  • An alkenyl group can be unsubstituted or substituted with one or more groups, including: halogen, —NH 2 , (C 1 -C 6 alkyl)N—, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—, —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6
  • Alkynyl refers to a straight or branched chain unsaturated hydrocarbon containing at least one triple bond.
  • Examples of a C 2 -C 6 alkynyl group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1-pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne, and isohexyne.
  • Examples of a C 3 -C 6 alkynyl group include, but are not limited to, prop-2-ynyl, but-3-ynyl, but-2-ynyl, pent-4-ynyl, and hex-5-ynyl.
  • Examples of a C 3 -C 8 alkynyl group include, but are not limited to, prop-2-ynyl, but-3-ynyl, but-2-ynyl, pent-4-ynyl, hex-5-ynyl, hept-3-ynyl, 2-methylhex-3-ynyl, oct-4-ynyl, and 2-methylhept-3-ynyl.
  • An alkynyl group can be unsubstituted or substituted with one or more groups, including: halogen, —NH 2 , (C 1 -C 6 alkyl)N—, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—, —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C
  • Alkoxy- refers to the group R—O— where R is an alkyl group, as defined above.
  • Exemplary C 1 -C 6 alkoxy- groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy.
  • An alkoxy group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, C 1 -C 6 alkoxy-, H 2 N—, (C 1 -C 6 alkyl)amino-, di(C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (C 1 -C 6 alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (C 1 -C 6 alkyl)NHC(O)—, di(C 1 -C 6 alkyl)NC(O)—, NC—, C 1 -C 6 alkoxy-, HO 2 C—, (C 1 -C 6 alkoxy)carbonyl-, (C 1 -C 6 alkyl)C(O)—, C 6 -C 14 aryl-, C 1 -C 9 heteroary
  • (Alkoxy)carbonyl- refers to the group alkyl-O—C(O)—.
  • Exemplary (C 1 -C 6 alkoxy)carbonyl-groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy.
  • An (alkoxy)carbonyl group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, H 2 N—, (C 1 -C 6 alkyl)amino-, di(C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (C 1 -C 6 alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (C 1 -C 6 alkyl)NHC(O)—, di(C 1 -C 6 alkyl)NC(O)—, NC—, C 1 -C 6 alkoxy-, HO 2 C—, (C 1 -C 6 alkoxy)carbonyl-, (C 1 -C 6 alkyl)C(O)—, C 6 -C 14 aryl-, C 1 -C 9 heteroaryl-, C 3
  • (Alkyl)amido- refers to a —C(O)NH— group in which the nitrogen atom of said group is attached to a C 1 -C 6 alkyl group, as defined above.
  • Representative examples of a (C 1 -C 6 alkyl)amido-group include, but are not limited to, —C(O)NHCH 3 , —C(O)NHCH 2 CH 3 , —C(O)NHCH 2 CH 2 CH 3 , —C(O)NHCH 2 CH 2 CH 2 CH 3 , —C(O)NHCH 2 CH 2 CH 2 CH 2 CH 3 , —C(O)NHCH(CH 3 ) 2 , —C(O)NHCH 2 CH(CH 3 ) 2 , —C(O)NHCH(CH 3 )CH 2 CH 3 , —C(O)NH—C(CH 3 ) 3 and —C(O)NHCH 2 C(CH 3 ) 3 .
  • (Alkyl)amino- refers to an —NH group, the nitrogen atom of said group being attached to a alkyl group, as defined above.
  • Representative examples of an (C 1 -C 6 alkyl)amino- group include, but are not limited to CH 3 NH—, CH 3 CH 2 NH—, CH 3 CH 2 CH 2 NH—, CH 3 CH 2 CH 2 CH 2 NH—, (CH 3 ) 2 CHNH—, (CH 3 ) 2 CHCH 2 NH—, CH 3 CH 2 CH(CH 3 )NH— and (CH 3 ) 3 CNH—.
  • An (alkyl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N—, (C 1 -C 6 alkyl)amino-, di(C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (C 1 -C 6 alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (C 1 -C 6 alkyl)NHC(O)—, di(C 1 -C 6 alkyl)NC(O)—, NC—, hydroxyl, C 1 -C 6 alkoxy-, C 1 -C 6 alkyl-, HO 2 C—, (C 1 -C 6 alkoxy)carbonyl-, (C 1 -C 6 alkyl)C(O)—, C 6 -C 14 aryl-, C 1
  • Aminoalkyl- refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with —NH 2 ; one or both H of the NH 2 may be replaced by a substituent.
  • Alkylcarboxyl- refers to an alkyl group, defined above that is attached to the parent structure through the oxygen atom of a carboxyl(C(O)—O—) functionality.
  • Examples of (C 1 -C 6 alkyl)carboxyl- include acetoxy, propionoxy, propylcarboxyl, and isopentylcarboxyl.
  • (Alkyl)carboxyamido- refers to a —NHC(O)— group in which the carbonyl carbon atom of said group is attached to a C 1 -C 6 alkyl group, as defined above.
  • Representative examples of a (C 1 -C 6 alkyl)carboxyamido- group include, but are not limited to, —NHC(O)CH 3 , —NHC(O)CH 2 CH 3 , —NHC(O)CH 2 CH 2 CH 3 , —NHC(O)CH 2 CH 2 CH 2 CH 3 , —NHC(O)CH 2 CH 2 CH 2 CH 2 CH 3 , —NHC(O)CH(CH 3 ) 2 , —NHC(O)CH 2 CH(CH 3 ) 2 , —NHC(O)CH(CH 3 )CH 2 CH 3 , —NHC(O)—C(CH 3 ) 3 and —NHC(O)CH 2 C(CH 3 ) 3
  • Alkylene alkenylene
  • alkynylene refers to alkyl, alkenyl and alkynyl groups, as defined above, having two points of attachment within a chemical structure.
  • Examples of C 1 -C 6 alkylene include ethylene, propylene, and dimethylpropylene.
  • examples of C 2 -C 6 alkenylene include ethenylene and propenylene.
  • Examples of C 2 -C 6 alkynylene include ethynylene and propynylene.
  • Aryl refers to an aromatic hydrocarbon group.
  • Examples of a C 6 -C 14 aryl group include, but are not limited to, phenyl, ⁇ -naphthyl, ⁇ -naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenanaphthyl.
  • Examples of a C 6 -C 10 aryl group include, but are not limited to, phenyl, ⁇ -naphthyl, ⁇ -naphthyl, biphenyl, and tetrahydronaphthyl.
  • An aryl group can be unsubstituted or substituted with one or more groups, including: C 1 -C 6 alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C 1 -C 6 alkyl)-, —NH 2 , aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 alkyl), N-alkylamido-, —C(O)NH 2 , (C 1 -C 6 alkyl)amido-, or —NO 2 .
  • groups including: C 1 -C 6 alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C 1 -C 6 alkyl)-, —NH 2 , aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C 1 -C 6
  • (Aryl)alkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with an aryl group as defined above.
  • (C 6 -C 14 Aryl)alkyl-moieties include benzyl, benzhydryl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like.
  • An (aryl)alkyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N—, hydroxyl, (C 1 -C 6 alkyl)amino-, di(C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (C 1 -C 6 alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (C 1 -C 6 alkyl)NHC(O)—, di(C 1 -C 6 alkyl)NC(O)—, NC—, hydroxyl, C 1 -C 6 alkoxy-, C 1 -C 6 alkyl-, HO 2 C—, (C 1 -C 6 alkoxy)carbonyl-, (C 1 -C 6 alkyl)C(O)—, C 6 -C 14 aryl-,
  • (Aryl)amino refers to a radical of formula (aryl)-NH—, wherein aryl is as defined above.
  • (Aryl)oxy refers to the group Ar—O— where Ar is an aryl group, as defined above.
  • Cycloalkyl refers to a non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system.
  • Representative examples of a C 3 -C 12 cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl, octahydro-1H-inden-2-yl, decahydro-1H-benzo[7]annulen-2-yl, and dodecahydros-indacen-4-yl.
  • C 3 -C 10 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl, and octahydro-1H-inden-2-yl.
  • Representative examples of a C 3 -C 8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and octahydropentalen-2-yl.
  • a cycloalkyl can be unsubstituted or substituted with one or more groups, including: halogen, —NH 2 , (C 1 -C 6 alkyl)N—, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—, —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C
  • Cycloalkenyl refers to a non-aromatic, unsaturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system containing at least one double bond connecting two ring carbon atoms.
  • Representative examples of a C 5 -C 8 cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexenyl, 4,4a-octalin-3-yl, and cyclooctenyl.
  • a cycloalkenyl can be unsubstituted or substituted with one or more groups, including: halogen, —NH 2 , (C 1 -C 6 alkyl)N—, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—, —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -
  • Di(alkyl)amino- refers to a nitrogen atom attached to two alkyl groups, as defined above. Each alkyl group can be independently selected. Representative examples of an di(C 1 -C 6 alkyl)amino- group include, but are not limited to, —N(CH 3 ) 2 , —N(CH 2 CH 3 )(CH 3 ), —N(CH 2 CH 3 ) 2 , —N(CH 2 CH 2 CH 3 ) 2 , —N(CH 2 CH 2 CH 2 CH 3 ) 2 , —N(CH(CH 3 ) 2 ) 2 , —N(CH(CH 3 ) 2 )(CH 3 ), —N(CH 2 CH(CH 3 ) 2 ) 2 , —NH(CH(CH 3 )CH 2 CH 3 ) 2 , —N(C(CH 3 ) 3 ) 2 , —N(C(CH 3 ) 3 )(CH 3 ), and —N(CH 3 )
  • the two alkyl groups on the nitrogen atom when taken together with the nitrogen to which they are attached, can form a 3- to 7-membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with —N(H)—, —N(C 1 -C 6 alkyl)-, —N(C 3 -C 8 cycloalkyl)-, —N(C 6 -C 14 aryl)-, —N(C 1 -C 9 heteroaryl)-, —N(amino(C 1 -C 6 alkyl))-, —N(C 6 -C 14 arylamino)-, —O—, —S—, —S(O)—, or —S(O) 2 —.
  • Halo or “halogen” refers to —F, —Cl, —Br and —I.
  • C 1 -C 6 Haloalkyl- refers to a C 1 -C 6 alkyl group, as defined above, wherein one or more of the C 1 -C 6 alkyl group's hydrogen atoms has been replaced with —F, —Cl, —Br, or —I. Each substitution can be independently selected from —F, —Cl, —Br, or —I.
  • C 1 -C 6 haloalkyl-group include, but are not limited to, —CH 2 F, —CCl 3 , —CF 3 , CH 2 CF 3 , —CH 2 Cl, —CH 2 CH 2 Br, —CH 2 CH 21 , —CH 2 CH 2 CH 2 F, —CH 2 CH 2 CH 2 Cl, —CH 2 CH 2 CH 2 CH 2 Br, —CH 2 CH 2 CH 2 CH 2 I, —CH 2 CH 2 CH 2 CH 2 CH 2 Br, —CH 2 CH 2 CH 2 CH 2 CH 21 , —CH 2 CH(Br)CH 3 , —CH 2 CH(Cl)CH 2 CH 3 , —CH(F)CH 2 CH 3 and —C(CH 3 ) 2 (CH 2 Cl).
  • Heteroaryl refers to a monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one ring atom selected from the heteroatoms oxygen, sulfur and nitrogen.
  • Examples of C 1 -C 9 heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, in
  • Bicyclic C 1 -C 9 heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heteroaryl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom.
  • monocyclic C 1 -C 4 heteroaryl groups include 2H-tetrazole, 3H-1,2,4-triazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, imidazole, and pyrrole.
  • a heteroaryl group can be unsubstituted or substituted with one or more groups, including: C 1 -C 6 alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C 1 -C 6 alkyl)-, —NH 2 , aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 alkyl), N-alkylamido-, —C(O)NH 2 , (C 1 -C 6 alkyl)amido-, or —NO 2 .
  • groups including: C 1 -C 6 alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C 1 -C 6 alkyl)-, —NH 2 , aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C 1 -C 6
  • (Heteroaryl)alkyl- refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a heteroaryl- group as defined above.
  • Examples of (C 1 -C 9 heteroaryl)alkyl- moieties include 2-pyridylmethyl, 2-thiophenylethyl, 3-pyridylpropyl, 2-quinolinylmethyl, 2-indolylmethyl, and the like.
  • a (heteroaryl)alkyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N—, hydroxyl, (C 1 -C 6 alkyl)amino-, di(C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (C 1 -C 6 alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (C 1 -C 6 alkyl)NHC(O)—, di(C 1 -C 6 alkyl)NC(O)—, NC—, hydroxyl, C 1 -C 6 alkoxy-, C 1 -C 6 alkyl-, HO 2 C—, (C 1 -C 6 alkoxy)carbonyl-, (C 1 -C 6 alkyl)C(O)—, C 6 -C 14 ary
  • heteroatom refers to a sulfur, nitrogen, or oxygen atom.
  • Heterocycle refers to monocyclic, bicyclic and polycyclic groups in which at least one ring atom is a heteroatom.
  • a heterocycle may be saturated or partially saturated.
  • Exemplary C 1 -C 9 heterocyclyl- groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran, thiane, thiine, piperazine, oxazine, 5,6-dihydro-4H-1,3-oxazin-2-yl, 2,5-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octan
  • C 1 heterocyclyl- radicals would include but are not limited to oxaziranyl, diaziridinyl, and diazirinyl
  • C 2 heterocyclyl- radicals include but are not limited to aziridinyl, oxiranyl, and diazetidinyl
  • C 9 heterocyclyl- radicals include but are not limited to azecanyl, tetrahydroquinolinyl, and perhydroisoquinolinyl.
  • a heterocyclyl group can be unsubstituted or substituted with one or more groups, including: C 1 -C 6 alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C 1 -C 6 alkyl)-, —NH 2 , aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 alkyl), N-alkylamido-, —C(O)NH 2 , (C 1 -C 6 alkyl)amido-, or —NO 2 .
  • groups including: C 1 -C 6 alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C 1 -C 6 alkyl)-, —NH 2 , aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C 1 -C
  • Heterocyclyl(alkyl)- refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a heterocycle group as defined above.
  • Heterocyclyl(C 1 -C 6 alkyl)- moieties include 2-pyridylmethyl, 1-piperazinylethyl, 4-morpholinylpropyl, 6-piperazinylhexyl, and the like.
  • a heterocyclyl(alkyl) group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N—, (C 1 -C 6 alkyl)amino-, di(C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (C 1 -C 6 alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (C 1 -C 6 alkyl)NHC(O)—, di(C 1 -C 6 alkyl)NC(O)—, NC—, hydroxyl, C 1 -C 6 alkoxy-, C 1 -C 6 alkyl-, HO 2 C—, (C 1 -C 6 alkoxy)carbonyl-, (C 1 -C 6 alkyl)C(O)—, 4- to 7-membered monocyclic heterocycle,
  • “Hydroxylalkyl-” refers to a alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with hydroxyl groups.
  • Examples of C 1 -C 6 hydroxylalkyl-moieties include, for example, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH(OH)CH 2 OH, —CH 2 CH(OH)CH 3 , —CH(CH 3 )CH 2 OH and higher homologs.
  • Perfluoroalkyl- refers to alkyl group, defined above, having two or more fluorine atoms. Examples of a C 1 -C 6 perfluoroalkyl- group include CF 3 , CH 2 CF 3 , CF 2 CF 3 and CH(CF 3 ) 2 .
  • a “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or gorilla.
  • optionally substituted means that at least one hydrogen atom of the optionally substituted group has been substituted with halogen, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(
  • salts include but are not limited to, e.g., water-soluble and water-insoluble salts, such as the acetate, aluminum, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzathine (N,N′-dibenzylethylenediamine), benzenesulfonate, benzoate, bicarbonate, bismuth, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate (camphorsulfonate), carbonate, chloride, choline, citrate, clavulariate, diethanolamine, dihydrochloride, diphosphate, edetate, edisylate (camphorsulfonate), esylate (ethanesulfonate), ethylenediamine, fumarate, gluceptate (glucoheptonate), gluconate, glucuronate, glutamate,
  • an “effective amount” when used in connection with a compound of this invention is an amount effective for inhibiting mTOR or PI3K in a subject.
  • Some compounds within the present invention possess one or more chiral centers, and the present invention includes each separate enantiomer of such compounds as well as mixtures of the enantiomers. Where multiple chiral centers exist in compounds of the present invention, the invention includes each combination as well as mixtures thereof. All chiral, diastereomeric, and racemic forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials.
  • the compounds of the present invention exhibit an mTOR inhibitory activity and therefore, can be utilized in order to inhibit abnormal cell growth in which mTOR plays a role.
  • the compounds of the present invention are effective in the treatment of disorders with which abnormal cell growth actions of mTOR are associated, such as restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, cancer, etc.
  • the compounds of the present invention possess excellent cancer cell growth inhibiting effects and are effective in treating cancers, preferably all types of solid cancers and malignant lymphomas, and especially, leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumor, advanced renal cell carcinoma, acute lymphoblastic leukemia, malignant melanoma, soft-tissue or bone sarcoma, etc.
  • the compounds of the present invention exhibit a PI3 kinase inhibitory activity and, therefore, can be utilized in order to inhibit abnormal cell growth in which PI3 kinases play a role.
  • the compounds of the present invention are effective in the treatment of disorders with which abnormal cell growth actions of PI3 kinases are associated, such as restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, cancer, etc.
  • the compounds of the present invention possess excellent cancer cell growth inhibiting effects and are effective in treating cancers, preferably all types of solid cancers and malignant lymphomas, and especially, leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumor, advanced renal cell carcinoma, acute lymphoblastic leukemia, malignant melanoma, soft-tissue or bone sarcoma, etc.
  • the pharmacologically active compounds of Formula I will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in association with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjutants and excipients employing standard and conventional techniques.
  • compositions of this invention include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous) bronchial or nasal administration.
  • parenteral including subcutaneous, intramuscular, intradermal and intravenous
  • nasal administration if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge.
  • the solid carrier may contain conventional excipients such as binding agents, fillers, tableting lubricants, disintegrants, wetting agents and the like.
  • the tablet may, if desired, be film coated by conventional techniques.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile vehicle for injection, an aqueous or non-aqueous liquid suspension, or may be a dry product for reconstitution with water or other suitable vehicle before use.
  • Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicle (including edible oils), preservatives, as well as flavoring and/or coloring agents.
  • a vehicle normally will comprise sterile water, at least in large part, although saline solutions, glucose solutions and like may be utilized. Injectable suspensions also may be used, in which case conventional suspending agents may be employed.
  • compositions are prepared by conventional techniques appropriate to the desired preparation containing appropriate amounts of the active ingredient, that is, the compound of Formula I according to the invention. See, for example, Remington: The Science and Practice of Pharmacy, 20th Edition. Baltimore, Md.: Lippincott Williams & Wilkins, 2000.
  • the dosage of the compounds of Formula I to achieve a therapeutic effect will depend not only on such factors as the age, weight and sex of the patient and mode of administration, but also on the degree of potassium channel activating activity desired and the potency of the particular compound being utilized for the particular disorder of disease concerned. It is also contemplated that the treatment and dosage of the particular compound may be administered in unit dosage form and that one skilled in the art would adjust the unit dosage form accordingly to reflect the relative level of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per day is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect.
  • a suitable dose of a compound of Formula I or pharmaceutical composition thereof for a mammal, including man, suffering from, or likely to suffer from any condition as described herein is an amount of active ingredient from about 0.01 mg/kg to 10 mg/kg body weight.
  • the dose may be in the range of 0.1 mg/kg to 1 mg/kg body weight for intravenous administration.
  • the dose may be in the range about 0.1 mg/kg to 5 mg/kg body weight.
  • the active ingredient will preferably be administered in equal doses from one to four times a day. However, usually a small dosage is administered, and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.
  • the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound of be administered, the chosen route of administration, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.
  • the amount of the compound of the present invention or a pharmaceutically acceptable salt thereof that is effective for inhibiting mTOR or PI3K in a subject can optionally be employed to help identify optimal dosage ranges.
  • the precise dose to be employed can also depend on the route of administration, the condition, the seriousness of the condition being treated, as well as various physical factors related to the individual being treated, and can be decided according to the judgment of a health-care practitioner.
  • Equivalent dosages may be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months.
  • the number and frequency of dosages corresponding to a completed course of therapy will be determined according to the judgment of a health-care practitioner.
  • the effective dosage amounts described herein refer to total amounts administered; that is, if more than one compound of the present invention or a pharmaceutically acceptable salt thereof is administered, the effective dosage amounts correspond to the total amount administered.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is administered concurrently with another therapeutic agent.
  • composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and an effective amount of another therapeutic agent within the same composition can be administered.
  • Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective amount range.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof and the other therapeutic agent can act additively or, in one embodiment, synergistically.
  • the effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof is less than its effective amount would be where the other therapeutic agent is not administered.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof and the other therapeutic agent act synergistically.
  • Schemes 1-3 can be adapted to produce the other compounds of Formula I and pharmaceutically acceptable salts of compounds of Formula I according to the present invention.
  • ACN is acetonitrile
  • AcOH is acetic acid
  • ATP is adenosine triphosphate
  • CHAPS is 3-[(3-cholamidopropyl)dimethylammonio]-propanesulfonic acid
  • DEAD is diethyl azodicarboxylate
  • DIAD is diisopropyl azodicarboxylate
  • DMAP is dimethyl aminopyridine
  • DMF N,N-dimethylformamide
  • DMF-DMA is dimethylformamide dimethyl acetal
  • DMSO is dimethylsulfoxide.
  • DowthermTM is a eutectic mixture of biphenyl(C 12 H 10 ) and diphenyl oxide (C 12 H 10 O).
  • DowthermTM is a registered trademark of Dow Corning Corporation.
  • DPBS is Dulbecco's Phosphate Buffered Saline Formulation
  • EDTA is ethylenediaminetetraacetic acid
  • ESI stands for Electrospray Ionization
  • EtOAc is ethyl acetate
  • EtOH is ethanol
  • HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
  • GMF Glass
  • Hunig's Base is diisopropylethylamine
  • HPLC high pressure liquid chromatography
  • LPS is lipopolysaccharide
  • MeCN is acetonitrile
  • MeOH is methanol
  • MS mass spectrometry
  • NEt 3 triethylamine
  • NMR nuclear magnetic resonance
  • PBS
  • SDS is dodecyl sulfate (sodium salt)
  • SRB is Sulforhodamine B
  • TBSCl is tert-butyldimethylsilyl chloride
  • TCA is tricholoroacetic acid
  • TFA is trifluoroacetic acid
  • THF is tetrahydrofuran
  • TLC thin-layer chromatography
  • TRIS is tris(hydroxymethyl)aminomethane.
  • Step 3 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
  • Step 2 Preparation of tert-butyl 3-(4-chloro-6-morpholine-1,3,5-triazin-2-2-ylamino)azetidine-1-carboxylate
  • Step 3 Preparation of tert-butyl-3-4-(4-(4-aminophenyl)-6-morpholine-1,3,5-triazin-2-ylamino)azetidine-1-carboxylate
  • Step 4 Preparation of tert-butyl 3- ⁇ [4-(4- ⁇ [(4-fluorophenyl)carbamoyl]amino ⁇ phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino ⁇ azetidine-1-carboxylate
  • the titled compound was prepared by starting from tert-butyl 3- ⁇ [4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino ⁇ azetidine-1-carboxylate (140 mg, 0.32 mmol) phenylisocyanate (58 mg, 0.49 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; Yield 40 mg (31%); (M+H) 547.6
  • the titled compound was prepared by starting from tert-butyl 3- ⁇ [4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino ⁇ azetidine-1-carboxylate (140 mg, 0.32 mmol) 3-pyridylisocyanate (70 mg, 0.58 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; Yield 40 mg (23%); (M+H) 548.7.
  • the titled compound was prepared by starting from tert-butyl 3- ⁇ [4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino ⁇ azetidine-1-carboxylate (130 mg, 0.27 mmol) 4-tolyl isocyanate (40 mg, 0.30 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; Yield 85 mg (47%); (M+H) 561.6.
  • Step 1 Preparation of 3-(4-chloro-6-morpholin-4-yl-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 2 Preparation of 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline
  • Step 3 Preparation of 1- ⁇ 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl ⁇ -3-phenylurea
  • the titled compound was prepared by starting from 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline (120 mg, 0.32 mmol) phenylisocyanate (80 mg, 0.67 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; mp: 242; Yield 35 mg (28%); (M+H) 488.56
  • the titled compound was prepared by starting from 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline (100 mg, 0.27 mmol)-4-fluoro phenylisocyanate (50 mg, 0.36 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; mp: 248; Yield 86 mg (86%); (M+H) 506.4.
  • the titled compound was prepared by starting from 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline (100 mg, 0.27 mmol)-4-tolylisocyanate (60 mg, 0.45 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; mp: 228; Yield 80 mg (80%); (M+H) 502.4
  • Step 2 Synthesis of 8-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3,2,1]octane
  • Step 3 Synthesis of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline
  • step 3 the following compounds were prepared.
  • Step 1 To a stirred solution of NaH (50% 460 mg) in dry THF tetrahydro-2H-pyran-4-ol (1.02 g, 10 mmol) was slowly added at room temperature. The reaction mixture was stirred at room temperature for 30 min and 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (2.35 g, 10 mmol) in THF (50 ml) was slowly added. The reaction mixture was stirred at room temperature for 48 hours and slowly quenched with ice-cold water. It was extracted with CHCl 3 ; washed well with water and dried over anhydrous MgSO 4 .
  • Step 2 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline was prepared by the procedure as described in example 1, step 2. Starting from 2-chloro-4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazine (1.5 g, 4.9 mmol) 980 mg (56% yield) of the product was isolated after purification using Silica gel column chromatography by eluting it with ethyl acetate. Mp. 188° C.; MS (ESI) m/z 358.2.
  • Step 3 1- ⁇ 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl ⁇ -3-pyridin-4-ylurea was prepared by the procedure as described in example 1, step 3. Starting from 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline (212 mg. 0.59 mmol) 190 mg (Yield, 67%) of the final product was isolated as a white solid. mp 238° C.; MS (ESI) m/z 478.3.
  • Step 2 Preparation of 4- ⁇ 4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl ⁇ aniline
  • Step 3 Preparation of 1-(4- ⁇ 4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl ⁇ phenyl)-3-pyridin-4-ylurea
  • Step 1 To a stirred solution of isopropanol (250 mg, 4.1 mmol) in dry THF (50 ml) at ⁇ 78° C., n-butyllithium (2.6 ml, 1.6 mol solution) was slowly added. The reaction mixture was stirred for 30 minutes and a solution of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (1.00 g, 4.25 mmol) in THF was added to the solution. The reaction mixture was stirred at room temperature for 24 hours and quenched with water and extracted with DCM. The crude product obtained was taken to next step without purification.
  • Step 2 A mixture of (crude) 4-(chloro-6-isopropoxyl-1,2,3-triazin-2-yl)morpholine of (2.91 g, 11.27 mmol) 4-amino-phenylboronic acid pinacol ester (3.59 g, 16.4 mmoles), tetrakis palladium triphenylphosphine (120 mg catalytic amount) and sodium carbonate solution (2M, 2 mL) was refluxed in DME (100 mL) for 24 hours. The solvent was removed and the residue was re-dissolved in methylene chloride and filtered through CeliteTM.
  • Step 2 Preparation of 4-[4-(3,6-Dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine
  • Step 3 Preparation of 1- ⁇ 4-[4-(3,6-Dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl ⁇ -3-pyridin-4-yl-urea
  • Step 1 Preparation of 3-(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane
  • tropine (1 g, 4.24 mmol) was suspended in (anhydrous) THF (15 mL). The mixture was cooled to ⁇ 78° C. and BuLi (2M in THF) (5.53 ml, 1.2 eq) was added dropwise and the mixture was allowed to warm to 25° C. over 30 minutes.
  • BuLi (2M in THF) 5.53 ml, 1.2 eq
  • ether 100 mL
  • Step 2 Preparation of 4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine
  • Step 3 Preparation of 1- ⁇ 4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl ⁇ -3-pyridin-4-yl-urea
  • Step 1 Preparation of 3-[(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino)-methyl]-azetidine-1-carboxylic acid tert-butyl ester
  • silica gel (20 g) was added to the reaction mixture and the solvent was removed so that product was adsorbed on the silica gel.
  • the silica gel plug was placed on top of a column to purify by flash chromatography using CH 2 Cl 2 /MeOH/NH3 (20:1:01) eluent. After unifying the product fraction, and evaporation of solvent, (750 mg, 46% yield) product was obtained as yellow solid; MS (ESI) m/z 385
  • Step 2 Preparation of 3- ⁇ [4-(4-Amino-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino]-methyl ⁇ -azetidine-1-carboxylic acid tert-butyl ester
  • Step 3 Preparation of 3-( ⁇ 4-Morpholin-4-yl-6-[4-(3-pyridin-4-yl-ureido)-phenyl]-[1,3,5]triazin-2-ylamino ⁇ -methyl)-azetidine-1-carboxylic acid tert-butyl ester
  • Step 1 Preparation of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate
  • Step 2 Preparation of tert-butyl 4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate
  • Step 3 Preparation of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate
  • Step 2 Preparation of 1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperidin-4-one
  • Step 3 Preparation of 1-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperidin-4-one
  • Step 4 Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • the titled compound was prepared by the procedure as outlined in example 118, by reacting 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) with N,N-dimethylethylenediamine (0.026 mL) and purified by HPLC and isolated as its tri-TFA salt; MS (ES+) 573.7 (M+H)+.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Vascular Medicine (AREA)
  • Dermatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pain & Pain Management (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Compounds of formula I
Figure US20090304692A1-20091210-C00001
    • wherein:
    • R1 is
Figure US20090304692A1-20091210-C00002
and R2, R4, and R6-9 are defined herein, and pharmaceutically acceptable salts and esters thereof. These compounds inhibit PI3 kinase and mTOR, and may be used to treat diseases mediated by PI3 kinase and mTOR, such as a variety of cancers. Methods for making and using the compounds of this invention are disclosed. Various compositions containing the compounds of this invention are also disclosed.

Description

    FIELD OF THE INVENTION
  • This invention relates to 2,4,6-substituted [1,3,5]triazine compounds in which one substituent is an optionally substituted morpholino, tetrahydropyranyl or dihydropyranyl group, which inhibit PI3 kinase and mTOR, to processes for preparing them, to methods of treatment using them and to pharmaceutical compositions containing them.
    • BACKGROUND OF THE INVENTION
  • Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of the phospholipids in cell membranes. In recent years it has become clear that PI plays an important role also in intracellular signal transduction. It is well recognized in the art that PI (4,5) bisphosphate (PI(4,5)P2 or PIP2) is degraded into diacylglycerol and inositol (1,4,5) triphosphate by phospholipase C to induce activation of protein kinase C and intracellular calcium mobilization, respectively [M. J. Berridge et al., Nature, 312, 315 (1984); Y. Nishizuka, Science, 225, 1365 (1984)].
  • Phosphatidylinositol-3 kinase (“PI3K”) is an enzyme that phosphorylates the 3-position of the inositol ring of phosphatidylinositol [D. Whitman et al., Nature, 332, 664 (1988)]. Pluralities of PI3K subtypes exist. Three major subtypes of PI3Ks have now been identified on the basis of their in vitro substrate specificity, and these three are designated class I (a & b), class 11, and class III [B. Vanhaesebroeck, Trend in Biol. Sci., 22, 267 (1997)].
  • The class Ia PI3K subtype has been most extensively investigated to date. Within the class Ia subtype there are three isoforms (a, b, & d) that exist as hetero dimers of a catalytic 110-kDa subunit and regulatory subunits of 50-85 kDa. The regulatory subunits contain SH2 domains that bind to phosphorylated tyrosine residues within growth factor receptors or adaptor molecules and thereby localize PI3K to the inner cell membrane. At the inner cell membrane PI3K converts PIP2 to PIP3 (phosphatidylinositol-3,4,5-trisphosphate) that serves to localize the downstream effectors PDK1 and Akt to the inner cell membrane where Akt activation occurs. Activated Akt mediates a diverse array of effects including inhibition of apoptosis, cell cycle progression, response to insulin signaling, and cell proliferation. Class Ia PI3K subtypes also contain Ras binding domains (RBD) that allow association with activated Ras providing another mechanism for PI3K membrane localization. Activated, oncogenic forms of growth factor receptors, Ras, and even PI3K kinase have been shown to aberrantly elevate signaling in the PI3K/Akt/mTOR pathway resulting in cell transformation. As a central component of the PI3K/Akt/mTOR signaling pathway PI3K (particularly the class Ia a isoform) has become a major therapeutic target in cancer drug discovery.
  • Substrates for class I PI3Ks are PI, PI(4)P and PI(4,5)P2, with PI(4,5)P2 being the most favored. Class I PI3Ks are further divided into two groups, class Ia and class Ib, because of their activation mechanism and associated regulatory subunits. The class Ib PI3K is p110γ that is activated by interaction with G protein-coupled receptors. Interaction between p110γ and G protein-coupled receptors is mediated by regulatory subunits of 110, 87, and 84 kDa.
  • PI and PI(4)P are the known substrates for class II PI3Ks; PI(4,5)P2 is not a substrate for the enzymes of this class. Class II PI3Ks include PI3K C2α, C2β and C2γ isoforms, which contain C2 domains at the C terminus, implying that their activity is regulated by calcium ions.
  • The substrate for class III PI3Ks is PI only. A mechanism for activation of the class III PI3Ks has not been clarified. Because each subtype has its own mechanism for regulating activity, it is likely that activation mechanism(s) depend on stimuli specific to each respective class of PI3K.
  • The compound PI103 (3-(4-(4-morpholinyl)pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)phenol) inhibits PI3Kα and PI3Kg as well as the mTOR enzymes with IC50 values of 2, 3, and 50-80 nM respectively. I.P. dosing in mice of this compound in human tumor xenograft models of cancer demonstrated activity against a number of human tumor models, including the glioblastoma (PTEN null U87MG), prostate (PC3), breast (MDA-MB-468 and MDA-MB-435) colon carcinoma (HCT 116); and ovarian carcinoma (SKOV3 and IGROV-1); (Raynaud et al, Pharmacologic Characterization of a Potent Inhibitor of Class I Phosphatidylinositide 3-Kinases, Cancer Res. 2007 67: 5840-5850).
  • The compound ZSTK474 (2-(2-difluoromethylbenzoimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine) inhibits PI3Kα and PI3Kg but not the mTOR enzymes with an IC50 values of 16, 4.6 and >10,000 nM respectively (Dexin Kong and Takao Yamori, ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms, Cancer Science, 2007, 98:10 1638-1642). Chronic oral administration of ZSTK474 in mouse human xenograft cancer models, completely inhibited growth which originated from a non-small-cell lung cancer (A549), a prostate cancer (PC-3), and a colon cancer (WiDr) at a dose of 400 mg/kg. (Yaguchi et al, Antitumor Activity of ZSTK474, a New Phosphatidylinositol 3-Kinase Inhibitor, J. Natl. Cancer Inst. 98: 545-556).
  • The compound NVP-BEZ-235 (2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)propanenitrile) inhibits both PI3Kα and PI3Kg as well as the mTOR enzymes with IC50 values 4, 5, and “nanomolar”. Testing in human tumor xenograft models of cancer demonstrated activity against human tumor models of prostrate (PC-3) and glioblastoma (U-87) cancer. It entered clinical trials in December of 2006 (Verheijen, J. C. and Zask, A., Phosphatidylinositol 3-kinase (PI3K) inhibitors as anticancer drugs, Drugs Fut. 2007, 32(6): 537-547).
  • The compound SF-1126 (a prodrug form of LY-294002, which is 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) is “a pan-PI3K inhibitor”. It is active in preclinical mouse cancer models of prostrate, breast, ovarian, lung, multiple myeloma, and brain cancers. (Verheijen, J. C. and Zask, A., Phosphatidylinositol 3-kinase (PI3K) inhibitors as anticancer drugs, Drugs Fut. 2007, 32(6): 537-547).
  • Although it seems clear that inhibition of the a isoform is essential for the antitumor activity of PI3K inhibitors, it is not clear whether a more selective inhibitor of a particular PI3K isoform may lead to fewer unwanted biological effects. It has recently been reported that non-PI3Kα class I isoforms (PI3Kβ, δ and γ) have the ability to induce oncogenic transformation of cells, suggesting that nonisoform-specific inhibitors may offer enhanced therapeutic potential over specific inhibitors.
  • Selectivity versus other related kinases is also an important consideration for the development of PI3K inhibitors. While selective inhibitors may be preferred in order to avoid unwanted side effects, there have been reports that inhibition of multiple targets in the PI3K/Akt pathway (e.g., PI3Kα and mTOR [mammalian target of rapamycin]) may lead to greater efficacy. It is possible that lipid kinase inhibitors may parallel protein kinase inhibitors in that nonselective inhibitors may also be brought forward to the clinic.
  • Mammalian Target of Rapamycin, mTOR, is a cell-signaling protein that regulates the response of tumor cells to nutrients and growth factors, as well as controlling tumor blood supply through effects on Vascular Endothelial Growth Factor, VEGF. Inhibitors of mTOR starve cancer cells and shrink tumors by inhibiting the effect of mTOR. All mTOR inhibitors bind to the mTOR kinase. This has at least two important effects. First, mTOR is a downstream mediator of the PI3K/Akt pathway. The PI3K/Akt pathway is thought to be over activated in numerous cancers and may account for the widespread response from various cancers to mTOR inhibitors. The over-activation of the upstream pathway would normally cause mTOR kinase to be over activated as well. However, in the presence of mTOR inhibitors, this process is blocked. The blocking effect prevents mTOR from signaling to downstream pathways that control cell growth. Over-activation of the PI3K/Akt kinase pathway is frequently associated with mutations in the PTEN gene, which is common in many cancers and may help predict what tumors will respond to mTOR inhibitors. The second major effect of mTOR inhibition is anti-angiogenesis, via the lowering of VEGF levels.
  • In lab tests, certain chemotherapy agents were found to be more effective in the presence of mTOR inhibitors. George, J. N., et al., Cancer Research, 61, 1527-1532, 2001. Additional lab results have shown that some rhabdomyosarcoma cells die in the presence of mTOR inhibitors.
  • There are three mTOR inhibitors, which have progressed into clinical trials. These compounds are Wyeth's Torisel, also known as 42-(3-hydroxy-2-(hydroxymethyl)-rapamycin 2-methylpropanoate, CCI-779 or Temsirolimus; Novartis' Everolimus, also known as 42-O-(2-hydroxyethyl)-rapamycin, or RAD 001; and Ariad's AP23573 also known as 42-(dimethylphopsinoyl)-rapamycin. The FDA has approved Torisel for the treatment of advanced renal cell carcinoma. In addition, Torisel is active in a NOS/SCID xenograft mouse model of acute lymphoblastic leukemia [Teachey et al, Blood, 107(3), 1149-1155, 2006]. On Mar. 30, 2009, the U.S. Food and Drug Administration (FDA) approved Everolimus (AFINITOR™) for the treatment of patients with advanced renal cell carcinoma. AP23573 has been given orphan drug and fast-track status by the FDA for treatment of soft-tissue and bone sarcomas.
  • The three mTOR inhibitors have non-linear, although reproducible pharmacokinetic profiles. Mean area under the curve (AUC) values for these drugs increase at a less than dose related way. The three compounds are all semi-synthetic derivatives of the natural macrolide antibiotic rapamycin. It would be desirable to find fully synthetic compounds, which inhibit mTOR that are more potent and exhibit improved pharmacokinetic behaviors.
    • SUMMARY OF THE INVENTION
  • This invention provides compounds of formula I
  • Figure US20090304692A1-20091210-C00003
  • wherein:
  • R1 is
  • Figure US20090304692A1-20091210-C00004
  • and R2, R4, and R6-9 are defined below, and pharmaceutically acceptable salts and esters thereof. These compounds are useful as inhibitors of mTOR and PI3 kinases.
  • This invention further provides compositions containing one or more of the aforementioned compounds, which compositions may contain a pharmaceutically acceptable carrier.
  • The present invention provides methods for making the compounds of the invention, as described below. Methods of using the invention are also provided, for example: a method for inhibiting mTOR, a method for inhibiting a PI3 kinase, and methods for treating various forms of cancer.
    • DETAILED DESCRIPTION OF THE INVENTION
  • In one aspect, the present invention provides compounds of formula I
  • Figure US20090304692A1-20091210-C00005
  • wherein:
  • R1 is
  • Figure US20090304692A1-20091210-C00006
  • wherein:
  • R6, R7, R8, R9 are each independently selected from the group consisting of a hydrogen atom, and a C1-C6alkyl optionally substituted with C2-C6alkenyl, C4-C6alkadienyl, C2-C6alkynyl or C4-C6alkadiynyl;
  • and one of R6 and R9, R6 and R8, or R7 and R8 are attached by a (CH2)y, (CH2—X—), or (CH2—X—CH2) linking group wherein one or two hydrogen atoms in the linking group may be independently replaced by C1-C6alkyl, (C1-C6alkyl)NH—, (C1-C6alkyl)2N—, (C6-C14aryl)alkyl-O—, halo, 3-10 membered C1-C9heterocyclyl optionally substituted with C1-C6alkyl-, HO—, or H2N—;
  • wherein any two hydrogen atoms on the same carbon atom of the linking group can be replaced by an oxygen atom to form an oxo (═O) substituent,
  • y is 1, 2 or 3;
  • X is O, S(O)n, or NR10;
  • n is 0, 1 or 2;
  • the dashed line ----- represents an optional second bond;
  • R10 is selected from the group consisting of H, C1-C6alkyl, —SO2(C1-C6alkyl), —COO(C1-C6alkyl), —CONH(C1-C6alkyl), —CON(C1-C6alkyl)2, —CO(C1-C6alkyl), and —SO2NHR11;
  • R11 is selected from the group consisting of H, C1-C6alkyl optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl, —CO(C1-C6alkyl), optionally substituted C6-C10aryl, and optionally substituted C1-C9heteroaryl;
  • R2 is optionally substituted C6-C14aryl-NH—COR3, optionally substituted C1-C9heteroaryl-NH—COR3, —CH═CH—C6-C10aryl-NH—COR3 or —CH═CH—C1-C9heteroaryl-NH—COR3;
  • R3 is OR5, NR5R5 or NHR5;
  • R5 is independently selected from the group consisting of C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, optionally substituted C6-C10aryl, C1-C6haloalkyl, optionally substituted C1-C9heteroaryl, C1-C6hydroxylalkyl-, C3-C10saturated or unsaturated mono or bicyclic C3-C10cycloalkyl optionally substituted with OH, NR11R11 or 3-7 membered C1-C6heterocyclyl, and 3-10 membered saturated or unsaturated mono or bicyclic C1-C9heterocyclyl, with the proviso that three-membered cycloalkyl and heterocyclyl rings are saturated;
  • or two R5 groups taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with C1-C6alkyl, which ring system is saturated or unsaturated and has, in addition to said nitrogen atom, 0 to 2 heteroatom ring members selected from O, S, S(O), S(O)2 and NR10;
  • R4 is selected from the group consisting of: a) C1-C6alkyl optionally substituted with: i) 3-10 membered C1-C9heterocyclyl optionally substituted with C1-C6alkyl-, ii) H2N—, iii) (C1-C6alkyl)NH—, iv) (C1-C6alkyl)2N—, v) NH(CH2)aN(C1-C6alkyl)2 wherein a is 2, 3 or 4, and yl) CHO, b) C3-C6alkenyl, c) C3-C6alkynyl, d) —O—C1-C8alkyl optionally substituted with —O—C1-C8alkyl, e) —O—C3-C8alkenyl, f) —O—C3-C8alkynyl, g) saturated or unsaturated mono or bicyclic C3-C8cycloalkyl, and h) saturated or unsaturated mono or bicyclic —O—C3-C12cycloalkyl, all the above optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl optionally substituted with C1-C6alkyl-, provided that an OH or NR11R11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom; i) —CH═CH—C6-C10aryl; j) —CH═CH—C1-C9heteroaryl; k) optionally substituted C6-C10aryl; l) optionally substituted 5-10 membered C1-C9heteroaryl attached to the triazine moiety via a carbon atom; m) 3-10 membered saturated or unsaturated mono or bicyclic C1-C9heterocyclyl attached to the triazine moiety through a carbon or nitrogen atom and optionally substituted with from 1 to 3 substituents independently selected from: OH, NR11R11, C1-C6alkyl, (C1-C6alkyl)amido-, (C1-C6alkyl)C(O)—, (C1-C6alkoxy)carbonyl-, adamantyl, C1-C6hydroxylalkyl-, or a 3-7 membered C1-C6heterocyclyl, with the proviso that 3 membered heterocyclyl is saturated and attached to the triazine moiety through a nitrogen atom, and 5 membered bicyclic heterocyclyl is saturated; n) optionally substituted —O—C6-C10aryl; o) optionally substituted —O—C1-C9heteroaryl; p) —O-(3-12 membered saturated or unsaturated mono or bicyclic)C1-C9heterocyclyl optionally substituted with (C1-C6alkoxy)carbonyl-, H2NS(O)2—, or C1-C6alkyl further optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl, with the proviso that three membered heterocyclyl is saturated; q) —NHC6-C10aryl, r) —NHC1-C9heteroaryl, s) —NHNH2, t) —NHNHC1-C6alkyl, u) —NHN(C1-C6alkyl)2, v) —NHOH, w) —COOH, x) —COO—C1-C6alkyl, y) —CONR12R13, z) —NR12R13,
  • wherein Z is CH2, O, S(O), or NR10;
    ee) halogen, ff) C6-C14aryl-S(O)2—NH—, gg) R11NHC(O)NH—O—, and hh) optionally substituted 5-membered monocyclic C1-C4heteroaryl attached to the triazine moiety via a nitrogen atom;
  • R12 and R13 are each independently selected from H, optionally mono or disubstituted C1-C8alkyl, optionally substituted C3-C8alkenyl, and optionally substituted C3-C8alkynyl, the optional substituents being selected from C1-C6alkoxy, OH, NR11R11, and 3-7 membered C1-C6heterocyclyl, provided that an OH or NR11R11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom;
  • or R12 and R13 taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with C1-C6alkyl, which ring system is saturated or
  • Figure US20090304692A1-20091210-C00007
  • unsaturated and has, in addition to said nitrogen atom, 0 to 2 heteroatom ring members selected from O, S(O)n and NR10;
  • or R12 and R13 taken together with the nitrogen atom to which they are attached form
  • Figure US20090304692A1-20091210-C00008
      • wherein a and b are each independently —CH2—, O, S, or NR10, and x is 1-3;
  • C1-C9heteroaryl refers to a 5-10 membered aromatic ring system having one or more rings and 1, 2, 3 or 4 ring members independently selected from O, NR10, and S(O)n;
  • C1-C9heterocyclyl refers to a 3-10 membered ring system having one or more rings and 1, 2, 3 or 4 ring members independently selected from O, NR10, and S(O)n; and
  • optionally substituted aryl and heteroaryl groups are unsubstituted or are substituted with 1 or 2 moieties selected from the group consisting of: a) C1-C6alkyl optionally substituted with OH, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, —NH(CH2)wN(C1-C6alkyl)2 wherein w is 2, 3 or 4, or 3-10 membered C1-C9heterocyclyl optionally substituted with from 1 to 3 independently selected C1-C6alkyl- substituents; b) halogen; c) hydroxy; d) NH2; e) NO2; f) SO2NH2; g) COOH; h) COO(C1-C6alkyl); i) NHCOO(C1-C6alkyl); j) NH(C1-C6alkyl); k) N(C1-C6alkyl)2; I) C(O)NRaRb, wherein Ra is H or C1-C6alkyl, and Rb is H, C1-C6alkyl, (C6-C14aryl)alkyl-, or (C1-C9heteroaryl)alkyl-; m) -Y-Q, wherein Y is: i) O, ii) NH, iii) N(C1-C6alkyl), iv) NHSO2, v) SO2NH, vi) NHCONH, vii) NHCON(C1-C6alkyl), viii) S(O)q, q is 0, 1 or 2, ix)-C(O)NH—, x) —C(O)N(CH3)—, xi)-NHC(O)— xii) C(O), or xiii) absent, and Q is selected from: i) C6-C10aryl, optionally substituted with from 1 to 3 substituents independently selected from: A) C1-C6alkoxy- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, 3) di(C1-C6alkyl)amino-, 4) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-, or 5) hydroxyl, B) (C1-C6alkoxy)carbonyl-, C) (C1-C6alkoxy)C(O)NH—, D) C1-C6alkyl- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, E) (C1-C6alkyl)amino-, F) di(C1-C6alkyl)amino-, G) (C1-C6alkyl)amido- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, H) (C1-C6alkyl)carboxyamido-, I) C1-C9heterocyclyl-optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-, J) heterocyclyl(C1-C6alkyl)- optionally substituted by C1-C6alkyl-, K) halogen, L) hydroxyl, M) C1-C6hydroxylalkyl-, N) perfluoro(C1-C6)alkyl-, O) H2N—, P) O2N—, Q) H2NSO2—, R) HO2C—, and S) NC—, ii) 5-10 membered C1-C9heteroaryl, optionally substituted with from 1 to 3 substituents independently selected from: A) C1-C6alkoxy-optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, 3) di(C1-C6alkyl)amino-, 4) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-, or 5) hydroxyl, B) (C1-C6alkoxy)carbonyl-, C) (C1-C6alkoxy)C(O)NH—, D) C1-C6alkyl- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, E) (C1-C6alkyl)amino-, F) di(C1-C6alkyl)amino-, G) (C1-C6alkyl)amido-optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, H) (C1-C6alkyl)carboxyamido-, I) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-, J) heterocyclyl(C1-C6alkyl)- optionally substituted by C1-C6alkyl-, K) halogen, L) hydroxyl, M) C1-C6hydroxylalkyl-, N) perfluoro(C1-C6)alkyl-, O) H2N—, P)O2N—, Q) H2NSO2—, R) HO2C—, and S) NC—, iii) 3-10 membered C1-C9heterocyclyl, optionally substituted with from 1 to 3 substituents independently selected from: A) C1-C6alkyl-, B) heterocyclyl(C1-C6alkyl)-, C) (C6-C14aryl)alkyl-, D) C1-C8acyl-, E) (C1-C6alkoxy)carbonyl-, F) (C1-C6alkyl)carboxyl-, G) halogen, H) C1-C6haloalkyl-, I) hydroxyl, J) C1-C6hydroxyalkyl-, K) H2N—, L) (C1-C6alkyl)amino-, M) di(C1-C6alkyl)amino-, N) HO2C—, O) (C1-C6alkoxy)carbonyl-, P) (C1-C6alkyl)carboxyl-, Q) (C1-C6alkyl)amido-, R) H2NC(O)—, S) (C1-C6alkyl)carboxyamido-, T) 5-10 membered C1-C9heteroaryl, U) C6-C14ary, V) C3-C8cycloalkyl W) 3-10 membered C1-C9heterocyclyl, and X) —NO2; iv) C3-C10cycloalkyl, v) C1-C6alkyl, vi) C2-C6alkenyl, vii) C2-C6alkynyl, viii) C1-C6hydroxyalkyl-, ix) (CH2)vO(C1-C6alkyl), x) (CH2)vNH2, xi) (CH2)vNH(C1-C6alkyl), xii) (CH2)vN(C1-C6alkyl)2, xiii) O(CH2)vN(C1-C6alkyl)2, xiv) (CH2)vC6-C10aryl, xv) —CN, xvi) (CH2)v 5-10 membered C1-C9heteroaryl, xvii) (CH2)v 3-10 membered C1-C9heterocyclyl, optionally substituted by C1-C6alkyl-, wherein v is 1, 2, 3 or 4, and xviii) C1-C6 perfluoroalkyl-; and n) C(O)Rc wherein Rc is: i) H, ii) C1-C6alkyl, or iii) C3-C6cycloalkyl,
  • and pharmaceutically acceptable salts and esters thereof.
  • In some embodiments of the invention, R1 and/or R4 is
  • Figure US20090304692A1-20091210-C00009
  • and pharmaceutically acceptable salts or esters thereof.
  • In some embodiments of the invention, R1 and/or R4 is
  • Figure US20090304692A1-20091210-C00010
  • and pharmaceutically acceptable salts thereof.
  • In some embodiments of the invention, R1 and/or R4 is
  • Figure US20090304692A1-20091210-C00011
  • and pharmaceutically acceptable salts thereof.
  • In some embodiments of the invention, R1 and/or R4 is independently selected from
  • Figure US20090304692A1-20091210-C00012
  • In some embodiments R4 is
  • Figure US20090304692A1-20091210-C00013
  • In some embodiments R4 is
  • Figure US20090304692A1-20091210-C00014
  • In some embodiments R4 is
  • Figure US20090304692A1-20091210-C00015
  • In some embodiments, R2 is optionally substituted C6-C14aryl-NH—COR3; in others R2 is optionally substituted phenyl-NH—COR3.
  • In some embodiments, R3 is NHR5 or OR5. In some embodiments, R5 is optionally substituted C6-C10aryl or C1-C9heteroaryl, such as pyridyl. In some embodiments, the C1-C9heteroaryl, is 4-pyridyl.
  • The following compounds exemplify illustrative compounds of Formula I:
    • 1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;
    • 1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea;
    • 2-hydroxyethyl[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamate;
    • 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
    • 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-ethylurea;
    • 1-cyclopropyl-3-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]urea;
    • 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea;
    • 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea;
    • 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-[4-(2-hydroxyethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 2-(diethylamino)ethyl 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;
    • 1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-cyanophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-isopropyl-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(2-hydroxyethyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • t-butyl 2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylamino)ethylcarbamate;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-{4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea;
    • 4-(3-{4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-ureido)-benzamide;
    • tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-{4-[4-(4-methylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-{4-[4-(4-benzylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-{4-[4-(4-acetylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-(4-{4-[4-(N,N-dimethylglycyl)piperazin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-{4-[4-(4-isonicotinoylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • methyl 4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)-amino]phenyl}-1,3,5-triazin-2-yl]piperazine-1-carboxylate;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-{4-[4-(4-hydroxypiperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-(4-{4-[4-(benzylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-(4-{4-[4-(methylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-(4-{4-[4-(ethylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-{4-[4-(4-{[2-(dimethylamino)ethyl]amino}piperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-{4-[4-(4-morpholin-4-ylpiperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-hydroxyethylamino)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-morpholinoethylamino)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • methyl 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate;
    • 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetamide tert-butyl 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate;
    • 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetic acid;
    • 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-1-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • methyl(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamate;
    • 1-cyclopropyl-3-(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
    • N′,N′″-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazine-2,4-diyl]di-4,1-phenylene}bis{1-[4-(4-methylpiperazin-1-yl)phenyl]urea};
    • 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-{4-[(2-aminoethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
    • 1-{4-[4-anilino-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-(4-{4-[(2-hydroxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
    • 1-{4-[4-(azetidin-3-ylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-(4-{4-[(2-morpholin-4-ylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
    • 1-(4-{4-[(3-aminopropyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
    • 1-(4-{4-[(4-cyclopentylpiperazin-1-yl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
    • 1-{4-[4-isopropoxy-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-{4-[4-isopropoxy-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
    • 1-{4-[4-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(piperidin-4-ylmethyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
    • 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(2-piperidin-4-ylethyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
    • 1-{4-[4-(3-methylimidazolidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-{4-[4-(3-methyltetrahydropyrimidin-1(2H)-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-1-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
    • 2-hydroxyethyl (4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamate;
    • 1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-methylurea;
    • 1-cyclopropyl-3-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
    • 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(piperidin-3-ylmethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-{4-[4-(4-aminobutoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-4-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(piperidin-4-ylmethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-(4-{4-morpholin-4-yl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-{4-[4-(methylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-{4-[4-(ethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-{4-[4-(dimethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-{4-[4-(isopropylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-{4-[4-(diethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]pyridinium;
    • 1-(4-{4-[ethyl(methyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
    • 1-{4-[4-(sec-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-{4-[4-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-(4-{4-[bis(2-hydroxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
    • 1-(4-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
    • 1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
    • 1-(4-{4-morpholin-4-yl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;
    • 1-methyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
    • 1-cyclopropyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
    • 1-(2-hydroxyethyl)-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
    • 1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea;
    • 1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
    • 1-{4-[(2,2-dimethylhydrazino)carbonyl]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
    • 4-{[(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-pyrrolidin-1-ylbenzamide;
    • 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
    • 1-[4-(hydroxymethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
    • 1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
    • 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea;
    • 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • tert-butyl(1R,4R)-5-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;
    • tert-butyl (1R,4R)-5-[4-(4-{[(4-acetylphenyl)carbamoyl]amino}-phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;
    • 1-(4-{4-[(2-methoxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
    • 1-{4-[4-{[(1S)-2-hydroxy-1-methylethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-{4-[4-{[(1R)-2-hydroxy-1-methylethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-(4-{4-[(2-hydroxy-1,1-dimethylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
    • 1-{4-[4-(tert-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-piperazin-1-ylphenyl)urea;
    • 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
    • 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[4-(6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • tert-butyl-7-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;
    • 1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;
    • N-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]piperazine-1-carboxamide;
    • 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea;
    • 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(methylamino)methyl]phenyl}urea;
    • 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]urea;
    • 1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • tert-butyl-(1R,4R)-5-{4-[4-({[4-(1-hydroxyethyl)phenyl]carbamoyl}amino)phenyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;
    • 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
    • 1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-piperazin-1-ylphenyl)urea;
    • 1-{4-[4,6-di-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
    • 1-(2-fluoroethyl)-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-cyclopropyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 4-[({4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • 1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;
    • 1-methyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;
    • 1-cyclopropyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;
    • 1-(2-fluoroethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;
    • 1-(2-hydroxyethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;
    • 4-{[(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide;
    • 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-phenylurea;
    • 1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-cyclopropyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(2-fluoroethyl)-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 4-[({4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-yl]phenyl}carbamoyl)amino]benzamide;
    • 1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;
    • 1-(2,3′-bipyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
    • 1-(6-chloropyridin-3-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-N2,N2-dimethylglycinnamide;
    • N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-pyrrolidin-1-ylacetamide;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-cyclopropylurea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-(2-fluoroethyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-(2-hydroxyethyl)urea;
    • 4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-phenylurea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;
    • 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea;
    • 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;
    • 1-(4-(aminomethyl)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)urea;
    • 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;
    • 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)urea;
    • 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea;
    • 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyethoxy)phenyl)urea;
    • N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(dimethylamino)acetamide;
    • N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(4-methylpiperazin-1-yl)acetamide;
    • N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(pyrrolidin-1-yl)acetamide;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(aminomethyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;
    • 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
    • 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea;
    • 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;
    • 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(1-oxidothiomorpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}urea
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
    • 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;
    • 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)urea;
    • 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;
    • 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;
    • 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(morpholine-4-carbonyl)phenyl)urea;
    • 1-(4-(2-aminoethylamino)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)urea;
    • 4-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • 3-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[4-(5-hydroxy-3-oxa-7-azabicyclo[4.1.1]oct-7-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridazin-4-ylurea;
    • N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-(4-methylpiperazin-1-yl)acetamide;
    • 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-;
    • 4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-;
    • 4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-(4-methylpiperazin-1-yl)acetamide;
    • 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
    • 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
    • 1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-[4-(2-hydroxyethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 2-(diethylamino)ethyl 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;
    • 1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-cyanophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-isopropyl-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(2-hydroxyethyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[4-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;
    • methyl 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;
    • N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • N,N-dimethyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • N-(2-hydroxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • N-[3-(dimethylamino)propyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • N-(2-morpholin-4-ylethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • 1-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]pyridinium;
    • 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea;
    • 1-(4-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • tert-butyl 7-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;
    • 1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-(2-chloropyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(2,3′-bipyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(6-chloropyridin-3-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1,3-bis{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • N-[2-(4-methylpiperazin-1-yl)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • 1-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[(4-cyclopentylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;
    • 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-morpholin-4-ylpiperidin-1-yl)carbonyl]phenyl}urea;
    • 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide;
    • 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-ylethyl)benzamide;
    • 1-[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;
    • 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(thiomorpholin-4-ylcarbonyl)phenyl]urea;
    • 1-[4-(morpholin-4-ylcarbonyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid;
    • 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea;
    • N-[2-(dimethylamino)ethyl]-4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-methylbenzamide;
    • 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;
    • methyl 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;
    • 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid;
    • 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;
    • 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}urea;
    • 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide;
    • 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-ylethyl)benzamide;
    • 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;
    • 1-[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea;
    • 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyridin-2-ylethyl)benzamide;
    • 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyridin-4-ylethyl)benzamide;
    • 1-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;
    • 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[35.3.]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • 4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide;
    • 4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-ylethyl)benzamide;
    • 1-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;
    • N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}urea;
    • 1-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
    • 1-(1,3-dimethyl-1H-pyrazol-5-yl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-(1H-pyrazol-3-yl)urea;
    • 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;
    • N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
    • 1-(4-{4-[(6S)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-(4-{4-[6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-(4-{4-[(6R)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-(4-{4-[(6R)-6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-{4-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-[4-(4,6-di-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
    • 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazinyl-4-yl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea;
    • 4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;
    • 4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;
    • 4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea;
    • 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;
    • 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;
    • 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-acetylphenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)acetyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-morpholinoacetyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyacetyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(methoxymethyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-methoxyethyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(1-hydroxyethyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropan-2-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxy-2-methylpropyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-acetylphenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)acetyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-morpholinoacetyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyacetyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(methoxymethyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-methoxyethyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(1-hydroxyethyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropan-2-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxy-2-methylpropyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-cyanophenyl)urea;
    • 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-cyanophenyl)urea;
    • 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;
    • 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide;
    • 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)urea;
    • 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;
    • 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;
    • 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)urea;
    • 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
    • 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
    • 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(propan-2-yl)piperazin-1-yl]carbonyl}phenyl)urea;
    • N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide;
    • 4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid;
    • 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)urea;
    • 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)urea;
    • 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;
    • 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)urea;
    • 1-{4-[4-(morpholin-4-yl)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(3,3,4-trimethylpiperazin-1-yl)carbonyl]phenyl}urea; and
    • 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea.
  • The invention also includes the following compounds, not of Formula I, made by the process illustrated in Scheme 13, which have mTOR inhibiting activity:
    • 8,8′-(6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane);
    • 8-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane;
    • 8-(4-morpholino-6-(2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane;
    • 8,8′-(6-(2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane);
    • 5,5′-(6-(2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(2-oxa-5-azabicyclo[2.2.1]heptane);
    • 5,5′-(6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(2-oxa-5-azabicyclo[2.2.1]heptane);
    • 5-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;
    • 5-(4-morpholino-6-(2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;
    • 8,8′-(6-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane);
    • 5,5′-(6-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(2-oxa-5-azabicyclo[2.2.1]heptane);
    • 8-(4-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane;
    • 5-(4-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;
    • 8,8′-(6-(2-methyl-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane);
    • 5,5′-(6-(2-methyl-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(2-oxa-5-azabicyclo[2.2.1]heptane);
    • 8-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane;
    • 5-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;
    • 8,8′-(6-(1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane);
    • 5,5′-(6-(1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(2-oxa-5-azabicyclo[2.2.1]heptane);
    • 8-(4-(1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane;
    • 5-(4-(1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;
    • 3,3′-(6-(1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane);
    • 3-(4-(1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane;
    • 3,3′-(6-(2-methyl-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane);
    • 3-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane;
    • 3,3′-(6-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane);
    • 3-(4-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane;
    • 3,3′-(6-(2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane);
    • 3-(4-morpholino-6-(2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane;
    • 8-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane;
    • 3-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane; and
    • 8-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane.
  • The invention also includes pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier. The invention includes a compound of formula I when provided as a pharmaceutically acceptable prodrug, hydrated salt, such as pharmaceutically acceptable salt, or mixtures thereof.
  • In other aspects, the invention provides that the pharmaceutically acceptable carrier suitable for oral administration and the composition comprises an oral dosage form.
  • In other aspects, the invention provides a composition comprising a compound of Formula I, a second compound selected from the group consisting of a topoisomerase I inhibitor, a MEK 1/2 inhibitor, a HSP90 inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil, docetaxel, paclitaxel, leucovorin, levamisole, irinotecan, estramustine, etoposide, nitrogen mustards, BCNU, carmustine, lomustine, vinblastine, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, imatinib mesylate, Avastin (bevacizumab), hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins, herbimycin A, genistein, erbstatin, hydroxyzine, glatiramer acetate, interferon beta-1a, interferon beta-1b, natalizumab and lavendustin A; and a pharmaceutically acceptable carrier.
  • In other aspects, the second compound is Avastin.
  • In other aspects, the invention provides a method of treating a PI3K-related disorder, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat a PI3K-related disorder.
  • In other aspects, the PI3K-related disorder is selected from restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, and cancer.
  • In other aspects, the PI3K-related disorder is cancer.
  • In other aspects, the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer.
  • In other aspects, the invention provides a method of treating an mTOR-related disorder, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat an mTOR-related disorder.
  • In other aspects, the mTOR-related disorder is selected from restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, and cancer.
  • In other aspects, the mTOR-related disorder is cancer.
  • In other aspects, the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer.
  • In other aspects, the invention provides a method of treating a hSMG-1-related disorder, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat a hSMG-1-related disorder.
  • In other aspects, the hSMG-1-related disorder is selected from restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, and cancer.
  • In other aspects, the hSMG-1-related disorder is cancer.
  • In other aspects, the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer.
  • In other aspects, the invention provides a method of treating advanced renal cell carcinoma, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat advanced renal cell carcinoma.
  • In other aspects, the invention provides a method of treating acute lymphoblastic leukemia, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat acute lymphoblastic leukemia.
  • In other aspects, the invention provides a method of treating acute malignant melanoma, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat malignant melanoma.
  • In other aspects, the invention provides a method of treating soft-tissue or bone sarcoma, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat soft-tissue or bone sarcoma.
  • In other aspects, the invention provides a method of treating a cancer selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer comprising administering to a mammal in need thereof a composition comprising a compound of Formula I; a second compound selected from the group consisting of a topoisomerase I inhibitor, a MEK 1/2 inhibitor, a HSP90 inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil, docetaxel, paclitaxel, leucovorin, levamisole, irinotecan, estramustine, etoposide, nitrogen mustards, BCNU, carmustine, lomustine, vinblastine, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, imatinib mesylate, Avastin (bevacizumab), hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins, herbimycin A, genistein, erbstatin, and lavendustin A; and a pharmaceutically acceptable carrier. in an amount effective to treat the cancer.
  • In other aspects, the invention provides a method of inhibiting mTOR in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit mTOR.
  • In other aspects, the invention provides a method of inhibiting PI3K in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit PI3K.
  • In other aspects, the invention provides a method of inhibiting hSMG-1 in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit hSMG-1.
  • In other aspects, the invention provides a method of inhibiting mTOR, PI3K, and hSMG-1 together in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit mTOR, PI3K, and hSMG-1.
  • In another aspect, the invention provides a method of synthesizing compounds of the Formula I, which are:
  • Figure US20090304692A1-20091210-C00016
  • said method comprising reacting 2,4,6-trichloro[1,3,5]triazine with
  • Figure US20090304692A1-20091210-C00017
  • to form the intermediate dichlorotriazine compound
  • Figure US20090304692A1-20091210-C00018
  • The method of synthesizing compounds of the Formula I further comprising reacting the intermediate dichlorotriazine compound with
  • Figure US20090304692A1-20091210-C00019
  • to form the intermediate compound
  • Figure US20090304692A1-20091210-C00020
  • The method of synthesizing compounds of the Formula I further comprising reacting the intermediate dichlorotriazine compound with
  • Figure US20090304692A1-20091210-C00021
  • to form the intermediate compound
  • Figure US20090304692A1-20091210-C00022
  • wherein each R6, R7, R8 and R9 is independently selected and defined according to formula I.
  • The method of synthesizing compounds of the Formula I wherein the reacting moiety
  • Figure US20090304692A1-20091210-C00023
  • is independently selected from
  • Figure US20090304692A1-20091210-C00024
  • Procedures used to synthesize the compounds of the present invention are described in Schemes 1-12 and are illustrated in the examples. Reasonable variations of the described procedures are intended to be within the scope of the present invention:
  • Figure US20090304692A1-20091210-C00025
  • Compounds of the present inventions were prepared by a multi-step sequence as depicted in Scheme 1. One chlorine atom at a time was selectively replaced at different temperatures. The commercially available cyanuric acid chloride 1 was reacted with morpholine or substituted morpholine derivatives at −10° C. to give the mono morpholine derivative 2. This pivotal intermediate 2 can be reacted with different nucleophiles. In this present invention, intermediates 2 were reacted with different amines and alcohols to give 3 and 5 respectively. The third chlorine atom in intermediates 3 and 5 was replaced with 4-aminoaryl and aminoheteroaryl boronic acid in the presence of (Ph3)4P(Pd)/Na2CO3/DME/Reflux or microwave condition to yield 4 and 8 respectively. The amino group was converted to the urea derivatives by different two procedures depending upon the availability of the starting material. Some of the examples reported here were transformed into the urea derivative by reacting 4 or 8 with an appropriately substituted isocyanate derivative. Many of the urea derivatives reported here were prepared by reacting intermediates 4 or 8 with triphosgene/Et3N and an appropriately substituted primary amine derivative. The corresponding carbamate derivatives were prepared by reacting intermediates 4 or 8 with an appropriately substituted chloroformate reagents. The intermediates 2 were also used to prepare derivatives of 6, where in R is a alkyl, alkene, alkyne, aryl or heteroaryl. Reacting 6 with the appropriately substituted alkyl introduced alkyl or cycloalkyl groups in intermediate 6 or cycloalkyl magnesium bromide or the corresponding appropriately substituted organo-zinc reagent. Alkenes can be introduced in compound 6 by a Pd catalyzed appropriately substituted vinyl tin derivatives. Similarly, aryl or heteroaryl substituents can be introduced either by reacting 6 with the corresponding boronic acid (Suzuki coupling) or aryl or heteroaryl magnesium bromide. Alkynes can be introduced by reacting compound 6 with an appropriately substitute alkyne and Pd(0). The alkyne and the alkene introduced can also be functionally converted into other derivatives such as alkyl, alcohol and amine moieties. Detailed procedures are described in the experimental section for each derivative prepared.
  • Figure US20090304692A1-20091210-C00026
  • Certain compounds of the invention were prepared by the methods outlined in Scheme 2.
  • Figure US20090304692A1-20091210-C00027
  • Compounds of the invention were also prepared according to the method illustrated in Scheme 3.
  • Figure US20090304692A1-20091210-C00028
  • appropriate amine as shown in Scheme 4.
  • Figure US20090304692A1-20091210-C00029
  • The 4-(alkoxy)aniline intermediates were prepared from 4-fluoronitrobenzene and the appropriate alcohol as shown in Scheme 5.
  • Figure US20090304692A1-20091210-C00030
    Figure US20090304692A1-20091210-C00031
  • The thiomorpholine and bis morpholine compounds were prepared from 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine and the appropriate morpholine and thiomorpholine reagents as shown in Scheme 6.
  • Figure US20090304692A1-20091210-C00032
  • The dihydropyran and tetrahydropyran compounds were prepared from 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine, tributyl(3,6-dihydro-2H-pyran-4-yl)stannane, and the appropriate morpholine as shown in Scheme 7.
  • Figure US20090304692A1-20091210-C00033
  • The (4-aminophenyl)(piperazin-1-yl)methanone intermediates were prepared from 4-nitrobenzoyl chloride and the appropriate amine as shown in Scheme 8.
  • Figure US20090304692A1-20091210-C00034
  • The 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-urea compounds were prepared from 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine, (R)-3-methylmorpholine, 3-oxa-8-azabicyclo[3.2.1]octane-hydrochloride, and the appropriate amine as shown in Scheme 9.
  • Figure US20090304692A1-20091210-C00035
    Figure US20090304692A1-20091210-C00036
  • The preparation of both the (6S′) and (6R′) isomers of tert-butyl 6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate from tert-butyl 1H-pyrrole-1-carboxylate is shown in Scheme 10.
  • Figure US20090304692A1-20091210-C00037
  • The (6S′)-tert-butyl 6-amino-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate and (6R′)-tert-butyl 6-fluoro-6-(alkyl, aryl, or heteroaryl)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate compounds could be prepared from tert-butyl 6-oxo-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (Scheme 10) and the appropriate amine or Grignard reagent as shown in Scheme 11.
  • Figure US20090304692A1-20091210-C00038
  • Compounds of formula I can be prepared from cyanuric chloride as shown in Scheme 12.
  • Figure US20090304692A1-20091210-C00039
  • (6-(1H-benzo[d]imidazol-1-yl)-1,3,5-triazine compounds can be prepared from cyanuric chloride as shown in Scheme 13. Cyanuric chloride is treated with one or two equivalents of bridged morpholine in aprotic solvent in the presence of base to give dichlorotriazine or chlorotriazine, respectively. The chlorotriazine is treated with benzoimidazole in aprotic solvent in the presence of base to give the benzoimidazole triazine. The dichlorotriazine is treated with a morpholine in aprotic solvent in the presence of base followed by benzoimidazole in aprotic solvent in the presence of base to give the benzoimidazole triazine.
    • DEFINITIONS
  • The following definitions are used in connection with the compounds of the present invention unless the context indicates otherwise. In general, the number of carbon atoms present in a given group is designated “Cx-Cy” where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like. Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming from left to right the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent “arylalkyloxycabonyl” refers to the group (C6-C14aryl)-(C1-C6alkyl)-O—C(O)—. Terms not defined herein have the meaning commonly attributed to them by those skilled in the art.
  • “Acyl-” refers to a group having a straight, branched, or cyclic configuration or a combination thereof, attached to the parent structure through a carbonyl functionality. Such groups may be saturated or unsaturated, aliphatic or aromatic, and carbocyclic or heterocyclic. Examples of a C1-C8acyl- group include acetyl-, benzoyl-, nicotinoyl-, propionyl-, isobutyryl-, oxalyl-, and the like. Lower-acyl refers to acyl groups containing one to four carbons. An acyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H2N—, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-, (C1-C6alkyl)C(O)N(C1-C3alkyl)-, (C1-C6alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (C1-C6alkyl)NHC(O)—, di(C1-C6alkyl)NC(O)—, —CN, hydroxyl, C1-C6alkoxy-, C1-C6alkyl-, HO2C—, (C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)—, C6-C14aryl-, C1-C9heteroaryl-, or C3-C8cycloalkyl-.
  • “Alkyl” refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a C1-C12alkyl group may have from 1 to 12 (inclusive) carbon atoms in it. Examples of C1-C6alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. Examples of C1-C8alkyl groups include, but are not limited to, methyl, propyl, pentyl, hexyl, heptyl, 3-methylhex-1-yl, 2,3-dimethylpent-2-yl, 3-ethylpent-1-yl, octyl, 2-methylhept-2-yl, 2,3-dimethylhex-1-yl, and 2,3,3-trimethylpent-1-yl. An alkyl group can be unsubstituted or substituted with one or more groups, including: halogen, —NH2, (C1-C6alkyl)N—, (C1-C6alkyl)(C1-C6alkyl)N—, —N(C1-C3alkyl)C(O)(C1-C6alkyl), —NHC(O)(C1-C6alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(C1-C6alkyl), —C(O)N(C1-C6alkyl)(C1-C6alkyl), —CN, hydroxyl, C1-C6alkoxy, C1-C6alkyl, —C(O)OH, —C(O)O(C1-C6alkyl), —C(O)(C1-C6alkyl), C6-C14aryl, C1-C9heteroaryl, C3-C8cycloalkyl, C1-C6haloalkyl-, C1-C6-aminoalkyl-, —OC(O)(C1-C6alkyl), C1-C6-carboxyamidoalkyl-, and —NO2.
  • “Alkadienyl” refer to a straight or branched chain unsaturated hydrocarbon containing at least two double bonds, and either may exist in the E or Z conformation. Examples of a C4-C6alkadienyl group include, but are not limited to, buta-1,3-dienyl, buta-2,3-dienyl, isoprenyl, penta-1,3-dienyl, and penta-2,4-dien-2-yl.
  • “Alkadiynyl” refer to a straight or branched chain unsaturated hydrocarbon containing at least two triple bonds. Examples of a C4-C6alkadiynyl group include, but are not limited to, buta-1,3-diynyl, buta-2,3-diynyl, penta-1,3-diynyl, and penta-2,4-diynyl.
  • “Alkenyl” refer to a straight or branched chain unsaturated hydrocarbon containing at least one double bond, and may exist in the E or Z conformation. Examples of a C2-C8alkenyl group include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, 1-octene, 2-octene, 3-octene, and 4-octene. Examples of a C2-C6alkenyl group include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene, and isohexene. Examples of a C3-C8alkenyl group include, but are not limited to, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, 1-octene, 2-octene, 3-octene, and 4-octene. Examples of a C3-C6alkenyl group include, but are not limited to, prop-2-enyl, but-3-enyl, but-2-enyl, 2-methylallyl, pent-4-enyl, and hex-5-enyl. An alkenyl group can be unsubstituted or substituted with one or more groups, including: halogen, —NH2, (C1-C6alkyl)N—, (C1-C6alkyl)(C1-C6alkyl)N—, —N(C1-C3alkyl)C(O)(C1-C6alkyl), —NHC(O)(C1-C6alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(C1-C6alkyl), —C(O)N(C1-C6alkyl)(C1-C6alkyl), —CN, hydroxyl, C1-C6alkoxy, C1-C6alkyl, —C(O)OH, —C(O)O(C1-C6alkyl), —C(O)(C1-C6alkyl), C6-C14aryl, C1-C9heteroaryl, and C3-C8cycloalkyl.
  • “Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing at least one triple bond. Examples of a C2-C6alkynyl group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1-pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne, and isohexyne. Examples of a C3-C6alkynyl group include, but are not limited to, prop-2-ynyl, but-3-ynyl, but-2-ynyl, pent-4-ynyl, and hex-5-ynyl. Examples of a C3-C8alkynyl group include, but are not limited to, prop-2-ynyl, but-3-ynyl, but-2-ynyl, pent-4-ynyl, hex-5-ynyl, hept-3-ynyl, 2-methylhex-3-ynyl, oct-4-ynyl, and 2-methylhept-3-ynyl. An alkynyl group can be unsubstituted or substituted with one or more groups, including: halogen, —NH2, (C1-C6alkyl)N—, (C1-C6alkyl)(C1-C6alkyl)N—, —N(C1-C3alkyl)C(O)(C1-C6alkyl), —NHC(O)(C1-C6alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(C1-C6alkyl), —C(O)N(C1-C6alkyl)(C1-C6alkyl), —CN, hydroxyl, C1-C6alkoxy, C1-C6alkyl, —C(O)OH, —C(O)O(C1-C6alkyl), —C(O)(C1-C6alkyl), C6-C14aryl, C1-C9heteroaryl, and C3-C8cycloalkyl.
  • “Alkoxy-” refers to the group R—O— where R is an alkyl group, as defined above. Exemplary C1-C6alkoxy- groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An alkoxy group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, C1-C6alkoxy-, H2N—, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-, (C1-C6alkyl)C(O)N(C1-C3alkyl)-, (C1-C6alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (C1-C6alkyl)NHC(O)—, di(C1-C6alkyl)NC(O)—, NC—, C1-C6alkoxy-, HO2C—, (C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)—, C6-C14aryl-, C1-C9heteroaryl-, C3-C8cycloalkyl-, C1-C6haloalkyl-, amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-, C1-C6-carboxyamidoalkyl-, or O2N—.
  • “(Alkoxy)carbonyl-” refers to the group alkyl-O—C(O)—. Exemplary (C1-C6alkoxy)carbonyl-groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An (alkoxy)carbonyl group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, H2N—, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-, (C1-C6alkyl)C(O)N(C1-C3alkyl)-, (C1-C6alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (C1-C6alkyl)NHC(O)—, di(C1-C6alkyl)NC(O)—, NC—, C1-C6alkoxy-, HO2C—, (C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)—, C6-C14aryl-, C1-C9heteroaryl-, C3-C8cycloalkyl-, C1-C6haloalkyl-, amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-, C1-C6-carboxyamidoalkyl-, or O2N—.
  • “(Alkyl)amido-” refers to a —C(O)NH— group in which the nitrogen atom of said group is attached to a C1-C6alkyl group, as defined above. Representative examples of a (C1-C6alkyl)amido-group include, but are not limited to, —C(O)NHCH3, —C(O)NHCH2CH3, —C(O)NHCH2CH2CH3, —C(O)NHCH2CH2CH2CH3, —C(O)NHCH2CH2CH2CH2CH3, —C(O)NHCH(CH3)2, —C(O)NHCH2CH(CH3)2, —C(O)NHCH(CH3)CH2CH3, —C(O)NH—C(CH3)3 and —C(O)NHCH2C(CH3)3.
  • “(Alkyl)amino-” refers to an —NH group, the nitrogen atom of said group being attached to a alkyl group, as defined above. Representative examples of an (C1-C6alkyl)amino- group include, but are not limited to CH3NH—, CH3CH2NH—, CH3CH2CH2NH—, CH3CH2CH2CH2NH—, (CH3)2CHNH—, (CH3)2CHCH2NH—, CH3CH2CH(CH3)NH— and (CH3)3CNH—. An (alkyl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen, H2N—, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-, (C1-C6alkyl)C(O)N(C1-C3alkyl)-, (C1-C6alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (C1-C6alkyl)NHC(O)—, di(C1-C6alkyl)NC(O)—, NC—, hydroxyl, C1-C6alkoxy-, C1-C6alkyl-, HO2C—, (C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)—, C6-C14aryl-, C1-C9heteroaryl-, C3-C8cycloalkyl-, C1-C6haloalkyl-, amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-, C1-C6-carboxyamidoalkyl-, or O2N—.
  • “Aminoalkyl-” refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with —NH2; one or both H of the NH2 may be replaced by a substituent.
  • “Alkylcarboxyl-” refers to an alkyl group, defined above that is attached to the parent structure through the oxygen atom of a carboxyl(C(O)—O—) functionality. Examples of (C1-C6alkyl)carboxyl- include acetoxy, propionoxy, propylcarboxyl, and isopentylcarboxyl.
  • “(Alkyl)carboxyamido-” refers to a —NHC(O)— group in which the carbonyl carbon atom of said group is attached to a C1-C6alkyl group, as defined above. Representative examples of a (C1-C6alkyl)carboxyamido- group include, but are not limited to, —NHC(O)CH3, —NHC(O)CH2CH3, —NHC(O)CH2CH2CH3, —NHC(O)CH2CH2CH2CH3, —NHC(O)CH2CH2CH2CH2CH3, —NHC(O)CH(CH3)2, —NHC(O)CH2CH(CH3)2, —NHC(O)CH(CH3)CH2CH3, —NHC(O)—C(CH3)3 and —NHC(O)CH2C(CH3)3.
  • “Alkylene”, “alkenylene”, and “alkynylene” refers to alkyl, alkenyl and alkynyl groups, as defined above, having two points of attachment within a chemical structure. Examples of C1-C6alkylene include ethylene, propylene, and dimethylpropylene. Likewise, examples of C2-C6alkenylene include ethenylene and propenylene. Examples of C2-C6alkynylene include ethynylene and propynylene.
  • Aryl refers to an aromatic hydrocarbon group. Examples of a C6-C14aryl group include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenanaphthyl. Examples of a C6-C10aryl group include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, and tetrahydronaphthyl. An aryl group can be unsubstituted or substituted with one or more groups, including: C1-C6alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C1-C6alkyl)-, —NH2, aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C1-C6alkyl), —OC(O)(C1-C6alkyl), N-alkylamido-, —C(O)NH2, (C1-C6alkyl)amido-, or —NO2.
  • “(Aryl)alkyl” refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with an aryl group as defined above. (C6-C14Aryl)alkyl-moieties include benzyl, benzhydryl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. An (aryl)alkyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H2N—, hydroxyl, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-, (C1-C6alkyl)C(O)N(C1-C3alkyl)-, (C1-C6alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (C1-C6alkyl)NHC(O)—, di(C1-C6alkyl)NC(O)—, NC—, hydroxyl, C1-C6alkoxy-, C1-C6alkyl-, HO2C—, (C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)—, C6-C14aryl-, C1-C9heteroaryl-, C3-C8cycloalkyl-, C1-C6haloalkyl-, amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-, C1-C6-carboxyamidoalkyl-, or O2N—.
  • “(Aryl)amino” refers to a radical of formula (aryl)-NH—, wherein aryl is as defined above. “(Aryl)oxy” refers to the group Ar—O— where Ar is an aryl group, as defined above.
  • “Cycloalkyl” refers to a non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system. Representative examples of a C3-C12cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl, octahydro-1H-inden-2-yl, decahydro-1H-benzo[7]annulen-2-yl, and dodecahydros-indacen-4-yl. Representative examples of a C3-C10cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl, and octahydro-1H-inden-2-yl. Representative examples of a C3-C8cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and octahydropentalen-2-yl. A cycloalkyl can be unsubstituted or substituted with one or more groups, including: halogen, —NH2, (C1-C6alkyl)N—, (C1-C6alkyl)(C1-C6alkyl)N—, —N(C1-C3alkyl)C(O)(C1-C6alkyl), —NHC(O)(C1-C6alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(C1-C6alkyl), —C(O)N(C1-C6alkyl)(C1-C6alkyl), —CN, hydroxyl, C1-C6alkoxy, C1-C6alkyl, —C(O)OH, —C(O)O(C1-C6alkyl), —C(O)(C1-C6alkyl), C6-C14aryl, C1-C9heteroaryl, C3-C8cycloalkyl, C1-C6haloalkyl-, C1-C6-aminoalkyl-, —OC(O)(C1-C6alkyl), C1-C6-carboxyamidoalkyl-, and —NO2. Additionally, each of any two hydrogen atoms on the same carbon atom of the carbocyclic ring can be replaced by an oxygen atom to form an oxo (═O) substituent.
  • “Cycloalkenyl” refers to a non-aromatic, unsaturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system containing at least one double bond connecting two ring carbon atoms. Representative examples of a C5-C8cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexenyl, 4,4a-octalin-3-yl, and cyclooctenyl. A cycloalkenyl can be unsubstituted or substituted with one or more groups, including: halogen, —NH2, (C1-C6alkyl)N—, (C1-C6alkyl)(C1-C6alkyl)N—, —N(C1-C3alkyl)C(O)(C1-C6alkyl), —NHC(O)(C1-C6alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(C1-C6alkyl), —C(O)N(C1-C6alkyl)(C1-C6alkyl), —CN, hydroxyl, C1-C6alkoxy, C1-C6alkyl, —C(O)OH, —C(O)O(C1-C6alkyl), —C(O)(C1-C6alkyl), C6-C14aryl, C1-C9heteroaryl, and C3-C8cycloalkyl. Additionally, each of any two hydrogen atoms on the same carbon atom of the carbocyclic ring can be replaced by an oxygen atom to form an oxo (═O) substituent.
  • “Di(alkyl)amino-” refers to a nitrogen atom attached to two alkyl groups, as defined above. Each alkyl group can be independently selected. Representative examples of an di(C1-C6alkyl)amino- group include, but are not limited to, —N(CH3)2, —N(CH2CH3)(CH3), —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH2CH2CH2CH3)2, —N(CH(CH3)2)2, —N(CH(CH3)2)(CH3), —N(CH2CH(CH3)2)2, —NH(CH(CH3)CH2CH3)2, —N(C(CH3)3)2, —N(C(CH3)3)(CH3), and —N(CH3)(CH2CH3). The two alkyl groups on the nitrogen atom, when taken together with the nitrogen to which they are attached, can form a 3- to 7-membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with —N(H)—, —N(C1-C6alkyl)-, —N(C3-C8cycloalkyl)-, —N(C6-C14aryl)-, —N(C1-C9heteroaryl)-, —N(amino(C1-C6alkyl))-, —N(C6-C14arylamino)-, —O—, —S—, —S(O)—, or —S(O)2—.
  • “Halo” or “halogen” refers to —F, —Cl, —Br and —I.
  • “C1-C6Haloalkyl-” refers to a C1-C6alkyl group, as defined above, wherein one or more of the C1-C6alkyl group's hydrogen atoms has been replaced with —F, —Cl, —Br, or —I. Each substitution can be independently selected from —F, —Cl, —Br, or —I. Representative examples of an C1-C6haloalkyl-group include, but are not limited to, —CH2F, —CCl3, —CF3, CH2CF3, —CH2Cl, —CH2CH2Br, —CH2CH21, —CH2CH2CH2F, —CH2CH2CH2Cl, —CH2CH2CH2CH2Br, —CH2CH2 CH2CH2I, —CH2CH2CH2CH2CH2Br, —CH2CH2CH2CH2CH21, —CH2CH(Br)CH3, —CH2 CH(Cl)CH2CH3, —CH(F)CH2CH3 and —C(CH3)2(CH2Cl).
  • “Heteroaryl” refers to a monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one ring atom selected from the heteroatoms oxygen, sulfur and nitrogen. Examples of C1-C9heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic C1-C9heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heteroaryl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom. Examples of monocyclic C1-C4heteroaryl groups include 2H-tetrazole, 3H-1,2,4-triazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, imidazole, and pyrrole. A heteroaryl group can be unsubstituted or substituted with one or more groups, including: C1-C6alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C1-C6alkyl)-, —NH2, aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C1-C6alkyl), —OC(O)(C1-C6alkyl), N-alkylamido-, —C(O)NH2, (C1-C6alkyl)amido-, or —NO2.
  • “(Heteroaryl)alkyl-” refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a heteroaryl- group as defined above. Examples of (C1-C9heteroaryl)alkyl- moieties include 2-pyridylmethyl, 2-thiophenylethyl, 3-pyridylpropyl, 2-quinolinylmethyl, 2-indolylmethyl, and the like. A (heteroaryl)alkyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H2N—, hydroxyl, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-, (C1-C6alkyl)C(O)N(C1-C3alkyl)-, (C1-C6alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (C1-C6alkyl)NHC(O)—, di(C1-C6alkyl)NC(O)—, NC—, hydroxyl, C1-C6alkoxy-, C1-C6alkyl-, HO2C—, (C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)—, C6-C14aryl-, C1-C9heteroaryl-, C3-C8cycloalkyl-, C1-C6haloalkyl-, amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-, C1-C6-carboxyamidoalkyl-, or O2N—.
  • The term “heteroatom” refers to a sulfur, nitrogen, or oxygen atom.
  • “Heterocycle” or “heterocyclyl” refers to monocyclic, bicyclic and polycyclic groups in which at least one ring atom is a heteroatom. A heterocycle may be saturated or partially saturated. Exemplary C1-C9heterocyclyl- groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran, thiane, thiine, piperazine, oxazine, 5,6-dihydro-4H-1,3-oxazin-2-yl, 2,5-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 6-oxa-3,8-diazabicyclo[3.2.1]octane, 7-oxa-2,5-diazabicyclo[2.2.2]octane, 2,7-dioxa-5-azabicyclo[2.2.2]octane, 2-oxa-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxa-5-azabicyclo[2.2.2]octane, 3,6-dioxa-8-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.1.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 5,7-dioxa-2-azabicyclo[2.2.2]octane, 6,8-dioxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, 2-methyl-2,5-diazabicyclo[2.2.1]heptane-5-yl, 1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl, 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl-, 7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl, 9-oxa-3-azabicyclo[3.3.1]nonan-3-yl, 3-oxa-9-azabicyclo[3.3.1]nonan-9-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl, thiazine, dithiane, and dioxane. The contemplated heterocycle rings or ring systems have a minimum of 3 members. Therefore, for example, C1heterocyclyl- radicals would include but are not limited to oxaziranyl, diaziridinyl, and diazirinyl, C2heterocyclyl- radicals include but are not limited to aziridinyl, oxiranyl, and diazetidinyl, C9heterocyclyl- radicals include but are not limited to azecanyl, tetrahydroquinolinyl, and perhydroisoquinolinyl. A heterocyclyl group can be unsubstituted or substituted with one or more groups, including: C1-C6alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C1-C6alkyl)-, —NH2, aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C1-C6alkyl), —OC(O)(C1-C6alkyl), N-alkylamido-, —C(O)NH2, (C1-C6alkyl)amido-, or —NO2.
  • “Heterocyclyl(alkyl)-” refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a heterocycle group as defined above. Heterocyclyl(C1-C6alkyl)- moieties include 2-pyridylmethyl, 1-piperazinylethyl, 4-morpholinylpropyl, 6-piperazinylhexyl, and the like. A heterocyclyl(alkyl) group can be unsubstituted or substituted with one or more of the following groups: halogen, H2N—, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-, (C1-C6alkyl)C(O)N(C1-C3alkyl)-, (C1-C6alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (C1-C6alkyl)NHC(O)—, di(C1-C6alkyl)NC(O)—, NC—, hydroxyl, C1-C6alkoxy-, C1-C6alkyl-, HO2C—, (C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)—, 4- to 7-membered monocyclic heterocycle, C6-C14aryl-, C1-C9heteroaryl-, or C3-C8cycloalkyl-.
  • “Hydroxylalkyl-” refers to a alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with hydroxyl groups. Examples of C1-C6hydroxylalkyl-moieties include, for example, —CH2OH, —CH2CH2OH, —CH2CH2CH2OH, —CH2CH(OH)CH2OH, —CH2CH(OH)CH3, —CH(CH3)CH2OH and higher homologs.
  • “Perfluoroalkyl-” refers to alkyl group, defined above, having two or more fluorine atoms. Examples of a C1-C6 perfluoroalkyl- group include CF3, CH2CF3, CF2CF3 and CH(CF3)2.
  • A “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or gorilla.
  • The term “optionally substituted” as used herein means that at least one hydrogen atom of the optionally substituted group has been substituted with halogen, —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)(C1-C6alkyl), —N(C1-C3alkyl)C(O)(C1-C6alkyl), —NHC(O)(C1-C6alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(C1-C6alkyl), —C(O)N(C1-C6alkyl)(C1-C6alkyl), —CN, hydroxyl, C1-C6alkoxy, C1-C6alkyl, —C(O)OH, —C(O)O(C1-C6alkyl), —C(O)(C1-C6alkyl), C6-C14aryl, C1-C9heteroaryl, or C3-C8cycloalkyl.
  • Representative “pharmaceutically acceptable salts” include but are not limited to, e.g., water-soluble and water-insoluble salts, such as the acetate, aluminum, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzathine (N,N′-dibenzylethylenediamine), benzenesulfonate, benzoate, bicarbonate, bismuth, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate (camphorsulfonate), carbonate, chloride, choline, citrate, clavulariate, diethanolamine, dihydrochloride, diphosphate, edetate, edisylate (camphorsulfonate), esylate (ethanesulfonate), ethylenediamine, fumarate, gluceptate (glucoheptonate), gluconate, glucuronate, glutamate, hexafluorophosphate, hexylresorcinate, hydrabamine(N,N′-bis(dehydroabietyl)ethylenediamine), hydrobromide, hydrochloride, hydroxynaphthoate, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate, iodide, isothionate (2-hydroxyethanesulfonate), lactate, lactobionate, laurate, lauryl sulfate, lithium, magnesium, malate, maleate, mandelate, meglumine (1-deoxy-1-(methylamino)-D-glucitol), mesylate, methyl bromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate (4,4′-methylenebis-3-hydroxy-2-naphthoate, or embonate), pantothenate, phosphate, picrate, polygalacturonate, potassium, propionate, p-toluenesulfonate, salicylate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate (8-chloro-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione), trieth iodide, tromethamine(2-amino-2-(hydroxymethyl)-1,3-propanediol), valerate, and zinc salts.
  • An “effective amount” when used in connection with a compound of this invention is an amount effective for inhibiting mTOR or PI3K in a subject.
  • Some compounds within the present invention possess one or more chiral centers, and the present invention includes each separate enantiomer of such compounds as well as mixtures of the enantiomers. Where multiple chiral centers exist in compounds of the present invention, the invention includes each combination as well as mixtures thereof. All chiral, diastereomeric, and racemic forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials.
  • The compounds of the present invention exhibit an mTOR inhibitory activity and therefore, can be utilized in order to inhibit abnormal cell growth in which mTOR plays a role. Thus, the compounds of the present invention are effective in the treatment of disorders with which abnormal cell growth actions of mTOR are associated, such as restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, cancer, etc. In particular, the compounds of the present invention possess excellent cancer cell growth inhibiting effects and are effective in treating cancers, preferably all types of solid cancers and malignant lymphomas, and especially, leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumor, advanced renal cell carcinoma, acute lymphoblastic leukemia, malignant melanoma, soft-tissue or bone sarcoma, etc.
  • The compounds of the present invention exhibit a PI3 kinase inhibitory activity and, therefore, can be utilized in order to inhibit abnormal cell growth in which PI3 kinases play a role. Thus, the compounds of the present invention are effective in the treatment of disorders with which abnormal cell growth actions of PI3 kinases are associated, such as restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, cancer, etc. In particular, the compounds of the present invention possess excellent cancer cell growth inhibiting effects and are effective in treating cancers, preferably all types of solid cancers and malignant lymphomas, and especially, leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumor, advanced renal cell carcinoma, acute lymphoblastic leukemia, malignant melanoma, soft-tissue or bone sarcoma, etc.
  • For therapeutic use, the pharmacologically active compounds of Formula I will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in association with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjutants and excipients employing standard and conventional techniques.
  • The pharmaceutical compositions of this invention include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous) bronchial or nasal administration. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The solid carrier may contain conventional excipients such as binding agents, fillers, tableting lubricants, disintegrants, wetting agents and the like. The tablet may, if desired, be film coated by conventional techniques. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile vehicle for injection, an aqueous or non-aqueous liquid suspension, or may be a dry product for reconstitution with water or other suitable vehicle before use. Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicle (including edible oils), preservatives, as well as flavoring and/or coloring agents. For parenteral administration, a vehicle normally will comprise sterile water, at least in large part, although saline solutions, glucose solutions and like may be utilized. Injectable suspensions also may be used, in which case conventional suspending agents may be employed. Conventional preservatives, buffering agents and the like also may be added to the parenteral dosage forms. Particularly useful is the administration of a compound of Formula I directly in parenteral formulations. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation containing appropriate amounts of the active ingredient, that is, the compound of Formula I according to the invention. See, for example, Remington: The Science and Practice of Pharmacy, 20th Edition. Baltimore, Md.: Lippincott Williams & Wilkins, 2000.
  • The dosage of the compounds of Formula I to achieve a therapeutic effect will depend not only on such factors as the age, weight and sex of the patient and mode of administration, but also on the degree of potassium channel activating activity desired and the potency of the particular compound being utilized for the particular disorder of disease concerned. It is also contemplated that the treatment and dosage of the particular compound may be administered in unit dosage form and that one skilled in the art would adjust the unit dosage form accordingly to reflect the relative level of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per day is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect.
  • A suitable dose of a compound of Formula I or pharmaceutical composition thereof for a mammal, including man, suffering from, or likely to suffer from any condition as described herein is an amount of active ingredient from about 0.01 mg/kg to 10 mg/kg body weight. For parenteral administration, the dose may be in the range of 0.1 mg/kg to 1 mg/kg body weight for intravenous administration. For oral administration, the dose may be in the range about 0.1 mg/kg to 5 mg/kg body weight. The active ingredient will preferably be administered in equal doses from one to four times a day. However, usually a small dosage is administered, and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.
  • However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound of be administered, the chosen route of administration, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.
  • The amount of the compound of the present invention or a pharmaceutically acceptable salt thereof that is effective for inhibiting mTOR or PI3K in a subject. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, the condition, the seriousness of the condition being treated, as well as various physical factors related to the individual being treated, and can be decided according to the judgment of a health-care practitioner. Equivalent dosages may be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months. The number and frequency of dosages corresponding to a completed course of therapy will be determined according to the judgment of a health-care practitioner. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one compound of the present invention or a pharmaceutically acceptable salt thereof is administered, the effective dosage amounts correspond to the total amount administered.
  • In one embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered concurrently with another therapeutic agent.
  • In one embodiment, a composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and an effective amount of another therapeutic agent within the same composition can be administered.
  • Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective amount range. The compound of the present invention or a pharmaceutically acceptable salt thereof and the other therapeutic agent can act additively or, in one embodiment, synergistically. In one embodiment, of the invention, where another therapeutic agent is administered to an animal, the effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof is less than its effective amount would be where the other therapeutic agent is not administered. In this case, without being bound by theory, it is believed that the compound of the present invention or a pharmaceutically acceptable salt thereof and the other therapeutic agent act synergistically.
  • Methods useful for making the compounds of Formula I are set forth in the Examples below and generalized in Schemes 1-3:
  • Scheme 1:
  • One of skill in the art will recognize that Schemes 1-3 can be adapted to produce the other compounds of Formula I and pharmaceutically acceptable salts of compounds of Formula I according to the present invention.
  • The following abbreviations are used herein and have the indicated definitions: ACN is acetonitrile, AcOH is acetic acid, ATP is adenosine triphosphate, CHAPS is 3-[(3-cholamidopropyl)dimethylammonio]-propanesulfonic acid, DEAD is diethyl azodicarboxylate, DIAD is diisopropyl azodicarboxylate, DMAP is dimethyl aminopyridine, DMF is N,N-dimethylformamide, DMF-DMA is dimethylformamide dimethyl acetal, DMSO is dimethylsulfoxide. Dowtherm™ is a eutectic mixture of biphenyl(C12H10) and diphenyl oxide (C12H10O). Dowtherm™ is a registered trademark of Dow Corning Corporation. DPBS is Dulbecco's Phosphate Buffered Saline Formulation, EDTA is ethylenediaminetetraacetic acid, ESI stands for Electrospray Ionization, EtOAc is ethyl acetate, EtOH is ethanol, HEPES is 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, GMF is Glass, Hunig's Base is diisopropylethylamine, HPLC is high pressure liquid chromatography, LPS is lipopolysaccharide, MeCN is acetonitrile, MeOH is methanol, MS is mass spectrometry, NEt3 is triethylamine, NMR is nuclear magnetic resonance, PBS is phosphate-buffered saline (pH 7.4), RPMI 1640 is a buffer (Sigma-Aldrich Corp., St. Louis, Mo., USA), SDS is dodecyl sulfate (sodium salt), SRB is Sulforhodamine B, TBSCl is tert-butyldimethylsilyl chloride, TCA is tricholoroacetic acid, TFA is trifluoroacetic acid, THF is tetrahydrofuran, TLC is thin-layer chromatography, and TRIS is tris(hydroxymethyl)aminomethane.
    • Methods
  • The following methods outline the synthesis of the compounds of Formula I. The following examples are presented to illustrate certain embodiments of the present invention, but should not be construed as limiting the scope of this invention.
    • Example 1 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea Step 1: Preparation of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine
  • To a stirred solution of cyanuric chloride (18.4 g, 10 mmol) in acetone (100 ml) and crushed ice (500 g), a mixture of triethylamine (30.0 g, excess) and morpholine (17.4 g, 20 mmol) was added at −10° C. After the addition, reaction mixture was stirred at room temperature and for 1 hour and diluted with 50 ml water. Separated white solid was filtered and washed with water. The white solid was dried and filtered. The crude product was found to be pure and taken to next step without purification. Yield: 25 g, 87%; (M+H) 286.7.
    • Step 2: Preparation of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline
  • A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (1.4 g, 4.9 mmoles), a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid pinacol ester (1.6 g, 7.3 mmoles) and DME (100 mL) was refluxed for 24 hours. The solvent was evaporated, and the residue was dissolved in methylene chloride and filtered through Celite™. The filtrate was washed with water (200 mL) and the organic layer was dried with magnesium sulfate. This was filtered and the solvent was evaporated. The residue was purified by Silica gel column chromatography and eluted with Ethyl acetate/hexanes (1:1) to give 1.40 g, (83% yield) of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline as an amorphous solid. (M+H) 343.
    • Step 3: Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
  • To a mixture of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.20 g 0.40 mmoles) in methylene chloride (80 mL) at 0° C. was added triphosgene (0.25 mg, 0.84 mmoles) and triethylamine (3 mL). The mixture was stirred for 20 minutes at 0° C. and 4-amino pyridine (0.10 g 0.83 mmoles) was added to the reaction mixture and stirred for another 2 hours at room temperature. The solvent was evaporated and the residue was submitted to the HPLC using acetonitrile/TFA as mobile phase to give 98.2 mg (36% yield) of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea. (M+H)=463.3.
    • Procedure A for Preparation of Ureas Using Aryl Isocyanates
  • To a stirred mixture of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (140 mg, 0.40 mmoles) and a catalytic amount of dimethylaminopyridine (DMAP) in methylene chloride 100 (mL), was added a small excess of aryl isocyanate (0.61 mmoles). The mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated to half of its original volume and the separated precipitate was collected by filtration and washed with methanol (15 ml) and then with diethyl ether. In some cases the crude product obtained was purified by Silica gel column chromatography by eluting it with appropriate solvents, depending upon the polarity of the products.
  • The following compounds were prepared according to Procedure A:
    • Example 2 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-3-ylurea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.08 g 0.23 mmoles) and 3-pyridyl isocyanate (30 mg, 0.25 mmoles) the title compound was isolated as a white solid. The product was purified by Silica gel column chromatography by eluting it with 10% MeOH: ethyl acetate. Yield; 60 mg (56%); (M+H)=463.5.
    • Example 3 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-phenylurea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (140 mg, 0.40 mmoles) and phenyl isocyanate (72 mg, 0.61 mmoles), the title compound was isolated as a white solid. The product was purified by Silica gel column chromatography by eluting it with ethyl acetate. Yield: 0.128 g (68%) (M+H)=462.3.
    • Example 4 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-thiophen-2-ylurea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (60 mg, 0.17 mmoles) and 2-thienyl isocyanate (18 mg, 0.14 mmoles), the title compound was isolated as a grey solid after Silica gel column chromatography by eluting with 5% ethyl acetate: methanol. Yield: 12 mg (14%); (M+H)=470.
    • Example 5 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-methylphenyl)urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-methylphenyl isocyanate (74 mg, 0.56 mmoles), the title compound was isolated as a white solid. Yield; 65 mg (33%) (M+H)=476.4.
    • Example 6 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-fluorophenyl)urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-fluorophenyl isocyanate (83 mg, 0.61 mmole), 65 mg (33% yield) of the title product was isolated as white solid. (M+H)=480.3.
    • Example 7 Preparation of 1-(2,4-dimethoxyphenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 2,4-dimethoxyphenyl isocyanate (131 mg, 0.73 mmoles), the title compound was isolated as a white solid. Yield; 76 mg (36%); (M+H)=522.4.
    • Example 8 Preparation of 1-(4-chlorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-chlorophenyl isocyanate (94 mg, 0.61 mmoles), the title compound was isolated as a white solid. Yield; 60 mg (30%); (M+H)=496.3.
    • Example 9 Preparation 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-methoxyphenyl)urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-methoxyphenyl isocyanate (91 mg, 0.63 mmoles) the title compound was isolated as a white solid. Yield; 48 mg (24%); (M+H)=492.3.
    • Example 10 Preparation of (4-chlorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-chlorophenyl isocyanate (94 mg, 0.61 mmoles) the title compound was isolated as a white solid. Yield; 60 mg (30%); (M+H)=496.3
    • Example 11 Preparation of (2,4-difluorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.105 g 0.30 mmoles) and 2,4-difluorophenyl isocyanate (71 mg, 0.45 mmoles) the title compound was isolated as a white solid. Yield; 40 mg (27%); (M+H)=498.6
    • Example 12 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-ethylurea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.130 g 0.38 mmoles) and ethyl isocyanate (260 mg, 10 fold excess) the title compound was isolated as a white solid. Yield; 38 mg (25%); (M+H)=414.4
    • Example 13 Preparation of tert-butyl 3-{[4-(4-{[(4-fluorophenyl)carbamoyl]-amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate Step 1: Preparation of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine
  • To a stirred solution of cyanuric chloride (18.4 g, 10 mmol) in acetone (100 ml) and crushed ice (500 g), a mixture of triethylamine (30.0 g, excess) and morpholine (8.7 g, 10 mmol) was added at −10° C. After the addition, reaction mixture was stirred at room temperature and for 1 hour and diluted with 50 ml water. Separated white solid was filtered and washed with water. The white solid was dried and filtered. The crude product was found to be pure and taken to next step with out purification. Yield: 18 g, 76%; (M+H) 236.4.
    • Step 2: Preparation of tert-butyl 3-(4-chloro-6-morpholine-1,3,5-triazin-2-2-ylamino)azetidine-1-carboxylate
  • To a stirred solution of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (2.35 g, 10 mmol) in acetone (50 ml) and crushed ice, a mixture of triethylamine and 1-boc-3-(amino)azetidine (1.72 g) was added slowly. The reaction mixture was stirred at room temperature for 6 hours and the separated solid was filtered. The product was dried and taken to next step with out purification. Yield: 3.0 g (81%); (M+H) 373.
    • Step 3: Preparation of tert-butyl-3-4-(4-(4-aminophenyl)-6-morpholine-1,3,5-triazin-2-ylamino)azetidine-1-carboxylate
  • A mixture of tert-butyl 3-(4-chloro-6-morpholine-1,3,5-triazin-2-2-ylamino)azetidine-1-carboxylate (1.1 g, 3.0 mmoles), tetrakis(triphenylphosphine)palladium (0) in catalytic amount (70 mg, 0061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid pinacol ester (0.97 g, 4.5 mmoles), DME (100 mL) was refluxed for 24 hours. The solvent was evaporated and the residue was dissolved in methylene chloride and filtered though Celite™. The organic layer was washed with water (200 mL) and dried over magnesium sulfate. It was filtered and the solvent was evaporated. The residue was chromatographed on silica gel column using Ethyl acetate/hexanes (1:1) as an eluent, to give 0.86 g, (68% yield) of tert-butyl-3-4-(4-(4-aminophenyl)-6-morpholine-1,3,5-triazin-2-ylamino)azetidine-1-carboxylate. (M+H) 428.
    • Step 4: Preparation of tert-butyl 3-{[4-(4-{[(4-fluorophenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate
  • A mixture of tert-butyl 3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate (100 mg, 0.23 mmol), 4-fluorophenylisocyanate (63 mg, 0.46 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; Yield 40 mg (30%); (M+H) 565.6.
    • Example 14 Preparation of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
  • The titled compound was prepared by starting from tert-butyl 3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate (140 mg, 0.32 mmol) phenylisocyanate (58 mg, 0.49 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; Yield 40 mg (31%); (M+H) 547.6
    • Example 15 Preparation of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridine-3-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
  • The titled compound was prepared by starting from tert-butyl 3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate (140 mg, 0.32 mmol) 3-pyridylisocyanate (70 mg, 0.58 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; Yield 40 mg (23%); (M+H) 548.7.
    • Example 16 Preparation of tert-butyl 3-{[4-(4-{[(4-methylphenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate
  • The titled compound was prepared by starting from tert-butyl 3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate (130 mg, 0.27 mmol) 4-tolyl isocyanate (40 mg, 0.30 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; Yield 85 mg (47%); (M+H) 561.6.
    • Example 17 Preparation of 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3- phenylurea
  • To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
  • 30 mg (0.055 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 20 (83%); (M+H) 447.
    • Example 18 Preparation of 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
  • 30 mg (0.055 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 21 (83%); (M+H) 448.5.
    • Example 19 Preparation of 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-fluorophenyl)urea To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(4-fluoro-phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
  • 30 mg (0.053 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 20 (83%); (M+H) 465.5.
    • Example 20 Preparation of 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-methylphenyl)urea To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(4-methyl-phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
  • 130 mg (0.23 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 40 (37%); (M+H) 461.5.
    • Example 21 Preparation of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridine-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
  • To a stirred solution of tert-butyl 3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate (200 mg, 0.47 mmol) in DCM (100 ml) at 0° C., triphosgene (300 mg) and triethylamine (3 ml) was added slowly. The reaction mixture was stirred for 15 minutes and 4-aminopyridine (200 mg. 2.1 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours and concentrated. It was quenched with cold water and the separated solid was filtered and washed with water. It was dried and purified by Gilson HPLC. Yield 100 mg (40%); (M+H) 548.6
    • Example 22 Preparation of 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridine-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
  • 40 mg (0.073 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 26 (81%); (M+H) 448.5.
    • Example 23 Preparation of 1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea Step 1: Preparation of 3-(4-chloro-6-morpholin-4-yl-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • To a stirred acetone/crushed ice suspension of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (1.5 g, 6.5 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (980 mg, 6.5 mmol) and triethylamine (3 ml) was added and stirred at room temperature for 6 h. At the end, the separated solid was filtered and washed with water. The crude product was found to be pure enough for further transformations. Yield: 2.0 g (99%); mp. 118; (M+H) 313.1.
    • Step 2: Preparation of 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline
  • A mixture of 3-(4-chloro-6-morpholin-4-yl-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (2.0 g, 6.4 mmol), tetrakis(triphenylphosphine)palladium (0) in catalytic amount (100 mg), sodium carbonate solution 2 M (5 mL), 4-aminophenylboronic acid pinacol ester (1.5 g, 6.43 mmoles), DME (200 mL) was refluxed for 24 hours. The solvent was evaporated and the residue was dissolved in methylene chloride and filtered though Celite™. The organic layer was washed with water (200 mL) and dried over magnesium sulfate. It was filtered and the solvent was evaporated. The residue was chromatographed on silica gel column using Ethyl acetate/hexanes (1:1) as an eluent, to give 1.4 g, (59% yield) of the titled product. mp. 154; (M+H) 369.4.
    • Step 3: Preparation of 1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea
  • The titled compound was prepared by starting from 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline (120 mg, 0.32 mmol) phenylisocyanate (80 mg, 0.67 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; mp: 242; Yield 35 mg (28%); (M+H) 488.56
    • Example 24 Preparation of 1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • The titled compound was prepared by starting from 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline (100 mg, 0.27 mmol)-4-fluoro phenylisocyanate (50 mg, 0.36 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; mp: 248; Yield 86 mg (86%); (M+H) 506.4.
    • Example 25 Preparation of 1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • The titled compound was prepared by starting from 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline (100 mg, 0.27 mmol)-4-tolylisocyanate (60 mg, 0.45 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 h. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; mp: 228; Yield 80 mg (80%); (M+H) 502.4
  • Following the procedure as outlined in example 25, compounds described in examples 26 to 32 were prepared.
    • Example 26 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea (M+H) 452.53 Example 27 2-hydroxyethyl[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamate (M+H) 483.54 Example 28 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea (M+H) 612.8 Example 29 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-ethylurea (M+H) 466.56 Example 30 1-cyclopropyl-3-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]urea (M+H) 478.55 Example 31 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea (M+H) 515 Example 32 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea (M+H) 544.6 Example 33 Preparation of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline Step 1: Synthesis of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine
  • To a solution of cyanuric chloride (2.5 g, 13.5 mmol) in CH2Cl2 (150 mL) was added dropwise morpholine (1.14 g, 13.5 mmol) at −78° C., followed by addition of Et3N (3.0 mL, 21.5 mmol). The resulting reaction mixture was stirred at −78° C. for 20 min, and then diluted with CH2Cl2. The organic phase was washed with water and brine, and dried over MgSO4. The solvent was removed in vacuum to give the title compound as white crystalline solid (3.027 g, 95% yield). MS (ESI) m/z 235.1.
    • Step 2: Synthesis of 8-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3,2,1]octane
  • To a solution of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (2.34 g, 10 mmol) in CH2Cl2 (100 mL) were added 3-oxa-8-azabicyclo[3,2,1]octane hydrochloride (1.645 g, 11 mmol) and Et3N (4.2 mL, 30 mmol). The mixture was stirred at room temperature over night. The reaction mixture was washed with water and brine, and dried over MgSO4. The solvent was removed in vacuum to give the title compound as white solid (3.0 g, 96% yield). MS (ESI) m/z 312.1.
    • Step 3: Synthesis of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline
  • To a 10 mL vial were added 8-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3,2,1]octane (311 mg, 1.0 mmol), 4-aminophenylboronic acid pinacol ester (328 mg, 1.5 mmol), Pd(PPh3)4 (58 mg, 5 mol %), 1,2-dimethoxyethane (DME, 2.5 mL) and 2M Na2CO3 aqueous solution (1.5 mL). The resulting mixture was heated at 130° C. for 30 min in microwave oven. The reaction mixture was cooled to room temperature. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over (MgSO4). The solvent was removed under reduced pressure and the residue was subjected to HPLC separation to give the title compound as off-white solid (280 mg, 76% yield). MS (ESI) m/z 369.2.
    • Example 34 Preparation of 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • To a solution of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) in CHCl3 (1 mL) were added Et3N (25 mL, 0.18 mmol) and triphosgene (18 mg, 0.06 mmol). The mixture was stirred at room temperature for 15 min and 4-aminopyridine (17 mg, 0.18 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was removed, and the residue was subjected to HPLC separation to give the title compound as off-white solid (1TFA salt, 8.8 mg, 24% yield). MS (ESI) m/z 489.2.
    • Example 35 Preparation of 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide
  • Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-aminobenzamide (25 mg, 0.18 mmol) gave the title compound as off-white solid (10.6 mg, 33% yield). MS (ESI) m/z 531.2.
    • Example 36 Preparation of 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 3-aminopyridine (17 mg, 0.18 mmol) gave the title compound as off-white solid (1TFA salt, 14.8 mg, 41% yield). MS (ESI) m/z 489.5.
    • Example 37 Preparation of 1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-fluoroaniline (20 mg, 0.18 mmol) gave the title compound as off-white solid (14.8 mg, 49% yield). MS (ESI) m/z 506.5.
    • Example 38 Preparation of 1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-aminobenzyl alcohol (22 mg, 0.18 mmol) gave the title compound as off-white solid (9.6 mg, 31% yield). MS (ESI) m/z 518.5.
    • Example 39 Preparation of 1-[4-(2-hydroxyethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-aminophenethyl alcohol (24 mg, 0.18 mmol) gave the title compound as off-white solid (10.6 mg, 33% yield). MS (ESI) m/z 532.5.
    • Example 40 Preparation of 2-(diethylamino)ethyl 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate
  • Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and procaine hydrochloride (50 mg, 0.18 mmol) gave the title compound as off-white solid (1TFA salt, 14.6 mg, 33% yield). MS (ESI) m/z 613.6.
    • Example 41 Preparation of 1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and p-toluidine (20 mg, 0.18 mmol) gave the title compound as off-white solid (9.2 mg, 31% yield). MS (ESI) m/z 502.5.
    • Example 42 Preparation of 1-(4-cyanophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-aminobezonitrile (21 mg, 0.18 mmol) gave the title compound as off-white solid (14.3 mg, 46% yield). MS (ESI) m/z 513.5.
    • Example 43 Preparation of 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-(4-methylpiperazin-1-yl)aniline (54 mg, 0.18 mmol) gave the title compound as off-white solid (2TFA salt, 3.2 mg, 7% yield). MS (ESI) m/z 586.6.
    • Example 44 Preparation of 1-isopropyl-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and isopropylamine (11 mg, 0.18 mmol) gave the title compound as off-white solid (13.6 mg, 50% yield). MS (ESI) m/z 454.5.
    • Example 45 Preparation of 1-(2-hydroxyethyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and ethanolamine (11 mg, 0.18 mmol) gave the title compound as off-white solid (14.4 mg, 53% yield). MS (ESI) m/z 456.5.
    • Example 46 Preparation of 1-[2-(dimethylamino)ethyl]-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ES+) 513.62 (M+H)+.
    • Example 47 Preparation of 1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 489.3.
    • Example 48 Preparation of 1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • mp 258° C.; MS (ESI) m/z 489.3.
  • Following the procedure as outlined in example 1, step 3 the following compounds were prepared.
    • Example 49 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methylpyridin-4-yl)urea MS (ESI) m/z 477.3. Example 50 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(2-hydroxyethyl)phenyl]urea MS (ESI) m/z 506.4 Example 51 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea Example 52 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethyl)phenyl]urea MS (ESI) m/z 506.4. Example 53 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluoromethyl)phenyl]urea MS (ESI) m/z 530.2. Example 54 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-hydroxyphenyl)urea MS (ESI) m/z 478.2. Example 55 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluoromethyl)pyridin-2-yl]urea MS (ESI) m/z 530.5. Example 56 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea MS (ESI) m/z 621.54. Example 57 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydroxyethyl)phenyl]urea MS (ESI) m/z 506.3. Example 58 methyl 4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate MS (ESI) m/z 520.3. Example 59 Preparation of 1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • Step 1: To a stirred solution of NaH (50% 460 mg) in dry THF tetrahydro-2H-pyran-4-ol (1.02 g, 10 mmol) was slowly added at room temperature. The reaction mixture was stirred at room temperature for 30 min and 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (2.35 g, 10 mmol) in THF (50 ml) was slowly added. The reaction mixture was stirred at room temperature for 48 hours and slowly quenched with ice-cold water. It was extracted with CHCl3; washed well with water and dried over anhydrous MgSO4. It was filtered and concentrated and 2-chloro-4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazine was purified by silica gel column chromatography by eluting it with 40% ethyl acetate:hexane. Yield: 1.5 g, 50%; White solid; mp 91° C.; MS (ESI) m/z 301.52
  • Step 2: 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline was prepared by the procedure as described in example 1, step 2. Starting from 2-chloro-4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazine (1.5 g, 4.9 mmol) 980 mg (56% yield) of the product was isolated after purification using Silica gel column chromatography by eluting it with ethyl acetate. Mp. 188° C.; MS (ESI) m/z 358.2.
  • Step 3: 1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea was prepared by the procedure as described in example 1, step 3. Starting from 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline (212 mg. 0.59 mmol) 190 mg (Yield, 67%) of the final product was isolated as a white solid. mp 238° C.; MS (ESI) m/z 478.3.
    • Example 60 Preparation of 1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea
  • 1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea was prepared by reacting the 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline and the corresponding phenylisocyanate. Product was purified by Gilson, HPLC. MS (ESI) m/z 476.5.
    • Example 61 Preparation of 1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • 1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea was prepared by reacting the 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline and the corresponding 3-pyridylisocyanate. Product was purified by Gilson, HPLC. MS (ESI) m/z 477.53.
    • Example 62 Preparation of 1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea
  • 1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea was prepared by the triphosgene procedure as described in example 1, step 3. Product was purified by Gilson, HPLC. MS (ESI) m/z 506.6.
    • Example 63 Preparation of 1-(2-methylpyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea
  • 1-(2-methylpyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea was prepared by the triphosgene procedure as described in example 1, step 3. Product was purified by Gilson, HPLC. MS (ESI) m/z 491.5.
    • Example 64 Preparation of 1-[2-(methylamino)ethyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea
  • 1-[2-(methylamino)ethyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea was prepared by the triphosgene procedure as described in example 1, step 3. Product was purified by Gilson, HPLC. MS (ESI) m/z 457.54.
    • Example 65 Preparation of 1-(3-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea
  • 1-(3-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea was prepared by reacting the 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline and the corresponding 3-acetylisocyanate. Product was purified by Gilson, HPLC. MS (ESI) m/z 518.58.
    • Example 66 Preparation of 1-[4-(dimethylamino)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea
  • 1-[4-(dimethylamino)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea was prepared by reacting the 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline and the corresponding 4-(N,N-dimethyl amino)phenylisocyanate. Product was purified by Gilson, HPLC. MS (ESI) m/z 519.61.
    • Example 67 Preparation of 4-[3-{4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl}ureido]benzoic acid
  • To a stirred mixture of methyl 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoate (1.4 g, 2.69 mmol), THF (10 mL), MeOH (5 mL) and H2O (2.5 mL) was added LiOH.H2O (339 mg, 8.07 mmol) then heated under reflux for 8 hrs. Concentrated and added H2O (5 mL) then acidified with 2N HCl. The solid was filtered washed with H2O and dried to give the product as a tan solid (1.3 g, 96% yield); MS (ESI) m/z=506.3
    • Example 68 Preparation of N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide
  • To a stirred solution of 4-[3-{4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl}ureido]benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 L, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was stirred for 1 hr. at room temperature and added N′,N′-dimethylethane-1,2-diamine (130 μL, 1.188 mmol) then stirred overnight. Added CH2Cl2 (40 mL) and washed with sat. NaHCO3 and H2O. Concentrated and purified by silica gel chromatography CH2Cl2:MeOH:7N NH3 in MeOH (10:1:0.22) to give the product as a white solid (98 mg, 57% yield); MS (ESI) m/z=576.4.
    • Example 68 Preparation N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide as an HCl salt
  • To the N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide (72 mg, 0.125 mmol) and MeOH (1 mL) was added 4N HCl in dioxane (1 mL) and stirred for 3 hrs. The solid was filtered and washed with ether to give the product as a white solid (73 mg, yield=95%); MS (ESI) m/z=576.4.
    • Example 69 Preparation of 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea hydrochloride
  • To a stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with 1-methylpiperazine (132 L, 1.188 mmol) to give 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea as a white solid (95 mg, 54% yield); MS (ESI) m/z=588.4.
  • To a 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea (70 mg, 0.119 mmol) and MeOH (1 mL) was added 4N HCl in Dioxane (1 mL), stirred for 3 hrs. The solid was filtered and washed with ether to give the product as a white solid (74 mg, yield=100%).
    • Example 70 Preparation of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide
  • To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with methylamine (594 μL, 2M solution. in THF) to give the product as a white solid (118 mg, 77% yield); MS (ESI) m/z=519.3.
    • Example 71 Preparation of N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide hydrochloride
  • To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with N1,N1,N2-trimethylethane-1,2-diamine (154 μL, 1.188 mmol) to give N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide as a white solid (88 mg, 50% yield); MS (ESI) m/z=590.2.
  • To the N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide (55 mg, 0.127 mmol) and MeOH (1 mL) was added 4N HCl in Dioxane (1 mL) and stirred for 3 hrs. The solid was filtered and washed with ether to give the product as a white solid (70 mg, yield=88%).
    • Example 72 Preparation of 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-morpholinopiperidine-1-carbonyl)phenyl)urea
  • To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 1 mL of NMP was reacted according to example 68 with 4-(piperidin-4-yl)morpholine (67 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (40.1 mg, 62% yield); MS (ESI) m/z=658.7.
    • Example 73 Preparation of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-(quinuclidin-3-yl)benzamide
  • To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to according to example 68 with quinuclidin-3-amine (79 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (24.3 mg, 40% yield); MS (ESI) m/z=614.7.
    • Example 74 Preparation of 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)urea
  • To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with 4-[1-pyrrolidinyl]piperidine (61 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product as a white solid (37 mg, 58% yield); MS (ESI) m/z=642.7
    • Example 75 Preparation of 1-(4-(1,4′-bipiperidine-1′-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea
  • To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with 1,4′-bipiperidine (67 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product as a white solid (39 mg, 60% yield); MS (ESI) m/z=656.8.
    • Example 76 Preparation of 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea
  • To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with N,N-dimethylpiperidin-4-amine (51 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (30.6 mg, 52% yield); MS (ESI) m/z=616.7.
    • Example 77 Preparation of 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea
  • To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with piperazine (34 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (17.2 mg, 30% yield); MS (ESI) m/z=573.6
    • Example 78 Preparation of 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyridin-2-yl)acetyl)phenyl)urea
  • To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with pyridin-2-ylmethanamine (43 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (9 mg, 15% yield); MS (ESI) m/z=596.6.
    • Preparation of 3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • To a solution of cyanuric chloride (2.00 g, 10.85 mmoles) in acetone (20 mL) and water (10 mL) at 0° C. was added a solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (1.46 g, 9.76 mmoles) in saturated aqueous NaHCO3 (25 mL) and acetone (25 mL) via addition funnel over 15 minutes. The reaction was stirred at 0° C. for 2 hours, then filtered to collect a white precipitate. The precipitate was washed with water (25 mL) and dried. The crude product was purified by column chromatography (30:70 ethyl acetate in hexanes) to provide 3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.55 g) as a white solid.
    • Procedure to prepare 3-(4-chloro-6-(substituted amino)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • To a solution of 3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.085 g, 0.33 mmoles) and Na2CO3 (0.041 g, 0.39 mmoles) in acetone (1 mL) and water (1 mL) was added the desired amine (0.36 mmoles). The solution was heated to 55° C. and stirred for 2 hours then concentrated to provide crude amino-triazine, which was used directly without purification. Following this procedure, the following compounds were prepared.
    • 3-(4-chloro-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • (310.3, M+H).
    • 3-(4-chloro-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • (296.3, M+H)
    • t-butyl 2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylamino)ethylcarbamate
  • (385.3, M+H).
    • 2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylamino)ethanol
  • (286.3, M+H).
    • 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-N-phenyl-1,3,5-triazin-2-amine
  • (318.3, M+H).
    • 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-N-cyclohexyl-1,3,5-triazin-2-amine
  • (324.3, M+H).
    • t-butyl 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylamino)azetidine-1-carboxylate
  • (397.3, M+H).
    • Method to prepare 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(substituted amino)-1,3,5-triazin-2-yl)aniline
  • A suspension of bis-amino triazine chloride (0.33 mmoles) in toluene (2 mL), ethanol (2 mL), and 2M aqueous Na2CO3 (0.700 mL) in a microwave vial was sparged with N2 for 5 minutes. Pd(PPh3)4 (0.021 mgs, 0.018 mmoles) and 4-aminophenylboronic acid pinacol ester (0.094 mgs, 0.43 mmoles) were added and the vial was sealed and heated to 110° C. for 1 hour. The mixture was cooled and filtered through Celite™. The filter cake was washed with ethyl acetate and the filtrate was washed with brine, dried, and concentrated. The crude material was purified by HPLC (Waters system, 5-70% CH3CN in H2O w/0.05% NH4OH) to provide the aryl-substituted triazine compounds. Following this procedure, the following compounds were prepared.
    • 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)aniline
  • (367.4, M+H).
    • 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline
  • (353.3, M+H).
    • 2-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-ylamino)ethanol;
  • (343.3, M+H).
    • 4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-phenyl-1,3,5-triazin-2-amine;
  • (375.3, M+H).
    • 4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-cyclohexyl-1,3,5-triazin-2-amine;
  • (381.4, M+H).
    • t-butyl 3-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-ylamino)azetidine-1-carboxylate;
  • (454.4, M+H).
    • Procedure to prepare 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(substituted amino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • A solution of triphosgene (0.034 mgs, 0.114 mmoles) in CH2Cl2 (1 mL) was prepared. A solution of the desired triazine aniline derivative (0.23 mmoles) in CH2Cl2 (1 mL) and triethylamine (0.095 mL, 0.68 mmoles) was added and the reaction was allowed to stir at room temperature for 15 minutes. A solution of 4-aminopyridine (0.043 mgs, 0.46 mmoles) in THF (1 mL) was then added and the solution was stirred at room temperature for 3 hours, then concentrated and purified by HPLC (Waters system, 5-70% CH3CN in H2O w/0.05% NH4OH) to provide the 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(substituted amino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea derivatives. The following compounds were prepared by this procedure:
    • Example 79 Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • 487.2, M+H.
    • Example 80 Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • 474.2, M+H.
    • Example 81 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethyl)phenyl]urea
  • To a stirred mixture of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140, 0.40 mmoles) in methylene chloride at 0° C. was added triphosgene (0.25, 0.84 mmoles) and Et3N (3 mL). The reaction mixture was stirred for 20 minutes at 0° C. Then 1-(4-aminophenyl)ethanol (0.10 g, 0.73 mmoles) was added to the mixture. The reaction mixture was stirred for about 16 hours at room temperature. The solvent was removed. The residue was dissolved in DMSO and place at HPLC using acetonitrile buffer TFA to give 48 mg (24%) of [4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethyl)phenyl]urea. M+H 506.4.
    • Example 82 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methylpyridin-4-yl)urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140, 0.40 mmoles) and 2-methyl-4-aminopyridine (80 mg, 0.73 mmol) and following the procedure as outlined in Example 81, 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methylpyridin-4-yl)urea was isolated by HPLC purification. Yield: 60 mg, 27%; MS (ESI) m/z=477.3.
    • Example 83 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140, 0.40 mmoles) and 4-aminophenylmethanol (100 mg, 0.81 mmol) and following the procedure described in example 81, 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)-phenyl]urea was isolated by HPLC purification. Yield: 58 mg, 26%; MS (ESI) m/z=492.3.
    • Example 84 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-hydroxyphenyl]urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140, 0.40 mmoles) and 4-aminophenol (89 mg, 0.81 mmol) and following the procedure as outlined in example 81, 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-hydroxyphenyl]urea was isolated by HPLC purification. Yield: 62 mg, 16%; MS (ESI) m/z=478.2.
    • Example 85 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluoromethyl)phenyl]urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140, 0.40 mmoles) and 4-trifluoromethylaniline (100 mg, 0.62 mmol) and following the procedure as outlined in example 81, 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluoromethyl)phenyl]urea was isolated by HPLC purification. Yield: 25 mg, 13%; MS (ESI) m/z=430.2.
    • Example 86 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140, 0.40 mmoles) and 4-trifluoromethylaniline (140 mg, 0.40 mmol) and following the procedure as outlined in example 81, 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea was isolated by HPLC purification. Yield: 40 mg, 16%; MS (ESI) m/z=628.3.
    • Example 87 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluoromethyl)pyridin-2-yl]urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.160, 0.47 mmoles) and 2-amino-5-trifluorophenylpyridine (100 mg, 0.61 mmol) and following the procedure as outlined in example 81, 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluoromethyl)pyridin-2-yl]urea was isolated by HPLC purification. Yield: 10 mg, 4.1%; MS (ESI) m/z=531.3.
    • Example 88 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydroxyethyl)phenyl]urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.160, 0.47 mmoles) and 1-(3-aminophenyl)ethanol (100 mg, 0.73 mmoles)and following the procedure as outlined in example 81, 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydroxyethyl)phenyl]urea was isolated by HPLC purification. Yield: 10 mg, 4.1%; MS (ESI) m/z=531.3.
    • Example 89 Preparation of 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea Step 1: Preparation of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazine
  • To a stirred solution of dichloromonomorpholino derivative of 1,3,5-triazine (2.0 g, 8.5 mmoles) in methylene chloride 200 mL, was added 3S-3-methylmorpholine (0.85 g, 8.5 mmoles) combined with two equivalents of triethylamine 1.7 mL dropwise manner. After the addition reaction mixture was stirred at room temperature for 3 hours and quenched with water. The aqueous layer was washed well with water; dried over anhydrous MgSO4 and filtered. The solvent was evaporated and the residue obtained was triturated with diethyl ether/hexane (1:1) and filtered. The solid was used without further purification. (1.0 g, 40% yield). M+H 357.3.
    • Step 2: Preparation of 4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline
  • A mixture of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazine (1.26, 4.2 mmol), sodium carbonate solution (2M, 2 mL), tetrakis palladium triphenylphosphine 70 mg (catalytic amount) and 4-aminophenyl boronic pinacol ester (1.37 g, 6.3 mmoles) in DME (100 mL) was heated to reflux for 24 hours. The solvent was evaporated, the residue was re-dissolved in methylene chloride and filtered through Celite™. The solvent was evaporated and the residue was chromatographed on silica gel eluting with first 26/4 hexanes/ethyl acetate then increased to 1/1 hexanes ethyl acetate to give 1.0 of 4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (71% yield); M+H 357.2.
    • Step 3: Preparation of 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • Starting from 4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (0.160, 0.44 mmoles) and 4-aminopyridine (100 mg, 1.06 mmoles) and following the procedure as outlined in example 81, 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea was isolated by HPLC purification. Yield: 125 mg, 60%; MS (ESI) m/z 477.3.
    • Example 90 Preparation of 1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea
  • Starting from 4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (0.160, 0.44 mmoles) and 4-(1-hydroxyethyl)aniline (137 mg, 1 mmole)and following the procedure described in example 81, 1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea was isolated by HPLC purification. Yield: 125 mg, 60%; MS (ESI) m/z 519.6
    • Example 91 Preparation of 1-[4-(2-hydroxymethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea
  • Starting from 4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (0.160, 0.44 mmoles) and 4-aminophenylmethanol (0.10 g, 0.81 mmoles) and following the procedure as outlined in example 81, 1-[4-(2-hydroxymethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea was isolated by HPLC purification. Yield: 55 mg, 16%; MS (ESI) m/z 506.3.
    • Example 92 Preparation of 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(2-methylpyridin-4-yl)urea
  • Starting from 4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (0.160, 0.44 mmoles) and 2-methyl-4-aminopyridine (0.10 g, 0.92 mmoles) and following the procedure as outlined in example 81, 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(2-methylpyridin-4-yl)urea was isolated by HPLC purification. Yield: 75 mg, 36%; MS (ESI) m/z 491.3.
    • Example 93 Preparation of 1-[4-(1-hydroxyethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea
  • Starting from 4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (0.160, 0.44 mmoles) and 1-(4-aminophenyl)ethanol (126 mg, 0.92 mmoles) and following the procedure as outlined in example 81, 1-[4-(1-hydroxyethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea was isolated by HPLC purification. MS (ESI) m/z 519.6.
    • Example 94 Preparation of 1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
  • Step 1: To a stirred solution of isopropanol (250 mg, 4.1 mmol) in dry THF (50 ml) at −78° C., n-butyllithium (2.6 ml, 1.6 mol solution) was slowly added. The reaction mixture was stirred for 30 minutes and a solution of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (1.00 g, 4.25 mmol) in THF was added to the solution. The reaction mixture was stirred at room temperature for 24 hours and quenched with water and extracted with DCM. The crude product obtained was taken to next step without purification.
  • Step 2: A mixture of (crude) 4-(chloro-6-isopropoxyl-1,2,3-triazin-2-yl)morpholine of (2.91 g, 11.27 mmol) 4-amino-phenylboronic acid pinacol ester (3.59 g, 16.4 mmoles), tetrakis palladium triphenylphosphine (120 mg catalytic amount) and sodium carbonate solution (2M, 2 mL) was refluxed in DME (100 mL) for 24 hours. The solvent was removed and the residue was re-dissolved in methylene chloride and filtered through Celite™. The solvent was evaporated and the residue was chromatographed on silica gel eluting with first 26:4 hexane:ethyl acetate then increased to 1/1 hexanes ethyl acetate to give 0.65 g (yield 18%) of 4-(4-isopropoxy-6-morpholino-1,3,5-triazin-2-yl)aniline. M+H 316.3.
  • Step 3: Starting from 4-(4-isopropoxy-6-morpholino-1,3,5-triazin-2-yl)aniline (0.140, 0.44 mmoles) and 4-aminopyridine (100 mg, 1.06 mmoles) and following the procedure as outlined in example 81, 1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea was isolated by HPLC purification. Yield: 15 mg, 7.8%; MS (ESI) m/z=436.3.
    • Example 95 Preparation of methyl 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate
  • A mixture of 4-(4-isopropoxy-6-morpholino-1,3,5-triazin-2-yl)aniline (1.3 g, 4.1 mmol), triethylamine (2 ml) and 4-carbomethoxy-phenylisocyanate (1451 mg, 8.2 mmol) was stirred for 48 hours and quenched with water and washed well. The organic layer was dried and filtered. It was concentrated and purified by column chromatography by eluting it initially with 10% ethyl acetate:hexane and latter with 40% ethyl acetate:hexane. White solid; 600 mg, 30%; MS (ESI) m/z 492.5.
    • Example 96 Preparation of 1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
  • Starting from methyl 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid (160 mg, 0.33 mmol) and 4-methylpiperazine following the procedure as outlined in Experimental 71, 80 mg (44% Yield) of the titled compound was isolated as white solid. MS (ESI) m/z 281.2.
    • Example 97 Preparation of 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide
  • Starting from methyl 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid (200 mg, 0.42 mmol) and 4-amino-1-methylpiperidine following the procedure as outlined in Experimental 71, 65 mg (27% Yield) of the titled compound was isolated as white solid. MS (ESI) m/z 574.68.
    • Example 98 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(1-methylpiperidin-4-yl)urea
  • Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (140 mg 0.40 mmoles) and 4-amino-1-methylpiperidine (70 mg, 0.62 mmol) and following the procedure as outlined in example 1, step 3, 20 mg (10% Yield) of the final compound was isolated as a solid. MS (ESI) m/z=483.4
    • Example 99 Preparation of 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(1-methylpiperidin-4-yl)urea
  • Starting from 4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (0.140, 0.39 mmoles) and 4-amino-1-methylpiperidine (70 mg, 0.62 mmol) and following the procedure as outlined in example 81, the titled product was prepared and purified by HPLC. Yield: 120 mg, 40%; 497.4.
    • Example 100 Preparation of 1-{4-[4-(3,6-Dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea Step 1: Preparation of 2-Chloro-4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazine
  • In a three necked flask under nitrogen equipped was dissolved 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (610 mg, 2.6 mmol), tributyldihydropyranylstannane (1.45 g, 3.89 mmol, 1.5 eq), and (Ph3P)2PdCl2 (150 mg, 0.21 mmol, 0.1 eq) in anhydrous dioxan (5 ml). The reaction mixture was heated under stirring to 90° C. for 16 hrs. For purification silica gel (10 g) was added to the mixture and the solvent was removed to let the product adsorbed on the silica gel. The silica gel plug was placed on a column and the mixture was flash chromatographed with hexane:ethyl acetate (10:1) to give after removal solvent the product as off white solid (345 mg=47% yield); MS (ESI) m/z 281.
    • Step 2: Preparation of 4-[4-(3,6-Dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine
  • To a microwave processing tube was added dimethoxyethane (4 mL), aqueous Na2CO3 (2 molar)(1 mL, 2 mmol, 2 eq), (Ph3P)4Pd (101 mg, 0.088 mmol), 4-anilinoboronic acid or ester (581 mg, 2.65 mmol, 1.5 eq) and the 2-chloro-4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazine (500 mg, 1.76 mmol) and the vessel was sealed. The mixture was heated to 140° C. for 60 minutes. The solvents were distilled and the crude compound was purified by silica gel chromatography using CH2Cl2/ethyl acetate (10:1) and later CH2Cl2/MeOH/NH3 (20:1:0.1) to give the product as a off-white solid (520 mg, 87% yield); MS (ESI) m/z 340.2
    • Step 3: Preparation of 1-{4-[4-(3,6-Dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea
  • To a stirred solution of triphosgene (140 mg, 0.47 mmol) in CH2Cl2 (6 mL) was added 4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine (200 mg, 0.59 mmol) at 25° C. The reaction mixture was stirred for 15 min and 4-aminopyridine (166 mg, 1.77 mmol) and NEt3 (814 μL, 5.89 mmol) were added and the reaction mixture was stirred for additional 1 hr. The solvents were distilled and the crude mixture was purified by semi-prep-HPLC (TFA-method) to give 1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea (75 mg, 22% yield); MS (ESI) m/z 460
    • Example 101 Preparation of 1-{4-[4-Morpholin-4-yl-6-(tetrahydro-pyran-4-yl)-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea
  • 1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea (130 mg, 0.28 mmol) and Pd—C (10%, wet) (113 mg) were suspended in methanol/THF/CH2Cl2 (4:1:1) (30 mL) and hydrogenated (at 1 atm pressure) for 3 h. After completion, the catalyst was removed by filtration over Celite™ and the solvents were removed in vacuo to obtain the crude product, which was purified by semi-prep-HPLC (TFA-method), to give (32 mg=20% yield) of 1-{4-[4-Morpholin-4-yl-6-(tetrahydro-pyran-4-yl)-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea; MS (ESI) m/z 462.
    • Example 102 Preparation of 1-{4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea Step 1: Preparation of 3-(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane
  • In a three neck flask equipped with stirring bar under N2 atmosphere tropine (1 g, 4.24 mmol) was suspended in (anhydrous) THF (15 mL). The mixture was cooled to −78° C. and BuLi (2M in THF) (5.53 ml, 1.2 eq) was added dropwise and the mixture was allowed to warm to 25° C. over 30 minutes. To the reaction mixture 2,4,-dichloro-6-morpholin-4-yl-[1,3,5]triazine (996 mg, 4.24, mmole) was added and allowed to stir overnight. For work up, ether (100 mL) was added. The organic layer was washed with water (20 mL) and brine (20 mL) and dried over MgSO4, filtered and the solvents were removed to obtain a colorless oil. Further purification by flash-chromatography using CH2Cl2/MeOH/NH3 (15:1:0.1) gave the product as white solid (600 mg, 42% yield); MS (ESI) m/z 340
    • Step 2: Preparation of 4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine
  • To a microwave processing tube was added dimethoxyethane (4 mL), aqueous Na2CO3 (2 molar)(1 mL, 2 mmol, 2 eq), (Ph3P)4Pd (85 mg, 0.074 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (482 mg, 2.21 mmol, 1.5 eq) and the 3-(4-chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane (500 mg, 1.47 mmol) and the vessel was sealed. The mixture was heated to 140° C. for 60 minutes. The solvents were distilled and the crude compound was purified by silica gel chromatography using CH2Cl2/ethyl acetate (10:1) and later with CH2Cl2/MeOH/NH3 (10:1:0.1) to give the product as an off-white solid (300 mg, 51% yield); MS (ESI) m/z 369.
    • Step 3: Preparation of 1-{4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea
  • To a stirred solution of triphosgene (60 mg, 0.20 mmol) in CH2Cl2 (3 mL) was added 4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine (100 mg, 0.25 mmol) at 25° C. The reaction mixture was stirred for 15 min and 4-aminopyridine (70 mg, 0.75 mmol) and NEt3 (346 μL, 2.5 mmol) were added and the reaction mixture was stirred for additional 1 hr. The solvents were removed and the crude mixture was purified by semi-prep-HPLC(NH3-method) to give 1-{4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea (28 mg, 22% yield); MS (ESI) m/z 517.
    • Example 103 Preparation of 4-(3-{4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-ureido)-benzamide
  • To a stirred solution of triphosgene (120 mg, 0.40 mmol) in CH2Cl2 (3 mL) was added 4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine (200 mg, 0.5 mmol) at 25° C. The reaction mixture was stirred for 15 min and 4-aminobenzamide (204 mg, 1.5 mmol) and NEt3 (692 μL, 5 mmol) were added and the reaction mixture was stirred for additional 1 hr. The solvents were removed and the crude mixture was purified by semi-prep-HPLC (NH3-method) to give 4-(3-{4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-ureido)-benzamide (42 mg, 15% yield) MS (ESI) m/z 559.
    • Example 104 Preparation of 3-({4-Morpholin-4-yl-6-[4-(3-pyridin-4-yl-ureido)-phenyl]-[1,3,5]triazin-2-ylamino}-methyl)-azetidine-1-carboxylic acid tert-butyl ester Step 1: Preparation of 3-[(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino)-methyl]-azetidine-1-carboxylic acid tert-butyl ester
  • To a solution of the 3-aminomethyl-azetidine-1-carboxylic acid tert-butyl ester HCl salt (945 mg, 4.24 mmol) and NEt3 (856 mg, 8.48 mmol) in THF (10 mL) at 0° C. was added a suspension of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (996 mg, 4.24 mmol) at 0° C. The reaction mixture was stirred for another 1 hr at 0° C. and allowed to warm to 20° C. and stirred for 1-4 hrs to drive the reaction to completion. Silica gel (20 g) was added to the reaction mixture and the solvent was removed so that product was adsorbed on the silica gel. The silica gel plug was placed on top of a column to purify by flash chromatography using CH2Cl2/MeOH/NH3 (20:1:01) eluent. After unifying the product fraction, and evaporation of solvent, (750 mg, 46% yield) product was obtained as yellow solid; MS (ESI) m/z 385
    • Step 2: Preparation of 3-{[4-(4-Amino-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester
  • To a microwave processing tube was added dimethoxyethane (15 mL), aqueous Na2CO3 (2 molar)(4 mL, 8 mmol, 2 eq), (Ph3P)4Pd (317 mg, 0.55 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1.81 g, 8.30 mmol, 1.5 eq) and 3-[(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino)-methyl]-azetidine-1-carboxylic acid tert-butyl ester (1.3 g, 5.53 mmol) and the vessel was sealed. The mixture was heated to 140° C. for 60 minutes. The solvents were removed and the crude compound was purified by silica gel chromatography using CH2Cl2/Ethyl acetate (10:1) and later CH2Cl2/MeOH/NH3 (15:1:0.1) to give the product as a off-white solid (1.3 g, 53% yield).
  • MS (ESI) m/z=442.
    • Step 3: Preparation of 3-({4-Morpholin-4-yl-6-[4-(3-pyridin-4-yl-ureido)-phenyl]-[1,3,5]triazin-2-ylamino}-methyl)-azetidine-1-carboxylic acid tert-butyl ester
  • To a stirred solution of triphosgene (269 mg, 0.90 mmol) in CH2Cl2 (5 mL) was added 3-{[4-(4-Amino-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester (500 mg, 1.13 mmol) at 25° C. The reaction mixture was stirred for 15 min and 4-aminopyridine (319 mg, 3.39 mmol) and NEt3 (1.56 mL, 11.3 mmol) were added and the reaction mixture was stirred for additional 1 hr. The solvents were removed on a rotary evaporator and the crude mixture was purified by semi-prep-HPLC (TFA-method) to give 3-({4-Morpholin-4-yl-6-[4-(3-pyridin-4-yl-ureido)-phenyl]-[1,3,5]triazin-2-ylamino}-methyl)-azetidine-1-carboxylic acid tert-butyl ester (150 mg, 16% yield); MS (ESI) m/z 562.
    • Example 105 Preparation of 1-(4-{4-[(azetidin-3-ylmethyl)-amino]-6-morpholin-4-yl-[1,3,5]triazin-2-yl}-phenyl)-3-pyridin-4-yl-urea
  • 3-({4-Morpholin-4-yl-6-[4-(3-pyridin-4-yl-ureido)-phenyl]-[1,3,5]triazin-2-ylamino}-methyl)-azetidine-1-carboxylic acid tert-butyl ester (100 mg, 0.18 mmol) was dissolved CH2Cl2 (1 mL) and TFA (1 mL) was added. It was stirred for 16 hrs at 25° C. and then the solvents were removed under reduced pressure and the residue was treated with acetonitrile/MeOH (1:1) (2 mL) to obtain a white solid, which was collected by filtration to obtain the product as bis-TFA salt (59 mg, 46% yield). MS (ESI) m/z 462.
    • Example 106 Preparation of Tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate
  • Tert-butyl 4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate was prepared according to Löwik, D. W. P. M. and Lowe, C. R. Eur. J. Org. Chem. 2001, 2825-2839.
    • Step 1: Preparation of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate
  • To a solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.49 g, 3.3 mmol) in water (18 mL) was added a suspension of tert-butyl 4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (1.0 g, 3.0 mmol) in acetone (about 10 mL). The suspension was stirred magnetically while solid sodium carbonate (0.70 g, 6.6 mmol) was added in a single portion. The mixture was stirred for two hours while heating in a 70-75° C. in an oil bath. After allowing the mixture to cool to room temperature, the title compound was removed by filtration, washed with water, and dried under vacuum.
  • MS (ES+) 411.0, 412.3 (M+H)+.
    • Step 2: Preparation of tert-butyl 4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate
  • A suspension of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (1.0 g, 2.4 mmol), 4-aminophenylboronic acid, pinacol ester (0.69 g, 3.2 mmol), and tetrakis(triphenylphosphine) palladium (0.28 g, 0.24 mmol) in aqueous 2 M sodium carbonate solution (3 mL) and 1:1 ethanol/toluene (12 mL) was irradiated in the microwave at 120° C. for 1 hour. After cooling, the biphasic mixture was extracted thrice with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound.
  • MS (ES+) 468.1 (M+H)+.
    • Step 3: Preparation of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate
  • Crude tert-butyl 4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate (approx. 1.4 mmol) was dissolved in tetrahydrofuran (20 mL) and then treated sequentially with triphosgene (0.30 g, 1.0 mmol) and triethylamine (2 mL). After 5 minutes, the mixture was treated with a solution of 4-aminopyridine (0.53 g, 5.6 mmol) in tetrahydrofuran. The mixture was concentrated under reduced pressure to give crude tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate, a sample of which was purified by reversed phase HPLC to give a pure title compound.
  • MS (ES+) 588.2 (M+H)+.
    • Example 107 Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • Crude tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate (approx 1.4 mmol) was taken up in dichloromethane (20 mL) and treated with trifluoroacetic acid (5 mL). The mixture was concentrated under reduced the pressure. To the residue was added diethyl ether to give the title compound as a solid di-TFA salt, which was collected by filtration and dried under house vacuum; MS (ES+) 488.1 (M+H)+.
    • Example 108 Preparation of 1-{4-[4-(4-methylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (115 mg) in 1:198% formic acid and 37% formalin (4 mL) was heated at 75° C. for 90 minutes, then concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 502.3 (M+H)+.
    • Example 109 Preparation of 1-{4-[4-(4-benzylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (130 mg) in dichloromethane (4 mL) and triethylamine (0.10 mL) was treated with benzaldehyde (0.10 mL), followed by sodium triacetoxyborohydride (80 mg). The mixture was concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 578.3 (M+H)+.
    • Example 110 Preparation of 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (150 mg) in dichloromethane (4 mL) and triethylamine (0.12 mL) was treated with 3-pyridinecarboxaldehyde (0.1 mL), followed by sodium triacetoxyborohydride (80 mg). The mixture was concentrated to dryness and purified on HPLC to give the title compound as its tri-TFA salt; MS (ES+) 579.3 (M+H)+.
    • Example 111 Preparation of 1-{4-[4-(4-acetylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (230 mg) in dichloromethane (4 mL) and triethylamine (1 mL) was treated with acetyl chloride. The mixture was concentrated to dryness and purified on HPLC to give the title compound as its TFA salt; MS (ES+) 530.3 (M+H)+.
    • Example 112 Preparation of 1-(4-{4-[4-(N,N-dimethylglycyl)piperazin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (64 mg) in dichloromethane (4 mL) and triethylamine (1 mL) was treated with dimethylaminoacetyl chloride hydrochloride (100 mg). The mixture was heated with a heat gun, then concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 573.3 (M+H)+.
    • Example 113 Preparation of 1-{4-[4-(4-isonicotinoylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (100 mg) in dichloromethane (4 mL) and triethylamine (1 mL) was treated with isonicotinoyl chloride (100 mg). The mixture was concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 593.1 (M+H)+.
    • Example 114 Preparation of Methyl 4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]piperazine-1-carboxylate
  • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (75 mg) in dichloromethane (2 mL), tetrahydrofuran (2 mL), and triethylamine (1 mL) was treated with methyl chloroformate (0.10 mL). The mixture was concentrated to dryness and purified on RP-HPLC to give the title compound as its TFA salt. MS (ES+) 546.3 (M+H)+.
    • Example 115 Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea Step 1: Preparation of 1-(4,6-dichloro-1,3,5-triazin-2-yl)piperidin-4-one
  • To magnetically stirred ice-water (72 mL) was added a solution of cyanuric chloride (2.2 g, 12 mmol) in acetone (48 mL), followed by piperidone monohydrate hydrochloride (1.8 g, 12 mmol) as a suspension in acetone (20 mL) and water (10 mL). To the mixture was added a suspension of sodium hydrogen carbonate (2.2 g, 24 mmol) in water (25 mL). The mixture was stirred at 0° C. for two hours. The title compound was collected by filtration, washed with water, and dried under vacuum.
  • MS (ES+) 248.8 (M+H)+.
    • Step 2: Preparation of 1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperidin-4-one
  • To an aqueous solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (66 mL) was added 1-(4,6-dichloro-1,3,5-triazin-2-yl)piperidin-4-one (2.7 g, 11 mmol) as a suspension in acetone (40 mL). To the mixture was added solid sodium carbonate (2.5 g, 24 mmol). The suspension was stirred at 80° C. for two hours and then allowed to cool to room temperature. The title compound was collected by filtration, washed with water, and dried under vacuum; MS (ES+) 324.4 (M+H)+.
    • Step 3: Preparation of 1-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperidin-4-one
  • A suspension of 1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperidin-4-one (1.0 g, 3.1 mmol), 4-aminophenylboronic acid, pinacol ester (1.0 g, 4.7 mmol), and tetrakis(triphenylphosphine) palladium (0.20 g, 0.17 mmol) in aqueous 2 M sodium carbonate solution (3 mL) and 1:1 ethanol/toluene (12 mL) was irradiated in the microwave at 120° C. for 1 hour. After cooling, the biphasic mixture was extracted thrice with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound as a golden yellow foam.
  • MS (ES+)=381.6 (M+H)+.
    • Step 4: Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • A mixture of crude 1-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperidin-4-one (approx. 3.1 mmol) and triethylamine (4 mL) in dichloromethane (30 mL) was treated with triphosgene (0.71 g, 2.4 mmol). The mixture was then treated with a solution of 4-aminopyridine (1.8 g, 19 mmol) in tetrahydrofuran (20 mL). The mixture was concentrated to dryness under reduced pressure and the residue purified by HPLC to give the title compound as its TFA salt. MS (ES+) 501.2 (M+H)+.
    • Example 116 Preparation of 1-{4-[4-(4-hydroxypiperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (56 mg) was taken up in methanol/tetrahydrofuran (1:1, 6 mL), and the mixture at 0° C. was treated with sodium borohydride (10 mg). After warming to room temperature, the mixture was concentrated to a residue which then was purified by HPLC to give the title compound as its TFA salt; MS (ES+) 503.0 (M+H)+.
    • Example 117 Preparation of 1-(4-{4-[4-(benzylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (85 mg) in dichloromethane (3 mL) and tetrahydrofuran (3 mL) was treated with benzylamine (0.030 mL), followed by glacial acetic acid (0.016 mL) and sodium triacetoxyborohydride (89 mg). After completion of the reaction, methanol was added and mixture was concentrated to dryness. The residue was purified by HPLC to give the title compound as its di-TFA salt.
  • MS (ES+) 592.3 (M+H)+.
    • Example 118 Preparation of 1-(4-{4-[4-(methylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) in tetrahydrofuran (5 mL) was treated with methylamine (2.0 M solution in tetrahydrofuran, 0.16 mL), followed by glacial acetic acid (0.009 mL) and sodium triacetoxyborohydride (51 mg). After completion of the reaction, methanol was added and mixture was concentrated to dryness. The residue was purified by HPLC to give the title compound as its di-TFA salt; MS (ES+) 516.3 (M+H)+.
    • Example 119 Preparation of 1-(4-{4-[4-(ethylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) in tetrahydrofuran (5 mL) was treated with ethylamine (2.0 M solution in tetrahydrofuran, 0.16 mL), followed by glacial acetic acid (0.009 mL) and sodium triacetoxyborohydride (51 mg). After completion of the reaction, methanol was added and mixture was concentrated to dryness. The residue was purified by HPLC to give the title compound as its di-TFA salt; MS (ES+) 530.3 (M+H)+.
    • Example 120 Preparation of 1-{4-[4-(4-{[2-(dimethylamino)ethyl]amino}piperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • The titled compound was prepared by the procedure as outlined in example 118, by reacting 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) with N,N-dimethylethylenediamine (0.026 mL) and purified by HPLC and isolated as its tri-TFA salt; MS (ES+) 573.7 (M+H)+.
    • Example 121 Preparation of 1-{4-[4-(4-morpholin-4-ylpiperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • By reacting 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) with 1-(2-aminoethyl)pyrrolidine (0.030 mL) and following the procedure as mentioned in Experimental 118, the title product was isolated as its tri-TFA salt; MS (ES+) 599.8 (M+H)+.
    • Example 122 Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • By reacting 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (40 mg) and 1-methylpiperazine (0.050 mL) and following the procedure as outlined in example 118, the titled compound was isolated after HPLC purification as its tri-TFA salt; MS (ES+) 585.9 (M+H)+.
    • Example 123 Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-hydroxyethylamino)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) and ethanolamine (0.020 mL) and following the procedure as outlined in example 118, the title compound was isolated as its di-TFA salt after HPLC purification. MS (ES+) 546.7 (M+H)+.
    • Example 124 Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-morpholinoethylamino)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg)and 1-(2-aminoethyl)morpholine (0.031 mL) and following the procedure as outlined in example 118, the titled compound was isolated as its tri-TFA salt after HPLC purification; MS (ES+) 615.9 (M+H)+.
    • Example 125 Preparation of Methyl 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate
  • Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) and glycine methyl ester hydrochloride (20 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118 the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 574.8 (M+H)+.
    • Example 126 Preparation of 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetamide
  • Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) and glycinamide hydrochloride (18 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118 the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 559.8 (M+H)+.
    • Example 127 Preparation of Tert-butyl 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate
  • Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (60 mg) and glycine tert-butyl ester hydrochloride (33 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118, the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 616.9 (M+H)+.
    • Example 128 Preparation of 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetic acid
  • Tert-butyl 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate (28 mg) in dichloromethane (3 mL) was treated with trifluoroacetic acid (1 mL) and then concentrated to dryness to give the title compound as its TFA salt.
  • MS (ES+) 560.2 (M+H)+.
    • Example 129 Preparation of 4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]aniline
  • MS (ES+) 399.47 (M+H)+.
    • Example 130 Preparation of 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ES+) 519.58 (M+H)+.
    • Example 131 Preparation of 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ES+) 519.58 (M+H)+.
    • Example 132 Preparation of 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-phenylurea
  • MS (ES+) 518.59 (M+H)+.
    • Example 133 Preparation of 1-[4-(dimethylamino)phenyl]-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ES+) 561.66 (M+H)+.
    • Example 134 Preparation of 1-(4-cyanophenyl)-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ES+) 543.60 (M+H)+.
    • Example 135 Preparation of 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(2-methylpyridin-4-yl)urea
  • MS (ES+) 533.61 (M+H)+.
    • Example 136 Preparation of 1-[2-(dimethylamino)ethyl]-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ES+) 513.62 (M+H)+.
    • Example 137 Preparation of 1-[4-(4-morpholin-4-yl-6-quinolin-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
  • HRMS: calcd for C28H24N8O2+H+, 505.20950; found (ESI, [M+H]+Obs'd), 505.2098; HRMS: calcd for C28H24N8O2+H+, 505.20950; found (ESI, [M+H]+ Calc'd), 505.2095.
    • Example 138 Preparation of 2-(difluoromethyl)-1-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)-1H-benzimidazole
  • A solution of cyanuric chloride (922 mg, 5 mmol) in acetone (5 mL) was added to ice. A solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (750 mg, 5 mmol) and triethylamine (2.1 mL, 15 mmol) in aqueous acetone was then added. After 20 min the precipitate was collected to give 1.0 g of a white powder which was a 7:3 mixture of 3-(4,6-dichloro-1,3,5-triazine-2,4-diyl)-8-oxa-3-azabicyclo[3.2.1]octane and 3,3′-(6-chloro-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane). Treatment of the mixture (400 mg) with 2-(difluoromethyl)-1H-benzo[d]imidazole (146 mg, 0.87 mmol) and K2CO3 (967 mg, 7 mmol) in DMF (2.5 mL) for 18 h, followed by addition of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (150 mg) gave, after 1 h, 3,3′-(6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane) after purification by HPLC. (M+H) 475.
    • Example 139 Preparation of 2-(difluoromethyl)-1-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1H-benzimidazole
  • To a stirred solution of 3-(4,6-dichloro-1,3,5-triazine-2,4-diyl)(8-oxa-3-azabicyclo[3.2.1]octane) (2.61 g, 10 mmol) in acetone/ice, morpholine (900 mg, 12 mmol) and triethylamine (5 ml) was added. The reaction mixture was stirred at room temperature for 3 h. Separated white solid was filtered and washed with water. The crude product obtained was pure enough and taken to next step without purification. Treatment of the mixture (270 mg. 0.87 mmol) with 2-(difluoromethyl)-1H-benzo[d]imidazole (146 mg, 0.87 mmol) and K2CO3 (967 mg, 7 mmol) in DMF (2.5 mL) for 18 hours gave 2-(difluoromethyl)-1-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1H-benzimidazole after purification by HPLC. (M+H) 445.
    • Example 140 Preparation of 1-[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
  • mp 212° C.; MS (ESI) m/z 433.3.
    • Example 141 Preparation of methyl 4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate
  • mp 212° C.; MS (ESI) m/z 490.2.
    • Example 142 Preparation of 1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
  • MS (ESI) m/z 561.6.
    • Example 143 Preparation of 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide
  • MS (ESI) m/z 575.6.
    • Example 144 Preparation of 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-1-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ESI) m/z 531.5.
    • Example 145 Preparation of methyl(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamate
  • MS (ESI) m/z 650.7.
    • Example 146 Preparation of 1-cyclopropyl-3-(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea
  • MS (ESI) m/z 675.8.
    • Example 147 Preparation of N′,N′″-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazine-2,4-diyl]di-4,1-phenylene}bis{1-[4-(4-methylpiperazin-1-yl)phenyl]urea}
  • MS (ESI) m/z 809.9.
    • Example 148 Preparation of 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 712.8.
    • Example 149 Preparation of 1-(4-{4-[(2-aminoethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea
  • HRMS: calcd for C23H27N9O2+H+, 462.23605; found (ESI, [M+H]+Obs'd), 462.2358.
    • Example 150 Preparation of 1-{4-[4-anilino-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • HRMS: calcd for C27H26N8O2+H+, 495.22515; found (ESI, [M+H]+Obs'd), 495.2249.
    • Example 151 Preparation of 4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(2-piperidin-1-ylethyl)benzamide
  • MS (ESI) m/2 308.6; HRMS: calcd for C32H41N9O4+H+, 616.33543; found (ESI, [M+H]+Obs'd), 616.3347; HRMS: calcd for C32H41N9O4+H+, 616.33543; found (ESI, [M+H]+ Calc'd), 616.3354.
    • Example 152 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(morpholin-4-ylcarbonyl)phenyl]urea
  • MS (ESI) m/z 575.3; HRMS: calcd for C29H34N8O5+H+, 575.27249; found (ESI, [M+H]+Obs'd), 575.2722; HRMS: calcd for C29H34N8O5+H+, 575.27249; found (ESI, [M+H]+ Calc'd), 575.2725.
    • Example 153 Preparation of 1-(4-{4-[(2-hydroxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea
  • MS (ESI) m/z 463.5.
    • Example 154 Preparation of 1-{4-[4-(azetidin-3-ylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 474.5
    • Example 155 Preparation of 1-(4-{4-[(2-morpholin-4-ylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea
  • MS (ESI) m/z 532.6.
    • Example 156 Preparation of 1-(4-{4-[(3-aminopropyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea
  • MS (ESI) m/z 476.5.
    • Example 157 Preparation of 1-(4-{4-[(4-cyclopentylpiperazin-1-yl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea
  • MS (ESI) m/z 571.7
    • Example 158 1-{4-[4-isopropoxy-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ESI) m/z 462.53.
    • Example 159 Preparation of 1-{4-[4-isopropoxy-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea Example 160 Preparation of 1-{4-[4-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ESI) m/z 438.8.
    • Example 161 Preparation of 1-[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
  • MS (ESI) m/z 391.5.
    • Example 162 Preparation of methyl 4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate
  • MS (ESI) m/z 449.2.
    • Example 163 Preparation of 1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
  • MS (ESI) m/z 584.7.
    • Example 164 Preparation of 4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide
  • MS (ESI) m/z 530.63.
    • Example 165 Preparation of N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide
  • MS (ESI) m/z 518.6.
    • Example 166 Preparation of 1-[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
  • MS (ESI) m/z 516.6.
    • Example 167 Preparation of 1-(4-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
  • HRMS: calcd for C31H39N9O4+H+, 602.31978; found (ESI, [M+H]+Obs'd), 602.3192;
    • Example 168 Preparation of 1-[4-({4-[2-(dimethylamino) ethyl]piperazin-1-yl}carbonyl)phenyl]-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
  • HRMS: calcd for C33H44N10O4+H+, 645.36198; found (ESI, [M+H]+Obs'd), 645.3615;
    • Example 169 Preparation of 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(piperidin-4-ylmethyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea
  • MS (ESI) m/z 515.6.
    • Example 170 Preparation of 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(2-piperidin-4-ylethyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea
  • MS (ESI) m/z 529.65.
    • Example 171 Preparation of 1-{4-[4-(3-methylimidazolidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 487.5.
    • Example 172 Preparation of 1-{4-[4-(3-methyltetrahydropyrimidin-1(2H)-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 501.6
    • Example 173 Preparation of 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-1-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 530.6.
    • Example 174 Preparation of 1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • MS (ESI) m/z 521.58
    • Example 175 Preparation of 1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
  • MS (ESI) m/z 618.7
    • Example 176 Preparation of 2-hydroxyethyl (4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamate
  • MS (ESI) m/z 489.53.
    • Example 177 Preparation of 1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-methylurea
  • MS (ESI) m/z 458.52.
    • Example 178 Preparation of 1-cyclopropyl-3-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea
  • MS (ESI) m/z 484.56.
    • Example 179 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea
  • MS (ESI) m/z 642.4; HRMS: calcd for C34H43N9O4+H+, 642.35108; found (ESI-FTMS, [M+H]1+), 642.3491;
    • Example 180 Preparation of 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(piperidin-3-ylmethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 516.61
    • Examples 181 Preparation of 1-{4-[4-(4-aminobutoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 490.57
    • Examples 182 Preparation of 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-4-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 530.63
    • Example 183 Preparation of 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(piperidin-4-ylmethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 516.61
    • Example 184 Preparation 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid
  • MS (ESI) m/z 476.53
    • Example 185 Preparation of N-[2-(dimethylamino)ethyl]-4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide
  • MS (ESI) m/z 562.6
    • Example 186 Preparation of 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
  • MS (ESI) m/z 433.5
    • Example 187 Preparation of N-[2-(dimethylamino)ethyl]-4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide
  • MS (ESI) m/z 548.67.
    • Example 188 Preparation of methyl 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate
  • MS (ESI) m/z 490.56.
    • Example 189 Preparation of 1-(4-{4-morpholin-4-yl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • HRMS: calcd for C24H26N8O3+H+, 475.22006; found (ESI, [M+H]+Obs'd), 475.2201.
    • Example 190 Preparation of 1-{4-[4-(methylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 432.49.
    • Example 191 Preparation of 1-{4-[4-(ethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 446.52
    • Example 192 Preparation of 1-{4-[4-(dimethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 446.52.
    • Example 193 Preparation of 1-{4-[4-(isopropylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 460.54
    • Example 194 Preparation of 1-{4-[4-(diethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 474.57.
    • Example 195 Preparation of 4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino) benzoic acid; mp 204° C.; MS (ESI) m/z 476.2 Example 196 Preparation of 1-[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
  • mp 170° C.; MS (ESI) m/z 558.2.
    • Example 197 Preparation of 4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[2-(dimethylamino)ethyl]-N-methylbenzamide
  • MS (ESI) m/z 280.7.
    • Example 198 Preparation of 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[2-(dimethylamino)ethyl]-N-methylbenzamide Example 199 Preparation of 1-{4-[4-(1-ethoxyvinyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ESI) m/z 447.499.
    • Example 200 Preparation of 1-{4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • HRMS: calcd for C22H25N7O4+H+, 452.20408; found (ESI, [M+H]+Obs'd), 452.2047;
    • Example 201 Preparation of 1-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]pyridinium
  • HRMS: calcd for C30H38N9O4+H+, 589.31195; found (ESI, [M+H]+), 589.3035;
    • Example 202 Preparation of 1-(4-{4-[ethyl(methyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea
  • MS (ESI) m/z 460.54.
    • Example 203 Preparation of 1-{4-[4-(sec-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 474.57.
    • Example 204 Preparation of 1-{4-[4-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 492.54.
    • Example 205 Preparation of 1-(4-{4-[bis(2-hydroxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea
  • MS (ESI) m/z 506.57
    • Example 206 Preparation of 1-(4-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea
  • MS (ESI) m/z 499.58.
    • Example 207 Preparation of 1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 592.71.
    • Example 208 Preparation of 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea
  • MS (ESI) m/z 578.68.
    • Example 209 Preparation of 1-[4-(4-acetyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
  • MS (ESI) m/z 419.406
    • Example 210 Preparation of 1-(4-{4-morpholin-4-yl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea
  • MS (ESI) m/z 654.3; HRMS: calcd for C35H43N9O4+H+, 654.35108; found (ESI-FTMS, [M+H]1+), 654.35129;
    • Example 211 Preparation of methyl 4-[({4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate
  • HRMS: calcd for C25H28N6O6+H+, 509.21431; found (ESI, [M+H]+Obs'd), 509.214.
    • Example 212 Preparation of 1-methyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea
  • MS (ESI) m/z 397.48.
    • Example 213 Preparation of 1-cyclopropyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea
  • MS (ESI) m/z 423.52.
    • Example 214 Preparation of 1-(2-hydroxyethyl)-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea
  • MS (ESI) m/z 427.51.
    • Example 215 Preparation of 1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • MS (ESI) m/z 460.54.
    • Example 216 Preparation of 1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea
  • MS (ESI) m/z 460.54.
    • Example 217 Preparation of 1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
  • MS (ESI) m/z 557.70.
    • Example 218 Preparation of 1-{4-[(2,2-dimethylhydrazino)carbonyl]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea
  • MS (ESI) m/z 545.65.
    • Example 219 Preparation of 4-{[(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-pyrrolidin-1-ylbenzamide
  • MS (ESI) m/z 571.69.
    • Example 220 Preparation of 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea
  • MS (ESI) m/z 546.68.
    • Example 221 Preparation of 1-[4-(hydroxymethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea
  • MS (ESI) m/z 489.58
    • Example 222 Preparation of 1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea
  • MS (ESI) m/z 503.61.
    • Example 223 Preparation of 1-{4-[4-(1-hydroxyethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ESI) m/z 421.46.
    • Example 224 Preparation of 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
  • MS (ESI) m/z 514.59.
    • Example 225 Preparation of methyl 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate
  • MS (ESI) m/z 462.51
    • Example 226 Preparation of methyl 4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate
  • MS (ESI) m/z 516.55.
    • Example 227 Preparation of 4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid
  • MS (ESI) m/z 502.53
    • Example 228 Preparation of 1-(4-{4-morpholin-4-yl-6-[2-(pyridin-4-ylamino)ethyl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • HRMS: calcd for C26H27N9O2+H+, 498.23605; found (ESI, [M+H]+Obs'd), 498.2383.
    • Example 229 Preparation of 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • HRMS: calcd for C31H39N9O3+H+, 586.32486; found (ESI, [M+H]+Obs'd), 586.3245;
    • Example 230 Preparation of 1-(4-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • HRMS: calcd for C28H31N7O4+H+, 530.25103; found (ESI, [M+H]+Obs'd), 530.2508;
    • Example 231 Preparation of 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[2-(dimethylamino)ethyl]benzamide
  • MS (ESI) m/z 546.676.
    • Example 232 Preparation of 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
  • MS (ESI) m/z 559.4.
    • Example 233 Preparation of 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid
  • MS (ESI) m/z 448.483
    • Example 234 Preparation of 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • HRMS: calcd for C23H30N8O3+H+, 467.25136; found (ESI, [M+H]+Obs'd), 467.2525.
    • Example 235 Preparation of 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • HRMS: calcd for C27H31N9O3+H+, 530.26226; found (ESI, [M+H]+Obs'd), 530.2638;
    • Example 236 Preparation of 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
  • MS (ESI) m/z 531.1.
    • Example 237 Preparation of N-[2-(dimethylamino)ethyl]-4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide Example 238 Preparation of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
  • MS (ESI) m/z 558.711
    • Example 239 Preparation of 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea
  • MS (ESI) m/z 462.554.
    • Example 240 Preparation of 4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2-(dimethylamino)ethyl]-N-methylbenzamide
  • MS (ESI) m/z 586.721.
    • Example 241 Preparation of 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea
  • MS (ESI) m/z 586.741.
    • Example 242 Preparation of N-[2-(dimethylamino)ethyl]-4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide
  • MS (ESI) m/z 532.649.
    • Example 243 Preparation of N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide
  • MS (ESI) m/z 534.62.
    • Example 244 Preparation of N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide
  • MS (ESI) m/z 520.60.
    • Example 245 Preparation of 4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methyl-N-[2-(methylamino)ethyl]benzamide
  • MS (ESI) m/z 520.60.
    • Example 246 Preparation of 1-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
  • MS (ESI) m/z 532.61.
    • Example 247 Preparation of 1-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
  • MS (ESI) m/z 546.63.
    • Example 248 Preparation of 4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(2-piperidin-1-ylethyl)benzamide
  • MS (ESI) m/z 560.66.
    • Example 249 Preparation of 1-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 514.3; HRMS: calcd for C28H31N7O3+H+, 514.25611; found (ESI, [M+H]+Obs'd), 514.2561.
    • Example 250 Preparation of 1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • HRMS: calcd for C32H41N9O3+H+, 600.34051; found (ESI, [M+H]+Obs'd), 600.3405.
    • Example 251 Preparation of 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[4-(4-methylpiperazin-1-yl)phenyl]benzamide; MS (ESI) m/z 621.77. Example 252 Preparation of 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]urea; MS (ESI) m/z 532.71. Example 253 Preparation of 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[4-(4-methylpiperazin-1-yl)phenyl]benzamide; MS (ESI) m/z 649.82. Example 254 Preparation of 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea; MS (ESI) m/z 544.728. Example 255 Preparation of 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-formylphenyl)urea; MS (ESI) m/z 461.2. Example 256 Preparation of tert-butyl(1R,4R)-5-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; mp 192° C.; MS (ESI) m/z 574.3. Example 257 Preparation of tert-butyl (1R,4R)-5-[4-(4-{[(4-acetylphenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; mp 202° C.; MS (ESI) m/z 615.3; Example 258 Preparation of 1-(4-{4-[(2-methoxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z 476.54 Example 259 Preparation of 1-{4-[4-{[(1S)-2-hydroxy-1-methylethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 476.54. Example 260 Preparation of 1-{4-[4-{[(1R)-2-hydroxy-1-methylethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 476.54.
    • Example 261 Preparation of 1-(4-{4-[(2-hydroxy-1,1-dimethylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea
  • MS (ESI) m/z 490.57.
    • Example 262 Preparation of 1-{4-[4-(tert-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • MS (ESI) m/z 474.57.
    • Example 263 Preparation of 4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(pyridin-2-ylmethyl)benzamide;
  • mp 296-298° C.; MS (ESI) m/z 298.6. HRMS: calcd for C31H33N9O4+H+, 596.27283; found (ESI, [M+H]+Obs'd), 596.2724; HRMS: calcd for C31H33N9O4+H+, 596.27283; found (ESI, [M+H]+ Calc'd), 596.2728.
    • Example 264 Preparation of 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-piperazin-1-ylphenyl)urea
  • HRMS: calcd for C32H39N9O3+H+, 598.32486; found (ESI, [M+H]+Obs'd), 598.3247; HRMS: calcd for C32H39N9O3+H+, 598.32486; found (ESI, [M+H]+ Calc'd), 598.3249;
    • Example 265 Preparation of 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
  • HRMS: calcd for C33H41N9O3+H+, 612.34051; found (ESI, [M+H]+Obs'd), 612.3402;
    • Example 266 Preparation of 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • HRMS: calcd for C30H38N8O4+H+, 575.30888; found (ESI, [M+H]+Obs'd), 575.3088; HRMS: calcd for C30H38N8O4+H+, 575.30888; found (ESI, [M+H]+ Calc'd), 575.3089.
    • Example 267 Preparation of 1-(4-{4-[2-(1,3-dioxan-2-yl)ethyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • HRMS: calcd for C25H29N7O4+H+, 492.23538; found (ESI, [M+H]+Obs'd), 492.2364.
    • Example 268 Preparation of 1-(4-{4-[2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • HRMS: calcd for C25H30N8O4+H+, 507.24628; found (ESI, [M+H]+Obs'd), 507.2471.
    • Example 269 Preparation of 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-{4-[2-(dimethylamino)ethoxy]phenyl}benzamide
  • MS (ESI) m/z 638.773.
    • Example 270 Preparation of 1-{4-[(4-benzylpiperidin-1-yl)carbonyl]phenyl}-3-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
  • MS (ESI) m/z 633.821.
    • Example 271 Preparation of 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide
  • MS (ESI) m/z 545.3.
    • Example 272 Preparation of 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide
  • MS (ESI) m/z 573.4.
    • Example 273 Preparation of 1-{4-[4-(6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ESI) m/z 504.551.
    • Example 274 Preparation of 1-(4-{4-[3-(dimethylamino)propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • MS (ESI) m/z 462.56.
    • Example 275 Preparation of 1-[4-(4-{3-[(1-methylethyl)amino]propyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
  • MS (ESI) m/z 476.59.
    • Example 276 Preparation of 1-{4-[4-morpholin-4-yl-6-(3-pyrrolidin-1-ylpropyl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ESI) m/z 488.60.
    • Example 277 Preparation of 1-(4-{4-[3-(4-methylpiperazin-1-yl)propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • MS (ESI) m/z 517.64.
    • Example 278 Preparation of 1-{4-[4-(3-{[2-(dimethylamino)ethyl]amino}propyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ESI) m/z 505.63.
    • Example 279 Preparation of 1-{4-[4-(3-hydroxypropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ESI) m/z 435.49.
    • Example 280 Preparation of 1-{4-[4-morpholin-4-yl-6-(3-oxopropyl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ESI) m/z 433.47.
    • Example 281 Preparation of tert-butyl-7-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate
  • HRMS: calcd for C30H37N9O5+H+, 604.29904; found (ESI, [M+H]+Obs'd), 604.2993.
    • Example 282 Preparation of 1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • HRMS: calcd for C24H26N8O4+H+, 491.21498; found (ESI, [M+H]+Obs'd), 491.2155.
    • Example 283 Preparation of 1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea
  • MS (ESI) m/z 612.759.
    • Example 284 Preparation of 4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2-(dimethylamino)ethyl]benzamide
  • MS (ESI) m/z 572.694.
    • Example 285 Preparation of 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea
  • MS (ESI) m/z 625.78
    • Example 286 Preparation of N-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]piperazine-1-carboxamide
  • MS (ESI) m/z 506.61
    • Example 287 Preparation of 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea
  • MS (ESI) m/z 543.63.
    • Example 288 Preparation of 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(methylamino)methyl]phenyl}urea
  • MS (ESI) m/z 556.67.
    • Example 289 Preparation of 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]urea
  • MS (ESI) m/z 600.73.
    • Example 290 Preparation of 1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ESI) m/z 503.57.
    • Example 291 Preparation of 1-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ESI) m/z 517.60.
    • Example 292 Preparation of 1-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ESI) m/z 545.61.
    • Example 293 Preparation of 1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-yl urea
  • MS (ESI) m/z 581.66.
    • Example 294 Preparation of 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-(4-morpholin-4-yl-6-propyl-1,3,5-triazin-2-yl)phenyl]urea
  • MS (ESI) m/z 517.4.
    • Example 295 Preparation of 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
  • MS (ESI) m/z 492.2.
    • Example 296 Preparation of 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
  • MS (ESI) m/z 503.
    • Example 297 Preparation of 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 530.701.
    • Example 298 Preparation of 1-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
  • MS (ESI) m/z 544.684.
    • Example 299 Preparation of 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylazetidin-3-yl)benzamide
  • MS (ESI) m/z 517.3; MS (ESI) m/z 259.2.
    • Example 300 Preparation of methyl 4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate
  • mp 218° C.; MS (ESI) m/z 477.3.
    • Example 301 Preparation of 4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid
  • MS (ESI) m/z 463.3.
    • Example 302 Preparation of tert-butyl-(1R,4R)-5-{4-[4-({[4-(1-hydroxyethyl)phenyl]carbamoyl}amino)phenyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
  • MS (ESI) m/z 617.4.
    • Example 303 Preparation of 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • HRMS: calcd for C33H41N9O3+H+, 612.34051; found (ESI, [M+H]+Obs'd), 612.3402; HRMS: calcd for C33H41N9O3+H+, 612.34051; found (ESI, [M+H]+ Calc'd), 612.3405.
    • Example 304 Preparation of 1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
  • MS (ESI) m/z 544.66.
    • Example 305 Preparation of N-[2-(dimethylamino)ethyl]-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide
  • MS (ESI) m/z 532.65.
    • Example 306 Preparation of N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide
  • MS (ESI) m/z 546.68.
    • Example 307 Preparation of N-(1-methylazetidin-3-yl)-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide
  • MS (ESI) m/z 530.63.
    • Example 308 Preparation of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 572.72.
    • Example 309 Preparation of 4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-pyridin-4-ylbenzamide
  • MS (ESI) m/z 538.61.
    • Example 310 Preparation of 4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-pyridin-3-ylbenzamide
  • MS (ESI) m/z 538.61.
    • Example 311 Preparation of N-cyclobutyl-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide
  • MS (ESI) m/z 515.62.
    • Example 312 Preparation of 1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
  • MS (ESI) m/z 583.70.
    • Example 313 Preparation of 1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-piperazin-1-ylphenyl)urea
  • MS (ESI) m/z 569.67.
    • Example 314 Preparation of 1-{4-[4,6-di-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
  • MS (ESI) m/z 583.70.
    • Example 315 Preparation of 1-(2-fluoroethyl)-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 561.6.
    • Example 316 Preparation of 1-cyclopropyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 555.71.
    • Example 317 Preparation of 1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 529.67.
    • Example 318 Preparation of 4-[({4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide
  • MS (ESI) m/z 634.745.
    • Example 319 1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea
  • MS (ESI) m/z 591.72.
    • Example 320 Preparation of 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-phenylpiperidin-1-yl)carbonyl]phenyl}urea
  • MS m/z 08-301429LMS.
    • Example 321 Preparation of 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(pyridin-4-ylmethyl)benzamide
  • MS (ESI) m/z 539.4; MS (ESI) m/z 270.2.
    • Example 322 Preparation of 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 558.711.
    • Example 323 Preparation of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 586.765.
    • Example 324 Preparation of N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide
  • MS (ESI) m/z 560.727.
    • Example 325 Preparation of 1-methyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea
  • MS (ESI) m/z 515.62.
    • Example 326 Preparation of 1-cyclopropyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea
  • MS (ESI) m/z 541.66.
    • Example 327 Preparation of 1-(2-fluoroethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea
  • MS (ESI) m/z 547.64.
    • Example 328 Preparation of 1-(2-hydroxyethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea
  • MS (ESI) m/z 545.65.
    • Example 329 Preparation of 4-{[(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide
  • MS (ESI) m/z 620.72.
    • Example 330 Preparation of 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-phenylurea
  • MS (ESI) m/z 577.69.
    • Example 331 Preparation of 1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 529.67.
    • Example 332 Preparation of 1-cyclopropyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 555.71.
    • Example 333 Preparation of 1-(2-fluoroethyl)-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 561.69.
    • Example 334 Preparation of 4-[({4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-yl]phenyl}carbamoyl)amino]benzamide
  • MS (ESI) m/z 634.745.
    • Example 335 Preparation of 1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea
  • MS (ESI) m/z 591.72;
    • Example 336 Preparation of 1-(2,3′-bipyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 566.4; HRMS: calcd for C30H31N9O3+H+, 566.26226; found (ESI, [M+H]+ Calc'd), 566.2623.
    • Example 337 Preparation of 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
  • MS (ESI) m/z 593.5.
    • Example 338 Preparation of N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide
  • MS (ESI) m/z 595.5.
    • Example 339 Preparation of 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 593.4.
    • Example 340 Preparation of 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • MS (ESI) m/z 468.3.
    • Example 341 Preparation of 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
  • MS (ESI) m/z 531.4.
    • Example 342 Preparation of 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid
  • MS (ESI) m/z 511.4.
    • Example 343 Preparation of 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
  • MS (ESI) m/z 565.4.
    • Example 344 Preparation of methyl 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate
  • MS (ESI) m/z 525.4.
    • Example 345 Preparation of 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]urea
  • MS (ESI) m/z 578.745.
    • Example 346 Preparation of 1-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
  • MS (ESI) m/z 454.1.
    • Preparation of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride
  • ((2S,5R)-1-benzylpyrrolidine-2,5-diyl)dimethanol (2.2 g, 10 mmol) was dissolved in ethanol/tetrahydrofuran (200 mL, 1:1), and the mixture was treated with 10% palladium on carbon (250 mg). The suspension was shaken under 50 psi of hydrogen until the consumption of hydrogen had ceased. The mixture was filtered through a pad of Celite™ diatomaceous earth, eluting with ethanol. The filtrate was concentrated to dryness to provide the title compound as a golden oil that solidified upon prolonged storage. MS (ES+)=132.2 (M+H)+.
    • Preparation of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol
  • A suspension of 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine (2.2 g, 8.0 mmol) in acetone (40 mL) was added to magnetically stirred ice water (60 mL). The mixture was treated with a solution of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride (1.0 g, 6.0 mmol) in acetone/water (20 mL, 3:1), followed by a suspension of sodium hydrogen carbonate (1.0 g, 12 mmol) in water (12 mL). After 30 minutes of stirring at 0° C., the mixture was treated with an additional quantity of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride (0.26 g, 1.6 mmol) in water (3 mL), followed by sodium hydrogen carbonate (0.35 g) in water (5 mL). The suspension was allowed to stir overnight while regaining room temperature. The title compound was isolated by Büchner filtration, washed with water, and dried under house vacuum. Compound identification by mass spectrometry was achieved via the analysis of the product reaction product of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol with excess morpholine in ethanol. MS (ES+)=417.2 (M+morpholine−Cl)+.
    • Preparation of ((2S,5R)-1-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol
  • A suspension of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol (0.91 g, 2.5 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.37 g, 2.5 mmol) in ethanol (13 mL) was treated with triethylamine (1 mL) and heated in a microwave reactor for 20 minutes at 130° C. The reaction mixture was purified by automated flash chromatography (methanol/chloroform) to provide the title compound as a hard peach colored foam. MS (ES+)=443.2 (M+H)+.
    • Preparation of 8-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • A solution of ((2S,5R)-1-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol (approximately 2.7 mmol) in dichloromethane (15 mL) was treated successively with tert-butyl dimethyl chlorosilane (1.0 g, 6.8 mmol) and imidazole (0.55 g, 8.1 mmol). The resulting suspension was stirred overnight at room temperature and then quenched with water. The aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified by automated flash chromatography (hexanes/ethyl acetate) to provide the title material. MS (ES+)=671.4 (M+H)+.
    • Preparation of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline
  • A suspension of palladium on charcoal (10%, 50 mg) and 8-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.55 g, 1.2 mmol) in tetrahydrofuran (20 mL) was stirred under a balloon of hydrogen overnight. The mixture was filtered through a pad of Celite™ diatomaceous earth and concentrated under reduced pressure to provide the title compound as a tan foam (0.42 g, 80%).
  • MS (ES+)=642.4 (M+H)+.
    • Example 347 Preparation of 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • A solution of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline (0.16 mmol) in dichloromethane (4 mL) was treated successively with triethylamine (1.6 mmol, 210 μL) and a triphosgene (24 mg, 0.08 mmol) solution in dichloromethane (500 μL). After 5 minutes, the mixture was treated with a solution of 4-aminopyridine (45 mg, 0.48 mmol) in warm tetrahydrofuran. After 1 hour, the reaction mixture was quenched with methanol and concentrated to dryness. The crude residue was treated with a saturated solution of hydrogen chloride in methanol. Upon complete desilylation, the mixture was concentrated to dryness and the residue purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy column running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 50% acetonitrile over 25 minutes. After concentration, the title compound was obtained as it trifluoroacetic acid salt (132 mg). MS (ES+)=533.3 (M+H)+.
    • Example 348 Preparation of 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
  • A solution of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline (0.16 mmol) in dichloromethane (4 mL) was treated successively with triethylamine (1.6 mmol, 210 μL) and a triphosgene (24 mg, 0.08 mmol) solution in dichloromethane (500 μL). After 5 minutes, the mixture was treated with 4-(4-methylpiperazin-1-yl)aniline (61 mg, 0.32 mmol). After 1 hour, the reaction mixture was quenched with methanol and concentrated to dryness. The crude residue was treated with a saturated solution of hydrogen chloride in methanol. Upon complete desilylation, the mixture was concentrated to dryness and the residue purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy column running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 50% acetonitrile over 25 minutes. After concentration, the title compound was obtained as it trifluoroacetic acid salt (100 mg). MS (ES+)=630.4 (M+H)+.
    • Example 349 Preparation of 1-(6-chloropyridin-3-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • HRMS: calcd for C25H27ClN8O3+H+, 523.19674; found (ESI, [M+H]+Obs'd), 523.1975.
    • Example 350 Preparation of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea
  • MS (ESI) m/z 614.8
    • Example 351 Preparation of 1-(4-aminophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
  • MS (ESI) m/z 477.1.
    • Example 352 Preparation of N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-N2,N2-dimethylglycinnamide
  • The 4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)aniline (50 mg, 0.127 mmol) was dissolved in dichloromethane (1.5 mL) and triethylamine (0.120 mL) and added to a solution of triphosgene (17 mg) in dichloromethane (0.5 mL). Stir for 5 minutes then added N-(4-aminophenyl)-N2,N2-dimethylglycinnamide (27 mg, 0.14 mmol). Purified by Gilson HPLC to provide the title compound as the TFA salt: 31.8 mg (35%) (M+H) m/z 614.3.
    • Example 353 Preparation of N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-pyrrolidin-1-ylacetamide
  • The 4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)aniline (50 mg, 0.127 mmol) was dissolved in dichloromethane (1.5 mL) and triethylamine (0.120 mL) and added to a solution of triphosgene (17 mg) in dichloromethane (0.5 mL). Stir for 5 minutes then added N-(4-aminophenyl)-2-pyrrolidin-1-ylacetamide (30 mg, 0.14 mmol) Purified by Gilson HPLC to provide the title compound as the TFA salt: 63.1 mg (66%) (M+H) m/z 640.3.
    • Example 354 Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea
  • Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilic aromatic substitution step. Following urea formation using methylamine, the Boc-piperazine intermediate was treated with TFA to provide the title compound. (M+H) 516.3.
    • Example 355 Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-cyclopropylurea
  • Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilic aromatic substitution step. Following urea formation using cyclopropylamine, the Boc-piperazine intermediate was treated with TFA to provide the title compound. (M+H) 542.3.
    • Example 356 Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-(2-fluoroethyl)urea
  • Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilic aromatic substitution step. Following urea formation using 2-fluoroethylamine, the Boc-piperazine intermediate was treated with TFA to provide the title compound. (M+H) 548.3.
    • Example 357 Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-(2-hydroxyethyl)urea
  • Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilic aromatic substitution step. Following urea formation using 2-aminoethanol, the Boc-piperazine intermediate was treated with TFA to provide the title compound. (M+H) 546.3.
    • Example 358 Preparation of 4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide
  • Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilic aromatic substitution step. Following urea formation using 4-aminobenzamide, the Boc-piperazine intermediate was treated with TFA to provide the title compound. (M+H) 621.3.
    • Example 359 Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-phenylurea
  • Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilic aromatic substitution step. Following urea formation using aniline, the Boc-piperazine intermediate was treated with TFA to provide the title compound. (M+H) 578.3.
    • Example 360 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea
  • Prepared as shown in Scheme 1, using commercially available tert-butyl 4-aminopiperidine-1-carboxylate in the second nucleophilic aromatic substitution step. Following urea formation using ethylamine, the Boc-piperidine intermediate was treated with TFA to provide the title compound. (M+H) 453.6.
    • Example 361 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea
  • Prepared as shown in Scheme 1, using N1-(2-(dimethylamino)ethyl)-N-1-methylbenzene-1,4-diamine in the urea formation step. (M+H) 614.3.
  • The required benzene-1,4-diamine intermediates for the following compounds were prepared as outlined in Scheme 4.
    • Example 362 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea
  • Prepared as shown in Scheme 1, using 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formation step. (M+H) 640.4.
    • Preparation of 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine
  • Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
    • Example 363 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea
  • Prepared as shown in Scheme 1, using N1-(2-methoxyethyl)benzene-1,4-diamine in the urea formation step. (M+H) 587.3.
    • Preparation of N1-(2-methoxyethyl)benzene-1,4-diamine
  • Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
    • Example 364 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea
  • Prepared as shown in Scheme 1, using 2-(4-aminophenylamino)ethanol in the urea formation step. (M+H) 573.3.
    • Preparation of 2-(4-aminophenylamino)ethanol
  • Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
    • Example 365 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea
  • Prepared as shown in Scheme 1, using N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine in the urea formation step. (M+H) 626.3.
    • Preparation of N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine
  • Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
    • Example 366 Preparation of 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate in the urea formation step. Following urea formation, the Boc-piperidine intermediate was treated with TFA to provide the title compound. (M+H) 612.3.
    • Example 367 Preparation of 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-((dimethylamino)methyl)aniline in the urea formation step. (M+H) 571.3.
    • Example 368 Preparation of 1-(4-(aminomethyl)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available tert-butyl 4-aminobenzylcarbamate in the urea formation step. Following urea formation, the Boc-amine intermediate was treated with TFA to provide the title compound. (M+H) 543.3.
    • Example 369 Preparation of 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. (M+H) 597.3.
    • Example 370 Preparation of 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)urea
  • Prepared as shown in Scheme 1, using 4-(2-(4-methylpiperazin-1-yl)ethoxy)aniline in the urea formation step. (M+H) 656.4.
  • The required 4-(alkoxy)aniline intermediates for the following compounds were prepared as outlined in Scheme 5.
    • Example 371 Preparation of 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea
  • Prepared as shown in Scheme 1, using 4-(2-(pyrrolidin-1-yl)ethoxy)aniline in the urea formation step. (M+H) 627.3.
    • Preparation of 4-(2-(pyrrolidin-1-yl)ethoxy)aniline
  • Prepared from 4-fluoronitrobenzene and the appropriate alcohol as shown in Scheme 5.
    • Example 372 Preparation of 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyethoxy)phenyl)urea
  • Prepared as shown in Scheme 1, using 2-(4-aminophenoxy)ethanol in the urea formation step. (M+H) 574.3.
    • Preparation of 2-(4-aminophenoxy)ethanol
  • Prepared from 4-fluoronitrobenzene and the appropriate alcohol as shown in Scheme 5.
    • Example 373 Preparation of N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(dimethylamino)acetamide
  • Prepared as shown in Scheme 1, using commercially available N-(4-aminophenyl)-2-(dimethylamino)acetamide in the urea formation step. (M+H) 614.3.
    • Example 374 Preparation of N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(4-methylpiperazin-1-yl)acetamide
  • Prepared as shown in Scheme 1, using commercially available N-(4-aminophenyl)-2-(4-methylpiperazin-1-yl)acetamide in the urea formation step. (M+H) 669.4.
    • Example 375 Preparation of N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(pyrrolidin-1-yl)acetamide
  • Prepared as shown in Scheme 1, using commercially available N-(4-aminophenyl)-2-(pyrrolidin-1-yl)acetamide in the urea formation step. (M+H) 640.3.
    • Example 376 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea
  • Prepared as shown in Scheme 1, using commercially available pyridin-3-amine in the urea formation step. (M+H) 461.2.
    • Example 377 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • Prepared as shown in Scheme 1, using commercially available pyridin-4-amine in the urea formation step. (M+H) 461.2.
    • Example 378 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. (M+H) 558.3.
    • Example 379 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-((4-methylpiperazin-1-yl)methyl)aniline in the urea formation step. (M+H) 572.3.
    • Example 380 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate in the urea formation step. Following urea formation, the Boc-piperazine intermediate was treated with TFA to provide the title compound. (M+H) 558.3.
    • Example 381 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-((dimethylamino)methyl)aniline in the urea formation step. (M+H) 517.3.
    • Example 382 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(aminomethyl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available tert-butyl 4-aminobenzylcarbamate in the urea formation step. Following urea formation, the Boc-amine intermediate was treated with TFA to provide the title compound. (M+H) 489.3.
    • Example 383 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. (M+H) 543.3.
    • Example 384 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea
  • Prepared as shown in Scheme 1, using 4-(2-(pyrrolidin-1-yl)ethoxy)aniline in the urea formation step. (M+H) 573.3.
    • Example 385 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea
  • Prepared as shown in Scheme 1, using 4-(2-(dimethylamino)ethoxy)aniline in the urea formation step. (M+H) 547.3.
    • Preparation of 4-(2-(dimethylamino)ethoxy)aniline
  • Prepared from 4-fluoronitrobenzene and the appropriate alcohol as shown in Scheme 5.
    • Example 386 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea
  • Prepared as shown in Scheme 1, using commercially available 5-(4-methylpiperazin-1-yl)pyridin-2-amine in the urea formation step. (M+H) 559.3.
    • Example 387 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the urea formation step. Following urea formation, the Boc-amine intermediate was treated with TFA to provide the title compound. (M+H) 544.3.
    • Example 388 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 1, using 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formation step. (M+H) 586.4.
    • Example 389 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. (M+H) 572.3.
    • Example 390 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-((dimethylamino)methyl)aniline in the urea formation step. (M+H) 531.3.
    • Example 391 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea
  • Prepared as shown in Scheme 1, using 4-(2-(dimethylamino)ethoxy)aniline in the urea formation step. (M+H) 561.3.
    • Example 392 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea (Scheme 6) Step 1: Preparation of 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • A solution of 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine (1.25 g, 4.61 mmol) in acetone (20 mL) and ice water (20 mL) was prepared. To this was added dropwise over 10 minutes a suspension of 3-oxa-8-azabicyclo[3.2.1]octane-hydrochloride (0.655 g, 4.38 mmol) and sodium bicarbonate (0.775 g, 9.22 mmol) in acetone (15 mL) and water (15 mL). The resulting tan solution was allowed to stir at 0° C. for 2 hours, then gradually allowed to warm to room temperature over 18 hours. The light brown suspension was filtered and washed with water. The crude product was purified by silica gel column chromatography, eluting with 0-1.5% methanol in methylene chloride to provide 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.89 g, 56%) as an off-white solid. (M+H) 348.1.
    • Step 2: Preparation of 8-(4-(4-nitrophenyl)-6-thiomorpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • A solution of 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.450 g, 1.29 mmol) in acetone (5 mL) and water (10 mL) was prepared. To this was added sodium carbonate (0.274 g, 2.59 mmoles), followed by thiomorpholine (0.134 ml, 1.42 mmol). The resulting light tan suspension was allowed to stir at 60° C. for 2.5 hours. The suspension was filtered and the solid was washed with water and dried in vacuo to provide 8-(4-(4-nitrophenyl)-6-thiomorpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.455 g, 85%) as a white solid. HRMS 415.1546 (M+H, calc.), 415.1526 (M+H, obs.).
    • Step 3: Preparation of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)aniline
  • A suspension of 8-(4-(4-nitrophenyl)-6-thiomorpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.418 g, 1.01 mmol) in pyridine (3 ml) and DMF (6 ml) was prepared. Tin(II) chloride dihydrate (0.569 g, 2.52 mmol) was then added and the off-white suspension was allowed to stir at room temperature for 16 hours, at which time the suspension was light yellow. The suspension was filtered, washing with methanol, and concentrated. LCMS indicated reaction had not gone to completion. The crude product was dissolved in DMF (6 ml) and pyridine (3 ml) and additional tin(II) chloride dihydrate (0.569 g, 2.52 mmol) was added. The solution was allowed to stir at room temperature for 18 hours, then filtered. The precipitate was washed with methanol and the filtrate was concentrated to provide 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)aniline (0.195 g, 50%) as a yellow solid. (M+H) 385.1.
    • Step 4: Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea
  • The method of urea formation using triphosgene and triethylamine in methylene chloride, described in Scheme 1, was utilized using commercially available pyridin-3-amine as the amine component. Purification by HPLC (5-95% acetonitrile in water over 20 minutes, 0.05% TFA buffer, Waters Atlantis column) provided 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea (0.032 g, 63%) as an off-white solid. (M+H) 505.2.
    • Example 393 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • Prepared as shown in Scheme 6, using commercially available pyridin-4-amine in the urea formation step. Yield; 28 mg (54%); (M+H) 505.2.
    • Example 394 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 6, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 44 mg (73%); (M+H) 602.3.
    • Example 395 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea
  • Prepared as shown in Scheme 6, using commercially available 4-((dimethylamino)methyl)aniline in the urea formation step. Yield; 19 mg (34%); (M+H) 561.3.
    • Example 365 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea
  • Prepared as shown in Scheme 6, using 4-(2-(dimethylamino)ethoxy)aniline in the urea formation step. Yield; 35 mg (59%); (M+H) 591.3.
    • Example 397 Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • Prepared as shown in Scheme 1, using commercially available pyridin-4-amine in the urea formation step. Yield; 44 mg (75%); (M+H) 491.2.
    • Example 398 Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea
  • Prepared as shown in Scheme 1, using commercially available pyridin-3-amine in the urea formation step. Yield; 46 mg (79%); (M+H) 491.2.
    • Example 399 Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-((dimethylamino)methyl)aniline in the urea formation step. Yield; 57 mg (81%); (M+H) 588.3.
    • Example 400 Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea
  • Prepared as shown in Scheme 1, using commercially available 5-(4-methylpiperazin-1-yl)pyridin-2-amine in the urea formation step. Yield; 56 mg (79%); (M+H) 589.3.
    • Example 401 Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-((dimethylamino)methyl)aniline in the urea formation step. Yield; 28 mg (43%); (M+H) 547.3.
    • Example 402 Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea
  • Prepared as shown in Scheme 1, using 4-(2-(dimethylamino)ethoxy)aniline in the urea formation step. Yield; 50 mg (72%); (M+H) 577.3.
    • Example 403 Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea
  • Prepared as shown in Scheme 1, using 4-(2-(pyrrolidin-1-yl)ethoxy)aniline in the urea formation step. Yield; 41 mg (57%); (M+H) 603.3.
    • Example 404 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea (Scheme 7) Step 1: Preparation of 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane: Prepared as shown in Scheme 6, described in Example 392, Step 1. Step 2: Preparation of 8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • A microwave vial was charged with 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.440 g, 1.27 mmoles). Toluene (6 mL) was then added and the solution was sparged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.088 g, 0.076 mmol) and tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (0.567 g, 1.52 mmol) were added. The vial was sealed and heated to 100° C. for 40 minutes via microwave. Additional tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (0.283 g, 0.76 mmoles) and tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol) were added and the suspension was heated to 110° C. by microwave for additional 90 minutes. The suspension was then cooled to room temperature and filtered through Celite™. The filter cake was washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with 0-2% methanol in methylene chloride, to provide 8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.430 g, 86%) as a light yellow solid. HRMS 396.1666 (M+H, calc.), 396.1668 (M+H, obs.).
    • Step 3: Preparation of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)aniline
  • A mixture of iron powder (0.071 g, 1.27 mmoles) in acetic acid (2 ml) was heated to 55° C. for 15 minutes. Water (2 ml) was then added and oil bath was turned off. A solution of 8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.100 g, 0.253 mmol) in ethyl acetate (2 ml) was then added to this warm solution over 5 minutes. The mixture was cooled to RT and allowed to stir for 16 hours. The mixture was extracted with ethyl acetate by decantation (4×) into a sep. funnel containing saturated aqueous sodium carbonate. The combined organic extracts were washed with water, brine, dried, and concentrated to provide 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)aniline (0.068 g, 74%), which was used in the next step without purification. (M+H) 366.4.
    • Step 4: Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • The method of urea formation using triphosgene and triethylamine in methylene chloride, described in Scheme 1, was utilized using commercially available pyridin-4-amine as the amine component. Purification by HPLC (5-95% acetonitrile in water over 20 minutes, 0.05% TFA buffer, Waters Atlantis column) provided 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea (0.034 g, 75%) as a light yellow solid. (M+H) 486.2.
    • Example 405 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 44 mg (82%); (M+H) 583.3.
    • Example 406 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • Prepared as shown in Scheme 7; representative synthesis described below.
    • Preparation of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)aniline
  • A solution of 8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (prepared as described in Example DJR-51, Step 2) (0.260 g, 0.658 mmol) in ethyl acetate (5 ml), methanol (5 ml), and methylene chloride (2 ml—added due to poor solubility of SM in EA/methanol) was prepared and 10% palladium on carbon (0.078 g, 30% by weight) was added. The flask was purged with hydrogen gas (balloon) and allowed to stir under positive pressure of hydrogen for 16 hours. Additional palladium on carbon (0.039 g) was added and the suspension was purged with hydrogen gas (balloon) and stirred for an additional 3 hours. The flask was purged with hydrogen gas and stirred for an additional 1 hour. The suspension was filtered through Celite™, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to provide 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)aniline (0.220 g, 91%) as an off-white solid. HRMS 368.2080 (M+H, calc.), 368.2085 (M+H, obs.).
    • Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • The method of urea formation using triphosgene and triethylamine in methylene chloride, described in Scheme 1, was utilized using commercially available pyridin-4-amine as the amine component. Purification by HPLC (5-95% acetonitrile in water over 20 minutes, 0.05% TFA buffer, Waters Atlantis column) provided 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea (0.0461 g, 82%) as an off-white solid. (M+H) 488.2.
    • Example 407 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 54 mg (79%); (M+H) 585.3.
    • Example 408 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea
  • Prepared as shown in Scheme 7, using 4-(2-(dimethylamino)ethoxy)aniline in the urea formation step. Yield; 49 mg (73%); (M+H) 572.3.
    • Example 409 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea
  • Prepared as shown in Scheme 7, using commercially available 4-((dimethylamino)methyl)aniline in the urea formation step. Yield; 21 mg (33%); (M+H) 544.3.
    • Example 410 Preparation of 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • Prepared as shown in Scheme 1, using commercially available pyridin-4-amine in the urea formation step. Yield; 45 mg (70%); (M+H) 489.2.
    • Example 411 Preparation of 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea
  • Prepared as shown in Scheme 1, using commercially available pyridin-3-amine in the urea formation step. Yield; 60 mg (95%); (M+H) 489.2.
    • Example 412 Preparation of 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 69 mg (90%); (M+H) 586.3.
    • Example 413 Preparation of 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-((4-methylpiperazin-1-yl)methyl)aniline in the urea formation step. Yield; 73 mg (94%); (M+H) 600.3.
    • Example 414 Preparation of 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. Yield; 56 mg (75%); (M+H) 571.3.
    • Example 415 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea
  • Prepared as shown in Scheme 1, using commercially available pyridin-3-amine in the urea formation step. Yield; 44 mg (66%); (M+H) 503.2.
    • Example 416 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • Prepared as shown in Scheme 1, using commercially available pyridin-4-amine in the urea formation step. Yield; 35 mg (53%); (M+H) 503.2.
    • Example 417 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 58 mg (62%); (M+H) 600.3.
    • Example 418 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. Yield; 41 mg (45%); (M+H) 585.5.
    • Example 419 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea
  • Prepared as shown in Scheme 1, using 4-(2-(dimethylamino)ethoxy)aniline in the urea formation step. Yield; 43 mg (47%); (M+H) 589.3.
    • Example 420 Preparation of (R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea
  • Prepared as shown in Scheme 7, using commercially available pyridin-3-amine in the urea formation step. Yield; 45 mg (77%); (M+H) 476.2.
    • Example 421 Preparation of (R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 53 mg (75%); (M+H) 573.3.
    • Example 422 Preparation of (R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the urea formation step. Following urea formation, the Boc-piperazine intermediate was treated with TFA to provide the title compound. Yield; 63 mg (90%); (M+H) 559.3.
    • Example 423 Preparation of 1-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((S)-3-methylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using (S)-tert-butyl 4-(4-aminophenyl)-3-methylpiperazine-1-carboxylate in the urea formation step. Following urea formation, the Boc-piperazine intermediate was treated with TFA to provide the title compound. Yield; 60 mg (71%); (M+H) 573.3.
    • Preparation of (S)-tert-butyl 4-(4-aminophenyl)-3-methylpiperazine-1-carboxylate
  • Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
    • Example 424 Preparation of 1-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((R)-3-methylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using (R)-tert-butyl 4-(4-aminophenyl)-3-methylpiperazine-1-carboxylate in the urea formation step. Following urea formation, the Boc-piperazine intermediate was treated with TFA to provide the title compound. Yield; 68 mg (90%); (M+H) 573.3.
    • Preparation of (R)-tert-butyl 4-(4-aminophenyl)-3-methylpiperazine-1-carboxylate
  • Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
    • Example 425 Preparation of 1-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-3-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using (3,5-cis)-tert-butyl 4-(4-aminophenyl)-3,5-dimethylpiperazine-1-carboxylate in the urea formation step. Following urea formation, the Boc-piperazine intermediate was treated with TFA to provide the title compound. Yield; 67 mg (77%); (M+H) 587.3.
    • Preparation of (3,5-cis)-tert-butyl 4-(4-aminophenyl)-3,5-dimethylpiperazine-1-carboxylate
  • Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
    • Example 426 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-sulfoxymorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 6. A solution of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea (0.020 g, 0.033 mmol) in acetonitrile (1.5 ml) and water (0.5 ml) was prepared and oxone (0.020 g, 0.033 mmol) was added. The solution was stirred at room temperature for 16 hours. The suspension was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was washed with brine, dried, and concentrated, then purified by HPLC (5-95% acetonitrile in water over 20 minutes, 0.05% TFA buffer, Waters Atlantis column) to provide the TFA salt of the sulfoxide of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-sulfoxymorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea (0.0029 g, 14%) as a white solid. (M+H) 618.4.
    • Example 427 Preparation of (R)-1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using 4-(2-(dimethylamino)ethoxy)aniline in the urea formation step. Yield; 34 mg (51%); (M+H) 562.3.
    • Example 428 Preparation of (R)-1-(4-(4-ethylpiperazin-1-yl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using commercially available 4-(4-ethylpiperazin-1-yl)aniline in the urea formation step. Yield; 66 mg (93%); (M+H) 587.3.
    • Example 429 Preparation of (R)-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using 4-(4-isopropylpiperazin-1-yl)aniline in the urea formation step. Yield; 66 mg (91%); (M+H) 601.4.
    • Preparation of 4-(4-isopropylpiperazin-1-yl)aniline
  • Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
    • Example 430 Preparation of (R)-1-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formation step. Yield; 69 mg (95%); (M+H) 601.4.
    • Example 431 Preparation of (R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea
  • Prepared as shown in Scheme 7, using (4-aminophenyl)(4-methylpiperazin-1-yl)methanone in the urea formation step. Yield; 38 mg (52%); (M+H) 601.3.
  • The (4-aminophenyl)(piperazin-1-yl)methanone intermediates prepared as shown in Scheme 8 were used to make the following compounds.
    • Example 432 Preparation of (R)-1-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using (4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone in the urea formation step. Yield; 68 mg (89%); (M+H) 629.3.
    • Preparation of (4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone
  • Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shown in Scheme 8.
    • Example 433 Preparation of (R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea
  • Prepared as shown in Scheme 7, using commercially available 6-(4-methylpiperazin-1-yl)pyridin-3-amine in the urea formation step. Yield; 69 mg (99%); (M+H) 574.3.
    • Example 434 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using commercially available 4-(4-ethylpiperazin-1-yl)aniline in the urea formation step. Yield; 32 mg (43%); (M+H) 599.3.
    • Example 435 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using 4-(4-isopropylpiperazin-1-yl)aniline in the urea formation step. Yield; 51 mg (66%); (M+H) 613.4.
    • Example 436 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using 4-(4-cyclopropylpiperazin-1-yl)aniline in the urea formation step. Yield; 11 mg (14%); (M+H) 611.3.
    • Preparation of 4-(4-cyclopropylpiperazin-1-yl)aniline
  • Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
    • Example 437 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 7, using 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formation step. Yield; 28 mg (36%); (M+H) 613.4.
    • Example 438 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea
  • Prepared as shown in Scheme 7, using (4-aminophenyl)(4-methylpiperazin-1-yl)methanone in the urea formation step. Yield; 36 mg (46%); (M+H) 613.3.
    • Example 439 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea
  • Prepared as shown in Scheme 7, using (4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone in the urea formation step. Yield; 41 mg (50%); (M+H) 641.3.
  • The following 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-urea compounds were prepared as shown in Scheme 9.
    • Example 440 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea Step 1: Preparation of (R)-4-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-methylmorpholine
  • A solution of 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine (1.25 g, 4.61 mmol) and sodium bicarbonate (0.775 g, 9.22 mmol) in acetone (20 mL) and ice water (20 mL) was prepared. To this was added dropwise over 5 minutes (R)-3-methylmorpholine (0.466 g, 4.61 mmol). The resulting tan solution was allowed to stir at 0° C. for 2 hours, then gradually allowed to warm to room temperature over 18 hours. The light brown suspension was filtered and washed with water to provide (R)-4-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-methylmorpholine (1.40 g, 90%) as a light brown solid. HRMS 336.0857 (M+H, calc.), 336.0845 (M+H, obs.).
    • Step 2: Preparation of 8-(4-((R)-3-methylmorpholino)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane:
  • A solution of (R)-4-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-methylmorpholine (0.94 g, 2.80 mmol) in acetone (10 mL) and ice water (10 mL) was prepared. To this was added dropwise over 10 minutes a suspension of 3-oxa-8-azabicyclo[3.2.1]octane-hydrochloride (0.419 g, 2.80 mmol) and sodium bicarbonate (0.470 g, 5.60 mmol) in acetone (10 mL) and water (10 mL). The resulting tan solution was allowed to stir at 0° C. for 2 hours, then gradually allowed to warm to room temperature over 3 hours. The light brown suspension was filtered and washed with water to provide 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.964 g, 83%) as a brown solid. HRMS 413.1931 (M+H, calc.), 413.1936 (M+H, obs.).
    • Step 3: Preparation of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)aniline
  • A solution of 8-(4-((R)-3-methylmorpholino)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.915 g, 2.22 mmol) in ethyl acetate (10 ml), methanol (10 ml), and methylene chloride (5 ml—added due to poor solubility of SM in EA/methanol) was prepared and 10% palladium on carbon (0.270 g, 30% by weight) was added. The flask was purged with hydrogen gas (balloon) and allowed to stir under positive pressure of hydrogen for 16 hours. The suspension was filtered through Celite™, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to provide 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)aniline (0.587 g, 69%) as an off-white solid. (M+H) 383.3.
    • Step 4: Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea
  • The method of urea formation using triphosgene and triethylamine in methylene chloride, described in Scheme 1, was utilized using commercially available 4-(4-ethylpiperazin-1-yl)aniline as the amine component. Purification by HPLC (5-95% acetonitrile in water over 20 minutes, 0.05% TFA buffer, Waters Atlantis column) provided 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea (0.0761 g, 95%) as a light yellow solid. (M+H) 614.3.
    • Example 441 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 9, using 4-(4-isopropylpiperazin-1-yl)aniline in the urea formation step. Yield; 82 mg (100%); (M+H) 628.4.
    • Example 442 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 9, using 4-(4-cyclopropylpiperazin-1-yl)aniline in the urea formation step. Yield; 32 mg (39%); (M+H) 626.3.
    • Example 443 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 9, using 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formation step. Yield; 77 mg (93%); (M+H) 628.4.
    • Example 444 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea
  • Prepared as shown in Scheme 9, using (4-aminophenyl)(4-methylpiperazin-1-yl)methanone in the urea formation step. Yield; 43 mg (52%); (M+H) 628.3.
    • Example 445 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea
  • Prepared as shown in Scheme 9, using (4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone in the urea formation step. Yield; 72 mg (84%); (M+H) 656.4.
    • Example 446 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea
  • Prepared as shown in Scheme 9, using commercially available 6-(4-methylpiperazin-1-yl)pyridin-3-amine in the urea formation step. Yield; 74 mg (94%); (M+H) 601.3.
    • Example 447 Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-(4-ethylpiperazin-1-yl)aniline in the urea formation step. Yield; 80 mg (99%); (M+H) 602.3.
    • Example 448 Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 1, using 4-(4-isopropylpiperazin-1-yl)aniline in the urea formation step. Yield; 74 mg (88%); (M+H) 616.4.
    • Example 449 Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea
  • Prepared as shown in Scheme 1, using 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formation step. Yield; 80 mg (96%); (M+H) 616.4.
    • Example 450 Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea
  • Prepared as shown in Scheme 1, using (4-aminophenyl)(4-methylpiperazin-1-yl)methanone in the urea formation step. Yield; 79 mg (95%); (M+H) 616.3.
    • Example 451 Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea
  • Prepared as shown in Scheme 1, using (4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone in the urea formation step. Yield; 18 mg (20%); (M+H) 644.4.
    • Example 452 Preparation of 4-(3-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide
  • Prepared as shown in Scheme 1, using commercially available 4-amino-N,N-dimethylbenzamide in the urea formation step. Yield; 43 mg (57%); (M+H) 561.3.
    • Example 453 Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea
  • Prepared as shown in Scheme 1, using commercially available 4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. Yield; 61 mg (79%); (M+H) 573.3.
    • Example 454 Preparation of 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide
  • Prepared as shown in Scheme 7, using commercially available 4-aminobenzamide in the urea formation step. Yield; 22 mg (21%); (M+H) 530.2.
    • Example 455 Preparation of 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide
  • Prepared as shown in Scheme 7, using commercially available 4-amino-N,N-dimethylbenzamide in the urea formation step. Yield; 22 mg (21%); (M+H) 558.3.
    • Example 456 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)urea
  • Prepared as shown in Scheme 7, using (4-aminophenyl)(pyrrolidin-1-yl)methanone in the urea formation step. Yield; 41 mg (36%); (M+H) 584.3.
    • Preparation of (4-aminophenyl)(pyrrolidin-1-yl)methanone
  • Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shown in Scheme 8.
    • Example 457 Preparation of 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide
  • Prepared as shown in Scheme 7, using 4-amino-N-(2-(dimethylamino)ethyl)benzamide in the urea formation step. Yield; 36 mg (32%); (M+H) 601.3.
    • Preparation of 4-amino-N-(2-(dimethylamino)ethyl)benzamide
  • Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shown in Scheme 8.
    • Example 458 Preparation of 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide
  • Prepared as shown in Scheme 7, using tert-butyl 2-(4-aminobenzamido)ethyl(methyl)carbamate in the urea formation step. Following urea formation, the Boc-amine intermediate was treated with TFA to provide the title compound. Yield; 25 mg (22%); (M+H) 587.3.
    • Preparation of tert-butyl 2-(4-aminobenzamido)ethyl(methyl)carbamate
  • Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shown in Scheme 8.
    • Example 459 Preparation of 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide
  • Prepared as shown in Scheme 7, using 4-amino-N-(2-(dimethylamino)ethyl)-N-methylbenzamide in the urea formation step. Yield; 10 mg (9%); (M+H) 615.3.
    • Preparation of 4-amino-N-(2-(dimethylamino)ethyl)-N-methylbenzamide
  • Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shown in Scheme 8.
    • Example 460 Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(morpholine-4-carbonyl)phenyl)urea
  • Prepared as shown in Scheme 7, using (4-aminophenyl)(morpholino)methanone in the urea formation step. Yield; 25 mg (21%); (M+H) 600.3.
    • Preparation of (4-aminophenyl)(morpholino)methanone
  • Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shown in Scheme 8.
    • Example 461 Preparation of 1-(4-(2-aminoethylamino)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)urea:
  • Prepared as shown in Scheme 1, using di-Boc protected N1-(2-aminoethyl)benzene-1,4-diamine in the urea formation step. Following urea formation, the di-Boc-amine intermediate was treated with TFA to provide the title compound. Yield; x mg (x %); HRMS 572.3092 (M+H, calc.), 572.3098 (M+H, obs.).
    • Preparation of di-Boc protected N1-(2-aminoethyl)benzene-1,4-diamine
  • Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
    • Example 462 Preparation of 4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino) benzamide Step 1: Preparation of phenyl 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate
  • To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (25.0 g, 114 mmol) and pyridine (4 mL, 57 mmol) in dry dichloromethane (250 mL) phenyl chloroformate (12 mL, 114 mmol) was added drop wise at −10° C. The reaction mixture was stirred at −10° C. for 30 min and then at room temperature for 30 minutes. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (2×70 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to get the crude product. Then the crude product was dissolved in diethyl ether (15 mL) and sonicated for 10 min and then pentane (30 mL) was added. the resulting solid was filtered and washed with pentane to give phenyl 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (26 g, 88% yield).
  • 1HNMR (300 MHz, CDCl3): δ7.8 (d, 2H) 7.5 (d, 2H), 7.4 (m, 2H), 7.2 (m, 3H), 7.0 (s, 1H), 1.3 (s, 12H).
    • Step 2: Preparation of 1-methyl-3-(4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea
  • A mixture of phenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (26 g, 76.6 mmol)), 2.0M Methylamine/THF (265 mL, 530 mmol) in 150 mL of THF was stirred at room temperature for 6 hours, then excess solvent was distilled off from the reaction mixture; residue was dissolved into water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure. The crude product was purified by silica gel column chromatography by using 5-60% ethyl acetate in pet-ether as an eluent. to give 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. (20 g, 88% yield) as white solid.
  • 1HNMR (300 MHz, CDCl3): δ7.7 (d, 2H), 7.2 (d, 2H), 6.7 (s, 1H), 5.0 (s, 1H), 2.8 (s, 3H), 1.2 (s, 12H).
    • Step 3: Preparation of 4-(4,6-dichloro-1,3,5-triazin-2-yl) morpholine
  • Morpholine (9.5 mL, 108 mmol)) was added to a solution of cyanuric chloride (20 g, 108 mmol) in chloroform (10 mL) and stirred at −5° C. for 1 hour. Reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Crude product was purified by silica gel (100-200 mesh) column chromatography using 5% ethyl acetate in pet-ether as an eluent to give 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 39% yield).
    • Step 4: Preparation of 1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea
  • A mixture of compound 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 42.7 mmol), Pd (PPh3)4 (2.46 g, 2.1 mmol), 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. (11.7 g, 42.4 mmol) and 1 N Na2CO3 (168 mL, 168 mmol) in degassed 1,2-dimethoxyethane (400 mL) was heated to 65° C. for 8 hours under N2 atmosphere. The reaction mixture filtered, diluted with water, extracted with ethyl acetate and washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Crude product was purified by silica gel (100-200 mesh) column chromatography using 20-60% ethyl acetate in pet-ether as an eluent. To give 1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea (5.0 g, 34% yield).
  • 1HNMR (300 MHz, DMSO-d6): δ 9.4 (br, 1H), 8.2 (d, 2H), 7.6 (d, 2H), 6.6 (br, 1H), 4.0 (m, 2H), 3.8 (m, 6H), 2.8 (s, 3H).
    • Step 5: Preparation of 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea
  • The title compound was prepared by following the procedure of Example 462 step 4 using 1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2 g, 45% yield.
    • Step 6: Preparation of phenyl 4-carbamoylphenylcarbamate
  • To a solution of 4-aminobenzamide (5.0 g, 36.7 mmol) and pyridine (2.9 g, 36.7 mmol)) in dry CH2Cl2 (100 mL) at −10° C., phenyl chloroformate (6.9 g, 44.1 mmol) was added dropwise, stirred at −10° C. for 30 min and then at room temperature for 30 minutes The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with water (2×70 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to get the crude product. The crude product was dissolved in diethyl ether (15 mL) and sonicated for 10 minutes and then pentane (30 mL) was added, the resulting solid was filtered and washed with pentane to give phenyl 4-carbamoylphenylcarbamate (7.2 g, 77% yield).
    • Step 7: Preparation of 4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino) benzamide
  • To a solution of 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea (0.6 g, 1.5 mmol) and triethylamine(4-5 mL) in dry DMF (10 mL), phenyl 4-carbamoylphenylcarbamate (1.15 g, 4.5 mmol).) was added at room temperature and mixture was heated to 90° C. for 10 hours under nitrogen atmosphere. After cooling to room temperature reaction mixture was quenched with ice water and resulting solid was filtered to get crude product. Crude product was purified by Preparative HPLC to give 4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide (45 mg, 5.3% yield).
    • Example 463 Preparation of 1-{4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea Step 1: Preparation of 4-(4,6-dichloro-1,3,5-triazin-2-yl)-3,5-dimethylmorpholine
  • The title compound was prepared by following the procedure of Example 462 step 3 using cyanuric chloride and 3,5-dimethylmorpholine. Yield 5 g, 35% yield.
  • 1HNMR (300 MHz, CDCl3): δ 4.6 (m, 2H), 3.6 (m, 2H), 2.8 (m, 2H), 1.2 (d, 6H).
    • Step 2: Preparation of 1-(4-(4-chloro-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea
  • The title compound was prepared by following the procedure of example 462 step 4 using 4-(4,6-dichloro-1,3,5-triazin-2-yl)-3,5-dimethylmorpholine and 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 1.15 g, 16% yield.
    • Step 3: Preparation of 1-(4-(4-(4-aminophenyl)-6-(3,5-dimethyl morpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea
  • The title compound was prepared by following the procedure of example 462 step 4 using 1-(4-(4-chloro-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2 g, 86% yield.
    • Step 4: Preparation of phenyl pyridin-3-ylcarbamate
  • The title compound was prepared by following the procedure of example 462 step 6 using 3-aminopyridine and phenyl chloroformate. Yield 7 g, 62% yield.
    • Step 5: Preparation of 1-{4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
  • The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-3-ylcarbamate. Yield 77 mg, 6% yield.
    • Example 464 Preparation of 4-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide Step 1: Preparation of 3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • The title compound was prepared by following the procedure of example 462 step 3 using cyanuric chloride and 8-oxa-3-azabicyclo[3.2.1]octane. Yield 10 g, 47% yield.
    • Step 2: Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)phenyl)-3-methylurea
  • The title compound was prepared by following the procedure of example 462 step 4 using 3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane and 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 5 g, 29% yield.
    • Step 3: Preparation of 1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea
  • The title compound was prepared by following the procedure of example 462 step 4 using 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)phenyl)-3-methylurea and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2.8 g, 49% yield.
    • Step 4: Preparation of 4-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide
  • The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 4-carbamoylphenylcarbamate. Yield 90 mg, 13% yield.
    • Example 465 Preparation of 3-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide Step 1: Preparation of phenyl 3-carbacarbamoylphenylcarbamate
  • The title compound was prepared by following the procedure of example 462 step 6 using 3-aminobenzamide and phenyl chloroformate. Yield 7 g, 74% yield.
    • Step 2: Preparation of 3-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide
  • The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 3-carbamoylphenylcarbamate. Yield 90 mg, 13% yield.
    • Example: 466 Preparation of 3-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino) benzamide
  • The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 3-carbamoylphenylcarbamate. Yield 51 mg, 4% yield.
    • Example 467 Preparation of 1-methyl-3-[4-(4-morpholin-4-yl-6-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)phenyl]urea
  • The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-3-ylcarbamate. Yield 77 mg, 6% yield.
    • Example 468 Preparation of 1-methyl-3-[4-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)phenyl]urea Step 1: Preparation of phenyl pyridin-4-ylcarbamate
  • The title compound was prepared by following the procedure of example 462 step 6 using 4-aminopyridine and phenyl chloroformate. Yield 6 g, 534% yield.
    • Step 2: Preparation of 1-methyl-3-[4-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)phenyl]urea
  • The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-4-ylcarbamate. Yield 75 mg, 3.9% yield.
    • Example 469 Preparation of 3-[({4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide
  • The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 3-carbamoylphenylcarbamate. Yield 56 mg, 4.1% yield.
    • Example 470 Preparation of 4-[({4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide
  • The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 4-carbamoylphenylcarbamate. Yield 70 mg, 12.8% yield.
    • Example 471 Preparation of 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}urea
  • The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-4-ylcarbamate. Yield 51 mg, 4% yield.
    • Example 472 Preparation of 1-{4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
  • The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-4-ylcarbamate. Yield 15 mg, 0.8% yield.
    • Example 473 Preparation of N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-2,2-difluoroacetamide Step 1: Preparation of 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine
  • A solution of morpholine (8.71 g, 100 mmol) in 100 mL of methylene was added dropwise to a mixture of cyanuric chloride (9.22 g, 50.0 mmol) and triethylamine (10.1 g, 100 mmol) in 200 mL of methylene chloride at 0° C. Then the reaction mixture was stirred at 0° C. for 1 hr and slowly warmed up to room temperature. After stirring at room temperature for 1 hr, the reaction mixture was filtered to remove the triethylamine hydrochloride salt. The filtrate was concentrated to give 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl) dimorpholine (14.2 g, 100 yield) as a white solid. HPLC: Rt=2.43 min; MS 286, 288 [M+H].
    • Step 2: Preparation of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline
  • A mixture of 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine (1.40 g, 4.90 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.62 g, 11.9 mmol) and tetrakis(triphenylphosphine) palladium (0) (282 mg, 0.240 mmol) in 2M sodium carbonate aqueous solution (10 mL, 20 mmol) and 40 mL of DME was stirred at 80° C. for 2 hr. The reaction mixture was diluted with 300 mL of ethyl acetate and washed with water. The organic layer was concentrated and purified by flash chromatography (ISCO, 120 g silica gel column, eluting with 0-100% EtOAc/Hexane) to give 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline (0.68 g, 40% yield). HPLC: Rt=2.09 min; MS 343 [M+H].
    • Step 3: Preparation of N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-2,2-difluoroacetamide
  • To a mixture of 2,2-difluoroacetic acid (20 mg, 0.21 mmol), HBTU (76 mg, 0.2 mmol), and DIEA (52 mg, 0.40 mmol) in 2 mL of DMF was added 4-(4,6-dimorpholino-1,3,5-triazin-2-yl) aniline (40 mg, 0.12 mmol). The reaction was stirred at 60° C. 16 hr. Then the reaction mixture was cooled to room temperature and purified by reverse phase chromatography to give N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-2,2-difluoroacetamide (23 mg, 46% yield). HPLC: Rt=2.19 min; MS 421 [M+H].
    • Example 474 Preparation of N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-4,5-dihydro-1H-imidazol-2-amine
  • A mixture of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline (40 mg, 0.12 mmol), imidazolidine-2-thione (15 mg, 0.15 mmol 0 and mercury(II) chloride (40 mg, 0.15 mmol) in 2 mL of DMF was stirred at 140° C. 16 hr. Then the reaction mixture was cooled to room temperature and filtered through Celite™. The filtration was concentrated and purified by reverse phase chromatography to give N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-4,5-dihydro-1H-imidazol-2-amine (9.0 mg, 22% yield). HPLC: Rt=1.74 min; MS 411 [M+H].
    • Example 475 Preparation of 2,4-dimorpholin-4-yl-6-[4-(2H-tetrazol-5-yl)phenyl]-1,3,5-triazine Step 1: Preparation of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)benzonitrile
  • The title compound was prepared by following the procedure of example 473 step 2 using 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl) dimorpholine and 4-cyanophenyl-boronic acid. Yield 86 mg, 50% yield; HPLC: Rt=2.60 min; MS 353 [M+H].
    • Step 2: Preparation of 2,4-dimorpholin-4-yl-6-[4-(2H-tetrazol-5-yl)phenyl]-1,3,5-triazine
  • A mixture of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)benzonitrile (11 mg, 0.031 mmol), sodium azide (5.5 mg, 0.085 mmol) and triethylamine hydrochloride (6.0 mg, 0.043 mmol) in 2 mL of DMF was stirred at 120° C. for 6 hr. Then the reaction mixture was cooled to room temperature and purified by reverse phase chromatography to give 2,4-dimorpholin-4-yl-6-[4-(2H-tetrazol-5-yl)phenyl]-1,3,5-triazine. Yield 12 mg, 97% yield; HPLC: Rt=2.09 min; MS 394 [M−H].
    • Example 476 Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea Step 1: Preparation of 1-Methyl-3-[4-(4, 4,5,5-tetramethyl-[1, 3, 2]dioxaborolan-2-yl)-phenyl]-urea
  • A mixture of 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (750 mg, 3.06 mmol), 2.0M Methylamine/THF (2.3 mL, 4.60 mmol) in 50 mL of THF was stirred at room temperature for 6 hr. Then the traction mixture was concentrated to give 1-methyl-3-[4-(4, 4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. (760 mg, 90% yield). Rt=2.21 min; 277 [M+H].
    • Step 2: Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea
  • The title compound was prepared by following the procedure of example 473 step 2 using 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine and 1-Methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 13 mg, 11% yield; HPLC: Rt=1.98 min; MS 400 [M+H].
    • Example 477 Preparation of 2-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-N-pyridin-3-ylacetamide Step 1: Preparation of 2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)acetic acid
  • A mixture of 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine (285 mg, 1.0 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid. (315 mg, 1.2 mmol) and tetrakis (triphenylphosphine) palladium (0) (58 mg, 0.05 mmol) in 2M sodium carbonate aqueous solution (3 mL, 8 mmol) and 20 mL of DME was stirred at 80° C. for 2 hr. Then the reaction mixture was diluted with 50 mL of ethyl acetate and extracted with 1 N NaOH (50 mL, three times)). The combined aqueous layers were neutralized to pH=6. Then the aqueous solution was extracted with ethyl acetate (50 mL, three times). The combined organic layers were washed with saturated sodium carbonate and brine. Then the organic layer was dried over anhydrous sodium sulfate and concentrated to give 2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)acetic acid (68 mg, 18% yield). HPLC: Rt=2.04 min; MS 386 [M+H].
    • Step 2: Preparation of 2-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-N-pyridin-3-ylacetamide
  • The title compound was prepared by following the procedure of example 473 step 3 using 2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)acetic acid and 3-aminopyridine. Yield 21 mg, 44% yield; HPLC: Rt=1.91 min; MS 462 [M+H].
    • Preparation of ((2S,5R)-1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol
  • A suspension of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol (1.3 g, 2.7 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.51 g, 3.4 mmol) in ethanol (15 mL) was treated with triethylamine (1.35 mL, 10 mmol) and heated with a heat gun briefly to reflux. The reaction mixture was purified by automated flash chromatography (methanol/chloroform) to provide the title compound as a hard peach colored foam. MS (ES+)=443.2 (M+H)+.
    • Preparation of 3-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • A solution of ((2S,5R)-1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol (1.5 g, 3.4 mmol) in dichloromethane (15 mL) was treated successively with tert-butyl dimethyl chlorosilane (1.3 g, 8.5 mmol) and imidazole (0.69 g, 10 mmol). The resulting suspension was stirred overnight at room temperature and then quenched with water. The aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue (a peach-colored solid) was carried on to the following step without further purification. MS (ES+)=671.4 (M+H)+.
    • Preparation of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline
  • A suspension of palladium on charcoal (10%, 100 mg) and crude 3-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (3.4 mmol maximum) in tetrahydrofuran (30 mL) was shaken for 8 hours under 50 psi of hydrogen. The mixture was filtered through a pad of Celite™ diatomaceous earth and concentrated under reduced pressure to provide the title compound as an orange foam. MS (ES+)=642.4 (M+H)+.
    • Example 667 Preparation of 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
  • A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline (0.24 g, 0.37 mmol) in dichloromethane (5 mL) was treated successively with triethylamine (500 μL) and a triphosgene (56 mg) solution in dichloromethane (1 mL). After 5 minutes, the mixture was treated with a solution of 4-aminopyridine (70 mg) in warm tetrahydrofuran. After 1 hour, the reaction mixture was quenched with methanol and concentrated to dryness. Half of the crude residue was treated with a saturated solution of hydrogen chloride in methanol. Upon complete desilylation, the mixture was concentrated to dryness and the residue purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy column running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 50% acetonitrile over 25 minutes. After concentration, the title compound was obtained as it trifluoroacetic acid salt (75 mg). MS (ES+)=533.3 (M+H)+.
    • Example 668 Preparation of 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
  • A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline (0.25 g, 0.39 mmol) in dichloromethane (5 mL) was treated successively with triethylamine (500 μL) and a triphosgene (59 mg, 0.08 mmol) solution in dichloromethane (1 mL). After 5 minutes, the mixture was treated with 4-(4-methylpiperazin-1-yl)aniline (150 mg). After 1 hour, the reaction mixture was quenched with methanol and concentrated to dryness. The crude residue was treated with a saturated solution of hydrogen chloride in methanol. Upon complete desilylation, the mixture was concentrated to dryness and the residue purified by reverse-phase high performance liquid chromatography using a Phenomenex Gemini column running a gradient elution of 5% acetonitrile/55% of 0.1% aqueous trifluoroacetic acid to 50% acetonitrile over 15 minutes. After concentration, the title compound was obtained as it trifluoroacetic acid salt (130 mg). MS (ES+)=630.4 (M+H)+.
    • Example 823 Preparation of 1-[4-(4,6-di-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
  • To a solution of cyanuric chloride (0.368 g, 2 mmol) in CH2Cl2 (20 mL) was added 3,7-dioxa-9-azabicyclo[3.3.1]nonane. HCO2H (0.718 g, 4.1 mmol), followed by addition of Et3N (0.98 mL, 7 mmol). The resulting reaction mixture was stirred for 24 h, and then diluted with CH2Cl2. The organic phase was washed with aqueous 1 N HCl (3×) and dried over MgSO4. The solvent was removed in vacuum to give 9,9′-(6-chloro-1,3,5-triazine-2,4-diyl)bis(3,7-dioxa-9-azabicyclo[3.3.1]nonane) as white solid (0.15 g, 95% yield).
  • To a 10 mL vial were added 9,9′-(6-chloro-1,3,5-triazine-2,4-diyl)bis(3,7-dioxa-9-azabicyclo[3.3.1]nonane) (150 mg, 0.406 mmol), 4-aminophenylboronic acid pinacol ester (133 mg, 0.61 mmol), Pd(PPh3)4 (10 mg), toluene (1 mL), EtOH (1 mL) and 2M Na2CO3 aqueous solution (0.305 mL). The resulting mixture was heated at 120° C. for 20 minutes in microwave oven. The reaction mixture was cooled to room temperature. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over (MgSO4). The solvent was removed under reduced pressure and the residue was subjected to HPLC separation to give 4-(4,6-di(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl)aniline as a white solid (120 mg).
  • To a solution of 4-(4,6-di(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl)aniline (120 mg, 0.281 mmol) in CH2Cl2 was added Et3N (0.237 mL, 1.69 mmol) and triphosgene (42 mg, 0.14 mmol). The mixture was stirred at room temperature for 15 minutes and 4-(4-methylpiperazin-1-yl)aniline (107 mg, 0.56 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was removed, and the residue was subjected to HPLC separation to give the title compound (1TFA salt) MS (ESI) m/z 644.3306.
    • Preparation of (6S)-tert-butyl 6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (Scheme 10) Step 1: (2R′,5S′)-1-tert-butyl 2,5-dimethyl 1H-pyrrole-1,2,5(2H,5H)-tricarboxylate (cis-diester) was synthesized by following the procedure described in literature: Organic Letters 2004, 6(18), 3055-8. Step 2: Reduction of cis-diester to (2R′,5S′)-tert-butyl 2,5-bis(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (cis-diol)
  • To a solution of (2R′,5S′)-1-tert-butyl 2,5-dimethyl 1H-pyrrole-1,2,5(2H,5H)-tricarboxylate (6.6 g, 23.1 mmol) in THF (100 mL) was added slowly of LiBH4 solution (2M in THF, 34.7 mL, 69.4 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 hours, then cooled to 0° C. again. HCl solution (1 M, 30 mL) was added to the reaction mixture, and stirred for 10 minutes before diluted with EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine, and dried (MgSO4). The organic solvent was removed in vacuo to give the crude product, which was purified by flash chromatography in silica gel with EtOAc:Hex:MeOH (50:50:10) to give the cis-diol (3.8 g, 72%).
    • Step 3: Preparation of (2R′,5S′)-tert-butyl 2,5-bis((tert-butyldimethylsilyloxy)methyl)-2,5-dihydro-1H-pyrrole-1-carboxylate
  • To a solution of the cis-diol (3.57 g, 15.6 mmol) in DMF (15 mL) were added TBSCl (5.16 g, 34.3 mmol) and imidazole (3.18 g, 46.7 mmol). The mixture was heated at 80° C. for 30 minutes in microwave oven (150 w). Cooled to room temperature, the mixture was taken up in water (50 mL) and EtOAc (50 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc. Combined organic phases were washed with water and brine, and dried (MgSO4). The organic solvent was removed in vacuo to give the crude product, which was purified by flash chromatography in silica gel with EtOAc:Hex (10:90) to give the title compound (7.12 g, 98%).
    • Step 4: Synthesis of (2R′,3S′,5R′)-tert-butyl 2,5-bis((tert-butyldimethylsilyloxy)methyl)-3-hydroxypyrrolidine-1-carboxylate (trans-alcohol)
  • To a solution of (2R′,5S′)-tert-butyl 2,5-bis((tert-butyldimethylsilyloxy)methyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4.8 g, 10.5 mmol) in THF (50 mL) was added slowly of BH3DMS solution (2M in THF, 6.97 mL, 13.9 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 hours, then cooled to 0° C. again. NaOH solution (5M, 12.6 mL, 63.2 mmol) was added to the reaction mixture, followed by addition of H2O2 (30%, 6.33 mL, 62.0 mmol). The resulting mixture was stirred for 5 hours before diluted with EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. Combined organic phases were washed with water and brine, and dried (MgSO4). The organic solvent was removed in vacuo to give the crude product, which was purified by flash chromatography in silica gel with EtOAc:Hex (30:70) to give the title compound (3.8 g, 77%).
    • Step 5: Benzyl Protection of the Trans Alcohol
  • To a solution of (2R′,3S′,5R′)-tert-butyl 2,5-bis((tert-butyldimethylsilyloxy)methyl)-3-hydroxypyrrolidine-1-carboxylate (2.515 g, 5.3 mmol) in THF (50 mL) were added NaH (60%, 0.423 g, 10.6 mmol). The mixture was stirred at room temperature for 30 minutes, and benzyl bromide (1.085 g, 6.3 mmol) and TBAI (0.195 g, 0.5 mmol) were added. The mixture was stirred at room temperature for 12 hours, and quenched by addition of sat. NH4Cl solution (20 mL). Concentrated in vacuo, and the residue was taken up in water and EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. Combined organic phases were washed with water and brine, and dried (MgSO4). The organic solvent was removed in vacuo to give the crude product, which was purified by flash chromatography in silica gel with EtOAc:Hex (10:90) to give (2R′,3S′,5R′)-tert-butyl 3-(benzyloxy)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidine-1-carboxylate (3.0 g, 100%) as colorless oil.
    • Step 6: Synthesis of (2R′,3S′,5R′)-tert-butyl 3-(benzyloxy)-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (benzyloxy diol)
  • To a solution of (2R′,3S′,5R′)-tert-butyl 3-(benzyloxy)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidine-1-carboxylate (3.0 g, 5.3 mmol) in THF (50 mL) was added slowly of TBAF solution (1 M in THF, 21.8 mL, 21.8 mmol) at 0° C. The resulting mixture was stirred at room temperature for 6, and quenched by addition of sat. NH4Cl solution (10 mL). Concentrated in vacuo, and the residue was treated with water and EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. Combined organic phases were washed with water and brine, and dried (MgSO4). The organic solvent was removed in vacuo to give the crude product, which was purified by flash chromatography in silica gel with EtOAc:Hex:MeOH (50:50:5) to give the title compound (1.15 g, 62.5%).
    • Step 7: Synthesis of (6S′)-tert-butyl 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate by cyclization
  • To a solution of (2R′,3S′,5R′)-tert-butyl 3-(benzyloxy)-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (1.15 g, 3.4 mmol) in THF (50 mL) was added NaH (60%, 0.409 g, 10.2 mmol). The mixture was stirred at room temperature for 30 minutes, and cooled down to 0° C. A solution of p-TsCl (0.65 g, 3.4 mmol) in THF (5 mL) was slowly added to the mixture. The reaction mixture was then stirred at room temperature for 12 hours, and quenched by addition of sat. NH4Cl solution (20 mL). Concentrated in vacuo, and the residue was taken up in water and EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. Combined organic phases were washed with water and brine, and dried (MgSO4). The organic solvent was removed in vacuo to give the crude product, which was purified by flash chromatography in silica gel with EtOAc:Hex (20:80) to give the title compound (716 mg, 66%) as off-white solid.
  • The compounds in Table I were made by the proceeding methods.
  • TABLE !
    MS (ESI)
    Example Name m/z
    478 1-(4-{[4-(dimethylamino)piperidin-1- 615.5
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-
    (tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    479 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-(4- 589.6
    {4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3-yloxy]-
    1,3,5-triazin-2-yl}phenyl)urea
    480 1-{4-[4-(5-hydroxy-3-oxa-7-azabicyclo[4.1.1]oct-7-yl)- 505.3 253.2
    6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin- 273.8
    4-ylurea
    481 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 464.2 253.1
    pyridazin-4-ylurea
    482 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 575.5
    [4-morpholin-4-yl-6-(oxetan-3-yloxy)-1,3,5-triazin-2-
    yl]phenyl}urea
    483 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 490.6
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
    pyridazin-4-ylurea
    484 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- 602.5
    yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-
    triazin-2-yl)phenyl]urea
    485 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 602.6
    yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-
    triazin-2-yl)phenyl]urea
    486 1-[4-(4-isopropyl-6-morpholin-4-yl-1,3,5-triazin-2- 545.1 293.5
    yl)phenyl]-3-{4-[(4-methylpiperazin-1- 273
    yl)carbonyl]phenyl}urea
    487 1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin- 497.3
    2-yl]phenyl}-3-(4-pyrimidin-5-ylphenyl)urea
    488 1-(4-{4-[(2,2-dimethoxyethyl)amino]-6-morpholin-4- 481.2 241.1
    yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea 261.6
    489 1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin- 496.3 248.6
    2-yl]phenyl}-3-(4-pyridin-4-ylphenyl)urea 269.1
    490 1-(4-iodophenyl)-3-{4-[4-(1-methylethyl)-6-morpholin- 545.1
    4-yl-1,3,5-triazin-2-yl]phenyl}urea
    491 1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin- 573.4 287.2
    2-yl]phenyl}-3-(4-{[4-(1-methylethyl)piperazin-1-
    yl]carbonyl}phenyl)urea
    492 1-[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2- 586.6
    yl)phenyl]-3-(4-{[4-(1-methylethyl)piperazin-1-
    yl]carbonyl}phenyl)urea
    493 1-{4-[2-(dimethylamino)pyrimidin-5-yl]phenyl}-3-{4-[4- 540.5
    (1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-
    yl]phenyl}urea
    494 tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 549.6
    ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
    yl)oxy]azetidine-1-carboxylate
    495 1-(4-{[4-(dimethylamino)piperidin-1- 616.4 308.7
    yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-
    triazin-2-yl)phenyl]urea
    496 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 507.1
    (4-nitrophenyl)urea
    497 1-(4-aminophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5- 477.1 259.6
    triazin-2-yl)phenyl]urea
    498 N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- 603.2 302.1
    yl)phenyl]carbamoyl}amino)phenyl]-4- 322.6
    methylpiperazine-1-carboxamide
    499 4-(dimethylamino)-N-[4-({[4-(4,6-dimorpholin-4-yl- 631.3
    1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)phenyl]piperidine-1-
    carboxamide
    500 1-[2-(dimethylamino)ethyl]-3-[4-({[4-(4,6-dimorpholin- 605.3
    4-yl-1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)phenyl]-1-methylurea
    501 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 631.3
    (4-{[(2-piperidin-1-
    ylethyl)carbamoyl]amino}phenyl)urea
    502 N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- 617.3
    yl)phenyl]carbamoyl}amino)phenyl]-4-methyl-1,4-
    diazepane-1-carboxamide
    503 N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- 617.3
    yl)phenyl]carbamoyl}amino)phenyl]-4-
    ethylpiperazine-1-carboxamide
    504 1-{4-[(dimethylcarbamoyl)amino]phenyl}-3-[4-(4,6- 548.3
    dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
    505 1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl- 613.4
    1,3,5-triazin-2-yl]phenyl}-3-(4-{[4-
    (dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea
    506 4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4- 587.4
    yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2-
    (dimethylamino)ethyl]-N-methylbenzamide
    507 1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl- 585.3
    1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-
    yl)carbonyl]phenyl}urea
    508 4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4- 573.3
    yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2-
    (dimethylamino)ethyl]benzamide
    509 N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl- 668.4
    1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-
    (4-methylpiperazin-1-yl)acetamide
    510 1-(4-{[4-(dimethylamino)piperidin-1- 615.5
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-
    (tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    511 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 587.3
    [4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-
    triazin-2-yl]phenyl}urea
    512 N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 575.3
    (tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    513 4-[({4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)- 601.3
    1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-
    pyrrolidin-1-ylethyl)benzamide
    514 4-[({4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)- 615.3
    1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-
    piperidin-1-ylethyl)benzamide
    515 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 616.3 308.6
    (4-{[4-(1-methylethyl)piperazin-1- 329.2
    yl]carbonyl}phenyl)urea
    516 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 627.7
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-
    8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    517 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 449.4
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-
    518 4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5- 616.4
    triazin-2-yl]phenyl}urea
    519 N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4- 616.4
    morpholin-4-yl-6-[(3S)-tetrahydrofuran-3-yloxy]-1,3,5-
    triazin-2-yl}phenyl)carbamoyl]amino}benzamide
    520 4-{[(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3- 616.4
    yloxy]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-
    (2-piperidin-1-ylethyl)benzamide
    521 4-{[(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3- 616.4
    yloxy]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-
    (2-pyrrolidin-1-ylethyl)benzamide
    522 1-(4-{[4-(1-methylethyl)piperazin-1- 616.4
    yl]carbonyl}phenyl)-3-(4-{4-morpholin-4-yl-6-[(3S)-
    tetrahydrofuran-3-yloxy]-1,3,5-triazin-2-
    yl}phenyl)urea
    523 1-(4-{[4-(1-methylethyl)piperazin-1- 616.4
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-
    (tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    524 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 616.4
    morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-
    triazin-2-yl]phenyl}carbamoyl)amino]benzamide
    525 4-[({4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5- 477.3
    triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid
    526 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 565.4
    triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-
    yl)phenyl]urea
    527 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 511.4
    triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid
    528 methyl 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl- 525.4
    1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate
    529 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4- 531.4
    ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
    530 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 468.3
    triazin-2-yl]phenyl}-3-pyridin-4-ylurea
    531 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-{4-[4- 593.4
    (4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-
    yl]phenyl}urea
    532 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(4- 595.5
    methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    533 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 593.5
    triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-
    yl)carbonyl]phenyl}urea
    534 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 594.5
    yl)phenyl]-3-{4-[(4-pyridin-2-ylpiperazin-1-
    yl)carbonyl]phenyl}urea
    535 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4- 579.5
    morpholin-4-yl-6-phenyl-1,3,5-triazin-2-
    yl)phenyl]urea
    536 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 531.1
    yl)phenyl]-3-{4-[(4-methylpiperazin-1-
    yl)carbonyl]phenyl}urea
    537 1-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 454.1
    yl)phenyl]-3-pyridin-4-ylurea
    538 methyl 4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5- 511
    triazin-2-yl)phenyl]carbamoyl}amino)benzoate
    539 N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4- 581.2
    morpholin-4-yl-6-phenyl-1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)benzamide
    540 methyl 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]- 548
    1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoate
    541 4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 497
    yl)phenyl]carbamoyl}amino)benzoic acid
    542 N-[2-(dimethylamino)ethyl]-4-[({4-[4-(4- 581.3
    methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    543 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 579.2
    (4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-
    yl)phenyl]urea
    544 1-(4-{[4-(dimethylamino)piperidin-1- 661.5
    yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-phenyl-
    1,3,5-triazin-2-yl)phenyl]urea
    545 N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl- 567.2
    6-phenyl-1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)benzamide
    546 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 604.4
    triazin-2-yl}phenyl)carbamoyl]amino}-N-[2-
    (dimethylamino)ethyl]benzamide
    547 1-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}-3- 621.5
    {4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-
    2-yl]phenyl}urea
    548 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 607.5
    triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-
    1-ylethyl)benzamide
    549 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 534.5
    triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid
    550 N-(2-methoxyethyl)-4-[({4-[4-(4-methylphenyl)-6- 568.2
    morpholin-4-yl-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    551 N-(2-methoxyethyl)-4-({[4-(4-morpholin-4-yl-6- 554.2
    phenyl-1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)benzamide
    552 4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 593.5
    yl)phenyl]carbamoyl}amino)-N-(2-pyrrolidin-1-
    ylethyl)benzamide
    553 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 567.6
    triazin-2-yl]phenyl}-3-[4-(pyrrolidin-1-
    ylcarbonyl)phenyl]urea
    554 N-[3-(dimethylamino)propyl]-4-[({4-[4-(4- 595.4
    methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    555 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 578.1
    triazin-2-yl]phenyl}-3-[4-(piperidin-1-
    ylcarbonyl)phenyl]urea
    556 N-[3-(dimethylamino)propyl]-4-({[4-(4-morpholin-4-yl- 581.4 291.2
    6-phenyl-1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)benzamide
    557 1-{4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- 460.2 230.6
    yl]phenyl}-3-pyridin-4-ylurea
    558 4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- 503.4
    yl]phenyl}carbamoyl)amino]benzoic acid
    559 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 585.5
    [4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-
    yl]phenyl}urea
    560 methyl 4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5- 517.2
    triazin-2-yl]phenyl}carbamoyl)amino]benzoate
    561 N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(2- 560.3
    thienyl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    562 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 587.3 294.1
    morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    563 N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 573.1
    (2-thienyl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    564 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 618.4 309.7
    triazin-2-yl}phenyl)carbamoyl]amino}-N-[2-
    (dimethylamino)ethyl]-N-methylbenzamide
    565 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 616.4 329.2
    triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1- 308.7
    yl)carbonyl]phenyl}urea
    566 1-{4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5- 477.2
    triazin-2-yl]phenyl}-3-pyridin-4-ylurea
    567 methyl 4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4- 534.4
    yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzoate
    568 1-(4-{[4-(dimethylamino)piperidin-1- 613.4 307.2
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-
    thienyl)-1,3,5-triazin-2-yl]phenyl}urea
    569 4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5- 520.3
    triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid
    570 N-[3-(dimethylamino)propyl]-4-[({4-[4-morpholin-4-yl- 587.3 294.2
    6-(2-thienyl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    571 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 587.5
    triazin-2-yl}phenyl)-3-[4-(pyrrolidin-1-
    ylcarbonyl)phenyl]urea
    572 N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 590.3 295.6
    (1,4-oxazepan-4-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    573 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 602.3 322.2
    [4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin- 301.7
    2-yl]phenyl}urea
    574 N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(1,4- 577.2
    oxazepan-4-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    575 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 599.3 300.2
    morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- 320.7
    yl]phenyl}urea
    576 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 593.3 317.7
    triazin-2-yl]phenyl}-3-{3-[(4-methylpiperazin-1- 521.3
    yl)carbonyl]phenyl}urea
    577 3-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 511.2
    triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid
    578 methyl 3-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl- 525.2
    1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate
    579 1-(3-{[4-(dimethylamino)piperidin-1- 521.3
    yl]carbonyl}phenyl)-3-{4-[4-(4-methylphenyl)-6-
    morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea
    580 N-[2-(dimethylamino)ethyl]-N-methyl-3-[({4-[4-(4- 595.3 298.2
    methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    581 methyl 3-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin- 463.5
    2-yl)phenyl]carbamoyl}amino)benzoate
    582 methyl 3-({[4-(4-morpholin-4-yl-6-thiophen-2-yl-1,3,5- 517.2
    triazin-2-yl)phenyl]carbamoyl}amino)benzoate
    583 N-[2-(dimethylamino)ethyl]-3-[({4-[4-(4- 581.3 291.1
    methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    584 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 604.4 302.7
    morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    585 3-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 449.4
    yl)phenyl]carbamoyl}amino)benzoic acid
    586 methyl 3-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5- 511.4
    triazin-2-yl)phenyl]carbamoyl}amino)benzoate
    587 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 594.6
    yl)phenyl]-3-{3-[(4-pyridin-2-ylpiperazin-1-
    yl)carbonyl]phenyl}urea
    588 N-[2-(dimethylamino)ethyl]-3-({[4-(4-ethyl-6- 533.3 267.1
    morpholin-4-yl-1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)-N-methylbenzamide
    589 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 531.3 266.1
    yl)phenyl]-3-{3-[(4-methylpiperazin-1- 286.7
    yl)carbonyl]phenyl}urea
    590 3-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 497.3
    yl)phenyl]carbamoyl}amino)benzoic acid
    591 methyl 4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5- 518.3
    triazin-2-yl)phenyl]carbamoyl}amino)benzoate
    592 1-[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2- 461.3
    yl)phenyl]-3-pyridin-4-ylurea
    593 4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin- 504..3
    2-yl)phenyl]carbamoyl}amino)benzoic acid
    594 methyl 4-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl- 504.5
    1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate
    595 1-(4-{[4-(1-methylethyl)piperazin-1- 604.5
    yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-
    piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea
    596 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4- 600.5
    morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-
    yl)phenyl]urea
    597 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 586.5
    (4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-
    yl)phenyl]urea
    598 1-(4-{[4-(dimethylamino)piperidin-1- 614.5
    yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-
    piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea
    599 4-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin- 490.5
    2-yl)phenyl]carbamoyl}amino)benzoic acid
    600 1-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin- 447.5
    2-yl)phenyl]-3-pyridin-4-ylurea
    601 N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl- 474.6
    6-piperidin-1-yl-1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)benzamide
    602 1-(4-{[4-(dimethylamino)piperidin-1- 600.4 300.7
    yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-
    pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea
    603 1-(4-{[4-(1-methylethyl)piperazin-1- 600.4 300.7
    yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-
    pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea
    604 N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4- 574.6
    morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)benzamide
    605 N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4- 588.3 294.6
    morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)benzamide
    606 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4- 586.3 293.7
    morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2- 286.7
    yl)phenyl]urea
    607 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 572.3
    (4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-
    yl)phenyl]urea
    608 N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl- 560.1 280.6
    6-pyrrolidin-1-yl-1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)benzamide
    609 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 491.2 266.6
    triazin-2-yl}phenyl)-3-pyridin-4-ylurea 246.1
    610 N-[3-(dimethylamino)propyl]-4-({[4-(4-morpholin-4-yl- 588.3 294.6
    6-piperidin-1-yl-1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)benzamide
    611 N-(2-methoxyethyl)-4-({[4-(4-morpholin-4-yl-6- 561.4 281.2
    piperidin-1-yl-1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)benzamide
    612 1-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin- 543.3
    2-yl)phenyl]-3-[4-(pyrrolidin-1-ylcarbonyl)phenyl]urea
    613 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 630.6
    triazin-2-yl}phenyl)-3-{4-[(4-ethylpiperazin-1-
    yl)carbonyl]phenyl}urea
    614 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 644.7
    triazin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)piperazin-
    1-yl]carbonyl}phenyl)urea
    615 methyl 4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6- 534.3
    morpholin-4-yl-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzoate
    616 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 644.6
    triazin-2-yl}phenyl)-3-(4-{[4-(dimethylamino)piperidin-
    1-yl]carbonyl}phenyl)urea
    617 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4- 602.3 322.2
    yl-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin- 301.7
    1-yl)carbonyl]phenyl}urea
    618 1-(4-{[4-(1-methylethyl)piperazin-1- 630.4315.7
    yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-
    4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea
    619 4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin- 520.2
    4-yl-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzoic acid
    620 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 616.4 308.7
    [(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5- 329.2
    triazin-2-yl}phenyl)urea
    621 N-[3-(dimethylamino)propyl]-4-{[(4-{4-[(3S)-3- 604.6
    methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-
    2-yl}phenyl)carbamoyl]amino}benzamide
    622 4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin- 616.5
    4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-
    pyrrolidin-1-ylethyl)benzamide
    623 1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3- 616.4 308.7
    methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4- 329.2
    [(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
    624 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 700.6 350.8
    triazin-2-yl}phenyl)-3-(4-{[4-(dipropylamino)piperidin-
    1-yl]carbonyl}phenyl)urea
    625 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 630.5 315.7
    [(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3-
    methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)urea
    626 4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3- 534.3
    methylmorpholin-4-yl]-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzoic acid
    627 1-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 658.6
    [(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3-
    methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)urea
    628 methyl 4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6- 548.2
    [(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzoate
    629 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 658.5 329.7
    triazin-2-yl}phenyl)-3-{4-[(4-butylpiperazin-1-
    yl)carbonyl]phenyl}urea
    630 1-(4-{[4-(1-methylethyl)piperazin-1- 644.5
    yl]carbonyl}phenyl)-3-(4-{4-[(3R)-3-methylmorpholin-
    4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-
    yl}phenyl)urea
    631 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 658.5
    triazin-2-yl}phenyl)-3-(4-{[4-(2-
    methylpropyl)piperazin-1-yl]carbonyl}phenyl)urea
    632 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 658.6
    triazin-2-yl}phenyl)-3-(4-{[4-(1-
    methylpropyl)piperazin-1-yl]carbonyl}phenyl)urea
    633 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 659.6
    triazin-2-yl}phenyl)carbamoyl]amino}-N-[2-(4-
    methylpiperazin-1-yl)ethyl]benzamide
    634 N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[(3R)-3- 604.5
    methylmorpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-
    yl]-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzamide
    635 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 626.5
    triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-pyrrolidin-
    1-ylethyl)benzamide
    636 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 643.4 322.2
    triazin-2-yl}phenyl)-3-{4-[(4-propylpiperidin-1-
    yl)carbonyl]phenyl}urea
    637 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 601.5
    triazin-2-yl}phenyl)-3-[4-(piperidin-1-
    ylcarbonyl)phenyl]urea
    638 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 643.5
    triazin-2-yl}phenyl)-3-{4-[(4-propylpiperazin-1-
    yl)carbonyl]phenyl}urea
    639 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 591.6
    triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-
    methoxyethyl)benzamide
    640 1-{4-[4-morpholin-4-yl-6-(4-tricyclo[3.3.1.13,7]dec-1- 596.7
    ylpiperazin-1-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-
    ylurea
    641 methyl 4-{[(4-{4-[4-(dimethylcarbamoyl)piperazin-1- 590.5
    yl]-6-morpholin-4-yl-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzoate
    642 N,N-dimethyl-4-(4-morpholin-4-yl-6-{4-[(pyridin-4- 533.6
    ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
    yl)piperazine-1-carboxamide
    643 N,N-dimethyl-4-(4-{4-[({4-[(4-methylpiperazin-1- 658.3 329.7
    yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6-
    morpholin-4-yl-1,3,5-triazin-2-yl)piperazine-1-
    carboxamide
    644 N,N-dimethyl-4-{4-morpholin-4-yl-6-[4-({[4-(pyridazin- 653.3
    4-ylcarbamoyl)phenyl]carbamoyl}amino)phenyl]-
    1,3,5-triazin-2-yl}piperazine-1-carboxamide
    645 N,N-dimethyl-4-(4-morpholin-4-yl-6-{4-[({4-[(4- 685.6
    propylpiperidin-1-
    yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-1,3,5-
    triazin-2-yl)piperazine-1-carboxamide
    646 4-{[(4-{4-[4-(dimethylcarbamoyl)piperazin-1-yl]-6- 576.2
    morpholin-4-yl-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzoic acid
    647 4-(4-{4-[({4-[(2- 633.3 317.1
    methoxyethyl)carbamoyl]phenyl}carbamoyl)amino]phenyl}-
    6-morpholin-4-yl-1,3,5-triazin-2-yl)-N,N-
    dimethylpiperazine-1-carboxamide
    648 4-[4-(4-{[(4-{[2- 660.3 330.7
    (dimethylamino)ethyl](methyl)carbamoyl}phenyl)carbamoyl]amino}phenyl)-
    6-morpholin-4-yl-1,3,5-triazin-
    2-yl]-N,N-dimethylpiperazine-1-carboxamide
    649 4-(4-{4-[({4-[(4-ethylpiperazin-1- 672.6
    yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6-
    morpholin-4-yl-1,3,5-triazin-2-yl)-N,N-
    dimethylpiperazine-1-carboxamide
    650 1-(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin- 554.2
    4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
    651 methyl 4-{[(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6- 611.2
    morpholin-4-yl-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzoate
    652 4-{[(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin- 597.7
    4-yl-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzoic acid
    653 N-[3-(dimethylamino)propyl]-4-{[(4-{4-[4- 681.2 341.1
    (ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-
    triazin-2-yl}phenyl)carbamoyl]amino}benzamide
    654 N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[4- 667.3 334.2
    (ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-
    triazin-2-yl}phenyl)carbamoyl]amino}benzamide
    655 4-{[(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6- 561.5
    morpholin-4-yl-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzoic acid
    656 methyl 4-{[(4-{4-[4-(acetylamino)piperidin-1-yl]-6- 575.4
    morpholin-4-yl-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzoate
    657 1-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6- 643.6
    morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-
    methylpiperazin-1-yl)carbonyl]phenyl}urea
    658 N-[1-(4-morpholin-4-yl-6-{4-[(pyridin-4- 518.5
    ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
    yl)piperidin-4-yl]acetamide
    659 4-{[(4-{4-[4-(acetylamino)piperidin-1-yl]-6-morpholin- 561.5
    4-yl-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzoic acid
    660 N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[4-(1- 631.5
    methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-
    1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzamide
    661 N-{1-[(4-{[(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]- 685.6
    6-morpholin-4-yl-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}phenyl)carbonyl]piperidin-
    4-yl}acetamide
    662 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 657.4 329.2
    [4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4- 219.8
    yl-1,3,5-triazin-2-yl}phenyl)urea
    663 1-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6- 671.4 336.2
    morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(1- 224.5
    methylethyl)piperazin-1-yl]carbonyl}phenyl)urea
    664 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 617.5
    triazin-2-yl}phenyl)-3-(4-{[(3S)-3-methylmorpholin-4-
    yl]carbonyl}phenyl)urea
    665 1-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 685.6
    [4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-
    yl-1,3,5-triazin-2-yl}phenyl)urea
    666 N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-
    1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-
    (4-methylpiperazin-1-yl)acetamide
    667 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1- 533.3
    yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-
    2-yl}phenyl)-3-pyridin-4-ylurea
    668 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1- 630.4
    yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-
    2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
    669 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 489.3
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
    pyridin-4-ylurea
    670 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 531.2
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    671 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 489.5
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
    pyridin-3-ylurea
    672 1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 506.5
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    673 1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl- 518.5
    6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    674 1-[4-(2-hydroxyethyl)phenyl]-3-{4-[4-morpholin-4-yl- 532.5
    6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    675 2-(diethylamino)ethyl 4-[({4-[4-morpholin-4-yl-6-(3- 631.6
    oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzoate
    676 1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 502.5
    8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    677 1-(4-cyanophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 513.5
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    678 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4- 586.6
    morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
    1,3,5-triazin-2-yl]phenyl}urea
    679 1-isopropyl-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 454.5
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    680 1-(2-hydroxyethyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 456.5
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    681 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 369.2
    8-yl)-1,3,5-triazin-2-yl]aniline
    682 {3-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 384.4
    8-yl)-1,3,5-triazin-2-yl]phenyl}methanol
    683 3-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 370.4
    8-yl)-1,3,5-triazin-2-yl]phenol
    684 5-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 409.4
    8-yl)-1,3,5-triazin-2-yl]-1H-benzimidazol-2-amine
    685 1-{4-[4-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-6- 502.5
    morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-
    phenylurea
    686 1-(4-{4-[(4-methylpiperazin-1-yl)amino]-6-morpholin- 490.5
    4-yl-1,3,5-triazin-2-yl}phenyl)-3-phenylurea
    687 1-(4-{4-[(1-methylpiperidin-4-yl)oxy]-6-morpholin-4- 491.5
    yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
    688 1-{4-[4-morpholin-4-yl-6-(piperidin-4-yloxy)-1,3,5- 477.5
    triazin-2-yl]phenyl}-3-pyridin-4-ylurea
    689 ethyl 4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 549.5
    ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
    yl)oxy]piperidine-1-carboxylate
    690 N-ethyl-4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 548.5
    ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
    yl)oxy]piperidine-1-carboxamide
    691 tert-butyl 4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 577.3
    ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
    yl)oxy]piperidine-1-carboxylate
    692 4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 556.5
    ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
    yl)oxy]piperidine-1-sulfonamide
    693 methyl 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 546.3
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzoate
    694 N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 602.4
    (3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    695 N,N-dimethyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 559.2
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    696 N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 545.2
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    697 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 614.3
    [4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-
    yl)-1,3,5-triazin-2-yl]phenyl}urea
    698 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 616.4
    morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
    1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    699 N-(2-hydroxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa- 575.4
    8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    700 N-[3-(dimethylamino)propyl]-4-[({4-[4-morpholin-4-yl- 616.4
    6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    701 N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4- 602.4
    morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
    1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    702 N-(2-morpholin-4-ylethyl)-4-[({4-[4-morpholin-4-yl-6- 644.4
    (3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    703 1-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-3- 628.4
    {4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-
    8-yl)-1,3,5-triazin-2-yl]phenyl}urea
    704 4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin- 399.3
    4-yl-1,3,5-triazin-2-yl]aniline
    705 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 519.7
    morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-
    ylurea
    706 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 519.2
    morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-
    ylurea
    707 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 518.2
    morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-
    phenylurea
    708 1-[4-(dimethylamino)phenyl]-3-{4-[4-(1,4-dioxa-8- 561.3
    azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-
    2-yl]phenyl}urea
    709 1-(4-cyanophenyl)-3-{4-[4-(1,4-dioxa-8- 543.2
    azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-
    2-yl]phenyl}urea
    710 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 533.7
    morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(2-
    methylpyridin-4-yl)urea
    711 1-[2-(dimethylamino)ethyl]-3-{4-[4-(1,4-dioxa-8- 513.7
    azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-
    2-yl]phenyl}urea
    712 1-[4-(4-morpholin-4-yl-6-quinolin-3-yl-1,3,5-triazin-2- 505.7
    yl)phenyl]-3-pyridin-4-ylurea
    713 1-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3- 588.3
    oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]pyridinium
    714 1-{4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5- 452.6
    triazin-2-yl]phenyl}-3-pyridin-4-ylurea
    715 methyl 4-[({4-[4-(2-methoxyethoxy)-6-morpholin-4-yl- 509.4
    1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate
    716 4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5- 395.3
    triazin-2-yl)aniline
    717 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5- 515.8
    triazin-2-yl)phenyl]-3-pyridin-4-ylurea
    718 1-(4-{4-morpholin-4-yl-6-[2-(pyridin-4-ylamino)ethyl]- 498.6
    1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
    719 1-(4-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 530.4
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    720 N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6- 535.5
    morpholin-4-yl-1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)-N-methylbenzamide
    721 N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6- 521.5
    morpholin-4-yl-1,3,5-triazin-2-
    yl)phenyl]carbamoyl}amino)benzamide
    722 4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- 521.5
    yl)phenyl]carbamoyl}amino)-N-methyl-N-[2-
    (methylamino)ethyl]benzamide
    723 1-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- 533.5
    yl)phenyl]-3-{4-[(4-methylpiperazin-1-
    yl)carbonyl]phenyl}urea
    724 1-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-3- 547.5
    [4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-
    yl)phenyl]urea
    725 4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- 561.5
    yl)phenyl]carbamoyl}amino)-N-(2-piperidin-1-
    ylethyl)benzamide
    726 1-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 514.3
    8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    727 1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4- 601.1
    morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
    1,3,5-triazin-2-yl]phenyl}urea
    728 1-(4-{4-[2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6- 508
    morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-
    ylurea
    729 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4- 575.5
    morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
    1,3,5-triazin-2-yl]phenyl}urea
    730 1-(4-{4-[2-(1,3-dioxan-2-yl)ethyl]-6-morpholin-4-yl- 492.9
    1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
    731 1-(4-{4-[3-(dimethylamino)propyl]-6-morpholin-4-yl- 463.4
    1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
    732 1-[4-(4-{3-[(1-methylethyl)amino]propyl}-6-morpholin- 477.4
    4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
    733 1-{4-[4-morpholin-4-yl-6-(3-pyrrolidin-1-ylpropyl)- 489.4
    1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
    734 1-(4-{4-[3-(4-methylpiperazin-1-yl)propyl]-6- 518.4
    morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-
    ylurea
    735 1-{4-[4-(3-{[2-(dimethylamino)ethyl]amino}propyl)-6- 506.5
    morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-
    ylurea
    736 1-{4-[4-(3-hydroxypropyl)-6-morpholin-4-yl-1,3,5- 436.3
    triazin-2-yl]phenyl}-3-pyridin-4-ylurea
    737 1-{4-[4-morpholin-4-yl-6-(3-oxopropyl)-1,3,5-triazin-2- 434.3
    yl]phenyl}-3-pyridin-4-ylurea
    738 4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6- 371.3
    morpholin-4-yl-1,3,5-triazin-2-yl]aniline
    739 tert-butyl 7-[4-(4-aminophenyl)-6-morpholin-4-yl- 484.4
    1,3,5-triazin-2-yl]-9-oxa-3,7-
    diazabicyclo[3.3.1]nonane-3-carboxylate
    740 1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6- 491.3
    morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-
    ylurea
    741 tert-butyl 7-(4-morpholin-4-yl-6-{4-[(pyridin-4- 604.4
    ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa-
    3,7-diazabicyclo[3.3.1]nonane-3-carboxylate
    742 1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7- 504.4
    diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-
    yl]phenyl}-3-pyridin-4-ylurea
    743 1-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3- 518.4
    yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-
    pyridin-4-ylurea
    744 1-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3- 546.4
    yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-
    pyridin-4-ylurea
    745 1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7- 582.5
    diazabicyclo[3.3.1]non-3-yl]-6-morpholin-4-yl-1,3,5-
    triazin-2-yl}phenyl)-3-pyridin-4-ylurea
    746 1-(2-chloropyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3- 523.3
    oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    747 1-(2,3′-bipyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 566.4
    8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    748 tert-butyl N-[4-morpholin-4-yl-6-(4-nitrophenyl)-1,3,5- 417.2
    triazin-2-yl]glycinate
    749 1-(6-chloropyridin-3-yl)-3-{4-[4-morpholin-4-yl-6-(3- 523.3
    oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    750 N-[4-morpholin-4-yl-6-(4-nitrophenyl)-1,3,5-triazin-2- 361.3
    yl]glycine
    751 1,3-bis{4-[4-morpholin-4-yl-6-(3-oxa-8- 763.5
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    752 1-(4-{[4-(dimethylamino)piperidin-1- 642.4
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-
    8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    753 N-[2-(4-methylpiperazin-1-yl)ethyl]-4-[({4-[4- 657.4
    morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
    1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    754 1-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}-3- 642.4
    {4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-
    8-yl)-1,3,5-triazin-2-yl]phenyl}urea
    755 1-{4-[(4-cyclopentylpiperazin-1-yl)carbonyl]phenyl}-3- 668.4
    {4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-
    8-yl)-1,3,5-triazin-2-yl]phenyl}urea
    756 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 600.4
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
    [4-(piperazin-1-ylcarbonyl)phenyl]urea
    757 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 684.4
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
    {4-[(4-morpholin-4-ylpiperidin-1-
    yl)carbonyl]phenyl}urea
    758 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 628.4
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-
    ylethyl)benzamide
    759 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 642.4
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-
    ylethyl)benzamide
    760 1-[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]-3-{4-[4- 682.5
    morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
    1,3,5-triazin-2-yl]phenyl}urea
    761 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 668.5
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
    {4-[(4-pyrrolidin-1-ylpiperidin-1-
    yl)carbonyl]phenyl}urea
    762 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 617.3
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
    [4-(thiomorpholin-4-ylcarbonyl)phenyl]urea
    763 1-[4-(morpholin-4-ylcarbonyl)phenyl]-3-{4-[4- 601.4
    morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
    1,3,5-triazin-2-yl]phenyl}urea
    764 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 532.3
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzoic acid
    765 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 505.3
    morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-
    ylurea
    766 1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-{4-[4- 587.4
    morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
    1,3,5-triazin-2-yl]phenyl}urea
    767 1-(4-{[4-(dimethylamino)piperidin-1- 658.4
    yl]carbonyl}phenyl)-3-{4-[4-(3,7-dioxa-9-
    azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-
    triazin-2-yl]phenyl}urea
    768 N-[2-(dimethylamino)ethyl]-4-[({4-[4-(3,7-dioxa-9- 632.4
    azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-
    triazin-2-yl]phenyl}carbamoyl)amino]-N-
    methylbenzamide
    769 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 630.4
    morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-
    methylpiperazin-1-yl)carbonyl]phenyl}urea
    770 methyl 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9- 562.3
    yl)-6-morpholin-4-yl-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzoate
    771 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 548.3
    morpholin-4-yl-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzoic acid
    772 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 616.3
    morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-
    (piperazin-1-ylcarbonyl)phenyl]urea
    773 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 658.3
    morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-
    isopropylpiperazin-1-yl)carbonyl]phenyl}urea
    774 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 644.3
    morpholin-4-yl-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-
    ylethyl)benzamide
    775 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 658.4
    morpholin-4-yl-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-
    ylethyl)benzamide
    776 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 684.4
    morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-
    pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea
    777 1-[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]-3-{4-[4- 698.4
    (3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-
    4-yl-1,3,5-triazin-2-yl]phenyl}urea
    778 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 652.4
    morpholin-4-yl-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]-N-(2-pyridin-2-
    ylethyl)benzamide
    779 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 652.4
    morpholin-4-yl-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]-N-(2-pyridin-4-
    ylethyl)benzamide
    780 N-[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin- 413.2
    2-yl]benzenesulfonamide
    781 N-(4-morpholin-4-yl-6-{4-[(pyridin-4- 533.4
    ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
    yl)benzenesulfonamide
    782 N-{4-[4-({[4-(4-methylpiperazin-1- 630.3
    yl)phenyl]carbamoyl}amino)phenyl]-6-morpholin-4-yl-
    1,3,5-triazin-2-yl}benzenesulfonamide
    783 N-(4-{4-[({4-[2- 619.3
    (dimethylamino)ethoxy]phenyl}carbamoyl)amino]phenyl}-
    6-morpholin-4-yl-1,3,5-triazin-2-
    yl)benzenesulfonamide
    784 N-(4-{4-[({4-[(4-methylpiperazin-1- 658.3
    yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6-
    morpholin-4-yl-1,3,5-triazin-2-yl)benzenesulfonamide
    785 N-{4-morpholin-4-yl-6-[4-({[4-(piperazin-1- 644.4
    ylcarbonyl)phenyl]carbamoyl}amino)phenyl]-1,3,5-
    triazin-2-yl}benzenesulfonamide
    786 N-[4-(4-{[(4-{[4-(dimethylamino)piperidin-1- 686.4
    yl]carbonyl}phenyl)carbamoyl]amino}phenyl)-6-
    morpholin-4-yl-1,3,5-triazin-2-yl]benzenesulfonamide
    787 N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4- 660.4
    morpholin-4-yl-6-[(phenylsulfonyl)amino]-1,3,5-
    triazin-2-yl}phenyl)carbamoyl]amino}benzamide
    788 N-[2-(dimethylamino)ethyl]-4-{[(4-{4-morpholin-4-yl- 646.4
    6-[(phenylsulfonyl)amino]-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzamide
    789 methyl 4-{[(4-{4-morpholin-4-yl-6- 590.3
    [(phenylsulfonyl)amino]-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzoate
    790 4-{[(4-{4-morpholin-4-yl-6-[(phenylsulfonyl)amino]- 576.2
    1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic
    acid
    791 1-{4-[4-morpholin-4-yl-6-(3-oxa-9- 503.2
    azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-
    3-pyridin-4-ylurea
    792 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 628.5
    [4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-
    yl)-1,3,5-triazin-2-yl]phenyl}urea
    793 1-{4-[4-morpholin-4-yl-6-(3-oxa-9- 614.5
    azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-
    3-[4-(piperazin-1-ylcarbonyl)phenyl]urea
    794 1-(4-{[4-(dimethylamino)piperidin-1- 656.5
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-
    9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    795 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 630.4
    morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-
    1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    796 N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 616.4
    (3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    797 N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa- 603.4
    9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    798 4-[({4-[4-morpholin-4-yl-6-(3-oxa-9- 642.4
    azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-
    ylethyl)benzamide
    799 4-[({4-[4-morpholin-4-yl-6-(3-oxa-9- 656.4
    azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-
    ylethyl)benzamide
    800 1-{4-[4-morpholin-4-yl-6-(3-oxa-9- 682.5
    azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-
    3-{4-[(4-pyrrolidin-1-ylpiperidin-1-
    yl)carbonyl]phenyl}urea
    801 N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-[({4-[4- 656.6
    morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-
    1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    802 N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4- 616.5
    morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-
    1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    803 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 628.3
    morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
    1,3,5-triazin-2-yl]phenyl}urea
    804 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 642.5
    morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-
    1,3,5-triazin-2-yl]phenyl}urea
    805 1-(4-{[4-(1-methylethyl)piperazin-1- 656.3
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-
    9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    806 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 644.5
    morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-
    ethylpiperazin-1-yl)carbonyl]phenyl}urea
    807 1-{4-[4-morpholin-4-yl-6-(2-oxa-5- 489.2
    azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-
    pyridin-4-ylurea
    808 1-(1,3-dimethyl-1H-pyrazol-5-yl)-3-{4-[4-morpholin-4- 506.2
    yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-
    2-yl]phenyl}urea
    809 1-{4-[4-morpholin-4-yl-6-(2-oxa-5- 478.2
    azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-
    (1H-pyrazol-3-yl)urea
    810 1-(4-{[4-(dimethylamino)piperidin-1- 642.2
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-
    5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    811 1-(4-{[4-(1-methylethyl)piperazin-1- 642.5
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-
    5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    812 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 628.2
    morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-
    1,3,5-triazin-2-yl]phenyl}urea
    813 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 614.2
    [4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-
    yl)-1,3,5-triazin-2-yl]phenyl}urea
    814 1-{4-[4-morpholin-4-yl-6-(2-oxa-5- 600.3
    azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-
    [4-(piperazin-1-ylcarbonyl)phenyl]urea
    815 N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 602.5
    (2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    816 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 616.3
    morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-
    1,3,5-triazin-2-
    yl]phenyl}carbamoyl)amino]benzamide
    817 2-tert-butoxy-4-morpholin-4-yl-6-(4-nitrophenyl)- 360.1
    1,3,5-triazine
    818 1-(4-{4-[(6S)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct- 505.2
    8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-
    pyridin-4-ylurea
    819 1-(4-{4-[6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct- 595.2
    8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-
    pyridin-4-ylurea
    820 1-(4-{4-[(6R)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct- 505.2
    8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-
    pyridin-4-ylurea
    821 1-(4-{4-[(6R)-6-(benzyloxy)-3-oxa-8- 595.2
    azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-
    triazin-2-yl}phenyl)-3-pyridin-4-ylurea
    822 1-{4-[(1,1-dioxidothiomorpholin-4- 649.1
    yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-
    8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    823 1-[4-(4,6-di-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl- 644.3306
    1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-
    yl)phenyl]urea
    824 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 628.5,
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 314.8, 356.8
    8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    825 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- 628.5,
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 314.8, 356.8
    8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl]phenyl}urea
    826 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 519.1,
    (6-morpholin-4-yl-4-oxo-4,5-dihydro-1,3,5-triazin-2- 280.5, 260
    yl)phenyl]urea
    827 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 628.5;
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 314.8;
    8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- 356.8;
    yl]phenyl}urea
    828 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- 628.5;
    yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 314.8;
    8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- 356.8;
    yl]phenyl}urea
    829 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8- 503.4;
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3- 272.7;
    pyridin-4-ylurea 252.2;
    830 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-
    (4-{[4-(propan-2-yl)piperazin-1-
    yl]carbonyl}phenyl)urea
    831 N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4-[(3S)-
    3-methylmorpholin-4-yl]-6-(3-oxa-8-
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl}phenyl)carbamoyl]amino}benzamide
    832 4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8- 546.2;
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- 568.2;
    yl}phenyl)carbamoyl]amino}benzoic acid
    833 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- 642.4;
    yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin- 664.3;
    4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5- 680.3;
    triazin-2-yl}phenyl)urea
    834 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 642.4;
    yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-
    4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-
    triazin-2-yl}phenyl)urea
    835 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8- 628.3;
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-
    {4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
    836 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-
    [(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
    yl}phenyl)urea
    837 1-{4-[4-(morpholin-4-yl)-6-(3-oxa-8- 642.4; 664.3;
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
    {4-[(3,3,4-trimethylpiperazin-1-
    yl)carbonyl]phenyl}urea
    838 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-
    azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-
    [4-(piperazin-1-ylcarbonyl)phenyl]urea
    • Biological Evaluation mTOR Kinase Assay Methods
  • Human mTOR assays (See Toral-Barza, et al. Biochem Biophys. Res. Commun. 2005 June 24; 332(1):304-10) with purified enzyme are performed in 96-well plates by DELFIA format as follows. Enzymes are first diluted in kinase assay buffer (10 mM HEPES (pH 7.4), 50 mM NaCl, 50 mM β-glycerophosphate, 10 mM MnCl2, 0.5 mM DTT, 0.25 mM microcystin LR, and 100 mg/mL BSA). To each well, 12 μL of the diluted enzyme is mixed briefly with 0.5 μL test inhibitor or control vehicle dimethylsulfoxide (DMSO). The kinase reaction is initiated by adding 12.5 μL kinase assay buffer containing ATP and His6-S6K to give a final reaction volume of 25 μL containing 800 ng/mL FLAG-TOR, 100 mM ATP and 1.25 mM His6-S6K. The reaction plate is incubated for 2 hours (linear at 1-6 hours) at room temperature with gentle shaking and then terminated by adding 25 μL Stop buffer (20 mM HEPES (pH 7.4), 20 mM EDTA, 20 mM EGTA). The DELFIA detection of the phosphorylated (Thr-389) His6-S6K is performed at room temperature using a monoclonal anti-P(T389)-p70S6K antibody (1A5, Cell Signaling) labeled with Europium-N-1-ITC (Eu) (10.4 Eu per antibody, PerkinElmer). The DELFIA Assay buffer and Enhancement solution can be purchased from PerkinElmer. 45 μL of the terminated kinase reaction mixture is transferred to a MaxiSorp plate (Nunc) containing 55 μL PBS. The His6-S6K is allowed to attach for 2 hours after which the wells are aspirated and washed once with PBS. 100 μL of DELFIA Assay buffer with 40 ng/mL Eu-P(T389)—S6K antibody is added. The antibody binding is continued for 1 hour with gentle agitation. The wells are then aspirated and washed 4 times with PBS containing 0.05% Tween-20 (PBST). 100 μL of DELFIA Enhancement solution is added to each well and the plates are read in a PerkinElmer Victor model plate reader. Data obtained is used to calculate enzymatic activity and enzyme inhibition by potential inhibitors.
    • PI3K-Alpha and PI3K-Gamma Fluorescence Polarization Assay Protocols
  • The reaction buffer was 20 mM HEPES, pH 7.5, 2 mM MgCl2, 0.05% CHAPS; and 0.01% βME (added fresh). The Stop/Detection Buffer was 100 mM HEPES, pH 7.5, 4 mM EDTA, 0.05% CHAPS; ATP 20 mM in water; PIP2 (diC8, Echelon, Salt Lake City Utah cat #P-4508) 1 mM in water (MW=856.5). The GST-GRP was 1.75 mg/mL or 1.4 mg/mL in 10% glycerol. The Red detector (TAMRA) was 2.5 μM. Nunc 384-well black polypropylene fluorescent plates were used for PI3K assays.
  • The assay is run by placing 5 μL of diluted enzyme per well, then 5 μL of diluted compound (or 9.5 μL enzyme then 0.5 μL compound in DMSO) is added and mixed. Then, 10 μL substrate is added to start the reaction. The samples are incubated 30-60 minutes, then the reaction is stopped by adding 20 μL stop/detector mix. PI3K is diluted with reaction buffer (e.g., 5 μL or 7.5 μL PI3K into 620 μL reaction buffer), and 5 μL of diluted enzyme is used per well. A 5 μL portion of reaction buffer or of drug diluted in buffer (e.g., 4 μL/100 so final DMSO is 1% in reaction) is added to each. Pipetting up and down mixes the samples. Alternatively, the enzyme can be diluted to 1215 μL. In this case 9.8 μL is added per well and 0.2 μL compound is added in DMSO.
  • To prepare 1 mL of substrate solution, 955 μL reaction buffer, 40 μL PIP2, and 2.5 μL ATP are mixed. 10 μL of substrate is added to each well to start the reaction. This results in 20 μM PIP2, and 25 μM ATP per reaction. The stop/detector mix is prepared by mixing 4 μL Red detector and 1.6 μL or 2.0 μL GST-GRP with 1 mL stop buffer, which results in 10 nM probe and 70 nM GST-GRP. 20 μL of the stop/detector mix is added to each well to stop the reaction. The plates are read after 30-90 minutes keeping the red probe solutions dark. For the zero time point, stop/detector mix is added to the enzyme just before adding substrate. For an extra control, stop/detector mix is added to buffer (no enzyme) and substrate or to just buffer (no substrate). Pooled PI3K preparations had a protein concentration of 0.25 mg/mL. The recommended reaction has 0.06 μL per 20 μL (0.015 μg/20 μL) or 0.01125 μg/15 μL or 0.75 μg/mL.
  • Plates are read on machines with filters for TAMRA. The units are mP with no enzyme controls reading app 190-220 mP units. Fully active enzyme reduces fluorescence polarization down to 70-100 mP after 30 minutes. An active compound raises the mP values halfway to control or to 120-150 mP units.
    • In Vitro Cell Culture Growth Assay Methods
  • Cell Lines used are human breast MDA-MB-361, human prostate PC3-mm2, and human prostate LNCap tumor cell lines. Cells are plated in 96-well culture plates at approximately 3000 cells per well. One day following plating, various concentrations of PI3K inhibitors in DMSO are added to cells (final DMSO concentration in cell assays is 0.25%). Three days after drug treatment, viable cell densities are determined by cell mediated metabolic conversion of the dye MTS, a well-established indicator of cell proliferation in vitro. Cell growth assays are performed using kits purchased from Promega Corporation (Madison, Wis.), following the protocol provided by the vendor. Measuring absorbance at 490 nm generates MTS assay results. Compound effect on cell proliferation is assessed relative to untreated control cell growth. The drug concentration that conferred 50% inhibition of growth is determined as IC50 (μM).
  • hSMG-1 Kinase Assay
  • The human SMG-1 (hSMG-1) kinase assay employs the recombinant hSMG-1 protein prepared from transiently transfected HEK293 cells and a GST-p53 (aa 1-70) fusion substrate protein derived from cellular tumor suppressor gene p53. The routine assay is performed in a 96-well plate format as follows. Enzymes were first diluted in kinase assay buffer (10 mM HEPES, pH 7.4, 50 mM NaCl, 0.2 mM DTT, 50 mM β-glycerophosphate, 0.5 μM microcystin LR, 10 mM MnCl2). To each well, 12 μL of the diluted enzyme were mixed briefly with 0.5 μL test inhibitor or control vehicle dimethylsulfoxide (DMSO). The kinase reaction was initiated by adding 12.5 μL kinase assay buffer containing ATP and GST-p53 to give a final reaction volume of 25 μL containing 400-800 ng/mL FLAG-hSMG-1, 0.5 μg GST-p53, 10 μM ATP. The reaction was carried out at room temperature for 1.0 hour before terminated by addition of 25 μl stop solution. The assay mixture was then transferred to FluoroNunc Plates with MaxiSorp Surface (Nunc #439-454). The plates were incubated at room temperature for 2 hr (4° C. for overnight) to achieve efficient binding of substrate protein to the plate. The plates were aspirated, washed with PBS. Phospho-substrate proteins were detected by incubating for 1 hour with 125 ng of europium-labeled anti-mouse secondary antibody (PerkinElmer AD2027) and the primary phospho(S15)-p53 monoclonal antibody (Cell Signal #9286) in 1001 DELFIA assay buffer (PerkinElmer #1244-111). Plates were then washed and incubated for 0.5 hour with 100 μl of DELFIA enhancement solution (PerkinElmer #1244-105). DELFIA assay results are recorded in a Victor Plate Reader (PerkinElmer). Data obtained were used to calculate enzymatic activity and enzyme inhibition by potential inhibitors.
  • Table 2 shows the results of the described PI3K-α, PI3K-γ, and mTOR kinase assays.
  • TABLE 2
    Example IC50 PI3Kα nM IC50 PI3Kγ nM IC50 mTOR μM
    1 3 29 0.0013
    2 2 35 0.001
    3 3 27 0.00385
    4 2 23 0.0017
    5 17 438 0.0063
    6 6 53 0.006
    7 >10000 >100000 >4,0000
    8 20 220 0.008
    9 10 65 0.004
    10 75 289 0.068
    11 61 528 0.00925
    12 248 815 0.011
    13 51 879 0.0115
    14 25 154 0.00845
    15 23 177 0.0025
    16 >10,000 >100000 0.01205
    17 8 90 0.01395
    18 9 71 0.036
    19 23 206 0.039
    20 41 258 0.0305
    21 22 92 0.00175
    22 12 142 0.00475
    23 18 51 0.00205
    24 22 99 0.0027
    25 58 105 0.00405
    26 680 10,000 0.0025
    27 1230 >10,000 0.00415
    28 54 5550 0.00095
    29 2690 >10,000 0.0028
    30 2120 >10,000 0.00265
    31 142 3520 0.00049
    32 45 2540 0.00029
    33 NA NA 0.091
    34 9 95 0.00049
    35 6 54 0.00021
    36 17 150 0.00051
    37 39 155 0.00195
    38 7 91 0.00028
    39 14 75 0.00032
    40 21 136 0.00066
    41 69 122 0.0013
    42 86 290 0.00335
    43 28 35 0.00165
    44 NA NA 0.0135
    45 NA NA 0.0036
    46 208 4920 0.024
    47 13 52 0.0016
    48 6 40 0.0018
    49 3 21 0.01
    50 1 21 0.002
    51 1 15 0.0019
    52 2 38 0.001
    53 45 403 0.024
    54 10 88 0.00475
    55 205 1580 0.05
    56 122 444 0.015
    57 8 74 0.0165
    58 13 85 0.0025
    59 3 30 0.00105
    60 5 36 0.0018
    61 9 32 0.00076
    62 2 24 0.00068
    63 5 36 0.00195
    64 1457 1190 1.5
    65 15 83 0.00505
    66 7 30 0.00165
    67 6 48 0.00145
    68 0.3 7 0.00057
    69 0.4 8 0.00085
    70 2 20 0.0007
    71 0.4 8 0.00067
    72 2 19 0.00085
    73 0.3 7 0.00077
    74 0.4 8 0.00063
    75 0.6 10 0.00075
    76 0.4 8 0.00067
    77 0.3 4 0.00068
    78 3 23 0.00085
    79 773 193 0.0051
    80 851 2120 0.00715
    81 2 38 0.001
    82 3 21 0.0089
    83 1 15 0.0019
    84 10 88 0.00475
    85 45 403 0.018
    86 122 444 0.01
    87 205 1580 0.05
    88 8 74 0.0165
    89 10 31 0.0016
    90 8 42 0.00083
    91 6 73 0.00071
    92 11 92 0.00235
    93 12 133 0.00855
    94 5 56 0.001
    95 48 101 0.00275
    96 NA NA 0.0012
    97 NA NA 0.0011
    98 1350 9000 2.1
    99 1520 7500 0.46
    100 5 38 0.0035
    101 6 33 0.00044
    102 6 84 0.0061
    103 3 73 0.0053
    104 19 234 0.015
    105 14 112 0.0305
    106 393 1840 0.00755
    107 115 1490 0.019
    108 586 4150 0.019
    109 1460 2960 0.0735
    110 884 3510 0.029
    111 116 1830 0.0023
    112 488 777 0.012
    113 NA NA 0.0037
    114 106 1180 0.00315
    115 109 2000 0.0032
    116 1740 2310 0.0027
    117 177 3000 0.083
    118 379 297 0.195
    119 1240 7530 0.14
    120 262 1550 0.079
    121 1850 4000 0.0435
    122 1160 9500 0.0745
    123 760 6350 0.115
    124 1650 9650 0.155
    125 840 8750 0.016
    126 510 5510 0.0195
    127 1390 4730 0.0515
    128 1330 10,000 0.031
    129 7217 10,000 2.35
    130 14 132 0.008
    131 25 336 0.0145
    132 14 234 0.026
    133 39 8890 0.043
    134 20 183 0.0245
    135 15 143 0.034
    136 208 4920 0.024
    137 9 117 0.00855
    138 123.5 459 0.0435
    139 24 43 0.074
    140 27 100 0.027
    141 241 3380 0.026
    142 3 50 0.0011
    143 2 22 0.0012
    144 NA NA NA
    145 574 1000 0.009
    146 >10000 >100000 0.003
    147 1930 6830 0.006
    148 300 620 0.008
    149 889 1400 0.08
    150 832 >10,000 0.005
    151 0.6 8117 0.007
    152 2 5 0.002
    153 868 10,000 0.015
    154 275 3820 0.064
    155 2300 4940 0.016
    156 746 10,000 0.053
    157 1451 7090 0.17
    158 300 1290 0.007
    159 133 3920 0.002
    160 358 9070 0.007
    161 39 155 0.03
    162 10 495 0.023
    163 2 9 0.0039
    164 378 1380 4
    165 9 101 0.028
    166 4 33 0.06
    167 0.8 7 0.00068
    168 1 3 0.0036
    169 408 7960 0.0083
    170 384 9500 0.004
    171 300 9500 0.0012
    172 435 10,000 0.008
    173 1210 10,000 0.084
    174 861 727 0.0021
    175 549 453 0.0048
    176 1120 3730 0.022
    177 5840 4120 0.0016
    178 >10,000 >10,000 0.014
    179 1 13 0.001
    180 531 8000 0.0016
    181 426 6730 0.011
    182 308 5000 0.003
    183 526 11000 0.014
    184 30 143 0.004
    185 1 18 0.0029
    186 28 221 0.006
    187 3 24 0.0035
    188 7540 2380 0.011
    189 19 203 0.028
    190 780 1320 0.0063
    191 435 4630 0.016
    192 1120 453 0.043
    193 401 3133 0.0008
    194 NA NA 0.027
    195 115 498 0.021
    196 6 55 0.013
    197 2 36 0.024
    198 2 33 0.002
    199 44 144 0.001
    200 14 128 0.0065
    201 28 606 0.0009
    202 NA NA 0.0055
    203 NA NA 0.001
    204 NA NA 0.0035
    205 NA NA 0.002
    206 NA NA 0.056
    207 NA NA 0.00084
    208 Na NA 0.0005
    209 24 99 0.009
    210 6 31 NA
    211 80 108 0.006
    212 902 8770 0.0064
    213 5280 10,000 0.0095
    214 2670 10,000 0.0029
    215 187 3160 0.0012
    216 521 7030 0.003
    217 253 3230 0.0032
    218 279 2780 0.0026
    219 561 8280 0.0059
    220 275 2830 0.0035
    221 214 4280 0.0027
    222 152 572 0.0005
    223 2 200 NA
    224 444 5870 0.0004
    225 109 388 0.047
    226 75 294 0.062
    227 23 81 0.0073
    228 46 280 0.051
    229 19 70 0.00077
    230 22 119 0.0012
    231 4 63 0.0025
    232 6 37 0.083
    233 55 121 0.0079
    234 4534 9534 NA
    235 3206 4110 NA
    236 3 15 0.011
    237 2 23 0.003
    238 1 10 0.0036
    239 11 38 0.0032
    240 1 6 0.0016
    241 6 23 0.009
    242 2 24 0.007
    243 1 9 0.0077
    244 1 9 0.0051
    245 1 13 0.01
    246 1 12 0.015
    247 2 5 0.019
    248 2 18 0.0064
    249 25 216 0.002
    250 21 190 0.0009
    251 2 21 0.006
    252 22 184 0.018
    253 8 267 0.009
    254 63 253 0.017
    255 48 85 0.016
    256 68 182 0.032
    257 90 323 0.085
    258 403 6170 0.0023
    259 408 5410 0.0024
    260 417 4730 0.0009
    261 158 2530 0.00031
    262 105 954 0.00029
    263 3 20 0.001
    264 947 5440 NA
    265 1079 10,000 0.0015
    266 16 93 0.0017
    267 17 58 0.0035
    268 12 41 0.00039
    269 6 140 0.08
    270 68 318 0.16
    271 2 23 0.013
    272 5 54 0.03
    273 4 33 0.0008
    274 34 616 0.059
    275 46 711 0.07
    276 34 597 0.06
    277 30 276 0.06
    278 26 344 0.25
    279 10 70 0.035
    280 5 29 0.004
    281 2188 4981 2.8
    282 10 32 0.0047
    283 1 11 0.0031
    284 0.7 12 0.0009
    285 1127 3433 0.001
    286 4195 10,000 120
    287 253 3304 0.00016
    288 226 2784 0.00097
    289 955 3880 0.0015
    290 97 166 0.15
    291 368 711 0.19
    292 1501 3693 0.07
    293 764 533 0.5
    294 9 26 0.018
    295 19 81 0.029
    296 13 35 0.021
    297 38 70 0.01
    298 2 24 0.021
    299 3 34 0.08
    300 39 106 0.0053
    301 21 58 0.0008
    302 35 263 0.036
    303 NA NA 0.017
    304 2 18 0.0025
    305 1 18 0.0006
    306 1 19 0.0021
    307 3 30 0.0028
    308 3 14 0.0029
    309 12 95 0.0035
    310 14 82 0.0059
    311 40 125 0.012
    312 3440 10,000 0.037
    313 1730 7490 0.037
    314 1820 10,000 0.08
    315 1100 7900 0.005
    316 1410 2690 0.071
    317 216 6830 0.084
    318 15.5 679 0.855
    319 80 1446 0.0044
    320 3.3 25 0.0129
    321 25 116 0.0165
    322 2.4 30 0.006
    323 2.9 32 0.007
    324 1 22 0.0052
    325 74 6244 0.0046
    326 830 6189 0.0122
    327 394 5899 0.0063
    328 261 14,000 0.0046
    329 9.5 385 0.00068
    330 42 827 0.0033
    331 NA NA 0.0035
    332 NA NA 0.011
    333 NA NA 0.0058
    334 16 680 0.0009
    335 81 144 0.004
    336 40 44 0.0036
    337 7 98 0.07
    338 3 77 0.022
    339 71 485 0.09
    340 92 706 0.046
    341 10 48 0.012
    342 20 127 0.0066
    343 97 6700 0.04
    344 1610 4140 1.5
    345 43 112 0.08
    346 43 89 0.023
    347 796 8440 NA
    348 1030 10,000 NA
    349 59 163 NA
    350 1 7 NA
    351 3 16 0.0042
    352 13.5 732 0.00024
    353 8.5 501 0.00022
    354 69 6224 0.0046
    355 830 6189 0.012
    356 394 5899 0.0063
    357 261 14000 0.0046
    358 9 363 0.00068
    359 42 827 0.0034
    360 6672 >10000 0.082
    361 6028 >10000 0.0013
    362 3090 >10000 0.00074
    363 1097 7142 0.00077
    364 1465 8038 0.0035
    365 6340 >10000 0.0012
    366 585 2996 0.0011
    367 499 4076 0.001
    368 109 1936 0.00068
    369 362 2560 0.0013
    370 483 3502 0.00085
    371 389 2256 0.00084
    372 961 7245 0.00025
    373 70 2962 0.00016
    374 64 3915 0.00014
    375 44 2589 0.00015
    376 2602 >10000 0.0023
    377 2614 4718 0.0039
    378 2506 5375 0.0054
    379 4749 5255 0.0073
    380 3344 3559 0.0051
    381 2955 5395 0.0059
    382 522 4306 0.0045
    383 2978 3609 0.0061
    384 4220 5381 0.0064
    385 3397 4692 0.0057
    386 5122 4476 0.0042
    387 3416 2858 0.0032
    388 3450 4285 0.0048
    389 4766 5663 0.0065
    390 2467 2354 0.012
    391 2398 4000 0.0096
    392 1178 2781 0.0055
    393 444 1539 0.0036
    394 592 3226 0.0088
    395 584 2221 0.014
    396 586 2432 0.01
    397 173 2073 0.00016
    398 644 3909 0.00021
    399 330 1691 0.0011
    400 846 4099 0.0017
    401 413 3247 0.002
    402 543 3643 0.0018
    403 314 2383 0.00075
    404 63 433 0.00069
    405 50 193 0.00064
    406 478 1881 0.00038
    407 766 2255 0.00052
    408 876 3342 0.00072
    409 856 4487 0.0015
    410 826 5684 0.0023
    411 1896 >10000 0.0036
    412 1230 7483 0.0073
    413 1518 >10000 0.0092
    414 969 5453 0.0069
    415 787 3263 0.00038
    416 446 2505 0.00055
    417 656 4299 0.0011
    418 520 3476 0.0015
    419 610 4272 0.0017
    420 593 4363 0.00063
    421 414 1571 0.00072
    422 269 1221 0.00079
    423 610 1854 0.0011
    424 576 1871 0.0014
    425 309 2383 0.0012
    426 1224 8477 0.053
    427 580 1419 0.0013
    428 450 840 0.0014
    429 483 1005 0.0019
    430 402 484 0.0017
    431 43 340 0.001
    432 90 480 0.00069
    433 220 1510 0.0023
    434 571 4740 0.00056
    435 643 4603 0.00075
    436 749 3119 0.00062
    437 381 1612 0.00056
    438 77 663 0.00081
    439 182 1283 0.00042
    440 1006 >10000 0.0012
    441 970 >10000 0.0012
    442 1756 >10000 0.0015
    443 427 1883 0.00089
    444 60 1099 0.00057
    445 100 1002 0.00041
    446 835 4013 0.00082
    447 390 2802 0.0019
    448 519 >10000 0.0023
    449 287 1640 0.0019
    450 76 888 0.0017
    451 85 702 0.0014
    452 41 502 0.00055
    453 659 4273 0.0033
    454 278 1490 0.0002
    455 113 1390 0.0003
    456 150 1547 0.0007
    457 63 839 0.0002
    458 33 512 0.0002
    459 26 483 0.0003
    460 143 1083 0.0004
    461 482 4415 0.0011
    462 <0.001
    463 0.017
    464 0.001
    465 0.001
    466 0.001
    467 <0.001
    468 <0.001
    469 0.023
    470 0.007
    471 0.000
    472 0.035
    473 0.035
    474 0.048
    475 18.500
    476 0.005
    477 14.000
    478 1.1 6.0 0.00089
    479 <2.1 14.0 0.0017
    480 13.0 53.0 0.0029
    481 11.0 65.0 0.0023
    482 0.6 10.0 0.00305
    483 28.5 150.0 0.00155
    484 1.0 8.0 0.00063
    485 1.4 10.0 0.00125
    486 1.1 7.0 0.0045
    487 32.3 27.0 0.0018
    488 42.0 180.0 0.0034
    489 3671.7 9045.0 0.0022
    490 586.0 1077.0 0.0116
    491 3.5 17.0 0.0011
    492 6.5 35.0 0.018
    493 2924.0 1078.0 0.0325
    494 16.5 104.0 0.0042
    495 <1.00 6.0 0.00195
    496 NA NA NA
    497 3.0 19.0 0.0046
    498 <1.70 2.5 0.00235
    499 <1.90 4.5 0.0022
    500 0.4 10.0 0.00109
    501 <1.75 6.5 0.00069
    502 0.5 6.0 0.001
    503 0.5 1.8
    504 1.8 10.0 0.00135
    505 0.6 5.0 NA
    506 0.3 7.0 NA
    507 1.6 8.7 0.0032
    508 <1.9 12.5 0.00097
    509 11.5 662.5 0.00045
    510 1.1 6.3 0.00089
    511 2.3 10.3 0.00052
    512 <1.9 10.0 0.00012
    513 <2.4 12.0 0.00012
    514 1.6 15.0 0.00017
    515 0.4 7.6 0.00155
    516 2.1 17.0 NA
    517 3.4 18.5 0.00106
    518 0.9 6.5 0.0011
    519 <1.1 4.8 0.00071
    520 1.4 8.0 0.00038
    521 1.4 6.0 0.0003
    522 1.4 7.5 0.00106
    523 3.2 9.5 0.00043
    524 0.8 10.0 0.00026
    525 NA NA NA
    526 96.5 6701.5 0.0475
    527 20.5 127.0 0.0093
    528 1612.0 4140.0 1.6
    529 10.5 48.5 0.0155
    530 92.0 705.5 0.0495
    531 71.5 484.5 0.08
    532 3.0 76.5 0.019
    533 7.0 98.5 0.0705
    534 2.1 11.1 0.0534
    535 43.5 112.0 0.0815
    536 1.5 13.0 0.0094
    537 43.5 89.0 0.000022
    538 333.0 197.0 0.000125
    539 1.1 16.0 0.0000085
    540 54.0 121.0 0.0000034
    541 28.000 57.000 0.017
    542 8.000 67.000 0.0215
    543 3.500 15.500 0.042
    544 3.500 20.500 0.017
    545 4.000 17.000 0.0109
    546 3.500 73.500 0.000225
    547 11.000 70.000 0.00775
    548 40.000 387.000 0.00975
    549 724.000 4541 0.0265
    550 47.000 374.000 0.0124
    551 24.000 117.500 0.01
    552 11.500 127.000 0.00355
    553 12.500 72.000 0.0195
    554 15.000 156.500 0.0119
    555 87.500 378.500 0.405
    556 8.500 54.000 0.0044
    557 18.000 64.000 0.00855
    558 17.000 41.000 0.0061
    559 2.000 13.500 0.01005
    560 269.000 504.500 0.1
    561 11.5 59.0 0.006
    562 1.0 10.5 0.004
    563 2.5 33.5 0.003
    564 0.6 16.5 0.001
    565 4.1 38.0 0.001
    566 2.6 18.0 0.002
    567 14.5 90.0 0.002
    568 3.5 18.0 0.010
    569 74.5 375.0 0.008
    570 5.5 48.0 0.013
    571 21.0 108.0 0.000
    572 0.9 15.0 0.000
    573 6.5 64.0 0.004
    574 1.0 12.5 0.006
    575 3.0 19.0 0.015
    576 761.0 2081.0 0.140
    577 63.0 104.0 0.030
    578 2406.0 2511.0 2.100
    579 462.0 658.0 0.120
    580 465.0 1315.0 0.100
    581 113.5 461.0 0.037
    582 513.0 1094.0 0.230
    583 123.0 718.0 0.048
    584
    585 65.0 131.0 0.012
    586 947.0 1246.0 0.365
    587 350.0 675.0 0.100
    588 524.5 2249.0 0.054
    589 718.0 1615.0 0.057
    590 343.0 403.5 0.049
    591 250.0 726.0 0.033
    592 25.5 122.0 0.009
    593 40.0 143.0 0.012
    594 349.5 744.0 0.022
    595 6.5 58.5 0.010
    596 5.0 40.5 0.013
    597 5.0 58.0 0.011
    598 5.5 40.0 0.010
    599 64.5 190.0 0.013
    600 45.5 161.5 0.008
    601 3.5 57.5 0.003
    602 7.0 46.5 0.011
    603 8.5 50.5 0.017
    604 3.5 55.5 0.010
    605 2.2 46.0 0.003
    606 12.0 87.0 0.026
    607 12.0 94.0 0.019
    608 9.0 107.0 0.005
    609 11.5 93.5 0.003
    610 3.5 50.5 0.005
    611 18.5 151.5 0.013
    612 5.5 67.0 0.061
    613 3.8 53.5 0.001
    614 2.7 32.5 0.001
    615 26.5 115.5 0.001
    616 4.0 58.5 0.001
    617 2.5 27.0 0.001
    618 2.0 18.5 0.001
    619 33.0 137.0 0.001
    620 4.0 32.5 0.003
    621 3.5 43.5 0.001
    622 3.0 50.5 0.000
    623 12.5 104.0 0.001
    624 17.5 58.5 0.001
    625 16.5 102.5 0.003
    626 59.0 207.5 0.001
    627 18.5 101.5 0.002
    628
    629 26.0 95.0 0.004
    630 13.5 84.5 0.001
    631 28.0 133.0 0.004
    632 15.0 74.5 0.001
    633 11.5 175.0 0.001
    634 6.0 121.5 0.000
    635 22.0 377.5 0.000
    636 231.0 468.5 0.027
    637 21.5 190.5 0.004
    638 16.0 113.5 0.002
    639 14.5 123.0 0.001
    640 345.0 795.0 2.800
    641 88.5 275.5 0.007
    642 69.0 254.5 0.001
    643 6.2 42.5 0.007
    644 7.8 59.5 0.001
    645 105.0 230.5 0.120
    646 23.0 85.5 0.006
    647 24.3 107.0 0.003
    648 2.0 27.0 0.003
    649 6.4 38.0 0.006
    650 23.5 103.5 0.022
    651 71.0 247.5 0.014
    652 36.0 84.5 0.004
    653 4.1 34.0 0.007
    654 6.0 70.0 0.008
    655 91.5 745.5 0.625
    656 73.0 651.0 0.019
    657 11.5 127.5 0.385
    658 41.5 265.0 0.020
    659 3621.0 10000.0 0.720
    660 7.5 168.5 0.305
    661 56.5 461.5 0.580
    662 34.3 197.0 0.770
    663 47.3 296.0 0.590
    664 NA NA NA
    665 71.0 283.5 0.445
    666 11.5 662.5 0.000
    667 102 1081 0.000405
    668 122 625.000 0.00056
    669 8.0 89.0 0.00048
    670 5.0 53.0 0.000212
    671 17.5 150.5 0.000505
    672 39.5 154.5 0.00195
    673 7.0 98.7 0.00043
    674 14.0 74.5 0.000325
    675 21.0 135.5 0.00066
    676 69.5 122.0 0.0013
    677 86.5 290.0 0.00335
    678 21.3 45.3 0.001168
    679 1575.0 9500.0 0.0135
    680 504.0 2083.0 0.0036
    681 2547 >10,000 0.091
    682 84.3 1282.5 0.0885
    683 121.3 1329.0 0.025
    684 154.3 2345.0 0.0235
    685 7.0 26.5 0.000825
    686 77.0 540.0 0.026
    687 4.0 39.5 0.00485
    688 3.0 35.5 0.008
    689 217.4 2482 0.03902
    690 5.0 83.5 0.000525
    691 6.0 199.0 0.00135
    692 3.2 29.0 0.00375
    693 69.0 289.0 0.00135
    694 2.0 40.0 0.000245
    695 4.0 70.5 0.00028
    696 4.5 73.5 0.000275
    697 2.7 42.7 0.000459
    698 2.7 44.7 0.000302
    699 5.0 62.5 0.0003
    700 2.5 41.5 0.00053
    701 2.0 25.0 0.00036
    702 6.5 125.5 0.000555
    703 1.5 23.5 0.00051
    704 7217 >10,000 2.35
    705 13.5 132.0 0.0124
    706 25.5 336.0 0.0145
    707 14.0 234.5 0.034
    708 39.5 8890.5 0.043
    709 20.0 182.5 0.0245
    710 15.5 143.5 0.034
    711 207.5 4919.5 0.02
    712 9.5 117.0 0.00855
    713 36.0 444.0 0.0009
    714 15.5 69.0 0.00645
    715 59.5 146.5 0.006
    716 NA NA NA
    717 444.0 5874.0 0.000395
    718 40.5 210.5 0.055
    719 17.5 96.0 0.00015
    720 0.4 7.0 0.0077
    721 0.6 10.5 0.00565
    722 0.8 9.5 0.0145
    723 1.3 13.5 0.0225
    724 1.5 4.0 0.0185
    725 2.0 20.5 0.0082
    726 25.0 216.5 0.0025
    727 21.0 189.5 0.000805
    728 10.5 47.0 0.00038
    729 14.5 100.0 0.00185
    730 15.5 64.5 0.0043
    731 33.0 413.0 0.059
    732 44.0 478.0 0.069
    733 31.5 412.0 0.0755
    734 25.5 210.0 0.0595
    735 26.5 289.5 0.1225
    736 9.5 53.5 0.0036
    737 7.0 30.0 0.00445
    738 NA NA NA
    739 NA NA NA
    740 11.5 34.5 0.00405
    741 2188 4981 2.80
    742 97.0 166.0 0.145
    743 368.0 711.0 0.19
    744 1501.0 3693.0 0.068
    745 764.0 533.0 0.47
    746 23.5 99.0 0.001265
    747 40.0 44.0 0.00345
    748 NA NA NA
    749 59.0 163.5 0.002
    750 NA NA NA
    751 143.0 403.5 0.003
    752 1.2 18.5 0.00029
    753 2.0 31.0 0.000315
    754 3.0 28.0 0.000327
    755 2.0 26.5 0.00057
    756 0.5 7.0 0.0002
    757 5.5 37.5 0.00028
    758 2.0 16.0 0.00017
    759 2.0 38.0 0.00016
    760 4.3 28.3 0.00021
    761 2.0 19.0 0.00012
    762 2.7 19.7 0.000428
    763 3.0 24.0 0.000445
    764 8.5 67.5 0.00021
    765 8.5 78.5 0.000195
    766 24.0 85.5 0.001315
    767 2.1 17.0 0.0002
    768 1.2 18.5 0.000115
    769 2.1 17.5 0.00023
    770 30.5 99.0 0.00027
    771 19.5 66.0 0.000215
    772 0.8 9.5 0.00029
    773 3.0 36.5 0.000305
    774 2.0 41.5 0.00023
    775 2.5 46.5 0.00023
    776 3.0 29.5 0.000345
    777 4.0 39.0 0.000265
    778 11.5 126.0 0.00028
    779 4.2 49.7 0.00023
    780 NA NA NA
    781 136.0 374.5 0.0305
    782 124.5 251.5 0.11
    783 346.0 736.0 0.295
    784 40.5 174.0 0.088
    785 6.0 45.5 0.0555
    786 30.5 129.0 0.089
    787 10.5 145.5 0.0585
    788 13.0 160.0 0.026
    789 870.0 1163.0 0.059
    790 244.0 593.0 0.065
    791 12.5 64.5 0.00068
    792 3.3 35.5 0.00081
    793 1.0 15.0 0.00042
    794 4.1 26.0 0.00063
    795 2.7 26.5 0.000425
    796 2.6 31.5 0.00039
    797 11.5 76.0 0.0013
    798 4.1 43.5 0.000445
    799 5.0 71.5 0.0005
    800 5.5 35.5 0.00072
    801 5.0 38.0 0.000455
    802 3.5 23.0 0.000675
    803 3.0 29.0 0.00019
    804 6.0 59.5 0.000425
    805 6.5 64.0 0.000415
    806 4.5 47.0 0.00024
    807 Na NA NA
    808 381.0 1261.0 0.26
    809 395.0 2189.0 0.067
    810 2.8 30.5 0.00205
    811 3.2 33.5 0.0015
    812 2.8 30.5 0.002
    813 3.1 30.0 0.0019
    814 0.8 10.0 0.00105
    815 1.9 24.0 0.000765
    816 2.4 26.0 0.001065
    817 NA NA NA
    818 37.7 185.0 0.002
    819 44.0 357.5 0.017
    820 6.1 67.0 0.000515
    821 9.3 58.3 0.0034
    822 3.0 31.5 0.000335
    823 661.0 2788.0 0.0000015
    824 2 17 NA
    825 2 13 NA
    826 15 96 1.200
    827 2.150 17.000 0.295
    828 2.050 13.000 0.185
    829 10.500 188.500 0.520
    830 4.150 70.500 0.305
    831 3.300 87.500 0.265
    832 61.500 341.500 0.165
    833 5.600 81.500 0.185
    834 4.800 86.500 0.680
    835 5.850 66.000 0.780
    836 5.100 41.000 0.665
    837 3.700 19.500 0.515
    838 4.000 69.500 1.550
  • Table 3 shows the results of the described hSMG-1 kinase assay.
  • TABLE 3
    hSMG-1 IC50
    Example (μM)
    462 0.001
    463 0.510
    464 0.003
    465 0.005
    466 0.000
    467 0.000
    468 <0.000
    469 0.130
    470 0.195
    471 0.005
    472 0.200
    473 3.650
    474 5.650
    475 >20
    476 0.019
    477 9.250
  • Table 4 shows the results of the described MDA-MB-361, PC3-mm2, and LNCap assays.
  • TABLE 4
    IC50 MDA-MB-
    361 IC50 PC3-mm2 IC50 LNCap
    Example (nM) (nM) (nM)
    1 45.0 43.0
    2 45.0 43.0
    3 45.0 43.0
    4 45.0 43.0
    5 45.0 43.0
    6 45.0 43.0
    7 ND ND
    8 407.0 293.0
    9 102.0 161.0
    10 2709.0 1782.0
    11 794.0 5630.5
    12 ND ND
    13 603.0 845.0
    14 376.0 590.0
    15 255.0 328.0
    16 ND ND
    17 501.0 994.0
    18 2656.0 7102.0
    19 1031.0 1596.0
    20 >10000 >10000
    21 129.0 246.0
    22 1424.0 2445.0
    23 104.0 147.0
    24 122.0 142.0
    25 264.0 258.0
    26 ND ND 190.0
    27 ND ND 350.0
    28 ND ND 2.4
    29 ND ND 180.0
    30 ND ND 90.0
    31 ND ND 45.0
    32 ND ND 0.7
    33 ND ND
    34 28.0 41.0
    35 22.5 27.5
    36 73.0 98.0
    37 98.0 176.0
    38 15.0 28.0
    39 22.0 30.0
    40 <30 62.0
    41 167.0 301.0
    42 345.0 3600.0
    43 35.8 40.0
    44 ND ND
    45 ND ND
    46 ND ND
    47 116.0 95.0
    48 38.0 48.0
    49 84.0 79.0
    50 36.0 39.0
    51 <30 <30
    52 <30 49.0
    53 662.0 987.0
    54 133.0 214.0
    55 ND ND
    56 ND ND
    57 119.0 187.0
    58 115.0 45.0
    59 14.0 16.0
    60 83.0 92.0
    61 48.0 23.0
    62 27.0 34.0
    63 69.0 62.0
    64 ND ND
    65 151.0 267.0
    66 59.0 66.0
    67 816.0 28.0
    68 <3 11.0
    69 10.0 13.0
    70 19.0 24.0
    71 <9.8 18.3
    72 1.0 13.0
    73 30.0 107.0
    74 <3 8.3
    75 <3 7.0
    76 4.0 13.1
    77 <30 <30
    78 68.0 31.0
    79 ND 320.0
    80 ND 320.0
    81 ND ND
    82 ND ND
    83 ND ND
    84 ND ND
    85 ND ND
    86 ND ND
    87 ND ND
    88 ND ND
    89 30.0 47.0
    90 19.0 19.0
    91 25.0 1567.0
    92 140.0 87.0
    93 42.0 60.0
    94 54.0 82.0
    95 333.0 364.0
    96 5.0 33.0
    97 <30 52.0
    98 ND ND
    99 ND ND
    100 56.0 56.0
    101 32.7 37.3 3.0
    102 592.0 854.0
    103 2917.0 4453.0
    104 412.0 684.0
    105 3710.0 >10000
    106 ND ND 370.0
    107 ND ND 1000.0
    108 ND ND 320.0
    109 ND ND 1900.0
    110 ND ND 220.0
    111 ND ND 58.0
    112 ND ND 300.0
    113 ND ND 120.0
    114 ND ND 38.0
    115 ND ND 200.0
    116 ND ND 70.0
    117 ND ND 700.0
    118 ND ND 3000.0
    119 ND ND 2800.0
    120 ND ND 1200.0
    121 ND ND 1000.0
    122 ND ND 900.0
    123 ND ND 4100.0
    124 ND ND 1950.0
    125 ND ND 1000.0
    126 ND ND 1300.0
    127 ND ND 1350.0
    128 ND ND 30000.0
    129 ND ND
    130 191.0 416.0
    131 696.0 839.0
    132 586.0 1012.0
    133 795.0 1950.0
    134 805.0 857.0
    135 533.0 509.0
    136 ND ND
    137 582.0 551.0
    138 ND ND 680.0
    139 ND ND 180.0
    140 225 279
    141 ND ND
    142 5 33
    143 ND 52
    144 ND ND 1500
    145 ND ND 120
    146 ND ND 5
    147 ND ND 1000
    148 ND ND 680
    149 ND ND 32000
    150 ND ND 290
    151 ND 14
    152 9 14
    153 ND ND 4200
    154 ND ND 22000
    155 ND ND 400
    156 ND ND 22000
    157 ND ND 2700
    158 ND ND 49
    159 ND ND 1.2
    160 ND ND 220
    161 328 675
    162 ND ND
    163 10.7 28.3
    164 ND ND
    165 210 333
    166 134 249
    167 ND 10
    168 ND ND
    169 ND ND 5000
    170 ND ND 4500
    171 ND ND 5200
    172 ND ND 9500
    173 ND ND 2500
    174 ND ND 4.25
    175 ND ND 9.5
    176 ND ND 1000
    177 ND ND 600
    178 ND ND 850
    179 ND 8.333
    180 ND ND 5800
    181 ND ND 3400
    182 ND ND 3500
    183 ND ND 8500
    184 1246 2094
    185 5 13
    186 473 703
    187 11 41
    188 ND ND
    189 84 99
    190 ND ND 950
    191 ND ND 220
    192 ND ND 620
    193 ND ND 105
    194 ND ND 600
    195 ND ND
    196 50 82
    197 17 49
    198 ND 43
    199 96 93
    200 162 248
    201 29 44
    202 ND ND 700
    203 ND ND 78
    204 ND ND 6000
    205 ND ND 400
    206 ND ND 5100
    207 ND ND 33.333
    208 ND ND 50
    209 174 278
    210 ND ND
    211 254 389
    212 ND ND 420
    213 ND ND 420
    214 ND ND 700
    215 ND ND 30
    216 0 ND 50
    217 ND ND 13
    218 ND ND 12
    219 ND ND 40
    220 ND ND 40
    221 ND ND 120
    222 ND ND 10
    223 187 229
    224 ND ND
    225 ND ND
    226 ND ND
    227 1495 4026
    228 3924 7174
    229 35.75 40
    230 ND ND
    231 20 121
    232 38 177
    233 1214 3337
    234 ND ND 10000
    235 ND ND 7900
    236 22.333 67
    237 28 69
    238 23 61
    239 184 317
    240 ND 12
    241 24 135
    242 11 49
    243 15 34
    244 ND 71
    245 110 374
    246 35 91
    247 30 111
    248 ND 69
    249 92 142
    250 14 31
    251 ND 65
    252 219 747
    253 12 574
    254 ND ND
    255 174 328
    256 ND ND
    257 ND ND
    258 ND ND 60
    259 ND ND 580
    260 ND ND 380
    261 ND ND 30
    262 ND ND 22
    263 68 31
    264 ND ND
    265 ND ND 1.7
    266 ND ND
    267 94 200
    268 59 107 38
    269 ND 144
    270 397 953
    271 68 129
    272 70 340
    273 32 80
    274 1000 1491
    275 3100 4309
    276 1347 1654
    277 530 572
    278 2297 3701
    279 176 247
    280 176 404
    281 ND ND
    282 83 84
    283 12.333 33.333
    284 12 36.333
    285 ND ND 4
    286 ND ND 32000
    287 ND ND
    288 ND ND 3
    289 ND ND 3
    290 ND ND
    291 ND ND
    292 ND ND
    293 ND ND
    294 69 154
    295 133 189
    296 83 133
    297 115 290
    298 38 165
    299 73 219
    300 297 340
    301 430 759
    302 299 539
    303 ND ND 0.8
    304 7 39.333
    305 4 46
    306 7 30
    307 ND 362
    308 4 53
    309 64 109
    310 44 117
    311 126 366
    312 ND ND 80
    313 ND ND 100
    314 ND ND 550
    315 ND ND 300
    316 ND ND 320
    317 ND ND 120
    318 ND ND 1000
    319 ND ND 220
    320 32.333 73.667
    321 106 325
    322 13 86
    323 ND 77
    324 4 35
    325 ND ND 310
    326 ND ND 580
    327 ND ND 400
    328 ND ND 1500
    329 ND ND 5900
    330 ND ND 260
    331 0 0 0
    332 0 0 0
    333 0 0 0
    334 0 0 0
    335 0 0 0
    336 56 45 0
    337 142 373
    338 122 266
    339 ND ND
    340 ND ND
    341 150 237
    342 1256 2429
    343 ND ND
    344 ND ND
    345 554 395
    346 ND ND
    347 ND ND 9
    348 ND ND
    349 87 81
    350 ND 8.5
    351 50 66
    352 ND ND <0.8
    353 ND ND <0.8
    354 ND ND 310
    355 ND ND 580
    356 ND ND 400
    357 ND ND 1500
    358 ND ND 5900
    359 ND ND 260
    360 ND ND 10000
    361 ND ND 2.2
    362 ND ND 1
    363 ND ND 1.2
    364 ND ND 70
    365 ND ND 3
    366 ND ND 2.8
    367 ND ND 5
    368 ND ND 0.7
    369 ND ND 3
    370 ND ND 0.8
    371 ND ND 0.8
    372 ND ND 0.8
    373 ND ND 1
    374 ND ND <0.8
    375 ND ND <0.8
    376 ND ND 50
    377 ND ND 90
    378 ND ND 50
    379 ND ND 140
    380 ND ND 300
    381 ND ND 140
    382 ND ND 48
    383 ND ND 150
    384 ND ND 50
    385 ND ND 70
    386 ND ND 140
    387 ND ND 70
    388 ND ND 110
    389 ND ND 240
    390 ND ND 650
    391 ND ND 300
    392 ND ND 480
    393 ND ND 580
    394 ND ND 800
    395 ND ND 590
    396 ND ND 280
    397 ND ND 7
    398 ND ND 12
    399 ND ND 3
    400 ND ND 12
    401 ND ND 21
    402 ND ND 7
    403 ND ND 8
    404 ND ND 60
    405 ND ND 25
    406 ND ND 2.4
    407 ND ND 0.8
    408 ND ND 9
    409 ND ND 50
    410 ND ND 110
    411 ND ND 250
    412 ND ND 25
    413 ND ND 150
    414 ND ND 120
    415 ND ND 29
    416 ND ND 12
    417 ND ND 6
    418 ND ND 40
    419 ND ND 12
    420 ND ND 2
    421 ND ND 1
    422 ND ND 2
    423 ND ND 2.8
    424 ND ND 1
    425 ND ND 2.8
    426 ND ND 700
    427 ND ND 7
    428 ND ND 1
    429 ND ND 9
    430 ND ND 16
    431 ND ND <0.8
    432 ND ND <0.8
    433 ND ND 40
    434 ND ND <0.8
    435 ND ND 4
    436 ND ND 10
    437 ND ND 1
    438 ND ND <0.8
    439 ND ND 1
    440 ND ND 1
    441 ND ND 6
    442 ND ND 13
    443 ND ND 8
    444 ND ND <0.8
    445 ND ND <0.8
    446 ND ND 15
    447 ND ND 8
    448 ND ND 18
    449 ND ND 40
    450 ND ND <0.8
    451 ND ND <0.8
    452 ND ND <0.8
    453 ND ND 30
    454 ND ND <0.8
    455 ND ND <0.8
    456 ND ND <0.8
    457 ND ND <0.8
    458 ND ND 8
    459 ND ND <0.8
    460 ND ND <0.8
    461 ND ND 68
    462 ND ND ND
    463 ND ND ND
    464 ND ND ND
    465 ND ND ND
    466 ND ND 420
    467 ND ND 170
    468 ND ND 50
    469 ND ND 2800
    470 ND ND 1000
    471 ND ND 130
    472 ND ND 3800
    473 ND ND ND
    474 ND ND ND
    475 ND ND ND
    476 ND ND ND
    477 ND ND ND
    478 <3.080 8.5
    479 6 21
    480 ND ND
    481 ND ND
    482 ND ND
    483 ND ND
    484 ND ND
    485 ND ND
    486 7.0 39.3
    487 175.0 339.0
    488 ND ND
    489 ND ND 4300
    490 ND ND
    491 8.0 35.0
    492 26.0 57.0
    493 ND ND
    494 115.0 276.0
    495 4.0 13.1
    496 ND ND
    497 50.0 66.0
    498 4.0 16.5
    499 21.0 31.0
    500 1.0 6.5
    501 <31 41
    502 4.0 11.0
    503 7.5 12.5
    504 22.5 25.5
    505 12.3 33.3
    506 <21.7 12
    507 10.7 28.3
    508 12.0 36.3
    509 ND ND <0.8
    510 ND ND
    511 2.0 10.0
    512 1.0 8.0
    513 2.0 13.0
    514 <3.2 12
    515 3 12
    516 ND ND
    517 18.0 7.0
    518 4.0 24.0
    519 3.0 9.0
    520 5.0 18.0
    521 8.0 27.0
    522 3.0 11.0
    523 ND ND
    524 ND ND
    525 ND ND
    526 ND ND
    527 1256.0 2429.0
    528 ND ND
    529 150.0 237.0
    530 ND ND
    531 ND ND
    532 122.0 266.0
    533 142.0 373.0
    534 32.3 73.7
    535 554.0 395.0
    536 22.3 67.0
    537 <31 <31
    538 ND ND
    539 9.0 161.0
    540 165.0 309.0
    541 964.0 1764.0
    542 281.0 569.0
    543 <31 262.0
    544 58.0 253.0
    545 30.0 219.0
    546 7.0 25.0
    547 68.0 197.0
    548 524.0 869.0
    549 ND ND
    550 315.0 711.0
    551 106.0 270.0
    552 105.0 243.0
    553 113.0 522.0
    554 521.0 >1000
    555 ND ND
    556 128.0 379.0
    557 34.0 31.0
    558 751.0 939.0
    559 8.0 149.0
    560 ND ND
    561 66.0 218.0
    562 3.0 93.0
    563 10.0 171.0
    564 1.0 7.0
    565 9.0 27.0
    566 28.0 55.0
    567 106.0 130.0
    568 18.0 107.0
    569 ND ND
    570 28.0 344.0
    571 90.0 168.0
    572 13.0 56.0
    573 99.0 206.0
    574 6.0 25.0
    575 15.0 242.0
    576 ND ND
    577 ND ND
    578 ND ND
    579 ND ND
    580 ND ND
    581 ND ND
    582 ND ND
    583 ND ND
    584 ND ND
    585 ND ND
    586 ND ND
    587 ND ND
    588 ND ND
    589 ND ND
    590 ND ND
    591 ND ND
    592 239.0 718.0
    593 >1000 >1000
    594 ND ND
    595 43.0 193.0
    596 26.0 155.0
    597 45.0 229.0
    598 22.0 214.0
    599 ND ND
    600 ND ND
    601 22.0 155.0
    602 17.0 122.0
    603 17.0 137.0
    604 4.0 73.0
    605 7.0 92.0
    606 28.0 173.0
    607 24.0 213.0
    608 52.0 298.0
    609 24.0 26.0
    610 28.0 297.0
    611 194.0 581.0
    612 38.0 227.0
    613 6.0 21.0
    614 4.0 15.0
    615 88.0 123.0
    616 4.0 21.0
    617 4.0 17.0
    618 2.0 13.0
    619 ND ND
    620 4.0 16.0
    621 8.0 35.0
    622 5.0 25.0
    623 6.0 32.0
    624 4.0 19.0
    625 12.0 43.0
    626 ND ND
    627 16.0 55.0
    628 ND ND
    629 28.0 133.0
    630 5.0 23.0
    631 28.0 120.0
    632 9.0 38.0
    633 15.0 64.0
    634 5.0 16.0
    635 26.0 106.0
    636 ND ND
    637 26.0 62.0
    638 9.0 44.0
    639 16.0 27.0
    640 ND ND
    641 ND ND
    642 ND ND
    643 19.0 59.0
    644 51.0 185.0
    645 ND ND
    646 32.0 223.0
    647 46.0 136.0
    648 12.0 34.0
    649 9.0 37.0
    650 ND ND
    651 ND ND
    652 ND ND
    653 ND ND
    654 ND ND
    655 ND ND
    656 ND ND
    657 ND ND
    658 ND ND
    659 ND ND
    660 ND ND
    661 ND ND
    662 ND ND
    663 ND ND
    664 ND ND
    665 ND ND
    666 ND ND
    667 ND ND 60.0
    668 ND ND 0.8
    669 28.0 41.0
    670 22.5 27.5
    671 73.0 98.0
    672 98.0 176.0
    673 15.0 28.0
    674 22.0 30.0
    675 <30 62.0
    676 167.0 301.0
    677 345.0 3600.0
    678 35.8 40.0
    679 ND ND
    680 ND ND
    681 ND ND
    682 1044.0 766.0
    683 673.0 584.0
    684 806.0 1015.0
    685 >10000 >10000
    686 569.0 1105.0
    687 355.0 389.0
    688 1412.0 1950.0
    689 53.0 85.0
    690 112.0 405.0
    691 52.0 131.0
    692 97.0 326.0
    693 ND ND
    694 <3 11.0
    695 6.0 7.0
    696 13.0 13.0
    697 <30 <30
    698 <3 6.0
    699 36.0 40.0
    700 5.0 20.0
    701 <30 <30
    702 4.0 14.0
    703 <3 13.0
    704 ND ND
    705 191.0 416.0
    706 696.0 839.0
    707 586.0 1012.0
    708 795.0 1950.0
    709 805.0 857.0
    710 533.0 509.0
    711 ND ND
    712 582.0 551.0
    713 29.0 44.0
    714 162.0 248.0
    715 254.0 389.0
    716 ND ND
    717 ND ND <0.8
    718 3924.0 7174.0
    719 <31 <31
    720 15.0 34.0
    721 <31 71.0
    722 110.0 374.0
    723 35.0 91.0
    724 30.0 111.0
    725 <31 69.0
    726 92.0 142.0
    727 14.0 31.0
    728 59.0 107.0 38.000
    729 <31 <31
    730 94.0 200.0
    731 1000.0 1491.0
    732 3100.0 4309.0
    733 1347.0 1654.0
    734 530.0 572.0
    735 2297.0 3701.0
    736 176.0 247.0
    737 176.0 404.0
    738 ND ND
    739 ND ND
    740 83.0 84.0
    741 ND ND
    742 ND ND
    743 ND ND
    744 ND ND
    745 ND ND
    746 93.0 118.0
    747 56.0 45.0
    748 ND ND
    749 87.0 81.0
    750 ND ND
    751 144.0 238.0
    752 <3 6.0
    753 4.0 14.0
    754 31.3 70.8
    755 3.0 13.0
    756 <3 12.000
    757 <3 6.000
    758 3.0 14.0
    759 1.0 10.0
    760 0.0 4.0
    761 <3 4.0
    762 8.0 7.0
    763 4.0 7.0
    764 628.0 678.0
    765 21.0 27.0
    766 26.0 50.0
    767 5.0 13.0
    768 7.0 8.0
    769 6.0 14.0
    770 40.0 25.0
    771 >1000 >1000
    772 5.0 15.0
    773 4.0 6.0
    774 14.0 19.0
    775 5.0 7.0
    776 <3.2 6.0
    777 2.0 4.0
    778 17.0 29.0
    779 13.0 23.0
    780 ND ND
    781 ND ND
    782 ND ND
    783 ND ND
    784 >1000 >1000
    785 >1000 >1000
    786 >1000 >1000
    787 >1000 >1000
    788 >1000 >1000
    789 ND ND
    790 ND ND
    791 11.0 42.0
    792 2.0 16.0
    793 2.0 26.0
    794 2.0 20.0
    795 <3.2 10.0
    796 2.0 18.0
    797 11.0 29.0
    798 3.0 24.0
    799 <3.2 24.0
    800 1.0 11.0
    801 3.0 32.0
    802 3.0 50.0
    803 1.0 6.0
    804 3.0 11.0
    805 3.0 13.0
    806 <3.2 9.0
    807 35.000 37.000
    808 ND ND
    809 ND ND
    810 2.0 26.0
    811 2.0 19.0
    812 3.0 23.0
    813 <3.2 24.0
    814 4.0 37.0
    815 3.0 24.0
    816 2.0 11.0
    817 ND ND
    818 129.0 237.0
    819 442.0 768.0
    820 ND ND
    821 ND ND
    822 ND ND
    823 ND ND 55.0
    823 ND ND
    825 ND ND
    826 >1000 >1000
  • While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
  • Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.

Claims (36)

1. A compound of the Formula I:
Figure US20090304692A1-20091210-C00040
wherein:
R1 is
Figure US20090304692A1-20091210-C00041
wherein:
R6, R7, R8, R9 are each independently selected from the group consisting of a hydrogen atom, and a C1-C6alkyl optionally substituted with C2-C6alkenyl, C4-C6alkadienyl, C2-C6alkynyl or C4-C6alkadiynyl;
and one of R6 and R9, R6 and R8, or R7 and R8 are attached by a (CH2)y, (CH2—X—), or (CH2—X—CH2) linking group wherein one or two hydrogen atoms in the linking group may be independently replaced by C1-C6alkyl, (C1-C6alkyl)NH—, (C1-C6alkyl)2N—, (C6-C14aryl)alkyl-O—, halo, 3-10 membered C1-C9heterocyclyl optionally substituted with C1-C6alkyl-, HO—, or H2N—;
wherein any two hydrogen atoms on the same carbon atom of the linking group can be replaced by an oxygen atom to form an oxo (═O) substituent,
y is 1, 2 or 3;
X is O, S(O)n, or NR10;
n is 0, 1 or 2;
the dashed line ----- represents an optional second bond;
R10 is selected from the group consisting of H, C1-C6alkyl, —SO2(C1-C6alkyl), —COO(C1-C6alkyl), —CONH(C1-C6alkyl), —CON(C1-C6alkyl)2, —CO(C1-C6alkyl), and —SO2NHR11;
R11 is selected from the group consisting of H, C1-C6alkyl optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl, —CO(C1-C6alkyl), optionally substituted C6-C10aryl, and optionally substituted C1-C9heteroaryl;
R2 is optionally substituted C6-C14aryl-NH—COR3, optionally substituted C1-C9heteroaryl-NH—COR3, —CH═CH—C6-C10aryl-NH—COR3 or —CH═CH—C1-C9heteroaryl-NH—COR3;
R3 is OR5, NR5R5 or NHR5;
R5 is independently selected from the group consisting of C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, optionally substituted C6-C10aryl, C1-C6haloalkyl, optionally substituted C1-C9heteroaryl, C1-C6hydroxylalkyl-, C3-C10saturated or unsaturated mono or bicyclic C3-C10cycloalkyl optionally substituted with OH, NR11R11 or 3-7 membered C1-C6heterocyclyl, and 3-10 membered saturated or unsaturated mono or bicyclic C1-C9heterocyclyl, with the proviso that three-membered cycloalkyl and heterocyclyl rings are saturated;
or two R5 groups taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with C1-C6alkyl, which ring system is saturated or unsaturated and has, in addition to said nitrogen atom, 0 to 2 heteroatom ring members selected from O, S, S(O), S(O)2 and NR10;
R4 is selected from the group consisting of: a) C1-C6alkyl optionally substituted with: i) 3-10 membered C1-C9heterocyclyl optionally substituted with C1-C6alkyl-, ii) H2N—, iii) (C1-C6alkyl)NH—, iv) (C1-C6alkyl)2N—, v) NH(CH2)aN(C1-C6alkyl)2 wherein a is 2, 3 or 4, and vi) CHO, b) C3-C6alkenyl, c) C3-C6alkynyl, d) —O—C1-C8alkyl optionally substituted with —O—C1-C8alkyl, e) —O—C3-C8alkenyl, f) —O—C3-C8alkynyl, g) saturated or unsaturated mono or bicyclic C3-C8cycloalkyl, and h) saturated or unsaturated mono or bicyclic —O—C3-C12cycloalkyl, all the above optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl optionally substituted with C1-C6alkyl-, provided that an OH or NR11R11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom; i) —CH═CH—C6-C10aryl; j) —CH═CH—C1-C9heteroaryl; k) optionally substituted C6-C10aryl; l) optionally substituted 5-10 membered C1-C9heteroaryl attached to the triazine moiety via a carbon atom; m) 3-10 membered saturated or unsaturated mono or bicyclic C1-C9heterocyclyl attached to the triazine moiety through a carbon or nitrogen atom and optionally substituted with from 1 to 3 substituents independently selected from: OH, NR11R11, C1-C6alkyl, (C1-C6alkyl)amido-, (C1-C6alkyl)C(O)—, (C1-C6alkoxy)carbonyl-, adamantyl, C1-C6hydroxylalkyl-, or a 3-7 membered C1-C6heterocyclyl, with the proviso that 3 membered heterocyclyl is saturated and attached to the triazine moiety through a nitrogen atom, and 5 membered bicyclic heterocyclyl is saturated; n) optionally substituted —O—C6-C10aryl; o) optionally substituted —O—C1-C9heteroaryl; p) —O-(3-12 membered saturated or unsaturated mono or bicyclic)C1-C9heterocyclyl optionally substituted with (C1-C6alkoxy)carbonyl-, H2NS(O)2—, or C1-C6alkyl further optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl, with the proviso that three membered heterocyclyl is saturated; q) —NHC6-C10aryl, r) —NHC1-C9heteroaryl, s) —NHNH2, t) —NHNHC1-C6alkyl, u) —NHN(C1-C6alkyl)2, v) —NHOH, w) —COOH, x) —COO—C1-C6alkyl, y) —CONR12R13, z) —NR12R13,
Figure US20090304692A1-20091210-C00042
wherein Z is CH2, O, S(O), or NR10;
ee) halogen, ff) C6-C14aryl-S(O)2—NH—, gg) R11NHC(O)NH—O—, and hh) optionally substituted 5-membered monocyclic C1-C4heteroaryl attached to the triazine moiety via a nitrogen atom;
R12 and R13 are each independently selected from H, optionally mono or disubstituted C1-C8alkyl, optionally substituted C3-C8alkenyl, and optionally substituted C3-C8alkynyl, the optional substituents being selected from C1-C6alkoxy, OH, NR11R11, and 3-7 membered C1-C6heterocyclyl, provided that an OH or NR11R11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom;
or R12 and R13 taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with C1-C6alkyl, which ring system is saturated or unsaturated and has, in addition to said nitrogen atom, 0 to 2 heteroatom ring members selected from O, S(O)n and NR10;
or R12 and R13 taken together with the nitrogen atom to which they are attached form
Figure US20090304692A1-20091210-C00043
wherein a and b are each independently —CH2—, O, S, or NR10, and x is 1-3;
C1-C9heteroaryl refers to a 5-10 membered aromatic ring system having one or more rings and 1, 2, 3 or 4 ring members independently selected from O, NR10, and S(O),;
C1-C9heterocyclyl refers to a 3-10 membered ring system having one or more rings and 1, 2, 3 or 4 ring members independently selected from O, NR10, and S(O)n; and
optionally substituted aryl and heteroaryl groups are unsubstituted or are substituted with 1 or 2 moieties selected from the group consisting of: a) C1-C6alkyl optionally substituted with OH, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, —NH(CH2)wN(C1-C6alkyl)2 wherein w is 2, 3 or 4, or 3-10 membered C1-C9heterocyclyl optionally substituted with from 1 to 3 independently selected C1-C6alkyl- substituents; b) halogen; c) hydroxy; d) NH2; e) NO2; f) SO2NH2; g) COOH; h) COO(C1-C6alkyl); i) NHCOO(C1-C6alkyl); j) NH(C1-C6alkyl); k) N(C1-C6alkyl)2; l) C(O)NRaRb, wherein Ra is H or C1-C6alkyl, and Rb is H, C1-C6alkyl, (C6-C14aryl)alkyl-, or (C1-C9heteroaryl)alkyl-; m) -Y-Q, wherein Y is: i) O, ii) NH, iii) N(C1-C6alkyl), iv) NHSO2, v) SO2NH, vi) NHCONH, vii) NHCON(C1-C6alkyl), viii) S(O)q, q is 0, 1 or 2, ix)-C(O)NH—, x) —C(O)N(CH3)—, xi) —NHC(O)— xii) C(O), or xiii) absent, and Q is selected from: i) C6-C10aryl, optionally substituted with from 1 to 3 substituents independently selected from: A) C1-C6alkoxy- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, 3) di(C1-C6alkyl)amino-, 4) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-, or 5) hydroxyl, B) (C1-C6alkoxy)carbonyl-, C) (C1-C6alkoxy)C(O)NH—, D) C1-C6alkyl- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, E) (C1-C6alkyl)amino-, F) di(C1-C6alkyl)amino-, G) (C1-C6alkyl)amido- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, H) (C1-C6alkyl)carboxyamido-, I) C1-C9heterocyclyl-optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-, J) heterocyclyl(C1-C6alkyl)- optionally substituted by C1-C6alkyl-, K) halogen, L) hydroxyl, M) C1-C6hydroxylalkyl-, N) perfluoro(C1-C6)alkyl-, O) H2N—, P)O2N—, Q) H2NSO2—, R) HO2C—, and S)NC—, ii) 5-10 membered C1-C9heteroaryl, optionally substituted with from 1 to 3 substituents independently selected from: A) C1-C6alkoxy-optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, 3) di(C1-C6alkyl)amino-, 4) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-, or 5) hydroxyl, B) (C1-C6alkoxy)carbonyl-, C) (C1-C6alkoxy)C(O)NH—, D) C1-C6alkyl- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, E) (C1-C6alkyl)amino-, F) di(C1-C6alkyl)amino-, G) (C1-C6alkyl)amido-optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, H) (C1-C6alkyl)carboxyamido-, I) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-, J) heterocyclyl(C1-C6alkyl)- optionally substituted by C1-C6alkyl-, K) halogen, L) hydroxyl, M) C1-C6hydroxylalkyl-, N) perfluoro(C1-C6)alkyl-, O) H2N—, P)O2N—, Q) H2NSO2—, R) HO2C—, and S)NC—, iii) 3-10 membered C1-C9heterocyclyl, optionally substituted with from 1 to 3 substituents independently selected from: A) C1-C6alkyl-, B) heterocyclyl(C1-C6alkyl)-, C) (C6-C14aryl)alkyl-, D) C1-C8acyl-, E) (C1-C6alkoxy)carbonyl-, F) (C1-C6alkyl)carboxyl-, G) halogen, H) C1-C6haloalkyl-, I) hydroxyl, J) C1-C6hydroxyalkyl-, K) H2N—, L) (C1-C6alkyl)amino-, M) di(C1-C6alkyl)amino-, N) HO2C—, O) (C1-C6alkoxy)carbonyl-, P) (C1-C6alkyl)carboxyl-, Q) (C1-C6alkyl)amido-, R) H2NC(O)—, S) (C1-C6alkyl)carboxyamido-, T) 5-10 membered C1-C9heteroaryl, U) C6-C14ary, V) C3-C8cycloalkyl W) 3-10 membered C1-C9heterocyclyl, and X) —NO2; iv) C3-C10cycloalkyl, v) C1-C6alkyl, vi) C2-C6alkenyl, vii) C2-C6alkynyl, viii) C1-C6hydroxyalkyl-, ix) (CH2)vO(C1-C6alkyl), x) (CH2)vNH2, xi) (CH2)vNH(C1-C6alkyl), xii) (CH2)vN(C1-C6alkyl)2, xiii) O(CH2)vN(C1-C6alkyl)2, xiv) (CH2)vC6-C10aryl, xv)-CN, xvi) (CH2)v 5-10 membered C1-C9heteroaryl, xvii) (CH2)v 3-10 membered C1-C9heterocyclyl, optionally substituted by C1-C6alkyl-, wherein v is 1, 2, 3 or 4, and xviii) C1-C6 perfluoroalkyl-; and n) C(O)Rc wherein Rc is: i) H, ii) C1-C6alkyl, or iii) C3-C6cycloalkyl,
and pharmaceutically acceptable salts thereof.
2. The compound of claim 1 wherein R1 is
Figure US20090304692A1-20091210-C00044
and pharmaceutically acceptable salts thereof.
3. The compound of claim 2 wherein R1 is
Figure US20090304692A1-20091210-C00045
and pharmaceutically acceptable salts thereof.
4. The compound of claim 3 wherein R2 is optionally substituted C6-C14aryl-NH—COR3.
5. The compound of claim 4 wherein R2 is optionally substituted phenyl-NH—COR3.
6. The compound of claim 5 wherein R3 is NHR5.
7. The compound of claim 6 wherein R5 is C1-C9heteroaryl.
8. The compound of claim 7 wherein R5 is pyridyl.
9. The compound of claim 8 wherein R5 is 4-pyridyl.
10. The compound of any one of claims 1-9 wherein R4 is
Figure US20090304692A1-20091210-C00046
and pharmaceutically acceptable salts thereof.
11. The compound of claim 10 wherein R4 is
Figure US20090304692A1-20091210-C00047
12. The compound selected from the group consisting of:
1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;
1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea;
2-hydroxyethyl[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamate;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-ethylurea;
1-cyclopropyl-3-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]urea;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea;
1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-[4-(2-hydroxyethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
2-(diethylamino)ethyl 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;
1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-cyanophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-isopropyl-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(2-hydroxyethyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
t-butyl 2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylamino)ethylcarbamate;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-{4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea;
4-(3-{4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-ureido)-benzamide;
tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-{4-[4-(4-methylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[4-(4-benzylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-{4-[4-(4-acetylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-(4-{4-[4-(N,N-dimethylglycyl)piperazin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-{4-[4-(4-isonicotinoylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
methyl 4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)-amino]phenyl}-1,3,5-triazin-2-yl]piperazine-1-carboxylate;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-{4-[4-(4-hydroxypiperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-(4-{4-[4-(benzylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[4-(methylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[4-(ethylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-{4-[4-(4-{[2-(dimethylamino)ethyl]amino}piperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[4-(4-morpholin-4-ylpiperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-hydroxyethylamino)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-morpholinoethylamino)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
methyl 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate;
2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetamide
tert-butyl 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate;
2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetic acid;
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-1-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
methyl(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamate;
1-cyclopropyl-3-(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
N′,N′″-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazine-2,4-diyl]di-4,1-phenylene}bis{1-[4-(4-methylpiperazin-1-yl)phenyl]urea};
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-{4-[(2-aminoethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-{4-[4-anilino-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-(4-{4-[(2-hydroxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-{4-[4-(azetidin-3-ylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-(4-{4-[(2-morpholin-4-ylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-(4-{4-[(3-aminopropyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-(4-{4-[(4-cyclopentylpiperazin-1-yl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-{4-[4-isopropoxy-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[4-isopropoxy-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-{4-[4-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(piperidin-4-ylmethyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(2-piperidin-4-ylethyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-{4-[4-(3-methylimidazolidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[4-(3-methyltetrahydropyrimidin-1(2H)-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-1-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
2-hydroxyethyl (4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamate;
1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-methylurea;
1-cyclopropyl-3-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(piperidin-3-ylmethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[4-(4-aminobutoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-4-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(piperidin-4-ylmethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-(4-{4-morpholin-4-yl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-{4-[4-(methylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[4-(ethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[4-(dimethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[4-(isopropylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[4-(diethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]pyridinium;
1-(4-{4-[ethyl(methyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-{4-[4-(sec-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[4-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-(4-{4-[bis(2-hydroxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-(4-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-(4-{4-morpholin-4-yl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;
1-methyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
1-cyclopropyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
1-(2-hydroxyethyl)-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea;
1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-{4-[(2,2-dimethylhydrazino)carbonyl]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
4-{[(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-pyrrolidin-1-ylbenzamide;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
1-[4-(hydroxymethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
tert-butyl(1R,4R)-5-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;
tert-butyl (1R,4R)-5-[4-(4-{[(4-acetylphenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;
1-(4-{4-[(2-methoxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-{4-[4-{[(1S)-2-hydroxy-1-methylethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[4-{[(1R)-2-hydroxy-1-methylethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-(4-{4-[(2-hydroxy-1,1-dimethylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-{4-[4-(tert-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-piperazin-1-ylphenyl)urea;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[4-(6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
tert-butyl-7-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;
1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;
N-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]piperazine-1-carboxamide;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(methylamino)methyl]phenyl}urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]urea;
1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
tert-butyl-(1R,4R)-5-{4-[4-({[4-(1-hydroxyethyl)phenyl]carbamoyl}amino)phenyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-piperazin-1-ylphenyl)urea;
1-{4-[4,6-di-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-(2-fluoroethyl)-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-cyclopropyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
4-[({4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;
1-methyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;
1-cyclopropyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;
1-(2-fluoroethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;
1-(2-hydroxyethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;
4-{[(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide;
1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-phenylurea;
1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-cyclopropyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(2-fluoroethyl)-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;
4-[({4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-yl]phenyl}carbamoyl)amino]benzamide;
1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;
1-(2,3′-bipyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-(6-chloropyridin-3-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-N2,N2-dimethylglycinnamide;
N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-pyrrolidin-1-ylacetamide;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-cyclopropylurea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-(2-fluoroethyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-(2-hydroxyethyl)urea;
4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-phenylurea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;
1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea;
1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;
1-(4-(aminomethyl)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)urea;
1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;
1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)urea;
1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea;
1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyethoxy)phenyl)urea;
N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(dimethylamino)acetamide;
N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(4-methylpiperazin-1-yl)acetamide;
N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(pyrrolidin-1-yl)acetamide;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(aminomethyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;
1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea;
1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(1-oxidothiomorpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}urea
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;
4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)urea;
4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;
4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;
4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(morpholine-4-carbonyl)phenyl)urea;
1-(4-(2-aminoethylamino)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)urea;
4-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
3-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[4-(5-hydroxy-3-oxa-7-azabicyclo[4.1.1]oct-7-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridazin-4-ylurea;
N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-(4-methylpiperazin-1-yl)acetamide;
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-;
4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-;
4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-(4-methylpiperazin-1-yl)acetamide;
1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-[4-(2-hydroxyethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
2-(diethylamino)ethyl 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;
1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-cyanophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-isopropyl-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(2-hydroxyethyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[4-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;
methyl 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;
N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
N,N-dimethyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
N-(2-hydroxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
N-[3-(dimethylamino)propyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
N-(2-morpholin-4-ylethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
1-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]pyridinium;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea;
1-(4-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
tert-butyl 7-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;
1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(2-chloropyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(2,3′-bipyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(6-chloropyridin-3-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1,3-bis{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
N-[2-(4-methylpiperazin-1-yl)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
1-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[(4-cyclopentylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;
1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-morpholin-4-ylpiperidin-1-yl)carbonyl]phenyl}urea;
4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide;
4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-ylethyl)benzamide;
1-[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;
1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(thiomorpholin-4-ylcarbonyl)phenyl]urea;
1-[4-(morpholin-4-ylcarbonyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid;
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea;
N-[2-(dimethylamino)ethyl]-4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-methylbenzamide;
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;
methyl 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;
4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid;
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}urea;
4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide;
4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-ylethyl)benzamide;
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;
1-[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea;
4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyridin-2-ylethyl)benzamide;
4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyridin-4-ylethyl)benzamide;
1-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;
1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[35.3.]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide;
4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-ylethyl)benzamide;
1-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;
N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}urea;
1-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-(1,3-dimethyl-1H-pyrazol-5-yl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-(1H-pyrazol-3-yl)urea;
1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;
N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
1-(4-{4-[(6S)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[(6R)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[(6R)-6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-{4-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-[4-(4,6-di-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;
1-(4-(4-((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazinyl-4-yl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea;
4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;
4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;
4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea;
4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;
4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;
4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-acetylphenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)acetyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-morpholinoacetyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyacetyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(methoxymethyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-methoxyethyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(1-hydroxyethyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropan-2-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxy-2-methylpropyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-acetylphenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)acetyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-morpholinoacetyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyacetyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(methoxymethyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-methoxyethyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(1-hydroxyethyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropan-2-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxy-2-methylpropyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-cyanophenyl)urea;
4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-cyanophenyl)urea;
4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;
4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl) ureido)-N,N-dimethylbenzamide;
4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)urea;
4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;
4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)urea;
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;
1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(propan-2-yl)piperazin-1-yl]carbonyl}phenyl)urea;
N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide;
4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid;
1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)urea;
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)urea;
1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)urea;
1-{4-[4-(morpholin-4-yl)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(3,3,4-trimethylpiperazin-1-yl)carbonyl]phenyl}urea; and
1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea.
13. The compound of claim 12, which is 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea.
14. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
15. The composition of claim 14, wherein the pharmaceutically acceptable carrier suitable for oral administration and the composition comprises an oral dosage form.
16. A composition comprising a compound of claim 1; a second compound selected from the group consisting of a topoisomerase I inhibitor, a MEK 1/2 inhibitor, a HSP90 inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil, docetaxel, paclitaxel, leucovorin, levamisole, irinotecan, estramustine, etoposide, nitrogen mustards, BCNU, carmustine, lomustine, vinblastine, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, imatinib mesylate, Avastin (bevacizumab), hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins, herbimycin A, genistein, erbstatin, hydroxyzine, glatiramer acetate, interferon beta-1a, interferon beta-1b, natalizumab and lavendustin A; and a pharmaceutically acceptable carrier.
17. The composition of claim 16, wherein the second compound is Avastin.
18. A method of treating a PI3K-related disorder, comprising administering to a mammal in need thereof a compound of claim 1 in an amount effective to treat a PI3K-related disorder.
19. The method of claim 18, wherein the PI3K-related disorder is selected from restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, and cancer.
20. The method of claim 19, wherein the PI3K-related disorder is cancer.
21. The method of claim 20, wherein the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer.
22. A method of treating an mTOR-related disorder, comprising administering to a mammal in need thereof a compound of claim 1 in an amount effective to treat an mTOR-related disorder.
23. The method of claim 22, wherein the mTOR-related disorder is selected from restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, and cancer.
24. The method of claim 23, wherein the mTOR-related disorder is cancer.
25. The method of claim 24, wherein the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer.
26. A method of treating advanced renal cell carcinoma, comprising administering to a mammal in need thereof a compound of claim 1 in an amount effective to treat advanced renal cell carcinoma.
27. A method of treating acute lymphoblastic leukemia, comprising administering to a mammal in need thereof a compound of claim 1 in an amount effective to treat acute lymphoblastic leukemia.
28. A method of treating acute malignant melanoma, comprising administering to a mammal in need thereof a compound of claim 1 in an amount effective to treat malignant melanoma.
29. A method of treating soft-tissue or bone sarcoma, comprising administering to a mammal in need thereof a compound of claim 1 in an amount effective to treat soft-tissue or bone sarcoma.
30. A method of treating a cancer selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer comprising administering to a mammal in need thereof the composition of claim 17 in an amount effective to treat the cancer.
31. A method of inhibiting mTOR in a subject, comprising administering to a subject in need thereof a compound of claim 1 in an amount effective to inhibit mTOR.
32. A method of inhibiting PI3K in a subject, comprising administering to a subject in need thereof a compound of claim 1 in an amount effective to inhibit PI3K.
33. A method of inhibiting mTOR, PI3K, and hSMG-1 together in a subject, comprising administering to a subject in need thereof a compound of claim 1 in an amount effective to inhibit mTOR, PI3K, and hSMG-1.
34. A method of making a compound of claim 1 having the formula
Figure US20090304692A1-20091210-C00048
said method comprising reacting 2,4,6-trichloro[1,3,5]triazine with
Figure US20090304692A1-20091210-C00049
to form the intermediate dichlorotriazine compound
Figure US20090304692A1-20091210-C00050
35. The method of claim 34 further comprising reacting the intermediate dichlorotriazine compound with
Figure US20090304692A1-20091210-C00051
to form the intermediate compound
Figure US20090304692A1-20091210-C00052
36. The method of claim 35 wherein the reacting moiety
Figure US20090304692A1-20091210-C00053
is independently selected from
Figure US20090304692A1-20091210-C00054
US12/470,525 2008-05-23 2009-05-22 Triazine compounds as pi3 kinase and mtor inhibitors Abandoned US20090304692A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/470,525 US20090304692A1 (en) 2008-05-23 2009-05-22 Triazine compounds as pi3 kinase and mtor inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5566108P 2008-05-23 2008-05-23
US12/470,525 US20090304692A1 (en) 2008-05-23 2009-05-22 Triazine compounds as pi3 kinase and mtor inhibitors

Publications (1)

Publication Number Publication Date
US20090304692A1 true US20090304692A1 (en) 2009-12-10

Family

ID=40911929

Family Applications (8)

Application Number Title Priority Date Filing Date
US12/470,521 Active 2029-12-17 US8039469B2 (en) 2008-05-23 2009-05-22 Triazine compounds as PI3 kinase and mTOR inhibitors
US12/470,525 Abandoned US20090304692A1 (en) 2008-05-23 2009-05-22 Triazine compounds as pi3 kinase and mtor inhibitors
US13/218,571 Active US8217036B2 (en) 2008-05-23 2011-08-26 Triazine compounds as PI3 kinase and mTOR inhibitors
US13/490,309 Active US8445486B2 (en) 2008-05-23 2012-06-06 Triazine compounds as PI3 kinase and mTOR inhibitors
US13/718,928 Active US8575159B2 (en) 2008-05-23 2012-12-18 Triazine compounds as PI3 kinase and mTOR inhibitors
US13/950,584 Active US8748421B2 (en) 2008-05-23 2013-07-25 Triazine compounds as P13 kinase and MTOR inhibitors
US14/259,414 Active US8859542B2 (en) 2008-05-23 2014-04-23 Triazine compounds as PI3 kinase and mTOR inhibitors
US14/477,650 Active US9174963B2 (en) 2008-05-23 2014-09-04 Triazine compounds as PI3 kinase and MTOR inhibitors

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US12/470,521 Active 2029-12-17 US8039469B2 (en) 2008-05-23 2009-05-22 Triazine compounds as PI3 kinase and mTOR inhibitors

Family Applications After (6)

Application Number Title Priority Date Filing Date
US13/218,571 Active US8217036B2 (en) 2008-05-23 2011-08-26 Triazine compounds as PI3 kinase and mTOR inhibitors
US13/490,309 Active US8445486B2 (en) 2008-05-23 2012-06-06 Triazine compounds as PI3 kinase and mTOR inhibitors
US13/718,928 Active US8575159B2 (en) 2008-05-23 2012-12-18 Triazine compounds as PI3 kinase and mTOR inhibitors
US13/950,584 Active US8748421B2 (en) 2008-05-23 2013-07-25 Triazine compounds as P13 kinase and MTOR inhibitors
US14/259,414 Active US8859542B2 (en) 2008-05-23 2014-04-23 Triazine compounds as PI3 kinase and mTOR inhibitors
US14/477,650 Active US9174963B2 (en) 2008-05-23 2014-09-04 Triazine compounds as PI3 kinase and MTOR inhibitors

Country Status (44)

Country Link
US (8) US8039469B2 (en)
EP (3) EP3216793B1 (en)
JP (2) JP2011520979A (en)
KR (1) KR101331341B1 (en)
CN (2) CN102036995B (en)
AP (2) AP2775A (en)
AR (2) AR071908A1 (en)
AU (2) AU2009248997A1 (en)
BR (1) BRPI0912294B8 (en)
CA (2) CA2721692C (en)
CL (2) CL2009001273A1 (en)
CO (1) CO6311070A2 (en)
CR (1) CR11757A (en)
CU (1) CU23887B1 (en)
CY (2) CY1118879T1 (en)
DK (2) DK2294072T3 (en)
DO (1) DOP2010000315A (en)
EA (1) EA020317B1 (en)
EC (2) ECSP10010623A (en)
ES (2) ES2728163T3 (en)
GE (1) GEP20125589B (en)
HK (2) HK1157328A1 (en)
HR (2) HRP20170637T1 (en)
HU (1) HUE043331T2 (en)
IL (2) IL209060A (en)
LT (2) LT2294072T (en)
MA (1) MA32319B1 (en)
ME (1) ME01111B (en)
MX (1) MX2010012808A (en)
MY (1) MY155653A (en)
NI (1) NI201000198A (en)
NZ (1) NZ588526A (en)
PA (2) PA8828101A1 (en)
PE (2) PE20091943A1 (en)
PL (1) PL3216793T3 (en)
PT (2) PT3216793T (en)
RS (2) RS58724B1 (en)
SA (1) SA109300314B1 (en)
SI (2) SI2294072T1 (en)
TR (1) TR201906123T4 (en)
TW (2) TW201008949A (en)
UA (1) UA99361C2 (en)
WO (2) WO2009143313A1 (en)
ZA (1) ZA201007204B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110172227A1 (en) * 2009-12-21 2011-07-14 Conn P Jeffrey Alkyl 3-((2-amidoethyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate analogs as selective m1 agonists and methods of making and using same
WO2011109833A2 (en) 2010-03-05 2011-09-09 President And Fellows Of Harvard College Induced dendritic cell compositions and uses thereof
US9763992B2 (en) 2014-02-13 2017-09-19 Father Flanagan's Boys' Home Treatment of noise induced hearing loss

Families Citing this family (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA99361C2 (en) * 2008-05-23 2012-08-10 Уайт Елелсі TRIAZINE COMPOUNDS AS PI3 KINASE AND mTOR INHIBITORS
AU2009248774B2 (en) 2008-05-23 2012-05-31 Novartis Ag Derivatives of quinolines and quinoxalines as protein tyrosine kinase inhibitors
US10022381B2 (en) * 2008-05-23 2018-07-17 Pfizer Inc. Triazine compounds as PI3 kinase and mTOR inhibitors
GB2465405A (en) * 2008-11-10 2010-05-19 Univ Basel Triazine, pyrimidine and pyridine analogues and their use in therapy
WO2010096619A1 (en) * 2009-02-23 2010-08-26 Wyeth Llc Process, purification and crystallization of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
RU2011143359A (en) 2009-03-27 2013-05-10 Патвэй Терапьютикс, Инк. PRIMIDINYL- AND 1,3,5-TRIAZINYLBENZIMIDAZOLSULFONAMIDES AND THEIR APPLICATION IN CANCER THERAPY
UY32582A (en) 2009-04-28 2010-11-30 Amgen Inc 3 KINASE PHOSPHINOSITI INHIBITORS AND / OR MAMMAL OBJECTIVE
EP3072890B1 (en) 2009-07-07 2018-10-17 MEI Pharma, Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazoles and their use in cancer therapy
US20130035326A1 (en) * 2009-08-19 2013-02-07 Ambit Biosciences Corporation Biaryl compounds and methods of use thereof
GB201004200D0 (en) * 2010-03-15 2010-04-28 Univ Basel Spirocyclic compounds and their use as therapeutic agents and diagnostic probes
WO2012101654A2 (en) * 2011-01-25 2012-08-02 Sphaera Pharma Pvt. Ltd Novel triazine compounds
CA2825825A1 (en) * 2011-01-27 2012-08-02 The Trustees Of Princeton University Inhibitors of mtor kinase as anti-viral agents
JP5766820B2 (en) * 2011-02-09 2015-08-19 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Heterocyclic compounds as PI3 kinase inhibitors
CA2831582C (en) 2011-03-28 2019-01-08 Mei Pharma, Inc. (alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
CN102250065B (en) * 2011-05-20 2015-05-13 浙江海正药业股份有限公司 Substituted triazine phenyl urea derivatives and application thereof
CN102887867B (en) * 2011-07-21 2015-04-15 中国科学院上海药物研究所 Triazine compound and preparation method and application of triazine compound
ES2609606T3 (en) 2011-09-21 2017-04-21 Cellzome Limited Urea and carbamate derivatives of 2-morpholino-1,3,5-triazine as mTOR inhibitors for the treatment of immunological or proliferative diseases
MX341577B (en) 2011-10-07 2016-08-25 Cellzome Ltd Morpholino substituted bicyclic pyrimidine urea or carbamate derivatives as mtor inhibitors.
CN102659765B (en) * 2011-12-31 2014-09-10 沈阳药科大学 Pyrimidine and triazine compound preparation method and application
KR20160027219A (en) 2012-05-23 2016-03-09 에프. 호프만-라 로슈 아게 Compositions and methods of obtaining and using endoderm and hepatocyte cells
WO2014005182A1 (en) * 2012-07-04 2014-01-09 Monash University Phosphoinositide 3-kinase (pi3k) inhibitors
EP2874632B1 (en) * 2012-07-23 2020-06-17 Sphaera Pharma Pte. Ltd Triazine compound having pi3k-alpha and mtor inhibiting activity
GB201309807D0 (en) 2013-05-31 2013-07-17 Pharma Mar Sau Antibody drug conjugates
TWI693937B (en) 2014-03-14 2020-05-21 美商輝瑞大藥廠 Therapeutic nanoparticles comprising a therapeutic agent and methods of making and using same
EP3201174A4 (en) * 2014-10-03 2018-06-06 The Royal Institution for the Advancement of Learning / McGill University Urea and bis-urea based compounds and analogues thereof useful in the treatment of androgen receptor mediated diseases or disorders
CN107106685A (en) 2014-10-10 2017-08-29 辉瑞公司 Cooperate with the auspicious statin combination of Australia
CN107428730B (en) 2014-11-20 2020-10-16 科学与工业研究会 1,3, 5-triazinyl PI3K inhibitors as anti-cancer agents and methods of making the same
PL3233054T3 (en) 2014-12-17 2021-12-20 Pfizer Inc. Formulations of a pi3k/mtor-inhibitor for intravenous administration
CN104725361B (en) * 2015-04-09 2017-05-31 江苏富比亚化学品有限公司 A kind of preparation method of hindered amine light stabilizer 3346
JP6987125B2 (en) 2016-05-12 2021-12-22 南京世其医▲薬▼科技有限公司 New 2,4,6-trisubstituted s-triazine compound and its production method and use
JP6991158B2 (en) 2016-05-18 2022-02-10 ピクール セラピューティクス アーゲー Treatment of neuropathy
JOP20190254A1 (en) 2017-04-27 2019-10-27 Pharma Mar Sa Antitumoral compounds
IT201700047189A1 (en) * 2017-05-02 2018-11-02 Fondazione St Italiano Tecnologia COMPOUNDS AND COMPOSITIONS FOR CANCER TREATMENT, RETINAL DISORDERS AND CARDIOMYOPATHIES
MX2019013862A (en) 2017-05-23 2020-01-20 Mei Pharma Inc Combination therapy.
WO2019036489A1 (en) 2017-08-14 2019-02-21 Mei Pharma, Inc. Combination therapy
HRP20211985T1 (en) 2017-08-25 2022-04-01 Pfizer Inc. Pharmaceutical aqueous formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
CN108191837A (en) * 2018-01-10 2018-06-22 贵州医科大学 PI3K α/mTOR bidifly enzyme inhibitors and its pharmaceutical composition and application
WO2019157516A1 (en) 2018-02-12 2019-08-15 resTORbio, Inc. Combination therapies
KR102022323B1 (en) * 2018-03-30 2019-09-18 정하윤 Triazine Compound And Use Thereof
KR102583563B1 (en) 2018-06-07 2023-10-05 화이자 인코포레이티드 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5 Aqueous formulations containing -triazin-2-yl)phenyl]urea
FI3813946T3 (en) 2018-06-15 2024-06-25 Janssen Pharmaceutica Nv Rapamycin analogs and uses thereof
JPWO2020130125A1 (en) 2018-12-21 2021-11-04 第一三共株式会社 Combination of antibody-drug conjugate and kinase inhibitor
CN109942562B (en) * 2019-02-27 2022-02-08 江西科技师范大学 Five-membered heterocyclic diazine compound containing aryl structure and preparation method and application thereof
KR20220128345A (en) 2019-12-05 2022-09-20 아나쿠리아 테라퓨틱스, 인코포레이티드 Rapamycin analogs and uses thereof
MX2022012339A (en) * 2020-04-07 2022-10-27 Mei Pharma Inc Preparation of a 1,3,5-triazinyl benzimidazole.
KR20220138575A (en) 2021-04-06 2022-10-13 부산대학교병원 Method for screening drugs for the treatment or prevention of translocation Renal Cell Carcinoma
CN113200969B (en) * 2021-05-19 2022-11-25 中国药科大学 PI3K alpha selective inhibitor and preparation method and application thereof
JP2024529430A (en) 2021-07-26 2024-08-06 セルキュイティー インコーポレイテッド 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea (gedatricib) and combinations thereof for use in the treatment of cancer
CN115109049B (en) * 2022-08-12 2023-08-15 江西科技师范大学 Triazine compound containing aryl urea structure and application thereof
CN115557908B (en) * 2022-09-28 2024-10-15 九江学院 Triazine derivative containing sulfur connecting bond, and synthesis method and application thereof
CN116102545A (en) * 2023-02-01 2023-05-12 贵州医科大学 Diaryl urea PI3K/mTOR/HDAC multi-target inhibitor, and pharmaceutical composition and application thereof
CN116239580A (en) * 2023-03-06 2023-06-09 中国药科大学 Triazine compound and preparation method, pharmaceutical composition and application thereof

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2297326C (en) * 1997-07-24 2007-03-20 Zenyaku Kogyo Kabushiki Kaisha Heterocyclic compound and antitumor agent containing the same as active component
HUP0202076A3 (en) * 1997-12-12 2003-12-29 Abbott Lab Triazine angiogenesis inhibitors
US7071189B2 (en) 2001-04-27 2006-07-04 Zenyaku Kogyo Kabushiki Kaisha Heterocyclic compound and antitumor agent containing the same as active ingredient
GB0512324D0 (en) * 2005-06-16 2005-07-27 Novartis Ag Organic compounds
GB0423653D0 (en) * 2004-10-25 2004-11-24 Piramed Ltd Pharmaceutical compounds
JP2008531537A (en) 2005-02-25 2008-08-14 クドス ファーマシューティカルズ リミテッド Compound
AU2007287428B2 (en) * 2006-08-24 2011-08-11 Astrazeneca Ab Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders
UA99361C2 (en) * 2008-05-23 2012-08-10 Уайт Елелсі TRIAZINE COMPOUNDS AS PI3 KINASE AND mTOR INHIBITORS

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110172227A1 (en) * 2009-12-21 2011-07-14 Conn P Jeffrey Alkyl 3-((2-amidoethyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate analogs as selective m1 agonists and methods of making and using same
WO2011087812A1 (en) * 2009-12-21 2011-07-21 Vanderbilt University Alkyl 3-((2-amidoethyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate analogs as selective m1 agonists and methods of making and using same
US8697691B2 (en) 2009-12-21 2014-04-15 Vanderbilt University Alkyl 3-((2-amidoethyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate analogs as selective M1 agonists and methods of making and using same
WO2011109833A2 (en) 2010-03-05 2011-09-09 President And Fellows Of Harvard College Induced dendritic cell compositions and uses thereof
US9763992B2 (en) 2014-02-13 2017-09-19 Father Flanagan's Boys' Home Treatment of noise induced hearing loss

Also Published As

Publication number Publication date
PT2294072T (en) 2017-05-29
US20090291079A1 (en) 2009-11-26
ES2625467T3 (en) 2017-07-19
HK1157328A1 (en) 2012-06-29
CU23887B1 (en) 2013-04-19
US8859542B2 (en) 2014-10-14
US20130005723A1 (en) 2013-01-03
CY1121699T1 (en) 2020-07-31
EP2294072B1 (en) 2017-03-29
PE20091957A1 (en) 2009-12-30
RS55960B1 (en) 2017-09-29
ME01111B (en) 2013-03-20
RS58724B1 (en) 2019-06-28
US20130315865A1 (en) 2013-11-28
KR101331341B1 (en) 2013-11-19
NI201000198A (en) 2011-05-09
CU20100229A7 (en) 2011-11-15
BRPI0912294B8 (en) 2021-05-25
CN102036995B (en) 2014-09-17
CY1118879T1 (en) 2018-01-10
US20150011752A1 (en) 2015-01-08
CN102036995A (en) 2011-04-27
TW201011010A (en) 2010-03-16
JP4948677B2 (en) 2012-06-06
US8445486B2 (en) 2013-05-21
BRPI0912294A2 (en) 2015-10-20
EP2300483A1 (en) 2011-03-30
DK3216793T3 (en) 2019-05-06
HRP20190680T1 (en) 2019-06-14
DOP2010000315A (en) 2010-12-15
CA2721710A1 (en) 2009-11-26
TW201008949A (en) 2010-03-01
HRP20170637T1 (en) 2017-06-30
PE20091943A1 (en) 2009-12-19
EP3216793A1 (en) 2017-09-13
US8575159B2 (en) 2013-11-05
CN104230831A (en) 2014-12-24
AR071908A1 (en) 2010-07-21
MX2010012808A (en) 2010-12-21
AP2775A (en) 2013-09-30
TWI389906B (en) 2013-03-21
MA32319B1 (en) 2011-05-02
EA201071232A1 (en) 2011-06-30
AU2009248993C1 (en) 2013-10-03
BRPI0912294B1 (en) 2019-11-12
ECSP10010623A (en) 2010-12-30
NZ588526A (en) 2012-08-31
IL209060A (en) 2014-05-28
TR201906123T4 (en) 2019-05-21
WO2009143317A1 (en) 2009-11-26
SA109300314B1 (en) 2012-09-26
PT3216793T (en) 2019-05-30
PL3216793T3 (en) 2019-09-30
US20130109670A1 (en) 2013-05-02
US20140248239A1 (en) 2014-09-04
EP3216793B1 (en) 2019-03-27
PA8828201A1 (en) 2009-12-16
CO6311070A2 (en) 2011-08-22
AU2009248993B2 (en) 2011-07-07
MY155653A (en) 2015-11-13
CR11757A (en) 2010-11-30
CA2721692A1 (en) 2009-11-26
US8039469B2 (en) 2011-10-18
AP2010005453A0 (en) 2010-12-31
UA99361C2 (en) 2012-08-10
JP2011522802A (en) 2011-08-04
IL209060A0 (en) 2011-01-31
KR20110002485A (en) 2011-01-07
LT3216793T (en) 2019-05-10
US20110312955A1 (en) 2011-12-22
US8748421B2 (en) 2014-06-10
WO2009143313A1 (en) 2009-11-26
HUE043331T2 (en) 2019-08-28
ECSP10010624A (en) 2010-12-30
CL2009001273A1 (en) 2009-11-27
CN104230831B (en) 2016-08-24
CL2009001274A1 (en) 2009-10-16
PA8828101A1 (en) 2009-12-16
JP2011520979A (en) 2011-07-21
AU2009248993A1 (en) 2009-11-26
SI2294072T1 (en) 2017-05-31
US9174963B2 (en) 2015-11-03
EA020317B1 (en) 2014-10-30
HK1203199A1 (en) 2015-10-23
CA2721692C (en) 2014-01-14
AU2009248997A1 (en) 2009-11-26
ZA201007204B (en) 2011-12-28
GEP20125589B (en) 2012-07-25
SI3216793T1 (en) 2019-06-28
DK2294072T3 (en) 2017-05-15
AR071909A1 (en) 2010-07-21
IL209061A0 (en) 2011-01-31
ES2728163T3 (en) 2019-10-22
LT2294072T (en) 2017-06-12
US8217036B2 (en) 2012-07-10
EP2294072A1 (en) 2011-03-16
AP2010005452A0 (en) 2010-12-31

Similar Documents

Publication Publication Date Title
US9174963B2 (en) Triazine compounds as PI3 kinase and MTOR inhibitors
CA2755554A1 (en) Pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses
US10022381B2 (en) Triazine compounds as PI3 kinase and mTOR inhibitors

Legal Events

Date Code Title Description
AS Assignment

Owner name: WYETH, NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:VENKATESAN, ARANAPAKAM MUDUMBAI;CHEN, ZECHENG;DEHNHARDT, CHRISTOPH MARTIN;AND OTHERS;REEL/FRAME:023035/0279;SIGNING DATES FROM 20090616 TO 20090727

AS Assignment

Owner name: WYETH LLC,NEW JERSEY

Free format text: CHANGE OF NAME;ASSIGNOR:WYETH;REEL/FRAME:024541/0922

Effective date: 20091109

Owner name: WYETH LLC, NEW JERSEY

Free format text: CHANGE OF NAME;ASSIGNOR:WYETH;REEL/FRAME:024541/0922

Effective date: 20091109

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION