WO2010120996A1 - 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses - Google Patents

5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses Download PDF

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WO2010120996A1
WO2010120996A1 PCT/US2010/031188 US2010031188W WO2010120996A1 WO 2010120996 A1 WO2010120996 A1 WO 2010120996A1 US 2010031188 W US2010031188 W US 2010031188W WO 2010120996 A1 WO2010120996 A1 WO 2010120996A1
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phenyl
oxa
alkyl
azabicyclo
oct
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PCT/US2010/031188
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French (fr)
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Ariamala Gopalsamy
Mengxiao Shi
Arie Zask
Aranapakam Mudumbai Venkatesan
Kevin Joseph Curran
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Wyeth Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to 5,6,7,8-tetrahydropyhdo[3,4-d]pyrimidine compounds and their ring homologues, compositions comprising such a compound, methods of synthesizing such compounds, and methods for treating mTOR-related diseases comprising the administration of an effective amount of such a compound.
  • the invention relates to methods for treating PI3K-related diseases comprising the administration of an effective amount of such a compound.
  • the invention also relates to methods for treating hSMG-1 -related diseases comprising the administration of an effective amount of such a compound.
  • Phosphatidylinositol (hereinafter abbreviated as "Pl") is one of the phospholipids in cell membranes.
  • Pl 4,5 bisphosphate
  • PIP2 Pl (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. Berhdge et al., Nature, 312, 315 (1984); Y. Nishizuka, Science, 225, 1365 (1984)].
  • PI3K phosphatidylinositol-3 kinase
  • the class Ia PI3K subtype has been most extensively investigated to date. Within the class Ia subtype there are three isoforms ( ⁇ , ⁇ , & ⁇ ) that exist as hetero dimers of a catalytic 1 10-kDa subunit and regulatory subunits of 50-85kDa.
  • 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- thsphosphate) 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 ⁇ isoform) has become a major therapeutic target in cancer drug discovery.
  • Class I PI3Ks are Pl, 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 p1 10 ⁇ that is activated by interaction with G protein-coupled receptors. Interaction between p1 10 ⁇ and G protein-coupled receptors is mediated by regulatory subunits of 1 10, 87, and 84 kDa.
  • Pl and PI(4)P are the known substrates for class Il PI3Ks; PI(4,5)P2 is not a substrate for the enzymes of this class.
  • Class Il 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 Pl 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 PM 03 (3-(4-(4-morpholinyl)pyhdo[3',2':4,5]furo[3,2-d]pyrimidin-2- yl)phenol) inhibits PI3K ⁇ and PI3K ⁇ as well as the mTOR enzymes with IC 5 O values of 2, 3, and 50-80 nM respectively.
  • 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 1 16); 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-thazine) inhibits PI3K ⁇ and PI3K ⁇ 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).
  • NVP-BEZ-235 (2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)- 2,3-dihydro-1 H-imidazo[4,5-c]quinolin-1 -yl)phenyl)propanenithle) inhibits both PI3K ⁇ and PI3K ⁇ 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-1 126 (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. It began clinical trials in April, 2007 for the solid tumors endometrial, renal cell, breast, hormone refractory prostate and ovarian 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
  • Exelixis Inc. (So. San Francisco, CA) recently filed INDs for XL-147 (a selective pan-PI3K inhibitor of unknown structure) and XL-765 (a mixed inhibitor of mTOR and PI3K of unknown structure) as anticancer agents.
  • TargeGen's short-acting mixed inhibitor of PI3K ⁇ and ⁇ , TG-1001 15 is in phase I/I I trials for treatment of infarct following myocardial ischemia-reperfusion injury.
  • Cerylid's antithrombotic PI3K ⁇ inhibitor CBL-1309 (structure unknown) has completed preclinical toxicology studies.
  • 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 42-0-(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), 1 149-1 155, 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.
  • Yamashita (Genes Dev. 2001 15: 2215-2228) characterized two isoforms of hSMG-1 proteins, p430 and p400, which are expressed in various cell lines of human, monkey, rat, and mouse. Yamashita's p400 hSMG-1 isoform is a 3529-amino-acid protein of 396,040 Daltons.
  • Brumbaugh (Molecular Cell, Volume 14, Issue 5, 4 June 2004, Pages 585-598) isolated a 3521 amino acid polypeptide with a deduced molecular mass of 395 kDa.
  • Brumbaugh's hSMG-1 is eight amino acids shorter at the amino terminus than the protein isolated by Yamashita.
  • Both hllpfl and p53 are physiological targets for hSMG-1 in intact cells. Rapamycin in the presence of purified recombinant FKBP12 does not inhibit the kinase activity of hSMG-1. Wortmannin, the modified steroidal anti-infective agent, and the purine caffeine inhibit the kinase activity of hSMG-1 with IC50 values of -60 nM and 0.3 mM, respectively. However, these are non-specific protein kinase inhibitors.
  • hSMG-1 Specific inhibition of hSMG-1 is a potential therapeutic strategy because inhibitors of hSMG-1 cause the accumulation of truncated p53 proteins from a premature translation termination codon (PTC) allele, as well as the increase in the level of mRNA with PTC, opening the possibility of the above strategy by specifically suppressing nonsense-mediated mRNA decay (NMD) through the inhibition of hSMG-1.
  • PTC premature translation termination codon
  • NMD nucleic acid deficiency virus
  • the specific inhibition of NMD may provide a novel therapeutic strategy based on the type of mutation rather than on the gene in which the mutation resides.
  • the inhibitors of SMG-1 can rescue the synthesis of mature proteins through two independent mechanisms (i.e., the inhibition of NMD to increase the mRNA level and the suppression of translational termination that leads to the synthesis of a read-through mature protein product). In this sense, the specific inhibitors of hSMG-1 will be of potential therapeutic importance for all the genetic diseases associated with PTC mutations.
  • PI3K inhibitors, mTOR inhibitors, and hSMG-1 inhibitors are expected to be novel types of medicaments useful against cell proliferation disorders, especially as carcinostatic agents.
  • the instant invention is directed to these and other important ends.
  • the invention provides compounds of the Formula I:
  • the invention provides compositions comprising a compound of the invention, and methods for making compounds of the invention.
  • the invention provides methods for inhibiting PI3K, mTOR and hSMG-1 in a subject, and methods for treating PI3K-related, mTOR-related and hSMG-1 -related disorders in a mammal in need thereof.
  • the invention provides compounds of the Formula I:
  • R 1 is independently C-i-C ⁇ alkyl-, C 6 -C- ⁇ 4 aryl-, d-Cgheteroaryl-, halogen, or hydroxyl;
  • p is 0, 1 , 2, 3, or 4;
  • het is a d-Cgheterocyclyl- group containing at least one oxygen atom;
  • m is 0 or 1 ;
  • Ar is C 6 -C- ⁇ 4 aryl- or C r C 9 heteroaryl- wherein the C 6 -C- ⁇ 4 aryl- or d-Cgheteroaryl- is optionally substituted with from 1 to 4 substituents independently selected from d- C 6 alkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl(C r C 6 alkyl)-, H 2 N-, aminoalkyl-, di(d- C6alkyl)amino-, HO 2 C-, (d-C ⁇ alkoxyJcarbonyl-, (d-Cealky ⁇ carboxyl-, di(d- C 6 alkyl)amido-, H 2 NC(O)-, (Ci-C 6 alkyl)amido-, and O 2 N-;
  • R 2 is H or CrC 6 alkyl-;
  • R 3 is R 6 , R 7 R 8 N-, R 9 S-, or R 9 O-
  • R 6 is H; CrC ⁇ alkyl- optionally substituted with from 1 to 3 substituents independently selected from d-C ⁇ alkoxy-, H 2 N-, (Ci-C6alkyl)amino-, di(d- C 6 alkyl)amino-, C 6 -Ci 4 aryl-, d-Cgheterocyclyl- optionally substituted by C r C 6 alkyl-, and d-Cgheteroaryl-; Ci-C6alkoxy-; Ci-Cgheteroaryl- optionally substituted with from 1 to 3 substituents independently selected from Ci-C6alkyl- optionally substituted with H 2 N-, (Ci-C 6 alkyl)amino-, or di(d-C 6 alkyl)amino-, heterocyclyl(d-C 6 alkyl)-, halogen, hydroxyl, H 2 N-, O 2 N-, H 2 NSO 2 -, HO 2 C-,
  • R 10 and R 11 are each independently H, CrC ⁇ alkyl-, Ci-C6alkoxy(C 2 -C6alkylene)-, (Ci-C6alkyl)amino-C 2 -C6alkylene-, di(Ci-C6alkyl)amino-C 2 -C6alkylene-, C 2 -C6alkenyl, C 2 -C 6 alkynyl, C 6 -Ci 4 aryl-, (C 6 -Ci 4 aryl)alkyl-, drCscycloalkyl-, Ci-Cgheteroaryl-, (d- Cgheteroaryl)alkyl-, Ci-Cgheterocyclyl-, or heterocyclyl(Ci-C 6 alkyl-); or R 10 and R 11 , when taken together with the nitrogen to which they are attached, form a 3- to 7- membered heterocycle wherein up to two of the carbon atoms of the hetero
  • R 7 and R 8 are each independently H; CrC ⁇ alkyl- optionally substituted with from 1 to 3 substituents independently selected from Ci-C ⁇ alkoxy-, H 2 N-, (Ci-C6alkyl)amino-, di(Ci-C 6 alkyl)amino-, halogen, C 6 -d 4 aryl-, Ci-Cgheterocyclyl- optionally substituted by Ci-C 6 alkyl-, and Ci-Cgheteroaryl-; Ci-C 6 alkoxy-; Ci-Cgheteroaryl- optionally substituted with from 1 to 3 substituents independently selected from CrC ⁇ alkyl- optionally substituted with H 2 N-, (d-C 6 alkyl)amino-, or di(d-C 6 alkyl)amino-, heterocyclyl(Ci- C ⁇ alkyl)- optionally substituted with d-C ⁇ alkyl, halogen, hydroxyl, H 2 N-,
  • R 9 is Ci-C ⁇ alkyl-, C 6 -C- ⁇ 4 aryl-, (C 6 -C- ⁇ 4 aryl)alkyl- optionally substituted by H 2 N-, C-i-Cgheterocyclyl-, C 3 -C 8 CyClOaIkVl-, CrC ⁇ hydroxylalkyl-, or C-i-Ceperfluoroalkyl-; n is O, 1 , or 2; R 4 is: a) hydrogen; b) C-i-Csacyl-, optionally substituted with from 1 to 3 substituents independently selected from: i) C-i-C ⁇ alkoxy-, ⁇ ) (Ci-C 6 )alkyl-, iii) (Ci-C6alkyl)amino-, iv) C 3 -C 8 CVClOaIkVl-, v) di(Ci-C 6 alkyl)amino-, vi)
  • I- optionally substituted with frx Om i) C- ⁇ -C 6 alkoxy-, ⁇ ) (Ci-C 6 alkoxy)carbonyl-, iii) (Ci-C6alkyl)amino-, iv) di(Ci-C6alkyl)amino-, v) C 3 -C 8 cycloalkyl-, vi) halogen, vii) HC(O)-, viii) HO 2 C-, ix) and H 2 N-; d) C-i-Ceaminoalkyl- optionally substituted with a substituent selected from: i) C 6 -Ci 4 aryl- optionally substituted with halogen, ii) (Ci-Cgheteroaryl)alkyl-, iii) (C 6 -Ci 4 aryl)alkyl-, iv) H 2 N-Ci-C 6 alkylene-, v) (Ci-C
  • R 12 and R 13 are each independently: a) H; b) C1 -C6alkyl- optionally substituted with a substituent selected from: i) CrC 6 alkylC(O)NH-, ii) H 2 N-, iii) (Ci-C6alkyl)amino-, iv) and di(Ci-C 6 alkyl)amino-, c) C 2 -C 6 alkenyl- d) Cs-Cscycloalkyl-; e) C6-C- ⁇ 4 aryl- optionally substituted with a substituent selected from: i) halogen, ii) and d-Cgheterocycle wherein the d-Cgheterocycle is optionally substituted with (C r C 6 alkoxy)carbonyl-; f) d-Cgheteroaryl-; g) (d-Cgheteroaryl)alkyl-; h) heterocycly
  • Ci-C 6 alkyl-, C 6 -Ci 4 aryl-, (C 6 -d 4 aryl)alkyl-, d-Cgheterocyclyl-, or drCscycloalkyl- is optionally substituted with a Ci-C 6 alkoxy-, Ci-C 6 alkyl-, C 3 -C 8 cycloalkyl-, NC-, or halogen;
  • R 5 are independently H or d-C ⁇ alkyl.
  • the invention provides compounds of the Formula II:
  • the invention provides compounds of the Formula III:
  • the invention provides compounds of the Formula IV:
  • the invention provides compounds of the Formula V:
  • the invention provides compounds of the Formula Vl:
  • the invention provides compounds of the Formula VII:
  • the invention provides compounds of the Formula VIII:
  • the invention provides compounds of the Formula IX:
  • R 2 is H.
  • R 3 is R 7 R 8 N-.
  • R 7 is C-i-Cgheteroaryk
  • R 7 is pyridyl. In one embodiment, R 7 is 3- or 4-pyridyl.
  • R 8 is H.
  • R 4 is R 14 S(O) 2 -.
  • R 14 is Ci-C ⁇ alkyl-.
  • R 14 is CH 3 -.
  • Illustrative compounds of the present Formula III are set forth below:
  • Illustrative compounds of the present Formula V are set forth below: i ⁇ - ⁇ S-oxa- ⁇ -azabicycloP ⁇ .iloct- ⁇ -yO-S ⁇ J ⁇ -tetrahydropyhdoP ⁇ -dlpyhmidin ⁇ - yl]phenyl ⁇ -3-pyhdin-3-ylurea;
  • Illustrative compounds of the present Formula VIII are set forth below: i ⁇ - ⁇ -oxa-a-azabicyclop ⁇ .iloct-a-ylJ- ⁇ J-dihydro- ⁇ H-pyrroloP ⁇ -dlpyrimidin ⁇ - yl]phenyl ⁇ -3-pyhdin-3-ylurea; 1-methyl-3- ⁇ 4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyhmidin-2-yl]phenyl ⁇ urea;
  • Illustrative compounds of the present Formula IX are set forth below: i ⁇ - ⁇ a-oxa- ⁇ -azabicyclop ⁇ .iloct- ⁇ -ylJ- ⁇ J-dihydro- ⁇ H-pyrroloP ⁇ -dlpyrimidin ⁇ - yl]phenyl ⁇ -3-pyhdin-3-ylurea;
  • the invention provides pharmaceutical compositions comprising compounds or pharmaceutically acceptable salts of the compounds of the present Formula I and a pharmaceutically acceptable carrier.
  • the invention provides a 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, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopuhne, 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, leucovohn, levamisole,mitotecan
  • 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 an hSMG-1 -related disorder, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat an 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 the compounds or a pharmaceutically acceptable salt of the compounds of the present 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 the compounds or a pharmaceutically acceptable salt of the compounds of any of the present 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 the compounds or a pharmaceutically acceptable salt of the compounds of any of the present 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 the compounds or a pharmaceutically acceptable salt of the compounds of any of the present 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, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopuhne, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin,
  • 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 a compound of
  • the invention provides a method of synthesizing a compound of Formula I further comprising: a) when NHR 2 is present, reacting compound 16 with an acylating agent R 3 C(O)X, wherein R 3 is as defined for Formula I to give 17:
  • compositions include but are not limited to, e.g., water-soluble and water-insoluble salts, such as the acetate, aluminum, amsonate
  • 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, diastereomehc, 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.
  • An "effective amount" when used in connection a compound of the present invention of this invention is an amount effective for inhibiting mTOR or PI3K in a subject.
  • the number of carbon atoms present in a given group is designated "C x -Cy", where x and y are the lower and upper limits, respectively.
  • a group designated as “CrC ⁇ ” 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.
  • 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 d-Csacyl- 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 r C 6 alkyl)amino-, di(C r C 6 alkyl)amino-, (CrC 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, -CN, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyl-, HO 2 C- , (C-i-CealkoxyJcarbonyl-, (CrC 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, C r C 9 heteroaryl-, or C 3 - Cs
  • Alkenyl- refer to a straight or branched chain unsaturated hydrocarbon containing at least one double bond.
  • Examples of a C 2 -Cioalkenyl- 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, 4-octene, 1-nonene, 2- nonene, 3-nonene, 4-nonene, 1 -decene, 2-decene, 3-decene, 4-decene and 5-decene.
  • An alkenyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (C r C 6 alkyl)amino-, di(C r C 6 alkyl)amino-, (Ci-C 6 alkyl)C(O)N(C r C 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyl-, HO 2 C-, (C r C6alkoxy)carbonyl-, (Ci-C6alkyl)C(O)-, C6-Ci 4 aryl-, d-Cgheteroaryl-, and C 3 -
  • Alkoxy- refers to the group R-O- where R is an alkyl group, as defined below.
  • Exemplary C-i-C ⁇ 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-i-C ⁇ alkoxy-, H 2 N-, (Ci-C 6 alkyl)amino-, di(C r C 6 alkyl)amino-, (C r C 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, C r C 6 alkoxy-, HO 2 C-, (Ci-Cealkoxyjcarbonyl-, (C r C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, d-Cgheteroaryl-, Cs-Cs
  • (Alkoxy)carbonyl- refers to the group alkyl-O-C(O)-.
  • Exemplary (Cr 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, H 2 N-, (Cr C 6 alkyl)amino-, di(C r C 6 alkyl)amino-, (C r C 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (Ci-C 6 alkyl)NHC(O)-, di(Ci- C 6 alkyl)NC(O)-, NC-, C r C 6 alkoxy-, HO 2 C-, (C r C 6 alkoxy)carbonyl-, (C r C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, d-Cgheteroaryl-, Cs-Cscycloalkyl-,
  • 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 Ci-Cioalkyl- group may have from 1 to 10 (inclusive) carbon atoms in it. In the absence of any numerical designation, “alkyl” is a chain (straight or branched) having 1 to 6 (inclusive) carbon atoms in it.
  • CrC ⁇ alkyl- groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • An alkyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (CrC6alkyl)amino-, di(d- C 6 alkyl)amino-, (CrC 6 alkyl)C(O)N(CrC 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (CrC 6 alkyl)NHC(O)-, di(CrC 6 alkyl)NC(O)-, NC-, hydroxyl, Ci-C 6 alkoxy-, d- C 6 alkyl-, HO 2 C-, (Ci-C 6 alkoxy)carbonyl-, (C r C 6 alkyl)C(O)-, C 6 -d 4 aryl-, C r Cgheteroaryl-, C 3 -C 8 CyClOaIk
  • (Alkyl)amino- refers to an -NH group, the nitrogen atom of said group being attached to an alkyl group, as defined above.
  • Representative examples of an (Cr C6alkyl)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-, (CHs) 2 CHCH 2 NH-,
  • An (alkyl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (Ci-C6alkyl)amino-, di(Ci-C 6 alkyl)amino-, (CrC 6 alkyl)C(O)N(C r C 3 alkyl)-, (d-CealkyOcarboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(d-C 6 alkyl)NC(O)-, NC-, hydroxyl, d- C 6 alkoxy-, C r C 6 alkyl-, HO 2 C-, (d-CealkoxyJcarbonyl-, (Ci-C 6 alkyl)C(O)-, C 6 -d 4 ary
  • Alkylcarboxyl- refers to an alkyl group, defined above, and attached to the parent structure through the oxygen atom of a carboxyl (C(O)-O-) functionality.
  • Examples of (d-Cealky ⁇ carboxyl- include acetoxy, propionoxy, propylcarboxyl, and isopentylcarboxyl.
  • alkylene- refers to alkyl-, alkenyl-, and alkynyl- groups, as defined above, having two points of attachment within a chemical structure.
  • Examples of -C-i-C ⁇ alkylene- include ethylene (-CH 2 CH 2 -), propylene (- CH 2 CH 2 CH 2 -), and dimethylpropylene (-CH 2 C(CHs) 2 CH 2 -).
  • alkynylene- examples include ethynylene (-C ⁇ C-) and propynylene (-C ⁇ C — CH 2 -).
  • Alkynyl- refers to a straight or branched chain unsaturated hydrocarbon containing at least one triple bond.
  • Examples of a C 2 -Cioalkynyl- 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, isohexyne, 1-heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne, 4-octyne, 1-nonyne, 2-nonyne, 3- nonyne, 4-nonyne, 1-decyne, 2-decyne, 3-decyne, 4-decyne and 5-decyne.
  • An alkynyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (C r C 6 alkyl)amino-, di(C r C 6 alkyl)amino-, (Ci-C 6 alkyl)C(O)N(CrC 3 alkyl)- , (d-CealkyOcarboxyamido-, HC(O)NH-, H 2 NC(O)-, (Ci-C 6 alkyl)NHC(O)-, di(Ci- C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyl-, HO 2 C-, (C r C 6 alkoxy)carbonyl-, (CrC 6 alkyl)C(O)-, C 6 -C- ⁇ 4 aryl-, C r C 9 heteroaryl-, and C 3 - Cscycl
  • Amine-protecting group refers to a radical when attached to a nitrogen atom in a target molecule is capable of surviving subsequent chemical reactions applied to the target molecule i.e. hydrogenation, reaction with acylating agents, alkylation etc. The amine-protecting group can later be removed.
  • Amine protecting groups include, but are not limited to, fluorenylmethoxycarbonyl (FMOC), tert-butoxycarbonyl (t-BOC), benzyloxycarbonyl (Z), those of the acyl type (e.g., formyl, benzoyl, thfluoroacetyl, p- tosyl, aryl- and alkylphosphoryl, phenyl- and benzylsulfonyl, o-nitrophenylsulfenyl, o- nitrophenoxyacetyl), and of the urethane type (e.g.
  • acyl type e.g., formyl, benzoyl, thfluoroacetyl, p- tosyl, aryl- and alkylphosphoryl, phenyl- and benzylsulfonyl, o-nitrophenylsulfenyl, o- nitrophenoxyacetyl
  • Amine-protecting groups are made using a reactive agent capable of transferring an amine-protecting group to a nitrogen atom in the target molecule.
  • an amine-protecting agent examples include, but are not limited to, C-i-C ⁇ aliphatic acid chlorides or anhydrides, C 6 -Ci 4 arylcarboxylic acid chlorides or anhydrides, t- butylchloroformate, di-tert-butyl dicarbonate, butoxycarbonyloxyimino-2- phenylacetonitrile, t-butoxycarbonyl azide, t-butylfluoroformate, fluorenylmethoxycarbonyl chloride, fluorenylmethoxycarbonyl azide, fluorenylmethoxycarbonyl benzotriazol-1-yl, ( ⁇ -fluorenylmethoxycarbonyOsuccinimidyl carbonate, fluorenylmethoxycarbonyl pentafluorophexoxide, trichloroacetyl chloride, methyl-, ethyl-, trichloromethyl- chloroformate, and other
  • Aryl- refers to an aromatic hydrocarbon group.
  • Examples of an C 6 -C- ⁇ 4 aryl- group include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, 3-biphen-1-yl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl.
  • An aryl group can be unsubstituted or substituted with one or more of the following groups: d- C ⁇ alkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl(CrC 6 alkyl)-, H 2 N-, aminoalkyl-, di(d- C 6 alkyl)amino-, HO 2 C-, (C r C 6 alkoxy)carbonyl-, (C r C 6 alkyl)carboxyl-, di(d- C 6 alkyl)amido-, H 2 NC(O)-, (C r C 6 alkyl)amido-, or O 2 N-.
  • (Aryl)alkyl- refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with an aryl group as defined above.
  • (C 6 -Ci 4 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 r C 6 alkyl)amino-, di(CrC 6 alkyl)amino-, (CrC 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (Ci-C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyl-, HO 2 C- , (CrC 6 alkoxy)carbonyl-, (CrC 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, C r C 9 heteroaryl-, C 3
  • Carboxyamidoalkyl- refers to a primary carboxyamide (CONH 2 ), a secondary carboxyamide (CONHR') or a tertiary carboxyamide (CONR 1 R"), where R' and R" are the same or different substituent groups selected from CrC ⁇ alkyl-, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 6 -Ci 4 aryl-, C r C 9 heteroaryl-, or C 3 -C 8 CyClOaIkVl-, attached to the parent compound by an -C-i-C ⁇ alkylene- group as defined above.
  • Cs-Cscycloalkyl- refers to a monocyclic, non-aromatic, saturated hydrocarbon ring.
  • Representative examples of a Cs-Cscycloalkyl- include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • a cycloalkyl can be unsubstituted or independently substituted with one or more of the following groups: halogen, H 2 N-, (Ci-C 6 alkyl)amino-, di(C r C 6 alkyl)amino-, (d- C 6 alkyl)C(O)N(C r C 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyl-, HO 2 C- , (Ci-C 6 alkoxy)carbonyl-, (CrC 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, C r C 9 heteroaryl-, or C 3 - C
  • 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(Ci-C6alkyl)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(CH2CH 2 CH 2 CH 3 )2,
  • 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(CrC 6 alkyl)-, -N(C 3 - Cscycloalkyl)-, -N(C 6 -Ci 4 aryl)-, -N(Ci-C 9 heteroaryl)-, -N(Ci-C 6 aminoalkyl)-, -N(C 6 - C- ⁇ 4 arylamino)-, -0-, -S-, -S(O)-, Or -S(O) 2 -.
  • Halo or halogen refers to fluorine, chlorine, bromine, or iodine.
  • Heteroaryl- refers to 5-10-membered mono and bicyclic aromatic groups containing at least one heteroatom selected from oxygen, sulfur and nitrogen.
  • monocyclic d-Cgheteroaryl- radicals include, but are not limited to, oxazinyl, thiazinyl, diazinyl, triazinyl, thiadiazoyl, tetrazinyl, imidazolyl, tetrazolyl, isoxazolyl, furanyl, furazanyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl, N-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.
  • bicyclic C r Cgheteroaryl- radicals include but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl, and indazolyl.
  • the contemplated heteroaryl- rings or ring systems have a minimum of 5 members.
  • dheteroaryl- radicals would include but are not limited to tetrazolyl
  • C 2 heteroaryl- radicals include but are not limited to triazolyl, thiadiazoyl, and tetrazinyl
  • Cgheteroaryl- radicals include but are not limited to quinolinyl and isoquinolinyl.
  • a heteroaryl group can be unsubstituted or substituted with one or more of the following groups: CrC ⁇ alkyl-, halogen, d-C ⁇ haloalkyl-, hydroxyl, d- Cehydroxylalkyl-, H 2 N-, C r C 6 aminoalkyl-, di(C r C 6 alkyl)amino-, -COOH, (C r C 6 alkoxy)carbonyl-, (CrC 6 alkyl)carboxyl-, di(Ci-C 6 alkyl)amido-, H 2 NC(O)-, (d- C 6 alkyl)amido-, or O 2 N-.
  • (Heteroaryl)alkyl- refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with a heteroaryl- group as defined above.
  • Examples of (d-CgheteroaryOalkyl- moieties include 2-pyhdylmethyl, 2-thiophenylethyl, 3-pyhdylpropyl, 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, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, (Ci-C 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (d- C 6 alkyl)NHC(O)-, di(Ci-C 6 alkyl)NC(O)-, NC-, hydroxyl, Ci-C 6 alkoxy-, Ci-C 6 alkyl-, HO 2 C- , (Ci-C 6 alkoxy)carbonyl-, (Ci-C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, C r C 9 heteroaryl-
  • Heteroatom refers to a sulfur, nitrogen, or oxygen atom.
  • Heterocycle or “heterocyclyl-” refers to 3-10-membered monocyclic, fused bicyclic, and bridged bicyclic groups containing at least one heteroatom selected from oxygen, sulfur and nitrogen.
  • a heterocycle may be saturated or partially saturated.
  • Exemplary d-Cgheterocyclyl- 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- diaza
  • dheterocyclyl- 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
  • Cgheterocyclyl- radicals include but are not limited to azecanyl, tetrahydroquinolinyl, and perhydroisoquinolinyl.
  • Heterocyclyl(alkyl)- refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with a heterocycle group as defined above.
  • Heterocyclyl(Ci-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-, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, (Ci- C 6 alkyl)C(O)N(C r C 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyl-, HO 2 C- , (Ci-C6alkoxy)carbonyl-, (Ci-C6alkyl)C(O)-, 4- to 7-membered monocyclic heterocycle, C 6 -Ci 4 aryl
  • Hydrolalkyl- refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with hydroxyl groups.
  • C-i-C ⁇ 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.
  • leaving group refers an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a specified reaction.
  • the leaving group is bromide.
  • the leaving group is trimethylamine.
  • the electrophilic nitration of benzene it is H + .
  • the term has meaning only in relation to a specified reaction. Examples of leaving groups include, for example, carboxylates (i.e.
  • Perfluoroalkyl- refers to alkyl group, defined above, having two or more fluorine atoms. Examples of a Ci-C ⁇ perfluoroalkyl- group include CF 3 , CH 2 CF 3 , CF 2 CF 3 and CH(CF 3 ) 2 .
  • optionally substituted means that at least one hydrogen atom of the optionally substituted group has been substituted with halogen, H 2 N-, (C r C 6 alkyl)amino-, di(Ci-C 6 alkyl)amino-, (d- C 6 alkyl)C(O)N(C r C 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyl-, HO 2 C- , (Ci-C 6 alkoxy)carbonyl-, (CrC 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, C r C 9 heteroaryl
  • 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 compounds of the present invention exhibit an mTOR inhibitory activity and, therefore, can be utilized 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.
  • parenteral dosage forms 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.
  • 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.
  • 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.
  • 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. Procedures used to synthesize the compounds of the present invention are described in Schemes 1 -7 and are illustrated in the examples. Reasonable variations of the described procedures are intended to be within the scope of the present invention:
  • One of the intermediates of formula 2 utilized for introducing the aryl ureido group was prepared starting from 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane of formula 1 as shown in Scheme 1.
  • PG is an amine-protecting group and X is independently a leaving group.
  • amine-protecting groups include BOC, FMOC, Z, formyl, benzoyl, thfluoroacetyl, p-tosyl, aryl- and alkylphosphoryl, phenyl- and benzylsulfonyl, o-nitrophenylsulfenyl, o- nitrophenoxyacetyl, tosyloxyalkyloxy-, cyclopentyloxy-, cyclohexyloxy-, 1 ,1 - dimethylpropyloxy, 2-(p-biphenyl)-2-propyloxy- and benzylthiocarbonyl.
  • leaving groups include iodide, bromide, chloride, fluoride, me
  • 6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyhmidine compounds 22 are made by a reductive amination process.
  • Schemes 1-7 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.
  • ATP is adenosine triphosphate
  • ⁇ ME is 2-mercaptoethanol
  • BOC is tertiary- butyloxycarbonyl
  • BSA Bovine Serum Albumin
  • CHAPS is (3-[(3- cholamidopropyl)dimethylammonio]-1-propanesulfonic acid
  • DELFIA Dissociation- Enhanced Lanthanide Fluorescent Immunoassay
  • DME is 1 ,2-dimethoxyethane
  • DMF is N,N-dimethylformamide
  • DMSO dimethylsulfoxide
  • DPBS Dulbecco's Phosphate Buffered Saline Formulation.
  • DTT is (2S,3S)-1 ,4-bis-sulfanylbutane-2,3-diol or dithiothreitol
  • EDTA is ethylenediaminetetraacetic acid
  • EGTA is ethylene glycol tetraacetic acid
  • EtOAc is ethyl acetate
  • FLAG-TOR is a FLAG-tagged TOR protein
  • HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
  • HPLC high-pressure liquid chromatography
  • microcrystin LR is a cyclic heptapeptide hepatotoxin produced Microcystis aeruginosa containing the amino acids leucine (L) and arginine (R) in the variable positions
  • MS is mass spectrometry
  • mTOR is Mammalian Target of Rapamycin (a protein)
  • MTS is 3-(4, 5-dimethylthiazol-2-yl
  • RaneyTM nickel is a sponge-metal catalyst produced when a block of nickel-aluminum alloy is treated with concentrated sodium hydroxide.
  • RaneyTM is a registered trademark of W. R. Grace and Company.
  • RT is retention time
  • SDS is dodecyl sulfate (sodium salt)
  • SRB is Sulforhodamine B
  • TAMRA is tetramethyl-6-carboxyrhodamine
  • TFA is thfluoroacetic acid
  • THF is tetrahydrofuran
  • TRIS tris(hydroxymethyl)aminomethane.
  • Step 1 Preparation of 1-pyridin-3-yl-3-[4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea A mixture of 2-(4-isocyanato-phenyl)-4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolane (1 ,
  • Step 3 Preparation of 1 -[4-(4-morpholin-4-yl-5,6,7,8-tetrahydro[3,4-d]pyhmidyl- 2-yl) phenyl]-3-pyhdin-3-ylurea
  • Example 8 Preparation of 1-methyl-3-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyrimidin-2-yl) phenyljurea
  • Step 1 Preparation of 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2- yl)-phenyl]-urea
  • Step 2 Preparation of 1 -methyl-3-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydro[3,4- d]pyhmidin-2-yl) phenyl]urea
  • Step 1 Preparation of 2-chloro-4-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-5,8- dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester
  • a mixture of 2,4-dichloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (3, 860 mg, 2.68 mmol), 3-oxa-8-aza-bicyclo[3.2.1]octane (384 mg, 3.39 mmol), and triethyl amine (343 mg, 3.39 mmol) in 20 ml.
  • Step 2 Preparation of 1 - ⁇ 4-[4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8- tetrahydro[3,4-d]pyhmidyl-2-yl]phenyl ⁇ -3-pyhdin-3-ylurea
  • the reaction mixture was filtered through a silica gel pad (eluting with 10 % methanol/EtOAc). The filtrate was concentrated to get the crude 4-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-2-[4-(3-pyridin-3-yl-ureido)-phenyl]- 5,8-dihydro-6H-pyhdo[3,4-d]pyhmidine-7-carboxylic acid tert-butyl ester. Then the crude product was dissolved in 10 mL of methylene chloride and treated with 2 mL of TFA for 1 hour.
  • Step 1 2-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-5,8-dihydro-6H- pyrido[3,4-d]pyhmidine-7-carboxylic acid tert-butyl ester
  • Step 2 Preparation of 1- ⁇ 4-[4-(8-Oxa-3-aza-bicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl]-phenyl ⁇ -3-pyridin-3-yl-urea
  • the title compound was prepared by following the procedure step 2 of Example 9 using 1-pyhdin-3-yl-3-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea and 2-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7- carboxylic acid tert-butyl ester.
  • Step 1 Preparation of (4-dimethylaminopiperidin-1 -yl)-(4-nitrophenyl)methanone Hydrochloride
  • Step 2 Preparation of (4-amino-phenyl)-(4-dimethylamino-piperidin-1-yl)- methanone
  • Step 3 Preparation of 1 -[4-(4-dimethylamino-piperidine-1-carbonyl)-phenyl]-3-[4- (4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea
  • 4-amino-phenyl)-(4-dimethylamino-pipehdin-1-yl)-methanone (0.59 g, 2.4 mmol)
  • 2-(4-isocyanato-phenyl)-4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolane (1 m 0.59 g, 2.4 mmol) in 30 mL of tetrahydrofuran was stirred at room temperature for 5 hours.
  • Step 4 Preparation of 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)-3- [4-(4-morpholin-4-yl- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl]urea
  • the title compound was prepared by following the procedure of Example 1 Step
  • Example 30 Preparation of N-tert-butyl-2- ⁇ 4-[(methylcarbamoyl)amino]phenyl ⁇ -4- (8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- carboxamide
  • Example 31 Preparation of 2- ⁇ 4-[(methylcarbamoyl)amino]phenyl ⁇ -4-(8-oxa-3- azabicyclo[S ⁇ .I]oct-3-yO-N-prop ⁇ -en-i-yl-5,8-dihydropyrido[S ⁇ -d]pyrimidine-
  • Example 4 Preparation of 1 -(4- ⁇ 7-[(2-methoxyphenyl)carbonyl]-4-( ⁇ -oxa-3- azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin ⁇ -y ⁇ phenyl)-3- methylurea
  • the following compounds were made using methods described above.
  • Example 49 Preparation of i- ⁇ -P-methyl ⁇ - ⁇ -oxa- ⁇ -azabicycloIS ⁇ .Iloct- ⁇ -yl)- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl ⁇ -3-pyridin-4-ylurea
  • Step 1 Preparation of 2-chloro-4-morpholin-4-yl-5,7-dihydro-pyrrolo[3,4- d]pyrimidine-6-carboxylic acid tert-butyl ester
  • 2,4-dichloro-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester 330 mg, 1.14mmol
  • morpholine 1 19 mg, 1.37 mmol
  • triethyl amine 167mg, 1 .65 mmol
  • Step 2 Preparation of 1-[4-(4-morpholin-4-yl-6, 7-dihydro-5H-pyrrolo[3,4- d]pyhmidin-2-yl)phenyl]-3- pyhdin-3-ylurea
  • Step 1 Preparation of 2-chloro-4- (8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,7- dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester
  • the title compound was prepared by following the procedure of Example 80
  • Step 2 Preparation of 1- ⁇ 4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-YL]phenyl ⁇ -3-pyridin-3-ylurea
  • Step 1 Preparation of 2-chloro-4- (3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,7- dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester
  • the title compound was prepared by following the procedure of Example 80 Step 1 using 2,4-dichloro-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert- butyl ester and 3-oxa-8-aza-bicyclo[3.2.1]octane, heating at 30 0 C overnight.
  • Step 2 Preparation of 1- ⁇ 4-[4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-yl]phenyl ⁇ -3-pyhdin-3-ylurea
  • the reaction buffer was 20 mM HEPES, pH 7.5, 2 mM MgCI 2 , 0.05% CHAPS; and 0.01 % ⁇ ME (added fresh).
  • the GST-GRP was 1 .75 mg/mL or 1.4 mg/mL in 10% glycerol.
  • the Red detector (TAMRA) was 2.5 ⁇ M.
  • PI3K assays Nunc 384-well black polypropylene fluorescent plates were used for PI3K assays. The assay is run by placing 5 ⁇ L of diluted enzyme per well, then 5 ⁇ L of diluted compound (or 9.5 ⁇ L enzyme then 0.5 ⁇ L compound in DMSO) is added and mixed. Then, 10 ⁇ L substrate is added to start the reaction. The samples are incubated 30-60 minutes, then the reaction is stopped by adding 20 ⁇ L stop/detector mix. PI3K is diluted with reaction buffer (e.g., 5 ⁇ L or 7.5 ⁇ L PI3K into 620 ⁇ L reaction buffer), and 5 ⁇ L of diluted enzyme is used per well.
  • reaction buffer e.g., 5 ⁇ L or 7.5 ⁇ L PI3K into 620 ⁇ L reaction buffer
  • reaction buffer or of drug diluted in buffer e.g., 4 ⁇ L/100 so final DMSO is 1 % in reaction
  • the enzyme can be diluted to 1215 ⁇ L. In this case 9.8 ⁇ L is added per well and 0.2 ⁇ L compound is added in DMSO.
  • reaction buffer 955 ⁇ L reaction buffer, 40 ⁇ L PIP2, and 2.5 ⁇ L ATP are mixed. 10 ⁇ L of substrate is added to each well to start the reaction. This results in 20 ⁇ M Pl P2, and 25 ⁇ M ATP per reaction.
  • the stop/detector mix is prepared by mixing 4 ⁇ L Red detector and 1.6 ⁇ L or 2.0 ⁇ L GST-GRP with 1 mL stop buffer, which results in 10 nM probe and 70 nM GST-GRP). 20 ⁇ L 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.
  • 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 ⁇ L per 20 ⁇ L (0.015 ⁇ g/20 ⁇ L) or 0.01 125 ⁇ g/15 ⁇ L or 0.75 ⁇ g/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.
  • Compounds of the invention had IC 50 S against PI3K-alpha ranging from 7 nM to 2,858 nM.
  • kinase reaction was initiated by adding 12.5 ⁇ L kinase assay buffer containing ATP and His6-S6K to give a final reaction volume of 25 ⁇ L containing 800 ng/mL FLAG-TOR, 100 ⁇ M ATP and 1.25 ⁇ M His6- S6K.
  • the reaction plate was incubated for 2 hours (linear at 1 -6 hours) at room temperature with gentle shaking and then terminated by adding 25 ⁇ L Stop buffer (20 mM HEPES (pH 7.4), 20 mM EDTA, 20 mM EGTA).
  • the DELFIA detection of the phosphorylated (Thr-389) His6-S6K was performed at room temperature using a monoclonal anti-P(T389)-p70S6K antibody (1A5, Cell Signaling) labeled with Europium- N1-ITC (Eu) (10.4 Eu per antibody, PerkinElmer).
  • the DELFIA Assay buffer and Enhancement solution were purchased from PerkinElmer.
  • 45 ⁇ L of the terminated kinase reaction mixture was transferred to a MaxiSorp plate (Nunc) containing 55 ⁇ L PBS.
  • the His6-S6K was allowed to attach for 2 hours after which the wells were aspirated and washed once with PBS.
  • 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 NaCI, 0.2 mM DTT, 50 mM ⁇ - glycerophosphate, 0.5 ⁇ M microcystin LR, 10 mM MnCI 2 ).
  • kinase reaction was initiated by adding 12.5 ⁇ L kinase assay buffer containing ATP and GST-p53 to give a final reaction volume of 25 ⁇ L containing 400-800 ng/mL FLAG-hSMG-1 , 0.5 ⁇ g GST-p53, 10 ⁇ M ATP. The reaction was carried out at room temperature for 1 .0 hour before terminated by addition of 25 ⁇ l stop solution. The assay mixture was then transferred to FluoroNunc Plates with MaxiSorp Surface (Nunc #439454).
  • the plates were incubated at room temperature for 2 hr (4 0 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 100 ⁇ l_ DELFIA assay buffer (PerkinElmer #1244-1 1 1 ). Plates were then washed and incubated for 0.5 hour with 100 ⁇ l 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.
  • the cell lines used were human prostate lines LNCap and PC3MM2, human breast lines MDA468 and MCF7, human renal line HTB44 (A498), human colon line HCT1 16, and human ovarian line OVCAR3. Cells were plated in 96-well culture plates.
  • the inhibitors were added to cells.
  • viable cell densities were determined by metabolic conversion (by viable cells) of the dye MTS, a well-established cell proliferation assay.
  • the assays were performed using an assay kit purchased from Promega Corp. (Madison, Wl) following the protocol supplied with the kit.
  • the MTS assay results were read in a 96-well plate reader by measuring absorbance at 490 nm. The effect of each treatment was calculated as percent of control growth relative to the vehicle-treated cells grown in the same culture plate.
  • the drug concentration that conferred 50% inhibition of growth was determined as IC50.
  • Compounds of the invention had IC50 activities against LNCap cells ranging from 6 nM to >60 uM.
  • Tables 1 and 2 show the results of the described biological assays.

Abstract

A compound of the Formula I: or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein, compositions comprising the compounds, and methods for making and using the compounds.

Description

5,6,7,8-TETRAHYDROPYRIDO[3,4-D]PYRIMIDINE COMPOUNDS, THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES
FIELD OF THE INVENTION The invention relates to 5,6,7,8-tetrahydropyhdo[3,4-d]pyrimidine compounds and their ring homologues, compositions comprising such a compound, methods of synthesizing such compounds, and methods for treating mTOR-related diseases comprising the administration of an effective amount of such a compound. The invention relates to methods for treating PI3K-related diseases comprising the administration of an effective amount of such a compound. The invention also relates to methods for treating hSMG-1 -related diseases comprising the administration of an effective amount of such a compound.
BACKGROUND OF THE INVENTION
Phosphatidylinositol (hereinafter abbreviated as "Pl") is one of the phospholipids in cell membranes. In recent years it has become clear that Pl plays an important role also in intracellular signal transduction. It is well recognized in the art that Pl (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. Berhdge et al., Nature, 312, 315 (1984); Y. Nishizuka, Science, 225, 1365 (1984)].
In the late 1980s, phosphatidylinositol-3 kinase ("PI3K") was found to be an enzyme that phosphorylates the 3-position of the inositol ring of phosphatidylinositol [D. Whitman et al., Nature, 332, 664 (1988)]. When PI3K was discovered, it was originally considered to be a single enzyme. Recently however, it was clarified that a plurality of PI3K subtypes exists. 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 II, 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 (α, β, & δ) that exist as hetero dimers of a catalytic 1 10-kDa subunit and regulatory subunits of 50-85kDa. 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- thsphosphate) 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 α isoform) has become a major therapeutic target in cancer drug discovery. Substrates for class I PI3Ks are Pl, 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 p1 10γ that is activated by interaction with G protein-coupled receptors. Interaction between p1 10γ and G protein-coupled receptors is mediated by regulatory subunits of 1 10, 87, and 84 kDa.
Pl and PI(4)P are the known substrates for class Il PI3Ks; PI(4,5)P2 is not a substrate for the enzymes of this class. Class Il 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 Pl 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 PM 03 (3-(4-(4-morpholinyl)pyhdo[3',2':4,5]furo[3,2-d]pyrimidin-2- yl)phenol) inhibits PI3Kα and PI3Kγ as well as the mTOR enzymes with IC5O 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 1 16); 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-thazine) inhibits PI3Kα and PI3Kγ 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-1 H-imidazo[4,5-c]quinolin-1 -yl)phenyl)propanenithle) inhibits both PI3Kα and PI3Kγ 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-1 126 (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. It began clinical trials in April, 2007 for the solid tumors endometrial, renal cell, breast, hormone refractory prostate and ovarian cancers. (Verheijen, J. C. and Zask, A., Phosphatidylinositol 3-kinase (PI3K) inhibitors as anticancer drugs, Drugs Fut. 2007, 32(6): 537-547).
Exelixis Inc. (So. San Francisco, CA) recently filed INDs for XL-147 (a selective pan-PI3K inhibitor of unknown structure) and XL-765 (a mixed inhibitor of mTOR and PI3K of unknown structure) as anticancer agents. TargeGen's short-acting mixed inhibitor of PI3Kγ and δ, TG-1001 15, is in phase I/I I trials for treatment of infarct following myocardial ischemia-reperfusion injury. Cerylid's antithrombotic PI3Kβ inhibitor CBL-1309 (structure unknown) has completed preclinical toxicology studies.
According to 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 α 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 Y) 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. The complete functions of the mTOR kinase and the effects of mTOR inhibition are not completely understood.
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 42-0-(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), 1 149-1 155, 2006]. On March 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.
The most recently described PI3K family member was identified in human cells and named human SMG-1 or hSMG-1. Yamashita (Genes Dev. 2001 15: 2215-2228) characterized two isoforms of hSMG-1 proteins, p430 and p400, which are expressed in various cell lines of human, monkey, rat, and mouse. Yamashita's p400 hSMG-1 isoform is a 3529-amino-acid protein of 396,040 Daltons. Brumbaugh (Molecular Cell, Volume 14, Issue 5, 4 June 2004, Pages 585-598) isolated a 3521 amino acid polypeptide with a deduced molecular mass of 395 kDa. Brumbaugh's hSMG-1 is eight amino acids shorter at the amino terminus than the protein isolated by Yamashita.
Both hllpfl and p53 are physiological targets for hSMG-1 in intact cells. Rapamycin in the presence of purified recombinant FKBP12 does not inhibit the kinase activity of hSMG-1. Wortmannin, the modified steroidal anti-infective agent, and the purine caffeine inhibit the kinase activity of hSMG-1 with IC50 values of -60 nM and 0.3 mM, respectively. However, these are non-specific protein kinase inhibitors.
Specific inhibition of hSMG-1 is a potential therapeutic strategy because inhibitors of hSMG-1 cause the accumulation of truncated p53 proteins from a premature translation termination codon (PTC) allele, as well as the increase in the level of mRNA with PTC, opening the possibility of the above strategy by specifically suppressing nonsense-mediated mRNA decay (NMD) through the inhibition of hSMG-1.
One-fourth of all mutations in human genetic diseases and cancers are of the type that can target the corresponding mRNA for NMD. Although NMD protects cells against deleterious gain-of-function mutations caused by the dominant negative effects of aberrant truncated proteins, there are some cases in which the truncated protein does not show such an effect, rather, it retains residual activity and can compensate for the normal gene function. Thus, the specific inhibition of NMD may provide a novel therapeutic strategy based on the type of mutation rather than on the gene in which the mutation resides. The inhibitors of SMG-1 can rescue the synthesis of mature proteins through two independent mechanisms (i.e., the inhibition of NMD to increase the mRNA level and the suppression of translational termination that leads to the synthesis of a read-through mature protein product). In this sense, the specific inhibitors of hSMG-1 will be of potential therapeutic importance for all the genetic diseases associated with PTC mutations.
As explained above, PI3K inhibitors, mTOR inhibitors, and hSMG-1 inhibitors are expected to be novel types of medicaments useful against cell proliferation disorders, especially as carcinostatic agents. Thus, it would be advantageous to have new PI3K inhibitors, mTOR inhibitors, and hSMG-1 inhibitors as potential treatment regimens for mTOR-, PI3K-, and hSMG-1 -related diseases. The instant invention is directed to these and other important ends.
SUMMARY OF THE INVENTION
In one aspect, the invention provides compounds of the Formula I:
Figure imgf000009_0001
or a geometric isomer there of or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined below. In other aspects, the invention provides compositions comprising a compound of the invention, and methods for making compounds of the invention. In further aspects, the invention provides methods for inhibiting PI3K, mTOR and hSMG-1 in a subject, and methods for treating PI3K-related, mTOR-related and hSMG-1 -related disorders in a mammal in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the invention provides compounds of the Formula I:
Figure imgf000010_0001
or a geometric isomer thereof or a pharmaceutically acceptable salt thereof wherein; R1 is independently C-i-Cδalkyl-, C6-C-ι4aryl-, d-Cgheteroaryl-, halogen, or hydroxyl; p is 0, 1 , 2, 3, or 4; het is a d-Cgheterocyclyl- group containing at least one oxygen atom; m is 0 or 1 ;
Ar is C6-C-ι4aryl- or CrC9heteroaryl- wherein the C6-C-ι4aryl- or d-Cgheteroaryl- is optionally substituted with from 1 to 4 substituents independently selected from d- C6alkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl(CrC6alkyl)-, H2N-, aminoalkyl-, di(d- C6alkyl)amino-, HO2C-, (d-CδalkoxyJcarbonyl-, (d-Cealky^carboxyl-, di(d- C6alkyl)amido-, H2NC(O)-, (Ci-C6alkyl)amido-, and O2N-; R2 is H or CrC6alkyl-; R3 is R6, R7R8N-, R9S-, or R9O-
R6 is H; CrCδalkyl- optionally substituted with from 1 to 3 substituents independently selected from d-Cδalkoxy-, H2N-, (Ci-C6alkyl)amino-, di(d- C6alkyl)amino-, C6-Ci4aryl-, d-Cgheterocyclyl- optionally substituted by CrC6alkyl-, and d-Cgheteroaryl-; Ci-C6alkoxy-; Ci-Cgheteroaryl- optionally substituted with from 1 to 3 substituents independently selected from Ci-C6alkyl- optionally substituted with H2N-, (Ci-C6alkyl)amino-, or di(d-C6alkyl)amino-, heterocyclyl(d-C6alkyl)-, halogen, hydroxyl, H2N-, O2N-, H2NSO2-, HO2C-, (CrC6alkoxy)carbonyl-, (CrC6alkoxy)C(0)NH-, (Ci-C6alkyl)amino-, di(d-C6alkyl)amino-, R10R11NC(O)-, R10O-, R10R11N-, R10R11NS(O)2-, R10S(O)2NR11-, R10R11NC(O)NH-, R10S-, R10S(O)-, R10S(O)2-, R10C(O)-, d-Cgheterocyclyl- optionally substituted by CrC6alkyl- or C-i-Cehydroxylalkyl-, d- Cδhydroxylalkyl-, and perfluoro(Ci-C6)alkyl-; d-Cδhydroxylalkyl-; d-Cgheterocyclyl-; Ce- Ci4aryl- optionally substituted with from 1 to 3 substituents independently selected from C-i-Cδalkyl- optionally substituted with H2N-, (Ci-C6alkyl)amino-, or di(Ci-C6alkyl)amino-, heterocyclyl(Ci-C6alkyl)-, halogen, hydroxyl, H2N-, O2N-, H2NSO2-, HO2C-, (d- C6alkoxy)carbonyl-, (CrC6alkoxy)C(0)NH-, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, R10R11NC(O)-, Z, wherein Z is R10O-, R10R11N-, R10R11NS(O)2-, R10S(O)2NR11-, R10R11NC(O)NH-, R10S-, R10S(O)-, R10S(O)2-, R10C(O)-, Ci-Cgheterocyclyl- optionally substituted by C-i-Cδalkyl- or C-i-Cδhydroxylalkyl-, d-Cδhydroxylalkyl-, and perfluoro(d- C6)alkyl-; or Cs-Cscycloalkyl-;
R10 and R11 are each independently H, CrCδalkyl-, Ci-C6alkoxy(C2-C6alkylene)-, (Ci-C6alkyl)amino-C2-C6alkylene-, di(Ci-C6alkyl)amino-C2-C6alkylene-, C2-C6alkenyl, C2-C6alkynyl, C6-Ci4aryl-, (C6-Ci4aryl)alkyl-, drCscycloalkyl-, Ci-Cgheteroaryl-, (d- Cgheteroaryl)alkyl-, Ci-Cgheterocyclyl-, or heterocyclyl(Ci-C6alkyl-); or R10 and R11, when taken together with the nitrogen to which they are attached, form a 3- to 7- membered heterocycle wherein up to two of the carbon atoms of the heterocycle are optionally replaced with -N(H)-, -N(d-C6alkyl)-, -N(C3-C8CyClOaIkYl)-, - N(C6-Ci4aryl)-, -N(Ci-Cgheteroaryl)-, -S-, -SO-, -S(O)2-, or -O- and wherein any carbon atom of the heterocycle is optionally substituted with from 1 or 2 substituents independently selected from CrC6alkyl-, H2N-, (d-C6alkyl)amino-, di(d-C6alkyl)amino- , and Ci-Cgheterocyclyl-;
R7 and R8 are each independently H; CrCδalkyl- optionally substituted with from 1 to 3 substituents independently selected from Ci-Cεalkoxy-, H2N-, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, halogen, C6-d4aryl-, Ci-Cgheterocyclyl- optionally substituted by Ci-C6alkyl-, and Ci-Cgheteroaryl-; Ci-C6alkoxy-; Ci-Cgheteroaryl- optionally substituted with from 1 to 3 substituents independently selected from CrCδalkyl- optionally substituted with H2N-, (d-C6alkyl)amino-, or di(d-C6alkyl)amino-, heterocyclyl(Ci- Cεalkyl)- optionally substituted with d-Cβalkyl, halogen, hydroxyl, H2N-, O2N-, H2NSO2-, HO2C-, (Ci-C6alkoxy)carbonyl-, (CrC6alkoxy)C(0)NH-, (d-C6alkyl)amino-, CIi(C1- C6alkyl)amino-, R10R11NC(O)-, R10O-, R10R11N-, R10R11NS(O)2-, R10S(O)2NR11-, R10R11NC(O)NH-, R10S-, R10S(O)-, R10S(O)2-, R10C(O)-, Ci-Cgheterocyclyl- optionally substituted by Ci-C6alkyl- or d-Cδhydroxylalkyl-, d-Cδhydroxylalkyl-, and perfluoro(d- C6)alkyl-; Ci-Cehydroxylalkyl-; Ci-Cgheterocyclyl-; C6-d4aryl- optionally substituted with from 1 to 3 substituents independently selected from Ci-C6alkyl- optionally substituted with H2N-, (C-i-C6alkyl)amino-, or di(C-i-C6alkyl)amino-, heterocyclyl(C-i-C6alkyl)- optionally substituted with CrC6alkyl, halogen, hydroxyl, H2N-, O2N-, H2NSO2-, HO2C-, (CrC6alkoxy)carbonyl-, (Ci-C6alkoxy)C(0)NH-, (CrC6alkyl)amino-, di(Cr C6alkyl)amino-, R10R11NC(O)-, Z, wherein Z is R10O-, R10R11N-, R10R11NS(O)2-, R10S(O)2NR11-, R10R11NC(O)NH-, R10S-, R10S(O)-, R10S(O)2-, R10C(O)-, Cr Cgheterocyclyl- optionally substituted by C-i-Cδalkyl- or Ci-Cδhydroxylalkyl-, Ci- C6hydroxylalkyl-, and perfluoro(Ci-C6)alkyl-; and C3-C8CyClOaIkVl-; or R7 and R8, when taken together with the nitrogen to which they are attached, form a 3- to 7- membered heterocycle wherein up to two of the carbon atoms of the heterocycle are optionally replaced with -N(H)-, -N(Ci-C6alkyl)-, -N(C6-C-ι4aryl)-, -S-, - SO-, -S(O)2-, or -0-;
R9 is Ci-Cδalkyl-, C6-C-ι4aryl-, (C6-C-ι4aryl)alkyl- optionally substituted by H2N-, C-i-Cgheterocyclyl-, C3-C8CyClOaIkVl-, CrCδhydroxylalkyl-, or C-i-Ceperfluoroalkyl-; n is O, 1 , or 2; R4 is: a) hydrogen; b) C-i-Csacyl-, optionally substituted with from 1 to 3 substituents independently selected from: i) C-i-Cδalkoxy-, ϋ) (Ci-C6)alkyl-, iii) (Ci-C6alkyl)amino-, iv) C3-C8CVClOaIkVl-, v) di(Ci-C6alkyl)amino-, vi) halogen, vii) Ci-C6perfluoroalkyl-, viii) H2N-, ix) and CF3O-;
I- optionally substituted with frx Om: i) C-ι-C6alkoxy-, ϋ) (Ci-C6alkoxy)carbonyl-, iii) (Ci-C6alkyl)amino-, iv) di(Ci-C6alkyl)amino-, v) C3-C8cycloalkyl-, vi) halogen, vii) HC(O)-, viii) HO2C-, ix) and H2N-; d) C-i-Ceaminoalkyl- optionally substituted with a substituent selected from: i) C6-Ci4aryl- optionally substituted with halogen, ii) (Ci-Cgheteroaryl)alkyl-, iii) (C6-Ci4aryl)alkyl-, iv) H2N-Ci-C6alkylene-, v) (Ci-C6alkyl)amino-Ci-C6alkylene-, vi) and di(Ci-C6alkyl)amino-Ci-C6alkylene-; e) Cs-Cscycloalkyl-; f) C6-Ci4aryl- optionally substituted with a substituent selected from: i) HO2C-, ii) d-Cehydroxylalkyl-, iii) R12Ri3NC(O)-, iv) and (Ci-C6alkoxy)carbonyl-; g) C-i-Cgheterocycle optionally substituted with from 1 to 3 substituents independently selected from: i) d-Cβacyl, wherein the d-Csacyl is optionally substituted with H2N-, ii) Ci-C6alkyl-, iii) (Ci-Cgheteroaryl)alkyl- wherein the ring portion of the (Cr Cgheteroaryl)alkyl- group is optionally substituted with from 1 to 3 substituents independently selected from:
A) CrC6alkylC(O)NH-, B) halogen,
C) H2N-,
D) and CrC6alkyl-, iv) heterocyclyl(CrC6alkyl)-, wherein the ring portion of the heterocyclyl(Ci-C6alkyl) group is optionally substituted by a (Cε- C14aryl)alkyl-, v) (C6-Ci4aryl)alkyl-, wherein the ring portion of the (C6- Ci4aryl)alkyl- group is optionally substituted by 1 to 3 substituents independently selected from:
A) halogen, B) Ci-C6alkyh
C) di(Ci-C6alkyl)amino-(CrC6alkylene)-0-,
D) and d-Cgheteroaryl-; vi) and (Ci-C6alkoxy)carbonyl-; h) heterocyclyl(CrC6alkyl) optionally substituted with a substituent selected from: i) Ci-C6alkyl-, ii) Cs-Cscycloalkyh iii) (C-i-C6alkoxy)carbonyl-, iv) C-i-Cδalkylcarboxy-, v) (C6-C-ι4aryl)alkyl- wherein the ring portion of the (Cε- C-ι4aryl)alkyl- group is optionally substituted with a substituent selected from: A) halogen,
B) d-Cgheteroaryl-,
C) and di(Ci-C6alkyl)amino-(Ci-C6alkylene)-0-, vi) (Ci-Cgheteroaryl)alkyl- wherein the ring portion of the (Cr C9heteroaryl)alkyl- group is optionally substituted by a halogen, vii) and d-Csacyl, wherein the d-Csacyl is optionally substituted with from 1 to 3 independently selected halogens, i) (d-Cgheteroaryl)alkyl- wherein the ring portion of the (d-Cgheteroaryl)alkyl- is optionally substituted by 1 to 3 substituents independently selected from: i) R12R13NC(O)NH-, ii) (Ci-C6alkoxy)carbonyl-, iii) HO2C-, iv) hydroxyl, v) and R12R13NC(O)-; j) (C6-C-ι4aryl)alkyl- wherein the ring portion of the (C6-d4aryl)alkyl- group is optionally by 1 to 3 substituents independently selected from:
A) R12R13NC(O)NH-,
B) (Ci-C6alkoxy)carbonyl-,
C) HO2C-,
D) hydroxyl, E) and R12R13NC(O)-; k) d-Cδhydroxylalkyl-;
I) Ci-Ceperfluoroalkyl-; m) d-Cgheteroaryl- optionally substituted with a substituent selected from:
A) HO2C-, B) d-Cehydroxylalkyl-,
C) R12R13NC(O)-,
D) and (d-C6alkoxy)carbonyl-; n) R12R13NC(O)-; o) R14OC(O)-, p) and R14S(O)2-;
R12 and R13 are each independently: a) H; b) C1 -C6alkyl- optionally substituted with a substituent selected from: i) CrC6alkylC(O)NH-, ii) H2N-, iii) (Ci-C6alkyl)amino-, iv) and di(Ci-C6alkyl)amino-, c) C2-C6alkenyl- d) Cs-Cscycloalkyl-; e) C6-C-ι4aryl- optionally substituted with a substituent selected from: i) halogen, ii) and d-Cgheterocycle wherein the d-Cgheterocycle is optionally substituted with (CrC6alkoxy)carbonyl-; f) d-Cgheteroaryl-; g) (d-Cgheteroaryl)alkyl-; h) heterocyclyl(Ci-C6alkyl)-; i) (C6-C-ι4aryl)alkyl-, wherein the chain portion of the (C6-C-ι4aryl)alkyl- group is optionally substituted by a hydroxyl; j) or C-i-Cgheterocyclyl- optionally substituted with a (Ci-C6alkoxy)carbonyl-; or R12 and R13, when taken together with the nitrogen to which they are attached, form a 3- to 7- membered heterocycle wherein up to two of the carbon atoms of the heterocycle are optionally replaced with -N(H)-, -N(CrC6alkyl)-, -N(C6-Ci4aryl)-, -S-, - SO-, -S(O)2-, or -O-; R14 is Ci-C6alkyl-, C6-Ci4aryl-, (C6-Ci4aryl)alkyl-, d-Cgheterocyclyl-, C3-
Cscycloalkyl-, d-Cδhydroxylalkyl-, or CrCδperfluoroalkyl-, wherein each Ci-C6alkyl-, C6-Ci4aryl-, (C6-d4aryl)alkyl-, d-Cgheterocyclyl-, or drCscycloalkyl-, is optionally substituted with a Ci-C6alkoxy-, Ci-C6alkyl-, C3-C8cycloalkyl-, NC-, or halogen; R5 are independently H or d-Cβalkyl.
In one aspect, the invention provides compounds of the Formula II:
Figure imgf000016_0001
or a geometric isomer thereof or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined for Formula I.
In one aspect, the invention provides compounds of the Formula III:
Figure imgf000016_0002
or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined above for Formula II. In one aspect, the invention provides compounds of the Formula IV:
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined above for Formula II. In one aspect, the invention provides compounds of the Formula V:
Figure imgf000017_0002
or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined above for Formula II. In one aspect, the invention provides compounds of the Formula Vl:
Figure imgf000018_0001
or a geometric isomer thereof or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined above for Formula I. In one aspect, the invention provides compounds of the Formula VII:
Figure imgf000018_0002
or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined above for Formula Vl. In one aspect, the invention provides compounds of the Formula VIII:
Figure imgf000019_0001
or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined above for Formula Vl. In one aspect, the invention provides compounds of the Formula IX:
Figure imgf000019_0002
or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined above for Formula Vl. In one embodiment, R2 is H.
In one embodiment, R3 is R7R8N-.
In one embodiment, R7 is C-i-Cgheteroaryk
In one embodiment, R7 is pyridyl. In one embodiment, R7 is 3- or 4-pyridyl.
In one embodiment, R8 is H.
In one embodiment, R4 is R14S(O)2-.
In one embodiment, R14 is Ci-Cδalkyl-.
In one embodiment, R14 is CH3-. Illustrative compounds of the present Formula III are set forth below:
1-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyhmidin-2-yl)phenyl]-3-pyridin-3- ylurea;
^^-(/-acetyl^-morpholin^-yl-δ^J^-tetrahydropyhdoP^-dlpyrimidin^-yOphenyll-S- pyridin-3-ylurea; 1 -{4-[7-(methylsulfonyl)-4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyrimidin-2- yl]phenyl}-3-pyhdin-3-ylurea;
1-{4-[4-morpholin-4-yl-7-(3,3,3-thfluoropropanoyl)-5,6,7,8-tetrahydropyrido[3,4- d]pyhmidin-2-yl]phenyl}-3-pyhdin-3-ylurea;
1-[4-(7-methyl-4-morpholin-4-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyhmidin-2-yl)phenyl]-3- pyridin-3-ylurea;
1-methyl-3-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4- d]pyhmidin-2-yl]phenyl}urea;
1-methyl-3-[4-(7-methyl-4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyrimidin-2- yl)phenyl]urea; 1-methyl-3-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyrimidin-2- yl)phenyl]urea;
1-(4-{[4-(dimethylamino)pipehdin-1 -yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-5, 6,7,8- tetrahydropyhdo[3,4-d]pyhmidin-2-yl)phenyl]urea and; and
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[7-(methylsulfonyl)-4- morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyhmidin-2-yl]phenyl}urea.
Illustrative compounds of the present Formula IV are set forth below:
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2- yl]phenyl}-3-pyhdin-3-ylurea;
1-{4-[7-(methylsulfonyl)-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyhdo[3,4-d]pyhmidin-2-yl]phenyl}-3-pyhdin-3-ylurea; 1-{4-[7-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyπrnidin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}urea; 1-methyl-3-{4-[7-(methylsulfonyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}urea;
1-methyl-3-{4-[7-methyl-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}urea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[4-(8-oxa-3- azabicyclotS^.iloct-S-yO-S^J^-tetrahydropyridotS^-dlpyrimidin^-yOpheny^urea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[7-(methylsulfonyl)-4-(8- oxa-3-azabicyclo[3.2.1]oct-3-yl)-5A7,8-tetrahydropyrido[3,4-d]pyrimidin-2- yl]phenyl}urea; butyl 2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,8- dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate;
2-methylpropyl 2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1]oct-
3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate;
N-butyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,8- dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxarnide; N-tert-butyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-
5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxarnide;
2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-N-prop-2- en-1-yl-5,8-dihydropyrido[3,4-d]pyrirnidine-7(6H)-carboxarnide;
N-hexyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)- 5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide;
N-cyclohexyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1]oct-3- yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide;
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-7-(phenylsulfonyl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}urea; 1-(4-{7-[(4-fluorophenyl)sulfonyl]-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl}phenyl)-3-methylurea;
1-(4-{7-[(4-cyanophenyl)sulfonyl]-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl}phenyl)-3-methylurea;
N,N-dimethyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3- yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-sulfonamide; 1-(4-{7-[(4-chlorophenyl)sulfonyl]-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl}phenyl)-3-methylurea;
1-{4-[7-(methoxyacetyl)-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-methylurea; 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-7-pentanoyl-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}urea;
1-{4-[7-heptanoyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}-3-methylurea;
1-{4-[7-(2,2-dimethylpropanoyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-methylurea;
1-{4-[7-(2-ethylhexanoyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-methylurea;
1-{4-[7-(3-cyclopentylpropanoyl)-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-methylurea; 1-(4-{7-[(2,6-difluorophenyl)carbonyl]-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl}phenyl)-3-methylurea;
1-(4-{7-[(2-fluorophenyl)carbonyl]-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl}phenyl)-3-methylurea;
1-(4-{7-[(4-tert-butylphenyl)carbonyl]-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl}phenyl)-3-methylurea; and
1-(4-{7-[(2-methoxyphenyl)carbonyl]-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl}phenyl)-3-methylurea.
Illustrative compounds of the present Formula V are set forth below: i^-μ^S-oxa-δ-azabicycloP^.iloct-δ-yO-S^J^-tetrahydropyhdoP^-dlpyhmidin^- yl]phenyl}-3-pyhdin-3-ylurea;
1-methyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyhmidin-2-yl]phenyl}urea;
1-{4-[7-methyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyhmidin-2-yl]phenyl}-3-pyhdin-3-ylurea; 1-{4-[7-(methylsulfonyl)-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8- tetrahydropyhdo[3,4-d]pyhmidin-2-yl]phenyl}-3-pyhdin-3-ylurea;
1-methyl-3-{4-[7-methyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8- tetrahydropyhdo[3,4-d]pyhmidin-2-yl]phenyl}urea;
1-methyl-3-{4-[7-(methylsulfonyl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8- tetrahydropyhdo[3,4-d]pyhmidin-2-yl]phenyl}urea; 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8- azabicycloP^.iloct-δ-yO-S^J^-tetrahydropyridoP^-dlpyrirnidin^-yllphenylϊurea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[7-(methylsulfonyl)-4-(3- oxa-8-azabicyclo[3.2.1]oct-8-yl)-5A7,8-tetrahydropyrido[3,4-d]pyrimidin-2- yl]phenyl}urea;
1-{4-[7-methyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[7-(N,N-dimethylglycyl)-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-pyndin-4-ylurea; 7,7-bis(2-fluoroethyl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-2-{4-[(pyridin-4- ylcarbamoyl)arnino]phenyl}-5,6,7,8-tetrahydropyrido[3,4-d]pyπrnidin-7-iurn trifluoroacetate; methyl 4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-2-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-
5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate; 1-{4-[7-(1-methylethyl)-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-pyndin-4-ylurea;
1-{4-[7-ethyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[7-(2-fluoroethyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}-3-pyridin-4-ylurea; tert-butyl 4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-{4-[(pyridin-4- yl carbamoyl )amino]phenyl}-5,8-dihydropyrido[3,4-d]pyrirnidine-7(6H)-carboxylate;
1-{4-[7-(2-methoxyethyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-pyndin-4-ylurea; 1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}-3-(2-fluoroethyl)urea;
1-cyclopropyl-3-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}urea;
1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}-3-phenylurea;
1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1 -yl)phenyl]urea;
1-{4-[7-(1-methylethyl)-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-pyndin-4-ylurea; 1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyπmidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;
1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}-3-[4-(pyrrolidin-1-ylmethyl)phenyl]urea; 1 -{4-[4-(dimethylamino)piperidin-1 -yl]phenyl}-3-{4-[7-ethyl-4-(3-oxa-8- azabicyclotS^.iloct-δ-yO-S^J^-tetrahydropyridotS^-dlpyrirnidin^-yllphenylϊurea;
1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1 -yl)carbonyl]phenyl}urea;
1-{4-[(dimethylamino)methyl]phenyl}-3-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}urea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-7-(2,2,2- trifluoroethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pynrnidin-2-yl]phenyl}urea; 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-7-(2,2,2-trifluoroethyl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyπmidin-2-yl]phenyl}carbamoyl)amino]-N,N-dimethylbenzamide;
1-(4-cyanophenyl)-3-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}urea;
1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}-3-[4-(trifluoromethyl)phenyl]urea;
1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}-3-[4-(pyrrolidin-1-ylcarbonyl)phenyl]urea; 4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}carbamoyl)amino]benzoic acid; methyl 4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}carbamoyl)amino]benzoate;
4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}carbamoyl)amino]-N-(1-methylethyl)benzamide;
4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}carbamoyl)arnino]-N-methylbenzarnide; and
4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}carbamoyl)amino]benzarnide. Illustrative compounds of the present Formula VII are set forth below: 1-[4-(4-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[3,4-d]pyπmidin-2-yl)phenyl]-3-pyπdin-3- ylurea;
1-methyl-3-[4-(4-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl]urea;
1-(4-{[4-(dimethylarnino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6,7- dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl]urea;
1-{4-[6-(methylsulfonyl)-4-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2- yl]phenyl}-3-pyridin-3-ylurea;
1-methyl-3-{4-[6-(methylsulfonyl)-4-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidin-2-yl]phenyl}urea; and 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[6-(methylsulfonyl)-4- morpholin-4-yl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrirnidin-2-yl]phenyl}urea.
Illustrative compounds of the present Formula VIII are set forth below: i^-^β-oxa-a-azabicyclop^.iloct-a-ylJ-βJ-dihydro-δH-pyrroloPΛ-dlpyrimidin^- yl]phenyl}-3-pyhdin-3-ylurea; 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyhmidin-2-yl]phenyl}urea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[4-(8-oxa-3- azabicyclotS^.iloct-S-yO-ej-dihydro-SH-pyrroloP^-dlpyhmidin^-yllpheny^urea;
1-{4-[6-(methylsulfonyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyhmidin-2-yl]phenyl}-3-pyhdin-3-ylurea; and
1-methyl-3-{4-[6-(methylsulfonyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}urea.
Illustrative compounds of the present Formula IX are set forth below: i^-^a-oxa-β-azabicyclop^.iloct-β-ylJ-βJ-dihydro-δH-pyrroloPΛ-dlpyrimidin^- yl]phenyl}-3-pyhdin-3-ylurea;
1-methyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyhmidin-2-yl]phenyl}urea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8- azabicyclotS^.iloct-δ-yO-δJ-dihydro-δH-pyrrolotS^-dlpyhmidin^-yllphenylϊurea; 1-{4-[6-(methylsulfonyl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyhmidin-2-yl]phenyl}-3-pyhdin-3-ylurea;
1-methyl-3-{4-[6-(methylsulfonyl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}urea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[6-(methylsulfonyl)-4-(3- oxa-8-azabicyclotS^.iloct-δ-yO-δJ-dihydro-5H-pyrrolotS^-dlpyhmidin^-yOphenylϊurea; 1-methyl-3-{4-[6-methyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}urea;
1-{4-[6-methyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyrirnidin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[6-methyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyrirnidin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[6-methyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyrirnidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1 -yl)phenyl]urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[6-methyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8- yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2- yl]phenyl}urea; and
2-hydroxyethyl {4-[6-methyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}carbamate.
In other aspects, the invention provides pharmaceutical compositions comprising compounds or pharmaceutically acceptable salts of the compounds of the present Formula I and a pharmaceutically acceptable carrier.
In other aspects, the invention provides a 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, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopuhne, 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, leucovohn, levamisole, ihnotecan, 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, lavendustin A, hydroxyzine, glatiramer acetate, interferon beta-1 a, interferon beta-1 b, and 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 an hSMG-1 -related disorder, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat an 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 the compounds or a pharmaceutically acceptable salt of the compounds of the present 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 the compounds or a pharmaceutically acceptable salt of the compounds of any of the present 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 the compounds or a pharmaceutically acceptable salt of the compounds of any of the present 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 the compounds or a pharmaceutically acceptable salt of the compounds of any of the present 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, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopuhne, 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, leucovohn, levamisole, ihnotecan, 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 other aspects, the invention provides a method of synthesizing a compound of
Formula 16:
Figure imgf000029_0001
comprising reacting a fused pyrimidine compound of the formula 14:
Figure imgf000029_0002
with a dioxaborolan-2-yl compound 15:
Figure imgf000029_0003
to give 16 wherein PG is an amine-protecting group, X is independently a leaving group, and the remaining variables are as defined for Formula I.
In other aspects, the invention provides a method of synthesizing a compound of Formula I further comprising: a) when NHR2 is present, reacting compound 16 with an acylating agent R3C(O)X, wherein R3 is as defined for Formula I to give 17:
Figure imgf000030_0001
b) removing the amine-protecting group from 17 to give 18:
Figure imgf000030_0002
c) optionally reacting 18 with R4X, wherein R4 is as defined in Formula I to give I:
Figure imgf000030_0003
or a geometric isomer there of or a pharmaceutically acceptable salt thereof.
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 (N1N'- 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, methyl nitrate, 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-1 H-purine-2,6-dione), thethiodide, tromethamine (2-amino-2-(hydroxymethyl)-1 ,3-propanediol), valerate, zinc salts, and 2- fluoroethyl quaternary ammonium thfluoroacetates.
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, diastereomehc, 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. An "effective amount" when used in connection a compound of the present invention of this invention is an amount effective for inhibiting mTOR or PI3K in a subject.
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 "CrCδ" 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.
"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 d-Csacyl- 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-, (CrC6alkyl)amino-, di(CrC6alkyl)amino-, (CrC6alkyl)C(O)N(Ci-C3alkyl)-, (CrC6alkyl)carboxyamido-, HC(O)NH-, H2NC(O)-, (Cr C6alkyl)NHC(O)-, di(CrC6alkyl)NC(O)-, -CN, hydroxyl, CrC6alkoxy-, CrC6alkyl-, HO2C- , (C-i-CealkoxyJcarbonyl-, (CrC6alkyl)C(O)-, C6-Ci4aryl-, CrC9heteroaryl-, or C3- Cscycloalkyl-.
"Alkenyl-" refer to a straight or branched chain unsaturated hydrocarbon containing at least one double bond. Examples of a C2-Cioalkenyl- 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, 4-octene, 1-nonene, 2- nonene, 3-nonene, 4-nonene, 1 -decene, 2-decene, 3-decene, 4-decene and 5-decene. An alkenyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H2N-, (CrC6alkyl)amino-, di(CrC6alkyl)amino-, (Ci-C6alkyl)C(O)N(Cr C3alkyl)-, (CrC6alkyl)carboxyamido-, HC(O)NH-, H2NC(O)-, (CrC6alkyl)NHC(O)-, di(Cr C6alkyl)NC(O)-, NC-, hydroxyl, CrC6alkoxy-, CrC6alkyl-, HO2C-, (Cr C6alkoxy)carbonyl-, (Ci-C6alkyl)C(O)-, C6-Ci4aryl-, d-Cgheteroaryl-, and C3- Cscycloalkyl-.
"Alkoxy-" refers to the group R-O- where R is an alkyl group, as defined below. Exemplary C-i-Cδalkoxy- 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-i-Cδalkoxy-, H2N-, (Ci-C6alkyl)amino-, di(CrC6alkyl)amino-, (CrC6alkyl)C(O)N(Ci-C3alkyl)-, (Cr C6alkyl)carboxyamido-, HC(O)NH-, H2NC(O)-, (CrC6alkyl)NHC(O)-, di(Cr C6alkyl)NC(O)-, NC-, CrC6alkoxy-, HO2C-, (Ci-Cealkoxyjcarbonyl-, (CrC6alkyl)C(O)-, C6-Ci4aryl-, d-Cgheteroaryl-, Cs-Cscycloalkyl-, C-i-Cδhaloalkyl-, CrCδaminoalkyl-, (Cr C6alkyl)carboxyl-, C-i-Cecarboxyamidoalkyl-, or O2N-. "(Alkoxy)carbonyl-" refers to the group alkyl-O-C(O)-. Exemplary (Cr 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-, (Cr C6alkyl)amino-, di(CrC6alkyl)amino-, (CrC6alkyl)C(O)N(Ci-C3alkyl)-, (Cr C6alkyl)carboxyamido-, HC(O)NH-, H2NC(O)-, (Ci-C6alkyl)NHC(O)-, di(Ci- C6alkyl)NC(O)-, NC-, CrC6alkoxy-, HO2C-, (CrC6alkoxy)carbonyl-, (CrC6alkyl)C(O)-, C6-Ci4aryl-, d-Cgheteroaryl-, Cs-Cscycloalkyl-, d-Cδhaloalkyl-, CrCδaminoalkyl-, (Cr C6alkyl)carboxyl-, d-Cecarboxyamidoalkyl-, or O2N-. "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 Ci-Cioalkyl- group may have from 1 to 10 (inclusive) carbon atoms in it. In the absence of any numerical designation, "alkyl" is a chain (straight or branched) having 1 to 6 (inclusive) carbon atoms in it. Examples of CrCδalkyl- groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. An alkyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H2N-, (CrC6alkyl)amino-, di(d- C6alkyl)amino-, (CrC6alkyl)C(O)N(CrC3alkyl)-, (CrC6alkyl)carboxyamido-, HC(O)NH-, H2NC(O)-, (CrC6alkyl)NHC(O)-, di(CrC6alkyl)NC(O)-, NC-, hydroxyl, Ci-C6alkoxy-, d- C6alkyl-, HO2C-, (Ci-C6alkoxy)carbonyl-, (CrC6alkyl)C(O)-, C6-d4aryl-, Cr Cgheteroaryl-, C3-C8CyClOaIkVl-, d-C6haloalkyl-, d-C6aminoalkyl-, (d-C6alkyl)carboxyl- , CrCδCarboxyamidoalkyl-, or O2N-.
"(Alkyl)amino-" refers to an -NH group, the nitrogen atom of said group being attached to an alkyl group, as defined above. Representative examples of an (Cr C6alkyl)amino- group include, but are not limited to CH3NH-, CH3CH2NH-, CH3CH2CH2NH-, CH3CH2CH2CH2NH-, (CH3)2CHNH-, (CHs)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-, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, (CrC6alkyl)C(O)N(CrC3alkyl)-, (d-CealkyOcarboxyamido-, HC(O)NH-, H2NC(O)-, (CrC6alkyl)NHC(O)-, di(d-C6alkyl)NC(O)-, NC-, hydroxyl, d- C6alkoxy-, CrC6alkyl-, HO2C-, (d-CealkoxyJcarbonyl-, (Ci-C6alkyl)C(O)-, C6-d4aryl-, d-Cgheteroaryl-, drCscycloalkyl-, d-C6haloalkyl-, d-C6aminoalkyl-, (Cr C6alkyl)carboxyl-, CrCδCarboxyamidoalkyl-, or O2N-.
"Alkylcarboxyl-" refers to an alkyl group, defined above, and attached to the parent structure through the oxygen atom of a carboxyl (C(O)-O-) functionality. Examples of (d-Cealky^carboxyl- include acetoxy, propionoxy, propylcarboxyl, and isopentylcarboxyl.
"-Alkylene-", "-alkenylene-", and "-alkynylene-" refer to alkyl-, alkenyl-, and alkynyl- groups, as defined above, having two points of attachment within a chemical structure. Examples of -C-i-Cδalkylene- include ethylene (-CH2CH2-), propylene (- CH2CH2CH2-), and dimethylpropylene (-CH2C(CHs)2CH2-). Likewise, examples of -C2- Cεalkenylene- include ethenylene (-CH=CH- and propenylene (-CH=CH — CH2-). Examples of -C2-C6alkynylene- include ethynylene (-C≡C-) and propynylene (-C≡C — CH2-). "Alkynyl-" refers to a straight or branched chain unsaturated hydrocarbon containing at least one triple bond. Examples of a C2-Cioalkynyl- 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, isohexyne, 1-heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne, 4-octyne, 1-nonyne, 2-nonyne, 3- nonyne, 4-nonyne, 1-decyne, 2-decyne, 3-decyne, 4-decyne and 5-decyne. An alkynyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H2N-, (CrC6alkyl)amino-, di(CrC6alkyl)amino-, (Ci-C6alkyl)C(O)N(CrC3alkyl)- , (d-CealkyOcarboxyamido-, HC(O)NH-, H2NC(O)-, (Ci-C6alkyl)NHC(O)-, di(Ci- C6alkyl)NC(O)-, NC-, hydroxyl, CrC6alkoxy-, CrC6alkyl-, HO2C-, (Cr C6alkoxy)carbonyl-, (CrC6alkyl)C(O)-, C6-C-ι4aryl-, CrC9heteroaryl-, and C3- Cscycloalkyl-.
"Amine-protecting group" refers to a radical when attached to a nitrogen atom in a target molecule is capable of surviving subsequent chemical reactions applied to the target molecule i.e. hydrogenation, reaction with acylating agents, alkylation etc. The amine-protecting group can later be removed. Amine protecting groups include, but are not limited to, fluorenylmethoxycarbonyl (FMOC), tert-butoxycarbonyl (t-BOC), benzyloxycarbonyl (Z), those of the acyl type (e.g., formyl, benzoyl, thfluoroacetyl, p- tosyl, aryl- and alkylphosphoryl, phenyl- and benzylsulfonyl, o-nitrophenylsulfenyl, o- nitrophenoxyacetyl), and of the urethane type (e.g. tosyloxyalkyloxy-, cyclopentyloxy-, cyclohexyloxy-, 1 ,1 -dimethylpropyloxy, 2-(p-biphenyl)-2-propyloxy- and benzylthiocarbonyl). Amine-protecting groups are made using a reactive agent capable of transferring an amine-protecting group to a nitrogen atom in the target molecule. Examples of an amine-protecting agent include, but are not limited to, C-i-Cδ aliphatic acid chlorides or anhydrides, C6-Ci4arylcarboxylic acid chlorides or anhydrides, t- butylchloroformate, di-tert-butyl dicarbonate, butoxycarbonyloxyimino-2- phenylacetonitrile, t-butoxycarbonyl azide, t-butylfluoroformate, fluorenylmethoxycarbonyl chloride, fluorenylmethoxycarbonyl azide, fluorenylmethoxycarbonyl benzotriazol-1-yl, (θ-fluorenylmethoxycarbonyOsuccinimidyl carbonate, fluorenylmethoxycarbonyl pentafluorophexoxide, trichloroacetyl chloride, methyl-, ethyl-, trichloromethyl- chloroformate, and other amine protecting agents known in the art. Examples of such known amine-protecting agents are found in pages 385- 397 of T. W. Green, P. G. M. Wuts, "Protective Groups in Organic Synthesis, Second Edition", Wiley-lnterscience, New York, 1991.
"Aryl-" refers to an aromatic hydrocarbon group. Examples of an C6-C-ι4aryl- group include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, 3-biphen-1-yl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl. An aryl group can be unsubstituted or substituted with one or more of the following groups: d- Cεalkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl(CrC6alkyl)-, H2N-, aminoalkyl-, di(d- C6alkyl)amino-, HO2C-, (CrC6alkoxy)carbonyl-, (CrC6alkyl)carboxyl-, di(d- C6alkyl)amido-, H2NC(O)-, (CrC6alkyl)amido-, or O2N-.
"(Aryl)alkyl-" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with an aryl group as defined above. (C6-Ci4Aryl)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, (CrC6alkyl)amino-, di(CrC6alkyl)amino-, (CrC6alkyl)C(O)N(Ci-C3alkyl)-, (Ci-C6alkyl)carboxyamido-, HC(O)NH-, H2NC(O)-, (Cr C6alkyl)NHC(O)-, di(CrC6alkyl)NC(O)-, NC-, hydroxyl, CrC6alkoxy-, CrC6alkyl-, HO2C- , (CrC6alkoxy)carbonyl-, (CrC6alkyl)C(O)-, C6-Ci4aryl-, CrC9heteroaryl-, C3- Cscycloalkyl-, CrC6haloalkyl-, Ci-C6aminoalkyl-, (CrC6alkyl)carboxyl-, Cr Cecarboxyamidoalkyl-, or O2N-.
"Carboxyamidoalkyl-" refers to a primary carboxyamide (CONH2), a secondary carboxyamide (CONHR') or a tertiary carboxyamide (CONR1R"), where R' and R" are the same or different substituent groups selected from CrCδalkyl-, C2-C6alkenyl, C2- C6alkynyl, C6-Ci4aryl-, CrC9heteroaryl-, or C3-C8CyClOaIkVl-, attached to the parent compound by an -C-i-Cδalkylene- group as defined above. Exemplary Cr Cecarboxyamidoalkyl- groups include but are not limited to NH2C(O)-CH2-, CH3NHC(O)- CH2CH2-, (CH3)ZNC(O)-CH2CH2CH2-, CH2=CHCH2NHC(O)-CH2CH2CH2CH2-,
HCCCH2NHC(O)-CH2CH2CH2CH2CH2-, C6H5NHC(O)-CH2CH2CH2CH2CH2CH2-, 3- PyHcIyINHC(O)-CH2CH(CH3)CH2CH2-, and cyclopropyl-CH2NHC(0)-CH2CH2C(CH3)2CH2-
"Cycloalkyl-" refers to a monocyclic, non-aromatic, saturated hydrocarbon ring. Representative examples of a Cs-Cscycloalkyl- include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl can be unsubstituted or independently substituted with one or more of the following groups: halogen, H2N-, (Ci-C6alkyl)amino-, di(CrC6alkyl)amino-, (d- C6alkyl)C(O)N(CrC3alkyl)-, (CrC6alkyl)carboxyamido-, HC(O)NH-, H2NC(O)-, (Cr C6alkyl)NHC(O)-, di(CrC6alkyl)NC(O)-, NC-, hydroxyl, CrC6alkoxy-, CrC6alkyl-, HO2C- , (Ci-C6alkoxy)carbonyl-, (CrC6alkyl)C(O)-, C6-Ci4aryl-, CrC9heteroaryl-, or C3- Cscycloalkyl-, CrC6haloalkyl-, Ci-C6aminoalkyl-, (CrC6alkyl)carboxyl-, Cr CδCarboxyamidoalkyl-, or O2N-. 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 (=0) substituent or the two hydrogen atoms can be replaced by an alkylenedioxy group so that the alkylenedioxy group, when taken together with the carbon atom to which it is attached, form a 5- to 7-membered heterocycle containing two oxygen atoms.
"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(Ci-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(CHa)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(CrC6alkyl)-, -N(C3- Cscycloalkyl)-, -N(C6-Ci4aryl)-, -N(Ci-C9heteroaryl)-, -N(Ci-C6aminoalkyl)-, -N(C6- C-ι4arylamino)-, -0-, -S-, -S(O)-, Or -S(O)2-.
"Halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.
"Heteroaryl-" refers to 5-10-membered mono and bicyclic aromatic groups containing at least one heteroatom selected from oxygen, sulfur and nitrogen. Examples of monocyclic d-Cgheteroaryl- radicals include, but are not limited to, oxazinyl, thiazinyl, diazinyl, triazinyl, thiadiazoyl, tetrazinyl, imidazolyl, tetrazolyl, isoxazolyl, furanyl, furazanyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl, N-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. Examples of bicyclic Cr Cgheteroaryl- radicals include but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl, and indazolyl. The contemplated heteroaryl- rings or ring systems have a minimum of 5 members. Therefore, for example, dheteroaryl- radicals would include but are not limited to tetrazolyl, C2heteroaryl- radicals include but are not limited to triazolyl, thiadiazoyl, and tetrazinyl, Cgheteroaryl- radicals include but are not limited to quinolinyl and isoquinolinyl. A heteroaryl group can be unsubstituted or substituted with one or more of the following groups: CrCδalkyl-, halogen, d-Cδhaloalkyl-, hydroxyl, d- Cehydroxylalkyl-, H2N-, CrC6aminoalkyl-, di(CrC6alkyl)amino-, -COOH, (Cr C6alkoxy)carbonyl-, (CrC6alkyl)carboxyl-, di(Ci-C6alkyl)amido-, H2NC(O)-, (d- C6alkyl)amido-, or O2N-.
"(Heteroaryl)alkyl-" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with a heteroaryl- group as defined above. Examples of (d-CgheteroaryOalkyl- moieties include 2-pyhdylmethyl, 2-thiophenylethyl, 3-pyhdylpropyl, 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, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, (Ci-C6alkyl)C(O)N(Ci-C3alkyl)-, (CrC6alkyl)carboxyamido-, HC(O)NH-, H2NC(O)-, (d- C6alkyl)NHC(O)-, di(Ci-C6alkyl)NC(O)-, NC-, hydroxyl, Ci-C6alkoxy-, Ci-C6alkyl-, HO2C- , (Ci-C6alkoxy)carbonyl-, (Ci-C6alkyl)C(O)-, C6-Ci4aryl-, CrC9heteroaryl-, C3- Cscycloalkyl-, CrC6haloalkyl-, d-C6aminoalkyl-, (d-C6alkyl)carboxyl-, d- CδCarboxyamidoalkyl-, or O2N-.
"Heteroatom" refers to a sulfur, nitrogen, or oxygen atom.
"Heterocycle" or "heterocyclyl-" refers to 3-10-membered monocyclic, fused bicyclic, and bridged bicyclic groups containing at least one heteroatom selected from oxygen, sulfur and nitrogen. A heterocycle may be saturated or partially saturated. Exemplary d-Cgheterocyclyl- 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, dheterocyclyl- radicals would include but are not limited to oxaziranyl, diaziridinyl, and diazirinyl, C2heterocyclyl- radicals include but are not limited to aziridinyl, oxiranyl, and diazetidinyl, Cgheterocyclyl- radicals include but are not limited to azecanyl, tetrahydroquinolinyl, and perhydroisoquinolinyl.
"Heterocyclyl(alkyl)-" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with a heterocycle group as defined above. Heterocyclyl(Ci-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-, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, (Ci- C6alkyl)C(O)N(CrC3alkyl)-, (CrC6alkyl)carboxyamido-, HC(O)NH-, H2NC(O)-, (Cr C6alkyl)NHC(O)-, di(CrC6alkyl)NC(O)-, NC-, hydroxyl, CrC6alkoxy-, CrC6alkyl-, HO2C- , (Ci-C6alkoxy)carbonyl-, (Ci-C6alkyl)C(O)-, 4- to 7-membered monocyclic heterocycle, C6-Ci4aryl-, CrC9heteroaryl-, or Cs-Cscycloalkyk
"Hydroxylalkyl-" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with hydroxyl groups. Examples of C-i-Cδhydroxylalkyl- moieties include, for example, -CH2OH, -CH2CH2OH, - CH2CH2CH2OH, -CH2CH(OH)CH2OH, -CH2CH(OH)CH3, -CH(CH3)CH2OH and higher homologs.
"Leaving group" refers an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a specified reaction. For example, in the heterolytic solvolysis of benzyl bromide in acetic acid: the leaving group is bromide. In the reaction of N,N,N-trimethyl- 1-phenylmethanaminium ion with methanethiolate, the leaving group is trimethylamine. In the electrophilic nitration of benzene, it is H+. The term has meaning only in relation to a specified reaction. Examples of leaving groups include, for example, carboxylates (i.e. CH3COO", CF3CO2 "), F", water, Cl", Br", I", N3 ", SCN", trichloroacetimidate, thiopyridyl, tertiary amines (i.e. trimethylamine), phenoxides (i.e. nitrophenoxide), and sulfonates (/. e. tosylate, mesylate, triflate).
"Perfluoroalkyl-" refers to alkyl group, defined above, having two or more fluorine atoms. Examples of a Ci-Cβperfluoroalkyl- group include CF3, CH2CF3, CF2CF3 and CH(CF3)2.
The term "optionally substituted", unless otherwise specified, as used herein means that at least one hydrogen atom of the optionally substituted group has been substituted with halogen, H2N-, (CrC6alkyl)amino-, di(Ci-C6alkyl)amino-, (d- C6alkyl)C(O)N(CrC3alkyl)-, (CrC6alkyl)carboxyamido-, HC(O)NH-, H2NC(O)-, (Cr C6alkyl)NHC(O)-, di(CrC6alkyl)NC(O)-, NC-, hydroxyl, CrC6alkoxy-, CrC6alkyl-, HO2C- , (Ci-C6alkoxy)carbonyl-, (CrC6alkyl)C(O)-, C6-Ci4aryl-, CrC9heteroaryl-, or C3- Cscycloalkyl-.
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 compounds of the present invention exhibit an mTOR inhibitory activity and, therefore, can be utilized 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. Procedures used to synthesize the compounds of the present invention are described in Schemes 1 -7 and are illustrated in the examples. Reasonable variations of the described procedures are intended to be within the scope of the present invention:
Scheme 1
Figure imgf000043_0001
One of the intermediates of formula 2 utilized for introducing the aryl ureido group was prepared starting from 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane of formula 1 as shown in Scheme 1.
Scheme 2
Figure imgf000043_0002
Compounds of formula 4 were prepared starting from tert-butyl 2,4-dichloro-5,6- dihydropyrido[3,4-d]pyhmidine-7(8H)-carboxylate 3 or other appropriately protected 2,4- dichloro-5,6,7,8-tetrahydropyhdo[3,4-d]pyhmidine intermediates. Reaction with morpholine in solvents like tetrahydrofuran or methylene chloride in the presence of base like triethyl amine or pyridine afforded compound of formula 4 as shown in Scheme 2. Reaction of 2,4-dichloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)- carboxylate 3 with 3-oxa-8-aza-bicyclo[3.2.1]octane gave the analogous 2-chloro-4-(3- oxa-δ-aza-bicyclotS^.iloct-δ-yO-S^-dihydro-eH-pyridoP^-dlpyrimidine compounds.
Scheme 3
Figure imgf000044_0001
As shown in Scheme 3, the aryl moiety was introduced in the 2-position of the 5,6,7,8-tetrahydropyhdo[3,4-d]pyhmidine by Suzuki coupling starting with an intermediate of formula 4 using appropriate boronic acid or boronate ester of formula 2. Removal of the protecting group afforded the intermediate of formula 6. An identical process was used with the analogous 2-chloro-4-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)- 5,8-dihydro-6H-pyhdo[3,4-d]pyrimidine compounds.
Scheme 4
Figure imgf000044_0002
Formula 6 could be readily converted to required amide, sulfonamide, amine, urea or carbamate compounds using appropriate electrophiles like acid chloride, sulfonyl chloride, halide, isocyanate, or chloroformate reagents as shown in Scheme 4. Scheme 5
Figure imgf000045_0001
An alternate scheme as shown Scheme 5 can be employed as well using the free amine 8. Addition of radical R4 occurs after removal of the protecting group from 10.
Scheme 6
Figure imgf000046_0001
As shown in Scheme 6, introduction of the heterocyclyl radical (R1)p-Het- to intermediate 13 can be followed by Suzuki coupling using the boronate 15. PG is an amine-protecting group and X is independently a leaving group. Examples of such amine-protecting groups include BOC, FMOC, Z, formyl, benzoyl, thfluoroacetyl, p-tosyl, aryl- and alkylphosphoryl, phenyl- and benzylsulfonyl, o-nitrophenylsulfenyl, o- nitrophenoxyacetyl, tosyloxyalkyloxy-, cyclopentyloxy-, cyclohexyloxy-, 1 ,1 - dimethylpropyloxy, 2-(p-biphenyl)-2-propyloxy- and benzylthiocarbonyl. Examples of leaving groups include iodide, bromide, chloride, fluoride, mesylate, tosylate, and triflate. Addition of radical R4 occurs after removal of the protecting group from 17. Scheme 7
Figure imgf000047_0001
As shown in Scheme 7, 6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyhmidine compounds 22 are made by a reductive amination process.
One of skill in the art will recognize that Schemes 1-7 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.
EXAMPLES
The following abbreviations are used herein and have the indicated definitions: ATP is adenosine triphosphate, βME is 2-mercaptoethanol, BOC is tertiary- butyloxycarbonyl, BSA is Bovine Serum Albumin, CHAPS is (3-[(3- cholamidopropyl)dimethylammonio]-1-propanesulfonic acid, DELFIA is Dissociation- Enhanced Lanthanide Fluorescent Immunoassay, DME is 1 ,2-dimethoxyethane, DMF is N,N-dimethylformamide, DMSO is dimethylsulfoxide, DPBS is Dulbecco's Phosphate Buffered Saline Formulation. DTT is (2S,3S)-1 ,4-bis-sulfanylbutane-2,3-diol or dithiothreitol, EDTA is ethylenediaminetetraacetic acid, EGTA is ethylene glycol tetraacetic acid, EtOAc is ethyl acetate, FLAG-TOR is a FLAG-tagged TOR protein, HEPES is 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, HPLC is high-pressure liquid chromatography, microcrystin LR is a cyclic heptapeptide hepatotoxin produced Microcystis aeruginosa containing the amino acids leucine (L) and arginine (R) in the variable positions, MS is mass spectrometry, mTOR is Mammalian Target of Rapamycin (a protein), MTS is 3-(4, 5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-( 4-sulfophenyl)-2H-tetrazolium, inner salt, PBS is phosphate- buffered saline (pH 7.4), PI3K is phosphoinositide 3-kinase (an enzyme), RPMI 1640 is a buffer (Sigma-Aldrich Corp., St. Louis, MO, USA), Raney™ nickel is a sponge-metal catalyst produced when a block of nickel-aluminum alloy is treated with concentrated sodium hydroxide. Raney™ is a registered trademark of W. R. Grace and Company. RT is retention time, SDS is dodecyl sulfate (sodium salt), SRB is Sulforhodamine B, TAMRA is tetramethyl-6-carboxyrhodamine, TFA is thfluoroacetic acid, THF is tetrahydrofuran, and TRIS is tris(hydroxymethyl)aminomethane.
SYNTHETIC METHODS
The following methods outline the synthesis of the Examples of the present invention.
Example 1 Preparation of 1 -[4-(4-morpholin-4-yl-5,6,7,8-tetrahydro[3,4- d]pyrimidyl-2-yl)phenyl]-3-pyridin-3-ylurea
Step 1 : Preparation of 1-pyridin-3-yl-3-[4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea A mixture of 2-(4-isocyanato-phenyl)-4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolane (1 ,
2.68g, 10.9 mmol) and 3-amino-pyhdine (1.13g, 12.0 mmol) in 75 ml. of THF was stirred at room temperature for 6 hours. The precipitate was filtered and washed with THF to give 1 -pyhdin-3-yl-3-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea (3.5Og, 94.3% yield) as a white solid. HPLC: RT = 1 .88 min; MS 340 [M+H]. Step 2: Preparation of 2-chloro-4-morpholin-4-yl-5,8-dihydro-6H-pyrido[3,4- d]pyhmidine-7-carboxylic acid tert-butyl ester
A mixture of 2,4-dichloro-5,8-dihydro-6H-pyrido[3,4-d]pyhmidine-7-carboxylic acid tert-butyl ester (3, 608 mg, 2.00mmol), morpholine (192 mg, 2.20 mmol) and triethyl amine (202 mg, 2.00 mmol) in 14 mL of THF was stirred at room temperature for 6 hours. Then the reaction mixture was diluted with 200 mL of ethyl acetate and the organic layer was washed with saturated sodium bicarbonate aqueous solution and brine. The organic layer then was collected and dried over anhydrous sodium sulfate and concentrated to give 2-chloro-4-morpholin-4-yl-5,,8-dihydro-6H-pyrido[3,4- d]pyhmidine-7-carboxylic acid tert-butyl ester (750 mg, 98.7% yield) as a white solid. HPLC: RT = 2.65 min; MS 355, 357 [M+H].
Step 3: Preparation of 1 -[4-(4-morpholin-4-yl-5,6,7,8-tetrahydro[3,4-d]pyhmidyl- 2-yl) phenyl]-3-pyhdin-3-ylurea
A mixture of 1-pyridin-3-yl-3-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- phenyl]-urea (51 mg, 0.15 mmol), 2-chloro-4-morpholin-4-yl-5,8-dihydro-6H-pyrido[3,4- d]pyrimidine-7-carboxylic acid tert-butyl ester (35 mg, 0.10 mmol) and tetrakis (triphenylphosphine) palladium (0) (6 mg, 0.005 mmol) in 2M sodium carbonate aqueous solution (0.30 ml_, 0.60 mmol) and 4 ml. of DME was stirred at 150 0C in a microwave oven for 30 minutes. The reaction mixture was filtered through a silica gel pad (eluting with 10 % methanol/EtOAc). The filtration was concentrated to get the crude 4-morpholin-4-yl-2-[4-(3-pyridin-3-yl-ureido)-phenyl]-5,8-dihydro-6H-pyrido[3,4- d]pyhmidine-7-carboxylic acid tert-butyl ester. Then the crude product was dissolved in 2 ml. of methylene chloride and treated with 0.5 mL of TFA for 1 hour. Then the reaction mixture was concentrated and the residue was purified by reverse phase chromatography to give 1-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin- 2-yl) phenyl]-3-pyhdin-3-ylurea (41 mg, 95% yield). HPLC: RT = 1 .40 min; MS 432 [M+H].
Example 2 Preparation of 1 -[4-(7-acetyl-4-morpholin-4-yl-5,6,7,8-tetrahydro[3,4- d]pyrimidin-2-yl) phenyl]-3-pyridin-3-ylurea
The title compound was prepared by following the procedure of Example 3 using
1-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyrimidin-2-yl) phenyl]-3-pyridin-3- ylurea and acetyl chloride. Yield 21 mg HPLC: RT = 1 .75 min; MS 474 [M+H]. Example 3 Preparation of 1 -{4-[7-(methylsulfonyl)-4-morpholin-4-yl-5,6,7,8- tetrahydro[3,4-d]pyrimidyl-2-yl]phenyl}-3-pyridin-3-ylurea
A mixture of 1-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyhmidin-2-yl) phenyl]-3-pyridin-3-ylurea (74 mg, 0.17 mmol) (Example 1 ), methanesulfonyl chloride (24 mg, 0.21 mmol) and triethyl amine (21 mg, 0.21 mmol) in 2 mL of methylene chloride was stirred at room temperature for 2 hours. Then the reaction mixture was concentrated and purified by reverse phase chromatography to give 1-{4-[7- (methylsulfonyl)-4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyrimidin-2-yl]phenyl}- 3-pyhdin-3-ylurea (44 mg, 50% yield). HPLC: RT = 1.63 min; MS 510 [M+H]. Example 4 preparation of 1 -{4-[4-morpholin-4-yl-7-(3,3,3-trifluoropropanoyl)- 5,6,7, 8-tetrahydro[3,4-d]pyrimidyl-2-yl]phenyl}-3-pyridin-3-ylurea
The title compound was prepared by following the procedure of Example 3 using 1 -[4-(4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyhmidin-2-yl) phenyl]-3-pyridin-3- ylurea and 3,3,3-thfluoro-propionyl chloride. Yield 17 mg; HPLC: RT = 1.87 min; MS 542 [M+H]. Example 5 preparation of 1-[4-(7-methyl-4-morpholin-4-yl-5,6,7,8-tetrahydro[3,4- d]pyrimidin-2-yl)phenyl]-3-pyridin-3-ylurea
A mixture of 1-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyπmidin-2-yl phenyl]-3-pyridin-3-ylurea (15 mg, 0.034 mmol) (Example 1 ) and methyl iodide (4.9 mg, 0.034 mmol) in 1 ml. of DMF was stirred at 60 0C for 6 hours. Then the reaction mixture was directly loaded on reverse phase column and purified give 1-[4-(7-methyl-4- morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyhmidin-2-yl) phenyl]-3-pyhdin-3-ylurea (4.3 mg, 28% yield). HPLC: RT = 1.40 min; MS 446 [M+H]. Example 6 Preparation of 1-methyl-3-{4-[7-(methylsulfonyl)-4-morpholin-4-yl- 5,6,7, 8-tetrahydro[3,4-d]pyrimidyl-2-yl]phenyl}urea
The title compound was prepared by following the procedure of Example 3 using 1-methyl-3-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyrimidin-2-yl) phenyl]urea and methanesulfonyl chloride. Yield 33 mg; HPLC: RT = 1.65 min; MS 447 [M+H]. Example 7 Preparation of 1-methyl-3-[4-(7-methyl-4-morpholin-4-yl-5, 6,7,8- tetrahydro[3,4-d]pyrimidyl-2-yl) phenyljurea
The title compound was prepared by following the procedure of Example 5 using 1-methyl-3-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyrimidin-2-yl) phenyl]urea and methyl iodide. Yield 5.0 mg; HPLC: RT = 1 .47 min; MS 383 [M+H]. Example 8 Preparation of 1-methyl-3-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydro[3,4- d]pyrimidin-2-yl) phenyljurea
Step 1 : Preparation of 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2- yl)-phenyl]-urea
The title compound was prepared by following the procedure step 1 of Example 1 using 2-(4-isocyanato-phenyl)-4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan 1 and methylamine. Yield 760 mg (90% yield) RT = 2.21 min; 277 [M+H].
Step 2: Preparation of 1 -methyl-3-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydro[3,4- d]pyhmidin-2-yl) phenyl]urea
The title compound was prepared by following the procedure step 3 of Example 1 using 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea and 2- chloro-4-morpholin-4-yl-5,8-dihydro-6H-pyhdo[3,4-d]pyrimidine-7-carboxylic acid tert- butyl ester 4. Yield 35 mg; HPLC: RT = 1.45min; MS 369 [M+H]. Example 9 Preparation of i -^-iyHS-oxa-δ-azabicycloβ^.iloct-δ-ylJ-S.ΘJ.δ- tetrahydro[3,4-d]pyrimidyl-2-yl]phenyl}-3-pyridin-3-ylurea
Step 1 : Preparation of 2-chloro-4-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-5,8- dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester A mixture of 2,4-dichloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (3, 860 mg, 2.68 mmol), 3-oxa-8-aza-bicyclo[3.2.1]octane (384 mg, 3.39 mmol), and triethyl amine (343 mg, 3.39 mmol) in 20 ml. of THF was stirred at 30 0C for 16 hours. Then the reaction mixture was diluted with 200 ml. of ethyl acetate and the organic layer was washed with saturated sodium bicarbonate aqueous solution and brine. The organic layer was concentrated and the residue was purified by Teledyne ISCO flash chromatography (eluting with 0-70% EtOAc/Hexane) to give 2-chloro-4-(3- oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-5,8-dihydro-6H-pyhdo[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (806 mg, 74.5% yield) as a white solid. HPLC: RT = 2.83 min; MS 381 ,383 [M+H]. Step 2: Preparation of 1 -{4-[4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8- tetrahydro[3,4-d]pyhmidyl-2-yl]phenyl}-3-pyhdin-3-ylurea
A mixture of 1-pyridin-3-yl-3-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- phenyl]-urea (187 mg, 0.551 mmol), 2-chloro-4-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-5,8- dihydro-6H-pyhdo[3,4-d]pyhmidine-7-carboxylic acid tert-butyl ester (140 mg, 0.367 mmol) and tetrakis (triphenylphosphine) palladium (0) (21 mg, 0.018 mmol) in 2M sodium carbonate aqueous solution (1.5 ml_, 3.0 mmol) and 10 mL of DME was stirred at 150 0C in a microwave oven for 30 minutes. The reaction mixture was filtered through a silica gel pad (eluting with 10 % methanol/EtOAc). The filtrate was concentrated to get the crude 4-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-2-[4-(3-pyridin-3-yl-ureido)-phenyl]- 5,8-dihydro-6H-pyhdo[3,4-d]pyhmidine-7-carboxylic acid tert-butyl ester. Then the crude product was dissolved in 10 mL of methylene chloride and treated with 2 mL of TFA for 1 hour. Then the reaction mixture was concentrated and the residue was purified by reverse phase chromatography to give 1 -{4-[4-(3-oxa-8-azabicyclo[3.2.1 ]oct- 8-yl)-5,6,7,8-tetrahydropyhdo[3,4-d]pyrimidin-2-yl]phenyl}-3-pyhdin-3-ylurea (133 mg, 79% yield). HPLC: RT = 2.22 min; MS 458 [M+H].
Example 10 Preparation of 1-methyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 5,6,7,8-tetrahydro[3,4-d]pyrimidyl-2-yl]phenyl} urea
The title compound was prepared by following the procedure step 2 of Example 9 using 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea and 2- chloro-4-(3-oxa-8-aza-bicyclo[3.2.1 ]oct-8-yl)-5,8-dihydro-6H-pyrido[3,4-d]pyrirnidine-7- carboxylic acid tert-butyl ester. Yield 36 mg; HPLC: RT = 1.97; MS 395 [M+H]. Example 11 Preparation of i-^-P-methyl^-β-oxa-δ-azabicycloIS^.Iloct-δ-yl)- 5,6,7, 8-tetrahydro[3,4-d]pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea
The title compound was prepared by following the procedure of Example 5 using
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyhdo[3,4-d]pyhmidin-2- yl]phenyl}-3-pyhdin-3-ylurea and methyl iodide. Yield 7.0 mg; HPLC: RT = 2.40 min; MS 472 [M+H].
Example 12 Preparation of 1-{4-[7-(methylsulfonyl)-4-(3-oxa-8-azabicyclo [3.2.1]oct-8-yl)-5,6,7,8-tetrahydro[3,4-d]pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea
The title compound was prepared by following the procedure of Example 3 using 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyhdo[3,4-d]pyhmidin-2- yl]phenyl}-3-pyhdin-3-ylurea and methanesulfonyl chloride. Yield 31 mg; HPLC: RT = 2.45 min; MS 536 [M+H]. Example 13 Preparation of 1-methyl-3-{4-[7-methyl-4-(3-oxa-δ- azabicycloβ^.iloct-δ-yO-S.ΘJ.δ-tetrahydroIS^-dlpyrimidyl^-yllphenyl} urea
The title compound was prepared by following the procedure of Example 5 using 1-methyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyhmidin-2-yl]phenyl} urea and methyl iodide. Yield 5.0 mg; HPLC: RT = 2.18 min; MS 409 [M+H].
Example 14 Preparation of 1-methyl-3-{4-[7-(methylsulfonyl)-4-(3-oxa-δ- azabicycloβ^.iloct-δ-yO-S.ΘJ.δ-tetrahydroIS^-dlpyrimidyl^-yllphenyl} urea
The title compound was prepared by following the procedure of Example 3 using 1-methyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyhmidin-2-yl]phenyl} urea and methanesulfonyl chloride. Yield 40 mg; HPLC: RT = 2.21 min; MS 473 [M+H].
Example 15 Preparation of i-^-iyHδ-Oxa-S-aza-bicycloβ^.iloct-S-yO-S.ΘJ.δ- tetrahydropyrido[3,4-d]pyrimidin-2-yl]-phenyl}-3-pyridin-3-yl-urea
Step 1 : 2-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-5,8-dihydro-6H- pyrido[3,4-d]pyhmidine-7-carboxylic acid tert-butyl ester
The title compound was prepared by following the procedure step 1 of Example 9 using 8-oxa-3-azabicyclo[3.2.1 ]octane and 2,4-dichloro-5,8-dihydro-6H-pyrido[3,4- d]pyrimidine-7-carboxylic acid tert-butyl ester 3. Yield 340 mg (61 % yield) RT = 2.67 min; 381 ,383 [M+H].
Step 2: Preparation of 1-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl]-phenyl}-3-pyridin-3-yl-urea The title compound was prepared by following the procedure step 2 of Example 9 using 1-pyhdin-3-yl-3-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea and 2-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7- carboxylic acid tert-butyl ester. Yield 23 mg; HPLC: RT = 2.16; MS 458 [M+H]. Example 16 Preparation of 1-{4-[7-Methanesulfonyl-4-(8-oxa-3-aza- bicycloia^.iloct-a-yO-S.ej.δ-tetrahydropyridoia^-dlpyrimidin^-yll-phenyl}^- pyridin-3-yl-urea
The title compound was prepared by following the procedure of Example 3 using 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2- yl]phenyl}-3-pyridin-3-ylurea and methanesulfonyl chloride. Yield 14 mg; HPLC: RT = 2.36 min; MS 536 [M+H].
Example 17 Preparation of 1-{4-[7-Methyl-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl) - 5,6,7, 8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]-phenyl}-3-pyridin-3-yl-urea
The title compound was prepared by following the procedure of Example 5 using 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2- yl]phenyl}-3-pyridin-3-ylurea and methyl iodide. Yield 3.9 mg; HPLC: RT = 2.50 min; MS 472 [M+H].
Example 18 Preparation of i-methyl-S-^-^-fδ-oxa-S-azabicyclotS^.iloct-S-yl)- 5,6,7, 8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}urea
The title compound was prepared by following the procedure step 2 of Example 15 using 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea and 2-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-5,8-dihydro-6H-pyhdo[3,4-d]pyhmidine-7- carboxylic acid tert-butyl ester. Yield 24 mg; HPLC: RT = 1.92; MS 395 [M+H]. Example 19 Preparation of 1-{4-[7-Methanesulfonyl-4-(8-oxa-3-aza- bicycloia^.iloct-S-yO-S.ej.δ-tetrahydropyπdoia^-dlpyrimidin^-yll-phenyl}^- methyl-urea
The title compound was prepared by following the procedure of Example 3 using 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}urea and methanesulfonyl chloride. Yield 33 mg; HPLC: RT =
2.17 min; MS 473 [M+H].
Example 20 Preparation of 1-methyl-3-{4-[7-methyl-4-(8-oxa-3-aza- bicycloIS^.Iloct-S-yO-S.ΘJ.δ-tetrahydropyridoIS^-dlpyrimidin^-yll-pheny^-urea
The title compound was prepared by following the procedure of Example 5 using
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyhmidin-2-yl]phenyl}urea and methyl iodide. Yield 5.5 mg; HPLC: RT = 2.28 Example 21 Preparation of 1 -(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl)phenyl]urea
Step 1 : Preparation of (4-dimethylaminopiperidin-1 -yl)-(4-nitrophenyl)methanone Hydrochloride
A mixture of 4-dimethylamminopipehdine (1.3Og, 10.1 mmol) and 4-nitro-benzoyl chloride (1 .9Og, 10.2 mmol) in 50 mL of toluene was stirred at room temperature for 1 hour. Then the precipitates were filtered and washed with toluene and vacuum to dryness to give (4-dimethylamino-pipehdin-1-yl)-(4-nitro-phenyl)-methanone hydrochloride (3.3Og, 100% yield) as white solid. HPLC: RT = 1.74 min; MS 278 [M+H].
Step 2: Preparation of (4-amino-phenyl)-(4-dimethylamino-piperidin-1-yl)- methanone A mixture of (4-dimethylamino-pipehdin-1-yl)-(4-nitro-phenyl)-methanone hydrochloride (3.30 g, 10.1 mmol) and Raney™ nickel, hydrazine monohydrate (2.0Og, 40 mmol), and 5N NaOH (5, mL, 25 mmol) in 100 mL of methanol was stirred at room temperature for 10 minutes. Then the reaction mixture was filtered through Celite™ and concentrated. The residue was dissolved in 200 mL of EtOAc and washed with sodium bicarbonate and brine. The organic layer was dried through anhydrous sodium sulfate and concentrated to give (4-amino-phenyl)-(4-dimethylamino-pipehdin-1-yl)-methanone (1 .79g, 72% yield). HPLC RT = 0.89 min; MS 248 [M+H].
Step 3: Preparation of 1 -[4-(4-dimethylamino-piperidine-1-carbonyl)-phenyl]-3-[4- (4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea A mixture of (4-amino-phenyl)-(4-dimethylamino-pipehdin-1-yl)-methanone (0.59 g, 2.4 mmol) and 2-(4-isocyanato-phenyl)-4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolane (1 m 0.59 g, 2.4 mmol) in 30 mL of tetrahydrofuran was stirred at room temperature for 5 hours. LC/MS showed the reaction was completed. Then the reaction solution was concentrated to give 1-[4-(4-dimethylamino-piperidine-1-carbonyl)-phenyl]-3-[4-(4,4,5,5- tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea (1.15g, 100% yield). HPLC RT = 2.67 min; MS 493 [M+H].
Step 4: Preparation of 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3- [4-(4-morpholin-4-yl- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl]urea The title compound was prepared by following the procedure of Example 1 Step
3 using 2-chloro-4-morpholin-4-yl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester 4 and 1 -[4-(4-dimethylamino-piperidine-1-carbonyl)-phenyl]-3-[4- (4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 47.6 mg. HPLC: RT = 2.15 min; MS 585 [M+H]. Example 22 Preparation of 1 -(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}urea
The title compound was prepared by following the procedure of Example 1 step 3 using 2-chloro-4- (3-oxa-8-aza-bicyclo[3.2.1 ]oct-8-yl)-5,8-dihydro-6H-pyhdo[3,4- d]pyhmidine-7-carboxylic acid tert-butyl ester and 1-[4-(4-dimethylamino-pipehdine-1- carbonyl)-phenyl]-3-[4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 43 mg. HPLC: RT = 2.28 min; MS 61 1 [M+H]. Example 23 Preparation of 1 -(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}urea
The title compound was prepared by following the procedure of Example 1 step 3 using 2-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-5,8-dihydro-6H-pyrido[3,4- d]pyhmidine-7-carboxylic acid tert-butyl ester and 1-[4-(4-dimethylamino-pipehdine-1- carbonyl)-phenyl]-3-[4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 56.6 mg. HPLC: RT = 2.23 min; MS 61 1 [M+H].
Example 24 Preparation of 1 -(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}urea
The title compound was prepared by following the procedure of Example 3 using 1-(4-{[4-(dimethylamino)pipehdin-1 -yl]carbonyl} phenyl)-3-[4-(4-morpholin-4-yl- 5,6,7,8- tetrahydropyhdo[3,4-d]pyhmidin-2-yl) phenyl]urea and methanesulfonyl chloride. Yield 15 mg. HPLC: RT = 2.22 min; MS 663 [M+H]. Example 25 Preparation of 1 -(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-{4-[7- (methylsulfonyl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}urea
The title compound was prepared by following the procedure of Example 3 using 1 -(4-{[4-(dimethylamino)pipehdin-1 -yl]carbonyl} phenyl )-3-{4-[4-(3-oxa-8- azabicyclotS^.iloct-δ-yO-δ^J^-tetrahydropyhdotS^-dlpyhmidin^-yOphenylϊ urea and methanesulfonyl chloride. Yield 21 mg. HPLC: RT = 2.41 min; MS 689 [M+H]. Example 26 Preparation of 1 -(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-{4-[7- (methylsulfonyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)- 5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}urea
The title compound was prepared by following the procedure of Example 3 using 1-[4-(4-dimethylamino-pipehdine-1-carbonyl)-phenyl]-3-{4-[4-(8-oxa-3-aza- bicyclotS^.iloct-S-yO-δ^J^-tetrahydropyhdotS^-dlpyhmidin^-yO-phenylϊ-urea and methanesulfonyl chloride. Yield 18 mg. HPLC: RT = 2.47 min; MS 689 [M+H]. The following compounds were prepared reacting 1-(4-(4-(8-oxa-3- azabicycloP^.iloctan-S-yO-δ^J^-tetrahydropyridoP^-dlpyhmidin^-yOphenyO-S- methylurea and the required chloroformate in methylene chloride using thethylamine as base.
Example 27 Preparation of butyl 2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa- 3-azabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate
Example 28 Preparation of 2-methylpropyl2-{4-[(methylcarbamoyl)amino]phenyl}-
4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- carboxylate
The following compounds were prepared reacting 1-(4-(4-(8-oxa-3- azabicycloP^.iloctan-S-yO-δ^J^-tetrahydropyridoP^-dlpyhmidin^-yOphenyO-S- methylurea and required isocyanates in methylene chloride using triethylamine as base. Example 29 Preparation of N-butyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8- oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- carboxamide
Example 30 Preparation of N-tert-butyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4- (8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- carboxamide Example 31 Preparation of 2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3- azabicyclo[S^.I]oct-3-yO-N-prop^-en-i-yl-5,8-dihydropyrido[S^-d]pyrimidine-
7(6H)-carboxamide
Example 32 Preparation of N-hexyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8- oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- carboxamide
Example 33 Preparation of N-cyclohexyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4-
(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- carboxamide
The following compounds were prepared reacting 1-(4-(4-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)-5A7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3- methylurea and the required sulfonyl chloride in methylene chloride using thethylamine as base. Example 34 Preparation of 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-7- (phenylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}urea
Example 35 Preparation of 1 -(4-{7-[(4-fluorophenyl)sulfonyl]-4-(8-oxa-3- azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyπdoIS^-dlpyrimidin^-y^phenyO-3- methylurea
Example 36 Preparation of 1-(4-{7-[(4-cyanophenyl)sulfonyl]-4-(8-oxa-3- azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyπdoIS^-dlpyrimidin^-y^phenyO-3- methylurea
Example 37 Preparation of N,N-dimethyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4-
(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- sulfonamide
Example 38 Preparation of 1-(4-{7-[(4-chlorophenyl)sulfonyl]-4-(8-oxa-3- azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyπdoIS^-dlpyrimidin^-y^phenyO-3- methylurea
The following compounds were prepared reacting 1-(4-(4-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)-5,6,7,8-tetrahydropyridoIS^-d]pyrimidin^-yl)phenyl)-3- methylurea and the required acid chloride in methylene chloride using triethylamine as base.
Example 39 Preparation of 1-{4-[7-(methoxyacetyl)-4-(8-oxa-3- azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin^-yl]phenyl}^- methylurea
Example 40 Preparation of i-methyl-3-^-^-(8-oxa-3-azabicycloβ^.i]oct-3- yl)-7-pentanoyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}urea
Example 41 Preparation of 1-{4-[7-heptanoyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)- 5,6,7, 8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-methylurea
Example 42 Preparation of 1-{4-[7-(2,2-dimethylpropanoyl)-4-(δ-oxa-3- azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin^-yllphenyl}^- methylurea
Example 43 Preparation of 1-{4-[7-(2-ethylhexanoyl)-4-(8-oxa-3- azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin^-yllphenyl}^- methylurea
Example 44 Preparation of 1-{4-[7-(3-cyclopentylpropanoyl)-4-(8-oxa-3- azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin^-yllphenyl}^- methylurea
Example 45 Preparation of 1 -(4-{7-[(2,6-difluorophenyl)carbonyl]-4-(8-oxa-3- azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin^-yl}phenyl)-3- methylurea
Example 46 Preparation of 1 -(4-{7-[(2-fluorophenyl)carbonyl]-4-(δ-oxa-3- azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin^-y^phenyl)-3- methylurea
Example 47 Preparation of 1-(4-{7-[(4-tert-butylphenyl)carbonyl]-4-(δ-oxa-3- azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin^-y^phenyl)-3- methylurea
Example 4δ Preparation of 1 -(4-{7-[(2-methoxyphenyl)carbonyl]-4-(δ-oxa-3- azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin^-y^phenyl)-3- methylurea The following compounds were made using methods described above. Example 49 Preparation of i-^-P-methyl^-β-oxa-δ-azabicycloIS^.Iloct-δ-yl)- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea
MS 472.2 [M+H]. Example 50 Preparation of 1-{4-[7-(N,N-dimethylglycyl)-4-(3-oxa-8- azabicycloia^.iloct-δ-yO-S.ΘJ.δ-tetrahydropyridoia^-dlpyrimidin^-yllphenyl}^- pyridin-4-ylurea
MS 543.3 [M+H].
Example 51 Preparation of 7,7-bis(2-fluoroethyl)-4-(3-oxa-δ-azabicyclo[3.2.1]oct-δ- yl)-2-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-7-ium trifluoroacetate
Example 52 Preparation of methyl 4-(3-oxa-δ-azabicyclo[3.2.1]oct-δ-yl)-2-{4-
[(pyridin-4-ylcarbamoyl)amino]phenyl}-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- carboxylate
MS 407.1 [M+H].
Example 53 Preparation of 1-{4-[7-(1-methylethyl)-4-(δ-oxa-3-azabicyclo[3.2.1]oct- 3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea
MS 500.3 [M+H].
Example 54 Preparation of i -^-P-ethyl^δ-oxa-S-azabicycloβ^.iloct-S-yl)- 5,6,7, 8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea
MS 486.3 [M+H].
Example 55 Preparation of 1-{4-[7-(2-fluoroethyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct- 3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea
MS 504.2 [M+H]. Example 56 Preparation of tert-butyl 4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-{4- [(pyridin-4-ylcarbamoyl)amino]phenyl}-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- carboxylate
MS 558.3 [M+H]. Example 57 Preparation of 1 -{4-[7-(2-methoxyethyl)-4-(8-oxa-3- azabicycloia^.iloct-a-yO-S.ej.δ-tetrahydropyridoia^-dlpyrimidin^-yllphenyl}^- pyridin-4-ylurea
MS 516.3 [M+H]. Example 58 Preparation of 1 -{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 5,6,7, 8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-(2-fluoroethyl)urea
MS 455.2 [M+H].
Example 59 Preparation of 1-cyclopropyl-3-{4-[7-ethyl-4-(3-oxa-8- azabicycloIS^.Iloct-δ-ylJ-S.ΘJ.δ-tetrahydropyridoIS^-dlpyrimidin^- yl]phenyl}urea
MS 449.3 [M+H].
Example 60 Preparation of 1 -{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 5,6,7, 8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-phenylurea
MS 485.3 [M+H]. Example 61 Preparation of 1 -{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 5,6,7, 8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1 - yl)phenyl]urea
MS 583.3 [M+H].
Example 62 Preparation of 1-{4-[7-(1-methylethyl)-4-(3-oxa-8-azabicyclo[3.2.1]oct- 8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea
MS 472.2 [M+H].
Example 63 Preparation of 1 -{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 5,6,7, 8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1- yl)methyl]phenyl}urea
MS 597.4 [M+H].
Example 64 Preparation of 1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 5,6,7, 8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-[4-(pyrrolidin-1- ylmethyl)phenyl]urea
MS 568.3 [M+H]. Example 65 Preparation of 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-{4-[7- ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}urea
MS 61 1.4 [M+H]. Example 66 Preparation of 1 -{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 5,6,7, δ-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1- yl)carbonyl]phenyl}urea
MS 61 1.3 [M+H].
Example 67 Preparation of 1-{4-[(dimethylamino)methyl]phenyl}-3-{4-[7-ethyl-4-(3- oxa-δ-azabicycloIS^.Iloct-δ-ylJ-S.βJ.δ-tetrahydropyridoIS^-dlpyrimidin^- yl]phenyl}urea
MS 542.3 [M+H].
Example 69 Preparation of 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[7-ethyl-4- (S-oxa-δ-azabicycloIS^.Iloct-δ-yO-S.βJ.δ-tetrahydropyridoIS^-dlpyrimidin^- yl]phenyl}urea
MS 572.3 [M+H].
Example 69 Preparation of 1 -[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-δ- azabicycloia^.iloct-δ-yO^^^^-trifluoroethylJ-S.ej.δ-tetrahydropyridoia^- d]pyrimidin-2-yl]phenyl}urea
MS 637.3 [M+H].
Example 70 Preparation of 1 -{4-[4-(3-oxa-δ-azabicyclo[3.2.1]oct-δ-yl)-7-(2,2,2- trifluoroethyl)-5,6,7,δ-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-pyridin-4- ylurea
MS 540.2 [M+H]. Example 71 Preparation of 4-[({4-[7-ethyl-4-(3-oxa-δ-azabicyclo[3.2.1]oct-δ-yl)- 5,6,7, δ-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}carbamoyl)amino]-N, N- dimethylbenzamide
MS 556.3 [M+H]. Example 72 Preparation of 1-(4-cyanophenyl)-3-{4-[7-ethyl-4-(3-oxa-8- azabicycloIS^.Iloct-δ-yO-S.ΘJ.δ-tetrahydropyridoβ^-dlpyrimidin^- yl]phenyl}urea
MS 510.3 [M+H]. Example 73 Preparation of 1 -{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 5,6,7, δ-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-[4- (trifluoromethyl)phenyl]urea
MS 553.2 [M+H].
Example 74 Preparation of i -^-P-ethyl^-β-oxa-δ-azabicycloIS^.Iloct-δ-yl)- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}-3-[4-(pyrrolidin-1 - ylcarbonyl)phenyl]urea
Example 75 Preparation of 4-[({4-[7-ethyl-4-(3-oxa-δ-azabicyclo[3.2.1]oct-δ-yl)-
S.ΘJ.δ-tetrahydropyridoIS^-dlpyrimidin^-yllpheny^carbamoylJaminolbenzoic acid
Example 76 Preparation of methyl 4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2- yl]phenyl}carbamoyl)amino]benzoate
Example 77 Preparation of 4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}carbamoyl)amino]-N-(1 - methylethyl)benzamide
Example 78 Preparation of 4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
S.ΘJ.δ-tetrahydropyridoIS^-dlpyrimidin^-yllpheny^carbamoylJaminol-N- methylbenzamide
Example 79 Preparation of 4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}carbamoyl)amino]benzamide
Example 80 Preparation of 1 -[4-(4-morpholin-4-yl-6, 7-dihydro-5H-pyrrolo[3,4- d]pyrimidin-2-yl)phenyl]-3-pyridin-3-ylurea
Step 1 : Preparation of 2-chloro-4-morpholin-4-yl-5,7-dihydro-pyrrolo[3,4- d]pyrimidine-6-carboxylic acid tert-butyl ester A mixture of 2,4-dichloro-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (330 mg, 1.14mmol), morpholine (1 19 mg, 1.37 mmol) and triethyl amine (167mg, 1 .65 mmol) in 14 mL of THF was stirred at room temperature for 6 hours. Then the reaction mixture was diluted with 200 mL of ethyl acetate and the organic layer was washed with saturated sodium bicarbonate aqueous solution and brine. The organic layer was concentrated and the residue was purified by reverse phase chromatography to give 2-chloro-4-morpholin-4-yl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine- 6-carboxylic acid tert-butyl ester (210mg, 54% yield) as a white solid. HPLC: RT = 2.47 min; MS 341 , 343 [M+H]. Step 2: Preparation of 1-[4-(4-morpholin-4-yl-6, 7-dihydro-5H-pyrrolo[3,4- d]pyhmidin-2-yl)phenyl]-3- pyhdin-3-ylurea
The title compound was prepared by following the procedure of Example 1 Step 3 using 2-chloro-4-morpholin-4-yl-5,7-dihydro-pyrrolo[3,4-d]pyhmidine-6-carboxylic acid tert-butyl ester and 1 -pyridin-3-yl-3- [4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)- phenyl]-urea. Yield 31.6 mg. HPLC: RT = 1 .83 min; MS 418 [M+H].
Example 81 Preparation of i -^-^δ-oxa-S-azabicycloIS^.Iloct-S-ylJ-ΘJ-dihydro- 5H-pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea
Step 1 : Preparation of 2-chloro-4- (8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,7- dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester The title compound was prepared by following the procedure of Example 80
Step 1 using 2,4-dichloro-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert- butyl ester and 8-oxa-3-aza-bicyclo[3.2.1]octane, heating at 30 0C over night. Yield 270 mg, 64% yield; HPLC: RT = 2.75 min; MS 367, 369 [M+H].
Step 2: Preparation of 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-YL]phenyl}-3-pyridin-3-ylurea
The title compound was prepared by following the procedure of Example 1 Step 3 using 2-chloro-4- (δ-oxa-S-aza-bicycloP^.IJoct-S-yO-δJ-dihydro-pyrroloβ^- d]pyhmidine-6-carboxylic acid tert-butyl ester and 1-pyridin-3-yl-3- [4-(4,4,5,5- tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 30.8 mg. HPLC: RT = 1.98 min; MS 444 [M+H].
Example 82 Preparation of 1 -{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro- 5H-pyrrolo[3,4-d]pyrimidin-2-YL]phenyl}-3-pyridin-3-ylurea
Step 1 : Preparation of 2-chloro-4- (3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,7- dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester The title compound was prepared by following the procedure of Example 80 Step 1 using 2,4-dichloro-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert- butyl ester and 3-oxa-8-aza-bicyclo[3.2.1]octane, heating at 30 0C overnight. Yield 260 mg, 62% yield; HPLC: RT = 2.77 min; MS 367, 369 [M+H]. Step 2: Preparation of 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}-3-pyhdin-3-ylurea
The title compound was prepared by following the procedure of Example 1 Step 3 using 2-chloro-4- (S-oxa-δ-aza-bicycloP^.IJoct-δ-yO-δJ-dihydro-pyrroloP^- d]pyhmidine-6-carboxylic acid tert-butyl ester and 1-pyridin-3-yl-3- [4-(4,4,5,5- tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 31 .3 mg. HPLC: RT = 1.98 min; MS 444 [M+H].
Example 83 Preparation of 1-methyl-3- [4-(4-morpholin-4-yl-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-yl)phenyl]urea
The title compound was prepared by following the procedure of Example 1 Step 3 using 2-chloro-4-morpholin-4-yl-5,7-dihydro-pyrrolo[3,4-d]pyhmidine-6-carboxylic acid tert-butyl ester and 1 -methyl-3- [4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)- phenyl]-urea. Yield 41.1 mg. HPLC: RT = 1 .47 min; MS 355 [M+H]. Example 84 Preparation of 1-methyl-3- {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)- 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}urea
The title compound was prepared by following the procedure of Example 1 Step
3 using 2-chloro-4- (δ-oxa-S-aza-bicycloβ^.iJoct-S-yO-SJ-dihydro-pyrroloβ^- d]pyhmidine-6-carboxylic acid tert-butyl ester and 1-methyl-3- [4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 34.4 mg. HPLC: RT = 1.68 min; MS 381 [M+H]. Example 85 Preparation of 1-methyl-3- {4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7- dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}urea
The title compound was prepared by following the procedure of Example 1 Step 3 using 2-chloro-4- (S-oxa-δ-aza-bicycloP^.IJoct-δ-yO-δJ-dihydro-pyrroloP^- d]pyhmidine-6-carboxylic acid tert-butyl ester and 1-methyl-3- [4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 48.8 mg. HPLC: RT = 1.66 min; MS 381 [M+H]. Example 86 Preparation of 1-(4-{[4-(dimethylamino)piperidin-1- yllcarbony^phenylJ-S-^^-morpholin^-yl-ΘJ-dihydro-SH-pyrroloIS^-dlpyrimidin-
2-yl)phenyl]urea
The title compound was prepared by following the procedure of Example 1 Step 3 using 2-chloro-4-morpholin-4-yl-5,7-dihydro-pyrrolo[3,4-d]pyhmidine-6-carboxylic acid tert-butyl ester and 1 -[4-(4-dimethylamino-piperidine-1-carbonyl)-phenyl]-3-[4-(4, 4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 15 mg. HPLC: RT = 2.0 min; MS 570 [M+H].
Example 87 Preparation of 1 -(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}urea
The title compound was prepared by following the procedure of Example 1 Step 3 using 2-chloro-4- (δ-oxa-S-aza-bicycloP^.IJoct-S-yO-δJ-dihydro-pyrroloβ^- d]pyhmidine-6-carboxylic acid tert-butyl ester and 1-[4-(4-dimethylamino-pipehdine-1- carbonyl)-phenyl]-3-[4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 5 mg. HPLC: RT = 1.95 min; MS 597 [M+H]. Example 88 Preparation of 1 -(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}urea
The title compound was prepared by following the procedure of Example 1 Step
3 using 2-chloro-4- (S-oxa-δ-aza-bicycloP^.IJoct-δ-yO-δJ-dihydro-pyrroloβ^- d]pyhmidine-6-carboxylic acid tert-butyl ester and 1-[4-(4-dimethylamino-pipehdine-1- carbonyl)-phenyl]-3-[4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 10 mg. HPLC: RT = 1 .90 min; MS 597 [M+H]. Example 89 Preparation of 1-{4-[6-(methylsulfonyl)-4-morpholin-4-yl-6, 7-dihydro- 5H-pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea
The title compound was prepared by following the procedure of Example 3 using 1-[4-(4-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[3,4-d]pyhmidin-2-yl)phenyl]-3-pyhdin-3- ylurea and methanesulfonyl chloride. Yield 6.0 mg. HPLC: RT = 2.13 min; MS 496 [M+H]. Example 90 Preparation of 1-{4-[6-(methylsulfonyl)-4-(8-oxa-3- azabicycloia^.iloct-a-yO-ej-dihydro-SH-pyrroloia^-dlpyrimidin^-yllphenyl}^- pyridin-3-ylurea
The title compound was prepared by following the procedure of Example 3 using 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2- yl]phenyl}-3-pyhdin-3-ylurea and methanesulfonyl chloride. Yield 7.5 mg. HPLC: RT = 2.21 min; MS 522 [M+H].
Example 91 Preparation of 1-{4-[6-(methylsulfonyl)-4-(3-oxa-8- azabicycloia^.iloct-δ-yO-ΘJ-dihydro-SH-pyrroloia^-dlpyrimidin^-yllphenyl}^- pyridin-3-ylurea
The title compound was prepared by following the procedure of Example 3 using 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2- yl]phenyl}-3-pyhdin-3-ylurea and methanesulfonyl chloride. Yield 10 mg. HPLC: RT = 2.27 min; MS 522 [M+H]. Example 92 Preparation of 1-methyl-3- {4-[6-(methylsulfonyl)-4-morpholin-4-yl-6, 7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}urea
The title compound was prepared by following the procedure of Example 3 using 1 -methyl-3- [4-(4-morpholin-4-yl-6, 7-dihydro-5H-pyrrolo[3,4-d]pyhmidin-2-yl) phenyl]urea and methanesulfonyl chloride. Yield 8.0 mg. HPLC: RT = 1 .86 min; MS 433 [M+H].
Example 93 Preparation of 1 -methyl-3- {4-[6-(methylsulfonyl)-4-(8-oxa-3- azabicycloIS^.Iloct-S-ylJ-ΘJ-dihydro-SH-pyrroloIS^-dlpyrimidin^-yllpheny^urea
The title compound was prepared by following the procedure of Example 3 using 1 -methyl-3- {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyhmidin-2-yl]phenyl}urea and methanesulfonyl chloride. Yield 16 mg. HPLC: RT = 1.99 min; MS 459 [M+H].
Example 94 Preparation of 1 -methyl-3- {4-[6-(methylsulfonyl)-4-(3-oxa-8- azabicycloIS^.Iloct-δ-ylJ-ΘJ-dihydro-SH-pyrroloIS^-dlpyrimidin^-yllpheny^urea
The title compound was prepared by following the procedure of Example 3 using 1 -methyl-3- {4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyhmidin-2-yl]phenyl}urea and methanesulfonyl chloride. Yield 14 mg. HPLC: RT = 2.02 min; MS 459 [M+H]. Example 95 Preparation of 1 -(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-{4-[6-(methylsulfonyl)-4-morpholin-4-yl-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}urea
The title compound was prepared by following the procedure of Example 3 using 1 -(4-{[4-(dimethylamino)pipehdin-1 -yl]carbonyl} phenyl)-3-[4-(4-morpholin-4-yl-6,7- dihydro-5H-pyrrolo[3,4-d]pyhmidin-2-yl) phenyl]urea and methanesulfonyl chloride. Yield 7.5 mg. HPLC: RT = 2.14 min; MS 649 [M+H]. Example 96 Preparation of 1 -(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-{4-[6-(methylsulfonyl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}urea
The title compound was prepared by following the procedure of Example 3 using 1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8- azabicycloP^.iloct-δ-yO-ΘJ-dihydro-SH-pyrroloβ^-dlpyrimidin^-yllphenylϊurea and methanesulfonyl chloride. Yield 3.8 mg. HPLC: RT = 2.40 min; MS 675 [M+H]. Example 97 Preparation of 1-Methyl-3-{4-[6-methyl-4-(3-oxa-8- azabicycloIS^.Iloct-δ-ylJ-ΘJ-dihydro-SH-pyrroloIS^-dlpyrimidin^-yllpheny^urea
tert-Butyl 4-(3-oxa-8-azabicyclo[3.2.1 ]octan-8-yl)-2-chloro-5H-pyrrolo[3,4- d]pyhmidine-6(7H)-carboxylate (990 mg) was treated with 4N HCI in dioxane (4 mL) to give the HCI salt of 8-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-oxa-8- azabicyclo[3.2.1]octane as a white solid (0.81 g). This material was dissolved in 1 ,2- dichloroethane (10 mL) and Et3N (0.53 mL) and treated with catalytic AcOH, excess 37% aqueous formaldehyde and Na(OAc)3BH (0.84 g). After 18h saturated aqueous. NaHCO3 was added and the mixture extracted with CH2CI2 (2X). Drying over Na2SO3, concentration, and trituration with hexane/Et2O gave 8-(2-chloro-6-methyl-6,7-dihydro- SH-pyrroloβ^-dJpyrimidin^-yO-S-oxa-δ-azabicycloβ^.iJoctane (410 mg). This material was treated with 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (380 mg), 2N aqueous Na2CO3 (0.6 mL) and Pd(PPh3)4 (85 mg) in 1 :1 toluene:ethanol (6 mL) and heated in a microwave to 12O0C for 20 min. Aqueous workup and chromatography gave 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4- d]pyhmidin-2-yl)aniline (206 mg). This material and thethylamine in dichloromethane were treated with a solution of thphosgene in dichloromethane. After -30 min methylamine was added. After ~4h, the reaction mixture was subjected to an aqueous workup and purified by chromatography to give the title compound as a TFA salt. Example 98 Preparation of 1-{4-[6-Methyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7- dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea
By an analogous method to that described above and substituting A- aminopyhdine for methylamine in the last step the title compound was obtained as a TFA salt.
Example 99 Preparation of i-^-te-Methyl^-β-oxa-δ-azabicycloIS^.Iloct-δ-yO-ΘJ- dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea
By an analogous method to that described above and substituting 3- aminopyhdine for methylamine in the last step the title compound was obtained as a TFA salt.
Example 100 Preparation of 1-{4-[6-Methyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1- yl)phenyl]urea)
By an analogous method to that described above and substituting A-(A- methylpiperazin-1-yl)aniline for methylamine in the last step the title compound was obtained as a TFA salt.
Example 101 Preparation of 1-{4-[2-(Dimethylamino)ethoxy]phenyl}-3-{4-[6- methyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidin-2-yl]phenyl}urea
By an analogous method to that described above and substituting 4-(2-
(dimethylamino)ethoxy)aniline for methylamine in the last step the title compound was obtained as a TFA salt.
Example 102 Preparation of 2-Hydroxyethyl {4-[6-methyl-4-(3-oxa-8- azabicycloIS^.Iloct-δ-yO-ΘJ-dihydro-SH-pyrroloIS^-dlpyrimidin^- yl]phenyl}carbamate
By an analogous method to that described above and substituting ethylene glycol for methylamine in the last step the title compound was obtained as a TFA salt.
BIOLOGICAL EVALUATION
PI3K-alpha and PI3K-qamma Fluorescence Polarization Assay Protocols The reaction buffer was 20 mM HEPES, pH 7.5, 2 mM MgCI2, 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 Pl P2, 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 0.01 125 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. Compounds of the invention had IC50S against PI3K-alpha ranging from 7 nM to 2,858 nM. mTOR Enzyme Assay
(See Toral-Barza, et al. Biochem Biophys. Res. Commun. 2005 June 24;332(1 ):304-10). The routine human TOR assays with purified enzyme were performed in 96-well plates by DELFIA format as follows. Enzymes were first diluted in kinase assay buffer (10 mM HEPES (pH 7.4), 50 mM NaCI, 50 mM β-glycerophosphate, 10 imM MnCI2, 0.5 mM DTT, 0.25 μM microcystin LR, and 100 μg/mL BSA). To each well, 12 μL of the diluted enzyme were mixed briefly with 0.5 μl_ test inhibitor or the control vehicle dimethylsulfoxide (DMSO). The kinase reaction was 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 μM ATP and 1.25 μM His6- S6K. The reaction plate was 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 was performed at room temperature using a monoclonal anti-P(T389)-p70S6K antibody (1A5, Cell Signaling) labeled with Europium- N1-ITC (Eu) (10.4 Eu per antibody, PerkinElmer). The DELFIA Assay buffer and Enhancement solution were purchased from PerkinElmer. 45 μL of the terminated kinase reaction mixture was transferred to a MaxiSorp plate (Nunc) containing 55 μL PBS. The His6-S6K was allowed to attach for 2 hours after which the wells were aspirated and washed once with PBS. 100 μL of DELFIA Assay buffer with 40 ng/mL Eu-P(T389)-S6K antibody was added. The antibody binding was continued for 1 hour with gentle agitation. The wells were then aspirated and washed 4 times with PBS containing 0.05% Tween-20 (PBST). 100 μL of DELFIA Enhancement solution was added to each well and the plates were read in a PerkinElmer Victor model plate reader. Data obtained were used to calculate enzymatic activity and enzyme inhibition by potential inhibitors. Compounds of the invention had IC50 activities ranging from <1 nM to 580 nM. 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 NaCI, 0.2 mM DTT, 50 mM β- glycerophosphate, 0.5 μM microcystin LR, 10 mM MnCI2). 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 #439454). The plates were incubated at room temperature for 2 hr (4 0C 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 100 μl_ DELFIA assay buffer (PerkinElmer #1244-1 1 1 ). 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.
In vitro cell growth assay
The cell lines used were human prostate lines LNCap and PC3MM2, human breast lines MDA468 and MCF7, human renal line HTB44 (A498), human colon line HCT1 16, and human ovarian line OVCAR3. Cells were plated in 96-well culture plates.
One day following plating, the inhibitors were added to cells. Three days after drug treatment, viable cell densities were determined by metabolic conversion (by viable cells) of the dye MTS, a well-established cell proliferation assay. The assays were performed using an assay kit purchased from Promega Corp. (Madison, Wl) following the protocol supplied with the kit. The MTS assay results were read in a 96-well plate reader by measuring absorbance at 490 nm. The effect of each treatment was calculated as percent of control growth relative to the vehicle-treated cells grown in the same culture plate. The drug concentration that conferred 50% inhibition of growth was determined as IC50. Compounds of the invention had IC50 activities against LNCap cells ranging from 6 nM to >60 uM.
Tables 1 and 2 show the results of the described biological assays.
Table 1 tetrahydropyrido[3,4-d]pyrimidine compounds
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Table 2 dihydro-5H-pyrrolo[3,4-d]pyrimidine compounds
Figure imgf000076_0001
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.
While particular embodiments 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.

Claims

WHAT IS CLAIMED IS:
1 ) A compound of Formula I:
Figure imgf000078_0001
or a geometric isomer thereof or a pharmaceutically acceptable salt thereof wherein;
R1 is independently CrCδalkyl-, C6-C-ι4aryl-, d-Cgheteroaryl-, halogen, or hydroxyl; p is 0, 1 , 2, 3, or 4; het is a d-Cgheterocyclyl- group containing at least one oxygen atom; m is 0 or 1 ;
Ar is C6-C-ι4aryl- or d-Cgheteroaryl- wherein the C6-C-ι4aryl- or d-Cgheteroaryl- is optionally substituted with from 1 to 4 substituents independently selected from d- Cεalkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl(Ci-C6alkyl)-, H2N-, aminoalkyl-, di(d- C6alkyl)amino-, HO2C-, (CrC6alkoxy)carbonyl-, (CrC6alkyl)carboxyl-, di(d- C6alkyl)amido-, H2NC(O)-, (CrC6alkyl)amido-, and O2N-; R2 is H or Ci-C6alkyl-; R3 is R6, R7R8N-, R9S-, or R9O-
R6 is H; Ci-C6alkyl- optionally substituted with from 1 to 3 substituents independently selected from d-C6alkoxy-, H2N-, (d-C6alkyl)amino-, di(Ci- C6alkyl)amino-, C6-d4aryl-, d-Cgheterocyclyl- optionally substituted by Ci-C6alkyl-, and d-Cgheteroaryl-; CrC6alkoxy-; d-Cgheteroaryl- optionally substituted with from 1 to 3 substituents independently selected from Ci-C6alkyl- optionally substituted with H2N-, (C-i-C6alkyl)amino-, or di(C-i-C6alkyl)amino-, heterocyclyl(CrC6alkyl)-, halogen, hydroxyl, H2N-, O2N-, H2NSO2-, HO2C-, (CrC6alkoxy)carbonyl-, (CrC6alkoxy)C(0)NH-, (CrC6alkyl)amino-, di(CrC6alkyl)amino-, R10R11NC(O)-, R10O-, R10R11N-, R10R11NS(O)2-, R10S(O)2NR11-, R10R11NC(O)NH-, R10S-, R10S(O)-, R10S(O)2-, R10C(O)-, d-Cgheterocyclyl- optionally substituted by CrCδalkyl- or d-Cδhydroxylalkyl-, Cr Cδhydroxylalkyl-, and perfluoro(Ci-C6)alkyl-; d-Cδhydroxylalkyl-; d-Cgheterocyclyl-; Cε- Ci4aryl- optionally substituted with from 1 to 3 substituents independently selected from C-i-Cδalkyl- optionally substituted with H2N-, (Ci-C6alkyl)amino-, or di(Ci-C6alkyl)amino-, heterocyclyl(CrC6alkyl)-, halogen, hydroxyl, H2N-, O2N-, H2NSO2-, HO2C-, (Cr C6alkoxy)carbonyl-, (CrC6alkoxy)C(0)NH-, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, R10R11NC(O)-, Z, wherein Z is R10O-, R10R11N-, R10R11NS(O)2-, R10S(O)2NR11-, R10R11NC(O)NH-, R10S-, R10S(O)-, R10S(O)2-, R10C(O)-, Ci-Cgheterocyclyl- optionally substituted by C-i-Cδalkyl- or C-i-Cδhydroxylalkyl-, d-Cδhydroxylalkyl-, and perfluoro(d- C6)alkyl-; or Cs-Cscycloalkyl-; R10 and R11 are each independently H, CrCδalkyl-, Ci-C6alkoxy(C2-C6alkylene)-,
(d-CealkyOamino-C^Cealkylene-, di(Ci-C6alkyl)amino-C2-C6alkylene-, C2-C6alkenyl, C2-C6alkynyl, C6-Ci4aryl-, (C6-Ci4aryl)alkyl-, d-Cscycloalkyl-, d-Cgheteroaryl-, (Cr Cgheteroaryl)alkyl-, Ci-Cgheterocyclyl-, or heterocyclyl(d-C6alkyl-); or R10 and R11, when taken together with the nitrogen to which they are attached, form a 3- to 7- membered heterocycle wherein up to two of the carbon atoms of the heterocycle are optionally replaced with -N(H)-, -N(d-C6alkyl)-, -N(C3-C8CyClOaIkYl)-, - N(C6-C-ι4aryl)-, -N(d-Cgheteroaryl)-, -S-, -SO-, -S(O)2-, or -O- and wherein any carbon atom of the heterocycle is optionally substituted with from 1 or 2 substituents independently selected from CrCδalkyl-, H2N-, (Ci-C6alkyl)amino-, di(CrC6alkyl)amino- , and Ci-Cgheterocyclyl-;
R7 and R8 are each independently H; CrCδalkyl- optionally substituted with from 1 to 3 substituents independently selected from CrCεalkoxy-, H2N-, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, C6-d4aryl-, halogen, Ci-Cgheterocyclyl- optionally substituted by CrCδalkyl-, and d-Cgheteroaryl-; CrCεalkoxy-; d-Cgheteroaryl- optionally substituted with from 1 to 3 substituents independently selected from CrCδalkyl- optionally substituted with H2N-, (Ci-C6alkyl)amino-, or di(Ci-C6alkyl)amino-, heterocyclyl(d- C6alkyl)- optionally substituted with d-C6alkyl, halogen, hydroxyl, H2N-, O2N-, H2NSO2-, HO2C-, (Ci-C6alkoxy)carbonyl-, (CrC6alkoxy)C(0)NH-, (Ci-C6alkyl)amino-, di(Cr C6alkyl)amino-, R10R11NC(O)-, R10O-, R10R11N-, R10R11NS(O)2-, R10S(O)2NR11-, R10R11NC(O)NH-, R10S-, R10S(O)-, R10S(O)2-, R10C(O)-, Ci-Cgheterocyclyl- optionally substituted by C-i-Cδalkyl- or C-i-Cδhydroxylalkyl-, C-i-Cδhydroxylalkyl-, and perfluoro(Cr C6)alkyl-; d-Cehydroxylalkyl-; CrC9heterocyclyl-; C6-Ci4aryl- optionally substituted with from 1 to 3 substituents independently selected from CrCδalkyl- optionally substituted with H2N-, (Ci-C6alkyl)amino-, or di(CrC6alkyl)amino-, heterocyclyl(d-C6alkyl)- optionally substituted with CrC6alkyl, halogen, hydroxyl, H2N-, O2N-, H2NSO2-, HO2C-, (Ci-C6alkoxy)carbonyl-, (Ci-C6alkoxy)C(0)NH-, (Ci-C6alkyl)amino-, di(Ci- C6alkyl)amino-, R10R11NC(O)-, Z, wherein Z is R10O-, R10R11N-, R10R11NS(O)2-, R10S(O)2NR11-, R10R11NC(O)NH-, R10S-, R10S(O)-, R10S(O)2-, R10C(O)-, Cr Cgheterocyclyl- optionally substituted by CrC6alkyl- or CrC6hydroxylalkyl-, Cr Cδhydroxylalkyl-, and perfluoro(Ci-C6)alkyl-; and Cs-Cscycloalkyl-; or R7 and R8, when taken together with the nitrogen to which they are attached, form a 3- to 7- membered heterocycle wherein up to two of the carbon atoms of the heterocycle are optionally replaced with -N(H)-, -N(Ci-C6alkyl)-, -N(C6-C-ι4aryl)-, -S-, - SO-, -S(O)2-, or -0-; R9 is CrC6alkyl-, C6-Ci4aryl-, (C6-Ci4aryl)alkyl- optionally substituted by H2N-,
C-i-Cgheterocyclyl-, Cs-Cscycloalkyl-, CrC6hydroxylalkyl-, or d-Ceperfluoroalkyl-; n is O, 1 , or 2;
R4 is: a) hydrogen; b) C-i-Csacyl-, optionally substituted with from 1 to 3 substituents independently selected from: i) C-i-Cδalkoxy-, ii) (Ci-C6)alkyl-, iii) (Ci-C6alkyl)amino-, iv) C3-C8cycloalkyl-, v) di(Ci-C6alkyl)amino-, vi) halogen, vii) Ci-Cδperfluoroalkyl-, viii) H2N-, ix) and CF3O-; c) C-i-Cδalkyl- optionally substituted with from 1 to 3 substituents independently selected from: i) C-i-Cδalkoxy-, ii) (Ci-C6alkoxy)carbonyl-, iii) (Ci-C6alkyl)amino-, iv) di(Ci-C6alkyl)amino-, v) Cs-Cscycloalkyl-, vi) halogen, vii) HC(O)-, viii) HO2C-, ix) and H2N-; d) C-i-Ceaminoalkyl- optionally substituted with a substituent selected from: i) C6-Ci4aryl- optionally substituted with halogen, ii) (CrC9heteroaryl)alkyl-, iii) (C6-Ci4aryl)alkyl-, iv) H2N-CrC6alkylene-, v) (Ci-C6alkyl)amino-CrC6alkylene-, vi) and di(Ci-C6alkyl)amino-CrC6alkylene-; e) C3-C8CVClOaIkVl-; f) C6-C-ι4aryl- optionally substituted with a substituent selected from: i) HO2C-, ii) CrCδhydroxylalkyl-, iii) R12R13NC(O)-, iv) and (d-CealkoxyJcarbonyl-; g) d-Cgheterocycle optionally substituted with from 1 to 3 substituents independently selected from: i) CrC8acyl, wherein the CrC8acyl is optionally substituted with a H2N-, ii) CrC6alkyl-, iii) (Ci-Cgheteroaryl)alkyl- wherein the ring portion of the (Cr Cgheteroaryl)alkyl- group is optionally substituted with from 1 to
3 substituents independently selected from:
A) CrC6alkylC(O)NH-,
B) halogen,
C) H2N-, D) and CrC6alkyl-, iv) heterocyclyl(CrC6alkyl)-, wherein the ring portion of the heterocyclyl(CrC6alkyl) group is optionally substituted by a (Cε- Ci4aryl)alkyl-, v) (C6-C-ι4aryl)alkyl-, wherein the ring portion of the (Cε- C-ι4aryl)alkyl- group is optionally substituted by 1 to 3 substituents independently selected from:
A) halogen,
B) Ci-C6alkyl-,
C) di(Ci-C6alkyl)amino-(Ci-C6alkylene)-0-, D) and d-Cgheteroaryl-; vi) and (CrC6alkoxy)carbonyl-; h) heterocyclyl(CrC6alkyl) optionally substituted with a substituent selected from: i) Ci-C6alkyl-, ii) d-Cscycloalkyl-, iii) (CrCδalkoxyJcarbonyl-, iv) C-i-Cδalkylcarboxy-, v) (C6-Ci4aryl)alkyl- wherein the ring portion of the (Cε- C-ι4aryl)alkyl- group is optionally substituted with a substituent selected from:
A) halogen,
B) C-i-Cgheteroaryl-,
C) and di(CrC6alkyl)amino-(Ci-C6alkylene)-0-, vi) (Ci-Cgheteroaryl)alkyl- wherein the ring portion of the (Cr
Cgheteroaryl)alkyl- group is optionally substituted by a halogen, vii) and d-Csacyl, wherein the d-Csacyl is optionally substituted with from 1 to 3 independently selected halogens, i) (d-Cgheteroaryl)alkyl- wherein the ring portion of the (d-Cgheteroaryl)alkyl- is optionally substituted by 1 to 3 substituents independently selected from: i) R12R13NC(O)NH-, ii) (Ci-C6alkoxy)carbonyl-, iii) HO2C-, iv) hydroxyl, v) and R12R13NC(O)-; j) (C6-Ci4aryl)alkyl- wherein the ring portion of the (C6-d4aryl)alkyl- group is optionally by 1 to 3 substituents independently selected from: i) R12R13NC(O)NH-, ii) (Ci-C6alkoxy)carbonyl-, iii) HO2C-, iv) hydroxyl, v) and R12R13NC(O)-; k) d-Cehydroxylalkyl-; I) Ci-Ceperfluoroalkyl-; m) d-Cgheteroaryl- optionally substituted with a substituent selected from: i) HO2C-, ii) d-Cehydroxylalkyl-, iii) R12R13NC(O)-, iv) and (CrC6alkoxy)carbonyl-; n) R12R13NC(O)-; o) R14OC(O)-, p) and R14S(O)2-; R12 and R13 are each independently: a) H; b) CrCδalkyl- optionally substituted with a substituent selected from: i) Ci-C6alkylC(O)NH-, ii) H2N-, iii) (Ci-C6alkyl)amino-, iv) and di(CrC6alkyl)amino-, c) C2-C6alkenyl- d) Cs-Cscycloalkyl-; e) C6-C-ι4aryl- optionally substituted with a substituent selected from: i) halogen, ii) and d-C9heterocycle wherein the d-Cgheterocycle is optionally substituted with (Ci-C6alkoxy)carbonyl-; f) d-Cgheteroaryl-; g) (d-Cgheteroaryl)alkyl-; h) heterocyclyl(Ci-C6alkyl)-; i) (C6-Ci4aryl)alkyl-, wherein the chain portion of the (C6-Ci4aryl)alkyl- group is optionally substituted by a hydroxyl; j) or C-i-Cgheterocyclyl- optionally substituted with a (CrC6alkoxy)carbonyl-; or R12 and R13, when taken together with the nitrogen to which they are attached, form a 3- to 7- membered heterocycle wherein up to two of the carbon atoms of the heterocycle are optionally replaced with -N(H)-, -N(CrC6alkyl)-, -N(C6-Ci4aryl)-, -S-, - SO-, -S(O)2-, or -0-;
R14 is Ci-C6alkyl-, C6-Ci4aryl-, (C6-Ci4aryl)alkyl-, d-Cgheterocyclyl-, C3- Cscycloalkyl-, d-Cδhydroxylalkyl-, or CrCδperfluoroalkyl-, wherein each Ci-C6alkyl-, C6-Ci4aryl-, (C6-d4aryl)alkyl-, d-Cgheterocyclyl-, or drCscycloalkyl-, is optionally substituted with a d-Cδalkoxy-, Ci-C6alkyl-, Cs-Cscycloalkyl-, NC-, or halogen;
R5 are independently H or Ci-C6alkyl. 2) A compound of claim 1 of the Formula II:
Figure imgf000084_0001
or a geometric isomer thereof or a pharmaceutically acceptable salt thereof. 3) A compound of claim 2 of the Formula III:
Figure imgf000084_0002
or a pharmaceutically acceptable salt thereof. 4) A compound of claim 2 of the Formula IV:
Figure imgf000085_0001
or a pharmaceutically acceptable salt thereof.
5) A compound of claim 2 of the Formula V:
Figure imgf000085_0002
or a pharmaceutically acceptable salt thereof. 6) A compound of claim 1 of the Formula Vl:
Figure imgf000086_0001
or a geometric isomer thereof or a pharmaceutically acceptable salt thereof.
7) A compound of claim 6 of the Formula VII:
Figure imgf000086_0002
or a pharmaceutically acceptable salt thereof. 8) A compound of claim 6 of the Formula VIII:
Figure imgf000087_0001
or a pharmaceutically acceptable salt thereof.
9) A compound of claim 6 of the Formula IX:
Figure imgf000087_0002
or a pharmaceutically acceptable salt thereof. 10) A compound of any one of claims 1-9 wherein R2 is H. 1 1 ) A compound of any one of claims 1-10 wherein R3 is R7R8N-.
12) A compound of claim 1 1 wherein R7 is 3- or 4-pyridyl.
13) A compound of any one of claims 1-12 wherein R4 is Ri4S(O)2-.
14) A compound of claim 13 wherein Ri4 is CH3-.
15) A compound of claim 1 selected from the group consisting of:
1-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyhmidin-2-yl)phenyl]-3-pyridin-3- ylurea;
^^-(/-acetyl^-morpholin^-yl-S^J^-tetrahydropyridoP^-dlpyrimidin^-yOphenyll-S- pyridin-3-ylurea; 1 -{4-[7-(methylsulfonyl)-4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyrimidin-2- yl]phenyl}-3-pyhdin-3-ylurea;
1-{4-[4-morpholin-4-yl-7-(3,3,3-thfluoropropanoyl)-5,6,7,8-tetrahydropyrido[3,4- d]pyhmidin-2-yl]phenyl}-3-pyhdin-3-ylurea;
1-[4-(7-methyl-4-morpholin-4-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyhmidin-2-yl)phenyl]-3- pyridin-3-ylurea;
1-methyl-3-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4- d]pyhmidin-2-yl]phenyl}urea;
1-methyl-3-[4-(7-methyl-4-morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyrimidin-2- yl)phenyl]urea; 1-methyl-3-[4-(4-morpholin-4-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2- yl)phenyl]urea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-5, 6,7,8- tetrahydropyhdo[3,4-d]pyhmidin-2-yl)phenyl]urea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[7-(methylsulfonyl)-4- morpholin-4-yl-5,6,7,8-tetrahydropyhdo[3,4-d]pyhmidin-2-yl]phenyl}urea;
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2- yl]phenyl}-3-pyhdin-3-ylurea;
1-{4-[7-(methylsulfonyl)-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyhdo[3,4-d]pyhmidin-2-yl]phenyl}-3-pyhdin-3-ylurea; 1-{4-[7-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyhmidin-2-yl]phenyl}-3-pyhdin-3-ylurea; 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}urea;
1-methyl-3-{4-[7-(methylsulfonyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}urea; 1-methyl-3-{4-[7-methyl-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}urea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[4-(8-oxa-3- azabicyclotS^.iloct-S-yO-S^J^-tetrahydropyridotS^-dlpyrimidin^-yllpheny^urea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[7-(methylsulfonyl)-4-(8- oxa-3-azabicyclo[3.2.1]oct-3-yl)-5A7,8-tetrahydropyrido[3,4-d]pyrimidin-2- yl]phenyl}urea; butyl 2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,8- dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate;
2-methylpropyl 2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1 ]oct- 3-yl)-5,8-dihydropyrido[3,4-d]pyrirnidine-7(6H)-carboxylate;
N-butyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,8- dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxarnide;
N-tert-butyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-
5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxarnide; 2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-N-prop-2- en-1-yl-5,8-dihydropyrido[3,4-d]pyrirnidine-7(6H)-carboxarnide;
N-hexyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-
5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxarnide;
N-cyclohexyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3- yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide;
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-7-(phenylsulfonyl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}urea;
1-(4-{7-[(4-fluorophenyl)sulfonyl]-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl}phenyl)-3-methylurea; 1-(4-{7-[(4-cyanophenyl)sulfonyl]-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl}phenyl)-3-methylurea;
N,N-dimethyl-2-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3- yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-sulfonamide;
1-(4-{7-[(4-chlorophenyl)sulfonyl]-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl}phenyl)-3-methylurea; 1-{4-[7-(methoxyacetyl)-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyndo[3,4-d]pynmidin-2-yl]phenyl}-3-methylurea;
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-7-pentanoyl-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}urea; 1-{4-[7-heptanoyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}-3-methylurea;
1-{4-[7-(2,2-dimethylpropanoyl)-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-methylurea;
1-{4-[7-(2-ethylhexanoyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-methylurea;
1-{4-[7-(3-cyclopentylpropanoyl)-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-methylurea;
1-(4-{7-[(2,6-difluorophenyl)carbonyl]-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl}phenyl)-3-methylurea; 1-(4-{7-[(2-fluorophenyl)carbonyl]-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl}phenyl)-3-methylurea;
1-(4-{7-[(4-tert-butylphenyl)carbonyl]-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl}phenyl)-3-methylurea;
1-(4-{7-[(2-methoxyphenyl)carbonyl]-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl}phenyl)-3-methylurea;
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2- yl]phenyl}-3-pyridin-3-ylurea;
1-methyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}urea; 1-{4-[7-methyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[7-(methylsulfonyl)-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-pyndin-3-ylurea;
1-methyl-3-{4-[7-methyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}urea;
1-methyl-3-{4-[7-(methylsulfonyl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}urea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8- azabicyclotS^.iloct-δ-yO-S^J^-tetrahydropyridotS^-dlpyrirnidin^-yllphenylϊurea; 1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[7-(methylsulfonyl)-4-(3- oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyndo[3,4-d]pyrirnidin-2- yl]phenyl}urea;
1-{4-[7-methyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[7-(N,N-dimethylglycyl)-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-pyndin-4-ylurea;
7,7-bis(2-fluoroethyl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-2-{4-[(pyridin-4- ylcarbamoyl)arnino]phenyl}-5,6,7,8-tetrahydropyrido[3,4-d]pyπrnidin-7-iurn trifluoroacetate; methyl 4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-2-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-
5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate;
1-{4-[7-(1-methylethyl)-4-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-pyndin-4-ylurea; 1-{4-[7-ethyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[7-(2-fluoroethyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}-3-pyridin-4-ylurea; tert-butyl 4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-{4-[(pyridin-4- ylcarbamoyl)arnino]phenyl}-5,8-dihydropyrido[3,4-d]pyrirnidine-7(6H)-carboxylate;
1-{4-[7-(2-methoxyethyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-pyndin-4-ylurea;
1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}-3-(2-fluoroethyl)urea; 1-cyclopropyl-3-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}urea;
1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}-3-phenylurea;
1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1 -yl)phenyl]urea;
1-{4-[7-(1-methylethyl)-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-pyndin-4-ylurea;
1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea; 1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyπrnidin-2-yl]phenyl}-3-[4-(pyrrolidin-1-ylmethyl)phenyl]urea;
1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-{4-[7-ethyl-4-(3-oxa-8- azabicyclotS^.iloct-δ-yO-S^J^-tetrahydropyridotS^-dlpyrirnidin^-yllphenylϊurea; 1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1 -yl)carbonyl]phenyl}urea;
1-{4-[(dimethylamino)methyl]phenyl}-3-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
5,6,7,8-tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]phenyl}urea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-7-(2,2,2- trifluoroethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pynrnidin-2-yl]phenyl}urea;
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-7-(2,2,2-trifluoroethyl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}-3-pyndin-4-ylurea; 4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyπmidin-2-yl]phenyl}carbamoyl)amino]-N,N-dimethylbenzamide;
1-(4-cyanophenyl)-3-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrirnidin-2-yl]phenyl}urea;
1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}-3-[4-(trifluoromethyl)phenyl]urea;
1-{4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}-3-[4-(pyrrolidin-1-ylcarbonyl)phenyl]urea;
4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}carbamoyl)amino]benzoic acid; methyl 4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}carbamoyl)amino]benzoate;
4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl]phenyl}carbamoyl)amino]-N-(1-methylethyl)benzamide;
4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}carbamoyl)arnino]-N-methylbenzarnide;
4-[({4-[7-ethyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrirnidin-2-yl]phenyl}carbamoyl)amino]benzarnide;
1-[4-(4-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrirnidin-2-yl)phenyl]-3-pyπdin-3- ylurea; 1-methyl-3-[4-(4-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrirnidin-2-yl)phenyl]urea; 1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4-morpholiri-4-yl-6,7- dihydro-5H-pyrrolo[3,4-d]pyrirnidin-2-yl)phenyl]urea;
1-{4-[6-(methylsulfonyl)-4-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2- yl]phenyl}-3-pyridin-3-ylurea; 1-methyl-3-{4-[6-(methylsulfonyl)-4-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidin-2-yl]phenyl}urea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[6-(methylsulfonyl)-4- morpholin-4-yl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrirnidin-2-yl]phenyl}urea; i^-^β-oxa-3-azabicyclop^.iloct-3-yl)-βJ-dihydro-5H-pyrroloPΛ-dlpyrimidin^- yl]phenyl}-3-pyridin-3-ylurea;
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidin-2-yl]phenyl}urea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[4-(8-oxa-3- azabicyclotS^.iloct-3-yO-ej-dihydro-5H-pyrrolotS^-dlpyrimidin^-yllpheny^urea; 1-{4-[6-(methylsulfonyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyrirnidin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-methyl-3-{4-[6-(methylsulfonyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}urea; i^-μ^S-oxa-8-azabicyclotS^.iloct-8-yO-ej-dihydro-5H-pyrrolotS^-dlpyrimidin^- yl]phenyl}-3-pyridin-3-ylurea;
1-methyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidin-2-yl]phenyl}urea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8- azabicyclotS^.iloct-8-yO-δJ-dihydro-5H-pyrrolotS^-dlpyrimidin^-yllphenylϊurea; 1-{4-[6-(methylsulfonyl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyrirnidin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-methyl-3-{4-[6-(methylsulfonyl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}urea;
1-(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-{4-[6-(methylsulfonyl)-4-(3- oxa-8-azabicyclotS^.iloct-δ-yO-ej-dihydro-5H-pyrrolotS^-dlpyrimidin^-yOphenylϊurea;
1-methyl-3-{4-[6-methyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}urea;
1-{4-[6-methyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyrirnidin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[6-methyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[6-methyl-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyrirnidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1 -yl)phenyl]urea; 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[6-methyl-4-(3-oxa-8- azabicyclo[3.2.1]oct- 8-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2- yl]phenyl}urea; and 2-hydroxyethyl {4-[6-methyl-4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-6,7-dihydro- 5H- pyrrolo[3,4-d]pyrimidin-2-yl]phenyl}carbamate.
16) A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
17) A composition comprising a compound of claim 1 ; a second compound selected from the group consisting of a topoisomerase I inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopuhne, 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, leucovohn, levamisole, ihnotecan, 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.
18) The composition of claim 17, wherein the second compound is Avastin.
19) A compound of claim 1 for use in treating a PI3K-related disorder wherein the compound is administered to a mammal in need thereof in an amount effective to treat a PI3K-related disorder.
20) A method of synthesizing a compound of Formula 16:
Figure imgf000094_0001
16 comprising reacting a fused pyrimidine compound of the formula 14:
14 with a dioxaborolan-2-yl compound 15:
Figure imgf000095_0001
to give 16 wherein PG is an amine-protecting group, X is independently a leaving group, and the remaining variables are as defined in claim 1.
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