US20050130954A1 - AKT protein kinase inhibitors - Google Patents

AKT protein kinase inhibitors Download PDF

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US20050130954A1
US20050130954A1 US10/993,173 US99317304A US2005130954A1 US 20050130954 A1 US20050130954 A1 US 20050130954A1 US 99317304 A US99317304 A US 99317304A US 2005130954 A1 US2005130954 A1 US 2005130954A1
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United States
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compound
heteroaryl
aryl
alkyl
alkynyl
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US10/993,173
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Inventor
Ian Mitchell
Keith Spencer
Peter Stengel
Yongxin Han
Nicholas Kallan
Mark Munson
Guy Vigers
James Blake
Anthony Piscopio
John Josey
Scott Miller
Dengming Xiao
Riu Xu
Chang Rao
Bin Wang
April Bernacki
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Array Biopharma Inc
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Array Biopharma Inc
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Priority to US10/993,173 priority Critical patent/US20050130954A1/en
Assigned to ARRAY BIOPHARMA INC. reassignment ARRAY BIOPHARMA INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: RAO, CHANG, BERNACKI, APRIL L., BLAKE, JAMES, HAN, YONGXIN, JOSCY, JOHN, KALLAN, NICHOLAS C., MITCHELL, IAN S., MUNSON, MARK, PISCOPIO, ANTHONY, SPENCER, KEITH L., STENGEL, PETER, VIGERS, GUY P. A., WANG, BING, XU, RUI, MILLER, SCOTT, XIAO, DENGMING
Publication of US20050130954A1 publication Critical patent/US20050130954A1/en
Priority to US12/567,258 priority patent/US8680114B2/en
Priority to US14/170,272 priority patent/US20160152576A9/en
Abandoned legal-status Critical Current

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Definitions

  • This invention relates to novel inhibitors of serine/threonine protein kinases (e.g., AKT and related kinases), pharmaceutical compositions containing the inhibitors, and methods for preparing these inhibitors.
  • the inhibitors are useful for the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals and especially in humans.
  • Protein kinases are a class of enzymes that catalyze the transfer of the ⁇ -phosphorate group from ATP to a recipient protein, acting as a substrate.
  • the specific target of the kinase is the hydroxyl group of a serine, threonine or tyrosine residue.
  • kinases are generally referred to as serine/threonine protein kinases or tyrosine protein kinases.
  • the human genome is estimated to encode in excess of 500 distinct protein kinases.
  • kinases are typically mediated by transmembrane cellular receptors, such as G-protein coupled receptors or growth factor receptors, which when activated by extracellular ligands cause the phosphorylation of intracellular proteins.
  • transmembrane cellular receptors such as G-protein coupled receptors or growth factor receptors
  • an interconnected series (or cascade) of protein kinases is necessary to exert the overall effect of this initial signal, which can ultimately result in effects as extreme as cell death (apoptosis).
  • the ratio of phosphorylated to unphosphorylated protein is a delicate equilibrium, with protein phosphatases acting as the negative regulator of protein kinases, removing the phosphoryl group as it is no longer required.
  • protein phosphatases acting as the negative regulator of protein kinases, removing the phosphoryl group as it is no longer required.
  • the phosphorylation state of kinases can control whether a cell undergoes division, arrests in the cell cycle or programmed cell death. Should this kinase/phosphatase relationship become disregulated, the potential consequences relating to disease are enormous.
  • abnormal protein kinase activity or expression may be correlated with numerous hyperproliferative diseases, inflammation and tissue repair, and has been associated with a large number of diseases ranging from the relatively non-life threatening, such as psoriasis, to those which are almost always fatal, such as glioblastoma multiforme, an aggressive brain cancer.
  • atypical protein phosphorylation and/or expression is often reported to be one of the causative effects of abnormal cellular proliferation, metastasis and cell survival in cancer.
  • the abnormal regulation and/or expression of various kinases including VEGF, ILK, AKT, ROCK, p70S6K, Bcl, PKA, PKC, Raf, Src, PDK1, ErbB2, MEK, IKK, Cdk, EGFR, BAD, CHK1, CHK2 and GSK3 amongst numerous others, has been specifically implicated in cancer.
  • PI3K phosphatidylinositol 3′-OH kinase pathway
  • RTKs receptor protein tyrosine kinases
  • P13K phosphoinositide-dependant kinase 1
  • AKT also known as Protein Kinase B.
  • Phosphorylation of such kinases then permits the activation or deactivation of numerous other pathways involving mediators such as GSK3, mTOR, PRAS40, FKHD, NF- ⁇ B, BAD, Caspase-9, etc.
  • PTEN a phosphatase that catalyses the dephosphorylation of PtdIns(3,4,5)P 3 to PtdIns(4,5)P 2
  • PTEN a phosphatase that catalyses the dephosphorylation of PtdIns(3,4,5)P 3 to PtdIns(4,5)P 2
  • PTEN is mutated into an inactive form, permitting the constitutive-activation of the PI3K pathway.
  • the majority of cancers are solid tumors, such an observation would suggest that by specifically targeting either PI3K itself or the individual downstream kinases in the PI3K pathway, one might able to mitigate the effects of various cancers and restore normal cellular function.
  • AKT serine/threonine protein kinase AKT
  • PKT Protein Kinase B
  • Akt3 Three isoforms of AKT are known to exist, namely Akt1, Akt2 and Akt3, which exhibit an overall homology of 80% (Staal, S. P, Proc. Natl. Acad. Sci., 1987, 84:5034; Nakatani, K, Biochem. Biophys. Res. Commun., 1999, 257:906).
  • both Akt2 and Akt3 exhibit splice variants.
  • AKT is phosphorylated (activated) by PDK1 at T308, T309 and T305 for isoforms Akt1, 2 and 3, respectively, and at S473, S474 and S472 for isoforms Akt1, 2 and 3, respectively.
  • PDK2 phosphorylated (activated) by PDK1 at T308, T309 and T305 for isoforms Akt1, 2 and 3, respectively, and at S473, S474 and S472 for isoforms Akt1, 2 and 3, respectively.
  • PDK2 as yet unknown kinase
  • PDK1 Balendran, A., Curr. Biol., 1999, 9:393
  • autophosphorylation Toker, A., J. Biol.
  • integrin-linked kinase (Delcommenne, M., Proc. Natl. Acad. Sci. USA, 1998, 95:11211) have been implicated in this process.
  • ILK integrin-linked kinase
  • monophosphorylation of AKT activates the kinase
  • bis(phosphorylation) is required for maximal kinase activity.
  • AKT is believed to assert its effect on cancer by suppressing apoptosis and enhancing both angiogenesis and proliferation.
  • AKT has been shown to be overexpressed in many forms of human cancer including, but not limited to, colon (Zinda, et al, Clin. Cancer Res., 2001, 7:2475), ovarian (Cheng, J. Q., et al., Proc. Natl. Acad. Sci. USA, 1992, 89:9267), brain (Haas Kogan, D., et al, Curr. Biol., 1998, 8:1195), lung (Brognard, J., et al, Cancer Res., 2001, 61:3986), pancreatic (Cheng, J.
  • kinase inhibitors that target abnormally regulated pathways and ultimately result in disease is of enormous ethical and commercial interest to the medical and pharmaceutical community.
  • a compound that inhibits (1) recruitment of AKT to the cell membrane, (2) activation by PDK1 or PDK2, (3) substrate phosphorylation, or (4) one of the downstream targets of AKT would therefore be a valid target as an anticancer agent, either as a stand-alone therapy or in conjunction with other accepted procedures.
  • This invention provides novel compounds that inhibit AKT protein kinases, methods for producing these compounds, and pharmaceutical compositions containing such compounds.
  • the compounds of the present invention have utility as therapeutic agents for diseases and conditions that can be treated by the inhibition of AKT protein kinases. More specifically, the present invention includes compounds, including resolved enantiomers and diastereomers, and pharmaceutically acceptable prodrugs, metabolites, salts and solvates thereof, having the general Formula I: A-L-CR (I) where:
  • the invention also relates to pharmaceutical compositions comprising an effective amount of an agent selected from compounds of Formula I. Methods of making the compounds of Formula I are also described.
  • the present invention provides methods of inhibiting the activity of AKT protein kinases utilizing compounds of Formula I.
  • the present invention provides a method of treating diseases or medical conditions mediated by AKT protein kinases.
  • this invention provides a method for treatment of a hyperproliferative disorder in a warm-blooded animal which comprises administering to such animal one or more compounds of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable prodrug thereof in an amount effective to treat or prevent said hyperproliferative disorder.
  • the present invention provides a method of inhibiting the production of AKT protein kinases, which comprises administering to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable prodrug thereof in an amount effective to inhibit production of an AKT protein kinase.
  • the present invention provides a method of providing AKT protein kinase inhibiting effect comprising administering to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable prodrug thereof.
  • the present invention provides treating or preventing an AKT protein kinase mediated condition, comprising administering to a mammal a compound having Formula I or a pharmaceutically-acceptable salt, in vivo cleavable prodrug or pharmaceutical formulation thereof, in an amount effective to treat or prevent said AKT protein kinase-mediated condition.
  • AKT protein kinase mediated conditions that can be treated according to the methods of this invention include, but are not limited to, cancer, inflammation and various proliferative, cardiovascular, neurodegenerative, gynecological & dermatological diseases.
  • Hyperproliferative conditions that can be treated according to the methods of this invention include, but are not limited to, cancers of the head, neck, lung, breast, colon, ovary, bladder, stomach, esophagus, uterus or prostate, among other kinds of hyperproliferative disorders.
  • compounds and methods of this invention can be used to treat diseases and conditions, including rheumatoid arthritis, osteoarthritis, endometriosis, atherosclerosis, vein graft stenosis, peri-anastomatic prothetic graft stenosis, prostate hyperplasia, chronic obstructive pulmonary disease, psoriasis, inhibition of neurological damage due to tissue repair, scar tissue formation (and can aid in wound healing), multiple sclerosis, inflammatory bowel disease, infections, particularly bacterial, viral, retroviral or parasitic infections (by increasing apoptosis), pulmonary disease, neoplasm, Parkinson's disease, transplant rejection (as an immunosupressant), macular degeneration and septic shock.
  • diseases and conditions including rheumatoid arthritis, osteoarthritis, endometriosis, atherosclerosis, vein graft stenosis, peri-anastomatic prothetic graft stenosis, prostate hyperp
  • the compounds of Formula I may be used advantageously in combination with other known therapeutic agents.
  • FIG. 1 shows a reaction scheme for the preparation of compounds 8-11.
  • FIG. 2 shows a reaction scheme for the preparation of compound 14.
  • FIG. 3 shows a reaction scheme for the preparation of compound 18.
  • FIG. 4 shows a reaction scheme for the preparation of compound 22.
  • FIG. 5 shows a reaction scheme for the preparation of compound 28.
  • FIG. 6 shows a reaction scheme for the preparation of compound 31.
  • FIG. 7 shows a reaction scheme for the preparation of compounds 35 and 36.
  • FIG. 8 shows a reaction scheme for the preparation of compounds 39 and 40.
  • FIG. 9 shows a reaction scheme for the preparation of compound 40.
  • FIG. 10 shows a reaction scheme for the preparation of compound 46.
  • FIG. 11 shows a reaction scheme for the preparation of compound 50.
  • FIG. 12 shows a reaction scheme for the preparation of compound 55.
  • FIG. 13 shows a reaction scheme for the preparation of compounds 57 and 58.
  • FIG. 14 shows a reaction scheme for the preparation of compounds 60 and 61.
  • FIG. 15 shows a reaction scheme for the preparation of compounds 69-71.
  • FIG. 16 shows a reaction scheme for the preparation of compounds 72-74.
  • FIG. 17 shows a reaction scheme for the preparation of compound 78.
  • FIG. 18 shows a reaction scheme for the preparation of compounds 80 and 81.
  • FIG. 19 shows a reaction scheme for the preparation of compounds 85 and 86.
  • FIG. 20 shows a reaction scheme for the preparation of compound 90.
  • FIG. 21 shows a reaction scheme for the preparation of compounds 93-97.
  • FIG. 22 shows a reaction scheme for the preparation of compounds 100 and 101.
  • FIG. 23 shows a reaction scheme for the preparation of compounds 104-109.
  • FIG. 24 shows a reaction scheme for the preparation of compounds 112-116.
  • FIG. 25 shows a reaction scheme for the preparation of compounds 120-125.
  • FIG. 26 shows a reaction scheme for the preparation of compounds 127 and 129.
  • FIG. 27 shows a reaction scheme for the preparation of compounds 132 and 134.
  • FIG. 28 shows a reaction scheme for the preparation of compounds 137 and 139.
  • FIG. 29 shows a reaction scheme for the preparation of compounds 141-144.
  • FIG. 30 shows a reaction scheme for the preparation of compound 148.
  • FIG. 31 shows a reaction scheme for the preparation of compounds 151-153.
  • FIG. 32 shows a reaction scheme for the preparation of compounds 155 and 156.
  • FIG. 33 shows a reaction scheme for the preparation of compounds 161 and 162.
  • FIG. 34 shows a reaction scheme for the preparation of compounds 171-175.
  • FIG. 35 shows a reaction scheme for the preparation of compounds 178-182.
  • FIG. 36 shows a reaction scheme for the preparation of compounds 179.
  • FIG. 37 shows a reaction scheme for the preparation of compound 190.
  • FIG. 38 shows a reaction scheme for the preparation of compounds 197-199.
  • FIG. 39 shows a reaction scheme for the preparation of compounds 205-208.
  • FIG. 40 shows a reaction scheme for the preparation of compounds 215 and 217.
  • FIG. 41 shows a reaction scheme for the preparation of compounds 219, 221 and 223.
  • FIG. 42 shows a reaction scheme for the preparation of compound 229.
  • FIG. 43 shows a reaction scheme for the preparation of compounds 232 and 234.
  • FIG. 44 shows a reaction scheme for the preparation of compounds 237-242.
  • FIG. 45 shows a reaction scheme for the preparation of compounds 244 and 247.
  • FIG. 46 shows a reaction scheme for the preparation of compounds 250, 251 and 254-256.
  • FIG. 47 shows a reaction scheme for the preparation of compounds 263 and 265.
  • FIG. 48 shows a reaction scheme for the preparation of compounds 269 and 271.
  • inventive compounds of Formula I are useful for inhibiting AKT protein kinases.
  • the compounds of Formula I may also be useful as inhibitors of tyrosine kinases as well as serine and threonine kinases in addition to AKT.
  • Such compounds have utility as therapeutic agents for diseases that can be treated by the inhibition of the AKT protein kinase signaling pathway and tyrosine and serine/threonine kinase receptor pathways.
  • the invention includes compounds, including resolved enantiomers and diastereomers, and pharmaceutically acceptable prodrugs, metabolites, salts and solvates thereof, having the general Formula I: AA-L-CR
  • CR is selected from:
  • CR is selected from
  • A is:
  • a group of Formula I according to this invention include, but are not limited to,
  • the A group of Formula I of this invention is a D- or L-amino acid selected from the 20 naturally occurring amino acids commonly designated by three letter symbols, and also includes unnatural amino acids including, but not limited to, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, omithine and methionine sulfone.
  • the A group of Formula I is alanine, phenylalanine, histidine, or tryptophan.
  • Still another example of a compound based on Formula I is:
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms, wherein the alkyl radical may be optionally substituted independently with one or more substituents described below.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like.
  • alkylene refers to a linear or branched-chain saturated divalent hydrocarbon radical of one to twelve carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
  • the alkylene radical may be optionally substituted independently with one or more substituents described herein.
  • heteroalkyl refers to saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms, wherein at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S, and wherein the radical may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical).
  • the heteroalkyl radical may be optionally substituted independently with one or more substituents described herein.
  • heteroalkyl encompasses alkoxy and heteroalkoxy radicals.
  • heteroalkylene refers to a linear or branched-chain saturated divalent hydrocarbon radical of two to twelve carbon atoms, wherein at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S, and wherein the radical may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical).
  • the heteroalkylene radical may be optionally substituted independently with one or more substituents described herein.
  • Alkenyl means a linear or branched-chain monovalent hydrocarbon radical of two to twelve carbon atoms containing at least one double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described below.
  • alkenyl groups include, but are not limited to: ethylene or vinyl (—CH ⁇ CH 2 ), allyl (—CH 2 CH ⁇ CH 2 ), 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 5-hexenyl (—CH 2 CH 2 CH 2 CH 2 CH ⁇ CH 2 ), 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.
  • Alkenylene refers to an a linear or branched-chain divalent hydrocarbon radical of one to twelve carbon atoms containing at least one double bond, e.g., 1,2-ethylene (—CH ⁇ CH—).
  • the alkenylene radical may be optionally substituted independently with one or more substituents described herein.
  • heteroalkenyl refers to a linear or branched-chain monovalent hydrocarbon radical of two to twelve carbon atoms and at least one double bond, wherein at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S, and wherein the radical may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical).
  • the heteroalkenyl radical may be optionally substituted independently with one or more substituents described herein.
  • heteroalkenyl encompasses alkenoxy and heteroalkenoxy radicals.
  • Heteroalkenylene refers to an a linear or branched saturated divalent hydrocarbon radical of one to twelve carbon atoms containing at least one double bond, wherein at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S, and wherein the radical may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical).
  • the heteroalkenylene radical may be optionally substituted independently with one or more substituents described herein.
  • allyl refers to a radical having the formula RC ⁇ CHCHR, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or any substituent as defined herein, wherein the allyl radical may be optionally substituted independently with one or more substituents described herein.
  • alkynyl means a linear or branched-chain monovalent hydrocarbon radical of two to twelve carbon atoms containing at least one triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described below.
  • alkynyl groups include, but are not limited to: acetylene (—C ⁇ CH) and propargyl (—CH 2 C ⁇ CH).
  • Alkynylene refers to a linear or branched-chain divalent hydrocarbon radical of one to twelve carbon atoms containing at least one triple bond.
  • the alkynylene radical may be optionally substituted independently with one or more substituents described herein.
  • Typical alkynylene radicals include, but are not limited to: acetylene (—C ⁇ C—), propargyl (—CH 2 C ⁇ C—), and 4-pentynyl (—CH 2 CH 2 CH 2 C ⁇ CH—).
  • heteroalkynyl refers to a linear or branched-chain monovalent hydrocarbon radical of two to twelve carbon atoms containing at least one triple bond, wherein at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S, and wherein the radical may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical).
  • the heteroalkynyl radical may be optionally substituted independently with one or more substituents described herein.
  • heteroalkynyl encompasses alkynoxy and heteroalkynoxy radicals.
  • heteroalkynylene refers to a linear or branched divalent hydrocarbon radical of two to twelve carbons containing at least one triple bond, wherein at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S, and wherein the radical may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical).
  • the heteroalkynylene radical may be optionally substituted independently with one or more substituents described herein.
  • cycloalkyl refers to saturated or partially unsaturated cyclic hydrocarbon radical having from three to ten carbon atoms.
  • cycloalkyl includes monocyclic and polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, wherein the polycyclic structures optionally include a saturated or partially unsaturated cycloalkyl fused to a saturated or partially unsaturated cycloalkyl or heterocycloalkyl ring or an aryl or heteroaryl ring.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • the cycloalkyl may be optionally substituted independently in one or more substitutable positions with various groups.
  • such cycloalkyl groups may be optionally substituted with, for example, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, amino(C 1 -C 6 )alkyl, mono(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl or di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl.
  • heterocycloalkyl refers to a saturated or partially unsaturated carbocyclic radical of 3 to 8 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen and sulfur, the remaining ring atoms being C, where one or more ring atoms may be optionally substituted independently with one or more substituent described below.
  • the radical may be a carbon radical or heteroatom radical.
  • the term further includes bicyclic and tricyclic fused ring systems which include a heterocycle fused one or more carbocyclic or heterocyclic rings.
  • “Heterocycloalkyl” also includes radicals where heterocycle radicals are fused with aromatic or heteroaromatic rings.
  • heterocycloalkyl rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolany
  • Spiro moieties are also included within the scope of this definition.
  • the foregoing groups, as derived from the groups listed above, may be C-attached or N-attached where such is possible.
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).
  • An example of a heterocyclic group wherein 2 ring carbon atoms are substituted with oxo ( ⁇ O) moieties is 1,1-dioxo-thiomorpholinyl.
  • heterocycle groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • such heterocycle groups may be optionally substituted with, for example, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, amino(C 1 -C 6 )alkyl, mono(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl or di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl.
  • heterocycloalkylene refers to a saturated or partially unsaturated divalent carbocyclic radical of 3 to 8 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen and sulfur, the remaining ring atoms being C, where one or more ring atoms may be optionally substituted independently with one or more substituent described herein. Examples include, but are not limited to, substituted and unsubstituted piperidinylenes.
  • aryl refers to a monovalent aromatic carbocyclic radical having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, trifluoromethyl, aryl, heteroaryl, and hydroxy.
  • heteroaryl refers to a monovalent aromatic radical of 5-, 6-, or 7-membered rings which includes fused ring systems (at least one of which is aromatic) of 5-10 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur.
  • heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,
  • Heteroaryl groups are optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl, and hydroxy.
  • halo represents fluoro, chloro, bromo or iodo.
  • halogen refers to a fluorine, chlorine, bromine, or iodine substituent.
  • arylalkyl means an alkyl moiety (as defined above) substituted with one or more aryl moiety (also as defined above). More preferred arylalkyl radicals are aryl-C 1-3 -alkyls. Examples include benzyl, phenylethyl, and the like.
  • heteroarylalkyl means an alkyl moiety (as defined above) substituted with a heteroaryl moiety (also as defined above). More preferred heteroarylalkyl radicals are 5- or 6-membered heteroaryl-C 1-3 -alkyls. Examples include, but are not limited to, oxazolylmethyl, pyridylethyl and the like.
  • heterocyclylalkyl means an alkyl moiety (as defined above) substituted with a heterocyclyl moiety (also defined above). More preferred heterocyclylalkyl radicals are 5- or 6-membered heterocyclyl-C 1-3 -alkyls. An example includes, but is not limited to, tetrahydropyranylmethyl.
  • cycloalkylalkyl means an alkyl moiety (as defined above) substituted with a cycloalkyl moiety (also defined above). More preferred heterocyclyl radicals are 5- or 6-membered cycloalkyl-C 1-3 -alkyls. An example includes, but is not limited to, cyclopropylmethyl.
  • Me means methyl
  • Et means ethyl
  • Bu means butyl
  • Ac means acetyl
  • the various moieties or functional groups of the compounds of Formula I may be optionally substituted by one or more substituents.
  • substituents suitable for purposes of this invention include, but are not limited to, halo, alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, G n -cycloalkyl, G n -heterocycloalkyl, G n -OR, G n -NO 2 , G n -CN, G n -CO 2 R, G n -(C ⁇ O)R, G n -O(C ⁇ O)R, G n -O-alkyl, G n -OAr, G n -SH, G n -SR, G n -SOR, G n -SO 2 R, G n -S—Ar G n -SOAr, G
  • radical arylalkyl is attached to the structure in question by the alkyl group.
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)— or (S)-stereoisomers or as mixtures thereof.
  • the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. Accordingly, this invention also includes racemates and resolved enantiomers, and diastereomers compounds of the Formula I. Methods for determining the stereochemistry and for the separation of stereoisomers are well known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 1992).
  • the invention also includes solvates, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable salts of such compounds.
  • solvate refers to an aggregate of a molecule with one or more solvent molecules.
  • a “pharmaceutically active metabolite” is a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein.
  • a “pharmaceutically acceptable prodrug” is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present invention.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • One preferred prodrug of this invention is a compound of Formula I covalently joined to a phosphate residue.
  • Another preferred prodrug of this invention is a compound of Formula I covalently joined to a valine residue.
  • prodrugs can be derivatized as amides or alkyl esters.
  • compounds of this invention comprising free hydroxy groups may be derivatized as prodrugs by converting the hydroxy group groups including to a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (C 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 -C 6 )alkoxycarbonyloxymethyl, N—(C 1 -C 6 )alkoxycarbonylaminomethyl, succinoyl, (C 1 -C 6 )alkanoyl, ⁇ -amino(C 1 -C 4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , —P(O)(O(C 1 -C 6 )alkyl
  • Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including, but not limited to, ether, amine and carboxylic acid functionalities.
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are each independently (C 1 -C 10 )alkyl, (C 3 -C 7 )cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl-natural ⁇ -aminoacyl, —C(OH)C(O)OY wherein Y is H, (C 1 -C 6 )alkyl or benzyl, —C(OY 0 )Y 1 wherein Y 0 is (C 1 -C 4
  • a “pharmaceutically acceptable salt” is a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable.
  • a compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable sale.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitromenzoates, hydroxybenzoates, methoxybenzoates,
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid such as glucuronic acid or galacturonic acid, an alphahydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid,
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • inventive compounds may be prepared using the reaction routes and synthesis schemes as described herein, employing the techniques available in the art using starting materials that are readily available.
  • the invention also provides a pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite or hydrate thereof, and a pharmaceutically acceptable carrier.
  • said pharmaceutical composition is for the treatment of cancer such as skin, brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, esophageal, testicular, gynecological, cardiac, liver, bone, meninges, spinal cord, blood, skin, adrenal or thyroid cancer.
  • said pharmaceutical composition is for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • the invention also relates to a method for the treatment of a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
  • an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
  • the invention also relates to a method of treating pancreatitis or kidney disease in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
  • the invention also relates to a method of preventing blastocyte implantation in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
  • the invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
  • said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
  • a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma,
  • the invention also relates to a pharmaceutical composition for treating a disease or condition related to inflammatory disease, autoimmune disease, destructive bone disorders, proliferative disorders, infectious disease, viral disease, fibrotic disease or neurodegenerative disease in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier.
  • diseases and/or conditions include but is not limited to rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes and diabetic complications, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, allergic responses including asthma allergic rhinitis and atopic dermatitis, renal disease and renal failure, polycystic kidney disease, acute coronary syndrome, congestive heart failure, osteoarthritis, neurofibromatosis, organ transplant rejection, cachexia and pain.
  • a compound of Formula I for use as a medicament in the treatment of the diseases and conditions described above in a warm-blooded animal, preferably a mammal, more preferably a human, suffering from such disorder. Also provided is the use of a compound of Formula I in the preparation of a medicament for the treatment of the diseases and conditions described above in a warm-blooded animal, preferably a mammal, more preferably a human, suffering from such disorder.
  • Patients that can be treated with compounds of the present invention, or pharmaceutically acceptable salts, prodrugs and hydrates of said compounds, according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis, restenosis, atherosclerosis, BPH, lung cancer, bone cancer, CMML, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands
  • This invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with an amount of a chemotherapeutic, wherein the amounts of the compound, salt, solvate, or prodrug, and of the chemotherapeutic are together effective in inhibiting abnormal cell growth.
  • chemotherapeutics are presently known in the art.
  • the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, antitumor antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
  • This invention further relates to a method for inhibiting abnormal cell growth in a mammal or treating a hyperproliferative disorder which method comprises administering to the mammal an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with radiation therapy, wherein the amounts of the compound, salt, solvate, or prodrug, is in combination with the radiation therapy effective in inhibiting abnormal cell growth or treating the hyperproliferative disorder in the mammal.
  • Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.
  • the administration of the compound of the invention in this combination therapy can be determined as described herein.
  • this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention or pharmaceutically acceptable salt or solvate or prodrug thereof, which amount is effective is sensitizing abnormal cells to treatment with radiation.
  • the amount of the compound, salt, or solvate in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.
  • Compounds and methods of this invention may also be used to treat other diseases and conditions (e.g., inflammatory disease), including rheumatoid arthritis, osteoarthritis, endometriosis, atherosclerosis, vein graft stenosis, peri-anastomatic prosthetic graft stenosis, prostate hyperplasia, chronic obstructive pulmonary disease, psoriasis, inhibition of neurological damage due to tissue repair, scar tissue formation (and can aid in wound healing), multiple sclerosis, inflammatory bowel disease, infections, particularly bacterial, viral, retroviral or parasitic infections (by increasing apoptosis), pulmonary disease, neoplasm, Parkinson's disease, transplant rejection (as an immunosuppressant), macular degeneration and septic shock.
  • diseases and conditions e.g., inflammatory disease
  • diseases and conditions e.g., inflammatory disease
  • inflammatory disease including rheumatoid arthritis, osteoarthritis, endometri
  • Therapeutically effective amounts of the compounds of the invention may be used to treat diseases mediated by modulation or regulation of AKT protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or dual specificity kinases.
  • An “effective amount” is intended to mean that amount of compound that, when administered to a mammal in need of such treatment, is sufficient to effect treatment for a disease mediated by the activity of one or more AKT protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or dual specificity kinases.
  • a therapeutically effective amount of a compound selected from Formula I or a salt, active metabolite or prodrug thereof is a quantity sufficient to modulate, regulate, or inhibit the activity of one or more AKT protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or dual specificity kinases such that a disease condition which is mediated by that activity is reduced or alleviated.
  • abnormal cell growth and “hyperproliferative disorder” are used interchangeably in this application.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • Treating is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is affected, at least in part, by the activity of one or more AKT protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or dual specificity kinases, and includes, but is not limited to, preventing the disease condition from occurring in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but has not yet been diagnosed as having it; modulating and/or inhibiting the disease condition; and/or alleviating the disease condition.
  • a pharmaceutical composition that comprises a compound of the Formula I, or a pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof, as defined hereinbefore in association with a pharmaceutically acceptable diluent or carrier.
  • a therapeutically or prophylactically effective amount of a compound of Formula I or pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof is preferably intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose.
  • a carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral.
  • suitable carriers include any and all solvents, dispersion media, adjuvants, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, sweeteners, stabilizers (to promote long term storage), emulsifiers, binding agents, thickening agents, salts, preservatives, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, flavoring agents, and miscellaneous materials such as buffers and absorbents that may be needed in order to prepare a particular therapeutic composition.
  • suitable carriers include any and all solvents, dispersion media, adjuvants, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, sweeteners, stabilizers (to promote long term storage), emulsifiers, binding agents, thickening agents, salts, preservatives, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, flavoring agents,
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, or intramuscular dosing or as a suppository for rectal dosing).
  • compositions intended for oral use may contain one or more coloring, sweetening, flavoring and/or preservative agents.
  • Suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
  • granulating and disintegrating agents such as corn starch or algenic acid
  • binding agents such as starch
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium al
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • preservatives such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil such as liquid paraffin, or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient, which is solid at ordinary temperature s but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • Topical formulations such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedures well known in the art.
  • compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 ⁇ m or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose.
  • the powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50 mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
  • Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • a formulation intended for oral administration to humans may contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients, which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • the compounds of this invention may be used alone in combination with other drugs and therapies used in the treatment of disease states which would benefit from the inhibition of MEK.
  • Such treatment may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumor agents:
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of treatment.
  • Such combination products employ the compounds of this invention within the dose range described hereinbefore and the other pharmaceutically active agent within its approved dose range.
  • a pharmaceutical product comprising a compound of Formula I as defined hereinbefore and an additional anit-tumor agent as definged hereinbefore for the conjoint treatment of cancer.
  • the compounds of Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to control AKT protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or dual specificity kinases. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the activity of the compounds of this invention may be assayed for AKT protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or dual specificity kinases in vitro, in vivo, or in a cell line.
  • In vitro assays include assays that determine inhibition of the kinase activity. Alternate in vitro assays quantitate the ability of the inhibitor to bind to kinases and may be measured either by radiolabelling the inhibitor prior to binding, isolating the inhibitor/kinase complex and determining the amount of radiolabel bound, or by running a competition experiment where new inhibitors are incubated with known radioligands.
  • the compounds of the present invention may be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • novel compounds of the present invention may be prepared using the reactions and techniques described in this section.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
  • the preparation of compounds of the present invention may be carried out in a convergent or sequential synthetic manner.
  • the skills required in preparation and purification of such compounds and the intermediates leading to these compounds are known to those in the art. Purification procedures include, but are not limited to, normal or reverse phase chromatography, crystallization, and distillation.
  • FIG. 1 An illustration of the preparation of compounds (8), (9), (10) and (11) of the present invention is shown in FIG. 1 .
  • the synthesis starts with the preparation of a substituted quinazolinone (3) made by, for example, by the condensation of a corresponding substituted aryl amino acid (1) and a corresponding substituted amide (2) (see, for example, LeMahieu, et al, J. Med. Chem., 1983, 26, 420-5 and references cited therein).
  • a leaving group into quinazolinone (3) may be accomplished by treatment with a halogenating agent (for example POCl 3 ) to give the chlorinated quinazoline (4.)
  • a halogenating agent for example POCl 3
  • the halogen leaving group is then displaced with substituted and protected piperazine (5) (e.g., Boc, but any suitable protecting group may be used; see, T. W. Greene et al., ‘ Protective groups in organic synthesis ’, John Wiley and Sons, 1999, 3 rd Ed., pp.494-653).
  • the piperazine (5) may be introduced to chlorinated quinazoline (4) either neat or in the presence of base.
  • the piperazine protecting group may then be removed by known methods (see, Greene et al, supra) (6).
  • Substitution of the piperazine secondary amine in quinazoline intermediate (6) may be accomplished using a variety of electrophiles and reaction conditions.
  • the piperazine may be acylated by a suitably N-substituted or protected amino acid (e.g., Boc, etc.) which may be introduced using a variety of standard peptide coupling procedures under both solution phase and solid phase conditions, to produce a product such as compound (8).
  • a suitably N-substituted or protected amino acid e.g., Boc, etc.
  • N-protected amino acid unit may then be deprotected using representative procedures (e.g., using acid on a Boc-group; Greene et al., supra), and then manipulated as desired according to procedures appreciated by those skilled in the art.
  • Compounds of the present invention similar to compound (8) may be a prepared from quinazoline intermediate (6) by acylation with a natural or an ‘unnatural’ amino acid (7).
  • the preparation of ‘unnatural’ amino acids is also well known to those skilled in the art, and their use is included in the present invention (for representative reviews, see, C. Najera, Synlett, 2002, 9,1388-1403, and J.-A. Ma, Angew. Chemie, Int. Ed., 2003, 42, 4290-4299, and references therein).
  • the piperazine (6) may be acylated with an acid or acid halide in the presence of base to generate a substituted amine (10).
  • a substituted tertiary amine (11) can be prepared by treating piperazine (6) with an appropriate aldehyde (or surrogate) in the presence of a reducing agent (e.g., sodium cyanoborohydride).
  • a reducing agent e.g., sodium cyanoborohydride
  • the piperazine (6) can also be treated with an epoxide to give the amino alcohol (9.)
  • All functional groups may be further manipulated under standard conditions (e.g., reductions, alkylations, oxidations, palladium or nickel mediated couplings, etc.) to further functionalize each compound.
  • the compounds described in FIG. 1 may be prepared either as either the racemate, or as a single enantiomer (for example, using an enantiomerically pure amino acid (7.)) If prepared as the racemate, the corresponding enantiomers may be isolated by separation of the racemic mixture of compound on a chiral stationary phase column utilizing normal or reverse phase HPLC techniques. Alternatively, a diastereomeric mixture of compound (8) can be prepared by treatment of racemic compound (8) with an appropriate chiral acid (or suitably activated derivative), for example dibenzoyl tartrate or the like (see, for example, Kinbara, K., et. al., J. Chem. Soc., Perkin Trans.
  • compound (14) of this invention may be prepared as shown in FIG. 2 .
  • the hydroxyl group of substituted a-hydroxy benzyl ester (12) is protected with an appropriate protecting group (such as acetate) to give compound 13.
  • the benzyl ester is then converted to the corresponding carboxylic acid (for example by hydrogenolysis) to give compound (14).
  • FIG. 3 shows the preparation of compound (18).
  • Substituted phenyl boronic acid (15), glyoxylic acid (16), and a chiral or achiral mono-protected (using the Boc protecting group, for example) diamine (17) (such as 3-Boc-aminopyrrolidine) are combined in an appropriate solvent such as 1,2-dichloroethane and stirred at elevated temperature to provide carboxylic acids (18).
  • FIG. 4 shows the preparation of compound (22).
  • 2-(2-Aminoethoxy)ethanol (19) is protected with an appropriate amine protecting group (such as Boc), and the hydroxyl group is oxidized to the carboxylic acid to provide intermediate (20).
  • the acid in compound (20) is then converted to an ester using an appropriate base (such as K 2 CO 3 ) and alkyl halide to furnish intermediate compound (21).
  • Enolization of intermediate compound (21) is accomplished with strong base (such as LDA or LHMDS), followed by addition of a substituted benzyl halide yields an alkylated ester, which is then converted by basic hydrolysis to the corresponding acid (22).
  • Compound (28) may be prepared as shown in FIG. 5 .
  • the substituted phenyl carboxylic acid (23) is transformed to the appropriate ester (24) under acidic (mineral acid, R 2 OH) or basic (K 2 CO 3 , R 2 X) conditions.
  • Enolization of ester (24) is accomplished with strong base (such as LDA), and addition of a haloacetate ester (for example tert-butyl bromoacetate) provides intermediate compound (25).
  • Selective ester deprotection is performed by treating compound (25) with acid (such as TFA) to provide carboxylic acid (26).
  • the carboxylic acid (26) is converted to an acyl azide (using diphenylphosphoryl azide, for example), which is then transformed to the corresponding carbamate-protected amine by heating in an appropriate alcohol solvent (tert-butyl alcohol, for example) in the presence or absence of a Lewis acid (such as SnCl 4 ) to provide compound (27).
  • an appropriate alcohol solvent tert-butyl alcohol, for example
  • a Lewis acid such as SnCl 4
  • FIG. 6 shows the preparation of carboxylic acid (31).
  • Lactam (29) is enolized with strong base (such as LDA/LiBr or LHMDS), and addition of a substituted benzyl halide furnishes alkylated intermediate compound (30).
  • the lactam is then opened under basic conditions (such as aq. LiOH, THF) to furnish carboxylic acid (31).
  • Compound (36) may be prepared as shown in FIG. 7 .
  • Condensation of an appropriately substituted benzaldehyde with ethyl cyanoacetate provides compounds of structure (32).
  • Treatment with a reducing agent such as NaBH 4 gives the saturated compound (33), which is followed by cobalt-mediated hydride reduction to give compound (34).
  • the amine can then be protected and the ester saponified to give compound (35).
  • Coupling with a piperazine can be accomplished using (for example) EDCI or PyBrop, followed by deprotection to give final compound (36).
  • FIG. 8 shows the preparation of amino acid (40).
  • Compound (39) can be prepared by condensation of benzaldehydes with ethyl cyanoacetate followed by catalytic hydrogenation according to the procedures described by Lee, J. et al. (1999), 3060-3065.
  • Compound (39) can be converted to compound amino acid (40) by protection of the primary amine followed by saponification under basic condition (for example, aqueous LiOH solution).
  • FIG. 9 An alternate approach to amino acid (40) is shown in FIG. 9 .
  • Compound (41), where Pg is an appropriate protecting group (for example, Boc) can be treated with a variety of organometallic agents such as LDA in a suitable solvent such as THF or ether at low temperature s to generate a dianion intermediate, which can be quenched by suitable amount of benzyl halides to afford the intermediate compound (42).
  • Saponification under basic conditions such as aqueous LiOH solution furnishes the desired product (40).
  • FIG. 10 summarizes a synthesis of amino alcohols (46) from compound (45).
  • Compound (45) may be prepared from compound (44) by a sequence of deprotonation, alkylation and saponification as described in FIG. 9 .
  • Phenyl acetic acid derivative (47) can be deprotonated by treatment with a suitable organometallic agent such as LDA in a suitable solvent such as THF or ether at low temperature s, and then reacted with compound (48), where X is a suitable leaving group (for example Br, Cl) and Pg is an appropriate protecting group (for example, Boc or Ts), to yield intermediate compound (49) (Ho-sam A. et al. (1997) J. Med. Chem., 40, 2196; Ohkanda et al. (2004), J. Med. Chem., 47, 432). Saponification of compound (49) under basic conditions (for example, aqueous LiOH solution) gives acid (50).
  • a suitable organometallic agent such as LDA
  • a suitable solvent such as THF or ether
  • Compound (55) may be prepared as shown in FIG. 12 .
  • Esterification of the appropriately substituted and commercially available acid (51) with an alcohol affords the desired ester (52).
  • ester (52) with appropriate base and electrophile (e.g., acrylate, etc. (53)) followed by ester cleavage with acid affords intermediate compound (54).
  • Introduction of azide (affords acyl-azide) with activating reagent followed by heating affects rearrangement of acid (54) to the requisite N-protected amino-ester intermediate (for example Boc, but any suitable protecting group may be used with the appropriate alcohol solvent; see, Greene et al., supra.
  • Treatment of ester intermediate with hydroxide base affords the N-protected amino acid (55).
  • Compound (58) may be prepared as shown in FIG. 13 .
  • Michael addition of phenylacetic acid ethyl esters with tert-butyl acrylate using catalytic base such as potassium tert-butoxide followed by acid hydrolysis of the tert-butyl ester provides compound (56).
  • Curtius rearrangement using diphenylphosphorylazide followed by saponification of the ester gives compound (57).
  • Coupling with a piperazine can be accomplished using EDCI or PyBrop, followed by deprotection of the Boc group to give final compound (58).
  • FIG. 14 shows the preparation of compound (61). Alkylation of phenylacetic acid ethyl esters with ⁇ -bromoacetate tert-butyl ester using a base such as lithium bis(trimethylsilyl)amide provides compound (59). The remainder of the sequence is as that described in FIG. 13 to provide compound (61).
  • Compound (71) may be prepared as shown in FIG. 15 .
  • the displacement of 4-chloroquinazoline with ethyl isonipecotate followed by saponification of the ester gives intermediate (68).
  • Treatment with a halogenating reagent such as thionyl chloride or oxalyl chloride provides acid chloride (69).
  • Reductive amination of an appropriately substituted benzaldehyde with N-Boc-ethylenediamine using NaCNBH 3 or NaH(OAc) 3 in MeOH, THF, or DCE as solvent gives the secondary amine (70).
  • Reaction of (69) with amine (70) followed by deprotection of the Boc group provides compound (71).
  • compound of formula (74) may be prepared as shown in FIG. 16 .
  • Reductive amination of an appropriately substituted aniline with tert-butyl N-(2-oxoethyl)carbamate using NaCNBH 3 or NaH(OAc) 3 in MeOH, THF, or DCE as solvent gives the secondary amine (72).
  • Compound (72) can be purified by removal of the Boc group followed by acid-base extraction and chromatography to give compounds of structure (73) and then converted back to compound (72) by treatment with Boc 2 O.
  • Reaction with intermediate (69) using DMAP as base followed by deprotection of the Boc group with (for example) ethereal HCl and substitution (if required) gives compound (74).
  • Compound (78) may be prepared as shown in FIG. 17 .
  • Compound (75) can be prepared from 7-azaindole according to literature procedures.
  • Introduction of the piperazine can be accomplished by melting N-benzylpiperidine with intermediate (75) to give intermediate (76).
  • Removal of the benzyl protecting group can be accomplished using (for example) hydrogenation in the presence of Pd—C in methanol.
  • Coupling of a Boc-protected amino acid with intermediate (77) can be accomplished using (for example) EDCI or PyBrop, followed by deprotection of the Boc group to give compound (78).
  • FIG. 18 shows preparation of compound (81).
  • Compound (79) can be prepared from 2-aminopyridine similar to literature procedure (A. R. Katritzky et al., J. Org. Chem., 2003, 68, 4935-4937). Deprotection of the Boc group using (for example) ethereal HCl gives intermediate (80). The piperazine can be coupled to N-protected amino acids using (for example) EDCI or PyBrop followed by deprotection to give final compound (81).
  • FIG. 19 illustrates the preparation of 5- and 6-substituted indazole (86).
  • Substituted nitro indazole (82), where R 5 and R 7 are substituents which are suitable for use in the subsequent reactions, may be reduced to amino indazole (83) using standard conditions (for example catalytic hydrogenation, zinc/acetic acid, Fe/HCl, SnCl 2 /MeOH or FeSO 4 in water).
  • Amino indazole (83) can react with compound (84) (for example, bis(2-chloroethyl)amine) in the presence of an acid scavenger (for example, Na 2 CO 3 , K 2 CO 3 , or the like) to afford the cyclized product (85).
  • an acid scavenger for example, Na 2 CO 3 , K 2 CO 3 , or the like
  • a suitable solvent for example, ethanol
  • a suitable acid for example a protected amino acids
  • the coupling product may require a separate deprotection step to remove any protecting groups in R to afford the product (86).
  • a Boc protecting group may be removed by treating with a strong acid such as trifluoroacetic acid (TFA) or hydrochloric acid in the presence of an inert solvent such as dichloromethane or methanol.
  • Removal of a Cbz group can be carried out by catalytic hydrogenation with hydrogen in the presence of a palladium catalyst or by transfer hydrogenation.
  • An Fmoc group can be removed with a low boiling point amine (for example piperidine or the like) in a solvent such as DMF.
  • FIG. 20 describes the synthesis of 3-alkyl and 3-aryl substituted indazole (90).
  • the iodo intermediate (87) can be prepared by the procedures shown in FIG. 20 .
  • Compound (87) is protected using a suitable protecting group and treated with an alkyl or aryl boronic acid or ester and a suitable Pd catalyst, for example, Pd(PPh 3 ) 4 , to afford the desired 3-substituted intermediate (89) which is then deprotected to give compound (90).
  • Compound (92) can be prepared by reacting a suitably monoprotected piperazine intermediate with a compound (91), where X is a suitable leaving group (for example, bromo, iodo or OTf), via Pd or Cu-mediated coupling (Buchwald et al. (2000), J. Org. Chem., 65, 1144; Hartwig et al. (1998) Angew. Chem. Int. Ed. Eng., 37, 2046) to furnish intermediate (92). Removal of the protecting group followed by amide coupling with an acid affords compound (93), which is then treated with hydrazine to give 3-amino indazole intermediate (94).
  • X is a suitable leaving group (for example, bromo, iodo or OTf)
  • Pd or Cu-mediated coupling Buchwald et al. (2000), J. Org. Chem., 65, 1144; Hartwig et al. (1998) Angew. Chem. Int. Ed. Eng
  • FIG. 22 describes a synthesis of a particular class of compounds bearing an isoquinoline ring.
  • Compound (100) can be prepared by reacting suitably mono-protected piperazine (99) with an isoquinoline compound substituted with a leaving group X, where X is halide (for example, chloro, bromo, and iodo), or sulfonate (for example OSO 2 CF 3 ), in the presence of a base and a palladium or a copper catalyst, according to known methods. Removal of the protecting group Pg of compound (100) affords an amine intermediate, which can be conveniently converted to compound (101) by amide coupling with acids followed by optional removal of protecting groups as described in FIG. 19 .
  • FIG. 23 presents a synthesis of a particular class of pyrimidines bearing a substituent at the 5-position.
  • Compound (104) can be prepared by S N Ar reaction between a suitably mono-protected piperazine compound (103) and a 4-chloro substituted pyrimidine intermediate (102), where X is Br or I, in the presence of an acid scavenger (for example, diisopropylethylamine or triethylamine). Removal of the protecting group Pg followed by amide coupling with an acid (106) affords intermediate (107).
  • Intermediate (107) can react with various coupling components (108) via metal-mediated reactions to furnish product (109).
  • compounds bearing an O— or S-linked substituent at the 5-position of the pyrimidine ring can be prepared by reactions between intermediate (107) and an alcohol or thiol in the presence of a base (for example, Cs 2 CO 3 ) and a Cu catalyst (for example, CuCl, CuI, or the like) under modified Ullman coupling conditions (Wolter, M. et. al. Org. Lett. 2002, 4, 973-976).
  • a base for example, Cs 2 CO 3
  • a Cu catalyst for example, CuCl, CuI, or the like
  • an additive for example, 2,2,6,6-tetramethyl-heptane-3,5-dione, pentane-2,4-dione, 1,10-phenethroline, or the like
  • an additive for example, 2,2,6,6-tetramethyl-heptane-3,5-dione, pentane-2,4-dione, 1,10-phenethroline, or the like
  • Y is a boronic acid or boronic ester, in the presence of a base (for example, Na 2 CO 3 and Et 3 N), a catalytic Pd(0) species (for example, Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd 2 (dba) 3 and Pd(OAc) 2 ) and a suitable ligand (such as PPh 3 and AsPh 3 ).
  • a base for example, Na 2 CO 3 and Et 3 N
  • a catalytic Pd(0) species for example, Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd 2 (dba) 3 and Pd(OAc) 2
  • a suitable ligand such as PPh 3 and AsPh 3
  • 5-alkyl and aryl substituted pyrimidines (109) may also be prepared by Nigeshi or Kumada couplings between compounds (107) and (108), wherein Y—R′ is an organo zinc reagent, in the presence of a Pd (for example, Pd(PPh 3 ) 4 ) or Ni (for example Ni(acac) 2 ) catalyst.
  • Y—R′ is an organo zinc reagent
  • Ni for example, Ni(acac) 2
  • 5-alkyl and aryl substituted pyrimidines (109) may also be prepared by Stille coupling between compounds (107) and (108), wherein Y—R′ is an organostannane reagent, in the presence of a Pd catalyst.
  • FIG. 24 describes an alternate synthesis of compounds bearing an O-linked substituent at the 5-position.
  • Compound (111) can be prepared by Cu-catalyzed coupling of intermediate (110) with benzyl alcohol. Removal of the benzyl group by hydrogenation affords 5-hydroxylpyrimidine intermediate (112), which can be converted to compound (115) by deprotection and amide coupling as described in FIG. 19 . Alkylation of compound (115) with alkyl halides in the presence of a base (for example, K 2 CO 3 , Cs 2 CO 3 , or the like) in an inert solvent (for example, DMF) provides the desired compound (116).
  • a base for example, K 2 CO 3 , Cs 2 CO 3 , or the like
  • an inert solvent for example, DMF
  • Compound (125) can be synthesized as described in FIG. 25 .
  • An appropriately substituted pyrimidine (119) may be prepared by the condensation of a corresponding substituted malonic acid diester (117) and a corresponding substituted formamidine (118) in the presence of a base (for example, NaOEt).
  • a base for example, NaOEt
  • a halogenating agent for example, POCl 3 or POBr 3
  • Displacing one of the halogens with protected piperazine (121) gives the mono-substituted compound (122), which can be converted to compound (123) by reduction (for example, catalytic hydrogenation) of the second halogen. Transformation of compound (123) into desired compound (125) can be accomplished by the procedures described in FIG. 22 .
  • FIG. 26 illustrates an approach to preparation of 5,6-disubstituted pyrimidines (129).
  • Treatment of compound (126) with a nucleophile for example, an amine
  • a nucleophile for example, an amine
  • compound (126) can be converted to compound (127) via various metal mediated coupling reactions such as described in FIG. 23 .
  • Transformation of compound (127) into desired compound (129) can be accomplished by a sequence of deprotection, amide coupling and optional deprotection as described in FIG. 22 .
  • FIG. 27 The preparation of compounds with an amino group at the 6-position of the pyrimidine ring is shown in FIG. 27 .
  • Compounds of formula (131) can be prepared by palladium catalyzed coupling reactions between intermediate (130) and an ammonia equivalent (for example, benzophenone imine).
  • an ammonia equivalent for example, benzophenone imine
  • Removal of the protecting group Pg 2 in compound (131) furnishes the amino intermediate (132). Transformation of (132) into desired compound (134) can be accomplished by the procedures described in FIG. 22 .
  • FIG. 28 summarizes the preparation of compounds of the invention bearing a cinnoline ring.
  • Compound (137) can be prepared by a one-pot process from 4-hydroxyl cinnoline (135) and protected piperazine (136) through a triflate intermediate (Cacchi, S. et al. Synlett, 1997, 1400). Sequential removal of the protecting group in compound (137) followed by amide coupling and optional deprotection affords compound (139).
  • FIG. 29 describes a synthesis of a compound containing a diamino group. Protection of the amino group in compound (140) gives a protected intermediate, which is subjected to Mitsunobu reaction with pthalimide to furnish compound (141). The phthalimide group can be selectively removed with a base (for example, hydrazine and low boiling point amines). Acylation of compound (142) with a acids using standard peptide coupling procedures followed by removal of the protecting group affords the product (144).
  • a base for example, hydrazine and low boiling point amines
  • the protecting group in compound (141) can alternatively be first selectively removed under known conditions to give compound (146), which can be coupled with an acid to afford the amide (147). Removal of the phthalimide group with a base (for example, hydrazine and a low boiling point amine) leads to the product (148).
  • a base for example, hydrazine and a low boiling point amine
  • FIG. 31 summarizes a preparation of 1-substituted quinolizinones (153).
  • Treatment of compound (149) with an organometallic base (for example, n-BuLi) followed by quenching with 2-ethoxymethylenemalonic acid diethyl ester yields the Michael addition product (150).
  • Cyclization occurs when heating compound (150) in an inert solvent (for example, xylene) to give intermediate (151).
  • the carboxylate group in intermediate (151) may be removed by heating in an acidic solution (for example, aqueous HCl or H 2 SO 4 solution). Sequential removal of the protecting group in compound (152) followed by amide coupling and optional deprotection affords compound (153).
  • FIG. 32 describes a synthesis of compounds with a 4-hydroxyl piperidine linker.
  • Compound (155) can be prepared by S N Ar reaction between a suitably N-protected 4-hydroxyl piperidine compound and a substituted quinazoline intermediate (154) where X is leaving group (for example Cl or Br), in the presence of a base (for example, NaH or triethylamine) in a suitable solvent such as DMF, TBF etc. Removal of the protecting group Pg in compound (155) followed by amide coupling with an acid and optional deprotection affords the desired compound (156).
  • a base for example, NaH or triethylamine
  • Ester (159) is then reacted with compound (160), where X is a leaving group (for example, chloro, bromo, iodo or OTf), under palladium catalysis to give intermediate (161).
  • X is a leaving group (for example, chloro, bromo, iodo or OTf)
  • intermediate (161) can be prepared by the reaction between compound (160), where X is a boronic acid or ester, with the triflate (158). Sequential removal of the protecting group in compound (161) followed by amide coupling and optional deprotection affords compound (162).
  • FIG. 34 describes the preparation of 5,6-disubstituted pyrrolopyrimidine (175).
  • Compound (168) can be obtained from commercial sources or can be prepared by literature methods (for example, Eger, K. et al. (1987), J. Heterocycl. Chem. 24, 425-430; Roth, H. J. et al. (1975), Arch. Pharm. 308, 179-185; Pichler, H. et al. (1986), Liebigs Ann. Chem. 1986, 1485-1505). Condensation of compound (168) with formic acid at elevated temperature affords intermediate (169) (Traxler, P. M. et al. (1996), J. Med. Chem., 39, 2285-2292).
  • Treating compound (169) with a halogenating agent yields the halide (170).
  • a halogenating agent for example, POCl 3
  • POCl 3 a halogenating agent
  • Removal of the protecting group Pg followed by displacement of the halogen with suitably protected piperazine (172), either neat or in the presence of an acid scavenger (for example, diisopropylethylamine or triethylamine) leads to intermediate (173). Transformation of intermediate (173) into compound (175) can be accomplished by the procedures described in FIG. 22 .
  • Compound (176) can be obtained from commercial sources or can be prepared by literature methods (for example, Hamaguchi, M. et al. (1986), Heterocycles. 24, 2111-2115; MaCall, M. A. et al. (1962), J. Org. Chem. 27, 2433-2439). Condensation of compound (176) with hydrazine affords the cyano intermediate (177), which can be converted to compound (178) by condensing with formic acid at elevated temperature.
  • compound (96) can first be hydrolyzed to afford the primary amide, which is then condensed with formamide at elevated temperature to give the cyclized product (178).
  • FIG. 36 An alternate route to the intermediate (179) for the synthesis of 3-substituted pyrazolopyrimidines is shown in FIG. 36 .
  • Regioselective deprotonation of 4,6-dichloropyrimidine at the C-5 position by treatment with an organometallic agent (for example, LDA), followed by quenching with aldehyde (184) furnishes the hydroxyl intermediate (185) (Radinov, R. et al. (1986), Synthesis, 11, 886-891; Radinov, R. et al. (1991), J. Org. Chem., 56, 4793-4796).
  • organometallic agent for example, LDA
  • Intermediate (185) can be oxidized with an oxidizing agent (for example, CrO 3 or MnO 2 ) to give ketone (186).
  • an oxidizing agent for example, CrO 3 or MnO 2
  • Treatment with hydrazine in an inert solvent such as THF or DCM yields the cyclized product (179). Transformation of (179) into desired compound (182) can be accomplished by the procedures described in FIG. 22 .
  • compound (190) may be prepared in two ways. First, the substitution of heterocyclic core (188) with aminoamido piperazine (189) followed by deprotection with acid affords the desired product (190). Second, substitution of the heterocyclic core (188) with N-protected piperazine (191) gives the intermediate (192), which was subject to deprotection, coupling with amino acid (193) and deprotection again with acid to provide the final compound (190).
  • the halide (188) may be obtained from commercial sources or prepared by means known to those in the art.
  • the tetrahydropyrado[2,3-d]pyrimidine derivative (199) may be prepared as shown in FIG. 38 .
  • a 2-amino-3-pyradocarboxylic acid (194) was heated with formamide to give the 4-hydroxypyradopyrimidine derivative (195), which was subject to chlorination with (for example) POCl 3 to afford the 4-chloro pyridopyrimidine derivative (196).
  • S N Ar reactions of the compounds (196) with 1-Boc-piperazine gave the intermediates (197).
  • Reduction of the intermediate (197) in the presence of catalytic amount of (for example) PtO 2 under hydrogen yielded the tetrahydropyrido[2,3-d]pyrimidine derivatives (198).
  • the compounds (198) were subject to amide coupling with N-protected amino acids and followed by deprotection with acid to offer the product (199).
  • Dihydropyrrolo[2,3-d]pyrimidine derivatives may be prepared as shown in FIG. 39 .
  • 2-Ethoxycarbonyl-succinic acid diethyl ester (200) was heated with formamidine to provide (4,6-Dihydroxypyrimidin-5-yl)-acetic acid methyl ester (201).
  • Halogenation of compound (201) with (for example) POCl 3 gave the dichloropyrimidine derivative (202).
  • base e.g., KH
  • Compound (217) of this invention may be prepared as shown in FIG. 40 .
  • palladium-catalyzed cross coupling of boronic acid (213) and properly substituted aryl halide (214) affords the ester intermediate, which is saponified by hydroxide base leading to acid (215).
  • the coupling of acid (215) and amine (216) under standard conditions e.g., EDCI, HOBt, etc.
  • gives the N-protected/substituted advanced intermediate for example Boc, but any suitable protecting group may be used; see, Greene et al., supra.
  • the N-protected/substituted intermediate e.g., Boc
  • Compound (223) may be prepared as shown in FIG. 41 .
  • Introduction of a leaving group into the appropriately substituted and commercially available 4,3,0-heterocycle (218) may be accomplished, for example, by treatment with a halogenating agent (for example POCl 3 ) to give the chloride (219).
  • a halogenating agent for example POCl 3
  • Displacement of the leaving group with an appropriately substituted and protected piperazine (220) for example Boc, but any suitable protecting group may be used; see, Greene et al., supra
  • an appropriately substituted and protected piperazine (220) for example Boc, but any suitable protecting group may be used; see, Greene et al., supra
  • Substitution of the piperazine secondary amine may then be accomplished using a variety of electrophiles and reaction conditions.
  • the piperazine may be acylated by a suitably N-substituted or protected amino acid (e.g., Boc, etc. (162)) which may be introduced using a variety of standard peptide coupling procedures under both solution phase and solid phase conditions to yield compound (223).
  • a suitably N-substituted or protected amino acid e.g., Boc, etc. (162)
  • the N-protected amino acid unit may then be deprotected using representative procedures (e.g., acid, for a Boc-group) referenced in Greene et al., supra, and then manipulated as desired according to procedures appreciated by those skilled in the art.
  • the amine (221) may be reacted with any other electrophile, including (but not limited to) epoxides, acid halides, aldehydes, etc., using procedures known to those in the art of organic synthesis.
  • Compounds of formula (229) may be prepared as shown in FIG. 42 .
  • An S N Ar reaction of compound (224) with a protected linker eg. Boc-piperazine
  • a protected linker eg. Boc-piperazine
  • An organometallic-mediated reaction may be used to install an activated acetylene group (226) and treatment with base (for example, KOtBu) gives the pyrrolopyrimidine (228).
  • Deprotection of the piperazine protecting group with, for example in the case of a Boc group, acid
  • acylation with for example a protected amino acid, followed by deprotection if necessary
  • FIG. 44 illustrates the general preparation of compounds of the formula (242).
  • Acylation of an appropriately substituted aminothiophene (235) using, for example, formic acid and ammonium acetate under heat
  • cyclisation using (for example) formamide and ammonium formate at high temperature gives the appropriate heterocycle.
  • Halogenation, using (for example) oxalyl chloride then gives the appropriately halogenated intermediate (237).
  • This intermediate may then be functionalised in multiple ways. For example, displacement with an appropriately substituted piperazine (using either heat or transition metal mediated reactions) will give the desired product (242).
  • the core may be halogenated, using (for example) an organolithium base and a halogen source (e.g., NCS, Br 2 , I 2 , etc.) to give compound (238).
  • a halogen source e.g., NCS, Br 2 , I 2 , etc.
  • bromination both non-regioselective and polybromination are observed, allowing an entry into more fully substituted and functionalised derivatives, (239).
  • These may then be subjected to any number of anionic or transition metal-mediated reactions (eg. Suzuki, Stille, Negishi, etc.) to provide further functionality (e.g., (240) or (241)).
  • subsequent displacement with an appropriately substituted piperazine (along with subsequent functionalisation, if desired) gives rise to the desired products (242).
  • Compounds (247) may be prepared as shown in FIG. 45 .
  • 4-Chloropyrrolo[2,3-d]pyrimidine (243) is oxidized with an appropriate oxidizing agent (pyridinium tribromide, for example) in an appropriate solvent (such as t-butanol), and the resulting gem-dibromide is reduced under appropriate conditions (using Zn/HOAc, for example) in an appropriate solvent (e.g., MeOH) to give the lactam 244.
  • an appropriate oxidizing agent pyridinium tribromide, for example
  • an appropriate solvent such as t-butanol
  • an appropriate solvent e.g., MeOH
  • FIG. 46 shows the general preparation of compounds (256).
  • a suitably substituted thiophenecarboxylic acid (248) may be converted to the protected aminothiophene (249) by means of a rearrangement, using (for example) diphenylphosphorylazide in the presence of a suitable base and solvent (e.g., t-BuOH) at elevated temperature.
  • a suitable base and solvent e.g., t-BuOH
  • a suitable malonate derivative eg. 2-ethoxymethylene malonate
  • Halogenation using (for example) POCl 3 in the presence of base eg. NEt 3
  • the ester may be saponified using aqueous basic conditions (e.g., LiOH in water and methanol) to give the acid (255) which may then be removed by decarboxylation by heating at high temperature in an appropriate solvent (e.g., diphenyl ether.) After any additional and necessary deprotection, the desired product is attained (256).
  • aqueous basic conditions e.g., LiOH in water and methanol
  • an appropriate solvent e.g., diphenyl ether.
  • FIG. 48 illustrates the general preparation of compound (271).
  • Coupling of the uracil derivative (266) with 3-aminopyrazole (267) in the presence of base gives the pyrazolopyridone (268).
  • Halogenation for example, using POCl 3
  • a suitably substituted linker e.g., Boc-piperazine using heat
  • removal of the protecting group e.g., TFA, for a Boc-group
  • acylation using for example
  • a protected amino acid followeded by the appropriate deprotection
  • the activity of the compounds described in the present invention may be determined by the following procedure: This procedure describes a kinase assay that measures the phosphorylation of a fluorescently-labeled peptide by full-length human recombinant active AKT-1 by fluorescent polarization using a commercially available IMAP kit.
  • the assay materials come from an IMAP AKT Assay Bulk Kit, product #R8059, from Molecular Devices, Sunnyvale, Calif.
  • the kit materials include an IAP Reaction Buffer (5 ⁇ ): The diluted 1 ⁇ IMAP Reaction Buffer contains 10 mM Tris-HCl, pH 7.2, 10 mM MgCl 2 , 0.1% BSA, 0.05% NaN3. DTT is routinely added to a final concentration of 1 mM immediately prior to use.
  • IMAP Binding Buffer (5 ⁇ ), and IMAP Binding Reagent.
  • the Binding Solution is prepared as a 1:400 dilution of IMAP Binding Reagent into 1 ⁇ IMAP Binding Buffer.
  • Fluorescein-labeled AKT Substrate having the sequence (F1)-GRPRTSSFAEG.
  • a stock solution of 20 ⁇ M is made up in 1 ⁇ IMAP Reaction Buffer.
  • the plates used include a Costar 3657 (382-well made of polypropylene and having a white, v-bottom) that is used for compound dilution and for preparing the compound-ATP mixture.
  • the assay plate was the Packard ProxyPlateTM-384 F.
  • the AKT-1 used was made from full-length, human recombinant AKT-1 that is activated with PDK1 and MAP kinase 2.
  • the assay procedure starts the preparation of stock solutions of compounds at 10 mM in DMSO.
  • the stock solutions and the control compound are serially diluted 1:2 nine times into DMSO (10 ⁇ L of compound+10 ⁇ L of DMSO) to give 50 ⁇ dilution series over the desired dosing range.
  • DMSO 10 ⁇ L of compound+10 ⁇ L of DMSO
  • 2.1- ⁇ L aliquots of the compounds in DMSO are transferred to a Costar 3657 plate containing 50 ⁇ L of 10.4 ⁇ M ATP in 1 ⁇ IMAP Reaction Buffer containing 1 mM DTT.
  • 2.5- ⁇ L aliquots are transferred to a ProxyPlateTM-384 F plate.
  • the assay is initiated by the addition of 2.5- ⁇ L aliquots of a solution containing 200 nM of fluorescently-labeled peptide substrate and 4 nM AKT-1.
  • the plate is centrifuged for 1 minute at 1000 g and incubated for 60 minute at ambient temperature.
  • the reaction is then quenched by the addition of 15 ⁇ L of Binding Solution, centrifuged again and incubated for an additional 30 minutes at ambient temperature prior to reading on a Victor 1420 Multilabel HTS Counter configured to measure fluorescence polarization.
  • the compounds of the present invention may be prepared either as either the racemate or as a single enantiomer (for example, using enantiomerically pure reagents. If prepared as the racemate, the corresponding enantiomers may be isolated by separation of the racemic mixture of on a chiral stationary phase column utilizing normal or reverse phase HPLC techniques. Alternatively, a diastereomeric mixture can be prepared by treatment of the racemic mixture with an appropriate chiral acid (or suitably activated derivative), for example dibenzoyl tartrate or the like (see, for example, Kinbara, K., et. al., J. Chern. Soc., Perkin Trans. 2, 1996, 2615; and Tomori, H., et. al., Bull.
  • reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
  • HPLC retention times (R t ) are reported in minutes. Unless stated otherwise, the following HPLC conditions were used to obtain the reported retention times: column: Waters YMC ODS-AQ, 3.0 ⁇ 50 mm; 5-95% gradient MeCN in water (0.01% HFBA, 1% IPA); flow rate: 1.00 mL/min; detected at 220 nm.
  • 1 H-NMR spectra were recorded on a Varian instrument operating at 400 MHz. 1 H-NMR spectra were obtained as CDCl 3 solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm). Other NMR solvents were used as needed. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets).
  • Step 1 To a solution of 4-chloroquinazoline (2.0 g, 12.2 mmol) (Tobe, Masanori, et al., Bioorg. Med. Chem. 2003, 11(3), 383) and DIEA (3.2 mL, 18.2 mmol) in 40 mL IPA was added Boc-piperazine (1.96 g, 12.81 mmol). The reaction mixture was heated to reflux and stirred for 20 hours, after which it was cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in dichloromethane (DCM) and washed with 1N NaOH. The organic layer was dried (Na 2 SO 4 ), filtered, and concentrated by rotary evaporation.
  • DCM dichloromethane
  • the resulting oil was dissolved in 25 mL dioxane, and 4M HCl/dioxane (46 mL, 182 mmol) was added dropwise. The suspension was sonicated for 2 minutes and stirred 13 hours at room temperature, after which the reaction mixture was concentrated to dryness by rotary evaporation. The resulting amine HCl salt was dissolved in 2N NaOH and extracted with DCM. The organic layer was dried (Na 2 SO 4 ), filtered, and concentrated by rotary evaporation. The resulting oil was purified on silica (9:1:0.02 DCM/MeOH/NH 4 OH) to give 4-piperazinylquinazoline as a yellow oil (2.5 g, 96%).
  • Step 2 To a Jones tube containing PS-CDI (Argonaut, 1.04 mmol/g, 2.2 equivalents) suspended in a solution of the 4-piperazinylquinazoline (1.0 equivalent) in CHCl 3 was added a solid Boc-protected amino acid (1.5 equivalents) (see Example 1B). The reaction mixture was shaken for 15 hours at room temperature, after which it was vacuum filtered, the resin rinsed with CHCl 3 , and the filtrate concentrated by rotary evaporation. If necessary, the crude coupled product was purified on silica (DCM/EtOAc or DCM/MeOH).
  • Boc-amino amide was dissolved in minimal dioxane, and 4M HCl/dioxane (10 equivalents) was added. The suspension was sonicated 5 minutes and stirred at room temperature for 12 hours, after which it was concentrated by rotary evaporation. The solids were dispersed in ether, isolated by filtration with nitrogen pressure, and dried under reduced pressure to give the corresponding 4-piperazinylquinazoline amino amide as the hydrochloride salt. If necessary, the hydrochloride salts were free-based with 1N NaOH, extracted with DCM, and the combined organic layers were dried (Na 2 SO 4 ), filtered, concentrated by rotary evaporation, and dried under reduced pressure.
  • Example 2-21 The compounds described in Examples 2-21 were prepared as described in Example 1, Step 2, using 4-piperazinylquinazoline and the appropriate amino acid shown in Example 1B.
  • the HPLC conditions used to obtain the reported retention times (minutes) were: column: Waters YMC ODS-AQ, 4.6 ⁇ 50 mm; 5-95% gradient MeCN in water (0.01% HFBA, 1% IPA); flow rate: 2.00 mL/min; detected at 220 nm.
  • Step 1 A solution of 6-bromoquinazolin-4-ol (1.0 g, 4.44 Mmol) in POCl 3 (10 mL) was stirred and heated at 110° C. in a sealed tube overnight. The solution was cooled to room temperature and poured onto ice (200 g.) The solution was extracted with DCM (300 mL), washed with water (200 mL), dried over Na 2 SO 4 and concentrated in vacuo to give the impure 6-bromo-4-chloroquinazoline as a brown solid that was not purified further (1.5 g.) MS (APCI+) [M+H] + 243.1.
  • Step 2 A solution of the crude product from Step 1 (1.5 g), piperazine-1-carboxylic acid tert-butyl ester (2.29 g, 12.3 mmol) and triethylamine (2.15 mL, 15.4 mmol) in N-methylpyrrolidinone (50 mL) was stirred and heated at 80° C. for 2 hours. The solution was cooled to room temperature, diluted with EtOAc (200 m]L), washed with water (3 ⁇ 200 mL) and dried over Na 2 SO 4 .
  • Step 3 HCl (1.0 M in Et 2 O, 30 mL) was added to a solution of 4-(6-bromo-quinazolin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.50 g, 3.81 mmol) in MeOH (50 mL) and stirred at room temperature overnight. The mixture was concentrated in vacuo to give 6-bromo-4-piperazin-1-yl-quinazoline as the bis-hydrochloride salt (1.3 g, 93%.) MS (APCI+) [M+H] + 295.1.
  • Step 4 EDCI.HCl (230 mg, 1.2 mmol), HOBt (160 mg, 1.2 mmol) and Boc-D-4-chlorophenylalanine (240 mg, 1.2 mmol) were added to a stirred solution of 6-bromo-4-piperazin-1-yl-quinazoline bis-hydrochloride (360 mg, 0.98 mmol) and triethylamine (0.30 mL, 1.2 mmol) in DMF (8 mL) at room temperature under nitrogen. Stirred at room temperature overnight. Diluted with EtOAc (100 mL) and washed with water (3 ⁇ 50 mL.) Dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 5 THF (5 mL) was added to a stirred mixture of Pd 2 dba 3 (8.0 mg, 0.0087 mmol) and triphenylarsine (11 mg, 0.035 mmol) at room temperature under nitrogen. The yellow solution was stirred at room temperature for 2 minutes and then transferred via cannula to a stirred solution of [2-[4-(6-bromoquinazolin-4-yl)-piperazin-1-yl]-1-(4-chlorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (50 mg, 0.087 mmol) and phenylboronic acid (21 mg, 0.17 mmol) in ethylene glycol dimethyl ether (5 mL) and aqueous sodium carbonate (2M, 5 mL) and stirred and heated at 80° C.
  • Step 6 Trifluoroacetic acid (4 mL) was added to a stirred solution of ⁇ 1-(4-chlorobenzyl)-2-oxo-2-[4-(6-phenyl-quinazolin-4-yl)-piperazin-1-yl]-ethyl ⁇ -carbamic acid tert-butyl ester (30 mg) in DCM (10 mL) at room temperature.
  • Step 1 NaH (60% in mineral oil, 0.24 g) in DMF (15 mL) was added Thieno[3,2-b]pyridin-7-ol (0.756 g) portionwise. The reaction mixture was warmed at 40° C. and stirred for 30 minutes. After cooling, N-phenyltrifluoromethanesulfonimide (2.1 g) was added, the reaction mixture was stirred at room temperature for 1 hour, and the Boc-piperazine (1.9 g) was added. The mixture was stirred at 80° C. for 2 hours.
  • Step 2 The 4-thieno [3,2-b]pyridin-7-piperazine-1-carboxylic tert-butyl ester (1.32 g) in DCM (20 mL) was added the 4 N HCl in dioxane (21 mL). The reaction was stirred at room temperature for 10 hours. The solvent was removed under reduced pressure and the resulting amine HCl salt was dissolved in saturated sodium bicarbonate (20 mL) and extracted with DCM (30 1L). The organic layer was dried (Na 2 SO 4 ), filtered, and concentrated by rotary evaporation to give 7-Piperazin-1-yl-thieno[3,2-b]pyridine as an off-white solid (0.85 g, 93.8%). R t 1.40 minutes. MS (ESI+) [M+H] + 220.
  • Step 3 DIEA (0.07 mL) and HBTU (0.12 g) was added to the solution of the (2R)-2-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionic acid (0.092 g) in THF (5 mL) at 0° C. The mixture was stirred at room temperature for 20 minutes, then 7-Piperazin-1-yl-thieno[3,2-b]pyridine (0.056 g) was added. The reaction was stirred at room temperature for 1 hr. 20 mL of EtOAc was added and the organic layer was separated. The aqueous layer extracted with EtOAc (20 mL).
  • Step 4 The resulting Boc-amino amide (0.056 mg) was dissolved in dioxane, and 4M HCl/dioxane (0.5 mL) was added. The suspension was stirred at room temperature for 3 hours, after which it was concentrated to give the corresponding amino amide as the hydrochloride salt (0.53 g, 98%). R t 1.77 minutes. MS (ESI+) [M+H] + 401.
  • Step 1 To a solution of Boc-D-Phe(4-Cl)—OH (3.65 g, 12.2 mmol), piperazine (10 g, 116 mmol) in DCM (200 mL) were added HOBT (3.3 g, 24 mmol) and EDCI (4.7 g, 25 mmol). The mixture was stirred at room temperature for 12 hours. The solution was washed with water, brine and dried over magnesium sulfate.
  • Step 2 To a solution of 3-aminothiophene-2-carboxylic methyl ester (20 g, 127 mmol) in formic acid (100 mL) was added ammonium acetate (13 g, 169 mmol). The mixture was refluxed for 3 hours. After cooling to room temperature, the precipitate was filtered, washed with water and dried under vacuum to afford 3-formylaminothiophene-2-carboxylic acid methyl ester (20.5 g, 87%).
  • Step 3 To a mixture of 3-formylaminothiophene-2-carboxylic acid methyl ester (20.5 g, 111 mmol) and ammonium formate (21 g, 333 mmol) was added formamide (29.8 g, 662 mmol). The slurry was heated to 140° C. for 10 hours. After cooling, the solid was filtered, washed with water and dried under vacuum to afford the product 3H-Thieno[3,2-d]pyrimidin-4-one (12.5 g, 74%).
  • Step 4 To a solution of DMF (13.2 mL, 170 mmol) in DCM (100 mL) at 0° C. was added oxalyl chloride (22 mL, 252 mmol) in DCM (100 mL) very slowly over 1 hour. To the resulting white gel solution was added the 3H-thieno[3,2-d]pyrimidin-4-one (12 g, 79 mmol). The mixture was refluxed for 4 hours. After cooling, the mixture was purred into water (500 mL) and extracted with DCM (3 ⁇ 250 mL).
  • Step 5 The solution of [1-(4-chlorobenzyl)-2-oxo-2-piperazin-1-yl-ethyl]-carbamic acid tert-butyl ester (60 mg, 0.163 mmol) and 4-Chlorothieno[3,2-d]pyrimidine 950 mg, 0.293 mmol) in Toluene (5 mL)/TEA (1 mL) was refluxed for 12 hours.
  • Step 6 To a solution of [1-(4-chlorobenzyl)-2-oxo-2-(4-thieno[3,2-d]pyrimidin-4-yl-piperazin-1-yl)-ethyl]-carbamic acid tert-butyl ester in DCM (2 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed to afford 2-amino-3-(4-chlorophenyl)-1-(4-thieno[3,2-d]pyrimidin-4-yl-piperazin-1-yl)-propan-1-one dihydrochloride quantitatively. MS (ESI+) [M+H] + 402.
  • Step 1 To a solution of 4, 6-dichloro-5-aminopyrimidine (1 g, 6.1 mmol) in TEA (2 mL) and toluene (10 mL) was added 1-Boc-piperazine (2.3 g, 12.3 mmol). The mixture was refluxed for 12 hours. The solvent was removed and the residue was subject to chromatography on silica gel to afford the product 4-(5-amino-6-chloropyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.9 g, 99%).
  • Step 2 To a solution of 4-(5-amino-6-chloropyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (1 g, 3.19 mmol) and TMS-acetylene (1.5 g, 15 mmol) in TEA (10 mL) and THF (30 mL) were added PdCl 2 (PPh 3 ) 2 (0.33 g, 0.47 mmol) and CuI (0.1 g, 0.53 mmol) under N 2 . The mixture was heated to 80° C. for 20 hours.
  • Step 3 To a solution of t BuOK (0.063 g, 0.56 mmol) in NMP (4 mL) was added 4-(5-Amino-6-trimethylsilanylethynyl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.1 g, 0.27 mmol) in NMP (1 mL) under N 2 . The mixture was vigorously stirred at room temperature for 4 hours. The reaction was quenched with water (1 mL) and ethyl acetate (50 mL). The organic phase was washed brine and water until NMP was gone, then dried over MgSO 4 , filtered and concentrated.
  • Step 4 To a solution of 4-(5H-Pyrrolo[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (43 mg, 0.14 mmol) in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed and the residue was treated with TEA (2 mL), Boc-D-Phe(4-Cl)—OH (43 mg, 0.14 mmol), HOBT (30 mg, 0.222 mmol) and EDCI (41 mg, 0.214 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 12 hours.
  • Step 5 To a solution of ⁇ 1-(4-chlorobenzyl)-2-oxo-2-[4-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl ⁇ -carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL) and stirred for 4 hours. The solvent was removed to afford 2-Amino-3-(4-chlorophenyl)-1-[4-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride quantitatively. MS (ESI+) [M+H] + 385.
  • Step 1 To a solution of 4-hydroxy-3-nitro-pyridine (2 g, 14 mmol) in POCl 3 (6 mL) was added PCl 5 (2.5 g, 12 mmol). The mixture was heated to reflux for 3 hours. The solvent was evaporated and the residue was cooled with ice-water and vigorously stirred with water (3 mL) and CHCl 3 (6 mL). The aqueous was extracted CHCl 3 (5 ⁇ 5 mL). The organic phase was combined and dried over MgSO 4 . After filtration, the solvent was removed to afford the product 4-Chloro-3-nitro-pyridine (2.24 g, 99%).
  • Step 2 To a solution of 4-chloro-3-nitro-pyridine (2 g, 13 mmol) in dry THF (100 mL) under N 2 at ⁇ 78° C. was added excess vinyl magnesium bromide (1.0M, 40 mL, 40 mmol). The mixture was stirred at -20° C. for 8 hours before the reaction was quenched with 20% NH 4 Cl (75 mL). The aqueous phase was extracted with ethyl acetate (3 ⁇ 100 mL). The combined organic layer was dried over MgSO 4 , filtered and concentrated. The residue was subject to chromatography on silica gel to afford 7-Chloro-1H-pyrrolo[3,2-b]pyridine (0.3 g, 16%).
  • Step 3 To a solution of 7-Chloro-1H-pyrrolo[3,2-b]pyridine (40 mg, 0.262 mmol) in xylene (4 mL) and TEA (1 mL) was added [1-(4-chlorobenzyl)-2-oxo-2-piperazin-1-yl-ethyl]-carbamic acid tert-butyl ester (0.1 g, 0.27 mol). The mixture was refluxed for 6 days.
  • Step 4 To a solution of ⁇ 1-(4-chlorobenzyl)-2-oxo-2-[4-(1H-pyrrolo[3,2-b]pyridin-7-yl)-piperazin-1-yl]-ethyl ⁇ -carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours. The solvent removed to afford the product 2-Amino-3-(4-chlorophenyl)-1-[4-(1H-pyrrolo[3,2-b]pyridin-7-yl)-piperazin-1-yl]-propan-1-one quantitatively. MS (ESI+) [M+H] + 384.
  • Step 1 To a solution of LDA (1.8M, 20.6 mL, 37.1 mmol) in THF (65 mL) at ⁇ 78° C. was added 4-chloro-thieno[3,2-d]pyrimidine (5.26 g, 31 mmol) in THF (50 mL) dropwise over 1 hour. After stirring for 20 minutes, I 2 (12.7 g, 50 mmol) in THF (40 mL) was added to the mixture at ⁇ 78° C. dropwise. The mixture was stirred at the same temperature for 20 minutes and then warmed up to room temperature for 2 hours. The mixture was poured into water (100 mL) and stirred for 30 minutes.
  • Step 2 To a solution of 4-chloro-6-ibdothieno[3,2-d]pyrimidine (0.22 g, 0.742 mmol) in DCE(5 mL)/TEA(2 mL) was added [1-(4-chlorobenzyl)-2-oxo-2-piperazin-1-yl-ethyl]-carbamic acid tert-butyl ester (25 mg, 0.68 mmol). The mixture was refluxed for 2 hours.
  • Step 3 To a solution of ⁇ 1-(4-chlorobenzyl)-2-[4-(6-iodothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours.
  • Step 1 To a solution of ZnBr 2 (70 mg, 0.311 mmol) in THF (2 mL) was added propargyl magnesium bromide (0.5M, 0.6 mL, 0.3 mmol) at room temperature. After stirring for 20 minutes, the 6-iodothieno[3,2-d]pyrimidine (50 mg, 0.08 mmol) was added. The mixture was flushed with N 2 and PdCl 2 (dppf) was added. The mixture was stirred at room temperature under N 2 for 12 hours.
  • Step 2 To a solution of ⁇ 1-(4-chlorobenzyl)-2-oxo-2-[4-(6-prop-1-ynyl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl ⁇ -carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred for 4 hours.
  • Step 1 To a solution of ⁇ 1-(4-chlorobenzyl)-2-[4-(6-iodothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester (50 mg, 0.080 mmol) in DMF (3 mL) were added 2M Na 2 CO 3 (0.1 mL) and 3-thiophenyl boronic acid (15 mg, 0.117 mmol). The mixture was bubbled N 2 for 20 minutes and then Pd(PPh 3 ) 4 (10 mg, 0.012 mmol) was added. The mixture was heated to 90° C for 12 hours.
  • Step 2 To a solution of product ⁇ 1-(4-chlorobenzyl)-2-oxo-2-[4-(6-thiophen-3-yl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl ⁇ -carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours.
  • Step 1 To a solution of ⁇ 1-(4-chlorobenzyl)-2-[4-(6-iodothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester (50 mg, 0.080 mmol), sodium methylthiolate (12 mg, 2.15 mmol) and 1,3-di-tert-butyl-propane-dione 940 mg, 0.22 mmol) was purged with N 2 . NMP (2 mL) and CuCl (5 mg, 0.05 mmol) were added. The mixture was heated to 130° C. for 3 hours.
  • Step 2 To a solution of ⁇ 1-(4-chlorobenzyl)-2-[4-(6-methylsulfanyl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours.
  • Step 1 To a solution of ⁇ 1-(4-chlorobenzyl)-2-[4-(6-iodothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester (50 mg, 0.080 mmol) in Pyridine (5 mL) was added CuCN (20 mg, 0.223 mmol). The mixture was refluxed under N 2 for 12 hours.
  • Step 2 To a solution of ⁇ 1-(4-chlorobenzyl)-2-[4-(6-cyanothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 10 hours.
  • Step 1 To a solution of 4-chloro-6-iodothieno[3,2-d]pyrimidine (0.5g, 1.7 mmol) in DCE (5 mL)/TEA (1 mL) was added 1-Benzyl-piperazine (0.3 g, 1.69 mmol). The mixture was refluxed for 1 hour. The solvent was removed and the residue was subject to chromatography on silica gel to afford (4-Benzyl-piperazin-1-yl)-6-iodothieno [3,2-d]pyrimidine (0.65 g, 88%).
  • Step 2 To a suspension of ZnBr 2 (0.5 g, 2.2 mmol) dried under vacuum in THF (10 mL) was added MeMgBr (3M, 0.6 mL, 1.8 mmol) at room temperature dropwise. After addition, the mixture was stirred for 1 hour, then (4-Benzyl-piperazin-1-yl)-6-iodothieno[3,2-d]pyrimidine (0.4 g, 0.92 mmol) was added followed by PdCl 2 (dppf) (30 mg) under N 2 . The mixture was heated to 60° C. for 2 hours. The reaction was quenched with water. The organic phase was separated and dried over MgSO 4 .
  • Step 3 To a solution of 4-(4-Benzyl-piperazin-1-yl)-6-methylthieno[3,2-d]pyrimidine (65 mg, 0.20 mmol) in MeOH (10 mL) was added Pd/C (10%, 20 mg) and two drop of TFA. The mixture was stirred under H 2 balloon for 4 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in DCM (6 mL) and TEA (2 mL), then Boc-D-Phe(4-Cl)—OH (59 mg, 0.20 mmol) was added, followed by HOBT (50 mg, 0.37 mmol) and EDCI (74 mg, 0.39 mmol). The mixture was stirred at room temperature for 12 hours.
  • Step 4 To a solution of ⁇ 1-(4-chlorobenzyl)-2-[4-(6-methylthieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred for 4 hours. The solvent was removed to afford the product 2-Amino-3-(4-chlorophenyl)-1-[4-(6-methylthieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride quantitatively. MS (ESI+) [M+H] + 416.
  • Step 1 A mixture of 5-aminoindazole (2.53 g, 19.0 mmol), bis(2-chloroethyl)amine hydrochloride (3.60 g, 20.1 mmol) and ethanol (30 mL) was heated at reflux overnight. The mixture was allowed to cool to room temperature. Na 2 CO 3 (2.14 g, 20.2 mmol) was added and the reaction mixture heated at reflux for 8 hours. After cooling, the mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in 1 N HCl (100 mL) and extracted with DCM (2 ⁇ 50 mL). The aqueous phase was made basic with 4 N NaOH (30 mL) and extracted with EtOAc (2 ⁇ 100 mL).
  • Step 2 To a solution of (D)-Boc-4-chlorophenylalanine (0.119 g, 0.396 mmol) and 5-Piperazin-1-yl-1H-indazole (0.100 g, 0.494 mmol) in DMF (5 ML) was added EDCI (0.152 g, 0.791 mmol), HOBt (0.121 g, 0.791 mmol) and triethylamine (0.110 mL, 0.791 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc.
  • Step 3 To a solution of(2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester (0.176 g, 0.364 mmol) in DCM (10 mL) was added 4 N HCl in dioxane (1 mL). The mixture was stirred at room temperature overnight and then evaporated. The resulting solid was suspended in isopropyl alcohol-ether (1:5) and stirred for 30 minutes.
  • Step 1 (2S)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester was prepared by the procedures described in Example 34, Step 2, substituting (D)-Boc-4-chlorophenylalanine with (L)-Boc-4-chlorophenylalanine.
  • Step 2 (2S)-2-Amino-3-(4-chlorophenyl)-1-[4-(1H-indazol-5-yl)-piperazin-1-yl]-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2S)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester.
  • Step 1 6-Piperazin-1-yl-1H-indazole was prepared by the procedures described in Example 34, Step 1, substituting 5-aminoindazole with 6-aminoindazole.
  • Step 2 (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-6-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester was prepared by the procedures described in Example 34, Step 2, substituting 5-Piperazin-1-yl-1H-indazole with 6-Piperazin-1-yl-1H-indazole.
  • Step 3 (2R)-2-Amino-3-(4-chlorophenyl)-1-[4-(1H-indazol-6-yl)-piperazin-1-yl]-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-6-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester.
  • Step 1 To a solution of 5-Piperazin-1-yl-1H-indazole (0.34 g, 1.3 mmol) in 1,4-dioxane (5 mL) was added 3N NaOH (0. 42 mL, 1.3 mmol). After cooling to 0° C., a solution of tert-butylcarbonate (0.25 g, 1.3 mmol) in 1,4-dioxane (1 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight and then poured into water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO 3 , water, brine, dried and concentrated.
  • Step 2 To a stirred suspension of NaH (60%, 4 mg, 0.1 mmol) in DMF (0.5 mL) was added dropwise a solution of 4-(1H-Indazol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.100 g, 0.33 mmol) in DMF (1 mL). After stirring for 30 minutes, methyl iodide (0.026 g, 0.18 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours and then partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated.
  • Step 3 1-Methyl-5-piperazin-1-yl-1H-indazole dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with 4-(1-Methyl-1H-indazol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester.
  • LCMS (APCI+) m/z 217 [M+H] + ; Rt 1.15 minutes.
  • Step 4 (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1-methyl-1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester was prepared by the procedures described in Example 34, Step 2, substituting 5-Piperazin-1-yl-1H-indazole with 1-Methyl-5-piperazin-1-yl-1H-indazole dihydrochloride.
  • Step 5 (2R)-2-Amino-3-(4-chlorophenyl)-1-[4-(1-methyl-1H-indazol-5-yl)-piperazin-1-yl]-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1-methyl-1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester.
  • Step 1 A round bottom flask charged with 6-bromo isoquinoline (prepared from 4-bromobenzaldehyde according to the literature: Neiko Nerenz, et al. (1998) J. Chem. Soc. Perkin Trans. 2, 437-447,0.200 g, 0.961 mmol), 1-Boc piperazine (0.215 g, 1.15 mmol), K 3 PO 4 (0.286 g, 1.35 mmol), (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (0.028 g, 0.072 mmol) and Pd 2 dba 3 (0.022 g, 0.024 mmol) in dry DME (2 mL) was purged under N 2 and heated at reflux for 5 hours.
  • 6-bromo isoquinoline prepared from 4-bromobenzaldehyde according to the literature: Neiko Nerenz, et al. (1998) J. Chem. Soc. Perkin Trans.
  • Step 2 6-Piperazin-1-yl-isoquinoline dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with 4-Isoquinolin-6-yl-piperazine-1-carboxylic acid tert-butyl ester.
  • Step 3 (2R)-[1-(4-chlorobenzyl)-2-(4-isoquinolin-6-yl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester was prepared by the procedures described in Example 34, Step 2, substituting 5-Piperazin-1-yl-1H-indazole with 6-Piperazin-1-yl-isoquinoline dihydrochloride.
  • Step 4 (2R)-2-Amino-3-(4-chlorophenyl)-1-(4-isoquinolin-6-yl-piperazin-1-yl)-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)-[1-(4-chlorobenzyl)-2-(4-isoquinolin-6-yl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester.
  • Step 1 (2R)-[1-(1H-Indol-3-ylmethyl)-2-(4-isoquinolin-6-yl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester was prepared by the procedures described in Example 34, Step 2, substituting 5-Piperazin-1-yl-1H-indazole with 6-Piperazin-1-yl-isoquinoline dihydrochloride and substituting (D)-Boc-4-chlorophenylalanine with (D)-Boc-tryptophan.
  • Step 2 (2R)-2-Amino-3-(1H-indol-3-yl)-1-(4-isoquinolin-6-yl-piperazin-1-yl)-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)-[1-(1H-Indol-3-ylmethyl)-2-(4-isoquinolin-6-yl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester.
  • Step 1 A mixture of 4-chloro-5-iodopyrimidine (3.00 g, 12.5 mmol) (prepared from 4(3H)-pyrimidinone according to the literature: Takao Sakamoto, et al. (1986) Chem. Pharm. Bull., 2719-2724), Et 3 N (5.22 mL, 37.4 mmol), 1-Boc piperazine (2.79 g, 15.0 mmol) and NMP (30 mL) was heated at 75° C. for 6 hours. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated.
  • Step 2 5-Iodo-4-piperazin-1-yl-pyrimidine dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with 4-(5-Iodo-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester.
  • Step 3 (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(5-iodopyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester was prepared by the procedures described in Example 34, Step 2, substituting 5-Piperazin-1-yl-1H-indazole with 5-Iodo-4-piperazin-1-yl-pyrimidine dihydrochloride.
  • Step 4 A round bottom flask was charged with sodium methanethiolate (17 mg, 0.25 mmol), (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(5-iodopyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester (71 mg, 0.12 mmol) and 2,2,6,6-tetramethyl-heptane-3,5-dione (6 mg, 0.25 equivalents). After vacuum purging and refilling of N 2 , NMP (3 mL) and CuCl (6 mg, 0.06 mmol) was added to this mixture. The reaction was stirred at 130° C. for 1 hour.
  • Step 5 (2R)-2-Amino-3-(4-chlorophenyl)-1-[4-(5-methylsulfanylpyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)- ⁇ I1-(4-chlorobenzyl)-2-[4-(5-methylsulfanylpyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester.
  • Step 1 (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(5-iodopyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester (0.150 g, 0.262 mmol), phenylboronic acid (0.042 g, 0.341 mmol) and 2N sodium carbonate solution (0.34 mL, 0.68 mmol) were stirred in DME (3 mL) and the mixture was degassed with N 2 for 15 minutes.
  • Tetrakis(triphenylphosphine) palladium (0) (0.015 g, 0.013 mmol) was added and the mixture heated at 80° C. for 24 hours. The mixture was cooled to room temperature and partitioned between DCM and water. The aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO 3 and brine, dried and concentrated.
  • Step 2 (2R)-2-Amino-3-(4-chlorophenyl)-1-[4-(5-phenylpyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)- ⁇ 1-(4-chlorobenzyl)-2-oxo-2-[4-(5-phenylpyrimidin-4-yl)-piperazin-1-yl]-ethyl ⁇ -carbamic acid tert-butyl ester.
  • Step 1 (2R)- ⁇ 1-(4-chlorobenzyl)-2-oxo-2-[4-(5-thiophen-3-yl-pyrimidin-4-yl)-piperazin-1-yl]-ethyl ⁇ -carbamic acid tert-butyl ester was prepared by the procedures described in Example 41, Step 1, substituting phenylboronic acid with 3-thiopheneboronic acid.
  • Step 2 (2R)-2-Amino-3-(4-chlorophenyl)-1-[4-(5-thiophen-3-yl-pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)- ⁇ 1-(4-chlorobenzyl)-2-oxo-2-[4-(5-thiophen-3-yl-pyrimidin-4-yl)-piperazin-1-yl]-ethyl ⁇ -carbamic acid tert-butyl ester.
  • Step 1 (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(5-chloropyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester was prepared by the procedures described in Example 40, Step 1, substituting 4-chloro-5-iodopyrimidine with 4,5-dichloropyrimidine (prepared from 5-chloropyrimidin-4-ol according to the literature: Chestfield J. et al. (1955) J. Chem. Soc.
  • Step 2 (2R)-2-Amino-3-(4-chlorophenyl)-1-[4-(5-chloropyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(5-yl)-piperazin-1-chloropyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester.
  • Step 1 (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(5-fluoropyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester was prepared by the procedures described in Example 40, Step 1, substituting 4-chloro-5-iodopyrimidine with 4-chloro-5-fluoropyrimidine (prepared from 5-fluoropyrimidin-4-ol according to the literature (Kheifets, G. M. et al., 2000, Russian J. Org.
  • Step 2 (2R)-2-Amino-3-(4-chlorophenyl)-1-[4-(5-fluoropyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(5-fluoropyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester.
  • Step 1 A sealed tube charged with 4-(5-Iodo-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (780 mg, 2.00 mmol), CuI (38 mg, 0.20 mmol), 1,10-phenathroline (72 mg, 0.4 mmol), Cs 2 CO 3 (912 mg, 2.8 mmol), benzyl alcohol (0.62 mL, 6.0 mmol) and toluene (2 mL) was heated at 110° C. for 40 hours. The resulting suspension was cooled to room temperature and filtered through a silica gel pad, eluting with EtOAc.
  • Step 2 5-Benzyloxy-4-piperazin-1-yl-pyrimidine dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with 4-(5-Benzyloxypyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester.
  • LCMS (APCI+) m/z 271 [M+H] 30 ; Rt 1.64 minutes.
  • Step 3 (2R)-[2-[4-(5-Benzyloxypyrimidin-4-yl)-piperazin-1-yl]-1-(4-chlorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester was prepared by the procedures described in Example 34, Step 2, substituting 5-Piperazin-1-yl-1H-indazole with 5-Benzyloxy-4-piperazin-1-yl-pyrimidine dihydrochloride.
  • Step 4 (2R)-2-Amino-1-[4-(5-benzyloxypyrimidin-4-yl)-piperazin-1-yl]-3-(4-chlorophenyl)-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)-[2-[4-(5-benzyloxypyrimidin-4-yl)-piperazin-1-yl]-1-(4-chlorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester.
  • Step 1 4-Piperazin-1-yl-pyrimidin-5-ylamine dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with 4-(5-aminopyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (prepared from 4,6-dichloro-nitropyrimidine according to the procedures described in U.S. Pat. No. 5,563,142).
  • LCMS (APCI+) m/z 180 [M+H] 30 ; Rt 1.12 minutes.
  • Step 2 (2R)-[2-[4-(5-aminopyrimidin-4-yl)-piperazin-1-yl]-1-(4-chlorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester was prepared by the procedures described in Example 34, Step 2, substituting 5-Piperazin-1-yl-1H-indazole with 4-Piperazin-1-yl-pyrimidin-5-ylamine dihydrochloride.
  • Step 3 (2R)-2-Amino-1-[4-(5-aminopyrimidin-4-yl)-piperazin-1-yl]3-(4-chlorophenyl)-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)-[2-[4-(5-aminopyrimidin-4-yl)-piperazin-1-yl]-1-(4-chlorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester.
  • Step 1 To a stirred solution of 4-(5-benzyloxypyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.540 g, 1.46 mmol) in MeOH (20 mL) under N 2 was cautiously added 10% Pd on carbon (40 mg). The reaction vessel was evacuated under vacuum and then put under an atmosphere of hydrogen using a balloon. The mixture was stirred for 2 hours at room temperature. At this time the hydrogen gas was evacuated and the catalyst was removed by filtration. The filtrate was concentrated.
  • Step 2 4-Piperazin-1-yl-pyrimidin-5-ol dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with 4-(5-Hydroxypyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester.
  • Step 3 (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(5-hydroxypyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester was prepared by the procedures described in Example 34, Step 2, substituting 5-Piperazin-1-yl-1H-indazole with 4-Piperazin-1-yl-pyrimidin-5-ol dihydrochloride.
  • Step 1 (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(5-isopropoxypyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester was prepared by the procedures described in Example 49, Step 2, substituting methyl iodide with isopropyl bromide.
  • Step 2 (2R)-2-Amino-3-(4-chlorophenyl)-1-[4-(5-isopropoxypyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(5-yl)-piperazin-1-isopropoxypyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester.
  • Step 1 A mixture of (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(5-iodopyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester (0.070 g, 0.12 mmol), methylboronic acid (0.022 g, 0.37 mmol), K 2 CO 3 (0.085 g, 0.61 mmol) and PdCl 2 (PPh 3 ) 2 (0.0086 g, 0.012 mmol) in DMF (2 mL) was heated at 100° C. for 16 hours under nitrogen. The mixture was cooled to room temperature and partitioned between EtOAc and water.
  • Step 2 (2R)-2-Amino-3-(4-chlorophenyl)-1-[4-(5-methylpyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(5-methylpyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester.
  • Step 1 To a suspension of NaH (60% in mineral oil, 0.099 g, 2.46 mmol) in DMF (5 mL) was added cinnolin-4-ol (prepared from 2-aminoacetophenone according to the procedures described in U.S. Pat. No. 4,620,000), 0.300 g, 2.05 mmol) in DMF (2 mL) dropwise. The reaction mixture was warmed at 40° C. and stirred for 30 minutes. After cooling, N-phenyltrifluoromethanesulfonimide (0.880 g, 2.46 mmol) in DMF (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour.
  • cinnolin-4-ol prepared from 2-aminoacetophenone according to the procedures described in U.S. Pat. No. 4,620,000
  • Step 2 4-Piperazin-1-yl-cinnoline dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with 4-Cinnolin-4-yl-piperazine-1-carboxylic acid tert-butyl ester.
  • Step 3 (2R)-[1-(4-chlorobenzyl)-2-(4-cinnolin-4-yl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester was prepared by the procedures described in Example 34, Step 2, substituting 5-Piperazin-1-yl-1H-indazole with 4-Piperazin-1-yl-cinnoline dihydrochloride.
  • Step 4 (2R)-2-Amino-3-(4-chlorophenyl)-1-(4-cinnolin-4-yl-piperazin-1-yl)-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)-[1-(4-chlorobenzyl)-2-(4-cinnolin-4-yl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester.
  • Step 1 (2R)-[1-Benzyl-2-(4-cinnolin-4-yl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester was prepared by the procedures described in Example 34, Step 2, substituting 5-Piperazin-1-yl-1H-indazole with 4-Piperazin-1-yl-cinnoline dihydrochloride, and substituting (D)-Boc-4-chlorophenylalanine with (D)-Boc-phenylalanine.
  • Step 2 (2R)-2-Amino-1-(4-cinnolin-4-yl-piperazin-1-yl)-3-phenylpropan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)-[1-Benzyl-2-(4-cinnolin-4-yl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester.
  • Step 1 (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(2-methylquinazolin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester was prepared by the procedures described in Example 40, Step 1, substituting 4-chloro-5-iodopyrimidine with 4-chloro-2-methylquinazoline, and substituting 1-Boc piperazine with [1-(4-chlorobenzyl)-2-oxo-2-piperazin-1-yl-ethyl]-carbamic acid tert-butyl ester.
  • Step 2 (2R)-2-Amino-3-(4-chlorophenyl)-1-[4-(2-methylquinazolin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(2-methylquinazolin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester.
  • Step 1 (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(2-chloroquinazolin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester was prepared by the procedures described in Example 40, Step 1, substituting 4-chloro-5-iodopyrimidine with 2,4-dichloroquinazoline, and substituting 1-Boc piperazine with [1-(4-chlorobenzyl)-2-oxo-2-piperazin-1-yl-ethyl]-carbamic acid tert-butyl ester.
  • Step 2 (2R)-2-Amino-3-(4-chlorophenyl)-1-[4-(2-chloroquinazolin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)- ⁇ 1-(4-chlorobenzyl)-2-[4-(2-chloroquinazolin-4-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester.
  • Step 1 To a solution of 4-chloroquinoline (2.0 g, 12.2 mmol) in toluene (100 mL) was added piperazine (7.98 g, 92.7 mmol). The reaction mixture was heated to reflux and stirred for 96 hours, after which it was cooled to room temperature and then further cooled to 0° C. The resulting mixture was filtered to remove the hydrochloride salts that had precipitated. After washing the salts with toluene, the combined filtrate was washed with 10% aqueous acetic acid (2 ⁇ 25 mL). The combined aqueous extracts were washed with diethyl ether (25 mL) and then basified to pH 8-10 by adding 1M NaOH.
  • Step 2 To a Jones tube containing PS-CDI (Argonaut, 1.04 mmol/g, 2.2 equivalents) suspended in a solution of 4-Piperazinylquinoline (1.0 equivalent) in CHCl 3 was added the solid Boc-protected amino acid (1.5 equivalents.). The reaction mixture was shaken for 15 hours at room temperature, after which it was vacuum filtered, the resin rinsed with CHCl 3 , and the filtrate concentrated by rotary evaporation. If necessary, the crude coupled product was purified on silica (DCM/EtOAc or DCM/MeOH). The resulting Boc-amino amide was dissolved in minimal dioxane, and 4M HCl/dioxane (10 equivalents) was added.
  • Step 1 Triethylamine (12.7 mL, 91.1 mmol) was added to a solution of 4-chloro-quinazoline (5.00 g, 30.4 mmol) and ethyl isonipecotate (4.78 g, 30.4 mmol) in THF (80 mL) at ambient temperature. After being refluxed for 12 hours, the mixture was concentrated in vacuo, and the resulting residue was partitioned between DCM and aqueous 0.1 M NaOH. The separated DCM layer was dried (Na 2 SO 4 ), filtered, and concentrated in vacuo.
  • Step 2 Thionyl chloride (1.37 mL, 18.8 mmol) was added to a suspension of 1-quinazolin-4-yl-piperidine-4-carboxylic acid (2.20 g, 8.55 mmol) in DCM (40 mL), which results in a clear solution. After being stirred for 2 hours, a precipitate forms and was filtered off to give 1-quinazolin-4-yl-piperidine-4-carbonyl chloride hydrochloride as a white solid (2.0 g).
  • Step 3 A solution of tert-butyl N-(2-aminoethyl)carbamate (1.00 g, 6.24 mmol) and 4-chlorobenzaldehyde (0.90 g, 6.37 mmol) in DCE (10 mL) was stirred for 30 minutes, followed by the addition of NaBH(OAc) 3 (1.98 g, 9.36 mmol) in a single portion. After being stirred for 12 hours, the mixture was acidified to pH 2 with 0.2 N HCl, and extracted with DCM (3 times, each discarded). The acidic aqueous layer was basified to pH 10 with 2.0 M NaOH, and extracted with DCM.
  • Step 4 1-Quinazolin-4-yl-piperidine-4-carbonyl chloride hydrochloride (197 mg, 0.63 mmol) was added to a solution of [2-(4-chlorobenzylamino)-ethyl]-carbamic acid tert-butyl ester (180 mg, 0.63 mmol) and DMAP (154 mg, 1.26 mmol) in DCM (6.5 mL) cooled in an ice bath. After being stirred for 12 hours, the mixture was partitioned between DCM (50 mL) and H 2 O (80 mL) containing 1 mL of 1.0 M HCl.
  • the DCM layer was drained off and the acidic aqueous layer was extracted 3 more times with DCM.
  • the combined DCM extracts were dried (Na 2 SO 4 ), filtered, and concentrated in vacuo.
  • the crude material was chromatographed (SiO 2 ) using EtOAc as eluent to give ⁇ 2-[(4-chlorobenzyl)-(1-quinazolin-4-yl-piperidine-4-carbonyl)-amino]-ethyl ⁇ -carbamic acid tert-butyl ester (190 mg).
  • Step 5 1 ⁇ 2-[(4-Chlorobenzyl)-(1-quinazolin-4-yl-piperidine-4-carbonyl)-amino]-ethyl ⁇ -carbamic acid tert-butyl ester (190 mg, 0.36 mmol) was dissolved in DCM (5 mL) followed by the addition of 2.0 M HCl in Et 2 O (2 mL). After being stirred for 12 hours, the mixture was diluted with DCE and concentrated in vacuo.
  • Step 1 A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (2.50 g, 16.4 mmol) and N-benzyl piperazine (3.18 g, 18.0 mmol) were melted at 175° C. for 3 hours in a sealed tube, resulting in the formation of a crystalline solid mass. A solution of 0.1 M aqueous NaOH (10 mL) was added and the solid was broken up to give a suspension. Filtration gave 4-(4-benzyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine as a white solid (3.90 g). LCMS (APCI+) m/z 293 [M+H] + .
  • Step 2 A solution of4-(4-benzyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (3.90 g, 13.3 mmol) and Pd(OH) 2 /C (937 mg, 1.33 mmol) in MeOH (60 mL) was stirred under 1 atmosphere of H 2 for 2 d. The mixture was diluted with MeOH, filtered through diatomaceous earth, and the filtrate was concentrated in vacuo to give 4-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine as a solid (100 mg kept as free base). The remaining material was suspended in MeOH and treated with 2.0 M HCl in Et 2 O.
  • Step 3 PyBrop (407 mg, 0.87 mmol) was added in a single portion to a solution of (R)-N-Boc-4-chlorophenylalanine (458 mg, 1.53 mmol) and 4-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.73 mmol) in DCM (5 mL) cooled in an ice bath. DIEA (0.66 mL, 3.78 mmol) was then dropped in, the ice bath was removed, and the mixture was stirred for 12 hours at ambient temperature. The mixture was diluted with DCM and washed with 0.1 N HCl. The separated DCM layer was dried (Na 2 SO 4 ), filtered, and concentrated in vacuo.
  • Step 1 n-BuLi (1.60M in hexanes, 40.7 mL, 65.1 mmol) was added to a 0° C. solution of diisopropylamine (9.4 mL, 67.0) in 280 mL THF. The mixture was allowed to stir at 0° C. for 30 minutes, then cooled to ⁇ 78° C. A solution of p-tolyl-acetic acid methyl ester (10.48 g, 63.8 mmol; prepared from p-tolyl-acetic acid) in 10 mL of THF was added to the ⁇ 78° C. LDA solution by syringe, which was then stirred for 45 minutes.
  • Neat tert-butyl bromoacetate (28 mL) was added by syringe, and the reaction was stirred 15 minutes at ⁇ 78° C. The bath was removed, and the reaction was allowed to warm to room temperature. After stirring an additional 5 hours, the reaction mixture was quenched with saturated NH 4 Cl solution, and the organics were removed in vacuo. The oily mixture was extracted with ethyl acetate, and the organics were combined. The organic was dried over MgSO 4 , filtered, and concentrated in vacuo.
  • Step 2 A solution of 2-p-tolyl-succinic acid 4-tert-butyl ester 1-methyl ester (15.3 g, 54.8 mmol) in 110 mL of DCM was treated with neat TFA (63 mL) at room temperature. The mixture was stirred for five hours to completion, after which the reaction mixture was concentrated and dried in vacuo overnight to afford a white solid. The solid was suspended in 190 mL of toluene, cooled to 0° C., and treated successively with diphenylphosphoryl azide (13.4 mL, 62.1 mmol) and triethyl amine (19.7 mL, 141 mmol).
  • the reaction mixture (homogeneous) was allowed to warm to room temperature and stirred for four hours to completion.
  • the solution was quenched with 1% citric acid solution and extracted with EtOAc.
  • the combined organic was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give a light brown oil.
  • the crude azide was dissolved in 190 mL of tert-butanol, treated with neat SnCl 4 (0.25 mL, 2.82 mmol), and carefully heated to 90° C. with evolution of nitrogen.
  • the mixture was stirred at 90° C. for 2.5 hours and cooled to room temperature.
  • the solution was quenched with saturated NaHCO 3 solution and then concentrated.
  • Step 3 The 3-tert-butoxycarbonylamino-2-p-tolyl-propionic acid methyl ester (12.3 g, 41.9 mmol) was dissolved in 200 mL 1:1 THF:water and treated with lithium hydroxide monohydrate (2.64 g, 62.9 mmol) at room temperature. The reaction was stirred at room temperature overnight to completion and concentrated in vacuo. The oily mixture was partitioned with water and washed with EtOAc (discarded). The aqueous was treated with solid KHSO 4 until pH ⁇ 2, then extracted with EtOAc.
  • Step 4 The 4-piperazin-1-yl-quinazoline dihydrochloride (50 mg, 0.174 mmol, free-based with 2N NaOH and extracted with DCM), HOBt monohydrate (27 mg, 0.174 mmol), and 3-tert-butoxycarbonylamino-2-p-tolyl-propionic acid (58 mg, 0.209 mmol) were dissolved in 1.3 mL of DCM/3-5 drops of THF. The reaction mixture was treated with DCC (43 mg, 0.209 mmol) and allowed to stir at room temperature for 2.5 hours to completion. The mixture was diluted with DCM, vacuum filtered through compressed Celite, and rinsed with DCM.
  • Step 1 The (4-chlorophenyl)-acetic acid (20.0 g, 106 mmol) was dissolved in 220 mL of ethanol at ambient temperature. A catalytic amount of sulfuric acid (10 drops) was added to afford a light yellow solution. The reaction was allowed to stir overnight to completion and was concentrated to 30 mL. The concentrate was partitioned between ethyl acetate and half-saturated NaHCO 3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined.
  • Step 2 The (4-chlorophenyl)-acetic acid ethyl ester (9.52 g, 47.9 mmol) was dissolved in 80 mL of THF, cooled to 0° C., and treated with potassium tert-butoxide (538 mg, 4.79 mmol). The resulting orange solution was allowed to stir for 15 minutes at 0° C., then cooled to ⁇ 78° C. The tert-butyl acrylate (7.72 mL, 52.7 mmol) was added in three equal portions over ten minutes. The solution was allowed to stir overnight warming slowly to room temperature. The reaction solution was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated NH 4 Cl solution.
  • Step 3 The 2-(4-chlorophenyl)-pentanedioic acid 5-tert-butyl ester 1-ethyl ester (9.00 g, 27.5 mmol) was dissolved in 40 mL of DCM at room temperature and treated slowly with 40 mL of TFA. The solution was allowed to stir for three hours to completion, then concentrated in vacuo. The residue was stored under vacuum overnight then dissolved in 80 mL of toluene. The solution was degassed under nitrogen, cooled to 0° C., treated with triethyl amine (8.44 mL, 60.6 mmol), and treated with diphenylphosphoryl azide (6.53 mL, 30.3 mmol), respectively.
  • the reaction was allowed to warm to room temperature and stir for three hours, then concentrated in vacuo.
  • the residue was re-dissolved in ethyl acetate and washed with 1 w/w % citric acid solution.
  • the organic was dried over MgSO 4 , filtered, and concentrated ( ⁇ 30° C.) to afford the intermediate azide as a yellow oil.
  • the material was immediately dissolved in 80 mL of tert-butanol and treated with SnCl 4 (1.65 mL of a 1.0M sol'n in DCM, 1.65 mmol).
  • the solution was heated to 80 C for one hour to give evolution of nitrogen gas.
  • the reaction mixture was treated with saturated NaHCO 3 (20 mL), and concentrated in vacuo to give a gel.
  • Step 5 The 4-piperazin-1-yl-quinazoline (60 mg, 0.21 mmol) and 4-tert-butoxycarbonylamino-2-(4-chlorophenyl)-butyric acid (62 mg. 0.21 mmol) were dissolved in 1.5 mL of DCM and cooled to 0° C. The solution was treated with PyBrop (98 mg, 0.21 mmol) and DIEA (74 ⁇ L, 0.42 mmol), respectively. The mixture was allowed to warm to room temperature overnight, and the contents were partitioned between ethyl acetate and saturated NH4Cl solution. The aqueous was extracted with ethyl acetate, and the organics were combined.
  • Step 1 To a solution of 4-chloroquinazoline (2.0 g, 12.2 mmol) in 45 mL IPA was added Boc-4-aminopiperidine (2.56 g, 12.8 mmol) and DIEA (3.2 mL, 18.2 mmol). The reaction mixture was heated to reflux and stirred 16 hours, after which the reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc and washed with water, 1N NaOH, brine, dried (Na 2 SO 4 ), filtered, and concentrated to provide 4-(4-Boc-aminopiperidin-1-yl)quinazoline, which was used directly in the next step.
  • Step 2 To a solution of crude 4-(4-Boc-aminopiperidin-1-yl)quinazoline in 40 mL 1:1 dioxane:DCM was added 20 mL 4M HCl/dioxane. The resulting suspension was stirred at room ternperature for 14 hours, after which it was concentrated to dryness. The residue was stirred in DCM and 1M NaOH, the phases were separated, and the aqueous phase was extracted with DCM. The combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated.
  • Step 3 3-Amino-4-phenyl-N-(1-quinazolin-4-yl-piperidin-4-yl)-butyramide dihydrochloride (10 mg, 33%) was prepared from 4-(4-aminopiperidin-1-yl)quinazoline according to the procedure employed for Example 1A, Step 2, using Boc- ⁇ -homophenylalanine.
  • LCMS (APCI+) m/z 390 [M+H] + . HPLC Rt 1.94 min.
  • Step 1 A solution containing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 32.6 mmol), Boc-piperazine (15 g, 81 mmol), and DIEA (19.8 mL, 114 mmol) in 130 mL IPA was stirred at 80 C for 18 hours, after which the reaction was concentrated.
  • the crude was flashed on silica gel (20:1 DCM:MeOH) to give a yellow powder, which was recrystallized from MeOH/minimal DCM to give 4-Boc-piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine as a white crystalline solid (3 crops).
  • Step 2 To a solution of 4-Boc-piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine in 225 mL DCM was added dropwise by addition finnel 120 mL 4M HCl/dioxane, and the resulting suspension was stirred at room temperature 18 hours. The reaction mixture was then diluted with ether, and the solids were isolated by filtration through a fritted funnel with nitrogen pressure, rinsed with ether, and dried in vacuo to give 4-piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (8.44 g, 94%) as a white powder.
  • Step 3 To a solution of 4-piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (30 mg, 0.11 mmol), HOBt.H2O (17 mg, 0.11 mmol), TEA (45 ⁇ L, 0.33 mmol), and (D)-Boc-4-chlorophenylalanine (39 mg, 0.13 mmol) in 1.6 mL DMF was added DCC (27 mg, 0.13 mmol.) The reaction mixture was stirred at room temperature for 4 hours, after which it was concentrated. The residue was suspended in DCM, and the solids were removed by vacuum filtration through cotton plug and rinsed with DCM.
  • Step 4 To a solution of (2R)-2-Boc-amino-3-(4-chlorophenyl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one in 1 mL dioxane was added 1 mL 4M HCl/dioxane. The resulting suspension was stirred at room temperature overnight, after which it was concentrated to dryness. The solids were dissolved in minimal MeOH and then triturated with ether.
  • Step 1 nBuLi (1.6M in hexanes, 20 mL, 32 mmol) was added to a stirred solution of (4R,5S)-4-Methyl-5-phenyl-oxazolidin-2-one (5.2 g, 29 mmol) in THF (60 mL) at ⁇ 78 C under N2. The solution was stirred at ⁇ 78° C. for 10 mL and then 3-(4-Chlorophenyl)-propionyl chloride (6.0 g, 29 mmol) was added and the solution allowed to warm to room temperature over 1 hour.
  • Step 2 NaHMDS (1.0M, 17 mL, 17 mmol) was added to a stirred solution of (4R,5S)-3-[3-(4-Chlorophenyl)-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one (4.8 g, 14 mmol) in THF (200 mL) at ⁇ 78° C. under N 2 . Stirred at ⁇ 78° C. for 45 minutes and then Bromo-acetic acid tert-butyl ester (2.5 mL, 17 mmol) was added dropwise over 10 minutes. The solution was allowed to warm to ⁇ 20° C. over 4 hours and then quenched with saturated aqueous NH 4 Cl.
  • Step 3 A solution of (3S)-3-(4-Chlorobenzyl)-4-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-4-oxo-butyric acid tert-butyl ester (5.1 g, 11 mmol) in DCM (100 mL) was treated with TFA (50 mL) and stirred at room temperature for 1 hour. The solution was concentrated in vacuo, taken up into toluene and then conc. in vacuo.
  • Step 4 NEt3 (700 uL, 5.0 mmol) was added to a stirred solution of (3S)-3-(4-Chlorobenzyl)-4-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-4-oxo-butyric acid (1.0 g, 2.5 mmol) in PhMe (50 mL) at 0° C. under N 2 . This was followed by the addition of the diphenylphosphoryl azide (650 ⁇ L, 3.0 mmol.) The solution was stirred at 0° C. for 15 minutes and then stirred at room temperature overnight.
  • Step 5 To a solution of [(2S)-2-(4-Chlorobenzyl)-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-3-oxo-propyl]-carbamic acid tert-butyl ester (300 mg, 0.63 mmol) in THF/H2O (30/10 mL) at 0° C. was added LiOH (80 mg, 1.9 mmol) and H2O2 (30% by volume, 3.0 mL, 0.63 mmol) and stirred at 0° C. for 30 minutes. Then Na 2 SO 3 (saturated solution, 10 mL) was added slowly & cautiously.
  • Step 6 NEt 3 (150 ⁇ L, 1.1 mmol) was added to a stirred suspension of 4-Piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (100 mg, 0.36 mmol), (S)-2-(tert-Butoxycarbonylamino-methyl)-3-(4-chlorophenyl)-propionic acid (130 mg, 0.40 mmol), EDCI (83 mg, 0.44 mmol) and HOBt (59 mg, 0.44 mmol) in DMF (15 mL) at RT. Stirred at RT overnight.
  • Step 1 The 4-hydroxypyrazolopyrimidine (2.5 g, 18 mmol) was dissolved in POCl3 (34 mL, 0.37 mol) and N,N-dimethyl aniline (4.7 mL, 37 mmol.) This mixture was heated to reflux (120° C.) for 1.5 hours to afford a dark red solution. The mixture was concentrated to a viscous oil and cooled to 0° C. in an ice bath. The oil was poured into a mixture of ice-water and was stirred for 5 minutes. The acidic melt was extracted with ether (4 ⁇ 100 mL), and the organics were combined.
  • Step 2 To a suspension of 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (1.1 g, 7.1 mmol) in CHCl 3 (50 mL) was added NBS (1.49 g, 8.4 mmol.) The mixture was stirred at room temperature for 5 hours, cooled to 0 C and the solids were isolated by vacuum filtration, rinsed with cold CHCl 3 , and air dried. The solid was purified by column chromatography on silica (50% EtOAc/hexanes) to give 3-Bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.3, 77%.)
  • Step 3 To a solution of 3-Bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.3 g, 5.5 mmol) in DMF (42 mL) at 0° C. was added NaH (180 mg, 7.7 mmol) in portions. The reaction mixture was stirred at 0° C. for 5 minutes, then stirred at room temperature for 1.5 hours, after which it was cooled back to 0° C. Neat PhSO 2 Cl (0.7 mL, 5.6 mmol) was added and the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH 4 Cl and diluted further with H 2 O.
  • Step 4 A solution of 1-Benzenesulfonyl-3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.8 g, 4.8 mmol), Boc-piperazine (1.4 g, 7.2 mmol) and DIPEA (2.1 mL, 12 mmol) in IPA (40 mL) was stirred and heated at reflux overnight.
  • Step 5 Anhydrous HCl (4N in dioxane, 10 mL) was added to a stirred solution of 1-Benzenesulfonyl-3-bromo-4-piperazin-1-yl-1H-pyrazolo[3,4-d]pyrimidine (210 mg, 0.40 mmol) in MeOH (20 mL) and stirred at room temperature overnight. The suspension was concentrated in vacuo to give 1-Benzenesulfonyl-3-bromo-4-piperazin-1-yl-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride (200 mg, 100%.) LCMS (APCI+) m/z 423 and 425 [M+H] + ; Rt: 1.98 min.
  • Step 6 DIPEA (84 ul, 0.48 mmol) was added to a suspension of 1-Benzenesulfonyl-3-bromo-4-piperazin-1-yl-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride (40 mg, 0.081 mmol) and (D)-2-tert-Butoxycarbonylamino-3-(4-chlorophenyl)-propionic acid (27 mg, 0.089 mmol) in DCM (10 mnL) at room temperature. Then, HBTU (34 mg, 0.089 mmol) was added and the reaction stirred at room temperature overnight.
  • DIPEA 84 ul, 0.48 mmol
  • Step 1 To a suspension of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 16 mmol) in CDCl 3 (65 mL) was added NBS (2.9 g, 16 mmol) and the reaction mixture stirred and heated at reflux for 2.5 hours. The mixture was cooled to room temperature, the solids isolated by vacuum filtration, rinsed with cold CHCl3 and air dried to give 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 79%.) LCMS (APCI+) m/z 232 and 234 [M+H] + ; Rt: 2.32 min. 1 H NMR (DMSO-d6, 400 MHz) ⁇ 12.98 (1H, br. s), 8.63 (1H, s), 7.96 (1H, s.)
  • Step 2 To a solution of 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 13 mmol) in DMF (40 mL) at 0° C. was added NaH (60% w/w in mineral oil, 720 mg, 18.1 mmol) and the mixture stirred at 0° C. under N 2 for 30 minutes. Then PhSO2Cl (1.7 g, 13 mmol) was added and the reaction stirred at room temperature for 2 hours, after which H2O (200 nmL) was added, causing precipitation.
  • Step 3 A suspension of 7-Benzenesulfonyl-5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.9 g, 13 mmol), Piperazine-1-carboxylic acid tert-butyl ester (3.7 g, 20 mmol), and DIPEA (5.7 mL, 33 mrnol) in IPA (30 mL) was stirred and heated at reflux for 6 hours.
  • Step 4 MeZnCl (2.0M in THF, 720 uL, 1.4 mmol) was added to a stirred solution 4-(7-Benzenesulfonyl-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.48 mmol) and tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.12 mmol) in THF (10 mL) at room temperature under N 2 .
  • Step 5 A solution of 4-(7-Benzenesulfonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (4.0 g, 13 mmol) in DCM (100 mL) was treated with anhydrous HCl (4M in dioxane, 100 mL) and stirred at room temperature overnight.
  • Step 6 DIPEA (120 ⁇ L, 0.70 mmol) was added to a suspension of 7-Benzenesulfonyl-5-methyl-4-piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (50 mg, 0.12 mmol) and (S)-2-(tert-Butoxycarbonylamino-methyl)-3-(4-chlorophenyl)-propionic acid (40 mg, 0.13 mmol) in DCM (10 mL) at room temperature. Then, HBTU (48 mg, 0.13 mnmol) was added and the reaction stirred at room temperature overnight.
  • DIPEA 120 ⁇ L, 0.70 mmol
  • Step 1 To a solution of4-(7-Benzenesulfonyl-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.29 mmol) in 4 mL DME (degassed with nitrogen prior to use) was added 0.94M aqueous Na 2 CO 3 (0.61 mL, 0.57 mmol) and Pd(PPh 3 ) 4 (66 mg, 0.057 mmol). The reaction mixture was stirred 5 minutes, then 2-thiophene boronic acid (55 mg, 0.43 mmol) was added.
  • Step 2 To a solution of 4-(7-Benzenesulfonyl-5-thiophen-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (120 mg, 0.23 mmol) in 2 mL dioxane was added 1.5 mL 4M HCl/dioxane.
  • Step 3 To a solution of 7-Benzenesulfonyl-4-piperazin-1-yl-5-thiophen-2-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (50 mg, 0.10 mmol), DIEA (0.10 mL, 0.60 mmol), and (2S)-2-(Boc-aminomethyl)-3-(4-chlorophenyl)-propionic acid (38 mg, 0.12 mmol) in 2 mL DCM was added HBTU (44 mg, 0.12 mmol). The reaction mixture was stirred at room temperature 2 hours, after which 2 mL MeOH and 0.5 mL 3M LiOH were added. The reaction mixture was heated to 35° C.
  • Step 4 To a solution of (2S)-2-Boc-aminomethyl-3-(4-chlorophenyl)-1-[4-(5-thiophen-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pip-erazin-1-yl]-propan-1-one in 1.5 mL dioxane was added 1.5 mL 4M HCl/dioxane. The resulting suspension was stirred at room temperature 16 hours, after which it was concentrated to dryness. The solids were dissolved in minimal MeOH, and the product was triturated by the addition of ether.
  • Step 1 A mixture containing 4-Chloro-2-methyl-benzoic acid (4 g, 23 mmol) and LiAlH4 (890 mg, 23.5 mmol) in 250 mL of THF under a nitrogen atmosphere was allowed to stir at room temperature for 2 hours. The reaction was quenched with sodium sulfate decahydrate. The mixture was filtered through a pad of Celite and the filter cake washed with THF. The filtrate was concentrated under reduced pressure. Purification of the residue via biotage eluting with 30% ethyl acetate/hexanes gave (4-Chloro-2-methyl-phenyl)-methanol (3.70 g, 100%) as a colorless oil.
  • 1 H NMR (CDCl3, 400 MHz) ⁇ 7.30-7.25 (1H, m), 7.18-7.14 (2H, m), 4.66 (2H, d, J 5.8 Hz), 2.32 (3H, s.)
  • Step 2 A solution containing gave (4-Chloro-2-methyl-phenyl)-methanol (2 g, 13 mmol) and PBr3 (1.3 mL, 14 mmol) in 150 mL of diethyl ether was allowed to stir at room temperature overnight. The reaction was diluted with ether and washed with water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 20% ethyl acetate/hexanes gave 1-Bromomethyl-4-chloro-2-methyl-benzene (1.89 g, 67%) as a colorless oil.
  • 1 H NMR (CDCl3, 400 MHz) ⁇ 7.26-7.11 (3H, m), 4.67 (2H, s), 2.39 (3H, s.)
  • Step 3 To a solution containing (Benzhydrylidene-amino)-acetic acid ethyl ester (2.3 g, 8.6 mmol) in 50 mL of DMSO under a nitrogen atmosphere was added potassium t-butoxide (1.2 g, 11 mmol) After stirring for 20 minutes, 1-Bromomethyl-4-chloro-2-methyl-benzene (1.89 g, 8.6 mmol) was added and the reaction allowed to stir at room temperature overnight. The reaction was diluted with ethyl acetate and washed with brine. The organic phase was dried over magnesium sulfate.
  • potassium t-butoxide 1.2 g, 11 mmol
  • Step 4 A mixture containing 2-(Benzhydrylidene-amino)-3-(4-chloro-2-methyl-phenyl)-propionic acid ethyl ester (1.7 g, 4.2 mmol) and 90 mL of 3N HCl was heated at 75 C overnight. The reaction was cooled to room temperature and washed with ethyl acetate. The aqueous phase was concentrated under reduced pressure to afford 2-Amino-3-(4-chloro-2-methyl-phenyl)-propionic acid (640 mg, 72%) as white solid.
  • Step 5 To a solution containing 2-Amino-3-(4-chloro-2-methyl-phenyl)-propionic acid (640 mg, 3.0 mmol), 25 mL of dioxane and 9 mL of 1N sodium hydroxide was added boc anhydride (0.73 g, 3.3 mmol.) The reaction was allowed to stir at room temperature for 3 hours. The reaction was diluted with water and washed with DCM. The aqueous phase was acidified with 1N HCl and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate.
  • Step 6 To a solution containing 2-tert-Butoxycarbonylamino-3-(4-chloro-2-methyl-phenyl)-propionic acid (200 mg, 0.64 mmol) in 30 mL of DMF was added HOBT (0.12 g, 0.76 mmol), EDCI (0.15 g, 0.76 mmol) and NMM (0.19 g, 1.9 mmol) under a nitrogen atmosphere. After stirring for 10 minutes, 4-Piperazin-1-yl-quinazoline (200 mg, 0.93 mmol) was added and stirring continued overnight. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate.
  • Step 7 To a solution containing [1-(4-Chloro-2-methylbenzyl)-2-oxo-2-(4-quinazolin-4-yl-piperazin-1-yl)-ethyl]-carbamic acid tert-butyl ester (0.30 g, 0.59 mmol) in 30 mL of DCM under a nitrogen atmosphere was added TFA (1.4 mL.) After stirring at room temperature overnight, the reaction was concentrated under reduced pressure. The residue was dissolved in DCM and 2N HCl in ether added.
  • Step 1 A solution of 4-chloro-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one (prepared according to the literature: Li Sun et al. Bioorg. and Med. Chem. Lett. 2002, 12, 2153-2157; 690 mg, 3.7 mmol), Boc-piperazine (630 mg, 3.7 mmol), and DIEA (0.96 mL, 5.5 mmol) in 20 mL IPA was heated to reflux and stirred 14 hours, after which the reaction mixture was concentrated.
  • 4-chloro-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one prepared according to the literature: Li Sun et al. Bioorg. and Med. Chem. Lett. 2002, 12, 2153-2157; 690 mg, 3.7 mmol
  • Boc-piperazine 630 mg, 3.7 mmol
  • DIEA 0.96 mL, 5.5 mmol
  • Step 2 To a solution of 4-Boc-piperazin-1-yl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one in 25 mL dioxane, was added 15 mL 4M HCl/dioxane. The resulting suspension was stirred at room temperature 15 hours, after which it was diluted with ether. The solids were isolated by filtration through a fritted funnel with nitrogen pressure, rinsed with ether, and dried in vacuo to furnish 4-piperazin-1-yl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one dihydrochloride (350 mg, 100%) as a red powder.
  • Step 3 To a solution of give 4-piperazin-1-yl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one dihydrochloride (40 mg, 0.14 mmol), HOBt.H 2 O (21 mg, 0.14 mmol), TEA (57 ⁇ L, 0.41 mmol), and 3-Boc-amino-2-(4-chlorophenyl)-propionic acid (prepared from 4-chlorophenylacetic acid methyl ester using the procedures described for the preparation of A109; 49 mg, 0.16 mmol) in 1.2 mL 5:1 DCM:THF was added DCC (34 mg, 0.16 mmol).
  • Step 4 To a solution of 4- ⁇ 4-[3-Boc-amino-2-(4-chlorophenyl)-propionyl]-piperazin-1-yl ⁇ -1,3-dihydropyrrolo[2,3-b]pyrimidin-2-one in 1.2 mL dioxane was added 1.2 mL 4M HCl/dioxane. The resulting suspension was stirred at room temperature 15 hours, after which it was concentrated to dryness. The solids were dissolved in minimal MeOH, and the product was triturated by the addition of ether.
  • Step 1 A solution of 4-chloromandelic acid (12.3 g, 65.9 mmol) in toluene (50 mL), EtOH (16 mL), and concentrated H 2 SO 4 (0.1 mL) was refluxed for 12 hours while removing water using a Dean-Stark trap. The mixture was concentrated in vacuo, diluted with DCM, and washed with dilute aqueous NaHCO 3 . The separated DCM layer was dried (MgSO 4 ), filtered, and concentrated in vacuo to give (4-chlorophenyl)-hydroxy-acetic acid ethyl ester as a colorless oil (10.0 g) that crystallized upon standing.
  • Step 2 (4-Chlorophenyl)-hydroxy-acetic acid ethyl ester (10.0 g, 46.6 mmol) in DCM (35 mL) was cannulated into a solution of [bis(2-methoxyethyl)amino]sulfur trifluoride (9.45 mL, 51.3 mmol) in DCM (35 mL) cooled at ⁇ 78° C. After being stirred for 12 hours and allowed to warm to ambient temperature, the mixture was poured into saturated aqueous NaHCO 3 . The mixture was extracted with DCM and the organic extracts were dried (MgSO 4 ), filtered, and concentrated in vacuo. The crude material was chromatographed (SiO 2 ) using DCM as eluent to give (4-chlorophenyl)-fluoroacetic acid ethyl ester as a colorless oil (7.0 g).
  • Step 3 Potassium tert-butoxide (155 mg, 1.38 mmol) was added to a solution of (4-chlorophenyl)-fluoroacetic acid ethyl ester (3.00 g, 13.8 mmol) in THF (25 mL) at 0° C. to give an orange-red color. After 15 minutes, the mixture was cooled to ⁇ 78° C. and t-butyl acrylate (2.23 mL, 15.2 mmol) was added neat. After being stirred and allowed to warm to ambient temperature for 12 hours, the mixture was quenched with saturated NH 4 Cl, concentrated in vacuo, diluted with H 2 O, and extracted with DCM.
  • the DCM extracts were dried (MgSO 4 ), filtered, and concentrated in vacuo.
  • the crude material was chromatographed (SiO 2 ) using DCM as eluent to give a colorless oil (1.20 g).
  • a solution of the oil in DCM (6 mL) and TFA (4 mL) was stirred overnight.
  • the mixture was diluted with toluene (40 mL) and concentrated in vacuo.
  • the crude product was dissolved in dilute aqueous NaHCO 3 and extracted with DCM (twice, discarded).
  • the aqueous layer was acidified to pH 1.0 with 1.0 N HCl and extracted with DCM (twice).
  • Step 4 Triethylamine (0.53 mL, 3.81 mmol) was added to a solution of 2-(4-chlorophenyl)-2-fluoro-pentanedioic acid 1-ethyl ester (1.00 g, 3.46 mmol) in t-BuOH (20 mL) followed by the addition of diphenylphosphoryl azide (0.82 mL, 3.81 mmol). The mixture was heated at 95° C. for 3 hours, concentrated in vacuo, and partitioned between dilute aqueous NaHCO 3 and DCM. The separated DCM layer was dried (Na 2 SO 4 ), filtered, and concentrated in vacuo.
  • Step 5 Lithium hydroxide monohydrate (0.27 g, 6.45 mmol) in H 2 O (5 mL) was added to a solution of 4-tert-butoxycarbonylamino-2-(4-chlorophenyl)-2-fluoro-butyric acid ethyl ester (580 mg, 1.61 mmol) in THF (5 mL) and MeOH (5 mL). After being stirred for 12 hours, the mixture was concentrated in vacuo, diluted with H 2 O, and extracted with DCM (3 times, discarded). The aqueous phase was then acidified to pH 1 and extracted with DCM (2 times).
  • Step 6 PyBrop (562 mg, 1.21 mmol) was added in a single portion to a solution of 4-tert-butoxycarbonylamino-2-(4-chlorophenyl)-2-fluoro-butyric acid (400 mg, 1.21 mmol) and 4-piperazin-1-yl-quinazoline dihydrochloride (346 mg, 1.21 mmol) in DCM (12 mL) cooled in an ice bath. DIEA (0.84 mL, 4.82 mmol) was added and the mixture was allowed to warm to ambient temperature and stirred for 12 hours. The mixture was diluted with DCM and washed with 0.1 N HCl.
  • Step 7 A solution of [3-(4-chlorophenyl)-3-fluoro-4-oxo-4-(4-quinazolin-4-yl-piperazin-1-yl)-butyl]-carbamic acid tert-butyl ester (226 mg, 0.43 mmol) in DCM (2 mL) and 2.0 M HCl in Et 2 O (1 mL) was stirred for 12 hours. The mixture was concentrated in vacuo and chromatographed (SiO 2 ) using 10% MeOH/DCM followed by 10% (7 N NH 3 in MeOH)/DCM as eluent.
  • Step 1 To a stirred solution of diisopropyl amine (1.3 mL, 9.0 mmol) in THF (20 mL) was added n-BuLi (1.6 M solution in hexanes, 5.6 mL, 9.0 mmol) at 0° C. The reaction was stirred at 0° C. for 15 minutes and then cooled to ⁇ 78° C. A solution of 3-tert-butoxycarbonylamino-propionic acid tert-butyl ester (1.0 g, 4.1 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at ⁇ 78° C. for 2 hours.
  • n-BuLi 1.6 M solution in hexanes, 5.6 mL, 9.0 mmol
  • Step 2 2-(4-Bromo-2-fluoro-benzyl)-3-tert-butoxycarbonylamino-propionic acid tert-butyl ester (1.30 g, 3.01 mmol) was dissolved in TBF (12 mL) and MeOH (12 mL). A solution of LiOH monohydrate (0.50 g, 12.0 mmol) in H 2 O (12 mL) was added. The mixture was heated at reflux overnight. After cooling, the solvents were evaporated in vacuo. The residue was dissolved in water and extracted with ether (2 ⁇ ). The aqueous phase was acidified with 1N HCl and extracted with EtOAc.
  • Step 3 3-Amino-2-(4-bromo-2-fluoro-benzyl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride was prepared by substituting 5-piperazin-1-yl-1H-indazole with 4-Piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride and substituting (D)-Boc-4-chlorophenylalanine with 2-(4-Bromo-2-fluoro-benzyl)-3-tert-butoxycarbonylamino-propionic acid in Example 34, Step 2, then removing the Boc protecting group as described in Example 34, Step 3.
  • Step 1 A mixture of tert-butyl 1-piperazinecarboxylate (7.45 g, 40.0 mmol) and benzotriazole (4.76 g, 40.0 mmol) in H 2 O (200 mL) was stirred for 1 hour. Glyoxal (40 wt. % in water, 2.90 g, 20 mmol) was then added and the mixture was stirred for 12 hours to produce a white precipitate. The precipitate was filtered off and washed with H 2 O.
  • Step 2 A mixture of 2-aminopyridine (282 mg, 3.00 mmol) and 1,2-(benzotriazol-1-yl)-1,2-(4-piperazine-1-carboxylic acid tert-butyl ester)ethane (1.90 g, 3.00 mmol) in dichloroethane (30 mL) was refluxed for 3 hours. Powdered KOH (555 mg, 9.90. mmol) was then added, and the mixture was stirred for 12 hours. The mixture was filtered and the filtrate was concentrated in vacuo.
  • Step 3 A solution of 4-imidazo[1,2-a]pyridin-3-yl-piperazine-1-carboxylic acid tert-butyl ester (950 mg, 3.14 mmol) in DCM (10 mL) and 2.0 N HCl in Et 2 O (5 mL) was stirred for 12 hours. A precipitate formed and was filtered off to give 3 -piperazin-1-yl-imidazo[1,2-a]pyridine dihydrochloride as a red solid (800 mg).
  • Step 4 Triethylamine (0.30 mL, 2.18 mmol) was added to a solution of (R)-N-Boc-4-chlorophenylalanine (392 mg, 1.31 mmol), 3-piperazin-1-yl-imidazo[1,2-a]pyridine dihydrochloride (300 mg, 1.09 mmol), and 1-hydroxybenzotriazole (177 mg, 1.31 mmol) in DMF (5 mL) followed by the addition of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (251 mg, 1.31 mmol) in a single portion.
  • Step 5 A solution of (R)-[1-(4-chlorobenzyl)-2-(4-imidazo[1,2-a]pyridin-3-yl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (350 mg, 0.72 mmol) in DCM (3 mL) and 2.0 N HCl in Et 2 O (2 mL) was stirred for 12 hours. The mixture was concentrated in vacuo and the resulting material was chromatographed (SiO 2 ) using 10% MeOH/DCM followed by 10% (7 N NH 3 in MeOH)/DCM as eluent.
  • Step 1 The 2-(4-chlorophenyl)-2-methyl-propionic acid (6.10 g, 30.7 mmol) was dissolved in 120 mL of dry THF at room temperature. A 70% w/w solution of Red-Al (28.25 mL, 0.101 mol) was added dropwise via syringe over 5 minutes (vigrous bubbling). The mixture was heated to reflux for three hours. The solution was cooled to 0 C and carefully quenched with the addition of saturated sodium tartrate solution (100 mL, violent hydrogen evolution) and 100 nL of water.
  • Red-Al 28.25 mL, 0.101 mol
  • Step 2 The DMSO (436 mL, 61.4 mmol) was dissolved in 100 mL of DCM and treated with oxalyl chloride (4.02 ⁇ L, 46.6 mmol) at ⁇ 78° C. The solution stirred for 30 minutes at ⁇ 78° C. before the 2-(4-chlorophenyl)-2-methyl-propan-1-ol (5.67 g, 30.7 mmol) was added dropwise as a solution in 10 mL of DCM. After addition was complete, the solution was stirred for two hours at ⁇ 78° C., and then treated with triethyl amine (25.7 mL, 184 mmol). The solution was allowed to warm to ambient temperature and stir for three hours.
  • Step 3 The 2-(4-chlorophenyl)-2-methylpropionaldehyde (5.60 g, 30.7 mmol) and (S)-4-methyl-benzenesulfinic acid amide (5.00 g, 32.2 mmol) were dissolved in 300 mL of DCM and treated with Ti(OEt) 4 (32.1 mL, 153 mmol). The mixture was heated to reflux under nitrogen for four hours. The solution was cooled in an ice bath and quenched with the dropwise-addition of 200 mL of water. The resulting precipitate (Ti salts) were removed by filtration through a plug of celite and washed with DCM. The resulting filtrate was separated, and the aqueous was extracted with more DCM.
  • Step 4 The diethyl aluminum cyanide (43.5 mL of a 1.0M solution in toluene, 43.5 mmol) was added to isopropanol (28.9 mL, 377 mmol) and stirred at 10° C. for 15 minutes. This solution was cannulated into the (R)-4-methylbenzenesulfinic acid[2-(4-chlorophenyl)-2-methyl-propylidene]-amide (9.28 g, 29.0 mmol) as a solution in 290 mL of THF at ⁇ 78° C. This solution was allowed to stir for 15 minutes at ⁇ 78° C. then allowed to warm slowly to room temperature overnight.
  • Step 6 The 4-piperazin-1-yl-quinazoline bis-hydrochloride (220 mg, 0.766 mmol), (S)-2-tert-butoxycarbonylamino-3-(4-chlorophenyl)-3-methyl-butyric acid (251 mg, 0.766 mmol, 1.0 equiv), 1-hydroxybenzotriazole (109 mg, 0.804 mmol, 1.05 equiv), and EDCI (154 mg, 0.804 mmol, 1.05 equiv) were dissolved/suspended in 6.0 mL of DMF. The mixture was treated with triethylamine (427 ⁇ L, 3.06 mmol) and allowed to stir overnight to completion.
  • the reaction was partitioned between ethyl acetate and diluted NaHCO 3 solution.
  • the aqueous was extracted with ethyl acetate, and the organics were combined.
  • the organic was washed with water, then brine, separated, dried over MgSO 4 , filtered, and concentrated in vacuo.
  • the residue was eluted through a small plug of silica gel with ethyl acetate and concentrated in vacuo.
  • the protected intermediate was immediately dissolved in 1 mL of dioxane and treated with 4M HCl in dioxane (1.92 mL, 7.66 mmol) at room temperature for four hours.
  • Step 1 4-(6,7,8,9-Tetrahydro-5H-1,3,9-triaza-fluoren-4-yl)-piperazine-1-carboxylic acid tert-butyl ester was prepared by the procedures described in Example 40, Step 1, substituting 4-chloro-5-iodopyrimidine with 4-Chloro-6,7,8,9-tetrahydro-5H-1,3,9-triaza-fluorene (prepared from 2-Amino-1-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile according to the literature: Traxler, P. M. et. al. (1996), J. Med. Chem., 39, 2285-2292).
  • Step 2 4-Piperazin-1-yl-6,7,8,9-tetrahydro-5H-1,3,9-triaza-fluorene dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-Chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with 4-(6,7,8,9-Tetrahydro-5H-1,3,9-triaza-fluoren-4-yl)-piperazine-1-carboxylic acid tert-butyl ester.
  • Step 3 To a suspension of 4-Piperazin-1-yl-6,7,8,9-tetrahydro-5H-1,3,9-triaza-fluorene dihydrochloride (20 mg, 0.061 mmol) and (D)-Boc-4-chlorophenylalanine (20 mg, 0.067 mmol) were added DIEA (63 ⁇ L, 0.36 mmol) and HBTU (25 mg, 0.067 mmol). The reaction was stirred at room temperature for 2 hours. The mixture was partitioned between water and EtOAc. The organic layer was washed with aqueous NaHCO 3 and brine, dried and concentrated.
  • Step 1 To a stirred suspension of NaH (60%, 0.146 g, 3.65 mmol) in DMF (15 mL) was added dropwise a solution of 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.611 g, 3.04 mmol) in DMF (5 mL) at 0° C. The reaction was stirred for 1 hour and then 4-chloroquinazoline (0.500 g, 3.04 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was partitioned between H 2 O and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated.
  • Step 2 (2R)- ⁇ 1-(4-Chlorobenzyl)-2-oxo-2-[4-(quinazolin-4-yloxy)-piperidin-1-yl]-ethyl ⁇ -carbamic acid 9H-fluoren-9-ylmethyl ester was prepared by the procedures described in Example 34, Step 2, substituting 5-Piperazin-1-yl-1H-indazole with 4-(Piperidin-4-yloxy)-quinazoline dihydrochloride and substituting (D)-Boc-4-chlorophenylalanine with (D)-Fmoc-4-chlorophenylalanine.
  • Step 3 To a stirred solution of (2R)- ⁇ 1-(4-Chlorobenzyl)-2-oxo-2-[4-(quinazolin-4-yloxy)-piperidin-1-yl]-ethyl ⁇ -carbamic acid 9H-fluoren-9-ylmethyl ester (0.166 g, 0.262 mmol) in DCM (5 mL) was added piperidine (1 mL). The reaction was stirred at room temperature for 4 hours. The volatiles were evaporated.
  • Step 1 An analogous reaction to that described in example 61 steps 1-3, but starting with (3,4-dichlorophenyl)-acetic acid methyl ester yielded 4-tert-butoxycarbonylamino-2-(3,4-dichlorophenyl)-butyric acid.
  • Step 2 The 4-piperazin-1-yl-quinazoline (20 mg, 0.070 mmol) was dissolved in 1 mL CHCl 3 and 4-tert-butoxycarbonylamino-2-(3,4-dichlorophenyl)-butyric acid (36 mg, 0.10 mmol) was added. PS-carbodiimide resin (0.21 mmol) was added and the mixture was shaken overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel eluted with 1:4 DCM/EtOAc) to afford the pure Boc-protected intermediate.
  • Step 1 To a solution of 4-Pyridin-2-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (prepared from 1-Pyridin-2-ylmethyl-piperazine according to the literature: J. Med. Chem. (1993), 36, 2984) (2.00 g, 7.21 mmol) in THF (15 mL) was added n-BuLi (1.6 M in hexanes, 5.0 mL, 7.9 mmol) at ⁇ 78° C. The mixture was allowed to warm to room temperature and stirred for 30 minutes. The solution was then cooled to ⁇ 78° C.
  • Step 2 2-[2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-1-ethoxy-2-pyridin-2-yl-ethyl]-malonic acid diethyl ester (2.40 g, 4.86 mmol) was dissolved in xylene (20 mL) and heated at 140° C. for 12 hours. After cooling, the volatiles were evaporated and the residue was purified by column chromatography (EtOAc) to give 1-(4-tert-Butoxycarbonyl-piperazin-1-yl)-4-oxo-1,9a-dihydro-4H-quinolizine-3-carboxylic acid ethyl ester (1.39 g, 71%) as an orange solid.
  • Step 3 A mixture of 1-(4-tert-Butoxycarbonyl-piperazin-1-yl)-4-oxo-1,9a-dihydro-4H-quinolizine-3-carboxylic acid ethyl ester (0.320 g, 0.797 mmol) in concentrated HCl (5 mL) was refluxed for 30 minutes. After cooling, the reaction was basified with aqueous NaHCO 3 solution and thoroughly extracted with DCM. The combined organic layers were washed with brine, dried and concentrated to give 1-Piperazin-1-yl-1,9a-dihydro-quinolizin-4-one (0.075 g, 41%) as a yellow oil.
  • Step 4 1- ⁇ 4-[4-Amino-2-(3,4-dichlorophenyl)-butyryl]-piperazin-1-yl ⁇ -quinolizin-4-one hydrochloride was prepared by substituting 5-piperazin-1-yl-1H-indazole with 1-Piperazin-1-yl-1,9a-dihydro-quinolizin-4-one and substituting (D)-Boc-4-chlorophenylalanine with 4-tert-Butoxycarbonylamino-2-(3,4-dichlorophenyl)-butyric acid in Example 34, Step 2, then removing the Boc protecting group as described in Example 34, Step 3.
  • Step 1 To a 25 mL flask was charged 4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (prepared from 4-Oxo-piperidine-1-carboxylic acid benzyl ester according to the literature: Wustrow, D. J. et. al. (1991), Synthesis, 993-995.
  • Step 2 To a stirred solution of 4-Quinazolin-4-yl-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (0.907 g, 2.63 mmol) in MeOH (30 mL) under N 2 was cautiously added 10% Pd on carbon (100 mg). The reaction was hydrogenated at 50 psi using a parr shaker for 3 days. The catalyst was removed by filtration. The filtrate was evaporated under vacuum.
  • Step 3 (2R)-[1-Benzyl-2-oxo-2-(4-quinazolin-4-yl-piperidin-1-yl)-ethyl]-carbamic acid tert-butyl ester was prepared by substituting 5-Piperazin-1-yl-1H-indazole with 4-(1,2,3,6-Tetrahydro-pyridin-4-yl)-quinazoline and substituting (D)-Boc-4-chlorophenylalanine with (D)-Boc-phenylalanine in Example 34, Step 2.
  • Step 4 (2R)-2-Amino-3-phenyl-1-(4-quinazolin-4-yl-piperidin-1-yl)-propan-1-one dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)- ⁇ 1-(4-Chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert-butyl ester with (2R)-[1-Benzyl-2-oxo-2-(4-quinazolin-4-yl-piperidin-1-yl)-ethyl]-carbamic acid tert-butyl ester.
  • LCMS (APCI+) m/z 361 [M+H] + ; Rt 2.38 min.
  • Step 1 To a nitrogen flushed flask containing 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (prepared from tert-butyl-4-oxopiperidine-1-carboxylate according to the literature: Eastwood, P. R. (2000), Tetrahedron Lett., 3705-3708.

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