WO2013078254A1 - Bicyclic heteroaryl derivatives as kinase inhibitors - Google Patents

Bicyclic heteroaryl derivatives as kinase inhibitors Download PDF

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Publication number
WO2013078254A1
WO2013078254A1 PCT/US2012/066153 US2012066153W WO2013078254A1 WO 2013078254 A1 WO2013078254 A1 WO 2013078254A1 US 2012066153 W US2012066153 W US 2012066153W WO 2013078254 A1 WO2013078254 A1 WO 2013078254A1
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phenyl
purin
cyclobutanamine
pyrrolo
pyridin
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PCT/US2012/066153
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French (fr)
Inventor
Nicholas Skelton
Stefan Gradl
James F. Blake
James M. Graham
Indrani W. Gunawardana
Martin Hentemann
Allison L. Marlow
Tony P. Tang
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Array Biopharma Inc.
Genentech, Inc.
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Publication of WO2013078254A1 publication Critical patent/WO2013078254A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular as 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 example, for the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals.
  • Protein kinases are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins by transfer of the terminal (gamma) phosphate from ATP. Through signal transduction pathways, these enzymes modulate cell growth, differentiation and proliferation, i.e., virtually all aspects of cell life in one way or another depend on PK activity (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book. I and II, Academic Press, San Diego, CA).
  • abnormal PK activity has been related to a host of disorders, ranging from relatively non-life threatening diseases, such as psoriasis, to extremely virulent diseases, such as glioblastoma (brain cancer).
  • Protein kinases are an important target class for therapeutic modulation (Cohen, P. (2002) Nature Rev. Drug Discovery 1 :309).
  • Protein kinases include two classes; protein tyrosine kinases (PTK) and serine- threonine kinases (STK).
  • the Protein Kinase B/Akt enzymes are a group of serine/threonine kinases that are overexpressed in a variety of human tumors.
  • One of the best-characterized targets of the PI3K lipid products is the 57 KD serine/threonine protein kinase Akt, downstream of PI3K in the signal transduction pathway (Hemmings, B.A. (1997) Science 275:628; Hay N. (2005) Cancer Cell 8:179-183).
  • Akt is the human homologue of the protooncogene v-akt of the acutely transforming retrovirus AKT8. Due to its high sequence homology to protein kinases A and C, Akt is also called Protein Kinase B (PKB) and Related to A and C (RAC). Three isoforms of Akt are known to exist, namely Aktl, Akt2 and Akt3, which exhibit an overall homology of 80% (Staal, S.P. (1987) Proc. Natl. Acad. Sci. 84:5034; Nakatani, K. (1999) Biochem. Biophys. Res. Commun. 257:906; Li et al (2002) Current Topics in Med. Chem.
  • the Akt isoforms share a common domain organization that consists of a pleckstrin homology domain at the N-terminus, a kinase catalytic domain, and a short regulatory region at the C-terminus.
  • both Akt2 and Akt3 exhibit splice variants.
  • Akt is phosphorylated (activated) by PDK1 at T308, T309 and T305 for isoforms Aktl (PKBa), Akt2 ( ⁇ ) and Akt3 ( ⁇ ), respectively, and at S473, S474 and S472 for isoforms Aktl, Akt2 and Akt3, respectively.
  • PKTa Aktl
  • Akt2 Akt2
  • Akt3 Akt3
  • S473, S474 and S472 isoforms Aktl, Akt2 and Akt3, respectively.
  • Akt activation requires its phosphorylation on residue Ser 473 in the C-terminal hydrophobic motif (Brodbeck et al (1999) J. Biol. Chem. 274:9133-9136; Coffer et al (1991) Eur. J. Biochem. 201 :475-481; Alessi et al (1997) Curr. Biol. 7:261-269). Although 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 (Toker et al. (2006) Cancer Res. 66(8):3963-3966). Akt is overexpressed in many forms of human cancer including, but not limited to, colon (Zinda et al (2001) Clin. Cancer Res. 7:2475), ovarian (Cheng et al (1992) Proc. Natl. Acad. Sci. USA 89:9267), brain (Haas Kogan et al (1998) Curr. Biol. 8:1195), lung (Brognard et al (2001) Cancer Res.
  • pancreatic Bosset et al (1995) Int. J. Cancer 64:280-285; Cheng et al (1996) Proc. Natl. Acad. Sci. 93:3636-3641
  • prostate Graff et al (2000) J. Biol. Chem. 275:24500
  • gastric carcinomas Staal et al (1987) Proc. Natl. Acad. Sci. USA 84:5034-5037.
  • PI3K/Akt/mammalian target of rapamycin (mTOR) pathway has been explored for targeted small molecule inhibitor therapy (Georgakis, G. and Younes, A. (2006) Expert Rev. Anticancer Ther. 6(1): 131-140; Granville et al (2006) Clin. Cancer Res. 12(3):679-689). Inhibition of PI3K/Akt signaling induces apoptosis and inhibits the growth of tumor cells that have elevated Akt levels (Kim et al (2005) Current Opinion in Investig. Drugs 6(12): 1250- 1258; Luo et al (2005) Molecular Cancer Ther. 4(6):977-986).
  • 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 could be a valuable 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.
  • 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.
  • the present invention includes compounds having the general formula
  • the invention also provides pharmaceutical compositions comprising a compound of Formula 1, or an enantiomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof.
  • the present invention provides a method of treating diseases or medical conditions in a mammal mediated by AKT protein kinases, comprising administering to said mammal one or more compounds of Formula 1 , or an enantiomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, in an amount effective to treat or prevent said disorder.
  • AKT protein kinase mediated conditions that can be treated according to the methods of this invention include, but are not limited to, inflammatory, hyperproliferative, cardiovascular, neurodegenerative, gynecological, and dermatological diseases and disorders.
  • the present invention provides a method of inhibiting the production of AKT protein kinases in a mammal, which comprises administering to said mammal a compound of Formula 1, or an enantiomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof in an amount effective to inhibit production of an AKT protein kinase.
  • the present invention provides methods of inhibiting the activity of AKT protein kinases, comprising contacting said kinase with a compound of Formula 1.
  • inventive compounds may be used advantageously in combination with other known therapeutic agents. Accordingly, this invention also provides pharmaceutical compositions comprising a compound of Formula 1 or an enantiomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, in combination with a second therapeutic agent.
  • This invention also provides compounds of Formula 1 and enantiomers, solvates, metabolites, and pharmaceutically acceptable salts and prodrugs thereof for use as medicaments in the treatment of AKT protein kinase-mediated conditions.
  • An additional aspect of the invention is the use of a compound of Formula 1, or an enantiomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, for therapy.
  • the therapy comprises the treatment of an AKT protein kinase-mediated condition.
  • kits for the treatment of an AKT protein kinase- mediated disease or disorder comprising a compound of Formula 1, or an enantiomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, a container, and optionally a package insert or label indicating a treatment.
  • the kits may further comprise a second compound or formulation comprising a second pharmaceutical agent useful for treating said disease or disorder.
  • This invention further includes methods of preparing, methods of separating, and methods of purifying of the compounds of this invention.
  • 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 (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n- Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1 -butyl (n-Bu, n-butyl, - CH 2 CH 2 CH 2 CH 3 ), 2-methyl-l -propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, - CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, - CH 2 CH 2 CH 2 CH 3 ), 2-pentyl
  • alkylene or "alkylenyl” as used herein refers to a linear or branched saturated divalent hydrocarbon radical of one to twelve carbon atoms, wherein the alkylene radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
  • cycloalkyl “carbocycle,” “carbocyclyl” and “carbocyclic ring” as used herein are used interchangeably and refer to saturated or partially unsaturated cyclic hydrocarbon radical having from three to twelve 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 ring fused to a saturated, partially unsaturated or aromatic cycloalkyl or heterocyclic ring.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Bicyclic carbocycles include those having 7 to 12 ring atoms arranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or as bridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane.
  • the cycloalkyl may be optionally substituted independently with one or more substituents described herein.
  • Aryl as used herein means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring.
  • Exemplary aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, indene, indane, 1 ,2-dihydronapthalene, 1,2,3,4-tetrahydronapthalene, and the like.
  • Aryl groups may be optionally substituted independently with one or more substituents described herein.
  • heterocycle 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 independently 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 substituents described below.
  • the radical may be a carbon radical or heteroatom radical.
  • heterocycle includes heterocycloalkoxy.
  • Heterocyclyl also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated, or aromatic carbocyclic or heterocyclic ring.
  • heterocyclic 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, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,
  • the heterocycle 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-l-yl (N-attached) or imidazol-3-yl (C- attached).
  • heterocycle groups herein are optionally substituted independently with one or more substituents described herein.
  • Non limiting examples of 5 to 6 membered heterocycloalkyl groups containing one, two or three heteroatoms selected from the group consisting of N, S and O can be selected from the group consisting of optionally substituted pyrrolidinyl, piperazinyl, pyrrolidinyl-2-one, thiomorpholine and 1,1 dioxide.
  • heteroaryl refers to a monovalent aromatic radical of a 5-
  • 6-, or 7-membered ring and includes fused ring systems (at least one of which is aromatic) of 5-10 atoms containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, 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, pur
  • Heteroaryl groups may be optionally substituted independently with one or more substituents described herein.
  • 5 or 6 membered heteroaryl can be selected from the group consisting of optionally substituted pyridinyl, pyrimidinyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinone and benzimidazolyl.
  • carbon bonded heterocycles and heteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5- pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles and heteroaryls are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3- pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2- pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of an isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1 -pyrrolyl, 1- imidazolyl, 1 -pyrazolyl, and 1-piperidinyl.
  • halogen or "halo" as used herein means fluoro, chloro, bromo or iodo.
  • haloalkoxyl refers to an alkoxyl group as defined herein that is substituted by 1, 2, 3, 4, 5 or 6 halogen as defined herein.
  • haloalkoxyl groups include, but are not limited to Ci-C 6 -haloalkoxyl groups, including trifluoromethoxyl and trifluoroethoxyl.
  • haloalkyl refers to an alkyl group as defined herein that is substituted by 1 , 2, 3, 4, 5 or 6 halogen as defined herein. Examples of haloalkyl groups include, but are not limited to Ci-C 6 -haloalkyl groups, including trifluoromethyl and trifluoroethyl.
  • hydroxyalkyl refers to an alkyl group as defined herein that is substituted by 1, 2, 3, 4, 5 or 6 hydroxyl as defined herein.
  • hydroxyalkyl groups include, but are not limited to CrC 6 -hydroxyalkyl groups, including hydroxymethyl and hydroxyethyl.
  • alkylsulfonamide refers to a group of the following formula: -NR'R"S(0) 2 -alkyl., wherein alkyl is as defined herein and R' and R" are as defined herein.
  • alkylsulfonamide group is methanesulfonyl.
  • hydroxyl refers to an alcohol group, -OH.
  • alkoxyl refers to an -O-alkyl group, wherein alkyl is as defined herein.
  • alkoxyl groups include, but are not limited to Ci-C 6 -alkoxyl, including methoxy and ethoxy.
  • the terms "compound of this invention,” “compounds of the present invention” and “compounds of Formula 1” includes compounds of Formula 1 and tautomers, resolved enantiomers, resolved diastereomers, racemic mixtures, solvates, metabolites, salts (including pharmaceutically acceptable salts) and pharmaceutically acceptable prodrugs thereof.
  • the compounds of Formula 1 include solvates, pharmaceutically acceptable prodrugs and salts (including pharmaceutically acceptable salts) of such compounds.
  • phrases "pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound of the invention.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate can also be used to refer to a complex wherein the solvent molecule is water.
  • a "prodrug” is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a 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 a compound 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 phosphoserine, phosphothreonine, phosphotyrosine, 4- hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.
  • prodrugs are also encompassed.
  • a free carboxyl group of a compound of Formula 1 can be derivatized as an amide or alkyl ester.
  • compounds of this invention comprising free hydroxy groups may be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, 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 (Ci-C 6 )alkanoyloxymethyl, l-((Ci-C 6 )alkanoyloxy)ethyl, 1- methyl-l-((Ci-C6)alkanoyloxy)ethyl, (Ci-C 6 )alkoxycarbonyloxymethyl, N-(C C 6 )alkoxy- carbonylaminomethyl, succinoyl, (Ci-C 6 )alkanoyl, a-amino(Ci-C 4 )alkanoyl, arylacyl and a- aminoacyl, or ⁇ -aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH) 2 , -P(0)(0(Ci-C 6 )alkyl) 2 or glycosyl (the radical resulting from
  • Free amines of compounds of Formula 1 can also be derivatized as amides, sulfonamides or phosphonamides. All of these 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, wherein R and R' are each independently (Ci-Cio)alkyl, (C 3 - C 7 )cycloalkyl, or benzyl, or R-carbonyl is a natural a-aminoacyl or natural oc-aminoacyl-natural a- aminoacyl, -C(OH)C(0)OY wherein Y is H, (d-C 6 )alkyl or benzyl, -C(OY 0 )Y !
  • Y 0 is (C C 4 ) alkyl and Yi is (Ci-C 6 )alkyl, carboxy(Ci-C6)alkyl, amino(Ci-C 4 )alkyl or mono-N- or di-N,N- (Ci-C 6 )alkylaminoalkyl, or -C(Y 2 )Y 3 wherein Y 2 is H or methyl and Y 3 is mono-N- or di-N,N-(Cr C 6 )alkylamino, mo ⁇ holino, piperidin-l-yl or pyrrolidin-l-yl.
  • compound of the invention may possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and accordingly react with any of a number of inorganic or organic bases or acids to form a salt.
  • 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, but not limited to, 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-
  • the desired salt may be prepared by any suitable method available in the art, for example, by treatment of the free base with an acidic compound, for example, 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 alpha hydroxy 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,
  • an acidic compound for example, an inorgan
  • the desired salt may be prepared by any suitable method, for example, by treatment of the free acid with an inorganic or organic base.
  • suitable inorganic salts include those formed with alkali and alkaline earth metals, such as lithium, sodium, potassium, barium and calcium.
  • suitable organic base salts include, for example, ammonium, dibenzylammonium, benzylammonium, 2- hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine, dibenzylethylenediamine, and the like salts.
  • salts of acidic moieties may include, for example, those salts formed with procaine, quinine and N-methylglucosamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine.
  • the salt is a "pharmaceutically acceptable salt" which, unless otherwise indicated, includes salts that retain the biological effectiveness of the corresponding free acid or base of the specified compound and are not biologically or otherwise undesirable.
  • the compounds of Formula 1 also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula 1 and/or for separating enantiomers of compounds of Formula 1.
  • the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen,
  • isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the phrase "effective amount” means an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to (i) treat or prevent a particular disease, condition, or disorder mediated by the activity of one or more AKT protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or dual specificity kinases, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • an effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
  • the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic.
  • efficacy can be measured, for example, by assessing the time to disease progression (TTP) and/or determining the response rate (RR).
  • the amount of a compound of Formula 1 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.
  • the terms “treat” and “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder as well as those found to be predisposed to having the disease condition but have not yet been diagnosed as having it; modulating and/or inhibiting the disease condition.
  • the terms “treating”, “treat”, or “treatment” embrace both preventative, i.e., prophylactic, and palliative treatment.
  • the term "mammal” refers to a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
  • inventive compounds of Formula 1 are useful for inhibiting AKT protein kinases. 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 compounds of Formula 1 may also be useful as inhibitors of tyrosine kinases as well as serine and threonine kinases in addition to AKT.
  • one aspect of the invention includes compounds of the Formula 1 :
  • X is N or CR 3 ;
  • Het is a roup selected from the grou consisting of:
  • R 1', R2", and R 3 J is a group of formula (L):
  • n 0, 1 or 2;
  • R' and R' are independently selected from the group consisting of H, Ci-C6-alkyl and
  • R"' is H, OH or C,-C 6 -alkyl; and the rest of R 1 , R 2 , and R 3 are independently selected from the group consisting of: H, cyano, Ci- C 6 -alkyl, aryl or heteroaryl, which aryl or heteroaryl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, cyano, oxo, C]-C6-alkyl, Ci-C6-alkoxyl and C i -C6-hydroxyalkyl;
  • R a and R b are independently selected from the group consisting of H, Ci-C6-alkyl, Ci-
  • the compounds of formula 1 and tautomers, resolved enantiomers, resolved diastereomers and pharmaceutically acceptable salts thereof is provided.
  • the compounds of formula 1 are those wherein R 1 is a group of formula (L):
  • the compounds of formula 1 are those wherein R' and R" are H, n is 0 and the remaining substituents are as defined herein.
  • the compounds of formula 1 are those wherein R 2 is a group of formula (L):
  • the compounds of formula 1 are those wherein R 4 is selected from the group consisting of: halo, , aryl, 5 or 6 membered heteroaryl or heterocycloalkyl, which, aryl, heteroaryl or heterocycloalkyl is unsubstituted or substituted by at least one halo and the remaining substituents are as defined herein.
  • the compounds of formula 1 are those wherein R 4 is aryl, 5 to 10 membered heterocycloalkyl containing one, two or three heteroatoms selected from the group consisting of N, S and O or 5 to 10 membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of N, S and O, which aryl heteroaryl or heterocycloalkyl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, oxo, hydroxyl, C C 6 -alkyl, C C 6 -alkoxyl, C C 6 -haloalkyl, Ci-C 6 -haloalkoxyl, COOH, C C 6 - hydroxyalkyl and C]-C6-alkylsulfonamide.
  • the compounds of formula 1 are those wherein R 4 is aryl, 5 to 6 membered heterocycloalkyl containing one, two or three heteroatoms selected from the group consisting of N, S and O or 5 to 6 membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of N, S and O, which aryl heteroaryl or heterocycloalkyl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, oxo, hydroxyl, C C 6 -alkyl, C C 6 -alkoxyl, C r C 6 -haloalkyl, C r C 6 -haloalkoxyl, COOH, C C 6 - hydroxyalkyl and CrCe-alkylsulfonamide.
  • the compounds of formula 1 are those wherein X is N and the remaining substituents are as defined herein.
  • the compounds of formula 1 are those wherein X is CR 3 and the remaining substituents are as defined herein.
  • the compounds of formula 1 are those wherein R 3 is H or
  • Ci-C6-alkyl and the remaining substituents are as defined herein.
  • the compounds of formula 1 are those wherein R 1 is phenyl and the remaining substituents are as defined herein.
  • R is selected from cyano, Ci-C 6 -alkyl, aryl or 5 or 6 membered heteroaryl, which aryl or heteroaryl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, cyano, Ci-Ce-alkyl, Ci-C6-alkoxyl and C ⁇ - C6-hydroxyalkyl; or is a group of formula (L):
  • R 1 is selected from cyano, Ci-Ce-alkyl, aryl or 5 or 6 membered heteroaryl, which aryl or heteroaryl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, cyano, Ci-C6-alkyl and Ci-C6-alkoxyl; or is a group of formula (L):
  • R 1 is selected from cyano, Ci-Ce-alkyl, aryl or 5 or 6 membered heteroaryl, which aryl or heteroaryl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, cyano, Ci-C6-alkyl and Ci-C6-alkoxyl.
  • R is selected from H, Ci-C 6 -alkyl and aryl; or or is a group of formula (L):
  • R 2 is selected from H, Ci-C6-alkyl and aryl.
  • R 2 is selected from the group consisting of:
  • R 3 is selected from H, C]-C6-alkyl and aryl; or or is a group of formula (L):
  • R 3 is selected from H, Ci-C 6 -alkyl and aryl.
  • R 3 is selected from the group consisting of:
  • the compounds of formula 2 have the following formula 2-A:
  • R 1 , R 2 , R 3 , R 4 and m are as defined herein.
  • Non-limiting examples of compounds of formula 2-A are:
  • Non-limiting examples of compounds of formula 2-B are:
  • the compounds of formula 2 have the following formula 2-C:
  • R 1 , R 2 , R 3 , R 4 and m are as defined herein.
  • Non-limiting examples of compounds of formula 2-C are:
  • the compounds of formula 2 have the following formula 2-D:
  • R 1 , R 2 , R 3 , R 4 and m are as defined herein.
  • a non limiting example of compound of formula 2-D is l-(4-(l- aminocyclobutyl)phenyl)-2-phenyl-lH-pyrrolo[3,2-b]pyridin-5-ol.
  • the compounds of formula 2 have the following formula 2-E:
  • R ! , R 2 , R 3 , R 4 and m are as defined herein.
  • Non-limiting examples of compounds of formula 2-E are: l-(4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl) cyclobutanamine,
  • the compounds of formula 2 have the following formula 2-F:
  • R 1 , R 2 , R 3 , R 4 and m are as defined herein.
  • Non-limiting examples of compounds of formula 2-F are:
  • the compounds of formula 2 have the following formula 2-G:
  • R 1 , R 2 , R 3 , R 4 and m are as defined herein.
  • a non-limiting example of a compound of formula 2-G is l-[4-(6-Phenyl- pyrrolo[2,3-b]pyrazin-5-yl)-phenyl]-cyclobutylamine.
  • the compounds of formula 2 have the following formula 2-H:
  • R 1 , R 2 , R 3 , R 4 and m are as defined herein.
  • the compounds of formula 2 have the following formula 2-1:
  • R 1 , R 2 , R 3 , R 4 and m are as defined herein.
  • the compounds of formula 2 have the following formula 2-J:
  • the compounds of formula 1 have the following formula 3:
  • R 1 and R 2 are as defined herein.
  • the compounds of formula 3 have the following formula 3-A:
  • Non-limiting examples of compounds of formula 3-A are:
  • the compounds of formula 3 have the following formula 3-B:
  • R 1 , R 2 , R 4 and m are as defined herein.
  • Non-limiting examples of compounds of formula 3-B are:
  • R 1 , R 2 , R 4 and m are as defined herein.
  • the compounds of formula 3 have the following formula 3-D:
  • the compounds of formula 3 have the following formula 3-E:
  • R 1 , R 2 , R 4 and m are as defined herein.
  • Non-limiting examples of compounds of formula 3-E are:
  • R 1 , R 2 , R 4 and m are as defined herein.
  • the compounds of formula 3 have the following formula 3-G:
  • R 1 , R 2 , R 4 and m are as defined herein.
  • Non-limiting examples of compounds of formula 3-G are:
  • R 1 , R 2 , R 4 and m are as defined herein.
  • the compounds of formula 3 have the following formula 3-J:
  • R 1 , R 2 , R 4 and m are as defined herein.
  • 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 diastereomers, and mixtures, racemic or otherwise, thereof. Accordingly, this invention also includes all such isomers, including diastereomeric mixtures, pure diastereomers and pure enantiomers of the compounds of this invention.
  • enantiomer refers to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • diastereomer refers to a pair of optical isomers which are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities.
  • tautomer or tautomeric form refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed wedge representing a particular configuration, then that stereoisomer is so specified and defined.
  • a "metabolite” is a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds of Formula 1, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Metabolites are identified, for example, by preparing a radiolabelled (e.g., I4 C or
  • H) isotope of a compound of the invention administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to a human, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples.
  • a detectable dose e.g., greater than about 0.5 mg/kg
  • an animal such as rat, mouse, guinea pig, monkey, or to a human
  • sufficient time for metabolism to occur typically about 30 seconds to 30 hours
  • isolating its conversion products from the urine, blood or other biological samples typically about 30 seconds to 30 hours
  • the metabolite structures are determined in conventional fashion, e.g., by MS, LC/MS or NMR analysis.
  • metabolites In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art.
  • the metabolites so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.
  • Compounds of this invention may be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources, such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements).
  • Compounds of Formula 1 may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds.
  • Libraries of compounds of Formula 1 may be prepared by a combinatorial 'split and mix' approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
  • a compound library comprising at least 2 compounds of Formula 1, or salts thereof.
  • Schemes 1-26 show a general method for preparing the compounds of the present invention, as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
  • a palladium source such as tris(dibenzylideneacetone) dipalladium
  • a ligand such as 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (Xantphos)
  • a base such as cesium carbonate
  • a suitable solvent such as dioxane
  • X may be fluoro, chloro, or methanesulfonyl
  • a suitably protected aniline 1.2 (see T.W. Greene, supra) with or without a suitable base, such as diisopropylethylamine, with or without a suitable solvent, such as dioxane, at temperatures ranging from 25 °C to 200 °C to produce nitro-anilines 1.3.
  • the temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
  • Reduction of the nitro group can be achieved by reacting nitro aniline 3 with hydrogen gas in the presence of a catalyst, such as Raney-nickel, in a suitable solvent, such as TFEF, at temperatures ranging from 25 °C to 200 °C, and at pressures ranging from 1 atm to 50 atm to produce amino-aniline 1.4.
  • a catalyst such as Raney-nickel
  • TFEF a suitable solvent
  • a chemoselective reduction method such as sulfided platinum on carbon in a suitable solvent, such as ethanol, at temperatures ranging from 25 °C to 200 °C, and at pressures ranging from 1 atm to 50 atm to produce amino-aniline 1.4.
  • Cyclization to the fused imidazo-heteroarene 1.6 can be achieved by reacting amino-aniline 1.4 with an aldehyde 1.5a in the presence of an oxidant, such as copper(II)acetate, in a suitable solvent, such as acetic acid, at temperatures ranging from 25 °C to 200 °C.
  • imidazo-heteroarenes 1.6 may be synthesized by treating amino-anilines 1.4 with an orthoester 1.5b in the presence of an acid, such as 4-methylbenzenesulfonic acid, in a solvent, such as toluene, at temperatures ranging from 25 °C to 150 °C.
  • the reduction of nitro anilines 1.3 can be performed in the presence of an orthoester 1.5b to affect the reduction and cyclization to imidazo-heteroarenes 1.6 in one step.
  • R 4 may be a halogen to yield compounds 1.6 which may be reacted further. It may be advantageous to mask such functional groups using a protecting group (for a review of protecting groups see T.W. Greene, P.G.M. Wuts - Protective groups in Organic Synthesis, 3rd ed., John Wiley & Sons, 1999).
  • Organic or inorganic bases e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates
  • additives e.g., lithium chloride, copper halides or silver salts
  • These cross coupling reactions may be carried out in suitable solvents such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N-methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C. The temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
  • organometallic derivative e.g., a boronic acid or ester, trifluoroborate salt, organomagnesium, organozinc or organotin compound.
  • organometallic derivative e.g., a boronic acid or ester, trifluoroborate salt, organomagnesium, organozinc or organotin compound.
  • Any functional groups present, may need to be protected by a suitable protecting group.
  • metals or metalloids can be achieved by generally well-known methods, such as metallation using metals or a metal-halogen exchange reaction.
  • Useful metals for metallation include alkaline or alkaline earth metals or activated forms of such metals.
  • Suitable reagents for use in metal-halogen exchange reactions include organolithium or organomagnesium compounds (e.g., N-butyllithium, tert-butyllithium or iso-propylmagnesium chloride or bromide).
  • Subsequent transmetalation reactions of the organometallic intermediate may be performed as needed with a suitable soluble and reactive metal compound, such as magnesium chloride, magnesium bromide, tri-N-butyltin chloride, trimethyltin chloride, trimethyl borate, triethyl borate, tri-iso-propyl borate, zinc triflate or zinc chloride.
  • a suitable soluble and reactive metal compound such as magnesium chloride, magnesium bromide, tri-N-butyltin chloride, trimethyltin chloride, trimethyl borate, triethyl borate, tri-iso-propyl borate, zinc triflate or zinc chloride.
  • boronic acid pinacol ester can be conveniently achieved by reacting the halogen derivative directly with bis(pinacolato)diboron in the presence of dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium(II) and suitable bases (e.g., potassium or sodium acetate) in solvents such as DMSO, DMF, DMA or N- methylpyrrolidone at temperatures ranging from 80-160 °C. Conventional heating or microwave irradiation may be employed to maintain the appropriate temperature (for literature precedent of similar transformations, see Ishiyama T. et al., J. Org. Chem., 60.750S (2003)).
  • organometallic derivatives may be utilized in cross- coupling reactions similar to those described above. Such couplings can be effected utilizing suitable coupling partners, such as aromatic, heteroaromatic halides or olefinic reagents under conditions identical or evidently similar and/or related to the methods described above.
  • suitable coupling partners such as aromatic, heteroaromatic halides or olefinic reagents under conditions identical or evidently similar and/or related to the methods described above.
  • Other methods may utilize the reactivity of organometallic derivatives generated from 3.2 by any of the methods described above.
  • alkaline or alkaline earth metals e.g., organolithium, organomagnesium or organozinc compounds
  • other electrophilic coupling partners such as, for example, activated olefins (MICHAEL-acceptors), aldehydes, nitriles, aromatic nitro compounds, carboxylic acid derivatives, oxiranes, aziridines, organic disulfides or organic halides.
  • MICHAEL-acceptors activated olefins
  • aldehydes aldehydes
  • nitriles aromatic nitro compounds
  • carboxylic acid derivatives e.g., oxiranes
  • aziridines organic disulfides or organic halides
  • This methodology may be extended to the incorporation of non-carbon based nucleophiles (e.g., alcohols, thiols, primary or secondary amines) that may optionally contain suitable protecting groups of alcohols, thiols or amines. Examples of such groups can be found in Greene T., supra. Exemplary methods of such utilization of non-carbon nucleophiles in related cross-coupling reactions may be found in Ley S. et al., Angew. Chem., /75:5558 (2003); Wolfe J. et al., Ace. Chem. Res., 31:805 (1998); Hartwig, Ace. Chem.
  • Some of the compounds in the present invention may be synthesized by treatment of chloro purine 3.2 with a nucleophile, such as a primary or secondary amine, or an alcohol, in the presence of carbon monoxide, a suitable catalyst, such as dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium(II), a base, such as triethylamine, and a solvent, such as dioxane, at temperatures ranging from 80-160 °C. Conventional heating or microwave irradiation may be employed to maintain the appropriate temperature (exemplary methods of carbonylation may be found in Brennbower, A. et al., Angew. Chem., 48(23):4114 (2009)).
  • a nucleophile such as a primary or secondary amine, or an alcohol
  • a suitable catalyst such as dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium(II)
  • compounds described in the invention may be synthesized by treating chloro-purine 3.2 with a suitably protected carbon-based nucleophiles (e.g., malonates) and non- carbon based nucleophiles (e.g., alcohols, thiols, primary or secondary amines) via nucleophilic aromatic substitution.
  • a suitably protected carbon-based nucleophiles e.g., malonates
  • non- carbon based nucleophiles e.g., alcohols, thiols, primary or secondary amines
  • the reactions may be accelerated using an appropriate acid, such as toluenesulfonic acid, or base, such as triethylamine, diisopropylethylamine, sodium hydride, or an alkaline carbonate base, in the presence or absence of a suitable solvent, such as, but not limited to, THF, dioxane, DMF, DMA, DMSO, or acetonitrile.
  • an appropriate acid such as toluenesulfonic acid
  • base such as triethylamine, diisopropylethylamine, sodium hydride, or an alkaline carbonate base
  • a suitable solvent such as, but not limited to, THF, dioxane, DMF, DMA, DMSO, or acetonitrile.
  • 6-Substituted-4-chloro-5-nitro-pyrimidine 4.1 can be treated with an aniline, such as 1.2, in a suitable solvent, such as THF.
  • the resulting nitro aniline 4.2 can be reduced with hydrogen gas in the presence of a suitable catalyst, such as raney nickel, in a suitable solvent, such as THF.
  • Dianiline 4.3 can be cyclized to purine 4.4 using aldehyde 1.5a in the presence of an oxidant, such as copper(II) acetate in acetic acid.
  • R 1 , R 2 , or R 4 may contain functional groups which have to be protected with a suitable protecting group.
  • R 1 , R 2 , or R 4 may also be functional handles which allow further elaboration of 4.4.
  • Purine 5.2 can by synthesized from 4,6-dichloro-5-nitro- pyrimidine 5.1 according to Scheme 4.
  • suitable reagents such as boronic acids and boronates, organoboranes, organostannanes, organozinc compounds, organomagnesium compounds, olefins or terminal alkynes (either purchased or obtained via generally well known protocols), can be carried out in the presence of a suitable transition metal catalyst (e.g., palladium compounds).
  • the coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines.
  • ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines.
  • Organic or inorganic bases e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates
  • additives e.g., lithium chloride, copper halides or silver salts
  • cross coupling reactions may be carried out in suitable solvents such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N-methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C.
  • suitable solvents such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N-methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C.
  • the temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
  • Tetrasubstituted purines from the invention described herein can be synthesized from dichloropurine 6.2 (Scheme 6) which may be synthesized from 2,4,6-trichloro-5- nitropyrimidine according to Scheme 4. Functionalization of 6.2 according to the conditions described above followed by functionalization of the resulting chloropurine 6.3 according to the conditions described above generates tetrasubstituted purines 6.4.
  • R 1 , R 2 , or R 4 may contain functional groups which have to be protected with a suitable protecting group.
  • R 1 , R 2 , or R 4 may also be functional handles which allow further elaboration of 7.4.
  • 6-Bromo-imidazo[4,5-b]pyridine 8.2 can be synthesized according to Scheme 7.
  • suitable reagents such as boronic acids and boronates, organoboranes, organostannanes, organozinc compounds, organomagnesium compounds, olefins or terminal alkynes (either purchased or obtained via generally well known protocols), can be carried out in the presence of a suitable transition metal catalyst (e.g., palladium compounds).
  • the coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines.
  • ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines.
  • Organic or inorganic bases e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates
  • additives e.g., lithium chloride, copper halides or silver salts
  • cross coupling reactions may be carried out in suitable solvents, such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N- methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C.
  • suitable solvents such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N- methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C.
  • the temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
  • 5-Chloro-imidazo[4,5-b]pyridine 9.2 can be synthesized according to Scheme 7.
  • suitable reagents such as boronic acids and boronates, organoboranes, organostannanes, organozinc compounds, organomagnesium compounds, olefins or terminal alkynes (either purchased or obtained via generally well known protocols), can be carried out in the presence of a suitable transition metal catalyst (e.g., palladium compounds).
  • the coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines.
  • ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines.
  • Organic or inorganic bases e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates
  • additives e.g., lithium chloride, copper halides or silver salts
  • cross coupling reactions may be carried out in suitable solvents, such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N- methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C.
  • suitable solvents such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N- methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C.
  • the temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
  • Dianiline 10.3 can be cyclized to imidazo[4,5- b]pyrazine 10.4 using aldehyde 1.5a in the presence of an oxidant, such as copper(II) acetate in acetic acid.
  • an oxidant such as copper(II) acetate in acetic acid.
  • R 1 , R 2 , or R 4 may contain functional groups which have to be protected with a suitable protecting group.
  • R 1 , R 2 , or R 4 may also be functional handles which allow further elaboration of 10.4.
  • Pg is an amine protecting group, e.g., acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethyleneoxycarbonyl (Fmoc).
  • amine protecting group e.g., acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethyleneoxycarbonyl (Fmoc).
  • alkynes 11.3 Treatment of alkynes 11.3 with a suitably protected aniline 1.2 (for a review of protecting groups see T.W. Greene, supra) in the presence of a palladium source, such as tris(dibenzylideneacetone) dipalladium, a ligand, such as 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (Xantphos), a base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 25 °C to 200 °C produces anilino-alkynes 1 1.4.
  • a palladium source such as tris(dibenzylideneacetone) dipalladium
  • a ligand such as 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (Xantphos)
  • a base such as cesium carbonate
  • a suitable solvent such as dioxane
  • anilino-alkynes 11.4 Treatment of anilino-alkynes 11.4 with a suitable catalyst, such as bis- tributylphosphine palladium, a suitable additive, such as potassium fluoride, a base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 25 °C to 200 °C produces aryl-pyrroles 11.5.
  • a suitable catalyst such as bis- tributylphosphine palladium
  • a suitable additive such as potassium fluoride
  • a base such as cesium carbonate
  • a suitable solvent such as dioxane
  • reaction to form aryl-pyrroles 11.5 from alkynes 11.3 may be performed as a one pot reaction.
  • an optionally substituted amino-heteroarene (selected from Figure 2, with X 1 being a bromide, iodide, or trifluoromethanesulfonato, and X 2 being a fluoride or chloride) can be used as compound 11.1 and may be treated with a suitably protected aniline 1.2 (for a review of protecting groups see T.W. Greene, P.G.M.
  • selected examples from the invention described herein can be synthesized from 4-chloro-3-iodopyridine 12.1.
  • a suitable catalyst such as dichloro- bis(triphenylphosphine)palladium (II)
  • a suitable additive such as copper(I)iodide
  • a base such as triethylamine
  • a catalyst such as tris(dibenzylideneacetone)dipalladium(0)
  • a suitable ligand such as 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (X-phos)
  • a suitable base such as cesium carbonate
  • a suitable solvent such as dioxane
  • 2-chloro-3-iodo-4-amino-pyridines (Scheme 13).
  • Treatment of an optionally protected 2-chloro-3-iodo-4-amino-pyridine 13.1 can be treated with nucleophiles such as, but not limited to, amines, alkoxides, or thioalkoxides, in the presence of a suitable solvent, such as dioxane, to yield iodopyridines 13.2.
  • iodide 13.2 Treatment of iodide 13.2 with an alkyne 11.2 in the presence of a suitable catalyst, such as dichloro-bis(triphenylphosphine)palladium (II), a suitable additive, such as copper(I)iodide, a base, such as triethylamine, with or without a suitable solvent, at temperatures ranging from 20 °C to 150 °C yields alkyne 13.3.
  • a suitable catalyst such as dichloro-bis(triphenylphosphine)palladium (II)
  • a suitable additive such as copper(I)iodide
  • a base such as triethylamine
  • iodide 13.4 Treatment of iodide 13.4 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields amino alkyne 13.5.
  • a catalyst such as tris(dibenzylideneacetone)dipalladium(0)
  • a suitable ligand such as 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (X-phos)
  • a suitable base such as cesium carbonate
  • a suitable solvent such as dioxane
  • Cyclization of amino alkyne 13.5 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert- butylphosphine)palladium(O), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield pyrrolo[3,2-c]pyridine 13.6.
  • a base such as cesium carbonate and potassium fluoride
  • a catalyst such as di(tri-tert- butylphosphine)palladium(O)
  • a suitable solvent such as dioxane
  • selected examples from the invention described herein can be synthesized from optionally substituted 2-bromo-3-chloropyridines 14.1 (Scheme 14).
  • a suitable catalyst such as dichloro- bis(triphenylphosphine)palladium (II)
  • a suitable additive such as copper(I)iodide
  • a base such as triethylamine
  • chloride 14.2 Treatment of chloride 14.2 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields amino alkyne 14.3.
  • a catalyst such as tris(dibenzylideneacetone)dipalladium(0)
  • a suitable ligand such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos)
  • a suitable base such as cesium carbonate
  • a suitable solvent such as dioxane
  • Cyclization of amino alkyne 14.3 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert-butylphosphine)palladium(0), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield pyrrolo[3,2-b]pyridines 14.4.
  • a base such as cesium carbonate and potassium fluoride
  • a catalyst such as di(tri-tert-butylphosphine)palladium(0)
  • selected examples from the invention described herein can be synthesized from optionally substituted 2-chloro-3-iodo-pyridines 15.1 (Scheme 15).
  • a suitable catalyst such as dichloro- bis(triphenylphosphine)palladium (II)
  • a suitable additive such as copper(I)iodide
  • a base such as triethylamine
  • chloride 15.2 Treatment of chloride 15.2 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields amino alkyne 15.3.
  • a catalyst such as tris(dibenzylideneacetone)dipalladium(0)
  • a suitable ligand such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos)
  • a suitable base such as cesium carbonate
  • a suitable solvent such as dioxane
  • Cyclization of amino alkyne 15.3 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert-butylphosphine)palladium(0), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield pyrrolo[2,3-b]pyridines 15.4.
  • a base such as cesium carbonate and potassium fluoride
  • a catalyst such as di(tri-tert-butylphosphine)palladium(0)
  • chloro alkyne 16.2 can be functionalized in a variety of ways. It may be advantageous to protect reactive functional groups, such as the amino group.
  • Treatment of chloro-pyridine 16.2 with suitable reagents such, as boronic acids and boronates, organoboranes, organostannanes, organozinc compounds, organomagnesium compounds, olefins or terminal alkynes (either purchased or obtained via generally well known protocols), can be carried out in the presence of a suitable transition metal catalyst (e.g., palladium compounds).
  • a suitable transition metal catalyst e.g., palladium compounds.
  • the coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines.
  • Organic or inorganic bases e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates
  • additives e.g., lithium chloride, copper halides or silver salts
  • These cross coupling reactions may be carried out in suitable solvents, such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N- methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C.
  • the temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
  • This methodology may be extended to the incorporation of non-carbon based nucleophiles (e.g., alcohols, thiols, primary or secondary amines) that may optionally contain suitable protecting groups of alcohols, thiols or amines. Examples of such groups can be found in Greene T. et al., supra. Exemplary methods of such utilization of non-carbon nucleophiles in related cross-coupling reactions may be found in Ley S. et al., Angew. Chem., /75:5558 (2003); Wolfe J. et al., Ace. Chem. Res., 31 :805 (1998); Hartwig, Ace. Chem.
  • non-carbon based nucleophiles e.g., alcohols, thiols, primary or secondary amines
  • compounds described in the invention may be synthesized by treating chloro-imidazo[4,5-b]pyridine 16.2 with a suitably protected carbon-based nucleophiles (e.g., malonates) and non-carbon based nucleophiles (e.g., alcohols, thiols, primary or secondary amines) via nucleophilic aromatic substitution.
  • a suitably protected carbon-based nucleophiles e.g., malonates
  • non-carbon based nucleophiles e.g., alcohols, thiols, primary or secondary amines
  • the reactions may be accelerated using an appropriate acid, such as toluenesulfonic acid, or base, such as triethylamine, diisopropylethylamine, sodium hydride, or an alkaline carbonate base, in the presence or absence of a suitable solvent, such as, but not limited to, THF, dioxane, DMF, DMA, DMSO, or acetonitrile.
  • a suitable solvent such as, but not limited to, THF, dioxane, DMF, DMA, DMSO, or acetonitrile.
  • Amino-alkyne 16.3 can be converted to bromo-alkyne 16.4 under diazotization conditions, such as sodium nitrate and toluenesulfonic acid, in a suitable solvent, such as acetonitrile, followed by sodium iodide.
  • bromide 16.4 Treatment of bromide 16.4 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields amino alkyne 16.5.
  • a catalyst such as tris(dibenzylideneacetone)dipalladium(0)
  • a suitable ligand such as 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos)
  • a suitable base such as cesium carbonate
  • a suitable solvent such as dioxane
  • Cyclization of amino alkyne 16.5 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert-butylphosphine)palladium(0), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield pyrrolo[2,3-b]pyridines 16.6.
  • a base such as cesium carbonate and potassium fluoride
  • a catalyst such as di(tri-tert-butylphosphine)palladium(0)
  • a suitable transition metal catalyst e.g., palladium compounds.
  • the coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines.
  • Organic or inorganic bases e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates
  • additives e.g., lithium chloride, copper halides or silver salts
  • THF trifluorofuran
  • dioxane dimethoxyethane
  • diglyme diglyme
  • dichloromethane dichloroethane
  • acetonitrile acetonitrile
  • DMF N-methylpyrrolidone
  • water or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C.
  • the temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
  • Selected examples from the invention described herein can be synthesized from optionally substituted 4-chloro-5-iodo-pyrimidine 18.1 (Scheme 18).
  • a suitable catalyst such as dichloro- bis(triphenylphosphine)palladium (II)
  • a suitable additive such as copper(I)iodide
  • a base such as triethylamine
  • chloride 18.2 Treatment of chloride 18.2 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields pyrrolo[2,3-d]pyrimidines 18.3.
  • a catalyst such as tris(dibenzylideneacetone)dipalladium(0)
  • a suitable ligand such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos)
  • a suitable base such as cesium carbonate
  • a suitable solvent such as dioxane
  • a suitable catalyst such as dichloro-bis(triphenylphosphine)palladium (II)
  • a suitable additive such as copper(I)iodide
  • a base such as triethylamine
  • Cyclization of amino alkyne 19.3 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert-butylphosphine)palladium(0), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield 2-chloro pyrrolo[2,3-d]pyrimidines 19.4.
  • a base such as cesium carbonate and potassium fluoride
  • a catalyst such as di(tri-tert-butylphosphine)palladium(0)
  • a suitable transition metal catalyst e.g., palladium compounds.
  • the coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines.
  • Organic or inorganic bases e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates
  • additives e.g., lithium chloride, copper halides or silver salts
  • the temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
  • the Pd catalyzed coupling or SnAr reaction from 19.4 to 19.5 may be performed similarly as in Scheme 3 (compound 3.2 to compound 2.4), and as such, the description of those potential reactions (see above) apply to Scheme 19 as well.
  • Selected examples from the invention described herein can be synthesized from optionally substituted 4,6-dichloro-5-iodo-pyrimidine 20.1 (Org. Lett.; 11(8), 2009; 1837 - 1840) as seen in Scheme 20.
  • Treatment of dichloride 20.1 with an aniline, such as 1.2, in the presence of a base, such as triethylamine, in a suitable solvent, such as THF results in the formation of iodoaniline 20.2.
  • Cyclization of amino alkyne 20.3 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert-butylphosphine)palladium(0), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield 4-chloro pyrrolo[2,3-d]pyrimidines 20.4.
  • a base such as cesium carbonate and potassium fluoride
  • a catalyst such as di(tri-tert-butylphosphine)palladium(0)
  • a suitable transition metal catalyst e.g., palladium compounds.
  • the coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines.
  • Organic or inorganic bases e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates
  • additives e.g., lithium chloride, copper halides or silver salts
  • THF trifluorofuran
  • dioxane dimethoxyethane
  • diglyme diglyme
  • dichloromethane dichloroethane
  • acetonitrile acetonitrile
  • DMF N-methylpyrrolidone
  • water or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C.
  • the temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
  • 2,4.6-trichloro-5-iodo-pyrimidine 21.1 (Scheme 21).
  • a suitable catalyst such as dichloro-bis(triphenylphosphine)palladium (II)
  • a suitable additive such as copper(I)iodide
  • a base such as triethylamine
  • Cyclization of amino alkyne 21.3 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert-butylphosphine)palladium(0), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield 2,4-dichloro pyrrolo[2,3- djpyrimidines 21.4.
  • a base such as cesium carbonate and potassium fluoride
  • a catalyst such as di(tri-tert-butylphosphine)palladium(0)
  • a suitable solvent such as dioxane
  • Scheme 20 can lead to 2-chloro-4-substituted-pyrrolo[2,3-d]pyrimidines 21.5, which can be functionalized according to Scheme 19 to lead to tetrasubstituted pyrrolo[2,3-d]pyrimidines 21.6.
  • Scheme 22
  • Selected examples from the invention described herein can be synthesized from optionally substituted 3-chloro-4-iodo-pyridine 22.1 (Scheme 22).
  • a suitable catalyst such as dichloro- bis(triphenylphosphine)palladium (II)
  • a suitable additive such as copper(I)iodide
  • a base such as triethylamine
  • chloride 22.2 Treatment of chloride 22.2 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields pyrrolo[2,3-d]pyrimidines 22.3.
  • a catalyst such as tris(dibenzylideneacetone)dipalladium(0)
  • a suitable ligand such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos)
  • a suitable base such as cesium carbonate
  • a suitable solvent such as dioxane
  • Selected examples from the invention described herein can be synthesized from optionally substituted 2,3-dichloro-pyrazines 23.1 (Scheme 23).
  • a suitable catalyst such as dichloro- bis(triphenylphosphine)palladium (II)
  • a suitable additive such as copper(I)iodide
  • a base such as triethylamine
  • chloride 23.2 Treatment of chloride 23.2 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields amino alkyne 23.3.
  • a catalyst such as tris(dibenzylideneacetone)dipalladium(0)
  • a suitable ligand such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos)
  • a suitable base such as cesium carbonate
  • a suitable solvent such as dioxane
  • Cyclization of amino alkyne 23.3 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert-butylphosphine)palladium(0), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield pyrrolo[3,2-b]pyrazines 23.4.
  • a base such as cesium carbonate and potassium fluoride
  • a catalyst such as di(tri-tert-butylphosphine)palladium(0)
  • Selected examples from the invention described herein can be synthesized from optionally substituted 2,4-dichloro-5-bromo-pyrimidine 24.1 (Scheme 24).
  • a suitable catalyst such as dichloro- bis(triphenylphosphine)palladium (II)
  • a suitable additive such as copper(I)iodide
  • a base such as triethylamine
  • a suitable transition metal catalyst e.g., palladium compounds.
  • the coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines.
  • Organic or inorganic bases e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates
  • additives e.g., lithium chloride, copper halides or silver salts
  • THF trifluorofuran
  • dioxane dimethoxyethane
  • diglyme diglyme
  • dichloromethane dichloroethane
  • acetonitrile acetonitrile
  • DMF N-methylpyrrolidone
  • water or mixtures of thereof
  • the temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
  • the Pd catalyzed coupling or SnAr reaction from 24.3 to 24.4 may be performed similarly as in Scheme 3 (compound 3.2 to compound 2.4), and as such, the description of those potential reactions (see above) apply to Scheme 24 as well.
  • Selected examples from the invention described herein can be synthesized from optionally substituted 4-chloro-5-iodo-pyrimidine 18.1 (Scheme 25).
  • Selected examples from the invention described herein can be synthesized from optionally substituted iodoaniline 19.2 (Scheme 26).
  • a suitable catalyst such as palladium(II) acetate
  • a suitable additive such as lithium chloride
  • a base such as potassium acetate
  • a suitable solvent such as DMF
  • Another aspect of this invention provides a method of preparing a compound of Formula 1, comprising the steps of reducing a compound having the formula:
  • the reaction between the two compounds is an oxidative cyclization.
  • Another aspect of this invention provides a method of preparing a compound of Formula 1, comprising the steps of reacting a compound having the formula:
  • Het, R 1 and R 2 are as defined herein and X 2 is halo, e.g., chloride or bromide.
  • Another aspect of this invention provides a method of preparing a compound of
  • R 2 wherein Het, R 1 and R 2 are as defined herein and X 3 is a halogen atom, Pg is an amine protecting group, e.g., acetyl, trifluoroacetyl, BOC, CBz and Fmoc.
  • Pg is an amine protecting group, e.g., acetyl, trifluoroacetyl, BOC, CBz and Fmoc.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, BOC, CBz and Fmoc. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, supra.
  • any of the synthetic methods for preparing compounds of Formula 1 it may be advantageous to separate reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • Another class of separation methods involves treatment of a reaction mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
  • reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
  • the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • converting e.g., hydrolyzing
  • some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be
  • a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., J. Chromatogr., (1975) 113(3):283-302).
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: “Drug Stereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl- ⁇ - phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S., supra at p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-)menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem., (1982) 47:4165), of the racemic mixture, and analyzing the l H NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers.
  • chiral esters such as a menthyl ester, e.g., (-)menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem., (1982) 47:4165), of the racemic mixture, and analyzing the l H NMR spectrum for the presence of the
  • Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse- phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/15111).
  • a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. of Chromatogr., (1990) 513:375-378).
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
  • the compounds of the present invention can be used as prophylactics or therapeutic agents for treating diseases or disorders mediated by modulation or regulation of AKT protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or dual specificity kinases.
  • AKT protein kinase mediated conditions that can be treated according to the methods of this invention include, but are not limited to, inflammatory, hyperproliferative cardiovascular, neurodegenerative, gynecological, and dermatological diseases and disorders.
  • said pharmaceutical composition is for the treatment of hyperproliferative disorders, including cancers of the following categories: (1) Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; (2) Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung, small cell lung; (3) Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma,
  • the AKT protein kinase-mediated condition is a hyperproliferative disease.
  • the hyperproliferative disease is cancer.
  • the cancer is selected from colon, ovarian, brain, lung, pancreatic, prostate, and gastric carcinomas.
  • Compounds and methods of this invention can be also used to treat diseases and conditions such as rheumatoid arthritis, osteoarthritis, Chron's disease, angiofibroma, ocular diseases (e.g., retinal vascularisation, diabetic retinopathy, age-related macular degeneration, macular degeneration, etc.), multiple sclerosis, obesity, Alzheimer's disease, restenosis, autoimmune diseases, allergy, asthma, 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 angiofibrom
  • another aspect of this invention provides a method of treating diseases or medical conditions in a mammal mediated by AKT protein kinases, comprising administering to said mammal one or more compounds of Formula 1 or a pharmaceutically acceptable salt or prodrug thereof in an amount effective to treat or prevent said disorder.
  • This invention also provides compounds of Formula 1 for use in the treatment of
  • AKT protein kinase-mediated conditions AKT protein kinase-mediated conditions.
  • An additional aspect of the invention is the use of a compound of Formula 1 in the preparation of a medicament for therapy, such as for the treatment or prevention of AKT protein kinase-mediated conditions.
  • the compounds of the present invention can be used in combination with one or more additional drugs such as described below.
  • the dose of the second drug can be appropriately selected based on a clinically employed dose.
  • the proportion of the compound of the present invention and the second drug can be appropriately determined according to the administration subject, the administration route, the target disease, the clinical condition, the combination, and other factors.
  • the second drug may be used in an amount of 0.01 to 100 parts by weight per part by weight of the compound of the present invention.
  • the second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of this invention such that they do not adversely affect each other.
  • Such drugs are suitably present in combination in amounts that are effective for the purpose intended.
  • another aspect of the present invention provides a composition comprising a compound of this invention in combination with a second drug, such as described herein.
  • a compound of this invention and the additional pharmaceutically active drug(s) may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time.
  • the amounts of the compound of this invention and the second drug(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the combination therapy may provide "synergy” and prove “synergistic", i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
  • a “chemotherapeutic agent” is a chemical compound useful in the treatment of cancer, regardless of mechanism of action. Chemotherapeutic agents include compounds used in "targeted therapy” and conventional chemotherapy.
  • chemotherapeutic agents include PLX4032 (Roche/Plexxikon),
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), mo holino-doxorubicin, cyanomo holino-doxorubicin, 2- pyrrolino-doxorubicin and deoxydoxorubicin), epigallocate, axoxo-L-norleucine
  • chemotherapeutic agent also included in the definition of "chemotherapeutic agent” are: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LYl 17018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMA
  • chemotherapeutic agent therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen pie), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
  • therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RIT
  • Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the PI3K inhibitors of the invention include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab,
  • the compounds of the invention may be administered by any route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. It will be appreciated that the preferred route may vary with for example the condition of the recipient. Where the compound is administered orally, it may be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable carrier or excipient. Where the compound is administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral vehicle and in a unit dosage injectable form, as detailed below.
  • a compound of this invention for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • a pharmaceutical composition that comprises a compound of this invention.
  • the pharmaceutical composition comprises a compound of Formula 1 in association with a pharmaceutically acceptable diluent or carrier.
  • compositions of the invention are formulated, dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the therapeutically effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the disorder.
  • the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
  • composition for use herein is preferably sterile.
  • formulations to be used for in vivo administration must be sterile. Such sterilization is readily accomplished, for example, by filtration through sterile filtration membranes.
  • the compound ordinarily can be stored as a solid composition, a lyophilized formulation or as an aqueous solution.
  • compositions of the compounds of the present invention may be prepared for various routes and types of administration.
  • a compound of this invention having the desired degree of purity may optionally be mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), in the form of a lyophilized formulation, a milled powder, or an aqueous solution.
  • Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8.
  • Formulation in an acetate buffer at pH 5 is a suitable embodiment.
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • the bull- drug substance i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more excipients.
  • solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof.
  • Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine,
  • the formulations may also include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • stabilizing agents i.e., surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • the active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin- microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules
  • a “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as a compound of Formula 1 and, optionally, an additional therapeutic agent) to a mammal.
  • a drug such as a compound of Formula 1 and, optionally, an additional therapeutic agent
  • the components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes. See also, Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
  • Sustained-release preparations of compounds of this invention may be prepared.
  • sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of Formula 1, which matrices are in the form of shaped articles, e.g., films, or microcapsules.
  • sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Patent No.
  • copolymers of L-glutamic acid and gamma-ethyl-L- glutamate non-degradable ethylene-vinyl acetate
  • degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT® (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid.
  • compositions of compounds of this invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • compositions of the invention may also 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)
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs
  • topical use for example as creams, ointments, gels, or aqueous or oily solutions or suspensions
  • inhalation for example as a finely divided powder or a liquid aerosol
  • 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
  • soft gelatin capsules in which the active ingredient is mixed with 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 for example 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, 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.
  • Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient that is solid at ordinary temperatures 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.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • 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 transdermal administration may be in the form of those transdermal skin patches that are well known to those of ordinary skill in the art.
  • Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • Suitable formulations include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis disorders as described below.
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution can include a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • the formulations may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • sterile liquid carrier for example water
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
  • the amount of a compound of this invention that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the subject treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician.
  • a suitable amount of a compound of this invention is administered to a mammal in need thereof.
  • Administration occurs in an amount between about 0.001 mg/kg of body weight to about 60 mg/kg of body weight per day. In another embodiment, administration occurs in an amount between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • kits containing materials useful for the treatment of the disorders described above.
  • the kit comprises a container comprising a compound of this invention.
  • Suitable containers include, for example, bottles, vials, syringes, blister pack, etc.
  • the container may be formed from a variety of materials such as glass or plastic.
  • the container may hold a compound of this invention or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the kit may further comprise a label or package insert on or associated with the container.
  • package insert is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.
  • the label or package inserts indicates that the composition comprising a compound of this invention can be used to treat a disorder mediated, for example, by AKT kinase.
  • the label or package insert may also indicate that the composition can be used to treat other disorders.
  • kits are suitable for the delivery of solid oral forms of a compound of this invention, such as tablets or capsules.
  • a kit preferably includes a number of unit dosages.
  • Such kits can include a card having the dosages oriented in the order of their intended use.
  • An example of such a kit is a "blister pack".
  • Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms.
  • a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.
  • a kit may comprise (a) a first container with a compound of this invention contained therein; and (b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a second compound useful for treating a disorder mediated by AKT kinase.
  • the kit may further comprise a third container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate- buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
  • BWFI bacteriostatic water for injection
  • the kit may further comprise directions for the administration of the compound of this invention and, if present, the second pharmaceutical formulation.
  • the kit may further comprise directions for the simultaneous, sequential or separate administration of the first and second pharmaceutical compositions to a patient in need thereof.
  • the kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet, however, the separate compositions may also be contained within a single, undivided container.
  • the kit comprises directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • kits for treating a disorder or disease mediated by Akt kinase comprising a) a first pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable salt thereof; and b) instructions for use.
  • the kit further comprises (c) a second pharmaceutical composition, wherein the second pharmaceutical composition comprises a second compound suitable for treating a disorder or disease mediated by Akt kinase.
  • the kit further comprises instructions for the simultaneous, sequential or separate administration of said first and second pharmaceutical compositions to a patient in need thereof.
  • said first and second pharmaceutical compositions are contained in separate containers. In other embodiments, said first and second pharmaceutical compositions are contained in the same container.
  • the compounds of Formula 1 are primarily of value as therapeutic agents for use in mammals, 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 activity of the compounds described in the present invention may be determined by the following kinase assay, which 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 are obtained from an IMAP AKT Assay Bulk Kit, product
  • the kit materials include an IMAP Reaction Buffer (5x).
  • the diluted lx IMAP Reaction Buffer contained 10 raM Tris-HCl, pH 7.2, 10 raM MgCl 2i 0.1% BSA. DTT is routinely added to a final concentration of 1 raM immediately prior to use.
  • IMAP Binding Buffer (5x) is also included.
  • the Binding Solution is prepared as a 1 :400 dilution of IMAP Binding Reagent into lx IMAP Binding Buffer.
  • the fluorescein-labeled AKT Substrate has the sequence (Fl)-
  • GRPRTSSFAEG A stock solution of 25 ⁇ is made up in lx 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 is a Packard ProxiPlateTM-384 F.
  • the AKT-1 used is made from full-length, human recombinant AKT-1 that is activated with PDK1 and MAP kinase 2.
  • the assay is initiated by the addition of 2.5- ⁇ . aliquots of a solution containing 200 nM of fluorescently-labeled peptide substrate and 20 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 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.
  • NMR spectra were obtained as CDC1 3 , CD 3 OD, D 2 0 or d6-DMSO solutions (reported in ppm), using tetramethylsilane (0.00 ppm) or residual solvent (CDC1 3 : 7.25 ppm; CD 3 OD: 3.31 ppm; D 2 0: 4.79 ppm; d6-DMSO: 2.50 ppm) as the reference standard.
  • peak multiplicities the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).
  • Step A To a solution of 2,4-Dichloro-5-nitro-pyrimidine (5.00 g, 26.00mmol) in
  • Step B ⁇ l-[4-(2-Chloro-5-nitro-pyrimidin-4-ylamino)-phenyl]-cyclobutyl ⁇ - carbamic acid tert-butyl ester (4.10 g, 9.78 mmol) was dissolved in THF (200 mL) and Raney- Ni (1.00 g) was added. The reaction mixture was stirred at ambient temperature under an atmosphere of hydrogen (balloon) for 4 h. The solvent was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate (200 mL). The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated.
  • Step C To a solution of ⁇ l-[4-(5-Amino-2-chloro-pyrimidin-4- ylamino)-phenyl]- cyclo-butyl ⁇ -carbamic acid tert-butyl ester (2.5 g, 6.42 mmol) in acetic acid (30 mL) was added benzaldehyde (0.89 g, 8.35 mmol) and Cu(OAc) 2 (0.58 g, 3.21 mmol). The reaction mixture was stirred at 100 °C for 2 h.. Then the solvent was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate (150 mL).
  • Step A ⁇ l-[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl ⁇ -carbamic acid tert-butyl ester (500 mg, 1.05 mmol), phenylboronic acid (256 mg, 2.10 mmol), Pd(dppf)Cl 2 (77 mg, 0.11 mmol), and Cs 2 C0 3 (684 mg, 2.10 mmol) were added into a mixed solution (dioxane: 20 mL, water: 4 mL). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 4 h.
  • Step B ⁇ l-[4-(2,8-Diphenyl-purin-9-yl)-phenyl]-cyclobutyl ⁇ -carbamic acid tert- butyl ester (200 mg, 0.39 mmol) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.
  • Examples 2-4 shown in Table 1 can also be made according to the above-described methods.
  • Step A To a solution of ⁇ l-[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclo- butylj-carbamic acid tert-butyl ester (70 mg, 0.147 mmol) in dioxane (20 mL) was added piperazine (63 mg, 0.737 mmol). Then the reaction mixture was stirred at 80 °C for 3h. The solvent was removed under reduced pressure, the resulting residue was dissolved in ethyl acetate (100 mL), washed with water (50 mL). The separated organic layer was dried over sodium sulfate, filtered and concentrated.
  • Step B ⁇ l-[4-(8-Phenyl-2-piperazin-l-yl-purin-9-yl)-phenyl]-cyclobutyl ⁇ -carbamic acid tert-butyl ester (-65 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.
  • Example 6 shown in Table 2 can also be made according to the above-described methods.
  • Step A To a solution of ⁇ l-[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclo- butyl ⁇ -carbamic acid tert-butyl ester (70 mg, 0.147 mmol) in methanol (20 mL) was added sodium methanolate (24 mg, 0.441 mmol). The reaction mixture was stirred at 80 °C for 3 h. Then the solvent was removed under reduced pressure, the resulting residue was dissolved in ethyl acetate (80 mL), washed with water (50 mL). The separated organic layer was dried over sodium sulfate, filtered and concentrated.
  • Step B tert-butyl l-(4-(2-methoxy-8-phenyl-9H-purin-9-yl)phenyl)cyclo- butylcarbamate (-65 mg) was dissolved in ethyl acetate (20 mL), the solution was cooled to 0 °C and a solution of HCl in ethyl acetate (4 M, 5 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.
  • Example 8 shown in Table 3 can also be made according to the above-described methods.
  • Step A ⁇ l-[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl ⁇ -carbamic acid tert-butyl ester (50 mg, 0.11 mmol), pyrrolidin-2-one (14 mg, 0.16 mmol), Pd 2 (dba) 3 (19 mg, 0.02 mmol), Xantphos (15 mg, 0.03 mmol) and Cs 2 C0 3 (68 mg, 0.21 mmol) were dissolved in dioxane (10 mL). The reaction mixture was stirred at 90 °C under nitrogen atmosphere for 6 h.
  • Step B (l- ⁇ 4-[2-(2-Oxo-pyrrolidin-l-yl)-8-phenyl-purin-9-yl]-phenyl ⁇ -cyclobutyl)- carbamic acid tert-butyl ester (30 mg, 0.057 mmol) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.
  • Step A To a solution of ⁇ 1 -[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl ⁇ - carbamic acid tert-butyl ester (150 mg, 0.32 mmol) in dioxane (4 mL) was added the aqueous methylamine amine solution (10 mL, 28% wt) at a sealed vessel. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with water (40 mL). The separated organic layer was dried over sodium sulfate, filtered and
  • Step B ⁇ l-[4-(2-Methylamino-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl ⁇ -carbamic acid tert-butyl ester (-120 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.
  • reaction mixture was allowed to be warmed to ambient temperature and stirred for another 2 h.
  • the reaction mixture was poured into an aqueous saturated NH 4 CI solution, and extracted with ethyl acetate. The separated organic layer was washed with water twice and dried over sodium sulfate, filtered and concentrated to afford 2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-4- (trimethylstannyl)-lH-imidazole (-420 mg), which was used in next step without further purification.
  • Step A 3-methyl- l-((2-(trimethylsilyl)ethoxy)methyl)-l H-pyrazole (500 mg, 2.35 mmol) was dissolved in THF (18 mL), and the solution was cooled to -78°C, followed by adding butyllithium (2.5 M, 0.94 mL, 2.35 mmol) slowly. The reaction mixture was stirred at this temperature for 1 h. Then, chlorotrimethylstannane (1 M in THF, 2.4 mL, 2.35 mmol) was added into the reaction mixture. It was allowed to be warmed to ambient temperature and stirred overnight. The reaction mixture was poured into aqueous saturated NH 4 CI solution, and extracted with ethyl acetate.
  • Step A To a solution of nitroethane (0.15 g, 2.00 mmol) in toluene (6 mL) was added l-chloro-3-isocyanatobenzene (0.61 g, 4.00 mmol). The reaction mixture was stirred at 50 °C for 10 minutes followed by addition of triethylamine (10 mg, 0.1 mmol) and tributyl(ethynyl)stannane (0.60 g, 1.91 mmol). The reaction mixture was stirred at 50 °C overnight. After cooling, the solution was diluted with water and filtered through a celite pad.
  • Step A To a solution of ⁇ l-[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclo- butyl ⁇ -carbamic acid tert-butyl ester (150 mg, 0.316 mmol) in dioxane (4 mL) was added an 2- Methyl-l-(2-trimethylsilanyl-ethoxymethyl)-4-trimethylstannanyl-lH- imidazole (-0.632 mmol, in THF) and Pd(PPh 3 ) 4 (36 mg, 0.032 mmol). The reaction mixture was irradiated by microwave at 120 °C for 50 minutes.
  • Step B [l-(4- ⁇ 2-[2-Methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4- yl]-8-phenyl-purin-9-yl ⁇ -phenyl)-cyclobutyl]-carbamic acid tert-butyl ester (-150 mg) was dissolved in Methanol (10 mL), and aqueous HC1 (36%, 5 mL) was added into the solution. It was heated at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure.
  • Step A To a solution of ⁇ 1 -[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl ⁇ - carbamic acid tert-butyl ester (250 mg, 0.526 mmol) in DMF (20 mL) were added methylamine hydrochloride (107 mg, 1.578 mmol), Pd(OAc) 2 (35 mg, 0.158 mmol), Xantphos (107 mg, 0.184 mmol) and sodium carbonate (178 mg, 1.683 mmol).
  • Step B ⁇ l-[4-(2-Methylcarbamoyl-8-phenyl-purin-9-yl)-phenyl]-cyclo-butyl ⁇ - carbamic acid tert-butyl ester (-200 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h..
  • Step A To a solution of ⁇ l-[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl ⁇ - carbamic acid tert-butyl ester (250 mg, 0.526 mmol) in methanol (30 mL) was added Pd/C (200 mg, 10%wt). The mixture was stirred at 50 °C under the atmosphere of hydrogen (50 psi) for 12 h. The catalyst was removed by filtration, the cake was washed with methanol.
  • Step B ⁇ l-[4-(8-Phenyl-purin-9-yl)-phenyl]-cyclobutyl ⁇ -carbamic acid tert-butyl ester (-120 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.
  • Step A To a. solution of ⁇ 1 -[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl ⁇ - carbamic acid tert-butyl ester (250 mg, 0.526 mmol) in THF (20 mL) was added pyridin-2- ylzinc(II) bromide (1.1 mL, 1M in THF) and Pd(PPh 3 ) 4 (36 mg, 0.032 mmol). The reaction mixture was stirred at 80 °C under the atmosphere of nitrogen for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water twice.
  • Step B ⁇ l-[4-(8-Phenyl-2-pyridin-2-yl-purin-9-yl)-phenyl]-cyclobutyl ⁇ -carbamic acid tert-butyl ester (-200 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.
  • Step B Compound ⁇ l-[4-(5-Nitro-2-phenyl-pyrimidin-4-ylamino)-phenyl]- cyclobutylj-carbamic acid tert-butyl ester (7.0 g, 15.18 mmol) was dissolved in THF (200 mL) and Raney- Ni (1.00 g) was added carefully. The reaction mixture was stirred at ambient temperature under an atmosphere of hydrogen (balloon) for 4 h.
  • Step A ⁇ l-[4-(5-Amino-2-phenyl-pyrimidin-4-ylamino)-phenyl]-cyclobutyl ⁇ - carbamic acid tert-butyl ester (0.25 g, 0.58 mmol) was dissolved in acetic acid (30 mL), then 4- methoxy-pyridine-3-carbaldehyde (87.7 mg, 0.64 mmol) and Cu(OAc) 2 (105 mg, 0.58 mmol) were added separately.
  • Step B (l- ⁇ 4-[8-(4-Methoxy-pyridin-3-yl)-2-phenyl-purin-9-yl]-phenyl ⁇ - cyclobutyl)-carbamic acid tert-butyl ester (-150 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and HC1 in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.
  • Examples 20 to 48 shown in Table 6 can also be made according to the above- described methods.
  • Step A Disulfurdichloride (6.6 mL, 101 mmol) was added to a solution of 2- chloroacetonitrile (3.0 g, 40.2 mmol) in CH 2 C1 2 (10 mL) at room temperature, under an insert atomosphere of nitrogen, the resulting mixture was stirred at room temperature for 18 hours.the reaction mixture was concentrated in vacuo to get crude product 4,5-Dichloro-[l,2,3]dithiazol-l- ylium chloride (8 g crude) which was used without purification.
  • Step B To a solution of ⁇ l-[4-(5-Amino-2-phenyl-pyrimidin-4-ylamino)-phenyl]- cyclobutyl ⁇ -carbamic acid tert-butyl ester (180mg, 0.414mmol) in THF (20ml) was added 4,5- Dichloro-[l,2,3]dithiazol-l-ylium chloride (99 mg, 0.45 mmol), then the reaction mixture was stirred at room temperature for 1 hour.
  • Step C (l- ⁇ 4-[5-(4-Chloro-[l,2,3]dithiazol-5-ylideneamino)-2-phenyl-pyrimidin-4- ylamino]-phenyl ⁇ -cyclobutyl)-carbamic acid tert-butyl ester (150 mg, 0.27 mmol) was dissolved in toluene (15 mL), the reaction mixture was stirred at reflux for 4 hours. The reaction mixture was concentrated in vacuo to afford ⁇ l-[4-(8-Cyano-2-phenyl-purin-9-yl)-phenyI]-cyclobutyl ⁇ -carbamic acid tert-butyl ester.
  • Step D The compound ⁇ l-[4-(8-Cyano-2-phenyl-purin-9-yl)-phenyl]-cyclobutyl ⁇ - carbamic acid tert-butyl ester (80-160 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 C and the solution of HCl in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.. The product was collected by filtration, dried in vacuo, to give target compounds as HCl salt. (15.4 mg)
  • Step A To a solution of compound ⁇ l-[4-(5-Amino-2-chloro-pyrimidin-4- ylamino)-phenyl]-cyclobutyl ⁇ -carbamic acid tert-butyl ester (0.3 g, 0.77 mmol) in dioxane (20 mL)/H 2 0 (4 ml) were added PhB(OH) 2 (2.31 mmol), Pd(dppf)Cl 2 (56.29 mg, 0.077 mmol), and Cs 2 C0 3 (501mg, 1.54mmol). The reaction mixture was stirred at 90 °C under nitrogen atmosphere for 3 h.
  • Step B (l- ⁇ 4-[5-Amino-2-(3-trifluoromethoxy-phenyl)-pyrimidin-4-yl-amino]- phenyl ⁇ -cyclobutyl)-carbamic acid tert-butyl ester (200 mg 0.77 mmol) was dissolved in acetic acid (30 mL), then 2-Methyl-2H-pyrazole-3-carbaldehyde (93.5 mg, 0.85 mmol) and Cu(OAc) 2 (140 mg, 0.77 mmol) were added separately. The reaction mixture was stirred at 100 °C for 2 h.
  • Step C (l- ⁇ 4-[2-(2-Fluoro-phenyl)-8-(2-methyl-2H-pyrazol-3-yl)-purin-9-yl]- phenyl ⁇ -cyclobutyl)-carbamic acid tert-butyl ester (150 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and HC1 in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.
  • Step A The tert-butyl l-(4-(5-amino-2-chloropyrimidin-4-ylamino)- phenyl)cyclobutylcarbamate (3.00 g, 7.71 mmol) was dissolved in acetic acid (50 mL), then picolinaldehyde (1.23 g, 11.5 mmol) and Cu(OAc) 2 (1.4 g, 7.71 mmol) were added separately. The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed with aqueous sat.
  • Step A tert-butyl l-(4-(2-chloro-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)- cyclobutylcarbamate (100 mg, ) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and HCl in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h..
  • Step A Tert-butyl l-(4-(2-chloro-8-(pyridin-2-yl)-9H-purin-9-yl)- phenyl)cyclobutylcarbamate (700 mg, 1.47 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole (342 mg, 1.76 mmol), Pd(dppf)Cl 2 (109.5 mg, 0.15 mmol), and Cs 2 C0 3 (1.4 g, 4.41 mmol) were dissolved in a mixed solution (dioxane: 20 mL, water: 4 mL).
  • Step B The tert-butyl l-(4-(2-(lH-pyrazol-4-yl)-8-(pyridin-2-yl)-9H-purin-9- yl)phenyl)cyclobutylcarbamate (700 mg crude) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and HCl in ethyl acetate (4 M, 10 mL) was added slowly. The resulting solution was stirred for 2 h.
  • Examples 59 and 60 shown in Table 8 can also be made according to the above- described methods.
  • Step A A solution of tert-butyl 1 -(4-(2-(lH-pyrazol-4-yl)-8-(pyridin-2-yl)-9H- purin-9-yl)phenyl)cyclobutylcarbamate (400 mg, 0.787 mmol) in dioxane(10 mL) and oxirane (10 mL) was stirred at 10 °C for 3 days..
  • Step B tert-butyl 1 -(4-(2-( 1 -(2-hydroxyethyl)- 1 H-pyrazol-4-yl)-8-(pyridine-2-yl)-
  • Step A A mixture of tert-butyl l-(4-(2-chloro-8-(pyridin-2-yl)-9H-purin-9- yl)phenyl) cyclobutylcarbamate (100 mg, 0.21 mmol) in ethane- 1,2-diamine (1 mL) was put in a sealed tube and stirred at 100 °C for 2 h. The reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate (50 mL), washed with water. The separated organic layer was dried over sodium sulfate, filtered and concentrated.
  • Step A The compound ⁇ l-[4-(2-Chloro-8-pyridin-2-yl-purin-9-yl)-phenyl]- cyclobutyl ⁇ - carbamic acid tert-butyl ester (200 mg, 0.42 mmol), pyrrolidin-3-ol (103 mg, 0.84 mmol) and K 2 C0 3 (176 mg, 0.84 mmol) were dissolved in l-methyl-pyrrolidin-2-one (10 mL). The reaction mixture was stirred at 120 °C under nitrogen atmosphere overnight. The mixture was diluted with ethyl acetate (50 mL) and washed with brine (20 mL).
  • Step B (l- ⁇ 4-[2-(3-Hydroxy-pyrrolidin-l-yl)-8-pyridin-2-yl-purin-9-yl]-phenyl ⁇ - cyclobutyl)-carbamic acid tert-butyl ester was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and the solution of HC1 in ethyl acetate (4M, 10 mL) was added slowly. The resulting solution was stirred for 2 hrs.
  • Step A The compound ⁇ l-[4-(2-Chloro-8-pyridin-2-yl-purin-9-yl)-phenyl]- cyclobutyl ⁇ -carbamic acid tert-butyl ester (150 mg, 0.315 mmol), Methanesulfonamide (60 mg, 0.63 mmol), Pd 2 (dba) 3 (29 mg, 0.032 mmol), Xantphos (18 mg, 0.032 mmol) and Cs 2 C0 3 (308 mg, 0.945 mmol) were dissolved in dioxane (10 mL). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for overnight. LC-MS indicated the reaction worked well.
  • Step B ⁇ l-[4-(2-Methanesulfonylamino-8-pyridin-2-yl-purin-9-yl)-phenyl]- cyclobutyl ⁇ -carbamic acid tert-butyl ester (107 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and the solution of HC1 in ethyl acetate (4M, 10 mL) was added slowly. The resulting solution was stirred for 2 hrs.
  • Step C To a solution of tert-butyl l-(4-(5-amino-6- chloropyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (200mg, 0.5mmol) in HOAc (20 mL) was added Cu(OAc) 2 46.7mg, 0.26mmol and benzaldehyde (109mg, lmmol). The reaction mixture was stirred at 80°C for lh.
  • Step D The solution of tert-butyl l-(4-(6-chloro-8-phenyl-9H-purin-9-yl) phenyl)cyclobutylcarbamate (40mg, 0.08mmol) in HC1 (2 mL, 10% wt) was stirred at 80 °C for lh. The reaction solution was concentrated to give title compound 9-(4-(l-aminocyclobutyl)phenyl)-8- phenyl-lH-purin-6(9H)-one (30mg) as HC1 salt.
  • Example 66 shown in Table 9 can also be made according to the above-described methods.
  • Step A To the solution of 4, 6-Dichloro-5-nitro-pyrimidine (1 g, 5.2 mmol) in THF
  • Step B To a solution of ⁇ l-[4-(6-Chloro-5-nitro-pyrimidin-4-ylamino)- phenyl]- cyclobutyl ⁇ -carbamic acid tert-butyl ester (2 g, 4.77 mmol) and dimethyl-amine (0.77 g, 9.54 mmol) in THF (50 mL) was added DIPEA (3.1 g, 23.9 mmol). The mixture was stirred 20 °C for 2 h. LC-MS showed the starting material was consumed completely. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with brine (2 X 20 mL).
  • Step C The compound ⁇ l-[4-(6-Dimethylamino-5-nitro-pyrimidin-4-ylamino)- phenyl]-cyclobutyl ⁇ -carbamic acid tert-butyl ester (2.0 g, 4.67 mmol) was dissolved in THF (60 mL) and Raney- Ni (2.00 g) was carefully added. The reaction mixture was stirred at ambient temperature under the atmosphere of H 2 (balloon) for 1 h..
  • Step D The ⁇ l-[4-(5-Amino-6-dimethylamino-pyrimidin-4-ylamino)-phenyl]- cyclo-butyl ⁇ -carbamic acid tert-butyl ester (500 mg, 1.29 mmol) was dissolved in acetic acid (20 mL), and benzaldehyde (204 mg, 1.93 mmol) and Cu(OAc) 2 (233 mg, 1.29 mmol) were added separately. The reaction mixture was heated at 80°C for 2 hrs.
  • Step E ⁇ l-[4-(6-Dimethylamino-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl ⁇ - carbamic acid tert-butyl ester (300 mg, 0.62 mmol) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0°C and the solution of HC1 in ethyl acetate (10 mL, 4M) was slowly added. The resulting mixture was stirred for 2 hrs.
  • Step A To a solution of 4,6-dichloro-5-nitropyrimidine (2.00 g, 10.3 mmol) in THF
  • Step B The tert-butyl l-(4-(6-chloro-5-nitropyrimidin-4-ylamino)phenyl)- cyclobutylcarbamate (1.5 g, 3.58 mmol) was dissolved in THF (50 mL) and Raney- Ni (1.50 g) was carefully added. The reaction mixture was stirred at 20°C under the atmosphere of H 2 (balloon) for 1 h.. After filtration ciliate pad, the filtrate was concentrated to give tert-butyl l-(4-(5-amino-6- chloropyrimidin-4-ylamino)phenyl)cyclobutylcarbamate. (1.3 g ,93% yield:). MS (ESI + ): 412.1 [M+Na] + , 414.1 [M+Na+2] +
  • Step C The tert-butyl l-(4-(5-amino-6-chloropyrimidin-4-ylamino)phenyl)- cyclobutylcarbamate (200 mg, 0.573 mmol), l-Methylpyrazole-4-boronic acid pinacol ester (143 mg, 0.688 mmol), Pd(dppf)Cl 2 (40 mg, 0.057 mmol), and Cs 2 C0 3 (560 mg, 1.72 mmol) were dissolved in a mixed solution (dioxane: 10 mL, water: 2 mL). The reaction mixture was charged with nitrogen thrice and heated at 80°C for 2 h.
  • Step D The compound tert-butyl l-(4-(5-amino-6-(l -methyl- lH-pyrazol-4- yl)pyrimidin-4-ylamino)phenyl)cyclobutylcarbamate (100 mg, 0.23 mmol) was dissolved in acetic acid (10 mL), benzaldehyde (36 mg, 0.34 mmol) and Cu(OAc) 2 (42 mg, 0.23 mmol) were added separately. The reaction mixture was heated at 80°C for 2 h.
  • Step E The tert-butyl 1 -(4-(6-( 1 -methyl- 1 H-pyrazol-4-yl)-8-phenyl-9H-purin-9- yl)phenyl)cyclobutylcarbamate (115 mg, 0.22 mmol) was dissolved in ethyl acetate (20 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (10 mL, 4M) was slowly added. The resulting solution was stirred for 2 h.
  • Step A To the solution of 2,4-Dichloro-6-methyl-5-nitro-pyrimidine (2.08 g, lO.OOmmol) in THF (50 mL) at -78 °C was slowly added the solution of [l-(4-Amino-phenyl)- cyclobutyl]-carbamic acid tert-butyl ester (2.62 g, 10.00 mmol) in THF (20 mL). The reaction mixture was stirred at ambient temperature for 30 min.. Then it was concentrated to remove the solvent. The obtained residue was dissolved in ethyl acetate (250 mL) and washed by saturated. NaHC0 3 solution, followed by brine.
  • Step B ⁇ l-[4-(2-Chloro-6-methyl-5-nitro-pyrimidin-4- ylamino)-phenyl]- cyclobutyl ⁇ -carbamic acid tert-butyl ester (4.3 g, 9.78 mmol) was dissolved in MeOH (100 mL) and Pd/C (1.00 g) was added. The reaction mixture was stirred at ambient temperature under an atmosphere of hydrogen (balloon) for 12 h.. Then the solvent was removed by concentration, and the residue was dissolved in ethyl acetate (200 mL).
  • Step C The ⁇ l-[4-(5-Amino-6-methyl-pyrimidin-4-ylamino)-phenyl]- cyclobutyl ⁇ - carbamic acid tert-butyl ester (2.0 g, 5.4 mmol) was dissolved in acetic acid (20 mL), and benzaldehyde (0.74 g, 7 mmol) and Cu(OAc) 2 (1.0 g, 5.4 mmol) were added separately. The reaction mixture was heated at 80 °C for 2 h.
  • Step D ⁇ l-[4-(6-Methyl-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl ⁇ - carbamic acid tert-butyl ester ( 0.3 g ) was dissolved in MeOH (30 mL), then added HC1 (aq) (4M, 8 mL) in drops. The mixture was heated to 80 °C, and stirred for 50 min. The product was purified by preparative HPLC to give (160 mg).
  • Step A To a suspension of 2,4,6-trichloro-5-nitropyrimidine (0.8g, 3.5mmol) in
  • Step B To a solution of tert-butyl l-(4-(2,6-dichloro-5-nitropyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (0.45 g, 1 mmol) in THF (20ml) was added MeONa (53 mg, 1 mmol) in MeOH(l mL). The mixture was stirred at 55 °C for 30mins. The reaction mixture was purified by preparative TLC to tert-butyl l-(4-(2-chloro-6-methoxy-5-nitropyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (120 mg, 26.6% yield). LC/MS: (ESI + ) e/z: 472 [M+Na] + , 474 [M+Na+2] +
  • Step C To a solution of tert-butyl l-(4-(2-chloro-6-methoxy-5-nitropyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (100 mg, 0.222 mmol) in THF (10 mL) was added Raney Ni (50 mg) under nitrogen. The suspension was degassed under vacuum and purged with H 2 (balloon). The reaction mixture was stirred at RT for 10 mins.
  • Step D To a solution of tert-butyl l-(4-(5-amino-2-chloro-6-methoxypyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (84 mg, 0.2 mmol) in AcOH(5 mL), Benzaldehyde(42.45 mg, 0.4 mmol) and Cu(OAc)2(18.2 mg, 0.1 mmol) was added. The reaction mixture was stirred at 70C for 30 mins.
  • Step E To a solution of tert-butyl l-(4-(2-chloro-6-methoxy-8-phenyl-9H-purin-9- yl)phenyl)cyclobutylcarbamate(15 mg, 0.03 mmol) in a mixture of Dioxane(5 mL) and H 2 O(0.5 mL), Pd(PPh 3 ) 4 (3 mg,0.0026 mmol), phenylboronic acid (54.87 mg,0.45 mmol) and Cs 2 C0 3 (29.3 mg, 0.09 mmol) was added. The reaction mixture was stirred under nitrogen at 80 °C for lh.
  • Step F A solution of tert-butyl l-(4-(6-methoxy-2,8-diphenyl-9H-purin-9- yl)phenyl)cyclobutylcarbamate (10 mg) in HCl (5 mL, conc.).was stirred at 80 °C for 30 mins. The mixture was purified by preparative TLC to give 9-(4-(l-aminocyclobutyl)phenyl)-2,8-diphenyl- lH-purin-6(9H)-one (3 mg).
  • Step A To a solution of 2-chloro-6-methyl-3-nitropyridine (600 mg, 3.5 mmol) and tert-butyl l-(4-aminophenyl)-cyclobutylcarbamate in THF (20 mL) was added DIPEA (900 mg, 7 mmol). The reaction mixture was stirred at 70°C for 5 h.
  • Step B The tert-butyl l-(4-(6-methyl-3-nitropyridin-2-ylamino)phenyl)- cyclobutylcarbamate (550 mg, 1.38 mmol) was dissolved in THF (50 mL) and Raney- Ni (1.00 g) was added. The reaction mixture was stirred at ambient temperature under an atmosphere of hydrogen (balloon) for 1 h. The suspension was filtered through a pad of Celite and the pad was withed with THF (20 mL).
  • Step C The tert-butyl l-(4-(3-amino-6-methylpyridin-2-ylamino)phenyl)- cyclobutylcarbamate (300 mg, 0.81 mmol) was dissolved in acetic acid (50 mL), and benzaldehyde (129 mg, 1.22 mmol) and Cu(OAc) 2 (76 mg, 0.42 mmol) were added separately. The reaction mixture was stirred at 100 °C for 2 h. Then the solvent was removed by concentration, and the residue was dissolved in ethyl acetate (50 mL). The organic layer was washed by saturated.
  • Step D The tert-butyl l-(4-(5-methyl-2-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)cyclobutylcarbamate (238 mg, 0.52 mmol) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0°C and the solution of HC1 in ethyl acetate (10 mL, 4M) was slowly added. The resulting solution was stirred at 20 °C for 20 min.
  • Step A A mixture of 5-bromo-2-chloro-3-nitropyridine (1 g, 4 mmol) and tert- butyl l-(4-aminophenyl)cyclobutylcarbamate (1.04 g, 4 mmol) in dioxane (30 mL) was added TEA (2ml) in one portion. Then the reaction mixture was warmed to 70 °C and stirred overnight.
  • Step B tert-butyl l-(4-(5-bromo-3-nitropyridin-2-ylamino)phenyl)cycIobutyl carbamate (1 g, 2 mmol) was dissolved in THF (50mL) and treated with the catalytical amount of Raney Ni(0.2 g), then the mixture was stirred under hydrogen (balloon) at room temperature for 30 minutes.
  • Step C benzaldehyde (0. 6 g, 1.3 mmol) and Cu(OAc) 2 (158 mg, 0.13 mmol) was added to a solution of tert-butyl l-(4-(3-amino-5-bromopyridin-2- ylamino)phenyl)cyclobutylcarbamate (1 g, 2.87 mmol) in glacial acetic acid (20 mL). The reaction mixture was stirred at 70 °C for lh. then the mixture was diluted with water and basified with saturate sodium bicarbonate and then extracted with ethyl acetate for three times.
  • Step D To a solution of tert-butyl l-(4-(6-bromo-2-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)cyclobutylcarbamate (0.3 g, 0.5 mmol) in EtOAc was added the solution of HC1 in EtOAc (4 mol/L , 10 ml) at 0 °C dropwise. The reaction mixture was stirred at room temperature for 1 h.
  • Step A A mixture of l-(4-(6-bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)cyclobutanamine (0.8 mmol), 2-fluorophenyl boronic acid (0.96 mmol), Cs 2 C0 3 (521 mg, 2.4 mmol) and Pd(dppf)Cl 2 (116 mg, 0.16 mmol) in dioxane and H 2 0 (10 ml, 5:1) was stirred at 80 °C for 2 hours under nitrogen atmosphere.
  • Step A A solution of tert-butyl l-(4-(6-bromo-2-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)cyclobutylcarbamate (80 mg) in MeOH (10 mL) was stirred under hydrogen (balloon) atmosphere in presence of Raney Ni (100 mg) at room temperature for 10 min. The reaction mixture was filtered through celite pad and the filtrate was concentrated to give 60 mg of crude desired compound tert-butyl l-(4-(2-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)cyclobutylcarbamate, which was used directly without further purification.
  • Step B To a solution of t tert-butyl l-(4-(2-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyI)cyclobutylcarbamate (60 mg crude) in EtOAc was added the solution of HCl in EtOAc (4 mol/L , 10 ml) at 0 °C dropwise. The reaction mixture was stirred at room temperature for 1 h.
  • Step A 2,3-Dichloro-pyrazine (14.8 g, 0.1 mol) was added in a 100 mL autoclave which contained 50 mL of the solution of N3 ⁇ 4 aqueous with stirring, and then the reaction mixture was warmed to 100°C and stirred overnight, Cooled to room temperature. Filtrated, the solid was washed with water and further with dichloromethane to afford a solid, which dried on vacuum to afford 3-Chloro-pyrazin-2-ylamine. (10 g, 80% yield).
  • Step B The solution of dimethyl sulfoxide (4 g, 0.05 mmol) in 30mL of dry dichloromethane was cooled to -78°C, then (13 g, 0.046 mmol) trifluoromethanesulfonic anhydride was added dropwise under nitrogen with stirring.

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Abstract

The present invention provides compounds, including resolved enantiomers, resolved diastereomers, solvates and pharmaceutically acceptable salts thereof, comprising the Formula 1: wherein Het, X, R1 and R2 are as defined herein.

Description

BICYCLIC HETEROARYL DERIVATIVES AS KINASE INHIBITORS
BACKGROUND OF THE INVENTION
Field of the Invention
[0001] This invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular as 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 example, for the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals.
Description of the State of the Art
[0002] Protein kinases (PK) are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins by transfer of the terminal (gamma) phosphate from ATP. Through signal transduction pathways, these enzymes modulate cell growth, differentiation and proliferation, i.e., virtually all aspects of cell life in one way or another depend on PK activity (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book. I and II, Academic Press, San Diego, CA). Furthermore, abnormal PK activity has been related to a host of disorders, ranging from relatively non-life threatening diseases, such as psoriasis, to extremely virulent diseases, such as glioblastoma (brain cancer). Protein kinases are an important target class for therapeutic modulation (Cohen, P. (2002) Nature Rev. Drug Discovery 1 :309).
[0003] Significantly, 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 Akt, VEGF, ILK, ROCK, p70S6K, Bel, PKA, PKC, Raf, Src, PDK1, ErbB2, MEK, IKK, Cdk, EGFR, BAD, CHKl, CHK2 and GSK3 amongst numerous others, has been specifically implicated in cancer.
[0004] Protein kinases include two classes; protein tyrosine kinases (PTK) and serine- threonine kinases (STK). The Protein Kinase B/Akt enzymes are a group of serine/threonine kinases that are overexpressed in a variety of human tumors. One of the best-characterized targets of the PI3K lipid products is the 57 KD serine/threonine protein kinase Akt, downstream of PI3K in the signal transduction pathway (Hemmings, B.A. (1997) Science 275:628; Hay N. (2005) Cancer Cell 8:179-183). Akt is the human homologue of the protooncogene v-akt of the acutely transforming retrovirus AKT8. Due to its high sequence homology to protein kinases A and C, Akt is also called Protein Kinase B (PKB) and Related to A and C (RAC). Three isoforms of Akt are known to exist, namely Aktl, Akt2 and Akt3, which exhibit an overall homology of 80% (Staal, S.P. (1987) Proc. Natl. Acad. Sci. 84:5034; Nakatani, K. (1999) Biochem. Biophys. Res. Commun. 257:906; Li et al (2002) Current Topics in Med. Chem. 2:939-971 ; WO 2005/1 13762). The Akt isoforms share a common domain organization that consists of a pleckstrin homology domain at the N-terminus, a kinase catalytic domain, and a short regulatory region at the C-terminus. In addition, both Akt2 and Akt3 exhibit splice variants. Upon recruitment to the cell membrane by PtdInd(3,4,5)P3, Akt is phosphorylated (activated) by PDK1 at T308, T309 and T305 for isoforms Aktl (PKBa), Akt2 (ΡΚΒβ) and Akt3 (ΡΚΒγ), respectively, and at S473, S474 and S472 for isoforms Aktl, Akt2 and Akt3, respectively. Such phosphorylation occurs by an as yet unknown kinase (putatively named PDK2), although PDK1 (Balendran, A., (1999) Curr. Biol. 9:393), autophosphorylation (Toker, A. (2000) J. Biol. Chem. 275:8271) and integrin-linked kinase (ILK) (Delcommenne, M. (1998) Proc. Natl. Acad. Sci. USA, 95:11211) have been implicated in this process. Akt activation requires its phosphorylation on residue Ser 473 in the C-terminal hydrophobic motif (Brodbeck et al (1999) J. Biol. Chem. 274:9133-9136; Coffer et al (1991) Eur. J. Biochem. 201 :475-481; Alessi et al (1997) Curr. Biol. 7:261-269). Although monophosphorylation of Akt activates the kinase, bis(phosphorylation) is required for maximal kinase activity.
[0005] Akt is believed to assert its effect on cancer by suppressing apoptosis and enhancing both angiogenesis and proliferation (Toker et al. (2006) Cancer Res. 66(8):3963-3966). Akt is overexpressed in many forms of human cancer including, but not limited to, colon (Zinda et al (2001) Clin. Cancer Res. 7:2475), ovarian (Cheng et al (1992) Proc. Natl. Acad. Sci. USA 89:9267), brain (Haas Kogan et al (1998) Curr. Biol. 8:1195), lung (Brognard et al (2001) Cancer Res. 61 :3986), pancreatic (Bellacosa et al (1995) Int. J. Cancer 64:280-285; Cheng et al (1996) Proc. Natl. Acad. Sci. 93:3636-3641), prostate (Graff et al (2000) J. Biol. Chem. 275:24500) and gastric carcinomas (Staal et al (1987) Proc. Natl. Acad. Sci. USA 84:5034-5037).
[0006] The PI3K/Akt/mammalian target of rapamycin (mTOR) pathway has been explored for targeted small molecule inhibitor therapy (Georgakis, G. and Younes, A. (2006) Expert Rev. Anticancer Ther. 6(1): 131-140; Granville et al (2006) Clin. Cancer Res. 12(3):679-689). Inhibition of PI3K/Akt signaling induces apoptosis and inhibits the growth of tumor cells that have elevated Akt levels (Kim et al (2005) Current Opinion in Investig. Drugs 6(12): 1250- 1258; Luo et al (2005) Molecular Cancer Ther. 4(6):977-986).
[0007] The development of 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 could be a valuable anticancer agent, either as a stand-alone therapy or in conjunction with other accepted procedures.
SUMMARY OF THE INVENTION
[0008] This invention provides novel compounds that inhibit AKT protein kinases. 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.
[0009] More specifically, the present invention includes compounds having the general
Formula 1 :
Figure imgf000004_0001
and tautomers, resolved enantiomers, resolved diastereomers, solvates, metabolites, salts and
1 2
pharmaceutically acceptable prodrugs thereof, wherein Het, X, R and R are as defined herein.
[0010] The invention also provides pharmaceutical compositions comprising a compound of Formula 1, or an enantiomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof.
[0011] In a further aspect, the present invention provides a method of treating diseases or medical conditions in a mammal mediated by AKT protein kinases, comprising administering to said mammal one or more compounds of Formula 1 , or an enantiomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, in an amount effective to treat or prevent said disorder. AKT protein kinase mediated conditions that can be treated according to the methods of this invention include, but are not limited to, inflammatory, hyperproliferative, cardiovascular, neurodegenerative, gynecological, and dermatological diseases and disorders.
[0012] In a further aspect, the present invention provides a method of inhibiting the production of AKT protein kinases in a mammal, which comprises administering to said mammal a compound of Formula 1, or an enantiomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof in an amount effective to inhibit production of an AKT protein kinase.
[0013] In a further aspect, the present invention provides methods of inhibiting the activity of AKT protein kinases, comprising contacting said kinase with a compound of Formula 1.
[0014] The inventive compounds may be used advantageously in combination with other known therapeutic agents. Accordingly, this invention also provides pharmaceutical compositions comprising a compound of Formula 1 or an enantiomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, in combination with a second therapeutic agent.
[0015] This invention also provides compounds of Formula 1 and enantiomers, solvates, metabolites, and pharmaceutically acceptable salts and prodrugs thereof for use as medicaments in the treatment of AKT protein kinase-mediated conditions.
[0016] An additional aspect of the invention is the use of a compound of Formula 1, or an enantiomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, for therapy. In one embodiment, the therapy comprises the treatment of an AKT protein kinase-mediated condition.
[0017] This invention further provides kits for the treatment of an AKT protein kinase- mediated disease or disorder, said kit comprising a compound of Formula 1, or an enantiomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, a container, and optionally a package insert or label indicating a treatment. The kits may further comprise a second compound or formulation comprising a second pharmaceutical agent useful for treating said disease or disorder.
[0018] This invention further includes methods of preparing, methods of separating, and methods of purifying of the compounds of this invention.
[0019] Additional advantages and novel features of this invention shall be set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following specification, or may be learned by the practice of the invention. The advantages of the invention may be realized and attained by means of the instrumentalities, combinations, compositions, and methods particularly pointed out in the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
[0020] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. DEFINITIONS
[0021] The term "alkyl" as used herein 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. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (n- Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, - CH2CH2CH2CH3), 2-methyl-l -propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, - CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, - CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2- butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l -butyl (-CH2CH2 CH(CH3)2), 2-methyl-l -butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2- hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (- C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3),4-methyl-2-pentyl (- CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2),2-methyl-3-pentyl (- CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2),3,3-dimethyl-2-butyl (- CH(CH3)C(CH3)3, 1-heptyl, 1-octyl, and the like.
[0022] The term "alkylene" or "alkylenyl" as used herein refers to a linear or branched saturated divalent hydrocarbon radical of one to twelve carbon atoms, wherein the alkylene radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
[0023] The terms "cycloalkyl," "carbocycle," "carbocyclyl" and "carbocyclic ring" as used herein are used interchangeably and refer to saturated or partially unsaturated cyclic hydrocarbon radical having from three to twelve carbon atoms. The term "cycloalkyl" includes monocyclic and polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, wherein the polycyclic structures optionally include a saturated or partially unsaturated cycloalkyl ring fused to a saturated, partially unsaturated or aromatic cycloalkyl or heterocyclic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Bicyclic carbocycles include those having 7 to 12 ring atoms arranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or as bridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. The cycloalkyl may be optionally substituted independently with one or more substituents described herein.
[0024] "Aryl" as used herein means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Exemplary aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, indene, indane, 1 ,2-dihydronapthalene, 1,2,3,4-tetrahydronapthalene, and the like. Aryl groups may be optionally substituted independently with one or more substituents described herein.
[0025] The terms "heterocycle", "hetercyclyl", "heterocycloalkyl" and "heterocyclic ring" as used herein are used interchangeably and refer to a saturated or partially unsaturated carbocyclic radical of 3 to 8 ring atoms in which at least one ring atom is a heteroatom independently 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 substituents described below. The radical may be a carbon radical or heteroatom radical. The term "heterocycle" includes heterocycloalkoxy. "Heterocyclyl" also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated, or aromatic carbocyclic or heterocyclic ring. Examples of heterocyclic 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, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.OJhexanyl, 3-azabicyclo[4.1.Ojheptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl quinolizinyl and N-pyridyl ureas. Spiro moieties are also included within the scope of this definition. The heterocycle may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-l-yl (N-attached) or imidazol-3-yl (C- attached). Examples of heterocyclic groups wherein 2 ring carbon atoms are substituted with oxo (=0) moieties are isoindoline-l,3-dionyl and 1,1-dioxo-thiomorpholinyl. The heterocycle groups herein are optionally substituted independently with one or more substituents described herein. Non limiting examples of 5 to 6 membered heterocycloalkyl groups containing one, two or three heteroatoms selected from the group consisting of N, S and O can be selected from the group consisting of optionally substituted pyrrolidinyl, piperazinyl, pyrrolidinyl-2-one, thiomorpholine and 1,1 dioxide.
[0026] The term "heteroaryl" as used herein refers to a monovalent aromatic radical of a 5-,
6-, or 7-membered ring and includes fused ring systems (at least one of which is aromatic) of 5-10 atoms containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, 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, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiro moieties are also included within the scope of this definition. Heteroaryl groups may be optionally substituted independently with one or more substituents described herein. 5 or 6 membered heteroaryl can be selected from the group consisting of optionally substituted pyridinyl, pyrimidinyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinone and benzimidazolyl.
[0027] By way of example and not limitation, carbon bonded heterocycles and heteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Further examples of carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5- pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
[0028] By way of example and not limitation, nitrogen bonded heterocycles and heteroaryls are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3- pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2- pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of an isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1 -pyrrolyl, 1- imidazolyl, 1 -pyrazolyl, and 1-piperidinyl.
[0029] The term "halogen" or "halo" as used herein means fluoro, chloro, bromo or iodo.
[0030] The term "haloalkoxyl" as used herein refers to an alkoxyl group as defined herein that is substituted by 1, 2, 3, 4, 5 or 6 halogen as defined herein. Examples of haloalkoxyl groups include, but are not limited to Ci-C6-haloalkoxyl groups, including trifluoromethoxyl and trifluoroethoxyl. [0031] The term "haloalkyl" as used herein refers to an alkyl group as defined herein that is substituted by 1 , 2, 3, 4, 5 or 6 halogen as defined herein. Examples of haloalkyl groups include, but are not limited to Ci-C6-haloalkyl groups, including trifluoromethyl and trifluoroethyl.
[0032] The term "hydroxyalkyl" as used herein refers to an alkyl group as defined herein that is substituted by 1, 2, 3, 4, 5 or 6 hydroxyl as defined herein. Examples of hydroxyalkyl groups include, but are not limited to CrC6-hydroxyalkyl groups, including hydroxymethyl and hydroxyethyl.
[0033] The term "alkylsulfonamide" as used herein refers to a group of the following formula: -NR'R"S(0)2-alkyl., wherein alkyl is as defined herein and R' and R" are as defined herein. A non limiting example of alkylsulfonamide group is methanesulfonyl.
[0034] The term "hydroxyl" as used herein refers to an alcohol group, -OH.
[0035] The term "alkoxyl" as used herein refers to an -O-alkyl group, wherein alkyl is as defined herein. Examples of alkoxyl groups include, but are not limited to Ci-C6-alkoxyl, including methoxy and ethoxy.
[0036] The term "oxo" refers to refers to a double-bonded oxygen (i.e., =0).
[0037] The term "a" as used herein means one or more.
[0038] As used herein, the terms "compound of this invention," "compounds of the present invention" and "compounds of Formula 1" includes compounds of Formula 1 and tautomers, resolved enantiomers, resolved diastereomers, racemic mixtures, solvates, metabolites, salts (including pharmaceutically acceptable salts) and pharmaceutically acceptable prodrugs thereof.
[0039] The compounds of Formula 1 include solvates, pharmaceutically acceptable prodrugs and salts (including pharmaceutically acceptable salts) of such compounds.
[0040] The phrase "pharmaceutically acceptable" indicates that the substance or composition is compatible chemically and/or toxicologically with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
[0041] A "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" can also be used to refer to a complex wherein the solvent molecule is water.
[0042] A "prodrug" is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a 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 a compound 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 phosphoserine, phosphothreonine, phosphotyrosine, 4- hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.
[0043] Additional types of prodrugs are also encompassed. For instance, a free carboxyl group of a compound of Formula 1 can be derivatized as an amide or alkyl ester. As another example, compounds of this invention comprising free hydroxy groups may be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, 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. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem., 1996, 39, 10. More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (Ci-C6)alkanoyloxymethyl, l-((Ci-C6)alkanoyloxy)ethyl, 1- methyl-l-((Ci-C6)alkanoyloxy)ethyl, (Ci-C6)alkoxycarbonyloxymethyl, N-(C C6)alkoxy- carbonylaminomethyl, succinoyl, (Ci-C6)alkanoyl, a-amino(Ci-C4)alkanoyl, arylacyl and a- aminoacyl, or α-aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH)2, -P(0)(0(Ci-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
[0044] Free amines of compounds of Formula 1 can also be derivatized as amides, sulfonamides or phosphonamides. All of these moieties may incorporate groups including, but not limited to, ether, amine and carboxylic acid functionalities. For example, 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, wherein R and R' are each independently (Ci-Cio)alkyl, (C3- C7)cycloalkyl, or benzyl, or R-carbonyl is a natural a-aminoacyl or natural oc-aminoacyl-natural a- aminoacyl, -C(OH)C(0)OY wherein Y is H, (d-C6)alkyl or benzyl, -C(OY0)Y! wherein Y0 is (C C4) alkyl and Yi is (Ci-C6)alkyl, carboxy(Ci-C6)alkyl, amino(Ci-C4)alkyl or mono-N- or di-N,N- (Ci-C6)alkylaminoalkyl, or -C(Y2)Y3 wherein Y2 is H or methyl and Y3 is mono-N- or di-N,N-(Cr C6)alkylamino, moφholino, piperidin-l-yl or pyrrolidin-l-yl.
[0045] For additional examples of prodrug derivatives, see, for example, a) Design of
Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309- 396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs," by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each of which is specifically incorporated herein by reference.
[0046] Alternatively or additionally, compound of the invention may possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and accordingly react with any of a number of inorganic or organic bases or acids to form a salt. Examples of 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, but not limited to, 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-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates, methanesulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, and mandelates. Since a single compound of the present invention may include more than one acidic or basic moiety, the compounds of the present invention may include mono, di or tri-salts in a single compound.
[0047] If the inventive compound is a base, the desired salt may be prepared by any suitable method available in the art, for example, by treatment of the free base with an acidic compound, for example, 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 alpha hydroxy 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.
[0048] If the inventive compound is an acid, the desired salt may be prepared by any suitable method, for example, by treatment of the free acid with an inorganic or organic base. Examples of suitable inorganic salts include those formed with alkali and alkaline earth metals, such as lithium, sodium, potassium, barium and calcium. Examples of suitable organic base salts include, for example, ammonium, dibenzylammonium, benzylammonium, 2- hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine, dibenzylethylenediamine, and the like salts. Other salts of acidic moieties may include, for example, those salts formed with procaine, quinine and N-methylglucosamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine.
[0049] In certain embodiments, the salt is a "pharmaceutically acceptable salt" which, unless otherwise indicated, includes salts that retain the biological effectiveness of the corresponding free acid or base of the specified compound and are not biologically or otherwise undesirable.
[0050] The compounds of Formula 1 also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula 1 and/or for separating enantiomers of compounds of Formula 1.
[0051] The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen,
2 3 1 1 13 carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as H, H, C, C, ,4C, 13N, 15N, 150, I70, , 80, 32P, 33P, 35S, , 8F, 36C1, 123I and 125I. Certain isotopically-labeled compounds of the present invention (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon- 14 (i.e., 14C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as 15 O, 13 N, 11 C and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
[0052] The phrase "effective amount" means an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to (i) treat or prevent a particular disease, condition, or disorder mediated by the activity of one or more AKT protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or dual specificity kinases, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, an effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and/or determining the response rate (RR).
[0053] The amount of a compound of Formula 1 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.
[0054] "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. The terms "treat" and "treatment" refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those found to be predisposed to having the disease condition but have not yet been diagnosed as having it; modulating and/or inhibiting the disease condition. The terms "treating", "treat", or "treatment" embrace both preventative, i.e., prophylactic, and palliative treatment.
[0055] As used herein, the term "mammal" refers to a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
[0056] It is to be understood that in instances where two or more radicals are used in succession to define a substituent attached to a structure, the first named radical is considered to be terminal and the last named radical is considered to be attached to the structure in question. Thus, for example, an arylalkyl radical is attached to the structure in question by the alkyl group.
AKT INHIBITORS
[0057] The inventive compounds of Formula 1 are useful for inhibiting AKT protein kinases. 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.
[0058] The compounds of Formula 1 may also be useful as inhibitors of tyrosine kinases as well as serine and threonine kinases in addition to AKT.
[0059] In general, one aspect of the invention includes compounds of the Formula 1 :
Figure imgf000014_0001
(1)
and tautomers, resolved enantiomers, resolved diastereomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs thereof, wherein:
X is N or CR3;
Het is a roup selected from the grou consisting of:
Figure imgf000014_0002
(A) (B) (C)
Figure imgf000015_0001
(J)
is O, 1, 2, 3 or 4;
least one ofR 1', R2", and R 3J is a group of formula (L):
Figure imgf000015_0002
(L)
wherein:
n is 0, 1 or 2;
R' and R' are independently selected from the group consisting of H, Ci-C6-alkyl and
(C=0)-Ci-C6-alkyl;
R"' is H, OH or C,-C6-alkyl; and the rest of R1, R2, and R3 are independently selected from the group consisting of: H, cyano, Ci- C6-alkyl, aryl or heteroaryl, which aryl or heteroaryl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, cyano, oxo, C]-C6-alkyl, Ci-C6-alkoxyl and C i -C6-hydroxyalkyl;
R4 is selected from the group consisting of: H, halo, cyano, hydroxyl, oxo, Ci-C6-alkyl, Ci-C6- alkoxyl, COOH, C,-C6-alkylsulfonamide, NRaRb, NRa(C=0)Ra, (C=0)NRaRb, (C=0)NRa- CrC6-alkylenyl-NRaRb, NRa-C C6-alkylenyl-COOH, NRa-Ci-C6-alkylenyl-NReRb, aryl, heteroaryl or heterocycloalkyl, which aryl heteroaryl or heterocycloalkyl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, oxo, hydroxyl, Ci-Ce-alkyl, C C6-alkoxyl, Ci-C6-haloalkyl, CrC6-haloalkoxyl, COOH, C C6- hydroxyalkyl and CrCe-alkylsulfonamide; and
Ra and Rb are independently selected from the group consisting of H, Ci-C6-alkyl, Ci-
C6-hydroxylalkyl or C3-C6-cycloalkyl.
[0060] In an embodiment, the compounds of formula 1 and tautomers, resolved enantiomers, resolved diastereomers and pharmaceutically acceptable salts thereof is provided.
[0061] In an embodiment, the compounds of formula 1, are those wherein R1 is a group of formula (L):
Figure imgf000016_0001
and the remaining substituents are as defined herein.
[0062] In another embodiment, the compounds of formula 1, are those wherein R' and R" are H, n is 0 and the remaining substituents are as defined herein.
[0063] In another embodiment, the compounds of formula 1, are those wherein R2 is a group of formula (L):
Figure imgf000017_0001
and the remaining substituents are as defined herein.
[0064] In another embodiment, the compounds of formula 1 are those wherein R4 is selected from the group consisting of: halo, , aryl, 5 or 6 membered heteroaryl or heterocycloalkyl, which, aryl, heteroaryl or heterocycloalkyl is unsubstituted or substituted by at least one halo and the remaining substituents are as defined herein.
[0065] In another embodiment, the compounds of formula 1 are those wherein R4 is aryl, 5 to 10 membered heterocycloalkyl containing one, two or three heteroatoms selected from the group consisting of N, S and O or 5 to 10 membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of N, S and O, which aryl heteroaryl or heterocycloalkyl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, oxo, hydroxyl, C C6-alkyl, C C6-alkoxyl, C C6-haloalkyl, Ci-C6-haloalkoxyl, COOH, C C6- hydroxyalkyl and C]-C6-alkylsulfonamide.
[0066] In another embodiment, the compounds of formula 1 are those wherein R4 is aryl, 5 to 6 membered heterocycloalkyl containing one, two or three heteroatoms selected from the group consisting of N, S and O or 5 to 6 membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of N, S and O, which aryl heteroaryl or heterocycloalkyl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, oxo, hydroxyl, C C6-alkyl, C C6-alkoxyl, CrC6-haloalkyl, CrC6-haloalkoxyl, COOH, C C6- hydroxyalkyl and CrCe-alkylsulfonamide.
[0067] In another embodiment, the compounds of formula 1 are those wherein X is N and the remaining substituents are as defined herein.
[0068] In another embodiment, the compounds of formula 1 are those wherein X is CR3 and the remaining substituents are as defined herein.
[0069] In another embodiment, the compounds of formula 1 are those wherein R3 is H or
Ci-C6-alkyl and the remaining substituents are as defined herein.
[0070] In another embodiment, the compounds of formula 1 are those wherein R1 is phenyl and the remaining substituents are as defined herein. [0071] In another emboidment, R is selected from cyano, Ci-C6-alkyl, aryl or 5 or 6 membered heteroaryl, which aryl or heteroaryl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, cyano, Ci-Ce-alkyl, Ci-C6-alkoxyl and C\- C6-hydroxyalkyl; or is a group of formula (L):
Figure imgf000018_0001
[0072] In another emboidment, R1 is selected from cyano, Ci-Ce-alkyl, aryl or 5 or 6 membered heteroaryl, which aryl or heteroaryl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, cyano, Ci-C6-alkyl and Ci-C6-alkoxyl; or is a group of formula (L):
Figure imgf000018_0002
[0073] In another emboidment, R1 is selected from cyano, Ci-Ce-alkyl, aryl or 5 or 6 membered heteroaryl, which aryl or heteroaryl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, cyano, Ci-C6-alkyl and Ci-C6-alkoxyl.
1 is selected from the group consisting of:
Figure imgf000018_0003
Figure imgf000019_0001
Figure imgf000020_0001
[0075] In a certain embodiment, R is selected from H, Ci-C6-alkyl and aryl; or or is a group of formula (L):
Figure imgf000020_0002
(L)
[0076] In a certain embodiment, R2 is selected from H, Ci-C6-alkyl and aryl.
[0077] In a certain embodiment, R2 is selected from the group consisting of:
H, methyl, ethyl, phenyl, and
Figure imgf000020_0003
[0078] In a certain embodiment, R3 is selected from H, C]-C6-alkyl and aryl; or or is a group of formula (L):
Figure imgf000020_0004
(L)
[0079] In a certain embodiment, R3 is selected from H, Ci-C6-alkyl and aryl.
[0080] In a certain embodiment, R3 is selected from the group consisting of:
Figure imgf000021_0001
20
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
and
[0082] In another embodiment, the compounds of formula 1 have the following formula 2
Figure imgf000025_0002
wherein Het, R 1 , R2 and R 3 are as defined herein.
[0083] In an embodiment, the compounds of formula 2 have the following formula 2-A:
Figure imgf000026_0001
(2-A)
wherein R1, R2, R3, R4 and m are as defined herein.
[0084] Non-limiting examples of compounds of formula 2-A are:
1 -(4-(2 -phenyl- 1 H-pyrrolo[2,3-b]pyridin- 1 -yl)phenyl)cyclobutanamine,
l-{4-[6-(2-Fluoro-phenyl)-2-phenyl-pyrrolo[2,3-b]pyridin-l-yl]-phenyl}-yclobutylamine, 1 -(4-(3 -phenyl- 1 H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)cyclobutanamine,
1 -(4-(2 -phenyl- 1 H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclobutanamine, and
1 -(4-( 1 -methyl-2 -phenyl- 1 H-pyrrolo[2,3-b]pyridin-3- yl)phenyl)cyclobutanamine.
[0085] In an embodiment the compounds of formula 2 have the following formula 2-B:
Figure imgf000026_0002
(2-B) wherein R1, R2, R3, R4 and m are as defined herein.
[0086] Non-limiting examples of compounds of formula 2-B are:
1 -(4-(2 -phenyl- 1 H-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)cyclobutanamine, and
1 -(4-(2 -phenyl- 1 H-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)cyclobutanamine.
[0087] In an embodiment, the compounds of formula 2 have the following formula 2-C:
Figure imgf000027_0001
(2-C)
wherein R1, R2, R3, R4 and m are as defined herein.
[0088] Non-limiting examples of compounds of formula 2-C are:
1 -(4-( 1 -phenyl- lH-pyrrolo[3,2-c]pyridin-2-yl)phenyl)cyclobutanamine and
1 -(4-( 1 -aminocyclobutyl)phenyl)-2 -phenyl- 1 H-pyrrolo[3,2-c]pyridin-4-ol.
[0089] In an embodiment, the compounds of formula 2 have the following formula 2-D:
Figure imgf000027_0002
(2-D)
wherein R1, R2, R3, R4 and m are as defined herein.
[0090] A non limiting example of compound of formula 2-D is l-(4-(l- aminocyclobutyl)phenyl)-2-phenyl-lH-pyrrolo[3,2-b]pyridin-5-ol.
[0091] In an embodiment, the compounds of formula 2 have the following formula 2-E:
Figure imgf000027_0003
(2-E)
wherein R!, R2, R3, R4 and m are as defined herein.
[0092] Non-limiting examples of compounds of formula 2-E are: l-(4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl) cyclobutanamine,
1 -(4-( 1 -phenyl- 1 H-pyrrolo [3 ,2-c]pyridin-2-yl)phenyl)cyclobutanamine,
1 -(4-( 1 -aminocyclobutyl)phenyl)-2-phenyl- 1 H-pyrrolo[3 ,2-c]pyridin-4-ol,
l-(4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutanamine,
l-(4-(2-(lH-pyrazol-4-yl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutanamine,
7-(4-(l-aminocyclobutyl)phenyl)-N-methyl-6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- amine,
l-(4-(2-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutanamine, 1 -(7-(4-( 1 -aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)pyrrolidin-3-ol,
l-(4-(6-methyl-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutanamine,
1- (4-(5-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutanamine,
(S)-l-(7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)pyrrolidin-3-ol,
7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, 7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-2- carboxamide,
(S)-l-(7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)pyrrolidine-2-carboxylic acid,
Nl-(7-(4-(l-aminocyclobutyl)phenyl)-6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)ethane- 1 ,2-diamine,
2- (7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)acetic acid,
N-(7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)cyclopropanecarboxamide,
7-(4-(l-aminocyclobutyl)phenyl)-N,N-dimethyl-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine,
4-{7-[4-(l-aminocyclobutyl)phenyl]-6-(pyridin-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-
1λ6,4- thiomorpholine-l,l-dione,
l-(4-(4-methoxy-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutanamine, l-(7-(4-(l-aminocyclobutyl)phenyl)-6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrrolidin-2-one,
l-[4-(5-Ethyl-6-pyridin-2-yl-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-cyclobutylamine, l-(4-(4-(lH-pyrazol-4-yl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutanamine,
7-(4-(l-aminocyclobutyl)phenyl)-N-methyl-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,
7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4- carboxamide,
7-(4-(l-aminocyclobu1yl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid,
1 - { 4- [4-Methoxy-2-( 1 H-pyrazol-4-yl)-6-pyridin-2-yl-pyrrolo [2,3 -d]pyrimidin-7-yl] -phenyl } - cyclobutylamine,
7-(4-(l-aminocyclobutyl)phenyl)-N,N-diethyl-6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,
7-[4-(l-Amino-cyclobutyl)-phenyl]-6-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid (2-dimethylamino-ethyl)-amide,
1 -(7-(4-( 1 -aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrrolidin-3-ol,
l-{4-[5-Methyl-6-phenyl-2-(lH-pyrazol-4-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}- cyclobutylamine,
l-{4-[2-(2-Fluoro-phenyl)-5-methyl-6-phenyl-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}- cyclobutylamine,
7-(4-(l-aminocyclobutyl)phenyl)-N,N-diethyl-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,
l-[4-(5-Methyl-2,6-diphenyl-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-cyclobutylamine, 1 -(4-(5-methyl-6-phenyl-2-(pyrrolidin- 1 -yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutanamine,
1 -(4-(7-methyl-5-phenyl-2-( 1 H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6- yl)phenyl)cyclobutanamine,
l-[4-(7-Methyl-2,5-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-cyclobutylamine, l-(4-(2-(2-fluorophenyl)-7-methyl-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6- yl)phenyl)cyclobutanamine,
N-(7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)methanesulfonamide,
7-(4-(l-aminocyclobutyl)phenyl)-6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol, l-{4-[2-(2-Fluoro-phenyl)-7-methyl-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}- cyclobutylamine, and
l-[4-(7-Methyl-5-phenyl-2-pyrimidin-5-yl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]- cyclobutylamine.
[0093] In an embodiment, the compounds of formula 2 have the following formula 2-F:
Figure imgf000030_0001
wherein R1, R2, R3, R4 and m are as defined herein.
[0094] Non-limiting examples of compounds of formula 2-F are:
1 - [4-(2-Chloro-6-phenyl-pyrrolo [3 ,2-d]pyrimidin-5 -y l)-phenyl] -cyclobutylamine,
{5-[4-(l-Amino-cyclobutyl)-phenyl]-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl}-dimethyl- amine,
l-(4-(6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)cyclobutanamine,
l-{4-[6-Phenyl-2-(lH-pyrazol-4-yl)-pyrrolo[3,2-d]pyrimidin-5-yl]-phenyl}-cyclobutylamine, l-[4-(6-Phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]-cyclobutylamine,
l-[4-(5-Methyl-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-phenyl]- cyclobutylamine, Nl-{5-[4-(l-Amino-cyclobutyl)-phenyl]-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl}-ethane- 1,2-diamine,
1- {5-[4-(l-Amino-cyclobutyl)-phenyl]-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl}-pyrrolidin-
3-ol,
5-[4-(l-Amino-cyclobutyl)-phenyl]-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-2-carboxylic acid, tert-butyl l-(4-(2-(ethylamino)-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-5- yl)phenyl)cyclobutylcarbamate,
2- {5-[4-(l-Amino-cyclobutyl)-phenyl]-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino}- ethanol,
l-(5-(4-(l-aminocyclobutyl)phenyl)-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidin-2- one,
l-[4-(2-Methoxy-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]-cyclobutylamine,
5-(4-(l-aminocyclobutyl)phenyl)-N-methyl-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-2- carboxamide,
l-(4-(5-methyl-6-phenyl-2-(lH-pyrazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-7- yl)phenyl)cyclobutanamine,
l-(4-(5-methyl-2,6-diphenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)cyclobutanamine, l-(4-(2-chloro-5-methyl-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)cyclobutanamine, and
3-amino-l-methyl-3-(4-(5-methyl-6-phenyl-2-(lH-pyrazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin- 7-yl)phenyl)cyclobutanol .
[0095] In an embodiment, the compounds of formula 2 have the following formula 2-G:
Figure imgf000031_0001
(2-G)
wherein R1, R2, R3, R4 and m are as defined herein.
[0096] A non-limiting example of a compound of formula 2-G is l-[4-(6-Phenyl- pyrrolo[2,3-b]pyrazin-5-yl)-phenyl]-cyclobutylamine.
[0097] In an embodiment, the compounds of formula 2 have the following formula 2-H:
Figure imgf000031_0002
(2-H)
wherein R1, R2, R3, R4 and m are as defined herein.
[0098] embodiment, the compounds of formula 2 have the following formula 2-1:
Figure imgf000032_0001
(2-1)
wherein R1, R2, R3, R4 and m are as defined herein.
[0099] In an embodiment, the compounds of formula 2 have the following formula 2-J:
Figure imgf000032_0002
(2-J) wherein R , R , R , R and m are as defined herein.
[00100] In an embodiment, the compounds of formula 1 have the following formula 3:
Figure imgf000032_0003
(3)
wherein R 1 and R 2 are as defined herein.
[00101] In an embodiment, the compounds of formula 3 have the following formula 3-A:
Figure imgf000032_0004
(3-A) wherein R1, R2, R4 and m are as defined herein.
[00102] Non-limiting examples of compounds of formula 3-A are:
l-(4-(5-methyl-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutanamine,
l-(4-(6-bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutanamine,
1 -(4-(6-(2-fluoropheny l)-2-pheny 1-3 H-imidazo [4, 5 -b]pyridin-3 -y l)phenyl)cyclobutanamine, l-(4-(2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutanamine, and
l-(4-(5-phenyl-2-( yridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutanamine.
[00103] In an embodiment, the compounds of formula 3 have the following formula 3-B:
Figure imgf000033_0001
(3-B)
wherein R1, R2, R4 and m are as defined herein.
[00104] Non-limiting examples of compounds of formula 3-B are:
1- (4-(3-phenyl-3H-imidazo[4,5-c]pyridin-2-yl)phenyl)cyclobutanamine and
2- (4-(l -aminocyclobutyl)phenyl)- 1 -phenyl- 1 H-imidazo[4,5-c]pyridin-6-ol.
[00105] In an embodiment the compounds of formula 3 have the following formula 3-C:
Figure imgf000033_0002
(3-C)
wherein R1, R2, R4 and m are as defined herein.
[00106] In an embodiment, the compounds of formula 3 have the following formula 3-D:
Figure imgf000033_0003
(3-D) wherein R1, R2, R4 and m are as defined herein.
[00107] In an embodiment, the compounds of formula 3 have the following formula 3-E:
Figure imgf000034_0001
(3-E)
wherein R1, R2, R4 and m are as defined herein.
[00108] Non-limiting examples of compounds of formula 3-E are:
l-(4-(2-chloro-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
7: 1 -(4-(2,8-diphenyl-9H-purin-9-yl)phenyI)cyclobutanamine;
10: N-(l-(4-(2,8-diphenyl-9H-purin-9-yl)phenyl)cyclobutyl)acetamide;
l-(4-(2-phenyl-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(2-(2-fluorophenyl)-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -[4-(8-Phenyl-2-piperazin- 1 -yl-purin-9-yl)-phenyl]-cyclobutylamine;
l-{4-[2-(2-Fluoro-phenyl)-8-phenyl-purin-9-yl]-phenyl}-cyclobutylamine;
{9-[4-(l-Amino-cyclobutyl)-phenyl]-8-phenyl-9H-purin-2-yl}-methyl-amine;
{ 9-[4-( 1 -Amino-cyclobutyl)-phenyl]-8-phenyl-9H-purin-2-yl } -dimethyl-amine;
28: 1 -(4-(2-chloro-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
9-[4-(l -Amino-cyclobutyl)-phenyl]-8-phenyl-9H-purine-2-carboxylic acid methylamide; l-{9-[4-(l-Amino-cyclobutyl)-phenyl]-8-phenyl-9H-purin-2-yl}-pyrrolidin-2-one;
l-[4-(8-Phenyl-purin-9-yl)-phenyl]-cyclobutylamine;
l-[4-(8-Phenyl-2-pyridin-2-yl-purin-9-yl)-phenyl]-cyclobutylamine;
9-(4-(l-aminocyclobutyl)phenyl)-8-phenyl-9H-purin-2-amine;
l-(4-(2-chloro-8-(thiazol-5-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(2-methoxy-8-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
l-{4-[2-(3 -Methyl-isoxazol-5 -yl)- 8-phenyl-purin-9-yl] -phenyl } -cyclobuty lamine ;
l-{4-[2-(5-Methyl-2H-pyrazol-3-yl)-8-phenyl-purin-9-yl]-phenyl}-cyclobutylamine;
l-{4-[2-(2-Methyl-3H-imidazol-4-yl)-8-phenyl-purin-9-yl]-phenyl}-cyclobutylamine; l-[4-(2-Phenyl-8-pyridin-3-yl-purin-9-yl)-phenyl]-cyclobutylamine;
l-(4-(2-phenyl-8-(pyridin-4-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-[4-(2-Ethoxy-8-phenyl-purin-9-yl)-phenyl]-cyclobutylamine;
9-(4-(l-aminocyclobutyl)phenyl)-N,N-dimethyl-8-phenyl-9H-purin-6-amine; l-{4-[8-Phenyl-2-(lH-pyrazol-4-yl)-purin-9-yl]-phenyl}-cyclobutylamine; l-{4-[2-(l-Methyl-lH-pyrazol-4-yl)-8-phenyl-purin-9-yl]-phenyl}-cyclobutylamine; l-(4-(8-(4-methoxypyridin-3-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(8-( 1 H-imidazol-2-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(2-phenyl-8-(thiazol-5-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(9-phenyl-9H-purin-8-yl)phenyl)cyclobutanamine;
1 -(4-(8-phenyl-2-(pyrrolidin- 1 -yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(8-(3 -methoxypyridin-2-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine ;
l-(4-(8-(5-methoxypyridin-3-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(6-( 1 -methyl- 1 H-pyrazol-4-yl)-8-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine; l-(4-(2-phenyl-8-(pyrimidin-5-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-[4-(6-Methyl-8-phenyl-purin-9-yl)-phenyl]-cyclobutylamine;
l-(4-(8-tert-butyl-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(2-( 1 H-pyrazol-4-yl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutanamine;
l-(4-(8-(4-methyl-lH-imidazol-5-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(8-( 1 H-imidazol-4-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(8-(4-methylthiazol-2-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(8-(l -methyl- 1 H-benzo[d]imidazol-2-yl)-2-phenyl-9H-purin-9- yl)phenyl)cyclobutanamine ;
1 -(4-(8-( 1 -methyl- 1 H-imidazol-2-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine; l-(4-(8-(5-methylisoxazol-3-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(8-(oxazol-4-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(8-( 1 -methyl- 1 H-pyrazol-4-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(8-( 1 -methyl- 1 H-imidazol-5-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
N 1 -(9-(4-(l -aminocyclobutyl)phenyl)-8-(pyridin-2-yl)-9H-purin-2-yl)ethane- 1 ,2-diamine;
N-(9-(4-(l-aminocyclobutyl)phenyl)-8-(pyridin-2-yl)-9H-purin-2-yl)methanesulfonamide; l-(4-(2-chloro-7-phenyl-7H-purin-8-yl)phenyl)cyclobutanamine;
1 -(4-(8-( 1 -methyl- 1 H-pyrazol-5-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(2-phenyl-8-( 1 H-pyrazol-4-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(2-phenyl-8-(thiazol-2-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(2-(lH-pyrazol-4-yl)-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(8-(6-methoxypyridin-2-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(7-phenyl-7H-purin-8-yl)phenyl)cyclobutanamine; 1- (4-(2-phenyl-8-(lH-pyrazol-5-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(9-(4-( 1 -aminocyclobutyl)phenyl)-8-(pyridin-2-yl)-9H-purin-2-yl)pyrrolidin-3-ol;
2- (4-(9-(4-( 1 -aminocyclobutyl)phenyl)-8-(pyridin-2-yl)-9H-purin-2-yl)- 1 H-pyrazol- 1 - yl)ethanol;
6-(9-(4-(l-aminocyclobutyl)phenyl)-2-phenyl-9H-purin-8-yl)pyridin-2(lH)-one; l-(4-(2-methoxy-7-phenyl-7H-purin-8-yl)phenyl)cyclobutanamine;
9-(4-( 1 -aminocyclobutyl)phenyl)-8-(pyridin-2-yl)-9H-purin-6-ol;
8- (4-( 1 -aminocyclobutyl)phenyl)-7-phenyl-7H-purin-2-ol ;
l-(4-(7-phenyl-2-(pyridin-3-yl)-7H-purin-8-yl)phenyl)cyclobutanamine;
l-(4-(7-phenyl-2-(pyrimidin-5-yl)-7H-purin-8-yl)phenyl)cyclobutanamine;
9- [4-(l-Amino-cyclobutyl)-phenyl]-2-phenyl-9H-purine-8-carbonitrile;
1 -(4-(8-(l -ethyl- lH-pyrazol-5-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(7-phenyl-2-( 1 H-pyrazol-4-yl)-7H-purin-8-yl)phenyl)cyclobutanamine;
1 -(4-(2-(2-fluorophenyl)-8-(l -methyl- 1 H-pyrazol-5-yl)-9H-purin-9- yl)phenyl)cyclobutanamine;
l-(4-(2-phenyl-8-o-tolyl-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(2,7-diphenyl-7H-purin-8-yl)phenyl)cyclobutanamine;
1 -(4-(7-phenyl-2-( 1 H-pyrazol- 1 -yl)-7H-purin-8-yl)phenyl)cyclobutanamine;
l-(4-(8-(3-bromopyridin-2-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine; l-(4-(8-(4-methylthiazol-5-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine; l-(4-(8-(l-methyl-lH-pyrazol-5-yl)-2-(3-(trifluoromethoxy)phenyl)-9H-purin-9- yl)phenyl)cyclobutanamine;
l-(4-(8-(l-methyl-lH-pyrazol-5-yl)-2-(3-(trifluoromethyl)phenyl)-9H-purin-9- yl)phenyl)cyclobutanamine;
l-(4-(7-phenyl-2-(thiazol-4-yl)-7H-purin-8-yl)phenyl)cyclobutanamine;
l-(4-(8-(3-methylpyridin-2-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1- (4-(2-(4-methoxyphenyl)-8-(l -methyl- lH-pyrazol-5-yl)-9H-purin-9- yl)phenyl)cyclobutanamine;
2- (9-(4-(l-aminocyclobutyl)phenyl)-2-phenyl-9H-purin-8-yl)benzonitrile;
1 -(4-(2-(2-methoxyphenyl)-8-( 1 -methyl- 1 H-pyrazol-5-yl)-9H-purin-9- yl)phenyl)cyclobutanamine;
4-(9-(4-( 1 -aminocyclobutyl)phenyl)-8-( 1 -methyl- 1 H-pyrazol-5-yl)-9H-purin-2-yl)-N- methylbenzenesulfonamide ;
1 -(4-(8-( 1 -methyl- 1 H-pyrazol-5-yl)-2-p-tolyl-9H-purin-9-yl)phenyl)cyclobutanamine; 1 -(4-(2-(2-fluorophenyl)-8-( 1 -methyl- 1 H-pyrazol-5-yl)-9H-purin-9- yl)phenyl)cyclobutanamine;
1 -(4-(8-( 1 -methyl- 1 H-pyrazol-5-yl)-2-m-tolyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(2-(4-fluorophenyl)-8-( 1 -methyl- 1 H-pyrazol-5-yl)-9H-purin-9- yl)phenyl)cyclobutanamine ;
l-(4-(8-(3-methoxypyridin-4-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine; and l-(4-(8-(4-methyl-lH-imidazol-5-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine.
[00109] In an embodiment the compounds of formula 3 have the following formula 3-F:
Figure imgf000037_0001
(3-F)
wherein R1, R2, R4 and m are as defined herein.
[00110] In an embodiment, the compounds of formula 3 have the following formula 3-G:
Figure imgf000037_0002
(3-G)
wherein R1, R2, R4 and m are as defined herein.
[00111] Non-limiting examples of compounds of formula 3-G are:
l-[4-(2-Phenyl-imidazo[4,5-b]pyrazin-l-yl)-phenyl]-cyclobutylamine; and
1 -(4-(2-phenyl-5-(l H-pyrazol-4-yl)- 1 H-imidazo[4,5-b]pyrazin- 1 -yl)phenyl)cyclobutanamine.
[00112] In an embodiment, the com ounds of formula 3 have the following formula 3-H:
Figure imgf000037_0003
(3-H) wherein R1, R2, R4 and m are as defined herein.
[00113] embodiment the compounds of formula 3 have the following formula 3-1:
Figure imgf000038_0001
(3-1)
wherein R1, R2, R4 and m are as defined herein.
[00114] In an embodiment, the compounds of formula 3 have the following formula 3-J:
Figure imgf000038_0002
(3-J)
wherein R1, R2, R4 and m are as defined herein.
[00115] 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. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and diastereomers, and mixtures, racemic or otherwise, thereof. Accordingly, this invention also includes all such isomers, including diastereomeric mixtures, pure diastereomers and pure enantiomers of the compounds of this invention. The term "enantiomer" refers to two stereoisomers of a compound which are non- superimposable mirror images of one another. The term "diastereomer" refers to a pair of optical isomers which are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities.
[00116] The compounds of the present invention may also exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons. [00117] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed wedge representing a particular configuration, then that stereoisomer is so specified and defined.
METABOLITES OF COMPOUNDS OF FORMULA 1
[00118] Also falling within the scope of this invention are the in vivo metabolic products of compounds of Formula 1 described herein. A "metabolite" is a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds of Formula 1, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
[00119] Metabolites are identified, for example, by preparing a radiolabelled (e.g., I4C or
H) isotope of a compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to a human, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS, LC/MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art. The metabolites, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.
SYNTHESIS OF COMPOUNDS OF FORMULA 1
[00120] Compounds of this invention may be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources, such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements).
[00121] Compounds of Formula 1 may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds. Libraries of compounds of Formula 1 may be prepared by a combinatorial 'split and mix' approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds of Formula 1, or salts thereof.
[00122] For illustrative purposes, Schemes 1-26 show a general method for preparing the compounds of the present invention, as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
[00123] Synthesis of substituted diaryl-imidazoles:
Scheme 1
Figure imgf000040_0001
[00124] The synthesis of certain compounds of the present invention is outlined in Scheme
1. These compounds can be synthesized from ortho-halo nitro-heteroarenes 1.1. Treatment of an optionally substituted nitro-heteroarene 1.1 (selected from Figure 1, where X is may be chloro, bromo, iodo, or trifluoromethanesulfonato) with a suitably protected aniline 1.2 (for a review of protecting groups see T.W. Greene, P.G.M. Wuts - Protective groups in Organic Synthesis, 3rd ed., John Wiley & Sons, 1999) in the presence of a palladium source, such as tris(dibenzylideneacetone) dipalladium, a ligand, such as 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (Xantphos), a base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 25 °C to 200 °C produces nitro-anilines 1.3. The temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
Figure 1
Figure imgf000041_0001
[00125] Alternatively an optionally substituted nitro-heteroarene 1.1 (selected from Figure
1 , where X is may be fluoro, chloro, or methanesulfonyl) may be treated with a suitably protected aniline 1.2 (see T.W. Greene, supra) with or without a suitable base, such as diisopropylethylamine, with or without a suitable solvent, such as dioxane, at temperatures ranging from 25 °C to 200 °C to produce nitro-anilines 1.3. The temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
[00126] Reduction of the nitro group can be achieved by reacting nitro aniline 3 with hydrogen gas in the presence of a catalyst, such as Raney-nickel, in a suitable solvent, such as TFEF, at temperatures ranging from 25 °C to 200 °C, and at pressures ranging from 1 atm to 50 atm to produce amino-aniline 1.4. Depending on the choice of R1 and R2 it may be advantageous to use a chemoselective reduction method, such as sulfided platinum on carbon in a suitable solvent, such as ethanol, at temperatures ranging from 25 °C to 200 °C, and at pressures ranging from 1 atm to 50 atm to produce amino-aniline 1.4.
[00127] Cyclization to the fused imidazo-heteroarene 1.6 can be achieved by reacting amino-aniline 1.4 with an aldehyde 1.5a in the presence of an oxidant, such as copper(II)acetate, in a suitable solvent, such as acetic acid, at temperatures ranging from 25 °C to 200 °C. Alternatively imidazo-heteroarenes 1.6 may be synthesized by treating amino-anilines 1.4 with an orthoester 1.5b in the presence of an acid, such as 4-methylbenzenesulfonic acid, in a solvent, such as toluene, at temperatures ranging from 25 °C to 150 °C. The reduction of nitro anilines 1.3 can be performed in the presence of an orthoester 1.5b to affect the reduction and cyclization to imidazo-heteroarenes 1.6 in one step.
[00128] Someone skilled in the art will recognize that it may be advantageous to use building blocks 1.1 and 1.2 which will incorporate a functional group for further synthetic transformations. For example R4 may be a halogen to yield compounds 1.6 which may be reacted further. It may be advantageous to mask such functional groups using a protecting group (for a review of protecting groups see T.W. Greene, P.G.M. Wuts - Protective groups in Organic Synthesis, 3rd ed., John Wiley & Sons, 1999).
Scheme 2
Figure imgf000042_0001
2.1 2.2 2.3 2.4
[00129] Selected examples from the invention described herein can be synthesized according to Scheme 2. 2-Substituted-4-chloro-5-nitro-pyrimidine 2.1 can be treated with aniline, such as 1.2, in a suitable solvent, such as THF. The resulting nitro aniline 2.2 can be reduced with hydrogen gas in the presence of a suitable catalyst, such as raney nickel, in a suitable solvent, such as THF. Dianiline 2.3 can be cyclized to purine 2.4 using aldehyde 1.5a in the presence of an oxidant, such as copper (II) acetate in acetic acid. It will appear to someone skilled in the art that R1, R2, or R4 may contain functional groups which have to be protected with a suitable protecting group. R!, R2, or R4 may also contain functional handles which allow further elaboration of 2.4.
Scheme 3
Figure imgf000042_0002
3.1 3.2 2.4
[00130] Specifically, selected examples from the invention described herein can be synthesized if R4 is chloride (
[00131] Scheme 3). Treatment of purine chloride 3.2 with suitable reagents, such as boronic acids and boronates, organoboranes, organostannanes, organozinc compounds, organomagnesium compounds, olefins or terminal alkynes (either purchased or obtained via generally well known protocols) can be carried out in the presence of a suitable transition metal catalyst (e.g., palladium compounds). The coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines. Organic or inorganic bases (e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates) and/or other well known additives (e.g., lithium chloride, copper halides or silver salts) maybe utilized to effect, assist or accelerate such transformations. These cross coupling reactions may be carried out in suitable solvents such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N-methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C. The temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
[00132] In some cases it may be advantageous to achieve cross-couplings to carbon or non- carbon atoms by first converting the respective halogen derivative into the corresponding organometallic derivative (e.g., a boronic acid or ester, trifluoroborate salt, organomagnesium, organozinc or organotin compound). Such compounds are accessible by means of substituting the halide moiety with an appropriate metal or metalloid. Any functional groups present, may need to be protected by a suitable protecting group.
[00133] Introduction of such metals or metalloids can be achieved by generally well-known methods, such as metallation using metals or a metal-halogen exchange reaction. Useful metals for metallation include alkaline or alkaline earth metals or activated forms of such metals. Suitable reagents for use in metal-halogen exchange reactions include organolithium or organomagnesium compounds (e.g., N-butyllithium, tert-butyllithium or iso-propylmagnesium chloride or bromide). Subsequent transmetalation reactions of the organometallic intermediate may be performed as needed with a suitable soluble and reactive metal compound, such as magnesium chloride, magnesium bromide, tri-N-butyltin chloride, trimethyltin chloride, trimethyl borate, triethyl borate, tri-iso-propyl borate, zinc triflate or zinc chloride. Introduction of a boronic acid pinacol ester can be conveniently achieved by reacting the halogen derivative directly with bis(pinacolato)diboron in the presence of dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium(II) and suitable bases (e.g., potassium or sodium acetate) in solvents such as DMSO, DMF, DMA or N- methylpyrrolidone at temperatures ranging from 80-160 °C. Conventional heating or microwave irradiation may be employed to maintain the appropriate temperature (for literature precedent of similar transformations, see Ishiyama T. et al., J. Org. Chem., 60.750S (2003)). Methods for conversion of the boronic acid pinacol ester obtained by this method into other boronic acid derivatives such as boronic acids, boronates, or trifluoroborate salts are generally well known. As will be apparent to the skilled artisan, such organometallic derivatives may be utilized in cross- coupling reactions similar to those described above. Such couplings can be effected utilizing suitable coupling partners, such as aromatic, heteroaromatic halides or olefinic reagents under conditions identical or evidently similar and/or related to the methods described above. [00134] Other methods may utilize the reactivity of organometallic derivatives generated from 3.2 by any of the methods described above. For example, derivatives containing alkaline or alkaline earth metals (e.g., organolithium, organomagnesium or organozinc compounds) may be employed in direct couplings to a range of other electrophilic coupling partners such as, for example, activated olefins (MICHAEL-acceptors), aldehydes, nitriles, aromatic nitro compounds, carboxylic acid derivatives, oxiranes, aziridines, organic disulfides or organic halides. Such transformations are generally well known in the art (for reactions with aromatic nitro compounds, see, e.g., Sapountzis L, et al., J. Am. Chem. Soc, J 24:9390 (2002)).
[00135] This methodology may be extended to the incorporation of non-carbon based nucleophiles (e.g., alcohols, thiols, primary or secondary amines) that may optionally contain suitable protecting groups of alcohols, thiols or amines. Examples of such groups can be found in Greene T., supra. Exemplary methods of such utilization of non-carbon nucleophiles in related cross-coupling reactions may be found in Ley S. et al., Angew. Chem., /75:5558 (2003); Wolfe J. et al., Ace. Chem. Res., 31:805 (1998); Hartwig, Ace. Chem. Res., 31 :852 (1998); Navarro O., et al., J. Org. Chem., 69:3173 (2004), Ji J. et al., Org. Lett, 5:461 1 (2003). The skilled artisan will recognize that the compounds obtained by such methods can be further elaborated by generally well known methods to obtain other compounds of the present invention.
[00136] Some of the compounds in the present invention may be synthesized by treatment of chloro purine 3.2 with a nucleophile, such as a primary or secondary amine, or an alcohol, in the presence of carbon monoxide, a suitable catalyst, such as dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium(II), a base, such as triethylamine, and a solvent, such as dioxane, at temperatures ranging from 80-160 °C. Conventional heating or microwave irradiation may be employed to maintain the appropriate temperature (exemplary methods of carbonylation may be found in Brennfuhrer, A. et al., Angew. Chem., 48(23):4114 (2009)).
[00137] Alternatively, compounds described in the invention may be synthesized by treating chloro-purine 3.2 with a suitably protected carbon-based nucleophiles (e.g., malonates) and non- carbon based nucleophiles (e.g., alcohols, thiols, primary or secondary amines) via nucleophilic aromatic substitution. The reactions may be accelerated using an appropriate acid, such as toluenesulfonic acid, or base, such as triethylamine, diisopropylethylamine, sodium hydride, or an alkaline carbonate base, in the presence or absence of a suitable solvent, such as, but not limited to, THF, dioxane, DMF, DMA, DMSO, or acetonitrile. Scheme 4
Figure imgf000045_0001
4.2 4.3 4.4
[00138] Selected examples from the invention described herein can be synthesized according to Scheme 4. 6-Substituted-4-chloro-5-nitro-pyrimidine 4.1 can be treated with an aniline, such as 1.2, in a suitable solvent, such as THF. The resulting nitro aniline 4.2 can be reduced with hydrogen gas in the presence of a suitable catalyst, such as raney nickel, in a suitable solvent, such as THF. Dianiline 4.3 can be cyclized to purine 4.4 using aldehyde 1.5a in the presence of an oxidant, such as copper(II) acetate in acetic acid. It will be evident to someone skilled in the art that R1, R2, or R4 may contain functional groups which have to be protected with a suitable protecting group. R1, R2, or R4 may also be functional handles which allow further elaboration of 4.4.
Scheme 5
Figure imgf000045_0002
[00139] Specifically, selected examples from the invention described herein can be synthesized if R4 is chloride (Scheme 5). Purine 5.2 can by synthesized from 4,6-dichloro-5-nitro- pyrimidine 5.1 according to Scheme 4. Treatment of purine chloride 5.2 with suitable reagents, such as boronic acids and boronates, organoboranes, organostannanes, organozinc compounds, organomagnesium compounds, olefins or terminal alkynes (either purchased or obtained via generally well known protocols), can be carried out in the presence of a suitable transition metal catalyst (e.g., palladium compounds). The coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines. Organic or inorganic bases (e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates) and/or other well known additives (e.g., lithium chloride, copper halides or silver salts) maybe utilized to effect, assist or accelerate such transformations. These cross coupling reactions may be carried out in suitable solvents such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N-methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C. The temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
[00140] The Pd catalyzed coupling or SnAr reaction from 5.2 to 4.4 may be performed similarly as in Scheme 3 (compound 3.2 to compound 2.4), and as such, the description of those potential reactions (see above) apply to Scheme 5 as well.
Scheme 6
Figure imgf000046_0001
6.1 6.2 6.3 6.4
[00141] Tetrasubstituted purines from the invention described herein can be synthesized from dichloropurine 6.2 (Scheme 6) which may be synthesized from 2,4,6-trichloro-5- nitropyrimidine according to Scheme 4. Functionalization of 6.2 according to the conditions described above followed by functionalization of the resulting chloropurine 6.3 according to the conditions described above generates tetrasubstituted purines 6.4.
Scheme 7
Figure imgf000046_0002
7.1 7.2 7.3 7.4
[00142] Selected examples from the invention described herein can be synthesized according to Scheme 7. Optionally substituted 2-chloro-3-nitro-pyridine 7.1 may be treated with an aniline 1.2 in the presence of base, such as diisopropylethylamine, and a suitable solvent, such as THF, to yield nitropyridines 7.2. Reduction of nitroaniline 7.2 using hydrogen and a suitable catalyst, such as Raney-nickel, in a solvent, such as TFiF, generates dianiline 7.3. Dianiline 7.3 can be cyclized to imidazo[4,5-b]pyridine 7.4 using aldehyde 1.5a in the presence of an oxidant, such as copper(II) acetate in acetic acid. It will be evident to someone skilled in the art that R1, R2, or R4 may contain functional groups which have to be protected with a suitable protecting group. R1, R2, or R4 may also be functional handles which allow further elaboration of 7.4.
Scheme 8
Figure imgf000047_0001
8.1 8.2 8.3
[00143] Selected examples from the invention described herein can be synthesized starting from 5-bromo-2-chloro-3-nitropyridine 8.1. 6-Bromo-imidazo[4,5-b]pyridine 8.2 can be synthesized according to Scheme 7. Treatment of 6-bromo-imidazo[4,5-b]pyridine 8.2 with suitable reagents, such as boronic acids and boronates, organoboranes, organostannanes, organozinc compounds, organomagnesium compounds, olefins or terminal alkynes (either purchased or obtained via generally well known protocols), can be carried out in the presence of a suitable transition metal catalyst (e.g., palladium compounds). The coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines. Organic or inorganic bases (e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates) and/or other well known additives (e.g., lithium chloride, copper halides or silver salts) maybe utilized to effect, assist or accelerate such transformations. These cross coupling reactions may be carried out in suitable solvents, such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N- methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C. The temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
[00144] The Pd catalyzed coupling or SnAr reaction from 8.2 to 8.3 may be performed similarly as in Scheme 3 (compound 3.2 to compound 2.4), and as such, the description of those potential reactions (see above) apply to Scheme 8 as well.
Scheme 9
Figure imgf000047_0002
9.1 9.2 9.3 [00145] Other selected examples from the invention described herein can be synthesized from 2,6-dichloro-3-nitro-pyridine 9.1 (Scheme 9). 5-Chloro-imidazo[4,5-b]pyridine 9.2 can be synthesized according to Scheme 7. Treatment of 5-chloro-imidazo[4,5-b]pyridine 9.2 with suitable reagents, such as boronic acids and boronates, organoboranes, organostannanes, organozinc compounds, organomagnesium compounds, olefins or terminal alkynes (either purchased or obtained via generally well known protocols), can be carried out in the presence of a suitable transition metal catalyst (e.g., palladium compounds). The coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines. Organic or inorganic bases (e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates) and/or other well known additives (e.g., lithium chloride, copper halides or silver salts) maybe utilized to effect, assist or accelerate such transformations. These cross coupling reactions may be carried out in suitable solvents, such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N- methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C. The temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
[00146] The Pd catalyzed coupling or SnAr reaction from 9.2 to 9.3 may be performed similarly as in Scheme 3 (compound 3.2 to compound 2.4), and as such, the description of those potential reactions (see above) apply to Scheme 9 as well.
Scheme 10
Figure imgf000048_0001
10.1 10.2 10.3 10.4
[00147] Selected examples from the invention described herein can be synthesized according to Scheme 10. Optionally substituted 2-chloro-3-nitro-pyrazine 10.1 (Hartman, G.D., et al., J. Het. Chem. 20, 947-950 (1983)) may be treated with an aniline 1.2 in the presence of base, such as triethylamine, and a suitable solvent, such as dioxane, to yield nitropyrazine 10.2. Reduction of nitroaniline 10.2 using hydrogen and a suitable catalyst, such as Raney-nickel, in a solvent, such as THF, generates dianiline 10.3. Dianiline 10.3 can be cyclized to imidazo[4,5- b]pyrazine 10.4 using aldehyde 1.5a in the presence of an oxidant, such as copper(II) acetate in acetic acid. It will be evident to someone skilled in the art that R1, R2, or R4 may contain functional groups which have to be protected with a suitable protecting group. R1, R2, or R4 may also be functional handles which allow further elaboration of 10.4.
Synthesis of substituted aryl-pyrroles:
Scheme 11
Figure imgf000049_0001
11.6 11.7
[00148] The synthesis of certain compounds of the present invention is outlined in Scheme
11. Many of these compounds may be synthesized using a suitably protected dihalide 11.1 (X1 = bromo, iodo) and X being chloro or bromo. Treatment of a suitably protected dihalide, such as compounds shown in Figure 2 (with X1 being a bromide, iodide, or trifluoromethanesulfonato, and X being a chloride or bromide) with a terminal alkyne 11.2, in the presence of a palladium catalyst, such as dichloro(bis-triphenylphosphine)palladium, an additive, such as copper iodide, and a base, such as triethylamine, yields alkynes 11.3 (For a review on alkynylations, see Negishi et al., Chem. Rev. 103(5), 1979-2013 (2003)). Pg is an amine protecting group, e.g., acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethyleneoxycarbonyl (Fmoc).
[00149] Treatment of alkynes 11.3 with a suitably protected aniline 1.2 (for a review of protecting groups see T.W. Greene, supra) in the presence of a palladium source, such as tris(dibenzylideneacetone) dipalladium, a ligand, such as 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (Xantphos), a base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 25 °C to 200 °C produces anilino-alkynes 1 1.4. [00150] Treatment of anilino-alkynes 11.4 with a suitable catalyst, such as bis- tributylphosphine palladium, a suitable additive, such as potassium fluoride, a base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 25 °C to 200 °C produces aryl-pyrroles 11.5.
[00151] Alternatively, the reaction to form aryl-pyrroles 11.5 from alkynes 11.3 may be performed as a one pot reaction.
Figure 2
Figure imgf000050_0001
[00152] Alternatively an optionally substituted amino-heteroarene (selected from Figure 2, with X 1 being a bromide, iodide, or trifluoromethanesulfonato, and X 2 being a fluoride or chloride) can be used as compound 11.1 and may be treated with a suitably protected aniline 1.2 (for a review of protecting groups see T.W. Greene, P.G.M. Wuts - Protective groups in Organic Synthesis, 3rd ed., John Wiley & Sons, 1999) in the presence of a base, such as diisopropylethylamine, with or without a suitable solvent, such as dioxane at temperatures ranging from 25 °C to 200 °C produces anilino-alkynes.
Scheme 12
Figure imgf000050_0002
[00153] Specifically, selected examples from the invention described herein can be synthesized from 4-chloro-3-iodopyridine 12.1. Treatment of optionally substituted 4-chloro-3- iodopyridine 12.1 with an alkyne 11.2 in the presence of a suitable catalyst, such as dichloro- bis(triphenylphosphine)palladium (II), a suitable additive, such as copper(I)iodide, a base, such as triethylamine, with or without a suitable solvent, at temperatures ranging from 20 °C to 150 °C yields alkyne 12.2. Treatment of 12.2 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields pyrrolo[3,2- cjpyridine 12.3.
Scheme 13
Figure imgf000051_0001
13.2 13.3 13.4
^IH2
Figure imgf000051_0002
13.5 13.6
[00154] Specifically, selected examples from the invention described herein can be synthesized starting from 2-chloro-3-iodo-4-amino-pyridines (Scheme 13). Treatment of an optionally protected 2-chloro-3-iodo-4-amino-pyridine 13.1 (such as tert-butyl 2-chloro-3- iodopyridin-4-ylcarbamate, R=Boc) can be treated with nucleophiles such as, but not limited to, amines, alkoxides, or thioalkoxides, in the presence of a suitable solvent, such as dioxane, to yield iodopyridines 13.2. Treatment of iodide 13.2 with an alkyne 11.2 in the presence of a suitable catalyst, such as dichloro-bis(triphenylphosphine)palladium (II), a suitable additive, such as copper(I)iodide, a base, such as triethylamine, with or without a suitable solvent, at temperatures ranging from 20 °C to 150 °C yields alkyne 13.3. Treatment of amino alkyne 13.3 (R=H, following a suitable deprotection) under diazotization conditions, such as sodium nitrate and toluenesulfonic acid, in a suitable solvent, such as acetonitrile, followed by sodium iodide, yields iodide 13.4. Treatment of iodide 13.4 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields amino alkyne 13.5. Cyclization of amino alkyne 13.5 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert- butylphosphine)palladium(O), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield pyrrolo[3,2-c]pyridine 13.6.
Scheme 14
Figure imgf000052_0001
[00155] Specifically, selected examples from the invention described herein can be synthesized from optionally substituted 2-bromo-3-chloropyridines 14.1 (Scheme 14). Treatment of bromide 14.1 with an alkyne 1 1.2 in the presence of a suitable catalyst, such as dichloro- bis(triphenylphosphine)palladium (II), a suitable additive, such as copper(I)iodide, a base, such as triethylamine, with or without a suitable solvent, at temperatures ranging from 20 °C to 150 °C yields alkyne 14.2. Treatment of chloride 14.2 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields amino alkyne 14.3. Cyclization of amino alkyne 14.3 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert-butylphosphine)palladium(0), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield pyrrolo[3,2-b]pyridines 14.4.
Scheme 15
YH2
Figure imgf000052_0002
[00156] Specifically, selected examples from the invention described herein can be synthesized from optionally substituted 2-chloro-3-iodo-pyridines 15.1 (Scheme 15). Treatment of iodide 15.1 with an alkyne 11.2 in the presence of a suitable catalyst, such as dichloro- bis(triphenylphosphine)palladium (II), a suitable additive, such as copper(I)iodide, a base, such as triethylamine, with or without a suitable solvent, at temperatures ranging from 20 °C to 150 °C yields alkyne 15.2. Treatment of chloride 15.2 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields amino alkyne 15.3. Cyclization of amino alkyne 15.3 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert-butylphosphine)palladium(0), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield pyrrolo[2,3-b]pyridines 15.4.
Scheme 16
Figure imgf000053_0001
16.5 16.6
[00157] Specifically, selected examples from the invention described herein can be synthesized starting from 6-chloro-3-iodo-2 -amino-pyridines (Scheme 16). Treatment of an optionally protected 2-amino-6-chloro-3-iodo-pyridine 16.1 with an alkyne 11.2 in the presence of a suitable catalyst, such as dichloro-bis(triphenylphosphine)palladium (II), a suitable additive, such as copper(I)iodide, a base, such as triethylamine, with or without a suitable solvent, at temperatures ranging from 20 °C to 150 °C yields alkyne 16.2. Someone skilled in the art will recognize that chloro alkyne 16.2 can be functionalized in a variety of ways. It may be advantageous to protect reactive functional groups, such as the amino group. Treatment of chloro-pyridine 16.2 with suitable reagents such, as boronic acids and boronates, organoboranes, organostannanes, organozinc compounds, organomagnesium compounds, olefins or terminal alkynes (either purchased or obtained via generally well known protocols), can be carried out in the presence of a suitable transition metal catalyst (e.g., palladium compounds). The coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines. Organic or inorganic bases (e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates) and/or other well known additives (e.g., lithium chloride, copper halides or silver salts) maybe utilized to effect, assist or accelerate such transformations. These cross coupling reactions may be carried out in suitable solvents, such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N- methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C. The temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
[00158] This methodology may be extended to the incorporation of non-carbon based nucleophiles (e.g., alcohols, thiols, primary or secondary amines) that may optionally contain suitable protecting groups of alcohols, thiols or amines. Examples of such groups can be found in Greene T. et al., supra. Exemplary methods of such utilization of non-carbon nucleophiles in related cross-coupling reactions may be found in Ley S. et al., Angew. Chem., /75:5558 (2003); Wolfe J. et al., Ace. Chem. Res., 31 :805 (1998); Hartwig, Ace. Chem. Res., 31 :852 (1998); Navarro O., et al., J. Org. Chem., 69:3173 (2004), Ji J. et al., Org. Lett, 5:4611 (2003). The skilled artisan will recognize that the compounds obtained by such methods can be further elaborated by generally well known methods to obtain other compounds of the present invention.
[00159] Some of the compounds in the present invention may be synthesized by treatment of
5-chloro-imidazo[4,5-b]pyridine 16.2 with a nucleophile, such as a primary or secondary amine, or an alcohol, in the presence of carbon monoxide, a suitable catalyst, such as dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium(II), a base, such as triethylamine, and a solvent, such as dioxane, at temperatures ranging from 80-160 °C. Conventional heating or microwave irradiation may be employed to maintain the appropriate temperature (Exemplary methods of carbonylation may be found in Brennfuhrer, A. et al., Angew. Chem., 48(23):4114 (2009)).
[00160] Alternatively, compounds described in the invention may be synthesized by treating chloro-imidazo[4,5-b]pyridine 16.2 with a suitably protected carbon-based nucleophiles (e.g., malonates) and non-carbon based nucleophiles (e.g., alcohols, thiols, primary or secondary amines) via nucleophilic aromatic substitution. The reactions may be accelerated using an appropriate acid, such as toluenesulfonic acid, or base, such as triethylamine, diisopropylethylamine, sodium hydride, or an alkaline carbonate base, in the presence or absence of a suitable solvent, such as, but not limited to, THF, dioxane, DMF, DMA, DMSO, or acetonitrile. [00161] Amino-alkyne 16.3 can be converted to bromo-alkyne 16.4 under diazotization conditions, such as sodium nitrate and toluenesulfonic acid, in a suitable solvent, such as acetonitrile, followed by sodium iodide. Treatment of bromide 16.4 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields amino alkyne 16.5. Cyclization of amino alkyne 16.5 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert-butylphosphine)palladium(0), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield pyrrolo[2,3-b]pyridines 16.6.
Scheme 17
Figure imgf000055_0001
[00162] An alternative method to synthesize selected examples from the invention described herein is shown in Scheme 17. Treatment of amino alkyne 16.2 with a suitable halide (such as bromide 11.8a) in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos), a base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 25 °C to 200 °C produces 6-chloro pyrrolo[2,3-b]pyridines 17.1. The temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
[00163] Treatment of 6-chloro pyrrolo[2,3-b]pyridines 17.1 with suitable reagents, such as boronic acids and boronates, organoboranes, organostannanes, organozinc compounds, organomagnesium compounds, olefins or terminal alkynes (either purchased or obtained via generally well known protocols), can be carried out in the presence of a suitable transition metal catalyst (e.g., palladium compounds). The coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines. Organic or inorganic bases (e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates) and/or other well known additives (e.g., lithium chloride, copper halides or silver salts) maybe utilized to effect, assist or accelerate such transformations. These cross coupling reactions may be carried out in suitable solvents, such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N-methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C. The temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
[00164] The Pd catalyzed coupling or SnAr reaction from 17.1 to 16.6 may be performed similarly as in Scheme 3 (compound 3.2 to compound 2.4), and as such, the description of those potential reactions (see above) apply to Scheme 17 as well.
Scheme 18
Figure imgf000056_0001
18.1 18.2 1 B J
[00165] Selected examples from the invention described herein can be synthesized from optionally substituted 4-chloro-5-iodo-pyrimidine 18.1 (Scheme 18). Treatment of iodide 18.1 with an alkyne 11.2 in the presence of a suitable catalyst, such as dichloro- bis(triphenylphosphine)palladium (II), a suitable additive, such as copper(I)iodide, a base, such as triethylamine, with or without a suitable solvent, at temperatures ranging from 20 °C to 150 °C yields alkyne 18.2. Treatment of chloride 18.2 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields pyrrolo[2,3-d]pyrimidines 18.3.
Scheme 19
^IH2
Figure imgf000057_0001
19.5
[00166] Selected examples from the invention described herein can be synthesized from optionally substituted 2,4-dichloro-5-iodo-pyrimidine 19.1 (Scheme 19). Treatment of dichloride
19.1 with an aniline, such as 1.2, in the presence of a base, such as triethylamine, in a suitable solvent, such as THF results in the formation of iodoaniline 19.2. Treatment of 19.2 with an alkyne
11.2 in the presence of a suitable catalyst, such as dichloro-bis(triphenylphosphine)palladium (II), a suitable additive, such as copper(I)iodide, a base, such as triethylamine, with or without a suitable solvent, at temperatures ranging from 20 °C to 150 °C yields alkyne 19.3. Cyclization of amino alkyne 19.3 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert-butylphosphine)palladium(0), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield 2-chloro pyrrolo[2,3-d]pyrimidines 19.4. Treatment of 2-chloro pyrrolo[2,3-d]pyrimidines 19.4 with suitable reagents such, as boronic acids and boronates, organoboranes, organostannanes, organozinc compounds, organomagnesium compounds, olefins or terminal alkynes (either purchased or obtained via generally well known protocols), can be carried out in the presence of a suitable transition metal catalyst (e.g., palladium compounds). The coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines. Organic or inorganic bases (e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates) and/or other well known additives (e.g., lithium chloride, copper halides or silver salts) maybe utilized to effect, assist or accelerate such transformations. These cross coupling reactions may be carried out in suitable solvents, such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N- methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C. The temperature may optionally be maintained with heating, conventional heating or microwave irradiation. [00167] The Pd catalyzed coupling or SnAr reaction from 19.4 to 19.5 may be performed similarly as in Scheme 3 (compound 3.2 to compound 2.4), and as such, the description of those potential reactions (see above) apply to Scheme 19 as well.
Scheme 20
^H2
Figure imgf000058_0001
20.5
[00168] Selected examples from the invention described herein can be synthesized from optionally substituted 4,6-dichloro-5-iodo-pyrimidine 20.1 (Org. Lett.; 11(8), 2009; 1837 - 1840) as seen in Scheme 20. Treatment of dichloride 20.1 with an aniline, such as 1.2, in the presence of a base, such as triethylamine, in a suitable solvent, such as THF results in the formation of iodoaniline 20.2. Treatment of 20.2 with an alkyne 11.2 in the presence of a suitable catalyst, such as dichloro-bis(triphenylphosphine)palladium (II), a suitable additive, such as copper(I)iodide, a base, such as triethylamine, with or without a suitable solvent, at temperatures ranging from 20 °C to 150 °C yields alkyne 20.3. Cyclization of amino alkyne 20.3 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert-butylphosphine)palladium(0), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield 4-chloro pyrrolo[2,3-d]pyrimidines 20.4. Treatment of 4- chloro pyrrolo[2,3-d]pyrimidines 20.4 with suitable reagents, such as boronic acids and boronates, organoboranes, organostannanes, organozinc compounds, organomagnesium compounds, olefins or terminal alkynes (either purchased or obtained via generally well known protocols), can be carried out in the presence of a suitable transition metal catalyst (e.g., palladium compounds). The coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines. Organic or inorganic bases (e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates) and/or other well known additives (e.g., lithium chloride, copper halides or silver salts) maybe utilized to effect, assist or accelerate such transformations. These cross coupling reactions may be carried out in suitable solvents, such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N-methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C. The temperature may optionally be maintained with heating, conventional heating or microwave irradiation.
[00169] The Pd catalyzed coupling or SnAr reaction from 20.4 to 20.5 may be performed similarly as in Scheme 3 (compound 3.2 to compound 2.4), and as such, the description of those potential reactions (see above) apply to Scheme 20 as well.
Scheme 21
}JH2
Figure imgf000059_0001
21.5 21.6
[00170] Selected examples from the invention described herein can be synthesized from
2,4.6-trichloro-5-iodo-pyrimidine 21.1 (Scheme 21). Treatment of trichloride 21.1 with an aniline, such as 1.2, in the presence of a base, such as triethylamine, in a suitable solvent, such as THF, results in the formation of iodoaniline 21.2. Treatment of 21.2 with an alkyne 11.2 in the presence of a suitable catalyst, such as dichloro-bis(triphenylphosphine)palladium (II), a suitable additive, such as copper(I)iodide, a base, such as triethylamine, with or without a suitable solvent, at temperatures ranging from 20 °C to 150 °C yields alkyne 21.3. Cyclization of amino alkyne 21.3 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert-butylphosphine)palladium(0), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield 2,4-dichloro pyrrolo[2,3- djpyrimidines 21.4. In scheme 21, the two R4 groups can be the same of can be different.
[00171] Someone skilled in the art will recognize that further functionalization according to
Scheme 20 can lead to 2-chloro-4-substituted-pyrrolo[2,3-d]pyrimidines 21.5, which can be functionalized according to Scheme 19 to lead to tetrasubstituted pyrrolo[2,3-d]pyrimidines 21.6. Scheme 22
^H2
Figure imgf000060_0001
22.1 22.2
[00172] Selected examples from the invention described herein can be synthesized from optionally substituted 3-chloro-4-iodo-pyridine 22.1 (Scheme 22). Treatment of iodide 22.1 with an alkyne 11.2 in the presence of a suitable catalyst, such as dichloro- bis(triphenylphosphine)palladium (II), a suitable additive, such as copper(I)iodide, a base, such as triethylamine, with or without a suitable solvent, at temperatures ranging from 20 °C to 150 °C yields alkyne 22.2. Treatment of chloride 22.2 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields pyrrolo[2,3-d]pyrimidines 22.3.
Scheme 23
Figure imgf000060_0002
23.1 23.2 23 3 23.4
[00173] Selected examples from the invention described herein can be synthesized from optionally substituted 2,3-dichloro-pyrazines 23.1 (Scheme 23). Treatment of dichloride 23.1 with an alkyne 11.2 in the presence of a suitable catalyst, such as dichloro- bis(triphenylphosphine)palladium (II), a suitable additive, such as copper(I)iodide, a base, such as triethylamine, with or without a suitable solvent, at temperatures ranging from 20 °C to 150 °C yields alkyne 23.2. Treatment of chloride 23.2 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields amino alkyne 23.3. Cyclization of amino alkyne 23.3 can be achieved by treatment with a base, such as cesium carbonate and potassium fluoride, with or without the use of a catalyst, such as di(tri-tert-butylphosphine)palladium(0), in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C to yield pyrrolo[3,2-b]pyrazines 23.4.
Scheme 24
Figure imgf000061_0001
[00174] Selected examples from the invention described herein can be synthesized from optionally substituted 2,4-dichloro-5-bromo-pyrimidine 24.1 (Scheme 24). Treatment of dichloride 24.1 with an alkyne 11.2 in the presence of a suitable catalyst, such as dichloro- bis(triphenylphosphine)palladium (II), a suitable additive, such as copper(I)iodide, a base, such as triethylamine, with or without a suitable solvent, at temperatures ranging from 20 °C to 150 °C yields alkyne 24.2. Treatment of 24.2 with a suitable aniline 1.2 in the presence of a catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand, such as 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (X-phos), a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at temperatures ranging from 50 °C to 200 °C yields 2-chloro pyrrolo[3,2- djpyrimidines 24.3.
[00175] Treatment of 2-chloro pyrrolo[3,2-d]pyrimidines 24.3 with suitable reagents, such as boronic acids and boronates, organoboranes, organostannanes, organozinc compounds, organomagnesium compounds, olefins or terminal alkynes (either purchased or obtained via generally well known protocols), can be carried out in the presence of a suitable transition metal catalyst (e.g., palladium compounds). The coupling may optionally be performed in the presence of ligands such as, but not limited to, phosphines, diphosphines, heterocyclic carbenes, or arsines. Organic or inorganic bases (e.g., tertiary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates) and/or other well known additives (e.g., lithium chloride, copper halides or silver salts) maybe utilized to effect, assist or accelerate such transformations. These cross coupling reactions may be carried out in suitable solvents, such as THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, acetonitrile, DMF, N-methylpyrrolidone, water, or mixtures of thereof, at temperatures ranging from 25 °C to 200 °C. The temperature may optionally be maintained with heating, conventional heating or microwave irradiation. [00176] The Pd catalyzed coupling or SnAr reaction from 24.3 to 24.4 may be performed similarly as in Scheme 3 (compound 3.2 to compound 2.4), and as such, the description of those potential reactions (see above) apply to Scheme 24 as well.
Scheme 25
Figure imgf000062_0001
25.1 25.3
[00177] Selected examples from the invention described herein can be synthesized from optionally substituted 4-chloro-5-iodo-pyrimidine 18.1 (Scheme 25). Treatment of chloride 18.1 with an aniline, such as 1.2, in the presence of a base, such as triethylamine, in a suitable solvent, such as THF results in the formation of iodoaniline 25.1. Treatment of 25.1 with a disubstituted alkyne 25.2 in the presence of a suitable catalyst, such as palladium(II) acetate, a suitable additive, such as lithium chloride, a base, such as potassium acetate, in a suitable solvent, such as DMF, at temperatures ranging from 50 °C to 200 °C yields 5,6-disubstituted pyrrolo[2,3-d]pyrimidines 20.4.
Scheme 26
Figure imgf000062_0002
[00178] Selected examples from the invention described herein can be synthesized from optionally substituted iodoaniline 19.2 (Scheme 26). Treatment of 19.2 with a disubstituted alkyne 25.2 in the presence of a suitable catalyst, such as palladium(II) acetate, a suitable additive, such as lithium chloride, a base, such as potassium acetate, in a suitable solvent, such as DMF, at temperatures ranging from 50 °C to 200 °C yields 5,6-disubstituted 2-chloro-pyrrolo[2,3- d]pyrimidines 26.1. Functionalization of 2-chloro-pyrrolo[2,3-d]pyrimidines 26.1 can be achieved under conditions similar to those outlined for Scheme 19. [00179] Another aspect of this invention provides a method of preparing a compound of Formula 1, comprising the steps of reducing a compound having the formula:
Figure imgf000063_0001
and reacting it with a compound of formula:
R1 O
wherein Het, R1 and R2 are as defined herein.
[00180] In an embodiment of the method of preparing a compound of formula 1 above, the reaction between the two compounds is an oxidative cyclization.
[00181] Another aspect of this invention provides a method of preparing a compound of Formula 1, comprising the steps of reacting a compound having the formula:
Figure imgf000063_0002
with a compound of formula:
f}JH2
R2
wherein Het, R1 and R2 are as defined herein and X2 is halo, e.g., chloride or bromide.
[00182] Another aspect of this invention provides a method of preparing a compound of
Formula 1 , comprising the steps of having the formula:
Figure imgf000063_0003
with a compound of formula: 3
R2 wherein Het, R1 and R2 are as defined herein and X3 is a halogen atom, Pg is an amine protecting group, e.g., acetyl, trifluoroacetyl, BOC, CBz and Fmoc.
[00183] In preparing compounds of Formula 1, protection of remote functionalities (e.g., primary or secondary amines, etc.) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, BOC, CBz and Fmoc. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, supra.
METHODS OF SEPARATION
[00184] In any of the synthetic methods for preparing compounds of Formula 1, it may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
[00185] Another class of separation methods involves treatment of a reaction mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
[00186] Selection of appropriate methods of separation depends on the nature of the materials involved. For example, boiling point and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One skilled in the art will apply techniques most likely to achieve the desired separation.
[00187] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Also, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column.
[00188] A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., J. Chromatogr., (1975) 113(3):283-302). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: "Drug Stereochemistry, Analytical Methods and Pharmacology," Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).
[00189] Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-β- phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
[00190] Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S., supra at p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-)menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem., (1982) 47:4165), of the racemic mixture, and analyzing the lH NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse- phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. of Chromatogr., (1990) 513:375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
METHODS OF TREATMENT WITH COMPOUNDS OF FORMULA 1
[00191] The compounds of the present invention can be used as prophylactics or therapeutic agents for treating diseases or disorders mediated by modulation or regulation of AKT protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or dual specificity kinases. AKT protein kinase mediated conditions that can be treated according to the methods of this invention include, but are not limited to, inflammatory, hyperproliferative cardiovascular, neurodegenerative, gynecological, and dermatological diseases and disorders.
[00192] In one embodiment, said pharmaceutical composition is for the treatment of hyperproliferative disorders, including cancers of the following categories: (1) Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; (2) Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung, small cell lung; (3) Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); (4) Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); (5) Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; (6) Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; (7) Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform. oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); (8) Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); (9) Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; (10) Skin: advanced melanoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; (11) Adrenal glands: neuroblastoma; (12) Breast: metastatic breast; breast adenocarcinoma; (13) Colon; (14) Oral cavity; (15) Hairy cell leukemia; (16) Head and neck; (17) and others including refractory metastatic disease; Kaposi's sarcoma; Bannayan-Zonana syndrome; and Cowden disease or Lhermitte-Duclos disease, among other kinds of hyperproliferative disorders.
[00193] In certain embodiments, the AKT protein kinase-mediated condition is a hyperproliferative disease.
[00194] In certain embodiments, the hyperproliferative disease is cancer.
[00195] In certain embodiments, the cancer is selected from colon, ovarian, brain, lung, pancreatic, prostate, and gastric carcinomas.
[00196] Compounds and methods of this invention can be also used to treat diseases and conditions such as rheumatoid arthritis, osteoarthritis, Chron's disease, angiofibroma, ocular diseases (e.g., retinal vascularisation, diabetic retinopathy, age-related macular degeneration, macular degeneration, etc.), multiple sclerosis, obesity, Alzheimer's disease, restenosis, autoimmune diseases, allergy, asthma, 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), septic shock, etc.
[00197] Accordingly, another aspect of this invention provides a method of treating diseases or medical conditions in a mammal mediated by AKT protein kinases, comprising administering to said mammal one or more compounds of Formula 1 or a pharmaceutically acceptable salt or prodrug thereof in an amount effective to treat or prevent said disorder.
[00198] This invention also provides compounds of Formula 1 for use in the treatment of
AKT protein kinase-mediated conditions.
[00199] An additional aspect of the invention is the use of a compound of Formula 1 in the preparation of a medicament for therapy, such as for the treatment or prevention of AKT protein kinase-mediated conditions.
COMBINATION THERAPY
[00200] The compounds of the present invention can be used in combination with one or more additional drugs such as described below. The dose of the second drug can be appropriately selected based on a clinically employed dose. The proportion of the compound of the present invention and the second drug can be appropriately determined according to the administration subject, the administration route, the target disease, the clinical condition, the combination, and other factors. In cases where the administration subject is a human, for instance, the second drug may be used in an amount of 0.01 to 100 parts by weight per part by weight of the compound of the present invention.
[00201] The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of this invention such that they do not adversely affect each other. Such drugs are suitably present in combination in amounts that are effective for the purpose intended. Accordingly, another aspect of the present invention provides a composition comprising a compound of this invention in combination with a second drug, such as described herein.
[00202] A compound of this invention and the additional pharmaceutically active drug(s) may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time. The amounts of the compound of this invention and the second drug(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. [00203] The combination therapy may provide "synergy" and prove "synergistic", i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
[00204] A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer, regardless of mechanism of action. Chemotherapeutic agents include compounds used in "targeted therapy" and conventional chemotherapy.
[00205] Examples of chemotherapeutic agents include PLX4032 (Roche/Plexxikon),
Erlotinib (TARCEVA®, Genentech/OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU 11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), Irinotecan (CAMPTOSAR®, Pfizer) and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), mo holino-doxorubicin, cyanomo holino-doxorubicin, 2- pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara- C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™ (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Illinois), and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above. [00206] Also included in the definition of "chemotherapeutic agent" are: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LYl 17018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1,3- dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H- Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKTN® rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such as bevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above.
[00207] Also included in the definition of "chemotherapeutic agent" are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
[00208] Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the PI3K inhibitors of the invention include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.
ROUTES OF ADMINISTRATION
[00209] The compounds of the invention may be administered by any route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. It will be appreciated that the preferred route may vary with for example the condition of the recipient. Where the compound is administered orally, it may be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable carrier or excipient. Where the compound is administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral vehicle and in a unit dosage injectable form, as detailed below.
PHARMACEUTICAL FORMULATIONS
[00210] In order to use a compound of this invention for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. According to this aspect of the invention there is provided a pharmaceutical composition that comprises a compound of this invention. In certain embodiments, the pharmaceutical composition comprises a compound of Formula 1 in association with a pharmaceutically acceptable diluent or carrier.
[00211] The pharmaceutical compositions of the invention are formulated, dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The therapeutically effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the disorder. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
[00212] The composition for use herein is preferably sterile. In particular, formulations to be used for in vivo administration must be sterile. Such sterilization is readily accomplished, for example, by filtration through sterile filtration membranes. The compound ordinarily can be stored as a solid composition, a lyophilized formulation or as an aqueous solution.
[00213] Pharmaceutical formulations of the compounds of the present invention may be prepared for various routes and types of administration. For example, a compound of this invention having the desired degree of purity may optionally be mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), in the form of a lyophilized formulation, a milled powder, or an aqueous solution. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8. Formulation in an acetate buffer at pH 5 is a suitable embodiment. The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bull- drug substance (i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more excipients.
[00214] The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). The formulations may also include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin- microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Osol, A., supra. A "liposome" is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as a compound of Formula 1 and, optionally, an additional therapeutic agent) to a mammal. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes. See also, Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
[00215] Sustained-release preparations of compounds of this invention may be prepared.
Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of Formula 1, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L- glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT® (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid.
[00216] The pharmaceutical compositions of compounds of this invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
[00217] Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
[00218] The compositions of the invention may also 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)
[00219] 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.
[00220] 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.
[00221] 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. 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).
[00222] 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.
[00223] 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.
[00224] 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 for example 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, 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.
[00225] 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.
[00226] Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient that is solid at ordinary temperatures 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. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. [00227] 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.
[00228] Compositions for transdermal administration may be in the form of those transdermal skin patches that are well known to those of ordinary skill in the art.
[00229] Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis disorders as described below.
[00230] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. For example, an article for distribution can include a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. The formulations may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
[00231] The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route. [00232] The amount of a compound of this invention that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the subject treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. In one embodiment, a suitable amount of a compound of this invention is administered to a mammal in need thereof. Administration in one embodiment occurs in an amount between about 0.001 mg/kg of body weight to about 60 mg/kg of body weight per day. In another embodiment, administration occurs in an amount between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day. For further information on routes of administration and dosage regimes, see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which is specifically incorporated herein by reference.
ARTICLES OF MANUFACTURE
[00233] In another embodiment of the invention, an article of manufacture, or "kit", containing materials useful for the treatment of the disorders described above is provided. In one embodiment, the kit comprises a container comprising a compound of this invention. Suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The container may be formed from a variety of materials such as glass or plastic. The container may hold a compound of this invention or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
[00234] The kit may further comprise a label or package insert on or associated with the container. The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. In one embodiment, the label or package inserts indicates that the composition comprising a compound of this invention can be used to treat a disorder mediated, for example, by AKT kinase. The label or package insert may also indicate that the composition can be used to treat other disorders.
[00235] In certain embodiments, the kits are suitable for the delivery of solid oral forms of a compound of this invention, such as tablets or capsules. Such a kit preferably includes a number of unit dosages. Such kits can include a card having the dosages oriented in the order of their intended use. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.
[00236] According to another embodiment, a kit may comprise (a) a first container with a compound of this invention contained therein; and (b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a second compound useful for treating a disorder mediated by AKT kinase. Alternatively, or additionally, the kit may further comprise a third container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate- buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
[00237] The kit may further comprise directions for the administration of the compound of this invention and, if present, the second pharmaceutical formulation. For example, if the kit comprises a first composition comprising a compound of this invention and a second pharmaceutical formulation, the kit may further comprise directions for the simultaneous, sequential or separate administration of the first and second pharmaceutical compositions to a patient in need thereof.
[00238] In certain other embodiments wherein the kit comprises a composition of this invention and a second therapeutic agent, the kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet, however, the separate compositions may also be contained within a single, undivided container. In certain embodiments, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
[00239] Accordingly, a further aspect of this invention provides a kit for treating a disorder or disease mediated by Akt kinase, wherein said kit comprises a) a first pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable salt thereof; and b) instructions for use.
[00240] In certain embodiments, the kit further comprises (c) a second pharmaceutical composition, wherein the second pharmaceutical composition comprises a second compound suitable for treating a disorder or disease mediated by Akt kinase. In certain embodiment comprising a second pharmaceutical composition, the kit further comprises instructions for the simultaneous, sequential or separate administration of said first and second pharmaceutical compositions to a patient in need thereof. In certain embodiments, said first and second pharmaceutical compositions are contained in separate containers. In other embodiments, said first and second pharmaceutical compositions are contained in the same container.
[00241] Although the compounds of Formula 1 are primarily of value as therapeutic agents for use in mammals, 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.
[00242] 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. These and other useful in vitro and cell culture assays are well known to those of skill in the art.
[00243] Although the invention has been described and illustrated with a certain degree of particularity, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the combination and arrangement of parts can be resorted to by those skilled in the art without departing from the spirit and scope of the invention, as hereinafter claimed.
BIOLOGICAL EXAMPLES
AKT-1 Kinase Assay
[00244] The activity of the compounds described in the present invention may be determined by the following kinase assay, which 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.
[00245] The assay materials are obtained from an IMAP AKT Assay Bulk Kit, product
#R8059, from Molecular Devices, Sunnyvale, CA. The kit materials include an IMAP Reaction Buffer (5x). The diluted lx IMAP Reaction Buffer contained 10 raM Tris-HCl, pH 7.2, 10 raM MgCl2i 0.1% BSA. DTT is routinely added to a final concentration of 1 raM immediately prior to use. Also included is IMAP Binding Buffer (5x), and IMAP Binding Reagent. The Binding Solution is prepared as a 1 :400 dilution of IMAP Binding Reagent into lx IMAP Binding Buffer.
[00246] The fluorescein-labeled AKT Substrate (Crosstide) has the sequence (Fl)-
GRPRTSSFAEG. A stock solution of 25 μΜ is made up in lx IMAP Reaction Buffer.
[00247] 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 is a Packard ProxiPlate™-384 F.
[00248] The AKT-1 used is made from full-length, human recombinant AKT-1 that is activated with PDK1 and MAP kinase 2.
[00249] To perform the assay, stock solutions of compounds at 10 mM in DMSO are prepared. The stock solutions and the control compound are serially diluted 1 :3 ten times into DMSO (5 of compound + 10 μΐ, of DMSO) to give 50x dilution series over the desired dosing range. Next, l-μΐ., aliquots of the compounds in DMSO are transferred to a Costar 3657 plate containing 49 \iL of 10.4 μΜ ATP in lx IMAP Reaction Buffer containing 1 mM DTT. After thorough mixing, 2.5-μΙ_- aliquots are transferred to a ProxyPlate™-384 F plate.
[00250] The assay is initiated by the addition of 2.5-μΙ. aliquots of a solution containing 200 nM of fluorescently-labeled peptide substrate and 20 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
Figure imgf000081_0001
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.
[00251] The compounds of Examples 1-175 were tested in the above assay and found to have an IC5o of less than <25 μΜ.
Figure imgf000081_0002
77 2-C 2.0043 2 3-E 0.0459
160 2-D 1.2789 1 3-E 0.069
130 2-E 0.0044 6 3-E 0.0737
129 2-E 0.0086 60 3-E 0.088
131 2-E 0.0239 59 3-E 0.1072
158 2-E 0.0419 3 3-E 0.1367
109 2-E 0.1436 21 3-E 0.1809
126 2-E 0.2186 32 3-E 0.1847
157 2-E 0.5117 20 3-E 0.2066
139 2-F 0.0077 51 3-E 0.2202
140 2-F 0.0195 11 3-E 0.2259
138 2-F 0.0611 35 3-E 0.2364
137 2-F 0.1 153 4 3-E 0.2367
136 2-F 0.4076 36 3-E 0.2419
116 2-F 0.6512 154 3-G 0.6607
PREPARATIVE EXAMPLES
[00252] In order to illustrate the invention, the following examples are included. However, it is to be understood that these examples do not limit the invention and are only meant to suggest a method of practicing the invention. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds of Formula 1, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.
[00253] In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge, and were used without further purification unless otherwise indicated. Tetrahydrofuran (TF1F), dichloromethane (DCM), toluene, and dioxane were purchased from Aldrich in Sure seal bottles and used as received. [00254] The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the 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.
[00255] Ή NMR spectra were recorded on a Varian instrument operating at 400 MHz. 1H-
NMR spectra were obtained as CDC13, CD3OD, D20 or d6-DMSO solutions (reported in ppm), using tetramethylsilane (0.00 ppm) or residual solvent (CDC13: 7.25 ppm; CD3OD: 3.31 ppm; D20: 4.79 ppm; d6-DMSO: 2.50 ppm) as the reference standard. 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). Coupling constants, when given, are reported in Hertz (Hz).
Examples
Example A
Figure imgf000083_0001
{ l-f4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl1-cyclobutyl}-carbamic acid tert-butyl ester
[00256] Step A: To a solution of 2,4-Dichloro-5-nitro-pyrimidine (5.00 g, 26.00mmol) in
THF (100 mL) was added the solution of [l-(4-Amino-phenyl)-cyclo-butyl]-carbamic acid tert- butyl ester (6.82 g, 26.00 mmol) in THF (20 mL) slowly at 0 °C. After addition, the reaction mixture was stirred at ambient temperature for 3 h. Then the reaction was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (250 mL) and washed with saturated sodium bicarbonate solution and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to afford { l-[4-(2-Chloro-5-nitro-pyrimidin-4-ylamino)- phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (9.50 g, 87% yield). 1H NMR (DMSO, 400 MHz), δ ppm: 10.41 (s, 1H), 9.14 (s, 1H), 7.61 (s, 1H), 7.48-7.46 (m, 2H), 7.43-7.41 (m, 2H), 2.41- 2.35 (m, 4H), 2.08-1.93 (m, 1H), 1.85-1.73 (m, 1H), 1.34 (s, 9H). MS (ESI+) e/z: 420.1/422.1 [M+l] +.
[00257] Step B: {l-[4-(2-Chloro-5-nitro-pyrimidin-4-ylamino)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester (4.10 g, 9.78 mmol) was dissolved in THF (200 mL) and Raney- Ni (1.00 g) was added. The reaction mixture was stirred at ambient temperature under an atmosphere of hydrogen (balloon) for 4 h. The solvent was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate (200 mL). The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel (eluted by ethyl acetate: hexane=l :l to 3:1) to give the desired product: { l-[4-(5-Amino-2-chloro-pyrimidin-4-ylamino)-phenyl]-cyclobutyl}-carbamic acid tert- butyl ester. (3.5 g, 92% yield), MS (ESI+) e/z: 390.1/392.1 [M+l]+
[00258] Step C: To a solution of { l-[4-(5-Amino-2-chloro-pyrimidin-4- ylamino)-phenyl]- cyclo-butyl} -carbamic acid tert-butyl ester (2.5 g, 6.42 mmol) in acetic acid (30 mL) was added benzaldehyde (0.89 g, 8.35 mmol) and Cu(OAc)2 (0.58 g, 3.21 mmol). The reaction mixture was stirred at 100 °C for 2 h.. Then the solvent was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate (150 mL). The organic layer was washed with sat. NaHC03 aqueous solution, followed by brine, dried over sodium sulfate, filtered and concentrated to yield 2.50 g of { l-[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl] -cyclobutyl} -carbamic acid tert-butyl ester.
[00259] Ή NMR (DMSO, 400 MHz), δ ppm: 9.21 (s, 1H), 7.84-7.56 (m, 5H), 7.51-7.40 (m,
2H), 7.38-7.30 (m, 3 H), 2.47-2.40 (m, 4H), 2.08-1.97 (m, 1H), 1.87-1.75 (m, 1H), 1.34 (s, 9H).MS (ESI+) e/z: 476.2/478.2 [M+l]+. (Containing 15% by-product N-{ 1 -[4-(2-Chloro-8-phenyl-purin-9- yl)-phenyl]-cyclobutyl}-acetamide. MS (ESI+) e/z: 418.1/420.1 [M+l]+).
Example 1
Figure imgf000084_0001
1 - [4-(2,8-Diphenyl-purin-9-yl)-phenvH-cvclobutylamine
[00260] Step A: { l-[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (500 mg, 1.05 mmol), phenylboronic acid (256 mg, 2.10 mmol), Pd(dppf)Cl2 (77 mg, 0.11 mmol), and Cs2C03 (684 mg, 2.10 mmol) were added into a mixed solution (dioxane: 20 mL, water: 4 mL). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 4 h. The solvents were removed under reduced pressure and the resulting residue was dissolved in ethyl acetate (150 mL). The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (ethyl acetate: Hexane=l :2) to give desired product: { l-[4-(2,8-Diphenyl-purin-9-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (200 mg, 37% yield), MS (ESI+) e/z: 518.3 [M+l]+.
[00261] Step B: { l-[4-(2,8-Diphenyl-purin-9-yl)-phenyl]-cyclobutyl}-carbamic acid tert- butyl ester (200 mg, 0.39 mmol) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The crude product was collected by filtration, which was further purified by preparative HPLC to afford l-[4-(2,8-Diphenyl-purin-9-yl)-phenyl]-cyclobutylamine (52 mg, 32% yield). 1H NMR (MeOD, 400 MHz), δ ppm: 9.19 (s, 1H), 8.36-8.35 (m, 2H), 7.71- 7.69 (m, 2H), 7.63-7.60 (m, 2H), 7.57-7.48 (m, 2H), 7.43-7.40 (m, 6H), 2.80-2.75 (m, 2H), 2.59- 2.52 (m, 2H), 2.29-2.20 (m, 1H), 2.05-1.95 (m, 1H).
[00262] Examples 2-4 shown in Table 1 can also be made according to the above-described methods.
Table 1
Figure imgf000085_0001
Figure imgf000086_0001
Example 5
Figure imgf000086_0002
1 -r4-(8-Phenyl-2-piperazin- 1 -yl-purin-9-yl)-phenyl]-cvclobutylamine
[00263] Step A: To a solution of { l-[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclo- butylj-carbamic acid tert-butyl ester (70 mg, 0.147 mmol) in dioxane (20 mL) was added piperazine (63 mg, 0.737 mmol). Then the reaction mixture was stirred at 80 °C for 3h. The solvent was removed under reduced pressure, the resulting residue was dissolved in ethyl acetate (100 mL), washed with water (50 mL). The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product { l-[4-(8-Phenyl-2-piperazin-l-yl-purin-9-yl)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester (-65 mg) was used without further purification. MS (ESI+) e/z: 526.2 [M+l]+).
[00264] Step B: {l-[4-(8-Phenyl-2-piperazin-l-yl-purin-9-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (-65 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The crude product was collected by filtration, which was further purified by preparative HPLC to afford l-[4-(8-Phenyl-2~ piperazin-l-yl-purin-9-yl)-phenyl]- cyclobutylamine (30 mg, 48% yield over two steps). MS (ESI+) e/z: 426.2 [M+1] +. 'HNMR (MeOD, 400MHz) δ ppm: 8.81 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.52-7.43 (m, 5H), 7.38-7.34 (m, 2H), 4.00 (t, J=4.8 Hz, 4H), 3.18 (t, J=5.0 Hz, 4H), 2.82-2.73 (m, 2H), 2.61-2.50 (m, 2H), 2.30-2.20 (m, 1H), 2.03-1.93 (m, 1H).
[00265] Example 6 shown in Table 2 can also be made according to the above-described methods.
Table 2
Figure imgf000087_0002
Example 7
Figure imgf000087_0001
l-(4-(2-methoxy-8-phenyl-9H-purin-9-vnphenyl)cyclobutanamine
[00266] Step A: To a solution of {l-[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclo- butyl}-carbamic acid tert-butyl ester (70 mg, 0.147 mmol) in methanol (20 mL) was added sodium methanolate (24 mg, 0.441 mmol). The reaction mixture was stirred at 80 °C for 3 h. Then the solvent was removed under reduced pressure, the resulting residue was dissolved in ethyl acetate (80 mL), washed with water (50 mL). The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product tert-butyl l-(4-(2-methoxy-8-phenyl-9H-purin-9- yl)phenyl)cyclobutylcarbamate (-65 mg) was used without further purification. MS (ESI+) e/z: 472.2 [M+l]+.
[00267] Step B: tert-butyl l-(4-(2-methoxy-8-phenyl-9H-purin-9-yl)phenyl)cyclo- butylcarbamate (-65 mg) was dissolved in ethyl acetate (20 mL), the solution was cooled to 0 °C and a solution of HCl in ethyl acetate (4 M, 5 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The crude product was collected by filtration, which was further purified by preparative HPLC to afford l-(4-(2-methoxy-8-phenyl-9H-purin— 9- yl)phenyl)cyclobutanamine (25 mg, 45% yield over two steps). MS (ESI+) e/z: 372.2 [M+1] +. 1 HNMR(MeOD,400MHz), δ ppm: 8.91 (s, 1H), 7.66-7.54 (m, 2H), 7.56-7.54 (m, 2H), 7.49-7.44 (m, 3H), 7.39-7.35 (m, 2H), 3.97 (s, 3H), 2.75-2.65 (m, 2H), 2.50-2.43 (m, 2H), 2.25-2.16 (m, 1H), 1.96-1.87 (m, 1H).
[00268] Example 8 shown in Table 3 can also be made according to the above-described methods.
Table 3
Figure imgf000088_0002
Example 9
Figure imgf000088_0001
1 - ( 9-[4-( 1 -Amino-cyclobutyl Vphenyl]-8-phenyl-9H-purin-2-yl } -pyrrolidin-2-one
[00269] Step A: { l-[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (50 mg, 0.11 mmol), pyrrolidin-2-one (14 mg, 0.16 mmol), Pd2(dba)3 (19 mg, 0.02 mmol), Xantphos (15 mg, 0.03 mmol) and Cs2C03 (68 mg, 0.21 mmol) were dissolved in dioxane (10 mL). The reaction mixture was stirred at 90 °C under nitrogen atmosphere for 6 h. Then the solvent was removed by under reduce pressure, the resulting residue was dissolved in ethyl acetate (30 mL). The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by prep-TLC (EtOAc:Hexane=l :l) to give (l-{4-[2- (2-Oxo-pyrrolidin-l-yl)-8-phenyl-purin-9-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (30 mg, 52% yield). MS (ESI+) e/z: 525.5 [M+l]+).
[00270] Step B: (l-{4-[2-(2-Oxo-pyrrolidin-l-yl)-8-phenyl-purin-9-yl]-phenyl}-cyclobutyl)- carbamic acid tert-butyl ester (30 mg, 0.057 mmol) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The crude product was collected by filtration, which was further purified by preparative HPLC to afford l-{9-[4-(l-Amino-cyclobutyl)- phenyl]-8-phenyl-9H-purin-2-yl}-pyrrolidin-2-one (20 mg, 83% yield). MS (ESI+) e/z: 425.5 [M+l]+. 1H NMR (MeOD, 400 MHz), δ ppm: 9.26 (s, 1H), 7.69-7.62 (m, 4H), 7.57-7.49 (m, 3H), 7.40 (t, J=7.8 Hz, 2H), 2.98 (s, 3H), 2.82-2.75 (m, 2H), 2.58-2.53 (m, 2H), 2.26-2.21 (m, 1H), 2.05- 1.92 (m, 1H).
Example 10
Figure imgf000089_0001
{ 9-[4-( 1 -Amino-cyclobutyl)-phenyll-8-phenyl-9H-purin-2-yl -methyl-amine
[00271] Step A: To a solution of { 1 -[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester (150 mg, 0.32 mmol) in dioxane (4 mL) was added the aqueous methylamine amine solution (10 mL, 28% wt) at a sealed vessel. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with water (40 mL). The separated organic layer was dried over sodium sulfate, filtered and
concentrated. The crude product {9-[4-(l-Amino-cyclobutyl)-phenyl]-8-phenyl-9H-purin-2-yl}- methyl-amine (-120 mg) was used in the step without purification. MS (ESI+) e/z: 471.4 [M+l]+).
[00272] Step B: { l-[4-(2-Methylamino-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (-120 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The crude product was collected by filtration, which was further purified by preparative HPLC to afford {9-[4-(l-Amino-cyclobutyl)-phenyl]-8-phenyl-9H-purin-2- yl}-methyl-amine (50 mg, 42% yield). MS (ESI+) e/z: 371.4 [M+lf. 1HNMR(MeOD,400MHz), δ ppm: 8.66 (s, 1H), 7.64-7.61 (m, 2H), 7.51-7.41 (m, 4H), 7.37-7.36 (m, 1H), 7.35-7.33 (m, 2H), 2.87 (s, 3H), 2.82-2.74 (m, 2H), 2.59-2.52 (m, 2H), 2.25-2.22 (m, 1H), 2.00-1.93 (m, 1H). [00273] Examples 1 1 and 12 shown in Table 4 can also be made according to the above- described methods.
Table 4
Figure imgf000090_0002
Example B
Figure imgf000090_0001
2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-4-(trimethylstannyl)-lH-imidazole
[00274] 4-iodo-2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole (600 mg, 1.77 mmol) was dissolved dichloromethane (25 mL), and the solution was cooled to -78 °C, followed by adding ethylmagnesium bromide (3 M in THF, 0.71 mL, 2.13 mmol) slowly. After addition, the reaction mixture was stirred at -78 °C for 1 h. Then chlorotrimethylstannane (1 in THF, 2.1 mL, 2.13 mmol) was added slowly into the reaction mixture at the same temperature. After addition, the reaction mixture was allowed to be warmed to ambient temperature and stirred for another 2 h. The reaction mixture was poured into an aqueous saturated NH4CI solution, and extracted with ethyl acetate. The separated organic layer was washed with water twice and dried over sodium sulfate, filtered and concentrated to afford 2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-4- (trimethylstannyl)-lH-imidazole (-420 mg), which was used in next step without further purification. MS (ESI+) e/z: 377.1 [M+l]+.
Example C
Figure imgf000091_0001
3-methyl- 1 -((2-(trimethylsilyl)ethoxy)methyl)-5-(trimethylstannyl)- 1 H-pyrazole
[00275] Step A: 3-methyl- l-((2-(trimethylsilyl)ethoxy)methyl)-l H-pyrazole (500 mg, 2.35 mmol) was dissolved in THF (18 mL), and the solution was cooled to -78°C, followed by adding butyllithium (2.5 M, 0.94 mL, 2.35 mmol) slowly. The reaction mixture was stirred at this temperature for 1 h. Then, chlorotrimethylstannane (1 M in THF, 2.4 mL, 2.35 mmol) was added into the reaction mixture. It was allowed to be warmed to ambient temperature and stirred overnight. The reaction mixture was poured into aqueous saturated NH4CI solution, and extracted with ethyl acetate. The separated organic layer was washed by water twice and dried over sodium sulfate, filtered and concentrated to afford 3-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-5- (trimethylstannyl)-l H-pyrazole (-300 mg), which was used without further purification. MS (ESI+) e/z: 377.2 [M+l]+.
Example D
Figure imgf000091_0002
3-methyl-5-(tributylstannyl)isoxazole
[00276] Step A: To a solution of nitroethane (0.15 g, 2.00 mmol) in toluene (6 mL) was added l-chloro-3-isocyanatobenzene (0.61 g, 4.00 mmol). The reaction mixture was stirred at 50 °C for 10 minutes followed by addition of triethylamine (10 mg, 0.1 mmol) and tributyl(ethynyl)stannane (0.60 g, 1.91 mmol). The reaction mixture was stirred at 50 °C overnight. After cooling, the solution was diluted with water and filtered through a celite pad. The resulting filtrate was extracted with toluene, the organic layer was dried over sodium sulfate, filtered and concentrated to afford 3-methyl-5-(tributylstannyl)isoxazole as a yellow oil (-300 mg), which was used without further purification. MS (ESI+) e/z: 374.2 [M+l]+.
Example 13
Figure imgf000092_0001
l-(4-[2-(2-Methyl-3H-imidazol-4-yl -8-phenyl-purin-9-yll-pheny -cyclobutylamine
[00277] Step A: To a solution of {l-[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclo- butyl}-carbamic acid tert-butyl ester (150 mg, 0.316 mmol) in dioxane (4 mL) was added an 2- Methyl-l-(2-trimethylsilanyl-ethoxymethyl)-4-trimethylstannanyl-lH- imidazole (-0.632 mmol, in THF) and Pd(PPh3)4 (36 mg, 0.032 mmol). The reaction mixture was irradiated by microwave at 120 °C for 50 minutes. The reaction mixture was diluted with ethyl acetate, and washed with water. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product [l-(4-{2-[2-Methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-8-phenyl- purin-9-yl}-phenyl)-cyclobutyl]-carbamic acid tert-butyl ester (-150 mg) was used without further purification.
[00278] Step B: [l-(4-{2-[2-Methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4- yl]-8-phenyl-purin-9-yl}-phenyl)-cyclobutyl]-carbamic acid tert-butyl ester (-150 mg) was dissolved in Methanol (10 mL), and aqueous HC1 (36%, 5 mL) was added into the solution. It was heated at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC to afford l-{4-[2-(2-Methyl-3H- imidazol-4-yl)-8-phenyl-purin-9-yl]-phenyl}-cyclobutylamine (25 mg, 19% yield, two steps). 1 HNMR(MeOD,400 MHz), δ ppm:9.12 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.62-7.57 (m, 5H), 7.48 (t, J=7.4 Hz, 1H), 7.38 (t, J=7.6 Hz, 2H), 2.88-2.81 (m, 2H), 2.68-2.60 (m, 2H), 2.43 (s, 3H), 2.32- 2.20 (m, 1H), 2.10-2.00 (m, 1H).
[00279] Examples 14 and 15 shown in Table 5 can also be made according to the above- described methods.
Table 5
Figure imgf000092_0002
Figure imgf000093_0001
Example 16
Figure imgf000093_0002
- 4-( 1 -Amino-cyclobutyl)-phenvn-8-phenyl-9H-purine-2-carboxylic acid methylamide [00280] Step A: To a solution of { 1 -[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester (250 mg, 0.526 mmol) in DMF (20 mL) were added methylamine hydrochloride (107 mg, 1.578 mmol), Pd(OAc)2 (35 mg, 0.158 mmol), Xantphos (107 mg, 0.184 mmol) and sodium carbonate (178 mg, 1.683 mmol). The reaction mixture was stirred at 100 °C under the atmosphere of carbon monoxide (balloon) overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product { l-[4-(2-Methylcarbamoyl-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (-200 mg) was used directly in next step without further purification. MS (ESI+) e/z: 499.3 [M+l]+.
[00281] Step B: { l-[4-(2-Methylcarbamoyl-8-phenyl-purin-9-yl)-phenyl]-cyclo-butyl}- carbamic acid tert-butyl ester (-200 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.. The crude product was collected by filtration, which was purified by preparative HPLC separation to afford 9-[4-(l-Amino-cyclobutyl)-phenyl]-8- phenyl-9H-purine-2-carboxylic acid methyl-amide (83 mg, 40% yield, two steps). MS (ESI+) e/z: 399.3 [M+l]+. 1 HNMR(MeOD,400MHz), δ ppm:9.26 (s, 1H), 7.69-7.62 (m, 4H), 7.57-7.49 (m, 3H), 7.40 (t, J=7.8 Hz, 2H), 2.98 (s, 3H), 2.82-2.75 (m, 2H), 2.58-2.53 (m, 2H), 2.26-2.21 (m, 1H), 2.05-1.92 (m, 1H)
Example 17
Figure imgf000094_0001
l-[4-(8-Phenyl-purin-9-yl)-phenyl -cvclobutylamine
[00282] Step A: To a solution of {l-[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester (250 mg, 0.526 mmol) in methanol (30 mL) was added Pd/C (200 mg, 10%wt). The mixture was stirred at 50 °C under the atmosphere of hydrogen (50 psi) for 12 h. The catalyst was removed by filtration, the cake was washed with methanol. The filtrate was concentrated to afford { l-[4-(8-Phenyl-purin-9-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (-120 mg), which was used in next steps without further purification. MS (ESI+) e/z: 442.1 [M+l]+. [00283] Step B: { l-[4-(8-Phenyl-purin-9-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (-120 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The crude product was collected by filtration, which was purified by preparative HPLC to afford l-[4-(8-Phenyl-purin-9-yl)-phenyl]-cyclobutylamine (50 mg, 28 % yield, two steps). MS (ESI+) e/z: 342.1 [M+l]+. 1 HNMR(MeOD,400 MHz), δ ppm:9.19 (s, 1H), 8.89 (s, 1H), 7.70-7.64 (m, 2H), 7.64-7.61 (m, 2H), 7.53-7.48 (m, 3H), 7.42-7.38 (m, 2H), 2.80- 2.73 (m, 2H), 2.65-2.50 (m, 2H), 2.27-2.19 (m, 1H), 1.99-1.91 (m, 1H).
Example 18
Figure imgf000095_0001
l-r4-(8-Phenyl-2-pyridin-2-yl-purin-9-yl)-phenyl1-cvclobutylamine
[00284] Step A: To a. solution of { 1 -[4-(2-Chloro-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester (250 mg, 0.526 mmol) in THF (20 mL) was added pyridin-2- ylzinc(II) bromide (1.1 mL, 1M in THF) and Pd(PPh3)4 (36 mg, 0.032 mmol). The reaction mixture was stirred at 80 °C under the atmosphere of nitrogen for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product { l-[4-(8-Phenyl-2-pyridin-2-yl-purin-9-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (-200 mg) was used directly without further purification. MS (ESI+) e/z: 519.5 [M+l]+.
[00285] Step B: { l-[4-(8-Phenyl-2-pyridin-2-yl-purin-9-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (-200 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The crude product was collected by filtration, which was further purified by preparative HPLC to afford l-[4-(8-Phenyl-2-pyridin-2-yl-purin-9-yl)-phenyl]- cyclobutylamine (48 mg, 22%, two steps). MS (ESI+) e/z: 419.5 [M+l]+ 'HNMR MeOD^OO MHz), δ ppm:9.32 (s, 1H), 8.70-8.68 (m, 1H), 8.48-8.45 (m, 1H), 7.95 (t, J=4.0 Hz, 1H), 7.69-7.63 (m, 4H), 7.56-7.49 (m, 4H), 7.43-7.39 (m, 2H), 2.77-2.71 (m, 2H), 2.49-2.42 (m, 2H), 2.38-2.17 (m, 1H), 1.98-1.88 (m, 1H).
Example E
Figure imgf000096_0001
tert-butyl l-(4-(5-amino-2-phenylpyrimidin-4-ylamino)phenyl)cyclobutylcarbamate
[00286] I Step A: To a solution of {l-[4-(2-Chloro-5-nitro-pyrimidin-4-ylamino)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (8.40 g, 20.04 mmol) in dioxane (200 mL)/H2O(40ml) were added PhB(OH)2 (3.43g, 28.2mmol), Pd(dppf)Cl2 (0.74g, 0.91mmol), and Cs2CO3(13.02g, 39.98mmol). The reaction mixture was stirred at 90 °C under Nitrogen atmospher for 3 hours. Then the mixture was concentrated under reduced pressure, the resulting residue was dissolved in Ethyl acetate (200 mL). The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (eluted by EtOAc:PE=l :l to 3:1), which gave 7.0 g of desired product { l-[4-(5-Nitro-2-phenyl-pyrimidin-4- ylamino)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester. (7.0 g, 76% yield).1!-! NMR (CDC13, 400 MHz), δ ppm: 10.16 (s, 1H), 9.32 (s, 1H), 8.36-8.34 (t, J=4.0 Hz, 2H), 7.64 (d, J=8.0 Hz, 2H), 7.51-7.40 (m, 5H), 5.13 (s, 1H), 2.53-2.49 (t, J=8.0 Hz, 4H), 2.09-2.06 (t, J=6.0 Hz, 1H), 1.87-1.83 (m, 1H), 1.33 (s, 9H).
[00287] Step B: Compound { l-[4-(5-Nitro-2-phenyl-pyrimidin-4-ylamino)-phenyl]- cyclobutylj-carbamic acid tert-butyl ester (7.0 g, 15.18 mmol) was dissolved in THF (200 mL) and Raney- Ni (1.00 g) was added carefully. The reaction mixture was stirred at ambient temperature under an atmosphere of hydrogen (balloon) for 4 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford {l-[4-(5-Amino-2-phenyl-pyrimidin-4- ylamino)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester. (6.54 g, 95% yield). LC/MS (ESI+): e/z: 432.2 [M+l]+.
Example 19
Figure imgf000096_0002
l-(4-(8-(4-methoxypyridin-3-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine [00288] Step A: {l-[4-(5-Amino-2-phenyl-pyrimidin-4-ylamino)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester (0.25 g, 0.58 mmol) was dissolved in acetic acid (30 mL), then 4- methoxy-pyridine-3-carbaldehyde (87.7 mg, 0.64 mmol) and Cu(OAc)2 (105 mg, 0.58 mmol) were added separately. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed with aqueous sat. NaHC03 solution, followed by brine, dried over sodium sulfate, filtered and concentrated to give crude desired product (-150 mg), which was used directly without further purification. LC/MS (ESI+): e/z: 549.2 [M+l]+.
[00289] Step B: (l-{4-[8-(4-Methoxy-pyridin-3-yl)-2-phenyl-purin-9-yl]-phenyl}- cyclobutyl)-carbamic acid tert-butyl ester (-150 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and HC1 in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The product was collected by filtration, which was further purified by preparative HPLC to give l-(4-(8-(4-methoxypyridin-3-yl)-2-phenyl-9H-purin- 9-yl)phenyl)cyclobutanamine (60 mg, 30% yield). LC/MS (ESI+): e/z: 449.2 [M+l]+, 451.2 [M+3]+. 1HNMR(MeOD,400 MHz), δ ppm:9.26 (s, 1H), 8.76 (s, 1H), 7.58 (d, J=6.0 Hz, 1H), 8.42- 8.39 (m, 2H), 7.71-7.68 (m, 2H), 7.59-7.57 (t, J=4.4 Hz, 2H),7.46-7.43 (m, 3H), 7.10 (d, J=6.0 Hz, 1H), 3.56 (s, 3H), 2.82-2.77 (m, 2H), 2.71-2.63 (m, 2H), 2.30-1.99 (m, 2H).
[00290] Examples 20 to 48 shown in Table 6 can also be made according to the above- described methods.
Table 6
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
purin-9- 7.83 (d, J=8.0 Hz, 1H),
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
9-r4-(l-Amino-cvclobutyl -phenyn-2-phenyl-9H-purine-8-carbonitrile
] Step A: Disulfurdichloride (6.6 mL, 101 mmol) was added to a solution of 2- chloroacetonitrile (3.0 g, 40.2 mmol) in CH2C12 (10 mL) at room temperature, under an insert atomosphere of nitrogen, the resulting mixture was stirred at room temperature for 18 hours.the reaction mixture was concentrated in vacuo to get crude product 4,5-Dichloro-[l,2,3]dithiazol-l- ylium chloride (8 g crude) which was used without purification.
[00292] Step B: To a solution of { l-[4-(5-Amino-2-phenyl-pyrimidin-4-ylamino)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (180mg, 0.414mmol) in THF (20ml) was added 4,5- Dichloro-[l,2,3]dithiazol-l-ylium chloride (99 mg, 0.45 mmol), then the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give crude product, which was purified by flash chromatography to give (l-{4-[5-(4-Chloro- [l,2,3]dithiazol-5-ylideneamino)-2-phenyl-pyrimidin-4-ylamino]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester. (150mg 65% yield). LC/MS (ESI+): 567.1 [M+H]+
[00293] Step C: (l-{4-[5-(4-Chloro-[l,2,3]dithiazol-5-ylideneamino)-2-phenyl-pyrimidin-4- ylamino]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (150 mg, 0.27 mmol) was dissolved in toluene (15 mL), the reaction mixture was stirred at reflux for 4 hours. The reaction mixture was concentrated in vacuo to afford {l-[4-(8-Cyano-2-phenyl-purin-9-yl)-phenyI]-cyclobutyl}-carbamic acid tert-butyl ester. LC/MS (ESI+): 467.2 [M+l]+
[00294] Step D: The compound { l-[4-(8-Cyano-2-phenyl-purin-9-yl)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester (80-160 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 C and the solution of HCl in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.. The product was collected by filtration, dried in vacuo, to give target compounds as HCl salt. (15.4 mg)
Example 50
Figure imgf000108_0001
l-(4-(8-(l-methyl-lH-pyrazol-5-yl)-2-(3-(trifluoromethoxy)phenyl)-9H-purin-9- vDphenvDcvclobutanamine
[00295] Step A: To a solution of compound { l-[4-(5-Amino-2-chloro-pyrimidin-4- ylamino)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (0.3 g, 0.77 mmol) in dioxane (20 mL)/H20 (4 ml) were added PhB(OH)2 (2.31 mmol), Pd(dppf)Cl2 (56.29 mg, 0.077 mmol), and Cs2C03 (501mg, 1.54mmol). The reaction mixture was stirred at 90 °C under nitrogen atmosphere for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (40 mL). The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (eluted by EtOAc:hexane=l :l to 3:1) to give the desired product (l-{4-[5-Amino-2-(3- trifluoromethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (200 mg, 20% yield). LC/MS (ESI+): (M+Na: 516.0).
[00296] Step B: (l-{4-[5-Amino-2-(3-trifluoromethoxy-phenyl)-pyrimidin-4-yl-amino]- phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (200 mg 0.77 mmol) was dissolved in acetic acid (30 mL), then 2-Methyl-2H-pyrazole-3-carbaldehyde (93.5 mg, 0.85 mmol) and Cu(OAc)2 (140 mg, 0.77 mmol) were added separately. The reaction mixture was stirred at 100 °C for 2 h. LC/MS showed there was about 40% desired product (l-{4-[8-(2-Methyl-2H-pyrazol-3-yl)-2-(3- trifluoromethoxy-phenyl)-purin-9-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester in the reaction mixture. Then the solvent was removed by concentration, and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed with sat. NaHC03 aqueous solution, followed by brine, dried over sodium sulfate, filtered and concentrated to give 150 mg of crude desired product with 80% purity, which was used directly without further purification. LC/MS (ESI+): e/z: 606.2 [M+l]+.
[00297] Step C: (l-{4-[2-(2-Fluoro-phenyl)-8-(2-methyl-2H-pyrazol-3-yl)-purin-9-yl]- phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (150 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and HC1 in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The product was collected by filtration, which was further purified by preparative HPLC to give l-(4-(8-(l-methyl-lH-pyrazol-5-yl)-2-(3- (trifluoromethoxy)phenyl)- 9H-purin-9-yl)phenyl)cyclobutanamine (26.9 mg, 34% yield). LC/MS (ESI+): e/z: 506.2 [M+l]+. Ή MR (MeOD, 400 MHz), δ ppm: 9.32 (s, 1H), 8.41 (d, J=6.8 Hz, 1H), 8.26 (s, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.0 Hz, 2H), 7.57-7.53 (t, J=7.8 Hz, 1H), 7.42- 7.37 (t, J=10.0 Hz, 2H), 6.02 (d, J=1.2 Hz, 1H), 4.27 (s, 3H), 2.88-2.81 (m, 2H), 2.62-2.55 (m, 2H), 2.32-2.27 (m, 1H), 2.05-2.00 (m, 1H).
[00298] Examples 51 to 56 shown in Table 7 can also be made according to the above- described methods.
Table 7
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
anamine 7.64 (d, J=8.4 Hz, 2H), 7.42 (s, 1H),
7.26 (d, J=8.4 Hz, 2H),
6.03 (s, 1H), 4.25 (s, 3H),
2.91-2.84 (m, 2H),
2.64-2.57 (m, 2H),
2.39 (s, 3H),
2.31-2.16 (m, 1H),
2.08-2.03 (m, 1H).
Exam le F
Figure imgf000112_0001
tert-butyl l-(4-(2-chloro-8-(pyridin-2-yl -9H-purin-9-yl phenyl)cyclobutylcarbamate
[00299] Step A: The tert-butyl l-(4-(5-amino-2-chloropyrimidin-4-ylamino)- phenyl)cyclobutylcarbamate (3.00 g, 7.71 mmol) was dissolved in acetic acid (50 mL), then picolinaldehyde (1.23 g, 11.5 mmol) and Cu(OAc)2 (1.4 g, 7.71 mmol) were added separately. The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed with aqueous sat. NaHC03 solution, followed by brine, dried over sodium sulfate, filtered and concentrated to give desired title compound: tert-butyl l-(4-(2-chIoro-8-(pyridin-2-yl)-9H-purin-9- yl)phenyl)cyclobutylcarbamate (1.8 g, 49% yield). LC/MS (ESI+): 477.0/479.1 [M+l]+.
Example 57
Figure imgf000112_0002
l-(4-(2-chloro-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)cyclobutanamine
[00300] Step A: tert-butyl l-(4-(2-chloro-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)- cyclobutylcarbamate (100 mg, ) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and HCl in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.. The crude product was collected by filtration, which was further purified by preparative HPLC to afford the desired product l-(4-(2-chloro-8-(pyridin-2-yl)- 9H-purin-9- yl)phenyl)cyclo-butanamine.(24.5 mg, 31% yield). Ή NMR (MeOD, 400 MHz), δ ppm: 9.10 (s, 1H), 8.38 (d, 1H, J=3.6 Hz), 8.15 (d, 1H, J=8.0 Hz), 7.98-7.94 (m, 1H), 7.30 (d, 2H, J=8.4 Hz), 7.47-7.45 (m, 3H), 2.77-2.72 (m, 2H), 2.53-2.46 (m, 2H), 2.21-2.14 (m, 1H), 1.97 -1.89 (m, 1H). MS (ESI+): 377.1/379.1 [M+l]+.
Exam le 58
Figure imgf000113_0001
1 -(4-(2-( 1 H-pyrazol-4-yl)-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)cyclobutanamine
[00301] Step A: Tert-butyl l-(4-(2-chloro-8-(pyridin-2-yl)-9H-purin-9-yl)- phenyl)cyclobutylcarbamate (700 mg, 1.47 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole (342 mg, 1.76 mmol), Pd(dppf)Cl2 (109.5 mg, 0.15 mmol), and Cs2C03 (1.4 g, 4.41 mmol) were dissolved in a mixed solution (dioxane: 20 mL, water: 4 mL). The resulting mixture was charged with nitrogen thrice and stirred at 100 °C under nitrogen atmosphere for 4 h. TLC showed the stating material was consumed completely. Then the solvents were removed under reduced pressure, the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated to give720 mg of crude desired product tert-butyl l-(4-(2-(lH-pyrazol-4-yl)-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)- cyclobutylcarbamate with purity about 50%, which was used directly without further purification. LC/MS (ESI+): 509.3 [M+l]+.
[00302] Step B: The tert-butyl l-(4-(2-(lH-pyrazol-4-yl)-8-(pyridin-2-yl)-9H-purin-9- yl)phenyl)cyclobutylcarbamate (700 mg crude) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and HCl in ethyl acetate (4 M, 10 mL) was added slowly. The resulting solution was stirred for 2 h. The product was collected by filtration, which was further purified by preparative HPLC to give l-(4-(2-(lH-pyrazol-4-yl)-8-(pyridin-2-yl)-9H-purin-9- yl)phenyl)cyclobutanamine (40 mg, 12.5 % yield, two steps). 1H NMR (MeOD, 400 MHz), δ ppm: 9.16 (s, 1H), 8.39-8.38 (m, 1H), 8.19 (s, 2H), 8.13-8.11 (m, 1H), 7.99-7.94 (m, 1H), 7.65 (d, 2H, J=8.4Hz), 7.53 (d, 2H, J=8.4 Hz), 7.47-7.40 (m, 1H), 2.86-2.78 (m, 2H), 2.60-2.53 (m, 2H), 2.29- 2.22(m, IH), 2.02-1.97 (m, IH). MS (ESf ): 409.2 [M+l]+.
[00303] Examples 59 and 60 shown in Table 8 can also be made according to the above- described methods.
Table 8
Figure imgf000114_0001
Example 61
Figure imgf000115_0001
2-(4-(9-(4-( 1 -aminocvclobutyl)phenyl)-8-(pyridin-2-yl -9H-purin-2-vn- 1 H-pyrazol- 1 -yDethanol
[00304] Step A: A solution of tert-butyl 1 -(4-(2-(lH-pyrazol-4-yl)-8-(pyridin-2-yl)-9H- purin-9-yl)phenyl)cyclobutylcarbamate (400 mg, 0.787 mmol) in dioxane(10 mL) and oxirane (10 mL) was stirred at 10 °C for 3 days.. The reaction mixture was concentrated to dryness to give the crude desired product: tert-butyl l-(4-(2-(l-(2-hydroxyethyl)-lH-pyrazol-4-yl)-8-(pyridin~2-yl)- 9H-purin-9- yl)phenyl)cyclobutylcarbamate with 70% purity. LC/MS (ESI+): 553.3 [M+l]+.
[00305] Step B: tert-butyl 1 -(4-(2-( 1 -(2-hydroxyethyl)- 1 H-pyrazol-4-yl)-8-(pyridine-2-yl)-
9H-purin-9-yl)phenyl)cyclobutylcarbamate (200 mg, 70% purity) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C, then HC1 in ethyl acetate (4M, 10 mL) was added slowly. The resulting solution was stirred for 2 hrs. The product was collected by filtration, which was further purified by preparative HPLC to give the title compound: 2-(4-(9-(4-(l-aminocyclobutyl)phenyl)-8- (pyridin-2-yl)-9H-purin-2-yl)-lH-pyrazol-l-yl)ethanol (35 mg, 10% yield, two steps). 1H NMR (MeOD, 400 MHz), <5 ppm: 9.17 (s, 1H), 8.39-8.38 (m, lH), 8.27 (s, 1H), 8.15-8.13 (m, 1H), 8.06 (s, 1H), 7.99-7.94 (m, 1H), 7.65 (d, 2H, J=8.4Hz), 7.53 (d, 2H, J=8.4 Hz), 7.46-7.43 (m, 1H), 4.27- 4.25 (m, 2H), 3.92-3.89 (m, 2H), 2.89-2.82 (m, 2H), 2.67-2.60 (m, 2H), 2.30-2.27(m, lH), 2.04- 2.02 (m, 1H). MS (ESI+): 453.2 [M+l]+.
Example 62
Figure imgf000115_0002
N 1 -(9-(4-( 1 -aminocyclobutyl)phenyl)-8-(pyridin-2-yl)-9H-purin-2-yl)ethane- 1 ,2-diamine
[00306] Step A: A mixture of tert-butyl l-(4-(2-chloro-8-(pyridin-2-yl)-9H-purin-9- yl)phenyl) cyclobutylcarbamate (100 mg, 0.21 mmol) in ethane- 1,2-diamine (1 mL) was put in a sealed tube and stirred at 100 °C for 2 h. The reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate (50 mL), washed with water. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC to give Nl-(9-(4-(l-aminocyclobutyl)phenyl)-8-(pyridin-2-yl)-9H-purin-2-yl)ethane-l,2- diamine.(45 mg 54% yield).1H NMR (MeOD, 400 MHz), δ ppm: 8.80 (s, IH), 8.33-8.32 (m, IH), 8.00-7.99 (m, IH), 7.93-7.89 (m, IH), 7.57-7.48 (m, IH), 7.58 (d, 2H, J=8.4 Hz), 7.42-7.38 (m, 3H), 3.65-3.64 (m, 2H), 3.16-3.13 (m, 2H), 2.77-2.70 (m, 2H), 2.57-2.50 (m, 2H), 2.22-2.21(m, IH), 1.96-1.91 (m, IH). MS (ESI+): 401.5 [M+l]+
Example 63
Figure imgf000116_0001
l-(9-(4-(l-aminocvclobutyl)phenyl)-8-(pyridin-2-yl)-9H-purin-2-yl)pyrrolidin-3-ol
[00307] Step A: The compound { l-[4-(2-Chloro-8-pyridin-2-yl-purin-9-yl)-phenyl]- cyclobutyl}- carbamic acid tert-butyl ester (200 mg, 0.42 mmol), pyrrolidin-3-ol (103 mg, 0.84 mmol) and K2C03 (176 mg, 0.84 mmol) were dissolved in l-methyl-pyrrolidin-2-one (10 mL). The reaction mixture was stirred at 120 °C under nitrogen atmosphere overnight. The mixture was diluted with ethyl acetate (50 mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give the (l-{4-[2-(3-Hydroxy-pyrrolidin-l-yl)-8- pyridin-2-yl-purin-9-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester. (210 mg, 95%,yield). LC/MS (ESI+): 528.2, [M+l]+ 528.2 [M+3]+.
[00308] Step B: (l-{4-[2-(3-Hydroxy-pyrrolidin-l-yl)-8-pyridin-2-yl-purin-9-yl]-phenyl}- cyclobutyl)-carbamic acid tert-butyl ester was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and the solution of HC1 in ethyl acetate (4M, 10 mL) was added slowly. The resulting solution was stirred for 2 hrs. Then the solvent was removed by concentration, and the residue was purified by preparative HPLC to give l-(9-(4-(l-aminocyclobutyl)phenyl)-8-(pyridin- 2-yl)-9H-purin-2-yl)pyrrolidin-3-ol. 1H NMR (MeOD, 400 MHz), «5 ppm: 8.82 (s, IH), 8.33-8.32 (m, IH), 8.10-8.02 (m, IH), 7.93-7.89 (m, IH), 7.63 (d, 2H, J=8.4 Hz), 7.50 (d, 2H, J=8.4 Hz), 7.44-7.41 (m, IH), 4.52 (s, IH), 3.70-3.59 (m, 4H), 2.88-2.80 (m, 2H), 2.67-2.60 (m, 2H), 2.30- 2.28(m, IH), 2.05-2.03 (m, IH), 1.96-1.94 (m, 2H). MS (ESI+): 428.5 [M+l]+, 429.5 [M+l]+.
Example 64
Figure imgf000117_0001
N-(9-(4-n-aminocvclobutyl)phenyl)-8-(pyridin-2-yl)-9H-purin-2-yl)methanesulfonamide
[00309] Step A: The compound { l-[4-(2-Chloro-8-pyridin-2-yl-purin-9-yl)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (150 mg, 0.315 mmol), Methanesulfonamide (60 mg, 0.63 mmol), Pd2(dba)3 (29 mg, 0.032 mmol), Xantphos (18 mg, 0.032 mmol) and Cs2C03 (308 mg, 0.945 mmol) were dissolved in dioxane (10 mL). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for overnight. LC-MS indicated the reaction worked well. Then the solvent was removed by concentration, and the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed by water, dried over sodium sulfate, filtered and concentrated to give { l-[4-(2- Methanesulfonylamino-8-pyridin-2-yl-purin-9-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (107 mg, yield: 63.4%). LC/MS (ESI+): 536.1 [M+l]+,538.1 [M+3]+
[00310] Step B: { l-[4-(2-Methanesulfonylamino-8-pyridin-2-yl-purin-9-yl)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (107 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and the solution of HC1 in ethyl acetate (4M, 10 mL) was added slowly. The resulting solution was stirred for 2 hrs. Then the solvent was removed by concentration, and the residue was purified by preparative HPLC to give N-(9-(4-(l-aminocyclobutyl)phenyl)-8- (pyridin-2-yl)-9H-purin-2-yl)methanesulfonamide (37 mg, 42.5% yield).1!! NMR (MeOD, 400 MHz), δ ppm: 8.98 (s, 1H), 8.35 (d, 1H, J=4.8 Hz), 8.09 (d, 1H, J=8.0 Hz), 7.96-7.92 (m, 1H), 7.60 (d, 1H, J=8.4Hz), 7.8 (d, 2H, J=8.8 Hz), 7.44-7.41 (m, 1H), 3.28 (s, 3H), 2.80-2.73 (m, 2H), 2.60- 2.55 (m, 2H), 2.24-2.22(m, 1H), 1.96-1.94 (m, 1H). MS (ESI+): 436.1 [M+l]+ ,438.1 [M+3]+
Example 65
Figure imgf000117_0002
9-(4-( 1 -aminocyclobutyl)phenyl)-8-phenyl- 1 H-purin-6(9H)-one
[00311] Step A: The solution of 4,6-dichloro-5-nitropyrimidine 500mg, 2.6mmol and tert- butyl l-(4-aminophenyl)cyclobutylcarbamate 609mg, 2.32mmol in THF (20 mL) was stirred at R.T. for 2hrs until TLC (Hexane/EtOAc=3:l) indicated the consumption of 4,6-dichloro-5- nitropyrimidine. The reaction mixture was concentrated to afford the crude residue, which was purified by flushing chromatography on silica gel (eluting with Hexane/EtOAc= 100/ 1-3/1) to give the product tert-butyl l-(4-(6-chloro-5-nitropyrimidin-4-ylamino)phenyl)cyclobutylcarbamate (350mg, 30.8%). MS (ESI+): 442.1 [M+Naf
[00312] Step B: The solution of tert-butyl l-(4-(6-chloro-5-nitropyrimidin-4-ylamino) phenyl)cyclobutylcarbamate (250mg, 0.6mmol) and Raney Ni (50 mg) in THF (20 mL) was stirred under H2 (balloon) atmosphere for 20 min until TLC (Hexane/EtOAc=l:l) showed the consumption of STM. The reaction was filtered through celite and the filtrate was concentrated under reduced pressure to give tert-butyl l-(4-(5-amino-6- chloropyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (180 mg, 77.6%, yield). MS (ESI+): 390.1 [M+lf, 392.1 [M+3]+
[00313] Step C: To a solution of tert-butyl l-(4-(5-amino-6- chloropyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (200mg, 0.5mmol) in HOAc (20 mL) was added Cu(OAc)2 46.7mg, 0.26mmol and benzaldehyde (109mg, lmmol). The reaction mixture was stirred at 80°C for lh. The reaction mixture was concentrated and purified by flushing chromatography on silica gel (eluting with Hexane/EtOAc=100/l~3/l) to give tert-butyl l-(4-(6-chloro-8-phenyl-9H- purin-9- yl)phenyl)cyclobutylcarbamate (80mg, 32.8% yield). MS (ESf ): 477.1 [M+H]+ ; 479.1 [M+3]+
[00314] Step D: The solution of tert-butyl l-(4-(6-chloro-8-phenyl-9H-purin-9-yl) phenyl)cyclobutylcarbamate (40mg, 0.08mmol) in HC1 (2 mL, 10% wt) was stirred at 80 °C for lh. The reaction solution was concentrated to give title compound 9-(4-(l-aminocyclobutyl)phenyl)-8- phenyl-lH-purin-6(9H)-one (30mg) as HC1 salt. 1H NMR (MeOD, 400 MHz), δ ppm: 8.04 (s, 1H), 7.67-7.65 (d, J=8.0 Hz, 2H), 7.53-7.50 (m, 3H), 7.43-7.41 (m, 1H), 7.36-7.32 (m, 2H), 2.84- 2.79(m, 2H), 2.64-2.63 (m, 2H), 2.29-2.2.20 (m, 1H), 2.05-1.95 (m, 1H), MS (ESI+): 358.2 [M+l]+, 360.2 [M+3]+
[00315] Example 66 shown in Table 9 can also be made according to the above-described methods.
Table 9
Figure imgf000118_0001
Figure imgf000119_0001
Example 67
Figure imgf000119_0002
9-(4-(l-aminocvclobutyl)phenyl')-N.N-dimethyl-8-phenyl-9H-purin-6-amine
[00316] Step A: To the solution of 4, 6-Dichloro-5-nitro-pyrimidine (1 g, 5.2 mmol) in THF
(20 mL) was added a solution of [l-(4-amino-phenyl)-cyclobutyl]-carbamic acid tert-butyl ester (1.36 g, 5.2 mmol) in THF (20 mL) dropwise at 0 °C. After addition, the reaction mixture was stirred at 0 °C for another 2 h. TLC showed the starting material was consumed completely. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with brine (20 mL) twice. The organic phase was concentrated to give 2 g of crude {l-[4-(6-Chloro-5-nitro-pyrimi-din-4- ylamino)- phenyl]-cyclobutyl}-carbamic acid tert-butyl ester. ( 95% yield)
[00317] Step B: To a solution of { l-[4-(6-Chloro-5-nitro-pyrimidin-4-ylamino)- phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (2 g, 4.77 mmol) and dimethyl-amine (0.77 g, 9.54 mmol) in THF (50 mL) was added DIPEA (3.1 g, 23.9 mmol). The mixture was stirred 20 °C for 2 h. LC-MS showed the starting material was consumed completely. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with brine (2 X 20 mL). The organic phase was concentrated to give 2 g of the crude product { l-[4-(6-Dimethylamino-5-nitro-pyrimidin-4- ylamino)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester. (98%, yield). MS (ESI+): 451.1 [M+Na]+ 453.1 [M+Na+2]+
[00318] Step C: The compound {l-[4-(6-Dimethylamino-5-nitro-pyrimidin-4-ylamino)- phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (2.0 g, 4.67 mmol) was dissolved in THF (60 mL) and Raney- Ni (2.00 g) was carefully added. The reaction mixture was stirred at ambient temperature under the atmosphere of H2 (balloon) for 1 h.. After filtration over ciliate pad, the fitrate was concentrated to give 1.8 g of desired product { l-[4-(5-Amino-6-dimethylamino- pyrimidin-4-ylamino)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester. ( 96.8%, yield). MS (ESI+): 399.3 [M+l]+, 401.3 [M+l]+
[00319] Step D: The {l-[4-(5-Amino-6-dimethylamino-pyrimidin-4-ylamino)-phenyl]- cyclo-butyl}-carbamic acid tert-butyl ester (500 mg, 1.29 mmol) was dissolved in acetic acid (20 mL), and benzaldehyde (204 mg, 1.93 mmol) and Cu(OAc)2 (233 mg, 1.29 mmol) were added separately. The reaction mixture was heated at 80°C for 2 hrs. The solvent was removed by concentration, and the residue was dissolved in ethyl acetate (50 mL), washed with H3.H2O (20 mL) and brine (20 mL). The organic phase was concentrated to give { l-[4-(6-Dimethylamino-8- phenyl-purin-9-yl)-phenyl]-cyclobutyl} -carba-mic acid tert-butyl ester. (600 mg, 96% yield). LC MS (ESI+): 485.2 [M+l]+ , 487.2 [M+3]+
[00320] Step E: { l-[4-(6-Dimethylamino-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester (300 mg, 0.62 mmol) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0°C and the solution of HC1 in ethyl acetate (10 mL, 4M) was slowly added. The resulting mixture was stirred for 2 hrs. After filtration, the solid was purified by preparative HPLC to give (9-[4-(l -Amino- cyclobutyl)-phenyl]-8-phenyl-9H-purin-6-yl}-dimethyl-amine. (82 mg, 34.4% yield). Ή NMR (DMSO-d6, 400 MHz), δ ppm: 8.21 (s, 1H), 7.45 (d, 2H, J=6.8 Hz), 7.43 (d, 2H, J=6.8 Hz), 7.45-7.38 (m, 5H), 2.51 (s, 6H), 2.65-2.51 (m, 2H), 2.36-2.39 (m, 2H), 2.12-2.08 (m, 1H), 1.81 -1.76 (m, 1H). MS (ESI+): 385.1 [M+l]+ , 387.1 [M+3]+
Example 68
Figure imgf000120_0001
1 -(4-(6-( 1 -methyl- 1 H-pyrazol-4-yl)-8-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine
[00321] Step A: To a solution of 4,6-dichloro-5-nitropyrimidine (2.00 g, 10.3 mmol) in THF
(40 mL) was slowly added a solution of tert-butyl l-(4-aminophenyl)cyclo- butylcarbamate (2.7 g, 10.3 mmol) in THF (60 mL) drop wise at 0°C. After addition, the reaction mixture was stirred at 0°C for 3 h. TLC showed the starting material was consumed completely. The mixture was washed brine (30 mL) twice and concentrated. The crude product was purified by column (eluted by Ethyl acetate : Hexane =1 :20) to give tert-butyl l-(4-(6-chloro-5-nitropyrimidin-4- ylamino)phenyl)cycIobutylcarbamate.( 1.5 g, 37.5% yield).
[00322] Step B: The tert-butyl l-(4-(6-chloro-5-nitropyrimidin-4-ylamino)phenyl)- cyclobutylcarbamate (1.5 g, 3.58 mmol) was dissolved in THF (50 mL) and Raney- Ni (1.50 g) was carefully added. The reaction mixture was stirred at 20°C under the atmosphere of H2 (balloon) for 1 h.. After filtration ciliate pad, the filtrate was concentrated to give tert-butyl l-(4-(5-amino-6- chloropyrimidin-4-ylamino)phenyl)cyclobutylcarbamate. (1.3 g ,93% yield:). MS (ESI+): 412.1 [M+Na]+, 414.1 [M+Na+2]+
[00323] Step C: The tert-butyl l-(4-(5-amino-6-chloropyrimidin-4-ylamino)phenyl)- cyclobutylcarbamate (200 mg, 0.573 mmol), l-Methylpyrazole-4-boronic acid pinacol ester (143 mg, 0.688 mmol), Pd(dppf)Cl2 (40 mg, 0.057 mmol), and Cs2C03 (560 mg, 1.72 mmol) were dissolved in a mixed solution (dioxane: 10 mL, water: 2 mL). The reaction mixture was charged with nitrogen thrice and heated at 80°C for 2 h. The reaction mixture was diluted with ethyl acetate (20 mL), washed with brine (10 mL), concentrated and purified by column separation (eluted by EA:PE=1 :1), to give tert-butyl l-(4-(5-amino-6-(l -methyl- lH-pyrazol- 4-yl)pyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (100 mg 40%, yield:). MS (ESf ): 436.2 [M+l]+, 438.2
[M+l]+
[00324] Step D: The compound tert-butyl l-(4-(5-amino-6-(l -methyl- lH-pyrazol-4- yl)pyrimidin-4-ylamino)phenyl)cyclobutylcarbamate (100 mg, 0.23 mmol) was dissolved in acetic acid (10 mL), benzaldehyde (36 mg, 0.34 mmol) and Cu(OAc)2 (42 mg, 0.23 mmol) were added separately. The reaction mixture was heated at 80°C for 2 h. The solvent was removed under reduced pressure, the residue was diluted in ethyl acetate (30 mL), washed with NH3.H2O (10 mL, 10%) and brine (2 xl5 mL). The organic layer was concentrated to give tert-butyl l-(4-(6-(l- methyl-lH-pyrazol-4-yl)-8-phenyl-9H- purin-9-yl)phenyl)cyclobutylcarbamate (115 mg, 95.8% yield). MS (ESI+): 522.3 [M+lf, 524.3 [M+3]+
[00325] Step E : The tert-butyl 1 -(4-(6-( 1 -methyl- 1 H-pyrazol-4-yl)-8-phenyl-9H-purin-9- yl)phenyl)cyclobutylcarbamate (115 mg, 0.22 mmol) was dissolved in ethyl acetate (20 mL), the solution was cooled to 0 °C and a solution of HC1 in ethyl acetate (10 mL, 4M) was slowly added. The resulting solution was stirred for 2 h. The solvent was removed by concentration, and the residue was purified by preparative HPLC to give l-(4-(6-(l -methyl- lH-pyrazol-4-yl)-8-phenyl- 9H-purin-9-yl)phenyl) cyclobutanamine. (60 mg, 64% yiekf/H NMR (MeOD, 400 MHz), δ ppm: 8.83 (s, IH), 8.72 (s, IH), 8.58 (s, IH), 7.71-7.66 (m, 4H), 7.55 (d, 2H, J=8.4 Hz), 7.40-7.36 (m, IH), 2.85-2.81 (m, 2H), 2.66-2.61 (m, 2H), 2.29-2.26 (m, IH), 2.01-1.96 (m, IH). MS (ESI+): 422.3 [M+l]+, 424.3 [M+3]+
Example 69
Figure imgf000122_0001
l- 4-(6-Methyl-8-phenyl-purin-9-yl)-phenyl1-cvclobutylamine
[00326] Step A: To the solution of 2,4-Dichloro-6-methyl-5-nitro-pyrimidine (2.08 g, lO.OOmmol) in THF (50 mL) at -78 °C was slowly added the solution of [l-(4-Amino-phenyl)- cyclobutyl]-carbamic acid tert-butyl ester (2.62 g, 10.00 mmol) in THF (20 mL). The reaction mixture was stirred at ambient temperature for 30 min.. Then it was concentrated to remove the solvent. The obtained residue was dissolved in ethyl acetate (250 mL) and washed by saturated. NaHC03 solution, followed by brine. The separated organic layer was dried over sodium sulfate, filtered and concentrated to give { l-[4-(2-Chloro-6-methyl-5-nitro-pyrimidin-4-ylamino)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester. (4.3 g, 98%yield). MS (ESI+) e/z: 370.9 / 372.9 [M+l]+.
[00327] Step B: { l-[4-(2-Chloro-6-methyl-5-nitro-pyrimidin-4- ylamino)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (4.3 g, 9.78 mmol) was dissolved in MeOH (100 mL) and Pd/C (1.00 g) was added. The reaction mixture was stirred at ambient temperature under an atmosphere of hydrogen (balloon) for 12 h.. Then the solvent was removed by concentration, and the residue was dissolved in ethyl acetate (200 mL). The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated to give { l-[4-(5-Amino-6-methyl-pyrimidin-4- ylamino)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester. (3.7 g, 97% yield) MS (ESI+) e/z: 370.9 / 372.9 [M+l]+.
[00328] Step C: The { l-[4-(5-Amino-6-methyl-pyrimidin-4-ylamino)-phenyl]- cyclobutyl}- carbamic acid tert-butyl ester (2.0 g, 5.4 mmol) was dissolved in acetic acid (20 mL), and benzaldehyde (0.74 g, 7 mmol) and Cu(OAc)2 (1.0 g, 5.4 mmol) were added separately. The reaction mixture was heated at 80 °C for 2 h. LC/MS showed there were { l-[4-(6-Methyl-8-phenyl- purin-9-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester. Then the solvent was removed by concentration, and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed by saturated. NaHC03 solution, followed by brine, dried over sodium sulfate, filtered and concentrated, purified by TLC to give { l-[4-(6-Methyl-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester. 0.3 g, MS (ESI+) e/z: 370.9 [M+l]+, 372.9 [M+l]+. [00329] Step D: { l-[4-(6-Methyl-8-phenyl-purin-9-yl)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester ( 0.3 g ) was dissolved in MeOH (30 mL), then added HC1 (aq) (4M, 8 mL) in drops. The mixture was heated to 80 °C, and stirred for 50 min. The product was purified by preparative HPLC to give (160 mg). l-[4-(6-Methyl-8-phenyl-purin-9-yl)-phenyl]-cyclobutylamine. Ή-NMR (400 MHz, CDC13) δ: 9.18 (s, 1H), 7.79 (d, J = 8.8Hz, 2H), 7.71-7.45 (m, 7H), 2.91 (s, 3H), 2.80- 2.75 (m, 2H), 2.59-2.52 (m, 2H), 2.29-2.20 (m, 1H), 2.05-1.99 (m, 1H). MS (ESI+) e/z: 355.8 [M+l]+, 357.8 [M+3]+
Example 70
Figure imgf000123_0001
9-(4-(l-aminocvclobutyl)phenyl)-2.8-diphenyl-lH-purin-6(9H)-one
[00330] Step A: To a suspension of 2,4,6-trichloro-5-nitropyrimidine (0.8g, 3.5mmol) in
THF (30ml) was added [l-(4-Amino-phenyl)-cyclobutyl]-carbamic acid tert-butyl ester (0.827g, 3.15mmol) at 15°C. The mixture was stirred for 30min at 15°C. The reaction mixture was concentrated and was purified by flushing chromatography on silica gel (eluting with Hexane EtOAc=100/l~3/l) to give tert-butyl l-(4-(2,6-dichloro-5-nitropyrimidin-4- ylamino)phenyl)cyclobutylcarbamateas a yellow solid (0.45g, 31.5% yield). 'HNMR (CDCI3, 400 MHz): S9AS(s, 1H), 7.49 (s, 4H), 5.12 (s, ΙΗ,), 2.55-2.51(m, 4Η), 2.13-2.04(m, 1H),1.89-I.86(m, lH),1.42(s, 9H); LC/MS: (ESI+) e/z: 454.3 [M+l]+, 456.3 [M+3]+
[00331] Step B: To a solution of tert-butyl l-(4-(2,6-dichloro-5-nitropyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (0.45 g, 1 mmol) in THF (20ml) was added MeONa (53 mg, 1 mmol) in MeOH(l mL). The mixture was stirred at 55 °C for 30mins.The reaction mixture was purified by preparative TLC to tert-butyl l-(4-(2-chloro-6-methoxy-5-nitropyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (120 mg, 26.6% yield). LC/MS: (ESI+) e/z: 472 [M+Na]+, 474 [M+Na+2]+
[00332] Step C: To a solution of tert-butyl l-(4-(2-chloro-6-methoxy-5-nitropyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (100 mg, 0.222 mmol) in THF (10 mL) was added Raney Ni (50 mg) under nitrogen. The suspension was degassed under vacuum and purged with H2 (balloon). The reaction mixture was stirred at RT for 10 mins. The reaction mixture was purified by preparative TLC to give tert-butyl l-(4-(5-amino-2-chloro-6-methoxypyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (84 mg, 90%). LC-MS: (ESI+) e/z: 442 [M+Na]+, 444 [M+Na+2]+
[00333] Step D: To a solution of tert-butyl l-(4-(5-amino-2-chloro-6-methoxypyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (84 mg, 0.2 mmol) in AcOH(5 mL), Benzaldehyde(42.45 mg, 0.4 mmol) and Cu(OAc)2(18.2 mg, 0.1 mmol) was added. The reaction mixture was stirred at 70C for 30 mins. The mixture was purified by preparative TLC directly to give tert-butyl l-(4-(2-chloro- 6-methoxy-8-phenyl-9H-purin-9-yl)phenyl)cyclobutylcarbamate (25 mg, 25%). LC/MS: (ESI+) e/z: 506 [M+l]+ 508 [M+3]+;
[00334] Step E: To a solution of tert-butyl l-(4-(2-chloro-6-methoxy-8-phenyl-9H-purin-9- yl)phenyl)cyclobutylcarbamate(15 mg, 0.03 mmol) in a mixture of Dioxane(5 mL) and H2O(0.5 mL), Pd(PPh3)4(3 mg,0.0026 mmol), phenylboronic acid (54.87 mg,0.45 mmol) and Cs2C03(29.3 mg, 0.09 mmol) was added. The reaction mixture was stirred under nitrogen at 80 °C for lh. The mixture purified by preparative TLC directly to give tert-butyl l-(4-(6-methoxy-2,8-diphenyl-9H- purin-9-yl)phenyl)cyclobutylcarbamate (10 mg, 61% yield ). LC/MS: (ESI+) e/z: 548 [M+l]+; 550 [M+3]+.
[00335] Step F: A solution of tert-butyl l-(4-(6-methoxy-2,8-diphenyl-9H-purin-9- yl)phenyl)cyclobutylcarbamate (10 mg) in HCl (5 mL, conc.).was stirred at 80 °C for 30 mins. The mixture was purified by preparative TLC to give 9-(4-(l-aminocyclobutyl)phenyl)-2,8-diphenyl- lH-purin-6(9H)-one (3 mg). 'HNMR (MeOD, 400 MHz): <57.97-7.95(d, 2H), 7.70- 7.68 (d, 2H), 7.6-7.46 (m, 8H), 7.39-7.37(m, 2H), 2.83(m, 2H,), 2.68-2.64(m, 2H), 2.35(m, 1H), 1.95(m, 1H). LC/MS: (ESI+) e/z: 434 [M+l]+, 436 [M+3]+.
Example 71
Figure imgf000124_0001
1 -(4-(5 -methyl-2-phenyl-3H-imidazo [4,5 -blpyridin-3 -vDphenyDcyclobutanamine
[00336] Step A: To a solution of 2-chloro-6-methyl-3-nitropyridine (600 mg, 3.5 mmol) and tert-butyl l-(4-aminophenyl)-cyclobutylcarbamate in THF (20 mL) was added DIPEA (900 mg, 7 mmol). The reaction mixture was stirred at 70°C for 5 h. The reaction mixture was concentrated and the residue was purified by flushing chromatography on silica gel (eluted with Hexane:Ehyl acetate = 20:1) to give tert-butyl l-(4-(6-methyl-3-nitropyridin-2- ylamino)phenyl)cyclobutylcarbamate (550 mg, 39% yield). LC/MS (ESI+): 399.2 [M+l]+, 401.2 [M+3]+.
[00337] Step B: The tert-butyl l-(4-(6-methyl-3-nitropyridin-2-ylamino)phenyl)- cyclobutylcarbamate (550 mg, 1.38 mmol) was dissolved in THF (50 mL) and Raney- Ni (1.00 g) was added. The reaction mixture was stirred at ambient temperature under an atmosphere of hydrogen (balloon) for 1 h. The suspension was filtered through a pad of Celite and the pad was withed with THF (20 mL). The combined filtrates were concentrated to give tert-butyl l-(4-(3- amino-6-methylpyridin-2-ylamino)phenyl)cyclobutylcarbamate (480 mg, 94.7% yield). LC/MS (ESI+): 368.9 [M+l]+, 370.9 [M+3]+.
[00338] Step C: The tert-butyl l-(4-(3-amino-6-methylpyridin-2-ylamino)phenyl)- cyclobutylcarbamate (300 mg, 0.81 mmol) was dissolved in acetic acid (50 mL), and benzaldehyde (129 mg, 1.22 mmol) and Cu(OAc)2 (76 mg, 0.42 mmol) were added separately. The reaction mixture was stirred at 100 °C for 2 h. Then the solvent was removed by concentration, and the residue was dissolved in ethyl acetate (50 mL). The organic layer was washed by saturated. NaHC03 solution, followed by brine, dried over sodium sulfate, filtered and concentrated to give tert-butyl l-(4-(5-methyl-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutyl-carbamate (238 mg, 64.5% yield). LC/MS (ESI+): 455.2 [M+l]+, 457.2 [M+3]+
[00339] Step D: The tert-butyl l-(4-(5-methyl-2-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)cyclobutylcarbamate (238 mg, 0.52 mmol) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0°C and the solution of HC1 in ethyl acetate (10 mL, 4M) was slowly added. The resulting solution was stirred at 20 °C for 20 min. The mixture was poured into 30 mL of aqueous NaHC03, the separated organic layer was washed with brine, dried over Na2S04 and concentrated to give l-(4-(5-methyl-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)- cyclobutanamine (71 mg, 38.4% yield).'H NMR (DMSO-d6, 400 MHz), S ppm: 8.08 (d, 1H, J=8.0 Hz), 7.79 (d, 2H, J=8.4 Hz), 7.52 (d, 2H, J=8.4 HZ), 7.46 (d, 2H, J=8.4 Hz), 7.48-7.37 (m, 3H), 7.26-7.25 (d, 1H, J=8.0 Hz), 2.60-2.54 (m, 4H), 2.51 (s, 3H), 2.23-2.16 (m, 1H), 1.92-1.87 (m, 1H). MS (ESI+): 355.1 [M+lf, 357.1 [M+l]+.
Example 72
Figure imgf000126_0001
l-(4-(6-bromo-2-phenyl-3H-imidazof4.5-b1pyridin-3-yl')phenyl)cvclobutanamine
[00340] Step A: A mixture of 5-bromo-2-chloro-3-nitropyridine (1 g, 4 mmol) and tert- butyl l-(4-aminophenyl)cyclobutylcarbamate (1.04 g, 4 mmol) in dioxane (30 mL) was added TEA (2ml) in one portion. Then the reaction mixture was warmed to 70 °C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated to dryness to give the residue, which was further purified by flash chromatography to afford tert-butyl l-(4-(5-bromo-3- nitropyridin-2-ylamino)phenyl) cyclobutylcarbamate. (1 g, 54% yield).LC/MS: (ESI+):463 [M+1J+, 465 [M+l]+.
[00341] Step B: tert-butyl l-(4-(5-bromo-3-nitropyridin-2-ylamino)phenyl)cycIobutyl carbamate (1 g, 2 mmol) was dissolved in THF (50mL) and treated with the catalytical amount of Raney Ni(0.2 g), then the mixture was stirred under hydrogen (balloon) at room temperature for 30 minutes. The reaction mixture was filtrated and the filtrate was concentrated to afford tert-butyl 1- (4-(3-amino-5-bromopyridin-2-ylamino)phenyl)cyclobutyl carb -amate, which was used for the next step without further purification (0.6 g, 64% yield). LC/MS (ESf ): 433 [M+l]+, 435 [M+3]+,
[00342] Step C: benzaldehyde (0. 6 g, 1.3 mmol) and Cu(OAc)2 (158 mg, 0.13 mmol) was added to a solution of tert-butyl l-(4-(3-amino-5-bromopyridin-2- ylamino)phenyl)cyclobutylcarbamate (1 g, 2.87 mmol) in glacial acetic acid (20 mL). The reaction mixture was stirred at 70 °C for lh. then the mixture was diluted with water and basified with saturate sodium bicarbonate and then extracted with ethyl acetate for three times. The combined organic layers were dried over Na2S04 and concentrated to give the crude product, which was purified by flash chromatography to afford tert-butyl l-(4-(6-bromo-2-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)cyclobutylcarbamate (0.4 g, 59 % yield). LC/MS (ESI+): 519 [M+l]+'521 [M+3]+.
[00343] Step D: To a solution of tert-butyl l-(4-(6-bromo-2-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)cyclobutylcarbamate (0.3 g, 0.5 mmol) in EtOAc was added the solution of HC1 in EtOAc (4 mol/L , 10 ml) at 0 °C dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give l-(4-(6- bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl) cyclobutanamine as HC1 salt was obtained (120 mg, 49.5% yield).'HNMR (DMSO-i/6, 400 MHz): δ 9.04 (s, 3H), 8.51 (s, 1H), 8.43 (s, 1H), 7.73-7.57 (m, 2H), 7.55-7.37 (m, 7H), 2.64-2.59 (m, 4H), 2.20 (m, 1H), 1.80 (m, 1H). LC/MS (ESI+): 419 [M+l]+'421 [M+3]+.
Example 73
Figure imgf000127_0001
l-(4-(6-(2-fluorophenyl)-2-phenyl-3H-imidazo[4,5-blpyridin-3-yl)phenyl)cyclobutanamine
[00344] Step A: A mixture of l-(4-(6-bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)cyclobutanamine (0.8 mmol), 2-fluorophenyl boronic acid (0.96 mmol), Cs2C03(521 mg, 2.4 mmol) and Pd(dppf)Cl2 (116 mg, 0.16 mmol) in dioxane and H20 (10 ml, 5:1) was stirred at 80 °C for 2 hours under nitrogen atmosphere. The cooled reaction mixture was poured into water and extracted with EtOAc for three times, then the combined organic layers were washed with water and brine, dried and concentrated to give the residue, which was further purified by flash chromatography to afford l-(4-(6-(2-fluorophenyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)cyclobut anamine (80 mg, 33 % yield .'HNMR (DMSO-</6, 400 MHz): δ 8.46(s, 1H), δ 8.34(s. 1H), 7.66-7.58(m, 5H), 7.47-7.33(m, 8H), 2.44-2.17(m, 4H), 2.14(m, 1H), 1.80(m, 1H). LC/MS (ESf ): 434.2 [M+l]+'436.2 [M+3]+
Exam le 74
Figure imgf000127_0002
l-(4-(2-phenyl-3H-imidazor4,5-b1pyridin-3-yl)phenyl)cyclobutanamine
[00345] Step A: A solution of tert-butyl l-(4-(6-bromo-2-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)cyclobutylcarbamate (80 mg) in MeOH (10 mL) was stirred under hydrogen (balloon) atmosphere in presence of Raney Ni (100 mg) at room temperature for 10 min. The reaction mixture was filtered through celite pad and the filtrate was concentrated to give 60 mg of crude desired compound tert-butyl l-(4-(2-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)cyclobutylcarbamate, which was used directly without further purification. LC/MS (ESI+): 441.3 [M+l]+, 443.3 [M+3]+
[00346] Step B: To a solution of t tert-butyl l-(4-(2-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyI)cyclobutylcarbamate (60 mg crude) in EtOAc was added the solution of HCl in EtOAc (4 mol/L , 10 ml) at 0 °C dropwise. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, the crude residue was purified by preparative HPLC to give l-(4-(2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutanamine (20 mg) 1HNMR (CD30D-^, 400 MHz): 68.35(s, 1H), 8.21(s, 1H), 7.66(s, 1H), 7.60-7.30(m, 8H), 2.80(m, 2H), 2.64(m, 2H), 2.20(m, 1H), 1.99(m, 1H). LC/MS (ESI+): 341.3 [M+l]+,343.3 [M+3]+.
Example 75
Figure imgf000128_0001
1 -[4-(2-Phenyl-imidazo 4.5-b1pyrazin- 1 -yl Vphenyl -cvclobutylamine
[00347] Step A: 2,3-Dichloro-pyrazine (14.8 g, 0.1 mol) was added in a 100 mL autoclave which contained 50 mL of the solution of N¾ aqueous with stirring, and then the reaction mixture was warmed to 100°C and stirred overnight, Cooled to room temperature. Filtrated, the solid was washed with water and further with dichloromethane to afford a solid, which dried on vacuum to afford 3-Chloro-pyrazin-2-ylamine. (10 g, 80% yield). LC/MS (ESI+): 130[M+1]+, 132[M+3]+
[00348] Step B: The solution of dimethyl sulfoxide (4 g, 0.05 mmol) in 30mL of dry dichloromethane was cooled to -78°C, then (13 g, 0.046 mmol) trifluoromethanesulfonic anhydride was added dropwise under nitrogen with stirring. After addition the solution was stirred for 2 hours, then was added a solution of 3-Chloro-pyrazin-2-ylamine (5.0 g, 0.039 mmol) in 30mL of dichloromethane and dimethyl sulfoxide (5:1), the resulting reaction mixture was continued stirred at -78°C for 3 hours, quenched by saturate NH4CI solution then diluted with dichloromethane (200 mL) and the organic phase was separated, the water phase was further extracted with dichloromethane twice. The combined organic phase was washed with brine. The organic phase was concentrated to afford S,S-dimethyl-N-(2-pyrazinyl)sulfilimine, which was use directly for next step. (7.5 g, 80% yield) LC/MS (ESI+): 190[M+1]+, 192[M+3]+. [00349] Step C: To m-chloroperbenzoic acid (8.0g, 0.46 mmol 85%) in dichloromethane
(100 mL)(cooled to -5°C) was added a solution of S,S-dimethyl-N-(2-pyrazinyl)sulfilimine (5.36 g, 0.028 mmol) in 30ml dichloromethane dorpwise at such a rate for 1 hour with the temperature not exceed 0°C, the reaction mixture was stirred for another 40min at 0°C, The solution of dimethyl sulfide in dichloromethane was added at 0°C. Filltered quickly to afford a orange clean solution .The solution was cooled to -78°C, then 03 was bubbled into the mixture until the orange solution was turned to be colorless. The resulting suspension was quenched with sodium dicarbonate solution and then extracted with dichloromethane for three times. The combined organic phase was concentrated to afford the crude product, which was further purified by flash chromatography to afford 2-Chloro-3-nitro-pyrazine. (0.5 g, yield: 7%).1HNMR (DMS0-< 400 MHz): δ 8.60 (s, 1H), δ 8.83 (s, 1H).
[00350] Step D: A mixture of 2-Chloro-3-nitro-pyrazine (0.5 g, 3 mmol) and [l-(4-Amino- phenyl)-cyclobutyl]-carbamic acid tert-butyl ester (0.98 g, 3.6 mmol) in dioxane (20mL) was added Et3N (2ml) in one portion. Then the reaction mixture was warmed to 70°C for overnight. Cooled to room temperature and Concentrated to dryness to afford the residue, which was further purified by flash chromatography to afford { l-[4-(3-Nitro-pyrazin-2-ylamino)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester. (0.57 g, 50% yield). LC/MS (ESI+): 386[M+1]+, 388[M+3]+
[00351] Step E: { l-[4-(3-Nitro-pyrazin-2-ylamino)-phenyl]-cyclobutyl}-carbamic acid tert- butyl ester (0.57 g, 1.5 mmol) was dissolved in THF (30mL) and treated with the catalyst amount of Raney Ni (0.2g ), then the reaction mixture was stirred under hydrogen (balloon) for 30 minutes at room temperature. Filtrated and the filtrate was concentrated to give { l-[4-(3-Amino-pyrazin-2- ylamino)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, which was used for next step without further purification (0.26g, 51% yield). LC/MS (ESI+): 356[M+1]+, 358[M+3]+
[00352] Step F: { l-[4-(3-Amino-pyrazin-2-ylamino)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (0.26 g, 0.75 mmol) and Cu(OAc)2 (158 mg, 0.13 mmol)was added to a solution of Benzaldehyde (1 g, 2.87 mmol) in glacial acetic acid (20 mL), the reaction mixture was stirred at 70°C for lh. the reaction mixture was diluted with water and bacified with saturates sodium bicarbonate. Extracted with ethyl acetate for three times, the combined organic layer was concentrated to give the crude product ,which was purified by flash chromatography to afford the{l-[4-(2-Phenyl-imidazo[4,5-b]pyrazin-l-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (92 mg, 80 % yield). LC/MS (ESI+): 442[M+1]+, 444[M+4]+
[00353] Step G: To a solution { l-[4-(2-Phenyl-imidazo[4,5-b]pyrazin-l-yl)-phenyl]- cyclobutylj-carbamic acid tert-butyl ester (90mg, 0.2mmol)in ethyl acetate (10 mL) was added a solution of HC1 in ethyl acetate (4mol/L HC1, 10ml) at 0°C dropwise , the reaction mixture was stirred at room temperature for 1 h. the reaction mixture was concentrated under reduced pressure to afford l-[4-(2-Phenyl-imidazo[4,5-b]pyrazin-l-yl)-phenyl]-cyclobutylamine as HC1 salt. (25 mg, yield: 49.5%). 1HNMR (CD30D-< 400 MHz): δ 8.59(m, 1H), δ 8.40(m, 1H), 7.65-7.35(m, 9H), 2.76(m, 2H), 2.58(m, 2H), 2.20(m, 1H), 1.91(m, 1H). LC/MS (ESI+): 342[M+l , 344[M+3]+
Exam le 76
Figure imgf000130_0001
l-(4-(5-phenyl-2-(pyridin-2-yl)-3H-imidazor4,5-blpyridin-3-yl)phenyl)cvclobutanamine
[00354] Step A: To a solution of 2,6-dichloro-3-nitropyridine (0.20 g, 1.036 mmol) in dioxane (20 mL) were added tert-butyl l-(4-aminophenyl)cyclobutylcarbamate (0.27 g, 1.036 mmol), DIPEA (0.134 g, 1.036 mmol). The reaction mixture was stirred at 70 °C overnight. Then it was concentrated to remove the solvent, and the residue was dissolved in ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated to afford tert-butyl l-(4-(6-chloro-3-nitropyridin-2-ylamino)phenyl)cyclobutylcarbamate (0.41 g, 94%yiedl ), which was pure enough to be used in next step without further purification. MS (ESI+) e/z: 419 [M+l]+, 421 [M+3]+
[00355] Step B: To a solution of tert-butyl l-(4-(6-chloro-3-nitropyridin-2- ylamino)phenyl)cyclobutylcarbamate (0.41 g, 0.98 mmol) in a mixed solution (dioxane:H20=15:3 mL) were added phenylboronic acid (0.17 g, 1.37 mmol), Pd(dppf)Cl2 (36 mg, 0.049 mmol), and Cs2C03 (0.64 g, 1.96 mmol). The reaction mixture was stirred at 100 C for 3 h.. Then it was concentrated to remove the solvent, and the residue was dissolved in ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column separation (EtOAc:hexane=3:l) to afford tert-butyl l-(4-(3- nitro-6-phenylpyridin-2-ylamino)phenyl)cyclobutylcarbamate (0.40 g, 89% yield). MS (ESI+) e/z: 461 [M+l]+, 463 [M+3]+
[00356] Step C: To a solution of tert-butyl l-(4-(3-nitro-6-phenylpyridin-2- ylamino)phenyl)cyclobutylcarbamate (0.40 g, 0.87 mmol) in THF (20 mL) was added Raney-Ni (0.20 g). The reaction mixture was stirred at ambient temperature under the atmosphere of hydrogen (balloon) for 1 h. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated to afford tert-butyl l-(4-(3- amino-6-phenylpyridin-2-ylamino)phenyl)cyclobutylcarbamate (0.35 g, 93% yield), which was used in next step without further pufiication. MS (ESI+) e/z: 431 [M+l]+, 432 [M+3]+
[00357] Step D: To a solution of tert-butyl l-(4-(3-amino-6-phenylpyridin-2- ylamino)phenyl)cyclobutylcarbamate (0.40 g, 0.929 mmol) in AcOH (20 mL) were added picolinaldehyde (0.149 g, 1.394 mmol), and Cu(OAc)2 (0.118 g, 0.650 mmol). The reaction mixture was stirred at 100 C for 1 h. It was concentrated to remove the solvent and the residue was dissolved in ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated to afford fert-butyl l-(4-(5-phenyl-2-(pyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutylcarbamate (-0.40 g), which was used in next step without further purification. MS (ESI+) e/z: 518 [M+l]+, 520 [M+3]+.
[00358] Step E: To a solution of tert-butyl l-(4-(5-phenyl-2-(pyridin-2-yl)-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)cyclobutylcarbamate (-0.4 g) in ethyl acetate (20 mL) was added the solution of HC1 in ethyl acetate (5 mL) at 0 C. Then it was allowed to reach ambient temperature for 3 h. The reaction mixture was concentrated to remove the solvent. The crude product was purified by preparative HPLC to afford l-(4-(5-phenyl-2-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)cyclobutanamine (90 mg, 23% yield, two steps). 1H NMR (MeOD, 400 MHz), δ ppm: 8.42-8.40 (m, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.10-7.95 (m, 5H), 7.66-7.64 (m, 2H), 7.59-7.56 (m, 2H), 7.47-7.38 (m, 4H), 2.87-2.82 (m, 2H), 2.65-2.57 (m, 2H), 2.31-2.20 (m, 1H), 2.08-1.96 (m, 1H). MS (ESI+) e/z: 418 [M+l]+ 420 [M+3]+
Example 77
Figure imgf000131_0001
1 -(4-(2 -phenyl- 1 H-pyrrolo[3,2-c1pyridin- 1 -yl)phenyl)cyclobutanamine
[00359] Step A: To a suspension of 4-chloropyridine (10 g, 0.067 mol) in THF (150 mL, dry) was dropping LDA (134 ml, 1 M in hexane) while keeping the temperature below -70°C. The mixture was stirred for 30min at was -78°C and then treated over 10 min with a solution of I2 (17 g, 0.067 mol) in dry THF keeping the internal temperature below -65 °C. The reaction mixture was allowed to warm to r.t. over 2h, followed by stirring at the same temperature for 30min. The reaction mixture was poured into Na2S03 (20%, 100 mL) aqueous solution and extracted with EtOAc (100 mL, three times). The organic layer was washed with NaHC03 aqueous solution (50 mL), saturated NaCl aqueous solution (50 mL) and dried. The solvent was evaporated and purified by washing with petroleum ether (20mL) to yield the desired product 4-chloro-3-iodopyridine (6.2g, 38% yield). 'HNMR (400MHZ, MeOD) δ 8.92(s, 1H), 8.43-8.41 (d, 1H, J=8), 7.62-7.60 (d, 1H, J=8).
[00360] Step B: To a solution of 4-chloro-3-iodopyridine (239 mg, 1 mmol), 1- ethynylbenzene (102 mg, 1 mmol) and Pd(PPh3)2Cl2 (70 mg, 0.1 mmol) in TEA (15 mL) was added Cul (19 mg, 0.1 mmol). The mixture degassed and charged with N2 for three times. The mixture was stirred at reflux for 60min.The reaction mixture was concentrated under reduced pressure and purified by flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=100/l~5/l), to give the title product 4-chloro-3-(2-phenylethynyl)pyridine (200 mg, 94% yield). LC/MS (ESI+): 214 [M+l]+. 216 [M+3]+
[00361] Step C: To a solution of 4-chloro-3-(2-phenylethynyl)pyridine (160 mg, 0.748 mmol), Pd2(dba)3 (68 mg, 0.0748 mmol), X-phos (172 mg, 0.299 mmol) and Cs2C03 (487 mg, 1.496 mmol) in Dioxane (8mL) was added tert-butyl l-(4-aminophenyl)cyclobutylcarbamate (196 mg, 0.748 mmol). The mixture degassed and charged with N2 for three times. And then the resulting mixture was stirred at 120 °C for 60min by microwave irradiation. The reaction mixture was filtered by filter paper. The filtrate was concentrated under reduced pressure to get crude product, which was purified by flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =100/1-1/1) to yield the desired product tert-butyl l-(4-(2-phenyl-lH- pyrrolo[3,2-c]pyridin-l-yl)phenyl)cyclobutylcarbamate (44 mg, 13% yield) as a yellow solid. 'HNMR (400 MHz MeOD) δ 8.87(s, 1H), 8.15(s, 1H), 7.55~7.53(m, 2H), 7.26-7.21 (m, 8H), 6.95 (s, 1H), 2.59-2.44 (m, 4H), 2.15-2.00 (m, 1H), 1.95-1.82 (m, 1H), 1.36 (s, 9H).
[00362] Step D: To a solution of HC1 in EtOAc (20 mL, 2 M) was added tert-butyl 1 - ( 4- (
2 -phenyl- lH-pyrrolo [ 3,2-c ] pyridin-l-yl ) phenyl ) cyclobutylcarbamate (44 mg, 0.10 mmol ). The mixture was stirred at r.t. for 60 min. The reaction mixture was filtered by filter paper to give l-(4-(2-phenyl-lH-pyrrolo[3,2-c]pyridin-l-yl)phenyl) cyclobutanamine (23 mg, 56% ).!HNMR (400MHz MeOD) δ 9.25(s, 1H), 8.41~8.39(d, 1H, J=8), 7.72~7.69(m, 3H), 7.54~7.52(m, 2H), 7.38~7.33(m, 6H), 2.85~2.75(m, 2H), 2.65~2.55(m, 2H), 2.30~2.20(m, 1H), 2.05-1.95(m, 1H). LC/MS (ESI+): 340.1 [M+l]+. 342.1 [M+3]+
Example 78
Figure imgf000133_0001
1 -(4-( 1 -aminocvclobutyl)phenyl)-2-phenyl- 1 H-pyrrolo [3 ,2-c1pyridin-4(5IT)-one
[00363] Step A: t-BuLi (280 mL, 364 mmol) was added dropwise to a solution of the tert- butyl 2-chloropyridin-4-ylcarbamate (20 g, 87.7 mmol) in THF (500 mL) under N2. The mixture is stirred at -78°C for 1 h. Then a solution of I2 in THF (lOOmL) was added drop wise to the mixture. The mixture was stirred at -78 °C for 1.5 h.. The mixture reaction is quenched with saturated NH4CI (lOOmL), the aqueous phase was extracted with EA (2*50mL). The combined organic layers were concentrated and purified by column separation (eluting with petroleum ether/ethyl acetate =1 :20) to give tert-butyl 2-chloro-3-iodopyridin-4-ylcarbamate. (12 g 37.5% yield) MS (ESI) m/z : 354.9 [M+l]+ 356.9 [M+3]+
[00364] Step B: A solution of the tert-butyl 2-chloro-3-iodopyridin-4-ylcarbamate (3 g, 0.85 mol) and NaOMe (4 g, 7.4 mmol) in MeOH (80 mL) was stirred at 100 °C for overnight in a 100 mL of autoclave.. After the solvent was removed by concentration, the residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The separated organic layer was concentrated and purified by column separation (eluted by EA:PE=1 :20), which gave 1.2 g of desired product 3- iodo-2-methoxypyridin-4-amine (Yield: 65.6%). MS (ESI) m/z : 250.9 [M+l]+. 252.9 [M+3]+.
[00365] Step C: To a solution of 3-iodo-2-methoxypyridin-4-amine (5 g, 22.6 mmol), 1- ethynylbenzene (2.3 g, 22.6 mmol), and Pd(PPh3)2Cl2(1.58 g, 2.26 mmol) in TEA (40ml) was added Cul (430 mg, 2.26 mmol). The mixture degassed and charged with N for three times. The mixture was stirred at reflux for 60 min. The reaction mixture was concentrated under reduced pressure and purified by flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=100/l~5/l), to give the title product 2-methoxy-3-(2-phenylethynyl) pyridine- amine (3g, 58% yield). 'HNMR (400MHz, CDC13) 6 7.78~7.76(d, 1H, J=8), 7.76-7.50 (m, 2H), 7.40-7.30 (m, 3H), 6.29-6.27 (d, 1H, J=8), 4.76 (s, 2H), 3.98(s, 3H) .
[00366] Step D: To a solution of 2-methoxy-3-(2-phenylethynyl)pyridin-4-amine (1.8 g, 8.04 mmol) in CH3CN (10 mL) was added toluene sulfonic acid (3.05g, 24mmol), the mixture was stirred at OoC for 10 min. A solution of NaN02 (830 mg, 16 mmol) and Nal (1.8 g, 16 mmol) in water (2 mL) was dropwise in the pre-solution, and stirred at 0°C for another lh. The reaction mixture was quenched with Na2S03 solution, and concentrated under reduced pressure to get crude product, which was purified by silica gel chromatography to give the title product 4-iodo-2- methoxy-3-(2-phenylethynyl)pyridine (1.1 g 42%). 'HNMR (400MHZ, MeOD) δ 8.15~7.95(d, 1H, J=8), 7.59~7.57(m, 2H), 7.40-7.30 (m, 3H), 6.59-6.57 (d, 1H, J=8), 3.91(s, 3H) .
[00367] Step E: To a solution of 4-iodo-2-methoxy-3-(2-phenylethynyl)pyridine (335 g, 1 mmol), Pd2(dba)3 (90 mg, 0.1 mmol), X-phos (190 mg, 0.4 mmol) and Cs2C03 (652 mg, 2 mmol) in Dioxane (lOmL) was added 4-(l-aminocyclobutyl) benzenamine (262mg, lmmol). The mixture degassed and charged with N2 for three times. And then the resulting mixture was stirred at 120 °C for 60 min by microwave irradiation. The reaction mixture was filtered by filter paper. The filtrate was concentrated under reduced pressure to get crude product, which was purified by flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=50/l~l/l) to yield the desired product tert-butyl l-(4-(2-methoxy-3-(2-phenylethynyl) pyridin-4-ylamino)phenyl) cyclobutylcarbamate (350mg, 74.6%). 'HNMR (400MHz, MeOD) δ 7.71~7.69(d, 1H, J=8), 7.55~7.49(m, 4H), 7.36-7.23 (m, 5H), 6.59-6.57 (d, 1H, J=8), 3.96(s, 3H), 2.56~2.48(m, 4H), 2.11~2.04(m, 1H), 1.89~1.80(m, 1H), 1.36(s, 9H) .
[00368] Step F: To a solution of Pd(t-Bu3P)2 (33 mg, 0.064 mmol), KF(150 mg, 1.92 mmol) and Cs2C03 (417 mg, 1.28 mmol) in Dioxane (8 mL) was added tert-butyl l-(4-(2-methoxy-3-(2- phenylethynyl) pyridin-4-ylamino)phenyl) cyclobutylcarbamate (300 mg, 0.64 mmol). The mixture degassed and charged with N2 for three times. And then the resulting mixture was stirred at 120 °C for 60min by microwave irradiation. The reaction mixture was filtered by filter paper. The filtrate was concentrated under reduced pressure to get crude product, which was purified flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=50/l~l/l) to yield the desired product tert-butyl l-(4-(4-methoxy-2-phenyl-lH-pyrrolo [3,2-c]pyridin-l-yl)phenyl) cyclobutylcarbamate (300mg, 85%). 'HNMR (400MHz, MeOD) δ 7.73~7.71(d, 1H, J=8), 7.53-7.5 l(m, 2H), 7.25-7.18 (m, 7H), 6.83(s, 2H), 4.06(s, 3H), 2.66~2.48(m, 4H), 2.18~2.04(m, 1H), 1.89~1.80(m, 1H), 1.36(s, 9H) .
[00369] Step G: Tert-butyl l-(4-(4-methoxy-2-phenyl-lH-pyrrolo [3,2-c]pyridin-l- yl)phenyl) cyclobutylcarbamate (150 mg) and PyHCl C 2 g) were added into a microwave vessel, which was stirred at 120 °C for 20min by microwave irradiation. The reaction mixture was purified by preparative HPLC, to yield the desired product l-(4-(l-aminocyclobutyl)phenyl)-2-phenyl-lH- pyrrolo[3,2-c]pyridin-4-ol (80 mg, 71%). !HNMR (400MHz, DMSO) δ 11.05(s,lH), 7.58~7.50(m, 2H), 7.38~7.20(m, 7H), 7.07-7.05 (d, 1H, J=8), 6.85(s, 1H), 6.05~6.03(d, 1H, J=8), 2.50~2.38(m, 2H), 2.30~2.14(m, 2H), 2.18~2.04(m, 1H), 1.69~1.60(m, 1H). MS (ESI) m/z : 356 [M+l]+. 358 [M+3]+
Example 79
Figure imgf000135_0001
l-(4-(l-aminocyclobutvnphenyl)-2-phenyl-lH-pyrrolo[3.2-blpyridin-5(4H)-one
[00370] Step A: To a solution of 2-bromo-6-methoxypyridine (3 g, 16 mmol) in DMF
(20mL) was added NCS (2.3 g, 17.6 mmol). The mixture was stirred at r.t. for 4 days. The reaction mixture was poured into 150ml water, followed by extraction with ethyl ether. The organic layer was washed with water, NaHC03 aqueous solution, NaCl saturated solution, dried over MgS04 and the solvent was distilled off under reduced pressure to give crude product 2-bromo-3-chloro-6- methoxypyridine (2 g, 57%), which was used to next step without further purification.. 1HNMR (400MHz, CDC13) δ 7.56~7.54(d, 1H, J=8), 6.67-6.65 (d, 1H, J=8), 3.92(s, 3H) .
[00371] Step B: To a solution of 2-bromo-3-chloro-6-methoxypyridine (1.5 g, 6.78 mmol),
1-ethynylbenzene (692 mg, 6.78 mmol), and Pd(PPh3)2Cl2(475 mg, 0.678 mmol) in TEA (40 mL) was added Cul (129 mg, 0.678 mmol). The mixture degassed and charged with N2 for three times. The mixture was stirred at reflux for 60 min. The reaction mixture was concentrated under reduced pressure and purified by flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=100/l~5/l), to give the title product 3-chloro-6-methoxy-2-(2-phenylethynyl ) pyridine (1.5 g, 91%). MS (ESI) m/z : 243.8 [M+l]+. 245.8 [M+3]+
[00372] Step C: To a solution of 3-chloro-6-methoxy-2-(2-phenylethynyl)pyridine (1.94 g,
8 mmol), Pd2(dba)3 (732 mg, 0.8 mmol), X-phos (1.5 g, 3.2 mmol) and Cs2C03 (5.2 g, 16 mmol) in Dioxane (10 mL) was added tert-butyl l-(4-aminophenyl)cyclobutylcarbamate (2.1 g, 8 mmol). The mixture degassed and charged with N2 for three times. And then the resulting mixture was stirred at 120 °C for 60 min by microwave irradiation. The reaction mixture was filtered by filter paper. The filtrate was concentrated under reduced pressure to get crude product, which was purified by flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=50/l~l/l) to yield the desired product tert-butyl l-(4-(6-methoxy-2-(2-phenylethynyl) pyridin-3-ylamino) phenyl) cyclobutylcarbamate (250mg, 7%). MS (ESI) m/z : 470.2 [M+l]+ ,472.2[M+3]+. [00373] Step D: To a solution of Pd(t-Bu3P)2 (25 mg, 0.05 mmol), KF(117 mg, 1.5 mmol) and Cs2C03 (326 mg, 1 mmol) in Dioxane (8 mL) was added tert-butyl l-(4-(6-methoxy-2-(2- phenylethynyl) pyridin-3-ylamino) phenyl) cyclobutylcarbamate (234 mg, 0.5 mmol). The mixture degassed and charged with N2 for three times. And then the resulting mixture was stirred at 120 °C for 60 min by microwave irradiation. The reaction mixture was filtered by filter paper. The filtrate was concentrated under reduced pressure to get crude product, which was purified flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=50/l~l/l) to yield the desired product tert-butyl l-(4-(5-methoxy-2 -phenyl- lH-pyrrolo[3,2-b] pyridin-l-yl) phenyl) cyclobutylcarbamate (200mg, 36%). MS (ESI) m/z : 470.2 [M+l]+. 472.2 [M+3]+
[00374] Step E: Tert-butyl l-(4-(5-methoxy-2-phenyl-lH-pyrrolo[3,2-b] pyridin-l-yl) phenyl) cyclobutylcarbamate (200 mg) and PyHCl(l g) were added into a microwave vessel, which was stirred at 120 °C for 20 min by microwave irradiation. The reaction mixture was purified by preparative HPLC, to yield the desired product l-(4-(l-aminocyclobutyl)phenyl) -2 -phenyl- 1H- pyrrolo[3,2-b]pyridin-5-ol (60 mg, 40%). 1HNMR (400MHz, MeOD) δ 7.62~7.60(m, 2H), 7.60~7.58(d, 1H, J=8), 7.38-7.36 (m, 2H), 7.26~7.24(m, 5H), 6.51(s,lH) 6.31~6.29(d, 1H, J=8), 2.50~2.68(m, 2H), 2.60~2.54(m, 2H), 2.28-2.14(m, 1H), 1.99~2.00(m, 1H). MS (ESI) m/z : 356 [M+l]+. 358 [M+3]+
Example 80
Figure imgf000136_0001
1 -(4-(2-phenyl- 1 H-pyrrolo[2.3-b1pyridin- 1 -vDphenyDcvclobutanamine
[00375] Step A: To a solution of 2-chloro-3-iodopyridine (239 mg, 1 mmol), ethynyl- benzene (102 mg, 1 mmol), and Pd(PPh3)2Cl2(70 mg, 0.1 mmol) in TEA (15 mLl) was added Cul (19 mg, 0.1 mmol). The mixture degassed and charged with N2 for three times. The mixture was stirred at reflux for 60min. The reaction mixture was concentrated under reduced pressure and purified by flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=100/l~5/l), to give the title product 2-chloro-3-(2-phenylethynyl)pyridine (130mg, 61%). 1HNMR: CDC13 400MHz δ 8.31~8.30(d, 1H, J=8), 7.81~7.82(d, 1H, J=8), 7.57~7.55(m, 2H), 7.37~7.35(m, 3H), 7.23~7.21(m, 1H) [00376] Step B: To a solution of 2-chloro-3-(2-phenylethynyl)pyridine (426 mg, 2 mmol),
Pd2(dba)3 (90 mg, 0.1 mmol), X-phos (190 mg, 0.4 mmol) and Cs2C03 (978 mg, 3 mmol) in Dioxane (8mL) was added tert-butyl l-(4-aminophenyl)cyclobutylcarbamate (524 mg, 2 mmol). The mixture degassed and charged with N2 for three times. And then the resulting mixture was stirred at 120 °C for 60min by microwave irradiation. The reaction mixture was filtered by filter paper. The filtrate was concentrated under reduced pressure to get crude product, which was purified by flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=l 00/1 -1/1) to yield the desired product tert-butyl l-(4-(3-(2-phenylethynyl)pyridin-2- ylamino)phenyl)cyclobutylcarbamate (220 mg, 25% yield^HNMR: MeOD 400MHz δ 8.08(s, lH), 7.71~7.69(d, 1H, J=8), 7.57~7.53(m, 4H), 7.38-7.36 (m, 5H), 6.75 (s, lH), 2.80-2.76 (m, 4H), 2.15-2.00 (m, 1H), 1.95-1.82 (m, 1H), 1.36 (s, 9H).
[00377] Step C: To a solution of Pd(t-Bu3P)2(25 mg, 0.05 mmol), KF(117 mg, 1.5 mmol) and Cs2C03 (326 mg, 1 mmol) in Dioxane (8mL) was added tert-butyl l-(4-(3-(2- phenylethynyl)pyridin-2-ylamino)phenyl)cyclobutylcarbamate (220 mg, 0.5 mmol). The mixture degassed and charged with N2 for three times. And then the resulting mixture was stirred at 120 °C for 60 min by microwave irradiation. The reaction mixture was filtered by filter paper. The filtrate was concentrated under reduced pressure to get crude product, which was purified flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate= 100/1 -1/1) to yield the desired product tert-butyl l-(4-(2-phenyl-lH-pyrrolo[2,3-b]pyridin-l- yl)phenyl)cyclobutylcarbamate (80mg, 36%). MS (ESI) m/z: 440 [M+l]+. 442 [M+3]+
[00378] Step D: To a solution of HC1 in EtOAc (30 mL, 2 M) was added tert-butyl l-(4-(2- phenyl-lH-pyrrolo[2,3-b]pyridin-l-yl)phenyl) cyclobutylcarbamate (80 mg, 0.18 mmol). The mixture was stirred at r.t. for 60 min. The reaction mixture was filtered to give l-(4-(2-phenyl-lH- pyrrolo[2,3-b]pyridin-l-yl)phenyl)cyclobutanamine (50mg). 'HNMR: MeOD 400MHz δ 8.63~8.61(d, 1H, J=8), 8.32~8.30(d,lH,J=8), 7.71~7.69(m,2H), 7.58~7.56(m,3H), 7.35~7.29(m,5H), 7.11(s,lH), 2.80~2.765(m,2H), 2.68~2.64(m,2H), 2.240~2.20(m,lH), 2.00-1.96(m,lH). MS (ESI) m/z: 340 [M+lf. 342 [M+3]+
Example 81
Figure imgf000137_0001
l-{4-[6-(2-Fluoro-phenyl)-2-phenyl-pyrrolor2 -blp idin-l-yl -phenyl|-vclobu amine
[00379] Step A: 6-Chloro-3-iodo-pyridin-2-ylamine (2.54g, 0.01 mol) and Ethynyl-benzene
(1.53 g, 0.015 mol) was added in a 100 mL of flask which contained 30mL of Et3N with stirring, and then the catalyst of Cul (0.38 g, 0.002 mol) and Pd(PPh3)2C12 (2 g, 0.002 mol) was added into the mixture. The reaction mixture was warmed to 80 °C for 30 minutes. When TLC indicated 6- chloro-3-iodo-pyridin-2-ylamine was consumed, the reaction mixture was cooled to room temperature. After filtrated, the filtrate was concentrated to give the crude product, which was purified by flash chromatography to afford 6-chloro-3-phenylethynyl-pyridin-2-ylamine (2 g, 71% yield:). LC/MS (ESI+): 229 [M+l]+, 231 [M+3]+
[00380] Step B: A mixture of 6-chloro-3-phenylethynyl-pyridin-2-ylamine (1 g, 4 mmol), 2- flurobenzene boronic (0.7 g, 4.8 mmol), Cs2C03 (3.9 g, 12 mmol) and Pd(dppf)C12 (0.3 g, 0.4 mmol) in the mixture of dioxane and water(10 ml, 5:1) was degassed and charged with nitrogen three times. The reaction mixture was stirred at 80 oC under nitrogen atmosphere for 2h. The cooled solution was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2S04 and concentrated to afford the crude product, which was further purified by flash chromatography to afford 6-(2-fluoro-phenyl)-3-phenylethynyl-pyridin-2- ylamine (1 g, 65 % yield).LC/MS (ESI+): 289 [M+l]+ ,291 [M+3]+
[00381] Step C: To a solution of tert-butyl nitrite (0.6 g, 6 mmol) in 20 mL of CH3CN was added CuBr2 (1.3 g, 6 mmol) at 0 oC. Then the mixture was stirred at this temperature for one hour, which further treated with the solution of 6-(2-fluorophenyI)-3-(phenylethynyl)pyridin-2- amine(lg, 3mmol) in CH3CN. After 6-(2-Fluoro-phenyl)-3-phenylethynyl-pyridin-2-ylamine was consumed, the mixture was treated with 6mol/L HC1 and stirred for 15 minutes. Then the mixture was diluted with water and extracted with ethyl acetate for three times. The organic phase was washed with water and brine, dried over Na2S04 and concentrated to afford the crude product, which was further purified by flash chromatography to afford 2-bromo-6-(2-fluoro-phenyl)-3- phenylethynyl-pyridine ( 0.5 g, 50 % yield) LC/MS (ESI+): 352 [M+l]+ ,354 [M+3]+
[00382] Step D: A mixture of 2-bromo-6-(2-fluoro-phenyl)-3-phenylethynyl-pyridine (0.5 g,
1.5 mmol), [l-(4-Amino-phenyl)-cyclobutyl]-carbamic acid tert-butyl ester (0.4 g, 1.5 mmol), Cs2C03 (0.98 g, 3 mmol) ,X-phos(0.14 g, 0.03 mmol) and Pd2(dba)3 (0.29 g, 0.03 mmol) in dioxane (10 ml) was degassed and then charged with nitrogen. The reaction mixture was stirred at 120 oC in microwave for lh. The cooled reaction mixture was poured into water and extracted with ethyl acetate, then the organic layer was washed with water, dried over Na2S04 and concentrated to afford the crude product, which was further purified by flash chromatography to afford (l-{4-[6- (2-Fluoro-phenyl)-3-phenylethynyl-pyridin-2-ylamino]-phenyl}-cyclobutyl)-carbamic acid tert- butyl ester (0. 3g, 37 % yield). LC/MS: (ESI+): 534 [M+l]+ ,536 [M+3]+
[00383] Step E: A mixture of (l-{4-[6-(2-Fluoro-phenyl)-3-phenylethynyl-pyridin-2- ylamino] -phenyl }-cyclobutyl)-carbamic acid tert-butyl ester (0.3 g, 0.5 mmol), KF (0.09 g, 1.5 mmol), Cs2C03 (0.33 g, 1.5 mmol), and Pd(t-Bu3P)2 (0.15 g, 0.01 mmol) in dioxane (10ml) was stirred at 130oC in microwave for lh. The cooled reaction mixture was poured into water and extracted with ethyl acetate for three times, then the organic layer was washed with water and brine, dried and concentrated to give the residue, which was further purified by flash chromatography to afford (l-{4-[6-(2-Fluoro-phenyl)-2-phenyl-pyrrolo[2,3-b]pyridin-l-yl]- phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (0.3 g, 100 % yield). LC/MS: (ESI+): 534 [M+l]+ ,536 [M+3]+.
[00384] Step F: The solution of (l-{4-[6-(2-Fluoro-phenyl)-2-phenyl-pyrrolo[2,3- b]pyridin-l-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (0.3 g, 0.7 mmol) in EtOAc was added the solution of HC1 in ethyl acetate (4mol/L HC1). The reaction mixture was stirred at room temperature for 1 h. After removal of the solvents under the reduced pressure, the residue was further purified by preparative FfPLC to affordl-{4-[6-(2-Fluoro-phenyl)-2-phenyl-pyrroIo[2,3- b]pyridin-l-yl]-phenyl}-cyclobutylamine. (120 mg, 49.5% yield).lH MR (DMSO-d6, 400 MHz): δ 8.13(d, J =8.0Hz lH), 7.87-7.67(m, 1H), 7.87-7.52(d, J =8.0Hz 1H), 7.51-7.18(m, 12H), 6.86(s, 1H), 2.8(m, 2H), 2.6(m, 2H), 2.3(m, 1H), 2.0(m, 1H). LC/MS: (ESI+): 434.2 [M+l]+ ,436.2 [M+3]+.
Example 82
Figure imgf000139_0001
8-(4-( 1 -aminocvclobutyl)phenyl)-7-phenyl-7H-purin-2-ol
[00385] This compounds can also be made according to the above-described methods.
Example 83
Figure imgf000140_0001
l-(4-(6-phenyl-7H-pyrrolo 2.3-d1pyrimidin-7-yl)phenyl) cvclobutanamine
[00386] Step A: To a solution of 4-chloro-5-iodopyrimidine (1.2 g, 5mmol), 1- ethynylbenzene (510 mg, 5 mmol), and Pd(PPh3)2Cl2 (350 mg, 0.5 mmol) in TEA (15mL) was added Cul (95mg, 0.5mmol). The mixture degassed and charged with N2 for three times. The mixture was stirred at reflux for 60min. The reaction mixture was concentrated under reduced pressure and purified by flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=100/l~5/l), to give the title product 4-chloro-5-(2-phenylethynyl) pyrimidine (1 g, 93%). 'H MR: CDCI3 400MHz 68.91(s, 1H), 8.80(s, 1H), 7.60~7.57(m, 2H), 7.43~7.25(m, 3H).
[00387] Step B: To a solution of 4-chloro-5-(2-phenylethynyl)pyrimidine (214 mg, 1 mmol), Pd2(dba)3 (45 mg, 0.05 mmol), X-phos (85 mg, 0.2 mmol) and Cs2C03 (439 mg, 1.5 mmol) in Dioxane (8mL) was added tert-butyl l-(4-aminophenyl)cyclobutylcarbamate (262 mg, 1 mmol). The mixture degassed and charged with N2 for three times. And then the resulting mixture was stirred at 120 °C for 60 min by microwave irradiation. The reaction mixture was filtered by filter paper. The filtrate was concentrated under reduced pressure to get crude product, which was purified by flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =100/1-1/1) to yield tert-butyl l-(4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutylcarbamate (20 mg, 4.5% yield). 1HNMR: MeOD 400MHz 59 .03(s, 1H), 8.70(s, 1H), 7.54~7.52(m 2H), 7.29~7.25(m, 7H), 6.94(s, 1H), 2.80~2.64(m, 4H), 2.24~2.20(m, 1H), 2.00-1.96(m, 1H), 1.36(s, 9H)
[00388] Step C: To a solution of HC1 in EtOAc (30mL, 2 M) was added tert-butyl l-(4-(6- phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl) cyclobutylcarbamate (20 mg, 0.045 mmol). The mixture was stirred at r.t. for 60 min. The reaction mixture was filtered to give the title product 1- (4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl) cyclobutanamine (3.5 mg). 'HNMR: MeOD 400MHz , δ 9.07(s, 1H), 8.73(s, 1H), 7.62~7.60(m, 2H), 7.46~7.44(m, 2H), 7.37~7.30(m, 5H), 6.98(s, 1H), 2.80~2.76(m, 2H), 2.68~2.64(m, 2H), 2.24~2.20(m,lH), 2.00-1.96(m,lH). MS (ESI) m/z: 341.2 [M+l]+. 343.2 [M+3]+
Example F
Figure imgf000141_0001
tert-butyl l-(4-(2-chloro-6-(,pyridin-2-yn-7H-pyrrolo 2.3-dlpyrimidin-7- vDphenvDcvclobutylcarbamate
[00389] Step A: To a solution of 2,4-dichloro-5-iodopyrimidine (5.50 g, 20.00 mmol) in dioxane (100 mL) was slowly added a solution of tert-butyl l-(4-aminophenyl) cyclobutylcarbamate (5.2 g, 20.00 mmol) in dioxane (20 mL) and triethylamine (5 ml). The reaction mixture was stirred at 80 °C overnight. Lc-ms indicated 2,4-dichloro-5-iodopyrimidine was completed consumed. The solvents were removed under reduced pressure to produce a residue, which was dissolved in ethyl acetate (250 mL). The mixture was washed with brine. The combined organic layer was dried over Na2S04 and then filtered. The filtrate was concentrated to give the crude product, which was purified by flash chromatography to afford tert-butyl l-(4-(2-chloro-5- iodopyrimidin-4-ylamino)phenyl)cyclobutylcarbamate. (5.00 g, 50% yield). LC/MS: (ESI+): 501 [M+l]+ , 503 [M+l]+ .
[00390] Step B: tert-butyl l-(4-(2-chloro-5-iodopyrimidin-4-ylamino)phenyl)cyclobutyl carbamate (5.00 g, 0.01 mol), and 2-ethynylpyridine (1.55 g, 0.015 mol) was added in a lOOmL of flask which contained 30 mL of Et3N with stirring, and then the catalyst of Cul(0.38 g, 0.002 mol)and Pd(PPh3)2Cl2(2 g, 0.002 mol) was added into the mixture. The reaction mixture was warmed to 80 °C for 30 minutes. The reaction mixture was cooled to room temperature. After Filtration, the filtrate was concentrated to give the crude product, which was further purified by flash chromatography to afford tert-butyl l-(4-(2-chloro-5-(pyridin-2-ylethynyl)pyrimidin-4- ylamino)phenyl)cyclobutylcarbamate. (3.8 g, 80% yield). LCMS (ESI+): 476.2 [M+l]+ 478.2 [M+3]+
[00391] Step C: A mixture of tert-butyl l-(4-(2-chloro-5-(pyridin-2-ylethynyl)pyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (3.8 g, 8 mmol), KF (0.058 g, 1 mmol), Cs2CO3(0.652 g, 2 mmol) in dioxane (10ml) was stirred at 130°C in microwave for 1 hours. After removed the excess solvent , the residue was washed with water to get a solid, which was dried on vacumn to afford title compound tert-butyl l-(4-(2-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutylcarbamate (3.4 g, 90% yield). . LC MS (ESI+): 476.2 [M+l]+ 478.2 [M+3]+
Example 84
Figure imgf000142_0001
l-(4-(2-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2 -d1pyrirnidin-7-yl')phenyl)cvclobutanamine
[00392] Step A: l-(4-(2-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutylcarbamate (120 mg) was dissolved in ethyl acetate (30 mL). The solution was cooled to 0 degree and the solution of HCl in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. LC/MS indicated tert-butyl l-(4-(2-(2- aminoethylamino)-6-(pyridin-2-yl)-7H -pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate was consumed. The product was collected by filtration, dried in vacuo to afford l-(4-(2-chloro-6- (pyridin-2-yl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl)phenyl)cyclobutanamine as HCl salt. (80mg). Ή MR (MeOD-d4, 400 MHz), δ ppm: 8.99 (s, 1H), 8.42 (s, 1H), 7.87-7.85 (m, 1H), 7.60-7.56 (m, 3H), 7.43-7.40 (m, 2H ), 7.22-7.20 (m, 1H ), 7.18 (S, 1H), 2.78-2.70 (m, 2H), 2.59-2.55 (m, 2H), 2.25-2.20 (m, 1H), 2.02-1.95 (m, 1H). LC/MS: (ESI+): 376.2 [M+l]+, 378.2 [M+3]+
Example 85
Figure imgf000142_0002
Nl-(7-(4-(l-aminocyclobutynphenyl)-6-(pyridin-2-yl)-7H-pyrrolo 2.3-d1pyrimidin-2-yl)ethane-
1 ,2-diamine
[00393] Step A: To the solution of tert-butyl l-(4-(2-chloro-6-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (238 mg, 0.50 mmol) in dioxane (20 mL) was added ethane- 1,2-diamine (1 mmol). Then the reaction mixture was stirred at 120 °C overnight. The reaction mixture was diluted with water and extracted with ethyl acetate for three times, the combined organic phase was washed water and brine. The combined organic layer was dried over Na2S04 and then filtered, the filtrate was concentrated to give the crude product, which was further purified by flash chromatography to afford tert-butyl l-(4-(2-(2-aminoethylamino)-6-(pyridin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl) cyclobutyl carbamate (120 mg, 49.5% yield) LC/MS (ESI+): 500.2 [M+l]+ 502.2 [M+3]+
[00394] Step B: The tert-butyl l-(4-(2-(2-aminoethylamino)-6-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (120 mg) was dissolved in ethyl acetate (30 mL). The solution was cooled to 0 degree and the solution of HCl in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The product was collected by filtration, dried in vacuo, to afford Nl-(7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)ethane-l,2-diamine as HCl salt. (80mg).1H NMR (MeOD-d4, 400 MHz), δ ppm: 8.69(s, lH), 8.39 (s, 1H), 7.74-7.70 (m, lH), 7.58-7.54 (m, 2H), 7.41-7.39 (m, 3H,), 7.39-7.37(m, 1H), 6.99 (s, 1H), 3.63-3.60(m, 2H), 3.17-3.14 (m, 2H), 2.80-2.73 (m, 2H,), 2.65-2.58 (m, 2H), 2.26-2.23(m, 1H), 1.97-1.94(m, 1H). LC/MS: (ESI+): 400.2 [M+l]+, 402.2 [M+3]+
[00395] Examples 86 and 87 shown in Table 10 can also be made according to the above- described methods.
Table 10
Figure imgf000143_0001
Figure imgf000144_0001
Example 88
Figure imgf000144_0002
7-(4-n-aminocvclobutyl)phenyl)-N-methyl-6-(pyri
[00396] Step A: To a solution of l-(4-(2-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (238 mg, 0.50 mmol) in dioxane (4 mL) was added the aqueous solution of methylamine (10 mL) at a sealed vessel. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with ethyl acetate (80 mL), and washed by water (40 mL) twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was used for step without purification. LC/MS (ESI+): 471.2 [M+l]+,473.2 [M+3]+
[00397] Step B: The tert-butyl l-(4-(2-(methylamino)-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (120 mg) was dissolved in ethyl acetate (30 mL). The solution was cooled to 0 °C and the solution of HCl in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The product was collected by filtration, dried in vacuo, to afford 7-(4-(l-aminocyclobutyl) phenyl)-N-methyl-6-(pyridin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2-amineas as HCl salt. Ή NMR (MeOD-d4, 400 MHz), δ ppm: 8.60(s, 1H), 8.44-8.40 (s, 1H), 7.68-7.64(m, 1H), 7.51-7.48 (m, 2H), 7.29-7.21(m, 4H ), 6.94 (s, 1H), 2.88(s, 3H), 2.59-2.54 (m, 2H), 2.29-2.26 (m, 2H), 2.15-2.10(m, 1H), 1.91-1.79(m, 1H). LC/MS: (ESI+): 371.4.2 [M+l]+, 373.4.2 [M+3]+ Exam le 89
Figure imgf000145_0001
(S)-l-(7-(4-(l-aminocvclobutyl)phenyl)-6-(p idin-2-vn-7H-pyrrolo[2,3-d1pyrimidin-2- yl pyrrolidine-2-carboxylic acid
[00398] Step A: To a solution of { l-[4-(2-Chloro-6-pyridin-2-yl-pyrrolo[2,3-d]pyrimidin-7- yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (0.20 g, 0.42 mmol) in MP(5 mL) were added Pyrrolidine-2-carboxylic acid (290 mg, 2.53 mmol) and K2C03 (232 mg, 1.684 mmol), the reaction mixture was heated at 120 °C for 12 hours. After cooling to room temperature, the mixture was concentrated in vacuo. Diluted with water and dried over sodium sulfate, then concentrated to give 160 mg of crude desired product which was used without purification.LC/MS (ESI+): 555.2 [M+l]+. 557.2 [M+l]+.
[00399] Step B: The l-{7-[4-(l-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-6-pyridin-2- yl-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-pyrrolidine-2-carboxylic acid (160 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and the solution of HCl in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.. The product was collected by filtration, dried in vacuo, to give target compounds as HCl salt. (44.4 mg, 33.9% yield). 1H NMR (MeOD, 400 MHz), δ ppm: 8.66 (s, 1H), 8.43 (s, 1H), 7.75-7.26 (m, 7H), 6.96 (s, 1H), 4.28 (s, 2H), 3.84 (s, 2H), 3.71 (d, J=4.4 Hz, 2H), 2.84-2.76 (m, 2H), 2.63-2.56 (m, 2H), 2:34- 2.09 (m, 4H), 2.04-1.95 (m, 2H). LC/MS (ESI+): 455.2 [M+lf
[00400] Examples 90 and 91 shown in Table 11 can also be made according to the above- described methods.
Table 11
Figure imgf000145_0002
Figure imgf000146_0001
N-(7-(4-(l-aminocvclobutyl)phenyl)-6-(p idin-2-ylV7H-p rolo[2,3-d1pyriniidin-2- vDcyclopropanecarboxamide
01] Step A: To a solution of compound { l-[4-(2-Chloro-6-pyridin-2-yl-pyrrolo[2,3- d]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (0.2g, 0.42mmol)in dioxane 10ml were added cyclopropanecarboxamide (98mg, 1.26mmol), Cs2C03 (258mg, 0.84mmol) and [(t-Bu)3P]2Pd (21.6mg, 0.042mmol) in a microwave tube, bubbled eith nitrogen for 5 minutes and heated to 140 °C for 30 minutes. After cooling to room temperature, filtered and concentrated it in vacuo, to give crude product (140 ,mg), which was used without further purification. LC/MS (ESI+): 525.2[M+1]+.
[00402] Step B: The (l-{4-[2-(Cyclopropanecarbonyl-amino)-6-pyridin-2-yl-pyrrolo[2,3- d]pyrimidin-7-yl] -phenyl }-cyclobutyl)-carbamic acid tert-butyl ester (140 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and the solution of HCl in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.. The product was collected by filtration, dried in vacuo, to give target compounds as HCl salt. (51.5 mg). 1H NMR (MeOD, 400 MHz), δ ppm: 8.97 (s, 1H), 8.43 (d, J=4.0 Hz, 1H), 7.81-7.31 (m, 7H), 7.16 (m, 1H), 2.28-2.22 (m, 1H), 2.04-1.94 (m, 2H), 1.02-0.99 (m, 2H), 0.90-0.86 (m, 2H).
Example 93
Figure imgf000147_0001
l-(4-(6-(pyridin-2-yl)-7H-pyrrolo|"2.3-d]pyrimidin-7-yl)phenyl)cyclobutanamine
[00403] Step A: To a solution of l-(4-(2-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)phenyl)cyclobutanamine (250 mg, 0.664 mmol) in methanol (30 mL) was added Pd/C (200 mg). The mixture was stirred at 50 C under the atmosphere of hydrogen (50 psi) for 12 h. The catalyst was moved by filtration, washed by methanol. The filtrate was concentrated to give l-(4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutanamine lH NMR (MeOD- (U, 400 MHz), δ ppm: 9.46 (s, 1H, ArH), 9.07 (s, 1H, ArH), 8.45 (s, 1H, ArH), 7.87-7.85 (m, 1H, ArH), 7.63-7.57 (m, 4H, ArH), 7.47-7.40 (m, 3H, ArH ), 2.75-2.70 (m, 2H, CH2), 2.60-2.53 (m, 2H, CH2), 2.25-2.20 (m, 1H, CH2), 2.02-1.95 (m, 1H, CH2). LC/MS: (ESI+): 342[M+1]+.
Example 94
Figure imgf000148_0001
1 -(4-(2-( 1 H-pyrazol-4-yl)-6-(pyridin-2-yl)-7H-pyrrolor2,3-d1pyrimidin-7- yDphenyPcyclobutanamine
[00404] Step A: The compound l-(4-(2-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl) phenyl)cyclobutyl carbamate (500 mg, 1.05 mmol), lH-pyrazol-4-ylboronic acid (2.10 mmol), Pd(dppf)Cl2 (77 mg, 0.11 mmol), and Cs2C03 (684 mg, 2.10 mmol) were dissolved in a mixed solution (dioxane: 20 mL, water: 4 mL). The reaction mixture was heated at 100 °C under nitrogen atmosphere for 4 h. Then the solvents were removed by concentration, and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed by water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatograhpy to give tert-butyl l-(4-(2-(lH-pyrazol-4-yl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutylcarbamate (160 mg) .LC/MS: (ESI+): 508.2 [M+l]+
[00405] Step B: The tert-butyl l-(4-(2-(lH-pyrazol-4-yl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (160 mg) was dissolved in ethyl acetate (30 mL). The solution was cooled to 0 °C and the solution of HCl in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The product was collected by filtration, dried in vacuo to afford l-(4-(2-(lH-pyrazol-4-yl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin -7-yl)phenyl) cyclobutanamine. LC/MS: (ESI+):408.2 [M+H]+. 1H NMR (MeOD-d4, 400 MHz), δ ppm: 9.07 (s, 1H), 8.45 (s, 1H), 8.18 (m, 2H), 7.81 (m, 1H), 7.62-7.31 (m, 6H ), 7.18 (s, 1H,), 2.85-2.80 (m, 2H), 2.65-2.58 (m, 2H), 2.25-2.20 (m, 1H), 2.02-1.95 (m, 1H). LC/MS: (ESI+):408.2 [M+H]+
Example 95
Figure imgf000148_0002
N-(7-(4-(l-aminocvclobutyl)phenyl)-6-(pyridin-2-vn-7H-pwolo[2,3-dlpyrimidin-2- yDmethanesulfonamide
[00406] Step A: The compound l-(4-(2-chloro-6-(pyridin-2-yl)-7H-pyrrolo [2,3 -d]pyrimidin -7-yl)phenyl)cyclobutylcarbamate (238 mg, 0.5 mmol), methanesulfonamide (1 mmol), Pd2(dba)3 (19 mg, 0.02 mmol), Xantphos (15 mg, 0.03 mmol) and Cs2C03 (326 mg, 1 mmol) were dissolved in dioxane (10 mL). The reaction mixture was stirred at 90 °C under nitrogen atmosphere for 6 h. Then the solvent was removed by concentration, and the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed by water dried over sodium sulfate, filtered and concentrated. The crude product was used for de-Boc step without purification. LC/MS: (ESI+): 536.2 [M+H]+.
[00407] Step B: The tert-butyl l-(4-(2-(methylsulfonamido)-6-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (150 mg) was dissolved in ethyl acetate (30 mL). The solution was cooled to 0 degree and the solution of HC1 in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The product was collected by filtration, dried in vacuoto afford N-(7-(4-(l -aminocyclobutyl)phenyl)-6-(pyridin-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methanesulfonamide as HC1 salt.. Ή NMR (MeOD-d4, 400 MHz), δ ppm: 8.91(s, 1H, ArH), 8.45 (s, 1H, ArH), 7.83-7.81(m, 1H, ArH), 7.59-7.53 (m, 3H, ArH), 7.48-7.45(m, 2H, ArH ), 7.38-7.36(m, 1H, ArH), 7.16 (s, 1H, ArH), 3.30(s, 3H, CH3), 2.80- 2.77 (m, 2H, CH2), 2.65-2.61 (m, 2H, CH2), 2.26-2.23(m, 1H, CH), 1.97-1.94(m, 1H, CH). LC/MS: (ESI+): 436.2 [M+l]+.
Example 96
Figure imgf000149_0001
7-(4-(l-aminocyclobutyl)phenyn-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d1pyrimidine-2-carbonitrile
[00408] Step A: l-(4-(2-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutylcarbamate (476 mg, 1 mmol), dicyanozinc (2 mmol), Pd2(dba)3 (190 mg, 0.2 mmol) and S-phos (82 mg, 0.2 mmol) were dissolved in l-methylpyrrolidin-2-one (10 mL). The reaction mixture was stirred at 150 °C under nitrogen atmosphere for 30 minutes. Then the solvent was removed by concentration, and the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed by water dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography give 200 mg tert-butyl l-(4-(2-cyano-6-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate. LC/MS: (ESI+): 467.2 [M+l]+, 489.2 [M+23]+.
[00409] Step B: The tert-butyl l-(4-(2-cyano-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-
7-yl)phenyl)cyclobutylcarbamate. (100 mg) was dissolved in ethyl acetate (30 mL). The solution was cooled to 0 degree and the solution of HC1 in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 2 h. The product was collected by filtration, dried in vacuo to afford 7-(4-(l-aminocyclobutyl)phenyl)-6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-2- carbonitrile as HC1 salt.'H NMR (DMSO-de, 400 MHz), δ ppm: 9.34(s, IH, ArH), 8.23 (s, IH, ArH), 7.85-7.81(m, IH, ArH), 7.59-7.52 (m, 4H, ArH, H2), 7.45(S, IH, ArH ), 7.38-7.30(m, 4H, ArH), 2.26-2.19 (m, 3H, CH2, CH), 2.06-2.04 (m, 2H, CH2), 1.74-1.70(m, IH, CH). LC/MS: (ESI+): 367.2 [M+l]+.
Example 97
Figure imgf000150_0001
7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo 2,3-dlpyrimidine-2-carboxamide
[00410] Step A: The tert-butyl l-(4-(2-cyano-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-
7-yl)phenyl)cyclobutylcarbamate. (100 mg) was dissolved in ethyl acetate (30 mL). The solution was cooled to 0 degree and the solution of HC1 in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for overnight. The product was collected by filtration, dried in vacuo to afford 7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidine-2-carboxamide as HC1 salt.. 1H NMR (MeOD-d4, 400 MHz), δ ppm: 8.60(s, IH, ArH), 8.44-8.40 (s, IH, ArH), 7.68-7.64(m, IH, ArH), 7.51-7.48 (m, 2H, ArH), 7.29-7.21(m, 4H, ArH ), 6.94 (s, IH, ArH), 2.88(s, 3H, CH3), 2.59-2.54 (m, 2H, CH2), 2.29-2.26 (m, 2H, CH2), 2.15- 2.10(m, IH, CH), 1.91-1.79(m, IH, CH). LC/MS: (ESI+): 385.2 [M+l]+
Example G
Figure imgf000151_0001
tert-butyl l-(4-(4-chloro-6-(pyridin-2-yl)-7H-pyrrolor2,3-d1pyrimidin-7- yPphenyDcyclobutylcarbamate
[00411] Step A: To the solution of 4,6-dichloro-5-iodopyrimidine (5.50 g, 20.00 mmol)
(prepared according to the ref of Organic Letters; English; 11; 8; 2009; 1837 - 1840; ) in dioxane (100 mL) was slowly added the solution of tert-butyl l-(4-aminophenyl)cyclobutylcarbamate (5.2 g, 20.00 mmol) in dioxane (20 mL) and Et3N(5 ml). The reaction mixture was stirred at 80C for overnight, lc-ms indicated 4,6-dichloro-5-iodopyrimidine was completed consumed. After removed the excess solvents under the reduced pressure to get a residue, which was dissolved in Ethyl acetate (250 mL) and washed water and brine. The combined organic layer was dried over Na2S04 and then filtered, the filtrate was concentrated to give the crude product, which was further purified by flash chromatography to afford tert-butyl l-(4-(6-chloro-5-iodopyrimidin-4- ylamino)phenyl)cyclobutylcarbamate. (5.00 g 50% yield).LC/MS: (ESI+): 501 [M+l], 523 [M+Na].
[00412] Step B: tert-butyl l-(4-(6-chloro-5-iodopyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (5.00 g, 0.01 mol),and 2-ethynylpyridine (1.55 g, 0.015 mol) was added in a lOOmL flask which contained 30 mL of Et3N with stirring, and then the catalyst of Cul(0.38 g, 0.002 mol)and Pd(PPh3)2Cl2(2 g, 0.002 mol) was added into the mixture. The reaction mixtute was warmed to 80 °C for 30 minutes, The reaction mixture was cooled to room
temperature. Filltered and the filtrate was concentrated to give the curde product, which was further purified by flash chromatography to afford tert-butyl l-(4-(6-chloro-5-(pyridin-2- ylethynyl)pyrimidin-4-ylamino)phenyl)cyclobutylcarbamate. (3.8 g, 80% yield). LC/MS (ESI+): 476.2 [M+l]+
[00413] Step C: A mixture of tert-butyl l-(4-(6-chloro-5-(pyridin-2-ylethynyl)pyrimidin-4- ylamino)phenyl)cyclobutylcarbamate (3.8 g, 8 mmol), KF(0.058 g, 1 mmol), Cs2CO3(0.652 g, 2 mmol) in dioxane(lOml) was stirred at 130°C in microwave for 1 hours. A residue was afford after removed the excess solvent , the residue was washed with water to get a solid, then the solid was dried on vacumn to afford tert-butyl l-(4-(4-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutylcarbamate (3.4 g, 90% yield). LC/MS (ESf ): 476.2 [M+lf. Example 98
Figure imgf000152_0001
l-(4-(4-methoxy-6-^yridin-2-vn-7H-pyrrolo[2 -d1pyrimidin-7-yl)phenyl)cyclobu1anamine
[00414] Step A: To a solution of tert-butyl l-(4-(4-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d] pyrimidin-7-yl)phenyl)cyclobutylcarbamate (476mg, lmmol) in methanol (10 mL) was slowly added CH3ONa (108mg, 2.00 mmol) in portions. The reaction mixture was stirred at room temperature overnight. Then it was concentrated to remove the solvent. The obtained residue was dissolved in Ethyl acetate (250 mL) and washed by water, followed by brine. The separated organic layer was dried in sodium sulfate, filtered and concentrated to give tert-butyl l-(4-(4-methoxy-6- (pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate. (450 mg 50% yield) .LC/MS (ESI+): 472.2 [M+l]+
[00415] Step B: The tert-butyl l-(4-(4-methoxy-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (120 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and the solution of HC1 in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 2 h. The product was collected by filtration, dried in vacuo, to afford l-(4-(4-methoxy-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) phenyl) cyclobutanamine as HC1 salt. (20mg). [M+l]+ nH NMR (MeOD-cU, 400 MHz), δ ppm: 8.41-8.39(m, 2H, ArH), 7.77-7.73 (m, 1H, ArH), 7.59-7.57(m, 2H, ArH), 7.48-7.40 (m, 3H, ArH), 7.29-7.27(m, 1H, ArH ), 7.1 l(s, 1H, ArH), 4.17(s, 3H, CH3), 2.81-2.75 (m, 2H, CH2), 2.64-2.59 (m, 2H, CH2), 2.15-2.10(m, 1H, CH), 1.91-1.79(m, 1H, CH). LC/MS (ESI+): 372.2
Example 99
Figure imgf000153_0001
7-(4-(l-aminocvclobutyl)phenyl)-N-methyl-6-(pyridin^
[00416] Step A: To a solution of l-(4-(4-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (238 mg, 0.50 mmol) in dioxane (4 mL) was added the aqueous solution of methylamine (10 mL) at a sealed vessel. The reaction mixture was stirred at 100 °C overnight. The mixture was diluted with ethyl acetate (80 mL), and washed by water (40 mL) twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was used without purification. LC/MS (ESI ): 471.2 [M+l]
[00417] Step B: The tert-butyl l-(4-(4-(methylamino)-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (120 mg) was dissolved in ethyl acetate (30 mL). The solution was cooled to 0 °C and the solution of HCl in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The product was collected by filtration, dried in vacuo, to afford 7-(4-(l-aminocyclobutyl)phenyl)-N-methyl-6-(pyridin-2-yl)-7H- pyrrolo [2,3-d] pyri midin-4-amine as HCl salt.: (M+H:371.4.2). 1H NMR (MeOD-d,, 400 MHz), δ ppm: 8.3 l(s, 1H, ArH), 8.07 (s, 1H, ArH), 7.77-7.67(m, 1H, ArH), 7.49-7.46 (m, 2H, ArH), 7.31- 7.17(m, 4H, ArH ), 7.03 (s, 1H, ArH), 3.03(s, 3H, CH3), 2.71-2.69 (m, 2H, CH2), 2.53-2.50 (m, 2H, CH2), 2.15-2.10(m, 1H, CH), 1.91-1.79(m, 1H, CH). LC/MS: (ESI+)
Example 100
Figure imgf000153_0002
7-(4-(l-aminocyclobutyl)phenyn-N,N-diethyl-6-(pyridin-2-yl)-7H-pwolo[2,3-d]pyrimidin-4- amine
[00418] Example 101 shown in Table 12 can also be made according to the above-described methods.
Table 12
Figure imgf000154_0002
Example 102
Figure imgf000154_0001
7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo 2,3-d1pyrimidin-4-ol
[00419] The tert-butyl l-(4-(4-methoxy-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutylcarbamate (120 mg) was dissolved in water (30 mL), the solution was cooled to 0 °C and the solution of HCl in water (12M, 8 mL) was added slowly. The mixture was stirred at 100 °C for 2 h. The mixture was concentrated, dried in vacuo to afford 7-(4-(l- aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol as HCl salt.. !H NMR (MeOD-dU, 400 MHz), δ ppm: 8.36(s, 1H, ArH), 7.91 (s, 1H, ArH), 7.74-7.70(m, 1H, ArH), 7.57- 7.54 (m, 2H, ArH), 7.43-7.23(m, 4H, ArH ), 7.16 (s, 1H, ArH), 2.79-2.74 (m, 2H, CH2), 2.63-2.58 (m, 2H, CH2), 2.35-2.30(m, 1H, CH), 1.91-1.79(m, 1H, CH). LC/MS: (ESI+): :358.2[M+H]+
Example 103
Figure imgf000155_0001
l-(7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-ylV7H-pyre^
one
[00420] Step A: The compound l-(4-(4-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (238 mg, 0.5 mmol), pyrrolidin-2-one (1 mmol), Pd2(dba)3 (19 mg, 0.02 mmol), Xantphos (15 mg, 0.03 mmol) and Cs2C03 (326 mg, 1 mmol) were dissolved in dioxane (10 mL). The reaction mixture was stirred at 90 °C under nitrogen atmosphere for 6 h.. Then the solvent was removed by concentration, and the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed by water dried over sodium sulfate, filtered and concentrated. The crude product was used without purification. LC/MS: (ESI+): 525.2 [M+l]+.
[00421] Step B: The tert-butyl l-(4-(4-(2-oxopyrrolidin-l-yl)-6-(pyridin-2-yl)-7H-pyrrolo
[2,3-d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (150 mg) was dissolved in ethyl acetate (30 mL). The solution was cooled to 0 degree and the solution of HC1 in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The product was collected by filtration, dried in vacuo, to afford l-(7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-one as HC1 salt. 1H NMR (MeOD-d4, 400 MHz), δ ppm: 8.52(s, 1H, ArH), 8.41 (s, 1H, ArH), 7.81-7.77(m, 1H, ArH), 7.59-7.29 (m, 7H, ArH), 4.26-4.22(m, 2H, CH2 ), 2.83-2.61 (m, 6H, 3CH2), 2.30-2.00 (m, 3H, CH2, CH), 1.91-1.79(m, 1H, CH). LC/MS: (ESI+): 425.2 [M+H]+
Example 104
Figure imgf000156_0001
1 -(4-(4-( 1 H-p azol-4-yl)-6-(pyridin-2-yl)-7H-pyrroloi2,3-d1pyrimidin-7- vDphenvPcyclobutanamine
[00422] Step A: The compound tert-butyl l-(4-(4-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)phenyI)cyclobutylcarbamate (500 mg, 1.05 mmol), lH-pyrazol-4-ylboronic acid (2.10 mmol), Pd(dppf)Cl2 (77 mg, 0.11 mmol), and Cs2C03 (684 mg, 2.10 mmol) were dissolved in a mixed solution (dioxane: 20 mL, water: 4 mL). The reaction mixture was heated at 100 °C under nitrogen atmosphere for 4 h. Then the solvents were removed by concentration, and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed by water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatograhpy to give 160 mg of tert-butyl l-(4-(4-(lH-pyrazol-4-yl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutylcarbamate.LC/MS: (ESI+): 508.2 [M+l]
[00423] Step B: The tert-butyl l-(4-(4-(lH-pyrazol-4-yl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (160 mg) was dissolved in ethyl acetate (30 mL). The solution was cooled to 0 degree and the solution of HCl in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The product was collected by filtration, dried in vacuo to afford l-(4-(4-(lH-pyrazol-4-yl) -6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)phenyl)cyclobutanamine,.. Ή NMR (MeOD-dt, 400 MHz), δ ppm: 8.73 (s, 1H, AxH), 8.61 (s, 1H, ArH), 8.40 (s, 1H, ArH), 7.80-7.76 (m, 1H, ArH), 7.66-7.56 (m, 4H, ArH), 7.45- 7.43 (m, 2H, ArH ), 7.29 (s, 1H, ArH), 2.80-2.74 (m, 2H, CH2), 2.62-2.55 (m, 2H, CH2), 2.25-2.20 (m, 1H, CH2), 2.02-1.95 (m, 1H, CH2). LC/MS: (ESI+): 408.2 [M+H]+
Example 105
l-(7-(4-(l-aminocyclobutyl)phenyl)-6-(p idin-2-yl)-^
ol
[00424] Step A: To a solution of tert-butyl l-(4-(4-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (238 mg, 0.50 mmol) in dioxane (20 mL) was added pyrrolidin-3-ol hydrochloride (1 mmol) and K2C03 (2 mmol). Then the reaction mixture was stirred at 120 °C overnight. The reaction mixture was diluted with water and extracted with ethyl acetate for several times, the combined organic phase was washed water and brine. The combined organic layer was dried over Na2S04 and then filtered, the filtrate was concentrated to give the crude product, which was further purified by flash chromatography to afford tert-butyl l-(4-(4-(3- hydroxypyrrolidin-l-yl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutylcarbamate (120 mg, 49.5% yield) LC-MS (ESI+): 527.2 [M+l]+
[00425] Step B: The tert-butyl l-(4-(4-(3-hydroxypyrrolidin-l-yl)-6-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (120 mg) was dissolved in ethyl acetate (30 mL). The solution was cooled to 0 degree and the solution of HCl in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The product was collected by filtration, dried in vacuo to afford l-(7-(4-(l-aminocyclobutyl)phenyl) -6-(pyridin-2- yl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)pyrrolidin-3-ol as HCl salt. (80 mg). Ή NMR (MeOD- U, 400 MHz), δ ppm: 8.28(s, 1H, ArH), 8.02 (s, 1H, ArH), 7.62-7.58(m, 1H, ArH), 7.49-7.46 (m, 2H, ArH), 7.31-7.26(m, 3H, ArH ), 7.21-7.14(m, 2H, ArH ), 4.5 l(s, 1H, CH), 4.01-3.82(m, 4H, 2CH2), 2.72-2.57 (m, 2H, CH2), 2.54-2.49 (m, 2H, CH2), 2.17-2.1 l(m, 3H, CH, CH2), 1.91-1.79(m, 1H, CH). LC/MS: (ESI+): 427.2 [M+l]+.
Example H
Figure imgf000158_0001
7-[4-(l-Amino-cvclobutyl)-phenyl]-6-pyridin-2-yl-7H-pmolo[2J-d1pyrimidine-4-carboxylic acid methyl ester
[00426] Step A: To the solution of l-[4-(4-Chloro-6-pyridin-2-yl-pyrrolo[2,3-d]pyrimidin-
7-yl)-phenyl]-cyclobutylamine (2.0 g, 4.2mmol) in a mixed solution (DMF: 35 ml and MeOH: 15ml) were added Pd(OcA)2 (lOOmg, 0.45mmol), dppf (234mg, 0.42mmol) and TEA (5ml). it was stirred at 80°C under the atmosphere of CO (50 psi) for 14 hours. It was concentrated to remove the solution, the residue was dissolved in EA and washed by water twice, the separated organic layer was dried over sodium sulfate, filtered and concentrated to get crude product, which was purified by flash chromatography, to give 7-[4-(l-Amino-cyclobutyl)-phenyl]-6-pyridin-2-yl-7H- pyrrolo[2,3-d]pyrimidine-4-carboxylic acid methyl ester (1.3g 62% yield) LC/MS: 500.2 [M+l]+
Example I
Figure imgf000158_0002
7-(4-(l-(tert-butoxycarbonylamino)cvclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3- dlpyrimidine-4-carboxylic acid
[00427] 7-[4-( 1 -tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-6-pyridin-2-yl-7H- pyrrolo[2,3-d]pyrimidine-4-carboxylic acid methyl ester (150 mg, 0.3 mmol) was dissolved in IN LiOH (10ml) and MeOH (10 mL) and then the reaction mixture was stirred at 30 °C for 2 hours. Methanol was removed under reduced pressure and the mixture was acidified with HC1 (6 N) carefully till PH= 5, the resulting solid was collected by filtration, dried over vaccum to give 7-(4- (l-(tert-butoxycarbonylamino)cyclobutyl)phenyl)-6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4- carboxylic acid.(120 mg, 82.3% yield).
Example 106
Figure imgf000159_0001
7-(4-n-aminocvclobutyl phenyl)-6-(p ^ acid
[00428] To a solution of 7-[4-(l-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-6-pyridin-
2-yl-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid (80 mg) in EtOAc (5ml) was added HC1/EA (15ml) at 0 °C. The reaction mixture was stirred at ambient temperature for 3 hours. It was concentrated to give crude product, which was purified by preparative HPLC to give 7-(4-(l- aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid, (37 mg, 58% yield) LC/MS (ESI+): 385.9[M+1]+.
Exam le 107
Figure imgf000159_0002
7-(4-(l-aminocvclobutynphenyl)-6-(pyridin-2-yl)-7H-pyrrolor2,3-d pyrimidine-4-carboxamide
[00429] Step A: To a solution of NH3 in THF (10 M, 20 mL) was added 7-[4-(l-tert-
Butoxycarbonylamino-cyclobutyl)-phenyl]-6-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine-4- carboxylic acid methyl ester (0.10 g, 0.2 mmol) in was dissolved in THF (20 mL) in at a sealed vessel , the reaction mixture was stirred at 120 °C for 6 hours. The reaction mixture was concentrated in vacuo, and pured into next reaction without purification. LC/MS (ESI+): 485.1 [M+H]+
[00430] Step B: { l-[4-(4-Carbamoyl-6-pyridin-2-yl-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (150 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and the solution of HC1 in ethyl acetate (4M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.. The product was collected by filtration, dried in vacuo to give 7-[4-(l-Amino-cyclobutyl)-phenyl]-6-pyridin-2-yl-7H-pyrrolo[2,3- d]pyrimidine-4-carboxylic acid amide as HCl salt (16.8mg). H NMR (MeOD, 400 MHz), δ ppm: 8.88(s, 1H), 8.46-8.44(m, 1H), 7.85-7.58(m, 5H), 7.46-7.43(m, 2H), 7.38-7.34(m, 1H), 2.82- 2.75(m, 2H), 2.60-2.53(m, 2H), 2.25-2.22(m,lH), 1.98-1.92(m, 1H). LC/MS (ESI+): 407.1 [M+Na]+
[00431] Example 108 shown in Table 13 can also be made according to the above-described methods.
Table 13
Figure imgf000160_0002
Examples J and K
Figure imgf000160_0001
ferf-butyl 1 -(4-(2-chloro-4-(diethylamino)-6- ferf-butyl 1 -(4-(2-chloro-4-methoxy-6-(pyridin-2-yl)-7H- (pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) pyrrolo[2,3-cf|pyrimidin-7-yl)phenyl)cyclobutylcarbamate -phenyl)cyclobutylcarbamate
[00432] Step A: To a solution of 2,4,6-Trichloro-5-iodo-pyrimidine (6.16 g, 20.00 mmol) in dioxane (100 mL) was slowly added the solution of tert-butyl l-(4- aminophenyl)cyclobutylcarbamate (5.2 g, 20.00 mmol) in dioxane (20 mL) and triethylamine (5 ml). The reaction mixture was stirred at 80 C for overnight, lc-ms indicated 2,4,6-Trichloro-5-iodo- pyrimidine was completed consumed. After removed the excess solvents under the reduced pressure to get a residue, which was dissolved in Ethyl acetate (250 mL) and washed water and brine. The combined organic layer was dried over Na2S04 and then filtered, the filtrate was concentrated to give the crude product, which was further purified by flash chromatography to afford { l-[4-(2,6-Dichloro-5-iodo-pyrimidin-4-ylamino)-phenyl]-cyclobutyl}-carbamic acid tert- butyl ester (5.50 g, yield: 50%).LC/MS: (ESI+): 535 [M+H]+.
[00433] Step B: { l-[4-(2,6-Dichloro-5-iodo-pyrimidin-4-ylamino)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester (5.30 g, 0.01 mol),and 2-ethynylpyridine (1.55 g, 0.015 mol) was added in a lOOmL flask which contained 30 mL of Et3N with stirring, and then the catalyst of Cul(0.38 g, 0.002 mol)and Pd(PPh3)2C12(2 g, 0.002 mol) was added into the mixture. The reaction mixtute was warmed to 80 oC for 90 minutes, lc-ms indicated {l-[4-(2,6-Dichloro-5-iodo- pyrimidin-4-ylamino)-phenyl]-cyclobutyl} -carbamic acid tert-butyl ester was consumed. The reaction mixture was cooled to room temperature. Filtrated, the filtrate was concentrated to give the curde product, which was further purified by flash chromatography to afford (4.1 g, yield:80%){l-[4-(2,6-Dichloro-5-pyridin-2-ylethynyl-pyrimidin-4-ylamino)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester and(2.1 g, yield:40%) LC/MS (ESI+): 510.2 [M+l]+ (M+Na:522).{l- [4-(2-Chloro-6-diethylamino-5-pyridin -2-ylethynyl -pyrimidin-4-ylamino)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester . (2.0 g, 40% yield). LC/MS (ESI+): 547.2 [M+l]+ .
[00434] Step C: A mixture of {l-[4-(2,6-Dichloro-5-pyridin-2-ylethynyl-pyrimidin-4- ylamino)-phenyl]-cyclobutyl} -carbamic acid tert-butyl ester (2.1 g, 8 mmol)and , KF(0.058 g, 1 mmol), Cs2CO3(0.652 g, 2 mmol) in dioxane(lOml) was stirred at 130°C in microwave for 1 hours. A residue was afford after removed the excess solvent , the residue was washed with water to get a solid, then the solid was dried on vacumn to afford {l-[4-(2,4-Dichloro-6-pyridin-2-yl-pyrrolo[2,3- d]pyrimidin-7-yl)-phenyl]-cyclobutyl} -carbamic acid tert-butyl ester (3.4 g, yield: 90%). . LC/MS (ESI+): 510.2 [M+l]+ 522 [M+Na].
[00435] Step D: A mixture of { l-[4-(2-Chloro-6-diethylamino-5-pyridin-2-ylethynyl- pyrimidin-4-ylamino)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (2.0 g, 7 mmol) and, KF (0.058 g, 1 mmol), Cs2C03 (0.652 g, 2 mmol) in dioxane (10ml) was stirred at 130°C in microwave for 1 hours. A residue was afford after removed the excess solvent , the residue was washed with water to get a solid, then the solid was dried on vacumn to afford { l-[4-(2-Chloro-4-diethylamino- 6-pyridin-2-yl-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (3.6 g, yield: 90%). LC/MS (ESI+): 547.2 [M+l]+
Example 109
Figure imgf000162_0001
7- 4-(l-Amino-cyclobutvD-phenyl]-2-(2-fluoro-phenyl)-6-p idin-2-yl-3J-dihydro-pyrrolo[2^ dlpyrimidin-4-one
[00436] Step A: To the solution of {l-[4-(2,4-Dichloro-6-pyridin-2-yl-pyrrolo[2,3- d]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (510 mg, 10 mmol) in methanol (10 mL) was slowly added CH3ONa (108 mg, 20.00 mmol) in portions. The reaction mixture was stirred at room temperature overnight. Then it was concentrated to remove the solvent. The obtained residue was dissolved in Ethyl acetate (250 mL) and washed by water, followed by brine. The separated organic layer was dried in sodium sulfate, filtered and concentrated to give { 1- [4-(2-Chloro-4-methoxy-6-pyridin-2-yl-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester. (450 mg, 50%yield) LC/MS: (ESI+): 506.3 [M+l]+
[00437] Step B: The { l-[4-(2-Chloro-4-methoxy-6-pyridin-2-yl-pyrrolo[2,3-d]pyrimidin-7- yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (253 mg, 0.50 mmol), boronic acid (0.75 mmol), Pd(dppf)Cl2 (77 mg, 0.11 mmol), and Cs2C03 (684 mg, 2.10 mmol) were dissolved in a mixed solution (dioxane: 20 mL, water: 4 mL). The reaction mixture was heated at 100 °C under nitrogen atmosphere for 4 h. Then the solvents were removed by concentration, and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed by water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatogrphy to afford of (l-{4-[2-(2-Fluoro-phenyl)-4-methoxy-6-pyridin-2-yl-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}- cyclobutyl)-carbamic acid tert-butyl ester (160 mg). LC/MS: (ESI+): 566.3 [M+l]+
[00438] Step C: The (l-{4-[2-(2-Fluoro-phenyl)-4-methoxy-6-pyridin-2-yl-pyrrolo[2,3- d]pyrimidin-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (120 mg) was dissolved in water (30 mL), the solution was cooled to 0 °C and the solution of HCl in water (12M, 10 mL) was added slowly. The mixture was stirred at 100 °C for 1 h. The crude product was collected by filtration, which was further purified by preparative HPLC to afford 7-[4-(l-Amino-cyclobutyl)- phenyl]-2-(2-fluoro-phenyl)-6-pyridin-2-yl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one. !H MR (MeOD-d4, 400 MHz), δ ppm: 8.31 (s, 1H, ArH), 7.67-7.65 (m, 2H, ArH), 7.64-7.49 (m, 3H, ArH), 7.47-7.36 (m, 3H, ArH), 7.22-7.16 (m, 3H, ArH ), 7.14 (s, 1H, ArH), 2.75-2.65 (m, 2H, CH2), 2.61- 2.50 (m, 2H, CH2), 2.15-2.10 (m, 1H, CH), 1.91-1.79 (m, 1H, CH). LC/MS (ESI+): 453.3 [M+l]+ Example 110
Figure imgf000163_0001
r7-r4-(l-Amino-cvclobutyl -phenyll-2- H-p azol-4-yl)-6-pyridin-2-yl-7H-pyrrolo[2,3- d]pyrimidin-4-yll-diethyl-amine
[00439] Step A: The { l-[4-(2-Chloro-4-diethylamino-6-pyridin-2-yl-pyrrolo[2,3- d]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (273 mg, 0.50 mmol), boronic acid (0.75 mmol), Pd(dppf)Cl2 (77 mg, 0.11 mmol), and Cs2C03 (684 mg, 2.10 mmol) were dissolved in a mixed solution (dioxane: 20 mL, water: 4 mL). The reaction mixture was heated at 100 °C under nitrogen atmosphere for 4 h. Then the solvents were removed by concentration, and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed by water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatogrphy to afford of (l-{4-[4-Diethylamino-2-(lH-pyrazol-4-yl)-6-pyridin-2-yl-pyrrolo[2,3- d]pyrimidin-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester(160 mg) . LC MS: (ESI+): 579.3 [M+l
[00440] Step B: The (l-{4-[4-Diethylamino-2-(lH-pyrazol-4-yl)-6-pyridin-2-yl-pyrrolo[2,3- d]pyrimidin-7-yl] -phenyl }-cyclobutyl)-carbamic acid tert-butyl ester (120 mg) was dissolved in water (30 mL), the solution was cooled to 0 °C and the solution of HCl in ethyl acetate(4M, 10 mL) was added slowly. The mixture was stirred at room temperature for 1 h. The crude product was collected by filtration, which was further purified by preparative HPLC to afford [7-[4-(l-Amino- cyclobutyl)-phenyl]-2-(lH-pyrazol-4-yl)-6-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-diethyl- amine. 1H NMR (MeOO-< , 400 MHz), δ ppm: 8.50(s, 1H, ArH), 8.38 (s, 1H, ArH), 7.72-7.70 (m, 1H, ArH), 7.54-7.52 (m, 2H, ArH), 7.45-7.41 (m, 3H, ArH), 7.29 (s, 1H, ArH), 7.26-7.23 (m, 1H, ArH), 3.70-3.65 (m, 4H, 2CH2), 2.86-2.78 (m, 2H, CH2), 2.67-2.59 (m, 2H, CH2), 2.23-2.06 (m, 1H, CH), 2.04-1.98 (m, 1H, CH),1.21-1.18 (m, 6H, 2CH3). LC/MS (ESI+): 479.3 [M+l]+
Example 111
Figure imgf000164_0001
l-{4-r4-Memoxy-2-(lH-pyrazol-4-yl)-6-pyridin-2-yl-pyro
cyclobutylamine
[00441] Step A: The { l-[4-(2-Chloro-4-methoxy-6-pyridin-2-yl-pyrrolo[2,3-d]pyrimidin-7- yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (253 mg, 0.50 mmol), boronic acid (0.75 mmol), Pd(dppf)Cl2 (77 mg, 0.11 mmol), and Cs2C03 (684 mg, 2.10 mmol) were dissolved in a mixed solution (dioxane: 20 mL, water: 4 mL). The reaction mixture was heated at 100 °C under nitrogen atmosphere for 4 h. Then the solvents were removed by concentration, and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed by water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatogrphy to afford ( 1 - {4- [4-Methoxy-2-( 1 H-pyrazol-4-yl)-6-pyridin-2-yl-pyrrolo [2,3 -d]pyrimidin-7-yl] -phenyl } - cyclobuty -carbamic acid tert-butyl ester (160 mg). LC/MS: (ESI+): 538.3 [M+l]+
[00442] Step B: The (l-{4-[4-Methoxy-2-(lH-pyrazol-4-yl)-6-pyridin-2-yl-pyrrolo[2,3- d]pyrimidin-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (120 mg) was dissolved in water (30 mL), the solution was cooled to 0 C and the solution of HC1 in water (12M, 10 mL) was added slowly. The mixture was stirred at 100 °C for 1 h.. The crude product was collected by filtration, which was further purified by preparative HPLC to afford l-{4-[4-Methoxy-2-(lH- pyrazol-4-yl)-6-pyridin-2-yl-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-cyclobutylamine. Ή NMR (MeOD-d4, 400 MHz), δ ppm: 8.50 (s, 1H, ArH), 8.41 (s, 1H, ArH), 8.29 (s, 1H, ArH), 7.76-7.72 (m, 2H, ArH), 7.59-7.53 (m, 3H, ArH), 7.30-7.26 (m, 1H, ArH), 7.00 (s, 1H, ArH), 4.21 (s, 3H, CH3), 2.86-2.78 (m, 2H, CH2), 2.67-2.59 (m, 2H, CH2), 2.23-2.06 (m, 1H, CH), 2.04-1.98 (m, 1H, CH). LC/MS (ESI+): 438.3 [M+l]+
Example 112
Figure imgf000164_0002
1 -(4-(2 -phenyl- 1 H-pyrrolo[2,3-c1pyridin- 1 -vPphenvPcvclobutanamine
[00443] Step A: To a solution of 3-chloro-4-iodopyridine (1 g, 4.2 mmol), 1-ethynylbenzene
(430 mg, 4.2 mmol), and Pd(PPh3)2Cl2(147 mg, 0.21 mmol) in TEA (30 mL) was added Cul (40 mg, 0.21 mmol). The mixture was stirred at reflux for 60min.The reaction mixture was concentrated under reduced pressure and purified by flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =100/1-5/1), to give the title product 3-chloro-4-(2- phenylethynyl)pyridine (0.85 g, 95%). 'HNMR: CDC13 400MHZ δ 8.67(s, 1H), 8.47~8.45(d, 1H, J=8), 7.70~7.68(m, 2H), 7.44~7.26(m, 4H).
[00444] Step B: To a solution of 3-chloro-4-(2-phenylethynyl)pyridine (426 mg, 2 mmol),
Pd2(dba)3 (90 mg, 0.1 mmol), X-phos (190 mg, 0.4 mmol) and Cs2C03 (978 mg, 3 mmol) in Dioxane (8 mL) was added tert-butyl l-(4-aminophenyl)cyclobutylcarbamate (524 mg, 2 mmol). The mixture degassed and charged with N2 for three times. And then the resulting mixture was stirred at 120 °C for 60 min by microwave irradiation. The reaction mixture was filtered by filter paper. The filtrate was concentrated under reduced pressure to get crude product, which was purified flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =100/1-1/1) to yield the desired product fert-butyl l-(4-(2-phenyl-lH-pyrrolo[2,3-c ] pyridin-1- yl)phenyl ) cyclobutylcarbamate (100 mg, 11%). 'HNMR: MeOD 400MHz δ 8.55(s,lH), 8.25~8.23(d, 1H, J=8), 7.84~7.82(d, 1H, J=8), 7.58-7.56 (m, 2H), 7.36-7.28 (m, 7H), 7.02 (s, 1H), 2.52-2.46 (m,4H), 2.15-2.00 (m,lH), 1.95-1.82 (m,lH), 1.36 (s,9H)
[00445] Step C: To a solution of HC1 in EtOAc (30 mL, 2 M) was added tert-butyl l-(4-(2- phenyl-lH-pyrrolo[2,3-c] pyridin-l-yl)phenyl) cyclobutylcarbamate (100 mg, 0.23 mmol). The mixture was stirred at r.t. for 60min. The reaction mixture was filtered to give l-(4-(2-phenyl-lH- pyrrolo[2,3-c]pyridin-l-yl)phenyl)cyclobutanamine (51 mg).1HNMR: MeOD 400MHz 6 8.79(s, 1H), 8.35~8.33(d, 1H, J=8), 8.23~8.21(d, 1H, J=8), 7.74~7.72(m, 2H), 7.59~7.57(m, 2H), 7.46~7.44(m, 3H), 7.39~7.37(m, 2H), 7.34(s, 1H), 2.80~2.76(m, 2H), 2.68~2.64(m, 2H), 2.24~2.20(m, 1H), 2.00-1.96(m, 1H). MS (ESI) m/z: 340.2 [M+l]+. 342.2 [M+3]+
Example 113
Figure imgf000165_0001
l-[4-(6-Phenyl-pyrrolo[2,3-b1pyrazin-5-yl)-phenyl1-cvclobutylamine [00446] Step A: 2,3-Dichloro-pyrazine (1.48 g, 0.01 mol),and Ethynyl-benzene (1.53 g, 0.015 mol) was added in a lOOmL flask which contained 30mL of Et3N with stirring, and then the catalyst of Cul(0.38 g, 0.002 mol)and Pd(PPh3) 2C12(2 g, 0.002 mol) was added into the mixture. The reaction mixture was warmed to 80°C for 0.5h, lc-ms indicated 2,3-Dichloro-pyrazine was consumed. The reaction mixture was cooled to room temperature. Filtrated, the filtrate was concentrated to give the crude product, the crude product was further purified by flash chromatography to afford 2-Chloro-3-phenylethynyl-pyrazine. (1.5 g, yield: 71%). LC/MS (ESI+): 215 [M+l]+ 217 [ +3]+
[00447] Step B: A mixture of 2-Chloro-3-phenylethynyl-pyrazine (1.5 g, 7 mmol), [l-(4-
Amino-phenyl)-cyclobutyl]-carbamic acid tert-butyl ester (2.2 g, 8.4 mmol), Cs2C03(4.5 g, 14 mmol) ,X-phos(0.65 g, 1.4 mmol) and Pd2(dba)3 (1.3 g, 1.4 mmol) in dioxane(10 ml) was stirred at 120°C in microwave for 1 hours. The reaction mixture was cooled to room temperature , then poured into water and extracted with ethyl acetate for three times, the combined organic layer was washed with water and brine, dried and concentrated to afford the which was further purified by flash chromatography to afford { l-[4-(3-PhenylethynyI-pyrazin-2-ylamino)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester (1.2 g, 40 % yield). LC/MS (ESI+): 441 [M+l]+ ,443 [M+3]+
[00448] Step C: A mixture of { l-[4-(3-Phenylethynyl-pyrazin-2-ylamino)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (0.44 g, 1 mmol), KF(0.058 g, 1 mmol), Cs2CO3(0.652 g, 2 mmol) , and Pd(t-Bu3P)2 (0.15 g, 0.01 mmol) in dioxane(lOml) was stirred at 130°C in microwave for lh. After cooled to room temperature ,the reaction mixture was poured into water and extracted with ethyl acetate for three times, then the combined organic layer was washed with water and brine, dried and concentrated to give a residue, which was further purified by flash chromatography to afford {l-[4-(6-Phenyl-pyrrolo[2,3-b]pyrazin-5-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (0.3 g, yield: 68%). LC/MS: (ESI+): 441 [M+l]+ ,443 [M+3]+
[00449] Step D: The solution of l-[4-(6-Phenyl-pyrrolo[2,3-b]pyrazin-5-yl)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (0.3 g, 0.7 mmol) in ethyl acetate was added the solution of HC1 in ethyl acetate (4mol/L HC1, 10 ml), the reaction mixture was stirred at room temperature for 1 h. After remove the solvents to afford a residue,which was further purified by prep-hplc to afford l-[4-(6-Phenyl-pyrrolo[2,3-b]pyrazin-5-yl)-phenyl]-cyclobutylamine. (120 mg, yield: 49.5%). 'HNM (DMSO-< , 400 MHz): δ 8.49 (d, J = 2.8Hz 1H,), δ 8.22 (d, J = 2.8Hz 1H,), δ 7.51 (d, J = 8.4Hz 2H,), δ 7.25(d, J=8.4Hz 2H,), 7.39 - 7.33 (m, 5H),7.07(s, 1H), 2.48 (m, 2H), 2.38 (m, 2H), 2.0 (m, 1H), 1.7 (m, 1H). LC/MS: (ESI+): 341 [M+l]+ ,343 [M+3]+
Example L
Figure imgf000167_0001
{ l-f4-(2-Chloro-6-phenyl-pyrrolof3,2-dlpyrimidin-5-yl)-phenyl1-cvclobutyll-carbamic acid tert- butyl ester
[00450] Step A: To a solution of 5-bromo-2,4-dichloropyrimidine (10.00 g, 43.88 mmol) in
TEA (100 mL) were added ethynylbenzene (4.48 g, 43.88 mmol), Pd(PPh3)2Cl2 (1.00 g, 1.42 mmol), and Cul (1.67 g, 8.76 mmol). The reaction mixture was stirred at 100 °C under the atmosphere of nitrogen for 2 h. After cooling, the solvent was removed by concentration, and the residue was dissolved in ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column separation (eluted by: hexane / ethyl acetate = 20: 1) to afford 5-bromo-2-chloro-4- (phenylethynyl)pyrimidine. (7.10 g, 55% yield). 1H MR (DMSO, 400 MHz), δ ppm: 9.11 (s, 1H), 7.73-7.71 (m, 2H), 7.62-7.52 (m, 3H). MS (ESI+) e/z: 295 [M+l]+.
[00451] Step B: To a solution of 5-bromo-2-chloro-4-(phenylethynyl)pyrimidine (1.80 g,
6.13 mmol) in dioxane (20 mL) were added [l-(4-Amino-phenyl)-cyclobutyl]-carbamic acid tert- butyl ester (1.45 g, 5.53 mmol), Pd2(dba)3 (0.28 g, 0.31 mmol), X-Phos (0.29 g, 0.61 mmol), and Cs2C03 (3.99 g, 12.25 mmol). The reaction mixture was stirred at 100 °C under the atmosphere of nitrogen for 4 h.. After cooling, the solvent was removed by concentration, and the residue was dissolved in ethyl acetate. The solution was washed by water twice. The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column separation (eluted by: hexane / ethyl acetate = 10 : l to 3 : l) to afford tert-butyl l-(4-(2- chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-5-yl)phenyl)cyclobutylcarbamate (2.10 g, 72% yield). Ή NMR (MeOD, 400 MHz), δ ppm: 8.52 (s, 1H), 7.59-7.56 (m, 2H), 7.40-7.29 (m, 7H), 6.92 (s, 1H), 2.63-2.45 (m, 4H), 2.18-2.01 (m, 1H), 1.99-1.82 (m, 1H). MS (ESI+) e/z: 475 [M+l]+.
Example 114
Figure imgf000168_0001
l-[4-(2-Chloro-6-phenyl-pyrrolor3.2-d]pyrimidin-5-yl)-phenyl1-cyclobutylamine
[00452] Step A: { l-[4-(2-Chloro-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (150 mg, 0.316 mmol) was dissolved in ethyl acetate (20 mL), the solution was cooled to 0 °C and the solution of HC1 in ethyl acetate (4 M, 5 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The product was collected by filtration, and the crude product was purified by HPLC separation to afford l-[4-(2-Chloro-6- phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]-cyclobutylamine (70 mg, mg, 59 % yield). Ή NMR (MeOD, 400 MHz), δ ppm: 8.52 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.41-7.32 (m, 5H), 6.94 (s, 1H), 2.81-2.74 (m, 2H), 2.60-2.53 (m, 2H), 2.24-2.21 (m, 1H), 2.02-1.95 (m, 1H). MS (ESI+) e/z: 375 [M+l]+.
Example 115
Figure imgf000168_0002
j5-r4-n-Amino-cvclobutyl)-phenyl1-6-phenyl-^
[00453] Step A: To the solution of { 1 -[4-(2-Chloro-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)- phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (200 mg, 0.42 mmol) in dioxane (3 mL) was added the aqueous dimethylamine solution (10 mL) at a sealed vessel. The reaction mixture was stirred at 100 C overnight. LC/MS indicated the reactions worked well. It was diluted with ethyl acetate (80 mL), and washed by water (40 mL) twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product { l-[4-(2-Dimethylamino-6-phenyl- pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was (-180 mg) used without purification. MS (ESI+) e/z: 484 [M+l]+.
[00454] Step B: { l-[4-(2-Dimethylamino-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (-180 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 C and the solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The crude product was collected by filtration, and purified by HPLC separation to afford {5-[4-(l-Amino-cyclobutyl)-phenyl]-6- phenyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl}-dimethyl-amine (53 mg, 33 %, two steps). 1H NMR (MeOD, 400 MHz), δ ppm: 8.30 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.37-7.28 (m, 7H), 6.63 (s, 3H), 3.21 (s, 6H), 2.79-2.72 (m, 2H), 2.57-2.50 (m, 2H), 2.25-2.18 (m, 1H), 1.98-1.90 ( m, 1H).MS (ESI+) e/z: 384 [M+l]+.
Example 116
Figure imgf000169_0001
1 - { 4- [6-Phenyl-2-( 1 H-pyrazol-4-yl)-pyrrolo [3 ,2-d]pyrimidin-5 -yl] -phenyl I -cyclobutylamine
[00455] Step A: { l-[4-(2-Chloro-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (250 mg, 0.53 mmol), 4-(4,4,5,5-Tetramethyl- [l,3,2]dioxaborolan-2-yl)-lH-pyrazole (153 mg, 0.79 mmol), Pd(dppf)Cl2 (31 mg, 0.04 mmol), and Cs2C03 (343 mg, 1.05 mmol) were dissolved in a mixed solution (dioxane: 15 mL, water: 3 mL). The reaction mixture was heated at 100 C under nitrogen atmosphere for 4 h. Then the solvents were removed by concentration, and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed by water, dried over sodium sulfate, filtered and concentrated. The crude product ( 1 - {4- [6-Phenyl-2-( 1 H-pyrazol-4-yl)-pyrrolo [3 ,2-d]pyrimidin-5-yl] -phenyl } -cyclobuty 1)- carbamic acid tert-butyl ester (-200 mg) was used in next step without further purification. MS (ESI+) e/z: 507 [M+l]+.
[00456] Step B: (l-{4-[6-Phenyl-2-(lH-pyrazol-4-yl)-pyrrolo[3,2-d]pyrimidin-5-yl]- phenyl}-cycIobutyl)-carbamic acid tert-butyl ester (-200 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and the solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.. The product was collected by filtration, and the crude product was purified by HPLC separation to afford l-{4-[6-Phenyl-2- (lH-pyrazol-4-yl)-pyrrolo [3, 2-d]pyrimidin-5-yl] -phenyl} -cyclobutylamine (80 mg, 37 % yield). 1H NMR (MeOD, 400 MHz), δ ppm: 8.62 (s, 1H), 8.30 (s, 2H), 7.66-7.63 (m, 2H), 7.48-7.32 (m, 7H), 6.94 (s, 1H), 2.81-2.74 (m, 2H), 2.59-2.51 (m, 2H), 2.26-2.22 (m, 1H), 1.99-1.93 (m, 1H). MS (ESf ) e/z: 407 [M+l]+.
Example
Figure imgf000170_0001
2- { 5-f 4-( 1 -Amino-cyclobutyl)-phenyl]-6-phenyl-5H-pyiTolo[3,2-d1pyrimidin-2-ylamino } -ethanol
[00457] Step A: {l-[4-(2-Chloro-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (200 mg, 0.42 mmol) and 2-Amino-ethanol (10 mL) were put into a sealed vessel. And it was stirred at 130 °C for 6 h. The reaction mixture was diluted with ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product (l-{4-[2-(2-Hydroxy-ethylamino)-6-phenyl- pyrrolo[3,2-d]pyrimidin-5-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (-160 mg) was used without further purification. MS (ESI+) e/z: 500 [M+l .
[00458] Step B: (l-{4-[2-(2-Hydroxy-ethylamino)-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl]- phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (-160 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and the solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h. The product was collected by filtration, and the crude product was purified by HPLC separation to afford 2-{5-[4-(l-Amino- cyclobutyl)-phenyl]-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino} -ethanol (75 mg, 45% yield, two steps). 1H MR (MeOD, 400 MHz), δ ppm: 8.24 (s, 1H), 7.60 (d, J-8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.35-7.28 (m, 5H), 6.61 (s, 1H), 3.75 (t, J=5.6 Hz, 2H), 3.54 (t, J=5.6 Hz, 2H), 2.83-2.76 (m, 2H), 2.63-2.56 (m, 2H), 2.27-2.22 (m, 1H), 1.99-1.96 (m, 1H). MS (ESI+) e/z: 400 [M+l]+.
[00459] Example 118 shown in Table 13 can also be made according to the above-described methods.
Table 13
Figure imgf000170_0002
Figure imgf000171_0001
The following compound can be made according to methods described herein:
Example 119
Figure imgf000171_0002
5-(4-(l-aminocvclobutyl)phenyl)-N-ethyl-6-phenyl-5H-pyrrolo[3,2-d1pyrimidin-2-amine
Example 120
Figure imgf000172_0001
l-{5-[4-(l-Amino-cvclobutyl)-phenyll-6-phenyl-5H-pyrrolo 3,2-d1pyrimidin-2-yll-py^
[00460] Step A: To the solution of { 1 -[4-(2-Chloro-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)- phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (250 mg, 0.53 mmol) in MP (30 mL) was added Pyrrolidin-3-ol (183 mg, 2.10 mmol), and K2C03 (363 mg, 2.63 mmol). Then the reaction mixture was stirred at 130 °C overnight. The solvent was removed by concentration, and the resulting residue was diluted with ethyl acetate (100 mL), washed by water (50 mL) twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product ( 1 - {4-[2-(3-Hydroxy-pyrrolidin- 1 -yl)-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl]-phenyl } -cyclobutyl)- carbamic acid tert-butyl ester (-180 mg) was used without further purification. MS (ESI+) e/z: 526 [M+l]+.
[00461] Step B: (l-{4-[2-(3-Hydroxy-pyrrolidin-l-yl)-6-phenyl-pyrrolo[3,2-d]pyrimidin-5- yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (-180 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and the solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.. The crude product was collected by filtration, and purified by HPLC separation to afford l-{5-[4-(l-Amino-cyclobutyl)- phenyl]-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl}-pyrrolidin-3-ol (39 mg, 17 % yield, two steps). 1H NMR (MeOD, 400 MHz), δ ppm: 8.26 (s, 1H), 7.58 (d, J=8.4 Hz, 2H ), 7.33-7.27 (m, 7H), 6.61 (s, 1H), 4.58-4.51 (m, 1H), 3.73-3.69 (m, 3H), 3.62-3.59 (m, 1H), 2.74-2.70 (m, 2H), 2.52-2.45 (m, 2H), 2.20-2.11 (m, 2H), 2.08-2.00 (m, 1H), 1.98-1.92 (m, 1H). MS (ESI+) e/z: 426 [M+l]+.
Example 121
Figure imgf000172_0002
1 - r4-(6-Phenyl-pyrrolo [3 ,2-d1pyrimidin-5 -yP-phenyl] -cyclobutylamine [00462] Step A: To a solution of { l-[4-(2-Chloro-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)- phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (250 mg, 0.53 mmol) in methanol (30 mL) were added Pd/C (200 mg) and KOAc(103 mg, 1.05 mmol). The mixture was stirred at ambient temperature under the atmosphere of hydrogen (balloon) for 12 h.. The catalyst was moved by filtration, washed by methanol. The filtrate was concentrated to give desired product {l-[4-(6- Phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (-100 mg), which was used in de-Boc reaction without purification. MS (ESI+) e/z: 441 [M+l]+.
[00463] Step B: {l-[4-(6-Phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester (-100 mg) was dissolved in ethyl acetate (20 mL), the solution was cooled to 0 °C and the solution of HC1 in ethyl acetate (4 M, 5 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.. The product was collected by filtration, and the crude product was purified by HPLC separation to afford l-[4-(6-Phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)- phenylj-cyclobutylamine (20 mg, 11 % yield). 1H NMR (MeOD, 400 MHz), δ ppm: 8.90 (s, 1H), 8.66 (s, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.41-7.33 (m, 7H), 7.00 (s, 1H), 2.72-2.65 (m, 2H), 2.45-2.39 (m, 2H), 2.20-2.13 (m, 1H), 1.98-1.82 (m, 1H). MS (ESI+) e/z: 341 [M+l]+.
Example N
Figure imgf000173_0001
5-(4-(l-(tert-butoxycarbonylamino)cvclobutyl)phenyl)-6-phenyl-5H-pyrrolo[3,2-d1pyrimidine-2- carboxylic acid
[00464] Step A: To the solution of { l-[4-(2-Chloro-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)- phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (450 mg, 0.95 mmol) in a mixed solution (DMF: 15 mL, MeOH: 5 mL) were added Pd(OAc)2 (21 mg, 0.10 mmol), dppf (53 mg, 0.10 mmol) and TEA (lmL). The reaction mixture was stirred at 80 C under the atmosphere of carbon monoxide (50 psi) overnight.. It was concentrated to remove the solvent, and the residue was dissolved in ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product purified by column separation (EtOAc:Hexane =1 :3) to afford 5-[4-(l -tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-6-phenyl-5H-pyrrolo[3,2- d]pyrimidine-2-carboxylic acid methyl ester (250 mg, 53% yield). MS (ESI+) e/z: 499[M+1]+. [00465] Step B: To a solution of 5-[4-(l-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-6- phenyl-5H-pyrrolo[3,2-d]pyrimidine-2-carboxylic acid methyl ester (250 mg, 0.502 mmol) in THF (10 mL) was added a solution of lithium hydroxide hydrate (84 mg, 2.00 mmol) in H20 (10 mL). The reaction mixture was stirred at ambient temperature for 3 h.. Then the solution was acidified by IN HC1 solution to pH 7-8. The solution was concentrated to give crude product 5-[4-(l-tert- Butoxycarbonylamino-cyclobutyl)-phenyl]-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-2-carboxylic acid (-220 mg), which was used without further purification. MS (ESI+) e/z: 485[M+1]+.
Example 122
Figure imgf000174_0001
5-[4-(l-Amino-cvclobutylVphenyll-6-phenyl-5H-pyrrolo[3.2-d1pyrimidine-2-carboxylic acid
[00466] Step A: 5-[4-(l-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-6-phenyl-5H- pyrrolo[3,2-d]pyrimidine-2-carboxylic acid (-220 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 C and the solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.. The product was collected by filtration, and the crude product was purified by HPLC separation to afford 5-[4-(l-Amino-cyclobutyl)- phenyl]-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-2-carboxylic acid (150 mg, 78 %, two steps). Ή NMR (MeOD, 400 MHz), δ ppm: 8.17 (s, IH), 7.66-7.59 (m, 2H), 7.49-7.34 (m, 7H), 7.08 (s, IH), 2.89-2.75 (m, 2H), 2.72-2.55 (m, 2H), 2.31-2.20 (m, IH), 2.05-1.95 (m, IH). MS (ESI+) e/z: 385 [M+l]+.
Example 123
Figure imgf000174_0002
5-(4-(l-aminocyclobutynphenyl)-N-methyl-6-phenyl-5H-pyrrolor3,2-d1pyrimidine-2-carboxamide
[00467] Step A: DIPEA (0.5 mL) was added a solution of 5-(4-(l-(tert-butoxy- carbonylamino)cyclobutyl)phenyl)-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-2-carboxylic acid (170 mg, 0.35 mmol), methanaminium chloride (118 mg, 1.75 mmol) and HATU (700 mg, 1.8 mmol) in DMF (5 mL). The mixture was stirred at 10°C for overnight. LC-MS showed the reaction worked well. The reaction mixture was diluted with Ethyl acetate (30 mL), washed with Na2C03 (20 mL, a.q.) and brine (2 x 20 mL). The organic phase was concentrated to dryness to give the product to give the product tert-butyl l-(4-(2-(methylcarbamoyl)-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-5- yl)phenyl)cyclobutylcarbamate (75 mg, 43% yield). LC/MS (ESI+): 498.2 [M+H]+
[00468] Step B: tert-butyl l-(4-(2-(methylcarbamoyl)-6-phenyl-5H-pyrrolo[3,2- d]pyrimidin-5-yl)phenyl)cyclobutylcarbamate (75 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 °C and the solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.. The product was collected by filtration, and the crude product was purified by preparative HPLC to afford 5-(4-(l- aminocyclobutyl)phenyl)-N-methyl-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-2-carboxamide. 1H NMR (MeOD, 400 MHz), δ ppm: 8.25 (s, 1H), 7.62 (d, 2H, J=6.8 Hz), 7.41 (d, 2H, J=6.8 Hz), 7.36-7.31 (m, 5H), 6.63 (s, 1H), 3.18 (s, 3H), 2.82-2.79 (m, 2H), 2.66-2.61 (m, 2H), 2.24-2.22(m, 1H), 1.96-1.94 (m, 1H). MS (ESI+) e/z: 398.2 [M+l]+
Example 124
1 -(5-(4-( 1 -aminocyclobutyl)phenyl)-6-phenyl-5H-pyrrolo|"3,2-d1pyrimidin-2-yl)pyrrolidin-2-one
[00469] Step A: The compound tert-butyl l-(4-(2-chloro-6-phenyl-5H-pyrrolo[3,2- d]pyrimidin-5-yl)phenyl)cyclobutylcarbamate (300 mg, 0.63 mmol), Pyrrolidin-2-one (161 mg, 1.89 mmol), Pd2(dba)3 (57.6 mg, 0.0063 mmol), Xantphos (36 mg, 0.0.63 mmol) and Cs2C03 (616 mg, 1.89 mmol) were dissolved in dioxane (20 mL). The reaction mixture was stirred at 100 °C under nitrogen atmosphere overnight. Then the solvent was removed by concentration, and the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed by water dried over sodium sulfate, filtered and concentrated to give tert-butyl l-(4-(2-(2-oxopyrrolidin-l-yl)-6-phenyl- 5H-pyrrolo[3,2-d]pyrimidin-5-yl)phenyl)cyclobutylcarbamate (186 mg, yield: 56%). LC/MS (ESI+): 524.2 [M+H]+ [00470] Step B: tert-butyl l-(4-(2-(2-oxopyrrolidin-l-yl)-6-phenyl-5H-pyrrolo[3,2- d]pyrimidin-5-yl)phenyl)cyclobutylcarbamate(186 mg) was dissolved in ethyl acetate (30 mL), the solution was cooled to 0 C and the solution of HC1 in ethyl acetate (4 M, 8 mL) was added slowly. The mixture was stirred at ambient temperature for 4 h.. The product was collected by filtration, and the crude product was purified by preparative HPLC to afford title compound: l-(5-(4-(l- aminocyclobutyl)phenyl)-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-one (54 mg). 1H NMR (MeOD, 400 MHz), δ ppm: 8.56 (s, IH), 7.52 (d, 2H, J= 6.8 Hz), 7.46 (m, 2H, J= 6.8 Hz), 7.41-7.32 (m, 5H), 6.93 (s, IH), 4.21-4.17 (t, 2H), 2.82-2.79 (m, 2H), 2.7 1-2.68 (t, 2H), 2.64-2.60 (m, 2H), 2.24-2.22(m, IH), 2.21-2.18 (m, 2H),2.06-1.96 (m, IH). LC/MS (ESI+): 424.3 [M+H]+
Exam le 125
Figure imgf000176_0001
l-f4-(2-Methoxy-6-phenyl-pyrrolo 3,2-d1pyrimidin-5-yl)-phenyll-cyclobutylamine
[00471] Step A: To the solution of { l-[4-(2-Chloro-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)- phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (190 mg, 0.4 mmol) and NaOMe ( 432 mg, 8 mmol) in MeOH (2 mL) was heated at 120°C by MW for 50 min.. The reaction mixture was concentrated to dryness. The residue was diluted with EA (20 mL), wished with brine (2*10 mL). The organic phase was concentrated to dryness to give the product { l-[4-(2-Methoxy-6-phenyl- pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]-cyclobutyl}-carbamic acid methyl ester (137 mg, 85% yield). LC/MS (ESI+): 484.2 [M+H]+
[00472] Step B: LiOH (178 mg, 7.4 mmol) was added a solution of { l-[4-(2-Methoxy-6- phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]-cyclobutyl}-carbamic acid methyl ester (130 mg, 0.304 mmol) in a mixture solution (dioxane:10 mL, H20: 5 mL). The mixture was heated at 120°C for overnight in a 30 mL of sealed rude.. The cooled mixture was diluted with Ethyl acetate (20 mL) and washed brine (2* 10 mL). The organic phase was concentrated to dryness, which was purified by preparative HPLC to give l-[4-(2-Methoxy-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)- phenyl]-cyclobutylamine (26 mg, 19% yield:). 1H NMR (MeOD, 400 MHz), δ ppm: 8.41 (s, IH), 7.62 (d, 2H, J=8.4 Hz), 7.42 (m, 2H, J=8.4 Hz), 7.39-7.30 (m, 5H), 6.80 (s, IH), 4.04 (s, 3H), 2.80- 2.73 (m, 2H), 2.59-2.52 (m, 2H), 2.47-2.22(m, IH), 1.97-1.94 (m, IH). MS (ESI+): 371.2 [M+H]+.
Examples 126 and 127
Figure imgf000177_0001
1-(4-(5-methyl-6-phenyl-7 - -pyrrolo[2.3-dlPyrimidin-7- 1-(4-(6-methyl-5-phenyl-7H-pyrro[o[2.3--yi yhphenyltoyclobutanamine pyrimidin-7-yl)phenyl)cyclobutanamine
[00473] Step A: To a solution of 4-Chloro-5-iodo-pyrimidine (200 mg, 0.83 mmol) and [1-
(4-Amino-phenyl)-cyclobutyl]-carbamic acid tert-butyl ester (218 mg, 0.83 mmol) in dioxane (10 mL) was added DIPEA (214 mg, 1.66 mmol). The mixture was heated at 100°C for 18 h. After removal of solvent by concentration, the residue was purified by silica gel chromatography eluted with Hexane Ethyl acetate = 10:1 to give { l-[4-(5-Iodo-pyrimidin-4-ylamino)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester. (230 mg, 59%yield). LCMS (ESI+): 466.8 [M+l]+
[00474] Step B: The { l-[4-(5-Iodo-pyrimidin-4-ylamino)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (200 mg, 0.42 mmol) and Prop-l-ynyl-benzene (73 mg, 0.63 mmol) were dissolved in DMF (5 mL), and then LiCl (17.6 mg, 0.42 mmol), Pd(OAc)2 (9.4 mg, 0.04 mmol) and KOAc (82 mg, 0.84 mmol) were added. The resulting mixture was charged with N2 thrice and irradiated at 120°C by MW for 1 h. TLC showed the starting material was consumed completely. The mixture was diluted with water (20 mL), extracted with EtOAc (3*20). The combined extracts were concentrated to give mixture cantaining {l-[4-(5-Methyl-6-phenyl-pyrrolo-[2,3-d]pyrimidin- 7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester and { l-[4-(6-Methyl-5-phenyl-pyrrolo[2,3- d]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester. (183 mg, 93%yield).
[00475] Step C: To the mixture of { 1 -[4-(5-Methyl-6-phenyl-pyrrolo[2,3-d]pyrimidin-7-yl)- phenyl]-cyclobutyl}-carbamic acid tert-butyl ester and { l-[4-(6-methyl-5-phenyl-pyrrolo[2,3- d]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (183 mg, 0.4 mmol) in ethyl acetate (20 mL) was added HCl/EtOAc (10 mL, 2M) at 0°C. The resulting solution was stirred for 2 hrs. After removal of solvent by concentration, the residue was purified by prep-HPLC to give l-[4- (5-Methyl-6-phenyl-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-cyclobutylamine (12 mg, yield: 8.4%). Ή MR (MeOD, 400 MHz), δ ppm: 9.07 (s, 1H), 8.74 (s, lH), 7.54 (d, 2H, J=8.4 Hz), 7.40-7.36 (m, 2H), 7.35-7.33 (m, 3H), 7.31-7.28 (m, 2H), 2.80-2.73 (m, 2H), 2.53-2.46 (m, 2H), 2.40 (s, 3H), 2.23-2.19(m, 1H), 1.96-1.91 (m, 1H). and l-[4-(6-Methyl-5-phenyl-pyrrolo[2,3-d]pyrimidin-7-yl)- phenyl]-cyclobutylamine (14 mg, yield: 9.8%): 1H NMR (MeOD, 400 MHz), δ ppm: 8.93 (s, 1H), 8.67 (s, 1H), 7.73 (d, 2H, J=8.4 Hz), 7.59-7.51 (m, 6H), 7.41-7.37 (m, 1H), 2.80-2.73 (m, 2H), 2.53-2.46 (m, 2H), 2.40 (s, 3H), 2.23-2.19(m, 1H), 1.96-1.91 (m, 1H).
Example 128
Figure imgf000178_0001
l-[4-(5-Ethyl-6-pyridin-2-yl-pyiTolo[23-d]pyrimidin-7-yl)-phenyl1-cyclobutylamine
[00476] Step A: To a solution of {l-[4-(2-Chloro-6-pyridin-2-yl-pyrrolo [2,3-d]pyrimidin-7- yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (240 mg, 0.5 mmol) in DCM (10 mL) was added NIS (110 mg, 0.5 mmol). The mixture was stirred at r.t. for overnight. The reaction mixture was filtered, and the solvent was concentrated under reduced pressure to get crude product, which was purified by flash chromatography (petroleum ether/ethyl acetate= 100/1-1/1) to yield the desired product { l-[4-(2-Chloro-5-iodo-6-pyridin-2-yl-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (210mg, 69%). MS (ESI) m/z: 602.2[M+1]+ ,624.1 [M+Na]+.
[00477] Step B: To a solution of { l-[4-(2-Chloro-5-iodo-6-pyridin-2-yl-pyrrolo[2,3-d] pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (300 mg, 0.5 mmol), potassium vinyltrifluoroborate (67 mg, 0.5 mmol), and Pd(dppf)Cl2(35 mg, 0.05 mmol) in n-PrOH (20 mL) was added TEA (0.5 mL). The mixture degassed and charged with N2 for three times. The mixture was stirred at 90°C for overnight. The reaction mixture was concentrated under reduced pressure and purified by flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=100/l~l/l), to give the title product { l-[4-(2-Chloro-6-pyridin-2-yl-5-vinyl-pyrrolo[2,3- d]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (30mg, 12%). MS (ESI) m/z: 502.2[M+1]+ ,524.4[M+Na]+.
[00478] Step C: To a solution of {l-[4-(2-Chloro-6-pyridin-2-yl-5-vinyl-pyrrolo [2,3- d]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (60 mg, 0.12 mmol) in MeOH(30 mL) was added Pd/C (50 mg). The mixture was stirred under H2 atmosphere at reflux for overnight. The reaction mixture was filtered, and the solvent was concentrated under reduced pressure to give the product {l-[4-(5-Ethyl-6-pyridin-2-yl-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (25 mg, 45%), which was used to next step without furthermore purification. MS (ESI) m/z : 470.3[M+1]+.
[00479] Step D: To a solution of HC1 in EtOAc (30 mL, 2M) was added { l-[4-(5-Ethyl-6- pyridin-2-yl-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (25 mg). The mixture was stirred at r.t. for lh. The reaction mixture was filtered to give the crude product, which was purified by preparative HPLC to yield l-[4-(5-Ethyl-6-pyridin-2-yl-pyrrolo[2,3- d]pyrimidin-7-yl)-phenyl]-cyclobutylamine (12mg, 63% yield). 'HNMR: MeOD 400MHz δ 9.1 l(s, 1H), 8.93(s, 1H), 8.64~8.62(t, 1H, J=8), 7.62~7.60(t, 1H, J=8), 7.41~7.39(m, 2H), 7.26~7.24(m, 2H), 7.17~7.15(m, 2H), 2.30~2.94(m, 2H), 2.58~2.54(m, 2H), 2.20-2.16(m, 2H), 2.10~1.98(m, 1H), 1.96~1.90(m, lH),1.33~1.24(m,3H). MS (ESI) m/z : 370.3[M+1]+
Example O
Figure imgf000179_0001
{ l-[4-(2-Chloro-5-methyl-6-phenyl-pyrrolo[2,3-d1pyrimidin-7-yl)-phenyl1-cvclobutvU-carbamic acid tert-butyl ester
[00480] Step A: To a solution of 2,4-Dichloro-5-iodo-pyrimidine (7.7 g, 28 mmol) and [1-
(4-Amino-phenyl)-cyclobutyl]-carbamic acid tert-butyl ester (6.2 g, 24 mmol) in dioxane (150mL) was added K2C03 (4.9 g, 36 mol). The mixture was stirred at 100°C overnight. The precipitate was filtered off, the solvent was concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography to give the desired product { l-[4-(2-Chloro-5-iodo- pyrimidin-4-ylamino)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (2.1g, 15% yield). MS (ESI) m/z : 501.1[M+1]+ ,523.0[M+Na]+.
[00481] Step B: To a solution of { l-[4-(2-Chloro-5-iodo-pyrimidin-4-ylamino)-phenyl] - cyclobutyl}-carbamic acid tert-butyl ester (200 mg, 0.4 mmol), Pd(OAc)2(9 mg, 0.04 mmol), PPh3(21 mg, 0.08 mmol), LiCl(17 mg, 0.4 mmol) and K2C03 (276 mg, 2 mmol) in DMF (1 mL) was added Prop-l-ynyl-benzene (0.15mL). The mixture was degassed and charged with N2 for three times. The reaction mixture was stirred at 120°C for 30min by microwave irradiation. The reaction mixture was concentrated, and pardoned with water and DCM. The organic layer was concentrated and purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate =20/1-0/1), to give the title product { l-[4-(2-Chloro-5-methyl-6-phenyl-pyrrolo[2,3-d]pyrimidin-7- yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (19mg,10% yield). MS (ESI) m/z :
489.2[M+1]+ .
Example 129
Figure imgf000180_0001
l-(4-r5-Methyl-6-phenyl-2-(lH-pyrazol-4-yl)-pyrrolo[2,3-dlpyrimidin-7-yl1-phenvn- cvclobutylamine
[0003] Step A: To a solution of { l-[4-(2-Chloro-5-methyl-6-phenyl-pyrrolo[2,3-d] pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (150 mg, 0.31 mmol), 4- (4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (120 mg, 0.62 mmol), and Cs2C03 (200 mg, 0.62 mmol) in DME/H20 (5/1, 30 mL) was added Pd(dppf)Cl2 (22 mg, 0.03 mmol). The mixture was degassed and charged with N2 for three times. The mixture was stirred at 100 C for overnight. The reaction mixture was filtrated, the filtrates was concentrated under reduced pressure and partioned with water and DCM. The organic layer was combined and removed by rotary evaporation to give crude product which was purified by silica gel chromatography to give the title product ( 1 - { 4- [5 -Methyl-6-phenyl-2-( 1 H-pyrazol-4-yl)-pyrrolo [2,3-d]pyrimidin-7-yl] -phenyl } - cyclobutyl)-carbamic acid tert-butyl ester (100 mg ). MS (ESI) m/z : 521.3[M+1]+ ,543.1[M+Na]+ .
[0004] Step B: To a solution of HC1 in EtOAc (30 mL, 2M) was added (l-{4-[5-Methyl-6- phenyl-2-(lH-pyrazol-4-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert- butyl ester (lOOmg). The mixture was stirred at r.t. for lh. The reaction mixture was filtered to yield the title product l-{4-[5-Methyl-6-phenyl-2-(lH-pyrazol-4-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]- phenyl}-cyclobutylamine (65.8 mg, 82% yield^HNMR: MeOD 400MHz δ 9.33(s, 1H), 8.39(s, 2H), 7.64~7.62(m, 2H), 7.51~7.49(m, 2H), 7.40~7.39(m, 3H), 7.35~7.33(m, 2H), 2.82~2.76(m, 2H), 2.66~2.59(m, 2H), 2.47(s,3H), 2.10~1.98(m, 1H), 2.01~1.97(m, 1H). MS (ESI) m/z : 421.3[M+1]+
[00482] Examples 130 and 131 shown in Table 13 can also be made according to the above- described methods.
Table 13
Figure imgf000181_0001
Example 132
Figure imgf000181_0002
l-(4-(2-phenyl-lH-pyrrolo[2,3-blpyridin-3-yl)phenyl)cyclobutanamine
[00483] Step A: To a solution of 3-bromopyridin-2-amine (200 mg, 1.16 mmol) in DMF (3 mL) were added tert-butyl l-(4-(phenylethynyl)phenyl)cyclobutylcarbamate (802 mg, 2.31 mmol), Pd(OAc)2 (26 mg, 0.12 mmol), LiCl (50 mg, 1.16 mmol) and KOAc (228 mg, 2.31 mmol). The reaction mixture was stirred at 130 °C under microwave for 3 h. LC/MS showed about 18% of desired products (3 and 4). The reaction mixture was diluted with ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude products were purified by pre-TLC (e luted by: ethyl acetate: hexane = 1 :1), which gave two desired products tert-butyl l-(4-(2-phenyl-lH-pyrrolo[2,3-b]pyridin-3- yl)phenyl)cyclobutylcarbamate and tert-butyl l-(4-(3-phenyl-lH-pyrrolo[2,3-b]pyridin-2- yl)phenyl)cyclobutylcarbamate (130 mg, 25% Yield). MS (ESI+) e/z: 440.2 [M+l] +.
[00484] Step B: To a solution of tert-butyl l-(4-(2-phenyl-lH-pyrrolo[2,3-b]pyridin-3- yl)phenyl)cyclobutylcarbamate and tert-butyl l-(4-(3-phenyl-lH-pyrrolo[2,3-b]pyridin-2- yl)phenyl)cyclobutylcarbamate (130 mg, 0.30 mmol) in ethyl acetate (20 mL) was added a solution of HC1 in ethyl acetate (5 mL) at 0 °C. Then it was allowed to reach ambient temperature for 3 h. The reaction mixture was concentrated to remove the solvent. The crude product was purified by HPLC separation, which gave l-(4-(2-phenyl-lH-pyrrolo[2,3-b]pyridin-3- yl)phenyl)cyclobutanamine (20 mg, 20% yield). Ή NMR (MeOD, 400 MHz), δ ppm: 8.63 (d, J=6.8 Hz, IH), 8.47 (d, J=4.8 Hz, IH), 7.68-7.60 (m, 7H), 7.56-7.40 (m, 3H), 2.86-2.79 (m, 2H), 2.68-2.61 (m, 2H), 2.30-2.25 (m, IH), 2.03-1.94 (m, IH). MS (ESI+) e/z: 340.2 [M+l] +, and l-(4- (3-phenyl-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)cyclobutanamine (26 mg, 26% yield ). 1H NMR (MeOD, 400 MHz), δ ppm: 8.07 (d, J=8.0 Hz, IH), 7.55-7.49 (m, 7H), 7.37-7.35 (m, 3H), 7.25- 7.22 (m, IH), 2.86-2.74 (m, 2H), 2.68-2.57 (m, 2H), 2.31-2.20 (m, IH), 2.06-1.97 (m, IH). MS (ESI+) e/z: 340.2 [M+l] +.
[00485] Example 133 shown in Table 14 can also be made according to the above-described methods.
Table 14
Figure imgf000182_0001
Figure imgf000183_0001
Example 134
Figure imgf000183_0002
l-(4-(l-methyl-2-phenyl-lH-pyrrolo[2 -blpyridin-3-yDphenyl)cvclobutanamine
[00486] Step A: To a solution of 3-methylpyridin-2-amine (5.0 g, 46.24 mmol) in pyridine (50 mL) was slowly added benzoyl chloride (6.50, 46.24 mmol) at 0 °C. After addition, the reaction mixture was stirred at ambient temperature overnight. Then the solvent was removed by concentration in vacuo, and the residue was dissolved in ethyl acetate, washed by water twice. The separated organic layer was concentrated. The obtained crude product was dissolved in methanol (50 mL), and an aqueous sodium hydroxide solution (2 N, 30 mL) was added. The mixture was heated at 80 °C for 2 h. Then the solvents were concentrated to remain about 20% volume, which then diluted with ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product N-(3-methylpyridin-2-yl)benzamide (6.2 g, 63% yield) was pure enough to be used in next step without further purification. MS (ESI+) e/z: 213.1 [M+l] +.
[00487] Step B: To a solution of N-(3-methylpyridin-2-yl)benzamide (2.5 g, 11.78 mmol) in
THF was slowly added w-BuLi (14.1 mL, 35.25 mmol) at -78 °C. After addition, the reaction mixture was stirred at ambient temperature for 2 h. The solvent was removed by concentration in vacuo. The residue was dissolved in ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column separation to give 2-phenyl-lH-pyrrolo[2,3-b]pyridine (2.0 g, 87% yield). MS (ESI+) e/z: 195.1 [M+1] +.
[00488] Step C: A solution of iodine (2.67 g, 10.56 mmol) in DMF (5 mL) was slowly added into a solution of 2-phenyl-lH-pyrrolo[2,3-b]pyridine (2.0 g, 10.30 mmol), and potassium hydroxide (82%, 2.11 g, 30.90 mmol) in DMF (35 mL). The reaction mixture was stirred at ambient temperature for 1 h. Then, iodomethane (2.19 g, 15.45 mmol) was slowly added into the mixture, and it was stirred for another 1 h. Then solvent was removed by concentration in vacuo. The residue was dissolved in ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product 3-iodo-l-methyl-2-phenyl- lH-pyrrolo[2,3-b]pyridine (3.0 g, 87% yield) was pure enough to be used in next step without further purification. MS (ESI+) e/z: 335.0[M+1] +.
[00489] Step D: To a mixed solution (Dioxane / H20 = 12 / 3 mL) of 3-iodo- 1 -methyl-2- phenyl-lH-pyrrolo[2,3-b]pyridine (400 mg, 1.20 mmol) were added tert-butyl l-(4-(4 ,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutylcarbamate (536 mg, 1.44 mmol),
Pd(dppf)Cl2 (70 mg, 0.10 mmol), and Cs2C03 (780 mg, 2.29 mmol). The reaction mixture was stirred at 80 °C under the atmosphere of nitrogen for 4 h. The solvents were removed by
concentration in vacuo, and the residue was dissolved in ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The obtained crude product was used in de-Boc reaction directly. MS (ESI+) e/z: 454.2[M+1] +.
[00490] Step E: To a solution of ter/-butyl l-(4-(l-methyl-2-phenyl-lH-pyrrolo[2,3- b]pyridin-3-yl)phenyl)cyclobutylcarbamate (350 mg, 0.64 mmol) in ethyl acetate (20 mL) was added a solution of HC1 in ethyl acetate (5 mL) at 0 °C. Then it was allowed to reach ambient temperature for 3 h. The reaction mixture was concentrated to remove the solvent. The crude product was purified by HPLC separation, which gave the desired product l-(4-(l-methyl-2- phenyl-lH-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclobutanamine (80mg, 19% yiled, two steps). Ή NMR (MeOD, 400 MHz), δ ppm: 8.68 (d, J=7.6 Hz, 1H), 8.54 (d, J=5.6 Hz, 1H), 7.67-7.61 (m, 1H), 7.52-7.43 (m, 9H), 3.86 (s, 3H), 2.81-2.73 (m, 2H), 2.66-2.56 (m, 2H), 2.22-2.21 (m, 1H), 1.99-1.91 (m, 1H). MS (ESI+) e/z: 354.2[M+1] +.
Example 135
Figure imgf000184_0001
l-(4-(6-phenyl-5H-pyrrolo 3,2-d]pyrimidin-7-yl)phenyl)cyclobutanamine
[00491] Step A: To a solution of 2,4-dichloro-6-methyl-5-nitropyrimidine (7 g, 34 mmol) and CH3COOK (9.8 g, 100 mmol) in MeOH (150 mL) was added Pd C (3 g). The mixture was stirred at H2 atmosphere for overnight. The reaction mixture was filtered, and the solvent was concentrated under reduced pressure to give the product 4-methylpyrimidin-5 -amine (1.5 g, 43%), which was used to next step without furthermore purification. 'HNMR: MeOD 400MHz δ 8.28(s, 1H), 8.04(s, 1H), 2.3 l(s, 3H).
[00492] Step B: 4-methylpyrimidin-5-amine (1.09 g, 10 mmol) was dissolved in dry THF
(150 mL) under nitrogen. The solution was cooled to -78°C and a solution of n-BuLi was added dropwise. The solution was kept at the same temperature for 30min and then warm to r.t., stirred for 2h. Then cooled to -78°C, ethyl benzoate (1.5 g, 10 mmol) in THF (30 mL) was added, and the resulting mixture was stirred at -78°C for 30min, and was warmed to r.t. for lh. The reaction mixture was quenched with drop some water, and neutralized with NaHC03. EtOAc and water were added, portioned. The organic layer was concentrated and purified by by flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =100/1-0/1), to give the title product 6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (0.8 g, 41%). MS (ESI) m/z :196.1 [M+1]+.
[00493] Step C: To a solution of 6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (700 mg, 3.5 mmol) in DMF (30 mL) was added KOH (703 mg, 7.2 mmol). The mixture was stirred at r.t. for 15min, then a solution of I2 in DMF was added dropwise and the mixture was stirred for another 15min at the same temperature. To the reaction mixture was added Na2S03 solution, and extracted with EtOAc. The organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by sical gel chromatography (eluting with PE/EA= 1/0-0/1) to give the product 7-iodo-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (400 mg, 35%). MS (ESI) m/z : 321.8[M+1]+.
[00494] Step D: To a solution of 7-iodo-6-phenyl-5H-pyrrolo[3,2-d] pyrimidin.? (320 mg,
1.0 mmol), tert-butyl l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phenyl) cyclobutylcarbamate (560mg, 1.5mmol), and Cs2C03 (652 mg, 2.0 mmol) in CH3CN/H20 (10/1 , 10ml) was added Pd(dppf)Cl2 (70 mg, O.lmmol). The mixture was irradiated by microwave at 80 C for lOmin.The reaction mixture was filtrated, the filtrates was washed was water and the organic layer was combined and removed by rotary evaporation to give crude product tert-butyl 1- (4-(6-phenyl-5H-pyrrolo [3,2-d]pyrimidin-7-yl)phenyl) cyclobutylcarbamate, which was to do next step without further purification. MS (ESI) m/z : 441.1 [M+l]+.
[00495] Step E: To a solution of HC1 in EtOAc (30 mL, 2 M) was added tert-butyl l-(4-(6- phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (200 mg). The mixture was stirred at r.t. for 4h. The reaction mixture was filtered to give the crude product, which was purified by pre-HPLC to yield the title product l-(4-(6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7- yl)phenyl)cyclobutanamine (7.4 mg). 1HNMR: MeOD 400MHz δ 8.91(s, 1H), 8.78(s, 1H), 8.35~8.33(d, 1H, J=8), 8.23~8.21(d, 1H, J=8), 7.74~7.72(m, 2H), 7.59~7.57(m, 2H), 7.62~7.56(m, 2H), 7.54~7.46(m, 4H), 7.45~7.35(m, 2H), 2.80~2.76(m, 2H), 2.68~2.64(m, 2H), 2.24~2.20(m, 1H), 2.00-1.96(m, 1H). Example 136
Figure imgf000186_0001
l-[4-(5-Methyl-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-phenyl]- cyclobutylamine
[00496] Step A: To a solution of 2,4-dichloro-6-methyl-5-nitropyrimidine (7 g, 34 mmol) and CH3COOK (9.8 g, 100 mmol) in MeOH (150 mL) was added Pd/C (3 g). The mixture was stirred at H2 atmosphere for overnight.The reaction mixture was filtered, and the solvent was concentrated under reduced pressure to give the product 4-methylpyrimidin-5-amine (1.5 g 43%), which was used to next step without furthermore purification. 'HNMR: MeOD 400MHz δ 8.28(s, 1H), 8.04(s, 1H), 2.3 l(s, 3H).
[00497] Step B: 4-methylpyrimidin-5-amine (1.09 g, 10 mmol) was dissolved in dry THF
(150 mL) under nitrogen. The solution was cooled to -78°C and a solution of n-BuLi was added dropwise. The solution was kept at the same temperature for 30min and then warm to r.t., stirred for 2h. Then cooled to -78°C, ethyl benzoate (1.5 g, 10 mmol) in THF (30 mL) was added, and the resulting mixture was stirred at -78°C for 30min, and was warmed to r.t. for lh. The reaction mixture was quenched with drop some water, and neutralized with NaHC03. EtOAc and water were added, portioned. The organic layer was concentrated and purified by by flush column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =100/1-0/1), to give the title product 6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (0.8 g, 41%). MS (ESI) m/z : 196.1[M+1]+.
[00498] Step C: To a solution of 6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (700 mg, 3.5 mmol) in DMF (30 mL) was added KOH (703 mg, 7.2 mmol). The mixture was stirred at r.t. for 15min, then a solution of I2 in DMF was added dropwise and the mixture was stirred for another 15 min at the same temperature. To the reaction mixture was added Na2S03 solution, and extracted with EtOAc. The organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by sical gel chromatography (eluting with petroleum ether/ethyl acetate =1/0-0/1) to give the product 7-iodo-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (400 mg, 35%). MS (ESI) m/z : 321.8[M+1]+.
[00499] Step D: To a solution of 7-Iodo-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (170 mg,
0.81 mmol) and K2C03 (225 mg, 1.62 mmol) in DMF (5 mL) was added Mel (116 mg, 0.81mmol) while keeping an ice-water bath. The mixture was stirred at for 3h. To the reaction mixture was added water and extracted with EtOAc. The organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate =1/0-0/1) to give the product 7-Iodo-5-methyl-6-phenyl-5H- pyrrolo[3,2-d]pyrimidine (70 mg, 40%). 'HNMR: CDC13 400MHz 69 .l l(s, 1H), 8.78(s, 1H), 7.61~7.57(m,3H), 7.52~7.48(m,2H), 3.80(s, 3H).
[00500] Step E: To a solution of 7-Iodo-5-methyl-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine
(150mg, 0.45mmol), {l-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]- cyclobutyl }- carbamic acid tert-butyl ester (167 mg, 0.45 mmol), and Cs2C03 (292 mg, 0.9 mmol) in CH3CN/H20 (5/1, 3mL) was added Pd(dppf)Cl2 (32 mg, 0.045 mmol). The mixture was irradiated by microwave at lOOC for 20 min.The reaction mixture was filtrated, the filtrates was washed was water and the organic layer was combined and removed by rotary evaporation to give crude product which was to do next step without further purification. MS (ESI) m/z : 455.1[M+1]+.
[00501] Step F: To a solution of HC1 in EtOAc (30 mL, 2M) was added {l-[4-(5-Methyl-6- phenyl-5H^yrrolo[3,2-dJpyrimidin-7-yl)-phenylJ-cyclobutyl}-carbamic acid tert-butyl ester (200 mg, crude). The mixture was stirred at r.t. for lh. The reaction mixture was filtered to give the crude product, which was purified by pre-HPLC to yield the title product l-[4-(5-Methyl-6-phenyl- 5H-pyrrolo[3,2-d]pyrimidin-7-yl)-phenyl]- cyclobutylamine (32 mg). 'HNMR: MeOD 400MHz δ 9.07(s, 1H), 8.89(s, 1H), 7.54~7.51(m, 5H), 7.45~7.38(m, 4H), 3.80(s, 3H), 2.80~2.76(m, 2H), 2.58~2.54(m, 2H), 2.24~2.20(m, 1H), 2.00-1.96(m, 1H).
Example 137
Figure imgf000187_0001
l-(4-(2-chloro-5-methyl-6-phenyl-5H-pyrrolo 3.2-d1pyrimidin-7-yl)phenyl)cyclobutanamine
[00502] Step A: To a solution of 5-bromo-2,4-dichloropyrimidine (10.00 g, 43.88 mmol ) in
TEA (100 mL) were added ethynylbenzene (4.48 g, 43.88 mmol), Pd(PPh3)2Cl2 (1.00 g, 1.42 mmol), and Cul (1.67 g, 8.76 mmol). The reaction mixture was stirred at 100 °C under the atmosphere of nitrogen for 2 h. After cooling, the solvent was removed by concentration in vacuo, and the residue was dissolved in ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column separation (eluted by: hexane / ethyl acetate = 20 : 1), which gave the desired product 5- bromo-2-chloro-4-(phenylethynyl)pyrimidine (7.10 g, 55% Yield). MS (ESI+) e/z: 292.9[M+1]+.
[00503] Step B: To a solution of 5-bromo-2-chloro-4-(phenylethynyl)pyrimidine (3.10 g,
10.56 mmol) in dioxane (80 mL) were added tert-butyl carbamate (1.61 g, 13.73 mmol), Pd2(dba)3 (484 mg, 0.53 mmol), X-phos (503 mg, 1.06 mmol), and Cs2C03 (6.88 g, 21.12 mmol). The reaction mixture was stirred at 100 °C under the atmosphere of nitrogen for 8 h. The solvent was removed by concentration, and the residue was dissolved in ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product tert-butyl 2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate was used in next step without further purification. MS (ESI+) e/z: 330.1, 332.1 [M+l]+.
[00504] Step C: To a solution of the crude product tert-butyl 2-chloro-6-phenyl-5H- pyrrolo[3,2-d]pyrimidine-5-carboxylate (3.0 g) in ethyl acetate (60 mL) was added a solution of HC1 in ethyl acetate (10 mL). The reaction mixture was heated to reflux overnight. After cooling, the resulting precipitate was collected by filtration, washed by ethyl acetate, dried in vacuo, which gave the desired product 2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (1.7 g, 70% yield, two steps). MS (ESI+) e/z: 230.0, 232.0[M+1]+.
[00505] Step D: A solution of I2 (3.99 g, 15.81 mmol) in DMF (10 mL) was slowly added to a solution of 2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (3.30 g, 14.37 mmol) and KOH (82%, 1.97 g, 28.74 mmol) in DMF (80 mL) at ambient temperature. The reaction mixture was stirred for 1 h. Then, iodomethane (3.06 g, 21.65 mmol) was slowly added into the mixture, and it was stirred for another 1 h. The solvent was removed by concentration in vacuo, and the residue was dissolved in ethyl acetate, washed with water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product 2-chloro-7-iodo-5-methyl-6-phenyl-5H- pyrrolo[3,2-d]pyrimidine (3.00 g, 89% yield) was pure enough to be used in next reaction. MS (ESI+) e/z: 369.9, 371.9[M+1]+.
[00506] Step E: To a mixed solution (dioxane / H20 = 25 / 5 mL) of 2-chloro-7-iodo-5- methyl-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (2.50 g, 6.78 mmol) were added tert-butyl l-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutylcarbamate (3.82 g, 10.17 mmol), Pd(dppf)Cl2 (496 mg, 0.68 mmol), and Cs2C03 (4.42 g, 13.56 mmol). The reaction mixture was stirred at 100 °C for 3 h. Then the solvents were removed by concentration in vacuo, and the residue was dissolved in ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude produce was purified by silica gel column separation (eluted by: hexane / ethyl acetate = 1 :1), which gave the desired product fert-butyl l-(4- (2-chloro-5-methyl-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (1.1 Og, 33%). MS (ESI+) e/z: 489.2, 491.2[M+1]+.
[00507] Step F: To a solution of tert-butyl l-(4-(2-chloro-5-methyl-6-phenyl-5H- pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (100 mg, 0.20 mmol) in ethyl acetate (10 mL) was added a solution of HC1 in ethyl acetate (5 mL) at 0 °C. Then it was allowed to reach ambient temperature for 3 h. The reaction mixture was concentrated to remove the solvent. The crude product was purified by HPLC separation, which gave the desired product l-(4-(2-chloro-5- methyl-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)cyclobutanamine (30 mg, 38% yiled). 1H NMR (MeOD, 400 MHz), <5 ppm: 8.95 (s, 1H), 7.55-7.50 (m, 4H), 7.46-7.39 (m, 5H), 3.78 (s, 3H), 2.76-2.71 (m, 2H), 2.57-2.51 (m, 2H), 2.25-2.18 (m, 1H), 1.95-1.89 (m, 1H). MS (ESI+) e/z: 389.2, 391.2[M+1] +.
Example 138
Figure imgf000189_0001
l-(4-(5-methyl-2,6-diphenyl-5H-pyrrolo[3,2-d1pyrimidin-7-yl)phenyl)cyclobutanamine
[00508] Step A: To a mixed solution (dioxane / H20 = 3 : 0.5 mL) of tert-butyl l-(4-(2- chloro-5-methyl-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (160 mg, 0.33 mmol) were added phenylboronic acid (80 mg, 0.65 mmol), Pd(dppf)Cl2 (24 mg, 0.03 mmol), and CS2CO3 (213 mg, 0.65 mmol). The reaction mixture was stirred at 110 °C for 0.5 h. The solvent was removed by concentration in vacuo. The residue was dissolved in ethyl acetate, washed by water twice. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column separation (eluted by: hexane : ethyl acetate = 1 : 3), which gave desired product tert-butyl l-(4-(5-methyl-2,6-diphenyl-5H-pyrrolo[3,2- d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (100 mg, 58% yield). MS (ESf) e/z: 531.3[M+1] +.
[00509] Step B: To a solution of tert-butyl l-(4-(5-methyl-2,6-diphenyl-5H-pyrrolo[3,2- d]pyrimidin-7-yl)phenyl)cyclobutylcarbamate (100 mg, 0.19 mmol) in ethyl acetate (10 mL) was added a solution of HC1 in ethyl acetate (4 mL) at 0 °C. Then it was allowed to reach ambient temperature for 3 h. The resulting precipitate was collected by filtration, washed by ethyl acetate, dried in vacuo, which gave the desired product l-(4-(5-methyl-2,6-diphenyl-5H-pyrrolo[3,2- d]pyrimidin-7-yl)phenyl)cyclobutanamine (80 mg, 99% yiled). 1H NMR (DMSO, 400 MHz), δ ppm: 9.38 (s, 1H), 8.69 (s, 3H), 8.50-8.47 (m, 2H), 7.64-7.44 (m, 12H), 3.73 (s, 3H), 2.67-2.52 (m, 4H), 2.22-2.15 (m, 1H), 1.84-1.78 (m, 1H). MS (ESI+) e/z: 431.3[M+1] +.
[00510] Example 140 shown in Table 15 can also be made according to the above-described methods.
Table 15
Figure imgf000190_0002
Example P
Figure imgf000190_0001
{l-f4-(2-Chloro-7-methyl-5-phenyl-7H-pyrrolo 2,3-d]pyrimidin-6-yl)-phenyl]-cvclobutvU- carbamic acid tert-butyl ester
[00511] Step A: Pd(PPh3)2Cl2 (2.00 g, 5.00mmol) and Cul (2.00 g, lO.OOmmol) were combined in a round-bottom flask, then degassed and refilled with N2 three times. To the mixture was added NEt3 (150 mL), Iodo-benzene (10.20 g, 50.00mmol), Ethynyl-trimethyl-silane (9.80 g, lOO.OOmmol), then the mixture was heated to 100 °C for 30 min. The solvent was removed by vacuum evaporator , then added EA, filtered through Celite. The solvent was removed , and purified by column (eluted by Hexane) to get Trimethyl-phenylethynyl-silane (8.20 g, 98% yield).
[00512] Step B: Methylamine (2.0 M in THF, 60 mL) was cooled to -78 °C, was added the solution of 2,4-Dichloro-5-iodo-pyrimidine in THF (200 mL) cooled to -78 °C. After addition, the mixture was stirred at room temperature for 1 h. The solution was removed by vacuum evaporator. To the residue, was added DCM, which made the residue just dissolved, then n-hexane was added to the solution. The desired product (2-Chloro-5-iodo-pyrimidin-4-yl)-methyl-amine was crystallized out, and collected by filtration. (7.0g, yield: 52%), MS (ESI+) e/z: 269.7 [M+l]+, 271.7 [M+3]+.
[00513] Step C: (2-Chloro-5-iodo-pyrimidin-4-yl)-methyl-amine(2.70 g, 10.00 mmol),
LiCl(0.42 g, lO.OOmmol) and Na2C03 (4.42 g, 40.00 mmol) are dissolved in DMF (100 mL). The mixture was heated to 100 °C for 12 h. The mixture was poured to water and extracted with EA, dried over Na2S04, purified by column (eluted by ethyl acetate: Hexane = 1 :10) to get desired product 2-Chloro-7-methyl-5-phenyl-6-trimethylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, yield: 32%). Ή MR (CDC13, 400 MHz), δ ppm: 8.29 (s, 1H), 7.25-7.19 (m, 3H), 7.13-7.06 (m, 2H), 3.76 (s, 3 H), 0.00 (s, 9H). MS (ESI+) e/z: 315.9 [M+l]+, 317.9 [M+3]+.
[00514] Step D: To a solution of 2-Chloro-7-methyl-5-phenyl-6-trimethylsilanyl-7H- pyrrolo[2,3-d]pyrimidine (315 mg, 1 mmol) and CF3C02Ag (221 mg, 1 mmol) in THF (15 mL) at - 78 °C under N2 was added dropwise a solution of I2 (254 mg, 1 mmol) in THF (10 mL). The reaction mixture was stirred for 2 h at -78 °C. The resulting mixture was diluted with DCM and then filtered through Celite. The filtrate was washed succeccively with 50% Na2S203, H20, and brine. After drying (MgS04), filtration, and evaporation, the residue was chromatographed on silica (eluted by ethyl acetate: Hexane = 1 :10) to afford 2-Chloro-6-iodo-7-methyl-5-phenyl-7H- pyrrolo[2,3-d] pyrimidine (333 mg, 90%) . MS (ESI+) e/z: 369.8 [M+l]+, 371.8 [M+3]+.
[00515] Step E: 2-Chloro-6-iodo-7-methyl-5-phenyl-7H-pyrrolo[2,3-d] pyrimidine (333 mg,
0.90 mmol), {l-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan- 2-yl)- phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (560 mg, 1.5 mmol), Pd(dppf)Cl2 (77 mg, 0.11 mmol), and Cs2C03 (684 mg, 2.10 mmol) were dissolved in a mixed solution (dioxane: 20 mL, water: 4 mL). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 12 h. LC/MS indicated the reaction worked well. Then the solvents were removed under reduced pressure, the resulting residue was dissolved in ethyl acetate (150 mL). The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column (ethyl acetate: Hexane - 1 :2) to give { l-[4-(2-Chloro-7-methyl-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (391 mg, 80% yield), MS (ESI+) e/z: 489.2 [M+l]+, 491.2 [M+3]+.
Example 140
Figure imgf000192_0001
l-[4-(7-Methyl-2.5-diphenyl-7H-pyrrolo[2 -d^
[00516] Step A: l-[4-(7-Methyl-2,5-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]- cyclobutylamine (80 mg, 0.16 mmol), phenylboronic acid (24 mg, 0.2 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), Cs2C03 (130 mg, 0.4 mmol) and a mixed solution (dioxane: 5 mL, water: 1 mL) were combined in a microwave tube, and heated to 130 °C for 30 min. LC/MS indicated the reaction worked well. Then the solvents were removed under reduced pressure, the resulting residue was dissolved in ethyl acetate (50 mL). The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by pre-TLC (ethyl acetate: Hexane=l :2) to give { l-[4-(7-Methyl-2,5-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl) -phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (70 mg, 82 % yield), MS (ESI+) e/z: 531.2 [M+l]+, 532.2 [M+2]+ .
[00517] Step B: { l-[4-(7-Methyl-2,5-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl) -phenyl]- cyclobutyl}-carbamic acid tert-butyl ester (70 mg, 0.13 mmol) was dissolved in MeOH (30 mL), then added HC1 (aq) (4M, 8 mL) in drops. The mixture was heated to 80 °C, and stirred for 50 min. LC/MS showed the reaction worked well. The product was purified by HPLC separation to give target compound (17 mg, yield: 30%). 1H-NMR (400 MHz, CDC13) δ: 9.18 (s, 1H), 7.79 (d, J = 8.8Hz, 2H), 7.71-7.45 (m, 7H), 2.91 (s, 3H), 2.80-2.75 (m, 2H), 2.59-2.52 (m, 2H), 2.29-2.20 (m, 1H), 2.05-1.99 (m, 1H). MS (ESI+) e/z: 431.1 [M+l]+
[00518] Examples 141 to 174 shown in Table 16 can also be made according to the above- described methods.
Table 16
Figure imgf000192_0002
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
[00519] The foregoing description is considered as illustrative only of the principles of the invention. Further, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown as described above. Accordingly, all suitable modifications and equivalents may be considered to fall within the scope of the invention as defined by the claims that follow.
[00520] The words "comprise," "comprising," "include," "including," and "includes" when used in this specification and in the following claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups.

Claims

What is claimed is:
1. A compound of Formula (1):
Figure imgf000199_0001
and tautomers, resolved enantiomers, resolved diastereomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs thereof, wherein:
X is N or CR3;
is a roup selected from the grou consisting of:
Figure imgf000199_0002
(J) m is 0, 1 , 2, 3 or 4;
at least one of R', R2, and R3 is a group of formula (L):
Figure imgf000200_0001
wherein:
n is 0, 1 or 2;
R' and R" are independently selected from the group consisting of H, C]-C6-alkyl and -
(C=0)-CrC6-alkyl;
R' " is H, OH or Ci-C6-alkyl; and the rest of R1, R2, and R3 are independently selected from the group consisting of: H, cyano, Ci- C6-alkyl, aryl or heteroaryl, which aryl or heteroaryl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, cyano, oxo, CrCe-alkyl, CrCe-alkoxyl and C i -C6-hydroxyalkyl;
R4 is selected from the group consisting of: H, halo, cyano, hydroxyl,oxo, C Ce-alkyl, Ci-C6- alkoxyl, COOH, d-Ce-alkylsulfonamide, NRaRb, NRa(C=0)Ra, (C=0) RaRb, (C=0) Ra- CrC6-alkylenyl-NRaRb, NRa-Ci-C6-alkylenyl-COOH, NRa-CrC6-alkylenyl-NRaRb, aryl, heteroaryl or heterocycloalkyl, which aryl, heteroaryl or heterocycloalkyl is unsubstituted or substituted by at least one substituent selected from the group consisting of: halo, oxo, hydroxyl, C C6-alkyl, C C6-alkoxyl, C C6-haloalkyl, C C6-haloalkoxyl, COOH, C C6- hydroxyalkyl and Ci-C6-alkylsulfonamide;
Ra and Rb are independently selected from the group consisting of H, Ci-C6-alkyl, Q-
C6-hydroxylalkyl or C3-C6-cycloalkyl.
2. The compounds of claim 1 , wherein R1 is a group of formula (L):
Figure imgf000201_0001
Figure imgf000201_0002
4. The compounds of any one of claim 1 to 3, wherein R' and R" are H, n is 0.
5. The compounds of any one of claim 1 to 4, wherein R4 is selected from the group consisting of: halo, aryl, 5 to 6 membered heteroaryl or heterocycloalkyl containing one, two or three heteroatoms selected from the group consisting of N, S and O, aryl and heteroaryl, which aryl, heteroaryl or heterocycloalkyl is unsubstituted or substituted by at least one halo.
6. The compounds of any one of claim 1 to 5, wherein R3 is H or C]-C6-alkyl.
7. The compounds of any one of claim 1 or 3 to 6, wherein R1 is phenyl.
8. The compounds of any one of claims 1 to 7, having the formula (2):
Figure imgf000202_0001
9. The compounds of claim 8, having the formula (2 -A):
Figure imgf000202_0002
(2-A)
10. The compounds of claim 9, wherein they are selected from the group consisting of:
1 -(4-(2 -phenyl- 1 H-pyrrolo[2,3-b]pyridin-l -yl)phenyl)cyclobutanamine,
l-{4-[6-(2-Fluoro-phenyl)-2-phenyl-pyrrolo[2,3-b]pyridin-l-yl]-phenyl}-yclobutylamine, l-(4-(3-phenyl-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)cyclobutanamine,
1 -(4-(2-phenyl- 1 H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclobutanamine, and
l-(4-(l-methyl-2-phenyl-lH-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclobutanamine.
11. The compounds of claim 8, having the formula (2-B):
Figure imgf000203_0001
12. The compounds of claim 11, wherein they are selected from the group consisting of:
1 -(4-(2-phenyl- lH-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)cyclobutanamine, and 1 -(4-(2 -phenyl- 1 H-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)cyclobutanamine.
13. The compounds of claim 8, having the formula (2-C):
Figure imgf000203_0002
14. The compounds of claim 13, wherein they are selected from the group consisting of: 1 -(4-(l -phenyl- lH-pyrrolo[3,2-c]pyridin-2-yl)phenyl)cyclobutanamine and
l-(4-(l-aminocyclobutyl)phenyl)-2-phenyl-lH-pyrrolo[3,2-c]pyridin-4-ol.
The compounds of claim 8, having the formula (2-D):
Figure imgf000204_0001
(2-D)
16. The compounds of claim 15, wherein it is l-(4-(l-aminocyclobutyl)phenyl)-2-phenyl-lH- pyrrolo[3,2-b]pyridin-5-ol.
17. The compounds of claim 8 having the formula (2-E):
Figure imgf000204_0002
(2-E)
18. The compounds of claim 17, wherein they are selected from the group consisting of:
l-(4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl) cyclobutanamine,
1 -(4-( 1 -phenyl- 1 H-pyrrolo[3 ,2-c]pyridin-2-yl)phenyl)cyclobutanamine,
4-{7-[4-(l-aminocyclobutyl)phenyl]-6-(pyridin-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-
1 λ6,4- thiomorpholine- 1 , 1 -dione,
1 -(4-( 1 -aminocyclobutyl)phenyl)-2-phenyl- 1 H-pyrrolo[3 ,2-c]pyridin-4-ol,
l-(4-(6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutanamine,
l-(4-(2-(lH-pyrazol-4-yl)-6-(jpyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutanamine,
7-(4-(l-aminocyclobutyl)phenyl)-N-methyl-6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- amine,
l-(4-(2-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutanamine, l-(7-(4-(l-aminocyclobutyl)phenyl)-6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)pyrrolidin-3-ol,
l-(4-(6-methyl-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutanamine,
1- (4-(5-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutanamine,
(S)-l-(7-(4-(l-aminocyclobutyl)phenyl)-6-^yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)pyrrolidin-3-ol,
7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, 7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyiTolo[2,3-d]pyrimidine-2- carboxamide,
(S)- 1 -(7-(4-( 1 -aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyriniidin-2- yl)pyrrolidine-2-carboxylic acid,
Nl-(7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)ethane- 1 ,2-diamine,
2- (7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)acetic acid,
N-(7-(4-(l-aminocyclobutyl)phenyl)-6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)cyclopropanecarboxamide,
7-(4-(l-aminocyclobutyl)phenyl)-N,N-dimethyl-6-(pyridin-2-yl)-7H-pyiTolo[2,3-d]pyrimidin- 4-amine,
l-{4-[5-Methyl-6-phenyl-2-(lH-pyrazol-4-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}- cyclobutylamine,
l-(4-(4-methoxy-6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)cyclobutanamine, l-(7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrrolidin-2-one,
l-[4-(5-Ethyl-6-pyridin-2-yl-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-cyclobutylamine,
1 -(4-(4-( 1 H-pyrazol-4-yl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutanamine,
7-(4-(l-aminocyclobutyl)phenyl)-N-methyl-6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,
7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4- carboxamide,
7-(4-(l-aminocyclobutyl)phenyl)-6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid,
l-{4-[4-Methoxy-2-(lH-pyrazol-4-yl)-6-pyridin-2-yl-pyiTolo[2,3-d]pyrimidin-7-yl]-phenyl}- cyclobutylamine,
7-(4-(l-aminocyclobutyl)phenyl)-N,N-diethyl-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine,
7-[4-(l-Amino-cyclobutyl)-phenyl]-6-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid (2-dimethylamino-ethyl)-amide,
1 -(7-(4-( 1 -aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrrolidin-3-ol,
l-{4-[5-Methyl-6-phenyl-2-(lH-pyrazol-4-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}- cyclobutylamine,
l-{4-[2-(2-Fluoro-phenyl)-5-methyl-6-phenyl-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}- cyclobutylamine,
7-(4-( 1 -aminocyclobutyl)phenyl)-N,N-diethyl-6-(pyridin-2-yl)-7H-pyrrolo[2,3 -d]pyrimidin-4- amine,
l-[4-(5-Methyl-2,6-diphenyl-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-cyclobutylamine, l-(4-(5-methyl-6-phenyl-2-(pyrrolidin-l-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutanamine,
l-(4-(7-methyl-5-phenyl-2-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6- yl)phenyl)cyclobutanamine,
l-[4-(7-Methyl-2,5-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-cyclobutylamine, l-(4-(2-(2-fluorophenyl)-7-methyl-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6- yl)phenyl)cyclobutanamine,
N-(7-(4-(l-aminocyclobutyl)phenyl)-6-( yridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)methanesulfonamide,
7-(4-(l-aminocyclobutyl)phenyl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol, l-{4-[2-(2-Fluoro-phenyl)-7-methyl-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}- cyclobutylamine, and
l-[4-(7-Methyl-5-phenyl-2-pyrimidin-5-yl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]- cyclobutylamine.
19. The compounds of claim 8, having the formula (2-F):
Figure imgf000207_0001
20. The compounds of claim 19, wherein they are selected from the group consisting of:
l-[4-(2-Chloro-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]-cyclobutylamine,
{ 5 - [4-( 1 - Amino-cyclobutyl)-phenyl] -6-phenyl-5H-pyrrolo [3 ,2-d]pyrimidin-2-yl } -dimethyl- amine,
l-(4-(6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)cyclobutanamine,
l-{4-[6-Phenyl-2-(lH-pyrazol-4-yl)-pyrrolo[3,2-d]pyrimidin-5-yl]-phenyl}-cyclobutylamine, l-[4-(6-Phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]-cyclobutylamine,
l-[4-(5-Methyl-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-phenyl]- cyclobutylamine, Nl-{5-[4-(l-Amino-cyclobutyl)-phenyl]-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl}-ethane- 1 ,2-diamine,
1- {5-[4-(l-Amino-cyclobutyl)-phenyl]-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl}-pyrrolidin-
3-ol,
5-[4-(l-Amino-cyclobutyl)-phenyl]-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-2-carboxylic acid, tert-butyl l-(4-(2-(ethylamino)-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-5- yl)phenyl)cyclobutylcarbamate,
2- {5-[4-(l-Amino-cyclobutyl)-phenyl]-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino}- ethanol,
l-(5-(4-(l-aminocyclobu1yl)phenyl)-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidin-2- one,
l-[4-(2-Methoxy-6-phenyl-pyrrolo[3,2-d]pyrimidin-5-yl)-phenyl]-cyclobutylamine,
5-(4-(l-aminocyclobutyl)phenyl)-N-methyl-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-2- carboxamide,
l-(4-(5-methyl-6-phenyl-2-(lH-pyrazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-7- yl)phenyl)cyclobutanamine,
l-(4-(5-methyl-2,6-diphenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)cyclobutanamine, l-(4-(2-chloro-5-methyl-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)cyclobutanamine, 5-(4-(l-aminocyclobutyl)phenyl)-N-ethyl-6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-2-amine, and 3-amino-l-methyl-3-(4-(5-methyl-6-phenyl-2-(lH-pyrazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin- 7-yl)phenyl)cyclobutanol.
21. The compounds of claim 8, having the formula (2-G):
Figure imgf000208_0001
(2-G)
22. The compounds of claim 21, wherein it is l-[4-(6-Phenyl-pyrrolo[2,3-b]pyrazin-5-yl)-phenyl]- cyclobutylamine.
23. The compounds of claim 8, having the formula (2-H):
Figure imgf000208_0002
(2-H)
24. The compounds of claim 8, having the formula (2-1):
Figure imgf000209_0001
(2-1)
25. The compounds of claim 8, having the formula (2 -J):
Figure imgf000209_0002
(2-J)
26. The compounds of any one of claims 1 to 7, having the formula (3):
Figure imgf000209_0003
(3)
27. The compounds of claim 26, having the formula (3-A):
Figure imgf000210_0001
(3-A)
28. The compounds of claim 27, wherein they are selected from the group consisting of: l-(4-(5-methyl-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutanamine, l-(4-(6-bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutanamine, l-(4-(6-(2-fluorophenyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutanamine, l-(4-(2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutanamine, and
l-(4-(5-phenyl-2-( yridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutanamine.
29. The compounds of claim 26, having the formula (3-B):
Figure imgf000210_0002
(3-B)
30. The compounds of claim 29, wherein they are selected from the group consisting of:
1- (4-(3-phenyl-3H-imidazo[4,5-c]pyridin-2-yl)phenyl)cyclobutanamine and
2- (4-(l-aminocyclobutyl)phenyl)-l-phenyl-lH-imidazo[4,5-c]pyridin-6-ol.
31. The compounds of claim 26, havin the formula (3-C):
Figure imgf000210_0003
(3-C)
32. The compounds of claim 26, having the formula (3-D):
Figure imgf000211_0001
33. The compounds of claim 26, having the formula (3-E)
Figure imgf000211_0002
(3-E)
34. The compounds of claim 33, wherein they are selected from the group consisting of: l-(4-(2-chloro-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(2,8-diphenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
N-(l-(4-(2,8-diphenyl-9H-purin-9-yl)phenyl)cyclobutyl)acetamide;
l-(4-(2-phenyl-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(2-(2-fluorophenyl)-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -[4-(8-Phenyl-2-piperazin- 1 -yl-purin-9-yl)-phenyl]-cyclobutylamine;
l-{4-[2-(2-Fluoro-phenyl)-8-phenyl-purin-9-yl]-phenyl}-cyclobutylamine;
{9-[4-(l-Amino-cyclobutyl)-phenyl]-8-phenyl-9H-purin-2-yl}-methyl-amine;
{ 9-[4-( 1 -Amino-cyclobutyl)-phenyl]-8-phenyl-9H-purin-2-yl } -dimethyl-amine;
l-(4-(2-chloro-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
9-[4-( 1 -Amino-cyclobutyl)-phenyl]-8-phenyl-9H-purine-2-carboxylic acid methylamide; l-{9-[4-(l-Amino-cyclobutyl)-phenyl]-8-phenyl-9H-purin-2-yl}-pyiTolidin-2-one;
l-[4-(8-Phenyl-purin-9-yl)-phenyl]-cyclobutylamine;
l-[4-(8-Phenyl-2-pyridin-2-yl-purin-9-yl)-phenyl]-cyclobutylamine;
9-(4-(l-aminocyclobutyl)phenyl)-8-phenyl-9H-purin-2-amine; l-(4-(2-chloro-8-(thiazol-5-yl)-9H-purin-9-yl)phenyl)cyclobutanamine; l-(4-(2-methoxy-8-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
l-{4-[2-(3-Methyl-isoxazol-5-yl)-8-phenyl-purin-9-yl]-phenyl}-cyclobutylamine; l-{4-[2-(5-Methyl-2H-pyrazol-3-yl)-8-phenyl-purin-9-yl]-phenyl}-cyclobutylamine; l-{4-[2-(2-Methyl-3H-imidazol-4-yl)-8-phenyl-purin-9-yl]-phenyl}-cyclobutylamine; l-[4-(2-Phenyl-8-pyridin-3-yl-purin-9-yl)-phenyl]-cyclobutylamine;
l-(4-(2-phenyl-8-(pyridin-4-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-[4-(2-Ethoxy-8-phenyl-purin-9-yl)-phenyl]-cyclobutylamine;
9-(4-(l-aminocyclobutyl)phenyl)-N,N-dimethyl-8-phenyl-9H-purin-6-amine;
l-{4-[8-Phenyl-2-(lH-pyrazol-4-yl)-purin-9-yl]-phenyl}-cyclobutylamine;
1 - {4-[2-( 1 -Methyl- 1 H-pyrazol-4-yl)-8-phenyl-purin-9-yl]-phenyl} -cyclobutylamine; l-(4-(8-(4-methoxypyridin-3-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(8-( 1 H-imidazol-2-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(2-phenyl-8-(thiazol-5-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(9-phenyl-9H-purin-8-yl)phenyl)cyclobutanamine;
l-(4-(8-phenyl-2-(pyrrolidin-l-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(8-(3-methoxypyridin-2-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine; l-(4-(8-(5-methoxypyridin-3-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(6-( 1 -methyl- 1 H-pyrazol-4-yl)-8-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine; l-(4-(2-phenyl-8-(pyrimidin-5-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-[4-(6-Methyl-8-phenyl-purin-9-yl)-phenyl]-cyclobutylamine;
l-(4-(8-tert-butyl-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(2-( 1 H-pyrazol-4-yl)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)cyclobutanamine;
1 -(4-(8-(4-methyl- 1 H-imidazol-5-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(8-( 1 H-imidazol-4-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(8-(4-methylthiazol-2-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(8-( 1 -methyl- 1 H-benzo[d]imidazol-2-yl)-2-phenyl-9H-purin-9- yl)phenyl)cyclobutanamine;
1 -(4-(8-( 1 -methyl- 1 H-imidazol-2-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine; l-(4-(8-(5-methylisoxazol-3-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine; l-(4-(8-(oxazol-4-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(8-( 1 -methyl- 1 H-pyrazol-4-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(8-( 1 -methyl- 1 H-imidazol-5-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine; 1 -(9-(4-( 1 -aminocyclobutyl)phenyl)-8-(pyridin-2-yl)-9H-purin-2-yl)ethane- 1 ,2-diamine;
N-(9-(4-(l-aminocyclobutyl)phenyl)-8-(pyridin-2-yl)-9H-purin-2-yl)methanesulfonamide; l-(4-(2-chloro-7-phenyl-7H-purin-8-yl)phenyl)cyclobutanamine;
l-(4-(8-(l-methyl-lH-pyrazol-5-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine; l-(4-(2-phenyl-8-(lH-pyrazol-4-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(2-phenyl-8-(thiazol-2-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(2-( 1 H-pyrazol-4-yl)-8-(pyridin-2-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(8-(6-methoxypyridin-2-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(7-phenyl-7H-purin-8-yl)phenyl)cyclobutanamine;
1- (4-(2-phenyl-8-(lH-pyrazol-5-yl)-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(9-(4-( 1 -aminocyclobutyl)phenyl)-8-(pyridin-2-yl)-9H-purin-2-yl)pyrrolidin-3-ol;
2- (4-(9-(4-( 1 -aminocyclobutyl)phenyl)-8-(pyridin-2-yl)-9H-purin-2-yl)- 1 H-pyrazol- 1 - yl)ethanol;
6-(9-(4-(l-aminocyclobutyl)phenyl)-2-phenyl-9H-purin-8-yl)pyridin-2(lH)-one;
l-(4-(2-methoxy-7-phenyl-7H-purin-8-yl)phenyl)cyclobutanamine;
9-(4-(l-aminocyclobutyl)phenyl)-8-(pyridin-2-yl)-9H-purin-6-ol;
8- (4-( 1 -aminocyclobutyl)phenyl)-7-phenyl-7H-purin-2-ol;
l-(4-(7-phenyl-2-(pyridin-3-yl)-7H-purin-8-yl)phenyl)cyclobutanamine;
l-(4-(7-phenyl-2-(pyrimidin-5-yl)-7H-purin-8-yl)phenyl)cyclobutanamine;
9- [4-(l-Amino-cyclobutyl)-phenyl]-2-phenyl-9H-purine-8-carbonitrile;
1 -(4-(8-( 1 -ethyl- 1 H-pyrazol-5-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine; l-(4-(7-phenyl-2-(lH-pyrazol-4-yl)-7H-purin-8-yl)phenyl)cyclobutanamine;
1 -(4-(2-(2-fluorophenyl)-8-( 1 -methyl- 1 H-pyrazol-5-yI)-9H-purin-9- yl)phenyl)cyclobutanamine;
l-(4-(2-phenyl-8-o-tolyl-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(2,7-diphenyl-7H-purin-8-yl)phenyl)cyclobutanamine;
1 -(4-(7-phenyl-2-( 1 H-pyrazol- 1 -yl)-7H-purin-8-yl)phenyl)cyclobutanamine;
l-(4-(8-(3-bromopyridin-2-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(8-(4-methylthiazol-5-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine;
l-(4-(8-(l-methyl-lH-pyrazol-5-yl)-2-(3-(trifluoromethoxy)phenyl)-9H-purin-9- yl)phenyl)cyclobutanamine;
l-(4-(8-(l-methyl-lH-pyrazol-5-yl)-2-(3-(trifluoromethyl)phenyl)-9H-purin-9- yl)phenyl)cyclobutanamine;
l-(4-(7-phenyl-2-(thiazol-4-yl)-7H-purin-8-yl)phenyl)cyclobutanamine; 1- (4-(8-(3-methylpyridin-2-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine; 1 -(4-(2-(4-methoxyphenyl)-8-( 1 -methyl- 1 H-pyrazol-5-yl)-9H-purin-9- yl)phenyl)cyclobutanamine ;
2- (9-(4-(l-aminocyclobutyl)phenyl)-2-phenyl-9H-purin-8-yl)benzonitrile;
1 -(4-(2-(2-methoxyphenyl)-8-( 1 -methyl- 1 H-pyrazol-5-yl)-9H-purin-9- yl)phenyl)cyclobutanamine;
4-(9-(4-( 1 -aminocyclobutyl)phenyl)-8-( 1 -methyl- 1 H-pyrazol-5-yl)-9H-purin-2-yl)-N- methylbenzenesulfonamide ;
l-(4-(8-(l-methyl-lH-pyrazol-5-yl)-2-p-tolyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(2-(2-fluorophenyl)-8-( 1 -methyl- 1 H-pyrazol-5-yl)-9H-purin-9- yl)phenyl)cyclobutanamine;
1 -(4-(8-( 1 -methyl- 1 H-pyrazol-5-yl)-2-m-tolyl-9H-purin-9-yl)phenyl)cyclobutanamine;
1 -(4-(2-(4-fluorophenyl)-8-( 1 -methyl- 1 H-pyrazol-5-yl)-9H-purin-9- y l)pheny l)cyclobutanamine ;
l-(4-(8-(3-methoxypyridin-4-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine; and
1 -(4-(8-(4-methyl- 1 H-imidazol-5-yl)-2-phenyl-9H-purin-9-yl)phenyl)cyclobutanamine.
. The compounds of claim 26, havin the formula (3-F)
Figure imgf000214_0001
(3-F)
36. The compounds of claim 26, h ing the formula (3-G)
Figure imgf000214_0002
(3-G)
37. The compounds of claim 36, wherein they are selected from the group consisting of:
l-[4-(2-Phenyl-imidazo[4,5-b]pyrazin-l-yl)-phenyl]-cyclobutylamine; and
l-(4-(2-phenyl-5-(lH-pyrazol-4-yl)-lH-imidazo[4,5-b]pyrazin-l-yl)phenyl)cyclobutanamine.
38. The compounds of claim 26, havin the formula (3-H):
Figure imgf000215_0001
(3-H)
39. The compounds of claim 26 having the formula (3-1):
Figure imgf000215_0002
(3-D
40. The compounds of claim 26, having the formula (3-J):
Figure imgf000215_0003
(3-J)
A pharmaceutical composition comprising a compound as claimed in any one of Claims 1
42. A method of treating an AKT-mediated disease or disorder in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a compound as claimed in any one of Claims 1-40.
43. The method of Claim 42, wherein said disease or disorder is an inflammatory, hyperproliferative, cardiovascular, neurodegenerative, gynecological, or dermatological disease or disorder.
44. A method of inhibiting the production of AKT protein kinase in a mammal, which comprises administering to said mammal an effective amount of a compound as claimed in any one of Claims 1-40.
45. A method of inhibiting the activity of AKT protein kinase in a mammal, which comprises contacting said kinase with a compound as claimed in any one of Claims 1-40.
46. A compound as claimed in any one of Claims 1-40 for use as a medicament in the treatment of AKT protein kinase-mediated conditions.
47. The use of a compound as claimed in any one of Claims 1-40 in the manufacture of a medicament for therapy.
48. A kit for treating an AKT protein kinase-mediated condition, wherein said kit comprises: a) a first pharmaceutical composition comprising a compound as claimed in any one of Claims 1-40; and
b) optionally instructions for use.
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