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WO2015011252A1 - Inhibiteurs pyrimidine-pyridinone de sérine/thréonine kinase - Google Patents

Inhibiteurs pyrimidine-pyridinone de sérine/thréonine kinase Download PDF

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Publication number
WO2015011252A1
WO2015011252A1 PCT/EP2014/066000 EP2014066000W WO2015011252A1 WO 2015011252 A1 WO2015011252 A1 WO 2015011252A1 EP 2014066000 W EP2014066000 W EP 2014066000W WO 2015011252 A1 WO2015011252 A1 WO 2015011252A1
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Prior art keywords
methyl
mmol
chloro
phenyl
pyrimidin
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Inventor
James John CRAWFORD
Joy Drobnick
Lewis J. Gazzard
Wendy Lee
Chudi Ndubaku
Joachim Rudolph
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F Hoffmann La Roche AG
Genentech Inc
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F Hoffmann La Roche AG
Genentech Inc
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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
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to compounds which inhibit serine/threonine kinases and which are useful for treating hyperproliferative and neoplastic diseases by inhibiting signal transduction pathways which commonly are overactive or over-expressed in cancerous tissue.
  • the present compounds are inhibitors of group 1 p21-activated protein kinases (PAK1 , PAK2 and PAK3).
  • PAK1 , PAK2 and PAK3 group 1 p21-activated protein kinases
  • the present invention further relates to methods for treating cancer or hyperproliferative diseases with compounds within the scope of the present invention.
  • Protein kinases are a family of enzymes that catalyze phosphorylation of the hydroxyl groups of specific tyrosine, serine, or threonine residues in proteins. Typically, such phosphorylation can dramatically change the function of the protein and thus protein kinases can be pivotal in the regulation of a wide variety of cellular process, including metabolism, cell proliferation, cell differentiation, and cell survival. The mechanism of these cellular processes provides a basis for targeting protein kinases to treat disease conditions resulting from or involving disorder of these cellular processes. Examples of such diseases include, but are not limited to, cancer and diabetes.
  • Protein kinases can be broken into two types, protein tyrosine kinases (PTKs) and serine -threonine kinases (STKs). Both PTKs and STKs can be receptor protein kinases or non-receptor protein kinases.
  • PAK is a family of non-receptor STKs.
  • serine/threonine protein kinases plays important roles in cytoskeletal organization, cellular
  • PAK family consists of six members subdivided into two groups: PAK 1-3 (group I) and PAK 4-6 (group II) which are distinguished based upon sequence homologies and the presence of an autoinhibitory region in group I PAKs.
  • PAKs p21-Activated kinases
  • PAKs Changes in the levels and activities of group 1 PAKs in particular, are frequently associated with human malignancies including, but not limited to bladder carcinoma, breast carcinoma, colorectal carcinoma, gastric carcinoma, glioblastoma, hepatocellular carcinoma, ovarian carcinoma and renal cell carcinoma, primary breast adenocarcinoma, squamous non-small cell lung cancer or a squamous head and necks cancer.
  • bladder carcinoma breast carcinoma, colorectal carcinoma, gastric carcinoma, glioblastoma, hepatocellular carcinoma, ovarian carcinoma and renal cell carcinoma
  • primary breast adenocarcinoma squamous non-small cell lung cancer or a squamous head and necks cancer.
  • PAK1 genomic amplification at 1 lql3 was prevalent in luminal breast cancer, and PAK1 protein expression was associated with lymph node metastasis.
  • PAK family members are important signaling proteins frequently over-expressed and/or overactive in many cancerous tissues. Design and development of new pharmaceutical compounds that inhibit or modulate their activity is essential. There is a continuing need for improved PAK inhibitors which exhibit selectivity for Group I vs. Group II PAKs and/or which selectively inhibit PAK in the presence of other kinases.
  • a compound according to formula I wherein:
  • R 1 is H, Ci_3 alkyl, Ci_ 3 fluoroalkyl, oxetan-3-yl or 3-methyl-oxetan-3-yl;
  • R 2 is (i) C 2 -6 hydroxyalkyl or C 2 _ 6 dihydroxyalkyl, (ii) (alkylene) n NR a R b wherein the alkylene chain is optionally substituted by a hydroxyl, (iii) (alkylene) 1 . 3 OR 5 wherein R 5 is (alkylene) 2 . 4 NR a R b , (alkylene) 2 .
  • heterocyclyl refers to substituted azetidinyl, pyrrolidinyl, 4,4-difluoro-pyrrolidin-3-yl, piperidinyl, 3,3-difluoro-piperidin-3-yl, azepinyl, morpholinyl, 4-methylmorpholin-2-yl,5-amino-l,3-dioxolan-2-yl, 5-methylamino-l,3-dioxolan-2-yl,3-aza- bicyclo[3.1.0]hexan-6-yl, 5-oxa-2-azaspiro[3.4]octan-7-yl, l-oxa-8-azaspiro[4.5]decan-3-yl, l-oxa-7- azaspiro[4.4]nonan-3-yl, 5,9
  • R c and R d are independently in each occurrence hydrogen, Ci_ 3 alkyl or oxetanyl
  • R e is hydrogen, Ci_ 3 alkyl or Ci_ 3 alkylsulfonyl
  • R f is hydrogen or Ci_ 3 alkyl
  • R 3 is heteroaryl wherein the heteroaryl ring is pyridine-2-yl, pyrazin-2-yl, thiazol-4-yl, thiazol-2-yl, pyrazol-3-yl,l,2,4-triazol-2-yl or l,2,4-oxadiazol-3-yl each optionally substituted by an R 4 or a Ci_ 3 hydroxyalkyl moiety;
  • R 4 is Ci_6 alkyl, cyclopropyl or halogen
  • n 2-6;
  • r is 1-6;
  • s 0, 1 or 2;
  • t is 0 - 6; or,
  • Another aspect of the present invention relates to a method for treating a hyperproliferative disorder by administering a therapeutically effective quantity of a compound according to formula I to a patient in need thereof.
  • Another aspect of the present invention relates to a method for treating cancer by administering a therapeutically effective quantity of a compound according to formula I to a patient in need thereof.
  • the compound can be administered alone or co-administered with at least one other anti- hyperproliferative or chemotherapeutic compound.
  • Another aspect of the present invention relates to a method for inhibiting PAK activity in a cell comprising treating a cell with a compound according to formula I in an amount effective to attenuate or eliminate PAK activity.
  • compositions containing a compound of formula I with one or more pharmaceutically acceptable excipients, diluents and/or carriers.
  • a or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound.
  • a compound refers to one or more compounds or at least one compound.
  • the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
  • the phrase “as defined herein above” refers to the broadest definition for each group as provided in the Summary of the Invention or the broadest claim. In all other embodiments provided below, substituents which can be present in each embodiment and which are not explicitly defined retain the broadest definition provided in the Summary of the Invention.
  • the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound or composition includes at least the recited features or components, but may also include additional features or components.
  • a bond drawn into ring system indicates that the bond may be attached to any of the suitable ring atoms.
  • variable can be equal to any integer value of the numerical range, including the end-points of the range.
  • variable can be equal to any real value of the numerical range, including the end-points of the range.
  • a variable which is described as having values between 0 and 2 can be 0, 1 or 2 for variables which are inherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value for variables which are inherently continuous.
  • the compounds of formula I may contain one or more chiral centers and therefore exist in two or more stereoisomeric forms.
  • the racemates of these isomers, the individual isomers and mixtures enriched in one enantiomer, as well as diastereomers when there are two chiral centers, and mixtures partially enriched with specific diastereomers are within the scope of the present invention.
  • substitution of the tropane ring can be in either endo- or ejcoconfiguration, and the present invention covers both configurations.
  • the present invention includes all the individual stereoisomers (e.g. enantiomers), racemic mixtures or partially resolved mixtures of the compounds of formulae I and, where appropriate, the individual tautomeric forms thereof.
  • Tautomeric compounds can exist as two or more interconvertable species.
  • Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium and attempts to isolate an individual tautomer usually produces a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates.
  • the compounds of formula I may contain an acidic or basic center and suitable salts are formed from acids or bases may form non-toxic salts which have similar antiviral activity.
  • suitable salts are formed from acids or bases may form non-toxic salts which have similar antiviral activity.
  • salts of inorganic acids include the hydrochloride, hydrobroniide, hydroiodide, chloride, bromide, iodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate.
  • salts of organic acids include acetate, fumarate, pamoate, aspartate, besylate, carbonate, bicarbonate, camsylate, D and L-lactate, D and L- tartrate, esylate, mesylate, malonate, orotate, gluceptate, methylsulfate, stearate, glucuronate, 2-napsylate, tosylate, hibenzate, nicotinate, isethionate, malate, maleate, citrate, gluconate, succinate, saccharate, benzoate, esylate, and pamoate salts.
  • suitable salts see Berge et al, J. Pharm. Sci., 1977 66: 1-19 and G. S. Paulekuhn et al. J. Med. Chem. 2007 50:6665.
  • alkylaryl haloalkylheteroaryl
  • arylalkylheterocyclyl alkylcarbonyl
  • alkoxyalkyl alkylcarbonyl
  • phenylalkyl refers to an alkyl group having one to two phenyl substituents, and thus includes benzyl (phenylmethyl) and phenylethyl.
  • An "alkylaminoalkyl” is an alkyl group having one to two alkylamino substituents.
  • “Hydroxyalkyl” includes 2-hydroxyethyl, 2-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2- hydroxybutyl, 2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth. Accordingly, as used herein, the term "hydroxyalkyl” is used to define a subset of heteroalkyl groups defined below.
  • -(ar)alkyl refers to either an unsubstituted alkyl or an aralkyl group.
  • (hetero)aryl or (het)aryl refers to a moiety that is either an aryl or a heteroaryl group.
  • alkyl as used herein without further limitation, alone or in combination with other groups, denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, «-butyl, wo-butyl, sec-butyl, or teri-butyl.
  • lower alkyl denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms.
  • Ci_6 alkyl as used herein refers to an alkyl composed of 1 to 6 carbons.
  • cycloalkyl denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms, particularly a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms.
  • Bicyclic means consisting of two saturated carbocycles having one (e.g., a spirocycle) two or more carbon atoms in common.
  • C3.7 cycloalkyl refers to a cycloalkyl composed of 3 to 7 carbons in the carbocyclic ring.
  • monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • bicyclic cycloalkyl are examples of bicyclic cycloalkyl.
  • hydroxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group.
  • hydroxyalky include hydroxymethyl, 2- hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-l-hydroxymethylethyl, 2,3- dihydroxybutyl, 3,4-dihydroxybutyl or 2-(hydroxymethyl)-3-hydroxypropyl.
  • alkylene denotes a divalent saturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g. , (CH 2 ) n ) or a branched saturated divalent hydrocarbon radical of greater than 2 to 6 carbon atoms (e.g. , -CHMe- or -CH 2 CH( -Pr)CH 2 -), unless otherwise indicated.
  • C 0 -4 alkylene or “(CH 2 V 4 " refers to a linear or branched saturated divalent hydrocarbon radical comprising 1-4 carbon atoms or, in the case of C 0 , the alkylene radical is omitted.
  • alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl -propylene, 1 ,1-dimethyl-ethylene, butylene, 2-ethylbutylene.
  • (alkylene) t (C 4 _6 -cycloalkyl NR c R d ) refers to the radical R'R"-, wherein R' is a cycloalkyl as defined herein substituted by NR c R d , and R" is an alkylene radical as defined herein with the understanding that the attachment point of the aminocycloalkylalkyl moiety will be on the alkylene radical.
  • Amino-C 3 .7 cycloalkyl-Ci_ 3 alkyl refers to the radical R'R" where R' is amino substituted C 3 . 7 cycloalkyl and R" is Ci_ 3 alkylene as defined herein.
  • the moiety (alkylene) t (C 4 _6-cycloalkyl NR c R d ) refers to ( ).
  • (alkylene) n -heterocyclyl denotes the radical of the formula R'R", wherein R' is a heterocyclic radical as defined herein, and R" is an alkylene radical as defined herein and the attachment point of the heterocycloalkyl radical will be on the alkylene radical.
  • Optionally substituted heterocyclyl as used herein refers at least to the following moieties wherein 2 hydrogen atoms on a carbon are optionally replaced by an oxo moiety and R e is hydrogen, Ci_ 3 alkyl or Ci_ 3 alkylsulfonyl:
  • 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.
  • terapéuticaally effective amount means an amount of a compound of the present invention that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • the therapeutically 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).
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • a “tumor” comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer ("NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
  • a "chemotherapeutic agent” is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA ® , Genentech/OSI Pharm.
  • alkylating agents such as thiotepa and CYTOXAN ® cyclosphosphamide
  • alkyl sulfonates such as busulfan, improsulfan and piposulfan
  • aziridines such as benzodopa, carboquone, meturedopa, and uredopa
  • antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin ⁇ and calicheamicin ⁇ (Angew Chem. Intl. Ed. Engl.
  • 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, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, ADRIAMYCIN ® (doxorubicin), morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino-doxorubicin and deoxy doxorubicin), epirubicin, esorubicin,
  • phenamet pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK ® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran;
  • spirogermanium 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, 111.), and TAXOTERE ® (docetaxel, doxetaxel; Sanofi-
  • 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.
  • 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, LY117018, 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,
  • SERMs selective estrogen receptor modulators
  • LURTOTECAN ® 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.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is (CH 2 ) n NR a R b
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl
  • R a and R b are (a) independently hydrogen or Ci-3 alkyl, or, (b) R a and R b together with the nitrogen to which they are attached form a four to seven-membered ring optionally containing another heteroatom selected from O, NR e or S(O) 0 -2
  • n is 2 -6.
  • R 3 is 2-methyl- pyrazin-6-yl.
  • R 3 is 2-methyl-pyridin-6-yl. In another subembodiment R 3 is 3- methyl-pyridin-2-yl. In another subembodiment R 3 is 2,4-dimethyl-pyridin-6-yl. In another subembodiment R 3 is 2-methyl-pyridin-6-yl. In another subembodiment R 3 is 3- methyl-pyridin-2-yl. In another subembodiment R 3 is 2,4-dimethyl-pyridin-6-yl. In another
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is (CH 2 ) n NR a R b ; n is 2-4 and R a and R b are independently hydrogen or Ci_ 3 alkyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridin-6- yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4- dimethyl-pyridin-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci -3 alkyl
  • R 2 is (CH 2 ) confrontNR a R b
  • n is 2-4 and R a and R b together with the nitrogen to which they are attached form a four to seven-membered ring optionally containing another heteroatom selected from O, NR e or S(O) 0 -2
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridin-6- yl.
  • R 3 is 3-methyl-pyridin-2-yl. In another subembodiment R 3 is 2,4- dimethyl-pyridin-6-yl. In another subembodiment R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci -3 alkyl
  • R 2 is (alkylene)i_ 3 OR 5 wherein R 5 is (alkylene) 24 NR a R b or a heterocycle selected from azetidine, pyrrolidine, piperidine or azepine
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridin-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridin-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci -3 alkyl
  • R 2 is (alkylene) 1 . 3 OR 5 wherein R 5 is (alkylene) 24 NR a R b ; R 3 is pyridinyl or pyrazinyl optionally substituted by methyl; R a and R b are (a) independently hydrogen or Ci_ 3 alkyl, or, (b) R a and R b together with the nitrogen to which they are attached form a four to seven- membered ring optionally containing another heteroatom selected from O, NR e or S(O) 0 - 2 .
  • R 3 is 2-methyl-pyrazin-6-yl. In another subembodiment R 3 is 2-methyl-pyridin-6-yl. In another subembodiment R 3 is 3-methyl-pyridin-2-yl. In another subembodiment R 3 is 2,4-dimethyl- pyridin-6-yl. In another subembodiment R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is (alkylene)i_ 3 OR 5 wherein R 5 is a heterocycle selected from azetidine, pyrrolidine, piperidine or azepine
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridin-6- yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4- dimethyl-pyridin-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is (CH 2 ) 2 0(CH 2 ) 2 NR a R b
  • R a and R b are (a) independently hydrogen or Ci_ 3 alkyl, or, (b) R a and R b together with the nitrogen to which they are attached form a four to seven-membered ring optionally containing another heteroatom selected from O, NR e or S(0)o- 2
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridin-6-yl. In another subembodiment R 3 is 3-methyl-pyridin-2-yl. In another subembodiment R 3 is 2,4-dimethyl-pyridin-6-yl. In another subembodiment R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is (CH 2 ) r C(0)NR a
  • R a and R b are (a) independently hydrogen or Ci_ 3 alkyl, or, (b) R a and R b together with the nitrogen to which they are attached form a four to seven-membered ring optionally containing another heteroatom selected from O, NR e or S(0)o-2
  • R e is hydrogen, Ci_ 3 alkyl or Ci_ 3 alkylsulfonyl
  • r is 1 to 6
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl;
  • R 3 is 2-methyl-pyrazin-6-yl. In another subembodiment R 3 is 2-methyl-pyridin-6-yl. In another subembodiment R 3 is 3-methyl-pyridin-2-yl. In another subembodiment R 3 is 2,4-dimethyl-pyridin-6-yl. In another subembodiment R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is (CH 2 ) r C(0)NR a R b and R a and R b are independently hydrogen or Ci_ 3 alkyl and r is 1 to 6
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl;.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridin-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl- pyridin-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is (CH 2 ) r C(0)NR a R b and R a and R b together with the nitrogen to which they are attached form a four to seven-membered ring optionally containing another heteroatom selected from O, NR e or S(O) 0 -2
  • R e is hydrogen, Ci_ 3 alkyl or Ci_ 3 alkylsulfonyl and r is 1 to 6.
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl. In one subembodiment R 3 is 2-methyl- pyrazin-6-yl.
  • R 3 is 2-methyl-pyridin-6-yl. In another subembodiment R 3 is 3- methyl-pyridin-2-yl. In another subembodiment R 3 is 2,4-dimethyl-pyridin-6-yl. In another subembodiment R 3 is 2-methyl-pyridin-6-yl. In another subembodiment R 3 is 3- methyl-pyridin-2-yl. In another subembodiment R 3 is 2,4-dimethyl-pyridin-6-yl. In another
  • R 1 is ethyl or methyl.
  • R 3 is 2-methyl-pyrazin-6-yl. In another subembodiment R 3 is 2-methyl-pyridin-6-yl. In another subembodiment R 3 is 3-methyl-pyridin-2-yl. In another subembodiment R 3 is 2,4-dimethyl-pyridin-6-yl. In another subembodiment R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is 3-amino-cyclopentylmethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridin-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridin-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is 3-amino-cyclopentylethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridin-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridin-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is 3-amino-cyclohexylmethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridin-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridin-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is 3-amino-cyclohexylethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridin-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridin-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is 4-amino-cyclohexylmethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridin-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridin-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is 4-amino-cyclohexylethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridin-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridin-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is (i), (ii), (iii), (iv), (v), (vi), (vii) or (viii)
  • n is 2-6
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6- yl.
  • R 3 is 2-methyl-pyridinyl-6-yl.
  • R 3 is 3-methyl- pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridinyl-6-yl.
  • R 1 is ethyl or methyl.
  • R 2 is 2- (5-amino-l,3-dioxan-2-yl)ethyl or 2-(5-amino-l,3-dioxan-2-yl)methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is azetidin-3-ylethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridinyl-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridinyl-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is azetidin-3-ylpropyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridinyl-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridinyl-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is pyrrolidin-3-ylethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridinyl-6-yl
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridinyl-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is pyrrolidin-3-ylpropyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridinyl-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridinyl-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is piperidin-4-ylpropyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridinyl-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • -In another subembodiment R 3 is 2,4-dimethyl-pyridinyl-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is piperidin-4-ylethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridinyl-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridinyl-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is (vii)
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl
  • R 3 is 2-methyl- pyridinyl-6-yl
  • R 3 is 3-methyl-pyridin-2-yl
  • R 3 is 2,4-dimethyl-pyridinyl-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is 5-amino-[l ,3]dioxan-2-ylmethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl
  • R 3 is 2-methyl-pyridinyl-6-yl
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridinyl-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is 5-amino-[l ,3]dioxan-2-ylethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridinyl-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridinyl-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is piperazin-l-ylmethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridinyl-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridinyl-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is piperazin-l-ylethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • -In another subembodiment R 3 is 2-methyl-pyridinyl-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridinyl-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is 4-methyl-piperazin-l-ylethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6-yl.
  • R 3 is 2-methyl-pyridinyl-6-yl.
  • R 3 is 3-methyl-pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridinyl-6-yl.
  • R 1 is ethyl or methyl.
  • R 1 is optionally substituted Ci_ 3 alkyl
  • R 2 is 3-aza-bicyclo[3.1.0]hex-6-ylamino)-ethyl]-2 -ethyl
  • R 3 is pyridinyl or pyrazinyl optionally substituted by methyl.
  • R 3 is 2-methyl-pyrazin-6- yl.
  • R 3 is 2-methyl-pyridinyl-6-yl.
  • R 3 is 3-methyl- pyridin-2-yl.
  • R 3 is 2,4-dimethyl-pyridinyl-6-yl.
  • R 1 is ethyl or methyl.
  • R 3 is optionally substituted pyrazinyl.
  • R 4 is 2-chloro or 2-methyl.
  • R 3 is 6-methylpyrazin-2-yl.
  • a compound according to formula I wherein R 3 is optionally substituted pyridinyl.
  • R 3 is optionally substituted pyridinyl and R 4 is 2-chloro or 2-methyl.
  • R 3 is 6-methylpyridin-2-yl.
  • R 3 is 3-methylpyridin-2-yl.
  • R 3 is 4,6-dimethylpyridin-2-yl.
  • a method of inhibiting PAK activity in a patient in need thereof comprising the step of administering to said patient a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , R c , R d , R e , n, r, s and t are as defined hereinabove.
  • a method of treating or ameliorating the severity of cancer or a hyperproliierative disorder in a patient in need thereof comprising administering to said patient a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , R c , R d , R e , n, r, s and t are as defined hereinabove.
  • a method of treating a cancer selected from the group consisting of lung cancer, breast cancer, ovarian cancer, bladder cancer and head and neck cancer comprising administering to a patient in need thereof a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , R c , R d , R e , n, r, s and t are as defined hereinabove.
  • a method of treating a cancer selected from the group consisting of primary breast adenocarcinoma, squamous non-small cell lung cancer or a squamous head and neck cancer comprising administering to a patient in need thereof a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , R c , R d , R e , n, r, s and t are as defined hereinabove.
  • a method of treating cancer or a hyperproliferative disease comprising co-administering to a patient in need thereof a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , R c , R d , R e , n, r, s and t are as defined hereinabove and at least one other chemotherapeutic agent used to treat or ameliorate cancer or a hyperproliferative disorder.
  • a method of treating cancer or a hyperproliferative disease comprising co-administering to a patient in need thereof a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , R c , R d , R e , n, r, s and t are as defined hereinabove and at least one other chemotherapeutic agent selected from the group consisting of inhibitor of apoptosis proteins (IAP), an EGFR inhibitor or antagonist, an inhibitor of Ras/Raf/Mek/Erk signaling cascade, an inhibitor of Akt kinase and a Src kinase inhibitor.
  • IAP inhibitor of apoptosis proteins
  • a pharmaceutical composition comprising a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , R c , R d , R e , n, r, s and t are as defined hereinabove and at least one pharmaceutically acceptable carrier, excipient or diluent.
  • a p21 -activated kinase (PAK) inhibitor for use in treating cancer or a hyperproliferative disorder.
  • PAK p21 -activated kinase
  • a composition containing a compound of selected from I-l to 1-202 in TABLE l for use in the manufacture of a medicament for the inhibition of abnormal cell growth or for treatment of a hyperproliferative disorder in a mammal.
  • R 1 is H or optionally substituted Ci_ 3 alkyl
  • R 2 is (i) C 2 _ 6 hydroxyalkyl, (ii)(alkylene) n NR a R b wherein the alkylene chain is optionally substituted by a hydroxyl, (iii) (alkylene)i_ 3 OR 5 wherein R 5 is (alkylene) 2 - 4 NR a R b or heterocycle selected from azetidine, pyrrolidine, piperidine or azepine, (iv) (alkylene) r C(0)NR a R b , (v) (alkylene) n -CN, (vi) (alkylene) r (C 4 - 6 -cycloalkyl NR c R d ), (vii) heterocyclyl- (alkylene) n wherein heterocyclyl refers to optionally substituted azetidinyl,
  • R 1 is H, optionally substituted Ci_ 3 alkyl, oxetan-3-yl or l-hydroxy-oxetan-3-yl
  • R 2 is (i) C 2 _ 6 hydroxyalkyl or C 2 _ 6 dihydroxyalkyl, (ii) (alkylene) n NR a R b wherein the alkylene chain is optionally substituted by a hydroxyl, (iii) (alkylene) 1 . 3 OR 5 wherein R 5 is (alkylene) 2 .
  • TsOH or pTsOH 4-Me-C 6 H 4 S0 2 - or tosyl (Ts), N-urethane-N-carboxyanhydride (UNCA),.
  • Conventional nomenclature including the prefixes normal (n), iso ( -), secondary (sec-), tertiary (tert- or -t) and neo- have their customary meaning when used with an alkyl moiety. (J. Rigaudy and D. P. Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford.).
  • the depicted structure is to be accorded more weight.
  • the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. The following numbering system is used herein.
  • the starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation,
  • the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78 °C to about 150 °C, more preferably from about 0°C to about 125 °C, and most preferably and conveniently at about room (or ambient) temperature, or, about 20 °C.
  • step 1 step 2
  • Compounds of the present invention can be prepared starting from 6-bromo-2-(methylthio)-pyrido[2,3- flf]pyrirnidin-7(8H)-one (CASRN 352328-87-1) by the process depicted in SCHEME A.
  • the first step can be accomplished by alkylation of the lactam nitrogen with an alkyl halide or sulfonate in the presence of base such as Cs 2 C0 3 in a polar aprotic solvent or by coupling utilizing a Mitsunobu coupling protocol.
  • Mitsunobu conditions D. L. Hughes, The Mitsunobu Reaction, in Organic Reactions, Volume 42, 1992, John Wiley & Sons, New York; pp.
  • 335-656 comprise activating alcohols with a mixture of a phosphine such as a trialkylphosphine like tributylphosphine ((ra-Bu) 3 P), a triphenylphosphine (Ph 3 P) and the like and a diethyl- azodicarboxylate (DEAD), diisopropyl-azodicarboxylate (DIAD) or di-ier/-butyl- azodicarboxylate in an inert solvent such as THF, toluene, DCM.
  • a phosphine such as a trialkylphosphine like tributylphosphine ((ra-Bu) 3 P), a triphenylphosphine (Ph 3 P) and the like
  • DEAD diethyl- azodicarboxylate
  • DIAD diisopropyl-azodicarboxylate
  • the aryl substituent is introduced utilizing a Suzuki protocol.
  • Typical catalysts include Pd(PPh 3 ) 3 , Pd(OAc) 2 and PdCl 2 (dppf).
  • the reaction can be carried out in a variety of organic solvents including toluene, THF, dioxane, 1,2-dichloroethane, DMF, PhMe, MeOH, DMSO and acetonitrile, aqueous solvents and under biphasic conditions. Reactions are typically ran from about room temperature to about 150° C. Additives (e.g. CsF, KF, TIOH, NaOEt and KOH) frequently accelerate the coupling reaction. There are a large number of parameters in the Suzuki reaction including the palladium source, ligand, additives and temperature and optimum conditions sometimes require optimization of the parameters for a given pair of reactants. One skilled in the art can determine optimal conditions without undue experimentation.
  • alkyl amine substituent on the pyrimidine ring is introduced in steps 3 and 4 by oxidation of the thiol to the corresponding sulfone and displacement of the sulfone with the desired amine.
  • Oxidation of the sulfide can be conveniently carried out with MCPBA or with potassium hydrogen persulfate. (B. M. Trost and D. P. Curran, Tetrahedron Lett. 1981 22(14): 1287)
  • the sulfone can then be directly displaced by the requisite amine.
  • step 3 I ⁇ B-3: X CH 2 OH
  • B-5 B-6 A-4
  • the compounds of the invention can be prepared from ethyl 4-chloro-2-(methylthio)-5- pyrimidinecarboxylate (B-1, CASRN 5909-24-0). Displacement of the chloride introduces the lactam nitrogen with requisite amine side chain in step 1. Reduction of the ester and reoxidation of the resulting alcohol to an aldehyde B-4 is carried out by standard methodology. Condensation of the resulting aldehyde B-4 with an appropriate arylacetic acid and formation of the lactam affords the requisite 6- phenylpyrido[2,3-d]pyrimidin-7(8H)-one B-5.
  • BIOLOGICAL ACTIVITY Determination of the PAK inhibitory activity of a compound of formula I was accomplished using the PAK1 inhibition assay in Biological Example 1. Potency values of exemplary compounds in PAK1 assays are reported TABLE 1. A cell-based mechanistic assay (Biological Example 2) was used to determine the effect of PAK inhibitors on down-stream signaling. Representative values for these assays can be found in TABLE 1. DOSAGE & ADMINISTRATION
  • the present invention provides pharmaceutical compositions or medicaments containing the compounds of the invention and at least one therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.
  • compounds of formula I with the desired degree of purity may be formulated by mixing with
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a dosage form at ambient temperature and at the appropriate pH.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but typically ranges anywhere from about 3 to about 8.
  • a compound of formula I is formulated in an acetate buffer, at pH 5.
  • the compounds of formula I are sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
  • compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
  • therapeutically effective amount denotes an amount of a compound of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
  • the therapeutically effective amount will vary depending on the particular disorder being treated, the severity of the disorder, the particular patient 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
  • treating includes (1) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or (2) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
  • 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 includes 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.
  • Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of formula I, 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, 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 DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.
  • a dose to treat human patients may range from about 0.1 mg to about 1000 mg of a compound of formula I.
  • a typical dose may be about 1 mg to about 300 mg of the compound.
  • a dose may be administered once a day (QID), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound.
  • toxicity factors may influence the dosage and administration regimen.
  • the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for a number of cycles of therapy.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g. , tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al. , Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents 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).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents 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
  • tablets containing various excipients such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia.
  • disintegrants such as starch, alginic acid and certain complex silicates
  • binding agents such as sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • An example of a suitable oral dosage form is a tablet containing about 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of the compound of the invention compounded with about 90-30 mg anhydrous lactose, about 5- 40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
  • An example of an aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired.
  • the solution may be filtered, e.g. , using a 0.2 micron filter, to remove impurities and contaminants.
  • the pharmaceutical composition also includes at least one additional anti-proliferative agent.
  • An embodiment therefore, includes a pharmaceutical composition comprising a compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • 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 compounds of formula I may be employed alone or in combination with other therapeutic agents for the treatment of a disease or disorder described herein, such as a hyperproliferative disorder (e.g. , cancer).
  • a compound of formula I is combined in a pharmaceutical combination formulation, or dosing regimen as combination therapy, with a second compound that has anti- hyperproliferative properties or that is useful for treating a hyperproliferative disorder (e.g. , cancer).
  • the second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of formula I such that they do not adversely affect each other.
  • 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.
  • the combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
  • the combined administration includes co-administration, using separate formulations or a single
  • Suitable dosages for any of the above co-administered agents are those presently used and may be lowered due to the combined action (synergy) of the newly identified agent and other chemotherapeutic agents or treatments.
  • Combination therapies thus comprise the administration of at least one compound of formula I, or a stereoisomer, geometric isomer, tautomer, metabolite, or pharmaceutically acceptable salt and the use of at least one other cancer treatment method.
  • the amounts of the compound(s) of formula I and the other pharmaceutically active chemotherapeutic agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • kits containing materials useful for the treatment of the diseases and disorders described above.
  • the kit comprises a container comprising a compound of formula I, or a stereoisomer, tautomer, or
  • the kit may further comprise a label or a 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.
  • 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 formula I 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).
  • At least one active agent in the composition is a compound of formula I.
  • the article of manufacture may further comprise a second container comprising a pharmaceutically diluent, 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
  • kits are suitable for the delivery of solid oral forms of a compound of formula I, such as tablets or capsules.
  • a kit can include a number of unit dosages.
  • 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 kit may comprise (a) a first container with a compound of formula I contained therein; and optionally (b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a second compound with anti-hyperproliferative activity.
  • 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
  • PAKl-KD kinase domain
  • Catalytically active human recombinant PAKl-KD protein is obtained by purification from Tini cells infected with a human PAKl-KD recombinant baculo virus expression vector.
  • the activity/inhibition of PAKl-KD was estimated by measuring the phosphorylation of a FRET peptide substrate (Ser/Thrl9) labeled with Coumarin and Fluorescein using Z'-LYTETM assay (Invitrogen).
  • the peptide substrate is a consensus sequence (KKRNRRLSVA) based on various PAK substrates reported in the scientific literature.
  • the 10 ⁇ assay mixtures contained 50 mM HEPES (pH 7.5), 0.01% Brij-35, 10 mM MgCl 2 , 1 mM EGTA, 2 ⁇ FRET peptide substrate, and 20 pM PAKl-KD.
  • Group I PAKs PAK1-3 are activated upon binding to the Rho GTPases, Racl and Cdc42. Activated group I PAKs phosphorylate MEKl at Serine 298 (S298), one of the two sites in the catalytic domain that is important for stable association between Raf and MEKl and subsequent MAPK activation.
  • S298 Serine 298
  • the inhibition of group I PAKs in EBC1 cells is assessed by detecting changes in the level of MEKl phosphorylation at S298 using homogenous time -resolved fluorescence (HTRF). Inhibitory activity was estimated by treating 2xl0 4 EBC1 cells for 2 h with PAK inhibitors in media containing 0.1% FBS.
  • HTRF homogenous time -resolved fluorescence
  • step 1 To a solution of 2-pyrrolidin-2-yl EtOH (1.0 g) and TEA (1.76 g, 17.4 mmol) in anhydrous DCM (17.4 mL) at 0°C was added dropwise benzyl chloroformate (1.48 g, 8.68 mmol), and the reaction mixture was stirred at RT under N 2 for 20 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with 10% aq. citric acid, water and brine, dried (Na 2 S0 4 ), filtered, and concentrated in vacuo.
  • step 2 Benzyl 2-(2-methylsulfonyloxyethyl)pyrrolidine-l -carboxylate was prepared using a procedure analogous to referential example 1 except benzyl 2-(2-hydroxyethyl)pyrrolidine-l -carboxylate was the starting material.
  • l U NMR 400 MHz, CDC1 3 ) ⁇ 7.40 - 7.27 (m, 5H), 5.12 (s, 2H), 4.40 - 4.14 (m, 2H),
  • tert-Butyl 3 -hydroxyazetidine-1 -carboxylate 200 mg, 1.16 mmol
  • TEA 120 mg, 1.16 mmol
  • tetrabutylammonium bromide 30 mg, 0.093 mmol
  • ethylene carbonate 155 mg, 1.74 mmol
  • the reaction mixture was concentrated in vacuo at RT, and the residue was purified by Si0 2 chromatography eluting with MeOH/DCM (100:6) to afford tert- butyl 3-(2-hydroxyethoxy)azetidine-l -carboxylate (100 mg, 39%) as yellow oil.
  • LCMS (ESI): m/z 162.3 [M-55] + .
  • step 1 To a solution of sodium hydride (0.94 g, 39 mmol) in anhydrous THF (200 mL) at 0 °C was added tert-butyl 3-hydroxypyrrolidine-l -carboxylate (5.61 g, 30 mmol). After stirring for 40 min, ethyl chloroacetate (4.14 mL, 30 mmol) was added dropwise, and the resulting dark purple solution was stirred overnight. The reaction mixture was quenched with 5% HC1 solution and extracted with EtOAc (150 mL). The extracts were combined, washed with brine, dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure.
  • step 2 Under a nitrogen atmosphere, a solution of tert-butyl 3-(2-ethoxy-2-oxoethoxy) pyrrolidine- 1- carboxylate (884 mg, 3.24 mmol) in anhydrous THF (20.0 mL) was added dropwise to a stirred mixture of LiAlH 4 (120 mg, 3.24 mmol) in anhydrous THF (10.0 mL) at 0 °C. The reaction was stirred for 40 min and then treated successively with water (2.0 mL) and 10% NaOH (0.9 mL). After stirring for 2 h the resulting mixture was extracted with EtOAc (50 mL).
  • step 3 To an ice cold solution of tert-butyl 3-(2-hydroxyethoxy)pyrrolidine-l-carboxylate (644 mg, 2.78 mmol) in DCM (10 mL) and THF (4.0 mL) was added TEA (0.77 mL) and TsCl (0.63 g, 0.69 mmol). The mixture was stirred at RT overnight. DMAP (0.18 g) was then added, and the reaction mixture was stirred for 2 h. A saturated aqueous NaHC0 3 solution (2.0 ml) was added and the layers separated. The organic layer was further washed with saturated CuS0 4 (2 x 1.0 mL), water (10 mL) and brine and then concentrated to dryness.
  • step 1 A 10 L 4-necked round-bottom flask was purged and maintained under a nitrogen atmosphere and then charged with 4-bromo-2-chloroaniline (300 g, 1.45 mol, 1.00 equiv) and oxolane (3000 mL).
  • di-teri-butyl dicarbonate (381 g, 1.75 mol, 1.20 equiv) dropwise with stirring at 0°C over 1 hr. The resulting solution was stirred overnight at RT. This reaction was repeated 1 more time.
  • step 2 A 10 L 4-necked round-bottom flask was purged and maintained under a nitrogen atmosphere then charged with tert-butyl N-(4-bromo-2-chlorophenyl)carbamate (477 g, 1.00 equiv, crude), dioxane (3500 mL), 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (371 g, 1.46 mol, 1.00 equiv), KOAc (428 g, 4.36 mol, 3.00 equiv), and Pd(dppf)Cl 2 (18 g, 24.60 mmol, 0.02 equiv). The resulting solution was stirred at 90°C for 4 h. This reaction was repeated for 1 more time. The solids were filtered out and the product was used in the next step without further purification,
  • step 3 A 10 L 4-necked round-bottom flask was purged and maintained under a nitrogen atmosphere and then charged with teri-butyl N-[2-chloro-4-(tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]carbamate from step 2 (1.00 equiv), 2-chloro-3-methylpyrazine (187 g, 1.45 mol, 1.00 equiv), a solution of Na 2 C0 3 (312 g, 2.92 mol, 2.00 equiv) in water (1460 mL) and (PPh 3 ) 4 Pd(II) (10 g). The resulting solution was stirred overnight at 85°C. This reaction was repeated 1 more time.
  • step 4 A 10 L 4-necked round-bottom flask was charged with tert-b tyl N-[2-chloro-4-(3-methylpyrazin- 2-yl)phenyl] carbamate (350 g, 1.09 mol, 1.00 equiv) and EtOAc (5 L) and then hydrogen chloride (gas) was introduced. The resulting solution was stirred at RT for 4 h and concentrated under vacuum. The solid was diluted with 3 L of water. The pH value of the solution was adjusted to 8 with K 2 C0 3 and the resulting solution was extracted with 2x3 L of EtOAc. The combined organic layers were dried over anhydrous Na 2 S0 4 and concentrated under vacuum to afford 240 g of 2-chloro-4-(3-methylpyrazin-2- yl)aniline as a white solid.
  • step 5 A 10 L 4-necked round-bottom flask was placed 2-chloro-4-(3-methylpyrazin-2-yl)aniline (120 g, 546.27 mmol, 1.00 equiv), water (2400 mL), CH 3 CN (800 mL), con HC1 (280 mL), followed by the dropwise addition of a solution of sodium nitrite (45.4 g, 658.02 mmol, 1.20 equiv) in water (500 mL) with stirring at 0°C over 1 nr. The resulting solution was stirred at 0°C for 1 h.
  • step 6 A 3 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen then charged with 2-(3-chloro-4-iodophenyl)-3-methylpyrazine (110 g, 332.78 mmol, 1.00 equiv), B(i- PrO) 3 (125.3 g, 666.49 mmol, 2.00 equiv), oxolane (1500 mL).
  • step 2 DMAP (0.3 g, 2 mmol), TEA (7.4 g, 73 mmol) and tosyl chloride (6.8 g, 36 mmol) were added to a mixture of teri-butyl-2-(2-hydroxyethoxy)ethylcarbamate (5.0 g, 24 mmol) in DCM (60 mL). The mixture was stirred at RT overnight, concentrated in vacuo and purified by Si0 2 chromatography using PE/EtOAc (3: 1) as eluent to afford 2-(2-(teri-butoxycarbonylamino)ethoxy)ethyl 4- methylbenzenesulfonate (8.0 g, 92 ) as a yellow oil.
  • LCMS (ESI): m/z 360.1 [M+l] + .
  • step 2 A mixture of teri-butyl (15,45)-4-(hydroxymethyl)cyclohexylcarbamate (480 mg, 2.09 mmol), TEA (423 mg, 4.18 mmol), tosyl chloride (478 mg, 2.51 mmol), and DMAP (26 mg, 0.21 mmol) in DCM (10 mL) was stirred at RT overnight.
  • teri-Butyl 2-oxo-4-(2-(tosyloxy)ethyl)piperidine- 1 -carboxylate step 1 A mixture of 2-(piperidin-4-yl)ethanol (1.00 g, 7.74 mmol), di-tert-butyl dicarbonate (1.86 g, 8.51 mmol) and TEA (1.57 g, 15.48 mmol) in DCM (20 mL) was stirred at 25 °C for 1 h. The mixture was then diluted with DCM (20 mL) and washed with HCl (1 N, 2 x 20 mL) and brine (20 mL).
  • step 2 A mixture of teri-butyl 4-(2-hydroxyethyl)piperidine-l -carboxylate (800 mg, 3.49 mmol), TEA (706 mg, 6.98 mmol), tosyl chloride (698 mg, 3.66 mmol), and DMAP (43 mg, 0.35 mmol) in DCM (10 mL) was stirred at RT overnight. The reaction mixture was then concentrated in vacuo and purified by Si0 2 chromatography eluting with PE/EtOAc (1:3) to afford tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-l- carboxylate as a white solid (400 mg, 30%).
  • step 3 A mixture of tert-butyl 4-(2-(tosyloxy)ethyl)piperidine- 1-carboxylate (400 mg, 1.04 mmol), sodium periodate (667 mg, 3.12 mmol), and ruthenium(IV) oxide (13 mg, 0.10 mmol) in EtOAc (10 mL) and water (10 mL) was stirred at RT overnight.
  • step 2 LiAlH 4 (900 mg, 24.3 mmol) was added slowly to o a 0 °C solution of tert-butyl 3-(2-ethoxy-2- oxoethoxy) pyrrolidine- 1-carboxylate (6.6 g, 24.1 mmol) under N 2 in anhydrous THF (150 mL). The reaction mixture was stirred for 40 min and then quenched with water (15 mL) and 10% sodium hydroxide (6.8 mL).
  • step 3 TEA (4.62 mL) and TsCl (3.78 g, 19.7 mmol) were added to solution of tert-butyl 3-(2- hydroxyethoxy)pyrrolidine- 1-carboxylate (3.92 g, 16.9 mmol) in DCM (6 mL) and THF (24 mL) cooled to 0 °C. The reaction mixture was stirred at RT overnight, then DMAP (1.08 g) was added and the reaction stirred for 2 h followed by quenching with saturated aqueous NaHC0 3 solution (12 ml).
  • teri-Butyl 3-(2-(tosyloxy)ethoxy)azetidine-l -carboxylate step 1 Tetrabutylammonium bromide (148 mg, 0.46 mmol) was added to a solution of teri-butyl 3- hydroxyazetidine-1 -carboxylate (4 g, 23 mmol) in TEA (2.467 g, 24 mmol). The reaction mixture was stirred for 5 h, and then 1, 3-dioxolan-2-one (2.228 g, 25 mmol) was added, and the mixture was heated at 100 °C for 2.5 days.
  • step 2 A mixture of tert-butyl 3-(2-hydroxyethoxy)azetidine-l -carboxylate (2.630 g, 12.1 mmol), tosyl chloride (2.768 g, 14.5 mmol), TEA (3.5 mL, 24.2 mmol), DMAP (370 mg, 3.025 mmol) in DCM (36 mL) and THF (9 mL) was stirred at 40 °C overnight. The reaction mixture was then concentrated, diluted with DCM (50 mL) and washed with an aqueous HC1 (0.5 M, 40 mL).
  • aqueous layer was then extracted with DCM (2 x 30 mL) and the combined organic layers washed with a NaHC0 3 solution (50 mL), brine (50 mL), dried (MgS0 4 ), filtered, and concentrated.
  • the residue was purified by Si0 2 chromatography, eluting with a gradient of EA/mixture of PE/DCM (1/1) (3% to 6% gradient) to give tert-butyl 3-(2-(tosyloxy)ethoxy)azetidine-l-carboxylate (2.36 g, 52%) as a yellow oil.
  • LCMS (ESI): m/z 316.0 [M-55] + .
  • step 1 To a solution of 2-morpholin-2-ylethanol (1.0 g, 7.62 mmol) and TEA (1.0 g, 9.9108 mmol) in anhydrous DCM (15 mL) at 0°C was added dropwise benzyl chloroformate (1.3 g, 7.62 mmol). The reaction mixture was slowly warmed to RT, stirred for 20 h, and diluted with EtOAc. The organic layer was washed with brine, dried (Na 2 S0 4 ), filtered, and concentrated under reduced pressure.
  • step 2 To a solution of benzyl 2-(2-hydroxyethyl)morpholine-4-carboxylate (1.71 g, 6.45 mmol) in anhydrous DCM (17 mL) at 0°C was added TEA (988 mg, 9.67 mmol). After 5 min. methanesulfonyl chloride (886 mg, 7.73 mmol) was added, and the resultant heterogeneous reaction mixture was stirred at RT under N 2 for 3 h. The reaction mixture was diluted with EtOAc.
  • H 2 N(H 2 C) 2 -N ⁇ ⁇ N-Boc step 1 To a mixture of NaH (430 mg, 1.8 mmol) in DMF (5 mL) was added teri-butyl 3 -oxopiperazine- 1- carboxylate (3.0 g, 1.5 mmol) and 2-bromoacetonitrile (1.8 g, 1.5 mmol) at 0 °C. The mixture was stirred at RT overnight. The reaction mixture was then diluted with EtOAc (10 mL) and H 2 0 (10 mL). The separated organic layer was washed with brine, dried (MgS0 4 ), filtered and concentrated in vacuo.
  • step 1 To a stirring solution of tert-butyl 3-hydroxyazetidine-l -carboxylate (4.00 g, 23.09 mmol) in dry DMF (20 mL) was added NaH (1.11 g, 46.18 mmol, 60 % in mineral) in portions at 0 °C. After the suspension was stirred at 0 °C for 30 min, ethyl 2-bromopropanoate (8.36 g, 46.18 mmol) was added. The resulting mixture was stirred at RT under N 2 overnight. The reaction was quenched by addition of saturated aqueous NH 4 C1 solution (40 mL) and extracted with EtOAc (50 mLx3).
  • step 1 To a solution of teri-butyl3-hydroxyazetidine (2.5 g, 14.5 mmol) in DMF (100 mL) was added NaH (1.45 g, 36.3 mmol) at 0 °C and stirred for 30 min. After addition of 4-methyl-l,3-dioxolane-2-one (3 g, 29 mmol) the reaction was stirred at 120 °C overnight. The reaction mixture was cooled to RT and quenched by adding a saturated aqueous NH 4 HC0 3 solution (5 mL).
  • step 1 A mixture of 3-aminocyclobutanol hydrochloride (1.91 g, 15.47 mmol), isobenzofuran-l,3-dione (2.52 g, 17.01 mmol) and DIPEA (6.0 g, 46.40 mmol) in PhMe (100 mL) was stirred at 110 °C for 18 h. The reaction mixture was concentrated and purified by Si0 2 chromatography eluting with PE/EA (3: 1) to afford 2-(3-hydroxycyclobutyl)isoindoline-l,3-dione as white solid (2.1 g, 62.6 ).
  • step 2 Manganese (IV) oxide (137.4 g, 1.58 mol) was added to a solution of (4-chloro-2- (methylthio)pyrimidin-5-yl)methanol (30.0 g, 0.158 mol) in DCM (1.5 L). The reaction was stirred overnight, filtered through CELITE, and the filtrate was concentrated in vacuo to give the crude product 4- chloro-2-(methylthio)pyrimidine-5-carbaldehyde as a white solid.
  • step 1 To a 2 L three -necked flask was added ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (100 g, 0.43 mol), THF (500 mL), and TEA (186 mL, 1.29 mol). Ammonium hydroxide (28% in water, 400 mL) was added by portions keeping the internal temperature below 30 °C. After 2 h, water (1000 mL) was added and THF was distilled off under vacuum. The resulting solid was filtrated and dried in vacuo at 50 °C to afford ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate (90 g, 99%).
  • step 2 To a 3 L three-necked flask was added LiAlH 4 (25.7 g, 0.68 mol) and THF (1 L), and the suspension was cooled to -10 to 0 °C.
  • step 3 To a 3 L three -necked flask was added (4-amino-2-(methylthio)pyrimidin-5-yl)methanol (100 g, 0.58 mol), activated Mn0 2 (152 g, 1.75 mol) and THF (2000 mL). The mixture was heated to 40-45 °C for 16 h.
  • step 1 Into a 20-L 3-necked round-bottom flask was placed THF (6 L) and NaH (325 g, 8.12 mol, 2.00 equiv, 60%). To this was added 2,6-dichloropyrazine (600 g, 4.03 mol, 1.00 equiv) in several batches while maintaining the temperature below 10°C, followed by the addition of 1,3-diethyl propanedioate (1386 g, 8.65 mol, 2.13 equiv) dropwise with stirring while maintaining the temperature below 10°C over 3 h. The resulting solution was heated to reflux overnight, cooled, quenched by the addition of water/ice and extracted with 2x3 L of EtOAc.
  • step 2 Into a 20-L 3-necked round-bottom flask was placed water (9 L), NaOH (900 g, 22.50 mol, 3.07 equiv) in portions, followed by the addition of 1,3-diethyl 2-(6-chloropyrazin-2-yl)propanedioate (2 kg, 1.00 equiv, crude) dropwise with stirring while maintaining the temperature below 10°C. The resulting solution was stirred overnight at RT and cooled to 0 °C. The pH value of the solution was adjusted to ca. 9-10 with HCI (37%) and the resulting solution was extracted with 3x2 L of EtOAc. The organic layers were combined, dried (Na 2 S0 4 ), filtered and concentrated in vacuo.
  • step 3 Into a 5-L sealed tube was placed 2-(6-chloropyrazin-2-yl)acetic acid (220 g, 1.27 mol, 1.00 equiv) and water (3 L). The resulting solution was stirred overnight at 130 °C, cooled and extracted with Et 2 0 2x3 L of ether. The organic layers were combined, dried (Na 2 S0 4 ), filtered and concentrated in vacuo to afford 238 g (73%) of 2-chloro-6-methylpyrazine as a yellow solid.
  • step 4 Into a 20-L 3-necked round-bottom flask was placed 4-bromo-2-chloroaniline (800 g, 3.87 mol, 1.00 equiv) and THF (10 L), followed by the dropwise addition of NaHMDS (3.9 L, 7.8 mol, 2.00 equiv, 2 mol/L) with stirring while maintaining the temperature below 10°C. The resulting solution was stirred at RT for 1 h. To this was added Boc 2 0 (1.012 kg, 4.64 mol, 1.20 equiv) dropwise with stirring while maintaining the temperature below 10°C. The resulting solution was stirred overnight at RT, quenched by the addition of 10 L of water/ice and extracted with EtOAc (3x5 L).
  • step 5 A 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with tert-butyl N-(4-bromo-2-chlorophenyl)carbamate (1.15 kg, 3.75 mol, 1.00 equiv), dioxane (3.5 L), KOAc (429 g, 4.37 mol, 1.17 equiv), 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (371 g, 1.46 mol, 0.39 equiv), and Pd(dppf)Cl 2 (18 g).
  • step 6 Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of tert-butyl N-[2-chloro-4-(tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl] carbamate, Na 2 C0 3 (2 N, 2.90 L), 2-chloro-6-methylpyrazine (236 g, 1.84 mol, 0.65 equiv; obtained in step 3), and Pd(PPh 3 ) 4 (20 g). The resulting solution was stirred overnight at 85°C and cooled. The solids were filtered out and the filtrate was diluted with 3 L of water.
  • step 7 A 10-L 4-necked round-bottom flask was charged with tert-butyl N-[2-chloro-4-(6-methylpyrazin- 2-yl)phenyl] carbamate (340 g, 1.06 mol, 1.00 equiv) and EtOAc (5 L). Hydrogen chloride (gas) was introduced in at 0 °C and the resulting solution was stirred at RT for 3-4 h. The resulting mixture was concentrated in vacuo, diluted with water (1 L) and extracted with EtOAc (3x1 L).
  • step 8 A 10-L 4-necked round-bottom flask was charged with 2-chloro-4-(6-methylpyrazin-2-yl)aniline (215 g, 978.74 mmol, 1.00 equiv), MeCN (1.43 L), HC1 (con., 501 mL), water (4.3 L), followed by the addition of a solution of NaN0 2 (80.9 g, 1.17 mol, 1.20 equiv) in water (500 mL) dropwise with stirring while maintaining the temperature at 0-5°C. The resulting solution was stirred at 0-5°C °C for 40 min.
  • step 9 A 3-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2-(3-chloro-4-iodophenyl)-6-methylpyrazine (110 g, 332.78 mmol, 1.00 equiv), tris(propan-2-yl)borate (125.3 g, 666.23 mmol, 2.00 equiv), THF (1.5 L).
  • n-BuLi 180 mL, 433 mmol, 1.30 equiv, 2.4 M was added dropwise with stirring at -78°C. The resulting solution was stirred at -78 °C for 30 min. This reaction was repeated for 2 more times.
  • step 1 To a solution of 4-bromo-2-methylbenzoic acidl (215.0 g, 1.0 mol) in THF (1 L) was added LiAlH 4 (76.0 g, 1.0 mol) portions at 0 °C. The reaction was stirred at this temperature for 1 h and then the reaction was quenched with 1 N HC1 (2.0 L). The mixture was extracted with EtOAc (2 x 1000 mL) and the organic layers were washed with brine (2 x 1000 mL) and dried over anhydrous (Na 2 S0 4 ), filtered and concentrated in vacuo.
  • LiAlH 4 76.0 g, 1.0 mol
  • step 2 To a solution of (4-bromo-2-methylphenyl)methanol (200.0 g, 1.0 mol) in DCM (500 mL) was added SOCl 2 (100 mL, 1.2 mol) dropwise at 0 °C.
  • step 3 To a solution of 4-bromo-l-(chloromethyl)-2-methylbenzene (200.0 g, 1.0 mol) in EtOH (500 mL) was added NaCN (72 g, 2.0 mol). The reaction mixture was heated to reflux and stirred at this temperature for 12 h. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was diluted with EtOAc (1 L) and washed with water (2 x 500 mL), sat. NaHC0 3 (1 L) and brine (1 L).
  • step 4 To a solution of 2-(4-bromo-2-methylphenyl)acetonitrile (200.0 g, 0.66 mol) in EtOH (500 mL) was added the aqueous KOH (10 M, 400 mL, 4 mol). The reaction was heated to reflux and stirred at this temperature for 2 h. The reaction mixture was cooled to RT and concentrated in vacuo.
  • step 5 To a solution of 2-(4-bromo-2-methylphenyl)acetic acid (150.0 g, 1 mol) in MeOH (500 mL) at 0 °C was added dropwise SOCl 2 (50 mL,1.2 mol).
  • step 6 A mixture of methyl 2-(4-bromo-2-methylphenyl)acetate (63.0 g, 259 mmol),
  • step 7 A solution of methyl 2-(2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetate (75.4 g, 259 mmol), Na 2 C0 3 (83.0 g, 780 mmol), Pd(dppf)Cl 2 (6.3 g, 7.7 mmol) and 2-bromo-6- methylpyridine (54.0 g, 312 mmol) in dioxane/H 2 0(4: 1 , 800 mL) under N 2 was heated and stirred at 100 °C for 18 h. The resulting mixture was diluted with H 2 0 (200 ml) and extracted with EtOAc (2 x 750 mL).
  • step 1 A 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with CC1 4 (5760 mL), 4-bromo-2-chloro-l-methylbenzene (800 g, 3.89 mol, 1.00 equiv), NBS (761.6 g, 4.28 mol, 1.10 equiv), and benzoyl peroxide (47.8 g, 186.54 mmol, 0.05 equiv). The resulting solution was stirred at 78°C for 5 h and filtered. The filtrate was washed with
  • step 2 Into a 20-L 4-necked round-bottom flask was placed water (4.5 L), DCM (4.5 L), 4-bromo-l- (bromomethyl)-2-chlorobenzene (1200 g, 4.22 mol, 1.00 equiv) and tetrabutyl ammonium bromide (126 g, 390.86 mmol, 0.10 equiv) followed by the addition of a solution of NaCN (292 g) in water (9 L) dropwise with stirring at RT. The resulting solution was stirred at RT for 15 h. The organic layers were washed with brine (1 x 500 mL), dried (Na 2 S0 4 ), filtered and concentrated in vacuo.
  • step 3 A 10-L 4-necked round-bottom flask was charged with MeOH (2950 mL) and 2-(4-bromo-2- chlorophenyl)acetonitrile (295 g, 1.28 mol, 1.00 equiv). Thionyl chloride (1500 mL) was added dropwise with stirring at 0 °C over 5 h. The resulting solution was stirred at RT overnight. This reaction was repeated.
  • step 4 A 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with dioxane (3.5 L), methyl 2-(4-bromo-2-chlorophenyl)acetate (310 g, 1.18 mol, 1.00 equiv), KOAC (347 g, 3.54 mol, 3.00 equiv), 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (299.4 g, 1.18 mol, 1.00 equiv), and Pd(dppf)Cl 2 (20 g).
  • step 5 A 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with the solution from Step 4, sodium carbonate (2N, 1178 mL), 2-bromo-6- methylpyridine (202 g, 1.17 mol, 1.00 equiv), and Pd(PPh 3 ) 4 (15 g, 12.98 mmol, 0.01 equiv). The resulting solution was stirred at 85 °C overnight. The reaction was repeated. The combined reaction mixtures were cooled to RT, filtered, and diluted with water (5 L). The resulting solution was extracted with EtOAc (3 x 5 L).
  • step 1 To a 3 L three -necked flask under nitrogen was added zinc dust (117 g, 1.79 mol) and THF (0.3 L). Chlorotrimethylsilane (10.4 mL) was added dropwise at a rate which maintained the internal temperature below 27 °C. The mixture was stirred at 25-27 °C for 30 min and then heated to 30 °C. A solution of ethyl bromoacetate (150 g, 0.90 mol) in THF (1.2 L) was slowly added dropwise to the reaction mixture (the internal temperature should maintained below 50 °C). After the addition was complete, the reaction mixture was allowed to cool back to 25-30 °C.
  • step 2 A 3 L three-necked flask under nitrogen was charged with 4-bromo-2-chloro-l-iodo-benzene (80 g, 0.25 mol), Pd(0)(dba) 2 (7.2 g, 0.0125 mol), Xantphos (7.2 g, 0.0125 mol) and THF (800 mL). The mixture was degassed and backfilled with nitrogen three times.
  • step 3 A 500 mL three-necked flask was charged with ethyl 2-(4-bromo-2-chlorophenyl)acetate (50 g, 0.18 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (62.5 g, 0.24 mol), potassium acetate
  • step 4 A 2 L three-necked flask was charged with ethyl 2-(2-chloro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)acetate (54 g, 0.17 mol), KOAc (33 g, 0.34 mol), Pd(dppf)Cl 2 (II DCM (10.4 g, 0.012 mol), 2-chloro-6 methylpyrazine (21.3 g, 0.17 mol) and 1 ,4-dioxane/water (2: 1, 750 mL). The mixture was degassed and backfilled with nitrogen three times then heated to 100 °C for 15 h.
  • step 1 A mixture of methyl 2-(4-bromo-2-chlorophenyl)acetate (13 g, 49.3 mmol), (PinB) 2 (16.3 g, 64.1 mmol), KOAc (9.7 g, 98.7 mmol) and Pd(dppf)Cl 2 (1.8 g, 2.47 mmol) was refluxed in dioxane (250 mL) under N 2 for 18 h. After cooling to RT, the mixture was partitioned between EtOAc (600 mL) and H 2 0. The organic layer was separated and dried (Na 2 S0 4 ), filtered and concentrated in vacuo.
  • step 2 To a solution of methyl 2-(2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetate (149 mg ,0.48 mmol), 2-bromo-l,l-diethoxy ethane (60 mg, 0.33 mmol), K 2 C0 3 (90 mg, 0.65 mmol) and Pd(dppf)Cl 2 (8 mg, 0.01 mmol) in dioxane (5 mL) was added water (1 mL). The mixture was stirred at 100 °C for 16 h under N 2 . After cooling to RT, EtOAc (150 mL) and H 2 0 were added.
  • step 1 A 100 mL three -necked flask was charged with 2-aminopropane-l,3-diol (5.0 g, 54.9 mmol, 1.0 eq.), phthalic anhydride (8.1 g, 54.9 mmol, 1.0 eq) and DMF (50 mL). The mixture was heated to 90 °C for 4 h, cooled to 20-25 °C then concentrated to dryness. The residue was taken up in EtOAc (50 mL), and, after filtration, the product was obtained as orange solid (11.2 g, 92%). !
  • step 1 A 1 L 3 -necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen was charged with a solution of tert-b tyl 3-iodoazetidine-l -carboxylate (29 g, 102.43 mmol, 1.00 equiv) in DMF (300 niL), ethyl 2-sulfanylacetate (17.2 g, 143.13 mmol, 1.40 equiv) and K 2 C0 3 (28.3 g, 204.76 mmol, 2.00 equiv).
  • step 2 A 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with a solution of tert-b tyl 3-[(2-ethoxy-2-oxoethyl)sulfanyl]azetidine-l- carboxylate (5.5 g, 19.97 mmol, 1.00 equiv) in DCM (100 mL) followed by the addition of MCPBA (8.63 g, 50.01 mmol, 2.50 equiv) in several batches at 0 °C. The resulting solution was stirred overnight at RT.
  • MCPBA 8.63 g, 50.01 mmol, 2.50 equiv
  • step 3 A 1 L 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of teri-butyl 3-[(2-ethoxy-2-oxoethane)sulfonyl]azetidine-l-carboxylate (20 g, 65.07 mmol, 1.00 equiv) in THF (400 mL), followed by the addition of LiBH 4 (7.2 g, 5.00 equiv) in several batches at 0 °C. The resulting solution was stirred overnight at RT, quenched by the addition of 200 mL of water/ice, diluted with EtOAc (300 mL) and extracted with EtOAc (2 x 200 mL).
  • T step 1 A mixture of piperidine-4-carbonitrile (1.1 g 10.0 mmol), di-tert-butyl dicarbonate (2.62 g, 12 mmol), and TEA (4.2 mL, 30 mmol) in DCM (15 mL) was stirred at RT overnight. HC1 (5% wt in water) was added until pH ⁇ 5 was reached. The aqueous phase was extracted with DCM. The organic layer was washed with brine, dried (Na 2 S0 4 ), filtered and concentrated in vacuo to afford tert-butyl 4- cyanopiperidine-l-carboxylate (2.0 g, 95.2%) as yellow oil, which was used in next step without further purification.
  • step 3 To a stirring mixture of l-tert-b ty ⁇ 4-ethyl 4-cyanopiperidine-l,4-dicarboxylate (1.3g crude, 4.61 mmol) in MeOH (15 mL) under a nitrogen atmosphere at 0°C was added NaBH 4 (350 mg, 9.22 mmol).
  • step 4 A mixture of tert-butyl 4-cyano-4-(hydroxymethyl)piperidine-l-carboxylate (300 mg 1.25 mmol), tosyl chloride (285 mg, 1.5 mmol), DMAP (16 mg, 0.13 mmol) and TEA (0.52 mL, 3.75 mmol) in DCM (5mL) was stirred at RT overnight. The mixture was concentrated in vacuo. The residue was purified by Si0 2 chromatography eluting with PE/EtOAc (6: 1) to afford tert-butyl 4-cyano-4-
  • teri-Butyl 3-cyano-3-(2-hydroxyethyl)pyrrolidine-l -carboxylate step 1 To a stirred solution of teri-butyl 3-cyanopyrrolidine-l-carboxylate (600 mg, 3.06 mmol) in THF (10 mL) was added lithium bis(trimethylsilyl)amide (1M in THF, 4.6mL, 4.6 mmol) dropwise under N 2 at -78 °C. 3-Bromoprop-l-ene (556 mg, 4.59 mmol) was added, and the mixture was stirred at -78 °C for 2 h. The mixture was warmed to RT and quenched with saturated aqueous NLLC1.
  • NaI0 4 (2.6g, 12.0 mmol) was added to a stirred solution of tert-butyl 3-allyl-3-cyanopyrrolidine-l- carboxylate (700 mg, 3.0 mmol) in a mixture of MeCN, CC1 4 and water (2: 2: 3, 40 mL respectively). The mixture was vigorously stirred for 5 min and RuCl 3 (25 mg, 0.12 mmol) was added. The mixture was stirred for a further 3 h and saturated aqueous NaHC0 3 was added until the pH was ca. 8. The aqueous solution was washed with DCM (3 x 20 ml).
  • teri-Butyl 2-(2-hydroxyethylsulfonyl)ethylcarbamate step 1 N-tert-Boc-ethanolamine (14 g, 87 mmol), TEA (27.3 mL, 195 mmol) and DCM (180 mL) were combined in a 500 mL round bottom flask and cooled in an ice bath. p-Toluenesulfonyl chloride (23.1 g, 122 mmol), dissolved in DCM (180 mL), was added and the ice bath removed. The mixture was stirred at RT overnight.
  • step 3 To a solution of teri-butyl 2-(2-hydroxyethylthio)ethylcarbamate (10.7 g, 48 mmol) in EtOH (150 mL) in a 500 mL RB flask was added 45 g of oxone in H 2 0 (150 mL). The ice bath was removed and stirring at RT continued for 2 h. The reaction mixture was diluted with H 2 0 (600 mL) and extracted with EtOAc (3x).
  • Benzyl 3-oxoazetidine-l-carboxylate (1.0 g, 4.7 mmol) and 2-(hydroxymethyl)propane-l,3-diol (650 mg, 1.05 equiv.) were dissolved in PhMe (32 mL) at RT.
  • p-Toluenesulfonic acid 183 mg, 0.2 equiv. was added and the reaction vessel was fitted with a Dean-Stark trap and condenser and stirred at 130 °C for 16 h.
  • the reaction mixture was cooled to RT and treated with sat. aqueous NaHC0 3 .
  • the solution was diluted with DCM, and the layers were separated.
  • the aqueous phase was extracted with DCM (2x), dried (Na 2 S0 4 ), filtered and concentrated in vacuo.
  • the crude product was absorbed onto CELITE and purified by Si0 2 chromatography eluting with a MeOH/DCM gradient (0 to 20% MeOH).
  • Benzyl 7-(hydroxymethyl)-5,9-dioxa-2-azaspiro[3.5]nonane-2-carboxylate was obtained after drying as a light yellow oil (937.2 mg, 68%).
  • step 2 To a solution of benzyl 7-(hydroxymethyl)-5,9-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (172 mg, 0.58 mmol) and DCM (1.6 mL) at 0 °C was added TEA (0.124 mL, 1.5 equiv.).
  • step 3 tert-butyl 3,3-difluoro-5-(hydroxymethyl)piperidine-l-carboxylate -
  • DCM dimethylethyl
  • NaBH 4 650 mg, 17.2 mmol
  • step 4 tert-butyl 3,3-difluoro-5-(tosyloxymethyl)piperidine-l-carboxylate -_To a solution of tert-butyl 3,3-difluoro-5-(hydroxymethyl)piperidine-l-carboxylate (1.2g ,4.78mmol) in DCM (10 mL) was added tosyl chloride (1.1 g, 5.73mmol), TEA (1.45 g ,14.3 mmol) and DMAP (58 mg, 0.478 mmol). The mixture was stirred at RT overnight and the solution was then concentrated in vacuo .
  • Step B To a solution of DMSO (177.2 g, 2.268 mol) in anhydrous DCM (800 ml), oxalyl chloride (196.9 g, 1.549 mol) in anhydrous DCM (800 mL) was slowly added at -45 °C. The reaction mixture was stirred for 20 min at -45 °C and then a solution of (9H-fluoren-9-yl)methyl (3-hydroxypropyl)carbamate (307 g, 1.032 mol) in anhydrous DCM (3.4 L) was added dropwise. After stirring for 30 min at -45 °C, DIPEA (399.8 g, 3.093 mol) was added dropwise.
  • step 1 To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (432 mg, 1.6 mmol) in DMF (7 mL) were added tert-butyl 3-(2-hydroxyethoxy)azetidine-l-carboxylate (0.750 g, 3.47 mmol), and PPh 3 (0.91 g, 3.47 mmol).
  • step 4 A mixture of crude tert-butyl 3-(2-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2- (methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethoxy)azetidine-l -carboxylate (350 mg, 0.53 mmol), DIPEA (0.2 mL) and ethylamine hydrochloride (215 mg, 2.6 mmol) in THF (10.0 mL) was stirred at RT under N 2 overnight. The reaction was quenched with H 2 0 followed by extraction with DCM (20 mLx3).
  • 6-(2-Chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-8-(2-(piperidin-3-yloxy)ethyl)pyrido[2,3- d]pyrimidin-7(8H)-one was analogously except tert-butyl 3-(2-hydroxyethoxy)piperidine-l-carboxylate replaced teri-butyl 3-(2-hydroxyethoxy)azetidine-l-carboxylate in step 1.
  • step 1 To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (3.00 g, 13.0 mmol) in dry THF (60 ml) under N 2 was added TEA (1.32 g, 13.04 mmol) and tert-butyl (lr,4r)-4- (aminomethyl)cyclohexylcarbamate (3.56 g, 15.65 mmol) at RT. The solution was stirred at RT overnight. Water (40 mL) was added and the solution was extracted with DCM (3x50 mL).
  • step 2 To a solution of 4-(((lr,4r)-4-(teri-butoxycarbonylamino)cyclohexyl)methylamino)-2- (methylthio)pyrimidine-5-carboxylate (2.1 g, 4.9 mmol) in THF (35 ml) was added portionwise LiAlH 4 (240 mg, 6.21 mmol) at -20 °C under N 2 . The mixture was then stirred at -20 °C for 2 h. The mixture was cooled to 0 °C and H 2 0 (0.5 ml) and 10% aqueous NaOH (0.5 ml) were added.
  • step 3 A mixture of teri-butyl (lr,4r)-4-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4- ylamino)methyl)cyclohexylcarbamate (1.2 g, 3.13 mmol), Mn0 2 (3.72 g, 42.5 mmol) in DCM (50 ml) was heated to reflux under N 2 overnight.
  • step 5 To a mixture of tert-butyl (lr,4r)-4-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)- 7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)cyclohexylcarbamate (57 mg, 0.09 mmol) in DCM (5.0 ml) under N 2 was added dropwise to a solution of MCPBA (80% , 22 mg, 0.10 mmol) in DCM ( 1.0 ml) at -10 °C. The mixture was stirred at RT overnight and the mixture quenched with saturated aqueous NaHC0 3 .
  • MCPBA 80% , 22 mg, 0.10 mmol
  • step 6 A mixture of crude teri-butyl (lr,4r)-4-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2- (methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)cyclohexylcarbamate (70 mg, 0.09 mmol), DIPEA (163 mg, 1.26 mmol) and ethanamine hydrochloride (40 mg, 0.5 mmol) in THF (5.0 mL) was stirred at RT under N 2 overnight. The mixture was quenched with H 2 0 and extracted with DCM (3x50 mL).
  • the title compound can be prepared in accord with Example 3by replacing methyl 2-(2-chloro-4-(6- methylpyrazin-2-yl)phenyl)acetate with methyl 2-(2-chloro-4-(6-methylpyridin-2-yl)phenyl)acetate in step 4. [M+l].
  • the title compound can be prepared prepared in accord with Example 3 by replacing methyl 2-(2-chloro- 4-(6-methylpyrazin-2-yl)phenyl)acetate with methyl 2-(2-chloro-4-(3-methylpyridin-2-yl)phenyl)acetate in step 4.
  • the title compound can be prepared in accord with Example 3 by replacing ethanamine hydrochloride with methanamine hydrochloride in step 6.
  • the title compound can be prepared in accord with Example 3 by replacing ethanamine hydrochloride with ammonium hydrochloride in step 6.
  • step 1 To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (435 mg, 1.6 mmol) in DMF (3 mL) was added tert-butyl 4-(hydroxymethyl)piperidine-l-carboxylate (750 mg, 3.5 mmol) and Ph 3 P (970 mg, 3.5 mmol) under a nitrogen atmosphere. The mixture was cooled to 0 °C and DIAD (710 mg, 3.5 mmol) was added drop wise while maintaining the temperature between 0-5 °C. The mixture was stirred at RT overnight. The reaction mixture was poured into ice water and extracted with EtOAc (3x100 mL).
  • step 2 A mixture of teri-butyl 4-((6-bromo-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)- yl)methyl)piperidine-l-carboxylate (239 mg, 0.5 mmol), MCPBA (80%, 275 mg, 1.2 mmol) in DCM (18 mL) was stirred at RT overnight. The reaction mixture was washed with saturated NaHC0 3 solution (2x50 mL) and saturated NaCl solution (2x50 mL).
  • step 3 A mixture of teri-butyl 4-((6-bromo-2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)- yl)methyl)piperidine-l-carboxylate (160 mg, 0.32 mmol), ethylamine hydrochloride (259 mg, 3.2mmol), DIPEA (1.5 mL) in IPA (4 mL) was heated at 90 °C in a sealed tube with stirring overnight.
  • step 4 tert-Butyl 4-((6-bromo-2-(ethylaniino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)piperidine- 1-carboxylate (100 mg, 0.021 mmol) was dissolved in a mixture of ethylene glycol dimethyl ether (3 mL), ethanol (2 mL), toluene (0.3 mL) and water (0.6 mL).
  • step 5 TFA (10 mL) was slowly added into the solution of tert-butyl 4-((6-(2-chloro-4-(6-methylpyrazin- 2-yl)phenyl)-2-(ethylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)piperidine-l-carboxylate
  • step 1 A mixture of 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8H-pyrido[2,3- d]pyrimidin-7-one (450 mg, 1.14 mmol), Cs 2 C0 3 (1.11 g, 3.41 mmol), and teri-butyl N-(3- bromopropyl)carbamate (541.3 mg, 2.28 mmol) in anhydrous DMF (5370 mg, 73.5 mmol, 5.69 mL) was stirred at RT overnight. The solvents were then removed and the crude product used in the next step without further purification.
  • step 4 teri-Butyl N-[3-[6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-(ethylamino)-7-oxo-pyrido[2,3- d]pyrimidin-8-yl]propyl]carbamate (312 mg, 0.567 mmol) was taken up in a solution of MeOH (2 mL) and DCM (2 mL). An HCl solution (4. OM in dioxane, 1.42 mL) was added. The reaction mixture was stirred overnight at RT.
  • Example 11 The title compound was prepared in accord with Example 11 Example 11 except in step 1 , tert-butyl N- (3-bromopropyl)carbamate was replaced with tert-butyl 4-(2-methylsulfonyloxyethyl)piperazine-l- carboxylate.
  • step 1 A mixture of 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8H-pyrido[2,3- J]pyrimidin-7-one (300 mg), l-(2-chloroethyl)-4-methyl-piperazine hydrochloride (271.6 mg, 1.36 mmol), cesium carbonate (2.1 g, 6.44 mmol) in anhydrous DMF (9.5 mL) in a sealed tube was stirred at 120 °C for 20 h. Water (100 mL) was added to the cooled reaction mixture and the reaction mixture was extracted with EtOAc (150 mL X 3). The organic layers were washed with brine, dried over Na 2 S0 4 , filtered, and concentrated under reduced pressure. The crude residue was purified by Si0 2
  • step 2 To 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-8-[2-(4-methylpiperazin-l-yl)ethyl]-2- methylsulfanyl-pyrido[2,3-(i]pyrimidin-7-one (89 mg) in anhydrous DCM (5.5 mL) at 0°C was added MCPBA (42 mg, 0.19 mmol). The reaction mixture was stirred at 0 °C for lh, and additional MCPBA (21 mg, 0.095 mmol) was added. After stirring at RT for 0.5 h, the reaction mixture was quenched with saturated aqueous NaHC0 3 solution (10 mL).
  • step 3 A mixture of 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-8-[2-(4-methylpiperazin-l-yl)ethyl]-2- methylsulfinyl-pyrido[2,3-d]pyrimidin-7-one (90 mg), ethylamine (2.0 M) in THF (8.5 mL), and DCM (2.1 mL) in a seal vial was stirred at 50°C for 4 days. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified by preparative HPLC to give the title compound as a solid (6.0 mg, 6.9%). !
  • step 1 6-[2-Chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8-(2-piperazin-l- ylethyl)pyrido[2,3-J]pyrimidin-7-one was prepared using procedure analogous to that described in step 1- of Example 11 except in step 1, tert-bvAyl 4-(2-methylsulfonyloxyethyl)piperazine-l-carboxylate replaced tert-bvAyl N-(3-bromopropyl)carbamate. The crude product was used in the next step without further purification. MS (ESI) m/z: 508.2 [M+l] + .
  • step 2 To a stirred solution of 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8-(2- piperazin-l-ylethyl)pyrido[2,3-d]pyrimidin-7-one (97 mg, 0.19 mmol) in DCE (9.6 mL) was added glacial HOAc (13.8 mg, 0.23 mmol) followed by 3-oxetanone (21.3 mg, 0.29 mmol). After 15 minutes, sodium triacetoxyborohydride (101 mg, 0.48 mmol) was added, and the reaction mixture was stirred at RT under N 2 for 4h. The reaction was diluted with EtOAc.
  • step 1 A mixture of 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8H-pyrido[2,3- d]pyrimidin-7-one (491 mg, 1.24 mmol), cesium carbonate (492 mg, 1.51 mmol, 1.22 equiv.) and 2- (chloromethyl)oxirane (120 ⁇ , 1.53 mmol, 1.23 equiv.) in DMF (5.0 ml) was stirred at ambient temperature for 48 h.
  • step 2 A mixture of 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8-(oxiran-2- ylmethyl)pyrido[2,3-d]pyrimidin-7-one (151 mg, 0.334 mmol), sodium azide (44.2 mg, 0.680 mmol, 2.03 equiv.) and ammonium chloride (35.8 mg, 0.669 mmol, 2.00 equiv.) in DMF (5.0 ml) was heated to 50 °C for 22 h.
  • step 3 A suspension of 8-(3-azido-2-hydroxy-propyl)-6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2- methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (163 mg, 0.330 mmol) in THF (5.0 ml) was treated with MCPBA (105 mg, 0.467 mmol, 1.41 equiv.) at ambient temperature for 1 h.
  • MCPBA 105 mg, 0.467 mmol, 1.41 equiv.
  • step 4 A mixture (-1: 1) of 8-(3-azido-2-hydroxy-propyl)-6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2- methylsulfenyl-pyrido[2,3-d]pyrimidin-7-one and 8-(3-azido-2-hydroxy-propyl)-6-[2-chloro-4-(6- methylpyrazin-2-yl)phenyl]-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one (0.330 mmol) was suspended in a solution of ethylamine in THF (5.0 mL, 2.0 M, 10 mmol, 30 equiv.) at ambient temperature to give a pale yellow solution.
  • ethylamine in THF 5.0 mL, 2.0 M, 10 mmol, 30 equiv.
  • step 5 A mixture of 8-(3-azido-2-hydroxy-propyl)-6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2- (ethylamino)pyrido[2,3-d]pyrimidin-7-one (0.330 mmol), tris(2-carboxyethyl)phosphine hydrochloride (473 mg, 1.65 mmol, 5.00 equiv.), TEA (230 ⁇ ,, 1.65 mmol, 5.00 equiv.) and water (500 uL) in THF (10 mL) was stirred at RT for 3 days.
  • step 1 A solution of 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-(ethylamino)-8-[3-(ethylamino)-2-hydroxy- propyl] pyrido [2,3 -d] pyrimidin-7-one (86.7 mg, 0.192 mmol) in DCM (2.0 ml) was treated MCPBA (51.0 mg, 0.228 mmol, 1.19 equiv.) at ambient temperature for 1 h.
  • step 2 The crude mixture of 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfonyl-8-(oxiran-2- ylmethyl)pyrido[2,3-d]pyrimidin-7-one and 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl] -2- methylsulfenyl-8-(oxiran-2-ylmethyl)pyrido[2,3-d]pyrimidin-7-one (0.192 mmol) was suspended in a solution of ethylamine in THF (3.0 mL, 2.0 M, 6.0 mmol, 31 equiv.) at ambient temperature for 3 d, and then heated to 60 °C for 22 h.
  • step 1 A suspension of 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8H-pyrido[2,3- d]pyrimidin-7-one (173 mg, 0.438 mmol) and Cs 2 C0 3 (184 mg, 0.565 mmol, 1.29 equiv.) in DMF (5.0 ml) was treated with 2-chloro-l-morpholino-ethanone (84.1 mg, 0.514 mmol, 1.17 equiv.) at RT for 16 h.
  • step 2 A suspension of crude 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8-(2- morpholino-2-oxo-ethyl)pyrido[2,3-d]pyrimidin-7-one (0.438 mmol) and MCPBA (157.1 mg, 0.7010 mmol, 1.600 equiv.) in THF (10 ml) was stirred at RT for 18 h.
  • step 3 The residue from step 2 was treated with a solution of ethylamine in THF (5.0 ml, 2.0 M, 10 mmol, 23 equiv.) at RT for 2 h.
  • step 1 6-[2-Chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.19 g, 3.01 mmol), tert-bvAyl 3-methylsulfonyloxypyrrolidine-l-carboxylate (1.7 equiv., 5.11 mmol, 1360 mg) and cesium carbonate (2.5 equiv., 7.51 mmol, 2450 mg) were mixed in DMF (17.4 mL), and the reaction was stirred at 90 °C for 18 h. The mixture was diluted with EtOAc and 10% citric acid was added to adjust the pH to 9, and the layers were separated.
  • step 2 The mixture from step 1 was dissolved in DCM (15 mL) and HOAc (1.05 equiv., 2.429 mmol, 0.1392 mL). MCPBA (1.05 equiv., 2.429 mmol, 544.3 mg) was added in one portion at 0 °C, and the reaction was stirred at 0 °C for 1 h. The reaction mixture was evaporated, and the yellow gel was dissolved in a solution of ethylamine (2 mol/L) in THF (17.0 equiv., 39.32 mmol, 19.66 mL).
  • step 3 The mixture obtained in step 2 (450 mg, 0.8006 mmol) was mixed with HC1 (4 mol/L) in 1,4- dioxane (44.0 equiv., 35.23 mmol, 8.806 mL) and maintained at 25 °C for 4 h. The reaction mixture was diluted with EtOAc and NaHC0 3 (s, aq) to pH 9 and the layers separated. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with water and brine, dried (MgS0 4 ), filtered, and finally concentrated in vacuo.
  • step 4 Boc-Gly-OH (4.0 equiv., 0.8745 mmol, 153.2 mg) and HATU (4.0 equiv., 0.8745 mmol, 339.3 mg) were mixed in 1,4-dioxane (1.0 mL) at 25 °C for 20 min.
  • the white suspension was transferred into a solution of 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-N-ethyl-7-pyrrolidin-3-yloxy-pyrido[2,3- d]pyrimidin-2-amine and 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-(ethylamino)-8-pyrrolidin-3-yl- pyrido[2,3-d]pyrimidin-7-one (101 mg, 0.2186 mmol) in 1,4-dioxane (1.0 mL) and DIPEA (5.0 equiv., 1.093 mmol, 0.191 mL).
  • the reaction was kept at 25 °C for 4 h.
  • the crude was diluted with EtOAc and the pH was adjusted to ⁇ 9 by addition of 10% citric acid.
  • the layers were separated, and the aqueous layer was extracted by EtOAc.
  • the organic layers were combined, washed with water and brine, dried (MgS0 4 ), filtered, and finally concentrated in vacuo.
  • step 5 tert-Butyl N-[2-[3-[6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-(ethylamino)-7-oxo- pyrido[2,3-d]pyrimidin-8-yl]pyrrolidin-l-yl]-2-oxo-ethyl]carbamate (63 mg, 0.1018 mmol) was mixed with HQ (4 mol/L) in 1,4-dioxane (41 equiv., 4.172 mmol, 1.043 mL), and the reaction was maintained at 40 °C for 4 h.
  • teri-Butyl 6-(((methylene-(p-tolyl)sulfinyl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was prepared by reacting teri-butyl 6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate [CASRN 850808-43-4] and tosyl chloride using conventional procedures.
  • 6-(2 -ethyl -4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared by condensation of methyl 2-(2-ethyl-4-(6-methylpyrazin-2-yl)phenyl)acetate and 4-amino-2- (methylthio)pyrimidine-5-carbaldehyde (K 2 C0 3 , DMF, 85 °C).
  • the title compound was prepared by alkylation of 6-(2-ethyl-4-(6-methylpyrazin-2-yl)phenyl)-2- (methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one with tert butyl [2 ⁇ 2-bromoethoxy)ethyl] carbamate. Introduction of the methyl amine and deprotection were carried out using standard protocols to afford I- 129.
  • step 1 tert- utyl N-(3-oxopropyl)carbamate (9.2 g, 53 mmol) was dissolved in toluene (250 mL) and chloroform (820 mL) then Na 2 S0 4 decahydrate ( 12 g) and TsOH (1.4 g) were added followed by benzyl N-[2-hydroxy-l-(hydroxymethyl)ethyl]carbamate (9.2 g, 41 mmol). The mixture is stirred at RT overnight. The resulting mixture was neutralized with Na 2 C0 3 and partitioned between water and DCM.
  • step 2 The product from step 1 (11.73 g) was dissolved in 4M HCl in dioxane and stirred at RT for 1.5 h.
  • step 3 An oven-dried tube was charged with 4,5-Ws-(diphenylphosphino)9,9-dimethylxanthene (0.149 g,.0.258 mmol), Pd(OAc) 2 (28.9 mg, 0.129 mmol), benzyl N-[2-(2-aminoethyl)-l,3-dioxan-5- yl]carbamate hydrochloride (1.6 g 5.16 mmol), ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1 g, 4.3 mmol) and Cs 2 C0 3 (2.8 g), then dioxane is added and the mixture degassed with N 2 for ca.
  • step 4 A mixture of LiAlH 4 (1.05 eq LAH in 0.77M THF) in anhydrous THF (5.08 mL) cooled to 0 °C was treated dropwise with a solution of ethyl 4-[2-[5-(benzyloxycarbonylamino)-l,3-dioxan-2- yl]ethylamino]-2-methylsulfanyl-pyrimidine-5-carboxylate (1.76 g, 3.727 mmol) in anhydrous THF (8.39 mL). The reaction mixture was stirred for 15 min, and then 0.34 mL of water was added dropwise with caution. The mixture was stirred for 30 min.
  • step 6 A mixture of benzyl N-[2-[2-[(5-formyl-2-methylsulfanyl-pyrimidin-4-yl)amino]ethyl]-l,3- dioxan-5-yl]carbamate (1.492 g, 3.450 mmol) and methyl 2-[2-chloro-4-(6-methylpyrazin-2- yl)phenyl] acetate (1.2 g, 3.622 mmol), K 2 C0 3 (3eq) in DMF (120 mL) was heated on the oil bath at 110 oC for 4h.
  • 6-(2-Chloro-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrirnidin-7(8H)-one was alkylated with 2-chloro-l-(4-morpholinyl)-ethanone [CASRN 1440-61-5] (tert-BuOK, DMF). Standard protocols were used to introduce the ethylamine.
  • step 1 A suspension of 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8H-pyrido-[2,3-(i] pyrimidin-7-one (126 mg, 0.319 mmol) and Cs 2 C0 3 (111 mg, 0.341 mmol, 1.07 equiv.) in DMF (5.0 ml) was treated with 3-(2-chloroethyl)-oxazolidin-2-one (62.5 mg, 0.418 mmol, 1.31 equiv.) at RT for 16 h and then heated to 60 °C for a further 14 h. The mixture was allowed to cool, diluted with water and extracted twice with EtOAc.
  • step 2 A solution of crude 3-(2-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)-7- oxopyrido[2,3-i/]pyrimidin-8(7H)-yl)ethyl)oxazolidin-2-one (0.319 mmol) in DCM (10 ml) was treated with solid MCPBA (96.9 mg, 0.432 mmol, 1.35 equiv.) at RT for 1.5 h and concentrated in vacuo to afford a 1.4: 1 mixture of 3-(2-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylsulfinyl)-7- oxopyrido[2,3-i/]pyrimidin-8(7H)-yl)ethyl)oxazolidin-2-one and 3-(2-(6-(2-chloro-4-(6-methylpyrazin-2
  • step 3 The crude mixture of sulfoxide and sulfone obtained in step 2 was treated with a solution of MeNH 2 in THF (1.6 mL, 2.0 M, 10 equiv.) at RT for 2.5 h. The mixture was treated with saturated aqueous NaHC0 3 and water, and extracted into DCM to which MeOH was added. The organic phase was washed with brine, dried (Na 2 S0 4 ), filtered, and concentrated in vacuo to afford a yellow solid (161.8 mg, 103%).
  • step 4 Crude 3-(2-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylamino)-7-oxopyrido-[2,3- i/]pyrimidin-8(7H)-yl)ethyl)oxazolidin-2-one (84.5 mg) was suspended in MeOH (10 ml), treated with aqueous LiOH (1.6 mL, 1.0 M, 10 equiv.) and heated to reflux for 18 h.
  • step 1 A mixture of tert-b tyl 3-(6-(4-bromo-2-chlorophenyl)-2-(methylthio)-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)propylcarbamate (216 mg, 0.4 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(l,3,2- dioxaborolane) (305 mg, 1.2 mmol), Pd(dppf)Cl 2 (59 mg, 0.08 mmol) and KOAc (79 mg, 0.8 mmol) in dioxane (5 mL) was stirred at 80 °C under N 2 overnight.
  • step 2 A mixture of 4-(8-(3-(teri-butoxycarbonylamino)propyl)-2-(methylthio)-7-oxo-7,8-dihydro- pyrido[2,3-d]pyrimidin-6-yl)-3-chlorophenylboronic acid (688 mg, crude), 4-bromo-2-methylthiazole (254 mg, 1.4 mmol), Pd(PPh 3 ) 4 (71 mg, 0.061 mmol) and Na 2 C0 3 (0.5 M in water, 4 mL) in MeCN (4 mL) was stirred at 90 °C under N 2 overnight.
  • teri-Butyl 4-[(2-aminoethyl)sulfonyl]-l-piperazinecarboxylate [CASRN 917562-08-4] was condensed with 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde (TEA, THF, IPA H 2 0, 0 °C) to afford tert-butyl 4-(2-(5-formyl-2-(methylthio)pyrimidin-4-ylamino)ethylsulfonyl)piperazine-l -carboxylate which was cyclized with methyl 2-[2-chloro-4-(6-methylpyridin-2-yl)phenyl]acetate (K 2 C0 3 , DMF, 100 °C) to afford 6-(2-chloro-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)-8-(2-(piperazin-l - ylsulfonyl)
  • 6-(2-Chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2 -d]pyrimidin-7(8H)-one was alkylated with ethyl chloroacetete (Cs 2 C0 3 , DMF, RT 64 h). Introduction of the methyl amine was accomplished with standard protocols. After hydrolysis of the ester (LiOH, MeOH, reflux), the acid was condensed with tert-butyl (35)-3-amino-l-pyrrolidinecarboxylate [CASRN147081-44-5] (HATU, DIPEA, DMF, RT) and the Boc protecting group removed (TFA) to afford 1-142.
  • N-(2-aminoethyl)-2-[6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-(methylamino)-7-oxo-pyrido[2,3- d]pyrimidin-8-yl]acetamide (1-156) was prepared in analogy with 1-153 except teri-butyl N-(2- aminoethyl)carbamate [CASRN 57260-73-8).
  • 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-8-[2-(3-hydroxypyrrolidin-l-yl)-2-oxo-ethyl]-2- (methylamino)pyrido[2,3-d]pyrimidin-7-one (1-157) was prepared analogously 2-(6-(2-chloro-4-(6- methylpyrazin-2-yl)phenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)acetic acid was condensed with 3-hydroxypyrrolidine (HATU, DIPEA, DMF, RT, 45 min).
  • the title compound was prepared in accord with Example 38 except 6-(2-chloro-4-(6-methylpyrazin-2- yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one was alkylated with a «i -2-(2-(bromomethyl)- l,3-dioxan-5-yl)isoindoline-l,3-dione. Incorporation of the ethylaniine moiety was carried out using standard protocols. Deprotection of the phthalimide was accomplished in the last step (MeNH 2 , MeOH) to afford 1-144.
  • yl]methyl]pyrido[2,3-d]pyrimidin-7-one (1-178) was prepared using similar procedures except tert-b tyl (2r,5r)-2-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2 -d]pyrirnidin- 8(7H)-yl)methyl)-l,3-dioxan-5-ylcarbamate was N-methylated (NaH, Mel) and deprotected (TFA) prior to introduction of the methylamine on the pyrimidine ring which was accomplished using standard procedures.
  • 6-[2-Chloro-4-(6-methyl-2-pyridyl)phenyl]-8-(5 9-dioxa-2-azaspiro[3.5]nonan-7-ylmethyl)-2- (methylamino)pyrido[2,3-d]pyrimidin-7-one (1-180) was prepared by alkylation (Cs 2 C0 3 , DMF, 100 oC, 48 h) with benzyl 7-(methylsulfonyloxymethyl)-5,9-dioxa-2-azaspiro[3.5]nonane-2-carboxylate to afford benzyl 7-((6-(2-chloro-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrirnidin- 8(7H)-yl)methyl)-5,9-dioxa-2-azaspiro[3.5]nonane-2-car
  • 6-[2-Chloro-4-(6-methylpyrazin-2-yl)phenyl]-8-[[(2R)-morpholin-2-yl]methyl]-2-(oxetan-3- ylamino)pyrido[2,3-d]pyrimidin-7-one (1-146) was prepared analogously except the lactam nitrogen was alkylated (NaH, DMF, 85 °C) with teri-butyl (2R)-2-(p-tolylsulfonyloxymethyl)morpholine-4-carboxylate (CASRN 135065-71 -3) and an oxetan-3-ylamino substituent was introduced using standard protocols. The final step was removal of the Boc group (TFA).
  • 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-(methylamino)-8-[[(2S)-morpholin-2- yl]methyl]pyrido[2,3-d]pyrimidin-7-one (1-150) was prepared in accord with the procedure for 1-149 except methyl amine replaced oxetan-3 -amine.
  • 6-[2-Chloro-4-(6-methyl-2 yridyl)phenyl]-8-[[(2R)-mo holin-2-yl]methyl]-2-(oxetan-3- ylamino)pyrido[2,3-d]pyrimidin-7-one (1-159) was prepared in accord with the procedure for 1-147 except 6-(2-chloro-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)pyrido[2 -d]pyrirnidin-7(8H)-one replaced 6-(2-methyl-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)pyrido[2 -d]pyrirnidin-7(8H)-one.
  • 6-(2-methyl-4-(6-methylpyridin-2-yl)phenyl)-2-(methylamino)-8-[[(2S)-morpholin-2- yl]methyl]pyrido[2,3-d]pyrimidin-7(8H)-one (1-171) was prepared analogously from 6-(2-methyl-4-(6- methylpyridin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one using with tert-butyl (2S)-2- (p-tolylsulfonyloxymethyl)morpholine-4-carboxylate to alkylate the lactam (Cs 2 C0 3 , DMF).
  • 6-[2-methyl-4-(6-methyl-2-pyridyl)phenyl]-8-[[(2S)-morpholin-2-yl]methyl]-2-(oxetan-3- ylamino)pyrido[2,3-d]pyrimidin-7-one (1-187) was prepared in accord with the procedure used for 1-171 except 3-amino-oxetane replaced methylamine.
  • 6-[2-chloro-4-(6-methyl-2-pyridyl)phenyl]-2-(methylamino)-8-[[(25)-morpholin-2-yl]methyl]pyrido[2,3- d]pyrimidin-7-one (1-173) was prepared by alkylation (Cs 2 C0 3 , DMF) of 6-(2-chloro-4-(6-methylpyridin- 2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one with (S)-tert -butyl 2- (tosyloxymethyl)morpholine-4-carboxylate to afford (S)-tert-buty ⁇ 2-((6-(2-chloro-4-(6-methylpyridin-2- yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)morpholine-4-carboxy
  • 6-[2-chloro-4-(6-methyl-2-pyridyl)phenyl]-8-[[(2S)-morpholin-2-yl]methyl]-2-(oxetan-3- ylamino)pyrido[2,3-d]pyrimidin-7-one (1-188) was prepared in accord with the procedure used to prepare 1-173 except methylamine was replaced by 3-amino-oxetane.
  • 6-[2-chloro-4-(6-methyl-2-pyridyl)phenyl]-2-(methylamino)-8-[[(2S)-4-methylmorpholin-2- yl]methyl]pyrido[2,3-d]pyrimidin-7-one (1-183) was prepared by reductive methylation of 1-172 (HCHO, NaBH 4 ).
  • 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one was condensed with l-(4-methoxyphenyl)-N-methylmethanamine (DIPEA, THF, 50 °C, 18 h) to afford 6-(2- chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-((4-methoxybenzyl)(methyl)amino)pyrido[2,3-d]pyrimidin- 7(8H)-one.
  • DIPEA l-(4-methoxyphenyl)-N-methylmethanamine
  • 6-(2-Chloro-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyriniidin-7(8H)-one was alkylated with tert-butyl 3-[(2-hydroxyethane)sulfonyl]azetidine-l-carboxylate (DIAD, PPh 3 , DMF, RT). Introduction of the ethylamine and removal of the Boc group were accomplished by standard protocols.
  • 3-Amino-l-propanesulfonamide was condensed with 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde (TEA, THF, H 2 0, RT) to afford 3-(5-formyl-2-(methylthio)pyrimidin-4-ylamino)propane-l -sulfonamide which was cyclized with ethyl 2-(2-methyl-4-(6-methylpyridin-2-yl)phenyl)acetate (K 2 C0 3 , DMF) to afford 3-(6-(2-methyl-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin- 8(7H)-yl)propane-l -sulfonamide.
  • TEA 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde
  • TEA 4-chloro-2-(methylthi
  • 6-(2-chloro-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one was alkylated (Cs 2 C0 3 , DMF, 100 °C)with tert-b tyl 4-[(bromomethyl)sulfonyl]-l-piperazinecarboxylate (CASRN 1443979-93-8) to afford 6-(2-chloro-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)pyrido[2,3- d]pyrimidin-7(8H)-one.
  • 6-(2 -Methyl -4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one was alkylated with 3-bromo-propan-l-ol (Cs 2 C0 3 , DMF). Introduction of the 3-amino-oxetane was accomplished by standard protocols.
  • step 2 To a stirring mixture of teri-butyl 4-cyanopiperidine-l -carboxylate (1.0 g crude, 4.76 mmol) in THF (10 mL) at -78°C under a nitrogen atmosphere was added dropwise LHMDS (1M in THF, 7.14 mL, 7.14 mmol). The mixture was stirred at -78 °C for 1 h. Then ethyl carbonochloridate (771 mg, 7.14 mmol) was added, and the mixture was stirred at -78°C for another 1 h. The mixture was quenched with saturated aqueous NH 4 C1 and the aqueous phase extracted with EtOAc.
  • step 3 To a stirring mixture of l-tert-b ty ⁇ 4-ethyl 4-cyanopiperidine-l ,4-dicarboxylate (1.3g crude, 4.61 mmol) in MeOH (15 mL) was added NaBH 4 (350 mg, 9.22 mmol) under a nitrogen atmosphere at 0°C. The mixture was stirred at 0 °C for 1.5 h then quenched with HC1 (5% wt in water, 5 mL). The aqueous phase was extracted with EtOAc and the organic layer was dried (Na 2 S0 4 ), filtered and concentrated in vacuo.
  • step 4 A mixture of teri-butyl 4-cyano-4-(hydroxymethyl)piperidine-l-carboxylate (300 mg 1.25 mmol), tosyl chloride (285 mg, 1.5 mmol), DMAP (16 mg, 0.13 mmol) and TEA (0.52 mL, 3.75 mmol) in DCM (5mL) was stirred at RT overnight.
  • 6-(2-chloro-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one was alkylated with tert-b tyl 4-cyano-4-(tosyloxymethyl)piperidine-l-carboxylate (Cs 2 C0 3 , DMF, 60 °C).
  • 6-(4-bromo-2-chlorophenyl)-2-(methylthio)pyrido[2 -d]pyrimidin-7(8H)-one was alkylated with tert- butyl 4-(tosyloxymethyl)piperidine-l-carboxylate to afford tert-bvAyl 4-((6-(4-bromo-2-chlorophenyl)-2- (methylthio)-7-oxopyrido[2 -d]pyrirnidin-8(7H)-yl)methyl)piperidine- 1 -carboxylate.
  • 6-(2-chloro-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one was alkylated with (lR,5S,6r)-teri-butyl 6-(bromomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Cs 2 C0 3 ,DMF, 0 °C 18 h).
  • 6-[2-chloro-4-(2-cyclopropylthiazol-4-yl)phenyl]-2-(methylamino)-8-[[(2S)-morpholin-2- yl]methyl]pyrido[2,3-d]pyrimidin-7-one (1-184) was prepared in accord with the procedure used to prepare 1-179 except 4-bromo-2-cyclopropylthiazole replaced 4-bromo-2-methylthiazole.
  • 6-[2-chloro-4-(2-cyclopropylthiazol-4-yl)phenyl]-2-(methylamino)-8-[[(2R)-morpholin-2- yl]methyl]pyrido[2,3-d]pyrimidin-7-one (1-185) was prepared in accord with the procedure used to prepare 1-182 except 4-bromo-2-cyclopropylthiazole replaced 4-bromo-2-methylthiazole.
  • 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde was condensed with 4-aminotetrahydro-2H-thiopyran- 4-yl-l-oxide [CASRN 919513-33-0] (TEA, THF, IPA, H 2 0, 0 °C) to afford 2-(methylthio)-4-(tetrahydro- 2H-thiopyran-4-ylamino)pyrimidine-5-carbaldehyde-l -oxide and subsequently cyclized with 4-bromo-2- chlorphenylacetic acid to afford 6-(4-bromo-2-chlorophenyl)-2-(methylthio)-8-(tetrahydro-2H-thiopyran- 4-yl-l-oxide)pyrido[2,3-d]pyrimidin-7(8H)-one.

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Abstract

Composés représentés par la formule (I) dans laquelle R1, R2, R3, R4, R5, Ra, Rb, Rc, Rd, Re, n, r, s et t sont tels que définis dans la description. Lesdits composés sont des inhibiteurs de Pak1. La présente invention concerne également des compositions et des méthodes permettant de traiter le cancer et les troubles hyperprolifératifs.
PCT/EP2014/066000 2013-07-26 2014-07-25 Inhibiteurs pyrimidine-pyridinone de sérine/thréonine kinase Ceased WO2015011252A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017050714A1 (fr) 2015-09-22 2017-03-30 Glaxosmithkline Intellectual Property (No.2) Limited Dicarboxamide de pyridinone à utiliser comme inhibiteur de bromodomaine
US9828373B2 (en) 2014-07-26 2017-11-28 Sunshine Lake Pharma Co., Ltd. 2-amino-pyrido[2,3-D]pyrimidin-7(8H)-one derivatives as CDK inhibitors and uses thereof
CN107778242A (zh) * 2017-09-29 2018-03-09 南京药石科技股份有限公司 一种8‑烷氧羰基‑7‑氧代氮杂螺[5．5]十一烷‑n‑羧酸叔丁酯的合成方法
CN108373472A (zh) * 2018-04-25 2018-08-07 西南大学 一种含原卟啉的杀菌材料及其制备方法和应用
CN112142733A (zh) * 2020-10-16 2020-12-29 湖南师范大学 一种泛fgfr共价抑制剂prn1371的合成路线

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011044535A2 (fr) * 2009-10-09 2011-04-14 Afraxis, Inc. 8-ethyl-6-(aryl)pyrido[2,3-d]pyrimidin-7(8h)-ones pour le traitement de troubles de snc
WO2013067423A1 (fr) * 2011-11-04 2013-05-10 Afraxis, Inc. Inhibiteurs de pak pour le traitement de troubles de prolifération cellulaire

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011044535A2 (fr) * 2009-10-09 2011-04-14 Afraxis, Inc. 8-ethyl-6-(aryl)pyrido[2,3-d]pyrimidin-7(8h)-ones pour le traitement de troubles de snc
WO2013067423A1 (fr) * 2011-11-04 2013-05-10 Afraxis, Inc. Inhibiteurs de pak pour le traitement de troubles de prolifération cellulaire

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9828373B2 (en) 2014-07-26 2017-11-28 Sunshine Lake Pharma Co., Ltd. 2-amino-pyrido[2,3-D]pyrimidin-7(8H)-one derivatives as CDK inhibitors and uses thereof
WO2017050714A1 (fr) 2015-09-22 2017-03-30 Glaxosmithkline Intellectual Property (No.2) Limited Dicarboxamide de pyridinone à utiliser comme inhibiteur de bromodomaine
CN107778242A (zh) * 2017-09-29 2018-03-09 南京药石科技股份有限公司 一种8‑烷氧羰基‑7‑氧代氮杂螺[5．5]十一烷‑n‑羧酸叔丁酯的合成方法
CN107778242B (zh) * 2017-09-29 2020-05-05 南京药石科技股份有限公司 一种8-烷氧羰基-7-氧代氮杂螺[5.5]十一烷-n-羧酸叔丁酯的合成方法
CN108373472A (zh) * 2018-04-25 2018-08-07 西南大学 一种含原卟啉的杀菌材料及其制备方法和应用
CN108373472B (zh) * 2018-04-25 2021-03-16 西南大学 一种含原卟啉的杀菌材料及其制备方法和应用
CN112142733A (zh) * 2020-10-16 2020-12-29 湖南师范大学 一种泛fgfr共价抑制剂prn1371的合成路线

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