WO2015184222A1 - Inhibitors of hepatocyte growth factor [hgf] and macrophage stimulating protein [msp] maturation - Google Patents

Inhibitors of hepatocyte growth factor [hgf] and macrophage stimulating protein [msp] maturation Download PDF

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WO2015184222A1
WO2015184222A1 PCT/US2015/033112 US2015033112W WO2015184222A1 WO 2015184222 A1 WO2015184222 A1 WO 2015184222A1 US 2015033112 W US2015033112 W US 2015033112W WO 2015184222 A1 WO2015184222 A1 WO 2015184222A1
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alkyl
methyl
piperidin
benzimidamide
oxotetrahydropyrimidin
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PCT/US2015/033112
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French (fr)
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Robert A. Galemmo
Namita BANSAL
Lidija KLAMPFER
Phanindra VENUKADASULA
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Southern Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present disclosure is concerned with certain cyclic urea compounds that are capable of inhibiting certain serine proteases, and especially the serine proteases matriptase, hepsin and hepatocyte growth factor activator (HGFA) involved in the maturation of hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP).
  • Compounds of the present disclosure can be used to treat a number of disorders caused by or associated with abnormal matriptase, hepsin and HGFA protease activity by inhibiting the proteolytic cleavage of pro-HGF to mature HGF and pro-MSP to mature MSP caused by these enzymes.
  • Compounds of the present disclosure can be used to treat disorders including precancerous conditions and cancer including metastatic disease, prevention and reversion of cancer resistance, and the inhibition of cancer stem cells.
  • the compounds of this invention are applicable to the treatment of cancers of many tissue types including solid and liquid tumors.
  • the present disclosure is also concerned with certain novel precursors of the cyclic urea compounds.
  • Active HGF and MSP are produced from their inactive pro-forms by the proteolytic action of three enzymes, the Type II Transmembrane Serine Proteases [TTSP] (Szabo R, Bugge TH; Int. J. Biochem. Cell Bio. 40; 1297-1316 (2008); Bugge TH, Antalis TM, Wu Q; J. Biol. Chem. 284; 23177-23181 (2009)) matriptase and hepsin, expressed on the surface of metastatic tumor cells, and the trypsin-like serine protease HGFA secreted by tumor cells.
  • TTSP Type II Transmembrane Serine Proteases
  • TTSPs matriptase and hepsin, localized on the surface of the metastatic tumor cells initiate the metastatic cascade (Del Rosso M, Fibbi G, Pucci M, et al.; Multiple pathways of cell invasion are regulated by multiple families of serine proteases. Clin. Exp.
  • Inhibitors of matriptase and hepsin provide an effective check on tumor growth and invasion in in vivo pre-clinical models of prostate cancer.
  • Selective small molecule inhibitors of matriptase suppress tumor growth in an in vivo model of androgen independent prostate cancer (Galkin AV; Mullen L; Fox WD et al. CVS-3983, a Selective Matriptase Inhibitor, Suppresses the Growth of Androgen Independent Prostate Tumor Xenografts. Prostate 61; 228-235 (2004)) and antagonize growth and metastasis in a PC-3 orthotopic model of prostate cancer
  • a pegylated Kunitz domain inhibitor is claimed to block hepsin and impede invasive tumor growth in an Ln-CaP orthotopic prostate tumor model (Li W; Wang B-E; Moran P et al. Pegylated Kunitz Domain Inhibitor Suppresses Hepsin-Mediated Invasive Tumor Growth and Metastasis. Cancer Res 69; 8395-8402 (2009)). Corresponding data does not appear to exist for matriptase, hepsin or HGFA inhibitors in pre-clinical models of breast cancer metastasis.
  • HAI-1 and -2 small molecule protease inhibitors with HAI-like specificity for use in the treatment or prophylaxis of many cancers and associated disease states. This is possible because the active sites of the serine protease domains of HGFA, matriptase and hepsin are closely related: i) they are regulated by substrate-like binding inhibition by the same inhibitors HAI-1 and -2 (Kojima K; et al. Roles of functional and structural domains of hepatocyte growth factor activator inhibitor type 1 in the inhibition of Matriptase. Biol. Chem. 283; 2487 (2008); Kirchhofer D; et al.
  • Hepsin activates pro-hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor-IB [HAI-1B] and HAI-2.
  • HAI-1B hepatocyte growth factor activator inhibitor-IB
  • HGF is a multifunctional growth factor which is secreted as a single inactive polypeptide and active HGF is produced from the inactive pro-form by the proteolytic action of one of three enzymes, the type II transmembrane serine proteases, matriptase, hepsin, or HGF activator (HGFA) a serine protease homologous to coagulation factor Xlla, which are highly expressed by many tumor cell lines (Bugge TH, et al. Type II transmembrane serine proteases. The Journal of Biological Chemistry. 2009; 284:23177-81 ; Lee SL, et al.
  • HGF hepatocyte growth factor
  • MSP macrophage stimulating protein
  • macrophage stimulating protein pathway promotes metastasis in a mouse model for breast cancer and predicts poor prognosis in humans.
  • Over production of these growth factors results from the dysregulated proteolytic activity of three trypsin- like serine proteases, HGF activator [HGFA], matriptase and hepsin. Inhibitors of these proteases which will return the system to stasis.
  • ⁇ -catenin/Wnt is a prognostic marker of tumor cell aggressiveness, thus providing evidence for a /?ro-metastatic interaction between the microenvironment in bone and breast cancer tumor cells.
  • inhibition of cMet RTK with a combination of a cMet kinase inhibitor [ARQ197] and silencing cMet expression by shRNA is highly effective in inhibiting metastatic progression in a murine model of bone metastasis.
  • KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Research. 2006; 66:3992-5) More troubling, patients that initially respond to EGFR inhibitors invariably relapse, underscoring the limitations of single-agent targeted anti-cancer therapy.
  • Fibroblasts have been shown to inhibit the response of melanoma cell lines to targeted therapy and HGF was sufficient to rescue tumor cells from therapy-induced apoptosis (Straussman R, et al. Tumor micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012; 487:500-4).
  • HGF/Met signaling contributes to innate and acquired resistance to EGFR inhibitors in lung cancer (Nguyen KS, et al. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clinical lung cancer. 2009; 10:281-9; Karamouzis MV, et al. Targeting MET as a strategy to overcome crosstalk-related resistance to EGFR inhibitors. The Lancet Oncology. 2009; 10:709-17) and a bi-specific
  • EGFR/Met antibody has been shown to have potent antitumor activity (Castoldi R, et al. A novel bispecific EGFR/Met antibody blocks tumor-promoting phenotypic effects induced by resistance to EGFR inhibition and has potent antitumor activity. Oncogene. 2013; 32:5593-601). Likewise, genome-wide expression analysis established that a group of genes involved in the HGF -MET signaling pathway is upregulated in cetuximab (CET)-resistant colon cancer cells (Troiani T, et al.
  • CCT cetuximab
  • TGF-alpha As a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR-MET Interaction and Activation of MET Signaling in Colon Cancer Cells.
  • HGF is predominantly produced by mesenchymal cells, some tumor cells produce HGF constitutively, which in an autocrine manner stimulates Met expressed on epithelial cells.
  • therapy-induced DNA damage response can also induce Met and/or HGF expression in tumor cells, a prosurvival arm of the DDR that is likely to limit therapeutic efficacy.
  • An important underlying mechanism of therapeutic failure is the survival of cancer stem cells.
  • the intensity of Wnt signaling is a crucial determinant of sternness of colon cancer cells, and cells exhibiting the highest levels of Wnt signaling display characteristics of cancer stem cells.
  • Fibroblast-derived HGF elevates Wnt-independent activation of ⁇ -catenin signaling in colon cancer cells, further enriching cells with cancer stem cell characteristics (Vermeulen L, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.
  • HGF activator inhibitor 1 HGF activator inhibitor 1
  • Hepatocyte growth factor activator inhibitor type 1 is a suppressor of intestinal tumorigenesis. Cancer Research. 2013; 73:2659-70).
  • colorectal cancer tissue display enhanced activation of pro-HGF Kerataoka H, et al. Activation of hepatocyte growth factor/scatter factor in colorectal carcinoma. Cancer Research. 2000; 60:6148-59).
  • HGF has an established pro- metastatic and pro-angiogenic activity, and HGFA inhibitor type 1 (HAI-1), the endogenous inhibitor of HGF activation, has been shown to suppress intestinal tumorigenesis (Hoshiko S, et al).
  • Ron an RTK related to cMet
  • Ron has been linked to osteolytic bone metastasis.
  • Ron is expressed by osteoclasts and activation by MSP causes bone resorption.
  • the MSP/Ron pathway drives bone metastasis in an MSP+ version of the polyoma middle T [PyMT] model and activation of this pathway correlates with poor clinical prognosis in breast cancer.
  • Patent for cyclic tetra- inhibitors Leduc R. Methods of using macrocyclic inhibitors peptide hepsin inhibitors.
  • n 2 in the broadest claim.
  • Certain cyclic compounds have been discovered according to the present disclosure that inhibit all three of the proteases, matriptase, hepsin and HGFA, and therefore find utility in a number of oncological disorders.
  • Compounds of the present disclosure can be used to treat disorders including precancerous conditions and cancer including metastatic disease, prevention and reversion of cancer resistance, and the inhibition of cancer stem cells.
  • the compounds of this invention are applicable to the treatment of cancers of many tissue types including solid and liquid tumors.
  • R is selected from the group consisting of:
  • Each R 1 ring may be optionally substituted once with a member selected from the group consisting of halo, -0(Ci-C 3 alkyl), -NH 2 , -NH(Ci-C 3 alkyl) and -N(Ci-C 3 alkyl);
  • R 2 may be optionally substituted.
  • n 0, 1 or 2;
  • R 4 , R 4' are independently selected from the group consisting of -H, Ci to Ci 2 alkyl, C 3 -C 10 cycloalkyl, Ci to C 6 alkyl attached to C 3 -C 10 cycloalkyl, 5- or 6-member-heterocycloalkyl containing one or two -0-, -N(R 6 ), S, S(O), or S(0) 2 ; Ci to C 6 alkyl attached to
  • R 4 and R 4' may be taken together to form a ring; R 4 , R 4 may be optionally substituted with 1 to 3 of the following substituents: -halogen, -OH, -0(Ci-C 3 alkyl), -NH 2 , -NH(Ci-C 3 alkyl),
  • R 5 is selected from the group consisting of Ci-Ci 2 alkyl, C3-C 10 cycloalkyl, aryl;
  • 5- or 6-member- heterocycloalkyl containing one or two -0-, -N(R 6 ), S, S(0), or S(0) 2 ;
  • R 5 may be optionally substituted with 1 to 3 of the following substituents: -halogen, -OH,
  • R 6 is selected from the group consisting of -H, C -Cn alkyl, and C 3 -C 6 cycloalkyl; R 6 may be optionally substituted; and pharmaceutically acceptable salts thereof, prodrugs thereof, solvates thereof, isomers thereof, deuterated forms, isomers, radio-actively labeled forms and mixtures thereof.
  • the present disclosure is also concerned with pharmaceutical compositions comprising a compound or derivative disclosed herein and a pharmaceutically acceptable carrier.
  • Another aspect of the present disclosure relates to a method of treating a patient with a disease caused by or associated with abnormal matriptase, hepsin and hepatocyte growth factor activator (HGFA) protease activity, which comprises administering to the patient an effective treatment amount of at least one compound or derivative disclosed herein.
  • HGFA hepatocyte growth factor activator
  • a further aspect of the present disclosure is directed to a method of treating a
  • precancerous condition or cancer in a patient comprising administering to the patient an effective treatment amount of a compound disclosed herein.
  • a still further aspect of the present disclosure is concerned with a method of treating a patient to prevent or reverse resistance in said patient to cancer treatment which comprises administering to the patient an effective treatment amount of at least one compound or derivative disclosed herein.
  • the present disclosure is directed to a method of inhibiting cancer stem cells in a patient in need thereof which comprises administering to the patient an effective treatment amount of at least one compound or derivative disclosed herein.
  • Another aspect of the present disclosure is concerned with certain novel precursors of the cyclic urea compounds of the present disclosure.
  • Figure 1 shows the inhibition of cellular scattering by EXAMPLE 26.
  • Certain cyclic compounds have been discovered according to the present disclosure that inhibit all three of the proteases matriptase, hepsin and HGFA, and therefore find utility in a number of oncological disorders.
  • Compounds of the present disclosure can be used to treat disorders including precancerous conditions and cancer including metastatic disease, prevention and reversion of cancer resistance, and the inhibition of cancer stem cells.
  • the compounds of this invention are applicable to the treatment of cancers of many tissue types including solid and liquid tumors.
  • R 1 is selected from the roup consisting of:
  • Each R 1 ring may be optionally substituted once with a member selected from the group consisting of halo, such as F-, CI and Br, -0(Ci-C3 alkyl) such as -OCH 3 , -NH 2 ,
  • R 1 is selected from the group consisting of H-, Ci to C 5 alkyl, and
  • Y is -H or -F;
  • -CH CH(Ci-Ci 2 alkyl)heterocycloaryl, -CH 2 (Ci-Ci 2 alkyl)C 3 -Ci 0 cycloalkyl,
  • R 2 may be optionally substituted.
  • n 0, 1 or 2;
  • R 4 , R 4' are independently selected from the group consisting of -H, Ci to Ci 2 alkyl, C 3 -Cio cycloalkyl, Ci to C 6 alkyl attached to C 3 -Cio cycloalkyl, 5- or 6-member-heterocycloalkyl containing one or two -0-, -N(R 6 ), S, S(O), or S(0) 2 ; Ci to C 6 alkyl attached to
  • R 4 and R 4' may be taken together to form a ring; R 4 , R 4 may be optionally substituted with 1 to 3 of the following substituents: -halogen, -OH, -0(Ci-C 3 alkyl), -NH 2 , -NH(Ci-C 3 alkyl),
  • R 5 is selected from the group consisting of Ci-Ci 2 alkyl, C 3 -Cio cycloalkyl, aryl;
  • R 5 may be optionally substituted with 1 to 3 of the following substituents: -halogen, -OH,
  • N-piperidine, N-morpholine, N-piperazine, 4-methylpiperizin-l-yl, 4-ethylpiperizin-l-yl, -NHC( 0)Ci-C 3 alkyl, -N(Ci-C 3 alkyl, -C0 2 H, C0 2 (Ci-C 3 alkyl),
  • R 6 is selected from the group consisting of -H, C -Cn alkyl, and C 3 -C 6 cycloalkyl; R 6 may be optionally substituted; and pharmaceutically acceptable salts thereof, prodrugs thereof, solvates thereof, deuterated forms, isomers, radio-actively labeled forms and mixtures thereof.
  • the heterocycloaryl rings can include one or two or three heteroatoms such as N, S or O and can be heteroaryl rings.
  • Examples of 5- and 6-membered N-heterocyclic groups are pyridyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrrolyl, pyrazolyl, pyrazinyl pyrimidinyl, pyridazinyl, imidazoyl, imidazolidinyl, 1,2,3-triazole, 1,2,4-triazole, indolyl and benzimidazolyl.
  • 9- and 10-membered N-heterocycloaryl rings are indole, benzimidazole, indazole, pyrazolo[l,5-a]pyridine, pyrazolo[l,5-a]pyrazine, 1,8-naphthyridine, quinoxaline,
  • pyrido[3,4-b]pyrazine cinnoline, quinoline, isoquinoline.
  • O-heterocyclic groups furanyl, pyranyl and benzofuranyl.
  • S-heterocyclic groups are thiopyranyl, thienyl and benzothiophene.
  • heterocycloalkyl groups containing both N and O are morpholinyl, oxazole, isooxazole and benzisoxazole.
  • heterocycloalkyl groups containing both N and S are thiomorpholine, thiazole, isothiazole and benzothiazole.
  • 5- or 6-member-heterocycloalkyl containing one or two -0-, -N(R 6 ), S, S(O), or S(0) 2 for R 4 , 4 ' are represented by the following formulae:
  • the 4- to 8-membered rings formed by NR 4 R 4 being taken together consist of the nitrogen atom to which R 4 and R 4 are bonded, carbon ring members and optionally an additional ring member selected from the group consisting of: O, S, SO, S0 2 , N, and N(Ci-C4-alkyl).
  • the rings may be unsaturated, partially saturated or aromatic. Examples of saturated rings include those enumerated for R 4 .
  • ring structures include pyridyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrrolyl, pyrazolyl, pyrazinyl pyrimidinyl, pyridazinyl, imidazoyl, imidazolidinyl, 1,2,3-triazole, 1,2,4-triazole, indolyl, benzimidazolyl, oxazole, isooxazole, benzisoxazole thiazole, isothiazole, benzothiazole and the partially hydrogenated or saturated counterparts thereof as well as thomorpholinyl.
  • R 4 ,R 4 are Ci to C 6 alkyl attached to a 5- or 6-member-heterocycloalkyl or Ci to C 6 alkyl attached to C 6 or Cio aryl or Ci to C 6 alkyl attached to C3-C 10 cycloalkyl or Ci to C 6 alkyl attached to a 5-, 6-, 9- or 10-member-heterocycloaryl describe systems wherein a straight or branched alkyl chain of 1 to 6 carbon atoms are attached as a linking group leading to the cycloalkyl, heterocycloalkyl or heterocycloaryl or aryl group specified.
  • the alkyl group typically contains 1-12 carbon atoms.
  • the alkyl group more typically contains 1-4 carbon atoms.
  • suitable alkyl groups include methyl, ethyl and propyl.
  • Examples of branched alkyl groups include isopropyl and t-butyl.
  • the alkyl group may optionally contain a double or triple bond
  • halogen groups are F, CI, Br and I.
  • Haloalkyl groups include any one of the foregoing alkyl groups in which one or more of the hydrogen atoms are replaced by a corresponding number of identical or different halogen.
  • Illustrative examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, bromomethyl, iodomethyl, chloro-difluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl,
  • C 3 -C 10 cycloalkyl rings are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, decahydronaphthalene and octahydro-lH-indene. These rings may be optionally substituted with double bonds.
  • substitutions can include at least one C 1 -C 3 alkyl group, halogen group, haloalkyl, hydroxyl, alkoxy group containing 1-12 carbon atoms and more typically 1-6 or 1-4 carbon atoms, amino group, aminoalkyl, a thiol or thioalkyl group.
  • the alkyl groups for the haloalkyl, aminoalkyl and thioalkyl groups are typically C 1 -C 3 .
  • “Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, solvates and combinations thereof.
  • the “combinations” mentioned in this context refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, and solvates.
  • the compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, and etc. groups as the prodrug forming moieties.
  • the hydroxymethyl position may form mono-, di- or triphosphates and again these phosphates can form prodrugs.
  • Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al, PCT WO 2000/041531, p. 30).
  • the nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.
  • “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • the compounds of this disclosure form acid addition salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this disclosure.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric acid, and the like.
  • Salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used.
  • Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate,
  • metaphosphate pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzene-sulfonate, /?-bromobenzenesulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, /?-toleunesulfonate, xylenesulfonate, tartarate, and the like.
  • the compounds of the present disclosure relate to all optical isomers and stereo-isomers at the various possible atoms of the molecule, unless specified otherwise.
  • Compounds may be separated or prepared as their pure enantiomers or diastereomers by crystallization, chromatography or synthesis.
  • the deuterated forms contain heavy hydrogen including deuterium.
  • the carbon labeled forms may contain carbon-13.
  • Examples of radio-actively labeled forms include compounds in which at least one of the following replacements has been made: i) one or more hydrogen are replaced by a corresponding number of tritium ( 3 H).
  • one or more carbon- 12 ( 12 C) are replaced by a corresponding number of carbon- 11, carbon-13 ( 13 C), and/or carbon-14 ( 14 C);
  • one or more hydrogen and/or fluorine- 19 ( 19 F) are replaced by a corresponding number of fluorine- 18 ( 18 F);
  • one or more acidic hydrogen and/or sodium-23 ( 23 Na) are replaced by a corresponding number of sodium-22 ( 22 Na);
  • one or more phosphorous-31 ( 31 P) are replaced by a corresponding number of phosphorous-32 ( 32 P); vi) one or more sulfur-32 ( 32 S) are replaced by a corresponding number of sulfur-35
  • Solvates refers to the compound formed by the interaction of a solvent and a solute and includes hydrates. Solvates are usually crystalline solid adducts containing solvent molecules within the crystal structure, in either stoichiometric or nonstoichiometric proportions.
  • precancerous condition refers to patients having a propensity for being afflicted with cancer.
  • Urea formation can be achieved by reaction of the commercially available 3- isocyanatobenzonitrile (I) with the primary amines (II) in a variety of solvents such as THF, toluene or DMF at temperatures ranging from ambient to the reflux temperature of the solvent selected.
  • the resulting urea III is alkylated using commercially available 3-chloro-2- (chloromethyl) prop-l-ene (IV).
  • This reaction is carried out with a strong base, such as sodium hydride, in a solvent, such as tetrahydrofuran (THF), 1,4-dioxane, dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO).
  • THF tetrahydrofuran
  • 1,4-dioxane dimethyl formamide
  • DMSO dimethyl sulfoxide
  • the base is added to the urea at low temperature (e.g. -10 to 0°C), when the evolution of H 2 gas subsides the dichloride IV is added.
  • the reaction is allowed to thaw to ambient temperature and can be heated to as high as 100°C to help drive the reaction to completion if necessary to give the cyclic urea V.
  • V can be derivatized in two ways to give intermediates that will be useful for the further functionalization to give various R 2 (Scheme 2).
  • the double bond of V can be treated with 9-borabicyclo[3.3.1]nonane (9-BBN) followed by cleavage of the intermediate boronate with peroxide to give the primary alcohol VIII; for references see: Loudon, Marc G. (2002). "Addition Reactions of Alkenes.” Organic Chemistry (Fourth Edition ed.). New York: Oxford University Press, pp. 168-172; J. V. B. Kanth, H. C. Brown, J. Org. Chem, 2001, 66, 5359-5365; J. M. Clay, E. Vedejs, J. Am. Chem. Soc, 2005, 127, 5766-5767; G. W. Kabalka, T. M. Shoup, N. M.
  • Intermediate ketone VI can be reduced to the alcohol VII with sodium borohydride in an alcohol solvent, such as MeOH or EtOH, at temperatures ranging from -10°C to ambient temperature.
  • alcohol solvent such as MeOH or EtOH
  • Other methods include: Schlesinger, H. I.; Brown, H. C; Abraham, B.; Bond, A. C; Davidson, N.; Finholt, A. E.; Gilbreath, J. R.; Hoekstra, FL; Horvitz, L.; Hyde, E. K.; Katz, J. J.; Knight, J.; Lad, R. A.; Mayfield, D. L.; Rapp, L.; Ritter, D. M.; Schwartz, A. M.; Sheft, I.; Tuck, L. D.; Walker, A. O.
  • Carboxylic acid X can be derived from V by oxidation with chromic acid.
  • Other methods include: Ruhoff, John R., “n-Heptanoic acid”, Org. Synth.; Coll. Vol. 2: 315; E. J. Eisenbraun (1973), "Cyclooctanone", Org. Synth.; Coll. Vol. 5: 310; Oxidation in Organic Chemistry. Edited by K. B. Wiberg, Academic Press, NY, 1965; Corey, E.J.; Schmidt, G. (1979). "Useful procedures for the oxidation of alcohols involving pyridinium dichromate in apoptotic media". Tetrahedron Lett. 20 (52): 399; Cornforth, R.H.; Cornforth, J.W.; Popjak, G. (1962).
  • alcohol intermediates VII and VIII can use similar synthetic procedures for further functionalization to various R 2 (Scheme 3).
  • carbonyl intermediates VI and IX can be derivatized by similar chemistries (Scheme 4).
  • Carboxylic acid intermediate X will require different methodolo (Scheme 5).
  • R' alkyl, allyl, phenyl, benzyl etc.
  • R alkyl, allyl, benzyl etc.
  • R alkyl, allyl, benzyl etc.
  • Alternative procedures involve two-step methods using a primary amine, such as allylamine, tritylamine or benzylamine, as a 'protected' source of ammonia, where the imine is formed then reduced with an agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxy borohydride in a solvent such as methanol, ethanol, dichloromethane, chloroform and the like.
  • an agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxy borohydride in a solvent such as methanol, ethanol, dichloromethane, chloroform and the like.
  • Transformation of the amines Vila and Villa to their amides Vllb and VHIb can be readily achieved by using any activated version of the appropriate acid, commonly an acid chloride, anhydride or mixed anhydride, a trialkylamine base to remove any acid that may be generated and a wide range of solvents, such as CH 2 CI 2 , CHCI 3 , THF or 1,4-dioxane or the like.
  • any activated version of the appropriate acid commonly an acid chloride, anhydride or mixed anhydride
  • a trialkylamine base to remove any acid that may be generated and a wide range of solvents, such as CH 2 CI 2 , CHCI 3 , THF or 1,4-dioxane or the like.
  • solvents such as CH 2 CI 2 , CHCI 3 , THF or 1,4-dioxane or the like.
  • many alternative amino acid coupling conditions will apply as well (for an extensive list of coupling agents that are suitable for the synthesis of amides see
  • One set of conditions useful for this reaction is a mixture of a carbonate base, such as sodium or potassium carbonate, and an alkyl ketone, such as acetone or butanone as solvent; a minor portion of DMF can be added for increasing solubility of the base.
  • a carbonate base such as sodium or potassium carbonate
  • an alkyl ketone such as acetone or butanone as solvent
  • a minor portion of DMF can be added for increasing solubility of the base.
  • These reactions are generally run at the reflux temperature of the solvent.
  • Alternative conditions include the use of a polar aprotic solvent, such as DMF, DMSO or acetonitrile with a strong base, such as sodium hydride at temperatures ranging from 0°C to the reflux temperature of the solvent.
  • Another method would include the use of phase transfer conditions.
  • the base is generated by using a concentrated portion of potassium or sodium hydroxide in water with a phase transfer catalyst such as 18-crown-6 or the tetra-n-butyl ammonium bromide or iodide. This reaction is usually run at reflux to effect this transformation, but the temperature of the reaction could be as low as ambient temperature.
  • Esters Vlld and VHId can be readily prepared from VII and VIII by the method shown in Scheme 3 or by using any appropriate activated version of the required carboxylic acid, such as the anhydride or mixed anhydride, with a trialkyl amine base in a solvent such as CH 2 CI 2 , CHCI 3 , THF or 1 ,4-dioxane or the like; temperatures for this reaction usually range from -10 °C to the reflux temperature of the solvent.
  • a solvent such as CH 2 CI 2 , CHCI 3 , THF or 1 ,4-dioxane or the like
  • temperatures for this reaction usually range from -10 °C to the reflux temperature of the solvent.
  • pyridine as both solvent and base.
  • temperatures for this reaction may range from -10°C to the reflux temperature of the solvent.
  • a solvent such as a CH 2 CI 2 , CHCI 3 , THF or 1,4-dioxane
  • Vila and Villa can be tranformed into their corresponding sulfonamides Vile and VHIe by reaction with CISO 2 -R' a trialkyl amine such as Et 3 N, N- methylmorpholine in a solvent such as a CH 2 CI 2 , CHCI 3 , THF, 1,4-dioxane or pyridine at temperatures ranging from -10°C to the reflux temperature of the solvent.
  • CISO 2 -R' a trialkyl amine such as Et 3 N, N- methylmorpholine
  • a solvent such as a CH 2 CI 2 , CHCI 3 , THF, 1,4-dioxane or pyridine at temperatures ranging from -10°C to the reflux temperature of the solvent.
  • solvents such as CH 2 CI 2 , CHCI 3 , THF, 1,4-dioxane, DMF, toluene and the like at temperatures ranging from -10°C to the reflux temperature of the solvent.
  • HC1 is generated it may be useful to add a
  • trialkylamine base such as Et 3 N, N-methyl morpholine or Hunig's Base.
  • R -H, alkyl, allyl, phenyl, benzyl, -C0 2 CH 3 etc.
  • R -H, alkyl, allyl, phenyl, benzyl etc.
  • amines Via and IXa (as well as Vila and Villa) can be transformed into their corresponding sulfonamides Vie and IXe as shown in Scheme 4 or by reaction with C1S0 2 -R' a trialkyl amine such as Et 3 N, N-methylmorpholine in a solvent such as a CH 2 C1 2 , CHCI 3 , THF, 1,4-dioxane or pyridine at temperatures ranging from -10°C to the reflux temperature of the solvent.
  • a solvent such as a CH 2 C1 2 , CHCI 3 , THF, 1,4-dioxane or pyridine at temperatures ranging from -10°C to the reflux temperature of the solvent.
  • solvents such as CH 2 C1 2 , CHC1 3 , THF, 1,4-dioxane, DMF, toluene and the like at temperatures ranging from -10°C to the reflux temperature of the solvent.
  • HCl a trialkylamine base
  • Et 3 N, N-methyl morpholine or Hunig's Base a trialkylamine base
  • Vic and IXc can be transformed to alkyl derivatives VId and IXd at R 2 .
  • the double bonds can be hydrogenated using palladium or platinum catalyst under an atmosphere of hydrogen gas at pressures ranging from 1 to 10 atmospheres of said gas in alcohol (such as methanol, ethanol, isopropanol and the like) or saturated hydrocarbon (such as petroleum ether, hexane, cyclohexane and the like) as solvent.
  • alcohol such as methanol, ethanol, isopropanol and the like
  • saturated hydrocarbon such as petroleum ether, hexane, cyclohexane and the like
  • R -H, alkyl, allyl, phenyl, benzyl amino acid esters etc.
  • the carboxylic acid X in Scheme 5 can be elaborated to the amide Xa by the method illustrated or by using any activated version of the acid X, commonly an acid chloride, anhydride or mixed anhydride, and reacting with the appropriate amine HN(R) 2 , a trialkylamine base to remove any acid that may be generated in a wide range of solvents, such as CH 2 C1 2 , CHCI 3 , THF or 1,4-dioxane or the like.
  • solvents such as CH 2 C1 2 , CHCI 3 , THF or 1,4-dioxane or the like.
  • many alternative amino acid coupling conditions will apply as well (for an extensive list of coupling agents that are suitable for the synthesis of amides see: http://www.peptidesynthesisreagents.com/).
  • amide couplings using amino acid coupling agents take place in the precedence of a trialkyl amine base (Et 3 N, N-methylmorpholine or Hunig's Base) in a solvent such as CHCI 3 , CH 2 CI 2 or DMF at temperatures ranging from 0°C to ambient temperature.
  • Esters are also available from carboxylic acid X; some references to useful methods are: A. Sakakura, K. Kawajiri, T. Ohkubo, Y. Kosugi, K. Ishihara, J. Am. Chem. Soc, 2007, 129, 14775-14779; G. Bartoli, M. Bosco, A. Carlone, R. Dalpozzo, E. Marcantoni, P.
  • the alcohols VII and VIII can be derivatized to the mesylate derivatives Vllf and VHIf (or any other sulfonate ester or halide desired, see discussion on Scheme 3).
  • the mesylate derivatives can be displaced to sulfides Vllg and Vlllg by a thiolate salt, most conveniently prepared by reaction of the corresponding thiol with NaH or NaOCH 3 or NaOC 2 Hs in an alcohol (methanol or ethanol and the like) or polar aprotic solvent (DMF, DMSO and the like).
  • the mixture of the thiolate and mesylate can be stirred in the selfsame solvents at ambient
  • a thiolate and mesylate mixture can be heated by microwave irradiation in a sealed reaction vessel and achieve reaction temperatures in excess of the reflux temperature of the solvent, if needed.
  • Oxidation of the sulfides Vllg and VHIg to the sulfones Vllh and VHIh or, in some cases the corresponding sulfoxides, can be effected by the method illustrated or meta-chloroperbenzoic acid at ambient temperature in a chlorocarbon solvent such as CH 2 C1 2 or CHC1 3 ; also a number of other oxidation methods are available (see: M. Kirihara, A. Itou, T. Noguchi, J. Yamamoto, Synlett, 2010, 1557-1561; R. S. Varma, K. P. Naicker, Org. Lett, 1999, 1, 189-191; K. Bahrami, M. M. Khodaei, M. S.
  • K. Bahrami M. M. Khodaei, M. Soheilizad, J. Org. Chem., 2009, 74, 9287- 9291.
  • Other methods to achieve this transformation include: K. Bahrami, M. M. Khodaei, M. Soheilizad, Synlett, 2009, 2773-2776; G. K. S. Prakash, T. Mathew, C. Panja, G. A. Olah, J. Org. Chem., 2007, 72, 5847-5850; A. Nishiguchi, K.
  • the Protecting Group used is assumed to be either the N-benzyl or N-t-butoxycarbonyl. While these groups are recommended, the practitioner is by no means limited to them.
  • One very convenient method for removal of the N-benzyl group, other than the standard hydrogenolysis conditions is a two-step method using a- chloroethylchloro-formate in a halocarbon solvent such as dichloroethane or chloroform and the like, first at 0°C then heated to the reflux temperature of the solvent.
  • the resulting a-chloroethyl-N-carbamate is heated at reflux in an alcohol solvent such as methanol or ethanol where upon XI is obtained (see Wuts & Greene for details).
  • an alcohol solvent such as methanol or ethanol
  • XI XI
  • the N-t-butoxycarbonyl group (-Boc) clean removal can be effected by 10 equivalents of trifiuoroacetic acid in a chlorocarbon solvent.
  • Intermediate XI can be alkylated to give XIa by one of two general approaches; standard N-alkylation with a halide or sulfonate ester or other active leaving group on a substrate appropriate to give the desired -R 3 or reductive alkylation using a carbonyl compound, most preferably an aldehyde but also in some cases a ketone.
  • Conditions for N-alkylation generally use a base (NaH, NaOH, Et 3 N, n-BuLi and the like), a primary or secondary halide (most preferentially an iodide or bromide) and solvent, such as an alcohol (MeOH or EtOH), THF, 1,4 dioxane, DMF, Hexamethylphosphoramide (HMTP), DMSO or a ketone (acetone or 2- butanone) at temperatures ranging from -78 °C to reflux temperature of the solvent.
  • solvent such as an alcohol (MeOH or EtOH), THF, 1,4 dioxane, DMF, Hexamethylphosphoramide (HMTP), DMSO or a ketone (acetone or 2- butanone) at temperatures ranging from -78 °C to reflux temperature of the solvent.
  • solvent such as an alcohol (MeOH or EtOH), THF, 1,4 dioxane, DMF, Hexamethylphosphoramide (HMTP), DMSO or
  • Reductive alkylation is a very useful method for forming a carbon to nitrogen bond; conditions used for this transformation include a mixture of an appropriate aldehyde or ketone to give the desired -R 3 with sodium cyanoborohydride or sodium triacetoxy borohydride in a variety of chlorocarbon solvents (CH 2 CI 2 or CHCI 3 ) or THF or 1 ,4-dioxane or an alcohol solvent (MeOH or EtOH) at 0°C up to the reflux temperature of the solvent,.
  • chlorocarbon solvents CH 2 CI 2 or CHCI 3
  • THF 1 ,4-dioxane
  • EtOH an alcohol solvent
  • amide couplings using amino acid coupling agents take place in the presence of a trialkyl amine base (Et 3 N (triethylamine), N- methylmorpholine or Hunig's Base) in a solvent such as CHCI 3 , CH 2 C1 2 or DMF at temperatures ranging from 0°C to ambient temperature.
  • a trialkyl amine base Et 3 N (triethylamine), N- methylmorpholine or Hunig's Base
  • a solvent such as CHCI 3 , CH 2 C1 2 or DMF
  • solvents such as CH 2 C1 2 , CHCI 3 , THF, 1,4-dioxane, DMF, toluene and the like at temperatures ranging from -10°C to the reflux temperature of the solvent.
  • HC1 it may be useful to add a trialkylamine base such as Et 3 N, N-methyl morpholine or Hunig's Base.
  • a solvent such as a CH 2 C1 2 , CHCI 3 , THF or 1,4-dioxane
  • amine XI can be transformed into the corresponding sulfonamides XIc as shown in Scheme 7 or by reaction with C1S0 2 -R' a trialkyl amine such as Et 3 N,
  • N-methylmorpholine in a solvent such as a CH 2 C1 2 , CHCI 3 , THF, 1,4-dioxane or pyridine at temperatures ranging from -10°C to the reflux temperature of the solvent.
  • the classical method of effecting this transformation is by formation of the imidate by using gaseous HC1 in a dry alcohol solution (MeOH, EtOH and the like) of XIa-c followed by removal of the solvent and stirring the resulting imidate salt with a solution of ammonia or ammonium acetate in a dry solvent such as an alcohol (MeOH, EtOH and the like), THF, 1,4-dioxane or a chlorocarbon (CHCI3 and the like).
  • a dry solvent such as an alcohol (MeOH, EtOH and the like), THF, 1,4-dioxane or a chlorocarbon (CHCI3 and the like).
  • isoquinoline analog XII can be readily prepared from the known
  • the oxime prepared above (180 mg) was dissolved in EtOH (30 ml) and shaken under an H2 atmosphere (38 psi) in the presence of Raney Nickel catalyst (170 mg) for 18 hours at ambient temperature. The reaction was purged with Ar then filtered through a Celite® pad and evaporated. The crude product was purified by column chromatography on silica gel on an Isco CombiFlash R f ® using a gradient of MeOH in CHC1 3 with 2% NH 4 OH as an additive; it was submitted as a trifluoroacetate salt following lyophilization.
  • EXAMPLE 3 was prepared by the same method used to prepare EXAMPLE 1 with l-(4- aminopiperidin-l-yl)ethanone substituted for l-benzylpiperidin-4-amine; HRMS: for
  • EXAMPLE 4 was prepared by the same procedure used for EXAMPLE 1 with 1- benzylpiperidin-4-amine replaced by l-(methylsulfonyl)piperidin-4-amine; HRMS:
  • EXAMPLE 5 was prepared by the same procedure used for EXAMPLE 1 with 1- benzylpiperidin-4-amine replaced by l-(phenylsulfonyl)piperidin-4-amine; HRMS:
  • EXAMPLE 12 was prepared from EXAMPLE 10: To a solution of tert-butyl (2-(4-(3-(3- carbamimidoylphenyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl)piperidin- 1 -yl)ethyl) carbamate (160 mg, 0.349 mmol) in dichloromethane (15 ml) was added 2,2,2-trifluoroacetic acid (0.323 ml, 4.19 mmol) . The solution was stirred for 3 hrs at room temperature.
  • EXAMPLE 18 was prepared by the method used for EXAMPLE 15 with
  • EXAMPLE 19 was prepared by the method used for EXAMPLE 15 with
  • EXAMPLE 20 was prepared by the method used for EXAMPLE 15 with
  • EXAMPLE 21 was prepared by the method used for EXAMPLE 15 with
  • EXAMPLE 22 was prepared by the method used for EXAMPLE 15 with
  • EXAMPLE 23 was prepared from INTERMEDIATE A by the same procedure used for EXAMPLE 14 with thiophene-2-sulfonyl chloride substituted for phenylmethanesulfonyl chloride.
  • the oxime prepared above (233 mg) was dissolved in EtOH (30 ml) and shaken under an H 2 atmosphere (38 psi) in the presence of Raney Nickel catalyst (250 mg) for 18 hours at ambient temperature.
  • the reaction was purged with Ar then filtered through a Celite® pad and evaporated.
  • the crude product was purified by column chromatography on silica gel on an Isco CombiFlash R f ® using a gradient of MeOH in CHC1 3 with 2% NH 4 OH as an additive; it was submitted as a trifluoroacetate salt following lyophilization.
  • EXAMPLE 27 was prepared from INTERMEDIATE C by the same two-step method used to prepare the amidine in EXAMPLE 26.
  • EXAMPLE 29 was prepared from INTERMEDIATE A by the same procedure used for EXAMPLE 14 with 1 -methyl- lH-pyrazole-4-sulfonyl chloride substituted for
  • EXAMPLE 35 is synthesized following similar synthetic sequence discussed in EXAMPLE 34 involving a four step synthetic route.
  • EXAMPLE 36 was prepared by the same method used for EXAMPLE 35 with benzyl bromide replaced by methyl iodide.
  • reaction mixture was transferred to a separatory funnel and the separated aqueous layer washed thrice with CH 2 C1 2 (10 ml).
  • CH 2 C1 2 10 ml
  • the combined organic layers were dried over MgS04 and concentrated under reduced pressure. After purification by column chromatography there was obtained the desired product as a gummy solid in quantitative yields (275 mg).
  • EXAMPLE 38 was prepared by the same method used to prepare EXAMPLE 37 with methanesulfonyl chloride replaced by phenylsulfonyl chloride.
  • EXAMPLE 39 was prepared by the same method used to prepare EXAMPLE 37 with methanesulfonyl chloride replaced by benzylsulfonyl chloride.
  • EXAMPLE 40 was prepared by the same method used to prepare EXAMPLE 37 with methanesulfonyl chloride replaced by acetic anhydride.
  • EXAMPLE 41 was prepared by the same method used to prepare EXAMPLE 37 with methanesulfonyl chloride replaced by benzoyl chloride.
  • EXAMPLE 42 was prepared by the same method used to prepare EXAMPLE 37 with methanesulfonyl chloride replaced by 2-phenylacetyl chloride.
  • EXAMPLE 43 was prepared by the same method used to prepare EXAMPLE 37 with methanesulfonyl chloride replaced by 3-phenylpropionyl chloride.
  • EXAMPLE 45 was prepared by the same procedure used for EXAMPLE 44 with phenethyl amine replaced by diethyl amine.
  • EXAMPLE 48 was prepared by the same procedure used for EXAMPLE 47 with methyl iodide replaced with benzyl bromide.
  • HRMS: for C 3 iH 37 N 5 0 2 calculated (M+2H) +2
  • Step 1 To tert-butyl 4-((3-(3-cyanophenyl)-5-hydroxy-2-oxotetrahydropyrimidin-l(2H)- yl)methyl)piperidine-l-carboxylate (1.93 g, 4.66 mmol) in CH 2 C1 2 (23.28 ml), TEA (1.947 ml, 13.97 mmol) followed by 4-dimethylaminopyiridine (DMAP) (0.057 g, 0.466 mmol) were added at 0°C.
  • DMAP 4-dimethylaminopyiridine
  • Step 2 To tert-butyl 4-((3-(3-cyanophenyl)-2-oxo-5-(tosyloxy)tetrahydropyrimidin- l(2H)-yl)methyl)piperidine-l-carboxylate (2.21 g, 3.89 mmol) in dimethyl formamide (DMF) (19.43 ml), sodium azide (3.03 g, 46.68 mmol) was added and the mixture was heated overnight at 60 °C. After this time the reaction was cooled to room temperature and the solvent was condensed under reduced pressure. The resulting material was taken up in CH 2 CI 2 (150 ml) and extracted with water (5x), then sat. NaHC0 3 and brine.
  • DMF dimethyl formamide
  • Step 3 To tert-butyl 4-((5-azido-3-(3-cyanophenyl)-2-oxotetrahydropyrimidin-l(2H)- yl)methyl)piperidine-l-carboxylate (550 mg, 1.251 mmol) in MeOH (2503 ⁇ ), 10% Pd-C (133 mg, 0.125 mmol) was added. This suspension was stirred under H 2 (gas) at atmospheric pressure for 1 h. After the reaction was complete, the flask was flushed with Ar gas, then was diluted with methanol and filtered through a Celite pad to remove the catalyst. Purification by column chromatography provided the desired product (517 mg) as a solid in quantitative yields.
  • EXAMPLE 50 was prepared by the same procedure used for EXAMPLE 49 with methanesulfonyl chloride replaced by phenylsulfonyl chloride.
  • EXAMPLE 51 was prepared by the same procedure used for EXAMPLE 49 with methanesulfonyl chloride replaced by benzylsulfonyl chloride.
  • EXAMPLE 52 was prepared by the same procedure used for EXAMPLE 49 with methanesulfonyl chloride replaced by acetyl chloride.
  • EXAMPLE 53 was prepared by the same procedure used for EXAMPLE 49 with methanesulfonyl chloride replaced by benzoyl chloride. HRMS: C31H36N6O2 calculated
  • EXAMPLE 54 was prepared by the same procedure used for EXAMPLE 49 with methanesulfonyl chloride replaced by phenylacetyl chloride. HRMS: C 32 H3 8 N 6 0 2 calculated
  • EXAMPLE 55 was prepared by the same procedure used for EXAMPLE 49 with methanesulfonyl chloride replaced by 3-(phenyl)propionyl chloride.
  • EXAMPLE 57 was prepared by the same method used to prepare EXAMPLE 56 with picolinaldehyde replaced by nicotinaldehyde.
  • EXAMPLE 58 was prepared by the same method used to prepare EXAMPLE 56 with picolinaldehyde replaced by isonicotinaldehyde.
  • BIOLOGICAL TESTING The compounds prepared above were tested for their ability to inhibit the proteases matriptase, hepsin and HGF activator (HGFA) according to the following assay conditions:
  • Assay Buffer 50 mM Tris, 20 mM NaCl, 0.01% (v/v) Tween® 20, pH 8.0

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Abstract

Provided are certain cyclic urea compounds that are capable of inhibiting certain serine proteases, and especially the serine proteases matriptase, hepsin and hepatocyte growth factor activator (HGFA) involved in the maturation of hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP), and novel precursors thereof. Compounds of the present disclosure can be used to treat a number of disorders caused by or associated with abnormal matriptase, hepsin and HGFA protease activity by inhibiting the proteolytic cleavage of pro-HGF to mature HGF and pro-MSP to mature MSP caused by these enzymes. Compounds of the present disclosure can be used to treat disorders including precancerous conditions and cancer including metastatic disease, prevention and reversion of cancer resistance, and the inhibition of cancer stem cells. The compounds of this invention are applicable to the treatment of cancers of many tissue types including solid and liquid tumors.

Description

INHIBITORS OF HEPATOCYTE GROWTH FACTOR [HGF] AND MACROPHAGE
STIMULATING PROTEIN [MSP] MATURATION
DESCRIPTION TECHNICAL FIELD
The present disclosure is concerned with certain cyclic urea compounds that are capable of inhibiting certain serine proteases, and especially the serine proteases matriptase, hepsin and hepatocyte growth factor activator (HGFA) involved in the maturation of hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP). Compounds of the present disclosure can be used to treat a number of disorders caused by or associated with abnormal matriptase, hepsin and HGFA protease activity by inhibiting the proteolytic cleavage of pro-HGF to mature HGF and pro-MSP to mature MSP caused by these enzymes. Compounds of the present disclosure can be used to treat disorders including precancerous conditions and cancer including metastatic disease, prevention and reversion of cancer resistance, and the inhibition of cancer stem cells. The compounds of this invention are applicable to the treatment of cancers of many tissue types including solid and liquid tumors. The present disclosure is also concerned with certain novel precursors of the cyclic urea compounds.
BACKGROUND OF THE DISCLOSURE
Active HGF and MSP are produced from their inactive pro-forms by the proteolytic action of three enzymes, the Type II Transmembrane Serine Proteases [TTSP] (Szabo R, Bugge TH; Int. J. Biochem. Cell Bio. 40; 1297-1316 (2008); Bugge TH, Antalis TM, Wu Q; J. Biol. Chem. 284; 23177-23181 (2009)) matriptase and hepsin, expressed on the surface of metastatic tumor cells, and the trypsin-like serine protease HGFA secreted by tumor cells. In normal tissue the proteolytic activity of these enzymes is held in check by the Kunitz-type inhibitors HAI-1 and -2 [HGFA inhibitor- 1 and -2] (Parr C; Sanders AJ; Jiang WG. Anti-Cancer Med. Chem. 10; 47-57 (2010); Parr C; Watkins G; Mansel RE; Jiang WG. Clin. Cancer Res. 10; 202-211 (2004)); dysregulation of inhibition by overexpression of HGFA (Kataoka H, Kawaguchi M; FEBS J. 277; 2230-2237 (2010); Ganesan R, Kolumam KA, Lin SJ, et al; Mol. Cancer Res. 9; 1175- 1186 (2011)), matriptase (Uhland K; Cell. Mol. Life Sci. 63; 2968-2978 (2006); Benaud CM; Oberst M; Dickson RB; Lin C-Y. Clin. Experiment. Metastasis 19; 639-649 (2002); Oberst M; Anders J; Xie B et al. Am. J. Pathol. 158; 1301-1311 (2001); Welman A; Sproul D; Mullen P et al. PLoS One 7; e34182 (2012)) and hepsin (Xing P; Li J-G; Jin F et al. J. Invest. Med. 59; 803- 810 (2011); Wu Q, Parry G; Frontiers Bioscience 12; 5052-5059 (2006)) or down-regulation of HAI correlate with high tumor grade.
Furthermore, TTSPs matriptase and hepsin, localized on the surface of the metastatic tumor cells initiate the metastatic cascade (Del Rosso M, Fibbi G, Pucci M, et al.; Multiple pathways of cell invasion are regulated by multiple families of serine proteases. Clin. Exp.
Metastasis 19; 193-207 (2002); Lee M-S; Matrix-degrading type II transmembrane serine protease Matriptase: its role in cancer development and malignancy. J. Cancer Mol. 2; 183-190 (2006)). Both activate /?ro-metastatic enzymes uPA and the MMPs, and degrade laminin in the ECM surrounding tumors. The current model for metastasis envisions extravasation to the circulation and invasion into the surrounding tissue requiring proteolytic degradation of the extracellular matrix and basement membrane. TTSPs have a central role in this proteolytic process.
Inhibitors of matriptase and hepsin provide an effective check on tumor growth and invasion in in vivo pre-clinical models of prostate cancer. Selective small molecule inhibitors of matriptase suppress tumor growth in an in vivo model of androgen independent prostate cancer (Galkin AV; Mullen L; Fox WD et al. CVS-3983, a Selective Matriptase Inhibitor, Suppresses the Growth of Androgen Independent Prostate Tumor Xenografts. Prostate 61; 228-235 (2004)) and antagonize growth and metastasis in a PC-3 orthotopic model of prostate cancer
(Steinmetzer T; Schweinitz A; Sturzebecher A et al. Secondary Amides of Sulfonylated 3- Amidinophenylalanine. New Potent and Selective Inhibitors of Matriptase. J. Med. Chem. 49; 4116-4126 (2006)). A pegylated Kunitz domain inhibitor is claimed to block hepsin and impede invasive tumor growth in an Ln-CaP orthotopic prostate tumor model (Li W; Wang B-E; Moran P et al. Pegylated Kunitz Domain Inhibitor Suppresses Hepsin-Mediated Invasive Tumor Growth and Metastasis. Cancer Res 69; 8395-8402 (2009)). Corresponding data does not appear to exist for matriptase, hepsin or HGFA inhibitors in pre-clinical models of breast cancer metastasis.
Disclosed are small molecule protease inhibitors with HAI-like specificity for use in the treatment or prophylaxis of many cancers and associated disease states. This is possible because the active sites of the serine protease domains of HGFA, matriptase and hepsin are closely related: i) they are regulated by substrate-like binding inhibition by the same inhibitors HAI-1 and -2 (Kojima K; et al. Roles of functional and structural domains of hepatocyte growth factor activator inhibitor type 1 in the inhibition of Matriptase. Biol. Chem. 283; 2487 (2008); Kirchhofer D; et al. Hepsin activates pro-hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor-IB [HAI-1B] and HAI-2. FEBS Lett. 579; 1945-1950 (2005)) ii) they share trypsin-like specificity and recognize the same KQLR-VVNG substrate sequence of pro-HGF (Lee S-L; et al. Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase an epithelial membrane serine protease. J. Biol. Chem. 47; 36720-36725 (2000)) and pro-MSF, and iii) the active sites share a high degree of sequence homology and 3-D architecture (Friedrich R; et al. Catalytic domain structures of MT-SPl/Matriptase, a matrix- degrading transmembrane serine proteinase. J. Biol. Chem. 277; 2160-2168 (2002); Somoza JR; et al. The structure of the extracellular region of human hepsin reveals a serine protease domain and a novel scavenger receptor cysteine -rich (SRCR) domain. Structure 1 1 ; 1 123-1 131 (2003); Eigenbrot C, et al. Hepatocyte growth factor activator (HGFA): molecular structure and interactions with HGFA inhibitor-1 (HAI-1). FEBS J. 277; 2215-2222 (2010)).
HGF is a multifunctional growth factor which is secreted as a single inactive polypeptide and active HGF is produced from the inactive pro-form by the proteolytic action of one of three enzymes, the type II transmembrane serine proteases, matriptase, hepsin, or HGF activator (HGFA) a serine protease homologous to coagulation factor Xlla, which are highly expressed by many tumor cell lines (Bugge TH, et al. Type II transmembrane serine proteases. The Journal of Biological Chemistry. 2009; 284:23177-81 ; Lee SL, et al. Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, an epithelial membrane serine protease. The Journal of Biological Chemistry. 2000; 275 :36720-5; Kirchhofer D, et al. Hepsin activates pro- hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor- IB (HAI-1B) and HAI-2. FEBS letters. 2005;579: 1945-50; Xuan JA, et al. Antibodies neutralizing hepsin protease activity do not impact cell growth but inhibit invasion of prostate and ovarian tumor cells in culture. Cancer Research. 2006; 66:361 1-9; Kataoka H, et al. Activation of hepatocyte growth factor/scatter factor in colorectal carcinoma. Cancer Research. 2000; 60:6148- 59; Tjin EP, et al. Multiple myeloma cells catalyze hepatocyte growth factor (HGF) activation by secreting the serine protease HGF-activator. Blood. 2004; 104:2172-5; Uhland K. Matriptase and its putative role in cancer. Cellular and molecular life sciences: CMLS. 2006; 63 :2968-78.). New evidence links the pathological overproduction of hepatocyte growth factor [HGF] (Previdi S; et al. Interaction between human breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and beta-catenin/Wnt pathways. Eur. J. Cancer 46; 1679- 1691 (2012); Previdi S; et al. Breast cancer-derived bone metastasis can be effectively reduced through specific cMet inhibitor Tivantinib [ARQ197] and shRNA cMet knockdown. Mil.
Cancer. Ther. 11; 214-223 (2012)) and macrophage stimulating protein [MSP] (Kretschmann, KL; et al. The macrophage stimulating protein/ Ron pathway as a potential therapeutic target to impede multiple mechanisms involved in breast cancer progression. Current Drug Targets 11; 1157-1168 (2010); Kurihara N; et al. Macrophage stimulating protein and its receptor, Ron, stimulate human osteoclast activity but not proliferation: effect of MSP distinct from that of hepatocyte growth factor.Exp. Hemotol. 26; 1080-1085 (1998); Welm AL; et al. The
macrophage stimulating protein pathway promotes metastasis in a mouse model for breast cancer and predicts poor prognosis in humans. Proc. Natl. Acad. Sci. USA 104; 7570-7575 (2007)) in the tumor microenvironment with the establishment of bone metastases in breast cancer. Over production of these growth factors results from the dysregulated proteolytic activity of three trypsin- like serine proteases, HGF activator [HGFA], matriptase and hepsin. Inhibitors of these proteases which will return the system to stasis.
Recent findings demonstrate that bone marrow cell derived HGF activates the cMet receptor tyrosine kinase [RTK] to trigger a c-Src/ -catenin-TCF/Wnt effector pathway.
Activation of β-catenin/Wnt is a prognostic marker of tumor cell aggressiveness, thus providing evidence for a /?ro-metastatic interaction between the microenvironment in bone and breast cancer tumor cells. In a follow-up study, inhibition of cMet RTK with a combination of a cMet kinase inhibitor [ARQ197] and silencing cMet expression by shRNA is highly effective in inhibiting metastatic progression in a murine model of bone metastasis.
Therapeutic resistance remains one of the biggest challenges in the treatment of cancer patients. This is particularly disappointing for the group of pre-selected patients that initially show a good response to targeted therapy, but ultimately develop resistance. Although WT KRas appears to confer sensitivity to inhibitors of EGFR, not all colon cancer patients with WT Ras (and WT BRAF, PIK3CA and PTEN) respond to these drugs (Lievre A, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. Journal of Clinical Oncology: official Journal of the American Society of Clinical Oncology. 2008; 26:374-9; Lievre A, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Research. 2006; 66:3992-5) More troubling, patients that initially respond to EGFR inhibitors invariably relapse, underscoring the limitations of single-agent targeted anti-cancer therapy.
The mechanisms of resistance to the anti EGFR drugs in colon cancer remain largely unknown. Recent studies have shown that resistance to anti-EGFR antibodies can develop due to selection of clones that harbor mutant kRas (Diaz LA, Jr., et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012; 486:537-40; Misale S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012; 486:532-6). In addition to the emergence of novel mutations, factors in the tumor microenvironment have been shown to play a major role in the development of acquired resistance. Fibroblasts have been shown to inhibit the response of melanoma cell lines to targeted therapy and HGF was sufficient to rescue tumor cells from therapy-induced apoptosis (Straussman R, et al. Tumor micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012; 487:500-4). HGF/Met signaling contributes to innate and acquired resistance to EGFR inhibitors in lung cancer (Nguyen KS, et al. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clinical lung cancer. 2009; 10:281-9; Karamouzis MV, et al. Targeting MET as a strategy to overcome crosstalk-related resistance to EGFR inhibitors. The Lancet Oncology. 2009; 10:709-17) and a bi-specific
EGFR/Met antibody has been shown to have potent antitumor activity (Castoldi R, et al. A novel bispecific EGFR/Met antibody blocks tumor-promoting phenotypic effects induced by resistance to EGFR inhibition and has potent antitumor activity. Oncogene. 2013; 32:5593-601). Likewise, genome-wide expression analysis established that a group of genes involved in the HGF -MET signaling pathway is upregulated in cetuximab (CET)-resistant colon cancer cells (Troiani T, et al. Increased TGF-alpha as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR-MET Interaction and Activation of MET Signaling in Colon Cancer Cells. Clinical Cancer Research: an official journal of the American Association for Cancer Research. 2013; 19:6751-65). While HGF is predominantly produced by mesenchymal cells, some tumor cells produce HGF constitutively, which in an autocrine manner stimulates Met expressed on epithelial cells. In addition, therapy-induced DNA damage response (DDR) can also induce Met and/or HGF expression in tumor cells, a prosurvival arm of the DDR that is likely to limit therapeutic efficacy. An important underlying mechanism of therapeutic failure is the survival of cancer stem cells. The intensity of Wnt signaling is a crucial determinant of sternness of colon cancer cells, and cells exhibiting the highest levels of Wnt signaling display characteristics of cancer stem cells. Fibroblast-derived HGF elevates Wnt-independent activation of β-catenin signaling in colon cancer cells, further enriching cells with cancer stem cell characteristics (Vermeulen L, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.
Nature Cell Biology. 2010; 12:468-76). Likewise, intestinal deletion of HGF activator inhibitor 1 (HAI-1), an endogenous inhibitor of HGF processing, augments Wnt signaling in Apc/Min/+ mice, both in tumor and normal mucosa, and enhances tumor formation (Hoshiko S, et al.
Hepatocyte growth factor activator inhibitor type 1 is a suppressor of intestinal tumorigenesis. Cancer Research. 2013; 73:2659-70). In accordance, colorectal cancer tissue display enhanced activation of pro-HGF (Kataoka H, et al. Activation of hepatocyte growth factor/scatter factor in colorectal carcinoma. Cancer Research. 2000; 60:6148-59). HGF has an established pro- metastatic and pro-angiogenic activity, and HGFA inhibitor type 1 (HAI-1), the endogenous inhibitor of HGF activation, has been shown to suppress intestinal tumorigenesis (Hoshiko S, et al).
Ron, an RTK related to cMet, has been linked to osteolytic bone metastasis. Ron is expressed by osteoclasts and activation by MSP causes bone resorption. The MSP/Ron pathway drives bone metastasis in an MSP+ version of the polyoma middle T [PyMT] model and activation of this pathway correlates with poor clinical prognosis in breast cancer.
This is in keeping with biology attributed to cMet and Ron. Activation of the cMet (de Bono JS; Yap TA. Future directions in the evaluation of cMet driven malignancies. Ther. Advan. Med. Oncol. 3; S51-S60 (2011); Peruzzi B, Bottaro DP; Targeting the c-Met signaling pathway in cancer. Clin. Cancer Res. 12; 3657- 3660 (2006)) and Ron (O'Toole JM, et al; Therapeutic Implications of a Human Neutralizing Antibody to the Macrophage-Stimulating Protein Receptor Tyrosine Kinase (RON), a c-MET Family Member. Cancer Res. 66; 9162-9170 (2006); Camp ER, et al.; Tyrosine kinase receptor RON in human pancreatic cancer: expression, function, and validation as a target. Cancer. 109; 1030-1039 (2007)) by their respective ligands HGF and MSP leads to an aggressive and invasive cell phenotype associated with metastatic cancers. Clinical studies show high levels of cMet (Eder JP, et al. Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer. Clin. Cancer Res. 15; 2207-2214 (2009)) and Ron receptor expression are associated with advanced tumor grade and poor patient prognosis in breast cancer. All of the effects noted above that are mediated by the receptor tyrosine kinases cMet and Ron can be ameliorated by inhibitors of the three serine proteases matriptase, hepsin and HGFA because these proteases give rise to mature HGF and MSP, the ligands that activate cMet and Ron, respectively. The compounds of this disclosure are designed to be inhibitors of all three enzymes and are highly effective in the treatment of disease states that result from the activation of the HGF/MET and MSP/RON pathways.
Others have recognized the importance of the enzymes that enable HGF and MSP production; however, no one has reported compounds that will inhibit all three proteases.
Several inhibitors have been reported and are shown in the table below:
Figure imgf000008_0001
Matriptase. Org Lett (2007) 9; 9-12.
Sisay MT; et al. Identification of the First Low-
Matriptase- 1 & -2
Molecular- Weight Inhibitors of Matriptase-2 J Med inhibitors
Figure imgf000009_0001
Chem (2010) 53; 5523-5535.
i) Steinmetzer T; et al. Secondary Amides of Sulfonylated 3-Amidinophenylalanine. New Potent and Selective Inhibitors of Matriptase. J Med Chem (2006) 49; 4116-4126.
ii) Schweinitz A; et al. Incorporation of neutral C- terminal residues in 3-amidinophenylalanine-
3 - Amidinopheny 1- derived matriptase inhibitors. Bioorg Med Chem alanines Lett (2009) 19; 1960-1965.
Target: matriptase
Figure imgf000009_0002
iii) Hammami M; et al. New 3- amidinophenylalanine-derived inhibitors of matriptase. Med Chem Comm (2012) 3; 807-813. iv) Steinmetzer T; et al. Modification of the N- terminal sulfonyl residue in 3- amidinophenylalanine-based matriptase inhibitors. Bioorg Med Chem Lett (2009) 19; 67-73.
RQAR-
0 Colombo E; et al. Design and Synthesis of Potent, peptidomimetic RQA-HNV /iL .N
Selective Inhibitors of Matriptase (2012) ACS Med inhibitors;
Chem Lett 3; 530-534.
Target: matriptase
Macrocyclic Marsault E; Leogane O; Mathieu A; Beaubien S;
Patent for cyclic tetra- inhibitors Leduc R. Methods of using macrocyclic inhibitors peptide hepsin inhibitors.
Target: hepsin of serine protease enzymes. WO 2011/050276 Al . Maduskuie, TP; et al. US 6 521,614 describe phenyl amidine cyclic ureas of the type:
Figure imgf000010_0001
where n = 2 in the broadest claim. These compounds are described only as anti-coagulants and inhibitors of factor Xa.
SUMMARY OF DISCLOSURE
Certain cyclic compounds have been discovered according to the present disclosure that inhibit all three of the proteases, matriptase, hepsin and HGFA, and therefore find utility in a number of oncological disorders. Compounds of the present disclosure can be used to treat disorders including precancerous conditions and cancer including metastatic disease, prevention and reversion of cancer resistance, and the inhibition of cancer stem cells. The compounds of this invention are applicable to the treatment of cancers of many tissue types including solid and liquid tumors.
The present disclosure is concerned with compounds represented by the formula I:
Figure imgf000010_0002
FORMULA 1
Where R is selected from the group consisting of:
Figure imgf000011_0001
Each R1 ring may be optionally substituted once with a member selected from the group consisting of halo, -0(Ci-C3 alkyl), -NH2, -NH(Ci-C3 alkyl) and -N(Ci-C3 alkyl);
R1 is selected from the group consisting of H-, Ci to C5 alkyl, and -C(=0)C1 to C5 alkyl; Y is -H or -F;
Where R2 is selected from the group consisting of C -Cn alkyl, =CH2, C6-Ci0 aryl, heterocycloaryl,
Figure imgf000011_0002
alkyl), =CH(Ci-Ci2 alkyl)C3-Ci0 cycloalkyl, =CH(Ci-Ci2)aryl, =CH(Ci-Ci2 alkyl)heterocycloalkyl, =CH(Ci-Ci2 alkyl)heterocycloaryl, -CH=CH(Ci-Ci2 alkyl), -CH=CH(Ci-Ci2 alkyl), -CH=CH(Ci-Ci2 alkyl)C3-Ci0 cycloalkyl, -CH=CH(Ci-Ci2 alkyl)aryl, -CH=CH(Ci-Ci2 alkyl)heterocycloalkyl, -CH=CH(Ci-Ci2 alkyl)heterocycloaryl,
-CH2(Ci-Ci2 alkyl)C3-Cio cycloalkyl, -CH2(C Ci2 alkyl)aryl,
-CH2(Ci-Ci2 alkyl)heterocycloalkyl, -CH2(Ci-Ci2 alkyl)heterocycloaryl, -CH(=0), =0, -O-R4, -CH2-0-R4, -C(=0)-0-R4, =CHC(=0)-0-R4, -CH2C(=0)-0-R4,-CH=CHC(=0)0-R4,
-CH2CH2C(=0)0-R4, -N(R4)R4', -CH2-N(R4)R4', -C(=0)-N(R4)R4', =CHC(=0)-N(R4)R4', -CH2C(=0)-N(R4)R4',-CH=CHC(=0)-N(R4)R4', -CH2CH2C(=0)-N(R4)R4', -S-R4, -CH2-S-R4, -S(0)-R4, -CH2-S(0)-R4, -S(0)2-R4, -CH2-S(0)2-R4, -S(0)NR4R4', -CH2-S(0) NR4R4 ,
-S(0)2 NR4R4 and -CH2-S(0)2 NR4R4 ; R2 may be optionally substituted.
Where R3 is selected from the group consisting of -H, -C(=0)NH2, and X-R5
X may be absent or is selected from the group consisting of -CH2-,-CH2CH2-, -CH(CH3)- , -C(CH3)2-, -CH2CH=CH-,-C(=0)-, -C(=0)CH=CH-, -C(=0)0-, -C(=0)NH2, -C(=0)NH-, -C(=0)N, -S-, -S(O)-, and -S(0)2-;
n = 0, 1 or 2;
R4, R4' are independently selected from the group consisting of -H, Ci to Ci2 alkyl, C3-C10 cycloalkyl, Ci to C6 alkyl attached to C3-C10 cycloalkyl, 5- or 6-member-heterocycloalkyl containing one or two -0-, -N(R6), S, S(O), or S(0)2; Ci to C6 alkyl attached to
a 5- or 6-member-heterocycloalkyl containing one or two -0-, -N(R6), S, S(0), or S(0)2; C6, C9 or Cio aryl, Ci to C6 alkyl attached to C6 or C10 aryl; 5-, 6-, 9- or 10-member-heterocycloaryl containing one, two or three -0-, -N, -N(R6), S; Ci to C6 alkyl attached to
a 5-, 6-, 9- or 10-member-heterocycloaryl containing one, two or three -0-, -N, -N(R6), S; R4 and R4' may be taken together to form a ring; R4, R4 may be optionally substituted with 1 to 3 of the following substituents: -halogen, -OH, -0(Ci-C3 alkyl), -NH2, -NH(Ci-C3 alkyl),
-N(Ci-C3 alkyl)Ci-C3 alkyl, N-pyrrolidine, N-piperidine, N-morpholine, N-piperizine,
4- methylpiperizin-l-yl, 4-ethylpiperizin-l-yl, -NHC(=0)Ci-C3 alkyl,
-N(Ci-C3 alkyl)C(=0)Ci-C3 alkyl, -C02H, C02(Ci-C3 alkyl), -CONH2-CONH(Ci-C3 alkyl), -CON(Ci-C3 alkyl)2, -OC02(Ci-C3 alkyl), -0C0NH(Ci-C3 alkyl), -OCON(Ci-C3 alkyl)2, -NHC02(Ci-C3 alkyl), -NHCONH(Ci-C3 alkyl), -NHCON(Ci-C3 alkyl)2, -SH, -S(Ci-C3 alkyl), -SO(Ci-C3 alkyl), -S02(d-C3 alkyl), -NHS02(d-C3 alkyl), -N(C C3 alkyl)S02(Ci-C3 alkyl), -S02NH2, -S02NH(Ci-C3 alkyl), -S02N(Ci-C3 and alkyl)2;
R5 is selected from the group consisting of Ci-Ci2 alkyl, C3-C10 cycloalkyl, aryl;
5- or 6-member- heterocycloalkyl containing one or two -0-, -N(R6), S, S(0), or S(0)2;
5-, 6, 9- or 10-member-heterocycloaryl containing one, two or three -0-, -N, -N(R6), S; R5 may be optionally substituted with 1 to 3 of the following substituents: -halogen, -OH,
-0(Ci-C3 alkyl), -NH2, -NH(Ci-C3 alkyl), -N(Ci-C3 alkyl)Ci-C3 alkyl, N-pyrrolidine,
N-piperidine, N-morpholine, N-piperazine, 4-methylpiperiazin-l-yl, 4-ethylpiperizin-l-yl, -NHC(=0)Ci-C3 alkyl, -N(Ci-C3 alkyl)C(=0)Ci-C3 alkyl, -C02H, C02(Ci-C3 alkyl),
-CONH2-CONH(Ci-C3 alkyl), -CON(C C3 alkyl)2, -OC02(d-C3 alkyl), -OCONH(C C3 alkyl), -OCON(Ci-C3 alkyl)2, -NHC02(Ci-C3 alkyl), -NHCONH(Ci-C3 alkyl), -NHCON(Ci-C3 alkyl)2, -SH, -S(Ci-C3 alkyl), -SO(Ci-C3 alkyl), -S02(Ci-C3 alkyl), -NHS02(Ci-C3 alkyl),
-N(Ci-C3 alkyl)S02(Ci-C3 alkyl), -S02NH2, -S02NH(Ci-C3 alkyl), and -S02N(Ci-C3 alkyl)2;
R6 is selected from the group consisting of -H, C -Cn alkyl, and C3-C6 cycloalkyl; R6 may be optionally substituted; and pharmaceutically acceptable salts thereof, prodrugs thereof, solvates thereof, isomers thereof, deuterated forms, isomers, radio-actively labeled forms and mixtures thereof.
The present disclosure is also concerned with pharmaceutical compositions comprising a compound or derivative disclosed herein and a pharmaceutically acceptable carrier. Another aspect of the present disclosure relates to a method of treating a patient with a disease caused by or associated with abnormal matriptase, hepsin and hepatocyte growth factor activator (HGFA) protease activity, which comprises administering to the patient an effective treatment amount of at least one compound or derivative disclosed herein.
A further aspect of the present disclosure is directed to a method of treating a
precancerous condition or cancer in a patient comprising administering to the patient an effective treatment amount of a compound disclosed herein.
A still further aspect of the present disclosure is concerned with a method of treating a patient to prevent or reverse resistance in said patient to cancer treatment which comprises administering to the patient an effective treatment amount of at least one compound or derivative disclosed herein.
Furthermore, the present disclosure is directed to a method of inhibiting cancer stem cells in a patient in need thereof which comprises administering to the patient an effective treatment amount of at least one compound or derivative disclosed herein.
Another aspect of the present disclosure is concerned with certain novel precursors of the cyclic urea compounds of the present disclosure.
Still other objects and advantages of the present disclosure will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described only the preferred embodiments, simply by way of illustration of the best mode. As will be realized, the disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the disclosure. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 shows the inhibition of cellular scattering by EXAMPLE 26.
BEST AND VARIOUS MODES FOR CARRYING OUT OUR DISCLOSURE Certain cyclic compounds have been discovered according to the present disclosure that inhibit all three of the proteases matriptase, hepsin and HGFA, and therefore find utility in a number of oncological disorders. Compounds of the present disclosure can be used to treat disorders including precancerous conditions and cancer including metastatic disease, prevention and reversion of cancer resistance, and the inhibition of cancer stem cells. The compounds of this invention are applicable to the treatment of cancers of many tissue types including solid and liquid tumors.
The present disclosure is concerned with compounds represented by the formula I:
Figure imgf000014_0001
FORMULA 1
Where R1 is selected from the roup consisting of:
Figure imgf000014_0002
Each R1 ring may be optionally substituted once with a member selected from the group consisting of halo, such as F-, CI and Br, -0(Ci-C3 alkyl) such as -OCH3, -NH2,
-NH(Ci-C3 alkyl) and -N(Ci-C3 alkyl);
R1 is selected from the group consisting of H-, Ci to C5 alkyl, and
-C(=0)Ci to C5 alkyl,
Y is -H or -F; Where R2 is selected from the group consisting of C1-C12 alkyl, =CH2, C6-Cio aryl, heterocycloaryl,
Figure imgf000015_0001
alkyl)C3-Ci0 cycloalkyl,
=CH(Ci-Ci2 alkyl)aryl, =CH(Ci-Ci2 alkyl)heterocycloalkyl, =CH(Ci-Ci2 alkyl)heterocycloaryl, -CH=CH(Ci-Ci2 alkyl), -CH=CH(Ci-Ci2 alkyl), -CH=CH(Ci-Ci2 alkyl)C3-Ci0 cycloalkyl, -CH=CH(Ci-Ci2 alkyl)aryl, -CH=CH(Ci-Ci2 alkyl)heterocycloalkyl,
-CH=CH(Ci-Ci2 alkyl)heterocycloaryl, -CH2(Ci-Ci2 alkyl)C3-Ci0 cycloalkyl,
-CH2(Ci-Ci2 alkyl)aryl, -CH2(Ci-Ci2 alkyl)heterocycloalkyl, -CH2(Ci-Ci2 alkyl)heterocycloaryl, -CH(=0), =0, -O-R4, -CH2-0-R4, -C(=0)-0-R4, =CHC(=0)-0-R4, -CH2C(=0)-0-R4,
-CH=CHC(=0)0-R4, -CH2CH2C(=0)0-R4, -N(R4)R4', -CH2-N(R4)R4', -C(=0)-N(R4)R4', =CHC(=0)-N(R4)R4', -CH2C(=0)-N(R4)R4',-CH=CHC(=0)-N(R4)R4',
-CH2CH2C(=0)-N(R4)R4', -S-R4, -CH2-S-R4, -S(0)-R4, -CH2-S(0)-R4, -S(0)2-R4,
-CH2-S(0)2-R4, -S(0)NR4R4', -CH2-S(0) NRV, -S(0)2 NR4R4' and -CH2-S(0)2 NR4R4 ; R2 may be optionally substituted.
Where R3 is selected from the group consisting of -H, -C(=0)NH2i and X-R5
X = may be absent or -CH2-,-CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH=CH-,-C(=0)-, -C(=0)CH=CH-, -C(=0)0-, -C(=0)NH2, -C(=0)NH-, -C(=0)N, -S-, -S(O)-, and -S(0)2-;
n = 0, 1 or 2;
R4, R4' are independently selected from the group consisting of -H, Ci to Ci2 alkyl, C3-Cio cycloalkyl, Ci to C6 alkyl attached to C3-Cio cycloalkyl, 5- or 6-member-heterocycloalkyl containing one or two -0-, -N(R6), S, S(O), or S(0)2; Ci to C6 alkyl attached to
a 5- or 6-member-heterocycloalkyl containing one or two -0-, -N(R6), S, S(O), or S(0)2; C6, C9 or Cio aryl, Ci to C6 alkyl attached to C6 or C10 aryl; 5-, 6-, 9- or 10-member-heterocycloaryl containing one, two or three -0-, -N, -N(R6), S; Ci to C6 alkyl attached to
a 5-, 6, 9- or 10-member-heterocycloaryl containing one, two or three -0-, -N, -N(R6), S; R4 and R4' may be taken together to form a ring; R4, R4 may be optionally substituted with 1 to 3 of the following substituents: -halogen, -OH, -0(Ci-C3 alkyl), -NH2, -NH(Ci-C3 alkyl),
-N(Ci-C3 alkyl)Ci-C3 alkyl, N-pyrrolidine, N-piperidine, N-morpholine, N-piperazine,
4-methylpiperizin-l-yl, 4-ethylpiperizin-l-yl, -NHC(=0)Ci-C3 alkyl,
-N(Ci-C3 alkyl)C(=0)Ci-C3 alkyl, -C02H, C02(Ci-C3 alkyl), -CONH2 -CONH(Ci-C3 alkyl), -CON(Ci-C3 alkyl)2, -OC02(Ci-C3 alkyl), -OCONH(Ci-C3 alkyl), -OCON(Ci-C3 alkyl)2, -NHC02(Ci-C3 alkyl), -NHCONH(C C3 alkyl), -NHCON(C C3 alkyl)2, -SH, -S(C C3 alkyl), -SO(Ci-C3 alkyl), -S02(Ci-C3 alkyl), -NHS02(Ci-C3 alkyl), -N(Ci-C3 alkyl)S02(Ci-C3 alkyl), -S02NH2, -S02NH(Ci-C3 alkyl),and -S02N(C C3 alkyl)2;
R5 is selected from the group consisting of Ci-Ci2 alkyl, C3-Cio cycloalkyl, aryl;
5- or 6-member- heterocycloalkyl containing one or two -0-, -N(R6), S, S(O), or S(0)2;
5-, 6-, 9- or 10-member-heterocycloaryl containing one, two or three -0-, -N, -N(R6), S; R5 may be optionally substituted with 1 to 3 of the following substituents: -halogen, -OH,
-0(Ci-C3 alkyl), -NH2, -NH(Ci-C3 alkyl), -N(Ci-C3 alkyl)Ci-C3 alkyl, N-pyrrolidine,
N-piperidine, N-morpholine, N-piperazine, 4-methylpiperizin-l-yl, 4-ethylpiperizin-l-yl, -NHC(=0)Ci-C3 alkyl, -N(Ci-C3
Figure imgf000016_0001
alkyl, -C02H, C02(Ci-C3 alkyl),
-CONH2- CONH(Ci-C3 alkyl), -CON(C C3 alkyl)2, -OC02(C C3 alkyl), -OCONH(C C3 alkyl), -OCON(Ci-C3 alkyl)2, -NHC02(Ci-C3 alkyl), -NHCONH(Ci-C3 alkyl), -NHCON(Ci-C3 alkyl)2, -SH, -S(Ci-C3 alkyl), -SO(Ci-C3 alkyl), -S02(Ci-C3 alkyl), -NHS02(Ci-C3 alkyl),
-N(Ci-C3 alkyl)S02(Ci-C3 alkyl), -S02NH2, -S02NH(Ci-C3 alkyl), and -S02N(Ci-C3 alkyl)2;
R6 is selected from the group consisting of -H, C -Cn alkyl, and C3-C6 cycloalkyl; R6 may be optionally substituted; and pharmaceutically acceptable salts thereof, prodrugs thereof, solvates thereof, deuterated forms, isomers, radio-actively labeled forms and mixtures thereof.
Certain of the above the compounds can be considered prodrugs such as Formula 1
Figure imgf000016_0002
An example of a C6 aryl ring is phenyl and examples of a C10 aryl ring are naphthyl, 1 ,2,3,4-tetrahydronaphthalene or a further unsaturated variation such as 1 ,2-dihydronaphthalene or an =0 substituted variation such as benzoquinone. Examples of a Cg aryl ring are 2,3-dihydro- lH-indene, lH-indene or an =0 substituted variation such as 2,3-dihydro-lH-inden-l-one. The heterocycloaryl rings can include one or two or three heteroatoms such as N, S or O and can be heteroaryl rings. Examples of 5- and 6-membered N-heterocyclic groups are pyridyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrrolyl, pyrazolyl, pyrazinyl pyrimidinyl, pyridazinyl, imidazoyl, imidazolidinyl, 1,2,3-triazole, 1,2,4-triazole, indolyl and benzimidazolyl. Examples of 9- and 10-membered N-heterocycloaryl rings are indole, benzimidazole, indazole, pyrazolo[l,5-a]pyridine, pyrazolo[l,5-a]pyrazine, 1,8-naphthyridine, quinoxaline,
pyrido[3,4-b]pyrazine, cinnoline, quinoline, isoquinoline. Examples of O-heterocyclic groups are furanyl, pyranyl and benzofuranyl. Examples of S-heterocyclic groups are thiopyranyl, thienyl and benzothiophene. Examples of heterocycloalkyl groups containing both N and O are morpholinyl, oxazole, isooxazole and benzisoxazole. Example of heterocycloalkyl groups containing both N and S are thiomorpholine, thiazole, isothiazole and benzothiazole. Examples of 5- or 6-member-heterocycloalkyl containing one or two -0-, -N(R6), S, S(O), or S(0)2 for R4, 4' are represented by the following formulae:
Figure imgf000017_0001
these rings may be optionally substituted or unsubstituted. The 4- to 8-membered rings formed by NR4 R4 being taken together consist of the nitrogen atom to which R4 and R4 are bonded, carbon ring members and optionally an additional ring member selected from the group consisting of: O, S, SO, S02, N, and N(Ci-C4-alkyl). The rings may be unsaturated, partially saturated or aromatic. Examples of saturated rings include those enumerated for R4. Other ring structures include pyridyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrrolyl, pyrazolyl, pyrazinyl pyrimidinyl, pyridazinyl, imidazoyl, imidazolidinyl, 1,2,3-triazole, 1,2,4-triazole, indolyl, benzimidazolyl, oxazole, isooxazole, benzisoxazole thiazole, isothiazole, benzothiazole and the partially hydrogenated or saturated counterparts thereof as well as thomorpholinyl. In sulfur containing rings, the sulfur ring member may by oxidized to form an -S(=0)- or -S(=0)2- ring member.
Examples where R4,R4 are Ci to C6 alkyl attached to a 5- or 6-member-heterocycloalkyl or Ci to C6 alkyl attached to C6 or Cio aryl or Ci to C6 alkyl attached to C3-C10 cycloalkyl or Ci to C6 alkyl attached to a 5-, 6-, 9- or 10-member-heterocycloaryl describe systems wherein a straight or branched alkyl chain of 1 to 6 carbon atoms are attached as a linking group leading to the cycloalkyl, heterocycloalkyl or heterocycloaryl or aryl group specified. The alkyl group typically contains 1-12 carbon atoms. The alkyl group more typically contains 1-4 carbon atoms. Examples of suitable alkyl groups include methyl, ethyl and propyl. Examples of branched alkyl groups include isopropyl and t-butyl. The alkyl group may optionally contain a double or triple bond.
Examples of halogen groups are F, CI, Br and I. Haloalkyl groups include any one of the foregoing alkyl groups in which one or more of the hydrogen atoms are replaced by a corresponding number of identical or different halogen. Illustrative examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, bromomethyl, iodomethyl, chloro-difluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl,
1 ,2-difluoroethyl, 2,2-difluoroethyl, l-chloro-2-fluoroethyl, 2-chloro-2-fluoroethyl,
l-bromo-2-fluoroethyl, 2-bromo-2-fluoroethyl, l-flouro-2-iodoethyl, 2-fluoro-2-iodoethyl, 1 , 1 ,2-trifluoroethyl, 1,2,2-trifluoroethyl, 2,2,2-trifluoroethyl, and the like.
Examples of C3-C10 cycloalkyl rings are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, decahydronaphthalene and octahydro-lH-indene. These rings may be optionally substituted with double bonds.
When any of the above groups is substituted, for instance the R2 and R6 groups , the substitutions can include at least one C1-C3 alkyl group, halogen group, haloalkyl, hydroxyl, alkoxy group containing 1-12 carbon atoms and more typically 1-6 or 1-4 carbon atoms, amino group, aminoalkyl, a thiol or thioalkyl group. The alkyl groups for the haloalkyl, aminoalkyl and thioalkyl groups are typically C1-C3.
"Derivatives" of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, solvates and combinations thereof. The "combinations" mentioned in this context refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, and solvates.
The compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, and etc. groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di- or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al, PCT WO 2000/041531, p. 30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.
"Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. The compounds of this disclosure form acid addition salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this disclosure. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric acid, and the like. Salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate,
chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o- acetoxybenzoate, naphthalene -2 -benzoate, bromide, isobutyrate, phenylbutyrate, β- hydroxybutyrate, butyne-l,4-dioate, hexyne-l,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate,
hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate,
metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzene-sulfonate, /?-bromobenzenesulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, /?-toleunesulfonate, xylenesulfonate, tartarate, and the like.
It is understood that the compounds of the present disclosure relate to all optical isomers and stereo-isomers at the various possible atoms of the molecule, unless specified otherwise. Compounds may be separated or prepared as their pure enantiomers or diastereomers by crystallization, chromatography or synthesis.
The deuterated forms contain heavy hydrogen including deuterium. The carbon labeled forms may contain carbon-13. Examples of radio-actively labeled forms include compounds in which at least one of the following replacements has been made: i) one or more hydrogen are replaced by a corresponding number of tritium (3H). ii) one or more carbon- 12 (12C) are replaced by a corresponding number of carbon- 11, carbon-13 (13C), and/or carbon-14 (14C); iii) one or more hydrogen and/or fluorine- 19 (19F) are replaced by a corresponding number of fluorine- 18 (18F); iv) one or more acidic hydrogen and/or sodium-23 (23Na) are replaced by a corresponding number of sodium-22 (22Na); v) one or more phosphorous-31 (31P) are replaced by a corresponding number of phosphorous-32 (32P); vi) one or more sulfur-32 (32S) are replaced by a corresponding number of sulfur-35
(35S); vii) one or more hydrogen and/or iodine- 127 (127I) are replaced by a corresponding number of iodine- 125 (125I) and/or iodine-131 (131I).
"Solvates" refers to the compound formed by the interaction of a solvent and a solute and includes hydrates. Solvates are usually crystalline solid adducts containing solvent molecules within the crystal structure, in either stoichiometric or nonstoichiometric proportions.
The term "precancerous condition" refers to patients having a propensity for being afflicted with cancer.
The term "comprising" (and its grammatical variations) as used herein is used in the inclusive sense of "having" or "including" and not in the exclusive sense of "consisting of." The terms "a" and "the" as used herein are understood to encompass the plural as well as the singular. Examples of compounds according to the present disclosure are shown in the table below:
Figure imgf000021_0001
oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3-(3-((l-(isoxazol-4-ylmethyl)piperidin-4-yl)methyl)-5-methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(3 -(( 1 -(isothiazol-4-ylmethyl)piperidin-4-yl)methyl)-5 -methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(5 -methyl-3 -(( 1 -(methylsulfonyl)piperidin-4-yl)methyl)-2-oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(5 -methyl-3 -((l-(oxazol-5 -ylsulfonyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(3 -(( 1 -(isopropylsulfonyl)piperidin-4-yl)methyl)-5 -methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3-(5-methyl-2-oxo-3-((l-(thiazol-5-ylsulfonyl)piperidin-4- yl)methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(5 -methyl-2-oxo-3 -(( 1 -(phenylsulfonyl)piperidin-4-yl)methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(5 -methyl-2-oxo-3 -(( 1 -(pyrimidin-4-ylsulfonyl)piperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(5 -methyl-2-oxo-3 -(( 1 -(pyridin-2-ylsulfonyl)piperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(3 -(( 1 -(( 1 ,3 ,5 -triazin-2-yl)sulfonyl)piperidin-4-yl)methyl)-5 -methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3-(5-methyl-2-oxo-3-((l-(pyridin-4-ylsulfonyl)piperidin-4- yl)methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3-(5-methyl-2-oxo-3-((l-(pyrazin-2-ylsulfonyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(5 -methyl-2-oxo-3 -(( 1 -(pyridin-3 -ylsulfonyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(5 -methyl-2-oxo-3 -(( 1 -(pyrimidin-2-ylsulfonyl)piperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(5 -methyl-3 -((1-((1 -methyl- lH-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(5 -methyl-2-oxo-3 -(( 1 -(pyrimidin-5 -ylsulfonyl)piperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(5 -methyl-3 -(( 1 -(( 1 -methyl- 1 H-imidazol-5 -yl)sulfonyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3-(3-((l-(isoxazol-4-ylsulfonyl)piperidin-4-yl)methyl)-5-methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3-(3-((l-(isothiazol-4-ylsulfonyl)piperidin-4-yl)methyl)-5-methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(5 -methyl-2-oxo-3 -(( 1 -(phenylsulfonyl)piperidin-4-yl)methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(5 -methyl-2-oxo-3 -(( 1 -tosylpiperidin-4-yl)methyl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide
a 3-(3-((l-((4-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(3 -(( 1 -((4-methoxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3-(3-((l-((4-aminophenyl)sulfonyl)piperidin-4-yl)methyl)-5-methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3-(3-((l-((3-aminophenyl)sulfonyl)piperidin-4-yl)methyl)-5-methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(3 -(( 1 -((3 -methoxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(3 -(( 1 -((4-hydroxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(3 -(( 1 -((3 -hydroxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(3 -(( 1 -((3 -chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-5 -methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
a 3 -(5 -methyl-2-oxo-3 -(( 1 -phenethylpiperidin-4-yl)methyl)tetrahydropyrimidin- 1 (2H)- yl)benzimidamide
6a 3 -(3 -(( 1 -(4-chlorobenzyl)piperidin-4-yl)methyl)-5 -methyl-2-oxotetrahydropyrimidin- 1
(2H)-yl)benzimidamide
7a 3 -(3 -(( 1 -(4-methoxybenzyl)piperidin-4-yl)methyl)-5 -methy 1-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
8a 3 -(3 -(( 1 -(4-aminobenzyl)piperidin-4-yl)methyl)-5 -methyl-2-oxotetrahydropyrimidin- 1
(2H)-yl)benzimidamide
9a 3 -(3 -(( 1 -(3 -aminobenzyl)piperidin-4-yl)methyl)-5 -methyl-2-oxotetrahydropyrimidin- 1
(2H)-yl)benzimidamide
50a 3 -(3 -(( 1 -(3 -methoxybenzyl)piperidin-4-yl)methyl)-5 -methy 1-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
51a 3 -(3 -(( 1 -(4-hydroxybenzyl)piperidin-4-yl)methyl)-5 -methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
52a 3 -(3 -(( 1 -(3 -hydroxybenzyl)piperidin-4-yl)methyl)-5 -methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
53a 3 -(3 -(( 1 -(3 -chlorobenzyl)piperidin-4-yl)methyl)-5 -methyl-2-oxotetrahydropyrimidin- 1
(2H)-yl)benzimidamide lb 3 -(5 -(hydroxymethy l)-3 -(( 1 -methylpiperidin-4-yl)methyl)-2-oxotetrahydropyrimidin- 1
(2H)-yl)benzimidamide
b 3 -(5 -(hydroxymethyl)-3-(( 1 -(oxazol-5 -ylmethyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
3b 3 -(3 -(( 1 -isopropylpiperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(thiazol-5 -ylmethyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
5b 3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -(hydroxymethyl)-2-oxotetrahydropyrimidin- 1
(2H)-yl)benzimidamide
6b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(pyrimidin-4-y lmethyl)piperidin-4- yl)methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide 7b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(pyridin-2-ylmethyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
8b 3 -(3 -(( 1 -(( 1 ,3 ,5 -triazin-2-yl)methyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
9b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(pyridin-4-ylmethyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
10b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(pyrazin-2-ylmethyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
l ib 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(pyridin-3 -ylmethyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
12b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(pyrimidin-2-ylmethyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
13b 3 -(3 -(( 1 -(( 1 H-pyrazol-4-yl)methyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
14b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(pyrimidin-5 -ylmethyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
15b 3-(3-((l-((lH-imidazol-5-yl)methyl)piperidin-4-yl)methyl)-5-(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
16b 3-(3-((l-(isoxazol-4-ylmethyl)piperidin-4-yl)methyl)-5-(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
17b 3 -(3 -(( 1 -(isothiazol-4-ylmethyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
18b 3 -(5 -(hydroxymethyl)-3 -(( 1 -(methylsulfonyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
19b 3-(5-(hydroxymethyl)-3-((l-(oxazol-5-ylsulfonyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
0b 3 -(3 -(( 1 -(isopropylsulfonyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
1b 3-(5-(hydroxymethyl)-2-oxo-3-((l-(thiazol-5-ylsulfonyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(phenylsulfonyl)piperidin-4-yl) methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(pyrimidin-4-ylsulfonyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(pyridin-2-ylsulfonyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(3 -(( 1 -(( 1 ,3 ,5 -triazin-2-yl)sulfonyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(pyridin-4-ylsulfonyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(pyrazin-2-ylsulfonyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(pyridin-3 -ylsulfonyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(pyrimidin-2-ylsulfonyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(5 -(hydroxymethyl)-3 -(( 1 -(( 1 -methyl- 1 H-pyrazol-4-yl)sulfonyl)piperidin-4-yl) methyl)-2-oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(pyrimidin-5 -ylsulfonyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(5 -methyl-3 -(( 1 -(( 1 -methyl- 1 H-imidazol-5 -yl)sulfonyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3-(3-((l-(isoxazol-4-ylsulfonyl)piperidin-4-yl)methyl)-5-methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3-(3-((l-(isothiazol-4-ylsulfonyl)piperidin-4-yl)methyl)-5-methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -(phenylsulfonyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(5 -(hydro xymethyl)-2-oxo-3 -(( 1 -tosylpiperidin-4-yl)methyl)tetrahy dropyrimidin- 1 (2H)-yl)benzimidamide b 3 -(3 -(( 1 -((4-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(3 -(( 1 -((4-methoxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(3 -(( 1 -((4-aminophenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(3 -(( 1 -((3 -aminophenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(3 -(( 1 -((3 -methoxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(3 -(( 1 -((4-hydroxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(3 -(( 1 -((3 -hydroxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(3 -(( 1 -((3 -chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(5 -(hydroxymethyl)-2-oxo-3 -(( 1 -phenethylpiperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3-(3-((l-(4-chlorobenzyl)piperidin-4-yl)methyl)-5-(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(3 -(( 1 -(4-methoxybenzyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(3 -(( 1 -(4-aminobenzyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(3 -(( 1 -(3 -aminobenzyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(3 -(( 1 -(3 -methoxybenzyl)piperidin-4-yl)methyl)-5 -(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
b 3 -(3 -(( 1 -(4-hydroxybenzyl)piperidin-4-yl)methyl)-5 -(hydro xymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide 52b 3 -(3 -(( 1 -(3 -hydroxybenzyl)piperidin-4-yl)methyl)-5 -(hydro xymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
53b 3-(3-((l-(3-chlorobenzyl)piperidin-4-yl)methyl)-5-(hydroxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide lc 3 -(5 -(methoxymethyl)-3 -(( 1 -methylpiperidin-4-yl)methyl)-2-oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl)-3 -(( 1 -(oxazol-5 -ylmethyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
3c 3 -(3 -(( 1 -isopropylpiperidin-4-yl)methyl)-5 -(methoxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(thiazol-5 -ylmethyl)piperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
5c 3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -(methoxymethyl) -2-oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
6c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(pyrimidin-4-ylmethyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
7c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(pyridin-2-ylmethyl)piperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
8c 3 -(3 -(( 1 -(( 1 ,3 ,5 -triazin-2-yl)methyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
9c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(pyridin-4-ylmethyl)piperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
10c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(pyrazin-2-ylmethyl)piperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
11c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(pyridin-3 -ylmethyl)piperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
12c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(pyrimidin-2-ylmethyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
13c 3-(3-((l-((lH-pyrazol-4-yl)methyl)piperidin-4-yl)methyl)-5-(methoxymethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(pyrimidin-5 -ylmethyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(3 -(( 1 -(( 1 H-imidazol-5 -yl)methyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(3 -((l-(isoxazol-4-ylmethyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(3 -(( 1 -(isothiazol-4-ylmethyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -3 -(( 1 -(methylsulfonyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -3-((l-(oxazol-5-ylsulfonyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(3 -(( 1 -(isopropylsulfonyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -2-oxo-3-((l-(thiazol-5-ylsulfonyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(phenylsulfonyl)piperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(pyrimidin-4-ylsulfonyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(pyridin-2-ylsulfonyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3-(3-((l-((l,3,5-triazin-2-yl)sulfonyl)piperidin-4-yl)methyl)-5-(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl)-2-oxo-3 -(( 1 -(pyridin-4-ylsulfonyl)piperidin-4-y l)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(pyrazin-2-ylsulfonyl)piperidin-4-y l)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(pyridin-3 -ylsulfonyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(pyrimidin-2-ylsulfonyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -3 -((1-((1 -methyl- lH-pyrazol-4-yl)sulfonyl)piperidin-4-yl) methyl)-2-oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(pyrimidin-5 -ylsulfonyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -3 -(( 1 -(( 1 -methyl- 1 H-imidazol-5 -yl)sulfonyl)piperidin-4-yl) methyl)-2-oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(3 -((l-(isoxazol-4-ylsulfonyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(3 -((l-(isothiazol-4-ylsulfonyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -(phenylsulfonyl)piperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -tosylpiperidin-4-yl)methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(3 -((l-((4-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(3 -(( 1 -((4-methoxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(3 -(( 1 -((4-aminophenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(3 -(( 1 -((3 -aminophenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(3 -(( 1 -((3 -methoxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(3 -(( 1 -((4-hydroxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
c 3 -(3 -(( 1 -((3 -hydroxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
4c 3 -(3 -(( 1 -((3 -chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
5c 3 -(5 -(methoxymethyl) -2-oxo-3 -(( 1 -phenethylpiperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
6c 3 -(3 -((l-(4-chlorobenzyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
7c 3 -(3 -(( 1 -(4-methoxybenzyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
8c 3 -(3 -(( 1 -(4-aminobenzyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
9c 3 -(3 -(( 1 -(3 -aminobenzyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
50c 3 -(3 -(( 1 -(3 -methoxybenzyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
51c 3 -(3 -(( 1 -(4-hydroxybenzyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
52c 3 -(3 -(( 1 -(3 -hydroxybenzyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
53c 3 -(3 -((1 -(3 -chlorobenzyl)piperidin-4-yl)methyl)-5 -(methoxymethyl) -2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Id 3 -(5 -((benzyloxy)methyl)-3 -(( 1 -methylpiperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(5-((benzyloxy)methyl)-3-((l-(oxazol-5-ylmethyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
3d 3-(3-((l-isopropylpiperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3 -(5 -((benzyloxy)methyl)-2-oxo-3-((l -(thiazol-5 -ylmethyl)piperidin-4- yl)methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide 5d 3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -((benzyloxy)methy l)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
6d 3 -(5 -((benzyloxy)methyl)-2-oxo-3 -(( 1 -(pyrimidin-4-ylmethyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
7d 3 -(5 -((benzyloxy)methyl)-2-oxo-3 -(( 1 -(pyridin-2-ylmethyl)piperidin-4-y l)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
8d 3 -(3 -(( 1 -(( 1 ,3 ,5 -triazin-2-yl)methyl)piperidin-4-yl)methyl)-5 -((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
9d 3 -(5 -((benzyloxy)methyl)-2-oxo-3 -(( 1 -(pyridin-4-ylmethyl)piperidin-4-y l)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
lOd 3 -(5 -((benzyloxy)methyl)-2-oxo-3 -(( 1 -(pyrazin-2-ylmethyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
l id 3 -(5 -((benzyloxy)methyl)-2-oxo-3 -(( 1 -(pyridin-3 -ylmethyl)piperidin-4-y l)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
12d 3 -(5 -((benzyloxy)methyl)-2-oxo-3 -(( 1 -(pyrimidin-2-ylmethyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
13d 3-(3-((l-((lH-pyrazol-4-yl)methyl)piperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
14d 3 -(5 -((benzyloxy)methyl)-2-oxo-3 -(( 1 -(pyrimidin-5 -ylmethyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
15d 3 -(3 -(( 1 -(( 1 H-imidazol-5 -yl)methyl)piperidin-4-yl)methyl)-5 -((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
16d 3-(3-((l-(isoxazol-4-ylmethyl)piperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
17d 3-(3-((l-(isothiazol-4-ylmethyl)piperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
18d 3 -(5 -methyl-3 -(( 1 -(methylsulfonyl)piperidin-4-yl)methyl)-2-oxo tetrahydropyrimidin- 1
(2H)-yl)benzimidamide
19d 3-(5-((benzyloxy)methyl)-3-((l-(oxazol-5-ylsulfonyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide d 3 -(3 -(( 1 -(isopropylsulfonyl)piperidin-4-yl)methyl)-5 -((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(5-((benzyloxy)methyl)-2-oxo-3-((l-(thiazol-5-ylsulfonyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3 -(5 -((benzyloxy)methyl)-2-oxo-3 -(( 1 -(phenylsulfonyl)piperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3 -(5 -((benzyloxy)methyl)-2-oxo-3 -(( 1 -(pyrimidin-4-ylsulfonyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(5-((benzyloxy)methyl)-2-oxo-3-((l-(pyridin-2-ylsulfonyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3 -(3 -(( 1 -(( 1 ,3 ,5 -triazin-2-yl)sulfonyl)piperidin-4-yl)methyl)-5 -((benzyloxy)methy l)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(5-((benzyloxy)methyl)-2-oxo-3-((l-(pyridin-4-ylsulfonyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(5-((benzyloxy)methyl)-2-oxo-3-((l-(pyrazin-2-ylsulfonyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(5-((benzyloxy)methyl)-2-oxo-3-((l-(pyridin-3-ylsulfonyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3 -(5 -((benzyloxy)methyl)-2-oxo-3 -(( 1 -(pyrimidin-2-ylsulfonyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(5-((benzyloxy)methyl)-3-((l-((l-methyl-lH-pyrazol-4-yl)sulfonyl)piperidin-4-yl) methyl)-2-oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(5-((benzyloxy)methyl)-2-oxo-3-((l-(pyrimidin-5-ylsulfonyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3 -(5 -((benzyloxy)methyl)-3 -(( 1 -(( 1 -methyl- 1 H-imidazol-5 -yl)sulfonyl)piperidin-4-yl) methyl)-2-oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(3-((l-(isoxazol-4-ylsulfonyl)piperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(3-((l-(isothiazol-4-ylsulfonyl)piperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide d 3-(5-((benzyloxy)methyl)-2-oxo-3-((l-(phenylsulfonyl)piperidin-4-yl)methyl) tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(5-((benzyloxy)methyl)-2-oxo-3-((l-tosylpiperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(3-((l-((4-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3 -(3 -(( 1 -((4-methoxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(3-((l-((4-aminophenyl)sulfonyl)piperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(3-((l-((3-aminophenyl)sulfonyl)piperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3 -(3 -(( 1 -((3 -methoxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3 -(3 -(( 1 -((4-hydroxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3 -(3 -(( 1 -((3 -hydroxyphenyl)sulfonyl)piperidin-4-yl)methyl)-5 -((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(3-((l-((3-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3 -(5 -((benzyloxy)methyl)-2-oxo-3 -(( 1 -phenethylpiperidin-4-yl)methyl)
tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(3-((l-(4-chlorobenzyl)piperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(3-((l-(4-methoxybenzyl)piperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(3-((l-(4-aminobenzyl)piperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
d 3-(3-((l-(3-aminobenzyl)piperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide 50d 3 -(3 -(( 1 -(3 -methoxybenzyl)piperidin-4-yl)methyl)-5 -((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
51d 3 -(3 -(( 1 -(4-hydroxybenzyl)piperidin-4-yl)methyl)-5 -((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
52d 3 -(3 -(( 1 -(3 -hydroxybenzyl)piperidin-4-yl)methyl)-5 -((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
53d 3-(3-((l-(3-chlorobenzyl)piperidin-4-yl)methyl)-5-((benzyloxy)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Examples of preferred precursors are represented by the following:
Figure imgf000035_0001
SYNTHESIS
Compounds according to the present disclosure can be prepared by the judicious use of the methods outlined below. A practitioner skilled in the art will understand the appropriate use of protecting groups [see: Greene and Wuts, Protective Groups in Organic Synthesis] and the preparation of known compounds found in the literature using the standard methods of organic synthesis. There may come from time to time the need to rearrange the order of the
recommended synthetic steps, however this will be apparent to the judgment of a chemist skilled in the art of organic synthesis.
Methods for the syntheses of compounds of Formula 1 are illustrated below. Urea formation (Scheme 1) can be achieved by reaction of the commercially available 3- isocyanatobenzonitrile (I) with the primary amines (II) in a variety of solvents such as THF, toluene or DMF at temperatures ranging from ambient to the reflux temperature of the solvent selected. The primary amines II where n = 0, 1 or 2 are commercially available with an N-benzyl or N-t-butoxycarbonyl protecting group (PG).
Figure imgf000036_0001
Y = -H or -F
Scheme 1. Urea formation and alkylation steps for the preparation of compounds of Formula 1.
The resulting urea III is alkylated using commercially available 3-chloro-2- (chloromethyl) prop-l-ene (IV). This reaction is carried out with a strong base, such as sodium hydride, in a solvent, such as tetrahydrofuran (THF), 1,4-dioxane, dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO). The base is added to the urea at low temperature (e.g. -10 to 0°C), when the evolution of H2 gas subsides the dichloride IV is added. The reaction is allowed to thaw to ambient temperature and can be heated to as high as 100°C to help drive the reaction to completion if necessary to give the cyclic urea V. The double bond of V can be derivatized in two ways to give intermediates that will be useful for the further functionalization to give various R2 (Scheme 2). Ozonolysis of V (03, - 78°C, methanol) followed by reduction with dimethyl sulfide gives the ketone VI; VI can be reduced selectively to the alcohol VII with sodium borohydride in either methanol or ethanol at 0°C to ambient temperature. For some references see: Ronald E. Claus and Stuart L. Schreiber (1990), "Ozonolytic Cleavage of Cyclohexene to Terminally Differentiated Products", Org. Synth.; Coll. Vol. 7: 168; Bailey, P. S.; Erickson, R. E. (1973), "Diphenaldehyde", Org. Synth.; Coll. Vol. 5: 489; Tietze, L. F.; Bratz, M. (1998), "Dialkyl Mesoxalates by Ozonolysis of Dialkyl Benzalmalonates", Org. Synth.; Coll. Vol. 9: 314; Veysoglu, Tarik; Mitscher, Lester A.; Swayze, John K. (1980). "A Convenient Method for the Control of Selective Ozonizations of Olefins". Synthesis: 807-810. doi: 10.1055/s-1980-29214.
The double bond of V can be treated with 9-borabicyclo[3.3.1]nonane (9-BBN) followed by cleavage of the intermediate boronate with peroxide to give the primary alcohol VIII; for references see: Loudon, Marc G. (2002). "Addition Reactions of Alkenes." Organic Chemistry (Fourth Edition ed.). New York: Oxford University Press, pp. 168-172; J. V. B. Kanth, H. C. Brown, J. Org. Chem, 2001, 66, 5359-5365; J. M. Clay, E. Vedejs, J. Am. Chem. Soc, 2005, 127, 5766-5767; G. W. Kabalka, T. M. Shoup, N. M. Goudgaon, J. Org. Chem., 1989, 5930- 5933; P. K. Patra, K. Nishide, K. Fuji, M. Node, Synthesis, 2004, 1003-1006; Concise Formation of 4-Benzyl Piperidines and Related Derivatives Using a Suzuki Protocol. S. Vice, T. Bara, A. Bauer, C. A. Evans, J. Fort, H. Josien, S. McCombie, M. Miller, D. Nazzareno, A. Palani, J. Tagat, J. Org. Chem, 2001, 66, 2487-2492.
Intermediate ketone VI can be reduced to the alcohol VII with sodium borohydride in an alcohol solvent, such as MeOH or EtOH, at temperatures ranging from -10°C to ambient temperature. Other methods include: Schlesinger, H. I.; Brown, H. C; Abraham, B.; Bond, A. C; Davidson, N.; Finholt, A. E.; Gilbreath, J. R.; Hoekstra, FL; Horvitz, L.; Hyde, E. K.; Katz, J. J.; Knight, J.; Lad, R. A.; Mayfield, D. L.; Rapp, L.; Ritter, D. M.; Schwartz, A. M.; Sheft, I.; Tuck, L. D.; Walker, A. O. (1953). "New developments in the chemistry of diborane and the borohydrides. General summary". J. Am. Chem. Soc. 75: 186-90; Y. Matsumura, K. Ogura, Y. Kouchi, F. Iwasaki, O. Onomura, Org. Lett., 2006, 8, 3789-3792; D.-M. Du, T. Fang, J. Xu, S.- W. Zhang, Org. Lett., 2006, 8, 1327-1330; B. H. Lipshutz, A. Lower, K. Noson, Org. Lett., 2002, 4, 4045-4048; J. S. Yadav, S. Nanda, P. T. Reddy, A. Bhaskar, Rao, J. Org. Chem., 2002, 67, 3900-3903; C.-T. Lee, B. H. Lipshutz, Org. Lett., 2008, 10, 4187-4190; I. P. Query, P. A. Squier, E. M. Larson, N. A. Isley, T. B. Clark, J. Org. Chem., 2011, 76, 6452-6456; T. Taniguchi, D. P. Curran, Org. Lett., 2012, 14, 4540-4543; Q. Zhao, D. P. Curran, M. Malacria, L. Fensterbank, J.- P. Goddard, E. Lacote, Synlett, 2012, 23, 433-437; J. W. Bae, S. H. Lee, Y. J. Jung, C.-O.
Maing, C. M. Yoon, Tetrahedron Lett., 2001, 42, 2137-2139; C. P. Casey, H. Guan, J. Am.
Chem. Soc, 2007, 129, 5816-5817; X. Wu, X. Li, W. Hems, F. King, J. Xiao, Org. Biomol. Chem., 2004, 2, 1818-1821; P. Dani, T. Karlen, R. A. Gossage, S. Gladiali, G. van Koten, Angew. Chem., 2000, 112, 759-761.
Intermediate VIII can then be oxidized to the aldehyde IX by either the Swern procedure or the Dess-Martin periodiane method. Other methods include: J. C. Collins, W. W. Hess and F. J. Frank (1968). "Dipyridine-chromium(VI) oxide oxidation of alcohols in dichloromethane". Tetrahedron Lett. 9 (30): 3363-3366; Ronald Ratcliffe and Ronald Rodehorst (1970). "Improved Procedure for Oxidations with the Chromium Trioxide-Pyridine Complex". J. Org. Chem 35 (11): 4000-4001; Omura, K.; Swern, D. (1978). "Oxidation of alcohols by "activated" dimethyl sulfoxide. A preparative, steric and mechanistic study". Tetrahedron 34 (11): 1651; Pfitzner, K. E.; Moffatt, J. G. (1963). "A New and Selective Oxidation of Alcohols". J. Am. Chem. Soc. 85: 3027; Tidwell, T. T. Org. React. 1990, 39, 297-572; Dess, D. B.; Martin, J. C. (1983). "Readily accessible 12-1-5 oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones". J. Org. Chem. 48: 4155; Ley, Steven V.; Norman, Joanne; Griffith, William P. (1994). "Tetrapropylammonium Perruthenate, Pr4N+Ru04-, TPAP: A Catalytic Oxidant for Organic Synthesis". Synthesis: 639-666.
Carboxylic acid X can be derived from V by oxidation with chromic acid. Other methods include: Ruhoff, John R., "n-Heptanoic acid", Org. Synth.; Coll. Vol. 2: 315; E. J. Eisenbraun (1973), "Cyclooctanone", Org. Synth.; Coll. Vol. 5: 310; Oxidation in Organic Chemistry. Edited by K. B. Wiberg, Academic Press, NY, 1965; Corey, E.J.; Schmidt, G. (1979). "Useful procedures for the oxidation of alcohols involving pyridinium dichromate in apoptotic media". Tetrahedron Lett. 20 (52): 399; Cornforth, R.H.; Cornforth, J.W.; Popjak, G. (1962).
"Preparation of R-and S-mevalonolactones". Tetrahedron 18 (12): 1351-4; Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D.M.; Grabowski, E.J.J.; Reider, P.J. (1998). "A novel chromium trioxide catalyzed oxidation of primary alcohols to the carboxylic acids". Tetrahedron Lett. 39 (30): 5323; Marcos Fernandez; Gabriel Tojo (2006). Oxidation of Primary Alcohols to Carboxylic Acids: A Guide to Current Common Practice (Basic Reactions in Organic Synthesis). Berlin: Springer. ISBN 0-387-35431-X.
Functionalization at R2: Some useful intermediates
Figure imgf000039_0001
IX
Y = -H or -F
Scheme 2. Useful carbonyl and alcohol intermediates from V to functionalize R2.
It will be recognized that alcohol intermediates VII and VIII can use similar synthetic procedures for further functionalization to various R2 (Scheme 3). In a similar fashion the carbonyl intermediates VI and IX can be derivatized by similar chemistries (Scheme 4). Carboxylic acid intermediate X will require different methodolo (Scheme 5).
Figure imgf000040_0001
VII: Z = -OH
VIII: Z = -CH2OH
NaH, DMF,
then R-l
Figure imgf000040_0002
Vlllc: Z = -CH2OR Vllb: Z=-NHC(=0)R'
Vlllb: Z = -CH2NHC(=0)R'
R' = alkyl, allyl, phenyl, benzyl etc.
Figure imgf000040_0003
R = alkyl, allyl, benzyl etc.
Y = -H or -F
Vila or Villa
Figure imgf000040_0004
R = alkyl, allyl, benzyl etc.
Scheme 3. Methods for further functionalization at R . While Scheme 3 presents a number of useful reaction conditions for achieving the transformations contemplated in this disclosure, the practioner is by no means limited to the methods outlined above. From VII and VIII to Vila and Villa, reductive amination to the primary amine can be achieved without resorting to a protected amine source to avoid dimerization using the method show (Dangerfield EM et al., J. Org. Chem. 2010, 75, 5470- 5477). Alternative procedures involve two-step methods using a primary amine, such as allylamine, tritylamine or benzylamine, as a 'protected' source of ammonia, where the imine is formed then reduced with an agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxy borohydride in a solvent such as methanol, ethanol, dichloromethane, chloroform and the like. With the reduced secondary amine in hand following reduction the 'protecting group' (allyl, benzyl, trityl etc.) can be removed by any appropriate method found in Wuts and Greene.
Transformation of the amines Vila and Villa to their amides Vllb and VHIb can be readily achieved by using any activated version of the appropriate acid, commonly an acid chloride, anhydride or mixed anhydride, a trialkylamine base to remove any acid that may be generated and a wide range of solvents, such as CH2CI2, CHCI3, THF or 1,4-dioxane or the like. Of course, many alternative amino acid coupling conditions will apply as well (for an extensive list of coupling agents that are suitable for the synthesis of amides see:
http://www.peptidesynthesisreagents.com/). Generally amide couplings using amino acid coupling agents take place in the presence of a trialkyl amine base (Et3N, N-methylmorpholine or Hunig's Base) in a solvent such as CHCI3, CH2CI2 or DMF at temperatures ranging from 0°C to ambient temperature.
Transformation of the alcohols VII and VIII to their ethers VIIc and VIIIc can be achieved by the Williamson Ether Synthesis (see: Organic Syntheses, Coll. Vol. 5, p.251 (1973); Vol. 46, p.28 (1966); Coll. Vol. 7, p.386 (1990); Vol. 60, p.92 (1981)). One set of conditions useful for this reaction (especially with a reactive alkylating agent such as a benzylic or allylic halide (preferably bromo- or iodo-)) is a mixture of a carbonate base, such as sodium or potassium carbonate, and an alkyl ketone, such as acetone or butanone as solvent; a minor portion of DMF can be added for increasing solubility of the base. These reactions are generally run at the reflux temperature of the solvent. Alternative conditions include the use of a polar aprotic solvent, such as DMF, DMSO or acetonitrile with a strong base, such as sodium hydride at temperatures ranging from 0°C to the reflux temperature of the solvent. Another method would include the use of phase transfer conditions. This is especially convenient when the halide to be used is cheap and can be practically used as the solvent for the organic phase of the reaction. The base is generated by using a concentrated portion of potassium or sodium hydroxide in water with a phase transfer catalyst such as 18-crown-6 or the tetra-n-butyl ammonium bromide or iodide. This reaction is usually run at reflux to effect this transformation, but the temperature of the reaction could be as low as ambient temperature.
Esters Vlld and VHId can be readily prepared from VII and VIII by the method shown in Scheme 3 or by using any appropriate activated version of the required carboxylic acid, such as the anhydride or mixed anhydride, with a trialkyl amine base in a solvent such as CH2CI2, CHCI3, THF or 1 ,4-dioxane or the like; temperatures for this reaction usually range from -10 °C to the reflux temperature of the solvent. One convenient alternative is to use pyridine as both solvent and base. Here again temperatures for this reaction may range from -10°C to the reflux temperature of the solvent.
It is understood that in addition to the methods illustrated above in Scheme 3, VII and VIII can be transformed into their carbonates directly by reaction with the corresponding activated carbonyl compound such as C1C(=0)-0R or an anhydride or mixed anhydride thereof, a trialkyl amine such as Et3N, N-methylmorpholine in a solvent such as a CH2CI2, CHCI3, THF or 1,4-dioxane at temperatures ranging from -10°C to the reflux temperature of the solvent.
In an analogous fashion, Vila and Villa can be tranformed into their corresponding sulfonamides Vile and VHIe by reaction with CISO2-R' a trialkyl amine such as Et3N, N- methylmorpholine in a solvent such as a CH2CI2, CHCI3, THF, 1,4-dioxane or pyridine at temperatures ranging from -10°C to the reflux temperature of the solvent. Alternatively, Vila and Villa can be transformed to their corresponding ureas by reaction with the appropriate isocyanate, such as 0=C=N-R', or carbamoyl chloride, such as C1-(C=0)NH-R', or the corresponding p-nitrophenyl carbamate thereof, in a variety of solvents, such as CH2CI2, CHCI3, THF, 1,4-dioxane, DMF, toluene and the like at temperatures ranging from -10°C to the reflux temperature of the solvent. In cases where HC1 is generated it may be useful to add a
trialkylamine base such as Et3N, N-methyl morpholine or Hunig's Base.
Figure imgf000043_0001
Vl la: Z=-NH2; if HN(R')2 = NH3
VI = Z: =0 Via: Z=N(R')2
IX = Z: -CHO Vi lla: Z = -CH2NH2; if HN(R')2 = NH3
IXa: Z= CH2N(R')2
Wittig or R' = -H , alkyl, allyl, phenyl, benzyl
Horner-Wadsworth-Emmons etc. or two R' are taken together to Reaction
form pyrollidine, piperidine etc.
tc.
Figure imgf000043_0002
R = -H, alkyl, allyl, phenyl, benzyl, -C02CH3 etc.
Figure imgf000043_0003
R = -H, alkyl, allyl, phenyl, benzyl etc.
Y = -H or -F
Scheme 4. Elaboration of intermediates VI and IX While Scheme 4 presents a number of useful reaction conditions for achieving the transformations contemplated in this disclosure, the practitioner is by no means limited to the methods outlined above. From VI and IX to Via and IXa, reductive amination to the primary amine can be achieved without resorting to a protected amine source to avoid dimerization using the method show (Dangerfield EM et al, J. Org. Chem. 2010, 75, 5470-5477). Alternative procedures involve two-step methods using a primary amine, such as allylamine, tritylamine or benzylamine, as a 'protected' source of ammonia, where the imine is formed and then reduced with an agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxy borohydride in a solvent such as methanol, ethanol, dichloromethane, chloroform and the like. With the reduced secondary amine in hand following reduction the 'protecting group' (either allyl, benzyl, trityl etc.) can be removed by any appropriate method found in Wuts and Greene An exhaustive review is available to delineate further methods for this transformation (see: Ellen W. Baxter and Allen B. Reitz, Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents, Organic Reactions, 1, 59, 2002).
When it is the case that at least one R' = -H, then it is possible to derivatize this compound further as shown for Via and IXa undergoing reaction to give the amides VIb and IXb. This can be achieved by the method in Scheme 4 or by using any activated version of the appropriate acid, commonly an acid chloride, anhydride or mixed anhydride, a trialkylamine base to remove any acid that may be generated and a wide range of solvents, such as CH2C12, CHCI3, THF or 1,4-dioxane or the like. Of course, many alternative amino acid coupling conditions will apply as well (for an extensive list of coupling agents that are suitable for the synthesis of amides see: http://www.peptidesynthesisreagents.com/). Generally amide couplings using amino acid coupling agents take place in the presence of a trialkyl amine base (Et3N, N-methylmorpholine or Hunig's Base) in a solvent such as CHCI3, CH2C12 or DMF at temperatures ranging from 0°C to ambient temperature.
Furthermore amines Via and IXa (as well as Vila and Villa) can be transformed into their corresponding sulfonamides Vie and IXe as shown in Scheme 4 or by reaction with C1S02-R' a trialkyl amine such as Et3N, N-methylmorpholine in a solvent such as a CH2C12, CHCI3, THF, 1,4-dioxane or pyridine at temperatures ranging from -10°C to the reflux temperature of the solvent. Alternatively, Via and IXa can be transformed to their corresponding ureas by reaction with the appropriate isocyanate, such as 0=C=N-R', or carbamoyl chloride, such as C1-(C=0)NH-R', or the corresponding p-nitrophenyl carbamate thereof, in a variety of solvents, such as CH2C12, CHC13, THF, 1,4-dioxane, DMF, toluene and the like at temperatures ranging from -10°C to the reflux temperature of the solvent. In cases where HCl is generated it may be useful to add a trialkylamine base such as Et3N, N-methyl morpholine or Hunig's Base.
The Wittig reaction or the Horner- Wadsworth Emmons modification of this reaction are two ways that VI and IX can conveniently be elaborated to alkenes Vic and IXc (for a reviews with a survey of reaction conditions see: B. E. Maryanoff and A. B. Reitz (1989). "The Wittig olefmation reaction and modifications involving phosphoryl-stabilized carbanions.
Stereochemistry, mechanism, and selected synthetic aspects". Chem. Rev. 89 (4): 863-927; Wadsworth, W. Org. React. 1977, 25, 73). Also, by palladium or platinum catalyzed
hydrogenation, Vic and IXc can be transformed to alkyl derivatives VId and IXd at R2.
Generally the double bonds can be hydrogenated using palladium or platinum catalyst under an atmosphere of hydrogen gas at pressures ranging from 1 to 10 atmospheres of said gas in alcohol (such as methanol, ethanol, isopropanol and the like) or saturated hydrocarbon (such as petroleum ether, hexane, cyclohexane and the like) as solvent. The reaction can generally be effected at room temperature; however it can be heated up to 75°C in some cases.
Figure imgf000045_0001
Xa
X
R = -H, alkyl, allyl, phenyl, benzyl amino acid esters etc.
Y = -H or -F
Scheme 5. Elaboration of intermediate X.
The carboxylic acid X in Scheme 5 can be elaborated to the amide Xa by the method illustrated or by using any activated version of the acid X, commonly an acid chloride, anhydride or mixed anhydride, and reacting with the appropriate amine HN(R)2, a trialkylamine base to remove any acid that may be generated in a wide range of solvents, such as CH2C12, CHCI3, THF or 1,4-dioxane or the like. Of course, many alternative amino acid coupling conditions will apply as well (for an extensive list of coupling agents that are suitable for the synthesis of amides see: http://www.peptidesynthesisreagents.com/). Generally amide couplings using amino acid coupling agents take place in the precedence of a trialkyl amine base (Et3N, N-methylmorpholine or Hunig's Base) in a solvent such as CHCI3, CH2CI2 or DMF at temperatures ranging from 0°C to ambient temperature. Esters are also available from carboxylic acid X; some references to useful methods are: A. Sakakura, K. Kawajiri, T. Ohkubo, Y. Kosugi, K. Ishihara, J. Am. Chem. Soc, 2007, 129, 14775-14779; G. Bartoli, M. Bosco, A. Carlone, R. Dalpozzo, E. Marcantoni, P. Melchiorre, L. Sambri, Synthesis, 2007, 3489-3496; Z. Huang, J. R. Reilly, R. N. Buckle, Synlett, 2007, 1026-1030; A. K. Chakraborti, B. Singh, S. V. Chankeshwara, A. R. Patel, J. Org. Chem., 2009, 74, 5967-5974; K. V. N. S. Srinivas, I. Mahender, B. Das, Synthesis, 2003, 2479- 2482; Y. Wang, B. A. Aleiwi, Q. Wang, M. Kurosu, Org. Lett., 2012, 14, 4910-4913; J. K.
Twibanire, T. B. Grindley, Org. Lett., 2011, 13, 2988-2991; S. T. Heller, R. Sarpong, Org. Lett., 2010, 12, 4572-4575; S. Velusamy, S. Borpuzari, T. Punniyamurthy, Tetrahedron, 2005, 61, 2011-2015; H. Sharghi, M. Hosseini Sarvari, Tetrahedron, 2003, 59, 3627-3633; M. Pittelkow, F. S. Kamounah, U. Boas, B. Pedersen, J. B. Christensen, Synthesis, 2004, 2485-2492; I.
Dhimitruka, J. SantaLucia, Org. Lett., 2006, 8, 47-50.
Figure imgf000047_0001
VII: Z = -OH Vllf: Z=-OS(0)2CH3
VIII: Z = -CH2OH Vlllf: Z = -CH2OS(0)2CH3
-H, alkyl, allyl, phenyl, benzyl etc.
-H or -F
if Y = -H
then
NaS-R
DMF, heat
Figure imgf000047_0002
Vllh: Z=-S02-R Vllg: Z=-S-R
Vlllh: Z = -CH2-S02-R Vlllg: Z = -CH2
Figure imgf000047_0003
ii) 2 eq R-NH2 VIIi: Z=-S02NHR
Vllg: Z=-SH pyridine Villi: Z = -CH2-S02NHR Vlllg: Z = -CH2
Scheme 6. Elaboration of VII and VIII to sulfones Vllh and Vlllh and sulfonamides VIIi and Villi via sulfides Vllg and Vlllg.
The alcohols VII and VIII can be derivatized to the mesylate derivatives Vllf and VHIf (or any other sulfonate ester or halide desired, see discussion on Scheme 3). The mesylate derivatives can be displaced to sulfides Vllg and Vlllg by a thiolate salt, most conveniently prepared by reaction of the corresponding thiol with NaH or NaOCH3 or NaOC2Hs in an alcohol (methanol or ethanol and the like) or polar aprotic solvent (DMF, DMSO and the like). The mixture of the thiolate and mesylate can be stirred in the selfsame solvents at ambient
temperature or heated up to the reflux temperature of the solvent. Alternatively, a thiolate and mesylate mixture can be heated by microwave irradiation in a sealed reaction vessel and achieve reaction temperatures in excess of the reflux temperature of the solvent, if needed.
Oxidation of the sulfides Vllg and VHIg to the sulfones Vllh and VHIh or, in some cases the corresponding sulfoxides, can be effected by the method illustrated or meta-chloroperbenzoic acid at ambient temperature in a chlorocarbon solvent such as CH2C12 or CHC13; also a number of other oxidation methods are available (see: M. Kirihara, A. Itou, T. Noguchi, J. Yamamoto, Synlett, 2010, 1557-1561; R. S. Varma, K. P. Naicker, Org. Lett, 1999, 1, 189-191; K. Bahrami, M. M. Khodaei, M. S. Arabi, J. Org. Chem., 2010, 75, 6208-6213; K. Bahrami, M. M. Khodaei, M. S. Arabi, J. Org. Chem., 2010, 75, 6208-6213; N. K. Jana, J. G. Verkade, Org. Lett., 2003, 5, 3787-3790; B. Karimi, M. Ghoreishi-Nezhad, J. H. Clark, Org. Lett., 2005, 7, 625-628; A.
Shaabania, P. Mirzaeia, S. Naderia, D. G. Leeb, Tetrahedron, 2004, 60, 11415-11420; R. J.
Gruffin, A. Henderson, N. J. Curtin, A. Echalier, J. A. Endicott, I. R. Hardcastle, D. R. Newell, M. E. M. Noble, L.-Z. Wang, B. T. Golding, J. Am. Chem. Soc, 2006, 128, 6012-6013).
The transformation from sulfides Vllg and VHIg (where R = H) to sulfonamides Vlli and Villi is detailed in K. Bahrami, M. M. Khodaei, M. Soheilizad, J. Org. Chem., 2009, 74, 9287- 9291. Other methods to achieve this transformation include: K. Bahrami, M. M. Khodaei, M. Soheilizad, Synlett, 2009, 2773-2776; G. K. S. Prakash, T. Mathew, C. Panja, G. A. Olah, J. Org. Chem., 2007, 72, 5847-5850; A. Nishiguchi, K. Maeda, S. Miki, Synthesis, 2006, 4131-4134; H. Veisi, R. Ghorbani-Vaghei, S. Hemmati, J. Mahmoodi, Synlett, 2011, 2315-2320.
Figure imgf000049_0001
Suitable intermediates from
Schema 3 to 6
Figure imgf000049_0002
Xlc
Scheme 7. Appending R3 to suitable intermediates of Schema 3 through 6.
In Scheme 7 it is understood that the practitioner of this invention would utilize intermediates prepared in Schema 3 through 6 that have any reactive functionality suitably protected with an orthogonal protecting group. An extensive discussion of protective group chemistry can be found in Wuts & Greene, Protective Groups in Organic Synthesis, 4th Ed. Wiley Interscience, ISBN 978-0-471-69754-1.
In the first step of Scheme 7 leading to the deprotected intermediate XI, the Protecting Group used (PG) is assumed to be either the N-benzyl or N-t-butoxycarbonyl. While these groups are recommended, the practitioner is by no means limited to them. One very convenient method for removal of the N-benzyl group, other than the standard hydrogenolysis conditions (see Wuts & Greene for details) is a two-step method using a- chloroethylchloro-formate in a halocarbon solvent such as dichloroethane or chloroform and the like, first at 0°C then heated to the reflux temperature of the solvent. In the second step the resulting a-chloroethyl-N-carbamate is heated at reflux in an alcohol solvent such as methanol or ethanol where upon XI is obtained (see Wuts & Greene for details). For the other recommended PG, the N-t-butoxycarbonyl group (-Boc), clean removal can be effected by 10 equivalents of trifiuoroacetic acid in a chlorocarbon solvent. A more extensive listing of conditions and references for the experimental procedures to remove this PG can be found in Wuts & Greene.
Intermediate XI can be alkylated to give XIa by one of two general approaches; standard N-alkylation with a halide or sulfonate ester or other active leaving group on a substrate appropriate to give the desired -R3 or reductive alkylation using a carbonyl compound, most preferably an aldehyde but also in some cases a ketone. Conditions for N-alkylation generally use a base (NaH, NaOH, Et3N, n-BuLi and the like), a primary or secondary halide (most preferentially an iodide or bromide) and solvent, such as an alcohol (MeOH or EtOH), THF, 1,4 dioxane, DMF, Hexamethylphosphoramide (HMTP), DMSO or a ketone (acetone or 2- butanone) at temperatures ranging from -78 °C to reflux temperature of the solvent. Other methods using an alcohol as a substrate to give -R3 include: A. Wetzel, S. Wockel, M.
Schelwies, M. K. Brinks, F. Rominger, P. Hofmann, M. Limbach, Org. Lett., 2013, 15; A. J. A. Watson, A. C. Maxwell, J. M. J. Williams, J. Org. Chem., 2011, 76, 2328-2331; M. H. S. A. Hamid, C. L. Allen, G. W. Lamb, A. C. Maxwell, H. C. Maytum, A. J. A. Watson, J. M. J.
Williams, J. Am. Chem. Soc, 2009, 131, 1766-1774; F. Zaragoza, H. Stephensen, J. Org. Chem, 2001, 66, 2518-2521.
Reductive alkylation is a very useful method for forming a carbon to nitrogen bond; conditions used for this transformation include a mixture of an appropriate aldehyde or ketone to give the desired -R3 with sodium cyanoborohydride or sodium triacetoxy borohydride in a variety of chlorocarbon solvents (CH2CI2 or CHCI3) or THF or 1 ,4-dioxane or an alcohol solvent (MeOH or EtOH) at 0°C up to the reflux temperature of the solvent,. An exhaustive review is available to delineate further methods for this transformation (see: Ellen W. Baxter and Allen B. Reitz, Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents, Organic Reactions, 1, 59, 2002). Other methods include: C. Guerin, V. Bellosta, G. GuiUamot, J. Cossy, Org. Lett., 2011, 13, 3478-3481; L. Blackburn, R. J. K. Taylor, Org. Lett., 2001, 3, 1637-1639.
It is possible to derivatize the intermediate XI to give the corresponding amides Xlb by using any activated version of the appropriate acid, commonly an acid chloride, anhydride or mixed anhydride, a trialkylamine base to remove any acid that may be generated and a wide range of solvents, such as CH2C12, CHC13, THF or 1,4-dioxane or the like. Of course, many alternative amine and acid coupling conditions will apply as well (for an extensive list of coupling agents that are suitable for the synthesis of amides see:
http://www.peptidesynthesisreagents.com/). Generally amide couplings using amino acid coupling agents take place in the presence of a trialkyl amine base (Et3N (triethylamine), N- methylmorpholine or Hunig's Base) in a solvent such as CHCI3, CH2C12 or DMF at temperatures ranging from 0°C to ambient temperature.
Alternatively, XI can be transformed to their corresponding ureas Xlb by reaction with the appropriate isocyanate, such as 0=C=N-R', or carbamoyl chloride, such as C1-(C=0)NH-R', or the corresponding p-nitrophenyl carbamate thereof, in a variety of solvents, such as CH2C12, CHCI3, THF, 1,4-dioxane, DMF, toluene and the like at temperatures ranging from -10°C to the reflux temperature of the solvent. In cases where HC1 is generated it may be useful to add a trialkylamine base such as Et3N, N-methyl morpholine or Hunig's Base.
It is understood that in addition to the methods illustrated above in Scheme 7, XI can be transformed into their carbamates Xlb directly by reaction with the corresponding activated carbonyl compound such as ClC(=0)-OR or an anhydride or mixed anhydride thereof, a trialkyl amine such as Et3N, N-methylmorpholine in a solvent such as a CH2C12, CHCI3, THF or 1,4-dioxane at temperatures ranging from -10°C to the reflux temperature of the solvent.
Furthermore amine XI can be transformed into the corresponding sulfonamides XIc as shown in Scheme 7 or by reaction with C1S02-R' a trialkyl amine such as Et3N,
N-methylmorpholine in a solvent such as a CH2C12, CHCI3, THF, 1,4-dioxane or pyridine at temperatures ranging from -10°C to the reflux temperature of the solvent.
Figure imgf000052_0001
Figure imgf000052_0002
Xla-c Formula 1 , an R
benzylamine derivative
Figure imgf000052_0003
XII: an R isoquinoline Xlla: an R isoquinolin-1 -amine derivative of Formula 1 of Formula 1
Scheme 8. Methods for preparing various R1 analogs of Formula 1. Phenylamidine analogs of Formula 1 can be derived from intermediates XIa-c where Y = -H by the method illustrated in Scheme 8 or under a variety of other conditions; for examples, see: K. Nadrah, M. Sollner Dolenc, Synlett, 2007, 1257-1258; FC Schaeffer, AP Krapcho J. Org. Chem., 1962, 27 (4), pp 1255-1258. The classical method of effecting this transformation is by formation of the imidate by using gaseous HC1 in a dry alcohol solution (MeOH, EtOH and the like) of XIa-c followed by removal of the solvent and stirring the resulting imidate salt with a solution of ammonia or ammonium acetate in a dry solvent such as an alcohol (MeOH, EtOH and the like), THF, 1,4-dioxane or a chlorocarbon (CHCI3 and the like).
It is recognized that the methodology for phenylamidine formation illustrated in Scheme 8 will also lead to other analogs of R1, such as the N-hydroxylamidine (-C(=NOH)NH2), an intermediate , or N-alkoxylamidine (-C(=NOR)NH2) by heating the either NH2OH or the appropriate analog of NH2OR in an alcohol solvent (MeOH, EtOH or the like) and simply omitting the reduction step. Furthermore, simple acylation of the N-hydroxylamidine will lead to the desired N-acetoxyamidine (-C(=NHO-C(=0)R)NH2) by omission of the reduction step.
For XIa-c where Y = -F the R1 benzo[d]isoxazol-3-amine derivative and the lH-indazol- 3-amine derivative can be obtained by the methods shown (PYS Lam, et al. J. Med. Chem. 2003, 46, 4405-4418). The intermediate XIa-c where Y = -Η can be readily reduced at the nitrile functionality to a benzylic amine R1 analog of Formula 1 with a hydride reducing agent such as lithium aluminum hydride or diborane and the like, in an aprotic solvent such as diethyl ether, THF or 1,4 dioxane at temperatures that range from -10°C to the reflux temperature of the solvent.
Finally, isoquinoline analog XII can be readily prepared from the known
7-isocyanatoisoquinoline by the application of the chemistry illustrated in Schema 1 through 7. XII, the R1 isoquinoline analog of Formula 1 can be transformed to Xlla,
the R1 isoquinolin-1 -amine analog of Formula 1, by the method describe in Scheme 8 (PYS Lam, et al. J. Med. Chem. 2003, 46, 4405-4418). The following non-limiting examples are presented to further facilitate an understanding of the present invention.
EXAMPLE 1
AminoQ -(3 -( 1 -benzylpiperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl)phenyl) methaniminium trifluoroacetate
Preparation of l-(l-benzylpiperidin-4-yl)-3-(3-cvanophenyl)urea
Figure imgf000054_0001
A solution of 3-cyanophenylisocyanate (2g, 13.88 mmol) and 4-amino-l- benzylpiperidine (3 ml, 15.26 mmol) in dry DMF (10 ml) was stirred at ambient temperature for 3h. The reaction was complete by tic (hexane: EtOAc 4: 1). This mixture was diluted with water (120 ml) then extracted with EtOAc (3x50 ml); the extracts were combined, washed with water (4x50 ml), brine (50 ml), dried and evaporated to give the product. This material was purified by silica gel chromatography on an Isco CombiFlash Rf ® using a gradient of CHCl3/MeOH; HRMS: for C20H22N4O calculated (M+H)+ = 335.18664 m/z, found (M+H)+ =335.18700 m/z.
Preparation of 3 -(3 -( 1 -benzylpiperidin-4-yl)-5 -methylene-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzonitrile
Figure imgf000054_0002
To a cooled solution (0°C) of (l-benzylpiperidin-4-yl)-3-(3-cyanophenyl)urea (4.8 g, 14.35 mmol) in Tetrahydrofuran (100 ml) and 3-chloro-2-(chloromethyl)prop-l-ene (4.15 ml, 35.9 mmol) was added sodium hydride (1.722 g, 43.1 mmol). The reaction mixture was allowed to come to room temperature and then was heated at 75°C for 5 hrs. TLC shows reaction complete. Added water to quench the reaction, solvent removed and the residue partitioned between sat NH4CI solution and EtOAc(2x75ml). The combined extracts were dried over Na2S04, filtered and evaporated. The crude product was purified by column chromatography on silica gel on an Isco CombiFlash Rf using a gradient of MeOH in CHC13; HRMS:C24H26N40 calculated (M+H)+ = 387.21794 m/z, found (M+H)+ = 387.21776 m/z.
Preparation of amino(3 -(3 -( 1 -benzylpiperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1
-yl)phenyl)methaniminium trifluoroacetate
Figure imgf000055_0001
EXAMPLE 1
A mixture of 3-(3-(l-benzylpiperidin-4-yl)-5-methylene-2-oxotetrahydropyrimidin- l(2H)-yl)benzonitrile (321 mg, 0.83 mmol), hydroxylamine hydrochloride (116 mg, 1.66 mmol) and diisopropyl ethylamine (0.28 ml, 1.66 mmol) in EtOH (15 ml) were heated at reflux for 4 h. Tic shows the reaction complete (5% MeOH in CHCI3); the solvent was removed and residue purified by column chromatography on silica gel on an Isco CombiFlash Rf ® using a gradient of MeOH in CHC13; HRMS: for C24H29N5O2 (M+2H)+2 = 210.62447 m/z; calculated (M+H)+ = 420.23940 m z, found (M+H)+ = 420.23871 m/z.
The oxime prepared above (180 mg) was dissolved in EtOH (30 ml) and shaken under an H2 atmosphere (38 psi) in the presence of Raney Nickel catalyst (170 mg) for 18 hours at ambient temperature. The reaction was purged with Ar then filtered through a Celite® pad and evaporated. The crude product was purified by column chromatography on silica gel on an Isco CombiFlash Rf ® using a gradient of MeOH in CHC13 with 2% NH4OH as an additive; it was submitted as a trifluoroacetate salt following lyophilization. HRMS: for C24H3iN50 found (M+2H)+2 = 203.6321 m z; calculated (M+H)+ = 406.26014 m/z, found (M+H) = 406.26004 m/z; H1 NMR (DMSO-d6, 400 MHz) δ: 9.2-8.8 (broad, 3H), 7.8-7.5 (m, 4H), 7.4-7.3 (m, 5H), 4.2 (m, 1H), 3.75 (dd, 1H), 3.55 (s, 2H), 3.5-3.4 (m, 2H), 3.05-2.9 (m, 3H), 2.25 (m, 1H), 2.1 (dd, 2H), 1.8 (m, 2H) and 1.6-1.5 ppm (m, 2H).
EXAMPLE 2
3 -(5 -Methyl-2-oxo-3 -(piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
INTERMEDIATE A Preparation of 3 -(5 -methylene-2-oxo-3 -(piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-y 1) benzonitrile
Figure imgf000056_0001
INTERMEDIATE A
To 3 -(3 -( 1 -benzylpiperidin-4-yl)-5 -methylene-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzonitrile (483 mg, 1.250 mmol) in dichloroethane was added 1-chloroethyl carbonochloridate (197 mg, 1.375 mmol) dropwise. The solution was refluxed for 1 hr. then cooled and evaporated to dryness. MeOH was then added and the reaction refluxed for 1 hr. The solvent removed by evaporation and crude separated by column chromatography an Isco CombiFlash Rf ® (12gm silica column) with a gradient of MeOH in CHC13 (5 to 10% MeOH gradient). The fractions containing product were combined and evaporated to give the title compound. HRMS: for C17H20N4O calculated (M+H)+ = 297.17099 m/z, found (M+H)+ = 297.17138 m/z; H1 NMR (D3COD, 400 MHz) δ: 8.0-7.5 (m, 4H), 5.2 (d, 2H), 4.4-4.3 (m, 2H), 4.3 (s, 2H), 4.0, (s, 2H), 3.6-3.4 (m, 2H), 3.2-3.0 (m, 2H) and 2.4-1.8 ppm (m, 4H).
3 -(5 -methyl-2-oxo-3 -(piperidin- -yl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000056_0002
EXAMPLE 2
The title compound was prepared from INTERMEDIATE A using the same two-step method used in the preparation of EXAMPLE 1 from 3-(3-(l-benzylpiperidin-4-yl)-5- methylene-2-oxotetrahydropyrimidin-l(2H)-yl)benzonitrile; HRMS: for C17H25N5O found (M+2H)+2= 158.61140 calculated (M+H)+ = 316.21319 m/z, found (M+H)+ = 316.21347 m/z. EXAMPLE 3
3 -(3 -( 1 -acetylpiperidin-4-yl)-5 -methyl-2-oxotetrahvdropyrimidin- 1 (2H)- vQbenzimidamide
Figure imgf000057_0001
EXAMPLE 3 was prepared by the same method used to prepare EXAMPLE 1 with l-(4- aminopiperidin-l-yl)ethanone substituted for l-benzylpiperidin-4-amine; HRMS: for
Ci7H27N502 calculated (M+H)+ = 358.22375m/z, found (M+H)+ = 358.22471m/z.
EXAMPLE 4
3 -(5 -methyl-3 -( 1 -(methylsulfonyl)piperidin-4-yl)-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000057_0002
EXAMPLE 4 was prepared by the same procedure used for EXAMPLE 1 with 1- benzylpiperidin-4-amine replaced by l-(methylsulfonyl)piperidin-4-amine; HRMS:
Ci8H27N503S calculated (M+H)+ = 394.19074 m/z, found (M+H)+ = 394.19154 m/z.
EXAMPLE 5
3 -(5 -methyl-2-oxo-3 -( 1 -(phenylsulfonyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000058_0001
EXAMPLE 5 was prepared by the same procedure used for EXAMPLE 1 with 1- benzylpiperidin-4-amine replaced by l-(phenylsulfonyl)piperidin-4-amine; HRMS:
C23H29N503S calculated (M+H)+ = 456.20639 m/z, found (M+H)+ = 456.20644 m/z.
EXAMPLE 6
3 -(5 -methyl-2-oxo-3 -( 1 -phenylpiperidin-4-yl)tetrahydropyrimidin- 1 (2H)- vQbenzimidamide
Figure imgf000058_0002
EXAMPLE 6 was prepared by the same method used to prepare EXAMPLE 1 with l-phenylpiperidin-4-amine substituted for l-benzylpiperidin-4-amine; HRMS: C23H29N5O found (M+2H)+2= 196.62821 calculated (M+H)+ = 392.24449 m/z, found (M+H)+ = 392.24321 m z.
EXAMPLE 7
3 -(5 -methyl-3 -( 1 -methylpiperidi -4-yl)-2-oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000058_0003
EXAMPLE 7 was prepared by the same method used to prepare EXAMPLE 1 with l-methylpiperidin-4-amine substituted for l-benzylpiperidin-4-amine; HRMS: C18H27N5O found (M+2H)+2= 165.61519 calculated (M+H)+ = 330.22884 m z, found (M+H)+ = 330.22849 m/z.
EXAMPLE 8
3 -(5 -methyl-2-oxo-3 -( 1 -(2-phenylacetyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000059_0001
EXAMPLE 8
Preparation of 3-(5-methyl-2-oxo-3-(l -(2-phenylacetyl)piperidin-4-yl)
tetrahydropyrimidin-l(2H)-yl)benzonitrile: To a mixture of 3-(5-methylene-2-oxo-3-(piperidin- 4-yl)tetrahydropyrimidin-l(2H)-yl)benzonitrile (296 mg, 0.999 mmol) and 2-phenylacetyl chloride (0.158 ml, 1.199 mmol) in dichloromethane (5ml) was added triethylamine (0.209 ml, 1.498 mmol) and the reaction was stirred at room temperature for 2.5 hrs, after which the reaction was evaporated to dryness and purified by column chromatography on an ISCO medium pressure chromatography device using a 12g silica column to give pure 3-(5-methyl-2-oxo-3-(l- (2-phenylacetyl)piperidin-4-yl)tetrahydropyrimidin-l(2H)-yl)benzonitrile.
3 -(5 -Methyl-2-oxo-3 -( 1 -(2-phenylacetyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl) benzonitrile was transformed into the amidine derivative, EXAMPLE 8, by the same two-step procedure used to prepare EXAMPLE 1; HRMS: for C25H3iN502 found (M+2H)+2= 217.63108 calculated (M+H)+ = 434.25505 m/z, found (M+H)+ = 434.25510 m/z.
EXAMPLE 9
3 -(3 -( 1 -benzoylpiperidin-4-y -5 -methyl-2-oxotetrahy dropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000059_0002
EXAMPLE 9 was prepared from INTERMEDIATE A by the same method used to prepare EXAMPLE 8 with benzoyl chloride replaced by 2-phenylacetyl chloride; HRMS: for C28H29N502 found (M+2H)+2= 210.62286 calculated (M+H)+ = 420.23940 m/z, found (M+H)+ = 420.23859 m/z. EXAMPLE 10
Tert-butyl (2-(4-(3 -(3 -carbamimidoylphenvO-5 -methyl-2-oxotetrahvdropyrimidin- 1 (2H)-yl) piperidin- 1 -yl)ethyl)carbamate
Figure imgf000060_0001
Preparation of tert-butyl (2-(4-(3-(3-cyanophenyl)-5-methylene-2- oxotetrahydropyrimidin-l(2H)-yl)piperidin-l-yl)ethyl)carbamate: A solution of 3 -(5 -methylene - 2-0X0-3 -(piperidin-4-yl)tetrahydropyrimidin-l(2H)-yl)benzonitrile (520 mg, 1.755 mmol), tert-butyl (2-bromoethyl)carbamate (472 mg, 2.105 mmol) and triethylamine (0.293 ml, 2.105 mmol) in dichloromethane (5 ml) was stirred at room temperature for 4 hrs. TLC shows no product formation. The reaction was heated at 40°C for 5hrs. After removing the solvent by evaporation, the crude was purified by column chromatography; LRMS: (M+H)+=440.2 .
EXAMPLE 10 was prepared from tert-butyl (2-(4-(3-(3-cyanophenyl)-5-methylene-2- oxotetrahydropyrimidin-l(2H)-yl)piperidin-l-yl)ethyl)carbamate by the same two-step amidine formation protocol used in EXAMPLE 1; HRMS: for C24H38N603 found (M+2H)+2= 230.15793 calculated (M+H)+ = 459.30782 m/z, found (M+H)+ = 459.30747 m/z.
EXAMPLE 11
Tert-butyl (2-(4-(3 -(3 -carbamimidoylphenvD-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) piperidin- 1 -yl)-2-oxoethyl)carbamate
Figure imgf000061_0001
EXAMPLE 1 1
Preparation of tert-butyl (2-(4-(3-(3-cyanophenyl)-5-methylene-2- oxotetrahydropyrimidin- 1 (2H)-yl)piperidin- 1 -yl)-2-oxoethyl)carbamate :
2-((tert-butoxycarbonyl)amino)acetic acid (222 mg, 1.265 mmol) and (2-(lH-benzotriazol-l-yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate) (HBTU) (576 mg, 1.518 mmol) were taken in acetonitrile (7 ml) and stirred at room temperature for 30 min. INTERMEDIATE A, 3-(5- methylene-2-oxo-3-(piperidin-4-yl)tetrahydropyrimidin-l(2H)-yl) benzonitrile, (450 mg, 1.518 mmol) was then added to the above solution followed by the addition of triethylamine (0.212 ml, 1.518 mmol). The reaction solution was stirred at room temperature overnight. Reaction was evaporated to dryness and the crude purified by column chromatography. HRMS: for
C24H3iN504: found (M-Boc)+= 354.19248, calculated (M+Na)+ = 476.22683 m/z, found
(M+Na)+ = 476.22678 m/z.
EXAMPLE 1 1 was prepared from tert-butyl (2-(4-(3-(3-cyanophenyl)-5-methylene-2- oxotetrahydropyrimidin-l(2H)-yl)piperidin-l-yl)-2-oxoethyl)carbamate by the same method used for EXAMPLE 1 ; HRMS: for C24H36N604 calculated (M+H)+ = 473.28708 m/z, found (M+H)+ = 473.28684 m/z.
EXAMPLE 12
2-(4-(3 -(3 -(amino(iminio)methyl)phenyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) piperidin- 1 -yOethanaminium tri-trifluroacetate
Figure imgf000062_0001
EXAMPLE 12 was prepared from EXAMPLE 10: To a solution of tert-butyl (2-(4-(3-(3- carbamimidoylphenyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl)piperidin- 1 -yl)ethyl) carbamate (160 mg, 0.349 mmol) in dichloromethane (15 ml) was added 2,2,2-trifluoroacetic acid (0.323 ml, 4.19 mmol) . The solution was stirred for 3 hrs at room temperature. TLC shows starting material still present then more 2,2,2-trifluoroacetic acid (0.323 ml, 4.19 mmol) was added and the reaction stirred for 4 hrs. The reaction mixture was evaporated and left in the freezer. The gummy residue was dried in vacuo for two hrs. and crystallized with EtOH and CH2C1; HRMS: for Ci9H3oN60 found (M+2H)+2= 180.12966 calculated (M+H)+ = 359.25539 m/z, found (M+H)+ = 359.25544 m/z.
EXAMPLE 13
2-(4-(3 -(3 -(amino(iminio)methyl)phenyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) piperidin- 1 -yl)-2-oxoethanaminium di-trifluroacetate
Figure imgf000062_0002
EXAMPLE 13 was prepared from EXAMPLE 1 1 by the same method used to prepare EXAMPLE 12; HRMS: for ^Η28Ν602 found (M+2H)+2= 187.12043 calculated (M+H)+ = 373.23465 m/z, found (M+H)+ = 373.23434 m z.
EXAMPLE 14
3 -(3 -( 1 -(benzylsulfonyl)piperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide INTERMEDIATE A
Figure imgf000063_0001
A solution of 3-(5-methylene-2-oxo-3-(piperidin-4-yl)tetrahydropyrimidin-l(2H)- yl)benzonitrile (INTERMEDIATE A , 450 mg, 1.518 mmol),phenylmethanesulfonyl chloride (347 mg, 1.822 mmol) and triethylamine (0.317 ml, 2.278 mmol) in dichloromethane (8ml) was stirred at room temperature overnight. The reaction mixture was evaporated and purified by column chromatography.
The product isolated above was treated by the same two step method used to form the amidine analog in EXAMPLE 1 to give EXAMPLE 14; HRMS:C24H3iN503S calculated (M+H)+ = 470.22204 m/z, found (M+H)+ = 470.22194 m/z.
EXAMPLE 15
3 -(5 -methyl-2-oxo-3 -( 1 -(pyridin-3 -ylmethyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000063_0002
EXAMPLE 15
Preparation of 3 -(5 -methylene -2-oxo-3 -( 1 -(pyridin-3 -ylmethyl)piperidin-4-yl) tetrahydropyrimidin-l(2H)-yl)benzonitrile: A solution of 3 -(5 -methylene -2-oxo-3 -(piperidin-4- yl)tetrahydropyrimidin-l(2H)-yl)benzonitrile (370 mg, 1.248 mmol),
3-(chloromethyl)pyridine, HC1 (225 mg, 1.373 mmol) and triethylamine (0.383 ml, 2.75 mmol) in DMF (10 ml) was heated at 50°C for 4 hrs. TLC shows reaction complete; it was poured into 100 mL of water, extracted aqueous layer with ethyl acetate (EtOAc) (3 X 50 ml). The combined organic layers were washed with saturated NaCl, dried and evaporated to give a crude product which was purified by column chromatography. HRMS: C23H25N50 calculated (M+H)+ = 388.21319 m/z, found (M+H)+ = 388.213.52m/z.
EXAMPLE 15 was prepared from 3-(5-methylene-2-oxo-3-(l-(pyridin-3- ylmethyl)piperidin-4-yl)tetrahydropyrimidin-l(2H)-yl)benzonitrile by the two step amidine formation procedure used to prepare EXAMPLE 1; HRMS: C23H3oN60 found (M+2H)+2= 204.13171 calculated (M+H)+ = 407.25539 m/z, found (M+H)+ = 407.25508 m/z.
EXAMPLE 16
3 -(5 -methyl-2-oxo-3 -( 1 -(pyridin-2-ylmethyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000064_0001
EXAMPLE 16 was prepared by the method used for EXAMPLE 15 with 3- (chloromethyl)pyridine, HCl replaced by 2-(chloromethyl)pyridine, HCl; HRMS:C23H3oN60 found (M+2H)+2= 204.13151 calculated (M+H)+ = 407.25539 m/z, found (M+H)+ = 407.25473 m/z.
EXAMPLE 17
3 -(5 -methyl-2-oxo-3 -( 1 -(pyridin-4-ylmethyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000064_0002
EXAMPLE 17 was prepared by the method used for EXAMPLE 15 with 3- (chloromethyl)pyridine, HCl replaced by 4-(chloromethyl)pyridine, HCl ; HRMS:C23H30N6O: found (M+2H)+2= 204.13090 calculated (M+H)+ = 407.25539 m/z, found (M+H)+ = 407.25484 m/z.
EXAMPLE 18
3 -(5 -methyl-2-oxo-3 -( 1 -(4-(trifluoromethyl)benzyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000065_0001
EXAMPLE 18 was prepared by the method used for EXAMPLE 15 with
3-(chloromethyl)pyridine, HCl replaced by l-(bromomethyl)-4-(trifluoromethyl)benzene;
HRMS: C25H3oF3N50: found (M+2H)+2= 237.62769 calculated (M+H)+ = 474.24752 m/z, found (M+H)+ = 474.24615 m/z.
EXAMPLE 19
3 -(5 -methyl-2-oxo-3 -( 1 -(3 -(trifluoromethyl)benzyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000065_0002
EXAMPLE 19 was prepared by the method used for EXAMPLE 15 with
3-(chloromethyl)pyridine, HCl replaced by l-(bromomethyl)-3-(trifluoromethyl)benzene;
HRMS: C25H30F3N5O: found (M+2H)+2= 237.63734 calculated (M+H)+ = 474.24752 m/z, found (M+H)+ = 474.24705 m/z.
EXAMPLE 20
3 -(5 -methyl-2-oxo-3 -( 1 -(2-(trifluoromethyl)benzyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000066_0001
CF3
EXAMPLE 20 was prepared by the method used for EXAMPLE 15 with
3-(chloromethyl)pyridine, HCl replaced by l-(bromomethyl)-2-(trifluoromethyl)benzene; HRMS: C25H3oF3N50: found (M+2H)+2= 237.62735 calculated (M+H)+ = 474.24752 m/z, found (M+H)+ = 474.24653 m/z.
EXAMPLE 21
3 -(3 -( 1 -(3 -fluorobenzyl)piperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000066_0002
EXAMPLE 21 was prepared by the method used for EXAMPLE 15 with
3-(chloromethyl)pyridine, HCl replaced by l-(bromomethyl)-3-fluorobenzene; HRMS:
C24H30FN5O: found (M+2H)+2= 212.62974 calculated (M+H)+ = 424.25072 m/z, found (M+H) = 424.25044 m/z.
EXAMPLE 22
3 -(3 -( 1 -(2-fluorobenzyl)piperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000066_0003
EXAMPLE 22 was prepared by the method used for EXAMPLE 15 with
3-(chloromethyl)pyridine, HCl replaced by l-(bromomethyl)-2-fluorobenzene; HRMS:
C24H30FN5O: found (M+2H)+2= 212.63075 calculated (M+H)+ = 424.25072 m z, found (M+H) = 424.25008 m/z. EXAMPLE 23
3 -(5 -methyl-2-oxo-3 -( 1 -(thiophen-2-ylsulfonyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000067_0001
EXAMPLE 23 was prepared from INTERMEDIATE A by the same procedure used for EXAMPLE 14 with thiophene-2-sulfonyl chloride substituted for phenylmethanesulfonyl chloride. HRMS: C2iH27N503S2 calculated (M+H)+ = 462.16281 m/z, found (M+H)+ =
462.16299 m/z.
EXAMPLE 24
3 -(5 -methyl-3 -( 1 -(morpholinosulfony l)piperidin-4-yl)-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000067_0002
EXAMPLE 24 was prepared from INTERMEDIATE A by the same procedure used for EXAMPLE 14 with morpholine-4-sulfonyl chloride substituted for phenylmethanesulfonyl chloride; HRMS: C21H32N604S calculated (M+H)+ = 465.22785 m/z, found (M+H)+ = 465.22839 m/z.
EXAMPLE 25
3 -(3 -( 1 -(( 1 H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)- yObenzimidamide
Figure imgf000068_0001
EXAMPLE 25 was prepared from INTERMEDIATE A by the same procedure used for EXAMPLE 14 with lH-imidazole-4-sulfonyl chloride substituted for phenylmethanesulfonyl chloride;
Figure imgf000068_0002
calculated (M+H)+ = 446.19688 m/z, found (M+H)+ =
446.19680 m/z.
EXAMPLE 26
AminoQ -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) phenyDmethaniminium trifluoroacetate
Preparation of tert-butyl 4-((3-(3-cvanophenyl)ureido)methyl)piperidine-l-carboxylate
Figure imgf000068_0003
A solution of 3-isocyanatobenzonitrile (6g, 41.6 mmol) and tert-butyl 4- (aminomethyl)piperidine-l-carboxylate (10.57 ml, 50.0 mmol) in DMF (30 ml) was stirred at room temperature overnight. The reaction solution was poured in water; a white gummy solid separated out. This material was dissolved in CHCI3 (200 ml), washed with brine, dried
(MgS04) and evaporated. This material was purified by column chromatography on silica gel on an Isco CombiFlash Rf ® using a gradient of MeOH in CHCI3.
INTERMEDIATE B
Preparation of tert-butyl 4-((3-(3-cyanophenyl)-5-methylene-2-oxotetrahydropyrimidin-l(2H)- yOmethyOpiperidine- 1 -carboxylate
Figure imgf000069_0001
INTERMEDIATE B
To tert-butyl 4-((3-(3-cyanophenyl)ureido)methyl)piperidine-l-carboxylate (15g, 41.8 mmol) in Tetrahydrofuran (250ml) was added 3-chloro-2-(chloromethyl)prop-l-ene (7.75 ml, 67.0 mmol) followed by the addition of sodium hydride (4.35 g, 109 mmol) at room temperature. After 10 min the reaction was heated at 75 °C for 5 h. After the reaction is complete (tic), water (1 ml) was added to quench the reaction and the solvent removed. The residue was partitioned between saturated NH4C1 solution and EtOAc (75ml); the aqueous layer was extracted with EtOAc (75 ml) a second time. The combined EtOAc extracts were dried over Na2S04, filtered and evaporated. This material was purified by column chromatography on silica gel on an Isco CombiFlash R ® using a gradient of MeOH in CHC13.
INTERMEDIATE C
Preparation of 3 -(5 -methylene-2-oxo-3 -(piperidin-4-ylmethyl)tetrahydropyrimidin- 1 (2H)-yl) benzonitrile
Figure imgf000069_0002
INTERMEDIATE C
To a solution of tert-butyl 4-((3-(3-cyanophenyl)-5-methylene-2-oxotetrahydropyrimidin- l(2H)-yl)methyl)piperidine-l-carboxylate (5.5g, 13.40 mmol) in dichloromethane (75 ml) was added 2,2,2-trifluoroacetic acid (10.32 ml, 134 mmol). The solution turned orange-red. TLC after 2 hours showed no starting material. The reaction was evaporated, 70 ml of EtOH added and then evaporated again to remove the last trace of acid. This material was dried in vacuo for 2 hours then triturated with 10 mis of CH2CI2 (2x) to give purified material. A second crop was obtained by combining the supernatant solutions and evaporating. Trituration of this material gave a second crop of product. LRMS: (M+H)+ = 311 m/z. INTERMEDIATE D
Preparation of 3-(3-((l-benzylpiperidin-4-yl)methyl)-5-methylene-2-oxotetrahydropyrimidin-l -yl)benzonitrile
Figure imgf000070_0001
INTERMEDIATE D
To a solution of 3-(5-methylene-2-oxo-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-l (2H)-yl)benzonitrile (260 mg, 0.838 mmol) and triethylamine (0.257 ml, 1.843 mmol) in DMF (4 ml) was added (bromomethyl)benzene (0.109 ml, 0.921 mmol), and the solution was stirred at room temperature for 4 hrs. The reaction was complete by LC/MS; it was poured into water and extracted with EtOAc (2x 40ml). The combined extracts were washed with brine, dried (Na2S04) then evaporated. This crude product was separated and purified by column chromatography on silica gel on an Isco CombiFlash R ® using a gradient of MeOH in CHC13; HRMS: for
C25H28N4O calculated (M+H)+ = 401.23359 m/z, found (M+H)+ = 401.23282 m/z.
Preparation of amino(3-(3-((l -benzylpiperidin-4-yl)methyl)-5-methyl-2-oxotetrahydropyrimidin- -yl)phenyl)methaniminium trifluoroacetate
Figure imgf000070_0002
A mixture of3 -(3 -((l-benzylpiperidin-4-yl)methyl)-5 -methylene -2- oxotetrahydropyrimidin-l(2H)-yl)benzonitrile (260 mg, 0.649 mmol),hydroxylamine, HC1 (90 mg, 1.298 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.226 ml, 1.298 mmol) in EtOH was refluxed for 5hrs. The solvent was removed and the residue purified by column chromatography on silica gel on an Isco CombiFlash R ® using a gradient of MeOH in CHC13; HRMS: for C25H3iN502 calculated (M+H)+ = 434.25505 m/z, found (M+H)+ = 434.25527 m/z; H1 NMR (D3COD, 400 MHz) δ: 7.6-7.2 (m, 3H), 5.2 (d, 2H), 4.3 (s, 2H), 4.05 (s, 2H), 3.9 (s (broad), 2H), 3.35 (s, 2H), 3.2 (m, 2H), 2.6-2.5 (m, 2H), 1.95-1.90 (m, 1H), 1.9-1.8 (m, 2H) and 1.5-1.4 ppm (m, 2H).
The oxime prepared above (233 mg) was dissolved in EtOH (30 ml) and shaken under an H2 atmosphere (38 psi) in the presence of Raney Nickel catalyst (250 mg) for 18 hours at ambient temperature. The reaction was purged with Ar then filtered through a Celite® pad and evaporated. The crude product was purified by column chromatography on silica gel on an Isco CombiFlash Rf ® using a gradient of MeOH in CHC13 with 2% NH4OH as an additive; it was submitted as a trifluoroacetate salt following lyophilization. HRMS: for C25H33NsO, calculated (M+2H)+2 = 210.64153 m/z; found (M+2H)+2 = 210.64215 m/z; (M+H -CH2C6H5)+ = 330.22801 m/z; H1 NMR (D3COD, 400 MHz) δ: 7.8-7.2 (m, 4H), 7.35 (s, 6H), 3.75 (d, 1H), 3.7 (s, 2H), 3.5 (t, 1H), 3.45 (dd, 1H), 3.2 (t, 1H), 3.0 (d, 1H), 2.4 (broad m, 1H), 2.2 (t, 2H), 1.8 (m, 1H), 1.75 (d, 2H), 1.4 (q, 2H) and 1.1 ppm (d, 3H).
EXAMPLE 27
3 -(5 -methyl-2-oxo-3 -(piperidin-4-ylmethyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000071_0001
INTERMEDIATE C
EXAMPLE 27 was prepared from INTERMEDIATE C by the same two-step method used to prepare the amidine in EXAMPLE 26.
EXAMPLE 28
3 -(3 -( 1 -(( 1 H-pyrazol-4-vDsulfonvDpiperidin-4-vD-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000071_0002
EXAMPLE 28 was prepared from INTERMEDIATE A by the same procedure used for EXAMPLE 14 with lH-pyrazole-4-sulfonyl chloride substituted for phenylmethanesulfonyl chloride;
Figure imgf000072_0001
calculated (M+H)+ = 446.19688 m/z, found (M+H)+ =
446.19682 m/z.
EXAMPLE 29
3 -(5 -methyl-3 -(!-(( 1 -methyl- lH-pyrazol-4-v0sulfonv0piperidin-4-yl)-2- oxotetrahydropyrimidin- 1 (2 -yl)benzimidamide
Figure imgf000072_0002
EXAMPLE 29 was prepared from INTERMEDIATE A by the same procedure used for EXAMPLE 14 with 1 -methyl- lH-pyrazole-4-sulfonyl chloride substituted for
phenylmethanesulfonyl chloride; HRMS:C2iH3oNy03S calculated (M+H)+ = 460.21254 m z, found (M+H)+ = 460.21291 m/z.
EXAMPLE 30
3 -(5 -methyl-2-oxo-3 -(( 1 -(phenylsulfonyl)piperidin-4-yl)methyl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide
Figure imgf000072_0003
EXAMPLE 30
Preparation of 3-(5-methylene-2-oxo-3-((l-(phenylsulfonyl)piperidin-4- yl)methyl)tetrahydropyrimidin-l(2H)-yl)benzonitrile: A solution of 3-(5-methylene-2-oxo-3- (piperidin-4-ylmethyl)tetrahydropyrimidin-l(2H)-yl)benzonitrile (250 mg, 0.805 mmol) benzenesulfonyl chloride (INTERMEDIATE C, 171 mg, 0.967 mmol) and N-ethyl-N- isopropylpropan-2-amine (0.168 ml, 0.967 mmol) in CH2CI2 (4 ml) was stirred at RT for 4 hrs. TLC after 4 hrs. shows no starting material. After evaporating the reaction mixture, the product was purified by column chromatography.
3 -(5 -methylene-2-oxo-3 -(( 1 -(phenylsulfony l)piperidin-4-yl)methyl)tetrahydropyrimidin- l(2H)-yl)benzonitrile prepared above was transformed to the amidine, and EXAMPLE 30 was prepared by the same two-step procedure used for EXAMPLE 26; HRMS:C24H3iN503S calculated (M+H)+ = 470.22204 m/z, found (M+H)+ = 470.22182 m/z.
EXAMPLE 31
3 -(5 -methyl-2-oxo-3 -(( 1 -(thiophen-2-ylsulfonyl)piperidin-4-yl)methyl)tetrahvdropyrimidin- 1
(2H)-yl)benzimidamide
Figure imgf000073_0001
EXAMPLE 31 was prepared by the same method used for EXAMPLE 30 with benzenesulfonyl chloride replaced by thiophene-2-sulfonyl chloride; HRMS: C22H29N503S2 calculated (M+H)+ = 476.17845 m/z, found (M+H)+ = 476.17790 m z.
EXAMPLE 32
3 -(5 -methyl-3 -(( 1 -(morpholinosulfonyl)piperidin-4-yl)methyl)-2-oxotetrahydropyrimidin- 1 (2H)- yObenzimidamide
Figure imgf000073_0002
EXAMPLE 32 was prepared by the same method used for EXAMPLE 30 with benzenesulfonyl chloride replaced by morpholine-4-sulfonyl chloride; HRMS:C22H34N604S calculated (M+H)+ = 479.24350 m/z, found (M+H)+ = 479.24307 m/z. EXAMPLE 33
l-(3-(aminomethv0phenv0-3-((4-benzylcvclohexyl)m
(lHVone
Figure imgf000074_0001
INTERMEDIATE D EXAMPLE 33
To a solution of 3-(3-((l-benzylpiperidin-4-yl)methyl)-5-methylene-2- oxotetrahydropyrimidin-l(2H)-yl)benzonitrile (INTERMEDIATE D, 291 mg, 0.727 mmol) in tetrahydrofuran (THF) (5 ml) was added aluminum(III) lithium hydride (0.799 ml, 0.799 mmol) (I molar solution in THF) under argon. The reaction mixture was stirred at room temperature for 30 min and refluxed for 2.5 hrs. TLC shows no starting material. The reaction was diluted with ether (40 ml) and there was added 30 mg of water followed by 30mg of IN NaOH and an additional 90 mg of water more. This was stirred at RT for 15 min, and MgSC"4 was added and stirred for 15 min more. The mixture was filtered and evaporated to give a crude material that was purified by column chromatography; HRMS: C25H33N4O: found (M+2H)+2= 203.13588 calculated (M+H)+ = 405.26489 m/z, found (M+H)+ = 405.26453 m/z.
EXAMPLE 34
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -(hydroxymethyl)-2-oxotetrahydropyrimidin- 1 (2FQ- vDbenzimidamide
Figure imgf000074_0002
INTERMEDIATE B INTERMEDIATE E tert-butyl 4-((3 -(3 -cyanophenyl)-5 -(hydroxymethyl)-2-oxotetrahydropyrimidin- 1 (2FQ- vDmethvDpiperidine- 1 -carboxylate : To a solution of tert-butyl 4-((3-(3-cyanophenyl)-5-methylene-2-oxotetrahydropyrimidin- l(2H)-yl)methyl)piperidine-l-carboxylate (250mg, 0.609 mmol) in THF (1 ml) was added 9- BBN (1.462 ml, 0.731 mmol) slowly and stirred at room temp for 6 hrs, followed by the addition of a suspension of sodium perborate (276mg) in water (3ml). The combined reaction mixture was then stirred overnight. After overnight stirring the crude reaction mixture was filtered, washed solid with diethyl ether, extracted the aqueous layer with more ether, combined ether extracts dried and evaporated to give crude material which was purified by column
chromatography. After purification 120 mg of the INTERMEDIATE E was obtained as a white solid in 46% yield.
HRMS: C23H32N4O4 Calculated (M+Na)+ = 451.23158 m/z, found (M+Na)+ = 451.23187 m/z. 1H NMR (400 MHz, DMSO-d6) δ 7.73 (dt, J= 2.2, 1.0 Hz, 1H), 7.62 (ddd, J= 7.9, 2.3, 1.5 Hz, 1H), 7.55 - 7.52 (m, 1H), 7.50 (d, J= 7.8 Hz, 1H), 4.79 (t, J= 5.2 Hz, 1H), 3.92 (d, J= 13.1 Hz, 2H), 3.74 - 3.67 (m, 1H), 3.60 - 3.52 (m, 1H), 3.46 (t, J= 5.8 Hz, 2H), 3.42 - 3.36 (m, 1H), 3.25 - 3.18 (m, 1H), 3.17 (d, J= 5.2 Hz, 1H), 3.12 (dd, J= 13.5, 7.0 Hz, 1H), 2.76-2.63 (m, 2H), 2.30-2.21 (m, 1H), 1.89-1.79 (1H), 1.64-1.53 (m, 2H), 1.39 (s, 9H), 1.00 (tq, J= 12.3, 7.4, 6.2
Hz, 2H).
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -(hvdroxymethyl)-2-oxotetrahydropyrimidin- 1 (2H)- vDbenzonitrile
Figure imgf000075_0001
INTERMEDIATE E
To a solution of tert-butyl 4-((3-(3-cyanophenyl)-5-(hydroxymethyl)-2- oxotetrahydropyrimidin-l(2H)-yl)methyl)piperidine-l-carboxylate (1.1 g, 2.57 mmol) in CH2CI2 (15 ml), 2,2,2-trifluoroacetic acid (TFA) (1.978 mmol, 25.7 mmol) was added and this mixture was stirred for 30 min at room temperature. After reaction was complete the crude material is triturated with chloroform followed by ethanol to obtain the desired Boc deprotected
intermediate as a gummy solid in quantitative yield (843 mg). The crude is used as such in next HRMS: C18H24N4O2: Calculated (M+Na)+ = 329.19720 m/z, found (M+Na)+ = 329.19733 m/z.
To a solution of 3-(5-(hydroxymethyl)-2-oxo-3-(piperidin-4- ylmethyl)tetrahydropyrimidin-l(2H)-yl)benzonitrile (0.843 g, 2.57 mmol) and
(bromomethyl)benzene (0.335 ml, 2.827) in dichloromethane (DCM) (15 ml) was added triethylamine (0.788 ml,5.654 mmol) and the reaction was stirred at room temperature for 15 min. After reaction was complete, it was evaporated and purified by column chromatography to obtain the desired product (590 mg, 55% yield) as a white solid.
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -(hydroxymethyl)-2-oxotetrahydropyrimidin- 1 (2H)- benzimidamide
Figure imgf000076_0001
EXAMPLE 34
A combined solution of 3-(3-((l-benzylpiperidin-4-yl)methyl)-5-(hydroxymethyl)-2- oxotetrahydropyrimidin-l(2H)-yl)benzonitrile (0.220 g, 0.526 mmol), hydroxylamine hydrochloride (73 mg, 1.051 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.183 ml, 0.526 mmol) in ethanol (10 ml) was stirred for 6 h at 85 °C followed by stirring overnight at room temperature. After reaction was complete, it was evaporated and purified by column
chromatography to obtain the desired product as a white solid (115 mg, 45% yield). LRMS: (M+H)+ = 452.3 m/z
The oxime, 3-(3-((l-benzylpiperidin-4-yl)methyl)-5-(hydroxymethyl)-2- oxotetrahydropyrimidin-l(2H)-yl)-N-hydroxybenzimidamide (112 mg , 0.284 mmol), from the previous reaction was taken up in ethanol (20 ml) and Raney Ni (100 mg, wet weight, washed with water and then ethanol) was added and the combined solution was placed on a Parr shaker and continued reaction under hydrogen atmosphere at 40 psi. After overnight reaction, the crude was filtered through Celite washing with methanol. The solvent was removed and the residue was purified the by column chromatography to obtain the desired product as a white solid (14 mg, 13% yield). HRMS: CzsHssNsC^: Calculated (M+H)+ = 436.27070 m/z, found (M+H)+ = 436.27050 m/z. 1H NMR (400 MHz, Methanol-^) δ 7.64 - 7.62 (m, 1H), 7.58 - 7.55 (m, 1H), 7.55 - 7.51 (m, 2H), 7.34 - 7.30 (m, 4H), 7.30 - 7.23 (m, 1H), 3.80 (dd, J= 11.6, 4.2 Ηζ,ΙΗ), 3.67 - 3.59 (m, 3H), 3.55-3.49 (m, 3H), 3.30 - 3.26 (m, 3H), 2.92 (br.d, J= 11.6 Hz, 2H), 2.43- 2.33 (m, 1H), 2.08 - 1.98 (m, 2H), 1.70 (d, J= 13.5 Hz, 3H), 1.33 (q, J= 10.8, 10.4 Hz, 2H).
EXAMPLE 35
3 -(5 -((benzyloxy)methyl)-3 -(( 1 -benzylpiperidin-4-yl)methyl)-2-oxotetrahydropyrimidin- 1 (2H)- yObenzimidamide
Figure imgf000077_0001
INTERMEDIATE E
Tert-butyl 4-((5 -((benzyloxy)methyl)-3 -(3 -cyanophenyl)-2-oxotetrahydropyrimidin- 1 (2H)- vDmethvDpiperidine- 1 -carboxylate :
To a solution of tert-butyl 4-((3-(3-cyanophenyl)-5-(hydroxymethyl)-2- oxotetrahydropyrimidin-l(2H)-yl)methyl)piperidine-l -carboxylate (429 mg, 1 mmol) in tetrahydrofuran (10ml) was added sodium hydride (52.0 mg, 1.300 mmol). This was stirred at room temperature for 5 min and then (bromomethyl)benzene (0.190 ml, 1.600 mmol) was added. The reaction was heated at 65 °C for 6 hrs. After reaction was complete by TLC, it was cooled to room temperature, quenched with sat.NH4Cl solution, then extracted with ethyl acetate (2 X 20ml). The combined organic extracts were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The resulting crude was purified by column chromatography to obtain the desired product as a white solid (197 mg, 38% yield). LRMS: (M+H-Boc)+ = 419.2 m/z, and (M+H-'Bu)+ = 463.2
3 -(5 -((benzyloxy )methyl)-3 -(( 1 -benzylpiperidin-4-yl)methyl)-2-oxotetrahydropyrimidin- 1 (2H)- yObenzimidamide
Figure imgf000078_0001
EXAMPLE 35
After benzylation of the INTERMEDIATE E as described above, EXAMPLE 35 is synthesized following similar synthetic sequence discussed in EXAMPLE 34 involving a four step synthetic route. HRMS: C32H39N5O2 Calculated (M+H)+ = 526.31765 m/z, found (M+H) = 526.31701 m z. 1H NMR (400 MHz, Methanol-i 4) δ 7.64 (dr.s, 1H), 7.61 - 7.58 (m, 3H), 7.52-7.45 (m, 5H), 7.34 - 7.25 (m, 5H), 4.54 (s, 2H), 4.22 (s, 2H), 3.85 (dd, J= 11.6, 4.2 Hz, 1H), 3.68 (dd, J= 11.7, 7.5 Hz, 1H), 3.61 (d, J= 6.7 Hz, 2H), 3.57 (dd, J= 12.0, 4.7 Hz, 1H), 3.45 - 3.34 (m, 5H), 2.90 (br.s, 2H), 2.63-2.51 (m, 1H), 2.05-1.98 (m, 1H), 1.92 (t, J= 12.6 Hz, 2H), 1.5-1.45 (m, 2H).
EXAMPLE 36
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -(methoxymethyl)-2-oxotetrahydropyrimidin- 1 (2H)- yObenzimidamide
Figure imgf000078_0002
EXAMPLE 36 was prepared by the same method used for EXAMPLE 35 with benzyl bromide replaced by methyl iodide. HRMS: C26H35N5O2: Calculated (M+H)+ = 450.28635 m/z, found (M+H)+ = 450.28638 m/z. 1H NMR (400 MHz, Methanol-^) δ 7.68 (dq, J= 1.8, 1.3 Hz, 1H), 7.65 - 7.59 (m, 3H), 7.45 (td, J= 7.4, 6.4, 3.2 Hz, 5H), 4.11 (br. s, 2H), 3.82 (ddd, J = 11.6, 4.3, 1.3 Hz, 1H), 3.66 (dd, J= 11.6, 8.0 Hz, 1H), 3.53 (ddd, J= 11.9, 4.8, 1.3 Hz, 2H), 3.50 (dd, J= 6.7, 1.5 Hz, 2H), 3.40-3.33 (m, 7H), 2.78 (br.s, 2H), 2.61 - 2.50 (m, 1H), 2.06-1.96 (m, 1H), 1.90 (d, J= 14.7 Hz, 2H), 1.49 (d, J= 14.2 Hz, 2H).
EXAMPLE 37
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -(methylsulfonamidomethyl)-2-oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000079_0001
INTERMEDIATE E INTERMEDIATE F tert-butyl 4-((3-(3-cyanophenyl)-5-formyl-2-oxotetrahydropyrimidin- 1 (2H)- yOmethyOpiperidine- 1 -carboxylate :
To a stirred solution of tert-butyl 4-((3-(3-cyanophenyl)-5-(hydroxymethyl)-2- oxotetrahydropyrimidin-l(2H)-yl)methyl)piperidine-l -carboxylate (277 mg, 0.646 mmol) in CH2C12 (3.5 ml), Dess-Martin Periodinane (548 mg, 1.293 mmol) followed by TFA (149 μΐ, 1.939 mmol) were added at RT and stirred for 90 min. After 90 min the reaction was quenched with 10% of Na2S203 (5 ml) followed by sat. NaHC03 solution (5 ml) and stirred vigorously for 30 min. Afterwards the reaction mixture was transferred to a separatory funnel and the separated aqueous layer washed thrice with CH2C12 (10 ml). The combined organic layers were dried over MgS04 and concentrated under reduced pressure. After purification by column chromatography there was obtained the desired product as a gummy solid in quantitative yields (275 mg).
HRMS: for hemiacetal C24H34N405: Calculated (M+Na)+ = 481.24214 m/z, found (M+Na)+ = 481.24163 m/z
1H NMR (400 MHz, Chloroform-^ ) δ 9.79 (s, 1H), 7.60 - 7.58 (m, 1H), 7.54 (dtd, J = 7.0, 2.3, 0.8 Hz, 1H), 7.47 - 7.43 (m, 2H), 4.18 - 3.95 (m, 4H), 3.80 (ddd, J= 12.1, 4.4, 1.4 Hz, 1H), 3.72 - 3.66 (m, 1H), 3.55 - 3.08 (m, 2H), 3.04 - 2.95 (m, 1H), 2.70 (t, J= 12.7 Hz, 2H), 1.91 (qdt, J = 10.6, 7.1, 3.9 Hz, 2H), 1.65 (t, J = 12.4 Hz, 2H), 1.59 - 1.54 (m, 1H), 1.45 (s, 9H), 1.29 - 1.11 (m, 2H). tert-butyl 4-(Y5 -(aminomethyl)-3 -(3 -cyanophenyl)-2-oxotetrahydropyrimidin- 1 (2H)- methvDpiperidine- 1 -carboxylate
Figure imgf000080_0001
INTERMEDIATE F INTERMEDIATE G
To a stirred solution of aldehyde (121 mg, 0.284 mmol) in saturated NH4OAc in EtOH (5 ml), was added sodium cynaoborohydride (53.5 mg, 0.851 mmol) and ammonia (2.2 mL, 102 mmol) (30% aq. solution, NH4OH solution) at room temperature. This reaction mixture was refluxed for 15 h. The reaction was then cooled to room temperature, the solvent was evaporated and the resulting heterogeneous residue was separated between H20 and CH2C12 . The aqueous layer washed twice with CH2C12 (2 X 10 mL). The combined organic layers were dried over anhydrous MgS04 and concentrated under reduced pressure to obtain an off white solid. Further purification over silica gel yielded 62 mg (51%) of the desired product as a colorless oil. HRMS: C23H33N503 calculated (M+Na)+ = 450.24756 m/z, found (M+Na)+ = 450.24684 m/z. 1H NMR (400 MHz, Chloroform-;/) δ 7.60 (dq, J= 1.9, 0.9 Hz, 1H), 7.59 - 7.54 (m, 1H), 7.41 - 7.38 (m, 2H), 4.10 (d, J= 11.9 Hz, 2H), 3.77 (ddd, J= 11.4, 4.3, 1.3 Hz, 1H), 3.56 (dd, J= 11.3, 8.6 Hz, 1H), 3.51 - 3.44 (m, 1H), 3.24 (dd, J= 11.7, 8.5 Hz, 2H), 2.83 (dd, J= 6.9, 1.2 Hz, 2H), 2.69 (t, J= 12.8 Hz, 2H), 2.30 - 2.18 (m, 1H), 1.91 (ddp, J= 11.4, 7.6, 3.7 Hz, 1H), 1.65 (dq, J= 12.8, 3.7, 2.9 Hz, 2H), 1.44 (d, J= 0.7 Hz, 9H), 1.37 - 1.23 (m, 2H), 1.24 - 1.11 (m, 3H). tert-butyl 4-((3 -(3 -cyanophenyl)-5 -(methylsulfonamidomethyl)-2-oxotetrahydropyrimidin-
1 (2H)-yl)methyl)piperidine- 1 -carboxylate
Figure imgf000081_0001
A stirred solution of amine (143 mg, 0.334 mmol) in DCM (3.5 mL), triethylamine (0.14 ml, 1.003 mmol) and DMAP (4.09 mg, 0.033 mmol) were stirred for 15 min at room
temperature, then, methanesulfonylchloride (0.029 ml, 0.368 mmol) was added. This mixture was stirred for an additional 30 min. After the reaction was complete, the solvent was evaporated under reduced pressure to give an off- white solid. Further purification over a silica gel (4 g column) provided 86 mg (51% yield) of the desired product as a colorless solid. LRMS: (M+H- Boc)+ = 406.2 m/z and LRMS: (M+H-iBu)+ = 450.2 m/z. 1H NMR (400 MHz, Chloroform-^/) δ 7.60 (dq, J= 2.2, 1.1 Hz, 1H), 7.56 (dddd, J= 5.2, 3.7, 2.9, 1.2 Hz, 1H), 7.41 (dt, J= 5.0, 1.1 Hz, 2H), 4.10 (s, 2H), 3.88 - 3.76 (m, 1H), 3.58 (dd, J= 11.6, 7.9 Hz, 1H), 3.52 (dd, J= 12.1, 4.8 Hz, 1H), 3.33 - 3.19 (m, 4H), 3.12 (qd, J= 7.3, 4.0 Hz, 4H), 2.97 (d, J= 1.1 Hz, 3H), 2.76 - 2.63 (m, 2H), 2.50 (td, J= 8.1, 7.6, 4.0 Hz, 1H), 1.88 (ddp, J= 12.0, 8.2, 3.9, 3.3 Hz, 1H), 1.67 - 1.57 (m, 2H), 1.44 (d, J = 1.1 Hz, 9H).
N-(( 1 -(( 1 -benzylpiperidin-4-yl)methyl)-3-(3 -cyanophenyl)-2-oxohexahydropyrimidin-5 - yl)methyl)methanesulfonamide
Figure imgf000081_0002
To a stirring solution of tert-butyl 4-((3-(3-cyanophenyl)-5-(methylsulfonamidomethyl)- 2-oxotetrahydropyrimidin-l(2H)-yl)methyl)piperidine-l-carboxylate (85 mg, 0.168 mmol) in CH2C12 (504 μΐ), TFA (336 μΐ) was added at room temperature and this mixture was stirred for 30 min. After the reaction was complete, chloroform was added and the solvent was evaporated. This process was repeated with ethanol to ensure removal of residual TFA; there was obtained a viscous oil which is directly used in next step. LRMS: (M+H)+ = 406.2 m/z.
The material from previous step, N-((l-(3-cyanophenyl)-2-oxo-3-(piperidin-4- ylmethyl)hexahydropyrimidin-5-yl)methyl)methanesulfonamide (100 mg, 0.247 mmol), was dissolved in acetonitrile (2466 μΐ), Hunig's Base (64.6 μΐ, 0.370 mmol) was added followed by benzylbromide (32.3 μΐ, 0.271 mmol). This reaction mixture was stirred for 1 h at ambient temperature after which the solvent was removed under reduced pressure to provide the product as a viscous oil. Further purification over silica gel gave 43 mg (35% yield over two steps) of the desired product as a colorless viscous oil. LRMS: (M+H)+ = 496.2 m/z. 1H NMR (400 MHz, Chloroform-;/) δ 7.58 - 7.55 (m, 1H), 7.52 - 7.45 (m, 1H), 7.43 - 7.36 (m, 7H), 4.19 - 4.07 (m, 2H), 3.77 (dd, J= 11.6, 4.0 Hz, 1H), 3.45 (s, 6H), 3.33 (dd, J= 13.5, 6.4 Hz, 2H), 3.15 (qd, J= 14.6, 13.7, 7.2 Hz, 3H), 2.92 (s, 3H), 2.64 (t, J= 11.6 Hz, 1H), 2.46 (s, 1H), 1.74 (d, J = 13.3 Hz, 5H).
N-acetoxy-3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -(methylsulfonamidomethyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000082_0001
To a stirred solution of N-((l-((l-benzylpiperidin-4-yl)methyl)-3-(3-cyanophenyl)-2- oxohexahydropyrimidin-5-yl)methyl)methanesulfonamide (43 mg, 0.087 mmol) in ethanol (1735 μΐ), hydroxylamine hydrochloride (12.06 mg, 0.174 mmol) followed by Hunig's Base (30.3 μΐ, 0.174 mmol) were added at room temperature. The combined reaction mixture stirred for 6 h at 85 °C followed by 15-18 h of stirring at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to give a viscous oil, this material was used in next step without further purification. LRMS: (M+H)+ = 529.3 m/z. 3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -(methylsulfonamidomethyl)-2- oxotetrahydropyrimidin-l(2H)-yl)-N-hydroxybenzimidamide (50 mg, 0.095 mmol)(from step 1) was dissolved in acetic acid (1892 μΐ), then acetic anhydride (26.8 μΐ, 0.284 mmol) was added at once and the mixture was stirred for 20 min at room temperature. After reaction was complete, EtOH was added and the solvent evaporated under reduced pressure to give a viscous oil.
Further purification over silica gel provided 30 mg (56% yield over two steps) of the desired compound as a colorless solid.
LRMS: (M+H)+ = 571.3 m/z. 1H NMR (400 MHz, Methanol-^) δ 7.64 (q, J = 1.3 Hz, 1H), 7.59 (dt, J = 6.6, 2.3 Hz, 1H), 7.43 (dd, J = 4.9, 2.3 Hz, 2H), 7.38 - 7.28 (m, 5H), 3.83 (dd, J = 11.7, 4.2 Hz, 1H), 3.62 (s, 3H), 3.60 - 3.54 (m, 2H), 3.37 (s, 1H), 3.21 (d, J = 7.0 Hz, 2H), 3.00 (dd, J = 11.3, 3.8 Hz, 2H), 2.41 (dtd, J = 11.8, 8.1, 7.6, 3.3 Hz, 2H), 2.21 (s, 3H), 2.15 (d, J = 11.8 Hz, 2H), 1.88 - 1.71 (m, 4H), 1.42 - 1.30 (m, 3H).
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -(methylsulfonamidomethyl)-2-oxotetrahydropyrimidin-
1 (2H)-yl)benzimidamide
Figure imgf000083_0001
EXAMPLE 37
N-acetoxy-3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -(methylsulfonamidomethyl)-2- oxotetrahydropyrimidin-l(2H)-yl)benzimidamide (30 mg, 0.053 mmol) was dissolved in ethanol (1 ml) and acetic acid (0.2 ml); then Raney Ni (30 mg) was added and the mixture was shaken in a Parr apparatus under an atmosphere of H2 at 40 psi for 16 h. After product formation the reaction was purged with N2 then was filtered through a Celite pad and washed with MeOH. After solvent removal, the resulting crude product was purified over silica gel (4 g column). There was obtained 12 mg of the desired product in 44% yield as a white solid. HRMS:
C^HseNeOsS calculated (M+H)+ = 513.26424 m/z; found (M+H)+ = 513.26375 m/z. 1H NMR (400 MHz, Methanol-^) δ 7.54 (dt, J= 1.9, 1.1 Hz, 1H), 7.47 (ddd, J= 5.6, 2.9, 1.8 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.24 - 7.13 (m, 5H), 3.73 (ddd, J= 11.9, 4.3, 1.3 Hz, 1H), 3.56 - 3.44 (m, 2H), 3.42 (s, 2H), 3.26 - 3.22 (m, 1H), 3.20 - 3.16 (m, 1H), 3.10 (d, J= 7.0 Hz, 2H), 2.85 (d, J = 0.5 Hz, 3H), 2.81 (dd, J= 8.8, 5.5 Hz, 2H), 2.36 - 2.25 (m, 1H), 1.93 (tat, J= 11.8, 2.5 Hz, 2H), 1.70 - 1.56 (m, 3H), 1.29 - 1.16 (m, 3H).
EXAMPLE 38
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-2-oxo-5 -(phenylsulfonamidomethyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000084_0001
EXAMPLE 38 was prepared by the same method used to prepare EXAMPLE 37 with methanesulfonyl chloride replaced by phenylsulfonyl chloride. HRMS: C31H38N6O3S calculated (M+H)+ = 575.27989 m/z; found (M+H)+ = 575.27950 m/z. 1H NMR (400 MHz, Methanol- d4) 5 8.54 (s, 2H), 7.86 (t, J= 1.3 Hz, 1H), 7.84 (d, J= 1.7 Hz, 1H), 7.67 (dt, J= 1.9, 1.1 Hz, 1H), 7.65 - 7.53 (m, 6H), 7.46 - 7.37 (m, 5H), 3.96 (d, J= 4.8 Hz, 2H), 3.86 - 3.80 (m, 1H), 3.63 - 3.50 (m, 2H), 3.25 (ddd, J= 15.7, 9.2, 3.4 Hz, 4H), 3.00 (d, J= 7.1 Hz, 2H), 2.58 (t, J= 11.8 Hz, 3H), 2.42 - 2.34 (m, 1H), 1.97 - 1.78 (m, 3H), 1.52 - 1.38 (m, 2H).
EXAMPLE 39
3-(3-((l-benzylpiperidin-4-yl)methyl)-2-oxo-5-
(((phenylmethyl)sulfonamido)methyl)tetrahvdropyrimidin-l(2H)-yl)benzimidamide
Figure imgf000084_0002
EXAMPLE 39 was prepared by the same method used to prepare EXAMPLE 37 with methanesulfonyl chloride replaced by benzylsulfonyl chloride. HRMS: C32H40N6O3S calculated (M+H)+ = 589.29420 m/z; found (M+H)+ = 589.29409 m/z. 1H NMR (400 MHz, Methanol-i 4) δ 7.66 (dd, J= 2.1, 1.0 Hz, 1H), 7.62 - 7.58 (m, 3H), 7.49 - 7.41 (m, 7H), 7.39 - 7.33 (m, 3H), 4.37 (s, 2H), 4.05 (s, 2H), 3.87 - 3.78 (m, 1H), 3.61 - 3.46 (m, 2H), 3.30 - 3.23 (m, 3H), 3.06 (d, J= 7.0 Hz, 2H), 2.77 - 2.65 (m, 2H), 2.29 (tt, J= 7.0, 4.4 Hz, 1H), 1.94 (s, 2H), 1.90 - 1.81 (m, 2H), 1.54 - 1.42 (m, 2H), 1.29 (s, 1H).
EXAMPLE 40
N-((l-((l-benzylpiperidin-4-yl)methyl)-3-(3-carbamimidoylphenyl)-2-oxohexahydropyrimidin- 5 -yl)methyl)acetamide
Figure imgf000085_0001
EXAMPLE 40 was prepared by the same method used to prepare EXAMPLE 37 with methanesulfonyl chloride replaced by acetic anhydride. HRMS: for C27H36N6O2 calculated (M+H)+ = 477.29725 m/z, found (M+H)+ = 477.29684 m/z. 1H NMR (400 MHz, Methanol-i 4) δ 7.74 - 7.70 (m, 1H), 7.69 - 7.60 (m, 3H), 7.43 (tt, J= 8.3, 3.6 Hz, 5H), 3.93 (s, 2H), 3.85 (dd, J = 11.7, 4.0 Hz, 1H), 3.66 - 3.54 (m, 2H), 3.39-3.26 (m, 3H), 3.23 (dd, J= 11.4, 3.8 Hz, 2H), 2.60 - 2.50 (m, 2H), 2.50 - 2.39 (m, 1H), 1.97 (d, J= 3.2 Hz, 5H), 1.91 - 1.81 (m, 2H), 1.54 - 1.39 (m, 2H), 1.32 (s, 1H).
EXAMPLE 41
N-((l-((l-benzylpiperidin-4-yl)methyl)-3-(3-carbamimidoylphenyl)-2-oxohexahvdropyrimidin- 5 -yQmethyObenzamide
Figure imgf000086_0001
EXAMPLE 41 was prepared by the same method used to prepare EXAMPLE 37 with methanesulfonyl chloride replaced by benzoyl chloride. HRMS: for C32H38N602 calculated (M+H)+ = 539.31290 m/z; found (M+H)+ = 539.31234 m/z. 1H NMR (400 MHz, Methanol-^) δ 7.85 - 7.79 (m, 2H), 7.68 (dq, J= 1.9, 0.9 Hz, 1H), 7.61 - 7.44 (m, 6H), 7.37 - 7.26 (m, 5H), 3.91 - 3.83 (m, 1H), 3.68 - 3.55 (m, 4H), 3.54 (s, 2H), 3.42 - 3.35 (m, 2H), 2.94 (dd, J= 10.6, 4.5 Hz, 2H), 2.61 (ddd, J = 7.2, 3.6, 3.0 Hz, 1H), 2.04 (tt, J= 11.8, 2.3 Hz, 2H), 1.76 (dqd, J = 20.4, 7.0, 6.5, 3.4 Hz, 3H), 1.43 - 1.28 (m, 4H).
EXAMPLE 42
N-((l-((l-benzylpiperidin-4-yl)methyl)-3-(3-carbamimidoylphenyl)-2-oxohexahydropyrimidin- 5 -yl)methyl)-2-phenylacetamide
Figure imgf000086_0002
EXAMPLE 42 was prepared by the same method used to prepare EXAMPLE 37 with methanesulfonyl chloride replaced by 2-phenylacetyl chloride. HRMS: for C33H40N6O2 calculated (M+H)+ = 553.32855 m/z; found (M+H)+ = 553.32858 m/z. 1H NMR (400 MHz, Methanol- d4) δ 7.67 (q, J= 1.5 Hz, 1H), 7.62 - 7.54 (m, 5H), 7.51 - 7.48 (m, 3H), 7.30 - 7.18 (m, 5H), 4.30 (s, 2H), 3.80 (dd, J= 11.7, 4.0 Hz, 1H), 3.52 (d, J= 1.7 Hz, 3H), 3.51 - 3.47 (m, 1H), 3.44 (d, J= 11.4 Hz, 2H), 3.39 (d, J= 7.2 Hz, 2H), 3.25 (dd, J= 12.0, 6.7 Hz, 2H), 3.05 - 2.92 (m, 2H), 2.44 (ddt, J= 8.5, 6.8, 3.5 Hz, 1H), 1.97 - 1.87 (m, 3H), 1.61 - 1.44 (m, 2H), 1.29 (s, 2H).
EXAMPLE 43 N-((l-((l-berizylpiperidin-4-yl)^
5 -yl)methvD-3 -phenylpropanamide
Figure imgf000087_0001
EXAMPLE 43 was prepared by the same method used to prepare EXAMPLE 37 with methanesulfonyl chloride replaced by 3-phenylpropionyl chloride. HRMS: for C34H42N6O2 calculated (M+H)+ = 567.34420 m/z; found (M+H)+ = 567.34314 m/z. 1H NMR (400 MHz, Methanol-^) δ 7.69 (t, J= 1.6 Hz, 1H), 7.62 (td, J= 5.5, 4.9, 3.5 Hz, 3H), 7.47 - 7.35 (m, 5H),
7.23 - 7.15 (m, 4H), 7.11 (ddd, J= 8.8, 5.7, 2.7 Hz, 1H), 3.67 (dd, J= 11.7, 4.1 Hz, 1H), 3.44 -
3.24 (m, 6H), 3.21 - 3.09 (m, 3H), 3.00 (q, J= 7.3 Hz, 1H), 2.91 (t, J= 7.3 Hz, 2H), 2.53 (t, J = 7.3 Hz, 2H), 2.46 (tt, J= 12.2, 3.2 Hz, 2H), 2.30 (ddt, J= 10.6, 7.3, 3.8 Hz, 1H), 1.88 - 1.76 (m, 3H), 1.51 - 1.37 (m, 2H), 1.34 - 1.27 (m, 1H).
EXAMPLE 44
Figure imgf000087_0002
INTERMEDIATE F
tert-butyl 4-(Y3 -(3 -cyanophenyl)-2-oxo-5 -((phenethylamino)methyl)tetrahydropyrimidin- 1 (2H)-
To a stirred solution of tert-butyl 4-((3-(3-cyanophenyl)-5-formyl-2- oxotetrahydropyrimidin-l(2H)-yl)methyl)piperidine-l-carboxylate (490 mg, 1.149 mmol) in CH2C12 (5744 μΐ) was added 2-phenylethanamine (144 μΐ, 1.149 mmol) followed by sodium (triacetoxy)borohydride (365 mg, 1.723 mmol). This mixture was stirred at room temperature; after 90 min, the reaction was quenched with sat. NaHC03. This was extracted with CH2CI2 (3 X 15 ml) and the combined organic layers were dried over MgSC^ and concentrated under reduced pressure. There was obtained a light brown solid which was purified by chromatography to provide the desired product as a viscous oil (140 mg, 23% yield). HRMS: for C3iH41N503 calculated (M+H)+ = 532.32822 m/z; found (M+H)+ = 532.32846 m/z. 1H NMR (400 MHz, Chloroform-i ) δ 7.58 - 7.56 (m, 1H), 7.54 (ddd, J= 5.2, 4.0, 2.3 Hz, 1H), 7.40 - 7.37 (m, 2H), 7.31 - 7.26 (m, 2H), 7.24 - 7.17 (m, 3H), 4.09 (s, 2H), 3.72 (ddd, J= 11.5, 4.2, 1.3 Hz, 1H), 3.50 (dd, J= 11.4, 8.3 Hz, 1H), 3.45 - 3.39 (m, 1H), 3.19 (dd, J= 11.8, 8.2 Hz, 2H), 2.93 - 2.88 (m, 2H), 2.83 - 2.77 (m, 2H), 2.70 (t, J= 7.3 Hz, 4H), 2.31 (tt, J= 7.5, 3.9 Hz, 1H), 1.94-1.71 (m, 4H), 1.44 (s, 9H), 1.23-1.09 (m, 3H). tert-butyl 4-((3 -(3 -cvanophenvD-5 -(((((4-nitrobenzyl)oxy)carbonyl)(phenethyl)amino)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)methyl)piperidine- 1 -carboxylate
Figure imgf000088_0001
To a solution of tert-butyl 4-((3-(3-cyanophenyl)-2-oxo-5- ((phenethylamino)methyl)tetrahydropyrimidin- 1 (2H)-yl)methyl)piperidine- 1 -carboxylate (140 mg, 0.263 mmol) in CH2C12 (5266 μΐ) was added Et3N (147 μΐ, 1.053 mmol) and DMAP (32.2 mg, 0.263 mmol) followed by 4-nitrobenzyl carbonochloridate (171 mg, 0.789 mmol). This mixture was stirred at room temperature for 5 h. After the reaction was complete the solvent was evaporated and the product isolated by column chromatography (154 mg, 82% yield) as a viscous oil. LRMS: (M+H-Boc)+ = 611.3 m/z and (M+H-tBu)+ = 655.3 m/z.
4-nitrobenzyl ((!-((! -benzylpiperidin-4-yl)methyl)-3 -(3 -cyanophenyl)-2- oxohexahydropyrimidin-5-yl)methyl)(phenethyl)carbamate
Figure imgf000089_0001
Tert-butyl 4-((3-(3-cyanophenyl)-5-(((((4- nitrobenzyl)oxy)carbonyl)(phenethyl)amino)methyl)-2-oxotetrahydropyrimidin-l(2H)- yl)methyl)piperidine-l-carboxylate (154 mg, 0.217 mmol) dissolved in CH2CI2 (1733 μΐ) and TFA (433 μΐ) were stirred for 30 min. After the reaction was complete, the solvent was removed and the residue evaporated with chloroform (2x) then with ethanol (2x) to obtain a colorless viscous oil in quantitative yields (132 mg). This material was used without further purification in next step. LRMS: (M+H)+ = 611.3 m/z.
The 4-nitrobenzyl ((l-(3-cyanophenyl)-2-oxo-3-(piperidin-4- ylmethyl)hexahydropyrimidin-5-yl)methyl)(phenethyl)carbamate (132 mg, 0.216 mmol) prepared above was dissolved in CH2CI2 (2161 μΐ); (bromomethyl)benzene (28.4 μΐ, 0.238 mmol) and Et3N (90 μΐ, 0.648 mmol) were added at room temperature and stirred for 30 min. After the reaction was complete, the solvent was removed and the residue purified by column chromatography to give the desired product (100 mg, 66% yield) as a gummy solid. LRMS: (M+H)+ = 701.3 m/z. 1H NMR (400 MHz, Chloroform-d) δ 8.22 - 8.18 (m, 2H), 7.57 - 7.47 (m, 2H), 7.47 - 7.42 (m, 2H), 7.42 - 7.18 (m, 10H), 7.18 - 7.05 (m, 2H), 5.15 (s, 2H), 3.68 (d, J = 11.9 Hz, 2H), 3.61 (dd, J = 11.2, 4.2 Hz, 1H), 3.49 (dq, J = 20.5, 11.7, 9.4 Hz, 3H), 3.40 - 3.33 (m, 1H), 3.33 - 3.11 (m, 5H), 3.02 (d, J = 8.8 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.48 (p, J = 7.1 Hz, 1H), 2.20 (s, 2H), 1.88-1.63 (m, 3H), 1.54 (s, 2H).
4-nitrobenzyl ((l-(3-(N-acetoxycarbamimidoyl)phenyl)-3-((l-benzylpiperidin-4-yl)methyl)-2- oxohexahydropyrimidin-5-yl)methyl)(phenethyl)carbamate
Figure imgf000090_0001
A combined solution of 4-nitrobenzyl ((l-((l-benzylpiperidin-4-yl)methyl)-3-(3-cyanophenyl)-2- oxohexahydropyrimidin-5-yl)methyl)(phenethyl)carbamate (100 mg, 0.143 mmol),
hydroxylamine hydrochloride (19.83 mg, 0.285 mmol) and Hunig's Base (49.8 μΐ, 0.285 mmol) in ethanol (2854 μΐ) were stirred for 6 h at 85 °C; this mixture was then stirred overnight at room temperature. After the reaction was complete, the solvent was evaporation to provide the product as a colorless solid. The crude is carried through next step without purification. LRMS: (M+H)+ = 734.3 m/z.
4-Nitrobenzyl ((1 -((1 -benzylpiperidin-4-yl)methyl)-3-(3-(N- hydroxycarbamimidoyl)phenyl)-2-oxohexahydropyrimidin-5-yl)methyl)(phenethyl)carbamate (105 mg, 0.143 mmol) from previous reaction was dissolved in acetic acid (1431 μΐ) to which acetic anhydride (40.6 μΐ, 0.429 mmol) was added; this mixture was stirred for 15 min. After the reaction was complete, the solvent was removed by evaporation and the residue was purified by column chromatography to give the desired product (54 mg, 49% yield) as a colorless gummy solid. LRMS: (M+H)+ = 776.3 m/z.
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-2-oxo-5 -((phenethylamino)methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000091_0001
EXAMPLE 44
To a combined solution of the carbamate (54 mg, 0.070 mmol) in ethanol (2 ml), Raney Ni (41 mg, 0.70 mmol) and acetic acid (0.5 ml) were added at room temperature. The resulting suspension was shaken under H2 atmosphere at 50 psi in a Parr apparatus for 12-16 h at room temperature. After the reaction was complete, as monitored by LCMS analysis, the solution was purged with N2 and filtered over Celite pad with washing with MeOH. The solvent was removed under reduced pressure to provide a solid. Further purification by column chromatography provided 25 mg of the product as a white solid in 67% yield. HRMS: for C33H42N6O calculated
(M+H)+ = 539.34929 m/z; found 539.34845 m/z. 1H NMR (400 MHz, Methanol-i 4) δ 8.50 (s, 3H), 7.71 (d, J= 1.9 Hz, 1H), 7.67 - 7.58 (m, 3H), 7.52 - 7.43 (m, 5H), 7.35 - 7.20 (m, 5H), 4.19 (s, 2H), 4.00 - 3.91 (m, 1H), 3.66 (ddd, J= 14.5, 12.2, 6.3 Hz, 2H), 3.38 (ddd, J= 16.8, 8.5, 3.4 Hz, 4H), 3.20 (dd, J= 9.7, 6.2 Hz, 2H), 3.10 (d, J = 6.2 Hz, 2H), 3.00 (dd, J= 9.7, 6.2 Hz, 2H), 2.87 (t, J= 11.7 Hz, 2H), 2.74 - 2.63 (m, 1H), 2.09 - 1.97 (m, 2H), 2.02 (br.s, 1H), 1.97 - 1.87 (m, 2H), 1.54 (d, J= 12.2 Hz, 2H).
EXAMPLE 45
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -((diethylamino)methyl)-2-oxotetrahy dropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000091_0002
EXAMPLE 45 was prepared by the same procedure used for EXAMPLE 44 with phenethyl amine replaced by diethyl amine. HRMS: for C29H43N6O calculated (M+H)+ = 491.34929 m/z; found (M+H)+ = 491.34904 m/z. 1H NMR (400 MHz, Methanol-i 4) δ 8.57 - 8.42 (m, 2H), 7.69 (dt, J= 2.2, 1.1 Hz, 1H), 7.64 (dtd, J= 5.8, 4.0, 1.9 Hz, 1H), 7.61 - 7.58 (m, 2H), 7.47 - 7.39 (m, 5H), 4.00 (s, 2H), 3.87 (ddd, J= 11.7, 4.2, 1.4 Hz, 1H), 3.66 - 3.54 (m, 2H), 3.34 (d, J= 4.0 Hz, 3H), 3.26 (dd, J= 10.7, 5.7 Hz, 2H), 2.73 (q, J= 7.1 Hz, 4H), 2.69 - 2.59 (m, 4H), 2.52 (ddt, J= 12.1, 8.2, 4.0 Hz, 1H), 2.00 - 1.82 (m, 3H), 1.54 - 1.41 (m, 2H), 1.29 (s, 1H), 1.09 (t, J = 7.1 Hz, 6H).
EXAMPLE 46
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -hvdroxy-2-oxotetrahydropyrimidin- 1 (2H)- yObenzimidamide
Figure imgf000092_0001
INTERMEDIATE B INTERMEDIATE H tert-butyl 4-(Y3 -(3 -cyanophenyl)-2,5 -dioxotetrahydropyrimidin- 1 (2H)-yl)methyl)piperidine- 1 - carboxylate:
tert-Butyl 4-((3 -(3 -cyanophenyl)-5 -methylene-2-oxotetrahydropyrimidin- 1 (2H)- yl)methyl)piperidine-l -carboxylate (440 mg, 1.072 mmol) was dissolved in MeOH (7 ml) and bubbled with O3 gas at -78 °C for 4 h. Once the starting material was consumed the reaction was purged with argon then was quenched with dimethylsulfide (0235 ml, 3.22 mmol). The quenched mixture was stirred at room temperature for an additional 1 h. After 1 h, the solvent was evaporated and the residue was dissolved in CH2C12 and washed with water. The layers were separated and the aqueous layer was extracted with CH2C12 (3x25 ml). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure to isolate the product as a viscous oil. Further purification by column chromatography provided the desired product (250 mg, 57%) as a white solid. HRMS: for C22H28N404 calculated (M+Na)+ = 435.02228 m/z;
found (M+H)+ = 435.19962 m/z. 1H NMR (400 MHz, Chloroform-^ ) δ 7.50 (dd, J= 2.4, 0.8 Hz, 1H), 7.48 - 7.44 (m, 3H), 4.24 (s, 2H), 4.09 (d, J= 18.9 Hz, 2H), 4.01 (d, J= 0.6 Hz, 2H), 3.32 (s, 2H), 2.70 (t, J= 12.7 Hz, 2H), 1.84 (dtq, J= 11.2, 7.4, 3.6 Hz, 1H), 1.65 (d, J= 14.3 Hz, 3H), 1.45 (d, J= 0.6 Hz, 9H), 1.30 - 1.12 (m, 3H). tert-butyl 4-(Y3 -(3 -cyanophenyl)-5 -hydroxy-2-oxotetrahydropyrimidin- 1 (2H)-
Figure imgf000093_0001
INTERMEDIATE H INTERMEDIATE I
To a stirring solution of tert-butyl 4-((3-(3-cyanophenyl)-2,5-dioxotetrahydropyrimidin- l(2H)-yl)methyl)piperidine-l-carboxylate (240 mg, 0.582 mmol) in MeOH (5 mL), sodium borohydride (44.0 mg, 1.164 mmol) was added in portions at room temperature; this reaction was stirred for 6 h. After the reaction was complete, the mixture was quenched with saturated NH4C1 and the solvent was removed under reduced pressure. The residue was taken up in CH2C12, water was added and the layers were separated. The aqueous layer was extracted with CH2CI2 (3x25 ml) and the combined organic layers were dried over Na2S04 then concentrated under reduced pressure. Purification of the residue by column chromatography provided the desired product (206 mg, 85%) as a white solid. HRMS: for C22H30N4O4 calculated (M+Na)+ = 437.21593 m/z; found (M+Na)+ = 437.21479 m/z.
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -hydroxy-2-oxotetrahydropyrimidin- 1 (2H)- yDbenzonitrile
Figure imgf000094_0001
INTERMEDI
Figure imgf000094_0002
To a stirring solution of tert-butyl 4-((3-(3-cyanophenyl)-5-hydroxy-2- oxotetrahydropyrimidin-l(2H)-yl)methyl)piperidine-l-carboxylate (188 mg, 0.454 mmol) in CH2C12 (3628 μΐ), TFA (907 μΐ) was added at room temperature; this mixture was stirred for 30 min. After the reaction was complete, the crude was evaporated with chloroform then ethanol; this process was repeated three times to remove residual TFA. There was obtained the desired product of suitable purity to be used directly in the next step. LRMS: (M+H)+ = 315.2 m/z.
To a solution of 3-(5-hydroxy-2-oxo-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-l(2H)- yl)benzonitrile (143 mg, 0.455 mmol) in acetonitrile (5 ml), benzylbromide (0.060 ml, 0.500 mmol) and triethylamine (0.190 ml, 1.365 mmol) were added; this mixture was stirred for 30 min. After the reaction was complete, the solvent was evaporated the the product isolated by column chromatography to give the desired material as a solid in quantitative yield. HRMS: for C24H28N402 calculated (M+H)+ = 405.22850 m/z; found (M+H)+ = 405.22848 m/z. 1H NMR (400 MHz, Chloroform-;/) δ 7.66 - 7.64 (m, 1H), 7.60 (s, 2H), 7.57-7.52 (m, 1H), 7.44 - 7.37 (m, 5H), 4.31 (s, 2H), 4.17 (s, 2H), 3.83 (d, J= 12.3 Hz, 1H), 3.69 (d, J= 12.3 Hz, 1H), 3.59 (d, J= 12.4 Hz, 1H), 3.55 - 3.40 (m, 3H), 2.98 (d, J= 12.6 Hz, 1H), 2.86 (s, 2H), 2.00 (s, 3H), 1.89- 1.75 (m, 3H)
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -hydroxy-2-oxotetrahydropyrimidin- 1 (2H)- yObenzimidamide
Figure imgf000095_0001
EXAMPLE 46
To a solution of 3-(3-((l-benzylpiperidin-4-yl)methyl)-5-hydroxy-2- oxotetrahydropyrimidin-l(2H)-yl)benzonitrile (200 mg, 0.494 mmol) in ethanol (5 ml), hydroxylamine hydrochloride (68.7 mg, 0.989 mmol) and Hunig's Base (173 μΐ, 0.989 mmol) were added at room temperature. The combined solution was stirred for 6 h at 85 °C then overnight at room temperature. After the reaction was complete, the solvent was removed by evaporation and the product purified by column chromatography to give the N- hydroxybenzimidamide (90 mg, 42% yield) as a white solid. HRMS: for C24H31N5O3 calculated (M+H)+ = 438.24997 m/z; found (M+H)+ = 438.24982 m/z.
Purified N-hydroxybenzimidamide (81 mg, 0.185 mmol) from above was dissolved in ethanol (5 ml), to which Raney Ni (110 mg, wet weight, washed with ethanol) was added. The combined mixture was placed on a Parr apparatus and shaken for 15-18 h under a hydrogen atmosphere at 50 psi. After the reaction was complete, the reaction mixture was purged with Ar gas and filtered through Celite pad with washing with methanol. The solvent was evaporated and the product isolated by column chromatography (13 mg, 17% yield). HRMS: for
C24H3 IN5O2 calculated (M+H)+ = 422.25505; found (M+H)+ = 422.25498 m/z; 1H NMR (400 MHz, Methanol-^) δ 7.71 (td, J= 1.9, 1.0 Hz, 1H), 7.65 - 7.61 (m, 1H), 7.60 - 7.57 (m, 2H), 7.36 - 7.33 (m, 4H), 7.32 - 7.28 (m, 1H), 4.26 (dt, J= 6.5, 3.2 Hz, 1H), 3.98 - 3.93 (m, 1H), 3.67 (ddd, J= 12.4, 3.4, 0.9 Hz, 1H), 3.61 (dd, J= 4.2, 2.2 Hz, 1H), 3.39 - 3.32 (m, 2H), 3.26 (dd, J= 13.8, 6.9 Hz, 1H), 3.04 - 2.97 (m, 2H), 2.19 (dd, J= 12.0, 2.5 Hz, 2H), 2.16 - 2.14 (m, 1H), 1.82 - 1.74 (m, 3H), 1.43-1.32 (m, 3H).
EXAMPLE 47
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -methoxy-2-oxotetrahydropyrimidin- 1 (2H)- yObenzimidamide
Figure imgf000096_0001
INTERMEDIATE I tert-butyl 4-((3 -(3 -cyanophenyl)-5 -methoxy-2-oxotetrahydropyrimidin- 1 (2H)- yl)methyl)piperidine- 1 -carboxylate :
To a solution of tert-butyl 4-((3-(3-cyanophenyl)-5-hydroxy-2-oxotetrahydropyrimidin- l(2H)-yl)methyl)piperidine-l -carboxylate (500 mg, 1.206 mmol in THF (8 ml), sodium hydride (73 mg, 1.809, 60% in mineral oil) was added in portions at room temperature; this mixture was stirred for 15 min. After 15 min, iodomethane (0.150 ml, 2.413 mmol) was added and the reaction was stirred for an additional 15 min at room temperature followed by heating at reflux for 2 h. After the reaction was complete, it was cooled to room temperature and the quenched with aq. NH4C1, extracted with CH2CI2 (3 X 25 ml), dried over Na2S04 and concentrated under reduced pressure. Further purification by column chromatography provided the desired product (323 mg, 65% yield) as a yellow oil. HRMS: for C23H32N4O4 calculated (M+Na)+ = 451.23158 m/z; found (M+Na)+ = 451.23128 m/z. 1H NMR (400 MHz, Chloroform-d) δ 7.59 (dp, J = 2.1 , 0.7 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.42 - 7.39 (m, 2H), 4.17 - 4.02 (m, 2H), 3.88 - 3.76 (m, 2H), 3.71 (ddd, J = 11.7, 4.7, 1.9 Hz, 1H), 3.61 - 3.53 (m, 1H), 3.44 (dd, J = 4.4, 1.9 Hz, 1H), 3.42 - 3.39 (m, 3H), 3.25 - 3.19 (m, 1H), 2.69 (t, J = 12.7 Hz, 2H), 1.89 (ddp, J = 11.3, 7.5, 3.8 Hz, 1H), 1.67 (s, 2H), 1.44 (d, J = 0.5 Hz, 9H), 1.28 - 1.10 (m, 3H).
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -methoxy-2-oxotetrahydropyrimidin- 1 (2H)- yDbenzonitrile
Figure imgf000096_0002
To a stirred solution of tert-butyl 4-((3-(3-cyanophenyl)-5-methoxy-2- oxotetrahydropyrimidin-l(2H)-yl)methyl)piperidine-l -carboxylate (303 mg, 0.707 mmol) in CH2CI2 (7071 μΐ) was added TFA (545 μΐ, 7.07 mmol); this mixture was stirred for 30 min at room temperature. After the reaction was complete, the crude was triturated with chloroform followed by ethanol. The trituration repeated three times with each solvent. After solvent evaporation an orange colored viscous oil was obtained. The crude carried through next step without any purification. LRMS: (M+H)+ = 329.2 m/z
To a solution of 3-(5-methoxy-2-oxo-3-(piperidin-4-ylmethyl)tetrahydropyrimidin- l(2H)-yl)benzonitrile (232 mg, 0.706 mmol) in CH2CI2 (7 mL), (bromomethyl)benzene (0.092 mL, 0.777 mmol) and triethylene amine (TEA) (0.295 mL, 2.119 mmol) were added at room temperature then stirred for 30 min. After reaction completion, the solvent was removed by evaporation off to obtain an orange colored viscous oil. Further purification by column chromatography provided the desired product as a solid in quantitative yields (350 mg). HRMS: for C25H30N4O2 calculated (M+H)+ = 419.24415 m/z; found (M+H)+ = 419.24424 m/z. 1H NMR (400 MHz, Chloroform-^ ) δ 7.62 - 7.57 (m, 1H), 7.56 - 7.47 (m, 3H), 7.44 - 7.36 (m, 5H), 4.15 (d, J= 18.2 Hz, 2H), 3.83 (dd, J= 11.9, 2.6 Hz, 1H), 3.74 (p, J= 3.4 Hz, 1H), 3.71 - 3.64 (m, 1H), 3.61 (dd, J= 12.4, 3.5 Hz, 1H), 3.48 (d, J= 11.9 Hz, 2H), 3.43 - 3.36 (m, 2H), 3.35 (d, J= 0.9 Hz, 2H), 3.27 (dd, J= 13.9, 6.1 Hz, 1H), 2.69 (s, 2H), 1.98 (q, J= 7.9, 6.9 Hz, 3H), 1.84 (d, J= 13.4 Hz, 1H).
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -methoxy-2-oxotetrahydropyrimidin- 1 (2H)- yObenzimidamide
Figure imgf000097_0001
ps EXAMPLE 47
To 3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -methoxy-2-oxotetrahydropyrimidin- 1 (2H)- yl)benzonitrile (340 mg, 0.812 mmol) in ethanol (16.200 mL), hydroxylamine hydrochloride (113 mg, 1.625 mmol) followed by Hunig's Base (0.284 mL, 1.625 mmol) were added at room temperature. The resulting orange colored reaction mixture was stirred for 6 h at 85 °C followed by overnight stirring at room temperature. After the reaction was complete, the solvent was evaporated and the product isolated by column chromatography (189 mg, 52% yield) as a yellow color solid. HRMS: for C25H33N503 calculated (M+H)+ = 452.26562 m/z; found (M+H)+ = 452.26590 m/z. 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.55 - 7.45 (m, 2H), 7.45 - 7.32 (m, 5H), 7.32 - 7.20 (m, 2H), , 5.79 (s, 2H), 4.35-3.94 (m, 2H), 3.88 - 3.77 (m, 2H), 3.67 - 3.60 (m, 1H), 3.55 (dd, J= 12.4, 3.4 Hz, 1H), 3.37-3.22 (m, 4H), 3.30 (s, 3H), 3.24 - 3.11 (m, 3H), 1.75 (s, 3H), 1.53 - 1.28 (m, 2H).
To 3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -methoxy-2-oxotetrahydropyrimidin- 1 (2H)- yl)-N-hydroxybenzimidamide (121 mg, 0.268 mmol) in ethanol (6 ml), Raney nickel (157 mg, 2.68 mmol,) was added and the suspension shaken overnight on a Parr apparatus under H2 atmosphere at 50 psi. After reaction completion, the crude was purged with Ar gas then filtered through a Celite pad with copious washing with methanol. Further purification of the product by column chromatography provided the desired product (44 mg, 38% yield) as a light yellow solid. HRMS: for C25H33N502 calculated (M+2H)+2 = 218.63899 m/z; found (M+2H)+2 = 218.63928 m/z. 1H NMR 1H NMR (400 MHz, Methanol-^) δ 7.67 (dt, J= 1.9, 1.1 Hz, 1H), 7.64 - 7.57 (m, 3H), 7.42 - 7.31 (m, 5H), 3.96 (dd, J= 12.4, 2.6 Hz, 1H), 3.89 - 3.85 (m, 1H), 3.83 (s, 2H), 3.78 (ddd, J= 12.4, 3.5, 2.5 Hz, 1H), 3.66 (dd, J= 12.9, 3.2 Hz, 1H), 3.50 (dt, J= 12.9, 2.9 Hz, 1H), 3.42 (s, 3H), 3.14 (dd, J= 11.5, 3.2 Hz, 2H), 2.42 (tt, J= 12.1, 3.0 Hz, 2H), 1.96 - 1.79 (m, 4H), 1.49 - 1.35 (m, 2H), 1.29 (br. S, 1H).
EXAMPLE 48
3 -(5 -(benzyloxy)-3 -(( 1 -benzylpiperidin-4-yl)methyl)-2-oxotetrahydropyrimidin- 1 (2H)- vDbenzimidamide
Figure imgf000098_0001
EXAMPLE 48 was prepared by the same procedure used for EXAMPLE 47 with methyl iodide replaced with benzyl bromide. HRMS: for C3iH37N502 calculated (M+2H)+2 =
256.64736 m z; found (M+2H)+2 = 256.65229 m/z. 1H NMR (400 MHz, Methanol-d4) δ 7.63 (dt, J = 1.9, 1.2 Hz, 1H), 7.61 - 7.54 (m, 3H), 7.37 - 7.24 (m, 10H), 4.64 (d, J = 1.0 Hz, 2H), 4.09 ( , J = 3.1 Hz, 1H), 3.97 (dd, J = 12.5, 2.6 Hz, 1H), 3.81 (ddd, J = 12.6, 3.6, 2.6 Hz, 1H), 3.71 - 3.64 (m, 3H), 3.53 (dt, J = 12.9, 2.9 Hz, 1H), 3.34 (dd, J = 7.9, 6.0 Hz, 1H), 3.22 (dd, J = 13.9, 6.8 Hz, 1H), 3.03 - 2.93 (m, 2H), 2.26 - 2.09 (m, 3H), 1.77 (td, J = 11.1, 10.6, 5.1 Hz, 3H), 1.34 (tdd, J = 16.5, 14.4, 12.2, 6.0 Hz, 3H).
EXAMPLE 49
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -(methylsulfonamido)-2-oxotetrahydropyrimidin- 1 (2H)- yDbenzimidamide
Figure imgf000099_0001
INTERMEDIATE I INTERMEDIATE K tert-butyl 4-((5 -amino-3 -(3 -cyanophenyl)-2-oxotetrahydropyrimidin- 1 (2H)-yl)methyl)piperidine- 1-carboxylate
Step 1 : To tert-butyl 4-((3-(3-cyanophenyl)-5-hydroxy-2-oxotetrahydropyrimidin-l(2H)- yl)methyl)piperidine-l-carboxylate (1.93 g, 4.66 mmol) in CH2C12 (23.28 ml), TEA (1.947 ml, 13.97 mmol) followed by 4-dimethylaminopyiridine (DMAP) (0.057 g, 0.466 mmol) were added at 0°C. This mixture was stirred for 20 min, then p-toluenesulfonyl chloride (0.976 g, 5.12 mmol) was added at 0 °C and this mixture was stirred for another 30 min. The reaction was left for overnight and stirred at room temperature. After 20 h the solvent was removed by
evaporation and the crude product was applied directly onto silica gel and purified by column chromatography. After purification the desired product (2.21 g, 83% yield) was obtained as a yellow color viscous oil. HRMS: for C^Hse^OeS calculated (M+Na)+ = 591.22478 m/z; found (M+Na)+ = 591.22453 m/z. 1H NMR (400 MHz, Chloroform-^/) δ 7.74 (d, J= 8.3 Hz, 2H), 7.46 - 7.37 (m, 4H), 7.31 (d, J= 8.1 Hz, 2H), 5.07 (dt, J= 5.9, 2.9 Hz, 1H), 4.06 (s, 2H), 3.90 (dd, J = 13.1, 2.5 Hz, 1H), 3.75 - 3.65 (m, 2H), 3.51 (dt, J= 13.5, 2.9 Hz, 1H), 3.16 (s, 2H), 2.64 (t, J = 12.7 Hz, 2H), 2.43 (s, 3H), 1.85-1.75 (m, 1H), 1.58 (s, 2H), 1.43 (s, 9H), 1.11 (dq, J= 11.5, 6.3, 5.4 Hz, 2H). Step 2: To tert-butyl 4-((3-(3-cyanophenyl)-2-oxo-5-(tosyloxy)tetrahydropyrimidin- l(2H)-yl)methyl)piperidine-l-carboxylate (2.21 g, 3.89 mmol) in dimethyl formamide (DMF) (19.43 ml), sodium azide (3.03 g, 46.68 mmol) was added and the mixture was heated overnight at 60 °C. After this time the reaction was cooled to room temperature and the solvent was condensed under reduced pressure. The resulting material was taken up in CH2CI2 (150 ml) and extracted with water (5x), then sat. NaHC03 and brine. The organic layer was dried over Na2S04 and evaporated. Further purification of the crude by column chromatography provided the desired product (1.53 g, 90% yield) as a colorless viscous oil. HRMS: C22H29Ny03 calculated (M+Na)+ = 462.22241 m/z, found (M+Na)+ = 462.22264 m/z. 1H NMR (400 MHz,
Chloroforn /) 5 7.59 (tq, J= 2.1, 1.1 Hz, 1H), 7.55 (dtd, J = 6.4, 2.5, 0.8 Hz, 1H), 7.47 - 7.42 (m, 2H), 4.13 - 4.07 (m, 2H), 4.01 - 3.94 (m, 1H), 3.70 (dddd, J= 9.3, 4.8, 2.4, 1.3 Hz, 2H), 3.44 (ddd, J= 12.6, 4.4, 2.1 Hz, 1H), 3.31 (s, 2H), 2.70 (t, J= 12.7 Hz, 2H), 1.88 (ddp, J= 11.3, 7.5, 3.7 Hz, 1H), 1.67 (h, J= 3.6 Hz, 3H), 1.44 (d, J= 0.8 Hz, 9H), 1.19 (tt, J= 13.5, 8.3 Hz, 2H).
Step 3: To tert-butyl 4-((5-azido-3-(3-cyanophenyl)-2-oxotetrahydropyrimidin-l(2H)- yl)methyl)piperidine-l-carboxylate (550 mg, 1.251 mmol) in MeOH (2503 μΐ), 10% Pd-C (133 mg, 0.125 mmol) was added. This suspension was stirred under H2 (gas) at atmospheric pressure for 1 h. After the reaction was complete, the flask was flushed with Ar gas, then was diluted with methanol and filtered through a Celite pad to remove the catalyst. Purification by column chromatography provided the desired product (517 mg) as a solid in quantitative yields. HRMS: C22H3iN503 calculated (M+K)+ = 452.20585 m/z, found (M+K)+ = 252.20590 m/z. 1H NMR (400 MHz, Chloroform-; ) δ 7.60 (dt, J= 2.2, 0.9 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.41 (dt, J= 4.2, 0.7 Hz, 2H), 4.10 (s, 2H), 3.87 - 3.77 (m, 1H), 3.60 - 3.53 (m, 1H), 3.52 - 3.45 (m, 2H), 3.21 (ddd, J= 11.5, 5.4, 1.9 Hz, 2H), 2.69 (t, J= 12.8 Hz, 2H), 1.90 (ttt, J= 11.1, 7.3, 3.7 Hz, 1H), 1.70-1.62 (m, 2H), 1.44 (s, 9H), 1.24 - 1.11 (m, 3H). tert-butyl 4-((3 -(3 -cyanophenyl)-5 -(methylsulfonamido)-2-oxotetrahydropyrimidin- 1 (2H)- yOmethyOpiperidine- 1 -carboxylate
Figure imgf000101_0001
INTERMEDIATE J
To tert-butyl 4-((5-amino-3-(3-cyanophenyl)-2-oxotetrahydropyrimidin-l(2H)- yl)methyl)piperidine-l-carboxylate (350 mg, 0.846 mmol) in CH2C12 (8464 μΐ), TEA (354 μΐ, 2.54 mmol) and DMAP (10.34 mg, 0.085 mmol) were added at 0 °C, then the mixture was stirred for 15 min. After 15 min, methanesulfonyl chloride (79 μΐ, 1.016 mmol) was added and stirring was continued at 0 °C for an additional 30 min followed by stirring at room temperature for 1 h. After the reaction was complete, the solvent was removed by evaporation and the product isolated by column chromatography (373 mg, 90% yield) as an amorphous solid.
HRMS: C23H33N505S calculated (M+Na)+ = 514.20976 m/z, found (M+Na)+ = 514.20946 m/z. 1H NMR (400 MHz, Chloroform-;/) δ 7.60 (dt, J= 2.2, 0.9 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.47 - 7.40 (m, 2H), 5.73 - 5.61 (m, 1H), 4.07 (dq, J= 8.5, 4.3 Hz, 3H), 3.94 (dd, J= 11.8, 3.4 Hz, 1H), 3.77 - 3.60 (m, 2H), 3.39 (ddd, J= 12.3, 4.8, 1.9 Hz, 2H), 3.02 (d, J= 0.8 Hz, 3H), 2.69 (t, J = 12.7 Hz, 2H), 1.86 (ddp, J= 11.1, 7.3, 3.7 Hz, 1H), 1.72 (br.s, 1H), 1.62 (t, J= 13.3 Hz, 2H), 1.44 (s, 9H), 1.23 - 1.09 (m, 2H).
N-( 1 -(( 1 -benzylpiperidin-4-yl)methyl)-3 -(3 -cyanophenyl)-2-oxohexahydropyrimidin-5 - methanesulfonamide
Figure imgf000101_0002
tert-Butyl 4-((3 -(3 -cyanophenyl)-5 -(methylsulfonamido)-2-oxotetrahydropyrimidin- l(2H)-yl)methyl)piperidine-l-carboxylate (373 mg, 0.759 mmol) in CH2C12 (7587 μΐ) and TFA (585 μΐ, 7.59 mmol) were stirred for 30 min at RT. After the reaction was complete the solvent was evaporated and the solid product was purified further by trituration with chloroform, followed by ethanol. This material was used in the next step without further purification.
LRMS: (M+H)+ = 392.1 m/z.
N-( 1 -(3 -cyanophenyl)-2-oxo-3 -(piperidin-4-ylmethyl)hexahydropyrimidin-5 - yl)methanesulfonamide (300 mg, 0.766 mmol) was dissolved in CH2CI2 (8 ml), then
(bromomethyl)benzene (100 μΐ, 0.843 mmol) and TEA (320 μΐ, 2.299 mmol) were added at room temperature . This mixture was stirred for 15 min then the solvent was evaporated and the product was by purified by column chromatography (370 mg). HRMS: C25H31N5O3S calculated (M+H)+ = 482.22204 m/z, found calculated (M+H)+ = 482.22215 m/z. 1H NMR (400 MHz, Chloroform-;/) δ 7.70 - 7.67 (m, 1H), 7.62-7.57 (m, 1H), 7.54 - 7.48 (m, 2H), 7.39 (qd, J= 6.2, 5.6, 2.5 Hz, 5H), 7.10 (s, 1H), 4.12 (d, J= 5.5 Hz, 2H), 4.04 (s, 1H), 3.89 (s, 2H), 3.62 (t, J= 5.6 Hz, 3H), 3.47 (d, J= 35.4 Hz, 3H), 3.07 (s, 3H), 2.76 (s, 2H), 2.10-1.83 (m, 3H), 1.39 (s, 2H).
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -(methylsulfonamido)-2-oxotetrahvdrop yrimidin- 1 (2H)- nzimidamide
Figure imgf000102_0001
N-( 1 -(( 1 -benzylpiperidin-4-yl)methyl)-3 -(3 -cyanophenyl)-2-oxohexahydropyrimidin-5 - yl)methanesulfonamide (405 mg, 0.841 mmol), hydroxylamine hydrochloride (117 mg, 1.682 mmol) and Hunig's Base (0.294 ml, 1.682 mmol) in ethanol (16.800 ml) were stirred at 85 °C for 6 h, then overnight at room temperature. After the reaction was complete, the solvent was evaporated and the product isolated by column chromatography to give the desired product (170 mg, 39%) as a light green color solid. HRMS: C25H34N6O4S calculated (M+H)+ = 515.24350 m/z, found (M+H)+ = 515.24254 m/z. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 2H), 7.70 (dd, J= 6.3, 2.1 Hz, 1H), 7.66 - 7.55 (m, 3H), 7.45 (dtt, J= 6.3, 4.7, 2.8 Hz, 5H), 7.32 (d, J= 2.1 Hz, 1H), 7.19 (d, J= 2.3 Hz, 1H), 4.25 (d, J= 4.7 Hz, 2H), 3.96 (p, J= 5.3 Hz, 1H), 3.89 (dd, J = 11.8, 3.6 Hz, 1H), 3.64 (dd, J= 11.7, 6.2 Hz, 1H), 3.58 (dd, J= 11.8, 4.2 Hz, 1H), 3.28 (s, 3H), 3.18 (dt, J= 13.6, 6.8 Hz, 1H), 3.07 (s, 1H), 3.00 (d, J= 2.1 Hz, 3H), 2.84 (q, J= 12.2, 11.6 Hz, 2H), 1.82 (t, J= 13.4 Hz, 3H), 1.57 (q, J= 12.8 Hz, 2H). To 3-(3-((l-benzylpiperidin-4-yl)methyl)-5-(methylsulfonamido)-2- oxotetrahydropyrimidin-l(2H)-yl)-N-hydroxybenzimidamide (85 mg, 0.125 mmol), in ethanol (6 ml), Raney nickel (100 mg, 1.652 mmol) was added; this suspension was shaken overnight in a Parr apparatus under ¾ (gas) atmosphere at 50 psi. After the reaction was complete, it was purged with Ar gas then filtered through a Celite pad washing with methanol. Further purification of the crude product by column chromatography provided the desired product (41 mg, 50% yield) as an off white solid. HRMS: C25H34N6O3S calculated (M+2H)+2 = 250-12793 m/z, found (M+2H)+2 = 250.12872 m/z. 1H NMR (400 MHz, Methanol-i 4) δ 7.74 (dt, J= 2.3, 0.9 Hz, 1H), 7.68 (ddd, J= 5.5, 3.4, 2.1 Hz, 1H), 7.62 - 7.59 (m, 2H), 7.49 - 7.40 (m, 5H), 4.06 (s, 4H), 3.80 - 3.71 (m, 2H), 3.52 - 3.45 (m, 1H), 3.39 - 3.35 (m, 1H), 3.35 - 3.32 (m, 1H), 3.20 (q, J= 7.3 Hz, 1H), 3.05 (s, 3H), 2.70 (dt, J= 13.9, 10.6 Hz, 2H), 1.97 (d, J= 4.8 Hz, 2H), 1.93 - 1.87 (m, 1H), 1.49 (q, J= 11.3, 10.8 Hz, 3H).
EXAMPLE 50
3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-2-oxo-5 -(phenylsulfonamido)tetrahydropyrimidin- 1 (2H)- yObenzimidamide
Figure imgf000103_0001
EXAMPLE 50 was prepared by the same procedure used for EXAMPLE 49 with methanesulfonyl chloride replaced by phenylsulfonyl chloride. HRMS: C30H36N6O3S calculated (M+2H)+2 = 281.13802 m/z, found (M+2H)+2 = 281.13765. 1H NMR (400 MHz, Methanol-i 4) δ 7.93 - 7.88 (m, 2H), 7.68 - 7.65 (m, 1H), 7.63 - 7.54 (m, 5H), 7.54 - 7.46 (m, 6H), 4.22 (s, 2H), 3.94 - 3.82 (m, 2H), 3.65 - 3.59 (m, 1H), 3.55 (ddd, J= 11.9, 4.4, 2.1 Hz, 1H), 3.43 - 3.35 (m, 3H), 3.24 - 3.16 (m, 1H), 2.90 (s, 2H), 2.00 - 1.86 (m, 4H), 1.49 (s, 2H).
EXAMPLE 51 3-(3-((l-benzylpiperidin-4-yl)methyl)-2-oxo-5-
((phenylmethyl)sulfonamido)tetrahvdropyrimidin-l(2H)-yl)benzimidam
Figure imgf000104_0001
EXAMPLE 51 was prepared by the same procedure used for EXAMPLE 49 with methanesulfonyl chloride replaced by benzylsulfonyl chloride. HRMS: C31H38N6O3S calculated (M+2H)+2 = 288.14358 m/z, found (M+2H)+2 = 288.14362 m/z. 1H NMR (400 MHz,
Methanol-^) δ 7.66 (s, 1H), 7.59 (d, J= 2.4 Hz, 3H), 7.44 (qd, J= 3.8, 1.8 Hz, 2H), 7.38 - 7.26 (m, 8H), 4.42 (s, 2H), 3.81 (dd, J= 11.6, 3.4 Hz, 1H), 3.70 (s, 2H), 3.58 - 3.49 (m, 2H), 3.37 (s, 1H), 3.29 - 3.22 (m, 1H), 3.20 - 3.11 (m, 1H), 2.99 (d, J= 11.7 Hz, 2H), 2.16 (s, 3H), 1.74 (d, J = 10.1 Hz, 3H), 1.40 - 1.27 (m, 3H).
EXAMPLE 52
N-( 1 -(( 1 -benzylpiperidin-4-yl)methyl)-3 -(3 -carbamimidoylphenyl)-2-oxohexahydropyrimidin-5 - yDacetamide
Figure imgf000104_0002
EXAMPLE 52 was prepared by the same procedure used for EXAMPLE 49 with methanesulfonyl chloride replaced by acetyl chloride. HRMS: C26H34N6O2 calculated (M+2H)+2 = 232.14444 m/z, found (M+2H)+2 = 232.14516 m z 1H NMR (400 MHz, Methanol-d4) δ 7.74-7.72 (M, 1H)7.68 - 7.63 (m, 1H), 7.62 - 7.59 (m, 2H), 7.54 (d, J= 1.5 Hz, 1H), 7.49 (dq, J = 5.5, 3.4, 2.9 Hz, 2H), 7.46 - 7.43 (m, 3H), 4.41 (tt, J= 5.7, 4.1 Hz, 1H), 3.98 (ddd, J= 11.8, 3.8, 0.9, 1H), 3.77 - 3.68 (m, 2H), 3.50 (dd, J= 13.9, 7.4 Hz, 2H), 3.44 - 3.38 (m, 1H), 3.38 - 3.35 (m, 1H), 3.27 (d, J= 7.3 Hz, 1H), 3.26 - 3.22 (m, 1H), 3.21 (d, J= 7.3 Hz, 1H), 2.85 - 2.75 (m, 2H), 2.00 (s, 3H), 1.52 (q, J= 12.3, 11.7 Hz, 3H), 1.43 (tt, J= 7.3, 1.7 Hz, 2H).
EXAMPLE 53
N-( 1 -(( 1 -benzylpiperidin-4-yl)methyl)-3 -(3 -carbamimidoylphenyl)-2-oxohexahvdropyrimidin-5 - yPbenzamide
Figure imgf000105_0001
EXAMPLE 53 was prepared by the same procedure used for EXAMPLE 49 with methanesulfonyl chloride replaced by benzoyl chloride. HRMS: C31H36N6O2 calculated
(M+2H)+2 = 263.15226 m/z, found (M+2H)+2 = 263.15277 m/z. 1H NMR (400 MHz, Methanol-^) δ 7.86 - 7.85 (m, 1H), 7.84 (d, J= 1.4 Hz, 1H), 7.75 (dt, J= 2.3, 1.0 Hz, 1H), 7.69 (ddd, J= 5.8, 3.1, 2.1 Hz, 1H), 7.63 - 7.59 (m, 2H), 7.59 - 7.56 (m, 1H), 7.56 - 7.52 (m, 2H), 7.50 - 7.46 (m, 5H), 4.65 (tt, J = 7.1, 4.5 Hz, 1H), 4.30 (s, 2H), 4.03 (ddd, J= 11.7, 4.2, 1.2 Hz, 1H), 3.94 (ddd, J= 11.6, 7.2, 0.9 Hz, 1H), 3.78 (ddd, J= 12.0, 4.7, 1.2 Hz, 1H), 3.68 - 3.62 (m, 1H), 3.53 - 3.41 (m, 3H), 3.08 - 2.93 (m, 2H), 2.00 (d, J= 14.7 Hz, 4H), 1.60 (t, J= 12.6 Hz, 2H).
EXAMPLE 54
N-( 1 -(( 1 -benzylpiperidin-4-yl)methyl)-3 -(3 -carbamimidoylphenyl)-2-oxohexahydropyrimidin-5 - yl)-2-phenylacetamide
Figure imgf000105_0002
EXAMPLE 54 was prepared by the same procedure used for EXAMPLE 49 with methanesulfonyl chloride replaced by phenylacetyl chloride. HRMS: C32H38N602 calculated
(M+H)+ = 539.31290 m/z, found (M+H)+ = 539.31331 m/z. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J= 7.3 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.52 - 7.44 (m, 2H), 7.35 - 7.16 (m, 9H), 3.87 (dd, J= 11.6, 3.5 Hz, 1H), 3.64 - 3.53 (m, 2H), 3.48 - 3.42 (m, 4H), 3.31 - 3.21 (m, 3H), 3.09 (dd, J = 13.7, 6.4 Hz, 1H), 2.77 (s, 2H), 1.87 (t, J= 11.6 Hz, 2H), 1.58 (d, J= 12.8 Hz, 2H), 1.14 (t, J = 11.4 Hz, 2H).
EXAMPLE 55
N-( 1 -(( 1 -benzylpiperidin-4-yl)methyl)-3 -(3 -carbamimidoylphenyl)-2-oxohexahydropyrimidin-5 - vD-3 -phenylpropanamide
Figure imgf000106_0001
EXAMPLE 55 was prepared by the same procedure used for EXAMPLE 49 with methanesulfonyl chloride replaced by 3-(phenyl)propionyl chloride. HRMS: C33H40N6O2 calculated (M+H)+ = 553.32855 m/z, found (M+H)+ = 553.32884 m z. 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.38 (s, 1H), 9.13 (s, 1H), 8.35 (d, J= 7.1 Hz, 1H), 7.70 - 7.57 (m, 4H), 7.53 (d, J= 7.7 Hz, 2H), 7.48 - 7.41 (m, 2H), 7.28 - 7.13 (m, 5H), 4.27 (dd, J= 14.9, 5.3 Hz, 3H), 3.83 (dd, J= 11.6, 3.9 Hz, 1H), 3.55 (ddd, J= 14.8, 11.7, 5.2 Hz, 2H), 3.32-3.16 (m, 3H), 3.12 - 3.02 (m, 2H), 2.79 (t, J= 7.8 Hz, 4H), 2.44 (dd, J= 8.9, 6.7 Hz, 2H), 1.80 (s, 3H), 1.54 (d, J= 13.3 Hz, 2H).
EXAMPLE 56
3 -(5 -hydroxy-2-oxo-3 -(( 1 -(pyridin-2-ylmethy l)piperidin-4-yl)methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000107_0001
INTERMEDIATE K
3 -(5 -hydroxy-2-oxo-3 -(( 1 -(pyridin-2-ylmethy l)piperidin-4-yl)methyl)tetrahydropyrimidin- 1 (2H)-yl)benzonitrile :
tert-Butyl 4-((3 -(3 -cyanophenyl)-5 -hydroxy-2-oxotetrahydropyrimidin- 1 (2H)- yl)methyl)piperidine-l-carboxylate (467 mg, 1.127 mmol) and TFA (0.868 ml, 11.27 mmol) in CH2CI2 (11 ml) were stirred at room temperature for 30 min. Then the solvent was evaporated off and the residue was triturated with chloroform followed by ethanol. This was repeated three times after which an off-white color gummy solid was obtained. The crude carried through next step without purification. LRMS : (M+H)+ = 315.2 m/z
To 3 -(5 -hydroxy-2-oxo-3 -(piperidin-4-ylmethyl)tetrahydropyrimidin- 1 (2H)- yl)benzonitrile (354 mg, 1.126 mmol) in CH2CI2 (6 ml), picolinaldehyde (118 μΐ, 1.239 mmol) followed by sodium triacetoxy borohydride (358 mg, 1.689 mmol) were added at room temperature. This was stirred for 1 h, then quenched with sat. NaHCC , extracted with CH2CI2 (3 X 15 ml) and the combined organic layers were dried over anhydrous Na2S04. The solution was concentrated under reduced pressure to obtain a light brown colored gummy solid. Further purification by column chromatography provided the desired product (261 mg, 57% yield) as an orange color gummy solid. HRMS: C23H27N5O2 calculated (M+H)+ = 406.22375 m/z, found
(M+H)+ = 406.22344 m z. 1H NMR (400 MHz, Chloroform-^/) δ 8.49 (dd, J= 4.9, 1.8 Hz, 1H), 7.64 (td, J = 7.7, 1.9 Hz, 1H), 7.60 - 7.57 (m, 1H), 7.53 (ddd, J= 7.0, 5.2, 2.9 Hz, 1H), 7.43 - 7.35 (m, 3H), 7.19 - 7.13 (m, 1H), 4.25 (p, J= 4.3 Hz, 1H), 3.81 (dd, J= 11.8, 3.0 Hz, 1H), 3.66 (s, 2H), 3.64 - 3.53 (m, 3H), 3.32 (ddd, J= 12.2, 4.4, 1.9 Hz, 1H), 3.23 (dd, J= 7.0, 2.5 Hz, 2H), 2.92 (d, J= 11.4 Hz, 2H), 2.17 - 2.07 (m, 2H), 1.82 - 1.63 (m, 3H), 1.38 (qt, J= 11.8, 3.6 Hz,
2H).
3 -(5 -hydroxy-2-oxo-3 -(( 1 -(pyridin-2-ylmethy l)piperidin-4-yl)methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000108_0001
3-(5-Hydroxy-2-oxo-3-((l-(pyridin-2-ylmethyl)piperidm^
l(2H)-yl)benzonitrile (240 mg, 0.592 mmol), hydroxylamine hydrochloride (82 mg, 1.184 mmol) and Hunig's Base (0.207 ml, 1.184 mmol) in ethanol (23.700 ml) were heated at 85 °C for 6 h then stirred overnight at RT. After the reaction was complete, the solvent was evaporated and the product was purified by column chromatography to give (114 mg, 44% yield) as a white solid. HRMS: C23H30N6O3 calculated (M+H)+ = 439.24522 m/z, found (M+H)+ = 439.24568 m/z. 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.47 (d, J= 5.0 Hz, 1H), 7.75 (t, J= 7.6 Hz, 1H), 7.53 (s, 1H), 7.46 - 7.36 (m, 2H), 7.25 (q, J= 6.6, 5.7 Hz, 3H), 5.77 (s, 2H), 5.31 (d, J= 4.0 Hz, 1H), 4.15 - 4.05 (m, 1H), 3.80 - 3.72 (m, 1H), 3.59 (s, 2H), 3.49 (dd, J= 11.8, 4.5 Hz, 2H), 3.15 (ddt, J= 20.3, 14.0, 7.3 Hz, 3H), 2.82 (d, J= 10.9 Hz, 2H), 2.00 (d, J= 10.1 Hz, 2H), 1.63 (d, J= 12.1 Hz, 3H), 1.26 - 1.12 (m, 2H).
N-Hydroxy-3-(5-hydroxy-2-oxo-3-((l-(pyridin-2-ylmethyl)piperidin-4- yl)methyl)tetrahydropyrimidin-l(2H)-yl)benzimidamide (114 mg, 0.260 mmol), Raney nickel (153 mg, 2.60 mmol) in ethanol (6 ml) and acetic acid (0.5 ml) were placed on a Parr shaker and shaken under an H2 (50 psi) atmosphere for 16 h. The reaction was purged with Ar gas and filtered through a Celite pad with copious washing with methanol. The product was purified by column chromatography to give the desired product (58 mg, 53%) as a white solid. HRMS: C23H3oN602 calculated (M+H)+ = 423.25030 m/z, found (M+H)+ = 423.25038 m/z. 1H NMR (400 MHz, DMSO-de) δ 9.63 - 9.10 (m, 3H), 8.49-8.39 (m, 1H), 7.79 - 7.60 (m, 3H), 7.53 - 7.36 (m, 3H), 7.24 (dd, J= 7.4, 5.0 Hz, 1H), 5.38 (s, 1H), 4.15 - 4.04 (m, 1H), 3.83 (dd, J = 11.8, 3.1 Hz, 1H), 3.56 (s, 3H), 3.23 - 3.05 (m, 3H), 2.79 (s, 2H), 1.98 (t, J= 11.3 Hz, 1H), 1.88 (d, J= 4.4 Hz, 2H), 1.62 (d, J= 12.8 Hz, 3H), 1.28 - 1.08 (m, 2H).
EXAMPLE 57
3 -(5 -hydroxy-2-oxo-3 -(( 1 -(pyridin-3 -ylmethy l)piperidin-4-yl)methyl)tetrahydropyrimidin-
1 (2H)-yl)benzimidamide
Figure imgf000109_0001
EXAMPLE 57 was prepared by the same method used to prepare EXAMPLE 56 with picolinaldehyde replaced by nicotinaldehyde. HRMS: C23H30N6O2 calculated (M+H)+ = 423.25030 m/z, found (M+H)+ = 423.24989 m/z. 1H NMR (400 MHz, DMSO-d6) δ 8.49 - 8.40 (m, 2H), 7.68 (dt, J= 8.8, 3.3 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.50 - 7.42 (m, 2H), 7.33 (s, 1H), 4.10 (s, 1H), 3.86-3.76 (m, 1H), 3.62 - 3.40 (m, 4H), 3.26 - 3.05 (m, 3H), 2.76 (s, 2H), 1.92 (t, J = 11.3 Hz, 2H), 1.78 (d, J= 5.6 Hz, 4H), 1.62 (d, J= 12.4 Hz, 3H), 1.16 (d, J= 12.4 Hz, 2H).
EXAMPLE 58
3 -(5 -hydroxy-2-oxo-3 -(( 1 -(pyridin-4-ylmethyl)piperidin-4-yl)methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000109_0002
EXAMPLE 58 was prepared by the same method used to prepare EXAMPLE 56 with picolinaldehyde replaced by isonicotinaldehyde. HRMS: C23H30N6O2 calculated (M+H)+ = 423.25030 m/z, found (M+H)+ = 423.25033 m/z. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 4.9 Hz, 2H), 8.39 (s, 1H), 7.67-7.60 (m, 2H), 7.51 - 7.46 (m, 2H), 7.30 (d, J = 4.9 Hz, 2H), 4.15- 4.09 (m, 1H), 3.87 - 3.79 (m, 1H), 3.61 - 3.49 (m, 2H), 3.48 (s, 2H), 3.27 - 3.17 (m, 2H), 3.12 (dd, J = 13.6, 6.8 Hz, 1H), 2.77 (d, J = 10.8 Hz, 2H), 1.99 - 1.89 (m, 2H), 1.63 (d, J = 12.6 Hz, 3H), 1.26 - 1.12 (m, 2H).
EXAMPLE 59
3-(5-hydroxy-3-((l-(3-(2-morpholinoethoxy)benzyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000110_0001
EXAMPLE 59 was prepared by the same method used to prepare EXAMPLE 56 with picolinaldehyde replaced by 3-(2-morpholinoethoxy)benzaldehyde. LRMS: (M+H)+ = 551.3 m/z
EXAMPLE 60
3-(5-hydroxy-3-((l-(4-(2-morpholinoethoxy)benzyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000110_0002
EXAMPLE 60 was prepared by the same method used to prepare EXAMPLE 56 with picolinaldehyde replaced by 4-(2-morpholinoethoxy)benzaldehyde. LRMS: (M+H)+ = 551.3 m/z
EXAMPLE 61
3-(5-hvdroxy-3-((l-(3-(4-morpholinobutoxy)benzyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000110_0003
EXAMPLE 61 was prepared by the same method used to prepare EXAMPLE 56 with picolinaldehyde replaced by 3-(4-morpholinobutoxy)benzaldehyde. LRMS: (M+H)+ = 579.3 m/z
EXAMPLE 62
3-(5-hydroxy-3-((l-(4-(4-morpholinobutoxy)benzyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide
Figure imgf000111_0001
EXAMPLE 62 was prepared by the same method used to prepare EXAMPLE 56 with picolinaldehyde replaced by 4-(4-morpholinobutoxy)benzaldehyde. LRMS: (M+H)+ = 579.3 m/z
EXAMPLE 63
3 -(5 -hydroxy-3 -(( 1 -(3 -methoxybenzyl)piperidin-4-yl)methyl)-2-oxotetrahydropyrimidin- 1 (2H)- vDbenzimidamide
Figure imgf000111_0002
EXAMPLE 63 was prepared by the same method used to prepare EXAMPLE 56 with picolinaldehyde replaced by 3-methoxybenzaldehyde. LRMS: (M+H)+ = 452.3 m/z
EXAMPLE 64
3 -(5 -hydroxy-3 -(( 1 -(4-methoxybenzyl)piperidin-4-yl)methyl)-2-oxotetrahvdropyrimidin- 1 (2H)- vDbenzimidamide
Figure imgf000111_0003
EXAMPLE 64 was prepared by the same method used to prepare EXAMPLE 56 with picolinaldehyde replaced by 4-methoxybenzaldehyde. LRMS: (M+H)+ = 452.3 m/z
BIOLOGICAL TESTING The compounds prepared above were tested for their ability to inhibit the proteases matriptase, hepsin and HGF activator (HGFA) according to the following assay conditions:
Activity Assay Protocol for Matriptase/Hepsin/ HGF Activator
Materials
• Assay Buffer: 50 mM Tris, 20 mM NaCl, 0.01% (v/v) Tween® 20, pH 8.0
• Recombinant Human Matriptase/ST14 Catalytic Domain (rafiMatriptase) (R&D Systems, Catalog # 3946-SE) or rh-hepsin (R&D Systems, Catalog # 4776-SE) or rh-HGFA (R&D Systems, Catalog # 1514-SE)
• Substrate: H2N-(EEdans)GKQLRVVNGG(Kdabcyl)-amide (Custom peptide from New England Peptide), 10 mM stock in DMSO
• Fluorescence micro-cuvets
• Aminco-Bowman Series 2 Luminescence Spectrometer Assay
1. Dilute rfiMatriptase or rhHepsin to 0.2 ug/mL in Assay Buffer; 2 ug/ml for HGFA.
2. Dilute Substrate to 20 uM in Assay Buffer.
3. Load 150 uL of 0.2 ug/mL rhMatriptase/rhHepsin into a microtube, add inhibitor or DMSO, and start the reaction by adding 150 uL of 20 uM substrate. Immediately transfer the assay solution to a cuvet and place it in the fluorometer.
4. Read at excitation and emission wavelengths of 340 nm and 490 nm, respectively, in kinetic mode for 5 minutes. Increase in fluorescence is recorded as RFU/sec.
Final Assay Conditions in Assay Buffer
• 0.2 μg/ml rfiMatriptase/ rhHepsin; 2 ug/ml HGFA.
• 10 μΜ Substrate
• 2% DMSO
For EXAMPLES 1-33 the following results were obtained: Matriptase IC50
EXAMPLE Hepsin IC50 [uM] HGFA IC50 [uM]
[uM]
1 1.08 4.1 10.8
2 9.4 22.4 5.4
3 79.7 118.7 23.5
4 42.6 87.9 24.4
5 2.2 19.8 16.5
6 29.9 47.7 30.2
7 23.2 42.4 7.7
8 87.1 56.5 6
9 119.2 85 20.4
10 34.9 95.6 7.4
11 >200 154.9 >200
12 18 19.4 2.3
13 34.9 72 5.1 14 2.8 11.6 9.6
15 58.2 35.7 24
16 12.7 30.3 14.9
17 47.1 61.3 27.5
18 60.3 18 4.9
19 61.8 8 7.9
20 65.5 4.5 26.5
21 32.8 4.3 4.4
22 15.9 4.1 8.1
23 3.8 6.6 18.2
24 43.1 33.8 18.2
25 9.3 29.3 18.7
26 0.75 0.82 0.47
27 9.9 11.9 2.5 28 70.6 44.4 35.9
29 72.6 37.4 25.1
30 9.5 7.5 1.9
31 5.8 11.3 0.79
32 15 12.1 2.4
33 21.1 53.5 21.6
34 0.76 0.83 0.25
35 1.1 0.67 0.47
36 1.1 1.1 0.18
37 1.01 2.36 1.17
38 1.02 1.07 1.14
39 1.2 1.19 1.54
40 0.94 2.29 1.39
41 0.61 1.32 1.21 42 0.96 0.37 1.19
43 1.71 2.53 1.52
44 1.74 2.23 2.4
45 4.23 5.83 2.63
46 0.36 0.25 0.97
47 1.05 0.91 2.11
48 2 0.91 2.11
49 0.43 0.86 0.39
50 0.67 0.8 0.57
51 0.45 0.64 0.48
52 2.19 2.59 1.58
53 0.85 2.18 0.97
54 1.67 1.34
55 1.67 1.34 56 0.7 0.86
57 0.63 1.26
58 0.56 0.83
HGF is also referred to as Scatter Factor because of the well-established activity of this cytokine to cause cell scattering. Assays to measure this characteristic activity of HGF are used to demonstrate the presence and absence of this biomolecule in a concentration dependent manner. To test the ability of these compounds to inhibit the activation of HGF in cells a scatter protocol was used for EXAMPLE 26.
Figure 1 shows the inhibition of cellular scattering by EXAMPLE 26: DU145 cells were serum starved, treated with HGF, conditioned medium from 18 Co fibroblasts and EXAMPLE 26 (10 μΜ) as indicated for 24 hours and colonies were stained with crystal violet. B: RKO cells were treated with increasing doses of EXAMPLE 26 (1 μΜ & 10 μΜ) as indicated.
Exemplary embodiments of the present disclosure include:
Embodiment A. A compound of Formula 1
FORMULA 1
Where R1 is selected from the group consisting of:
Figure imgf000118_0001
Each R1 ring may be optionally substituted once with a member selected from the group consisting of halo, -0(Ci-C3 alkyl), -NH2, -NH(Ci-C3 alkyl) and -N(Ci-C3 alkyl);
R1 is selected from the group consisting of H-, Ci to C5 alkyl, and -C(=0)C1 to C5 alkyl, and Y is -H or -F;
Where R2 is selected from the group consisting of C1-C12 alkyl, =CH2, C6-Cio aryl, heterocycloaryl,
Figure imgf000118_0002
alkyl)C3-Ci0 cycloalkyl,
=CH(Ci-Ci2 alkyl)aryl, =CH(Ci-Ci2 alkyl)heterocycloalkyl, =CH(Ci-Ci2 alkyl)heterocycloaryl, -CH=CH(Ci-Ci2 alkyl), -CH=CH(Ci-Ci2 alkyl), -CH=CH(Ci-Ci2 alkyl)C3-Ci0 cycloalkyl,
-CH=CH(Ci-Ci2 alkyl)aryl, -CH=CH(Ci-Ci2 alkyl)heterocycloalkyl,
-CH=CH(Ci-Ci2 alkyl)heterocycloaryl, -CH2(Ci-Ci2 alkyl)C3-Ci0 cycloalkyl,
-CH2(Ci-Ci2 alkyl)aryl, -CH2(Ci-Ci2 alkyl)heterocycloalkyl, -CH2(Ci-Ci2 alkyl)heterocycloaryl, -CH(=0), =0, -O-R4, -CH2-0-R4, -C(=0)-0-R4, =CHC(=0)-0-R4, -CH2C(=0)-0-R4,
-CH=CHC(=0)0-R4, -CH2CH2C(=0)0-R4, -N(R4)R4', -CH2-N(R4)R4', -C(=0)-N(R4)R4', =CHC(=0)-N(R4)R4', -CH2C(=0)-N(R4)R4',-CH=CHC(=0)-N(R4)R4',
-CH2CH2C(=0)-N(R4)R4', -S-R4, -CH2-S-R4, -S(0)-R4, -CH2-S(0)-R4, -S(0)2-R4,
-CH2-S(0)2-R4, -S(0)NR4R4', -CH2-S(0) NR4R4 , -S(0)2 NR4R4 and -CH2-S(0)2 NR4R4 ; R2 may be optionally substituted;
Where R3 is selected from the group consisting of -H, -C(=0)NH2, and X-R5 X may be absent or is selected from the group consisting of -CH2-,-CH2CH2-, -CH(CH3)- , -C(CH3)2-, -CH2CH=CH-,-C(=0)-, -C(=0)CH=CH-, -C(=0)0-, -C(=0)NH2, -C(=0)NH-, -C(=0)N, -S-, -S(O)-, and -S(0)2-; n = 0, 1 or 2;
R4, R4' are independently selected from the group consisting of -H, Ci to Ci2 alkyl, C3-C10 cycloalkyl, Ci to C6 alkyl attached to C3-Cio cycloalkyl, 5- or 6-member-heterocycloalkyl containing one or two -0-, -N(R6), S, S(O), or S(0)2; Ci to C6 alkyl attached to
a 5- or 6-member-heterocycloalkyl containing one or two -0-, -N(R6), S, S(O), or S(0)2; C6, C9 or Cio aryl, Ci to C6 alkyl attached to C6 or Ci0 aryl; 5-, 6-, 9- or 10-member-heterocycloaryl containing one, two or three -0-, -N, -N(R6), S; Ci to C6 alkyl attached to
a 5-, 6-, 9- or 10-member-heterocycloaryl containing one, two or three -0-, -N, -N(R6), S; R4 and R4' may be taken together to form a ring; R4, R4 may be optionally substituted with 1 to 3 of the following substituents: -halogen, -OH, -0(C C3 alkyl), -NH2, -NH(C C3 alkyl),
-N(Ci-C3 alkyl)Ci-C3 alkyl, N-pyrrolidine, N-piperidine, N-morpholine, N-piperazine,
4- methylpiperizin-l-yl, 4-ethylpiperizin-l-yl, -NHC(=0)Ci-C3 alkyl,
-N(Ci-C3 alkyl)C(=0)Ci-C3 alkyl, -C02H, C02(Ci-C3 alkyl), -CONH2- -CONH(Ci-C3 alkyl), -CON(Ci-C3 alkyl)2, -OC02(C C3 alkyl), -0C0NH(C C3 alkyl), -OCON(C C3 alkyl)2, -NHC02(Ci-C3 alkyl), -NHCONH(Ci-C3 alkyl), -NHCON(Ci-C3 alkyl)2, -SH, -S(Ci-C3 alkyl), -SO(Ci-C3 alkyl), -S02(Ci-C3 alkyl), -NHS02(Ci-C3 alkyl), -N(Ci-C3 alkyl)S02(Ci-C3 alkyl), -S02NH2, -S02NH(Ci-C3 alkyl), -S02N(Ci-C3 alkyl)2;
R5 is independently selected from the group consisting of Ci-Ci2 alkyl, C3-Cio cycloalkyl, aryl; 5- or 6-member- heterocycloalkyl containing one or two -0-, -N(R6), S, S(0), or S(0)2;
5- , 6, 9- or 10-member-heterocycloaryl containing one, two or three -0-, -N, -N(R6), S; R5 may be optionally substituted with 1 to 3 of the following substituents: -halogen, -OH,
-0(Ci-C3 alkyl), -NH2, -NH(Ci-C3 alkyl), -N(Ci-C3 alkyl)Ci-C3 alkyl, N-pyrrolidine,
N-piperidine, N-morpholine, N-piperazine, 4-methylpiperizin-l-yl, 4-ethylpiperizin-l-yl, -NHC(=0)Ci-C3 alkyl, -N(C C3 alkyl)C(=0)C C3 alkyl, -C02H, C02(C C3 alkyl),
-CONH2- CONH(Ci-C3 alkyl), -CON(Ci-C3 alkyl)2, -OC02(Ci-C3 alkyl), -OCONH(Ci-C3 alkyl), -OCON(Ci-C3 alkyl)2, -NHC02(Ci-C3 alkyl), -NHCONH(Ci-C3 alkyl), -NHCON(Ci-C3 alkyl)2, -SH, -S(Ci-C3 alkyl), -SO(Ci-C3 alkyl), -S02(Ci-C3 alkyl), -NHS02(Ci-C3 alkyl), -N(Ci-C3 alkyl)S02(Ci-C3 alkyl), -S02NH2, -S02NH(C C3 alkyl), -S02N(CrC3 alkyl)2;
R6 is selected from the group consisting of -H, C -Cn alkyl, C3-C6 cycloalkyl; and may optionally be substituted; and pharmaceutically acceptable salts thereof, prodrugs thereof, solvates thereof, isomers thereof, deuterated forms, radio-actively labeled forms and mixtures thereof.
Embodiment B. The Embodiment according to Embodiment A, being selected from the group consisting of:
Amino(3 -(3 -( 1 -benzylpiperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) phenyl)methaniminium trifluoroacetate;
3 -(5 -Methyl-2-oxo-3 -(piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(3 -( 1 -acetylpiperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl)
benzimidamide;
3 -(5 -methyl-3 -( 1 -(methylsulfonyl)piperidin-4-yl)-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(phenylsulfonyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -phenylpiperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl)
benzimidamide;
3 -(5 -methyl-3 -( 1 -methylpiperidin-4-yl)-2-oxotetrahydropyrimidin- 1 (2H)-yl)
benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(2-phenylacetyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide;
3 -(3 -( 1 -benzoylpiperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl)
benzimidamide; Tert-butyl (2-(4-(3 -(3 -carbamimidoylphenyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)- yl)piperidin- 1 -yl)ethyl)carbamate;
Tert-butyl (2-(4-(3 -(3 -carbamimidoylphenyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)- yl)piperidin- 1 -yl)-2-oxoethyl)carbamate;
2-(4-(3 -(3 -(amino(iminio)methyl)phenyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) piperidin- 1 -yl)ethanaminium tri-trifluroacetate;
2-(4-(3 -(3 -(amino(iminio)methyl)phenyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) piperidin- 1 -yl)-2-oxoethanaminium di-trifluroacetate;
3 -(3 -( 1 -(benzylsulfonyl)piperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(pyridin-3 -ylmethyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)- yl)benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(pyridin-2-ylmethyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)- yl)benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(pyridin-4-ylmethyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)- yl)benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(4-(trifluoromethyl)benzyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(3 -(trifluoromethyl)benzyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(2-(trifluoromethyl)benzyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(3 -( 1 -(3 -fluorobenzyl)piperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide; 3 -(3 -( 1 -(2-fluorobenzyl)piperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(thiophen-2-ylsulfonyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(5 -methyl-3 -( 1 -(morpholinosulfonyl)piperidin-4-yl)-2-oxotetrahydropyrimidin- 1 (2H)- yl)benzimidamide;
3 -(3 -( 1 -(( 1 H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
Amino(3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)- yl)phenyl)methaniminium trifluoroacetate;
3 -(5 -methyl-2-oxo-3 -(piperidin-4-ylmethyl)tetrahydropyrimidin- 1 (2H)-yl)
benzimidamide;
3 -(3 -( 1 -(( 1 H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(5 -methyl-3 -(1-((1 -methyl- lH-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(5 -methyl-2-oxo-3 -(( 1 -(pheny lsulfonyl)piperidin-4-yl)methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3-(5-methyl-2-oxo-3-((l-(thiophen-2-ylsulfonyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(5 -methyl-3 -(( 1 -(morpholinosulfonyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide; and
1 -(3 -(aminomethyl)phenyl)-3 -((4-benzylcyclohexyl)methyl)-5 - methylenetetrahydropyrimidin-2( 1 H)-one; and pharmaceutically acceptable salts thereof, prodrugs thereof, solvates thereof, deuterated forms, radio-actively labeled forms and mixtures thereof.
Embodiment C. The Embodiment according to Embodiment A, being amino(3-(3-((l- benzylpiperidin-4-yl)methyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl)
phenyl)methaniminium trifluoroacetate; a pharmaceutically acceptable salt thereof, prodrug thereof, solvate thereof, isomers thereof, deuterated form thereof, a radio-actively labeled form thereof or mixtures thereof.
Embodiment D. A compound according to any one of Embodiments A, B or C and pharmaceutically acceptable salts thereof, prodrugs thereof, solvates thereof, deuterated forms, radio- actively labeled forms, and mixtures thereof; wherein the isomers are enantiomers or diastereomers thereof.
Embodiment E. The compound according to Embodiment A, represented by the following formula:
Figure imgf000123_0001
Embodiment F. A pharmaceutical composition comprising a compound or derivative according to any one of Embodiments A, B, C, D or E and a pharmaceutically acceptable carrier.
Embodiment G. A compound selected from the group consisting of
Figure imgf000124_0001
Figure imgf000124_0002
, and mixtures thereof.
Embodiment H. A method of treating a patient with a disease caused by or associated with abnormal matriptase, hepsin and hepatocyte growth factor activator (HGFA) protease activity, which comprises administering to the patient an effective treatment amount of at least one compound or derivative according to any one of Embodiments A, B, C, D or E.
Embodiment I. A method of treating a precancerous condition or cancer in a patient comprising administering to the patient an effective treatment amount of a compound according to any one of Embodiments A, B, C, D or E.
Embodiment J. The method of Embodiment I wherein the patient is a mammal. .
Embodiment K. The method of Embodiment J wherein the mammal is a human.
Embodiment L. The method according to Embodiment I wherein said cancer comprises metastatic cancer. Embodiment M. The method according to Embodiment I wherein the cancer comprises a solid or liquid tumor.
Embodiment N. A method of treating a patient to prevent or reverse resistance in said patient to cancer treatment which comprises administering to the patient an effective treatment amount of at least one compound or derivative according to any one of Embodiments A, B, C, D or E.
Embodiment O. A method of inhibiting cancer stem cells in a patient in need thereof which comprises administering to the patient an effective treatment amount of at least one compound or derivative according to any one of Embodiments A, B, C, D or E.
In keeping with the present disclosure, the cyclic urea compounds of the present disclosure can be used alone or in appropriate association, and also may be used in combination with pharmaceutically acceptable carriers and other pharmaceutically active compounds. The active agent may be present in the pharmaceutical composition in any suitable quantity.
The pharmaceutically acceptable carriers described herein, for example, vehicles, adjuvants, excipients, or diluents, are well-known to those who are skilled in the art. Typically, the pharmaceutically acceptable carrier is chemically inert to the active compounds and has no detrimental side effects or toxicity under the conditions of use. The pharmaceutically acceptable carriers can include polymers and polymer matrices.
The choice of carrier will be determined in part by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intra-arterial, intramuscular, intraperitoneal, intrathecal, rectal, and vaginal administration are merely exemplary and are in no way limiting.
Formulations suitable for oral administration can comprise (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granule; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water, cyclodextrin, dimethyl sulfoxide and alcohols, for example, ethanol, benzyl alcohol, propylene glycol, glycerin, and the polyethylene alcohols including polyethylene glycol, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard-or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can include one or more of the following: lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acadia, emulsions, and gels containing, the addition to the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acadia, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
The cyclic urea compounds of the present disclosure alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, and nitrogen. They also may be formulated as
pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol such as poly(ethyleneglycol) 400, glycerol ketals, such as 2,2-dimethyl-l, 3-dioxolane-4-methanol, ethers, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.
Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyldialkylammonium halides, and alkylpyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl β-aminopropionates, and 2- alkylimidazoline quaternary ammonium salts, and (e) mixtures thereof.
The parenteral formulations typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
Pharmaceutically acceptable excipients are also well-known to those who are skilled in the art. The choice of excipient will be determined in part by the particular compound, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present disclosure. The following methods and excipients are merely exemplary and are in no way limiting. The pharmaceutically acceptable excipients preferably do not interfere with the action of the active ingredients and do not cause adverse side-effects. Suitable carriers and excipients include solvents such as water, alcohol, and propylene glycol, solid absorbants and diluents, surface active agents, suspending agent, tableting binders, lubricants, flavors, and coloring agents.
The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia, PA, Banker and Chalmers, Eds., 238-250 (1982) and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., 622-630 (1986).
Formulations suitable for topical administration include lozenges comprising the active ingredient in a flavor, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier; as well as creams, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
Additionally, formulations suitable for rectal administration may be presented as suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
One skilled in the art will appreciate that suitable methods of exogenously administering a compound of the present disclosure to an animal are available, and, although more than one route can be used to administer a particular compound, a particular route can provide a more immediate and more effective reaction than another route.
As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the inhibition of serine proteases and especially the serine proteases matriptase, hepsin and hepatocyte growth factor activator (HGFA) involved in the maturation of hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP).
Compounds of the present disclosure can be used to treat a number of disorders caused by or associated with abnormal matriptase, hepsin and HGFA protease activity by inhibiting the proteolytic cleavage of pro-HGF to mature HGF and pro-MSP to mature MSP caused by these enzymes. Compounds of the present disclosure can be used to treat disorders including precancerous conditions and cancer including metastatic disease, prevention and reversion of cancer resistance, and the inhibition of cancer stem cells.
The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal, the body weight of the animal, as well as the severity and stage of the cancer.
The total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 10 mg/kg and about 1000 mg/kg of body weight for mice, and between about 100 mg/kg and about 500 mg/kg of body weight, and more preferably between 200 mg/kg and about 400 mg/kg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.
The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.
The term "comprising" (and its grammatical variations) as used herein is used in the inclusive sense of "having" or "including" and not in the exclusive sense of "consisting of." The terms "a", "an" and "the" as used herein are understood to encompass the plural as well as the singular, unless indicated otherwise.
The foregoing description illustrates and describes the disclosure. Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and/or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in the art to utilize the disclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments.
All documents (patent literature and non-patent literature) cited in this specification are herein incorporated by reference, and for any and all purposes, as if each individual document was specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any one of the documents incorporated herein by reference, the present disclosure controls.

Claims

What is claimed is:
1. A compound of Formula 1
Figure imgf000131_0001
FORMULA 1
Wher R1 is selected from the group consisting of:
Figure imgf000131_0002
Each R1 ring may be optionally substituted once with a member selected from the group consisting of halo, -0(d-C3 alkyl), -NH2, -NH(Ci-C3 alkyl) and -N(Ci-C3 alkyl);
R1 is selected from the group consisting of H-, Ci to C5 alkyl, and -C(=0)C1 to C5 alkyl; and Y is -H or -F;
Where R2 is selected from the group consisting of C1-C12 alkyl, =CH2, C6-Cio aryl, heterocycloaryl, =CH(Ci-Ci2 alkyl), =CH(Ci-Ci2 alkyl)C3-Ci0 cycloalkyl,
=CH(Ci-Ci2 alkyl)aryl, =CH(Ci-Ci2 alkyl)heterocycloalkyl,
Figure imgf000131_0003
alkyl)heterocycloaryl, -CH=CH(Ci-Ci2 alkyl),
Figure imgf000131_0004
alkyl)C3-Ci0 cycloalkyl, -CH=CH(Ci-Ci2 alkyl)aryl,
Figure imgf000131_0005
alkyl)heterocycloalkyl,
-CH=CH(Ci-Ci2 alkyl)heterocycloaryl, -CH2(Ci-Ci2 alkyl)C3-Ci0 cycloalkyl,
-CH2(Ci-Ci2 alkyl)aryl, -CH2(Ci-Ci2 alkyl)heterocycloalkyl, -CH2(Ci-Ci2 alkyl)heterocycloaryl, -CH(=0), =0, -O-R4, -CH2-0-R4, -C(=0)-0-R4, =CHC(=0)-0-R4, -CH2C(=0)-0-R4, -CH=CHC(=0)0-R4, -CH2CH2C(=0)0-R4, -N(R4)R4', -CH2-N(R4)R4', -C(=0)-N(R4)R4',
=CHC(=0)-N(R4)R4', -CH2C(=0)-N(R4)R4',-CH=CHC(=0)-N(R4)R4',
-CH2CH2C(=0)-N(R4)R4', -S-R4, -CH2-S-R4, -S(0)-R4, -CH2-S(0)-R4, -S(0)2-R4,
-CH2-S(0)2-R4, -S(0)NR4R4', -CH2-S(0) NR4R4 , -S(0)2 NRV and -CH2-S(0)2 NR4R4 ; R2 may be optionally substituted;
Where R3 is selected from the group consisting of -H, -C(=0)NH2i and X-R5
X may be absent or is selected from the group consisting of -CH2-,-CH2CH2-, -CH(CH3)-
, -C(CH3)2-, -CH2CH=CH-,-C(=0)-, -C(=0)CH=CH-, -C(=0)0-, -C(=0)NH2, -C(=0)NH-,
-C(=0)N, -S-, -S(O)-, and -S(0)2-;
n = 0, 1 or 2;
R4, R4' are independently selected from the group consisting of -H, Ci to Ci2 alkyl, C3-Cio cycloalkyl, Ci to C6 alkyl attached to C3-Cio cycloalkyl, 5- or 6-member-heterocycloalkyl containing one or two -0-, -N(R6), S, S(O), or S(0)2; Ci to C6 alkyl attached to
a 5- or 6-member-heterocycloalkyl containing one or two -0-, -N(R6), S, S(O), or S(0)2; C6, C9 or Cio aryl, Ci to C6 alkyl attached to C6 or Cio aryl; 5-, 6-, 9- or 10-member-heterocycloaryl containing one, two or three -0-, -N, -N(R6), S; Ci to C6 alkyl attached to
a 5-, 6-, 9- or 10-member-heterocycloaryl containing one, two or three -0-, -N, -N(R6), S; R4 and R4' may be taken together to form a ring; R4, R4 may be optionally substituted with 1 to 3 of the following substituents: -halogen, -OH, -0(C C3 alkyl), -NH2, -NH(C C3 alkyl),
-N(Ci-C3 alkyl)Ci-C3 alkyl, N-pyrrolidine, N-piperidine, N-morpholine, N-piperazine,
4- methylpiperizin-l-yl, 4-ethylpiperizin-l-yl, -NHC(=0)Ci-C3 alkyl,
-N(Ci-C3 alkyl)C(=0)Ci-C3 alkyl, -C02H, C02(Ci-C3 alkyl), -CONH2- -CONH(Ci-C3 alkyl), -CON(Ci-C3 alkyl)2, -OC02(C C3 alkyl), -0C0NH(C C3 alkyl), -OCON(C C3 alkyl)2,
-NHC02(Ci-C3 alkyl), -NHCONH(Ci-C3 alkyl), -NHCON(Ci-C3 alkyl)2, -SH, -S(Ci-C3 alkyl),
-SO(Ci-C3 alkyl), -S02(Ci-C3 alkyl), -NHS02(Ci-C3 alkyl), -N(Ci-C3 alkyl)S02(Ci-C3 alkyl), -S02NH2, -S02NH(Ci-C3 alkyl), -S02N(Ci-C3 alkyl)2;
R5 is independently selected from the group consisting of C -Cn alkyl, C3-Ci0 cycloalkyl, aryl; 5- or 6-member- heterocycloalkyl containing one or two -0-, -N(R6), S, S(0), or S(0)2;
5- , 6, 9- or 10-member-heterocycloaryl containing one, two or three -0-, -N, -N(R6), S; R5 may be optionally substituted with 1 to 3 of the following substituents: -halogen, -OH,
-0(Ci-C3 alkyl), -NH2, -NH(C C3 alkyl), -N(C C3 alkyl)C C3 alkyl, N-pyrrolidine, N-piperidine, N-morpholine, N-piperazine, 4-methylpiperizin-l-yl, 4-ethylpiperizin-l-yl, -NHC(=0)Ci-C3 alkyl, -N(C C3 alkyl)C(=0)C C3 alkyl, -C02H, C02(CrC3 alkyl),
-CONH2 -CONH(Ci-C3 alkyl), -CON(Ci-C3 alkyl)2, -OC02(Ci-C3 alkyl), -OCONH(Ci-C3 alkyl), -OCON(Ci-C3 alkyl)2, -NHC02(Ci-C3 alkyl), -NHCONH(Ci-C3 alkyl), -NHCON(Ci-C3 alkyl)2, -SH, -S(Ci-C3 alkyl), -SO(Ci-C3 alkyl), -S02(Ci-C3 alkyl), -NHS02(Ci-C3 alkyl),
-N(Ci-C3 alkyl)S02(C C3 alkyl), -S02NH2, -S02NH(C C3 alkyl), -S02N(C C3 alkyl)2;
R6 is selected from the group consisting of -H, Ci-Ci2 alkyl, C3-C6 cycloalkyl; and may optionally be substituted; and pharmaceutically acceptable salts thereof, prodrugs thereof, isomers thereof, solvates thereof, deuterated forms, radio-actively labeled forms and mixtures thereof.
2. The compound according to claim 1, being selected from the group consisting of:
Amino(3 -(3 -( 1 -benzylpiperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) phenyl)methaniminium trifluoroacetate;
3 -(5 -Methyl-2-oxo-3 -(piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(3 -( 1 -acetylpiperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl
)benzimidamide;
3 -(5 -methyl-3 -( 1 -(methylsulfonyl)piperidin-4-yl)-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(phenylsulfonyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -phenylpiperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl)
benzimidamide;
3 -(5 -methyl-3 -( 1 -methylpiperidin-4-yl)-2-oxotetrahydropyrimidin- 1 (2H)-yl)
benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(2-phenylacetyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl) benzimidamide; 3 -(3 -( 1 -benzoylpiperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide;
Tert-butyl (2-(4-(3 -(3 -carbamimidoylphenyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)- yl)piperidin- 1 -yl)ethyl)carbamate;
Tert-butyl (2-(4-(3 -(3 -carbamimidoylphenyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)- yl)piperidin- 1 -yl)-2-oxoethyl)carbamate;
2-(4-(3 -(3 -(amino(iminio)methyl)phenyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) piperidin- 1 -yl)ethanaminium tri-trifluroacetate;
2-(4-(3 -(3 -(amino(iminio)methyl)phenyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl )piperidin- 1 -yl)-2-oxoethanaminium di-trifluroacetate;
3 -(3 -( 1 -(benzylsulfonyl)piperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(pyridin-3 -ylmethyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)- yl)benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(pyridin-2-ylmethyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)- yl)benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(pyridin-4-ylmethyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)- yl)benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(4-(trifluoromethyl)benzyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(3 -(trifluoromethyl)benzyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(2-(trifluoromethyl)benzyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide; 3 -(3 -( 1 -(3 -fluorobenzyl)piperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide;
3 -(3 -( 1 -(2-fluorobenzyl)piperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl) benzimidamide;
3 -(5 -methyl-2-oxo-3 -( 1 -(thiophen-2-ylsulfonyl)piperidin-4-yl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(5 -methyl-3 -( 1 -(morpholinosulfonyl)piperidin-4-yl)-2-oxotetrahydropyrimidin- 1 (2H)- yl)benzimidamide;
3 -(3 -( 1 -(( 1 H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
Amino(3 -(3 -(( 1 -benzylpiperidin-4-yl)methyl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)- yl)phenyl)methaniminium trifluoroacetate;
3 -(5 -methyl-2-oxo-3 -(piperidin-4-ylmethyl)tetrahydropyrimidin- 1 (2H)-yl)
benzimidamide;
3 -(3 -( 1 -(( 1 H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5 -methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(5 -methyl-3 -(1-((1 -methyl- lH-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(5 -methyl-2-oxo-3 -(( 1 -(pheny lsulfonyl)piperidin-4-yl)methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3-(5-methyl-2-oxo-3-((l-(thiophen-2-ylsulfonyl)piperidin-4-yl)
methyl)tetrahydropyrimidin- 1 (2H)-yl)benzimidamide;
3 -(5 -methyl-3 -(( 1 -(morpholinosulfonyl)piperidin-4-yl)methyl)-2- oxotetrahydropyrimidin- 1 (2H)-yl)benzimidamide; and 1 -(3 -(aminomethyl)phenyl)-3 -((4-benzylcyclohexyl)methyl)-5 - methylenetetrahydropyrimidin-2( 1 H)-one; and pharmaceutically acceptable salts thereof, prodrugs thereof, solvates thereof, isomers thereof, deuterated forms, radio-actively labeled forms and mixtures thereof.
3. The compound according to claim 1, being amino(3-(3-((l-benzylpiperidin-4-yl)methyl)-5- methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl)phenyl)methaniminium trifluoroacetate; a pharmaceutically acceptable salt thereof, prodrug thereof, solvate thereof, isomers thereof, deuterated form thereof, a radio-actively labeled form thereof or mixtures thereof
4. The compound according to any one of claims 1, 2 or 3, and pharmaceutically acceptable salts thereof, prodrugs thereof, solvates thereof, deuterated forms, radio-actively labeled forms and mixtures thereof; wherein the isomers are enantiomers or diastereomers.
5. The compound according to claim 1, represented by the following formula:
Figure imgf000136_0001
6. A pharmaceutical composition comprising a compound or derivative according to any one of claims 1, 2, 3, 4 or 5 and a pharmaceutically acceptable carrier.
7. A compound selected from the group consisting of
Figure imgf000137_0001
, and mixtures thereof.
8. A method of treating a patient with a disease caused by or associated with abnormal matriptase, hepsin and hepatocyte growth factor activator (HGFA) protease activity, which comprises administering to the patient an effective treatment amount of at least one compound or derivative according to any one of claims 1, 2, 3, 4 or 5.
9. A method of treating a precancerous condition or cancer in a patient comprising administering to the patient an effective treatment amount of a compound according to any one of claims 1, 2, 3, 4 or 5.
10. The method of claim 8 or 9 wherein the patient is a mammal. .
11. The method of claim 10 wherein the mammal is a human.
12. The method according to claim 9 wherein said cancer comprises metastatic cancer.
13. The method according to claim 9 wherein the cancer comprises a solid or liquid tumor.
14. A method of treating a patient to prevent or reverse resistance in said patient to cancer treatment which comprises administering to the patient an effective treatment amount of at least one compound or derivative according to any one of claims 1, 2, 3, 4 or 5.
15. A method of inhibiting cancer stem cells in a patient in need thereof which comprises administering to the patient an effective treatment amount of at least one compound or derivative according to any one of claims 1, 2, 3, 4 or 5.
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