Patent Grant
8563714
This application is the national phase application of PCT/IB2010/052170, filed May 17, 2010, which claims the benefit of PCT/IB2009/052056, filed May 18, 2009, the contents of each of which are hereby incorporated by reference in their entirety.
The present invention relates to bridged spiro[2.4]heptane derivatives of formula (I) and their use as pharmaceuticals. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and especially their use as ALX receptor and/or FPRL2 agonists.
ALXR (alias Lipoxin A4 Receptor, FPRL1, FPR2; disclosed in WO2003/082314 as nucleotide sequence SEQ ID NO:1 and amino acid sequence SEQ ID NO:2) is a member of the G-protein coupled receptor family. ALXR was found to mediate calcium mobilisation in response to high concentration of the formyl-methionine-leucyl-phenylalanine peptide. Furthermore, a lipid metabolite, lipoxin A4 (LXA4), and its analogues, were found to bind ALXR with high affinity and increase arachidonic acid production and G-protein activation in ALXR transfected cells (Chiang et al., Pharmacol. Rev., 2006, 58, 463-487). The effects of LXA4 have been evaluated in a variety of animal models of diseases; and LXA4 was demonstrated to have potent anti-inflammatory and pro-resolution activities. The disease models where LXA4, or derivatives, or stable analogs, demonstrated in vivo activities are for example dermal inflammation, dorsal air pouch, ischemia/reperfusion injury, peritonitis, colitis, mesangioproliferative nephritis, pleuritis, asthma, cystic fibrosis, sepsis, corneal injury, angiogenesis, periodontitis, carrageenan-induced hyperalgesia, and graft-vs-host disease (GvHD) (Schwab and Serhan, Current Opinion in Pharmacology, 2006, 414-420). ALXR was also identified as a functional receptor of a various number of peptides, including a fragment of the prion protein, a peptide derived from gp120 of the Human Immunodeficiency Virus (HIV)-1LAI strain, and amyloid-beta 1-42 (Ab42) (for review, Le et al., Protein Pept Lett., 2007, 14, 846-853), and has been suggested to participate in the pathogenesis of Alzheimer's Disease (AD) in several crucial ways (Yazawa et al., FASEB J., 2001, 15, 2454-2462). Activation of ALXR on macrophages and microglial cells initiates a G protein-mediated signalling cascade that increases directional cell migration, phagocytosis, and mediator release. These events may account for the recruitment of mononuclear cells to the vicinity of senile plaques in the diseased areas of AD brain where Ab42 is overproduced and accumulated. Although accumulation of leukocytes at the sites of tissue injury may be considered an innate host response aimed at the clearance of noxious agents, activated mononuclear phagocytes also release a variety of substances such as superoxide anions that may be toxic to neurons. Thus, ALXR may mediate pro-inflammatory responses elicited by Ab42 in AD brain and exacerbate disease progression. It was also reported that humanin (HN), a peptide with neuroprotective capabilities, shares the human ALXR with Ab42 on mononuclear phagocytes and neuronal cell lines and it has been suggested that the neuroprotective activity of HN may be attributed to its competitive occupation of ALXR (Ying et al., J. Immunol., 2004, 172, 7078-7085).
FPRL2 (alias Formyl Peptide Receptor Like-2, FPR3; disclosed in US2006/0078559 as nucleotide sequence SEQ ID NO:1 and amino acid sequence SEQ ID NO: 2) is a member of the G-protein coupled receptor family. The mRNA of FPRL2 was detected in various tissues, including heart, aorta, vein, spleen, lung, trachea, liver, pancreas, adrenal gland, cervix, rectum, small intestine, ileum chronic inflammation, placenta, spinal cord, lymph node, dorsal rot ganglia, pons, cerebral meninges, postcentral gyrus, Alzheimer brain frontal lobe and breast tumor. FPRL2 is expressed in human monocytes, macrophages, myeloid dendritic cells, plasmacytoid dendritic cells, eosinophils, but not in neutrophils (Migeotte et al, J. Exp. Med., 2005, 201, 83-89; Devosee et al., J. Immunol., 2009, 4974-4984). Humanin, and its analogues, were found to bind FPRL2 with high affinity (Harada et al., Biochem. Biophys. Res. Commun., 2004, 324, 255-261). Humanin was found to protect neuronal cells from a number of toxic insults. This includes neurotoxicity mediated by three mutant genes that cause FAD as well as Abeta (Hashimoto et al., Biochem. Biophys. Res. Commun., 2001, 283, 460-468). Humanin has also been reported to have protective activity for neurons against serum deprivation (Takahashi et al., Neuroreport, 2002, 13, 903-907) and against excitotoxic death (Caricasole et al., FASEB J., 2002, 1331-1333). Humanin has also been shown to rescue cortical neurons from prion-peptide-induced apoptosis. Humanin has been further shown to improve learning and memory impairment in mice, thereby evidencing utility as a beneficial agent for the prevention or treatment of learning or memory impairement (Mamiya et al., 2001, Br. J. Pharmacol., 134, 1597-1599). Humanin has also been shown to be protective for muscle cells and rescues human cerebrovascular smooth muscle cells from Abeta-induced toxicity. Furthermore, FPRL2 was found to recognize F2L, a Heme Binding Protein (HBP) polypeptide (Migeotte et al., US2006/0078559). Migeotte et al. (J. Exp. Med., 2005, 201, 83-89) suggested that F2L could be released from HBP after cell suffering or cell death. This molecule would thereafter mediate the recruitment of monocytes and Dendritic cells via FPRL2. Immature and mature dendritic cells (iDC and mDC, respectively) migrate to different anatomical sites, e.g., sites of antigen (Ag) deposition and secondary lymphoid organs, respectively, to fulfill their roles in the induction of primary, Ag-specific immune responses. The trafficking pattern of iDC and mDC is based on their expression of functional chemotactic receptors and the in vivo sites expressing the corresponding ligands including chemokines and/or classical chemoattractants. FPRL2 expressed by DC must be functional and mediate the effect of some known ligands on DC, suggesting that the interaction of FPRL2 and its endogenous ligand(s) may be involved in regulating DC trafficking during Ag uptake and processing in the periphery as well as the T cell-stimulating phase of the immune responses. Kang et al. (J. Immunol, 2005, 175, 685-692) demonstrated that FPRL2 ligands, Helicobacter pylori-derived peptide Hp(2-20) and F2L, inhibited IL-12 production in Monocyte-derived DC (MoDC) induced by LPS, supporting the notion that FPRL2 participates in the inhibition of MoDC maturation by LPS. Therefore, FPRL2 might be involved in the initiation of a variety of inflammatory diseases based on cell death and could represent an attractive target for therapeutic approaches.
The biological properties of ALXR agonists include, but are not limited to, monocyte/macrophage/microglia/dendritic cell migration/activation, neutrophil migration/activation, regulation of lymphocyte activation, proliferation and differentiation, regulation of inflammation, regulation of cytokine production and/or release, regulation of proinflammatory mediator production and/or release, regulation of immune reaction.
The biological properties of FPRL2 agonists include, but are not limited to, monocyte/macrophage/microglia migration/activation, regulation of lymphocyte activation, proliferation and differentiation, maturation and migration of dendritic cells, regulation of inflammation, regulation of cytokine production and/or release, regulation of proinflammatory mediator production and/or release, regulation of immune reaction.
The present invention provides bridged spiro[2.4]heptane derivatives, which are non-peptide agonists of human ALX and/or FPRL2 receptor. Different bridged spiro[2.4]heptane derivatives have been disclosed in WO9502587. The compounds are useful for the prevention or treatment of diseases, which respond to the modulation of the ALX receptor and/or FPRL2 such as inflammatory diseases, obstructive airway diseases, allergic conditions, HIV-mediated retroviral infections, cardiovascular disorders, neuroinflammation, neurological disorders, pain, prion-mediated diseases and amyloid-mediated disorders (especially Alzheimer's disease); in addition they are useful for the prevention or treatment of autoimmune diseases and for the modulation of immune responses (especially those elicited by vaccination).
Various embodiments of the invention are presented hereafter:
wherein
W represents —CH2CH2— or —CH═CH—;
Y represents a bond or a (C1-C4)alkandiyl group and R1 represents
or Y represents together with R1 a (C4-C6)alkyl group or a amino-(C4-C6)alkyl group;
Z represents —C(O)NR3—* or —CH2NR4C(O)—*,
wherein the asterisks indicate the bond which is linked to R2;
R2 represents
R3 represents hydrogen, (C1-C3)alkyl or 2-methoxy-ethyl; or
R2 and R3 form, together with the nitrogen that carries them, a ring of 5 to 7 members, which ring is substituted with amino-(C1-C4)alkyl;
R4 represents hydrogen or methyl;
R5 represents hydrogen, (C1-C3)alkyl or tert-butoxycarbonyl;
R6 represents hydrogen or (C1-C3)alkyl;
R7 and R8 represent independently from each other hydrogen or methyl; or
R7 and R8 form, together with the nitrogen that carries them, a pyrrolidine or piperidine ring; and
R9 represents hydrogen or tert-butoxycarbonyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
For avoidance of any doubt, the term “Z represents —C(O)NR3—*, wherein the asterisk indicates the bond which is linked to R2” means that the residue R2 is linked to the nitrogen atom of the amide moiety.
The configuration of compounds of formula (I) according to embodiment 1) is such that the substituent R1—Y—NH—C(O)— is in relative proximity to the group W (endo-position), whereas the substituent R2—Z— is in relative proximity to the cyclopropyl-moiety (exo-position).
Formula I comprises compounds of formula ISt1 and of formula ISt2 and mixtures thereof.
For avoidance of any doubt, compounds of formula (I) are denominated in analogy to the following examples:
a mixture of enantiomers of structure
is denominated (5R*)—N5-(4-Bromophenyl)-(6R*)—N6-(5-amino-pentyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide;
the pure stereoisomer of structure
is denominated (5R)—N5-(5-Acetyl-furan-2-yl-methyl)-(6R)—N6-(4-pyrrolidin-1-yl-butyl)-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5,6-dicarboxamide; and
a mixture of enantiomers of structure
is denominated (5R*)—N5-(4-Bromo-phenyl)-(6R*)-6-[(3-(3,5-dimethyl-pyrazol-1-yl)-propionylamino)-methyl]-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide.
The compounds of formula (I) according to embodiment 1) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. Substituents at a double bond may be present in the (Z)- or (E)-configuration unless indicated otherwise. The compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
The following paragraphs provide definitions of the various chemical moieties for the compounds according to the invention and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader or narrower definition.
The term “alkyl”, used alone or in combination, refers to a straight or branched chain alkyl group containing one to six carbon atoms. The term “(Cx-Cy)alkyl” (x and y each being an integer), refers to an alkyl group as defined before containing x to y carbon atoms. For example a (C1-C6)alkyl group contains from one to six carbon atoms. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, the isomeric pentyls and the isomeric hexyls. The alkyl group may be unsubstituted or substituted as explicitly defined.
In case a (C1-C4)alkyl group is a substituent to an aryl-, a heteroaryl- or a heterocyclyl-group, the term “(C1-C4)alkyl” means (C1-C4)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred are methyl, ethyl and iso-butyl, and most preferred is methyl.
In case a (C1-C6)alkyl group is a substituent to a heterocyclyl-group, the term “(C1-C6)alkyl” means (C1-C6)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, the isomeric pentyls and the isomeric hexyls. Preferred are methyl, ethyl and 3-methyl-but-1-yl. Most preferred is 3-methyl-but-1-yl.
In case a (C1-C4)alkyl group is a substituent to a cyclohexyl- or a cyclohexenyl-group, the term “(C1-C4)alkyl” means (C1-C4)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred are methyl and tert-butyl, and most preferred is methyl.
In case “R2” represents “(C1-C6)alkyl which is unsubstituted or mono-substituted with fluorine, trifluoromethyl, (C1-C4)alkylthio, (C1-C4)alkoxy-carbonyl, hydroxy, cyano, —NR5R6, —COOH, —C(O)NR7R8 or optionally mono-substituted (C1-C4)alkoxy, wherein the substituent is selected from hydroxy and heterocyclyl” the term “(C1-C6)alkyl” means (C1-C6)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, the isomeric pentyls and the isomeric hexyls. Preferred are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, 2,2-dimethyl-prop-1-yl, 3-methyl-but-1-yl, 3,3-dimethyl-but-1-yl, pent-1-yl, pent-2-yl, 4-methyl-pent-2-yl and hex-1-yl. Most preferred are methyl, ethyl, n-propyl, n-butyl, iso-butyl, 2,2-dimethyl-prop-1-yl and pent-1-yl. The above-mentioned (C1-C6)alkyl groups are unsubstituted or mono-substituted with fluorine, trifluoromethyl, (C1-C4)alkylthio, (C1-C4)alkoxy-carbonyl, hydroxy, cyano, —NR5R6, —COOH, —C(O)NR7R8 or optionally mono-substituted (C1-C4)alkoxy, wherein the substituent is selected from hydroxy and heterocyclyl. Preferably the substituent is selected from the group consisting of fluorine, trifluoromethyl, methoxy, ethoxy, ethylthio, hydroxy, cyano, —NR5R6 or —C(O)NR7R8.
In the other case wherein “R2” represents “(C1-C6)alkyl” the term means (C1-C6)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, the isomeric pentyls and the isomeric hexyls.
Preferred are methyl, ethyl, n-propyl, n-butyl and n-pentyl. More preferred are n-butyl and n-pentyl and most preferred is n-butyl. The above-mentioned (C1-C6)alkyl groups are mono-substituted with (C3-C6)cycloalkyl, which cycloalkyl is unsubstituted or mono-substituted with —NR5R6 or hydroxy; with heterocyclyl, which heterocyclyl is unsubstituted or mono-substituted at a nitrogen atom with (C1-C4)alkyl, (C1-C2)alkyl-carbonyl or tert-butoxycarbonyl, and/or mono- or di-substituted at one or two of the carbon atoms with substituents independently selected from halogen, (C1-C4)alkyl and (C1-C2)alkoxy-(C1-C2)alkyl; or with an aryl- or heteroaryl-group, which groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl, —CH2NHR9, —SO2NH2 and phenyl. In a preferred embodiment the (C1-C6)alkyl groups are substituted with a heterocyclyl group, which is unsubstituted, mono-substituted at a nitrogen atom with methyl or ethyl or mono-substituted at a carbon atom with fluorine. In another preferred embodiment the (C1-C6)alkyl groups are substituted with an aryl- or heteroaryl-group, which groups are independently unsubstituted, mono- or di-substituted (preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, methyl, ethyl, —CH2NH2 and —SO2NH2.
In case “R3” represents “(C1-C3)alkyl” the term means (C1-C3)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl and iso-propyl. Preferred are methyl, ethyl and n-propyl. Most preferred are methyl and ethyl.
In case “R5” represents “(C1-C3)alkyl” the term means (C1-C3)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl and iso-propyl. Preferred are methyl, ethyl and n-propyl. Most preferred are methyl and ethyl.
In case “R6” represents “(C1-C3)alkyl” the term means (C1-C3)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl and iso-propyl. Preferred are methyl, ethyl and n-propyl. Most preferred are methyl and ethyl.
The term “(C1-C4)alkandiyl group” as used in Y refers to a carbon chain containing from one to four carbon atoms, which is attached to the residue R1 and to the amide-nitrogen atom of the rest of the molecule as depicted in formula (I). The respective two residues may be attached to the same or to different carbon atoms of the alkandiyl group. Preferred examples of (C1-C4)alkandiyl groups are methandiyl, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,3-diyl and butan-1,4-diyl. More preferred are methandiyl and ethan-1,2-diyl. Most preferred is methandiyl.
In case “Y together with R1” represents “(C4-C6)alkyl” the term means (C4-C6)alkyl groups as defined above. Examples of said groups are n-butyl, iso-butyl, sec-butyl, tert-butyl, the isomeric pentyls and the isomeric hexyls. Preferred are n-butyl, 3-methyl-butyl, 2-ethyl-butyl and n-pentyl. Most preferred is n-pentyl.
In case “Y together with R1” represents a “amino-(C4-C6)alkyl” group the term means a (C4-C6)alkyl group as defined above in which one hydrogen atom has been replaced with an amino group. Examples of said groups are 4-amino-butyl, 5-amino-pentyl and 6-amino-hexyl. Most preferred are 4-amino-butyl and 5-amino-pentyl.
The term “amino-(C1-C4)alkyl” refers to an (C1-C4)alkyl group as defined above in which one hydrogen atom has been replaced with an amino group. A preferred example is amino-methyl.
The term “(C3-C6)cycloalkyl”, alone or in combination, means a cycloalkyl group with 3 to 6 carbon atoms. Examples of (C3-C6)cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The (C3-C6)cycloalkyl group may be unsubstituted or substituted as explicitly defined.
In case “R2” represents “(C3-C6)cycloalkyl” the term means (C3-C6)cycloalkyl groups as defined above. Examples of said groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferred are cyclopropyl, cyclopentyl and cyclohexyl. Most preferred are cyclopentyl and cyclohexyl. The above-mentioned (C3-C6)cycloalkyl groups are unsubstituted or mono-substituted with hydroxy, hydroxy-methyl, R5R6N—CH2—, heterocyclyl-methyl or —CONH2 (preferably with hydroxy or pyrrolidin-1-yl-methyl).
In case “R2” represents “(C1-C6)alkyl, which is mono-substituted with (C3-C6)cycloalkyl” the term “(C3-C6)cycloalkyl” means the above-mentioned groups. Preferred are cyclopropyl and cyclohexyl. The above-mentioned (C3-C6)cycloalkyl groups are unsubstituted or mono-substituted with —NR5R6 or hydroxy (preferably with hydroxy).
The term “alkoxy”, used alone or in combination, refers to an alkyl-O— group wherein the alkyl group is as defined before. The term “(Cx-Cy)alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (C1-C4)alkoxy group contains from one to four carbon atoms. Representative examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. The alkoxy group may be unsubstituted or substituted as explicitly defined.
In case a (C1-C4)alkoxy group is a substituent to an aryl- or a heteroaryl-group, the term “(C1-C4)alkoxy” means (C1-C4)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred are methoxy, ethoxy and iso-propoxy. Most preferred is methoxy.
In case “R2” represents “(C1-C6)alkyl which is mono-substituted with optionally mono-substituted (C1-C4)alkoxy” the term “optionally mono-substituted (C1-C4)alkoxy” means a (C1-C4)alkoxy group as defined above, which is unsubstituted or mono-substituted. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred are methoxy and ethoxy. The above-mentioned (C1-C4)alkoxy group is unsubstituted or mono-substituted with hydroxy or heterocyclyl and preferably unsubstituted or mono-substituted with heterocyclyl.
The term “(C1-C2)alkoxy-(C1-C2)alkyl” refers to an (C1-C2)alkyl group as defined above in which one hydrogen atom has been replaced with an (C1-C2)alkoxy group as defined above. Examples of (C1-C2)alkoxy-(C1-C2)alkyl groups are methoxy-methyl, methoxy-ethyl, ethoxy-methyl and ethoxy-ethyl. Preferred is methoxy-methyl.
The term “alkylthio”, used alone or in combination, refers to an alkyl-S— group wherein the alkyl group is as defined before. The term “(Cx-Cy)alkylthio” (x and y each being an integer) refers to an alkylthio group as defined before containing x to y carbon atoms. For example a (C1-C4)alkylthio group contains from one to four carbon atoms. Representative examples of alkylthio groups include methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio and tert-butylthio. Preferred are methylthio and ethylthio. Most preferred is ethylthio.
The term “(C1-C2)alkyl-carbonyl”, used alone or in combination, refers to a (C1-C2)alkyl-C(O)— group wherein the (C1-C2)alkyl group is as defined before. Representative examples of (C1-C2)alkyl-carbonyl groups include methyl-carbonyl (acetyl) and ethyl-carbonyl (propionyl). Preferred is acetyl.
The term “(C1-C4)alkoxy-carbonyl”, used alone or in combination, refers to a (C1-C4) alkoxy-C(O)— group wherein the (C1-C4)alkoxy group is as defined before. Representative examples of (C1-C4)alkoxy-carbonyl groups include methoxy-carbonyl, ethoxy-carbonyl, n-propoxy-carbonyl, iso-propoxy-carbonyl, n-butoxy-carbonyl, iso-butoxy-carbonyl, sec-butoxy-carbonyl and tert-butoxy-carbonyl. Preferred are methoxy-carbonyl and tert-butoxy-carbonyl. Most preferred is methoxy-carbonyl.
The term “(Cx-Cy)fluoroalkyl” (x and y each being an integer) refers to an alkyl group as defined before containing x to y carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The fluoroalkyl group may be unsubstituted or substituted as explicitly defined.
In case a (C1-C2)fluoroalkyl group is a substituent to an aryl- or a heteroaryl-group, the term “(C1-C2)fluoroalkyl” means (C1-C2)fluoroalkyl groups as defined above. Examples of said groups are trifluoromethyl, difluoromethyl and 2,2,2-trifluoroethyl. Preferred are trifluoromethyl and 2,2,2-trifluoroethyl. Most preferred is trifluoromethyl.
In case “R2” represents “(C3-C5)fluoroalkyl” the term means a (C3-C5)fluoroalkyl group as defined above. Examples of said groups are 2-fluoro-propyl, 2,2-difluoro-propyl, 2-fluoro-butyl, 2,2-difluoro-butyl, 3-fluoro-butyl, 3,3-difluoro-butyl, 2-fluoro-pentyl, 2,2-difluoro-pentyl, 3-fluoro-pentyl, 3,3-difluoro-pentyl, 4-fluoro-pentyl and 4,4-difluoro-pentyl. Preferred are 3-fluoro-butyl and 3,3-difluoro-butyl. Most preferred is 3-fluoro-butyl. The above-mentioned (C3-C5)fluoroalkyl groups are mono-substituted with heterocyclyl.
The term “(Cx-Cy)fluoroalkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. For example a (C1-C2)fluoroalkoxy group contains from one to two carbon atoms in which one to five hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy and 2,2,2-trifluoroethoxy. Preferred are (C1)fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy. Most preferred is trifluoromethoxy.
The term halogen means fluoro, chloro, bromo or iodo.
In case the halogen is a substituent to an aryl- or a heteroaryl-group, the term means preferably fluoro, chloro or bromo and most preferably chloro or bromo.
In case the halogen is a substituent to a heterocyclyl-group, the term means most preferably fluoro.
The term “aryl”, used alone or in any combination, means a phenyl or a naphthyl group. Preferred is a phenyl group. The aryl group may be unsubstituted or substituted as explicitly defined.
In case R1 represents “aryl” the term means the above-mentioned groups (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably mono- or di-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C2)alkyl-carbonyl, (C1-C2)fluoroalkyl, (C1-C2)fluoroalkoxy, nitro, cyano and phenyl, wherein the phenyl is unsubstituted or mono-substituted with halogen. Preferably the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C2)alkyl-carbonyl, trifluoromethyl and trifluoromethoxy (and most preferably from fluoro, bromo, methoxy and trifluoromethyl). Examples of such aryl groups are phenyl, 4-methyl-phenyl, 2,4-dimethyl-phenyl, 2,5-dimethyl-phenyl, 3,4-dimethyl-phenyl, 3,5-dimethyl-phenyl, 2-methoxy-phenyl, 4-methoxy-phenyl, 2,4-dimethoxy-phenyl, 3,4-dimethoxy-phenyl, 4-ethoxy-phenyl, 2-iso-propoxy-phenyl, 4-iso-propoxy-phenyl, 3-acetyl-phenyl, 4-acetyl-phenyl, 4-trifluoromethyl-phenyl, 3-difluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 4-fluoro-phenyl, 2,3,5-trifluoro-phenyl, 2,4,6-trifluoro-phenyl, 4-chloro-phenyl, 2,4-dichloro-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 4-iodo-phenyl, 3-chloro-2-fluoro-phenyl, 2-chloro-3,6-difluoro-phenyl, 2-bromo-4-fluoro-phenyl, 3-bromo-4-fluoro-phenyl, 4-bromo-2-fluoro-phenyl, 4-bromo-3-fluoro-phenyl, 4-bromo-2,3-difluoro-phenyl, 4-bromo-2,5-difluoro-phenyl, 4-bromo-2,6-difluoro-phenyl, 4-bromo-3,5-difluoro-phenyl, 4-bromo-3-chloro-phenyl, 5-methyl-2-methoxy-phenyl, 4-bromo-2-methyl-phenyl, 2-chloro-6-fluoro-3-methyl-phenyl, 2,3-difluoro-4-methoxy-phenyl, 2,6-difluoro-4-methoxy-phenyl, 3,5-difluoro-4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl, 3-chloro-4-methoxy-phenyl, 3-bromo-4-methoxy-phenyl, 2-fluoro-3-trifluoromethyl-phenyl, 2-fluoro-5-trifluoromethyl-phenyl, 3-fluoro-5-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 2-chloro-5-trifluoromethyl-phenyl and 4-bromo-3-trifluoromethyl-phenyl (and preferably 4-methoxyphenyl, 4-trifluoromethylphenyl, 2,4-dichloro-phenyl, 4-bromophenyl, 4-bromo-2-fluoro-phenyl, 4-bromo-3-fluoro-phenyl and 4-bromo-2,6-difluoro-phenyl).
In case R2 represents “aryl” the term means the above-mentioned groups (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably mono- or di-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl and phenyl (and preferably from halogen). Examples of such aryl groups are 4-bromophenyl and 2-chloro-3-fluorophenyl.
In case R2 represents “(C1-C6)alkyl, which is mono-substituted with an aryl group” the term “aryl” means the above-mentioned groups (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted and most preferably mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl, —CH2NHR9, —SO2NH2 and phenyl. Preferably the substituents are independently selected from the group consisting of halogen, —CH2NHR9 and —SO2NH2 (and most preferably from —CH2NH2 and —SO2NH2). Examples of such aryl groups are 4-fluorophenyl, 2-chlorophenyl, 3-aminomethyl-phenyl, 4-aminomethyl-phenyl, 3-(tert-butoxycarbonylamino-methyl)-phenyl, 4-(tert-butoxycarbonylamino-methyl)-phenyl and 4-sulfamoyl-phenyl (and preferably 3-aminomethyl-phenyl, 4-aminomethyl-phenyl and 4-sulfamoyl-phenyl).
The term “aryloxy”, used alone or in combination, refers to an aryl-O— group wherein the aryl group is as defined before. A preferred example of an aryloxy group is phenoxy.
The term “heteroaryl”, used alone or in any combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of such heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl and phthalazinyl. The heteroaryl group may be unsubstituted or substituted as explicitly defined.
In case R1 represents “heteroaryl” the term means the above-mentioned groups. Preferred heteroaryl groups as used in R1 are furanyl (notably furan-2-yl), oxazolyl (notably oxazol-2-yl and oxazol-5-yl), isoxazolyl (notably isoxazol-3-yl), oxadiazolyl (notably[1,2,5]oxadiazolyl), thienyl (notably thiophen-2-yl and thiophen-3-yl), thiazolyl (notably thiazol-2-yl, thiazol-4-yl and thiazol-5-yl), thiadiazolyl (notably [1,2,4]thiadiazol-5-yl and[1,3,4]thiadiazol-5-yl), imidazolyl (notably imidazol-1-yl and imidazol-2-yl), pyridyl (notably pyridin-2-yl and pyridin-3-yl), pyrimidyl (notably pyrimidin-5-yl), pyrazinyl (notably pyrazin-2-yl), indolyl (notably indol-1-yl and indol-5-yl), benzimidazolyl (notably benzimidazol-2-yl), benzoxazolyl (notably benzoxazol-6-yl), benzothiazolyl (notably benzothiazol-2-yl and benzothiazol-5-yl), benzoisothiazolyl (notably benzoisothiazol-5-yl) and benzo[2,1,3]oxadiazolyl (notably benzo[2,1,3]oxadiazol-4-yl). Most preferred heteroaryl groups are furanyl (notably furan-2-yl), thiazolyl (notably thiazol-2-yl), pyridyl (notably pyridin-2-yl and pyridin-3-yl), pyrazinyl (notably pyrazin-2-yl) and benzothiazolyl (notably benzothiazol-5-yl). The above-mentioned heteroaryl groups as used in R1 are unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C2)alkyl-carbonyl, (C1-C2)fluoroalkyl, (C1-C2)fluoroalkoxy, nitro, cyano and phenyl, wherein the phenyl is unsubstituted or mono-substituted with halogen. Preferably the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C2)alkyl-carbonyl, (C1-C2)fluoroalkyl, nitro, cyano and phenyl, wherein the phenyl is unsubstituted or mono-substituted with halogen. Most preferably the substituents are independently selected from halogen, methyl and acetyl. Examples of such unsubstituted, mono-, di- or tri-substituted heteroaryl groups as used in R1 are furan-2-yl, 5-acetyl-furan-2-yl (preferred), 5-methyl-furan-2-yl, 4-methyl-oxazol-2-yl, 2-acetyl-oxazol-4-yl, 2-acetyl-oxazol-5-yl, 4-acetyl-oxazol-2-yl, 5-methyl-isoxazol-3-yl, 5-iso-butyl-isoxazol-3-yl, 5-tert-butyl-isoxazol-3-yl, 5-acetyl-thiophen-2-yl, 5-bromo-thiophen-3-yl, 5-chloro-thiazol-2-yl, 2-bromo-thiazol-5-yl, 4-bromo-thiazol-2-yl, 5-bromo-thiazol-2-yl (preferred), 4-methyl-thiazol-2-yl, 5-methyl-thiazol-2-yl, 4,5-dimethyl-thiazol-2-yl, 4-tert-butyl-thiazol-2-yl, 2-acetyl-thiazol-4-yl, 2-acetyl-thiazol-5-yl, 4-acetyl-thiazol-2-yl, 5-acetyl-thiazol-2-yl, 4-trifluoromethyl-thiazol-2-yl, 5-nitro-thiazol-2-yl, 5-cyano-thiazol-2-yl, 4-(4-chloro-phenyl)-thiazol-2-yl, 4-methyl-[1,2,5]oxadiazol-3-yl, 3-phenyl-[1,2,4]thiadiazol-5-yl, 2-trifluoromethyl-[1,3,4]thiadiazol-5-yl, imidazol-1-yl, 4,5-dimethyl-imidazol-2-yl (preferred), pyridin-2-yl, 2-methoxy-pyridin-4-yl, 2,6-dichloro-pyridin-4-yl, 5-bromo-pyridin-2-yl (preferred), 5-methyl-pyridin-2-yl (preferred), 5-trifluoromethyl-pyridin-2-yl, 6-chloro-pyridin-3-yl (preferred), 6-bromo-pyridin-3-yl (preferred), 6-bromo-5-fluoro-pyridin-3-yl, 6-methoxy-pyridin-3-yl, 6-trifluoromethyl-pyridin-3-yl, 2-chloro-pyrimidin-5-yl, 5-bromo-pyrazin-2-yl (preferred), indol-1-yl, 2-methyl-indol-1-yl, indol-5-yl, 1-methyl-benzimidazol-2-yl, benzoxazol-6-yl, benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, 6-chloro-benzothiazol-2-yl, benzothiazol-5-yl (preferred), 2-methyl-benzothiazol-5-yl, 3-methyl-benzoisothiazol-5-yl and benzo[2,1,3]oxadiazol-4-yl.
In case R2 represents “heteroaryl” the term means the above-mentioned groups. Preferred heteroaryl groups as used in R2 are isoxazolyl (notably isoxazol-4-yl), pyrazolyl (notably pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl) and pyridyl (notably pyridin-3-yl). The above-mentioned heteroaryl groups as used in R2 are unsubstituted, mono-, di- or tri-substituted (preferably mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl and phenyl. Preferably the substituents are independently selected from the group consisting of methyl and phenyl. Examples of such unsubstituted, mono-, di- or tri-substituted heteroaryl groups as used in R2 are 5-phenyl-isoxazol-4-yl (preferred), 1,5-dimethyl-pyrazol-3-yl, 5-chloro-1,3-dimethyl-pyrazol-4-yl, 1-phenyl-pyrazol-5-yl (preferred) and 4-methyl-pyridin-3-yl.
In case R2 represents “(C1-C6)alkyl, which is mono-substituted with a heteroaryl group” the term “heteroaryl” means the above-mentioned groups. Preferred heteroaryl groups are furanyl (notably furan-3-yl), isoxazolyl (notably isoxazol-4-yl), thiazolyl (notably thiazol-4-yl), imidazolyl (notably imidazol-1-yl and imidazol-2-yl), pyrazolyl (notably pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl), triazolyl (notably [1,2,4]triazol-1-yl), pyridyl (notably pyridin-2-yl and pyridin-3-yl), indolyl (notably indol-3-yl) and benzimidazolyl (notably benzimidazol-2-yl). The above-mentioned heteroaryl groups are unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or disubstituted), wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl, —CH2NHR9, —SO2NH2 and phenyl. Preferably the substituents are independently selected from the group consisting of (C1-C4)alkyl and phenyl. Examples of such unsubstituted, mono-, di- or tri-substituted heteroaryl groups are furan-3-yl, 5-methyl-3-phenyl-isoxazol-4-yl, 2-methyl-thiazol-4-yl, 2,5-dimethyl-thiazol-4-yl, imidazol-1-yl (preferred), 4,5-dimethyl-imidazol-2-yl (preferred), pyrazol-1-yl (preferred), 3,5-dimethyl-pyrazol-1-yl (preferred), 1-ethyl-5-methyl-pyrazol-3-yl (preferred), 5-methyl-pyrazol-4-yl, 1-ethyl-3-methyl-pyrazol-5-yl, [1,2,4]triazol-1-yl (preferred), pyridin-2-yl, pyridin-3-yl, indol-3-yl), benzimidazol-2-yl (preferred) and 1-methyl-benzimidazol-2-yl.
The term “heterocyclyl”, used alone or in combination, means a 4- to 7-membered (notably 4- to 6-membered) saturated monocyclic ring containing 1 or 2 heteroatoms independently selected from the group consisting of sulfur, oxygen and nitrogen (preferably oxygen and nitrogen), wherein one or two methylene groups adjacent to a nitrogen atom are optionally replaced by carbonyl groups. Examples of such heterocyclyl groups are azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinonyl, oxazolidinyl, oxazolidinonyl, thiazolidinyl, thiazolidinonyl, piperidinyl, piperidonyl, piperazinyl, piperazinonyl, piperazine-dionyl, tetrahydro-2H-pyranyl, morpholinyl, morpholinonyl, thiomorpholinyl, thiomorpholinonyl, dioxanyl, 1,4-diazepanyl and 1,4-diazepanonyl. Preferred examples are azetidinyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, imidazolidinonyl, piperidinyl, piperidonyl, piperazinyl, tetrahydro-2H-pyranyl, morpholinyl, dioxanyl and 1,4-diazepanyl. The heterocyclyl group may be unsubstituted or substituted as explicitly defined.
In case R2 represents “(C3-C6)cycloalkyl, which is mono-substituted with heterocyclyl-methyl” the term “heterocyclyl” means the above-mentioned groups. Preferred heterocyclyl groups are azetidinyl (notably azetidin-1-yl), pyrrolidinyl (notably pyrrolidin-1-yl) and piperidinyl (notably piperidin-1-yl). Most preferred is pyrrolidinyl (notably pyrrolidin-1-yl).
In case R2 represents “heterocyclyl” the term means the above-mentioned groups. Preferred heterocyclyl groups as used in R2 are azetidinyl (notably azetidin-3-yl), pyrrolidinyl (notably pyrrolidin-3-yl), piperidinyl (notably piperidin-3-yl and piperidin-4-yl) and tetrahydro-2H-pyranyl (notably tetrahydro-2H-pyran-3-yl). Most preferred are pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl and tetrahydro-2H-pyran-3-yl. The above-mentioned heterocyclyl groups are unsubstituted or mono-substituted at a nitrogen atom with (C1-C6)alkyl, benzyl or tert-butoxycarbonyl or mono-substituted at a carbon atom with pyrrolidin-1-yl-methyl. Examples of such unsubstituted or mono-substituted heterocyclyl groups are azetidin-3-yl, 1-tert-butoxycarbonyl-azetidin-3-yl, pyrrolidin-3-yl (preferred), 1-tert-butoxycarbonyl-pyrrolidin-3-yl, piperidin-3-yl (preferred), 1-tert-butoxycarbonyl-piperidin-3-yl, piperidin-4-yl (preferred), 1-methyl-piperidin-4-yl, 1-ethyl-piperidin-4-yl, 1-(3-methyl-butyl)-piperidin-4-yl, 1-benzyl-piperidin-4-yl, 1-tert-butoxycarbonyl-piperidin-4-yl and 6-(pyrrolidin-1-ylmethyl)-tetrahydro-2H-pyran-3yl.
In case R2 represents “(C1-C6)alkyl, which is mono-substituted with heterocyclyl” the term “heterocyclyl” means the above-mentioned groups. Preferred heterocyclyl groups are azetidinyl (notably azetidin-1-yl), pyrrolidinyl (notably pyrrolidin-1-yl and pyrrolidin-2-yl), pyrrolidinonyl (notably pyrrolidin-2-on-1-yl), tetrahydrofuranyl (notably tetrahydrofuran-2-yl), imidazolidinonyl (notably imidazolidin-2-on-1-yl), piperidinyl (notably piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl), piperazinyl (notably piperazin-1-yl), morpholinyl (notably morpholin-4-yl), dioxanyl (notably 1,4-dioxan-2-yl) and 1,4-diazepanyl (notably 1,4-diazepan-1-yl). Most preferred are azetidinyl (notably azetidin-1-yl), pyrrolidinyl (notably pyrrolidin-1-yl and pyrrolidin-2-yl), tetrahydrofuranyl (notably tetrahydrofuran-2-yl), imidazolidinonyl (notably imidazolidin-2-on-1-yl), piperidinyl (notably piperidin-1-yl, piperidin-2-yl and piperidin-4-yl), piperazinyl (notably piperazin-1-yl), morpholinyl (notably morpholin-4-yl) and 1,4-diazepanyl (notably 1,4-diazepan-1-yl). The above-mentioned heterocyclyl groups are unsubstituted or mono-substituted at a nitrogen atom with (C1-C4)alkyl, (C1-C2)alkyl-carbonyl or tert-butoxycarbonyl, and/or mono- or di-substituted at one or two of the carbon atoms with substituents independently selected from halogen, (C1-C4)alkyl and (C1-C2)alkoxy-(C1-C2)alkyl. Preferably the heterocyclyl groups are unsubstituted or mono-substituted at a nitrogen atom with (C1-C4)alkyl (notably methyl or ethyl), or mono- or di-substituted at one or two of the carbon atoms with substituents independently selected from fluorine, methyl and methoxymethyl. Examples of such unsubstituted or substituted heterocyclyl groups are azetidin-1-yl, pyrrolidin-1-yl, 3-fluoro-pyrrolidin-1-yl (notably (R)-3-fluoro-pyrrolidin-1-yl and (S)-3-fluoro-pyrrolidin-1-yl), 3,3-difluoro-pyrrolidin-1-yl, 2,5-dimethyl-pyrrolidin-1-yl, 2-methoxymethyl-pyrrolidin-1-yl, pyrrolidin-2-yl, 1-methyl-pyrrolidin-2-yl, 1-ethyl-pyrrolidin-2-yl, 1-tert-butoxycarbonyl-pyrrolidin-2-yl, pyrrolidin-2-on-1-yl, tetrahydrofuran-2-yl, imidazolidin-2-on-1-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, 1-tert-butoxycarbonyl-piperidin-3-yl, piperidin-4-yl, 1-tert-butoxycarbonyl-piperidin-4-yl, 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-acetyl-piperazin-1-yl, morpholin-4-yl, 1,4-dioxan-2-yl and 4-methyl-1,4-diazepan-1-yl. Preferred examples of such unsubstituted or mono-substituted heterocyclyl groups are azetidin-1-yl, pyrrolidin-1-yl, (R)-3-fluoro-pyrrolidin-1-yl, (S)-3-fluoro-pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-1-yl, 2,5-dimethyl-pyrrolidin-1-yl, 2-methoxymethyl-pyrrolidin-1-yl, pyrrolidin-2-yl, 1-methyl-pyrrolidin-2-yl, tetrahydrofuran-2-yl, imidazolidin-2-on-1-yl, piperidin-1-yl, piperidin-2-yl, piperidin-4-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, 1,4-dioxan-2-yl and 4-methyl-1,4-diazepan-1-yl.
In case R2 represents “(C1-C6)alkyl, which is mono-substituted with optionally mono-substituted (C1-C4)alkoxy, wherein the substituent is heterocyclyl” the term “heterocyclyl” means the above-mentioned groups. Preferred heterocyclyl groups are azetidinyl (notably azetidin-1-yl), pyrrolidinyl (notably pyrrolidin-1-yl) and piperidinyl (notably piperidin-1-yl). Most preferred is pyrrolidin-1-yl.
In case R2 represents “(C3-C5)fluoroalkyl, which is mono-substituted with heterocyclyl” the term “heterocyclyl” means the above-mentioned groups. Preferred heterocyclyl groups are azetidinyl (notably azetidin-1-yl), pyrrolidinyl (notably pyrrolidin-1-yl and pyrrolidin-2-yl), pyrrolidinonyl (notably pyrrolidin-2-on-1-yl), tetrahydrofuranyl (notably tetrahydrofuran-2-yl), imidazolidinonyl (notably imidazolidin-2-on-1-yl), piperidinyl (notably piperidin-1-yl, piperidin-3-yl and piperidin-4-yl), piperazinyl (notably piperazin-1-yl), morpholinyl (notably morpholin-4-yl), dioxanyl (notably 1,4-dioxan-2-yl) and 1,4-diazepanyl (notably 1,4-diazepan-1-yl). More preferred heterocyclyl groups are azetidinyl (notably azetidin-1-yl), pyrrolidinyl (notably pyrrolidin-1-yl) and piperidinyl (notably piperidin-1-yl). Most preferred is pyrrolidin-1-yl. The above-mentioned heterocyclyl groups are unsubstituted (preferred) or mono- or di-substituted at one or two of the carbon atoms with substituents independently selected from halogen (notably fluoro) and (C1-C4)alkyl (notably methyl).
The term “a ring of 5 to 7 members”, as used in “R2 and R3 form, together with the nitrogen that carries them, a ring of 5 to 7 members”, refers to a heterocyclic ring selected from pyrrolidinyl (notably pyrrolidin-1-yl), piperidinyl (notably piperidin-1-yl) and azepanyl (notably azepan-1-yl). Preferred is piperidinyl (notably piperidin-1-yl). The ring with 5 to 7 members is substituted with amino-(C1-C4)alkyl.
For compounds of formula Ip the following definitions are preferred:
wherein
W represents —CH2CH2— or —CH═CH—;
Y represents a bond or a (C1-C4)alkandiyl group and R1 represents
or Y represents together with R1 a (C4-C6)alkyl group;
Z represents —C(O)NR3—* or —CH2NR4C(O)—*,
wherein the asterisks indicate the bond which is linked to R2;
R2 represents
R3 represents hydrogen, (C1-C3)alkyl or 2-methoxy-ethyl;
R4 represents hydrogen or methyl;
R5 represents hydrogen, (C1-C3)alkyl or tert-butoxycarbonyl;
R6 represents hydrogen or (C1-C3)alkyl;
R7 and R8 represent independently from each other hydrogen or methyl; and
R6 represents hydrogen or tert-butoxycarbonyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
W represents —CH2CH2— or —CH═CH—;
Y represents a bond or a (C1-C4)alkandiyl group;
R1 represents an aryl- or a heteroaryl-group, which groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C2)alkyl-carbonyl, (C1-C2)fluoroalkyl, (C1-C2)fluoroalkoxy, nitro, cyano and phenyl, wherein the phenyl is unsubstituted or mono-substituted with halogen;
Z represents —C(O)NR3—* or —CH2NR4C(O)—*,
wherein the asterisks indicate the bond which is linked to R2;
R2 represents
R3 represents hydrogen, (C1-C3)alkyl or 2-methoxy-ethyl; or
R2 and R3 form, together with the nitrogen that carries them, a piperidine ring, which ring is substituted with amino-(C1-C4)alkyl (preferably amino-methyl);
R4 represents hydrogen or methyl;
R5 represents hydrogen, (C1-C3)alkyl or tert-butoxycarbonyl;
R6 represents hydrogen or (C1-C3)alkyl;
R7 and R8 represent independently from each other hydrogen or methyl; or
R7 and R8 form, together with the nitrogen that carries them, a pyrrolidine ring;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
W represents —CH2CH2— or —CH═CH—;
Y represents a bond or a (C1-C4)alkandiyl group;
R1 represents an aryl- or a heteroaryl-group, which groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C2)alkyl-carbonyl, (C1-C2)fluoroalkyl, (C1-C2)fluoroalkoxy, nitro, cyano and phenyl, wherein the phenyl is unsubstituted or mono-substituted with halogen;
Z represents —C(O)NR3—* or —CH2NR4C(O)—*,
wherein the asterisks indicate the bond which is linked to R2;
R2 represents
R3 represents hydrogen, (C1-C3)alkyl or 2-methoxy-ethyl;
R4 represents hydrogen or methyl;
R5 represents hydrogen, (C1-C3)alkyl or tert-butoxycarbonyl;
R6 represents hydrogen or (C1-C3)alkyl; and
R7 and R8 represent independently from each other hydrogen or methyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
W represents —CH2CH2— or —CH═CH—;
Y represents a bond;
R1 represents an aryl- or a heteroaryl-group, which groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen (preferably bromo), (C1-C4)alkyl (preferably methyl), (C1-C4)alkoxy (preferably methoxy), (C1-C2)alkyl-carbonyl (preferably acetyl), and (C1-C2)fluoroalkyl (preferably trifluoromethyl);
Z represents —C(O)NR3—*,
wherein the asterisk indicates the bond which is linked to R2;
R2 represents
R3 represents hydrogen, (C1-C3)alkyl (preferably methyl or ethyl) or 2-methoxy-ethyl;
R5 represents hydrogen, (C1-C3)alkyl (preferably methyl or ethyl) or tert-butoxycarbonyl; and
R6 represents hydrogen or (C1-C3)alkyl (preferably methyl or ethyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
W represents —CH2CH2— or —CH═CH—;
Y represents a bond;
R1 represents an aryl- or a heteroaryl-group, which groups are independently unsubstituted or mono-substituted, wherein the substituent is selected from the group consisting of halogen (preferably bromo), (C1-C4)alkyl (preferably methyl), (C1-C4)alkoxy (preferably methoxy), (C1-C2)alkyl-carbonyl (preferably acetyl) and (C1-C2)fluoroalkyl (preferably trifluoromethyl);
Z represents —C(O)NR3—*,
wherein the asterisk indicates the bond which is linked to R2;
R2 represents
R3 represents hydrogen, (C1-C3)alkyl (preferably methyl or ethyl) or 2-methoxy-ethyl;
R5 represents hydrogen, (C1-C3)alkyl (preferably methyl or ethyl) or tert-butoxycarbonyl; and
R6 represents hydrogen or (C1-C3)alkyl (preferably methyl or ethyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
W represents —CH2CH2—;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
W represents —CH═CH—;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
Y represents a bond;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
Y represents a (C1-C4)alkandiyl group (preferably methandiyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R1 represents an aryl- or a heteroaryl-group, which groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C2)alkyl-carbonyl, (C1-C2)fluoroalkyl, (C1-C2)fluoroalkoxy, nitro, cyano and phenyl, wherein the phenyl is unsubstituted or mono-substituted with halogen;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R1 represents an aryl- or a heteroaryl-group, which groups are independently unsubstituted or mono-substituted, wherein the substituent is selected from the group consisting of halogen (preferably bromo), (C1-C4)alkyl (preferably methyl), (C1-C4)alkoxy (preferably methoxy), (C1-C2)alkyl-carbonyl (preferably acetyl) and (C1-C2)fluoroalkyl (preferably trifluoromethyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R1 represents aryloxy (preferably phenoxy), cyclohexyl, 4-methyl-cyclohexyl, (C1-C2)alkyl-carbonyl (preferably acetyl) or (C1-C4)alkoxy-carbonyl (preferably methoxy-carbonyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
Y represents together with R1 a (C4-C6)alkyl group or a amino-(C4-C6)alkyl group;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
Y represents together with R1 a (C4-C6)alkyl group;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
Y represents together with R1 a amino-(C4-C6)alkyl group;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
Y represents a (C1-C2)alkandiyl group (preferably ethan-1,2-diyl) and R1 represents
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
Z represents —C(O)NR3—*, wherein the asterisk indicates the bond which is linked to R2;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
Z represents —CH2NR4C(O)—*, wherein the asterisk indicates the bond which is linked to R2; and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents
(C3-C6)cycloalkyl, which is unsubstituted or mono-substituted with hydroxy, pyrrolidin-1-yl-methyl or —CONH2; or
(C1-C6)alkyl, which is unsubstituted or mono-substituted with fluorine, trifluoromethyl, (Cr C4)alkylthio, (C1-C4)alkoxy-carbonyl, hydroxy, cyano, —NR5R6, —C(O)NR7R8 or optionally mono-substituted (C1-C4)alkoxy, wherein the substituent is selected from hydroxy and heterocyclyl; or
(C1-C5)alkyl, which is mono-substituted with heterocyclyl, which heterocyclyl is unsubstituted or mono-substituted at a nitrogen atom with (C1-C4)alkyl, or mono- or di-substituted at one or two of the carbon atoms with substituents independently selected from halogen, (C1-C4)alkyl and (C1-C2)alkoxy-(C1-C2)alkyl; or
(C1-C5)alkyl, which is mono-substituted with an aryl- or heteroaryl-group, which groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl, —CH2NH2 and —SO2NH2; or
(C3-C5)fluoroalkyl, which is mono-substituted with heterocyclyl; or
heterocyclyl, which is unsubstituted or mono-substituted at a nitrogen atom with (C1-C6)alkyl, benzyl or tert-butoxycarbonyl or mono-substituted at a carbon atom with pyrrolidin-1-yl-methyl; or
an aryl- or a heteroaryl-group, which groups are independently unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl and phenyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents
(C3-C6)cycloalkyl, which is unsubstituted or mono-substituted with hydroxy or —CONH2; or
(C1-C6)alkyl, which is unsubstituted or mono-substituted with fluorine, trifluoromethyl,
(C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkoxy-carbonyl, hydroxy, cyano, —NR5R6 or —C(O)NR7R8; or
(C1-C4)alkyl, which is mono-substituted with heterocyclyl, which is unsubstituted or mono-substituted at a nitrogen atom with (C1-C4)alkyl; or
(C1-C4)alkyl, which is mono-substituted with an aryl- or heteroaryl-group, which groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl, —CH2NH2 and —SO2NH2; or
heterocyclyl, which is unsubstituted or mono-substituted at a nitrogen atom with (Cr C6)alkyl, benzyl or tert-butoxycarbonyl; or
an aryl- or a heteroaryl-group, which groups are independently unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl and phenyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents
(C3-C6)cycloalkyl, which is unsubstituted or mono-substituted with hydroxy or pyrrolidin-1-yl-methyl; or
(C1-C6)alkyl, which is unsubstituted or mono-substituted with fluorine, trifluoromethyl, (C1-C4)alkylthio (preferably ethylthio), hydroxy, cyano, —NR5R6, —C(O)NH2 or optionally mono-substituted (C1-C4)alkoxy (preferably methoxy or ethoxy), wherein the substituent is selected from hydroxy and heterocyclyl; or
(C1-C5)alkyl, which is mono-substituted with heterocyclyl, which heterocyclyl is unsubstituted or mono-substituted at a nitrogen atom with methyl or ethyl (preferably methyl), or mono- or di-substituted at one or two of the carbon atoms with substituents independently selected from fluorine, methyl and methoxy-methyl; or
(C1-C5)alkyl, which is mono-substituted with an aryl- or heteroaryl-group, which groups are independently unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-C4)alkyl (preferably methyl) and —CH2NH2; or
(C3-C5)fluoroalkyl, which is mono-substituted with heterocyclyl (preferably pyrrolidin-1-yl); or
heterocyclyl, which is unsubstituted or mono-substituted at a carbon atom with pyrrolidin-1-yl-methyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents
(C3-C6)cycloalkyl, which is unsubstituted or mono-substituted with hydroxy; or
(C1-C6)alkyl, which is unsubstituted or mono-substituted with fluorine, trifluoromethyl, (C1-C4)alkoxy (preferably methoxy or ethoxy), (C1-C4)alkylthio (preferably ethylthio), hydroxy, cyano, —NR5R6 or —C(O)NH2; or
(C1-C4)alkyl, which is mono-substituted with heterocyclyl, which is unsubstituted or mono-substituted at a nitrogen atom with methyl; or
(C1-C4)alkyl, which is mono-substituted with an aryl- or heteroaryl-group, which groups are independently unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-C4)alkyl (preferably methyl) and —CH2NH2; or
heterocyclyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents (C3-C6)cycloalkyl (preferably cyclopentyl or cyclohexyl), which is unsubstituted or mono-substituted with hydroxy, hydroxy-methyl, amino-methyl, pyrrolidin-1-yl-methyl or —CONH2 (and preferably unsubstituted or mono-substituted with hydroxy or pyrrolidin-1-yl-methyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents (C3-C6)cycloalkyl (preferably cyclopentyl or cyclohexyl), which is unsubstituted or mono-substituted with hydroxy;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents (C1-C6)alkyl, which is unsubstituted or mono-substituted with fluorine, trifluoromethyl, (C1-C4)alkylthio, hydroxy, cyano, —NR5R6, —C(O)NR7R8 or optionally mono-substituted (C1-C4)alkoxy, wherein the substituent is selected from hydroxy and heterocyclyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents (C1-C6)alkyl, which is unsubstituted or mono-substituted with fluorine, trifluoromethyl, (C1-C4)alkoxy, (C1-C4)alkylthio, hydroxy, cyano, —NR5R6 or —C(O)NH2 (preferably fluorine, trifluoromethyl, methoxy, ethoxy, hydroxy, cyano, —NR5R6 or —C(O)NH2);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents (C2-C5)alkyl, which is unsubstituted or mono-substituted with fluorine, trifluoromethyl, hydroxy, —NR5R6, —C(O)NR7R8, methoxy, ethoxy or 2-(pyrrolidin-1-yl)-ethoxy;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents
(C1-C5)alkyl, which is mono-substituted with heterocyclyl, which heterocyclyl is unsubstituted or mono-substituted at a nitrogen atom with (C1-C4)alkyl (preferably methyl or ethyl), or mono- or di-substituted at one or two of the carbon atoms with substituents independently selected from halogen, (C1-C4)alkyl and (C1-C2)alkoxy-(C1-C2)alkyl (preferably from fluorine, methyl and methoxy-methyl); or
(C1-C5)alkyl, which is mono-substituted with an aryl- or heteroaryl-group, which groups are independently unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl, —CH2NH2 and —SO2NH2 (and preferably from methyl and —CH2NH2);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents (C1-C4)alkyl, which is mono-substituted with heterocyclyl, which is unsubstituted or mono-substituted at a nitrogen atom with methyl; or
(C1-C4)alkyl, which is mono-substituted with an aryl- or heteroaryl-group, which groups are independently unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-C4)alkyl (preferably methyl) and —CH2NH2;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents (C1-C5)alkyl, which is mono-substituted with heterocyclyl, which heterocyclyl is unsubstituted or mono-substituted at a nitrogen atom with methyl or ethyl (preferably methyl), or mono- or di-substituted at one or two of the carbon atoms with substituents independently selected from fluorine, methyl and methoxy-methyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents (C1-C4)alkyl (preferably methyl or n-butyl and most preferably n-butyl), which is mono-substituted with heterocyclyl, which is unsubstituted (preferred) or mono-substituted at a nitrogen atom with methyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
the heterocyclyl is selected from the group consisting of azetidinyl (preferably azetidin-1-yl), pyrrolidinyl (preferably pyrrolidin-1-yl and pyrrolidin-2-yl), tetrahydrofuranyl (preferably tetrahydrofuran-2-yl), imidazolidinonyl (preferably imidazolidin-2-on-1-yl), piperidinyl (preferably piperidin-1-yl, piperidin-2-yl and piperidin-4-yl), piperazinyl (preferably piperazin-1-yl), morpholinyl (preferably morpholin-4-yl) and 1,4-diazepanyl (preferably 1,4-diazepan-1-yl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents (C1-C5)alkyl (preferably (C1-C3)alkyl), which is mono-substituted with an aryl- or heteroaryl-group, which groups are independently unsubstituted, mono- or di-substituted (preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C1-C4)alkyl, —CH2NH2 and —SO2NH2 (and preferably from methyl and —CH2NH2);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents (C1-C4)alkyl (preferably methyl, ethyl or n-propyl), which is mono-substituted with an aryl- or heteroaryl-group, which groups are independently unsubstituted, mono- or di-substituted (preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of (C1-C4)alkyl (preferably methyl) and —CH2NH2;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents (C1-C5)alkyl (preferably (C1-C3)alkyl), which is mono-substituted with a heteroaryl-group, which is unsubstituted, mono- or di-substituted (preferably unsubstituted or di-substituted) with (C1-C4)alkyl (preferably methyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents (C3-C5)fluoroalkyl, which is mono-substituted with heterocyclyl (preferably pyrrolidin-1-yl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
(C3-C5)fluoroalkyl means 3-fluorobutyl (preferred) or 3,3-difluorobutyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents heterocyclyl, which is unsubstituted or mono-substituted at a nitrogen atom with (C1-C6)alkyl or mono-substituted at a carbon atom with pyrrolidin-1-yl-methyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 represents heterocyclyl, which is unsubstituted (preferred) or mono-substituted at a nitrogen atom with (C1-C6)alkyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R3 represents hydrogen (preferred), methyl, ethyl or 2-methoxy-ethyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R2 and R3 form, together with the nitrogen that carries them, a piperidine ring, which ring is substituted with amino-(C1-C4)alkyl (preferably amino-methyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R5 represents hydrogen, methyl or ethyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R6 represents hydrogen, methyl or ethyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R7 and R8 represent hydrogen;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
R9 represents hydrogen;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
or salts (in particular pharmaceutically acceptable salts) of such compounds;
it is to be understood for any of the above listed compounds, that a stereogenic center, which is not specifically assigned, may be in absolute (R) — or absolute (S)-configuration and that a double bond, which is not specifically assigned, may be in (E)- or (Z)-configuration. Especially, for a compound mentioned in the above list to have the relative (4S*,5R*,6R*,7R*)-configuration it is to be understood that also the respective enantiomer with the absolute (4R,5S,6S,7S)-configuration and/or the respective enantiomer with the absolute (4S,5R,6R,7R)-configuration is encompassed.
or salts (in particular pharmaceutically acceptable salts) of such compounds;
it is to be understood for any of the above listed compounds, that a stereogenic center, which is not specifically assigned, may be in absolute (R)- or absolute (S)-configuration and that a double bond, which is not specifically assigned, may be in (E)- or (Z)-configuration. Especially, for a compound mentioned in the above list to have the relative (4S*,5R*,6R*,7R*)-configuration it is to be understood that also the respective enantiomer with the absolute (4R,5S,6S,7S)-configuration and/or the respective enantiomer with the absolute (4S,5R,6R,7R)-configuration is encompassed.
The present invention also includes isotopically labelled, especially 2H (deuterium) labelled compounds of formula (I), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially 2H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
The term “pharmaceutically acceptable salts” refers to non-toxic, inorganic or organic acid and/or base addition salts, Lit. e.g. “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33, 201-217.
Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.
The compounds of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof, are suitable for use as medicaments. In particular, compounds of formula (I) modulate the ALX receptor and/or FPRL2, i.e. they act as ALX receptor agonists and/or as FPRL2 agonists, and are useful for the prevention or treatment of diseases which respond to the activation of the ALX receptor and/or FPRL2 such as inflammatory diseases, obstructive airway diseases, allergic conditions, HIV-mediated retroviral infections, cardiovascular disorders, neuroinflammation, neurological disorders, pain, prion-mediated diseases and amyloid-mediated disorders (especially Alzheimer's disease); in addition they are useful for the modulation of immune responses (especially those elicited by vaccination). Especially, compounds of formula (I) are useful for the prevention or treatment of diseases such as inflammatory diseases, obstructive airway diseases, allergic conditions, cardiovascular disorders, neuroinflammation, neurological disorders, pain, prion-mediated diseases and amyloid-mediated disorders (especially Alzheimer's disease).
In particular, the compounds of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of diseases selected from inflammatory diseases, obstructive airway diseases and allergic conditions.
Inflammatory diseases, obstructive airway diseases and allergic conditions include, but are not limited to, one, several or all of the following groups of diseases and disorders:
Further, the compounds of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of organ or tissue transplant rejection, for example for the treatment of the recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin or corneal transplants, and the prevention of graft-versus-host disease, such as sometimes occurs following bone marrow transplantation, particularly in the treatment of acute or chronic allo- and xenograft rejection or in the transplantation of insulin producing cells, e g pancreatic islet cells.
Further, the compounds of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of HIV-mediated retroviral infections.
HIV-mediated retroviral infections include, but are not limited to, one, several or all of the groups of diseases and disorders caused by HIV-1 and HIV-2 strains such as GUN-4v, GUN-7wt, AG204, AG206, AG208, HCM305, HCM308, HCM342, mSTD104, and HCM309.
Further, the compounds of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of cardiovascular disorders.
Cardiovascular disorders refer to one or more disease states of the cardiovascular tree (including the heart) and to diseases of dependent organs. Disease states of the cardiovascular tree and diseases of dependent organs include, but are not limited to, disorders of the heart muscle (cardiomyopathy or myocarditis) such as idiopathic cardiomyopathy, metabolic cardiomyopathy which includes diabetic cardiomyopathy, alcoholic cardiomyopathy, drug-induced cardiomyopathy, ischemic cardiomyopathy, and hypertensive cardiomyopathy; atheromatous disorders of the major blood vessels (macrovascular disease) such as the aorta, the coronary arteries, the carotid arteries, the cerebrovascular arteries, the renal arteries, the iliac arteries, the femoral arteries, and the popliteal arteries; toxic, drug-induced, and metabolic (including hypertensive and/or diabetic) disorders of small blood vessels (microvascular disease) such as the retinal arterioles, the glomerular arterioles, the vasa nervorum, cardiac arterioles, and associated capillary beds of the eye, the kidney, the heart, and the central and peripheral nervous systems; and, plaque rupture of atheromatous lesions of major blood vessels such as the aorta, the coronary arteries, the carotid arteries, the cerebrovascular arteries, the renal arteries, the iliac arteries, the femoral arteries and the popliteal arteries.
Further, the compounds of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of neuroinflammation. Neuroinflammation refers to cell signalling molecule production, activation of glia or glial activation pathways and responses, proinflammatory cytokines or chemokines, activation of astrocytes or astrocyte activation pathways and responses, activation of microglia or microglial activation pathways and responses, oxidative stress-related responses such as nitric oxide synthase production and nitric oxide accumulation, acute phase proteins, loss of synaptophysin and Post Synaptic Density-95 Protein (PSD-95), components of the complement cascade, loss or reduction of synaptic function, protein kinase activity (e.g., death associated protein kinase activity), behavioral deficits, cell damage (e.g., neuronal cell damage), cell death (e.g., neuronal cell death), and/or amyloid β deposition of amyloid plaques.
Further, the compounds of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of neurological disorders.
In particular, neurological disorders include, but are not limited to, epilepsy, stroke, cerebral ischemia, cerebral palsy, relapsing remitting multiple sclerosis, progressive multiple sclerosis, neuromyelitis optica, clinically isolated syndrome, Alpers' disease, amyotrophic lateral sclerosis (ALS), senile dementia, dementia with Lewy bodies, Rett syndrome, spinal cord trauma, traumatic brain injury, trigeminal neuralgia, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, glossopharyngeal neuralgia, Bell's palsy, myasthenia gravis, muscular dystrophy, progressive muscular atrophy, progressive bulbar inherited muscular atrophy, herniated, ruptured or prolapsed vertebral disk syndromes, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathies, mild cognitive decline, cognitive decline, Alzheimer's disease, Parkinson's disease, and Huntington's chorea (and especially epilepsy, stroke, cerebral ischemia, cerebral palsy, relapsing remitting multiple sclerosis, progressive multiple sclerosis, Alpers' disease, amyotrophic lateral sclerosis (ALS), senile dementia, dementia with Lewy bodies, Rett syndrome, spinal cord trauma, traumatic brain injury, trigeminal neuralgia, glossopharyngeal neuralgia, Bell's palsy, myasthenia gravis, muscular dystrophy, progressive muscular atrophy, progressive bulbar inherited muscular atrophy, herniated, ruptured or prolapsed vertebral disk syndromes, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathies, mild cognitive decline, cognitive decline, Alzheimer's disease, Parkinson's disease, and Huntington's chorea).
Further, the compounds of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of pain. Pain includes, but is not limited to, neuropathic pain exemplified by conditions such as diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, painful diabetic polyneuropathy, post-stroke pain, post-amputation pain, myelopathic or radiculopathic pain, atypical facial pain and causalgia-like syndromes.
Further, the compounds of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of prion-mediated diseases. Prion-mediated diseases, also known as transmissible spongiform encephalopathies (TSEs), include, but are not limited to, kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS), Fatal Familial Insomnia (FFI) and Creutzfeldt-Jakob Disease (CJD).
Further, the compounds of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof, are suitable for the treatment of amyloid-mediated disorders. Amyloid-mediated disorders are defined as diseases and disorders, that are caused by or associated with amyloid or amyloid-like proteins. Diseases and disorders caused by or associated with amyloid or amyloid-like proteins include, but are not limited to, Alzheimer's Disease (AD), including diseases or conditions characterized by a loss of cognitive memory capacity such as, for example, mild cognitive impairment (MCI); dementia with Lewy bodies; Down's syndrome; cerebral hemorrhage with amyloidosis. In another embodiment, diseases and disorders caused by or associated with amyloid or amyloid-like proteins include progressive supranuclear palsy, amyloid light chain amyloidosis, familial amyloid neuropathies, multiple sclerosis, Creutzfeld Jakob disease, Parkinson's disease, HIV-related dementia, Amyotrophic Lateral Sclerosis (ALS), inclusion-body myositis (IBM), Adult Onset Diabetes, and senile cardiac amyloidosis (and especially progressive supranuclear palsy, multiple sclerosis, Creutzfeld Jakob disease, Parkinson's disease, HIV-related dementia, Amyotrophic Lateral Sclerosis (ALS), inclusion-body myositis (IBM), Adult Onset Diabetes, and senile cardiac amyloidosis).
Further, the compounds of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof, are suitable for the modulation of immune responses.
The modulation of immune responses includes, but is not limited to, methods based on the administration to a subject a composition of at least one antigen and at least one compound of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof. In some cases, the antigen-containing composition is administrated first, followed by administration of a composition of at least one compounds of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof. In other cases, the antigen-containing composition is administrated last. The different compositions may be administrated simultaneously, closely in sequence, or separated in time. Those methods and compositions are provided for therapeutic and prophylactic immunisation (i.e., the deliberate provocation, enhancement, intensification or modulation of an adaptative and/or innate immune response). Particular advantages may include one or more of the following:
Further, the compounds of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of cystic fibrosis, pulmonary fibrosis, pulmonary hypertension, wound healing, diabetic nephropathy, reduction of inflammation in transplanted tissue, inflammatory diseases caused by pathogenic organisms.
Especially, compounds of formula (I) according to any one of embodiments 1) to 51), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of diseases selected from one, several or all of the following groups of diseases and disorders:
The invention also relates to the use of a compound of formula (I) according to any one of embodiments 1) to 51) for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of the above-mentioned diseases.
The present invention also relates to pharmaceutically acceptable salts and to pharmaceutical compositions and formulations of compounds of formula (I) according to any one of embodiments 1) to 51).
A pharmaceutical composition according to the present invention contains at least one compound of formula (I) according to any one of embodiments 1) to 51) (or a pharmaceutically acceptable salt thereof) as the active agent and optionally carriers and/or diluents and/or adjuvants.
The compounds of formula (I) according to any one of embodiments 1) to 51) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parenteral administration.
The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
The present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) according to any one of embodiments 1) to 51), or a pharmaceutically acceptable salt thereof.
Any reference to a compound of formula I, IP, IST1 or IST2 in this text is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient. The preferences indicated for the compounds of formula I of course apply mutatis mutandis to the compounds of formula IP, to the compounds of formula IST1 and the compounds of formula IST2 as well as to the salts and pharmaceutically acceptable salts of the compounds of formula I, of formula IP, of formula IST1 or of formula IST2. The same applies to these compounds as medicaments, to pharmaceutical compositions containing these compounds as active principles or to the uses of these compounds for the manufacture of a medicament for the treatment of the diseases according to this invention.
Unless used regarding temperatures, the term “about” (or alternatively “around”) placed before a numerical value “X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term “about” (or alternatively “around”) placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10° C. to Y plus 10° C., and preferably to an interval extending from Y minus 5° C. to Y plus 5° C. Besides, the term “room temperature” (rt) as used herein refers to a temperature of about 25° C.
The compounds of Formula (I) can be manufactured by the methods given below, by the methods given in the Examples or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures.
If not indicated otherwise, the generic groups R1, R2, R3, R4, R5, R6, R7, R8, R9, W, Y and Z are as defined for formula (I). Other abbreviations used are defined in the experimental section.
Reactions of alcohols with methanesulfonyl chloride may result in the formation of the respective chloride or the respective mesylate derivative depending on the reaction conditions used; it is well known in the art that already small changes in such reaction conditions may have an influence on the outcome of said reactions; it should be understood that normally both reagents, the chloride and the mesylate, might be useful as electrophiles in reactions discussed below.
In some instances the generic groups R1, R2, R3, R4, R5, R6, R7, R8, R9, W, Y and Z might be incompatible with the assembly illustrated in the schemes below and will therefore require the use of protecting groups (PG). The use of protecting groups is well known in the art (see for example “Protective Groups in Organic Synthesis”, T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups are as necessary in place.
A. Synthesis of Final Products
Sections A.a) to A.g) hereafter describe general methods for preparing compounds of formula (I).
Compounds of structure 1 can be obtained by saponification of the ester moiety of compounds of structure 2 using a base such as LiOH or NaOH in a solvent such as a mixture of water and an organic solvent such as THF or EtOH.
Compounds of structure 2 wherein W represents —CH═CH— can be prepared by the following sequence (see scheme 1): a) Diels-Alder reaction between spiro[2.4]hepta-4,6-diene (prepared according to J. W. Coe et al. Org. Letters 2004, 6, 1589) and commercially available (E)-but-2-enedioic acid monoethyl ester in a suitable solvent such as MeOH to obtain a mixture of endo and exo products; b) iodolactonization using KI and I2 in the presence of a base such as NaHCO3 in a solvent such as CH2Cl2 at a temperature about rt to enable separation of the isomers (iodolactone 1 (ester) and iodolactone 2 (carboxylic acid)); c) retro-iodolactonization of the resulting iodolactone 1 using an excess of zinc in a solvent such as AcOH at a temperature about 65° C.; and d) amide coupling of the resulting carboxylic acid with an appropriate amine R1—Y—NH2 via formation of the acyl chloride (using standard conditions such as oxalyl chloride and a catalytic amount of DMF in a solvent such as toluene or CH2Cl2) in the presence of a base such as DIPEA, Et3N or pyridine and in a suitable solvent such as CH2Cl2, THF or acetone or via activation of the carboxylic acid using standard amide coupling conditions such as EDC/HOBt/DMAP in the presence of a base such as DIPEA in a suitable solvent such as CH2Cl2. It is to be understood that, in case the substituent R1 represents or contains a (C1-C2)alkylcarbonyl group, the respective keto-function may be protected in the amines used in step d) as a ketal or as a silylated alcohol; the obtained intermediates may then be transferred to compounds of structure 5 or 6 respectively (see below).
Compounds of structure 2 wherein W represents —CH2—CH2— can be prepared by the following sequence (see scheme 1): a) Diels-Alder reaction between spiro[2.4]hepta-4,6-diene and commercially available (E)-but-2-enedioic acid monoethyl ester in a suitable solvent such as MeOH to obtain a mixture of endo and exo products; b) iodolactonization using KI and I2 in the presence of a base such as NaHCO3 in a solvent such as CH2Cl2 at a temperature about rt to enable separation of the isomers (iodolactone 1 (ester) and iodolactone 2 (carboxylic acid)); c) retro-iodolactonization of the resulting iodolactone 1 using an excess of zinc in a solvent such as AcOH at a temperature about 65° C.; d) reduction of the double bond using cyclohexene in the presence of Pd/C in a suitable solvent such as THF; and e) amide coupling of the resulting carboxylic acid with an appropriate amine R1—Y—NH2 via formation of the acyl chloride (using standard conditions such as oxalyl chloride and a catalytic amount of DMF in a solvent such as toluene or CH2Cl2) in the presence of a base such as DIPEA, Et3N or pyridine and in a suitable solvent such as CH2Cl2, THF or acetone or via activation of the carboxylic acid using standard amide coupling conditions such as EDC/HOBt/DMAP in the presence of a base such as DIPEA in a suitable solvent such as CH2Cl2. In case the substituent R1 represents or contains a (C1-C2)alkylcarbonyl group, the respective keto-function may be protected as described above (compounds of structure 2 wherein W represents —CH═CH—).
Compounds of structure 3 wherein W represents —CH═CH— can be prepared by the following sequence (see scheme 1): a) amide coupling of iodolactone 2 with an appropriate amine R2R3NH, wherein R2, if containing a primary or secondary amine function, might require protection for example as a N-tert-butoxycarbonyl protected amine, via formation of the acyl chloride (using standard conditions such as oxalyl chloride and a catalytic amount of DMF in a solvent such as toluene) in the presence of a base such as DIPEA and in a suitable solvent such as CH2Cl2 or via activation of the carboxylic acid using standard amide coupling conditions such as EDC/HOBt/DMAP in the presence of a base such as DIPEA in a suitable solvent such as CH2Cl2; and b) retro-iodolactonization of the resulting iodolactone 3 using an excess of zinc in a solvent such as AcOH at a temperature about 65° C.
Compounds of structure 3 wherein W represents —CH2—CH2— can be prepared by reduction of the double bond of compounds of structure 3 wherein W represents —CH═CH— using for example hydrogen in the presence of Pd/C in a suitable solvent such as EtOH or cyclohexene in the presence of Pd/C in a suitable solvent such as THF (see scheme 1).
Compounds of structure 4 can be prepared by reduction of the ester of compounds of structure 2 using a reducing agent such as LiBH4 in a suitable solvent such as THF at a temperature about 65° C. followed by formation of the corresponding sulfonate (e.g. triflate) by reaction of the alcohol with a sulfonyl chloride or anhydride derivative (e.g. trifluoromethane sulfonic anhydride) in a suitable solvent such as CH2Cl2 in the presence of a base such as DIPEA at a temperature ranging from −78° C. to 0° C. and subsequent reaction with R4NH2 in a suitable solvent such as CH2Cl2 at a temperature ranging from −78° C. to rt. Alternatively the intermediate sulfonate can be converted into the corresponding azide using sodium azide in a suitable solvent such as DMF at a temperature about 80° C. and subsequent reduction of the azide to the amine using Ph3P in a suitable solvent such as THF/H2O.
Compounds of structures 5 and 6 can be prepared from carboxylic esters of structure 2 wherein R1 represents or contains a masked (C1-C2)alkyl-carbonyl group (for example a silylated alcohol or an acetal protected ketone) by saponification of the ester moiety using a base such as LiOH or NaOH in a solvent such as a mixture of water and an organic solvent such as THF or EtOH, followed by reaction of the obtained carboxylic acid with an appropriate amine R2R3NH using standard amide coupling conditions such as EDC /HOBt/DMAP or DCC/HOAt in the presence of a base such as DIPEA at a temperature about rt in a suitable solvent such as CH2Cl2. Alternatively, compounds of structures 5 and 6 can be prepared from esters of structure 2 wherein R1 represents or contains a masked (C1-C2)alkyl-carbonyl group with an appropriate amine R2R3NH using AIMe3 in a suitable solvent such as CH2Cl2. Compounds of structure 2 wherein R1 represents or contains a masked (C1-C2)alkyl-carbonyl group can be prepared according to scheme 1 using an appropriate amine R1—Y—NH2, wherein R1 represents or contains a masked (C1-C2)alkyl-carbonyl group (see above).
Alternatively, compounds of structures 5 and 6 can be prepared from compounds of structure 3 by reaction with an appropriate amine R1—Y—NH2 wherein R1 represents or contains a masked (C1-C2)alkyl-carbonyl group as defined above using standard amide coupling conditions such as EDC/HOBt/DMAP or DCC/HOAt in the presence of a base such as DIPEA at a temperature about rt in a suitable solvent such as CH2Cl2.
Enantiopure compounds of structure 1 can be obtained by saponification of the ester moiety of enantiopure compounds of structure 2 using a base such as LiOH or NaOH in a solvent such as a mixture of water and an organic solvent such as THF or EtOH.
Enantiopure compounds of structure 2 wherein W represents —CH═CH— can be prepared by the following sequence (see scheme 2): a) Diels-Alder reaction between spiro[2.4]hepta-4,6-diene and commercially available (E)-1,2-bis-[((1S)-1-ethoxycarbonyl-ethoxy)-carbonyl]-ethene in a suitable solvent such as hexane; the assignment of the stereogenic centers of the obtained intermediates was made based on a literature reference (G. Helmchen et al., Angew. Chem. Int. Ed. 1987, 26, 1143), describing the Diels-Alder reaction between cyclopentadiene and (E)-1,2-bis-[((1S)-1-ethoxycarbonyl-ethoxy)-carbonyl]-ethene; b) saponification of the ester moieties using a base such as LiOH in a suitable solvent such as a mixture of THF and water; c) iodolactonization using KI and I2 in the presence of a base such as NaHCO3 in a solvent such as CH2Cl2 at a temperature about rt to give enantiopure iodolactone 2; d) esterification of the resulting carboxylic acid using standard conditions such as TMSCH2N2 in a suitable solvent such as MeOH or via formation of the acyl chloride (using standard conditions such as oxalyl chloride and a catalytic amount of DMF in a solvent such as toluene or CH2Cl2) and subsequent reaction with MeOH; e) retro-iodolactonization of the resulting iodolactone ester using an excess of zinc in a solvent such as AcOH at a temperature about 65° C.; and f) amide coupling of the resulting carboxylic acid with an appropriate amine R1—Y—NH2 via formation of the acyl chloride (using standard conditions such as oxalyl chloride and a catalytic amount of DMF in a solvent such as toluene or CH2Cl2) in the presence of a base such as DIPEA, Et3N or pyridine and in a suitable solvent such as CH2Cl2, THF or acetone or via activation of the carboxylic acid using standard amide coupling conditions such as EDC/HOBt/DMAP in the presence of a base such as DIPEA in a suitable solvent such as CH2Cl2. It is to be understood that, in case the substituent R1 represents or contains a (C1-C2)alkylcarbonyl group, the respective keto-function may be protected in the amines used in step f) as a ketal or as a silylated alcohol.
Enantiopure compounds of structure 2 wherein W represents —CH2—CH2— can be prepared by the following sequence (see scheme 2): a) esterification of enantiopure iodolactone 2 using standard conditions such as TMSCH2N2 in a suitable solvent such as MeOH or via formation of the acyl chloride (using standard conditions such as oxalyl chloride and a catalytic amount of DMF in a solvent such as toluene or CH2Cl2) and subsequent reaction with MeOH to give enantiopure iodolactone 1; b) retro-iodolactonization of the resulting iodolactone ester using an excess of zinc in a solvent such as AcOH at a temperature about 65° C.; c) reduction of the double bond using cyclohexene in the presence of Pd/C in a suitable solvent such as THF; and d) amide coupling of the resulting carboxylic acid with an appropriate amine R1—Y—NH2 via formation of the acyl chloride (using standard conditions such as oxalyl chloride and a catalytic amount of DMF in a solvent such as toluene or CH2Cl2) in the presence of a base such as DIPEA, Et3N or pyridine and in a suitable solvent such as CH2Cl2, THF or acetone or via activation of the carboxylic acid using standard amide coupling conditions such as EDC/HOBt/DMAP in the presence of a base such as DIPEA in a suitable solvent such as CH2Cl2. It is to be understood that, in case the substituent R1 represents or contains a (C1-C2)alkylcarbonyl group, the respective keto-function may be protected in the amines used in step d) as a ketal or as a silylated alcohol.
Enantiopure compounds of structure 3 wherein W represents —CH═CH— can be prepared by the following sequence (see scheme 2): a) amide coupling of enantiopure iodolactone 2 with an appropriate amine R2R3NH, wherein R2, if containing a primary or secondary amine function, might require protection for example as a N-tert-butoxycarbonyl protected amine, via formation of the acyl chloride (using standard conditions such as oxalyl chloride and a catalytic amount of DMF in a solvent such as toluene) in the presence of a base such as DIPEA and in a suitable solvent such as CH2Cl2 or via activation of the carboxylic acid using standard amide coupling conditions such as EDC/HOBt/DMAP in the presence of a base such as DIPEA in a suitable solvent such as CH2Cl2; and b) retro-iodolactonization of the resulting enantiopure iodolactone 3 using an excess of zinc in a solvent such as AcOH at a temperature about 65° C.
Enantiopure compounds of structure 3 wherein W represents —CH2—CH2— can be prepared by reduction of the double bond of enantiopure compounds of structure 3 wherein W represents —CH═CH— with, for instance, hydrogen in the presence of Pd/C in a suitable solvent such as EtOH or cyclohexene in the presence of Pd/C in a suitable solvent such as THF (see scheme 2).
Enantiopure compounds of structure 4 wherein W represents —CH═CH— or —CH2—CH2— can be prepared from enantiopure compounds of structure 2 by analogy to the synthesis described in scheme 1.
Enantiopure compounds of structures 5 and 6 wherein W represents —CH═CH— or —CH2—CH2— can be prepared by analogy to scheme 1.
In a general way, enantiopure compounds of structure 1 can be obtained either in analogy to the synthesis of racemic compounds of structure 1 starting from enantiopure iodolactone 1 or 2 or by chiral HPLC purification of a mixture of enantiomers.
B2. Synthesis of Amines R1—Y—NH2
Amines of formula R1—Y—NH2, if not commercially available, may be prepared for instance by the following sequence: a) conversion of alcohol R1—Y—OH into the corresponding mesylate or chloride using for example MsCl in the presence of a base such as Et3N and DMAP in a suitable solvent such as CH2Cl2; b) conversion of the mesylate or chloride into the corresponding azide using for example NaN3 in a solvent such as DMF at a temperature about 80° C.; c) reduction of the azide moiety either using Ph3P and water in a solvent such as THF at a temperature about 60° C., or by hydrogenation using a metal catalyt such as Pd/C in a suitable solvent such as MeOH. The paragraphs below describe the synthesis of some of these amines.
1-(5-Aminomethyl-furan-2-yl)-ethanone may be prepared using the following sequence: a) protection of commercially available 5-hydroxymethyl-2-furaldehyde using 3,4-dihydro-2H-pyran in the presence of pyridinium toluene-4-sulfonate in a solvent such as CH2Cl2; b) methylation of the aldehyde using for example methylmagnesium chloride in a solvent such as THF at a temperature about 0° C.; c) oxidation of the resulting secondary alcohol using an oxidizing agent such as MnO2 in a solvent such as CH2Cl2 at a temperature about 45° C.; d) removal of the protecting group using an acid such as Amberlyst 15 in a suitable solvent such as MeOH at a temperature about 35° C.; e) chlorination of the alcohol using for example Ms-Cl in the presence of a base such as Et3N and DMAP in a solvent such as CH2Cl2 at a temperature ranging from 0° C. to rt; f) formation of the corresponding azide using NaN3 in a solvent such as DMF at a temperature about 80° C.; and g) reduction of the azide moiety using Ph3P and water in a solvent such as THF at a temperature about 60° C.
3-(2-Methyl-[1,3]dioxolan-2-yl)-propylamine may be prepared using the following sequence: a) condensation of commercially available methyl vinyl ketone and nitromethane in the presence of a catalyst such as activated KF/Al2O3; b) protection of the resulting ketone with ethylene glycol and a catalyst such as p-TsOH in a solvent such as toluene at a temperature about 120° C.; and c) reduction of the nitro group using a metal catalyst such as Pd/C in a solvent such as MeOH under an H2 atmosphere.
4-(2-Methyl-[1,3]dioxolan-2-yl)butylamine may be prepared using the following sequence: a) condensation of commercially available ethyl acetoacetate and acrylonitrile in the presence of a base such as sodium ethylate; b) decarboxylation using a base such as Na2CO3 in a solvent such as water at a temperature about 100° C.; c) protection of the resulting ketone with ethylene glycol and a catalyst such as p-TsOH in a solvent such as toluene at a temperature about 120° C.; and d) reduction of the nitrile using a reducing agent such as LiAlH4 in a solvent such as Et2O at a temperature about 35° C.
[4-(2-Methyl-[1,3]dioxolan-2-yl)-thiazol-2-yl]-methylamine may be prepared using the following sequence: a) reaction of commercially available 2,4-dibromo-thiazole with an organolithium reagent such as n-butyl lithium in a solvent such as ether at a temperature about −78° C. and subsequent formylation with N,N-dimethylformamide at a temperature ranging from −78° C. to rt; b) reduction with a reducing agent such as NaBH4 in a solvent such as MeOH at a temperature about rt; c) protection of the alcohol with a protecting group such as tert-butyldimethylsilyl chloride in the presence of a base such as imidazole in a solvent such as dichloromethane; d) reaction of the protected alcohol with an organolithium reagent such as n-butyl lithium in a solvent such as ether at a temperature about −78° C. and subsequent acetylation with N,N-dimethylacetamide at a temperature ranging from −78° C. to rt; e) ketal formation in the presence of trimethylorthoformate and a catalyst such as LiBF4 in a solvent such as ethylene glycol at a temperature about 95° C.; f) deprotection of the silyl protecting group under standard conditions such as TBAF in a solvent such as THF at a temperature about rt or 0° C.; g) mesylation using a reagent such as methanesulfonyl chloride in a solvent such as CH2Cl2 in the presence of a base such as Et3N and DMAP at a temperature about 0° C.; h) formation of the corresponding azide using NaN3 in a solvent such as DMF at a temperature about 80° C.; and i) reduction of the azide moiety using Ph3P and water in a solvent such as THF at a temperature about 60° C.
[5-(2-Methyl-[1,3]dioxolan-2-yl)thiophen-2-yl]-methylamine may be prepared using the following sequence: a) lithiation of commercially available 2-methyl-2-thiophen-2-yl-[1,3]dioxolane with an organolithium reagent such as n-butyl lithium in the presence of N,N,N′,N′-tetramethyl-ethylenediamine in a solvent such as THF at a temperature about -78° C. and subsequent addition of DMF; b) reduction with a reducing agent such as NaBH4 in a solvent such as MeOH at a temperature about 0° C.; c) chlorination of the alcohol using for example Ms-Cl in presence of a base such as Et3N and DMAP in a solvent such as CH2Cl2 at a temperature about 0° C.; d) formation of the corresponding azide using NaN3 in a solvent such as DMF at a temperature about 80° C.; and e) reduction of the azide moiety using Ph3P and water in a solvent such as THF at a temperature about 60° C.
2-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-yl-methylamine may be prepared using the following sequence: a) reaction of commercially available 1,3-oxazole with an organomagnesium reagent such as iso-propylmagnesium chloride in a solvent such as THF at a temperature about −10° C. and subsequent acetylation with N-methoxy-N-methyl-acetamide at a temperature ranging from −10° C. to rt; b) reduction of the ketone with a reducing agent such as NaBH4 in a solvent such as MeOH at a temperature ranging from 0° C. to rt; c) protection of the alcohol with a protecting group such as tert-butyldimethylsilyl chloride in the presence of a base such as imidazole in a solvent such as THF; d) reaction of the protected alcohol with an organolithium reagent such as tert-butyllithium in a solvent such as THF at a temperature ranging from −78° C. to −40° C. and subsequent formylation with N,N-dimethylformamide at a temperature ranging from −78° C. to rt; e) reduction of the aldehyde with a reducing agent such as NaBH4 in a solvent such as MeOH at a temperature ranging from 0° C. to rt; f) chlorination using a reagent such as methanesulfonyl chloride in a solvent such as CH2Cl2 in the presence of a base such as Et3N and DMAP at a temperature about 0° C.; g) formation of the corresponding azide using NaN3 in a solvent such as DMF at a temperature about 80° C.; and h) reduction of the azide moiety using Ph3P and water in a solvent such as THF at a temperature about 60° C.
4-Bromo-2,3-difluorobenzylamine can be prepared using the following sequence: a) reaction of commercially available 1,2-difluorobenzene and trimethylsilyl chloride in the presence of a base such as lithium diisopropylamide in a suitable solvent such as THF at a temperature about −78° C.; b) conversion of the resulting (2,3-difluoro-1,4-phenylene)-bis(trimethylsilane) to the corresponding 1,4-dibromo-2,3-difluorobenzene using a source of bromine such as bromine at a temperature ranging from 0° C. to 58° C.; c) reaction with an organolithium reagent such as n-butyllithium in a solvent such as THF at a temperature ranging about −78° C. and subsequent carboxylation with solid carbon dioxide for example at a temperature ranging from −78° C. to rt; d) reduction of the resulting carboxylic acid to the corresponding benzyl alcohol using a suitable reducing agent such as borane in a suitable solvent such as THF at a temperature ranging from 0° C. to 50° C.; e) mesylation using a reagent such as methanesulfonyl chloride in a solvent such as CH2Cl2 in the presence of a base such as Et3N and DMAP at a temperature about 0° C.; f) formation of the corresponding azide using NaN3 in a solvent such as DMF at a temperature about 80° C.; and g) reduction of the azide moiety using Ph3P and water in a solvent such as THF at a temperature about 60° C.
B3. Synthesis of Amines R2—NH2
Amines of formula R2—NH2, if not commercially available, may be prepared for instance by the following sequence: a) conversion of alcohol R2—OH into the corresponding mesylate or chloride using for example MsCl in the presence of a base such as Et3N and DMAP in a suitable solvent such as CH2Cl2 or conversion of alcohol R2—OH into the corresponding iodide using for example iodine and Ph3P in the presence of a base such as imidazole in a suitable solvent such as CH2Cl2; b) conversion of the mesylate, chloride or iodide into the corresponding azide using for example NaN3 in a solvent such as DMF at a temperature about 80° C.; c) reduction of the azide moiety either using Ph3P and water in a solvent such as THF at a temperature about 60° C., or by hydrogenation using a metal catalyst such as Pd/C in a suitable solvent such as MeOH.
Alternatively, if not commercially available, amines of formula R2—NH2, which are also amines of formula R2aCH2—NH2, may be prepared by reduction of nitriles R2a—CN either using a reducing agent such as LiAlH4 in a suitable solvent such as THF at a temperature ranging from 0° C. to rt, or by hydrogenation using a metal catalyt such as Pd/C in a suitable solvent such as MeOH.
Whenever the compounds of formula (I) are obtained in the form of mixtures of enantiomers, the enantiomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 μm) column, a Daicel ChiralCel OD-H (5-10 μm) column, or a Daicel ChiralPak IA (10 μm) or AD-H (5-10 μm) column. Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as Et3N or diethylamine) and eluent B (hexane), at a flow rate of 0.8 to 150 mL/min.
For instance, enantiopure compounds of structure 2 may be obtained by chiral HPLC separation of a mixture of enantiomers; for example, (5R)—N5-(4-bromo-phenyl)-(6R)-6-ethoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide may be obtained by chiral HPLC separation of (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide. Preferably such separations are performed using a Deicel ChiralPak AD-H column with a mixture of EtOH and hexane (15/85) as eluent.
Abbreviations (as used herein and in the description above)
I Chemistry
General. All temperatures are stated in degrees Celsius (° C.). Unless otherwise indicated, the reactions take place at rt.
As SCX material SiliaBond® SCX from Silicycle was used.
As polymer supported DCC, PL-DCC from Polymer Laboratories was used.
As polymer supported SO2Cl, PL-SO2Cl from Polymer Laboratories was used.
Analytical thin layer chromatography (TLC) was performed with 0.2 mm plates: Merck, Silica gel 60 F254. Preparative thin layer chromatography (TLC) was performed with 0.2 or 0.5 mm plates: Merck, Silica gel 60 F254. Detection was done with UV or with a solution of KMnO4 (3 g), K2CO3 (20 g), NaOH 5% (3 mL) and H2O (300 mL) with subsequent heating.
Flash column chromatography (FC) and filtration were performed using silica gel 60 Merck (0.063-0.200 mm) or Macherey-Nagel silica gel (0.063-0.200 mm): elution with EA, Et2O, hept, hexane, CH2Cl2, CHCl3, MeOH, NH4OH or mixtures thereof.
MPLC were performed using Isolute® SPE Flash SI II columns from international sorbent technology, elution with EA, Et2O, hept, hexane, CH2Cl2, CHCl3, MeOH, NH4OH or mixtures thereof.
LC-MS-conditions 01 (if not indicated otherwise): Analytical: Thermo Finnigan MSQ Surveyor MS with Agilent 1100 Binary Pump and DAD. Column: Zorbax SB-AQ 5 μm, 4.6×50 mm ID from Agilent Technologies. Eluents: A: H2O+0.04% TFA; B: AcCN; Gradient: 5% B→95% B over 1 min. Flow: 4.50 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
LC-MS-conditions 01b (if not indicated otherwise): Analytical: Thermo Finnigan MSQ Surveyor MS with Agilent 1100 Binary Pump and DAD. Column: Xbridge C18 5 μM, 4.6×50 mm ID from Waters. Eluents: A: H2O+0.04% TFA; B: AcCN; Gradient: 5% B→95% B over 1 min. Flow: 4.50 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
LC-MS-conditions O2 (if not indicated otherwise): Analytical: Thermo Finnigan MSQ Plus MS with Agilent 1100 Binary Pump and DAD. Column: Zorbax SB-AQ 5 μm, 4.6×50 mm ID from Agilent Technologies. Eluents: A: H2O+0.04% TFA; B: AcCN; Gradient: 5% B→95% B over 1 min. Flow: 4.50 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
LC-MS-conditions 05 (if not indicated otherwise): Analytical: Dionex GHP 3200 Binary Pump, MS: Thermo MSQ Plus, DAD: Dionex PDA 3000, ELSD: Sedere Sedex 85, column: Xbridge C18 5 μM, 4.6×50 mm ID from Waters, thermostated in the Dionex TCC-3200 compartment. Eluents: A: H2O+0.04% TFA; B: AcCN. Method: Gradient: 5% B→95% B over 1 min. Flow: 4.5 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
LC-MS-conditions 05b (if not indicated otherwise): Analytical: Dionex GHP 3200 Binary Pump, MS: Thermo MSQ Plus, DAD: Dionex PDA 3000, ELSD: Sedere Sedex 85. Column: Zorbax Extend C18 1.8 μM, 4.6×20 mm from Agilent Technologies, thermostated in the Dionex TCC-3200 compartment. Eluents: A: H2O+0.04% TFA; B: AcCN. Method: Gradient: 2% B→95% B over 1.20 min. Flow: 4.5 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
LC-MS-conditions 05c (if not indicated otherwise): Analytical: Dionex GHP 3200 Binary Pump, MS: Thermo MSQ Plus, DAD: Dionex PDA 3000, ELSD: Sedere Sedex 85. Column: Zorbax SB-AQ 1.8 μm, 4.6×20 mm ID from Agilent Technologies, thermostated in the Dionex TCC-3200 compartment. Eluents: A: H2O+0.04% TFA; B: AcCN. Method: Gradient: 5% B→95% B over 1 min. Flow: 4.5 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
LC-MS-conditions 06 (if not indicated otherwise): Analytical: Dionex HPG-3000 Binary Pump, MS: Thermo MSQ MS, DAD: Dionex PDA 3000, ELSD: PolymerLab ELS 2100. Column: Ascentis C18 2.7 μm, 3×30 mm ID from Sigma-Aldrich, thermostated in the Dionex TCC-3000 compartment. Eluents: A: H2O+0.05% FA; B: AcCN. Method: Gradient: 5% B→95% B over 1.40 min. Flow: 3.0 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
LC-MS-conditions 07 (if not indicated otherwise): Analytical. Pump: Dionex HPG-32001RS, MS: Thermo MSQ Plus, DAD: Dionex DAD-3000RS, ELSD: Sedere Sedex 85. Column: Xbridge C18 2.5 μM, 4.6×30 mm ID from Waters, thermostated in the Dionex TCC-3200 compartment. Eluents: A: H2O+0.04% TFA; B: AcCN. Method: Gradient: 5% B→95% B over 1.00 min. Flow: 4.5 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
LC-MS-conditions 07b (if not indicated otherwise): Analytical. Pump: Dionex HPG-3200RS, MS: Thermo MSQ Plus, DAD: Dionex DAD-3000RS, ELSD: Sedere Sedex 85. Column: Zorbax SB-Aq 3.5 μM, 4.6×50 mm ID from Agilent Technologies, thermostated in the Dionex TCC-3200 compartment. Eluents: A: H2O+0.04% TFA; B: AcCN. Method: Gradient: 5% B→95% B over 1.00 min. Flow: 4.5 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
LC-MS-conditions 07c (if not indicated otherwise): Analytical. Pump: Dionex HPG-3200RS, MS: Thermo MSQ Plus, DAD: Dionex DAD-3000RS, ELSD: Sedere Sedex 85. Column: Atlantis T3 5 μM, 4.6×30 mm ID from Waters, thermostated in the Dionex TCC-3200 compartment. Eluents: A: H2O+0.04% TFA; B: AcCN. Method: Gradient: 5% B→95% B over 1.00 min. Flow: 4.5 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
LC-MS-conditions 07d (if not indicated otherwise): Analytical. Pump: Dionex HPG-3200RS, MS: Thermo MSQ Plus, DAD: Dionex DAD-3000RS, ELSD: Sedere Sedex 85. Column: Ascentis Express C18 2.7 μm, 4.6×30 mm ID from Sigma-Aldrich, thermostated in the Dionex TCC-3200 compartment. Eluents: A: H2O+0.04% TFA; B: AcCN. Method: Gradient: 2% B→95% B over 1.20 min. Flow: 4.5 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
LC-MS-conditions 04 (if not indicated otherwise): Analytical. Pump: Dionex HPG-3200RS, MS: Thermo MSQ Plus, DAD: Dionex DAD-3000RS, ELSD: Sedere Sedex 85. Column: Xbridge C18 5 μM, 4.6×50 mm ID from Waters, thermostated in the Dionex TCC-3200 compartment. Eluents: A: H2O/NH3 (c(NH3)=13 mmol/L); B: AcCN. Method: Gradient: 2% B→95% B over 1.20 min. Flow: 4.5 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
LC-MS-conditions FA (if not indicated otherwise): Analytical. Pump: Waters Acquity Binary Solvent Manager, MS: Waters SQ Detector, DAD: Acquity HPLC PDA Detector, ELSD: Acquity HPLC ELSD. Column: Acquity HPLC BEH C18 1.7 μm 2.1×50 mm ID from Waters, thermostated in the Acquity HPLC Column Manager. Eluents: A: H2O+0.05% FA; B: AcCN+0.05% FA. Method: Gradient: 2% B→98% B over 2.00 min. Flow: 1.2 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
LC-MS-conditions TFA (if not indicated otherwise): Analytical. Pump: Waters Acquity Binary Solvent Manager, MS: Waters SQ Detector, DAD: Acquity HPLC PDA Detector, ELSD: Acquity HPLC ELSD. Column: Acquity HPLC BEH C18 1.7 μm 2.1×50 mm ID from Waters, thermostated in the Acquity HPLC Column Manager. Eluents: A: H2O+0.05% TFA; B: AcCN+0.05% TFA. Method: Gradient: 2% B→98% B over 2.00 min. Flow: 1.2 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
HPLC preparative: X-Bridge C18 5 μm, 50×19 mm ID from Waters. Eluents: A: H2O+0.5% NH4OH; B: AcCN; Gradient: 10% B 90% B over 5 min. Flow: 40.0 mL/min. Detection: UV/Vis and/or ELSD, and MS, tR is given in min.
HPLC chiral, analytical: a) Regis Whelk column, 4.6×250 mm, 10 μm. Eluent A: EtOH+0.05% Et3N. Eluent B: hexane. Flow: 1 mL/min. b) ChiralPak AD, 4.6×250 mm, 5 μm. Eluent A: EtOH+0.05% Et3N. Eluent B: hexane. Flow: 1 mL/min. c) ChiralCel OD, 4.6×250 mm, 10 μm. Eluent A: EtOH+0.1% Et3N. Eluent B: hexane. Flow: 0.8 mL/min. Detection: UV/Vis, tR is given in min.
HPLC chiral, preparative: a) Regis Whelk 01 column, 50×250 mm. Flow: 100 mL/min. b) ChiralPak AD, 20×250 mm. Flow: 10 mL/min. c) ChiralCel OD, 20 μm, 50 mm×250 mm. Flow: 100 mL/min. Detection: UV/Vis, tR is given in min.
GC-MS-conditions 01: Thermo Trace GC Ultra, Thermo DSQ II MS detector, Thermo TriPlus Autosampler, Column: Zebron ZB-5 MS, 15 m×0.25 mm ID, 0.25 μm film, Column flow: 2.0 mL/min, Carrier gas: Helium, Split ratio: 20, SSL Inlet Temperature: 200° C., Temperature gradient: 60° C. to 300° C. from 0.0 min to 4.0 min, 300° C. isotherm from 4.0 min to 5.0 min, Ionization: chemical ionization with CH4 as reagent gas.
NMR: Bruker Avance 400 (400 MHz); Varian Mercury 300 (300 MHz); chemical shifts are given in ppm relative to the solvent used; multiplicities: s=singlet, d=doublet, t=triplet, q =quadruplet, p=pentuplet, hex=hextet, hept=heptet, m=multiplet, br=broad, coupling constants are given in Hz.
As continuous-flow hydrogenation reactor H-Cube® from ThalesNano was used.
The following examples illustrate the invention but do not at all limit the scope thereof.
General Procedures
General Procedure A: Amide Coupling (1):
In a glass vial, under inert atmosphere (N2), to an amine (3.0 eq.) in CH2Cl2 (0.3 M) were added DMAP (0.25 eq.), EDC.HCl (2.0 eq.) and DIPEA (1.0-3.0 eq., when necessary). A solution of the carboxylic acid (1.0 eq.) in CH2Cl2 (0.1 M) was then added and the reaction mixture stirred at rt overnight. The reaction mixture was poured on a syringe containing diatomaceous earth (Isolute® HM-N from Separtis) treated with 1M HCl (1.0 mL per g of Isolute®). The product was eluted with CH2Cl2 (3×1 mL) and the solvent was removed under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
General Procedure B: Amide Coupling (2):
In a glass vial, under inert atmosphere (N2), a mixture of the carboxylic acid (1.0 eq.), an amine (3.0 eq.) and HOAt or HOBt (1.0 eq.) in CH2Cl2 (10 mL per 0.5 mmol of HOAt) was added to PL-DCC Resin (4.0 eq.) in CH2Cl2 (0.2 M) in the presence of PS-DIPEA when needed. The reaction mixture was stirred at rt for 2 days. The reaction mixture was filtered over an Isolute® Phase Separator syringe washed with CH2Cl2 (3×1 mL) and the solvent was removed under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
General Procedure C: Amide Coupling (3):
In a glass vial, under inert atmosphere (N2), a mixture of the carboxylic acid (1.0 eq.) and an amine (1.0 eq.) in DCE/pyridine (1:1, 0.2 M) was cooled to −10° C. POCl3 (2.5 eq.) in DCE/pyridine (1:1, 1.2 M) was added and the reaction mixture was stirred at −10° C. for 1 h. The reaction mixture was poured on a syringe containing diatomaceous earth (Isolute® HM-N from Separtis) treated with 1 M NaOH (1.0 mL per g of Isolute®). The product was eluted with CH2Cl2 (3×2 mL) and the solvent was removed under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
General Procedure D: Amide Coupling (4):
In a glass vial, under inert atmosphere (N2), to a mixture of the amine (1.0 eq.) and a carboxylic acid (1.2 eq.) in CH2Cl2 (10 mL per mmol of acid) was added a solution of HOBt (1.25 eq.), DMAP (0.25 eq.), EDC HCl (1.5-2.0 eq.) and DIPEA (4.0-5.0 eq.) in CH2Cl2 (6 mL per mmol of HOBt). The reaction mixture was stirred at rt overnight. The reaction mixture was poured on a syringe containing diatomaceous earth (Isolute® HM-N from Separtis) treated with 1M HCl (1.0 mL per g of Isolute®). The product was eluted with CH2Cl2 (3×1 mL) and the solvent was removed under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
General Procedure E: Amide Coupling (5):
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of the carboxylic acid (1.0 eq.) in CH2Cl2 (0.2 M) were added an amine (1.0-2.0 eq.), EDC HCl (2.0-3.0 eq.), DIPEA (3.0-6.0 eq., when necessary) and DMAP (0.25 eq.). The reaction mixture was stirred at rt until completion of the reaction. Water was then added, the layers separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
General Procedure F: Weinreb Amidation:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of an amine (2.0 eq.) in CH2Cl2 (0.4 M) was added AIMe3 (1.0 M in heptane, 6.0 eq.). The reaction mixture was stirred at rt for 1 h and was then cooled to 0° C. A solution of the ester (1.0 eq.) in CH2Cl2 (0.2 M) was added and the reaction mixture stirred at rt until completion of the reaction. Aq. sat. NaHCO3 was carefully added, the layers separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
General Procedure G: Dioxolane Deprotection:
In a glass vial, under inert atmosphere (N2), a 0.06 M solution of the dioxolane (1.0 eq.) in THF was treated with 1N HCl (2.7 eq.) and the reaction mixture was stirred at rt until completion. Aq. 1N NaOH was added and the product extracted with EA (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
General Procedure H: Boc Deprotection:
In a glass vial, under inert atmosphere (N2), a 0.06 M solution of the Boc-protected amine (1.0 eq.) in CH2Cl2 (+1 drop of MeOH) was treated with 4N HCl in dioxane (15 mL/mmol amine) and the reaction mixture was stirred at rt for 1 h. The reaction mixture was then concentrated under reduced pressure and the residue purified by FC or HPLC to give the desired compound.
General Procedure I: Amide Coupling (6):
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of the carboxylic acid (1.0 eq.) in CH2Cl2 (0.2 M) were added HOBt (1.2 eq.), DMAP (0.25 eq.), EDC HCl (2.5 eq.) and DIPEA (4.0 eq.). The reaction mixture was stirred at rt for 30 min. A solution of an amine (1.0 eq.) in CH2Cl2 (0.2 M) was then added and the reaction mixture stirred at rt overnight. Water was added, the layers separated, and the org. layer dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
General Procedure J: Amide Coupling (7):
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of the carboxylic acid (1.0 eq.) in CH2Cl2 (0.1 M) were added oxalyl chloride (1.1 eq.) and a few drops of DMF. The reaction mixture was stirred at rt until completion. A solution of an amine (2.2 eq.) in CH2Cl2 (0.4 M) was then added and the reaction mixture stirred at rt until completion of the reaction. Water and CH2Cl2 were then added, the layers separated and the aq. layer extracted with CH2Cl2 (2×). The combined org. extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
General Procedure K: Amide Coupling (8):
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of the carboxylic acid (1.0 eq.), an amine (1.0 eq.) and HOBt (1.2 eq.) in CH2Cl2 (1 mL per 0.3 mmol of HOBt) was added to PL-DCC Resin (2.0 eq.) in CH2Cl2 (0.2 M). The reaction mixture was stirred at rt for 1 day. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
General Procedure L: Amide Coupling (9):
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a mixture of the carboxylic acid (1.0 eq.), an amine (1.1 eq.) and HATU (1.2 eq.) in THF/DMF 4:1 (1 mL per 0.2 mmol of HATU) was added DIPEA (3.0 eq.). The reaction mixture was stirred at rt for 1 day. Water was then added and the mixture extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
General Procedure M: Carboxamide Formation:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), the ester (1.0 eq.) was dissolved in THF (0.2 M) and treated with aq. 1N NaOH (2.0 eq.) at rt until completion of the reaction. The reaction mixture was poured into aq. 1N HCl and extracted with EA (3×). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. To a solution of the crude carboxylic acid (1.0 eq.) and Et3N (1.0 eq.) in dry THF (0.1 M) was added ethyl chloroformate (1.0 eq.) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and an amine (aq. NH3 (excess) or MeNH2 (1.0 eq.)) was then added. The reaction mixture was stirred at 0° C. until completion of the reaction then concentrated under reduced pressure. The residue was partitioned between water and CH2Cl2, the layers separated and the aq. layer extracted with CH2Cl2 (2×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
General Procedure N: Amide Coupling (10):
In a glass vial, under inert atmosphere (N2), to a solution of the carboxylic acid (1.0 eq.) in CH2Cl2 (0.25 M) were added HOBt (1.20 eq.), DMAP (0.25 eq.), EDC HCl (2.5 eq.) and DIPEA (4.0 eq.). The reaction mixture was stirred at rt for 30 min. An amine (2.0 eq.) was then added and the reaction mixture stirred at rt until completion of the reaction. DMF (0.3 vol. CH2Cl2) and PL-SO2Cl2 (1.0 eq.) were added and after stirring at rt for 1 h the mixture was filtered (CH2Cl2) and concentrated under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of benzyltriethylammonium chloride (18.0 g, 78 mmol) in 50% aqueous NaOH solution (1.2 L) was heated to 45° C. A chilled solution of cyclopentadiene (formed by cracking of cyclopentadiene dimer at 180° C., 140 mL, 1.70 mol) in 1,2-dichloroethane (122 mL, 1.55 mol) was added to the stirred NaOH solution while keeping the internal temperature below 55° C. After completion of the addition (ca. 1.75 h), the reaction mixture was stirred at 50° C. for 2 h and allowed to cool down to rt. The layers were separated, the organic layer washed with 1M NaOH, dried (Na2SO4) and filtered. The crude brown liquid was distilled under reduced pressure (85-95 mbar) and the title compound was obtained as a colorless liquid (bp=45-50° C. at 80 mbar). 1H NMR (400 MHz, CDCl3) δ 6.58 (m, 2H), 6.19 (m, 2H), 1.71 (s, 4H).
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (E)-but-2-enedioic acid monoethyl ester (63.8 g, 0.44 mol) in MeOH (425 mL) was treated with spiro[2.4]hepta-4,6-diene (57.6 mL, 0.57 mol) at rt. The reaction mixture was stirred at this temperature for 11 days. The mixture was concentrated under reduced pressure and the crude residue recrystallized from EA and pentane. (6R*)-6-Ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-(5R*)-5-carboxylic acid (exo product) was obtained as a white solid. The mother liquor was then concentrated under reduced pressure, the residue purified by FC (heptane/acetone, 2-5% of acetone) and the product obtained as a mixture of endo/exo products (yellow solid). TLC:rf (7:3 hept-acetone)=0.29. LC-MS-conditions 02: tR=0.89 min; [M+H]+=373.99. 1H NMR (400 MHz, CDCl3) δ 6.42 (m, 1H), 6.24 (dd, J=5.8, 2.5 Hz, 1H), 4.20 (qd, J=7.3, 1.3 Hz, 2H), 3.74 (t, J=4.0 Hz, 1H), 2.82 (d, J=4.5 Hz, 1H), 2.74 (br s, 1H), 2.69 (br s, 1H), 1.30 (t, J=7.0 Hz, 3H), 0.50 (m, 4H) for pure isomer. 1H NMR (400 MHz, CDCl3) δ 6.40 (m, 1Ha+1Hb), 6.23 (dd, J=5.8, 2.8 Hz, 1Ha), 6.16 (dd, J=5.8, 2.8 Hz, 1Hb), 4.18 (qd, J=7.0, 1.3 Hz, 2Ha), 4.12 (qd, J=7.3, 2.0 Hz, 2Hb), 3.73 (t, J=4.3 Hz, 1Ha), 3.62 (t, J=4.3 Hz, 1Hb), 2.92 (d, J=4.5 Hz, 1Hb), 2.81 (d, J=4.5 Hz, 1Ha), 2.75 (br s, 1Hb), 2.72 (br s, 1Ha), 2.67 (br s, 1Ha+1Hb), 1.28 (t, J=7.3 Hz, 3Ha), 1.25 (t, J=7.0 Hz, 3Hb), 0.50 (m, 4Ha+4Hb) for mixture of stereoisomers.
To a solution of 6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxylic acid (15.00 g, 63.5 mmol, mixture of isomers as obtained above) in CH2Cl2 (95 mL) were added NaHCO3 (5.87 g, 69.8 mmol), water (286 mL), KI (39.00 g, 234.9 mmol) and I2 (3.55 g, 11.0 mmol). The reaction mixture was stirred at rt overnight. The reaction was quenched by the addition of sat. aq. Na2S2O3. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were successively washed with aq. sat. NaHCO3 and brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure to give (±)-iodolactone 1 (R10=Et) (ethyl ester) as a pale yellow oil. TLC:rf (4:1 hept-acetone)=0.25. LC-MS-conditions 02: tR=1.02 min; [M+H]+=363.53.
The aq. layer was then acidified (pH=1) and extracted with EA. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude solid was purified by FC to give (±)-iodolactone 2 (carboxylic acid) as a white solid. TLC:rf (70:30:1.1 hept-acetone-MeOH)=0.15. LC-MS-conditions 02: tR=0.86 min; [M+AcCN+H]+=376.49.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (±)-iodolactone 1 (R10=Et) (5.00 g, 13.8 mmol) in acetic acid (50 mL) was added zinc powder (13.54 g, 207.1 mmol). The reaction mixture was stirred at 65° C. for 2 h, cooled down to rt, filtered and partitioned between water and EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 1:0->1:1) and the title compound was obtained as a white solid. TLC:rf (7:3 hept-EA)=0.18. LC-MS-conditions 02: tR=0.89 min; [M+H]+=237.30.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-(5R*)-5-carboxylic acid (17.9 g, 75.6 mmol) in dry toluene (350 mL) were added a few drops of DMF and oxalyl chloride (10.1 mL, 113.5 mmol). The reaction mixture was stirred at reflux for 40 minutes, cooled down to rt, concentrated under reduced pressure and the residue dried under high vacuum.
To a solution of this acyl chloride in dry CH2Cl2 (350 mL) were added 4-bromoaniline (26.8 g, 151.3 mmol) and DIPEA (38.8 mL, 151.3 mmol). The reaction mixture was stirred at rt for 2 h. 1N HCl was added, the layers separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was triturated with MeOH and the title compound obtained as a pale brown solid. TLC:rf (7:3 hept-EA)=0.46. LC-MS-conditions 02: tR=1.09 min; [M+H]+=390.30.
A mixture of (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (2.70 g, 6.92 mmol) in EtOH (69 mL) and 1N NaOH (69 mL) was stirred at 80° C. for 1 h. The reaction mixture was then cooled down to rt and EtOH was removed under reduced pressure. The residue was partitioned between 2N HCl and EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid. LC-MS-conditions 02: tR=0.98 min; [M+H]+=362.20.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (200 mg, 0.55 mmol) in dry toluene (1.7 mL) were added a few drops of DMF and oxalyl chloride (1.1 eq.). The reaction mixture was stirred at rt for 90 min, concentrated under reduced pressure and the residue co-evaporated with toluene (2×). The residue was then redissolved in CH2Cl2 (0.7 mL) and added to a mixture of beta-alanine methyl ester hydrochloride (85 mg, 0.61 mmol) and DIPEA (0.28 mL, 3.0 eq.) at rt. The reaction mixture was stirred at rt for 20 minutes, diluted with CH2Cl2 and washed with aq. 1N HCl. The layers were separated, and the aq. layer back-extracted with CH2Cl2 (2×). The combined org. extracts were washed with aq. sat. NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA) and the title compound obtained as a white solid. TLC:rf (6:4 hept-EA)=0.35. LC-MS-conditions 02: tR=0.98 min; [M+H]+=446.90.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (±)-iodolactone 2 (1.00 g, 2.99 mmol) in dry toluene (17 mL) were added a few drops of DMF and oxalyl chloride (0.38 mL, 4.49 mmol). The reaction mixture was stirred at reflux for 20 minutes, cooled down to rt, concentrated under reduced pressure and the residue dried under high vacuum.
To a solution of this acyl chloride in dry CH2Cl2 (5 mL) were added 4-bromoaniline (730 mg, 4.24 mmol) and DIPEA (1.5 mL, 8.98 mmol). The reaction mixture was stirred at rt for 20 min. 1N HCl was added, the layers separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 7:3) and the pure amide was obtained as a pale orange foam. TLC:rf (7:3 hept-EA)=0.21. LC-MS-conditions 02: tR=1.08 min. In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of the above iodolactone (1.29 g, 2.64 mmol) in acetic acid (10 mL) was added zinc powder (2.59 g, 39.64 mmol). The reaction mixture was stirred at 65° C. for 2 h, cooled down to rt, filtered and partitioned between water and EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 4:6) and the title compound was obtained as a white foam. TLC: rf (4:6 hept-EA)=0.43. LC-MS-conditions 02: tR=0.98 min; [M+H]+=362.31.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a deoxygenated suspension of (6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-(5R*)-5-carboxylic acid (2.00 g, 8.46 mmol), Pd/C 10% (339 mg) and cyclohexene (1.72 mL, 7.93 mmol) in dry THF (31 mL) was stirred at reflux for 4 h. The reaction mixture was filtered through celite and the filter cake washed with EtOH. The filtrate was concentrated under reduced pressure and the title compound obtained as a white solid. TLC:rf (7:3 hept-EA)=0.26. LC-MS-conditions 02: tR=0.93 min; [M+H]+=239.34.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethylene-spiro[2.4]heptane]-(5R*)-5-carboxylic acid (2.00 g, 8.46 mmol) in dry toluene (40 mL) were added a few drops of DMF and oxalyl chloride (1.13 mL, 12.70 mmol). The reaction mixture was stirred at reflux for 40 minutes, cooled down to rt, concentrated under reduced pressure and the residue dried under high vacuum.
To a solution of this acyl chloride in dry CH2Cl2 (40 mL) were added 4-bromoaniline (3.00 g, 16.93 mmol) and DIPEA (4.35 mL, 25.40 mmol). The reaction mixture was stirred at rt for 1 h. 1N HCl was added, the layers separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 7:3) and the title compound obtained as a pale brown solid. TLC:rf (7:3 hept-EA)=0.46. LC-MS-conditions 02: tR=1.13 min; [M+H]+=392.30.
A mixture of (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide (2.78 g, 7.09 mmol) in EtOH (71 mL) and 1N NaOH (71 mL) was stirred at 80° C. for 1 h. The reaction mixture was then cooled down to rt and EtOH was removed under reduced pressure. The residue was partitioned between 2N HCl and EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as an orange powder. TLC:rf (7:3 hept-EA)=0.18. LC-MS-conditions 02: tR=1.01 min; [M+H]+=364.30.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (±)-iodolactone 2 (6.92 g, 20.71 mmol) in dry CH2Cl2 (42 mL) were added a few drops of DMF and oxalyl chloride (1.96 mL, 22.78 mmol). The reaction mixture was stirred at rt for 30 min, after which 4-(1-pyrrolidino)-butylamine (3.00 g, 20.71 mmol) and DIPEA (3.55 mL, 20.71 mmol) were added. The reaction mixture was stirred at rt for 15 minutes, diluted with CH2Cl2 and washed with sat. aq. NH4Cl. The layers were separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC(CH2Cl2/MeOH, 95:5) and the title compound obtained as a white solid. TLC:rf (95:5 CH2Cl2/MeOH)=0.12. LC-MS-conditions 02: tR=0.74 min; [M+H]+=459.30.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (±)-iodolactone 3 (R2=4-pyrrolidin-1-yl-butyl and R3=H) (7.11 g, 15.51 mmol) in acetic acid (100 mL) was added zinc powder (15.21 g, 232.70 mmol). The reaction mixture was stirred at 65° C. for 2 h, cooled down to rt, filtered, washed with CH2Cl2 and the filtrate concentrated under reduced pressure. The crude residue was purified by FC(C-18 reverse phase silica, H2O/MeOH, 1:0 then 0:1) and the title compound was obtained as a white solid. LC-MS-conditions 02: tR=0.64 min; [M+H]+=333.34.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (10.00 g, 25.62 mmol) in dry THF (120 mL) was added LiBH4 (2.55 g, 64.06 mmol). The reaction mixture was stirred at 65° C. for 2.5 h and cooled down to rt. Sat. aq. NH4Cl and EA were added, the layers separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 7:3) and the title compound was obtained as a white solid. TLC:rf (7:3 hept-EA)=0.25. LC-MS-conditions 02: tR=0.99 min; [M+H]+=348.30.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-(hydroxymethyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (1.00 g, 2.87 mmol) in dry CH2Cl2 (20 mL) was added DIPEA (1.23 mL, 7.18 mmol). The reaction mixture was cooled to −78° C. and trifluoromethane sulfonic anhydride (0.55 mL, 3.33 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h. NH3 in dioxane (0.5 M, 15 mL, 7.50 mmol) was then added and the reaction mixture allowed to warm up to rt and stirred at this temperature overnight. Water was added, the layers separated and the org. layer successively washed with sat. aq. NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The title compound was obtained as an orange solid. TLC:rf (9:1:0.1 CH2Cl2-MeOH—NH4OH)=0.28. LC-MS-conditions 02: tR=0.82 min; [M+H]+=347.24.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-(hydroxymethyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (120 mg, 0.35 mmol) in dry CH2Cl2 (2.4 mL) was added DIPEA (0.15 mL, 0.86 mmol). The reaction mixture was cooled to −78° C. and trifluoromethane sulfonic anhydride (0.09 mL, 0.57 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h. Methylamine (2 M in THF, 1.73 mL, 3.46 mmol) was then added and the reaction mixture allowed to warm up to rt and stirred at this temperature for 1 h30. Water and EA were added, the layers separated and the org. layer successively washed with sat. aq. NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The title compound was obtained as an orange solid. LC-MS-conditions 02: tR=0.82 min; [M+H]+=361.29.
In a flame dried round-bottomed flask under inert atmosphere (N2), to a mixture of 5-hydroxymethyl-2-furaldehyde (100 g, 0.79 mol) and pyridinium toluene-4-sulfonate (10 g, 0.04 mol) in CH2Cl2 (1 L) was added 3,4-dihydro-2H-pyran (150 mL, 1.62 mol) while keeping the internal temperature below 28° C. (water bath). The reaction mixture was stirred at rt for 5 h. Water (1 L) was added, the layers separated and the org. layer washed with water (500 mL) and evaporated to dryness to give crude 5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-carbaldehyde as a yellow oil.
Crude 5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-carbaldehyde (171 g) was dissolved in THF (1 L) and cooled to 1° C. Methylmagnesium chloride (3 M in THF, 325 mL, 0.97 mol) was then added while keeping the internal temperature below 5° C. After the addition, the reaction mixture was stirred at rt for 1 h. Water (1 L), TBME (1 L) and 40% aq. citric acid (200 mL) were added, the layers separated and the org. layer washed with water (500 mL) and evaporated to dryness to give crude 1-[5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-yl]-ethanol. Part of the crude material (96 g, 0.43 mol) was dissolved in CH2Cl2 (1 L) and treated with MnO2 (371 g, 4.26 mol) at rt. The reaction mixture was heated to 45° C. and stirred at this temperature for 24 h. The mixture was then filtered over celite and the filter cake washed with CH2Cl2. The filtrate was evaporated to dryness to give crude 1-[5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-yl]-ethanone as a yellow oil.
Crude 1-[5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-yl]-ethanone (89 g, 0.40 mol) was dissolved in MeOH (500 mL) and treated with Amberlyst 15 (15 g) at rt. The reaction mixture was stirred at 35° C. for 1 h, cooled to rt and filtered over celite. Et3N (1 mL) was added and the mixture was evaporated to dryness. The residue was stripped with methylcyclohexane and 1-(5-hydroxymethyl-furan-2-yl)ethanone was obtained as a yellow oil that solidified on standing.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(5-hydroxymethyl-furan-2-yl)-ethanone (2.00 g, 14.27 mmol) in dry CH2Cl2 (29 mL) was treated at 0° C. with Et3N (2.58 mL, 18.55 mmol) followed by DMAP (178 mg, 1.43 mmol) and Ms-Cl (1.33 mL, 17.13 mmol). After stirring at rt for 3 h, the reaction was quenched with water. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 1-(5-chloromethyl-furan-2-yl)-ethanone as a brown oil. Part of this crude material (2.33 g, 14.72 mmol) was dissolved in dry DMF (50 mL) and treated with NaN3 (2.90 g, 44.16 mmol) at 80° C. for 24 h. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the aq. layer extracted with EA (1×). The combined org. extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 1-(5-azidomethyl-furan-2-yl)-ethanone as a brown oil. LC-MS-conditions 02: tR=0.81 min; [M+AcCN+H]+=207.50.
To a solution of the crude azide (500 mg, 3.03 mmol) in THF (15 mL) were added Ph3P (polymer-supported, 3.0 mmol/g, 1.5 eq.) and water (5 mL). The reaction mixture was stirred at 60° C. until reaction completion, cooled down to rt and filtered. Sat. aq. NaHCO3 and EA were then added, the layers separated and the aq. layer extracted with EA (1×). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (9:1 CH2Cl2/MeOH) and the title compound was obtained as an orange oil. LC-MS-conditions 02: tR=0.27 min; [M+AcCN+H]+=181.61.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of methyl vinyl ketone (2.32 mL, 28.53 mmol) in nitromethane (29.6 mL) was added activated KF/Al2O3 (323 mg, prepared by mixing KF and basic Al2O3 in water followed by concentrating and drying) at 0° C. The reaction mixture was then allowed to warm up to rt and stirred at this temperature for 18 h. The mixture was filtered through neutral Al2O3 and washed with CH2Cl2. The filtrated was concentrated under reduced pressure to give the title compound as a colorless oil.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus and under inert atmosphere (N2), crude 5-nitro-pentan-2-one (28.53 mmol) was dissolved in dry toluene (28 mL). Ethylene glycol (10.2 mL, 183.02 mmol) and p-TsOH (696 mg, 3.66 mmol) were added and the reaction mixture stirred at 120° C. for 5 h. The reaction mixture was then cooled down to rt and sat. aq. NaHCO3 was added. The layers were separated and the org. layer washed with brine (2×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 4:1) to give the title compound as a pale brown oil. TLC:rf (4:1 hept-EA)=0.21.
In a flame dried round-bottomed flask equipped with a magnetic stir bar, a mixture of 2-methyl-2-(3-nitro-propyl)-[1,3]dioxolane (1.80 g, 10.27 mmol) and Pd/C 10% (176 mg) in dry MeOH (35 mL) was stirred at rt under atmospheric H2 for 11 h. The reaction mixture was then filtered and concentrated under reduced pressure to give the title compound as a colorless oil. LC-MS-conditions 02: tR=0.25 min; [M+H]+=146.41.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to sodium ethylate (prepared from 62 mg sodium in 8 mL of EtOH) was added ethyl acetoacetate (9.7 mL, 76.1 mmol). Acrylonitrile (5 mL, 76.1 mmol) was then added dropwise at 40-45° C. and the reaction mixture was stirred at this temperature overnight. Ethanol was removed and the residue washed with 65 mL of water containing 3.5 mL of acetic acid, diluted with CH2Cl2 and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was distilled (bp=95-105° C. at 1 atm) to give the title compound. TLC:rf (7:3 hept-EA)=0.29.
A mixture of 2-acetyl-4-cyano-butyric acid ethyl ester (5.70 g, 31.1 mmol) and Na2CO3 (5.52 g, 52.1 mmol) in water (55 mL) was stirred at reflux for 4 h. After cooling, K2CO3 (1.9 g) was added and the reaction mixture extracted with Et2O (3×) then with CH2Cl2 (4×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 65:35) to give the title compound as a colorless oil. TLC:rf (65:35 hept-EA)=0.21.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus and under inert atmosphere (N2), 5-oxo-hexanenitrile (1.69 g, 15.2 mmol) was dissolved in dry toluene (10 mL). Ethylene glycol (4.24 mL, 76.0 mmol) and p-TsOH (289 mg, 1.5 mmol) were added and the reaction mixture stirred at 120° C. for 5 h. The reaction mixture was then cooled down to rt and sat. aq. NaHCO3 was added. The layers were separated and the aq. layer extracted with CH2Cl2 (2×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow oil. LC-MS-conditions 02: tR=0.94 min.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-(2-methyl-[1,3]dioxolan-2-yl)-butyronitrile (2.23 g, 14.4 mmol) in dry Et2O (2.5 mL) was added to a suspension of LiAlH4 (1.36 g, 35.9 mmol) in dry Et2O (50 mL). The reaction mixture was stirred at reflux for 3 h, cooled down to rt and treated with water (2 mL), 15% aq. NaOH (2 mL) and water (4 mL). The precipitate was filtered off and washed with Et2O. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a light brown oil. LC-MS-conditions 02: tR=0.32 min; [M+H]+=160.29.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 2,4-dibromo-thiazole (3.50 g, 14.41 mmol) in dry Et2O (120 mL) was treated with n-BuLi (5.9 mL of a 2.5 M solution in hexanes, 14.72 mmol) at −78° C. The reaction mixture was stirred at this temperature for 30 min. N,N-Dimethylformamide (1.35 mL, 14.47 mmol) was then added and the mixture allowed to warm to rt over a period of 1 h. The reaction was quenched by the addition of sat. aq. NH4Cl (50 mL). The layers were separated and the aq. layer extracted with Et2O (3×50 mL). The combined org. extracts dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (10:1->3:1 hept-EA) gave the title compound as a pale yellow solid. TLC:rf (1:1 hept-EA)=0.21. LC-MS-conditions 02: tR=0.81 min.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 4-bromo-thiazole-2-carbaldehyde (1.68 g, 8.75 mmol) was dissolved in MeOH (10 mL). NaBH4 (428 mg, 10.86 mmol) was added portionwise at 0° C. and the reaction mixture stirred at rt for 1 h. Water (10 mL) was added and the mixture extracted with EA (3×20 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (6:1->2:1 hept-EA) gave the title compound as a pale yellow solid. TLC:rf (1:1 hept-EA)=0.31. LC-MS-conditions 02: tR=0.62 min [M+H]+=194.31.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), (4-bromo-thiazol-2-yl)-methanol (1.37 g, 7.06 mmol) was dissolved in dry CH2Cl2 (21 mL). tert-Butyldimethylsilyl chloride (1.17 g, 7.77 mmol) was added at 0° C. followed by imidazole (985 mg, 14.47 mmol). The reaction mixture was stirred at rt for 2 h. 10% Aq. K2CO3 (10 mL) was added, the layers separated and the aq. layer extracted with CH2Cl2 (2×20 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a colorless oil. TLC:rf (1:1 hept-EA)=0.80.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 4-bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-thiazole (1.94 g, 6.29 mmol) in dry Et2O (50 mL) was added n-BuLi (2.76 mL of a 2.5 M solution in hexanes, 6.92 mmol) at −78° C. The reaction mixture was then stirred for 30 min at −78° C. before N,N-dimethylacetamide (1.17 mL, 12.58 mmol) was added dropwise. The reaction mixture was allowed to warm up to rt over a period of 1 h and stirred at this temperature for 20 min. Sat. aq. NH4Cl (20 mL) was added, the layers separated and the aq. layer extracted with Et2O (3×30 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1->5:1 hept-EA) gave the title compound as a yellow solid. TLC:rf (1:1 hept-EA)=0.51. LC-MS-conditions 02: tR=1.11 min; [M+H]+=272.39.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[2-(tert-butyl-dimethyl-silanyloxymethyl)-thiazol-4-yl]-ethanone (1.77 g, 6.52 mmol) in ethylene glycol (7 mL) was treated with trimethylorthoformate (1.46 mL, 13.29 mmol) followed by LiBF4 (125 mg, 1.30 mmol). The reaction mixture was heated at 95° C. for 4 h. Sat. aq. Na2CO3 (5 mL) was added and the mixture was extracted with Et2O (2×20 mL). The org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1->3:1 hept-EA) gave the title compound as a brown oil. TLC:rf (1:1 hept-EA) =0.56. LC-MS-conditions 02: tR=1.11 min; [M+H]+=316.36.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-4-(2-methyl-[1,3]dioxolan-2-yl)-thiazole (1.30 g, 4.12 mmol) in dry THF (10 mL) was treated at 0° C. with TBAF (6.2 mL of a 1M solution in THF, 6.20 mmol). The reaction mixture was stirred at 0° C. for 5 min and at rt for 1 h30. The mixture was then diluted with EA (10 mL), washed with brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (5:1->1:3 hept-EA) gave the title compound as a yellow oil. TLC:rf (1:2 hept-EA)=0.20. LC-MS-conditions 02: tR=0.59 min; [M+H]+=202.48.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-yl]-methanol (745 mg, 3.70 mmol) in dry CH2Cl2 (5 mL) was treated at 0° C. with Et3N (0.67 mL, 4.79 mmol) followed by DMAP (46 mg, 0.37 mmol) and Ms-Cl (0.37 mL, 4.67 mmol). After stirring at 0° C. for 1 h30, the reaction was quenched with water (5 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude methanesulfonic acid 4-(2-methyl-[1,3]dioxolan-2-yl)thiazol-2-ylmethyl ester as a yellow oil. Part of this crude material (200 mg, 0.72 mmol) was dissolved in dry DMF (2.5 mL) and treated with NaN3 (50 mg, 0.76 mmol) at 80° C. for 24 h. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-azidomethyl-4-(2-methyl-[1,3]dioxolan-2-yl)thiazole as a yellow oil. LC-MS-conditions 02: tR=0.82 min; [M+H]+=227.46.
To a solution of the crude azide (160 mg, 0.71 mmol) in THF (4.5 mL) were added Ph3P (371 mg, 1.41 mmol) and water (1 mL). The reaction mixture was stirred at 60° C. for 4 h and cooled down to rt. Sat. aq. NaHCO3 and EA were then added, the layers separated and the aq. layer extracted with EA (1×). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (1:0->9:1 CH2Cl2-MeOH) to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.37 min; [M+H]+=201.54.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of commercially available 2-methyl-2-thiophen-2-yl-[1,3]dioxolane (5.00 g, 28.49 mmol) in THF (145.0 mL) at −78° C. was added dropwise N,N,N′,N′-tetramethyl-ethylendiamine (4.41 mL, 29.06 mmol) followed by n-BuLi (18.14 mL of a 1.6 M solution in hexanes, 29.06 mmol), maintaining the temperature at −78° C. The reaction mixture was then stirred for 2 h at −78° C. before DMF (6.74 mL, 87.22 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was stirred for 16 h. The reaction mixture was poured in sat. aq. NaH4CI (200 mL) and extracted with EA (2×200 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude 5-(2-methyl-[1,3]dioxolan-2-yl)-thiophene-2-carbaldehyde as an yellow oil. LC-MS-conditions 02: tR=0.87 min; [M+AcCN+H]+=240.32. The crude material was dissolved, under inert atmosphere (N2) in MeOH (51.2 mL) and treated at 0° C., portionwise, over 20 min, with NaBH4 (1.35 g, 34.19 mmol in five equal portions). The reaction mixture was stirred at rt for 45 min. The reaction mixture was poured in water (90 mL) and the aq. layer was extracted with EA (2×225 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound. TLC:rf (50:50 hept-EA)=0.40. LC-MS-conditions 02: tR=0.72 min; [M+H]+=201.46.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)thiophen-2-yl]-methanol (5.00 g, 25.0 mmol) in dry CH2Cl2 (46 mL) was treated at 0° C. with Et3N (4.5 mL, 32.5 mmol) followed by DMAP (305 mg, 2.5 mmol) and Ms-Cl (2.3 mL, 30.0 mmol). After stirring at rt for 2 h, the reaction was quenched with water (50 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 2-(5-chloromethyl-thiophen-2-yl)-2-methyl-[1,3]dioxolane as a yellow oil. Part of this crude material (953 mg, 4.36 mmol) was dissolved in dry DMF (15 mL) and treated with NaN3 (859 mg, 13.08 mmol) at 80° C. for 24 h. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 2-azidomethyl-5-(2-methyl-[1,3]dioxolan-2-yl)thiophene as a yellow oil. LC-MS-conditions 02: tR=0.97 min; [M+H]+=226.50.
To a solution of the crude azide (150 mg, 0.67 mmol) in THF (6 mL) were added Ph3P (polymer-supported, 1.6 mmol/g, 2.0 eq.) and water (2 mL). The reaction mixture was stirred at 60° C. until reaction completion, cooled down to rt and filtered. Sat. aq. NaHCO3 and EA were then added, the layers separated and the aq. layer extracted with EA (1×). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The title compound was obtained as a yellow oil. LC-MS-conditions 01: tR=0.50 min; [M+H]+=199.99.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 1,3-oxazole (3.25 mL, 48.49 mmol) in dry THF (34.00 mL) was treated with isopropylmagnesium chloride (24.00 mL of a 2.0 M solution in THF, 48.00 mmol) at −15° C. (while the internal temperature was kept below −10° C.). The reaction mixture was stirred at this temperature for 40 min. A solution of N-methoxy-N-methylacetamide (4.12 mL, 38.79 mmol) in dry THF (10 mL) was then added dropwise while keeping the internal temperature below −14° C. The reaction mixture was allowed to warm to rt and stirred at this temperature overnight. The reaction was quenched by the addition of 20% aq. NH4Cl (150 mL). The layers were separated and the aq. layer extracted with Et2O (3×100 mL). The combined org. extracts dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (6:4 hexane-Et2O) gave the title compound as an orange oil. TLC:rf (6:4 hexane-Et2O)=0.27. LC-MS-conditions 02: tR=0.47 min.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 1-oxazol-2-yl-ethanone (1.76 g, 15.84 mmol) was dissolved in MeOH (30 mL). NaBH4 (811 mg, 20.59 mmol) was added portionwise at 0° C. and the reaction mixture stirred at rt for 1 h30. Water (30 mL) was added and the MeOH removed under reduced pressure. The mixture was then extracted with EA (7×50 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The title compound was obtained as a pale yellow oil. LC-MS-conditions 02: tR=0.33 min.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 1-oxazol-2-yl-ethanol (1.21 g, 10.71 mmol) was dissolved in dry THF (50 mL). tert-Butyldimethylsilyl chloride (3.23 g, 21.43 mmol) was added at rt followed by imidazole (1.46 g, 21.43 mmol). The reaction mixture was stirred at rt for 16 h. Sat. aq. NH4Cl (100 mL) and EA (100 mL) were added, the layers separated and the aq. layer extracted with EA (1×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (4:1 hexane-Et2O) gave the title compound as a colorless oil. TLC:rf (4:1 hexane-Et2O)=0.39. LC-MS-conditions 02: tR=1.08 min; [M+H]+=228.56.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazole (733 mg, 3.22 mmol) in dry THF (16 mL) was added tert-BuLi (2.62 mL of a 1.6 M solution in pentane, 4.19 mmol) at −78° C. The reaction mixture was then stirred for 1 h at −40° C. and cooled to −78° C. before N,N-dimethylformamide (0.49 mL, 6.44 mmol) was added dropwise. The reaction mixture was allowed to warm up to rt over a period of 1 h and stirred at this temperature for 2 h. Water (30 mL) and sat. aq. NH4Cl (20 mL) were added, the layers separated and the aq. layer extracted with EA (2×30 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a colorless oil. TLC:rf (4:1 hept-EA)=0.33. LC-MS-conditions 02: tR=1.08 min; [M+H]+=256.37.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazole-5-carbaldehyde (457 mg, 1.79 mmol) was dissolved in MeOH (8 mL). NaBH4 (92 mg, 2.33 mmol) was added portionwise at 0° C. and the reaction mixture stirred at rt for 20 min. Water (16 mL) was added and the MeOH removed under reduced pressure. The mixture was then extracted with EA (2×20 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The title compound was obtained as a colorless oil. LC-MS-conditions 02: tR=0.97 min; [M+H]+=258.37.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-yl-methanol (760 mg, 2.95 mmol) in dry CH2Cl2 (15 mL) was treated at 0° C. with Et3N (0.53 mL, 3.82 mmol) followed by DMAP (36 mg, 0.30 mmol) and Ms-Cl (0.30 mL, 3.73 mmol). After stirring at 0° C. until reaction completion, the reaction was quenched with water (50 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-chloromethyl-oxazole as a yellow oil. The crude material (2.95 mmol) was dissolved in dry DMF (15 mL) and treated with NaN3 (205 mg, 3.01 mmol) at 80° C. for 40 h. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 5-azidomethyl-2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazole as a yellow oil. LC-MS-conditions 02: tR=1.12 min; [M+H]+=283.55.
To a solution of the crude azide (700 mg, 2.48 mmol) in THF (12 mL) were added Ph3P (polymer-supported, 1.6 mmol/g, 3.0 eq.) and water (4 mL). The reaction mixture was stirred at 60° C. until reaction completion, cooled down to rt and filtered. Sat. aq. NaHCO3 and EA were then added, the layers separated and the aq. layer extracted with EA (1×). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (1:0->9:1 CH2Cl2-MeOH+2% Et3N) to give the title compound as a yellow oil. LC-MS-conditions 01: tR=0.75 min; [M+H]+=257.08.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 2-bromo-thiazole-5-carbaldehyde (10.66 g, 55.51 mmol) was dissolved in MeOH (150 mL). NaBH4 (2.71 g, 68.91 mmol) was added portionwise at 0° C. and the reaction mixture stirred at 0° C. for 1 h. Water (10 mL) was added and the mixture extracted with EA (3×70 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude (2-bromo-thiazol-5-yl)-methanol as an orange oil. TLC:rf (1:1 hept-EA)=0.25. LC-MS-conditions 01: tR=0.56 min [M+H]+=193.81.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), (2-bromo-thiazol-5-yl)-methanol (10.65 g, 54.88 mmol) was dissolved in dry CH2Cl2 (150 mL). tert-Butyldimethylsilyl chloride (9.58 g, 60.37 mmol) was added at 0° C. followed by imidazole (7.66 g, 112.51 mmol). The reaction mixture was stirred at rt until completion of the reaction. Water (100 mL) was added, the layers separated and the org. layer dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (1:0 to 30:1 hept-EA) gave the title compound as a yellow oil. TLC:rf (9:1 hept-EA)=0.46. LC-MS-conditions 01: tR=1.13 min [M+H]+=309.90.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of n-BuLi (4.3 mL of a 2.5 M solution in hexanes, 10.75 mmol) in dry Et2O (15 mL) was added a solution of 2-bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-thiazole (3.03 g, 9.83 mmol) in dry Et2O (10 mL) at −78° C. The reaction mixture was then stirred for 30 min at −78° C. before N,N-dimethylacetamide (1.9 mL, 20.43 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h. Sat. aq. NH4Cl (20 mL) was added, the layers separated and the aq. layer extracted with Et2O (2×30 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as an orange oil. TLC:rf (2:1 hept-EA)=0.60. LC-MS-conditions 02: tR=1.14 min; [M+H]+=272.32.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[5-(tert-butyl-dimethyl-silanyloxymethyl)-thiazol-2-yl]-ethanone (1.00 g, 3.68 mmol) in ethylene glycol (4 mL) was treated with trimethylorthoformate (0.82 mL, 7.51 mmol) followed by LiBF4 (70 mg, 0.74 mmol). The reaction mixture was heated at 95° C. for 2 days. Sat. aq. Na2CO3 (5 mL) was added and the mixture was extracted with Et2O (3×20 mL). The org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude residue (mixture of silylated/desilylated products) in dry THF (10 mL) was treated at rt with TBAF (1.1 mL of a 1M solution in THF, 1.10 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then diluted with EA, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (4:1->1:2 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (EA)=0.47. LC-MS-conditions 02: tR=0.60 min; [M+H]+=202.46.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(2-methyl-[1,3]dioxolan-2-yl)thiazol-5-yl)methanol (389 mg, 1.93 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.35 mL, 2.50 mmol) followed by DMAP (24 mg, 0.19 mmol) and Ms-Cl (0.19 mL, 2.40 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification by FC (1:1->1:2 hept-EA+1% Et3N) gave pure (2-(2-methyl-[1,3]dioxolan-2-yl)thiazol-5-yl)methyl methanesulfonate as a pale yellow oil. Part of this material (140 mg, 0.50 mmol) was dissolved in dry DMF (1 mL) and treated with NaN3 (35 mg, 0.53 mmol) at 80° C. for 1 h30. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 5-(azidomethyl)-2-(2-methyl-[1,3]dioxolan-2-yl)thiazole as a brown oil. LC-MS-conditions 01: tR=0.80 min; [M+H]+=226.96.
To a solution of the crude azide (113 mg, 0.50 mmol) in THF (6 mL) were added polymer supported Ph3P (262 mg, 1.00 mmol) and water (2 mL). The reaction mixture was stirred at 60° C. for 1 h, cooled down to rt, filtered and concentrated under reduced pressure. The residue was redissolved in CH2Cl2/MeOH 9:1, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 02: tR=0.48 min.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 2-bromo-thiazole-5-carbaldehyde (1.96 g, 10.00 mmol) in CH2Cl2 (20 mL) was treated at 0° C. with trimethylaluminum (15 mL of a 2M solution in toluene, 30.00 mmol). The reaction mixture was then stirred at 0° C. for 45 min. CH2Cl2 (100 mL) was then added followed by sat. aq. NH4Cl (100 mL). The mixture was then treated with 1N HCl (50 mL) and the aq. layer was extracted with CH2Cl2 (150 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an orange oil. TLC:rf (1:1 hept-EA)=0.38. LC-MS-conditions 02: tR=0.70 min; [M+H]+=208.38.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-bromo-thiazol-5-yl)-ethanol (14.85 g, 71.37 mmol) in CH3CN (160 mL) was treated at rt with MnO2 (34.47 g, 356.84 mmol) and the reaction mixture was stirred for 20 h at rt before being filtered through Celite. The solvent was removed under reduced pressure to give the title compound as a yellow solid. TLC:rf (1:1 hept-EA)=0.54. LC-MS-conditions 02: tR=0.79 min.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a condenser under inert atmosphere (N2), a solution of 1-(2-bromo-thiazol-5-yl)-ethanone (16.22 g, 78.71 mmol) in ethylene glycol (85 mL) was treated with trimethylorthoformate (18 mL, 164.19 mmol) followed by LiBF4 (1.51 g, 15.74 mmol). The reaction mixture was heated at 95° C. for 2 days. Sat. aq. NaHCO3 was added and the mixture was extracted with Et2O (3×). The org. extracts were washed with brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 to 3:1 hept-EA) gave the title compound as a yellow solid. TLC:rf (1:1 hept-EA)=0.63. LC-MS-conditions 02: tR=0.89 min; [M+H]+=250.24.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-bromo-5-(2-methyl-[1,3]dioxolan-2-yl)thiazole (5.00 g, 20.00 mmol) in dry Et2O (40 mL) was added to a n-BuLi (8.40 mL of a 2.5M solution in hexanes, 21.00 mmol) at −78° C. The reaction mixture was then stirred for 30 min at −78° C. before DMF (2.5 mL, 32.29 mmol) was added dropwise. The reaction mixture was stirred at −60° C. for 1 h. Sat. aq. NH4Cl (100 mL) was added, followed by aq. 1N HCl (50 mL). The layers separated and the aq. layer extracted with Et2O (5×). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as an orange oil. TLC:rf (1:1 hept-EA)=0.50. LC-MS-conditions 01: tR=0.78 min; [M+H]+=199.93.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 5-(2-methyl-[1,3]dioxolan-2-yl)thiazole-2-carbaldehyde (5.12 g, 25.70 mmol) was dissolved in MeOH (60 mL). NaBH4 (1.26 g, 31.89 mmol) was added portionwise at 0° C. and the reaction mixture stirred at 0° C. for 1 h. Water was added and the mixture extracted with EA (3×). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an orange oil. TLC:rf (1:1 hept-EA)=0.31. LC-MS-conditions 02: tR=0.64 min; [M+H]+=202.52.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-yl]-methanol (500 mg, 2.48 mmol) in dry CH2Cl2 (15 mL) was treated at 0° C. with Et3N (0.45 mL, 3.21 mmol) followed by DMAP (31 mg, 0.25 mmol) and Ms-Cl (0.25 mL, 3.14 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (5-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-yl)methyl methanesulfonate as a brown oil. This material was dissolved in dry DMF (10 mL) and treated with NaN3 (175 mg, 2.66 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-(azidomethyl)-5-(2-methyl-[1,3]dioxolan-2-yl)-thiazole as a yellow oil. LC-MS-conditions 02: tR=0.86 min; [M+H]+=227.47.
To a solution of the crude azide (565 mg, 2.50 mmol) in THF (12 mL) were added polymer-supported Ph3P (2.0 eq.) and water (4 mL). The reaction mixture was stirred at 60° C. until completion of the reaction, cooled down to rt, filtered and partitioned between EA and sat. aq. NaHCO3. The layers were separated and the aq. layer extracted with EA. The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a brown oil after purification by FC (CH2Cl2-MeOH 1:0 to 9:1). LC-MS-conditions 01: tR=0.38 min; [M+H]+=200.96.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-bromo-thiazol-2-yl)-methanol (695 mg, 3.58 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.67 mL, 4.74 mmol) followed by DMAP (44 mg, 0.36 mmol) and Ms-Cl (0.36 mL, 4.65 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromothiazol-2-yl)methyl methanesulfonate as a brown oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (257 mg, 3.91 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-(azidomethyl)-4-bromothiazole as a yellow oil. LC-MS-conditions 01: tR=0.83 min.
To a solution of the crude azide in THF (12 mL) were added polymer supported Ph3P (5.16 mmol) and water (4 mL). The reaction mixture was stirred at 60° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3, the layers separated and the aq. layer extracted with EA. The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 02: tR=0.24 min; [M+H]+=192.85.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of alpha-methylcinnamic acid (19.0 g, 116 mmol) and Et3N (17.1 mL, 122 mmol) in dry THF (500 mL) was treated with ethyl chloroformate (11.4 mL, 117 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min then aq. NH3 (250 mL) in THF (150 mL) was added. The reaction mixture was vigorously stirred at 0° C. for 30 min and at rt for 1 h30. The layers were then separated, the aq. layer extracted with CH2Cl2 (2×) and the combined organic extracts were concentrated under reduced pressure. The residue was partitioned between water and CH2Cl2, the layers separated and the aq. layer extracted with CH2Cl2 (2×). The combined org. extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound as a white solid. LC-MS-conditions 01: tR=0.75 min; [M+H]+=162.07.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of (E)-2-methyl-3-phenylacrylamide (29.4 g, 0.18 mol) and NaHCO3 (68.7 g, 0.82 mol) in THF (500 mL) was treated with 3-bromo-2-oxo-propionic acid ethyl ester (35.6 mL, 0.24 mol) and the reaction mixture was heated at reflux for 20 h. 3-Bromo-2-oxo-propionic acid ethyl ester (10.0 mL, 0.68 mol) was added again and the reaction mixture was stirred at reflux for 10 h. The reaction mixture was then filtered over celite and the solvents were evaporated under reduced pressure. The residue was dissolved in THF (500 mL) and treated at 0° C., dropwise, with trifluoroacetic anhydride (78.0 mL, 0.55 mol). The reaction mixture was then stirred at rt overnight. Sat. aq. Na2CO3 was added and the mixture was extracted with EA (4×), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (0:1->1:9 EA-Hept) gave the title compound as a brown oil. TLC:rf (1:9 EA-Hept)=0.13. LC-MS-conditions 01: tR=1.02 min; [M+H]+=257.97.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of NaIO4 (23 g, 108 mmol) in water (150 mL) was slowly added to a vigorously stirred suspension of silica gel (110 g) in acetone (500 mL). The mixture was then concentrated under reduced pressure and the lumpy solid slurried in CH2Cl2 and the solvent was evaporated under reduced pressure. CH2Cl2 (500 mL) was added and the reaction mixture was treated at rt with (E)-2-(1-phenylprop-1-en-2-yl)oxazole-4-carboxylic acid ethyl ester (8.3 g, 32 mmol) and RuCl3 hydrate (1.1 g, 2 mmol). The reaction mixture was stirred at rt in the dark for 60 min, filtered and concentrated under reduced pressure. Purification of the residue by FC (1:0 to 1:5 petroleum ether-Et2O) gave the title compound as a pale yellow solid. TLC:rf (1:1 EA-Hept)=0.52. LC-MS-conditions 01: tR=0.70 min; [M+H]+=183.99.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-acetyl-oxazole-4-carboxylic acid ethyl ester (7.0 g, 38.0 mmol) in ethylene glycol (42.7 mL) was treated with trimethylorthoformate (10.5 mL, 96.0 mmol) followed by LiBF4 (0.73 g, 8.0 mmol). The reaction mixture was heated at 95° C. until completion of the reaction. Aq. 0.5 M Na2CO3 was added and the mixture was extracted with Et2O. The org. layer was washed with aq. 0.5 M Na2CO3 (2×), dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 01: tR=0.76 min; [M+H]+=227.99.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of 2-(2-methyl-[1,3]dioxolan-2-yl)-oxazole-4-carboxylic acid ethyl ester (5.05 g, 22.2 mmol) in dry THF (80 mL) was added an ice-cold solution of LiAlH4 (1.0 M in THF, 24.7 mL, 24.7 mmol). The reaction mixture was stirred at 0° C. until completion of the reaction. Water (2.0 mL) was carefully added at 0° C. followed by aq. 1 M NaOH (2.0 mL) and water (2.0 mL). The resulting suspension was stirred at rt for 1 h, filtered (+EA) and the filtrate concentrated under reduced pressure to give the title compound as a yellow oil. TLC: rf (EA)=0.18. LC-MS-conditions 05c: tR=0.22 min; [M+H]+=186.30.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(2-methyl-[1,3]dioxolan-2-yl)oxazol-4-yl)methanol (235 mg, 1.27 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.24 mL, 1.68 mmol) followed by DMAP (16 mg, 0.13 mmol) and Ms-Cl (0.13 mL, 1.65 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (2-(2-methyl-[1,3]dioxolan-2-yl)oxazol-4-yl)methyl methanesulfonate as a brown oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 4-(azidomethyl)-2-(2-methyl-1,3-dioxolan-2-yl)oxazole as a brown oil. To a solution of the crude azide in THF (6 mL) were added polymer-supported Ph3P (1.2 eq.) and water (2 mL). The reaction mixture was stirred at 60° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was concentrated under reduced pressure, the residue triturated in EtOH and the solid filtered off. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 01: tR=0.31 min; [M+H]+=185.01.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-bromo-thiazol-5-yl)-methanol (621 mg, 3.20 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.60 mL, 4.23 mmol) followed by DMAP (39 mg, 0.32 mmol) and Ms-Cl (0.33 mL, 4.15 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (2-bromothiazol-5-yl)methyl methanesulfonate as a colorless oil. The crude material was dissolved in dry DMF (15 mL) and treated with NaN3 (223 mg, 3.40 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer washed with water (2×), dried over MgSO4, filtered and concentrated under reduced pressure to give crude 5-(azidomethyl)-2-bromothiazole as a yellow oil. To a solution of the crude azide in THF (12 mL) were added polymer-supported Ph3P (1.2 eq.) and water (4 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. 1N NaOH/aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 01: tR=0.16 min; [M+CH3CN+H]+=233.91.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 3-phenyl-acrylamide (10.31 g, 67.95 mmol) and NaHCO3 (28.47 g, 339.73 mmol) in THF (260 mL) was treated with 3-bromo-2-oxo-propionic acid ethyl ester (13.04 mL, 88.33 mmol) and the reaction mixture was heated at reflux for 15 h. 3-Bromo-2-oxo-propionic acid ethyl ester (13.04 mL, 88.33 mmol) was added again and the reaction mixture was stirred at reflux for 15 h. The reaction mixture was then filtered over celite and the solvents were evaporated under reduced pressure. The residue was dissolved in THF (30 mL) and treated at 0° C., dropwise, with trifluoroacetic anhydride (30.0 mL, 215.83 mmol). The reaction mixture was then stirred at rt overnight. Sat. aq. Na2CO3 was added and the mixture was extracted with EA (3×150 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1:9 EA-Hept) gave the title compound as a yellow solid. TLC:rf (1:9 EA-Hept)=0.1. LC-MS-conditions 02: tR=1.01 min; [M+H]+=244.48.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of NaIO4 (3.21 g, 15.00 mmol) in water (26.0) mL was slowly added to a vigorously stirred suspension of silica gel (15.0 g) in acetone (60.0 mL). The mixture was then concentrated under reduced pressure and the lumpy solid slurried in CH2Cl2 and the solvent was evaporated under reduced pressure. CH2Cl2 (40.0 mL) was added and the reaction mixture was treated at rt with (E)-2-styryl-oxazole-4-carboxylic acid ethyl ester (1.22 g, 5.00 mmol) and RuCl3 hydrate (82 mg, 0.15 mmol). The reaction mixture was stirred at rt in the dark for 30 min, filtered and concentrated under reduced pressure. Purification of the residue by FC (1:9 to 1:2 EA-Hept) gave the title compound as a yellow solid. TLC:rf (3:2 EA-Hept)=0.21. LC-MS-conditions 02: tR=0.51 min; [M+H2O+H]+=188.50.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 2-formyl-oxazole-4-carboxylic acid ethyl ester (272 mg, 1.61 mmol) was dissolved in EtOH (5.0 mL). NaBH4 (112 mg, 2.84 mmol) was added portionwise at 0° C. and the reaction mixture stirred at 0° C. for 1 h. Sat. aq. NH4Cl was added and the mixture extracted with EA (5×10 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (EA)=0.50. LC-MS-conditions 02: tR=0.58 min; [M+H]+=172.03.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 2-hydroxymethyl-oxazole-4-carboxylic acid ethyl ester (275 mg, 1.61 mmol) was dissolved in dry CH2Cl2 (5.0 mL). tert-Butyldimethylsilyl chloride (510 mg, 3.22 mmol) was added at rt followed by imidazole (221 mg, 3.22 mmol). The reaction mixture was stirred at rt for 30 min. Water was added, the layers were separated and the org. layer was dried over Na2SO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (1:20 to 1:9 EA-Hept) gave the title compound as a colorless oil. TLC:rf (9:1 hept-EA)=0.15. LC-MS-conditions 02: tR=1.10 min; [M+H]+=286.38.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazole-4-carboxylic acid ethyl ester (283 mg, 0.99 mmol) in CH2Cl2 (5.0 mL) was treated at −78° C. with DiBAL (1.85 mL of a 1M sol in toluene, 1.85 mmol) and the reaction mixture was stirred for 1 h at −78° C. MeOH (70 μL) and H2O (100 μL) were added and the reaction mixture was allowed to warm to rt. The reaction mixture was filtered, and the solvent removed under reduced pressure to give the title compound as a colorless oil. TLC:rf (1:1 hept-EA)=0.61. LC-MS-conditions 02: tR=1.03 min; [M+H2O+H]+=260.50.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazole-4-carbaldehyde (223 mg, 0.92 mmol) in CH2Cl2 (8.0 mL) was treated at 0° C. with trimethylaluminum (2.50 mL of a 2M solution in toluene, 5.00 mmol). The reaction mixture was then stirred at 0° C. for 45 min. Sat. aq. NH4Cl was then added and the aq. layer was extracted twice with CH2Cl2 and twice with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a colorless oil. TLC:rf (1:1 hept-EA)=0.32. LC-MS-conditions 02: tR=0.97 min, [M+H]+=258.30.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-yl]-ethanol (193 mg, 0.75 mmol) in AcCN (5.0 mL) was treated at rt with MnO2 (362 mg, 3.75 mmol). The reaction mixture was stirred for 16 h at rt before being filtered through Celite. The solvent was removed under reduced pressure to give the title compound as a white solid. TLC:rf (1:1 hept-EA)=0.69. LC-MS-conditions 02: tR=1.04 min, [M+H]+=255.84.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-yl]-ethanone (3.82 g, 14.96 mmol) in ethylene glycol (16 mL) was treated with trimethylorthoformate (3.35 mL, 30.51 mmol) followed by LiBF4 (0.29 g, 2.99 mmol). The reaction mixture was heated at 95° C. until completion of the reaction. Aq. 0.5 M Na2CO3 was added and the mixture was extracted with Et2O. The org. layer was washed with aq. 0.5 M Na2CO3 (2×), dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a brown oil. LC-MS-conditions 01: tR=1.03 min; [M+H]+=300.08.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-{[(tert-butyldimethylsilyl)oxy]methyl}-4-(2-methyl-[1,3]dioxolan-2-yl)oxazole (3.50 g, 11.69 mmol) in dry THF (70 mL) was treated at 0° C. with TBAF (15.2 mL of a 1M solution in THF, 15.20 mmol). The reaction mixture was stirred at 0° C. for 1 h. Sat. aq. NH4Cl was added, the layers separated and the aq. layer extracted with EA. The combined org. extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (2:3 to 1:0 EA-Hept) gave the title compound as a pale yellow oil. TLC: rf (EA)=0.20. LC-MS-conditions 01: tR=0.45 min, [M+H]+=186.00.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-(2-methyl-[1,3]dioxolan-2-yl)-oxazol-2-yl)-methanol (230 mg, 1.24 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.23 mL, 1.64 mmol) followed by DMAP (15 mg, 0.12 mmol) and Ms-Cl (0.13 mL, 1.61 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-(2-methyl-[1,3]dioxolan-2-yl)oxazol-2-yl)methyl methanesulfonate as a colorless oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-(azidomethyl)-4-(2-methyl-[1,3]dioxolan-2-yl)oxazole as a colorless oil. To a solution of the crude azide in THF (9 mL) were added polymer-supported Ph3P (1.4 eq.) and water (3 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was concentrated under reduced pressure, the residue triturated in EtOH and the solid filtered off. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 01: tR=0.22 min; [M+H]+=185.00.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of amino-thioxo-acetic acid ethyl ester (7.29 g. 54.74 mmol) in toluene (58 mL) was treated with 1,3-dichloroacetone (8.41 g, 62.95 mmol). The resulting mixture was stirred at reflux for 2 h. EA (60 mL) was added and the org. layer was washed with sat. aq. NaHCO3, brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (70:30 hept-EA) gave the title compound as an orange oil. TLC:rf (4:1 hept-EA)=0.26. LC-MS-conditions 02: tR=0.89 min; [M+H]+=206.45.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-chloromethyl-thiazole-2-carboxylic acid ethyl ester (8.51 g, 41.38 mmol) in THF (413 mL) was treated at −78° C. with DiBAL (124 mL of a 1M sol in THF, 124 mmol) and the reaction mixture was stirred for 1 h at −78° C. The mixture was then allowed to warm up to rt and poured into a Rochelle's salt solution. After stirring for 1 h, the layers were separated and the aq. layer extracted with EA. The combined org. extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by FC (hept-EA) gave the title compound as a yellow oil. TLC:rf (1:1 hept-EA)=0.29. LC-MS-conditions 02: tR=0.59 min; [M+H]+=164.08.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-chloromethyl-thiazol-2-yl)-methanol (4.20 g, 25.67 mmol) in CH3CN (257 mL) was treated at rt with MnO2 (18.60 g, 192.55 mmol). The reaction mixture was stirred at rt until completion of the reaction, and then filtered through Celite. The solvent was removed under reduced pressure to give the title compound as a pale yellow oil after purification by FC (hept-EA 4:1). TLC:rf (4:1 hept-EA)=0.37. LC-MS-conditions 02: tR=0.77 min, [M+H2O+H]+=180.56.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-chloromethyl-thiazol-2-yl)-carbaldehyde (2.00 g, 12.37 mmol) in CH2Cl2 (124 mL) was treated at 0° C. with trimethylaluminum (62 mL of a 1M solution in heptane, 62.00 mmol). The reaction mixture was then stirred at 0° C. for 45 min. Sat. aq. NH4Cl and aq. 1N HCl were then added and the aq. layer was extracted twice with CH2Cl2. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.66 min, [M+H]+=178.54.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(4-chloromethyl-thiazol-2-yl)-ethanol (2.19 g, 12.31 mmol) in CH3CN (122 mL) was treated at rt with MnO2 (5.94 g, 61.52 mmol). The reaction mixture was stirred at rt until completion of the reaction, and then filtered through Celite. The solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.84 min.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(4-chloromethyl-thiazol-2-yl)-ethanone (1.08 g, 6.13 mmol) in dry DMF (21 mL) and treated with NaN3 (1.20 g, 18.39 mmol) at 65° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(4-(azidomethyl)-thiazol-2-yl)-ethanone as a yellow oil. To a solution of the crude azide (200 mg, 1.10 mmol) in THF (6 mL) were added polymer-supported Ph3P (2.0 eq.) and water (2 mL). The reaction mixture was stirred at 60° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The org. layer was dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a brown oil after purification by FC (CH2Cl2-MeOH-Et3N). LC-MS-conditions 01: tR=0.26 min; [M+H]+=157.04.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 3-bromo-acetophenone (2.11 g, 10.60 mmol) in ethylene glycol (12 mL) was treated with trimethylorthoformate (2.3 mL, 21.02 mmol) followed by LiBF4 (204 mg, 2.13 mmol). The reaction mixture was heated at 95° C. for 18 h. Sat. aq. Na2CO3 was added and the mixture was extracted twice with ether and the combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 hept-EA) gave the title compound as a pale yellow oil. TLC:rf (9:1 hept-EA)=0.41. LC-MS-conditions 02: tR=1.01 min.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-(3-bromo-phenyl)-2-methyl-[1,3]dioxolane (2.37 g, 9.74 mmol) in THF (20.0 mL) at −78° C. was added dropwise n-BuLi (4 mL of a 2.5M solution in hexane, 10.00 mmol). The reaction mixture was then stirred for 30 min at −78° C. before DMF (1.0 mL, 12.92 mmol) was added dropwise. The reaction mixture was allowed to warm to rt over 1 h. Sat. aq. NH4Cl was added and the mixture was extracted three times with Et2O. The combined org. extracts were dried over NaSO4, filtered, and the solvent was removed under reduced pressure to give the crude title compound as a pale yellow oil. LC-MS-conditions 02: tR=0.87 min.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a ice-cold solution of 3-(2-methyl-[1,3]dioxolan-2-yl)benzaldehyde (1.84 g, 9.59 mmol) in MeOH (20 mL) was added NaBH4 (456 mg, 12.05 mmol in four portions). The reaction mixture was then stirred for 1 h at 0° C. Water was added and the mixture was extracted twice with EA. The combined org. extracts were washed with brine, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a pale yellow oil. TLC:rf (4:1 hept-EA)=0.12. LC-MS-conditions 02: tR=0.74 min.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [3-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-methanol (1.68 g, 8.65 mmol) in dry CH2Cl2 (20 mL) was treated at 0° C. with Et3N (1.60 mL, 11.38 mmol) followed by DMAP (109 mg, 0.88 mmol) and Ms-Cl (0.80 mL, 10.13 mmol). After stirring at 0° C. for 0.5 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude residue was purified by FC (hept-EA 9:1 to 0:1) to give pure (3-(2-methyl-[1,3]dioxolan-2-yl)-phenyl)methyl methanesulfonate as a white solid. Part of this material (300 mg, 1.10 mmol) was dissolved in dry DMF (5 mL) and treated with NaN3 (220 mg, 3.35 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 3-(azidomethyl)-(2-methyl-[1,3]dioxolan-2-yl)benzene as a yellow oil. LC-MS-conditions 02: tR=0.99 min.
A mixture of the crude azide (194 mg, 0.88 mmol) in MeOH (5 mL) was hydrogenated in the presence of Pd/C (10%) at rt until completion of the reaction. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a pale yellow solid. LC-MS-conditions 02: tR=0.59 min; [M+H]+=194.64.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-2,6-difluorobenzyl alcohol (1.00 g, 4.48 mmol) in dry CH2Cl2 (20 mL) was treated at 0° C. with Et3N (0.81 mL, 5.79 mmol) followed by DMAP (55 mg, 0.45 mmol) and Ms-Cl (0.37 mL, 4.71 mmol). After stirring at 0° C. for 0.5 h and at rt for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromo-2,6-difluorophenyl)methyl methanesulfonate as a yellow oil. This material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(azidomethyl)-4-bromo-2,6-difluorobenzene as a yellow oil. LC-MS-conditions 01: tR=1.00 min.
To a mixture of the crude azide (330 mg, 1.33 mmol) in THF (12 mL) were added polymer-supported Ph3P (2.0 eq.) and water (2 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow solid. LC-MS-conditions 02: tR=0.54 min; [M+CH3CN+H]+=263.45.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-3-fluorobenzoic acid (250 mg, 1.14 mmol) in dry THF (5 mL) was treated at 0° C. with Et3N (0.16 mL, 1.14 mmol) and ethyl chloroformate (0.11 mL, 1.14 mmol). The reaction mixture was stirred at 0° C. for 15 min then aq. NH3 (3 mL) was added. The reaction mixture was vigorously stirred at 0° C. for 30 min and at rt for 2 h and then concentrated under reduced pressure. The residue was partitioned between water and CH2Cl2, the layers separated and the aq. layer extracted with CH2Cl2 (2×). The combined org. extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by FC (EA-MeOH 1:0 to 10:1) and the corresponding carboxamide obtained as a white solid. TLC:rf (9:1 EA-MeOH)=0.40. LC-MS-conditions 01: tR=0.73 min; [M+H]+=217.83.
Part of this material (150 mg, 0.69 mmol) was dissolved in dry THF (5 mL) and treated with BH3.Me2S complex (1.0 M in THF, 1.6 mL, 1.60 mmol) at 0° C. The reaction mixture was then warmed to 50° C. and stirred at this temperature until completion of the reaction. The mixture was cooled to 0° C. and water was added followed by EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a white solid. LC-MS-conditions 07: tR=0.33 min; [M+CH3CN+H]+=245.12.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of lithium diisopropylamide (11.25 mmol) in dry THF (8 mL) was added a mixture of 1,3-difluorobenzene (600 mg, 5.26 mmol) and Me3SiCl (1.48 mL, 11.57 mmol) at −78° C. After stirring at −78° C. for 75 min, the reaction was quenched by the addition of aq. 1M H2SO4. The mixture was warmed to rt, diluted with TBME and saturated with solid NaCl. The layers were separated and the aq. layer extracted with TBME. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (2,3-difluoro-1,4-phenylene)-bis(trimethylsilane) as a white solid. This material (1.33 g, 5.15 mmol) was treated with bromine (1.06 mL, 20.58 mmol) at 0° C. The reaction mixture was then warmed to 58° C. and stirred at this temperature until completion of the reaction. The reaction mixture was then cooled down to 0° C. and an ice-cold sat. NaHCO3 solution was carefully added. The mixture was then extracted with TBME (2×) and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give 1,4-dibromo-2,3-difluorobenzene as a colorless oil after distillation (0.05 mbar, 90° C.). LC-MS-conditions 07: tR=0.93 min.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1,4-dibromo-2,3-difluorobenzene (490 mg, 1.80 mmol) in dry Et2O (6 mL) was added to a n-BuLi (0.72 mL of a 2.5M solution in hexanes, 1.80 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 2 h before solid CO2 was added. The reaction mixture was stirred at −78° C. for 10 min and then allowed to warm up to rt. The mixture was then diluted with EA and aq. 1N HCl was added. The layers separated and the org. layer dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the crude carboxylic acid as a pale yellow solid. The crude material (360 mg, 1.52 mmol) was dissolved in dry THF (7 mL) and treated with BH3.Me2S complex (1.0 M in THF, 3.0 mL, 3.00 mmol) at 0° C. The reaction mixture was then warmed to 50° C. and stirred at this temperature until completion of the reaction. The mixture was cooled to 0° C. and water was added followed by EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA 9:1 to 2:1) to give the title compound as a colorless oil. TLC:rf (1:1 EA-hept)=0.50.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-2,3-difluorobenzyl alcohol (175 mg, 0.70 mmol) in dry CH2Cl2 (2 mL) was treated at 0° C. with Et3N (0.14 mL, 1.01 mmol) followed by DMAP (10 mg, 0.08 mmol) and Ms-Cl (0.06 mL, 0.82 mmol). After stirring at 0° C. for 0.5 h and at rt for 1 h, the reaction was quenched with water (2 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromo-2,3-difluorophenyl)methyl methanesulfonate as a yellow oil. This material was dissolved in dry DMF (3 mL) and treated with NaN3 (46 mg, 0.71 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(azidomethyl)-4-bromo-2,3-difluorobenzene as a colorless oil. LC-MS-conditions 07: tR=0.89 min.
To a mixture of the crude azide (164 mg, 0.60 mmol) in THF (3 mL) were added polymer-supported Ph3P (2.0 eq.) and water (1 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.42 min; [M+CH3CN+H]+=263.15.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-3,5-difluoroiodobenzene (790 mg, 2.48 mmol) in dry Et2O (12 mL) was added to a n-BuLi (0.98 mL of a 2.5M solution in hexanes, 2.45 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 2 h before solid CO2 was added. The reaction mixture was stirred at −78° C. for 10 min and then allowed to warm up to rt. The mixture was then diluted with EA and aq. 1N HCl was added. The layers separated and the org. layer dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the crude carboxylic acid as a pale yellow solid. The crude material (270 mg, 1.14 mmol) was dissolved in dry THF (6 mL) and treated with BH3.Me2S complex (1.0 M in THF, 2.3 mL, 2.30 mmol) at 0° C. The reaction mixture was then warmed to 50° C. and stirred at this temperature until completion of the reaction. The mixture was cooled to 0° C. and water was added followed by EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA 9:1 to 2:1) to give the title compound as a white solid. TLC:rf (1:1 EA-hept)=0.53.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-3,5-difluorobenzyl alcohol (100 mg, 0.45 mmol) in dry CH2Cl2 (3 mL) was treated at 0° C. with Et3N (0.081 mL, 0.58 mmol) followed by DMAP (5 mg, 0.045 mmol) and Ms-Cl (0.037 mL, 0.47 mmol). After stirring at 0° C. for 0.5 h and at rt for 0.5 h, the reaction was quenched with water (2 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromo-3,5-difluorophenyl)methyl methanesulfonate as a yellow oil. This material was dissolved in dry DMF (3 mL) and treated with NaN3 (29 mg, 0.45 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(azidomethyl)-4-bromo-3,5-difluorobenzene as a yellow oil. LC-MS-conditions 07: tR=0.90 min.
To a mixture of the crude azide (70 mg, 0.28 mmol) in THF (4 mL) were added polymer-supported Ph3P (3.0 eq.) and water (1 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.37 min; [M+CH3CN+H]+=263.15.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1,4-dibromo-2,5-difluorobenzene (600 mg, 2.21 mmol) in dry Et2O (8 mL) was added to a n-BuLi (0.88 mL of a 2.5M solution in hexanes, 2.20 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 2 h before solid CO2 was added. The reaction mixture was stirred at −78° C. for 10 min and then allowed to warm up to rt. The mixture was then diluted with EA and aq. 1N HCl was added. The layers separated and the org. layer dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the crude carboxylic acid as a pale yellow solid. The crude material (530 mg, 2.24 mmol) was dissolved in dry THF (20 mL) and treated with BH3.Me2S complex (1.0 M in THF, 4.5 mL, 4.50 mmol) at 0° C. The reaction mixture was then warmed to 50° C. and stirred at this temperature until completion of the reaction. The mixture was cooled to 0° C. and water was added followed by EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA 3:1 to 1:1) to give the title compound as a white solid. TLC:rf (1:1 EA-hept)=0.53.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-2,5-difluorobenzyl alcohol (160 mg, 0.72 mmol) in dry CH2Cl2 (4 mL) was treated at 0° C. with Et3N (0.13 mL, 0.93 mmol) followed by DMAP (9 mg, 0.07 mmol) and Ms-Cl (0.06 mL, 0.75 mmol). After stirring at 0° C. for 0.5 h and at rt for 1 h, the reaction was quenched with water (3 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromo-2,5-difluorophenyl)methyl methanesulfonate as a yellow oil. This material was dissolved in dry DMF (3 mL) and treated with NaN3 (51 mg, 0.78 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(azidomethyl)-4-bromo-2,5-difluorobenzene as a yellow oil. LC-MS-conditions 07: tR=0.89 min.
To a mixture of the crude azide (110 mg, 0.44 mmol) in THF (3 mL) were added polymer-supported Ph3P (3.0 eq.) and water (1.5 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.40 min; [M+CH3CN+H]+=263.14.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 3-amino-5-fluoropyridine (900 mg, 8.03 mmol) in dry DMF (13 mL) was treated at 0° C. with N-bromo-succinimide (1.43 g, 8.03 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then partitioned between Et2O and water. The layers were separated and the org. layer successively washed with water, sat. aq. NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA 9:1 to 1:1) and the title compound obtained as an orange solid. LC-MS-conditions 07: tR=0.52 min; [M+H]+=191.30.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of trimethylene imine (300 mg, 5.25 mmol) and DBU (0.79 mL, 5.23 mmol) in dry Et2O (4 mL) was added 4-bromobutyronitrile (0.54 mL, 5.27 mmol) at 0° C. The reaction mixture was stirred at rt until completion of the reaction. The mixture was filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (4 mL) and treated with LiALH4 (230 mg, 6.06 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Aq. 1N NaOH (2 mL) was then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 4-(azetidin-1-yl)butan-1-amine as a pale yellow oil. GC-MS-conditions 01: tR=1.35 min; [M+H]+=129.00.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-(2-aminoethoxy)ethanol (536 mg, 5.00 mmol) in THF (3 mL) was added aq. 2M NaOH (2.6 mL, 5.20 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min and a solution of di-tert-butyl dicarbonate (1.16 g, 5.20 mmol) in THF (3 mL) was then added dropwise. The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was diluted with CH2Cl2, filtered and the layers separated. The organic layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. The crude alcohol was redissolved in dry CH2Cl2 (20 mL) and treated with triphenylphoshine on polystyrene (5.63 mmol) and imidazole (190 mg, 2.76 mmol). To this mixture cooled to 0° C. was added iodine (808 mg, 3.15 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was then filtered, CH2Cl2 removed under reduced pressure. The residue was redissolved in EA, successively washed with 10% aq. Na2SO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude iodide was redissolved in CH3CN (15 mL) and treated with pyrrolidine (0.17 mL, 1.99 mmol) and K2CO3 (465 mg, 3.36 mmol). The reaction mixture was stirred at rt until completion of the reaction, filtered and concentrated under reduced pressure. The amine was purified by FC (hept-EA-acetone, 1:0:0->0:0:1) and then the Boc group was removed by treatment with HCl (4.0 M in dioxane, 10 eq.) in dry CH2Cl2 (3 mL). The title compound was obtained after trituration in hot EA/acetone/MeOH as a beige solid. LC-MS-conditions 01: tR=0.13 min; [M+H]+=159.11.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of (3R,6S)-6-hydroxymethyl-tetrahydro-2H-pyran-3-yl carbamic acid tert-butyl ester (328 mg, 1.40 mmol, H. S. Overkleeft et al. Eur. J. Org. Chem. 2003, 2418), triphenylphoshine on polystyrene (6.16 mmol) and imidazole (203 mg, 2.95 mmol) in dry CH2Cl2 (14 mL) was added iodine (891 mg, 3.48 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was then filtered, CH2Cl2 removed under reduced pressure. The residue was redissolved in EA, successively washed with 10% aq. Na2SO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by FC, the iodide was redissolved in CH3CN (15 mL) and treated with pyrrolidine (1.13 mL, 13.57 mmol) and K2CO3 (750 mg, 5.43 mmol). The reaction mixture was stirred at 85° C. until completion of the reaction, filtered and concentrated under reduced pressure. The amine was purified by FC (hept-EA-acetone, 1:0:0->0:0:1) and then the Boc group was removed by treatment with HCl (4.0 M in dioxane, 9 eq.) in dry CH2Cl2 (2 mL). The title compound was obtained after trituration in hot EA/acetone/MeOH as an off-white solid. LC-MS-conditions 01: tR=0.15 min; [M+H]+=185.06.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 1-acetylpiperazine (256 mg, 2.00 mmol) and DBU (0.30 mL, 2.00 mmol) in dry Et2O (2 mL) was added 4-bromobutyronitrile (0.21 mL, 2.00 mmol) at 0° C. The reaction mixture was stirred at rt until completion of the reaction. The mixture was filtered and concentrated under reduced pressure. A 0.087 mol/L solution of the crude nitrile in EtOH (10 mL) was hydrogenated at 50° C. using the H-Cube® (1 mL/min) with a Raney Nickel cartridge (30 mm) under 50 bar until completion of the reaction. The solution was then concentrated under reduced pressure to give crude 1-(4-(4-aminobutyl)piperazin-1-yl)ethanone as a colorless oil. GC-MS-conditions 01: tR=2.94 min; [M+H]+=200.40.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of cis-4-benzyloxycarbonylaminocyclohexanecarboxylic acid (417 mg, 1.50 mmol) in THF (15 mL) was added BH3.Me2S complex (2.0 M in THF, 1.5 mL, 3.00 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h30. More BH3.Me2S complex (2.0 M in THF, 1.0 mL, 2.00 mmol) was added at 0° C. followed by NaBH4 (12 mg, 0.30 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. MeOH was carefully added to quench the reaction, the volatiles were removed under reduced pressure and the residue co-evaporated with MeOH (2×). Purification by FC (hept-EA, 1:0->3:2) gave pure cis-4-benzyloxycarbonylaminocyclohexane-methanol as a colorless oil. TLC:rf (1:2 hept-EA)=0.45. LC-MS-conditions 01: tR=0.82 min; [M+H]+=264.07.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of cis-4-benzyloxycarbonylaminocyclohexane-methanol (267 mg, 1.01 mmol), triphenylphoshine on polystyrene (3.20 mmol) and imidazole (97 mg, 1.42 mmol) in dry CH2Cl2 (40 mL) was added iodine (416 mg, 1.62 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was then filtered, successively washed with 10% aq. Na2SO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude iodide was redissolved in CH3CN (15 mL) and treated with pyrrolidine (0.32 mL, 3.86 mmol) and K2CO3 (533 mg, 3.86 mmol). The reaction mixture was refluxed until completion of the reaction, filtered and concentrated under reduced pressure. The amine was purified by FC (hept-EA, 1:0->1:1) and then the Cbz group was removed by treatment with 10% Pd/C (116 mg) in EtOH (20 mL) under a H2 atmosphere. The title compound was obtained as a white solid. LC-MS-conditions 04: tR=0.99 min; [M+H]+=183.35.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of trans-4-benzyloxycarbonylaminocyclohexanecarboxylic acid (417 mg, 1.50 mmol) in THF (15 mL) was added BH3.Me2S complex (2.0 M in THF, 1.5 mL, 3.00 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h30. More BH3.Me2S complex (2.0 M in THF, 1.0 mL, 2.00 mmol) was added at 0° C. followed by NaBH4 (12 mg, 0.30 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. MeOH was carefully added to quench the reaction, the volatiles were removed under reduced pressure and the residue co-evaporated with MeOH (2×). Purification by FC (hept-EA, 1:0->3:2) gave pure trans-4-benzyloxycarbonylaminocyclohexane-methanol as a white solid. TLC:rf (1:2 hept-EA)=0.35. LC-MS-conditions 01: tR=0.82 min; [M+H]+=264.05.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of trans-4-benzyloxycarbonylaminocyclohexane-methanol (292 mg, 1.11 mmol), triphenylphoshine on polystyrene (3.52 mmol) and imidazole (107 mg, 1.55 mmol) in dry CH2Cl2 (40 mL) was added iodine (455 mg, 1.77 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was then filtered, successively washed with 10% aq. Na2SO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude iodide was redissolved in CH3CN (15 mL) and treated with pyrrolidine (0.34 mL, 4.09 mmol) and K2CO3 (566 mg, 4.09 mmol). The reaction mixture was refluxed until completion of the reaction, filtered and concentrated under reduced pressure. The amine was purified by FC (hept-EA, 1:0->1:1) and then the Cbz group was removed by treatment with 10% Pd/C (147 mg) in MeOH (10 mL) under a H2 atmosphere. The title compound was obtained as a colorless oil. LC-MS-conditions 07d: tR=0.97 min; [M+H]+=183.37.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (R)-3-fluoropyrrolidine hydrochloride (400 mg, 3.09 mmol) and 4-bromobutyronitrile (0.32 mL, 3.09 mmol) in dry CH3CN (16 mL) was added K2CO3 (2.35 g, 16.99 mmol) at rt followed by KI (51 mg, 0.31 mmol). The reaction mixture was stirred at rt for 15 h. The mixture was filtered and the filtrate partitioned between water and CH2Cl2. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (23 mL) and treated with LiALH4 (214 mg, 5.47 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Aq. 1N NaOH (7 mL) was then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude (R)-4-(3-fluoropyrrolidin-1-yl)butan-1-amine as a colorless oil. GC-MS-conditions 01: tR=1.71 min; [M+H]+=161.10.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (S)-3-fluoropyrrolidine hydrochloride (200 mg, 1.54 mmol) and 4-bromobutyronitrile (0.16 mL, 1.54 mmol) in dry CH3CN (8 mL) was added K2CO3 (1.17 g, 8.50 mmol) at rt followed by KI (26 mg, 0.15 mmol). The reaction mixture was stirred at rt for 15 h. The mixture was filtered and the filtrate partitioned between water and CH2Cl2. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (10 mL) and treated with LiALH4 (92 mg, 2.35 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Aq. 1N NaOH (3 mL) was then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude (S)-4-(3-fluoropyrrolidin-1-yl)butan-1-amine as a yellow oil. GC-MS-conditions 01: tR=1.70 min; [M+H]+=161.10.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 5-bromovaleronitrile (0.21 mL, 1.80 mmol), pyrrolidine (0.15 mL, 1.81 mmol), K2CO3 (498 mg, 3.60 mmol) and KI (60 mg, 0.36 mmol) in dry CH3CN (15 mL) was refluxed for 1 h. The mixture was filtered and concentrated under reduced pressure. A 0.05 mol/L solution of the crude nitrile (59 mg, 0.39 mmol) in EtOH (8 mL) was hydrogenated at rt using the H-Cube® (1 mL/min) with a Raney Nickel cartridge (30 mm) under 50 bar until completion of the reaction. The solution was then concentrated under reduced pressure to give crude 5-(pyrrolidin-1-yl)pentan-1-amine as a colorless oil. LC-MS-conditions 01: tR=0.16 min; [M+H]+=157.19.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2,5-dimethylpyrrolidine (250 mg, 2.34 mmol) and 4-bromobutyronitrile (0.24 mL, 2.34 mmol) in dry CH3CN (12 mL) was added K2CO3 (1.78 g, 12.89 mmol) at rt followed by KI (39 mg, 0.23 mmol). The reaction mixture was stirred at rt for 15 h. The mixture was filtered and the filtrate partitioned between water and CH2Cl2. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (19 mL) and treated with LiALH4 (176 mg, 4.50 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Aq. 1N NaOH (7 mL) was then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 4-(2,5-dimethylpyrrolidin-1-yl)butan-1-amine as a yellow oil. GC-MS-conditions 01: tR=1.75 and 1.83 min; [M+H]+=171.30.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 4-(tert-butoxycarbonyl-amino)butyric acid (1.00 g, 4.77 mmol) in dry CH3CN (24 mL) were added N,O-dimethyl-hydroxylamine hydrochloride (475 mg, 4.77 mmol), EDC.HCl (934 mg, 4.77 mmol), HOBt (658 mg, 4.77 mmol) and N-methylmorpholine (2.68 mL, 23.86 mmol) at rt. The reaction mixture was stirred at rt until completion of the reaction. The mixture was then concentrated under reduced pressure. The residue was redissolved in EA, successively washed with water, 10% aq. KHSO4, sat. aq. NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was dissolved in dry THF (20 mL) and treated with MeMgBr (3.0M solution in Et2O, 3.25 mL, 9.75 mmol) at 0° C. The reaction mixture was stirred at 0° C. until completion of the reaction. 10% Aq. KHSO4 was then carefully added, the layers separated and the aq. layer extracted with EA (3×). The combined org. extracts were successively washed with aq. sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA 3:2) to give the title compound as a colorless oil. TLC:rf (3:2 hept-EA)=0.38.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of pyrrolidine (79 mg, 1.11 mmol) in dry CH3CN (6 mL) was added tert-butyl (4-oxopentyl)carbamate (291 mg, 1.44 mmol) followed by Na(OAc)3BH (680 mg, 2.88 mmol) at rt. The reaction mixture was stirred at rt until completion of the reaction. Sat. aq. NaHCO3 was then added and the mixture extracted with EA (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC(CH2Cl2-MeOH—NH3) to give pure N-tert-butoxycarbonyl-4-(pyrrolidin-1-yl)pentan-1-amine as a colorless oil. LC-MS-conditions 05c: tR=0.53 min; [M+H]+=257.41. The title compound was obtained after Boc deprotection using 4N HCl in dioxane (10.0 eq.) in CH2Cl2 at rt as a colorless oil.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 4-amino-1-butene (2.00 g, 25.31 mmol) in dry CH2Cl2 (100 mL) were added di-tert-butyl dicarbonate (8.45 g, 37.96 mmol) and DIPEA (8.66 mL, 50.62 mmol) at 0° C. The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were washed with sat. aq. NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC(hept-EA) and 4-(N-tert-butoxycarbonyl-amino)-1-butene was obtained as a colorless oil, which was redissolved in dry CH2Cl2 (175 mL) and treated with m-chloroperbenzoic acid (1.4 eq.) at rt. The reaction mixture was stirred at rt until completion of the reaction. Aq. 1N NaOH was then added, the layers separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA 3:2) and the title compound obtained as a colorless oil. TLC:rf (3:2 hept-EA)=0.33.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of tert-butyl (2-(oxiran-2-yl)ethyl)carbamate (1.50 g, 8.01 mmol) in pyrrolidine (2 mL) was heated at 85° C. until completion of the reaction. The reaction mixture was evaporated to dryness to give a yellow oil. Part of this crude material (300 mg, 1.16 mmol) was dissolved in dry CH2Cl2 (34 mL) and treated with (diethylamino)sulphur trifluoride (0.18 mL, 1.37 mmol) at 0° C. The reaction mixture was stirred at 0° C. until completion of the reaction. Sat. aq. NaHCO3 was then added, the layers separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was then redissolved in dry CH2Cl2 (1 mL) and treated with 4N HCl in dioxane (1 mL) at rt. The reaction mixture was stirred at rt until completion of the reaction, and the solvents removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07b: tR=0.14 min; [M+H]+=161.18.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-(methoxymethyl)pyrrolidine (300 mg, 2.61 mmol) and 4-bromobutyronitrile (0.31 mL, 2.99 mmol) in dry CH3CN (13 mL) was added K2CO3 (1.51 g, 10.94 mmol) at rt followed by KI (43 mg, 0.26 mmol). The reaction mixture was stirred at rt for 15 h. The mixture was filtered and the filtrate partitioned between water and CH2Cl2. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (21 mL) and treated with LiALH4 (192 mg, 5.07 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Sat. aq. Rochelle's salt solution and EA were then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 4-(2-(methoxymethyl)pyrrolidin-1-yl)butan-1-amine as a pale yellow oil. GC-MS-conditions 01: tR=2.1 min; [M+H]+=187.20.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 3,3-difluoropyrrolidine hydrochloride (250 mg, 1.69 mmol) and 4-bromobutyronitrile (0.17 mL, 1.69 mmol) in dry CH3CN (9 mL) was added K2CO3 (1.28 g, 9.29 mmol) at rt followed by KI (28 mg, 0.17 mmol). The reaction mixture was stirred at rt for 15 h. The mixture was filtered and the filtrate partitioned between water and CH2Cl2. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (8 mL) and treated with LiALH4 (75 mg, 1.92 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Sat. aq. Rochelle's salt solution and EA were then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 4-(3,3-difluoropyrrolidin-1-yl)butan-1-amine as a colorless oil. GC-MS-conditions 01: tR=1.56 min; [M+H]+=179.10.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of trans-4-benzyloxycarbonylaminocyclohexane-methanol (110 mg, 0.42 mmol) in MeOH (5 mL) was hydrogenated in the presence of Pd/C (10%) at rt until completion of the reaction. The mixture was then filtered and concentrated under reduced pressure. The title compound was obtained as a light brown solid. LC-MS-conditions 07: tR=0.11 min; [M+H]+=130.24.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of cis-4-benzyloxycarbonylaminocyclohexane-methanol (235 mg, 0.89 mmol) in MeOH (5 mL) was hydrogenated in the presence of Pd/C (10%) at rt until completion of the reaction. The mixture was then filtered and concentrated under reduced pressure. The title compound was obtained as a colorless oil. LC-MS-conditions 07: tR=0.12 min; [M+H]+=130.26.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of cis-4-benzyloxycarbonylaminocyclohexane-methanol (1.53 g, 5.81 mmol), triphenylphoshine on polystyrene (17.43 mmol) and imidazole (559 mg, 8.13 mmol) in dry CH2Cl2 (150 mL) was added iodine (2.38 g, 9.30 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was then filtered, successively washed with 10% aq. Na2SO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude iodide (1.94 g, 5.20 mmol) was redissolved in DMF (15 mL) and treated with sodium azide (358 mg, 5.46 mmol). The reaction mixture was heated to 80° C. until completion of the reaction. The mixture was then diluted with EA, washed with brine (3×), dried over MgSO4, filtered and concentrated under reduced pressure. To a mixture of the crude azide (1.50 g, 5.20 mmol) in THF (27 mL) were added polymer-supported Ph3P (2.0 eq.) and water (9 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. 0.5M Na2CO3 and the layers separated. The aq. layer was extracted with EA (2×) and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give benzyl (cis-4-(aminomethyl)cyclohexyl)carbamate as a yellow oil. LC-MS-conditions 07b: tR=0.57 min; [M+H]+=263.46.
To a solution of the crude amine (467 mg, 1.78 mmol) in THF (4 mL) was added aq. 1M NaOH (1.85 mL, 1.85 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min and a solution of di-tert-butyl dicarbonate (412 mg, 1.85 mmol) in THF (3 mL) was then added dropwise. The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was diluted with CH2Cl2, filtered and the layers separated. The organic layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. The crude residue was purified by FC (hept-EA, 1:0->7:3) and then the Cbz group was removed by treatment with 10% Pd/C (150 mg) in EA/MeOH 1:1 (10 mL) under a H2 atmosphere. The title compound was obtained as a colorless oil. LC-MS-conditions 07b: tR=0.52 min; [M+H]+=229.46.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of trans-4-benzyloxycarbonylaminocyclohexane-methanol (1.32 g, 5.01 mmol), triphenylphoshine on polystyrene (15.04 mmol) and imidazole (483 mg, 7.02 mmol) in dry CH2Cl2 (150 mL) was added iodine (2.06 g, 8.02 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was then filtered, successively washed with 10% aq. Na2SO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude iodide (1.64 g, 4.39 mmol) was redissolved in DMF (15 mL) and treated with sodium azide (303 mg, 4.61 mmol). The reaction mixture was heated to 80° C. until completion of the reaction. The mixture was then diluted with EA, washed with brine (3×), dried over MgSO4, filtered and concentrated under reduced pressure. To a mixture of the crude azide (1.27 g, 4.40 mmol) in THF (21 mL) were added polymer-supported Ph3P (2.0 eq.) and water (7 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. 0.5M Na2CO3 and the layers separated. The aq. layer was extracted with EA (2×) and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give benzyl (trans-4-(aminomethyl)cyclohexyl)carbamate as a white solid. LC-MS-conditions 07b: tR=0.57 min; [M+H]+=263.46.
To a solution of the crude amine (466 mg, 1.78 mmol) in THF (4 mL) was added aq. 1M NaOH (1.85 mL, 1.85 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min and a solution of di-tert-butyl dicarbonate (412 mg, 1.85 mmol) in THF (3 mL) was then added dropwise. The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was diluted with CH2Cl2, filtered and the layers separated. The organic layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. The crude residue was purified by FC (hept-EA, 1:0->7:3) and then the Cbz group was removed by treatment with 10% Pd/C (120 mg) in EA/MeOH 1:1 (10 mL) under a H2 atmosphere. The title compound was obtained as a white solid. LC-MS-conditions 07b: tR=0.51 min; [M+H]+=229.47.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide (150 mg, 0.45 mmol) in dry CH2Cl2 (5 mL) were added HOBt (73 mg, 0.54 mmol), EDC.HCl (216 mg, 1.13 mmol), DMAP (14 mg, 0.11 mmol) and DIPEA (0.31 mL, 1.81 mmol). The reaction mixture was stirred at rt for 30 minutes, then a solution of 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-yl-methylamine (116 mg, 0.45 mmol) in dry CH2Cl2 (4 mL) was added. The reaction mixture was stirred at rt until reaction completion. Water was added, the layers separated, and the org. layer dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (9:1 CH2Cl2-MeOH+1% NH4OH) to give the title compound as a yellow oil. LC-MS-conditions 01: tR=0.88 min; [M+H]+=571.24.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-(5R*)-5-carboxylic acid (400 mg, 1.69 mmol) in dry CH2Cl2 (9 mL) were added EDC.HCl (828 mg, 4.23 mmol), DMAP (53 mg, 0.42 mmol) and DIPEA (1.45 mL, 8.46 mmol). The reaction mixture was stirred at rt for 30 minutes, then 2-amino-5-methyl-thiazole (197 mg, 1.69 mmol) was added. The reaction mixture was stirred at rt for 2 days. Water was added, the layers separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (1:1 hept-EA) to give the title compound as a white solid. TLC:rf (1:1 hept-EA)=0.37. LC-MS-conditions 02: tR=0.99 min; [M+H]+=333.41.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-(5R*)-5-carboxylic acid (2.50 g, 10.58 mmol) in dry CH2Cl2 (53 mL) were added EDC.HCl (5.17 g, 26.45 mmol), DMAP (330 mg, 2.64 mmol) and DIPEA (9.1 mL, 52.91 mmol). The reaction mixture was stirred at rt for 30 minutes, then 4-bromo-benzylamine hydrochloride (2.40 g, 10.58 mmol) was added. The reaction mixture was stirred at rt for 2 days. Water was added, the layers separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (3:2 hept-EA) to give the title compound as a yellow oil. TLC:rf (3:2 hept-EA)=0.45. LC-MS-conditions 02: tR=1.06 min; [M+H]+=404.00.
A mixture of (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (3.43 g, 8.48 mmol) in EtOH (85 mL) and 1N NaOH (85 mL) was stirred at rt until completion of the reaction. EtOH was removed under reduced pressure and the residue partitioned between 1N HCl and EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.94 min; [M+H]+=376.10.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-(5R*)-5-carboxylic acid (500 mg, 2.12 mmol) in dry CH2Cl2 (5 mL) were added a few drops of DMF and oxalyl chloride (0.20 mL, 2.33 mmol). The reaction mixture was stirred at rt for 30 minutes. To the solution of the resulting acyl chloride was added a solution of 2-amino-5-bromo-thiazole hydrobromide (851 mg, 3.17 mmol) and DIPEA (1.45 mL, 8.47 mmol) in dry CH2Cl2 (2.5 mL). The reaction mixture was stirred at rt for 2 h. 1N HCl was added, the layers separated, and the aq. layer extracted with EA (2×). The combined org. extracts were successively washed with aq. sat. Na2CO3, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (7:3 hept-EA) to give the title compound as a white foam. TLC:rf (7:3 hept-EA)=0.30. LC-MS-conditions 02: tR=1.05 min; [M+H]+=397.25.
A mixture of (5R*)—N5-(5-bromo-thiazol-2-yl)-(6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (1.13 g, 2.86 mmol) in EtOH (29 mL) and 1N NaOH (29 mL) was stirred at rt until completion of the reaction. EtOH was removed under reduced pressure and the residue partitioned between 1N HCl and EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a beige solid. LC-MS-conditions 02: tR=0.93 min; [M+H]+=369.21.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-(5R*)-5-carboxylic acid (970 mg, 4.11 mmol) in dry CH2Cl2 (15 mL) were added EDC.HCl (1.97 g, 10.26 mmol), DMAP (125 mg, 1.02 mmol) and DIPEA (2.81 mL, 16.42 mmol). The reaction mixture was stirred at rt for 30 minutes, then (4-(2-methyl-[1,3]dioxolan-2-yl)thiazol-2-yl)methanamine (822 mg, 4.11 mmol) in dry CH2Cl2 (15 mL) was added. The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated, and the org. layer dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (5:1->1:4 hept-EA) to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.93 min; [M+H]+=419.02.
A mixture of (5R*)—N5-(4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-yl-methyl)-(6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (1.50 g, 3.58 mmol) in EtOH (35 mL) and 1N NaOH (35 mL) was stirred at rt until completion of the reaction. EtOH was removed under reduced pressure and the residue partitioned between 2N HCl and EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude carboxylic acid as a yellow solid. Part of this crude material (800 mg, 2.05 mmol) was dissolved in THF (10 mL) and treated with aq. 1N HCl (6 mL) at rt. The reaction mixture was stirred at rt until completion of the reaction. Water was added and the product extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid. LC-MS-conditions 02: tR=0.77 min; [M+H]+=347.07.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-(5R*)-5-carboxylic acid (250 mg, 1.06 mmol) in dry CH2Cl2 (5 mL) were added EDC.HCl (517 mg, 2.64 mmol), DMAP (33 mg, 0.26 mmol) and DIPEA (0.91 mL, 5.29 mmol). The reaction mixture was stirred at rt for 30 minutes, then 2-amino-4-acetyl-thiazole hydrobromide (236 mg, 1.06 mmol) was added. The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA 1:1) to give the title compound as a pale pink solid. TLC:rf (1:1 hept-EA)=0.41. LC-MS-conditions 02: tR=0.97 min; [M+H]+=361.27.
A mixture of (5R*)—N5-(4-acetyl-thiazol-2-yl)-(6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (80 mg, 0.22 mmol) in EtOH (2.2 mL) and 1N NaOH (2.2 mL) was stirred at rt until completion of the reaction. EtOH was removed under reduced pressure and the residue partitioned between 2N HCl and EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as an off-white foam. LC-MS-conditions 02: tR=0.84 min; [M+H]+=333.29.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-(5R*)-5-carboxylic acid (300 mg, 1.27 mmol) in dry CH2Cl2 (6.5 mL) were added EDC.HCl (621 mg, 3.17 mmol), DMAP (40 mg, 0.32 mmol) and DIPEA (1.09 mL, 6.35 mmol). The reaction mixture was stirred at rt for 30 minutes, then 4-methyl-1,3-oxazol-2-amine (138 mg, 1.27 mmol) was added. The reaction mixture was stirred at rt for 36 h. Water was added, the layers separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (1:4 hept-EA) to give the title compound as a colorless oil. TLC:rf (1:4 hept-EA)=0.53. LC-MS-conditions 02: tR=0.88 min; [M+H]+=317.50.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-(5R*)-5-carboxylic acid (238 mg, 1.01 mmol) in dry CH2Cl2 (5 mL) were added EDC.HCl (493 mg, 2.52 mmol), DMAP (31 mg, 0.25 mmol) and DIPEA (0.86 mL, 5.04 mmol). The reaction mixture was stirred at rt for 30 minutes, then 2-amino-4,5-dimethyl-thiazole hydrochloride (169 mg, 1.01 mmol) was added. The reaction mixture was stirred at rt for 36 h. Water was added, the layers separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (3:2 hept-EA) to give the title compound as a colorless oil. TLC:rf (3:2 hept-EA)=0.25. LC-MS-conditions 02: tR=1.00 min; [M+H]+=347.51.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (E)-1,2-bis-[((1S)-1-ethoxycarbonyl)-ethoxy-carbonyl]-ethene (7.40 g, 22.7 mmol) in n-hexane (76 mL) was added spiro[2.4]hepta-4,6-diene (3.14 g, 34.0 mmol) at rt. The reaction mixture was stirred at this temperature overnight. The mixture was concentrated under reduced pressure and the crude residue purified by FC (hept/EA, 9:1). The title compound was obtained as a pale yellow oil. TLC:rf (9:1 hept-EA) =0.25. LC-MS-conditions 02: tR=1.12 min; [M+H]+=409.00. 1H NMR (400 MHz, CDCl3) δ 6.44 (dd, J=5.5, 3.0 Hz, 1 H), 6.32 (dd, J=5.5, 2.8 Hz, 1 H), 5.12 (q, J=7.1 Hz, 1 H), 5.06 (q, J=7.1 Hz, 1 H), 4.28-4.14 (m, 4 H), 3.76 (app. t, J=4.0 Hz, 1 H), 2.92 (d, J=4.8 Hz, 1 H), 2.86 (m, 1 H), 2.80 (m, 1 H), 1.55-1.47 (m, 6 H), 1.29 (t, J=7.3 Hz, 3 H), 1.29 (t, J=7.3 Hz, 3 H), 0.70 (m, 1 H), 0.56-0.44 (m, 3 H).
To a solution of (5R,6R)-5,6-bis-[(1-(1S)-ethoxycarbonyl)-ethoxy-carbonyl]-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane] (9.51 g, 23.28 mmol) in THF/H2O (1:1, 232 mL) was added LiOH (3.91 g, 93.13 mmol). The reaction mixture was stirred at rt overnight. 1N HCl was added in order to adjust the pH of the reaction mixture to pH=3, the layers separated and the aq. layer extracted with EA (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (CH2Cl2/MeOH, 9:1) to give the title compound as a colorless oil. TLC:rf (9:1 CH2Cl2/MeOH)=0.31. LC-MS-conditions 02: tR=0.72 min; [M+AcCN+H]+=250.18.
To a solution of (4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R,6R)-5,6-bis-carboxylic acid (5.60 g, 22.32 mmol) in CH2Cl2 (33 mL) were added NaHCO3 (2.06 g, 24.56 mmol), water (100 mL), KI (1.37 g, 82.60 mmol) and I2 (6.80 g, 26.79 mmol). The reaction mixture was stirred at rt for 3 h. The reaction was quenched by the addition of sat. aq. Na2S2O3. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude foam was purified by FC (EA) to give enantiopure iodolactone 2 as a white solid. TLC: rf (EA)=0.33.
In a flame dried round-bottomed flasked equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of enantiopure iodolactone 2 (5.00 g, 14.96 mmol) in dry MeOH (75 mL) was added TMSCH2N2 (2.0 M in hexanes, 37.0 mL, 74.83 mmol). The reaction mixture was stirred at rt overnight, concentrated under reduced pressure and purified by FC (hept-EA, 4:1) to give enantiopure iodolactone 1 (R10=Me) as a white solid. TLC:rf (4:1 hept-EA)=0.18.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of enantiopure iodolactone 1 (R10=Me) (2.86 g, 8.21 mmol) in acetic acid (29 mL) was added zinc powder (8.06 g, 123.23 mmol). The reaction mixture was stirred at 65° C. for 4 h, cooled down to rt, filtered and partitioned between water and EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 1:1) and the title compound was obtained as a colorless oil. TLC:rf (1:1 hept-EA)=0.41.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (80 mg, 0.36 mmol) in dry toluene (2 mL) were added a few drops of DMF and oxalyl chloride (0.048 mL, 0.54 mmol). The reaction mixture was stirred at reflux for 40 minutes, cooled down to rt, concentrated under reduced pressure and the residue dried under high vacuum.
To a solution of this acyl chloride in dry CH2Cl2 (2 mL) were added 4-bromoaniline (96 mg, 0.54 mmol) and DIPEA (0.18 mL, 1.08 mmol). The reaction mixture was stirred at rt for 1 h. 1N HCl was added, the layers separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (3:2 hept-EA) to give the title compound as an orange solid. TLC:rf (3:2 hept-EA)=0.50. LC-MS-conditions 02: tR=1.06 min; [M+H]+=376.20.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (200 mg, 0.90 mmol) in dry CH2Cl2 (3 mL) were added EDC.HCl (440 mg, 2.25 mmol), DMAP (28 mg, 0.22 mmol) and DIPEA (0.46 mL, 2.70 mmol). The reaction mixture was stirred at rt for 30 minutes, then 1-(5-aminomethyl-furan-2-yl)-ethanone (125 mg, 0.90 mmol) was added. The reaction mixture was stirred at rt for 16 h. Water was added, the layers separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (4:6 hept-EA) to give the title compound as a colorless oil. TLC:rf (4:6 hept-EA)=0.21. LC-MS-conditions 02: tR=0.89 min; [M+H]+=344.49.
To a solution of (5R)—N5-(5-acetyl-furan-2-yl-methyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (210 mg, 0.61 mmol) in EtOH (6.1 mL) was added aq. 1N NaOH (6.1 mL, 6.10 mmol). The reaction mixture was stirred at rt overnight and concentrated under reduced pressure. The residue was partitioned between 1N HCl and EA, the layers separated and the aq. layer extracted with EA (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow foam. TLC:rf (9:1 CH2Cl2/MeOH)=0.38. LC-MS-conditions 02: tR=0.79 min; [M+H]+=329.94.
A mixture of (5R)—N5-(4-bromo-phenyl)-(6R)-6-ethoxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide (prepared from the racemic compound using chiral HPLC, 500 mg, 1.28 mmol) and 1N aq. NaOH (13 mL) in EtOH (13 mL) was stirred at rt overnight. The reaction mixture was then concentrated under reduced pressure and partitioned between 2M HCl and EA. The layers were separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=0.97 min; [M+H]+=362.20.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a deoxygenated suspension of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (220 mg, 0.99 mmol), Pd/C 10% (44 mg) and cyclohexene (0.20 mL, 1.98 mmol) in dry THF (2.5 mL) was stirred at reflux for 2 h. The reaction mixture was filtered through celite and the filter cake washed with THF. The filtrate was concentrated under reduced pressure and the title compound obtained as a white solid. TLC:rf (2:3 hept-EA)=0.48.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (220 mg, 0.98 mmol) in dry toluene (5 mL) were added a few drops of DMF and oxalyl chloride (0.13 mL, 1.47 mmol). The reaction mixture was stirred at reflux for 40 minutes, cooled down to rt, concentrated under reduced pressure and the residue dried under high vacuum.
To a solution of this acyl chloride in dry CH2Cl2 (5 mL) were added 4-bromoaniline (261 mg, 1.47 mmol) and DIPEA (0.50 mL, 2.94 mmol). The reaction mixture was stirred at rt for 1 h. 1N HCl was added, the layers separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 4:1) and the title compound obtained as a white foam. TLC:rf (4:1 hept-EA)=0.35. LC-MS-conditions 02: tR=1.10 min; [M+H]+=378.22.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (200 mg, 0.89 mmol) in dry CH2Cl2 (3 mL) were added EDC.HCl (436 mg, 2.23 mmol), DMAP (28 mg, 0.22 mmol) and DIPEA (0.46 mL, 2.68 mmol). The reaction mixture was stirred at rt for 30 minutes, then 1-(5-aminomethyl-furan-2-yl)-ethanone (124 mg, 0.89 mmol) was added. The reaction mixture was stirred at rt for 16 h. Water was added, the layers separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (4:6 hept-EA) to give the title compound as a colorless oil. TLC:rf (4:6 hept-EA)=0.35. LC-MS-conditions 01: tR=0.88 min; [M+H]+=346.05.
To a solution of (5R)—N5-(5-acetyl-furan-2-yl-methyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide (110 mg, 0.32 mmol) in EtOH (3.2 mL) was added aq. 1N NaOH (3.2 mL, 3.20 mmol). The reaction mixture was stirred at rt overnight and concentrated under reduced pressure. The residue was partitioned between 1N HCl and EA, the layers separated and the aq. layer extracted with EA (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow foam. TLC:rf (9:1 CH2Cl2/MeOH)=0.38. LC-MS-conditions 02: tR=0.82 min; [M+H]+=332.37.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (1.11 g, 5.00 mmol) in dry CH2Cl2 (20 mL) were added a few drops of DMF and oxalyl chloride (0.48 mL, 5.50 mmol). The reaction mixture was stirred at rt for 30 minutes, concentrated under reduced pressure and the residue dried under high vacuum.
To a suspension of 2-amino-5-bromo-thiazole monohydrobromide (1.34 g, 5.00 mmol) in dry THF (10 mL) was added a solution of the acyl chloride in dry THF (10 mL) followed by Et3N (1.4 mL, 10.0 mmol). The reaction mixture was stirred at rt for 1 h, diluted with EA and washed with brine. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1) and the title compound obtained as a pale yellow oil. TLC:rf (1:1 hept-EA)=0.60. LC-MS-conditions 01: tR=0.98 min; [M+H]+=382.92.
To a solution of (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (2.14 g, 5.58 mmol) in THF (30 mL) was added aq. 2N NaOH (11 mL, 22.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then washed with Et2O, the aq. layer acidified and extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow solid. LC-MS-conditions 01: tR=0.88 min; [M+H]+=368.87.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (222 mg, 1.00 mmol) in dry CH2Cl2 (4 mL) were added a few drops of DMF and oxalyl chloride (0.10 mL, 1.13 mmol). The reaction mixture was stirred at rt for 30 minutes and a solution of 5-amino-2-bromo-pyridine (265 mg, 1.50 mmol) and DIPEA (0.70 mL, 4.00 mmol) in dry CH2Cl2 (2 mL). The reaction mixture was stirred at rt for 20 minutes, diluted with EA and washed with aq. 1N HCl. The layers were separated and the aq. layer extracted with EA (2×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1->3:1) and the title compound obtained as a colorless oil. LC-MS-conditions 01: tR=0.95 min; [M+H]+=376.97.
To a solution of (5R)—N5-(2-bromo-pyrid-5-yl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (323 mg, 0.86 mmol) in THF (4 mL) was added aq. 2N NaOH (1.7 mL, 3.40 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then poured into aq. 1N HCl and extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow foam. LC-MS-conditions 02: tR=0.87 min; [M+H]+=362.93.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (111 mg, 0.50 mmol) in dry CH2Cl2 (2 mL) were added EDC.HCl (244 mg, 1.25 mmol) and DMAP (12 mg, 0.10 mmol). The mixture was cooled to 0° C. and a solution of 4-bromo-3-fluoroaniline (95 mg, 0.50 mmol) in dry CH2Cl2 (1 mL) was added followed by DIPEA (0.35 mL, 2.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated and the org. layer washed with aq. 1N HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1 to 1:1) and the title compound obtained as a colorless solid. TLC:rf (1:1 hept-EA)=0.55. LC-MS-conditions 02: tR=1.07 min; [M+H]+=393.86.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (59 mg, 0.26 mmol) in dry CH2Cl2 (2 mL) were added EDC.HCl (129 mg, 0.66 mmol) and DMAP (6 mg, 0.05 mmol). The mixture was cooled to 0° C. and a solution of 4-bromo-2-fluoroaniline (50 mg, 0.26 mmol) in dry CH2Cl2 (1 mL) was added followed by DIPEA (0.18 mL, 1.05 mmol). The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated and the org. layer washed with aq. 1N HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1 to 1:1) and the title compound obtained as a yellow oil. LC-MS-conditions 02: tR=1.07 min; [M+H]+=393.65.
To a solution of (5R)—N5-(4-bromo-2-fluorophenyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (20 mg, 0.05 mmol) in EtOH (1 mL) was added aq. 1N NaOH (0.5 mL, 0.50 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then concentrated under reduced pressure, the residue partitioned between 2N HCl and EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.97 min; [M+H]+=380.22.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (111 mg, 0.50 mmol) in dry CH2Cl2 (2 mL) were added EDC.HCl (244 mg, 1.25 mmol) and DMAP (12 mg, 0.10 mmol). The mixture was cooled to 0° C. and a solution of 4-bromo-2-methylaniline (93 mg, 0.50 mmol) in dry CH2Cl2 (1 mL) was added followed by DIPEA (0.35 mL, 2.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated and the org. layer washed with aq. 1N HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1 to 1:1) and the title compound obtained as a yellow oil. LC-MS-conditions 02: tR=1.06 min; [M+H]+=389.98.
To a solution of (5R)—N5-(4-bromo-2-methylphenyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (93 mg, 0.24 mmol) in EtOH (2 mL) was added aq. 1N NaOH (1.0 mL, 1.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then concentrated under reduced pressure, the residue partitioned between 2N HCl and EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a pale brown foam. LC-MS-conditions 02: tR=0.97 min; [M+H]+=376.26.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (111 mg, 0.50 mmol) in dry CH2Cl2 (2 mL) were added EDC.HCl (244 mg, 1.25 mmol) and DMAP (12 mg, 0.10 mmol). The mixture was cooled to 0° C. and a solution of 4-bromo-3-fluoroaniline (66 mg, 0.50 mmol) in dry CH2Cl2 (1 mL) was added followed by DIPEA (0.35 mL, 2.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated and the org. layer washed with aq. 1N HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1 to 1:1) and the title compound obtained as a white foam. LC-MS-conditions 02: tR=0.96 min; [M+H]+=333.27.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (111 mg, 0.50 mmol) in dry CH2Cl2 (2 mL) were added EDC.HCl (244 mg, 1.25 mmol) and DMAP (12 mg, 0.10 mmol). The mixture was cooled to 0° C. and a solution of 2-amino-5-bromopyridine (86 mg, 0.50 mmol) in dry CH2Cl2 (1 mL) was added followed by DIPEA (0.35 mL, 2.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated and the org. layer washed with aq. 1N HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1 to 1:1) and the title compound obtained as a yellow oil. LC-MS-conditions 02: tR=1.03 min; [M+H]+=376.72.
To a solution of (5R)—N5-(5-bromo-pyridin-2-yl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (29 mg, 0.08 mmol) in EtOH (1 mL) was added aq. 1N NaOH (0.5 mL, 0.50 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then concentrated under reduced pressure, the residue partitioned between 2N HCl and EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow solid. LC-MS-conditions 02: tR=0.94 min.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (222 mg, 1.00 mmol) in dry CH2Cl2 (4 mL) were added 2-amino-5-methylpyridine (109 mg, 1.00 mmol), EDC.HCl (489 mg, 2.50 mmol) and DMAP (25 mg, 0.20 mmol). The mixture was cooled to 0° C. and DIPEA (0.70 mL, 4.00 mmol) was added. The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated and the org. layer washed with aq. 1N HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1 to 2:1) and the title compound obtained as a yellow oil. TLC:rf (2:1 hept-EA)=0.43. LC-MS-conditions 02: tR=0.79 min; [M+H]+=313.40.
To a solution of (5R)—N5-(5-methyl-pyridin-2-yl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (56 mg, 0.18 mmol) in THF (1 mL) was added aq. 2N NaOH (0.4 mL, 0.80 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then poured into aq. 1N HCl and extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow solid. LC-MS-conditions 02: tR=0.71 min; [M+H]+=298.61.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (111 mg, 0.50 mmol) in dry CH2Cl2 (2 mL) were added EDC.HCl (244 mg, 1.25 mmol) and DMAP (12 mg, 0.10 mmol). The mixture was cooled to 0° C. and a solution of 4-bromo-2,5-difluoroaniline (104 mg, 0.50 mmol) in dry CH2Cl2 (1 mL) was added followed by DIPEA (0.35 mL, 2.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated and the org. layer washed with aq. 1N HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1 to 3:1) and the title compound obtained as a yellow oil. LC-MS-conditions 02: tR=1.09 min; [M+H]+=412.39.
To a solution of (5R)—N5-(4-bromo-2,5-difluorophenyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (170 mg, 0.41 mmol) in THF (2 mL) was added aq. 1N NaOH (0.8 mL, 0.80 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then poured into aq. 1N HCl and extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by FC(CH2Cl2-MeOH—NH4OH) gave the title compound as a pale yellow oil. LC-MS-conditions 02: tR=1.00 min; [M+H]+=398.40.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (200 mg, 0.90 mmol) in dry CH2Cl2 (4 mL) were added 3 drops of DMF and oxalyl chloride (0.09 mL, 1.02 mmol). The reaction mixture was stirred at rt for 60 minutes and concentrated under reduced pressure.
To a suspension of 4-bromo-2,6-difluoroaniline (187 mg, 0.90 mmol) in pyridine (1.1 mL) was added a solution of the acyl chloride in acetone (5 mL). The reaction mixture was stirred at rt for 2 h, diluted with EA and successively washed with aq. 1N HCl, sat. aq. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1 to 3:1) and the title compound obtained as a colorless oil. TLC:rf (2:3 hept-EA)=0.40. LC-MS-conditions 02: tR=1.03 min; [M+H]+=411.86.
To a solution of (5R)—N5-(4-bromo-2,6-difluorophenyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (240 mg, 0.58 mmol) in THF (2 mL) was added aq. 1N NaOH (1.1 mL, 1.10 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then poured into aq. 1N HCl and extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a white foam. LC-MS-conditions 02: tR=0.94 min; [M+H]+=398.02.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (150 mg, 0.67 mmol) in dry CH2Cl2 (4 mL) were added 3 drops of DMF and oxalyl chloride (0.07 mL, 0.77 mmol). The reaction mixture was stirred at rt for 60 minutes and concentrated under reduced pressure.
To a suspension of 4-bromo-2,3-difluoroaniline (140 mg, 0.67 mmol) in pyridine (0.8 mL) was added a solution of the acyl chloride in acetone (4 mL). The reaction mixture was stirred at rt for 1 h, diluted with EA and successively washed with aq. 1N HCl, sat. aq. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound obtained as a yellow oil. TLC:rf (1:1 hept-EA)=0.63. LC-MS-conditions 02: tR=1.08 min; [M+H]+=411.93.
To a solution of (5R)—N5-(4-bromo-2,3-difluorophenyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (260 mg, 0.63 mmol) in THF (2.5 mL) was added aq. 1N NaOH (1.2 mL, 1.20 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then poured into aq. 1N HCl and extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a white foam. LC-MS-conditions 02: tR=0.99 min; [M+H]+=398.38.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (111 mg, 0.50 mmol) in dry CH2Cl2 (2 mL) were added EDC.HCl (244 mg, 1.25 mmol) and DMAP (12 mg, 0.10 mmol). The mixture was cooled to 0° C. and a solution of 4-bromo-3,5-difluoroaniline (109 mg, 0.50 mmol) in dry CH2Cl2 (1 mL) was added followed by DIPEA (0.35 mL, 2.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated and the org. layer washed with aq. 1N HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1 to 1:1) and the title compound obtained as a yellow oil. LC-MS-conditions 01: tR=1.06 min; [M+H]+=411.90.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (111 mg, 0.50 mmol) in dry CH2Cl2 (2 mL) were added EDC.HCl (244 mg, 1.25 mmol) and DMAP (12 mg, 0.10 mmol). The mixture was cooled to 0° C. and a solution of 4-bromo-3-(trifluoromethyl)aniline (120 mg, 0.50 mmol) in dry CH2Cl2 (1 mL) was added followed by DIPEA (0.35 mL, 2.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated and the org. layer washed with aq. 1N HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1 to 1:1) and the title compound obtained as a colorless oil. LC-MS-conditions 02: tR=1.11 min; [M+H]+=443.88.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (150 mg, 0.67 mmol) in dry CH2Cl2 (4 mL) were added 3 drops of DMF and oxalyl chloride (0.07 mL, 0.77 mmol). The reaction mixture was stirred at rt for 60 minutes and concentrated under reduced pressure.
To a suspension of 4-bromo-2-fluorobenzylamine hydrochloride (162 mg, 0.67 mmol) in pyridine (0.80 mL) was added a solution of the acyl chloride in acetone (4 mL). The reaction mixture was stirred at rt for 1 h, diluted with EA and successively washed with aq. 1N HCl, sat. aq. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound obtained as a yellow oil. LC-MS-conditions 01: tR=0.99 min; [M+H]+=407.94.
To a solution of (5R)—N5-(4-bromo-2-fluorophenyl-methyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (250 mg, 0.61 mmol) in THF (5 mL) was added aq. 1N NaOH (2.9 mL, 2.90 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then poured into aq. 1N HCl and extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a white foam. LC-MS-conditions 02: tR=0.94 min; [M+H]+=394.00.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (80 mg, 0.36 mmol) in dry CH2Cl2 (4 mL) were added 3 drops of DMF and oxalyl chloride (0.04 mL, 0.41 mmol). The reaction mixture was stirred at rt for 60 minutes and concentrated under reduced pressure.
To a suspension of 4-bromo-3-fluorobenzylamine (90 mg, 0.44 mmol) in pyridine (0.43 mL) was added a solution of the acyl chloride in acetone (4 mL). The reaction mixture was stirred at rt for 1 h, diluted with EA and successively washed with aq. 1N HCl, sat. aq. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by FC (hept-EA 1:1 to 1:2) gave the title compound as a colorless oil. LC-MS-conditions 07: tR=0.84 min; [M+H]+=408.01.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (120 mg, 0.54 mmol) in dry CH2Cl2 (4 mL) were added 3 drops of DMF and oxalyl chloride (0.05 mL, 0.62 mmol). The reaction mixture was stirred at rt for 60 minutes and concentrated under reduced pressure.
To a suspension of 4-bromo-2,3-difluorobenzylamine (120 mg, 0.54 mmol) in pyridine (0.64 mL) was added a solution of the acyl chloride in acetone (4 mL). The reaction mixture was stirred at rt for 2 h, diluted with EA and successively washed with aq. 1N HCl, sat. aq. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by FC (hept-EA 9:1 to 1:1) gave the title compound as a yellow oil. TLC:rf (1:1 hept-EA)=0.65. LC-MS-conditions 07: tR=0.86 min; [M+H]+=426.05.
To a solution of (5R)—N5-(4-bromo-2,3-difluorophenyl-methyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (120 mg, 0.28 mmol) in THF (4 mL) was added aq. 1N NaOH (1.3 mL, 1.30 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then poured into aq. 1N HCl and extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a white foam. LC-MS-conditions 07: tR=0.77 min; [M+H]+=411.93.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (55 mg, 0.25 mmol) in dry CH2Cl2 (4 mL) were added 2 drops of DMF and oxalyl chloride (0.025 mL, 0.28 mmol). The reaction mixture was stirred at rt for 60 minutes and concentrated under reduced pressure.
To a suspension of 4-bromo-3,5-difluorobenzylamine (55 mg, 0.25 mmol) in pyridine (0.24 mL) was added a solution of the acyl chloride in acetone (4 mL). The reaction mixture was stirred at rt for 2 h, diluted with EA and successively washed with aq. 1N HCl, sat. aq. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil. TLC:rf (1:1 hept-EA)=0.65. LC-MS-conditions 07: tR=0.85 min; [M+H]+=426.08.
To a solution of (5R)—N5-(4-bromo-3,5-difluorophenyl-methyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (80 mg, 0.19 mmol) in THF (2 mL) was added aq. 1N NaOH (1.5 mL, 1.50 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then poured into aq. 1N HCl and extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a brown foam. LC-MS-conditions 07: tR=0.75 min; [M+H]+=412.08.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (90 mg, 0.40 mmol) in dry CH2Cl2 (4 mL) were added 2 drops of DMF and oxalyl chloride (0.04 mL, 0.46 mmol). The reaction mixture was stirred at rt for 60 minutes and concentrated under reduced pressure.
To a suspension of 4-bromo-2,5-difluorobenzylamine (90 mg, 0.40 mmol) in pyridine (0.39 mL) was added a solution of the acyl chloride in acetone (4 mL). The reaction mixture was stirred at rt for 2 h, diluted with EA and successively washed with aq. 1N HCl, sat. aq. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil. TLC:rf (1:1 hept-EA)=0.65. LC-MS-conditions 07: tR=0.86 min; [M+H]+=426.08.
To a solution of (5R)—N5-(4-bromo-2,5-difluorophenyl-methyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (170 mg, 0.40 mmol) in THF (4 mL) was added aq. 1N NaOH (1.6 mL, 1.60 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then poured into aq. 1N HCl and extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a brown foam. LC-MS-conditions 07: tR=0.76 min; [M+H]+=412.08.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (120 mg, 0.54 mmol) in dry CH2Cl2 (2 mL) were added 2 drops of DMF and oxalyl chloride (0.054 mL, 0.61 mmol). The reaction mixture was stirred at rt for 60 minutes and concentrated under reduced pressure.
To a suspension of 5-amino-2-bromo-3-fluoropyridine (103 mg, 0.54 mmol) in pyridine (0.64 mL) was added a solution of the acyl chloride in acetone (3 mL). The reaction mixture was stirred at rt for 1 h, diluted with EA and successively washed with aq. 1N HCl, sat. aq. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by FC (hept-EA 9:1 to 4:1) gave the title compound as a white foam. TLC:rf (2:3 hept-EA)=0.51. LC-MS-conditions 07: tR=0.86 min; [M+H]+=395.30.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (800 mg, 3.60 mmol) in dry CH2Cl2 (10 mL) were added a few drops of DMF and oxalyl chloride (0.33 mL, 3.96 mmol). The reaction mixture was stirred at rt for 30 minutes and a solution of 2-(4-chlorophenyl)ethylamine (857 mg, 5.40 mmol) and DIPEA (2.5 mL, 14.40 mmol) in dry CH2Cl2 (5 mL) was added. The reaction mixture was stirred at rt for 10 min, diluted with CH2Cl2 and washed with aq. 1N HCl. The layers were separated and the aq. layer extracted with CH2Cl2 (2×). The combined org. extracts were successively washed with aq. Na2CO3 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 4:1 to 1:1) and the title compound obtained as a yellow oil. TLC:rf (1:1 hept-EA)=0.55. LC-MS-conditions 01: tR=1.00 min; [M+H]+=360.03.
To a solution of (5R)-N-5-(2-(4-chlorophenyl)ethyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (550 mg, 1.53 mmol) in EtOH (15 mL) was added aq. 1N NaOH (7.5 mL, 7.50 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then concentrated under reduced pressure and the residue partitioned between EA and aq. 2N HCl. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow solid. LC-MS-conditions 01: tR=0.91 min; [M+H]+=346.00.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (110 mg, 0.50 mmol) in dry DMF (5 mL) were added HATU (188 mg, 0.50 mmol) and DIPEA (0.13 mL, 0.75 mmol) at rt. The reaction mixture was stirred at rt for 1 h and a solution of 2-(2,4-dichlorophenyl)ethylamine (94 mg, 0.50 mmol) in dry DMF (2.5 mL) was added. The reaction mixture was stirred at rt for 30 min, diluted with EA and washed with water. The layers were separated and the org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1 to 3:2) and the title compound obtained as a colorless oil. LC-MS-conditions 01: tR=1.03 min; [M+H]+=394.02.
To a solution of (5R)—N5-(2-(2,4-dichlorophenyl)ethyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (170 mg, 0.43 mmol) in EtOH (4 mL) was added aq. 1N NaOH (2 mL, 2.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then concentrated under reduced pressure and the residue partitioned between EA and aq. 2N HCl. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a white foam. LC-MS-conditions 02: tR=0.97 min; [M+H]+=380.36.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (160 mg, 0.71 mmol) in dry CH2Cl2 (4 mL) were added 3 drops of DMF and oxalyl chloride (0.07 mL, 0.81 mmol). The reaction mixture was stirred at rt for 60 minutes and concentrated under reduced pressure.
To a suspension of 4-bromo-2-fluorobenzylamine hydrochloride (171 mg, 0.71 mmol) in pyridine (0.84 mL) was added a solution of the acyl chloride in acetone (4 mL). The reaction mixture was stirred at rt for 1 h, diluted with EA and successively washed with aq. 1N HCl, sat. aq. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound obtained as a yellow oil. LC-MS-conditions 02: tR=1.06 min; [M+H]+=410.67.
To a solution of (5R)—N5-(4-bromo-2-fluorophenyl-methyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide (290 mg, 0.71 mmol) in THF (5 mL) was added aq. 1N NaOH (2.8 mL, 2.80 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then poured into aq. 1N HCl and extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a white foam. LC-MS-conditions 01: tR=0.93 min; [M+H]+=395.95.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (4.70 g, 20.9 mmol) in dry CH2Cl2 (80 mL) were added 10 drops of DMF and oxalyl chloride (2.2 mL, 25.1 mmol). The reaction mixture was stirred at rt for 60 minutes and concentrated under reduced pressure. To a suspension of 2-amino-5-bromo-thiazole monohydrobromide (5.67 g, 21.1 mmol) in pyridine (5 mL) was added a solution of the acyl chloride in acetone (80 mL). The reaction mixture was stirred at rt for 1 h, diluted with EA and successively washed with aq. 1N HCl, sat. aq. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1) and the title compound obtained as a pale yellow solid. TLC:rf (2:1 hept-EA)=0.38. LC-MS-conditions 07c: tR=0.98 min; [M+H]+=385.12.
To a solution of (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide (2.90 g, 7.53 mmol) in THF (60 mL) was added aq. 2N NaOH (15 mL, 30.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then washed with Et2O, the aq. layer acidified and extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a light brown solid. LC-MS-conditions 07c: tR=0.84 min; [M+H]+=371.11.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (2.55 g, 11.37 mmol) in dry CH2Cl2 (60 mL) were added 10 drops of DMF and oxalyl chloride (1.20 mL, 13.65 mmol). The reaction mixture was stirred at rt for 60 minutes and concentrated under reduced pressure.
To a suspension of 5-amino-2-bromo-pyridine (1.97 g, 11.37 mmol) in pyridine (2.75 mL) was added a solution of the acyl chloride in acetone (60 mL). The reaction mixture was stirred at rt for 30 minutes, diluted with EA and successively washed with aq. 1N HCl, sat. aq. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 1:0->1:1) and the title compound obtained as a white solid. TLC:rf (2:1 hept-EA)=0.44. LC-MS-conditions 07: tR=0.84 min; [M+H]+=379.04.
To a solution of (5R)—N5-(2-bromo-pyrid-5-yl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide (3.81 g, 10.05 mmol) in THF (100 mL) was added aq. 2N NaOH (20 mL, 40.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then poured into aq. 1N HCl and extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a white solid. LC-MS-conditions 07: tR=0.72 min; [M+H]+=365.22.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-(5R)-5-carboxylic acid (121 mg, 0.54 mmol) in dry CH2Cl2 (2 mL) were added 2 drops of DMF and oxalyl chloride (0.054 mL, 0.61 mmol). The reaction mixture was stirred at rt for 60 minutes and concentrated under reduced pressure.
To a suspension of 5-amino-2-bromo-3-fluoropyridine (103 mg, 0.54 mmol) in pyridine (0.64 mL) was added a solution of the acyl chloride in acetone (3 mL). The reaction mixture was stirred at rt for 1 h, diluted with EA and successively washed with aq. 1N HCl, sat. aq. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by FC (hept-EA 9:1 to 4:1) gave the title compound as a white foam. TLC:rf (2:3 hept-EA)=0.52. LC-MS-conditions 07: tR=0.91 min; [M+H]+=397.18.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of enantiopure iodolactone 2 (3.40 g, 10.18 mmol) in dry toluene (32 mL) were added a few drops of DMF and oxalyl chloride (1.11 mL, 12.58 mmol). The reaction mixture was stirred at rt for 60 min, concentrated under reduced pressure and the residue co-evaporated with toluene (2×). The residue was then redissolved in CH2Cl2 (32 mL) and beta-alanine methyl ester hydrochloride (1.59 g, 11.19 mmol) and DIPEA (5.37 mL, 30.53 mmol) were added at rt. The reaction mixture was stirred at rt for 25 minutes, diluted with CH2Cl2 and washed with sat. aq. NH4Cl. The layers were separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 5:1->1:1) and the title compound obtained as a pale yellow foam. TLC:rf (95:5 hept-EA)=0.38. LC-MS-conditions 02: tR=0.87 min; [M+H]+=420.00.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of enantiopure iodolactone 3 (R2=2-methoxycarbonyl-ethyl and R3═H) (3.21 g, 7.66 mmol) in acetic acid (15 mL) was added zinc powder (0.60 g, 9.20 mmol). The reaction mixture was stirred at 65° C. for 2 h, cooled down to rt, filtered and the filter cake rinsed with EA. The filtrate was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 1:1->1:2) and the title compound was obtained as a colorless oil. TLC: rf (EA)=0.27. LC-MS-conditions 02: tR=0.71 min; [M+H]+=294.00.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of enantiopure iodolactone 2 (1.59 g, 4.76 mmol) in dry CH2Cl2 (30 mL) were added a few drops of DMF and oxalyl chloride (0.45 mL, 5.23 mmol). The reaction mixture was stirred at rt for 2 h, after which 4-(1-pyrrolidino)-butylamine (0.69 g, 4.76 mmol) and DIPEA (0.81 mL, 4.76 mmol) were added. The reaction mixture was stirred at rt for 30 minutes, diluted with CH2Cl2 and washed with sat. aq. NH4Cl. The layers were separated, and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (CH2Cl2/MeOH, 9:1) and the title compound obtained as a pale yellow oil. TLC:rf (9:1 CH2Cl2/MeOH)=0.22. LC-MS-conditions 01: tR=0.68 min; [M+H]+=458.65.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of enantiopure iodolactone 3 (R2=4-pyrrolidin-1-yl-butyl and R3=H) (1.29 g, 2.81 mmol) in acetic acid (5 mL) was added zinc powder (276 mg, 4.22 mmol). The reaction mixture was stirred at 65° C. for 0.5 h, cooled down to rt, filtered, washed with EA and the filtrate concentrated under reduced pressure. The crude residue was purified by FC(C-18 reverse phase silica, H2O/MeOH, 1:0 then 0:1) and the title compound was obtained as a white foam. LC-MS-conditions 02: tR=0.64 min; [M+H]+=333.54.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a deoxygenated suspension of (5R)-5-hydroxycarbonyl-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide (500 mg, 1.70 mmol), Pd/C 10% (181 mg) and cyclohexene (0.80 mL, 7.80 mmol) in dry THF (15 mL) was stirred at reflux for 16 h. The reaction mixture was filtered through celite and the filter cake washed with THF. The filtrate was concentrated under reduced pressure and the title compound obtained as a colorless oil. TLC: rf (EA)=0.37. LC-MS-conditions 02: tR=0.77 min; [M+H]+=296.26.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R)-5-hydroxycarbonyl-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide (59 mg, 0.20 mmol) in dry CH2Cl2 (2 mL) was added 4-bromo-benzylamine (39 mg, 0.20 mmol) in dry CH2Cl2 (0.5 mL) at rt followed by EDC.HCl (98 mg, 0.50 mmol) and DMAP (5 mg, 0.04 mmol). DIPEA (0.14 mL, 0.80 mmol) was then added dropwise at 0° C. The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated, and the org. layer successively washed with aq. 1N HCl (2×), brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a pale brown oil. TLC:rf (1:2 hept-EA)=0.31. LC-MS-conditions 02: tR=0.92 min; [M+H]+=461.08.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R)-5-hydroxycarbonyl-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide (88 mg, 0.30 mmol) in dry CH2Cl2 (2 mL) was added 2-amino-5-bromopyridine (58 mg, 0.33 mmol) in dry CH2Cl2 (0.5 mL) at rt followed by EDC.HCl (147 mg, 0.75 mmol) and DMAP (7 mg, 0.06 mmol). DIPEA (0.21 mL, 1.20 mmol) was then added dropwise at 0° C. The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated, and the org. layer successively washed with aq. 1N HCl (2×), brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil. TLC:rf (1:1 hept-EA)=0.37. LC-MS-conditions 02: tR=0.96 min; [M+H]+=448.40.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R)-5-hydroxycarbonyl-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide (88 mg, 0.30 mmol) in dry CH2Cl2 (2 mL) was added 5-amino-2-chloropyridine (44 mg, 0.33 mmol) at rt followed by EDC.HCl (147 mg, 0.75 mmol) and DMAP (7 mg, 0.06 mmol). DIPEA (0.21 mL, 1.20 mmol) was then added dropwise at 0° C. The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated, and the org. layer successively washed with aq. 1N HCl (2×), brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid. TLC:rf (1:1 hept-EA)=0.13. LC-MS-conditions 02: tR=0.88 min; [M+H]+=404.06.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R)-5-hydroxycarbonyl-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide (88 mg, 0.30 mmol) in dry CH2Cl2 (3 mL) was added 4-bromo-2-fluoro-benzylamine hydrochloride (72 mg, 0.30 mmol) at rt followed by EDC.HCl (147 mg, 0.75 mmol) and DMAP (7 mg, 0.06 mmol). DIPEA (0.21 mL, 1.20 mmol) was then added dropwise at 0° C. The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated, and the org. layer successively washed with aq. 1N HCl (2×), brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow oil. TLC:rf (1:2 hept-EA)=0.42. LC-MS-conditions 02: tR=0.96 min; [M+H]+=479.10.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R)-5-hydroxycarbonyl-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide (88 mg, 0.30 mmol) in dry CH2Cl2 (2 mL) was added (2-bromo-thiazol-5-yl)methanamine (58 mg, 0.30 mmol) in dry CH2Cl2 (0.5 mL) at rt followed by EDC.HCl (147 mg, 0.75 mmol) and DMAP (7 mg, 0.06 mmol). DIPEA (0.21 mL, 1.20 mmol) was then added dropwise at 0° C. The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated, and the org. layer successively washed with aq. 1N HCl (2×), brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a brown oil. TLC:rf (1:2 hept-EA)=0.21. LC-MS-conditions 02: tR=0.85 min; [M+H]+=467.57.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R)-5-hydroxycarbonyl-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide (88 mg, 0.30 mmol) in dry CH2Cl2 (2 mL) was added 4-methoxy-aniline (41 mg, 0.33 mmol) in dry CH2Cl2 (0.5 mL) at rt followed by EDC.HCl (147 mg, 0.75 mmol) and DMAP (7 mg, 0.06 mmol). DIPEA (0.21 mL, 1.20 mmol) was then added dropwise at 0° C. The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated, and the org. layer successively washed with aq. 1N HCl (2×), brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil. TLC:rf (1:2 hept-EA)=0.37. LC-MS-conditions 02: tR=0.90 min; [M+H]+=399.02.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R)-5-hydroxycarbonyl-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-6-carboxamide (88 mg, 0.30 mmol) in dry CH2Cl2 (2 mL) was added 4-bromo-benzylamine (64 mg, 0.33 mmol) in dry CH2Cl2 (0.5 mL) at rt followed by EDC.HCl (147 mg, 0.75 mmol) and DMAP (7 mg, 0.06 mmol). DIPEA (0.21 mL, 1.20 mmol) was then added dropwise at 0° C. The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated, and the org. layer successively washed with aq. 1N HCl (2×), brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow solid. TLC:rf (1:2 hept-EA)=0.39. LC-MS-conditions 02: tR=0.97 min; [M+H]+=462.80.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R)-5-hydroxycarbonyl-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-6-carboxamide (88 mg, 0.30 mmol) in dry CH2Cl2 (2 mL) was added 5-amino-2-chloropyridine (44 mg, 0.33 mmol) in dry CH2Cl2 (1 mL) at rt followed by EDC.HCl (147 mg, 0.75 mmol) and DMAP (7 mg, 0.06 mmol). DIPEA (0.21 mL, 1.20 mmol) was then added dropwise at 0° C. The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated, and the org. layer successively washed with aq. 1N HCl (2×), brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a light brown solid. LC-MS-conditions 02: tR=0.92 min; [M+H]+=406.25.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R)-5-hydroxycarbonyl-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-6-carboxamide (88 mg, 0.30 mmol) in dry CH2Cl2 (3 mL) was added 4-bromo-2-fluoro-benzylamine hydrochloride (80 mg, 0.33 mmol) at rt followed by EDC.HCl (147 mg, 0.75 mmol) and DMAP (7 mg, 0.06 mmol). DIPEA (0.21 mL, 1.20 mmol) was then added dropwise at 0° C. The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated, and the org. layer successively washed with aq. 1N HCl (2×), brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a white solid. TLC:rf (1:2 hept-EA)=0.45. LC-MS-conditions 02: tR=0.98 min; [M+H]+=481.00.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R)-5-hydroxycarbonyl-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-6-carboxamide (88 mg, 0.30 mmol) in dry CH2Cl2 (3 mL) was added 4-methoxy-aniline (41 mg, 0.33 mmol) at rt followed by EDC.HCl (147 R)—Nl mg, 0.75 mmol) and DMAP (7 mg, 0.06 mmol). DIPEA (0.21 mL, 1.20 mmol) was then added dropwise at 0° C. The reaction mixture was stirred at rt until completion of the reaction. Water was added, the layers separated, and the org. layer successively washed with aq. 1N HCl (2×), brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as an orange oil. TLC:rf (1:2 hept-EA)=0.45. LC-MS-conditions 02: tR=0.93 min; [M+H]+=401.28.
Following general procedures A then H, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 5-(tert-butoxycarbonyl-amino)-pentylamine.
LC-MS-conditions 05c: tR=0.55 min; [M+H]+=446.12.
Following general procedure F, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(1-pyrrolidino)-butylamine.
LC-MS-conditions 02: tR=0.85 min; [M+H]+=486.21.
Following general procedures A then H, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-(4-amino)-piperidine.
LC-MS-conditions 05c: tR=0.54 min; [M+H]+=444.00.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and isobutylamine.
LC-MS-conditions 05c: tR=0.84 min; [M+H]+=417.18.
Following general procedures A then H, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(tert-butoxycarbonyl-amino)-butylamine.
LC-MS-conditions 05c: tR=0.54 min; [M+H]+=432.05.
Following general procedure E, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-(dimethylamino)-ethylamine.
LC-MS-conditions 02: tR=0.82 min; [M+H]+=432.24.
Following general procedures A then H, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(tert-butoxycarbonyl-aminomethyl)-benzylamine.
LC-MS-conditions 05c: tR=0.58 min; [M+H]+=479.90.
Following general procedures A then H, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-4-(amino-methyl)-piperidine.
LC-MS-conditions 05c: tR=0.55 min; [M+H]+=458.00.
Following general procedures A then H, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (±)-1-tert-butoxycarbonyl-3-amino-pyrrolidine.
LC-MS-conditions 05c: tR=0.54 min; [M+H]+=429.97.
Following general procedures A then H, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-3-amino-2,2-dimethyl-propylamine.
LC-MS-conditions 05c: tR=0.57 min; [M+H]+=446.08.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(diethylamino)-butylamine.
LC-MS-conditions 05b: tR=0.56 min; [M+H]+=488.28.
Following general procedure E, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-amino-1-propanol.
LC-MS-conditions 02: tR=0.92 min; [M+H]+=418.92.
Following general procedure E, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and beta-alaninamide hydrochloride.
LC-MS-conditions 02: tR=0.88 min; [M+H]+=432.20.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (±)-3-amino-N-tert-butoxycarbonyl-pyrrolidine.
LC-MS-conditions 05c: tR=0.78 min; [M+H]+=530.03.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and cyclopentylamine.
LC-MS-conditions 05b: tR=0.85 min; [M+H]+=429.15.
Following general procedures A then H, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-3-amino-propylamine.
LC-MS-conditions 05c: tR=0.53 min; [M+H]+=417.99.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-ethoxypropylamine.
LC-MS-conditions 05b: tR=0.79 min; [M+H]+=447.17.
Following general procedures A then H, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-tert-butoxycarbonyl-2-(amino-methyl)-pyrrolidine.
LC-MS-conditions 05c: tR=0.55 min; [M+H]+=444.06.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2,2,2-trifluoro-ethylamine.
LC-MS-conditions 05b: tR=0.80 min; [M+H]+=443.07.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-fluoro-ethylamine.
LC-MS-conditions 05b: tR=0.73 min; [M+H]+=407.10.
Following general procedures A then H, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-N-methyl-2-amino-ethylamine.
LC-MS-conditions 05c: tR=0.54 min; [M+H]+=418.17.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-tetrahydrofuranyl-methylamine.
LC-MS-conditions 05b: tR=1.10 min; [M+H]+=445.31.
Following general procedure E, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and trans-4-amino-cyclohexanol hydrochloride.
LC-MS-conditions 05: tR=0.83 min; [M+H]+=459.20.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-ethylsulfanyl-ethylamine.
LC-MS-conditions 05b: tR=0.83 min; [M+H]+=449.20.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(N,N-diethyl-amino)-1-methyl-butylamine.
LC-MS-conditions 05b: tR=0.92 min; [M+H]+=502.11.
Following general procedures A then H, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (±)-N-tert-butoxycarbonyl-(3-amino)-piperidine.
LC-MS-conditions 05c: tR=0.55 min; [M+H]+=444.01.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-tert-butoxycarbonyl-amino-ethylamine.
LC-MS-conditions 05c: tR=0.75 min; [M+H]+=504.02.
Following general procedure E, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and
LC-MS-conditions 05: tR=0.81 min; [M+H]+=419.07.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-imidazolidin-2-on-1-yl-ethylamine.
LC-MS-conditions 05b: tR=0.96 min; [M+H]+=472.98.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(1-pyrrolidino)-propylamine.
LC-MS-conditions 05b: tR=0.86 min; [M+H]+=472.10.
Following general procedure E, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-methoxy-ethylamine.
LC-MS-conditions 02: tR=0.98 min; [M+H]+=418.98.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(1H-benzoimidazol-2-yl)-propylamine.
LC-MS-conditions 05b: tR=0.59 min; [M+H]+=519.28.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-(1-methyl-pyrrolidin-2-yl)-ethylamine.
LC-MS-conditions 05b: tR=0.85 min; [M+H]+=472.17.
Following general procedure E, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-amino-ethanol.
LC-MS-conditions 02: tR=0.90 min; [M+H]+=405.26.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and bis-(2-methoxy-ethyl)-amine.
LC-MS-conditions 05b: tR=0.78 min; [M+H]+=477.20.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and amino-acetonitrile.
LC-MS-conditions 05b: tR=0.70 min; [M+H]+=400.09.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-1H-pyrazol-1-yl-propylamine.
LC-MS-conditions 05b: tR=0.73 min; [M+H]+=469.15.
Following general procedures A then H, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(tert-butoxycarbonyl-aminomethyl)-benzylamine.
LC-MS-conditions 05c: tR=0.57 min; [M+H]+=480.04.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-ethyl-2-(N,N-diethyl-amino)-ethylamine.
LC-MS-conditions 05b: tR=0.60 min; [M+H]+=488.21.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(1H-imidazol-1-yl)-propylamine.
LC-MS-conditions 05b: tR=0.54 min; [M+H]+=469.20.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and [1,4]-dioxan-2-yl-methylamine.
LC-MS-conditions 05b: tR=1.06 min; [M+H]+=460.97.
Following general procedure E, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-amino-butanol.
LC-MS-conditions 05: tR=0.81 min; [M+H]+=433.21.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(4-methyl-piperazin-1-yl)-propylamine.
LC-MS-conditions 05b: tR=0.74 min; [M+H]+=501.10.
Following general procedures A then H, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-2-amino-ethylamine.
LC-MS-conditions 05c: tR=0.53 min; [M+H]+=404.06.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-methyl-2-(N,N-dimethyl-amino)-ethylamine.
LC-MS-conditions 05b: tR=0.55 min; [M+H]+=446.17.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-tert-butoxycarbonyl-amino-butylamine.
LC-MS-conditions 05c: tR=0.78 min; [M+H]+=532.07.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-N-methyl-2-amino-ethylamine.
LC-MS-conditions 05c: tR=0.78 min; [M+H]+=517.63.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-pyrrolidino-ethylamine.
LC-MS-conditions 05b: tR=0.54 min; [M+H]+=458.14.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-1H-[1,2,4]-triazol-1-yl-ethylamine.
LC-MS-conditions 05: tR=0.78 min; [M+H]+=456.13.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and furan-3-yl-methylamine.
LC-MS-conditions 05b: tR=0.79 min; [M+H]+=441.18.
Following general procedure E, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 5-dimethyl-amino-pentylamine.
LC-MS-conditions 02: tR=0.84 min; [M+H]+=474.32.
Following general procedure E, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-dimethyl-amino-propylamine.
LC-MS-conditions 02: tR=0.82 min; [M+H]+=446.09.
Following general procedure E, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-methoxy-propylamine.
LC-MS-conditions 02: tR=1.00 min; [M+H]+=432.99.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (1-ethyl-pyrrolidin-2-yl)-methylamine.
LC-MS-conditions 05b: tR=0.88 min; [M+H]+=472.12.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-1H-[1,2,4]-triazol-1-yl-propylamine.
LC-MS-conditions 05b: tR=0.63 min; [M+H]+=470.22.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (±)-3-amino-N-tert-butoxycarbonyl-piperidine.
LC-MS-conditions 05c: tR=0.81 min; [M+H]+=544.06.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-tert-butoxycarbonyl-amino-propylamine.
LC-MS-conditions 05c: tR=0.77 min; [M+H]+=517.58.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-methyl-butylamine.
LC-MS-conditions 05b: tR=0.89 min; [M+H]+=431.13.
Following general procedure E, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (2S)-2-amino-4-methyl-pentan-1-ol.
LC-MS-conditions 05: tR=0.93 min; [M+H]+=461.21.
Following general procedure E, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and beta-alanine methylester hydrochloride.
LC-MS-conditions 02: tR=0.99 min; [M+H]+=446.94.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-(4-aminosulfonyl-phenyl)-ethylamine.
LC-MS-conditions 05b: tR=1.06 min; [M+H]+=544.03.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-(1-ethyl-5-methyl-1H-pyrazol-3-yl)-ethylamine.
LC-MS-conditions 05: tR=0.87 min; [M+H]+=497.14.
Following general procedure E, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and bis-(2-methoxy-ethyl)-amine. LC-MS-conditions 02: tR=1.02 min; [M+H]+=477.24.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-(4,5-dimethyl-1H-imidazol-2-yl)-ethylamine.
LC-MS-conditions 05b: tR=0.88 min; [M+H]+=483.00.
Following general procedure E, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (2S)-2-amino-propionamide.
LC-MS-conditions 02: tR=0.89 min; [M+H]+=431.92.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-diethyl-amino-ethylamine.
LC-MS-conditions 05b: tR=0.86 min; [M+H]+=460.09.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and pentylamine.
LC-MS-conditions 05b: tR=0.89 min; [M+H]+=431.10.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 5-tert-butoxycarbonyl-amino-pentylamine.
LC-MS-conditions 05c: tR=0.80 min; [M+H]+=546.04.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-amino-1-isopentyl-piperidine.
LC-MS-conditions 05b: tR=0.96 min; [M+H]+=514.10.
Following general procedure E, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-pyridin-2-yl-ethylamine.
LC-MS-conditions 02: tR=0.83 min; [M+H]+=465.93.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2,2-dimethyl-3-tert-butoxycarbonyl-amino-propylamine.
LC-MS-conditions 05c: tR=0.84 min; [M+H]+=546.02.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-phenyl-2H-pyrazol-3-ylamine. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=503.04.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide (1.0 eq.) in DMF (0.2 M) were added cyclopropylamine (1.5 eq.), PyBOP (1.5 eq.) and DIPEA (3.0 eq.). The reaction mixture was stirred at rt until completion of the reaction. The reaction mixture was then partitioned between water and EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
LC-MS-conditions 02: tR=1.00 min; [M+H]+=401.13.
Following general procedure E, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and butylamine.
LC-MS-conditions 02: tR=1.07 min; [M+H]+=416.25.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and hexylamine.
LC-MS-conditions 05b: tR=1.25 min; [M+H]+=445.11.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-ethylamine.
LC-MS-conditions 05b: tR=1.04 min; [M+H]+=497.09.
(5R*)—N5-(4-Bromophenyl)-(6R*)—N6-(2-phenyl-2-morpholino-ethyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-phenyl-2-morpholino-ethylamine.
LC-MS-conditions 05b: tR=0.94 min; [M+H]+=550.09.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-diethylamino-propylamine.
LC-MS-conditions 05b: tR=0.88 min; [M+H]+=474.07.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-pyrrolidin-2-yl-methylamine.
LC-MS-conditions 05c: tR=0.83 min; [M+H]+=544.06.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-morpholino-ethylamine.
LC-MS-conditions 05b: tR=0.83 min; [M+H]+=474.05.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and cis-2-amino-cyclohexane-carboxylic acid amide.
LC-MS-conditions 05b: tR=1.05 min; [M+H]+=486.06.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-amino-1-piperidin-1-yl-propan-1-one.
LC-MS-conditions 05b: tR=1.13 min; [M+H]+=500.08.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-amino-N-benzyl-piperidine.
LC-MS-conditions 05b: tR=0.60 min; [M+H]+=534.24.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-methyl-hexylamine.
LC-MS-conditions 05b: tR=0.97 min; [M+H]+=459.15.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3,3-dimethyl-butylamine.
LC-MS-conditions 05b: tR=0.93 min; [M+H]+=445.13.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-amino-N-methyl-piperidine.
LC-MS-conditions 05b: tR=0.83 min; [M+H]+=458.11.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-morpholino-propylamine.
LC-MS-conditions 05b: tR=0.84 min; [M+H]+=488.15.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(5-methyl-1H-pyrazol-4-yl)-propylamine.
LC-MS-conditions 05b: tR=0.97 min; [M+H]+=483.05.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-tert-butoxycarbonyl-propylamine.
LC-MS-conditions 05b: tR=1.21 min; [M+H]+=503.06.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(tert-butoxycarbonyl-aminomethyl)-benzylamine.
LC-MS-conditions 05c: tR=0.82 min; [M+H]+=580.00.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-(cyclopropyl-methyl)-propylamine.
LC-MS-conditions 05b: tR=0.93 min; [M+H]+=457.16.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-4-(amino-methyl)-piperidine.
LC-MS-conditions 05c: tR=0.81 min; [M+H]+=558.03.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and cyclohexylamine.
LC-MS-conditions 05b: tR=1.22 min; [M+H]+=443.05.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-amino-N-tert-butoxycarbonyl-piperidine.
LC-MS-conditions 05c: tR=0.80 min; [M+H]+=544.04.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (2S)-2-amino-3-phenyl-propionamide.
LC-MS-conditions 05b: tR=1.08 min; [M+H]+=508.04.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (2S)-2-amino-3,3,N-trimethyl-butyramide.
LC-MS-conditions 05b: tR=1.11 min; [M+H]+=488.11.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(tert-butoxycarbonyl-aminomethyl)-benzylamine.
LC-MS-conditions 05c: tR=0.82 min; [M+H]+=580.03.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-amino-N-tert-butoxycarbonyl-azetidine.
LC-MS-conditions 05c: tR=0.77 min; [M+H]+=516.07.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-(N-tert-butoxycarbonyl-piperidin-3-yl)-ethylamine.
LC-MS-conditions 05b: tR=1.25 min; [M+H]+=572.15.
(5R*)—N5-(4-Bromophenyl)-(6R*)—N6-[(1S)-2-methoxy-1-benzyl-ethyl]-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (1S)-1-benzyl-2-methoxy-ethylamine.
LC-MS-conditions 05b: tR=1.19 min; [M+H]+=509.01.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (5-methyl-3-phenyl-isoxazol-4-yl)-methylamine.
LC-MS-conditions 05b: tR=0.86 min; [M+H]+=531.77.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 3-aminopropionamide.
LC-MS-conditions 05b: tR=0.63 min; [M+H]+=433.63.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 3-methoxy-propylamine.
LC-MS-conditions 05b: tR=0.77 min; [M+H]+=435.12.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and tetrahydrofuran-2-yl-methylamine.
LC-MS-conditions 05b: tR=0.78 min; [M+H]+=447.12.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 2-imidazolidin-2-on-1-yl-ethylamine.
LC-MS-conditions 05b: tR=0.65 min; [M+H]+=475.14.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide (1.0 eq.) in DMF (0.1 M) were added cyclopropylamine (1.0 eq.), HATU (1.5 eq.), DMAP (0.25 eq.) and DIPEA (5.0 eq.). The reaction mixture was stirred at rt until completion of the reaction. The reaction mixture was then partitioned between sat. aq. NH4C1 and CH2Cl2. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC or HPLC gave the desired compound.
LC-MS-conditions 02: tR=1.03 min; [M+H]+=403.00.
Following general procedure E, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 3-amino-propanol.
LC-MS-conditions 05: tR=0.84 min; [M+H]+=421.07.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 3-(1H-imidazol-1-yl)-propylamine .
LC-MS-conditions 05b: tR=0.57 min; [M+H]+=471.18.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 5-dimethyl-amino-pentylamine.
LC-MS-conditions 05b: tR=0.58 min; [M+H]+=476.20.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 3-pyrrolidino-propylamine.
LC-MS-conditions 05b: tR=0.58 min; [M+H]+=474.20.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 3-(4-methyl-piperazin-1-yl)-propylamine.
LC-MS-conditions 05b: tR=0.50 min; [M+H]+=503.22.
Following general procedure A, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 2-(4,5-dimethyl-1H-imidazol-2-yl)-ethylamine.
LC-MS-conditions 05b: tR=0.59 min; [M+H]+=485.20.
Following general procedure F, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 4-(1-pyrrolidino)-butylamine.
LC-MS-conditions 02: tR=0.87 min; [M+H]+=487.96.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 5-amino-2-bromo-pyridine.
LC-MS-conditions 05: tR=0.68 min; [M+H]+=487.04.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-methoxy-phenylamine.
LC-MS-conditions 05c: tR=0.55 min; [M+H]+=438.29.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 5-amino-2-chloro-pyridine.
LC-MS-conditions 05: tR=0.66 min; [M+H]+=443.15.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 5-amino-benzothiazole.
LC-MS-conditions 05: tR=0.65 min; [M+H]+=465.18.
Following general procedure E, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and p-bromo-benzylamine hydrochloride.
LC-MS-conditions 05: tR=0.72 min; [M+H]+=500.17.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-amino-5-bromo-pyridine.
LC-MS-conditions 05: tR=0.69 min; [M+H]+=487.16.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-amino-5-bromo-thiazole.
LC-MS-conditions 05: tR=0.73 min; [M+H]+=493.03.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-amino-5-methyl-pyridine.
LC-MS-conditions 05c: tR=0.40 min; [M+H]+=423.32.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and pentylamine.
LC-MS-conditions 05c: tR=0.56 min; [M+H]+=401.96.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-methyl-benzylamine.
LC-MS-conditions 05: tR=0.72 min; [M+H]+=435.88.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-methoxycarbonyl-ethylamine.
LC-MS-conditions 05c: tR=0.45 min; [M+H]+=417.83.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and cyclohexyl-methylamine.
LC-MS-conditions 05c: tR=0.56 min; [M+H]+=428.38.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-methyl-cyclohexylamine.
LC-MS-conditions 05c: tR=0.57 min; [M+H]+=428.39.
Following general procedures E then G, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-(2-methyl-[1,3]dioxolan-2-yl)butylamine.
LC-MS-conditions 02: tR=0.70 min; [M+H]+=430.02.
Following general procedure C, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-amino-5-nitro-thiazole.
LC-MS-conditions 05: tR=0.66 min; [M+H]+=460.09.
Following general procedure C, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-amino-5-chloro-thiazole.
LC-MS-conditions 05: tR=0.68 min; [M+H]+=449.13.
Following general procedure C, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-amino-5-cyano-thiazole.
LC-MS-conditions 05: tR=0.63 min; [M+H]+=440.23.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and furan-2-yl-methylamine.
LC-MS-conditions 05c: tR=0.47 min; [M+H]+=412.32.
Following general procedure E, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 1-(4-Bromophenyl)-ethylamine.
LC-MS-conditions 05: tR=0.77 min; [M+H]+=513.73.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-trifluoromethoxy-aniline.
LC-MS-conditions 05: tR=0.81 min; [M+H]+=492.15.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-phenoxy-ethylamine.
LC-MS-conditions 05c: tR=0.53 min; [M+H]+=452.30.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and isopentylamine.
LC-MS-conditions 05c: tR=0.52 min; [M+H]+=401.97.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and butylamine.
LC-MS-conditions 05c: tR=0.52 min; [M+H]+=388.38.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (5-methyl-furan-2-yl)-methylamine.
LC-MS-conditions 05c: tR=0.50 min; [M+H]+=426.33.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 5-amino-2-methyl-benzothiazole.
LC-MS-conditions 05: tR=0.68 min; [M+H]+=479.17.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-phenyl-ethylamine.
LC-MS-conditions 05c: tR=0.53 min; [M+H]+=436.32.
Following general procedures E then G, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3-(2-methyl-[1,3]dioxolan-2-yl)-propylamine.
LC-MS-conditions 02: tR=0.68 min; [M+H]+=416.47.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3-1H-imidazol-1-yl-propylamine.
LC-MS-conditions 05c: tR=0.32 min; [M+H]+=440.36.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 5-amino-2-chloro-pyrimidine.
LC-MS-conditions 05: tR=0.63 min; [M+H]+=444.13.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3-bromo-benzylamine.
LC-MS-conditions 05: tR=0.74 min; [M+H]+=499.62.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-amino-benzothiazole.
LC-MS-conditions 05: tR=0.74 min; [M+H]+=465.18.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3-amino-5-tert-butyl-isoxazole.
LC-MS-conditions 05: tR=0.76 min; [M+H]+=455.21.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 5-amino-3-methyl-benzoisothiazole.
LC-MS-conditions 05: tR=0.71 min; [M+H]+=479.19.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 5-amino-1H-indole.
LC-MS-conditions 05: tR=0.65 min; [M+H]+=447.17.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-amino-6-fluoro-benzothiazole.
LC-MS-conditions 05: tR=0.76 min; [M+H]+=483.10.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-ethyl-butylamine.
LC-MS-conditions 05: tR=0.75 min; [M+H]+=416.28.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-amino-4-(4-chlorophenyl)-thiazole.
LC-MS-conditions 05: tR=0.86 min; [M+H]+=525.10.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-amino-benzo[2,1,3]oxadiazole.
LC-MS-conditions 05: tR=0.73 min; [M+H]+=450.19.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-amino-4-tert-butyl-thiazole.
LC-MS-conditions 05: tR=0.81 min; [M+H]+=471.19.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 5-amino-3-phenyl-[1,2,4]thiadiazole.
LC-MS-conditions 05: tR=0.80 min; [M+H]+=492.17.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-amino-6-chloro-benzothiazole.
LC-MS-conditions 05: tR=0.82 min; [M+H]+=499.01.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3-(2-methyl-1H-indol-1-yl)-propylamine.
LC-MS-conditions 05: tR=0.79 min; [M+H]+=503.30.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-(1-methyl-1H-benzimidazol-2-yl)-ethylamine.
LC-MS-conditions 05: tR=0.48 min; [M+H]+=490.19.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-(1H-indol-1-yl)-ethylamine.
LC-MS-conditions 05: tR=0.70 min; [M+H]+=475.19.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-(2-methoxy-phenyl)-ethylamine.
LC-MS-conditions 05: tR=0.72 min; [M+H]+=466.22.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(3,5-dimethyl-pyrazol-1-yl)-propionic acid.
LC-MS-conditions 05: tR=0.84 min; [M+H]+=497.18.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 5-phenyl-isoxazole-4-carboxylic acid.
LC-MS-conditions 05: tR=1.09 min; [M+H]+=518.11.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(2-oxo-pyrrolidin-1-yl)-butyric acid.
LC-MS-conditions 05: tR=0.80 min; [M+H]+=499.65.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (2-chloro-phenyl)-acetic acid.
LC-MS-conditions 05: tR=1.00 min; [M+H]+=499.18.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-methoxy-propionic acid.
LC-MS-conditions 05: tR=0.85 min; [M+H]+=433.13.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N,N-dimethyl-succinamic acid.
LC-MS-conditions 05: tR=0.81 min; [M+H]+=474.17.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2,2-dichloro-1-methyl-cyclopropanecarboxylic acid.
LC-MS-conditions 05: tR=1.00 min; [M+H]+=497.04.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and pentanedioic acid monomethyl ester.
LC-MS-conditions 05: tR=0.88 min; [M+H]+=475.14.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and pentanoic acid.
LC-MS-conditions 05: tR=0.96 min; [M+H]+=431.20.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (2,5-dimethyl-thiazol-4-yl)-acetic acid.
LC-MS-conditions 05: tR=0.89 min; [M+H]+=499.54.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-phenyl-2H-pyrazole-3-carboxylic acid.
LC-MS-conditions 05: tR=0.97 min; [M+H]+=517.14.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and succinamic acid.
LC-MS-conditions 05: tR=0.75 min; [M+H]+=446.14.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-methyl-nicotinic acid.
LC-MS-conditions 05: tR=0.75 min; [M+H]+=466.20.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and isobutyric acid.
LC-MS-conditions 05: tR=0.92 min; [M+H]+=417.18.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-ethyl-piperidine-4-carboxylic acid.
LC-MS-conditions 05: tR=0.72 min; [M+H]+=486.20.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-pyridin-3-yl-propionic acid.
LC-MS-conditions 05: tR=0.71 min; [M+H]+=480.16.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-[(methyl-amino)-methyl]-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-methoxy-propionic acid.
LC-MS-conditions 05: tR=0.90 min; [M+H]+=447.15.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-chloro-3-fluoro-benzoic acid.
LC-MS-conditions 05: tR=0.98 min; [M+H]+=503.04.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-pyrrolidin-1-yl-butyric acid.
LC-MS-conditions 05: tR=0.73 min; [M+H]+=486.23.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
LC-MS-conditions 05: tR=0.93 min; [M+H]+=468.91.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and cyclopentanecarboxylic acid.
LC-MS-conditions 05: tR=0.97 min; [M+H]+=443.15.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (2-methyl-thiazol-4-yl)-acetic acid.
LC-MS-conditions 05: tR=0.89 min; [M+H]+=485.96.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and dimethylamino-acetic acid.
LC-MS-conditions 05: tR=0.75 min; [M+H]+=432.13.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-[(methyl-amino)-methyl]-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (2-chloro-phenyl)-acetic acid.
LC-MS-conditions 05: tR=1.06 min; [M+H]+=513.13.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-[(methyl-amino)-methyl]-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
LC-MS-conditions 05: tR=0.91 min; [M+H]+=483.27.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and cyclopropyl-acetic acid.
LC-MS-conditions 05: tR=0.92 min; [M+H]+=429.20.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(1-methyl-1H-benzoimidazol-2-yl)-propionic acid.
LC-MS-conditions 05: tR=0.78 min; [M+H]+=533.12.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(1H-indol-3-yl)-propionic acid.
LC-MS-conditions 05: tR=0.96 min; [M+H]+=518.20.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and butyric acid.
LC-MS-conditions 02: tR=1.02 min; [M+H]+=417.45.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(4-fluoro-phenyl)-propionic acid.
LC-MS-conditions 05: tR=0.99 min; [M+H]+=497.16.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-phenyl-acrylic acid.
LC-MS-conditions 05: tR=0.99 min; [M+H]+=477.13.
Following general procedure D, starting from (5R*)—N5-(4-bromo-phenyl)-6-(6R*)-(amino-methyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid.
LC-MS-conditions 05: tR=0.95 min; [M+H]+=502.99.
Following general procedures I then G, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and [4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-yl]-methylamine.
LC-MS-conditions 01: tR=0.66 min; [M+H]+=471.17.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 1-(4-amino-phenyl)-ethanone.
LC-MS-conditions 02: tR=0.78 min; [M+H]+=450.55.
Following general procedure F, starting from (5R*)—N5-(5-methyl-thiazol-2-yl)-(6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(1-pyrrolidino)-butylamine.
LC-MS-conditions 02: tR=0.77 min; [M+H]+=429.17.
Following general procedures I then G, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and [5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-methylamine.
LC-MS-conditions 02: tR=0.74 min; [M+H]+=470.48.
Following general procedure J, starting from (5R)—N5-(5-acetyl-furan-2-yl-methyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(1-pyrrolidino)-butylamine.
LC-MS-conditions 02: tR=0.71 min; [M+H]+=454.27.
Following general procedure J, starting from (5R)—N5-(5-acetyl-furan-2-yl-methyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 4-(1-pyrrolidino)-butylamine.
LC-MS-conditions 02: tR=0.73 min; [M+H]+=456.18.
Following general procedure I, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-aminobenzotrifluoride.
LC-MS-conditions 01: tR=0.85 min; [M+H]+=476.13.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5R*)—N5-(2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-yl-methyl)-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide (1.0 eq.) in THF (0.05 M) was added a 1 M solution of TBAF in THF (1.5 eq.) at 0° C. The reaction mixture was stirred at rt until completion of the reaction. The reaction mixture was diluted with EA, washed with brine (3×), dried over MgSO4, filtered, and the solvents were removed under reduced pressure in order to give (5R*)—N5-(2-(1-hydroxy-ethyl)-oxazol-5-yl-methyl)-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide. The crude material was dissolved in AcCN (0.06 M) and treated with MnO2 (5.5 eq.) at 50° C. Once the reaction was completed, the mixture was filtered and concentrated under reduced pressure. Purification by HPLC gave the title compound.
LC-MS-conditions 01: tR=0.66 min; [M+H]+=455.23.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-bromo-phenyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-(4,5-dimethyl-1H-imidazol-2-yl)-ethylamine.
LC-MS-conditions 05c: tR=0.59 min; [M+H]+=483.20.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-iodo-benzylamine hydrochloride.
LC-MS-conditions 06: tR=0.68 min; [M+H]+=547.75.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 1-(5-isobutyl-isoxazol-3-yl)-methylamine.
LC-MS-conditions 06: tR=0.64 min; [M+H]+=468.89.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (2-bromothiophen-4-yl)-methylamine.
LC-MS-conditions 06: tR=0.67 min; [M+H]+=506.49.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-bromo-2-fluorobenzylamine hydrochloride.
LC-MS-conditions 06: tR=0.69 min; [M+H]+=517.75.
Following general procedure J, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-amino-N,N-dimethylpropanamide.
LC-MS-conditions FA: tR=0.94 min; [M+H]+=460.11.
Following general procedure J, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-aminobutanamide hydrochloride.
LC-MS-conditions FA: tR=0.87 min; [M+H]+=446.08.
Following general procedure J, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-amino-1-(pyrrolidin-1-yl)propan-1-one hydrochloride.
LC-MS-conditions FA: tR=0.98 min; [M+H]+=486.11.
Following general procedure J, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-aminoacetamide hydrochloride.
LC-MS-conditions FA: tR=0.84 min; [M+H]+=418.04.
Following general procedure E, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(4-ethylpiperazin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.57 min; [M+H]+=529.20.
Following general procedure E, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(piperidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.67 min; [M+H]+=500.14.
Following general procedure E, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(azetidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.64 min; [M+H]+=472.12.
Following general procedure E, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-morpholinobutan-1-amine.
LC-MS-conditions TFA: tR=0.63 min; [M+H]+=502.19.
Following general procedure K, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(4-methyl-1,4-diazepan-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.56 min; [M+H]+=529.19.
Following general procedure K, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(4-methylpiperazin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.58 min; [M+H]+=515.17.
Following general procedure E, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-amino-1-(pyrrolidin-1-yl)butan-1-one hydrochloride.
LC-MS-conditions FA: tR=1.00 min; [M+H]+=500.13.
Following general procedure K, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-(2-(pyrrolidin-1-yl)ethoxy)ethanamine hydrochloride.
LC-MS-conditions TFA: tR=0.66 min; [M+H]+=502.15.
Following general procedure K, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (3R,6S)-6-(pyrrolidin-1-ylmethyl)tetrahydro-2H-pyran-3-amine hydrochloride.
LC-MS-conditions TFA: tR=0.68 min; [M+H]+=528.20.
Following general procedure I, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-(4-(4-aminobutyl)piperazin-1-yl)ethanone.
LC-MS-conditions TFA: tR=0.62 min; [M+H]+=543.15.
Following general procedure L, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and cis-4-(pyrrolidin-1-ylmethyl)cyclohexanamine.
LC-MS-conditions TFA: tR=0.68 min; [M+H]+=526.25.
Following general procedure E, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (R)-4-(3-fluoropyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.66 min; [M+H]+=504.18.
Following general procedure E, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and (S)-4-(3-fluoropyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.65 min; [M+H]+=504.16.
Following general procedure K, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 5-(pyrrolidin-1-yl)pentan-1-amine.
LC-MS-conditions TFA: tR=0.67 min; [M+H]+=500.14.
Following general procedure L, starting from (5R)—N5-(4-bromo-phenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and trans-4-(pyrrolidin-1-ylmethyl)cyclohexanamine.
LC-MS-conditions TFA: tR=0.69 min; [M+H]+=526.19.
Following general procedure N, starting from (5R*)—N5-(4-bromo-phenyl)-(6R*)—N6-(2-methoxycarbonyl-ethyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide and methylamine.
LC-MS-conditions FA: tR=0.88 min; [M+H]+=446.10.
Following general procedures I then G, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (2-(2-methyl-[1,3]dioxolan-2-yl)thiazol-5-yl)methanamine.
LC-MS-conditions TFA: tR=0.48 min; [M+H]+=471.25.
Following general procedure K, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-pyrrolidin-1-yl-butylamine.
LC-MS-conditions TFA: tR=0.61 min; [M+H]+=493.09.
Following general procedure I, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2,6-difluoro-4-methoxybenzylamine.
LC-MS-conditions TFA: tR=0.59 min; [M+H]+=488.26.
Following general procedure I, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2,3-difluoro-4-methoxybenzylamine.
LC-MS-conditions FA: tR=0.73 min; [M+H]+=488.28.
Following general procedure I, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3-fluoro-4-methoxybenzylamine.
LC-MS-conditions TFA: tR=0.56 min; [M+H]+=470.28.
Following general procedure I, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3,5-difluoro-4-methoxybenzylamine.
LC-MS-conditions FA: tR=0.74 min; [M+H]+=488.29.
Following general procedure I, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-chlorobenzylamine.
LC-MS-conditions FA: tR=0.77 min; [M+H]+=456.24.
Following general procedure I, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-fluorobenzylamine.
LC-MS-conditions FA: tR=0.70 min; [M+H]+=440.27.
Following general procedure I, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-trifluoromethoxybenzylamine.
LC-MS-conditions FA: tR=0.86 min; [M+H]+=506.26.
Following general procedure I, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-isopropoxybenzylamine.
LC-MS-conditions FA: tR=0.81 min; [M+H]+=480.33.
Following general procedure I, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (4-bromothiazol-2-yl)methanamine.
LC-MS-conditions TFA: tR=0.52 min; [M+H]+=507.12.
Following general procedures I then G, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (2-(2-methyl-[1,3]dioxolan-2-yl)oxazol-4-yl)methanamine.
LC-MS-conditions TFA: tR=0.47 min; [M+H]+=455.33.
Following general procedure B, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(pyrrolidin-1-yl)propan-1-amine.
LC-MS-conditions TFA: tR=0.62 min; [M+H]+=486.17.
Following general procedure B, starting from (5R*)—N5-(5-bromo-thiazol-2-yl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(pyrrolidin-1-yl)propan-1-amine.
LC-MS-conditions TFA: tR=0.60 min; [M+H]+=479.09.
Following general procedure F, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.65 min; [M+H]+=495.19.
Following general procedure E, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 3-aminopropanamide hydrochloride.
LC-MS-conditions FA: tR=0.84 min; [M+H]+=441.06.
Following general procedure E, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-aminopropanamide hydrochloride.
LC-MS-conditions FA: tR=0.79 min; [M+H]+=439.04.
Following general procedure M, starting from (5R)—N5-(4-bromophenyl-methyl)-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide and NH4OH.
LC-MS-conditions FA: tR=0.81 min; [M+H]+=446.11.
Following general procedure E, starting from (5R)—N5-(2-bromo-pyrid-5-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-aminopropanamide hydrochloride.
LC-MS-conditions FA: tR=0.70 min; [M+H]+=433.07.
Following general procedures I then G, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (4-(2-methyl-[1,3]dioxolan-2-yl)-oxazol-2-yl)methanamine.
LC-MS-conditions TFA: tR=0.43 min; [M+H]+=455.23.
Following general procedure B, starting from (5R*)—N5-(4-acetyl-thiazol-2-yl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and isobutylamine.
LC-MS-conditions FA: tR=0.83 min; [M+H]+=402.18.
Following general procedure B, starting from (5R*)—N5-(5-bromo-thiazol-2-yl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and isobutylamine.
LC-MS-conditions FA: tR=1.10 min; [M+H]+=424.06.
Following general procedure B, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and isobutylamine.
LC-MS-conditions FA: tR=1.10 min; [M+H]+=431.12.
Following general procedure B, starting from (5R*)—N5-(4-acetyl-thiazol-2-yl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(1H-benzo[d]imidazol-2-yl)propan-1-amine.
LC-MS-conditions FA: tR=0.63 min; [M+H]+=504.18.
Following general procedure B, starting from (5R*)—N5-(5-bromo-thiazol-2-yl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(1H-benzo[d]imidazol-2-yl)propan-1-amine.
LC-MS-conditions FA: tR=0.83 min; [M+H]+=526.05.
Following general procedure B, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(1H-benzo[d]imidazol-2-yl)propan-1-amine.
LC-MS-conditions FA: tR=0.86 min; [M+H]+=533.15.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 6-methoxypyridin-3-amine.
LC-MS-conditions TFA: tR=0.48 min; [M+H]+=439.27.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 5-bromopyrazin-2-amine.
LC-MS-conditions TFA: tR=0.58 min; [M+H]+=488.15.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 5-(trifluoromethyl)pyridin-2-amine.
LC-MS-conditions TFA: tR=0.66 min; [M+H]+=477.26.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 6-methylpyridin-3-amine.
LC-MS-conditions TFA: tR=0.40 min; [M+H]+=423.28.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and benzo[d]oxazol-6-amine.
LC-MS-conditions TFA: tR=0.51 min; [M+H]+=449.26.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (5-methylisoxazol-3-yl)methanamine.
LC-MS-conditions TFA: tR=0.47 min; [M+H]+=427.25.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-methylthiazol-2-amine.
LC-MS-conditions TFA: tR=0.52 min; [M+H]+=429.24.
(5R*)—N5-(5-Trifluoromethyl -1,3,4-thiadiazol-2-yl)-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide, hydrochloride
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine.
LC-MS-conditions TFA: tR=0.62 min; [M+H]+=484.21.
Following general procedure E, starting from (5R)—N5-(2-bromo-pyrid-5-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-pyrrolidino-butylamine.
LC-MS-conditions TFA: tR=0.56 min; [M+H]+=487.20.
Following general procedure B, starting from (5R*)—N5-(5-bromo-thiazol-2-yl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-fluoroethanamine.
LC-MS-conditions FA: tR=0.94 min; [M+H]+=414.02.
Following general procedure B, starting from (5R*)—N5-(5-bromo-thiazol-2-yl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-(2-aminoethyl)imidazolidin-2-one.
LC-MS-conditions FA: tR=0.82 min; [M+H]+=480.05.
Following general procedure B, starting from (5R*)—N5-(4-acetyl-thiazol-2-yl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-aminopropanamide hydrochloride.
LC-MS-conditions FA: tR=0.54 min; [M+H]+=417.14.
Following general procedure B, starting from (5R*)—N5-(4-acetyl-thiazol-2-yl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(diethylamino)butylamine.
LC-MS-conditions TFA: tR=0.46 min; [M+H]+=473.30.
Following general procedure B, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-ethoxy-propylamine.
LC-MS-conditions FA: tR=1.03 min; [M+H]+=461.12.
Following general procedure B, starting from (5R*)—N5-(4-acetyl-thiazol-2-yl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-(3-aminopropyl)pyrrolidine.
LC-MS-conditions TFA: tR=0.44 min; [M+H]+=457.22.
Following general procedure B, starting from (5R*)—N5-(5-bromo-thiazol-2-yl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-(3-aminopropyl)-4-methylpiperazine.
LC-MS-conditions TFA: tR=0.53 min; [M+H]+=508.14.
Following general procedure B, starting from (5R*)—N5-(4-acetyl-thiazol-2-yl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-dimethylamino-ethylamine.
LC-MS-conditions TFA: tR=0.43 min; [M+H]+=417.18.
Following general procedure B, starting from (5R*)—N5-(4-acetyl-thiazol-2-yl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-dimethylamino-1-propylamine.
LC-MS-conditions TFA: tR=0.43 min; [M+H]+=431.24.
Following general procedure B, starting from (5R*)—N5-(4-acetyl-thiazol-2-yl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-(3-aminopropyl)-4-methyl-piperazine.
LC-MS-conditions TFA: tR=0.40 min; [M+H]+=486.22.
Following general procedure B, starting from (5R*)—N5-(4-acetyl-thiazol-2-yl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-(2-aminoethyl)imidazolidin-2-one.
LC-MS-conditions FA: tR=0.58 min; [M+H]+=458.19.
Following general procedure B, starting from (5R*)—N5-(5-bromo-thiazol-2-yl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(diethylamino)butylamine.
LC-MS-conditions TFA: tR=0.62 min; [M+H]+=495.13.
Following general procedure B, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-fluoroethylamine hydrochloride.
LC-MS-conditions FA: tR=0.95 min; [M+H]+=421.08.
Following general procedure B, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(diethylamino)butylamine.
LC-MS-conditions TFA: tR=0.64 min; [M+H]+=502.16.
Following general procedure B, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-(3-aminopropyl)-4-methyl-piperazine.
LC-MS-conditions TFA: tR=0.55 min; [M+H]+=515.21.
Following general procedure B, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-dimethylamino-ethylamine.
LC-MS-conditions TFA: tR=0.60 min; [M+H]+=446.16.
Following general procedure B, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-(2-aminoethyl)imidazolidin-2-one.
LC-MS-conditions FA: tR=0.84 min; [M+H]+=487.12.
Following general procedure B, starting from (5R*)—N5-(5-bromo-thiazol-2-yl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-methoxy-ethylamine.
LC-MS-conditions FA: tR=0.93 min; [M+H]+=426.04.
Following general procedure B, starting from (5R*)—N5-(5-bromo-thiazol-2-yl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-dimethylamino-1-propylamine.
LC-MS-conditions TFA: tR=0.58 min; [M+H]+=453.10.
Following general procedure E, starting from (5R)—N5-(2-bromo-pyrid-5-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 3-aminopropanamide hydrochloride.
LC-MS-conditions FA: tR=0.76 min; [M+H]+=435.10.
Following general procedure E, starting from (5R)—N5-(2-bromo-pyrid-5-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 4-(1-pyrrolidino)butylamine.
LC-MS-conditions TFA: tR=0.60 min; [M+H]+=489.17.
Following general procedure M, starting from (5R)—N5-(5-bromopyrid-2-yl)-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide and NH4OH.
LC-MS-conditions FA: tR=0.79 min; [M+H]+=433.08.
Following general procedure M, starting from (5R)—N5-(2-chloropyrid-5-yl)-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide and NH4OH.
LC-MS-conditions FA: tR=0.68 min; [M+H]+=389.14.
Following general procedure M, starting from (5R)—N5-(4-bromo-2-fluorophenyl-methyl)-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide and NH4OH.
LC-MS-conditions FA: tR=0.83 min; [M+H]+=464.06.
Following general procedure M, starting from (5R)—N5-[(2-bromothiazol-5-yl)methyl]-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide and NH4OH.
LC-MS-conditions FA: tR=0.64 min; [M+H]+=453.01.
Following general procedure I, starting from (5R)-5-hydroxycarbonyl-(6R)—N6-(4-pyrrolidin-1-yl-butyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-bromo-2-fluorobenzylamine hydrochloride.
LC-MS-conditions TFA: tR=0.64 min; [M+H]+=518.13.
Following general procedure I, starting from (5R)-5-hydroxycarbonyl-(6R)—N6-(4-pyrrolidin-1-yl-butyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-amino-anisole.
LC-MS-conditions TFA: tR=0.56 min; [M+H]+=438.25.
Following general procedure I, starting from (5R)-5-hydroxycarbonyl-(6R)—N6-(4-pyrrolidin-1-yl-butyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-bromo-benzylamine.
LC-MS-conditions TFA: tR=0.63 min; [M+H]+=500.10.
A solution of (5R)—N5-(4-methoxy-phenyl)-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide in THF (0.09 M) was treated with aq. 1N NaOH (4.0 eq.) at rt until completion of the reaction. The reaction mixture was poured into aq. 2N HCl and extracted with EA (3×). The combined organic extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a brown oil.
LC-MS-conditions FA: tR=0.75 min; [M+H]+=385.15.
Following general procedure F, starting from (5R)—N5-(4-bromo-3-fluorophenyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.68 min; [M+H]+=504.13.
Following general procedure F, starting from (5R)—N5-(2-chloro-pyridin-5-yl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.54 min; [M+H]+=443.21.
Following general procedure M, starting from (5R)—N5-(4-methoxy-phenyl)-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide and NH4OH.
LC-MS-conditions FA: tR=0.69 min; [M+H]+=384.19.
Following general procedure M, starting from (5R)—N5-(4-bromophenyl-methyl)-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5,6-dicarboxamide and NH4OH.
LC-MS-conditions FA: tR=0.86 min; [M+H]+=448.11.
Following general procedure M, starting from (5R)—N5-(4-bromo-2-fluorophenyl-methyl)-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5,6-dicarboxamide and NH4OH.
LC-MS-conditions FA: tR=0.88 min; [M+H]+=466.10.
Following general procedure M, starting from (5R)—N5-(4-methoxy-phenyl)-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5,6-dicarboxamide and NH4OH.
LC-MS-conditions FA: tR=0.76 min; [M+H]+=386.20.
Following general procedure I, starting from (5R)—N5-(5-bromo-pyridin-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.63 min; [M+H]+=487.16.
Following general procedure I, starting from (5R)—N5-(4-bromo-2-fluorophenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.67 min; [M+H]+=504.16.
Following general procedure E, starting from (5R)—N5-(4-bromo-2-methylphenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.67 min; [M+H]+=500.14.
Following general procedure L, starting from (5R)-5-hydroxycarbonyl-(6R)—N6-(4-pyrrolidin-1-yl-butyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-bromo-3-chloroaniline.
LC-MS-conditions TFA: tR=0.72 min; [M+H]+=520.16.
Following general procedure M, starting from (5R)—N5-(2-chloropyrid-5-yl)-(6R)—N6-(2-methoxycarbonyl-ethyl)-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5,6-dicarboxamide and NH4OH.
LC-MS-conditions FA: tR=0.74 min; [M+H]+=391.15.
Following general procedures B then H, starting from (5R*)—N5-(4-acetyl-thiazol-2-yl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-1,3-propanediamine.
LC-MS-conditions TFA: tR=0.41 min; [M+H]+=403.18.
Following general procedures B then H, starting from (5R*)—N5-(4-acetyl-thiazol-2-yl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-tert-butoxycarbonyl-4-(aminomethyl)piperidine.
LC-MS-conditions TFA: tR=0.45 min; [M+H]+=443.20.
Following general procedures B then H, starting from (5R*)—N5-(5-bromo-thiazol-2-yl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-N-methylethylenediamine.
LC-MS-conditions TFA: tR=0.56 min; [M+H]+=425.03.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-bromo-2-fluorobenzylamine hydrochloride.
LC-MS-conditions TFA: tR=0.60 min; [M+H]+=453.04.
Following general procedures B then H, starting from (5R*)—N5-(5-bromo-thiazol-2-yl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-(N-tert-butoxycarbonyl-aminomethyl)-4-(aminomethyl)benzene.
LC-MS-conditions TFA: tR=0.61 min; [M+H]+=487.09.
Following general procedures B then H, starting from (5R*)—N5-(5-bromo-thiazol-2-yl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(tert-butoxycarbonyl-amino)-2,2-dimethyl-propylamine.
LC-MS-conditions TFA: tR=0.61 min; [M+H]+=453.09.
Following general procedures B then H, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-N-methylethylenediamine.
LC-MS-conditions TFA: tR=0.59 min; [M+H]+=432.18.
Following general procedures B then H, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-4-aminopiperidine.
LC-MS-conditions TFA: tR=0.60 min; [M+H]+=458.17.
Following general procedures B then H, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-1,3-propanediamine.
LC-MS-conditions TFA: tR=0.59 min; [M+H]+=432.06.
Following general procedures B then H, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-(N-tert-butoxycarbonyl-aminomethyl)-3-(aminomethyl)benzene.
LC-MS-conditions TFA: tR=0.64 min; [M+H]+=494.17.
Following general procedures B then H, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-(N-tert-butoxycarbonyl-aminomethyl)-4-(aminomethyl)benzene.
LC-MS-conditions TFA: tR=0.63 min; [M+H]+=494.12.
Following general procedures B then H, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-(tert-butoxycarbonyl-amino)-2,2-dimethyl-propylamine.
LC-MS-conditions TFA: tR=0.63 min; [M+H]+=460.13.
Following general procedures B then H, starting from (5R*)—N5-(4-bromophenyl-methyl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-tert-butoxycarbonyl-4-(aminomethyl)piperidine.
LC-MS-conditions TFA: tR=0.60 min; [M+H]+=472.16.
Following general procedure I, starting from (5R)-5-hydroxycarbonyl-(6R)—N6-(4-pyrrolidin-1-yl-butyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (2-bromo-thiazol-5-yl)methanamine.
LC-MS-conditions TFA: tR=0.52 min; [M+H]+=507.13.
Following general procedure E, starting from (5R)—N5-(5-methyl-pyridin-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-aminopropanamide hydrochloride.
LC-MS-conditions FA: tR=0.56 min; [M+H]+=369.19.
Following general procedure E, starting from (5R)—N5-(4-bromo-2,5-difluorophenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.70 min; [M+H]+=522.17.
Following general procedure E, starting from (5R)—N5-(4-bromo-2,6-difluorophenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.62 min; [M+H]+=522.17.
Following general procedure E, starting from (5R)—N5-(4-bromo-2,3-difluorophenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.69 min; [M+H]+=522.14.
Following general procedure E, starting from (5R)-5-hydroxycarbonyl-(6R)—N6-(4-pyrrolidin-1-yl-butyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (4-bromo-2,6-difluorophenyl)-methanamine.
LC-MS-conditions TFA: tR=0.64 min; [M+H]+=536.12.
Following general procedure I, starting from (5R)—N5-(4-bromo-2-fluorophenyl-methyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.68 min; [M+H]+=520.20.
Following general procedures I then H, starting from (5R)—N5-(4-bromo-2-fluorophenyl-methyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-1,5-pentanediamine.
LC-MS-conditions TFA: tR=0.62 min; [M+H]+=478.13.
Following general procedures I then H, starting from (5R)—N5-(4-bromo-2-fluorophenyl-methyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-1,4-butanediamine.
LC-MS-conditions TFA: tR=0.61 min; [M+H]+=464.12.
Following general procedure F, starting from (5R)—N5-(4-bromo-3-fluorophenyl-methyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.65 min; [M+H]+=518.16.
Following general procedures I then H, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-1,5-pentanediamine.
LC-MS-conditions TFA: tR=0.61 min; [M+H]+=453.05.
Following general procedures I then H, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-amino-1-tert-butoxycarbonyl-piperidine.
LC-MS-conditions TFA: tR=0.57 min; [M+H]+=451.10.
Following general procedures I then H, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(aminomethyl)-1-tert-butoxycarbonyl-piperidine.
LC-MS-conditions TFA: tR=0.58 min; [M+H]+=465.16.
Following general procedures I then H, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(tert-butoxycarbonyl-aminomethyl)piperidine.
LC-MS-conditions TFA: tR=0.57 min; [M+H]+=465.07.
Following general procedures I then H, starting from (5R)—N5-(4-bromo-2-fluorophenyl-methyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-1,5-pentanediamine.
LC-MS-conditions TFA: tR=0.64 min; [M+H]+=480.12.
Following general procedure I, starting from (5R)—N5-(4-bromo-2,3-difluorophenyl-methyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.64 min; [M+H]+=536.17.
Following general procedure I, starting from (5R)—N5-(4-bromo-3,5-difluorophenyl-methyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.64 min; [M+H]+=536.12.
Following general procedure I, starting from (5R)—N5-(4-bromo-2,5-difluorophenyl-methyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.65 min; [M+H]+=536.22.
Following general procedures I then H, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 4-amino-1-tert-butoxycarbonyl-piperidine.
LC-MS-conditions TFA: tR=0.60 min; [M+H]+=453.04.
Following general procedure I, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and isobutylamine.
LC-MS-conditions FA: tR=1.15 min; [M+H]+=426.08.
Following general procedure I, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-1,4-butanediamine.
LC-MS-conditions FA: tR=1.16 min; [M+H]+=541.09.
Following general procedure I, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-1,5-pentanediamine.
LC-MS-conditions FA: tR=1.20 min; [M+H]+=555.12.
Following general procedures I then H, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-1,5-pentanediamine.
LC-MS-conditions TFA: tR=0.63 min; [M+H]+=455.11.
Following general procedures I then H, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-1,4-butanediamine.
LC-MS-conditions TFA: tR=0.61 min; [M+H]+=441.10.
Following general procedures I then H, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 4-(tert-butoxycarbonyl-aminomethyl)piperidine.
LC-MS-conditions TFA: tR=0.61 min; [M+H]+=467.15.
Following general procedures I then H, starting from (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 1-tert-butoxycarbonyl-4-(aminomethyl)piperidine.
LC-MS-conditions TFA: tR=0.62 min; [M+H]+=467.12.
Following general procedure F, starting from (5R)—N5-(2-bromo-3-fluoro-pyridin-5-yl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.61 min; [M+H]+=505.12.
(5R*)—N5-(4-Aminobutyl)-(6R*)—N6-(4-bromophenyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide
Following general procedures A then H, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-bromo-phenyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and N-tert-butoxycarbonyl-1,4-butanediamine.
LC-MS-conditions TFA: tR=0.63 min; [M+H]+=432.12.
Following general procedures A then H, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-bromo-phenyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and N-tert-butoxycarbonyl-1,5-pentanediamine.
LC-MS-conditions TFA: tR=0.65 min; [M+H]+=446.14.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-(1-cyclohexenyl)ethylamine.
LC-MS-conditions TFA: tR=0.66 min; [M+H]+=440.36.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-tert-butylcyclohexylamine.
LC-MS-conditions TFA: tR=0.78 min; [M+H]+=470.39.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-(2-aminoethyl)pyridine.
LC-MS-conditions TFA: tR=0.35 min; [M+H]+=437.27.
Following general procedure E, starting from (5R*)—N5-(4-acetyl-thiazol-2-yl)-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.50 min; [M+H]+=457.26.
Following general procedure C, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-trifluoromethyl-thiazole-2-ylamine.
LC-MS-conditions TFA: tR=0.64 min; [M+H]+=483.20.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2,4,6-trifluorobenzylamine.
LC-MS-conditions TFA: tR=0.58 min; [M+H]+=476.24.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2,4-dimethylbenzylamine.
LC-MS-conditions TFA: tR=0.649 min; [M+H]+=450.31.
Following general procedure I, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (2-acetyl-thiazol-4-yl)-methanamine.
LC-MS-conditions TFA: tR=0.49 min; [M+H]+=471.23.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3-chloro-2-fluorobenzylamine.
LC-MS-conditions TFA: tR=0.62 min; [M+H]+=474.23.
Following general procedure F, starting from (5R*)—N5-(4-methyl-oxazol-2-yl)-(6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.46 min; [M+H]+=413.25.
Following general procedures I then G, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (5-(2-methyl-[1,3]dioxolan-2-yl)thiazol-2-yl)methanamine.
LC-MS-conditions TFA: tR=0.46 min; [M+H]+=471.23.
Following general procedure I, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 1-(3-aminophenyl)ethanone.
LC-MS-conditions TFA: tR=0.55 min; [M+H]+=450.28.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-bromo-4-fluorobenzylamine hydrochloride.
LC-MS-conditions TFA: tR=0.63 min; [M+H]+=518.18.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3-bromo-4-fluorobenzylamine hydrochloride.
LC-MS-conditions TFA: tR=0.63 min; [M+H]+=518.21.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2,3,5-trifluorobenzylamine.
LC-MS-conditions TFA: tR=0.60 min; [M+H]+=476.26.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (4-methyl-1,2,5-oxadiazol-3-yl)methanamine hydrochloride.
LC-MS-conditions TFA: tR=0.48 min; [M+H]+=428.26.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-fluoro-3-(trifluoromethyl)benzylamine.
LC-MS-conditions TFA: tR=0.65 min; [M+H]+=508.25.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3,5-dimethylbenzylamine.
LC-MS-conditions TFA: tR=0.66 min; [M+H]+=450.31.
Following general procedures I then G, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (3-(2-methyl-[1,3]dioxolan-2-yl)-phenyl)methanamine.
LC-MS-conditions TFA: tR=0.52 min; [M+H]+=464.28.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3-(difluoromethoxy)benzylamine.
LC-MS-conditions TFA: tR=0.60 min; [M+H]+=488.27.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (2-methoxypyridin-4-yl)methanamine.
LC-MS-conditions TFA: tR=0.40 min; [M+H]+=453.25.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3-fluoro-5-(trifluoromethyl)benzylamine.
LC-MS-conditions TFA: tR=0.66 min; [M+H]+=508.27.
Following general procedure I, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 1-(4-(aminomethyl)phenyl)ethanone.
LC-MS-conditions TFA: tR=0.51 min; [M+H]+=464.24.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-chloro-5-(trifluoromethyl)benzylamine.
LC-MS-conditions TFA: tR=0.68 min; [M+H]+=524.22.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-fluoro-5-(trifluoromethyl)benzylamine.
LC-MS-conditions TFA: tR=0.65 min; [M+H]+=508.24.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-fluoro-3-(trifluoromethyl)benzylamine.
LC-MS-conditions TFA: tR=0.66 min; [M+H]+=508.26.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (2,6-dichloropyridin-4-yl)methanamine.
LC-MS-conditions TFA: tR=0.58 min; [M+H]+=491.18.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2,5-dimethylbenzylamine.
LC-MS-conditions TFA: tR=0.64 min; [M+H]+=450.30.
Following general procedure F, starting from (5R*)—N5-(4,5-dimethyl-thiazol-2-yl)-(6R*)-6-ethoxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.55 min; [M+H]+=443.25.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (2-methoxy-5-methylphenyl)methanamine hydrochloride.
LC-MS-conditions TFA: tR=0.62 min; [M+H]+=466.32.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-chloro-3,6-difluorobenzylamine.
LC-MS-conditions TFA: tR=0.61 min; [M+H]+=492.20.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and (2-isopropoxyphenyl)methanamine.
LC-MS-conditions TFA: tR=0.66 min; [M+H]+=480.31.
Following general procedure A, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-chloro-6-fluoro-3-methylbenzylamine.
LC-MS-conditions TFA: tR=0.64 min; [M+H]+=488.27.
Following general procedure N, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3-chloro-4-methoxybenzylamine hydrochloride.
LC-MS-conditions FA: tR=0.75 min; [M+H]+=486.24.
Following general procedure N, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3,4-dimethoxybenzylamine.
LC-MS-conditions FA: tR=0.64 min; [M+H]+=482.32.
Following general procedure N, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2,4-dimethoxybenzylamine.
LC-MS-conditions FA: tR=0.73 min; [M+H]+=482.30.
Following general procedure N, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-(3,4-dimethoxyphenyl)ethylamine.
LC-MS-conditions TFA: tR=0.56 min; [M+H]+=496.30.
Following general procedure N, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-(4-methoxyphenyl)ethylamine.
LC-MS-conditions TFA: tR=0.58 min; [M+H]+=466.32.
Following general procedure N, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-bromophenethylamine.
LC-MS-conditions TFA: tR=0.65 min; [M+H]+=514.23.
Following general procedure N, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3,4-Dimethylphenethylamine hydrochloride.
LC-MS-conditions TFA: tR=0.67 min; [M+H]+=464.28.
Following general procedure N, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2-(p-tolyl)ethylamine.
LC-MS-conditions TFA: tR=0.63 min; [M+H]+=450.33.
Following general procedure N, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-fluorophenethylamine.
LC-MS-conditions TFA: tR=0.59 min; [M+H]+=454.29.
Following general procedure N, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3,4-methylenedioxyphenethylamine hydrochloride.
LC-MS-conditions TFA: tR=0.57 min; [M+H]+=480.28.
Following general procedure N, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 3-bromo-4-methoxyphenethylamine.
LC-MS-conditions TFA: tR=0.63 min; [M+H]+=544.22.
Following general procedure N, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 2,4-dimethylphenethylamine.
LC-MS-conditions TFA: tR=0.67 min; [M+H]+=464.32.
Following general procedure N, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 4-ethoxybenzylamine.
LC-MS-conditions TFA: tR=0.60 min; [M+H]+=466.32.
Following general procedure I, starting from (5R)—N5-(2-(4-chlorophenyl)ethyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.64 min; [M+H]+=470.25.
Following general procedure D, starting from (5R)—N5-(2-(4-chlorophenyl)ethyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-dimethylamino-ethylamine.
LC-MS-conditions TFA: tR=0.61 min; [M+H]+=416.21.
Following general procedure D, starting from (5R)—N5-(2-(4-chlorophenyl)ethyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 2-(2-aminoethyl)pyridine.
LC-MS-conditions FA: tR=0.80 min; [M+H]+=450.21.
Following general procedure D, starting from (5R)—N5-(2-(4-chlorophenyl)ethyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(2-aminoethyl)benzene sulfonamide.
LC-MS-conditions FA: tR=0.95 min; [M+H]+=528.16.
Following general procedure I, starting from (5R)—N5-(2-(2,4-dichlorophenyl)ethyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.69 min; [M+H]+=504.22.
Following general procedure I, starting from (5R)—N5-(2-(4-chlorophenyl)ethyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 1-(3-methyl-butyl)-piperidin-4-ylamine hydrochloride.
LC-MS-conditions TFA: tR=0.70 min; [M+H]+=498.30.
Following general procedure F, starting from (5R)—N5-(4-bromo-3,5-difluorophenyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.71 min; [M+H]+=522.13.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a freshly prepared solution of lithium di-isopropylamide (3.4 eq.) in THF (0.3 M) was added a 0.1 M solution of (5R)—N5-(5-bromo-thiazol-2-yl)-(6R)—N6-(4-pyrrolidino-butyl)-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5,6-dicarboxamide at 0° C. The reaction mixture was stirred at 0° C. until completion of the reaction. Water (3.0 eq.) was added and the mixture stirred at rt for 15 h, diluted with EA, washed with brine, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification by FC gave the title compound.
LC-MS-conditions TFA: tR=0.59 min; [M+H]+=493.15.
Following general procedure F, starting from (5R)—N5-(4-bromo-3-trifluoromethylphenyl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.75 min; [M+H]+=554.16.
Following general procedures B then H, starting from (5R*)—N5-[(4-acetyl-thiazol-2-yl)methyl]-(6R*)-6-hydroxycarbonyl-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-N-methylethylenediamine.
LC-MS-conditions TFA: tR=0.42 min; [M+H]+=403.19.
Following general procedure E, starting from (5R)—N5-(4-bromophenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(2,5-dimethylpyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.69 min; [M+H]+=514.19.
Following general procedure E, starting from (5R)—N5-(4-bromophenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)pentan-1-amine hydrochloride.
LC-MS-conditions TFA: tR=0.67 min; [M+H]+=500.16.
Following general procedure E, starting from (5R)—N5-(4-bromophenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 3-fluoro-4-(pyrrolidin-1-yl)butan-1-amine hydrochloride.
LC-MS-conditions TFA: tR=0.66 min; [M+H]+=504.15.
Following general procedure E, starting from (5R)—N5-(4-bromophenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(2-(methoxymethyl)pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.68 min; [M+H]+=530.20.
Following general procedure E, starting from (5R)—N5-(4-bromophenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and 4-(3,3-difluoropyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.67 min; [M+H]+=522.14.
Following general procedure F, starting from (5R)—N5-(2-bromo-3-fluoro-pyridin-5-yl)-(6R)-6-methoxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 4-(pyrrolidin-1-yl)butan-1-amine.
LC-MS-conditions TFA: tR=0.65 min; [M+H]+=507.17.
Following general procedure I, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and ethanolamine.
LC-MS-conditions FA: tR=0.87 min; [M+H]+=414.03.
Following general procedure I, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 3-aminopropan-1-ol.
LC-MS-conditions FA: tR=0.90 min; [M+H]+=428.03.
Following general procedure I, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 4-aminobutan-1-ol.
LC-MS-conditions FA: tR=0.92 min; [M+H]+=442.06.
Following general procedure I, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 2-amino-2-methylpropan-1-ol.
LC-MS-conditions FA: tR=1.00 min; [M+H]+=442.06.
Following general procedure I, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 2-(2-aminoethoxy)ethanol.
LC-MS-conditions FA: tR=0.88 min; [M+H]+=458.05.
Following general procedure I, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and trans-4-amino-cyclohexanol hydrochloride.
LC-MS-conditions FA: tR=0.96 min; [M+H]+=468.06.
Following general procedure I, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 1-aminomethyl-1-cyclohexanol hydrochloride.
LC-MS-conditions FA: tR=1.08 min; [M+H]+=482.08.
Following general procedure I, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and (trans-4-aminocyclohexyl)methanol.
LC-MS-conditions FA: tR=1.01 min; [M+H]+=482.09.
Following general procedure I, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and (cis-4-aminocyclohexyl)methanol.
LC-MS-conditions FA: tR=0.99 min; [M+H]+=482.08.
Following general procedures I then H, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 3-amino-1-tert-butoxycarbonyl-pyrrolidine hydrochloride.
LC-MS-conditions 07: tR=0.60 min; [M+H]+=439.41.
Following general procedures I then H, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and N-tert-butoxycarbonyl-N-methylethylenediamine.
LC-MS-conditions 07: tR=0.60 min; [M+H]+=427.16.
Following general procedures I then H, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and N-(3-aminopropyl)-N-methylcarbamic acid tert-butyl ester.
LC-MS-conditions 07: tR=0.61 min; [M+H]+=441.16.
Following general procedures I then H, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 3-amino-N-tert-butoxycarbonyl-piperidine.
LC-MS-conditions 07: tR=0.61 min; [M+H]+=453.20.
Following general procedures I then H, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 2-aminomethyl-N-tert-butoxycarbonyl-pyrrolidine.
LC-MS-conditions 07: tR=0.62 min; [M+H]+=453.20.
Following general procedures I then H, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 2-aminomethyl-N-tert-butoxycarbonyl-piperidine.
LC-MS-conditions 07: tR=0.63 min; [M+H]+=467.23.
Following general procedures I then H, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 3-aminomethyl-N-tert-butoxycarbonyl-piperidine.
LC-MS-conditions 07: tR=0.62 min; [M+H]+=467.22.
Following general procedures I then H, starting from (5R)—N5-(5-bromothiazol-2-yl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethylene-spiro[2.4]heptane]-5-carboxamide and 3-amino-N-tert-butoxycarbonyl-azetidine.
LC-MS-conditions 07: tR=0.60 min; [M+H]+=425.15.
Following general procedures L then H, starting from (5R)—N5-(4-bromophenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and tert-butyl ((cis-4-aminocyclohexyl)methyl)carbamate.
LC-MS-conditions 07b: tR=0.69 min; [M+H]+=472.07.
Following general procedures L then H, starting from (5R)—N5-(4-bromophenyl)-(6R)-6-hydroxycarbonyl-(4S,7R)-[4,7-ethenylene-spiro[2.4]heptane]-5-carboxamide and tert-butyl ((trans-4-aminocyclohexyl)methyl)carbamate.
LC-MS-conditions 07b: tR=0.70 min; [M+H]+=472.09.
Following general procedure B, starting from (5R*)-5-hydroxycarbonyl-(6R*)—N6-(4-pyrrolidin-1-yl-butyl)-(4S*,7R*)-[4,7-ethenylene-spiro[2.4]heptane]-6-carboxamide and 5-amino-2-(trifluoromethyl)pyridine.
LC-MS-conditions TFA: tR=0.60 min; [M+H]+=477.20.
II. Biological Assays
In Vitro Assay
The ALX receptor and FPRL2 agonistic activities of the compounds of formula (I) are determined in accordance with the following experimental method.
Experimental Method:
Intracellular Calcium Measurements:
Cells expressing recombinant human ALX receptor and the G-protein Gα16 (HEK293-hALXR-Gα16) were grown to 80% confluency in Growing Medium (GM). Cells were detached from culture dishes with a cell dissociation buffer (Invitrogen, 13151-014), and collected by centrifugation at 1,000 rpm at rt for 5 min in Assay Buffer (AB) (equal parts of Hank's BSS (Gibco, 14065-049) and DMEM without Phenol Red (Gibco, 11880-028)). After 60 min incubation at 37° C. under 5% CO2 in AB supplemented with 1 μM Fluo-4 (AM) (Invitrogen, F14202), and 20 mM HEPES (Gibco, 15630-056), the cells were washed and resuspended in AB. They were then seeded onto 384-well FLIPR assay plates (Greiner, 781091) at 50′000 cells in 70 μl per well and sedimented by centrifugation at 1,000 rpm for 1 min. Stock solutions of test compounds were made up at a concentration of 10 mM in DMSO, and serially diluted in AB to concentrations required for activation dose response curves. WKYMVm (Phoenix Peptides) was used as a reference agonist. FLIPR384 or FLIPR Tetra instruments (Molecular Devices) were operated according to the manufacturer's standard instructions, adding 4 μl of test compound dissolved at 10 mM in DMSO and diluted prior to the experiment in assay buffer to obtain the desired final concentration. Changes in fluorescence were monitored before and after the addition of test compounds at lex=488 nm and lem=540 nm. Emission peak values above base level after compounds addition were exported after base line subtraction. Values were normalized to high-level control (WKYMVm compound, 10 nM final concentration) after subtraction of the base line value (AB addition).
Cells expressing recombinant human FPRL2 and the G-protein Gα16 (HEK293-hFPRL2-Gα16) were grown to 80% confluency in Growing Medium (GM). Cells were detached from culture dishes with a cell dissociation buffer (Invitrogen, 13151-014), and collected by centrifugation at 1,000 rpm at rt for 5 min in Assay Buffer (AB) (equal parts of Hank's BSS (Gibco, 14065-049) and DMEM without Phenol Red (Gibco, 11880-028)). After 60 min incubation at 37° C. under 5% CO2 in AB supplemented with 1 μM Fluo-4 (AM) (Invitrogen, F14202), and 20 mM HEPES (Gibco, 15630-056), the cells were washed and resuspended in AB. They were then seeded onto 384-well FLIPR assay plates (Greiner, 781091) at 50′000 cells in 70 μl per well and sedimented by centrifugation at 1,000 rpm for 1 min. Stock solutions of test compounds were made up at a concentration of 10 mM in DMSO, and serially diluted in AB to concentrations required for activation dose response curves. Gly14-Humanin (Humanin peptide with replacement of Serine by Glycine at position 14, Phoenix Peptides) was used as a reference agonist. FLIPR384 or FLIPR Tetra instruments (Molecular Devices) were operated according to the manufacturer's standard instructions, adding 4 μl of test compound dissolved at 10 mM in DMSO and diluted prior to the experiment in assay buffer to obtain the desired final concentration. Changes in fluorescence were monitored before and after the addition of test compounds at lex=488 nm and lem=540 nm. Emission peak values above base level after compounds addition were exported after base line subtraction. Values were normalized to high-level control (GLY14-Humanin compound, 100 nM final concentration) after subtraction of the base line value (AB addition).
Agonistic activities of exemplified compounds are displayed in Table 1.
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/IB2009/052056 | May 2009 | WO | international |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IB2010/052170 | 5/17/2010 | WO | 00 | 11/18/2011 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2010/134014 | 11/25/2010 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 20060078559 | Migeotte et al. | Apr 2006 | A1 |
| 20100331378 | Bur et al. | Dec 2010 | A1 |
| 20110034516 | Bur et al. | Feb 2011 | A1 |
| 20110319454 | Beard et al. | Dec 2011 | A1 |
| 20120101138 | Bur et al. | Apr 2012 | A1 |
| 20120115916 | Bur et al. | May 2012 | A1 |
| Number | Date | Country |
|---|---|---|
| WO 9502587 | Jan 1995 | WO |
| WO 03082314 | Oct 2003 | WO |
| WO 2005047899 | May 2005 | WO |
| WO 2009077954 | Jun 2009 | WO |
| WO 2009077990 | Jun 2009 | WO |
| WO 2010143116 | Dec 2010 | WO |
| WO 2010143158 | Dec 2010 | WO |
| Entry |
|---|
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| Number | Date | Country | |
|---|---|---|---|
| 20120115841 A1 | May 2012 | US |
