Patent Application
20240368150
The present invention relates to bicyclic tetrahydroazepine compounds which inhibit Diacylglycerol kinases (DGK) α and ζ and are useful as T-Cell signal 2 enhancers, their manufacture and pharmaceutical compositions comprising said compounds.
The present compounds may be useful as immunotherapeutic agents for the treatment of human diseases. More specifically, the present compounds can be used alone or in combination with other immunotherapeutic agents in order to boost anti-cancer immunity.
Cancer immunity is a multistep process that is regulated by a series of negative immune checkpoint and positive co-stimulatory receptors and related intracellular signaling cascades that when effectively triggered can achieve antitumor response (Mellman, I., et al. (2011) Cancer Immunotherapy Comes of Age, Nature 480(7378), 480-489). Indeed, PD1/PDL1 targeting and other immune-checkpoint inhibitors have revolutionized cancer immunotherapy, but still more than 70% of patients do not benefit from immune-checkpoint inhibition. Similarly, for T-cell bispecific antibodies, even in the most promising indication (Non-Hodgkin lymphoma), these T-cell binders (TCBs) achieve complete remissions in less than 50% of patients. T-cell exhaustion seems to play an important role in many of these examples of primary or secondary resistance to cancer immunotherapy. A possible reason for this lack of efficacy is that T-cell activation occurs via targeting and crosslinking of CD3 (signal 1), but co-stimulation e.g. via CD28 or 4-1BB (signal 2) is missing. This hypothesis was verified clinically for CAR T-cell therapy where it was shown that only after the incorporation of co-stimulatory domains, clinically relevant efficacy was observed.
Diacylglycerol kinases (DGKs) are lipid kinases that catalyze the conversion of Diacylglycerol (DAG) to phosphatidic acid (PA), thus limiting DAG-regulated and promoting PA-dependent functions (Merida, I., Avila-Flores, A., and Merino, E. 2008: Diacylglycerol kinases: at the hub of cell signalling. Biochem. J. 409 (1), 1-18). The DGK family consist of ten isoforms that can be grouped into five subtypes based on the presence of different regulatory domains within their structure. Beyond that, the lack of structural data as of now still hinders a more thorough understanding of the DGKs mode of action. Also information on certain prokaryotic DGK and other lipid kinases like sphingosine kinase and phosphatidylinositol-3-kinase (PI3K) has provided only limited insight into the DGK catalytic mechanisms which seems to be distinct from classical kinases (Arranz-Nicolis, J. and Merida, I., 2020. Biological regulation of diacylglycerol kinases in normal and neoplastic tissues: New opportunities for cancer immunotherapy, Advances in Biological Regulation, Volume 75; Ma, Q., Gabelli, S. B., Raben, D. M., 2019: Diacylglycerol kinases: relationship to other lipid kinases. Adv Biol Regul 71, 104-110).
Although several isoforms within the DGK family have been described to play a role in cancer, the a and (isoforms are the ones that have been most deeply studied in this regard. As PA producers, both enzymes have been implicated in various processes promoting tumor growth and metastasis. On the other hand, as DAG consumers, DGKα and ζ have been extensively characterized as negative regulators of T cell responses (Riese, M. J., Moon, E. K., Johnson, B. D., Albelda, S. M., 2016. Diacylglycerol kinases (DGKs): novel targets for improving T cell activity in cancer. Front Cell Dev Biol 4,108; Noessner, E., 2017. DGK-alpha: a checkpoint in cancer—mediated immuno—inhibition and target for immunotherapy. Front Cell Dev Biol 5, 16; Sakane, F., Mizuno, S., Komenoi, S., 2016. Diacylglycerol kinases as emerging potential drug targets for a variety of diseases: an update. Front Cell Dev Biol 4, 82; Arranz-Nicolis, J. and Merida, I., 2020. Biological regulation of diacylglycerol kinases in normal and neoplastic tissues: New opportunities for cancer immunotherapy, Advances in Biological Regulation, Volume 75) These two isozymes DGKα and DGKζ are active downstream of CD28 and other costimulatory receptors as well as the T cell receptor (TAR), and their function is to limit the amount of DAG generated—and ultimately T-cell activation (Merida, I., Andrada, E., Gharbi, S. I., Avila-Flores, A., 2015. Redundant and specialized roles for diacylglycerol kinases alpha and zeta in the control of T cell functions. Sci. Signal. 8 (374); Shula, Y. V., Topham, M. K., Epand, R. M., 2011. Regulation and functions of diacylglycerol kinases. Chem. Rev. 111 (10), 6186-6208.) A summary of representative DGK-regulated signaling pathways is shown in
Experimental evidence suggests that enhanced DGK function and/or expression in tumor infiltrating T-cells (TILs) limits tumor destruction. Experiments with CAR T cells directed against human mesothelioma engrafted into nude mice demonstrated that tumor-infiltrating CAR T cells express elevated concentrations of surface inhibitory receptors, as well as the inhibitory enzymes SHIP-1, DGKα and DGKζ (Moon et al., 2014). Further, high DGKα expression was also observed in TIL isolated from human renal tumors (Prinz et al., 2012). In mouse mesoCAR T cells, dual deletion of DGKα and DGKζ results in enhanced cytokine expression and cytotoxicity against tumor cells (Riese et al., 2013). Similar results have been reported for human CAR T cells in which both DGKα and DGKζ expression were silenced using CRISPR/Cas9 (Jung et al., 2018). All these studies support a rationale for targeting DGKαζ (in the development of anti-cancer therapies (Arranz-Nicolis, J. and Mérida, I., 2020. Biological regulation of diacylglycerol kinases in normal and neoplastic tissues: New opportunities for cancer immunotherapy, Advances in Biological Regulation, Volume 75; Riese, M. J., Moon, E. K., Johnson, B. D., Albelda, S. M., 2016. Diacylglycerol kinases (DGKs): novel targets for improving T cell activity in cancer. Front Cell Dev Biol 4, 108.). Knock out mouse models provide further evidence: Mice lacking either DGKα or DGKζ showed a hyper-responsive T cell phenotype and improved anti-tumor immune activity (Riese, M. J., Grewal, J., Das, J., Zou, T., Patil, V., Chakraborty, A. K., Koretzky, G. A., 2011. Decreased diacylglycerol metabolism enhances ERK activation and augments CD8+ T cell functional responses. J. Biol. Chem. 286 (7), 5254-5265; Zha, Y., Marks, R., Ho, A. W., Peterson, A. C., Janardhan, S., Brown, I., Praveen, K., Stang, S., Stone, J. C., Gajewski, T. F., 2006. T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-alpha. Nat. Immunol. 7 (11), 1166-1173; Olenchock, B. A., Guo, R., Carpenter, J. H., Jordan, M., Topham, M. K., Koretzky, G. A., Zhong, X. P., 2006a. Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nat. Immunol. 7 (11), 1174-1181.)
Taken together, there is substantial evidence that DGKα and DGKζ are high value targets for cancer immunotherapy. At the same time, there is a lack of compounds with the ability to potently inhibit both DGKα and DGKζ with good selectivity over other diacylglycerol kinases, protein kinases, and/or other lipid kinases.
This invention describes such dual DGKa/z inhibitors with excellent selectivity over other protein kinases, across safety/off-target panels and vs. other lipid kinases. These compounds potently activate suboptimally stimulated T-cells and thereby act as intracellular enhancers of co-stimulatory signaling cascades. These DGKa/z inhibitors have the potential to increase proliferation, cytotoxicity and the life span of targeted T-cells which may result in improved anticancer activity of CPIs, CD3 engaging T-cell bispecifics and CAR T-cells. Further, by engaging a signaling node central to both TCR and co-stimulatory receptors, it is plausible that these molecules enhance both signals 1 and 2 and thus single agent activity can be achieved, e.g. in inflamed tumors.
There is an ongoing need for new compounds capable of activating and proliferating T-cells, thus enabling the treatment, prevention and/or delay of progression of cancer.
It is, therefore, an object of this invention to provide compounds useful as T-cell signal 2 enhancers for the treatment or prevention or amelioration of such diseases with improved therapeutic properties, in particular improved pharmacokinetic properties.
A first object of the present invention is a compound of formula (I)
A second object of the present invention is a compound is of formula (I)
A third object of the present invention is a compound of formula (I)
A further object of the present invention is a process for the preparation of a compound as described herein, or a pharmaceutically acceptable salt thereof, comprising
wherein X, Y, R1, R2, R3, R4, R6, R6a are as described herein and PG is an amino protecting group, with a suitable deprotection agent to form said compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X, Y, R1, R2, R3, R4, R6, R6a are as described herein and R5 is hydrogen; or
wherein X, Y, R1, R2, R3, R4, R6, R6a are as described herein and R5 is hydrogen, with a carboxylic acid derivative of formula R9CO2H wherein R9 is as described herein, in the presence of a base to form a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5 is —C(O)(R9).
A further object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to the process as described above.
A further object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.
A further object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A further object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and/or delay of progression of cancer.
A further object of the present invention is the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment, prevention and/or delay of progression of cancer.
A further object of the present invention is the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and/or delay of progression of cancer.
A further object of the present invention is a method for the treatment, prevention and/or delay of progression of cancer, which method comprises administering a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below.
All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.
The nomenclature used in this application is based on IUPAC systematic nomenclature, unless indicated otherwise.
The following definitions of the general terms used in the present description apply irrespectively of whether the terms in question appear alone or in combination with other groups. The term “alkyl” refers to a saturated linear (i.e. unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., C1-10 means one to ten carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-20 alkyl”), having 1 to 12 carbon atoms (a “C1-12 alkyl”), having 1 to 10 carbon atoms (a “C1-10 alkyl”), having 1 to 8 carbon atoms (a “C1-8 alkyl”), having 1 to 6 carbon atoms (a “C1-6 alkyl”), having 2 to 6 carbon atoms (a “C2-6 alkyl”), or having 1 to 4 carbon atoms (a “C1-4 alkyl”). Examples of alkyl group include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
The term “alkynyl” refers to an unsaturated linear (i.e. unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) having the number of carbon atoms designated (i.e. C2-10 means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C2-20 alkynyl”), having 2 to 8 carbon atoms (a “C2-8 alkynyl”), having 2 to 6 carbon atoms (a “C2-6 alkynyl”), having 2 to 4 carbon atoms (a “C2-4 alkynyl”). Examples of alkynyl group include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.
The term “alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms (“C1-12-alkoxy”), preferably 1 to 10 carbon atoms (“C1-10-alkoxy”), more preferably 1 to 6 carbon atoms (“C1-6-alkoxy”). In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. In still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.
The term “alkoxyalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group. Preferably, “alkoxyalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably one hydrogen atom of the alkyl group have been replaced by an alkoxy group. Particularly preferred, yet non-limiting examples of alkoxyalkyl is methoxymethyl and 2-methoxyethyl.
The term “amino”, alone or in combination with other groups, refers to NH2.
The term “aminoalkyl” refers to an alkyl group wherein one or more of the hydrogen atoms of the alkyl group have been replaced by an amino moiety.
The term “aromatic” denotes the conventional idea of aromaticity as defined in the literature, in particular in IUPAC—Compendium of Chemical Terminology, 2nd Edition, A. D. McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).
The term “cyano”, alone or in combination with other groups, refers to CN (i.e. nitrile).
The term “cyanoalkyl” refers to an alkyl group wherein one or more of the hydrogen atoms of the alkyl group have been replaced by a cyano moiety.
The term “cycloalkyl” means a saturated or partially unsaturated carbocyclic moiety having mono-, bi-(including bridged bicyclic and cycloalkyl spiro moieties) or tricyclic rings and 3 to 10 carbon atoms i.e., (C3-C10)cycloalkyl) in the ring. The cycloalkyl moiety can optionally be substituted with one or more substituents. In particular aspects cycloalkyl contains from 3 to 8 carbon atoms (i.e., (C3-C8)cycloalkyl). In other particular aspects cycloalkyl contains from 3 to 6 carbon atoms (i.e., (C3-C6)cycloalkyl). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and partially unsaturated (cycloalkenyl) derivatives thereof (e.g. cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, bicyclo[3.1.1]heptenyl and bicyclo[1.1.1]pentane. The cycloalkyl moiety can be attached in a “spiro-cycloalkyl” or “cycloalkyl spiro” fashion such as “spirocycloprpyl”:
“Halo” or “Halogen” refers to fluoro, chloro, bromo and/or iodo. Where a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which can be but are not necessarily the same halo; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which one or more hydrogen is replaced with a halo group is referred to as a “haloalkyl”, for example, “C1-6 haloalkyl.” A preferred haloalkyl group is trifluoroalkyl (—CF3).
Similarly, “haloalkoxy” refers to an alkoxy group in which at least one halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a haloalkoxy group is difluoromethoxy (—OCHF2), trifluoromethoxy (—OCF3).
The term “heteroaryl” refers to an aromatic heterocyclic mono-, bi- or tricyclic ring system of 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, more preferably from 5 to 6 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In some aspects, monocyclic heteroaryl rings may be 5-6 membered. Bicyclic heteroaryl ring systems include fused bicyclics having two fused five-membered heteroaryl rings (denoted as 5-5), having a five-membered heteroaryl ring and a fused six-membered heteroaryl ring (denoted as 5-6 and 6-5), and having two fused six-membered heteroaryl rings (denoted as 6-6).
The heteroaryl group can be optionally substituted as defined herein. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, benzothiophenyl, indolyl, aza-indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, and furopyrazinyl. Most preferably, “5-membered heteroaryl” refers to the following groups:
The terms “heterocycle” or “heterocyclyl” refer to a 3, 4, 5, 6, 7, 8, 9, 10-membered monocyclic, 7, 8, 9 and 10-membered bicyclic (including bridged bicyclic and cycloalkyl spiro moieties) or 10, 11, 12, 13, 14 and 15-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated, and has one or more (e.g., 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring with the remaining ring atoms being carbon. In some aspects, the heterocycle is a heterocycloalkyl. In particular aspects heterocycle or heterocyclyl refers to a 4, 5, 6 or 7-membered heterocycle. When used in reference to a ring atom of a heterocycle, a nitrogen or sulfur may also be in an oxidized form, and a nitrogen may be substituted with one or more (C1-C6)alkyl or groups. The heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Any of the heterocycle ring atoms can be optionally substituted with one or more substituents described herein. Examples of such saturated or partially unsaturated heterocycles include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, pyrrolidine 1-oxide, N-hydroxypiperidine, 1-methylpyrrolidine N-oxide, diazirinyl and quinuclidinyl. The term heterocycle also includes groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.
The term “aryl” refers to a cyclic aromatic hydrocarbon moiety having a mono-, bi- or tricyclic aromatic ring of 5 to 14 carbon ring atoms (“C5-14-aryl”). Bicyclic aryl ring systems include fused bicyclics having two fused five-membered aryl rings (denoted as 5-5), having a five-membered aryl ring and a fused six-membered aryl ring (denoted as 5-6 and as 6-5), and having two fused six-membered aryl rings (denoted as 6-6). The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like. The term “aryl” also includes partially hydrogenated derivatives of the cyclic aromatic hydrocarbon moiety provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic, each being optionally substituted.
The term “haloaryl” refers to an aryl wherein at least one hydrogen has been substituted with an halogen.
The term “hydroxy”, alone or in combination with other groups, refers to OH.
The term “hydroxyalkyl” refers to an alkyl group wherein one or more of the hydrogen atoms of the alkyl group have been replaced by a hydroxy moiety. Examples include alcohols and diols.
The term “oxo”, alone or in combination with other groups, refers to ═O.
The term “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein.
Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.
The term “protecting group” (PG) denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry.
Protective groups can be removed at the appropriate point. Exemplary protective groups are amino-protective groups, carboxy-protective groups or hydroxy-protective groups. Particular protective groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Further particular protective groups are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc). More particular protective group is the tert-butoxycarbonyl (Boc). Exemplary protective groups and their application in organic synthesis are described, for example, in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.
The terms “moiety” and “substituent” refer to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds thereby forming part of a molecule.
When indicating the number of substituents, the term “one or more” refers to the range from one substituent to the highest possible number of substitution, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents, in particular wherein “one or more” refers to one, two or three, most particularly “one or more” refers to one or two.
The term “optionally substituted” means unsubstituted or substituted. Generally these substituents can be the same or different. “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “aryl group optionally substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes situations where the aryl group is substituted with an alkyl group and situations where the aryl group is not substituted with the alkyl group.
The term “substituted” refers to the replacement of at least one of hydrogen atoms of a compound or moiety with another substituent or moiety. Examples of such substituents include, without limitation, halogen, —OH, —CN, oxo, alkoxy, alkyl, alkylene, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl and heterocycle. For example, the term “haloalkyl” refers to the fact that one or more hydrogen atoms of an alkyl (as defined below) is replaced by one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.). In one aspect, substituted as used herein can refer to replacement of at least one hydrogen atom of a compound or moiety described herein with halogen or alkyl.
The term “therapeutically inert carrier” denotes any ingredient having no therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products. The term “therapeutically effective amount” denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
Whenever a chiral carbon is present in a chemical structure, it is intended that all stereoisomers associated with that chiral carbon are encompassed by the structure as pure stereoisomers as well as mixtures thereof.
All separate embodiments may be combined.
The term “ECx” is the half maximal effective concentration and denotes the plasma concentration of a particular compound required for obtaining x % of the maximum of a particular effect in vivo. Examples of “ECx” are EC20, EC50 and EC100 denoting the plasma concentration of a particular compound required for obtaining 20%, 50% and 100%, respectively, of the maximum of a particular effect in vivo.
The term “prophylaxis” as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.
The term “cancer” refers to a disease characterized by the presence of a neoplasm or tumor resulting from abnormal uncontrolled growth of cells (such cells being “cancer cells”). As used herein, the term cancer explicitly includes, but is not limited to, hepatocellular cancer, malignancies and hyperproliferative disorders of the colon (colon cancer), lung cancer, breast cancer, prostate cancer, melanoma, and ovarian cancer.
The following abbreviations are used in the present text: BOP=benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, Brine=saturated aqueous NaCl solution, CAS=chemical abstracts registration number, CDI=1,1′-Carbonyldiimidazole, DBU=1,8-diazabicyclo[5,4,0]undec-7-ene, DCM=dichloromethane, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DMF=N,N-dimethylformamide, DIPEA=N,N-diisopropylethylamine, EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, ESI=electrospray ionization, EtOAc=ethyl acetate, EtOH=ethanol, h=hour(s), HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HBTU=O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate, HFIP=hexafluoroisopropanol, HOBt=hydroxybenzotriazole, HPLC=high performance liquid chromatography, m-CPBA=meta-chloroperoxybenzoic acid, MeCN=acetonitrile, Mel=methyliodide, MeOH=methanol, min=minute(s), MS=mass spectrum, NBS=N-bromosuccinimide, PE=petroleum ether, PyBroP=bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, RT=room temperature, TBAF=tetrabutylammonium fluoride, TBAOH=tetrabutylammonium hydroxide, TBDMS=tert-butyldimethylsilyl, TEA=triethylamine, TFA=trifluoroacetic acid, THE=tetrahydrofuran, TMSOTF=trifluoromethanesulfonic acid trimethylsilylester, TLC=thin layer chromatography
In a particular embodiment, the present invention comprises a compound of formula (I)
In an other embodiment the present invention comprises a compound is of formula (I)
A particular embodiment of the present invention relates to a compound of formula (I)
In one embodiment, there is provided a compound as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IA)
Further, it is to be understood that every embodiment relating to a specific X, Y, R1, R2, R3, R4, R5, R6, R6a, R7, R8, R8a, R9, R9a, R9b, R10, R10a, R10b, R10c, R10d, R10e, R10f, R10g, R10h, R10i, R10j, R10k, R10l, R10m, R10n, R10o, R10p, R10p′, R10q, R11, R11a, R11b, R11c, R11d, R11e, R11f, R11g, R11h, R11i, R11j, R11k, R11l, R11m, and Ry as disclosed herein may be combined with any other embodiment relating to another X, Y, Ru, R2, R3, R4, R5, R6, R6a, R7, R8, R8a, R9, R9a, R9b, R10i, R10a, R10b, R10c, R10d, R10e, R10f, R10g, R10h, R10i, R10j, R10k, R10l, R10m, R10n, R10o, R10p, R10p′, R10q, R11, R11a, R11b, R11c, R11d, R11e, R11f, R11g, R11h, R11i, R11j, R11k, R11l, R11m, and Ry as disclosed herein.
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X is N or C(R7), wherein R7 is hydrogen or halogen.
In a particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X is CH.
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein Y is SO or S(O)2.
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1 is substituted with at least one R10, more particularly with one R10.
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from
wherein R1 is optionally substituted with one or more R10 which can be the same or different as defined herein, more particularly wherein R1 is optionally substituted with one R10.
In a particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen, halogen, C1-6-alkyl, hydroxy or N(R8R8a).
In a more particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein wherein R1 is selected from
wherein R1 is optionally substituted with one or more R10 which can be the same or different as defined herein, more particularly wherein R1 is optionally substituted with one R10.
In a particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R8 and R8a are each independently selected from hydrogen and C1-6-alkyl.
In another particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen, halogen or C1-6-alkyl.
In a particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen, fluorine or methyl.
In a more particularly embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen, fluorine.
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from
wherein R4 is optionally substituted with one or more R11 as defined herein, more particularly R4 is optionally substituted with one R11.
In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4 is
In yet another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4 is
wherein R4 is optionally substituted with one or more R11 as defined herein, more particularly R4 is optionally substituted with one R11.
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen or —C(O)(R9).
In a particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen or —C(O)(amino-C1-6-alkyl).
In a more particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen or —C(O)(CH2NH2).
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R6 and R6a are hydrogen.
In a particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R10 is selected from:
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R10 is selected from C1-10-alkyl, C1-10-alkyl substituted with C2-6-alkynyl, C1-10-haloalkyl, amino-C1-10-alkyl, hydroxy-C1-10-alkyl, C3-10-cycloalkyl, C3-10-cycloalkyl substituted with one or more halogen, phenyl substituted with one or more halogen, (C1-10-alkyl)-phenyl substituted with one or more halogen, (alkoxy-C1-10-alkyl)-phenyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl substituted with one or more C1-10-alkyl and halogen, and —N(R10eR10f).
In a particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R10 is selected from C1-10-alkyl, C1-10-alkyl substituted with C2-6-alkynyl, C1-10-haloalkyl, amino-C1-10-alkyl-, hydroxy-C1-10-alkyl, C3-10-cycloalkyl, C3-10-cycloalkyl substituted with one or more halogen, phenyl substituted with one or more halogen, —(C1-10-alkyl)-phenyl substituted with one or more halogen, -(alkoxy-C1-10-alkyl)-phenyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl substituted with one or more C1-10-alkyl and halogen, heteroaryl, heteroaryl substituted with one or more C1-10-alkyl, heteroaryl substituted with one or more halogen, and —N(R10eR10f).
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R10 is selected from C1-10-alkyl, C1-10-haloalkyl, C3-10-cycloalkyl substituted with one or more halogen, hydroxy-C1-10-alkyl, C1-10-alkyl substituted with C2-6-alkynyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl substituted with one or more C1-10-alkyl and halogen, and —NH(C3-7-cycloalkyl).
In a more particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R10 is selected from tert-butyl, methyl 3-azabicyclo[3.1.1]heptane-3-carboxylate, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 3,3-(difluorocyclobutyl)aminoyl, (trifluoromethyl)cyclopropyl, 2,2-difluoromorpholin-4-yl, 5,5-difluoro-1-methyl-3-piperidyl, 2,2,2-trifluoroethyl, (3,3-difluoro-1-methyl-cyclobutyl)aminoyl, o-tolyl, cyclobutylaminoyl, 2-methyl-propanenitrile, 6-fluoro-2-methyl-3-pyridyl, 1,2,2,2-tetrafluoro-1-methoxy-ethyl, 4-oxa-7-azaspiro[2.5]octan-7-yl, ethyl, 1-amino-2,2,2-trifluoro-1-methyl-ethyl, morpholinyl, 1-amino-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl, methyl(2,2,2-trifluoroethyl)amino, 2,2-difluoromorpholin-4-yl, tert-butylaminoyl, cyclohexylaminoyl, methyl 4-methylpiperidine-1-carboxylate, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 2-(trifluoromethyl)morpholin-4-yl, 3,3-difluorocyclohexyl, 1,1-dimethylbut-3-ynyl, 3,3-difluorocyclobutyl, isobutyl, methyl 3,3-difluoropiperidine-1-carboxylate, difluorocyclopentyl, trifluoromethylmorpholinyl, 2,2-difluorospiro[3.3]heptan-6-yl, difluorocyclohexyl, 5,5-difluoro-1-(2-methoxyethyl)-3-piperidyl, 1-ethyl-5,5-difluoro-3-piperidyl, 2-cyclopropyltetrahydrofuran-2-yl, 3-fluoro-1-methyl-3-piperidyl, 6-fluoro-2-methyl-3-pyridyl, 2-fluoro-6-methyl-phenyl, fluorophenyl, 1,2,2,2-tetrafluoro-1-methoxy-ethyl.
In a particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R11 is selected from ethyl, tertbutyl, isopropyl, —CH2CF3, —C((CH3)2)F, —C((CH3)2)CH2OH, —C((CH3)2)CH2CCH3, difluorocyclohexyl, difluorocyclobutyl, piperidyl substituted with fluorine and methyl, morpholinyl, and —NH(cyclopentyl).
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R11 is selected from halogen, C1-6-haloalkoxy, C1-6-alkoxy, —O—R11a, C1-6-alkyl, C1-6-alkyl substituted with cyano.
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R11 is selected from halogen, C1-6-haloalkoxy, C1-6-alkoxy, —O-arly, —O—C3-10-cycloalkyl, C1-6-alkyl, C1-6-alkyl substituted with cyano.
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R11 is selected from halogen, —O(R11a), cyano, amino-C1-10-alkyl, —SO2(C1-6-alkyl) and 3-10 membered heterocyclyl substituted with one or more halo-C1-6-alkyl.
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R11 is selected from chloro, fluoro, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, phenoxy, 2-methyl-propanenitrile, isopropoxy, methoxy, cyclopentoxy.
In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R11 is selected from halogen, —O(R11a), cyano, amino-C1-10-alkyl, —SO2(C1-6-alkyl) and 3-10 membered heterocyclyl substituted with one or more halo-C1-6-alkyl.
In a particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R11 is selected from C1-12-alkyl, halo-C1-6-alkyl, 3-7 membered heterocycloalkyl and amino-C1-12-alkyl.
In a more particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R11 is selected from halogen, —O(halo-C1-6-alkyl), —O(C1-6-alkyl), cyano and 3-10 membered heterocyclyl substituted with one or more halo-C1-6-alkyl.
In an even more particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R11 is selected from chlorine, —OCF3, —OCH3, cyano and 3-trifluoromethyl-diazirin-3-yl.
In yet a more particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein
In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein
In a particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein
In a a more particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein
In another particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
In a more particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein
wherein R1 is optionally substituted with one or more R10 which can be the same or different;
In another particular embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein
In an yet more particular embodiment, there is provided a compound of formula (I) as described herein, selected from:
In a particular embodiment, there is provided a compound of formula (I) as described herein, selected from:
In a most particular embodiment, there is provided a compound of formula (I) as described herein, selected from:
In a particular embodiment, there is provided a compound of formula (I) as described herein, selected from:
In the description herein, if there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold wedged, or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. In some cases, however, where more than one chiral center exists, the structures and names may be represented as single enantiomers to help describe the relative stereochemistry.
Unless otherwise indicated, the terms “a compound of the formula” or “a compound of formula” or “compounds of the formula” or “compounds of formula” refer to any compound selected from the genus of compounds as defined by the formula (including any pharmaceutically acceptable salt of any such compound if not otherwise noted).
Certain compounds may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertable species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate an individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates. Common prototropic tautomers include keto/enol (—C(═O)—CH—↔—C(—OH)═CH—), amide/imidic acid (—C(═O)—NH—↔—+—C(—OH)═N—) and amidine (—C(═NR)—NH—↔—C(—NHR)═N—) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings and the present invention encompasses all tautomeric forms of the compounds. Furthermore, the invention includes all optical isomers, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and/or tautomers as well as their solvates of the compounds of formula (I).
The compounds of formula (I) may contain one or more asymmetric centers and can therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within this invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
In the embodiments, where optically pure enantiomers are provided, optically pure enantiomer means that the compound contains >90% of the desired isomer by weight, particularly >95% of the desired isomer by weight, or more particularly >99% of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound. Chirally pure or chirally enriched compounds may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate.
In some embodiments, the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
Processes for the manufacture of compounds of formula (I), or pharmaceutically acceptable salts thereof, as described herein are also an object of the invention.
The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein, unless indicated to the contrary.
If one of the starting materials, intermediates or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protective groups (as described e.g., in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.) can be introduced before the critical step applying methods well known in the art. Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature.
If starting materials or intermediates contain stereogenic centers, compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically/enantiomerically enriched starting materials and intermediates. Using such diastereomerically/enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will typically lead to the respective diastereomerically/enantiomerically enriched compounds of formula (I).
A person skilled in the art will acknowledge that in the synthesis of compounds of formula (I) -insofar not desired otherwise—an “orthogonal protection group strategy” will be applied, allowing the cleavage of several protective groups one at a time each without affecting other protective groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in literature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).
A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates.
In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent.
The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between −78° C. to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered.
If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section.
In one embodiment, compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, may be prepared by a process comprising
The present compounds of formula (I), or their pharmaceutically acceptable salts, may be prepared by a process described below (Scheme 1), together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skilled in the art.
Suitable starting materials for the preparation of compounds of formula (I) are nitro compounds of formula (II) wherein X2 is F or Cl and X1 is either already R1 or a group such as Br or —CO2Alkyl which can later be elaborated into R1. Compounds of formula (II) can be reacted with suitably protected cysteine derivatives (III) in the presence of a base such as DIPEA at elevated temperatures in a solvent such as 1,2-dichloroethane to obtain compounds of formula (IV). The preferred protecting group (PG) of the cysteine derivative (III) is Boc. The nitro group in formula (IV) compounds can be reduced using iron in the presence of either hydrogen chloride or ammonium chloride at elevated temperatures in a solvent mixture of water and ethanol to obtain compounds of formula (V). Alternatively, this conversion can be achieved by catalytic hydrogenation. Compounds of formula (V) can be cyclized to compounds of formula (VI) using standard amide coupling conditions. Preferably, this cyclization is conducted using 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in EtOAc) and employing a base such as DIPEA in a solvent such as DMF at room temperature. Reaction of formula (VI) compounds with compounds of formula (VII) wherein Y1 is Cl, Br, I or a sulfonate group in the presence of a base such as potassium carbonate and if necessary with an additive such as potassium iodide in a solvent such as DMSO or DMF at room temperature affords compounds of formula (VIII). For compounds of formula (VIII) wherein X1 is Br or —CO2Alkyl, these groups can be elaborated into substituents R1 at this stage as described in the schemes below. Compounds of formula (VIII) can then be converted into compounds of formula (IX) wherein Y is S(O) or S(O)2 by reaction with an appropriate amount of an oxidant such m-CPBA in a solvent such as DCM at room temperature. Alternatively, compounds of formula (VIII) can be converted into compounds of formula (IX) wherein Y is S(O)N(Ry) and Ry is hydrogen. Typical conditions include iodobenzene diacetate in the presence of ammonium carbonate in a solvent such as methanol at room temperature. Compounds of formula (IX) wherein Y is S(O)N(Ry) and Ry is C1-6-alkyl can be obtained from compounds of formula (IX) wherein Y is S(O)N(Ry) and Ry is hydrogen by reaction with a C1-6-alkylboronic acid in the presence of copper(II) acetate and pyridine as a base in a solvent such as dioxane at reflux temperature [Org. Biomol. Chem., 2017, 15, 8493]. Final deprotection provides compounds of formula (I). If the N-protecting group (PG) is Boc, typical conditions for this deprotection step include TFA in a solvent such as DCM at room temperature, hydrogen chloride in solvents such as dioxane or ethyl acetate at room temperature or hexafluoroisopropanol at reflux temperature. Alternatively, the protecting group (PG) of compounds of formula (VIII) can be cleaved accordingly to provide compounds of formula (I) wherein Y is S. Additionally, substituents R1 and R4 might contain functional groups that could be either modified prior to the removal of the N-protecting group (PG) or that might require the use of suitable protecting groups during the synthesis. These protecting groups might be removed prior to the removal of the N-protecting group (PG) or they might be removed simultaneously using suitable methods [Peter G. M. Wuts, Greene's protective groups in organic synthesis, 5th edition, Hoboken, N.J.: Wiley-Interscience]. Compounds of formula (I) wherein R5 is hydrogen can be converted into formula (I) compounds wherein R5 is —C(O)(R9) by reaction with carboxylic acid derivatives R9CO2H using standard amide coupling conditions such as HATU in the presence of a base such as DIPEA in a solvent such as THE at room temperature. If the substituent R9 contains a functional group that requires to be protected during this coupling step, the protecting group can be removed in an additional step using suitable conditions.
Alternatively, compounds of formula (I) wherein Y is S(O)2 may be prepared as illustrated in scheme 2.
Compounds of formula (VI) can be converted into compounds of formula (X) upon reaction with an oxidant such as m-CPBA in a solvent such as DCM at room temperature. The reaction of formula (X) compounds with compounds of formula (VII) to afford compounds of formula (XI) and the subsequent conversion into compounds of formula (I) wherein Y is S(O2) can be achieved using reaction conditions as described for the similar steps in scheme 1. If X1 is Br or —CO2Alkyl, these groups can be elaborated into substituents R1 at any stage of the synthesis (for compounds of formula (VI), (X) or (XI)) using methods as described for the schemes below).
Compounds of formula (I) wherein the 5-membered heteroaryl R1 is a 1,3,4-oxadiazolyl group may be prepared as illustrated in scheme 3.
Compounds of formula (VIII) wherein X1 is CO2Me can be converted into compounds of formula (XII) by reaction with alkali hydroxides such as LiOH, NaOH or KOH in a mixture of solvents such as MeOH, THE and water at room temperature. Compounds of formula (XII) can be reacted with hydrazine hydrate after activation with suitable reagents such as CDI in a solvent such as THE at room temperature to obtain compounds of formula (XIII). Compounds of formula (XIII) can be reacted with carboxylic acids R10CO2H using standard amide coupling conditions such as HATU in the presence of a base such as DIPEA in a solvent such as THE at room temperature. The coupling products of formula (XIV) can be cyclized to compounds of formula (XV) using a dehydrating reagent such as Burgess reagent at room temperature. The conversion of compounds of formula (XV) into compounds of formula (XVI) and the subsequent conversion into compounds of formula (I) can be achieved using reaction conditions as described for the similar steps in scheme 1.
Compounds of formula (I) wherein the 5-membered heteroaryl R1 is a 1,2,4-oxadiazolyl group may be prepared as illustrated in scheme 4.
Compounds of formula (XII) can be reacted with amidines R10C(NH)NH2 using standard amide coupling conditions such as HBTU in the presence of a base such as DIPEA in a solvent such as DMF at room temperature to obtain compounds of formula (XVII). Reaction of formula (XVII) compounds with NBS in the presence of DBU in EtOAc at room temperature can afford compounds of formula (XVIII) [Tetrahedron 74 (2018) 4613-4618]. The conversion of compounds of formula (XVIII) into compounds of formula (XIX) and the subsequent conversion into compounds of formula (I) can be achieved using reaction conditions as described for the similar steps in scheme 1.
Compounds of formula (I) wherein the 5-membered heteroaryl R1 is a 1,2,3-triazolyl group may be prepared as illustrated in scheme 5.
Compounds of formula (VIII) wherein X1 is Br can be converted into compounds of formula (XX) by Sonogashira coupling with trimethylsilylacetylene. Typical conditions include bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide as catalysts in the presence of a base such as DIPEA in a solvent such as THE at room temperature. Reaction of compounds of formula (XX) with KF in MeOH affords compounds of formula (XXI) which can be transformed into compounds of formula (XXII) by reaction with azides R12N3 in the presence of CuSO4·5H2O and sodium ascorbate in a solvent mixture of MeOH and water. If necessary, azides R12N3 can be prepared in situ from amines R12NH2 and 1H-imidazole-1-sulfonyl azide hydrochloride. The conversion of compounds of formula (XXII) into compounds of formula (XXIII) and the subsequent conversion into compounds of formula (I) can be achieved using reaction conditions as described for the similar steps in scheme 1.
Compounds of formula (I) wherein the 5-membered heteroaryl R is a pyrazolyl group may be prepared as illustrated in scheme 6.
Compounds of formula (VIII) wherein X1 is Br can be converted into compounds of formula (XXV) by Suzuki coupling with boronic acids or boronic acid esters (XXIV). Typical reaction conditions include the use of Pd(dppf)Cl2 as catalyst in the presence of K3PO4 in a mixture of dioxane and water at reflux temperature. The conversion of compounds of formula (XXV) into compounds of formula (XXVI) and the subsequent conversion into compounds of formula (I) can be achieved using reaction conditions as described for the similar steps in scheme 1. Alternatively, compounds of formula (I) wherein the 5-membered heteroaryl R1 is a pyrazolyl group may be prepared as illustrated in scheme 7.
Compounds of formula (VIII) wherein X1 is Br can be converted into compounds of formula (XXVIII) by reaction with pyrazoles (XXVII) in the presence of CuI, trans-N,N′-dimethylcyclohexane-1,2-diamine and potassium carbonate in toluene as a solvent at reflux temperature. The conversion of compounds of formula (XXVIII) into compounds of formula (XXIX) and the subsequent conversion into compounds of formula (I) can be achieved using reaction conditions as described for the similar steps in scheme 1.
Alternatively, compounds of formula (I) wherein the 5-membered heteroaryl R1 is a pyrazolyl group may also be prepared as illustrated in scheme 8.
Compounds of formula (VIII) wherein X1 is Br can be converted into compounds of formula (XXX) by reaction with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane in the presence of Pd(dppf)Cl2·CH2Cl2 and potassium acetate in dioxane at 80° C. Compounds of formula (XXX) can be transformed into compounds of formula (XXXII) by Chan-Lam coupling with pyrazoles (XXXI). Typical reaction conditions include Cu(OAc)2 in the presence of TEA in acetonitrile at 30° C. under an atmosphere of oxygen. The conversion of compounds of formula (XXXII) into compounds of formula (XXXIII) and the subsequent conversion into compounds of formula (I) can be achieved using reaction conditions as described for the similar steps in scheme 1.
Compounds of formula (I) wherein the 5-membered heteroaryl R1 is a 1,2,4-triazolyl group may be prepared as illustrated in scheme 9.
Suzuki coupling of compounds of formula (XXX) with triazolylbromides (XXXIV) provides compounds of formula (XXXV). Typical reaction conditions include the use of Pd(dppf)Cl2 as catalyst in the presence of K3PO4 in a mixture of dioxane and water at reflux temperature. The conversion of compounds of formula (XXXV) into compounds of formula (XXXVI) and the subsequent conversion into compounds of formula (I) can be achieved using reaction conditions as described for the similar steps in scheme 1.
Compounds of formula (I) wherein the 5-membered heteroaryl R is a tetrazolyl group may be prepared as illustrated in scheme 10.
Compounds of formula (VIII) wherein X1 is Br can be converted into compounds of formula (XXXVII) using a mixture of zinc cyanide, zinc powder, t-Bu3P and Pd2(dba)3 in DMF at elevated temperature. The conversion of compounds of formula (XXXVII) to compounds of formula (XXXVIII) can be achieved by reaction with azide reagents such as azidotrimethylsilane in the presence of tetra-N-butylammonium fluoride trihydrate in toluene at elevated temperature. To obtain compounds of formula (XXXIX) from compounds of formula (XXXVIII), substituents R10 can be introduced by a variety of methods such as reaction with a reagent R10Y (wherein Y is Cl, Br or I) in the presence of a base such as potassium carbonate in a solvent such as DMF at room temperature. The conversion of compounds of formula (XXXIX) into compounds of formula (XL) and the subsequent conversion into compounds of formula (I) can be achieved using reaction conditions as described for the similar steps in scheme 1.
Compounds of formula (I) wherein the 5-membered heteroaryl R1 is a 1,2,3-triazolyl group may be prepared as illustrated in scheme 11.
Suitable starting materials for the synthesis of compounds of formula (I) wherein the 5-membered heteroaryl R1 is a 1,2,3-triazolyl group are fluoro-nitro-amines of formula (XLI). Reaction of compounds of formula (XLI) with cysteine derivatives (III) to obtain compounds of formula (XLII), subsequent cyclization to compounds of formula (XLIII) and reaction with compounds of formula (VII) to afford compounds of formula (XLIV) can be accomplished using conditions as described for the similar reaction steps in scheme 1. Conversion of nitro compounds of formula (XLIV) into anilines of formula (XLV) can be achieved using zinc powder in the presence of ammonium chloride in a solvent such as MeOH at elevated temperatures. Reaction of compounds of formula (XLV) with first isopentyl nitrite and azidotrimethylsilane and then with acetylenes of formula (XLVI) in the presence of copper(I) oxide in a solvent such as acetonitrile at room temperature affords compounds of formula (XLVII). The conversion of compounds of formula (XLVII) into compounds of formula (XLVIII) and the subsequent conversion into compounds of formula (I) can be achieved using reaction conditions as described for the similar steps in scheme 1.
Compounds of formula (I) wherein the 5-membered heteroaryl R is an isoxazolyl group may be prepared as illustrated in scheme 12.
Acetylene compounds of formula (XXI) can be reacted with oximes of formula (XLIX) in the presence of aqueous sodium hypochlorite solution and TEA in a solvent such as DCM at 30° C. to obtain compounds of formula (L). The conversion of compounds of formula (L) into compounds of formula (LI) and the subsequent conversion into compounds of formula (I) can be achieved using reaction conditions as described for the similar steps in scheme 1.
Compounds of formula (I) wherein the 5-membered heteroaryl R1 is a 1,2,4-triazolyl group and Y is S(O2) may be prepared as illustrated in scheme 13.
Carboxylic acids of formula (XII) can be reacted with amidrazones of formula (LII) in the presence of an activating reagent such as HATU and a base such as TEA in a solvent such as DMF to obtain the corresponding coupling products, which will cyclize to compounds of formula (LIII) upon heating. Oxidation of compounds of formula (LIII) with m-CPBA in a solvent such as DCM and subsequent cleavage of the N-protecting group (PG) affords compounds of formula (I).
Compounds of formula (I) wherein the 5-membered heteroaryl R1 is a 1,2,4-oxadiazolyl group may be prepared as illustrated in scheme 14.
Nitrile compounds of formula (XXXVII) can be reacted with hydroxylamine hydrochloride in presence of a base such as potassium carbonate in a solvent such as ethanol at elevated temperatures to obtain amidoxime compounds of formula (LV wherein R is H). Reaction of compounds of formula (LV wherein R is H) with carboxylic acids R10CO2H using standard amide coupling conditions with activating agents such CDI, EDC/HOBt or HATU in the presence of a base such as DIPEA in a solvent such as DMF, THF or acetonitrile, provides coupling intermediates (LV wherein R is —C(O)R10) which upon heating cyclize to the corresponding compounds of formula (LVI). Alternatively, coupling intermediates (LV wherein R is —C(O)R10) can be isolated and the cyclization step can be conducted either by heating in a solvent such as toluene or by reaction with TBAOH in a solvent such as THF. The conversion of compounds of formula (LVI) into compounds of formula (LVII) and the subsequent conversion into compounds of formula (I) can be achieved using reaction conditions as described for the similar steps in scheme 1.
Compounds of formula (I) wherein the 5-membered heteroaryl R is an oxazolyl group may be prepared as illustrated in scheme 15.
Compounds of formula (XII) can be reacted with amino alcohols of formula (LVIII) using standard amide coupling conditions such as HATU in the presence of a base such as DIPEA in a solvent such as DMF at room temperature to obtain compounds of formula (LIX). Cyclization of compounds of formula (LIX) to compounds of formula (LX) can be accomplished with a dehydrating reagent such as Burgess reagent in a solvent such as THE at elevated temperatures. Reaction of compounds of formula (LX) with DDQ in toluene at elevated temperatures provides compounds of formula (LXI). The conversion of compounds of formula (LXI) into compounds of formula (LXII) and the subsequent conversion into compounds of formula (I) can be achieved using reaction conditions as described for the similar steps in scheme 1.
Compounds of formula (I) wherein the 5-membered heteroaryl R1 is a 1,3,4-oxadiazolyl group, R10 is N(R10eR10f) and Y is S(O2) may be prepared as illustrated in scheme 16.
Compounds of formula (XIII) can be reacted first with CS2 in DMF at elevated temperature and then with methyl iodide in the presence of TEA at room temperature to obtain compounds of formula (LXIII). Oxidation of compounds of formula (LXIII) with an oxidation agent such as KMnO4 in a solvent mixture of water and acetic acid at a temperature between 0 and 5° C. provides compounds of formula (LXIV). Compounds of formula (LXIV) can be transformed into compounds of formula (LXV) by reaction with amines HN(R10eR10f) in presence of a base such as potassium carbonate in a solvent such as DMF at room temperature. Cleavage of the N-protecting group (PG) affords compounds of formula (I).
Alternatively, compounds of formula (I) wherein the 5-membered heteroaryl R1 is a 1,3,4-oxadiazolyl group, R10l s N(R10eR10f) and Y is S(O2) may be prepared as illustrated in scheme 17.
Compounds of formula (XIII) can be reacted with CDI in THF in the presence of a base such as TEA at room temperature to obtain compounds of formula (LXVI). Oxidation of compounds of formula (LXVI) with an oxidation agent such as m-CPBA in a solvent such as DCM at room temperature provides compounds of formula (LXVII). Compounds of formula (LXVII) can be transformed into compounds of formula (LXV) by reaction with amines HN(R10eR10f) in presence of DIPEA and BOP in a solvent such as DMF at room temperature or at elevated temperatures [Org. Lett., 2008, Vol. 10, 1755-1758]. Cleavage of the N-protecting group (PG) affords compounds of formula (I).
Compounds of formula (I) wherein the 5-membered heteroaryl R1 is a 1,2,4-oxadiazolyl group, R10 is N(R10eR10f) and Y is S(O2) may be prepared as illustrated in scheme 18.
Compounds of formula (LV wherein R is H) can be reacted with CDI in THE in the presence of a base such as TEA at room temperature to obtain compounds of formula (LXVIII). Compounds of formula (LXVIII) can be transformed into compounds of formula (LXIX) by reaction with amines HN(R10eR10f) in presence of DIPEA and PyBroP in a solvent such as dioxane at elevated temperatures. Oxidation of compounds of formula (LXIX) with an oxidation agent such as m-CPBA in a solvent such as DCM at room temperature provides compounds of formula (LXX). Cleavage of the N-protecting group (PG) affords compounds of formula (I).
Alternatively, compounds of formula (I) wherein the 5-membered heteroaryl R1 is a 1,2,4-oxadiazolyl group, R10 is N(R10eR10f) and Y is S(O2) may be prepared as illustrated in scheme 19.
Reaction of compounds of formula (XXXVII) with an oxidation agent such as m-CPBA in a solvent such as DCM at room temperature provides compounds of formula (LXXI) which can be converted into compounds of formula (LXXII) by reaction with hydroxylamine hydrochloride in presence of a base such as sodium bicarbonate in a solvent such as methanol at elevated temperatures. The subsequent conversion of formula (LXXII) compounds into compounds of formula (I) can be achieved using reaction conditions as described for the similar steps in scheme 18.
Compounds of formula (I) wherein the 5-membered heteroaryl R1 is a 1,3,4-oxadiazolyl group, R10 is N(R10eR10f) and Y is S(O2) may be prepared as illustrated in scheme 20.
Reaction of amines HN(R10e)(R10f) with triphosgene in presence of a base such as aqueous sodium bicarbonate in a solvent such as 1,2-dichloroethane and subsequent reaction with a hydrazide compound of formula (XIII) provides compounds of formula (LXXIV). Compounds of formula (LXXIV) can be cyclized to formula (LXXV) compounds by employing reagents such as p-toluenesulfonyl chloride and DIPEA at room temperature. Oxidation of compounds of formula (LXXV) to compounds of formula (LXV) and conversion to compounds of formula (I) can be achieved using reaction conditions as described for the similar steps in scheme 1.
Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions). The administration can also be effected topically, e.g. transdermal administration, or in form of eye drops or ear drops.
The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations, such as tablets, coated tablets, dragées, hard gelatin capsules, injection solutions or topical formulations. Lactose, corn starch or derivatives thereof, talc, stearic acids or salts thereof, and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules.
Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatin capsules.
Suitable carriers for the production of solutions and syrups are, for example, water, alcohols, polyols, saccharose, glucose, invert sugar, vegetable oil, etc.
Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.
Suitable carriers for topical ocular formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.
Medicaments containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula (I) and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more pharmaceutically acceptable excipients.
The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. In the case of topical administration, the formulation can contain 0.001% to 15% by weight of medicament and the required dose, which can be between 0.1 and 25 mg, and can be administered either by single dose per day or per week, or by multiple doses (2 to 4) per day, or by multiple doses per week. It will, however, be clear that the upper or lower limit given herein can be exceeded when this is shown to be indicated.
The pharmaceutical composition according to the invention may be prepared as follows.
A compound of formula (I) is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.
The compounds of formula (I) can be used in an effective amount to treat a subject, in particular a human, affected by cancer.
In one aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable thereof, for use as a therapeutically active substance.
In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable thereof, for use in the treatment, prevention and/or delay of progression of cancer.
In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment, prevention and/or delay of progression of cancer.
In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and/or delay of progression of cancer.
In a further aspect, the present invention provides a method for the treatment, prevention and/or delay of progression of cancer, which method comprises administering a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.
By the term “treatment” or “treating” and grammatical variations thereof as used herein, is meant therapeutic therapy. In reference to a particular condition, treating means: (1) to ameliorate the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition. Prophylactic therapy using the methods and/or compositions of the invention is also contemplated. The skilled artisan will appreciate that “prevention” is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof. Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.
As immunotherapeutic agents acting on immune cells rather than directly acting on the cancer cells, the present disclosure could also be foreseen for the use as anti-cancer vaccines. This also comprises approaches in which immune cells are cultured and manipulated ex vivo and the herein disclosed molecules are used as a way of conferring co-stimulation of the ex vivo manipulated cells.
In one embodiment, the cancer is a hematologic cancer such as lymphoma, a leukemia or a myeloma. A hematologic cancer contemplated herein includes, but is not limited to, one or more leukemias such as B-cell acute lymphoid leukemia (“BALL”), T-cell acute lymphoid leukemia (“TALL”), acute lymphoid leukemia (ALL); one or more chronic leukemias including but not limited to chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL); additional hematologic cancers or hematologic conditions including, but not limited to B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, Marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and “preleukemia,” which are a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells.
In a further embodiment, the cancer is a non-hematologic cancer such as a sarcoma, a carcinoma, or a melanoma. A non-hematologic cancer contemplated herein includes, but is not limited to, a neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, stomach cancer, brain cancer, lung cancer (e.g. non-small cell lung cancer —NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer and head and neck cancer.
The compounds of formula (I) or salts thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof may be employed alone or in combination with other agents for treatment. For example, the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound of formula (I) such that they do not adversely affect each other. The compounds may be administered together in a unitary pharmaceutical composition or separately. In one embodiment a compound or a pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.
The term “co-administering” refers to either simultaneous administration, or any manner of separate sequential administration, of a compound of formula (I) or a salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof and a further active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation treatment. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
Typically, any agent that has anti-cancer activity may be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Heilman (editors), 6th edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.
In one aspect, the present invention provides a pharmaceutical composition described herein, further comprising an additional therapeutic agent.
In one embodiment, said additional therapeutic agent is a chemotherapeutic agent.
In one embodiment, said additional therapeutic agent is a cytotoxic agent.
In one embodiment, said additional therapeutic agent is an immuno-oncology agent.
The term “cytotoxic agent” as used herein refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212 and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.
Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signaling inhibitors; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism. “Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®., Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; Eiziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin I and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CBI-TM I); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ{acute over (ι)}{umlaut over ( )} and calicheamicin coll (Angew Chem. Inti. Ed. Engl. 1994 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-I I; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.
Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene,LYl 17018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, R1VISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN®, rIL-2; a topoisomerase I inhibitor such as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.
Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti-interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories) which is a recombinant exclusively human-sequence, full-length IgGi λ antibody genetically modified to recognize interleukin-12 p40 protein.
Chemotherapeutic agent also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.” Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies which bind toEGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No. 4,943,533, Mendelsohn et al.) and variants thereof, such as chimerized 225 (C225 or Cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see, WO 96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in U.S. Pat. No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen); EMID 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and described in U.S. Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al, J. Biol. Chem. 279(29):30375-30384 (2004)). The anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules such as compounds described in U.S. Pat. Nos. 5,616,582, 5,457,105,5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: WO98/14451, WO98/50038, WO99/09016, and WO99/24037. Particular small molecule EGFRantagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (Cl 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3′-Chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(I-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/IER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3 fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).
Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; small molecule FIER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-I inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-I signaling; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor Cl-1040 (available from Pharmacia); quinazolines, such as PD 153035,4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Wamer-Lamber); antisense molecules (e.g. those that bind to HER-encoding nucleic acid); quinoxalines (U.S. Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI—1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinib mesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC—IC1 I (Imclone), rapamycin (sirolimus, RAPAMUNE®); or as described in any of the following patent publications: U.S. Pat. No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).
Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.
Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (PEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNFa) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin I (IL-I) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); Interleukin 13 (IL-13) blockers such as lebrikizumab; Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-Ml prime;Secreted homotrimeric LTa3 and membrane bound heterotrimer LTa I/β2 blockers such as Anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g., At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212 and radioactive isotopes of Lu); miscellaneous investigational agents such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or famesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTQNEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CCI-779; tipifamib (R11577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone; famesyltransferase inhibitors such as lonafamib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN™) combined with 5-FU and leucovorin.
In another embodiment, compounds of formula (I) can be co-formulated with an immuno-oncology agent. Immuno-oncology agents include, for example, a small molecule drug, antibody, or other biologic or small molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human. In another aspect, the antibody is a bispecific antibody.
In one aspect, the immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators).
Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTfiR, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin α/TNPβ, TNFR2, TNF a, LT R, Lymphotoxin a 1β2, FAS, FASL, RELT, DR6, TROY, NGFR.
In one aspect, T cell responses can be stimulated by a combination of a compound of formula (I) and one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.
Other agents that can be combined with compounds of formula (I) for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, compounds of formula (I) can be combined with antagonists of KIR, such as lirilumab.
Yet other agents for combination therapies include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 or FPA-008.
In another aspect, compounds of formula (I) can be used with one or more of agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell anergy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites.
In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. In another aspect, the immuno-oncology agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). The immuno-oncology agent may also include pidilizumab (CT-011), though its specificity for PD-1 binding has been questioned. Another approach to target the PD-1 receptor is the recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl, called AMP-224
In another aspect, the immuno-oncology agent is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, TECENTRIQ (atezolizumab) (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), and MSB0010718C (WO2013/79174).
In another aspect, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO2010/19570, WO2014/08218), or IMP-731 or IMP-321 (WO2008/132601, WO2009/44273).
In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO2012/32433).
In another aspect, the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO2006/105021, WO2009/009116) and MK-4166 (WO2011/028683).
In another aspect, the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO2006/122150, WO2007/75598, WO2008/36653, WO2008/36642), indoximod, or NLG-919 (WO2009/73620, WO2009/1156652, WO2011/56652, WO2012/142237).
In another aspect, the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469. In another aspect, the immuno-oncology agent is an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06/029879).
In another aspect, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.
In another aspect, the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.
In another aspect, the immuno-oncology agent is MGA271 (to B7H3) (WO2011/109400).
The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.
All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.
A suspension of an intermediate of formula (XLI) (5.7 mmol), (tert-butoxycarbonyl)-L-cysteine (III) (5.7 mmol) and potassium carbonate (17.2 mmol) was stirred in DMF (10 mL) at RT overnight. The reaction was filtered, the solid washed with 5 mL DMF. The desired product (XLII) was used crude in the next step or was purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of an intermediate of formula (IV) (23 mmol) in EtOH (112 mL) and water (18.7 mL) was added 1N aqueous hydrogen chloride solution (2.3 mL). The reaction mixture was heated to 50° C. and iron (8.99 g, 161 mmol) was added to the hot and stirred solution. The temperature was raised to 80° C. and stirred for 3.5 h. The reaction mixture was cooled to RT and filtered over celite, washed with ethyl acetate and concentrated under reduced pressure. The desired product (V) was used crude in the next step.
To a solution of of an intermediate of formula (V) (5.74 mmol) in DMF (15 mL) were added DIPEA (1.85 g, 2.51 mL, 14.4 mmol, 2.5 eq) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide 50% solution in EtOAc (7.31 g, 6.76 mL). The reaction mixture was stirred at RT for 3 h. The reaction mixture was quenched with water and extracted twice with DCM, washed with 1M aqueous NaOH solution, 1M aqueous HCl solution and sat. aqueous NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo. The desired product (VI) was used crude in the next step or was purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of an intermediate of formula (VI) (2.74 mmol) in DMSO (10 mL) were added at RT potassium carbonate (1.14 g, 8.23 mmol), potassium iodide (228 mg, 1.37 mmol) and a reagent of formula (VII) (3.29 mmol). The reaction was stirred at RT for 2 h, quenched with water and extracted twice with DCM. The combined organic layers were washed with water, saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The desired product (VIII) was used crude in the next step or was purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
A solution of an intermediate of formula (VIII) (2.74 mmol) and m-CPBA (1.18 g, 6.85 mmol) in DCM (10 mL) was stirred at RT for 1 day. The reaction was diluted with ethyl acetate and THF, washed with 2N aqueous sodium hydroxide solution, 1N aqueous HCl solution and saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The desired product (IX) was used crude in the next step or was purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of an intermediate of formula (IX) (38.9 μmol) in DCM (1 mL) was added 4M HCl in dioxane (200 μl, 800 μmol, 20.6 eq) and the reaction was stirred at RT overnight. The solvent was evaporated and the residue was suspended in DCM and diethyl ether. The solid was filtered off, washed with diethyl ether and dried in vacuo to yield desired product (I).
To a solution of an intermediate of formula (IX) (0.250 mmol) in EtOAc (4 mL) was added HCl/EtOAc (4.0 mL, 16 mmol, 63 eq) at 0° C. The reaction mixture was stirred at 20° C. for 3 h and then concentrated in vacuo. The remaining residue was purified by prep-HPLC and dried by lyophilization to obtain the desired product (I).
A solution of an intermediate of formula (IX) (22.7 μmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (1.5 mL) was stirred at reflux for 5 days. The solvent was evaporated and the remaining residue was dried under high vacuum to yield desired product (I).
To a solution of an intermediate of formula (IX) (0.250 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (4 mL) was added HCl/dioxane or HCl/Et2O (0.5 mmol, 2 eq) at 0° C. The reaction mixture was stirred at 20° C. for 2 h. The solvent was evaporated and the resulting solid taken up in DCM and concentrated again to remove trace 1,1,1,3,3,3-hexafluoropropan-2-ol. This process was repeated two times followed by drying under high vacuum to obtain the desired product (I).
A solution of an intermediate of formula (IX) (80 μmol) in DCM (2.5 mL) and TFA (0.5 mL) was stirred at room temperature for 1 hour. The solvent was evaporated and the remaining residue was dried under high vacuum to yield desired product (I) or was taken up in MeOH and purified by e.g. prep-HPLC.
To a solution of an intermediate of formula (XIII) (0.3 mmol) in THE (3 ml) was added a carboxylic acid of formula R10CO2H (0.45 mmol), DIPEA (0.6 mmol) and HATU (0.45 mmol). The resulting solution was stirred for 4 h at RT. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous phase extracted twice with EtOAc. The combined organic layers were washed with brine and then dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The desired product (XIV) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of an intermediate of formula (XIII) (0.5 mmol) in THE (5 ml) was added a carboxylic acid of formula R10CO2H (0.5 mmol), DIPEA (1.5 mmol) and T3P (50% in EtOAc, 1.5 mmol). The resulting solution was stirred at 60° C. for 2 h. The reaction was then cooled to RT and diluted with water. The mixture was extracted three times with EtOAc. The combined organic layers were washed with brine and then dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The desired product (XIV) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of an intermediate of formula (XIV) (0.3 mmol) in THE (3 ml) was added Burgess reagent (0.9 mmol). The resulting solution was stirred at RT overnight. Water was added and the mixture was extracted three times with EtOAc. The combined organic layers were washed with brine and then dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The desired product (XV) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of an intermediate of formula (XIV) (0.1 mmol) in acetonitrile (1.3 ml) was added p-toluenesulfonyl chloride (0.3 mmol) and DIPEA (0.2 mmol). The resulting solution was stirred at RT for 30 min. The reaction was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine and then dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The desired product (XV) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of a carboxylic acid of formula R10CO2H (2.4 mmol) in DMF (5 ml) was added CDI (2.64 mmol) and stirred for 60 min. Then, a solution of an intermediate of formula (LV, wherein R is H) (1.2 mmol) in DMF (5 ml) was added and the resulting mixture heated to 120° C. for 4 h.
The reaction was allowed to cool RT and water and EtOAc were added. The layers were separated and the aqueous phase extracted twice with EtOAc. The combined organic layers were washed with 1N HCl, dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure. The desired product (LVI) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of of an intermediate of formula (LV, wherein R is H) (0.3 mmol) in THE (5 mL) were added a carboxylic acid of formula R10CO2H (0.45 mmol), DIPEA (0.76 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide 50% solution in EtOAc (0.6 mmol) and the reaction was stirred at RT for 16 h. The reaction mixture was quenched with water and extracted twice with EtOAc, washed with 1M aqueous NaOH solution, 1M aqueous HCl solution and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The desired product (LVI) was used crude in the next step or was purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To solution of an intermediate of formula (LV, wherein R is H) (0.2 mmol) in DMF (1.5 ml) was added a carboxylic acid of formula R10CO2H (0.24 mmol), EDC hydrochloride (0.4 mmol), DIPEA (0.6 mmol) and HOBt (0.3 mmol) and the resulting mixture was heated to 80° C. for 8 h. The reaction was allowed to cool RT and water and EtOAc were added. The layers were separated and the aqueous phase extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure. The desired product (LVI) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of an intermediate of formula (LV, wherein R is H) (1.0 mmol) in THE (8.5 ml) was added a carboxylic acid of formula R10CO2H (0.12 mmol), DIPEA (2.0 mmol) and HATU (0.15 mmol) and the reaction was stirred at RT for 4 h. Water and EtOAc were added and the layers were separated. The aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure. The desired product (LV, wherein R is —CO(R10)) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To solution of an intermediate of formula (LV, wherein R is H) (0.2 mmol) in DMF (1.5 ml) was added a carboxylic acid of formula R10CO2H (0.24 mmol), EDC hydrochloride (0.4 mmol), DIPEA (0.6 mmol) and HOBt (0.3 mmol) and the resulting mixture was stirred at RT for 16 h. Water and EtOAc were added, the layers were separated and the aqueous phase extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure. The desired product (LV, wherein R is —CO(R10)) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of a carboxylic acid of formula R10CO2H (0.11 mmol) in acetonitrile (0.33 ml) was added CDI (0.12 mmol) and stirred at RT for 60 min. To this mixture was then added a solution of an intermediate of formula (LV, wherein R is H) (0.1 mmol) in acetonitrile (0.33 ml) and stirred for 60 min at RT. The reaction was diluted with DCM and water was added. The layers were separated and the aqueous phase extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure. The desired product (LV, wherein R is —CO(R10)) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
A solution of an intermediate of formula (LV, wherein R is —CO(R10)) (0.15 mmol) in toluene (1 ml) was heated to 120° C. for 16 h. The solvent was then evaporated under reduced pressure. The desired product (LVI) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of an intermediate of formula (LV, wherein R is —CO(R10)) (0.12 mmol) in THE (1.2 ml) was added tetrabutylammonium hydroxide (0.06 mmol) and stirred at RT for 30 min. The reaction was diluted with EtOAc and washed with sat. aq. NaHCO3. The aqueous phase was then washed twice with EtOAc and the combined organic layers dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure. The desired product (LVI) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of an intermediate of formula (XXXVII) (0.3 mmol) in EtOH (2.5 ml) was added solid NaHCO3 (1.5 mmol) and hydroxylamine hydrochloride (0.6 mmol). The resulting suspension was heated to 80° C. for 90 min and then allowed to cool to RT. The suspension was filtered and the filter cake washed with EtOH and DCM. The filtrate was concentrated under reduced pressure and the remaining solid was dissolved in DCM and washed with water and brine, dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure. The desired product (LV) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of an intermediate of formula (VII) (4 mmol) in THE (18 ml), MeOH (3 ml) and water (6 ml) was added LiOH hydrate (8 mmol) and stirred at RT for 2 h. 1N HCl was added and the resulting suspension extracted three times with EtOAc. The combined organic layers were washed with brine and then dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The desired product (XII) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of an intermediate of formula (XII) (4.5 mmol) in THE (20 ml) was added CDI (5.7 mmol) and stirred at RT for 90 min. To this solution was then added a mixture of hydrazine hydrate (13.5 mmol) in THF (3.3 ml) and stirred for 1 h. The reaction mixture was diluted with water and EtOAc. The layers were separated and the aqueous phase washed twice with EtOAc. The combined organic layers were washed with brine and then dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The desired product (XIII) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of an amine of formula HN(R10eR10f) (0.1 mmol) in 1,2-dichloroethane (0.4 ml) was added sat. aqueous sodium bicarbonate (3.7 mmol) and triphosgene (0.1 mmol) at 0° C. The cooling bath was removed and stirring was continued for 2 h. To this solution was then added an intermediate of formula (XIII) and stirred for 2 h at RT. Water and DCM were added and the layers were separated. The aqueous layer was extracted twice with DCM and the combined organic layers were dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure. The desired product (LXXIV) was used crude in the next step or purified bxy flash column chromatography on silica gel or by reverse phase preparative HPLC.
To a solution of an intermediate of formula (LXVIII) (0.06 mmol) in 1,4-dioxane (0.6 ml) was added an amine of formula HN(R10eR10f) (0.12 mmol), DIPEA (0.18 mmol) and PyBroP (0.072 mmol). The mixture was heated to 50° C. for 90 min. After cooling to RT, EtOAc and water were added and the reaction stirred vigorously for 5 min. The layers were separated and the aqueous phase extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The desired product (LXIX) was used crude in the next step or purified bxy flash column chromatography on silica gel or by reverse phase preparative HPLC.
The title compound was prepared in analogy to general procedure 1a using 2,4-difluoro-5-nitroaniline (CAS 123344-02-5) (1 g, 5.74 mmol, Eq: 1) and (tert-butoxycarbonyl)-L-cysteine (1.27 g, 5.74 mmol, Eq: 1) to yield the title compound (and 10% of a regioisomeric product) as a light yellow foam (109% yield). The product was used crude in the next step. MS (ESI): 374.3 [M−H]−.
The title compound was prepared in analogy to general procedure 3 from (2R)-3-(2-amino-5-fluoro-4-nitro-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (2.15 g, 5.74 mmol, Eq: 1) and was obtained as an orange solid (0.98 g, 47% yield). MS (ESI): 356.3 [M−H]−.
The title compound was prepared in analogy to general procedure 4 using 1-(bromomethyl)-4-chlorobenzene (676 mg, 3.29 mmol, Eq: 1.2) and tert-butyl N-[(3R)-8-fluoro-7-nitro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (0.98 g, 2.74 mmol, Eq: 1) to yield the title compound as a light yellow foam (1.43 g, 97% yield, 90% purity). MS (ESI): 480.3 [M−H]−.
To a suspension of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-nitro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (4.53 g, 9.4 mmol, 1 eq) and ammonium chloride (1.01 g, 18.8 mmol, 2 eq) in MeOH (50 mL) was added zinc powder (6.15 g, 94 mmol, 10 eq) at 25° C. The reaction mixture was purged with nitrogen three times and then heated to 70° C. and stirred for 2 h. The mixture was filtered and the filter cake was washed with hot MeOH (3×20 mL). The combined filtrates were concentrated in vacuo to obtain the crude product as a yellow oil. The crude product was purified by column chromatography on silica gel (EtOAc:PE=1:4 to 100:0) to afford the desired title compound (3.29 g, 7.28 mmol, 77% yield) as a light yellow solid. MS (ESI): 396.0 [M-isobutene+H]+.
To a solution of tert-butyl tert-butyl N-[(3R)-7-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (300.0 mg, 0.660 mmol, 1 eq) in MeCN (6 mL) were added isopentyl nitrite (0.13 mL, 1 mmol, 1.5 eq) and azidotrimethylsilane (0.13 mL, 1 mmol, 1.5 eq) at 0° C. The reaction mixture was purged with nitrogen three times and then stirred for 2 h at 25° C. To the mixture were then added copper(I) oxide (9.5 mg, 0.070 mmol, 0.1 eq) and 1-butyne (98+% purity) (71.81 mg, 1.33 mmol, 2 eq) in MeCN (3 mL) at 25° C. The mixture was stirred for 2 h at 25° C., filtered, extracted with EtOAc (3×6 mL), washed with brine (8 mL) and dried with Na2SO4. After filtration, the organic layer was concentrated in vacuo to obtain the crude product (571 mg) as a brown oil. The crude product was purified by column chromatography on silica gel (EtOAc:PE=1:9 to 2:3) to afford the desired title compound (254 mg, 0.48 mmol, 72% yield) as yellow oil. MS (ESI): 532.0 [M+H]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(4-ethyltriazol-1-yl)-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (55.0 mg, 0.1 mmol) and was obtained as a brown gum, as hydrochloride salt (48 mg, 0.1 mmol, 98% yield). MS (ESI): 432.0 [M+H]+.
Example 2 of the following table was prepared in analogy to Example 1, using the appropriate alkyne building block.
The title compound was prepared according to general procedure 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(4-ethyltriazol-1-yl)-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 1, step e) (199.0 mg, 0.370 mmol) and was obtained as yellow oil (220 mg) which was used in the next reaction step without further purification. MS (ESI): 564.0 [M+H]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(4-ethyltriazol-1-yl)-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (220 mg, 0.39 mmol) and was obtained as a white solid and as a hydrochloride salt (75.3 mg, 0.150 mmol, 39% yield). MS (ESI): 464.0 [M+H]+.
Examples 4 to 5 of the following table were prepared in analogy to Example 3, using the appropriate alkyne building blocks.
To a suspension of tert-butyl N-[(3R)-8-fluoro-7-nitro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 1, step b)) (6.0 g, 16.7 mmol, 1 eq) and ammonium chloride (2.05 g, 38.3 mmol, 2.29 eq) in MeOH (60 mL) was added zinc powder (7.0 g, 107.07 mmol, 6.38 eq) in batches at 25° C. Then the mixture was heated to 80° C. and stirred for 6 h under an atmosphere of nitrogen. The reaction mixture was filtered and the filter cake was washed with hot MeOH (3×20 mL). The combined filtrates were concentrated in vacuo and the remaining residue was dissolved with EtOAc (20 mL). The organic layer was washed with brine, dried with Na2SO4 and concentrated in vacuo to afford the title compound (5.1 g, 15.58 mmol, 93% yield) as a brown solid. MS (ESI): 272.1 [M-isobutene-CO2+H]+.
To a mixture of tert-butyl N-[(3R)-7-amino-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (5.5 g, 10.9 mmol, 1 eq), copper(I) bromide (200 mg, 1.39 mmol, 0.13 eq) and copper(II) bromide (0.57 mL, 12.09 mmol, 1.11 eq) in MeCN (60 mL) was added dropwise tert-butyl nitrite (2.0 g, 19.39 mmol, 1.78 eq) at 0° C. under an atmosphere of nitrogen. The mixture was stirred for 0.5 h at 0° C. and then warmed to 25° C. and stirred for 3.5 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with brine. The organic layer was then dried with Na2SO4, filtered and concentrated in vacuo to afford a crude product which was purified by column chromatography on silica gel (4% to 25% EtOAc in PE) to obtain the title compound (1.9 g, 4.86 mmol, 44% yield) as yellow solid. MS (ESI): 337.0 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-bromo-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (2000.0 mg, 5.11 mmol, 1 eq) and 1-(bromomethyl)-4-chlorobenzene (1157.89 mg, 5.64 mmol, 1.1 eq) in analogy to general procedure 4 and was obtained as orange solid (2000 mg, 3.88 mmol, 72% yield). MS (ESI): 461.1 [M-isobutene+H]+.
To a mixture of tert-butyl N-[(3R)-7-bromo-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (200.0 mg, 0.390 mmol, 1 eq) in THE (2 mL) were added DIPEA(0.14 mL, 0.800 mmol, 2.08 eq), trimethylsilylacetylene (200.0 mg, 2.04 mmol, 5.25 eq), copper iodide (16.0 mg, 0.080 mmol, 0.220 eq) and bis(triphenylphosphine)palladium(II) chloride (52.0 mg, 0.070 mmol, 0.190 eq) under an atmosphere of nitrogen at 25° C. The mixture was stirred for 16 h at 25° C. and then concentrated. The remaining residue was purified by column chromatography on silica gel (10% to 50% EtOAc in PE) to afford the title compound (200 mg, 0.38 mmol, 97% yield) as a brown solid. MS (ESI): 477.1 [M-isobutene+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-(2-trimethylsilylethynyl)-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (139.0 mg, 0.260 mmol, 1 eq) in MeOH (3 mL) was added potassium fluoride (55.08 mg, 0.950 mmol, 3.64 eq) at 15° C. and the mixture was stirred at 15° C. for 5 h. The mixture was concentrated in vacuo and the remaining residue was purified by preparative-TLC (PE:EtOAc=3:1) to afford the title compound (96 mg, 0.21 mmol, 71% yield) as a dark brown oil. MS (ESI): 405.1 [M-isobutene+H]+.
K2CO3 (70.0 mg, 0.51 mmol, 2.6 eq), CuSO4·5H2O (2.0 mg, 0.01 mmol, 0.04 eq) and 1H-imidazole-1-sulfonyl azide hydrochloride (70.0 mg, 0.330 mmol, 1.71 eq) were added to a solution of ethylamine (18.0 mg, 0.400 mmol, 2.04 eq) in MeOH (2 mL). The mixture was stirred for 14 h at 20° C. and then tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-ethynyl-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (90.0 mg, 0.2 mmol, 1 eq), water (0.4 mL), CuSO4·5H2O (10.0 mg, 0.04 mmol, 0.21 eq) and sodium ascorbate (8.0 mg, 0.040 mmol, 0.210 eq) were added. The reaction mixture was stirred vigorously for 14 h at 20° C. and poured into 1N NH3·H2O solution (5 mL). The mixture was extracted with EtOAc (3×5 mL) and the combined organic extracts were washed with brine (10 mL), dried with Na2SO4 and concentrated. The remaining residue was purified by column chromatography on silica gel (3-25% EtOAc in PE) to afford the title compound (100 mg, 0.19 mmol, 96% yield) as a brown oil. MS (ESI): 476.2 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(1-ethyltriazol-4-yl)-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (70.0 mg, 0.130 mmol) in analogy to general procedure 5 to obtain a white solid (85 mg) containing the title compound which was used in the next reaction step without further purification. MS (ESI): 508.2 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(1-ethyltriazol-4-yl)-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (85.0 mg, 0.150 mmol) in analogy to general procedure 6a and was obtained as white solid, as a hydrochloride salt (48.8 mg, 0.1 mmol, 65% yield). MS (ESI): 464.2 [M+H]+.
To a solution of tert-butyl tert-butyl N-[(3R)-7-bromo-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 6, step c) (300.0 mg, 0.58 mmol, 1 eq) in DMF (9 mL) were added Zn(CN)2 (102.43 mg, 0.870 mmol, 1.5 eq), Zn powder (38.02 mg, 0.580 mmol, 1 eq), t-Bu3P (0.12 mL, 0.120 mmol, 0.2 eq) and Pd2(dba)3 (53.26 mg, 0.060 mmol, 0.100 eq). The mixture was degassed with nitrogen and stirred at 50° C. for 16 h. The reaction was cooled to RT, EtOAc (30 mL) was added and the mixture was filtered through Celite (the celite was pre-washed with NaClO solution (20 mL) and 1 N HCl (15 mL)). The filtrate was washed with CaCl2 solution (10 mL), water (2×5 mL) and brine (5 mL) and then it was dried with Na2SO4, filtered, and concentrated. The remaining residue was purified by column chromatography on silica gel (5 to 40% EtOAc in PE) to afford the title compound (260 mg, 0.56 mmol, 97% yield) as an off-white solid. MS (ESI): 406.1 [M-isobutene+H]+.
To a mixture of tert-butyl tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-cyano-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (250.0 mg, 0.540 mmol, 1 eq) in toluene (2.5 mL) were added tetra-N-butylammonium fluoride trihydrate (85.38 mg, 0.27 mmol, 0.5 eq) and azidotrimethylsilane (0.11 mL, 0.810 mmol, 1.5 eq) at 25° C. The mixture was purged with nitrogen for three times and then heated to 85° C. and stirred for 16 h. The reaction was quenched by addition of saturated NH4Cl solution (2 mL) and the mixture was then extracted with EtOAc (3×3 mL) and washed with brine (3×2 mL). The organic layer was concentrated in vacuo to afford the crude title compound (334 mg) as a brown oil which was used in next step without further purification. MS (ESI): 449 [M-isobutene+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-(2H-tetrazol-5-yl)-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (334.0 mg, 0.660 mmol, 1 eq) in DMF (3 mL) were added iodoethane (0.08 mL, 0.990 mmol, 1.5 eq) and potassium carbonate (137.12 mg, 0.990 mmol, 1.5 eq) at 25° C. and the mixture was stirred for 16 h at 25° C. Then water (3 mL) was added and the mixture was extracted with EtOAc (3×3 mL). The organic extracts were washed with brine (3×8 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to afford a crude material (579 mg) as a yellow oil. The crude product was purified by column chromatography on silica gel (10% to 50% EtOAc in PE) to afford desired title compound (30 mg, 0.06 mmol, 8.5% yield) as a yellow oil. MS (ESI): 477 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(2-ethyltetrazol-5-yl)-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (30.0 mg, 0.060 mmol) in analogy to general procedure 5 and was obtained as yellow oil (30 mg, 0.05 mmol, 94% yield). MS (ESI): 509 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(2-ethyltetrazol-5-yl)-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (30.0 mg, 0.05 mmol) in analogy to general procedure 6b and was obtained as white solid, as a hydrochloride salt (12.6 mg, 0.03 mmol, 47% yield). MS (ESI): 464.9 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-cyano-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (400.0 mg, 0.870 mmol, 1 eq) in analogy to general procedure 5 and was obtained as yellow solid (45 mg, 0.080 mmol, 65% yield). MS (ESI): 438.1 [M-isobutene+H]+.
A solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-cyano-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (440.0 mg, 0.890 mmol, 1 eq) and azidotrimethyltin (550.06 mg, 2.67 mmol, 3 eq) in p-xylene (10 mL) was stirred for 6 h under an atmosphere of nitrogen at 120° C. After cooling to ambient temperature, a solution of NaNO2 (172 mg) in water (0.8 mL) was added to the mixture with stirring. Then the mixture was slowly acidified by addition of aqueous HCl (1 N) to adjust the pH to 3 and stirring was continued for 1 h until no more gas evolution was observed. After that, the mixture was basified with aqueous NaOH (1 N) to pH=8 and extracted with EtOAc (5 mL×2). The combined organic layers were washed with brine (10 mL×3), dried over anhydrous Na2SO4 and concentrated under vacuum. To the remaining residue mixture was added PE (20 mL) slowly until no more precipitation was observed. After filtration, the filter cake was dried under vacuum to afford the title compound (570 mg, 1.06 mmol, 104.87% yield) as a yellow solid. MS (ESI): 481.1 [M-isobutene+H]+.
A solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-(2H-tetrazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (200.0 mg, 0.370 mmol, 1 eq) and tBuOH (0.04 mL, 0.450 mmol, 1.2 eq) in H2SO4 (2.0 mL, 0.370 mmol, 1 eq) was stirred at 25° C. for 2 h. The reaction mixture was added into saturated Na2CO3 aqueous (10 mL) drop-wise. The resulting mixture was extracted with EtOAc (5 mL×2) and the combined organic phases were washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated. The remaining residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 um; water (0.05% ammonia hydroxide v/v)-MeCN;B %: 33%-63%,11.5 min) affording the title compound (39.5 mg, 0.080 mmol, 21.3% yield) as a white solid. MS (ESI): 493.2 [M+H]+.
4 M HCl in dioxane (29.2 uL, 0.11 mmol, 2.5 eq) was stirred with tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-[2-[(3S)-1-methylpyrrolidin-3-yl]tetrazol-5-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (29 mg, 0.047 mmol, 1 eq) in 1,1,1,3,3,3-hexafluoro-2-propanol (2.34 mL) at room temperature for 75 min The solvent was evaporated and the crude resuspended in DCM and concentrated again. This process was repeated 2× and the resulting solid then dried in vacuo to afford the title compounds as a bis hydrochloride salt (27.5 mg, 99% yield) as white solid. MS (ESI): 260.7 [M/2+H]+.
Examples 10 to 15 of the following table were prepared in analogy to Example 9 in two steps, using the appropriate alcohol building block.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-(2H-tetrazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (30.0 mg, 0.06 mmol) and methyliodide in analogy to Example 7, step c) and was obtained as yellow solid (24 mg, 0.04 mmol, 60% yield). MS (ESI): 495.1 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(2-methyltetrazol-5-yl)-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (60 mg, 0.11 mmol) in analogy to general procedure 6b and was obtained as white solid as a hydrochloride salt (24 mg, 0.05 mmol, 43% yield). MS (ESI): 451.1 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-(2H-tetrazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (100 mg, 0.19 mmol) and 1-boc-4-hydroxypiperidine in analogy to example 9, step a) and was obtained as white solid (130 mg, 0.18 mmol, 96% yield). MS (ESI): 620.2 [M-isobutene-CO2+H]+.
The title compound was prepared from tert-butyl 4-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]tetrazol-2-yl]piperidine-1-carboxylate (130 mg, 0.18 mmol) in analogy to general procedure 6b and was obtained as white solid as a dihydrochloride salt (107 mg, 0.18 mmol, 99% yield). MS (ESI): 520.1 [M+H]+.
To a solution of (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1-dioxo-7-[2-(4-piperidyl)tetrazol-5-yl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one dihydrochloride salt (100 mg, 0.17 mmol, 1 eq) in DCM (2 mL) was added NEt3 (54.6 mg, 0.54 mmol, 3.2 eq) and methanesulfonyl chloride (0.02 mL, 0.20 mmol, 1.2 eq), the mixture was stirred at 10° C. for 0.5 h, concentrated and purified by prep-HPLC. The elution was lyophilized to yield the title compound (25.7 mg, 0.04 mmol, 24% yield) as a white solid as the hydrochloride salt. MS (ESI): 598.0 [M+H]+.
Example 18 of the following table was prepared in analogy to Example 17 in three steps, using the appropriate alcohol and sulfonylating building block.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-(2H-tetrazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50.0 mg, 0.09 mmol) and 1-Cbz-3-pyrrolidinol in analogy to example 9, step a) and was obtained as light brown solid (47 mg, 0.06 mmol, 6200 yield). MS (ESI): 640.2 [M isobutene-CO2+H]+.
To a solution of benzyl 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]tetrazol-2-yl]pyrrolidine-1l-carboxylate (47.0 mg, 0.06 mmol, 1 eq) in MeOH (1 mL) was added Pd/C (0.03 mL, 0.13 mmol, 2 eq) the mixture was degassed with H2 for 3 times, then stirred at 25° C. for 2 h. After filtration, the filtrate was concentrated to afford the crude title compound (28 mg, 0.05 mmol, 34% yield, 47% purity) as a light brown solid. MS (ESI): 606.2 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-(2-pyrrolidin-3-yltetrazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (40 mg, 0.07 mmol) and methanesulfonyl chloride in analogy to example 17, step c) and was obtained as light yellow gum (24 mg, 0.04 mmol, 53% yield). MS (ESI): 584.2 [M-isobutene-CO2+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[2-(1-methylsulfonylpyrrolidin-3-yl)tetrazol-5-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (60.0 mg, 0.11 mmol) in analogy to general procedure 6a and was obtained as white solid, as a hydrochloride salt (7.3 mg, 0.01 mmol, 32% yield). MS (ESI): 584.0 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-(2H-tetrazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50 mg, 0.09 mmol) and benzyl 3-hydroxypiperidine-1-carboxylate in analogy to example 9, step a) and was obtained as white solid (20 mg, 0.03 mmol, 26% yield). MS (ESI): 754.2 [M+H]+.
To a solution of benzyl 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]tetrazol-2-yl]piperidine-1-carboxylate (20 mg, 0.03 mmol) in EtOH (3 mL) was added HC\EtOAc (0.01 mL, 0.05 mmol, 2 eq) and Pd(OH)2/C (wet. 10%) (10.0 mg), the mixture was degassed with H2 for three times, then stirred at 25° C. for 8 h. Additional HC\EtOAc (0.01 mL, 0.03 mmol, 1 eq) was added into the mixture, then degassed with H2 for three times and stirred for another 6 h. The mixture was filtered by diatomite and washed with EtOH (5 mL), concentrated and purified by prep-HPLC to afford the title compound (3 mg, 16% yield) as a white solid. MS (ESI): 620.2 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-[2-(3-piperidyl)tetrazol-5-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50 mg, 0.08 mmol, 1 eq) in MeOH (2 mL) was added formaldehyde (0.01 mL, 0.16 mmol, 2 eq) at 20° C. After stirred for 0.5 h, sodium cyanoborohydride (9.88 mg, 0.16 mmol, 2 eq) was added and the mixture was stirred for 16 h at 20° C. The reaction mixture was quenched by aqueous 0.5 M HCl (1 mL), extracted with EtOAc (3 mL×3). The combined organic phase was washed with brine (5 mL×2), dried over anhydrous Na2SO4, concentrated under vacuo. The crude product which was purified by prep-HPLC. The eluent was concentrated under vacuo, the residue was freeze dried to afford the title compound (25 mg, 0.04 mmol, 50% yield) as a white solid which contained 51% de-Boc. MS (ESI): 634.1 [M+H]+.
The title compound was prepared tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[2-(1-methyl-3-piperidyl)tetrazol-5-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (25 mg, 0.04 mmol) in analogy to general procedure 6b and was obtained as white solid, as a dihydrochloride salt (8.4 mg, 0.01 mmol, 33% yield). MS (ESI): 534.2 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-(2H-tetrazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50 mg, 0.09 mmol) and benzyl 3,3-difluoro-5-hydroxy-piperidine-1-carboxylate (30.3 mg, 0.11 mmol, 1.2 eq) in analogy to example 9, step a) and was obtained as white solid (32 mg, 0.04 mmol, 41% yield). MS (ESI): 690.2 [M-isobutene-CO2+H]+.
The title compound was prepared from benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]tetrazol-2-yl]piperidine-1-carboxylate (130 mg, 0.16 mmol) in analogy to example 19, step b) and was obtained as white solid (75 mg, 45% yield). MS (ESI): 600.1 [M-isobutene+H]+.
The title compounds were prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[2-(5,5-difluoro-3-piperidyl)tetrazol-5-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (24.0 mg, 0.04 mmol) and tert-butyl N-[(3R)-5-benzyl-7-[2-(5,5-difluoro-3-piperidyl)tetrazol-5-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (16.0 mg, 0.03 mmol) in analogy to example 20, step c) and were obtained as a white solid as a crude mixture (16 mg, 0.030 mmol, 68% yield and 21 mg, 0.030 mmol, 85% yield)). MS (ESI): 670.3 [M+H]+ and MS (ESI): 636.3 [M+H]+.
The title compounds were prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[2-(5,5-difluoro-1-methyl-3-piperidyl)tetrazol-5-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (21.0 mg, 0.03 mmol) and tert-butyl N-[(3R)-5-benzyl-7-[2-(5,5-difluoro-1-methyl-3-piperidyl)tetrazol-5-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (16.0 mg, 0.03 mmol) in analogy to general procedure 6b and (3R)-3-amino-5-[(4-chlorophenyl)methyl]-7-[2-(5,5-difluoro-1-methyl-3-piperidyl)tetrazol-5-yl]-8-fluoro-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one was obtained after prep-HPLC as white solid (4.5 mg, 25% yield) (MS (ESI): 570.2 [M+H]+) and (3R)-3-amino-5-benzyl-7-[2-(5,5-difluoro-1-methyl-3-piperidyl)tetrazol-5-yl]-8-fluoro-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one as white solid (4.4 mg, 25% yield) (MS (ESI): 536.3 [M+H]+).
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[2-(5,5-difluoro-3-piperidyl)tetrazol-5-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (90 mg, 0.06 mmol) and methane sulfonylchloride in analogy to example 17, step c) and was obtained as light yellow gum (46 mg, 0.06 mmol, 96% yield). MS (ESI): 678.0 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[2-(5,5-difluoro-1-methylsulfonyl-3-piperidyl)tetrazol-5-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (46.0 mg, 0.06 mmol) in analogy to general procedure 6b and was obtained as white solid (22.1 mg, 0.03 mmol, 54% yield) after prep-HPLC. MS (ESI): 634.1 [M+H]+.
To a solution tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[2-(5,5-difluoro-3-piperidyl)tetrazol-5-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (75 mg, 0.11 mmol, 1 eq) in DCM (2 mL) was added acetic anhydride (0.01 mL, 0.11 mmol, 1 eq) at 0° C. The mixture was stirred for 3 hr at 25° C. The reaction solution was concentrated in vacuo and purified by prep-TLC (PE:EtOAc=1:1) to afford the title compound (50 mg, 0.07 mmol, 41% yield) as a white solid. MS (ESI): 598.1 [M-isobutene-CO2+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-[2-(1-acetyl-5,5-difluoro-3-piperidyl)tetrazol-5-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50 mg, 0.07 mmol) in analogy to general procedure 6b and was obtained as white solid after prep-HPLC (10.9 mg, 0.02 mmol, 24% yield). MS (ESI): 598.2 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[2-(5,5-difluoro-3-piperidyl)tetrazol-5-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (200 mg, 0.18 mmol) and methyl chloroformate in analogy to example 17, step c) and was obtained as a white solid (66 mg, 0.09 mmol, 46% yield) after prep-TLC. MS (ESI): 614.1 [M-isobutene-CO2+H]+.
The title compound was prepared from methyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]tetrazol-2-yl]piperidine-1-carboxylate (66 mg, 0.09 mmol) in analogy to general procedure 6b and was obtained as white solid (13 mg, 0.02 mmol, 22% yield) after prep-HPLC. MS (ESI): 614.1 [M+H]−.
To a solution of benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]tetrazol-2-yl]piperidine-1-carboxylate (300 mg, 0.38 mmol) in DCM (30 mL) was added trimethylsilyl iodide (0.14 mL, 0.95 mmol, 2.5 eq), the mixture was degassed with N2 for three times, then stirred at 25° C. for 1 h. The mixture was quenched by addition of water (10 mL) and basified with saturated aqueous NaHCO3 to pH=8, then extracted with EtOAc (10 mL×2). The combined organic phase was dried over anhydrous Na2SO4, concentrated to give crude product which was triturated with EtOAc:PE (2:1, 5 mL) and filtered, the cake was dried in vacuo to provide the title compound (88 mg, 0.16 mmol, 33% yield) as a white solid. MS (ESI): 556.2 [M+H]+.
The title compound was prepared from (3R)-3-amino-5-[(4-chlorophenyl)methyl]-7-[2-(5,5-difluoro-3-piperidyl)tetrazol-5-yl]-8-fluoro-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one (88.0 mg, 0.13 mmol) in analogy to example 24, step a) and was obtained as white solid (21.3 mg, 25% yield) after prep-HPLC (water(0.05% HCl)-MeCN) as the hydrochloride salt. MS (ESI): 598.1 [M+H]+.
A suspension of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-(2H-tetrazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (270 mg, 0.50 mmol), 2,2-dimethyloxirane (0.18 mL, 1.5 mmol, 3 eq) and CuS (53.9 mg, 0.55 mmol, 1.1 eq) in water (5 mL) was heated to 50° C. and the mixture was stirred for 16 h. After cooled to ambient temperature, the mixture was filtered and the cake was washed with EtOAc (5 mL×2). The water phase was extracted with EtOAc (5 mL×2), the combined organic phase was dried over anhydrous Na2SO4, concentrated and purified by prep-TLC (PE:EA=2:1) and subsequently by SFC (DAICEL CHIRALCEL OD, 0.1% NH3 H2O MeOH) to provide the title compounds as a mixture (100 mg, 0.16 mmol, 32% yield) as a white solid. MS (ESI): 553.1 [M-isobutene+H]+.
The title compounds were prepared from a mixture of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[2-(2-hydroxy-2-methyl-propyl)tetrazol-5-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (82.0 mg, 0.13 mmol) and tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[2-(2-hydroxy-1,1-dimethyl-ethyl)tetrazol-5-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (15.0 mg, 0.02 mmol) in analogy to general procedure 6b. (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[2-(2-hydroxy-2-methyl-propyl)tetrazol-5-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one (33.7 mg, 0.06 mmol, 74% yield) was obtained as a white solid as hydrochloride salt and (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[2-(2-hydroxy-1,1-dimethyl-ethyl)tetrazol-5-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one (4.6 mg, 0.01 mmol, 9% yield) was obtained as a white solid as hydrochloride salt after prep-HPLC (water 0.05% HCl-MeCN). MS (ESI): 509.1 [M+H]+.
To a solution of Boc-glycine (10.6 mg, 0.061 mmol, 1.5 eq), DIPEA (15.7 mg, 21.2 uL, 0.12 mmol, 3 eq) and HATU (30.8 mg, 0.081 mmol, 2 eq) in DMF (0.3 mL) was added (3R)-3-amino-7-(2-tert-butyltetrazol-5-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one (Example 8, step c) (20 mg, 0.041 mmol, 1 eq) and the reaction mixture was stirred at 25° C. overnight. The reaction was purified by column chromatography on silica gel (heptane:EtOAc 1:0 to 0:1) to obtain the title compound (30 mg, 113% yield) as a white solid. MS (ESI): 594.3 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[2-[[(3R)-7-(2-tert-butyltetrazol-5-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]amino]-2-oxo-ethyl]carbamate (30 mg, 0.046 mmol) and was obtained as a withe solid (14 mg, 55% yield). MS (ESI): 550.3 [M+H]+.
The title compound was prepared from N-[(3R)-7-cyano-8-fluoro-4-keto-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (600 mg, 1.78 mmol) and 1-(bromomethyl)-4-(trifluoromethoxy)benzene in DMF in analogy to general procedure 4 and was obtained as light yellow solid (752 mg, 82% yield). MS (ESI): 456.3 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (750 mg, 1.47 mmol) in analogy to general procedure 5 and was obtained as off-white solid (475 mg, 53% yield). MS (ESI): 488.2 [M-isobutene+H]+.
To a solution of tert-butyl N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (200 mg, 0.370 mmol) in toluene (4 mL) was added trimethylsilyl azide (169 mg, 1.47 mmol, 4 eq), and dibutyltin oxide (13.7 mg, 0.06 mmol, 0.15 eq), the mixture was degassed with N2 for 2 mins, then stirred at 100° C. for 3 h. After cooled to room temperature, the mixture was quenched by water (5 mL), saturated aqueous KF (5 mL), and stirred for 1 h. Then the pH of the mixture was adjusted to over 9 and stirred for 10 mins. After separated, the aqueous phase was extracted with EtOAc (5 mL×3), the combined organic phase was washed with brine (10 mL×3), dried over anhydrous Na2SO4, concentrated to give crude product which was triturated with toluene (5 mL) and filtered to afford the title compound (240 mg, 0.41 mmol, 92% yield) as a light brown solid. MS (ESI): 531.4 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-7-(2H-tetrazol-5-yl)-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (220 mg, 0.38 mmol) in analogy to Example 8, step c) and was obtained as white solid (41.7 mg, 0.08 mmol, 20% yield). MS (ESI): 543.1 [M+H]+.
Example 31 of the following table was prepared in analogy to Example 30 in four steps, using the appropriate amide building block.
Example 32 of the following table was prepared in analogy to Example 30 in four steps, using the appropriate alkylating building block.
The title compound was prepared from N-[(3R)-7-cyano-8-fluoro-4-keto-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (250 mg, 0.74 mmol) and 4-[[4-(chloromethyl)phenoxy]methyl]tetrahydropyran (196 mg, 0.82 mmol,) in DMF in analogy to general procedure 4 and was obtained as light yellow solid (200 mg, 49% yield). MS (ESI): 564.2 [M+Na]+.
The title compound was prepared from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[[4-(tetrahydropyran-4-ylmethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (190 mg, 0.35 mmol) in analogy to general procedure 5 and was obtained as-white solid (180 mg 89% yield). MS (ESI): 596.2 [M+Na]+.
The title compound was prepared from tert-butyl N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-5-[[4-(tetrahydropyran-4-ylmethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (180 mg, 0.31 mmol) in analogy to example 30, step c) and was obtained as-white solid (100 mg 51% yield). MS (ESI): 639.2 [M+Na]+.
To tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-5-[[4-(tetrahydropyran-4-ylmethoxy)phenyl]methyl]-7-(2H-tetrazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (70 mg, 0.14 mmol, 1 eq) in tert-butanol (2 mL) was added TFA (4.0 mL, 53 mmol, 397 eq) at 25° C., then heated to 30° C. for 2 h. The reaction was concentrated, purified by prep-HPLC (neutral) and lyophilized to afford the title compound (26.5 mg, 0.05 mmol, 33% yield) as a white solid. MS (ESI): 573.3 [M+H]+.
(3R)-3-amino-7-(2-tert-butyltetrazol-5-yl)-5-(4-chlorobenzyl)-8-fluoro-2,3-dihydro-1,5-benzothiazepin-4-one (105 mg, 0.23 mmol) was stirred in DCM (2.5 mL) at room temperature. (Boc)2O (54.6 mg, 58.2 uL, 0.25 mmol, 1.1 eq) was added and the reaction was stirred overnight at room temperature. The crude material was purified by column chromatography on silica gel (heptane:EtOAc (0-100%)) affording the title compound (88 mg, 55% yield) as light yellow solid. MS (ESI): 505.2 [M-isobutene+H]+.
tert-butyl N-[(3R)-7-(2-tert-butyltetrazol-5-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (40 mg, 0.071 mmol, 1 eq) was stirred with 3-chloroperoxybenzoic acid (15.9 mg, 0.071 mmol, 1 eq) in DCM (1 mL) at room temperature overnight. The solvent was evaporated. 1,1,1,3,3,3-hexafluoro-2-propanol (1.5 mL) was added followed by HCl in dioxane 4M (5 drops). The mixture was stirred for 3 h at room temperature. The solvent was evaporated and the crude was purified by prep-HPLC affording the title compound Epimer A (9.1 mg, 26% yield) as white solid and Epimer B (12.5 mg, 36%, yield) as a white solid. MS (ESI): 477.1 [M+H]−.
To a solution of 4-fluoro-3-nitrobenzonitrile (10.0 g, 60.2 mmol) in DCM (200 mL) was added (2R)-2-(tert-butoxycarbonylamino)-3-sulfanyl-propanoic acid (14.65 g, 66.2 mmol, 1.1 eq) and DIPEA (20.5 mL, 120.4 mmol, 2 eq), the mixture was stirred at 25° C. for 16 h. After concentrated under vacuo, the residue was diluted with EtOAc (200 mL) and washed with 1 N aqueous HCl (50 mL) and water (100 mL), then brine (50 mL×2), dried over Na2SO4, filtered and concentrated to give the crude title compound (24 g, 65.3 mmol, 77% yield) as a yellow solid. MS (ESI): 390.1 [M+Na]+.
The title compound was prepared from (2R)-2-(tert-butoxycarbonylamino)-3-(4-cyano-2-nitro-phenyl)sulfanyl-propanoic acid (10.0 g, 27.2 mmol) in analogy to general procedure 2 and was obtained as-brown solid (10 g, 87% yield). MS (ESI): 338.2 [M+H]−.
The title compound was prepared from (2R)-3-(2-amino-4-cyano-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (11.3 g, 33.5 mmol) in analogy to general procedure 3 and was obtained as-white solid (5 g, 45% yield). MS (ESI): 263.9 [M-isobutene+H]+.
The crude title compound was prepared from tert-butyl N-[(3R)-7-cyano-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (1.0 g, 3.1 mmol) in analogy to general procedure 4 and was obtained as-white solid (2 g, 143% yield). MS (ESI): 388.1 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-cyano-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (2000 mg, 4.51 mmol) in analogy to general procedure 5 and was obtained as-white solid (1700 mg, 77% yield). MS (ESI): 498.4 [M+Na]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-cyano-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (1500 mg, 3.15 mmol) in analogy to example 30, step c) and was obtained as-white solid (940 mg, 55% yield) after prep-HPLC. MS (ESI): 463.1 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-7-(2H-tetrazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (100 mg, 0.19 mmol) in analogy to Example 8, step c) and was obtained as white solid (18.6 mg, 0.04 mmol, 20% yield) after prep-HPLC. MS (ESI): 475.1 [M+H]−.
The title compound was prepared from tert-butyl N-[(3R)-7-bromo-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 6, step c) (550.0 mg, 1.07 mmol) in analogy to general procedure 5 and was obtained as light yellow solid (590 mg, 1.08 mmol, 96% yield). MS (ESI): 493.1 [M-isobutene+H]+.
To a solution of tert-butyl N-[(3R)-7-bromo-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (130.0 mg, 0.24 mmol, 1 eq) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (99.01 mg, 0.360 mmol, 1.5 eq) in 1,4-dioxane (2.6 mL) were added bis(triphenylphosphine)palladium dichloride (16.66 mg, 0.02 mmol, 0.1 eq) and sodium carbonate (60.62 mg, 0.570 mmol, 2.41 eq) (as a solution in water (0.650 mL)) at 25° C. The mixture was stirred at 80° C. for 16 h. Then water (2 mL) was added and the mixture was extracted with EtOAc (3×2 mL). The combined extracts were washed with brine (3×6 mL) and dried with Na2SO4. After filtration, the organic layer was concentrated in vacuo to afford the crude product (230 mg) as a yellow oil. The crude product was purified by column chromatography on silica gel (10% to 25% EtOAc in PE) to obtain the desired title compound (160 mg, 0.26 mmol, 96% yield) as a white solid. MS (ESI): 479 [M-isobutene-dihydropyranyl+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-(2-tetrahydropyran-2-ylpyrazol-3-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (160.0 mg, 0.230 mmol) in analogy to general procedure 6b and was obtained as white solid, as a hydrochloride salt (71.7 mg, 0.15 mmol, 66% yield). MS (ESI): 435.1 [M+H]+.
To a stirred solution of (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (CAS 2002449-40-1) (200.0 mg, 0.420 mmol, 1 eq) in DMF (4 mL) were added NEt3 (0.12 mL, 0.830 mmol, 2 eq) and HATU (173.92 mg, 0.460 mmol, 1.1 eq) and the mixture was stirred for 10 min at 20° C. Then N-aminopropanamidine (40.25 mg, 0.420 mmol, 1 eq) was added and the reaction mixture was stirred at 20° C. for 4 h. The mixture was diluted with H2O (15 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were washed with H2O (5 mL), saturated CaCl2 solution (5 mL) and brine (5 mL) and then dried with Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (10% to 50% EtOAc in PE) to afford the title compound (135 mg, 0.250 mmol, 61% yield) as light yellow gum. MS (ESI): 532.2 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(5-ethyl-1H-1,2,4-triazol-3-yl)-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (65.0 mg, 0.120 mmol) in analogy to general procedure 5 and was obtained as light yellow gum (45 mg, 0.080 mmol, 65% yield). MS (ESI): 564.2 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(5-ethyl-1H-1,2,4-triazol-3-yl)-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (45.0 mg, 0.080 mmol) in analogy to general procedure 6b and was obtained as white solid, as a hydrochloride salt (13 mg, 0.030 mmol, 32% yield). MS (ESI): 463.9 [M+H]+.
To a solution of methyl 6-amino-5-bromopyridine-2-carboxylate (CAS 178876-82-9) (4500 mg, 19.48 mmol, 1 eq) in toluene (54.15 mL) were added DIPEA (6.78 mL, 38.95 mmol, 2 eq), (2R)-2-(tert-butoxycarbonylamino)-3-sulfanyl-propanoic acid (4309.52 mg, 19.48 mmol, 1 eq), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (2253 mg, 3.9 mmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium(0) (1783 mg, 1.95 mmol, 0.1 eq) at 25° C. The reaction mixture was heated to 100° C. and stirred for 1.5 h under an atmosphere of nitrogen. The reaction mixture was then filtered, the filter cake was washed with EtOAc (3×20 mL) and the volume of the filtrate was reduced in vacuo. The filtrate was extracted with H2O (3×60 mL) and the combined aqueous layers were dried by lyophilization to obtain the crude title compound (7.84 g, 21.11 mmol, 97% yield) as light yellow solid which was used in next step without further purification. MS (ESI): 372 [M+H]+.
To a solution of (2R)-3-[(2-amino-6-methoxycarbonyl-3-pyridyl)sulfanyl]-2-(tert-butoxycarbonylamino)propanoic acid (7.48 g, 18.13 mmol, 1 eq) and DIPEA (6.31 mL, 36.25 mmol, 2 eq) in THE (74.8 mL) was added propylphosphonic anhydride solution (50% in EtOAC) (16.69 g, 36.25 mmol, 2 eq) at 0° C. The mixture was stirred for 4 h at 25° C. and then concentrated in vacuo. The remaining residue was diluted with EtOAc (100 mL) and the organic layer was washed with brine (3×100 mL), dried with Na2SO4, filtered and concentrated in vacuo to obtain the crude product (4.92 g) as a yellow oil. The crude product was purified by column chromatography on silica gel (PE:EA=10:1 to 3:1) to obtain the desired title compound (2.6 g, 7.36 mmol, 41% yield) as a white solid. MS (ESI): 354 [M+H]+.
The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-pyrido[3,2-b][1,4]thiazepine-7-carboxylate (12.5 g, 35.3 mmol) and 1-(bromomethyl)-4-chlorobenzene (7.6 g, 37.0 mmol) in analogy to general procedure 4 and was obtained as white solid (14.0 g). MS (ESI): 478.2 [M+H]+.
To a solution of methyl (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydropyrido[3,2-b][1,4]thiazepine-7-carboxylate (500.0 mg, 1.05 mmol, 1 eq) in THF (15 mL) was added a solution of LiOH·H2O (50.48 mg, 1.2 mmol, 1.15 eq) in water (5 mL) at 0° C. The reaction mixture was stirred for 0.5 h at 0° C. The reaction mixture was poured into a mixture of aqueous HCl (0.5 M, 3.6 mL) and EtOAc (20 mL) at 0° C. with stirring. The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic phases were washed with brine (3×20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (480 mg, 1.03 mmol, 97% yield) as a light yellow solid which was used into next step without any further purification. MS (ESI): 408.0 [M-isobutene+H]+.
To a solution of (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydropyrido[3,2-b][1,4]thiazepine-7-carboxylic acid (220.0 mg, 0.470 mmol, 1 eq) in DMF (4 mL) was added CDI (84.58 mg, 0.520 mmol, 1.1 eq) at 25° C. After the mixture was stirred for 1 h at 25° C., a solution of 3,3,3-trifluoro-N′-hydroxy-propanamidine (CAS 1016726-53-6) (0.3 M in DMF, 8.4 mL, 2.52 mmol, 5.31 eq) was added into the mixture. Then the mixture was heated to 80° C. and stirred for 16 h. After the mixture was cooled to RT, it was diluted with EtOAc (20 mL), then washed with brine (3×30 mL), dried with anhydrous Na2SO4, filtered and concentrated. The remaining crude product (300 mg) was purified by column chromatography on silica gel (PE:EtOAc=5:1 to 1:1) to give the title compound (68 mg, 0.120 mmol, 22% yield) as a light brown gum. MS (ESI): 514.0 [M-isobuten+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-4-oxo-7-[3-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-5-yl]-2,3-dihydropyrido[3,2-b][1,4]thiazepin-3-yl]carbamate (68.0 mg, 0.120 mmol) in analogy to general procedure 5 and was obtained as light yellow solid (55 mg, 0.090 mmol, 67% yield). MS (ESI): 546 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-7-[3-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-5-yl]-2,3-dihydropyrido[3,2-b][1,4]thiazepin-3-yl]carbamate (55.0 mg, 0.090 mmol) in analogy to general procedure 6b and was obtained as a white solid (15.1 mg, 0.030 mmol, 32% yield). MS (ESI): 502.0 [M+H]+.
(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (CAS 2002449-40-1) (50 mg, 104 μmol, Eq: 1) was combined with cyclopropanecarboximidamide hydrochloride (12.5 mg, 104 μmol, Eq: 1), HBTU (43.4 mg, 114 μmol, Eq: 1.1) and DIPEA (53.7 mg, 72.6 μl, 416 μmol, Eq: 4) in DMF (500 pL). The reaction was stirred at RT for 45 min. The reaction was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated affording a brown oil (73 mg) containing the title. MS (ESI): 547.3 [M+H]+.
NBS (27.3 mg, 154 μmol, Eq: 1.2) and DBU (23.4 mg, 23.1 μl, 154 μmol, Eq: 1.2) were added to a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(cyclopropanecarboximidoylcarbamoyl)-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (70 mg, 128 μmol, Eq: 1) in EtOAc (1 mL) and the reaction mixture was stirred at RT for 10 min. The reaction was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude residue was purified by flash chromatography on silica gel (0-50% EtOAc in heptane) affording the title compound (37 mg, 67.9 μmol, 53% yield) as a white solid. MS (ESI): 489.2 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (35 mg, 64.2 μmol, Eq: 1) in analogy to general procedure 5 to yield the title compound (33 mg, 57.2 μmol, 89% yield) as a white solid. MS (ESI): 521.2 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (30 mg, 52 μmol, Eq: 1) in analogy to general procedure 6a to yield the title compound (26 mg, 50.6 mol, 9700 yield) as a white solid, as a hydrochloride salt. MS (ESI): 477.1 [M+H][.
Examples 41 to 45 of the following table were prepared in analogy to Example 40, using the appropriate amidine building block.
3-hydroxy-2,2-dimethyl-propionitrile (50 mg, 0.504 mmol) was combined with hydroxylamine hydrochloride (175 mg, 2.5 mmol, 5 eq) and Et3N (306 mg, 421 μL, 3.0 mmol, 6 eq) in THE (0.5 mL). The reaction was heated to 80° C. and was stirred over night. EtOAc was added and the reaction was extracted with aq. sat. NaHCO3. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated affording the crude title compound (27 mg, 40% yield) as colorless oil.
The title compound was prepared in analogy to general procedure 10b from 3-hydroxy-2,2-dimethyl-propanehydroxamic acid (27 mg, 0.204 mmol) and (3R)-3-(tert-butoxycarbonylamino)-5-(4-chlorobenzyl)-8-fluoro-4-keto-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (98.2 mg, 0.204 mmol) after column chromatography on silica gel (heptane:EtOAc=1:0 to 1:1) as a white solid (22 mg, 18% yield). MS (ESI): 521.3 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (22 mg, 0.037 mmol) after column chromatography on silica gel (heptane:EtOAc=1:0 to 1:1) as a white solid (14 mg, 61% yield). MS (ESI): 553.2 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (14 mg, 0.023 mmol) as a white solid as a hydrochloride salt (12 mg, 95% yield). MS (ESI): 509.2 [M+H]+.
The title compound was prepared in analogy to general procedure 10c from tert-butyl N-[(3R)-8-fluoro-7-[(Z)—N′-hydroxycarbamimidoyl]-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (130 mg, 0.32 mmol) and 2-fluoroisobutyric acid (68.5 mg, 0.65 mmol, 2 eq) as a yellow oil (70 mg, 0.14 mmol, 25% yield). MS (ESI): 636.9 [M+Na]+.
The title compound was prepared in analogy to general procedure 11a from [[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepine-7-carbonyl]amino] 2-fluoro-2-methyl-propanoate (70 mg, 0.11 mmol) as a yellow oil (60 mg, 0.10 mmol, 37% yield). MS (ESI): 618.9 [M+Na]+.
The title compound was prepared in analogy to general procedure 6b tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-fluoro-1-methyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (60 mg, 0.10 mmol) after prep-HPLC (HCl) as an orange solid as a hydrochloride salt (11.9 mg, 0.02 mmol, 21% yield). MS (ESI): 496.8 [M+H]+.
The title compound was prepared in analogy to general procedure 10a from tert-butyl N-[(3R)-8-fluoro-7-[(Z)—N′-hydroxycarbamimidoyl]-5-[(4-isopropoxyphenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (350 mg, 0.67 mmol,) and 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-propanoic acid (229 mg, 0.94 mmol, 1.4 eq) after prep-HPLC as a yellow oil (200 mg, 0.27 mmol, 3700 yield). MS (ESI): 688.3 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 11a from [[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-5-[(4-isopropoxyphenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carbonyl]amino] 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-propanoate (50 mg, 0.07 mmol) after prep-TLC (PE:EA=3:1) as a white solid (70 mg, 0.10 mmol, 129% yield). MS (ESI): 726.4 [M+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)-2,2,2-trifluoro-ethyl]-1,2,4-oxadiazol-3-yl]-8-fluoro-5-[(4-isopropoxyphenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (60 mg, 0.08 mmol) and was obtained after prep-TLC (PE:EA=2:1) as a white solid (60 mg, 0.08 mmol, 87% yield). MS (ESI): 780.2 [M+Na]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)-2,2,2-trifluoro-ethyl]-1,2,4-oxadiazol-3-yl]-8-fluoro-5-[(4-isopropoxyphenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (54 mg, 0.07 mmol) and was obtained after prep-HPLC as a white solid as a hydrochloride salt (12.5 mg, 0.020 mmol, 27% yield). MS (ESI): 558.1 [M+H]+.
(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (200 mg, 416 μmol, Eq: 1) was combined with (Z)-3,3,3-trifluoro-N′-hydroxypropanimidamide (59.1 mg, 416 μmol, Eq: 1), HATU (174 mg, 457 μmol, Eq: 1.1) and DIPEA (107 mg, 145 μl, 832 μmol, Eq: 2) in THE (4 mL) and the reaction was stirred at RT for 2 h to form the intermediate tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[[(Z)—N-hydroxy-C-(2,2,2-trifluoroethyl)carbonimidoyl]carbamoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate. Burgess Reagent (495 mg, 2.08 mmol, Eq: 5) was added, the reaction was heated to 100° C. and was stirred over night. The solvent was evaporated. The crude residue was purified by chromatography on silica gel (0-30% EtOAc in heptane) affording the title compound (85 mg, 89.8 μmol, 22% yield) as a yellow oil. MS (ESI): 531.1 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-[3-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-5-yl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (85 mg, 89.8 μmol, Eq: 1) in analogy to general procedure 5 and was obtained as a white solid (84 mg, 89.6 μmol, 100% yield). MS (ESI): 563.1 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-[3-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-5-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (80 mg, 85.3 μmol, Eq: 1) in analogy to general procedure 6a and was obtained as a white solid, as a hydrochloride salt (43 mg, 82.9 μmol, 97% yield). MS (ESI): 519.1 [M+H]+.
Example 50 of the following table was prepared in analogy to Example 49, using the appropriate imidamide building block.
(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (CAS 2002449-61-6) (50 mg, 108 μmol, Eq: 1) was combined with propanimidamide hydrochloride (11.7 mg, 108 μmol, Eq: 1), HBTU (45.1 mg, 119 μmol, Eq: 1.1) and DIPEA (55.8 mg, 75.5 μL, 432 μmol, Eq: 4) in DMF (500 μL). The reaction mixture was stirred at RT for 45 min. The reaction was quenched with water and was extracted with EtOAc.
The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated affording the intermediate tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-4-oxo-7-(propanimidoylcarbamoyl)-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate as an orange oil. This material was dissolved in EtOAc (1 mL). NBS (23.1 mg, 130 μmol, Eq: 1.2) and DBU (19.7 mg, 19.5 μL, 130 μmol, Eq: 1.2) were added successively and the reaction was stirred at RT for 10 min. The reaction was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude residue was purified by chromatography on silica gel (0-50% EtOAc in heptane) affording the title compound (30 mg, 56.5 μmol, 52% yield) as a light yellow oil. MS (ESI): 459.2 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (30 mg, 58.2 μmol, Eq: 1) in analogy to general procedure 5 and was obtained as a white solid (13 mg, 23.3 μmol, 40% yield). MS (ESI): 491.1 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (11 mg, 20.1 μmol, Eq: 1) in analogy to general procedure 6a and was obtained as a white solid, as a hydrochloride salt (7 mg, 14.5 μmol, 72% yield). MS (ESI): 447.2 [M+H]+.
tert-butyl-N-[(3R)-5-[(4-chlorophenyl)methyl]-7-ethynyl-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 6, step e) (100 mg, 217 μmol, Eq: 1) was dissolved in DCM (3 mL) and the colorless solution was cooled down to 0° C. (1E)-2,2-dimethylpropanal oxime (35.1 mg, 40.8 μl, 347 μmol, Eq: 1.6), NEt3 (439 mg, 605 μl, 4.34 mmol, Eq: 20) and sodium hypochlorite 12% in water (2.02 g, 1.67 ml, 3.25 mmol, Eq: 15) were added successively. The reaction was heated to 30° C. and was stirred overnight. The solvent was evaporated. EtOAc was added and the mixture was washed with saturated aqueous NaHCO3 solution, water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. The crude residue was purified by chromatography on silica gel (0-30% EtOAc in heptane) affording the title compound (103 mg, 153 μmol, 70% yield) as a white solid. MS (ESI): 504.1 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(3-tert-butylisoxazol-5-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 179 μmol, Eq: 1) in analogy to general procedure 5 and was obtained as a white solid (64 mg, 94 μmol, 53% yield). MS (ESI): 536.1 [M-isobutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(3-tert-butylisoxazol-5-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (60 mg, 101 μmol, Eq: 1) in analogy to general procedure 6a and was obtained as a white solid (21 mg, 42.7 μmol, 42% yield). MS (ESI): 492.1 [M+H]−.
To a solution of methyl (R)-3-((tert-butoxycarbonyl)amino)-8-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carboxylate (1.24 g, 3.35 mmol, Eq: 1) (CAS: 2002449-38-7) in DMSO (15 mL) were added 1-(bromomethyl)-4-(trifluoromethoxy)benzene (1.28 g, 803 μl, 5.02 mmol, Eq: 1.5), potassium carbonate (1.39 g, 10 mmol, Eq: 3) and potassium iodide (278 mg, 1.67 mmol, Eq: 0.5) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was poured into water (100 mL) and the mixture was extracted with EtOAc (2×100 mL), dried over magnesium sulfate, filtered and evaporated. The crude residue was purified by chromatography on silica gel (0-40% EtOAc in heptane) affording the title compound (1.535 g, 2.26 mmol, 68% yield) as a white solid. MS (ESI): 489.0 [M-isobutene+H]+.
Methyl (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (1.535 g, 2.82 mmol, Eq: 1) was dissolved in a mixture of THF (28 mL), MeOH (4 mL) and water (8 mL). Lithium hydroxide (135 mg, 5.64 mmol, Eq: 2) was added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was washed with aqueous 1M HCl and brine. The organic layer was dried with magnesium sulfate. After filtration the solvent was evaporated affording the crude title compound (1.53 g, 2.81 mmol, 99% yield) as an off-white solid. MS (ESI): 529.1 [M−H]−.
A mixture of (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylicacid (250 mg, 471 μmol, Eq: 1) and CDI (99.3 mg, 613 μmol, Eq: 1.3) in THF (3 mL) was stirred for 30 min at RT and then a solution of hydrazine hydrate (70.8 mg, 68.6 μl, 1.41 mmol, Eq: 3) in THF (1 mL) was added. The reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into water (20 mL) and was extracted with EtOAc (3×20 mL), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by chromatography on silica gel (0% to 50% EtOAc in heptane) affording the title compound (167 mg, 307 μmol, 65% yield) as colorless solid. MS (ESI): 489.0 [M-isobutene+H]+.
A mixture of tert-butyl N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (50 mg, 91.8 μmol, Eq: 1), 2,2-difluorocyclohexane-1-carboxylic acid (16.6 mg, 101 μmol, Eq: 1.1) in THE (1 mL), HATU (38.4 mg, 101 μmol, Eq: 1.1) and DIPEA (23.7 mg, 32.1 μl, 184 μmol, Eq: 2) was stirred at RT for 30 min. Burgess reagent (109 mg, 459 μmol, Eq: 5) was added and stirring was continued at RT overnight. The solvent was evaporated and the crude material was purified by column chromatography on silica gel (0-50% EtOAc in heptane), affording the title compound (33 mg, 41.1 μmol, 45% yield) as white solid. MS (ESI): 617.0 [M-isobutene+H]+.
The title compound was prepared according to general method 5 from tert-butyl N-[(3R)-7-[5-(2,2-difluorocyclohexyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (33 mg, 49.1 μmol) and was obtained as white solid (18.3 mg, 22.1 μmol, 45% yield). MS (ESI): 649.1 [M-isobuten+H]+.
The title compound was prepared according to general method 6c from tert-butyl N-[(3R)-7-[5-(2,2-difluorocyclohexyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (16 mg, 22.7 μmol, Eq: 1) and was obtained as a light yellow solid, as a 1,1,1,3,3,3-hexafluoropropan-2-ol adduct. (17.5 mg, 20.6 μmol, 91% yield). MS (ESI): 605.4 [M+H]+.
The title compound was prepared according to the method used in Example 53, step d) from (R)-3-((tert-butoxycarbonyl)amino)-8-fluoro-4-oxo-5-(4-(trifluoromethoxy)benzyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carboxylic acid (50 mg, 94.3 μmol) and was obtained (45 mg, 73.7 μmol, 7800 yield) as a light yellow oil. MS (ESI): 555.3 [M-isobutene+H]+.
The title compound was prepared according to general method 6c from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (12 mg, 19.7 μmol) with additional 500 HCl (4M in dioxane) and was obtained as a white solid, as a hydrochloride salt (11 mg). MS (ESI): 511.2 [M+H]+.
Examples 55 to 60 of the following table were prepared in analogy to Example 53, using the appropriate carboxylic acids.
To a solution of (R)-3-amino-8-fluoro-7-(5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl)-5-(4-(trifluoromethoxy)benzyl)-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one, 1,1-dioxide hydrochloride (Example 56) (20 mg, 33.1 μmol, Eq: 1) in DMF (200 μl) were added N-(tert-butoxycarbonyl)-N-methyl-L-alanine (10.1 mg, 49.6 μmol, Eq: 1.5), HATU (37.7 mg, 99.2 μmol, Eq: 3) and DIPEA (17.1 mg, 23.1 μl, 132 μmol, Eq: 4) and the yellow solution was stirred at RT for 30 min. The solvent was evaporated and the remaining residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) affording the title compound (16.5 mg, 21.9 μmol, 66.2% yield) as a white solid. MS (ESI): 752.3 [M−H]−.
The title compound was prepared in analogy to method 6c from tert-butyl N-[(1S)-2-[[(3R)-8-fluoro-1,1,4-trioxo-7-[5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (16 mg, 21.2 μmol) with additional 4 drops of HCl (4M in dioxane) and was obtained as an off-white solid, as hydrochloride salt and 1,1,1,3,3,3-hexafluoropropan-2-ol adduct (17 mg, 19.8 μmol, 9300 yield). MS (ESI). 654.5 [M+H]+.
To a solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.16 mmol) in DCM (5 mL) was added m-CPBA (16.6 mg, 0.08 mmol, 0.5 eq). The mixture was stirred at 15° C. for 16 h, quenched by sat. aqueous Na2SO3 (5 mL), extracted DCM (10 mL), washed with H2O (5 mL), brine (5 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (EtOAc:PE=9:1 to 1:4) to afford the title compound, epimer A (32 mg, 0.05 mmol, 24% yield) and epimer B (35 mg, 0.06 mmol, 27% yield) as a light yellow gum. MS (ESI): 571.1 [M-isobutene+H]+.
The title compound was prepared in analogy to method 6b from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1,4-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (100 mg, 0.16 mmol) and was obtained after prep-HPLC as a white solid (35 mg, 0.070 mmol, 41% yield). MS (ESI): 527.1 [M+H]+.
The title compound was prepared in analogy to the method used in Example 53, step c) from (R)-3-((tert-butoxycarbonyl)amino)-5-(4-chlorobenzyl)-8-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carboxylic acid (CAS:2002449-40-1) (284 mg, 467 μmol, Eq) and was obtained as a light yellow solid (306 mg, 402 μmol, 86% yield). MS (ESI): 439.1 [M-isobutene+H]+.
The title compound was prepared in analogy to the method used in Example 53, step d) from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (250 mg, 505 μmol) and was obtained as a light yellow solid (158 mg, 268 μmol, 53% yield). MS (ESI): 505.1 [M-isobutene+H]+.
The title compound was prepared according to general method 5 from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (176 mg, 314 μmol) and was obtained as white solid (80 mg, 135 μmol, 43% yield). MS (ESI): 537.1 [M-isobuteneH]+.
The title compound was prepared in analogy to the method used in 6a from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1)6,5-benzothiazepin-3-yl]carbamate (133 mg, 224 μmol) and was obtained as a light yellow solid (88 mg, 170 μmol, 76% yield). MS (ESI): 493.97 [M+H]+.
To a solution of oxalyl dichloride (0.25 mL, 2.9 mmol, 1.2 eq) in DCM (12 mL) was added DMSO (0.27 mL, 3.87 mmol, 1.6 eq) dropwise with stirring at −78° C. over 5 mins under N2. After stirred for 10 mins at −78° C., a solution of benzyl 3-hydroxy-2,2-dimethyl-propanoate (500 mg, 2.4 mmol, 1 eq) in DCM (9 mL) was added dropwise to the mixture over 15 mins keeping the temperature below −65° C. After stirred for 40 mins at −78° C., NEt3 (0.95 mL, 6.79 mmol, 2.83 eq) was added dropwise into the mixture for 10 min below −65° C. The reaction mixture was stirred at −78° C. for 30 min and then allowed to warm to 25° C. and stirred for 2 hrs. The reaction mixture was diluted with EtOAc (30 mL) and washed with brine (50 mL×3), dried over anhydrous Na2SO4 and concentrated, purified by column chromatography on silica gel (PE:EtOAc=1:0 to 3:2) to obtain the title compound (300 mg, 1.45 mmol, 52% yield) as a colorless oil. MS (ESI): 229.1 [M+Na]+.
To a solution of benzyl 2,2-dimethyl-3-oxo-propanoate (400 mg, 1.94 mmol) in DCE (16 mL) was added 4-aminobutyric acid (0.31 mL, 3.1 mmol, 1.6 eq) and stirred at 25° C. for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (739 mg, 3.49 mmol, 1.8 eq) and stirred at 25° C. for 16 hrs. The mixture was quenched by water (15 mL) and extracted with EtOAc (15×2), the combined organic phase was washed with brine (30 mL×2) concentrated under vacuum and purified by column chromatography on silica gel (PE:EA=15:1 to 2:1) to provide the title compound (280 mg, 1.0 mmol, 48% yield) as a colorless oil. MS (ESI): 276.2 [M+H]+.
To a solution of benzyl 2,2-dimethyl-3-(2-oxopyrrolidin-1-yl)propanoate (180 mg, 0.65 mmol,) in methanol (6 mL) was added Pd/C (69.5 mg, 0.07 mmol, 0.1 eq) under N2 atmosphere. After the mixture was degassed with H2 balloon for 3 times, it was stirred at 25° C. for 16 hr. The reaction mixture was filtered and concentrated to obtain the title compound (90 mg, 0.49 mmol, 74% yield) as a grey solid which was used crude in the next step. MS (ESI): 186.0 [M+H]+.
To a solution of 1-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester (1500 mg, 10.4 mmol) in DMF (10 mL) was added NaH (499 mg, 12.5 mmol, 1.2 eq) at 0-10° C. under N2. After stirring at 25° C. for 0.5 h benzyl bromide (1.48 mL, 12.5 mmol, 1.2 eq) in DMF (5 mL) was added at 0-10° C. under N2. The reaction was stirred at RT for 12 h, quenched with sat. aqueous NH4Cl solution (20 mL) and extracted with EtOAc (50 mL×3). The combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, concentrated under vacuum and purified by column chromatography on silica gel (PE:EA=100:1) to give the title compound (1600 mg, 6.83 mmol, 65% yield) as colourless oil. MS (ESI): 235.1 [M+H]+.
To a solution of ethyl 1-(benzyloxymethyl)cyclopropanecarboxylate (700 mg, 2.99 mmol) in THE (7 mL), MeOH (3.5 mL) and water (7 mL) was added LiOH H2O (376 mg, 8.96 mmol, 3 eq) at 25° C. The reaction was stirred at 25° C. for 2 h, concentrated under vacuum and extracted with EtOAc (5 mL×2). The aqueous phase was carefully acidified with 2 N aqueous HCl to pH=3-4 and extracted with EtOAc (20 mL×3). The organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford the title compound (1000 mg, 4.85 mmol, 162% yield) as light yellow oil. MS (ESI): 229.1 [M+Na]+.
The title compound was prepared in analogy to starting material for starting material for Example 64 step b and c) from benzyl 2,2-dimethyl-3-oxo-propanoate (400 mg, 1.94 mmol) and 5-aminovaleric acid (0.35 mL, 3.1 mmol, 1.6 eq) and was obtained as a grey solid. MS (ESI): 200.0, [M-isobutene+H]+.
Examples 64 to 122 and Intermediate 120 of the following table were prepared in analogy to Example 63, using the appropriate carboxylic acid building block.
To a solution of tert-butyl N-[(3R)-7-[5-[1-(benzyloxymethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (450 mg, 0.65 mmol) in MeOH (5 mL) and DCM (5 mL) was added Pd/C (300 mg) under N2 at 25° C. The reaction was stirred at 25° C. for 1 h under H2, filtered, concentrated under vacuum and purified by prep-HPLC to provide the title compound (160 mg, 0.26 mmol, 40% yield) as white solid. MS (ESI): 607.2 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[[(2-hydroxy-2-methyl-propanoyl)amino]carbamoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (290 mg, 0.5 mmol) in DMF (12 mL) was added 4-dimethylaminopyridine (487 mg, 4.0 mmol, 8 eq) and tert-butyldimethylchlorosilane (188 mg, 1.25 mmol, 2.5 eq) at 25° C. and stirred at 25° C. for 16 h. The mixture was diluted with EtOAc (20 mL), washed with brine (20 mL×3). The organic layer was dried with Na2SO4, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel (PE:EtOAc 9:1 to 3:1) to afford the title compound (320 mg, 0.46 mmol, 91% yield) as a light yellow solid. MS (ESI): 639.4 [M-isobutene+H]+.
(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one 1:2 hydrochloride salt (Intermediate 120, 12 mg, 0.019 mmol) was stirred with methyl chloroformate (1.81 mg, 1.49 uL, 0.019 mmol, 1 eq) and DIPEA (7.44 mg, 10.05 uL, 0.058 mmol, 3 eq) in DCM at room temperature for 1.5 h. The solvent was evaporated and submitted to prep-HPLC affording the title compound (4 mg, 32%) as white solid. MS (ESI): 592.4 [M+H]+.
The title compound was prepared according to general procedure 7a and 8a from N-[(3R)-7-carbazoyl-5-(4-chlorobenzyl)-8-fluoro-4-keto-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (400 mg, 0.727 mmol) and 3-ethoxy-3-keto-2,2-dimethyl-propionic acid (128 mg, 114 μL, 0.80 mmol, 1.1 eq) in one pot and was obtained as a yellow oil (320 mg, 71% yield). MS (ESI): 619.3 [M-isobutene+H]+.
ethyl 2-methyl-2-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]propanoate (320 mg, 0.517 mmol) was dissolved in THF (2.6 mL) and 1M aqueous NaOH (620 uL, 0.62 mmol, 1.2 eq) was added and the reaction was stirred at RT over night. 1 M aqueous HCl (620 uL, 0.620 mmol, 1.2 eq) was added until pH=1. The reaction was extracted with EtOAc. The organic layers were combined, dried over magnesium sulfate, filtered and evaporated affording the title compound (140 mg, 38%) as white foam. MS (ESI): 591.4 (M+H)+.
The title compound was prepared according to general procedure 7a from 2-methyl-2-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]propanoic acid (70 mg, 0.101 mmol) and methylamine (15 mg, 20 μL, 0.2 mmol, 2 eq) and was obtained after chromatography on silica gel (heptane:EtOAc=7:3 to 0:1) as a colorless solid (30 mg, 42% yield). MS (ESI): 604.2 (M+H), [M+H]+.
The title compound was prepared according to general procedure 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-[1,1-dimethyl-2-(methylamino)-2-oxo-ethyl]-1,3,4-oxadiazol-2-yl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (30 mg, 0.05 mmol) and was obtained after column chromatography on silica gel (heptane:EtOAc=1:0 to 1:1) as a colorless oil (12 mg, 32% yield). MS (ESI): 591.4 [M-isobutene+H]+.
The title compound was prepared according to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-[1,1-dimethyl-2-(methylamino)-2-oxo-ethyl]-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (12 mg, 0.019 mmol) and was obtained as off-white powder (5 mg, 4500 yield). MS (ESI): 536.3 [M+H]+.
Example 125 of the following table were prepared in analogy to Example 124, steps c to e), using the appropriate amine building block.
The title compound was prepared according to general method 5 from methyl (R)-3-((tert-butoxycarbonyl)amino)-5-(4-chlorobenzyl)-8-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carboxylate (1.0 g, 2.0 mmol) and was obtained as a light yellow solid (1.14 g, 96% yield). MS (ESI): 471.3 [M-isobutene+H]+.
To a solution of methyl (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepine-7-carboxylate (1 g, 1.9 mmol, 1) in THF (10 mL) was added lithium hydroxide hydrate (106 mg, 2.52 mmol, 1.33 eq) in water (8 mL) at 0° C. The mixture was stirred at 0° C. for 0.5 h. To the reaction was added dropwise 0.5 M aqueous HCl (6 mL). The mixture was extracted with EtOAc (8 mL), DCM (5 mL). The organic layer was washed with brine (15 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the crude title compound (1020 mg, 1.9 mmol, 103% yield) as a light yellow solid. MS (ESI): 457.0 [M-isobutene+H]+.
The title compound was prepared according to general method 7b from (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepine-7-carboxylic acid (819 mg, 1.6 mmol) and hydrazine hydrate (374 mg, 363 μL, 4.79 mmol, 3 eq) and was obtained as a light yellow solid (659 mg, 78% yield). MS (ESI): 471.2 [M-isobutene+H]+.
The title compound was prepared according to general procedure 7a from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (30 mg, 0.057 mmol) and 1-(trifluoromethyl)cyclopropanecarboxylic acid ((9.65 mg, 0.063 mmol, 1.1 eq) and was obtained as a yellow oil (48.8 mg, 108% yield). MS (ESI): 607.3 [M-isobutene+H]+.
The title compound was prepared according to general procedure 8b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-[[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]carbamoyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (48.8 mg, 0.074 mmol) and was obtained as an off-white solid (24.9 mg, 51% yield). MS (ESI): 589.3 [M-isobutene+H]+.
The title compound was prepared in analogy to the method used in 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (24.9 mg, 0.038 mmol) and was obtained as a light yellow solid as a hydrochloride salt (18.6 mg, 83% yield). MS (ESI): 545.3 [M+H]+.
Examples 127 to 135 of the following table were prepared in analogy to Example 126 step d to f), using the appropriate carboxylic acid building block.
To 3-amino-4,4,4-trifluoro-2,2-dimethyl-butyric acid methyl ester hydrogen chloride (116 mg, 0.49 mmol) in DMF (2 mL) was added NEt3 (149 mg, 205 μL, 1.48 mmol, 3 eq) and allyl chloroformate (71 mg, 63 μL, 0.59 mmol, 1.2 eq; it was a 1:1 mixture of allyl and methyl chloroformate) carefully, keeping the reaction mixture at 20-25° C. and stirred vigorously for 1 h. Allyl chloroformate (71 mg, 63 μL, 0.59 mmol, 1.2 eq) and NEt3 (149 mg, 205 μL, 1.48 mmol, 3 eq) were carefully added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with DCM and extracted with 1N aqueous HCl. The layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine (20 ml) and dried over MgSO4, filtered and concentrated, purified by column chromatography on silica gel (heptane:EtOAc=1:0 to 1:1) to yield the title compound (59.4 mg, 38% yield) as white semisolid. MS (ESI): 284.2 [M+H]*, MS (ESI): 244.1 [M+H]+.
3-(allyloxy/methoxycarbonylamino)-4,4,4-trifluoro-2,2-dimethyl-butyric acid methyl ester (59.4 mg, 0.19 mmol) was dissolved in THF (0.5 mL), MeOH (0.5 mL) and water (0.3 mL). LiOH monohydrate (16 mg, 0.38 mmol, 2 eq) was added and the reaction mixture was stirred at RT for 2 hours. The reaction mixture was extracted with EtOAc (2×20 ml). The aq. phase was acidified with 1N aqueous HCl and extracted with EtOAc (3×20 ml)). The combined organic phase was dried with MgSO4, filtered and concentrated to the title compound (46.8 mg, 46% yield) as light brown solid. MS (ESI): 270.1 [M+H]+. MS (ESI): 258.2 [M+H]+.
The title compound was prepared in analog of general procedure 7a from 3-(allyl/methyloxycarbonylamino)-4,4,4-trifluoro-2,2-dimethyl-butyric acid (45 mg, 0.17 mmol, 1.1 eq) to yield the crude title compound (161 mg, 27% yield) as yellow gum. MS (ESI): 776.4 [M+H]+. MS (ESI): 750.4 [M+H]+.
The title compound was prepared in analog of general procedure 8a from allyl N-[2,2-dimethyl-3-oxo-3-[2-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepine-7-carbonyl]hydrazino]-1-(trifluoromethyl)propyl]carbamate and methyl N-[2,2-dimethyl-3-oxo-3-[2-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepine-7-carbonyl]hydrazino]-1-(trifluoromethyl)propyl]carbamate (161 mg, 0.042 mmol) to yield after column chromatography on silica gel (PE:EtOAc=1:0 to 1:1) the title compound (30 mg) as yellow solid and the second title compound (49.6 mg) as a light yellow solid. MS (ESI): 758.4 [M−H]−. MS (ESI): 732.4 [M−H]−.
A solution of tetrakis(triphenylphosphine) palladium (2.17 mg, 0.002 mmol, 0.05 eq) and N-[(3R)-7-[5-[2-(allyl/methoxycarbonylamino)-3,3,3-trifluoro-1,1-dimethyl-propyl]-1,3,4-oxadiazol-2-yl]-5-(4-chlorobenzyl)-8-fluoro-1,1,4-triketo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (30 mg, 0.037 mmol) in DCM (0.5 mL) was degassed 3 times with argon and phenylsilan (20.9 mg, 23.8 uL, 0.19 mmol, 5 eq) was added. The reaction was stirred at RT for 2 h, diluted with water and DCM. Aq. NaHCO3 and 1M aqueous NaOH solution was added to the aqueous layer until pH 13. The aqueous layer was then extracted with DCM (2×15 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (11.2 mg, 44% yield) as a white solid. MS (ESI): 620.3 [M-isobutene+H]+.
The title compound was prepared in analogy to the method used in 6d from tert-butyl N-[(3R)-7-[5-(2-amino-3,3,3-trifluoro-1,1-dimethyl-propyl)-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (11.2 mg, 0.017 mmol) and was obtained as a light yellow solid as a hydrochloride salt (9.3 mg, 86% yield). MS (ESI): 620.3 [M+HCOO]−.
The title compound was prepared in analogy to the general method 6d from N-[2-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-(4-chlorobenzyl)-8-fluoro-1,1,4-triketo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-1-(trifluoromethyl)propyl]carbamic acid methyl ester (49.6 mg, 0.066) and was obtained as a light yellow solid as a hydrochloride salt (28.6 mg, 61% yield). MS (ESI): 634.3 [M+H]−.
To a solution of benzyl 2,2-dimethyl-3-oxo-propanoate (500 mg, 2.42 mmol) in DCE (25 mL) was added thiomorpholine (0.39 mL, 3.88 mmol, 1.6 eq) and stirred at 25° C. for 1 h. sodium triacetoxyborohydride (925 mg, 4.36 mmol, 1.8 eq) at 0° C. was added and stirred at 25° C. for 16 hrs. The reaction mixture was cooled to 0° C. and added dropwise aqueous NH4Cl (30 mL) to quench NaBH(OAc)3. The mixture was extracted with EtOAc (30 mL), the organic phase was washed with brine (10 mL×3), dried over Na2SO4, filtered, the organic phase was concentrated, diluted with MeOH (6 mL) and purified by prep-HPLC then freeze-dried to obtain the title compound (180 mg, 0.61 mmol, 25% yield) as a light yellow oil. MS (ESI): 294.4 [M+H]+.
The title compound was prepared according to general method 5 from benzyl 2,2-dimethyl-3-thiomorpholino-propanoate (180 mg, 0.61 mmol) using 4.5 eq MCPBA and was obtained as a light yellow solid after prep-TLC (EtOAc) (140 mg, 0.41 mmol, 54% yield). MS (ESI): 342.1 [M+H]+.
To a solution of benzyl 2,2-dimethyl-3-(4-oxido-1,1-dioxo-1,4-thiazinan-4-ium-4-yl)propanoate (120 mg, 0.30 mmol) in MeOH (4 mL) was added Pd/C (37.4 mg, 0.04 mmol, 0.1 eq) under N2 atmosphere and degassed 3 times with H2. The reaction was stirred at 25° C. for 16 h, filtered with diatomite, concentrated to yield the title compound (100 mg, 0.42 mmol, 99% yield) as a light yellow solid. MS (ESI): 236.1 [M+H]+.
The title compound was prepared according to general procedure 7a from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (180 mg, 0.36 mmol) and 3-(1,1-dioxo-1,4-thiazinan-4-yl)-2,2-dimethyl-propanoic acid (100 mg, 0.42 mmol, 1.2 eq) and was obtained after prep-TLC (PE:EA=1:3) as a light yellow solid (170 mg, 0.24 mmol, 59% yield). MS (ESI): 712.2 [M+H]−.
The title compound was prepared according to general procedure 8a from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[[[3-(1,1-dioxo-1,4-thiazinan-4-yl)-2,2-dimethyl-propanoyl]amino]carbamoyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (170 mg, 0.24 mmol) and was obtained as a white solid (155 mg, 0.22 mmol, 93% yield). MS (ESI): 638.1 [M-isobutene+H]+.
The title compound was prepared according to general procedure 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-[2-(1,1-dioxo-1,4-thiazinan-4-yl)-1,1-dimethyl-ethyl]-1,3,4-oxadiazol-2-yl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (155 mg, 0.22 mmol) using 5.5 eq MCPBA and was obtained as a light yellow solid (360 mg, 0.49 mmol, 50% yield). MS (ESI): 742.2 [M+H]+.
To the solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-[1,1-dimethyl-2-(4-oxido-1,1-dioxo-1,4-thiazinan-4-ium-4-yl)ethyl]-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (360 mg, 0.49 mmol) in 1,2-dichloroethane (8 mL) was added phenylboronic acid (147 mg, 1.2 mmol, 2.5 eq) at 25° C. The mixture was stirred at 80° C. for 0.5 h. The reaction mixture was diluted with EtOAc (10 mL), washed with water (3×15 mL) followed by brine (15 mL). The organic layer was dried with Na2SO4, filtered, concentrated in vacuo and purified by prep-TLC (PE:EA=1:1) to obtain the title compound (140 mg, 0.19 mmol, 29% yield) as a light yellow solid. MS (ESI): 670.1 [M-isobutene+H]+.
The title compound was prepared in analogy to the method used in 6b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-[2-(1,1-dioxo-1,4-thiazinan-4-yl)-1,1-dimethyl-ethyl]-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (140 mg, 0.19 mmol) and was obtained as a white solid after prep-HPLC (52.7 mg, 43% yield). MS (ESI): 626.2 [M+H]+.
The title compound was prepared in analogy to starting material for example 64 step b and c) from benzyl 2,2-dimethyl-3-oxo-propanoate (500 mg, 2.42 mmol) and 2-[tert-butyl(dimethyl)silyl]oxy-N-methyl-ethanamine (734.56 mg, 3.88 mmol, 1.6 eq) and was obtained as a light yellow solid. MS (ESI): 290.1 [M-isobutene+H]+.
To a solution of 4-amino-2,2-dimethyl-butanoic acid;hydrochloride (example 149, step b)) 400 mg, 2.39 mmol) and formaldehyde (0.85 mL, 7.16 mmol, 3 eq) in MeOH (20 mL) was added NaBH3CN (599 mg, 9.54 mmol, 4 eq) at 25° C. The mixture was degassed with N2 and stirred for 16 h. Then additional NaBH3CN (599 mg, 9.54 mmol, 4 eq) and formaldehyde (0.85 mL, 7.16 mmol, 3 eq) was added into the reaction mixture and stirred for another 16 h. The reaction was diluted with water (10 mL), acidified by 1N aqueous HCl to pH=6 and concentrated under vacuum, extracted with EtOAc (10 mL×3). The organic phase was concentrated and freeze dried to give the crude title compound as a hygroscopic white solid (110 mg, 0.69 mmol, 29% yield). MS (ESI): 160.2 [M+H]+.
To a solution of tert-butyl-(1-methoxy-2-methyl-prop-1-enoxy)-dimethyl-silane (500 mg, 2.31 mmol, 1 eq) in DCE (6 mL) was added 2,6-ditert-butyl-4-methylpyridine (0.36 mL, 2.57 mmol, 1.1 eq). After cooled to 0° C., Tf2O (0.43 mL, 2.57 mmol, 1.1 eq) was added into the mixture rapidly and stirred for 2 mins. Then N-formylpiperidine (0.26 mL, 2.31 mmol, 1 eq) was added and the mixture was heated to 60° C. for 16 h. The reaction was cooled to 0° C. and NaBH3CN (871 mg, 13.8 mmol, 6 eq) was added. The reaction was stirred for 16 h, diluted with EtOAc (10 mL) and washed with brine (10 mL×2), dried over anhydrous Na2SO4, concentrated and was purified by column chromatography on silica gel (PE:EA=1:1 to 0:1) to give crude title compound (500 mg, 2.51 mmol, 108% yield) as a colorless gum. MS (ESI): 200.2 [M+H]+.
To a solution of methyl 2,2-dimethyl-3-(1-piperidyl)propanoate (400 mg, 2.0 mmol,) in THE (6 mL) and water (6 mL) was added LiOH (63.9 mg, 2.67 mmol, 1.3 eq). The resulting mixture was heated to 50° C. and stirred for 22 h. After cooled to ambient temperature, the mixture was basified with 1N aqueous NaOH to pH=8., extracted with EtOAc (5 mL), the aqueous layer was acidified to pH=5 with 1N aqueous HCl. The aqueous phase was freeze dried to give crude product which was washed with EtOAc (10 mL×4), the organic phase was concentrated to give the title compound (250 mg, 1.35 mmol, 67% yield) as a colorless gum. MS (ESI): 186.1 [M+H]+.
The title compound was prepared in analogy to starting material for Example 64, in 2 steps from benzyl 2,2-dimethyl-3-oxo-propanoate (500 mg, 2.42 mmol) and 4,4-difluoropiperidine (0.3 mL, 2.67 mmol, 1.1 eq) and was obtained as a light yellow solid. MS (ESI): 222.1 [M+H]+.
The title compound was prepared in analogy to starting material for Example 140 from 5-amino-2,2-dimethyl-pentanoic acid hydrochloride (Example 149, step b)) (500 mg, 2.75 mmol) and formaldehyde (0.98 mL, 8.26 mmol, 3 eq) and was obtained after prep-HPLC as a light brown gum (330 mg, 1.9 mmol, 69% yield). MS (ESI): 174.2 [M+H]−.
The title compound was prepared in analogy to starting material for Example 64, step b and c) in from benzyl 2,2-dimethyl-3-oxo-propanoate (500 mg, 2.42 mmol) and 1-methylpiperazine (0.43 mL, 3.88 mmol, 1.6 eq) and was obtained as a light yellow solid (100 mg). MS (ESI): 201.1 [M+H]+.
Examples 139 to 148 of the following table were prepared in analogy to Example 138 step d to h), using the appropriate carboxylic acid building block.
To a solution of LiHMDS (13.8 mL, 13.8 mmol, 2.75 eq) in THE (14 mL) was added a solution of 1-Boc-2-piperidone (1 g, 5.0 mmol, 1 eq) in THE (6 mL) dropwise at −70° C. under N2, then the mixture was warmed up to 25° C. and stirred for 1 h. The mixture was re-cooled to −70° C. and Mel (1.56 mL, 25 mmol, 5 eq) was added dropwise. The resulting mixture was warmed up to 25° C. and stirred for 2 h. The reaction was quenched with water (20 mL) under 0° C. After separated, the aqueous phase was extracted with EtOAc (10 mL×3), the combined organic phase was washed with brine (30 mL×3), dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel (PE:EA=15:1 to 5:1), concentrated under vacuum to give the title compound (470 mg, 2.1 mmol, 33% yield) as a light brown oil. MS (ESI): 172.2 [M-isobutene+H]+.
tert-butyl 3,3-dimethyl-2-oxo-piperidine-1-carboxylate (370 mg, 1.63 mmol) was dissolved in 6N aqueous HCl (7.4 mL, 44.4 mmol, 27 eq) and refluxed for 16 hours. The mixture was cooled to room temperature, concentrated under vacuum twice with THE to give the crude title compound as a hydrochloride salt (220 mg, 1.2 mmol, 74% yield) as a brown solid. MS (ESI): 146.1 [M+H]+.
To a solution of 5-amino-2,2-dimethyl-pentanoic acid hydrochloride (220 mg, 1.2 mmol) in 1,4-dioxane (2.5 mL) was added dropwise a solution of 1N aqueous NaOH (5.45 mL, 5.45 mmol, 4.5 eq) at 0° C. The mixture was stirred 0.25 h at 0° C. To the solution was added benzyl chloroformate (413 mg, 2.42 mmol, 2 eq) at 0° C., and stirred for 5 h at 25° C. The mixture was diluted with water (3 mL), extracted with PE:EtOAc (4:1, 5 mL*3). The water layer was acidified by 1N aqueous HCl to pH ˜5, extracted with EtOAc (10 mL*2). The combined organic phase was dried over anhydrous Na2SO4, concentrated in vacuo to obtain the crude title compound (380 mg, 1.36 mmol, 70% yield) as brown oil confirmed. MS (ESI): 280.3 [M+H]+.
The title compound was prepared according to general procedure 7a from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (290 mg, 0.59 mmol) and 5-(benzyloxycarbonylamino)-2,2-dimethyl-pentanoic acid (280 mg, 0.63 mmol, 1.1 eq) and was obtained after column chromatography on silica gel (PE:EA=5:1 to 2:1) as a white solid (450 mg, 0.6 mmol, 100% yield). MS (ESI): 756.3 [M+H]−.
The title compound was prepared according to general procedure 8a from benzyl N-[4,4-dimethyl-5-oxo-5-[2-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carbonyl]hydrazino]pentyl]carbamate (300 mg, 0.4 mmol) and was obtained as a light brown gum (400 mg, 0.54 mmol, 132% yield). MS (ESI): 738.3 [M+H]+.
The title compound was prepared according to general procedure 5 from benzyl N-[4-methyl-4-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]pentyl]carbamate (300 mg, 0.41 mmol) was obtained as a light yellow solid (210 mg, 0.27 mmol, 61% yield). MS (ESI): 770.3 [M+H]+.
To solution of benzyl N-[4-methyl-4-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]pentyl]carbamate (160 mg, 0.21 mmol) in methanol (6 mL) was added EtOAc\HCl (1.04 mL, 4.15 mmol, 20 eq) and Pd/C (44 mg, 0.42 mmol, 2 eq), the reaction mixture was stirred at 25° C. for 0.5 h under a balloon with hydrogen. Then EtOAc\HCl (1.56 mL, 6.23 mmol, 30 eq) was added into the mixture and stirred for 1 h. After filtered by diatomite, the filtrate was blow-dried by N2 flow to 2 mL, the residue was purified by prep-HPLC and freeze dried to give the title compound as the bis hydrochloride salt (68 mg, 0.11 mmol, 51% yield) as a white solid. MS (ESI): 536.2 [M+H]+.
The title compound was prepared according to general procedure 7a from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (2.9 g, 5.86 mmol) and 1-benzyloxycarbonyl-5,5-difluoro-piperidine-3-carboxylic acid (2.1 g, 7.03 mmol, 1.2 eq) and was obtained after chromatography on silica gel (PE:EA=10:1 to 1:1) as a white solid (4.77 g, 6.14 mmol, 105% yield). MS (ESI): 776.3 [M+H]+.
The title compound was prepared according to general procedure 8a from benzyl 3,3-difluoro-5-[[[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carbonyl]amino]carbamoyl]piperidine-1-carboxylate (4.0 g, 5.15 mmol) and was obtained after chromatography on silica gel (PE:EA=10:1 to 1:1) as a white solid (2.66 g, 3.51 mmol, 68% yield). MS (ESI): 758.2 [M+H]−.
The title compound was prepared according to general procedure 5 from benzyl 3,3-difluoro-5-[[[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carbonyl]amino]carbamoyl]piperidine-1-carboxylate (42.6 g, 3.43 mmol) and was obtained after chromatography on silica gel as a white solid (2.6 g, 3.29 mmol, 94% yield). MS (ESI): 734.3 [M-isobutene+H]+.
To a solution of benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (400 mg, 0.51 mmol) in MeOH (5 mL) was added Pd/C/H2O (100 mg). The mixture was stirred at 25° C. for 0.5 h under H2. The mixture was filtered and purified by prep-HPLC to afford the title compound (800 mg, 1.22 mmol, 240% yield) as white solid. MS (ESI): 656.3 [M+H]+.
To a solution of acetaldehyde (0.1 mL, 1.79 mmol, 14 eq) in MeOH (3 mL) was added tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (80.0 mg, 0.12 mmol). After the mixture was stirred for 30 min, sodium triacetoxyborohydride (259 mg, 1.2 mmol, 10 eq) was added. The mixture was stirred at 25° C. for 1 h, poured to water (10 mL) and extracted by DCM (10 mL×2). The organic layers were washed by brine (10 mL×2), dried over Na2SO4, concentrated in vacuo and purified by column chromatography on silica gel (PE:EA=10:1 to 1:1) to afford the title compound (70 mg, 0.1 mmol, 83% yield) as white solid. MS (ESI): 684.2 [M+H]+.
The title compound was prepared according to general procedure 6b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (70.0 mg, 0.1 mmol) and was obtained after prep-HPLC as a white solid (35.4 mg, 0.06 mmol, 37% yield). MS (ESI): 584.1 [M+H]+.
Examples 151 to 153 of the following table were prepared in analogy to Example 150 step e-f), using the appropriate aldehyde building block.
Examples 154 to 157 of the following table were prepared in analogy to Example 150 step a-f), using the appropriate acid and aldehyde building block.
The title compound was prepared according to general procedure 7b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (1.0 g, 2.02 mmol) and 1-benzyl-4,4-difluoro-piperidine-3-carboxylic acid (860.0 mg, 3.37 mmol, 1.67 eq) and was obtained after prep HPLC as a white solid (1.24 g, 1.69 mmol, 83% yield).
The title compound was prepared according to general procedure 8a from tert-butyl N-[(3R)-7-[[(1-benzyl-4,4-difluoro-piperidine-3-carbonyl)amino]carbamoyl]-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (0.9 g, 1.23 mmol) and was obtained after prep-HPLC as a white solid (430 mg, 0.6 mmol, 48% yield). MS (ESI): 714.2 [M+H]+.
To a solution of tert-butyl N-[(3R)-7-[5-(1-benzyl-4,4-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (210 mg, 0.29 mmol) in MeOH (3 mL) was added formaldehyde (0.02 g, 0.29 mmol, 1 eq) and Pd/C/H2O (100) under nitrogen. The mixture was stirred at 25° C. for 1 h under H2, filtered and purified by prep-TLC (PE:EA=1:1) to afford the title compound (120 mg, 0.19 mmol, 63% yield) as white solid. MS (ESI): 638.2 [M+H]−.
The title compound was prepared according to general procedure 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(4,4-difluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (120 mg, 0.19 mmol) and was obtained as a yellow solid (120 mg, 0.17 mmol, 93% yield). MS (ESI): 686.3 [M+H]+.
The title compound was prepared according to Example 138, step g) from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(4,4-difluoro-1-methyl-1-oxido-piperidin-1-ium-3-yl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (90 mg, 0.13 mmol) and was obtained after-prep-TLC (PE:EA=1:1) as a white solid (40 mg, 0.060 mmol, 45% yield). MS (ESI): 670.4 [M+H]+.
The title compound was prepared according to general procedure 6b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(4,4-difluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (35.0 mg, 0.05 mmol) and was obtained as a white solid as a hydrochloride salt (27 mg, 0.040 mmol, 88% yield). MS (ESI): 570.2 [M+H]+.
To a solution of N-[(3R)-5-(4-chlorobenzyl)-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-triketo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (16 mg, 0.023 mmol, 1 eq) in THF (0.12 mL) and MeOH (0.12 mL) was added (1-ethoxycyclopropoxy)trimethylsilane (8.16 mg, 9.38 uL, 0.047 mmol, 2 eq), NaBH3CN (2.21 mg, 0.035 mmol, 1.5 eq), and acetic acid (2.39 mg, 2.28 uL, 0.04 mmol, 1.7 eq). The reaction mixture was kept at 60° C. and stirred overnight. The reaction was diluted with DCM and sat. aq. NaHCO3was added. Phases were separated and the aq. phase was washed twice with DCM. The combined organic phases were dried over Na2SO4, filtered, concentrated in vacuo, purified using flash column chromatography (heptane:EtOAC=1:0 to 1:1) to afford the title compound as a white solid (5 mg, 28% yield). MS (ESI): 696.3 [M+H]+.
The title compound was prepared according to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(1-cyclopropyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (6 mg, 0.009 mmol) and was obtained as a white solid as a hydrochloride salt (35 mg, 87% yield). MS (ESI): 596.2 [M+H]+.
The title compound was prepared according to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50.0 mg, 0.08 mmol) and was obtained after prep-HPLC as a white solid (25.9 mg, 0.05 mmol, 6000 yield). MS (ESI): 556.3 [M+H]+.
Example 161 of the following table were prepared in analogy to Example 160 using the appropriate Boc-protected building block.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (80.0 mg, 0.12 mmol) in DCM (4 mL) was added acetic anhydride (25.0 mg, 0.24 mmol, 2.0 eq), DIPEA (0.07 mL, 0.37 mmol, 3.0 eq). Then the mixture was stirred at 2° C. for 1 h. The reaction was poured onto water (10 ml), extracted with DCM (10 mL×3), washed with brine (10 mL×3), dried over Na2SO4, concentrated in vacuo and purified by column chromatography on silica gel (PE:EA=10:1 to 2:1) to afford the title compound (90 mg, 0.13 mmol, 105% yield) as white solid. MS (ESI): 698.4 [M+H]+.
The title compound was prepared according to general procedure 6b from tert-butyl N-[(3R)-7-[5-(1-acetyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (90.0 mg, 0.130 mmol) and was obtained as a white solid (42.2 mg, 0.070 mmol, 5300 yield) as the hydrochloric acid salt. MS (ESI): 598.3 [M+H]+.
Examples 163 and 164 of the following table were prepared in analogy to Example 162 using the appropriate acylating building block.
Examples 165 to 168 of the following table were prepared in analogy to Example 150, step a to d) and to Example 162 a,b), using the appropriate acid and acylating building block.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(4-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (Example 161, step d)) (50 mg, 0.08 mmol) in DCM (3 mL) was added acetyl chloride (0.01 mL, 0.120 mmol, 1.5 eq) under N2. Then the mixture was stirred at 25° C. for 2 h, concentrated in vacuo to afford the title compound (40 mg, 0.06 mmol, 75% yield) as colorless solid. MS (ESI): 676.2 [M+H]−.
The title compound was prepared according to general procedure 6b from tert-butyl N-[(3R)-7-[5-(1-acetyl-4-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (40 mg, 0.06 mmol) and was obtained after chromatography on silica gel as a white solid as a hydrochloride salt (22.3 mg, 0.04 mmol, 60% yield). MS (ESI): 576.2 [M+H]+.
Examples 170 to 172 of the following table were prepared in analogy to Example 169 using the appropriate amine and acylating building block.
The title compound was prepared according to general procedure 7a from tert-butyl N-[(3R)-7-[5-(1-acetyl-4-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (500.0 mg, 1.0 mmol) and 3-tert-butoxycarbonyl-3-azabicyclo[3.1.1]heptane-1-carboxylic acid (243 mg, 1.0 mmol) and was obtained after chromatography on silica gel as a light yellow solid (730 mg, 1.0 mmol, 100% yield). MS (ESI): 618.3 [M-isobutene-CO2+H]+.
The title compound was prepared according to general procedure 8a from tert-butyl 1-[[[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carbonyl]amino]carbamoyl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (730 mg, 1.0 mmol) in dioxane and was obtained after column chromatography on silica gel (PE:EA=3:1 to 1:2) as a light yellow solid (570 mg, 0.810 mmol, 80% yield). MS (ESI): 700.3 [M+H]+.
The title compound was prepared according to general procedure 5 tert-butyl 1-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (370.0 mg, 0.53 mmol) and was obtained as a light yellow solid (310 mg, 0.42 mmol, 80% yield). MS (ESI): 732.3 [M+H]+.
The title compound was prepared according to general procedure 6b tert-butyl 1-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (150 mg, 0.2 mmol) and was obtained after prep-HPLC as a white solid (35.1 mg, 0.07 mmol, 31% yield). MS (ESI): 532.2 [M+H]+.
To a solution of (3R)-3-amino-7-[5-(3-azabicyclo[3.1.1]heptan-1-yl)-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one (50 mg, 0.09 mmol) in DCM (1 mL) was added DIPEA (24 mg, 0.19 mmol, 2 eq). The mixture was purged with nitrogen and cooled to 0° C., then acetic anhydride (9.6 mg, 0.09 mmol, 1 eq) (dilute with 1 ml DCM) was added dropwise. The reaction was stirred at 20° C. for 12 h, poured into water (5 ml), extracted with EtOAc (5 ml×3). The combined organic layer was dried over Na2SO4 and concentrated in vacuum and purified with prep-HPLC and lyophilized to get the title compound (24.7 mg, 0.04 mmol, 40% yield) as withe solid. MS (ESI): 574.2 [M+H]+.
Examples 174 to 184 of the following table were prepared in analogy to Example 173 using the appropriate carboxylic acid and acylating building block.
To a solution of tert-butyl N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Intermediate 219b) (800 mg, 2.16 mmol) and NEt3 (2.4 mL, 17.2 mmol, 8 eq) in DCM (16 mL) was added 2,2,3,3,3-pentafluoropropanoyl 2,2,3,3,3-pentafluoropropanoate (5357 mg, 17.2 mmol, 8 eq) at 0° C. The reaction was stirred for 16 h at 25° C., concentrated under vacuum, diluted with EtOAc (10 mL), washed with brine (10 mL×2), dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel (PE:EA=3:1 to 1:1) and by prep-HPLC to provide the title compound (130 mg, 0.26 mmol, 9% yield) as a white solid. MS (ESI): 443.0 [M-isobutene+H]+.
The title compound was prepared according to general procedure 5 from tert-butyl N-[(3R)-8-fluoro-4-oxo-7-[5-(1,1,2,2,2-pentafluoroethyl)-1,3,4-oxadiazol-2-yl]-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (130 mg, 0.26 mmol) and was obtained as a white solid (140 mg, 0.260 mmol, 95% yield). MS (ESI): 475.0 [M-isobutene+H]+.
The title compound was prepared according to general procedure 4 from tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-7-[5-(1,1,2,2,2-pentafluoroethyl)-1,3,4-oxadiazol-2-yl]-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (48 mg, 0.09 mmol) and 4-chlorobenzyl bromide (15.81 mg, 0.080 mmol, 0.85 eq) and was obtained after prep-TLC (PE:EtOAc=2:1) as a white solid (40 mg, 0.06 mmol, 62% yield). MS (ESI): 598.9 [M-isobutene+H]+.
The title compound was prepared according to general procedure 6b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-[5-(1,1,2,2,2-pentafluoroethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (40 mg, 0.06 mmol) and was obtained after prep-HPLC as a white solid (2.7 mg, 7% yield). MS (ESI): 555.0 [M+H]+.
To a solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 63, step b) (280 mg, 0.5 mmol) in DCM (5 mL) was added a solution of m-CPBA (53.8 mg, 0.25 mmol, 0.5 eq). The mixture was stirred at 20° C. for 16 h., diluted with Na2SO3 (25 mL), Na2CO3 (25 mL) and DCM (10 mL), washed with water (15 mL), brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography (EtOAc:PE=0:1 to 1:4) to afford the title compound (Epimer B) (120 mg, 0.21 mmol, 41% yield) and epimer A (140 mg, 0.24 mmol, 48% yield) as colorless gum. MS (ESI): 521.2 [M-isobuteneH]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,4-dioxo-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (Epimer A) (120 mg, 0.2 mmol) and was obtained as a white solid (54.5 mg, 0.11 mmol, 54% yield). MS (ESI): 477.0 [M+H]+.
Examples 187 of the following table was prepared in analogy to Example 186
The title compound was prepared in analogy to general procedure 4 from 4-(bromomethyl)benzonitrile (291 mg, 1.48 mmol, 1.1 eq) and (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-keto-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid methyl ester (500 mg, 1.35 mmol) after column chromatography on silica gel (heptane:EtOAc=1:0 to 0:1) as a light yellow solid (616 mg, 93% yield). MS (ESI): 430.3 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 13 from (3R)-3-(tert-butoxycarbonylamino)-5-(4-cyanobenzyl)-8-fluoro-4-keto-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid methyl ester (616 mg, 1.27 mmol) as a light yellow solid (617 mg, 99% yield). MS (ESI): 470.4 [M−H]−.
(3R)-3-(tert-butoxycarbonylamino)-5-(4-cyanobenzyl)-8-fluoro-4-keto-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (567 mg, 1.15 mmol) and CDI (243 mg, 1.5 mmol, 1.3 eq) in THF(5 mL) was stirred at r.t. for 45 min. This solution was then slowly added to a second solution of hydrazine monohydrate (168 mg, 164 μL, 3.46 mmol, 3 eq) in THE (1.68 mL) and the reaction was stirred at r.t. for 30 min, diluted with EtOAc, washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to the title compound (578 mg, 99% yield) as light yellow solid. MS (ESI): 430.3 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 7a from 3-hydroxy-2,2-dimethyl-propionic acid (40.1 mg, 0.34 mmol, 1.1 eq) and N-[(3R)-7-carbazoyl-5-(4-cyanobenzyl)-8-fluoro-4-keto-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (150 mg, 0.31 mmol) as a light yellow solid (209 mg, 98% yield). MS (ESI): 584.5 [M−H]−.
N-[(3R)-5-(4-cyanobenzyl)-8-fluoro-7-[[(3-hydroxy-2,2-dimethyl-propanoyl)amino]carbamoyl]-4-keto-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (209 mg, 0.3 mmol), TBDMS-Cl (59 mg, 0.39 mmol, 1.3 eq) and imidazole (51.6 mg, 0.75 mmol, 2.5 eq) were in THE (3 mL) was stirred at RT for 12 h. Water was added and the reaction was diluted with EtOAc. The organic layer was washed with water and brine, dried using magnesium sulfate, concentrated in vacuo an purified by column chromatography on silica gel (EtOAc in heptane, 0-100%) to yield the title compound (135 mg, 63% yield) as a white solid MS (ESI): 498.6 [M−H]−.
The title compound was prepared in analogy to general procedure 8a from tert-butyl N-[(3R)-7-[[[3-[tert-butyl(dimethyl)silyl]oxy-2,2-dimethyl-propanoyl]amino]carbamoyl]-5-[(4-cyanophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (135 mg, 0.19 mmol) as a light yellow solid (150 mg, 96% yield). MS (ESI): 682.5 [M+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-7-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]-1,3,4-oxadiazol-2-yl]-5-[(4-cyanophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (150 mg, 0.187 mmol) as a white solid (42.4 mg, 31% yield). MS (ESI): 714.5 [[M+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-7-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]-1,3,4-oxadiazol-2-yl]-5-[(4-cyanophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (35 mg, 0.049 mmol) as a light yellow solid as a hydrogen chloride salt (10 mg, 34% yield). MS (ESI): 500.3 [[M+H]+.
4-hydroxybenzyl alcohol (150 mg, 1.2 mmol, 1 eq), benzyl N-(11-bromoundecyl)carbamate (510 mg, 1.33 mmol, 1.1 eq) and potassium carbonate (360 mg, 2.6 mmol, 2.16 eq) in MeCN (8 mL) was stirred for 6 h at 80° C. The mixture was poured into water (60 mL), and extracted with EtOAc (50 mL×2), the combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE:EA=1:0 to 3:1) to afford the title compound (410 mg, 0.96 mmol, 76% yield) as a light yellow solid. MS (ESI): 410.2 [M−OH]+.
To a mixture of benzyl N-[11-[4-(hydroxymethyl)phenoxy]undecyl]carbamate (300 mg, 0.7 mmol) and DIPEA (0.3 mL, 1.72 mmol, 2.45 eq) in DCM (8 mL) was added methanesulfonyl chloride (0.2 mL, 2.62 mmol, 3.73 eq) at 0° C., and then the mixture was stirred at 25° C. for 1 h. DCM (40 mL) was added to the mixture. The organic layer was washed water (20 mL), brine (20 mL), dired over Na2SO4, filtered and concentrated in vacuum to give the crude title compound (280 mg, 0.55 mmol, 78% yield) as yellow oil. MS (ESI): 410.2 [M−MeSO3+.
The title compound was prepared in analogy to general procedure 4 from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (120 mg, 0.27 mmol) and [4-[11-(benzyloxycarbonylamino)undecoxy]phenyl]methyl methanesulfonate (280 mg, 0.55 mmol, 2. eq) after prep-TLC (PE:EA=2:1) as a colorless oil (160 mg, 0.19 mmol, 63% yield). MS (ESI): 846.4 [M+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-5-[[4-[11-(benzyloxycarbonylamino)undecoxy]phenyl]methyl]-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (160 mg, 0.19 mmol) after prep-TLC (PE:EA=3:1) as a colorless oil (150 mg, 0.170 mmol, 88% yield). MS (ESI): 878.3 [M+H]−.
tert-butyl N-[(3R)-5-[[4-[11-(benzyloxycarbonylamino)undecoxy]phenyl]methyl]-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (120 mg, 0.14 mmol) and Pd/C (10 mg) in MeOH (4 mL) was stirred at 25° C. for 2 h under H2 (15.0 Psi) atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC. Lyophilization afforded the title compound as a hydrochloride salt (18.4 mg, 0.02 mmol, 17% yield) as a white solid. MS (ESI): 744.3 [M+H]+.
The title compound was prepared in analogy to general procedure 7d from N-[(3R)-5-[4-(11-aminoundecoxy)benzyl]-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1,1,4-triketo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester hydrochloride salt (5 mg, 0.006 mmol) after prep-HPLC as a white solid (5.2 mg, 126% yield). MS (ESI): 644.5 [M+H]+.
To (3R)-3-amino-5-[4-(11-aminoundecoxy)benzyl]-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1,1-diketo-2,3-dihydro-1λ6,5-benzothiazepin-4-one (1.3 mg, 0.002 mmol) and 3-[2,2-difluoro-12-(1H-pyrrol-2-yl)-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-5-yl]propionic acid succinimido ester (1.2 mg, 0.003 mmol, 1.39 eq) was added DMF (0.05 mL). The reaction was stirred overnight at room temperature. The reaction was purified by prep-HPLC affording the title compound (0.66 mg, 23%) as purple solid. MS (ESI): 955.6 [M+H]+.
The title compound was prepared in analogy to general procedure 14 from (2R,3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-2-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (CAS 2002451-02-5) (258 mg, 0.52 mmol) and was obtained as a light yellow foam (269 mg, 99% yield). MS (ESI): 453.1 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 7a from tert-butyl N-[(2R,3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-2-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (50 mg, 0.096 mmol) using pivalic acid (CAS 75-989) (10.8 mg, 0.106 mmol) and was obtained as a white solid (47 mg, 77% yield) MS (ESI): 493.2 [M-isobutene-CO2+H]+.
The title compound was prepared in analogy to general procedure 8a from tert-butyl N-[(2R,3R)-5-[(4-chlorophenyl)methyl]-7-[(2,2-dimethylpropanoylamino)carbamoyl]-8-fluoro-2-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (50 mg, 0.078 mmol) and was obtained as a white solid (32 mg, 70% yield). MS (ESI): 575.3 [M+H]+.
The title compound was prepared in analogy to general procedure 9b from tert-butyl N-[(2R,3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-2-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (32 mg, 0.056 mmol) and was obtained as a white solid (28 mg, 81% yield). MS (ESI): 551.3 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(2R,3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-2-methyl-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (28 mg, 0.045 mmol) and was obtained as a white solid (25 mg, 78% yield) as a hydrochloride salt and 1,1,1,3,3,3-hexafluoropropan-2-ol adduct. MS (ESI): 507.3 [M+H]−.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 63, step a)) (1000.0 mg, 2.02 mmol, 1 eq) in DMF (20 mL) was added CS2 (0.37 mL, 6.06 mmol, 3 eq) at 25° C. The reaction mixture was stirred for 15 min under an atmosphere of nitrogen at 25° C. and then heated to 70° C. for 4 h. After the mixture was cooled to 25° C., TEA (1.12 mL, 8.08 mmol, 4 eq) and Mel (0.15 mL, 2.42 mmol, 1.2 eq) were added and the reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with EtOAc (25 mL) and washed with brine (3×25 mL), dried over anhydrous Na2SO4 and concentrated to give crude product (1 g) which was purified by column chromatography on silica gel (PE:EtOAc 5:1 to 2:1) to give the title compound (650 mg, 1.18 mmol, 58% yield) as a light yellow solid. MS (ESI): 495.1 [M-isobutene+H]+.
A solution of KMnO4 (476.67 mg, 3.02 mmol, 5.04 eq) in water (2.02 mL) was added dropwise to a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(5-methylsulfanyl-1,3,4-oxadiazol-2-yl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (330.0 mg, 0.600 mmol, 1 eq) in a mixture of acetic acid (6.72 mL) and water (4.03 mL) at 0° C. under an atmosphere of nitrogen. The mixture was stirred for 2 h, keeping the internal temperature below 5° C. The reaction mixture was poured into a cold saturated aqueous Na2SO3 solution (50 mL). Then the mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were washed with brine (2×40 mL), dried over anhydrous Na2SO4 and concentrated to give a crude product (400 mg) which was purified by prep-HPLC. The organic solvent was removed under vacuum and the title compound was obtained after freeze drying (140 mg, 0.230 mmol, 34% yield) as a white solid. MS (ESI): 559.2 [M-isobutene+H]+.
A mixture of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(5-methylsulfonyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (120.0 mg, 0.200 mmol, 1 eq), azetidine (0.02 mL, 0.23 mmol, 1.2 eq) and K2CO3 (32.36 mg, 0.23 mmol, 1.2 eq) in DMF (12 mL) was stirred for 1 h at 25° C. The reaction mixture was diluted with EtOAc (15 mL), washed with brine (3×10 mL), dried over anhydrous Na2SO4 and concentrated to give crude product (150 mg) which was purified by prep-HPLC. The organic solvent was removed under vacuum and the title compound was obtained after freeze drying as a white solid (30 mg, 0.050 mmol, 26% yield). MS (ESI): 592.3 [M+H]+.
To a solution of tert-butyl N-[(3R)-7-[5-(azetidin-1-yl)-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (30.0 mg, 0.050 mmol, 1 eq) in DCM (1 mL) were added TMSOTf (0.03 mL, 0.150 mmol, 3 eq) and 2,6-lutidine (0.01 mL, 0.130 mmol, 2.5 eq) and the mixture was stirred for 2 h at 25° C. The mixture was concentrated under vacuum and the remaining residue was purified by prep-HPLC (column: Phenomenex Gemini NX—C18<75*30 mm*3 um>; mobile phase:[water<10 mM NH4HCO3>—MeCN];B %: 22%-52%,8 min) followed by freeze drying to give the title compound (13.5 mg, 0.030 mmol, 52% yield) as a white solid. MS (ESI): 492.2 [M+H]+.
To a solution of N-[(3R)-5-(4-chlorobenzyl)-7-cyano-8-fluoro-4-keto-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (419 mg, 0.83 mmol, 1 eq) in MeOH (4.17 mL) was added hydroxylamine hydrochloride (89.6 mg, 1.25 mmol, 1.5 eq) followed by NaHCO3 (350.5 mg, 4.17 mmol, 5 eq). The reaction mixture was heated to reflux for 90 min, cooled to room temperature, filtered and the filter cake was further washed with DCM. The filtrate was then concentrated in vacuo and the residue was taken up in DCM and washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (215 mg, 9800 yield) as white solid (purity 890%). MS (ESI): 539.3 [M−H+HCO2H]−.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-[(Z)—N′-hydroxycarbamimidoyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.18 mmol, 1 eq) in THF (1.86 mL) was added CDI (31.2 mg, 0.19 mmol, 1.06 eq) and triethylamine (19.5 mg, 26.7 uL, 0.19 mmol, 1.06 eq) at room temperature. The reaction mixture was heated to 70° C. and stirred for 3 hours and after cooling taken up in EtOAc (30 mL), washed with 1N aqueous HCl solution (20 ml) and brine (50 ml), dried over sodium sulfate, filtered and evaporated to afford the title compound (117 mg. 92% yield) as light brown solid (purity 750. MS (ESI): 519.4 [M−H]
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (33 mg, 0.06 mmol, 1 eq) in 1,4-dioxane (1.03 mL) was added 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride (19.5 mg, 0.14 mmol, 2 eq), DIPEA (37.2 mg, 50.2 uL, 0.29 mmol, 4 eq) and bromotripyrrolidinophosphonium hexafluorophosphate (42.4 mg, 0.086 mmol, 1.2 eq). The mixture was heated to 50° C. for 90 min. The reaction was cooled to RT and diluted with EtOAc and water and stirred vigorously. The phases were separated and the aqueous phase washed twice with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by column chromatography on silica gel (EtOAc:heptanes gradient) to afford the desired title compound (36 mg, 76% yield) as white solid (purity 91%). MS (ESI): 546.3 [M+H-isobutene]*.
tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-1,2,4-oxadiazol-3-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (36 mg, 0.054 mmol) was stirred with 3-chloroperoxybenzoic acid (36.5 mg, 0.16 mmol, 3 eq) in DCM (1.09 mL) at room temperature for 2.5 hours. The reaction solution was then diluted with DCM and 1N aqueous NaOH was added (washed 2× with DCM). The organic layers were washed with water, brine, dried over Na2SO4, filtered and evaporated to give crude product, which was purified by column chromatography on silica gel (EtOAc:heptanes gradient) to afford the desired title compound (28 mg, 81% yield) as white solid (purity 100%). MS (ESI): 632.5 [M−H]−.
2 M HCl in Et2O (39.4 uL, 0.079 mmol, 2 eq) was stirred tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (25 mg, 0.039 mmol, 1 eq) in 1,1,1,3,3,3-hexafluoro-2-propanol (1.31 mL) at room temperature for 40 min. The solvent was evaporated in vacuo. The solid was suspended in DCM, sonicated for 30 seconds and again concentrated. This process was repeated twice then dried in vacuo to afford the title compound (21 mg, 91% yield) as white solid (purity 100%). MS (ESI): 534.3 [M+H]+.
Example 193 to 199 of the following table was prepared in analogy to Example 192 in three steps, using the appropriate amine building block.
The title compound was prepared in analogy to example 192, step a) from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-cyano-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (832 mg, 1.68 mmol) as a yellow solid (563 mg, 63% yield). MS (ESI): 471.1 [M-isobutene+H]+.
The title compound was prepared in analogy to example 192, step b) from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-[(Z)—N′-hydroxycarbamimidoyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (100 mg, 0.19 mmol) as an orange solid (80 mg, 72% yield, 94% purity). MS (ESI): 497.0 [M-isobutene+H]+.
The title compound was prepared in analogy to example 192, step c) from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (45 mg, 0.069 mmol) as an orange solid (3.4 mg, 7% yield, 95% purity). MS (ESI): 592.3 [M-isobutene+H]+.
The title compound was prepared in analogy to example 192, step e) from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-[5-[rac-(1S,5R)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl]-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (3 mg, 0.005 mmol) as a light yellow solid, as a hydrochloride salt (3 mg, 100% yield, 93% purity). MS (ESI): 548.3 [M+H]+.
Example 201 to 206 of the following table was prepared in analogy to Example 200 in two steps, using the appropriate amine building block.
To a solution of 4-methyl-4-nitro-1-(2-prop-2-ynoxyethoxy)pentane (350.0 mg, 1.53 mmol) in MeOH (3.5 mL) and aqueous hydrogenchloride (3.5 mL, 42 mmol, 27.51 eq) was added Zinc (598.8 mg, 9.16 mmol, 6 eq) portionwise at 0° C. After finished, the mixture was allowed to warm to room temperature and stirred for 3 h, concentrated under vacuum to remove most of the solvent, and the residue was added into saturated aqueous NaHCO3 (10 mL) dropwise, the suspension was then extracted with EtOAc (10 mL), filtered through celite to separated the precipitated Zn salt. The water phase was extracted with EtOAc (10 mL) again. The combined organic phase was dried over anhydrous Na2SO4, concentrated under vacuum to give crude title compound (250 mg, 1.25 mmol, 82% yield) as a light brown oil.
The title compound was prepared in analogy to general procedure 16 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 192, step b) (100 mg, 0.154 mmol, 1 eq) and 2-oxa-5-azabicyclo[4.1.0]heptane (CAS 1354952-28-5) (20.82 mg, 0.154 mmol, 1 eq) and was obtained as a white crystalline (63.3 mg, 65% yield). MS (ESI): 546.2 [M-isobutene+H]+.
tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-1,2,4-oxadiazol-3-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (63.3 mg, 0.1 mmol) was stirred with 3-chloroperoxybenzoic acid (22.4 mg, 0.1 mmol, 1 eq) in DCM (2 mL) at RT for 1:5 hours. The reaction solution was diluted with DCM and 1N aqueous NaOH. The aqueous layer was extracted twice with DCM. The organic layers were washed with water, brine, dried over Na2SO4, filtered and evaporated and purified by column chromatography on silica gel (heptane:EtOAc=1:0 to 1:2) to afford the title compound (epimer A) (24.7 mg, 40%) as white powder (MS (ESI): 616.3 [M+HCOOH−H]) and epimer B (18.3 mg, 29.6%) as white powder (MS (ESI): 616.3 [M+HCOOH−H]−).
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-1,2,4-oxadiazol-3-yl]-1,4-dioxo-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (Epimer A) (24.7 mg, 40 mol) and was obtained (15.3 mg, 67% yield) as a white powder as a hydrochloride salt. MS (ESI): 518.1 [M+H]+.
Examples 208 to 213 of the following table were prepared in analogy to Example 207.
The title compound was prepared in analogy to general procedure 5 from Example 321, step c) (7 g, 20.75 mmol) and was obtained as a white solid (7.4 g, 96% yield). MS (ESI): 314.1 [M-isobutene+H]+.
To a mixture of tert-butyl N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (500 mg, 1.35 mmol, 1 eq), KI (226 mg, 1.35 mmol, 1 eq), 1M aqueous Na2CO3 solution (0.42 ml, 4.03 mmol, 3 eq) in DMF (10 mL) was added 5-(bromomethyl)-2-(1-methylethoxy)pyridine (CAS: 1382866-91-2) (398 mg, 1.5 mmol, 1.1 eq) and stirred at room temperature for 16 h. The reaction mixture was poured into ethyl acetate (20 mL) and the organic layer was washed with brine (3×20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (PE:EA=5:1 to 1:1) affording the title compound (640 mg, 1.23 mmol, 66% yield) as a yellow solid. MS (ESI): 519.2 [M+H]+.
The title compound was prepared in analogy to general procedure 12 from tert-butyl N-[(3R)-7-cyano-8-fluoro-5-[(6-isopropoxy-3-pyridyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (640 mg, 1.23 mmol) and was obtained as a yellow solid (220 mg, 29% yield). MS (ESI): 552.3 [M+H]+.
To a mixture of tert-butyl N-[(3R)-8-fluoro-5-[(6-isopropoxy-3-pyridyl)methyl]-1,1,4-trioxo-7-[(Z)—N′-hydroxycarbamimidoyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (220 mg, 0.4 mmol) and triethylamine (0.11 ml, 0.8 mmol, 2eq) in DCM (5 mL) was added N.N′-carbonyldiimidazole (97 mg, 0.6 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 3 h. The reaction mixture was diluted with EtOAc (10 mL) and the layer was washed with brine (2×10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (PE:EA=2:1 to 0:1) affording the title compound (185 mg, 0.32 mmol, 69% yield) as an off-white solid. MS (ESI): 578.3[M+H]+.
The title compound was prepared in analogy to general procedure 16 from tert-butyl N-[(3R)-8-fluoro-5-[(6-isopropoxy-3-pyridyl)methyl]-1,1,4-trioxo-7-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (100 mg, 0.17 mmol) and was obtained as a white solid (160 mg, 100% yield). MS (ESI): 673.3 [M+H]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-8-fluoro-5-[(6-isopropoxy-3-pyridyl)methyl]-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (160 mg, 0.24 mmol) further purified by prep-HPLC (column: Waters Xbridge 150*25 mm*Sum; mobile phase:water(10 mM NH4HCO3)—MeCN;B %: 36%-66%,8 min). The eluent was concentrated under vacuum to remove MeCN the residue was freeze dried and the title compound was obtained as a white solid (31.2 mg, 61% yield). MS (ESI): 573.3 [M+H]+.
The title compound was prepared in analogy to general procedure 5 from Example 321, step c) (7 g, 20.7 mmol) and was obtained as a white solid (7.4 g, 96% yield). MS (ESI): 314.1 [M-isobutene+H]+.
To a mixture of tert-butyl N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (500 mg, 1.35 mmol), 5-(1-methylethoxy)-2-pyridinemethanol (CAS:1198166-00-5) (249 mg, 1.49 mmol, 1.1 eq), Ph3P (710 mg, 2.71 mml, 2 eq) in toluene (10 mL) was added DIAD (0.53 mL, 2.71 mmol, 2 eq) at 0° C. The reaction mixture was diluted with ethyl acetate (10 mL) and the organic layer was washed with three portions of brine (10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude material was purified by prep-HPLC (column: Waters Xbridge 150*50 mm* 10 um; mobile phase:water(10 mM NH4HCO3)-MeCN;B %: 40%-70%,10 min). The eluent was concentrated under vacuum to remove MeCN, the residue was freeze dried, affording the title compound (260 mg, 0.5 mmol, 36% yield) as a light brown solid. MS (ESI): 518.9 [M+H]+.
The title compound was prepared in analogy to general procedure 12 from tert-butyl N-[(3R)-7-cyano-8-fluoro-5-[(6-isopropoxy-2-pyridyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (86 mg, 0.16 mmol, 1 eq) and was obtained as a light brown solid (80 mg, 76.2% yield). MS (ESI): 552.3 [M+H]+.
To a mixture of tert-butyl N-[(3R)-8-fluoro-5-[(6-isopropoxy-2-pyridyl)methyl]-1,1,4-trioxo-7-[(Z)—N′-hydroxycarbamimidoyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (86 mg, 0.16 mmol) and NEt3 (0.04 ml, 0.31 mmol, 2eq) in DCM (2 mL) was added N.N′-carbonyldiimidazole (37.9 mg, 0.23 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 3 h. The reaction mixture was poured into water (5 mL). The aqueous layer was extracted with three portion of EtOAc (5 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (PE:EA=1:1 to 0:1) affording the title compound (80 mg, 0.14 mmol, 76% yield) as a light brown solid. MS (ESI): 578.3[M+H]+.
The title compound was prepared in analogy to general procedure 16 from tert-butyl N-[(3R)-8-fluoro-5-[(6-isopropoxy-2-pyridyl)methyl]-1,1,4-trioxo-7-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (60 mg, 0.1 mmol) and was obtained as a light brown solid (60 mg, 80% yield). MS (ESI): 673.4 [M+H]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-8-fluoro-5-[(6-isopropoxy-2-pyridyl)methyl]-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (60 mg, 0.09 mmol) and purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase:[water(0.05% HCl)-MeCN];B %: 24%-44%,6 min) The eluent was concentrated under vacuum to remove MeCN. The residue was freeze dried and the title compound was obtained as a light brown solid (11.2 mg, 19% yield). MS (ESI): 573.3 [M+H]+.
(R)-3-((tert-butoxycarbonyl)amino)-5-(4-chlorobenzyl)-8-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carboxylic acid (CAS:2002449-40-1) (70 mg, 146 μmol, Eq: 1) was dissolved in DMF (0.5 mL) and DIPEA (75.2 mg, 102 μl, 582 μmol, Eq: 4) was added to the reaction mixture. The reaction mixture was cooled to 0° C. and HATU (166 mg, 437 μmol, Eq: 3) was added and the mixture was stirred for 30 minutes. The reaction mixture was then warmed to RT and 2-aminobutan-1-ol (19.5 mg, 20.6 μl, 218 μmol, Eq: 1.5) was added and the mixture was stirred at RT for 1 h. The reaction mixture was adsorbed on silica gel and purified by flash chromatography on silica gel (0-50% EtOAc in heptane), affording the title compound (28 mg, 49.7 μmol, 34% yield) as a orange solid. MS (ESI): 496.3 [M-isobutene+H]+.
tert-butyl N-[(3R)-5-[(4-chlorocyclohexa-2,4-dien-1-yl)methyl]-8-fluoro-7-[1-(hydroxymethyl)propylcarbamoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (25 mg, 45.3 μmol, Eq: 1) was dissolved in THF (0.4 mL). Burgess reagent (50.8 mg, 226 μmol, Eq: 5) was added and the reaction mixture was stirred at 60° C. for 2 h. The solvent was evaporated and the remaining residue was purified by chromatography on silica gel (0-60% EtOAc in heptane), affording the title compound (8.6 mg, 16.1 μmol, 36% yield) as a white solid. MS (ESI): 534.4 [M+H]+.
tert-butyl-N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(4-ethyl-4,5-dihydrooxazol-2-yl)-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (8 mg, 15 μmol, Eq: 1) was dissolved in toluene (0.5 mL). DDQ (3.4 mg, 15 μmol, Eq: 1) was added and the reaction mixture was stirred at 50° C. for 30 minutes and then stirred at 80° C. over night. DDQ (3.4 mg, 15 μmol, Eq: 1) was added to the reaction mixture and it was stirred for two days at 110° C. The reaction mixture was adsorbed on silica gel and purified by chromatography on silica gel (0-50% EtOAc in heptane), affording the title compound (2.3 mg, 4.32 μmol, 29% yield) as a white solid. MS (ESI): 532.4 [M+H]+.
The title compound was prepared according to general method 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(4-ethyloxazol-2-yl)-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 216, step c) (2.1 mg, 3.95 μmol) and was obtained as a white solid (1.25 mg, 2.22 μmol, 56% yield). MS (ESI): 564.4 [M+H]+.
The title compound was prepared in analogy to method 6b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(4-ethyloxazol-2-yl)-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (1.25 mg, 2.22 μmol) and was obtained as a white solid, as a hydrochloride salt (1 mg, 1.68 μmol, 76% yield). MS (ESI): 464.3 [M+H]+.
The title compound was prepared in analogy to general method 1b from methyl 2,4-difluoro-3-nitrobenzoate (600 mg, 2.76 mmol, Eq: 1) and was obtained as an off-white solid (1.16 g, 2.77 mmol, 100% yield). MS (ESI): 319.0 [M-isobutene-CO2+H]+.
The title compound was prepared in analogy to general method 2 from (2R)-2-(tert-butoxycarbonylamino)-3-(3-fluoro-4-methoxycarbonyl-2-nitro-phenyl)sulfanyl-propanoic acid (1.15 g, 2.75 mmol, Eq: 1) and was obtained as a dark brown amorphous solid (854 mg, 1.93 mmol, 70% yield). MS (ESI): 387.2 [M−H]−.
The title compound was prepared in analogy to general method 3 from (2R)-3-(2-amino-3-fluoro-4-methoxycarbonyl-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (400 mg, 1.03 mmol) and was obtained as a light yellow oil (222 mg, 599 μmol, 58% yield). MS (ESI): 369.2 [M−H]−.
The title compound was prepared in analogy to general method 4 from methyl (3R)-3-(tert-butoxycarbonylamino)-6-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (220 mg, 594 μmol) and was obtained as a light yellow solid (201 mg, 191 μmol, 32% yield). MS (ESI): 439.0 [M-isobutene+H]+.
Methyl-(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-6-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (195 mg, 394 μmol, Eq: 1) was dissolved in a mixture of THF (3.5 mL), MeOH (500 μl) and water (1 mL). Lithium hydroxide hydrate (33.1 mg, 788 μmol, Eq: 2) was added and the reaction mixture was stirred at RT for 1 h. The solvent was evaporated and the remaining residue was dissolved in EtOAc and the mixture was washed with 1N aq. HCl, water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford the title compound (195 mg, 215 μmol, 55% yield) as a yellow solid. MS (ESI): 479.1 [M−H]−.
A mixture of (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-6-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (40 mg, 83.2 μmol, Eq: 1), 3,3,3-trifluoropropanehydrazide (11.8 mg, 83.2 μmol, Eq: 1), HATU (31.6 mg, 83.2 μmol, Eq: 1) and DIPEA (21.5 mg, 29.1 μl, 166 μmol, Eq: 2) in THF (800 μl) was stirred at RT. After 30 min. Burgess reagent (59.5 mg, 250 μmol, Eq: 3) was added and stirring was continued at RT overnight. The reaction mixture was adsorbed on silica gel and purified by column chromatography on silica gel (0-50% EtOAc in heptane) to afford the title compound (29 mg, 34.1 μmol, 41% yield) as a light yellow oil. MS (ESI): 531.1 [M-isobutene+H]+.
The title compound was prepared in analogy to general method 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-6-fluoro-4-oxo-7-[5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (27 mg, 46 μmol) and was obtained (18 mg, 29.1 μmol, 63% yield) as an off-white solid. MS (ESI): 563.1 [M-isobutene+H]+.
The title compound was prepared in analogy to general method 6c from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-6-fluoro-1,1,4-trioxo-7-[5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (16 mg, 25.8 μmol) with addition of 4 drops of HCl (4M in dioxane) and was obtained (5.2 mg, 10 μmol, 39% yield) as a white solid. MS (ESI): 519.0 [M+H]+.
Concentrated nitric acid (2.49 mL, 56.09 mmol, 3.73 eq) was added dropwise to a mixture of methyl 2,4-difluoro-3-methyl-benzoate (CAS 1206675-31-1) (2.8 g, 15.04 mmol, 1 eq) in concentrated sulfuric acid (3.11 mL, 58.05 mmol, 3.86 eq) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and then poured onto ice. The mixture was extracted with EtOAc(3×20 mL) and the combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate and concentrated in vacuum to get a residue which was purified by column chromatography on silica gel (PE/EA=20:1 to 5:1) to obtain the title compound (540 mg, 2.34 mmol, 16% yield) as light yellow oil. 1H-NMR (CDCl3, 400 MHz) δ=8.60 (t, J=7.8 Hz, 1H), 4.12 (s, 1H), 3.99 (s, 3H), 2.35 (t, J=2.3 Hz, 3H).
The title compound was prepared from methyl 2,4-difluoro-3-methyl-5-nitro-benzoate (2000.0 mg, 8.65 mmol, 1 eq) in analogy to general procedure 1b and was obtained as yellow oil (3700 mg, 8.56 mmol, 99% yield). MS (ESI): 431.1 [M−H]−.
To a suspension of (2R)-2-(tert-butoxycarbonylamino)-3-(3-fluoro-4-methoxycarbonyl-2-methyl-6-nitro-phenyl)sulfanyl-propanoic acid (1.0 g, 2.31 mmol, 1 eq) in MeOH (10 mL) was added Pd/C (100.0 mg, 2.31 mmol, 1 eq) and the mixture was stirred under an atmosphere of hydrogen at 20° C. for 12 h. The reaction mixture was filtered and filtrate was concentrated in vacuum to get the crude title compound (700 mg, 1.74 mmol, 75% yield) as light yellow oil which was used in the next reaction step without further purification.
The title compound was prepared from (2R)-3-(6-amino-3-fluoro-4-methoxycarbonyl-2-methyl-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (2100.0 mg, 5.22 mmol, 1 eq) in analogy to general procedure 3 and was obtained as brown solid (350 mg, 0.910 mmol, 17% yield). MS (ESI): 383.1 [M−H]−.
The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-9-methyl-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (320.0 mg, 0.830 mmol, 1 eq) in analogy to general procedure 4 (DMF instead of DMSO as solvent) and was obtained as light yellow oil (300 mg, 0.590 mmol, 71% yield). MS (ESI): 453.3 [M-isobuten+H]+.
To a solution of methyl (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-9-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (200.0 mg, 0.390 mmol, 1 eq) in a solvent mixture of MeOH (1 mL), THE (1 mL) and water (1 mL) was added LiOH (56.63 mg, 2.36 mmol, 6 eq) and the mixture was stirred at 20° C. for 12 h. The reaction mixture was concentrated in vacuum to remove all solvents, the remaining residue was re-dissolved in water (10 mL) and the pH of the solution was adjusted to 6 by addition of 1M HCl (10 mL). The mixture was extracted with EtOAc (3×10 mL) and the combined organic layers were washed with water (10 mL) and brine(10 mL), dried over sodium sulfate and concentrated in vacuum to afford a light yellow oil (250 mg) containing the title compound which was used in the next reaction step without further purification. MS (ESI): 439.3 [M-isobuten+H]+.
The title compound was prepared from (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-9-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (200.0 mg, 0.400 mmol, 1 eq) in analogy to general procedure 14 and was obtained as light yellow oil. MS (ESI): 453.3 [M-isobuten+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-9-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (230.0 mg, 0.450 mmol, 1 eq) in analogy to general procedure 7a and was obtained as light yellow oil. MS (ESI): 593.4 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[(2,2-dimethylpropanoylamino)carbamoyl]-8-fluoro-9-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (230.0 mg, 0.390 mmol, 1 eq) in analogy to general procedure 8a and was obtained as light yellow oil (200 mg, 0.350 mmol, 90% yield). MS (ESI): 519.3 [M-isobuten+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-9-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (200.0 mg, 0.350 mmol, 1 eq) in analogy to general procedure 5 and was obtained as light yellow oil (200 mg, 0.330 mmol, 95% yield). MS (ESI): 607.4 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-9-methyl-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (200.0 mg, 0.330 mmol, 1 eq) in analogy to general procedure 6b and was obtained as white solid (42.7 mg, 0.080 mmol, 25% yield). MS (ESI): 507.1 [M+H]+.
Methyl-(R)-3-((tert-butoxycarbonyl)amino)-8-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carboxylate (CAS 2002449-38-7) (3.1 g, 8.37 mmol, Eq: 1) was dissolved in a mixture of THE (60 mL) and water (18 mL). Sodium hydroxide (445 mg, 11.1 mmol, Eq: 1.33) was added to the reaction mixture and it was stirred at RT for 7 h. The reaction was quenched by addition of HCl aq. 1N (11.1 ml, 11.1 mmol, Eq: 1.33) and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (3.13 g, 6.76 mmol, 81% yield) as a yellow solid. MS (ESI): 301.0 [M-isobutene+H]+.
(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid (3.13 g, 6.76 mmol, Eq: 1) was dissolved in THE (30 mL) and CDI (1.43 g, 8.79 mmol, Eq: 1.3) was added and the yellow solution was stirred for 30 min. This first solution was then dropwise added to a second solution of hydrazine hydrate (1.02 g, 984 μl, 20.3 mmol, Eq: 3) in THE (10 mL) at RT. The reaction mixture was poured on water and was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (3.06 g, 6.2 mmol, 92% yield) as a yellow solid. MS (ESI): 315.0 [M-isobutene+H]+.
To a solution of tert-butyl N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (2.98 g, 6.03 mmol, Eq: 1) in THE (60 mL) were added pivalic acid (678 mg, 6.64 mmol, Eq: 1.1), HATU (2.52 g, 6.64 mmol, Eq: 1.1) and DIPEA (1.56 g, 2.11 ml, 12.1 mmol, Eq: 2) and the reaction mixture was stirred at RT for 2 h. The solvent was evaporated and the remaining residue was purified by chromatography on silica gel (50-100% EtOAc in heptane), affording the title compound (2.69 g, 5.92 mmol, 98% yield) as a light yellow solid. MS (ESI): 399.1 [M-isobutene+H]+.
Burgess reagent (7.05 g, 29.6 mmol, Eq: 5) was added to a yellow solution of tert-butyl (R)-(8-fluoro-4-oxo-7-(2-pivalylhydrazine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)carbamate (2.69 g, 5.92 mmol, Eq: 1) in THE (50 mL) and the reaction mixture was stirred at RT for 3 h. The solvent was evaporated and the crude residue was purified by chromatography on silica gel (0-10% MeOH in DCM) to obtain the title compound (2.57 g, 5.36 mmol, 91% yield) as a light yellow solid. MS (ESI): 381.1[M-isobutene+H]+.
m-CPBA (117 mg, 521 μmol, Eq: 2.5) was added to a colorless solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (100 mg, 208 μmol, Eq: 1) in DCM (2 mL) and the reaction mixture was stirred at RT over night. 1N aqueous NaOH solution was added and the mixture was extracted with DCM. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude residue was purified by chromatography on silica gel (0-50% EtOAc in heptane), affording the title compound (65 mg, 135 μmol, 65% yield) as a white solid. MS (ESI): 413.0[M-isobutene+H]+.
tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (60 mg, 128 μmol, Eq: 1) was combined with 1-(bromomethyl)-3-chlorobenzene (28.9 mg, 18.5 μl, 141 μmol, Eq: 1.1), K2CO3 (53.1 mg, 384 μmol, Eq: 3) and KI (10.6 mg, 64 μmol, Eq: 0.5) in DMSO (0.6 mL) and the reaction mixture was stirred at RT for 1 h. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude residue was purified by flash chromatography on silica gel (0-50% EtOAc in heptane) to afford the title compound (53 mg, 89.4 μmol, 70% yield) as a white solid. MS (ESI): 537.1 [M-isobutene+H]+.
tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(3-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50 mg, 84.3 μmol, Eq: 1) was dissolved in HFIP (14.2 mg, 2 ml, 84.3 μmol, Eq: 1) and a few drops of HCl (4N in dioxane) were added. The reaction mixture was heated to 70° C. and was stirred for 5 h. Saturated aqueous NaHCO3 solution was added and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated, affording the title compound (42 mg, 84 μmol, 100% yield) as a white solid. MS (ESI): 493.0[M+H]+.
A mixture of N—[(E)-(5-bromo-3-pyridyl)methyleneamino]-4-methyl-benzenesulfonamide (CAS 2415435-97-9) (2000.0 mg, 5.65 mmol, 1 eq), 4-chlorophenylboronic acid (1324.35 mg, 8.47 mmol, 1.5 eq) and K2CO3 (2205.92 mg, 16.94 mmol, 3 eq) in 1,4-dioxane (40 mL) was heated to 110° C. and stirred for 1 h under an atmosphere of nitrogen. The mixture was cooled to RT and filtered and the filter cake was washed with EtOAc (10 mL). The filtrate was washed with brine (2×20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to give a crude product which was purified by column chromatography on silica gel (PE/EA=9:1 to 4:1) to obtain the title compound (1540 mg, 5.45 mmol, 94% yield) as a colorless oil. MS (ESI): 283.9 [M+H]+.
A solution of 3-bromo-5-[(4-chlorophenyl)methyl]pyridine (840.0 mg, 2.97 mmol, 1 eq), TEA (0.82 mL, 5.95 mmol, 2 eq) and Pd(dppf)Cl2 (217.52 mg, 0.300 mmol, 0.100 eq) in a solvent mixture of MeOH (10 mL) and DMF (10 mL) was degassed with argon three times and then purged with CO three times. The mixture was heated to 80° C. and stirred under CO (50 psi) for 24 h. The mixture was filtered, the filter cake was washed with MeOH (2×5 mL) and the filtrate was concentrated to remove all MeOH. EtOAc (10 mL) was added to the residue and the mixture was washed with brine (3×10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to give residue which was purified by column chromatography on silica gel (PE/EA=9:1 to 4:1) to obtain the title compound (570 mg, 2.18 mmol, 70% yield) as a colorless oil. MS (ESI): 262.1 [M+H]+.
To a suspension of LiAlH4 (79.76 mg, 2.1 mmol, 1.1 eq) in THE (10 mL) was added a solution of methyl 5-[(4-chlorophenyl)methyl]pyridine-3-carboxylate (500.0 mg, 1.91 mmol, 1 eq) in THE (2 mL) dropwise at 0° C. under an atmosphere of nitrogen. The mixture was stirred for 10 min at 0° C. and then warmed to 25° C. and stirred for 2 h. The reaction was quenched by addition of water (0.013 mL) at 0° C. and then 15% NaOH aqueous solution (0.013 mL) and water (0.039 mL) were added. Then the suspension was filtered through a pad of celite and the filter pad was washed with EtOAc (2×5 mL). The filtrate was washed with brine (2×10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude title compound (340 mg, 1.45 mmol, 34% yield) as a colorless oil which was unused in the next reaction step without any further purification. MS (ESI): 234.1 [M+H]+.
To a solution of [5-[(4-chlorophenyl)methyl]-3-pyridyl]methanol (50.0 mg, 0.210 mmol, 1 eq) in DCM (1 mL) was added thionyl chloride (0.09 mL, 1.28 mmol, 6 eq) at 0° C. The mixture was warmed to 25° C. and stirred for 3 h. The reaction mixture was concentrated under vacuum, THE (3 mL) was added and then evaporated again to give the crude title compound (65 mg, 0.230 mmol, 76% yield) as a light brown solid which was used in the next reaction step without further purification. MS (ESI): 252.0 [M+H]+.
To a solution of (6-isopropoxy-3-pyridyl)methanol (CAS 1104461-69-9) (50 mg, 0.299 mmol, 1 eq) in DCM (1.25 mL) was added TEA (30.26 mg, 41.68 uL, 0.299 mmol, 1 eq). The reaction mixture was purged with argon and cooled to 0° C. Then mesyl chloride (34.25 mg, 23.3 uL, 0.299 mmol, 1 eq) was added dropwise and the mixture was stirred for 1.5 h. The reaction mixture was diluted with water and extracted with DCM three times. The combined organic layers were dried with MgSO4 and filtered. The solvent was evaporated to obtain a colorless oil (126 mg) containing the title compound. This oil was used in the next reaction step without further purification.
A mixture of tert-butyl N-tert-butoxycarbonyl-N-[11-[4-(hydroxymethyl)phenoxy]undecyl]carbamate (Example 257, step b) (500.0 mg, 1.01 mmol, 1 eq) in hydrochloric acid in EtOAc (15.0 mL, 60 mmol, 59.24 eq) was stirred at 20° C. for 2 h. The mixture was concentrated in vacuum to give the crude title compound (330 mg, 1 mmol, 99% yield) as white solid which was used for next reaction step without further purification. MS (ESI): 276.3 [M+H−H2O]+.
To a mixture of [4-(11-aminoundecoxy)phenyl]methanol, hydrochloride (200.0 mg, 0.610 mmol, 1 eq) and TEA (0.42 mL, 3.03 mmol, 5 eq) in DCM (8 mL) was added acetic anhydride (0.07 mL, 0.760 mmol, 1.26 eq) at 0° C. under an atmosphere of nitrogen and the mixture was stirred at 0° C. for 10 min and then at 20° C. for 50 min. The mixture was poured into water (20 mL) and then extracted with DCM (20 mL). The combined organic layers were washed with brine (20 mL), dried over (Na2SO4), filtered and concentrated in vacuum to give a residue which was purified by column chromatography on silica gel (PE/EA=10:1 to 1:1) to afford the title compound (106 mg, 0.320 mmol, 52% yield) as a white solid. MS (ESI): 318.3 [M+H−H2O]+.
To a mixture of N-[11-[4-(hydroxymethyl)phenoxy]undecyl]acetamide (100.0 mg, 0.300 mmol, 1 eq) and TEA (0.15 mL, 1.09 mmol, 3.65 eq) and in DCM (4 mL) was added methanesulfonyl chloride (0.05 mL, 0.610 mmol, 2.05 eq) at 0° C. and then the mixture was stirred at 20° C. for 2 h. The mixture was concentrated in vacuum to give a yellow semisolid (300 mg) containing the title compound which was used as such in the next reaction step.
The intermediate was prepared in analogy to intermediate 12 from [4-(1,1,2,2-tetrafluoroethoxy)phenyl]methanol (CAS 773868-39-6) and was obtained as yellow liquid.
Examples 220 to 251 of the following table were prepared in analogy to Example 219, using the appropriate benzyl halide or benzyl sulfonate building block.
To a solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 219, step d) (100.0 mg, 0.230 mmol, 1 eq) in DMF (3 mL) were added potassium carbonate (158.31 mg, 1.15 mmol, 5 eq), potassium iodide (19.02 mg, 0.110 mmol, 0.500 eq) and a solution of 3-(chloromethyl)-5-[(4-chlorophenyl)methyl]pyridine hydrochloride (Intermediate 11) (86.24 mg, 0.270 mmol, 1.2 eq) in DMF (1.5 mL) at 25° C. and the reaction mixture was stirred at 25° C. for 3 h. The mixture was diluted with EtOAc (5 mL), washed with brine (3×5 mL) and dried over anhydrous Na2SO4. After filtration, the organic layer was concentrated to dryness in vacuo to get the crude product which was purified by prep-TLC (PE:EA=1:1) to obtain the title compound (110 mg, 0.170 mmol, 72% yield) as a white solid. MS (ESI): 652.3 [M+H]+.
To a solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[5-[(4-chlorophenyl)methyl]-3-pyridyl]methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (110.0 mg, 0.170 mmol, 1 eq) in DCM (4 mL) was added m-CPBA (90.95 mg, 0.420 mmol, 2.5 eq) and the mixture was stirred for 5 h at 25° C. The reaction mixture was diluted with DCM (10 mL) and then washed with saturated aqueous Na2SO3 solution (10 mL), saturated aqueous NaHCO3 solution (2×15 mL) and brine (15 mL), dried over anhydrous Na2SO4 and concentrated to give a white solid containing the title compound (113 mg) which was used in the next reaction step without any further purification. MS (ESI): 700.3 [M+H]+.
To a solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[5-[(4-chlorophenyl)methyl]-1-oxido-pyridin-1-ium-3-yl]methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (118.41 mg, 0.170 mmol, 1 eq) in MeCN (4 mL) was added bis(pinacolato)diboron (42.94 mg, 0.170 mmol, 1 eq). The mixture was degassed with nitrogen for three times, stirred for 10 min at 25° C. and then it was heated to 70° C. and stirred for 7 h. The reaction mixture was concentrated under vacuum to give a brown oil containing the title compound (150 mg) which was used in the next step without any further purification. MS (ESI): 684.2 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[5-[(4-chlorophenyl)methyl]-3-pyridyl]methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin--3-yl]carbamate (150.0 mg, 0.220 mmol, 1 eq) in analogy to general procedure 6b and was obtained as white solid as the hydrochloride salt (19.1 mg, 0.030 mmol, 14% yield). MS (ESI): 584.3 [M+H]+.
To a solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 219, step d) (200.0 mg, 0.460 mmol, 1 eq) in DMF (3 mL) were added potassium carbonate (126.65 mg, 0.920 mmol, 2 eq), potassium iodide (38.03 mg, 0.230 mmol, 0.500 eq) and a solution of 1-(chloromethyl)-4-(cyclopentoxy)benzene (CAS 1041579-01-4) (193.08 mg, 0.920 mmol, 2 eq) in DMF (1.5 mL) at 25° C. and the mixture was stirred for 3 h. The reaction mixture was diluted with EtOAc (5 mL), washed with brine (3×5 mL) and dried over anhydrous Na2SO4. After filtration, the organic layer was concentrated to dryness in vacuo to get the crude product which was purified by column chromatography on silica gel (PE/EtOAc=9:1 to 3:2) to obtain the title compound (250 mg, 0.410 mmol, 60% yield) as a light yellow solid. MS (ESI): 611.3 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(cyclopentoxy)phenyl]methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (200.0 mg, 0.330 mmol, 1 eq) in analogy to general procedure 5 and was obtained as light yellow solid (220 mg, 0.340 mmol, 87% yield). MS (ESI): 665.1 [M+Na]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(cyclopentoxy)phenyl]methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (220.0 mg, 0.340 mmol, 1 eq) in analogy to general procedure 6b and was obtained as white solid (81.4 mg, 0.140 mmol, 40% yield). MS (ESI): 543.3 [M+H]+.
Examples 254 and 255 of the following table were prepared in analogy to Example 253, using the appropriate benzyl halide or benzyl sulfonate building block.
To a stirred mixture of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (Example 219, step e) (150.0 mg, 0.320 mmol, 1 eq), Na2CO3 (74.66 mg, 0.700 mmol, 2.2 eq) and KI (33.21 mg, 0.200 mmol, 0.620 eq) in DMF (4 mL) was added a solution of 2-(bromomethyl)-5-chloro-benzonitrile (88.56 mg, 0.380 mmol, 1.2 eq) in DMF (4 mL) within 4 h at 25° C. and then the mixture was stirred at 25° C. for 4 h. The reaction mixture was filtered and the filter cake was washed with EtOAc (10 mL). To the filtrate was added EtOAc (10 mL) and the resulting organic phase was washed with brine (15 mL×3), dried over anhydrous Na2SO4 and concentrated under vacuum to afford the title compound (200 mg, 0.320 mmol, 79% yield) as a yellow solid. MS (ESI): 562.1 [M-isobutene+H]+.
To a solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chloro-2-cyano-phenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (160.0 mg, 0.260 mmol, 1 eq) in a mixture of MeOH (4 mL) and THE (8 mL) were added Raney-Ni (33.55 mg, 0.260 mmol, 1 eq) and ammonium hydroxide (0.4 mL, 3.2 mmol, 12.34 eq) and the mixture was stirred under an atmosphere of hydrogen at 25° C. for 16 h. The reaction mixture was carefully filtered with diatomite and the filter cake was washed with THE (5 mL). The filtrate was concentrated under vacuum affording the title compound (100 mg, 0.160 mmol, 53% yield) as a white solid. MS (ESI): 622.2 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[[2-(aminomethyl)-4-chloro-phenyl]methyl]-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (100.0 mg, 0.160 mmol, 1 eq) in EtOAc (0.500 mL) was added EtOAc/HCl (2.0 mL, 8 mmol, 49.77 eq) at 0° C. The mixture was stirred at 25° C. for 2 h. After the reaction mixture was concentrated under vacuum, the residue was purified by prep-HPLC affording the title compound (41.6 mg, 0.070 mmol, 45% yield) as a yellow solid as a hydrochloride salt. MS (ESI): 522.1 [M+H]−.
To a mixture of 1,11-dibromoundecane (8000.0 mg, 25.47 mmol, 1.84 eq) and cesium carbonate (9000.0 mg, 27.62 mmol, 2 eq) in MeCN (80 mL) was added di-tert-butyl iminodicarboxylate (3000.0 mg, 13.81 mmol, 1 eq) at 20° C. and then the mixture was stirred at 70° C. for 8 h. The mixture was poured into water (600 mL) and was then extracted with EtOAc (300 mL×2), the combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuum to give a residue which was then purified by column chromatography (PE:EtOAc=1:0 to 80:1) to afford the title compound (4000 mg, 8.88 mmol, 64% yield) as a colorless oil. MS (ESI): 474.2 [M+Na]+.
A mixture of 4-hydroxybenzyl alcohol (500.0 mg, 4.03 mmol, 1 eq), tert-butyl N-(11-bromoundecyl)-N-tert-butoxycarbonyl-carbamate (1905.0 mg, 4.23 mmol, 1.05 eq) and potassium carbonate (1200.0 mg, 8.68 mmol, 2.16 ea) in MeCN (40 mL) was stirred for 8 h at 80° C. The mixture was poured into water (300 mL) and was then extracted with EtOAc (250 mL×2), the combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuum to give a residue which was then purified by column chromatography (PE:EtOAc=1:0 to 6:1) to afford the title compound (1490 mg, 3.02 mmol, 75% yield) as a colorless oil. MS (ESI): 516.4 [M+Na]+.
To a mixture of tert-butyl N-tert-butoxycarbonyl-N-[11-[4-(hydroxymethyl)phenoxy]undecyl]carbamate (100.0 mg, 0.200 mmol, 1 eq) and NEt3 (0.1 mL, 0.720 mmol, 3.54 eq) in DCM (4 mL) was added methanesulfonyl chloride (0.03 mL, 0.440 mmol, 2.15 eq) at 0° C. and then the mixture was stirred at 20° C. for 3 h. The mixture was poured into water (20 mL) and was then extracted with DCM (25 mL). The organic layer was separated and washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuum affording a residue containing the title compound (150 mg, 0.260 mmol) as yellow oil.
To a mixture of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (Example 219, step e) (80.0 mg, 0.580 mmol, 3.87 eq) and potassium iodide (20.0 mg, 0.120 mmol, 0.810 eq) in DMF (4 mL) was slowly added a solution of [4-[11-[bis(tert-butoxycarbonyl)amino]undecoxy]phenyl]methyl methanesulfonate (150.0 mg, 0.260 mmol, 1.76 eq) in DMF (1 mL) at 20° C. and then the mixture was stirred at 20° C. for 4 h. The mixture was poured into water (60 mL) and then extracted with EtOAc (40 mL*2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuum to give a residue which was purified by column chromatography (PE:EtOAc=15:1 to 3:1) to afford the title compound (50 mg, 0.050 mmol, 35% yield) as a colorless oil. MS (ESI): 966.5 [M+Na]+.
To a mixture of tert-butyl N-tert-butoxycarbonyl-N-[11-[4-[[(3R)-3-(tert-butoxycarbonylamino)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-5-yl]methyl]phenoxy]undecyl]carbamate (50.0 mg, 0.050 mmol, 1 eq) in EtOAc (1 mL) was added HCl in EtOAc (2.0 mL, 8 mmol, 151.07 eq) at 20° C., and then the mixture was stirred at 20° C. for 1 h. The mixture was concentrated in vacuum to give a crude product. The crude was then purified by prep-HPLC affording the title compound (10.3 mg, 0.010 mmol, 26% yield) as a white solid, as a hydrochloride salt. MS (ESI): 644.4 [M+H]+.
To a solution of acetic acid (0.01 mL, 0.120 mmol, 1.2 eq), DIPEA (0.05 mL, 0.290 mmol, 3 eq) and HATU (54.95 mg, 0.140 mmol, 1.5 eq) in THE (1 mL) was added (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one (Example 63) (47.37 mg, 0.100 mmol, 1 eq) and the reaction mixture was stirred at 25° C. for 12 h. The mixture was quenched with water (2 mL), extracted with EtOAc (3 mL×2) and purified by prep-HPLC affording the title compound (23.53 mg, 0.040 mmol, 45% yield) as a white powder. MS (ESI): 535.1 [M+H]+.
Examples 259 to 261 of the following table were prepared in analogy to Example 258, using the appropriate carboxylic acid building block.
To a solution of (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one (Example 63) (100 mg, 0.2 mmol, 1 eq), DIPEA (0.11 mL, 0.61 mmol, 3 eq) and HATU (116.01 mg, 0.3 mmol, 1.5 eq) in THE (1 mL) was added Boc-Ala-OH (0.04 mL, 0.240 mmol, 1.2 eq) and the reaction mixture was stirred at 25° C. for 12 h. The mixture was concentrated under vacuum to obtain the crude title compound (134 mg, 0.2 mmol, 79% yield) as a white solid. MS (ESI): 608.2 [M-isobuten+H]+.
Tert-butyl N-[(1S)-2-[[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]carbamate (134 mg, 0.2 mmol, 1 eq) was dissolved in HCl/EtOAc (4.0 mL, 16 mmol, 78.87 eq), the reaction mixture was stirred at 25° C. for 0.5 h. The mixture was concentrated under vacuum and purified by prep-HPLC affording the title compound (28 mg, 0.050 mmol, 23% yield) as a white powder, as a hydrochloride salt. MS (ESI): 564.2 [M+H]+.
Examples 263 to 267 of the following table were prepared in analogy to Example 262, using the appropriate carboxylic acid building block.
To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (49.5 mg, 0.24 mmol, 1.2 eq), DIPEA (0.11 mL, 0.61 mmol, 3 eq) and HATU (116 mg, 0.3 mmol, 1.5 eq) in THE (1 mL) was added (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one (Example 63, step d) (100 mg, 0.2 mmol) and the reaction mixture was stirred at 25° C. for 12 h, concentrated under vacuum to obtain the title compound (137 mg, 0.2 mmol, 85% yield) as white solid MS (ESI): 622.1 [M-isobuteneH]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(1S)-2-[[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (137 mg, 0.2 mmol, 1 eq) and was obtained as a withe powder (48 mg, 0.08 mmol, 3900 yield). MS (ESI): 578.1 [M+H]+.
Examples 269 and 270 of the following table were prepared in analogy to Example 268, using the appropriate boc-protected amino acid building block.
To a solution of methyl 2-bromo-4-fluoro-5-nitro-benzoate (28.5 g, 102.51 mmol, 1 eq) in DCE (300 mL) were added TEA (20706.4 mg, 205.01 mmol, 2 eq) and (2R)-2-(tert-butoxycarbonylamino)-3-sulfanyl-propanoic acid (34022.56 mg, 153.76 mmol, 1.5 eq) and the reaction mixture was stirred at 20° C. for 12 h. The mixture was poured into water (150 ml) and the pH was adjusted to 4 by addition of 1M HCl. The mixture was then extracted with DCM (150 mL×3) and the combined organic layers were washed with water (120 mL×2) and brine (20 mL), dried over Na2SO4 and concentrated in vacuum to give the crude title compound (50 g) as a light yellow gum which was used in next step directly. MS (ESI): 381.0 [M-isobutene-CO2+H]+.
To a solution of (2R)-3-(5-bromo-4-methoxycarbonyl-2-nitro-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (50.0 g, 104.32 mmol, 1 eq) in MeOH (300 mL) was added NiCl2 (26.66 g, 208.64 mmol, 2 eq). Then NaBH4 (7.92 g, 208.64 mmol, 2 eq) was added in portions keeping the temperature at 0° C. for 12 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give the title compound (40 g, 89.02 mmol, 85% yield) as black oil which was used in next step directly. MS (ESI): 351.0 [M-isobutene+H]+.
To a solution of (2R)-3-(2-amino-5-bromo-4-methoxycarbonyl-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (40 g, 89 mmol, 1 eq) in THE (500 mL) were added T3P (45.40 g, 178 mmol, 2 eq) and DIPEA (22.9 g, 178 mmol, 2 eq) and the reaction mixture was stirred at 25° C. for 12 h. The mixture was concentrated in vacuum to remove the solvent and the remaining residue was purified with silica gel chromatography (PE:EtOAc=10:1 to 1:1) to afford the title compound (5.6 g, 12.98 mmol, 15% yield) as light yellow solid. MS (ESI): 375.2 [M-isobutene+H]+.
To a mixture of methyl (3R)-8-bromo-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (9.0 g, 20.87 mmol, 1 eq), potassium carbonate (6.02 g, 43.53 mmol, 2.09 eq) and potassium iodide (0.62 mL, 11.65 mmol, 0.560 eq) in DMF (85.94 mL) was added dropwise a solution of 4-chlorobenzyl bromide (4.73 g, 23 mmol, 1.1 eq) at 0° C. The mixture was stirred for 16 h at 25° C. and then diluted with EtOAc (150 mL), washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to afford a crude product which was then purified by silica gel chromatography (3% to 10% EtOAc in PE) to give the title compound (7 g, 12.59 mmol, 30% yield) as an orange solid. MS (ESI): 500.4 [M-isobutene+H]+.
To a solution of methyl (3R)-8-bromo-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (7.0 g, 12.59 mmol, 1 eq) in a mixture of THF (25 mL), water (25 mL) and MeOH (25 mL) was added lithium hydroxide (0.71 mL, 75.56 mmol, 6 eq) and the reaction mixture was stirred at 25° C. for 12 h. The mixture was diluted with EtOAc (150 mL) and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated under vacuum to give the title compound (7 g, 12.92 mmol, 62% yield) as orange oil. MS (ESI): 487.0 [M-isobutene+H]+.
A mixture of (3R)-8-bromo-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (6.4 g, 11.81 mmol, 1 eq), NEt3 (2.04 mL, 23.62 mmol, 2 eq) and ethyl chloroformate (1.46 mL, 15.36 mmol, 1.3 eq) in THE (90 mL) was stirred for 1.5 h at 0° C. and then for 0.5 h at 25° C. Then the mixture was added into a solution of NH2NH2·H2O (2.92 mL, 59.06 mmol, 5 eq) in THF (34 mL) slowly at 25° C. within 1 h. Then the reaction mixture was stirred for 20 h at 25° C. To the reaction mixture was added water (20 mL) at 0° C. and the solution was stirred for 15 min. Then the mixture was concentrated in vacuo to obtain a crude product which was purified by prep-HPLC to obtain the title compound (2.38 g, 4.28 mmol, 36% yield) as a light brown solid. MS (ESI): 501.1 [M-isobutene+H]+.
To a solution of tert-butyl N-[(3R)-8-bromo-5-[(4-chlorophenyl)methyl]-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate;2,2,2-trifluoroacetic acid (2.28 g, 3.4 mmol, 1 eq), pivalic acid (461.0 mg, 4.51 mmol, 1.33 eq) and HATU (1.87 g, 4.92 mmol, 1.45 eq) in THE (65 mL) was added DIPEA (2.14 mL, 12.29 mmol, 3.61 eq) and the mixture was stirred at 25° C. for 2.5 h. The mixture was concentrated under vacuum to remove THE and the remaining residue was purified by silica gel chromatography (PE:EtOAc=5:1 to 1:1), to obtain the title compound (2.0 g, 3.13 mmol, 91% yield) as a light yellow solid. MS (ESI): 541.2 [M-isubutene-CO2+H]+.
To a solution of tert-butyl N-[(3R)-8-bromo-5-[(4-chlorophenyl)methyl]-7-[(2,2-dimethylpropanoylamino)carbamoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (1.8 g, 2.81 mmol, 1 eq) in 1,4-dioxane (36 mL) was added Burgess reagent (2.68 g, 11.25 mmol, 4 eq) at 25° C. and the mixture was heated to 80° C. for 16 h. After cooling to ambient temperature, the mixture was concentrated under vacuum to remove the dioxane and the remaining residue was purified by column chromatography (PE:EtOAc=5:1 to 1:1) to afford the title compound (2000 mg, 3.22 mmol, 99% yield) as an off-white solid. MS (ESI): 567.0 [M-isobuten+H]+.
The title compound was prepared in analogy to general method 5 from tert-butyl N-[(3R)-8-bromo-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (150.0 mg, 0.240 mmol) and was obtained (100 mg, 0.150 mmol, 47% yield) as a white solid. MS (ESI): 655.3 [M+H]+.
The title compound was prepared according to general method 6b from tert-butyl N-[(3R)-8-bromo-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (75.0 mg, 0.110 mmol) and was obtained (3.4 mg, 0.010 mmol, 5% yield) as a white solid, as a hydrochloride salt. MS (ESI): 555.1 [M+H]−.
A suspension of tert-butyl N-[(3R)-8-bromo-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 271, step h) (200.0 mg, 0.320 mmol, 1 eq), trimethylboroxine (50% in EtOAc) (0.11 mL, 0.390 mmol, 1.2 eq), Cs2CO3 (209.54 mg, 0.640 mmol, 2 eq) and Pd(dppf)Cl2 (35.29 mg, 0.050 mmol, 0.150 eq) in a mixture of 1,4-dioxane (2.8 mL) and water (0.400 mL) was degassed with nitrogen for three times and the resulting reaction mixture was heated to 110° C. for 16 h. After cooling to ambient temperature, the reaction mixture was concentrated under vacuum to remove the solvent and to the remaining residue was added EtOAc (10 mL). The mixture was filtered and the filtrate was washed with brine (5 mL×3), dried with anhydrous Na2SO4 and concentrated to give the residue which was purified by silica gel chromatography (PE:EtOAc=10:1 to 5:1) to afford the title compound (80 mg, 0.140 mmol, 44% yield) as a white solid. MS (ESI): 501.1 [M-isobuten+H]+.
The title compound was prepared in analogy to general method 5 from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100.0 mg, 0.180 mmol) and was obtained (100 mg, 0.17 mmol, 92% yield) as a white solid. MS (ESI): 533.1 [M-isobuten+H]+.
The title compound was prepared according to general method 6b from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-methyl-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (100.0 mg, 0.170 mmol) and was obtained (43.3 mg, 0.080 mmol, 48% yield) as a white solid, as a hydrochloride salt. MS (ESI): 489.1 [M+H]+.
To a solution of tert-butyl N-[(3R)-8-bromo-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] (Example 271, step h) (130.0 mg, 0.210 mmol, 1 eq) in 1,4-dioxane (1 mL) were added tris(dibenzylideneacetone)dipalladium (0) (19.14 mg, 0.020 mmol, 0.100 eq), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (17.75 mg, 0.040 mmol, 0.200 eq) and potassium hydroxide (35.18 mg, 0.630 mmol, 3 eq) at 25° C. and the reaction mixture was heated to 90° C. for 16 h. The mixture was poured into water (1.5 mL). The aqueous phase was extracted with ethyl acetate (1.5 mL×3). The combined organic phases were washed with brine (3 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The remaining residue was purified by prep-TLC (DCM/MeOH=30:1) to afford the title compound (85 mg, 0.153 mmol, 60% yield) as a light red oil. MS (ESI): 559.3 [M+H]+.
The title compound was prepared in analogy to general method 5 from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-hydroxy-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100.0 mg, 0.180 mmol) and was obtained (40 mg, 0.07 mmol, 34% yield) as a light red solid. MS (ESI): 535.2 [M-isobuten+H]+.
The title compound was prepared according to general method 6b from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-hydroxy-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (40 mg, 0.07 mmol) and was obtained (15.4 mg, 0.030 mmol, 43% yield) as a light red solid. MS (ESI): 491.3 [M+H]+.
To tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (Example 63) (60.0 mg, 0.100 mmol, 1 eq) was added dimethylamine (1.2 mL, 2.4 mmol, 23.72 eq) at 25° C. and the mixture was heated to 45° C. for 4 h. The mixture was poured into brine (2 mL). The aqueous phase was extracted with ethyl acetate (2 mL×3). The combined organic phases were washed with brine (5 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The remaining residue was purified by prep-TLC (DCM:MeOH=20:1) to afford the title compound (47 mg, 0.077 mmol, 72% yield) as a yellow oil. MS (ESI): 618.3 [M+H]+.
The title compound was prepared according to general method 6b from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-(dimethylamino)-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (40.0 mg, 0.060 mmol) and was obtained (15 mg, 0.030 mmol, 46% yield) as a light yellow solid, as a hydrochloride salt. MS (ESI): 518.3 [M+H]+.
To a solution of tert-butyl N-[(3R)-8-bromo-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 271, step h) (100.0 mg, 0.16 mmol, 1 eq) in 1,4-dioxane (1.5 mL) were added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18.61 mg, 0.03 mmol, 0.2 eq), cesium carbonate (104.77 mg, 0.32 mmol, 2 eq), tert-butyl carbamate (37.67 mg, 0.32 mmol, 2 eq) and palladium (II) acetate (3.61 mg, 0.020 mmol, 0.100 eq) under an atmosphere of nitrogen at 25° C. and the mixture was stirred for 16 h at 100° C. The mixture was poured into water (1.5 mL). The aqueous phase was extracted with ethyl acetate (2 mL×3). The combined organic phases were washed with brine (3 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The remaining residue was purified by prep-TLC (PE:EtOAc=2:1) to afford the title compound (33 mg, 0.050 mmol, 30% yield) as a white solid. MS (ESI): 658.4 [M+H]+.
The title compound was prepared in analogy to general method 5 from tert-butyl N-[(3R)-3-(tert-butoxycarbonylamino)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-8-yl]carbamate (40.0 mg, 0.060 mmol) and was obtained (40 mg, 0.060 mmol, 64% yield) as a light red solid. MS (ESI): 578.3 [M-(2×isobutene)+H]+.
The title compound was prepared according to general method 6b from tert-butyl N-[(3R)-3-(tert-butoxycarbonylamino)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-8-yl]carbamate (40.0 mg, 0.060 mmol) and was obtained (6.3 mg, 0.010 mmol, 20% yield) as an off-white solid, as a trifluoroacetic acid salt. MS (ESI): 490.2 [M+H]+.
To a solution of methyl 4-fluoro-2-methyl-5-nitro-benzoate (CAS 1163287-01-1) in MeCN was added DIPEA (Eq. 3) and N-Boc-L-Cysteine (CAS 20887-95-0) (Eq 1). The mixture was stirred for 16 hours at 48° C. The obtained residue was purified by prep-HPLC to obtain the desired product in 35% yield.
The title compound was prepared in analogy to the general procedure 2 from (2R)-2-(tert-butoxycarbonylamino)-3-(4-methoxycarbonyl-5-methyl-2-nitro-phenyl)sulfanyl-propanoic acid in dioxane:water (4:1) and was obtained in 60% yield.
To a solution of (2R)-3-(2-amino-4-methoxycarbonyl-5-methyl-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid in DMF was added DIPEA (Eq. 1.1.) and HATU (Eq. 1). The mixture was stirred at 22° C. for 16 hours. The mixture was extracted and the organic layer was washed with water. The combined organic layers were dried over sodium sulfate and evaporated in vacuo to afford the title compound in 50% yield.
The title compound was prepared in analogy to general procedure 4 from methyl (3R)-3-(tert-butoxycarbonylamino)-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (2 g, 5.46 mmol) and 1-(bromomethyl)-4-chloro-benzene (1.79 g, 8.7 mmol, 1.6 eq) and was obtained as a yellow solid (2.37 g, 79% yield). MS (ESI): 435.2 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 13 from methyl (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (2.37 g, 4.83 mmol) and was obtained as a yellow solid (2.29 g, 94% yield). MS (ESI): 475.3 [M−H]−.
The title compound was prepared in analogy to general procedure 14 from (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (1.0 g, 2.1 mmol) and was obtained as alight yellow solid (1.08 g, 94% yield). MS (ESI): 435.2 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 8a from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[[(2-cyano-2-methyl-propanoyl)amino]carbamoyl]-8-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.204 mmol) and 2-cyano-2-methyl-propionic acid (CAS 22426-30-8) (27.6 mg, 0.244 mmol) and was obtained as a colorless solid (97 mg, 77% yield). MS (ESI): 586.3 [M+H]+.
The title compound was prepared in analogy to general procedure 8a from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[[(2-cyano-2-methyl-propanoyl)amino]carbamoyl]-8-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (96 mg, 0.164 mmol) and was obtained as a white solid (39.2 mg, 40% yield). MS (ESI): 512.2 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-8-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (74.9 mg, 0.132 mmol) and was obtained as a white solid (76 mg, 91% yield). MS (ESI): 544.2 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6d tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(1-cyano-]-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-8-methyl-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (76 mg, 0.127 mmol) and was obtained as a white solid, as a hydrochloride salt (59.7 mg, 83% yield). MS (ESI): 500.2 [M+H]+.
Example 277 of the following table was prepared in analogy to Example 276, steps g-j), using the appropriate building block.
To a solution of tert-butyl N-[(3R)-7-bromo-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 6 step b) (102.8 mg, 0.2 mmol, 1.0 eq) and 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (CAS 1256359-15-5, 75.0 mg, 0.3 mmol, 1.5 eq) in a mixture of aqueous K3PO4 (2.0 M, 0.3 mL, 0.6 mmol, 3.0 eq) and dioxane (3.0 mL) was added Pd(dppf)Cl2 (7.31 mg, 0.01 mmol, 0.05 eq) under an atmosphere of nitrogen. The reaction mixture was stirred at reflux for 3 h and then concentrated under reduced pressure to remove dioxane. The remaining residue was extracted with EtOAc and the combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product which was purified by preparative TLC to give the title compound (89.3 mg, 0.16 mmol) as solid. MS (ESI): 559.2 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(1-tert-butylpyrazol-4-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (89.3 mg, 0.16 mmol) in analogy to general procedure 5 to obtain the crude title compound which was used in the next reaction step without further purification. MS (ESI): 591.3 [M+H]+.
To a solution of crude tert-butyl N-[(3R)-7-(1-tert-butylpyrazol-4-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate in DCM (3.0 mL) was added TFA (1.0 mL) and the mixture was stirred at 30° C. for 2 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to give the desired title compound (46.5 mg, 0.095 mmol). MS (ESI): 491.1 [M+H]+.
Examples 279 to 280 of the following table were prepared in analogy to Example 278, using the appropriate boronic acid ester building blocks.
3,3-difluoro-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.63 mmol) was stirred in 1,4-dioxane with 4 M HCl in dioxane (1 mL, 4 mmol, 6.33 eq). 9-fluorenylmethyl chloroformate (179 mg, 0.69 mmol, 1.1 eq) was added and stirred overnight at room temperature. The solvent was evaporated and the reaction diluted in DCM (5 mL). Et3N (192 mg, 264 μL, 1.9 mmol, 3 eq) were added, the reaction cooled to 0° C. and 9-fluorenylmethyl chloroformate (179 mg, 0.69 mmol, 1.1 eq) was added. The reaction mixture was stirred overnight at room temperature, partitioned between 50 ml DCM and 30 ml 1M aq. HCl. The phases were separated and the aqueous layer was extracted once with 30 ml DCM. The organic layers were combined, dried over Na2SO4 and filtered. The solvent was evaporated. The crude material was purified by column chromatography on silica gel (n-heptane:EtOAc=100:0 to 70:30) to afford:the title compound (156 mg, 61% yield) as white solid. MS (ESI): 360.2 [M+H]+.
To a solution of 9H-fluoren-9-ylmethyl 3,3-difluoro-5-hydroxy-piperidine-1-carboxylate (495 mg, 1.1 mmol) in DCM (10 mL) was added p-toluenesulfonyl chloride (315 mg, 1.65 mmol, 1.5 eq), Et3N (278 mg, 384 μL, 2.75 mmol, 2.5 eq) and 4-dimethylaminopyridine (134 mg, 1.1 mmol, 1 eq). The reaction was stirred at room temperature for 1 hour, partitioned between DCM (40 ml) and H2O (40 ml). The layers were separated. The aqueous layer was extracted with two 40 ml portions of DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (n-heptane:EtOAc=100:0 to 70:30), to afford the title compound (416 mg, 66% yield) as white solid. MS (ESI): 514.2 [M+H]+.
A suspension of 9H-fluoren-9-ylmethyl 3,3-difluoro-5-(p-tolylsulfonyloxy)piperidine-1-carboxylate (308 mg, 0.6 mmol, 1), 4-bromo-1H-pyrazole (99 mg, 0.66 mmol, 1.1 eq) and cesium carbonate (293 mg, 0.9 mmol, 1.5 eq) in DMF was heated at 60° C. for 1 h. The reaction mixture was partitioned between EtOAc (40 ml) and 0.5 M aqueous HCl (40 ml). The layers were separated. The organic layer was extracted with one 20 ml portion of 1M aqueous HCl. The pH of the combined aq. layer was set basic and extracted with three 50 ml portions of EtOAc:THF (1:1). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by prep-HPLC to afford the title compound (31 mg, 15% yield) as an off-white solid. MS (ESI): 266.1/268.1 [M+H]−.
A suspension of 5-(4-bromopyrazol-1-yl)-3,3-difluoro-piperidine (31 mg, 0.12 mmol) and sodium acetate (9.56 mg, 0.12 mmol, 1 eq) in DCM (1 mL) was degased with argon for 5 min and stirred for 1 h. Then formaldehyde (aq.) (12.6 mg, 11.6 uL, 0.15 mmol, 1.3 eq) was added at room temperature. Stirring was continued for 45 min. sodium triacetoxyborohydride (49 mg, 0.23 mmol, 2 eq) was added in one portion. The reaction mixture was stirred for 2 h, partitioned between EtOAc:THF (1:1) (50 ml) and sat. aqueous NaHCO3 (40 ml). The layers were separated. The aqueous layer was extracted with two 40 ml portions of EtOAc:THF (1:1). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to afford the crude title compound (20 mg, 55% yield) as light yellow oil. MS (ESI): 279.1/281.8 [M+H]+.
A suspension of N-[(3R)-5-(4-chlorobenzyl)-8-fluoro-4-keto-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (90 mg, 0.11 mmol, 1.5 eq), 5-(4-bromopyrazol-1-yl)-3,3-difluoro-1-methyl-piperidine (21 mg, 0.075 mmol) and 2 M aq. tripotassium phosphate solution (112 uL, 0.225 mmol, 3 eq) in 1,4-dioxane (0.5 mL) was degased with argon for 5 min. 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) (8.23 mg, 0.011 mmol, 0.15 eq) was added. The reaction mixture was heated at 120° C. and stirred for 3 h. The reaction mixture was partitioned between EtOAc (50 ml) and sat. aqueous NaHCO3 (40 ml). The layers were separated. The aqueous layer was extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (n-heptane:(EtOAc:EtOH:ammonia 75:25:2)=100:0 to 40:60) to afford the title compound (28.1 mg, 55% yield) as white solid. MS (ESI): 637.2 [M+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[1-(5,5-difluoro-1-methyl-3-piperidyl)pyrazol-4-yl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (28 mg, 0.044 mmol) as a white solid (36 mg, 100% yield). MS (ESI): 684.3 [M+H]+.
To a suspension of N-[(3R)-5-(4-chlorobenzyl)-7-[1-(5,5-difluoro-1-methyl-1-oxido-piperidin-1-ium-3-yl)pyrazol-4-yl]-8-fluoro-1,1,4-triketo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (36 mg, 0.039 mmol) in 1,2-dichloroethane (0.75 mL) was added phenylboronic acid (5.29 mg, 0.043 mmol, 1.1 eq) at room temperature. The reaction mixture was heated to reflux for 2 h. The reaction mixture was partitioned between DCM (40 ml) and 0.5M aqueous NaOH (40 ml). The layers were separated. The aqueous layer was extracted with EtOAc (2×40 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (DCM:MeOH=100:0 to 95:5) to afford the title compound (12.5 mg, 45% yield) as white solid. MS (ESI): 668.4 [M+H]+.
The title compound was prepared in analogy to general procedure 6d from N-[(3R)-5-(4-chlorobenzyl)-7-[1-(5,5-difluoro-1-methyl-3-piperidyl)pyrazol-4-yl]-8-fluoro-1,1,4-triketo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (11 mg, 0.016 mmol) after prep-HPLC as a yellow oil as a bis hydrochloride salt (10.2 mg, 91% yield). MS (ESI): 284.9 [M/2+H]+.
To a mixture of tert-butyl N-[(3R)-7-bromo-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 6 step b) (102.8 mg, 0.20 mmol, 1.0 eq), 4-tert-butyl-1H-pyrazole (CAS 105285-21-0, 37.2 mg, 0.3 mmol, 1.5 eq), K2CO3 (191.8 mg, 1.4 mmol, 7.0 eq) and CuI (56.7 mg, 0.3 mmol, 1.5 eq) in toluene (3.0 mL) was added trans-N, N′-dimethylcyclohexane-1,2-diamine (17.04 mg, 0.12 mmol, 0.6 eq) under an atmosphere of nitrogen and the mixture was stirred at reflux for 16 hrs. The reaction mixture was then concentrated under reduced pressure to remove toluene. To the residue was added water (5 mL) and then the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (0 to 100% EtOAc in PE) to give the title compound (62.13 mg, 0.11 mmol) as solid. MS (ESI). 559.3 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(4-tert-butylpyrazol-1-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (62.13 mg, 0.11 mmol) in analogy to general procedure 5 to obtain the crude title compound which was used in the next reaction step without further purification. MS (ESI): 591.3 [M+H]+.
The title compound (22.6 mg, 0.046 mmol) was prepared in analogy to Example 278, step c) from crude tert-butyl N-[(3R)-7-(4-tert-butylpyrazol-1-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate. MS (ESI): 491.2 [M+H]+.
Examples 283 to 284 of the following table were prepared in analogy to Example 282, using the appropriate pyrazole building blocks.
To a solution of tert-butyl N-[(3R)-7-bromo-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 6 step b) (2 g, 3.88 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.97 g, 7.75 mmol, 2 eq) in dioxane (6 mL) were added KOAc (1.14 g, 11.63 mmol, 3 eq) and Pd(dppf)Cl2CH2Cl2 (316.63 mg, 388 μmol, 0.1 eq) under an atmosphere of nitrogen and the mixture was stirred at 80° C. for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (0 to 50% EtOAc in PE) to obtain a still crude title compound (2.3 g) as a yellow solid which was used as such in the next reaction step. MS (ESI): 507.2 [M-isobutene+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (140.8 mg, 0.25 mmol, 1.0 eq) and 3-bromo-1-ethyl-1,2,4-triazole (57.2 mg, 0.325 mmol, 1.3 eq) in a mixture of aqueous K3PO4 (2.0 M, 0.375 mL, 0.75 mmol, 3.0 eq) and dioxane (4.0 mL) was added Pd(dppf)Cl2 (27.4 mg, 0.04 mmol, 0.15 eq) under an atmosphere of nitrogen and the reaction mixture was stirred at reflux for 3 h. Then water (4 mL) was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound, which was used in the next reaction step as such. MS (ESI): 532.2 [M+H]+.
The title compound was prepared from crude tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(1-ethyl-1,2,4-triazol-3-yl)-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate in analogy to general procedure 5 to obtain the crude title compound which was used in the next reaction step without further purification. MS (ESI): 508.1 [M-isobutene+H]+.
The title compound (6.68 mg, 0.014 mmol) was prepared in analogy to Example 278, step c) from crude tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(1-ethyl-1,2,4-triazol-3-yl)-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate. MS (ESI): 464.1 [M+H]+.
Examples 286 to 287 of the following table were prepared in analogy to Example 285, using the appropriate bromo pyrazole or bromo triazole building blocks.
[3-(trifluoromethyl)pyrazin-2-yl]amine (1 g, 6.13 mmol) was combined with N-(thioxomethylene)carbamic acid ethyl ester (964 mg, 869 μL, 7.36 mmol, 1.2 eq) in 1,4-dioxane (10 mL) and the reaction was stirred at room temperature over night. N-(thioxomethylene)carbamic acid ethyl ester (964 mg, 869 μL, 7.36 mmol, 1.2 eq) was added again and stirring at room temperature was continued for another night. The reaction was heated to 60° C. and stirring was continued overnight. The solvent was evaporated, the mixture was purified by column chromatography on silica gel (heptane;EtOAc=1:0 to 1:1) affording the title compound (1.87 g, 92% yield) as light brown oil. MS (ESI): 295.0 [M+H]+.
Ethyl N-[[3-(trifluoromethyl)pyrazin-2-yl]carbamothioyl]carbamate (1.87 g, 5.66 mmol) was combined with hydroxylamine hydrochloride (707 mg, 10.2 mmol, 1.8 eq) and DIPEA (2.19 g, 2.96 mL, 16.97 mmol, 3 eq) in EtOH (14 mL) and MeOH (14 mL). The reaction was heated to 65° C. and stirred overnight. The solvent was partly evaporated, the precipitate was filtered off and washed with DCM/MeOH (98:2). The white solid was dried in vacuo affording the title compound (1.04 g, 90% yield) as grey solid. MS (ESI): 204.0 [M+H]+.
tert-butyl nitrite (380 mg, 439 μL, 3.69 mmol, 1.5 eq) and copper(I) bromide (529 mg, 3.69 mmol, 1.5 eq) were combined in MeCN (12.5 mL) and the dark green mixture was heated to 60° C. [8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]amine (500 mg, 2.46 mmol) was added, the reaction was heated to 80° C. and stirred overnight. Copper(II) bromide (412 mg, 1.85 mmol, 0.75 eq) was added and stirring was continued for 1 h at 80° C. The solvent was evaporated. The crude residue was purified by column chromatography on silica gel (heptane;EtOAc=1:0 to 1:1) affording the title compound (426 mg, 60% yield) as a white solid. MS (ESI): 268.9 [M+H]+.
tert-butyl N-[(3R)-7-bromo-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (300 mg, 0.77 mmol) was stirred with 1-(bromomethyl)-4-(trifluoromethoxy)benzene (215 mg, 134 μL, 0.843 mmol, 1.1 eq), potassium carbonate (318 mg, 2.3 mmol, 3 eq) and potassium iodide (63.64 mg, 0.383 mmol, 0.5 eq) in DMSO (6 mL) at RT overnight. 0.5eq of 1-(bromomethyl)-4-(trifluoromethoxy)benzene was added again and stirring was continued for 2 h. The crude material was purified by column chromatography (heptane;EtOAc=1:0 to 0:1) affording the title compound (433 mg, 99%) as colorless foam. MS (ESI): 510.9 [M-isobutene+H]+.
tert-butyl N-[(3R)-7-bromo-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (430 mg, 0.76 mmol) was stirred with 3-chloroperoxybenzoic acid (426 mg, 1.9 mmol, 2.5 eq) in DCM (7 mL) at RT overnight. The crude material was purified by column chromatography (heptane;EtOAc=1:0 to 0:1) affording the title compound (510 mg, 88% yield) as a white solid. MS (ESI): 543.0 [M+H]+.
tert-butyl N-[(3R)-7-bromo-8-fluoro-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (250 mg, 0.33 mmol) was stirred with bis(pinacolato)diboron (184.7 mg, 0.727 mmol, 2.2 eq), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane adduct (31 mg, 0.038 mmol, 0.115 eq) and potassium acetate (97.3 mg, 0.99 mmol, 3 eq) in 1,4-dioxane (4.5 mL) at 100° C. for 1 h in a closed vial. Water was added and extracted three times with EtOAc. The organic layer was dried over magnesium sulfate, filtered and evaporated, affording the crude title compound (510 mg) as light brown solid. MS (ESI): 507.1 [M-isobutene+H]+.
[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6, 5-benzothiazepin-7-yl]boronic acid (315 mg, 0.56 mmol), 2-bromo-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrazine (Intermediate 15) (149 mg, 0.560 mmol), Na2CO3 (178 mg, 1.68 mmol, 3 eq) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (68.6 mg, 0.084 mmol, 0.15 eq) in 1,4-dioxane (11.6 mL) and water (2.32 mL) in a sealed tube was heated to 100° C. for 3.5 h. The solvent was evaporated, the crude residue purified by column chromatography on silica gel (heptane;EtOAc=1:0 to 1:1) affording the title compound (75 mg, 18% yield) as light yellow solid. MS (ESI): 649.2 [M-isobutene+H]+.
tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-7-[8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (65 mg, 0.093 mmol) was hydrogenated under H2 at 50 bar using 5% Pt/C as catalyst. The reaction was shaken overnight at 80° C. The catalyst was filtered off, washed and the solvent was evaporated and dried under high vacuum affording the title compound (49 mg, 59% yield) as light yellow solid. MS (ESI): 653.1 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-7-[8-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (47 mg, 0.066 mmol) and was obtained as a white solid (20 mg, 49% yield). MS (ESI): 609.3 [M+H]+.
A mixture of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-cyano-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 7 step a) (200.0 mg, 0.430 mmol, 1 eq), K2CO3 (155.58 mg, 1.13 mmol, 2.6 eq) and hydroxylamine hydrochloride (78.22 mg, 1.13 mmol, 2.6 eq) in DMF (5 mL) was stirred at 80° C. for 16 h. The reaction mixture was cooled to room temperature and EtOAc (10 mL) and H2O (10 mL) were added. The layers were separated and the organic layer was washed with brine (10 mL×3) and dried over Na2SO4, filtered and concentrated. The remaining residue was purified by silica gel chromatography (0 to 20% EtOAc in PE) to afford the crude product (150 mg) as a light yellow solid, which was then further purified by prep-TLC (PE.EtOAc=1:1) to afford the title compound (40 mg, 0.080 mmol, 18% yield) as a light yellow solid. MS (ESI): 439.0 [M-isubutene+H]+.
To a solution of pivalic acid (39.62 mg, 0.390 mmol, 1.2 eq) in MeCN (4 mL) were added EDCI (80.56 mg, 0.420 mmol, 1.3 eq) and HOBT (64.35 mg, 0.420 mmol, 1.3 eq) at 25° C. After the mixture stirred for 0.5 h at 25° C., DIPEA (0.11 mL, 0.650 mmol, 2 eq) and tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-[(Z)-N′-hydroxycarbamimidoyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (160 mg, 0.323 mmol) were added and the mixture was stirred for 3 h at 25° C. After that, the mixture was heated to 80° C. and stirred for another 24 h. The reaction mixture was concentrated under vacuum, the residue was diluted with EtOAc (5 mL), washed with brine (5 mL×3), dried over anhydrous Na2SO4 and concentrated under vacuum. The remaining residue was purified by column chromatography on silica gel (PE:EtOAc=10:1 to 2:1) to obtain the title compound (160 mg, 0.290 mmol, 88% yield) as a light brown gum. MS (ESI): 505.1 [M-isubutene+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (160 mg, 0.285 mmol) in analogy to general procedure 5 and was obtained as light yellow solid (150 mg, 86%). MS (ESI): 537.3 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (150 mg, 0.253 mmol) and was obtained as a white solid (37 mg, 29% yield). MS (ESI): 493.1 [M+H]+.
Examples 290 to 303 of the following table was prepared in analogy to Example 289, using the appropriate carboxylic acid building block.
The title compound was prepared in analogy to general procedure 9a from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 289, step a)) (703 mg, 1.21 mmol, 1 eq) and 1-benzyloxycarbonyl-4-methyl-piperidine-4-carboxylic acid (CAS 203522-12-7) and was obtained as a white solid (764 mg, 82% yield). MS (ESI): 636.2 [M-isobutene-CO2+H]+.
The title compound was prepared in analogy to general procedure 5 from benzyl 4-[3-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-4-methyl-piperidine-1-carboxylate (764 mg, 1.04 mmol, 1 eq) and was obtained as a white solid (596 mg, 70% yield). MS (ESI): 668.3 [M-isobutene-CO2+H]+.
A solution of benzyl 4-[3-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-4-methyl-piperidine-1-carboxylate (596 mg, 0.729 mmol, 1 eq) in MeOH (15 mL) was purged with argon three times. Then Pd/C (38.8 mg, 0.036 mmol, 0.05 eq) was added and the mixture was stirred for 60 min under an atmosphere of hydrogen gas. The mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated in vacuo and the remaining was purified by column chromatography on silica gel (DCM/MeOH 100:0 to 90:10) to afford the title compound (317 mg, 67%) as white solid. MS (ESI): 634.3 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(4-methyl-4-piperidyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50 mg, 0.079 mmol, 1 eq) and pyridine (18.71 mg, 19.13 μL, 0.237 mmol, 3 eq) in 1,2-dichloroethane (1.25 mL) was added triphosgene (16.38 mg, 0.055 mmol, 0.700 eq) at 0° C. in one portion. The cooling bath was removed and stirring was continued for 2 h. Methylamine (2M in THF, 118.27 μL, 0.237 mmol, 3 eq) was added and the mixture was stirred for 1 h. The reaction mixture was partitioned between DCM (50 mL) and water (25 mL) and the layers were separated.
The aqueous layer was extracted with two 20 mL portions of DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The remaining material was purified by column chromatography on silica gel (DCM/MeOH 100:0 to 95:5) to afford the title compound (6.5 mg, 11% yield) as white solid as a hydrochloride salt. MS (ESI): 691.3 [M+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-[4-methyl-1-(methylcarbamoyl)-4-piperidyl]-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (6.5 mg, 0.009 mmol, 1 eq) and was obtained as a white solid (4.5 mg, 76% yield). MS (ESI): 591.2 [M+H]+.
Example 305 of the following table was prepared in analogy to Example 304, using the appropriate amine building block.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(4-methyl-4-piperidyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (Example 304, step c)) (20 mg, 0.032 mmol, 1 eq) in MeOH (0.297 mL) were added acetaldehyde (13.89 mg, 17.81 μL, 0.315 mmol, 10 eq) and sodium triacetoxyborohydride (66.85 mg, 0.315 mmol, 10 eq). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and the mixture was extracted with DCM (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (EtOAc in heptane, 0 to 100% EtOAc) to afford the title compound (12.1 mg, 56% yield) as orange solid. MS (ESI): 662.4 [M+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(1-ethyl-4-methyl-4-piperidyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (12.1 mg, 0.018 mmol, 1 eq) and was obtained as a hydrochloride salt as a brown solid (10 mg, 85% yield). MS (ESI): 562.2 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(4-methyl-4-piperidyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (Example 304, step c) (20 mg, 0.032 mmol, 1 eq) in DCM (0.631 mL) were added methyl chloroformate (3.28 mg, 2.69 μL, 0.035 mmol, 1.1 eq) and DIPEA (10.1 mg, 13.77 μL, 0.079 mmol, 2.5 eq) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured on water and extracted with DCM. The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered and evaporated in vacuo affording the title compound (22.5 mg, 100% yield) as white solid. MS (ESI): 592.2 [M-isobutene-CO2+H]+.
The title compound was prepared in analogy to general procedure 6d from methyl 4-[3-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-4-methyl-piperidine-1-carboxylate (22.5 mg, 0.033 mmol, 1 eq) and was obtained as a hydrochloride salt as an off-white solid (18.2 mg, 89% yield). MS (ESI): 592.3 [M+H]+.
The title compound was prepared in analogy to general procedure 10a from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 289, step a)) (150 mg, 0.270 mmol, 1 eq) and 4-methyl-1-(2,2,2-trifluoroethyl)piperidine-4-carboxylic acid (CAS 1340224-92-1) and was obtained as a light red solid (96 mg, 51% yield). MS (ESI): 703.3 [M+H]+.
The title compound was prepared in analogy to general procedure 11b from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]methylene]amino] 4-methyl-1-(2,2,2-trifluoroethyl)piperidine-4-carboxylate (96 mg, 0.137 mmol, 1 eq) and was obtained as a red solid (81.1 mg, 86% yield). MS (ESI): 684.3 [M+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-[4-methyl-1-(2,2,2-trifluoroethyl)-4-piperidyl]-1,2,4-oxadiazol-3-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (81.1 mg, 0.117 mmol, 1 eq) and was obtained as a light yellow solid (12.7 mg, 15% yield). MS (ESI): 716.4 [M+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-[4-methyl-1-oxido-1-(2,2,2-trifluoroethyl)piperidin-1-ium-4-yl]-1,2,4-oxadiazol-3-yl]-1,4-dioxo-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (12 mg, 0.017 mmol, 1 eq) and was obtained as a hydrochloride salt as an light yellow solid (18.2 mg, 89% yield). MS (ESI): 616.3 [M+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-[4-methyl-1-(2,2,2-trifluoroethyl)-4-piperidyl]-1,2,4-oxadiazol-3-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 308, step b) (81.1 mg, 0.117 mmol, 1 eq) and was obtained as a light yellow solid (8.1 mg, 9.4% yield). MS (ESI): 732.3 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-[4-methyl-1-oxido-1-(2,2,2-trifluoroethyl)piperidin-1-ium-4-yl]-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (8 mg, 0.011 mmol, 1 eq) in 1,2-dichloroethane (0.320 mL) was added phenylboronic acid (1.47 mg, 0.012 mmol, 1.1 eq) and the reaction mixture was heated to 85° C. for 1 h. The solution was concentrated and the remaining residue was purified by preparative TLC (heptane/EtOAc 1:1) affording the title compound (7.7 mg, 98%) as white solid. MS (ESI): 716.4 [M+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-[4-methyl-1-(2,2,2-trifluoroethyl)-4-piperidyl]-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (7.7 mg, 0.011 mmol, 1 eq) and was obtained as a hydrochloride salt as a white solid (5.7 mg, 79% yield). MS (ESI): 616.3 [M+H]+.
The title compound was prepared in analogy to general procedure 12 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-cyano-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (Example 8 step a) (2.05 g, 3.24 mmol, 1 eq) and was obtained as a yellow foam (1.47 g, 76% yield). MS (ESI): 471.2 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 10a from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50 mg, 0.083 mmol, 1 eq) and 4-methylpyridine-3-carboxylic acid (CAS 3222-50-2) and was obtained as a yellow oil (1.47 g, 76% yield). MS (ESI): 646.15 [M+H]+.
To a solution of [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]methylene]amino] 4-methylpyridine-3-carboxylate (80.6 mg, 0.110 mmol, 1 eq) in THE (1.82 mL) was added TBAF (1M in THF, 164.7 μL, 0.165 mmol, 1.5 eq) at room temperature and the mixture was stirred for 2 h at room temperature. Then water and EtOAc were added and the layers were separated. The aqueous layer was extracted twice with EtOAc and the combined organic layers were washed with brine, dried over MgSO4 and concentrated. The remaining residue was purified by column chromatography on silica gel (EtOAc in heptane 0 to 70%) to afford the title compound (31.3 mg, 45%) as white solid. MS (ESI): 628.3 [M+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(4-methyl-3-pyridyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (31.3 mg, 0.050 mmol, 1 eq) and was obtained as a hydrochloride salt as a white solid (21.3 mg, 74% yield). MS (ESI): 528.1 [M+H]+.
The examples 311 to 314 of the following table were prepared in analogy to Example 310, using the appropriate carboxylic acid building block.
The title compound was prepared in analogy to general procedure 9a from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 289, step a)) (150 mg, 0.3 mmol, 1 eq) and 3-tert-butoxycarbonyl-3-azabicyclo[3.1.1]heptane-1-carboxylic acid (CAS 1000931-22-5) and was obtained as a white solid (120 mg, 57% yield). MS (ESI): 722.3 [M+Na]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (120 mg, 0.170 mmol, 1 eq) and was obtained as a white solid (125 mg, 98% yield). MS (ESI): 754.3 [M+Na]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (125 mg, 0.170 mmol, 1 eq) and was obtained as a dihydrochloride salt as a white solid (100 mg, 97% yield). MS (ESI): 532.2 [M+H]+.
To a solution of (3R)-3-amino-7-[5-(3-azabicyclo[3.1.1]heptan-1-yl)-1,2,4-oxadiazol-3-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one;dihydrochloride (70.0 mg, 0.120 mmol, 1 eq) in DCM (5 mL) were added DIPEA (49.0 mg, 0.380 mmol, 3.28 eq) and ethyl chloroformate (12.0 mg, 0.110 mmol, 0.960 eq) and the mixture was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo and the remaining residue was purified by prep. HPLC affording the title compound (26.2 mg, 0.040 mmol, 37% yield) as white solid. MS (ESI): 604.2 [M+H]+.
The examples 316 and 317 of the following table were prepared in analogy to Example 315, using the appropriate chloroformate building block.
The title compound was prepared in analogy to general procedure 10a from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (Example 310, step a) (80 mg, 0.152 mmol, 1 eq) and 1-(trifluoromethyl)cyclopropanecarboxylic acid (CAS 277756-46-4) and was obtained as a yellow oil (120 mg, 115.6% yield). MS (ESI): 607.0 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 11a [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]methylene]amino] 1-(trifluoromethyl)cyclopropanecarboxylate (100 mg, 0.150 mmol, 1 eq) and was obtained as a yellow oil (80 mg, 64% yield). MS (ESI): 589.0 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-[5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (80 mg, 0.120 mmol, 1 eq) and was obtained as a hydrochloride salt as a white solid (42.5 mg, 59% yield). MS (ESI): 545.0 [M+H]+.
The examples 319 and 320 of the following table were prepared in analogy to Example 318, using the appropriate carboxylic acid building block.
To a solution of 2,4-difluoro-5-nitro-benzonitrile (9.4 g, 50 mmol) and (tert-butoxycarbonyl)-L-cysteine (11.07 g, 50 mmol) in DCM (157 mL) was added DIPEA (17.48 mL, 100 mmol, Eq: 2). The reaction mixture was stirred for 24 hours at 22° C., diluted with DCM (40 mL) and washed once with 1N aqueous HCl solution and extracted twice with DCM. The combined organic layers were washed with brine solution, dried over sodium sulfate, filtrated and concentrated in vacuo to yield the title compound as a yellow solid (23.5 g, 118% yield). MS (ESI): 286.1 [M-CO2-isobutene+H]+.
The title compound was prepared in analogy to general procedure 2 from (2R)-2-(tert-butoxycarbonylamino)-3-(4-cyano-5-fluoro-2-nitro-phenyl)sulfanyl-propanoic acid (23 g, 57.9 mmol) and was obtained as a black solid (23 g, 48.1 mmol, 80% yield). MS (ESI): 300.1 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 3 from (2R)-3-(2-amino-4-cyano-5-fluoro-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (23 g, 48.1 mmol) and was obtained as a light yellow solid (8.4 g, 24.9 mmol, 48% yield). MS (ESI): 282.1 [M-isobutene+H]+.
To a solution of tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate(2R)-3-(2-amino-4-cyano-5-fluoro-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (200 mg, 0.59 mmol) in MeOH (2 mL) were added hydroxylamine hydrochloride (63.7 mg, 0.89 mmol, Eq: 1.5) and sodium bicarbonate (249 mg, 2.96 mmol, Eq: 5). The mixture was stirred for 16 hours at 70° C., cooled to 22° C., filtered and the filter cake was washed with DCM. The combined filtrates were concentrated in vacuo. The reaction was diluted with DCM and washed with water and brine. The organic layer was then dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (444 mg, 1.19 mmol, 74% yield) as yellow solid. MS (ESI): 315.1 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 10c from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 321, step d)) (100 mg, 0.270 mmol, 1 eq) and 2-cyano-2-methyl-propanoic acid (CAS 22426-30-8) and was obtained as a white solid (13.2 mg, 11% yield). MS (ESI): 410.1 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 11b from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]methylene]amino] 2-cyano-2-methyl-propanoate (13 mg, 0.028 mmol, 1 eq) and was obtained as a light yellow solid (9.4 mg, 72% yield). MS (ESI): 392.1 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 4 from tert-butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (9.4 mg, 0.02 mmol, 1 eq) and was obtained as a white solid (7 mg, 55% yield). MS (ESI): 516.1 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(1-cyano-1-methyl-ethyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (7 mg, 0.011 mmol, 1 eq) and was obtained as a white solid (5 mg, 64% yield). MS (ESI): 548.1 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(1-cyano-1-methyl-ethyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (5 mg, 0.007 mmol, 1 eq) and was obtained as a hydrochloride salt as a white solid (5 mg, 118% yield). MS (ESI): 504.2 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 289, step a)) (223 mg, 0.266 mmol, 1 eq) in 1,2-dichloroethane (4 mL) was added 5-methyl-1,3,4-oxadiazole-2-carbonyl chloride (CAS 889131-28-6) (77.9 mg, 0.53 mmol, 2 eq) as a solution in1,2-dichloroethane (4 mL) at 0-5° C. The ice bath was removed and the reaction mixture was stirred for 3 h. The reaction mixture was partitioned between DCM and sat. NaHCO3 solution and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The remaining residue was purified by column chromatography on silica gel (n-heptane/EtOAc 100:0 to 20:80) affording the title compound (65.4 mg, 40% yield) as light yellow solid. MS (ESI): 603.4 [M−H]−.
The title compound was prepared in analogy to general procedure 11a from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]methylene]amino] 5-methyl-1,3,4-oxadiazole-2-carboxylate (65.4 mg, 0.107 mmol, 1 eq) and was obtained as a white solid (43.3 mg, 38% yield). MS (ESI): 531.2 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,2,4-oxadiazol-3-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (43.3 mg, 0.074 mmol, 1 eq) and was obtained as a white solid (16.9 mg, 37% yield). MS (ESI): 617.3 [M−H]−.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (16.9 mg, 0.027 mmol, 1 eq) and was obtained as hydrochloride as a white solid (12.5 mg, 78% yield). MS (ESI): 519.2 [M+H]+.
The title compound was prepared in analogy to general procedure 10c from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 289, step a)) (80 mg, 0.158 mmol) and 1-benzyloxycarbonyl-5,5-difluoro-piperidine-3-carboxylic acid (CAS 1356338-81-2) and was obtained as a white solid (105 mg, 79% yield). MS (ESI): 776.3 [M+H]+.
The title compound was prepared in analogy to general procedure 11b from O3-[(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]methylene]amino] 01-benzyl 5,5-difluoropiperidine-1,3-dicarboxylate (100 mg, 0.120 mmol, 1 eq) and was obtained as a white solid (58 mg, 63% yield). MS (ESI): 658.2 [M-isobutene-CO2+H]+.
The title compound was prepared in analogy to general procedure 5 from benzyl 5-[3-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3,3-difluoro-piperidine-1-carboxylate (58 mg, 0.075 mmol, 1 eq) and was obtained as an off-white solid (57 mg, 83% yield). MS (ESI): 690.2 [-isobutene-CO2+H]+.
To a solution of benzyl 5-[3-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3,3-difluoro-piperidine-1-carboxylate (57 mg, 0.072 mmol, 1 eq) in MeOH (0.721 mL) was added Pd/C (16 mg). The suspension was carefully degassed and then recharged with argon (3 times). The same procedure was repeated but with recharging with hydrogen and the reaction was stirred for 4 h under an atmosphere of hydrogen. The reaction mixture was filtered through a plug of celite and the celite plug was washed with MeOH. The filtrate was concentrated and the remaining residue was purified by column chromatography on silica gel (0 to 100% EtOAc in heptane) affording the title compound (21 mg, 37% yield) as white solid. MS (ESI): 656.2 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-3-piperidyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (21 mg, 0.027 mmol, 1 eq) in MeOH (0.672 mL) were added formaldehyde aqueous solution (37%) (21.82 mg, 26.78 μL, 0.269 mmol, 10 eq) and sodium triacetoxyborohydride (56.9 mg, 0.269 mmol, 10 eq) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and the mixture was extracted with DCM (3 times). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo and the remaining residue was purified by column chromatography on silica gel (EtOAc in heptane) to afford the title compound (14 mg, 72% yield) as white solid. MS (ESI): 670.2 [M+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-1-methyl-3-piperidyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (14 mg, 0.019 mmol, 1 eq) and was obtained as a white solid (6 mg, 5400 yield). MS (ESI): 570.2 [M+H]+.
The example 324 of the following table were prepared in analogy to Example 323, using the appropriate carboxylic acid building block.
The title compound was prepared in analogy to general procedure 9c from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 289, step a)) (159 mg, 0.321 mmol, 1 eq) and 2-(dimethylamino)acetic acid (CAS 1118-68-9) and was obtained as a light yellow oil (140 mg, 78% yield). MS (ESI): 562.1 [M+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (120 mg, 0.214 mmol, 1 eq). The compound was obtained as a crude product (light yellow solid, 268 mg) and was used as such in the next reaction step. MS (ESI): 610.4 [M+H]+.
To the solution of 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-N,N-dimethyl-methanamine oxide (300 mg, 0.49 mmol, 1 eq) in 1,2-dichloroethane (3 mL) was added phenylboronic acid (149.9 mg, 1.23 mmol, 2.5 eq) at 25° C. and the mixture was heated to 80° C. for 0.5 h. The reaction mixture was concentrated under vacuum and the remaining residue was purified by column chromatography on silica gel (40% to 80% EtOAc in PE) to afford the title compound (34 mg, 0.06 mmol, 12% yield) as a white solid. MS (ESI): 594.4 [M+H]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (34 mg, 0.057 mmol, 1 eq) and was obtained as a white solid (11.3 mg, 40% yield). MS (ESI): 494.0 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (Example 310, step a)) (100.0 mg, 0.190 mmol, 1 eq) in DCM (2 mL) were added 2,2,3,3,3-pentafluoropropanoyl 2,2,3,3,3-pentafluoropropanoate (CAS 356-42-3) (0.19 mL, 0.950 mmol, 5 eq) and TEA (0.08 mL, 0.570 mmol, 3 eq) at 0° C. and the mixture was stirred for 16 h at 20° C. The mixture was concentrated under vacuum to remove DCM, then diluted with water (3 mL) and extracted with EtOAc (2 mL×3). The organic extracts were dried over Na2SO4 and concentrated and the remaining residue was purified by column chromatography on silica gel (4% to 40% EtOAc in PE) to afford the title compound (60 mg, 40% yield) as colorless oil. MS (ESI): 599.0 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-[5-(1,1,2,2,2-pentafluoroethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (60 mg, 0.092 mmol, 1 eq) and was obtained as hydrochloride salt as a white solid (17.3 mg, 34% yield). MS (ESI): 555.0 [M+H]+.
To a solution of 2-(2-prop-2-ynoxyethoxy)ethanol (CAS 7218-43-1) (1.0 g, 6.94 mmol, 1 eq) in THE (40 mL) was added NaH (60% in mineral oil, 305.2 mg, 7.6 mmol, 1.1 eq) at 0° C. and the mixture was stirred for 0.5 h at 0° C. Then ethyl 5-bromo-2,2-dimethyl-pentanoate (CAS 77858-42-5) (1.64 g, 6.94 mmol, 1 eq) and NaI (103.97 mg, 0.690 mmol, 0.1 eq) were added at 0° C. The reaction mixture was stirred at 20° C. for 0.5 h and then at 70° C. for 16 h. The mixture was diluted in water (10 mL) and extracted with EtOAc (10 ml×3). The combined extracts were dried over Na2SO4 and concentrated and the remaining residue was purified by column chromatography on silica gel (4% to 80% EtOAc in PE) to afford the title compound (450 mg, 19% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ=4.21 (d, J=2.3 Hz, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.72-3.68 (m, 4H), 3.66-3.62 (m, 2H), 3.60-3.56 (m, 2H), 3.43 (t, J=5.8 Hz, 2H), 2.43 (t, J=2.3 Hz, 1H), 1.57-1.51 (m, 4H), 1.24 (t, J=7.2 Hz, 3H), 1.16 (s, 6H).
To a mixture of ethyl 2,2-dimethyl-5-[2-(2-prop-2-ynoxyethoxy)ethoxy]pentanoate (200 mg, 0.67 mmol, 1 eq) in MeOH (4 mL) was added a solution of KOH (149.41 mg, 2.66 mmol, 4 eq) in water (2 mL) under an atmosphere of nitrogen at 15° C. and the mixture was stirred for 16 h at 20° C. The mixture was concentrated under vacuum to remove the MeOH and the pH was adjusted to 2-3 by addition of 1N HCl. The mixture was then extracted with EtOAc (5 mL×3) and the combined extracts were dried over Na2SO4 and concentrated under vacuum to afford the title compound (190 mg, 94% yield) as yellow oil. MS (ESI): 271.0 [M−H]−.
The title compound was prepared in analogy to general procedure 10b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (Example 310, step a)) (250 mg, 0.474 mmol, 1 eq) and 2,2-dimethyl-5-[2-(2-prop-2-ynoxyethoxy)ethoxy]pentanoic acid (167.96 mg, 0.620 mmol, 1.3 eq) (Example 327, step b)) and was obtained as a red solid (140 mg, 78% yield). MS (ESI): 781.1 [M+H]+.
The title compound was prepared in analogy to general procedure 11a from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]methylene]amino] 2,2-dimethyl-5-[2-(2-prop-2-ynoxyethoxy)ethoxy]pentanoate (100 mg, 0.128 mmol, 1 eq) and was obtained as a yellow oil (40 mg, 36% yield). MS (ESI): 707.0 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-[1,1-dimethyl-4-[2-(2-prop-2-ynoxyethoxy)ethoxy]butyl]-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (150 mg, 0.197 mmol, 1 eq) and was obtained as hydrochloride salt as a white solid (72 mg, 52% yield). MS (ESI): 663.0 [M+H]+.
The title compound was prepared in analogy to general procedure 12 from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 30, step a)) (324 mg, 0.633 mmol, 1 eq) and was obtained as a yellow solid (300 mg, 65% yield). MS (ESI): 545.2 [M+H]+.
The title compound was prepared in analogy to general procedure 9c from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.138 mmol, 1 eq) and 2-(dimethylamino)-2-keto-acetic acid (19.4 mg, 0.165 mmol, 1.2 eq) and was obtained as an orange solid (20.3 mg, 20% yield). MS (ESI): 624.2 [M−H]−.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-7-[5-(dimethylcarbamoyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (20.2 mg, 0.032 mmol, 1 eq) and was obtained as a white solid (20.3 mg, 20% yield). MS (ESI): 656.2 [M−H]−.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-7-[5-(dimethylcarbamoyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6, 5-benzothiazepin-3-yl]carbamate (12.3 mg, 0.019 mmol, 1 eq) and was obtained as hydrochloride salt as a white solid (9.4 mg, 79% yield). MS (ESI): 558.3 [M+H]+.
The examples 329 and 330 of the following table were prepared in analogy to Example 328, using the appropriate carboxylic acid building block.
The title compound was prepared in analogy to general procedure 12 from tert-butyl N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (Example 30, step b)) (766 mg, 1.41 mmol, 1 eq) and was obtained as a light yellow foam (479.1 mg, 59% yield). MS (ESI): 577.3 [M+H]+.
The title compound was prepared in analogy to general procedure 10a from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (250 mg, 0.434 mmol, 1 eq) and 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-methyl-propanoic acid (CAS 1900683-56-8). The compound was obtained as a crude product as a light brown oil (546.4 mg) and was used as such in the next reaction step. MS (ESI): 816.5 [M+H]+.
The title compound was prepared in analogy to general procedure 11a from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]methylene]amino] 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-methyl-propanoate (540 mg, 0.662 mmol, 1 eq) and was obtained as a light brown oil (111.7 mg, 21% yield). MS (ESI): 796.4 [M−H]−.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-2,2,2-trifluoro-1-methyl-ethyl]carbamate (112 mg, 0.140 mmol, 1 eq) and was obtained as dihydrochloride salt as a white solid (69.6 mg, 7400 yield). MS (ESI): 598.3 [M+H]+.
The examples 332 and 333 of the following table were prepared in analogy to Example 331, using the appropriate carboxylic acid building block.
To a solution of tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 328, step a)) (103 mg, 0.189 mmol, 1 eq) and pyridine (44.99 mg, 46.01 μL, 0.569 mmol, 3.01 eq) in 1,2-dichloroethane (3.54 mL) was added 5-methyl-1,3,4-oxadiazole-2-carbonyl chloride (CAS 889131-28-6) (41.58 mg, 0.284 mmol, 1.5 eq) as a solution in 1,2-dichloroethane (3.54 mL) at 0-5° C. The ice bath was removed and the reaction mixture was stirred for 2 h. The mixture was partitioned between DCM and sat. NaHCO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo affording the title compound (36 mg, 28%) as light yellow solid. MS (ESI): 653.4 [M−H]−.
The title compound was prepared in analogy to general procedure 11a from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]methylene]amino] 5-methyl-1,3,4-oxadiazole-2-carboxylate (36 mg, 0.052 mmol, 1 eq) and was obtained as a white solid (16 mg, 48% yield). MS (ESI): 635.5 [M−H]−.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-8-fluoro-7-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,2,4-oxadiazol-3-yl]-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (6 mg, 0.025 mmol, 1 eq) and was obtained as a white solid (12.7 mg, 73% yield). MS (ESI): 667.3 [M−H]−.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-8-fluoro-7-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6, 5-benzothiazepin-3-yl]carbamate (12.7 mg, 0.018 mmol, 1 eq) and was obtained as hydrochloride salt as a light brown solid (10.8 mg, 91% yield). MS (ESI): 569.6 [M+H]+.
The title compound was prepared in analogy to general procedure 10a from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 328, step a)) (90 mg, 0.17 mmol, 1 eq) and 3-tert-butoxycarbonyl-3-azabicyclo[3.1.1]heptane-1-carboxylic acid (CAS 1000931-22-5) and was obtained as a yellow oil (120 mg, 95% yield). MS (ESI): 768.3 [M+H]+.
The title compound was prepared in analogy to general procedure 11a from 01-[(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]methylene]amino] O3-tert-butyl 3-azabicyclo[3.1.1]heptane-1,3-dicarboxylate (110 mg, 0.150 mmol, 1 eq) and was obtained as a yellow oil (110 mg, 94% yield). MS (ESI): 650 [M-isobutene-C02+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (150 mg, 0.2 mmol, 1 eq) and was obtained as a white solid (90 mg, 58% yield). MS (ESI): 626 [M-isobutene-C02+H]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (80 mg, 0.100 mmol, 1 eq) and was obtained as dihydrochloride salt as a white solid (50 mg, 75% yield). MS (ESI): 582.1 [M+H]−.
To a solution of (3R)-3-amino-7-[5-(3-azabicyclo[3.1.1]heptan-1-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one; dihydrochloride (40.0 mg, 0.060 mmol, 1 eq) in DCM (3 mL) were added DIPEA (24.0 mg, 0.190 mmol, 3.04 eq) and methyl chloroformate (6.0 mg, 0.060 mmol, 1.04 eq) and the mixture was stirred at 20° C. for 1 h. The solvent was evaporated and the crude product was purified by prep. HPLC affording the title compound (19.7 mg, 0.030 mmol, 50% yield) as a white solid. MS (ESI): 640.1 [M+H]+.
To a solution of tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (Example 328, step b)) (150.0 mg, 0.200 mmol, 1 eq) in DCM (2 mL) was added m-CPBA (33.0 mg, 0.160 mmol, 0.810 eq) and the solution was stirred at 20° C. for 12 h. The mixture was poured into water (20 mL) and extracted with DCM (60 mL). The organic phase was washed with brine (50 mL), dried (Na2SO4) and concentrated on vacuum. The remaining residue was purified by preparative TLC(PE/EA=1:1) to afford tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,4-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate [Epimer A] (60 mg, 39% yield) as a white solid (MS (ESI): 610.0 [M-Boc-isobutene+H]) and tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,4-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate [Epimer B] (30 mg, 19% yield) as a light yellow solid (MS (ESI): 610.0 [M-Boc-isobutene+H]+).
A solution of tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,4-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate [Epimer A] (55.0 mg, 0.070 mmol, 1 eq) and trifluoroacetic acid (1.0 mL, 12.98 mmol, 180.72 eq) in DCM (10 mL) was stirred at 20° C. for 1 h. The solvent was evaporated to afford the title compound (60 mg, 97% yield) as a TFA salt as a white solid. MS (ESI): 566.1 [M+H]+.
To a solution of (3R)-3-amino-7-[5-(3-azabicyclo[3.1.1]heptan-1-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-4-one [Epimer A] (60.0 mg, 0.070 mmol, 1 eq) and DIPEA (26.38 mg, 0.200 mmol, 3 eq) in DCM (5 mL) was added dropwise a solution of methyl chloroformate (6.43 mg, 0.070 mmol, 1 eq) in DCM (0.500 mL) at 20° C. and the mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated under vacuum and the remaining residue was purified by prep. HPLC to afford the title compound (24.7 mg, 58% yield) as a white solid. MS (ESI): 624.1 [M+H]−.
A solution of tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,4-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate [Epimer B] (Example 336, step a)) (25.0 mg, 0.030 mmol, 1 eq) and trifluoroacetic acid (0.5 mL, 6.49 mmol, 198 eq) in DCM (5 mL) was stirred at 20° C. for 1 h. The solvent was evaporated to afford the title compound (25 mg, 90% yield) as a TFA salt as a white solid. MS (ESI): 566.0 [M+H]+.
To a solution of (3R)-3-amino-7-[5-(3-azabicyclo[3.1.1]heptan-1-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-4-one [Epimer B] (25.0 mg, 0.030 mmol, 1 eq) and DIPEA (11.36 mg, 0.09 mmol, 3 eq) in DCM (5 mL) was added dropwise a solution of methyl chloroformate (2.77 mg, 0.03 mmol, 1 eq) in DCM (0.5 mL) at 20° C. and the mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated under vacuum and the remaining residue was purified by prep. HPLC to afford the title compound (12.1 mg, 0.020 mmol, 64% yield) as a light yellow solid. MS (ESI): 624.1 [M+H]+.
The title compound was prepared in analogy to general procedure 9a from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 289, step a)) (120 mg, 0.175 mmol, 1 eq) and 2,3,3,3-tetrafluoro-2-methoxy-propanoic acid (CAS 10186-64-8) and was obtained as a light yellow solid (23 mg, 20% yield). MS (ESI): 579.1 [M-isobutene+H]+.
tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (23 mg, 0.034 mmol, 1 eq) was stirred with 3-chloroperoxybenzoic acid (7.63 mg, 0.034 mmol, 1 eq) in DCM (0.681 mL) at room temperature for 30 min. The reaction solution was diluted with DCM and 1N NaOH and was extracted with DCM twice. The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated and the remaining residue was purified by column chromatography on silica gel (0% to 50% EtOAc in heptane) to afford tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,4-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate [Epimer A at S] (9 mg, 39%) as off-white solid (MS (ESI): 551.0 [M-BOC+H]+) and tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,4-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate [Epimer B at S] (6 mg, 26%) as off-white solid (MS (ESI): 651.3 [M+H]+).
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,4-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate [Epimer A at S] (9 mg, 0.014 mmol, 1 eq) and was obtained as hydrochloride salt as a off-white solid (8 mg, 95% yield). MS (ESI): 551.1 [M+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,4-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate [Epimer B at S] (Example 338, step b)) (6 mg, 0.009 mmol, 1 eq) and was obtained as hydrochloride salt as a light green solid (5 mg, 98% yield). MS (ESI): 551.1 [M+H]+.
The title compound was prepared in analogy to general procedure 9a from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 289, step a)) (210 mg, 0.424 mmol, 1 eq) and 2,2-dimethylpropanoic acid (CAS 75-98-9) and was obtained as a white solid (202 mg, 85% yield). MS (ESI): 505.1 [M-isobutene+H]+.
tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (30 mg, 0.053 mmol, 1 eq) was stirred with 3-chloroperoxybenzoic acid (11.98 mg, 0.053 mmol, 1 eq) in DCM (1.07 mL) at room temperature for 3 h. The reaction solution was diluted with DCM and 1N NaOH and was extracted with DCM twice. The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated and the remaining residue was purified by column chromatography on silica gel (0% to 80% EtOAc in heptane) to afford tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,4-dioxo-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate [Epimer A] (17 mg, 55%) as white solid (MS (ESI): 521.1 [M-isobutene+H]+) and tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,4-dioxo-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate [Epimer B] (9 mg, 29%) as white solid (MS (ESI): 521.1 [M-isobutene+H]+).
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,4-dioxo-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate [Epimer A] (17 mg, 0.029 mmol, 1 eq) and was obtained as hydrochloride salt as a white solid (14 mg, 93% yield). MS (ESI): 477.1 [M+H]+.
The title compound was prepared in analogy to general procedure 6d from from tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,4-dioxo-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate [Epimer B] (9 mg, 0.016 mmol, 1 eq) and was obtained as hydrochloride salt as a white solid (8 mg, 100% yield). MS (ESI): 477.1 [M+H]+.
benzyl 5-[3-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3,3-difluoro-piperidine-1-carboxylate (Example 323, step b)) (426 mg, 0.562 mmol, 1 eq) was stirred with 3-chloroperoxybenzoic acid (125.92 mg, 0.562 mmol, 1 eq) in DCM (6 mL) at room temperature for 1.5 h. The mixture was concentrated and the remaining residue was purified by column chromatography on silica gel (0% to 100% EtOAc in heptane) to afford the title compound (356 mg, 72% yield) as white foam. MS (ESI): 674.3 [M-isobutene-CO2+H]+.
A mixture of benzyl 5-[3-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,4-dioxo-2,3-dihydro-1λ4,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3,3-difluoro-piperidine-1-carboxylate (356 mg, 0.46 mmol, 1 eq) and Pd/C 10% (48.9 mg, 0.046 mmol, 0.1 eq) in MeOH (10 mL) was stirred under an atmosphere of hydrogen for 2 days at room temperature. The catalyst was filtered off, the filtrate was concentrated and the remaining residue was purified by column chromatography on silica gel (first 0% to 100% EtOAc in heptane and then 0% to 10% MeOH in EtOAc) to afford the title compound (92 mg, 28% yield) as colorless oil. MS (ESI): 640.3 [M+H]+.
A mixture of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-3-piperidyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,4-dioxo-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (92 mg, 0.144 mmol, 1 eq), formaldehyde (37% in water, 116.66 mg, 107.03 μL, 1.44 mmol, 10 eq) and sodium triacetoxyborohydride (304.63 mg, 1.44 mmol, 10 eq) in MeOH (3 mL) was stirred for 1 h at room temperature. A small amount of water was added and the material was absorbed on silica gel and then purified by column chromatography on silica gel (0% to 100% EtOAc in heptane) to afford the title compound (68 mg, 67% yield) as colorless oil. MS (ESI): 654.3 [M+H]+.
A mixture of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-1-methyl-3-piperidyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,4-dioxo-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (25 mg, 0.038 mmol, 1 eq) and 4M HCl in dioxane (5 drops) was stirred in 1,1,1,3,3,3-hexafluoro-2-propanol (1 mL) at room temperature for 30 min. The solvent was evaporated and the crude material submitted to preparative HPLC affording (3R)-3-amino-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-1-methyl-3-piperidyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1-oxo-2,3-dihydro-1λ4,5-benzothiazepin-4-one [Epimer A at S] (7.3 mg, 35% yield) as white solid (MS (ESI): 554.3 [M+H]+) and (3R)-3-amino-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-1-methyl-3-piperidyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1-oxo-2,3-dihydro-1λ4,5-benzothiazepin-4-one [Epimer B at S] (9.3 mg, 44% yield) as white solid (MS (ESI): 554.3 [M+H]+).
The title compound was prepared in analogy to general procedure 10a from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (Example 331, step a)) (30 mg, 0.052 mmol, 1 eq) and 1-(trifluoromethyl)cyclopropanecarboxylic acid (CAS 277756-46-4) and was obtained as a yellow solid (59.1 mg, 96% yield). MS (ESI): 657.3 [M-isobutene+H]+.
[(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6, 5-benzothiazepin-7-yl]methylene]amino] 1-(trifluoromethyl)cyclopropanecarboxylate (59 mg, 0.083 mmol, 1 eq) was dissolved in a solvent mixture of toluene (3 mL) and THE (0.5 mL) and the mixture was heated to 100° C. and stirred for 16 h. The solution was concentrated under vacuum and the remaining residue was purified by preparative HPLC affording the title compound (48.8 mg, 99.15%) as white solid. MS (ESI): 595.3 [M+H]+.
The title compound was prepared in analogy to general procedure 9a from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 321, step d)) (268 mg, 0.615 mmol, 1 eq) and 1-benzyloxycarbonyl-5,5-difluoro-piperidine-3-carboxylic acid (CAS 1356338-81-2) and was obtained as a light yellow solid (256 mg, 92% yield). MS (ESI): 578.2 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 5 from benzyl 5-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3,3-difluoro-piperidine-1-carboxylate (254 mg, 0.381 mmol, 1 eq) and was obtained as an off-white solid (219 mg, 86% yield). MS (ESI): 610.3 [M-isobutene+H]+.
benzyl 5-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3,3-difluoro-piperidine-1-carboxylate (219 mg, 0.329 mmol, 1 eq) was dissolved in MeOH (10 mL) at room temperature. Pd/C (50 mg, 0.047 mmol, 0.143 eq) was added and the reaction mixture was stirred under an atmosphere of hydrogen for 2 h. The mixture was filtered over a pad of celite and the celite pad was washed thoroughly with MeOH. The filtrate was concentrated to afford the title compound (179 mg, 60% yield) as white solid. MS (ESI): 476.1 [M-isobutene+H]+.
A mixture of tert-butyl N-[(3R)-7-[5-(5,5-difluoro-3-piperidyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (175 mg, 0.194 mmol, 1 eq), formaldehyde (37% in water, 157.66 mg, 144.65 μL, 1.94 mmol, 10 eq) and sodium triacetoxyborohydride (411.71 mg, 1.94 mmol, 10 eq) in MeOH (4 mL) was stirred for 1 h at room temperature. A small amount of water was added and the material was absorbed on silica gel and then purified by column chromatography on silica gel (50% to 100% EtOAc in heptane) to afford the title compound (131 mg, 96% yield) as white solid. MS (ESI): 546.3 [M+H]+.
The title compound was prepared in analogy to general procedure 4 from tert-butyl N-[(3R)-7-[5-(5,5-difluoro-1-methyl-3-piperidyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (40 mg, 0.085 mmol, 1 eq) and (4-isopropoxyphenyl)methyl methanesulfonate (CAS 329045-48-9) and was obtained as a white solid (19 mg, 48% yield). MS (ESI): 694.6 [M+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-7-[5-(5,5-difluoro-1-methyl-3-piperidyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-5-[(4-isopropoxyphenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (19 mg, 0.027 mmol, 1 eq) and was obtained as a hydrochloride salt as a white solid (12.5 mg, 72% yield). MS (ESI): 594.2 [M+H]+.
The examples 346 and 347 of the following table were prepared in analogy to Example 345, using the appropriate benzyl halide building block.
The title compound was prepared in analogy to general procedure 4 from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 321, step c)) (180 mg, 0.534 mmol, 1 eq) and 1-(chloromethyl)-4-(cyclopentoxy)benzene (CAS 1041579-01-4) and was obtained as a white solid (172 mg, 57% yield). MS (ESI): 510.4 [M−H]−.
The title compound was prepared in analogy to general procedure 12 from tert-butyl N-[(3R)-7-cyano-5-[[4-(cyclopentoxy)phenyl]methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (172 mg, 0.306 mmol, 1 eq) and was obtained as a white solid (182 mg, 96% yield). MS (ESI): 545.5 [M+H]−.
The title compound was prepared in analogy to general procedure 9a from tert-butyl N-[(3R)-5-[[4-(cyclopentoxy)phenyl]methyl]-8-fluoro-7-(N-hydroxycarbamimidoyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (60 mg, 0.097 mmol, 1 eq) and 1-benzyloxycarbonylpyrrolidine-3-carboxylic acid (CAS 188527-21-1) and was obtained as a white foam (53 mg, 71% yield). MS (ESI): 658.5 [M-isobutene-CO2+H]+.
The title compound was prepared in analogy to general procedure 5 from benzyl 3-[3-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(cyclopentoxy)phenyl]methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboxylate (53 mg, 0.069 mmol, 1 eq) and was obtained as a white solid (30 mg, 53% yield). MS (ESI): 690.5 [M-isobutene-CO2+H]+.
benzyl 3-[3-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(cyclopentoxy)phenyl]methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboxylate (30 mg, 0.036 mmol, 1 eq) was suspended in MeOH (3 mL) and argon was bubbled through the mixture for 5 min. Then Pd/C (3.88 mg, 0.004 mmol, 0.1 eq) was added and the reaction mixture was stirred under an atmosphere of hydrogen at room temperature for 2 h. The reaction mixture was filtered over Dicalite and the Dicalite was washed thoroughly with MeOH. The filtrate was concentrated to afford a light yellow solid (31 mg) containing the title compound. MS (ESI): 656.6 [M+H]+.
A mixture of tert-butyl N-[(3R)-5-[[4-(cyclopentoxy)phenyl]methyl]-8-fluoro-1,1,4-trioxo-7-(5-pyrrolidin-3-yl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (31 mg, 0.038 mmol, 1 eq), methyl chloroformate (3.93 mg, 3.22 μL, 0.042 mmol, 1.1 eq) and DIPEA (12.22 mg, 16.51 μL, 0.095 mmol, 2.5 eq) in DCM (1 mL) was stirred at room temperature for 2 h. The solvent was evaporated and the remaining residue was purified by column chromatography on silica gel (0% to 100% EtOAc in heptane) to afford the title compound (15 mg, 53%) as white solid. MS (ESI): 614.4 [M-isobutene-CO2+H]+.
The title compound was prepared in analogy to general procedure 6d from methyl 3-[3-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(cyclopentoxy)phenyl]methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboxylate (15 mg, 0.020 mmol, 1 eq) and was obtained as a white solid (8 mg, 64% yield). MS (ESI): 614.5 [M+H]+.
The example 349 of the following table was prepared in analogy to Example 348, using the appropriate benzyl mesylate building block.
The title compound was prepared in analogy to general procedure 9a from tert-butyl N-[(3R)-5-[[4-(cyclopentoxy)phenyl]methyl]-8-fluoro-7-(N-hydroxycarbamimidoyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 348, step b)) (50 mg, 0.081 mmol, 1 eq) and 2,2-dimethylpropanoic acid (CAS 75-98-9) and was obtained as a white foam (41 mg, 74% yield). MS (ESI): 555.5 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-[[4-(cyclopentoxy)phenyl]methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (41 mg, 0.060 mmol, 1 eq) and was obtained as a white solid (32 mg, 75% yield). MS (ESI): 641.4 [M−H]−.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-[[4-(cyclopentoxy)phenyl]methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (32 mg, 0.045 mmol, 1 eq) and was obtained as hydrochloride salt as a white solid (29 mg). MS (ESI): 543.5 [M+H]+.
The title compound was prepared in analogy to general procedure 4 from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 321, step c)) (250 mg, 0.741 mmol, 1 eq) and bromomethylbenzene (CAS 100-39-0) and was obtained as alight yellow solid (289 mg, 77% yield). MS (ESI): 472.2 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 12 from tert-butyl N-[(3R)-5-benzyl-7-cyano-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (289 mg, 0.676 mmol, 1 eq) and was obtained as a light yellow solid (266 mg, 76% yield). MS (ESI): 461.3 [M+H]−.
The title compound was prepared in analogy to general procedure 9a from tert-butyl N-[(3R)-5-benzyl-8-fluoro-7-(N-hydroxycarbamimidoyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (201 mg, 0.436 mmol, 1 eq) and 2,3,3,3-tetrafluoro-2-methoxy-propanoic acid (CAS 10186-64-8) and was obtained as a white solid (26 mg, 8% yield). MS (ESI): 545.3 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-5-benzyl-8-fluoro-4-oxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (26 mg, 0.043 mmol, 1 eq) and was obtained as a white solid (19 mg, 53% yield). MS (ESI): 631.3 [M−H]−.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-5-benzyl-8-fluoro-1,1,4-trioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (14 mg, 0.022 mmol, 1 eq) and was obtained as hydrochloride salt as a white solid (8.6 mg, 62% yield). MS (ESI): 533.3 [M+H]+.
The title compound was prepared in analogy to general procedure 4 from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 321, step c)) (200 mg, 0.593 mmol, 1 eq) and 1-(bromomethyl)-4-(1,1,2,2-tetrafluoroethoxy)benzene (CAS 67033-41-4) and was obtained as a white solid (261 mg, 77% yield). MS (ESI): 542.1 [M−H]−.
The title compound was prepared in analogy to general procedure 12 from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (261 mg, 0.480 mmol, 1 eq) and was obtained as a white solid (284 mg, 92% yield). MS (ESI): 577.4 [M+H]+.
The title compound was prepared in analogy to general procedure 9c from tert-butyl N-[(3R)-8-fluoro-7-(hydrazinecarboximidoyl)-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (125 mg, 0.217 mmol, 1 eq) and 2-(dimethylamino)-2-oxo-acetic acid (CAS 32833-96-8) and was obtained as a light yellow solid (22.7 mg, 15% yield). MS (ESI): 558.2 [M-isobutene-CO2+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-7-[5-(dimethylcarbamoyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (22.7 mg, 0.035 mmol, 1 eq) and was obtained as a white solid (17.4 mg, 72% yield). MS (ESI): 688.2 [M−H]−.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-7-[5-(dimethylcarbamoyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (17.4 mg, 0.025 mmol, 1 eq) and was obtained as hydrochloride salt as an off-white solid (13 mg, 82% yield). MS (ESI): 590.3 [M+H]−.
The title compound was prepared in analogy to general procedure 4 from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 321, step c)) (200 mg, 0.593 mmol, 1 eq) and 4-[[4-(chloromethyl)phenoxy]methyl]tetrahydropyran (CAS 1248950-37-9) and was obtained as a white solid (290 mg, 87% yield). MS (ESI): 564.1 [M+Na]+.
The title compound was prepared in analogy to general procedure 12 from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[[4-(tetrahydropyran-4-ylmethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (220 mg, 0.408 mmol, 1 eq) and was obtained as a light yellow oil (230 mg, 99% yield). MS (ESI): 575.1 [M+H]+.
To a mixture of tert-butyl N-[(3R)-8-fluoro-7-(N-hydroxycarbamimidoyl)-4-oxo-5-[[4-(tetrahydropyran-4-ylmethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (180.0 mg, 0.310 mmol, 1 eq) in toluene (5 mL) was added 2,2-dimethylpropanoyl 2,2-dimethylpropanoate (175 mg, 0.94 mmol, 3 eq) at 25° C. The reaction was heated to 100° C. and was stirred for 12 h. The solvent was evaporated and the remaining residue was purified by preparative TLC (PE/EtOAc=3:1) to afford the title compound (100 mg, 50% yield) as a white solid. MS (ESI): 641.3 [M+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-4-oxo-5-[[4-(tetrahydropyran-4-ylmethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.156 mmol, 1 eq) and was obtained as a white solid (80 mg, 76% yield). MS (ESI): 695.3 [M+Na]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-1,1,4-trioxo-5-[[4-(tetrahydropyran-4-ylmethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (80 mg, 0.119 mmol, 1 eq) and was obtained as a white solid (41.7 mg, 61% yield). MS (ESI): 573.3 [M+H]+.
The title compound was prepared in analogy to general procedure 12 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-cyano-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 36, step d)) (400 mg, 0.901 mmol, 1 eq) and was obtained as a white foam (368 mg, 86% yield). MS (ESI): 477.4 [M+H]+.
The title compound was prepared in analogy to general procedure 9c from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.210 mmol, 1 eq) and 2-(tert-butylamino)-2-oxo-acetic acid (CAS 169772-25-2) and was obtained as a white foam (110 mg, 90% yield). MS (ESI): 586.2 [M+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-7-[5-(tert-butylcarbamoyl)-1,2,4-oxadiazol-3-yl]-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.170 mmol, 1 eq) and was obtained as a white solid (76 mg, 72% yield). MS (ESI): 562.0 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-7-[5-(tert-butylcarbamoyl)-1,2,4-oxadiazol-3-yl]-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (66 mg, 0.110 mmol, 1 eq) and was obtained as a white solid (31.9 mg, 58% yield). MS (ESI): 518.1 [M+H]−.
The title compound was prepared in analogy to general procedure 4 from tert-butyl N-[(3R)-7-cyano-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 36, step c)) (150 mg, 0.470 mmol, 1 eq) and 1-(bromomethyl)-4-(trifluoromethoxy)benzene (CAS 50824-05-5). A colorless oil (273 mg) containing the title compound was obtained which was used in the next reaction step without further purification. MS (ESI): 438.0 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 12 from tert-butyl N-[(3R)-7-cyano-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (273 mg, 0.553 mmol, 1 eq) and was obtained as a white foam (237 mg, 81% yield). MS (ESI): 471.1 [M+H]+.
The title compound was prepared in analogy to general procedure 9c from tert-butyl N-[(3R)-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.190 mmol, 1 eq) and 2-(tert-butylamino)-2-oxo-acetic acid (CAS 169772-25-2) and was obtained as a light yellow oil (111 mg, 93% yield). MS (ESI): 580.4 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-7-[5-(tert-butylcarbamoyl)-1,2,4-oxadiazol-3-yl]-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (107 mg, 0.170 mmol, 1 eq). A colorless oil (119 mg) containing the title compound was obtained which was used in the next reaction step without further purification. MS (ESI): 612.0 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-7-[5-(tert-butylcarbamoyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6, 5-benzothiazepin-3-yl]carbamate (119 mg, 0.180 mmol, 1 eq) and was obtained as a white solid (48.1 mg, 48% yield). MS (ESI): 568.0 [M+H]+.
Example 357 of the following table was prepared in analogy to Example 289, using the appropriate benzylhalogenide building block.
Example 358 of the following table was prepared in analogy to Example 357, using the appropriate carboxylic acid building block.
In a 25 mL round-bottomed flask, tert-butyl (R)-(8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)carbamate (200 mg, 540 μmol, Eq: 1), 2,2-dimethylpent-4-ynoic acid (74.9 mg, 594 μmol, Eq: 1.1), DIPEA (140 mg, 189 μl, 1.08 mmol, Eq: 2) and HATU (411 mg, 1.08 mmol, Eq: 2) were combined with THE (5.35 ml) to give a colorless solution. The reaction mixture was stirred at RT for 2 h. Burgess reagent (643 mg, 2.7 mmol, Eq: 5) was added and the reaction mixture was stirred at RT for 5 h. The mixture was concentrated and the remaining residue was purified by silica gel chromatography (0% to 70% EtOAc in heptane) to yield the title compound (157 mg, 63% yield) as a white solid. MS (ESI): 461.2 [M+H]+.
The title compound was prepared in analogy to general method 4 from tert-butyl N-[(3R)-7-[5-(1,1-dimethylbut-3-ynyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (66 mg, 143 μmol) and was obtained as a light yellow oil (115 mg). MS (ESI): 659.3 [M+H]+.
The title compound was prepared according to general method 5 from tert-butyl N-[(3R)-7-[5-(1,1-dimethylbut-3-ynyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-4-oxo-5-[[4-[3-(trifluoromethyl)diazirin-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (110 mg, 167 μmol) and was obtained as white solid (57.5 mg, 83.3 μmol, 50% yield). MS (ESI): 689.3 [M−H]−.
The title compound was prepared in analogy to method 6c from tert-butyl N-[(3R)-7-[5-(1,1-dimethylbut-3-ynyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-5-[[4-[3-(trifluoromethyl)diazirin-3-yl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (55 mg, 79.6 μmol) with additional 4 drops of HCl (4M in dioxane) and was obtained as a white solid as hydrochloride salt and HFIP adduct (68.8 mg). MS (ESI): 591.2 [M+H]+.
A mixture of (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (CAS:2002450-47-5) (580.0 mg, 1.13 mmol, 1 eq) and CDI (238.56 mg, 1.47 mmol, 1.3 eq) in THE (10 mL) was stirred for 1 h at 40° C. Then a solution of hydrazine hydrate (169.96 mg, 3.4 mmol, 3 eq) in THE (5 mL) was slowly added and the reaction mixture was stirred for another 4 h at 40° C. The mixture was concentrated under vacuum to remove most of the THF and the remaining residue was diluted with EtOAc. The mixture was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the crude product which was purified by column chromatography on silica gel to afford the title compound (550 mg, 1.04 mmol, 88% yield) as a yellow solid. MS (ESI): 471.0 [M-isobutene+H]+.
To a mixture of tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (550.0 mg, 1.04 mmol, 1 eq), pivalic acid (117.35 mg, 1.15 mmol, 1.1 eq) and HATU (476.61 mg, 1.25 mmol, 1.2 eq) in THE (6 mL) was added DIPEA (0.55 mL, 3.13 mmol, 3 eq) at 25° C. and the reaction mixture was stirred at 25° C. for 2.5 h. The mixture was concentrated under vacuum to remove THE and the remaining residue was purified by silica gel column chromatography (PE:EtOAc=5:1 to 1:1) to give the title compound (650 mg, 1.06 mmol, 89% yield) as a yellow liquid. MS (ESI): 555.1 [M-isobutene+H]+.
To a solution of tert-butyl N-[(3R)-7-[(2,2-dimethylpropanoylamino)carbamoyl]-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (630.0 mg, 1.03 mmol, 1 eq) in 1,4-dioxane (8 mL) was added Burgess reagent (983.4 mg, 4.13 mmol, 4 eq) at 25° C. and then the reaction mixture was stirred at 80° C. for 16 h. After cooling to ambient temperature, the mixture was concentrated under vacuum to remove dioxane and the remaining residue was purified by silica gel column chromatography (PE:EtOAc=10:1 to 5:1) to give the title compound (570 mg, 0.960 mmol, 93% yield) as a yellow liquid. MS (ESI): 537.1 [M+H]+.
The title compound was prepared in analogy to general method 5 from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (250.0 mg, 0.420 mmol) and was obtained (180 mg, 0.290 mmol, 5500 yield) as a yellow oil. MS (ESI): 569.0 [M-isobutene+H]+.
The title compound was prepared according to general method 6b from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (180.0 mg, 0.290 mmol) and was obtained as a white solid (20 mg 0.040 mmol, 13% yield). MS (ESI): 525.0 [M+H]+.
Example 361 of the following table was prepared in analogy to Example 360, using the appropriate benzylbromid building block.
To a solution of methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (5 g, 14.19 mmol, Eq: 1) (CAS: 2089150-62-7) in DMSO (55 mL) was added 1-(bromomethyl)-4-chlorobenzene (4.37 g, 21.28 mmol, Eq: 1.5), potassium carbonate (5.88 g, 42.56 mmol, Eq: 3) and potassium iodide (1.18 g, 7.09 mmol, Eq: 0.5) at RT. The reaction mixture was stirred overnight and then partitioned between EtOAc (300 ml) and water (200 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2×200 ml). The combined organic layers were washed with water (100 ml) and sat. NH4Cl (100 ml), dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (0-30% EtAOc in heptane) to afford methyl (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (5.88 g, 86% yield) as off-white solid. MS (ESI): 421.1 [M-isoubtene+H]+
Methyl (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (1.99 g, 4.17 mmol, Eq: 1) was stirred with lithium hydroxide hydrate (350.13 mg, 8.34 mml, Eq: 2) in THE (18 mL), MeOH (3 mL) and water (6 mL) at RT overnight. 1N HCl was added and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford (3R)-3-(tert-butoxycarbonylamino)-5-(4-chlorobenzyl)-4-keto-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (2.01 g, 98% yield) as light yellow oil. MS (ESI): 461.2 [M−H]−.
(3R)-3-(tert-butoxycarbonylamino)-5-(4-chlorobenzyl)-4-keto-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (2.11 g, 4.57 mmol, Eq: 1) was dissolved in THE (19.7 mL). Then CDI (940 mg, 5.8 mmol, Eq: 1.27) was added in one portion and the light yellow solution was stirred for 90 min. A solution of hydrazine hydrate (691.44 mg, 670 μL, 13.81 mmol, Eq: 3) in THE (3.3 mL) was then added via syringe and the reaction stirred overnight at RT. The reaction mixture was partitioned between EtOAc (100 ml) and water (80 ml). 10 ml of brine were added to help with phase separation. The layers were separated and the aqueous layer was extracted with EtOAc (2×100 ml). The combined organic layers were washed with one 80 ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (2.29 g, 86% yield) as yellow waxy solid. MS (ESI): 521.1 [M+H]+.
tert-Butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.193 mmol, Eq: 1) was stirred with 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-methyl-propionic acid (CAS 170462-68-7) (74.42 mg, 0.289 mmol, Eq: 1.5) and DIPEA (49.86 mg, 66.03 μL, 0.386 mmol, Eq: 2) in THE (1.59 mL) at RT. HATU (110.01 mg, 0.289 mmol, Eq: 1.5) was added and stirring was continued for 4 hours. The reaction solution was diluted with EtOAc and water. The layers were separated and the aqueous phase extracted EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude was purified by column chromatography on silica gel (0-100% EtOAc in heptane) to give tert-butyl N-[1-[2-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carbonyl]hydrazino]-2,2,2-trifluoro-1-methyl-ethyl]carbamate (100 mg, 68% yield) as white solid. MS (ESI): 604.1 [M−2isobutene+H]+.
tert-butyl N-[(3R)-7-[[[2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-methyl-propanoyl]amino]carbamoyl]-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.131 mmol, Eq: 1) was stirred with Burgess Reagent (93.83 mg, 0.394 mmol, Eq: 3) in THE (2.63 mL) for 2 hours at RT. The reaction was then diluted with EtOAc and washed with water and then brine. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified using column chromatography on silica gel (0-35% EtOAc in heptane) to afford tert-butyl N-[1-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2,2,2-trifluoro-1-methyl-ethyl]carbamate (61 mg, 67% yield) as white solid. MS (ESI): 586.1 [M−2isobutene+H]+.
The title compound was prepared from tert-butyl N-[1-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2,2,2-trifluoro-1-methyl-ethyl]carbamate (61 mg, 0.087 mmol) in analogy to general procedure 5 and was obtained as a white solid (34 mg, 54% yield). MS (ESI): 618.1 [M−2isobutene+H]+, 728.3 [M−H]−.
4 M HCl in dioxane (23.28 μL, 0.093 mmol, Eq: 2) was added to a solution of tert-butyl N-[1-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2,2,2-trifluoro-1-methyl-ethyl]carbamate (34 mg, 0.047 mmol, Eq: 1) in 1,1,1,3,3,3-hexafluoro-2-propanol (2.3 mL) at RT and stirred for 1 hour. The solvent was evaporated and the crude dissolved in DCM and concentrated again to remove trace HFIP. This process was repeated three times. The so obtained white powder was dried in vacuo to afford (3R)-3-amino-7-[5-(1-amino-2,2,2-trifluoro-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one as white solid, as hydrochloride salt (24 mg, 91% yield). MS (ESI): 530.1 [M+H]+.
The examples 363 to 381 of the following table were prepared in analogy to Example 362, using the appropriate carboxylic acid building block.
The title compound was prepared from N-[(3R)-7-carbazoyl-5-(4-chlorobenzyl)-4-keto-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (350 mg, 0.734 mmol) in analogy to general procedure 7a using 1-carbobenzoxy-4-methyl-isonipecotic acid (348.84 mg, 1.26 mmol, 1.71 eq) and was obtained as light yellow solid (420 mg, 72% yield). MS (ESI): 734.3 [M−H]−.
The title compound was prepared from benzyl 4-[[[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carbonyl]amino]carbamoyl]-4-methyl-piperidine-1-carboxylate (420 mg, 0.570 mmol) in analogy to general procedure 8b and was obtained as white solid (325 mg, 65% yield) as white solid. MS (ESI): 618.3 [M+H-Boc]+.
The title compound was prepared from benzyl 4-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-4-methyl-piperidine-1-carboxylate (325 mg, 0.452 mmol) in analogy to general procedure 5 and was obtained as colourless waxy (332 mg, 97% yield) as colorless waxy solid. MS (ESI): 694.2 [M+H-isobutene]+.
To a solution of benzyl 4-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-4-methyl-piperidine-1-carboxylate (145 mg, 0.193 mmol, 1 eq) in MeOH (3.6 mL) under Ar atmosphere was added Pd/C (20.6 mg) and the mixture was stirred under an atmosphere of hydrogen for 60 min. The mixture was filtered through a plug of celite, which was washed with MeOH and THF. The filtrate was concentrated and the remaining crude was purified using column chromatography on silica gel (0-50% EtOAc in heptane) to give tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(4-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (112 mg, 88% yield) as white solid. MS (ESI): 616.4 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(4-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (22 mg, 0.036 mmol, 1 eq) in DCM (0.73 mL) was added DIPEA (11.54 mg, 15.59 μL, 0.089 mmol, 2.5 eq) and 2,2,2-trifluoroethyl chloroformate (6.38 mg, 4.28 μL, 0.039 mmol, 1.1 eq) at RT and stirred for 3 h. The crude material was concentrated and directly purified by column chromatography on silica gel (0-50% EtOAc in heptane) to afford 2,2,2-trifluoroethyl 4-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-4-methyl-piperidine-1-carboxylate (12 mg, 41% yield) as colorless solid. MS (ESI): 642.1 [M+H-Boc]+.
The title compound was prepared from 2,2,2-trifluoroethyl 4-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-4-methyl-piperidine-1-carboxylate (21.6 mg, 0.029 mmol, 1 eq) in analogy to general procedure 6d and was obtained as white solid, as hydrochloride salt (10 mg, 48% yield). MS (ESI): 642.2 [M+H]−.
Example 383 of the following table were prepared in analogy to Example 382, using the appropriate carboxylic acid building block.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.210 mmol, 1 eq, Example 362, step c) and 3-fluoro-1-methyl-nipecotic acid hydrochloride (62.15 mg, 0.314 mmol, 1.5 eq) in analogy to general procedure 7a. The title compound was obtained as colourless amorphous solid (55.5 mg, 40% yield). MS (ESI): 620.5 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[[(3-fluoro-1-methyl-piperidine-3-carbonyl)amino]carbamoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (53 mg, 0.085 mmol) in analogy to general procedure 8a and was obtained as colourless amorphous solid (50 mg, 91% yield). MS (ESI): 602.3 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(3-fluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (50 mg, 0.083 mmol, 1 eq in analogy to general procedure 5 and was obtained as light yellow amorphous solid (17 mg, 32% yield). MS (ESI): 650.3 [M+H]+.
tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(3-fluoro-1-methyl-1-oxido-piperidin-1-ium-3-yl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (15 mg, 0.023 mmol, 1 eq) was dissolved in 1,2-dichloroethane (0.500 mL) and phenylboronic acid (3.09 mg, 0.025 mmol, 1.1 eq) was added in one portion. The mixture was heated to 85° C. for one hour and then concentrated. The crude material was purified by column chromatography on silica gel (100% EtOAc) to afford tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(3-fluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (11 mg, 75% yield) as white solid. MS (ESI): 643.3 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(3-fluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (11 mg, 0.017 mmol) in analogy to general procedure 6d and was obtained as white solid, as hydrochloride salt (9 mg, 89% yield) as white solid. MS (ESI): 534.2 [M+H]+.
N-[(3R)-7-carbazoyl-5-(4-chlorobenzyl)-4-keto-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (250 mg, 0.524 mmol, 1 eq, Example 362, step c) was stirred in THE (5 ml) with 1-carbobenzoxy-5,5-difluoro-nipecotic acid (156.86 mg, 0.524 mmol, 1 eq), T3P (50% in EtOAc, 1 g, 926.49 μL, 1.57 mmol, 3 eq) and DIPEA (203.22 mg, 274.62 μL, 1.57 mmol, 3 eq) at 60° C. for 2 h. Water (10 ml) was added and extracted with EtOAc (3×20 ml). The combined organic layers were dired over magnesium sulfate, filtered and concentrated. The crude material was purified by perp-HPLC. The organic solvent was removed under vacuum and the title compound obtained after freeze drying (164 mg, 41% yield) as white solid. MS (ESI): 756.3 [M−H]−.
To a solution of benzyl 5-[[[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carbonyl]amino]carbamoyl]-3,3-difluoro-piperidine-1-carboxylate (173 mg, 0.228 mmol, 1 eq) in toluene (2 ml) was added Burgess reagent (271.86 mg, 1.14 mmol, 5 eq) and heated to 110° C. for 1 h. Water (5 ml) was added and extracted with EtOAc (3×10 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford a orange oil (284 mg) containing the title compound which was used in the next step without further purification. MS (ESI): 740.3 [M+H]+.
The title compound was prepared from benzyl 5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3,3-difluoro-piperidine-1-carboxylate (284 mg, 0.341 mmol) in analogy to general procedure 5 and was obtained as light yellow oil (190 mg, 67% yield). MS (ESI): 716.3 [M+H-isobutene]+.
To a solution of benzyl 5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3,3-difluoro-piperidine-1-carboxylate (181 mg, 0.234 mmol, 1 eq) in MeOH (2.5 mL) under Ar atmosphere was added Pd/C (20 mg) and the mixture was stirred under an atmosphere of hydrogen for 30 min. The mixture was filtered through a plug of celite and the filtrate concentrated to give tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (104 mg, 62% yield) as light yellow oil. MS (ESI): 638.3 [M+H]+.
tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (30 mg, 0.047 mmol, 1 eq) was stirred with formalin (37% in H2O, 12.95 μL, 0.470 mmol, 10 eq) and sodium triacetoxyborohydride (269.31 mg, 0.470 mmol, 10 eq) for 1 h at RT. A small amount of water was added and the crude material was applied on silica gel and purified by column chromatography using on silica gel (0-100% EtOAc in Heptane) to afford tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (24 mg, 70% yield) as white solid. MS (ESI): 652.4 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (24 mg, 0.037 mmol) in analogy to general procedure 6b and was obtained as white solid (11 mg, 54% yield) as white solid. MS (ESI): 552.2 [M+H]+.
Example 386 of the following table were prepared in analogy to Example 385, using the appropriate carboxylic acid building block and the indicated method.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.210 mmol, 1 eq, Example 362, step c) in THE (1.5 ml) was added 2-hydroxyspiro[3.3]heptane-6-carboxylic acid (36.02 mg, 0.231 mmol, 1.1 eq), ethyl(diisopropyl)amine (54.19 mg, 71.78 μL, 0.419 mmol, 2 eq), and HATU (87.69 mg, 0.231 mmol, 1.1 eq). The reaction was stirred at RT overnight. Water (10 ml) and EtOAc (10 ml) were added. The layers were separated and the aqueous phase extracted with EtOAC (2×). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to a white foam (220 mg) containing the title compound which was used in the next step without further purification. MS (ESI): 559.2 [M+H-isobutene]+.
tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[[(2-hydroxyspiro[3.3]heptane-6-carbonyl)amino]carbamoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (220 mg, 0.210 mmol, 1 eq) was stirred with TBDMS-Cl (37.92 mg, 0.252 mmol, 1.2 eq) and imidazole (35.68 mg, 0.524 mmol, 2.5 eq) in THE (1.5 mL) at RT for 1 h. The reaction was concentrated and purified by column chromatography on silica gel (0-100% EtOAc in heptanes) to give tert-butyl N-[(3R)-7-[[[2-[tert-butyl(dimethyl)silyl]oxyspiro[3.3]heptane-6-carbonyl]amino]carbamoyl]-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (112 mg, 70% yield) as colourless amorphous solid. MS (ESI): 629.3.1 [M+H-Boc]+.
The title compound was prepared from tert-butyl N-[(3R)-7-[[[2-[tert-butyl(dimethyl)silyl]oxyspiro[3.3]heptane-6-carbonyl]amino]carbamoyl]-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (111 mg, 0.152 mmol) in analogy to general procedure 8a and was obtained as colourless amorphous solid (51 mg, 47% yield). MS (ESI): 611.1 [M+H-Boc]+.
The title compound was prepared from tert-butyl N-[(3R)-7-[5-[2-[tert-butyl(dimethyl)silyl]oxyspiro[3.3]heptan-6-yl]-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (49 mg, 0.069 mmol) in analogy to general procedure 5 and was obtained as light yellow oil (44 mg, 82% yield). MS (ESI): 643.3 [M+H-Boc]+.
The title compound was prepared from tert-butyl N-[(3R)-7-[5-[2-[tert-butyl(dimethyl)silyl]oxyspiro[3.3]heptan-6-yl]-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (42 mg, 0.056 mmol) in analogy to general procedure 6b and was obtained as white solid (21.3 mg, 71%). MS (ESI): 529.1 [M+H]+.
2,3,3,3-tetrafluoro-2-methoxy-propionic acid methyl ester (0.500 g, 2.63 mmol, 1 eq) was dissolved in EtOH (2.63 ml). Hydrazine monohydrate (65%, 155.63 mg, 1.2 eq) was added and the reaction heated to 80° C. for 8 hours. The mixture was concentrated to afford 2,3,3,3-tetrafluoro-2-methoxy-propanehydrazide (437 mg, 85%) as white solid. MS (ESI): 191.0 [M+H]+.
The title compound was prepared from (3R)-3-(tert-butoxycarbonylamino)-5-(4-chlorobenzyl)-4-keto-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (100 mg, 0.212 mmol, 1 eq, Example 362, step c) and 2,3,3,3-tetrafluoro-2-methoxy-propionohydrazide (53.93 mg, 0.275 mmol, 1.3 eq) in analogy to general procedure 7a and was obtained as white solid (101 mg, 75% yield). MS (ESI): 633.3 [M−H]−.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-4-oxo-7-[[(2,3,3,3-tetrafluoro-2-methoxy-propanoyl)amino]carbamoyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.157 mmol, 1 eq) in analogy to general procedure 8a and was obtained as white solid (65 mg, 67% yield). MS (ESI): 561.1 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-4-oxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (60 mg, 0.097 mmol) in analogy to general procedure 5 and was obtained as white solid (45 mg, 71% yield). MS (ESI): 593.1 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (15 mg, 0.023 mmol) in analogy to general procedure 6d and was obtained as white solid (12 mg, 87% yield). MS (ESI): 549.0 [M+H]+.
To a solution of (3R)-3-(tert-butoxycarbonylamino)-5-(4-chlorobenzyl)-4-keto-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (200 mg, 0.419 mmol, 1 eq, Example 362, step c) in THE (3.76 ml) was added 1-tert-butoxycarbonyl-4-cyano-isonipecotic acid (117.28 mg, 0.461 mmol, 1.1 eq), HATU (175.38 mg, 0.461 mmol, 1.1 eq) and DIPEA (108.38 mg, 146.07 μL, 0.839 mmol, 2 eq). The mixture was stirred for 2 h at RT. The reaction was then concentrated in vacuo. The crude was dissolved in THF (3.76 ml) and Burgess reagent (499.6 mg, 2.1 mmol, 5 eq) was added and stirred for 16 h at RT. The reaction was concentrated and directly purified by column chromatography on silica gel (0-50% EtOAc in heptane) to afford tert-butyl 4-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-4-cyano-piperidine-1-carboxylate. MS (ESI): 539.2 [M+H-Boc-isobutene]+.
The title compound was prepared from tert-butyl 4-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-4-cyano-piperidine-1-carboxylate (110 mg, 0.158 mmol, 1 eq) in analogy to general procedure 5 and was obtained as light yellow solid (85 mg, 75% yield). MS (ESI): 725.3 [M−H]−.
The title compound was prepared from tert-butyl 4-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-4-cyano-piperidine-1-carboxylate (86 mg, 0.118 mmol, 1 eq) in analogy to general procedure 6d and was obtained as light yellow solid, as dihydrochloride salt (76 mg, 102% yield). MS (ESI): 571.1 [M−H+HCO2H]+.
4-[5-[(3R)-3-amino-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-4-carbonitrile (40 mg, 0.067 mmol, 1 eq) was suspended in DCM (433.71 μL) and DIPEA (25.85 mg, 34.84 μL, 0.200 mmol, 3 eq) was added at 0° C. The mixture was stirred for 5 min and methyl chloroformate (5.67 mg, 4.64 μL, 0.060 mmol, 0.9 eq) was added. After stirring for 1 hour, water (1 ml) was added. The aqueous phase was extracted with DCM (3×, 10 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude was purified by prep-HPLC to afford methyl 4-[5-[(3R)-3-amino-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-4-cyano-piperidine-1-carboxylate (1.8 mg, 4% yield) as white solid. MS (ESI): 585.2 [M+H]+.
The title compound was prepared from (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (1.36 g, 2.94 mmol, 1 eq, Example 362, step b) in analogy to general procedure 5 and was obtained as white solid (0.943 g, 64% yield). MS (ESI): 439.1 [M+H-isobutene]+.
To a solution of (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepine-7-carboxylic acid (0.940 g, 1.9 mmol, 1 eq) in THE (8 mL) at RT was added CDI (369.54 mg, 2.28 mmol, 1.2 eq) in one portion. The solution was then stirred for 45 min. To this solution was added a mixture of hydrazine hydrate (445.66 mg, 431.84 μL, 5.7 mmol, 3 eq) in THF (1.5 mL) and stirred for 30 min. The reaction mixture was diluted with EtOAc and brine and the layers were separated. The aqueous layer was extracted twice more with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was then purified using column chromatography using on silica gel (0-5% MeOH in EtOAc) to give the title compound as light yellow solid (357 mg, 37% yield). MS (ESI): 453.1 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(hydrazinecarbonyl)-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50 mg, 0.098 mmol, 1 eq) and 6-methylnicotinic acid (14.82 mg, 0.108 mmol, 1.1 eq) in analogy to general procedure 7a to afford a yellow oil (96 mg) containing the title product, which was used in the next step without further purification. MS (ESI): 628.3 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[[(6-methylpyridine-3-carbonyl)amino]carbamoyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (96 mg, 0.118 mmol, 1 eq) in analogy to general procedure 8b and was obtained as white solid (27.6 mg, 37% yield). MS (ESI): 610.3 [M+H]−.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(6-methyl-3-pyridyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (27.6 mg, 0.044 mmol, 1 eq) in analogy to general procedure 6d and was obtained as white solid, as hydrochloride salt (17.9 mg, 75%). MS (ESI): 554.2 [M−H+HCO2H]−.
To a solution of 2,2-difluoromorpholine hydrochloride (CAS 1820647-38-8, 150 mg, 0.940 mmol, Eq: 1) and pyridine (223.08 mg, 228.1 μL, 2.82 mmol, Eq: 3) in 1,2-dichloroethane (4 mL) was added triphosgene (278.97 mg, 0.940 mmol, Eq: 1) at 0° C. in one portion. The cooling bath was removed and stirring was continued for 2 h. The reaction mixture was then partitioned between EtOAc (50 ml) and 1M HCl (25 ml). The layers were separated. The aqueous layer was extracted with two 20 ml portions of EtOAc and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in 1,2-DCE (4 mL) and tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (224.2 mg, 0.470 mmol, 0.5 Eq: 1) was added and the reaction mixture was stirred for 4 h at RT. The reaction mixture was partitioned between EtOAc (50 ml) and water (25 ml). The layers were separated and the aqueous layer was extracted with two 20 ml portions of EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford a yellow solid (365 mg) containing the title compound, which was used in the next step without further purification. MS (ESI): 624.2 [M−H]−.
tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[[(2,2-difluoromorpholine-4-carbonyl)amino]carbamoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (365 mg, 0.583 mmol, Eq: 1) in acetonitrile (10 mL) was added p-toluenesulfonyl chloride (333.45 mg, 1.75 mmol, Eq: 3) and DIPEA (150.69 mg, 203.64 μL, 1.17 mmol, Eq: 2). The reaction mixture was stirred at RT for 4 h and then partitioned between EtOAc (50 ml) and water (40 ml). The layers were separated and the aqueous layer was extracted with two 40 ml portions of EtOAc. The combined organic layers were washed with one 20 ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by column chromatography on siliga gel (0-50% EtOAc in heptane) to afford tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (155 mg, 35% yield) as yellow solid. MS (ESI): 608.2 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (155 mg, 0.255 mmol, Eq: 1) in analogy to general procedure 5 and was obtained as white solid (97.8 mg, 57% yield). MS (ESI): 640.2 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (97.8 mg, 0.145 mmol, 1 eq) in 1,1,1,3,3,3-hexafluoro-2-propanol (1 mL) was added 4M HCl in dioxane (5.29 mg, 4.41 μL, 0.145 mmol, Eq: 1) at RT. The reaction mixture was stirred for 3 h. The solvent was evaporated and the crude dissolved in DCM and concentrated again to remove trace HFIP. This process was repeated three times to afford (3R)-3-amino-5-[(4-chlorophenyl)methyl]-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one (55.4 mg, 66% yield) as white solid, as hydrochloride salt. MS (ESI): 540.1 [M+H]−.
Example 392 to 394 of the following table were prepared in analogy to Example 391, using the appropriate amine building block.
A solution of N-[(3R)-7-carbazoyl-5-(4-chlorobenzyl)-4-keto-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (2 g, 4.19 mmol, Eq: 1) in THE (42.79 mL) was degassed with argon for 10 min. Then CDI (720.7 mg, 4.44 mmol, Eq: 1.05) and NEt3 (449.75 mg, 616.1 μL, 4.44 mmol, Eq: 1.05) were added at RT. The reaction mixture was stirred for 2 h. The reaction mixture was diluted with EtOAc (150 ml) and then washed with 1N HCl solution (50 ml), sat. aq. NaHCO3 solution (50 ml) and brine (50 ml), dried over sodium sulfate, filtered and evaporated to afford tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-4-oxo-7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (1.79 g, 80% yield) as light yellow solid. MS (ESI): 501.2 [M−H]−.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-4-oxo-7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (1.79 g, 3.56 mmol) in analogy to general procedure 5 and was obtained as white solid (1.31 g, 65% yield). MS (ESI): 533.1 [M−H]−.
To a colorless solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50 mg, 0.093 mmol, Eq: 1) in DMF (1 mL) was added DIPEA (48.32 mg, 63.58 μL, 0.374 mmol, Eq: 4) and BOP (51.66 mg, 0.117 mmol, Eq: 1.25) and a yellow solution resulted. After 5 min, 2,2-dimethylmorpholine (CAS: 147688-58-2, 12.92 mg, 0.112 mmol, Eq: 1) was added in one portion and the reaction mixture was stirred at RT for 3 h. The reaction was diluted with EtOAc and water. The layers were separated and the aqueous phase extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude was purified by column chromatography on silica gel (0-50% EtOAc in heptane) to afford tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(2,2-dimethylmorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (33.1 mg, 56% yield) as white solid. MS (ESI): 632.2 [M+H]−.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(2,2-dimethylmorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (33.1 mg, 0.052 mmol, 1 eq) in 1,1,1,3,3,3-hexafluoro-2-propanol (1 mL) was added 4M HCl in dioxane (8 drops) at RT. The reaction mixture was stirred for 3 h. The solvent was evaporated and the crude dissolved in DCM and concentrated again to remove trace HFIP. This process was repeated three times to afford (3R)-3-amino-5-[(4-chlorophenyl)methyl]-7-[5-(2,2-dimethylmorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one (25.1 mg, 84.32%) as white solid, as hydrochloride salt. MS (ESI): 532.2 [M+H]+.
The examples 396 to 412 of the following table were prepared in analogy to Example 395, using the appropriate amine building block.
To a solution methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (300 mg, 0.851 mmol, 1 eq) (CAS: 2089150-62-7) in DMSO (3.54 mL) was added 1-(bromomethyl)-4-phenoxy-benzene (336. mg, 1.28 mmol, 1.5 eq), potassium carbonate (352.95 mg, 2.55 mmol, 3 eq) and potassium iodide (70.66 mg, 0.426 mmol, 0.5 eq) at RT and the reaction was stirred for 24 h. The mixture was partitioned between EtOAc (75 ml) and sat. NaHCO3 (50 ml). The layers were separated and the aqueous layer was extracted with one 50 ml portions of EtOAc. The combined organic layers were washed with one 25 ml portion of water and one 25 ml portion of sat. NH4Cl, dried over sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel (0-30% EtOAc in heptane) to afford methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (250 mg, 22% yield) as brown oil. MS (ESI): 535.4 [M+H]+.
To a yellow suspension of methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (250 mg, 0.187 mmol, 1 eq) in THF (1 mL) and water (0.5 mL) was added 1 M LiOH (196.4 μL, 0.196 mmol, 1.05 eq) at RT and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated to remove most of THF and to the remaining solution was added EtOAc (50 ml) and 1M HCl (30 ml). The layers were separated and the aqueous layer was extracted with two 50 ml portions of EtOAc. The combined organic layers were washed with one 50 ml portion of brine, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (0-20% EtOAc in heptane) to afford (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (31 mg, 26% yield) as white solid. MS (ESI): 519.3 [M−H]−.
(3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (31 mg, 0.057 mmol, 1 eq) was dissolved in THE (0.245 mL) and CDI (13.9 mg, 0.086 mmol, 1.5 eq) was added in one portion to give a yellow solution which was stirred for 90 min at RT. To this solution, a mixture of hydrazine hydrate (13.41 mg, 13. μL, 0.171 mmol, 3 eq) in THF (0.041 mL) was added and stirred for 90 min. The reaction mixture was partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with two portions of EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (44 mg, 101%) as light yellow solid. MS (ESI): 479.3 [M+H-isobutene]+.
To a solution of 2,2-difluoromorpholine hydrochloride (CAS 1820647-38-8, 150 mg, 0.940 mmol, Eq: 1) and pyridine (223.08 mg, 228.1 μL, 2.82 mmol, Eq: 3) in 1,2-dichloroethane (4 mL) was added triphosgene (278.97 mg, 0.940 mmol, Eq: 1) at 0° C. in one portion. The cooling bath was removed and stirring was continued for 2 h. The reaction mixture was then partitioned between DCM (50 ml) and 1M HCl (25 ml). The layers were separated. The aqueous layer was extracted with two 20 ml portions of DCM and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in 1,2-dichloroethane (4 mL) and tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (66 mg, 0.123 mmol, Eq: 0.13) was added and the reaction mixture was stirred overnight. The reaction mixture was partitioned between EtOAc (50 ml) and water (25 ml). The layers were separated and the aqueous layer was extracted with two 20 ml portions of EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford a light yellow oil (224 mg) containing the title compound, which was used in the next step without further purification. MS (ESI): 682.4 [M−H]−.
tert-butyl N-[(3R)-7-[[(2,2-difluoromorpholine-4-carbonyl)amino]carbamoyl]-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (224 mg, 0.229 mmol, Eq: 1) in acetonitrile (3.93 mL) was added p-toluenesulfonyl chloride (131.17 mg, 0.688 mmol, Eq: 3) and DIPEA (59.28 mg, 0.459 mmol, Eq: 2). The reaction mixture was stirred at RT for 4 h and then partitioned between EtOAc (50 ml) and water (40 ml). The layers were separated and the aqueous layer was extracted with two 40 ml portions of EtOAc. The combined organic layers were washed with one 20 ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (0-50% EtOAc in heptane) to afford tert-butyl N-[(3R)-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (86.4 mg, 56% yield) as white solid. MS (ESI): 666.4 [M+H]+.
The title compound was prepared tert-butyl N-[(3R)-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (86.4 mg, 0.128 mmol) in analogy to general procedure 5 and was obtained as white solid (88 mg, 93% yield). MS (ESI): 642.3 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (88 mg, 0.126 mmol) in analogy to general procedure 6d and was obtained as white solid, as hydrochloride salt (58.9 mg, 71% yield). MS (ESI): 598.3 [M+H]+.
To a solution of methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (5 g, 14.19 mmol, 1 eq) (CAS: 2089150-62-7) in DMSO (55 mL) was added 1-(bromomethyl)-4-(trifluoromethoxy)benzene (5.43 g, 21.28 mmol, 1.5 eq), potassium carbonate (5.88 g, 42.56 mmol, 3 eq) and potassium iodide (1.18 g, 7.09 mmol, 0.500 eq) at RT and the reaction mixture was stirred overnight. Water (200 ml) and EtOAc (200 ml) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×100 ml). The combined organic layers were washed with water (100 ml), aq. sat. NH4Cl (100 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (0-30% EtOAc in heptane) to afford methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (7.1 g, 93% yield) as orange waxy solid. MS (ESI): 471.2 [M+H-isobutene]+.
To a solution of methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (7.1 g, 13.48 mmol, 1 eq) in THF (66 mL), MeOH (11 mL) and water (18 mL) was added lithium hydroxide hydrate (647 mg, 27.01 mmol, 2 eq) and the mixture was stirred at RT for 3 hr. Organic solvent was evaporated and 1M HCl (100 ml) and EtOAc (100 ml) was added. The layers were separated and the aqueous layer extracted with EtOAc (2×). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (6.79 g, 96% yield) as off-white solid. MS (ESI): 457.1 [M+H-isobutene]+.
To a solution of (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (160 mg, 3.12 mmol, 1 eq) in THE (10 mL) was added CDI (758.87 mg, 4.68 mmol, 1.5 eq) and the mixture was stirred at 40° C. for 1 h. After that, the solution was added dropwise to a stirring solution of hydrazine monohydrate (318.89 mg, 6.24 mmol, 2 eq) in THE (10 mL). The resulting mixture was stirred at RT for 1 h. The reaction was poured into water (30 ml) and extracted with EtOAc (3×30 ml). The combined organic layers were washed with water (2×20 ml) and brine (20 ml), dried over sodium sulfate and concentrated in vacuum to afford tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (1.4 g, 2.66 mmol, 85% yield) as light yellow oil. MS (ESI): 471.1 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (200.0 mg, 0.380 mmol) and Boc-cycloleucine (95.8 mg, 0.420 mmol, 1.1 eq) in analogy to general procedure 7a and was obtained as light yellow oil (230 mg, 0.310 mmol, 82% yield) as light yellow oil. MS (ESI): 738.3 [M+H]−.
The title compound was prepared from tert-butyl N-[(3R)-7-[[[1-(tert-butoxycarbonylamino)cyclopentanecarbonyl]amino]carbamoyl]-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (220 mg, 0.3 mmol) in analogy to general procedure 8a and was obtained as light yellow oil (200 mg, 0.28 mmol, 93% yield). MS (ESI): 720.3 [M+H]+.
The title compound was prepared form tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)cyclopentyl]-1,3,4-oxadiazol-2-yl]-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (200.0 mg, 0.280 mmol) in analogy to general procedure 5 and was obtained as light yellow solid (160 mg, 0.210 mmol, 76.59% yield). MS (ESI): 752.6 [M+H]−.
The title compound was prepared from tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)cyclopentyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6, 5-benzothiazepin-3-yl]carbamate (150.0 mg, 0.200 mmol) in analogy to general procedure 6b and was obtained as white solid (63.5 mg, 0.120 mmol, 57% yield). MS (ESI): 552.2 [M+H]+.
The examples 415 to 420 of the following table were prepared in analogy to Example 414, using the appropriate carboxylic acid building block.
tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (200 mg, 0.380 mmol, 1 eq, Example 414, step c) was dissolved in THF (3.76 mL) and 1-carbobenzoxy-5,5-difluoro-nipecotic acid (125.04 mg, 0.418 mmol, 1.1 eq), HATU (158.87 mg, 0.418 mmol, 1.1 eq) and DIPEA (98.18 mg, 132.68 μL, 0.760 mmol, 2 eq) were added to give a yellow solution. The mixture was stirred for 45 minutes at RT. Burgess reagent (452.59 mg, 1.9 mmol, 5 eq) was added and the reaction mixture stirred for 60 min at RT. The solution was concentrated and the crude purified by column chromatography on silica gel (0-100% EtOAc in heptane) to give benzyl 5-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3,3-difluoro-piperidine-1-carboxylate (217 mg, 65% yield) as light yellow solid. MS (ESI): 790.4 [M+H]+.
The title compound was prepared from benzyl 5-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3,3-difluoro-piperidine-1-carboxylate (217 mg, 0.275 mmol) in analogy to general procedure 5 and was obtained as light yellow solid (161 mg, 64% yield). MS (ESI): 822.3 [M+H]+.
To a solution of benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6, 5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (185 mg, 0.225 mmol, 1 eq) in MeOH (6 mL) under Ar atmosphere was added Pd/C (47.92 mg, 0.023 mmol) and stirred under hydrogen atmosphere for 2 h. The mixture was filtered through celite and the filtrate concentrated to afford tert-butyl N-[(3R)-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6, 5-benzothiazepin-3-yl]carbamate (78 mg, 46% yield) as light yellow solid. MS (ESI): 688.3 [M+H]−.
Tert-butyl N-[(3R)-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6, 5-benzothiazepin-3-yl]carbamate (78 mg, 0.113 mmol, 1 eq) was dissolved in MeOH (1.07 mL) and formalin (35% in H2O, 92.05 mg, 84.45 μL, 1.13 mmol, 10 eq) and sodium triacetoxyborohydride (240.41 mg, 1.13 mmol, 10 eq) were added. Gas formation was observed and the mixture was kept stirring at 22° C. RT or 1 h. The solution was poured onto water (20 ml) and extracted with DCM (3×30 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude was purified by column chromatography on silica geld (0-60% EtOAc in heptane) to afford tert-butyl N-[(3R)-7-[5-(5,5-difluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6, 5-benzothiazepin-3-yl]carbamate (29 mg, 35% yield) as white solid. MS (ESI): 702.5 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-[5-(5,5-difluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (29 mg, 0.041 mmol) in analogy to general procedure 6d and was obtains as white solid, as hydrochloride salt (25 mg, 90%). MS (ESI): 602.2 [M+H]+.
To a solution of tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (170.0 mg, 0.320 mmol, 1 eq, Example 414, step c) in pyridine (4 mL) was added 3-tert-butoxycarbonyl-3-azabicyclo[3.1.1]heptane-1-carboxylic acid (95.0 mg, 0.390 mmol, 1.22 eq) and EDCI (198.55 mg, 1.04 mmol, 3.21 eq). The reaction mixture was stirred at RT for 1 h. The mixture was poured into water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo. The crude yellow residue was purified by column chromatography on silica gel (10-50% EtOAc in petroleum ether) to afford tert-butyl 1-[[[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6, 5-benzothiazepine-7-carbonyl]amino]carbamoyl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (250 mg, 0.330 mmol, 92% yield) as white solid. MS (ESI): 750.1 [M+H]+.
The title compound was prepared from tert-butyl 1-[[[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-7-carbonyl]amino]carbamoyl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (250.0 mg, 0.330 mmol) in analogy to general procedure 8a and was obtained as yellow oil (170 mg, 0.230 mmol, 70% yield). MS (ESI): 732.4 [M+H]+.
The title compound was prepared from tert-butyl 1-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (150.0 mg, 0.200 mmol) in analogy to general procedure 5 and was obtained as white solid (137 mg, 0.180 mmol, 88% yield). MS (ESI): 664.0 [M+H-Boc]+.
The title compound was prepared from tert-butyl 1-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (120.0 mg, 0.160 mmol) in analogy to general procedure 6b and was obtained as white solid, as dihydrochloride salt (75 mg, 0.120 mmol, 85% yield). MS (ESI): 564.2 [M+H]+.
To a solution of (3R)-3-amino-7-[5-(3-azabicyclo[3.1.1]heptan-1-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one (35 mg, 0.05 mmol, 1 eq) in DCM (2 mL) was added DIPEA (25 mg, 0.19 mmol, 3.5 eq) and methyl chloroformate (6 mg, 0.06 mmol, 1.15 eq). The reaction was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to afford the crude as white solid which was purified by prep-HPLC to afford methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (18.7 mg, 0.03 mmol, 5500 yield) as white solid. MS (ESI): 622.2 [M+H]+.
Example 423 of the following table was prepared in analogy to Example 422, using the appropriate carboxylic acid building block.
(3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (100 mg, 0.191 mmol, 1 eq, Example 414, step b) was stirred with 2,3,3,3-tetrafluoro-2-methoxy-propanehydrazide (48.72 mg, 0.249 mmol, 1.3 eq, Example 388, step a) and DIPEA (49.43 mg, 65.47 μL, 0.38 mmol, 2 eq) in THE (1.58 mL) at RT. HATU (109.06 mg, 0.287 mmol, 1.5 eq) was added and stirring was continued for 16 h. The crude material was diluted with EtOAc and water and the layers were separated. The aqueous phase was extracted with EtOAc (2×). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude was purified by column chromatography on silica gel (0%-100% EtOAc in heptane) to give tert-butyl N-[(3R)-4-oxo-7-[[(2,3,3,3-tetrafluoro-2-methoxy-propanoyl)amino]carbamoyl]-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (94 mg, 72% yield) as white solid. MS (ESI): 683.3 [M−H]−.
The title compound was prepared from tert-butyl N-[(3R)-4-oxo-7-[[(2,3,3,3-tetrafluoro-2-methoxy-propanoyl)amino]carbamoyl]-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.146 mmol) in analogy to general procedure 8a and was obtained as colourless foam (65 mg, 67% yield). MS (ESI): 611.3 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-4-oxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (52 mg, 0.078 mmol) in analogy to general procedure 5 and was obtained as white solid (45 mg, 83% yield). MS (ESI): 643.1 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-1,1,4-trioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (39 mg, 0.056 mmol) in analogy to general procedure 6d and was obtained as white solid, as hydrochloride salt (33 mg, 93% yield). MS (ESI): 599.1 [M+H]+.
The title compounds were prepared from tert-butyl N-[(3R)-4-oxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (20 mg, 0.03 mmol, Example 424, step b) in analogy to general procedure 5 using m-CPBA (6.72 mg, 0.03 mmol, 1 eq). The two epimers at S were separated and obtained as white solid (10 mg, 49% yield, epimer 1 at S) and white solid (8 mg, 39% yield, epimer 2 at S). MS (ESI): 627.1 [M+H-isobutene]+ for both products.
The title compound was prepared from tert-butyl N-[(3R)-1,4-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate [epimer 1 at S] (10 mg, 0.015 mmol) in analogy to general procedure 6d and was obtained as light yellow solid, as hydrochloride salt (8 mg, 86% yield). MS (ESI): 583.4 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-1,4-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate [epimer 2 at S] (7 mg, 0.01 mmol) in analogy to general procedure 6d and was obtained as light yellow solid, as hydrochloride salt (5 mg, 80%). MS (ESI): 583.2 [M+H]+.
The title compound was prepared from (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (300 mg, 0.57 mmol, 1 eq, Example 414, step b) and 3,3,3-trifluoropropionic acid (102 mg, 0.8 mmol, 1.4 eq) in analogy to general procedure 7a and was obtained as light yellow solid (280 mg, 0.44 mmol, 77% yield). MS (ESI): 581.1 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-7-[(3,3,3-trifluoropropanoylamino)carbamoyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (260 mg, 0.41 mmol) in analogy to general procedure 8a and was obtained as white solid (180 mg, 0.29 mmol, 71% yield). MS (ESI): 563.3 [M+H-isobutene]+.
The title compounds were prepared from tert-butyl N-[(3R)-4-oxo-7-[5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (20 mg, 0.03 mmol) in analogy to general procedure 5 using m-CPBA (7.17 mg, 0.032 mmol, 1 eq). The two epimers were separated and obtained as white solid (8 mg, 38% yield, epimer A) and white solid (3 mg, 14% yield, epimer B). MS (ESI): 579.2 [M+H-isobutene]+ for both products.
The title compound was prepared from tert-butyl N-[(3R)-1,4-dioxo-7-[5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate [epimer A] (7 mg, 0.011 mmol) in analogy to general procedure 6d and was obtained as light yellow solid, as hydrochloride salt (5 mg, 81% yield). MS (ESI): 535.1 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-1,4-dioxo-7-[5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate [epimer B] (3 mg, 0.005 mmol) in analogy to general procedure 6d and was obtained as light yellow solid, as hydrochloride salt (2.5 mg, 97% yield). MS (ESI): 535.1 [M+H]+.
To a solution of methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (30.0 g, 85.13 mmol, 1 eq) (CAS: 2089150-62-7) in THE (300 mL) was added a solution of NaOH (5.11 g, 127.69 mmol, 1.5 eq) in water (300 mL) at 0° C. The mixture was stirred at RT for 7 h. At 0° C., 0.5 M HCl was added to the reaction mixture which was then allowed to warm to RT. EtOAc was added and the layers were separated. The aqueous phase was extracted with EtOAc (2×200 mL). The combined organic layer were washed with brine (3×200 mL), dried over sodium sulfate, filtered and concentrated to afford (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid (29.4 g, 86.88 mmol, 91% yield) as yellow solid. MS (ESI): 283.0 [M+H-isobutene]+.
To a solution of (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid (29.4 g, 86.88 mmol, 1 eq) and DIPEA (45.4 mL, 260.65 mmol, 3 eq) in DCM (400 mL) was added T3P (50 wt % in EtOAc, 66.88 mL, 130.33 mmol, 1.5 eq) at RT and the reaction was stirred for 30 min. The reaction mixture was then transferred via dropping funnel to a solution of hydrazine hydrate (17.2 mL, 347.54 mmol, 4 eq) in DCM (190 mL). The reaction mixture was stirred for 3 h at RT and a yellow precipitate formed. The mixture was concentrated and the crude purified by prep-HPLC to afford tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (6 g, 17.03 mmol, 19% yield) as white solid. MS (ESI): 297.1 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (4.5 g, 7.39 mmol, 1 eq) and pivalic acid (889.0 mg, 8.7 mmol, 1.18 eq) in analogy to general procedure 7a and was obtained as light yellow solid (2.95 g, 6.76 mmol, 84% yield). MS (ESI): 381.1 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-7-[(2,2-dimethylpropanoylamino)carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (2.9 g, 6.64 mmol) in analogy to general procedure 8a and was obtained as light yellow solid (1.6 g, 3.82 mmol, 54% yield). MS (ESI): 363.1 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (241.0 mg, 0.580 mmol) in analogy to general procedure 5 and was obtained as white solid (270 mg, 0.600 mmol, 94.5% yield). MS (ESI): 395.2 [M+H-isobutene]+.
To a solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (50.0 mg, 0.11 mmol, 1 eq) in DMF (1 mL) was added potassium carbonate (33.7 mg, 0.24 mmol, 2.2 eq) and KI (3.68 mg, 0.02 mmol, 0.2 eq) at RT and stirred for 5 min. To this mixture was then added dropwise 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (29.8 mg, 0.11 mmol, 1 eq) in DMF (1 mL) via syringe. The mixture was stirred for 16 h at RT. The mixture was then poured into water (40 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The remaining residue was purified by preparative TLC (PE/EtOAc=1:1) to afford desired title compound (50 mg, 0.08 mmol, 52% yield) as a light yellow solid. MS (ESI): 583.1 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-5-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50.0 mg, 0.080 mmol) in analogy to general procedure 6b and was obtained as white solid (20.8 mg, 0.04 mmol, 48% yield). MS (ESI): 539.1 [M+H]−.
The examples 123 and 430 to 440 of the following table were prepared in analogy to Example 362, using the appropriate benzyl halide building block.
To a solution of 4-hydroxybenzyl alcohol (1 g, 8.06 mmol, 1 eq) in DMF (8 mL) was added potassium carbonate (2226 mg, 16.1 mmol, 2 eq), KI (0.04 mL, 0.810 mmol, 0.1 eq) and 1-bromo-2-butyne (1339 mg, 10 mmol, 1.25 eq). The mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with EtOAc (20 mL) and filtered through celite. The filtrate was washed with brine (3×25 mL) and the organic phase was dried over sodium sulfate, filtered and concentrated.
The resulting oil was purified by column chromatography on silica gel (8%-40% EtOAc in PE) to afford (4-but-2-ynoxyphenyl)methanol (950 mg, 5.39 mmol, 48% yield) as a brown oil. MS (ESI): 159.0 [M+H−H2O]+.
To a solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (50.0 mg, 0.110 mmol, 1 eq) in toluene (1.5 mL) was degassed by bubbling through N2 for 5 min. To this solution was then added (4-but-2-ynoxyphenyl)methanol (20.0 mg, 0.110 mmol, 1.02 eq), Ph3P (0.05 mL, 0.220 mmol, 2 eq) and DIAD (0.04 mL, 0.220 mmol, 2 eq) and the reaction was stirred at 50° C. for 4 h. The reaction mixture was diluted with EtOAc (5 mL) and washed with brine (3×10 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The remaining residue was purified by preparative TLC (PE/EtOAc=2:1) to obtain the title compound (50 mg, 0.08 mmol, 74% yield) as light yellow solid, MS (ESI): 553.2 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[(4-but-2-ynoxyphenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (45.0 mg, 0.070 mmol) in analogy to general procedure 6b and was obtained as white solid (14.3 mg, 0.030 mmol, 38% yield). MS (ESI): 509.1 [M+H]+.
To a solution of methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (250 mg, 0.71 mmol, 1 eq) (CAS: 2089150-62-7) in DMSO (3 mL) was added 1-(bromomethyl)-4-(1,1,2,2-tetrafluoroethoxy)benzene (300 mg, 0.99 mmol, 1.4 eq, CAS 67033-41-4), potassium carbonate (294.13 mg, 2.13 mmol, 3 eq) and potassium iodide (58.8 mg, 0.355 mmol, 0.5 eq) at RT. The reaction mixture was stirred for 2.5 h at RT. The reaction mixture was partitioned between EtOAc (100 ml) and water (100 ml). The layers were separated and the aqueous layer was extracted with two 100 ml portions of EtOAc. The combined organic layers were washed with one 50 ml portion of water and one 50 ml portion of sat. NH4Cl, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (0-30% EtOAc in heptane) to afford the title compound (394 mg, 98% yield) as yellow oil. MS (ESI): 503.2 [M+H-isobutene]+.
To a solution of methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (394 mg, 0.7 mmol, 1 eq) in THE (3.5 mL), MeOH (0.58 mL) and water (0.93 mL) was added 1 M lithium hydroxide (1M in H2O) (1.41 mL, 1.41 mmol, 2 eq). The mixture was stirred at RT for 4 hr. The reaction mixture was diluted with 100 ml EtOAc and washed once with 50 ml 1M HCl. The layers were separated and the aqueous layer was extracted with two 70 ml portions of EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (400 mg, 99% yield) as light yellow oil. MS (ESI): 543.2 [M−H]−.
(3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (0.4 g, 0.73 mmol, 1 eq) was dissolved in THE (3.18 mL). Then CDI (151 mg, 0.93 mmol, 1.27 eq) was added in one portion and the resulting light yellow solution was stirred for 90 min. To this solution was added a mixture of hydrazine hydrate (45.9 mg, 44.5 μL, 0.918 mmol, 1.25 eq) in THE (0.535 mL) and stirred for 90 min. The reaction mixture was partitioned between EtOAc (100 ml) and water (80 ml) and 5 ml of brine were added to help with phase separation. The layers were separated and the aqueous layer was extracted with two 100 ml portions of EtOAc. The combined organic layers were washed with one 80 ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound (422 mg, 93% yield) as yellow oil. MS (ESI): 559.2 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (200 mg, 0.36 mmol) and pivalic acid (36.57 mg, 0.36 mmol, 1 eq) in analogy to general procedure 7b and was obtained as light red foam (181 mg, 0.28 mmol, 76% yield). MS (ESI): 543.1 [M+H-Boc]+.
The title compound was prepared from tert-butyl N-[(3R)-7-[(2,2-dimethylpropanoylamino)carbamoyl]-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (181 mg, 0.28 mmol) in analogy to general procedure 8a and was obtained as colourless oil (170 mg, 0.27 mmol, 97% yield). MS (ESI): 625.2 [M+H]+.
The title compound as prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (170.0 mg, 0.270 mmol) in analogy to general procedure 5 and was obtained as white foam (60 mg, 0.09 mmol, 34% yield). MS (ESI): 657.5 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (75 mg, 0.11 mmol) in analogy to general procedure 6b and was obtained as white solid (46.5 mg, 0.08 mmol, 73% yield). MS (ESI): 557.2 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (110 mg, 0.2 mmol, 1 eq) and 3-tert-butoxycarbonyl-3-azabicyclo[3.1.1]heptane-1-carboxylic acid (55.0 mg, 0.23 mmol, 1.16 eq) in analogy to general procedure 7a and was obtained as yellow solid (120 mg, 0.15 mmol, 78% yield). MS (ESI): 782.3 [M+H]+.
The title compound was prepared from tert-butyl 1-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carbonyl]amino]carbamoyl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (120 mg, 0.15 mmol) in analogy to general procedure 8a and was obtained as white solid (85 mg, 0.11 mmol, 73% yield) as white solid. MS (ESI): 708.2 [M+H-isobutene]+.
The title compound was prepared from tert-butyl 1-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (85 mg, 0.11 mmol) in analogy to general procedure 5 and was obtained as white solid (50 mg, 57% yield). MS (ESI): 740.3 [M+H-isobutene]+.
The title compound was prepared from tert-butyl 1-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (50 mg, 0.07 mmol) in analogy to general procedure 6b and was obtained as white solid (27 mg, 0.040 mmol, 69% yield). MS (ESI): 596.2 [M+H]+.
To a solution of (3R)-3-amino-7-[5-(3-azabicyclo[3.1.1]heptan-1-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one (22 mg, 0.03 mmol, 1 eq) in DCM (2 mL) was added DIPEA (17 mg, 0.13 mmol, 4 eq) and methyl chloroformate (4 mg, 0.04 mmol, 1.29 eq). The mixture was stirred at RT for 1 h and then concentrated in vacuo. The remaining crude was purified by prep-HPLC to afford the title compound (5.5 mg, 0.01 mmol, 23% yield) as white solid. MS (ESI): 654.2 [M+H]+.
Ethyl chloroformate (87.0 mg, 77.06 μL, 0.8 mmol, 1 eq) was added to a solution 1-benzyloxycarbonylpyrrolidine-3-carboxylic acid (200 mg, 0.8 mmol, 1 eq (CAS 188527-21-1) and NEt3 (85.2 mg, 117 μL, 0.84 mmol, 1.05 eq) in THE (2 mL) at 0° C. and the reaction was stirred for 1 hour. The resulting white suspension was filtered and the filtrate was directly added to a solution of hydrazine hydrate (123 mg, 120 μL, 1.6 mmol, 2 eq) in MeOH (2 mL) at 0° C. The reaction was allowed to warm up to RT and stirred for 5 h. The solution was diluted with EtOAc and washed once with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated to afford the title compound (138 mg, 59% yield) as white solid. MS (ESI): 264.2 [M+H]+.
To a solution of methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (220 mg, 0.624 mmol, 1 eq) (CAS: 2089150-62-7) in DMSO (2 ml) was added sequentially 1-(chloromethyl)-4-(cyclopentoxy)benzene (144 mg, 0.687 mmol, 1.1 eq), KI (51.81 mg, 0.312 mmol, 0.5 eq) and K2CO3 (258.84 mg, 1.87 mmol, 3 eq). The reaction was stirred at RT overnight. The reaction was diluted with EtOAc and washed once with water and once with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The remaining residue was purified by column chromatography on silica gel (0-30% EtOAc in heptane to give the title compound (213 mg, 62% yield) as light yellow solid. MS (ESI): 471.3 [M+H-isobutene]+.
Lithium hydroxide monohydrate (32.58 mg, 0.777 mmol, 2 eq) was added to a yellow solution of methyl (3R)-3-(tert-butoxycarbonylamino)-5-[[4-(cyclopentoxy)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (213 mg, 0.388 mmol, 1 eq) in THE (1.4 mL), MeOH (0.2 mL) and water (0.4 mL) and the reaction was stirred at RT for 2 hours. 1N aq. HCl was added to give a white suspension and the mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as light yellow solid (193 mg, 93% yield). MS (ESI): 457.3 [M+H-isobutene]+.
The title compound was prepared from (3R)-3-(tert-butoxycarbonylamino)-5-[[4-(cyclopentoxy)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (40 mg, 0.075 mmol, 1 eq) and benzyl 3-(hydrazinecarbonyl)pyrrolidine-1-carboxylate (29.5 mg, 0.11 mmol, 1.5 eq) in analogy to general procedure 7b and was obtained as white solid (35 mg, 62% yield). MS (ESI): 758.5 [M+H]+.
The title compound was prepared from benzyl 3-[[[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(cyclopentoxy)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carbonyl]amino]carbamoyl]pyrrolidine-1-carboxylate (35 mg, 0.046 mmol) in analogy to general procedure 8a and was obtained as white solid (23 mg, 67%). MS (ESI): 640.4 [M+H-Boc]+.
The title compound was prepared from benzyl 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(cyclopentoxy)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]pyrrolidine-1-carboxylate (23 mg, 0.031 mmol) in analogy to general procedure 5 and was obtained as white solid (21 mg, 84%). MS (ESI): 672.4 [M+H-Boc]+.
Benzyl 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(cyclopentoxy)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]pyrrolidine-1-carboxylate (21 mg, 0.026 mmol, 1 eq) was suspended in MeOH (0.67 mL). Argon was bubbled through the suspension for 5 min. Pd/C (2.78 mg, 0.003 mmol, 0.1 eq) was added in one portion and the resulting black suspension was stirred under hydrogen atmosphere at RT for 2 h. The reaction mixture was filtered through a plug of celite. The filter cake was washed thoroughly with MeOH and the filtrate concentrated in vacuo to afford the title compound as yellow solid (14 mg, 81%). MS (ESI): 638.5 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[[4-(cyclopentoxy)phenyl]methyl]-1,1,4-trioxo-7-(5-pyrrolidin-3-yl-1,3,4-oxadiazol-2-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (14 mg, 0.021 mmol, 1 eq) in DCM (0.5 ml) was added methyl chloroformate (2.19 mg, 1.8 μL, 0.023 mmol, 1.1 eq) and DIPEA (6.81 mg, 9.2 μL, 0.053 mmol, 2.5 eq). The reaction was stirred at RT for 2 h. The solvent was evaporated and the remaining residue purified by column chromatography on silica gel (0-100% EtOAc in heptane) to afford a white solid (18 mg) containing the title compound, which was used in the next step without further purification. MS (ESI): 596.4 [M+H−Boc]+.
The title compound was prepared from methyl 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(cyclopentoxy)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]pyrrolidine-1-carboxylate (18 mg, 0.025 mmol) in analogy to general procedure 6d and was obtained as off-white solid, as hydrochloride salt (16 mg, 92%). MS (ESI): 596.5 [M+H]+.
To a solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (100 mg, 0.22 mmol, 1 eq, Example 429, step e)) in toluene (1.5 mL) was added [4-(4-cyclopropylpiperazin-1-yl)phenyl]methanol (61.88 mg, 0.27 mmol, 1.2 eq, CAS 1303477-83-9), Ph3P (116.44 mg, 0.440 mmol, 2 eq) and di-tert-butyl azodicarboxylate (102.22 mg, 0.44 mmol, 2 eq). The mixture was degassed with N2 and stirred at 50° C. for 3 h. The reaction was diluted with water (5 mL) and EtOAc (5 ml). The layers were separated and the aqueous phase extracted with EtOAc (3×5 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The remaining crude was purified using column chromatography on silica gel (5-80% EtOAc in PE) to obtain the title compound (50 mg, 0.08 mmol, 28% yield) as yellow oil. MS (ESI): 665.3 [M+H]+
The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(4-cyclopropylpiperazin-1-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50 mg, 0.08 mmol) in analogy to general procedure 6b and was obtained as white powder (6.5 mg, 0.01 mmol, 15% yield). MS (ESI): 565.2 [M+H]+
Example 446 to 448 of the following table were prepared in analogy to Example 445, using the appropriate benzylic alcohol building block.
Step a) tert-butyl N-[(3R)-7-[5-(1,1-dimethylbut-3-ynyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate
The title compound was prepared according to general method 4 from tert-butyl N-[(3R)-7-[5-(1,1-dimethylbut-3-ynyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 359, step a)) (80 mg, 174 μmol) and was obtained (111.9 mg) as a light brown viscous oil. MS (ESI): 635.2 [M+H]+.
The title compound was prepared in analogy to general method 5 from tert-butyl N-[(3R)-7-[5-(1,1-dimethylbut-3-ynyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (39.5 mg, 62.2 μmol) and was obtained (51 mg) as a white solid. MS (ESI): 611.1 [M-isobutene+H]+.
The title compound was prepared according to general method 6b from tert-butyl N-[(3R)-7-[5-(1,1-dimethylbut-3-ynyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6, 5-benzothiazepin-3-yl]carbamate (50.0 mg, 75 μmol) and was obtained (8.9 mg, 15.68 μmol, 21% yield) as a white waxy solid. MS (ESI): 567.2 [M+H]+.
To a solution of 1-benzyloxycarbonyl-5,5-difluoro-piperidine-3-carboxylic acid (328.0 mg, 1.1 mmol, 1.21 eq) in DMF (8 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium; hexafluorophosphate (519.0 mg, 1.36 mmol, 1.5 eq) and DIPEA (0.48 mL, 2.75 mmol, 3.02 eq) and the mixture was stirred for 30 min. To the mixture was added tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 63, step a) (450.0 mg, 0.910 mmol, 1 eq) in DMF (2 mL) and the mixture was stirred at 25° C. for 30 min. The mixture was poured into water and was extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated in vacuo. The remaining residue was purified by column chromatography affording the title compound (350 mg, 0.450 mmol, 49% yield) as a yellow solid. MS (ESI): 776.2 [M+H]+.
To a solution of benzyl 3,3-difluoro-5-[[[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carbonyl]amino]carbamoyl]piperidine-1-carboxylate (100 mg, 0.12 mmol, 1 eq) in 1,4-dioxane (6 mL) was added Burgess reagent (120.0 mg, 0.94 mmol, 14.54 eq). The mixture was stirred at 115° C. for 12 h under an atmosphere of nitrogen. The mixture was poured into water and was extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography affording the title compound (100 mg, 0.130 mmol) as yellow solid. MS (ESI): 758.2 [M+H]+.
To a solution of benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (90.0 mg, 0.120 mmol, 1 eq) in DCM (4 mL) was added m-CPBA (62.0 mg, 0.360 mmol, 3.03 eq). The mixture was stirred at 25° C. for 12 h and then washed with aqueous NaHCO3 and aqueous Na2SO3 solution. Then the mixture was extracted with EtOAc, the organic layers were combined and washed with brine, dried over Na2SO4 and concentrated in vacuo affording the title compound (74 mg, 0.090 mmol, 57% yield) as a white solid. MS (ESI): 790.3 [M+H]+.
To a solution of benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (55.0 mg, 0.070 mmol, 1 eq) in MeOH (2 mL) was added Pd/C (40.0 mg) and the mixture was stirred at 25° C. for 25 min under an atmosphere of hydrogen. The mixture was filtered and purified by prep-HPLC affording the title compound (30 mg, 0.050 mmol, 66% yield) as a white solid. MS (ESI): 656.1 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (20.0 mg, 0.030 mmol, 1 eq) in MeOH (2 mL) was added formaldehyde (33.0 mg, 0.410 mmol, 13.34 eq). After the mixture was stirred for 10 min sodiumtriacetoxyborohydride (66.0 mg, 0.310 mmol, 10.21 eq) was added. Then the mixture was stirred at 25° C. for 1 h and then poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The remaining residue was purified by prep-HPLC affording the title compound (11 mg, 0.020 mmol, 43% yield) as a white solid. MS (ESI): 670.2 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (11.0 mg, 0.020 mmol, 1 eq) in EtOAc (2 mL) was added HCl in EtOAc (2.0 mL, 8 mmol, 487.35 eq). The mixture was stirred at 25° C. for 1 h and then concentrated in vacuo. The remaining residue was purified by prep-HPLC and after lyophilisation the title compound (4.6 mg, 0.010 mmol, 45% yield) was obtained as white solid as a formic acid salt. MS (ESI): 570.2 [M+H]+.
To a solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 54, step b)) (230.0 mg, 0.380 mmol, 1 eq) in DCM (10 mL) was added m-CPBA (40.63 mg, 0.190 mmol, 0.500 eq), the mixture was stirred at 20° C. for 16 h. The mixture was diluted with aqueous Na2SO3 sol., aqueous Na2CO3 sol. and DCM, washed with H2O and brine, dried over Na2SO4, filtered and concentrated to give a residue which was purified by column chromatography, affording the title compound epimer A (120 mg, 0.190 mmol, 51% yield) as colorless gum (MS (ESI): 571.1 [M-isobutene+H]+) and tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1,4-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (epimer B) (100 mg, 0.160 mmol, 42% yield) as colorless gum. MS (ESI): 571.1 [M-isobutene+H]+.
A solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1,4-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (epimer A) (100.0 mg, 0.160 mmol, 1 eq) in HCl/EtOAc (10.0 mL, 40 mmol, 250.65 eq) was stirred at 20° C. for 1 h. The mixture was concentrated to give a residue, which was purified by prep-HPLC (HCl). The elution was lyophilized and the residue was again purified by prep-HPLC. The elution was lyophilized affording the title compound (29.6 mg, 0.050 mmol, 33% yield) as a white solid as a hydrochloride salt. MS (ESI): 527.0 [M+H]+.
Example 453 of the following table was prepared in analogy to Example 452.
To a solution of tert-butyl (R)-(5-(4-chlorobenzyl)-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)carbamate (Example 63, step a) (462 mg, 0.905 mmol, 1 eq) in dry tetrahydrofuran (9.24 mL) were added NEt3 (97.11 mg, 133 μL, 0.96 mmol, 1.06 eq) and CDI (155.62 mg, 0.960 mmol, 1.06 eq) under an atmosphere of nitrogen. The light yellow solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuo and the residue was taken up in EtOAc, washed with aqueous 1N HCl solution, aqueous sat. NaHCO3 solution and brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (406 mg, 84%) as a light yellow foam. MS (ESI): 465.2 [M-isobutene+H]+.
To a colorless solution of N-[(3R)-5-(4-chlorobenzyl)-8-fluoro-4-keto-7-(2-keto-3H-1,3,4-oxadiazol-5-yl)-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (40 mg, 0.075 mmol, 1 eq) in dry DMF (1 mL) were added DIPEA (19.45 mg, 25.59 μL, 0.150 mmol, 2 eq) and morpholine (13.11 mg, 13.02 μL, 0.150 mmol, 2 eq). BOP (36.6 mg, 0.083 mmol, 1.1 eq) was added after stirring for 5 min. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured on ice-water and the resulting mixture was extracted with EtOAc three times. The organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated under vacuum to obtain the crude product as light yellow oil. The crude residue was purified by column chromatography on silica gel (heptane:EtOAc 1:0 to 1:1) affording the title compound (32 mg, 72% yield) as a white solid. MS (ESI): 590.4 [M+H]+.
To a solution of N-[(3R)-5-(4-chlorobenzyl)-8-fluoro-4-keto-7-(5-morpholino-1,3,4-oxadiazol-2-yl)-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (29 mg, 0.049 mmol, 1 eq) in tetrahydrofuran, extra dry (0.500 mL) was added m-CPBA (27.54 mg, 0.123 mmol, 2.5 eq). The reaction mixture was stirring at room temperature for 6 h. NaOH 1N aq. was added and the mixture was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude residue was purified by column chromatography on silica gel (heptane:EtOAc 1:0 to 1:1) affording the title compound (20 mg, 66%) as a white solid. MS (ESI): 622.4 [M+H]+.
The title compound was prepared in analogy to method 6c from N-[(3R)-5-(4-chlorobenzyl)-8-fluoro-1,1,4-triketo-7-(5-morpholino-1,3,4-oxadiazol-2-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (17 mg, 0.027 mmol) with additional 4 drops of HCl (4M in dioxane) and was obtained as a white solid, as a hydrochloric salt and HFIP adduct (13.2 mg, 67%). MS (ESI): 522.3 [M+H]+.
To a colorless solution of N-[(3R)-5-(4-chlorobenzyl)-8-fluoro-1,1,4-triketo-7-(2-keto-3H-1,3,4-oxadiazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (Example 454, step a)) (50 mg, 0.081 mmol, 1 eq) in dry DMF (0.909 mL) were added DIPEA (21.04 mg, 28.43 μL, 0.163 mmol, 2 eq) and cyclopentylamine (13.86 mg, 16.58 μL, 0.163 mmol, 2 eq). Then BOP (39.58 mg, 0.090 mmol, 1.1 eq) was added and the mixture was stirred over night. The reaction mixture was poured on ice-water and extracted with EtOAc three times. The organic layers were combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel to afford the title compound (24.5 mg, 46%) as an off-white solid. MS (ESI): 620.4 [M+H]+.
The title compound was prepared in analogy to method 6c from N-[(3R)-5-(4-chlorobenzyl)-7-[5-(cyclopentylamino)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-triketo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (20.19 mg, 0.031 mmol) with additional 4 drops of HCl (4M in dioxane) and was obtained as a light yellow solid, as a hydrochloric salt (16.9 mg, 97%). MS (ESI): 520.3 [M+H]+.
The examples 456 to 482 of the following table were prepared in analogy to Example 455, using the appropriate amine building block:
To a solution of 2-(1-aminocyclohexyl) ethanol (CAS 24682-53-9) (50 mg, 0.349 mmol, 1 eq) in THE (3.49 ml) was added tert-butyldimethylsilyl chloride (68.4 mg, 0.454 mmol, 1.3 eq) and imidazole (59.41 mg, 0.873 mmol, 2.5 eq). The light yellow solution was stirred at RT for 1 d. Water and EtAOc were added to the reaction mixture. The layers were separated and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc in heptane, 0-100%) to afford the title compound (52.3 mg, 58%) as light yellow oil. MS (ESI): 258.4 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (20 mg, 0.038 mmol) in analogy to general procedure 15 and was obtained as light yellow solid (29.6 mg, 96% yield). MS (ESI): 808.6 [M−H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-[[[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]cyclohexyl]carbamoylamino]carbamoyl]-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (29.6 mg, 0.037 mmol) in analogy to general procedure 8b and was obtained as white solid (17.4 mg, 600% yield). MS (ESI) 792.6 [M+H]+.
The title compound was prepared from tert-butyl acetate-(3R)-3-amino-7-[5-[[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]cyclohexyl]amino]-1,3,4-oxadiazol-2-yl]-5-[(4-hlorophenyl)methyl]-8-fluoro-1,1-dioxo-2,3-dihydro-1lambda6,5-benzothiazepin-4-one (17.4 mg, 0.022 mmol) in analogy to general procedure 6d and was obtained as a light-yellow solid (12.3 mg, 90% yield), as hydrochloride salt. MS (ESI): 576.3 [M−H]−.
The title compound was prepared from 3-amino-1,1,1-trifluoro-2-methyl-propan-2-ol (CAS 354-68-7) (50 mg,0.349 mmol) in analogy to Example 483, step a) and was obtained as light yellow liquid (67.9 mg, 76% yield). MS (ESI): 258.2 [M+H]+
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl) methyl]-8-fluoro-7-(hydrazinecarbonyl)-1,1,4-trioxo-3,5-dihydro-2H-1λ6-benzothiepin-3-yl]carbamate (20 mg, 0.038 mmol) in analogy to general procedure 15 and was obtained as light yellow solid (33.7 mg, 93% yield). MS (ESI): 808.5 [M−H]−.
The title compound was prepared from tert-butyl N-[(3R)-7-[[[2-[tert-butyl(dimethyl)silyl]oxy-3,3,3-trifluoro-2-methyl-propyl]carbamoylamino]carbamoyl]-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ6-benzothiepin-3-yl]carbamate (31.1 mg, 0.033 mmol) in analogy to general procedure 8b and was obtained as light yellow solid (10.7 mg, 41% yield). MS (ESI): 792.5 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-[5-[[[2-[tert-butyl(dimethyl)silyl]oxy-3,3,3-trifluoro-2-methyl-propyl]amino]-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ6-benzothiepin-3-yl]carbamate (10.7 mg, 0.014 mmol) in analogy to general procedure 6d and was obtained as an off-white solid (10.0 mg, 99% yield). MS (ESI): 690.4 [M−H]−.
To a colorless solution of (3R)-3-amino-7-[5-[[[2-[tert-butyl(dimethyl)silyl]oxy-3,3,3-trifluoro-2-methyl-propyl]amino]-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1-dioxo-3,5-dihydro-2H-1λ6-benzothiepin-4-one (10 mg, 0.014 mmol) in dry THE (0.144 mL) was slowly added TBAF (1M in THF) (17.34 μL,0.017 mmol, 1.2 eq). The reaction mixture was stirred at RT for 1 hour. Then the mixture was quenched with water and extracted twice with EtOAc. The combined organic layer was washed with 1N HCL and brine, dried over magnesium sulfate, filtered and concentrated under recued pressure to obtain the title compound as brown solid (8 mg, 96% yield). MS (ESI): 578.3 [M+H]+.
To a suspension of NaH (52.93 mg, 1.32 mmol, 1 eq) in THE (2.83 mL) under Ar atmosphere at 5° C. was added (4,4-difluoro-3-piperidyl)methanol (CAS 1331823-62-1) (200 mg, 1.32 mmol, 1 eq). The reaction was stirred at RT for 1 hour. Then, a solution of TBDMS-Cl (199.43 mg, 1.32 mmol, 1 eq) in THF (0.472 mL) was added dropwise at 0° C. and the mixture stirred at RT overnight. The reaction mixture was quenched with 10 ml of MeOH and concentrated. Heptane was added and the mixture washed with water, brine, dried over MgSO4, filtered and concentrated to afford the title compound (335 mg, 86% yield) as colorless oil. MS (ESI): 266.2 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (30 mg, 0.054 mmol) in analogy to Example 455, step a) and was obtained as white solid (30 mg, 69% yield). MS (ESI) 800.5 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-[5-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4,4-difluoro-1-piperidyl]-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (30 mg, 0.037 mmol) in analogy to general procedure 6d and was obtained as white solid (15 mg, 68% yield). MS (ESI): 586.2 [M+H]+.
Tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.202 mmol, Example 63, step a) was stirred in THE (1 mL) at RT. 2-isocyanato-2-methyl-propanenitrile (CAS 52161-43-0) (22.25 mg, 0.202 mmol) was added as a solution in THF (1 mL) via syringe and stirred at RT for 15 min. Then, a solution of 2-isocyanato-2-methyl-propanenitrile (4.45 mg, 0.040 mmol) in THE (0.5 ml) was added and stirring was continued for 1 hour. The reaction was concentrated under reduced pressure and the crude material purified by column chromatography on silica gel (0-100% EtOAc in heptane) to afford the title compound (110 mg, 84% yield) as white solid. MS (ESI): 605.3 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[[(1-cyano-1-methyl-ethyl)carbamoylamino]carbamoyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (110 mg, 0.182 mmol) in analogy to general procedure 8a and was obtained as colorless oil (30.5 mg, 27% yield). MS (ESI): 587.3[M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-[(1-cyano-1-methyl-ethyl)amino]-1,3,4-oxadiazol-2-yl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (30.5 mg, 0.052 mmol) in analogy to general procedure 5 and was obtained as white solid (21 mg, 65% yield). MS (ESI): 563.2 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-[(1-cyano-1-methyl-ethyl)amino]-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (21 mg, 0.034 mmol) in analogy to general procedure 6d and was obtained as white solid (18.2 mg, 97% yield), as hydrochloride salt. MS (ESI): 519.3 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 63, step a)) (50 mg, 0.098 mmol, 1 eq) in THF (0.653 mL) was added NEt3 (29.75 mg, 40.97 μL, 0.294 mmol, 3 eq) and 1,1,1-trifluoro-2-isocyanato-ethane (CAS 371-92-6) (14.7 mg, 10.6 μL, 0.118 mmol, 1.2 eq). The solution was stirred at RT for 2 hours. To this solution was added p-toluenesulfonyl chloride (56.04 mg, 0.294 mmol, 3 eq) in one portion and stirred for 2 h. The reaction mixture was concentrated and the remaining crude purified by column chromatography on silica gel (0-50% EtOAc in heptane) to afford the title compound (41 mg, 63% yield) as white solid. MS (ESI): 546.1 [M+H−isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-[5-(2,2,2-trifluoroethylamino)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (38 mg, 0.057 mmol) in analogy to general procedure 5 and was obtained as a white solid (26 mg, 72% yield). MS (ESI): 578.1 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-[5-(2,2,2-trifluoroethylamino)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (25 mg, 0.039 mmol) in analogy to general procedure 6d and was obtained as a white solid (21 mg, 90% yield), as hydrochloride salt. MS (ESI): 534.1 [M+H]+.
Example 488 of the following table was prepared in analogy to Example 487 using the appropriate isocyanate building block.
To a solution of tert-butyl N-(5,5-difluoro-3-piperidyl)carbamate (500 mg, 2.01 mmol, 1 eq) in THE (5 ml) at 0° C. was added DIPEA (259 mg, 351 μL, 2.01 mmol, 1 eq) and 9H-fluoren-9-ylmethyl carbonochloridate (520 mg, 2.01 mmol, 1 eq). The reaction mixture was allowed to warm to RT and was overnight. The reaction mixture was partitioned between EtOAc and 0.5M NaOH.
The layers were separated and the organic layer washed with 1M HCl and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The remaining crude material was purified by column chromatography on silica gel (0-50% EtOAc in heptane) to afford the title compound (806 mg, 74% yield) as a white solid. MS (ESI): 359.2 ([M-isobutene-CO2+H]+.
The title compound was prepared from 9H-fluoren-9-ylmethyl 5-(tert-butoxycarbonylamino)-3,3-difluoro-piperidine-1-carboxylate (672.6 mg, 1.47 mmol, 1 eq) in analogy to general procedure 6a and was obtained as a white solid (814 mg, 100%), as hydrochloride salt. MS (ESI): 359.4 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (218 mg, 0.354 mmol, Example 63, step a)) and 9H-fluoren-9-ylmethyl 5-amino-3,3-difluoro-piperidine-1-carboxylate (250 mg, 0.443 mmol) in analogy to general procedure 15 and was obtained as a white solid (194 mg, 38% yield). MS (ESI): 877.2 [M−H]−.
The title compound was prepared from 9H-fluoren-9-ylmethyl 3,3-difluoro-5-[[[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carbonyl]amino]carbamoylamino]piperidine-1-carboxylate (244 mg, 0.208 mmol) in analogy to general procedure 8b and was obtained as a white solid (156 mg, 78% yield). MS (ESI) 861.4 [M+H]+.
The title compound was prepared from 9H-fluoren-9-ylmethyl 3,3-difluoro-5-[[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]amino]piperidine-1-carboxylate (156 mg, 0.163 mmol) in analogy to general procedure 5 and was obtained as a white solid (127 mg, 83% yield). MS (ESI): 893.4 [M+H]+.
To a solution of 9H-fluoren-9-ylmethyl 3,3-difluoro-5-[[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]amino]piperidine-1-carboxylate (127 mg, 0.135 mmol, 1 eq) in DCM (1 mL) was added 4-methylpiperidine (107.15 mg, 127.86 μL, 1.08 mmol, 8 eq) at RT and stirred for 2 h. The reaction mixture was partitioned between EtOAc and sat. NaHCO3. The layers were separated and the aqueous layer extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The remaining residue was purified by column chromatography on silica gel (0-5% MeOH in DCM) to give the title compound (34.5 mg, 36% yield) as a white solid. MS (ESI) 671.4 [M+H]−.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-[(5,5-difluoro-3-piperidyl)amino]-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (10 mg, 0.015 mmol) in analogy to general procedure 6d and was obtained as a white solid (7.6 mg, 78% yield), as hydrochloride salt. MS (ESI): 569.2 [M−H]−.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-[(5,5-difluoro-3-piperidyl)amino]-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (Example 489, step e) (22.5 mg, 0.032 mmol, 1 eq) in DCM (0.652 mL) was added DIPEA (10.29 mg, 13.91 μL, 0.080 mmol, 2.5 eq) and methyl chloroformate (3.31 mg, 2.71 μL, 0.035 mmol, 1.1 eq) at RT and the reaction mixture was stirred for 3 h. The reaction was concentrated and purified by column chromatography on silica gel (0-3% MeOH in DCM) to afford the title compound (15.7 mg, 67% yield) as a white solid. MS (ESI) 729.3 [M+H]+.
The title compound was prepared from methyl 3,3-difluoro-5-[[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]amino]piperidine-1-carboxylate (15.7 mg, 0.022 mmol, 1eq) in analogy to general procedure 6d and was obtained as a white solid (8.4 mg, 58% yield), as hydrochloride salt. MS (ESI): 630.0 [M+H]−.
Tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (250 mg, 0.505 mmol, 1 eq) was stirred with sodium bicarbonate (127 mg, 1.52 mmol, 3 eq) and cyanogen bromide (CAS 506-68-3) (160 mg, 1.52 mmol, 3 eq) in 1,4-dioxane (8 mL) and water (5 mL) at RT for 45 min. Water was added and the mixture extracted three times with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound (283 mg, 99% yield) as a light yellow solid. MS (ESI): 520.2 [M+H]+.
tert-butyl N-[(3R)-7-(5-amino-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (282 mg, 0.542 mmol, 1 eq) was dissolved in acetonitrile (2.5 mL) and CuBr2 (127.19 mg, 0.569 mmol, 1.05 eq) was added at RT. To the resulting green mixture was added isopentyl nitrite (CAS 110-46-3) (127.07 mg, 146.05 mmol, 2 eq) in one portion and the reaction mixture was stirred at RT overnight. The reaction was concentrated and the remaining crude directly purified by column chromatography on silica gel (0-80% EtOAc in heptane) to give the title compound (60 mg, 19% yield) as a colorless oil. MS (ESI): 529.5 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(5-bromo-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (30 mg, 0.051 mmol) in analogy to general procedure 5 and was obtained as a white solid (22 mg, 67% yield). MS (ESI): 615.2 [M+H]+.
Tert-butyl N-[(3R)-7-(5-bromo-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (22 mg, 0.036 mmol, 1 eq) was stirred with 3,3-dimethylmorpholine (4.94 mg, 5.28 μL, 0.043 mmol, 1.2 eq) and sodium carbonate (3.79 mg, 0.036 mmol, 1 eq) in DMF (100 μL) at RT overnight. The crude material was concentrated and the remaining crude directly purified by column chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (12.5 mg, 44% yield) as light yellow solid. MS (ESI): 650.3 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(3,3-dimethylmorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (12.5 mg, 0.016 mmol) in analogy to general procedure 6d and was obtained as a white solid (6.1 mg, 71% yield). MS (ESI): 550.3 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (80 mg, 0.129 mmol, 1 eq, Example 63, step a) and 1-(2,2,2-trifluoroethyl)piperidin-3-amine dihydrochloride (CAS 1803583-68-7) (51.18 mg, 0.201 mmol, 1.55 eq) in analogy to general procedure 15 and was obtained as light yellow solid (122 mg, 59% yield). MS (ESI): 703.4 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-[[[1-(2,2,2-trifluoroethyl)-3-piperidyl]carbamoylamino]carbamoyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (122 mg, 0.076 mmol) in analogy to general procedure 8b and was obtained as light yellow solid (40 mg, 74% yield). MS (ESI): 685.4 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-[5-[[1-(2,2,2-trifluoroethyl)-3-piperidyl]amino]-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (40 mg, 0.058 mmol, 1 eq) in analogy to general procedure 5 using m-CPBA (39 mg, 3.75 eq) to give an off-white solid (77 mg) containing the title compound. MS (ESI): 733.3 [M+H]+.
tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-[[1-oxido-1-(2,2,2-trifluoroethyl)piperidin-1-ium-3-yl]amino]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (77 mg, 0.105 mmol, 1 eq) was dissolved in 1,2 dichloroethane (2 mL) and phenylboronic acid (14.09 mg, 0.116 mmol, 1.1 eq) was added in one portion and the resulting mixture heated to 85° C. for one hour. The reaction was allowed to cool to RT and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (100% EtOAc) to afford the title compound (20 mg, 26% yield) as a white solid. MS (ESI): 717.4 [M+H]−.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-7-[5-[[1-(2,2,2-trifluoroethyl)-3-piperidyl]amino]-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (20 mg, 0.028 mmol) in analogy to general procedure 6d and was obtained as white solid (12 mg, 70% yield). MS (ESI): 617.2 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 63, step a)), 80 mg, 0.129 mmol) and 1-(3,3-difluorocyclobutyl)ethylamine hydrochloride (CAS 1780822-89-0) (34.43 mg, 0.201 mmol) in analogy to general procedure 15 and was obtained as yellow solid (115 mg, 95% yield). MS (ESI): 556.2 [M+H-Boc]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[[1-(3,3-difluorocyclobutyl)ethylcarbamoylamino]carbamoyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5 benzothiazepin-3-yl]carbamate (110 mg, 0.117 mmol) in analogy to general procedure 8b and was obtained as white solid (41 mg, 53% yield). MS (ES): 638.2 [M+H-]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-[1-(3,3-difluorocyclobutyl)ethylamino]-1,3,4-oxadiazol-2-yl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (36 mg, 0.054 mmol) in analogy to general procedure 5 and was obtained as white solid (25 mg, 69% yield). MS (ESI): 670.2 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-[1-(3,3-difluorocyclobutyl)ethylamino]-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (20 mg, 0.03 mmol) in analogy to general procedure 6d and was obtained as white solid (18 mg, 99% yield). MS (ESI): 570.2 [M+H]+.
The examples 494 to 506 of the following table were prepared in analogy to Example 493, using the appropriate amine building block.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 63, step a)) (200 mg, 0.392 mmol, 1 eq) in DCM (2 mL) was added NEt3 (39.66 mg, 54.63 μL, 0.392 mmol, 1 eq) and the mixture was cooled down to 0° C. 2-bromoacetyl bromide (126 mg, 54.5 μL, 0.627 mmol, 1.6 eq) was added dropwise. Upon complete addition, the reaction was allowed to warm to RT and was stirred for 1 hour. The reaction mixture was poured on water and extracted three times with DCM. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The remaining crude residue was purified by column chromatography on silica gel (0-50% EtOAc in heptane) to afford the title compound (135 mg, 48% yield) as a white solid. MS (ESI): 615.3 [M−H]−.
The title compound was prepared from tert-butyl N-[(3R)-7-[5-(bromomethyl)-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (85 mg, 0.138 mmol, 1 eq) in analogy to general procedure 8a and was obtained as a colorless gum (22.5 mg, 20% yield). MS (ESI): 595.3 [M−H]−.
To a solution of tert-butyl N-[(3R)-7-[5-(bromomethyl)-1,3,4-oxadiazol-2-yl]-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (30 mg, 0.05 mmol, 1 eq) in DCM (0.5 mL) was added DIPEA (16.21 mg, 21.91 μL, 0.125 mmol, 2.5 eq) and 3-methylazetidine hydrochloride (CAS 935669-28-6) (11.88 mg, 0.11 mmol, 2.2 eq). The reaction mixture was stirred at RT overnight. The mixture was poured on water and extracted three times with DCM. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography on silica gel (0-100% EtOAc in heptane) to afford the title compound (17.2 mg, 55% yield) as a colorless oil. MS (ESI): 588.3 [M+H]+.
The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-[(3-methylazetidin-1-yl)methyl]-1,3,4-oxadiazol-2-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (17.2 mg, 0.028 mmol) in analogy to general procedure 6d and was obtained as off-white solid (13.3 mg, 66% yield), as hydrochloride salt and 1,1,1,3,3,3-hexafluoropropan-2-ol adduct. MS (ESI): 244.7 [M+H]2+.
N-[(3R)-7-bromo-5-(4-chlorobenzyl)-8-fluoro-1,1,4-triketo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (Example 37, step a)) (66 mg, 0.120 mmol, 1 eq) was stirred with bis(pinacolato)diboron (67.31 mg, 0.265 mmol, 2.2 eq), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane adduct (11.31 mg, 0.014 mmol, 0.115 eq) and potassium acetate (35.47 mg, 0.361 mmol, 3 eq) in dry 1,4-dioxane (1.2 mL) at 100° C. for 1 h in a closed vial. Water was added and the mixture was extracted three times with EtOAc. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to afford the crude title compound (143 mg) as a light brown oil. MS (ESI): 457.1 [M-isobutene+H]+.
[(3R)-3-(tert-butoxycarbonylamino)-5-(4-chlorobenzyl)-8-fluoro-1,1,4-triketo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]boronic acid (61 mg, 0.119 mmol, 1 eq) was stirred with 2-bromo-5-tert-butyl-1,3,4-thiadiazole (26.31 mg, 0.119 mmol, 1 eq), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane adduct (14.57 mg, 0.018 mmol, 0.15 eq) and Na2CO3 (37.83 mg, 0.357 mmol, 3 eq) in a mixture of 1,4-dioxane (2.5 mL) and water (0.5 mL) at 100° C. for 2 h in a closed vial. The crude material was purified by column chromatography on silica gel (heptane:EtOAc 1:0 to 0:1) affording the title compound (6.4 mg, 9%) as a white solid. MS (ESI): 609.3 [M+H]+.
The title compound was prepared in analogy to method 6c from N-[(3R)-7-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-5-(4-chlorobenzyl)-8-fluoro-1,1,4-triketo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamic acid tert-butyl ester (6.4 mg, 0.011 mmol) with additional 4 drops of HCl (4M in dioxane) and was obtained as a white solid as a formic acid salt (3.8 mg, 65%). MS (ESI): 509.2 [M+H]+.
To a solution of 2,4-difluoroaniline (40 g, 309 mmol) in HCl (6N, 309.81 mL, 1859 mmol, 6 eq) was added NaNO2 (23.51 g, 340 mmol, 1.1 eq) while the temperature was kept at 0° C. After stirring at this temperature for 30 min, the mixture was added to a stirred solution of NaOAc (33.03 g, 402.76 mmol, 1.3 eq) and ethyl 2-chloroacetoacetate (56.09 g, 340.79 mmol, 1.1 eq) in EtOH (400 mL) while the temperature was kept below 5° C. and then the reaction mixture was stirred at 0° C. for another 3 h. The reaction mixture was filtered and the filter cake was washed with EtOH and water. The solid material was recrystallized from EtOH, affording the desired product (48 g, 182 mmol, 59% yield) as light yellow solid.
To a solution of ethyl (2E)-2-chloro-2-[(2,4-difluorophenyl)hydrazono]acetate (48.0 g, 182 mmol, 1 eq) in THE (182 mL) was added NH3·H2O (136.0 mL, 182 mmol, 1 eq) dropwise and the mixture was stirred at 20° C. for 12 h. The reaction mixture was diluted with petroleum ether and EtOAc. After 10 min of stirring the two layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuum to afford the title compound (43.3 g, 178 mmol, 97% yield) as light yellow solid.
Acetic acid (42.47 g, 707.21 mmol, 4 eq) was added to a stirred solution of ethyl (2E)-2-amino-2-[(2,4-difluorophenyl)hydrazono]acetate (43.0 g, 176 mmol, 1 eq) in THE (400 mL) and the mixture was heated to 85° C. Then NaNO2 (14.64 g, 212 mmol, 1.2 eq) in water (40 mL) was added to the reaction mixture dropwise over 30 min. The reaction mixture was stirred at 85° C. for 11 h 30 min. The mixture was concentrated in vacuum to remove the solvent and the remaining residue was re-dissolved in EtOAc. The EtOAc solution was washed with saturated NaHCO3 solution, water and brine, dried over Na2SO4 and concentrated in vacuum to afford the title compound (29.3 g, 115 mmol, 65% yield) as light yellow solid.
MeMgBr (13.11 mL, 39.3 mmol, 2 eq) and NEt3 (9933 mg, 98.35 mmol, 5 eq) were added to a stirred solution of ethyl 2-(2,4-difluorophenyl)tetrazole-5-carboxylate (5000 mg, 19.6 mmol, 1 eq) in toluene (20 mL) at −10° C. for 3 h. To the mixture was added saturated NH4Cl solution (20 ml) and the temperature was kept at 0° C. The mixture was then extracted with EtOAc two times. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuum to afford the title compound (2.2 g, 9.81 mmol, 50% yield) as yellow solid.
To a solution of 1-[2-(2,4-difluorophenyl)tetrazol-5-yl]ethanone (2.2 g, 9.81 mmol, 1 eq) in MeOH (30 mL) was added NaBH4 (597.1 mg, 15.7 mmol, 1.6 eq) and the temperature was kept at 0° C. The reaction mixture was stirred at this temperature for 1 h. The reaction mixture was treated with 1M aqueous HCl and extracted with EtOAc two times. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuum to afford the title compound (2 g, 8.84 mmol, 90% yield) as light yellow oil.
To a solution of 1-[2-(2,4-difluorophenyl)tetrazol-5-yl]ethanol (2 g, 8.84 mmol, 1 eq) in MeCN (10 mL) was added SOCl2 (5212.66 mg, 44.21 mmol, 5 eq) while the temperature was kept at 0° C. for 1 h and then the mixture was stirred at 25° C. for 11 h. The reaction mixture was poured into sat. NaHCO3 solution and this mixture was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuum to get crude product, which was purified by column chromatography to afford the title compound (1.7 g, 6.95 mmol, 79% yield) as light yellow oil.
To a suspension of Raney Ni (170.0 mg) in MeOH (10 mL) was added 5-(1-chloroethyl)-2-(2,4-difluorophenyl)tetrazole (1.7 g, 6.95 mmol, 1 eq) and the mixture was stirred under an atmosphere of hydrogen at 25° C. for 12 h. The reaction mixture was filtered and concentrated in vacuum, affording the title compound (1.0 g, 4.76 mmol, 69% yield) as light yellow oil.
To a solution of 2-(2,4-difluorophenyl)-5-ethyl-tetrazole (750 mg, 3.57 mmol, 1 eq) in sulfuric acid (370 mg, 3.78 mmol, 1.06 eq) was added nitric acid (247 mg, 3.93 mmol, 1.1 eq) while the temperature was kept at 0° C. and the mixture was stirred at 0° C. for 3 h. The reaction mixture was poured into ice water and the resulting mixture was extracted with DCM three times. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuum to afford the title compound (800 mg, 3.14 mmol, 88% yield) in 10 ml DCM as a light yellow liquid.
To a solution of 2-(2,4-difluoro-5-nitro-phenyl)-5-ethyl-tetrazole (480.0 mg, 1.88 mmol, 1 eq) in DCM (10 mL) were added NEt3 (379 mg, 3.76 mmol, 2 eq) and (2R)-2-(tert-butoxycarbonylamino)-3-sulfanyl-propanoic acid (499 mg, 2.26 mmol, 1.2 eq) and the mixture was stirred at 25° C. for 12 h. The reaction mixture was diluted with EtOH (10 mL) and then concentrated at 20° C. under reduced pressure to remove the DCM. The liquid was used directly for the next step. MS (ESI): 357.3 [M-isobutene-CO2+H]+.
To a solution of (2R)-2-(tert-butoxycarbonylamino)-3-[4-(5-ethyltetrazol-2-yl)-5-fluoro-2-nitro-phenyl]sulfanyl-propanoic acid (700 mg, 1.53 mmol, 1 eq) and ammonium chloride (246 mg, 4.6 mmol, 3 eq) in a mixture of ethanol (30 mL) and water (10 mL) was added iron powder (257 mg, 4.6 mmol, 3 eq) and the mixture was stirred at 20° C. for 12 h. The reaction mixture was filtered and filtrate was concentrated in vacuum to afford a residue containing the title compound (700 mg) as light yellow oil. MS (ESI): 371.2 [M-isobutene+H]+.
To a solution of (2R)-3-[2-amino-4-(5-ethyltetrazol-2-yl)-5-fluoro-phenyl]sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (700 mg, 1.64 mmol, 1 eq) and DIPEA (423 mg, 3.28 mmol, 2 eq) in THE (10 mL) was added T3P (1.56 g, 2.46 mmol, 1.5 eq) and the mixture was stirred at 20° C. for 12 h. The reaction mixture was concentrated in vacuum to obtain a yellow residue which was purified by column chromatography on silica gel, affording the title compound (100 mg, 0.24 mmol, 15% yield) as light yellow solid. MS (ESI): 353.3 [M-isobutene+H]+.
To a mixture of tert-butyl N-[(3R)-7-(5-ethyltetrazol-2-yl)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (95.0 mg, 0.230 mmol, 1 eq) and potassium carbonate (64.3 mg, 0.47 mmol, 2 eq) in DMF (1 mL) were added 1-(bromomethyl)-4-chlorobenzene (56.9 mg, 0.28 mmol, 1.2 eq) and potassium iodide (0.02 mmol, 0.1 eq) and the mixture was stirred at 20° C. for 12 h. The reaction mixture was poured into water and the resulting mixture was extracted with EtOAc three times. The combined organic layers were washed with water (twice) and brine, dried over Na2SO4 and concentrated in vacuum to obtain a crude product which was purified by column chromatography on silica gel to afford the title compound (110 mg, 0.210 mmol, 89% yield) as light yellow oil. MS (ESI): 477.3 [M-isobutene+H]+.
The title compound was prepared in analogy to general method 5 from N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(5-ethyltetrazol-2-yl)-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (22.0 mg, 0.040 mmol, 1 eq) and was obtained (10 mg, 0.020 mmol, 43% yield) as a yellow solid. MS (ESI): 481.3 [M-isobutene-N2+H]+.
The title compound was prepared according to general method 6b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(5-ethyltetrazol-2-yl)-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (88.0 mg, 0.160 mmol, 1 eq) and was obtained as a white solid (17.3 mg, 0.040 mmol, 23% yield). MS (ESI): 437.1 [M-N2+H]+.
(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (CAS 2002449-40-1) (200 mg, 0.416 mmol, 1 eq) was dissolved in THF (1.8 mL). CDI (87.66 mg, 0.541 mmol, 1.3 eq) was added and the light yellow solution was stirred at RT for 30 min. This solution was then transferred via syringe to a separate solution of tert-butylhydrazine hydrochloride (51.82 mg, 0.416 mmol, 1 eq) in THE (0.6 mL) at RT and stirred overnight. The reaction mixture was poured on water and was extracted three times with EtOAc. The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. The remaining crude material was purified by column chromatography on silica gel (0-100% EtOAc in heptane) to afford the title compound (114 mg, 50% yield) as white solid. MS (ESI): 551.3 [M+H]+.
To a colorless solution of tert-butyl N-[(3R)-7-[(tert-butylamino)carbamoyl]-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.181 mmol, 1 eq) in THF (2 mL) was added pyridine (43.06 mg, 44.03 μL, 0.544 mmol, 3 eq) and the solution was cooled 0° C. A solution of trichloromethyl carbonochloridate (CAS 503-38-8) (39.49 mg, 24.08 μL, 0.200 mmol, 1.1 eq) in THE (2 mL) was added dropwise over a time of 5 min and stirred for further 10 min. The ice-bath was removed and the reaction mixture was stirred at RT for 90 min. The reaction was quenched by slow addition of aqueous ammonia. The mixture was then extracted three times with EtOAc. The combined organic layers washed with water and 0.1 N HCl, dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound (63.6 mg, 61% yield) as white solid. MS (ESI): 521.2 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(4-tert-butyl-5-oxo-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (63 mg, 0.109 mmol) in analogy to general procedure 5 and was obtained as white solid (61.8 mg, 93% yield). MS (ESI): 553.2 [M+H-isobutene]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(4-tert-butyl-5-oxo-1,3,4-oxadiazol-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (61.8 mg, 0.101 mmol) in analogy to general procedure 6d and was obtained as a white solid (47.5 mg, 85% yield), as hydrochloride salt. MS (ESI): 509.2 [M+H]+.
The title compound was prepared in analogy to general procedure 4 from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 321, Step c) (450 mg, 1.33 mmol) using 1-(bromomethyl)-4-(1,1,2,2-tetrafluoroethoxy)benzene (CAS 67033-41-4) (459 mg, 1.6 mmol) and was obtained as a light yellow solid (680 mg, 94% yield). MS (ESI): 488.0 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 12 from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (700 mg, 1.29 mmol) and was obtained as a light yellow solid (660 mg, 89% yield). MS (ESI): 521.1 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 10a from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (400 mg, 0.69 mmol) using 3-tert-butoxycarbonyl-3-azabicyclo[3.1.1]heptane-1-carboxylic acid (CAS 1250995-41-5) (200 mg, 0.83 mmol) and was obtained as a light yellow solid (500 mg, 90% yield). MS (ESI): 644.2 [M−2isobutene-CO2+H]+.
The title compound was prepared in analogy to general procedure 11a from 01-[(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]methylene]amino] O3-tert-butyl 3-azabicyclo[3.1.1]heptane-1,3-dicarboxylate (500 mg, 0.625 mmol) and was obtained as a white solid (380 mg, 77% yield). MS (ESI): 626.1 [M-CO2-2isobutene+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (170 mg, 0.217 mmol) and were obtained as a colorless oil (Epimer A, 95 mg, 49% yield) (MS (ESI): 624.1 [M-CO2-2isobutene+H]+) and as a colorless oil (Epimer B, 65 mg, 30% yield) (MS (ESI): 624.1 [M-CO2-2isobutene+H]+).
The title compound was prepared in analogy to general procedure 6e from tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,4-dioxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (Epimer A) (85 mg, 0.107 mmol). and was obtained as a light yellow solid (73 mg, 75% yield). MS (ESI): 598.2 [M+H]+.
To a solution of tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,4-dioxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (Epimer A) (73 mg, 0.088 mmol) and DIPEA (34.328 mg, 0.265 mmol) in DCM (2 mL) was added a solution of methyl chloroformate (8.36 mg, 0.088 mmol) in DCM (0.5 mL) at RT. The mixture was stirred for 1 hour at RT. The mixture was evaporated to dryness to obtain a light yellow oil which was purified by prep-HPLC affording the title compound (23.6 mg, 41% yield). MS (ESI): 656.2 [M+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (Example 511, Step d) (150 mg, 0.192 mmol) and was obtained as a white solid (165 mg, 106% yield). MS (ESI): 714.3 [M−Boc+H]+.
The title compound was prepared in analogy to Example 511, steps f to g) from tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (160 mg, 0.037 mmol) and was obtained as a white solid (47.3 mg, 39% yield). MS (ESI): 672.2 [M+H]+.
The title compound was prepared in analogy to general procedure 9a from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 321, Step d) (94 mg, 0.535 mmol) and was obtained as a white solid (14 mg, 5% yield). MS (ESI): 509.1 [M−H]−.
The title compound was prepared in analogy to general procedure 4 from tert-butyl N-[(3R)-8-fluoro-4-oxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,2,4-oxadiazol-3-yl]-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (14 mg, 0.027 mmol) and 4-fluorobenzyl bromide (7.78 mg, 5.08 μL, 0.041 mmol, 1.5 eq) and was obtained as a brown solid (18.3 mg, 86% yield). MS (ESI): 563.0 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-8-fluoro-5-[(4-fluorophenyl)methyl]-4-oxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (18.3 mg, 0.024 mmol) and was obtained as a white solid (7.3 mg, 45% yield). MS (ESI): 595.1 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-8-fluoro-5-[(4-fluorophenyl)methyl]-1,1,4-trioxo-7-[5-(1,2,2,2-tetrafluoro-]-methoxy-ethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (7.3 mg, 0.011 mmol) and was obtained as a white solid (5.7 mg, 87% yield). MS (ESI): 551.1 [M+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-8-fluoro-5-[(4-fluorophenyl)methyl]-4-oxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (Example 513, Step b) (18.3 mg, 0.024 mmol) and was obtained as a white solid (1.5 mg, 9% yield). MS (ESI): 633.3 [M−H]−.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-8-fluoro-5-[(4-fluorophenyl)methyl]-1,4-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (1.5 mg, 0.002 mmol) and was obtained as a colorless solid (1 mg, 63% yield). MS (ESI): 535.1 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 338, step a) (21 mg, 0.033 mmol) in MeOH (0.165 mL) were added ammonium carbamate (6.45 mg, 0.083 mmol) and iodobenzene diacetate (31.96 mg, 0.099 mmol) and the reaction was stirred at RT for 30 mins. Isolute was added and the reaction was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (EtOAc:heptane=0:10 to 8:2) to afford the desired title compound as an off-white solid (7.0 mg, 30% yield). MS (ESI): 610.0 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-1-imino-1,4-dioxo-7-[5-(1,2,2,2-tetrafluoro-]-methoxy-ethyl)-], 2,4-oxadiazol-3-yl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (7 mg, 0.01 mmol) and was obtained as a light yellow solid, as a hydrochloric salt (6 mg, 8900 yield). MS (ESI): 566.0 [M+H]+.
Example 516 of the following table was prepared in analogy to Example 515, steps a to b), using the appropriate building block.
The title compound was prepared in analogy to general procedure 7a from (3R)-3-amino-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (Example 53, Step b) (1000 mg, 1.89 mmol) and was obtained as a light yellow solid (470 mg, 36% yield). MS (ESI): 651.2 [M+Na]+.
The title compound was prepared in analogy to general procedure 8a from tert-butyl N-[(3R)-7-[(2,2-dimethylpropanoylamino)carbamoyl]-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (470 mg, 0.748 mmol) and was obtained as a light yellow gum (250 mg, 55% yield). MS (ESI): 611.4 [M+H]+.
To a solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (250 mg, 0.409 mmol) in MeOH (2 mL) were added ammonium carbamate (103.2 mg, 1.64 mmol) and iodobenzene diacetate (395 mg, 1.23 mmol) and the reaction was stirred at 15° C. for 16 hours. The crude was evaporated to dryness and purified by column chromatography on silica gel (PE:EtOAc=9:1 to 1:4) and the title compound obtained as a light yellow gum (88 mg, 30% yield) MS (ESI): 642.2 [M+H]−.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-]-imino-1,4-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (88 mg, 0.137 mmol) and the epimers were separated by prep-HPLC. They were obtained as white solids (Epimer A, 12.5 mg, 15% yield) as a hydrochloric salt (MS (ESI): 542.1 [M+H]+) and (Epimer B, 24.1 mg, 30% yield) as a hydrochloric salt (MS (ESI): 542.1 [M+H]+).
To a solution of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1-imino-1,4-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (Example 517, Step c) (98 mg, 0.153 mmol) in 1,4-dioxane (5 mL) were added methylboronic acid (36.5 mg, 0.61 mmol), copper(II) acetate (41.1 mg, 0.23 mmol) and pyridine (29 mg, 0.37 mmol) and the reaction was stirred at 90° C. for 3 hours. The solvent was evaporated to dryness and purified by column chromatography (PE:EtOAc=9:1 to 1:4). The title compound was obtained as a white solid (58 mg, 53% yield) MS (ESI): 656.3 [M+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1-methylimino-1,4-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (83.7 mg, 0.128 mmol). and the epimers were separated by prep-HPLC. They were obtained as white solids (Epimer A, 7.4 mg, 10% yield) as a hydrochloric salt (MS (ESI): 556.3 [M+H]+) and (Epimer B, 22.3 mg, 26% yield) as a hydrochloric salt (MS (ESI): 556.3 [M+H]+.
To a solution of tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (Example 511, Step d) (190 mg, 0.243 mmol) in MeOH (5 mL) were added ammonium carbamate (76.6 mg, 1.22 mmol) and iodobenzene diacetate (469 mg, 1.46 mmol) and the reaction was stirred at 40° C. for 12 hours. The solvent was evaporated to dryness and purified by prep TLC ((PE:EtOAc=1:1) and prep-SFC and the two epimers were obtained as a white solid (Epimer A, 13 mg, 7% yield) (MS (ESI): 813.3 [M-BOC-isobutene+H]+) and as a white solid (Epimer B, 36 mg, 17% yield) (MS (ESI): 624.1 [M+H]+).
The title compound was prepared in analogy to Example 511, steps f to g) from tert-butyl 1-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1-imino-1,4-dioxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (Epimer B) (30 mg, 0.037 mmol) and was obtained as a light yellow solid (11 mg, 40% yield). MS (ESI): 671.2 [M+H]+.
The title compound was prepared in analogy to general procedure 4 from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 321, step c) (150 mg, 0.445 mmol) and was obtained as a white solid (213 mg, 81% yield) MS (ESI): 464.4 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 12 from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (200 mg, 0.339 mmol) and was obtained as a white solid (210 mg, 95% yield) MS (ESI): 553.4 [M+H]+.
The title compound was prepared in analogy to general procedure 7a from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (100 mg, 0.154 mmol) using tetrahydro-2-(hydroxymethyl)-2-furancarboxylic acid (CAS 442877-01-2) (26.9 mg, 0.185 mmol) and was obtained as a light yellow solid (78.9 mg, 60% yield) MS (ESI): 681.4 [M+H]+.
The title compound was prepared in analogy to general procedure 11a from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ4,5-benzothiazepin-7-yl]methylene]amino] 2-(hydroxymethyl)tetrahydrofuran-2-carboxylate (78.9 mg, 0.093 mmol) and was obtained as a white powder (41 mg, 67% yield) MS (ESI): 607.3 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-8-fluoro-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,2,4-oxadiazol-3-yl]-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (41 mg, 0.049 mmol) and was obtained as a white solid (26.3 mg, 76% yield) MS (ESI): 639.2 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 6d from tert-butyl N-[(3R)-8-fluoro-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate;5-(3-fluoro-1-methyl-3-piperidyl)-1,2,4-oxadiazole (26.3 mg, 0.038 mmol) and was obtained as a white powder, as a hydrochloride salt (23.3 mg, 97% yield) MS (ESI): 595.3 [M+H]+.
Examples 522 of the following table was prepared in analogy to Example 521, step a to f), using the appropriate building block.
Methyl 2-chloro-4-fluoro-5-nitrobenzoate (CAS 85953-30-6) (2 g, 8.56 mmol, Eq: 1) was dissolved in EtOH (35 mL) and (tert-butoxycarbonyl)-L-cysteine (2.08 g, 9.42 mmol, Eq: 1.1) in water (8.75 ml) was added to the reaction mixture. Then sodium bicarbonate (2.16 g, 25.7 mmol, Eq: 3) was added and the reaction mixture was stirred at 80° C. for 2.5 hours. The solvent was evaporated, EtOAc was added and the mixture was extracted with water. The combined aqueous layers were acidified by addition of 1N aq. HCl and they were extracted with EtOAc. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (4.349 g, 6.2 mmol, 72% yield) as a yellow solid which was used in the next reaction step without further purification.
To a solution of (2R)-2-(tert-butoxycarbonylamino)-3-(5-chloro-4-methoxycarbonyl-2-nitro-phenyl)sulfanyl-propanoic acid (5.0 g, 11.5 mmol, 1 eq) in EtOAc (50 mL) was added Pd/C (500.0 mg, 0.470 mmol, 0.040 eq). The mixture was degassed with nitrogen three times, then purged with hydrogen three times and then stirred at 25° C. for 16 h under an atmosphere of hydrogen. The reaction mixture was filtered and the filter cake was washed with EtOAc (3×50 mL). The filtrate was concentrated under vacuum to obtain a brown oil (5.52 g) containing the title compound which was used in the next reaction step without further purification.
The title compound was prepared from (2R)-3-(2-amino-5-chloro-4-methoxycarbonyl-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (5.52 g) in analogy to general procedure 3 and was obtained as a light yellow solid (566 mg, 1.46 mmol, 11% yield). MS (ESI): 408.9 [M+Na]+.
The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-8-chloro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (566.0 mg, 1.46 mmol, 1 eq) in analogy to general procedure 4 (DMF instead of DMSO as solvent) and was obtained as light yellow oil (714 mg, 1.4 mmol, 95% yield). MS (ESI): 455.3 [M-isobuten+H]+.
The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-8-chloro-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (714.0 mg, 1.4 mmol, 1 eq) in analogy to Example 218, step f) and was obtained as yellow oil (600 mg, 1.21 mmol, 86% yield). MS (ESI): 441.0 [M-isobuten+H]+.
To a solution of (3R)-3-(tert-butoxycarbonylamino)-8-chloro-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (600.0 mg, 1.21 mmol), pivalic acid hydrazide (280.42 mg, 2.41 mmol) and HATU (688.0 mg, 1.81 mmol) in DMF (11 mL) was added DIPEA (0.43 mL, 2.41 mmol) at 25° C. and the mixture was stirred at 25° C. for 4.5 h. The reaction mixture was poured into water (10 mL) and the mixture was extracted with ethyl acetate (3×10 mL). The combined extracts were washed with brine (3×15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The remaining residue was purified by column chromatography on silica gel (PE/EtOAc=5:1 to 1:1) to afford the title compound (300 mg, 0.500 mmol) as a yellow solid. MS (ESI): 539.1 [M-isobuten+H]+.
The title compound was prepared from tert-butyl N-[(3R)-8-chloro-5-[(4-chlorophenyl)methyl]-7-[(2,2-dimethylpropanoylamino)carbamoyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (300.0 mg, 0.500 mmol, 1 eq) in analogy to general procedure 8a and was obtained as light yellow solid (260 mg, 0.450 mmol, 72% yield). MS (ESI): 521.2 [M-isobuten+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-chloro-5-[(4-chlorophenyl)methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (260.0 mg, 0.450 mmol, 1 eq) in analogy to general procedure 5 and was obtained as light yellow solid (170 mg, 0.280 mmol, 39% yield). MS (ESI): 553.1 [M-isobuten+H]+.
The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-chloro-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (170.0 mg, 0.280 mmol, 1 eq) in analogy to general procedure 6b and was obtained as white solid (13 mg, 0.020 mmol, 9% yield) as the hydrochloride salt. MS (ESI): 509.1 [M+H]+.
The title compound was prepared in analogy to general procedure 7b from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(hydrazinecarbonyl)-8-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Example 276, Step c) (250 mg, 0.509 mmol) and 1-(phenylmethyl) 5,5-difluoro-1,3-piperidinedicarboxylate (CAS 1356338-81-2) (152 mg, 0.509 mmol) and was obtained as a white solid (200 mg, 51% yield). MS (ESI): 772.4 [M+H]+.
The title compound was prepared in analogy to general procedure 8a from benzyl 5-[[[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carbonyl]amino]carbamoyl]-3,3-difluoro-piperidine-1-carboxylate (200 mg, 0.256 mmol) and was obtained as a light yellow foam containing the desired product (333 mg, 156% yield). MS (ESI): 654.3 [M-isobutene-CO2+H]+.
The title compound was prepared in analogy to general procedure 5 benzyl 5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-methyl-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3,3-difluoro-piperidine-1-carboxylate (333 mg, 0.406 mmol) and was obtained as a light yellow oil (140 mg, 41% yield). MS (ESI): 730.3 [M-isobutene+H]+.
To a solution of benzyl 5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-methyl-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3,3-difluoro-piperidine-1-carboxylate (131 mg, 0.167 mmol) in MeOH (2.5 mL) was added Pd/C 10% (CAS 7440-05-3) and the mixture was stirred under a hydrogen atmosphere at RT for 30 min. The mixture was filtered off, the solvent evaporated to afford the title compound as a colourless amorphous solid (92.2 mg, 73% yield), MS (ESI): 652.4 [M+H]+.
To a solution of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-8-methyl-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (30 mg, 0.046 mmol) in MeOH (0.978 mL) were added formaldehyde in water (37% solution, CAS 50-00-0) (13.8 mg, 0.46 mmol) and sodium triacetoxyborohydride (CAS 56553-60-7) (263 mg, 0.46 mmol) and the reaction was stirred at RT for 1 h. Few drops of water were added to the reaction mixture and the mixture was purified by column chromatography on silica gel (heptane:EtOAc=1:0 to 0:1) affording the title compound as a white solid (17.2 mg, 53% yield), MS (ESI): 666.4 [M+H]+.
The title compound was prepared in analogy to general procedure 6d tert-tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-[5-(5,5-difluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-8-methyl-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (17.2 mg, 0.026 mmol) and was obtained as a white solid (12 mg, 82% yield). MS (ESI): 566.2 [M+H]+.
To a solution of (3R)-3-amino-7-bromo-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one (2.2 g, 4.0 mmol, 1 eq) in 1,4-Dioxane (50 mL) was added bis(pinacolato)diboron (2.44 g, 9.63 mmol, 2.4 eq), potassium acetate (1.22 g, 12.45 mmol, 3.1 eq) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.34 g, 0.470 mmol, 0.12 eq) under Ar atmosphere and stirred at 120° C. for 3 h. The mixture was poured into water and extracted three times with EOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The remaining crude was purified by reverse phase prep-HPLC to afford (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]boronic acid (1.01 g, 42% yield) as light yellow solid. MS (ESI): 457.2 [M-isobutene+H]+.
To a mixture of cupric acetate (187.52 mg, 1.03 mmol, 2.65 eq), NEt3 (0.26 mL, 1.85 mmol, 4.75 eq) and 3-ethyl-1H-1,2,4-triazole (CAS:7411-16-7) (189 mg, 1.95 mmol, 5 eq) in MeCN (5 mL) was added a solution of (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]boronic acid (200 mg, 0.39 mmol) inMeCN (10 mL) in five portions. The reaction mixture was stirred at 20° C. for 12 h, poured into water (10 mL), extracted with EtOAc (50 mL) and the combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by prep-TLC (PE:EA=2:1) affording the title compound (30 mg, 0.05 mmol, 9.9% yield) as a yellow solid. MS (ESI): 564.1 [M+H]+.
The title compound was prepared in analogy to general procedure 6f (using HCl/EtOH instead of HCl/EtOAc) from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7-(3-ethyl-1,2,4-triazol-1-yl)-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (30 mg, 0.053 mmol) and was obtained as a white powder (2.9 mg, 11% yield). MS (ESI): 464.3 [M+H]+.
To a mixture of N-(2-bromo-4,5-difluoro-phenyl)acetamide (CAS:64695-81-4) (5.0 g, 20 mmol) and tBu3P—Pd—G2 (CAS 1375325-71-5) (2.05 g, 4 mmol, 0.2 eq) in tert-amyl alcohol (70 mL) were added (2R)-2-(tert-butoxycarbonylamino)-3-sulfanyl-propanoic acid (CAS 20887-95-0) (4.87 g, 22 mmol, 1.1 eq) and cesium carbonate (9.77 g, 30 mmol, 1.5 eq). The reaction mixture was heated at 110° C. and stirred for 12 h under an atmosphere of nitrogen. The reaction mixture was poured into water (300 mL) and the pH was adjusted to 4 by addition of 1M aq HCl. The mixture was extracted with EtOAc (300 mL) and the organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4 and concentrated in vacuum. The crude product was purified by prep-HPLC. The eluent was extracted with ethyl acetate (500 mL) affording the title compound (4.4 g, 49% yield) as a yellow solid. MS (ESI): 291.2 [M-isobutene-CO2+H]+.
To a solution of (2S)-3-(2-acetamido-4,5-difluoro-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (4.3 g, 11.01 mmol, 1eq) in a solvent mixture of THF/EtOH (80 mL, 1:1) was added 2M aqueous HCl (200 mL, 400 mmol, 36 eq). The reaction mixture was heated to 80° C. and stirred for 8 h. The solvent was removed to afford the title compound (3 g, 98% yield) as a yellow solid, which was used without further purification in the next reaction step. MS (ESI): 249.1 [M+H]+.
A mixture of (2S)-2-amino-3-(2-amino-4,5-difluoro-phenyl)sulfanyl-propanoic acid (3.0 g, 10.7 mmol, 1 eq), sodium hydrogen carbonate (2.46 g, 29.3 mmol, 2.73 eq) and di-tert-butyldicarbonate (2.55 g, 11.7 mmol, 1.09 eq) in THF (30 mL) and water (15 mL) was stirred at 20° C. for 1 h. The solution was poured into water (100 mL) and the mixture was extracted with EtOAc (200 mL). The layers were separated and the organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated to afford the title compound (2.6 g, 53% yield) as a yellow solid, which was used without further purification in the next reaction step. MS (ESI): 293.0 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 3 (in THE instead of DMF) from (2S)-3-(2-amino-4,5-difluoro-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (2.6 g, 5.97 mmol) and was obtained as a light yellow solid (1.02 g, 39% yield). MS (ESI): 275.0 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 4 (in DMF instead of DMSO) from tert-butyl N-[(3R)-7,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (1.0 g, 3.03 mmol) and was obtained as a light yellow solid (1.01 g, 63% yield). MS (ESI): 399.3 [M-isobutene+H]+.
The title compound was prepared in analogy to general procedure 5 from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7,8-difluoro-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (1.0 g, 2.2 mmol, 1 eq) and was obtained as a light yellow solid (1.01 g, 83% yield). MS (ESI): 431.0 [M-isobutene+H]+.
To a suspension of tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-7,8-difluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (100 mg, 0.21 mmol) and potassium carbonate (120 mg, 0.87 mmol, 4.23 eq) in DMSO (1 mL) was added 3-tert-butyl-4H-1,2,4-triazole (CAS:96440-78-7) (110 mg, 0.88 mmol, 4.28 eq) at 20° C. and the mixture was stirred for 3 h. The solution was poured into water (20 mL) and the mixture was extracted with EtOAc (50 mL). The layers were separated and the organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuum. The crude product was purified by prep-TLC (PE:EA=2:1) affording the title compound (51 mg, 42% yield) as a white solid. MS (ESI): 592.0 [M+H]+.
The title compound was prepared in analogy to general procedure 6b from tert-butyl N-[(3R)-7-(3-tert-butyl-1,2,4-triazol-1-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (40 mg, 0.07 mmol) and was obtained as a white solid (21.9 mg, 64% yield). MS (ESI): 492.1 [M+H]+.
Example 527 of the following table was prepared in analogy to Example 526, step g,h) using the appropriate imidazole building block.
DGK α and ζ kinase use ATP to phosphorylate the substrate 1,2-dilauroyl-sn-glycerol (DLG, incorporated in the liposomes). ATP is converted to ADP as a result of this enzymatic reaction. After the kinase reaction, an ATP-depletion reagent is added to terminate the kinase reaction and deplete any remaining ATP, leaving only ADP. Second, a detection reagent is added to simultaneously convert ADP to ATP and allow the newly synthesized ATP to be converted to light using a coupled luciferase/luciferin reaction.
Full length DGKA and Z were expressed in Sf21 insect cells by infecting the cells with the baculovirus stock at MOI of 2. Purification of both enzymes was performed as previously described by Takahashi et al., PeerJ, 2018 (Takahashi, D.; Sakane, F. Expression and purification of human diacylglycerol kinase alpha from baculovirus-infected insect cells for structural studies. PeerJ 2018, 6, No. e5449).
A concentrated liposome solution was prepared in assay buffer without DTT and BSA: 2 mM of DLG in 21 mM of total liposome (2 mM DLG/8 mM PS/11 mM PC). The reaction mixtures contain the assay buffer with a final DLG concentration of 125 uM ATP concentrations of 25 μM (for DGKA assay) or 50 μM (for DGKZ assay). The reactions were started by addition of DGK α and ζ kinases at 4 nM and 2 nM final concentrations, respectively. After 1 hour reaction, the amount of ADP formed was detected with the ADP-Glo kinase assay (Promega) according to the manufacturer instructions. Compounds were added in 11-points dose response, starting at 10 mM, 1:3 dilutions, with a final DMSO concentration of 2%. The multidrop combi was used as a liquid handler and luminescence was read with 0.5 s by the envision reader (PE).
As readouts for T-cell activation, IL2 secretion after 24 hours and proliferation after 5 days was measured. Increases in IL2 secretion and proliferation upon compound treatment were assessed as the % of the maximum of reference compound A1. WO 2016/139181 discloses reference compound A1 as example 70. As a counter screen and to make sure that no unwanted TCR-independent activation was triggered, PBS conditions were run for all compounds.
Expanded primary human T-cells were thawed and cultured in RPMI 1640 (Gibco, #61870-010)+5% human serum (HS, Sigma, #H3667)+1 mM Sodium Pyruvate (Gibco, #11360-039)+50 μM 2-mercaptoethanol (Gibco, #31350-010) and 1× Pen-Strep (Life Technologies, #15140122) medium at density of 2 Mio/ml for 3 hours in 5% CO2, 37° C. and 95% humidity. For coating of plates, PBS++ with PBS−− or PBS++ with CD3 antibody (concentration depending on donor and determined by CD3 titrations) was added 100 μl/well to Poly-D Lysine coated 96-well plates. Plates were sealed and incubated at room temperature for 3 hours on a table-top rocking platform. After incubation, plates were washed once with PBS−− and filled with 40 μl/well culture medium only. Compounds were then added (see next section) to medium only plates. After 3 hours of culturing the T-cells, cells were filtered through a cell strainer (Miltenyi Biotech, #130-041-407), counted again and concentration was adjusted to 1.25 Mio/ml.
Cells were then seeded 80 μl/well to the 40 μl/well including dispensed compounds according to plate layout. By adding cells, compounds were further diluted 1:3, and resulting in 100 k cells/120 μl/well. After 24 hours 40 μl of supernatant was collected carefully from the top while not disturbing the cells and transferred into a round bottom 96 well plate. Collected and frozen supernatant was used for detection of IL2 using the IL-2 Human ProQuantum Immunoassay Kit (Invitrogen) or using the Human IL-2 ELISA Kit (Thermo Fisher).
Compounds were added in a 5 or 6pt dose response with the Tecan D300e Digital Dispenser, all conditions 3 times more concentrated than the end-concentration, since cells are added afterwards (80 μl cells to 40 μl prepared medium with treatment). The DR was starting at 20 μM or 10 μM final top concentration and a dilution factor of 3.333. The positive control was the reference compound A1 that was added in a dose response as well, additionally to 3 wells of only 20 μM representing the positive stimulator control. All wells were normalized with DMSO to a final concentration of 0.6% (0.2% end-concentration).
The immunoassay is done following the manufacturer's manual (Invitrogen, #A35603). Additional information: For the immunoassay, MicroAmp™ EnduraPlate™ Optical 384-Well plates are used. Frozen supernatant is thawed and centrifuged for 5 minutes at 1000×g, both steps at 4° C. After centrifugation, required sample amount is taken from the top, and in a separate LightCycler V-bottom plate (working plate) diluted with assay dilution buffer, dilution factor depending on the PBS or CD3 condition but at least 1:3. IL-2 standard and blanks are prepared in the same V-bottom plate, standard with a range of 0.0128-5000 pg/ml (extended version). After preparation, 5 μl of sample dilutions or standard/blanks are transferred to the optical 384-well plate (assay plate) and the 10 μl reaction protocol is being followed. For measurement, the QuantStudio 12K Flex system is used. Raw data is extracted and IL-2 concentrations are calculated with the Thermo Fisher online app (apps.thermofisher.com/apps/proquantum).
ELISA is done following the manufacturer's manual (Thermo Fisher Scientific, #88-7025-88). Additional information: For the ELISA Nunc MaxiSorp 96 well plates are used. Frozen supernatant is thawed and centrifuged for 5 minutes at 1000×g, both steps at 4° C. After that, required sample amount is taken from the top, and in a separate V-bottom plate diluted with ELISA diluent, dilution factor depending on the PBS or CD3 condition. IL-2 standard and blanks are prepared in the same V-bottom plate. After preparation, 50 μl of sample dilutions and 100 μl of standard or blanks are transferred to the Nunc plates.
CD3 and PBS plates were analysed separately in Genedata Screener using Roche Normalization PCT_POS_CTRL with DMSO set as Neutral Control and 20 μM of the reference compound A1 set as Stimulator Control/100%.
For CD3 conditions EC50 and Emax of the fitted sigmoidal curve were reported. If no curve could be fitted, the EC50 was reported as blank field and the Emax was based on individual data points. The Emax did not always correspond to the highest concentration tested (20 μM), which is why the concentration at which the maximum activation was achieved was also reported (“Concentration @ Max IL2 activation”). Compounds which activate unstimulated cells or compounds which negatively affected viability (see proliferation assay) were flagged.
Expanded primary human T-cells are thawed and cultured in RPMI 1640 (Gibco, #61870-010)+5% human serum (HS, Sigma, #H3667)+1 mM Sodium Pyruvate (Gibco, #11360-039)+50 M 2-mercaptoethanol (Gibco, #31350-010) and 1× Pen-Strep (Life Technologies, #15140122) medium at density of 2 Mio/ml for 3 hours in 5% CO2, 37° C. and 95% humidity. For coating of plates, PBS++ only or PBS++ with CD3 antibody (concentration depending on donor and determined by CD3 titrations) is added 100 μl/well to Poly-D Lysine coated 96-well plates. Plates are sealed and incubated at room temperature for 3 hours on a table-top rocking platform. After incubation, plates are washed once with PBS−− and filled with 40 μl/well culture medium only. Compounds are then added (see next section) to medium only plates. After 3 hours of culturing the T-cells, cells are filtered through a cell strainer (Miltenyi Biotech, #130-041-407), counted again and concentration is adjusted to 1.25 Mio/ml.
Cells are then seeded 80 μl/well to the 40 μl/well including dispensed compounds according to plate layout. By adding cells, compounds are further diluted 1:3, and resulting in 100 k cells/120 μl/well. After 48 hours 40 μl of supernatant is collected carefully from the top while not disturbing the cells. Cells are assessed for proliferation 5 days later by measuring ATP consumption using CellTiterGlo (Promega).
Compounds were added in a 5 or 6pt dose response with the Tecan D300e Digital Dispenser, all conditions 3 times more concentrated than the end-concentration, since cells are added afterwards (80 μl cells to 40 μl prepared medium with treatment). The DR was starting at 20 μM or 10 μM final top concentration and a dilution factor of 3.333. The positive control was the reference compound A1 that was added in a dose response as well, additionally to 3 wells of only 20 μM representing the positive stimulator control. All wells were normalized with DMSO to a final concentration of 0.6% (0.2% end-concentration).
After 5 days, for detection of ATP which is directly proportional to the number of cells present per well, the CellTiter-Glo® 2.0 Reagent is used. After visual control for toxicity or precipitations of the tested compounds, the plates are equilibrated to room temperature for 45 minutes. CellTiter-Glo® 2.0 Reagent is equilibrated to room temperature as well. After equilibration, an equal amount of CellTiter-Glo reagent is added to the cells (80 μl/well) with an electronic multichannel pipette. Plates are placed on a rocking platform for 15 minutes at room temperature. After incubation, the bottom of the plates is sealed with backing tape. Luminescence is measured with PHERAstar FSX (interval time 0.5 sec, gain 3000, focal height 15 mm) and exported as CSV file for analysis in Genedata screener.
CD3 and PBS plates were analysed separately in Genedata Screener using Roche Normalization PCT_POS_CTRL with DMSO set as Neutral Control and 2@˜M of the reference compound A1 set as Stimulator Control/100%.
For CD3 conditions EC50 and Emax of the fitted sigmoidal curve were reported. If no curve could be fitted, the EC50 was reported as blank field and the Emax was based on individual data points. The Emax did not always correspond to the highest concentration tested (20 μM), which is why the concentration at which the maximum proliferation was achieved was also reported (“Concentration @ Max proliferation”). Compounds which activate unstimulated cells (see IL2 measurements) or compounds which negatively affected viability were flagged.
All culturing steps are executed at 5% CO2, 37° C. and 95% humidity.
MV-3 RFP cells are cultured in MV-3 medium (DMEM+10% FBS, 1× PenStrep and 0.5 μg/mL Puromycin) for at least 3 weeks. Cultured MV-3 cells at 80% confluency are washed once with PBS−− and trypsinized until detached. Cells are then counted and resuspended to 1*105 cells/mL in T-cell medium (RPMI 1640+5% human serum+1 mM Sodium Pyruvate+50 μM 2-mercaptoethanol and 1× Pen-Strep). Cells are seeded with 100 μL/well into a 96-well plate (TTP, #92696), and placed for 40 minutes without moving at room temperature in order to achieve evenly distributed attachment of cells. Plates are then incubated until further use.
On the next day, expanded primary human T-cells are thawed and resuspended in T-cell medium to 4*106 cells/mL. For 3 hours, they are cultured in a 6-well plate with 6 mL per well at maximum. After culturing the T-cells, they are filtered through a cell strainer (Miltenyi Biotech, #130-041-407), counted again, and cell concentration is adjusted to 2*106 cells/mL.
MCSP-TCB or PBS are pre-diluted in T-cell medium (concentration depending on T-cell donor), 4 times more concentrated than the end-concentration. 60 μL/well of pre-dilutions are then distributed into a round bottom plate (Costar, #3799) according to plate layout. Compounds are added in a 9pt dose response with the Tecan D300e Digital Dispenser, as well 4 times more concentrated than the end-concentration. DMSO concentration of all wells is adjusted to 0.8%, resulting in 0.2% as final concentration.
60 μL per well of T-cell suspension are added to the prepared round bottom plate and resuspended with a manual multichannel. 100 μL/well of the resuspended T-cell suspension including treatments are then transferred cautiously to the overnight cultured MV-3 cells according to plate layout. 100 μL T-cell medium only is added to the outer MV-3 wells only. Final compound DR is starting at 20 μM with a dilution factor of 3.333. Final TCB concentration is between 1.5 μM to 5 μM and was determined for each T-cell donor individually by running TCB titrations. For each donor, a TCB concentration was chosen which corresponds to 10-20% of MV3 baseline cell killing in the absence of compound treatment. Positive control is the reference compound A1 which is added in a DR, as well as additional wells with only 20 μM. 20 μM of reference compound A1 represent the positive stimulator control, TCB only (DMSO wells) the neutral control.
After transfer of T-cells with treatment pre-dilutions, MV-3 cells are imaged by time-lapse microscopy using IncucyteZOOM™ (Essen BioScience, MI, USA). Imaging is performed every 3 hours for a total of 120 hours (10× objective, phase and red image channels, acquisition time 400 ms, Green/Red 4614 optical module). RFP object count per well is analysed in the IncucyteZOOM™ Software (Version 2019B Rev2) with a mask that was previously created and optimized for MV-3 cells. Raw data is exported as object count/well and values are normalized as 0% TCL compared to wells with MV-3 only, representing 10000 growth and therefore 000 TCL.
Calculated 00 TCL values are analysed in Genedata Screener using Roche Normalization PCT_POS_CTRL with MCSP-TCB only set as Neutral Control and 20 μM of the reference compound A1 set as Stimulator Control/100%.
EC50 and Emax values were provided in the table below.
Induced TCL by compounds without TCB treatment or toxicity (observed in the PBS condition) were be flagged.
| Number | Date | Country | Kind |
|---|---|---|---|
| 21156877.9 | Feb 2021 | EP | regional |
| 21186928.4 | Jul 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/053257 | 2/10/2022 | WO |
