TW200902026A - Agents for treating disorders involving modulation of ryanodine receptors - Google Patents

Abstract

The present invention provides new agents and compounds effective for treating disorders and diseases associated with RyRs, including cardiac, muscular and cognitive disorders and diseases. These agents are derivatives of benzoxazepines, benzodiazepines and benzazapines. More particularly, the invention provides compounds which include derivatives of benzoxazepine, and their enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes, polymorphs, metabolites, and prodrugs thereof.

Description

200902026 IX. Description of the Invention: [Technical Field] The present invention relates to a compound, and a use thereof for treating a condition and a disease associated with a ryanodine receptor (RyR), which regulates function in a cell Calcium channel. More specifically, the present invention discloses compounds which can be classified into derivatives of benzoxazepines, benzodiazepines, and benzodiazepines, and can be used to treat the heart, Skeletal muscle and cognitive disorders. The invention also discloses pharmaceutical compositions comprising the compounds, and the use thereof for treating diseases and conditions associated with RyR. [Prior Art] The sarcoplasmic reticulum (SR) is a structure in cells which is used as a special intracellular calcium (Ca2+) reservoir. RyR is a channel in the SR that opens and closes to regulate the release of Ca2+ from the SR into the intracellular cytoplasm of the cell. The release of Ca2+ from SR into the cytoplasm increases cytosolic Ca2+ concentration. The RyR opening probability refers to the possibility that the RyR channel will open at any given time and therefore release Ca2+ from the SR into the cytoplasm. There are three types of RyR, all of which are highly homologous Ca2+ channels: RyRl, RyR2 and RyR3. RyRl is mainly found in skeletal muscle and other tissues. RyR2 is mainly found in the heart and other tissues, while RyR3 is found in the brain and other tissues. The RyR channel is composed of four RyR polypeptides that bind to four FK5〇6 binding proteins (FKBP), particularly FKBP12 (calstabin 1) and FKBP12.6 (calstabin 2). Formed. The calstabin 1 line binds to RyRl and RyR3, whereas the calstabin 2 binds to RyR2. Calstabin is incorporated into 131494 200902026

The RyR channel (one molecule per RyR subunit) stabilizes the RyR channel function, aids in the coupling strobe between adjacent RyR channels, and prevents abnormal activation of the channel (Ca2+ leakage by stabilizing the closed state of the channel) ). In addition to calstabin, protein kinase A (PKA) binds to the cytoplasmic surface of RyR via the protein mAKAP as a target. The phosphorylation of RyR by PKA causes a partial dissociation of Kastabine from RyR, which in turn causes an increased probability of RyR opening, and an increase in Ca2+ release from SR into the intracellular cytoplasm. -f 1 In skeletal muscle and heart cells, Ca2+ release from SR is a key physiological mechanism for controlling muscle performance, as the increased concentration of Ca2+ in the intracellular cytoplasm causes muscle contraction. The excitation-contraction (EC) coupling in skeletal muscle involves electrical depolarization of the serosa in a transverse small catheter (T-small catheter) that activates the voltage-gated L-type Ca2+ channel (LTCC). In skeletal muscle, LTCC triggers Ca2+ to release from SR through physical interaction with RyRl, causing muscle contraction. In myocardial f, RyR2 is activated via Ca2 + influx of LTCC to release Ca2+, resulting in \ , muscle contraction. An increase in the concentration of cytoplasmic Ca2+ formed results in actin-myosin interaction and muscle contraction. To be able to relax, the intracellular Ca2+ is pumped back to the SR via the SR Ca2+-ATPase pump (SERCA), which is regulated in the heart by the acid-filled phospholamamban (PLB), depending on the muscle fiber type. And set. The disease form that has been shown to cause sustained activation of the sympathetic nervous system and increased plasma catecholamine levels may cause unsuitable activation of the intracellular pressure pathway, resulting in the deactivation of the RyRl and RyR2 channels in a closed state. 131494 200902026 Effect and intracellular Ca2+ leakage. It has been found that SR through the RyRJ or RyR2 channel with 2 + leakage depletes the intracellular calcium storage and causes heart failure and weakened motion. Muscle defects caused by stress permanently reduce the performance of isolated muscles and in vivo, especially in situations where increased demand is required. It has also been demonstrated that the de-stabilization of the RyR!-off state occurs under pathological conditions that increase sympathetic activation and involves the depletion of the calstabin 1-channel subunit. Experiments have shown that PKA activation as a terminal effector of the sympathetic nervous system increases RyRi, PKA phosphorylation at Ser-2843, which reduces the binding affinity of Carstacin 1 to RyRl' and increases Channel open probability. In the heart striated muscle, RyR2 is the primary Ca2-release channel required for EC coupling and muscle contraction. Depolarization during the phase zero period of the cardiomyocyte membrane during the EC coupling activates the voltage-gated Ca2+ channel. The Ca2+ influx through the open voltage gating channel in turn causes ca2+ to be released from the SR via RyR2. This process is called Ca2+-induced Ca2+ release. Then, (Ca2+-induced Ca2+ release causes activation of contractile proteins in cardiac cells, causing myocardial contraction. Cardiac RyR2 is phosphatized by PKA as “combat or flight” An important part of the 'increased cardiac EC coupling gain by increasing the amount of Ca2+ released for a particular trigger. This signaling pathway provides a mechanism by which the activation of the sympathetic nervous system is caused by an increased heart. Turning out, responding to stress. The PKA phosphorylation of RyR2 increases the probability of opening of the channel by dissociating the calstabin 2 from the channel complex. This in turn selects RyR2 for Ca2+-dependent activation. Sensitivity. 131494 200902026 Progress in the treatment of sputum 1 visceral failure is still an important cause of death in the West (four) home. The important Orthography of heart failure is marked as the reduction of the systolic abnormality due to the The changes in the heart-speaking path caused the 'cardiac action potential to trigger Ca2+ release via the coffee channel and muscle contraction. In particular, in the heart of failure, the sputum cell Ca2+ The magnitude of the transient is reduced and the duration is extended. The common feature of the heart failure, which causes arrhythmia, causes many deaths associated with 4 diseases. Heart and atrial fibrillation (af) is The most common in humans is the law, which is a major cause of morbidity and mortality. ', "Construction and electrical transformation - including the shortening of atrial reversal, the rate of collateral-related adaptation and the deduction The shortening of the wavelength of the wave into the wavelet is accompanied by the sustained heart rate tachycardia. This transformation is mostly in the development, maintenance and progress of atrial fibrillation, and the research is on the transformation of atrial fibrillation. It plays a role. About 5% of all patients with heart disease die from fatal heart rhythm. In some cases, 'the ventricular dysfunction in the heart is fast and fatal--the species is called For the sudden death of heart disease, (SCD). Deadly heart and irregularities and SCD also occur in young and otherwise healthy individuals who are not aware of structural heart disease. In fact, ventricular rhythm Miscellaneous for others Healthy individuals face the most common cause of sudden death.

The catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder in an individual with a structurally normal heart. It is characterized by pressure-induced ventricular tachycardia - a type of fatal rhythm that causes SCD. In patients with CPVT 131494 200902026, 'physical exertion and/or stress can cause bidirectional and/or multi-ventricular tachycardia', which can lead to SCO, even in the absence of detectable structural heart disease. Also. CPVT is mainly transmitted in a positive chromosomal manner. When individuals with CPVT receive exercise, they have ventricular rhythm irregularities but do not develop rhythm at rest. Studies have been performed in individuals with CpVT 'confirmed on chromosome Iq42-q43' in the human RyR2 gene mutations in the heart of the heart (eg in patients with heart failure, and in the heart of the heart) Animal mode) is characterized as unsuitable for response, including chronic high adrenergic stimulation. In heart failure, the chronic adrenergic stimulating system is associated with the activation of the 5-/5-adrenergic receptor in the heart, which is activated by coupling with G-protein shell: y: base ring Enzymes, and thereby increase intracellular cAMP concentration. CAMP activates CAMP-dependent PKA, which has been shown to cause RyR2 to undergo phosphorylation. Therefore, chronic heart failure is a chronic sputum adrenergic state, which causes several pathological findings, including hyperphosphorization of PKA.

The PKA hyperphosphorization of RyR2 has been proposed as a factor contributing to the reduction of contractile function and arrhythmia in heart failure. Consistent with this hypothesis, PKA hyperphosphorization of RyR2 in depleted hearts has been smashed in vivo, in animal models and in patients with heart-exposed and heart transplants. In the heart of failure, RyR2 is over-phosphorylated by pyrene, causing the dissociation of calstabin 2 from the RyR2 channel. This causes significant changes in the biophysical properties of the RyR2 channel, including increased openness. This 131494 10· 200902026 is due to the increased sensitivity to Ca2+-dependent activation; the de-stabilization of the channel leads to sub-conduction. The state; and the weakening of the channel, the strobe, resulting in defective EC coupling and cardiac dysfunction. Therefore, PKA-over-phosphorylated thiolated RyR2 is extremely sensitive to low-level Ca2+ stimulation systems, and this is a PKA hyperphosphorus-denominated RyR2 channel, which is shown to be diastolic SR Ca2+ leakage. An unsuitable response to stress in heart failure results in the depletion of calstabin 2 from the channel macromolecular complex. This results in a shift in the sensitivity of RyR2 to Ca2+-induced Ca2+ release to the left, resulting in a channel that is more active at low to moderate Ca2+ concentrations. Over time, an increase in π leakage through RyR2 will cause the SR Ca2+ content to be reset to a lower level, which in turn will reduce the EC coupling enhancement and contribute to the reduced contraction and contraction of the heart. In addition, it has a special "leakage" The subgroup of RyR2 of sexuality can release SR Ca2+ during the resting phase (diastolic phase) of the cardiac cycle. This causes depolarization of the myocardial cell membrane, known as post-delay depolarization (DAD), which is known to trigger fatal ventricular arrhythmia. In patients with a CPVT mutation, similar phenomena are occurring in the RyR2 and other structurally normal hearts. Specifically, it is known that exercise and stress cause the release of catecholamines, which activate the/5-adrenergic receptors in the heart. Activation of the adrenergic receptors leads to hyperphosphorization of the PKA in the RyR2 channel. The evidence also indicates that the PKA hyperphosphorization of RyR2 caused by the activation of /3-adrenergic receptors makes the mutated RyR2 channel more likely to open during the relaxation phase of the cardiac cycle, increasing the likelihood of irregular rhythm. It is known that in patients with a CPVT mutation, in a structurally normal heart of RyR2 and other aspects 131494 -11 - 200902026, cardiac arrhythmia is associated with diastolic SR Ca2+ leakage. In these cases, the most common mechanism for the induction and maintenance of ventricular tachycardia is abnormal automata. A form of abnormal automatism called triggered arrhythmia is associated with the release of SR Ca2+, which triggers DAD. DAD is an aberrant depolarization in cardiomyocytes that occurs after repolarization of cardiac action potentials. The molecular basis for the release of abnormal DAD from SR Ca2+ has not been fully elucidated. However, DAD is known to be blocked by ryanodine, providing evidence that RyR2 plays a key role in the pathogenesis of this Ca2+ release. U.S. Patent Application No. 2004/0229781 discusses JTV-519 (4-[3-(4-benzylhexanitro?)-based propyl) methoxy-2,3,4,5-tetrazine- 1,4-Benoxathiazolidine monohydrochloride; also known as k201 or ICP-Calstan 100), a 1,4-benzothiazepine, a novel regulator of RyR calcium ion channels. U.S. Published Patent Application Nos. 2005/0187386 and 2005/0215540 discuss RyR2 as a subject for the treatment and prevention of heart failure and cardiac arrhythmia, including atrial fibrillation and cardiac arrhythmia, which cause motion SCD. It has been found that RyR2 channel systems with seven different CPVT mutants (eg, S2246L, R2474S, N4104K, R4497C, P2328S, Q4201R, V4653F) have a channel that becomes leaky (meaning calcium infiltration) when stimulated during exercise. Functional defects of leaks). The VT mechanism in CPVT has been shown to be identical to the VT mechanism in heart failure. It has been confirmed that the rhythm caused by exercise and sudden cardiac death (in patients with CPVT) are caused by the reduced affinity of calstabin 2 for RyR2, and its calcium leakage Related. In addition, it has been confirmed that 131494 -12- 200902026 exercise 曰 activates %R2 as a result of phosphorus enzymatic action by 3,5'·cyclic adenine acid (eAMp)-dependent protein kinase (PKA). In the basal state, the mutant RyR2 channel with normal function in the genus Ganoderma lucidum is a sensitive to the activation by PKA phosphorylation - showing increased activity (opening probability) With the extended open state, the PKA-phosphorylated mutated RyR2 channel is resistant to inhibition by Mg2+ (a physiological inhibitor of the channel) when compared to the wild-type channel. It also shows a reduced combination of the Castelbin 2, which stabilizes the channel in the closed state. These I are not in the exercise phase. When RyR2 is ρκΑ_phosphonylated, the mutant CPVT channel is more likely to open during the relaxation phase of the cardiac cycle, increasing the likelihood of arrhythmia triggered by 狃Ca2+ leakage. In addition, the published patent application No. 2G_13433i discusses a method for modulating the heart contraction of a patient by administering a compound which modulates the PKA^fe of RyR2 and specifically reduces the waking effect of ρκΑphosphorus. The United States announced the special account number 2_Cai Q also discussed - a treatment disk to prevent rapid atrial heartbeat and the rhythm caused by exercise and stress, the = formula is to inhibit RyR2 pKA Galgification Pharmacy. In view of the above, there is a need to identify novel compounds that are effective in treating conditions and diseases associated with RyR, including musculoskeletal and cardiac disorders and diseases. More specifically, there is still a need to identify novel agents that can be used to treat _ associated disorders' by, for example, leaking in the repair channel, and enhancing the calstabin egg self-quality versus _ _ _ _ The combination of RyR 'the latter in other cases has a reduced affinity for Kastagbin' or does not bind to Kastagbin. The present invention now provides a solution to the need for 131494 200902026. SUMMARY OF THE INVENTION Accordingly, the present invention generally provides compounds which can be classified as derivatives of benzoxazepines, benzothiazepines, and benzodiazepines. It is sometimes referred to as "RyCal." More particularly, the present invention provides compounds which include derivatives of benzoxazepines, and their palmier isomers, diastereomers, tautomers, which are pharmaceutically acceptable Salts, hydrates, solvates, complexes, polymorphs, metabolites, and prodrugs. Particularly preferred compounds include compounds of formula Ia as disclosed herein, or disclosed herein as ARM136, ARM137, ARM138, ARM139, ARM140, ARM146, ARM147, ARM148, ARM149, ARM150, ARM151, ARM152, ARM153, ARM156, ARM157 , ARM159, ARM160, ARM161, ARM166, ARM167, ARM182, ARM186, ARM189, ARM203, ARM217, ARM251, ARM252, ARM258, ARM277, ARM279, ARM282, ARM291, ARM293, ARM296, ARM301, ARM302, ARM306, ARM311, ARM312, ARM313 , ARM318, ARM322, ARM324, ARM326, ARM331, ARM335, ARM337, ARM351, ARM352, ARM353, ARM354, ARM397, ARM398, ARM399, ARM423, ARM454, ARM463, ARM466, ARM470, ARM473 and ARM477 compounds, and their differences Constructs, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes, polymorphs, metabolites, and prodrugs thereof. The compounds of the invention may optionally comprise a labeling group such as a fluorescent, bioluminescent, chemiluminescent, colorimetric or radioactive labeling group. 131494 14 200902026 The invention also provides methods for synthesizing the compounds of the invention, as well as salts, hydrates, sodium complexes, complexes, polymorphs, metabolites, and prodrugs thereof. The present invention further provides a method for treating or preventing various diseases associated with RyR, such as heart, muscle and cognitive disorders and diseases, including administering a quantity of effective prevention to a patient in need of such treatment. Or a compound of the invention and a salt, hydrate, bath complex, complex, polymorph, metabolite, and prodrug thereof, which are associated with a condition or disease associated with RyR. The invention also provides a method for preventing or treating RyR in a patient (including

RyRl, RyR2, and RyR3) methods for leaching - which include administering to a patient - a compound of the present invention effective in preventing or treating leakage of RyR and salts, hydrates, solvates, complexes thereof, polycrystals thereof Shapes, metabolites and prodrugs. The methods of the invention can be practiced in an in vitro system (e.g., cultured, cell or tissue) or in vivo (e.g., in a non-human animal or human). Further, the present invention provides a method of modulating the binding of RyR to Carstabin Mstabm in a patient, which comprises administering to the patient an amount of a compound of the present invention and a salt thereof which are effective in regulating the amount of the combined calistabine. , hydrates, solvates, complexes, polymorphs, metabolites, and prodrugs. The invention also provides a pharmaceutical composition comprising one or more compounds of the invention and at least one additive selected from the group consisting of analgesic antioxidants, formulas, buffers, binders, colorants, disintegrants, dilutions Agent, emulsifier, excipient, extender, taste modifier, gelling agent, glidant 131494 -15· 200902026 Preservatives 'skin penetration enhancer, solubilizer' stabilizer, suspending agent, sweetener, A penetrating agent, a vehicle, and a viscosity increasing agent. The pharmaceutical composition is presented in the form of a fine capsule, granule, powder, solution, suspension or tablet. The article of manufacture is provided with instructions for the various conditions that the pharmaceutical composition can treat and/or prevent. DETAILED DESCRIPTION OF THE INVENTION It is to be understood that the following description of the embodiments of the present invention This artist has been explained in detail since then. As used herein and in the accompanying claims, the singular forms """""""""""""""""""""""""""""" All publications, patent applications, patents and other references mentioned herein are hereby incorporated by reference in their entirety. "RyCal" - the term "々" refers to the compound of the general formula provided by the present invention, / I. and as provided by the present invention, "ARM, and the specific compound of the numerical number 丨36 to 477" It is collectively referred to herein as "compounds of the invention." As used herein, "burning" means a linear or sub-(four) saturated cigarette having from 1 to 6 carbonogens. Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl. Base, butyl I, 筮^ t isohexyl and neohexyl. The term 'is a linear or branched hydrocarbon, having isoamyl, neopentyl, hexyl, as used herein, alkenyl,

- Carbon double bond. The group may have 2 to 6 carbon atoms and have at least one carbon in a particular alkenyl moiety. In the embodiment, the alkenyl group has one or two double bonds. The 131494-16-200902026 or z configuration exists and the compounds of the invention include both configurations. As used herein, the term "block base" as used refers to a linear or branched hydrocarbon having from 2 to 6 carbon atoms and having a small to. I VIII/, having a carbon-carbon bond to J. . - The aryl group used herein contains 1A3 of a group of atoms, whether fused or linked, containing μ carbon atoms. , "cyclic" wow" and heterocyclic group as used herein. The term "formation group", which is used in the context of this article, to refer to the term "cyclosylphite" or "ring ring group" as used herein to mean two to seven-member saturated or partially (four) and carbocyclic. Any suitable ring position may be covalently linked to the defined ring propyl, cyclobutyl, cyclopentyl, =. Illustrative cycloalkyl coated pentamidine, % hexyl and cycloheptyl. The term "dentin" refers to gas, chlorine, and moisture. The "heterocyclic group" or "heterocyclic" or "heterocyclic" or "heterocyclic" may be used interchangeably herein. "Terminal" means fully saturated or partially or fully unsaturated 'including aromatic (ie, ''heteroaryl") cyclic group (eg, 4 to 7 membered monocyclic 7 to 11 shelled bicyclic or 1〇 to 16 membered tricyclic ring system) having at least one hetero atom 'in at least one ring containing a carbon atom. Each ring of a heterocyclic group containing a hetero atom may have U, 3 or 4 a hetero atom selected from a gas atom, an oxygen atom and/or a ^ atom, wherein a nitrogen and a sulfur hetero atom may optionally be quaternized by an oxygen-nitrogen hetero atom. Heterocyclic groups which may be attached to the remainder of the ring or any hetero atom or carbon atom of the system include, but are not limited to, qiqiyuanxuan, qiqiyuanzu aziridine, and Oxygen sulfhydryl, furyl, furfuryl, high hexahydropyrene, tetrahydroimidazolyl, diarlimidazolyl, isoxazolyl, isoxazole 131494 • 17- 200902026 ke, whiffinyl... Dijungi, tetrahydroindenyl "Saltyl, tetrasodium sulphate, yl, morphine, aryl, "m-methane, hexammine, piperidyl, pyridinyl, tetrahydrogen Pyrazolyl, dihydropyrazolyl, pyrazolyl, fluorenyl, pyridooxazolyl, pyridoimidazolyl, pyridopyrimidyl, octagonal, octagonal, tetrahydro (tetra), n Base, feed bite group, tetrahydrofuran-based base, p-dithiol, thiophene, p-septene far-salt, pyrimenyl, phenazolyl, thiomorpholinyl, Thiophenyl, tri-negative and triazolyl. Examples of bicyclic heterocyclic groups include fluorenyl, isodecyl, and phenyl, succinyl, benzoxanthyl, benzo pf dipyridyl Benzo benzophene group Base, quinal, tetrahydroisolinyl, iso-linyl, benzoxazolyl, benzopyranyl, ♦ well base, benzofuranyl, benzofurazyl, color I Base, coumarinyl, benzo-based, cleavage, basal, ketone, pyridine, biting, squeaking, and biting (such as 啥 〇 〇 〇 〇 比 吱 南 南 南 南 南 南 南 南 南 南 南 南 南, 2-b wind bite base] or smoulder [2, 3 handsome than bite base), two gas (5) sulfhydryl, dihydro sulphate (such as 3,4_ dihydro hail forest base), three coffee

Alkyl-seven-decenyl, tetrahydro as a forest, and the like. Exemplary tricyclic heterocyclic groups include (tetra), benzoxanyl, morphyl, and morphine. Base,

咄基等. I. The term "phenyl" as used herein refers to the term "substituent, syllabic,, and "quot;,,,,, alkynyl," as used in the substituted or unsubstituted benzene. "aryl", "phenyl", "cyclic group", "cycloalkyl", "heterocyclic group,"heterocyclic "and,heterocyclic" - The step is replaced by a substituent. Exemplary substituents include, but are not limited to, - or more than one of the following groups H, (iv), 131494 200902026 CF3, OCF3, cyano, nitro, N3, keto, cycloalkyl, alkenyl, alkynyl, heterocycle, Aryl, alkylaryl, heteroaryl, 〇Ra, SRa, S(=0)Re, S(=0)2Re, P(=0)2Re, S(=0)2ORa, P(=0) 20Ra, NRbRc, NRbS(=0)2Re, NRbP(=0)2Re, S(=0)2NRbRc, P(=0)2NRbRc, C(=0)0Ra, C(=0)Ra, C(=0 )NRbRc, 0C(=0)Ra, 0C(=0)NRbRc, NRbC(=0)0Ra, NRd C(=0)NRb Rc, NRd S(=0)2 NRb Rc, NRd P(=0)2 NRb Rc, NRb C(=0)Ra or NRbP(=0)2Re, wherein Ra is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, alkylaryl, heteroaryl, heterocyclic or aryl Rb, & and Rd are independently hydrogen, decyl, cycloalkyl, alkylaryl, heteroaryl, heterocyclic, aryl, or Rb and R. The N in combination with them may form a heterocyclic ring; and Re is an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkylaryl group, a heteroaryl group, a heterocyclic group or an aryl group. In the above-exemplified substituents, some groups, such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, alkylaryl, heteroaryl, heterocyclic and aryl, may themselves be any The aforementioned substituent is substituted. Exemplary substituents may further optionally comprise at least one labeling group, such as fluorescent, bioluminescent, chemiluminescent, colorimetric, and radioactive labeling groups. The fluorescent labeling group can be selected from bodipy, dimethylaminosulfonyl, luciferin, daramine, Texas Red, cyanine dye, alfalfa, couma Cascade BlueT M, Pacific Blue, Marina Blue, Oregon Green, 4',6-Dimercapto-2-phenylindole (0 卩1), 吲嗓'1 ratio (丨11( 1〇9>^) dye, luciferin yellow, propidium iodide, called, forest, arginine and its variants and derivatives. For further information on fluorescence technology, see, for example, 蒡 涿 涿 舆砰 舆砰 允 允 允 允 R R Richard P. Haughland, Sixth Edition, Molecular Probes, (1996), based on this 131494 -19- 200902026 For reference, those skilled in the art can readily select appropriate labeling groups and make such labeling groups common to any of the compounds of the invention, overexperiencing. ' "Four grade nitrogen" A positively charged nitrogen atom, including, for example, a positively charged rat in a tetrazoan (eg, tetramethyl, "base, ingot, etc."), in a protonated ammonium species (eg, a positively charged nitrogen in the methyl-hydrogen ammonium, N_hydrogen bond, a positively charged nitrogen in a secret oxide (eg, N.Methyl. ruthenium-oxide) than a bite-N-oxide And a positively charged nitrogen in the N-amino-ammonium group (eg, N-aminopyridinium). Unless otherwise indicated, otherwise, throughout this patent specification, the benzoxazepine compound of the present compound is used. The nitrogen in the ring may be a quaternary nitrogen. The compounds of the invention may exist in tautomeric forms (for example, with a guanamine or an imino ether). All such tautomeric forms are ' It is intended to be encompassed herein as part of the invention. As used herein, the term "prodrug" means a compound which, when administered to a patient, undergoes chemical transformation by metabolic or chemical processes. Whereas the compounds of the invention are produced. All stereoisomers of the compounds of the invention (for example, which may be due to asymmetric carbons on different substitutions), including palmoisomeric forms and diastereomeric forms' It is intended to be embraced as i within the scope of the invention. The stereoisomer may, for example, be free of other isomers (for example, an optically or purely optically pure isomer having the specified activity), or D may be mixed, for example, as a racemate, or with all other Or other selected stereoisomers may be mixed. The center of the palm of the present invention may have an 8 or square configuration as defined by the brewing c 131494 • 20- 200902026 1974. The b/red form can be obtained by physical means. Analytical, for example, fractional crystallization, separation or crystallization of diastereomeric compounds == separation of palmar column chromatography. Individual optical isomers can be borrowed from two methods, but they are derived from external (four), including but not It is limited to a conventional method, for example, formation of a salt of an optically active acid, followed by crystallization. Certain preferred compounds of the invention are referred to by the words "she" and the numbers 136 to 477. The compounds of the invention, after their preparation, are preferably isolated, purified and obtained to obtain a composition a compound containing a quantity, hydrazine weight, equal to or greater than 90%, 95% of the compound '❿ and more preferably ("substantially pure', compound), which is then used or formulated as described herein. . Such a compound of the invention, which is substantially pure, is also intended to be encompassed herein as part of the invention. All of the configurational isomers of the compounds of the invention are intended to be encompassed, whether in a blend or in pure or substantially pure form. The definition of the compound of the present invention is cis (Z) #trans (E) both olefin isomers' and cis and trans isomers of cyclic hydrocarbons or heterocyclic rings. The entire group and its substituents are selected throughout this patent specification to provide a stable moiety and compound. The present invention provides compounds which are capable of treating disorders and diseases associated with RyR. More specifically, the present invention provides compounds which are capable of treating or preventing leakage on the RyR channel. In a specific embodiment, the compounds of the invention enhance the binding of RyR to calstabin and/or inhibit its dissociation (eg, RyRl and Casitabin; RyR2 and Casitabin 2; RyR3 and Card History 131494 -21 - 200902026 Tabin 1). "Diseases and diseases associated with RyR" means disorders and diseases that can be treated and/or prevented by modulating RyR. "Disorders and diseases associated with RyR" include, but are not limited to, heart, muscle And cognitive disorders and diseases, malignant hyperthermia, diabetes and sudden infant death syndrome. Cardiac disorders and diseases include, but are not limited to, irregular heartbeats and diseases caused by irregular heartbeats and movements; sudden heart disease deaths; sudden cardiac death caused by exercise; septic heart failure; chronic obstructive pulmonary disease; Cardiac hypertrophy and high blood pressure. Irregular heartbeat disorders and diseases include, but are not limited to, atrial and ventricular arrhythmias, atrial and ventricular fibrillation, rapid atrial and ventricular rapids; atrial and ventricular tachycardia, changes in CPVT and its movement.

Muscle disorders and diseases include, but are not limited to, skeletal muscle fatigue, central core disease, skeletal muscle fatigue caused by exercise, bladder disorders, incontinence, age-related muscle fatigue, congenital myopathy, core-and-rod myopathy, Granuloid myopathy, selected from the group consisting of Kearns_Sayre syndrome, melas (granuloid myopathy, encephalopathy, lactic acidosis and stroke) and merrf (myoclonic epilepsy with broken red fiber) syndrome, endocrine Myopathy, muscle glycogen storage disease' is selected from the group consisting of: type glycogen storage disease, Shi's disease and myosin urine, including from the version & disease, Dingca disease and DiMauro disease Dermatomyositis, ossifying myositis 'family periodic itching, polymyositis, inclusion body myositis, neuromuscular rigidity, systemic stiffness syndrome, malignant hyperthermia, common muscle spasm, spasm, facial scapular malnutrition, severe Muscle weakness 'muscle malnutrition, selected from limb muscle malnutrition, congenital muscular dystrophy, peripheral muscle dystrophy, Emery-Dre-s muscle 131494 • 22- 200902026%%* Bad, myotonic muscular dystrophy and eye pharyngeal muscular dystrophy, Duchenne muscular dystrophy and Becker's muscular dystrophy. Cognitive disorders and diseases include, but are not limited to, (i) peripheral neuropathy or central neuropathy, selected from the group consisting of vestibular neuropathy 'optic neuropathy, optic neuropathy, retinal neuropathy, the god of diabetes, house disease/酉 and f, 纟^ disease, God caused by Chare〇t_Marie_T disease (cmt), Flett's disease, Gullain-Barre syndrome, nodular eclampsia, sarcoidosis, systemic lupus erythematosus, rheumatism Arthritis, Sjogren HIV infection, syphilis infection, cancer infection, hepatitis infection, Corolla (c-, flatworm fever infection, diphtheria infection, leprosy, disease, bacterial infection, viral sensation, inflammatory Process, exposure to toxins, drug treatment, chemical treatment of sputum; Second, bottom ^ .. dry mouth sputum ~ treatment, cancer, undernutrition, vitamin B_12 lack, biotin B1 deficiency, trauma, in Neurological stress, heritable symptoms, loss of myelin sheath, car injury, uremia, uterine degeneration, Shishen poisoning, nitrous oxide exposure or heavy metal exposure; (9) epilepsy or non-seizures Including epilepsy, partial seizures, onset of seizures, distribution episodes, systemic seizures, simple partial seizures, (4) partial seizures, myoclonic seizures, clonic seizures, nervous seizures, tension clonic seizures, no tension episodes, Attack, __ episode, Jia ^ Sen's episode 'psychotic seizures, temporal lobe episodes, non-seizures, unstimulated episodes, dynasty episodes, infant 痉 f, w shouting 襄, with: 中~颞穗Benign childhood epilepsy, benign Roland's epilepsy, benign childhood epilepsy with occipital second burst, juvenile myoclonus epilepsy (dirty), temporal lobe epilepsy ^ ^ Lennox-Gastaut, u^ ^ # ^ # , ^ ^ g| 131494 -23 - 200902026 Spectral disorders (FASD), psychogenic seizures and fever; and (iv) cognitive disorders, selected from the group consisting of Alzheimer's disease-dependent memory disorders, cancer, delusions, memory loss, two-year blood vessels Dementia, multi-infarct dementia, Binswang_ = dementia of dementia (DLB), alcohol induced by 捭娣, Fu, Ge, and frontal bone and sacral leaf degeneration (FTLD), Pick's disease, amount n + , rhyme and sacral dementia, forehead type F TLD, literal dementia: 颞 (four) FTLD, progressive non-fluent aphasia,

Creutzfeldt-Jakob disease, Huntington's disease, guilty to life's disease, AIDS dementia relapse, attentional disorder, stress and dysfunction (ADD), attention deficit hyperactivity disorder (ADHD) ), cognitive dysfunction associated with age-old ageing, and cognitive dysfunction caused by stress, including post-traumatic stress disorder. Compound

V

131494 •24· 200902026 where n is 〇, 1,2, 3 or 4; each R is independently selected from Ζ, R5, _〇r5, _Sr5 -NR5C(=0)0R5 . -C(=〇)N( R5)2 > -C(=〇)〇R5 . -C(=〇)R5 , N〇2, CN, cz3, 〇cz3 Hp(=0)r8R9 ; ' -n(r5)2, ' -OC (=〇) R5 R! and R3 are each independently selected from the group consisting of _ group, R5, even qR5, even 〇c(=〇^, C(0)0R5, -C(=〇)NHR5 ' -C(=〇) R5 ^ _〇C(=〇)R5 ; /

& € from R5 ' _C(=o)R6, _C(=S)R6 and even) m Ri 〇, where m is 1, 2, 3, 4, 5 or 6; or R] and R2 and their The individual linked carbons together with the nitrogen form an unsubstituted or substituted heterocyclic ring; or 2., & and their individually linked nitrogen together with carbon form an unsubstituted or substituted hexahydropyrazine Rings; or 3〃, 4#, each of the individually linked carbon atoms together form an unsubstituted or substituted cycloalkyl or heterocyclic ring; or R4 is selected from the group consisting of R5 and a keto group; Hydrogen, alkyl, alkenyl, fast radical, cyclohexyl, heterocyclylaryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, alkylaryl and pyridylheteroaryl; Is selected from the group consisting of R5, _(CH2)bNR13R14 '-Nr5〇r5, _OR5, _q_C)PR5, _(CH2)cY and -C(=0)R5, where b is 0' l 2, 3, 4, 5 or 6 ' and c is l 2, 3, 4 or 5; 1 〇 2', including R5, -OR5, -S〇2 Rn, -0(=0)1^ 2, -NHCOO)!^ 2 , -o(c'r12 and sonar) R8R9; 131494 -25 200902026

RsA'Rh and R12 are independently selected from the group consisting of ruthenium and rhodium; γ is selected from the group consisting of Z, _〇) 2R5, (4) 浑一" and _〇r5; Z is halogen, selected from F, C1, 玢 and 1; R13 and R14 are independently selected from the group consisting of a core, or Ri3 and Ri4, and the N combined with them to form an unsubstituted or substituted heterocyclic ring; and = each of the alkyl, county, block, and ring-burning a group, a heterocyclic group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocyclic group, a aryl group and an alkyl group, which may be substituted or unsubstituted; The nitrogen in the heptacyclic ring may be a quaternary nitrogen; and all of its palmomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes , polymorphs, metabolites, and prodrugs; the condition is (i) when R is hydrogen, at position 7 of the benzoxanthine seven ring, R2 is not chlorine, alkyl, ketone or An oxygen-burning base, (8) when R3 is a ketone group, & not a keto group or -C(,NHr5; Q) when the center of mind is H, & is not a phenyl group. And (4) when Han 2 and the heart and they The individual connected nitrogen forms a soil together with carbon. Or with a substituent of the heterocycle, the heart is not a ketone group. The present invention further provides a variety of preferred structures that fall within the general structure of the formula & Preferred compounds of the present invention include: • a compound of the formula La where 'n Jk R r's a bucket, τ want" "T, Rl_R4 are as in the formula & and each of the Han systems

Independently selected from Z, 〇CZ3, OR 3 K5 〇R5, CN, N〇2, -c(o)n(r5)2, -C(=0)0R and _p 5 and P(〇)R8R9 Wherein R8 and R9 are independently 5, and the two pure are independently hydrogen' or unsubstituted or substituted alkyl, alkylaryl, aryl or heterocyclic. 131494 -26 - 200902026 • A compound of formula I_a, wherein the ruth is called, and at position 7 of the benzoxanthine seven ring, η and Ri'R4 are both of formula Ia, and wherein R5 is selected from the group consisting of ammonia, or not A substituted or substituted aryl, alkylaryl, aryl or heterocyclic group. In a preferred embodiment of the invention, R is methoxy. • a compound of the formula wherein, 丨, 心, and 114 are as defined, and wherein Μ is selected from the group consisting of '(9)_C(=0)R6' and (called _Taohua, wherein & ^ hydrogen' or unsubstituted Or a substituted ortho, aryl, aryl, hetero or heteroaryl group, wherein the uldent 6 is _NRi3R14, a gate or -(iv)OR5; and wherein Ri 3 and Ri 4 are combined with N _ Forming an unsubstituted or substituted heterocyclic ring; and wherein m is 1, 2, 3, 4, 5 or 6, wherein R 〇 is R 5 or (C =0) 〇 R 5 . 11,11,111,113 and 114 are as in the formula ", and wherein R2 is selected from the group consisting of r5, net (C, 0R5, _c (, he "r", _ch:r丨. and example) C (four) dish] 3R Wherein R 5 is ammonia, or unsubstituted or substituted pit, aryl, alkyl aryl, heterocyclic or heteroaryl I; and _/~ Λ ' and Rl 4 are each Η, or a combination to form NVy/Rd as CH2, NH, Ο, N-benzo(10) fluorenyl icyl or N_c(=〇) 〇c= ~ wherein the nitrogen in Rd may be a quaternary nitrogen; And wherein Ri is 仏 or (c' 〇 R5. In a preferred embodiment '~ is · c (which is zero. • Formula Ia , wherein n, R, ^ and heart are of the formula Η, and the nitrogen and carbon which are individually linked to R and 1 together with carbon form 2 unsubstituted or substituted heterocyclic rings other than hexahydrochloroquinone. a compound of 1-a, wherein ... and ~ are both of the formula !-a, and wherein R3 131494 -27- 200902026 /, R4 and the carbon atoms to which they are individually attached together form an unsubstituted or substituted cycloalkyl or hetero Still other preferred compounds of the invention include those of formula Ia wherein (a) η is 1 or 2 and R is Z, OCZ3, R5, 〇R5, CN, N02, N(R5)2, -C( =〇)N(R5)2, -C(=〇)〇R5 or _p(=〇)r8r9, at position 7 or 8 of the benzodiazepine heptacyclic ring; or (b) η is 1 'R Is z, 〇CZ3, R5, 〇R5, CN, N02, -N(R5)2, -C(=0)N(R5)2, -C(=0)0R5 or -P(=〇)r8r9, At position 6 of the benzodiazepine heptacyclic ring; or (c) R2 is (:(=0)&, the center of which is selected from the group consisting of _c(=〇)R5, •c(=o)or5, _c(=0)NRi3Ri4 and (CH2)bNRi3Ri4, where b=〇, and R! 4, whether 疋 or 结合, is combined to form Λ /d , where Rd is Ο, CH 2 or NRa; and Ra is Η , alkoxy, c(=〇)oc(C H3)3 or (Ci-based)-aryl, wherein the aryl group is

a disubstituted phenyl or benzo[L3] di-n-based y-5-yl group, wherein the nitrogen in the v3 is optionally a quaternary nitrogen; or (4) R2 is R5 or (CH2)mRl 〇, wherein R is 〇 It is selected from the group consisting of R5, -C(=0)N(R5)2, -(C=0)0R5 or 视5; and m is 】, 2, 3, 4, 5 or 6. (4) A more preferred compound includes Rs and A independently of 0R5. Also in (aHd), preferred compounds of (8) to (4) include each of the R5 groups independently being hydrogen, or an unsubstituted or substituted alkyl, alkylaryl, aryl or heterocyclic group. Preferred compounds of the invention specifically include those having the formula La, wherein η is 1, and R is OR5, 〇CZ3, z, CN, & 'n(R5)2, _c(=〇) n, 131494 -28- 200902026 -C(=0)OR5 or _P(=0)(0R5 L, N〇2, at position 6, 7 or 8 of the benzodiazepine seventh ring, or n is 2, each R It is independently 〇R5, at positions 7 and 8 of the benzodiazepine heptacyclic ring.

More preferred compounds of the invention include those of the formula wherein: A) η is 1, R is 0R5 or 0CZ3, at position 7 of the benzoxylene seven-ring ring, and ruler 2 is (i) 虱'(ii) R5,(iii) (CH2 hR! 〇, where m is 1, 2, 3, 4, 5 or ό, and R10 is r5 or (〇o)or5; (iv) _c卜〇)c (=〇)〇R5; (7) -c(=o)NR13R14, or (vi) _C(=0)C(=0)N^^4, where each is H' or a combination of structures A where WCH2 , NH 〇, N_ stupid [I3] diketo _5_ group or NC (=0) 0C (R5) 3, wherein the nitrogen in the heart can be regarded as a quaternary nitrogen; or chemistry and their The individual linked nitrogen together with carbon form an unsubstituted or substituted heterocyclic ring other than hexahydropyrrole; or if i ' R is z, CN, R5, N(R5)2, _c(=〇)N ( R5)2, c(=〇)〇R5 or ·Ρ(=〇)(〇1)2, at position 7 of the benzoxanthine seven-ring ring, and & is 1; or 1, R is Ν 〇2, at position 8 of the benzodiazepine heptacyclic ring, and the heart is () hydrogen '(8) R5, (10) _C(=〇)C(=〇)〇R5; or (iv) _c(=〇)NRhR ", its - Γ~\ ', 中反" and !^4 are either Η or 结合Forming a NwRd, wherein CH2, ΝΗ, 〇, NC(=〇)〇c(R5)3 or Ν•Benz# [u] bis-yl group, wherein the nitrogen in Rd may be a quaternary nitrogen; or ~ and the heart and the other: the nitrogen and carbon of the individual connection together form an unsubstituted or unsubstituted heterocyclic ring other than the hexahydrogen well; or 131494 -29- 200902026 D) η is 2, each r is independent 〇R5, at positions 7 and 8 of the benzodiazepine heptacyclic ring, and R2 is (1) hydrogen; (9) c(=〇)c(=〇)〇R5; or (iii)_c Bu(7) nr" , —νλ ~\ where R!3 and R! 4 are each η, or are combined to form \__/Rd, and their R Rd is CH2, NH, 〇, N_benzo π, 3] diketo _5 _ base or NC(=0)0C(R5)3 'where the nitrogen in Rd may be a quaternary nitrogen; or E) n is 1, R is 〇R5, at position 6 of the benzodiazepine ring The heart and their individual connected nitrogen together with carbon form an unsubstituted or substituted heterocyclic ring other than hexahydropyrrol; or F) each HR3 and rah, n=1, ruler Called, 〇cz3, z, cN, R5, N(RS)2, ((iv) can 5)2, _C(=〇)〇R5 or ·ρ(=〇χ〇Ι15)2, n〇2, and in benzene and The position of the oxygen-nitrogen seven-ring ring is 7. (AHF) The daring compound includes r as a position J, today, v sheep, and a seven-ring ring, wherein each ~ is independently hydrogen or an unsubstituted or substituted alkyl or alkyl aryl group. , aryl or heterocyclic group. Still other preferred compounds are those which are represented by the structure of sigma, I-e, W4, and samarium in any one of the formulas. 131494

I-b •30· 200902026 r2

R 〇

I-c 〇 (R)n

.OHAV 〆

N

〇 I-d 〇

I-f

〇 R

131494 -31 - 200902026 I-g (R)r

OH

I-h R

OH Ii wherein R and R2 are both as in the formula ^, and the heart is CH2, NH, 〇, N_benzene and is a diketo-5-yl or N-CH))OC(R5)3, wherein the nitrogen in the heart It can be a four-stage nitrogen as the case may be. The preferred compounds of formula Ib to Ii include those in which the ruthenium is at position 7 of the benzoxazepine® ring wherein each R5 is independently hydrogen or an unsubstituted or substituted alkyl or alkane Alkyl, aryl or heterocyclic group. R is preferably a methoxy group at position 7 of the benzothiazepine heptacyclic ring. In a more general embodiment, the invention provides a compound of the formula: R.1

Wherein η, R and Rl_R4 are as defined herein, and wherein the parent is 〇, _NR5 or -C(K>5)2. The claim has been carefully prepared so that only the compounds unknown to the present inventors are known from the present inventors. The inventors reserve the right to further exclude any of the compounds disclosed in the prior art, which may be cited to resist the claim in future firm actions. Particularly preferred compounds include compounds of Formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and Ii as disclosed herein, or are disclosed herein as compounds, such as, without limitation, ARM136, ARM137, ARM138, ARM149, ARM150, ARM159, ARM160, ARM187, ARM189, ARM252, ARM258, ARM296, ARM301, ARM318, ARM322, ARM351, ARM352, ARM423, ARM454,. These compounds are / ARM139, ARM140, ARM146, ARM147, ARM148, ARM151, ARM152, ARM153, ARM156, ARM157, ARM161, ARM166, ARM167, ARM182, ARM186, ARM200, ARM203, ARM205, ARM217, ARM251, ARM277, ARM279, ARM282 , ARM291, ARM293, ARM302, ARM306, ARM311, ARM312, ARM313, ARM324, ARM326, ARM331, ARM335, ARM337, ARM353, ARM354, ARM397, ARM398, ARM399, ARM463, ARM466, ARM470, ARM473 and ARM477 have the following structure: ARM137 ARM136

131494 •33 - 200902026 ARM138

MeO. ARM139-ARM140-ARM 146

,r\^Y^N ARM147 ARM 148

ARM149 one 131494 200902026

ARM 152

ARM153

ARM156

131494 -35- 200902026 ARM 160 ARM161 ARM 166 ARM 167

N / ARM 182

ARM 186 ARM187 131494 0 200902026 ARM189

〇 ARM252

〇, 131494 -37- 200902026 ARM258

ARM277

ARM282

ARM291

131494 -38- 200902026

ARM302

ARM311

131494 -39- 200902026 /-

〇 ARM324

ARM331

ARM337

131494 -40- 200902026 ARM352

ARM353

ARM398

\

131494 -41 - 200902026 ARM463

ARM466

ARM473

ARM477 Pharmaceutical Compositions The compounds of the present invention are formulated into pharmaceutical compositions for administration to human patients in a biologically compatible form suitable for in vivo administration. According to another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a pharmaceutically acceptable diluent and/or carrier. A pharmaceutically acceptable carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. The pharmaceutically acceptable carrier used herein is selected from various organic or inorganic substances, which are used as a pharmaceutical formulation for substances 131494-42-200902026, and which are incorporated as a stagnation, @^ 涌4 Buffers, binders, disintegrating mash, thinners, emulsifiers, fumes, ^^~~ agents, gelling agents' glidants,

Skin sub-permeation enhancer, solubilizer, g + U combined with female elixirs, suspending agent, osmotic agent, vehicle and viscosity increasing agent. Mang Φ film ‘,, also add pharmaceutical additives, such as k oxidant, aromatic compounds, and ^ ^ ^. Color y improve improver, preservatives and i 曰 sweetener. Acceptable pharmaceutical carriers include, among others, carboxymethyl π-two-dimensional, glycerin, acacia, lactose, glacial stearate, powder, saline, sodium alginate, yum, powder, talc, and water. The pharmaceutical formulations of the present invention are prepared by methods well known in the art of medicinal techniques. Example: Combining a compound of the invention with a carrier and/or a diluent: a liquid or a cold. One or more accessory ingredients (eg, buffer ^, dwarfing agent 'surfactant, etc.) are also added as appropriate. The choice of carrier is determined by the combination of: degree: chemical and chemical properties, selected routes of administration, and standard pharmaceutical practice. The compound of the present invention is administered to a patient by contacting the target cells (e.g., cardiomyocytes) with the compound in the living body. The compound is contacted with (e.g., introduced into) a patient's cells using known techniques for the introduction and administration of peptones, nucleic acids, and other drugs. Examples of methods of contacting a cell with a compound of the invention (ie, treating a cell with a compound of the invention) include, but are not limited to, absorption, electroporation, immersion, injection introduction, liposome transfer, transfection, blood transfusion, vehicle and Other drugs pass the media d and method. When the target cell is localized to a particular part of the patient, as is desired to introduce the compound of the invention into another body fluid by injection or by some other means (Section 131494 -43 - 200902026 via the introduction of the compound into the blood ) Straight. The target cell line is contained in, directly penetrated into the tissue of the patient in the thin pole 匕3, known as the macro; I;»Huaizhan.3, Futian wins the land from the 孜 疋 疋The quasi-detection method detects 1 & ^ M ai^ru, , A /, reed, examples include and is not limited to micromirror technology. *Color) Labor First Imaging Technology and Display In addition, the compounds of the present invention are borrowed? It is known that I sequence is administered to human or animal patients. 6 Hai private order includes, without limitation, oral administration, ^ sublingual or cheek administration, parenteral medicine, transdermal administration, and inhalation. Seven 4 sighs 4 from the intranasal, vaginal, rectal and intramuscular modes. The compound of the present invention is in a parenteral manner, by intramuscular, intradermal, intradermal, intramuscular, intraorbital, intraperitoneal, intraspinal, intrasternal, intravascular, intravenous, Subjective, subcutaneous or sublingual left-shot or administered via a catheter. In one embodiment, the medicament is administered to the patient by transmission to the muscle of the patient including, but not limited to, the myocardium of the patient. In one embodiment, the agent is administered to the patient via a catheter inserted into the heart of the patient by delivery of the target to the cardiomyocytes. For oral administration, the formulations of the compounds of the invention may be presented as capsules, tablets, powders, granules or as suspensions or solutions. Formulated with conventional additives, such as lactose, mannitol, corn starch or horse macadamia. The formulation is also presented as a binder such as crystalline cellulose, cellulose derivatives, gum arabic, corn powder or gelatin. In addition, the formulation is presented as a disintegrant such as corn powder, horse starch or sodium carboxymethyl cellulose. The formulation is also presented as anhydrous dibasic calcium phosphate or sodium starch glycolate. Finally, the formulation is presented as a lubricant such as talc or magnesium stearate. For parenteral administration (i.e., by injection through a route other than the digestive tract 131494 -44 · 200902026), the compound of the present invention is combined with a sterile aqueous solution which is isotonic with blood. Such a formulation is prepared by dissolving a solid active ingredient: s having a physiologically compatible substance, such as sodium chloride, glycine, etc., and having 2 buffered pH waters compatible with physiological conditions, The solution is sterilized after the broth is produced. Formulations are presented in unit or multi-dose containers, such as sealed ampoules or vials. Formulations are by any injection mould: transmission, including but not limited to fascia, intracapsular, intracranial, intradermal, intrathecal: intramuscular, intra-abdominal, intraspinal, intrasternal, intravascular, intravascular, intravenous Internally, subcutaneously or sublingually, or through a catheter into the heart of a patient. For transdermal administration, the compound of the present invention is impregnated with a skin enhancer, such as propylene glycol 1 ethylene glycol, isopropanol, ethanol, oleic acid, tetrahydroxanthone, etc., which increases the skin to the compound of the present invention. Permeability, the afternoon mouth permeates through the skin and into the bloodstream. The compound/enhancer composition may also be further combined with a polymeric material such as ethylcellulose 7 : propylcellulose, ethylene/vinyl acetate, % vinyl tetrahydropyrrolidone, etc.: to provide a gel form The composition, which is dissolved in a solvent such as a rolled methane, is "cured to the desired viscosity" and then applied to the backing to provide a patch. And: the substance can be provided in unit dosage form, such as tablets, capsules or single-dose vials. The appropriate unit dose 'is intended to be a therapeutically effective amount, which can be determined during the test period. The read & A~ Go test system is appropriately designed to respond to the need to administer the selected symptoms, and will of course depend on the desired clinical endpoint. change. The invention also provides articles of manufacture for use in treating and preventing a condition, such as a heart condition, in a patient. The article of manufacture is a composition comprising - or a plurality of compounds of the invention 131494 - 45 - 200902026. The article of manufacture is provided with instructions for the various conditions that the pharmaceutical composition is capable of treating and/or preventing. For example, the article of manufacture comprises a unit dose of a compound disclosed herein that is capable of treating or preventing a muscle disorder, and an indication that the unit dose is capable of treating or preventing a condition, such as a rhythm. The present invention further provides compounds which can be classified as derivatives of benzoxazepines, including, by way of example, without limitation, preferred compounds ARM136, ARM137, ARM138, ARM139, ARM140, ARM146, ARM147, ARM148 , ARM149, ARM150, ARM151, ARM152, ARM153, ARM156, ARM157, ARM159, ARM160, ARM161, ARM166, ARM167, ARM182, ARM186, ARM189, ARM203, ARM217, ARM251, ARM252, ARM258, ARM277, ARM279, ARM282, ARM291, ARM293 , ARM296, ARM301, ARM302, ARM306, ARM311, ARM312, ARM313, ARM318, ARM322, ARM324, ARM326, ARM331, ARM335, ARM337, ARM351, ARM352, ARM353, ARM354, ARM397, ARM398, ARM399, ARM423, ARM454, ARM463, ARM466 , ARM470, ARM473 and ARM477. These and any other compounds of the invention may be combined with a pharmaceutically acceptable carrier as described above to form a pharmaceutical composition. According to the method of the present invention, any such compound can be administered to a patient (or to a cell of a patient) in an amount effective to limit or prevent RyR binding in the patient, particularly in the patient's cells. The reduction in calstabin content. This amount is readily determined by the skilled artisan, based on known procedures, including analysis of the titration curve established in vivo and the methods and assays disclosed herein. A suitable amount of a compound of the invention effective to limit or prevent a decrease in the RastR binding of the statin in a patient is in the range of about 0.01 mg/kg 131494-46-200902026/day to about 20 mg/kg/day, and/or It is sufficient to achieve a plasma content ranging from about 300 ng/ml to about 1000 ng/ml. Alternatively, the amount of the compound derived from the present invention ranges from about 1 mg/kg/day to about 1 mg/kg/day. Also included is an amount of about 001 mg/kg/day or 0.05 mg/kg/day to about 5 mg/kg/day or about 1 mg/kg/day that can be administered. Uses The present invention provides a range of novel therapeutic treatments for patients suffering from various conditions involving RyR modulation, particularly skeletal muscle disorders (RyRl), cardiac disorders (RyR2), and cognitive disorders (RyR3). In a particular embodiment of the invention, the patient has not developed a condition, such as a heart rhythm caused by exercise. In another embodiment of the invention, the patient is in need of treatment for a condition, including a different cardiac condition.

K The various conditions for the treatment or prevention of the compounds of the invention are those associated with RyR as described above. Based on the information provided herein, those skilled in the art will recognize that other compounds of the invention may be used to treat, including but not limited to, muscle and heart conditions. The amount of the compound of the present invention which effectively limits or prevents the decrease in the RyR2 binding to the calstatin 2 in a patient is an amount of cardiac rhythm caused by effective prevention of exercise in a patient. Heart rhythm is a disorder of cardiac electrical activity, which is characterized by abnormalities in heart rate or cardiac rhythm. As used herein, "effective prevention of exercise caused by arrhythmia, the amount of the compound of the invention, including effective prevention of exercise caused by cardiac rhythm (such as palpitations, fainting, ventricular fibrillation, ventricular pulsation The amount of the compound of the invention for clinical damage or signs of development of a rapid or sudden heart attack 131494 • 47. 200902026. f

The amount of the compound that causes heart rhythm caused by exercise prevention is changed according to the factors of = = 疋, including the type of heart rhythm caused by exercise, the weight of the disease, the severity of the symptoms of the patient, and the mode of administration of the compound. This amount is: The field is determined by the skilled technician and is based on known procedures, including the methods disclosed in this article. In one embodiment, the amount of the compound of the present invention effective to prevent heart rhythm caused by exercise is the amount of sudden cardiac death caused by effective prevention of exercise. In another embodiment, the compounds of the present invention are used to prevent cardiac heart failure caused by irregular heart rhythm and exercise in a patient. Since the compound of the present invention stabilizes the RyR-bonded statin, and restores or restores the ability to balance the dynamic PKA phase interaction with the RyR in the % of the biomass, it can also be used for treatment. Patients with clinical signs of various conditions. For example, if the signs of the condition are detected early enough, the compounds of the invention are effective in limiting or preventing further reduction in the caltopab content of RyR binding in the patient. Furthermore, the patient's condition of the present invention is caused by a heart attack such as exercise caused by exercise. Candidates for irregular rhythms. The heart rhythm caused by exercise is a heart condition developed during/after the patient has exercised (eg, ventricular fibrillation or ventricular tachycardia) including any death that causes a sudden heart attack. "Candidates for heart disease caused by exercise" are patients who develop a risk of heart disease during/after physical exercise. Examples of candidates for cardiac arrhythmia caused by exercise include, but are not limited to, Suffering from CPVT, or/and developing a heart rhythm during and after physical exercise 131494 -48- 200902026. Therefore, in yet another embodiment of the invention, the patient is already exercising , or currently exercising, and have developed a condition caused by exercise. In this condition, the amount of the compound of the present invention which is effectively limited or prevented in the patient's combination with the amount of the statin 3 is An amount effective to treat a condition caused by exercise in a patient. As used herein, "the amount of a compound of the invention effective to treat a condition caused by exercise" includes effectively alleviating or improving the condition caused by exercise. (For example, in the case of irregular heart rhythm, palpitations, fainting, heart to fibrillation, ventricular tachycardia, and sudden heart attack) or the amount of the compound of the present invention. The amount of the compound of the present invention which is effective in treating a condition caused by exercise in a patient varies depending on the specific factors of each case, including the type of the condition caused by exercise, the weight of the patient, the serious symptoms of the patient's symptoms, and the mode of administration of the compound. The amount is readily determined by the skilled artisan, based on known procedures, including clinical trials and the disclosure herein, in a particular embodiment, the compound of the invention is caused by a treatment in a patient The present invention further provides a method for treating a condition caused by exercise in a patient, the method comprising administering to the patient a compound of the present invention in an amount effective to treat a disease caused by exercise in the patient The appropriate amount of a compound effective to treat, for example, a cardiac arrhythmia caused by exercise in a patient ranges from about mM mg/α kg/day to about 20 mg/kg/day, and/or is sufficient to achieve a blood I 3 setting range. The permeation is from about 300 ng/ml to about 1000 ng/ml. In addition, the compound is pre-treated in patients with heterozygous defects 131494-49-200902026 in the calstatin 2 gene. Irregular heartbeat disorder. The compounds of the present invention can be used alone or in combination with other agents, which are not limited to diuretics, platelet-damping agents, anti-arrhythmic drugs. Affects contractile force, -B speed (four), ... blockers, angiotensin inhibitors, inhibitors and vasodilators. Further, this combination of η κ σ and other cardiovascular drugs is used individually or in combination In addition, the administration of one element of the combination is preceded by the administration of other agents, at the same time, or after π in different embodiments of the above method, the heart rhythm caused by the movement in the patient is accompanied by VT. In some embodiments, ντ' force, in other specific embodiments of the method, the patient is a candidate for cardiac arrhythmia caused by the operation' including sudden heart disease caused by exercise Candidate for death. The method of the present invention also provides a method for the use of the compound of the present invention in a method for limiting or preventing a decrease in the statin content of yR, ' alpha. The invention also provides for the use of a compound of the invention in a method of treating or preventing a muscle disorder in a patient. Further, the present invention provides a compound of the present invention which is used in a method of preventing or treating a muscle disorder caused by exercise in a patient. The present invention further provides a method of detecting the effect of a compound of the present invention in preventing a condition and disease associated with RyR. The method comprises the steps of: (8) obtaining or producing a culture of cells containing RyR; (8) contacting, ', the cell with one or more compounds of the invention; (6) exposing the cells to one or 131494 -50 · 200902026 The conditions for the phosphorylation of RyR in the cells; and (4) determining whether or not the compounds of the present invention limit or prevent a decrease in the calstatin content of the machine-bound cells in the cells. When used in this article _," contains

The cells of RyR" are the cells of RyR, including RyR1, RyR2 and Qing, or their derivatives or homologues, which naturally or naturally occur. Conditions known to increase the phosphorylation of RyR in cells include Without limitation, the presence of PKA. In the method of the present invention, the cell line is one of the compounds of the present invention by any standard method that achieves drug/agent-to-cell contact, including any of the modes of administration described herein. Contact. Card history of RyR binding in cells: The guest content is measured by any of the known methods described in the art or herein. In a particular embodiment of the invention, - or a plurality of compounds of the invention are prevented A decrease in the amount of RastR in the cell, and a decrease in the content of the statin. In a specific embodiment, the method of the present invention comprises the steps of: or - or a plurality of compounds of the present invention and a cell culture containing RyR Contact 'and test & - or a number of compounds have a biological event associated with RyR in the cell. The biological events associated with the use of Na in this article, ',, A biochemical or physiological process in which RyR activity has been implicated 'for example, without limitation, EC coupling and contractility in cardiomyocytes. According to the invention, the JV 5H one or more compounds are associated with one or more cells ( For example, cardiomyocytes are exposed to in vitro humans. For example, cultures of cells are cultured in the form of three or more compounds of the invention. The effects of such characters on the biological events of 峨(四) are then In the art of craftsmanship, it has been measured or evaluated by methods, including immunostaining, single channel 131494-51 - 200902026, and any other methods disclosed herein. The present invention is further directed to the confirmation by the above confirmation method. One or more of the compounds of the present invention, and the compositions of the compounds and the pharmaceutically acceptable carriers and/or diluents, such compounds, can be used in patients for pre-I Sudden heart attack caused by exercise, and symptoms used to treat or prevent other yR. The "symptoms associated with" used in this article are: RyR content or activity has been A symptom, disease, or condition that is implicated, and a biological event. Symptoms associated with RyR are caused by a patient who is treated or prevented by administering a compound that is effective in treating or preventing the patient. This amount is easily determined by aging =. The present invention provides a method for sudden heart attack death caused by exercise, in the form of == administration of one or more compounds of the present invention, the amount of which can effectively prevent exercise in patients Sudden heart attack. Secondly, an in vivo method for detecting the effectiveness of the compounds of the present invention in preventing RyR-related disorders and diseases is also provided. The method comprises the following:: seeding or producing an animal containing RyR; (b) administering to the animal a -== compound; (C) exposing the animal to - or a plurality of known RyR in the field cell The card that limits or prevents the warfare in the phosphorylation animal: tower = = compound in degree. The method further comprises the steps of: (or administering a compound of the invention or a plurality of compounds of the invention; and a biological event associated with the animal of 3 yR); a pharmaceutical composition of the compound in the animal (tetra); In patients, it also provides a sudden heart caused by this prevention campaign 131494 • 52- 200902026

The method of dying from visceral disease, the 4 HI-producing * by the female & 5 patients with this disease, this compound: a: the amount of T in the heart of the political prevention campaign has been blocked will block Ρκ A activation (4) disease death. The activation of the channel, resulting in a compound of =, is expected to reduce the peach 纴 罟 罟 罟 ’ ’ ’ ’ ’ ’ ’ 释 释 释 释 释 释 释 释 ’ ’ ’ ’ ’ ’ Kasta

Negative, , · σ & position binding to RR. In, ^ Road 'but when the channel is PKA phosphorylated 犄 'will not leave the channel of the human sigma ' is also expected to reduce the activity of the channel, in response It will activate KA activation or other triggering of the RyR channel. This compound also causes less calcium to be released into the cells. For example, diagnostic tests use _ sensitive fluorescent dyes (eg

Screening of F1U〇-3, FUm_2, etc.) is released into the cells via the postal channel. The cells are filled with the selected fluorescent dye, and then stimulated with a RyR activator to determine the decrease in the relying glory signal. (5) Llan (four) human 'by removing the 6_binding protein paste channel (Renolidine---receptor) function Stability: C Cheng 77: 513-23, 1994; Gill0 et al., in the mouse erythroleukemia cells during the induced differentiation into the 81: 783_92, back; Jayaraman et al, inositol M, 5_ triphosphate Regulation of vinegar receptors by phosphorylation of valine. s- 272: 1492·94, 1996). Calcium dependent fluorescence signals were monitored by photomultiplier tubes and analyzed in appropriate software. This assay can be easily automated to screen for compounds of the invention using multi-well culture dishes. To demonstrate a compound that inhibits the ρΚΑ-dependent activation of intracellular calcium release by RyR, the assay involves the expression of recombinant RyR channels in a heterologous expression system such as Sf9, HEK293 or CHO cells. RyR can also be expressed in combination with adrenergic receptors. This allows for the assessment of the effect of the compounds of the invention on RyR activation in response to the addition of a sheet adrenergic receptor agonist. 131494 -53- 200902026 The degree of PKA phosphorylation of RyR2 associated with the degree of heart failure was also tested and then used to determine the efficacy of the compounds of the invention in blocking the ρκΑ phosphorylation of the RyR2 channel. This assay is based on the use of antibodies specific for the RyR2 protein. For example, the 'RyR2-channel protein system is immunosuppressed and then phosphatylated with PKA and [r32P]-ATP. Next, the amount of radioactive [3 2 P] marker transferred to the RyR2 protein is measured using a lining machine (Marx et al., PKA phosphonium is derived from the calcium release channel (ryanodine receptor). Dissociation of FKBP12.6: Defective regulation in depleted hearts Ce", 101: 365-76, 2000). Another assay for the compounds of the invention involves the use of a phosphonium-based epitope-specific antibody that detects RyRl phosphorylated by PKA on Ser 2843 or RyR2 phosphorylated by PKA on Ser 2809. . Immunoabsorption using such antibodies can be used to assess the efficacy of such compounds for heart failure and cardiac arrhythmia therapy. In addition, RyR2 S2809A and RyR2 S2809D were added to the mouse line to evaluate the efficacy of heart failure and cardiac rhythm therapy. This mouse line further provides evidence that RyR2 S28〇9A mutants inhibit heart failure and arrhythmia, and that RyR2 S2809D mutations can worsen heart failure and arrhythmia, %1%1 High phosphorus deuteration is a contributing factor to heart failure and heart rhythm. Accordingly, in a particular embodiment, the present invention provides a method of treating cardiac arrhythmia caused by heart failure, atrial fibrillation or exercise comprising administering a therapeutically effective amount of a compound to an animal in need thereof, It is selected from the compounds of the present invention. Intracellular Ca2+ leakage was proposed as a major mediator of reduced muscle performance and dystrophic muscle 131494 -54· 200902026 '4. Muscular malnutrition is a hereditary disease of the genus, and 乂 is weak and progressive muscle consumption. Duchenne muscular dystrophy () is one of the most frequently occurring genetic diseases (X-link; 1 in 3,500 males), where death due to respiratory and/or heart failure usually occurs in 3G patients at 3G Before the age. Effective therapy is highly desirable because genetic screening does not eliminate the high incidence of incidents due to sporadic conditions. Since the change in intracellular Ca2+ concentration in DMD muscle fibers indicates that f pathogen mechanism is involved, it is highly desirable to prevent intracellular Ca2+ abnormality from becoming a cause of skeletal muscle degeneration. It has been suggested that an increase in intracellular Cy + concentration ([CP],) at rest will directly contribute to the co-activation of toxic myocytes (muscle fibers) and Ca2+-dependent proteases, such as calcium pain: By inhibiting intracellular. The promotion of 2+ elevation to prevent the activation of calcium-dependent egg whites is a strategy for preventing muscle consumption in the face. Elevated intracellular sputum is prevented by administration of a medicament comprising a compound of the invention. According to the method of the present invention, the decrease in the calstatin content of the RyR-binding is in the patient by reducing the limitation of the priming in the patient or the pre-H specific embodiment, in the patient H Prevents the card φ weight h of RyR2 binding. Human θ π double 丨艮 or Kasta negative 2 contains the amount of reduction in summer, is = effective treatment or prevention of heart failure, atrial fibrosis = 丨: it: the amount of rhythm. In another embodiment, the amount of the drug that is intentionally inhibited or prevented by the RyR2 combination is reduced by the amount of the drug, and the i + 3 is in the heart of the mind: "effectively preventing the movement in the patient W The dose of a sudden death of a visceral disease. Large hair 131494 -55- 200902026 Synthetic method The present invention provides, in a further aspect, a compound of the present invention and salts, solvates, hydrates, complexes, polymorphs, metabolites and prodrugs thereof, and such A method of pharmaceutically acceptable salt of a pharmaceutically acceptable drug. More specifically, the present invention provides the preparation of the following preferred compounds, ARM136, ARM137, ARM138, ARM139, ARM140, ARM146, ARM147, ARM148, ARM149, ARM150, ARM151, ARM152, ARM153, ARM156, ARM157, ARM159, ARM160, ARM161 , ARM166, ARM167, ARM182, ARM186, ARM189, ARM203, ARM217, ARM251, ARM252, ARM258, ARM277, ARM279, ARM282, ARM291, ARM293, ARM296, ARM301, ARM302, ARM306, ARM311, ARM312, ARM313, ARM318, ARM322, ARM324 , ARM326, ARM331, ARM335, ARM337, ARM351, ARM352, ARM353, ARM354, ARM397, ARM398, ARM399, ARM423, ARM454, ARM463, ARM466, ARM470, ARM473 and ARM477, and their salts, solvates, hydrates, complexes , polymorphs, metabolites and prodrugs, and methods of pharmaceutically acceptable salts of such prodrugs. Various synthetic routes to compounds are described in the Examples. Some synthetic systems utilize solvents. In one embodiment, the solvent is an organic solvent. In another embodiment, the organic solvent is dichloromethane (CH2C12), gas (CC14), citric acid (CH20) or methanol (CH3OH). Some syntheses also use alkali catalysts. In one embodiment, the base catalyst is an amine compound. In another embodiment, the base catalyst is an alkylamine such as triethylamine (TEA). In yet another embodiment, the base catalyst is pyridine. Some synthesis also utilizes an alkaline solution. In one embodiment, the alkaline solution is 131494 - 56 - 200902026 sodium bicarbonate or calcium carbonate. In another embodiment, the alkaline solution is saturated sodium bicarbonate or saturated calcium carbonate. - This ‘δ system uses an acidic solution. In one embodiment, the acidic solution is a horse tendon solution, a hydrochloric acid solution or a tartaric acid solution. In one embodiment, the combined solution is IN HC1. Solvents, organic solvents, reactants, catalysts, washing and solubilization, the 专 Temple special system is added at a suitable temperature (for example, room temperature or about 2 (TC -25 ° C, 0 ° C, etc.). The compound of the present invention can be used Various chemical synthesis preparations. In particular, the present invention also relates to a method for synthesizing a compound of the formula Ia·· r2 (R)n-

The intermediate substituents are as disclosed herein with respect to this chemical formula. When R2 and R3 are oxime, the process comprises the following steps: (4) A compound having the formula: is treated with the formula: -ΐ NH2RP compound, wherein Rp represents a nitrogen protecting group. Compound: to obtain

(9) reacting the compound formed in step (a) with a reducing agent to form

131494 •57· 200902026 Compound of the formula: (R)n,

RP

Ri (c) reacts the compound formed in step (b) with a compound of the formula: 〇 X,

X r4 wherein each X system is independently i or a sulfonate to form a compound of the formula (R) n-

R! Ο (d) reacting the compound formed in the step (c) with a base to form a compound of the formula:

Ri ,Rp (R)n-

〇

Dioxane R4 (e) The compound formed in step (d) is treated with a reducing agent to form a compound of the formula:

Ri

-r3 131494 -58- 200902026 (1) The nitrogen protecting group Rp is removed to form a compound of the formula:

Ri

To react with a transition metal catalyst such as Cul under conditions sufficient to form a compound of the formula:

These methods may further comprise: (1) a compound of the formula:

X X (R), compound treatment of the following formula R3

R2 ' NH

OH R4 or

(9) The compound of the formula ^/CHO (R) ntAx The following compound: 131494 -59- 200902026

Rs R2\ NH

OH is treated under reductive amination conditions; wherein ω or (g) is formed by the underlayer 71 R3 wherein X is independently a halogen or sulfonate leaving group. The synthesis method may also include the following steps: (4) Compounds of the formula

R3 is sufficient to form 脱离 as a detachment group, selected from dentate and sulfonate, using a base, and treated under the conditions of a compound of the formula: (R) n〇^5~R3 R4 0 Step to make a compound of the formula:

Ri

Wherein R2 is the condition of the ruthenium' and the formula Cl-C(=〇)〇Raa ruthenium chloride, which is sufficient to form a reaction: Lower formula 131494 -60- 200902026

The aforementioned compound can be followed by

Preferred compounds are represented by the following formula:

The 'NV synthesis method can further include a compound of the formula: (R)r

-R2 R3 r4 where & is Η, reacts with any of the following: (i) triphosgene and base' to form a compound of the formula

Occu R3 r4 (R), and further reacting the compound with one equivalent of the formula HNR7aR7b amine or (ii) a formula of Cl-CO-NR7a:R7b, or 131494 -61 · 200902026 (iii) Formula Cl3 C0 (C=0 a compound of NR7aR7b under conditions sufficient to form a compound of the formula

Wherein NR7aR7b in (1), (ii) or (iii) is selected from the group consisting of NH2, NEt2, NHCH2Ph, hydrazine,

R4 wherein R2 is Η' with methoxy (ch2〇) and sodium cyanoborohydride (NaBCNH3), which is sufficient to form a compound of formula I: (R)nOC^)~R3 ^ ; or a compound of the formula or Its salt:

Treat with ruthenium dichloride or gasified grass mash under conditions sufficient to form a compound of the formula: 131494 -62- 200902026

The compound described below can be combined with a compound of the formula HX wherein X is 〇CH3 or NHEt,

Other synthetic methods include the following compounds:

Where & is Η, with the following compound··

x^X 〇Ra wherein x is a dentate or a rhenium salt, and Ra4c is further reacted under the condition of forming a compound of the formula: 〇r4 and then the compound is acid or tested to form Compound of the formula:

(R)n〇^J^H Unless otherwise expressly disclosed in the combination, and in the formula, the substituents of the prepared 5 are referred to herein as T, E r JK The I-Mb compound is generally defined with respect to the more specific compounds of the formula Ib to ^. 131494 -63- 200902026 The compounds of the present invention are prepared in various forms, such as salts, hydrates, cold compositions, complexes, polymorphs, metabolites, prodrugs or salts of steroids, and The invention includes all variations of the compounds. "3 π pharmaceutical composition" means one or more of the compounds described herein or a pharmaceutically acceptable salt, hydrate or prodrug thereof, and other chemical components to avoid physiologically acceptable carriers and forms A mixture of agents is intended to aid in the administration of a compound to an organism. "Prodrug" means an agent that will be converted into a parent drug in vivo. < Body drugs are often useful & 'in some cases, they are easier to administer than parent drugs:. It is bioavailable, for example, by oral administration, whereas the parent drug is not. Prodrugs have also been improved in pharmaceutical compositions: : Degree of resolution, better than maternal drugs. For example, the compound carries a protecting group which is cleaved by hydrolysis in a body fluid, for example in the bloodstream, by releasing the active compound, or being oxidized or reduced in a body fluid to release the compound i: the compound of the invention It can also be formulated as a pharmaceutically acceptable salt, = salt or test salt, and its complex. The injury of such a salt can be aided by the pharmacological use of the physical characteristics of the change = without preventing it: Drop: & Examples of useful changes in physical properties include, but are not limited to, comparison! To help: through the mucosal administration, and increase the solubility to help the drug to be administered. Ding Xiang: The term "salt acceptable salt" means that it is suitable or can be treated with a patient == 'The patient is treated with a human patient, or an animal such as a dog is used" is pharmaceutically acceptable. Acid addition salt, I - word means 131494 -64 - 200902026 Any basic compound of the invention or any non-toxic organic or inorganic salt of any intermediate thereof. An illustrative inorganic hydrazine which forms a suitable acid addition salt: Including hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable acid addition salts include mono-, di- and tricarboxylic acids, such as Glycolic acid, lactic acid, malonic acid, 'malonic acid, succinic acid, glutaric acid, antibutanic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, acetic acid, three Fluoroacetic acid, phenylacetic acid, cinnamic acid and salicylic acid, and sulfonic acids, such as p-toluenesulfonic acid and methanesulfonic acid, can form either mono- or di-acid salts, and such salts are hydrated, solvent In a compound or substantially anhydrous form. Generally speaking The acid addition salts of the compounds of the present invention are more soluble in water and various hydrophilic solvents, and in comparison with their free state forms, hydrazine often exhibits a higher melting point. The selection of suitable salts is a skill in cooking. Other non-pharmaceutically acceptable salts, such as oxalates, are used, for example, for early isolation from the compounds of the invention for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts. God T on g W and "test: add salt" is the meaning of any acidic compound or any non-toxic organic or inorganic salt of any of its intermediates. Examples include alkali metal salts (such as lithium, Sodium or potassium salt), test metal salt (for example, 5 islands, M Kite 醆 3 times magnesium salt), 4 female salts, Cl -a alkylamine (triethylamine, etc.) 1 C6 alcoholic moon female (one Ethanolamine, triethanolamine, etc.), procaine salt, amine (dicyclohexylamine, etc.) salt, sulphamine (N-methylamine, N-ethyl sulphate, earth benzene, N, N, m, ethylene, diamine, m, heterocyclic amine (Mflin, team ethyl bite, etc.) 131494 •65- 200902026 :: A compound is a hydrate or solvate which is included in the dry:. When the compound of the invention is a regioisomer, configuration, conformation, conformational isomer or non-pair In the presence of the enantiomeric form, all such formulae and various mixtures thereof are included in the scope of the compounds of the present invention, and the known separation and purification methods can be used. For example, when the compound of the present invention is external, " ... when the two are outside, when the red is red, the other racemate can be separated into (8> compounds and (RM complexes). Individual optical isomers and mixtures thereof are included in the range of the compounds of the present invention. "Solvate" as used herein means a compound of the present invention or a pharmaceutically acceptable salt thereof, wherein a molecular system of a suitable solvent is incorporated into a crystal lattice. Suitable solvents are physiologically tolerable under the amount of the sword administered. Examples of suitable solvents are ethanol, water, and the like. When water is the solvent, the molecule is called "hydrate". As used herein, the term "metabolite," refers to a by-product of the production of a compound in a living body, such as a patient. The term "polymorph" refers to a specific crystalline state of a substance having specific physical properties such as X-ray diffraction, IR spectroscopy, melting point, etc. The "effective amount" of the agent used herein is, , a sufficient amount of "therapiously effective amount", is sufficient to achieve the amount of # or desired result, & clinical outcome &"effectiveamount" is dependent on the environment in which it is being administered And set. The response is for prevention and/or treatment. The term "effective amount" also includes "therapeutically effective" and the amount of a compound of the invention which will avoid or substantially attenuate undesirable side effects, as used herein, and fully understood in the art, 131494 • 66 - 200902026 == Path to benefit or desired outcome, including clinical outcomes. Advantages or benefits may include, but are not limited to, - or a variety of signs or symptoms reduced / the degree of disease is reduced, the disease is stabilized (meaning that it will not be evil:::::: prevent proliferation, disease Delay or slowing of progression, disease can be (10) ° or diminished, and relief (whether part or all), whether it is 'yes - not measurable., treatment' can also mean # compared with expected survival, Prolonging the survival period. The present invention: (iv) further provides a radioactively labeled compound of the invention, a heart substance. The identity of the compound is achieved using one of a plurality of non-f権 identifiers known in the art. The identifier is, for example, a radioisotope. The radioisotope is any one that includes the emission of the measurable radiation and is not limited to 358, 1251~14. By radiation, the radioactivity can be known from the art. Techniques (iv) The 7-send homologous 7-emitting system uses r imaging techniques (4) and 'special sputum scintillation imaging. For example, the radiolabeled compounds of the invention are prepared as follows: Compounds of the invention may be used On the benzene ring Demethylation with ·3. =, the formed complex is a radiolabeled methyl group such as dimethyl sulfate), and the v 5 is given by the 3H_ mark. Remethylation in the presence of the following examples. Examples Diisopropyl provides the following examples as a description of the preferred compounds according to the invention. The following abbreviations are used in the exemplary synthetic procedures. DffiA = 131494 -67- 200902026 Ethylethylamine, DMAC = dimercaptoacetamide, DMF = dimethylformamide, DMSO = diterpenoid, NBS = N-bromosuccinimide, and THF = tetrahydrofuran. Example 1: ARMl36_l4〇 Preparation (Figure 1)

MeO NH2Bn, p-TsOH -► 曱 stupid, reflux

NaBH4

MeO >NBn CH2CI2,/-PrOH MeO〆

α人 -> CH2CI2j NaOH

2-((benzylimido)methyl)-4-methoxyphenol

Add p-toluenesulfonic acid monohydrate (100 mg, 0.526) to a solution of 2-hydroxy-5-nonyloxybenzaldehyde (10.0 g, 65.7 mmol, 1.0 eq.) in toluene (70 mL). Millol, 0.008 eq.) with benzylamine (6.84 mL, 62.6 mmol, 0.95 eq.). The reaction mixture was refluxed with a EtOAc EtOAc (EtOAc)EtOAc. This product was used directly in the next step without further purification. !H NMR (300 MHz, DMSO-d6): 3.71 (s, 3H), 4.79 (s, 2H), 6.79 (d, J=9.3 Hz, 1H), 6.93 (dd, J=3.0 Hz, J=8.7 Hz, 1H), 7.06 (d, J=9.3 Hz, 1H), 7.34 (m, 5H), 8.65 (s, 1H). 2-((Benzylamino)methyl)·4-methoxyphenol 131494 -68- 200902026 化合物 The compound 2-((indenyl imino)methyl) 4-methoxyphenol (7.84 g, 32.5 mmol) was dissolved in CH2C12 (50 mL) at i. In -PrOH (50 mL), the solution was cooled to 〇 °C. NaBH4 (1.57 g, 44.9 mmol, 1.38 equivalents) was added in one portion and the ice bath was removed. The reaction mixture was allowed to warm to 2; rc and stirred for 17 h. The solvent was evaporated, EtOAc EtOAc m. The combined organic layers were washed (brine), dried (Na2SO4), and concentrated to give the desired product. This product was used directly in the next step without further purification. 1 H NMR (300 MHz, CDC13): 3.73 (s, 3H), 3.80 (s, 2H), 3.96 (s, 2H), 6.55 (m, 1H), 6.76 (m, 2H), 7.29 (m, 5H) N-benzyl-2-gas-N-(2-hydroxy-5-methoxybenzyl)acetamide

MeO \ Make the compound 2-((Yu-amino)methyl)-4-methoxyl g (assumed to be 32·5 mmol) bath in CH2 (3⁄4 (250 ml)' and add NaOH in one part Aqueous solution (5.2 g '130 mmol, 4 〇 equivalent, in 氐0, 250 ml). Cool the resulting mixture down to 〇. (:, and add vaporized chloroacetate (5.4 ml, 68 mM) Moore ' 2.09 eq.) over 5 min. The reaction mixture was stirred under stirring for 30 min, concentrated and THF (200 mL) was added. The reaction mixture was stirred at <RTI ID=0.0> Diluted and extracted with CH2C12 (3 x 150 mL). The combined organic layers were washed (brine), dried (NdO4) and concentrated to give the desired product. The product was directly used for 131494 - 69 · 200902026 In the step, no further purification is required. 1 H NMR (300 MHz, CDC13): 3.69 (m, 3H), 4.12 (s, 1H), 4.34 (s, 1H), 4.43 (s, 1H), 4.65 (s, 1H) ), 4.69 (s, 1H), 4.77 (s, 1H), 6.35 (d, J=2.7 Hz, 0.5H), 6.49 (d5 J=2.7 Hz, 0.5H), 6.77 (m, 1H), 6.88 ( d, J=8.7 Hz, 0.5H), 7.00 (d , J=8.7 Hz, 0.5H), 7.32 (m, 5H), 8.55 (bs, 0.5H).

4-benzyl-7-methoxy-4,5-dihydrobenzo[f|[l,4]oxo-nitrogen-7_2(2H)-one (ARM136) at 0 ° C in compound N - mercapto-2-chloro-N-(2-transpyridin-5-nonyloxyl) Ethyl acetate (8.6 g, 27 moles) in DMF (50 ml) in a solution Add NaH (1_6 g, 60% in mineral oil, 40 mmol, ι·48 equivalent). The reaction mixture was continuously pour at 0 C: mix for 30 minutes and add another batch of material.

NaH (1.5 g '60%, in mineral oil, 37.5 mmol, 1.39 equivalent). The reaction mixture was stirred at 23 ° C for 30 min and diluted with EtOAc EtOAc EtOAc (EtOAc &lt;RTI ID=0.0&gt; , concentrating, and the residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc , 2H), 4.69 (s, 2H), 4.77 (s, 2H), 6.35 (d, J=3.0 Hz, 1H), 6.76 (dd, J=3.0 Hz, J=9.0 Hz, 1H), 7.00 (d , J=9.0 Hz, 1H), 7.29 (m, 5H).

4-Benzyl-7-decyloxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxonitrogen (ARM137) at 23 ° C 'on 4-benzyl- 7-Methoxy-4,5-dihydrobenzo[f][l,4]oxazin-7(2H)-one (3.5 g, 12-4 mmol, 1 〇 equivalent) in anhydrous χΗρ ( 12 〇 ml) Add the LiAlH4 (1.55 g, 40.7 mmol, 3·2 δ equivalent) in the solution in 131494 -70- 200902026. The reaction mixture was refluxed for 17 h and cooled to EtOAc EtOAc EtOAc. The solid Na2S04·10Η2Ο was slowly added until the reaction mixture became a gel-like suspension. The ice bath was removed, THF (100 mL) was added and mixture was stirred for 30 min. The mixture was then filtered through celite and the solid was washed with THF (2×100 mL). The filtrate was collected and concentrated to give the desired product. This product was used directly in the next step without further purification. 1 H NMR (300 MHz, CDC13): 3.08 (m, 2H), 3.63 (s, 2H), 3.74 (s, 3H), 3.78 (s, 2H), 4.02 (m, 2H), 6.53 (d, J =3.〇Hz, 1H), 6.68 (dd, J=3.0 Hz, J=8.7 Hz, 1H), 6.93 (d, J=8.7 Hz, H), 7.30 (m, 5H). 7-methoxy _2,3,4,5-tetrahydrobenzo[f][i,4]oxynitrogen seven gardens (ARM138)

Me〇^OC^T at 231: under '4- 4-yl-7-decyloxy-2,3,4,5-tetrahydrobenzo[£][1,4]oxynitrogen sulfoxide (3.4 g 'Assumed to be 12.4 millimoles' l_〇 equivalent) In a solution of Et〇H (66 ml), 10% Pd/c (0.55 g) was added. The reaction mixture was stirred for 1 hour under h.sub.2 then filtered over Celite and washed with &lt;RTI ID=0.0&gt;&gt; Collect the liquid, and concentrate to obtain the desired product. This product was used directly in the next step without further purification. 1 H NMR (300 MHz, CDC13): 3.20 (m, 2H), 3.76 (s, 3H), 3.91 (s, 2H), 3.97 (m, 2H), 6.67 (m, 2H), 6.94 (m, 1H) 2-(7-decyloxy-2,3-dihydrobenzopyrene(1)4]oxo-7-yl)2-ketoacetate (ARM139) 131494 -71 - )0 200902026

7-decyloxy-2,3,4,5-tetrahydrobenzopyrene [1,4]oxenyl sulfonium (0.5 g, 2.79 mmol, 1.0 eq.) in CH2C12 (100 mL) The solution (〇.〇, added DIEA (1_46 ml, 8.38 mmol, 3.0 eq.) and chloro ketone acetate (0. 31 mL ' 3.36 mmol, 1.2 eq.). Stirring was continued for 30 minutes, diluted with ι·〇Μ HC1 (100 mL), and extracted with CH2C12 (3×100 rnL). The combined organic layers were washed (salt), dried (Na2S04) and concentrated. Column chromatography purification (Et〇Ac/oil shouting 0-50%) gave the desired product. lU NMR (300 MHz, CDC13): 3.78 (m, 4H), 3.84 (s, 1.5H), 3.91 (s , 1.5H), 3.98-4.08 (m, 3H), 4.51 (s, 1H), 4.61 (s, 1H), 6.62 (d, J-3.0 Hz, 0.5H), 6.73 (m, 1H), 6.87 ( d, J=3.〇Hz, 0.5H), 6.96 (m, 1H). 2-(7-Methoxy-2,3-dihydrobenzindole, 4]oxynitrogen-7圜(4H) )_base)_2_ketoacetic acid (ARM140)

At 23 ° C 'in 2-(7-decyloxy-2,3-dihydrobenzo 4)oxenyl-7-(5H)-yl)-2,ylacetic acid methyl ester (〇·32 g , 121 mmol, 1 〇)) In a solution of MeOH (10 liters) and butyl HF (1 liter), add Li〇H·Miso aqueous solution (250 mg, 5 95 mmol, 4 〇) Equivalent, in H2 ,, 1 〇 ml, the reaction mixture was stirred at the same temperature for 3 hrs, concentrated, diluted with hydrazine (50 ml), and extracted with hydrazine (3 ml). 131494 -72- 200902026 The aqueous layer was neutralized to pH = 3 ' and extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The combined organic layers were washed (salt) and dried (Na2SO4) and concentrated to give the desired product. NMR (300 MHz, DMSO-d6): 3.71 (m, 4H), 3.83 (m, 1H), 3.99 (m, 2H), 4.53 (m, 2H), 6.67 (m, 0.5H), 6.76 (m, 1H), 6.85 (m, 0.5H), 6.93 (m, 1H). Example 2: Preparation of ARM148, 150, 151, 152 (Figure 2)

7_decyloxy-2,3-dihydrobenzo[fj[i,4]oxynitrogen seven _4(5H)-tricarboxylic acid triterpene ester

Add a 7-methoxy-2,3,4,5 solution to a solution of phosgene (2.5 g '8.4 μm, h88 equivalent) in ch2C12 (20 ml) (-30 ° (:)) _ tetrahydrobenzo[f][1,4] oxynitride (0.8 g, 4.47 mmol, 1 〇 equivalent) with pyridine (21 ml, 25 75 mM '5.76 eq.) in CH 2 Cl 2 (l 〇 The solution in ML) was passed for 10 minutes. The reaction mixture was stirred at -20 ° C for 2 Torr for 2 〇 in 〇. (: 30 min, diluted with 0.5 M HCl (100 mL), with CH 2 Cl 2 (3×l 〇〇 The combined organic layers were washed (brine), dried, dried, and concentrated. The residue was purified by column chromatography (Et?Ac / hexane 5 - 33%) to obtain the desired product. 131494 -73 · 200902026 1 H NMR (300 MHz, CDC13): 3.78 (m, 3H), 3.97 (m, 1H), 4.05 (m, 3H), 4.58-4.66 (d, 2H), 6.76 (m, 1H), 6.84 (m, 1H), 6.99 (m, 1H). (7-methoxy-2,3-dihydrobenzo[fl[1,4]oxynitrogen-7_5(5H)-yl) (six Hydropyridine small base) ketone (ARM148)

At 23 C 'in a 25 ml flask, hexahydropyridine (5 ml, 5 〇 6 mmol, 57 _ 5 equivalents) was added to the compound 7-methoxy 2,3-dihydrobenzo-μ] oxygen Nitrogen sulphate-4(5H)-sodium sulphate (3 g, 〇88 mmol, 丨〇 equivalent). The white suspension formed was stirred at 23 ° C for 17 hours, diluted with ethyl acetate (200 mL), washed with EtOAc EtOAc EtOAc. Obtain the desired product. !H NMR (300 MHz, CDC13): 1.61 (bs, 6H), 3.21 (m, 4H), 3.64 (m, (2H), 3.80 (s, 3H), 4.07 (m, 2H), 4.31 (s, 2H), 6.72 (m, 2H), 6.93 (d, J=8.4

Hz, 1H). (7-Methoxy-2,3-dihydrobenzindole (4) Oxygen Nitrogen 7 _4(5H)-based oxabulinyl)methanone (ARM150)

Add morphine (5 ml, 57 mM '108) to the compound 7-methoxy-2,3-dihydrobenzene in a 25 ml flask at 23 ° C, 4 Oxygen nitrogen 131494 -74- 200902026 Hepta-4(5H)-carboxylic acid trichloromethyl ester (〇18 g, 〇53 mmol, 1 〇 equivalent). The resulting white suspension was stirred at 23 ° C for 17 hours, diluted with ethyl acetate (200 mL), washed with EtOAc EtOAc (3··········· 〇 4), concentrate to obtain the desired product. 1 H NMR (300 MHz, CDC13): 3.28 (m, 4H), 3.68 (m, 6H), 3.77 (s, 3H), 4.08 (m, 2H), 4.33 (s, 2H), 6.71 (m, 2H ), 6.95 (m, 1H). 13C NMR (67 MHz, CDC13): 47.85, 52.31, 53.15, 55.74, 66.76, 72.72, 113.32, 115.26, 121.63, 131.52, 153.39, 155.25, 164.05. (7-methoxy -2,3-dihydrobenzo-""oxyzol-7-(5H)-yl)(hexahydropyrazine)methanone (ARM151)

Hexahydropyrazine (1. gram, U.6 亳mol, 22 equivalents) was added to the compound 7-methoxy-2,3-dihydrobenzo[f][1, at 23 °C. 4] Oxygen nitrite _4(5H)-carboxylic acid trichloromethyl ester (0.18 g, 0.53 mmol, ι·〇 equivalent) in a solution of Ch2CI2 (5 mL). The resulting solution was continuously stirred at 23 ° C for 17 hours and passed. The filtrate was diluted with CHCI3 (50 mL) and saturated aqueous NaHC03. The aqueous layer was extracted with CHC13 (3×70 mL). The combined organic layers were washed (h2 〇, brine) &lt;&quot;&&&&&&&&&&&&&&&&& 1H NMR (300 MHz, CDC13): 2.52 (m, 1H), 2.91 (m, 4H), 3.27 (m, 4H), 3-66 (m, 2H), 3.77 (s, 3H), 4.08 (m5 2H) ), 4.32 (s, 2H), 6.73 (m, 2H), 6.94 (d, J = 7.8 Hz, 1H). (4 (this is [d][l,3]-oxo-soil--5-based Methyl)hexahydrop ratio p well _i_base)(7_methoxydihydro cumin tf][1,4]oxynitrogen seven _4(5H)-yl)methanone (ARM152) 131494 - 75- 200902026

1-Sunflower-based hexamidine pyridin (0.37 g, 1.68 mmol, 3.0 eq.) was added to the compound 7-methoxy-2,3-dihydrobenzo[f][l, at 23 °C. 4] Oxygen nitros-7-(5H)-carboxylic acid trichloromethyl ester (0.19 g, 0.56 mmol, 1.0 eq.) in CH2C12 (5 mL). The resulting solution was stirred at 23 ° C for 17 hours, diluted with CH 2 Cl 2 (150 mL), washed (aq. NaH.sub.3, brine), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (EtOAc/hexanes 20-100%) to afford desired product. 1 H NMR (300 MHz, CDC13): 2.44 (t, J = 4.8 Hz, 4H), 3.29 (t, J = 4.8 Hz, 4H), 3.43 (s, 2H), 3.64 (m, 2H), 3.76 ( s, 3H), 4.07 (m, 2H), 4.30 (s, 2H), 5.94 (m, 2H), 6.72 (m, 4H), 6.84 (s, 1H), 6.95 (dd, J=0.6 Hz, J =7.2 Hz, 1H). Example 3: Preparation of ARM146, 147, 149, 153, 156, 157, 159, 160, 161, (166, 186, 189 (Figure 3)

XN〆 wBn

Gn

X^CI

23°C, 17 hours 100%

NBn

[Pd] or [Cu] r

131494 •76 200902026

2-((nodalimino)methyl)_4_

Add p-toluenesulfonic acid monohydrate to a solution of 2-hydroxy-5-glycosyloxybenzaldehyde (52.8 g, 〇·263 mol, ι〇 equivalent) in toluene (300 mL) , 1_58 耄 Mo Er, 0.006 equivalents;) with benzylamine (27 4 ml, 〇25 mol, 0.95 ^ 1 ). The reaction mixture was refluxed with a Dea]&gt; Stark gas cylinder, cooled to 23 &lt;0&gt;C, and concentrated to give the desired compound as a yellow solid. This product was used directly in the next step without further purification. ]H NMR (300 MHz, DMSO-d6): 2.28 (s, 1H), 4.79 (s, 2H), 6.84 (d, J-8.7 Hz, 1H), 7.11-7.38 (m, 5H), 7.44 (dd , J=2.7 Hz, J=8.7 Hz, 1H), 7.68 (d, J=2.7 Hz, 1H), 8.66 (s, 1H). 2_((benzylamino)methyl)-4-bromophenol

The compound 2-((arginylamido)indolylphenol (7.6 g, assumed to be 26.3 mmol) was dissolved in CH2C12 (16 mL) and i-PrOH (16 mL) at 23 °C. And add NaBH4 solution (1.4 g, 40 mmol, 1.52 eq.) in one portion, and remove the ice bath. The reaction mixture was warmed to 23 ° C, and stirred for 17 hours, and with aqueous citric acid ( The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAcjjjjjjjjj (Brine), dehydrated (NazSO4), EtOAc (EtOAc): (s, 2H), 6.72 (d, J=8.4

Hz, 1H), 7.08 (m, 1H), 7.33 (m, 6H). 4下基-7-/ 臭基-4,5_Dihydrobenzo[幻叫]Oxygen nitrogen seven garden_3(2H) Ketone (ARMi46)

B The compound 2-((benzylamino)methyl)_4_bromophenol (7.8 g, assumed to be % 2 mmol) was dissolved in CH 2 C 12 (250 mL), and Na?H aqueous solution was added in portions. (4 2 grams, 105 moles, 4_0 equivalents, in H2 ,, 25 〇 ml). The resulting mixture was cooled down to 〇 ° C and vaporized chloroacetone (418 mL, 5 4 mM, 2 eq.) was added over 5 minutes. The reaction mixture was stirred under hydrazine for 30 min, concentrated and THF (200 mL). The reaction mixture was stirred at 23 &lt;0&gt;C for hrs, diluted with EtOAc &lt;RTI ID=0.0&gt;&gt; The combined organic layers were washed (brine), dried (N^SO4) and concentrated to give the desired product. This product was used directly in the next step without further purification. The analytical sample was purified by column chromatography (EtOAc / petroleum ether 0-30%) to afford the desired product. H NMR (3〇〇MHz, CDC13): 4.35 (s, 2H), 4.75 (s, 2H), 4.76 (s, 2H), 6.94 (m, 2H), 7.23 (m, 2H), 7.34 (m5 4H ).

Benzyl-7(bromo)_2,3,4,5-tetrahydroerobylidene, 4]oxine-7 (ARM147) at 23 ° C in 4-mercapto-7-bromo- 4,5-Dihydrobenzo[i.e., 4]oxine-7 Park 131494-78- 200902026 -3(2H)-one (8.8 g, 26.2 mmol, 1.0 eq.) in anhydrous THF (150 mL) Add BH3 · SMeM.O mL, 94.8 mmol, 3.6 equivalents in solution. The reaction mixture was refluxed for 14 hours and cooled to 23. (: NaOH aqueous solution (3.0 M, 35 mL) was added slowly. The reaction mixture was refluxed for 1 hr then cooled to 23. (:, and concentrated. The residue was diluted with aqueous NaHC03 and extracted with Et EtOAc (3×150 mL) The combined organic layers were washed with EtOAc EtOAc (EtOAc m. 300 MHz, CDC13): 3.08 (m, 2H), 3.65 (s, 2H), 3.77 (s, 2H), 4.07 (m, 2H), 6.89 (d, J=8.4 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.31 (m, 6H). 4-benzyl-2,3,4,5-tetrahydrobenzo[fl[l,4]oxynitrogen-7--7-indene nitrile (ARM149 )

At 23 ° C, 4-mercapto-7-bromo-2,3,4,5-tetrahydrobenzo[f][l,4]oxenazane (2.3 g '7_23 mmol), 1_0 equivalent) Na2CO3 (0.64 g, 6 mmol, 0.83 eq.), K4[Fe(CN)6] • 3Η20 (0·9 g, 2.13 mmol) in a solution of anhydrous DMAC (10 mL) , 0.29 equivalents) and Pd(OAc) 2 (50 mg, 0.22 house moles, 0.03 equivalents). The reaction mixture was degassed, refilled with argon, stirred at 120 ° C for 3 hours and cooled to 23 °C. The reaction mixture was diluted with ethyl acetate (300 mL) and filtered over Celite. The filtrate was concentrated, and the residue was purified (jjjjjjjjjjjjjj 1 H NMR (300 MHz, CDC13): 3.10 (m, 2H), 3.66 (s, 2H), 3.78 (s, 2H), 4.15 (m, 2H), 7.07 (d, J=8.1 z, 1H), 7.30 (m, 6H), 7.49 (dd, J=2.1 Hz, J=8.1 Hz, 1H). 131494 -79- 200902026 Benzene [(1][1,3]dioxene _5_yl )_4_benzyl-2,3 4,5 tetrahydrobenzene is 1,4] oxygen nitrogen seven garden (ARM153) '

At 23 C, 4-mercapto-7-bromo-2,3,4,5-tetrahydrobenzora[1,4]oxynitrogen sulfoxide (U g, 3_46 mmol, 1_〇) Equivalent) In a solution of CH3CN (4 mL), add 1 ^ 033 aqueous solution (717 mg '5.19 mmol, 1.5 equivalents in 4 ,, 12 mL), 3,4-(Methylenedioxy) Phenyldihydroxyborane (64 mg, 3.86 mmol, 1.11 eq.) and Pd(PPh3) 4 (80 mg, 〇_mole, 〇〇2 eq.). The reaction mixture was degassed, refilled with argon, refluxed for 17 hours and cooled to 23 °C. Concentrated <RTI ID=0.0></RTI> EtOAc <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> ), get the desired product. 1 H NMR (300 MHz, CDC13): 3.13 (m, 2H), 3.71 (s, 2H), 3.88 (s, 2H), 4.13 (m, 2H), 5.99 (s, 2H), 6.86 (dd, J =0.6 Hz, J=7.8 Hz, 1H), 7.〇〇(m 2H), 7.07 (d, J=8.1 Hz, 1H), 7.15 (d5 J=2.4 Hz, 1H), 7.33 (m, 6H) .4·Benzyl_7-(biphenyl-2-yloxy)-2,3,4,5-tetrahydrobenzonitrile [1,4] Oxygen and Nitrogen Seven Parks (ARM156)

At 23 C, in 4-aryl-7-&gt; odoryl-2,3,4,5-tetrahydrobenzo[£][1,4]oxynitrogen sulfoxide 131494 •80· 200902026 (1· 〇克, 3.14 家莫耳, ι·〇 equivalent) Add K3p〇4 (13 g, 612 mmol, 2.0) in a solution of anhydrous phosin p (5 ml, 57.4 mmol) 18.3 eq. Equivalent), 2-phenylphenol (1〇7 mg, 〇·63 mmol, 0.2 eq.) and Cul (30 mg, 0.157 mmol) <0.05 eq.) The reaction mixture was degassed and refilled with argon. Stir at 100 ° C for 17 hours and cool to 23. (:. The reaction mixture was diluted with aq. NaHC03 and extracted with Et.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.3 (3 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Purification (EtOAc / hexanes 0-50%) eluted eluted elute elute elute elute elute elute -〇5 (m, 2H), 6.61 (d, J=2.7 Hz, 1H), 6.75 (dd, J-2.7 Hz, J=8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.96 (dd, J=1.2 Hz, J=8.4 Hz, 1H), 7.15-7.45 (m, HH), 7.53 (m, 2H). 4-mercapto-7-morpholinyl 2,3,4 ,5_tetrahydrobenzo[f][l,4]oxynitrogen seven gardens (ARM157)

At 23° (: under ' 4- 4-mercapto-7-bromo-2,3,4,5-tetrahydrobenzo-iso- 1,4]oxy-nitrogen sulfonium (1.0 g, 3.14 mmol) 1. 〇 equivalent) in a solution of anhydrous porphyrin (5 ml, 57.4 mmol [ 18.3 eq.]), Κ3ρ〇4 (13 g '612 mmol, gi 〇7 mg, 0,63 mmol, 0.2 eq.) and Cul (30 mg, 0.157 mmol, 0.05 eq.). The reaction mixture was degassed and refilled with argon at 17 Torr for 17 hours and cooled to The reaction mixture was diluted with EtOAc (3 mL, EtOAc) (EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc (EtOAc) 3.81 (s, 2H), 3.86 (m, 4H), 4.04 (m, 2H), 6.56 (d, J=3.0 Hz, 1H), 6.74 (dd, J=3.0 Hz, J=8.7 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.30 (m&gt; 5H) 1-(4-benzyl-2,3,4,5-tetrahydrobenzo[fl[1,4]oxine seven gardens_ 7_base) tetrahydropyrrole_2- (ARM159)

6 at 23 C, on 4-benzyl-7-bromo-. , "-tetrahydrobenzo hydrazine (4) oxynitridin (1.0 g, 3.14 mmol, 1. 〇 equivalent) in the anhydrous dioxane (9 ml) in the solution, add 2-four Nitrogen is the same as 嘻g (〇.3 house liter, 3.9 mM, 125 pats), Cs2C03 (1.4 gram '4.3 mol' 1.4 eq), yellow phosphorus (xantph〇s) (11 〇 mg, 0.19 mmol, 0. 6 equivalents) and Pd2 (dba) 3 (60 mg, 〇〇65 mmol, 〇〇2 δ). Degas the reaction and refill with argon. After 17 hours, it was cooled to 23 ° C. The reaction mixture was diluted with brine (100 ml) and extracted with ethyl acetate (3 χ 100 ml). The combined organic layers were washed (brine), dried (NagSO4), concentrated And the residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc (EtOAc) (t, J=8.1 Hz, 2H), 3.08 (m, 2H), 3.65 (s, 2H), 3.80 (t, J=6.9 Hz, 2H), 3.83 (s, 2H), 4.05 (m, 2H) , 7.01 (d, J=8.7 Hz, 1H), 7.28 (m, 6H), 7.40 (dd, J=3.0 Hz, J=8.4 Hz, 1H). 3-(4-benzyl-2,3,4 , 5-four The benzo 1,4] _7_ Park nitrogen seven-yl) tetrahydro-yl baa _2 • one (ARM160) (Π.

NBn 131494 -82- 200902026 4-benzyl-7-bromo-2,3,4,5-tetrahydrobenzo-x]oxynitrogen sulfoxide (1.0 g, 3-14 Torr) at 23 ° C '1.0 eq.' in a solution of anhydrous dioxanthine (9 ml) 'addition of K2CO] (0.87 g, 6.29 mmol, 2.0 eq.), 2-11 oxazolone (273 mg ' 3.14 mil) Moore, 1.0 eq.), trans _i, 2 -diaminocyclohexane (0.04 mL, 0.3 mM '0.1 eq.) and CuI (3 〇 mg, 〇16 mmol, 0.05 eq.). The reaction mixture was degassed, refilled with argon, stirred at 9 ° C for hrs and cooled to 23 °C. The reaction mixture was diluted with aq. EtOAc (EtOAc) (EtOAc) The combined organic layers were washed (brine) dried <RTI ID=0.0>(</RTI> <RTI ID=0.0></RTI> <RTI ID=0.0> MHz, CDC13): 3.09 (m, 2H), 3.65 (s, 2H), 3.83 (s, 2H), 4.05 (m, 4H), 4.47 (t, J=7.5 Hz, 2H), 7.02 (d, J =8.7 Hz, 1H), 7.19 (d, J=3.0 Hz, 1H), 7.31 (m, 6H). 4-G-N,N-dimethyl-2,3,4,5-tetrahydrobenzene And niobium oxide seven garden _7_amine

At 23 ° C, 4-mercapto-7-bromo-2,3,4,5-tetrahydrobenzo[f][i,4]oxynitrogen sulfoxide (0.75 g, 2.25 house moles, 1. 〇 equivalent) in a solution of anhydrous benzene (14 ml) 'Add Cs2C 〇 3 (l · 35 g ' 4. 丨 4 millimoles, 184 equivalents), yellow dish (xantph〇s) (no mg '〇_19 mmol, 〇〇 8 equivalents) and pd2 (dba) 3 (6 〇 mg, 0.065 mmol, 〇 _ 〇 3 equivalents). The reaction mixture was degassed, refilled with argon&apos; and decylamine (2.0 liters, &lt;RTI ID=0.0&gt;&gt; The reaction mixture was sealed in a pressure-resistant tube, stirred at 11 Torr for 13 hrs, and then cooled to 23 Torr. The reaction mixture was diluted with EtOAc (3×150 mL). The combined organic layers were washed with EtOAc (EtOAc)EtOAc. 1H NMR (300 MHz, CDC13): 3.88 (s, 6H), 3.10 (m, 2H), 3.66 (s, 2H), 3.82 (s, 2H), 4.02 (m, 2H), 6.40 (d, J= 3.0 Hz, lH), 6.57 (dd, J=3.0 Hz, J=9.0 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 7.29 (m, 5H). 4-benzyl-2,3 ,4,S-tetrahydrobenzo[f|[1,4]oxynitrogen seven _7-ylphosphonic acid diethyl ester (ARM166)

At 23 ° C, 4-mercapto-7-bromo-2,3,4,5-tetrahydrobenzo[f][1,4]oxynitrogen sulfoxide (1-7 g, 5.35 mmol, ΐ·〇 equivalent) in a solution of anhydrous Et〇H (2〇ml), add Pd(OAc)2卩4mg, 〇.1〇7mmol, 〇〇2 equivalent)' pph3 (84 gram , 0.32 mmol, 〇·〇 6 equivalents), diethyl phosphate (〇83 ml, 6 45 mM '1_2 eq.) and DIEA (1.4 ml, 8_05 mmol, 15 eq.). The reaction mixture was degassed, refilled with argon, refluxed for 17 hours and cooled to 23 °C. The reaction mixture was concentrated. The residue was diluted with aq. EtOAc (EtOAc) The combined organic layers were washed (brine), dried (EtOAcjjjjjjjjj 1 H NMR (300 MHz, CDC13): 1.32 (m, 6H), 3.06 (m, 2H), 3.65 (s 2H) 3.83 (s, 2H), 4.00-4.17 (m, 6H), 7.06 (dd, J =3.9 Hz, J=8.4 Hz, 1H) 7 29 (m, 5H), 7.48 (dd, J-1.8 Hz, J=12.9 Hz, 1H), 7.62 (ddd, J=i.8 Hz J=8 4 131494 -84 - 200902026

Hz, J=12.9 Hz, 1H). 4-Yuji_7·(4)Bite-4-yl)_2,3,4,5_Tetrahydrobenzo-,4]Oxygen-nitrogen seven garden (arm °ί〇Βη At 23 ° C 'in 4-ylidene-7-indiyl-2,3,4,5-tetrahydro cumene _1,4] oxynitridin (0.8 g, 2.52 mmol, 1 〇 Equivalent) A solution of K2C03 (717 mg ' 5.19 mmol, 21 equivalents in η 2 ,, 12 mL), 4-pyridine dihydroxyborane (640 mg, 5_2) in CH3CN (40 mL) Millol, 2 J equivalents) and Pd(PPh3)4 (80 mg, 0.069 mmol, 〇·〇3 equivalent). Degas the reaction mixture 'with argon. Fill' reflux for 17 hours and cool to 2 ; rc. &gt; </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 10-100%), to obtain the desired product. 1 H NMR (300 MHz, CDC13): 3.12 (m, 2H), 3.70 (s, 2H), 3.88 (s, 2H), 4.14 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 7.31 (m, 6H), 7.43 (dd, J=2.1 Hz, J=4.8 Hz, 2H), 7.48 (dd, J=2.4 Hz, J-8.1 Hz, 1H ), 8.60 (dd, J-1.8 H) z, J=4.8 Hz, 2H). 4-mercapto-7-butyl-2,3,4,5-tetrahydrobenzindole mi,4]oxine seven garden (ARM189)

Add a% (1.375 ml ' 1.375 mmol) in a solution of BuMgCl (0.625 liters, 1.25 mmol, 2 〇μ solution in ether, 2.0 eq.) in THF (5 mL). Ear '1 〇M solution in ether, 218 equivalents). The reaction mixture was stirred at 23 C for 15 minutes, and Pd(PPh3)2?2 (22 5 亳 131494 •85. 200902026 g, 0.03 mmol, 0.05 eq.) followed by 4-mercapto-7-bromo- 2,3,4,5-Tetrahydrobenzo[f][l,4]oxynitrogen sulfoxide (200 mg, 0-63 mmol, 1.0 eq.). The reaction mixture was refluxed for 17 h then cooled to EtOAc (EtOAc) The combined organic layers were washed with aq. EtOAc EtOAc EtOAc EtOAc. 1H NMR (300 MHz, CDC13): 0.95 (t, J = 7.5 Hz, 3H), 1.37 (m, 2H), 1.58 (m, 2H), 2.54 (t, J = 7.5 Hz, 2H), 3.10 (m , (2, 2H) 13 C NMR (67 MHz, CDC13): 14.23, 22.57, 33.99, 35.04, 58.33, 58.45, 58.86, 70.28, 120.43, 127.19, 128.26, 128.35, 129.07, 130.76, 131.45, 137.86, 138.70, 157.87. Example 4: Preparation of ARM182, 203, 217 (Figure 4)

NaN3, ZnBr2 i-PrOH, H20

4-benzyl-7-(lH-tetrazol-5-yl)-2,3,4,5-tetrahydrobenzo[f] [1,4]oxynitrogen seven gardens (ARM182) 131494 86- 200902026

At 23 ° C 'in 4-mercapto-2,3,4,5-tetrahydrobenzo[ phantom [1,4] oxazepine 圜7-carbonitrile (0.5 g '1_89 mmol, 1.0 Equivalent) in a solution of i-pr〇H (5 ml), add Η? Ο (5 ml), Na% (246 mg, 3.78 mmol, 2.0 eq.) and ΖηΒι*2 (425 克克' 1.89 House Moer '1.0 equivalent). The reaction mixture was refluxed for 17 h &lt;~&gt; to &lt;RTI ID=0.0&gt;&gt; The combined organic layers were washed with aq. EtOAc EtOAc (EtOAc) 1H NMR (300 MHz, CDC13): 3.22 (m, 2H), 3.93 (s, 2H), 3.99 (s, 2H), 4.14 (m, 2H), 6.91 (d, J=8.4 Hz, 1H), 7.26 (m, 5H), 7.68 (bs, 1H), 7.80 (dd, J=1.8 Hz, J=8.4 Hz, 1H).

4 Jinji 2,3,4,5-tetrahydrobenzo[fj[i,4]oxynitrogen seven _7_ slow oxime (ARM2〇3) at 23 C, in the crude 4-mercapto- 2,3,4,5-tetrahydrobenzopyrene[1,4]oxenazin-7-carbonitrile compound (320 mg, 1.21 mmol, 1 〇 equivalent) in DMS 〇 (2 mL) To the solution, 30% H 2 〇 2 (0.15 ml, ι·4 mmol, 1.22 eq.) and K:2C 〇3 (25 mg, hydrazine, 18 mM, 015 eq.) were added. The reaction mixture was stirred at the same temperature for 30 minutes, and TLC showed only starting material. Add 3% H 2 〇 2 (l_5 liter, η mmol, 12 2 eq.) to Na 〇 H aqueous solution ML '3.0 M '4.5 mM '3.7 equivalents) to the reaction mixture, followed by MeOH (5 ml) with THF (5 ml). The reaction mixture was at 23. 〇 131494 • 87- 200902026 was stirred for 20 minutes, diluted with brine (200 mL) and EtOAc (3×50 mL). The combined organic layers were washed with EtOAc EtOAc EtOAc EtOAcjjjjjjj 1 H NMR (300 MHz, CDC13): 3.07 (t, J = 4.5 Hz, 2H), 3.65 (s, 2H), 3.83 (s, 2H), 4.11 (m, 2H), 6.15 (s, 2H), 7.03 (d, J=8.1 Hz, 1H), 7.30 (m, 5H), 7.51 (d, J=2.1 Hz, 1H), 7.62 (dd, J=2.1 Hz, J=8.1 Hz, 1H). 13C NMR (67 MHz, CDC13): 57.71, 58.53, 59.39, 70.81, 121.01, f 127.35, 127.93, 128.26, 128.45, 128.92, 130.34, 131.86, 138.26, 163.05, 168.96. 4-mercapto-2,3,4,5 -tetrahydrobenzo[f][l,4]oxonitrogen-7-carboxylic acid (ARM217)

Under 23, in a crude 4-benzyl-2,3,4,5-tetrahydrobenzo[!][1,4]oxazin-7-indenenitrile (150 mg, 0.57 mmol, 1.0 eq.) In a solid mixture of KOH (375 mg, 85%, purity, 5.7 mmol, 10.0 eq.), EtOAc (10 mL). The reaction mixture was stirred at 160 ° C for 17 hours and cooled to 23 . (:, diluted with a 0.5 M aqueous HCl solution, and extracted with ethyl acetate. The aqueous layer was neutralized to pH = 5 with aq. EtOAc, and extracted with CH2Cl2 (2×100 mL). Washing, dehydration (Na2SO4), EtOAc (EtOAc (EtOAc)EtOAc. m, 2H), 3.77 (s, 2H), 3.93 (s, 2H), 4.17 (m, 2H), 7.13 (d, J=8.4 Hz, 1H), 7.29 (m, 5H), 7.83 (m, 1H) ), 7.92 (dd, 131494 -88- 200902026 J=1.8 Hz, J=8.4 Hz, 1H). Example 5: Preparation of ARM251, 252, 291, 293, 296 (Figure 5) / x γ

NBS, (PhCOO) 2 CCI4, reflux

Cul, K2CO3 i-PrOH, reflux xXTBr-^ Y Br DIEA, CH2CI2

IfX, Y= ocf3ih NaOH -] H20, THF, MeOH

2-&gt;Smelly-l-(i-odorylmethyl)-4-stone-based benzene

Br N〇2 \ makes 2-bromo-4-nitrotoluene (25 g, 116 mmol) NBS (20.6 g, 116 mmol) and dibenzoquinone peroxide (280 mg, 1.16 mmol) The ear was suspended in carbon tetrachloride (180 ml). The mixture was refluxed for 16 hours and cooled to room temperature. Remove solids by filtration. The filtrate was evaporated. This compound was used directly in the next step without any purification. 2-(2-bromo-4-nitrobenzylamino)ethanol

Add 2-bromo-based thiol oxime to 2-aminoethanol (35 g, 580 mmol) and DIEA (20 mL, 116 135 494 -89 - 200902026 Mo) in 200 mL CH2% -4-ylbenzene (116 mmol, in 1 mL of dichloromethane). The solution was stirred at room temperature for 3 hours. The solution was loaded directly onto the cartridge column. The column was washed with chloroform and chloroform/methanol 10/1 to give the desired product. !H NMR (300 MHz, CDC13): 8.42 (d, J=2.1 Hz, 1H), 8.14 (dd, J=8.4, 2.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 3.96 ( s, 3H), 3.72 (m, 2H), 2.82 (m, 2H). f 8-nitro-2,3,4,5_tetrahydrobenzo- 1,4]oxy-nitrogen seven garden (ARM251)

2-(2-Bromo-4-nitrobenzylamino)ethanol (6-gram, 21.8 mmol), copper (1) (410 mg) and potassium carbonate (4.62 g, 43.6 mmol) ) Mix in 120 ml of 1- PrOH. The solution was degassed under vacuum for 5 minutes&apos; and the flask was scrubbed with argon twice. The solution was refluxed for 6 hours. After the solution was cooled to room temperature, 400 ml of a gas sample was added to dilute it. Remove solids by filtration. The filtrate was evaporated to dryness. Pure compounds were obtained by column chromatography (Et〇Ac/methanol, 5:1). 1H NMR (300 MHz, CDC13): 7.80 (m, 2H), 7.28 (d, J=8.7, 1H), 4.1-4.0 (m, 4H), 3.25 (m, 2H). 2- (8-tank -2,3-dihydrobenzo[fl[1,4]oxonitrogen-7_5(5H)-yl)_2-ketoacetate (ARM252) ^ OMe ο2ν human 8-nitro-2, 3,4,5-Tetrahydrobenzopyrene [1,4]oxynitrogen hydrazine (eight reading 251) (1. gram, 5.15 house Moer), chloro ketone methyl acetate (523 μl, 5 · 66 millimoles) and 131494 -90- 200902026 DIEA (1.6t liter, u.2 亳 Mo ear) mixed in ω ml ch said. The solution was stirred at room temperature for 3 hours. The solution is loaded directly onto the column. The column was washed with ethyl acetate. Therefore, the title compound was obtained. NMR (3〇〇MHz, CDC13): 7.94 (m, 2H), 7,4 (d, ^8, Hz, 0.6H), 7.30 (d5 J=8.l Hz, 0.4H), 4.71, 4.64 ( Ss, 2H), 4.21 (m, 1.90H), 4.07 (m, 1.1H), 3.85 (m, 4H). oxyl-2-(molylmethyl(trifluoromethoxy)benzene

1-Bromo-2-methyl-4-(trifluoromethoxy)benzene (2 g, 78 3 mmol), (15.3 g, 86 mmol) and dibenzoguanidine peroxide ( 380 mg, 1.56 mmol) suspended in carbon tetrachloride (10 ml). The hydrazine mixture was refluxed for 16 hours and allowed to cool. Remove solids by filtration. The filtrate was evaporated. This compound was used directly in the next step without any purification. 2-(2-carbyl-5-(trifluoromethoxy)benzylamino)ethanol

1- Add 1-bromo-2-(in the solution of 2-aminoethanol (5.8 ml, 96 mmol) with DIEA (8.4 mL, 48 mmol) in 200 mL of dichloromethane. The hydrazino)-4-(trifluoromethoxy)benzene (24 mmol) in 1 ml of dichloromethane. The solution was stirred at room temperature overnight. The solution was loaded directly onto the silicone f-column. The column was washed with chloroform, chloroform/methanol 1 〇/1. Obtain the title compound. H NMR (300 MHz, CDC13): 7.56 (d, J=8.4 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.4, 2.1 Hz, 1H), 3.96 (s , 2H)S 3.69 (m, 2H), 2.81 (m, 2H). 131494 91 · 200902026 7 (-Fluoromethoxy)_2,3,4,5·tetrahydrobenzo-""Oxygen-nitrogen seven gardens ( ARM291) The compound 2-(2-bromo-5-(trifluoromethoxy) arylamino)ethanol (44 g, 14 mmol), copper iodide (1) (530 mg, 2.8 mmol) And potassium carbonate (4 gram, 28 mil) mixed in 120 liters of i-PrOH. The solution was degassed under vacuum for 5 knives, and the flask was argon gas twice. After 16 hours, the solution was cooled to room temperature, and 400 ml of chloroform was added. The solid was removed by filtration, and the solution was evaporated to dryness. The pure compound was obtained by column chromatography of methanol, 5 . 1 H NMR (300 MHz, CDC13 ): 7.00 (m, 3H), 4.02 (m, 2H), 3.92 (s, 2H), 3.25 (m, 2H). 2-keto-2-(7-(trifluoromethoxy)·2, 3_Dihydrobenzo-p-M]Oxygen-nitrogen-7 Park_4(sh)_yl)Acetyl acetate (ARM293)

The compound 7-(trifluorodecyloxy) 2,3,4,5-tetrahydrobenzopyrene, oxynitridinium (400 mg, 1.61 mol), ketone ketoacetate (221 micron) L, 2 4 moules) and DIEA (0.6 liters, 5.6 mmol) were mixed in 5 ml of dichloromethane. The solution was stirred at room temperature for 3 hours. Load the solution directly onto the column. The column was washed with ethyl acetate. The title compound was obtained. 1 H NMR (300 MHz, CDC13): 7.22 (m, 0.5H), 7.04 (m, 2H), 6.96 (m, 0.5H), 4.71, 4.64 (ss, 2H), 4.14 (m, 2H), 4.01 (m, 1.1H), 3.85 (m, 4H). 2-keto-2-(7-(trifluoromethoxy)_2,3_dihydrobenzo-]oxy-nitrogen seven garden_4 (sh )_131494 -92- 200902026 base) acetic acid (ARM296)

2- 2-keto-2-(7-(trifluoromethoxy)-2,3-dihydrobenzo[f][l,4]oxenazin-4(5H)-yl)acetate The ester (200 mg) was dissolved in 15 ml of a mixture of THF, methanol and 1M NaOH (1:1:1, v/v). The solution was stirred at room temperature for three hours and acidified to pH 2. The solvent was removed and the solid was collected and dried under vacuum. The title compound was obtained. 1 H NMR (300 MHz, DMSO-d6): 7.40-7.00 (m, 3H), 4.62 (ss, 2H), 4.16 (m, 2H), 3.87 (m, 0.8H), 3.74 (m, 1.2H) Example 6: Preparation of ARM277, 279, 282 (Figure 6) h3co

B"2, AcOH - h3co

H2n ~0H -► DIEA, CH2CI2 h3co

n~0H h3co h3co h3co

1-bromo-2-(exyl)-4-,5-dimethoxybenzene

3,4-Dimethoxynonanol (100 g) was dissolved in 200 ml of glacial acetic acid. To this solution, a solution of bromine (36.4 ml) in 100 ml of acetic acid was slowly added. The reaction was stirred at room temperature overnight. The solid was collected and washed with methanol. Obtain the title product. 131494 -93 - 200902026 NMR (300 MHz, CDC13): 6.99 (s, 1H), 6.89 (s, 1H), 4.54 (s, 2H) 3.87 (ss, 6H). 2-(2-bromo-4, 5-dimethoxybenzylamino)ethanol

1-Bromo-2-(bromomethyl)-4,5-dimethoxybenzene (48 mmol), ethanolamine (194 mmol) and DIEA (112 mmol) at 2〇 The mixture was stirred at room temperature for one hour in 5% acetonitrile. Remove the solvent and fill the residue directly onto the column. The column was washed with chloroform followed by ethyl acetate. Thus, the title compound was obtained. 1 H NMR (300 MHz, CDC13): 6.97 (s, 1H), 6.84 (s, 1H), 3.86 (ss, 6H), 3.80 (s, 2H), 3.66 (t, J = 6.3 Hz, 2H), 2.81 (t, J = 6.3 Hz, 2H). 7,8--methoxy-2,3,4,5-tetrahydrobenzo[£^,4]oxine-7 garden hydrochloride (ARM277) 2-(2-Bromo-4,5-monomethoxybenzylamino)ethanol (45 mmol) with (850 mg, 4·5 mmol) and potassium carbonate (12 5 g, 89 mmol) Ear) mixed in 15 ml of iota-PrOH. The mixture was stirred at reflux overnight. After cooling to room temperature, 300 ml of dichloromethane was added and the solid was removed by filtration. The desired compound was obtained by column chromatography using 丨〇8-5/2 EMI/methanol as a solvent. The compound was obtained. The title compound was then converted to the hydrochloride salt by the addition of 15 mL of a 4M solution of H? in dioxane. 1 H NMR (300 MHz, DMSO-d6): 9.66 (br, 2H), 7.06 (s, 1H), 6.72 (s, 1H), 4.12 (m, 4H), 3.73 (ss, 6H), 3.39 (m , 2H). -^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

7,8-Dimethoxy-2,3,4,5-tetrahydrobenzo[f][l,4]oxazinium hydrochloride (ARM277) (1.52 mmol), chloroketone The decyl acetate (200 μl, 2-14 mmol) and DIEA (5.47 mmol) were mixed in 10 mL CH2C12. The solution was stirred at room temperature for 3 hours. The resulting solution was loaded directly onto the column. The column was washed with ethyl acetate. The title compound was obtained. !H NMR (300 MHz, CDC13): 6.82 (s, 0.7H), 6.60 (m, 1.3H), 4.57 (ss, 2H), 4.06 (m, 2H), 3.95-3.78 (m, 11H). 2 -(7,8-dimethoxy-2,3-dihydrobenzo[f][l,4]oxo-7-(5H)-yl)-2-ketoacetic acid (ARM282)

2-(7,8-Dimethoxy-2,3-dihydrobenzo[f][l,4]oxazin-7(5H)-yl)-2-ketoacetate ( 220 mg) was dissolved in 15 ml of a mixture of THF, decyl alcohol and 1 M NaOH (1:1:1, v/v). The solution was stirred at room temperature for three hours and acidified to pH 2. The solvent was removed and the solid was collected and dried under vacuum. The title compound was obtained. 1 H NMR (300 MHz, DMSO-d6): 6.85 (s, 6H), 6.63 (m, 1.4H), 4.50 (m, 2H), 4.03 (m, 2H), 3.82-3.66 (m, 8H). 131494 -95 · 200902026 Example 7: ARM167, 258, 397 398, (10) q 匍偌 匍偌 f圃. 7,

X, Y = och3.h X, Y = Η , N〇2 Χ· Y = OCF3 , Η (S)-(l-(2-Molyl-5-methoxybenzyl)tetrahydropyrrole_2_ Methanol

Addition of (S)-(+)-2-tetrahydroindole to methanol (3 6 g, 35-6 mmol, 1.03 equivalent) in anhydrous CH3CN (25 mL) at 23 C DffiA (2 mM, 115 mM '3.3 eq.) followed by 2 bromo-5-methoxy guanidinium bromide (9.7 g, 34.6 mM, 1. 〇 equivalent). The reaction mixture was stirred at <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; The combined organic layers were washed (brine), dried (Na 2 s s 4) and concentrated to give the desired product. 1H NMR (300 MHz, CDC13): 1.75 (m, 2H), 1.90 (m, 2H), 2.33 (m, 1H), 2.78 (m, 2H), 2.99 (m, 1H), 3.43 (m, 2H) , 3.72 (dd, J=3.3 Hz, J=ll.l Hz, 1H), 3.80 (s, 3H), 4.00 (d, J=13.5 Hz, 1H), 6.69 (dd, J=3.〇Hz, J=8.7 Hz, 1H), 6.94 (d, J=3.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H). (S)-7-methoxy-1,2,3,5, Ll,lla-hexahydrobenzo[f]pyha[2,lc][i,4]oxygen seven garden (ARM167)

131494 -96- 200902026 at (S&gt;(1-(2-Molyl-5-methoxy)-tetrahydropyrrole-2-yl)methanol (1.0 g, 3.33 耄m, at 23 ° C, 1.0 equivalent) in a solution of anhydrous i pr〇H )), add NaOH (0_3 g, 7.5 mmol, 2-25 equivalents) and C (jI (6 〇 克, 0.32 耄 Mo, (7) equivalents) The reaction mixture was degassed, refilled with argon, refluxed for 17 h and cooled to 23 ° C. The reaction mixture was diluted with MeOH (100 mL), filtered over Celite, and concentrated. Purification (EtOAc/hexanes 50-100%) eluted elute elute elute elute elute elute elute , 1H), 2.73 (m, 1H), 3.17 (m, 1H), 3.47 (dd, J=9.3 Hz, J=11.7 Hz, 1H), 3.70 (s, 2H), 3.76 (s, 3H), 4_30 (dd, J=2'4 Hz, J=12.0 Hz, 1H), 6.70 (m, 2H), 6.95 (m, 1H). 2-bromo-1-(exylmethyl)-4-decyl Benzoquinone 2N-^-xBr

Br mixed 2-bromo-4-nitrotoluene (25 g, 116 mmol), dibenzoyl peroxide (280 mg, U6 mmol) and NBS (20.6 g, 116 mmol). And at 200 homes CCI4 A reflux overnight. After allowing the mixture to cool to room temperature, the solid was teared out. The filtrate was evaporated to dryness. The compound was used directly in the next step without any further purification. (S)-(l-(2-bromo-4-nitroindenyl)tetraapyrrole-2-yl)methanol

2- 2-'Smellyl-1-(bromomethyl)_4_; ε Schottylbenzene (35.2 mmol), (§)_(+)_2_tetrahydropyrrole methanol (4.27 g, 42.3 mmol) And DIEA (14.7 ml, 84·6 mmol 131494-97-200902026 ear), in a milliliter of acetonitrile, stir at room temperature for one hour. The solvent is removed and the residue is loaded directly onto the column. Wash the knee column with chloroform followed by ethyl acetate. The title compound was obtained. NMR (300 MHz, CDC13): 8.41 (d, J=2.l Hz, 1H), 8.15 (dd, J=8.4, 2.1 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 4.08 ( d, J=14.4 Hz, 1H), 3.70-3.58 (m, 2H), 3.47 (dd, 1=13.5, 2.7 Hz, 1H), 2.90 (m, 2H), 2.46 (m, 1H), 2.00-1.70 (m, 5H). (S)-8-Nitro-1,2,3,5,11,113-hexahydrobenzo[1]pyrroloindole 2,1_(;]丨1,4]Oxygen nitrogen Seven Miles (ARM258)

(S)-(l-(2-Bromo-4-nitroindenyl)tetrahydropyrrole-2-yl) decyl alcohol (3 g, 9 55 mmol), copper iodide (1) (180 mg , 〇 _ 955 mM) and potassium carbonate (2.6 g, 19 house Mo) mixed in 15 〇 ml i_pr 〇 H. The mixture was degassed for 5 minutes and heated to reflux overnight under argon. After the solution was cooled to room temperature, 200 ml of ethyl acetate was added. The inorganic solids are removed by filtration. The solvent is removed and the residue is loaded onto the column. The column was washed with EtOAc/methanol (10:1). Thus, the title compound was obtained. 1 H NMR (300 MHz, CDC13): 7.86 (m, 2H), 7.30 (d, J = 7.2 Hz, 1H), 4.41 (dd, J=i2.3, 2·4 Hz, 1H), 3.84 (dd , J=42, 13.8 Hz, 2H), 3.54 (m, 1H), 3.15 (m, 1H), 2.81 (m, 1H), 2.58 (m, 1H), 1.89 (m, 3H), 1.40 (m, 1H). 1-Momotyl_2-(Henylmethyl)_4_(trifluoromethoxy)benzene

131494 -98- 200902026 I-bromo-2-methyl-4-(trifluoromethoxy)benzene (9) 〇 9 g, 39 6 mmoles / in tetrachlorinated (100 ml), It was treated with NBS (7.74 g, 43 5 mmol l·1^) and with benzoic acid peroxide (190 mg, 0.78 mmol). The reaction mixture was stirred under reflux overnight. Remove all volatiles under reduced pressure. The residue was filtered through a pad of EtOAc (EtOAc: EtOAc:EtOAc) (RHH2-exyl-5-(trifluoromethoxy)benzyl)tetrahydropyrrole·2yl)methanol

Dirty (3.3 equivalents) was added to a solution of (S)-tetrahydropyrrol-2-ylmethanol (3. <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The reaction mixture was stirred at ambient temperature for 10 minutes, followed by the addition of 丨 _ _ _ _ _ 冬 漠 漠 漠 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 。 。 。 。 。 。 。 。 。 。 。 。 After stirring for 3 hours, all the volatiles were removed under reduced pressure and the residue was purified eluting with EtOAc EtOAc The combined organic extracts were dried over sodium sulfate, dried and evaporated. Purification of the residue by flash chromatography (Shiqi gum, hexane: = acid vinegar '9:1 to 6:1 to 3:1) 'providing a rigid side group _5_(three methoxy) lower group Tetrahydropyrrol-2-yl)methanol is a yellow oil. Η Dirty (MHz, CDCl3 (4) 58 (...7 Hz, ih), 7 release s, 吼7-〇3 (dd, Hz, 1H), 4,9 (d, J=13, Ηζ? 1H)? 3 ?3 J=n 4 ^3.3HZs 1H, 131494 •99· 200902026 3.04 (br m, 1H), 2.89 (br s, 1H), 2.39 (br m, 1H), 2.06-1.74 (m, 4H). ( 8)-7-(Trifluorodecyloxy)-1,2,3,5,11,113-hexahydrobenzo[£]pyrrolo[2,1_(;][1,4]oxynitrogen (ARM397)

(R)-(l-(2-Bromo-5-(trifluoromethoxy)octyl)tetrahydropyrrole-2-yl)methanol (0.55 g '1.55 mmol), copper iodide (59 Mg, 0_31 mmol, ο. eq.) and potassium carbonate (428 mg '3.1 mmol, 2_0 equivalent) were transferred to the reaction flask. The mixture was suspended in anhydrous isopropanol (2 mL) and degassed. It was stirred overnight under reflux conditions. After cooling to room temperature, the gas imitation was added in small portions, and the mixture was filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (hexane, ethyl acetate, ethyl acetate, 3:1) to afford (8)-7-(trifluoromethoxy)-1,2,3, 5,11,11 hexahydrobenzo[morphine] [2, lc] [l, 4] oxynitride. 4 NMR (300 MHz, CDC13) δ 7.01 (m, 3H), 4.35 (dd, J = 12.3 and 2.4 Hz, 1H), 3_73 (ABq, J = 13.8 and 3_3 Hz, 2H), 3·53 (dd, J=12 and 9.6 Hz, 1H), 3.17 (m, 1H), 2.78 (m, 1H), 2.54 (dt, J=8.7 Hz, 1H), 1.97-1.79 (m, 3H), 1.45 (m, 1H) (S)-(l-(2-Molyl-5-(trifluoromethoxy)benzyl)tetrahydroindole _2_yl) sterol

Add DIEA (1.84 mL, 1 〇.6 mmol, 3) to a solution of (R)-tetrahydropyrrol-2-ylmethanol (0.33 g, 3.26 mmol) in dry EtOAc (5 mL) 3 131494 -100· 200902026 equivalent). The reaction mixture was stirred at ambient temperature for 10 minutes, followed by the addition of 1-bromo-2-(·; odorylmethyl &gt; 4 -(trifluoromethoxy)benzene (1 〇 7 g ' 3 2 〇 millimolar The reaction mixture was stirred at ambient temperature for 3 hours. All the volatiles were removed under reduced pressure and the residue was purified eluted with sat. The combined organic extracts are dried over sodium sulfate, filtered, and concentrated. The residue is purified by flash chromatography (hexane, hexane: ethyl acetate, 9:1 to 6:1 to 3:1) ), (s&gt;(1_(2_ '/ odoryl-5-(difluoromethoxy)-yl)tetrahydro-bilo- 2 -yl)methanol. !H NMR (300 MHz, CDC13) 5 7.58 (d, J=8.7 Hz, 1H), 7.36 (br s, 1H), 7.03 (dd, J=8.7 and 2.1 Hz, 1H), 4.09 (d, J=14.1 Hz, 1H), 3.73 (dd, J =11.4 with 3.3 Hz, 1H), 3.59 (d, J = 13.2 Hz, 1H), 3.50 (dd, J=ll.l and 2_4 Hz, 1H), 3.04 (br m, 1H), 2.89 (br s, 1H), 2.39 (br m, 1H), 2.06-1.74 (m, 4H). (8)^ Dimethoxymethoxy^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ARM398)

(S)-(l-(2-Mercapto-5-(trifluoromethoxy)-yl)tetrahydropyrrole-2-yl)methanol (0.63 g, 1.78 mmol), copper iodide (68 mg , 〇 2 eq.) and potassium carbonate (492 mg, 2.0 eq.) were transferred to a reaction flask. The mixture was suspended in anhydrous isopropanol (20 liters) and degassed. It was mixed overnight under reflux conditions. After cooling to room temperature, chloroform was added in small portions, and the mixture was filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure and the residue was purified (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 5, ll, lla-hexahydrobenzo[f]pyrrolopyrene (4) oxygen nitrogen heptazone. 131494 -101- 200902026 'H NMR (300 MHz, CDCI3) 5 7.01 (m, 3H), 4.35 (dd , J = 12.3 and 2,4 Hz, 1H), 3.73 (ABq, J = 13_8 and 3.3 Hz, 2H), 3.53 (dd, J = 12 and 9.6 Hz, 1H) 3.17 (m, 1H), 2.78 (m , 1H), 2.54 (dt, J=8.7 Hz, 1H), 1.97-1.79 (m, 3H), 1-45 (m, 1H). (R)-(l-(2-bromo)_5_甲Oxybenzyl)tetrahydropyrrole_2-yl)methanol

To a solution of (R)-tetrahydropyrrol-2-yl decyl alcohol (3.29 ml, 33.7 mmol) in dry acetonitrile (25 mL), DIEA (18.8 mL, EtOAc &lt; ). The reaction mixture was stirred at ambient temperature for 1 min, then 1-bromo-2-(indolylmethyl)-4-methoxybenzene ( 916 g, 32 7 m. The reaction mixture was stirred at ambient temperature for 3 hours. All the volatiles were removed under reduced pressure and the residue was crystallisjjjjjjjjjjj The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (purine, hexane: ethyl acetate, 4:1 to 3:1 to 1:1) to provide (RMl-(2. _5_methoxyl) Tetrahydro-p-bi-2-yl) decyl alcohol is a pale yellow oil. Sleepy (ARM399) (R) 7-methoxy-1,2,3,5,11,11^hexahydrobenzindole[2,1_also 14]oxygen seven

Transfer (R)-(l-(2-bromo 2.03 mmol), 131494-102-200902026 potassium (562 mg, 4·06 mmol, 2 eq.) to the reaction flask. Isopropanol (2 mL) and degassed. Stir it under reflux overnight. After cooling to room temperature, add the mixture in a small amount and filter the mixture through a short pad. The filtrate was concentrated and the residue was purified by flash chromatography eluting eluting eluting - hexahydrobenzo[5|pyrrolo[2,1-(;][1,4]oxynitrogen-7. 1 H NMR (300 MHz, CDC13) &lt;5 6.93 (m, 1H), 6.70 (m , 2H), 4.29 (dd, 1H), 3.75 (s, 3H), 3.70 (s, 2H), 3.46 (dd, 1H), 3.15 (m, 1H), 2.74 (m, 1H), 2.51 (dt, 1H), 1.95-1.75 (m, 3H), 1.42 (m, 1H). Example 8: Preparation of ARM301, 302 (Figure 8)

To a solution of serine (9_9 g, l〇9 mmol) with DIEA (38 ml '218 mmol) 131494 -103 - 200902026 in 200 ml of chloroform in a solution of '100 m| and, 2 -bromo-5-methoxy bromide (28

(7-Methoxy-2,3,4,5-tetrahydrobenzoxazepine 7-mer) Methanol (ARM3〇1) 1H NMR (3〇〇MHz, CDC13): 7.40 (d, J=9.0 Hz: 1H), 6.64 (dd, J=8.7, 2.7 Hz, 1H), 3.85 (s, 2H),: J=5.1, 11.1 Hz, 2H), 2.90 (m, 1H).

2_(2_/ odoryl-5 oxime benzylamino)propanone-1,3-diol (18.9 g, 65 mmol), copper iodide (1) (1-23 g, 6.5 mmol) and Potassium carbonate (18 g, 13 Torr) was mixed in 120 ml of isobutanol. The solution was degassed under vacuum for 5 minutes and the flask was purged twice with argon. The solution was refluxed for 48 hours. It was allowed to cool to room temperature and diluted with 400 ml of chloroform. The solids were removed by filtration and the filtrate was sent to dryness. The pure compound was obtained by column chromatography (Et 〇Ac / decyl alcohol, 5). [ NMR (300 MHz, CDC13) · 6.94 (d, J = 8.1 Hz, 1H), 6.68 (m, 2H) 4.25 (dd , J = 12.6, 2.7 Hz, 1H), 3.94 (m, 2H), 3.78-3.42 (m, 6H), 3.26 (m, 2H). 2-(bis(2-bromo-5-methoxybenzyl) Amino)propane-w•diol

131494 -104· 200902026 Add 2-bromo-5-oxime to a solution of serine (9,9 g, 109 mmol) and DIEA (38 ml, 218 mmol) in 200 ml of chloroform. A solution of bromine (28 g '100 mmol) in 1 ml of chloroform. The solution was stirred at 5 °C overnight. The solution was loaded directly onto the cartridge column. The column was washed with chloroform, ethyl acetate/methanol (1% to 8%). Obtain the title product. 1 H NMR (300 MHz, CDC13 ): 7.36 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 3.3 Hz, 2H), 6.64 (dd, J-9.0, 2.7 Hz, 2H), 3.85 ( s, 5H), 3.76 (m, 9H), 3.00 (m5 1H), 2.1 (br, 2H). (ARM302)

, 3-diol (9.0 g, (1) (700 mg, 3.68 mol) and potassium carbonate (10 ΐ: liter / butanol mixed. Allow the solution to vacuum under argon twice under vacuum. 48 hours. Dilute with 400 ml of chloroform. Remove solid-solid/solid compound by filtration column chromatography (Et〇Acc/ 2-(bis(2-bromo-5-decyloxybenzyl)) Amino) propylene xylate ^ two I8 · 4 millimoles), copper iodide (1) (700 mg 'Μ 8 亳 Moer gram, 73 millimoles) mixed in 〇 2 〇 ml of iso-butanol. The solution was degassed for 5 minutes, and the flask was purged with argon twice. The solution was allowed to cool the solution to room temperature, and the mixture was taken to 400 liters of the carcass and the filtrate was evaporated to dryness. .

1 H NMR (300 -------- 4.24 (dd, J=12.6, 1H). 131494 -105- 200902026 Example 9: Preparation of ARM306, 326, 351, 352, 353, 534 (Figure 9)

BH3i THF reflux

(7-methoxy-4-(2-decyloxy-2-ketoethyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxonitrogen-7 3_base) methyl oxalate (ARM3〇6)

(7-Methoxy-2,3,4,5-tetrahydrobenzo[f][l,4]oxen-7-yl) decyl alcohol (400 mg, 1.90 mmol), gas Methyl ketoacetate (470 μL, 4.56 mmol) and DIEA (1.0 mL, 5.7 mmol) were combined in 5 mL of dioxane. 131494 -106- 200902026 The solution was stirred at room temperature for 3 hours. The solution was loaded onto a cartridge column and dissolved in ethyl acetate. !H NMR (300 MHz, CDC13): 6.98-6.92 (m, 1.6H), 6.83 (m, 1H), 6.58 (d, J=2.4 Hz, 0.4H), 5.10 (m5 1H), 4.82 (m, 1H), 4.64 (m, 1.4H), 4.40 (m, 2H), 4.21 (m, 0.6H), 4.00-3.76 (m, 10H). 8-methoxy-4,6,12,123-four Hydrobenzopyrene [1,4] 呤耕丨3,4_&lt;;]丨1,4]Oxygen-nitrogen-7--3(1H)-one (ARM351)

(7-Methoxy-2,3,4,5-tetrahydrobenzo-W[1,4]oxazoindolyl)sterol (3 mg, 1.44 mmol) with DIEA (0.5 Methyl bromoacetate (132 μl, 144 mmol) was added to a solution of 1 mL of dry acetonitrile in 1 mL of dry acetonitrile. The solution was stirred at 30 ° C overnight, then at 60 ° for 4 hours. The solvent was removed and the residue was dissolved in a dichlorohydrazine and loaded onto a stone gel. The column was washed with ethyl acetate/hexane (1:1). Obtain the title product. !H NMR (300 MHz, CDC13): 6.94 (d? J=8.7 Hz, 1H), 6.70 (m, 2H), 4.38 (dd, J=4.0, 11.4 Hz, 1H), 4.12 (m, 3H), 3.76 (m, 4H), 3.53 (m, 2H), 3.28 (d, J=18 Hz, 1H), 3.20 (m, 1H). 7-methoxy-ll,lla-dihydro-1H_benzo [fjcarbazole oxime oxynitride-7(5H)-one (ARM352)

(7-Methoxy-2,3,4,5-tetrahydrobenzo[fp,4]oxazo-7-yl)methanol (3〇〇131494 •107· 200902026 耄克,1.44 mmol Ear), diethyl carbonate (1·7 ml, 14·3 mmol) and sodium decylate (4.37 M in MeOH, 〇·65 ml, 2.86 mmol) mixed in 1 mL of absolute ethanol . The solution was refluxed overnight. The solution was acidified with TFA and the solvent was removed. The pure title compound was obtained by column chromatography (ethyl acetate / hexane, 1:1). NMR NMR (300 MHz, CDC13): 6.94 (d, J=8.7 Hz, 1H), 6.70 (m, 2H), 4.64 (d, J=15 Hz, 1H), 4.35 (m, 4H), 3.86 (m , 1H), 3.75 (s, 3H)S 3.60 (m, 2-chloro-1-(3-(hydroxyindole)_7_methoxy 2,3_dihydrobenzopyrene] oxygen nitrogen Seven Garden °&gt;^c,

(7-Methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazo-7 _3-yl)methanol (627 mg, 3.0 mmol) with DIEA ( 575 microliters, 33 millimoles) was mixed in 1 milliliter of dichloromethane. The solution was cooled in an ice-methanol bath. A solution of chlorinated ethylene bromide (263 μL, 3.3 mmol) in 5 mL of dioxane was added to the cooled solution. The solution was stirred for 30 minutes and then allowed to reach room temperature overnight. The title compound was obtained by column chromatography. 8-methoxy-3,6,12,:123-tetrahydrobenzene and w], cultivating and (3) "like (4) oxygen and nitrogen seven gardens

131494 200902026 圜-4(5H)-yl) acetamidine in a solution of 10 ml of anhydrous THF

Remove the solvent. The desired compound is obtained by column chromatography.

1H), 6.70 (dd, J-8.7, 3.0 Hz, 1H), 5.28 (d, J = 14.4 Hz, 1H), 4.30 (m 1H) 4.10-3.75 (m, 10H). 8-methoxy-1 , 3,4,6,12,123_hexahydrobenzidine 1,4] 噚耕和丨3,4_(;][1,4]Oxygen and nitrogen seven sleepy (ARM354)

8-Methoxy-3,6,12,123-tetrahydrobenzo[£][1,4]噚[[,4_(:][1,4] Oxygen Nitrogen-7圜(1H) A solution of the ketone (280 mg, 1.12 mmol) in 5 mL of dry THF was added 1M EtOAc / THF complex (5.0 mL). The solution was refluxed overnight. This was stirred and refluxed for 3 h. The title compound was obtained eluted eluted elute elute elute elute elute elute elute 3.60 (m, 9H), 3.29 (d, J=13.5 Hz, 1H), 3.26 (m, 1H), 2.79 (m, 2H) 2.51 (m, 1H). Example 10: Preparation of ARM311, 312, 313 ( Figure l〇) 131494 109- 200902026

2-keto-2-(7-(trifluoromethoxy)_2,3-dihydrobenzo[fni,4]oxoazinium-4(5h) group) gasification of acetamidine to 2-keto group -2-(7-(Trifluoromethoxy)_2,3-dihydrobenzo[[丨[(氧^^^^^^^^^^^^^^^^) In the solution, SOC12 (0-5 ml, excess) and DMF (〇〇5 ml) were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure to give the title gas. It was dissolved in 1 mL and used for the next-reaction without further purification. 4-(2-keto-2-(7-(trifluoromethoxy)_2,3-dihydrobenzo[叩,4]oxynitrogen-7,4(5H)-yl)ethenyl)hexahydro Pyridinium small carboxylic acid tert-butyl ester (arm3ii) in cesium chloride CI^Cl2 solution (6.6 ml, ou millimoles), add 4_B〇c_ hexamidine pyridin (20 mg, 〇_12 mmol) With shame 1^ (〇 5 ml, excess). The reaction mixture was stirred at room temperature for 2 hr and washed with EtOAc (3 mL EtOAc) The solvent was evaporated and the product surface was purified by chromatography (Si02, CH.sub.2Cl.sub.2/MeOH 10:1). NMR (CDC13): 7.2 〇, broad, 1H), 7.05 (s, 1H), 6.9 (s, broad, 1H), 4·65 (s, ~1H), 4·60 (s, ~1H), 4 · 2 (4), 4_08 (m), 3.8 (4), 3.6 (m), 3.4 (m), 3.3 (m), 3.2 (m), 2.9 (m), 1.4 (m, 9H). 1- (hexahydropyridyl) Plung-1-yl)-2-(7-(trifluoromethoxy)_2,3-dihydrobenzo[f][i,4]oxo-7,5(5H)-yl) 1,2-dione (ARM312) 4-(2-keto-2-(7-(trifluoromethoxy)-2,3-dihydrobenzene, dissolved in CH2 (3⁄4 (3 mL)) And [f][l,4]oxynitrazin_4(5H)-yl)ethenyl) hexahydropyridinic acid tri-butyl ester (9·08 mg) was added to TFA (〇 5 ml). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed by evaporation under reduced pressure to give EtOAc (yield: iHNMR^CDCl;): ?]^ broad, 1H), 7.0 (s, broad, 1H), 6.9 (s, broad, 1H), 4.6 (s, broad, ~1H), 4.4 (s, broad, ~1H), 4_2-3_8 (10), 3.4-3.0 (m). 2 - keto-2-(7-(trifluoromethoxy)_2,3-dihydrobenzo[ phantom (1)^ oxynitrogen-7 _4(5h)-yl) acetamidine (ARM313) Corresponding gasification Prepared in step 1 of Ct ^ Cl2 solution, 3.3 mL) and Yue alcoholic solution of NH3 (2〇%, 5 ml of square) made of the reaction.咜尔尺(10)(五): Outer, broad, called 7.2 (8, 1 printed, 7.0 (3, broad, called 5.6 (s, NH2), 5.05 (s, 1H), 4.6 (s, 1H), 4.4 (m, 1H), 4.1 (m, 2H), 4.0 (m5 1H). 131494 -Ill - 200902026 Example 11: Preparation of ARM318, 322, 324, 331, 335, 337 (Figure 11)

X, y=h, no2 X, Y= och3, och3 X, Y= OCF3, Η Preparation of ARM318, 322, 324, 326: General procedure for amine or amine hydrochloride (1.1 mmol), DIEA (0.7 ML, 3.7 mmol) and 4-oxocarbonyl-hexahydropyrazine-1-carboxylic acid tert-butyl ester (300 mg, 1.2 mmol) mixed in 5 ml of di-methane. The solution was stirred at room temperature for 24 hours. The solution was evaporated to dryness and the residue was taken crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 3,4,5-tetrahydrobenzo[f][l,4]oxazo-7--4-carbonyl)hexahydropyrrol-1-carboxylic acid tert-butyl ester (ARM318)

NMR (300 MHz, CDC13): 7.86 (m, 2H), 7.35 (d, J=8.4 Hz, 1H), 4.43 (s, 2H), 4.21 (m, 2H), 3.72 (m, 2H), 3.42 ( m, 4H), 3.18 (m, 4H), 1.44 (s, 9H). 4-(7,8-Dimethoxy-2,3,4,5-tetrahydrobenzo[f][l,4 Oxygen nitrogen seven-pot-4-carbonyl) hexahydropyrrol-1-carboxylic acid third-butyl ester (ARM322)

^ NMR (300 MHz, CDC13): 6.66 (s, 1H), 6.56 (s, 1H), 4.30 (s, 2H), 131494 -112- 200902026 4.10 (m, 2H), 3.82 (s, 6H), 3.66 (m, 2H), 3.42 (m, 4H), 3.20 (m, 4H), I.44 (s, 9H). 4-(7-(trifluorodecyloxy)-2,3,4,5- Tetrahydrobenzopyrene [1,4]oxygen seven hemi-_4-carbonyl) hexahydropyrrol-1-carboxylic acid tert-butyl ester (ARM324)

1 H NMR (300 MHz, CDC13): 7.24 (m, 1H), 7.01 (m, 2H), 4.34 (s, 2H), 4.12 (m, 2H), 3.66 (m, 2H), 3.42 (m, 4H) ), 3.19 (m, 4H), 1.44 (s, 9H). 4-(3-(Hydroxymethyl)-7-methoxy-2,3,4,5-tetrahydrobenzo[fj[i, 4] Oxygen and nitrogen seven gardens _ Benji) hexahydropyrazine-1-carboxylic acid third-butyl vinegar (ARM326)

1 H NMR (300 MHz, CDC13): 6.88 (d, J=8.4 Hz, 1H), 6.72 (dd, J=8.7 3.0 Hz, 1H), 6.60 (d, J=3.0 Hz, 1H), 4.67 (ss , 1H), 4.34 (m, 0.8H), 4.21 (m, 1.2H), 4.06 (m, 4H), 3.77 (m, 4H), 3.42 (m, 4H), 3.14 (m, 4H), 1.44 ( S} 9H). Preparation of ARM 331, 335, 337: General procedure In a solution of Boc-protected hexahydropyrazine compound in 3 ml of diethyl ether, 5.0 ml of a 4 MHC 1 solution in dioxanol was added. The solution was stirred for 3 hours, the solvent was removed and excess HCb was taken and the residue was crystallised from 1 EtOAc. Discard the supernatant clear solvent. The solid was dissolved in a mixture of methane and methanol and transferred to a vial. Removal of solvent ^ 131494 -113 - 200902026 Provide the target product. (8-Nitro-2,3-dihydrobenzo[f][l,4]oxo-7-(5H)-yl)(hexahydropyrylene-1-yl)methanone hydrochloride ( ARM331)

1H NMR (3〇〇MHz, DMSO-d6): 9.40 (br, 2H), 7.86 (dd, J=8.1, 2.1 Hz, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.53 (d , J=8.1 Hz, 1H), 4.54 (s, 2H), 4.32 (t, J=4.2 Hz, 2H), 3.66 (t, J=5.1 Hz, 2H), 3.62 (m, 2H), 3.28 (m , 4H), 3.06 (m, 4H). (7,8-Dimethoxy-1 2,3-dihydrobenzo[f|[i,4]oxo-7--4(5H)-yl) (hexahydropyrrol-1-yl)methanone hydrochloride (ARM335)

I

!H NMR (300 MHz, DMSO-d6): 9.20 (br, 2H), 6.83 (s, 1H), 6.58 (s, 1H), 4.32 (s, 2H), 4.07 (m, 2H), 3.69 (ss , 6H), 3.55 (m, 2H), 3.27 (m, 4H), 3.10 (m, 4H). Hexahydropyridin-1-yl (7-(trifluoromethoxy)_2,3-dihydrobenzene And 丨f|[l,4]Oxygen nitrogen seven gardens•4(5H)_yl)methanone hydrochloride (ARM337)

NH HCI 131494 114· 1 H NMR (300 MHz, DMSO-d6): 9.20 (br, 2H), 7.31 (d, J=2.1 Hz, 1H), 2 7.14 (dd, J=8.4, 3.0 Hz, 1H) , 6.98 (d, J=8.7 Hz, 1H), 4.43 (s, 2H), 4.20 (m, 2H), 3.62 (m, 2H), 3.24 (m, 4H), 3.07 (m, 4H). 200902026 Example L2 : Preparation of ARM423 (Figure Π)

OH

,, 'NH2

Boc2〇 - Et3N, CH2CI2

OH ^^',, NHBoc CH3S02CI (IPr)2NEt, CH2CI2 OSO2CH3

O. /^/CHO

OH

NaBH4 Cl (iPr)2NEt -&gt; ,0

EtOH.THF

SOCI2

o

CHCU

',, NH2 HCI CH3CN

O' ‘0 (lR,2R)-2-hydroxycyclohexylaminocarboxylic acid tert-butyl ester

OH

, 'NHBoc in a solution of trans-2-aminocyclohexanol hydrochloride (15.8 g, 104.2 mmol) and triethylamine (36.5 mL, 260 mmol) in 200 mL of di-methane. Boc anhydride (22.7 g, 104.2 mmol) was added. The solution was stirred overnight at room temperature, diluted with 400 mL of di-methane, and extracted with 120 mL of 1M EtOAc. The organic solution was dried over sodium sulfate. Removal of the solvent provided the title compound. 1 H NMR (300 MHz, CDC13 ): 4.56 (br, 1H), 3.28 (m, 2H), 1.99 (m, 2H), 1.72 (m, 2H), 1.49-1.16 (m, 13H). methanesulfonic acid (lR,2R)-2-(Thr-Butoxycarbonylamino)cyclohexyl oso2ch3 ^^, ', NHBoc in (lR, 2R)-2-hydroxycyclohexylamino decanoic acid tert-butyl ester ( 22 g, 102 mmol) and DIEA (26.3 ml, 153 mmol) in 100 ml of dioxane, 131494 -115 - 200902026 cooled to 0 C of the mixed solution, added gasification dropwise曱 醯 醯 (IQ.] 宅升 ' 133 millimoles). After the addition, the solution was stirred under a pot for 1 hour and at room temperature for 2 hours. The solution was diluted with 400 ml of dichloromethane and extracted with a 2 liter aqueous solution of 0. 1M HCl. The organic layer was dehydrated and dried over sodium sulfate, and the solvent was removed. The title compound was obtained by column chromatography (EtOAc, hexane, 1:1). 1H NMR (300 MHz, CDC13): 4.65 (br, 1H), 4.40 (m, 1H), 3.59 (m, 1H), 3.00 (s, 3H), 2.10 (m, 2H), 1.72-1.16 (m, 15H). (lR,2S)-2-(2-Methyl--4-methoxyphenoxy)cyclohexylaminocarboxylic acid tert-butyl ester ^^, ', NHBoc methane sulfonic acid (lR, 2R)-2-(Third-butoxycarbonylamino)cyclohexyl ester (1 〇 5 g, 35.8 mmol), 2-hydroxy-5-methoxybenzaldehyde (7_1 g, 46.6 mmol) (26.3 liters '153 mmol) and potassium carbonate (13 g, 93.2 mmol) were mixed in 1 mL of anhydrous DMF. The mixture was stirred at rt EtOAc (EtOAc) EtOAc (EtOAc)EtOAc. Desalting with sodium sulfate. Removal of solvent 'A mixture of the title compound and starting material. JH NMR (300 MHz, CDC13): 10.42 (s, 1H), 7.28 (d5 J=8.4 Hz, 1H), 7.10-7.00 (m, 2H), 4.60 (br, 1H), 4.10 (m, 1H), 3.79 (m, 4H), 2.05 (m, 2H), 1.72-1.16 (m, 15H). (lR, 2S)-2 -(2-(Hydroxymethyl)-4_methoxyphenoxy)cyclohexylaminocarboxylic acid tert-butyl ester 131494 -116- 200902026 &quot;ΌΓοη [y'NHBoc in 30 minutes, at (ir, a solution of 2S)-2-(2-carbamidinophenoxyphenoxy)cyclohexylaminocarbamic acid tert-butyl vinegar (35.8 mmol) in 100 ml absolute ethanol/THF (1:1) Sodium borohydride (137 g, % mmol) was added in three portions. The solution was stirred at room temperature for 3 hours, and the solvent was removed. The residue was mixed with 2 ml of water and 3x250 ml) extraction. The combined organic fractions were dried and dried with Na2S〇4 The title compound was obtained by column chromatography (yellow). NMR (3 〇〇MHz, CDC13): 6.74 (m, 3H)5 4.B0 (m, 1H), 4.50 (d, J = 8.1 Hz, 1H ), 4.34 (br m, 1H), 3.97 (m, 1H), 3.73 (s, 3H), 3.27 (br, 1H), 2.06 (m, 2H), 1.67-1.21 (m, 15H). (lR, 2S)-2-(2-(gas sulfhydryl)-4-decyloxyphenoxy)cyclohexylamine hydrochloride 0',,, nh2

HCI at 〇C, tris-butyl ester of (lR,2S)-2-(2-(hydroxyindenyl)-4-methoxyphenoxy)cyclohexylaminocarbamic acid (8.6 g, 24.6 mmol) Ear) In a solution of 20 ml of gas, add liquefied sulfoxide (6.4 ml '450 mmol). The solution was stirred at room temperature overnight, then heated to 5 Torr for 2 hours. After cooling to room temperature, decyl alcohol (1 liter ml) was added to the above solution under 〇t: to decompose ruthenium dichloride. The solvent was removed under reduced pressure, EtOAc (EtOAc) was evaporated and evaporated. The title compound was obtained as 胄_, which was collected by filtration. NMR (300 MHz, DMSO-d6): 8.21 (s br, 3H), 6.98-6.90 (m, 2H), 6.79 (dd, J=9.0, 1.0 Hz, 1H), 5.03 (d, J = 11.7 Hz, 1H), 4.41 (m, 2H), 3.73 (Sj 3H), 2.76 (br, 1H), 2.10 (m, 2H), 1.65-1.10 (m, 6H). '(5aS,9aR)-2-methoxy Base-5a,6,7,8,9,9a,10,ll&quot;\ Hydrogen dibenzo[b,叩4]oxygen seven garden (ARM423)

(lR,2S)-2-(2-(Chloromethyl)_4-methoxyphenoxy)cyclohexylamine hydrochloride (6.60 g, 21.6 mmol) with DIEA (7-7 mL, 43 m Mohr) was mixed in 4 ml of acetonitrile. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc EtOAc EtOAc. The water was allowed to be liquidated and killed by diclosan (3χΐ5〇 ml). The &quot;one snail solution was dehydrated and dried with Na 〇S〇4. Removal of the solvent gave the title compound. ^ NMR (300 MHz, CDC13): 6.95 (d, J=9.0 Hz, 1H), 6.65 (m, 2H), 4.16 (d, 1=14.7 Hz, 1H), 3.76 (m, 4H), 3.15 (m , 1H), 2.76 (m, 1H), 2.16 (m5 1H), 1.98-1.00 (m, 7H). 131494 -118- 200902026 Example 13: Preparation of ARM463, 466, 470, 473 (Figure 13)

2-((5aS,9aR)-2-methoxy-5a,6,7,8,9,9a-hexahydrodibenzo[b,f][l,4]oxynitrogen-7-IO(IIH )-yl)-2-ketoacetate methyl ester (ARM463)

(5&amp;8,9 Wang 11)-2-methoxy-5&amp;,6,7,8,9,9110,11-octahydrodibenzo[1), £][1,4]oxygen Add sulfo-ketoacetate (162 μl, 2.4 mmol) to a solution of saponin (372 mg, 1.6 mmol) with DIEA (0.6 mL, 3.5 mmol) in 10 mL of dioxane. ear). The solution was stirred at 0 ° C for 4 hours. The title compound was obtained after column chromatography (EtOAc /hexane). 2-((538,93拗-2-methoxy-53,6,7,8,9,93-hexahydrodibenzo[1^[1,4]oxynitrogen-7--10(11H)- Base-2-ketoacetic acid (ARM466)

2-((5 ugly 8, 9 &amp;ft.)-2-methoxy-5&amp;,6,7,8,9 is -hexahydrodibenzo[1),1][1,4]oxygen Methyl sulphate-10-(11H)-yl)-2-ketoacetate (210 mg) was stirred at room temperature for 6 hours in 30 mL of a mixture of THF, methanol and 1M LiOH (1:1:1:1) And acidified with IN HC1. The organic solvent was removed, and the formed 131494 - 119 - 200902026 precipitate was collected by filtration and washed with water. The solid was dried under vacuum to give the title compound. H NMR (300 MHz, DMSO-d6): 6.8-6.7 (m, 3H), 5.06 (d, J = 16.2 Hz, 0.5H), 4.88 (d, J = 16.2 Hz, 0.5H), 4.65 (d , J=16.2 Hz, 0.5H), 4.32 (m, 1.4H), 4.04 (m, 0.5H), 3.67 (ss, 36H), 3.37 (m, 2H), 2.1-1.2 (m, 8H). 4 -((538,9811)-2-decyloxy-53,6,7,8,9,93,10,11-octahydrodibenzo[15, phantom [1,4] oxynitrogen seven garden-10 -carbonyl) hexamidine pyridin-1-carboxylic acid tert-butyl ester (ARM470)

(5&amp;8,9&amp;11)-2-methoxy-5屯6,7,8,9,9&amp;,10,11-octahydrodibenzo[13,叩,4]oxynitrogen sulfoxide (256 mg, 1.1 mmol), DIEA (0-3 ml, 1.32 mmol) and 4-gas carbonyl-hexahydropyrrol-1-carboxylic acid tert-butyl ester (29 mg, 1.16 mmol) The solution in 5 ml of dichloromethane was stirred at room temperature for 24 hours. The reaction solution was evaporated to dryness. !H NMR (300 MHz, CDC13): 6.84 (d, J=8.7 Hz, 1H), 6.68 (dd, J=9.0, 3.0 Hz, 1H), 6.55 (d, J=3.0 Hz, 1H), 4.56 ( d, J = 17.1 Hz, 1H), 4.44 (d, J = 17.4 Hz, 1H), 3.86 (m, 1H), 3.67 (m, 4H), 3.31 (m, 4H), 2.99 (m, 4H), 2.12 (m, 2H), 1.80-1.23 (m, 15H). ((5aS,9aR)_2_methoxy-5a,6,7,8,9,9a-hexahydrodibenzo[b,f|[ l,4]Oxygen nitrogen seven garden 10 (11H)-yl) (hexahydrou ratio p well-l-group) ketone hydrochloride (ARM473) 131494 -120- 200902026

4-((5aS,9aR)-2-methoxygo 6,7,8,9 is 1,〇,11-octahydrodibenzo[1),!][1,4] oxynitride -10-carbonyl) hexahydropyrazine-1_carboxylic acid tert-butyl ester (27 mg) was added in a solution of 3-0 ml of ethyl bond to a 4 M solution (5.0 ml) of HCl in dioxane. The reaction was stirred for 3 hours, the solvent was removed and excess H.sub.2, and the residue was taken from &lt Discard the supernatant clear solvent. The solid was dissolved in a dichloromethane/methanol mixture and transferred to a small vial. Removal of the solvent provided the title compound. 1 H NMR (300 MHz, DMSO-d6): 9.17 (br, 2H): 6.84-6.65 (m, 3H), 4.72 (d, J = 17.1 Hz, 1H), 4.44 (d, J = 17.4 Hz, 1H ), 4.06 (m, 1H), 3.67 (s, 3H), 3-50 (m, 1H), 3.10-2.96 (m, 8H), 1.99 (m, 2H), 1.67 (m, 2H), 1.49 ( m, 2H), 1-29 (m, 2H). Example I4: Preparation of ARM454 (Figure 14)

(S)-(l-(2-Bromo-6-methoxybenzyl)tetrahydropyrrole_2-yl)methanol \〇 γΟΗ

ν Br dissolves 2-bromo-6-nonyloxybenzaldehyde (1.65 g, 7.67 mmol) with (s)_tetrahydropyrrole-2-ylnonanol (0·85 g, 8_44 mmol) The solution was stirred at ambient temperature for <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The reaction mixture was stirred at room temperature Π 1494 -121 - 200902026. Ethyl acetate and saturated sodium bicarbonate solution were continuously added to the reaction mixture. After the extraction, the liquid layer was separated, and the organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (purine, hexane·ethyl acetate 1:3, to pure ethyl acetate) to afford (8) syloxy-6-methoxyindenyl)tetrahydropyrrol-2-yl ) Methanol. !H NMR (300 MHz, CDC13) δ 7.18-7.06 (m, 2Η), 6.82 (dd, 1H), 3.99 (d, 1H), 3.84 (s, 3H), 3.78 (dd, 1H), 3.71 (d , 1H), 3.37 (dd, 1H), 2.88-2.72 (m, 2H), 2.56 (ddd, 1H), 1.97-1.84 (m, 1H), 1.82-1.55 (m, 3H). (S)-6 -methoxyhydrobenzobenzopyrrolopyrene 2 ^]^ 4] Oxygen and nitrogen seven gardens (ARM454)

(S)-(l-(2-Bromo-6-decyloxybenzyl)tetrahydropyrrole-2-yl) decyl alcohol (35 g, 1.16 mmol), copper iodide (44 mg, 〇 23 mmol, 〇 2 equivalents) and potassium carbonate (322 mg, 2.33 mmol, 2.0 eq.) were transferred to a reaction flask. The mixture was suspended in anhydrous isopropanol (15 mL) and degassed. It was stirred under reflux for 6 hours. After cooling to room temperature, chloroform was added in small portions and the mixture was filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (ethyl acetate, ethyl acetate) to afford (s) _6_methoxy-1,2,3,5,ll,lla-hexahydrobenzene And [fj pyrrole and sputum to the state of oxygen and nitrogen seven. NMR (300 MHz, CDC13) ^ 7.10 (dd, 1H), 6.63 (m, 2H), 4.56 (d, 1H), 4.35 (dd, 1H), 3.78 (s, 3H), 3.54 (dd, 1H), 3.36-3.10 (br m, 2H), 2.78 (br s, 1H), 2.56 (br d, 1H), 1.98-1.72 (m, 3H), 1.45 (br m, 1H). 131494 -122· 200902026 Example 15 : Preparation of ARJVM77 (scheme is)

2-(7-(trifluoromethoxy)_2,3-dihydrobenzopyrene, 4]oxoqi-7--4(5H)-yl)acetic acid tert-butyl ester

OtBu in a round bottom flask, 7-(trifluoromethoxy)_2,3,4,5-tetrahydrobenzo[£][1,4] oxynitride (590 mg '2.53 mmol) Anhydrous CH3CN (15 ml) was added to a mixture of &lt;(03) (1.75 g, 12.65 mmol), followed by tri-butyl bromoacetate (〇_37 mL, 2_53 mmol). The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was partitioned between water (~5 mL) and ethyl acetate (~50 mL). Concentrate and purify by column chromatography (Shixi gum, 25% Et〇Ac / hexane) to obtain the title product. 2-(7-(dimethoxymethoxy)_2,3-dihydrobenzoindole Oxygen nitrogen hepta-7(5H)-based acetic acid hydrochloride (ARM477)

F3CX〇T

0 HCI in 2-(7-(difluorodecyloxy)·2,3-dihydrobenzo[^丨(4)oxynitro-7,4(5h)-yl)acetic acid tert-butyr (776 mg, 2·23 mmoles) In a solution of anhydrous CH 2 ci 2 (7 mL), HCl (4M solution in dioxin, 28 mM, 11.2 Torr) was added. The reaction mixture was stirred at ambient temperature for π hours. An insoluble white solid formed. By filtration, separation (4), and (4) Su 131494 123 · 200902026 into the title product, as a white powder. ^-NMR (300 MHz, DMSO-d6) δ = 7.40-7.42 (m, 2 Η), 7.19-7.22 (d, J = 10.2 Hz, 1H), 4.51 (bs, 2H), 4.32 (bs, 2H), 4.16 (bs, 2H), 3.69 (bs, 2H) (NH+ and COOH signals were not found due to the relatively large amount of H20 in DMSO-d6). Example 16: Preparation of ARM187 (Figure 16)

10-methoxy-6,7-dihydro-5H-benzo[c]tetrazolo[l,5-a]-azeptenene (ARMI87)

Ν'

MeO at a temperature of 0 ° C in a cold suspension of 7-decyloxy-1-tetrahydrofurfurone (5.21 g, 29.56 mmol, 1.0 eq.) in concentrated HCl (26 mL). Gram, 30.46 millimoles, 1.03 equivalents), after 30 minutes. Next, the reaction mixture was stirred at 23 ° C for 2 hours and cooled to 0 ° C by ice water. NaN3 (4.5 g, 69.22 mmol, 2.34 eq.) was added over 1 hour. The reaction mixture was allowed to warm to 23 ° C and stirred for 17 hours. The reaction mixture was poured into EtOAc (EtOAc)EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAc EtOAc EtOAc 131494 -124- 200902026 Example 17: Preparation of ARM2〇0, 2〇5 (Figure Π)

H20, MeOH THF 2-(8-Methoxy-4,5-dihydro-1H-benzo[c]nitroazetene-2(3H)-yl)-2-ketoacetate (ARM200) )

At 0 ° (:, in the crude 8-methoxy-2,3,4,5-tetrahydro-1 benzobenzo[〇|-a heptadecene (assumed to be 14.7 mmol, 1.0 equivalent, according to Med C/zem. 2005, made by you 3586-3604) In a cold solution (0 ° C) in CH 2 Cl 2 (200 mL), add pyridine (2.38 mL, 29.4 mmol, 2.0 eq.) with ketone Ethyl acetate (1.6 ml, 17.3 mmol, 1.2 eq.). The reaction mixture was stirred at 0 ° C for 30 min then diluted with EtOAc EtOAc EtOAc EtOAc. The organic layer was washed with EtOAc (EtOAc (EtOAc)EtOAc. : 1.87 (m, 2H), 2.94 (m, 2H), 3.65 (t, J=5.4 Hz, 2H), 3.80 (m, 3H), 3.85 (m, 3H), 4.55 (m, 2H), 6.60 ( d, J-2.7 Hz, 1/3H), 6.72 (dd, J=2.7 Hz, J-8.1 Hz, 1H), 6.94 (d, J=2.4 Hz, 2/3H), 7.07 (m, 1H). MS (ESI): 263.9 [M+l] +, 304.9 [M+CH3 CN] + 2-(8-methoxy-4,5-dihydro-1H-benzo[c]-nitros-decenene- 2(3H)-yl)-2-ketoacetic acid (ARM205) 131494 -125 - 200902026

2-(8-Methoxy-4,5-dihydro-1H-benzo[c]nitroseptene-2-(3H)-yl)-2-ketoacetate at 23 ° C Ester (0.17 g, 0.65 mmol, 1.0 eq.) in MeOH (5 mL) EtOAc (EtOAc) ML). The reaction mixture was stirred at the same temperature for 15 minutes, concentrated, diluted with EtOAc EtOAc (EtOAc) The aqueous layer was neutralized to pH 3&apos; and extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The combined organic layers were washed (brine), dried (Na2SO4) elute elute elute elute The desired fractions were collected and concentrated in CH2C12 and washed with brine. The organic layer was dried (Na2SO4). 1H NMR (300 MHz, DMSO-d6): 1.65 (m, 2H), 2.84 (m, 2H), 3.57 (m, 2H), 3.68 (m, 3H), 4.36 (m, 2H), 6.66 (m, 2/3H), 6.68 (m, 2/3H), 6.77 (m, 2/3H), 7.04 (m, 1H). Compound 155 can be prepared as described in the literature, for example in the novel vasopressin V2 Among the body-selective antagonists: pyrrolo[2,la]porphyrin and pyrrolopyran P,lc][l,4]benzodiazepine derivatives. Ohtake, Yasuhiro ; Naito, Akira ; Hasegawa, Hisashi Kawano, Katsuhiro; Morizono, Daisuke; Taniguchi, Makoto; Tanaka, Yoko; Matsukawa, Hidehiko; Naito, Kenji; Oguma, Touru; Ezure, Yohji; Tsuriya, Yoshihiro. Sagami Research Laboratory, Wakamoto Pharmaceutical Company, Kanagawa, Japan· Bioorganic and Medicinal Chemistry (1999), 7(6), 131494-126 - 200902026 1247-1254; and the internal protons induced by Lewis acid are returned to the complex of the palmitic amines Vedejs, Edwin; Lee, Namkyu• Department of Chemistry, University of Wisconsin, Madison, WI, USA. Journal of the American Chemical Society (1995), 117(3), 891-900. The contents of the aforementioned references are incorporated herein by reference. Example 18: calstabin 2 binding of PKA phosphonylated RyR2 to cardiac SR cell membranes as previously described (Marx et al., ρκΑphosphonization from calcium release channels (Renin) 〇dine)Receptor) Dissociation of FKBP12.6: Defective regulation in failing hearts · Cell, 101: 365-76, 2000; Kaftan et al., rapamycin for ryanodine receptors derived from myocardium /Ca2 + - The role of the release channel. Circ. Res·, 78: 990-97, 1996). Immunostaining of microsomes (50 μg) was performed at room temperature using an anti-Carstitabin antibody (1:1,000) (Jayaraman et al., with calcium release channels (Renin) 〇dine) receptor binding to FK506 binding protein.j. Biol. Chem., 267: 9474-77, 1992), after 1 hour (Reiken et al., /3-blocker will recover in human heart failure) Mom releases channel function and improves myocardial performance. Circulation, 107 : 2459-66, 2003). After incubation with HRP-labeled anti-rabbit igG (1:5,000 dilution; transduction laboratory, Lexington, Ky.), the blotting system was performed using ECL (Amersham Pharmacia, Piscataway, NJ) or from Li-Cor Biotechnology. The device (Odyssey type) is expanded. The EC50 value is calculated by quantitative blotting as is known in the art. As shown in Figure 1A-I, the presence of any of the compounds ARM137, ARM138, ARM139, ARM140, ARM147, ARM148, ARM149, ARM151, ARM152, ARM166, ARM167, ARM217, ARM251, ARM258, ARM291 and ARM296 will prevent the card Stabin 2 dissociates from PKA phosphonylated RyR2, and/or 131494 -127- 200902026 enhances the binding of Kastabine 2 to PKA phosphonylated RyR2. Examples of EC50 values derived from RyR2 Rycal screening data are shown in Table 1 〇 Table 1

EC50 EC50 ARM 140 50 nM ARM 147 800 nM ARM 148 1500 nM ARM 149 1000 nM ARM151 60 nM ARM152 175 nM ARM 167 40 nM In addition, when tested in the aforementioned Kastagbin 2 recombination test, the following compounds were also found Prevent the dissociation of Kastababin 2 from PKA phosphorylation RyR2: ARM150, ARM189 and ARM203. Example 19: calstabin 1 binding to PKA phosphonylated RyRl derived from skeletal muscle SR cell membrane system in a manner similar to that of Example 8, and further in US Patent Application Publication No. 2004/0224368 The description is made and its contents are incorporated herein by reference. The immunostaining system of microsomes (50 μg) was carried out as described using an anti-carbastib antibody (1:1,000). The suction system was developed and quantified as described in Example 18. As shown in 囷2A, B, C, and D, the presence of any of the compounds ARM140, ARM148, ARM150, ARM151, ARM167, ARM312, ARM313, and ARM337 will prevent the use of the Psitabin 1 from PKA phosphorylation RyRl Dissociation, and/or enhancement of the binding of Kastabine 1 to PKA phosphonylated RyRl. Examples of EC50 values derived from RyRl Rycal screening data are shown in Table 2 〇 131494 -128 - 200902026

Table 2 EC50 ARM 140 45 nM ARM150 125 nM ARM151 65 nM ARM 167 100 nM Example 20: In isoproterenol-treated mice, calstabin 2 of RyR2 is recombined with isoproterenol, A /3 adrenergic receptor agonist that causes heart failure in mice via over-stimulation of /3 adrenergic receptors. At the same time, the activation of PKA, the phosphorylation of RyR2 to the sarcoplasmic reticulum and the reduction of RyR2 by Kastabin-2 (FKBP12.6). A similar cascade of events occurs in skeletal muscle, where PKA activation by isopropyl adrenaline causes phosphorylation of RyRl, resulting in a reduced binding of R.R. As described in detail in the International Application No. PCT/US2007/085289, the disclosure of which is incorporated herein by reference in its entirety in its entirety in the the the the the the the the the the the the A faster and more reliable method of quantifying RyR biochemical changes. These changes include an increase in RyR phosphorylation combined with a concomitant reduction in Karlastim. Materials and Methods Animals and Reagents C57B1/6 mice were maintained and studied according to the permit. A synthetic adrenergic agonist (isoproterenol (ISO)) was obtained from Sigma (165627), 131494-129-200902026 and was prepared as a 100 mg/ml stock solution in water. The lysis buffer is prepared by adding sucrose (1 mM), dithiothreitol (320 mM) and a protease inhibitor tablet (10X) to 10 ml stock solution (10 mM HEPES, 1 mM EDTA, 20 Made with mM NaF, 2 mM Na3 V04). Osmotic pump preparation and surgical implantation The rats were implanted subcutaneously into an osmotic perfusion pump (Alzet Micro Osmotic Pump, Model 2001, Durect, Cupertino, CA) to 10 mg/ml isoproterenol (1 μl) /hour) Continuously infused for seven days. Regarding drug loading, the osmotic pump is fixed in a vertical manner, and 2 〇〇 microliter of the drug solution is injected through a 1 ml syringe (connected to the cannula) containing an excess of the drug solution (~25 〇 _ 3 〇〇 microliter). In the pump. Slowly inject the drug solution while slowly raising the syringe until the pump is full. When the pump is capped, the displacement -&quot; into the q field · 兀 兀 〇 The filled osmotic pump is implanted subcutaneously by the following steps. In the 〇 2 in the l / min! 5_2% isoflurane (iv) Qiu called, anesthetized f mice, then measured and recorded their body weight. Next, the mouse was placed down on the styrene foam. The face was tied to the nose cone. Cut the neck lice it hair and extend it over the head to the top of the head. Apply this area: Wipe gently and place the suture holder on the neck line of the head with alcohol, insert it into the incision, and open the tissue of the back = down to remove the skin. To comply with the fruit, extend this opening ==:::,r a...where: the square spleen is read and cut, and it is allowed to rest under the skin with minimum tension, and the knife edge is closed with a 5.G nylon suture. (4) Suture: 131494 -130- 200902026 The area is gently rubbed with 70% alcohol. After surgery, the mice are placed in individual cages to minimize damage and possible activation of the sympathetic nervous system. Isolation and homogenization of cardiac tissue The heart is removed from the peritoneal cavity and self-sufficiently removed to remove any residual fat and then frozen in liquid nitrogen. For each tissue sample, three standard microcentrifuge tubes were labeled with a 5 ml tube. Transfer tissue to 5 ml tubing in approximately 0.5-0.7 ml of new lysis buffer, depending on tissue size. The tissue is homogenized until a uniform lysate is formed without a large tissue mass. The homogenate was transferred to a microcentrifuge tube and centrifuged at 4 °C for 15 minutes at 4,000 xg. The supernatant was transferred to a new microcentrifuge tube and centrifuged at 4 ° C for 15 minutes at 1 Torr, 〇〇〇 Xg. Remove the supernatant and transfer to the new microcentrifuge tube. The small fraction was removed to measure the protein concentration and the remaining samples were frozen at -8 °C. RyR2 immunoprecipitation of self-organizing lysates by homogenizing 200-500 μg at 4 °C with 2 μl of anti-RyR antibody (RyR2-5029; Jayaraman et al., 〇/. 1992; 267: 9474 -77), cultured in 0.5 ml of modified RIPA buffer (50 mM Tris-HCl (pH 7.4), 0.9% NaCl, 5.0 mM NaF, 1.0 mM Na3V04, 0.5% Triton-ΧΙΟΟ and protease inhibitor) RyR2 was immunoprecipitated from the sample for 1.5 hours. Then, the sample was incubated at 4 ° C for 1 hour with Protein A Liposaccharide Beads (Amersham Pharmacia Biotech, Piscatawy, NJ), and then the beads were washed three times with RIPA. The sample was heated to 95 ° C and classified by SDS-PAGE (RDS for SDS-PAGE 6%, and 15% SDS-PAGE for calstabin) 131494 -131 - 200902026 from. Immunostaining was performed using an anti-RyR antibody (RyR2-5029) diluted 1:5,000 at a 1:10,000 dilution of phosphonyl-specific antibody (RyR2-P2809, Zymed Laboratories, San Francisco, CA) or Anti-FKBP antibody (FKBB12/12/6, Jayaraman et al., J. 〇/. C/zew. 1992; 267: 9474-77) was developed at 1:2,000 dilution. The antibody was diluted in 5% milk or TBS-T (20 mM Tris-HCl, pH 7.5, 0.5 M NaCl, 0.05% Tween® 20, 0.5% Triton X-100). Results The efficacy of the compounds ARM140, ARM151 and ARM167 in enhancing the binding of R.R2 to RyR2 was examined in isoproterenol-treated mice. Each compound was administered as an osmotic pump at the indicated concentrations. On day 6, each mouse was sacrificed and the heart tissue was isolated and used to analyze the Kastabilin 2 binding in the RyR2 immunoprecipitation. As shown in 圊3A and B, each of these compounds increased the amount of carbitabin 2 in isoproterenol-treated mice to a level similar to that found with 3.6 mM ARM036. It has been shown to be effective in both primary screening and isoproterenol screening. Example 21: In an isoproterenol-treated mouse, the calstabin 1 of RyRl recombines the compounds ARM140, ARM148, ARM150, ARM151 and ARM167 in an enhanced binding to RyRl's Casitabin 1 Efficacy was examined in isoproterenol-treated mice as described in Example 19. The mouse skeletal muscle tissue was isolated as follows. The skin of the foot is exposed by cutting the skin on the ankle and pulling it up. The tissue was treated with Tyrode's buffer (10 mM HEPES, 140 mM NaCl, 2.68 mM KC1, 0.42 mM Na2HP04, 131494 • 132. 200902026 l_7mMMga2, ll_9 mM NaHC03, 5 mM glucose, 1.8 mM CaCl2 by adding 20 mg of CaCl2 to It was made without 100 ml of 1X buffer of CaCl2 solution and kept moist. The following muscles were isolated and frozen in liquid nitrogen. The longissimus rehmannia extensor (EDL) is separated by inserting the scissors between the lateral ridge formed by the EDL and the X and the humerus, and cutting upward toward the knee; cutting the tibia muscle to expose the shape of the gastrocnemius腱; insert the scorpion into the X and under the muscle to relax the EDL 腱; cut the EDL 腱 and pull the muscle; and finally cut the relaxed EDL. The soleus muscle is isolated by removing the tibia muscle from above the gastrocnemius muscle; exposing the soleus muscle to the bottom side of the gastrocnemius muscle by cutting and lifting the Achilles tendon; cutting the soleus muscle above the muscle behind the knee; Finally, the soleus muscle is pulled and cut away from the calf muscle. Separate the cavity by cutting the humerus before the sputum, pulling the 腱 up and cutting it away. Separate the femoral muscles (thigh muscles) from your feet in a way that cuts the muscles on the knees and removes the muscle bundles. The sample was frozen in liquid nitrogen. Muscle tissue homogenate was prepared as in Example 18. . On day 5, each of the compounds was immunoprecipitated by analysis of RyRl. The mice were sacrificed at the indicated concentrations and the tibia tissues were isolated and bound with the statin. τ Each of these compounds will be administered in a drug treated with elastin, according to the number of ancient + s 4 隹, propyl; 楗 1 &quot; statin 1 , which is similar to that administered by 3 mM ARM036 It has been proven to be effective in the serotonin screening of the main sieves. All the publications, 夂多考-贝料, patents and patents 申 131 131494 • 133 - 200902026 cited in this article are incorporated by reference in their entirety for the purposes of individual applications, patents or patent applications. The individual and the individual are shown to be incorporated in their entirety for the same extent as the reference. BRIEF DESCRIPTION OF THE DRAWINGS Other features and advantages of the present invention will become apparent from the Detailed Description and the accompanying drawings, in which: Figure 1A-I uses the immunostaining of a calstabin 2 antibody, as indicated ARM140, ARM151, ARM152 and ARM167 (A); ARM137 and ARM148 (B); ARM147 and ARM149 (C); ARM166 (D); ARM217 (E); ARM258 (F); ARM291 and ARM296 (G); ARM138 (Bottom plate surface) and ARM139 (plate surface) (H); and ARM251 (I) in the absence or presence of (Neg) or in combination, the combination of calstabin 2 and PKA phosphorylation RyR2. ARM036, a benzothiazepine described in U.S. Patent Application Publication No. 2005/0187386, is used as a control group. Pos: positive control (non-PKA phosphonylated RyR2) ° Figure 2A-D immunoassay using calstabin 1 antibody, shown in compounds ARM148 and ARM150 (A); ARM140, ARM151 and ARM167 (B); ARM313 and ARM337 (C); and ARM312 (D) in the absence or presence of (Neg) or in combination, the combination of calstabin 1 and PKA phosphorylation RyRl. ARM036 was used as a control group. Pos: positive control group (non-PKA phosphonylated RyR2). Figure 3A-B shows immunological blotting using calastabin 2 antibody showing 131494-134-200902026 vehicle administered at the indicated concentrations (50:50 DMSO/PEG), isopropyl adrenal alone Prime (0), or isoproterenol accompanied by ARM140 (A); and ARM151 and ARM167 (B) mice, from the cardiac lysate immunoprecipitation RyR2 complex in calastabin (calstabin) 2 content. ARM036 was used as a control group at 3.6 mM.

Figure 4A-C Immunoblotting using a calastabin 1 antibody showing the vehicle administered at the indicated concentrations (50:50 DMSO/PEG), isoproterenol alone, or isopropyl Epinephrine is associated with calstabin in the RyRl complex of the immunosuppressive sacral lysate in ARM150, ARM151 and ARM167 (A); ARM140 (B); and ARM148 (C) mice. 1 content. ARM036 was used as a control group at 3.6 mM. 131494 135-

Claims (1)

200902026 X. Patent application scope: 1 · A compound of formula I: Wherein η is 0, 1, 2, 3 or 4; X is Ο, -NR5 or -C(R5)2; each R is independently selected from the group consisting of z, &amp;, _〇R5, _SR5, pe) 2 NR5C(=〇)〇R5 . ~C(=〇)N(R5)2 . .C(=〇)〇r5 &gt; -C(=〇)R5 , -〇c(=o)R5,N〇2 , CN, _%, 〇cz3, mother and _p(=〇)R^; Rl and R3 are each independently selected from _ base, R5, _ch2qr5, _ch2〇c(=0)R6 ' _cX-〇xm5, _CdNHRs ' _c(=〇)R5 and _〇c(=〇)R5 \ R2 are selected from the group consisting of R5 m -c(=s)r6 and -(ch2 )mRl❶, where m is 1,2, 3, 4, 5 Or 6; or, Xing A and their individually linked or substituted heterocyclic rings; or W and their individually linked nitrogen together with carbon to form an unsubstituted or substituted heterocyclic ring other than hexahydro Or an oxime or heterocyclic ring which is unsubstituted or substituted with an aryl group which is attached or substituted with each other; or R4 is selected from the group consisting of R5 and a keto group; Hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic 131494 200902026 base, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, alkylaryl and alkylheteroaryl ; R6 series Including R5, -(CH2)bNR13R14, -NR5〇R5, -〇R5, -C(=0)OR5, -c(=〇)nr13r14, -(CH2)CY and -c(=o)R5, b is 0, 1, 2, 3, 4, 5 or 6, and c is l, 2, 3, 4 or 5; Κ·ιο is selected from the group consisting of R5, -〇r5, _S〇2Ru, _c(=〇 Ri2, _NH(C&lt;))R12, -〇(c=o)r12 and -P(=0)R8R9; /R8, R9, R丨1 and ruler 12 are independently selected from the group consisting of R5 and 〇R5A-N (R5)2; lanthanide is selected from the group consisting of 2, - (: 〇 2 feet 5, -0: (= 〇) _13 heart 4 and _ (^5; z is halogen 'selected from F, cl, Br and I; Ri3 and Ri4 are independently selected from the group consisting of Rs, or Ri 3 together with Ri 4 and the N to which they are combined may form an unsubstituted or substituted heterocyclic ring; and wherein each alkyl, alkenyl, alkynyl, cycloalkane The group, heterocyclic group, aryl group, heteroaryl group, % alkylalkyl group, heterocyclylalkyl group, alkylaryl group and alkylheteroaryl group may be substituted or unsubstituted; wherein in the benzooxazole The nitrogen in the heptacyclic ring may be a quaternary nitrogen; and all of its palmomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes , polymorphs, new generations Products and prodrugs; Six 丨 疋 疋 (1) When R is hydrogen, at the position 7 of the stupid and oxygen nitrogen heptacyclic ring, ~ is not mm or silk 6 base, (ii) tR3 is ^ base, h Not a keto group or -C(〇)nhr5; (when the ruler 2 is 11, Ri is not a base; and (iv) when R2 and R3 and their respective nitrogen and carbon are unsubstituted Or a substituted heterocyclic ring, the heart is not a ketone group. 131494 200902026 2. The compound of claim 1 which has the formula Ia R3 3. The compound of claim 1 or 2, wherein (8) η is 1 or 2, and R is z, 0Cz3, &amp;, 〇R5, CN, N〇2, N(R5)2, -C(-〇) N(R5)2, _c(=〇)〇R5 or -P(=〇)R8R9 at position 7 or 8 of the benzodiazepine heptacyclic ring; (b) η is 1, r is z, 〇CZ3 , R5, 〇r5, CN, N〇2, n(r5, _C(=0)N(R5)2, -C(=0)0r5 or -PK))R8R9, in the benzoxanthine Position 6; (c) R2 is C(=0)R6' where r6 is selected from the group consisting of _c(n _c(four)ο%, -c(=〇)NRl3Rl4, and (CH2)bNRi3Ri4, where (iv) and &amp; A Γ~\ is each Η, or a combination of them to form r^〇, ch2 f NRa ' and Ra is H 'alkoxy, succinyl or % A alkyl) _ square base is disubstituted Phenyl or benzo(10)didecyl-5-yl, wherein the nitrogen in NRa may optionally be a quaternary nitrogen; (4) R2 is RHaoh2)m Rl G, wherein Ri. Is selected from the group consisting of R5, _c (= 〇) slightly) 2, - (c = o) or 5 or _ 〇 R; /, 5 melon is 1, 2, 3, 4, 5 or 6; or (e) And the unsubstituted or substituted heterocyclic ring of the hexahydropyrazine together with R3 and the enthalpy of the ring; or (f) I and R4 and their individual or substituted H帛^ atoms together form unsubstituted 131494 200902026 where, in (4) the 'heart and heart are independent of 〇R5; and in (a)-(d) ten' each series are 虱, or unsubstituted or Substituted alkyl, pendant aryl, aryl or heterocyclic. 4. The compound of claim 1 or 2, wherein the center is (1) hydrogen; (ii) R5 « ί (4) 仰 "'its ^ is ... seven or ^ and wherein ^ is pure or (C = 0) 〇 r5; (iv) -C(=〇)C(=〇)〇r5 ; (v) _CH})NR13Ri4, or (vi) -(:(=〇)(:(=〇)]3 Ri 4 Its ^\3 and Rl4 Each is H, or is combined to form ~~'N Rd \~/, whose core is CH2, ΝΗ, 〇, N-benzo[1,3]dione-5-yl or NC (=〇 OC(r5)3, wherein the nitrogen in ~ is optionally a quaternary nitrogen; or R4R3 and the nitrogen to which they are individually attached together with carbon form an unsubstituted or substituted heterocyclic ring other than argon. 5_The compound of claim 4, wherein..., and m〇R5, 〇CZ3, z, CN &gt; R5 . N(r5)2 . -C(=〇)N(R5)2 . -C(=〇 〇R5^.P(=〇)(〇R5)2, N〇2, at position 6, 7 or 8 of the benzoxanthene quinone ring, or n is 2, each &amp; is independently OR5, In positions 7 and 8 of the benzoxanthine seven ring. 6. The compound of claim 1 or 2, wherein: 131494 200902026 A) n is 1, R is Ο% or 0CZ3, in benzoxanthine 圜At position 7 of the ring, and R2 is (i) hydrogen; (ii) R5, (iii) (CH2 mR1〇, where „1 is 1, 2, 3 4 5 or 6, and wherein 〇 is R5 or (C=〇) 〇 R5; eg _c(=〇)c(=〇)〇R5 ; (v) -C(=0)NR13 Rj 4 The argument is that each is H, or the combination is combined to form Wherein R13 and R14 are absent, wherein Rd is CH2'NH, hydrazine, N-benzo[1,3]dione-5-yl or NC(=0)0C(R5)3, wherein the nitrogen in Rd may be Is a quaternary nitrogen; or &amp; and &lt;and their individually linked nitrogen and carbon together form an unsubstituted or substituted heteropolysaccharide other than hexahydropyridin; or Β) η is 1 'R is Z, CN, r5, n(r5)2, _c(=〇)N(R5)2, _c(=〇)〇R5 or -P(=〇X〇R5)2, at the position of the benzoxanthine quinone ring 7, and r2 is r5; or C) η is 1 'R is n〇2' at position 8 of the benzoxazepine ring, and &amp; is (Ο hydrogen; (ii) R5, (iii) -C(=0)C(=〇)〇R5; or (iv)-C(=〇)NR13R14, where R!3 and R!4 are each H, or are combined to form \_/d, Wherein Rd is CH2, NH, hydrazine, NC(=〇)〇c(R5)3 or N-benzo[1,3]dione-5-yl' wherein the nitrogen in the heart is optionally a quaternary nitrogen; Or &amp; and their individually linked nitrogen and carbon together form an unsubstituted or substituted heterocyclic ring other than tillage; or D) η is 2 'each R is independently 〇r5 ' Benzooxazine heptacyclic ring positions 7 and 8 'and R2 is (i) hydrogen; (ii) C(=0)C(=〇)〇R5; or (iii) -CpC^NR〗3 Heart 4' where Ri3 and heart 4 are each Η, or Combine to form 131494 200902026, which is converted to 03⁄4, NH, 〇, N_benzo[cut 嗣 _5_ base or nC(=o)oc(R5)3, wherein the nitrogen in ~ can be regarded as four Or the gas of the first hydrogen; or Unsubstituted or substituted heterocyclic ring; or F) each ~, R2, R3 and (4), W〇R5, Ο%, z, cn, chemistry, can 5) 2, 〇 〇 5 5) 2, _c ( =〇)〇R5 or snoring)(〇R5)2, n〇2, and at position 7 of the benzoxanthylene sulfonium ring; 2 each of the R5 systems is independently hydrogen, or unsubstituted or substituted An alkyl group, an alkylaryl group, an aryl group or a heterocyclic group. 7. The compound of claim 1 or 2 wherein the ruler is selected from the group consisting of z, 〇 cz3, R5, 〇R5 ^ CN . N 〇 2 . N(R5 ) 2 . _C(=〇)N(R5 ) 2 ^ _C(=〇)〇R5 ^ _p(=〇)Rg R9 The compound of the formula 7, such as Han, is at the benzooxazole position 7. 9. For example: the compound of claim 1 or 2 * where ~ is selected from the group consisting of (1), (8) 7〇)r6 ' and (iiiHCH2)mR10', or unsubstituted or substituted alkyl, aryl, An alkylaryl group, a heterocyclic group or a heteroaryl group; wherein &amp; is taken as l3Rl4, _C(=〇) dish &quot;Rl4 or -(C=0)0R5; and wherein R13 and R14 are combined with each other Starting to form an unsubstituted or substituted heterocyclic ring. • a compound of claim 9, wherein R2 is r5, _C(=0)(C=0)0R5 '-°)NR13R14 &gt; -CH2R10^-C(=〇)C(=〇)NR13R14 0 Π· A compound of the formula 1 or 2 wherein the compound is combined with the ruler 3 and the individually attached thereto 131494 200902026 The nitrogen together with the carbon forms an unsubstituted or substituted heterocyclic ring other than hexahydropyrrolidine. 12. A compound according to claim 1 or 2, wherein R3 together with R4 and the carbon atoms to which they are attached are taken together to form an unsubstituted or substituted cycloalkyl or heterocycle. 13. The compound of claim 1, wherein the compound is selected from the group consisting of ARM136, ARM137, ARM138, ARM139, ARM140, ARM146, ARM147, ARM148, ARM149, ARM150, ARM151, ARM152, ARM153, ARM156, ARM157, ARM159, ARM160, ARM161 , ARM166, ARM167, ARM182, ARM186, ARM189, ARM203, ARM217, ARM251, ARM252, ARM258, ARM277, ARM279, ARM282, ARM291, ARM293, ARM296, ARM301, ARM302, ARM306, ARM311, ARM312, ARM313, ARM318, ARM322, ARM324 , ARM326, ARM331, ARM335, ARM337, ARM351, ARM352, ARM353, ARM354, ARM397, ARM398, ARM399, ARM423, ARM454, ARM463, ARM466, ARM470, ARM473 and ARM477 〇14. A pharmaceutical composition comprising claim 1 The compound according to any one of 13 and at least one additive selected from the group consisting of analgesics, antioxidants, aromatic compounds, buffers, binders, colorants, disintegrators, diluents, emulsifiers, excipients, Extenders, taste modifiers, gelling agents, glidants, preservatives, skin penetration enhancers, solubilizers, stabilizers, suspending agents, sweeteners, penetrants, vehicles and viscosity increasing agents. 15. The pharmaceutical composition of claim 14 in the form of a capsule, granule, powder, solution, suspension or tablet, and designed for oral, sublingual, buccal, parenteral, intravenous Administration in the internal, transdermal, inhalation, intranasal, vaginal, intramuscular or rectal mode. 131494 200902026 16. A method for the manufacture of a pharmaceutical composition for use in the treatment or treatment of Ryanodine M (RyR) ^ ^ ^ ^ ^ ^ ^ ^ ^ § Functional action comprising combining a compound according to any one of claims 1 to 13 with at least one additive selected from the group consisting of analgesics, antioxidants, aromatics, buffers, viscers, disintegrants , diluents, emulsifiers, excipients, extenders 'taste improvers, gelling agents, glidants, preservatives, skin penetration enhancers, solubilizers, stabilizers, suspending agents, sweeteners, permeability Agent, vehicle and viscosity increase agent. 17. The method of claim 16 wherein the condition and disease are selected from the group consisting of heart, muscle, and disease and disease, malignant hyperthermia, diabetes, and sudden infant death syndrome. • The method of requesting the item 'where the heart condition and disease are selected from the group consisting of irregular heartbeat disorders and diseases; irregular heartbeat disorders and diseases caused by exercise; sudden heart disease deaths; sudden heart caused by exercise Death of the disease; septic heart failure; chronic obstructive pulmonary disease; and hypertension. 19. The method of claim 18, wherein the irregular heartbeat disorder and the irregular heartbeat disorder and disease caused by the disease and exercise are selected from the group consisting of atrial and cardiac to rhythm, atrial and ventricular fibrillation; atrial and Ventricular heartbeat is rapid, ^ room and heart to heart beat too fast; catechin is expected to be multi-type ventricular pulsation (CPTV); and its movement caused by the variant. The method of claim 17, wherein the muscle condition and the disease are selected from the group consisting of skeletal muscle fatigue, skeletal muscle fatigue caused by exercise, muscular dystrophy, bladder disorders, and incontinence. 131494 200902026 21. As requested in item 17 Gansin, /, where (4) the condition and disease are selected from the group consisting of Alzheimer's disease, t & + ^ 5 recalled form and age-dependent memory loss. 22. The use of a compound according to any one of claims 1 to 13 for the preparation of a pharmaceutical composition, a medicinal, and a &lt;&lt;&gt;&gt; system for treatment with Ryanodine Also associated with the disease (yR), the receptor regulates the function of the dance channel in the cell. The compound of any of the items 1 to 13 is treated with a Reynolds receptor ((sufficient). The use of the condition and the disease] regulates the calcium channel function in the cell. 22 or 23, wherein the condition and the disease are selected from the group consisting of heart muscle and &lt; knowledge of diseases and diseases, malignant hyperthermia, diabetes, and sudden infant death syndrome. 25. The use of claim 24, wherein the heart condition and the disease system Except for irregular heartbeat disorders and diseases; irregular heartbeat disorders and diseases caused by exercise; sudden heart attack deaths; sudden cardiac death caused by exercise; t blood heart failure; chronic obstructive pulmonary disease; High blood pressure. 26_ The use of claim 25, wherein the irregular heartbeat disorder and the irregular heartbeat disorder and disease caused by the disease and exercise are selected from the group consisting of atrial and cardiac to arrhythmia, atrial and ventricular fibrillation; Atrial and ventricular rapid heartbeat, atrial and ventricular tachycardia; catecholaminergic multimodal ventricular tachycardia (CPTV); and variants resulting from its movement. 27. As requested in claim 24 Pathway, wherein the muscle disorders and diseases are selected from the group consisting of skeletal muscle fatigue, central core disease, skeletal muscle fatigue caused by exercise, muscular dystrophy, bladder disorders, and incontinence. 131494 200902026 28. The use of claim 24, wherein the cognitive disorder And the disease is selected from the group consisting of Alzheimer's disease-memory loss form and age-dependent memory loss. 29. A method of synthesizing the compound of claim 2, wherein &amp; and % is η, which includes the following Steps: (a) A compound having the formula: Treated with the formula .-NH2 Rp compound, wherein \ represents a nitrogen protecting group to obtain a compound of the formula: (b) reacting the compound formed in the step (a) with a compound of the formula: (6) The compound formed in the step (b) is reacted with a compound of the formula: wherein each X-form is independently a sulfonate or a sulfonate to form a compound of the formula: 131494 200902026 X (d) reacting the compound formed in the step (c) with a base to form a compound of the formula: Ri / (e) treating the compound formed in the step (4) with a reducing agent to form a compound of the formula: Ri (7) removing the nitrogen protecting group RP ' to form a compound of the formula R3 30. A method of synthesizing a compound of claim 2, which comprises the step of: formulating a compound of the formula: Ri R3 (R)r N R2 R4 X OH should be reacted with a transition metal catalyst under conditions sufficient to form a compound of the formula: 131494 -11 · 200902026 31. The method of claim 30, further comprising (1) formulating a compound of the formula: Ri f compound of the formula: R3 Ά〇η R4 or (ii) compound of the formula ^WCHO (r)ocx compound of the formula: r3 R2' NH OH R4 is treated under reductive amination conditions; wherein the treatment of (i) or (ii) forms a compound of the formula: Ri R3 (R) nO^R2 R4 wherein x is independently a ruthenium of ii or a sulfonate. 32. The method of claim 30, wherein the transition metal catalyst is Cul. 33. A method of synthesizing a compound of claim 2, comprising the steps of: (a) formulating a compound of the formula: 131494 -12 - X 200902026 Nhr2 wherein X is a cleavage group Treatment from _ prime and performance conditions: acid salt, using alkali, in sufficient shape 34. The method of any one of claims 29 to 33, wherein the method of the compound of the formula: Wherein Han 2 is ruthenium, and the gasification enthalpy of the formula C1_c(=〇)〇Raa is reacted under conditions sufficient to form a compound of the formula: Wherein alkyl or aryl. 35. The method of clause 34, which further comprises reacting the compound formed in the claim with an acid or a base in a state sufficient to form a compound of the formula: ~ salt conditions 131494 • 13- 200902026 36. The method of claim 35, wherein the compound is represented by the following formula: The method of any one of claims 29 to 33, further comprising: formulating a compound of the formula: Wherein R 2 is hydrazine and reacts with any of the following: (i) triphosgene and a base to form a compound of the formula And further reacting the compound with one equivalent of the formula HNR7 aR7 b amine, or (ii) a compound of the formula Cl-CO-NR7 a R7 b, or (iii) a compound of the formula Cl3 CO(C=0)NR7 aR7 b Under the conditions of forming a compound of the formula 131494 • 14· 200902026 wherein NR7aR7b in (i), (ii) or (iii) is selected from the group consisting of NH2, NEt2 NHCH2Ph, ΝΗΟΗ, -Ο And the method of any one of claims 29 to 33, further comprising: formulating a compound of the formula In the case where R2 is hydrazine, and is reacted with formaldehyde (CH2?) and sodium cyanoborohydride (NaBCNH3) sufficient to form a compound of the formula: 39. The method of claim 35, which further comprises the compound of the formula: R)r R4 R, V/OH N r3' or its salt, with - outside gas; human 4, a sulfinium or chlorinated herbicide, treated under conditions sufficient to form a compound of the formula: Η' _^R3 40. If the method of r4 item 39 is requested, # &amp; , it further includes the following steps to make the following formula: 131494 -15- 200902026 And a compound of the formula HX wherein hydrazine is hydrazine CH3 or NHEt and is reacted under conditions sufficient to form a compound of the formula: The method of any one of claims 29 to 33, which further comprises the compound of the formula: Wherein &amp; is Η ' and a compound of the formula: 〇Ra wherein hydrazine is a halogen or a sulfonate, and the heart is a tetraalkyl group, which is reacted under conditions sufficient to form a compound of the formula: 〇 r4 (R), 42. The method of claim 41, further comprising reacting a compound of the formula: with an acid or a base to form a compound of the formula: 131494 -16- 200902026 131494 -17