TW201036969A - CGRP receptor antagonists - Google Patents

Abstract

The disclosure generally relates to the novel compounds of formula I, including their salts, which are CGRP receptor antagonists. The disclosure also relates to pharmaceutical compositions and methods for using the compounds in the treatment of CGRP related disorders including migraine and other headaches, neurogenic vasodilation, neurogenic inflammation, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases such as asthma, and chronic obstructive pulmonary disease (COPD).

Description

201036969 VI. INSTRUCTIONS OF THE INVENTION: FIELD OF THE INVENTION The present disclosure relates generally to novel compounds of formula I, including pharmaceutically acceptable salts, which are CGRP-receptor antagonists. The present disclosure also relates to pharmaceutical compositions, and methods of using the compounds in the treatment of CGRP-related disorders, including migraine, neurovascular dilatation, neuroinflammation, thermal injury, circulatory shock, and flushing associated with menstrual periods. , airway inflammatory diseases, such as asthma, and chronic obstructive pulmonary disease (COPD). This application claims the benefit of U.S. Provisional Application Serial No. 61/044,198, filed on Apr. 11, 2008. [Prior Art] The calcitonin gene-related peptide (CGRP) is a naturally occurring 37-amino acid peptide which was originally confirmed in 1982 (Amara, SG et al., Science 1982, 298, 240-244). . The two forms of the peptide (oCGRP and ySCGRP) are individually expressed in rats and humans with a difference of one and three amino acids. This peptide is widely distributed in both the peripheral (PNS) and central nervous system (CNS), which are primarily localized in sensory afferents and central neurons, and exhibit a variety of biological effects, including vasodilation. When released from the cell, CGRP binds to specific cell surface G protein-coupled receptors and exerts its biological effects primarily by activation of intracellular adenylate cyclase (Poyner, DR et al., Br J Pharmacol 1992, 105, 441-7; Van Valen, F. et al., Neurosci Lett 1990, 119, 195-8). Two classes of CGRP receptors, CGRP1 and CGRP2, have been proposed based on the antagonistic nature of the peptide fragment CGRP (8-37) and the ability of linear analogs of CGRP to activate CGRP2 139424 201036969 receptors (Juaneda, C. Et al., TiPS 2000, 21, 432-438). However, there is a lack of molecular evidence for the CGRP2 receptor (Brain, S. D. et al., TiPS 2002, 23, 51-53). The CGRP1 receptor has three components: (i) 7 transmembrane-like calcitonin receptor receptor (CRLR); (9) single transmembrane receptor activity alters protein type one (RAMP1); and (iii) intracellular receptor Component Protein (RCP) (Evans, BN ' et al, J Biol Chem. 2000, 275, 31438-43). RAMP 1 is required for CRLR delivery to the 'serosin membrane and ligand binding to CGRP-receptors (McLatchie, L. Μ. et al,

Nature 19 fierce, 393, 333_339). RCP is required for message transduction (Evans Β. Ν. 〇 et al., J Biol Chem. 2000, 275, 31438-43). There are known species-specific differences in the binding of small molecule antagonists to CGRP-receptors, where antagonism for human receptors is seen with greater affinity for other species (Brain, SD et al., TiPS 2002). , 23, 51-53). The amino acid sequence of RAMP1 determines species selectivity. Specifically, the amino acid residue Trp74 is responsible for the phenotype of human receptors (Mallee et al, J Biol Chem 2002, 277, 14294-8). The inhibitor at the receptor level of CGRP is assumed to be useful in the pathophysiological symptoms of Q in which excessive CGRP receptor activation has occurred. Some of these include neurovascular dilatation, neurological inflammation, migraine, cluster headaches and other headaches, thermal damage, circulatory shock, menstrual flushing, and asthma. Activation of CGRP receptors has been implicated in the pathogenesis of migraine • (Edvinsson L. CNS Drugs 2001; 15(10): 745-53; Williamson, D. J. Microsc.

Res. Tech. 2001, 53, 167-178. ; Grant, A. D. Brit. J. Pharmacol. 2002, 135, 356-362). Serum levels of CGRP are elevated during migraine (Goadsby PJ et al, Ann Neurol 1990; 28: 183-7), and anti-migraine medications return CGRP levels to normal, consistent with headache reduction (Gallai V. et al. 139424 201036969, Cephalalgia 1995; 15: 384-90). Migraines showed an increased baseline CGRP content compared to the control group (Ashina et al., Pain 2000, 86(1-2): 133-8. 2000). Intravenous CGRP perfusion produces persistent headaches in migraine (Lassen LH et al, Cephalalgia 2002 February; 22(1): 54-61). Preclinical studies in dogs and rats have reported that systemic CGRP repression with the peptide antagonist CGRP (8-37) does not alter resting system hemodynamics and does not alter regional blood flow (Shen, YT· Et al, J Pharmacol Exp Ther 2001, 298, 551-8). Thus, CGRP-receptor antagonists may present novel treatments for migraine that would avoid the triptan with non-selective 5-HT1B/1D promoters (eg, sumatriptan) There is a cardiovascular burden associated with active vasoconstriction. CGRP antagonists have demonstrated efficacy in human clinical trials. See Davis CD, Xu C. Curr Top Med Chem. 2008 8(16)· 1468-79^ Benemei S, Nicoletti P, Capone JG, Geppetti P. Curr Opin Pharmacol. 2009 9(1) · 9-14. Epub 2009 January 20th; Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, Leibensperger H, Froman S, Assaid C, Lines C, Koppen H, Winner PK. Lancei. 2008 372 : 2115. Epub November 25, 2008; Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, Lines CR, Rapoport AM ; Neurology 2008 70 : 1304. Epub October 3, 2007. The present invention provides technical advantages such as the novelty of the compound and the inhibition of CGRP. In addition, the compounds provide advantages with respect to medical use, e.g., with respect to one or more of its mechanisms of action, binding, inhibitory efficacy, target selectivity, solubility, safe action morphology, or bioavailability.

CGRP receptor antagonists are disclosed in PCT Publication Nos. WO 2004/092166, WO 139424 201036969 2004/092168, and WO 2007/120590. SUMMARY OF THE INVENTION The present invention encompasses a range of CGRP antagonist compounds, including pharmaceutically acceptable salt' compositions, methods of making the same, and methods of using them in therapeutic treatment. One aspect of the invention is a compound of formula I

R1 I wherein: R1 is hydrogen, cyano, _yl, alkyl, _alkyl, alkoxy, haloalkoxy, alkyl S〇2, amine, alkylamino, dialkylamine, mononitrogen Tetradecyl, tetrahydropyrrolyl, hexahydropyridyl, hexahydropyrrole, N-alkylhexahydropyrazine or morpholinyl; Qr2 is hexahydropyridyl' substituted by one substituent, The substituent is selected from the group consisting of:

139424 201036969

R3 is oxime, i group, cyano group, alkyl group, alkyl group, alkoxy group or haloalkoxy group; is a halogen, a halogen group, a cyano group, a decyl group, a halogen group, an alkoxy group or a dentate oxy group. Ari is phenyl, substituted by 〇3 substituents, and the substituents are selected from the group consisting of cyano, dentate, alkyl, calcinyl, alkoxy and alkoxy. X is hydrazine, CH2 or NH; and Y is a bond, hydrazine, CH2 or NH; or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a compound of formula I, wherein R1 is hydrogen, cyano'amine, alkylamino or dialkylamino; R2 is hexahydropyridyl is substituted with 1 substituent, and the substituent is selected from the group consisting of Group of groups:

R3 is hydrogen or a halogen group; R4 is hydrogen or a halogen group;

Ar1 is phenyl, 〇_2 halo substituent; X is hydrazine, CH2 or NH; and Y is hydrazine; or a pharmaceutically acceptable salt thereof. 139424 201036969

The present invention is a compound of the formula wherein R1 is chlorine, an aryl group, an amine methylamino group or a second butylamino group; and r2 is a hexahydropyridyl group, which is selected from a substituent. A group consisting of: k/-°Y° fVNH and . benzophenone or monofluorophenyl; hydrazine is hydrazine, CH 2 or NH; and γ is hydrazine; a pharmaceutically acceptable salt thereof. -

Another aspect of the invention is a compound of formula I, and a further aspect of the invention is a compound of formula I, which is a base and is 4-substituted. Another aspect of the invention is a compound of formula I, which is substituted by a substituent selected from the group consisting of: wherein R1 is hydrogen or cyano. Wherein R 2 is Ν-hexahydropyrrol. Where R2 is Ν-hexahydro ρ than π

versus

" Aspects are compounds of formula I wherein Ari is a stupid group substituted with two halo substituents. 00 ^ a y, ^ Surface is a compound of formula 1, wherein Ar1 is 2,3-difluorophenyl. Another aspect of the invention is a compound of formula I, wherein X is 0. The other ancient surface is a compound of the formula having the following stereochemistry.

R1 139424 201036969 Another aspect of the invention is a compound of formula II

〇 Π wherein: R 2 is a hexahydropyridyl group and is substituted by one substituent selected from the group consisting of:

R3 is hydrogen or an alkyl group; R4 is hydrogen, a halogen group, a cyano group, a halogen group, an alkoxy group or an alkoxy group; Ar1 is a phenyl group substituted by a hydrazine-3 substituent, and the substituent is selected. From cyano, diodor, alkyl, ii alkyl, alkoxy and ii alkoxy; X is hydrazine, CH2 or NR3; Y is a bond, a fluorenylene, hydrazine or NR3; or it is pharmaceutically acceptable Salt. Variables, including ruler 1, ruler 2, 113, ruler 4, eight 1:1, and any range of conditions, 139424 -10- 201036969 can be used independently with any other range of variable substituents. Accordingly, the invention includes combinations of different aspects. These terms have the following meanings unless otherwise specified. "Alkyl," a straight or branched alkylalkenyl group consisting of from 1 to 6 carbons, preferably from 丨 to 3 carbons, meaning consisting of 2 to 6 carbons, having at least A double bond or a branched base. The "ring-burning system" means a group of 3 to 7 carbons, an early ring system. "School-based", "alkoxy", and Other terms having a substituted thiol moiety, including a straight chain and a branched isomer consisting of 1 to 6 carbon atoms. "Halogen & And, alkoxy groups include all dentate isomers, from monohalo substituted alkyl groups to fully dentate substituted alkyl groups. The aryl group includes both carbocyclic and heterocyclic aromatic ring systems. The amine group _" includes the primary, secondary and tertiary amine moiety." Carbonyl, which means C0 ^ "milk-based 'meaning means -〇-.,,aminocarbonyl'' means -N(R)C(=〇)-,,oxycarbonyl" means -oc(=o)-. "Methylenecarbonyl" means _CH2C(=〇)_.,, amine group (Cyano)imidomethyl" means _NHC(=NCN)_. brackets and multi-array slang It is intended to clarify the binding relationship for those skilled in the art. For example, the term ((R)alkyl) means an alkyl substituent further substituted with a substituent R. 'The invention includes all pharmaceutically acceptable compounds of the compound Salt form of peony. An acceptable salt is one in which the counterion does not significantly contribute to the physiological activity or toxicity of the compound, and is itself a pharmacological equivalent: these salts can be based on general organic techniques Made from commercially available reagents. Some anionic salt forms include acetate, aspirate (acistrat^, besylate, desert, vapor, citrate, antibutmentate, Portuguese: tartrate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, 139424 201036969 maleate, decane sulfonate, nitrate, barium pamoate, Filled with acid salts, succinates, sulfates, tartrates, sulfonium sulfonates and oxacinol. Some cationic salt forms include ammonium, aluminum, comet fine, strontium, calcium, choline, Ethylamine, diethanolamine, lithium, magnesium, glucosamine, 4 benzene Cyclohexylamine, hexahydropyridinium, potassium, sodium, butylamine, and zinc. Some of the compounds of the present invention may exist in stereoisomeric forms, an example of which is shown below. The present invention includes such compounds. All stereoisomers and tautomeric forms.

Such compounds can be made by methods known in the art, including the following, f' and variations included within the technical scope of the art. Some 4 agents and intermediates are known in the art. Other reagents and intermediates can be prepared by methods known in the art using readily available materials. The following methods are for illustrative purposes and are not intended to limit the scope of the invention.暗 Dark this artist should be aware that there are many methods available for the synthesis of such compounds, and the synthesis thereof is not limited to the methods provided in the examples below. It is not within the technical scope of this technology that the variants of the program and the manufacture of such programs are not included. In the Synthetic®-style towel, describe the variables of the general structural formula and characteristics. Γ The requirements or the variables in the rest of this patent specification, and... These variables are only meant to illustrate how to make this compound. ~ 2 1 匕 139424 -12- 201036969 The abbreviations used in Figure = are generally used in accordance with the techniques in this technique. The chemical abbreviations used in the present specification and examples are defined as follows: ,, by deleting, is a sodium bis(trimethylsulfonyl)amine;, DMF, is N'N-methylmethylamine; Me〇H,, is methanol; “Peng” is (4) base breaking 醯 m m aryl; “TFA” is trifluoroacetic acid; "pass is hydrogen hydride; B〇C DMSO is dimethyl sulfoxide; h" is the hour; ",, is room temperature or residence time (the text will be referred to); W is the minute; "Et〇Ac, is the acetic acid EHF "tetrahydrofuran" is the ethylenediamine four Acetic acid; "Et2〇" is B_; DMAP is 4-methylaminopyridine; "DCE" is u-dichloroethane; "A, is B, DME is 1,2-dimethoxy Ethane; "H〇Bt, is i-based benzotriazole hydrate, "DIEA" is triisopropylethylamine, "Nf, is "Dinna, is formic acid trimethyl vinegar." The scheme exemplifies a process which can be used to prepare a compound of formula j. The synthesis described in Scheme I begins with compound m, which is a known compound D m from a commercially available material in a single step. And Fang Fund The reaction of a reagent such as ArLi or ArMgX can produce IV which can form V under ring closed metathesis (RCM). The tertiary alcohol v can be dehydroxylated to an olefin VI which can be obtained under standard dihydroxylation conditions. Νπ. The mono-protection of the diol affords VIII, which can be oxidized to obtain a protected hydroxyketone oxime. A conventional reaction to modify an alcohol, ketone or alpha carbon can result in other formulae! Modification to produce a plurality of fused heterocyclyl-cycloheptane derivatives as X. Removal protection affords its corresponding alcohol X!, which can be activated and reacted with different amines to give compounds of formula II, x = 〇. χι can also be oxidized to ketone XIII, followed by carbon extension (Wittig), reduction, and hydrolysis to acid 139424 -13- 201036969 XIV, which can result in the formation of octagonal sigma by guanamine formation. It is such that x = c. The alcohol can be converted to an amine followed by urea to form a compound of formula (IV) wherein X = NH. Figure 2 provides an alternative procedure for the manufacture of a compound of formula J. Grubbs cyclization, followed by conversion to _, which can then introduce aryl moiety Further fine work can result in alcohol, which can then be converted by methods known in the art.

139424 .14-201036969 Scheme 2 depicts some methods for the use of Grubbs cyclization to produce a pyridine ring structure in which a cycloheptane ring is fused. Further elaborate production of the compound of formula I is carried out. Figure 2.

Mitsunobu Scheme 3 describes an alternative method for the use of Grubbs cyclization to produce a cyclohexane ring fused pyridine ring structure. Further elaborate production of the compound of formula I is carried out. 139424 -15- 201036969 Figure 3.

PhNTf2, LDA

Scheme 2 depicts an alternative method for the formation of a cyclohexane ring fused pyrido ring structure followed by selective reduction of the diketo intermediate. Further elaborate production of the compound of formula I is carried out. I39424 16- 201036969 ο

,co2h, schema 4·

0 selective enzyme reduction 0

Or 0

, C02H Ο

1. DIAD (1.5 equivalents) Ph3P{1.5 equivalents) Acid (1.5 equivalents > THF (0.36M), 0-rt. 15h 2. UOH (3t*) " Water, 2h Ο

TIPSOTf (1·0 eq.) Et3N (2.0 eq.) CH2CI2 (0.36M) f0°C, 1h Ο

Ο 78213-022

UBH4 or super hydride 1) NaBH4, 30 minutes F 2) MsCI/Et3NT 3h 3> LAH, 20 minutes

TBAF

TIPSO TIPSO TIPSO 〇 Figure 5 depicts a method for producing a compound of formula I with a carbon chain fused to a pyridine cycloheptane core. 17- 139424 201036969 Figure 5.

Scheme 6 depicts some methods for producing additional substituents on a fused pyridocycloheptane core. Further elaborate production of the compound of formula I is carried out. 139424 -18- 201036969 Figure 6.

Ο

Η2ν 04 ΗΝ )~Ν Ν

SEM

CI 三光气 ο -Ν人 N-SEM Ν Ο

F 1) TFA 2 > palmar HPLC Ν Ο hn hn^.^Vn^nh 0 ' , Ν

Hf7.__ /~\ , ΑνΜ VN^/ V/N

- SEM meaning Q, -〇,

HN > - Ν NH

Cl

Cbz_N again

Ο -Ν' 'NH -- Cbz-N >-n person rrSEM

NaH

HCI HCI ^ N

SEMCI

Pd/C

O HN h-N^N^SEM ❹ Figure 7 depicts some methods for the production of other aryl substituents on a fused pyridocycloheptane core. Further elaborate production of the compound of formula I is carried out. 19- 139424 201036969

TIPSO OTf Figure 7. Suzuki

Separated trans and cis isomers

Scheme 8 depicts some methods for producing other nitrogen-bonded substituents on a fused p-bite-and-loop-glow-burning core. Further, the production of the compound I is carried out in a delicate manner. 139424 -20- 201036969

Figure 8.

Scheme 9 depicts some methods for producing an N-oxide analog of p-precipitated cycloheptane. Further elaborate production of the compound of formula I is carried out. 139424 -21 - 201036969 Figure 9.

In vitro pharmacological biological methods. Group. Scale culture. Make SK-N-MC cells contain Earle's salt at 37 ° C in 5% CO 2 supplemented with 10% fetal bovine serum (Invitrogen). The medium of MEM of L-face decylamine (Invitrogen) was grown in a single layer. , Zhiying廯裘#/. The crude cell membrane system was made from SK-N-MC cells expressing CGRP receptors. The cells were washed twice with phosphate buffered saline (155 mM NaC1, 3·3 mM 丨.1 Fu 4 2? 4, pH 7.4) and at 4 ° C '-22- 139424 201036969 in H) mM Tris (PH 74) Incubate for 5-10 minutes with 5 _Cai Bazhi low sensitizing lysis buffer. The cells were transferred from the plates to a polypropylene tube (ΐ6χΐ〇〇) and homogenized using Ρ〇1_η. Let the hooks be centrifuged for 32 minutes under 32 grams. The pellet was resuspended in cold hypotonic lysis buffer with 0.1% mammalian protease inhibitor solution (Sigma) and tested for protein concentration. The SK-N-MC homogenate was divided into several portions and stored under _8 。. , 翕 翕 coordination, combined with Detective. Using 100% DMSO, the compound of the present invention 四 (d) solution and serial dilution. The aliquot from the compound (4) dilution was further diluted 25-fold into the assay buffer (5 〇 should TrisC1 pH 7.5, 5 ng MgCh, 0_005% Triton X-100) and transferred (volume 5 〇 microliters) to 96 Well detection board. 2 51]-CGRP (GE Healthcare or Perkin_Elmer) was diluted to 72 PM ' in assay buffer and 50 μl volume was added to each well. The SK_N_Mc cell membrane was thawed, diluted in assay buffer with a new 01% mammalian protease inhibitor solution (Sigma), and rehomogenized. SK N MC homogenate (7 μg/well) was added in a 1 liter microliter volume. Then, the test plate was incubated at room temperature for 2 hours. The assay was stopped by the addition of excess cold wash buffer (50 mM Tris-Cl pH 7.5, 0.1% BSA) and immediately filtered on a glass fiber filter (Whatman GF/B) previously immersed in 〇 5% pEi . The non-specific binding system is defined by 丨_ /3-CGRP (Bachem). The radioactivity of protein binding is determined using a scintillation counter. The resulting data was analyzed using a four parameter competitive binding procedure (XLfit ν2.0) and the Han: system was defined as the concentration of the compound of the invention required to replace 5 〇 % of the radioligand binding. The final detection concentration of [125I]-CGRP was 18 pM. The average of [ΐ25Ικχ}κρ seems to be 却. All compounds of the invention were evaluated in at least two separate experiments. See Table 1 for an excerpt from the 139424 • 23· 201036969 data. Table 1. Human _ CGRP combination..... Example - Human CGRP ^_^IC5〇(nM) 1 ---- s 2.86 2 — 〜°·23 3 1 25 ---- 4 0.44 5 4.04 6 0.89 7 >100 8 1.60 9 >1000 10 1 8.89 11 4.14 12 7.41 13 1.55 14 0.25 15 0.98 16 6.96 17 0.80 18 0.78 19 0.76 20 0.12 21 0.12 Yuhe / Scaic / wri / min #. in human CGRP peptide The nature of the interaction with Example 2 is studied in detail using a saturation binding experiment. The binding of increasing concentrations of C1251]-CGRP to SK-N-MC cell membranes was measured at 3 〇〇 pM and 600 pM Example 20 absent (control conditions) and presence. The saturated data was analyzed using a 139424 -24- 201036969 one position combined equation to estimate the apparent equilibrium dissociation constant (iq) and the highest number of binding positions (Bmax) (Prizm v4.0, Graphpad). Addition Example 2〇 The impact of the binding parameter (3⁄4, Bm a x) of the f12 51]-CGRP combination was measured and compared. Example 20 dose-dependently increased the Kd of [i25l]-CGRP binding without significantly altering the highest binding position (B) of [125I]-CGRP binding. This is an indicator that I;12 51]-CGRP binds to the competitive mechanism inhibited by Example 20. Example 20 was evaluated in 3 separate experiments (for a representative data set, see Figure 1. t125I] - CGRP saturation / Scatchard analysis). Functional antagonism/Schild analysis · CGRY-free sputum-stimulated silver gas motility stimulation leads to guanidine via Gs-dependent activation of adenylate cyclase> (adenosine 3'5'-cyclic monophosphate) Production (Juaneda C et al., TiPS, 2000; 21: 432-438). Thus, CGRP receptor antagonists inhibit CGRP-induced cyclic AMP formation in SK-N-MC cells that naturally exhibit CGRP receptor complexes (Doods et al, Br J Pharmacol, 2000; 129(3) : 420-423). Example 20 was evaluated for its ability to block the formation of cAMP caused by CGRP using the commercially available cAMP HTRF kit (catalog number 62AM2PEC, CisBio International). The Schild analysis format is used, which allows the study of mechanisms of antagonism. In this format, the dose response of CGRP-stimulated cAMP production was produced as CGRP alone and in the presence of Example 20 at various concentrations. Briefly, Example 2 was pre-incubated with SK-N-MC cells for 15 minutes. Different concentrations of CGRP were added and the cells were incubated for 30 minutes at room temperature. The cells were solubilized with a lysis reagent and the cAMP concentration was determined by HTRF according to the manufacturer's instructions. A standard curve using a known amount of cAMP was evaluated in a parallel manner to allow the HTRF ratio to be converted to nM cAMP. Then, the resulting curve is used individually by Gaddum/ 139424 -25- 201036969

The Schild equation 'and evaluated as a general fit (Prizm v4.0 ' Graphpad). Example 20 will cause a shift on the right side of the CGRP EC50 without changing the maximum response. To achieve an overall fit, the following parameters (top, bottom, l〇gEC50, Hill slope, and PA2) were shared and all curves were matched at the same time. Regarding the overall agreement between the two separate experiments using the unconstrained Schild slope, the slope returned to the schiid slope value of 1.17 and 0.8, which is consistent with the expected schiid slope of the simple competitive antagonist (for the method of operation, see Moltulsky et al. People, 2003, Graphpad Software Inc.). The average Kb (using the Schild slope of 1) for the two example 20 data sets is 247 ± 40 pM (for a representative overall anastomosed data set for the example 20 plotted with a Schild slope of 1), see Figure 2. Functional antagonism /Schild analysis). A non-Zhu Duan method for assessing the in vivo function of small molecule CGRP-receptor antagonists in mammals. Blocking the cascade of events caused by the blood-reducing peptides related to the olfactory gene (CGRP), Neurovascular vasodilation, including intracranial arteries, has been proposed as a treatment for migraine (Edvinsson et al., CNS Drugs 2001 15: 745; Benemei et al., Curr Opin Pharmacol 2009 9: 9), however, novel small molecule CGRP - Receptor antagonists have demonstrated species-specific differences in rodents with relatively poor activity (Mallee et al, J Biol Chem 2002 277: 14294), requiring novel patterns for assessing efficacy in vivo. Non-human primates (eg, ticks) are the only animals known to have pharmacological kinetics of human CGRP receptors conferred by the presence of a specific amino acid residue (Trp74) in which they are responsible for human acceptance. The phenotype of the RAMP1 sequence (Mallee et al, J Biol Chem 2002 277: 14294). Since the current migraine pattern is mainly used in the 139424 -26* 201036969 mouse (Escott et al, Brain Res 1995 669: 93; Williamson et al, Cephalalgia 1997 17 : 525), or an invasive end procedure in primates (Doods et al., Br J Pharmacol 2000 129: 420) developed a novel non-invasive survival pattern in non-human primates for in vivo efficacy evaluation of CGRP-receptor antagonists. Although it is known that trigeminal activation increases both Guadsby and Edvinsson (1993) and facial blood flow (Doods et al., 2000), facial blood flow and intracranial artery dilation are performed in the same animal. The evidence of the direct relationship between the two is not known. Therefore, prior to the initiation of studies in non-human primates, the laser Doppler metric of facial blood flow was directly confirmed in rats as a substitute for endovascular dilatation in the end study. Both the intracranial artery diameter and the change in facial blood flow were measured in the same animal (see Figure 3. Direct and effective confirmation of facial blood flow in rats as a substitute for intracranial artery dilatation). In both measures, comparable increases were induced by intravenous CGRP and blocked by the peptide antagonist hoCGRP (8-37). Next, the method of changing CGRP- in the vein in the blood flow of the face was a recovery mode of haCGRP (8-37) in a rat which was effectively confirmed to be anisoflurane anesthesia. This rodent survival method was then established in non-human primates and a dose-response study characterized by intravenous CGRP activity was completed (see Figure 4. Non-human primate laser Doppler facial blood flow) Response to the dose of h α CGRP). Peptides and small molecule CGRP-receptor antagonists are used to confirm non-human primate patterns. Pretreatment with small molecule antagonists or haCGRP (8-37) dose-dependently inhibits venous CGRP-stimulation on vertebrate facial blood flow (see Table 2. Non-human primates) (Example, 139424 -27- 201036969, as in general 狨), the increase in cGRp caused by the blood flow of the Doppler's face in the laser). Post-antagonist treatment also reverses the increase in CGRP-in the facial blood flow (not shown). This survival model provides a novel approach to assessing the preventive and frustrating effects of CGRp receptor antagonists in non-human primates with similar CGRP receptor pharmacology or transgenic animals with humanized RAMP1 (Trp74). A non-invasive recovery procedure, as a surrogate marker for activity, is expressed as the diameter of the intracranial artery. Suffering #. Adult males and females are generally paralyzed (Camthrix batch ice is purchased from Harlan and weighs 350-550 grams, which is used as a patient. Hertz hand spans the animals in the induction chamber by isoflurane inhalation Being anesthetized (4-5% rapid induction 'maintained at 1-25%; 5〇1 〇, etc.), kept in a private way by delivering air through a mask: oxygen (50:50) and ifuflue Constant supply, or by intubation and ventilation (using liquid gas monitoring). Body temperature is maintained under sinking by placement on an automated temperature control surface with rectal probes. Small area fur (about 1.5) Square centimeters) is removed from one or both of the faces by applying a depilatory cream and or shaving. Clamp the hand county, prepared as betadine. Place the intravenous line in Anyone can enter a vein (such as the saphenous vein) for administration of the test compound and CGRp_receptor priming agent, and if necessary, take a blood sample (maximum 2.5 liters) for blood gas monitoring and Content analysis. At the end of the study, 'intravenous administration of 5% dextrose solution to maintain blood sugar content The depth of anesthesia is monitored by using a non-invasive armband method and a pulse finder to measure blood pressure and hop rate. Intravenous administration of guanethidine 5-1 mg/kg and intravenous supplementation of 5 mg / kg, on demand, 139424 -28- 201036969 to be set, in order to stabilize the peak flux in the facial flow, see the changes caused by repeated stimulation of blood flow (Escott et al., 1999). Blood flow is monitored by attaching a self-adhesive laser Doppler flow probe to the skin of the face. 允合匆犮#• The test compound can be intravenous (〇〇15 ml/kg), intramuscular (0· 01-0.5 ml/kg), subcutaneous (0.01-5 ml/kg) or orally. (〇.MO ml/kg) is administered (Diehl et al., 2001). CGRP_receptor stimulant can be intravenously administered intravenously (0.01_5 ml / kg), intradermal (10-100 μl / position) or subcutaneous (10-100 μl / position) transmission. 'Additional ^ ^ 0 ° ^ 〇;. on the face blood flow The increase in the control group is caused by the administration of a vasodilator, such as CGRP (0.05-100 μg/kg intravenous) or 2 -20 picomol/position inside the skin). The test compound or vehicle is administered prior to (before or after) (after treatment) administration of the vasodilator, providing the ability to assess prophylactic or therapeutic effects. The blood pressure system is continuously measured to ensure the appropriate depth of anesthesia, and the anesthetic is adjusted to maintain the stability of the value of the value of ° ° during the data collection of the laser Doppler flowmeter method, is〇flUrane It was reduced to 〇25_〇75% because previous electrophysiological studies in 狨. have been found to be sensitive to isoflurane concentrations (S〇1〇mon, 1999). To reduce the number of animals used, the effect of the test compound on the changes caused by intravenous vasodilators on blood flow can be repeated up to 6 times in a single period. The skin is returned to the delivery cage, which is placed on a temperature control surface to keep the animal warm until it is fully awake and able to act. Animals can be tested again after 7-14 days of rest, and the 139424 -29- 201036969 test can be repeated at 714-day intervals, depending on the health of the animal. See Diehl KH, Hull R, Morton D, Pfister R, Rabemampianina, Y, Smith D, Vidal JM, van de Vorstenbosch C. Good practice guidelines for material handling and jk fluid removal including pathways and volumes. J Appl Toxicol. 2001 January-February; 21(1): 15-23; Doods H, Hallermayer Q Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W. BIBN4096BS, the first selective small molecule CGRP-receptor antagonist Pharmacological action morphology. Br J Pharmacol. February 2000; 129(3): 420-3; Edvinsson L. Calcitonin gene-related peptide (CGRP) and pathophysiology of headache: therapeutic relevance. CNS drug 2001; 15(10): 745-53; Escott KJ, Beattie DT, Connor HE, Brain SD. Trigeminal ganglion stimulation increases facial skin blood flow in rats: the main role of calcitonin gene-related peptides. Brain Res. January 9, 1995; 669(1): 93-9; Goadsby PJ, Edvinsson L. Trigeminal Nerve Management System and Migraine: A study of changes in cerebrovascular and neuropeptides seen in humans and cats. Ann Neurol January 1993; 33(1): 48-56; Lassen LH, Haderslev PA, Ja Cobsen VB, Iversen HK, Sperling B, Olsen J· CGRP can play a causative role in migraine · Cephalalgia, 2002, 22, 54-61; Mallee JJ, Salvatore CA, LeBourdelles B, Oliver KR, Longmore J, Koblan KS, Kane SA. RAMP1 determines the species selectivity of non-peptide CGRP receptor antagonists. J Biol Chem. February 14, 2002 [epub before printing]; Solomon SQ White AJ, Martin PR. in New World Monkey 狨 Callithrix jacchus Temporary contrast sensitivity in the lateral geniculate nucleus, J Physiol. June 15, 1999; 517 (Pt 3): 907-17. 139424 -30- 201036969 Table 2. Inhibition of CGRP-induced increase in blood flow at the Doppler's facial surface in non-human primates (eg, general sputum) inhibits % inhibition in human primates, After a single transfer of the compound (at _3 〇 to 〇 minutes), repeat the transfer of haCGRp (1 μg/kg 'intravenous) at each time point (15-105 minutes).

Ο Ο <0·05 ‘medical compositions and methods of treatment The compounds of formula I inhibit the CGRP receptor. Thus, it can be used to treat a condition or disorder in which the CGRP content is associated with, or where the modulation of CGRp content may have therapeutic benefit. Accordingly, another aspect of the invention is a pharmaceutical composition comprising a compound of the formula' accompanied by a pharmaceutically acceptable adjuvant, carrier or diluent. The compound is generally administered as a pharmaceutical composition. The composition comprises a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, and may contain conventional excipients. # By the practitioner in the art: When deciding, the therapeutically effective amount is the amount needed to provide a meaningful patient benefit. A pharmaceutically acceptable carrier is a conventionally known carrier having an acceptable safe action. The compositions cover all common solid and liquid forms' including capsules, tablets, gums and powders, as well as liquid suspensions, sugars, brews and solutions. The solid composition can be formed on a timely or sustained release formulation of 139424 • 31· 201036969. The compositions are prepared using conventional formulation techniques with conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols). The solid compositions are usually formulated in dosage units and provide from about 1 to about 1000 mg of active ingredient per dose. Some examples of solid dosage units are 0.1 mg, 1 mg, 10 mg, 1 mg, 500 mg, and 1000 mg. The liquid composition will generally be in the unit dosage range of 1-100 mg/ml. Some examples of liquid dosage units are 0.1 mg/ml, 1 mg/ml, 10 mg/ml, 25 mg/ml, 50 mg/ml, and 100 mg/ml. The present invention encompasses all conventional modes of administration, including oral, parenteral, intranasal, sublingual, and transdermal methods. Typically, the dose is 0.01-100 mg/kg body weight per ounce. In general, more compounds are required in the oral mode and less in the parenteral mode. However, the specific medication use method should be determined by the physician using safe and reliable medical judgment. The inhibitor at the receptor level of CGRP is assumed to be useful in pathophysiological symptoms in which excessive CGRP receptor activation has occurred. Some of these include neurovascular dilatation, neurological inflammation, migraine, cluster headaches and other headaches, thermal damage, circulatory shock, menstrual flushing, and asthma. Activation of CGRP receptors has been implicated in the pathogenesis of migraine (Edvinsson L. CNS Drug 2001; 15(10): 745-53; \\^1 he 1118〇11,0.].]^〇:〇8. Res. Tech. 2001, 53, 167-178. ; Grant, AD Brit. J. Pharmacol. 2002, 135, 356-362). Serum levels of CGRP are elevated during migraine (Goadsby PJ et al, Ann Neurol 1990; 28: 183-7), and anti-migraine medications return CGRP levels to normal, consistent with headache reduction (Gallai V. et al., Cephalalgia 1995; 15: 384-90). Migraines showed an improved basis 139424 -32- 201036969 Bottom CGRP content compared with the control group (Ashina et al, Pain 2000, 86 (1-2): 133-8). Intravenous CGRP perfusion produces persistent headaches in migraine (Lassen LH et al, Cephalalgia 2002; 22(1): 54-61). Preclinical studies in dogs and rats have reported that systemic CGRP repression with the peptide antagonist CGRP (8-37) does not alter resting system hemodynamics and does not alter regional blood flow (Shen, YT. Et al, J Pharmacol Exp Ther 2001, 298, 551-8). Thus, CGRP-receptor antagonists may present novel treatments for migraine that would avoid association with the non-selective 5-HT1BAD promoter "triptan" (eg, sumatriptan) Cardiovascular Burden of Active Vascular Contraction. Another aspect of the invention is a method of inhibiting a CGRP receptor comprising contacting a CGRP receptor with a compound of Formula I or a pharmaceutically acceptable salt thereof. A method of treating a condition associated with a vaginal content of CGRP comprising administering to a patient a therapeutically effective amount of a compound of formula I. Another aspect of the invention is the use of a compound of formula I in the manufacture of a medicament, the medicament It is used to treat symptoms associated with the vaginal content of CGRP. Another aspect of the invention is a method of treating migraine or headache. Another aspect of the invention relates to a treatment for inflammation (especially neurological inflammation), pain , thermal injury, circulatory shock, diabetes, Reynaud's syndrome, peripheral arterial insufficiency, subarachnoid/cephalic hemorrhage, tumor growth, flushing and other symptoms associated with menstrual period A method of treating the same by antagonism of a CGRP receptor by administering a pharmaceutical composition comprising a compound of formula (I) as defined herein. In another aspect of the invention, Groups of the following composition: 139424 - 33 - 201036969 Group: (8) immunomodulation in the intestinal mucosa, (b) protection against allergic damage to the heart, (c) stimulation or prevention of bone depletion between the leucorrhizin-lb ( IL-lb)-stimulation, (6) modulation of NK1 receptor expression in spinal cord neurons, and (6) airway inflammatory disease and chronic obstructive pulmonary disease, including asthma. See (8) system of rheumatoid receptors shown in the gastrointestinal tract Immune cells. Hagner, Stefanie; Knauer, Jens! Haberberger, Rainer; Goeke, Burkhard; Voigt, Karlheinz; McGregor, Gerard Patrick. Philipps University Institute of Physiology, Marburg, Germany. Digestion (2002), 66(4), 197 - 203 ; (b) The protective effect of evodiamine, which is mediated by blood-lowering I gene, on the allergic reaction of guinea pig heart. Rang, Wei-Qing; Du, Yan-Hua; Hu, Chang-Ping; Ye, Feng Tan, Gui-Shan Deng, Han-Wu ; Li, Yuan-Jian. Central South University, Department of Pharmacology, School of Medical Sciences, Xiang-Ya Road 88, Changsha, Hunan, Naunyn-Schmiedeberg's Pharmacology Tan (2003), 367 (3) ), 306-311; (c) Experimental study on the effect of calcitonin gene-related peptide on bone depletion by interleukolysin-1. Lian, Kai; Du, Jingyuan; Rao, Zhenyu; Luo, Huaican. Huazhong University of Science and Technology, Tongji Medical College, Xiehe Hospital, Department of Plastic Surgery, Wuhan, Peop·Rep. China. Journal of Tongji Medical University (2001), 21(4), 304-307, (d) Calcitonin Gene-related peptides regulate the expression of neurokinin receptors by spinal cord neurons in rats. Seybold VS, McCarson KE, Mennelstein PG, Groth RD, Abrahams LG. J. Neurosci. 2003 23 (5): 1816-1824. Minnesota University, Department of Neuroscience, Minneapolis, Minnesota 55455 and Kansas Medical Center University, Department of Pharmacology, Toxicology and Therapeutics, Kansas City, Kansas 66160, (e) Airway hyperresponsiveness caused by antigens in CGRP-deficient mice Attenuated. Aoki-Nagase, Tomoko; Nagase, 139424 -34- 201036969

Takahide; Oh-Hashi, Yoshio; Shindo, Takayuki; Kurihara, Yukiko; Yamaguchi, Yasuhiro ί Yamamoto, Hiroshi; Tomita, Tetsuji; Ohga, Eijiro; Nagai, Ryozo; Kurihara, Hiroki; Ouchi, Yasuyoshi. Department of Scientology and Medicine, Tokyo, Japan. American Journal of Physiology (2002), 283 (5, Pt. 1), L963-L970; (f) Calcitonin gene-related peptides as inflammatory mediators. Springer, Jochen; Geppetti, Pierangelo; Fischer, Axel; Groneberg, David A. Charite Campus-Virchow, Humboldt-University Berlin, Department of Allergic Reaction Research, Department of Pediatric Pulmonology and Immunology, Berlin, Germany. Pulmonary Pharmacology and Therapeutics (2 〇〇3),16(3),121-130; and (g) pharmacological markers for neuroinflammation inhibition. Helyes, Zsuzsanna; Pinter, Erika; Nemeth, Jozsef; Szolcsanyi, Janos. Pecs University, Department of Medicine, Department of Pharmacology and Medicine, Pecs, Hung. Modern Pharmaceutical Chemistry: Anti-inflammatory and Anti-Allergic Agents (2〇〇3), 2(2), 191-218. Another aspect of the invention relates to a method of treatment using a combination of a compound of formula I and one or more agents selected from the group consisting of COX-2 inhibitors, NSAIDs, aspirin, acetamide Acetaminophen, triptan, ergotamine and caffeine for the treatment of migraine. π migraine M, "headache" and related terms are as defined by medical practitioners. Migraine covers all types of migraine, including common, classical, cluster, lightning-like sensation, hemiplegia, eye muscle spasm, and ophthalmia. "Therapeutic effective" means that there is a meaningful patient benefit, as recognized by medical practitioners. "Patient" means that people who are treated by a medical practitioner can benefit from treatment. 139424 - 35 - 201036969 [Embodiment] Description of the Specific Embodiments The abbreviations are generally used in accordance with the idioms used in the art. The chemical abbreviations used in this patent specification and examples are defined as follows: nNaHMDS" is sodium bis(trimethyldecyl)amine; "dmf· is N,N-dimethylformamide; "MeOH"Methanol;〃NBS" is N-bromosuccinimide; "Ar, is aryl; "TFA" is trifluoroacetic acid; "LAH, is lithium aluminum hydride; "B〇c"," DMSO" is dimethyl hydrazine; "h" is hour; "rt" is room temperature or residence time (the text will be referred to as minutes; "EtOAc) is ethyl acetate; "THp is tetrahydrofuran; EDTA is ethylene Amine tetraacetic acid; "Segment 2 〇, is diethyl ether; „DMAp" is 4 曱 曱 峨 ' ' ' 'DCE' is 1,2-diethylene acetonitrile; "ACN, acetonitrile; „DME” ❻ Dimethoxyethane; TM, Μ • benzotristrihydrate; · dirty, diisopropylethylamine, “Nf, CF3(CF2)3S〇2_ ; and “TM 〇F, is tridecyl orthoformate. π π ".丄x" is once, "2 χ" % twice, "3 X" is three times,,, °C, · is taken, the number of people is taken, One equivalent or several g, "g" One gram or several grams, "mg" A ^ . ^ , , ^ g is one milligram or several milligrams, "L" is - liter or liter, "mL" or "ml" is - milli 幵 or number Soaring, "this" is one or several microliters ' "N" is the equivalent concentration, ..... for the m ·, & + Μ for the molar concentration, "mmol', for - milli Ear or a few millimeters, "min" for 187 knives or minutes, "h" for a small day: or hours, "rt" for room temperature, "RT" for A ^ Time ',, atm' is atmospheric, "psi is pound / thousand square," c〇nc." is concentrated for molecular weight ~ is the melting point, "ee" is for the palm ^

Spec" for mass spectroscopy', ESr for, over, MS or "Ma spray ionization mass spectrum 13942 • 36 - 201036969 "HR" for high resolution, "HRMS" for high resolution mass spectrometry, "LCMS" is liquid chromatography mass spectrometry, "HPLC" is high pressure liquid chromatography, "RP HPLC" is reverse phase HPLC, "TLC, or "tic," is thin layer chromatography, &quot ; NMR" is nuclear magnetic resonance spectroscopy, MlH" is proton, "5" is delta (5), "sn is a singlet, "d" is a doublet, 丫 is a triplet, and "q" is a quadruple , "m" is a multiple peak, "br" is broad, 'ΉζΜ is Hertz, and π cf, " /3", "R", "S", Έ" and "Z" are familiar The stereochemistry name familiar to this artist. Proton magnetic resonance (1H NMR) spectroscopy was recorded on a Brnker AC 300 or AC 500. All spectra were measured in the indicated solvents and the chemical shifts were reported in 5 units of the low magnetic field from the standard tetradecyl decane (TMS), while the inter-proton coupling constants were reported in Hertz (Hz). The split pattern is as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad absorption peak. Low resolution mass spectrometry (MS) and apparent molecular (MH+) or (M-H)+ systems were measured on a Micromass platform. Elemental analysis is reported as a percentage by weight. The product was purified by preparative HPLC using a column of YMC S5 ODS (30 X 100 mm) at a flow rate of 40.0 mL/min and a gradient of 8.0 minutes from 40% MeOH - 60% H20 - 0.1% TFA The solvent composition begins and is terminated with a solvent composition of 95% MeOH - 5% H20 - 0.1% TFA. The product was analyzed by HPLC instrument using a XTERA column (3.0 X 50 mm S7) starting from solvent A (10% MeOH - 90% water - 0.1% trifluoroacetic acid (TFA)) and reaching solvent B (10%) Water - 90% sterol - 0.1% TFA) over a 2 minute gradient time. The flow rate was 5 ml/min and the residence time (Rf) of the product was measured at 220 nm. 139424 -37· 201036969 Intermediate 1 4-mercapto-1-ene·In a 500 ml round bottom flask (t=g) dried in a box, 'to make triphenylphosphine (22.40 g, 85 mmol) and Imidazole (5 82 g, Magic Mill) The solution in CHfl2 (200 mL) was cooled to hydrazine. 〇, a colorless solution was obtained. Care was added to add iodine (21.68 g, 85 mmol). After 15 minutes, 3_buten-1-ol (7.0 mL, 81 mmol) was added dropwise and the mixture was warmed to room temperature overnight. The CH2^2 was removed under a hood vacuum, but without heating (the product was extremely volatile!) to provide an orange slurry which was diluted with pentane and filtered through a pad of diatomaceous earth and a layer of silicone. The solvent was then removed under vacuum under the hood and no warmth was used. A slightly yellow oil was obtained, which was crudely taken from <RTI ID=0.0>> Intermediate 2

5-(2,3-Difluorophenyl)indole·ι,8·diene_5-alcohol·In a 500 ml round bottom flask (t=g), add 'EkO (1 mL) to the crude 4 _ escaping small olefin (η 51 g, 63.2 mmol) to give a colorless solution. After cooling to _7yc under nitrogen, tBuLi (80 mL, 136 mmol) was added dropwise via a syringe, and the mixture was slowly warmed to room temperature while stirring for 2 hours. After 2 minutes at room temperature, the mixture was cooled to -78 ° C, and 2,3-difluorobenzoic acid (4.28 mL, 28.7 mmol) was added dropwise via a syringe. The mixture was gradually warmed to room temperature over 30 minutes. The reaction is quenched by water and the volatiles are evaporated. The residue of 139424 -38- 201036969 was partitioned between water and EtO Ac. The liquid layer was separated, and the organic layer was washed with brine, dried over Na.sub.2.sub.4, and concentrated to a pale yellow oil. To 40% El in 20% El; the desired product was obtained as a colorless oil: (1.41 g, 19%). iHNMR (400MHz, CDa3)5 7.31-7.22(m, 1H), 7.10-7.03 (m, 2H), 5.82-5.70 (m, 2H), 4.97-4.85 (m, 4H), 2.20-2.00 (κι, 4H ), 2.00_1.75 (m, 4H). ' Intermediate 3

Ο (Z)_l-(2,3-Difluorophenyl)cyclohepta-4-enol· 5-(2) in CH2Cl2 (50 ml) in a 500 ml round bottom flask (t=g) , 3-Difluorophenyl)indole-1,8-dien-5-ol (1.15 g '4.56 mmol) afforded a colourless solution. Grubbs η (〇 193 g '0.228 mmol) was added, and the mixture was heated at 45 ° C for 19 hours. The TLC display is completely converted to a more polar spot. The material was combined with 68908-184, q and concentrated to dry s <> and the residue was taken up to 50% Et20 / hexane. The main absorption peaks were pooled and concentrated to a colorless oil (0.761 g, 74.5%). 1H NMR showed that most of the desired product (same as the compound synthesized using Grubbs I catalyst) and the lesser component of the isomerized double bond. ' Intermediate 4

KJ] (z)_5-(2,3·difluorophenyl)cyclohept-1-ene· (z)- in a 100 ml round bottom flask (t=g) 'addition of CH2Cl2 (16 ml) L-(2,3-Difluorophenyl)cyclohept-4-enol 139424-39-201036969 (872 mg ' 3.89 mmol) afforded a colorless solution. Triethyl daylight (m mL, 19.44 mmol) was added followed by TFA (8 mL). The mixture was stirred at room temperature for 2.5 hours. TLC showed complete conversion to lower polarity compounds. The product was reduced in size and purified by FCC to up to 2% in 20% of hexane. The desired product was obtained as colorless oil (769 mg, 95%). The product is quickly dissolved. 1H NMR (the main absorption peak is the same as that described later in the synthesis) confirms the structure. Intermediate 5

5-(2,3-Difluorophenyl)_2_ylcycloheptanone. References Plietker, B. J. 〇rg. Chem. 2004, 69, 8287-8296. In a 500 ml round bottom flask (t = g), sodium hydrogencarbonate (827 mg, 9.84 mmol) was added using a stir bar. Cerium chloride (111) (8.17 mg, 0.039 mmol) was added (the aqueous solution was used in the reference material but it was difficult to completely dissolve). Water (3_94 ml), EtOAc (20 mL) and MeCN (20 mL). The addition of an oxygen generating agent (〇xone) (1.21E + 04 mg, 19.69 mmol) resulted in the formation of a clear yellow suspension. The mixture was allowed to cool to _2 ° °c. (z)_5_(2,3-P-Fluorophenyl)cyclohept-1-ene (820 mg ' 3.94 mmol) was added (7,2 mL 1/1 EtOAc/MeCN wash). The color immediately turned into a yellowish brown. The reaction was stirred at -20 ~ -15 C for 1.5 hours. TLC showed no reaction. Warm to the heat. Hey, after 10 minutes, but by TLC, the reaction did not improve much. Allow to warm to room temperature for 15-20 minutes. TLC shows the disappearance of a major lower-polarity spot 139424 201036969 (a less residual residue) and a slightly more polar uv_active spot. The solid was filtered and washed with EtOAc. The organic solution was washed with a NaHS03 aqueous solution. The organic layer was dried over Na 2 SO 4 and concentrated to a colorless oil. It was purified by FCC up to 5% MeOH/CH.sub.2Cl.sub.2. One or more more polar absorption peaks were pooled and concentrated to a colorless oil (169 mg, 18%). This is carried out directly to the next protection reaction.

4-(2-keto-2,3.dihydro.m-imidazo[4,51)>pyridinyl)dihydropyridine small carboxylic acid 5-(2,3-difluorophenyl)_2 _ ketocycloheptyl ester · 5 〇 ml dried in an oven

Gram, o.ioi millimolar), obtained a colorless solution. Add DMAp (15 66

毫克 mg, 〇.128 mmol, and the mixture was stirred at room temperature for 3 hours. TLC

- Add 1_(/,hydropyridin-4-yl)-1Η-imidazo[4,5-b]pyridine-2(3H)-one (53.6 mg, 〇·ΐ 84 mmol), 0.230 mmol ear). The resulting mixture showed two near small absorption peaks which were diluted with water and extracted with EtOAc. Drying with Na2SO4, and then 'Hunig's base (0.040 ml. The resulting mixture was stirred overnight at room temperature. LCMS small absorption peak with MW of 484. 22 hours: X 〇Ac was extracted. The organic layer was washed 3 times with water and brine, dried and condensed into a yellow-brown oil. FCC up to 8% 139424 •41 · 201036969

MeOH/CI^Cl2 gave the desired product as a mixture of two diastereomers, 11.7 mg (26%). LCMS: M+H = 485. Intermediate 6

壬-1,8-di-saturate 5-ketone·Vaporized 4-pentene oxime (6.04 ml, 54.7) in an oven-dried 500 ml round bottom flask (t=g) in THF (80 mL) Millions), a yellow-brown solution was obtained. After cooling to -78 ° C, 3-butenylmagnesium bromide (115 ml, 575 mmol) was added via a syringe over 9 min. After warming to room temperature for 3 hours, the reaction was quenched with saturated n^CI solution. The THF was stripped off and the residue was extracted with Et EtOAc. The organic layer was washed with brine and dried over Na.sub.2SO.sub.4. Purification by FCC up to 40% EkO / hexanes (two batches) afforded product as colorless oil: (5.13 g, 68%) 〇4 NMR (400 MHz, CDC13) (5 5.84-5.68 (m, 2H) ), 5.05-4.90 (m, 4H), 2·49 (t, J = 7.4 Hz, 4H), 2.35-2.20 (m, 4H). Intermediate 7

5-(2,3-Difluorophenyl)indole-1,8-di-salt-5-alcohol. In an oven-dried 250 ml round bottom flask (t=g), add THF (60 mL) 1-Bromo-2,3-difluorobenzene (2.304 mL ' 20.58 mmol) afforded a colorless solution. After cooling to _78 °c, BuLi (8.23 mL, 20.58 mmol) was added dropwise via a syringe. The mixture was stirred at -78 °C for 20 minutes, and 壬^, cardadiene-5-one (2.37 g '17.15 mmol) (azeotrope with anhydrous benzene) was added via a cannula (plus 6 ml) 139424 • 42- 201036969 THF rinse). The mixture was allowed to warm to room temperature over 1 hour. The reaction was quenched with water and the THF solvent was stripped. The residual mixture was extracted with EtO Ac. The liquid layer was separated and the organic layer was washed with brine, dried over Na 2SO 4 and evaporated The residue was purified by FCC up to 35% Et20 / hexanes. The desired fractions were pooled and concentrated to a colorless oil (2 39 g ' 55.3%). 1 η NMR (400 MHz, CDC13) 6 7.30-7.22 (m, 1H), 7.10-7.03 (m, 2H), 5.82-5.70 (m, 2H), 4.97-4.85 (m, 4H), 2.20-2.00 ( m, 4H), 2.00-1.75 (m, 4H) 〇 Intermediate 8

(Ζ)-1·(2,3-·Τ·Fluoryl)cycloheptan-4-enol·In a 1 liter round bottom flask (t=g), add 5 of (3⁄43⁄4 (600 ml)) (2,3-difluorophenyl)phosphonium],8-diene-5-ol

(1.76 g ' 6.98 mmol), a colorless solution was obtained. Gmbbs I (0.175 g '0.209 mmol) was added and the mixture was heated under 4 Torr for 2 hours. The TLC shows complete conversion to a more polar spot (some impurities remaining from the starting material). Consolidate with 68908-198 and concentrate to dryness and allow the residue to be taken up to 50% E 〖20/hexane purified (twice). The main absorption peaks were pooled and concentrated to light green oil (1.4 gram ' 89.2%). NMR (400 MHz, CDCI3) <5 7.34-7.25 (m, 1H), 7.08-7.00 (m, 2H), 5.90-5.80 (m, 2H), 2.60-2.48 (m, 2H), 2.21 (t, J = 7.0 Hz, 2H), 2.10-1.98 (m, 2H), 1.90- 1.75 (m, 2H). Intermediate 9 139424 -43- 201036969

(Ζ)-5<2,3·difluorophenyl)cycloheptene·ene·In a 250 ml round bottom flask (t=g), added CH2C12 (40 ml) (ZH_(2,3_: Fluorophenyl)cycloheptene-4 enol (2.05 g, 9.14 house moles) afforded a colorless solution. Triethyl decane (7 3 mL, 45.7 mmol) was added followed by χρΑ (2 mL). The mixture was stirred at room temperature for 3 hours: TLC showed complete conversion (Rf = 〇42, eluted with pure hexanes) - Concentrated to reduce to a double oil (the lower layer was not hexane soluble). Purified by FCC 0 , using only hexane, to give the desired product as a colorless oil (1 684 g, 88%) = NMR (400 MHz, CDC13) ¢5 7.00-6.90 (m, 3H), 5.90-5.82 (m, 2H), 3.20-3.05 (m, 1H), 2.40-2.15 (m, 4H), 1.90-1.78 (m, 2H), 1.60-1.40 (m, 2H) ° Intermediate 10

5-(2,3-Difluorophenyl)cycloheptane-1,2-diol. See: D. A. Spiegel et al, Tetrahedron 2002, 58, 6545-6554. In a 250 ml round bottom flask (t=g), add (z)_5_(2,3-difluorophenyl)cyclohept-1-ene (1.249) in propylene (9 ml) and water (0.18 ml). Gram, 6·00 mM) and ΝΜΟ (1·546 g, 13.19 mmol), obtained a white suspension. Iron tetraoxide (0 3 〇 1 ml, 0.024 mmol) (2 - 5 wt% solution in 2-methyl-2-propanol) was added. The mixture was stirred at room temperature. The ΝΜ0 system gradually dissolved in 30 minutes to become a yellow solution. 1 small 139424 201036969 hours: TLC shows complete conversion into extremely polar spots. Sodium bisulfite (200 mg) was added and stirring was continued for 3 minutes. Acetone was stripped and the residue was extracted three times with Et 〇Ac. The combined organic layers were washed with brine, dried and dried, and evaporated It is carried directly to the next reaction. Intermediate 11

2-(Third-butyldimethylsilyloxy)_5_(2,3-difluorophenyl)cycloheptanol. In a 250 mL round bottom flask (t=g), DMF (20 mL) 5-(2,3-Difluorophenyl)cycloheptane-1,2-diol (1.454 g, 6.0 mmol) (crude, azeotrope with anhydrous benzene) afforded a colourless solution. TBS_C1 (0 995 g, 6.60 mmol) and imidazole (0.980 g, 14.40 mmol) were added, and the mixture was stirred at room temperature for 5 hours. TLC (2/1 hexanes / EtOAc) showed complete conversion to two major spots. It was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Nad.sub.4, and concentrated to a colorless oil. Purification by FCC up to 30% EtOAc/hexanes afforded the desired mono-protected product as a broad absorption peak. The product was taken up in vacuo and concentrated to a colourless oil ( 1.79 g, 84% over two steps). 1 η NMR (400 MHz, CDC13) 5 7.02-6.85 (m, 3H), 3.98-3.70 (m, 2H), 3.18-3.02 (m, 1H), 2.15-1.82 (m, 4H), 1.80-1.45 ( m, 4H), 0.91 (s, 9H), 0.90 (2s, 6H). 139424 -45- 201036969

(2R,5R)-2-(t-butyldidecylfluorenyloxy)_5_(2,3-difluorophenyl)-heptanone in a 250 ml round bottom flask (t=g), added 2-(Third-butyldimethylsilyloxy)_5_(2,3-difluorophenyl)cycloheptanol (1.73 g, 4.85 mmol) in CH2Cl2 (5 mL) Solution. Add απ-Μαηίη periodinane (2.264 g, 5.34 mmol) in one portion, and stir the mixture at room temperature. 17 hours. TLC showed complete conversion. It was diluted with % , and treated with 40 ml of saturated NaJ^3 and Na2HCO3 solution (1A mixture) until the milky white solution became clear (10 min). The liquid layer was separated and the aqueous layer was extracted with EbO. The combined organic layers were washed with brine, dried with Na 2 EtOAc EtOAc EtOAc. Two absorption peaks were obtained by FCC purification up to 40% Et20 in hexane. Collect them individually and concentrate. The lower polarity major (978 mg, 55%) was a colorless oil. 1H NMR (500 MHz, CDC13) 5 7.02-6.90 (m, 3H), 4.34

(d, J = 4.6 Hz, 1H), 2.82-2.75 (m, 2H), 2.54-2.46 (m, 1H), 2.45-2.32 (m, 1H), 2.17-1.98 (m, 2H), 1.90-1.68 (m, 3H), 0.94 (s, 9H), 0.08 (s, 6H) ; 1 3C NMR (125 MHz, CDC13) (5 213.4, 150.7 (dd, J = 247.6 and 13.4 Hz), 147.8 (dd, J = 245.7 and 13.4 Hz), 137.5 (d, J = 11.5 Hz), 127.7, 122.2, 114.7 (d, J = 17.3 Hz), 79.0, 40.0, 39.2, 33.2, 30.7, 29.4, 25.8, 18.2, -5.0. More extreme

The lesser ones solidified to a white solid upon standing (698 mg, 39%). It was recrystallized from hexane, and X-ray analysis confirmed the anti-stereochemical relationship. iH 139424 -46- 201036969 NMR (500 MHz, CDC13) <5 7.10-6.97 (m, 2H), 6.97-6.90 (m, 1H), 4.34 (dd, J = 3.0 and 9.7 Hz, 1H), 3.04- 2.94 (m, 1H), 2.80-2.70 (m, 1H), 2.62-2.50 (m, 1H), 2.18-1.72 (m, 6H), 0.90 (s, 9H), 0.10 (s, 3H), 0.06 ( s, 3H) ; 13C NMR (125 MHz, CDC13) (5 211.0, 150.8 (dd, J = 248.6 and 13.5 Hz), 148.1 (dd, J = 246.7 and 12.5 Hz), 136.4 (d, J = 11.5 Hz) , 124.2, 122.3, 115.1 (d, J = 17.3 Hz), 78.4, 40.3, 39.4, 34.3, 33.0, 30.4, 25.9, 18.5, -4.5, -5, 1. Intermediate 14

(6,9-pair)·9·(Third-butyldimethylmercaptoalkyloxy)_6_(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H· (2S,5S)_2_(Third-butyl dimethyl decyloxy)-5- in ethanol (4 ml) in a 25 ml flask (t=g). (2,3-Difluorophenyl)cycloheptanone (279 mg, 0.787 mmol) gave a colorless solution. Four gas gold (III) naphthalate dihydrate (9 39 mg, 〇 24 mil) was added with propargylamine (0.101 ml, 1.574 mmol). The reaction was heated at 8 ° C for 5 hours. After the yellow-brown mixture was allowed to cool to room temperature, it was diluted with hydrazine & FCc to 20% EtOAc/hexanes gave the desired product as the major peaks (60.33⁄4 g, 20%) and a small amount of starting material recovered. 1hnmr(4〇〇MHz, CDC13) d 8.45-8.40 (m, 1H), 7.32-7.29 (m, 1H), 7.08-7.04 (m, 1H), 7.04-6.92 (m, 2H), 6.92-6.80 ( m, 1H), 5.13-5.07 (m, 1H), 3.30-3.00 (m,

0.042 (s, 3H). Intermediate 15 139424 -47- 201036969

(6,9-pair)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5Η·cyclohepta[b]pyridine-9-ol········ In a round bottom flask (t=g), '6R,9R)-9-(tris-butyldiindenylalkyloxy)_6_(2,3-difluorophenyl) was added to THF (3 mL) -6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (60.3 mg, 0.155 mmol) afforded a colorless solution. TBAF (0.310 mL, 0.310 mmol) was added and the mixture was stirred at room temperature overnight. 19 hours: LCMS and TLC showed complete conversion. The THF was stripped and the residue was diluted with EtOAc EtOAc EtOAc. FCC up to 30% EtOAc / hexanes afforded an mp. LCMS : [M+H] = 276 ; 1 H NMR (400 MHz, CDC13) 5 8.42-8.40 (m, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.16 (dd, J = 7.2 and 5.0 Hz, 1H), 7.15-7.00 (m, 3H), 5.97 (wide, 1H), 4_88 (dd, J = 11.6 and 1.6 Hz, 1H), 3.19 (t, J = 12.8 Hz, 1H), 2.99-2.83 (m, 1H), 2.80 (d, J = 14.4 Hz, 1H), 2.38-2.23 (m, 1H), 2.23-2.05 (m, 2H), 1.69-1.50 (m, 1H); 13C NMR (125 MHz , CDC13) <5 160.7, 150.8 (d, J = 247.4 Hz), 148.1 (d, J = 261.2 Hz), 145.1, 137.8, 136.5 (d, J = 12.3 Hz), 133.6, 124.2, 122.4, 122.1, 115.1 (d, J = 16.9 Hz), 71.8, 40.5, 37.6, 36.2, 35.8. Example 2

4-(2-keto-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)hexahydropyridine-1-carboxyl 139424 -48- 201036969 acid (6,9- Contralateral)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro.5H-cyclohepta[b]pyridine·9-yl ester·in 丨〇〇ml round bottom In a flask (t=g), (6R,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetra-argon-5H-cycloheptane was added in THF (3 ml). [b]P than bite _9_ alcohol (22.2 Zuck '0.081 love; Moer) (azeotrope with anhydrous benzene) and 4_(2__ base_2,3_dihydro-1H-imiphthene [4,5 -b&gt; than hexane-1-yl) hexahydrop was obtained as a yellow-brown suspension than the bit of carboxylic acid 4 nitrophenyl ester (93 mM, 0.242 mmol). Add NaH (19.35 ' mg, 0.806 mmol) (overdose) in one portion. The mixture was stirred under nitrogen at room temperature overnight. 18 hours. LCMS showed complete conversion. The reaction was quenched with water (gas evolution!) and extracted with EtOAc. The layers were separated and the aqueous layer was extracted with Et.sub.Ac (LCMS showed no product in aqueous). The combined organic layers were washed with brine and dried over Naz SO. </ RTI> <RTIgt; 5 10.5 (wide, 1H), 8'47 (d, J = 3.6 Hz, 1H), 8.07 (d, J = 4.4 Hz, 1H), 7.44 (wide, 2H), 7.15 (wide, 1H), 7.09- 6.95 (m, 4H), 6.03 (d, J = 10.8 Hz, 1H), 4.77-4.52 (width Q wide, 2H), 4·52·4·30 (broad, 1H), 3.36 (t, J = 12.6) Hz, 1H), 3.20-2.90 (m, 3H)' 2.83 (d, J = 14.4 Hz, 1H), 2.42-2.12 (m, 4H), 2.02-1.78 (m, 4H); mp 248 ° C. 3

4·(2·keto-4,5-dihydro-1H·benzo[d][l,3]diazepine-7(2H)-yl)hexahydropyridin-1·carboxylic acid (6 , 9·contrast) _6-(2,3·difluorophenyl)·6,7,8,9·tetrahydro-5Η-cyclohepta[b] 139424 -49· 201036969 Pyridine-9-yl ester. Add (6R,9R)-6-(2,3-difluorophenyl)_6,7,8,9-four in THF (2 ml) in a 1 mL round bottom flask (t=g) Hydrogen-5H-cyclohepta[b]pyridine·9-ol (13.5 mg, 0.049 mmol) (azeotrope with anhydrous benzene) and 4_(2 keto-4,5-dihydro-1 fluorene-benzo[1 , 3] diazepine-7(2Η)-yl)hexahydropyridine small carboxylic acid 4-nitrophenyl ester (60.4 mg, 0.147 mmol) afforded a tan suspension. Add NaH (11.77 mg, 0 '490 mmol) in excess. The mixture was stirred overnight at room temperature under nitrogen. 18 hours: LCMS showed complete conversion. The reaction was quenched with water (gas evolution) and extracted with EtOAc. The layers were separated and the aqueous extracted with EtOAc. The combined organic layers were washed with brine, dried over Na.s. Purification by FCC up to Me 〇H/cH2Cl2 afforded product as a white powder. LCMS showed a lesser absorption peak (M+Br), but 1H NMR appeared to be very good. Treatment with NaHS03 in MeOH/water for 2 days did not improve. The recovered material did not change (195 mg, 73%). LCMS : [M+H] = 547 ; 1H NMR (400 MHz, CDC13) δ 8.41 (d, J = Hz, 1H), 7.39 (d, J = Hz, 1H), 7.12-6.95 (m, 5H), 6.88 (t, J = Hz, 1H), 6.72 (d, J = Hz, 1H), 6.65 (s, 1H), 5.98 (d, J = Hz, 1H), 4.60-4.18 (broad, 3H), 3.51 (wide, 2H), 3.33 (t, J = Hz, 1H), 3.15-2.89 (m, 6H), 2.82 (d, J = Hz, 1H), 2.32-2.10 (m, 3H), 2.05-1.89 ( m, 1H), 1.89-1.55 (m, 4H). Intermediate 16

(6,9-trans)-6-(2,3-difluorophenyl&gt;9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 1-oxide · Add (6,9-trans)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5 in CH2C12 (4 mL) in a 250 mL round bottom flask沁 庚 庚 [13] pyridine 139424 -50- 201036969 -9-alcohol (191 mg, 0.694 mmol), obtained a colorless solution. Add mCpBA (202 mg '0.902 mmol) and mix the mixture at room temperature The mixture was stirred for 24 hours. LCMS showed complete conversion to the main product absorption peak. It was diluted with Et 〇Ac and treated with 0.5 N NaOH. The liquid layer was separated, and the organic layer was washed with water and brine, dried over Na 2 SO 4 and dried. Concentrate to a waxy solid/oil (crude: 100%) ° LCMS: [M+H] = 292; *H NMR (400 MHz, CDC13) δ 8.06 (s, 1 Η), 7.24-6.40 (m, 5H) , 5.27 (br, 1H), 3.42-3.02 (m, 2H), 3.02-2.68 (m, 2H), 2.30.95 (m, 3H), 1.80-1.60 (m, 1H).

(6,9-trans)-6-(2,3-difluorophenyl)-9.carboxyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]

Pyridine-2·carbonitrile·crude (6,9-trans)-6-(2,3-difluorophenyl)-9-carbyl-- in CH2C12 (4 mL) 6,7,8,9-Tetrahydro-5-cyclohepta[b]pyridine 1-oxide (0.202 g, 0.694 mmol) (azeotroped with anhydrous benzene) afforded a colourless solution. Dimethylammonium chloride formazan (0.064 ml, 0.694 mmol) was added. After 2 hours, trimethylsulfonyl cyanide (〇 111 mL, 833 833 mmol) was added and mixture was stirred overnight under nitrogen for 16 hours. Further, dimethylammonium chloride (0064 ml, 694 694 mmol) and trimethyl decane cyanide (O.Ui ml, 833 833 mmol) were added. The mixture was heated under reflux (bath temperature: 45 ° C) for 22 hours. LCMS showed multiple absorption peaks with only a small amount of starting material left behind. The reaction was quenched with saturated aq. NaHCO3 and extracted withEtOAc. The layers were separated, and the organic layer was washed with brine, dried and evaporated and evaporated. It was dissolved in 4 ml of THF and treated with TBAF 139424 - 51 - 201036969 (0.694 ml, 0.694 mmol) for 4 hours. Treated with aqueous EtOAc to give a brown brown residue. The product was obtained as a colorless solid (53 mg, 23%). LCMS: [M+H]= 372; *H NMR (400 MHz, CDC13) δ 7.65-7.52 (m, 2 Η), 7.10-6.95 (m, 3H), 5.15 (d, J = 4.0 Hz, 1H), 4.94 (d, J = H.6 Hz, 1H), 3.24 (t, J = 12.8 Hz, 1H), 2.92-2.83 (m, 2H), 2.40-2.30 (m, 1H), 2.20-2.10 (m, 2H), 1.68-1.53 (m, 1H) 〇Example 4

4-(2-keto- 2,3-dihydro-1H-mi- s[4,5-b&gt; than bite·1·yl) hexahydrop than bite_1-rebel (6,9-reverse 2-cyano-6-(2,3-difluorophenyl)·6,7,8,9·tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester. In 100 ml In a round bottom flask, (6,9-trans)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5 was added to THF (2 mL). ^1-Cyclohepta|&gt;]pyridine-2-carbonitrile (52.6 mg, 0.175 mmol) (azeotrope with anhydrous benzene) and '(2-keto-2,3-dihydro-1?-?) Rice bran [4,5-b> than biti-1-yl) hexahydrop ratio. _ι_Resin 4-mercaptophenyl ester (201 mg '0.525 mmol) was obtained as a tan suspension. Add NaH (42_0 mg 'L752 mmol) (overdose) in one portion. The mixture was stirred overnight under nitrogen at room temperature for 16 hours. LCMS showed complete conversion. The reaction was quenched with water (gas evolution!) and extracted with EtOAc. The liquid layer was separated, and the organic layer was washed with brine, dried over Na2SO4, and concentrated. The product was obtained as a white powder (76 mg, 72%). LCMS: [M+H] = 545; 1 H NMR (400 MHz, CDC13) 139424 -52 - 201036969 δ 8.07 (br, 1 Η), 7.75-7.24 (m, 4H), 7.20-6.90 (m, 4H), 5.98 (d, J = U 2

Hz, 1H), 4.83-4.20 (m, 3H), 3.40 (t, J = 12.8 Hz, 1H), 3.28-2.75 (m, 3H) 2.60-2.10 (m,5H), 2.10-1.78 (m,4H ). Intermediate 18

2-Momotyl-3-Ethyl p to bite · See Spivey, A.C. ; Shukla, L. ; Haylei: J.F. Og. kii· 2007, 9, 891-894. Butyllithium (22.75 ml, 59, 1 mmol) was added to a suspension of methyltriphenyl bromide (21.13 g, 59.1 mmol) in THF (450 mL). The solution was turned into orange and the reaction was allowed to warm to room temperature over 30 min then cooled to EtOAc. 2-Bromonicotinaldehyde (1 g, 53.8 mmol) in 5 ml of THF was added to the reaction solution through a cannula. A precipitate formed and the reaction was allowed to warm to room temperature. The color of the reactants turns into a greenish gray. After a while, the color of the reactants turned orange again. The reaction was stirred at room temperature over the weekend. Most of the solvent was removed via vacuum and the crude material was partitioned between water and diethyl ether. The organic layer was separated and the aqueous layer was extracted twice with diethyl ether. The ethereal layer was combined, dried (Na2SO4), filtered and concentrated. The product was obtained as a yellow oil (8 78 g &apos;&lt; MS (ESI) [M+H+] = 184.04; 1H NMR (5 ppm (400 MHz, chloroform-d) 8.21-8.29 (m,1H) 7.78 (dd,J = 7.68, 1.89 Hz, 1H) 7.20-7.28 ( m, 1H) 6.96 (dd, J = 17.37, 11.08 Hz, 1H) 5.72 (d, J = 17.37 Hz, 1H) 5.46 (d, J = 11.08 Hz, 1H) Intermediate 19 139424 •53- 201036969

2-(pent-4-enyl)-3-vinylpyridine·In a 500 ml round bottom flask was added 2-bromo-3-vinylpyridine (4.151 g, 22.56 mmol) in THF (40 mL). (Azeotrope with anhydrous benzene) to obtain a colorless solution. Pd(Ph3P)4 (0.782 g, 0.677 mmol) was added under nitrogen. While stirring under nitrogen, 4-pentenylzinc bromide (46 ml, 23 Torr 0 mmol) was added via a syringe, and the resulting dark mixture was stirred at room temperature for 5 min. Then, it was heated under reflux (70 ° C) overnight (4:00 pm). 17 hours: LCMS showed complete conversion to the desired product. Steam raised THF. The reaction was quenched with NH4C1 solution and diluted with Et. The layers were separated and the organic layer was washed with brine, dried and dried and evaporated. FCC up to 30% EtOAc / hexanes afforded the desired product as a colourless oil (2.54 g, 65%). MS (ESI) [M+H+] = 174; 1H NMR (400 MHz, chloroform-d) (5 ppm 8.39 (dd, J = 4.78, 1.51 Hz, 1H) 7.69 (dd, J = 7.81, 1.76 Hz, 1H ) 7.07 (dd, J = 7.81, 4.78 Hz, 1H) 6.89 (dd, J = 17.37, 11.08 Hz, 1H) 5.80 (dddd, J = 17.06, 10.26, 6.67, 6.55 Hz, 1H) 5.62 (d, J = 17.37 Hz, 1H) 5.34 (d, J = 11.08 Hz, 1H) 4.85-5.09 (m, 2H) 2.76-2.92 (m, 2H) 2.11 (q, J = 7.13 Hz, 2H) 1.67-1.83 (m, 2H) ; 13C NMR (101 MHz, chloroform-d) 5 ppm 159.17 (s, 1C) 148.31 (s, 1C) 138.38 (s, 1C) 133.22 (s, 1C), 133.19 (s, 1C), 131.73 (s, 1C) 121.40 (s, 1C) 117.22 (s, 1C) 114.87 (s, 1C) 34,99 (s, 1C) 33.64 (s, 1C) 28.60 (s, 1C). Intermediate 20

(Ζ)_8,9·Dihydro-7H-cyclohepta[b]p-pyridyl. Add 2-ether in the 2 liter round bottom flask with ether 139424-54- 201036969 (4 ml) Benzyl-3-vinylpyridine (2.1 g, 12.12 mmol) afforded a colorless solution. Add HC1 (30 ml, 60.0 mmol) and stir the mixture for 5 minutes. The volatile material was evaporated to give a colorless oil which was then azeotroped with anhydrous benzene to a white solid. Then, it was dissolved in CH2C12 (1 liter) (degassed with argon) to obtain a colorless solution. Grubbs II (0.515 g, 0.606 mmol) was added and the mixture was heated in a 40 ° C oil bath and stirred under nitrogen for 5 h. LCMS showed complete conversion (TLC showed the main spot, which was less polar than the starting material). The mixture was concentrated to a tan oil. This was dissolved in EtOAc and washed with EtOAc EtOAc EtOAc EtOAc. FCC up to 40% EtOAc / EtOAc (EtOAc) MS (ESI) [M+H+] = 146.06; 1H NMR (400 MHz, chloroform-d) 5 ppm 8.20 (d, J = 4.78 Hz, 1H) 7.32 (d, J = 7.55 Hz, 1H) 6.99 (dd, J = 7.55, 5.04 Hz, 1H) 6.21 (dt, J = 12.28, 2.05 Hz, 1H) 5.90 (dt, J = 12.34, 4.41 Hz, 1H) 2.93-3.06 (m, 2H) 2.30-2.49 (m, 2H) 1.82-2.02 (m, 2H) ; 13C NMR (101 MHz, chloroform-d) ¢5 ppm 160.56 (s, 1C) 146.26 (s, 1C) 137.79 (s, 1C) 134.18 (s, 1C) 131.32 (s , 1C) 127.24 (s, 1C) 121.16 (s, 1C) 39.10 (s, 1C) 32.54 (s, 1C) 24.87 (s, 1C). Intermediate 21

6-Bromo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl acetate. Add acetic acid (1 ml) to a 500 ml round bottom flask ( Z)-8,9-dihydro-7H-cyclohepta[b]pyridine (5.16 g, 35.5 mmol), lithium acetate (9.38 g, 142 mmol 139424-55-201036969) Yellow-brown suspension. Add team bromoacetamide (5 gram ' 36.2 mmol). The flask was coated with aluminum foil and the mixture was stirred overnight at room temperature. 16 hours: no solids remained, and LCms showed complete conversion to the desired more polar product as the main absorption peak. The AcOH was stripped under high vacuum. The residue was diluted with water and EtOAc. Na2C03 was added to neutralize the mixture until no gas was released. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The crude material is used as it is. MS (ESI) [M+H+] = 284.17. Intermediate 22

Epoxyacetic acid 6-bromo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl ester. Add acetic acid in THF (100 ml) to a 500 ml round bottom flask. 6-Momot-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl ester (10.09 g, 35.5 mmol) (azeotrope with anhydrous benzene) Solution. Methanol (9.59 g, 178 moles) was added and the mixture was stirred at room temperature under nitrogen. 2 hours: tlc shows complete conversion to a more polar product spot. 2.5 hours: THF was stripped and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2sssssssssssssssssssssssssssssssss MS (ESI) [M+H+] = 1621.21. Intermediate 23 139424 -56- 201036969

6,7,8,9-Tetrahydro-5H-cyclohepta[b]pyridine-6 Ethyl alcohol. Add epoxide (5.72 g, 35.5) in MeOH (100 mL) in a 5 mL round bottom flask. Millions) with Pd/C (1.889 g, 1.775 mmol), obtained a black suspension. It was stirred under i atmospheric pressure (cylinder) for 2 hours. LCMS showed a small amount of starting material to leave. An additional 0.95 grams of Pd/C was added and stirring was continued for an additional hour. The TLC shows no change (the trace substance may not be the starting material). It was filtered and concentrated to a tan oil (6 g, EtOAc EtOAc). Intermediate 24

8,9-Dihydro- 5Η·cyclohepta[b]pyridine_6(7Η)-one·In a 500 ml round bottom flask dried in an oven at -55 ° C under nitrogen, add CH2C12 (1〇〇) Chlorophyll (3.42 ml, 39.1 mmol) in ML) gave a colorless solution. DMSO (5.54 mL, 78 mmol) was added dropwise over 1 min. After the solution was stirred for another 30 minutes, 6,7,8,9-tetrahydro-5H_ which had been dissolved in 2 ml of (:] 9 [2 (: 12 (plus 20 ml of rinse)) was added via cannula. Cyclohepta[b]pyridine-6 alcohol (5 79 g, 35.5 mmol) (azeotroped with anhydrous benzene) over 5 minutes. The reaction mixture was stirred at -50-55^ for a further 40 minutes (the solution became Milky white. At _5 ° °c, add Et3N (2474 ml, 178 mmol) via syringe and stir the reaction mixture for 30 minutes (like gel and difficult to stir. Occasionally oscillate at ambient temperature). Add 1 ml of water, and the liquid layer was separated. The aqueous layer was extracted with 139424-57·201036969 (2×100 ml). The combined organic layers were dried over Na 2 SO 4 and concentrated to a tan oil with some solids. Purification of up to 10% MeOH/CH.sub.2 C.sub.2 to afford the desired product as an orange oil (4.947 g, 86% over 4 steps). 1H NMR (500 MHz, EMI-D) &lt;5 ppm 8.28-8.38 (m , 1H) 7.37 (d, J = 7.63 Hz, 1H) 7.00-7.13 (m, 1H) 3.65 (s, 2H) 3.10-3.18 (m, 2H) 2.50-2.60 (m, 2H) 2.01 (dd, J = 6.71, 4.88 Hz, 2H); 13C NMR (126 MHz, chloroform-d) &lt;5 ppm 207.23 (s, 1C) 160.24 (s, 1C) 147.98 (s, 1C) 137.20 (s, 1C) 128.85 (s, 1C) 122.25 (s, 1C) 48.89 (s, 1C) 43.96 (s, 1C) 36.15 (s, 1C) 24.70 (s, 1C). Intermediate 25

6-(2,3·Difluorophenyl)-6,7,8,9·tetrahydro-5H-cyclohepta[b]acridine·6·alcohol. At -78 ° C under nitrogen, An oven-dried 500 ml round bottom flask was charged with EtOAc (17.19 mL, 43.0 mmol) in THF (100 mL). 1-Bromo-2,3-difluorobenzene (4.81 ml, 43.0 mmol) was added dropwise via a syringe. The mixture was stirred at -78 °C for 20 minutes, and 8,9-dihydro-5H-cyclohepta[b]pyridine-6(7H)-one dissolved in 10 ml of THF was added dropwise via a cannula. (4.947 g, 30.7 mmol) (azeotroped with anhydrous benzene and dried under high vacuum) (plus 10 mL THF rinse). The mixture was allowed to warm to room temperature over 1 hour. The TLC shows that a portion is converted to a slightly more polar spot. After quenching the reaction with a saturated NH4Cl solution, THF was stripped. The residual mixture was subjected to liquid separation between water and EtO Ac. The liquid layer was separated, and the organic layer was washed with brine, 139424 - 58 - 201036969, dried over Na2S04, and concentrated to a dark oil. The residue was purified by FCC up to 10% MeOH / CH.sub.2C. The impure fractions were pooled and purified by EtOAc / CH.sub.2 C. The starting material recovered was 1.88 g (38%). The product fractions were combined and concentrated to a tan solid which was washed repeatedly with Et20 to a tan solid (1.79 g, 21%). 1H NMR (400 MHz, chloroform-d) δ ppm 8.27 (dd, J = 4.91, 1.38

Hz, 1H) 7.38-7.47 (m, 1H) 7.30-7.35 (m, 1H) 6.97-7.12 (m, 3H) 3.93 (dd, J = 14.60, 2.52 Hz, 1H) 3.06-3.20 (m, 2H) 2.86 (dd, J = 14.60, 1.76 Hz, 1H)

O 2.37-2.68 (m, 2H) 1.68-1.94 (m, 2H) 1.17 (t, J = 7.05 Hz, 1H) ° Intermediates 26 and 27

Difluorophenyl)-8,9-di-argon-5H-cyclohepta[b]pyridine. Add 6-(2,3-difluorophenyl)-6,7,8 to a 250 ml round bottom flask. 9-Tetrahydro-5H-cyclohepta[b]pyridine-6-ol (1.23 g, 4.47 mmol). HC1 (20 ml of a 6 M solution, 120 mmol) was added and the mixture was heated at 100 ° C ( reflux) for 2 hours. LCMS showed completion and complete conversion. After cooling to room temperature, it was diluted with EtOAc and slowly basified with 15 mL EtOAc. The layers were separated and the organic layer was washed with brine, dried and dried and evaporated FCC up to 80% EtOAc in hexanes gave a major absorption peak (1) (0.71 g), and a less absorptive peak (7) (90 mg), and some mixtures (0.34 g). Total: 1.14 grams (97%: approximately 75% for 1 and 22% for 2). 1H NMR system 139424 -59- 201036969 confirmed these two structures. About 6-(2,3-difluorophenyl)-8,9-dihydro-711-cyclohepta[b]pyridine (1) : 1H NMR (400 MHz, chloroform-d) (5 ppm 8.33 (dd, J = 5.04, 1.51 Hz, 1H) 7.40-7.51 (m, 1H) 6.98-7.18 (m, 4H) 6.53 (s, 1H) 3.04-3.22 (m, 2H) 2.63 (t, J = 6.55) Hz, 2H) 2.17-2.32 (m, 2H). Regarding (E)-6-(2,3-difluorophenyl)-8,9-dihydro-5H-cyclohepta[b]pyridine (2): 1H NMR (400 MHz, chloroform-d) (5 ppm 8.35 (dd, J = 4.91, 1.38 Hz, 1H) 7.39 (d, J = 7.55 Hz, 1H) 6.81-7.10 (m, 4H) 5.67 (t, J = 4.28 Hz, 1H) 3.73 (s, 2H) 3,23-3.34 (m, 2H) 2.48-2.65 (m, 2H). Intermediate 28

6-(2,3-Difluorophenyl)-6,7,8,9·tetrahydro-5H-cyclohepta[b]p than a bite in a 250 ml round bottom flask with MeOH (4 mL) (e)-6-(2,3-Difluorophenyl)-8,9-dihydro-5H-cyclohepta[b]pyridine (112 mg, 0.435 mmol) afforded a colourless. Pd/C (46.3 mg '0.044 mmol) was added and the mixture was stirred under a hydrogen kettle for 2 hours. TLC showed a major absorption peak as the starting material, y and LCMS showed neither the starting material nor the product parent ion, but was co-dissolved. An additional 23 mg of Pd/C was added and the mixture was stirred under hydrogen overnight (19 h). LCMS showed complete conversion (single absorption peak&apos; only had the product: M+H = 26 〇). It was filtered and washed with MeOH. Concentrate the solution to a colorless oil (1〇6 mg,

94%). The crude 1H NMR confirmed the structure' and showed superior purity. NMR (400 MHz, gas-d) (5 ppm 8.30 (dd, J = 4.78, 1.51 Hz, 1H) 7.35 (dd, J = 7.55, 1.51 Hz, 1H) 6.89-7.12 (m, 4H) 3.17-3.31 (m, 1H) 3.01-3.17 (m, 2H) 139424 -60- 201036969 2.88-3.00 (m, 1H) 2.74 (d, J = 14.10 Hz, 1H) 2.01-2.19 (m, 2H) 1.85-2.01 (m , 1H) 1.46-1.70 (m, 1H).

Racemic trans-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]P-pyridin-9-ol with cis-6 -(2,3-difluorophenyl)·6,7,8,9-tetrahydro-5H-cyclohepta[b]p-pyridin-9- oo alcohol. Add to a 1 〇〇 ml round bottom flask 6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine in CH2C12 (4 ml) (1 〇 6 mg, 〇, 4 〇) 9 millimoles) 'Get a colorless solution. mCPBA (137 mg, 0.613 mmol) was added and the resulting solution was stirred at room temperature overnight. 19 hours: LCMS showed complete conversion to N-oxide. The mixture was diluted with Et0Ac and washed with a 1N NaH solution. The organic layer was washed with brine, dried over Na 2 EtOAc and evaporated This was carried on to the next reaction without further purification and characterization. MS (ESI) [M+H+] = 276.21. Add 6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b> to CH2C12 (4 mL) in a 1 mL round bottom flask. η定1-oxide (113 mg, 0.409 mmol) (yellow-yellow oil &lt;RTI ID=0.0&gt; After cooling, TFAA (0.144 mL, 1.023 mmol) was added and mixture was stirred at room temperature for 4 hours. LCMS shows only 10% of the desired product and is primarily the starting material (or may be a slow rearrangement of the guanidinium-oxide). An additional 15 ml of TFAA&apos; was added and the mixture was stirred at room temperature overnight. The LCMS showed a slight improvement. The mixture was refluxed at 45 ° C for 4 hours, and the reaction did not improve. 139424 -61 - 201036969 /•L proposed a volatile substance, and added 2 ml of acetic anhydride, and the mixture was heated at 13 ° C (preheated bath) for 1-5 hours. LCMS did not show the starting material. It was allowed to cool down and diluted with Et〇Ac. The solution was alkalized with Na〇j^s and the liquid layer was separated. The organic layer was washed with water and concentrated to a tan oil. Then, it was dissolved in 2 ml of THF and treated with 1.5 ml of IN NaOH for 1 hour. LCMS primarily shows an absorption peak for the desired product* (M+H=276). The mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried and dried and evaporated. Purification by Fcc up to 5 % Et〇Ac / hexane afforded two compounds (very close to the spot on TLC): a and b. Further dissociation to up to 80% EtOAc/hexanes gave a more polar absorption peak, c. As confirmed by 1H NMR, a is the desired trans-alcohol (32 3 mg '29%) (analytical data is the same as previously described); b is the dehydrated product (1 〇 4 g, 9.9%), And c is cis-alcohol (36 mg, 32%). The cis-g|· is more polar than the trans-alcohol (Rf = 0.16 for cis and 0,77 for 50% EtOAc/hexane for trans). 1H NMR for cis-alcohol: m NMR (5 〇〇 MHz, chloroform-d) (5 ppm 8.26 (d, J = 4.58 Hz, 1H) 7.30 (d, J = 7.63 Hz, 1H) 7.04 ( Dd, J = 7.32, 4.88 Hz, 1H) 6.85-6.98 (m, 2H) 6.79 (t, J = 6.87 Hz, 1H) 5.37 (broad s) 1H) 5.01 (dd, J = 7.17, 3.81 Hz, 1H) 3.28-3.52 (m, 2H) 2.93 (d, J = 13.73 Hz, 1H) 2.17-2.33 (m, 1H) 1.89-2.15 (m, 3H) Intermediate 31

(E)-6-(2,3-difluorophenyl)-8,9-dihydro-7H-cyclohepta[b]pyridin-9-ol. Add to the 139424-62-201036969 250 ml round bottom flask (E)-6-(2,3-difluorophenyl)-8,9-dihydro-7H-cyclohepta[b]pyridine (546 mg, 2.122 mmol) in CH2C12 (15 mL) A colorless solution was obtained. mCPBA (571 mg, 2.55 mmol) was added and the resulting solution was stirred at room temperature overnight. 4 hours: LCMS only shows trace amounts of starting material left behind. 21 hours: The mixture was diluted with EtOAc and washed with a 1N NaOH solution. The organic layer was washed with water and brine, dried over Na 2 EtOAc, and concentrated in vacuo. This was carried on to the next reaction without further purification and characterization. MS (ESI) [M+H+] = 274.21. References: Kaiser, S.; Smidt, S.P.; Pfaltz, A. CTiem. Tni. 2006, Must, 5194-5197. Add (Ε)-6-(2,3-difluorophenyl)-8,9-dihydro-7Η-cyclohepta[b]pyridine 1- in CH2C12 (16 ml) in a 100 mL round bottom flask Oxide (0.580 g, 2.122 mmol) (azeotroped with anhydrous benzene) afforded a colourless solution. After cooling to 0 ° C, TFAA (0.749 mL, 5.31 mmol) was added and the mixture was stirred at room temperature for 4 hr. Leave it in the refrigerator for the weekend. LiOH (6.37 mL, 6.37 mmol) was added and the mixture was stirred for 2 h. It was diluted with EtOAc and water and the layers were separated. The organic layer was washed with brine, dried and dried and concentrated to a brown oil. Purification by FCC to up to 50% EtOAc / EtOAc afforded EtOAc (EtOAc) MS (ESI) [M+H+] = 274.19; 1H NMR (400 MHz, EMI-D) δ ppm 8.36 (dd, J = 4.78, 1.51 Hz, 1H) 7.50 (dd, J = 7.81, 1.26 Hz, 1H 7.20 (dd, J = 7.68, 4·91 Hz, 1H) 6.96-7.11 (m, 3H) 6.44 (s, 1H) 5.63 (broad, 1H) 4.77 (dd, J = 10.45, 2.64 Hz, 1H) 2.78 - 2.95 (m, 1H) 2.64-2.77 (m, 1H) 2.44-2.62 (m, J = 13.60, 5.48, 5.48, 2.64 Hz, 1H) 1.92-2.15 (m, 1H); 13C NMR (101 MHz, chloroform -d) 5 ppm 158.49 (s, 1C) 149.39-152.62 (m, 139424 -63- 201036969 1C) 146.03-149.25 (m, 1C) 145.24 (s, 1C) 143.70 (s, 1C) 139.94 (s, 1C) 138.79 (s, 1C) 134.46 (d, J = 10.79 Hz, 1C) 128.51 (d, J = 11.56 Hz, 1C) 124.37 (broad s·, 1C) 123.81-124.14 (m, 1C) 122.44 (s, 1C) 116.24 (d, J = 16.95 Hz, 1C) 71.49 (s, 1C) 34.88 (s, 1C) 32.74 (d, J = 3.08 Hz, 1C). Intermediates 32 and 33

Racemic trans-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro·5Η_cyclohepta[b&gt;bipyridin-9-ol and cis-6- (2,3-Difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b&gt; pyridine-9-ol· MeOH (20) in a 5 liter round bottom flask (E)-6-(2,3-difluorophenyl)_8,9-dihydro-7H-cyclohepta[b]pyridin-9-ol (660 mg ' 2.415 mmol) in cc) A colorless solution was obtained. Pd/c (257 mg, 〇.242 mmol) was added and the mixture was stirred under a helium cylinder for 4 hours. LCMS shows complete conversion. Filter and concentrate to a colorless oil. Purification by FCC up to 8〇% Et〇Ac/hexane gave two products: trans-alcohol (1〇4 3 mg, 16%) and cis-alcohol (492.8 mg, 74%), both All are white solids. The analysis data for the two alcohols is in accordance with the above. Intermediate 34

Despin (6,9_trans-6-(2,3-difluorophenyl).6,7,8,9-tetrahydro-5H-cyclohepta[b] (15 ml) in pyridine -9·Alcohol·Add THF fl5 in a 100 ml round bottom flask. 彳 1394 139424 -64 - 201036969 (6,9-cis)-6-(2,3-difluorophenyl)-6,7 , 8,9-tetrahydro-511-cyclohepta[13]pyridine-9-ol (489 mg, 1.776 mmol) (azeotropic with anhydrous benzene) afforded a colorless solution. 594 mg (3.55 mmol) and ph3P (932 mg, 3.55 mmol), and the mixture was cooled to 〇t. Diisopropyl azodicarboxylate (0.699 mL, 3.55 mM) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 5 h. LCMS showed complete conversion to the desired intermediate with a small amount of dehydrated product, which was left to stand overnight and LCMS showed no change. LiOH (8.88 mL, 8.88 mmol) was added. ', and the mixture was stirred at room temperature for 3 hours. LCMS showed the intermediate was completely converted to product. The mixture was evaporated to dryness, and the residue was partitioned between EtOAc and 0.2 N NaOH. The material is washed with brine, dehydrated and dried. Concentrated to a tan oil micro .FCC up to 50% EtOAc / hexanes to give the desired product (378 mg, 77%) '. Analysis of the data line in line with those previously described as a white solid. Intermediate 35

Diisopropyl (1-(2-ethylphenyl)pent-4-enyloxy) sec. - 1 - dimethyl-2-vinylbenzene (2.8146 g, 15.38 mmol) by Anhydrous benzene was azeotroped twice 'and then dissolved in THF (50 mL). Allow the solution to cool to -78. Hey. BuLi (6.77 ml, 16.91 mmol) was added to the reaction mixture at -78 °C, and the mixture was stirred at this temperature for 20 minutes. A pentane-4-thracement (1.670 ml, μ 91 mmol) was added to the reaction mixture and was stirred for 4 hours while allowing the bath temperature to slowly warm. Chlorotriisopropyldecane (3.58 ml, 16.91 mmol) was added to the 139424-65-201036969 reaction mixture and the reaction was stirred overnight while allowing the reaction to warm to room temperature. Most of the solvent was removed via vacuum and the crude material was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. The product was obtained by flash column eluting with 0 to 30% of ether in hexane (3.9 g, 74% yield). MS (ESI) [M+H+] = 346.46. Intermediate 36

(Z)-9-(Triisopropyldecyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridine. Hydrogen chloride (5.64 mL, 11.28 mmol) (10 mL, 2M Add diethyl ether solution to a solution of 2-(1-(triisopropyldecyloxy)pent-4-enyl)-3-vinylpyridine (3.9 g, 11.28 mmol) in CPKCl2 (25 mL) . The solvent was removed via vacuum and the corresponding HCl salt was azeotroped twice with benzene. The reaction was charged with CH.sub.2Cl.sub.2 (500 mL) and then N.sub.2 for 10 min. then then Grubb II (0.192 g, 0.226 m.m.). The reaction was heated to 40 ° C for 3 hours and LCMS showed no starting material remained. The reaction was washed once with a saturated NaHC03 solution. The CH2C12 was separated, dried (Na2SO4), filtered and concentrated. The desired product was obtained as a yellow oil (2.54 g, 71% yield) from EtOAc. MS (ESI) [M+H+] = 318.35. Intermediate 37 139424 -66- 201036969

Acetate 6-lysyl-9-(diisopropylpropenyloxy)-6,7,8,9-tetrahydro-5Η-cycloheptyl • and [b&gt;pyridin-5-yl ester·N -Bromoacetamide (2.021 g, 14.65 mmol) at

Add to (Z)-9-(triisopropyldecyloxy)_8,9-dihydro-7H-cyclohepta at room temperature and under N2 [noise ratio (4.5597 g, 14.36 mmol) and vinegar • Acid clock (3.79 g, 57 4 ¢) 耄 Moel) in AcOH (100 ml) suspension. The flask was covered with alumina foil and allowed to stir at room temperature overnight. The reaction turned into a clear yellow solution. The solvent was evaporated by high vacuum. The crude material was subjected to liquid separation between water and ethyl acetate. Add Na2C03 until no blistering. The organic material was separated and the aqueous solution was extracted again with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, The crude is used as it is. MS (ESI) [M+H+] = 45836.

Epoxidized Acetic Acid 6·Bromo-{9-(Triisopropyldecyloxy)_6,7,8,9-tetrahydro-5H-cyclohepta[b]P-pyridyl-5-yl ester Sodium (3.77 g, 69.8 mmol) was added at room temperature and Ν2 to acetic acid 6-bromo-{9.(triisopropyldecyloxy)-6,7,8,9-tetrahydro-5- Cycloheptyl and pyridine-5-yl ester (6 37 g, 13% mmol) in THF (100 mL). The reaction was stirred for 2 hours. 139424 -67- 201036969 shows that there is no longer a starting material, and the product is a more polar spot than the starting material. The solvent was removed via vacuum and the crude material was partitioned between ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried <RTI ID=0.0>(~~~~~~~~~~~~~~~ MS (ESI) [M+H+] = 334.30. Intermediate 39

9·(Triisopropyldecyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-6-ol · epoxide (4.22 g ' 12.65 mmol) A mixture of palladium on carbon (0.45 g, 0.423 mmol) in MeOH (100 mL). TLC showed no more starting material, and a more polar spot was the desired product. The reaction was filtered through a pad of silica and washed with methanol. The filtrate was concentrated to give the desired product as a brown oil (yield: 41 g, 97%). MS (ESI) [M+H+] = 336.37. Intermediate 40

9-(Triisopropyldecyloxy)_8,9-dihydro·5H-cyclohepta[b]pyridine·6(7H)_ was packed in an oven-dried 500 ml round bottom flask under N2. Gasified grasshopper (6.49 ml, 72.9 mmol), CH2C12 (150 ml). Make 139424 -68- 201036969

The bottle was cooled to -60 ° C and DMSO (6.90 mL, 97 mmol) was added dropwise to the reaction mixture. After completion of the addition, the reaction was stirred at _6 〇〇c for 30 minutes, then, at -60 ° C, 9-(triisopropyldecyloxy)_6,789_tetrahydro-5H- Cyclohepta [bM pyridine-6-ol (8.1557 g, 24.31 mmol) (dissolved in 20 mL of CH2C12 and rinsed with 20 mL of CH2C12) was cannulated to the reaction mixture. The reaction was stirred at -55 °C for 40 min then TEA (16.94 mL &apos; The reactant appeared to form a thick suspension. The reaction was disturbed for 1 hour' and water was added to the reaction mixture. The organic layer was separated&apos; and the aqueous layer was extracted twice by CH2C12. The CH2C12 layer was combined, dehydrated and dried (Na2S04)' filtered, and hanked. The flash column was obtained as a yellow oil (1.49 g, 18.4%) from 25% to 50% of ethyl acetate. MS (ESI) [M+H+] = 334.30; 1H NMR (400 MHz,

Ppm 8.36 (d, J = 5.04 Hz, 1H) 7.46 (d, J = 7.55 Hz, 1H) 7.16 (dd, J = 7.55, 4.78 Hz, 1H) 5.22 (dd, J = 4.78, 2.27 Hz, 1H) 4.66 (d, J = 14.35 Hz, 1H) 3.26 (d, J = 14.60 Hz, 1H) 2.94-3.05 (m, 1H) 2.42-2.55 (m, 1H) 2.36 (dd, J ❹ =14·1〇, 5.04 Hz, 1H) 2.03-2.17 (m, 1H) 1.03-1.16 (m, 3H) 0.96-1.00 (m, 9H) 0.89-0.92 (m, 9H) ° Intermediate 41 Tf \

Trifluoromethanesulfonic acid (Ε)·9·(triisopropyldecyloxy)-8,9-dihydro-711-ring

庚[b]acridin-6-yl ester. Add LDA (3.73 ml, 7.45 mmol) to -DM ° 139424 -69 - 201036969 to DMPU (2.073 ml, 17.20 mmol) and 9- (Triisopropylsilyloxy)-8,9-dihydro-5H-cyclohepta[b&gt; pyridine-6(7H)-one (1.9119 g, 5.73 mmol) in THF (25 mL) In solution. The reaction was spoiled at this temperature for 2 hours and then 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) sulfonamide (2.66 g, 7.45 m) was added. Moore). The reaction was stirred overnight while gradually warming to room temperature. The solvent was removed in vacuo and the crude material was loaded onto a flash column to &lt;RTI ID=0.0&gt;&gt; MS (ESI) [M+H+] = 466.33; 1H NMR (400 MHz, EMI-D) δ ppm 8.37 (dd, J = 4.78, 1.51 Hz, 1H) 7.47-7.54 (m, 1H) 7.20 (dd, J = 7.81, 4.78 Hz, 1H) 6.43 (d, J = 2.01 Hz, 1H) 5.26 (d, J = 7.55 Hz, 1H) 3.16-3.32 (m, 1H) 2.58-2.69 (m, 1H) 2.29- 2.39 (m, 1H) 1.85-1.98 (m, 1H) 1.01-1.09 (m, 3H) 0.93-1.00 (m, 9H) 0.85 (d, J = 7.05 Hz, 9H). Intermediate 42

(Ε)-6-(2,3·difluorophenyl)-9-(triisopropyldecyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridine. 2, 3-difluorophenyldihydroxyborane (0.936 g, 5.93 mmol), sodium carbonate (4.57 ml, 9.14 mmol), trifluoromethanesulfonic acid (E)-9-(triisopropyldecyl) Oxy))8,9-dihydro-7H-cyclohepta[b]pyridin-6-yl ester (2.3 g '4.94 mmol) and hydrazine (triphenylphosphine) (9) (0.285 g, 0.247 mmol) A mixture of terpene (30 ml) and MeOH (6 ml) was added to N2 under a charge of 139424-70-201036969 heat to 80 ° C for 3 hours. LCMS showed no more starting material. The reaction was diluted with ethyl acetate and washed once with water. The ethyl acetate layer was separated, dried (Na2SO4) filtered and concentrated. The desired column (0.8797 g, 54%) was obtained from EtOAc (EtOAc) EtOAc. MS (ESI) [M+H+] = 430.43. Intermediate 43

氓)-6-(2,3-difluorophenyl)·8,9·dihydro_7Η·cyclohepta[b>gt; pyridine-9-alcohol. (E)-6-(2,3- Difluorophenyl)-9-(triisopropylsulfonyloxy)·8,9-dihydro-7H-cyclohepta[b]pyridine (1.6072 g, 3.74 mmol) with TBAF (7.48 ml, 7 • 48 mmol of the mixture in THF (10 mL) was stirred at room temperature for a few hours. LCMS showed no more conversion of the starting material and the desired product. The solvent was removed via vacuum. The reaction was purified by flash column eluting with EtOAc EtOAc EtOAc (EtOAc) All analytical data are consistent with those described above. Intermediate 44

• 1 liter of round _9~tetrahydro-5H-cyclo(R)_9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine_5_鲖·2_enzyme The reduction bottom flask was charged with (3)_9-hydroxy-6,7,8,9hepta[b]pyridin-5-one (19.14 g, 108 mmol) in THF (300 mL) (by two 139424-71). Obtained in 201036969, obtained a light orange solution. 4-Nitrobenzoic acid (27.1 g, 162 mmol) and Ph3P (42.5 g, 162 mmol) were added under nitrogen and the mixture was cooled to 0 °C. Diisopropyl azodicarboxylate (31.9 mL, 162 mmol) was added dropwise. The mixture was gradually warmed to room temperature and stirred overnight (5:00 pm). The color changes to a tan. 15 hours: LCMS showed complete conversion. 80 ml of water was added followed by LiOH (7.76 g, 324 mmol). The mixture was stirred at room temperature for 2 hours (some of the LiOH was not completely dissolved). 2 hours: LCMS showed complete conversion (product / dehydration ~ 7/1, by integration). The THF was stripped and the residual mixture was slowly acidified with 40 mL of concentrated HCl (12N). Add 300 ml of EtOAc. The mixture was shaken in a 1 liter separatory funnel (for better separation, 10 ml of hexane was added). The layers were separated and the organic layer was extracted with water (2×50 mL). The combined aqueous layers were washed with EtOAc (4×100 mL). Then, a yellow-brown aqueous solution was slowly basified with 50 mL EtOAc EtOAc (EtOAc) The aqueous layer was saturated with NaCl and extracted with EtOAc (2×100 mL). The combined yellow-brown organic layers (TLC showed the desired product, dehydrated product and one part of the base) were washed with brine, dried and dried, and concentrated to a tan oil (crude weight: 19.24 g, 100%). In the next step. MS (ESI) [M+H+] = 178.24. Intermediate 45

(R)-9-(Triisopropyldecyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-5-one. Add to a 1 liter round bottom flask (R)-9-hydroxyl 139424-72- 201036969 in CH2C12 (300 ml) -6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (19.14 g, 108 Milligram) (azeotrope with anhydrous benzene) to obtain a tan solution. After cooling to 〇 °c, TIPS-OTf (29.3 ml, 1 〇 8 mmol) and Et3N (30.1 ml, 216 house moles) were added via a syringe and the mixture was stirred at 〇 ° C for 1 hour. LCMS shows the complete conversion. The volatile material was stripped off, and the residue was subjected to liquid separation between the NaHC〇3 solution and a〇Ac. The layers were separated and the org. The product was obtained as a white solid (26.3 g, 73% over two steps). MS (ESI) [M+H+] = 344.37. Intermediate 46

(6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropyldecyloxy)_6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine -5-ketone. See Fox, JM; Huang, X.; Chieffi, Q A.; Buchwald, SL丄Am. C/iem. Soc. 2000, J22, 1360-1370. A third liter of sodium butoxide (13.19 g '137 mmol), palladium acetate (9) (〇·948 g, 422 mmol) and 2 weighed in a nitrogen bag were placed in an oven-dried 1 liter flask. -(Dicyclohexylphosphino)-2'-methylbiphenyl (1 539 g, 4.22 mmol). (R)-9-(diisopropyl oxalyloxy)-6,7,8,9-tetrahydro-5-cyclohepta[b]pyridin-5-one (35.21 g, 1) was added under nitrogen. 〇 6 mM), benzene (106 ml) (already degassed by nitrogen in the original plate) and 丨 bromo 2,3-difluorobenzene (14 18 ml, 127 mmol). The flask was stirred at 80 ° C for 20 hours in a preheated oil bath. The volatiles were stripped off and the residue was partitioned between Et 〇Ac (400 mL) and water (4 〇〇 139424 • 73 - 201036969 liters). Separate the liquid layer. The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over Celite, and concentrated to dark oil. It was packed through a silica gel cartridge (filled with CH2C12 and eluted with Et 〇Ac/hexane to up to 30% EtOAc). The crude product was obtained as a dark red oil (86% mass.). 1H NMR showed an approximate 6/1 ratio of the desired trans isomer to the cis isomer. MS (ESI) [M+H+] = 446.21. Intermediate 47

(6R,9R)-6_(2,3-Fluoro-yl)-6,7,8,9-tetrahydro-5H-cyclohepta [Lingbite 9. Alcohol. In a 250 ml round bottom flask Add (9R)_6_(2 3 -difluorobenyl)-9-(diisopropyl sulphonyloxy)-6,7,8,9-tetrahydro-5H-cyclohexane in MeOH (50 mL) The heptano[b]p ratio was determined by -5-_ (9.59 g ' 21.52 ^: mole) to obtain a pale yellow solution. NaBH4 (1.628 g, 43.0 mmol) was added and the mixture was stirred at room temperature for 4 min. LCMS showed complete conversion (the main absorption peak and the lesser absorption peak of the isomer). 1 hour: MeOH was stripped in vacuo and the residue was partitioned between water and Et EtOAc. Separate the liquid layer. The organic layer was washed with brine, dried and dried and concentrated to a pale yellow oil (9.63 g, 100%). MS (ESI) [M+H+] = 448.40. Add (9R)-6-(2,3--random base) winter (diisopropyl sulphate) to 6,7,8 in CH2C12 (1 mL) in a 500 mL round bottom flask. , 9-tetrahydro-5H-cyclohepta[b]pyridin-5-ol (9.63 g, 21.52 mmol) (azeotroped with anhydrous benzene) afforded a pale yellow solution. After cooling to an ice bath (TC, slowly add Ms-Cl (1.845 mL, 23.67 mmol) and Et3N (9.00 139424-74-201036969 mL, 64.6 mmol) via a syringe under nitrogen. After a few minutes, the cooling bath was removed and the mixture was stirred at room temperature for 2 h (color changed to reddish brown). LCMS showed complete conversion. The solvent was stripped and the residue was taken from NaHC03 and EtOAc (150 Separate the liquid layer between the milliliters. Separate the liquid layer. Wash the organic layer with brine, dehydrate dry and concentrate to a yellow oil and dry overnight (10.82 g, 96%). MS (ESI) [M+H+] = 526.28. Add to a 500 ml round bottom flask with decanesulfonic acid (9R)-6-(2,3-difluorophenyl)-9-(triisodecylpropyl decane) in THF (100 mL)氧基oxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl ester (1131 g, 21.52 mmol) gave a pale yellow solution. Slowly add LAH (16.14 ml, 32.3 mmol) (2M in THF) to the syringe and mix the mixture for 1 hour at room temperature (color converted to red). LCMs are displayed. Conversion. Add anhydrous Na2SO4 and slowly quench the reaction with water to form a gel. Combine with aqueous solution to give a pale yellow oil. Purify by FCC up to 70% EtOAc / hexane to give the first The absorption peak, the desired product, is a dense yellow-brown oil (dry, after 4 days: L44 g, Q 24%), and its 1H NMR and HPLC/LCMS meet the racemates described above. Recyclable to 22% higher Hydrolyzed glycols. Intermediate 48

(5S,6S,9R)-6-(2,3-I-phenyl)_9·(triisopropylpropenyloxy)_6,7,8,9·tetrahydro-5Η_cyclohepta[noisy (9R)-6-(2,3-difluorophenyl)-9-(triisopropyl) in a 1 liter round bottom flask with cyclopentyl methyl ether (400 ml) Base decane 139424 -75- 201036969 oxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-5-one (48 g, ι 8 mmol), obtained yellow Brown solution. After cooling to _15 〇c in an ice MeOH bath, lithium borohydride (9.39 g, 431 mmol) was added, and the mixture (uneven) was gradually warmed to KTC over 4 hours and stirred at room temperature. 30 minutes. 11:]^5 shows a very good conversion. It was slowly quenched with 30 mL of MeOH and most of the volatiles were stripped under high vacuum. The residual material was diluted with hydrazine and the reaction was quenched slowly with water and stirred well. The mixture was stirred at room temperature overnight. Separate the liquid layer. The dark organic layer was washed with brine, dried and dried and evaporated todield. It is carried directly to the next reaction. MS (ESI) [M+H+] = 448.14. Intermediate 49

Methanesulfonic acid (58,68,9 6-(2,3-difluorophenyl)-9-(triisopropyldecyloxy)-6,7,8,9-tetradec-5H-ring Geng and [b> than bite-5-base vinegar. Add 1% liter round bottom flask to C6H5CF3 (500 ml) (55 wind 911)-6-(2,3-difluorophenyl)-9-( Diisopropylcarbyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]bite_5-alcohol (47.17 g '105 mmol) (with anhydrous benzene) Boil), a yellow-brown solution was obtained. Ms-Cl (24.63 ml, 316 mmol) was added at 0 C, then Et3N (73.4 mL, 527 mmol) was added in a dropping funnel under nitrogen (11 pm) :00) After adding Et3N dropwise, the suspension was stirred at room temperature for 2 hours. LCMS mainly showed the product parent ion (overlapped with the starting material in LCMS). The solvent was stripped' and the residue was NaHC03 The solution (300 ml) was slowly processed. Add 139424 -76- 201036969

EtOAc (400 mL). The layers were separated and aqueous brine evaporated with EtOAc The combined organic layers were washed with brine, dried w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ MS(ESI)[M+H+] = 526.14 » Intermediate 50

(6R,9R)-6-(2,3-difluorophenyl)-9-(triisopropyldecyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b Pyridine·In a 2 liter flask, methanesulfonic acid (53,65,9 ft)-6-(2,3-difluorophenyl)-9-(triisopropyldecyl) in THF (300 mL) was added. Oxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl ester (55.2 g, 1 〇 5 mmol) (azeotrope with anhydrous benzene), obtained yellow Brown solution. Superhydride (525 ml, 525 mmol) (1.0 M in THF) was added dropwise via a dropping funnel, and the mixture was stirred at room temperature for 4 hr. The THF was stripped and the tan oil was partitioned between water (300 mL) and EtOAc (400 mL). The layers were separated and the organic layer was washed with brine, dried and dried, and concentrated to a brown oil (n. Purified by FCC (2.5 liter packed column) up to 30% EtOAc / hexane, good purification will not be obtained 'but it will remove the baseline (not very uv activity) useless (only use Shishi gum to fill the column, And &lt;10% EtOAc/hexane should also be acceptable). All of the lower polar fractions collected were combined and concentrated to a tan oil (33.58 g) and used directly in the next step. MS (ESI) [M+H+] = 422.21. Intermediate 51 139424 •77- 201036969

(6R,9R)-6-(2,3-difluorophenyl)·6,7,8,9·tetrahydro·5Η·cyclohepta[b]pyridine-9-ol. In a 1 liter round bottom flask (6R,9R)-6-(2,3-difluorophenyl)-9-(triisopropyldecyloxy)-6,7,8,9-tetra was added to THF (400 ml) Hydrogen-5H-cyclohepta[b]pyridine (19.58 g, 45.4 mmol) afforded a tan. TBAF (54.4 mL, 54.4 mmol) was added via syringe and the mixture was stirred at room temperature overnight. 15 hours: LCMS showed complete conversion. Steam raised THF. The residue was combined with 78213-100 and partitioned between 400 mL EtOAc and 300 mL water. Separate the liquid layer. The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried and dried and evaporated. Carefully purified by FCC with gradients up to 20% EtOAc/hexanes to remove slightly less polar spots. All products were recrystallized from MeOH. Obtained an X-ray structure. The total yield from TIPS-protected hydroxyketones was over 26%. All analytical data are consistent with those described above. MS (ESI) [M+H+] = 276.15; 1H NMR (500 MHz, chloroform-d) ά ppm 8.45 (d, J = 4.88 Hz, 1 Η) 7.50 (d, J = 7.63 Hz, 1H) 7.20 (dd, J = 7.48, 5.04 Hz, 1H) 7.01-7.11 (m, 3H) 4.92 (dd, J = 11.29, 2.14 Hz, 1H) 3.18-3.30 (m, 1H) 2.90-2.99 (m, 1H) 2.84 (d, J = 14.04 Hz, 1H) 2.33-2.43 (m, 1H) 2.16-2.26 (m, 2H) 1.56-1.73 (m, 1H). Intermediate 52

139424 -78- 201036969 6-(2,3-Difluorophenyl)-7,8-dihydro-5H-cyclohepta[b]pyridine-9(6H)-one. Under -55 ° C under nitrogen To a 100 ml round bottom flask dried in an oven was added chlorinated hydrazine (0.131 ml, 1.497 mmol) in CH2C12 (4 mL). DMSO (0.212 mL, 2.99 mmol) was added dropwise over 10 minutes. After the solution was stirred for an additional 30 minutes, (6R,9R)-6-(2,3-difluorophenyl)-6,7 was dissolved in 2 ml of CH2C12 (plus 2 ml of rinse) via cannula. , 8,9-Tetrahydro-5H-cyclohepta[b]pyridin-9-ol (206 mg, 0.748 mmol) (racemic, azeotroped with anhydrous benzene) over 5 min. The reaction mixture was stirred at -50-55 ° C for an additional 40 minutes (the solution turned milky white). Et3N (0.521 mL, 3.74 mmol) was added via syringe at -50 °C and the reaction mixture was stirred for 30 min. Water and EtOAc were added and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated to a brown oil. TLC (1/1 EtOAc/hexane) showed two spots: predominantly more polar (comparable to cis-alcohol) and a small amount of starting material. Purification by FCC up to 60% EtOAc / hexanesield MS (ESI) [M+H+] = 274.30. 1H NMR (400 MHz, chloroform-d) 5 ppm 8.57 (dd, J = 4.66, 1.64 Hz, 1H) 7.39 (d, J = 7.81 Hz, 1H) 7.20-7.31 (m, 1H) 6.83-7.04 (m, 2H) 6.72 (t, J = 6.92 Hz, 1H) 3.50 (dd, J = 9.32, 6.30 Hz, 1H) 3.09 (d, J = 6.30 Hz, 2H) 2.84-2.99 (m, 1H) 2.68-2.84 (m , 1H) 2.03-2.17 (m, 1H) 1.85-2.02 (m, 1H); 13C NMR (100 MHz, chloroform-(1) (5??111 203.43, 154.56, 152.00-149.39 (dd, J = 13.4 with 247 Hz), 149.52-146.94 (dd, J = 12.5 and 247 Hz), 148.83, 138.77, 134.44, 134.22 (d, J = 11.0 Hz), 125.87, 124.16, 122.36, 115.40 (d, J = 17.0 Hz), 39.62, 36.83, 35.19, 27.33. 139424 -79- 201036969 Intermediate 53

(Ε)-2·(6-(2,3-difluorophenyl)-7,8-dihydro-5H-cyclohepta[b]pyridin-9(6H)·yl) See Nagarajan, SR et al., fiz'oorg. Med CTze/n. 2007, 75, 3390-3412. To a 100 ml round bottom flask was added 6-(2,3-difluorophenyl)-7,8-dihydro-5H-cyclohepta[b]pyridine-9(6H)- in toluene (6 mL). _ (148 mg, 0.542 mmol) (azeotrope with anhydrous benzene)' gave a colorless solution. (Triphenylphosphoranylidene)acetate (208 mg, 0.596 mmol) was added and the mixture was heated at reflux overnight (4:30 pm). 16 hours: LCMS showed complete conversion to the desired product. TLC (1/1 EtOAc/hexanes) showed a predominantly lower polarity (slightly less polar than the initial trans-alcohol). The toluene was stripped and the residue was purified by EtOAc EtOAc EtOAc (EtOAc) Both 1H NMR and 13C NMR were obtained, and the structure was confirmed to be a single isomer. MS (ESI) [M+H+] = 346.46; 1H NMR (400 MHz, EMI-D) 5 ppm 8.43 (dd, J = 4.78, 1.76 Hz, 1H) 7.33 (dd, J = 7.55, 1.51 Hz, 1H 7.13 (dd, J = 7.55, 4.78 Hz, 1H) 6.91-7.00 (m, 2H) 6.80-6.90 (m, 1H) 6.36 (s, 1H) 4.17 (q, J = 7.05 Hz, 2H) 3.25-3.43 (m, 2H) 3.04- 3.14 (m, 1H) 2.93-3.05 (m, 1H) 2.88 (dd, J = 14.86, 3.27 Hz, 1H) 2.04- 2.21 (m, 1H) 1.83-2.02 (m, 1H) 1.25 (t, J = 7.05 Hz, 3H); 13C NMR (100 MHz, chloroform-d) 5 ppm 166.45, 159.22, 158.59, 151.99-149.47 (dd, J = 13.4 and 247 Hz), 149.39-146.90 (dd, J = 12.7 and 245 Hz), 147.55, 137.88, 139424-80-201036969 135.46 (d, J = 11.4 Hz), 133.41, 123.98, 123.25, 122.43, 120.89, 115.09 (d, J = 16.9 Hz), 59.94, 38.62 , 36.30, 32.49, 28.85, 14.27. Intermediate 54

(Ε)-2·(6-(2,3-difluorophenyl)-7,8-dihydro-5H-cyclohepta[b]adenine bite_9(6H)_yl)acetate·50 (E)-2-(6-(2,3-Fluorophenyl)-7,8-dihydro-5H-cyclohepta[b]pyp in THF (1 mL) More than a bit of _9(6H)-yl)ethyl acetate (11.8 mg, 0.034 mmol) afforded a colorless solution. Add u〇H (0.2 mL, 0.200 mmol) and stir the mixture at room temperature overnight (4:30 pm). 16 hours: LCMS showed a small amount of starting material to leave. 〇 5 ml of MeOH was added and the mixture was stirred for additional 24 hours. LCMS showed complete conversion. Concentrate and further dry under high vacuum to remove water to a white solid. It was further dried by azeotropy with anhydrous benzene and under high vacuum for 4 hours. Then, the white solid was directly subjected to the next reaction. MS (ESI) [M+H+] = 316.21. Intermediate 55

(E)-l-(l-(2-(6-(2,3-difluorophenyl)·7,8·dihydro-5H_cyclohepta[b]pyridinium 139424 •81, 201036969 -9(6H )-yl)ethinyl)hexa-argon-p-buty-4-yl)·1Η-flavored saliva[4,5_b]p ratio bite.2(3H)_ ketone. Add in 1 〇〇 ml round bottom flask (e)-2-(6_(2,3-difluorophenyl)-7,8-dihydro-5H-cyclohepta[b]pyrene-pept-9(6H) in CH2C12 (2 ml) -yl)acetic acid (10.72 mg '0.034 mmol) with 1-(hexahydropyridin-4-yl)-iH-imidazo[4,5-b]pyridine-2(3H)-one (22.26 mg ' 0.102 Millol) (bis-HC1 salt) to give a colorless suspension. Add Hunig's base (0.030 ml, 0.170 mmol) with 3-(diethoxyphosphonyloxy)-1,2,3-benzo-three-till-4(3H)-one (20.35 mg, 0.068 millimolar). The reaction mixture was diluted with DMF (0.5 mL). Most of the solids are dissolved. It was stirred at room temperature for 44 hours. It was diluted with EtOAc and washed with water. The organic layer was washed with brine, dried over Na2SO4, and concentrated to a brown oil/gel. Purification by FCC to 8% MeOH in CH2C12 afforded the desired product as white foam (18 mg, 100%). MS (ESI) [M+H+] = 516.27; 1H NMR (400 MHz, chloroform-d) &lt;5 ppm 11.18 (broad s·, 1H) 8.45 (dd, J = 4.78, 1.26 Hz, 1H) 8.04 (d , J = 5.04

Hz, 1H) 7.39 (d, J = 6.55 Hz, 1H) 7.23-7.30 (m, 1H) 7.15 (dd, J = 7.68, 4.91 Hz, 1H) 6.84-7.08 (m, 4H) 6.73 (d, J = 2.52 Hz, 1H) 4.91 (d, J = 12.59 Hz, 1H) 4.61 (td, J = 12.15, 3.65 Hz, 1H) 4.34 (d, J = 12.84 Hz, 1H) 3.37 (broad s·, 1H) 3.02- 3.31 (m,3H) 2.66-2.97 (m,3H) 2.05-2.36 (m, 4H) 1.86-2.00 (m, 2H) 〇Intermediate 56 and 57

139424 -82 201036969 2-((6,9_trans)-6-(2,3-difluorophenyl)-6,7,8,9-tetradecyl-511-cyclohepta[13]pyridine- 9·) ethyl acetate and 2-((6,9-cis)-6-(2,3-difluorophenyl)-6,7,8,9·tetrahydro-5Η·cyclohepta[ b&gt; pyridine-9-yl)ethyl acetate. In a 50 ml round bottom flask was added (E)-2-(6-(2,3-difluorophenyl)-7 in MeOH (6 mL). Ethyl 8-dihydro-5H-cyclohepta[b]pyridin-9(6H)-yl)acetate (113.6 mg, 0.331 mmol) obtained as a colourless. Add Pd/C (35.2 mg, 0.033 mmol). The mixture was stirred under a hydrogen cylinder for 4 hours. It was filtered, washed, and concentrated. FCC up to 50% EtOAc/hexanes gave two desired products, both of which were colorless oils. 1H NMR and 13C NMR of 1 (50.0 mg, 40.5%) and 2 (66.7 mg, 54%) were obtained, and the structure was confirmed. The lower polarity (1) is most likely a trans isomer when compared to an amino phthalate analog (r/cis ratio of 1/1.33). MS (ESI) [M+H+] = 346.25 (tR = 2.20 and 2.42 min, using a 4 min operation on an XBridge 4.6 x 50 mm S5 column). Trans product: 1H NMR (400 MHz, chloroform-d) (5 ppm 8.32 (dd, J = 4.78, 1.51 Hz, 1H) 7.36 (dd, J = 7.43, 1.64 Hz, 1H) 6.93-7.09 (m, 4H ) 4.06-4.23 (m, 2H) 3.68 Q (ddd, J = 10.20, 7.68, 7.55 Hz, 1H) 3.32-3.47 (m, 1H) 3.22 (dd, J = 16.24, 7.93 Hz, 1H) 2.85-3.00 ( m, 1H) 2.74 (d, J = 14.10 Hz, 1H) 2.59 (dd, J = 16.12, 7.05 Hz, 1H) 2.04-2.17 (m, 2H) 1.91 (dt, J = 13.85, 3.40 Hz, 1H) 1.43 -1.61 (m, 1H) U7-1.28 (m, 3H) ; 13C NMR (100 MHz, gas-d-d) ' 5 ppm 173.58, 162.50, 152.01-149.41 (dd, J = 13.3 and 246 1^), 149.41 - 146.73 (dd, J = 24.0 and 244 Hz), 146.28, 136.95, 136.86, 135.45, 124.15, 122.10, 121.41, 114.88 (d, J = 17.0 Hz), 60.13, 41.59, 40.78, 38.58, 38.38, 37.76, 32.90 , 14.27. cis product: 1H NMR (400 MHz, chloroform-d) 5 ppm 8.35 (dd, J = 4.91, 1.64 Hz, 1H) 7.29 (dd, J = 7.30, 1.51 Hz, 1H) 7.02 (dd, 139424 -83- 201036969 J = 7.55, 4.78 Hz, 1H) 6.89-6.97 (m, 2H) 6.79-6.89 (m, 1H) 4.03-4.16 (m, 2H) 3.77 (dt, J = 7.62, 3.87 Hz, 1H) 3.26 (broad s) 1H) 3.10 (d, J = 6.04

Hz, 2H) 2.99 (dd, J = 15.23, 7.43 Hz, 1H) 2.76 (dd, J = 15.23, 8.18 Hz, 1H) 1.77-2.07 (m, 4H) 1.14-1.25 (m, 3H) ; 13C NMR ( 100 MHz, chloroform-d) 5 ppm 172.62, 161.47, 152.00-149.40 (dd, J = 13.7 and 247 out), 149.53-146.75 (dd, J = 20.2 and 245 Hz), 146.90, 137.97, 136.72 (d, J = 11.4 Hz), 133.82, 123.96, 122.41, 121.71, 114.82 (d, J = 17.1 Hz), 60.34, 39.41, 36.84, 36.70, 35.68, 31.42, 29.64, 14.21. Intermediate 58

2-((6,9-cis)-6-(2,3-diphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl) Acetic acid in a 50 ml round bottom flask was charged 2-((6,9-cis)-6-(2,3-fluorofluoro)-6,7,8,9- in THF (2 mL). Tetrahydro-5H-cyclohepta [noise. -9-amino) ethyl acetate (66.7 mg, 0.193 mmol) afforded a colourless solution. LiOH (0.4 mL, 0.400 mmol) was added and the mixture was stirred at room temperature overnight. 16 hours: LCMS showed good conversion with possible starting materials. 1 ml of MeOH was added and the mixture was stirred for additional 24 hours. 1^ River 5 shows complete conversion. / Chen shrink, and further drying under vacuum to remove water into a white solid. It was further dried by azeotropy with anhydrous benzene and under high vacuum for 4 hours. The white solid was then directly subjected to the next reaction. MS (ESI) [M+H+] = 318.22. 139424 -84· 201036969 Example 5

1-(1-(2-(6,9-cis)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b] Pyridine-9-yl)ethenyl)hexahydropyridyl)-1Η-imidazo[4,5-b>pyridin-2(3H)-ketone·In a 100 ml round bottom flask, add CH2C12 (4 ml) 2-((6,9-cis)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-511-cyclohepta[13]pyridine-9 -yl)acetic acid (61.2 mg, 0.193 mmol) and 1-(hexahydropyridin-4-yl)-1 oxime-imidazo[4,5-b]pyridine-2(3H)-one (126 mg, 0.579) Millol) (bis-HC1 salt) to give a colorless suspension. Add Hunig's test (0.169 ml, 0.965 mmol) with 3-(diethoxyphosphonyloxy)-1,2,3-bromo-three-till-4(3H)-one (115 mg, 0.386 millimoles). The reaction mixture was diluted with DMF (1 mL). Most of the solids are dissolved. It was stirred at room temperature overnight for 20 hours: LCMS showed no starting material and the product showed a lower polarity absorption peak. It was diluted with 扱0 Ac &gt; and washed with water. Separate the liquid layer. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to yellow brown oil. Purification by fcC (ISCO) up to 8% MeOH in CH2C12 afforded the desired product as yellow brown foam (91 mg, 87% over 2 steps). LCMS: &gt; 95%. The structure was confirmed by 1H NMR. MS (ESI) [M+H+] = 518.34; 1H NMR (400 MHz, EMI-D) 5 ppm 11.57 (broad s·, 1H) 8.36 (broad s·, 1H) 8.04 (d, J = 4.78 Hz, 1H) 7.26-7.39 (m, 1H) 7.17-7.27 (m, 1H) 6.69-7.07 (m, 5H) 4.81 (t, J = 139424 -85- 201036969 15.36 Hz, 1H) 4.61 (td, J = 12.21, 4.03 Hz, 1H) 4.16-4.39 (m, 1H) 3.77-4.00 (m, 1H) 3.07-3.49 (m, 4H) 2.53-3.04 (m, 3H) 1.65-2.47 (m, 8H). Intermediate 59

2-((6,9-trans)-6-(2,3-difluorophenyl)_6,7,8,9-tetrahydro-5Η·cyclohepta[b&gt;pyridyl 9-yl)acetic acid Add 2-((6,9-trans)-6-(2,3-difluorophenyl)-6,7,8,9-four in THF (2 ml) in a 50 ml round bottom flask Hydrogen-5-cycloheptyl and ethyl pyridin-9-yl)acetate (50.0 mg, 0.145 mmol) afforded a colourless. LiOH (0.4 mL, 0.400 mmol) was added and the mixture was stirred at room temperature overnight. 16 hours: LCMS showed a small amount of starting material to leave. 1 ml of MeOH was added and the mixture was stirred for a further 24 hours. LCMS showed complete conversion. The mixture was concentrated and further dried under high vacuum to remove water to a white solid. It was further dried by azeotropy with anhydrous benzene and under high vacuum for 4 hours. Then, the white solid was allowed to directly accept the next reaction. MS (ESI) [M+H+] = 318.22. Examples 6 and 7

L-(l-(2-((6R,9S)-6-(2,3c fluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b&gt; is more than 139424-86- 201036969 pyridin-9-yl)ethynyl)hexahydropyridin-4yl)-1Η-imidazo[4,5-b]pyridine-2(3H)-one with l-(l-(2-(( 6S,9R)_6-(2,3-difluorophenyl)-6,7,8,9·tetrahydro-5H-cyclohepta[b]acridin-9-yl)ethenyl)hexahydropyridine -4-yl)-1Η-imidazo[4,5-b]pyridine-2(3H)-one·In a 100 ml round bottom flask, 2-((6,9-reverse) was added to CH2C12 (4 ml) -6-(2,3-Difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetic acid (46.0 mg, 0.145 mmol) And 1-(hexahydropyridin-4-yl)-1 Η-imidazo[4,5-b]pyridine-2(3H)-one (95 mg '0.435 mmol) (bis-HC1 salt) obtained A colorless suspension. Add Hunig's base (0.127 ml, 0.725 mmol) with 3-(diethoxyphosphonyloxy)-1,2,3-benzo-three-till-4(3H)-one (87 mg, 0,290 millimoles). The reaction mixture was diluted with DMF (1 mL). Most of the solids are dissolved. It was stirred at room temperature overnight. 44 hours: LCMS showed complete conversion. It was diluted with EtO Ac' and washed with water. Separate the liquid layer. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to a tan oil. Purification by FCC (ISC0) up to 8% MeOH in CH2C12 afforded the desired product as a tan-yellow foam (68 mg, 86%, over 2 steps). MS (ESI) [M+H+] = 518.27; 1H NMR (400 MHz, chloroform-d) 5 ppm 11.44 (broad s) 1H) 8.25-8.42 (m,1H) 8.05 (d, J = 5.29 Hz, 1H) 7_38 (t, J = 8.44 Hz, 1H) 7.20-7.31 (m, 1H) 6.83-7.10 (m, 5H) 4.87 (d, J = 12.34 Hz, 1H) 4.53-4.73 (m, 1H) 4.43 (t, J = 15.36 Hz, 1H) 3.81-4.00 (m, 1H) 3.36-3.60 (m, 2H) 3.24 (t, J = 12.97 Hz, 1H) 2.94 (t, J = 11.21 Hz, 1H) 2.33-2.80 (m , 4H) 2.05-2.31 (m,3H) 1.80-2.05 (m,3H) 1.38-1.63 (m,1H). The racemic product was analyzed by palmar HPLC (Chiralpak AD-H analytical column, 4.6 χ) 250 mm, 5 μm; mobile phase: 40% MeOH in C02; temperature: 35 ° C; flow rate: 2.0 ml/min, after 26 minutes; injection: 5 μl to 2 mg 139424 -87- 201036969 / ML, in MeOH. Compound (6R, 9S) is the first absorption peak with tR = 13.88 minutes, while compound (6S, 9R) is the second absorption peak with ' 19.19 minutes. Intermediate 60

Trans-2-(-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)iso-β-lin -1,3_dione·In a 500 ml round bottom flask, (6,9-cis)-6-(2,3-difluorophenyl)-6,7,8 in CH2C12 (40 mL). 9_tetrahydro-5 Η-cyclohepta[b]pyridin-9-ol (1.56 g, 5.67 mmol) (azeotroped with anhydrous benzene) afforded a colourless solution. Isoporphyrin-1,3-dione (1.667 g, 11.33 mmol) and triphenylphosphine (2.97 g, 11.33 mmol) were added at 0 ° C, followed by DIAD (1.653 mL ' 8.50 mmol) ear). The mixture was allowed to warm to room temperature under nitrogen overnight. 17 hours: LCMS shows complete conversion. Concentrate to dryness. Direct FCC up to 50% EtOAc/hexanes gave two near absorption peaks. The combined absorption peaks (including dehydration by-products) were combined and concentrated to give a white solid which was used directly in the next step. MS (ESI) [M+H+] = 405.21. Intermediate 61

139424 -88- 201036969 trans-6-(2,3-difluorophenyl)·6,7,8,9-tetrahydro·5Η-cyclohepta[b]pyridin-9-amine. In 500 ml round To the bottom flask was added 2-((6,9-trans)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohexane in MeOH (50 mL) Hepto[b]pyridin-9-yl)iso(5)11-dolin-1,3-dione (2·293 g ' 5.67 mmol) afforded a white suspension. Add hydrazine (5 ml '159 mmol) (using 5 ml hydrazine hydrate) and mix the mixture in a 70 C preheated oil bath under nitrogen for 5 hours (solids gradually disappear and new solids gradually formed) . LCMS showed complete conversion. The residue was partitioned between EtOAc and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and dried and concentrated. FCC up to 10% MeOH in CH2C12 (with 2M ammonia), the desired product 'is a colorless oil (0.65 g, 42%, after two steps, one part may have been lost during purification), making it Cured to a white solid upon standing. MS (ESI) [M+H+] = 275.26; 1H NMR (400 MHz, chloroform-d) &lt;5 ppm 8.38 (d, J = 4.78 Hz, 1H) 7.30-7.41 (m, 1H) 6.89-7.10 (m , 4H) 4.28 (d, J = 10.58 Hz, 1H) 3.13-3.29 (m, 1H) 2.63-3.00 (m, 4H) 2.02-2.15 (m, 3H) 1.51-1.70 (m,1H) ; 13C NMR ( 100 MHz, chloroform-d) 5 ppm 170.83, 151.85-149.39 (dd, J = 13.3 and 246 Hz), 149.29-146.72 (d, J = 12.5 and 245 Hz), 146.24, 137.11, 136.62 (d, J = 11.6 Hz), 134.30, 124.17, 122.10, 121.78, 114.95 (d, J = 17.1 Hz), 55.25, 40.52, 37.57, 37.04, 37.00. Intermediate 62 〇

4·(2_keto-2,3-dihydro-1H·imidazo[4,5-b>pyridyl-1-yl)hexa-argonpyridine-1•Rebel 139424 •89- 201036969 An oven-dried 500 ml round bottom flask was charged with 1-(hexahydropyridin-4-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-one mono-salt in CH2C12 (50 mL). The acid salt (2.91 g '9.99 MeOH) was obtained as a tan suspension. Et3N (5.57 mL, 40.0 mmol) was added under nitrogen. Addition of carboxylic acid decyl ester (1.421 ml '9.99 mmol) was added dropwise via a syringe. The mixture was stirred at room temperature overnight (2:00 pm). LCMS showed good conversion (with some starting material left). The reaction mixture was diluted with EtOAc and water. Separate the liquid layer. The organic layer was washed with brine and dried to dryness. The residue was purified by EtOAc (EtOAc:EtOAc) MS (ESI) [M+H+] = 353.30. It is carried on to the next step without further characterization. Intermediate 63 〇

4-(2-keto-3-((2-(trimethyldecyl)ethoxy)indolyl)-2,3-dihydro-1H-indole[4,5-b]acridine- 1-yl) hexahydropyridine carboxylic acid benzyl ester. In a 500 ml round bottom ◎ flask was added 4-(2-keto-2,3-dihydro-1H-imidazo[4] in THF (40 mL). '5-7&gt;bipyridin-1-yl)hexahydropyridine_丨-carboxylic acid benzyl vinegar (1 62 g, 4 6 〇 mmol) gave a colorless solution. Add NaH (0.552 g, 22.99 mmol) (excess). After stirring for 5 minutes under a gas atmosphere, SEM-C1 (0.897 ml, 5.06 mmol) was added. The mixture was stirred at room temperature overnight for 16 hours: LCMS showed good conversion. The reaction mixture was diluted with EtO Ac and the reaction was slowly quenched with water (gas evolution!). Separate the liquid layer. The organic layer was washed with brine, dehydrated and dried, 139424 • 90 - 201036969 and concentrated to a slightly green oil. TLC (10% MeOH/CH2C12) showed the major blue spot (Rf~ 0.25) (slightly less polar than the starting material). Purified by FCC up to 10% MeOH/CH.sub.2 C.丨92 g '87%). MS (ESI) [M+H+] = 483, 33; 1H NMR (400 MHz, chloroform-d) 5 ppm 7.25-7.40 (m, 6H) 6.82-6.94 (m, 1H) 6.60 (t, J = 7.05 Hz , 1H) 5.66 (s, 2H) • 5.11 (s, 2H) 4.45-4.63 (m, 1H) 4.33 (broad s) 2H) 3.55-3.69 (m, 2H) 2.88 (d, J = 1.01 Hz, 2H) 2.06 (d, J = 9.06 Hz, 2H) 1.80 (d, J = 11.58 Hz, 2H) 0.82-1.00 (m, 2H) -0.13 - -0.03 (m, 9H) 〇 Intermediate 64

ο 1-(Hexahydropyridin-4-yl)-3-((2-(trimethyldecyl)ethoxy)methyl)·1Η_imidazo[4,5-b]pyridine-2 (3Η )-嗣·In a 500 ml round bottom flask, 4-(2-keto-3-((2-(trimethyldecyl)ethoxy)methyl)) 2,3_ in MeOH (30 mL) Dihydro-1H-«m. Sit and [4,5-7&gt;bipyridin-1-yl)hexahydropyridine small carboxylic acid (1.85 g ' 3.83 mmol) to obtain a colorless solution. Pwc (0.408 g, 0,383 mmol) was added and the mixture was stirred under a hydrogen atmosphere overnight. 17 hours: LCMS shows complete conversion. It was filtered & washed and concentrated under high vacuum to a colorless foam (1.31 g &apos; 100%). MS (ESI) [M+H+] = 349.29; 1H NMR (400 MHz, chloroform-d) 5 ppm 9.55 (broad, 1H) 7·64-8·06 (m,1H) 7·42 (broad s., 1Η) 6.81 (broad s., 1Η) 5.66 (broad s., 2Η) 4.73 (d, J = 13.85 Hz, 1Η) 3.42-3.89 (m, 4H) 3Ό8-3.42 (m, 2H) 2.88 (broad s. , 2H) 1.72-2.16 (m, 2H) 0.76-0.94 (m, 2H) -0.22 - -0.08 (m, 9H). 139424 -91 · 201036969 Intermediate 65

N-((6,9-trans)·6_(2,3-difluorophenyl)-6,7,8,9·tetrahydro-5H-cyclohepta[bl·this pyridine-9-yl) 4-(2-keto-3-((2-(trimethyldecyl)ethoxy)methyl)-2,3-dihydro·-1H- miso[4,5-b] P-biti-1-yl) hexahydro-p-biten-1-reaminer. In a 100 ml round bottom flask dried in an oven 0, 1-(hexahydropyridin-4-yl) in CH2C12 (8 ml) was added. -3((2-(Trimethyldecyl)ethoxy)methyl)-iH-imidazo[4,5-b]pyridine-2(3H)-one (262 mg, 0.752 mmol) ), obtaining a colorless solution. Et3N (0.192 mL, 1.379 mmol) was added under nitrogen and the mixture was cooled to -20. Trioxoformate (〇.〇, 61 mL, 0.502 mmol) was added dropwise. The mixture was gradually warmed to 1 ° C for 1 hour and stirred, during which time the solution turned yellowish. TLC (1〇% Me〇H/CH2C12) showed that the predominantly lower polarity bright blue spot&apos; did not have a starting material at baseline. ο Let it shrink to dryness (white solid) under a vacuum of the frame and dry out under high vacuum. Add (6 9 trans) 6 (2 3 difluorophenyl sulfonium 7,8,9-tetrahydro-) dissolved in 1 ml of THF (plus 2 liters of rinsing solution) via cannula at room temperature. 5H-J 庚 并 and [b] pyridine 9-amine (172 mg, 〇 627 mM) with paragraph (1) 192 - ml, 1,379 mmol). Additional light Et3N (0.192 mL, 1.379 mmol) was added and the resulting pale yellow suspension was stirred overnight under nitrogen. W hours ♦ LCMS shows complete conversion. It was diluted with water and Et〇Ac. Separation 139424 -92- 201036969 Liquid layer. The organic layer was washed with brine, dried over Na 2 EtOAc and concentrated. Purification by FCC up to 10% MeOH / CH.sub.2C to afford the desired product (465 mg, 93%). MS (ESI) [M+H+] = 649.34; 1H NMR (500 MHz, EMI-D) δ ppm 8.36 (d, J = 4.88 Hz, 1H) 7.96-8.09 (m, 1H) 7.55 (d, J = 4.27 Hz, 1H) 7.46 (d, J = 7.63 Hz, 1H) 7.29 (d, J = 7.93 Hz, 1H) 7.13 (t, J = 6.10 Hz, 1H) 6.97-7.09 (m, 3H) 6.93 (dd, J = 7.32, 5.49 Hz, 1H) 5.39 (s, 2H) 5.11 (dd, J = 10.38, 3.66 Hz, 1H) 4.53-4.66 (m, 1H) 4.33 (t, J = 11.29 Hz, 2H) 3.70 (t , J = 8.24 Hz, 2H) 3.25-3.44 (m, 1H) 2.84-3.05 (m, 3H) 2.77 (d, J = 14.04 Hz, 1H) 2.19-2.50 (m, 4H) 2.11 (d, J = 14.04 Hz, 1H) 1.91 (d, J = 11.29 Hz, 2H) 1.53 (t, J = 12.05 Hz, 1H) 0.95 (t, J = 8.24 Hz, 2H) -0.06 (s, 9H). Examples 8 and 9

N-((6R,9R)-6-(2,3.Difluorophenyl)-6,7,8,9-tetrahydro.5Η·cyclohepta[b&gt;pyridin-9-yl)-4 -(2-keto-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)hexapyridine-1-carboxamide and N-((6S,9S)- 6-(2,3.Difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-4-(2-keto-2,3 · Dihydro-1H·imidazo[4,5-b]pyridine·1·yl)hexahydropyridine-1-carboxamide. Add 250% to 250 ml round bottom flask with CH2C12 (4 mL). 6,9-trans)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5Η-cyclohepta[b]pyridin-9-yl)-4-( 2-keto-3-((2-(tridecyldecyl)ethoxy)methyl)-2,3-dihydro 139424-93- 201036969 -1H-P m. Sit and [4,5- b&gt;biter-1-yl) hexahydrop is a bite-l-indole amine (racemate) (200 mg, 0.308 mmol) to obtain a tan solution. TFA (1.000 mL) was added, and the mixture was stirred at room temperature for one hour. LCMS showed complete conversion. Vapor volatiles. The residue was partitioned between 〇.5N NaOH and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (EtOAc (EtOAc) The combined organic layers were washed with brine, dried over EtOAc EtOAc EtOAc The desired racemic product (118 mg, 74%) was obtained as a colorless foam / solid. LCMS shows &gt;95% impurities. MS (ESI) [M+H+] = 519.24. 1H NMR (400 MHz, chloroform-d) 5 ppm 11.78 (b s., 1H) 8.23-8.41 (m, 1H) 7.98 (d, J = 4.28 Hz, 1H 7.56 (d, J = 4.28 Hz, 1H) 7.34-7.47 (m, 1H) 7.19-7.33 (m, 1H) 7.07 (dd, J = 7.43, 4.91 Hz, 1H) 6.90-7.02 (m, 3H) 6.87 (dd, J = 7.81, 5.29 Hz, 1H) 5.12 (dd, J = 10.45, 3.90 Hz, 1H) 4.46-4.64 (m, 1H) 4.19-4.42 (m, 2H) 3.28 (t, J = 12.59 Hz, 1H) 2.88-3.05 (m, 2H) 2.77-2.86 (m, 1H) 2.71 (d, J = 13.85 Hz, 1H) 2.41 (d, J = 13.35 Hz, 1H) 2.14-2.34 (m, 3H) 2.04 ( d, J = 12.09 Hz, 1H) 1.86 (d, J = 10.32 Hz, 2H) 1.37-1.58 (m, 1H). The racemic product was resolved by palmar HPLC (Chiralpak AD-H analytical column, 4.6 x 250 mm, 5 μm; mobile phase: 40% MeOH in C02; temperature: 35 ° C; flow rate: 2.0 ml / min, after 32 minutes; UV monitoring, @ 292 nm; injection: 5 μl ~ 2 mg / ml in MeOH). The compound (6R, 9R) was the first absorption peak with tR = 15.26 minutes, while the compound (6S, 9S) was the second absorption peak with tR = 24.98 minutes. Intermediate 66 139424 -94- 201036969

(E) _6-phenyl·9·(triisopropyldecyloxy)_8,9·dihydro-7H-cyclohepta[b]pyridine. Phenyldihydroxyborane (0.060 g, 0.495 m) Mohr), sodium carbonate (0.382 ml, hydrazine, 764 mmol), trifluoromethanesulfonic acid (E) _9_(triisopropyl fluorenyloxy)-8,9-dihydro-7H-ring Hepto[b]pyridin-6-yl ester (0.1922 g, 0.413 mmol) and hydrazine (triphenylphosphine) red (0) (0.024 g, 0.021 mmol) in toluene (5 mL) with MeOH (1) The mixture was heated to 8 (TC for 3 hours) under N2. LCMS showed that there was no more starting material. The reaction was diluted with ethyl acetate and washed once with water. The ethyl acetate layer was separated and dried. (Na2S04), filtered, and concentrated to give a crude material. </RTI> <RTI ID=0.0></RTI> <RTIgt;

(Ε)·6-(2,5-difluorophenyl)-9-(triisopropyldecyloxy)·8,9-dihydro·7Η·cyclohepta[b&gt;bipyridine·2 , 5-difluorophenyl dihydroxyborane (0.088 g, 0.554 mmol), sodium carbonate (0.427 ml, 0.854 mmol), [reactant] and hydrazine (triphenylphosphine) (9) (0.027 g' A mixture of 0.023 mmol was heated in a mixture of toluene (5 mL) and EtOAc (1 mL). LCMS showed no more starting material. The reaction was diluted with ethyl acetate and washed once with water 139424 - 95 - 201036969. The ethyl acetate layer was separated, dried (Na2SO4), filtered, and concentrated to give crude. The crude is used as it is. MS (ESI) [M+H+] = 430.29. Intermediate 68

(E)-6-(3,4-difluorophenyl)-9-(triisopropylsulfonyloxy)_8,9_dioxin·7H_ 0 Cycloheptylene bite ·3,4 -Difluorophenyl di-basic burning (〇〇83 g, 0.527 house Moule), sodium carbonate (0.406 ml, 0.813 mmol), trifluorodecanesulfonic acid (E)-9-(triisopropyl矽Alkyloxy)_8,9-dihydro·7Ηcycloheptylpyridinyl-6-yl ester (0.2045 g, 0.439 mmol) and hydrazine (triphenylphosphine) (9) (〇〇25 g, α〇 A mixture of 22 mmoles in toluene (5 mL) and MeOH (1 mL). LCMS showed no more starting material. The reaction was diluted with ethyl acetate and washed once with water. The ethyl acetate layer was separated and dried (Na 2 SO 4 ), filtered and concentrated to give a crude material. Use the crude mash for its own use. MS (ESI) [M+H+] = 43 〇 36. Intermediate 69

(E)-6-Benzyl-8,9-dihydro·7Η_cyclohepta[b]p ratio bit-9-ol. Add TBAF (1.041 ml, 1.041 mmol) to room temperature ( E) _6_phenyl_9 (triisopropyl 139424-96-201036969 夕 烧 methoxy)-8,9-dihydro-7H-cyclohepta[b]P ratio bite (0.2049 g, 〇· 521 mmol (THF) in THF (5 mL). The reaction was stirred at room temperature for 6 hours. The solvent was removed via vacuum to give a crude material. MS (ESI) [M+H+] = 238.25. Intermediate 70

(E)-6-(2,5-difluorophenyl)_8,9·dihydro-7 Η·cyclohepta[b]pyridinol·Through TBAF (0.954 ml, 0.954 mmol) at room temperature Add to (e)-6-(2,5-difluorophenyl)-9-(triisopropyldecyloxy)-8,9-dihydro-7H-cycloheptapyridine (0.2049 g, 0.477) Millol) in THF (5 mL). The reaction was stirred at room temperature for 6 hours. The solvent was removed via vacuum and the product was purified by flash column eluting with ethyl acetate from hexane to 50% to 1% (102.2 mg &apos; 78%). MS (ESI) [M+H+] = 274.23 1H NMR (400 MHz, chloroform-d) 5 ppm 8.37 (dd, J = 4.78, 1.26 Hz, 1H) 7.51 (dd, J = 7.81, 1.26 Hz, 1H) 7.17 -7.27 (m, 1H) 6.87-7Ό5 (m,3H) 6.44 (s,1H) 5.74 (broad s.,1H) 4.77 (dd, J = 10.45, 2.64 Hz, 1H) 2.79-2.93 (m, 1H) 2.66-2.77 (m, 1H) 2.48-2.60 (m, J = 13.53, 5.45, 5.45, 2.77 Hz, 1H) 1.97-2.11 (m, 1H). Intermediate 71

(Ε)_6-(3,4·difluorophenyl)·8,9-dihydro-7H-cyclohepta[b]pyridine_9-ol. Will be 139424-97- 201036969 TBAF (0·878 house liter '0878 mmol" was added at room temperature as (8)-6 (34 difluorophenyl &gt; 9-(triisopropyldecyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridine ( The reaction was stirred at room temperature for 6 hours. The solvent was removed in vacuo and the product was purified by flash column with EtOAc EtOAc. The ethyl ester was autolyzed to 5 % to 1% by weight (935 g, 78%). MS (ESI) [M+H+] = 274.23. General reduction procedure: Pd with MeOH (5 mL) The /C (10% activated carbon) (5% molar) substrate (from ΤΒΑ 去除 removal protection) was hydrogenated overnight in a H2 cylinder at room temperature. The reaction was filtered through a pad of diatomaceous earth and treated with ethyl acetate. The ester is washed, the filtrate is concentrated, and the product is purified via a flash column, and the ethyl acetate in hexane is dissolved from 0 to 5 % to 1% by weight. The trans product is first dissolved, which is less, The cis product is more polar and is the main product. Intermediate 72

HO (6,9-trans)-6·phenyl-6,7,8,9-tetrahydro-SH-cyclohepta[b]pyridine·9·ol. Obtained from 0.224 mmol of starting material. 15 mg of product. Combined with the cis isomer, the yield was 98%. MS (ESI) [M+H+] = 240.32. Intermediate 73

HO 139424 •98- 201036969 (6,9-cis)_6-phenyl·6,7,8,9·tetrahydro-5H-cyclohepta[b]pyridine·9-ol. From 0.224 mmol Starting material, 38 mg of product was obtained. Combined with the trans isomer, the yield was 98%. MS (ESI) [M+H+] = 240.32. Intermediate 74

Ο (6,9·trans)-6-(2,5-difluorophenyl)·6,7,8,9-tetraindole-5H-cyclohepta[b]pyridine-9-ol········· Millol starting material gave 19.3 mg of product (trans, lower polarity spot 'Rf~0.7, 25% ethyl acetate in hexane). Merged with the cis isomer&apos; yield was 90%. 1H NMR (400 MHz, chloroform-yield (5??1118.36- 8.45 (m, 1H) 7.46 (dd, J = 7.55, 1.26 Hz, 1H) 7.16 (dd, J = 7.43, 4.91 Hz, 1H) 6.94-7.04 (m, 2H) 6.83-6.92 (m, 1H) 4.87 (dd, J = 11.33, 2.01 Hz, 1H) 3.05-3.19 (m, 1H) 2.74-2.89 (m, 2H) 2.25-2.35 (m, 1H) 2.06-2.17 (m, 2H) 1.56-1.68 (m, 2H) ° Intermediate 75

(6,9-cis)-6-(2,S.difluorophenyl)·6,7,8,9·tetrahydro-5H-cyclohepta[b]acridine_9· alcohol·from 0· 374 mmol of starting material gave 92.4 mg of product (cis, more polar absorption peak, Rf~0.5, 5% ethyl acetate in hexane). Combined with the trans isomer, the yield was 90%. 1H NMR (400 MHz, gas-d-d) (5 ppm 139424 -99- 201036969 8.18-8.33 (m, 1H) 122-135 (m, 1H) 7.03 (dd, J = 7.55, 5.04 Hz, 1H) 6.93 ( Td, J = 9.25, 4.66 Hz, 1H) 6.70-6.87 (m, 2H) 4.92-5.07 (m, 1H) 3.34-3.45 (m, 1H) 3.29 (t, J = 8.44 Hz, 1H) 2.89 (dd, J = 14.10, 2.27 Hz, 1H) 2.14-2.30 (m, 1H) 1.91-2.11 (m, 3H). Intermediate 76

(6,9-trans)-6-(3,4-difluorophenyl)·6,7,8,9·tetrahydro-5H-cyclohepta[b]pyridin-9-ol·from 0.342 m Mohr starting material gave 15 mg of product. Combined with the cis isomer, the yield was 86%. MS (ESI) [M+H+] = 276.23; 1H NMR (400 MHz, EMI-D) δ ppm 8.30-8.48 (m,1H) 7.41-7.49 (m, 1H) 6.88-7.18 (m, 4H) 5.93 (br, s, 1H) 4.85 (dd, J = 11.21, 2.14 Hz, 1H) 3.10 (dd, J = 14.10, 11.58 Hz, 1H) 2.71-2.85 (m, 1H) 2.47-2.57 (m, 1H) 2.27 -2.36 (m, 1H) 1.97-2.18 (m, 2H) 1.47-1.68 (m, 1H). Intermediate 77

(6,9-cis)·6-(3,4-difluorophenyl)·6,7,8,9·tetrahydro_5H_cyclohepta[b&gt;bipyridin-9-ol·from 0.342 Millol starting material gave 66.4 mg of product. Combined with the trans isomer, the yield was 86%. MS (ESI) [M+H+] = 276.23; 1H NMR (400 MHz, chloroform-d) 5 ppm 8.33 (dd, J = 5.04, 1.51 Hz, 1H) 7.23-7.31 (m,1H) 139424 -100· 201036969 7.07 (dd, J = 7.43, 4.91 Hz, 1H) 6.93-6.99 (m, 1H) 6.80-6.85 (m, 1H) 6.75 (dd, J = 4.15, 2.14 Hz, 1H) 5.27 (broad s) 1H) 4.95 (dd, J = 9.19, 2.64 Hz, 1H) 3.15-3.33 (m, 1H) 3.00-3.13 (m, 2H) 2.01-2.25 (m, 3H) 1.83-1.97 (m, 1H). Example 10

4-(2-keto-2,3-dihydro-1H-imidazo[4,5-b>pyridin-1-yl)hexahydropyridine-1·carboxylic acid (6,9-trans)_6 _Phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester. Add NaH (0.025 g, 1.003 mmol) to 4- at room temperature (2-keto-2,3-dihydro-1H-imidazo[4,5-b>pyridin-1-yl)hexahydropyridine small carboxylic acid 4-nitrophenyl ester compound with triethylamine (1 :3) Trihydrochloride (0.080 g, 0.100 mmol) and (6R,9R)-6-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-9 - A suspension of alcohol (0.016 g, 0.067 house moles) in THF (5 mL). The reaction was stirred at room temperature for 4 hours. The reaction was quenched by the addition of water. The reaction was further partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed twice with water, then dried (Na2SO4), filtered and concentrated. A flash column (from 5% to 10% autolysis of methanol in CH2C12) was carried out (31.1 mg &apos; 87%). MS (ESI) [M+H+] = 484.20; 1HNMR (500 MHz, chloroform-d) 5 ppm 8.45 (d, J = 4.58 Hz, 1H) 8.08 (d, J = 5.19 Hz, 1H) 7.40 (d, J = 7.32 Hz, 2H) 7.33 (t, J = 7·78 Hz, 2H) 7.23 (d, J = 7.93 Hz, 3H) 7.12 (broad s., 1H) 6.93-7.00 (m,1H) 6.05 (d, J = 10.99 Hz, 1H) 4.64 (wide s) 3H) 139424 201036969 3.33 (dd, J 2 13.89, 11.75 Hz, 1H) 3.05 (broad s., 2H) 2.88 (d, J = 14.34 Hz, 1H) 2.61 ( Td, J = 11.06, 3.20 Hz, 1H) 1.79-2.35 (m, 9H). Example 11

4-(2-keto-2,3-dihydro-1H·^ salino[4,5-b]p ratio bit-1-yl) hexahydro-u-bite-1-carboxylic acid (6,9- Trans)·6-(2,5-difluorophenyl)-6,7,8,9-tetrahydro-5H·cyclohepta[b]pyridin-9-yl ester· NaH at room temperature (0.036 g, 1.417 mmol) was added to 4-(2-mercapto-2,3-dihydro-1H-P mβ sitting and [4,5-b&gt; ratio.-1-yl)hexahydrogen p-Bit-1-Retinic 4-nitrophenyl ester compound with triethylamine (1:3) trihydrochloride (0.113 g, 0.142 mmol) and (6R,9R)-6-(2,5 -difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol compound and 95,-6-(2,5-difluorophenyl) A suspension of -6,7,8,9-tetrahydro-511-cyclohepta[13]pyridin-9-ol (1:1) (0.052 g, <RTI ID=0.0></RTI> </RTI> <RTIgt; The reaction was stirred at room temperature for 4 hours. The reaction was quenched by the addition of water. The reaction was further partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed twice with water, then dried (Na2SO 4), filtered, and concentrated. The desired column (32.2 mg, 63%) was obtained from a flash column (from decant to 5% to 10% eluted from CH2C12). MS (ESI) [M+H+] = 520.25; 1H NMR (400 MHz, EMI-D) (5 ppm 10.77 (b. s., 1H) 8.45 (d, J = 4.03 Hz, 1H) 8.07 (d, J = 4.78 Hz, 1H) 7.42 (d, J = 6.80 Hz, 2H) 7.13 (broad s) ih) 6.93-7.05 (m,3H) 6.84-6.92 (m,1H) 6.02 (d,J = 10.83

Hz, 1H) 4.34-4.81 (m, 3H) 3.30 (t, J = 12.59 Hz, 1H) 2.87-3.19 (m, 3H) 139424 -102- 201036969 2.81 (d, J = 14.35 Hz, 1H) 2.63 (wide) s" 1H) 2.23-2.39 (m, 2H) 2.12-2.22 (m, 2H) 1.90 (broad s., 3H); 19F NMR (376 MHz, chloroform-d) 5 ppm -118.29 (d, J = 17.24 Hz , IF) -124.51 (d, J = 17.24 Hz, IF). Example 12

4-(2-keto-2,3-dihydro-1H-flavored [4,5-b]p ratio bite 1-yl) hexahydrop ratio bite-1·rebel (6,9- Trans)-6-(3,4-difluorophenyl)_6,7,8,9-tetrahydro-511-cyclohepta[1)]pyridin-9-yl ester · NaH at room temperature (0.056 g, 2.231 mmol) added to 4-(2-mercapto-2,3-dihydro-1Η-σ米峻[4,5-1)]? Hydrogen p is suspended in a THF (5 ml) of trimethylamine (1:3) trihydrochloride (0.178 g, 0.223 mmol) and [reactant] in THF (5 mL). In the liquid. The reaction was allowed to stand at room temperature for 4 hours. The reaction was quenched by the addition of water. The reaction was further partitioned between acetic acid acetate and water. The ethyl acetate layer was separated and washed twice with water, then dried (Na2SO4), filtered and concentrated. The column was purged (from 0 to 5% to 10% methanol in CH2C12) to give the desired product (33.7 mg, 41.9%). MS (ESI) [M+H+] = 520.27; 1H NMR (400 MHz, EMI-D) 5 ppm 10.75 (broad s., 1H) 8.45 (d, J = 3.78 Hz, 1H) 8.07 (d, J = 5.04 Hz, 1H) 7.40 (d, J = 7.05 Hz, 2H) 6.86-7.16 (m, 5H) 6.00 (d, J = 10.83 Hz, 1H) 4.33-4.76 (m, 3H) 3.26 (dd, J = 13.85 , 11.58 Hz, 1H) 3.03 (broad s·, 2H) 2.80 (s, 1H) 2.50-2.66 (m, 1H) 1.82-2.21 (m,6H) 1.19-1.28 (m,2H); 19F NMR (376 MHz , gas-d) d ppm -138.37 - 139424 -103· 201036969 -139.34 (m, IF) 〇-135.13 (m, IF) -141.92 Intermediate 78. Righteousness

2 _嗣基-1',2'-dihydrospiro [hexahydropurine bite than bite [2,3-d][l,3] 哼耕]-1- decanoic acid 4- surely basic ester · at 50 In a milliliter round bottom flask, snail in CH2C12 (6 ml) was added [hexahydropyridine_4 4, _pyridine and [2,3_d][1,3] 噚耕]_2, (1Ή)嗣(187 宅克' 0.853 Millol) (azeotrope with anhydrous benzene) and 4 nitrophenyl carbonate (Π4 mg '0.861 mmol) gave a tan solution. Et3N (〇238 升升 1.706 mmol) was added and the mixture was stirred at room temperature under nitrogen overnight (4:00 pm) and then over the weekend. The mixture still has some solids. Add 5 liters of CHC13' to dissolve the solids and mix the clear yellow solution for another day. TLC did not show the starting amine. It was concentrated to dryness and further dried under high vacuum. The residue is then used as it is. Example 13

2-keto-1,2-dihydrospiro[benzo[d][l,3]indole 4,4'-hexahydropyridine]-1'-carboxylic acid (6,9-trans)_6 (2,3-Difluorophenyl)-6,7,8,9-tetrahydro-5-cyclohepta[b]pyridin-9-yl ester. Add THF to a 1 〇〇 ml round bottom flask ( (5,9-anti-139424 201036969)-6-(2'3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 9-alcohol (79.3 mg, 0.288 mmol) (azeotrope with anhydrous benzene) and 2, keto-r, 2, dihydrospiro [hexahydropyridine-4, 4 Lp pyridine [2, 3.1, 3] H-acidified 4-nitrophenyl ester (221 mg, 0.576 mmol) was obtained, and a brown-brown suspension was obtained. NaH (69 mg, 2.88 mmol) (excess) was added under nitrogen. The mixture was stirred under nitrogen at room temperature. 17 hours. LCMS showed two small absorption peaks with one possible product. The reaction was quenched with water (gas evolution enthalpy) and extracted with Et EtOAc. The liquid layer was separated and the aqueous layer was extracted with EtO Ac. The combined organic layers were washed with brine, dried over Na 2 EtOAc and evaporated. Purification by FCC up to 8% Me.sup.H/CH.sub.2 C.sub.2 to afford the desired product as a colourless solid (1. 8 mg, 7.2%). MS (ESI) [M+H+] = 521.39; 1H NMR (400 MHz, chloroform-d) 5 ppm 9.88 (broad s) 1H) 8.23-8.53 (m, 2H) 7.50 (broad s) 1H) 7.36-7.45 ( m,1H) 6.91-7.18 (m,5H) 5_99 (d,J = 10.32 Hz,1H) 4·39 (broad s.,2H) 3.22-3.71 (m, 3H) 2.90-3.05 (m, 1H) 2.81 (d, J = 14.35 Hz, 1H) 1.85-2.55 (m, 6H) 1.67 (s, 2H). Q Intermediate 79

(6R,9R)-6-(2,3cfluorophenyl)-3.Wall base_6,7,8,9_tetrahydro-5H·cycloheptaco-pyridin-9-ol··5〇〇 (6R,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta in CH2C12 (8 mL) was added to a milliliter round bottom flask. b] Pyridine-9, alcohol (2.912 g, 10.58 mmol) (for palm and 'anhydrous) and tetrabutylammonium nitrate (6.44 g, 21.16 mmol) afforded a colorless solution. Under nitrogen, 139424 • 105- 201036969 tfaa (3·29 liters, 2327 millimoles) was added via syringe (3 pm). The mixture was stirred at room temperature overnight (4: pm). 17 hours: The volatiles were stripped and the residue was dissolved in 60 mL of THF. Add 15 ml of water with lithium hydroxide (1.267 g, 52.9 mmol). The mixture was stirred at room temperature for 2 hours. LCMS showed the CF3CO-product was hydrolyzed. It was diluted with EtO Ac. Separate the liquid layer. The organic layer was washed with brine, dried and dried and concentrated to a brown oil. Purification by FCC up to 50% EtOAc / hexane afforded a &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&& MS (ESI) [M+H+] = 32 U1; 1H NMR (400 MHz, EMI-D) 5 ppm 9.29 (d, J = 2.27 Hz, 1H) 8.32 (d, J = 2.27 Hz, 1H) 7.00-7.18 (m, 3H) 5.48 (d, J = 3.02 Hz, 1H) 5.06 (d, J = 11.58 Hz, 1H) 3.28-3.44 (m, 1H) 2.88-3.08 (m, 2H) 2.36-2.48 (m, 1H) ) 2.16-2.34 (m, 2H) 1.66-1.74 (m, 1H). Intermediate 80

N-((6R,9R)-6-(2,3-difluorophenyl)-3-nitro-6,7,8,9-tetrahydro-5H-cyclohepta[b]p than 唆_ 9·基)-4-(2-mercapto-2,3·&gt;-nitrogen-ΙΗ-味° sit and compare 唆-I-base) six winds p than bite-1-rebel amine · at 1〇 Add hexyl round bottom flask to (6R,9R)-6-(2,3-difluorophenyl)-3-nitro-6,7,8,9-tetrahydro-5H in THF (4 mL) -cyclohepta[b]p is a pyridin-9-ol (76.3 mg, 0.238 mmol) (azeotrope with anhydrous benzene) and 4-(2-keto-139424-106-201036969-2,3-dihydrogen -1H-Imidazo[4,5-b]pyridin-1-yl)hexahydropyridine-1-carboxylic acid 4-nitrophenyl ester (285 mg, 0.357 mmol) was obtained as a yellow suspension. NaH (57.2 mg ' 2.382 mmol) (excess) was added at room temperature under nitrogen. The mixture was allowed to stand under nitrogen for 4 hours. The reaction was quenched with water and extracted with EtOAc. Separate the liquid layer. The organic layer was washed with brine, dried and dried, and concentrated. The dark oil was purified by FCC up to 10% MeOH/CH2C12. '' The desired product (which is the main absorption peak) was concentrated to a pale orange solid (17.1 mg &apos; 13%). MS (ESI) [M+H+] = 565.实例 Example 14

N-((6R,9R)_3-Amino-6·(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b] acridine-9· 4-(2-keto-2,3-dihydro-1Η-imidazo[4,5-b]pyridin-1-yl)hexahydropyridin-1-carboxamide in 100 ml round bottom To the flask was added 4-(2-keto-2,3-dihydro-1H-imidazo[4,5-bipyridin-1-yl)hexahydropyridine-1-acidic acid in MeOH (2 mL). 6R,9R)-6-(2,3cfluorophenyl)_3_definitely _6,7,8,9-tetrahydro-5H-cyclohepta[b]11 than bit-9-yl ester (17.1 mg ' 〇·〇3〇 millimolar), obtained a yellow-brown suspension. Pd/C (17 mg, 0.016 mmol) was added and the mixture was stirred under hydrogen (cylinder) for 4 hours (10:30 am). LCMS showed complete conversion. It was filtered and concentrated. The residue was purified with EtOAc (EtOAc:EtOAc) MS (ESI) [M+H+] 139424 -107-201036969 =535.05 ; 1H NMR (400 MHz, chloroform-d) δ ppm 10.05 (broad s., 1H) 8.05-8.15 (m,1H) 8.00 (broad s· ,1H) 7.36-7.59 (m, 1H) 7.28 (s,1H) 6.91-7.13 (m, 4H) 5.97 (d, J = 10.32 Hz, 1H) 4.28-4.80 (m, 3H) 3.54-4.04 (m, 1H) 3.16-3.36 (m,1H) 3.04 (broad s·, 3H) 2.76 (d, J = 14.35 Hz, 1H) 2.23-2.44 (m, 2H) 2.05-2.23 (m,3H) 1.77-2.05 (m , 4H). Intermediate 81

(6R,9R)-3-Amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol·Pd /C (37 mg '0.035 mmol) with (6R,9R)-6-(2,3-difluorophenyl)-3-stone-based-6,7,8,9-tetrahydro-5H-cycloheptane And [b]p was hydrogenated for 4 hours under a H2 (cylinder) mixture of -9-ol (300 mg, 0.937 mmol) in methanol (10 mL). LCMS showed the end of the reaction. The reaction was filtered through a pad of Celite. The filtrate was concentrated to give a crude product. MS (ESI) [M+H+] = 291.29; 1H NMR (400 MHz, gas-d-d) δ ppm 7.84 (broad s·, 1H) 7.02 (broad s., 3H) 6.79 (broad s) 1H) 5.90 ( Wide s" 1H) 4.74 (d, J = 10.32 Hz, 1H) 3.87 (wide s" 2H) 3.06 (t, J = 12.34 Hz, 1H) 2.86 (broad s., 1Η) 2.62 (d, J = 13.85 Hz , 1H) 2.26 (d, J = 12.34 Hz, 1H) 1.96-2.12 (m, 3H) 1.52 (broad s) 1H). Intermediate 82

139424 •108- 201036969 (6R,9R)-6-(2,3-Difluorophenyl)-3-(diguanylamino)_6,7,8,9-tetrahydro-5H-cyclohepta[b&gt Bis--9-ol. Sodium cyanoborohydride (242 mg, 3.86 mmol) was added to (6R,9R)-3-amino-6-(2,3-difluorobenzene at room temperature )6,7,8,9_tetrahydro-5H-cyclohepta[b]pyridin-9-ol (56 mg, 0.193 mmol) with formaldehyde (1 mL, 13.43 mmol) of acetonitrile (2) ML) solution. The reaction was allowed to mix for 4 hours at room temperature. Acetic acid (0.5 ml, 8.73 mmol) was added to the reaction mixture (Note: heat generation was found to cause acetonitrile to reflux) and the reaction was stirred overnight. Most of the volatiles were removed via vacuum and NaOH (1 N) was added to the crude material and extracted twice with ethyl acetate. The ethyl acetate layer was dried (Na2SO4), filtered, and concentrated. The desired product (27.6 mg, 45%) was obtained from 0 to 4%' MS (ESI) [M+H+] = 319.35.

Example 15

Acid (6R,9R)-6-(2,3-difluorophenyl)-3-(dimethylamino)-6,7,8,9-tetrahydro·5Η·cyclohepta[b&gt; · 9 · base ester · using a stir bar to make (6R, 9R)-6-(2,3-difluorophenyl)-3-(dimethylamino)-6,7,8,9-tetrahydro- 5H-Cyclohepta[b]pyridin-9-ol (27.6 mg, 0.087 mmol) was azeotroped with benzene. Sodium hydride (20.80 mg, 0.867 mmol) was added to (6R,9R)-6-(2,3-difluorophenyl)-3-(diguanylamino)-6,7 at room temperature. 8,9-Tetrahydro-5H-cyclohepta[b]pyridin-9-ol (27.6 mg, 0.087 mmol) and 4-(2-keto139424-109-201036969-2,3-dihydro- 1H-Imidazo[4,5-b]pyridin-1-yl)hexahydropyridine-i-carboxylic acid 4-nitroester (43.2 mg '0.113 mmol) in THF (3 mL). The reaction was stirred overnight at this temperature. The reaction was quenched by water and partitioned between ethyl acetate and water. The ethyl acetate layer was washed twice more with water, then dried (Na 2 SO 4 ), filtered, and concentrated. The flash column was obtained from hydrazine in CH2C12 from 4% to 8% to obtain the desired product (19.8 mg &gt; 36%). MS (ESI) [M+H+] = 563.35; 1H NMR (500 MHz, EMI-D) 6 ppm 10.30 (broad s., 1H) 8.08 (d, J = 5.49 Hz, 1H) 7.95-8.05 (m, 1Η) 7.37-7.53 (m,1H) 6.94-7.14 (m,4H) 6.79 (broad s·,1H) 6.00 (d, J = 10.38 Hz, 1H) 4.66 (broad m., 3H) 3.32 (t, J = 12.67 Hz, 1H) 3.08 (broad m., 2H) 2.91-3.02 (m, 6H) 2.29 (d, J = 13.73 Hz, 2H) 2.13-2.24 (m, 2H) 1.86-2.07 (m, 2H) 1.20 -1.40 (m, 3H) 0.75-0.98 (m, 1H). Intermediate 83

(6R,9R)-6-(2,3-difluorophenyl)·9-(triisopropyldecyloxy)·6,7,8,9-tetrahydro-5Η-cyclohepta[b] Pyridine 1_oxide. Add mCPBA (1.239 g, 5.53 mmol) to (6R,9R)-6-(2,3-difluorophenyl)-9-(triisopropyldecane) at room temperature A solution of the oxo)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (2.17 g, 5.03 mmol) in CH2C12 (30 mL). The reaction was stirred at room temperature overnight. The solvent was removed via vacuum. The product was purified by flash column and dissolved from 0 to 50% to 85% of ethyl acetate in hexane. The product was obtained by flushing the column with 85% ethyl acetate in hexane (1·572 g, 69%). MS (ESI) [M+H+] 139424-110-201036969 =448.21 ; 1H NMR (400 MHz, EMI-D) (5 ppm 8.14 (broad s) 1H) 6.94-7.11 (m, 2H) 6.84-6.92 ( m, 2H) 6.66-6.72 (m, 1H) 6.42 (t, J = 4.28 Hz, 1H) 4.04 (dd, J = 14.73, 4.41 Hz, 1H) 3.73-3.88 (m, 1H) 2.96 (dd, J = 14.48, 5.41 Hz, 1H) 2.50 (d, J = 5.79 Hz, 1H) 2.13-2.25 (m, 2H) 1.80-1.94 (m, 1H) 1.18-1.32 (m, 3H) 1.09 (d, J = 7.55 Hz , 9H) 1.00 (d, J = 7.55 Hz, 9H). Intermediate 84

(6R,9R)-6&lt;2,3c fluorophenyl)-9·yl group-6,7,8,9_tetrahydro-5H_cyclohepta[crush than bite 1_oxide·will TBAF (4丨 8 ml ' 4.18 mmoles) was added to (6R,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsulfonyloxy)_6 7 at room temperature 8,9_Tetraindole-5H-cyclohepta[b]p is in a solution of 1-oxide (1.56 g, 3.48 mmol) in THF (10 mL). The reaction was stirred at room temperature for 2 hours and LCMS showed hydr. The solvent was removed in vacuo and the crude material was taken to a flash crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Ms(esi)_h+] = 292 1〇 ; 1H NMR _ MHz, gas-φ δ ppm 8.16-8.26 (Hi,1H) 7.14-7.20 (m,

1.79-1.94 (m, 1H). Intermediate 85 139424 -111· 201036969

(R)-6_(2,3-difluorophenyl)-9-keto-6,7,8,9-tetrahydro-5Η-cyclohepta[1ψpyridinium 1-oxide· Des-Martin Transiodane (1.227 g, 2.89 mmol) was added to (6R,9R)-6-(2,3-difluorophenyl)-9-carbyl-6,7,8,9- at room temperature Tetrahydro-5H-cyclohepta[b]pyridine 1-oxide (0.7662 g, 2.63 mmol) in CH2C12 (8 mL). The reaction was stirred at room temperature for 1 hour. The reaction was loaded directly into the column and separated by 10% decyl alcohol (〇 to 1% gradient) in CH2C12 (0.54 g, 42%). MS (ESI) [M+H+] = 290.03. Intermediate 86

(R)-2·(Third-butylamino)·6·(2,3·difluorophenyl).7,8-Dihydro-5Η·Cyclohepta[b]p-pyridin-9 ( 6Η)-ketone. Add 4-indolylbenzenesulfonic anhydride (0.930 g, 2.85 mmol) to (R)-6-(2,3-difluorophenyl)-9-one at 0 °C -6,7,8,9-tetrahydro-5-cyclohepta[b]pyridine 1-oxide (ο.4^g, 1.424 mmol) and 2-mercaptopropan-2-amine (0.604 ml) ' 5.70 mmol of trifluoro-indole (3 ml) / CH2C12 (3.00 ml) in suspension. The reaction is in the hydrazine. Stir under the arm for 30 minutes and then dilute with ethyl acetate. The crude material was washed twice with NaOH (1 EtOAc) and then evaporated and evaporated. The desired column (0.1861 g, 38%) was obtained from EtOAc (EtOAc: EtOAc). MS (ESI) [M+H+] = 345.1; 1H NMR (400 MHz, 139424-112-201036969 EMI-D) 5 ppm 7.18 (d, J = 8.56 Hz, 1H) 6.95-7.10 (m, 2H) 6.82 -6.95 (m, 1H) 6.60 (d, J = 8.56 Hz, 1H) 4.95 (broad s., 1H) 3.45-3.58 (m, 1H) 2.91-3.05 (m, 3H) 2.73-2.85 (m, 1H) 2.13-2.27 (m, 1H) 1.95-2.11 (m, 1H) 1.43 (s, 9H). Intermediate 87

(6R,9R)-2-(Tertiarybutylamino)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro·5Η-cyclohepta[b> Pyridin-9-alcohol· Sodium borohydride (0.072 g, 1.893 mmol)

Add to (R)-2-(t-butylamino)-6-(2,3-difluorophenyl)-7,8-dihydro-5H-cyclohepta[b]pyridine-9 (at room temperature) 6H)-ketone (0.2 Π 3 g, 0.631 mmol) in MeOH (ίο ml). The reaction was stirred at room temperature for 1 hour. LCMS showed the reaction was completed. The solvent was removed via vacuum. The crude product was separated via a flash column and eluted from ethyl acetate in hexane to 35% to 65% to give the Q compound. It is a less polar compound (134.9 mg, 61%). HPLC tR = 2.43 min; MS (ESI) [M+H+] = 347.33; 1HNMR (400 MHz, EMI-D) 5 ppm 7.18 (d, J = 8.06 Hz, 1H) 6.99-7.11 (m, 3H) 6.28 (d, J = 8.06

Hz, 1H) 4.76 (dd, J = 11.33, 2.01 Hz, 1H) 4.53 (broad s., 1H) 3.03 (d, J = 13.85 Hz, 1H) 2.89 (d, J = 4.28 Hz, 1H) 2.64 (d , J = 14.10 Hz, 1H) 2.28 (dd, J = 12.59, 2.01 Hz, 1H) 2.13 (dd, J = 9.82, 3.78 Hz, 2H) 1.58-1.71 (m, 1H) 1.42-1.55 (m, 9H) . Intermediate 88 139424 -113- 201036969

(6R,9S)-2-(Third-butylamino)(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 9. Alcohol · This is the more polar compound (51.1 mg, 23%) obtained from the above reaction. HPLC tR = 2.31 min; MS (ESI) [M+H+] = 347.33; 1H NMR (400 MHz, EMI - (1) 4 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> J = 8.31 Hz, 1H) 4.84 (dd, J = 9.69, 3.15 Hz, 1H) 4.40-4.56 (m, 1H) 3.44-3.56 (m, 1H) 2.92-3.07 (m, 2H) 2.14-2.25 (m, 1H) 2.05-2.13 (m, 2H) 1.84-1.99 (m, 1H) 1.38-1.55 (s, 9H). Example 16

4·(2·keto·2,3·dihydro-1H-imidazo[4,5-b]acridin-1-yl)hexahydropyridine-1-carboxylic acid (6R,9R)-2·( Third-butylamino) winter (2,3·difluorophenyl)·6,7,8,9-tetrahydro-5H-cyclohepta[b&gt;pyridin-9-yl ester·using a stir bar , (6R,9R)-2-(Thr-butylamino)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5-cyclohepta[ 1)] Pyridine-9-ol (69.1 mg '0.199 mmol) azeotroped with benzene. Sodium hydride (47.9 mg ' 1.995 mmol) was added to (6R,9R)-2-(t-butylamino)-6-(2,3-difluorophenyl)- at room temperature. 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (69.1 mg, 0.199 mmol) and 4-(2-keto-2,3-dihydro-1H -Imidazo[4,5-b]pyridin-1-yl)hexahydropyridine-1-carboxylic acid 4-nitrophenyl ester compound with triethylamine (1:3) trihydrochloride (238 mmol 139424 -114 - 201036969 g, 0.299 mmoles in THF (3 ml) suspension. The reaction was stirred overnight at room temperature. The reaction was quenched by water and separated between ethyl acetate and water. The ethyl acetate layer was washed twice with water, then dried (Na2SO4), filtered, and concentrated. The desired column was obtained as a white solid from MeOH from &lt;RTI ID=0.0&gt;&gt; The product was further purified by preparative HPLC (69.2 mg, 26%). 1H NMR (500 MHz, gas-d-d) (5 ppm 8.07 (d, J = 5.19 Hz, 1H) 7.34-7.44 (m, 1H) 6.96-7.15 (m, 4H) 6.08-6.28 (m, 1H) 5.83 -5.99 (m, 1H) 4.42-4.77 (m, 3H) 3.16-3.25 (m, 1H) 2.86-3.14 (m, 3H) 2.62-2.72 (m, 1H) 2.11-2.38 (m, 5H) 1.94 (d , J = 11.90 Hz, 3H) 1.52-1.60 (m, 1H) 1.46 (s, 9H). Example 17

4-(2-mercapto-2,3-dihydro-1H-imidazo[4,5-b]p is more than -1-yl) hexahydrop than bite _i_rebel (6R,9R) 2-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-9-yl vinegar · 4-( 2-keto-2,3-dihydro-lH-bee and [4,5-b]iO-1,4-yl)hexahydropyridine-1-carboxylic acid (6R,9R)-2-( Tri-butylamino)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester (0.1537 g, A mixture of 0.117 mmoles and TFA (4 mL, 1.18E + 04 mmol) was heated to 70 ° C over 1 hour. LCMS showed that most of the starting material was converted to the desired product. There is no evidence of hydrolysis of the carbamate to alcohol. The TFA was removed via vacuum and the crude material was partitioned between ethyl acetate and NaOH (1N). 139424 -115- 201036969 Separation of ethyl acetate layer Dehydrated (Na2S04), filtered, and concentrated. The flash column is self-twisted to 3.5% to 5% by methanol in CH2C12. The desired product was not dissolved. The product was obtained as a white solid (648 mg, 90%). MS (ESI) [M+H+] = 535; 1H NMR (400 MHz, EMI-D) 5 ppm 11.44 (broad s) 1H) 8.13 (d, J = 4.53 Hz, 1 Η) 7.36 (broad s., 1H) 7.14-7.24 (m, 1H) 6.99-7.10 (m, 4H) 6.37 (d, J = 7.55 Hz, 1H) 5.87 (d, J = 10.32 Hz, 1H)

5.57 (d, J = 1.51 Hz, 1H) 4.48-4.83 (m, 2H) 4.17 (broad s., 1H) 3.23 (dd, J = 13.72, 11.96 Hz, 1H) 2.95 (d, J = 10.32 Hz, 3H 2.69 (d, J = 14.10 Hz, 2H) 2.08-2.31 (m, 3H) 1.83-2.08 (m, 3H) 1.19-1.35 (m, 1H) 0.81-0.95 (m, 1H). Example 18

4-(2-keto-2,3-dihydro·1Η·imidazo[4,5-b>pyridin-1-yl)hexahydropyridine small carboxylic acid (6R,9R)-6-(2, 3-:fluorophenyl)-2-(dimethylamino)_6,7,8,9-tetrahydro-5H-cyclohepta[b&gt;pyridin-9-yl ester·sodium cyanoborohydride 1〇8 mg, 1.721 mmoles) was added to 4-(2-keto-2,3-dihydro-1H-imidazo[4,5-b>pyridin-1-yl) at room temperature Hydropyridine-1'carboxylic acid (6R,9R)-2-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b] p is more than a solution of bit-9-yl ester (46 mg '0.086 mmol) with acetonitrile (1 ml, 13.43 mmol) in acetonitrile (2 mL). The reaction was stirred at room temperature for 4 hours. Acetic acid (0.5 mL, 8.73 mmol) was added to the reaction mixture 139424 • 116- 201036969 in the compound. Most of the volatiles were removed via vacuum and Na.sub.2H (1N) was then weighed and then stirred at room temperature for one hour and then extracted with ethyl acetate. The ethyl acetate layer was dried (Na2SO4), filtered, and concentrated. For the flash column, the desired product (19 8 mg, 39%) was obtained from MeOH from &lt;RTI ID=0.0&gt; MS (ESI) [M+H+] = 56.42. Example 19

4-(2-keto-2,3-dihydro-1H-imidazo[4,Sb]p is a pyridyl group) hexahydropyridine small carboxylic acid (6R,9R)-2-ylyl-6-( 2,3-difluorophenyl)_6,7,8,9·tetrahydro-_SH cycloheptamole than bite-9-yl vinegar at 4-(2-keto-2) at _5 °C ,3-dihydro-1H-imidazo[4,5-b] succinyl) hexahydropyridine-1-carboxylic acid (6R,9R)-2-amino-6-(2,3-difluoro Phenyl)_6,7,8,9-tetraindole-5H-cyclohepta[b]u than -9-yl vinegar (45 mg, 0.084 mmol), hydrochloric acid (3 liters, 36.5 mmol) To the mixture of the ear, copper chloride 1 (16 67 house grams '0.168 mmol) and sodium wall sulfate (21.47 mg, 0.253 mmol) were added. The reaction was stirred at this temperature for 1 hour' and stirred at room temperature for a few hours. NaOH (1 N) was added to the reaction mixture, which was then extracted twice with ethyl acetate. The ethyl acetate layer was washed with brine and then separated, dehydrated (you 2^〇4), filtered, and concentrated. The desired column product (6.4 mg, 12%) was obtained from the sulphuric acid in CH2C12 from 4% to 8%. MS (: ESI) [M+H+] = 554.09. 139424 -117- 201036969 Intermediate 89

4-(2-keto-2,3-dihydro-1H-imidazo[4,5-b>pyridinyl)dinitropyridine small carboxylic acid 4-nitrophenyl ester. Small 2-keto group (hexahydropyridinium)_2,3_dihydro-out-imidazo[4'5-b]chlorinated pirin (10·&quot;g,% 8 mmol) in THF (3〇〇 Mix the mixture in DM) with DMF (167 mL) at room temperature under N2 for 1 min. The reaction mixture is still in suspension at this time. 4-Mercaptophyrin (27 5 ml, 25 mM mmol) k was slowly added to the reaction mixture. The internal reaction temperature becomes 22 (from 20 ° C). The reaction was stirred for an additional 1 minute, then added with a portion of the fluorenyl-dihydro-ex-imidazole and pyridine pyridine + substrate hydropyridine-1-carboxylic acid 4-nitrobenzene in one portion at room temperature. ester. The reaction temperature is increased to 27π. The reaction was stirred for 2 hours. 1000 ml of water was slowly added to the reaction mixture, and all the heart floating liquid was dissolved, and then the solution became cloudy. The reaction was stirred at room temperature overnight. The reaction was filtered and the solid was washed with water and CH3CN. The product was combined with 79044-022 as an off-white powder (74 g, 54%) and used as such. Example 20

4-(2-keto-2,3-dihydro-1H-imidazo[4,s_b oxaridinyl)hexahydropyridine small carboxylic acid (6R,9R)-2-ylyl-6-(2, 3-diphenylphenyl)_6,7,8,9_tetrahh-cycloheptyl cation] 峨唆.9· vinegar. Under nitrogen, add 139424 to the i liter round bottom flask which is dried in a box. 118- 201036969 (6R,9R)-6-(2,3-Difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine in DMF (200 ml) -9-alcohol (12.74 g, 46.3 mmol) (&gt;99.9% purity) and 4-(2-keto-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1 4-Phenylpyridinium-1-carboxylic acid 4-nitrophenyl ester (26.6 g, 69.4 mmol) afforded a pale yellow suspension. After cooling to -15 °C in a MeOH ice bath, NaHMDS (139 mL, 139 mM) was added dropwise. After forming a gel (addition of 1.5 equivalents of base), the cooling bath was removed and the remaining base was added dropwise. The mixture was stirred under nitrogen at room temperature for 2 hours. LCMS shows complete conversion. 3 hours: The reaction was quenched with saturated NaHC03 (400 mL). This suspension was partitioned between 500 ml of water and 700 ml of EtOAc. The layers were separated and the aqueous extracted with EtOAc EtOAc No product remained in the aqueous solution by LCMS. The combined organic layers were washed with EtOAc EtOAc EtOAc EtOAc. The crude product was purified by FCC (~900 g EtOAc) up to 4% MeOH/CH. The resulting product (as a tan solid) was further purified (1. 64 g, 90%) from iPrOH (yield: EtOAc, EtOAc: ); melting point 248 ° C. Single crystal X-ray measurement. The rotating anodic generator with a Cu Κα emission (λ = 1.54 Π 8 persons) was used to collect the diffraction data at room temperature. The indexing and processing of the measured intensity data is based on the APEX2 package software/package program (APEX2 Data Collection and Processing User Interface: APEX2 User Manual, vl. 27; BRUKER AXS, 5465 East Cheryl Parkway, Madison, WI 53711 USA )get on. The last unit cell parameter is measured using the overall data set. The 139424 201036969 structure was refined by direct method and refined using the SHELXTL packaging software (Sheldrick, GM. 1997, SHELXTL. Structural Measurement Program. Version 5.10, Bmker AXS, Madison, Wisconsin, USA) by the full matrix least squares technique. The function that is minimized in this refining is Σw(丨FQ丨-|Fe丨)2. The R system is defined as Σ ||F0| - |FC||/Z |F0|, and Rw = [Ew( |F0| - |FC|)2/EW |Fo|2]1/2, where w is The appropriate weighting function is based on the error in the found intensity. The differential Fourier diagram is tested at all stages of refining. All non-hydrogen atoms were refined with anisotropic thermal shift parameters. Hydrogen bonded hydrogen bonds are located in the final differential Fourier diagram, whereas other hydrogen atoms are calculated from the idealized geometry by standard bond length and angle. It is assigned an isotropic temperature factor and is included in the calculation of the building factor using fixed parameters. The crystal data for the compound of Example 20 is shown below. Some of the atomic coordinates are listed in Table 2. It will be apparent to those skilled in the art that slight deviations in coordinates are possible and are considered to be within the scope of the present disclosure. Temperature: room temperature; wavelength: 0.71070; crystal space group: orthorhombic P2(1)2(1)2(1); unit cell size: a = 7.5941(1) A, α = 90 degrees; b = 13.8789(2) A , cold = 90 degrees; c = 24.7319 (3) A, r = 90 degrees; volume: 2606.69 (6) A3; Z, calculated density: 4, 1.324 mg / m3. Atom XY Ζ U(eq) 0(1) -3138(3) -3128(1) -795(1) 52(1) 〇(2) -4445(3) -2737(1) -1587(1) 59(1) 0(3) 874 (3) -7046(2) -2345(1) 76(1) N(1) -249(3) -2383(2) -1185(1) 59(1) N(2) -3324(3) -4230(2) -1451(1) 58(1) N(3) 752(3) -5384(2) -2444(1) 59(1) 139424 -120- 201036969 Atomic XYZU(eq) N(4) 2908(4) -6179(2) -2849(1) 60(1) N(3) 4345(4) -4861(2) -3287(1) 67(1) F(1) -5198(4) 864(2) -133(1) 120(1) F(2) -6096(7) 2376(2) 450(2 ) 169(2) C(l) -4103(7) 1133(3) 266(1) 86(1) c(2) -4607(9) 1936(3) 572(2) 110(2) c(3) -3566(11) 2247(3 987(2) 117(2) c(4) -2071(10) 1750(4) 1105(2) 115(2) c(3) -1557(6) 961(3) 798(2) 88(1) c(6) -2606(5 ) 631(2) 368(1) 69(1) C(7) -2092(4) -273(2) 61(1) 60(1) C(8) -1890(5) -73(2) -550(1) 66(1) c(9) -732(4) -785(2) -837(1) 59(1) C(10) 892(5) -517(3) -1040(1) 75(1) C(ll) 1939(5) -1169(3 ) -1310(1) 76(1) C(12) 1308(4) -2088(3) -1376(1) 66(1) C(13) -1215(4) -1750(2) -914(1) 51( 1) C(14) -2915(4) -2126(2) -662(1) 50(1) C(15) -2877(4) -2071(2) -46(1) 54(1) C(16) -3363(4) -1096(2) 186(1) 60(1) C(17) -3664(3) -3316(2) -1307(1) 49(1) C(18) -3817(4) -4559 (2) -1991(1) 66(1) C(19) -2208(4) -4617(2) -2360(1) 67(1) C(20) -805(4) -5238(2) -2104(1) 60(1) C (21) -320(4) -4856(2) -1544(1) 60(1) C(22) -1952(5) -4816(2) -1191(1) 65(1) C(23) 1452(4) -6298( 2) -2527(1) 59(1) C(24) 3110(4) -5225(2) -2978(1) 54(1) C(25) 4272(5) -3902(3) -3342(2) 79(1) C(26) 3046(6) -3334(3) -3100(2) 85(1) 139424 201036969 Atomic XY Ζ U(eq) C(27) 1 1738(5) -3728(2) -2770(2) 73(1) C(28 ) 1 1776(4) 4716 (2) -2715(1) 56(1)

L-(l-((6R,9R)-6-(2,3-difluorophenyl)·6,7,8,9_tetrahydro- 5Η·cyclohepta[b]bitone-9·yl Oxy)) benzyl) hexahydropyridine _4_yl). 2-keto·1,2·dihydroimidazo[4,5-b]pyridine_3_potassium·1 ml round in oven drying 4-(2-keto-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)hexahydroguanidine-1- in ethanol (10 ml) was added to the bottom flask Carboxylic acid (6R,9R) each (2,3-difluorophenyl)_6,7 8,9 tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester (1·08 g, 2〇79 毫Mohr), obtaining a colorless solution. Add a third potassium butoxide (0.233 g, 2.079 mmol) to one portion. Use heat to grab the solution slightly to heat the solution and swirl it until the solids are completely dissolved. Eight proposed volatile materials into a white foam / powder. The powder was allowed to dry under high vacuum with occasional warming at 5 (rc bath and then at room temperature under vacuum overnight for 3 days. LCMS and HPLC were obtained. HPLC was not 98% pure. Not having a single purity %.m (Glycer?, d6 DMSO) 8.44 (s, 1H), 7.61-7.55 (m, 2H), 7.31-7.21 (m, 4H), 6.91 (s, 1H), 6.41 (s , 1H), 5.93 (d, J=i2 Hz, 1H), 4.38 (br, 2H), 4.11 (br, 1H), 3.50-3.41 (m, 1H), 3.21-2.78 (m, 5H), 2 3 (M 5 〇 (m, π).

Those skilled in the art will recognize the B-monthly sputum, and the disclosure of the present invention is not limited to the foregoing description, and the basin can be used in other specific forms without deviating from its basic characteristics. The examples are considered to be in all respects and are not to be construed as limiting the scope of the claims and the scope of the claims. The system is therefore intended to be included. [Simple diagram of the diagram] Figure 1. [125I]-CGRP saturation/Scatchard analysis. [12 5I] CGRP saturation, using SK-N-MC cell membrane, in the absence of CGRP antagonist Example 2 (filled square shape) and presence (all other parts). Illustrations depict the same data

Scatchard diagram. 〇 Figure 2. Functional antagonism/Schild analysis. CGRP dose response in SK-N-MC cells (stimulated cAMP production), CGRP antagonist example 20 at increasing concentrations (left to right, 0.3 to 24 nM) was absent (open square) and present (all other Partially). Figure 3. Direct and effective confirmation of facial blood flow in rats as an alternative to intracranial arterial dilatation. Intravenous transmission of intravenous haCGRP causes the diameter of the central meningeal artery in rats to be comparable to the blood flow in the face of the rat. © percentage increase (100-120% of baseline) (individually left and right striped bars). Pretreatment with the peptide antagonist CGRP (8_37) produced 50% inhibition of the subsequent intravenous haCGRP administration (filled bars) for both measurements. The internal artery diameter and facial blood flow were measured simultaneously in each animal (n = 5 large white milk). The data is the mean soil Sem *P &lt; 〇〇 5, ** p &lt; 〇〇 1 pair of corresponding hoCGRP ° Figure 4. The dose of h aCGRP on the non-human primate laser D〇ppier facial blood flow Respond. The transmission of h aCGRP (intravenously) causes a dose-dependent increase in 13324 • 123 - 201036969 on the blood flow of the laser Doppler in non-human primates (eg, general sputum). Animals (n=6) received increasing doses of hoCGRP at 30 minute intervals. Data are ± sem % change from baseline, with each animal serving as its own control group. 139424-124,

Claims (1)

201036969 VII. Patent application scope: 1. A compound of formula I Wherein: R1 is hydrogen, cyano, functional group, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkyl group so2, amine group, alkylamino group, dialkylamino group, mononitrotetradecyl group, Tetrahydropyrrolyl, hexahydropyridyl, hexahydropyridinyl, N-alkylhexahydropyridinyl or whufyl; R2 is hexahydropyridyl, substituted by 1 substituent selected from the group consisting of Group of groups: % is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy; R is hydrogen, halo, cyano, alkyl, _alkyl, alkoxy or haloalkoxy 139424 201036969 Ar1 is a phenyl group substituted by 〇3 substituents selected from the group consisting of cyano, functional 'alkyl, _alkyl, alkoxy, haloalkoxy and Alkyl S02; X is hydrazine, CH2 or NH; and Y is a bond, hydrazine, CH2 or NH; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which has the specified stereochemistry 3. The compound of claim 2, wherein R1 is hydrogen, halo, cyano, amine, alkylamino or dialkylamino; R2 is hexahydropyridyl, substituted by 1 substituent, and the substituent is selected from Groups of the following groups: R3 is hydrogen or a halogen group; R4 is a nitrogen or i group; Ar1 is a phenyl group, 0-2 halogen substituents; X is hydrazine, CH2 or NH; and Y is hydrazine; or a pharmaceutically acceptable salt thereof. 4. The compound of claim 3, wherein R1 is hydrogen, chloro, cyano, amine, 139424 201036969 tri-butylamino 'R2 is a hexahydro-P-bite group, substituted by one substituent' substituent Groups from the following groups: CrNH,. The 丫〇 and the heart are phenyl or difluorophenyl; X is hydrazine, CH2 or NH; and Y is hydrazine; or a pharmaceutically acceptable salt thereof. 5. The compound of claim 1, wherein R1 is hydrogen, halo or cyano. 6. The compound of claim 1 wherein R2 is N-hexahydropyridyl and is 4-substituted. 7. A compound as claimed in claim 6 8. A compound such as the phenyl group of claim 1. Wherein the substituent is Wherein Ar1 is a 139424 201036969 substituted by two halo substituents. (6) seven trans-p-difluorophenyl groups from a long-term tetrahydrogen hydrazine and a pyridyl ester; or a pharmaceutically acceptable salt thereof . 12. The compound of claim 1 which is selected from the group consisting of 4-(2-keto-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl Hexahydropyridine·carboxylic acid (6,9-trans)-2-cyano-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta [b]pyridine-9-yl ester; 4-(2-keto-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)hexahydropyridine small carboxylic acid (6R , 9R)-2-carbyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester; 4- (2-keto-2,3-dihydro-1H-imidazo[4,5-b>pyridin-1-yl)hexahydropyridine small (4S,9S)-2-chloro-6 -(2,3-difluorophenyl)-6,7,8,9-tetraar-5H-cyclohepta[b]pyridin-9-yl ester; 4-(2-keto-2,3- Dihydro-1H-imidazo[4,5-b>pyridin-1-yl)hexahydropyridine small carboxylic acid (6,9-trans)-6-phenyl-6,7,8,9-tetra Hydrogen-5H-cyclohepta[b]pyridin-9-yl vinegar; 4-(2-keto-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)6 Hydrogen pyridine small carboxylic acid (6,9-trans)-6-(2,5-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptadol-10-9 Base ester; and 4-(2-keto-2,3-dihydro-1H-imidazo[4,5-b-azulidine-1-yl)hexahydropyrazole Carboxylic acid (6,9-trans)-6-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]p ratio bit-9-yl Vinegar; or a pharmaceutically acceptable salt thereof. 13. The compound of claim 1 which is selected from the group consisting of: 1-(1-(2-((6,9-cis))-6-(2,3-difluorophenyl)- 6,7,8,9-tetrahydro-5H-cycloheptane 139424 201036969 [b]pyridin-9-yl)ethinyl)hexahydropyridin-4-yl)-1Η-imidazo[4,5-b Pyridine-2(3H)-one; l-(l-(2-((6R,9S)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H) - Cyclohepta [b wind bite-9-yl) acetamyl) hexamidine p than bite-4-yl)-1 Η-taste and [4,5-b]u ratio bite-2(3H)· ketone ; with ^ 1-(1-(2-pin, 91^6_(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine, 11 Winter base) ethinyl) hexahydropyridin-4-yl)-1 Η-imidazo[4,5-bM pyridine-2(3H)-one; ❹ N-((6R,9R)-6-(2, 3-difluorophenyl)_6,7,8,9-tetrahydro-5H-cyclohepta[b]P than bit-9-yl)-4-(2-keto-2,3-dihydro- 1H-imidazo[4,5-seven>pyridin-1-yl)hexahydropyridin-1-carboxamide; and N-((6S'9S)-6-(2,3-·^·fluorobenzene) _6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-4-(2-keto-2,3-dihydro-1H"carbazolo[4 , 5-b]p-pyridin-1-yl)hexahydropyridine carboxamide; or a pharmaceutically acceptable salt thereof. 〇I4. The compound of claim 1, which is selected from the group consisting of 4-(2-retentry-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1- Hexahydropyridine_1_decanoic acid (6R,9R)-2-(tris-butylamino)_6_(2,3-difluorophenyl)_6,7,8,9·tetrahydro-5H- Cyclohepta[b]acridinyl-based ester; 4-(2-keto-2,3-dihydro-1H-«moxa[4,5-b]pyridin-1-yl)hexahydropyridine- 1-nonanoic acid (6R,9R)-2-amino-6-(2,3-difluorophenyl)_6,7,8,9-tetrahydro-5H-cyclohepta[b] 9-yl g; 4-(2-keto-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)hexahydropyridine-1-acid (6R,9R - 6-(2,3:fluorophenyl)-2-(dimethylamino)-6,7,8,9-tetrahydro-5H-cyclo 139424 201036969 heptoh[b]pyridin-9-yl ester; N-((6R,9R)Ethylamino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl) 4-(2-keto-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)hexahydropyridine-1-carboxamide; and 4-(2-ketone Benzyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)hexahydropyridine-1-carboxylic acid (6R,9R)-6-(2,3-difluorobenzene 3-(diamino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl An ester; and or a pharmaceutically acceptable salt thereof. 15. The compound of claim 1 which is selected from the group consisting of 4-(2-keto-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl Hexahydropyridine-1-carboxylic acid (6,9-trans)-6-(2,3-difluorophenyl)_6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine -9-yl ester; and 1-(1-(((6,9))-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[ b] pyridyl-9-yloxy) benzyl) hexahydropyridine _4_yl) 2 keto-a dihydroimidazo[4, 5-1) &gt; bite-3-chemical &lt; potassium Or a pharmaceutically acceptable salt thereof. 16·—a compound Or a pharmaceutically acceptable salt thereof. The compound of claim 16, wherein the pharmaceutically acceptable salt is potassium. 18. A composition comprising the compound of claim i or pharmaceutically acceptable a salt, and a pharmaceutically acceptable wearing agent. 139424 201036969 19. The composition of claim 18 wherein the compound of claim 1 is F Or a pharmaceutically acceptable salt thereof. 2. Use of a compound of claim i or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of symptoms associated with the ambitious content of CGRp. 21. If the use of item 20 is used, the symptom is a head 〇 Or a pharmaceutically acceptable salt thereof. 23. The use of claim 22, wherein the symptom is partial pain. 139424