TW200813031A - S1P receptor modulating compounds and use thereof - Google Patents

Abstract

The present invention relates to compounds of the general formula (I) that have activity as S1P receptor modulating agents and the use of such compounds to treat diseases associated with inappropriate S1P receptor activity. The compounds may be used as immunomodulators, e.g., for treating or preventing diseases such as autoimmune and related immune disorders including systemic lupus erythematosus, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, type I diabetes, uveitis, psoriasis, myasthenia gravis, rheumatoid arthritis, non-glomerular nephrosis, hepatitis, Behcet's disease, glomerulonephritis, chronic thrombocytopenic purpura, hemolytic anemia, hepatitis and Wegner's granuloma; and for treating other conditions.

Description

200813031 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD The present invention relates to compounds having activity as S1P receptor modulators and the use of such compounds for the treatment of diseases associated with inappropriate S1P receptor activity. [Prior Art] Sphingosine-1-phosphate (S1P) has been shown to induce a number of cellular effects, including their production of platelet aggregation, cell proliferation, cell metamorphosis, tumor cell invasion, endothelial cell chemotaxis, and endothelial cell in vitro. The effect of angiogenesis. Thus 'S<1>P receptors are good targets for therapeutic applications such as wound healing and tumor growth inhibition. The S1P moiety signals cells via a group of G-protein coupled receptors named S1P1, S1P2, S1P3, S1P4, and S1P5 (formerly known as EDG-1, EDG-5, EDG-3, EDG-6, and EDG-8, respectively). Signaling. These receptors are associated with three other structurally related lysole fatty acid (LPA) receptors (LPA1, LPA2 and LPA3 (formerly known as EDG_2, £00-4 and £00-7)). 5% amino acid and cluster consistency. The conformational shift in the quino-protein coupled receptor (GPCR) is induced when the ligand binds to the receptor resulting in GTP replacement in the subunit of the relevant G protein and subsequent release of the prion protein into the cytoplasm. The alpha subunit is then separated from the beta gamma subunit and each subunit can then be associated with an effector protein that activates the second messenger to produce a cellular response. Finally, the GTP on the G protein is hydrolyzed to GDP and the subunits of the G protein are again associated with each other and subsequently associated with the receptor. Amplification plays an important role in the general GPCR pathway. Binding of a ligand to a receptor results in a number of G protein activities that are each associated with a number of effector proteins. / The individual receptors are tissue specific and reaction specific, so the S1P receptor becomes a good drug dry standard. The tissue specificity of the S1P receptor is important because the development of an agonist or antagonist that is selective for one receptor limits the cellular response to tissues containing the receptor and thereby limits inappropriate side effects. It is also important because the specificity of the reaction of the S1P receptor allows the development of agonists or antagonists that initiate or inhibit certain cellular responses without affecting other things. For example, the specificity of the reaction of the Slp receptor can make sip (the mimetic initiates platelet aggregation without affecting cell morphology. s1P is a metabolite of ceramide in the form of ceramide and ceramide kinase Formed in the reaction and stored in large amounts in platelet aggregates in which high levels of sphingosine kinase are present and lack of sphingosine dissociating enzyme. S1P is released during platelet aggregation, accumulates in serum and is also found in malignant ascites. S1P organisms Degradation is most likely carried out via hydrolysis of extracellular phosphorus hydrolase (especially sphingosine 1-phosphate phosphoryl hydrolase). SUMMARY OF THE INVENTION The present invention relates to, for example, agonists, partial agonists, reverse agonism. Use of novel compositions of S1P modulators of agents and antagonists and their use in the treatment, prevention or cure of various s 1P receptor related disorders. The present invention relates to compounds which are S1P steroid modulators; The compounds include those compounds having the formula:

119664.doc 200813031 and pharmaceutically acceptable salts thereof, wherein Ι^, Ζ2, (:, Β, Α, ζ, and X are defined herein. [Embodiment] In one embodiment, the invention relates to a compound of formula I.

In the formula I, hydrazine may be an aryl or heteroaryl-halogen substituted by one, two or three substituents which may include the following groups, a trans group, sr2, S(0). 2R2, s(o)2nr2, nhs(o)2r2, C0R2, c〇2R2, an aryl group, an amine group, a Cw alkylamino group/arylamino group/heteroarylamino group, a Cw alkyl group, a Ch hospital A thio group, a Cw alkoxy group, a carboxylic acid substituted alkyl group, and a self-substituted 5 iCw alkoxy group. Two adjacent substituents, as the case may be, may form a fused ring containing one or more heteroatoms, optionally together with zi and the ring A to which it is attached. R'2 may be independently selected from the group consisting of hydrogen, hydroxy, amine, alkylamino/arylamine, cl-6 alkyl, c, .5 alkoxy, (:w thiol, _ _ Substituted Ci_6 alkyl group and = cetophan-substituted Cl_5 alkoxy group; or aryl/heteroaryl ❶A may be expected to have a C16 cyclic ring (alicyclic or aromatic) having - or a plurality of hetero atoms. And C is a bicyclic system of the genus to the genus, for example, a bicyclic aryl group, a bicyclic heteroaryl group, a dihydrobicyclo or a tetrahydrobicycloaryl group, and a heteroaryl group. The bicyclic ring system may be (1), for example, a C1_6 alkyl group, Substituted by a substituent of a thiol group, a C15 alkoxy group, a functional group r', a thiol group, a cyano group, and a (tetra) substituted group, and a substituent substituted by an i-substituted Cl.5 alkoxy group. Z1 and Z2 may be independent. Selected from 〇, nr3, s, s(〇), s(〇)2, 119664.doc 200813031

s(9), (CRV)n, 〇〇, c = s, C=N R3 or a chemical bond. R may be hydrogen, (tetra)yl, Cl4oxyuthio, Ci. substituted by pylorin and pyridyl substituted by (tetra); aryl or heteroaryl. Μ and R5 can independently be hydrogen, dentate, thiol, cyano, m-based, Cw saponin, Ci 5 sulphur-based, dentate-substituted Cm alkyl and dentate-substituted cl-5 Alkyl; aryl or heteroaryl...form together to form "C=〇"; η can be 0, 2 or 3. In an embodiment wherein 22 is a chemical bond, R can be a C3_c6 ring optionally containing a hetero atom. = can be Cw alkyl, c2_6 alkenyl, C2 6 alkynyl, C3 6 cycloalkyl, Ci 5 alkoxy, Cw alkylamino, aryl or heteroaryl. R1 may be optionally substituted with, for example, a hydroxyl group, a dentate, a cyano group, an amine group, an alkylamino group, an arylamino group, a heteroarylamino group, and the aryl group and the heteroaryl group may optionally be 丨5, for example Substituted by a substituent of a hydroxyl group, an i group, a cyano group, a Cl 6 alkyl group, a Ci 5 alkylthio group, a Cm alkoxy group, or a C 3 .6 cycloalkyl group. X may be WC(0)0R6a, WP(0)R6bR6C, ws(〇)2〇H, WC0NHS03H or 1Η·tetrazole·5· group. w may be a chemical bond, oxygen or a Ci 4 alkyl group having a substituent independently selected from the group consisting of dentate, hydroxyl, cyano, amine, alkylamine, arylamine, hetero An arylamine group, a cw alkoxy group; and R6a may be hydrogen or. 4 alkyl; R6b and R6. It may be hydrogen, a mercapto group, a Ci-4 alkyl group or a Cw-substituted group substituted with a phenyl group. Y can be the residue of formula (a), wherein the left and right asterisks indicate the connection point··

H9664.doc -10 - 200813031 where Q can be a chemical bond, 〇〇, 〇S, s〇2, c=〇NR4 (CR1GR")m; m can be 〇, 丨, 2 or 3; r7&r8 can be independent The ground is hydrogen, dentate, amine, Cw alkylamino, hydroxy, cyano, Ci 6 alkyl, 6 hydroxyalkyl (such as hydroxy-terminated alkyl), Cm alkylthio, Ci-5 alkoxy, The Cw alkyl group substituted by a gemin and the Cy alkoxy group substituted by a dentate; or r7 and R8 may be bonded to the atom to which they are attached to form a 4- to 7-membered ring having a hetero atom as the case may be. R9 may be hydrogen, halogen, hydroxy, cyano, Gw alkyl, Cw alkylthio, Cw alkoxy, halogen-substituted Ci6 alkyl or halogen-substituted Cl-5 alkoxy; R1G and R11 It may be hydrogen, halogen, hydroxy, cyano, Cw alkyl, Cl.5 alkoxy, Cw alkylthio, carboxylic acid substituted Cl.6 alkyl or halogen substituted Ci-5 alkoxy . In another embodiment, the invention includes a compound having the formula:

And pharmaceutically acceptable salts thereof. In style! In the above, A may be a Cy cyclic ring (alicyclic or aromatic) which may have one or more hetero atoms. Wherein a is an aryl or heteroaryl group, and A may be substituted by one, two or three substituents which may include the following groups: _, hydroxy, s, s(〇) 2r2, s(c〇2Nr2 Nhs(〇)2r, C0R2, c〇2R2, cyano group, amine group, a.alkylamino group/arylamino group/heteroarylamine group, Cw alkyl group, Cis alkylthio group, CM alkoxy group f, a hexyl-substituted alkyl group substituted with dentate and a CM alkoxy group substituted with a phenyl group. Optionally, two adjacent substituents may form an alicyclic or heterocyclic ring together with the ring to which they are attached, for example, a thiol group. R2 may be hydrogen, _, an amine group, an alkylamino group / 119664.doc -11 - 200813031 arylamine group, Cw alkyl group, Ci-5 alkoxy group, Cw alkylthio group, halogen-substituted Cw And a halogen-substituted Cw alkoxy group; or an aryl/heteroaryl group. B and C are at least partially aromatic bicyclic systems, such as bicyclic aryl, bicyclic heteroaryl, dihydrobicyclo or tetrahydrobicycloaryl And a heteroaryl group. The bicyclic ring system may be substituted with 1 to 5, for example, a Cl-6 alkyl group, a cKS alkylthio group, a Ci 5 alkoxy group, a dentate group, a hydroxyl group, a cyano group, a halogen-substituted Cw alkyl group, and a phenyl group. Substituted by a substituent of a Cw alkoxy group; Z 1 and Z2 may be independently selected from 〇, 'nr3, s, s(〇), s(o)2, S(〇)2NR3' (CR4R5)n, c=〇, OS, C=N-R3 Or a chemical bond. R3 can be hydrogen, hydroxy, s(〇)2, oo, c=s, brilliant, Cl_6 alkyl, Cl-5, oxy, Ci 5 thio, substituted by halogen Alkyl and _-substituted 〇 1_5 alkoxy; aryl or hydroxy group. R and R 5 may independently be hydrogen, halogen, thiol, cyano, C" alkyl, Ci-5 alkoxy, Ci·5 thiol group, halogen-substituted q 6 alkyl group and halogen-substituted Cw alkoxy group; aryl or heteroaryl group, or co-formed ("C=0"); n can be 0, 1, 2 or 3. R1 may be Cle6 alkyl 'c2-6 alkenyl, C2. 6 alkynyl, c: 3-6 cycloalkyl, Cy alkoxy, Ci-5 alkylamine, aryl or heteroaryl R1 may be optionally substituted by, for example, a hydroxyl group, a halogen, a cyano group, an amine group, an alkylamino group, an amino group, a heteroarylamino group, and the aryl group and the heteroaryl group may be optionally one to five For example, a substituent of a hydroxyl group, a cyano group, a cyano group, a Cl_6 alkyl group, a Cl.5 alkylthio group, a Cw alkoxy group, or a C3.6 cycloalkyl group may be substituted. X may be WC(0)0R6a, WP(〇)R6bR6e ,w s(o)2〇h, WC0NHS03H or 1H-tetrazol-5-yl. w may be a chemical bond, oxygen or a Ci-4 alkyl group having a substituent independently selected from the group consisting of: H9664. Doc -12- 200813031 Halogen, hydroxy, cyano, amine, alkylamino, arylamino, heteroarylamino, CV4 alkoxy and C002H; 1^ may be hydrogen or c1-4 alkyl; R6b and R6e may be hydrogen, hydroxy, Ci. 4 alkyl or halogen substituted c" alkyl. γ has the following formula:

Wherein Q may be a chemical bond, C = 0, C = s, S〇2, c=ONR or (CR Rll)m; m may be 0, 1, 2 or 3, and R7-R8 may be hydrogen, halogen, Amine group, Cw alkylamino group, hydroxyl group, cyano group, c1-6 alkyl group, Cl_5 alkyl fluorenyl group, Cm alkoxy group, 〇1 substituted 〇1·6 alkyl group and Ci_5 substituted oxygen Or R7 and R8 may be joined to the atoms to which they are attached to form a 4 to 7 membered ring. R9 may be hydrogen, halogen, hydroxy, cyano, ci6 alkyl, Cu alkylthio, Cw alkoxy, cyano substituted Ci 6 alkyl or halogen substituted saponin, R1G and R11 may be independently It is hydrogen, halogen, light, cyano, Cw alkyl, Cw alkoxy, Cm alkylthio, dentate substituted Cw alkyl or cyano substituted c1-5 alkoxy. In another embodiment, the invention is directed to a compound having the formula:

Wherein A is an optionally substituted aryl or heteroaryl; 119664.doc • 13 - 200813031 B and C are at least partially aromatic bicyclic systems; X is selected from WC(0)0R6a, WP(0)R6bR6c, a group consisting of ws(〇)2〇h, WCONHSAH or m-tetrazol-5-yl; wherein % is 1 chemical bond, oxygen or C having one or more substituents independently selected from the group consisting of:丨_4 alkyl: halogen t, hydroxy, cyano, amine, alkylamino, arylamine, heteroarylamine, Cl_4 alkoxy and c〇〇2H '·3 is hydrogen or heart a Cw alkyl group which is hydrogen, a thiol group, or a halogen group; Y is a residue of the formula (a), wherein the left and right asterisks indicate a point of attachment: cx(a) wherein Q is selected From 00, C = s, S02, OONR and; m is 0, 1, 2 or 3; R7 and R8 are independently selected from the group consisting of hydrogen, -, amine, c丨_5 alkylamine a group, a C.6 carbonyl group, a ci.6 hydroxy group (for example, a hydroxy-terminated group), a Cw-sulphur group, a Ci 5 methoxy group, a Ci_6-substituted group substituted by _- and a dentate-substituted (^ a group of .5 alkoxy groups; or R7 and R8 may be attached to the atom to which they are attached Together to form a 4 or 5 membered ring; and / is selected from the group consisting of hydrogen, anion, a trans group, a cyano U group, a c15 burnt earth 15 alkoxy group, a self-substituted Cu group or a self-substituted Cl. a group of 5 alkoxy groups; R and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, Cb6 119664.doc -14-200813031 alkyl, Cw alkoxy, Cw sulphur, _ a group consisting of a substituted c16 alkyl group or a halogen-substituted Cle5 alkoxy group; and Z1 is selected from the group consisting of ruthenium, NR3, S, S(O), s(0)2, S(0)2NR3, (CR4R5)n , C=0, C=S, and C=N-R3; and z2 is selected from 〇, NR3, S, S(0), S(0)2, S(0)2NR3, (CR4R5)n, 〇〇 , C = S and C = N_R3; wherein R3 is selected from the group consisting of hydrogen, hydroxyl, s〇2, C = 0, C = S, ONH, C" alkyl, Cu alkoxy, Cu a sulfur-burning group, a halogen-substituted Cw alkyl group, and a cyano-substituted Cl_5 alkoxy group; an aryl group or a heteroaryl group, or when Z2 is a chemical bond, R3 is a c3-c6 ring optionally containing a hetero atom; R4 and R5 are independently selected from the group consisting of hydrogen, halogen, thiol, cyano, Cw alkyl, Cw alkoxy, 〇^-5 a halogen-substituted Cu alkyl group and a halogen-substituted Cu alkoxy group; an aryl group or a heteroaryl group, or a combination of C = 0; and η is 0, 1, 2 or 3; and R1 is selected from Ci a group consisting of -6 alkyl, C2-6 alkenyl, C2-6 fast radical, C3-6 cycloalkyl, Cw alkoxy, Ci.5 alkylamino, aryl or heteroaryl. In another embodiment, the invention includes a compound of formula (II):

(II) wherein A may be aryl or heteroaryl; X is -C(0)0R6a, wherein R6a is chloro or (^.4 alkyl; Y is a residue of formula (a): 119664.doc -15 - 200813031

Wherein Q is (CR10Rn)m; m is 〇, 1, 2, 3 or 4; R7 and R8 are independently hydrogen, hydroxy or lower alkyl; or R7 and R8 together with the atom to which they are attached form a ring; R9 Is selected from, for example, hydrogen, halogen, trans- or cyano; and z1 and z2 are independently hydrazine or (CR4R5)n, wherein cyclization 5 is independently hydrogen, a cycline, a thiol group, a cyano group, a Cw alkane a, Ci-5 alkoxy; η is 0, 1, 2 or 3; and R1 is selected from, for example, Ci-6 alkyl, c2-6 alkenyl, c2-6 alkynyl, c3-6 'cycloalkyl a Ci-5 alkoxy group, an alkylamino group, an aryl group or a heteroaryl group; or a pharmaceutically acceptable salt thereof. The aryl or heteroaryl group may be substituted with one, two or three substituents such as the following groups: _, hydroxy, S, S(0)2R2, s(0)2NR2, NHS(〇)2R2, C 〇R2, C〇2r2, cyano group, amine group, Ci 5 alkylamino group / arylamino group / heteroaryl amine group, Cl-0 alkyl group, Cl_5 alkylthio group, c1-5 alkoxy group, Substituting a Cw alkyl group or a sulfonate-substituted (^15 alkoxy group, wherein R2 is, for example, hydrogen, a hydroxyl group, an amine group, an alkylamino group/arylamino group, a Cw alkyl group, a Cw alkoxy group a base, a Ci_5 thiol group, a ketone-substituted alkyl group, and an i-substituted (^-5 alkoxy group; or an aryl/heteroaryl group; or, optionally, two adjacent substituents on A An alicyclic or heterocyclic ring may be formed together with z1 and the ring to which it is attached. R2 may be selected from the group consisting of hydrogen, hydroxy, amine, alkylamino/arylamino-based C.6 alkyl, Cl.5 succinyl, Cl _5 thiol group, a sulphur-substituted alkyl group and a halogen-substituted Cw alkoxy group; or an aryl/heteroaryl group. The awkward furanyl ring may have 1 to 5, for example, a Cl-6 alkyl group, a Ci 5 alkyl sulfide. Base, Cw alkoxy, _, hydroxy, cyano, alkyl substituted by _ or 119664.doc •16- 200813031 Substituted by a halogen-substituted Cw alkoxy substituent. Ri may be Ci6 alkyl, C2-6 alkenyl, c2-6 alkynyl, c3-6 cycloalkyl, Cw alkoxy, Cw alkylamino, aryl or a heteroaryl group; R1 may be optionally substituted with, for example, a hydroxyl group, a halogen, a cyano group, an amine group, an alkylamino group, an arylamino group or a heteroarylamino group. The aryl group and the heteroaryl group may be through 1 to 5 such as a hydroxyl group. Substituted by a substituent of a halogen, a cyano group, a Ci6 alkyl group, a C!-5 alkylthio group, a Cl_5 alkoxy group, and a Cw cycloalkyl group. In one embodiment, the present invention relates to a compound of the formula. A is preferred. Is a substituted or unsubstituted aryl or heteroaryl group which may be one of the groups described below wherein R12 is hydrogen or Cl-6 alkyl; and the left and right asterisks indicate the point of attachment of formula (I) ; - 〇 Ο Ν Ν Ν Ν ΑΧ Ν Ν Ν 分 令 令 令 令 令 令 令 令 令 令 令 令 令 令 令 令 令 令 R R R R R R R R R R R R R R 「 「 「 「 「 「 「 「 「 「 「 「 「 The aryl or heteroaryl B and C are preferably more preferably, for example, an unsubstituted aryl or heteroaryl group, for example, 119664.doc -17- 200813031

Among the groups directly shown in the above two tables, the groups described in the asterisk can be attached to the molecule as shown or "turned over." These groups, which are described immediately above herein, may be expected to be present in the molecule in the orientation indicated. Wherein R 2 is hydrogen or Cw alkyl; and the left and right asterisks indicate the point of attachment of formula (1), W!, w2, w3 or W4 may be c, N, C-OH, C-OR13 or CR, and R 3 is hydrogen Or a Cw alkyl group, a c1-5 alkylthio group, a Cw alkoxy group, a halogen group, a cyano group, a Ci 6-substituted Ci 6 alkyl group, and a halogen-substituted C 1-5 alkoxy group. Preferably, hydrazine and hydrazine are CH2, hydrazine, S or - chemical bonds. R3 is preferably a methyl group. R and R are preferably hydrogen or methyl. n is preferably 丨 or 2. X can be combined with γ, for example:

119664.doc -18- 200813031

Optionally, two adjacent substituents on ring A form a fused ring with Z1, which may contain one or more heteroatoms, and wherein X may be combined with Y, for example:

In another embodiment of the invention, in combination with the above and below examples, A is an aryl or heteroaryl group which is optionally substituted with one, two or three substituents selected from the group consisting of halogens and hydroxy groups. , SR2, S(0)2R2, S(0)2NR2, NHS(0)2R2, COR2, C02R2, cyano, amine, Cu alkylamino, arylamine, heteroarylamine, Ci. 6 alkyl, Cw alkylthio, Cu alkoxy, Ci_6 alkyl substituted by i, and substituted by _ 119664.doc -19- 200813031

Cw alkoxy; wherein in each instance R2 is independently selected from the group consisting of hydrogen, hydroxy, amine, alkylamino, arylamine, Cl.6 alkyl, Ci5 alkoxy, Cu alkylthio, a substituted C1-6 alkyl group, a halogen substituted C decane: a aryl group, an aryl group and a heteroaryl group. In another embodiment of the invention 'in combination with the above and below examples, A is a 1,4-disubstituted phenyl group which is additionally substituted, as the case may be, by one, two or three substituents selected from the group consisting of : dentate, hydroxyl, sr2, s(〇) 2R2

S(9)2NR2, deleted (9)2R2, C〇r2, c〇2R2, cyano group, amine group, alkylamino group, aryl group, heteroarylamine group, Cw alkyl group, Cl_5 alkyl sulfide

a group, a Cl.5 silk group, a phenyl group substituted group, and a (tetra) substituted 15 alkoxy group. In each of the examples, the rule 2 is independently selected from the group consisting of hydrogen, a thiol group, an amine group, an alkyl group, and an aromatic group. Amino group, q ritual U oxy group, CM 立:, Cl.6 alkyl group substituted by work element, substituted by i element (^_5 alkoxy group, aryl group and heteroaryl group).

In another embodiment of the present invention, in combination with the above and the following examples, a aryl or heteroaryl substituted with two or three _ prime atoms is another aspect of the present invention. The case is one, and the other in the present invention is one by one, and the other in the present invention is a disordered phenyl group. In the examples, in combination with the above and the following examples, a phenyl group in which two or three atoms are substituted. In the examples, the above and the following examples are combined, and a phenyl group in which two or two fluorine atoms are substituted. In the embodiment of the present invention, in combination with the above and the following examples, in another embodiment of the present invention, in combination with the above and the following embodiments, A is 119664.doc -20. In another embodiment of 200813031 s month, And in the following examples, A is a heteroaryl group substituted with H, two or three (tetra) atoms.

In another embodiment of the invention, in combination with the above and below examples, A is a heteroaryl group. In another embodiment of the present invention, in combination with the above and the following examples, B and c are, as the case may be, 1 to 5 selected from Ci 6 alkyl, Ci 5 alkylthio, Cl-5 alkoxy, hydrazine. a bicyclic heteroaryl group substituted with a hydroxy group, a cyano group, a Ci 6 alkyl group substituted with a phenyl group, and a substituent substituted with a C-5 alkoxy group substituted by a γ group. In another embodiment of the present invention, in combination with the above and the following examples, B and C are together a bicyclic heteroaryl group selected from the group consisting of

119664.doc • 21 - 200813031 Micro-丨"α;π \ UvN_i and any of them, depending on the case, 1 to 5, selected from Cl-6 alkyl, Cl_5 alkylthio, Cl·5 alkoxy, hydroxyl Substituted by a hydroxyl group, a cyano group, a halogen-substituted Cw alkyl group, and a halogen-substituted Cw alkoxy group. In another embodiment of the present invention, in combination with the above and following examples, B and c are in common bicyclic heteroaryl groups selected from the group consisting of:

-^119664.doc -22- 200813031 'ΧΧ; Η r: Hl 丨 及 and _, any of which is substituted with 1 to 5 selected from Cw alkyl, halogen and substituted by cyano Substituent substitution.

B 119664.doc -23- 200813031 丨 /\ C 'XX" 4 CX^ A [H \ s Θ and K Oh In another embodiment of the invention, in combination with the above and below embodiments, B and C together Is a bicyclic heteroaryl group selected from the group consisting of:

119664.doc -24· 200813031 X;H /Να;π r:H 丨 and Xh \ In another embodiment of the invention, in combination with the above and below examples, R1 is selected from Cw alkyl, C2-6 olefin a base, a c2 6 alkynyl group, a 6-cycloalkyl group, a Ci-5 alkoxy group, a Cw alkylamino group, an aryl group and a heteroaryl group; any of which may optionally be via a hydroxyl group, a halogen, a cyano group, an amine group or an alkane group. Substituted with an amino group, an arylamino group or a heteroarylamino group, wherein the aryl group and the heteroaryl group such as S, optionally, are optionally selected from the group consisting of hydroxyl, halogen, cyano, C1-6 alkyl, Substituent substitution of c15 alkylthio, c15 alkoxy and C3-6 cycloalkyl. In another embodiment of the invention, in combination with the above and below examples, R1 is selected from the group consisting of phenyl and heteroaryl; both of which are optionally substituted by dentate. In another embodiment of the present invention, in combination with the above and below examples, R1 is a phenyl group substituted with _ _. In another embodiment of the invention, in combination with the above and below examples, r1 is a heteroaryl group optionally substituted with _. In another embodiment of the invention, in combination with the above and below examples, R1 is phenyl. In another embodiment of the invention, in combination with the above and below examples, R1 is a heteroaryl group. 119664.doc -25- 200813031 In another embodiment of the present invention, in combination with the above and below examples, R1 is an atom comprising N, Ο and S and another 〇, 1, 2 or 3 N atoms. 5 or 6 member unsaturated ring. In another embodiment of the invention, in combination with the above and below examples, R1 is selected from the group consisting of oxaridinyl, pyrimidinyl, thiazolyl, oxazolyl, furyl and thienyl.

In another embodiment of the present invention, in combination with the above and the following examples, X is WC(0)0R6a, WP(〇)R6bR6c, ws(0)20H, WCO丽so3h (or 1H-tetrazole_5_ The group w is a chemical bond, oxygen and has a substituent independently selected from the group consisting of a halogen, a thiol group, a cyano group, an amine group, an alkylamino group, an arylamine group, a heteroarylamino group, and a C?. a ci4 alkyl group; and R6a is hydrogen and ci4 alkyl 'R and R6e are independently selected from the group consisting of hydrogen, hydroxy, C14 alkyl and halogen-substituted Cw alkyl. In another embodiment of the present invention, In the above and following examples, X is CO2H 〇I.. In another embodiment of the present description, in combination with the above and the following examples, Y is

Wherein R9 is selected from the group consisting of hydrogen, cis, ci-5 alkoxy, and Ci-5 alkoxy. In a further embodiment of the invention, dentin, hydroxy, cyano, Cw alkyl, Cw alkyl sulphide, cyano substituted CN6 alkyl and dentate substituted, in combination with the above and following examples, Y is 119664 .doc •26- 200813031

V wherein R is far from oxygen, γ and meridine. In another embodiment of the invention, in combination with the above and below examples, R9 is nitrogen. In another embodiment of the invention, in combination with the above and below examples, R9 is a warp group. In another embodiment of the present invention, in combination with the above and the following examples, Z1 is CW; wherein R4 and R5 are independently hydrogen, _, hydroxy, cyano, Cu, Cw alkoxy, Cl_5 alkyl sulphide a Cw alkyl group substituted by a halogen or a 2Ci_5 alkoxy group substituted by a γ element. In another embodiment of the invention, in combination with the above and following examples, Z1 is cr4r5; wherein R4 and R5 are independently hydrogen, halogen, Cw alkyl or a halogen-substituted Cw alkyl group. In another embodiment of the invention, in combination with the above and below embodiments, Z1 is CH2. In another embodiment of the present invention, in combination with the above and below embodiments, Z is selected from the group consisting of 0, NR3, S, s(o), s(o)2, s(o)2nr3, (CR4R5)n, c. = 〇, c=s and C=N-R3; R is hydrogen, hydroxy, Cl_6 alkyl, C1-5 alkoxy, Cl.5 alkylthio, halogen substituted C1-0 alkyl or via Substituted alkoxy; R4 and R5 are independently selected from the group consisting of hydrogen, dentate, hydroxy, cyano, Ci6 alkyl Ci.5 alkoxy, Cl_s alkylthio, ci 6 alkyl substituted by autotin and 119664.doc -27· 200813031 Halogen substituted ci-5 alkoxy groups, or together form ', c=0,,; and η is 1 '2 or 3. In another embodiment of the present invention, in combination with the above and below embodiments, Ζ2 is selected from the group consisting of 〇, NR3, S, S(〇), s(0)2, S(0)2NR3, CR4R5, c=〇, c=SAC=N-R3; R is hydrogen, hydroxy, Cw alkyl, Cw alkoxy, Cw alkylthio, substituted by i. ^6 alkyl or pentacene substituted Cl-5 alkoxy; and R4 and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, Cl-6 alkyl, Cw alkoxy, Ci5 alkylthio, Ci 6 alkyl substituted by halogen and Cm alkoxy substituted by halogen. In another embodiment of the present invention, in combination with the above and the following examples, z2 is selected from the group consisting of ruthenium, NR3, s, CR4R5, c=0, C=S, and C=N-R3; R3 is hydrogen, thiol, a Cw alkyl group, a Cw alkoxy group, a Cl.5 alkylthio group, a halogen-substituted Ci.6 alkyl group or a c1-5 alkoxy group substituted by a conjugated compound; and R and R5 are independently selected from hydrogen and halogen. a hydroxy group, a cyano group, an alkyl group, a Cy alkoxy group, a C.5 alkylthio group, a ci 6 group substituted with a γ group, and a (^-5 alkoxy group substituted by an i element. In one embodiment, in combination with the above and below examples, Z2 is selected from the group consisting of 〇, s, ch2, 〇〇, OS, and C=N-0H. The scope of the application and the patent application include the use of terms, selected from... and .,, and, as a list of substances for (or sometimes referred to as Markush groups). When the term is used in the context, unless otherwise stated, it is meant to include A group or any individual member thereof or any subgroup thereof. The term is used for shorthand purposes only and does not imply any limitation (if necessary) of the removal of individual members or subgroups. The present invention is directed to a method for modulating S 1P-1 receptor-mediated biological activity. The present invention also provides the use of a modulator (ie, an agonist or a booster) for the treatment or The subject of prevention treats or prevents the following diseases; and prescriptions such as nest cancer, peritoneal cancer, endometrial cancer, cervical cancer, cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer , kidney cancer, pancreatic cancer and prostate cancer; acute lung disease, adult respiratory distress syndrome ("ARDS"), acute inflammation of chronic lung diseases such as asthma U It such as keratoconus or skin burns And cardiovascular diseases such as ischemia. In two cases, the present invention provides methods for treating or preventing diseases such as, but not limited to, the use of S1P-1 modulators: cerebral arterial vasoconstriction, including the body of the body [sheng, work Autoimmune and related immune disorders of lupus erythematosus, inflammatory bowel disease such as Crohn's disease and / or colitis, type I diabetes, uveal cavity, psoriasis, myasthenia gravis, rheumatoid Arthritis, Glomerulonephritis, hepatitis, Behcet's disease, spheroid nephritis, chronic thrombocytopenia: (d), hemolytic ash, hepatitis, and Wegener's granulomatosis. In another sample, 'the invention provides treatment with Slp] modulator Or a method of preventing a disease or condition of a subject, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of a U1IM modulator (eg, a stimulating immune system, a agonist). In the embodiment, the subject is afflicted with the infectious agent. In other embodiments, the subject is immunocompromised. II. The present invention provides a method for modulating the biological activity of the S1P-1 receptor JV type of a cell. The cells expressing the wp-丨 receptor are contacted with an S1P-1 receptor modulator having a biological activity of 119664.doc -29-200813031 sufficient to modulate the S 1P -1 receptor-mediated biological activity. In another aspect, the invention provides a method of inserting, 々々6^丄H 禋, i.e., the subject's S1P-1 receptor-mediated biological activity. In this method, the subject is administered an effective amount of a (tetra) purine receptor modulator for regulating S1IM receptor-mediated biological activity.

In another aspect, the invention provides a method of treating, preventing or ameliorating a S1P-1 receptor vector disorder in a subject. In this method, the subject is administered an effective amount of S1P_K modulating S1IM receptor-mediated biological activity. The d S 1 P_ 1 X-mediated vector disorder can be, for example, a transplant rejection (solid organ transplantation). And islet cells); transplant rejection (tissue);: disease; autoimmune/inflammatory disease; rheumatoid joints; lupus; TB-dependent diabetes mellitus (type I); non-insulin-dependent diabetes mellitus (type II) Multiple sclerosis; + skin rash; ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemia and lymphoma. Features and other details of the present invention will now be described more specifically. It is to be understood that the particular embodiments disclosed herein are shown by way of illustration The present invention: The main features can be used in various embodiments without departing from the scope of the invention. All parts and percentages are by weight unless otherwise indicated. Definitions For convenience, certain terms used in the specification and examples are concentrated herein. /treatment' includes, for example, alleviating, reducing, modulating or eliminating any effects that cause amelioration of the condition, disease, condition, etc., 119,664.doc -30-200813031. "Alkyl" includes saturated aliphatic groups such as linear alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl and decyl; branched alkyl (eg isopropyl, tert-butyl and isobutyl); cycloalkyl (alicyclic), such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; substituted by alkyl a cycloalkyl group; and an alkyl group substituted with a cycloalkyl group. ''Alkyl'' may also optionally include a heteroatom, i.e., wherein an oxygen, nitrogen, sulfur or r-phosphorus atom replaces one or more hydrocarbon backbone carbon atoms, particularly where substitution does not adversely affect the efficacy of the resulting compound. A linear or branched alkyl group may have 6 or fewer carbon atoms in its main chain (for example, (^-(:6 linear, C^C: 6 branches) and more preferably 4 or less carbons) The atomic ring is based on having 3 to 8 carbon atoms in its ring structure and more preferably having 5 or 6 carbons in the ring structure." C^-C, including an alkyl group having 1 to 6 carbon atoms. "Substituted alkyl," refers to an alkyl moiety having a substituent replacing a hydrogen at one or more carbons of the hydrocarbon backbone. The substituents may include alkyl, alkenyl, V. Base, _, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl , aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonic acid, phosphinic acid, cyano, amine, hydrazine Amine, formazan, imido, sulfhydryl, alkylthio, thioacetic acid sulfonate, sulfuric acid from the group, alkyl thiol, acid group, amine sulfhydryl, decylamine a nitro group, a cyano group, a cyano group, an azido group or a heterocyclic group. 119664.doc -31- 200813031 The square group includes an aromatic group including 5 to 4 hetero atoms. And 6 member non-common (ie, monocyclic) aromatic groups and conjugated (ie, polycyclic) systems having at least one aromatic ring. Examples of aryl groups include benzene, phenyl, tolyl, and the like. Polycyclic aryl groups include tricyclic and bicyclic systems, such as naphthalene, benzoquinone W, benzoquinone dioxin, sit, benzoquinone (tetra), benzoxazole, benzoquinone, methylene dioxybenzene Base, quinoline, isoquinoline, bite, called budo, benzoquinone, anthracene, benzoquinone, aza-n-natch" pyridazine, tetralin and methylene dioxyphenyl The aryl group having a hetero atom in the ring structure may also be referred to as "aryl heterocycle,", "heterocycle", "heteroaryl, or, heteroaromatic"; for example, each, 吱, porphin, thiazole, isothiophene , imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine and pyrimidine. The aromatic ring may be substituted at one or more ring positions via, for example, the following groups: halogen, hydroxy , alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylamine Carbocarbonyl, alkenylamino group, alkyl group, aryl group, arylalkyl group, thiol group, alkoxy group, amine carbonyl group, alkylthiocarbonyl group, carboxylic acid ester Base, phosphonic acid group, phosphinic acid group, cyano group, amine group, decylamino group, decyl group, imido group, sulfhydryl group, alkylthio group, arylthio group, thiocarboxylate group, sulfate Alkyl, sulfinyl, sulfonate, sulfonyl, sulfonylamino, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic Or heteroaromatic parts. The "alkylaryl" or "aralkyl" moiety is an alkyl group substituted with an aryl group (e.g., phenylmethyl (benzyl)). 119664.doc -32- 200813031 π-alkenyl" includes unsaturated aliphatic groups which are similar in length and possibly substituted to those described above but which contain at least one double bond. For example, the term alkenyl includes straight chain. Alkenyl (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl); branched alkenyl; such as cyclopropenyl, cyclo a cycloalkenyl group of a pentenyl group, a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group; a cycloalkenyl group substituted with an alkyl group or an alkenyl group; and an alkenyl group substituted with a cycloalkyl group or a cycloalkenyl group. "Thin base" may also include heteroatoms, i.e., wherein oxygen, nitrogen, sulfur or phosphorus atoms are substituted for one or more hydrocarbon backbone carbon atoms, especially where substitution does not adversely affect the efficacy of the resulting compound. The linear or branched alkenyl group may have 6 or less carbon atoms in its main chain (e.g., C^C: 6 linear, c^C: 6 branched). Preferably, the cycloalkenyl group has 3 to 8 carbon atoms in its ring structure and more preferably 5 or 6 carbons in the ring structure. The term "CrC6" includes alkenyl groups having 2 to 6 carbon atoms. Substituted alkenyl π refers to an alkenyl moiety having a substituent replacing a hydrogen at one or more hydrocarbon backbone carbon atoms. The group may include an alkyl group, an alkynyl group, a quinone, a hydroxyl group, an alkylcarbonyloxy group, an arylcarbonyloxy group, an alkoxycarbonyloxyaryloxycarbonyloxy group, a carboxylate group, an alkylcarbonyl group, an aryl group. Carbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl & benzyl, alkoxy, phosphate, phosphonic acid, phosphinic acid, cyanide Γ-amino group, guanamine group, formyl group, imido group, sulfhydryl group, alkylthio group, arylthio group, thiocarboxylate group, sulfate group, alkyl sulfinyl group, sulphate Alkyl, sulfonyl, sulfonyl, nitro, trifluoromethyl, cyano, azido or heterocyclic. 119664.doc • 33 - 200813031 ''Alkynyl' includes length and possible substitutions Similar to the alkyl s s as described above, there is an unsaturated aliphatic group to j/a triple bond. For example, alkynyl includes straight-chain alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, decynyl, decynyl) a branched fast group and an alkynyl group substituted by a cycloalkyl or cycloalkenyl group. ''Alkynyl') may also include heteroatoms, that is, wherein an oxygen, nitrogen, sulfur or hydrazine atom replaces one or more hydrocarbon backbone carbon atoms, especially where substitution does not adversely affect the efficacy of the resulting compound. A branched alkynyl group may have 6 or fewer carbon atoms in its main chain (for example, a c2-c6 straight chain, a c3-C6 branch). The term "c2-c6" includes an alkyne having 2 to 6 carbon atoms. 'Substituted alkynyl' refers to a fast-radical moiety having a substituent replacing a hydrogen at one or more carbon atoms of a hydrocarbon backbone. These substituents may include alkyl, fast-acting, _-, hydroxy , alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxywei, amino group , anthranyl-Wilyl, dialkylaminocarbonyl, alkylthio group, alkoxy group, phosphate group, phosphonic acid group, phosphinic acid group, cyano group, amine group (including alkylamino group) , dialkylamino, arylamino, diarylamino and alkylarylamino), decylamino (including alkylcarbonylamino, arylcarbonylamino, Mercapto and ureido), indolyl, imido, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkyl sulfhydryl, acid base, Amine, arginyl, decyl, trifluoromethyl, cyano, azido or heterocyclic. Unless otherwise stated in the carbon number, ''lower alkyl π includes 119664 as defined above. Doc-34-200813031 an alkyl group having 1 to 1 , more preferably 1 to 6 carbon atoms in its main chain structure. "Lower alkenyl" and "low carbon block" have, for example, 2-5 The chain length of one carbon atom. The π-mercapto group π includes a compound and a moiety containing a mercapto group (CHsCO-) or a carbonyl group. The 'substituted sulfhydryl group' includes a group in which one or more hydrogen atoms are replaced by, for example, the following groups. Base: alkyl, alkynyl, dentate, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, aryl Carbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbyl, monoalkylamino, alkylthio, alkoxy, acid ester, phosphonate, phosphine Acid group, cyano group, amine group (including alkylamino group, dialkylamino group, arylamino group, diarylamino group and alkylarylamino group), decylamino group (including alkylcarbonylamino group) , arylcarbonylamino, amine-mercapto and ureido), indolyl, imine, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkyl Sulfonyl, sulfonate, amine sulfhydryl, sulfonylamino, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moiety . The π-amino group π includes a moiety in which a thiol moiety is bonded to an amine group. By way of example, the term includes alkylcarbonylamino, arylcarbonylamino, amidino and ureido. "Alkylamino"' includes a moiety in which an alkyl moiety is bonded to an amine group; ''dialkylamino π, π arylamino group', 'diarylamine group', and "alkylaryl group" The amine group '' is similarly named. In certain embodiments, "amine" can include an amidino group and/or an alkylamine group. ''Alkoxyalkyl""alkylaminoalkyl" and, thioalkoxyalkyl" includes oxygen and nitrogen further comprising one or more hydrocarbon backbone carbon atoms as described above. -35- 200813031 or an alkyl group of a sulfur atom such as an oxygen, nitrogen or sulfur atom. "Alkoxy group" includes alkyl, alkenyl and alkynyl groups covalently bonded to an oxygen atom. Examples of the alkoxy group include a methoxy group, an ethoxy group, an isopropoxy group, a propoxy group, a butoxy group, and a decyloxy group. Examples of the substituted alkoxy group include an alkoxy group. The substituted calcined base may include a dilute group, an alkynyl group, a halogen, a transyl group, a pyrenyloxy group, an arylcarbonyloxy group, an alkoxycarbonyloxy group, an aryloxycarbonyloxy group, a sulphuric acid group. , alkylcarbonyl, arylcarbonyl, alkoxycarbonyl 'aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonic acid, sub Phosphonic acid group, cyano group, amine group, decylamino group, fluorenyl group, imido group, thiol group, alkylthio group, arylthio group, thiocarboxylate group, sulfate group, alkyl sulfinium sulfonate a sulfonate, sulfonate, sulfonamide, nitro, trifluoromethyl, cyano, azide or heterocyclyl substituent. Examples of the alkoxy group substituted by a functional element include a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a chloromethoxy group, a dichloromethoxy group, and a trimethoxy group. The term n heterocyclyl" or "heterocyclic group" includes ring closure structures, for example, a 3 to 10 membered ring or a 4 to 7 membered ring including one or more heteroatoms. The heterocyclic group can be saturated or unsaturated and Including pyrrolidine, oxolane, sulfonium cyclopentane, piperidine, piperazine, morpholine, lactone, decylamine such as azetidinone and pyrrolidone, intramolecular acid amine, within the performance I. The heterocyclic ring may be substituted at one or more positions via the substituents such as the following: i, hydroxy, alkylcarbonyloxy, arylcarbonyloxy , alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxy, phosphorus 119664.doc -36 - 200813031 Acid ester group, phosphonic acid group, phosphinic acid group, cyano group, amine group, decylamino group, decyl group, imido group, sulfhydryl group, alkylthio group, arylthio group, thiocarboxylate group , sulphuric acid, sulphate, sulphonyl, sulfonyl, nitro, trifluoromethyl, cyano, azido, heterocyclic, or aromatic or heteroaromatic moieties. Thiocarbonyl "Or '' comprises a π sulfur containing carboxyl carbon atom via a double bond to a sulfur compound and a connecting portion of the term 'ether' 'include those containing different carbon atoms bonded to an oxygen heteroatom or a compound of two or partially. For example, the term includes "alkoxyalkyl", which refers to an alkyl, a dilute or a fast radical covalently bonded to an oxygen atom covalently bonded to another alkyl group. The term ''ester π Included are compounds and moieties containing a carbon or heteroatom bonded to an oxygen atom bonded to a carbon of a carbonyl group. The term "ester" includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxy A carbonyl group, a pentyloxycarbonyl group or the like. The alkyl, alkenyl or alkynyl group is as defined above. The term "thioether" includes compounds and moieties which contain a sulfur atom bonded to two different carbon atoms and a hetero atom. Examples of the thioether include, but are not limited to, an alkylthioalkyl group, an alkylthioalkenyl group, and an alkylthioalkynyl group. The term 'alkylsulfanylalkyl" includes compounds having an alkyl group, a thiol group or a fast group bonded to a sulfur atom bonded to a burnt group. Similarly, the term 'alkylthioalkenyl" and alkylthio. Alkynyl 11 means a compound or moiety in which an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom covalently bonded to an alkynyl group. The term "hydroxy" includes a radical having -ΟΗ or -0. Halogen π includes fluorine, bromine, chlorine, iodine, etc. The term ''fully halogenated π refers to a moiety in which all hydrogens are replaced by an atom of an im group. 119664.doc -37- 200813031 Heteroatoms of heteroatoms' include carbon removal or Examples of atoms of any element other than hydrogen include nitrogen, oxygen, sulfur, and scales. ''At least partially aromatic bicyclic system'" means a bicyclic system in which either or both of the rings forming a bicyclic ring are aromatic.

It should be noted that the structures of certain compounds of the invention include asymmetric carbon atoms. It will therefore be appreciated that, unless otherwise indicated, isomers (e.g., all mirror image isomers and diastereomers) that are present due to this asymmetry are included in the target domains of the present invention. The isomers in substantially pure form can be obtained by conventional separation techniques and by controlled synthesis of stereochemistry. In addition, the structures and other compounds and moieties discussed in this application also include all tautomers thereof. When appropriate, the olefins may comprise a £ or 2 geometry. ''Combination therapy' (or "synergistic therapy") includes administration of a sip receptor ancient circumstance agent of the present invention and at least a second agent as a specific treatment regimen intended to provide a beneficial effect by the synergistic action of such therapeutic agents. Advantageous effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic synergistic effects resulting from a combination of therapeutic agents. m often has a defined time limit (usually a number of knives, depending on the combination selected, A combination of such therapeutic agents may be administered in combination for several days or weeks. • Combination therapy may (but generally not) be intended to cover the administration of two or more such treatments] as occasional and arbitrarily producing the present invention The combination of separate single treatment regimens., combination therapy" is intended to include administering the therapeutic agents in a sequential manner (i.e., wherein each therapeutic agent is administered at different times) and administering the same in a substantially simultaneous manner. The therapeutic agent or at least two of the therapeutic agents. Substantially simultaneous 119664.doc -38-200813031 can be achieved, for example, by administering to the subject a single capsule of a fixed ratio of each therapeutic agent or a plurality of single-agents administered to each of the therapeutic agents. Cast. Sequentially or substantially simultaneously, each treatment is administered by oral route, sputum, and sputum (but not limited to direct absorption, intramuscular route, and via mucosal tissue, Geyue is not appropriate) (4) Administration can be by the same route. For example, the first therapeutic agent of the selected combination can be administered by intravenous injection, and the group, mouth &force; oral therapy can be administered orally.

Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The order in which these therapeutic agents are administered is not exactly the key. The combination therapy " may also comprise administering a therapeutic agent as described above when additionally combined with other biologically active ingredients and non-musical treatments (e. g., surgery or radiation therapy). When the combination therapy additionally comprises non-pharmacological treatment, non-pharmaceutical (four) therapy can be performed between any of the combinations as long as a beneficial effect from the synergistic effect of the combination of the therapeutic agents and the non-pharmacological treatment is achieved. For example, if appropriate, t-non-pharmacological treatments are temporarily self-administered and removed from these treatments, perhaps achieving beneficial effects for days or even weeks. As used herein, "anionic group" refers to a group that is negatively charged at physiological pH. Preferred anionic groups include carboxylate, sulfate, sulfonate, sulfinate, amine sulfonate, tetrazole. a base, a phosphate, a phosphonate, a phosphinate or a thiophosphate or a functional equivalent thereof. An anionic group, a functional 4 effect π is intended to include a bioisostere, such as a bioelectron of a carboxylate group Isosteres. Bioisosteres cover typical bioelectronic isosteric equivalents and atypical bioelectron isosteric equivalents. Typical and atypical bioisosteres are known in the art (see, for example, Silverman, r. B. 772e

Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc.: San Diego, Calif, 1992, pp. 19-23 119664.doc-39-200813031) An especially preferred anionic group is a slow acid root. The term "heterocyclyl" is intended to include a closed loop structure in which one or more of the atoms in the ring are elements other than carbon, such as nitrogen or oxygen or sulfur. The heterocyclic group may be saturated or unsaturated, and a heterocyclic group such as an alkaloid group and a sulfhydryl group may have a fused ring structure such as hydrazine and hydrazine. Other examples of heterocyclic groups include a snap base and a thiol group. The heterocyclic group may also be bonded to one or more constituent atoms via, for example, a halogen, a low carbon yard group, a low carbon base, a low carbon alkoxy group, a lower alkyl alkyl group, a lower alkyl group, a lower alkyl group. Substituted by a carboxyl group, a nitro group, a trans group, -CF3, -CN or the like. The s 1 p-plubber "includes an amount of at least 10 ° / increase or decrease that is capable of inducing s丨p receptor activity in vivo or in vitro, for example, as determined by a given assay, such as the bioassay described below. A compound or composition that detects a change. The ECw" of a π agent includes a combination of a sphingosine or other ligand to the S1P receptor and/or a functional activity of the Sip receptor (eg, signal transduction activity) The concentration given is 5〇% of the maximum value of the S1P receptor. In other words, when 100% activation is set, the Slp receptor activity does not increase with the addition of the oxime ligand/activator and 〇 0. The activation is set to the amount of activity in the absence of the added ligand/activator in the assay, and ECw is the concentration at which the agent achieves 50% activation. ''Purification' and similar terms refer to the molecule Or the compound is isolated into a form that is substantially free of impurities typically associated with the molecule or compound in a natural or natural environment. "effective amount'' includes an amount sufficient to produce the selected effect. For example, an effective amount of an S1P receptor antagonist is to reduce the cellular signal transduction activity of the S1P receptor. 119664.doc -40 - 200813031

πImmune regulation" includes effects on immune system function and includes enhancement of immune response and suppression of immune response.

The compound of the present invention and another pharmacologically active agent can be administered to the patient simultaneously, sequentially or in combination. It will be appreciated that when a combination of the invention is used, the compound of the invention and the other pharmacologically active agent may be in the same pharmaceutically acceptable carrier and thus administered simultaneously. It can be in a separate pharmaceutical carrier such as a conventional oral dosage form for simultaneous administration. The term "combination" further refers to the case where a compound such as = is provided in a separate dosage form and administered sequentially. The patient (animal and human) to be treated with Shai can be administered to the present invention in an agent that provides optimal medical efficacy. Compounds. It will be appreciated that the dosage required for any particular application will depend on the particular patient, not only on the particular formulation or composition selected, but also on the route of administration, the nature of the condition to be treated, the condition: age and condition, The patient then accepts the coexisting drug or special hunger: other enthusiasm for the subject is changed by the clinician. The appropriate amount: the standard level will usually be the weight per kilogram of the patient per gram. Gu $ $ 克 ' It can be administered in early or multiple doses. The dose of 7JC is preferably about 0. 01 mg / kg to the mother 至 to about 〇 W + v see / kg, more preferably daily, Pg / kg to about 10 mg / kg. Clip you to prevent central nervous system Li Siwei + human cattle and sputum, in the > gt; or mg / 8: the appropriate dose level is about 0.001 baht / kg per 曰Up to 10 m/kg, > mg/m斤和尤伊 — 軏佳母母约0.005 mg / kg to 5 equals two 曰 · 1 · 1 mg / kg to 1 mg / kg. The S can be 1 to 4 times a day, preferably daily - or twice the program voted 119664.doc -41 . 200813031

It should be determined by the condition. It will be appreciated that the amount of a compound of the invention required for any treatment will not only be selected for a particular compound or composition, but will vary with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be invented by the attending physician. The compositions and combination therapies can be combined with a variety of pharmaceutical excipients including stabilizers, carriers, and/or encapsulating formulations as described herein; Ports Only The aqueous compositions of the present invention comprise an amount of the compound of the invention dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. Also "pharmaceutically or pharmacologically acceptable, including molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal or human. "Pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, and such media and medicaments for use in medicine The use of active substances is well known in the art. Unless any conventional medium or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the compositions. In terms of formulation, the formulation should meet sterility, pyrogenicity, general safety, and purity standards as defined by the FDA Office 〇f Biologies standard. The compositions and combination therapies of the invention will then typically be formulated for parenteral administration, for example, via Formulation for injection via intravenous, intramuscular, subcutaneous, intralesional or even intraperitoneal routes. Preparation of aqueous compositions containing the compositions or active ingredients or ingredients of the present invention will be familiar to the present disclosure 119,664.doc -42- 200813031, known to the surgeon. Typically, such compositions may be prepared in injectable form: in the form of a liquid solution or suspension; Once the shell member before launching] suitable for preparing a solution or suspension of the solid forms;. The formulation may also be emulsified and $

/ 2; pharmaceutical forms for left-handed use include sterile aqueous solutions or dispersions; : Formulations: including sesame oil, peanut oil or aqueous propylene glycol; & sterile powder for temporary "dish sterile spray solution or dispersion". In this case, the formula must be sterile and must be a part of the body that is easy to inject. It must be stable under manufacturing and storage conditions and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. A solution of the active compound in the form of a free base or a pharmaceutically acceptable salt can be prepared in water suitably mixed with a surfactant such as propylcellulose. The dispersion can also be in glycerol or liquid polyethylene glycol. And mixtures thereof and/or from the medium I. Under normal conditions of storage and use, the preparations contain a preservative to prevent the growth of microorganisms. The treatment of the present invention Pharmacology # composition will often contain 35 : A component of a combination therapy that is dispersed in a pharmaceutically acceptable medium. The medium or carrier of the pharmaceutical agent includes any and all solvents, dispersion media, coatings. Antibacterial and antifungal agents, isotonic agents, absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Supplementary active ingredients can also be combined with the therapeutic combination of the present invention. The preparation of pharmaceutical or pharmacological compositions will be known to those skilled in the art in light of the present disclosure. In general, such compositions may be prepared in injectable form, 119664.doc -43-200813031 such as a liquid solution or Suspensions; solids suitable for liquid suspension preparation prior to injection; lozenges or other solids for oral administration; timed release: sachets, or any other form currently used, including creams, mouthwashes Inhalation agents and the like. The solution is prepared by injecting the required amount of the active compound into a suitable solvent having a plurality of the ingredients listed therein, and optionally if necessary, followed by filtration sterilization. The dispersion is prepared by injecting a plurality of sterilized active ingredients into 3 sterile dispersion media and from the sterile vehicles which are listed above. In the case of a bacterial injectable solution, the preferred method of preparation is vacuum drying and cold; East Dry Technology Street, which obtains the active ingredient plus ingredients from its previous sterile filtrate. It also covers more for intramuscular injection or Preparation of a highly densified solution. In this respect, it is preferred to use DMS0 as a solvent because it will produce extremely rapid penetration and deliver a high concentration of active compound or agent to a smaller area. i i is also particularly suitable for use by surgeons, physicians. Or the caregiver uses a bacterial formulation, such as a saline base solution, to clean a particular area of the workplace. The therapeutic formulation according to the present invention may also be reconstituted in the form of a mouthwash or in combination with an antifungal agent. The therapeutic formulation of the present invention can also be prepared into a form of m cream and lotion suitable for topical administration. Suitable preservatives for the solution include ammonium molybdenum sulphate, sulphonium, butyl sulphate, thimerosal And its analogues. Suitable buffering agents are included in an amount sufficient to maintain a pH between about pH 6 and pH 8 and preferably between about pH 7 and ρ Η 7·5 119664.doc -44- 200813031

Boric acid, hydrogencarbonate steel and potassium hydrogencarbonate, sodium and potassium borate, sodium carbonate and potassium carbonate, sodium acetate, sodium dihydrogenate and the like. Suitable penetrants are dextran 40, dextran 70, dextrose, glycerol, chlorinated sulphate, propylene glycol, sodium chloride and the like, so that the sodium chloride equivalent of the ophthalmic solution is between 0.9 and Or minus 0.2%. Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea, and the like. Suitable humectants and fining agents include polysorbate 8 oxime, polysorbate 20, poloxamer 282 and tyloxapol. Suitable tackifiers include dextran 4〇, dextran 7〇, gelatin, glycerin, hydroxyethyl cellulose, hydroxydecyl propyl cellulose, lanolin, methyl cellulose, paraffin, polyethylene glycol, polyvinyl alcohol , polyvinyl labronidin, carboxymethyl cellulose and the like. Once formulated, the therapeutic agent will be administered in a manner compatible with the dosage formulation and in a pharmacologically effective amount. Such formulations are readily administered in a variety of dosage forms, such as injectable solutions as described above, but may also employ pharmaceutical release capsules and the like.隹 上下文 上下文 ... v ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... The precise amount of active compound required for administration will depend on the diagnosis of the practitioner and is limited to the individual. Months The minimum volume of the composition required to disperse the active compound is usually employed. The human-applicable regimen can also vary 'but it will be characterized by the start of administration of the compound and the second control result and subsequent administration of other controlled doses at longer intervals: words, for non-(four)«, _t buffer will be prepared and (must) Aqueous solution and use it intravenously, intramuscularly, subcutaneously or: 119664.doc •45· 200813031. A dose can be dissolved in 1 mL of isotonic NaC solution and added to 1000 mL of subcutaneous injection fluid or injected. It is recommended to be in the injection site (see, for example, Remington's Pharmaceutical Sciences® version 5, pages\Q35-1038 and pages 1570-1580). In certain embodiments, the active compound can be administered orally. An agent that is resistant or resistant to proteolysis caused by an enzyme. These compounds are expected to include chemically designed or modified agents; dextrin; and in the form of timed release caprants to avoid degradation of peptidases and lipases. Peptides and lipid formulations. The carrier may also contain, for example, water, ethanol, polyols (eg, glycerol, propanol, and liquid polyethylene glycols and the like), A solvent or dispersion medium for the mixture and plant 7 oil. It can be maintained, for example, by the use of a coating (such as imprinted phospholipids), by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Fluidity. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents such as benzoic acid vinegar, butanol, phenol, sorbic acid, thimerosal, and the like. In most cases, it preferably includes, for example, sugar or Isotonicity agent for sodium chloride. The composition of the injectable composition can be achieved by using a composition of a delayed absorbent (for example, monostearic acid and gelatin) by injecting the desired amount of the active compound into a plurality of </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The preparation of the dispersion is carried out in the other components of the I agent. The preparation method is as follows: in the case of using a sterile powder to prepare a sterile solution of 119664.doc • 46 · 200813031, the preferred preparation method is vacuum drying. And the cold-drying technique; the preparation of the active ingredient plus any other desired and more concentrated or highly concentrated solution for direct injection, which is expected to use DMSQ as a solution for extremely rapid penetration. The Southern Concentration Active Agent is delivered to a smaller area. Once formulated, the solution will be administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. The formulations are readily administered in a variety of dosage forms, such as: The above-mentioned can be used as a liquid type, but a drug-releasing capsule can also be used. , 颂" For parenteral administration in the form of an aqueous solution, for example, the solution should be properly: flushed (if necessary) and firstly The amount of saline or glucose causes the liquid diluent to be infiltrated. These particular aqueous solutions are especially suitable for intravenous, intramuscular, and intraperitoneal administration. In this connection, the non-dewatering medium that can be used by hydrazine will be known to those skilled in the art in light of this disclosure. In addition to being formulated for parenteral administration (such as intravenous or intramuscular drugs, other pharmaceutically acceptable forms include, for example, a key or &quot;he: solids for oral administration; Timed release capsules; and any other form currently used, including creams. Other formulations suitable for other modes of administration include suppositories. For suppositories 'conventional binders and carriers can include, for example, poly-stretched vinegar These suppositories may be formed from a mixture containing the active ingredients in the range of (4) to (10), preferably 1% to 2%: The oral formulation includes such commonly used excipients, for example, pharmaceutical grade nectar 119664.doc -47- 200813031 Alcohol, lactose, powder, magnesium stearate, sodium saccharin, cellulose, acid sulphate and the like. The compositions are in the form of solutions, suspensions, lozenges, pills, sachets, sustained release formulations or In the form of a powder, in certain prescribed embodiments, the oral pharmaceutical composition will comprise an inert diluent or an assimilable edible carrier, or it may be enclosed in a hard gelatin capsule or a soft gelatin capsule, or it may be compressed into Lozenges, or they can be mixed directly with dietary foods

Hehe. For oral administration, the active compound can be mixed with excipients and in the form of ingestible lozenges, buccal tablets, tablets, sachets, elixirs, suspensions, syrups, wafers, and the like. Form use. Such compositions and preparations should contain at least 〇_1% of active compound. The percentages (of course) of the compositions and formulations may vary and may conveniently be between about 2% and about 5% by weight or preferably between 25 and 6%. The amount of active compound in such therapeutically useful compositions will be such that a suitable dosage will be obtained. Mosquitoes, tablets, pills, pouches • Eight...—·zv vr μ ί 卜 ,, j grains, adhesives, such as yellow gum, gum arabic, corn starch or gelatin; shaping, such as calcium hydrogen phosphate a disintegrant such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetener: such as an added sugar, lactose or saccharin; or a flavoring agent such as = plate: Γ, wintergreen oil or cherry flavoring. When the unit dosage form is a capsule 铷', the liquid carrier substance which may contain substances other than the above types may be a right-handed bucket, a six-bucket, or a ^^. By way of example, the dosage unit is modified. , tablets, pills or sachets can be shellac, glycoside prevention = (4) can contain active compounds: as a sweetener sucrose, two ',, θ of methyl p-hydroxybenzoate and propyl paraben, Dyes 119664.doc -48 - 200813031 and flavorings such as cherry or orange flavors. The pharmaceutical composition of the present invention may be in the form of a pharmaceutical preparation, for example, a solid, half = = Γ, which contains the active ingredient as an active ingredient in an external, enteral or parenteral period: =; excipient Or the evening. The active ingredient can be mixed with (for example, a pharmaceutically acceptable carrier) into a granule, granule, capsule: a solution, a suspension, and any other suitable form. Water, glucose, lactose, gum arabic, alum, mannitol, (iv) paste, triple feed, =, corn house powder, keratin, gelatinous dioxygen, horse bell in solid, semi-solid or liquid form箸 粉 powder, urea and other suitable for the manufacture of (4), and in addition to the use of auxiliaries, stabilizers, thickeners and colorants and fragrances. The active target compound is sufficient to produce the desired effect on the course or condition of the disease. And included in a pharmaceutical composition. For the preparation of a solid composition such as a tablet, the main active ingredient is combined with a pharmaceutical carrier (for example, a conventional tablet ingredient such as corn starch, lactose, sucrose, sorbitol, talc, hard a solid premix of a mixture of fatty acids, stearic acid, strontium phosphate or gum, and other pharmaceutical diluents such as water to form a homogeneous mixture of a compound of the invention or a non-toxic pharmaceutically acceptable salt thereof Cascade When it is mentioned that the pre-formulation compositions are in the form of a uniform sentence, the active ingredient is uniformly dispersed throughout the composition so that the composition can be readily re-averaged into effective unit dosage forms such as lozenges, pills and sachets. The mouthwash composition is subdivided into unit dosage forms of the type described above containing from about 1 to about the active ingredient of the invention. The novel composition of 119664.doc -49-200813031 tablets or pills may be coated or It is otherwise compounded to provide a dosage form having the advantage of prolonged action. For example, a lozenge or pill may comprise an internal dosage component and an external dosage component, the latter being in the form of a former package. The two components may be Used to prevent disintegration in the stomach and allow the inner component to pass intact through the duodenum or delayed release of the casing layer. The casing layer or coating may use a variety of materials including a plurality of polymeric acids and polymeric acids and the like a mixture of materials of shellac, cetyl alcohol, and cellulose acetate. The liquid form in which the composition of the present invention is incorporated for oral administration or injection administration includes an aqueous solution. a properly flavored syrup, an aqueous or oily suspension, and an emulsion with an acceptable oil (such as cottonseed oil, sesame oil, coconut oil or peanut oil) or a dissolving or emulsifying agent suitable for intravenous use, and tinctures And similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, Polyvinylpyrrolidone or gelatin. The composition for inhalation or insufflation comprises a solution and suspension in a pharmaceutically acceptable aqueous or organic solvent or a mixture thereof, and a powder. The liquid or solid composition may contain, for example Suitable pharmaceutically acceptable excipients as set forth above. For topical or systemic effects, such compositions are preferably administered by the oral or nasal route of administration. Preferred sterile pharmaceutically acceptable solvents The composition in the mixture can be atomized by using an inert gas. The nebulized solution can be directly absorbed from the spray device or it can be attached to a mask, stopper or intermittently pressurized ventilator. The device, suspension or powder composition can be administered orally or nasally by means of (iv) w suitable means for initiating the formulation. 119664.doc -50- 200813031 For the treatment of the clinical conditions and diseases indicated above, it may be administered orally, topically, parenterally, by inhalation or rectal to contain a conventional non-toxic pharmaceutically acceptable carrier, adjuvant. The dosage unit formulation of the vehicle and the vehicle are administered as a compound of the invention. The term parenteral as used herein includes subcutaneous injections, intravenous injections, intramuscular injections, intracranial injections or injection techniques. The compounds of the present invention are high affinity agonists of various S1P receptors (or antagonists are also expected to cause lymphocytopenia when introduced into rodents, non-human primates or humans. Thus, the present invention The compounds are useful as immunomodulators' and are useful in the treatment or prevention of pathologies mediated by the action of lymphocytes, including acute or chronic rejection of tissue transplants (such as organ transplants) and autoimmune diseases. Treatment with the compounds of the invention Autoimmune diseases include systemic lupus erythematosus, multiple sclerosis, Behcet's disease, spheroid nephritis, rheumatoid arthritis, inflammatory properties such as Crohn's disease and ulcerative colitis Intestinal disease type diabetes, uveitis, psoriasis, myasthenia gravis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, hepatitis, and Wegener's granulomatosis. The compounds are also suitable for the treatment of inflammatory conditions, including allergic sputum, inflammatory glomerular injury and ischemia Perfusion damage. Lysophospholipids, S1P, and lysophosphatidic acid (LPA) stimulate cell proliferation and affect many cellular functions by signal transduction via the (3 protein-coupled endothelial cell differentiation gene encoding (S1P) receptor. The receptor modulators of the invention have immunomodulatory effects, for example, for anti-angiogenic therapies, such as for the treatment of neoplastic diseases. 119664.doc -51 - 200813031 In one embodiment of the invention, mammalian species (including humans) Administration of a pharmaceutical composition comprising one or more of the S1P receptor agonists of the invention to enhance wound repair, improve neuronal function or enhance immune responses in such species. S1P is also reported to inhibit fibrosis in a variety of organs. Therefore, the S1P receptor agonist of the present invention can be used for the prevention/treatment of diseases associated with organ fibrosis such as pulmonary fibrosis, interstitial pneumonia, chronic hepatitis, cirrhosis, chronic renal insufficiency or glomerular sclerosis. In one embodiment, a composition comprising an S1P receptor agonist of the invention is used to treat a wound, including burns, cuts, scratches, surgical incisions Acne and slow healing ulcers such as those found in diabetic patients. Furthermore, the S1P modulating compounds of the present invention mobilize lymphocytes and increase their arrest in secondary lymphoid tissues. Therefore, the compounds of the present invention can be used directly away from Lymphocytes or healthy cells of transplanted organs (eg, allografts) (eg, islet cells in type I diabetes), myelin sheath (multiple sclerosis), or other tissue that can withstand an inappropriate immune response, and thus Damage to the tissues caused by the immune system. In another embodiment, the subject is administered a S1P receptor modulating compound of the invention to treat or prevent disorders of abnormal cell growth and differentiation, including Alz Alzheimer's disease, abnormal corpus luteum formation, osteoporosis, anovulation, parkinson's disease, and cancer. In one embodiment, an S1P antagonist is administered to a patient to treat a disease associated with abnormal growth. In one embodiment, the compounds of the invention are used as immunomodulators to alter the activity of the immune system and prevent damage to healthy tissues that would otherwise occur in autoimmune diseases and organ transplants 119,664.doc -52 - 200813031 . In particular, these compounds can be administered to patients as part of a treatment associated with organ transplantation, including pancreas, pancreatic islets, kidneys, heart and lung transplants. The S1 Ρ modulators can be administered alone or in combination with known immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, thiopurine, and ring. Phytorexate, methotrexate and such as corticosterone, des-oxymetasone, betametasone, desametasone, flunisolide, dehydrogenation Corticosteroids of cortisol, prednisone, amcinomide, desonide, methylprednisolone, triamcinolone, and alclometas〇ne. S 1P is also used as a survival factor for many cell types. In particular, it is expected that the compounds of the present invention having S1P antagonistic activity are useful for protecting cells and tissues from hypoxic conditions. According to one embodiment, a compound of the invention is administered to a patient who is determined to be in need of treatment or who actually needs treatment to treat cells and tissues exposed to hypoxic conditions, including persistent damage due to ischemia. According to an embodiment, the entity exhibiting Slp receptor antagonist activity can be used to treat ischemia-reperfusion injury. Interference to hypoxic blood is defined as ischemia. It is known that the effect of ischemia is progressive, so that cell viability is reduced at any time and tissue becomes bad. Completely persistent ischemia leads to cell death in the presence of your hu 艮 艮 主 主 主 主 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且The injury associated with ischemia is a result of an event associated with reperfusion of 119664.doc-53-200813031 ischemic tissue, thereby forming the term reperfusion injury. Can include local, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, intraorbital, sublingual or transrectal A variety of routes are administered to a subject in need thereof to a pharmaceutical composition comprising a compound of the invention. For most cases where a compound of the invention is desired, the oral route is usually employed. For acute treatment, intravenous injection or injection is preferred. For maintenance therapy, oral or parenteral routes such as intramuscular or subcutaneous routes are preferred. According to one embodiment, a composition comprising a compound of the invention and albumin (e.g., a compound of the invention, a pharmaceutically acceptable carrier, and 01-10% albumin) is provided. Albumin acts as a buffer and improves the solubility of the compound. The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. According to one embodiment, a kit for treating a patient in need of immunomodulation is provided, which includes instructions for use of the kit. In this embodiment, the kit comprises one or more of the S1P modulators of the invention and may also include one or more known immunosuppressive agents. Such medicines can be packaged in a variety of containers, such as vials, =, microliter plates, bottles, and the like. Other reagents may be included in a separate container and equipped in a kit; for example, a positive control sample, a negative control sample, a buffer, a cell culture medium, and the like. These kits should preferably also include instructions for use. The activity of the compounds of the invention can be determined by assays for detecting Slp receptor activity (such as the [γ_35 S]GTP binding assay) and assaying for activity in the presence of Slp and test compound 119664.doc -54-200813031 . More specifically, in the method described by Ding Qiao Nai et al., 1995, M. /. 47: 848_854, which is incorporated herein by reference, the membrane-coupled prion protein can be measured by measurement. The combination of labeled GTP was evaluated. For example, in the presence of radiolabeled GTP and unlabeled GDp (eg, at 20 mM HEPES, pH 7.4, 1 mM mM NaC1 and 1 mM MgCl2, 80 PM 35S-GTPYS &amp; 3 μΜ GDP), A sample comprising a membrane isolated from cells expressing the Slp polypeptide is incubated in buffer with or without an alternative modulator to increase binding of the polypeptide to the ligand (i.e., Slp). The assay mixture is incubated for a suitable period of time to allow binding and activation of the receptor (e.g., 60 minutes at 30 ° C) after which time unbound label GTP is removed (e.g., by filtration on a GF/B filter). The bound label GTP can be measured by liquid scintillation counting. The labeled GTP binding measured by scintillation counting in the sample containing the alternative modulator was reduced by 1% or more relative to the sample without the modulator, indicating that the candidate modulator is an inhibitor of Slp receptor activity. . A similar GTP binding assay can be performed in the absence of a ligand (S1P) to identify an agent that acts as an agonist. In this case, ligand-excited GTP binding was used as a standard. If the agent induces at least 50% of the GTP binding level induced by S1P when present in 1 〇 or less, and preferably induces a level equal to or higher than the level induced by the ligand, then This agent is considered to be an agonist. GTPase activity can be measured by culturing a cell membrane extract containing an S1P receptor with Y32P-GTP. The active GTPase releases the label to the inorganic phosphate 119664.doc -55-200813031 salt, which can be detected by isolating the free inorganic phosphate in a 5 〇/〇 suspension of activated carbon in 20 mM H3p〇4. Then, the flicker count is performed. Controls will include assays using membrane extracts isolated from cells that do not express S1 p receptors (e. g., mock transfected cells) to rule out possible non-specific effects of alternative modulators. To characterize the effect of alternative modulators on slp-regulating GTPase activity&apos; Cell membrane samples can be incubated with ligands (S1P) with or without modulators and GTPase assays can be performed as described above. A 10% or more change (increase or decrease) in GTP binding or GTPase activity levels relative to a sample without modulator indicates a Slp modulation effect caused by the alternative modulator. The s 1P receptor activity can also be measured by the Ca2+Flux protocol of the s 1 p receptor (eg, hS 1P1, hSlP3, rSIP1, rSlP3, and parental cells) as follows: 1. Materials

a· FLIPR buffer: lxHBSS; 10 mM HEPES b·cell growth medium: i·human and rat S1P1 and S1P3: F12-Ham, s medium; 10% FBS (qualified); lxPen/Strep/Glu; 300 pg/ mLHygromycin; 400 pg/mL Geneticin ii_Parental cells··Human and rat S1P1 and S1P3 : F12-HamS medium; 10% FBS (qualified); lxPen/Strep/Glu 300 pg/mL homogenic acid; c·cell inoculation medium; F12-Ham, s medium; 10% FBS (charcoal/stripped dextran); 1 xPen/Strep/Glu; 119664.doc -56- 200813031 d. Cell Dissociation Buffer: Versene e-Activator (SIP) Lysis Buffer from Invitrogen: 0.4% (w/v) Fatty Acid-Free BSA in FLIPR Buffer (Sigma # A8 806) f. FLIPR Dye: BD PBX calcium assay kit; catalog number 641077 contains calcium indicator (catalog number 850000) and sputum signal enhancer (catalog number 850001). The sputum signal enhancer was diluted 1:1 Torr in FLIPR buffer and then the calcium indicator was added at a 1:1 〇〇〇 ratio. g·cell plate (96 well): Greiner, catalog number 655090 h· compound plate (96 well): Costar, No. 33 65 i·S1P stock solution preparation: S1P purchased from CalBioChem (catalog number 970471; 1 mg vial; used Methanol was prepared conventionally and the inside of the glass vial was dried using nitrogen; stored at -20 ° C). Dissolve 1 vial of S1P in 26.4 ml of buffer in which the agonist was dissolved in a 50 ml centrifuge tube; remove the marker from the S1P vial and open the entire vial and drip into the tube. Ultrasonic processing at 37 C for V2 hours. A clear solution of 丨〇〇 will be obtained. The stock solution was aliquoted and stored at _8 〇. 2 · Maintain cell lines

a· Add the V5 marker to the ends of hslP1, hsip3, rSlpi&amp;rSlp3tN. All four genes were transfected into ch〇 K1 cells stably expressing Gqi5. b. Establish hSIPl and hSlP3 as stable pure lines and classify them according to anti-V5 markers and establish stable libraries after classification. c·Use parental cell lines (::11〇/尺1 Gqi5 as control) d. Keep all of these cells in cell growth medium and use 119664.doc •57- 200813031

Versene splits it twice a week. e. All of these cell lines were used after 30 passages. 3. Assay protocol a. Cell seeding: Cells were plated from Versene from the flask and seeded in cell plates at 50 K/well in cell culture medium. The cells were grown overnight at 37 °C. b. Cell filling: Clear the cell inoculation medium. The cells were loaded with 50 μΐ FLIPR dye at room temperature. The signal is stable for up to 5 hours after dye loading. c. Preparation of agonist (S1P): The frozen stock of S1P was thawed and sonicated for 30 minutes at 37 °C before each use. The stock was then diluted in the FLIPR buffer at the appropriate concentration. d. Compound preparation: The compound was dissolved in DMSO. Compounds were subjected to 3 10-point dilutions in DMSO. The compounds were then diluted 133-fold in assay buffer to a DMSO concentration of 0.75%. e. Activity measurements: Fluorescent signal changes that are added to the cells with the compound are monitored in FLIPRtetra. 25 μM compound was transferred to a cell plate (50 μM FLIPR dye; DMSO concentration: 0.25%). The signal was recorded for 90 seconds after the addition of the compound. 50 μΐ 500 nM S1P was then added to the cell plate and the signal was recorded for 90 seconds after addition. 4. Data analysis a. Calculate the peak value of each compound/S1P addition b. Use the peak of S1P at 200 nM as the high control (100%) and use the peak of buffer only 119664.doc -58-200813031 as the low control (〇 %). c. Normalize the data against the high and low controls using the following equation: POC_S=100* (RAW-LO)/(HI-LO) d. Peak the concentration for the compound. e. Fit the curve using 4 fitting parameters: Y = (A + (B + (1 + ((x / 〇 aD)))) where: Y is POC-S (or POC) X is the compound concentration 1 A is the minimum value (EC50min or IC50min) B is the maximum value (EC50max or IC50max) C is the inflection point (EC50IP or IC50IP) D is the slope (EC50 slope or IC50 slope). The identified S1P receptor agonists and antagonists are available. For the treatment of a variety of human diseases and conditions, including but not limited to the treatment of infections, such as bacterial, fungal, protozoal and viral infections, especially caused by HIV-1 or HIV-2; pain; cancer; diabetes, obesity Anorexia; bulimia; asthma; Parkinson's disease; acute heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; stroke; ulcer; asthma; Benign prostatic hypertrophy; migraine; vomiting; psychotic and neurological disorders, including anxiety, schizophrenia, dysthymia, depression, delirium, dementia and severe mental retardation 0 Pain is a comprehensive subjective reflection of real or potential tissue damage sense And emotional response to it. Acute pain is a physiological letter indicating potential or actual injury 119664.doc -59- 200813031. Chronic pain can be either a body-derived (organism) or a psychogenic &quot; diffuse pain often accompanied Or follow the phytopathogenic symptoms that usually lead to depression. / Source (4) Pain may have a nociceptive cause, an inflammatory cause, or a neuropathic cause. Nociceptive pain is judged with the body or visceral pain sensitivity. The activation state corresponds. Neuropathic pain is caused by the dysfunction of the nervous system; it is maintained by the abnormal nervous system induction process of the peripheral nervous system, CNS or both. Chronic pain causes the individual to suffer a relatively large degree of socioeconomic loss. Learning pain therapy is generally unsatisfactory in terms of efficacy and safety. In embodiments, the S1P modulator of the present invention is used as an immunomodulator to inhibit the immune system and prevent damage to healthy tissues that would otherwise occur In autoimmune diseases and organ transplants, these compounds can be administered to patients as organ transplants ( Part of the treatment associated with pancreas, membrane islands, kidneys, heart and lung transplantation. These S1P modulators can be administered alone or in combination with known immunosuppressive agents such as cyclosporine, tacrolimus, Azathioprine, dexamethasone, cyclophosphamide, corticosterone, betamethine FK 5〇6 (-the fungus macrocyclic vinegar immunosuppressant dexamethasone, flunisolide, dehydrocortisol, Prednisone, amnesillin, dexamethasone, methylprednisolone, triamcinolone acetonide, amoxicillin and methotrexate. The dose used depends on the specific condition to be treated and includes age, weight, health status, and severe symptoms. The degree, frequency of treatment, and other factors associated with other medications. These doses are usually administered several times a day and preferably one to three times a day. The amount of individual active compound is readily determined by conventional procedures known to those skilled in the art. 119664.doc 200813031 h The effect of ischemia is known to be progressive, thus causing cell viability to decrease over time and tissue to become necrotic. Completely persistent ischemia results in cell death with minimal oxygen perfusion in the tissue and eventually leads to coagulation-induced necrosis even with reperfusion of arterial blood. SIP is also used as a survival factor for many cell types. The sip receptor modulator is expected to have activity to protect cells and mites and to be woven from hypoxic conditions. The compounds of the invention are administered according to an embodiment to treat cells and tissues exposed to hypoxic conditions, including maintenance of damage due to ischemia. According to one embodiment, the anti-reactive S1P modulators are useful for treating reperfusion-type injury. The provision of oxygenated blood to the tissue is defined as a partial deficiency, and the compound of the present invention and the additional-pharmacologically active agent are administered simultaneously, sequentially or in combination. It will be appreciated that when a combination of the invention is used, the compound of the invention and the additional pharmacologically active agent may be in the same carrier as the pharmaceutically acceptable carrier and thus administered simultaneously. It can be in a separate pharmaceutical carrier such as a conventional oral dosage form for simultaneous administration. The term 'combination,' further refers to the case where the compounds are provided in separate dosage forms and administered sequentially.患者 Compounds of the invention may be administered to patients (animals and humans) in need of such treatment. It will be appreciated that the desired dosage for any particular application will depend on the particular patient, not only on the particular compound or composition selected, but also on the basis of the route of administration, the nature of the condition being treated, the patient's condition, and the patient's subsequent acceptance. The drug or special diet and other factors that will be considered by those skilled in the art will change, and the final appropriate dose = the discretion of the visitor.曰 背 ] 里 里 里 里 里 里 里 里 里 里 里 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常Daily about 〇on and (4) the best level is about 〇.〇5 二 2 kg to about 25 mg / kg; better for each pen to see / kg to about 〇 〇 mg / kg. Prevention of the central oracle silk Wide σ, in the treatment or r,, systemic disease, the appropriate dose of fire mg / kg to 10 ^ / eight + Α for the mother day about 0.00i Gusike kg, preferably about 0.005 millis / 8 kg per day ^ ^ / kg and especially about 0. 0 mg / kg to 1 mg / 8 kg per compound can be daily! Up to 4 times, preferably daily kg to write / kg. The drug. Or twice the amount of the compound of the invention required for any treatment will not only vary widely, but will vary depending on the route of administration, the nature of the treatment to be treated, and the age and condition of the patient, and ultimately The compositions and combination therapies of the present invention will be administered by a visiting physician to a variety of pharmaceuticals including stabilizers, carriers and/or package formulations as described herein. Combination of Formulations The aqueous composition of the present invention comprises an effective amount of a compound of the invention dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. &quot;Pharmaceutically or pharmacologically acceptable &quot;Molecular entities and compositions that do not produce adverse, allergic or other adverse effects when properly administered to an animal or human." Pharmaceutically acceptable carrier&quot; includes any and all solvents, dispersion media , coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art, unless any conventional medium or agent is used. The active ingredient may not be included in the therapeutic composition. Supplement 119664.doc -62 - 200813031 The active ingredient may also be incorporated into the composition. For human administration, the preparation should be sterile, pyrogenic, The general standard of purity and the purity standards specified by the FDA 〇fflce 〇f Bi〇1〇gics standard. The compositions and combination therapies of the invention will then be formulated for parenteral use. Administration, for example, for administration via intravenous, intramuscular, subcutaneous, intralesional or even intraperitoneal routes of administration. The preparation of aqueous compositions containing the compositions or active ingredients or ingredients of the present invention will be described in the present disclosure. Familiar

This technique is known to those skilled in the art. In general, the compositions may be prepared in injectable form, such as in the form of a liquid solution or suspension, or may be prepared in a solid form suitable for the preparation of a solution or suspension prior to injection; Emulsified. The pharmaceutical form of k can be used for the main purpose includes a sterile aqueous solution or dispersion; Formulation: including sesame oil, peanut oil or aqueous propylene glycol; and a sterile powder for temporary: food: fungus, main spray bath or dispersion. In any case, the ancient &quot;Hybrids and must be a part of the body that is easy to inject. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. : &amp; Active compound / gluten solution in the form of a free base or a pharmacologically acceptable salt, mixed with a surfactant such as transpropylcellulose. Dispersions can also be prepared from glycerol, liquid polyethylene glycols, and mixtures thereof in ancient oils. Under ordinary conditions of storage and use, the preparations contain a preservative to prevent the growth of microorganisms. The therapeutic or pharmacological compositions of the present invention will generally comprise an effective amount of a component which dissolves the combination therapy in a medium of medically acceptable medium.医H9664.doc -63 200813031 pharmaceutically acceptable medium or carrier "1" includes any and all solvents, dispersions, "clothings, antibacterial and antifungal agents, isotonic and absorption delaying agents" Analogs. The use of such media and agents for pharmaceutically active substances is well known in the art. Supplemental active ingredients may also be incorporated into the therapeutic compositions of the present invention. Preparation of pharmaceutical or pharmacological compositions It will be known to those skilled in the art in light of the present disclosure. In general, such compositions may be prepared in injectable form, - night body + liquid or suspension liquid - suitable for making a liquid solution or suspension before injection. a solid, a rotatory or other solid for oral administration; a timed release capsule; or any other form currently used, including creams, lotions, mouthwashes, inhalants, and the like. The active compound is incorporated into a suitable solvent having a plurality of the other ingredients listed above and, if necessary, followed by filter sterilization to prepare a sterile injectable solution. In general, by sterilizing various activities The dispersion is prepared by injecting into a sterile medium containing an inert dispersion medium and other ingredients as listed above. In the case of preparing a sterile injectable solution using a sterile powder, the preferred preparation method is vacuum drying. And cold-beam drying technology, which is obtained from a sterile filtrate to obtain a powder of the active ingredient plus any other desired ingredients. It also covers the preparation of more or highly concentrated solutions for intramuscular injection. In this respect, DMS0 is used as a solvent. Preferably, because it will produce extremely rapid penetration and deliver a high concentration of active compound or agent to a smaller area. It may also be especially suitable for use by a surgeon, physician or caregiver using sterile 119664.doc -64-200813031 formulation (such as saline) The cleaning solution according to the present invention may also be reconstituted in the form of a mouthwash or in combination with an antifungal agent. Inhalation forms are also contemplated. The therapeutic formulations of the present invention may also be prepared. Forms suitable for topical administration, such as creams and lotions. Suitable preservatives for the solution include benzyl chloride Alkanolammonium, benzethonium chloride, chlorobutanol, thimerosal, and the like. Suitable buffering agents are included in an amount sufficient to maintain a value between about pH 6 and pH 8, and preferably between about pH 7 and 1311 75. Boric acid, sodium hydrogencarbonate and potassium hydrogencarbonate, sodium borate and potassium borate, sodium carbonate and potassium carbonate, sodium acetate, sodium dihydrogen phosphate and the like. Suitable penetrants are dextran 40, dextran 70, dextrose, glycerol, Potassium chloride, propylene glycol, sodium chloride and the like, such that the vaporized sodium equivalent of the ophthalmic solution is in the range of plus or minus 0.2%. Suitable antioxidants and stability The agents include sodium hydrogen sulfite, sodium metabisulfite, sodium thiosulfite, thiourea and the like. Suitable wetting agents and clarifying agents include polysorbate 8 聚, polysorbate S 20, poloxamer 282 and tylos Shapo. Suitable tackifiers include dextran 40, dextran 7 〇, gelatin, glycerin, hydroxyethyl cellulose, methyl propyl cellulose, lanolin, methyl cellulose, paraffin, polyethylene glycol, polyvinyl alcohol, Polyvinylpyrrolidone, carboxymethylcellulose and the like. Once formulated, the therapeutic agent will be administered in a manner compatible with the dosage formulation and in a pharmacologically effective amount. Such formulations are readily administered in a variety of dosage forms, such as injectable solutions as described above, although drug release capsules and the like may also be employed. In this context, the amount of active ingredient to be administered and the body of the composition 119664.doc -65- 200813031 depends on the subject animal to be treated. The precise amount of active compound required for administration will depend on the diagnosis of the practitioner and is limited to the individual. The minimum volume of the composition required to disperse the active compound is usually employed. A suitable dosing regimen can also vary, but will be characterized by the onset of administration of the compound and monitoring of the results and subsequent administration of other controlled doses at longer intervals. For example, for parenteral administration, an appropriately buffered (and if necessary) isotonic aqueous solution will be prepared and administered for intravenous, intramuscular, subcutaneous or even intraperitoneal administration. A dose can be dissolved in i mL isotonic 1 solution and added to 1000 mL of subcutaneous injection fluid or injected into the recommended injection site (see, for example, and (4) (7) to (10) 乂Phr, like the 15th edition, Pages 1038 and 1570-1 580). In certain embodiments, the active compound can be administered orally. It encompasses agents that are generally resistant or resistant to proteolysis caused by digestive enzymes. Such compounds are expected to include chemically designed or modified agents; dextral peptides; and peptide and lipid formulations in the form of timed release capsids to avoid degradation of peptidases and lipases. The pharmaceutically acceptable salts include acid addition salts, and the acid addition salts are formed from the following acids: inorganic acids such as hydrochloric acid, hydrobromic acid, boric acid, scaly acid, sulfuric acid or phosphoric acid; or organic acids, Such as acetic acid, oxalic acid, tartaric acid, maleic acid 'fumaric acid, citric acid, succinic acid, methanesulfonic acid, mandelic acid, succinic acid, benzoic acid, ascorbic acid, decanesulfonic acid, a-ketopentane Acid, a-glycerophosphate, glucose-rhodium phosphate and the like. The salt formed by the free carboxyl group may also be derived from an inorganic base such as sodium hydroxide, potassium hydroxide, hydrogen hydroxide, calcium hydroxide, magnesium hydroxide or iron hydroxide and the like 119664.doc • 66 - 200813031 Organic base of propylamine, trimethylamine, histidine, procaine (prGeaine) and its analogues. Other examples of pharmaceutically acceptable salts include quaternary derivatives and internal salts such as N-oxides. The carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycols and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of an surfactant. Prevention of the action of microorganisms can be accomplished by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In most cases, it will be preferred to include isotonic agents such as sugar or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use of compositions compositions compositions compositions compositions compositions compositions, compositions, compositions, compositions, compositions, compositions, compositions, compositions, compositions, compositions, compositions, compositions, compositions, compositions, compositions, compositions, compositions, compositions, compositions, compositions The sterile injectable solution is prepared by injecting the required amount of the active compound into a suitable solvent having a plurality of the other ingredients enumerated, if necessary, followed by filter sterilization. Generally, dispersions are prepared by incorporating a plurality of sterilized active ingredients into a sterile vehicle containing an aqueous dispersion medium and the other ingredients enumerated above. In the case of preparing a sterile injectable solution using a sterile powder, the preferred method of preparation is vacuum drying and freeze-drying techniques, from which the active ingredient is added to the powder of any other desired ingredient. Preparation of more or highly concentrated solutions for direct injection is also contemplated, with DMSO being used as a solvent to produce extremely rapid permeation for delivery while the active agent is concentrated to a smaller area. 119664.doc -67- 200813031 ...After the formulation, the solution will be administered in a dose effective dose.嗲箄 奋 之 且 且 且 且 且 且 且 且 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄 嗲箄释放 释放 释放 释放 释放 及其 及其 释放 释放 释放 对于 对于 对于 对于 对于 对于 对于 对于 对于 对于 对于 对于 对于 对于 释放 释放 释放 对于 释放 释放 释放 释放 释放 释放 释放 释放| Water or glucose makes liquid diluent specific. These particular aqueous solutions are especially suitable for intraperitoneal administration. And two: muscle, subcutaneous

ί. , ^ The use of the non-functional aqueous medium will be known to those skilled in the art in light of this disclosure. In addition to being formulated for parenteral administration (such as intravenous or intramuscular injection of compounds, other medically acceptable forms include, for example, tablets, which are used for oral administration (4); Lipid formulations; timed release capsules; and any other form currently used, including creams. Other formulations suitable for other modes of administration include assays. For assays, conventional binders and carriers may include, for example, poly An alkylene glycol or triacetin; these suppositories may be formed from a mixture of active ingredients in the range of from 5% to 1%, preferably from 1% to 2%. Oral formulations include such conventional forms. Agents, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. The compositions are in the form of solutions, suspensions, lozenges, pills, sachets, and sustained In a defined embodiment, the oral pharmaceutical composition will comprise an inert diluent or an assimilable edible carrier, or it may be encapsulated in a hard gelatin capsule or a soft gelatin capsule, or it may be compression a tableting agent, or it may be directly combined with a dietary food 119664.doc-68-200813031. For oral administration, the active compound may be mixed with excipients and ingestible lozenges, buccal tablets, tablets, The use of a sachet, an elixir, a suspension, a sugar, a savory, and the like. The compositions and preparations should contain at least 1% of the active compound. The compositions and preparations The percentage (of course) may vary and may conveniently be between about 2% and about 75% by weight or preferably between 25 and 60%. The amount of active compound in such therapeutically useful compositions will The amount of the appropriate dose is obtained.

Keys, tablets, pills, sachets and the like may also contain the following: binders such as gum, gum arabic, corn starch or gelatin; excipients such as calcium hydrogen phosphate; disintegrants, Such as corn starch, potato genus, alginic acid and the like; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose or saccharin added; or flavoring agents such as peppermint, wintergreen oil Or cherry flavoring. When the unit dosage form is a sachet, it may contain a liquid carrier other than those of the above type. A variety of other materials may be present in the form of a coating or otherwise modify the dosage unit. For example, lozenges, pills or sachets may be coated with shellac, sugar or both. The tincture syrup may contain the following active compounds: sucrose as a sweetener, hydroxyparaben and propylparaben as a preservative, a dye, and a flavor such as cherry or orange flavor. The pharmaceutical compositions of the present invention can be used in the form of a pharmaceutical preparation, for example, in a solid, semi-solid liquid form, containing as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral application. The present invention is one or more of the compounds. The active ingredient can be mixed with (for example, a non-toxic pharmaceutically acceptable carrier into a tablet, granule, capsule, plug 119664.doc -69-200813031 wj, / liquid, liquid, suspension and any Other suitable forms. These carriers can be used in the form of solid, semi-solid or liquid water, glucose, lactose, acacia, gelatin, mannitol, starch paste, three-stone acid, talc, corn starch, Keratin, colloidal cerium oxide, horse yam starch, urea and other carriers suitable for the manufacture of the preparation, and in addition, auxiliaries, stabilizers, gamma coloring agents and perfumes can be used. The active target compound is sufficient for the disease. The course of the disease or condition produces the desired effect and is included in the pharmaceutical composition. For the preparation of a solid composition such as a lozenge, the main drug carrier (for example, a conventional spinner ingredient such as corn powder, ::; sugar, sorbose) Mixture of alcohol, talc, stearic acid, magnesium stearate, calcium hydrogen phosphate or gum) and other pharmaceutical diluents such as water to form a compound containing a compound of the invention or a non-toxic pharmaceutically acceptable salt thereof A solid pre-formulation composition of the mixture. When it is mentioned that the pre-formulation composition is homogeneous, it means that the active ingredient is dispersed throughout the composition so that the composition can be easily divided into, for example, tablets, pills and An effective unit dosage form of the sachet. The solid pre-formulation composition is then subdivided into units (4) of the type described above containing from 1 mg to about 5 Å of the active ingredient of the invention. Lozenges or pills of the new mer. The dosage form may be coated or otherwise compounded to provide the advantage of prolonged action. For example, the lozenge or pill may comprise an internal dosage component and an external dosage component, the latter being in the form of a former package. The two components can be prevented by the heart from disintegrating the gastric tissue and allowing the (4) component to be completely separated by the duodenum or the delayed release of the casing layer. These casing layers or coatings can be used with a variety of polymeric acids and polymerizations. a mixture of an acid and such a substance as 519664.doc -70-200813031 shellac, cetyl alcohol and cellulose acetate. The composition of the present invention can be incorporated into it for oral administration or injection. The liquid form of the drug includes an aqueous solution, a properly flavored syrup, an aqueous or oily suspension, and an acceptable oil (such as cottonseed oil, sesame oil, scorpion/yellow oil or peanut oil) or has a solubility suitable for intravenous use. Emulsions of emulsifiers and emulsifiers, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums, such as tragacanth, arabic, alginate, dextran, rebel Cellulose sodium, methylcellulose, polyvinylpyrrolidone or gelatin. The composition for inhalation or insufflation comprises a solution and suspension in a pharmaceutically acceptable aqueous or organic mixture or mixture thereof, The liquid or oral composition may contain a suitable pharmaceutically acceptable form as set forth above for local or systemic effects, preferably by oral or nasal route of administration. Preferably, the composition in a sterile pharmaceutically acceptable solvent can be atomized by using an inert gas. The atomized solution can be directly absorbed from the spray device or it can be attached to a mask, stopper or intermittent housekeeping machine. Preferably, the solution, suspension or powder composition is administered orally or nasally by means for delivering the formulation in a suitable manner. For the treatment of the above-mentioned clinical conditions and diseases, oral, topical, intestinal inhalation or rectal administration can be carried out in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Invest in this hair. The term parenteral as used herein includes subcutaneous injection, , 'intrapulmonary injection, intramuscular injection, intracranial injection or injection technique. The following examples are provided for the purpose of illustrating the invention, but are not intended to be limiting of the scope of the invention, 119664.doc-71 - 200813031. The compounds of the invention can be prepared as described in the Schemes below. Process 1 f \

Br

OEt OEt KOH, DMSO, 20 h Step 1

1.BuLi, THF, -78 °C 2. B('PrO)3 3. 2 N HCI or NH4CI (8) Step 3

PPA Benzene Step 2 R1

PdCI2(Ph3P)2 &gt; n Et3N, EtOH Y - Drot/Tfo j W· I w R2 Step 4

COOH

NaCNBH3f DCM/MeOH AcOH Step 5 Process 2

I.BuLi, THF, -78 ° C

100 ° C, microwave Step 3

AcOH Step 4 119664.doc 72- 200813031 Process 3

110 ° C, microwave step 1

Pd(dpp〇2CI2l dppf

1. BuLi, THF, -78 °C 2. B(〇iPr)3 3. 2N HCI Step 2

TEA, Pd(PPh3)2CI2 100' microwave Step 3 Ο

Step 4 Process 4

BBr3

DCM

OH Step 1 DEAD, PPh3 or Polymer-PPh3 Step 2 119664.doc -73 - 200813031 Process 5

1. BuLi.THF, -78 °C 2. B(Vr〇h * 3.2NHC_H4CI(s) Step 1

PdCI2(Ph3P)2

Et3N, EtOH

Br or Tf〇 Step 2

ΤΡΑΡ, NMO Step 4 Step 3

Step 5 Process 6

1.Mg/THF/reflow

Step 1 119664.doc •74- 3200813031 Process 7

Br

LiAIH4, H2SQ4 THF Br

NH2 Step 1 (CF3C0)20 2,6-Dimethyl'pyridine Step 2

(CHO)ni AcOH H2S04 Step 3

CXXQ~b(〇h)2 Pd(PPh3)4 Toluene/Ethanol 2 M Na2C〇3 Heating 1〇(TC,’24h Step 4 f

CH2=CHC00tBu DIEA ' 90 0C, microwave Step 5

Ot-Bu

TFA CH2CI2 Step 6

Flow 8 v.

CH2=CHC〇OtBu HBr DIEA 90 0C,·Microwave ♦1

R(X)v〇^b(oh)2 (cf2s〇2)2〇 pyridine o°c Step 2

R(X)

Pd(PPh3)4 Toluene/Ethanol 2 M Na2〇〇3 Heating 100 &lt;24 h

〇 O-t-Bu Step 3

TFA CH2CI2 Step 4

119664.doc -75- 200813031 Process 9

R2 Βγ^^Τ^^ΟΗ OH

Ri~0^bPH

OH iPrOH NaOH (2 N) Step 2 Example Compounds were prepared using the general procedure described below:

0 (11, 111 are equal to 0 small 2) A: General procedure for coupling C_C bond with Rieke reagent Rieke reagent (0·5 Μ, 2.9) in which 5-bromophenylpyran (1.0 mmol) is dissolved in a microwave reaction tube. Methyl) in THF solution. Pd(PtBu3) 2 (0.05 mmol) was added to the solution. The mixture was purged with N2 gas for 3-5 minutes and heated under microwave irradiation (Personal Chemistry EmrysTM Optimizer microwave reactor) for 30 minutes at 100 °C. After completion of the reaction, the reaction mixture was diluted with EtOAc. The filtrate was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (ISCO system) to afford pure product. B: General procedure for NC bond coupling reaction 119664.doc -76- 200813031 5 - benzoquinone ° 17 South (1.0 mmol), tourism (1.2 mmol), Pd (dppf) Cl2 (〇.〇 3 mmol) Dppf (0.045 mmol) and tributanol (1.5 mmol) were mixed in toluene (2 mL). The mixture was purged with N 2 gas for 3-5 minutes and heated under microwave irradiation (Personal Chemistry EmrysTM Optimizer microwave reactor) for 30 minutes at 120 °C. After completion of the reaction, the reaction mixture was directly loaded onto a silica gel column and purified on an ISCO system (5% EtOAc in hexane) to obtain a pure product. C: General preparation procedure for the formation of benzofuran acid. A solution of the heart BuLi (1.2 mmol, 2.5 Μ in hexane) was added dropwise at -78 ° C to the benzofuran compound (1.0 mmol). In a solution of anhydrous THF (20 mL). The resulting mixture was stirred at -78 °C for 20 min and treated with EtOAc (EtOAc). The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction was cooled in an ice bath and quenched with 2 N EtOAc or sat. NH4CI and extracted with Et20. The combined organic extracts were washed with EtOAc EtOAc (EtOAc m. D: General procedure for coupling a face acid with an aryl group - benzofuran-acid (1.1 mmol), aryl compound (1. 0 mmol), triethylamine (20 mmol) and bis(triphenyl) chloride a mixture of phosphine)|bar (11) (0.05 mmol) in ethanol (30 mL) was irradiated in a microwave oven at 10 (TC for 20 minutes. The reaction mixture was cooled and the solvent was removed. The residue was treated with water and Extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo (aq.), then purified from silica gel chromatography to afford the desired product. E: General procedure for reductive amination reaction 119664.doc -77- 200813031 Acetic acid (1·〇mmol), acetic acid (1.5 mmol) &amp; σ丫丁定定-3-carboxylic acid or piperidine-4-carboxylic acid (1.2-1.5 mmol) in DCM/MeOH (1:1, 10 mL) The mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.5 mmol) was added and the reaction mixture was stirred at room temperature for 2-3 hr. After concentrating solvent under reduced pressure, the obtained residue was dissolved in DMSO. Medium, filtered and prepared by reverse phase preparative HPLC (Phenomenex reverse phase Luna 5μ C18(2) column, 60x21.2 mm ID, mobile phase: Α=0.05% in water TFA; B = 0_05% TFA in acetonitrile at a flow rate of 10-12 ml/min) was purified to obtain the desired final product with a purity greater than 95%. In addition to compound 59, all final products were obtained in the form of the TFA salt. Alternatively, the crude mixture of the reductive amination reaction can be purified by wet milling with MeOH and water. Compound 1 1-(4-(5-phenylbenzoquinan-2-yl)-glycol) 1-(2,2-diethoxyethoxy)-4_phenylbenzene of indole-3-carboxylic acid (Step 1 in Scheme 1):

a mixture of 4-phenylphenol (5 g, 29.4 mmol), bromoacetaldehyde diethyl acetal (4.56 mL, 29.4 mmol) and KOH (1.94 g, 29.4 mmol) in DMSO (15 mL) Stir for 6 hours. The reaction mixture was cooled to room temperature and poured onto ice containing 0.60 g KOH and diluted with water to 100 mL. The solution was extracted three times with EtOAc (20 mL). EtOAc (EtOAc)EtOAc. No further pure 119664.doc -78 - 200813031 can be used: 1H NMR (400 MHz, CDC13) δ 7.56-7.50 (m, 4H), 7·41 (t, 2H), 7.30 (t, 1H), 7.00 (dt5 2H), 4·86 (t, 1H), 4·05 (d, 2H), 3.82-3.74 (m, 2H), 3·69-3·62 (m, 2H). 5-Phenylbenzofuran (Step 2 in Scheme 1):

a mixture of 1-(2,2-diethoxyethoxy)-4-phenylbenzene (3.52 g, 12.3 mmol) and polyphosphoric acid (2.95 g, 29.4 mmol) in benzene (60 mL) Stir under 2 hours. The reaction mixture was cooled to room temperature, decanted from EtOAc and filtered over EtOAc. The filtrate and the washings were combined and concentrated under reduced pressure to give 2.00 g of crude benzofuran: b NMR (400 MHz, CD3 〇D) δ 7.79 (dd, 1H), 7.66 (d, 1H), 7.63-7. m, 2H), 7.58-7.51 (m, 2H), 7.45 (t, 2H), 7.36-7.33 (m, 1H), 6·82 (dd, 1H). 5-Phenylbenzofuran-2-yl-2-gponic acid (Step 3 in Scheme 1):

Add a solution of BuLi (2.0 mL, 2.5 Torr in hexane) to 5-phenylbenzofuran (816 mg, 4.21 mmol) in anhydrous THF (20 mL). In solution. The resulting mixture was stirred at -78 &lt;0&gt;C for 20 min and treated with &lt;RTI ID=0.0&gt;&gt; The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction was quenched with 2 N HCl and extracted with EtOAc. The combined extracts were washed with brine, dried and concentrated under EtOAc EtOAc s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s 7.83 (dd,1H), 7.64-7.55 (m,4Η), 7.48-7.42 (m,3Η), 7.38-7.32 (m 1Η) 〇4-(5-phenylbenzofuran-2-yl)benzaldehyde (Step 4 in Process 1):

5-Phenylbenzofuran-2-yl-2-guanic acid (527 mg, 2.22 mmol), cardiac bromobenzaldehyde (3 15 mg, 1.70 mmol), palladium dichlorobis(triphenylphosphine) (60 mg , a solution of 0.085 mmol) and triethylamine (4.74 mL, 34 mmol) in EtOH was irradiated in a microwave for 1 s. The formed precipitate was filtered and washed with ethanol to give 217 mg of the desired benzaldehyde: iH NMR (400 MHz, CD3 〇D) δ 10.06 (s, 1H), 8.05 (d, 2H), 7.98 (d, 2H) ), 7.82 (br s, 1H), 7.65-7.52 (m, 4H), 7.48 (dd, 2H), 7·37 (t, 1H). MS (ESI) m/z: calc.: 298.10; observed: 299.1 (M++1) 〇l_(4-(5-phenylbenzofuran-2-yl)benzyl)azetidine-3- Formic acid (Step 5 in Process 1):

4_(5-Benzyl benzoquinone-based fluoren-2-yl)benzoic acid (49 mg, 0.14 mmol) and azetidin-3-carboxylic acid (30 mg, 〇·28 mmol) in MeOH (1 mL) The mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (6 mg, 0.28 mmol) was added in two portions and the reaction mixture was stirred 16 hr. The 119664.doc-80-200813031 solvent was concentrated under reduced pressure to give a yellow solid, which was dissolved in DMSO (3 mL) and filtered to obtain a yellow solution, which was purified by HPLC to obtain 3 mg. Product required [hSIPl EC5〇=1200 nM] : 4 NMR (400 MHz, CD3〇D) δ 8.03 (d, 2H), 7.84 (br s, 1H), 7.66-7.58 (m, 6H), 7.45 (t, 2H), 7.36-7.32 (m, 2H), 4.47 (s, 2H), 4.40-4.32 (m, 4H), 3.72 (m, 1H). MS (ESI) m/z: Calcd.: 303. Compound 2 ^((Μ5·butylbenzofuran-2-yl)phenyl)indolylbutyridinecarboxylic acid (2,2-diethoxyethoxy)_4_butylbenzene:

As in the case of the example compound 1 (step 丨 in Scheme 1) in the general yield as described above): AH NMR (400 MHz, ), 6, 83 (d, J = 8.8, 2H), 4.83 (t, 2H) , 3.80-3.72 (m? 2H) 5 3.67-2H), 1.59-1.51 (m, 2H), 1.36 - Method The title compound (90% yield): 0.91 (t,J=7.3, 3H). CDC13) δ 7.07 (d, J=8.8, 2H), 6,83 (J-5·!, 1H), 3·98 (d, J=5.1, 2H), 3·ί 3·59 (m, 2H ), 2.54 (t, /= 7.7, 2H), 1. • 30 (m, 2H), 1.24 (t, J = 7.0, 6H), 0.9 5-butyl astringent:

The title compound (91% yielding CDCl3) δ 7.58 (Step 2 of ά. 7) was obtained as in the above-mentioned general compound (91% yield): ijj NMR ( 400 ΜΗζ, 58 (d, J=2.2, 1Η), 7·41-7·36 (m5 2Η), 7·11 (dd, 119664.doc -81 - 200813031 , 1.8, 1H), 6·70 (dd , /=2.2,1·1,iH), 2.70 (t,J=7.7, ),167-1.60 (m,2H),1·42-1·32 (m,2H),0.93 (t,/= 7.3, 3H) 〇5 Butyl benzophene 2 - 2 - 2 -g-p-acid:

^ Uh The compound (67 〇 / 〇 yield) is prepared as described above in the example compound i (Step 3 in Scheme!): iH NMR (4 〇〇 MHz, 7 3) δ 7·43 &quot; 7·31 (m, 2Η), 7·22-7·14 (m, 2H), 2.70 (t, ' 2H), ^67]·59 (m, 2H), 1.41-1.32 (m, 2H), 0.93 (t, /==7·3, 3H). 4 butyl benzofuranyl) benzofural: =\ p

Example, the example compound 丨 (Step 4 in the scheme) is as described above for the general gas preparation & compound (72% yield): 1] H NMR (400 MHz, CDCl, only Λ 3 · 〇 3 (s, 1H), 8·00 (d, J=8.4, 2Η), 7·94 (d, J=8.4, )' 7.45-7.41 (m, 2H), 7.17-7.15 (m, 2H), 2.71 (t, "7=7.7, 9jj\ 1 •68-1.61 (m? 2H)5 1.41-1.33 (m? 2H)? 0.94 (t5 J=7.3? 3H) 〇((4 (5-butyl) Furfuran-2-yl)phenyl)indenyl)azetidine-3-carboxylic acid:

COOH

119664.doc -82 - 200813031 The title compound (42% yield) was prepared by the general procedure as described above in Example 1 (Step 5 in Scheme 1) [hSIP1 EC5 〇 = 200 nM, 510 η Μ, 867 η Μ] : 4 NMR (400 MHz, CD3OD) δ 7.98 (d, •==8.4, 2Η), 7·55 (d, J=8.4, 2Η), 7·43-7·41 (m, 2Η), 7.23 ( s, 1H), 7.15 (d, deduction 8.8, 1H), 4·40 (s, 2H), 4.25-4.23 (m, 4H), 3.52-3.46 (m, 1H), 2.71 (t, J = 7.7, 2H), 1.67-1.61 (m, 2H), 1-41-1.33 (m, 2H), 0.95 (t, /= 7.3, 3H). MS (ESI) m/z: Calcd.: 363. Compound 3 1-((4-(5• Butoxybenzofuran-2-yl)phenyl)methyl)azetidine_3_carboxylic acid 1-(2,2-diethoxyethoxyl Butoxybenzene··

The title compound (84% yield) was obtained by the general procedure as described above in the procedure , J=5.1,1H),3·96 (d, J=5.1, 2H)5 3.90 (t5 J=6.6, 2H)5 3.79-3.72 (m5 2H)5 3.67- 3.59 (m5 2H)5 1.77-1.70 (m? 2H)5 1.52-1.43 (m3 2H)5 1.24 (t, /=7.0, 6H), 〇·96 (t, J=7 4, 3H). 5-butoxybenzoquinone:

The title compound (8 1%, 1 μ, 6 i / yield) H NMR (prepared as described in Example 2, step 2) of Example 1 in the general procedure 119664.doc - 83 - 200813031. 40G MHz CDCl3)S7.58 (〇2.2,1H), 7 38 (dj=92,iH)7〇5(d' •/=2.5, m), 6.90 (dd, J=2.5, 8 8, 1H) ,6 69 (9) d,j=2 2, 1H), 3.99 (t, «/=6.6, 2H) 1 8? i 7ς / Λττλ , m), i.82-1.75 (m, 2H), 1.56-1.47 (m, 2H), 0.99 (t, J = 7.3, 3H). 5-Phenylbenzofuran-2-yl-2_-acid (Step 3 of the process):

Heart BuBu solution (2.5 mL, 2. 5 m solution in hexane) was added dropwise to 5-butoxybenzofuran (1·〇g, 5.21 mmol) at _78t in anhydrous In a solution of THF (20 rnL). The resulting mixture was stirred for 2 knives and treated with B(Pr) 3 (i 8 〇 mL, 7 8 mm 〇 1). The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction was quenched with 2 N HCl and extracted with EtOAc. The combined extracts were washed with brine, dried EtOAc EtOAc EtOAcjjjjjjj (d,1H), 7.30(d,lH),7.06(s,lH),6.98(d,lH),4.44(s,2H),1.81-1·71 (m,2Η),1.58-1.50 (m , 2Η), 1.00 (t, 3Η). Heart (5-butoxybenzofuran-2-yl)benzaldehyde (Step 4 in Scheme 1):

5. 5 本 幷吱 幷吱 幷吱 -2--2-yl-2-acid (702 mg, 3 · 0 mmol), 4-indiprofen (427 mg, 2.30 mmol), palladium dichlorobis (triphenylphosphine) (80 mg '〇·11 mmol) and triethylamine (6.5 mL, 45 mmol) in EtOH (2 119664.doc -84-200813031 mL) were irradiated in a microwave at i〇〇°c 12 Leap second. The formed precipitate was filtered and washed with ethanol to give a crude product (yield: </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; (s, 1H), 8.05 (d, 2H), 7·98 (d5 2Η), 7.82 (d, 1Η), 7.18 (d, 1Η), 7·16 (d, 1Η), 6.94 (s, 1Η), 4.44 (s, 2H), 1.81-1.71 (m, 2H), 1.58-1.50 (m, 2H), 1.00 (t, 3H). MS (ESI) m/z: Calcd.: 295. Azetidine-3-carboxylic acid (Step 5 in Scheme 1):

4-(5-Butoxybenzoquinone-2-yl)benzoic acid (70 mg, 0.3 mmol), triterpenic acid-3-dicarboxylic acid (46 mg, 0.45 mmol) and acetic acid (0·50) The mixture was stirred at rt for 1 h. Sodium triethoxysulfonate (2 11 mg, 1.00 mmol) was added and the reaction mixture was stirred 16 h. The solvent was concentrated under reduced pressure to give a yellow solid, which was taken in EtOAc (3 mL). )[hSIPl EC5〇=520 nM] : 4 NMR (400 MHz, CD3〇D) δ 7.97 (d, 2H), 7·55 (d, 2H), 7.40 (d, 1H), 7.21 (s, 1H) , 7.10 (d, 1H), 6.92-6.89 (dd, 1H), 4.44 (s, 2H), 4.37 (q, 4H), 4.00 (t, 2H), 3.72-3.64 (m, 1H), 1.81-1.71 (m, 2H), 119664.doc -85- 200813031 15 8-1.5 0 (m, 2H), 1 · 〇〇 (t, 3H). Ms (ESI) m/z ··calculated value·· 379·45 ; observed value: 38〇 3 &lt;Μ++1). Compound 4 1((4-(5-Benzylbenzofuranyl)phenyl)methyl)azetidine_3_carboxylic acid 1-(4-(2,2-diethoxyethoxy)benzyl )benzene:

〇Et The title compound (84% yield) was obtained in the general procedure as described above in the procedure of Example 1 (Step 1 in Scheme 1): NMR (400 MHz, CDC13) δ 7·30-7·25 (m) , 2H), 7·20-7·15 (m, 3H), 7·09 (d, 8·8, 2Η), 6.84 (d, J=8.8, 2Η), 4.82 (t, J=5.5, 1Η) ),3·98 (d,&gt;5·5, 2H)5 3·92 (s,2H),3.79-3.72 (m,2H),3.66-3.59 2H)?1.24 (t, 7.153H)〇5 _ 基 phenyl benzofuran:

The title compound (89% yield) was obtained by the general procedure of the title compound (1 NMR (400 MHz, CDC13) δ 7.58 (d5 J=2.2, 1H), 7.42. -7.40 (m, 2H)3 7.31- 7·7·26 (m,3H), 7.25-7.12 (m,3H), 6.70 (m,1H),4.08 (s, 2H) 〇5_ phenyl hydrazine Furan_2_yl-2__acid:

OH 119664.doc -86 - 200813031 The title compound (66% yield) was obtained by the general procedure as described above in </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (m,1H), 7.42 (d, "/=8.4, 1H), 7.32-7.26 (m, 4H), 7.25-7.19 (m, 3H), 4.81 (s, 2H), 4.08 (s, 2H) 〇 4_(5-benzylbenzofuran-2-yl)benzaldehyde:

The ruthenium compound (76°/. yield) was prepared as in the general procedure of Example 1 (Step 4 in Scheme 1): 1H NMR (4 〇〇 MHz, CDC13) δ 10.03 (s, 1H) , 7.99 (d, J=8.4, 2H), 7.94 (d, J=8.4, 2H)5 7.46^7.41 (m? 2H)5 7.32-7.17 (m5 6H)5 7.13 (br s5 1H), 4.08 (s , 2H). 1-((4-(5-Benzylbenzofuranyl)phenyl)indenyl)azetidine_3_carboxylic acid:

COOH 1 / The title compound (62% yield) was obtained by the general procedure as described above as Example Compound 1 (Step 5 in Scheme 1) [hSIP1 EC5〇=400 nM, 460 nM, 420 nM, 1〇7 nM ] : 4 NMR (400 MHz, CD3OD) δ 7.98 (d, J=8.4, 2H), 7.55 (d, J=8.4, 2H), 7.45-7.42 (m5 2H), 7·28_7·15 (m, 7H) ), 4.44 (s, 2H), 4.37-4.22 (m, 4H), 4.06 (s, 2H), 3.72-3.64 (m, ih). MS (ESI) m/z: Calcd: 399. Compound 5 119664.doc -87 - 200813031 ((4 phenyl hydrazine n aceton-2-yl) phenyl) methyl) σ 丫 butyl benzoic acid (2_(2,2-diethoxyethoxy) benzyl) Base) benzene:

The title compound (99% yield) was obtained by the general procedure as described above in Step 1).

Cl3) δ 7.27-7.21 (m, 4Η), 7.19-7.15 (m, 2Η), 7·08 (br d,

• 'Old', 6.90-6.83 (m5 2H), 4.78 (t, J=5.1, 1H), 4.00-3.98 V, 4H), 3.76-3.69 (m, 2H), 3.63-3.56 (m, 2H) , 1.22 (t, /==7·〇, 6H). 7-Phenylbenzofuran: The title compound (84% yield) was prepared as described above for compound 1 (Step 2 in Scheme i). L3) δ 7·62 (d, J=2, 2, 1Η), 7·45 (d, /=7.7, 1H), 7.36 (s, )' 7.29-7.26 (m, 3), 7.25-7.13 ( m,2),7.05 (d,J=7.4, 1H), 6,76 (d5 J-2.2, 1H), 4.27 (s5 2H) 〇7_ benzyl benzofuran-2-yl-2-phenylene: The title compound (67% yield) was obtained as described above for compound 1 (Step 3 in Scheme 1) as described above in general 119664.doc -88 - 200813031: 1H NMR (400 MHz, CDC13) δ 7 · 5 〇 (dd, /= 7.7, 1H), 7.36 (s, 1H), 7.29-7.25 (m, 4H), 7·ΐ8々·〇9 (m, 3H), 4.29 (s, 2H). 4 one (7_knot abbreviated furan-2-yl) benzaldehyde:

The title compound (72% yield) was obtained as mpqqqqqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ (m, 4H), 7.50 (d, J = 9.9, 1H), 7.47-7.27 (m, 4H) 5 7.24-7.17 (m, 3H), 7.11 (d, "7=7.3, 1H), 4.33 (s , 2H). 1β((4_(7·benzylbenzofuranyl)phenyl)methyl)azetidinecarboxylic acid:

COOH

The title compound (81% yield) was obtained by the general procedure as described above in Example 1 (Step 5 in Scheme 1) [hSIP1 EC5 〇 &gt; l nM]: towel NMR (4 〇〇 MHz, CD3OD) δ 7.97 (d, /=8·0, 2H), 7.56 (d, J=8.〇, 2H), 7.48 (d, J=7.7, 1H), 7.34-7.24 (m, 5H), 7.19- 7"〇(m,3H),4·44 (s,2H),4·32-4·25(ηι,6H), 3.66-3.56 (m, 1H). MS (ESI) m/z: Calculated: 397.17; observed: 397.9 (M++1) 〇 119664.doc •89-200813031 Compound 6 l (4-(5-cyclohexylbenzofuran-2-yl)benzyl Base) azetidine-3-carboxylic acid 5-cyclohexyl benzofuran (Step 1 in Scheme 2):

5-oxabenzoin (5 〇〇 mg, 2.55 mmol) was dissolved in a THF solution of cyclohexylzinc bromide (11) (0.5 Μ, 15 mL, 7.40 mmol) in a microwave reaction tube.卩(1(?4113)2 (65 mg, 0.128 mmol, 0.05 eq.) was added to the solution. The mixture was purged with A gas for 3-5 minutes and heated under microwave irradiation for 30 minutes at 1 Torr. After completion of the reaction, the reaction mixture was diluted with EtOAc EtOAc EtOAc EtOAc EtOAc. Purification of 5% hexanes in hexanes to give the desired product (43% yield): 4 NMR (400 MHz, CDC13) δ 7.57 (d, 1 Η), 7.41 (d, 2 Η), 7.15 (d,1Η),6·72 (d,1Η),2·58 (m, 1H),1.92-1.74 (m,4H),1.51-1.35 (m,4H),1.31-1.25 (m, 2H 5-cyclohexyl benzophene shouts-2-yl self-powder acid (step 2 in process 2):

Heart BuLi solution (360 pL, 〇·9 mm〇i, 2.5 Μ in hexane) was added dropwise at -78 °C to 5-cyclohexyl phenylfuranium 5 〇mg, 〇·75 mmol ) in a solution of anhydrous THF (5 mL). The resulting mixture was stirred at 119664.doc -90-200813031 -78 °C for 40 minutes and treated with B(,pr〇)3 (260 μΙ&gt;, 1.13 mmol). The reaction mixture was allowed to slowly warm to room temperature and stirred for a few hours. TLC indicates that the reaction is complete. The reaction was cooled in an ice-bath and quenched with &lt The combined organic extracts were washed with EtOAc EtOAc m. NMR (400 MHz, CDC13) δ 7.46 (s, 1H), 7·43 (d, 1H), 7·32 (s, 1H), 7·25 (d, 1H), 2.62 (m, 1H), 1.93 -1.85 (m, 4H), 1.78-1.75 (m, 4H), 1.34-1.22 (m, 2H) ° 4-(5-cyclohexylbenzofuran-2-yl)benzaldehyde (Step 3 in Scheme 2) ):

5-cyclohexyl benzofuran-2-yl-acid (75 mg, 0.37 mmol), 4-&gt; stinky carbamide (62 mg '0.34 mmol), triethylamine (1 · 1 mL, 7.5) A mixture of mmol) and bis(triphenylphosphine)palladium(11) chloride (13 mg, 0.05 mmol) in ethanol (11 mL) was irradiated in a microwave oven at 100 ° C for 2 min. The reaction mixture was cooled and the solvent was removed. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 4 NMR (400 MHz, CDC13) δ 10·〇3 (s, 1H), 8·00 (d, 2H), 7.95 (d, 2H), 7·46 (d, 2H), 7.19 (d, lH) , 7.16(S,lH),2.63-2.58 (m,lH),1.94-1.76 (m,4H),1·53-1·42 (m,4H),1·38-1·25 (m,2H) ). MS (ESI) m/z: Calcd.: 384. 119664.doc -91 - 200813031 1-(4-(5-Cyclohexylindolefuran-2-yl)benzyl)azetidine-3-furic acid (Step 4 in Scheme 2)

4-(5-Cyclohexylbenzofuran-2-yl)benzaldehyde (30 mg, 〇.1 mmol), acetic acid (9 gL, 0.15 mmol) and azetidine-3-carboxylic acid (15 mg, 0·) A mixture of 15 mmol) in DCM / MeOH (1:1; 2 mL) was eluted for 1 hour at room temperature. The cyano shed was added to sodium (3.1 mg, 0.05 mmol) and the reaction mixture was stirred at room temperature for 3 hours. After concentrating the solvent under reduced pressure, the obtained residue was dissolved in hot MeOH and filtered. The filtrate was purified by reverse phase preparative HPLC (Phenomenex reverse phase Luna 5 μ C18 (2) column, 60 x 21.2 mm ID) with a white solid redissolved in hot DMSO to give the desired white powder. Product (16 mg, 42% yield) [hSIP1 EC50 = 970 nM, 400 nM, 440 nM, 421 nM]: purity by LCMS &gt; 95%, ESI-MS: 459.1 (M+H)+, 4 NMR (400 MHz, CD3OD) δ 7.95 (d, 2H), 7.56 (d, 2H), 7.45 (d, 1H), 7.42 (d, 1H), 7.24 (s, 1H), 7.19 (dd, 1H) ), 4.45 (s, 2H), 4·34 (dd, 4H), 3.69 (m, 1H), 2.64-2.57 (d, 1H), 1.89 (t, 4H), 1.58-1.40 (m5 4H), 1.38 -1.26 (m, 2H). Compound 7 1-(4-(5-cyclohexylbenzoquinone-2-yl)) group) brigade-4-formic acid

119664.doc -92- 200813031 4-(5-J-hexylbenzoquinone σ-propan-2-yl)benzoic acid (22 mg, 0.07 mmol), acetic acid (7 pL, 0.11 mmol) and 唆-4 A mixture of the formic acid (14 mg, 0.11 mmol) in DCM /MeOH (1:1; Sodium cyanoborohydride (2.3 mg, 0. 05 mmol) was added and the mixture was stirred at room temperature for 4 hr. After concentrating the solvent under reduced pressure, the obtained residue was dissolved in DMSO, filtered and purified by reverse phase preparative HPLC (Phenomenex reverse phase Luna 5 μ C18 (2) column, 60 x 21.2 mm ID) to obtain The final product was required (15.4 mg, 51 〇/c 〇 [hsipi EC5 〇 = 1600 nM, &gt; 25000 nM]: purity by LCMS &gt; 95%, ESI-MS: 418.1 (M+H)+, towel NMR (400 MHz, CD3OD) δ 8.00 (d, /=8.0 Hz, 2H), 7.59 (d, /=8.0 Hz, 2H), 7.45 (d, J-1·6Ηζ, 1H), 7.43 (d, /= 8.4 Hz, 1H), 7.26 (s, 1H), 7.21 (dd, J = 8.4 Hz, &gt; 1.6 Hz), 4.35 (s, 2H), 3.57 (d, / = 11.6 Hz, 2H), 3.07 (t , J=12 Hz, 2H), 2.64-2.53 (m, 2H), 2.24 (d, 2H), 1.19-1.86 (m, 4H), 1.79 (t, 2H), 1.58-1.42 (m, 4H) ), 1 · 3 8 -1 · 2 6 (m, 2 H) 〇Compound 8 1-((4-(5-butylbenzofuran-2-yl)phenyl)methyl)piperidinecarboxylic acid

The title compound (57% yield) was prepared by the general procedure as described above (H.sub.5). ;25000 nM] : 4 NMR (400 119664.doc -93- 200813031 MHz, CD3OD) δ 8·00 (d, J=8.1, 2H), 7.59 (d, J=8.1, 2H), 7.43-7.41 (m , 2H), 7.25 (s, 1H), 7.15 (d, J=8.8, 1H), 4.35 (s, 2H), 3.57 (br d5 J=ll.7, 2H), 3.07 (br t, /=12.5) , 2H), 2.71 (t, J=7.7, 2H), 2.70-2.59 (m, 1H), 2.25 (br d, &gt;14·6, 2H), 1.93-1.79 (m, 2H), 1.67-1.61 (m, 2H), 1.43-1.33 (m, 2H), 0.95 (t, J = 7.3, 3H). Ms (ESI) m/z: Calcd.: 391.21. Compound 9 () benzylbenzofuran-2-yl)phenyl)indolyl)piperidinecarboxylic acid

The title compound [hSlPl EC5〇=4800 nM^25000 ηΜ] was prepared as in the general procedure described above except for the use of the acridine-4-carboxylic acid as in Example Compound 1 (Step 5 in Scheme 1): !H NMR ( 400 MHz, CD3OD) δ 7.99 (br d, &gt; 8.0, 2Η), 7.58 (br d, J=8.0, 2Η), 7.44-7.42 (m, ( 2H)5 7.28-7.16 (m, 7H)? 4.34 (br s, 2H), 4.05 (br s, 2H), 3.57 (br d, J=ii.7, 2H), 3 〇5 (br t, J= 12 4, 2H), 2 65 2 62 (m , 1H), 2.23 (br d, J = 13.5, 2H), 1.89-1.80 (m, 2H). MS (ESI) m/z: Calculated: 425.20; observed: 426.0 (M++1). 10 1-((4-(5-isobutylbenzofuran-2-yl)phenyl)indenyl)azetidine_3_carboxylic acid (Scheme 2) 5-Isobutylbenzofuran (Process 2 Step 1): 119664.doc -94- 200813031

5-Bromobenzopyran (500 mg, 2.56 mmol) was dissolved in a solution of lysyl isobutyl zinc (Π) (0.5 M, 15 mL, 7.40 mmol) in THF. Ρ(1(ΡιΒιι3) 2 (65 mg, 0.128 mmol, 0·05 eq.) was added to the solution. The mixture was purged with A gas for 3-5 minutes and heated under microwave irradiation at 10 °C. After the completion of the reaction, the reaction mixture was diluted with EtOAc EtOAc EtOAc EtOAc. (ISCO system, 5% EtOAc in hexane) was purified to afford 0.331 g (yield: 74% yield): 4 NMR (400 MHz, CDC13) δ 7.59 (s, 1 Η), 7.35 (d, 1 Η) , 7.07 (d, 1 Η), 6.70 (s, 1 Η), 2·59 (d, 2 Η), 1.9 (m, 1H), 0.9 (d, 6H). 5. Isobutyl benzopyrene-2_ Base acid (step 2 in Process 2):

Heart BuLi solution (912 μί, 2.28 mmol, 2.5 Μ in hexane) was added dropwise at -78 °C to 5-isobutylbenzofuran (331 mg, l9 mmol) in dry THF (12) In the solution in mL). The resulting mixture was spoiled at _78 °C for 40 minutes and treated with ΒΠ&gt;Γ〇3 (658, 2 85 mm 〇1). The reaction mixture was allowed to slowly warm to room temperature and stirred for a few hours. TLC indicates that the reaction is complete. The reaction was cooled in an ice-bath and quenched with &lt The combined organic extracts were washed with brine, dried and concentrated under reduced vacuum affording crude succinic acid ( s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s . 4-(5-isobutylbenzofuran-2-yl)benzaldehyde (Step 3 in Scheme 2):

5-isobutylbenzofuran-2-yl-acid (70 mg, 0.33 mmol), 4-bromobenzoic acid (61 mg, 0·33 mmol), triethylamine (1·7 mL, 12 6 mmol) A mixture of gasified bis(triphenylphosphine)palladium(Π) (12 mg, 0.017 mmol) in ethanol (10 mL) was irradiated in a microwave oven at 1 °C for 20 minutes. The reaction mixture was cooled and the solvent was removed. The residue was treated with water and extracted with ethyl hexanoate. The organic layer was dried and concentrated in vacuo (hydrophilic treatment as appropriate). The title compound (5 9 mg, 65% yield) was obtained by EtOAc (EtOAc): EtOAc (EtOAc): 1-((4-(5-isobutylbenzoquinone-2-yl)phenyl)methylglycolic acid (Step 4 in Scheme 2):

4·(5-Isobutylbenzofuran-2-yl)benzaldehyde (3〇mg, 〇11 mmol), acetic acid (10 pL, 〇·ΐ 5 mmol) and 丫丁丁-3-carboxylic acid (16 The mixture was stirred at room temperature for 1 hour at rt. Sodium cyanoborohydride (34 mg, 〇 54 mmol) was added and the mixture was stirred at room temperature for 3 hr. After concentrating the solvent under reduced pressure, the obtained residue was dissolved in an aliquot of DMSO and was subjected to reverse phase preparative HPLC (Phenomenex reverse phase Luna 5μ C18(2) column, 60x21 by 119664.doc -96-200813031 .2 mm ID) Purification to obtain the desired final product (25.6 mg, 65% yield) as a colorless film [hSIP1 EC50=270 nM, 490 nM, 383 nM]: purity by LCMS &gt;95〇/ 〇, eSI-MS: 364.0 (M+H)+ » lU NMR (400 MHz, CD3〇D) δ 7.99 (d5 2H 7.55 (d, 2H), 7.42 (d, 1H), 7.39 (s, 1H), 7·24 (s, 1H), 7.12 (dd, 1H), 4.44 (s, 2H), 4.33 (d, 4H), 3.68 (m, 1H), 2.57 (d, 2H), 1.90 (m, 1H) , 0.92 (d, 6H).

Compound 11 1-((4-(5-Phenylethylbenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid

The title compound [hS 1P1 EC50 = 5 80 nM, 25000 nM] was obtained in the same manner as the compound of Example 6: purity &lt;95% by LCMS, £81-MS: 411.9 (M+H) + ^1H NMR ( 400 MHz, CD3OD) δ 7,99 (d, 2H), 7.55 (d, 2H), 7.41 (d, 1H), 7.38 (s, 1H), 7.24-7.21 (m, 3H), 7.17-7.14 (m, 4H), 4.44 (s, 2H), 4.34 (d, 4H), 3.70 (m, 1H), 3.01-2.90 (m, 4H). Compound 12 1-(4-(5-(° 咬 )))) 幷 幷 _2 _2 _2 _2 -3 -3 -3 _ _ _ _ _ _ _ 3- 3- 3- 3- 3- 3- In addition to Suzuki coupling, step 1) in Process 2: 119664.doc -97- 200813031

5-Pyridin-3-yl-acid (390 mg, 3.18 mmol), 5-bromobenzofuran (500 mg, 2.54 mmol), |barodichlorobis(triphenylphosphine) (111 mg, 0.16) A solution of mmol) and triethylamine (8.8 mL, 63.5 mmol) in EtOH was irradiated in a microwave at 100 ° C for 1200 s. After concentrating the solvent under reduced pressure, the solvent was removed, then dissolved in CH2C12 and filtered to afford residue. The compound was purified on EtOAc to afford 3 16 mg (yield::::::::::: ), 7.80 (s, 1H), 7.69 (s, 1H), 7.55 (d, 1H), 7·50 (d, 1H) 7.38 (dd, 1H), 6.85 (dd, 1H). MS (ESI) m/z: Calcd.:195. 5-(pyridin-3-yl)benzofuran-2-yl-acid (Step 2 in Scheme 2):

V-BuCl solution (0.76 mL, 2.5 Torr in hexane) was added dropwise at -78 °C to 3-(benzofuran-5-yl)pyridine (310 mg, 1.59 mmol) in dry THF In a solution (10 mL). The resulting mixture was stirred at 78 ° C for 30 minutes and treated with ruthenium (3) (0-55 mL, 2.39 mmol). The reaction mixture was allowed to warm to room temperature and was quenched for 1 hour. The reaction was quenched with 2 N HCl and extracted with EtOAc. The aqueous layer was neutralized with 5 N NaOH (pH = 6) and then extracted three times with THF: ether (1:1). The combined extracts were washed with brine, dried and concentrated under reduced pressure to afford 241 mg of crude 119664. doc -98 - 200813031 acid which was used without further purification. Aldehyde (Step 4-(5-(Acridine-3-yl)benzofuran-2-yl)benzene in Scheme 2 3):

Μ工广惊地如如例例6 Like L, ν π teach W title compound (44% yield): iH NMR (4〇〇 MHz, CDCl3) § 1 screening &amp;

8.91 (br s, 1H), 8.61 (br s, 1H), 8.07 (d, 2H), 7.98 (d, 2H)! 7.93 (d, 1H), 7.65 (d, 1H), 7.55 (d, 1H) , 7.82 (m, 1H)? ? 39 (m, 1H), 7.27 (m, 1H). MS (ESI) m/z: calc. m observed: 300.30 (M++1). 1 (4-(5 decyl-3-yl)phenyl hydrazinyl) benzyl) butyl butyl benzoate (Step 4 in Process 2):

The title compound (22% yield) was obtained by the general procedure as described above as the compound of compound 6 [hsipl </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1Η), 8.70 (m, 2Η), 8·06 (m, 3H), 7.98 (m, 1H), 7.74 (m, 2H), 7·60 (d, 2H), 7.44 (s, 1H), 4.47 (s, 2H), 4·4 (Μ·38 (m, 4H), 3.72 (m, 1H). MS (ESI) m/z • Calculated value · · 384·2〇; observed value: 385.00 (M+ +1). Compound 13 (4 (5-isobutyl oxime · 2 · base)) base biting formic acid 119664.doc -99· 200813031

4-(5-Isobutylphthalidin-2-yl)benzoquinone (22 mg, 0.08 mmol), acetic acid (7 μΐ^, 0.12 mmol) and BTS-4-decanoic acid (15 mg, A mixture of 0.12 mmol) in DCM / MeOH (1:1; 1.4 mL) Cyanonahydride (2.5 mg, 0.04 mmol) was added and the reaction mixture was stirred at room temperature for 4 h. After concentrating the solvent under reduced pressure, the obtained residue was dissolved in an aliquot of DMSO and purified by reverse phase preparative HPLC (Phenomenex reverse phase Luna 5 μ C18 (2) column, 60 x 21.2 mm ID) The desired final product was obtained (16.9 mg, 55%) [hSlPl.sup.sup.sup.sup.sup.sup.sup.sup.ssssssssssssssssssssssssssssssssssssssssss NMR (400 MHz, CD3OD) δ 8.01 (d, 2H), 7.59 (d, 2H), 7.43 (d, 1H), 7.39 (s, 1H), 7.26 (s, 1H), 7.13 (dd, 1H), 4·36 (s, 2H), 3.58 (m, 2H), 3.10 (m, 2H), 2.65 (m, 1H), 2.57 (d, 2H), 1.90 (m, 1H), 0.92 (d, 6H) 〇Compound 14 1-((4-(5-Carbinobenzoquinone) 2-2-fluorophenyl)methyl)u 丫 唆·3_carboxylic acid 4-(5-benzylphenylhydrazine Furan-2-yl) 2-fluorobenzaldehyde:

H NMR (400 MHz, mp. , 1H), 7.92 (dd, /=8.1, 7.0, 2H), 7.69 (d, ^- δ 5 • ' 1Ή), 7.63 (d, J=11.4, 1H), 7.46-7.42 (m, 2H), 7.33-7·19 (m, 6H), 7.13 (s, 1H), 4.09 (s, 2H). Le((4_(S_Phenylbenzofuran-2-yl)2-fluorophenyl)methyl)azetidine-3-carboxylic acid:

COOH

The title compound (54% yield) was obtained by the general procedure of compound 1 (m.p. 7.78 (d, "7=8.1,1H), • (d, J==9.9, 1H), 7.58 (t, J=7.7, 1H), 7.46-7.44 (m, 2H), 7.29-7.16 (m, 7H), 4 39 (s, 2H), 417 4 15 (m, 4H), 4 〇 6 (s, 2H)' 3.72-3.64 (m, 1H). MS (ESI) m/z: Calcd. Compound 15 1((^(5-benzylbenzofuran-2-yl)_3_fluorophenyl)methyl)azetidinecarboxylic acid 4_(^-p-phenylphenylfuran-2-yl)_3_fluorobenzaldehyde : 119664.doc

The title compound (65% yield) was obtained by the general procedure as described above in the procedure of Compound 1 (Step 4 in Scheme 1): NMR (400 MHz, CDC13) δ 10.01 (s5 1H)5 8.20 (t, J = 7.75 1H)5 7.77 (d? J=8.03 -101- 200813031 1H), 7.68 (d, J==l1·3, Gang, 7.47-7.45 (m, 2H), 7·37·7·20 (m 7H ), 4.10 (s, 2H) 1-((4-(5-Benzylbenzofuran-2-yl) 3-fluorophenyl)methyl)butyrate-3-carboxylic acid:

COOH The title compound (56% yield) was obtained by the general procedure as described above in Example 1 (Step 5 in the scheme) [hSIP1 EC5 〇=160 nM, 38 nM]: 1h NMR (400 MHz, CD3OD) δ 8·09 (t, J=7.9, 1H), 7.47-7.45 (m, 2H), 7·40_7·37 (m, 2H), 7.28-7.16 (m, 7H), 4.34 (s, 2H), 4.17-4.15 (m, 4H), 4.07 (s, 2H), 3.53-3.45 (m, 1H). MS (ESI) m/z: Calcd. Compound 16 l_((4-(5-Butoxybenzofuran-2-yl)phenyl)methyl)piperidine _4-carboxylic acid

4-(5·Butoxybenzofuran-2-yl)benzaldehyde (5 〇mg, 〇·2〇mmol), piperidine-4_carboxylic acid (41 mg, 0.31 mmol) and acetic acid (0.50 mmol) The mixture in MeOH-DCM (3:1; 2 mL) was stirred at room temperature for one hour. Sodium triethoxyhydride borohydride (135 mg, 〇·64 mm 〇l) was added and the reaction mixture was stirred for 16 hours. The solvent was concentrated under reduced pressure to give a yellow solid s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s product

[hSIPl EC5〇=170 bump]: 咕NMR (400 MHz, CD3OD) δ 7·98 (d, 1Η), 7·97 (d, 1Η), 7·58 (d, 2Η), 7·40 (d,1Η), 7.24 (s,1H),7·11 (d,1H), 6.90 (dd,1H), 4.35 (s,2H),4·00 (dd, 2H),3.55 (m,2H) ), 3.3 (m, 1H), 3·10 (m, 2H), 2.2 (m, 2H), 1.8 (m, 2H), 1.52 (m, 2H), 1.28 (m, 2H), 1.00 (dd, 3H). MS (ESI) m/z: Calculated: 4: 7.21. Observed: 4 〇7·9 〇 (M++1). Compound 17 1-((6-(5-cyclohexylbenzofuran-2-yl)-pyridin-3-yl)methyl)azetidinecarboxylic acid

The title compound RS1P1 EC5G = 720 nM, 302 nM]: purity by LCMS &gt; was prepared in the same manners as the compound of Example 6 except for the use of 6-bromo-3-pyridylfurfural in Step-3 (Scheme 2). 95%, ESI-MS: 391.1 (M+H)+, 4 NMR (400 MHz, CD3OD) δ 8·81 (d, 1H), 7·94 (d, 1H), 7·65 (d, 1H) , 7.59 (s, 1H), 7.50 (m, 2H), 7.35 (m, 1H), 4.44 (s, 2H), 4.45 (s, 2H), 4.34 (dd, 4H), 3.69 (m, 1H), 2.64-2.57(d,1H), 1.89 (t,4H), 1.58-1.41 (m,4H),1·38-1·26 (m,2H) 〇Compound 18 l-(4_(5-(6- Methylpyridin-2-yl)benzofuran-2-yl)benzyl)azetidine-3- 119664.doc -103- 200813031 Citrate (Scheme 2)

The title compound [hSIP1 EC5 〇 = 2900 nM] was prepared in the same manners as the compound of Example 6 except for using (6-purinylpyridine-2-yl)zinc(II) br. Purity by LCMS &gt; 95%, ESI-MS: 391.1 (M+H)+, 4 NMR (400 MHz, CD3OD) δ 8.42 (t, 1H), 8.22 (d, 1 Η), 8.07-8.10 (m , 3Η), 7.77-7.88 (m, 3Η), 7.62 (d, 2Η), 7.50 (dd, 1H), 4.48 (s, 2H), 4.36 (d, 4H), 3.71 (m, 1H), 2.85 (s, 3H) hydrazine compound 19 l_(4-(5-phenoxybenzofuran-2-yl)benzyl)azetidine-3-decanoic acid 1-(2,2-diethoxy- Ethoxy)_'phenoxy-benzene:

The title compound was prepared in the usual manner as described above, as in the compound of Example 1 (Step s in Scheme 1). 5-phenoxy-benzofuran:

The title compound (65% yield) was obtained in the general procedure as described above in the procedure of Example 1 (Step 2 in the scheme): 1H NMR (400 MHz 119664.doc -104 - 200813031 CDC13) δ 7.63 (d, 1H) ), 7.45 (d, 1H), 7.29 (m5 2H), 7.22 (d, 1H), 7.00-7.08 (m, 4H), 6.71 (m 1H). 5-phenoxybenzofuran-2-yl-acid··

The title compound (74% yield) was obtained in the general procedure as described above in the title compound (1). 4_(5-phenoxybenzofuran-2-yl)benzaldehyde:

The title compound (65% yield) was obtained in the general procedure as described above in Example 1 (Step 4 in the scheme): iH NMR (400 MHz, DMS 〇-d6) δ 1G.G5 (s, 1H) ), 8.13 (d, 2H), 8.G3 (d, 2H), 7·70 (d, old), 7.66 (br s, 1H), 7·39 (m, 4H), 7.10 (m, 2H) , 7.00 (dd' 1H). MS (ESI) m/z: Calculated: 314.10; observed: 3 ΐ5·1 〇 (M++l). l Phenoxybenzofuranyl)benzyl)azetidinecarboxylic acid:

The title compound (7% yield) [hSIP1 EC5 () = 510 nM, 92 nM]: 4 NMR (400 MHz, </ RTI> </ RTI> </ RTI> </ RTI> CD3OD) δ 7.90 (d, 2H), 7·55 (m, 3H) 5 7.32 (m, 2H), 7.27 (s, 1H), 7.22 (d, 1H), 7.03 (m, 4H), 4 47 ( • (s, 2H), 4.34 (m, 4H), 3.62 (m, 1H). MS (ESI) m/z: 119664.doc </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 399.20; observed: 399.90 (M++1). Compound 20 1-((4-(5-isoamylbenzofuran-2-yl)phenyl)methyl)azetidine_3_isoamylbenzoate

The title compound (75% yield) was obtained by the general procedure as described above in the procedure of Example Compound 6 (Step 1 in Scheme 2): lH NMR (4 〇〇mHz, CDC13; U 7.58 (d? J=2.0, 1H) )5 7.41-7.39 (m, 2II)5 7.11 (dd5 2.0, 1H), 6.70 (br s5 1H), 2.72-2.68 (m5 2H)5 1.62- L51 (m,3), 0.94 (d, J=66 , 6H). 5_Isoamylbenzofuran-2-yl-2-acid:

The title compound (53% yield) was obtained by the general procedure as described above in the procedure of the compound of Example 6 (Step 2 in Scheme 2): lH surface (passive, CDCI3) δ 7.43-7.38 (m, 2H), 7.30 ( s, 1H), 7.I8 (d, J=8.5, ^)^.72-2.68 (m? 2H)j l.6〇.li5〇3)?〇94 4-(S-isoamylbenzoquinone Furan_2_yl)benzaldehyde:

The title compound (79% yield) was obtained as mp mp </ </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 8.00 (d, J=8.5, 2H), 7.95 (d, J=8.5, 2H), 7.46-7.42 (m, 2H), 7.18-7.15 (m, 2H), 2.73-2.69 (m, 2H) , 1.62-1.54 (m, 3), 0.95 (d, J = 6.2, 6H). 1-((4-(5-Isoamylbenzofuran-2-yl)phenyl)methyl)azetidine_3-indole acid:

The title compound (63% yield) was obtained as mpqqqqqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ ·98 (d, J=8.3, 2Η), 7.55 (d, &gt;8.3, 2H), 7.43-7.41 (m, 2H), 7·23 (s, 1H), 7.15 (d, J=8.8, 1H ), 4.44 (s, 2H), 4.38-4.30 (m, 4H), 3.73-3.65 (m, 1H), 2.73-2.69 (m, 2H), 1.62-1.52 (m, 3), 0.96 (d, J =7.6, 6H). MS (ESI) m/z: Calcd.: 377. Compound 21 1-((4-(6-butoxybenzofuranyl)phenyl)methyl)azetidine_3_carboxylic acid 1-(2,2-diethoxyethoxybutoxybenzene) ·

The title compound (86% yield) was obtained by the general procedure of the procedure of the compound (1) (1) NMR (400 MHz, CDC13) δ 7.15 (t, J = 7.4), 6. 6.49 (m,3H),4.83 (t,J=5.1, 119664.doc -107- 200813031 1H), 3.99 (d, /=5.1, 2H), 3.93 (t, J=6.6, 2H), 3.80-3.72 (m, 2H), 3.67-3.60 (m, 2H), 1.79-1.72 (m, 2H), 1.53-1.43 (m, 2H), 1.25 (t, J=7.3, 6H), 〇·97 (t, J==7 3, 3H). 6-Butoxybenzifuran: The title compound (83% yield) was obtained by the general procedure as described in 1H NMR (4〇〇MHz, CDC13) δ 7.52 (d, J=2.2, 1H), 7·44 (d, J=8.5, 1H), 7·03 (d, J-2.2, 1H), 6.87 ( Dd, J=8.8, 2·5, 1H), 6.69-6.68 (m, 1H), 4.00 (t, J=6.6, 2H), 1.83-1.76 (m, 2H), 1.56-1.47 (m, 2H) , 0.99 (t, J = 7.4, 3H). 6-Butoxybenzofuran-2-yl-2-carboxalic acid: 1. Gu: as in the case of Example Compound 1 (Step 3 in Scheme 1) General procedure for the preparation of the title compound (76% yield): iH NMR (4 〇〇 MHz, CDC13) δ 7.52-7.42 (m, 2H), 7.00 (br s, 1H), 6.90-6.85 (m, IH), 4.00 (t, /=6.6, 2H), 1.82-1.78 (m, 2H), 1.56-1.48 (m, 2H), 0.98 (t, J = 7.3, 3H) 4-(6-butoxybenzoquinone bite_2_yl) benzoquinone:

The title compound (62% yield) was obtained by the procedure of mp </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1H), 7.94-7.89 (m, 4H), 7.45 (d, "7=8.5, 2H), 7_10 (s, 1H), 7·05 (br d, J=2.2, 1H), 6.89 (dd, J = 8.5, 2.2, 1H) 5 4.02 (t? J = 6.2), 1.85-1.78 (m5 2H) 5 1.57-1.52 (m, 2H), 1.00 (t, J = 7.3, 3H). 1-((4-(6-Butoxybenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylate:

COOH The title compound (46% yield) was obtained by the general procedure as described above in Example 1 (Step 5 in Scheme 1). [H.sub.1.sup.. d, "7=8.4, 2H), 7.53 (d, •/=8.4, 2H), 7.47 (d, /=8.5, 1H), 7.21 (s, 1H), 7.11 (br d, •/=2· 2,1H), 6.88 (dd, /=8.5, 2.2), 4.43 (s, 2H), 4.34 - 4.32 (m, 4H), 4.04 (t, J = 6.2), 3.71-3.63 (m, 1H), 1.81-1.76 (m, 2H), 1.57-1.52 (m, 2H), 1.01 (t, J = 7.3, 3H). MS (ESI) m/z: calcd. · 379 18; observed: 379·8 (M++1). Compound 22 1-((2-(5-butoxybenzofuran-2-yl)thiazol-5-yl)methyl)azetidine_3_carboxylic acid 2-(5-butoxy alum furan-2- Thiazole-5-formaldehyde: 119664.doc -109- 200813031

The title compound (29% yield) was obtained by the general procedure as described above: 4 NMR (400 MHz, CDC13) δ 1 〇·〇7 (s, m), 8.46 (dd, 1H) , 7.45 (dd, 2H), 7.03 (dd, 2H), 4·01 (dd, 2H), 174 (m, 2H), 1.54 (m, 2H), 1.01 (t, 3H). MS (ESI) m/z: Calcd.: 303. 1-((2-(5-Butoxybenzin) 2 唉 唉 )))))))))

The title compound (36% yield) was obtained by the general procedure as described above in Example 1 (Step 5 in Scheme 1) [hSIP1 EC5G=3200 nM, 1100 nM]: ιϋ NMR (400 MHz, CD3OD) δ 8.06 (br s, 1H)5 7.344 (m, 2H), 7.18 (m, 1H), 7.01 (ddd, 1H), 4.79 (s, 2H), 4.36 (m, 4H), 3.98 (m, 2H), 3.69 (m, 1H), 1.75 (m, 2H), 1·5〇 (m, 2H), l.oo (t, 3H). Ms (ESI) m/z ··calculated value: 386.13; observed value··386 9〇 (M++1). Compound 23 ((4-(5-Butoxybenzofuran-2-yl) 4-fluorophenyl)methyl)azetidine-3-carboxylic acid 4-(5-butoxybenzofuran-2_ Base) 4 • Fluorobenzaldehyde: 119664.doc -110- 200813031 I. The title compound (36% yield) was obtained as in the title compound (m. T5 J=7.75 IH), 7.73 (d? /=8.0, 1H)^ 7.66 (d5 /=11.2, 1H)5 7.44-7.39 (m5 2H)5 7.09 (d5 J-2.4,lH), 6.92 (dd, J = 2.4, 8.8, lH), 4.01 (t, J = 6.2), 1.81 - h76 (m, 2H), 1_57 - 1.51 (m, 2H), 1.01 (t, J = 7 2, 3H). 1 ((4-(5-Butoxybenzofuran-2-yl)4-fluorophenyl)methyl)azetidine_3_carboxylic acid:

The title compound (51% yield) was obtained by the general procedure as described above in Example 1 (Step 5 in Scheme 1) [hSIP1 EC5G=520 nM]: 4 NMR (400 MHz, CD3〇D) δ 8.08 ( t, "7=7.7,1H), 7.44-7.37 (m,3H), 7.25 (d, /=3.7, 1H), 7.14 (d, "7=2.2, 1H), 6.94 (dd, piece", 2.2 ), 4.35 (s5 2H), 4.18-4.15 (m, 4H), 4.01 (t, J = 6.2), 3·45-3·37 (m, 1H), 1.82-1.75 (m, 2H), 1· 57·1·49 (m, 2H), U0 (t, J=7.2, 3H). MS (ESI) m/z: Calcd. Compound 24 ((4-(5-butoxybenzoquinone-2-yl)-3-methoxyphenyl)butyrate-3-carboxylic acid 119664.doc -111 - 200813031 4-(5-butyl Oxybenzophenan-2-yl)-3-methoxybenzaldehyde:

The title compound (65% yield) was obtained by the general procedure as described above in the procedure of the compound i (Step 4 in Scheme i): lH NMR (4 〇〇 MHz, CD3C1) δ 10.03 (s? 1H), 8· 22 (d,1H), 7.59 (s,1H), 7.50 (s, 1H), 7·45 (d,1H), 7.41 (s,1H),7.08 (d,1H),6.93 (d,1H) , 4.16 (s? 3H)5 4.05 (t5 2H)? 1.84 (m5 2H)5 1.61 (m5 2H), 1.04 丄vi. (ESI) m/z · Calculated value: 324"4; observed value: 324.9 (M++1) 〇1-((4-(5-butoxybenzofuranylmethoxyphenyl)anthracene Butyl _3_carboxylic acid:

The title compound (36% yield) was obtained by the general procedure as described above in Example 1 (Step 5 in Scheme 1) [hSIP1 EC5 〇=420 η Μ, 700 ηΜ]: 咕NMR (400 MHz, CD3OD) δ 8·04 (d,1Η), 7.39 (s, 1H), 7.38 (s,1H), 7.21 (s,1H),7·15 (d,1H),7.08 (s,1H), 6.83 (d, 1H), 4.44 (s, 2H), 4.38 (m, 7H), 4.02 (m, 2H), 3.62 (m, 1H), 1.82 (m, 2H), 1.63 (m, 2H), 1.01 (t, 3H) ). MS (ESI) m/z: Calcd. Compound 25 119664.doc -112- 200813031 l-((5-(5-Butoxybenzoquinone-2-yl) thio-l-yl)methyl)azetidine-3-carboxylic acid 5-(5-butoxybenzene) Furfuran-2-yl)thiophene-2-formaldehyde

The title compound (32% yield) was prepared in the same manner as in the above-mentioned compound 1 (Step 4 in Scheme 1) as described above for the general formula.

Rate): H NMR (400 MHz, CDCIO “(1) δ 9·92 (s, 1H), 7.73 (d, =, m(cM, lH), 7.39 (d, 1H), 7 96 (m, 2H) ), 6 94 (dd, ), 3.98 (dd, 2H), uo (m, 2H), i % (called 2h), i heart, 3H) 〇H(5-(5-T oxybenzoquinone.鸣-24) 嗔 I I base) methyl ^ 丫 bite ^ formic acid:

OH The title compound (27% yield) was obtained in the general procedure as described above in Example 1 (Step 5 in Scheme 1) [hSIP1 EC50=1600 nM]: NMR (400 MHz, CD30D) δ 7·49 ( Br s,1H), 7.35 (m, 2H), 7.03 (d, 2H), 6.89 (dd, 1H), 4.67 (s, 2H), 4·35 (m, 4H), 3.98 (m, 2H), 3.67 (m, 1H), 1.73 (m, 2H), ι·51 (m, 2H), 0·99 (t, 3H). MS (ESI) m/z: Calcd.: 385.13; observed: 385.70 (M++1). Compound 26 H9664.doc -113 - 200813031 1-((6-(5-Butyl benzoquinone) 2) 曱 丫 丫 咬 咬 咬 4- 4-(5-butoxybenzene幷furanyl)pyridine-3-carbaldehyde:

The title compound (48%) was obtained eluted eluted elut elut elut elut elut elut elut elut elut elut eluting (s, 1H), 8.24 (d, 1H), 8.01 (d, 1H), 〇7·56 (s, out), 7·47 (d, 1H), 7.02 (s, 1H), 6.99 (d, 1H), 4.03 (q, 4H), 1.84-1.77 (m, 2H), 1.50-1.48 (m, 2H), 1 · 〇〇 (t, 3H). MS (ESI) m/z: Calcd.: 295. 1-((6-(5-Butoxybenzofuranyl)pyridine-3-yl)methyl)azetidine_3_ decanoic acid:

The title compound (68% yield) was prepared as described in step 5 (1) of the general procedure as previously described [hSIP1 EC5 〇=260〇nM, 201 nM] : ^ NMR (400 MHz, CDC13) δ 8·86 ( s,iH),8·19 (d,1H), 7.90 (d, 1H), 7.49 (s,1H), 7.47 (d,1H),7·23 (d,1H),6.86 (s,1H) , 3.80 (q, 2H), 4.52-4.40 (m, 4H), 3.80 (t, 2H), 3.52-3.47 (m, 1H), 1.68-1.66 (m, 2H), 1·44_1·37 (m, 2H), 0.94 (t,3H) 〇 MS (ESI) m/z: Calculated: 380.44; observed: 381.0 (M++1). 119664.doc -114- 200813031 Compound 27 1_(4-(5-Cyclohexylbenzofuranyl) 3-fluorophenyl)methyl)azetidinecarboxylic acid 5-cyclohexylbenzofuran (Step 1 in Scheme 2) :

Dissolve 5_indiprofen (5 〇〇mg, 2.5 5 mmol) in a microwave reaction tube &gt; odorized cyclohexyl hydrazine (〇·5 Μ, 15 mL, 7.40 mmol) in THF . will? #?泊113)2 (65 mg, 0.128 nimol, 0.05 eq.) was added to the solution. The mixture was purged with N2 gas for 3-5 minutes and at 1 Torr. Underarm Heating under microwave irradiation for 30 minutes. After completion of the reaction, the mixture was diluted with EtOAc EtOAc. The filtrate was dried over NaJO4 and concentrated. The residue was purified by EtOAc (EtOAc EtOAc) elute elut elut elut elut elut 1Η),7·41 (d,2Η),7·15 (d,1Η), 6.72 (d,1Η), 2.58 (m, 1H),1.92-1.74 (m,4H),1.51-1.35 (m, 4H), 1.31_1·25 (m, 2H). 5-cyclohexyl benzofuran-2-ylfolic acid (step 2 in Scheme 2):

Add /7-BuLi solution (3 60 pL, 〇·9 mmol, 2. 5 Μ in hexane) at -78 C dropwise to 5-cyclohexyl phenyl hydrazone (150 mg, 0.75) 119664.doc -115- 200813031 mmol) in a solution of anhydrous THF (5 mL). The resulting mixture was stirred at -78 °C for 40 minutes and treated with B(,Pr0)3 (26 〇, 1β13 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. TLC indicated the reaction was completed. The reaction was cooled in an ice-bath and quenched with &lt The combined organic extracts were washed with EtOAc EtOAc EtOAc m. Ipj NMR (400 MHz, CDC13) δ 7·46 (s, 1H), 7·43 (d, 1H), 7.32 (s, 1H), 7·25 (d, 1H), 2.62 (m, 1H), 1.93-1.85 (m, 4H), 1.78-1.75 (m, 4H), 1.34-1.22 (m, 2H). 4-(5-cyclohexyl basic 幷n-furan-2_yl) 2-fluorobenzidine (step number 3 in Scheme 2):

5-cyclohexyl benzofuran-2-yl-acid (75 mg, ο." mm〇1), 4_ / odor-2 - fluoro-formic acid (48 mg, 0.24 mmol), triethylamine (1.1 mL, 7 5 mmol) and a mixture of bis(triphenylphosphine)palladium(11) chloride (12 mg, 〇〇5 mm〇1) in ethanol (11 mL) in a microwave oven at i〇(rc irradiation 2 The reaction mixture is cooled and the solvent is removed. The residue is taken up in water and extracted with ethyl acetate. The organic layer is dried and concentrated in vacuo (as appropriate). Purification of the title compound (51 mg, 49% yield). A NMR (400 MHz, CDC13) δ 1 〇·〇4 (s, 1 Η), 8.00-7.97 (m, 2 Η), 7.46 (s, 1 Η) ),7·43 (d,2Η), 119664.doc -116- 200813031 7.32 (s,1H), 7.25 (d,1H), 2.62 (m,1Η),1·95·1·77(ιη,4H ), 1.58-1.56 (m, 4H), ΐ·46_1·44 (m, 2H). MS (ESI) m/z : Measured value: 322.27, observed: 323.2 (M++1). 1-( 4-(5-Cyclohexyl phenylfurfuryl) 3-fluorophenyl)methyl)azetidinecarboxylic acid (Step 4 in Scheme 2):

4(5-Cyclohexyl benzofuran-2-yl) 3-fluorobenzaldehyde (4〇, 〇12 mmol), acetic acid (10, 〇·ΐ 5 mmol) and π丁定 _3_ formic acid (15 mg A mixture of 0.15 mmol) in DCM / EtOAc (1, 2 mL) was stirred at room temperature for one hour. Sodium cyanoborohydride (3. 〇 mg, 〇. 〇 5 mmol) was added and the mixture was stirred at room temperature for 3 hours. After concentrating the solvent under reduced pressure, the obtained residue was dissolved in hot MeH and filtered. The mash and the white solid re-dissolved in hot DMSO were purified by reverse phase preparative HPLC (Phenomenex reverse phase Lima 5μ C18 (2) column, 60 x 21.2 mm ID) to obtain the desired final white powder. Product (12 mg, 42% yield) [hSIP1, EC5 〇 = 160 nM, 361 nM]: purity by LCMS &gt; 95%: lU NMR (400 MHz, CD3OD) δ 8.12 (d? 1H), 7.47. 7·38 (m, 4H), 7.28-7.20 (m, 2H), 4.66 (s, 2H), 4.34 (m, 4H), 3.72 (m, lH), 2.61 (m, lH), 1.95-1.82 ( m, 4H), 1.6 〇 · 1.56 (m, 4H), 1.42-1.40 (m, 2H). MS (ESI) m/z ······················ Compound 28 119664.doc -117- 200813031 l_((4-(5-(thiophen-2-yl)benzofuran-2-yl)phenyl)methyl)azetidine_3 formic acid 5-(thiophene-2 -based) benzofuran:

In addition to the use of thiophen-2-yl oxime, step 1), as described above, the general method 掣 1 slave Wan 沄 version of the title compound (55. / 〇 production

rate). H NMR (400 MHz, CD3C1) δ 7 r 1T, (s5 1H), 7.62 (s5 III), 7.55-7.03 (m, 511), 6·79 (d, 1H) 〇5-(single-2- Benzofuran-2-yl--acid:

2) General JH NMR (400 MHz, 7.66-7.34 (m, 4H), 7·08) as described above, mp.

CD3C1) δ 7.92 (s, 1H), 7.88 (s, 1H), (d, 1Η). 4-(5-(thiophen-2-yl)benzoquinone-2-yl)benzaldehyde: square

For example, the title compound (61% yield) CD3C1. δ 10.01 m), 8.19 (d, 1H), 1H), 7.62-7.24 (m, 7H), 7.16 Dd,1H) 3) Generally as described above: lH NMR (400 MHz? 8.01 (d, 1H), 7.82 (s, . MS (ESI) m/z: 119664.doc -118- 200813031 :304.06 ; observed: 304.9 (M++1). 1-((4_(5-(thienyl)benzofurazan-2-yl)phenyl)methylbutyridinyl formic acid:

The title compound (31% yield) was obtained by the general procedure as described above in Example Compound 6 (Step 4 in Scheme 2) [hSIP1 EC5G=1800 nM, 25000 nM]: lU NMR (400 MHz, DMSO-d6) δ 8.01 (d? 2H)5 7.87 (s, 1H), 7.64-7.44 (m, 7H), 7.19 (dd, 1H), 4.25 (m, 2H), 3.55 (m, 5H). MS (ESI) m/z: Calcd. Compound 29 3-(6-(5-benzylbenzofuran-2-yl)-3,dihydroisoquinoline-2(111)-yl)propan-2-(3-bromophenyl)ethylamine (Step 1 in Process 7):

A suspension of UA1H4 (3.04 g, 80 mmol) in dry THF (1 mL) was cooled to -5 °C. Concentrated HjO4 (3·9 g, 40 mmol) was added dropwise and the mixture was stirred at -5 °C for one hour. A solution of 3-bromo-phenylacetonitrile (9.80 g' 50 mmol) in Thf (5 mL) was added dropwise and the mixture was warmed to room temperature. The reaction was stirred at rt for 1 h and then cooled to 0 &lt;0&gt;C and quenched by 1:1 THF:H.sub.2 mixture (12·4 mL) 119664.doc - 119 - 200813031. Add Et20 (50 mL) followed by 3.6 M NaOH solution (24.4 mL). The mixture was filtered through celite and the solid was washed thoroughly with Et.sub.2. The org. <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> The crude compound was used in the next step: *1HNMR (400 MHz, CDCl3) 5 7.38-7.30 (m, 2H), 7.20-7.10 (m, 2H), 2.96 (t, 2H), 2.72 (t, 2H), 1.35 (br s, 2H). MS (ESI) m/z: Calcd. N-(3-Bromophenethyl)-2,2,2-trifluoroacetamide (Step 2 in Scheme 7): 3-Phenylethylamine (9.70 g, 48.5 mmol) and 2 The mixture of 6-lutidine (5·8 mL '50.0 mmol) in anhydrous cH2Cl2 (150 mL) was cooled to 0. Trifluoroacetic anhydride (5·6 mL, 40 mmol) was added dropwise; the reaction was then warmed to room temperature and stirred for 24 hours. Water (12 〇 mL) was added to the reaction, the phases were separated and the aqueous layer was extracted with Ch.sub.2 C.sub.2 (2×100^mL). The combined organic phases were washed with EtOAc EtOAc (EtOAc (EtOAc) . This crude compound was used in the subsequent step. 4 NMR (400 MHz, CDC1J δ 7/0(4) J=8.0 Ηζ, 1Η), 7·36 (s, 1Η), 7·21 (t, J=7.6 Ηζ, 1Η), 7.12 (t, J=7.6 Hz5 1H)5 6.31 (br s5 1H), 3.59 (q? J=6.8 Hz5 2H), 2.87 (t, /=7.2 Hz, 2H) 〇 1-(6-bromo-3,4-dihydroisoquinoline _ 2(1Η)-yl)_2,2,2-trifluoroethanone and i(8_ 119664.doc -120- 200813031 溪-3,4-monohydroisoindole _2(111)_yl)-2, 2,2-tris-ethyl ketone (Step 3 in Scheme 7):

Add a mixture of glacial acetic acid (68 mL) and concentrated sulfuric acid (45 mL) to N-(3-phenylethyl)-2,2,2-trifluoroacetamide (12.3 g, 41.54 mmol) In a mixture of aldehydes (2.0 g). The reaction was stirred at room temperature for 24 hours and then poured into 300 mL cold water. The aqueous solution was extracted with EtOAc (3×150 mL). The combined organic phases were washed with saturated NaHC03 (200 mL) and water (2×200 mL). The organic phase was then dried over Na.sub.2.sub.4, filtered and concentrated in vacuo. The residue was purified with EtOAc EtOAc EtOAc EtOAc 4 NMR (400 MHz, CDC13) δ 7.46 (dd, J=2.0 Hz, /=8.0 Hz, 0.33H), 7.38-7-31 (m,1·33Η), 7·15_7·09 (m,0.67H) ), 7.05-6.98 (m, 0.67H), 4.75, 4.73, 4.69 (3 xs, 2H), 3.90-3.80 (m, 2H), 3.00-2.90 (m, 2H). MS (ESI) m/z: calcd.: 306.98; observed: 308/310 (M++1) 〇6-(5_benzyl 幷 幷 -2- 基 -2-) _ tetrahydroisoindole (step 4 in Process 7):

Add a solution of 5-benzylbenzofuran-2-ylphenic acid (252 mg, 1·〇 mmol) in ethanol 119664.doc -121 - 200813031 (3 mL) to 丨-^·演_ 3,4_Dihydroisoquinoline_2(m)-yl)_ 2,2,2-Trifluoroethyl and H8-invigo...3,4-dihydroisoquinoline_2(1拗_yl) a mixture of _2,2,2_ trifluoroethanone (308 mg '1.0 mmol), pd (pph3) 4, toluene and 2 m NhCO3 (3.5 mL). The resulting mixture was heated under reflux. The reaction was concentrated in vacuo and the residue was diluted with water. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine &apos; dried over Na 2 SO 4 to dryness and concentrated in EtOAc. The residue was purified by EtOAc EtOAc EtOAc (EtOAc: EtOAc (EtOAc) (dd, 1H), 7.37 (s, 1H), 7.25 (m, 5H), 7.10 (dd,

2H), 6.90 (s, 1H), 4.10 (s, 2H), 3.40 (Ss 2H), 3.18 (m, 2H)S 2.94 (m, 2H). MS (ESI) m/z: calcd.: 339, s, s,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Isophthalene-2 (lH)-based) tert-butyl propionate (Step 5 in Scheme 6):

M5-nodal benzoquinone-2-yl)tetrazoisoindole (nine), 0.2 mm 〇l) was dissolved in methanol (2 mL). Add mEA (〇35 and acrylic acid butyl vinegar (51 mg, 〇.4mm ♦ The mixture was heated to 9 using microwave irradiation for 30 minutes. Evaporate all solvents and 3_(6_(5_) phenyl benzofuran- The crude product of 2-yl)-3,4-diisoiso(tetra)-2-propionic acid terpene vinegar was used in the next step without further purification.ms (esi) m/z : 119664.doc -122- 200813031 calcd.: 467.25; observed: 468.30 (M++1). 3-(6-(5-benzylphenylfuran-2-yl) 3,4-dihydroisoquinoline-2 (111) Propionate (step 6 in Scheme 7):

Add TFA (1 mL) to 3-(6-(5-benzylbenzofuran-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propionic acid tert-butyl ester ( 40 mg, 0.086 mmoles in a solution of CH2Cl2 (1 mL). The mixture was stirred at room temperature for 3 hours. Evaporate all solvents. The mixture was purified by reverse phase preparative HPLC to give the title compound (14 mg, 40%). iH NMR (400 MHz, CD3OD) δ 7·77 (m, 2H), 7·42 (dd, 1H), 7·40 (s, 1H), 7.20-7.30 (m, 5H), 7.10 (m, 3H) ), 4·50 (s, 2H), 4.04 (s, 2H), 3.64 (dd, 2H), 3·55 (dd, 2H), 3·26 (dd, 2H), 2.90 (dd, 2H). MS (ESI) m/z: Calcd.: 4121. Compound 30 1 (4-(5-cyclopentylbenzofuranyl)benzyl)azetidine_3_carboxylic acid 5_cyclopentylphenylhydrazone α:

The title compound (67. / oxime yield) was prepared by the general H NMR (400 MHz, as described in Example Compound 6 (Step 1 in Scheme 2) as described above: 4 119664.doc -123- 200813031

(m, 6H). Between, 7.45 (br d, J = 1.8, 1H), 7.41 ^ 8.8, 1.8, 1H), 6.71 (dd, J = ll, !H) 5 2.14-2.07 (m5 2H) 5 1.88-1.58 5 · cyclopentane Awkward and sour:

The title compound (yield) was prepared as described in Example 6 (Step 2 in Scheme 2) as described above: (4U 〇 MHz, CDC13) δ , 1H), 7.31 (s, 1H), 3 · 12_ 1.80-1.60 (m, 6H). 7.50-7.45 (m,2H),7.43-7.39 (m,1) 3.05 (m5 1H)5 2.14-2.06 (m5 2H)51.8i 4-(5-cyclopentylbenzofuranyl)benzaldehyde:

The title compound (95% yield) was prepared in the general procedure as described above for the compound of Example 6 (Step 3 in Scheme 2). iH NMR (4 〇〇 MHz, CDC13) δ 10.03 (s, 1H), 8 ·00 (d, J=8.0, 2H), 7.94 (d, J=8.0, 2H), 7.51-7.44 (m5 3H), 7.15 (s, 1H), 3·14-3·06 (m, 1H) , 2.20-2.10 (m, 2H), 1.88-1.62 (m, 6H). 1-(4-(5-Cyclopentylbenzopyran-2-yl)benzyl)butyrate (Step 4 in Scheme 2): 119664.doc -124- 200813031

The title compound (71% yield) [hsipi <RTI ID=0.0># </ RTI> </ RTI> <RTIgt; 4 NMR (400 MHz, CD3OD) δ 8.02 (d, 2H), 7.57 (d, 2H), 7.49 (s, 1H), 7.44 (d, 1H), 7.25 (d, 2H), 4.56 (s, 2H) , 4.30 (m, 4H), 3.62 (m, 1H), 3.11 (m, 1H), 2.25-2.12 (m, 2H), 1.90-1.66 (m, 6H). MS (ESI) m/z: Calculated: 376. 46; observed: 375.9 (M++1). Compound 31 1-(3-Fluoro-4-(5-(piperidin-1-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid phenylfurfuryl)piperidine (Scheme 3 Step 1):

5_Bromo, benzopyran (2 g, 10 mmol), brigade (1.2 mL, 12 mmol), Pd (dppf) Cl2 (245 mg, 0.3 mmol), dppf (250 mg, 〇·45 mmol) Sodium tert-butoxide (1.44 g, 15 mmol) was mixed in toluene (10 mL). The mixture was purged with N 2 gas for 3-5 minutes and heated at 120 ° C for 30 minutes under microwave irradiation (Personal Chemistry EmrysTM Optimizer). After completion of the reaction, the reaction mixture was directly loaded onto a silica gel column and purified on ISCO system (&lt;2% EtOAc in hexane) to obtain 0.539 g of the desired product (27% yield): ESI-MS: 202.3 (M+H)+, h 119664.doc -125- 200813031 NMR (400 MHz, CDC13) δ 7.58 (s,1H)5 7.40 (d,1H),7.15 (s,1H), 7.00 (d,1H) , 6·65 (s, 1H), 3.10 (m, 4H), 17〇 (m, 4H), 1.48 (m, 2H). Note: The title compound appears to be extremely volatile. The solvent should be evaporated with great care. 5-(piperidin-1-yl)benzofuran-2-ylfolic acid (step 2 in Scheme 3):

/?-BuLi solution (334 kL, 0.83 mmol, 2.5 Μ in hexane) was added dropwise to 1-(benzofuran-5-yl)piperidine (14 在) at -78 °C. Mg, 0.70 mmol) in dry THF (5 mL). The resulting mixture was stirred at -78 &lt;0&gt;C for 4 min and treated with B (zPrO)3 (241 pL, 1.04 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. TLC indicates completion of the reaction. The reaction was cooled in an ice-bath and quenched with &lt;RTI ID=0.0&gt;&gt; The separated aqueous layer was neutralized to a pH of about 5. The solution became cloudy. It was extracted three times with acetic acid. The combined organic extracts were concentrated in vacuo to afford EtOAc EtOAc (EtOAc: EtOAc: ESI-MS: 246.3 (M+H)+. 3-fluoro-4-(5-(piperidin-1-yl)benzofuranyl)benzaldehyde (step of Scheme 3 Q. Ο

\ CHO 119664.doc •126- 200813031 5-(Piperidine-;ι-yl)benzofuran-2-yl-based sun-acid (5〇mg, 0.204 mmol), 4-bromo-3-fluorobenzaldehyde (37 a mixture of mg, 0.184 mmol), triethylamine (〇·5ό mL, 4·1 mmol) and gasified bis(triphenylphosphine)palladium (Π) (14 mg, 〇·〇 2 mmol) in ethanol mL) In the microwave instrument at 1 〇〇. The armpit is irradiated for 20 minutes. The reaction mixture was cooled and the solvent was removed. The residue was purified by EtOAc EtOAc EtOAc (EtOAc): 10.00 (s,1H), 8.19 (t,1H),7·75 (d,1H),7·67 (d, 1H), 7.43 (d,1H),7·35 (d,1H),7.14- 7.11 (m, 2H), 3.13 (m, 4H), 1.77 (m, 4H), 1.59 (m, 2H). 1·(3-Fluoro-4-(5-(piperidin-1-yl)benzofuran-2-yl)benzyl)azetidine•carboxylic acid trifluoroacetate (Step 4 of Scheme 3):

3-Fluoro-4-(5-(piperidin-1-yl)benzofuran-2-yl)benzaldehyde (9 mg, 0.028 mmol), acetic acid (2.5 μΐ^, 0.042 mm〇l) and butyl A mixture of pyridine·3_ decanoic acid (4.2 mg, 0.042 mmol) in DCM /MeOH (2:1 Sodium cyanoborohydride (1·〇 mg, 0.014 mmol) was added and the reaction mixture was stirred at room temperature for 3 hr. After concentrating the solvent under reduced pressure, the obtained residue was dissolved in DMS and purified by reverse phase preparative HPLC (Phenomenex reverse phase Luna 5μ C18(2) column, 6〇χ21·2 mm ID, mobile phase: A =〇〇5% τρΑ in water; 119664.doc •127- 200813031 B = 0.05% TFA in acetonitrile at a flow rate of 12 ml/min, gradient time of 2% B to 52% over 25 minutes B) Purification The desired final product (1 〇 3 mg, 7 〇〇 / 〇 yield) was obtained as a white powder (di(trifluoroacetic acid) salt) [hsipi EC50 = 860 nM, 307 nM]: purity by LCMS &gt 95%, ew-MS: 409.1 (M+H)+ , 咕NMR (400 MHz, CD3〇D) δ 8·17 (t, 1Η), 8.02 (d, 1Η), 7·81 (d, 1Η) ), 7·66 (dd, 1Η), 7.49-7.47 (m, 3H), 4.50 (s, 2H), 4·39 (dd, 4H), 3.72-3.70 (m, 5H), 2.08 (m, 4H) ), 1.84 (m, 2H). Compound 32 1((6-(5-benzylbenzofuran-2-yl)pyridin-3-yl)methyl)azetidine_3_carboxylic acid 6-(5-p-phenylbenzofuran-2-yl) Nicotinic aldehyde:

The title compound (53% yield) was obtained by the general procedure as described above: 4 NMR (400 MHz, DMS0j6). δ 10·13 (s, 1H), 9 15 (s, 1H), 8.36 (d, 1H), 8·14 (m, 1H), 7.76 (d, 1H), 7·62 (m, 2H), 7.29 (m, 6H), 4. 〇 7 (s, 2H). Ms (ESI) m/z: Calculated: 313·11; observed: 314.20 (M++1). 1-((6·(5-benzylbenzofuran-2-yl)acridine_3_yl)methyl)azetidine_3•carboxylic acid: 119664.doc 200813031

COOH

The title compound (33% yield) was obtained in the general procedure as described above in Example 1 (Step 5 in Scheme 1) [hslPl EC5G=2600 nM, 516 nM]: 4 NMR (400 MHz, CD30D) δ 8.68 (s,1H), 8·01 (br s3 2H), 7.45 (m, 3H)? 7.16 (m5 6H), 4.50 (s5 2H)5 4.35 (m,4H), 4.04 (s,2H), 3.70 ( m, 1H). MS (ESI) m/z: Calcd.: 398.16; observed: 399 〇〇 (M++1). Compound 33 benzyl benzofuran-2-yl)-3 methoxyphenyl)methyl) π 丫 butyl pyridine 3-carboxylic acid 4 _ (5-benzyl benzofuranyl) _ 3 methoxy benzaldehyde :

MeO

The title compound (6 〇 % yield) was prepared as described above for the compound 丨 (Step 4 in Scheme 1) in the general manner as described above: lfi NMR (400 MHz, 4 guang 3) δ 1 〇.03 (s, 1Η), 8.22 (d, 1H), 7.64-7.44 (m, 11H), (m, 5H). MS (ESI) m/z: Calcd.: 342. 1 ((4'd benzoquinone bite-2·ylmethoxyphenyl)methyl) oxime 唆-3_carboxylic acid: 119664.doc 129- 200813031

COOH

The title compound (50% yield) was obtained by the general procedure as described above in Example 1 (Step 5 in Scheme 1) [hSlPl EC5G=1000 nM, 1900 cans, 196 nM]: towel NMR (400 MHz, DMSO) -d6) δ 7.98 (d,1H),7·42_7.07 (m,11H), 4.18 (m,2H),3·82 (m,5H), 3·57 (m,1H), 3.14 (m , 4H). MS (ESI) m/z: Calcd.: 427. Compound 34 l_(4-(5-(piperidin-i-yl)benzofuran-2-yl)benzyl)azetidine_3_carboxylic acid 4-(5-(Bistidine-:)ylbenzofuran Benzoaldehyde (Step 3 of Process 3):

CHO

Q 5-(piperidin-1-yl)benzofuranyl-acid (9〇^, 0.367 mmol), 4, bromobenzaldehyde (62 mg, 0.330 mmol), triethylamine (1·〇mL ' A mixture of 7.3 mmol and bis(triphenylphosphine)palladium(n) (12_8 mg, 0.02 mmol) in ethanol (9 mL) was irradiated in a microwave oven for 20 min. The reaction mixture was cooled and the solvent was removed. The residue was purified by EtOAc EtOAc (EtOAc) ESI-MS: 306.4 (M+H)+, 4 NMR (400 MHz, CDC13) δ 10.02 (s, 1H), 7.95 (dd, 4H), 7.42 (d, 1H), 7·11 (m, 2H) , 7.07 (dd, 1H), 3.13 (t, 4H), 1.78-1.74 (m, 4H), 1.62-1.56 (m, 2H). 119664.doc •130- 200813031 1-(4-(5-(piperidin-1-yl)benzofuran-2-yl)benzyl)azetidine 3carboxylic acid (Step 4 of Process 3) ··

4-(5-(piperidin-1-yl)benzofuran-2-yl)benzaldehyde (31 mg, 〇.1〇2 mmol), acetic acid (9 μ):, 0.15 mmol) and azetidine The mixture of formic acid (12 3 mg, 0.122 mmol) in DCM / MeOH (2:1, 1.5 mL) Sodium cyanoborohydride (3 s 2 mg, 〇 51 mmol) was added and the mixture was stirred at room temperature for 3 hr. After concentrating the solvent under reduced pressure, the obtained residue was dissolved in DMSO and purified by reverse phase preparative HPLC (Phenomenex reverse phase Luna 5μ C18(2) column, 60x21.2 mm ID 'moving phase: Α=0· 05% of TFA in water; Β = 0. 05% of TFA in acetonitrile) was purified to give the desired final product (29.1 mg, 7% yield) as a white powder (di(triacetic acid) salt) [hSIPl EC5〇=1500 ηΜ]: purity by LCMS &gt; 95%, ESI-MS: 391.1 (Μ+Η)+, 4 NMR (400 MHz, CD3OD) δ 8.05 (t, 3H), 7.79 (d , 1H), 7.65 - 7.62 (m, 3H), 7·47 (s, lH), 4.48 (m, 2H), 4.38_4.32 (m, 4H), 3.73_3.70 (m, 5H), 2.15 (m, 4H), 1.16 (m, 2H). Compound 35 6-(5-Benzylbenzofuran-2-ylcarboxyethyl)-3, argon diazoisoquinolinium 2,2,2-trifluoroacetic acid (Step 6 in Scheme 7): 119664. Doc -131- 200813031

The title compound was isolated by reverse phase preparative hplc during purification of compound 29. H NMR (4〇〇MHz, CD3〇D) δ 9.17 (s, 1H), 8.04 (m 2Η), 7.90 (d, 1Η), 7·50 (m, 3Η), 7·23 (m, 6Η), 4·28 (10) 2H), 4.16 (dd, 2H), 4.08 (s, 2H), 3.34 (m, 2H), 3.03 (m 2H). MS (ESI) m/z: Calculated: 41 〇 18; observed: 4l 〇 % (M+).

Compound 36 1-((4-(5-Benzylbenzofuran-2-ylphenyl)methyl)azetidinecarboxylic acid 4-(ethoxycarbonyl)-octane phenyl trifluoromethanesulfonate:

Trifluoroacetic anhydride (4.6 mL, 27.2 mmol) was added dropwise at -10 °C

To a solution of ethyl 3- oxy-4-hydroxybenzoate (5. 〇2 g, 25.0 mmol) and pyridine (2.2 mL, EtOAc. The reaction mixture was stirred at -10 °C for 1 hour, allowed to warm to room temperature and stirred for additional 2 hours. The reaction mixture was quenched with H20 and the resulting mixture was stirred for 15 min. The layers were separated and the organic layer was washed with 0.2 N EtOAc, water and brine. The final organic layer was dried (Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.) and concentrated under reduced pressure to afford 6.8 g of a white solid containing a mixture of trifluorosulfonate and residual phenol. The mixture was redissolved in DCM and passed through a plug to provide 3.8 g (45%) of 119664.doc-132-200813031 pure trifluoromethyl acid and 3 g of product doped with starting material f. 1h stupid (0 MHz, CDC13) δ 8.21 (d, J = 1, 8 H), 8 〇 3 (dd, J = 8 5, 7.43 (d, , = 8.5, 1H)} 4.42 (q, , = 7.3 , 2H), 1.41 (t, j=7.3 5 3H) 〇(benzyl benzofuran-2-yl)_3_ benzoquinone ethyl ester (step in Scheme 5)

The title compound (94% yield) was obtained according to the general procedure of the title compound 40 (Step 2 in Scheme 5): lH NMR (4 〇〇 MHz, CDCl3) δ 8.15-8.12 (m, 2H) ), 8.00 (br d, J = 8.4, 1H), 7.62 (s, 1H), 7.45-7.44 (m, 2H), 7.32-7.19 (m, 6H), 4.42 (q, &gt; 7.3, 2H 54. 〇9 (s52H)5 1.42 (t, ^7.3, 3H) 〇(4 (5-benzylbenzofuranyl 3-ethylphenyl)methanol (Step 3 in Scheme 5): Example compound 40 (Step 3 of Scheme 5) The title compound was obtained as a general procedure as described above (1 1:1 mixture of &lt;RTI ID=0.0&gt; Phenylfurfuryl-2-yl)_3_gasbenzaldehyde (Step 4 in Scheme 5):

The title compound (63% for two steps) was prepared in the general procedure as described above for Example Compound 40 (Step 4 of Scheme 5): 4 NMR (4〇0 119664.doc - 133 - 200813031 MHz, CDC13) δ 10.00 (s,1H),8·24 (d,/=8.4,1H), 7.99 (d5 J=1.4,1H), 7.86 (dd,/=8·0,1.5), 7.69 (s,1H),7.47 -7.45 (m, 2H), 7.32-7.19 (m, 6H), 4.10 (s, 2H). 1-(4-(5-Benzylbenzofuran-2-yl)-3-ylbenzyl)azetidine-3-carboxylic acid (Step 5 in Scheme 5):

The title compound (42% yield) was obtained as mpqqqqqqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ d, J = 7.8, 1H), 7.76-7.72 (m, 1H), 7.59-7.54 (m, 4H), 7.27-7.16 (m, 6H), 4.46-4.36 (m, 2H), 4.32-4.16 (m , 4H), 4.03 (s, 2H), 3.64-3.58 (m, 1H). MS (ESI) m/z: calc.: 431.13; observed: 431.9 (M++1) 〇 Compound 37 3-(6-(5-cyclopentylphenylpyrene-2-one)_3,4- Dihydroisoindolene_2(1H)-yl) propionic acid 3_(6.hydroxy-3,4.dihydroisoquinolin-2(1H)-yl)propionic acid tert-butyl ester (step in Scheme 8) 1):

1,2,3,4-tetrahydroisoquinol-6 alkanol hydrochloride (345 mg, 1.5 119664.doc -134-200813031 mmol), tert-butyl acrylate (〇·44 mL, 3.0 mmol) And a solution of N-ethyl-oxime-isopropylpropan-2-amine (2.6 mL, 15.0 mmol) in MeOH was irradiated in a microwave at 1800 C for 1800 s. The solvent was removed to give a residue which was purified on an ISCO column (2% to 5% MeOH/EtOAc)

The title compound (332 mg, 80%). 4 NMR (400 MHz, CD3〇D) δ 6.85 (d,1Η),6·55 (dd,1Η),6·54 (s,1Η),3·55 (s,2Η),2.83 (m,4H) ), 2.76 (m, 2H), 2.54 (dd, 2H), 1.45 (s5 9H). MS (ESI) m/z: Calcd.: 277. 3-(6-(Difluoroindolyloxy)oxy-3,4-dihydroisoquinolin-2(ih)-yl)tributyl acrylate (Step 2 in Scheme 8):

Trifluoro acid anhydride (87 pL, 0.52 mmol) was added to 3_(6-ylamino-3,4-dihydroisoquinolin-2(1H).yl)propionic acid tert-butyl ester (m mg) at 0C , 0.4 mmol) in a solution of ton bite (5 mL). The reaction mixture was stirred with EtOAc EtOAc EtOAc. 4 NMR (400 MHz, CD3OD) δ 7·20 (d, 1H), 7.12 (s, 1H), 7.10 (s, 1H), 3.68 (s, 2Η), 2.94 (dd, 2Η), 2·83 ( Dd, 2Η), 2.78 (dd, 2Η), 2·54 (dd, 2H), 1·44 (s, 9H). MS (ESI) m/z: calc.: 409.12; observed: 409.80 (M++1) 〇3_(Μ5_cyclopentylbenzofurfuryl)-3,4-dihydroisoquinolin-2 1Η)·Base) Tert-butyl propionate (Step 3 in Scheme 8): 119664.doc -135- 200813031

5-cyclopentylbenzopyran-2-yl-acid (78 mg, 0.34 mmol), 3-(6-(trifluoromethylsulfonyloxy)-3,4-dihydroisoquinoline- 2(1H)-yl)tert-butyl propionate (93 mg, 0.23 mmol), triethylamine (〇·95 mL, 6.8

A mixture of mmol) and bis(triphenylphosphine)palladium (ruthenium) chloride (16 mg, 0_〇2 mmol) in ethanol (5 mL) was irradiated in a microwave oven at 10 ° C for 20 min. The reaction mixture was cooled and the solvent was removed. The residual oxime was purified by EtOAc EtOAc (EtOAc) 1H NMR (400 MHz, CDC13) δ 7.59 (m, 2H), 7.40 (d, 2H), 7·15 (dd, 1H), 7.07 (d, 1H), 6.91 (s, 1H), 3.70 (s, 2H), 3.08 (m, 1H), 2.96 (dd, 2H), 2.85 (dd, 2H), 2·78 (dd, 2H), 2.54 (dd, 2H), 2.11 (m, 2H), 1.84 (m , 2H), 1.68 (m, 4H), 1.46 (s, 9H). MS (ESI) m/z: Calcd: 437. 3-(6-(5-Cyclopentylbenzofuran-2-yl)-3,4-diarisoisoquinoline_2(1H)-yl)propionic acid (Step 4 in Scheme 8):

Add TFA (0.5 mL) to 3-(6-(5-cyclopentylbenzofuran-2-yl)-3,4-dihydroisoquinolin-2(111)-yl)propanoic acid tributyl The ester (25 11^, 0.05 6 119 664. doc - 136 - 200813031 mole) was stirred in a solution of CH 2 C 12 (0.5 mL). The mixture was stirred at room temperature for 3 hours. The solvent and excess TFA were removed under reduced pressure to give a yellow oil which was washed with CH2C12 / hexane (1:4) and then rinsed with diethyl ether. The solvent was removed under vacuum to give the title compound (19 mg, 90%). 4 NMR (400 MHz, CD3OD) δ 7.82 (m, 2H), 7.47 (s, 1H), 7.40 (d, 1H), 7.30 (d, 1H), 7.20 (d, 1H), 7.19 (s, 1H) , 4.54 (br, 2H), 3.69 (br, 2H), 3.60 (dd, 2H), 3.28 (m, 2H), 3·10 (m, 1H), 2.96 (dd, 2H), 2.10 (m, 2H) ), 1.85 (m, 2H), 1.74 (m, 2H), 1.65 (m, 2H). MS (ESI) m/z: Calcd. Compound 38 1-(4-(5-(cyclopentylmethoxy)benzofuran-2-yl)_3-fluorobenzyl)azinium 3-carboxylic acid 5-hydroxybenzofuran (Step 4 of Scheme 4:

The dibrominated side (3.4 mL, 3.3 7 mmol, 1 Torr in DCM) was added to 5-methylbenzofuran (〇·5 g, 3.37 mmol) in DCM (7 mL). Ice-cooled solution. The light brown solution was stirred at 〇 ° C for 1 hour, followed by the addition of another equivalent of boron tribromide (3.4 mL). The mixture was stirred at room temperature for 2 hours. TLC analysis indicated completion of the reaction. The mixture was poured into ice and the pH was adjusted to 7 with NazCO3. The aqueous solution was extracted twice with DCM. The combined organic layers were washed with brine, dried over NajEtOAc and concentrated. Yield 119664.doc -137-200813031 Light brown solid with satisfactory purity without further purification - next step: 0.36 g (79.6% yield), 4 NMR (400 MHz, CD3OD) δ 7.59 (d , /=2·〇Hz,1H),7.35(d,J=9.2 Hz,1H), 7.01(d,J=2.4 Hz,1H),6.82 (dd,/=8.8 Hz, J=2.8 Hz, 1H ), 6·67 (m, 1H), 4.73 (s, 1H). 5-(cyclopentylmethoxy)benzofuran (Step 2 of Scheme 4)

DEAD (362 mg, 2.09 mmol) was slowly added to 5-hydroxybenzoquinone (200 mg, 1.49 mmol), triphenylphosphine (547 mg, 2.09 mmol) and cyclopentyl-methanol (203 11^, 2.02 111111) 〇 1) In a solution of 3 1111^丁11卩. The mixture was stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by EtOAc EtOAc EtOAc. The title compound (0.208 g, 65% yield) was obtained as a white solid: &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&& =8.4 Hz, 1H)? 7.06 (s5 1H)5 6.91 (d, J=9.2 Hz? 1H), 6.69 (m, 1H), 3.82 (d, 2H), 2.39 (m, 1H), 1.85 (m, 2H), 1.63 (m, 4H), 1.39 (m, 2H). 5-(cyclopentylmethoxy)benzofuran-2-ylfolic acid (Step 3 of Scheme i)

&lt;X&gt; The title compound (94.7% yield) was obtained by the general procedure C as described above as Example Compound 1 (Step 3 in Scheme 1): 4 NMR (400 MHz, 119664.doc -138 - 200813031 CD3OD δ 7·39 (d, J=9.2 Hz, 1H), 7.30 (S, 1H), 7.07 (d, 1H), 6.99 (dd, /=9.2 Hz, "7=2.4 Hz, 1H), 3.82 ( d, J = 7.0 Hz, 2H), 2.39 (m, 1H), 1.86 (m, 2H), 1.63 (m, 4H), 1.39 (m, 2H). 4-(5-(cyclopentylmethoxy)benzofuran-2-yl)-3-fluorobenzaldehyde (Step 4 of Scheme 1)

The title compound (53% yield) was obtained by EtOAc EtOAc: EtOAc: CD3〇D) δ 10.0 (s,1H), 8.20 (t,1Η),7·30 (s,1Η),7·77 (d,1Η), 7.68 (d,1Η),7·43 (d, 1H), 7.36 (d, 1H), 7.09 (s, 1H), 6.99 (dd, 1H), 3.88 (d, /=7.0 Hz, 2H), 2.39 (m, 1H), 1.86 (m, 2H), 1.63 (m, 4H), 1.39 (m, 2H) 〇 1-(4-(5-(cyclopentylmethoxy)benzofuran-2-yl)-3-fluorobenzyl)azetidine-3 - Formic acid (Step 5 of Process 1)

The title compound (79% yield) was obtained by the general procedure E as described above as the compound of Example 1 (Step 5 in Scheme 1) [hSIP1 EC5 〇 = 803 119664.doc - 139 - 200813031 nM] : ESI_MS: 423 · 9 (M+H)+, 4 NMR (400 MHz, CD3OD) δ 8.11 (t, 1H), 7.45-7.40 (m, 3H), 7.28 (d, 1H), 7.15 (d, 1H), 6.95 ( Dd,1H), 4.46 (s,2H),4·36·4·34(γπ5 4H), 3.88 (d, J=7.4 Hz, 2H), 3.68 (m, 1H), 2.38 (m, 1H), 1.85 (m, 2H), 1.65 (m, 4H), 1.43 (m, 2H). Compound 39 1-(4-(5-(cyclopentylmethoxy)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid 4-(5-(cyclopentyloxy)benzene幷furan-2-yl)benzaldehyde (Step 4 of Scheme 1)

The title compound (33% yield) was prepared by the general procedure D as described above. ESI-MS: 321.2 (M+H) + ln NMR (400 MHz, CD3OD) δ 10.0 (s, 1Η)? 7.98 (dd, 4Η), 7·43 (d, 1Η), 7.14 (s, 1Η), 7.07 (d, 1Η), 6.96 (dd, 1H) , 3.88 (d, J = 7.0 Hz, 2H), 2.41 (m, 1H), 1.86 (m, 2H), 1·63 (m, 4H), 1.39 (m, 2H). 1-(4-(5-(cyclopentyl decyloxy)benzofuran-2-yl))) 丫 冬 冬 冬 ( (Step 5 of Scheme 1)

119664.doc • 140- 200813031 The title complex (π% yield) was prepared by the general procedure E as described above, as in Example Compound 1 (Step 5 in Scheme 1): ESI-MS: 4〇5· 9 (M+H)+, ijj NMR (400 MHz, CD3OD) δ 7.97 (d, 2H), 7.55 (d, 2H), 7.40 (d5 1H), 7·23 (s, 1H), 7.11 (d, 1H), 6.95(dd, !H)5 4.44 (Sj 2H)5 4.35-4.33 (m5 4H)5 3.88 (d5 J=7.0 Hz? 2H), 3.69 (m, 1H), 2·38 (m, ih ), 1.87 (m, 2H), 1.65 (m, 4H), 1.43 (m, 2H). Compound 40-Benzyl benzofuran-2-yl)-3-cyanophenyl)methylazetidine-3-carboxylic acid: 4-(ethoxycarbonyl)-2-cyanophenyl sulfonate :

TfO

COOEt The title compound (92% yield) was obtained by the general procedure as described above: NMR (400 MHz, CDC13) δ 8.61 (s, 1H), 8·40 (d, 1 Η), 7 · 96 (d, 1Η), 4.23 (q, 2Η), 1.21 (t, 3Η). (5-V-benzoquinone n-propan-2-yl)-3-cyanobenzoic acid ethyl ester (step 4, process 1):

COOEt NC The title compound (26% yield) was obtained in the general procedure as described above as the compound i (Step 4, Scheme 1): lfI NMR (4 〇〇 MHz, CDC13) (s, !H), 8.31 ( d,1H), 8.19 (d,1H), 7.81 (s,1H), 7.42 119664.doc 200813031 (d,2H),7·32-7·17 (m5 6H),4.38 (q,2H),4 ·06 (s,2H),1·41 (t,3H) 〇2_ (5-benzylphenyridin-2-yl)-5-(methyl)benzonitrile (step 3, Scheme 5 ):

^~&lt;^-ch2〇H

NC 4-(5-Benzylbenzofuran-2-yl)-3-cyanobenzoic acid ethyl ester (〇.〇5 g, 〇· 13 mmol), shed sodium hydride (〇·〇ι g, 0 A solution of 26 mmol) and gasification (〇·〇1 5 g; 〇· 13 mmol) in ethanol (2.5 mL) was stirred at room temperature for 1 hour. Water was added and the aqueous layer was extracted with ethyl acetate (×2, 1 〇 mL). The organic layer was washed with water and brine and dried over sodium sulfate to yield 75% yield: 1 hnMr (400 MHz, CDC13) δ 8·06 (d, 1H), 7.79 (s, 1H), 7·64 (d, 1 Η ), 7.63 (s, 1Η), 7.43-7.21 (m, 8Η), 4.78 (s, 2Η), 4.06 (s, 3H) 〇' 2_(5_benzylbenzofuran-2-yl)methyl fluorenyl Benzoonitrile (step 4, process

2-(5-Benzylbenzofuranyl)_5-(hydroxymethyl)benzonitrile g, hydrazine (0.0016 mg, 0.004 g, 0.18 mmol) in acetonitrile suspension · 09 mm 〇 1), molecular sieve 4A (0.2 g) morpholinyl oxide (〇〇2)

The title compound (Step 4 can be filtered with the diatomaceous earth to obtain 93% yield, Scheme 5): NMR (400 MHz, CDC13) δ 119664.doc -142· 200813031 10.05 (S, 1H), 8.25 (s,1Η),8·24 (d, 1Η),8·14 (d,1Η),7·84 (s,1H), 7.45 (m,2h),7.38-7.18 (m,6H), 4.06 (s, 2H). 1-((4-(5)-based alkoxy-2-yl)_3-cyanophenyl)methyl)tJ azetidin I formic acid (Step 5, Scheme 1):

COOH

NC

The title compound (28% yield) was obtained in the general procedure as described above for the compound of Example 1 (Step 5, Scheme 1): 111]^11(40〇]^1^, 01^0-d6) δ 8.18 ( d,1H), 8.09 (s,1H), 7.82 (d,1H), 7.64 (s,1H), 7.61 (s,1H),7·59 (d,1H),7.38-7.18 (m,6H) , 4.85 (bs, 2H), 4.42 (s, 2H), 4.38-4.25 (m, 4H), 4.06 (s, 2H), 3.74-3.66 (m, 1H). MS (ESI) m/z: Calculated: 422 16; observed: 423 〇(M++1) o Compound 41 1-((4-(5-benzylbenzofuran-2-yl)_3_fluoro Phenyl)methyl)pyrrolidine_3·formic acid

The compound (60% yield) was prepared according to the reductive amination procedure under the title of the racemic mixture as described in Step 5 of Scheme 1 [hsipi 119664.doc -143 - 200813031 EC50=315 nM] 〇4 NMR ( 400 MHz, CD3OD) δ 8.11 (t, 1H), 7.47-7.44 (m, 4H), 7.27-7.19 (m, 7H), 4.45 (s, 2H), 4.05 (s, 2H), 3.73-3.52 (m , 2H&gt;, 3.48-3.34 (m, 3H), 25 1 - 2.38 (m, 2H). MS (ESI) m/z: calc.: 429.48; observed: 430.0 (M++1) 〇 compound 42 1 -(4-(5-cyclopentylbenzofuran-2-yl)-3-fluorobenzyl)azetidine-3-furic acid 4-(5-cyclopentylbenzofuran-2-yl)- 3-fluorobenzaldehyde (steps in Process 2)

5- 衣 戊 幷吱 _2 _2 _2 _ _ _ _ 276 276 276 276 (276 mg, 1.2 mmol), 4-bromobenzaldehyde (162 mg, 0.80 mmol), palladium dichlorobis (triphenylphosphine) (56 mg A solution of '0.08 mmol) and triethylamine (2.2 mL, 16 mmol) in EtOH (5 mL) was then taken in a microwave for 20 min. The reaction mixture ij was cooled and the solvent was removed. The residue was purified by EtOAc EtOAc (EtOAc) 1h NMR (400 MHz5 CDCI3) δ 10.0 (s5 1Η), 8.21 (dd? 1H)5 1.11 (d? 1H)? 7.66 (d,1H),7.51 (s,1H),7.46 (d,1H), 7.38 (d, 1H), 7.28 (d, 1H), 3.11 (m, 1H), 2.12 (m, 2H), 1.84 (m, 2H), 1.72 (m, 2H), 1.64 (m, 2H). 1-(4-(5-Cyclopentylbenzofuran-2-yl)_3-fluorobenzyl)azetidine_3_decanoic acid (Step 5 in Process 1): 119664.doc -144- 200813031

COOH

The title compound (20 mg, 18% yield) was obtained by the general procedure as described above in Example 1 (Step 5 in Scheme 1): iH NMR (400 MHZ, CD3 〇D) δ 8.09 (dd, 1H) ),7·51 (s,1H),7·44 (d,1H), 7·4〇(s,1Η),7·37 (d,1Η),7·29 (m,2Η),4· 34 (s, 2Η), 4.14 (m5 4Η) 5 3.39 (m? 1Η), 3.11 (m, 1H), 2.12 (m, 2H)? 1.85 (m5 f ' 2H), h74 (m, 2H), 1.65 (m, 2H). MS (ESI) m/z: calc. 393·17; observed: 393.90 (M+i 1). Compound 43-based phenylfurfurfuran-2-yl)-3-methylphenyl)methyl)azetidine-3-carboxylic acid: 4-(5-benzylphenylfuran-2-yl)-3-methyl Ethyl benzoate (Step 2 in Scheme 5):

The title compound (52% yield) was triturated in the general procedure as described above for Example Compound 40 (Step 2, Scheme 5): 4 NMR (400 MHz, CDC13) δ 7 r .9 (rn, 2H)5 7.61 (d, 1H), 7.42-7.17 (m, 8H), 6.95 (s, 1H), 4.06 (s, 2H), 3.82 (s5 3H), 2.61 (s, 3H). (4_(S_Phenylbenzofuran-2-yl)-3-methylphenyl)methanol (Step 3 in Scheme 5): 119664.doc -145- 200813031

The title compound (86% yield) was obtained by the general procedure: mp NMR (400 MHz, CDC 13) δ 7·94 (s, 1H), 7.82 (d) , 1H), 7.48-7.07 (m, 9H), 6.85 (s, 1H), 4.67 (brs, 1H), 4.06 (s, 4H), 2.58 (s, 3H). 4-(S_Benzylbenzofuran-2-ylpybenzaldehyde (Step 4 in Scheme 5):

The title compound (9 % yield) was prepared in the general procedure as described above for the compound compound 40 (Step 4, Scheme 5): NMR (400 MHz, CDC13) δ 1 〇·〇3 (s, 1H), 8.07 (d,1H),7·81 (m,2H),7.46-7.17 (m, 8H)5 7.01 (s? 1H), 4.08 (s? 2H)? 2.63 (s5 3H) 〇((4 (5- ~ Benzene oxime · 2 _ base) methyl phenyl) methyl) 丫 丫 bit _3_ formic acid (Step 5 in Process 1):

COOH

The title compound (62% yield) was obtained by the general procedure as described above (q.

NMR (400 MHz, CD3OD) δ 7.92 (d, 1 Η), 7.51-7.17 (m, l〇H), 7.03 (s, 1H), 4·84 (bs, 2H), 4.41 (s, 2H), 4.37 -4.22 (m, 4H), 4.08 (s, 2H), 3.68-3.61 (m, 1H), 2.63 (s, 3H). MS 119664. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Compound 44 3-(6-(5-butoxybenzofuranyl) 3,4-dihydroisoquinolin-2(ih)-yl) Propionic acid 3_(6·(5-butoxybenzoquinone) Furyl_heart_yl)_3,4_dihydroisoquineline madame) tert-butyl propionate (step 3 in Scheme 8):

The title compound (57 mg, 50% yield) was obtained by the general procedure as described above in Example Compound 37 (Step 3 in Scheme 8): iH NMR (4 〇〇f MHz, CDC13) δ 7.57 (m) ,2H),7·36 (d,1H),7.06 (d,1H), 7·〇〇(d5 1H)5 6.88 (s5 1H)5 6.85 (d? 1H)? 3.99 (dd? 2H)5 3.68 (s, 2H), 2·96 (dd, 2H), 2.85 (dd, 2H), 2.78 _, 2H), 2 53 l (dd5 2H)? 1 580 (m, 2H), 1.56 (m5 2H), 1.45 (s, 9H), l.〇〇 (t3 3H). MS (ESI) m/z: Calcd.: 449. 119664.doc (6 (5-butoxybenzamide 2 - keb'I dihydroisoquinoline 2 (1H)-yl) propionic acid (step 4 in Scheme 8):

The title compound (25 mg, 75% yield) was obtained as described above for compound compound 37 (Step 4 in Scheme 8) as described above. [hSIP1 EC5G=4440 •147-200813031 nM]: lH NMR (400 MHz5) CD3OD) δ 7.79 (m5 2H)5 7.38 (d? 1H), 7.30 (d, 1H), 7·17 (s, 1H), 7.09 (d, 1H), 6.88 (dd, 1H), 4.54 (br s , 2H), 4.00 (dd, 2H), 3.68 (m, 2H), 3.60 (dd, 2H), 3.21 (m, 1H), 2.95 (dd, 2H), 1.78 (m, 2H), 1.53 ( m, 2H), 1.00 (t, 2H). MS (ESI) m/z: Calcd.: 393.19; observed: 394.20 (M++1) 〇 compound 45 3-(5-(5-benzylbenzofuran-2-yl)_2,3-dihydro -1 Η-茚-2-ylamino)-propionic acid

The title compound (60% yield) [hSIPl.sup. 4 NMR (400 MHz, CD3CI3) δ 7.80-7.74 (m? 2H), 7.54 (d? 1H), 7.40- 7.22 (m,7H), 7.18 (d,1H),6·92 (s,1H), 4.79 (s, 1H), 4.02 (s, 2H), 3.28-2.92 (m, 4H), 2.73 (t, 2H), 2·48-2·30 (m, 2H, MS (ESI) m/z: Calculated: 411.49; observed: 412 7 (M++1) 〇 Compound 46 3_((4-(5-benzylphenylfurfuryl)-3-fluorophenyl)methylaminomethylbutyric acid:

As in the case of the example compound 1 (step 5 in the scheme), as described above, general 119664.doc -148- 200813031

Method but using 3-amino-3-methylbutyric acid in place of azetidine-3-carboxylic acid to prepare the title compound (46% yield) [hSIP1 EC5 〇 &gt; 25000 nM]: 4 NMR (400 MHz, CD3 〇D δ 8·11 (t, /= 7.8, 1H), 7.50-7.17 (m, 12H), 4.28 (s, 2H), 4·07 (s, 2H), 1·51 (s, 6H). MS (ESI) m/z · </ RTI> </ RTI> 431.19; observed: 432.0 (M++1). Compound 47 1-((4-(5-Cyclopentylbenzofuran-2-ylmethoxyphenyl)methyl)indole-3-carboxylic acid 4_(5-cyclopentylbenzofuran-2-(2-) Alkyloxybenzaldehyde:

The title compound (56q/() yield) was obtained by the general procedure as described above in the procedure of Example 1 (1H NMR (400 MHz, CDC13) δ 10.04 (Sj 1H)? 8.21 (d5) 1H)? 7.77 (d? 1H), 7.59-7.19 (m5 5H), 4.04 (s, 3H), 3.U (m, 1H), 2·15丄77 (m, 4H), 1.58-1.56 (m , 4H) 〇

The title compound (71% yield) was obtained by the general procedure as previously described for the reductive amination reaction as in Example Compound 1 (Step 5 in the scheme). EC50==i〇7〇nM] 〇ιΗ NMR (4〇 〇ΜΗζ5 CD3OD) δ 8.16 (d5 )' 7·45 (s, 1Η), 7·41·7·36 (m, 2Η), 7.26-7.17 (m, 3Η), 5 (bs, 2Η), 4· 41 (s, 2Η), 4.32 (m, 4Η), 4.04 (s, 3Η), 3.62 ^ 3.11 (m5 ih)5 2.25-2.12 (m5 2H)5 1.90-1.66 (m, 119664.doc -149- 200813031 6H). MS (ESI) m/z: Calculated: 405.19; observed ········································· Phenyl)methyl)azetidine _ 3-carboxylic acid: 4_(5-p-phenylphenylfuranyl)_3,5-difluorobenzaldehyde:

The title compound (66% yield) was obtained by the general procedure of the title compound (1 NMR (400 MHz, CDC13) δ s. , 1H), 7.45 (d, 1H), 7.417.17 (m, 8H), 4.G8 (s, 2H). 1((4-(5-Benzylbenzofuran-2-yl)_3,5-difluorophenyl)methyl)azetidine_3_carboxylic acid:

COOH The title compound (62% yield) was obtained by the general procedure as described above as Example Compound 1 (Step 5, Scheme 1) [hSIP1 EC5 〇=89 nM]: ιΗ NMR (400 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.47 (d, 1H), 7.41-7.12 (m, 8H), 4.42 (s, 2H), 4.37-4.22 (m, 7H), 4·06 (s, 2H), 3.72-3.64 (m, 1H). MS (ESI) m/z: Calcd.: 437. 119664.doc -150- 200813031 Compound 49 1-(4-(5-(cyclopentyloxy)benzofuran-2-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid 5-( Cyclopropylmethoxy)benzoquinone (Step 2 of Scheme 4):

The title compound (49% yield) was obtained by the general procedure: NMR (400 MHz, CD3 〇D) δ 7.60 (d, 1H), 7.38 d,1H),7.05 (s,1H), 6.94 (d, 1H), 6.69 (m5 1H), 3.84 (d,2H), 1.31 (m,1H),0.66 (m,2H), 〇_37 ( m, 2H). 5-(cyclopropylmethoxy)benzoquinone-2-yl-based acid (Step 3 of Scheme 1)

The title compound (98% yield) was obtained by the general procedure C: NMR (400 MHz, CD3 〇D) δ 7·39 (d, 1H) as in Example Compound 1 (Step 3 in Scheme 1) ), 7.29 (s, 1H), 7·〇6 (d5 1H), 7·00 (dd, 1Η), 3.83 (d, /=6.9 Ηζ, 2Η), 1·30 (m, 1Η), 0.66 ( m, 2H), 0.38 (m, 2H). 4-(5-(cyclopropylmethoxy)benzofuranyl)fluorobenzaldehyde (Step 4 of Scheme i) 119664.doc -151 - 200813031

The title compound (5 % yield) was prepared by the general procedure D as described above as in Example Compound 1 (Step 4 in Scheme 1): ESI_MS· 311 2 (M+H)+, NMR (400 MHz, CD3OD) δ 10.01 (s,1Η),8·20 (t,1H), 7.78 (d,1H), 7.69 (d,1H), 7.44 (d,1H),7·36 (d, 1H),7.08 ( s, 1H), 7.01 (d, 1H), 3.85 (d, /=7.1 Hz, 2H), 1·32 (m, 1H), 0.68 (m, 2H), 0.38 (m, 2H). 1-(4-(5-(Cyclopentylmethoxy)benzofuranyl&gt;3_fluorobenzyl)azetidine_ 3-decanoic acid:

The title compound (68% yield) was obtained by the general procedure E as described above as mp. + &gt; lU NMR (400 MHz, CD3OD) δ 8.01 (t, 1H), 7.35-7.30 (m, 3H), 7.17 (d, 1H), 7.04 (d, 1H), 6.87 (dd, 1H), 4.37 (s, 2H), 4.28-4.25 (m5 4H), 3.76 (d, /=6·7 Hz, 2H), 3.60 (m, 1H), 1·18 (m, 2H), 0.54-0.51 (m , 2H), 0.28-0.26 (m, 2H) hydrazine compound 50 1-((4-(5-butoxybenzofuranyl 3-chlorophenyl)indolyl) agidine 119664.doc -152- 200813031 2-methyl-4-carbophenyl benzoate:

CI

The title compound (92/〇 yield) was prepared by the general method of the above-mentioned compound 36 using the general method described above but using 3_chloro·4· 搜基甲甲甲 instead of 3-chloro-4-hydroxybenzoic acid ethyl acetate: lH NMR (400 MHz, CDC13) δ 10.00 (s, 1Η), 8·06 (d, J=1.8, 1Η), 7 88 (dd, J=8 4, i 8,1Η), 7 55 (4) 1Η) 〇 ' Butoxybenzofuran-2-yl)-3-air benzaldehyde:

The title compound (72% yield) was obtained in the general procedure as described above in Example 1 (Step 4 in Scheme i): iH NMR (4 〇〇 MHz, CDC13) δ 10.00 (s, 1H), 8.25 ( d, J==8 〇, 1H), 7 99 (d, J=1 4, 1H)5 7.86 (dd5 ^8.45 1.5)5 7.70 (Sj 1H)) 7.42 (d5 J=8.8)5 U 7·10 (d, /=2·6, 1H), 6·99 (dd, &gt;8·8, 2.5), 4.01 (t, &gt; 6.5, 2H)? 1.84-1.77 (m5 2H)5 1.54-1.49 ( m, 2H)5 !.〇〇(t5 J=7.3, 3H) 〇1-((4-(5-butoxybenzofuran-2-yl)_3_gasphenyl)indenyl)azetidine _3_ formic acid 119664.doc

The title compound (66% yield) was obtained by the general procedure as described above in Example 1 (Step 5 in Scheme 1) [hSIP1 EC5 〇 = 266 nM]: NMR (400 MHz, CD3OD) δ 8· 13 (d, J=8.4, 1H), 7.70 (d, /=1·8, 1H), 7.57 (s, 1H), 7.53 (dd, /=8.4, 1·8, 1H), 7·42 ( d, /==9·1,1H), 7.15 (d, /=2.5 1H), 6.95 (dd, "7=9.1,2.5), 4.45 (s,2H), 4.40-4.32 (m,4H), 4.00 (t, J = 6.5, 2H), 3.74 - 3.66 (m, iH), 1.81-1.74 (m, 2H), 1.58-1.49 (m, 2H), 1.00 (t, 7 · 3, 3H). Calculated: 41314; observed: 413·9 (M++1). Compound 51 1_((3-Gas-4-(5-cyclopentylphenylfurfuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid 3-Gas-4_(5-Cyclopentylbenzene Ethyl furoyl)benzoate:

The title compound (73% yield) was obtained as mpqqqqqqqqqq , 8.00 (d, J=8.1? 1H), 7.64 (s5 1H), 7·51-7·44 (m, 3H), 4·42 (q,, /=7.0, 2H), 3.12-3.08 (m , 1H)^ 2.16-2.08 (m5 2H)5 1.84- 1.58 (m? 6H), 1.42 (t3 J=7.3, 3H) 〇 (3 gas-4_(5-cyclopentylbenzofuran-2-yl) Phenyl)methanol:

The title compound (142 mg of a mixture of a primary alcohol and acetaldehyde, which can be used without further purification) was prepared in the general procedure as described above. Gas cyclopentyl benzofuran-2-yl) benzaldehyde:

The title compound was prepared as described in the general procedure of Example 4 (Step 4 of Scheme 5) (yield 61% yield for two steps): 4 NMR (400 MHz, CDC13) δ 10.00 (s, 1 Η) , 8·25 (d, J=8.1, 1H), 7.99 (s, 1H), 7.86 (d, J=8.1), 7.71 (s, 1H), 7.52 (s, 1H), 7.47 (d, JU, 1H), 7.27 (d, J = 8.8, 1H), 3.16-3.06 (m, 1H), 2.18-2·〇6 (m, 2H), 1.88-1.60 (m, 6H). M(3_气_4_(5·cyclopentylbenzofuran-2-yl)phenyl)methylazetidine_3-formic acid

The title compound (60% yield) was obtained as mpqqqqqqqqqqqqq d, J = 8.15 1H), 7.70 (d, ^=1.5, 1H), 7.61 (s5 1H), 7.55-7.53 (m, 2H), 7.45 (d, &gt; 8.8, 1H), 7.28 (dd, J =8_4, 1.5), 4.45 (s, 2H), 4.40-4.34 (m, 4H), 3.72-3.64 (m, 1H), 3.16-3.10 (m, 1H), 2.15-2.06 (m, 2H), 119664 .doc -155- 200813031 1.87-1.66 (m,6H). Calculated value: 409.14 ; s mesh, 曰丨 y 蚬 measured value ·· 409 9 (M++l) 〇· Compound 52 3-(N-((4-(5-(cyclopentylmethoxy))phenylhydrazine) (4) 2 -yl) gas phenyl)methyl)-N-(2-ethyl)amino) propylene warm: 〇

The title compound (13% yield) was prepared in the general procedure as described above using the procedure of the compound 丨 (Step 5, </ RTI> </ RTI> </ RTI> <RTIgt; (400 MHz, DMSO-d6) δ 7 57 (dm 7·55-7·47 (m, 2H), 7.26 (m, 2H), 7.22 (s, 1H), 6.96 (d, 1H) 4·82 ( Bs,3H),4.42 (s,2H),4.06 (s,2H),3.92-3.65 (m,4H)5 2·75_2·33 (m,4H),1.95-1.31 (m,9H).MS ( ESI) m/z: calcd.: 455.21. Found: 459. (M++1). Compound 53 1 -((3-fluoro-4-(5-morpholinylbenzofuran-2-yl)phenyl) Methyl)azetidine_3_ formic acid 4-(adolfurfuran-5-yl)morpholine:

〇Q The title compound (52% yield) was obtained by the general procedure as described above as the compound of compound (1) (1 Step 1) in the procedure as described above. [hSIP1 EC5〇=2〇9〇nM]: 119664.doc -156 - 200813031 4 NMR (400 MHz, CDC13) δ 7.46 (s, 1H), 7.36 (d, 1H), 6.95 (s, 1H), 6.81 (d, 1H), 6.58 (s, 1H), 3.78 (m, 4H), 2.95 (m, 4H) 〇5-Maline basic bite taste_2_yl-2-folate: °〇^ ^^C^-b(oh)2 as example compound 3 1 (in process 3) The title compound (72% yield) was obtainedjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Fluoro-4-(5-morphinylbenzofuranyl)benzaldehyde

The title compound (52% yield) was prepared as described above for the compound of Example 31 (Step 3, Scheme 3): 4 NMR (400 MHz, CDC13) J 1 〇·〇1 (s, 1 Η), 7.76 (d, 1H), 7.61 (d, lH)j 7.55-7.06 (m, 5ii), 3·86 (m, 4H), 3.15 (m, 4H). Fluoro-4_(S_morpholinylbenzofuran-2-yl)phenyl)methyl)azetidine_3_

The title compound (28% yield) was prepared as described above for the compound i (Step 5 in Scheme i): lH nmr (4〇〇MHz, 119664.doc -157-200813031 CD3OD) δ 8 .G3 (t,1H), 7.56 (d,1H), 7.53 (d,1H), 7.43 (d, 1H), 7.22 (d,1H),7·19 (d,1H) 7.05 (dd,1H) , 4.50 (s, 2H), 4.39 (dd5 4H) 5 3.72-3.70 (m? 6H)? 2.08 (m5 4H) 5 1.84 (m5 2H). MS (ESI) m/z: Calculated: 4 ΐ〇·ι; observed: 4U1 (M++1) 〇 compound 54 4-((4-(5-benzylbenzoquinone-2-yl)- 3-fluorophenyl)methyl)morphine_2_ formic acid: factory,

Fv ( V-COOH

The title compound (57% yield) was prepared as in the compound of Example 1 (Step 5 in Scheme 1) using the general procedure as described above but using morpholin-2-carboxylic acid instead of azetin-3-carboxylic acid [hSIPl EC5 〇 = 1860 nM] : 4 NMR (400 MHz, CD3OD) δ 8.09 (t, J = 7.8, 1H), 7·46·7·42 (m, 4H), 7.28-7.14 (m, 7H), 4.38 (brd, J=9.5, lH), 4.30-4.21 (m, 2H), 4.13-4·04 (m, 1H), 4.06 (s, 2H), 3.83 (br t, J = 10.6, 1H), 3.53 (br d '7=12.4,1H), 3.30-3.22 (m,1H), 3.13-3.00 (m,2H). MS (ESI) m/z: Calcd.: 445. Compound 55 4_((4_(5-(5-(cyclopentyl)oxy)benzofuran-2-yl)-3-fluorophenyl)methyl)morpholine-2-carboxylic acid: 119664.doc -158- 200813031

The title compound (57% yield) [hSIPl EC5] was obtained as the compound of Example 1 (Step 5 in Scheme 1) in the general procedure as described above but using morpholin-2-indoleic acid instead of azetidine-3-carboxylic acid. 〇&gt;25000 nM] : 4 NMR (400 MHz, CD3OD) δ 8.06 (t, J=7.8, 1H), 7.44-7.42 (m, 3H), 7.24 (d5 /=3.3,1H), 7·13 ( d, J = 2.5, 1H), 6.95-6.92 (m, 1H), 4.38 (dd, /=9·5, 2.6, 1H), 4.21-4.09 (m, 3H), 3.88 (d, J = 7.0, 2H), 3.81 (t, J=l〇.2, 1H), 3.45 (br d, /=11.4, 1H), 3.15 (br d, J = 12.4, lH), 3_03-2.91 (m, 2H), 2.41-2.34 (m, lH), 1.90-1.83 (m, 2H), 1.71-1.57 (m, 4H), 1.46-1.37 (m, 2H). MS (ESI) m/z: Calcd.: 453. Compound 56 1-(5-(5-Benzylbenzofuranyl)-2,3_di-argon-1Β[_茚-2-yl)azetidine- 3-carboxylic acid

The title compound was prepared according to the reductive amination procedure as described in step 5 of Scheme 1 (69% yield). 4 NMR (400 MHz, CD3C13) δ 7.78-7.68 (m, 2 Η), 7.45-7.22 (m, 8 Η), 7·22 (d, 1 Η), 6.94 (s, lH), 4.73 (s, lH) ), 4.05 (s, 2H), 3.52-3.20 (m, 2H), 3.29-2.62 (m, 7H), 2.48-2.31 (m5 2H). MS (ESI) m/z ··················· Compound 57 (6 (5-(cyclopentylmethoxy)benzofuranyl)_3,4-dihydroisoquinolin-2(1H)-yl)propionic acid 3_(6-(S_(cyclopentyl) Oxy)phenyl benzofuranyl &gt; 3, 'dihydroisoquinoline _ 2(1H)-yl) propionic acid tert-butyl ester (step 3 in Scheme 8) ··

The title compound (73 mg, 40% yield) was obtained in the general procedure as described above in EtOAc (m. δ 7.57 (m, 2H), 7.36 (d,

1H)' 7·06 (d,1H), 7.01 (d,1H),6·85 (m,2H), 3.85 (d,2H), 3·69 (s,2H), 2.96 (dd,2H) , 2.86 (dd, 2H), 2.79 (dd, 2H), 4 (dd, 2H), 2.38 (m, 1H), 1.66 (m, 2H), 1.59 (m, 4H), h45 (s, 9H), 1.39 (t, 2H). MS (ESI) m/z: Calcd: 495. (cyclopentylmethoxy)benzofuran-2-yl)-3,4-dihydroisoquinoline-2(111)-yl)propionic acid (Step 4 in Scheme 8):

The title compound (19 mg, 72% yield): NMR (400 MHz, CD3 〇D) δ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 7.78 (m, 2H), 7.38 (d, 1H), 7.30 (d, 1H), 7.17 (s, 1H), 7.09 (d, 1H), 6.88 (dd, 1H), 4.53 (s, 2H), 3.87 (d,2H),3·68 (m,2H),3.58 (dd,2H),3·27 (m,1H),2·93 (dd,2H),2·37 (m,ih),1.86 (m, 2H), ΐ·63 (m, 4H), 141 (m, 2H). MS (ESI) m/z: Found: 422.21. Compound 58 3-(4 _(5-Cyclopentylbenzofurfuryl)-3-fluoro- benzylamino)propanoic acid (Step 5 in Scheme 1):

The title compound (4.1 mg, 4.6% yield) was obtained by the general procedure as described above in Example 1 (Step 5 in Scheme 1) [hSIP1 EC5 〇 = 1070 nM]: NMR (400 MHz, CD3〇D) ) δ 8.10 (dd, 1H), 7.50 (s, 1H), 7.42 (m, 3H), 7.25 (m, 2H), 4.30 (s, 2H), 3.25 (m, 2H), 3.10 (m, 1H) , 2.25 (dd, 2H), 2.18 (m, 2H), 1.84 (m, 2H), 1 · 65 (m, 4H). MS (ESI) m/z: Calcd.: 381. Compound 59 3-(4_(5_~Phenylbenzoin-2-yl)_3-cyclophenoxy)propanone _i,2-diylam 4-(5-benzylbenzofuran-2-yl) -3_fluorophenol (Step 4 in Scheme 1): 119664.doc -161 - 200813031

The title compound was prepared in the same manner as described above using </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 3-(4-(5-Hydroxybenzoquinone_2-ylphenoxy)propanepyrenediol (Step 2 in Scheme 9):

OH 4-(5-benzylbenzofuran-2-yl)_3_fluorophenol (22 mg, 〇.〇69

Methyl) and 3-bromopropane·ι,2-diol (48 mg, 〇 31 mmol) and 2 N

The mixture in NaOH (200 μΐ^κ^ϊ^ΟΗ (1 mL) was heated at 9 Torr. After concentration of the solvent under reduced pressure, the obtained residue was dissolved in DMSO and purified by reverse phase. (Phenomenex reverse phase Luna 5 μ C18(2) column, 60x21.2 mm ID, mobile phase: Α=0·05% in water

The desired final product (4.4 mg, 16% yield): NMR (400 MHz, CD3 〇D) δ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 7.89 (m,1Η), 7.40 (m,2Η),7·23 (m, 4Η), 7·1〇(m,2H),6·99 (m,1H),6.89 (m,2H),4 · 10 (m, 1H), 4.04 (s, 2H), 3.96 (m, 2H), 3.65 (m, 2H). MS (ESI) m/z: Calcd.: 372. Compound 60 1-((3-fluoro-4-(5-(1-(methylsulfonyl)piperidin-4-yl)benzofuran-2-yl)benzene 119664.doc -162- 200813031 base) Indole) azetidin-3-decanoic acid ((2-ethoxyethoxy)-1-(indenyl) brigade bite:

OEt The title compound (70% yield) was obtained by the general procedure as described above in </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; , 2H), 4·81 (t, 1H), 3.96 (d, outside H)' '90 (ί, 2H), 3.79-3.72 (m, 2H), 3.67-3.59 (m, 2H), 2·81 (s, 3H), 2.77 (t, 2H), 2.61 (m, 1H), 1.77-1.70 (m, 2H), L21 (t, 6H). (本幷0夫嚼)-1-(曱基醯 ))) bite:

The title compound (20% yield) was obtained from mpqqqqqqqqqqqqqq s,1H),7.13 (d,1H),6·62 (s,1H),4.03 (m,4H),2.83 (s,3H),2.78 (t,1H),1.82-1.75 (m, 4H) 〇5 (l(methyl succinyl) brigade bite-4_yl) benzoquinone 0 phoranyl_2__ acid: 119664.doc -163- 200813031

The title compound (84% yield) was obtained mjjjjjjjjjjjjjjjjjjjjjj (M++1). Fluorine 4-(5-(1-(methylsulfonyl) piperidinyl-4-yl)benzoquinone-2-yl)benzene

CHO The title compound (62% yield) was obtained by the general procedure as described above in the procedure of Example Compound 1 (Step 4 in the scheme): lH earned (paste, CDCl3)Sl〇.〇3 (s, lH), 8.21(tj 1H), 7.79 (d, 1H), 7.72 (d, ί 1H), 7.51-7.21 (m, 4H), 3.98 (m, 4H), 2.84 (s, 3H), 2.76 (m, 1H) , 2.05-1.81 (m, 4H). W(3-Gas-4-(5-(H-methyl)) Niobium _4_yl)phenylhydrazine^2_yl)phenyl)indenyl)azetidine_3·carboxylic acid:

The title compound (7% yield) was prepared in the general procedure as described above for Example Compound 1 (Step 5 in Scheme i): lH nmr (Cach, DMS 〇-d6) U.21 (t, 1H) , 7.84(d,1H),7 77 (d,iH),75i_ 119664.doc -164- 200813031 7·21 (m,4H),4.85 (bs,2H),4.46 (s,2H),3.98 (m , 4H), 3.68 (m, 1H), 3.62 (m, 4H), 2.84 (s, 3H), 2.76 (m, 1H), 1.91-1.71 (m, 4H). MS (ESI) m/z······················································· _4-yl)phenylhydrazone-2-yl)phenyl)methyl)azetidine-3-carboxylic acid 4_(alumfuran-5-yl)-tetrahydro-2H-piperidin-4-ol (flow Step 1 in 6:

5-&gt; Oxanthene (3·9 g, 20.0 mmol) was added in a portion of a suspension of Mg (5 50 mg, 23.0 mmol) in anhydrous THF (15 mL). . The crystals were filled and then the contents were refluxed for 3 hours. The reaction was then brought to ambient temperature and then cooled to -4 Torr. Piperazine-4-one (3.0 g, 30.0 mmol) was added dropwise and the resulting solution was allowed to reach room temperature. The reaction mixture was quenched by the addition of 1 N HCl (5 mL) and then diluted with diethyl ether (30 v. This was washed with water (2 x 15 mL) and the combined organic extracts were washed with brine (15 mL), dried and concentrated under reduced pressure to give a crude oil. Purification by column chromatography eluting with EtOAc EtOAc (EtOAc) iH NMR (400 MHz, CDC13) δ 7.74 (d, 1H), 7.64 (d, 1H), 7·51-7·44 (m, 2H), 6.78 (d, lH), 4.00-3.88 (m, 4H) ), 2.25(t, 2H), 1.78-1_74 (m, 2H) 〇5-(tetrahydro-211_娘____) benzoquinone (Step 2 in Scheme 6): 119664.doc - 165- 200813031

Triethyldecane (175 mg, 1.5 mmol) followed by TFA (570 mg, 5.0 mmol) was added to 4_(benzopyran-5-yl)-tetraindole-2H under a nitrogen atmosphere at 〇 °C. Mouth. A solution of Nan-4-ol (109 mg, 0.5 mmol) in DCM (5 mL). After stirring at the same temperature for 15 minutes, the cooling bath was removed and the reaction mixture was allowed to reach room temperature. It was stirred for an additional 6 hours at room temperature and then poured into a crushed ice-water mixture (10 mL). It was extracted in DCM (3×10 mL) and combined organic layers were washed with brine (1 mL), dried and evaporated. The crude compound was purified by EtOAc EtOAc EtOAc EtOAc 4 NMR (400 MHz, CDC13) δ 7.61 (d, 1 Η), 7·44 (d, 2 Η), 7·15 (d, 1 Η), 6.73 (d, 1 Η), 4·11 (dd, 2H), 3.56 (t, 2H), 2.89-2.81 (m, 1H), 1.93-1.79 (m, 4H). 5-(tetrahydro-2H-piperazin-4-yl-benzofuranyl acid (Step 3 in Scheme j):

The title compound (86/.)·H NMR (400 MHz, CDC13) δ 7.48-7.41 (m, 2H), 7.28 (d, lH), 7.20 (d). , lH), 4.10 (t, 2H), 3.60 (t, 2H), 2.98 - 2·94 (m' 1H), 1.97_1·8 〇 (m, 4H). MS (ESI) m/z: Calcd.: 324. 3-gas 4-(5_(tetrazo-2H-bathing_4 benzoquinone furan-2-yl)benzaldehyde (step 119664.doc -166 - 200813031 1 step 4): with the steps of process I The title compound (68%) was prepared in the same manner as described in 4: NMR (400 MHz, CDCl3) s 1 〇〇 1 (s, 1H), 8 〇 4 "1H), 7.80 (t, 1 Η), 7.74 ( d,1Η),7·52 (t,2H),7 4〇,, 7.22 (s,1H),4.10 (t,2H),3·60 (t5 2H),2.98-2.94 (m,1Ή) (\ i·97-1·80 (m, 4H). MS (ESI) m/z ·· Calculated value: 324.35; Observed value: 325·1 (M++1). “ 1-(3- Fluoro-4-(5-(tetrahydro-2Η-piperazin-4-yl)benzoquinone-2-yl)phenyl)methyl)σ丫丁乙-3-carboxylic acid (Step 5 in Scheme 1) :

The title compound (73% yield) [hSIP1 EC50 = 207 nM] was obtained according to the reductive amination procedure as described in step 5 of Scheme 1. 4 NMR (400 MHz, CD3〇D) δ 8.12 (t,1Η), 7.54 (s,1Η), 7.49 (d 1H), 7.43 (s,1H),7·41 (d,1H),7·31_7 ·27 (m,2H)5 4.46 (s 2H), 4.39-4.31 (m,4H),4·05 (d,2H),3.71-3.64 (m,1H) 3.59 (t,2H),l.95_L89 (m, 4H). MS (ESI) m/z: Calculated: 409.45; observed: 41 〇 〇 (M++1). The following examples are provided to illustrate the invention, but are not intended to be limiting of the scope or spirit of the invention. 119664.doc -167- 200813031 The compounds of the invention can be prepared as described in the Schemes below. Process A-2

+ R-ZnBr Μ(ιΒυ3Ρ) 2100. . , balance skin Step 1

1. BuLi, THF, -78 °C 2. Β{〇νή3

3. 2Ν HCI Step 2

100. . , microwave Step 3

AcOH Step 4

I.BuLi.THF, -78 0C

NaKDMF

step 1

/〇Η ΟΗ,ΟΗ 2· Β('·Ρ“0)3 3· 2 Ν HCI_H4CI (s) Step 2

Process A-3-b

Step 1 1. 巳uLi, THF, -78 °C XYVb?h OH 2·Β(^ΡγΟ)3, 3.2 NHCI or SlKtCKs) Step 2

-168- 119664.doc 200813031 Process A-4

PhBr, Pd2(dba)^ Xantphos

OH Step 1 &quot;OEt Br QEt r K2C〇3, DMF, 110°C6h

OEt Step 2

Step 3

1. BuLi.THF 2. Β(σΡΓ)3, THF 3. 2 N HCI

b(oh)2 Step 4

PdCI2(Ph3P)2 Et3N, EtOH i〇〇ec, microwave

COOH hnU

NaCNBH3, DCM/MeOH AcOH Step β Step 5

COOH Process A-5

Mcpba (3 eq) -15 °C-rt O/N Step 1

Secondary product COOH

Main product

Η Step 2

NaCNBH3&gt; DCM/MeOH AcOH Step 3

COOH 119664.doc -169- 200813031 Process A-6

CsC03 MeCN Step 1

Br

NaCNBH3 Znl CICH2CH2CI Step 2

Br Γ

PdCI2(Ph3P)2 [ &lt;OOOH Et3N, EtOH f Λ / HN-* ^ i〇〇. . , microwave &quot;, 〇^C^-B(OH)2 Step 3 MX ν\^〇Η〇 NaCNBH3, DCM/MeOH AcOH Step 4

Process A-7

PhCH2ZrBr

Pd(PtBu3)2 Step 1

Pd(Ph3P)4

CH3COOK, CH3CONMe2 heating.160 0C

NaCNB3H Me OH CH2CI2

119664.doc -170- 200813031 Process A-8

TMS-N3

Bu2-Sn=0 Step 1 Ή

PdCOH^· Η+ Η2, MeOH Step 2

HCI

Process A-9

1. (COCI)2 DMF (several drops) ch2ci2

Et3N CH2CI2 Step 1

° Step 2 4-(4-Benzylbenzimidamide)-3-fluorobenzoic acid ethyl ester

Step 4 119664.doc -171 - 200813031 Process A-10

ο

DIBAL-H Step 5

119664.doc -172- 200813031 Scheme A-11, F NBS peroxide B, , N...〇丨 Step 1 π Ac〇THA, NaBH3CN. 'Cl ~7~Ζ ΗΝ-, Step 2 Ν Cl Ο COOH_ Step 3

COOH ci- COOH 『】分--.s painting ki coupling·Buchwaldi Cuihua system Pd(OAc)2/CsF/ Y,P(tBu)2

COOH f Step 4 Process A-12 R2 CO Me

PH, 〇_BbH + B"

PdCI2(Ph3P)2 Et3N, EtOH

100 °C, imK step 1

;OOMe

LiOH thf/h2o

OOH Step 2 Process A-13

3 HN-R3 \=|=/ ^ --

丄2 ° NaCNBH3, DCM/MeOH

R AcOH Step 1 Prepare the compound using the general procedure described below 173 - 119664.doc 200813031

R

Ar

(n, m, etc., 1, 2) Compound 62 (3R)-l_((4-(5-Benzylbenzofuranyl)_3_fluorophenyl)methyl)piperidine _3_ decanoic acid

It was synthesized according to Scheme 1 and General Procedure E to give benzyl benz-2-yl)-3-fluorophenyl)methyl)piperidine _3_decanoic acid [hSlpi ec 50 = 5451 nM]. MS (ESI) m/z: 443·2; observed: 444.1 (Μ++1). Compound 63 (3S)-l-((4-(5-Benzylbenzofuran-2-yl)-3-fluorophenyl)methyl)piperidine-3-carboxylic acid

Synthesis according to Scheme 1 and General Procedure E to obtain (3 s)-1-((4-(5-benzylbenzofuran-2-yl)-3-fluorophenyl)indolyl) _3_曱Acid [hSIPl EC50 = 3340 nM]. MS (ESI) m/z: Calcd. Compound 64 119664.doc -174- 200813031 1-(3-Fluoro-4-(5-phenylthio)benzoquinone-Bry-2-yl)cobalt) °丫丁-3 -carboxylic acid (4-(2) ,2-diethoxyethoxy)phenyl)(phenyl)sulfane (Step 2 in Scheme A-4):

〇Et 4-(phenylthio)phenol (4.7 g, 23 mmol), bromoacetaldehyde diethyl acetal (4.3 mL, 28 mmol) and K2C03 (3.82 g, 28 mmol) in DMF (40 mL) The mixture was stirred at reflux for 6 hours. The reaction mixture was cooled to room temperature and poured over ice and diluted with water to &lt The solution was extracted with EtOAc (20 mL EtOAc): EtOAc (EtOAc) NMR (400 MHz, CDC13) δ 7.42 (d, 2 Η), 7.27-7.06 (m, 5 Η), 6.92 (d, 2 Η), 4.84 (t, 1 Η), 4.02 (d, 2H), 3.84-3.68 (m , 4H), 1.13 (m, 6H). 5-(phenylthio)benzofuran (Step 3 of Process Α·4):

(4-(2,2-Diethoxyethoxy)phenyl)(phenyl)sulfane (2.7 g, 8.5 mmol) and polychloric acid (2.7 g, 27 mmol) in benzene ( The mixture in 70 mL) was stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature, poured with EtOAc (EtOAc)EtOAc. The filtrate and washings were combined and concentrated under reduced pressure to give 1.7 g (89%) of benzofuran: iH NMR (400 MHz? CDC13) δ 7.74 (d5 1H)5 7.64 (dd5 1H), 7.49-7.39 (m , 2H), 7.29-7.16 (m, 5H), 6_74 (dd, 1H). 119664.doc -175- 200813031 5-(phenylthio)benzofuran-2-ylfolic acid (Step 4 in Process Ad):

PH B,

OH Add a solution of BuLi (10.5 mL, 2.5 mL in hexane) to 5-(phenylthio)benzoquinone at -78 °C (〇·7 g, 3.1). Methyl) in a solution of anhydrous THF (20 mL). The resulting mixture was stirred at _78.degree. C. for 20 min and was worked up with &lt;RTI ID=0.0&gt;&gt; The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction was quenched with 2 N HCl and extracted with EtOAc. The combined extracts were washed with brine, dried and concentrated under reduced vacuum to afford &lt;RTI ID=0.0&gt;&gt;&gt; , 7.58 7.42 (m, 2H), 7.38-7.17 (m, 6H). 3-Fluoro-4_(5-(phenylthio)benzofuran-2-yl)benzaldehyde (Step 5 in Scheme A_4):

5-(Phenylthio)benzoin-2-yl-acid (610 mg, 2.26 mmol), 4-bromobenzaldehyde (38 mg, 1.87 mmol), palladium dichlorobis(triphenylphosphine) (66 mg, 0.094 mmol) and a solution of triethylamine (5 mL, 68 mmol) in Et.sub.2 (5 mL). The crude reaction mixture was purified by chromatography (9 / 1 hexane / ethyl acetate) to afford the desired benzaldehyde. 1H NMR (400 MHz, CDC13) δ 10.05 (s, 1H), 8.21 (t, 1Η), 7·75 (d, 1Η), 7·72 (s, 1Η), 7·68 (d, 1Η), 7·52-7·16 (m, 8H). MS (ESI) m/z: Calculated: 348.06; observed: 349 1 119664.doc -176 - 200813031 (M++1) 〇 1-(3-fluoro-4-(5-phenylthio)benzoquinone Furan-2-yl)benzyl)azetidine_3_carboxylic acid (step Α-4_ step 6):

3-Fluoro-4-(5-(phenylthio)benzofuran-2-yl)benzaldehyde (35 〇mg, 1_04 mmol), azetidine-3-carboxylic acid (120 mg, 0.28 mmol) and acetic acid The mixture (0.12 mL, 2.0 mmol) in EtOAc (EtOAc) Sodium triethoxysulfonate (340 mg, 1.6 mmol) was added in two portions and the mixture was stirred 16 h. The solvent was concentrated under reduced pressure to give a yellow solid, which was dissolved in DMSO (3 mL) and filtered to give a yellow solution, which was purified by HPLC to obtain the desired product [hSIP1 EC5 〇 = 142 nM ]. 4 NMR (400 MHz, CD3OD) S8.17 (t, lH), 7.78 (s, lH), 7.59 (d, lH), 7.47-7.39 (m, 3H), 7·36_7.17 (m, 6H) , 4.46 (s, 2H), 4·39 (m, 4H), 3.74 (m, 1H). MS (ESI) m/z ···························· Compound 65 1-(3- gas- 4-(5-phenyl arginine) benzoquinone 11 fumar-2 base) benzyl butyl butyl bitrate - 3-carboxylic acid (step 7 in Scheme Α-4) :

COOH

119664.doc -177- 200813031 1-(3-Fluoro-4-(5-phenylthio)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid (50 mg, 0·12 mmol And a mixture of m-chloroperbenzoic acid (35 mg, 0. 12 mmol) in chloroform (9 mL) and MeOH (1 mL). The solvent was concentrated under reduced pressure to give a white solid. m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m ].咕NMR (400 MHz, CD3OD) δ 8.17 (t, 1H), 7.96 (s, 1H), 7.94 (d, 1H), 7.75-7.43 (m, 9H), 4·45 (s, 2H), 4.39 ( m, 4H), O 3.74 (m, 1H). MS (ESI) m/z: Calcd.: 449. 5-(3-fluoro-benzyl)azetidine-3-carboxylic acid 5-((cyclopropylmethoxy)methyl)benzofuran (Step 1 in Scheme A-3-a):

混合物 A mixture of benzofuran-5-ylmethanol (1_〇g, 6.8 mmol) and sodium hydride (〇·25 g, 10·0 mmol) in DMF (20 mL) bell. The propyl propyl methyl ester (0 97 g, 7.0 mmol) was added and the resulting reaction mixture was slowly warmed to room temperature and kept stirring overnight. The reaction mixture was diluted with water to 1 mL. The solution was extracted with Et20 (20 mL×3); the combined extracts were washed with 1 N NaOH solution, water and brine, dried and concentrated under reduced pressure in cerium (4/1 hexane/ethyl acetate) The desired product is obtained after purification. 4 NMR (400 MHz, CDC13) δ 7.61 (d, 2H), 119664.doc -178- 200813031 7·44 (d,1H), 7.27 (d,1Η),6·76 (s,1H), 4.62 ( s, 2Ή) 3 ” (d, 2H), 1.41 (m, 1H), 0.58 (m, 2H), 0.21 (m, 2H). 5-((cyclopropylmethoxy)methyl)benzofuran- 2-based S-Phenic Acid (Step 2 of Process A_3_a$):

The title compound was prepared in the usual procedure as described above for Example Compound A (Step 3) and was used in the next step without further purification: iH Nmr (400 MHz, CDC13) δ 7·72 (m, 1H), 7.52 (m, IH), 7 32 (1H), 7.21 (m, 1H), 4.62 (s, 2H) 3.37 (d, 2H), h4l (m, ih), 0.58 (m, 2H), 0.21 ( m, 2H). '4-(5-(Cyclopropylmethoxy)methyl)benzofuran-2-yl)-3-fluoroindole (Step 3 in Scheme A-3-a):

v^° The compound was prepared in the usual manner as described above, using the compound of Example A (Step 4). 1H NMR (400 MHz, CDC13): δ in no / υ.υ2 (s,1H), 8·24 (t,lH), 7.78 (d,1H),7·69 (d,1H), 7.63 (s ,1H) 7 54 (d,^), 7.36 (m,2H), 4.62 (s,2H) 3.38 (d,2H),i 41 (calendar 1H),〇·58 (m,2H),0.21 (m , 2H). '(Cyclopropylmethoxy)methyl)benzoquinone-2-yl)_3_ gas ^ base ^ 丫 bite -3 - formic acid (step 4 in Scheme A_3-a): 119664.doc -179 - 200813031

OOH

The title compound was prepared as in the general procedure described above as in the case of the compound of Example A (Step 5). The compound was isolated by wet milling into the free base form [hSIP1 EC50 = 75 nM]. 4 NMR (400 MHz, DMSO-d6): 7.79 (t, 1H), 7·43 (m, 2H), 7·18 (m, 4H), 4.41 (s, 2H), 3, 35 (m, 4H) ), 3·14 (d, 2H), 3·13 (m, 1H), 0.93 (m, 1H), 0.38 (m, 2H), 0.05 (m, 2H). MS (ESI) m/z: Calculated: 409.17; observed: 409.9 πντ ++1, 〇\ / Compound 67 1-(4-(5-(cyclobutoxymethyl)benzofuran-2-yl )-3-fluoro-benzyl)azetidine_3-carboxylic acid 5-(cyclobutoxymethyl)benzofuran (Step 1 in Scheme A-3-b):

A mixture of cyclobutanol (1.0 mL, 14.0 mmol) and sodium hydride (0.5 g, 14.0 mmol) in DMF (20 mL) Stir under the arm for 30 minutes. Add odor methyl) benzoquinone (2. 9 g, 14.0 mmol) and the mixture was slowly warmed to room temperature and kept stirring overnight. The reaction mixture was diluted with water to 100 mL. The solution was extracted with EhO (20 mL×3); the combined extracts were washed with 1 N NaOH solution, water and brine, dried and decompressed under reduced pressure at 4/1 hexane/acetic acid. Ethyl ester) was purified to give the desired product. 4 NMR (400 MHz, CDC13) δ 7.58 (d, 2H), 7.42 (d, 119664.doc -180 - 200813031 1H), 7.27 (d, 1H), 6.78 (s, 1H), 4.54 (s, 2H) 4.03 (m, 1H), 2.21 (m, 2H), 1.94 (m, 2H), 1.76 (m, 1H), 1·52 (m, 1H). 5-(cyclobutoxyindolyl)benzoquinone-2-yl@ponic acid (step in process A-3-b 2):

The title compound was prepared using EtOAc (m.m.) m,1H),7·32 (m,1H),7.21 (m,1H),4.48 (s,2H),4.03 (m,1H), 2.24 (m, 2H),2.02 (m,2H),1 · 76 (m, 1H), 1.56 (m, 1H). 4 (5-(cyclobutoxymethyl)benzoquinone) _3_襄Benzene (Step 3 in Scheme b):

The title compound (67 〇 /. Yield) in two steps: iH NMR (400 MHz, CDCI3): δ 10.01 (s, 1H). ) 5 8.21 (t? 1H)5 7.76 (d, 1H)? 7.63 (d, 1H), 7.61 (s, 1H), 7.46 (d, 1H), 7.39 (m, 2H), 4.51 (s, 2H) 4.〇4 (m,1H), 2.22 (m,2H), 2.01 (m,2H), 1.74 (m,1H), m (m,1H). , (4 (5-(cyclobutoxymethyl) Benzofuran-2-yl)_3_fluoro-benzyl)azetidine-3-carboxylic acid (Step 4 in Scheme A-3-b) ·· 119664.doc 200813031

The Minozaki compound [hSIP 1 EC5 〇 = 25 nM] was prepared as in the general procedure described above as in the case of the example compound A (step 5). The product was separated into a free form by wet milling: 4 NMR (400 MHz, DMSO_d6): 7.91 (t

C〇〇H 1Η),7·61 (m,2H), 7.23 (m,4H),4·42 (s,2H),3.94 (m,1H), 3.61 (s,2H),3.37 (m, 1H), 3.35 (m, 4H), 2.18 (m, 2H), 1·82 (m' 2H), 1·61 (m, 1H), 1.45 (m, 1H). MS (ESI) m/z: Calcd: 409. Compound 68 1-(4-(benzofuran-2-yl)-3-fluoro-benzyl)azetidine_3_carboxamidine-4-(apodoxime-2-yl)-3_fluorobenzaldehyde ( Step 4) in Process A-1:

The title compound (42% yield) was obtained in the general procedure of mp. t, 1Η), 7.79-7.17 (m, 7Η). 1(4-(benzofuran-2-ylhexylfluoro-benzyl)azetidinecarboxylic acid (Step 5 in Scheme A-1): 119664.doc

The title compound was prepared as described in the general procedure E as described above, as described for example compound A (step 5). The product [hSIP1 EC5G=706 nM] was isolated by wet milling to a free base: 4 NMR (400 MHz, DMSO-d6): δ 7.96 (t, 1H), 7.74 (d5 1H), 7.62 (d, 1H), 7.39-7.28 (m, 5H), 4.34 (s, 2H), 4.16 (m, 4H), 3·49 (m, 1H). MS (ESI) m/z: Calcd. Compound 69 1-(3-Fluoro-4-(phenoxymethyl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid hydrazine 5_(phenoxymethyl)benzofuran (flow Step 1) in A-3-b:

The title compound was prepared as in Example Compound 5 (Step 1): iH NMR (400 MHz, CDC 13) δ 7·63 (d, 2H), 7.47 (d, 1H), 7·29 (d, 1 Η), 7·27 (m, 2Η), 6.99 (m, 3Η), 6.79 (s, 1Η), 5·18 (s, 2H).

U 5 —(phenoxymethyl)benzofuran-2-yl-acid (Step 2 in Scheme A-3-b):

The title compound was prepared using EtOAc EtOAc (m.m. 7.64 (m, 1H), 7 49 (m, 3H), 6.99 (m, 3H), 5.16 (s, 2H). 119664.doc -183 - 200813031 3-Fluoro-4-(5-(phenoxymethyl)benzofuran-2-yl)benzaldehyde (Step 3 in the scheme):

The title compound was prepared as in Example Compound A (Step 4) using General Method D as described above. iH NMR (400 MHz, CDC13) δ 10.01 (s, 1H) 8·22 (t, 1Η), 7·78 (d, 1Η), 7_75 (s, 1Η), 7·69 (d, 1Η) 5 7.58 (d' !H), 7.42-7.27 (m, 2H), 7·02 (m, 5H), 5·18 (s, 2H). Fluoro-4-(5-(phenoxymethyl)benzofuran-2-yl)benzyl)azetidine_3_carboxylic acid (Step 4 of Scheme A-3_b):

The title compound was prepared in the usual manner as described above for the compound of Example A (Step 5). The compound [hSIP1 EC5〇=87 nM] was separated into the free ridge form by wet milling: NMR (400 MHz, DMSO-d6) δ 7.87 (t, 1H) • U, 1 Η), 7·63 (d, 1H), 7.43 (d,1H), 7.39-7.26 (m,5H), (Melon 6 (m, 2H), 6.97 (t, 1H), 5.18 (s, 2H), 4.46 (s, 2H), 4.39, 4H) , 3.74 (m, 1H). MS (ESI) m/z: Calcd. Compound 7 0 ((s_(cyclohexyloxymethyl)benzofuran-2_ylbu 3_fluoro-benzyl)azetidine 3-carboxylic acid 119664.doc 200813031 5-(cyclohexyloxymethyl)benzene幷μ (step in process m)

The title compound was prepared as in Example Compound 5 (Step 丨): lH.sup.ss.sssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss s,2H) 3.41 (m,1H), L99 (m,2H), 1.78 (m5 2H), 1.58 (m5lH)? 1.41 (m5 2H)5l.23 (m5 3H) 〇5-(cyclohexyloxymethyl) Benzofuran-2-yl-acid (step 2 in Scheme A_3_b)

The title compound was prepared in the usual procedure as described above for the title compound (1) and used in the next step: lH (400 MHz, CDC13) δ 7·71 (m, 2H), 7.58 (m,1H), 7.47 (m 1H), 4.63 (s,2H) 3.42 (m,1H),1·99 (m,2H), 1.78 (m,2Ii) 1.58 (m,ih),1.41 (m , 3H), 0.95 (m, 3H). ' 4 —(5-(Cyclohexyloxyindenyl)benzoquinone-2-yl)-3_fluorobenzaldehyde (Step 3 in Scheme n b):

As in the case of the example compound A (step 4), the general title compound is as described above. 1H NMR (400 MHz, CDC13) δ 10.01 Method D Preparation (s, 1H), 119664.doc -185- 200813031 8·21 (t,1H), 7.78 (d,1H), 7.64 (d,1H), 7.61 (s, ΐΗ), 7·54 (d, old), 7.39 (m, 2H), 4.63 (s, 2H) 3.39 (m, 1H), 1.98 (m, 2H), 1·78 (m, 2H) , 1.34 (m, 2H), 1. 21 (m, 4H). Cyclohexyloxymethyl)benzofuran-2-yl)-3-fluoro-benzyl)azetidine_3_carboxylic acid (Step 4 in Scheme A_3-b):

The title compound was prepared as in Example Compound A (Step 5) using General Method E as described above. The product [hSIP1 EC5G=91 nM] was isolated by wet milling to the free base form: NMR (400 MHz, DMSO-d6) δ 7.84 (t, 1H), 7·62 (s, 1 Η), 7·58 (d, 1Η), 7.24 (m, 4Η), 4.58 (s, 2Η), 3.63 (m, 1H), 3.61 (s5 2H), 3.37 (m, 1H), 3_35 (m, 4H), 1_78 (m, 2H) , 1.61 (m5 2H) 1.41 (m, 1H), 1.18 (m, 5H). MS (ESI) m/z: Calcd.: 437. Compound 71 1-4-(5-(cyclopentyloxymethyl)benzofuran-2-yl)-3-fluoro-benzyl)azetidine-3-carboxylic acid 5-(cyclopentyloxymethyl)benzene Furfuran (Step 1 in Scheme A-3-b):

The title compound was prepared as in Example Compound 5 (Step 1). iH NMR (400 MHz, CDC13) δ 7.57 (d, 2H), 7·45 (d, 1H), 7.27 (d, 119664.doc -186 - 200813031 1H), 6.77 (s, 1H), 4.53 (s, 2H), 4·01 (m, 1H), 1.76 (m, 4H), 1·57 (m, 2H), 1.24 (m, 1H), 〇·94 (m, 1H). 5-(cyclopentyloxymethyl)benzofuran-2-yl-acid (step 2 in Scheme B-3-b):

The title compound was prepared in EtOAc (m.m.). m,1H), 7.38 (m,1H), 7.21 (m,1H),4·58 (s,2H),4.03 (m,1H),1·78 (m, 4H),1·56 (m, 2H), 1.24 (m, 1H), 0.96 (m, 1H). 4_(5_(cyclopentyloxyindolyl)benzofuran-2-yl)-3-fluorobenzaldehyde (Step 3 in Scheme A-3_b):

The title compound was prepared as in Example Compound A (Step 4) in the general procedure d as described above. 4 NMR (400 MHz, CDC13): δ 10.01 (s, 1Ή) 8.23 (t,1Η), 7.86 (d,1Η),7·66 (d,1Η),7·61 (s,1Η),7· 52 (d,1H),7·39 (m,2H),4.73 (s,2H) 4.03 (m,1H), 1.78 (m 4H),1·61 (m,2H),1.21 (m,ih) , 0.95 (m, 1H). Cyclopentyloxy fluorenyl)benzofuran-2-ylpyr-3-fluoro-benzyl)azetidine-3-carboxylic acid (Step 4 in Scheme A-3): 119664.doc -187- 200813031

CO OH

The title compound was prepared as in Example Compound A (Step 5) in General Method E as described above. NMR (400 MHz, CD3〇D) δ 8.14 (t, 1H), 7·48 (s, 1Η), 7.52 (d, 1Η), 7·41 (d, 2Η), 7.37 (m, 2Η), 4.58 (s, 2H), 4.43 (s, 2H), 4·39 (m, 4H), 4.04 (m, 1H), 3.63 (m, 1H), 1.78 (m, 4H), u (m, 2H) 121 (m, 2H). MS (ESI) m/z: Calcd: 422. Compound 72 (3-fluoro-4-(5-phenyl-n-decyl)benzoquinone n-glycosyl)benzyl)-butylate_3_ formic acid (3-fluoro-4-(5-phenylsulfonyl) Phenylfurfuryl)phenyl)methanol (Step 1 in Scheme A-5):

1-(3-Fluoro-4-(5-phenylthio)benzofuran-2-yl)benzyl)butyrate-3-carboxylic acid (50 mg, 0.12 mmol) and m-chloroperbenzoic acid ( A mixture of 100 mg, 0.36 mmol) in EtOAc (1 mL) MeOH (1 mL) was stirred at -20 °C for one hour and slowly warmed to room temperature overnight. The solvent was concentrated under reduced pressure to give a white solid. m.jjjjjjjjjjjjj 1Η), 8.03 (dd, 2Η), 7.71 (d, 1Η), 7.61 (d, 1Η), 7·58-7·43 (m, 3H), 7·22 (m, 4H), 4.77 (s, 2H). MS (ESI) m/z: Calcd. </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 382.07; observed: 383.0 (M++1). m (5-stupyl thiol) benzoquinone bite _2-yl) benzoyl (step 2 in silk A5):

(3fluoro-4_(5-phenylsulfonyl)benzofuranyl)phenyl)methanol (46 mg'0.12mm〇1) dM^A (〇25g), TpAp (〇〇〇21mg,

CHO 06·06 mm 〇 1) AN_ morpholinyl oxide (〇·〇29 g, 0.24 mmol) was stirred in acetonitrile + 1 s for 1 h and then filtered over Celite to give the title compound: NMR (400 MHz, CDC13) δ 10.02 (s,1H), 8.36 (s, 1Η), 8.20 (t,1Η), 8.01 (dd,2Η), 7.79 (d,1Η),7·71 (d,1Η), 7.62 (d, 1H), 7.56 (m, 5H), 4.77 (s, 2H). 1-(3-Fluoro-4-(5-phenylsulfonyl)benzofuran-5(benzyl)pyridinium_3_carboxylic acid (Step 3 in Scheme A-5):

3-Fluoro-4_(5-(p-thiophenyl)benzofuran-2-yl)benzaldehyde (49 mg, 0.14 mmol) and azetidin-3-carboxylic acid (3 〇mg, 〇28^^οΐ) The mixture in MeOH (1 mL) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (60 mg, 0.28 mmol) was added in two portions and the mixture was stirred 16 hr. The solvent was concentrated under reduced pressure to give a yellow solid, which was dissolved in EtOAc (3 mL) and filtered to afford a yellow Product: iH NMR (400 119664.doc -189-200813031 MHz, CD3〇D) δ 8.39 (s,1Η),8·16 (t,1Η),8·01 (d,2H), 7.96 (d,1H ), 7.76 (d, 1H), 7·62·7·41 (m, 6H), 4.46 (s, 2H), 4.38 (m, 4H), 3.64 (m, 1H). MS (ESI) m/z: Calcd.: 465. Azetidine-3-carboxylic acid 5-(4-fluorobenzyl)benzofuran:

The title compound (85% yield) was obtained from mpqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1H), 7.42 (d, "7=8.5, 1H), 7.37 (br s' 1H), 7.17-7.05 (m, 3H), 7.00-6.93 (m, 2H), 6.70 (dd, 2.2 , 0.7, 1H), 4.04 (s, 2H). 5_(4_fluorobenzyl)benzoquinone-2-yl-acid··

&amp; The title compound (64% yield) was obtained as one of the ones described above, as in Example Compound B (Step 2 in Scheme A2): 1 h nmr (4 〇〇 MHz, C13) δ 7·43, 7·41 (m, 2H), 7.30 (br s, 1H), 7.18-7.13 (m, 3H), 6·99-6·95 (m, 2H) 4 〇 4 (s 2H). Fluorine 4 (5-(4-fluorobenzyl)benzofuranyl)benzaldehyde: H9664.doc 200813031

The title compound was prepared as in the above-mentioned compound B (Step 3 in Scheme A2) in one of the above. 1H NMR (400 MHz, CDC13) δ 1〇·00 (d' J==1·8,1Η), 8·20 (t, J=7.7,1Η), 7·77 (dd, J=8.0, K5 ' iH)' 7·67 (dd, J=11.4, 1.5, 1H), 7.48-7.43 (m, 2H), 7·36 (dd, J==3·6, 0·8, 1H), 7.19- 7.15 (m, 3H), 7.00-6.96 (m, 2H), 4.06 (s, 2H). 1 (4-(S-Benzyl albinofuran-2-yl)_3_gasbenzyl)azetidine_3_carboxylic acid:

The title compound [hSlPl EC5 〇 = 53 nM] was prepared by the usual procedure as described above in the procedure of Compound B (Step 4 in Scheme A-2). 4 NMR

(400 MHz, DMSO-d6) δ 8.12 (d, J = 8.0, 1H), 7.49-7.40 (m, 4H), 7.29-7.20 (m, 4H), 7.02-6.97 (m, 2H), 4.47 (br s, 2H), 4.41-4.33 (m, 4H), 4·06 (s, 2H), 3.75-3.66 (m, 1H). MS (ESI) m/z: Calcd. Compound 74 1-(4-(5-(cyclohexylmethyl)benzofuran-2-yl)-3-fluorobenzyl)azetidine_3-carboxylic acid 5-(cyclohexylmethyl)benzofuran : 119664.doc -191 - 200813031 CTO) The title compound was prepared as in Example Compound B (Step 1 in Scheme A-2) in the same manner as described above. iH NMR (400 MHz, CDC13) δ 7·58 (d, J=2.2, 1Η), 7·39 (d, J=8.4, 1Η), 7.34 (br s,1Η), 7·07 (dd5 J= 8.23 i.5? iH)5 6.70 (dd, J=2.25 0.8, 1H)5 2.57 / j ' 7·3, 2H), 1.70-1.60 (m, 5H), 1.58-1.48 (m, 1H), 1.22 - i·15 (m, 3H), 1·00_0·94 (m, 2H). - (4_ Benzyl) benzofuran-2-yl-based acid: The title compound was prepared as one of the above-mentioned compound B (Step 2 in Scheme a-2). 1H NMR (400 MHz, CDC13) δ 7·41·7·39 (m, 2Η), 7·3! (s, 1Η), 7·14 (dd, piece ·1,1.5, 1Η), 2·57 (d, J=7.9, 2Η), 1·7 (Μ·52 (m, 6Η), 1.25-0.94 (m, 5Η). l 3_Fluoro-4·(5_(4_fluorobenzyl)benzoquinone Furanyl)benzaldehyde: The title compound was prepared as in Example Compound B (Step 3 in Scheme A-2) in General Method D as described above. 1H NMR (400 MHz, CDC13) δ: 〇:0 (d , J==1·8, 1Η), 8·2〇(t, wind 3, 1Η), 7·77 (dd, J=8.0, ·4', 7.67 (dd, J=11.2, 1.6, 1H ), 7.45-7.37 (m, 3H), 7·15 (dd, &gt;8·4, 1&gt;5, 1H), 2.58 (d, J=6.9, 2H), mu H9664.doc -192- 200813031 ( m,6H),ΐ·26-〇·94 (m,5H). 1-(4-(5-Phenylbenzofuran-2•yl)_3_qibenzyl)azetidine-3_carboxylic acid:

The title compound [hSIP1 EC5G = 400 nM] was prepared by the usual procedure as described above in the procedure of Compound B (Step 4 in Scheme A-2). 4 NMR (400 MHz, DMSO-d6) δ 8·12 (d, J=8.0, 1H), 7.46-7.40 (m, 4H), 7.27 (d, J=3.5, ih), 7·ι6 (br d , J=i0.2, iH), 4.46 (br s' 2H)5 4.36-4.34 (m, 4H), 3.71-3.63 (m, 1H), 2.58 (d, J-7.1, 2H), 1.76" 55 (m,6),! 3(M 〇6 (m,5H). MS (ESI) m/z: calc.: 4221.21. Obs. (2-fluorobenzyl)benzofuran-2-yl)benzyl)azetidine 5-(2-fluorobenzyl)benzofuran:

The title compound was prepared as in Example Compound B (Step 1 in Scheme A2) as in one of Method A above. iH NMr (4〇〇MHz, CD3OD) δ 7.68 (s,1H), 7.40 (d, J=l〇.4 Hz, 1H), 7·38 (d, J=8.0 Hz, 1H), 6.97-7.22 (m, 5H), 6.74 (S, 1H), 4.06 (s, 2H). 5-(2-fluorobenzyl)benzofuran-2-yl-acid: 119664.doc -193 - 200813031

pH OH I Compound B (manufacturing the title compound in the same manner as in the next step. In the next step, step 2), a compound of the above-mentioned compound is used as described above without further purification. Take a ride:

The title compound was prepared in the same manner as described above for the compound Β (Step 3 in Scheme Α-2). Lfi nmr (4〇〇MHz, cDclj δ 9·99 (s, 1Η), 8.19 (t, J=7.2 Ηζ, 1Η), 7.76 (d, J=8.0 Ηζ, 1Η), 7·67 (d, / =11·2 Hz,1H),7·47 (d,/=9·2 Hz, 2H), 7.35 (d, J 3·6 Hz, 1H), 7.25 (m, 3H), 7.26 (m, 2H) ), 4.10 (s, 2H). 1-(3-Fluoro-4_(5-(2-fluorobenzyl)benzofuran-2-yl)benzyl)azetidine_3•decanoic acid:

0H

The title compound [hSIP1 EC5 〇 = 129 nM] was prepared as in Example Compound B (Step 4 in Scheme A-2). 4 NMR (400 MHz, CD30D) δ 8.12 (dd, J = 7.6, 8.4 Hz, 1H), 7·49 (m, 2H), 7.43 (m, 2H), 7.24 (m, 4H), 7.07 (m, 2H), 4.47 (s, 2H), 4.37 (m, 4H), 4·10 (s, 2H), 3.71 (m, 1H). 19F NMR (376 MHz, CD30D) δ-77·6 (TFA), -113.1, -120.6. MS (ESI) m/z: </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Compound 76 1 (3-Fluoro-4-(5-(3-fluorobenzyl)benzofuran-2-yl)benzyl)azetidine-3_carboxylic acid fluorobenzyl)benzoquinone

The title compound was prepared by one of the methods described above as in the procedure of the compound </RTI> (Step 1 in Scheme </RTI>-2). iH NMR (400 MHz, CD3〇D) δ 7·68 (s, 1Η), 7·41 (d5 /=6.8 Ηζ, 1Η), 7·40 (d, J=8.4 Ηζ, 1H)5 7.26 (m ? 1H)? 7.13 (d5 J=8.0 Hz, 1H)? 7.02 (d, /=8.0 Hz, 1H), 6.89 (m, 2H), 6.76 (m, 1H), 4.04 (s, 2H). 5-(3-fluorobenzyl)benzofuran-2-ylfolic acid:

PH day,

OH The title compound was prepared as described in the title compound C (Step 2 in Scheme A-2). 1H NMR (400 MHz, DMSO-d6) δ η Cry • (s, 1Η), 7·48 (d, /=8.4 Ηζ, 1Η), 7·38 (s, 1Η), 7.31 (m, 1H), 7.21 (d, J = 5.2 Hz, 1H), 7·20 (m, 2H), 6.98 (m, 1H), 4·04 (s, 2H). 3-gas, 4-(5-(3-fluorobenzyl)benzofuran-2-yl)benzaldehyde:

CHO The title compound was prepared as in Example Compound B (Step 3 in Scheme </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; iH NMr (400 MHz, CDC13) δ 10.03 (S, 1H), 8.20 (t, Hz, 1H), 7.79 (dd, /= 8.4, 1.2 Hz, 1H), 7.69 (dd, J=li_6, i 2 Hz , ih), 7.49 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 6. Hz, 1H), 7.37 (d, J = 3.6 Hz, 1H), 7.26 (m, 1H), 7.21. (dd, /=8.8,1·2 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.92 (m, 2H), 4.08 (s, 2H). 1-(3-Fluoro-4-(5-(3-fluorobenzyl)benzofuranyl)benzyl)azetidine_3_carboxylic acid: q,

OH

The title compound [hsipi ec5 〇 = 169 nM] was prepared as in Example Compound B (Step 4 in Scheme A-2). 4 NMR (400 MHz, CD3OD) δ 8.10 (t, J = 8.0 Hz, 1H), 7.49 (dd, &gt; 9.6, 9·6 Hz, 2H), 7.43 (dd, J=8.0, 11.2 Hz, 1H) , 7.40 (dd, LJ=3·2, 10.8 Hz, 1H), 7.28 (m, 3H), 7.06 (d, "7=7.6 Hz, 1H), 6.92 (m, 2H), 4.45 (s, 2H) , 4.34 (m, 4H), 4.08 (s, 2H), 3.68 (m, 1H). 19F NMR (376 MHz, CD3OD) δ -77.4 (TFA), -116_2. MS (ESI) m/z: Found: 437. Compound 77 1 (3-Fluoro-4-(5-phenoxybenzofuran-2-yl)benzyl)azetidine-3-carboxylic acid 1-(3-fluoro-4-(5-phenoxybenzene) Methyl furan-2-yl)benzyl)azetidine-3-carboxylate: 119664.doc -196- 200813031

Except for the use of methyl 1-(4-bromo-3-trifluorobenzyl)azetidine-3-carboxylate, as in the case of the example compound A (step 5 in Scheme A-1), as described in the general procedure described above The title compound (54% yield). The product was separated into the free form by wet-milling: MS (ESI) m/z: Calculated: 431·15; observed: 432.00 (Μ++1). 1-(3_Fluorophenoxybenzoxanyl)benzyl)ρ丫丁唆-formic acid:

Lithium hydroxide hydrate (30 mg, ι·25 mm 〇1) in 1 mL of water was added to a solution of the ester (110 mg, 0.25 mmol) in 2 mL THF. The mixture was stirred until complete. The solvent was removed and the solid was suspended in 2 mL water. Three equivalents of 2 N HCl were then added to neutralize the base and the mixture was sonicated. Add 4 mL of 1 M pH 6 citrate buffer and sonicate the reaction. The syrup was filtered and the solid was washed with water and EtOAc (EtOAc EtOAc) 4 NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.65 (s, 1H), 7.30 (m, 6H), 6.97 (m, 4H), 3.58 (m, 3H), 3.40 ( m, 4H). 19F NMR (376 MHz, DMSO-d6) δ _113·7. Ms (ESI) m/z: Calcd.: 417.14; observed: 417.90 (M++1). Compound 78 119664.doc •197- 200813031 5-(1-(4-(5-Benzylbenzofuran-2-yl)_3_fluorobenzyl)azetidine_3_yl)_ 2H-tetrasodium 5_ (1·- ~ base mouth biting _3_ base) -211- four saliva (step 1 in process a-8):

1-1,4-Benzyl-butadiene-α-nitrile (2.48 g, 1〇mm〇i), trimethyl-stone-azide azide (2.30 g, 20 mmol) and oxidized (dibutyl)tin (498) Mg, 2.0 mmol) was dissolved in toluene (20 mL) and heated to reflux for 32 h. The reaction mixture was then cooled to room temperature and applied directly to the ISCO system with 1% methanol in methylene chloride to afford product. 4 NMR (400 MHz, CDC13) δ 7·54 (m, 4H), 7·31 (m, 6H), 5·11 (s, 1H), 4·47 (m, 1Η), 4.05 (t, J =7.2 Ηζ, 2Η), 3·91 (t, /=7.2 Ηζ, 2Η). MS (ESI) m/z: calc.: 291.15; observed: 291.90 (M++1) 〇5-(吖丁乙-3-yl)-2H-tetrasole hydrochloride (Process A-8) Step 2):

To a solution of (500 mg, 1.72 mmol) in MeOH (5 mL) and EtOAc (5 mL), EtOAc. The mixture was stirred under a hydrogen atmosphere for 72 hours. The catalyst was removed by filtration from 119664.doc 198-200813031 and solvent was removed under reduced pressure to afford crude compound which was used in the next step without further purification. Ms (ESI) m/z: Calcd.: 5-(1-(4-(5-Benzylbenzofuranyl)_3_fluorobenzyl)azetidine_3_yl)_ 2H-four jun:

The title compound [hSIPl EC5〇] was prepared as described in the general procedure e as described above, except for the use of the butyl 3-amino-2H-tetrahydrochloride salt, as in the compound of Example A (Step 5 in Scheme A-1). =2090 nM]. 4 NMR (400 MHz, CD3OD) δ 8·13 (t, J = 8.8 Hz, 1H), 7.48 (m, 4H), 7.25 (m, 7H), 4.63 (m, 4H), 4·51 (m, 3H), 4.07 (s, 2H). 19F NMR (376 MHz, CD3OD) δ -77.4 (TFA), -113.1. MS (ESI) m/z: Calcd.: 437. Compound 79 1-(4-(4-Benzylbenzylidinamide)_3_fluorobenzyl)azetidine-3-carboxylic acid 4-(4-benzylbenzimidino)-3-fluorobenzoic acid Ethyl ester (Step 1 in Process A-9):

Ethylene dichloride dichloride (1 mL) followed by a few drops of DMF was added to 4-119664.doc -199-200813031 benzylbenzoic acid (1.06 g, 53⁄4 mol) in dichloromethane mL) at 0 °C In the solution. The resulting mixture was stirred at room temperature for 3 hours. The solvent was removed to give a residue which was dissolved in dichloromethane (2 mL). Add it to diethylamine (1.4 mL, 1 〇mm〇i) &amp; 4_Amino_3_fluorobenzoic acid ethyl ester (916 mg, 5 mmol) in dichloromethane (5 mL) In the solution. After stirring at room temperature for 48 hours, the mixture was washed with saturated sodium bicarbonate and 1 N EtOAc. The combined organic extracts were washed with brine, dried and dried then evaporated. The desired product was obtained as a milky white solid. Η NMR (400 MHz, CDC13) δ 8·63 (t, J = 8.8 Hz, 1H), 8·20 (s, 1H), 7.83 (m, 4H), 7.18-7.35 (m, 6H), 4.39 ( q, J = 7.2 Hz, 1H), 4.07 (s, 2H), 1.40 (t, "/= 7.2 Hz, 3H). 4-benzyl-N-(2-fluoro-4-(hydroxymethyl)phenyl)benzamide (Step 2 in Scheme a-9):

Adding sodium borohydride (2 〇〇 mg, 5 · 3 mmol) to 4_(4-membered basic formamidine)-3-fluorobenzoic acid methyl ethane at room temperature (1 〇〇 mg, 0.265 Methyl) in MeOH (1 mL). The mixture was stirred at room temperature for 3 days. The solvent was removed to give a residue. EtOAc m. The organic layer was separated, dried and concentrated. The residue was purified on an ISCO system (1%MeOHMeOHMeOH) NMR (400 MHz, 119664.doc -200-200813031 CDC13) δ 8.44 (t, J=8.0 Hz, 1H), 8.02 (s, 1H), 7_80 (d, J=8.4 Hz, 2H), 7.15-7.34 ( M5 8H), 4.69 (d, J = 6.0 Hz, 1H), 4.06 (s, 2H) 0 4_nodyl_N-(2_fluoro-4-methylformamide)benzamide (flow a- Step 9 of 9):

f, 4-benzylfluoro-4-(hydroxymethyl)phenyl)benzamide (2 mg, 0.60 mmol), 4-methylmorpholine N-oxide (14 mg, 1.2 mmol) And a mixture of 4 A molecular sieves (1 g) in 10 ml of CHsCN was treated with tetrapropylammonium perruthenate (10 mg, 0- 03 mmol) and the mixture was stirred at room temperature for 12 hours. The solid was filtered and the filtrate was concentrated. The residue was purified on an ISC0 system (yield: hexanes: hexanes) 1h NMR (400 MHz, CDC13) δ 9.93 (s,1H), 8.80 (t, J=8.〇Ηζ,1Η),8·25 (s,1Η),7·84 (d,J=7.2 Ηζ, 2Η),7·74 U (d5 J=8.4 Hz5 1H)? 7.69 (d5 7=10.8 Hz, 1H), 7.19-7.37 (m, 6H), 4·〇7 (s, 2H). 1(4-(4-Benzylbenzylidinium)-3-fluorobenzyl)azetidinecarboxylic acid:

As in the case of the example compound A (step 5 in the scheme A-2) as described above

</ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; ), 4.33 (m, 4H), 4.06 (s, 2H), 3.71 (m, 1H). 19F NMR (376 MHz, CD3OD) δ-77·4 (TFA), -123.4. MS (ESI) m/z: Found: 437. Compound 80 1-(4-(2-Benzylbenzofuranylfluorobenzyl)azetidinecarboxylic acid (5-phenylenefuran-2-yl)(phenyl)methanone (steps in Scheme A-6) 1):

5-Bromo salicylaldehyde (2.01 g, 1 mmol), carbonated (3·26 g, 1 mmol) and acetonitrile (100 mL) were combined and heated to reflux for 30 min. The mixture was cooled to 〇 ° C and a solution of 2-bromo-1-phenylethyl ketone (1.99 g, 10 mmol) in acetonitrile (20 mL). The cooling bath was removed, the mixture was spoiled for 5 hrs, and the precipitate was collected to give the desired product as a white solid: 4 NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 2.0 Hz, 1H), 7·98 (d, J=7.6 Hz, 2H), 7.68_7·78 (m, 4H), 7.60 (dd, &gt;7·6, 8·0 Hz, 2H). 2-benzyl-5-bromobenzofuran (Step 2 in Scheme a-6):

(5-Xibenzofuran-2-yl)(phenyl)methanone (2〇g, 6.6 mmol), chaotic sodium (3·2 g, 51 mmol), zinc moth 2.6 g, 13 2 mmol) and 1,2-dialdehyde (5 〇 mL) were combined and heated to reflux overnight. The 119664.doc -202-200813031 was cooled, saturated with saturated ammonium chloride, acidified with concentrated HCl and stirred for 30 / kn. The layers were separated, the aqueous layer was extracted with methylene chloride (2.times.ssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss The residue was purified by silica gel column chromatography (ISCO system, 20% of hexanes of hexane) to afford product as a white solid. H NMR (4 〇〇 MHz, CDC13) δ 7.59 (s, 1H) ), 7.27-7.34 (m, 7Η), 6.32 (s, 1Η), 4·10 (s, 2Η). 4-(2-Phenylbenzofuran-5-yl)-3_fluorobenzaldehyde (Step 3 in Scheme a-6):

2-Fluoro-4-carboxylphenyl phthalic acid (58 mg, 0.348 mmol), 2-pyristyl-5-bromobenzopyran (5 〇 mg, 0174 mmol), hydrazine (triphenylphosphine)| A solution of saponin (0) (20 mg, 0.0174 mmol) and sodium carbonate (106 mg, 1.0 mmol) in 1,4-dioxane (4 mL) and water (1 mL) Heat for 12 hours. The mixture was partitioned between brine (20 ml) and EtOAc (20 mL). Dry the organic layer. The solvent was removed to give a residue, which was purified eluted eluted eluted elut elut CDC13) δ 1〇.〇(s,1Η), 7.61-7.75 (m,5Η), 7.27-7.51 (m,7Η), 6.45 (s,1Η), 4.14 (s,2H). 1-(4-(2-Benzylbenzofuran-5-yl)-3-fluorobenzyl)azetidine_3_carboxylic acid: 119664.doc -203 - 200813031

OH

The title compound was prepared in the form of a white TFA salt as described in Example Compound A (Step 5 in Scheme A-2) as the title compound as a white TFA salt [hSIPl c, EC50=59 nM] 〇4 NMR (400 MHz, CD3OD) δ 7.66 (s,1H), 7.61 (t, J=8.8 Hz, 1H), 7.48 (d, /=8.4 Hz, 1H), 7.29-7.39 (m,7H),7·25 (m,1H), 6.50 (s, 1H), 4.45 (s, 2H), 4.35 (m, 4H), 4.13 (s, 2H), 3.71 (m, 1H). 19F NMR (376 MHz, CD3OD) δ·77·4 (TFA), -118.3. MS (ESI) m/z: Calcd. Compound 81 1-(4-(5-~Basic 幷[b] 嗟 ··2 -yl)-3 - agglomerate 丫丁丁-3_carboxylic acid 5-benzylbenzoquinone thiophene (in Scheme A-7) step 1):

5-Bromoquinonethiophene (2.13 g, 10 mmol) was dissolved in a THF solution of benzylzinc bromide (11) (0.5 Μ, 10 mL, 20 mmol) in a microwave reaction. will? 4 (?$113) 2 (255 mg, 0.5 mmol) was added to the solution. The mixture was purged with N 2 gas for 3-5 minutes and heated under microwave irradiation for 3 Torr at 10 °C. After the reaction was completed, the~~~~~~~~~~~~~ The filtrate was dried over Na 2 SO 4 and concentrated. The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut elut 7·79 (d, /=8.4 Hz, 1H), 7.63 (s, 1H), 7.40 (d, J = 5.6 Hz, 1H), 7.18-7.30 (m, 7H), 4.10 (s, 2H). 4-(5-Benzylbenzoquinone[b]thiophene-2-ylfluorobenzaldehyde (Step 2 in Scheme A-7):

4-&gt;Smell-3_Ibenzoic acid (40 mg, 0.198 mmol), 5-benzylbenzophenone (44 mg, 0.198 mmol), acetic acid (5 mg, 0.05 mmol), hydrazine (diphosphine) a mixture of (0) (11 mg, 0.010 mmol) and N,N-dimethylacetamide (5 mL) was heated at i5 (rc) for 12 h. The solvent was evaporated in vacuo and the residue was taken from water (50 mL) wet-milled and extracted with dichloromethane (2×1 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (ISCO system, 5% Purification of EtOAc in hexanes to give the desired product: 4 NMR (400 MHz, CDC13) δ 9.90 (s, 1H), '64-7.85 (m, 6 Η), 7.22-7.33 (m, 6 Η), 4· 11 (s, 2Η). (4-(5-Benzylbenzoquinone[b]thiophen-2-yl)-3-fluorobenzyl)azetidine_3•carboxylic acid:

The title compound [hSIP1 EC5 〇 = ll nM] was prepared by the usual method E as described above, except for the compound of Compound A (Step 5 in Scheme A-2). Towel NMR (400 MHz, CD3〇D) δ 7.79 (t, /=8.4 Ηζ,1Η), 7.69 (m,2Η), 119664.doc 200813031 7.59 (s,1Η),7·30 (m,2H), 7.06-7.20 (m, 6H), 4.35 (s, 2H), 4.27 (m, 4H), 3.99 (s5 2H), 3.61 (m, 1H). 19F NMR (376 MHz, CD3 〇D) δ-77·4 (TFA), -113.5. MS (ESI) m/z: Calcd.: 431. Compound 82 3-(4-(5-Benzylbenzofuranyl)_3_fluorobenzylamino)_2-mercaptopropionic acid 3-(4-(5-benzylphenylfurfuryl)-3-fluoro Benzylaminomethylpropionic acid (Step 1 of Scheme A-13)

By using 4-(5-phenylbenzofuran-2-yl)-3·fluorobenzaldehyde (80 mg, 0.24 mmol), DL_3_aminoisobutyric acid in a similar manner to that described in General Procedure E (49.9 mg, 〇·48 mmol), sodium cyanoborohydride (30.4 mg, 0·48 mmol), acetic acid (3 〇μ[), methanol (3.5 mL) and dichloromethane (2·5 mL) 3-(4-(5-Benzylbenzofuran-2-yl)-3-fluorobenzylamino)-2-methylpropanoic acid as a TFA salt (white solid [hS1P1 eC5 〇=1300 nM]) . lR NMR (400 MHz, CD3OD) δ 8.11 (t5 J=8.0 Hz?lH), 7.49- 7.43 (m,4H)5 7.29-7.14 (m,7H),4.31 (s,2H),4.07 (s,2H) ), 3.32-3.28 (m, 1H), 3.10 (dd, "7=4.6, 12.2 Hz, 1H), 2_88 (m, 1H), 1.29 (d, J = 7.2 Hz, 3H); 19F NMR (376 MHz , CD3OD) δ-77·5 (TFA), -113.5 〇 MS (ESI) m/z: Calculated (N/TF): 417.47; observed: 417.9 (M++1). Compound 83 4-amino-2-(4-(5-benzylbenzofuran-2-yl)_3-fluorobenzylamine oxime ' side oxygen 119664.doc -206- 200813031 4-butyl acid -2-(4-(5-Benzylbenzofuranyl)_3_fluorobenzylamino)_4_ oxobutyric acid (step y of Scheme A-13

By using 4-(5-phenylbenzofuran-2-yl)_3_fluoro-benzaldehyde (83·9 mg, 〇·25 mm〇1), in a manner similar to that described in General Procedure E, Dl·aspartic acid glutamic acid monohydrate (76.3 mg, 0.51 mmol), acetic acid (30 pL), sodium cyanoborohydride (32 mg, 0.5 i mmoi), decyl alcohol (3.5 mL) and two gases 4-Amino-2_(4-(5-benzylbenzofuran-2-yl)-3-fluorobenzylamino)_4_sideoxy group obtained as a TFA salt in decane (2.5 mL) Butyric acid (white solid [hSIPl EC5 〇 = 2300 nM]). 4 NMR (400 MHz, CD3OD) δ 8.10 (t, &gt;8·0 Hz, 1H), 7·48_7·44 (m, 4H), 7.29-7.15 (m,7H),4·39 (q,/ = 12.8 Hz, 2H), 4·26 (b, 1H), 4.07 (s, 1H), 3.60 (q, J = 6.8 Hz, 1H), 3.13 - 2.88 (m, 2H); 19F NMR (376 MHz, CD3〇D) δ -77.5 (TFA), -113.5. MS (ESI) m/z: calcd. (m.m.): 446.47; observed: 446.9 (M++1). Compound 84 1-((6-(5-benzylbenzofuran-2-yl)-5-fluoropyridin-3-yl)indolyl)azetidine-3-carboxylic acid 5-(methyl)-2 - gas _3_ fluoropyridine (step 1 of Scheme A-11)

Addition of gasified benzamidine (100 mg, 41 mmol) to 2- gas-3-fluoro-5-119664.doc-207-200813031 methylpyrazine (5.0 g, 34.35 mmol) and NBS (6.73 g) , 37.79 mmol) in a refluxing mixture in CCU (180 mL). After stirring the mixture for 15 minutes, an additional amount of benzoquinone (400 mg, 1.65 mmol) was added in four portions over 1 hour and stirring was continued for 1 hour. The reaction mixture was cooled to room temperature, filtered and the solid was washed with dichloromethane. The combined mash was washed with water, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The crude product was purified by silica gel column chromatography (hexanes / ethyl acetate) to afford 5 _ (bromomethyl)-2-chloro-3-fluoropyridine: NMR (400 MHz, CDC13) δ 8.23 (d, /=2.0 Ηζ, 1Η), 7.55 (dd, /=2.0, 8·8 Ηζ, 1Η), 4.45 (s, 2H). 6-gas _5-fluoronicotinaldehyde (Step 2 of Process A-u)

5-(Bromomethyl)-2-chloro-3-fluoro-3-one (2. 0 g, 8.91 mmol) and hexamethylenetetramine (2.75 g, 19.6 mmol) in 50% aqueous acetic acid (53 ml The mixture in the mixture is heated to reflux. After 1 hour, the mixture was cooled to room temperature, carefully neutralized with solid NaHC03 (73.7 g), diluted with water (4 mL) and extracted with di-methane (2 x 1 〇〇 mL). The combined organic extracts were dried over anhydrous sodium sulfate, EtOAc (EtOAc m. Nicotinic aldehyde: NMR (400 MHz, CDC13) δ 10.12 (d, J = 2.4 Hz, 1H), 8.72 (d5 J = 1.6 Hz, 1H), 7.94 (dd, /=2·0,8·0 Hz, 1H); 19F NMR (376 MHz, CDC13) δ -116.3. 119664.doc -208 - 200813031 1-((6-Gapent-5-fluoropyridin-3,yl)methyl)azetidine-3_carboxylic acid (Step 3 of Scheme A-ll)

COOH was tested in a similar manner to that described in General Procedure E by using 6-chloro-5-fluoroacetic acid (2 84 mg, 1.78 mmol), succinimin-3-carboxylic acid (184 mg, 1.82 mmol), Preparation of sodium cyanoborohydride (112 mg, 1.78 mmol), acetic acid O (0355 mL), decyl alcohol (6 mL) and dioxane (6 mL). σ定_3_基)methyl) 丫丁丁定_3_carboxylic acid (2〇3 mg, 0.83 mmol, white solid). MS (ESI) m/z: calcd (m.m.): 244.65; observed: 245.1 (M++1) 〇1-((6-(5-V-phenylbenzophene-2-yl)-5 - defeat. than bite _3_ base) methyl butyl bite _ 3-carboxylic acid (step 4 of process A-11)

COOH is used in a similar manner to that described in General Procedure D by using 5-benzylbenzofuran-2-yl-acid (272 mg, 108 mm 〇1), fluoropyridin-3-yl)methyl) hydrazine Butyridine_3_carboxylic acid (2〇3 mg, 〇83 mm〇1), palladium acetate (9.3 mg, 41.5 μιηοΐ), 2-(di-t-butylphosphino)biphenyl (24·8 mg, 83 Ηηιοί) and THF (15 mL) gave 1-((6-(5-benzylbenzofuran-2-yl)-5-fluoropyridyl)methyl)azetidine-3_曱 as a TFA salt Acid (fire n color solid [hSIPl EC50 = 470 nM]). 1h NMR (400 MHz, 119664.doc -209-200813031 CD3OD)5 8.59 (S,lH), 7.91 (d,J=11.7 Hz, lH), 7.56-7.51 (m, 3H), 7.30-7.12 (m, 6H), 4.55 (s, 2H), 4·4〇 (m, 4H), 4.08 (s, 2H), 3.72 (m, 1H); 19F NMR (376 MHz, CD3OD) δ -77.5 (TFA),- 120.8. MS (ESI) m/z: Calcd. (t.): 416.44; observed: 416.9 (M++1). Compound 85 4-Amino-3-(4-(5-benzylbenzofuran-2-yl)-3-fluorobenzylamino)-4-yloxybutanoic acid 4-Amino-3-(4 -(5-benzylbenzofuran-2-yl)-3-fluorobenzylamino)-4-oxobutanoic acid (Step 1 of Scheme A-13)

By using 4-(5-phenylbenzoin-2-yl)_3_fluorobenzoic acid (80 mg, 0.24 mmol), DL-3,4-di, in a similar manner as described in General Procedure E Amino-4-oxobutyric acid (32 mg, 0.48 mmol), acetic acid (30 μ! 〇, sodium cyanoborohydride (30·4 mg, 0.48 mmol), decyl alcohol (3.5 mL) and Methane (2.5 mL) was obtained as a TFA salt in the form of a 4-amino-3-(4-(5-benzylbenzofuran-2-yl)-3-fluorobenzylamino)-4- side Oxybutyric acid (white solid [hSIP1 EC50 = 1 880 nM]). 4 NMR (400 MHz, DMSO-d6) δ 7·91 (t, / = 8.0 Ηζ, 1 Η), 7·62 (s, 1 Η) , 7.54 - 7.52 (m, 2 Η), 7.43 (d, / = 12.8 Hz, 1H), 7.34 (d, / = 7.6 Hz, 1H), 7.29-7.14 (m, 6H), 4.02 (s, 2H), 3.95-3.75 (m, 2H), 3·54 (b, 1H), 2·65-2·40 (m, 2H); 19F NMR (376 MHz, DMSO-d6) δ-77·5 (TFA), -117.4. 119664.doc -210-200813031 MS (ESI) m/z: calcd (t (t)): 446·47; observed: 446·9 (M++1). 4-(5-(4-methylbenzyl)benzofuranyl)benzyl)azetidine_3_carboxylic acid 5-(4-methylbenzyl)benzoquinone (flow a_2 step 1)

(y) By using (4-mercaptobenzyl)zinc(11) chloride (14.7 mL of a 0.5 Μ solution in THF, 7.35 mmol), 5-bromobenzene, in a similar manner as described in General Procedure A幷吱 ( (5 〇〇 mg, 2.53 mmol) and Pd(tBu3) 2 (64·8 mg, 〇·ΐ 27 mmol) gave 5-(4-methylbenzyl)benzofuran as a colorless oil. 1H NMR (400 MHz, CDC13) δ 7.55 (d, / = 2.0 Ηζ, 1 Η), 7.40-7.37 (m, 2 Η), 7.12-7.06 (m, 5 Η), 6.66 (m, 1H), 4.02 (s, 2H) ), 2·30 (s, 3H) 5-(4-mercaptobenzyl)benzofuran-2-yl-acid (Step 2 in Scheme a-2)

CJ 5-(4-methylbenzyl)benzoquinone (253 mg, 1.138 mmol) was converted to 5-(4-methyl) as a white solid in a similar manner as described in General Procedure C Benzene furan-2-yl-acid·· iH NMR (400 MHz, CDC13) δ 7.44-7.38 (m, 2H), 7·30 (s, 1H), 7.19 (d, J=8.4 Hz, 1H ), 7·1〇(s, 4H), 5.04 (b, 2H), 4.04 (s, 2H), 2.32 (s, 3H). 1-(3-Aza-4_(5-(4-methylbenzyl)benzofuran-2-yl)benzyl)azetidine 119664.doc -211 · 200813031 Methyl formate (Steps of Scheme B-12) 1)

5-(4-Methylbenzyl)-benzoquinone was obtained in a similar manner to that described in General Procedure D. Southern-2-yl-fatanoic acid (150 mg, 0.56 mmol) was reacted with ι_(4- -3- fluoro fluoro) butyl hydrazide-3-carboxylic acid methyl ester (155 mg, 0.51 mmol) to give a white solid. Methyl 1-(3-fluoro-4-(5-(4-methylbenzyl)benzofuran-2-yl)benzyl)azetidine-3-carboxylate: MS (ESI) m/z: Calculated: 443.51; observed: 444.0 (M++1). 1-(3-Fluoro-4-(5-(4-methylbenzyl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid (Step 2 of Scheme B-12)

In a manner similar to that described in the general procedure, fluoro-4-(5-(4-methylindenyl)benzifur-2-yl)pyrrolidine succinyl _3_carboxylic acid Hydrolysis to obtain 1-(3-fluoro-4-(5-(4-methylbenzyl)benzoquinone-2-yl)benzyl)indole as a white foam Butyridine_3_carboxylic acid [hsipi EC5〇=12 nM] : ln NMR (400 MHz, DMSO-d6) δ 7.87 (t5 /=8.0 Hz, 1H), 7.52 (d, J = 8 Hz, 1H), 7 · 48 (d, /=1.2 Hz, 1H), 7.25 (d, J=6.8 Hz, 1H), 7.23 (s, 1H), 7.21 (d, /=3.2 Hz, 1H), 7.17 (dd, /= 1.2,8_8 Hz,1H),7.11 (d, "7=7.6 Hz, 2H), 7.07 (d, /=8.0 Hz, 2H)· 3.96 (s, 2H), 3·58 (s, 2H), 3.39 119664.doc -212- 200813031 (m,2H), 3.18 (m,3H), 2.22 (s,3H); 19F NMR (376 MHz, DMSO-D6) δ-113·7. MS (ESI) m/z ··············· Compound 87 l-(4_(5-Benzyl-2H-indazol-2-yl)-3-fluorobenzyl)azetidine_3_carboxylic acid 5-bromo-2-nitrobenzaldehyde (Process A-10 Step 1)

BrV^/CHO

XX no2 γ, .

5-Nial-2-nitrophenylhydrazine (11.71 mL, 100 mmol) was added dropwise to concentrated nitric acid (10 mL) in concentrated sulfuric acid (120 mL) at 5 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured onto ice and the obtained crystals were evaporated, evaporated, evaporated The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford 5-bromo-2-nitrobenzaldehyde: H NMR (400 MHz, CDC13) δ 10.42 (s, 1H), 8.07 (d, J = 2.0 Hz, 1H), , 8·03 (d, ^/=8.6 Hz, 1H), 7·88 ( Dd, &gt; 2·0, 8.6 Hz, 1H). v (E)-4-(5-Bromo-2-nitrobenzylideneamino)-3-fluorobenzoic acid ethyl ester (Step 2 of Scheme A-10)

C〇2Et 5-bromo-2-nitrobenzaldehyde (2.79 g, 12.13 mmol) and ethyl 4-amino-3-fluorobenzoate (2.22 g, 12.12 mmol) in ethanol (6 mL) The mixture was stirred under reflux for 2 hours. After removing the solvent under reduced pressure, the mixture of 119664.doc - 213 - 200813031 was purified by silica gel column chromatography to obtain a pale yellow solid. -4-(5-bromo-2 nitro Benzylamino)_3_fluorobenzoic acid ethyl ester...η NMR (400 MHz5 CDC13) δ 9.01 (S? 1Η)5 8.47 (d? J=2.0 Hz? 1H)5 8.02 (d, /=8.6 Hz, 1H ), 7.91 (dd, 2.3, 9.0 Hz, 1H), 7.85 (dd, J=1.6, 11.0 Hz, 1H), 7.80 (dd5 /=2.3, 8·6 Hz, 1H), 7.24 (t, /=8 〇 Hz, 1H), 4.40 (q, J = 7. 〇 Hz, 2H), 1.42 (t, J-7.0 Hz, 3H); 19F NMR (376 MHz, CDC13) δ -125.6. 4-(5-Bist-2H-indazol-2-yl)-3-fluorobenzoic acid ethyl ester (Step 3 of Scheme a_i〇)

a mixture of ethyl 4-(5-bromo-2-nitrobenzylideneamino)-3-fluorobenzoate (432 mg, 1.09 mmol) and triethyl phosphate (1.5 mL, 9.0 mmol) Irradiation at 150 ° C for 1 · 5 hours in a microwave oven. The cooled reaction mixture was purified by silica gel chromatography (hexane / ethyl acetate) to afford 4-(5-bromo-2-indole-indazole-2-yl)-3-fluorobenzene as a pale yellow solid. Ethyl formate. 1Η NMR (400 MHz, CDC13) δ 8.56 (d5 J=2.0 Hz? 1H)5 8.25 (t? J=7.8 Hz, 1H), 8.02-7.90 (m, 2H), 7.89 (d, deduction 0.8 Hz, 1H ), 7.66 (d, J=9.2 Hz, 1H), 7.40 (dd, J=1.6, 9.2 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1·44 (t, J=7.2 Hz) , 3H); 19F NMR (376 MHz, CDC13) δ -123.4. MS (ESI) m/z: Calcd.: 363. Ethyl 4-(5-benzyl-2H-indazol-2-yl)-3-fluorobenzoate and 4-(5-benzyl-2H-indazol-2-yl)-3-fluorobenzoic acid benzyl Ester (Step 4 of Process A-10) 119664.doc -214- 200813031

In a manner similar to that described in General Procedure A, by using 4-(5-bromo-2 Η-σ 弓 -2 -2 -yl)-3·fluorobenzoic acid ethyl ester (135 mg, 0.372 mmol), evolved benzyl 4-(5-benzyl-2H·carbazole-2-) was obtained as a solution of zinc(II) in THF (2.66 mL, 1.08 mmol) and Pd(tBu3P)2 (9.5 mg, 19 μηιοί) A mixture of ethyl 3-fluorobenzoate and benzyl 4-(5-benzyl-2indole-indol-2-yl)-3-fluorobenzoate (171 mg). Ethyl 4-(5-benzyl-2H-indazol-2-yl)-3-fluorobenzoate: MS (ESI) m. Benzyl 4-(5-benzyl-2H-indazole-2-yl)-3-fluorobenzoate: MS (ESI) m. (4·(5-Benzyl-2H-indazol-2-yl)-3-fluorophenyl)methanol (step of Process A-10)

A 1.0 Μ solution of DIBAL-H (1.3 7 mL, 1.3 7 mmol) in dioxane was slowly added to 4-(5-benzyl-2H-indazol-2-yl)-3- at -78 C. Ethyl fluorobenzoate and a mixture of benzyl 4-(5-benzyl-2H-indazol-2-yl)-3-fluorobenzoate in di-methane (10 mL) (171 mg). The mixture was at _78. 〇 119664.doc -215- 200813031 Stir for 1 hour, then stop at -78 °C with 0.5 mL of ammonium sulphate saturated solution. Hydrochloric acid (2 N, 0.6 mL) was added, the cooling bath was removed and the mixture was stirred for 1 hour. The mixture was then extracted with dichloromethane and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give (4-(5-benzyl-211-oxazol-2-yl)-3-fluorophenyl)methanol. MS (ESI) m/z: Calcd: 303.21. 4-(5-Benzyl-2H-indazol-2-yl)-3-fluorobenzaldehyde (Step 6 of Scheme A-10)

Add TPAP (1 〇_6 mg, 0.03 mmol) to (4-(5-benzyl-2H-indazol-2-yl)-3-fluorophenyl)methanol (1 〇〇 mg, at room temperature, 〇.3〇mmol), 4·methylmorpholine N-oxide (43 mg, 0·36 mmol) and activated molecular sieve (200 mg) in a mixture of di-methane (10 mL). After stirring overnight, the reaction mixture was filtered, dried and purified eluting elut elut )-3·Fluorobenzaldehyde: 4 NMR (400 MHz, CD3OD) δ 10.0 (d, “7=1.6 Ηζ, 1Η), 8·55 (m, 1H), 8.41 (t5 J=7.4 Ηζ, 1Η), 7.84 (m, 2H), 7·68 (d, J = 9.0 Hz, 1H), 7.46 (s, 1H), 7.34-7.30 (m, 2H), 7.27-7.19 (m, 4H), 4.06 (s, 2H) ; 19F NMR (376 MHz, CD3OD) δ -122.3. MS (ESI) m/z: Calcd. 1-(4-(5-Benzyl-2H-indazol-2-yl)_3_fluorobenzyl)azetidine_3·carboxylic acid (Step 117 of 119664.doc-216-200813031 A-10)

By using 4-(5-benzyl-2H-called 1 唆-2-yl)-3-fluorobenzoic acid (108 mg, 0.328 mmol) in a similar manner as described in the general procedure E Oral-3-carboxylic acid (66 mg, 0.657 mmol), acetic acid (45 pL), cyanomethanol (41 mg, 0.66 mmol), methanol (7.5 mL) and methylene chloride (4.5 mL) TFA Sleeping News 4 - 1 - M-Π筚 -9FT-(8) kouqi-7-Kiononyl, azetidine-3-carboxylic acid (white foam [hSIPl EC50=94 nM]). 4 NMR (400 MHz, CD3OD) δ 8.61 (d, J = 2.0 Hz, 1H), 8.09 (t, J = 8_2 Hz, 1H), 7.61-7.49 (m, 4H), 7.30-7.18 (m, 6H) , 4.52 (s, 2H), 4.43-4.35 (m, 4H), 4·05 (s, 2H), 3.76-3.67 (m, 1H); 19F NMR (376 MHz, CD3OD) δ-77·5 (TFA ), -124.3. MS (ESI) m/z: calcd. (m.): 415.46; observed: 416.2 (M++1). Process B1

119664.doc -217- 200813031 Process Bla

Step 3 Process B2

NaCNBH3, MeOH AcOH: H2SO4, MeOH Step 1

CQ2Me

LiOH THF/H2〇 Step 3

KOAc, EtOH

Process B3

/^-C02Me

R

PdCI2(Ph3P)2 Cul, TEA

LiOH THF/H2O Step 3 Step 4

119664.doc -218 200813031

step 1

EtOH, H+ (EtO)3CH

Process B4

Condition Step 5 n-BuLi; C02 Step 2

Process B5 (COCI>2, Catalyst DJ/IF Step 3

CHO )=

PdCI2(PPh3)2

Dioxane, 130 °C, 30 min Step 1

25 °C, 15 min

NBS, THF Step 2

CHO

EtO, Bu3Sn

THF, 25 °C Step 4 HCI, H2〇,

F: General procedure for coupling lysine and aryl dentate bis(di-t-butyl(phenyl)phosphine)palladium (0.0285 mmol), hydrazine-bromo-3-fluorobenzyl)azetidine dichloride Methyl 3-carboxylate or 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylic acid B g (0.474 mmol), _acid (0.617 mmol), acetic acid (0.949 mmol) combination It can be sealed in a sealable tube and diluted with EtOH. The mixture was flushed with nitrogen and heated to 80 °C for several hours. The reaction was cooled and partitioned between EtOAc and 1N EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography to give 119 664. G: General procedure for cyclization of alkyne: PdCl2(PPh3)2 (0.129 mmol), copper (1) (0.129 mmol), 2-halophenol or 2-haloaniline (1.29 mmol) and 1-(4- Ethynylidene-3-fluorobenzyl) sigma-butyl-3-indole methyl ester (ι. 54 mmol) was combined in a sealable tube and 3 mL of DMF and 3 mL of TEA were added. Argon was bubbled through the solvent for 3 minutes and the homogenate brown reaction was sealed and heated to 1 °C. After completion of the reaction, the reaction was concentrated in vacuo and taken up on 5 g of silica gel and purified by silica gel chromatography to obtain the desired product. Η: General procedure for ester hydrolysis Add hydrated lithium hydroxide (1·29 mm〇1) in 1 mL of water to a solution of (MM mmol) in 2 mL of THF. Stir the light yellow reaction until Completely. Remove THF and suspend the solids in 2 mL of water. Add HCl (3 equivalents, 2 N) to neutralize the base and ultrasonically treat the mixture. Add phosphate buffer (4 mL, 1 Μ, pH 6) and super The reactants were sonicated. The slurry was filtered and the solid was washed with water and EtOAc and dried in vacuo to give the desired product. I: General procedure for reductive amination, acetaldehyde (1.0 mmol), acetic acid (1· A mixture of 5-2 mm 〇 1) and azetidine _3·carboxylic acid or piperidine-4-carboxylic acid (1-3 mmol) in DCM / MeOH (1:1, 1 mL) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (〇ϋ mmol) was added and the reaction mixture was stirred at room temperature for 2-3 h. The reaction mixture was filtered and the residue was washed with DCM. 1 · 0 M pH 6 in the citrate buffer, which was oversprayed 119664.doc -220-200813031 and rinsed with water, then rinsed with EtOH Product desired. Common intermediate: Intermediate 1 3-hydroxyazetidine·3-methylformate 1-dibenzylazetidin-3-ol NaOH (5 Ν aqueous solution ' 26· 1 niL, 13 1 mmol) Add to a mixture of 1 - dibenzylazetidin-3-ol hydrochloride (30.00 g, 109 mmol) in water (15 mL). The mixture was stirred for 15 min, extracted with AcOEt and dried over MgSCU Obtained bis-butyryl 1,3-alcohol. nmr (3〇〇MHz, CDC13) δ ppm 7.35-7.44 (m, 4H), 7.22-7.32 (m, 4H), 7.13-7.22 (m, 2H), 4.40-4.52 (m, 1H), 4.35 (s, m), 3 47 -3·60 (m, 2H), 2.80-2.97 (m, 2H). MS (ESI) m/z: Calculated: 23 9.1 Observed value: 340.1 (m++i). l Dibenzylazetidin-3-one was charged with a bismuth dichloride (10.6 mL, 119 mmol) and DCM (loo.oo mi, 3 二) 6 mm〇i) and the solution was cooled to. Dimethyl sulfoxide (16·9 mL, 238 in DCM (50 mL) was added to the mixing solution for 30 minutes from the dropping funnel. The mixture was stirred for another 5 minutes, and then kDcm (5 〇 mL) and DMSO were added dropwise over 5 minutes (1 〇 ^ 中 二 二 二 二 二 咬⑺ ⑽ mm〇1 column) (maintaining the temperature of the heart 60. . ). The solution was stirred for an additional 20 minutes at -78 °C = and Et3N (75.3 mL, 541 mm 〇1) was added slowly. The reaction was allowed to reach room temperature over 3 knives and water (2 〇〇 mL) was added. The mixture was extracted with Et.sub.sub.sub.sub.sub.sub.sub.sub.sub. 119664.doc -221 - 200813031 was purified by flash chromatography using 2% EtsN/hexane to give the bis-dibenzylazetidine-3-one. Towel NMR (300 MHz, CDC13) δ ppm 7.41-7.52 (m5 4H)5 7.26- 7.35 (m, 4H), 7.16-7.26 (m, 2H), 4.59 (s, 1H), 3.90-4.07 (m, 4H) ). 1-Dibenzyl_3_(trimethyldecyloxy)azetidine_3_carbonitrile Adds cyanide dimethyl sulphur (4. 5 mL, 34 mmol) to 1 _ 2 基 丫 丫A solution of pyridine-3-one (4·00 g, 17 mmol) in DCM (8 5 mL), followed by EtOAc (45 g, 1·7 mmol) in DCM (85 mL) Solution in the middle. The solution was stirred at room temperature for 1 hour, treated with water, extracted with EtOAc, dried over <RTI ID=0.0>M </ RTI> </ RTI> </ RTI> <RTIgt; 1H NMR (300 MHz, CDC13) δ ppm 7.15-7.28 (m, 4Η), 7.03-7.14 (m, 4Η), 6.92-7.03 (m, 2Η), 4.15 (s, 1H), 3·34_3·62 ( m, 2H), 2.72-2.94 (m, 2H), 0·00 (s, 9H). MS (ESI) m/z: calc.: 336.2; observed: 337.1 (M++1) bis benzyl -3- hydroxy butyl butyl 3-carboxylic acid The decyloxy)azetidin-3-carbonitrile (2.85 g, 8.47 mmol) was dissolved in a 1:1 mixture of EtOAc, EtOAc (30 mL). The mixture was heated to 95 ° C for 1 hour. The solvent was removed and the residue was taken to pH 7 using 5N NaOH. The solid was separated by filtration and washed with Et20 to give 1-dibenzyl-3-hydroxyindole

Oral-3-carboxylic acid. NMR (300 MHz, DMSO-A) δ ppm 7.36-7.47 (m, 4H), 7_22-7·33 (m, 4H), 7.13-7.23 (m, 2H), 4.52 (s, 1H), 3.46 (d) , J = 8.3 Hz, 2H), 3.02 (d, J = 8 · 2 Hz, 2H) 〇 MS 119664.doc -222- 200813031 (ESI) m/z : calculated: 283.1 ; observed: 284.1 (M+ +1). Methyl 1-dibenzyl-3-hydroxyazetidine-carboxylate Sulfuric acid (4.00 mL, 47.3 mmol) was added to 1-dibenzyl-3-carboxyl succinyl-3-carboxylic acid (2.13 g, 7.50 mmol) in a mixture of MeOH (20 mL). The mixture was heated to 80 &lt;0&gt;C for 18 h, diluted with EtOAc EtOAc EtOAc. The solid was washed with Et 2 hydrazine to obtain 1-dibenzyl-3-carbyl succinyl-3-carboxylate. 4 NMR (300 MHz, CDC13) δ ppm 7.43-7.49 (m? 4H)? 7.24- 7.31 (m, 4H), 7.15-7.23 (m, 2H), 4.54 (s, 1H), 3.90 (s, 3H) , 3.59-3.72 (m, 2H), 3.24 - 3.39 (m, 2H). MS (ESI) m/z: Calcd.: 297.21. 3-Hydroxyazetidine-3·decylcarboxylate The reactor was charged with 1·dibenzyl-3-hydroxyazetidine-3·carboxylic acid methyl ester (1.6 g, 5-4 mmol) in MeOH (30 mL) 10% Pd/C (0.300 g, 2·8 mmol) and glacial acetic acid (0.300 mL, 5.2 mmol). The mixture was stirred at 50 psig of H2 for 3 hours. The crude product was filtered over celite and washed with MeOH. After evaporation, the solid was washed with Et20 to give methyl 3-hydroxyazetidine-3-carboxylate as the acetate. 1H NMR (300 MHz, DMSO 〇 δ ppm 3·74 (d, /= 9.1 Hz, 2H), 3.69 (s, 3H), 3.44 (d, J = 8.9 Hz, 2H), 1.88 (s, 3H) 〇 Intermediate 2 1 -(4-bromo-3-fluorobenzyl)azetidine-3-carboxylic acid methyl ester 119664.doc -223 - 200813031

吖 Azetidine-3_carboxylic acid (43 g, 421 mmol), 4_gly-3-gas benzoic acid (81·4 g ' 401 mmol), orthoformate formazan in a Ν2 atmosphere at room temperature ( 219 mL, 2005 mmol) and AcOH (34 mL, 601 mmol) were added to DCM (700 mL). The mixture was stirred for 15 minutes at which time sodium triacetoxyborohydride (127 g, 601 mmol) was added portionwise. After 2 hours, the solvent was exchanged with MeOH (257 g, 8019 mmol) and sulfuric acid (79 g, 802. The mixture was heated under reflux for 18 hours. The solvent was removed and the mixture was extracted with DCM and water. The organic layer was purified using a Biotage column (isopropanol / heptane) to afford methyl 1-(4-bromo-3-fluorobenzyl)azetidine _3- decanoate as a clear oil. MS (ESI) m/z: Calcd. Intermediate 3 ethyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate

It was synthesized in a similar manner to methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-decanoate but the Me〇H from Step 1 was removed and EtOH was used in Step 2. MS (ESI) m/z: Calculated: 315 〇; observed: 316 〇 (M++1). Intermediate 4 methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate 119664.doc • 224. 200813031 1-(3-Fluoro-4_(2-(trimethyldecyl) Ethyl acetyl)benzyl)azetidine-3-carboxylate

Methyl 1-(4•bromo-3-fluorobenzyl)azetidine-3-carboxylate (25.00 g, 82.7 mmol), copper (1) (3.14 g, 16.5 mmol), (trimethyl sulphate) Acetylene (81.9 mL, 579 mmol), bis(triphenylphosphine)palladium chloride (ii) (5.81 g, 8.27 mmol) and Hunig (115 mL, 662 mmol) and 100 mL THF were added to the sealable tube . The reaction was sealed and heated to 80 °C for 24 hours with vigorous stirring. The mixture was cooled to room temperature, filtered and evaporated. The resulting oil was purified using Biotage (75 L, 0-50% EtOAc / hexanes) to afford 1-(3-fluoro- 4-(2-(trimethyl)alkyl) acetylene as a clear brown oil. Methyl)benzyl)azetidine_3_carboxylic acid methyl ester. MS (ESI) m/z: Calcd. Methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-furate

1β(3-Fluoro-4-(2-(trimethylsilyl)ethynyl)benzyl)butyrate _3_ methyl formate (20.9 g, 65 mmol) and fluorinated planer (11 g, 72 mm 〇i) Add to DMF (50 mL). Add MeOH (1 〇〇 mL). After 2 hours, MeOH was removed and the mixture was extracted with DCM &amp; The organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed and the material was purified using EtOAc (EtOAc EtOAc EtOAc EtOAc EtOAc ) Azetidine-3-carboxylic acid methyl ester. MS (ESI) m/z: calcd. Intermediate 5 2-Fluoro-4-Methyl Benzobenzopyrene 1-Bromo-4_(diethoxyindolyl)-2-fluorobenzene

F Add B with milk (2 · 04 mL ' 29 · 6 mmo 1) to a solution of 3 to fluoro, 4 benzophenone (20.0 g, 98.5 mmol) in anhydrous EtOH (120 mL·), then add Diethyl orthoformate (6.55 mL, 39.4 mmol) and the contents were heated to 70 C for 3 hours. The contents were cooled to room temperature and transferred to a rotary evaporator and subjected to reduced pressure (280 mm Hg) for 45 minutes at a constant bath temperature of 65 °C. The pressure is further reduced to remove all solvent. Fresh ethanol (60 mL), acetonitrile chloride (1.5 mL), triethyl orthoformate (5 mL) was added to the mixture and heated to 7 (r) over 2 s. Diluted with 200 mL), washed with saturated sodium bicarbonate (3 χ 1 mL), brine and dried over anhydrous sulfur. The solvent was evaporated and the residue was purified by EtOAc EtOAc EtOAc · Et 〇Ac / hexane, 1/2 〇) purified to give a colorless oil: U brom 4 - (diethoxymethyl) 2 - fluorobenzene. 4 NMR (4 〇〇 MHz, CDCl3) Sppm8〇3(t,J=8iHz,iH) 7 36- 7.33 (m5 2H)5 5.54 (Sj iH)5 3.63-3.52 (m5 4H)5 1.25 (m 6H) 〇' 2-Fluorine_4-A 醯Benzoic acid 119664.doc -226 - 200813031

n-Butyl (2·5 Μ in hexane, 16.5 mL, 43.83 mmol) was added dropwise over a minute to 1-bromo-4-(diethoxymethyl)- cooled to -78 °C. A solution of 2-fluorobenzene (ι〇·ΐ2 g, 36.53 mmol) in dry THF (9 mL). The contents were stirred for an additional 30 minutes and C〇2 was bubbled through the mixture for 0.5 hour (fever). The cooling bath was removed and the contents were allowed to warm to room temperature. The mixture was treated with aqueous NaOH (1 N, 100 mL) and washed with EtOAc. The aqueous layer was acidified to pH 2 with EtOAc (5N) and EtOAc (3.times. The combined organic layers were washed with water and brine and dried by MgSCU and evaporated. The residue was dissolved in diethyl ether (3 mL), TFA (1. 5 mL) and water (2.OmL) and stirred overnight. The volatiles were removed under reduced pressure and co-evaporated with toluene. The residue was taken up in diethyl ether (75 mL) and filtered. The filter cake was dried under vacuum without further purification to give 2-fluoro- 4-mercaptobenzoic acid as a white solid. 1η NMR (400 MHz, DMSO-d6) δ ppm 13.48 (s, 1 Η), 10.06 (s, 1 Η), 8_06 (t, J = 7.4 Hz, 1H), 7.84-7.79 (m, 2H). MS (ESI) m/z: Calculated: 168.0; observed: 167.0 (Μ, 1). 2-fluoro-4-methylmercaptobenzoquinone

Add ethylene dichloride (0.168 mL, 1.89 mmol) and catalytic DMF (2 drops) to 2-fluoro-4-indolylbenzoic acid (0.531 g, 3.16 mmol) in 10 mL 119664.doc •227-200813031 In the slurry in DCM. In the case where the leaf outlet is open to the air, the reaction is carried out under argon gas. After 2 hours, it was determined whether the aliquot (MeOH) of the discontinued reaction would be absent ^ ^ t J疋Φ s acid. The reaction was concentrated in vacuo and dried on a shield pump for 1 minute. The yellow solid was obtained and it was used without further purification. Intermediate 6 4-(2-bromoethenyl-3-fluorobenzaldehyde 1-bromo-4·(diethoxymethyl)-2_fluorobenzene

Dibutyl(1-ethoxyvinyl)stannane (17 mL, 5·2 mm〇l) and

Pd(PPh3)2Cl2 (0.069 g, 0.099 mmol) was added to a solution of 4-bromo-3-fluorobenzaldehyde (1·〇〇 g, 4.9 mmol) in dioxane (1 mL). The resulting solution was purged with argon for 2 minutes and then heated (microwave) in a sealed tube at 丨3 〇 〇c for 30 minutes. The cooled reaction solution was filtered through a pad of EtOAc (EtOAc) eluting The residue was purified by chromatography (EtOAc mjjjjjjjjj . 1H NMR (400 MHz, chloroform-d) δ ppm 9.98 (s, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.57 (d, /=11.0) Hz, 1H), 4.90 (d, /=2.0 Hz, 1H), 4·58 (s, 1H), 3.94 (q, J=7.0 Hz, 2H), 1·42 (t, /=6.8 Hz, 3H ). 4·(2-bromoethenyl)-3-fluorobenzaldehyde 119664.doc -228- 200813031

CHO

Ο &gt;~JF Add N-bromobutanimide (505 mg, 2837 μπιοί) in one portion at 25 C to 1-di·4_(diethoxyindenyl)_2-fluorobenzene ( 551 mg, 2837 μπιοί) in a solution of 3:1 THF_H2Q (6.0 mL), and the resulting solution was stirred at 25 C for 1 min. The solution was partitioned between Et EtOAc (50 mL) and brine (8 mL). The organic layer was separated, dried over sodium sulfate and dried in vacuo. Chromatographic purification of the residue (ISC 〇, 4〇g, 〇_1〇〇% Et〇Ac / hexane) ί, , 1 长, 4-(2- ethoxyethyl)-3- Benzene. NMR (400 MHz, CDC13) δ ppm 10.08 (d? J=1.8 Hz, 1H), 8.06-8.12 (m5 1H)5 7.79 (dd, J=8.0? 1.4 Hz5 1H)5 7.69 (dd? ^=10.6 , 1.4 Hz? 1H)5 4.52 (d, J=2.3 Hz, 2H) 〇' Compound 88 1-((4-(5-Benzylbenzofuran-2-yl)-3-fluorophenyl)methyl) _3_Hydroxybutyrate bite-3-carboxylic acid 1 ((^(54-phenylphenyl-2-yl)_3_fluorophenyl)methyl)_3_ 吖 吖 L L/ bite J-formic acid methyl ester

According to Scheme B 1 and monofluorobenzoic acid (0.100 g (0.058 g, 0.30 procedure I consists of 4-(5-benzyl-benzofuran-2-yl)_3_ '0.30 mm〇1) and 3-hydroxyindole Synthesis of pyridine·3_carboxylic acid methyl mm〇1) to obtain W(4_(5_节基幷幷,119664.doc -229-200813031 -2-2_yl)-3-mer-phenyl)methyl)-3 - via base σ 丫 bite 3-carboxylic acid methyl vinegar. 1 NMR (300 MHz, DMSO_A) δ ppm 7.91 (t, J = 7.9 Ηζ, 1 Η), 7.40-7.61 (m, 2H), 7.15-7.36 (m, 8H), 6.26 (s, lH), 4.04-4.10 (m,1H),4·04 (s,2H), 3.70 (s,3H), 3.68-3.69 (m,1H), 3.63 (d,J=7.9 Hz,1H),3.12-3.18 (m,4H ). MS (ESI) m/z: Calcd. 1-((4-(5-Benzylbenzofuran-2-yl)-3-fluorophenyl)methyl)-3-hydroxyazinidine-3-carboxylic acid

OH = 〇 according to the general procedure Η from 1-(4-(5-benzylbenzofuran-2-yl)-3-fluorobenzyl)-3_ylpyridinium-3-yl decanoate (〇 〇78 g, 〇18 mmol) was synthesized to obtain 1-((4-(5-benzylbenzofuran-2-yl)_3_fluorophenyl)methyl)_3_hydroxy-hydroxybutidine-3-carboxylic acid [hSIPl EC5〇=105 nM]. 4 NMR (400 MHz, DMSO 〇 δ ppm 8.05 (t, /=7·5 Hz, 1H), 7.54-7.65 (m, 3H), 7.44-7.54 (m, lH), 7.36 (s, lH), 7.23 -7.33 (m, 5H), 7.13 - 7.23 (m, 1H), 4.43-4.58 (m, 4H), 3_64·4·23 (m, 4H). MS (ESI) m/z: Calculated: 431.2; Observed value: 432.1 (M++1). Compound 89 1-((Heart (5-mercaptophenylhydrazone [d]thiazol-2-yl)_3_fluorophenyl)methylmethyl-3-hydroxyazetidine- 1-((4-(5-benzylbenzothiazol-2-yl)-3-hydroxyphenyl)methyl)_3_hydroxyindole 119664.doc 200813031 methyl butyrate-3-carboxylate

According to Scheme B1 and General Procedure I, 4-(5-benzyl-benzoquinone[d]thiazolyl)-3-fluorobenzaldehyde (0.057 g, 0.16 mmol) and 3-hydroxyazetidinecarboxylic acid methyl ester (0.031) Synthesis of g,0·16 mm〇l) to obtain 1-((4_(5-benzylphenylhydrazine[d]thia('indol-2-yl)-3-fluorophenyl)methyl)_3_hydroxyindole Methyl butyrate-3-carboxylate. Towel NMR (300 MHz, CDC13) δ ppm 8.37 (t? J=7.7 Hz5 1H)5 7.93 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.21. -7.35 (m,8H), 4.15 (s 2H)5 3.93-4.07 (m, 7H), 3.52-3.67 (m5 2H) 〇MS (ESO m/z: calculated: 462.1; observed: 463el (M+ +1). l-((4_(5-Phenylbenzoquinone[_嗤_2_yl)_3_fluorophenyl)methyl)_3_ via azetidine-3-carboxylic acid

ϋ According to the general procedure, 1-(4-(5_芊f its surname r ^ V Θ卞 幷 幷 [d]thiazol-2-yl)-3·fluorobenzyl)-3 -glycol-based butyl- 3 - formic acid methyl cool (〇m ς Τ夂Τ Τ夂Τ 八 (eight) · 〇 35 g, 0 076 mm 〇 1) synthesis to obtain 1 - ((4-(5-benzyl benzoquinone [d*] 唉 9 9 I1 ^ LJ泰里-2_基)_3_fluorophenyl)methyl)_3_ 经基丫丁丁-3-carboxylic acid [hS1Pl EC5〇=27nM]jHNMR(4〇〇MHz, DMSO·...ppm 7.23 咖t, J=8 g Hz shoulder, 6 6i 6 plus 119664.doc -231 - 200813031 (br· s, 2H), 6.21-6.34 (m, 2H), 5.85-6.06 (m, 6), 3.29-3.20 ( m, 4H), 2.92-2.97 (br. m, 2H), 2.86 (br. s, 2H). MS (ESI) m/z · Measured value: 448.1 ; observed value · 449.2 (M++1) Compound 90 1-((3-Fluoro-4-(5-(1-phenylethyl)phenyl)furanyl)phenyl)methyl)azetidine-3-carboxylic acid benzofuran-5-yl ( Phenyl)methanol was added to a solution of phenylmagnesium bromide in diethyl ether (739 mL, 22·2 mm 〇1) to ι benzofuran _5•formaldehyde (2.7() g under N2. 185 paws 〇 1) in a solution of 50 mL of THF. The reaction was stirred for 1 hour, followed by saturation &gt;^4&lt;: 1 Water solution was suspended, extracted with diethyl ether, washed with brine, dried over anhydrous sodium sulphate, filtered, and concentrated to a solid in vacuo to afford phenylfuranfuran-5 (meth) methanol without further purification. Can be used. nmR (400 MHz, DMSO-J,) δ ppm 7.94 (d, J=2.0 Hz5 1H), 7.64 (S,lH), 7.49 (d, J=8.5Hz, lH), 7.36-7.42 (m , 2H), 7.26- 7.33 (m? 3H)5 7.19 (t5 7=7.3 Hz? 1H)5 6.92 (d? J=1.5 Hz? 1H), 5.88 (d, J=4.0 Hz, 1H), 5.77- 5.83 (m, ih). Benzofuran-5-yl (phenyl) ketone

A solution of S〇3*py (8.5 g, 54 mm〇1) K2〇mL 119664.doc -232-200813031 DMSO was added dropwise to the benzofuran-5-yl group via an addition funnel under nitrogen at TC. (Phenyl)methanol (4·0 g, 18 mmol) and triethylamine (7.3 mL, 54 mmol) in 30 mL of 1:1 DCM / DMSO. The reaction was stirred for 5 hours under ye and borrowed The organic layer was washed with water, 1 N HCl, 1 N NaOH, brine and dried over sodium sulfate, filtered and concentrated. The obtained solid benzofuran-5-yl (phenyl) The ketone was used without further purification. MS (ESI) m/z: Calculated: 222.1; observed value ·································

The 3.0 mg of methyl magnesium in diethyl ether (2.2 mL, 6.7 mmol) was added dropwise via syringe to the benzofuran-5-yl (phenyl) formamidine at 0 ° C under nitrogen (1· 〇g, 4.5 mmol) in 20 mL of THF. The reaction was slowly warmed to ambient temperature. The reaction was quenched with saturated aqueous NH4Cl and DCM. The aqueous layer was extracted twice with DCM and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1-(benzofuran-5-yl)l-phenylethanol as an oil. It can be used without further purification. MS (ESI) m/z: Calcd. 5-(1-phenylethyl)benzoquinone

119664.doc -233 - 200813031 Triethyl chopping (0.88 mL, 5·5 mmol) under nitrogen at 〇C, followed by trifluoroacetic acid (0.39 mL, 5-1 mmol) was added dropwise from the syringe to the i- (Phenylpyrano-5-yl)-1-phenylethanol (1.1 g, 4.6 mmol) in 20 mL of DCM. Each drop of TFA produces a slightly persistent yellow color upon completion of the addition. After 1.5 hours at 0 °C, it was quenched from saturated aqueous NaHCO3. The aqueous layer was extracted twice with DCM and dried EtOAc m. This material was further purified by gelatin chromatography (ISC®, 4〇g, 〇_1〇% Et〇Ac/hexane) to obtain 〇·94 g 5-(1_phenylethyl)benzoquinone furan. Mixture with 5-(1-phenylvinyl)benzoquinone. This material was dissolved in 1 mL of DCM under 〇〇c and triethyl decane (〇 629 mL, 3·94 mm 〇1) was added dropwise via a syringe, followed by the addition of trifluoroacetic acid (1.52 mL, 19.7 mmol). Upon completion of the addition, the reactants turned yellow. After 15 minutes, I was at the end. (The reaction was quenched by the addition of 1 N NaOH and diluted with DCM. The aqueous layer was extracted once with DCM, and the combined organics were dried over anhydrous sodium sulfate filtered and concentrated in vacuo. Purify by gelatin chromatography (ISCO, 80 g, 〇 15% Et EtOAc / hexanes). The product fractions were concentrated in vacuo to give a clear, colorless oil 5-- Phenyl) Benfvnan. H NMR (400 MHz, DMSO-A) δ ppm 7.94 (d5 J 2.0 Hz5 ih), 7.53 (s? 1H)5 7.48 (d, J=8.5 Hz, 1H)5 7.24^ 7.34 (m5 4H)5 7.12-7.22 (m, 2H)5 6.89 (d5 ^2.0 Hz5 1H), 4·26 (q, J=7·5 Hz, 1H), 1·62 (d, J=7.0 Hz , 3H) 5-(1-phenylethyl)benzoquinone furanoleic acid 119664.doc -234- 200813031

Add to 5-(1-phenylethyl)benzoquinone (0.713 g, 3·21 _〇1) in 32 ^ THF / sol. The reaction was stirred for 25 minutes at which time diisopropyl borate (1.08 mL, 4.72 mmol) was slowly added dropwise. After 5 hours, the constant temperature bath was removed and the reaction was allowed to warm to ambient temperature. After 5 hours, add 50 mL of 2 N HCl. The mixture was extracted twice with MTBE and the combined organics were washed with brine, dried over anhydrous sodium sulfate, and evaporated and evaporated. Treatment with 30 mL of hexanes and sonication for 5 minutes gave a white solid which was collected by the mixture and dried in vacuo to give 5-(1-phenylethyl)benzofuran-2-yl-acid. lH nmr (4〇〇MHz5 DMSO-d6) δ ppm 8.49-8.57 (m5 2H)5 7.58 (s5 1H)5 7.46 (d3 J=8.5 Hz5 1H), 7.40 (s5 1H)? 7.12-7.32 (m5 6H) 4.26 (q, J = 7.5 Hz, 1H), 1.62 (d, J = 7.0 Hz, 3H). 1-((3-fluoro-4-(5-(1-phenylethyl)phenyl)furanyl)phenyl)methyl)

According to the procedure B2 and the general procedure F, 丨_(4_bromo-3-trifluorobenzyl)azetidine-3-decanoate (〇·241 g, 〇·797 111111〇1) and 5_(1_) are used. Phenylethyl)benzoquinone-2-yl-acid (0.212 g, 〇·797 mmol) to obtain 1_((3-fluoro-heart (5-(1-phenylethyl)benzofuran-2) Phenyl)methyl)azetidine-3-carboxylic acid 119664.doc -235 - 200813031 Methyl ester. According to the procedure B2 and the general procedure, 1-((3-fluoro-4-(5-(1-phenylethyl)benzofuran-2-yl)phenyl)-methyl)azinium-3 Methyl formate (0.275 g, 0.620 mmol) afforded ((3·fluorophenylethyl)benzofuran-2-yl)phenyl)methyl)azetidine_3_carboxylic acid as a white solid. hSIPl EC5〇= 99 nM] 〇lH NMR (400 MHz, DMSO-^) δ ppm 7.89 (t, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H) , 7.20-7.35 (m,8H), 7.12-7.20 (m,1 H), 4.28 (q,J=7.0 Hz, 1H), 3.60 (s,2H), 3.18-3.46 (m, 5 H),1 · 64 (d, J = 7.5 Hz, 〇 3H). MS (ESI) m/z: calcd.: 429.2; observed: 430.2 (M++1) 〇 Compound 91 l-((4-(5-(difluoro(phenyl)methyl)benzofurfuran_2_ 5-fluorophenyl)methyl)azetidine-3-carboxylic acid 5-(2-phenyl-1,3-dithiomyl)benzoquinone furan trifluoride at 1 coat temperature Diethyl ether (1.38 mL, 11.0 〇1) was added to benzofuran-5-yl(phenyl)methanone (2.45 g, 11.0 mm 〇1), glacial acetic acid (1·27 mL, 22.0 mmol) and 2. Ethane dithiol (1·39 mL, ι 6 · 5 mm 〇 1) K3 〇 〇 乙 D DcM solution. The reaction was stirred overnight and quenched by the addition of EtOAc. The aqueous layer was extracted in dcm: - and the combined organics dried over sodium sulfate, filtered and concentrated. Purified by Shihic Glue Chromatography (ISC0, 0-20% EtOAc / hexanes) to afford 5-(2-phenyl-1,3-) as a clear/colorless oil. Dithioin-2-yl)benzofuran. 1Η NMR (400 MHz? OMSO^d6) δ ppm 7.99 (d? J=2.0 Hz, 1H)? 7.84 (d, /=2.0 Hz, 1H), 7.48-7.57 (m, 3H), 7.38-7.45 (m , 1H), 7.29-7.36 (m, 2H), 7.24 (t5 J=7.3 Hz, 1H), 6.96 (d, «7=2.0 Hz, 1 Η) 3·43 (s5 4H). 5-(difluoro(phenyl)methyl)benzofuran

a solution of ·% (2·buy-1,-disulfan-2-yl) alum-furan (1·56 g, 5.23 mmol) in 15 mL DCM (5 mL) at 0 °C A solution of selectfluor (tm) fluorinating reagent (3.70 g, 10.5 mmol) in 30 mL of HF*py was added slowly via a pipette to a nalgene bottle. The dark red reaction was stirred for 15 minutes, at which time it was quenched with ice and 1 n NaOH and 10 N

NaOH is alkalized. Et20 (2 50 mL) was added and the organic layer was washed twice with EtOAc EtOAc. The obtained material was purified by silica gel chromatography (ISC 〇, 〇 2〇% Et EtOAc / hexane) to obtain 5-(difluoro(phenyl)methyl)benzofuran.咕nmr (400 MHz, DMSO^,) δ ppm 8.10 (d5 J==2.0 Hz, 1H), 7.83 (s5 1H)3 7.71 (d5 /=9.0 Hz, 1H)5 7.48-7.58 (m3 5H)5 7.45 (d5 /=8.5 Hz, 1H), 7.04 (s, 1H). 1-((4-(5-(dioxa(phenyl)methyl)benzoquinone) _3 gas phenyl)methyl) azetidine-3_carboxylic acid ethyl ester 119664.doc -237- 200813031

2.5 M solution of butyl hydrazine in hexane (1.3 mL, 3 · 4 mmol) was added dropwise to 5-(difluoro(phenyl)methyl)phenylhydrazine under nitrogen at -78C. Silane (0.684 g, 2.8 mmol) in 28 mL THF. The clarified solution was stirred for 30 minutes at which time triisopropyl borate (ο 』 ? mL, 4.2 was added.

Mm). After 30 minutes, the thermostatic bath was removed and the reaction allowed to reach ambient temperature. After 30 minutes '28 mL of 2 N HCl was added and the reaction was diluted with MTBE. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Hexane was added to obtain a white solid, which was collected by filtration. A portion of the unpurified material is treated as follows: according to process B2 and the general procedure? 1_(4_bromo-3-ylfluoro)-pyridinium formate (0.150 g, 0.474 _〇1) and 5-(difluoro(phenyl)methyl)benzofuran-2-ylfolic acid ( G. 273 g, 0.949 mmol) was reacted to obtain (dioxa(phenyl)methyl)benzofuran-2-yl)-3-fluorophenyl)methyl)azetidinecarboxylic acid ethyl acetate.丨H NMR (400 MHz, DMS0 〇 s ppm 7 % (t, 〇 〇

Hz, 1H), 7.S9 (s, 1H), 7.76 (d, , = 3.5 Hz, 1H), 7.45-7.60 (m 6H), 7.38 (d, , =3.0 Hz, 1H), 7.26-7.33 ( m, 2H), 4 1〇(q TMHZj 2H)j3.63 (s, 2H), 3.43-3.51 (m> 2H), 3.2〇.3.3{ (m,3H), 1.19 (t, j=7 .〇Hz, 3H). -2-yl)-3-fluorophenyl)methyl) 1-((4-(5-(difluoro(phenyl)methyl)benzoquinonefuranidine-3-carboxylic acid 119664.doc -238 - 200813031

1-((4-(5-(Difluoro(phenyl)methyl)benzofuran-2-yl)-3-fluorophenyl)methyl)azetidine-3 was used according to Scheme B2 and General Procedure Synthesis of ethyl decanoate (0.181 g, 0.377 mmol) to give 1-((4-(5-(difluoro(phenyl)methyl)benzofuran-2-yl)_3_fluoro -Phenyl)methyl)azetidine-3-decanoic acid [hSIPl EC50=13 nM]. 4 NMR (400 MHz, DMSO-A) δ ppm 7.93 (t; ./=8.0 Hz, 1H), 7.89 (s, 1H), 7.76 (d, ./=8.5 Hz; 1H), 7.45-7.61 (m , 6H), 7.38 (d, "7=3.0 Hz, 1H), 7.26-7.33 (m, 2H), 3.62 (s, 2H), 3.39-3.48 (m, 2H), 3.17-3.32 (m5 3H). MS (ESI) m/z: calcd. ) mercapto) azetidine-3-carboxylic acid 6-benzylbenzofuran-2-ylfolic acid

B(OH)2 1,1,1-Trifluoro-n-phenyl-n-((trifluoromethyl)sulfonyl)methanesulfonamide (4.93 g, 13·8 mmol) was added to phenylhydrazine Furan-6-alcohol (185 g, 138 mmol) and N,N-isopropylethylamine 99% (7.21 mL, 41.4 mmol) in a purple mixture of 50 mL DCM. The reaction turned pale blue. After 2 hours, the reaction turned pale yellow. The reaction was quenched with DCM EtOAc EtOAc EtOAc. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained material was purified by silica gel chromatography (0-1 Et0Ac / hexanes) to afford phenyl hydrazide D </ RTI> trifluoromethanesulfonate as a semi-solid. 0.5 Μ in THF (23 mL, „ mm. 丨) 9 _ base _9 for bicyclo[3.3"] brothel, benzoquinone „ 喃 _6• propyl trifluoroformate (i 5〇g , 5.6 mmol), phosphate desorption (3.6 g, 17匪〇1), benzoquinone cyanyl trifluoromethanesulfonate (1.50 g, 5·6 mm〇1), s_ph〇s (〇i9 g, 〇 A mixture of 45 mmol), Pd(OAc)2 (〇·〇5 1 g, 〇·23 awake 1) was flushed with argon and sealed to 60 C overnight. The green/grey reactant was cooled and passed through a crucible. The celite was filtered and washed with 玢2 。. The filtrate was concentrated and taken up on 15 g of silica gel and dried. The material was purified by gelatin chromatography (ISC 〇, 8 〇g EtOAc / hexane) to obtain 6-benzylbenzene. A portion of this material was treated as follows: 1-75 M of 1-butyllithium in hexane (153, 3.82 mmol) was slowly added dropwise to 6-benzylbenzofuran under -78. 0.663 g, 3.18 mmol) in 30 mL of THF. The mixture was stirred for 25 minutes. At this time, triisopropyl benzoate (1 · 〇$ mL, 4.68 mmol) was slowly added dropwise. After 0.5 hours, the constant temperature bath was removed and the reaction was allowed to warm to ambient. After 10 minutes, 5 〇 mL of 2 N HCl was added. The mixture was diluted with MTBE and the organics were washed with brine, dried over anhydrous MgSO.sub.4, and taken in vacuo to give an oil. The material was treated with hexanes to give a solid and the material was filtered and washed with hexanes and dried in vacuo to give 6-benzylbenzofuran-2-yl-acid as a white solid. 1 NMR (400 MHz, DMSO 〇 δ ppm 8.47 (s, 2 Η), 7·57 (d, 119664.doc -240- 200813031 pneumatic Hz, 1H), 7.42 (s, 1H), 7.39 (s, 1 Η), 7·24 ·7·33 (m,4 H), 7.15-7.22 (m,1H), 7.10 (d, /=8.0 Hz, 1H), 4.06 (s 2H). 5 l-((4-(6-benzyl) Phenylfurfuryl)-3-fluorophenyl)methyl)azetidine_3_carboxylic acid ethyl ester

According to Scheme B2 and General Procedure F, 1-(4-bromo-3-fluorobenzyl)pyridinium 3-decanoate (0.150 g, 0.474 mmol) and 6-benzylbenzoin-2-yl are used. Synthesis of acid (0.155 g, 〇·617 mm〇l) to obtain 1-((4-(6-benzyl amidofuran-2-yl)-3-fluorophenyl)methyl)azetidine-3 - ethyl formate. MS (ESI) m/z: Calcd. 1-((4-(6-Benzylbenzofuran-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylic acid

According to the procedure B2 and the general procedure, 1 彳 (4 gas 6-benzylbenzofuranyl)-3-fluorophenyl)methyl)azetidine-3-carboxylic acid ethyl acetate (〇·190 g, 〇·428) Methyl) to obtain a white solid ((4-(6-benzylbenzofuran-2-yl)-3-fluorophenyl)indolyl)azetidine-3-carboxylic acid [hS1P1 EC5〇= 7 nM]. 119664.doc -241 - 200813031 lU NMR (400 MHz? DMSO-^) δ ppm 7.89 (t5 J=8.0 Hz5 1H), 7.60 (d, /=8.0 Hz, 1H), 7.50 (s, 1H), 7.21 7.34 (m, 7H), 7.15-7.21 (m, 2H), 4.07 (s, 2H), 3.60 (s, 2H), 3·37· 3.49 (m, 2H), 3.15-3.3 0 (m, 3H) . MS (ESI) m/z: Calcd. Compound 93 1-((3-Fluoro-4-(5-(oxaridin-2-ylmethyl)benzofuran-2-yl)phenyl)indolyl)azetidine-3-carboxylic acid f 'benzoquinone Furan-5-yl(pyridin-2-yl)methanol

OH

A mixture of 2-bromopyridine (1.11 g, 7.05 mmol) in THF (30 mL) over EtOAc (EtOAc) The BuLi) in hexane was treated dropwise and stirred for 1 minute. The resulting brown solution was treated dropwise with a solution of benzofuran-5-carbaldehyde (0.937 g, 6.41 mmol) in THF (10 mL) and stirring at -78 °C for 15 min. The mixture was treated with MeOH (3 mL) then H20 (20 mL) and warm. The mixture was treated with EtOAc. The combined organic layers were dried with EtOAc EtOAc (EtOAc)EtOAc. 2-(benzofuran-5-ylmethyl)pyridinium

119664.doc -242- 200813031 A solution of benzoquinone-5-yl (0-pyridin-2-yl)methanol (500 mg, 2220 μιηοΐ) in DCM (1 mL) at 〇C Treat with bromophosphine (314 pL, 3330 μιηοΐ) and stir! ·5 hours. The mixture was diluted with CHCU, washed with a saturated aqueous solution of KHCO3, dried over EtOAc and evaporated. The material and a suspension of 10% Pd-C (50 mg) in EtOAc (5 mL) and MeOH (3 mL) were stirred at <RTIgt; The solid was filtered off (D.) and washed with EtOAc. The filtrate was evaporated and purified by flash chromatography (EtOAc to EtOAc to EtOAc EtOAc NMR (400 MHz, CD3OD) δ ppm 8.71 (br· s, 1H), 8.17 (t, J = 7.6 Hz, 1H), 7.70-7.64 (m, 3H), 7.50-7.48 (m, 2H), 7.29 ( d, J = 8.1 Hz, 1H), 6_76 (s, 1H), 4.71 (s, 2H). MS (ESI) m/z ················ 5-(Acridine-2-ylmethyl)benzofuran-2-yl-acid

Cool down a solution of 2_(Ben σ南南-5-ylmethyl) hydrazine (66 mg, 315 μηιοί) in THF (2 mL) to _78 cc (under argon) to 2_5 μ η- BuLi (2.5 eq, 0.315 mL in hexanes) was taken and stirred for 2 min, warmed to 0 ° C for 30 min and cooled to _78. It was treated with triisopropyl borate (178 pL '946 946 μιηοΐ). After 5 minutes, the cooling was removed, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The mixture was diluted with EtOAc (br. EtOAc). MS (ESI) m/z: Calcd.: </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 1-((3-Fluoro-4-(5-(acridin-2-ylindenyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid ethyl ester

In a sealed flask, a mixture of 5-(pyridin-2-ylmethyl)benzofuran-2-yl decanoic acid ◎ (214 mg, 846 μιηοΐ) and potassium acetate (166 mg, 1691 μιηοΐ) was placed in argon. Treated with bis(monobutyl)phenylhydrazine 6(Η) (32 mg, 51 μηιοί), followed by ι_(4-bromo-3-fluorobenzyl)azetidine-3- Ethyl citrate (267 mg, 846 μιηοΐ) was treated with a solution of EtOH (5 mL). The resulting suspension was again degassed and heated to 80 ° C for 2.5 hours. The mixture was cooled to about 10 ° C and treated dropwise with H 2 〇 (15 mL). The mixture was extracted twice with EtOAc. The combined organic layers were dried over MgS 4 and evaporated. Purification by flash chromatography (DCM to DCM / MeOH = 4:1) to afford Q (yield of 4-fluoro-4-(5-(pyridin-2-ylmethyl)benzofuran) Ethyl 2-(phenyl)phenyl)azetidine-3-carboxylate. Μ(3-Fluoro-4-(5-(.bipyridin-2-ylmethyl)benzofuran-2-yl)phenyl)methyl)indolebutyridin-3-indole

1·(3-Fluoro-4-(5-(acridin-2-ylindenyl)benzofuran-2-yl)) 丫 664 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫A mixture of (31 mg, 70 μιηοΐ) in THF (2 mL) was taken in EtOAc EtOAc (EtOAc) . Purification by SFC (Supercritical Flash Chromatography) gave the title compound in the form of the diethylamine salt [hSIP1 EC50 = 31 nM] 〇4 NMR (400 MHz, CD3OD) δ ppm 8.48 (d, J = 0.8 Hz, 1H ), 8.02 (t, J=7-9 Hz, 1H), 7.78 (t, /=5.9 Hz, 1H), 7.54 (s, 1H), 7.48 (d, J = 10.0 Hz, 1H), 7·33_7 · 22 (m, 6H), 4.25 (s, 2H), 3.95 (s, 2H), 3.82 (t, J = 8.6 Hz, 2H), 3.68 i (t, J = 8.5 Hz, 2H), 3.3 6- 3.34 (m, 1H, partially overlapping with the CD3OH signal), 3·05 (q, J = 7.4 Hz, 2H), 1.31 (t, /= 7.2 Hz, 3 H). MS (ESI) m/z: Found: 41. Compound 94 1-((3-Fluoro-4-(5-(thiazol-2-ylmethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid benzofuran-5 -yl (thiazol-2-yl)methanol

A mixture of thiazole (1·13 g, 13.2 mmol) in THF (50 mL) was obtained over a period of 10 min at -78 °C with 2·5 M n-BuLi (1.05 eq, 5 · 04 mL, in the case of hexane, was treated dropwise and spoiled for 45 minutes. The resulting yellow mixture was treated dropwise with a solution of benzopyran-5-carboxylic acid (1.76 g, 12.0 mmol) in THF (10 mL). The cooling is removed after the addition. When the mixture reached room temperature, it was treated with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc幷furan-5-yl(thiazol-2-yl)methanol CDC13) δ ppm 7·71-7·75 (m, 2H, Ί ', &quot;64 (d5 J=2.2 Ηζ,1Η), 7·50 ( d, J=8.6 Ηζ,1Η),7·39 (dd /^〇^ ,J~8.6,1·7 Ηζ,1Η),7·29 (d,J=3.1 Ηζ,1Η), 6.76-6.75 ( m,lm ... ,6·17 (s,1H) 〇2-(Benzene yoke-5-ylmethyl) 嗟 ( (' under argon at 24 ° 0, crude benzofuran-5 -yl (thiazol-2-yl)methanol (2.50 g, 10.8 mmol) dissolved in 1,2-dichloroethane (4 mL), triethyl decane (3.14 g, 27·0 mmol) and Treated with ruthenium fluoroacetate (25 mL, 16 2 mmol) and heated to reflux for 2 hrs. The mixture was diluted with Et.sub.Ac and ice. Purification by flash chromatography (hexane to hexanes / EtOAc / 3:2) to afford of y. Thioquinone. 1H NMR (400 MHz, CDC13) δ ppm 7.71 (d, J=3.3 Hz, (J 1H)5 7.61 (d? /=2.3 Hz, 1H)? 7.55 (br. s, 1H), 7.47 (d? /=8.4 6.73 (m,ih), 4.44 (s,2H). MS (ESI) m/z : Calculated: 215.0; observed: 2161 (M++1). 5_(sigh 2-ylmethyl)benzoquinone-2-yl-acid

/0H 3

OH

Cool the solution of 2_(benzofuran-5-ylmethyl)thiazole (0·68 g, 3 mmol) in THF 119664.doc -246-200813031 (2 mL) to _78 ° C (under argon) B), treated with 2.5 M n_BuU (3·〇 equivalent, 3.6 mL in hexane) and stirred for 2 minutes, warmed to hydrazine.冷却 After 30 minutes, cool to _78. It was treated with triisopropyl borate (1 mL, 6 mmol). After 5 minutes, the cooling was removed, and the mixture was slowly warmed to warmness and stirred for 2 hours. The mixture was diluted with EtOAc, EtOAc (EtOAc m.) MS (ESI) m/z: Calcd.: 259. 1-((3-Fluoro-4_(S-(thiazolylmethyl)benzofuranyl)phenyl)methyl)methyl σ丫丁丁-3-carboxylate

In a flask to be sealed, a mixture of 5-(thiazol-2-ylmethyl)benzofuranylg-ganoic acid (373 mg '1440 μΐη〇ΐ) and potassium acetate (283 mg, 2879 μιη〇ι) was placed. Treatment with bis(di(t-butyl)phenyl}palladium(Η) (53·7 mg, 86·4 μηη〇1) under argon, followed by fluorobenzyl)azetidine-3 - Ethyl formate (455 mg, 1440 μηιοί) in EtOH (10 mL) / solution. The resulting suspension was again degassed and heated to 8 Torr. It lasted for 2 hours. The mixture was cooled to 24 &lt;0&gt;C, EtOAc (EtOAc)EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 and evaporated. Purification by flash chromatography (dcm to DCM/Me 〇H = 19.1) to obtain a yellow foam 丨 ((3_ fluoro_4·(5_(thiazole_2• 119664.doc -247- 200813031) Ethyl) phenyl)methylazetidine _3_carboxylic acid ethyl ester. Ms (ESI) m/Z: Calculated: 45 〇 5; observed: 45 ΐ 2 (Μ+ +(1) 1-((3-Fluoro-4-(5-(thiazolyl-2-ylindolyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid

Ethyl 1-((3-fluoro-4-(5-(thiazol-2-ylmethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylate (290 mg, A mixture of 644 <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The obtained solid was collected by filtration and purified by RP-HPLC to afford 1-((3-fluoro-4-(5-(thiazol-2-ylmethyl)benzofuran-2-yl) as a white solid. Phenyl)methyl)azetidine-3-carboxylic acid [hSIPl EC5〇=76 nM]. 4 NMR (400 MHz, DMSO-d6) δ ppm 7.93-7.91 (m, 1H), 7.73 (s, 1H), 7.66-7.58 (m, 3H), 7.32-7.28 (m, 4H), 4.44 (s5 2H ), 3.65 (br·· s, 2H), 3.46 (br· s, 2H), 3.30-3.26 (m, 3H). MS (ESI) m/z: Calcd.: 4221. Compound 95 1-((3-fluoro-4-(5-(1-phenylpropyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid 1- (benzoquinone) Shouting -5 -yl)-1 -phenylpropan-1-ol 119664.doc -248 - 200813031

Zinc chloride (0.5 Torr in tetrahydroanthracene π, 5 67 mL, 2.84 mmol) was added via syringe to ethyl magnesium chloride (2 Μ in tetrahydrofuran, 10.63 mL) at room temperature under nitrogen. , 21.26 mmol) in solution. The mixture was stirred at room temperature for 1 hour. The reaction mixture was allowed to reach hydrazine. And benzofuran-5-yl(phenyl)methanone (315 g, 14·17 mmol) in tetrahydrofuran (10 mL) was added via a syringe. The reaction mixture was stirred at 〇t: for 2.5 hours. The reaction mixture was cooled to room temperature and quenched with saturated aqueous NH4CI. EtOAc was added and the aqueous layer was separated and extracted with EtOAc EtOAc. The combined organic layers were washed with brine, dried (MgSO.sub.4) and concentrated to afford crude oil. The crude product was purified by cerium dioxide flash chromatography (〇1 〇〇% DCM / hexane) to give a white oily oily _(benzofuran_5_yl)- phenyl phenyl _ Bulk. 1H NMR (400 MHz, chloroform 4 δ ppm 7·69 (1 H, d, /=1 6)

Hz),7·60 (1H,d,J=2.2 Hz), 7.39-7.45 (3H,m), 7.28-7.34 (3H5 m)3 7.22 (1H5 tt5 J=7.2? 1.4 Hz)5 6.73 (1H, Dd? J=2.25 1·0 Hz), 2·38 (2H, q5 /=7.3 Hz), 2.09 (1H, s)5 0.90 (3H, t5 «/=7·3 Hz) 〇5-(1- Phenylpropyl)benzophenone furan was added dropwise to the hydrazine _(benzofuran _5_ group) via a granule under a nitrogen atmosphere at 〇C with trifluoroacetic acid (4·62 mL, 62·2 mm 〇1). ) 丨 苯基 phenyl phenyl hydrazine 丨 醇 醇 醇 g g g g g g g g 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 119 . The reaction mixture was stirred at 〇〇c for 3 hours. Additional triethyldecane (2.39 mL, 14.9 mmol) was then added via syringe followed by trifluoroacetic acid (4·62, 62·2 mmol) and the mixture was warmed and stirred for 2 hr. The reaction mixture was quenched with aqueous i NaOH. DCM was added and the aqueous layer was separated and extracted again in dcm. The combined organic layers were dried (MgSO4) and concentrated to give a crude oil. The crude product was purified by flash chromatography eluting with EtOAc (EtOAc EtOAc). MS (ESI) m/z: Calcd.: 236·1; 5-(1-p-propylpropyl)benzofuran-2-yl g-p-acid

b(oh)2 was synthesized according to Scheme 1 and General Procedure C using 5-(1-phenylpropyl)benzoquinone (2·30 g, 9.73 mmol) to give 5-(1·phenylpropyl) stupid Furfuran-2-yl-acid. iH NMR (4〇〇MHz, DMS〇_^) δ ppm 8 5〇(2H, s), 7.60(lH,S), 7.45(lH,d,/=8.6HZ), 7.39(lH,s), 7.23-7·34 (5H,m),7·ΐ4 (1H,t,J=7.1 Hz), 3.91 (1H, t, /=7.7 Hz), 2·〇8 (2H, dq, /=7.7, 7.2 Hz), 0.83 (3H, t, &gt; 7.2 Hz). 1-((3-Fluoro-4-(5-(1-phenylpropyl)benzofuran-2-yl)phenyl)methyl)pyrene

119664.doc -250 · 200813031 According to Scheme B2 and General Procedure F, 1-(4-bromo-3-fluoroindolizidine 3 -carboxylate (1.76 g, 5.81 mmol) and 5^1-phenylpropane were used. Synthesis of benzophenone-2-yl-acid (1.63 g, 5.81 mmol) to give 4 (1-phenylpropyl)benzofuran-2-yl)phenyl)methyl)azetidine 3_methyl formate. MS (ESI) m/z: Calculated: 457.2; observed: 458.3 (M++1). 1-((3-fluoro-4-(5-(l-phenylpropyl)benzofuran-2-yl)phenyl)methyl)pyridinium-3-carboxylic acid

1-((3-Fluoro-4-(5-(l-phenyl-carto))benzofuran-2-yl)phenyl)methyl) ruthenium _3_carboxylic acid according to the procedure B2 and the general procedure Methyl ester (l5 j mg, 330 μιηοΐ) was synthesized to provide a white solid ((3•fluoro_4_(5_(1-phenylpropyl)benzofuran-2-yl)phenyl)indolyl) Azeidine _3_carboxylic acid. 〇 NMR (400 MHz, DMSOO δ ppm 7.89 (1Η, dd, J=8.0, 8.0 Hz), 7.62 (1H, s), 7.53 (1H, d, J=8.6 Hz), 7.22-7.35 (8H m),7·15 (1H,t,J=7.1 Hz), 3.93 (1H,t,/=7.7 Hz), 3.60 (2H,s), 3.37-3.45 (2H,m), 3.16-3.24 (3H,m), 2.09 (2H,dq, «/=7.7, 7·1 Hz), 〇·84 (3H, t, J=7.1 Hz). MS (ESI) m/z : Measured value: 443.2 Observed value: 444.2 (m++1). Compound 96 1-(3-(5-benzylbenzofuranyl)benzyl)azetidinecarboxylic acid 119664.doc -251 - 200813031 1·(3-bromobenzyl) Azetidine-3-carboxylic acid methyl ester

Synthesis of 3-bromobenzaldehyde and azetidine-3_carboxylic acid according to Step 1 of Scheme B2 to give methyl 1-(3-bromobenzyl)azetidine-3-carboxylate as a clear oil. MS (ESI) m/z: Calcd. Methyl 1-(3-(5-benzylphenylfurfuryl)benzyl)azetidine-3-furate

According to the step 2 of the scheme B2 and the general procedure F, it is synthesized from 5-benzylbenzofuran-2-yl-acid and methyl 1-(3-bromobenzyl)azetidine-3-furate to obtain a pale color. The oil is 1-1-3-(5-mercaptobenzoquinone). MS (ESI) m/z: calcd: 4121. Found: 412 (M++1) 〇 1-(3-(5-benzylbenzofuran-2-yl)benzyl)azetidine-3 - citric acid

According to Step 3 of Scheme B2 and the general procedure, it is synthesized from 1-(3-(5-benzylbenzoquinone-2-yl)benzyl)azetidine-3-carboxylic acid decyl ester to obtain a white solid. 1-3-(5-Benzylbenzofuran-2-yl)benzyl)azetidine_3-carboxylic acid [hsipi EC50=4834 nM]. 4 NMR (400 MHz, DMSO-A) δ ppm 7·76_7·85 (m, 2Η), 7·54 (d, J=8.4 Ηζ, 1Η), 7·49 (s, 1Η), 119664.doc - 252- 200813031 7.45 (t5 /=7.6 Hz5 1H)5 7.3 8 (s, 1 H)5 7.30-7.35 (m? 1H)? 7.25-7.30 (m, 4H), 7.16-7.21 (m, 2H), 4.04 (s, 2H), 3·74 (s, 2 H), 3, 54 (s, 2H), 3.31 (s, 4H). MS (ESI) m/z: Calcd. Compound 97 1 ((3-fluoro-4-(5-(2-phenylpropan-2-yl)benzofuranyl)phenyl)indolyl)pyrene-3-carboxylic acid 1-(2,2_ Diethoxyethoxy)-4-(2-phenylpropan-2-yl)benzene

OEt is synthesized from (4-(2-phenylisopropyl)phenol) and 2-bromo-arylene diethoxyethane according to step 1 of Scheme 1 to obtain 1_(2,2) as a yellow-orange oil. _Diethoxyethoxy)-4-(2-phenylpropan-2-yl)benzene. 1η NMR (400 MHz, chlorine U) δ ppm 7.19-7.29 (m, 4H), 7·14·7·19 (m, 1H), 7.13 (d, /=9.0 Hz, 2H), 6.82 (d, / =8.5 Hz, 2H), 4.82 (t5 J=5.3 Hz, 1H), 3.98 (d, J=5.0 Hz, 2H), 3.70-3.81 (m, 2H), 3.57-3.68 (m, 2H), 1.65 ( s, 6H), 1.24 (t, ^/=7.0 Hz, 6H). 5-(2_phenylpropan-2-yl)benzofuran

Synthesis according to step 2 of Scheme 1 from 1-(2,2-diethoxyethoxy) 4-(2-phenylpropan-2-yl) to give 5-(2) as a pale yellow oil. -Phenylpropan-2-yl)benzoquinone. 1H NMR (400 MHz, gas δ δ ppm 7.58 (d, 119664.doc - 253 - 200813031 UHz, lH), 7.22-(d, &gt; 8.5 Hz, 1 H), J = 2.0 Hz, 1 H), 7.52 (s, 1 H), 7.36 (d5 j 7.30 (m, 4 Η), 7.14-7.20 (m, 1 H), 7.U 6.71 (s, 1 H), 1.74 (s, 6 H). 5- (2-phenylpropan-2-yl)benzoquinone bite _2_yl-folic acid

5-(2-Phenylpropionic acid. 1H NMR (400 MHz, DMSO-heart) δ 2 _ group) was obtained from 5-(2-phenylpropane) as a white solid. Synthesis of 2-yl)benzoquinan-2-yl_pen PPm 8.50 (s, 2Η), 7.59 (d, piece.8 Hz, 1H), 7·39_7.44 (m, 2H), 7 2 〇7 3〇(m, 4H), 7.15 (m, /=6.7 Hz, 1H), 7.09 (10), J=8 6, 2 〇Hz,m), 3.31 (s,6 H) 〇1-((3 -Fluoro-4-(5-(2-phenylpropan-2-yl)benzofuranyl)benzyl)azetidine 3·carboxylate

C02Et

U According to step 2 of Scheme B2 and the general procedure f consists of 5·(2-phenylpropan-2-yl) awkward, 2-yl-S-p-acid and 1-(4-di-3-1-benzyl) σ丫丁唆_3_carboxylic acid B was synthesized from the following to obtain 1-(3-fluoro-4-(5-(2-phenylpropan-2-yl)benzofuran-2-yl) as a yellow foam Ethyl benzyl) azetidin-3-carboxylate. MS (ESI) m/z: Calculated: 471.2; observed: 472 (M++1). 1-((3-Fluoro-4·(5-(2-phenylpropan-2-yl)benzoquinone-2-yl)phenyl)methyl)n丫119664.doc -254- 200813031 Butyridine -3-decanoic acid

OH

〇

According to Step 3 of Scheme B2 and the general procedure, 1-(3-fluoro-4-(5-(2-phenylpropan-2-yl)benzofuran-2-yl)benzyl)azetidine-3 Synthesis of ethyl decanoate to give 1-(3-fluoro-4-(5-(2-phenylpropan-2-yl)benzoquinone-2-yl)phenyl)methyl as a white solid ) azetidine-3_ decanoic acid [hSIPl EC50=365 nM]. b NMR (400 MHz, DMSO-A) δ ppm 7.89 (t, / = 8.2 Hz, 1H), 7·61 (d, / = 1.8 Hz, 1H), 7.51 (d, J = 8_8 Hz, 1H), 7.22-7.31 (m,7H), 7.15-7.19 (m,1H), 7.12 (dd,J=8.8, 2.0 Hz, 1H), 3.60 (s,2H), 3.42 (s,1H),3·32 ( s, 4H), 3.21 (s, 1 H), 1_70 (s, 6H). MS (ESI) m/z: Calcd. Process B3

U

C02Me TMS W Ding MS—^ PdCI2(Ph3P)2 )~r Cul, DIPEA F Step 1

Compound 98 1-((3-Fluoro-4-(5-(phenylmethyl)furano[2,3-b].pyridin-2-yl)phenyl)methyl)-3-azetidine Formic acid 119664.doc -255 - 200813031 5-Benzyl-2.methoxypyridineN OMe The sealable tube is packed with S-phos (0.22 g, 0.53 mm〇l) under 虱 rolling, 酉· 060 g, 〇·27 mm〇l), phosphate (8·5 g, 40 mmol) and 5/odor-2·methoxypyridine (1.8 mL, 13 mmol). 〇·5 M was added to 9-block _9 piped bicyclo[3·31]nonane in THF (53 mL '27 mmol), and the vessel was sealed and heated to 6 〇 c overnight. The mixture was diluted with ether and filtered through celite: EtOAc. The filtrate was evaporated and purified by flash chromatography (0-40% EtOAc / hexanes) to afford 5-benzyl-2-methoxypyridine. MS (ESI) m/z: Calculated: 199.1; observed: 2 〇〇j (M++1). 5-benzyl·biti-2-ol

15 mL of 483⁄4 HBr was added to 5 -benzyl 2 -methoxypyridine (2.6 g, 13 mmol) in 15 mL of AcOH. The mixture was heated to 14 ° C for 3 hours (J 3 hours, cooled and poured onto ice. The mixture was basified to pH 6-7 and the solid was collected by filtration, rinsed with water and dried in vacuo to afford 5-Benzyl octazone 2-alcohol as a milky white solid. MS (ESI) m/z: calc.: 185.1; observed: 186.0 (M++1). -2-ol

1.5 mL of TFA followed by Ν-iodosuccinimide (ι·34 g 119664.doc -256 - 200813031 5.94 mmol) was added to 5-benzylpyridin-2-ol (1·1〇g, 5 under Ar) · 94 mm 〇 1) M 22 mL· AcOH in a yellow solution. The red homogeneous solution was stirred overnight, poured onto ice and neutralized with concentrated NH4 〇H. The solid was collected by suction, washed with water &lt;&quot;&gt; The resulting brown solid was purified by chromatography (ISCO, 80 g, 0-70% EtOAc (EtOAc)吼唆-2_ alcohol. MS (ESI) m/z: Calcd. 1-((3-fluoro-4-(5-(phenylmethyl)indole][2,3-1)]咐|Bist-2-yl)phenyl)methyl)-3-azetidinecarboxylic acid Methyl ester

According to Scheme B3 and General Procedure G, 5-benzyl-3-indolylpyridin-2-ol (0.400 g, 1.29 mmol) and 1-(4-ethynyl-3-fluorobenzyl)azetidine-3 Synthesis of decylcarboxylate (0.381 g, 1.54 mmol): light yellow solid. MS (ESI) m/z: Calcd.: 437. 1-((3-Fluoro-4-(5-(phenylmethyl))furanium [2,3-b]acridin-2-yl)phenyl)methyl)-3-azetidinecarboxylic acid

According to the procedure B3 and the general procedure, 1_(4-(5-benzylfuranium [2,3-b]pyr 119664.doc -257 - 200813031 pyridin-2-yl)-3 -fluorobenzyl)azetidine- Synthesis of methyl 3-formate (0.146 g, 0.339 mmol): white solid [h. 4 NMR (400 MHz, DMSO 〇 δ ppm 8·26 (d, / = 1.5 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.25- 7.35 (m,7H), 7.16-7.25 (m,1H),4.09 (s,2H),3.62 (s,2H),3·37_3·48 (m, 2H), 3.26-3.36 (m,1H), 3.16-3.25 (m, 2H). MS (ESI) m/z: Calculated: 416.2; observed: 417.2 (M++1) Compound 99 1-((3-fluoro-4-(5-(benzene) 1-(4-(5-benzyl_1H-吲哚_2-yl)-3, benzyl)-1 Η-indol-2-yl)phenyl)methyl)-3-azetidinecarboxylic acid _Fluorobenzyl) succinyl _3_carboxylic acid methyl ester

C02Me 4-benzyl-2-iodoaniline (0.20 g, 0.65 mmol) and 1·(4-ethynyl-3-(fluorobenzyl)azetidine_3_carboxylic acid methyl ester in THF (15 mL) (〇·32 g, 1_3 mmol) was added to the sealed flask. pdCl2(pph3)2 (〇45 g, 0.065 mmol), Cul (0.025 g, 〇·13 mmol) and ethyldiisopropylamine (0.90 mL, 5.2 mmol) were added to the solution. The flask was flushed at eight plants and sealed in a preheated oil bath for 1 hour under 1 Torr. The mixture was concentrated under reduced pressure to give abr. EtOAc (EtOAc:EtOAc. The title compound is a yellow oil. MS (ESI) m/z: Calcd.: 428.1; observed: 429.1 (M++1). 119664.doc -258 - 200813031 1-((3-Fluoro-4_(5-(phenylmethyl)-1Η-indol-2-yl)phenyl)indolyl)-3•吖丁 pyridine

Add lithium hydroxide (0.025 g, 1.1 mmol) to 1-(4-(5-benzyl-1H-σbendo-2-yl)-3-fluorobenzyl)azetidine-3-decanoic acid Methyl ester (0.090 g, 0.21 mmol) in THF (1.0 mL) EtOAc. The solution was stirred at the main r for 1 hour or until it was no longer observed by LCMS; to the starting material υ the solvent was removed under reduced pressure and 〇·5 Μ phosphate buffer (3.0 mL, pH 6·〇) was added (ρΗ The value is about 9_10). The mixture was acidified to pH 6.0 with 1 N HCl and sonicated for 5 min. The aqueous solution was extracted with EtOAc (3 mL EtOAc) The oil was dissolved in AcOH (3.0 mL) and excess AcOH was removed under reduced pressure. Diethyl ether (15 mL) was added and the obtained precipitate was collected by filtration. The brown solid was washed with water (10 mL) EtOAc (EtOAc) MS (ESI) m/z: Found: 4121. Compound 100 1-((3-Fluoro-4-(5-(pyrimidin-2-ylmethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid (4-(bromo) Methyl)phenoxy)(t-butyl)dimethyl decane 119664.doc -259- 200813031

4-Hydroxybenzaldehyde (8.86 mL, 81.9 mmol) was added via syringe to a suspension of sodium hydride (2.36 g, 98.3 mmol) in THF (100 mL). The mixture was stirred until gas evolution ceased and chloro-tributyl dimethyl decane (18.5 g, 123 mmol) was added as a solution in THF (50 mL). The reaction was stirred for 1.5 hours and quenched with 1 N NaOH. The mixture was extracted twice with EtOAc and the extract was washed with water, and then washed with brine, and dried over anhydrous EtOAc. The oil was dissolved in EtOH (200 mL) and cooled to 0. Sodium borohydride (3.41 g, 90.1 mmol) was added and the mixture was stirred at 0 ° C for 30 min. The reaction was quenched with saturated NH4C1 and extracted twice with Et20. The organic extract was dried over MgSO4 and concentrated to give an oil. Cesium sulfonium sulfonate (0.56 mL, 7.06 mmol) was added dropwise to triethylamine (1.79 mL, 12.8 mmol) and the above oil (1.53 g, 6.42 mmol) in DCM (25 mL) In the solution. The mixture was stirred at 0 ° C for 1 hour, Et20 was added and the mixture was washed once with water, washed once with 1 N HCl, washed once with saturated NaHC Ο3, dried over MgSO 4 and concentrated in vacuo to give an oil. . The oil was dissolved in acetone (50 mL) and evolved lithium (2.79 g, 32.1 mmol). The mixture was stirred under reflux for 15 minutes, cooled to room temperature, diluted with EtOAc (EtOAc) and washed twice with water, washed twice with sodium thiosulfate, dried and concentrated with EtOAc EtOAc EtOAc EtOAc (4-(Bromoindolyl)phenoxy) (t-butyl) dimethyl decane. !H NMR (400 MHz, MV 4) δ ppm 7.26 (2H, d, J = 8.5 Hz), 6.79 (2H, d, J = 8.0 Hz), 4.48 (2H, s), 0·98 (9H, s), 0.19 (6H, m). 2-(4-(Tertiary butyl dimethyl decyloxy) benzyl pyrimidine

Zinc (0.33 g, 4.97 mmol) and iodine (0.008 g, 0.033 mmol) were added to the dried flask (25 mT,). The mixture was vacuumed and heated with air for 10 minutes, cooled to room temperature, placed under an argon atmosphere, suspended in 3 mL of DMF (anhydrous, degassed by bubbling nitrogen through it for 1 minute) and cooled. To 0 °C. (4-(Bromoindolyl)phenoxy)(t-butyl)dimethyloxane (1·〇〇g, 3.31 mmol) was added as a solution in 3 DMF, the mixture was taken at 〇 ° C Stir for 3 minutes, then stir the 3 〇 facet at room temperature. Then 2-bromopyrimidine (526 mg, 3.31 mmol), Pd2dba3 (〇·〇91 mg, 〇·〇 99 mmol) and S-Phos (0.163 g, 0.40 mmol) were added. The flask was purged with argon and heated at 6 ° C for 1 h, cooled to room temperature, filtered over EtOAc (EtOAc)EtOAc. The resulting solid was purified by flash chromatography to give the title compound. MS (ESI) m/z: calcd.···················· 4-(pyrimidin-2-ylmethyl)phenol

119664.doc -261 - 200813031 Add tetrabutylammonium fluoride (1.68 mL, 1.68 mmol, 1 Μ in THF) to 2-(4-(t-butyldimethyl decyloxy) at 〇 °C A solution of benzyl)pyrimidine (0.50 g, 1.68 mmol) in THF (5 mL). The mixture was stirred for 30 minutes, diluted with water and extracted three times with DCM. The combined organic extracts were dried over MgSO4, EtOAc (EtOAc) MS (ESI) m/z: Calculated: 186.1; observed: 187.3 (M++1). 2-iodo-4-(pyrimidin-2-ylmethyl)phenol

Add bis(pyridine) tetrafluoroborate (379 mg, 1·〇2 mmol) to 4-(pyrimidin-2-ylmethyl)phenol (2〇〇mg, 1 ·〇7 mm〇) at 〇 °C l) in a solution of 9:1 DCM:TFA (6 mL). The mixture was stirred for 1 h, partitioned between EtOAc and water. The organic layer was dried over MgSO4, concentrated in vacuo and purified by column column chromatography to afford 2- </RTI> <RTIgt; Ms (ESI) m/z: Calcd. 1-((3-Fluoro-4-(5-(pyrimidin-2-ylmethyl)benzoquinone-2-yl)phenyl)methyl)indolebutyrate-3-carboxylic acid methyl ester

119664.doc -262- 200813031 According to Scheme B3 and General Procedure G consisting of 2-based-4-(oxaindole-2-ylmethyl)benzene (0.230 g, 0.74 mmol) and 1-(4-ethynyl-3 Synthesis of -fluorobenzyl)azetidine-3-carboxylate (0.220 g, 〇·89 mmol). MS (ESI) m/z: Calcd. 1-((3-Fluoro-4-(5-(pyrimidin-2-ylmethyl)benzofuran-2-yl)phenyl)methyl)indole 4-carboxylic acid

According to the procedure B3 and the general procedure, 1-((3-fluoro-4-(5-(pyrimidin-2-ylmethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3- Synthesis of methyl formate (0.180 g, 0.42 mmol): white solid [h. 4 NMR (400 MHz, DMSO-d6) δ ppm 8.74 (d? J=4.9 Hz5 2 H)5 7.90 (t, J=8_0 Hz, 1 H), 7.61 (s, 1 H), 7.55 (d, / =8.4 Hz,1 H),7.35 (t,/=4.9 Hz,1 H), 7.21-7.32 (m,4 H), 4.30 (s,2 H),3.61 (s,2 H),3·38 -3·46 (m, 2H), 3_19-3·26 (m, 3 H). MS (ESI) m/z: Found: 41:21. Compound 101 1-((3-Fluoro-4_(5-(oxaridin-3-ylmethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid 3-(4-A Oxyl group

〇Me 119664.doc -263 - 200813031 Add (0.976 g '14·9 mmol) and broken (0.025 g, 0.100 mmol) to a flame-dried flask (25 mL) and heat under vacuum with an air heat gun 10 minutes. The flask was cooled to 〇 ° C and DMF (5 mL) was added. The oxime methyl)-4-methoxybenzene (1.43 mL, 9.95 mmol) was added as a solution in DMF (5 mL) and the mixture was stirred for 2 hrs and then stirred at room temperature for 20 min. S_Phos (0.490 g, 1.19 mmol), Pd2dba3 (0.273 g, 0.299 mmol) and 3-di-sigma ratio (0.976 mL, 9.95 mmol) were added and the mixture was heated at 60 ° C for 1 hour. The mixture was cooled to room temperature, filtered over EtOAc EtOAc (EtOAc)EtOAc. MS (ESI) m/z: calc.: 199.1; observed: 200.3 (M++1) 〇 3-(3·iodo-4-methoxybenzyl) acridine

Add bis(bite) tetrahydroborate (1.35 g, 3.64 mmol) to 3-(4-methoxybenzyl)acridine (720 mg, 3.64 mmol) in 9:1 TFA: DCM (20 mL) The solution was stirred and stirred at 〇 ° C for 1 hour. The ice bath was removed and the reaction was stirred for 2 h. EtOAc was added and the mixture was washed twice with water EtOAc EtOAc EtOAc EtOAc. 3_(3_Carbon_4_methoxybenzyl) π is determined by σ. MS (ESI) m/z: Calcd. 2-iodo-4-(pyridin-3-ylmethyl)phenol 119664.doc -264- 200813031

Add 2&gt; odor (11 1 mL, 11 · 1 mmol, 1 Μ in DCM) to 3-(3•iodo-4-methoxybenzyl)pyridine (720 mg, 2.21) at 〇C Mm 〇 1) In a solution of DCM (3 mL), and the mixture was stirred for 1 hour. The mixture was stopped by careful addition of water, the layers were separated and the organic layer was washed twice with water. The combined organic extracts were dried over MgSO4, EtOAc (EtOAc) Benzene age. MS (ESI) m/z: Calcd. 1-((3-Fluoro-4-(5-indolepyridin-3-ylmethyl)benzofuran-2-yl)phenyl)methyl)indole

According to Scheme B3 and General Procedure G, 2-iodo-4-(pyridin-3-ylmercapto)phenol (0.305 g, 0.98 mmol) and 1-(4-ethynyl-3-fluorobenzyl) Synthesis of methyl 3-carboxylate (0.220 g, 0.89 mmol): yellow solid. MS (ESI) m/z: Calcd. 1-((3-Fluoro-4-(5-(.pyridin-3-ylmethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid 119664.doc -265 - 200813031

According to the procedure B3 and the general procedure, 1-((3-fluoro-4-(5-(pyridin-3-ylmethyl)benzofuran-2-yl)phenyl)indenyl)azetidine_3_ Synthesis of methyl formate (〇·〇68 g, 0.16 mmol): white solid. 1η NMR (400 MHz, MeOH) δ ppm 8.47 (s? 1H)? 8.39 (d, /=4.5 Hz, 1H)? 8.11 (dd, J=8.2, 7·6 Hz, 1H), 7.73 (d, 6_4 Hz, 1H), 7.50-7.55 (m, 2H), 7.43 (s, 1H), 7·35_7·42 (m, 2H), 7.29 (d, J=2_9 Hz, 1H), 7.25 (d, J= 8.6 Hz, 1H), 4.40 (s, 2H), 4·20_4·31 (m, 4H), 4.15 (s, 2H), 3.53 (dt, J = 8.8, 7.8 Hz, 1H). MS (ESI) m/z: Found: 41:21. Compound 102 1-((4-(5-本甲基基基幷叫_2_基)-3-fluorophenyl)methyl 丫丁__ 3-carboxylic acid (4-hydroxy-3-iodophenyl) (phenyl)ketone

A solution of (4-.yl)(phenyl)methanone (2.0 g, 1 mmol) in saturated aqueous ammonium hydroxide (130 mL) was stirred at 25 ° C for 15 min and then (8. 2 g, 49 mmol) and a solution of broken (2.6 g, 10 mmol) in water (260 mL). After 30 minutes, the mixture was taken to aq. EtOAc (EtOAc) The organic extract 119664.doc - 266 - 200813031 was washed sequentially with saturated aqueous sodium thiosulfate (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and evaporated. The residue was chromatographed (EtOAc, EtOAc (EtOAc): MS (ESI) m/z: Calcd. 1-(4-(5-Benzylmercaptofuran-2-yl)_3_fluorobenzyl)azinium-3-carboxylic acid methyl ester

According to Step 3 of Scheme B3 and General Procedure G from (4-hydroxy-3-iodophenyl)(phenyl)methanone and 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylic acid Synthesis of oxime ester: yellow-orange solid. MS (ESI) m/z: Calcd. 1-((4-(5-phenylmercaptofuran-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylic acid

According to the step 4 of the scheme B3 and the general procedure, it is synthesized from methyl 1-(4-(5-benzylidenebenzofuran-2-yl)-3-fluorobenzyl)azetidine·3-carboxylate:milk White solid [hSIPl EC50 = 80 nM]. Towel NMR (400 MHz, DMS0-O δ ppm 8.13 (s? 1H), 7.97 (t? J=8.0 Hz, 1H)5 7.80-7.85 (m5 119664.doc -267- 200813031 2H), 7.75-7.80 (m , 2H), 7·70 (t, /=7.4 Hz, 1H), 7.59 (t, J=7.5 Hz, 2H), 7.45 (d, J=3.1 Hz, 1H), 7.32 (d, /=4.1 Hz , 1H), 7_30 (s5 1H), 3.63 (s, 2H), 3.40-3.48 (m, 2H), 3.32 (s, 2H), 3.19-3.27 (m, 2H). MS (ESI) m/z : Calculated: 429.1; observed: 430 (M++1). Compound 103 (E/Z)_l-((3-fluoro-4-(5-((hydroxyimino))phenyl)) Benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid f

Add 50 wt% aqueous hydroxylamine solution (146 μΕ, 2375 μιηοΐ) to 1-((4-(5-benzylidenebenzofuran-2yl)-3-fluorophenyl)methyl)azetidine- 3-carboxylic acid (34.0 mg, 79 μπιοί) in a solution of acetic acid (〇·560 mL), and the obtained yellow solution was stirred at 60 ° C for 15 hours. 1 M pH 6 phosphate buffer (6.0 mL) was added to the resulting solution, and the mixture was subjected to ultrasonic treatment for 1 minute. The resulting white syrup was filtered and washed with EtOAc EtOAc (EtOAc) 4 NMR (400 MHz, DMSO 〇 δ ppm 11.34 (s, 〇·5Η), 11.25 (s, 〇·5Η), 7.87-8.00 (m, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.61 -7.68 (m,1H), 7.59 (s,1H), 7.44-7.52 (m,2H), 7.42 (dd,J=7.3, 3·3 Hz,1H), 7.30-7.39 (m,3H), 7.24 -7.30 (m, 2H), 3.62 (d, J = 5.5 Hz, 2H), 3.39_ 119664.doc • 268 · 200813031 3·48 (m, 3H), 3.23 (d, &gt; 4.5 Hz, 2H). MS (ESI) m/z: Calcd.: 444.2; observed: 445 (M++1). Compound 104 (E/Z)-l_((3-fluoro-4-(5-((methoxy) Amino)(phenyl)methyl)benzoquinone furan-2-yl)phenyl)methyl)azetidine·3·carboxylic acid, trifluoroacetate

Add 25% of 0-formamidine hydrochloride in water (257 μί, 848 μιηοΐ) to 1-((4-(5-phenylmercaptofuran-2-yl)-3-fluorophenyl) Methyl) succinicin-3-carboxylic acid (3 6.4 mg, 85 μιηοΐ) and sodium acetate (70 mg, 848 μπιοί) in acetic acid (700 mL, 0.13 Μ), and the resulting yellow solution at 70 Stir at °C for 17 hours. The solution was filtered through a tampon and concentrated in vacuo. The residue was taken up in MeOH (EtOAc) (EtOAc) (EtOAc) ((3-Fluoro-4-(5-((methoxyimino)(phenyl)methyl)phenyl)furan-2-yl)phenyl)methyl)azetidine_3_carboxylic acid, three Fluoroacetate. 1H NMR (400 MHz, MeOH-A) δpPm8·18- 8.23 (m, 0.5H), 8.16 (t, /=7.0 Hz, 0.5H), 7.68 (d, /=1.6 Hz, 0.5H), 7.64-7.67 (m, 0.5 H), 7.59-7.62 (m, 0.5 H), 7.55-7.59 (m, 0.5H), 7.44-7.51 (m, 4H), 7.40-7.44 (m, 2H), 7.37-7.40 (m , 1H), 7.30-7.37 (m, 2H), 4.51 (s, 1H), 4.50 (s, 1H), 4.34-4.44 (m5 4H) 5 3.96 (s, l.5H)? 3.96 (s3 1.5H) 3.67-3.79 119664.doc -269- 200813031 (m,1H). MS (ESI) m/z: Calcd. Compound 105 (E/Z)-l-((3-fluoro-4-(5-((ethoxyimino)(phenyl)methyl)phenyl)furan-2-yl)phenyl)methyl Azetidine-3-carboxylic acid, trifluoroacetate

Add 0 ethylhydroxylamine hydrochloride (86 mg, 885 μηιοί) to 1-((4-(5-本甲甲基幷)-2-)-phenylphenyl)methylpyrene σ Ding-3-carboxylic acid (38.0 mg ' 88 μιηοΐ) and sodium acetate (73 mg, 885 μηιοί) in acetic acid (700 pL, 0·13 Μ) and water (2 〇 0 μΜ) and the resulting yellow solution Stir for 17 hours at 70 ° C. The solution was concentrated in vacuo and the residue was taken crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (E/Z)-1-((4-(5-((ethoxyimino))(phenyl)methyl)benzoquinan-2-yl)-3 -ILbenzene as a white solid Methyl) σ 丫 butyl-3-carboxylic acid, trifluoroacetate. ijj NMR (400 MHz, MeOD-A) δ ppm 8.18-8.23 (m, 0.5H), 8·14·8·18 (m , 0.5H), 7.66-7.69 (m, 0·5Η), 7.66 (d, J=3 7 Hz, 0.5H), 7.58-7.62 (m, 0.5H), 7.55-7.58 (m, 0.5H), 7.44_ 7.51 (m, 4H), 7.40-7.44 (m, 1H), 7.31-7.40 (m, 4H), 4·5ΐ (s, 1H), 4.50 (s, 1H), 4.34-4.44 (m, 4H) ), 4.24 - 4.27 (m, 1H), 4.20-4.24 (m, 1H), 3.68-3 .77 (m,1H),1.30 (t,J=7.0 Hz, 119664.doc -270-200813031 3H). MS (ESI) m/z : calculated: 472·2 ; observed value · · 473 (M+ +1). Compound 106 (士)_l-((3 -Fluoro-4_(5-(light (phenyl)methyl)phenylhydrazinyl-2-yl)phenyl)methyl)azetidine-3- Formic acid, trifluoroacetate (±)-1-((3_败_4_(5_(trans)(phenyl)methyl)phenylhydrazine), 2,yl)phenyl)methyl)-rutin Methyl pyridine-3-carboxylate

Add shed-salted sodium (130 mg, 343 8 μιηοΐ) to ι_((4-(5- 曱醢 曱醢 曱醢 -2-2-yl)-3-fluorophenyl)methyl) oxime at 0C Ding bite _3_formic acid

Methyl ester (190 mg, 428 μηιοί) in MeOH (5.0 mL, 0.14 Μ) and THF (1·0 mL), and the mixture was stirred in the underside for a few minutes. Mix for 30 minutes under C. Saturated aqueous ammonium chloride (10 mL) was added and the mixture was extracted twice with EtOAc (30 mL). The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (EtOAc EtOAc (EtOAc:EtOAc) Hydroxy(phenyl)indenyl)benzoquinan-2-yl)phenyl)methyl)azetidine-3-carboxylate. MS (ESI) m/z: Calcd. (Phenyl (phenyl)methyl)benzophenone furyl] phenyl)methyl)azetidine-3-carboxylic acid, trifluoroacetate 119664.doc -271 - 200813031

Add lithium hydroxide monohydrate (i7 6 mg, 420 μιηοΐ) to (soil) 4-((3-fluoro_4_(5_(hydroxy(phenyl))) in water (2.0 mL) at 25 °C a solution of methyl benzofuran-2-yl)phenyl)methyl)azetidine_3_decanoate (62 3 , 140 μιηοΐ) in THF (3.0 mL), and the resulting solution Stir for 1.5 hours. 2 N HCl (0.210 mL) was added and the resulting solution was concentrated in vacuo. The residue was dissolved in DMSO (3.0 mL) EtOAc (EtOAc) (EtOAc (EtOAc) EtOAc (EtOAc) 1-((3_Fluoro-4_(5-(hydroxy(phenyl)methyl)benzofuran-2-yl)phenylmethyl)azetidine_3_carboxylic acid, trifluoroacetate. NMR (400 MHz, MeOH-Heart) δ ppm 8.13 (t, /=8·0 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.40 -7.46 (m,4H), 7.38 (dd, "/=8.6, 1.8 Hz, 1H), 7.30-7.36 (m,3H), 7.21-7.27 (m,1H), 5.91 (s,1H), 4.47 ( s, 2H), 4.38 (d, J = 3.1 Hz, 2H), 4.36 (d, / = 1.2 Hz, 2H), 3.65-3.75 (m, 1H). MS (ESI) m/z : Calculated value: 43i · 2 ; Observed value: 432 (M++1). Compound 107 l_((4-(5-Benzyl-7-furfuran[2,3-c] acridine-2-yl)·3-fluoro Phenyl) indenyl) azetidin-3-carboxylic acid 2-gas-6-block pyridin-3-ol 119664.doc -272- 200813031 χχ0Η NN human ci Add iodine (2.38 mL, 46.3 mmol) to 孓Chloro-3-1,3-pyridinol (5 〇〇g, 38.6 mmol) in water containing potassium carbonate (18·7 g, 135(f)(f)) The solution was stirred at room temperature for 2 hours. The mixture was treated with sodium thiosulfate, acidified to pH 2 using aqueous 12HCI, and extracted with EtOAc. 〇4 was dried and evaporated. EtOAc was purified eluting with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc ( EtOAc d, J = 8.3 Hz, 1H). MS (ESI) m/z: Calculated: 254.9; observed: 255.8 (M++1). 6-benzyl· 2-pyridin-3-ol

A mixture of Κ3Ρ04 (12 g, 55 mmol), S-Phos (0.45 g, 1.1 mm 〇i) and palladium acetate (0.21 g, 0.91 mmol) in THF (5 5 mL) was prepared in a m. The mixture was treated with 2- gas-6-iodopyridin-3-ol (4.67 g, 18 mmol) and &lt;RTI ID=0.0&gt;&gt; Heat to 80 ° C for 2 hours. The crude mixture was diluted with EtOAc (EtOAc)EtOAc. Purification by flash chromatography (EtOAc / hexanes) to afford 6- &lt;&quot;&&&&&&&&&&&&&&&&&&&&&&& , 1 H), 5.49 (br· s, 1 H), 4.06 (s, 2 H). MS (ESI) m/z ······························

Add hydrazine (5_87 g, 23.1 mmol) to 6-benzyl-2-chlorocepsin-3-ol (2·54 g, 11.6 mmol) in water containing potassium carbonate (3.20 g, 23.1 mmol) (45 mL) In the solution. The mixture was stirred at room temperature for 3 h, then treated with EtOAc (EtOAc EtOAc EtOAc EtOAc EtOAc. Purification using EtOAc/hexanes to afford 6-benzyl-2-chloro-4-pyridinyl-3-ol. 1H NMR (300 MHz, DMSO-A) δ ppm 10.36 (br. s, 1H), 7.68 ( s, 1H), 7.15-7.35 (m, 5H), 3.93 (s, 2H)· MS (ESI) m/z: Calculated: 345.0; observed: 345.9 (M++1). -(5-benzyl-7-furfuran fluorophenyl)methyl)azetidine-3-decanoate

According to Scheme B3 and the general procedure, G consists of 6•benzyl-2-chloro-4-iodopyridin-3-ol (1·00 g, 2.89 mmol) and 1-(4-ethynyl-3-fluorobenzyl) Synthesis of azetidin-3-carboxylate (0.859 g, 3.47 mmol). 4 NMR (300 MHz, CDC13) δ ppm 8·03 (t, /=7.8 Hz, 1H), 6.98-7.40 (m, 9H), 119664.doc 274- 200813031 4·22 (s, 2H), 3.72 ( s, 3H), 3.66 (s, 2H), 3.52-3.61 (m, 2H), 3.26-3.40 (m, 3H). MS (ESI) m/z: Calcd. 1-((4·(5-benzyl-7-furfuran[2,3-c] η-pyridin-2-yl)-3-fluorophenyl)methyl)azetidine-3-furic acid

Synthesis of [hSIP1 EC50=2583 nM] from 1-((4-(5-benzyl-7-furfuranylfluorophenyl)methyl)azetidine-3-carboxylic acid methyl ester according to procedure B3 and general procedure. 4 NMR (400 MHz, DMSO-A) δ ppm 7.95 (br. t, J=8.0 Hz, 1H), 7·59 (br· s5 1H), 7.16-7.45 (m,8H), 4.15 (br·s , 2H), 3.63 (br*· s, 2H), 3.42 (br. s, 2H), 3.17-3.26 (m, 3H). MS (ESI) m/z : Calculated: 45. M++1). Compound 108 1-((4-(5-)-based oxime [2,3-(^]0-biti-2-yl)-3-fluorophenyl)methyl) Butyl _3_carboxylic acid 1-((4_(5_] 吱 吱 [2,3-c]n than 唆-2-yl)-3-fluorophenyl)methylazetidine _3_carboxylic acid Methyl ester 119664.doc -275 - 200813031

4-(5-Benzyl-7-chlorofurantho[2,3-c]acridin-2-yl)·3_Met's Ethyl) azetidine-3-carboxylic acid methyl ester (0.320 g, Mixture of 0.69 mmol), cycloheximide (1 〇〇mL, 9.9 mmol), (10 wt% on activated carbon, 〇32〇g, 3 · 〇mmol) in EtOH (6.0 mL) in a sealed tube Prepared and heated to 80 ° C for 4 hours under N2. The mixture was passed through celite, and the evaporated filtrate was purified by flash chromatography using EtOAc/hexane to afford compound. 1H NMR (300 MHz, CDC13) δ ppm 8·82 (s, 1H) 7.96 (t, J=7.7 Ηζ, 1Η), 6.99-7.38 (m, 9Η), 4.25 (s, 2Η) 3.72 (s, 3H), 3.65 (s, 2H), 3.48-3.59 (m, 2H), 3.33-3.39 (m 3 Ή). MS (ESI) m/z: Calculated: 430.2; observed: 431.2 (M++1) 1-((4-(5-Benzylfurano[2,3-c]acridin-2-yl)_3_fluorophenyl)methyl)σ丫丁 Ij bite-3-carboxylic acid

According to the procedure B3 and the general procedure η, 1-((4-(5-p-hydroxyfuranium [2,3&lt;] 吼-2-yl)-3-fluorobenzyl)methyl)azetidine-3- Synthesis of methyl formate [hSiPi EC50 = 409 nM]. NMR (400 MHz, DMSO-d6) δ ppm 8.88 119664.doc -276- 200813031 (br.s, lH), 7.96 (br.t, J = 8.0 Hz, lH), 7.57 (s, lH), 7.16- 7·34 (m, 8H), 4.17 (br· s, 2H), 3.62 (br. s, 2H), 3.40-3.45 (m, 2H), 3.20-3.25 (m, 3H). MS (ESI) m/z: Calcd. Compound 109 1-((4-(5-]-based ketone[3,2_b]0-bito)_3_fluorophenyl)methyl)azetidine-3-carboxylic acid 6-nodal σ ratio Bite-3-ol V,

In a sealed tube, a mixture of Κ3Ρ〇4 (16 g, 78 mmol), S-Phos (〇·64 g, 1.6 mmol) and acetic acid (0.29 g, 1.3 mmol) in THF (70 mL) • Bromoquinone*唆-3_ol (4.50 g, 26 mmol) and β-benzyl- 9-oxime (0.5 Μ solution in THF, 103 mL, 52 mmol). The mixture was heated to 80 °C for 18 hours and diluted with EtOAc. The organic phase was washed with 2 M aqueous NaOH solution, brine, dried over EtOAc and concentrated. Purification by flash chromatography using EtOAc/hexanes afforded 6-benzylpyridin. 1H NMR (300 MHz, DMSO-A) δ ppm 9.66 (br·s, 1H), 8·03 (t, /=1.8 Hz, 1H), 7.13-7.30 (m, 4H), 7·07 (d, &gt;1.9 Hz, 2H), 3.95 (s, 2H). MS (ESI) m/z ····················· 6-nodal base 2_ moth ° bite-3-ol 119664.doc -277- 200813031

Add moth (3.21 g, 12.6 mmol) to 6-benzylpyridin-3-ol (2.34 g, 12.6 mmol) and anhydrous sodium sulphate (1.06 mL, 25.3 mmol) in water (60 niL) and THF (60 mL) In the solution. The mixture was stirred at room temperature for 1 hour, treated with sodium thiosulfate and acidified to pH 3 using 5 M aqueous EtOAc. It was extracted and subjected to flash chromatography using EtOAc / hexane to give 6-benzyl-2-iodopyridin-3-ol. 1H NMR (300 MHz, DMSO-A) δ ppm 10.62 (s, 1 Η), 7.13-7.34 (m, 5 Η), 6.99-7.11 (m, 2 Η), 3.95 (s, 2H). MS (ESI) m/z: Calcd. L-((4-(5-Benzylfuranium [3,2-b]pyridin-2-yl)-3-fluorophenyl)methyl)azinidine-3-decanoate

According to Scheme B3 and the general procedure G, 6-membered-2 - gas-4-based 0-indol-3-ol (0.500 g, 1.61 mmol) and 1-(4-ethynyl-3-fluorobenzyl)indole Butyl-3-carboxylic acid formazan (0.477 g, 1.93 mmol) was synthesized. ^ NMR (300 MHz, CDC13) δ ppm 7.93 (t, J = 7.9 Hz, 1H), 7·65 (d, "7=8.5 Hz, 1H), 7.37 (d, J = 3.1 Hz, 1H), 7.10 -7.33 (m,7H),7.04 (d, J=8.5 Hz,1H), 4.27 (s,2H), 3.72 (s,3H), 3.65 (s,2H), 3.48-3.60 (m,2H), 3.30-3.40 (m, 3H). MS (ESI) m/z: </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1-((4-(5-Benzylfuranium P,2-b)indolepyridin-2-yl)-3-fluorophenyl)methyl)σ丫丁丁-3-carboxylic acid

Synthesis of methyl 1-(4-(5•benzylfurano[3,2_b]% pyridine-2-yl)-3-fluorobenzyl)azetidin-3-indole according to Scheme 3 and general procedures [hsipi EC50=409 nM]. 4 NMR (400 MHz, DMSO_A) δ ppm 7 82_ 8.07 (m, 2H), 7.20-7.42 (m5 8H), 7.14-7.23 (m, 1H), 419 (s, 2H), 3.62 (s, 2H), 3.37-3.49 (m, 2H), 3·ΐ4_3 29 (m 3H). MS (ESI) m/z: Calculated: 416.2; observed: 417 (M++1) 化合物 Compound 110

1-((4-(6-benzyl-5-furfuran[3,2-bp-pyridin-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylic acid 5-benzyl Base-6-gas. Specific bite-3-ol

The starting material (5-bromo-6-chloropyridine-3-ol) was obtained by the public 3-step procedure: Office--, 1990, 499_501. Add the words (2 45 g, 37 4 匪〇 1) and iodine crystals to the dried flask. The mixture was heated under an air heated gun for 10 minutes under vacuum and then allowed to cool under an Ar atmosphere. After the flask was charged with DMF (10 mL), which was degassed from 119664.doc - 279 - 200813031, the mixture was cooled to 0 ° C and benzyl bromide (2.96 mL, 24.9 mmol) was added. After stirring the resulting mixture for 30 minutes at 0 ° C, Pd2(dba)3 (0.571 g, 0.624 mmol), S-Phos (1.02 g, 2.49 mmol) and 5·bromo-6-chlorotonate bite 3-ol A mixture of (2.60 g, 12.5 mmol) was quickly added to the flask, and then the reaction was rinsed with Ar and placed in an oil bath at 60 ° C for 4 hours or until the starting material could not be detected by LCMS. The reaction was cooled to room temperature and filtered through a fine fritted funnel. The effluent was concentrated to give a yellow oil which was taken on EtOAc EtOAc (EtOAc) The product was further purified by column chromatography after recrystallization by self-burning and minimal cold air to afford a white solid. MS (ESI) m/z: Calcd.:21.21. 5-benzyl-6-gas-2-molybdenyl-3-ol

CCCC Add 5-benzyl-6-chloropyridin-3-ol (0.73 g, 3. 3 mmol) and Ι2 (0·21 mL, 4.0 mmol) to K2C03 (1·6 g, 12 mmol) in water ( In a solution of 25.0 mL). After stirring for 16 hours, the mixture became homogeneous and developed a color. The mixture was washed with sodium thiosulfate (1 〇〇 mL) and then carefully treated with concentrated HCl until pH 2 was measured from pH paper. The solution was extracted with EtOAc (3×5 mL) and EtOAc evaporated. The solid was purified by wet milling with minimal DCM and hexanes to afford a beige solid.士 nmr (300 MHz, DMSO^d6) δ ppm 10.90-11.09 (1H? br s)? 7.30-7.37 119664.doc 〇〇Λ 200813031 (2H,m), 7.17-7.28 (3H,m),6.99 ΠΜ ,

UH^ s)5 3.95 (2H5 s); MS (ESI) m/Z: Calculated: 344.9; observed: 345 9 (m++i). WOK6-f base_5_ gas, husband shouts [3,2_b] tons 唆_2_ base) 3_gas phenyl)methyl)azetidine-3-carboxylic acid methyl ester

5H6-chloro-2+ ratio σ s | alcohol (15 〇 g, 4 3 _ 〇 1), (, PdCl 2 (PPh3) 2 (0.30 g, 〇 · 43 mmol), hardened copper (1) (〇 17 g, 〇 87 mm〇1), N·ethyl-...isopropylpropan-2-amine (61 machine, 35 faces, ^ (4-ethynyl-3-gas group), bamboo bite-3_formic acid methyl vinegar ( 12 §, 4 8 and DMF (10 mL, 129 combined in a sealed burn. The flask was flushed with nitrogen, sealed and placed in an oil bath for 16 hours. The reaction was concentrated to remove solvent and the resulting Black mixture adsorbed to cerium oxide

on. Flash chromatography (10%% Et?Ae) was carried out to afford a yellow oil which was further purified on a Varian HF </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The resulting solid was triturated with diethyl ether to give a cream white solid. iH NMR (3 〇〇 MHz, chloroform δ 7.83-7.90 (lH, m), 7.49 (lH, s), 7.27-7.40 (5H, m), 7.22-7.24 (1H, m), 7.12-7.19 (2H , m), 4.20 (2H, s), 3.72 (3H, s), 3.65 (2H, s)3 3.52-3.59 (2H, m)5 3.32-3.38 (3H, m) ; MS (ESI) m/z Calculated value: 464 1 ; observed: 465 1 (M++1). l-((4-(6-Benzylfurfuran[3,2-b].pyridin-2-yl)-3 -fluorophenyl)methyl)azetidine-3-carboxylic acid 119664.doc •281 - 200813031 co2h

In THF (2.0 mL), ΐ-((4·(6-benzyl_5_furfuran[3,2_b]indole-2-yl)-3-fluorophenyl)methyl) Kenting bite-methyl decanoate (〇·〇84 g, 0.18 mmol) was added to Li0H (0.022 g, 〇9〇mm〇1) in water (3 〇mL)

In the solution in P. The solution was stirred for 3 minutes and then the solvent was removed under reduced pressure to provide a white suspension. 〇·5 Μ phosphate buffer, ρΗ 6〇 (3 mL) was added to the mixture, and then 1 ν HC1 was added until the pH test paper indicated a pH of 6.0. The resulting suspension was filtered and the milky white solid was collected and dried at 50 &lt;0&gt;C under vacuum. 1η NMR (400 MHz, DMSO-A and 1 drop of TFA-deny δ ppm 8.04-8.21 (2H, m), 7.44-7.70 (3H, m), 7·18·7·40 (5H, m), 4.45- 4.60 (2H,m),4·13·4·40 (6H,m), 3.60-3.76 (1H,m); MS (ESI) m/z: Calculated: 45 〇1; observed: 451.1 (M ++1) 〇Compound 111 v 1 (4-(6-benzylphenylhydrazone [d]oxazol-2-yl)-3-fluorophenyl)methyl)azetidin-3- 4-pyringyl -2-filled aniline

Add moth (2.49 g, 9.82 mmol), followed by 30% hydrogen peroxide in water (1.67 mL, 16.4 mmol) to 4_benzyl aniline (3. 〇〇g, 164 mm 〇1) in 16 mL MeOH In the solution. The dark solution was stirred overnight. The anti-119664.doc -282- 200813031 solution was partitioned between water/saline and Et〇Aci. The organic layer was washed once with brine &lt;&gt; dried over <RTIgt; The resulting oil was purified by EtOAc (EtOAc (EtOAc)EtOAc. Ms (ESI) m/z: Calculated: 309.0; observed: 310.0 (M++1). N-(4-benzyl-2-iodophenyl)_2-fluoro-4-carboxybenzamide

Add N-ethyl-N-isopropylpropan-2-amine (0.39 mL, 2.2 mmol) and 4-benzyl-2-indananiline (〇·41 g, 1.3 mmol) to 2-fluoro- 4-Mercaptobenzoic acid (1.5 mmol) in a slurry of 5 mL THF. After 30 minutes, the reaction was treated with 1 N HCl and EtOAc. The organic layer was washed once with 1 n HCl and washed once with saturated aqueous NaHC.sub.2 and once with brine. The organic layer was dried over MgSO.sub.s, filtered and concentrated in vacuo. The resulting material was purified by EtOAc (EtOAc) (EtOAc (EtOAc) 4-Mercaptobenzoyl brewing. MS (ESI) m/z: Calcd.: 459.

1,10-Carlin (0.016 g, 0.087 mmol), cuprous telluride (〇〇〇8 g '0.044 mmol), cesium carbonate (〇·21 g, 0.65 mmol) and N-(4_benzyl _ 119664.doc -283 - 200813031 2-iodophenyl)_2_fluoro_4_mercaptobenzamide (〇·2〇〇g, 〇·44 mni〇l) was combined under nitrogen. Dioxane (2 mL) was added and the reaction was sealed and heated to 90 C for 24 hours. The reaction was cooled and separated between Et EtOAc and water. The organics were washed with brine, dried over sodium s The residue was purified by EtOAc EtOAc (EtOAc) - Fluorine plate. MS (ESI) m/z: calcd.: 331.1; observed: 332.1 (M++1) 〇1_((4_(6_benzylbenzoquinone[d]oxazol-2-yl)-3_fluorobenzene Methyl)azetidine_3_ formate

A white solid [hsiPi EC5 〇 = 8 nM] was synthesized according to the procedure B4 and the general procedure I using 4-(6-mercaptobenzo[d]oxazol-2-yl)-3-fluorobenzoic acid. 4 (J NMR (400 MHz, DMSO 〇 δ ppm 8.12 (t, /= 7.8 Hz, 1H), 7.73 (d, /=8.0 Hz, 1H), 7.69 (s, 1H), 7.26-7.38 (m, 7H) ), 7.16-7.25 (m, 1H), 4.11 (s, 2H), 3.65 (s, 2H), 3.19-3.48 (m, 5H). MS (ESI) m/z: Calculated: 416.2 ; 417.2 (M++1). Compound 112 1-((4-(5-Benzylbenzoquinone[d]oxazol-2-yl)-3-fluorophenyl)methyl)azetidine-3_carboxylic acid 119664 .doc -284- 200813031 4_Benzyl-2-nitrophenol

A solution of red fuming nitric acid (2.28 mL, 54.3 mmol) in 100 mL AcOH was slowly added dropwise to benzyl alcohol (10.0 g, 54.3 mmol) in 300 mL AcOH at rt. In the solution. The reaction was stirred for 3 hours, poured onto ice, and the obtained solid was collected by filtration &lt;&apos;&gt; 〇 MS (ESI) m/z: Calculated: 2221. 2-amino-4_knotylbenzene age

1 〇%! bar/carbon charcoal, pearlman (50% humidity) (2.3 g, 2.2 mmol) and 4-benzyl-2-nitrobenzene (5.00 g, 22 mmol) were combined under nitrogen and delivered via syringe Dilute with 80 mL of MeOH. The vessel was pressurized to 40 psi and shaken in a Parr shaker for approximately 24 hours. The resulting material was flushed with nitrogen and filtered through EtOAc (EtOAc). The filtrate was concentrated in vacuo to give 2-amino-4-benzylphenol as a brown solid. MS (ESI) m/z: Calculated: 199.1; observed: 200.0 (M++1). N-(5-benzyl-2-hydroxyphenyl 2-fluoro_'mercaptobenzamide

119664.doc -285 - 200813031 Add ethylene dioxide (0.374 mL, 4.28 mmol) and N,N-dimethylformamide (0.00261 g, 0.03 57 mmol) (several drops) to 2_fluoro-4 - Mercaptobenzoic acid (0.600 g, 3.57 mmol) in a mixture of 15 mL DCM. The mixture was stirred for several hours, additionally treated with (COC1) 2 (0.100 mL) and then stirred for 1 hour, concentrated in vacuo and semi-solid suspended in 15 mL THF. N,N-Diisopropylethylamine (0.808 mL ' 4.64 mmol) was added followed by 2-amino-4-benzylphenol (0.711 g, 3.57 mmol). After 4 hours the reaction was treated with EtOAc, water and 1 N EtOAc. The organic layer was washed once with brine, dried over sodium sulfate, filtered and concentrated. The material was purified by EtOAc (EtOAc) elute MS (ESI) m/z: Calcd. Keto-2-(4-(dimethoxymethyl)-2-phenylene)phenylhydrazone [d]"

N-(5-Benzyl-2-hydroxyphenyl)-2-fluoro-4-methylmercaptobenzamide (0.500 g, 1.43 mmol), p-toluenesulfonic acid monohydrate (〇817 g, 4 A mixture of 29 mmol) in 14 mL of hydrazine was heated to 115 ° C under nitrogen in a tortoise equipped with a water-cooled reflux condenser. After 3 hours, the reaction was cooled and diluted with DCM and MeOH to give a solution and 15 g of cesium carbonate (silicycle) was added and the mixture was dried. The material was purified by EtOAc (EtOAc:EtOAc) MS (ESI) m/z: Calcd.: 377: s:::::::::::::::::::::::::::: [d]oxazole 119664.doc -286- 200813031

Dissolve 5-benzyl-2-(4-(dimethoxyindenyl)_2-fluorophenyl)phenylhydrazone [d]oxazole (0.160 g '0.424 mmol) in 2 mL THF and add 1 mL 5 N HC1. The mixture was stirred for 1 hour, diluted in dcm, and quenched with 1 〇 n NaOH until basic. The aqueous layer was extracted twice with DCM. The combined organics were dried with sodium sulfate, filtered and concentrated to afford &lt;RTIgt;&lt;/RTI&gt;&gt; (5-benzylphenyl hydrazide [d] oxazol-2-yl)-3-fluorobenzaldehyde as an orange solid. 1H NMR (400 MHz, DMSO-^) δ ppm 10.09 (s7 lHyV 8.43 (t, , /=7,3 Hz, 1H)3 7.90-8.04 (m,2H),7·72_7·83 (m,2H) , 7.38 (d, J = 8.5 Hz, 1H), 7.26-7.33 (m, 4H), 7.17-7.24 (m, 1 H), 4.11 (s, 2H). 1-((4-(5-benzyl) Benzo[d]oxazol-2-yl)-3-fluorophenyl)methyl)azetidine-3-furic acid

A white solid [hSIP1 EC50 = 19 nM] was synthesized using 4-(5-benzyl·benzoquinone[d]oxazol-2-yl)-3-fluorobenzaldehyde according to the procedure B4 and General procedure. 4 NMR (400 MHz, DMSO-ύ^) δ ppm 8.13 (t, /== 8.0 Hz, 1H), 7.67-7.74 (m, 2H), 7.26-7.39 (m, 7H), 7.16-7.24 (m, 1H), 4.09 (s, 2H), 3.66 (s, 2 H), 3.39-3.51 (m, 2H), 3.20-3.36 (m, 3H). MS (ESI) m/z: calcd.················ 119664.doc -287 - 200813031 Compound 113 1-((4-(5-Benzylbenzoquinone[d]oxazole-2-yl)phenyl)methyl)azetidine-3_decanoic acid

In addition to 4-methylmercaptobenzhydryl chloride, with 1_((4_(5-benzylphenylhydrazone [d] oxime-2-yl)-3-fluorophenyl)methyl)azetidine _ A white solid [hSIP1 EC50 = 364 nM] was synthesized in a similar manner. 4 NMR (400 MHz, DMSO-^5) δ ppm 8.12 (d7 -/=8.0 Hz, 2H), 7.61-7.72 (m, 2H),

7.49 (d, J=8.〇Hz, 2H), 7.25-7.35 (m, 5H), 7.15-7.24 (m, 1H), 4·08 (s, 2H), 3.64 (s, 2H), 3.19- 3.48 (m, 5H). MS (ESI) m/z: Calcd.: 398. Compound 114 1-((4-(6-Phenylbenzoquinone[d]thiazol-2-yl)_3·fluorophenyl)indolyl)γ-butyridine_3-carboxylic acid S-4-~yl-2-trim Phenyl phenyl thioamino carboxylic acid vinegar

Sodium hydride (0.38 g, 9.6 mmol) was added to a yellow solution of 4-mercapto-2-stone phenol (2.0 g, 8-7 mmol) in 20 mL DMF at EtOAc. The reaction turned into a dark light, and after 30 minutes, dimethylamine (thiomethane) chloride (1.2 g, 9.6 mmol) was added. The reaction was stirred at room temperature over the end of the week. Water was added and the mixture was extracted 3 times with DCM. The combined extracts 119664.doc -288 - 200813031 were washed with 0.55 NaHCCh, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. The oil was heated to 160 ° C for a total of 2 hours. The reaction was cooled and the obtained oil was taken directly on a 120 g ISCO column and eluted from 0-30-50% EtOAc / hexanes to afford &lt Thiocarbamino phthalate. MS (ESI) m/z: Calculated: 3 16 · 1; observed: 3 17.1 (M++1). S-2-Amino-4-benzylphenyldimethylthiourethane

Adding (negative size activated powder) (1.63 g, 25.0 mmol) and ammonium chloride (2.67 g, 49.9 mmol) to S-4-benzyl-2-nitrophenyldimethylsulfide under a gas atmosphere A minoester (1.58 g, 4.99 mmol) in 25 mL of a 5:1 acetone/water solution. The reaction heats up and is cooled in an ice bath. The heterogeneous reaction solution was stirred for about 4 hours. The reaction was kept overnight and partitioned between 2 mL of EtOAc and water. The organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated to give &lt;RTIgt;&lt;/RTI&gt; MS (ESI) m/z: Calcd. 2-(2-(2-Amino-4-benzylphenyl)dithio)_5-benzylaniline

Potassium hydroxide (0.840 g, 15.0 mmol) (solid, finely pulverized) was added to S-2-amino-4-benzylphenyldimethylthiocarbamate (143 g, 119664.doc 200813031 4_99 mmol) in a slurry of 15 mL of ethylene glycol. The reaction was heated to 6 (TC) under nitrogen. 10 mL of 2-BuOH was added as a cosolvent and the resulting solution was heated for 2 hours. The reaction was equipped with a water-cooled reflux condenser and heated to 90 ° C for 3 hours. The material was cooled and concentrated in vacuo. The material was partitioned between EtOAc and water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give an oil. Chromatography (ISCO, 0-30% EtOAc / hexanes) Ms (ESI) m/z: Calculated: 428.1; observed: 429.0 (M++1). 4-(5-benzylphenylindole[d]thiazol-2-yl)-3-fluorobenzaldehyde 2 -Fluoro-4-methylmercaptopurine chloride (3·ι6 mm〇1) was dissolved in $ mL of THF, and N,N-diisopropylethylamine (〇·879) was added dropwise via a syringe.

a solution of mL,5·05 mmol) and 2-(2-(2-amino-4-benzylphenyl)dithio)-5-benzylaniline (0.541 g, 1.26 mmol) in 5 mL THF The syringe was rinsed with 1 mL of THF. The mixture turned brown and then a precipitate formed. Stir the mixture; mix overnight. The reaction was diluted with EtOAc and 1 N NaOH. The organic layer was washed with brine, dried over anhydrous sodium sulfate The resulting brown oil was treated with 16 mL of EtOH, 2 mL of water and &lt;RTI ID=0.0&gt;&gt; The heterogeneous reactants were equipped with a water-cooled reflux condenser and heated to reflux overnight. The reaction was cooled to 〇〇c and basified with 10 N NaOH. The reaction was partitioned between water and DCM. The aqueous layer 119664.doc -290-200813031 was extracted 3 times with DCM, and the combined organic layers dried over anhydrous sodium sulfate filtered and concentrated in vacuo. The substance is at 1 〇〇/. Treated with MeOH in DCM and adsorbed on 5 g of silica gel and passed through a Redi-Sep® pre-filled silica gel column (80 g) using 〇_i5% EtOAc/hexane. The title compound containing the product was concentrated to give the title compound as a pale yellow solid. MS (ESI) m/z: Calcd.: 437. 1-((4-(5-Benzylbenzoquinone[d]thiazol-2-yl)-3-fluorophenyl)methyl)azetidine_3·carboxylic acid

Synthesis of 4-(5-mercaptobenzoquinone [d] sin-2-yl)-3-fluorobenzaldehyde according to Scheme B4 and General Procedure I: light yellow solid [hSIPl.sup. !H NMR (400 MHz? DMSO-J5) δ ppm 8.27 (t5 J==8.〇Hz 1H), 8-07 (d, J=8.5 Hz, 1H), 7.95 (s, 1H), 7.27-7.44 (m, Q 7H), 7.16-7.25 (m, lH), 4.13 (S, 2H), 3.65 (S, 2H), 3.4 〇 - 3.50 (m, 2H), 3.20-3.30 (m, 3H). MS (ESI) m/z: Calcd. Compound 115 l-((4_(5-Benzyl-1H-benzoquinone[d]imidazol-2-yl)-3-fluorophenyl)indolyl)σ丫丁丁_3_carboxylic acid 4-mercapto-2 -Accord aniline 119664.doc -291 - 200813031

4_Aminodiphenylmethane (5.00 g, 27 mmol) was added portionwise to acetic anhydride (26 mL, 273 mmol) with stirring. A solid formed which was precipitated by the addition of about 15 mL of acetic anhydride. The reaction was cooled to ambient temperature and nitric acid (2.0 mL, 4 1 mmol) was slowly added dropwise over 30 min. Mix the homogeneous red mixture overnight and pour into a fast stirred solution of 30 mL water, 7 mL concentrated HC1 and 24 mL EtOH (fever!). The reaction was cooled and then heated to reflux for about 4 hours, cooled and poured

On the ice and with ιυ In iNauh, the main ph value is s-y. The aqueous layer was extracted three times with uuM and dried over sodium sulfate filtered and concentrated. The resulting dark red oil was purified by EtOAc EtOAc (EtOAc) MS (ESI) m/z: Calcd. Ν-(4-benzyl-2-nitrophenyl)-4-(dimethoxymethyl)-2-fluorobenzamide

2-Fluoro-4-carboxylbenzoic acid (0.300 g, 1.78 mmol) was slurried in 10 mL DCM and catalytic DMF was added followed by hexanes (0.317 mL, 3.57 mmol). The reaction was stirred for several hours. Once the acid was consumed, the reaction was concentrated in vacuo and diluted with 7 mL EtOAc. 4-Benzyl-2-nitroaniline (0.611 g, 2.68 mmol) and diisopropylethylamine (0.622 mL, 3.5 7 mmol) were added as a solution in 5 mL THF. Reaction 119664.doc - 292 - 200813031 was stirred overnight EtOAc / sat. The residue was treated with p-toluenesulfonic acid monohydrate (〇. 丨 7 〇 g </ RTI> 0.892 mmol) and MeOH. After H, the mixture was concentrated and adsorbed on silica gel and purified by chromatography to obtain N-(4-benzyl-2-nitrophenyl)-4-(dimethoxymethyl)-2- Fluorobenzamide. MS (ESI) m/z: Calcd.: 424. (4-(5-Benzyl-1 fluorene-benzoquinone [d]imidazolium-2-yl)_3_fluorophenyl)methanol

Add iron powder -325 mesh (0.078 mL, 11 mmol) to n_(4-memberyl-2·salt base)-4-(monomethoxymethyl)-2-benzoyl with amine (0.466 g, 1.1 mmol) in an orange-yellow solution in 5 mL of 3:2 AcOH/EtOAc. The reaction was equipped with a reflux condenser and stirred rapidly under a constant temperature bath at 120 °C. After 丨0 minutes, the reactants almost became solid, and 3 niL of 2:1 AcOH/EtOH was added to promote stirring. After 3 hours, the mixture was pale yellow. The reaction was diluted with water, EtOAc and brine and the layers were separated. The aqueous layer was extracted twice with EtOAc (br.) and the combined organic layer was washed twice with 1 N NaOH and brine, dried over sodium sulfate, filtered and concentrated to give an orange oil. This material was purified by EtOAc (EtOAc) (EtOAc (EtOAc) MS (ESI) m/z: Calcd. 4-(5-Benzyl-1H-benzoquinone[d]imidazol-2-yl)-3-fluorobenzaldehyde 119664.doc -293 - 200813031

CHO F A solution of S〇3*py (〇·13 g, 0.83 mmol) in 0.75 mL DMSO at 0 ° C under nitrogen to (4-(5•benzyl-1H-benzoquinone [d] A solution of imidazole-2-yl)-3-fluorophenyl)methanol (0.055 g, 0.17 mmol) and triethylamine (0.12 mL, 0.83 mmol) in 1.5 mL 1:1 DCM/DMSO. The reaction was stirred for 2 hours and then diluted with EtOAc and water. The organic layer was washed once with water, once with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified with EtOAc (EtOAc)EtOAc (EtOAc) -3 - fluorobenzaldehyde. MS (ESI) m/z: calcd.: 303 (m. 3-fluorophenyl)methyl)butyrate _3_formic acid

According to the procedure B 4 and the general procedure I, 4-(5-benzyl-1H-benzoquinone [d] miso-2-yl)-3-indole benzaldehyde was synthesized to obtain a white solid 1_((4_( 5_Benzyl-1H-benzoquinone [d]-ton-2-yl)-3-fluorophenyl)methyl)butyrate_3_carboxylic acid [hSIPl EC5〇=4954 nM]. MS (ESI) m/z ············· Compound 116 119664.doc -294- 200813031 1_((3_象-4-(5-phenoxybenzoquinone [dpoxan-2-yl)phenyl)methyl) butyl butyl 3-carboxylic acid 2- Nitro-4-phenoxyphenol

Nitric acid (69-70%, 3.2 mL, 54 mmol) was slowly added dropwise from the addition funnel to 4-phenoxyphenol (1 〇. g, 54 mmol) in 1 mL mL AcOH over a period of about 3 min. In solution. The reaction heats up and is cooled in a water bath. After 1 hour f), the reaction was poured onto ice and allowed to warm to room temperature. A gelatinous solid was obtained which was partitioned between MTBE and water. The organic layer was washed once with water, brine brine, dried over anhydrous sodium sulfate. It was adsorbed onto 36 g of tannin and dried, and purified by gelatin chromatography (ISCO, (MO% EtOAC/hexane) in two portions. The fractions containing the product were combined and concentrated to give an orange oil. 2-Nitro-4-phenoxyphenol. MS (ESI) m/z: Calculated: 231····························

10% palladium on carbon, 50% water (1.43 g, 1.34 mmol) and 2·nitro-4-phenoxybenzene (3.10 g, 13.4 mmol) were combined under nitrogen and 30 mL MeOH was added. The mixture was exposed to H2 from the balloon and stirred rapidly overnight. The reaction was flushed with EtOAc (EtOAc) EtOAc. MS (ESI) m/z: </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 3-Fluoro-4-(5-phenoxyphenylhydrazone [d]caustin-2-yl)benzophenone CX〇XXVp- 2 drops of N,N-^-methylcartoamine (0·0 11 g, 〇· 15 mmol), then ethanedioxime (〇·3 9 mL, 4.5 mmol) was added to 2-fluoro-4-carbamidobenzoic acid (0.500 g, 3.0 mmol) in 8 mL DCM In the slurry. 30 minutes Ο

After G, the reactants became clear, pale yellow and uniform. The reaction was evaporated and dried in vacuo. The obtained solid was suspended in 1 mL of THF and added 2-amino-4-phenoxyphenol (0.60 g, 3.0 mmol) in solid form, followed by Hunig (0.67 mL, 3. 9 mmol). The brown solution warmed up and allowed to stir overnight. The reaction was diluted with DCM and 1 N HCl. The aqueous layer was extracted once with DCM and organics dried over sodium sulfate, filtered and evaporated. This was treated with 4-methylbenzenesulfonic acid hydrate (〇·85 g, 4.5 mmol) and 10 mL of toluene. The reaction was equipped with a water-cooled reflux condenser and a drying tube, and placed in a constant temperature bath at 120 ° C for about 4 hours to cool and dissolve between DCM and 1 N NaOH with stirring. The reaction was filtered and the aqueous layer was extracted once with DCM. The combined organics were dried with EtOAc EtOAc (EtOAc)EtOAc. The title compound. 4 NMR (400 MHz, DMSO-form 〇δ PPm 1〇.1〇(s,1H)5 8.45 (t,/=7.5 Hz,1H),7.94-8.02 (m, 2H), 7.90 (dj /=9.0 Hz, 1H)? 7.54 (d5 J=2.0 Hz, 1H)? 7.37-7·46 (m, 2H), 7·22 (dd, /=8.8, 2.3 Hz, 1H), 7.15 (t, J=7.3 119664.doc -296- 200813031

Hz,1Η),7·04 (d, “7=8.5 Hz, 2H) 〇1-((3-fluoro-4·(5-phenoxybenzoquinone[d] chelate-2·yl)phenyl ) methyl) butyl butyl 3-carboxylic acid

Synthesis according to Scheme B4 and General Procedure I using 3-fluoro-4-(5-phenoxyphenylhydrazone [d]oxan-2-oxa-2-yl)benzaldehyde (0.035 g, 0.11 mmol) to give a white solid. 1-(3-Fluoro-4_(5-phenoxybenzoquinone[d]oxazol-2-yl)benzyl)azetidine-3-carboxylic acid [hSlPlEC50=12 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (t, J = 7.8 Hz? 1H)5 7.84 (d, 7 = 8.5 Hz5 1H)5 7.48 (d, /=2.0 Hz, 1H), 7.31-7.44 ( m,4H), 7.10-7.20 (m, 2H), 7.03 (d, J=8.5 Hz, 2H), 3.67 (s, 2H), 3.40-3.51 (m, 2H), 3.21-3.35 (m, 3H). MS (ESI) m/z: Found: 41:21. 〇Compound 117 1-((3-fluoro-4-(5-(phenylthio))phenylhydrazone [d]oxazol-2-yl)phenyl)methyl)pyrene-3-carboxylic acid 5-(benzene Thio)benzoquinone [d]oxazole

150 mL pressure bottle was charged with 5-bromobenzoquinone [d]oxazole (2.43 g, 12.3 mmol), N,N-diisopropylethylamine (4·28 mL, 24.5 mm〇1) &amp; 24 mL Two σ bad burns. N2 was bubbled through the solution for 3 minutes, at which time the ginseng (two subunits 119664.doc -297-200813031 bisdiacetone) I bar (0) (0.281 g, 0.307 mmol), 4,5-double (two) was added. Phenylphosphino)-9,9-dimethyl-9H-diphenylhydrazine (0.355 g, 0.614 mmol) and thiophenol (1·26 mL, 12.3 mmol). The dark brown solution was sealed and heated to 100 ° C overnight. The mixture was diluted with EtOAc and NaOH and the organic layer was extracted twice with 1 N EtOAc. The organic layer was dried over anhydrous EtOAc EtOAc (EtOAc)EtOAc. 5-(phenylthio)benzoquinone [d]oxazole. MS (ESI) m/z: Calcd. 2-amino-4-(phenylthio)phenol hydrochloride

5-(phenylthio)benzoquinone [d]oxazole (1·04 g, 4.6 mmol) and concentrated HC1 (0.97 mL, 11 mmol) in 50 mL of rbf equipped with a water-cooled reflux condenser under nitrogen. The solution in 4.6 mL of EtOH was placed at 1 Torr. 〇 In a constant temperature bath. After 2 hours, the mixture was cooled, concentrated in vacuo and dried to give a yellow solid. The material was sonicated in 10 mL DCM, filtered, washed with DCM and dried to afford 2-amino-4-(phenylthio) phenol hydrochloride as a milky white solid. 4 NMR (400 MHz, DMSO-A) δ ppm 10.72 (s, 1 Η), 8.75 (br. s·, 1 Η), 7.28-7.35 (m, 2 Η), 7.12-7.25 (m, 5H), 6.99 (d , /=8.0 Hz, 1H), 4·32 (br. s·, 2H). 2-fluoro-4-indolyl-N-(2-hydroxy-5-(phenylthio)phenyl)benzamide 119664.doc -298- 200813031

3 drops of DMF, followed by ethylene dichloride (0.380 mL, 4.28 mmol), were added to a slurry of 2-fluoro-4-carboxamidinebenzoic acid (0.600 g, 3.57 mmol) in 10 mL dry DCM. in. The reaction was stirred under N2. The reaction was stirred for 4 h and concentrated in vacuo to afford a yellow oil. This material was dissolved in 10 mL of THF and added to 2-amino-4-(phenylthio)phenol hydrochloride (0.906 g, 3.57 mmol) and diisopropyl Ethylamine (1.55 mL, 8.92 mmol) in EtOAc. EtOAc (EtOAc m. Concentration in the middle. The orange oil was dissolved in 5 mL of DCM to give a thick yellow solid, which was collected by filtration and rinsed with DCM <RTIgt; Fluoro-4-(5-(phenylthio)benzoquinone[d]oxazol-2-yl)benzaldehyde 2-fluoro-4-methylindolyl-:^-(2-hydroxy-5-(phenylsulfonate) a mixture of phenyl)phenylhydrazine (0.180 g, 0.490 mmol) and p-toluenesulfonate (0.123 g, 0.490 mmol) in 5.0 mL of toluene was heated to 130 ° C in a sealed tube for a total of 6 The reaction was cooled and partitioned between 1 N NaOH and EtOAc. Wash once with water, dry over sodium sulfate, filtered and EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc 3_Fluorum_4_(5·(phenylthio)benzoquinone[d]oxazol-2-yl)phenylfurfural. MS (ESI) m/z: calc.: 349.1; observed: 350.0 (M+ +1) 1-((3-fluoro-4-(5•(phenylthio))phenylhydrazone [d]oxazole-2-yl)phenyl)methyl)azetidine_3_carboxylic acid

According to the procedure B4 and the general procedure I, 3-fluoro-4-(5-(phenylthio)benzoquinone [d] ° ° ° -2 base) benzyl (0.116 g, 〇·33 mmol) was synthesized: White solid [hSIPl EC50 = 3 nM]. 1H NMR (400 MHz, DMSO 〇 δ ppm 8.15 (t, J = 7.8 Ηζ, 1 Η), 7.82-7.91 (m, 2 Η), 7·48 (d, J = 8.5 Hz, 1H), 7.25-7.42 (m , 7H), 3.67 (s, 2H), 3.40-3.50 (m, 2H), 3.18-3.38 (m, 3H). MS (ESI) m/z: Calculated: 434.1; observed: 435.2 (M++ 1) Compound 118 1-((4-(6-Benzylbenzoquinone[d]thiazol-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylic acid 6-benzylphenylhydrazine [d]thiazol-2-amine

NH- 4 - benzyl aniline (10.37 g, 56.6 mmol) and ammonium thiocyanate (3·30 mL, 56.6 mmol) in a mixture of AcOH (100 mL) at 12-18 °C to 119664.doc - 300 - 200813031 Βι*2 (2·93 mL) is treated dropwise. Keep the temperature below 18〇c during the addition. After the addition was completed, the mixture was at 24. The mixture was stirred for 2 hours under stirring and the solvent was partially evaporated. The precipitate was collected by filtration, partially dissolved in EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc (16.17 g). This material was recrystallized from acetone to give 6-benzylbenzoquinone [d]thiazole-2-amine as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.89 (br) · s, 2H), 7.67 (s, 1H), 7.35 (d, ^=9.2 Hz, 1H), 7.29-7.20 (m, 6H), 3.98 (s, 2H). MS (ESI) m/z : Value: 240.3; observed: 241.1 (M++1). 4-(6-Benzylbenzoquinone[d]thiazol-2-yl)-3-fluorobenzaldehyde

A solution of 12.3 g of KOH in H20 (15 mL) was mixed with ethylene glycol (8 mL). 6-Benzylbenzoquinone [d] 嗟η sit-2-amine (3.00 g, 12.5 mm 〇l) was added to the mixture under N2 atmosphere. The mixture was scrambled at 13 5 °C for 6 hours, added to a 100 mL volume of ice and acidified to a pH of about 6 using a 5 μl aqueous HCl solution. The resulting suspension was extracted twice with DCM. The organic layer was washed once with brine, dried over EtOAc EtOAc (EtOAc) A solution of the crude material (0.695 g, 3.23 mmol) in THF (5 <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> </RTI> <RTIgt; The mixture in 0.844 mL, 4.84 mmol) was stirred at 24 °C for 17 hours. The mixture was diluted with EtO Ac, washed once with saturated aqueous NaHC 3 solution and washed with brine for one time, 119664.doc -301 - 200813031

It was dried by MgSCU and evaporated to obtain a red foam (〇.916 g for the next step). The crude material was taken up in EtOH (16 mL), water (2 mL) and concentrated aqueous hydrochloric acid (8 mL), then sssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss The mixture was cooled to 0 ° C, basified with 1N aqueous NaOH solution and partitioned between water and EtOAc. The aqueous layer was extracted with DCM (3 times) and the combined organic layers were dried over EtOAc and evaporated. Purification by flash chromatography (hexane/EtOAc = 5:1) afforded 4-(6-benzylphenylindole[d]n sss. 4 NMR (400 MHz, CDC13) δ ppm 10.06 (s, 1H), 8.67 (t, J=7_0 Hz, 1Η), 8·09 ((1,/=8·4Ηζ,1Η),7·83(ί1 , /=8·0Ηζ,1Η),7·76- 7.73 (m, 2H), 7.43-7.40 (m5 1H)3 7.33-7.3 1 (m5 2H), 7.26-7.23 (m,3H), 4.16 (s , MS (ESI) m/z: calc.: 347.4; observed: 348.1 (M++1) 1-((4-(6-benzylphenylhydrazide[d]thiazol-2-yl) -3·fluorophenyl)methyl)azetidine-3-decanoic acid

4-(6-Benzylbenzoquinone[d]thiazol-2-yl)-3-fluorobenzaldehyde (190 mg, 547 μιηοΐ), azetidine-3-carboxylic acid (166 mg) at 24 °C The mixture was stirred for 1 hour in MeOH (2 mL) and DCM (2 mL). The pale yellow solution was treated with sodium cyanoborohydride (34 mg, 547 EtOAc). The mixture was stirred for 12 hours. The solid was filtered off and washed 3 times with DCM, suspended in 4 mL of aq. </ br> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The mixture was dried and the solid was washed with water and dried in vacuo to give benzyl phenyl hydrazide [d] thiazol-2-yl) _3 _ fluorophenyl)methyl) as a white solid. - Formic acid [hSIPl EC50 = 149 nM]. 4 NMR (400 MHz, DMSO-d6) δ ppm 8.27 (t, Hz, 1H), 8·04 (s, 1H), 8.01 (d, / = 8.4 Hz, 1H), 7·44 (d, J = 6.6 Hz, 1H), 7.34-7.29 (m, 6H), 7.21-7.20 (m, 1 H), 4.11 (s, 2H), 3·83·3·82 (br· m, 1H), 3.63 (s , 2H), 3.41 (t, J = 6.8 Hz, 2H), 3.21 (t, J = 7.0 Hz, 〇 2H). MS (ESI) m/z: Calcd.: 437. Compound 119 1-((4-(7-benzyl-1H-imidazolium[i,2-a]n-pyridin-2-yl)_3_fluorobenzyl)indole_3_carboxylic acid, trifluoroacetate 4-benzylpyridin-2-amine

A mixture of 4-benzylpyridine (14.1 mL, 88.6 mmol), sodium amine (5.71 g, 146 mmol) and p-isopropyl toluene (105 mL) was heated to i. After 1 day, the mixture was cooled; water (3 〇 mL) and concentrated hydrochloric acid (3 〇 mL) were sequentially added to separate the aqueous layer, and the organic layer was extracted with 6 〇 〇 2 2 HCl (aqueous solution). The aqueous extracts were then combined, washed with diethyl ether (5 mL) and strongly basic with solid potassium hydroxide, during which time brown oil was isolated. The oil was extracted in DCM (2 X 150 mL). The combined extracts were then dried over sodium sulfate, filtered and concentrated to give a brown oil. Tubes 119664.doc -303 - 200813031 Column chromatography (ISCO, 80 g, 50-&gt; 100% EtOAc/Hex) afforded 4-bromobite-2-amine as a tan solid. MS (ESI) m/z: Calcd. - 节基_1H_ 嗤幷 [l,2-a]fl than bite · 2_ base)-3-fluorobenzene

CHO

4- 4-Benzyl acridine-2-amine (175 mg, 949 μηιοί) and 4-(2-bromoethenyl)-3-fluorobenzaldehyde (232·5 mg, 949 μmol) in EtOH (3.0 mL) The solution was heated under reflux for 2 hours, then cooled to 25 ° C and concentrated in vacuo. The residue was dissolved in THF (8.0 mL), concentrated aqueous hydrochloric acid ( 788 g, 1576 &lt; Then NaOH (1 Torr, aqueous solution; 5.2 eq.) was added to the reaction mixture, which was then partitioned between EtOAc (20 mL) and brine (3 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed (EtOAc, EtOAc EtOAc EtOAc EtOAc EtOAc MS just ^ calculated value: road 1; view (four)): ^ (M + + 1). WWW base-mW嗤幷U, 2 outer ratio bite_2_base)_3_fluorof group) azeidine pyridine-3-decanoic acid, trifluoroacetate

OH 119664.doc •304 - 200813031 4-(7_nodal-1H-mouth rice bran [1,2-冱]° 唆_2_yl)_3-benzoic acid (47.3 mg, 143 μιηοΐ) It was dissolved in 1.0 mL of DCM, and ι·〇mL MeOH was added to the resulting solution, followed by the addition of butyl benzoate _3-carboxylic acid (43 mg, 43 0 μιηοΐ) and acetic acid (25 μΐ^, 430 μηιοί). The mixture was stirred rapidly for 1 hour and then sodium cyanoborohydride (9.0 mg, 143 μπιοί) was added in one portion. After 15 hours, the reaction was concentrated in vacuo and EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m 1-(4-(7-Benzyl-1H-imidazolium[1,24]pyridin-2-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid as a clear oil, Trifluoroacetic acid salt [hSIP1 EC50=54 nM] NMR (400 MHz, MeOH 〇 δ δ 8.71 (d, J = 6.8 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.05 (t,

Hz, 1H), 7.69 (s, 1H), 7.52-7.64 (m, 1H), 7.38-7.43 (m, 2H), 7.36 (d, J = 6.1 Hz, 3H), 7_33 (dd, "7=6.1 , 1.6 Hz, 1H), 7.28-7.32 (m, 1H), 4.55 (s, 2H), 4.36-4.47 (m, 4H), 4·28 (s, 2H), 3.76 (t, J = 8.2 Hz, 1H). MS (ESI) m/z: calcd. Compound 120 1-((4-(6-]-yl-1H-flavored olfactory [l,2-a]° bite ·2·yl)-3·Arsine-based azetidine-3-carboxylic acid, trifluoro Acetate 5 - ~yl" than bite-2 -amine

Νη2 Add 9·benzyl-9-boron-bicyclo[3·3_1]nonane (a solution of 〇·5 Μ in THF, 119664.doc - 305 - 200813031 12727 μί, 6363 μιηοΐ) to a sealable reaction vial 5-carbon port specific ratio of 2-amine (700 mg, 3182 μιηοΐ), acid removal (2026 mg, 9545 μιηοΐ), Pd2dba3 (58 mg, 64 μιηοΐ) and X-Phos (61 mg, 127 μιηοΐ) Suspended in a mixture of H2 hydrazine (1 mL). The vial was flushed with argon and then sealed and heated (microwave) at 120 °C for 30 minutes. The crude mixture was diluted with EtOAc and the solution was washed sequentially with &lt The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in MeOH (5 mL). EtOAc. Solid NaOH (120 mg) was then added and the resulting solution was concentrated on silica gel. The product was purified (ICO, EtOAc (EtOAc) (EtOAc) H NMR (400 MHz, chloroform-d) δ ppm 7.95 (s, 1H), 7.28 (t, J = 7.5 Hz, 2H), 7·23 (d, "7=11.0 Hz, 2H), 7.17 (t, J=8.5 Hz, 2H), 6.44 (d, J=8.5 Hz, 1H), 4.34 (s, 2H), 3.80-3.86 (m, 2H) 〇6-benzyl-2-(4-(diethoxy) Methyl)_2-fluorophenyl)H-imidazolium [l,2-a]

A solution of 5-benzylpyridylamine (340.9 mg, 1850 μιηοΐ) and 4-(2-bromoethenyl)-3-fluorobenzaldehyde (453.4 mg, 1850 μηιοί) in ethanol (6.0 mL) was heated under reflux 5 hours. The solution was cooled to 25 t, triethylamine (260 μM) was added, and the resulting solution was concentrated on silica gel and purified by column chromatography (ISCO, 4 g, 0-&gt;1〇0% Et0Ac/Hex, Purification of the crude 6-benzyl-2-(4-(diethoxymethyl)-2-fluorophenyl)H as an orange oil from </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 306 - 200813031 - Ii salivation [i, 2-a] pyridine. The oil was dissolved in thf (10.0 mL), a concentrated aqueous HCl solution (1.24 mL, 2487 μηιοί) was added, and the mixture was stirred at 25 ° C 20 NaOH (1 Torr, aqueous solution; 5.2 eq.) was added to the reaction solution, and the obtained mixture was partitioned between EtOAc (40 mL) and brine (5 mL). Concentration in vacuo. The residue was purified (jjjjjjjjjjjj </ RTI> </ RTI> <RTIgt; 1) 1-((4-(6-benzyl-1H-imidazolium [l,2_a] acridine-2-yl)_3_fluoro]pyrene)_3_carboxylic acid Trifluoroacetate

4-(6·Benzyl-1H-imidazolium [l,2-a] η-pyridin-2-yl)_3_fluorobenzaldehyde (100.5 mg, 304 μηιοί) was dissolved in 2.0 mL DCM with 2.0 1111^]\^011, followed by the addition of azetidine-3-carboxylic acid (92.3 11^, 913 4111〇1) and acetic acid (52.7 μΕ, 913 μηιοί). The mixture was stirred rapidly for 1 hour, at which time sodium cyanoborohydride (19.1 mg, 304 μηιοί) was added in one portion. After 2.5 days, the mixture was diluted with 2 mL DCM and the slurry was filtered and rinsed with DCM. The filtrate was concentrated in vacuo to give a white foam, which was dissolved in MeOH (3.0 mL), filtered over EtOAc EtOAc EtOAc EtOAc EtOAc -100% CH3CN/H2O + 0.1% TFA) was purified to afford 1-(4-(6-pyrimidin-1H-imidazolium [l,2-ap-pyridin-2-yl)·3 as a clear oil Fluorobenzyl) azetidin-3-decanoic acid, trifluoroacetate. 1H NMR (400 MHz, MeOH) δ ppm 8.66 (s, 1 Η), 8.59 (s, 1 Η), 8.07 (t, / = 7.8 Ηζ, 1 Η), 7·87 (s, 2 Η), 7.53-7.62 ( m, 2H), 7·32, 7·40 (m, 4H), 7·28 (t, /=6.8 Hz, 1H), 4.55 (s, 2H), 4.35-4.48 (m, 4H), 4.18 ( s, 2H), 3.70-3.81 (m, 1H). MS (ESI) m/z: Calcd. O compound 121 1- ((2-(5-^τ basic 幷. 夫 -2 - yl) shouting 嗓-5-yl) methyl butyl butyl _3_ formic acid 2- (5-benzyl benzofuran - 2-yl)pyrimidine-5-formaldehyde

CHO The 25 mm tube was charged with trifuran-2-ylphosphine (〇_0737 g, 0.317 mmol), Pd2dba3 (0.0411 g, 0.0397 mmol), 5-benzylbenzofuran-2-yl-acid under argon. (〇·500 g, ι · 98 mmol), CuTC (0.492 g, 2.58 mmol), 2_(methylthio)pyrimidine-5-carbaldehyde (0.306 g, 1.98 mmol). The reaction was diluted in 8 mL THF, sealed and heated to 5 () ° C overnight. The mixture was filtered through celite and rinsed with 2 mL EtOAc. The green solution was concentrated and taken up on 5 g of EtOAc. EtOAc (EtOAc) MS) (ESI) m/z: calcd.: 3141; observed: 3 15·1 (M++1). 119664.doc -308 - 200813031 ((2-(5-benzyl) Alkaloid furan-2-yl)pyrimidinyl)methyl)azetidinecarboxylic acid

Synthesis from 2-(5-benzylbenzofuran-2-yl)pyrimidine-5-furfural (0·110 g, 0.35 mmol) according to General procedure I: White solid [h. 4 NMR (400 MHz, DMSO 〇 δ ppm 8.79 (s, 2H), 7.70 (s, lH), 7.57-7.65 (m, 2H), 7.25-7.37 (m, 5H), 7.14-7.23 (m, 1H), 4.06 (s, 2H), 3·62 (s7 2H), 3.40-3.51 (m7 2H) 7 3.17-3.30 (m, 3h). MS (ESI) m/z : Calculated: 399.2 ; :400.2 (M++1) 〇Compound 122 1-((6-(5-benzylbenzofuran-2-yl)_2-methyl-0-pyridin-3-yl)methyl)azetidine-3 -formic acid 6-(5-p-phenylbenzofuranyl)-2-methylnicotinaldehyde

In a sealed flask, a mixture of 5-benzylbenzofuran-2-yl-acid (525 mg, 2.1 mmol) and potassium acetate (0.41 g, 4·2 mm〇1) was placed under argon. Bis(di(tert-butyl)phenyl) bar (8) (〇〇78 g, 〇12 mmol) followed by 6-chloro-2-methylnicotinaldehyde (〇29 g, i 9 mm〇1) Solution treatment in KEt〇H (10 mL). The resulting suspension was again degassed and heated to 80 ° C for 2 hours. The mixture was cooled to 24. 〇, treated at 〇 〇 且 and washed with saturated NaHCCh aqueous solution and brine. The combined organic layers 119664.doc -309- 200813031 were dried over MgSCU and evaporated. Purification by flash chromatography (hexane to hexane / EtOAc / EtOAc: EtOAc) Alkali aldehyde. iH NMR (400 MHz, CDC13) δ ppm 10·33 (s, 1Η), 8·27 (d, J=8.0 Ηζ, 1Η), 7.97-7.95 (m, 2Η), 7.51-7.49 (m, 2H) 5 7.3 1-7.29 (m, 2H), 7.24-7.21 (m, 3H), 4.10 (s, 2H), 3.07 (s, 3H). MS (ESI) m/z: Calcd. 1-((6-(5-benzylbenzofuran-2-yl)-2-methylpyridin-3-yl)methyl)anthracene _ 3 -carboxylic acid

M5-Benzylbenzofuran-2-ylpyridylaldehyde (16 mg, 489 μηιοί) and 3-azetidinecarboxylic acid (49.4 mg, 489 μηιοί) in MeOH (8 mL) and glacial acetic acid (44.0 mg) The suspension in , 733 μηιοί) was stirred at 24 ° C for 1 hour to treat with cyanoside hydrogenation (15.4 mg, 244 μηιοί) and scrambled for 2 hours. The mixture was diluted with 30 mL of 1 M HCl in EhO and evaporated. The residue was purified by EtOAc (EtOAc-EtOAc) 4 NMR (400 ΜΗΖ, DMSO-A) δ ppm 7.72 (s, 2Η), 7·55-7·53 (m, 2Η), 7.43 (s, lH), 7.28-7.18 (m, 6H), 4.04 ( s, 2H), 3.59 (s, 2H), 3.45-3.23 (m, 8H). MS (ESI) m/z: Found: 41:21. Compound 123 119664.doc -310- 200813031 _(1_(4_(S•p-phenylbenzofuran-2-yl)-3-fluorophenyl)ethyl)azetidine-3-carboxylic acid (4-(5- Alkyl benzofuran-2-yl)-3_fluorophenyl)ethanol

Methylmagnesium bromide (1.4 Μ in toluene / THF = 3:1 solution) 2.40 mL at 0 C, added dropwise to 4-gas 5-benzylbenzoquinone fluorofurfurfural (0.559 g, 2 mmol) in THF. The mixture was stirred at EtOAc EtOAc (EtOAc) EtOAc. (Et〇Ac/hexane) was purified to obtain 1-(4-(5-benzylbenzofuran-2-yl)-3-phenylphenyl)ethanol. NMR (300 MHz, CDC13) δ ppm 7.98 ( t, «/=8.0 Hz, 1H)3 7.38-7.46 (m, 2H)5 7.10-7.34 (m5 9H), 4.77- 5.04 (m,1H), 4.08 (s,2H),1.85 (d,/= 3.8 Hz, 1H), 1.46·1·6〇(m, 3H). MS (ESI) m/z: calc.: 346.1; observed: 347.1 (M++1) 〇1-(4-(5- Benzyl benzofuran-2-yl)-3_fluorophenyl)ethanone

Dess-Martin reagent (0.411 g, 0.970 mmol) was added to 1-(4-(5-carradin-2-yl)-3-fluorobenzyl)ethanol (0.280 g, 0.808 mm 〇i) The solution in DCM (25 mL) was stirred at room temperature for 1 hour. The mixture was treated with a saturated aqueous solution of NaHH3, stirred for 5 min and taken from DCM 119 664.doc. 311 - 200813031. The combined organic layers were dried over MgSO 4 and evaporated. Purification by EtOAc/hexanes to give 1-(4-(5-benzylbenzofuran-2-yl)-3-fluorophenyl)ethanone. NMR (300 MHz, CDC13) δ ppm 8.11 (t, /=7.7 Ηζ, 1Η), 7·68-7·88 (m, 2Η), 7.41-7.48 (m5 2H), 7.12-7.35 (m, 7H) , 4·09 (s, 2H), 2.63 (s, 3H). MS (ESI) m/z: Calcd. 1-(1-(4-(5-benzylbenzofuran-2-yl)_3_fluorophenyl)ethyl)azetidine-carboxylic acid

Oryzae-3-carboxylic acid (0.015 g, 0.15 mmol), 1-(4-(5-benzyl-benzofuran-2-yl)-3-fluorophenyl)ethanone (〇·〇5) A mixture of 〇g, 0.15 mmol), EtOAc (EtOAc (EtOAc) Sodium triethoxyhydride borohydride (〇.037 g, 〇17 mmol) was added and the mixture was stirred at room temperature for 1 hour. Evaporation and purification by flash chromatography (5% acetic acid in CHCU and MeOH). The obtained solid was suspended in a buffered aqueous solution (pH 6, phosphate buffer) and subjected to ultrasonic treatment. The solid was collected by filtration, washed with water and EtOAc (m.). 1H NMR (400) V [Hz, DMSO-d6) δ ppm 7.89 (t, /=7.9 Hz5 1H)5 7.5 1-7.59 (m5 2H)5 7.14- 7.34 (m,9H), 4.04 (s, 2H), 2.92-3.50 (m, 6H partially overlaps with HDD signal), 1.11 (d, /=6.3 Hz, 3H). MS (ESI) m/z: Calcd. Activity of a Compound of the Invention The ability of a compound of the invention prepared according to the above-described synthesis to modulate a SilM receptor is tested. The ability of a compound to induce S1P1 specific receptor internalization is assessed using a standard in vitro receptor internalization assay. And the activity of the compound measured by the internalization of the receptor as the agonist of the Slpi receptor was demonstrated as an immunomodulatory agent (greater than 50/〇 of the sip control group at 1 或 or 300 nM). ). Gj is expected to be suitable for use as a sputum modulator, e.g., in the treatment of a variety of S1P-1 receptor mediated clinical conditions. Such conditions include transplant rejection (solid organ transplantation and islets, 'field cells'' transplant rejection (tissue); cancer; autoimmune/inflammatory disease, rheumatoid arthritis; lupus; insulin-dependent diabetes type" Non-insulin-dependent diabetes mellitus (type 11); multiple sclerosis; psoriasis; ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemia and lymphoma. The compounds of the invention are used as S1P-1 receptor modulators for the suitability of U for treating disorders, and the compounds of the invention are evaluated in experimental animals such as transplant rejection; cancer; autoimmune/fat k disease, rheumatoid arthritis; wolf therapy; diabetes; multiple sclerosis; psoriasis; ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemia and lymphoma, of which Immunosuppression is central (thus where the reduction in lymphocytes is a recognized indicator). Protocol 119664.doc -313- 200813031 Mice will C 57BL/6J mice (B6, Jackson Laboratories, Bar Harbor, ME) were maintained in a non-specific pathogen environment under a micro-isolated breeding box blockade system. Adult male mice were matched with female age mice for all by the University of Virginia. In an experiment reviewed and approved by the Animal Care and Use Committee (University of Virginia), each time the mice were administered intraperitoneally with ketamine hydrochloride (125 mg/kg; Sanofi Winthrop Pharmaceuticals) , New York, NY), toluene plug noise (12.5 mg/kg TranquiVed; Phoenix Scientific, St. Joseph, MO) and atopine sulfate (0.025 mg/kg; Fujisawa USA, Deerfield, IL) anesthesia. Apparatus preparation and analysis followed by blood collection from at least 6 mice at each time point on days 1, 3, or 7 after the daily administration of the test compound at 0, 4, 8, 24, 48, and 72 hours. After the last blood collection, the brain and some other tissues were collected from all the treated animals. The number of cells was determined from whole blood, and the number of cells per kiloliter of fine cells (K/1L) was obtained. The lymphocyte subsets were quantified and the cell suspension was analyzed by flow cytometry. After the erythrocyte lysis, the cells were resistant to CD3, CD4, CD8, CD19 and NK1.1 (BD Biosciences, San Jose, CA). Murine monoclonal antibody staining. Cells were analyzed by four-color flow cytometry on a FACSCalibur (BD Biosciences) in the University of Virginia Cancer Center Core Facility. Lymphocyte subsets were analyzed, including B cells, whole T cells, CD4 T cells, CD8 T cells, double 119664.doc-314-200813031 positive thymocytes, double negative thymocytes, NK cells, and NK/Τ cells. The size of each cell population was calculated as the product of the total lymphocyte count recorded by Hemavet or Golden Globe and the percentage of positive lymphocytes recorded by flow cytometry. All data were analyzed using BD Biosciences Cell Quest analysis software. Statistical analysis Statistical significance was determined using Student's t-test to compare all time points with the 24 hour group. 〇 Compounds tested:

COOH 1-((4-(5-butoxybenzoquinone-2-yl)phenyl)methyl)azetidine-3-carboxylic acid COOH cr〇v^N 1 -((4-(5 -benzylbenzofuran-2-yl)phenyl)methylbutyridin-3-carboxylic acid 1-(4-(5-3⁄4-hexylbenzoquinone-2-yl)benzyl)azetidine-3- Formic acid ^OH 1-((4-(5-isobutylbenzoquinone-2-yl)phenyl)methyl)azetidine-3-carboxylic acid cooH 1-((4-(5-phenylene benzene) Bite-drink-2-yl)-3_fluorophenyl)methylbutyridin-3-carboxylic acid 1-((4-(5-5 succinylbenzoquinone-2-yl)) 3-fluorobenzene Base) 曱基户丫丁丁-3-carboxylic acid 119664.doc 315- 200813031

Ο

Η3_Fluoric (5-7-indol-1-yl)phenylhydrazone-2-yl)benzyl)azetidine_3_carboxylic acid trifluoroacetate 1-(4-(5-(cyclopentyl) Methoxycarbonyl)_3_fluorobenzyl)azetidine;

COOH Ν

1-(4-(5-(cyclopropylmethoxy)benzoquinan-2-yl)_3_fluorobenzyl)azetidine_3_carboxylic acid 1-((4-(5-butoxy) Benzofuran-2-yl)-3-oxybenzyl)azetidine-3-carboxylic acid 3-(6-(5-cyclopentylbenzofuran-2-yl)_ 3,4-monohydroisoindole Lin-2(1H)-yl)propionic acid cooh

1^(4-(5-benzylbenzofuran-2-yl)-3_fluorobenzyl)pyrrole-3-carboxylate is not compared to the baseline at a dose of 〇3 to 1〇mg/kg. Lymphocytes are reduced by 35% to 90%. The last two compounds of T in the above table did not show lymphopenia under the conditions tested. Thus, the compounds of the invention are contemplated to be useful in the treatment of a medicament such as a transplant rejection; cancer; autoimmune/inflammatory disease; rheumatoid arthritis; lupus; diabetes; multiple sclerosis; psoriasis; ulcerative colon Inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemia and its immunosuppression is a central lymphoma. 119664.doc -316- 200813031 Rat Lymphocytopenia Test Protocol Animals: • Female Lewis rats (150-175 grams, 6-8 weeks old) from ci^les

River Laboratories and adapt it to the new environment prior to testing - at least weekly procedures: 1) Administration of compounds to rats (n==4/group) by oral (P〇, 10 mL/kg) at time 0 Or vehicle (12.5% captisol in water). 〇 2) Sequential administration (1, 4, 8 or 24 hours) at each time point, and the animals were killed by inhalation of c〇2. 3) Blood was collected by cardiac puncture using a 20G needle and a 1 cc syringe. 4) Place approximately 500 pL of blood in a microtainer tube containing EDTA (BD #365973) and mix the samples thoroughly. 5) Differential cell counting was performed using Bayer's Advia 120 hematology system. The following compounds show hS1P1: hSlP3 EC5G selection ratio over the range of 1:100 U 1-((4-(5-benzylbenzofuran-2-yl)-3-fluorophenyl)methyl)azetidine- 3-carboxylic acid; 1-(4-(5-phenoxybenzofuran-2-yl)benzyl)azetidin-3-indole; 1-((6-(5-butoxyphenyl) σ南-2-yl)dine-3-yl)methyl)σ丫丁丁-3-carboxylic acid; 1-((4-(5-p-phenylphenyl sigma)-2-yl)-3 -曱oxyphenyl)methyl)σ丫丁丁-3-carboxylic acid; 1-(3_1_4-(5-(tetrahydro-2-indole-l-yl-4-yl)benzoquinone-2-yl)phenyl 119664.doc -317- 200813031 methyl)azetidine-3-formic acid; (Ε/Ζ)-1-((3•fluoro_4_(5-((hydroxyimino)(phenyl)methyl)) Benzofuran-2-yl)phenyl)methyl)azetidine_3_decanoic acid; 1-((3-fluoro-4-(5-(phenylmethyl))furanium [2,3_bp pyridine _2_yl)phenyl)methyl)-3-azetidinecarboxylic acid; 1-((3-fluoro-4-(5-(phenylthio))benzoquinone[d]oxazolyl)phenyl) Azetidine-3-carboxylic acid; 1-((3-fluoro-4_(5-(pyridin-2-ylmethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3 -formic acid; 1-((3-fluoro-4-(5-(pyrimidin-2-yl)methyl)benzene Furan-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; 1-((3-fluoro-4-(5-(thiazolylmethyl)benzofuran-2-yl)phenyl) Methyl) azetidin-3-carboxylic acid; 1-((4-(5-(difluoro(phenyl)methyl)benzofuran-2-yl)_3_fluorophenyl)methyl)azetidine -3-carboxylic acid; , Bu ((heart (5-mercaptophenylhydrazone [d]thiazol-2-yl)-3_fluorophenyl)methylindole 唆-ϋ 3·carboxylic acid; 1-((4- (6-Benzylbenzofuran-2-yl)_3_fluorophenyl)methyl)azetidine_3_decanoic acid; M3_fluoro·4_(5·(4-methyl) benzofuran· 2_yl) benzyl) azetidine -3- 3-carboxylic acid; 1-(3-fluoro-4-(5-(phenoxymethyl) adolinofuran-2-yl)benzyl)azetidine _ 3 -carboxylic acid; b (3fluoro-4-(5-phenyloxybenzofuran-2-yl)benzyl)azetidine_3_methyl 119664.doc -318- 200813031 acid; 1-(3-fluoro-4 -(5-phenylsulfinyl)benzoquinone-2-yl)benzyl)azetidine-3-carboxylic acid; 1-(3-fluoro-4-(5-phenylthio)benzofuran- 2_yl)benzyl)azetidin-3-indole-1-(4-(5-(cyclobutoxymethyl)benzofuran-2-yl)_3_fluoro-benzyl)azetidine-3 -formic acid; 1-(4-(5-benzylphenylhydrazone [b]thiophen-2-yl) ·3·fluorobenzyl)azetidine-3-decanoic acid; and 1-((4-(7-pyringyl-1Η-imidazolium[l52_a]T1 pyridine-2-yl)_3_fluoro node ) butyl butyl 3-carboxylic acid 'di-gas acetate. Equivalents 烈白扣# The text will recognize or be able to use only routine experimentation to determine the equivalent of many of the specific procedures described herein. These equivalents are considered to be within the material of the present invention. The present invention may be variously modified and modified without departing from the spirit and scope of the invention. Other aspects, advantages and issues:: (4). The content of the patent application filed in the entire disclosure of the present application is hereby incorporated by reference in its entirety in its entirety in the the the the the the example. 119664.doc -319-

Claims (1)

200813031 X. The scope of application for patents·· 1. A compound having the following formula, Wherein A is an optionally substituted aryl or heteroaryl; B and C are at least partially aromatic bicyclic systems; X is selected from the group consisting of WC(0)0R6a, WP(〇)R6, 6c, Ws(〇)2〇h, WCONHS03H or 1H-tetrazol-5-yl; one of the chemical bonds, oxygen or one or more Cm alkyl groups independently selected from the group consisting of: a hydroxyl group, a hydroxyl group, a cyano group, an amine group, an alkylamino group, an arylamino group, a heteroarylamino group, a Ci4 alkoxy group And C002H; R6a is hydrogen or Cl_4 alkyl; and R6b and R6e are independently hydrazine, light base, C!·4 alkyl or cyano substituted c1-4^; Y is a residue of formula (a) , where the left and right asterisks indicate the connection point: *(8) wherein Q is selected from the group consisting of a chemical bond, C=0, C=S, S02, C=〇NR or (CR1GRu)m; m is 0, 1, 2 or 3; R7 and R8 are independently selected from Hydrogen, halogen, amine, Cl-5 alkylamino, trans, cyano, Cl-6 alkyl, Cl-6 hydroxyalkyl (eg hydroxy 119664.doc 200813031 base terminated alkyl), Cm alkane a group consisting of a thio group, a Ci5 alkoxy group, a halogen-substituted Cw alkyl group, and a dentate-substituted Ci5 alkoxy group; or R7 and R8 may be bonded to an atom to which they are bonded to form a hetero atom a 4 to 7 membered ring; and R9 is selected from the group consisting of hydrogen 'halogen, hydroxy, cyano, alkyl, Cl" alkylthio, Cy alkoxy, ci-substituted ci 6 alkyl or dentate a group of Cw alkoxy groups; R10 and R11 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, Cw alkyl, Cw alkoxy, Ci5 alkylthio, dentate substituted a group consisting of or substituted with a 2Ci_5 alkoxy group; and z and z2 are independently selected from 〇, nr3, s, s(〇), s(〇)2, S(0)2NR, (CR R ) n, c = 〇, c = S, C = N-R3 or a chemical bond group a group of Ο R3 selected from the group consisting of hydrogen, hydroxyl, s〇2, c=o, c=s, C=NH, Ci 6 alkyl, Ci 5 alkoxy, Cw alkane a thio group, a halogen-substituted hexa-alkyl group, and a halogen-substituted Cy5 alkoxy group; an aryl group or a heteroaryl group, or when Z2 is a chemical bond, R is a C3-C6 optionally containing a hetero atom Rings; R4 and R5 are independently selected from the group consisting of nitrogen, dentate, _-based HCl-6 alkyl, Ci. oxy, "μ, substituted by halogen.", alkyl and Halogen-substituted alkoxy, aryl or heteroaryl, or together form C^q; and η is 〇, 1, 2 or 3; and, C2_6 alkynyl, 〇3-6 ring R is selected from Cle6 alkyl , c2-6 alkenyl 119664.doc 200813031 Group of alkyl, Ci·5 alkoxy, Cw alkylamino, aryl or heteroaryl groups. 2. The compound of claim ,, where A is as appropriate C1 - 6 - sized J or a mixture of one or more heteroatoms. 3. A compound according to claim 1, wherein the lanthanide is selected from one, two or three Substituent substitution of groups of each group consisting of: halogen Base, SR, S(〇) 2r2, S(〇) 2NR2, NHS(0)2R2, COR2, C〇2R, cyano, amine, cis alkylamino/arylamino/heteroarylamine a Cl.6 alkyl group, a Cm sulphur group, a Cu alkoxy group, a cyano substituted Ci-6 alkyl group, and a halogen-substituted cl5 alkoxy group. 4. A compound according to claim 1, wherein A is substituted with two adjacent substituents which, together with Z1 and the ring A to which they are attached, form a fused ring containing one or more heteroatoms as appropriate. 5. The compound of claim 2, wherein A is optionally substituted with one, two or three substituents selected from the group consisting of: _, hydroxy, S, S(〇) 2R2, S (〇) 2NR2, NHS(〇)2R2, c〇r2, c〇2r2, cyano group, amine group, Cw alkylamino group/arylamino group/heteroarylamine group, c1-6 alkyl group, Cw sulfur group a Cl5 alkoxy group, a halogen-substituted ci6 alkyl group, and a halogen-substituted Cl.5 alkoxy group, wherein R2 is selected from the group consisting of hydrogen, hydroxyl, amine, alkylamine/aryl Alkyl group, ci-6 alkyl group, Cw alkoxy group, c1-5 alkylthio group, c1-6 alkyl group substituted by γ and 2C·5 alkoxy group substituted by 1S element; and aryl/heteroaryl Or alternatively, two adjacent substituents on 'A' may form an alicyclic or heterocyclic ring together with ζι and the ring to which they are attached. 6. The compound of claim 5, wherein R2 is selected from the group consisting of hydrogen, hydroxyl, amine, alkylamino/arylamine, c16 alkyl, C1·5 An oxy group, a Cw alkylthio group, a halogen-substituted Cl-6 alkyl group, and a halogen-substituted Cw alkoxy group; or an aryl/heteroaryl group. 7. The compound of claim 1, wherein the B&amp;C system is selected from the group consisting of a bicyclic aryl group, a bi-alkali heteroaryl group, a dihydrobicyclo ring, and a tetrahydrobicycloaryl group and a heteroaryl group. 8. The compound of claim 7, wherein the bicyclic system is optionally deuterated to a residue selected from the group consisting of a ci-6 alkyl group, a Cw thiol group, a Cw alkoxy group, a halogen group, a thiol group, and a cyano group. Substituents substituted with a group of a group substituted with an iCy alkoxy group. 9. If requested! a compound wherein 21 and 22 are independently selected from the group consisting of ruthenium, nr3, S, s(0), s(0)2, s(9)2NR3, (CR4R5)n, c=〇, OS, C==N_R3 or a chemical bond. Group. The compound of claim 9, wherein R3 is selected from the group consisting of the following groups: gas, meridine, S(0)2, c=0, C=s, C=NH, Ci-6 alkyl , Ci-5 alkoxy, Cw alkylthio, ci-substituted ci 6 alkyl and halogen-substituted Cl-5 alkoxy; aryl or heteroaryl. 11. The compound of claim 9, wherein ... and ... are independently selected from the group consisting of hydrogen, _, thiol, aryl, C16 alkyl, C15 alkoxy, Cw alkylthio, Ci-alkyl substituted with _- and alkyl substituted with cyano, aryl or heteroaryl, or together form c=〇. 12. The compound of claim 、, wherein is selected from the group consisting of cw alkyl, cw alkenyl, c2-6 alkynyl, c3-6 cycloalkyl, alkoxy, ci5 alkylamine 119664.doc 200813031 ke, fang A group consisting of a base or a heteroaryl group. 3. The compound of claim 12, wherein R1 is optionally substituted with a group selected from the group consisting of a hydroxyl group, a halogen, a cyano group, an amine group, an alkylamino group, an arylamino group, and a heteroarylamine group; . 14. The compound of claim 13, wherein the aryl group and the heteroaryl group are optionally selected from the group consisting of a hydroxyl group, a cyano group, a cyano group, a Ci6 alkyl group, a Ci5 alkylthio group, a Ci-5 alkoxy group, Substituted by a group of Cw cycloalkyl groups. a compound according to the formula, wherein the pharmaceutically acceptable salt is selected from the group consisting of a 1k salt, a maleic acid salt, a citrate 'fumarate salt, an amber salt, a tartrate salt, a group consisting of mesylate, sodium, potassium, magnesium and calcium salts. 16. a compound having the formula Wherein 〇 A is aryl or heteroaryl; X is _C(〇)〇R6a, wherein R6a is hydrogen or ci4 alkyl; Y is a residue of formula (a): (8) wherein Q is (CR10RU)m; m is 〇, ι, 2, 3 or 4; 119664.doc 200813031 R7 and R8 are independently hydrogen, hydroxy, lower alkyl; or r7&amp;r8 forms a ring with the atom to which it is attached And R is selected from the group consisting of hydrogen, halogen, thiol or cyano; Z1 and Z2 are independently hydrazine or (CR4R5)n, wherein R4 and R5 are independently hydrazine, halogen, hydroxy, cyano, C16 a group, a Ci_5 alkoxy group; and η is 〇, ι, 2 or 3; and R1 is selected from Cw alkyl, C2-6 alkenyl, C2-6 alkynyl, 〇3-6 cycloalkyl, Cw alkoxy, a group consisting of Cw alkylamino, aryl or heteroaryl; or a pharmaceutically acceptable salt thereof. 17. The compound of claim 16, wherein a is a Ci-6 cyclic ring (alicyclic or aromatic ring) optionally having one or more heteroatoms. 1 8 · A compound of the formula 6, wherein a is substituted with one, two or three substituents selected from the group consisting of: _, hydroxy, Sr2, S(〇) 2R2, S (0) 2NR2, NHS(0)2R2, COR2, C〇2R, cyano group, amine group, Cw alkylamino group/arylamino group/heteroarylamine Cl·*6 alkyl group, Ci_5 sulfur group, Ci-5 is an alkoxy group, a C1·6 alkyl group substituted with a γ group, and a C1-5 alkoxy group substituted with a γ element. 19. The compound of claim 16, wherein a is substituted by two adjacent substituents. The substituent such as ruthenium, together with oxime and its attached ring A, form a fused ring containing one or more heteroatoms as appropriate. 2. The compound of claim 16, wherein A is substituted by one, two or three substituents selected from the group consisting of +, and below: _ 素, hydroxy 119664.doc 200813031, s, s(o)2r2, S(0)2NR2, NHS(0)2R2, COR2, C02R2, cyano, amine, Ci-5 alkylamino/arylamino/heteroarylamine, Cu a base group, a C-sulfuryl group, a Cι-s alkoxy group, a Cw-alkyl group substituted with a γ group, and a C 5 alkyl group substituted with a halogen, wherein R 2 is selected from the group consisting of hydrogen, a hydroxyl group, and an amine. Alkyl, an alkylamino/arylamino group, a C.6 alkyl group, a Cu alkoxy group, a Ci_5 alkylthio group, a quinone-substituted Cl-6 alkyl group, and a _-substituted Cl_5 alkoxy group; And aryl/heteroaryl; or, optionally, two adjacent substituents on A may form an alicyclic or heterocyclic ring along with Z1 and the ring to which they are attached. 21. The compound of claim 17, wherein R2 is selected from the group consisting of hydrogen, hydroxy, amine, alkylamino/arylamine, C1-6 alkyl, ci-5 alkoxy a Cw alkylthio group, a halogen-substituted Cl-6 alkyl group, and a halogen-substituted iCu alkoxy group; or an aryl/heteroaryl group. 22) A compound of the formula 6 wherein the benzoquinone ring is optionally substituted by a Cw alkyl group, a Cw alkylthio group, a Cw alkoxy group, a halogen group, a hydroxyl group, a cyano group, or a halogen. Substituting a substituent of the group consisting of c alkoxy groups substituted with a C alkoxy group. The compound of claim 16 wherein the compound is selected from the group consisting of Gy alkyl, C 2-6 olefin alkynyl, a group of C; 3·6 cycloalkyl, C!·5 alkoxy, Cb5 alkylamino, aryl or heteroaryl. 24. The compound of claim 22, wherein R1 is selected from the group consisting of a group substituted with a group consisting of a hydroxyl group, a halogen, a cyano group, an amine group, an alkylamino group, an arylamine group, and a heteroarylamine group. 25. The compound of claim 22, wherein the aryl group and the heteroaryl group are The situation is 1 to 5 119664.doc 200813031 selected from the group consisting of a thiol, a cyano group, a cyano group, a (^.6 alkyl group, a q-5 thiol group, a Cw alkoxy group, a C3-6 cycloalkyl group) The compound of claim 16, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, maleate, citrate, fumarate, amber a group of salts, tartrates, carboxates, sodium salts, sulphates, salts, and calcium salts. 27. A pharmaceutical composition comprising a request for treatment of a S1P-1 receptor vector disorder The pharmaceutical composition of claim 18, wherein the S1P-1 receptor vector disorder is selected from the group consisting of transplant rejection (solid organ transplantation and islet cells); Transplant rejection (tissue); cancer; autoimmune/inflammatory disease, rheumatoid arthritis; wolf therapy; temsin-dependent diabetes mellitus (type I); non-insulin-dependent diabetes mellitus (sputum type); multiple sclerosis Psoriasis; ulcerative colitis; inflammatory bowel disease; Crohn's disease (Cr disease); acute and chronic lymphocytic leukemia and lymphoma. {) 29 - Regulation 811 > 1 A method comprising contacting the 811&gt;_1 receptor with a compound of claim 1. 30. A method of treating 81]?1 receptor vector disorder comprising administering to a patient in need thereof An effective amount of the condition as requested A pharmaceutical composition according to claim 30, wherein the 811&gt;_1 receptor vector disorder is selected from the group consisting of: transplant rejection (solid organ transplantation and islet cell transplant rejection) Reaction (tissue); cancer; autoimmune/inflammation 119664.doc 200813031 disease; rheumatoid arthritis; lupus; insulin-dependent diabetes mellitus (type I); non-insulin-dependent diabetes mellitus (type 11); multiple sclerosis; Psoriasis; ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemia and lymphoma. 32. A method of immunomodulation comprising administering to a patient in need thereof a pharmaceutical composition comprising a compound of claim 1 or i6 in an amount that causes immunomodulation. 33. The method of claim 32, wherein the 811)-1 receptor vector disorder is selected from the group consisting of: transplant rejection (solid organ transplantation and islet cells); transplant rejection (tissue) Cancer; autoimmune/inflammatory disease; rheumatoid arthritis; lupus; insulin-dependent diabetes mellitus (type 1); non-insulin-dependent diabetes mellitus (sputum type); multiple sclerosis; psoriasis; ulcerative colitis; Sexual enteric disease; Crohn's disease; acute and chronic lymphocytic leukemia and lymphoma. 34. A pharmaceutical composition comprising an effective amount for treating 81]?_1 receptor vector disorder as claimed in claim 1 or The pharmaceutical composition of claim 35, wherein the S1P-1 receptor vector disorder is selected from the group consisting of transplant rejection (solid organ transplantation and islet cells); transplant rejection Reaction (tissue); cancer; autoimmune/inflammatory disease; rheumatoid arthritis; lupus; insulin-dependent diabetes mellitus (type I); non-insulin-dependent diabetes mellitus (type 11); Sclerosing disease 'psoriasis, ulcerative colitis, inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemia and lymphoma. 36. A method of treating a S1P-1 receptor vector disorder, A pharmaceutical composition comprising a compound according to claim 1 or 16 which requires its 119664.doc 200813031, comprising a compound effective for treating the condition. 37. The method of claim 36, wherein the (10) receptor-mediated disorder Is selected from the group consisting of transplant rejection (solid organ transplantation and islet cells); transplant rejection (tissue); cancer; autoimmune/inflammatory disease; rheumatoid arthritis; lupus; insulin-dependent diabetes (work type); non-insulin dependent diabetes mellitus (π type); multiple sclerosis; cattle U dermatitis; ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemia and lymphoma. a compound or a pharmaceutically acceptable salt or hydrate thereof, which is selected from the group consisting of 3-fluoro-4-(5-phenylthio)benzofuran-2-yl)benzyl)azetidine _ 3-(3-Fluoro-4-(5-phenylsulfinyl)benzoquinone-2-yl)benzyl)azetidine-3-oxanoic acid; 1-(4-(5) -(cyclopropylmethoxymethyl)adolfurfuran-2-yl)fluoro-benzyl)azetidine-3-carboxylic acid; 1-(4-(5-(cyclobutoxymethyl)phenylhydrazine) Furan-2-yl)-3-fluoro-benzyl)azetidine-3-carboxylic acid; 1-(4-(benzofuran-2-yl)-3-fluoro-benzyl)azetidine_3_carboxylic acid ; 1-(3-fluoro-4-(5-(phenoxymethyl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; 1-(4-(5-(cyclohexyl) Oxymethyl)benzophenan-2-yl)fluoro-benzyl)azetidin-3-indole; 119664.doc -10- 200813031 1-(4-(5-(cyclopentyloxymethyl)) Benzofuran-2-yl)_3_mer_knotyl kappa butyridine-3-carboxylic acid; 1-(3-fluoro-4-(5-phenyl hydrazino) alum 幷 _2_2_yl) )) 丫 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 4-(5-(cyclohexylmethyl)phenylhydrazine喃_2-yl)_3_gas group) azetidine·3-carboxylic acid; ° 1-(3_gas_4_(5_(2_2_ qi) benzoquinone bit. South-2-yl) section Base) butyl butyl 3-carboxylic acid; 1-(3-fluoro-4-(5-(3-1) phenylhydrazone)-based sulfhydryl; -(3-Fluoro-4-(5-phenoxybenzofuran-2-yl)benzyl)azetidinecarboxylic acid; 5-(1-(4-(5·$ phenylbenzoquinone) _基)_3_气节基丫丁基基)_ 2Η-四峻; ^ 'Bu (4-(4-pyrimidinyl)-3-yl-f-), azetidine _3·formic acid ; 1-(4-(2-Phenylphenylhydrazone)-_3 fluoro] ketone). Butadiene bite small formic acid; 1-(4-(5-benzylphenylhydrazine[b]thiophene-2-yl) Fluorobenzyl)azetidinecarboxylic acid; 3-(4-(5-f-phenylbenzoquinone-2-yl)_3-dumpyylamino&amp;methylpropionic acid; 4-month female base·2 ·(4-(5·节基幷幷,夫坦士基)” Fluorosuccinylidene ^ cardinyloxybutyric acid; 119664.doc 200813031 1 ((6 (5-mercaptobenzofuran_2_) Fluoroacridine_3_yl)methyl)azetidine-3-carboxylic acid; 4amino-3-(4-(5-benzylbenzofuran-2-yl)_3_fluorobenzylamino) _4_ oxobutyric acid; 1 (3 gas -4-(5- (4-methylbenzyl)benzofuran-2-yl)benzyl)azetidine_3_carboxylic acid; 1-(4-(5-fluorenyl-2Hh2_pybyl)-benzylidene-pyridinic acid; (4-(5-phenylbenzofuran-2-yl)benzyl)azetidine_3_decanoic acid; butylphthalide-2-yl)phenyl)indenyl)azetidine-3 -formic acid; 1-((4-(5•butoxybenzofuran-2-yl)phenyl)methyl)azetidinic acid; benzyl benzofuran-2-yl)phenyl)methyl Azetidin-3-carboxylic acid; 1-((4-(7-benzylphenylfurfuran-2-yl)phenyl)methyl)azetidinecarboxylic acid; 1-(4-(5-1⁄4-hexyl)幷furan_2-yl)benzyl)azetidinecarboxylic acid·, 1-(4-(5-cyclohexylbenzoquinone-2-yl)benzyl)piperidinic acid; Bu ((4-(5- Butyl benzofuran-2-yl)phenyl)methyl)piperidine _4_decanoic acid; 1-((4-(5-benzylbenzofuran-2-yl)phenyl)methyl)per Acridine_4_carboxylic acid; 1-((4-(5-isobutylbenzofuran-octa)phenyl)methyl)azetidine-3-carboxylic acid; 1-((4-(5-phenylethyl) Benzofuran-2-yl)phenyl)methyl)azetidine-3-pyruic acid; ^(4-(5-(3⁄4 pyridine-3-yl)benzofuran-2-yl)benzyl) Azetidine·3- Acid; 1-(4-(5-isobutylbensyl-2-yl))) brittle _4_carboxylic acid; 119664.doc -12- 200813031 • 2-yl) 2-fluorophenyl)methyl ) azetidin-3_methyl-2-yl)-3-fluorophenyl)methyl)butyrate _3_ ··2-yl)phenyl)methyl)piperidinecarboxylic acid; indole-2-yl) Pyridyl)methyl)azetidine_ ηcarboxylic acid; (methylpyrazine).定-2_基) phenylhydrazine 0 nan-2-yl) benzyl) 〇丫 唆 唆 3 3 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 3 3 3 3 3 3 3 3 3 3 3 3 _ formic acid; (5) phenyl phenyl group m) phenyl) methyl) w3_carboxylic acid ·, acid (6-butenyl benzofuran-2-yl) phenyl) methyl) agidine _3_A 3 ψ Oxyloindolefuranyl)thiazol-5-yl)methyl)azetidine-3-oxide; υ 1-((4-(5-benzylbenzofuranoic acid; ^((4-(5-benzyl) Benzofuranfurancarboxylic acid; ^((4-(5-butoxy oxyfurfuryl)(6-(5-cyclohexylbenzoquinone 3-carboxylic acid; formic acid oxybenzofuranyl) 4-fluorobenzene Methyl)azetidine-3- 1 methyl (Γ (5-butoxybenzoquinone ° °南·2_yl)_3_methoxyphenyl) ° 咬丁 bite _3· formic acid; Oxyphenyl benzofuran-2-yl)thiophen-2-yl)methyl)azetidine _ 3 -carboxylic acid; oxy oxime furan-2-yl) σ-pyridyl _3·yl)methyl) Acridine _ 119664.doc 13- 200813031 i-((4-(5-%-hexyl cumene furan-2-yl)3_fluorophenyl)indenyl)azetidine_3_carboxylic acid; i-((4- 5-(Phenyl-2-yl)benzoquinone-2-yl)phenyl)methyl)azetidine_3_carboxylic acid; 3-(6-(5-benzyl) Benzofuran-2-yl)_3,4-dihydroisoquinoline 2〇h)-yl) propionic acid; 1-(4-(5-3⁄4-pentylbenzofuran-2-yl)benzyl) Azetidine _3_carboxylic acid; H3-gas-4-(5-(Bet _ 丨_yl) benzoquinone-2-yl)benzyl)azetidine _3_ ζ\ formic acid trifluoroacetate; (6-(5-Benzylindolefuran-2-yl)pyridine-3-yl)methyl)azetidine_3_carboxylic acid, 1-((4-(5-benzylbenzofuran))-2-yl )-3-methoxyphenyl)methyl)pyrene sigma-3-carboxylic acid, 1-(4-(5-(piperidinyl)benzofuran-2-yl)benzyl)azetidinecarboxylic acid ; 6-(5-Benzylbenzofuranyl&gt;2_(2-carboxyethyl)_3,4-dihydroisoquinoline G 2,2,2-trifluoroacetate; Bu (4-( 5-benzylbenzofuran-2-yl)chlorobenzyl)azetidine_3_carboxylic acid; 3-(6-(5-benzylbenzofuran-2-yl)_3,4-dihydroisoquine Porphyrin_2(1η)·yl)propionic acid; 1-(4-(5-(cyclopentylmethoxy)benzofuran-2-yl)fluorobenzyl)azinium-3-decanoic acid; -(4-(5-(%-pentylmethoxy)benzofuran-2-yl)benzyl)azetidine_3_carboxylic acid; 119664.doc •14· 200813031 -2--2-yl)_3_cyanide Benzyl)azetidine_3_ (4 (5 = alkaloid furan-2-yl)_3_fluorobenzyl)pyrrolidine_3_carboxylic acid; 1 (4 (5 % pentylbenzoquinone) 2___丁唆_3_甲南-2-yl)-3-methyl) σ丫丁淀_3一甲3-(6-(5-butoxybenzofuran-2-yl)_3,4_ 1-(5-(5-Benzylbenzofuranoic acid; acid; 1-(4-(5-benzylbenzofuranoic acid)-based propionic acid; 3-(5-(5-benzylbenzofuran) 2_yl)_propionic acid; 2,3-dihydro-1H-indol-2-ylamino)-3-(4-(5-f-phenylphenylhydrazone) Methyl butyric acid; 1-(4-(5-cyclopentylbenzoquinone) methoxymethyl η-butyryl winter formic acid; 1-(4-(5-Phenylbenzopyrano-3,5-difluoro)-glyoxime_3_carboxylic acid; 1_(4_(5-(cyclopropylmethoxy))phenylpyran -2-yl)·3-fluoro-yl)π-butyridin-3-carboxylic acid; butyridine-3-methylpyridine-3·methyl-1-(4-(5-butoxybenzofuran-2-yl) )_3_chlorobenzyl"decanoic acid; H3-chloro-4·(5-cyclopentylbenzoquinone Xinnan_2_yl) nodal acid; 3-((4-(5-(cyclopentyl) Methoxy)phenyl hydrazone-2-yl)_3_gas group (2_ethyl)amino)propionic acid; 119664.doc -15- 200813031 1- (3 -fluoro-4-( 5-(4-(5-benzylphenylfurfuran-2-yl)-3-fluorobenzyl 5-mercaptobenzoyl benzoate 4-(4-(5-(cyclopentylmethoxy)benzofuran-2-yl)-3-fluorobenzyl)morpholine-2-carboxylic acid; 3- 6-(5-(cyclopentylmethoxy)benzofuran-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propionic acid; 3-(4-(5-ring) Butyl benzofuran-2-yl)-3-fluorobenzylamino)propionic acid; Γ 3-(4_(5-p-phenylbenzofuran-2-yl)-3-cyclophenoxy)propane i,2-diol; 1-(3-fluoro-4-(5-(1-(methylsulfonyl)piperidine-4-yl)benzene幷furanyl) benzyl)azetidine-3-carboxylic acid; 1-(3,4-(5·(tetrahydro-2H_pyran-4-yl)benzoquinone-2-yl) Butyridine-3-carboxylic acid; 1-((4-(5-p-phenylphenylhydrazone.sup.2~yl)_3_fluorophenyl)methyl)·3_pyridinium-3-butyric acid; 〇 1-((4-(5-peptidyl benzoquinone [d] sputum_2_yl)_3_fluorophenyl)indolyl)_3_pyridinium-3-formic acid; 1-((3 -Fluoro-4-(5-(1-phenylethyl)benzoquinan-2-yl)phenyl)methyldipyridin-3-carboxylic acid; 1-((4-(5-(II) Fluorine (phenyl)methyl)benzoquinone-2-yl)_3_gasphenyl)methyl)azetidine-3-carboxylic acid; W(4-(6-benzyl benzoquinone) )· 3-fluorophenyl)methyl W butyryl _3_ formic acid; 119664.doc • 16 - 200813031 1-((3-fluoro-4-(5-〇b σ-decyl-2-ylindenyl)phenylhydrazine Indole-2-yl)phenyl)methyl)azetidine-3-furic acid; 1-((3-fluoro-4-(5-(thiazol-2-ylindenyl)benzofuran-2- Phenyl)methyl)azetidine-3·carboxylic acid; 1-((3-fluoro-4-(5-(1-phenylpropyl)benzoquinone-2-yl)phenyl)methyl ) azetidine-3-carboxylic acid; 1-(3-(5-benzylphenylpyran-2-yl)benzyl丫 丫 咬 _3_ decanoic acid; 1-((3-fluoro-4-(5-(2-phenylpropan-2-yl)benzofuran-2-yl)phenyl)methyl) ( Azetidine-3-carboxylic acid; 1-((3-fluoro-4-(5-(phenylmethyl)furano[2,3-b]acridin-2-yl)phenyl)methyl)- 3-吖-butyric acid; 1-((3-fluoro-4-(5-(phenylindolyl)-lH-indol-2-yl)phenyl)indolyl)-3-azetidinecarboxylic acid; 1-((3-fluoro-4-(5-(pyrimidin-2-ylindenyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; 1-((3- Fluoro-4-(5_〇b-pyridin-3-ylindenyl)benzofuran-2-yl)phenyl)methyl)indole azetidine-3-carboxylic acid; 1-((4-(5-benzene) Mercaptofuran-2-yl)_3_fluorophenyl)methyl)azetidine-3-f acid; (E/Z)_l-((3-fluoro-4_(5-((hydroxy) (Ethyl)(phenyl)indenyl)benzoquinone-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; (E/Z)-l-((3-fluoro-4-(5) -((methoxyimino)phenyl)methyl)benzofuran-2-yl)phenyl)methyl)azetidine_3_carboxylic acid, trifluoroacetate; (Ε/Ζ)·1 ·((3•Fluoro-4-(5-((ethoxyiminophenyl)methyl)benzofuran 119664.doc -17· 200813031 2-yl) phenyl) methyl) azetidine _3_ Methyl aglycolic acid, trifluoroacetate; -2-yl)phenyl) Azetidine-3-carboxylic acid; Butyridine-3-carboxylic acid; ((4-(5-knotylpyridinium [3,2_b]n ratio bite 2_yl)i gas phenyl)methylglycidyl-3 -decanoic acid; (4-(6-nodal _5_chloropyrano[3,2_b]n-pyridyl-2-yl)_3_ phenyl)methyl) hydrazine. _3 - formic acid; 1-( (4-(6-Benzylbenzoquinone[d]oxazole-2-yl)fluorophenyl)indenyl)azetidine-3-carboxylic acid; 1-((4-(5-benzyl alum)[d Oxazol-2•yl)_3_fluorophenyl)indenyl)azetidine-3-carboxylic acid; 1-((4-(5-benzylbenzoquinone[d]oxazole-2-yl)phenyl) )methyl)azetidine _3_carboxylic acid; 1-((4_(6-p-phenylbenzothiazole-2-methylxyl-3-fluorophenyl)methyl)azetidine-3-carboxylic acid; 1-(( (4-(5-Benzyl-1H-benzoquinone[d]imidazolium-2-yl)_3_fluorophenyl)indolyl)azetidine-3-carboxylic acid; 1β·((3-1·4_(5 Phenoxybenzoquinone [d]oxazol-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; 1-((3-fluoro-4-(5•(phenylthio))phenylhydrazine [d]oxazole_2•yl)phenyl)methyl)anthine 119664.doc -18- 200813031 pyridine-3-carboxylic acid; 1-((4-(6-p-phenylphenylhydrazine[d]thiazole_2 _ base)-3_dendyl)methyl η 唆 唆 _ 3-carboxylic acid; 1-((4-(7·]-yl-1 Η-imidazolium [Ujp pyridine -2- base ) _3_ fluoro] butyl ketone-3-carboxylic acid, trifluoroacetate; 1-((4-(6-nodyl)imidazolium [i,2-a] aridinyl)-3_fluoro Butyridine-3-carboxylic acid, trifluoroacetate; 1-((2-(5-benzylphenylfuran-2-yl)pyrimidinyl)methyl)azetidine_3_carboxylic acid; (6-(5-mercaptobenzofuran-2-yl)-2-methylpyridin-3-yl)methyl)pyrene-3-carboxylic acid; and 1-(1-(4-(5-) Benzofuran-2-yl)-3-fluorophenyl)ethyl)azetidine_3_ formic acid. 〇119664.doc -19- 200813031 VII. Designated representative figure: (1) The representative representative of the case is: ( (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 119664.doc