JP2000514061A - Fibrinogen receptor antagonist - Google Patents

Abstract

(57) [Summary] For example, the formula (I) Having the structure XYZAB wherein X is a 5-, 6- or 7-membered aromatic or non-aromatic ring, and Y is a 5- or 6-membered aromatic ring Receptor antagonists and their pharmaceutically acceptable salts.

Description

DETAILED DESCRIPTION OF THE INVENTIONTitle of invention Fibrinogen receptor antagonistBackground of the Invention   The present invention generally relates to modulating cell adhesion and fibrinogen and other Inhibiting the binding of proteins to platelets, as well as the gp IIb / IIIa It is concerned with inhibiting platelet aggregation specifically at the ibrinogen receptor site. Fi Brinogen is a glycoprotein that is present in plasma and is associated with platelet aggregation and fibrin form. Involved in the formation. Platelets are cell-like nuclei found in the blood of any mammal (an ucleaved fragments, which are also involved in blood doubts. Fibrinogen Interaction between lipase and the IIb / IIIa receptor site is essential for normal platelet function It has been known.   When blood vessels are damaged or damaged by other causative factors, the destroyed subendothelial layer ( Platelets adhere to the surface of the substrate. Sticky platelets Subsequently, the bioactive ingredient is released and aggregates. Aggregation is limited to thrombin, epinephrine, Or AD Is initiated by binding of an agonist such as P to a specific platelet membrane receptor You. Fibrinogen receptor latent on platelet surface as a result of agonist stimulation Is exposed and fibrinogen binds to glycoprotein IIb / IIIa receptor complex You.   Attempts to identify the mechanisms of adhesion and platelet aggregation using natural products and synthetic peptides Has been done many times. For example, Rouslahti and Pierschbac her is described in Science 238, pp. 139-143. 491-497, 1987, extracellular Fibronatatin, vitronectin, Opontin, collagen, thromphospondin, fibrinogen and von Describes adhesive proteins, such as the virulent factor. These tampa Is the tripeptide arginine as its glycoprotein IIb / IIIa recognition site. Glycine-aspartic acid (RGD). Arginine-glycine-a The tripeptide consisting of spartic acid is a structurally related receptor or integrin. Recognized by at least one receptor belonging to the family of The two sub-units are located across the membrane (membrane-spanning). It is a heterodimeric protein having a knit. The authors noted that the conformation of the tripeptide sequence of individual proteins was States that it can be decisive for heterogeneous recognition.   Cheresh is described in Proc. Natl. Acad. Sci. USA 84, p p. 6471-6475, 1987, Arg expressed in human endothelial cells. -Gly-Asp directed adhesive receptor, which is a Although structurally similar to the IIb / IIIa complex, they are distinguished antigenically and functionally. This receptor is associated with fibrinogen, von Willebrand factor and Directly involved in attachment to tronectin.   Pierschbacher and Rouslahti are described in J. Am. of Biol. Chem. 262 (36) pp. 17294-17298, 1987 The Arg-Gly-Asp sequence alone is sufficient for receptor recognition and binding. And thus the conformation of this tripeptide sequence is limited (d supposed to be terminative). Various synthetic peptides are produced And the authors have enantiomer-positions of Arg-Gly-Asp relative to the sequence. Again Indicates that the stereochemical conformation affected by the addition is in the receptor-ligand phase It concludes that it has a significant effect on the interaction. The author also notes that the non-terminal residue Pe the decapeptide to a ring by forming a disulfide bridge between n and Cys. Cyclization inhibits the attachment of the peptide to fibronectin It also shows that the effectiveness of the method is significantly reduced.   Proc. Natl. Acad. Sci. USA 81 pp. 5985-59 88, 1984, the same author promoted adhesion of fibronectin cell recognition sites. Describes tetrapeptide variants that retain activity. Tetrapeptide recognition Peptides having a moiety are disclosed in U.S. Pat. Nos. 4,589,881 and 4,614. No. 517. The number of fibronectin cell binding domains Some large polypeptide fragments have cell adhesion activity. US Patent Nos. 4,517,686, 4,661,111 and 4,578,07 See No. 9.   Ruggeri et al., Proc. Natl. Acad. Sci. USA 83, p p. In 5708-5712, 1986, RGD and RGD aspartic acid residues Join (at a series of synthetic peptides designed to be 16 residues long, including These synthetic peptides bind fibrinogen to platelets To prevent See Koczewiak et al., Biochem. 23 pp. 17 67-1774, 1984; Ginsberg et al. Biol. Chem. 2 60 (7), p. 3931-3936, 1985; and Haverick Et al., Blood 66 (4), p. 946-952, 1985 . European Patent Application Nos. 275,748 and 298,820 disclose other restrictions. A factor is disclosed.   Several low molecular weight polypeptide factors have been isolated from snake venom. These factors clearly have a high affinity for the gp IIb / IIIa complex You. See, for example, Huang et al. Biol. Chem. 262, pp. 1615 7-16163, 1987; Huang et al., Biochemistry 28, pp. 661-666, 1989 include 72 amino acids with an RGD subunit. Of the acid polypeptide, the snake venom trigramin The primary structure is described. Echistatin is also gp II b / It is one of the compounds having high affinity for the IIIa complex. This polypeptide is Consisting of 49 amino acids, RGD subunits and various disulfide bridges Have. Gan et al. Biol. Chem. 263 pp. 19827-19 832, 1988. See also Dennis et al., Proc. Natl. Acad . Scj. USA 87 pp. See also 2471-2475, 1989 . However, these snake venom factors do not respond to vitronectin and fibronectin receptors. Higher parents to other receptors in the adhesive protein receptor family, including the body It is not selective for the gp IIb / IIIa complex because of its compatibility.   Doubles or suppresses the cell adhesion promoting effect of fibronectin and vitronectin Tripeptide sequence Arg-Gly-Asp is present in some of the resulting polypeptides It is known that the activity of this tripeptide Arg-Gly-Asp Low. Currently, other amino acids coupled to the sequence are coupled The understanding of how it affects specificity is poorly understood. US Patent 5, No. 023,233, which has the sequence Arg-Gly-Asp and is useful for inhibiting platelet aggregation. Small ring that is a factor Hexapeptides are disclosed. U.S. Pat. No. 5,037,808 contains Ibrinogen and / or extracellular matrix protein and platelet gp IIb / IIIa is thought to act by antagonizing its interaction with the receptor The use of drill platelet aggregation inhibitors is disclosed. US Patent 5,037,8 No. 08 discloses a guanidino peptidomimetic compound having an Asp residue. This compound inhibits platelet aggregation. International Patent Application Publication No. 90/14103 The antibody includes an antibody and a polypeptide having an Arg-Gly-Asp (RGD) sequence. The use of conjugates is disclosed.   In WO 91/11458, a proline residue is bound at both ends. The use of a large cyclic peptide with RGD is disclosed, wherein the peptide is It is a plate aggregation inhibiting factor. International Patent Application Publication No. WO 91/01331 states that Synthetic ring having lipopeptide sequence Arg-Gly-Asp and thioether linkage A small cyclic platelet aggregation inhibitor that is a linear pentapeptide has been disclosed. US special No. 5,051,405 also discloses platelet aggregation and thrombus form in mammalian blood. -Amidino-piperidine-3-carboxylglycyl-L-as Peptides such as partyl-L-valine and pseudopeptides (pseudopept) (ides) are disclosed. In European Patent No. 445 796, Disclosed are linear compounds that can include internal piperazinyl or piperidinyl derivatives I have. European Patent No. 437 367 discloses a linear polypeptide fibrinogene. Receptor antagonists have been disclosed. U.S. Pat. No. 5,256,812 includes the formula R¹-A- (W)_a-X- (CH_Two)_b-(Y)_c-B-Z-COOR [wherein R¹Is An anodino or an amidino moiety, where A and B are specific Selected from among monosubstituted aryl or heterocyclic moieties) I have.   Inhibits platelet aggregation by inhibiting fibrinogen binding to platelets Although many compounds and peptide analogs are thought to be known, the present invention Novel fibrino which has a distinct binding activity and is therefore useful for the reasons described herein Provide an antigen receptor antagonist. Some very serious diseases and disorders are blood Hyperthrombotic causing thrombus and emboli in the vessel With complications. For myocardial infarction, stroke, phlebitis, and some other serious conditions , New and valid There is a need for fibrinogen receptive antagonists.Summary of the Invention   The present invention uses the formula                         XYZAB (In the formula X has one, two or three heteroatoms selected from N, O and S 5-, 6-, or 7-membered aromatic or non-aromatic ring, wherein this ring is unsubstituted Squid, R at carbon and nitrogen atoms¹Mono-substituted or with carbon and nitrogen R in the elementary atom¹And R^TwoWherein R is¹And R^TwoIs hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   amino,   Amino C_{1 ~ 8}Alkyl,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Independently selected from X has one, two or three heteroatoms selected from N, O and S A 9- or 10-membered fused aromatic or non-aromatic ring, wherein the ring is unsubstituted. Squid, carbon and nitrogen atoms Then R¹Or at the carbon and nitrogen atoms¹And R^Two Wherein R is¹And R^TwoIs   hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   amino,   Amino C_{1 ~ 8}Alkyl,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Independently selected from among Y represents 0, 1, 2, or 3 heteroatoms selected from N, O and S A 5- or 6-membered aromatic or non-aromatic ring, wherein the ring is unsubstituted. Squid or R at carbon and nitrogen atoms^ThreeWith R^ThreeIs   hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   amino,   Amino C_{1 ~ 8}Alkyl,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Dialkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Selected from or The structure of X and Y togetherConstitute Z is -CH_TwoCH_Two−, -CH = CH-, -CH_Two-O-, -O-CH_Two−, -CH_TwoNR^Four−, -NR^FourCH_Two−,Or Z is a bond, R^FourIs hydrogen, C_{1 ~Four}Alkyl, or C_{Three ~ 6}Cycloalkyl And A represents 0, 1, 2, or 3 heteroatoms selected from N, O and S A 5- or 6-membered aromatic ring, which ring is unsubstituted, carbon and nitrogen R in the elementary atom^FiveOr R at carbon and nitrogen atoms^FiveAnd R⁶ In two places Or at the carbon and nitrogen atoms^Five, R⁶And R⁷Trisubstituted by In that case, R^Five, R⁶And R⁷Is   hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   Arylsulfonylamino,   amino,   Amino C_{1 ~ 8}Alkyl,   Nitro,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 3}Alkylsulfonylamino,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Dialkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Trihaloalkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Selected independently from each other, or A represents 0, 1, 2, or 3 heteroatoms selected from N, O and S A 9- or 10-membered fused aromatic ring having no unsubstituted or And at the nitrogen atom R^FiveOr R at carbon and nitrogen atoms^Five And R⁶At the carbon and nitrogen atoms^Five, R⁶as well as R⁷Wherein R is^Five, R⁶And R⁷Is   hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   amino,   Amino C_{1 ~ 8}Alkyl,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Dialkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Are selected independently from each other, B is -O (CH_Two)_mCO_TwoR⁹, − (CH_Two)_nCO_TwoR⁹,-OCH (R⁸) (CH_Two)_pCO_TwoR⁹ At that time m is 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3; R⁸Is hydrogen, C_{1 ~Ten}Alkyl, C_{Three ~ 8}Cycloalkyl, Aryl, Aryl C_{1 ~ 8}Alkyl, amino, Amino C_{1 ~ 8}Alkyl, C_{1 ~ 3}Acylamino, C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl, C_{1 ~ 6}Alkylamino, C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl, C_{1 ~ 6}Dialkylamino, C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl, C_{1 ~ 6}Alkoxy, C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl, Aryl C_{1 ~ 6}Alkyloxy, Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl, Carboxy, Carboxy C_{1 ~ 6}Alkyl, C_{1 ~ 3}Alkoxycarbonyl, C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl, Carboxy C_{1 ~ 6}Alkyloxy, Hydroxy, and Hydroxy C_{1 ~ 6}Alkyl Selected from R⁹Is hydrogen, C_{1 ~ 8}Alkyl, Aryl, Aryl C_{1 ~ 6}Alkyl, C_{1 ~ 8}Alkylcarbonyloxy C_{1 ~ 6}Alkyl, Arylcarbonyloxy C_{1 ~ 6}Alkyl, Aryl C_{1 ~ 6}Alkylcarbonyloxy C_{1 ~ 6}Alkyl, C_{1 ~ 8}Alkylaminocarbonyl C_{1 ~ 6}Alkyl, or C_{1 ~ 8}Dialkylaminocarbonyl C_{1 ~ 6}Alkyl And the pharmaceutically acceptable salts thereof.   The present invention relates to suppression of platelet aggregation, prevention of thrombotic thrombosis and thrombosis in mammals. The use of the compound of the present invention in the manufacture of a medicament for use in preventing embolism or preventing reocclusion. Or the drug is acceptable It also includes the use of salts.Detailed description of the invention   The present invention uses the formula                         XYZAB (In the formula X has one, two or three heteroatoms selected from N, O and S 5-, 6-, or 7-membered aromatic or non-aromatic ring, wherein this ring is unsubstituted Squid, R at carbon and nitrogen atoms¹Mono-substituted or with carbon and nitrogen R in the elementary atom¹And R^TwoWherein R is¹And R^TwoIs   hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   amino,   Amino C_{1 ~ 8}Alkyl,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Independently selected from X has one, two or three heteroatoms selected from N, O and S A 9- or 10-membered fused aromatic or non-aromatic ring, wherein the ring is unsubstituted. Squid, carbon and nitrogen atoms Then R¹Or at the carbon and nitrogen atoms¹And R^Two Wherein R is¹And R^TwoIs   hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   amino,   Amino C_{1 ~ 8}Alkyl,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Independently selected from among Y represents 0, 1, 2, or 3 heteroatoms selected from N, O and S A 5- or 6-membered aromatic or non-aromatic ring, wherein the ring is unsubstituted. Squid or R at carbon and nitrogen atoms^ThreeWith R^ThreeIs   hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   amino,   Amino C_{1 ~ 8}Alkyl,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Dialkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Selected from The structure of X and Y together Constitute Z is -CH_TwoCH_Two−, -CH = CH-, -CH_Two-O-, -O-CH_Two−, -CH_TwoNR^Four−, -NR^FourCH_Two−, Or Z is a bond, R^FourIs hydrogen, C_{1 ~Four}Alkyl, or C_{Three ~ 6}Cycloalkyl And A represents 0, 1, 2, or 3 heteroatoms selected from N, O and S A 5- or 6-membered aromatic ring, which is unsubstituted or Or R at the nitrogen atom^Five Is monosubstituted or R^FiveAnd R⁶Or disubstituted with R^Five, R⁶ And R⁷Wherein R is^Five, R⁶And R⁷Is   hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   Arylsulfonylamino,   amino,   Amino C_{1 ~ 8}Alkyl,   Nitro,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 3}Alkylsulfonylamino,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Dialkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Trihaloalkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Independently selected from A represents 0, 1, 2, or 3 heteroatoms selected from N, O and S A 9- or 10-membered fused aromatic ring, which is unsubstituted or Represents R at a carbon or nitrogen atom^FiveIs monosubstituted or R^FiveAnd R⁶In two places Has been replaced or R^Five, R⁶And R⁷Tri-substituted by R^Five, R⁶And R⁷Is   hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   amino,   Amino C_{1 ~ 8}Alkyl,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Dialkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Independently selected from among B is -O (CH_Two)_mCO_TwoR⁹, − (CH_Two)_nCO_TwoR⁹Or-OCH (R⁸) (CH_Two)_pCO_TwoR⁹ At that time m is 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3; R⁸Is hydrogen, C_{1 ~Ten}Alkyl, C_{Three ~ 8}Cycloalkyl, Aryl, Aryl C_{1 ~ 8}Alkyl, amino, Amino C_{1 ~ 8}Alkyl, C_{1 ~ 3}Acylamino, C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl, C_{1 ~ 6}Alkylamino, C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl, C_{1 ~ 6}Dialkylamino, C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl, C_{1 ~ 6}Alkoxy, C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl, Aryl C_{1 ~ 6}Alkyloxy, Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl, Carboxy, Carboxy C_{1 ~ 6}Alkyl, C_{1 ~ 3}Alkoxycarbonyl, C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl, Carboxy C_{1 ~ 6}Alkyloxy, Hydroxy, and Hydroxy C_{1 ~ 6}Alkyl Selected from R⁹Is hydrogen, C_{1 ~ 8}Alkyl, Aryl, Aryl C_{1 ~ 6}Alkyl, C_{1 ~ 8}Alkylcarbonyloxy C_{1 ~ 6}Alkyl, Arylcarbonyloxy C_{1 ~ 6}Alkyl, Aryl C_{1 ~ 6}Alkylcarbonyloxy C_{1 ~ 6}Alkyl, C_{1 ~ 8}Alkylaminocarbonyl C_{1 ~ 6}Alkyl, or C_{1 ~ 8}Dialkylaminocarbonyl C_{1 ~ 6}Alkyl And the pharmaceutically acceptable salts thereof.   One class of compounds of the invention has the structure                         XYZAB (In the formula X is a 5-, 6- or 7-membered aromatic ring having one, two or three nitrogen atoms or Is a non-aromatic ring, which is unsubstituted or NH_TwoHas been replaced by And Y is a 5- or 6-membered aromatic ring having 0, 1, 2, or 3 nitrogen atoms or Is a non-aromatic ring, which ring is unsubstituted or_{1 ~ 3}Substitute with alkyl Has been or X and Y together form a fused ring systemConstitute Z is a bond, A is a 5- or 6-membered aromatic ring having 0, 1, 2, or 3 nitrogen atoms The ring is unsubstituted or at the carbon or nitrogen atom^FiveOne Substituted or identical or different R^FiveAnd R⁶Di-substituted by Or R which is the same or different from each other^Five, R⁶And R⁷Trisubstituted by In that case, R^Five, R⁶And R⁷Is   Arylsulfonylamino,   C_{1 ~ 3}Alkylsulfonylamino,   C_{1 ~ 3}Alkyl,   -CF_Three,   C_{1 ~ 3}Alkyloxy,   halogen,   Nitro Selected from or A is a 9-membered fused ring having 0, 1, 2, or 3 nitrogen atoms Is aromatic, or A is isoindolinone or indolinone, B is -OCH (R⁸) (CH_Two)_pCO_TwoR⁹, − (CH_Two)_nCO_TwoR⁹ At that time n is 0, 1, 2 or 3; p is 0, 1, 2 or 3; R⁸Is hydrogen or C_{1 ~ 3}Alkyl, R⁹Is hydrogen,-(CH_Two)_{1 ~ 3}C (O) NH (CH_Two)_{0 ~ 2}CH_ThreeOr-(CH_Two )_{1 ~ 3}C (O) N ((CH_Two)_{0 ~ 2}CH_Three)_TwoAnd a pharmaceutical thereof. Consisting of an acceptable salt.   One of the subclasses of the above class is the structure                         XYZAB (In the formula X is a 5- or 6-membered aromatic or non-aromatic ring having one or two nitrogen atoms The ring is unsubstituted or NH_TwoHas been replaced by Y is a 6-membered aromatic ring having 0 or 1 nitrogen atom or non-aromatic Ring, which is unsubstituted or CH_ThreeHas been replaced by Is X and Y are fused ring systemsConstitute Z is a bond, A is unsubstituted or R^FiveIs monosubstituted or R^FiveAnd R⁶Di-substituted by Or R^Five, R⁶Or R⁷Is phenyl trisubstituted with In the case of R^Five, R⁶And R⁷Is   -NHSO_TwoC₆H_Five,   -NHSO_TwoCH_Three,   -CH_Three,   -CF_Three,   -OCH_Three,   -Cl,   -NO_Two,as well as   -Br Selected from or A is a 9-membered fused aromatic ring system having one nitrogen atom, or A is isoindolinone or indolinone, B is -OCH (R⁸) CO_TwoR⁹, − (CH_Two)_nCO_TwoR⁹ At that time n is 1 or 2, R⁸Is hydrogen or C_{1 ~ 3}Alkyl, R⁹Is hydrogen,-(CH_Two)_{1 ~ 3}C (O) NH (CH_Two)_{0 ~ 2}CH_ThreeOr-(CH_Two )_{1 ~ 3}C (O) N ((CH_Two)_{0 ~ 2}CH_Three)_TwoAnd a pharmaceutical thereof. Consisting of an acceptable salt.   One group within the above subclass is the structure                         XYZAB (In the formula X is And Y isOr X and Y are fused ring systems Constitute Z is a bond, A isAnd B is -OCH_TwoCO_TwoH, -OCH_TwoCO_TwoCH_TwoC (O) NHCH_Three, -OCH_TwoCO_TwoCH_TwoC (O) N (CH_TwoCH_Three)_Two, -OCH_TwoCO_TwoCH_TwoCH_Three, -CH_TwoCH_TwoCO_TwoH, -CH_TwoCOOH, -OCH (CH_Three) CO_TwoH, or -OCH (CH_Three) CO_TwoCH_TwoCH_Three And a pharmaceutically acceptable salt thereof.   Examples of compounds belonging to the above group include: 3- (4- (4-piperazin-1-ylphenylcarbonylamino) phenyl) Propanoic acid, 2- (4- (4-piperazinyl-1-yl) phenylcarbonylamino) pheno Xy) acetic acid, Ethyl 2- (4- (4- (1-piperazinyl) phenylcarbonylamino) Nonoxy) acetate, hydrochloride, 2- (5- (4- (1-piperazinyl) phenylcarbonylamino) indole- 1-yl) acetic acid, 3- (3- (4-piperazin-1-ylphenyl) carbonylamino) phenyl ) Propanoic acid, Ethyl 2- (4- (4- (piperazin-1-yl) phenylcarbonylamino) Phenoxy) propanoate, 2- (4- (4- (piperazin-1-yl) phenylcarbonylamino) pheno Xy) propionic acid, 2- (4-(((2-piperazin-1-yl) pyridin-5-yl) carbonyl Amino) phenoxy) acetic acid, 3-methyl-4-((1,2,3,4-tetrahydro-9H-pyrido [3,4- b] indol-7-yl) carbonylamino) phenoxyacetic acid, 2- (4- (5- (4- (1,1-dimethylethoxycarbonyl) -piperazine -1-yl) -2-thienylcarbonylamino) -3-methylphenoxy) -vinegar acid, 4- (2- (1,1-dimethylethoxycarbonyl) -1,2,3,4-tetra Hydro-9H-pyrido [3,4-b] benzofuran-7-yl) carbonylamido G) -3-methylphenoxyacetic acid, 4-((2,3,4,5-tetrahydro-pyrazino [1,2-a] indole-8 -Yl) carbonylamino) -3-methylphenoxyacetic acid, and (±) 4-((3- (1,1-dimethylethoxycarbonyl) -1,1a, 2, 3,4,5-hexahydro-pyrazino [1, 2-a] Indol-8-yl) carbonylamino) -3-methylphenoxyacetic acid Is included.   One test used to evaluate fibrinogen receptor antagonist activity is AD Based on evaluation of P-stimulated platelet inhibition. In order for platelets to aggregate, fibrino Must bind to and occupy the fibrinogen receptor site on platelets No. Fibrinogen binding inhibitors suppress platelet aggregation. Of the present invention The ADP-stimulated platelet aggregation assay used to identify compound-related inhibition Centrifuge, then contain 2% bovine serum albumin in Sepharose 2B Filtration into Tyrode buffer (pH 7.4) containing no divalent ions Isolates human platelets from fresh blood and converts them into citrate / dextrose to recover.   Platelet aggregation is measured at 37 ° C. in a Chronolog agglutination detector. Anti The reaction mixture was added to gel-filtered human platelets (2 × 10⁸/ Ml) and fibrinogene (100 μg / ml) and Ca²⁺(1 mM) and the compound to be tested Let it. Add 10 mM ADP one minute after adding the other components. To initiate aggregation. The initiated reaction is allowed to proceed for at least 2 minutes. Coagulation The degree of cluster suppression is expressed as a percentage (%) based on the aggregation observed in the absence of the inhibitor. Express. IC₅₀Inhibits aggregation occurring in controls lacking certain compounds by 50% The compound dose.   The following compounds of the present invention were tested and showed an IC of 10 nM to 50 mM.₅₀Has value It turned out to be: 3- (4- (4-piperazin-1-ylphenylcarbonylamino) phenyl) Propanoic acid, 2- (4- (4-piperazinyl-1-yl) phenylcarbonylamino) pheno Xy) acetic acid, Ethyl 2- (4- (4- (1-piperazinyl) phenylcarbonylamino) Nonoxy) acetate, hydrochloride, 2- (5- (4- (1-piperazinyl) phenylcarbonylamino) indole- 1-yl) acetic acid, 3- (3- (4-piperazin-1-ylphenyl) carbonylamino) phenyl ) Propanoic acid, Ethyl 2- (4- (4- (piperazin-1-yl) phenylcarbonylamino) Phenoxy) propanoate, 2- (4- (4- (piperazin-1-yl) phenylcarbonylamino) pheno Xy) propionic acid, 2- (4-(((2-piperazin-1-yl) pyridin-5-yl) carbonyl Amino) phenoxy) acetic acid, 3-methyl-4-((1,2,3,4-tetrahydro-9H-pyrido [3,4- b] indol-7-yl) carbonylamino) phenoxyacetic acid, 2- (4- (5- (4- (1,1-dimethylethoxycarbonyl) -piperazine -1-yl) -2-thienylcarbonylamino) -3-methylphenoxy) -vinegar acid, 4- (2- (1,1-dimethylethoxycarbonyl) -1,2,3,4-tetra Hydro-9H-pyrido [3,4-b] benzofuran-7-yl) carbonylamido G) -3-methylphenoxyacetic acid, 4-((2,3,4,5-tetrahydropyrazino- [1,2-a] indole-8 -Yl) carbonylamino) -3-methylphenoxyacetic acid, and (±) 4-((3- (1,1-dimethylethoxycarbonyl) -1,1a, 2, 3,4,5-hexahydropyrazino- [1, 2-a] Indol-8-yl) carbonylamino) -3-methylphenoxyacetic acid .   In addition, these compounds may have bone-like properties induced or mediated by increased bone resorption. It is also useful in the treatment of mammals suffering from and in need of such conditions . The above-mentioned compound including a pharmaceutically acceptable salt thereof is pharmacologically effective for the mammal. Administered in an amount thereby inhibiting the activity of mammalian osteoclasts.   The compounds according to the invention are also useful for treating angiogenesis (formation of new blood vessels). You. Tumor growth depends on the availability of blood, It is said that it depends on whether new blood vessels extend into the tumor. Blood vessels Inhibition of formation can cause tumor regression in animal models ("Harrison ’S Principles of Internal Medicine,” 12th ed. , 1991). Therefore, the above compounds inhibit tumor growth. (Eg Brooks et al., Cell 79, pp. 115). 7-1164, 1994).   The term "pharmaceutically acceptable salt" usually refers to the form of the free base in a suitable organic or inorganic acid. The compound of the present invention produced by reacting Shall mean toxic salt. Representative salts include acetate, benzenesulfonate, Benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, edetate Lucium, camsylate, carbonate, chloride, clavulanate, citrate, disalt Acid salt, edetate, edisylate, estolate, esylate, fumarate, Luceptate, gluconate, glutamate, glycolyl arsanylate (g lycyllarsanilate), hexyl resorcinate, hydrava Hydramine, hydrobromide, hydrochloride, hydroxynaptoa (Hydroxynapthoate), iodide, isothionate, lactic acid Salt, lactobionate, laurate, malic acid Salt, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, sulfuric acid Methyl, mucate, napsylate, nitrate, oleate, oxalate Acid, pamoate, palmitate, pantothenate, phosphate / diphosphate, polyphosphate Regalacturonate, salicylate, stearate, basic acetate, succinate , Tannate, tartrate, teoclate, tosylate, Triethiodide, valerate included.   The compounds of the present invention may be chiral, have racemic mixtures, and have the general formula shown above. The individual enantiomers included are within the scope of the present invention. In addition, the general All diastereomers, including E, Z isomers having the formula, are also included within the scope of the invention. It is. In addition, hydrates and anhydrous compositions and polymorphs having the general formula given above are also provided. It is within the scope of the present invention.   Prodrugs such as ester derivatives of the above compounds are absorbed into the bloodstream of warm-blooded animals. Decomposes to release the drug form when entrained, thereby providing better cure for the drug. It is a compound derivative that can exert therapeutic effect.   The term “pharmaceutically effective amount” is used by researchers or clinicians to identify drugs or drugs. The amount that elicits the biological or medical response of a tissue, system or animal And The term "anticoagulant" includes heparin and warfarin. I do. The term "thrombolytic" refers to streptokinase and tissue plasminogen. It includes substances such as inactivators. "Anti-platelet aggregation agents" The term is intended to cover substances such as aspirin and dipyridamole.   The term "alkyl" refers to a straight or branched chain alkyl having from 1 to about 10 carbon atoms. Alkane such as methyl, ethyl, n-propyl, isopropyl, n-butyl, i Sobutyl, s-butyl, t-butyl, pentyl, isoamyl, hexyl, octyl The term "alkenyl" means two to about ten carbon atoms. Linear or branched alkenes such as propylenyl, buten-1-yl, iso Butenyl, pentenen-1-yl, 2,2-methylbuten-1-yl, 3-meth Tilbuten-1-yl, hexen-1-yl, hepten-1-yl, otaten- The term "alkynyl" refers to a 1-yl radical and the like, and is a mixture of two to about ten carbon atoms. Straight-chain or branched alkynes having a substituent, such as ethynyl, propynyl, butyne- 1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3- Methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyne -3-yl, 3,3-dimethylbutyn-1-yl radical and the like.   The term "aryl" refers to zero heteroatoms selected from O, N and S. A 5- or 6-membered aromatic ring having one or two, such as phenyl, pyridine, Limidine, imidazole, Thiophene, oxazole, isoxazole, thiazole, and their Mino and halogen substituted derivatives are meant.   The terms “alkyloxy” or “alkoxy” are defined above where alkyl is Alkyl moieties such as methyloxy, propyloxy and butyric Loxy.   The terms "arylalkyl" and "alkylaryl" refer to an alkyl as Encompasses an alkyl moiety as defined, and wherein aryl is as defined above. Aryl moieties. The symbol "C_{0 ~ N}(N is an integer from 1 to 10) Get) or "C_{1 ~ N}"(N can be an integer from 2 to 10) is an arylalkyl Or an alkyl component of an alkylaryl unit. Aryla Examples of alkyl include benzyl, fluorobenzyl, chlorobenzyl, phenylethyl , Phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienyl Dimethyl, thienylethyl and thienylpropyl. Alkylaryl Examples include toluene, ethylbenzene, propylbenzene, methylpyridine, Tylpyridine, propylpyridine, butylpyridine, butenylpyridine and pen Includes thenyl pyridine.   The term "halogen" includes fluorine, chlorine, iodine and bromine.   The term "oxy" means an oxygen (O) atom. The word “thio” is sulfur ( S) means an atom. Under standard nomenclature used throughout this disclosure, The side chain shown first describes its terminal part and then moves from the adjacent functional group to the point of attachment. Is described. For example, C_{1 ~Five}C substituted with alkyl-carbonylamino_{1 ~ 6} Alkyl is be equivalent to.   In the reaction schemes and examples below, various reagent symbols have the following meanings.   BOC (or Boc): t-butyloxycarbonyl   Pd-C: Palladium-activated carbon catalyst   DMF: dimethylformamide   DMSO: dimethyl sulfoxide   CBZ: Carbobenzyloxy   CH_TwoCl_Two： Methylene chloride   CHCl_Three: Chloroform   EtOH: ethanol   MeOH: methanol   EtOAC: ethyl acetate   HOAc: Acetic acid   BOP: benzotriazol-1-yloxytris (di                               Methylamino) phosphonium hexafluoroli                               Phosphate   EDC: 1- (3-dimethylaminopropyl) -3-e                               Tyl carbodiimide, hydrochloride   Oxone: Peroxy-potassium sulfate   LDA: lithium diisopropylamide   PYCLU: chloro-N, N, N ', N'-bis (pentame                               Tylene) formamidinium, hexafluoro                               Phosphate   NMM: N-methylmorpholine   The compounds of the present invention can be used in the form of tablets, capsules (sustained release formulations or timed release formulations). Pills, powders, granules, elixirs, tinctures, suspensions, syrups and And oral forms such as emulsions. In addition, the compound of the present invention is intravenously (bolus). Or as an infusion), it is equally possible to administer it intraperitoneally, subcutaneously or intramuscularly. In that case, administration by any route is well known to those skilled in the pharmaceutical field. Can be used. Effective but toxic Not an amount of the desired compound of the invention may be used as an anti-aggregating agent.   The compound of the present invention is capable of receiving fibrinogen receiving platelet membrane glycoprotein IIb / IIIa. Patients who want to prevent thrombosis by suppressing binding to the receptor complex May be administered. The compounds of the invention may be used to treat arteries and organs, and / or Surgery on peripheral arteries where interaction with the surface of the artifact leads to platelet aggregation and depletion ( Arterial transplantation, carotid endarterectomy) and cardiovascular surgery. Aggregated blood The plate can form thrombi and thromboemboli. Compounds of the present invention The administration of a substance can prevent the formation of thrombi and thromboemboli.   In cardiovascular surgery, extracorporeal circulation is usually used to supply oxygen to the blood. Outside the body Platelets adhere to the surface of the circuit. This adhesion is due to gp IIb / IIIa on the platelet membrane. And fibrinogen adsorbed on the surface of the circuit (Glus Zko et al., Amer. J. Physiol. 252 (H), pp. 615-62 1, 1987). The hemostatic function of platelets away from the surface of the artifact is reduced. Departure The sticking can be prevented by the administration of a bright compound.   Other uses of the compounds of the invention include during thrombolytic therapy and Prevention of thromboembolism, thromboembolism and reocclusion after administration, and angiogenesis or Includes prevention of thrombotic thrombosis, thromboembolism, and reocclusion after coronary artery bypass procedures You. The compounds of the present invention can also be used for preventing myocardial infarction.   Dosage regimens using the compounds of the present invention will depend on the type, species, age, weight, Severity of the condition to be treated; route of administration; renal and hepatic function of the patient; The choice is made according to various factors, including the particular compound or salt thereof. Normal skill Prevent, overcome, or progress the condition if you are a qualified doctor or veterinarian It is easy to determine and prescribe the effective amount of drug needed to prevent .   When the compound of the present invention is orally administered to obtain the above-mentioned effect, the dose may be 1 day. To about 0.01 to about 100 mg / kg of body weight (about 0.01 to about 100 mg / k g / day), preferably 0.01 to 100 mg / kg / day, and most preferably 0 to 100 mg / kg / day. . The range is from 01 to 20 mg / kg / day. For example, for a typical patient weighing 90 kg From about 0.9 mg / day to about 9 g / day, most preferably from about 0.9 mg / day to about 1. 8 g / day is administered orally. Oral pharmaceutical compositions such as suitable tablets or capsules 10-500mg, example For example, it may contain 10 mg, 100 mg, 200 mg and 500 mg of active drug . The most preferred intravenous dose is about 1 to about 10 mg / kg / min for a constant rate infusion.   It is effective to administer the daily dose of the compound of the present invention in two, three or four divided doses. In some cases, it is beneficial. In addition, preferred compounds of the present invention are suitable excipients for intranasal administration. Skin for intranasal administration via topical use or in forms well known to those skilled in the art It can be administered via the transdermal route using a skin patch. Form of transdermal delivery system Of course, the dose should not be intermittent throughout the regimen. Administer continuously.   In the method of the present invention, the compound of the present invention described in detail herein can be used as an active ingredient. Formally, the compound, the desired dosage form, ie, oral tablet, capsule, elixir, Appropriately selected according to the syrup, etc. Pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier substances") ).   For example, for oral administration in the form of a tablet or capsule, the active drug component may be Lactose, starch, sucrose, glucose, methylcellulose, stearic acid Magnesium, dicalcium phosphate Non-toxic and pharmaceutically acceptable, such as calcium, calcium sulfate, mannitol, sorbitol Can be combined with an inert carrier for oral administration. Oral drug components, any non-toxic and pharmaceutically acceptable, such as ethanol, glycerol, water Inactive carriers for oral administration. Besides, if desired or necessary Suitable binders, lubricants, disintegrants and coloring agents can also be added to the mixture. Appropriate Binders include starch, gelatin, natural sugars such as glucose and β-lactose, Sweeteners (corn-sweeteners), gum arabic, tragacantogo Natural and synthetic rubbers such as Includes lulose, polyethylene glycol, wax and the like. In the above dosage form Lubricants used include sodium oleate, sodium stearate, stearyl Magnesium phosphate, sodium benzoate, sodium acetate, sodium chloride, etc. included. Disintegrators include starch, methyl cellulose, agar, bentonite, xan Non-limiting examples include tongue rubber.Reaction scheme 1 Reaction scheme 1(Continued) Methyl 4- (1-piperazinyl) benzoate (1-3)   Amine1-1(20.0; 132 mmol, amine1-2(23.6 g; 13 2 mmol) and n-butanol (500 ml) at reflux for 168 hours I let it. The solution was cooled to ambient temperature. Collect the crystals and Et_TwoWashed with O and true Air dry and ester1-3Was obtained as a white solid.¹ H NMR (CD_ThreeOD) δ: 7.86 (d, J = 9 Hz, 2H), 7.98 ( d, J = 9 Hz, 2H), 3.78 (s, 3H), 3.53 (m, 4H), 3. 31 (m, 4H). Methyl 4- (4- (1,1-dimethylethoxycarbonyl) piperazine-1-i Le) Benzoate (1-4)   Amine1-3(15.0 g; 61.1 mmol), NEt_Three (7.42 g; 73.4 mmol) and DMF (150 ml) Stir and add Boc_TwoO (14.7 g; 67.2 mmol) was added. 1. After 0 hours, the solution was diluted with EtOAc and then diluted with H_TwoO, 10% KHSO_Four,bra And then dried (MgSO 4)_Four) And concentrate the ester1-4The yellow Obtained as a solid. TLCR_f= 0.63 (silica; 40% EtOAc / hexane)¹ H NMR (CD_ThreeOD) δ: 7.91 (d, J = 9 Hz, 2H), 7.01 ( d, J = 9 Hz, 2H), 3.88 (s, 3H), 3.59 (m, 4H), 3. 38 (m, 4H). 4- (4- (1,1-dimethylethoxycarbonyl) piperazin-1-yl) an Benzoic acid (1-5)   ester1-4(21.1 g; 61.1 mmol), 1N NaOH (100 ml; 100 mmol) and EtOH (200 ml) for 2 hours 60 Heated each time. 1 solution 0% KHSO_FourAnd then extracted with EtOAc. Block the EtOAc phase Wash in line and dehydrate (MgSO 4_Four) And concentrate the acid1-5The white solid As obtained.¹ H NMR (CD_ThreeOD) δ: 7.81 (d, J = 9 Hz, 2H), 6.88 ( d, J = 9 Hz, 2H), 3.49 (m, 4H), 3.24 (m, 4H), 1. 40 (s, 9H). N- (4-bromophenyl) -4- (4- (1,1-dimethylethoxycarbonyl) Ru) piperazin-1-yl) benzamide (1-7)   acid1-5(400 mg; 1.31 mmol), amine1-6(248 mg; 1 . 44 mmol), BOP reagent (867 mg; 1.97 mmol), NMM (5 75 μl; 5.24 mmol) and DMF is heated at 60 ° C. for 72 hours did. The solution was diluted with EtOAc and then diluted with H_TwoO, NaHCO_ThreeSaturated solution of 10 % KHSO_FourWashed with brine, dehydrated (MgSO_Four) And concentrated. Flash chromatography (silica; 20% Amide by EtOAc / hexane)1-7Was obtained as a yellow solid. TLCR_f= 0.36 (silica; 20% EtOAc / hexane)¹ H NMR (CDCl_Three) Δ: 7.78 (d, J = 9 Hz, 2H), 7.70 ( s, IH), 7.54 (d, J = 9 Hz, 2H), 7.46 (d, J = 9 Hz, 2H), 6.92 (d, J = 9 Hz, 2H), 3.58 (m, 4H), 3.30 (M, 4H), 1.49 (s, 9H). (E) -methyl 3- (4- (4- (4- (1,1-dimethylethoxycarbonyl) ) Piperazin-1-yl) phenylcarbonylaminophenyl) prop-3-e Noate (1-8)   Amide1-7(300 mg; 0.6519 mmol), methyl acrylate (5 87 μl; 6.52 mmol), O (tolyl)_ThreeP (120 mg; 0.311 m mol), NEt_Three(184 μl; 1.30 mmol), Pd (OAc)_Two(15 mg; 0.0512 mmol) and CH_ThreeCN (5 ml) Was heated to 100 ° C. in a sealed tube for 18 hours. Dilute the solution with EtOAc And then H_TwoO, NaHCO_ThreeSaturated solution of 10% KHSO_FourIn the brine Wash and dehydrate (MgSO 4_Four) And concentrated. Flash chromatography Lica; 25% → 40% EtOAC / Hexane)1-8The yellow Obtained as a colored solid. TLCR_f= 0.36 (silica; 50% EtOAc / hexane)¹ H NMR (CDCl_Three) Δ: 7.87 (s, 1H), 7.81 (d, J = 9H) z, 2H), 7.68 (m, 3H), 7.53 (d, J = 9 Hz, 2H), 6.9 4 (d, J = 9 Hz, 2H), 6.39 (d, J = 16 Hz, 1H), 3.81 (S, 3H), 3.61 (m, 4H), 3.30 (m, 4H), 1.50 (s, 9H). Methyl 3- (4- (4- (4- (1,1-dimethylethoxycarbonyl) pipera) Zin-1-yl) phenylcarbonylaminophenyl) propanoate (1-9 )   ester1-8(260 mg; 0.56 mmol) and 1 A mixture of 0% Pd / C (100 mg) and EtOH (10 ml) was added at 1 atm. H_TwoStirred down for 18 hours. Filter the reaction mixture through a pad of celite and concentrate Then ester1-9Was obtained as a brown solid.¹ H NMR (CDCl_Three) Δ: 7.79 (d, J = 9 Hz, 2H), 7.67 ( s, 1H), 7.54 (d, J = 8 Hz, 2H), 7.19 (d, J = 8 Hz, 2H), 6.92 (d, J = 9 Hz, 2H), 3.67 (s, 3H), 3.60 (M, 4H), 3.29 (m, 4H), 2.94 (t, J = 8 Hz, 2H), 2 . 63 (t, J = 8 Hz, 2H), 1.49 (s, 9H). 3- (4- (4- (4- (1,1-dimethylethoxycarbonyl) piperazine- 1-yl) phenylcarbonylaminophenyl) propanoic acid (1-10)   ester1-9(250 mg; 0.53 mmol), 1N NaOH (1 ml 1.00 mmol) and EtOH (3 ml) at ambient temperature for 1.5 Stirred for hours. 1 solution 0% KHSO_FourAnd then extracted with EtOAc. EtOAC phase Wash in line and dehydrate (MgSO 4_Four) And concentrate the acid1-10The tan Obtained as a solid. TLCR_f= 0.11 (silica; 10: 0.2: 0.2 CH_TwoCl_Two/ MeO               H / AcOH)¹ H NMR (CD_ThreeOD) δ: 7.86 (d, J = 9 Hz, 2H), 7.55 ( d, J = 8 Hz, 2H), 7.20 (d, J = 9 Hz, 2H), 7.08 (d, J = 8 Hz, 2H), 3.60 (bs, 4H), 3.45 (m, 4H), 2.8 9 (t, J = 8 Hz, 2H), 2.59 (t, J = 8 Hz, 2H), 1.48 ( s, 9H). 3- (4- (4-piperazin-1-ylphenylcarbonylamino) phenyl) Propanoic acid (1-11)   acid1-10(215 mg; 0.4743 mmol), TFA (3.0 ml) and And CH_TwoCl_Two(3.0 ml) was stirred at ambient temperature for 1.5 hours. Dissolution Concentrate the liquid and then Azeotroped with Ruen. The residue was treated with 10: 0.2: 0.2 EtOH / NH_FourOH / H_Two Crush with O, filter, Et_TwoWash with O and dry under vacuum, acid1-11The yellow brown Obtained as a colored solid. TLCR_f= 0.55 (silica; 10: 1: 1 EtOH / NH_FourOH / H_Two             O)¹ H NMR (D_TwoO) δ: 7.83 (d, J = 9 Hz, 2H), 7.42 (d, J = 8 Hz, 2H), 7.31 (d, J = 8 Hz, 2H), 7.16 (d, J = 9Hz, 2H), 3.25 (m, 4H), 2.96 (m, 4H), 2.89 (t , J = 8 Hz, 2H), 2.49 (t, J = 8 Hz, 2H).Reaction scheme 2 N- (4-hydroxyphenyl) -4- (4- (1,1-dimethylethoxycal Bonyl) piperazinyl-1-yl) benzamide (2-3)   carboxylic acid2-1(400 mg; 1.31 mmol), 4-aminophenyl2 -2 (210 mg; 1.44 mmol), BOP reagent (867 mg; 1.97 m) mol), NMM (575 μl; 5.24 mmol) and DMF (10 ml) The resulting solution was heated to 60 ° C. for 72 hours. The reaction mixture was diluted with EtOAc and After H_TwoO, NaHCO_ThreeSaturated solution of 10% KHSO_FourAnd then dehydrated (Mg SO_Four) And then concentrated. Flash chromatography (silica; 50% Amide by EtOAc / hexane)2-3Was obtained as a white solid. TLCR_f= 0.25 (silica; 50% EtoAC / hexane)¹ H NMR (CD_ThreeOD) δ: 7.82 (d, J = 9 Hz, 2H), 7.40 ( d, J = 9 Hz, 2H), 7.0 (d, J = 9 Hz, 2H), 6.75 (d, J = 9 Hz, 2H), 3.57 (bs, 4H), 3.30 (bs, 4S), 1.4 7 (S, 9H). t-butyl 2- (4- (4- (4- (1,1-dimethylethoxycarbonyl) pi Perazinyl-1-yl) phenylcarbonylamino) phenoxy) acetate ( 2-5)   Amide2-3(400 mg; 1.01 mmol) and DMF (5 ml). The resulting solution was stirred, followed by cesium carbonate (820 mg; 2.53 mmol), followed by Was added t-butyl bromoacetate (195 μl; 1.21 mmol). 20:00 After a while, the reaction mixture is diluted with EtOAc and then_TwoO, 10% KHSO_Four,bra And then dried (MgSO 4)_Four) And concentrated. Flash chromatography -(Silica; 25% EtOAc / hexane)2-5The white Obtained as a solid. TLCR_f= 0.40 (silica; 50% EtOAc / hexane)¹ H NMR (CDCl_Three) Δ: 7.79 (d, J = 9 Hz, 2H), 7.63 (S, 1H), 7.54 (d, J = 9 Hz, 2H), 6.92 (m, 4H), 4 . 51 (s, 2H), 3.60 (m, 4H), 3.30 (m, 4H), 1.50 (S, 18H). 2- (4- (4-piperazinyl-1-yl) phenylcarbonylamino) pheno Xy) acetic acid (2-6)   ester2-5(275 mg; 0.5378 mmol), TFA (5 ml) and And CH_TwoCl_Two(5 ml) was stirred at ambient temperature for 2.0 hours. The solution Concentrated and then azeotroped with toluene. The residue was treated with 10: 0.5: 0.5 EtOH / NH_FourOH / H_TwoCrush with O, filter, wash with EtOH, then wash with EtOH Cleanse and acid2-6Was obtained as a white solid. TLCR_f= 0.34 (silica; 10: 0.5: 0.5 EtOH / NH_FourOH               / H_TwoO)¹ H NMR (CD_ThreeOD) δ: 7.83 (d, J = 9 Hz, 2H), 7.50 ( d, J = 9 Hz, 2H), 7.00 (d, J = 9 Hz, 2H), 6.92 (d, J J = 9 Hz, 2H), 4.36 (s, 2H), 3.30 (m, 4H), 2.96 (M, 4H).Reaction scheme 3 t-butyl 2- (4- (4- (4- (1,1-dimethylethoxycarbonyl) pi Perazin-1-yl) phenylcarbonyl (N-methyl) amino) phenoxy) Acetate (3-1)   ester2-5(200 mg; 0.3911 mmol) Cesium carbonate (318 mg; 0.9778 mmol) followed by CH_ThreeI (29 μl: 0.47 mmol) was added. After heating at 60 ° C. for 2 hours, the reaction mixture was diluted with tOAc, then H_TwoO, 10% KHSO_FourWashed with brine, dehydrated (MgSO_Four) And concentrated. Flash chromatography (silica; 40%   Ester by EtOAC / hexane)3-1Was obtained as a yellow solid. TLCR_f= 0.45 (silica; 50% EtOAc / hexane)¹ H NMR (CDCl_Three) Δ: 7.21 (d, J = 9 Hz, 2H), 6.97 (D, J = 9 Hz, 2H), 6.75 (d, J = 9 Hz, 2H), 6.63 (d , J = 9 Hz, 2H), 4.45 (s, 2H), 3.52 (bt, 4H), 3. 43 (s, 3H), 3.13 (bt, 4H), 1.47 (s, 18H). 2- (4- (4- (1-piperazinyl) phenylcarbonyl (N-methyl) amido No) Phenoxy) -acetic acid (3-2)   ester3-1(190 mg; 0.3617 mmol), TFA (3 ml) and And CH_TwoCl_Two(3 ml) was stirred at ambient temperature for 30 minutes. Concentrate the solution And then azeotroped with toluene. Flash chromatography (silica; 1 0: 0.2: 0.2 EtOH / NH_FourOH / H_TwoO) by acid3-2The white Obtained as a solid. TLCR_f= 0.42 (silica; 10: 0.2: 0.2 EtOH / NH_FourOH               / H_TwoO)¹ H NMR (CD_ThreeOD) δ: 7.25 (d, J = 9 Hz, 2H), 7.06 ( d, J = 9 Hz, 2H), 6.91 (d, J = 9 Hz, 2H), 6.82 (d, J J = 9 Hz, 2H), 4.66 (s, 2H), 3.50 (m, 4H), 3.41 (S, 3H), 3.35 (m, 4H).                               Reaction Scheme 4 Ethyl 2- (4- (4- (1-piperazinyl) phenylcarbonylamino) Nonoxy) acetate hydrochloride (4-1)   Acid at 0 ° C2-6(40 mg; 0.1125 mmol) and EtOH (2 ml) was stirred and HCl gas was bubbled through it for 3 minutes. At ambient temperature After 24 hours, the solution is concentrated to ethyl ester4-1Was obtained as a white solid .¹ H NMR (D_TwoO) δ: 7.87 (d, J = 9 Hz, 2H), 7.44 (d, J = 9 Hz, 2H), 7.19 (d, J = 9 Hz, 2H), 7.05 (d, J = 9Hz, 2H), 4.80 (s, 2H), 4.31 (q, J = 7Hz, 2H), 3.62 (m, 4H), 3.43 (m, 4H), 1.30 (t, J = 7 Hz, 3 H).Reaction scheme 5 N- (5-indolyl) -4- (4- (1,1-dimethylethoxycarbonyl) Piperazin-1-yl) benzamide (5-2)   acid2-1(500 mg; 1.63 mmol), NMM (715 μl; 6.52). mmol) and DMF (5 ml) were stirred and the BOP reagent (1 . 08 g; 2.45 mmol) was added. 30 minutes later, amine5-1(Aldr -ich; 260 mg; 1.96 mmol) was added. 18 hours at 60 ° C Later, the solution was diluted with EtOAc and then H_TwoO, washed with brine, dehydrated (M gSO_Four) And concentrated. Flash chromatography (silica; 20% Et OAc / CHCl_Three) By amide5-2Was obtained as a yellow solid. TLCR_f= 0.13 (silica; 20% EtOAc / CHCl_Three)¹ 1 H NMR (10% CD_ThreeOD / CDCl_Three) Δ: 7.90 (s, 1H), 7 . 83 (d, J = 9 Hz, 2H), 7.63 (m, 2H), 7.22 (9 s, 1 H), 6.94 (d, J = 9 Hz, 2H), 6.52 (d, J = 3 Hz, 1H); 59 (m, 4H), 3.28 (m, 4H), 1.49 (s, 9H). t-butyl 2- (5- (4- (4- (1,1-dimethylethoxycarbonyl) pi Perazin-1-yl) phenylcarbonylamino) indol-1-yl) acete (5-4)   Amide5-2(300 mg; 0.71 mmol) and THF (5 ml). The solution was stirred and NaH (60% dispersion in mineral oil; 29 mg; 0.713 7 mmol) was added. After 10 minutes, bromide5-3(115 μl; 0.71 mmo l) was added. After 30 minutes, the solution was diluted with EtOAc and then H_TwoO, Bly And then dehydrated (MgSO 4)_Four) And concentrated. Flash chromatography (Silica; 40% EtOAc / hexane)5-4The yellow solid Obtained as body. TLCR_f= 0.18 (silica; 40% EtOAc / hexane)¹ 1 H NMR δ: 7.92 (s, 1H), 7.83 (d, J = 9 Hz, 2H) 5.77 (s, 1H), 7.39 (dd, J = 9 Hz, 2 Hz, 1H); 93 (d, J = 9 Hz, 2H), 6.52 (d, J = 3 Hz, 1H), 4.72 (S, 2H), 3.60 (m, 4H), 3.28 (m, 4H), 1.49 (s, 2H) 9H), 1.43 (s, 9H). 2- (5- (4- (1-piperazinyl) phenylcarbonylamino) indole- 1-yl) acetic acid (5-5)   Ester at 0 ° C5-2(250 mg; 0.4678 mmol), aniso (203 μl; 1.87 mmol) and CH_TwoCl_Two(3 ml) solution Was stirred and TFA was added thereto. After 30 minutes, the solution is concentrated and then toluene Azeotropic. Flash chromatography (silica; 10: 0.1: 0.1 E tOH / NH_FourOH / H_TwoO) gave the crude acid. Preparative HPLC of this crude material Purified by acid5-5To Obtained. TLCR_f= 0.31 (silica; 10: 0.5: 0.5 EtOH / NH_FourOH               / H_TwoO)¹ 1 H NMR (50:50 d₆-DMSO / D_TwoO + 2 drops of 1N NaOD) δ : 7.87 (d, J = 9 Hz, 2H), 7.71 (s, 1H), 7.24 (m, 3H), 7.07 (d, J = 9 Hz, 2H), 6.47 (d, J = 3 Hz, 1H) ), 4.63 (s, 2H), 3.25 (m, 4H), 2.89 (m, 4H).Reaction scheme 6 Reaction scheme 6(Continued) N- (3-bromophenyl) -4- (4- (1,1-dimethylethoxycarbonyl) Ru) piperazin-1-yl) benzamide (6-2)   acid1-5(400 mg; 1.31 mmol), amine6-1(248 mg; 1 . 44 mmol), BOP reagent (867 mg; 1.97 mmol), NMM (5 Solution consisting of 75 μl; 5.24 mmol) and DMF (10 ml) for 72 hours Heated to 60 ° C. The solution was diluted with EtOAc and then diluted with H_TwoO, NaHCO_ThreeTired of Japanese solution, 10% KHSO_Four, Washed with brine, dried (MgSO 4)_Four), Concentrate Was. Flash chromatography (silica; 25% EtOAc / hexane) By amide6-2Was obtained as a yellow solid. TLCR_f= 0.31 (silica; 25% EtOAc / hexane)¹ H NMR (CD_ThreeOD) δ: 7.99 (s, 1H), 7.84 (d, J = 9H) z, 2H), 7.60 (m, 1H), 7.25 (m, 2H), 7.02 (d, J = 9 Hz, 2H), 3.57 (m, 4H), 3.31 (m, 4H), 1.47 ( s, 9H). (E) -methyl (3- (3- (4- (4- (1,1-dimethylethoxycarbonyl) Ru) piperazin-1-yl)) phenyl) carbonylaminophenyl) prop- 3-enoate (6-3)   Amide6-2(400 mg; 0.86 mmol), methyl acrylate (783 μl; 8.69 mmol), O (tri Le)_ThreeP (159 mg; 0.415 mmol), NEt_Three(245 μl; 1.74 mmol), Pd (OAc)_Two(20 mg; 0.069 mmol) and CH_ThreeCN (5 ml) was heated to 100 ° C. in a sealed tube for 18 hours. Etch the solution Diluted with OAc and then H_TwoO, NaHCO_ThreeSaturated solution of 10% KHSO_Four, Wash with brine, dehydrate (MgSO 4)_Four) And concentrated. Flash chromatography Olefin by fee (silica; 20% → 30% EtOAc / hexane)6-3 Was obtained as a yellow solid. TLCR_f= 0.47 (silica; 50% EtOAc / hexane)¹ H NMR (CD_ThreeOD) δ: 7.94 (s, 1H), 7.87 (dd, J = 2 Hz, 9 Hz, 2H), 7.71 (m, 2H), 7.36 (m, 2H), 7.0 3 (dd, J = 2 Hz, 9 Hz, 2H), 6.52 (d, J = 16 Hz, 1H) 3.78 (s, 3H), 3.57 (m, 4H), 3.29 (m, 4H), 1. 47 (s, 9H). Methyl (3- (3- (4- (4- (1,1-dimethylethoxycarbonyl) pipe) Razin-1-yl)) phenyl) carbonylaminophenyl) propanoate ( 6-4)   ester6-3(300 mg; 0.64 mmol) and 10% Pd / C (1 00 mg) and EtOH (10 ml) at 1 atm H_Two18 hours down Stirred. The reaction mixture was filtered through a pad of celite and concentrated to give the ester6- 4 Was obtained as a yellow oil.¹ H NMR (CDCl_Three) Δ: 7.80 (m, 3H), 7.54 (s, 1H), 7.47 (d, J = 8 Hz, 1H), 7.27 (m, 1H), 6.96 (d, J = 8 Hz, 1H), 6.92 (d, J = 9 Hz, 2H), 3.68 (s, 3H) 3.60 (m, 4H), 3.29 (m, 4H), 2.96 (t, J = 8 Hz, 2H), 2.66 (t, J = 8 Hz, 2H), 1.50 (s, 9H). 3- (3- (4- (4- (1,1-dimethylethoxycarbonyl) piperazine- 1-yl)) phenyl) carbonylamino Phenyl) propanoic acid (6-5)   ester6-4(260 mg; 0.5563 mmol), 1N NaOH (1 ml; 1 mmol) and EtOH (3 ml) at ambient temperature for 1.0 h. While stirring. The solution was made 10% KHSO_FourAnd then extracted with EtOAc Was. The EtOAc phase was washed with brine, dried (MgSO 4)_Four) And concentrate, acid6-5Was obtained as a white solid. TLCR_f= 0.08 (silica; 10: 0.2: 0.2 CH_TwoCl_Two/ MeO               H / AcOH)¹ H NMR (CD_ThreeOD) δ: 7.84 (d, J = 9 Hz, 2H), 7.51 ( m, 2H), 7.25 (t, J = 8 Hz, 1H), 7.03 (m, 3H), 3. 57 (m, 4H), 3.29 (m, 4H), 2.91 (t, J = 8 Hz, 2H) , 2.60 (t, J = 8 Hz, 2H), 1.47 (s, 9H). 3- (3- (4-piperazin-1-ylphenyl) carbonylamino) phenyl ) Propanic acid (6-6)   acid6-5(210 mg; 0.4633 mmol), TFA (3 ml) and CH_Two Cl_Two(3 ml) was stirred at ambient temperature for 1.0 hour. Concentrate the solution And then azeotroped with toluene. Flash chromatography (silica; 10: 0.1: 0.1 → 10: 0.5: 0.5 EtOH / NH_FourOH / H_TwoO) Acid6-6Was obtained as a tan solid. TLCR_f= 0.59 (silica; 10: 1: 1 EtOH / NH_FourOH / H_Two               O)¹ H NMR (D_TwoO) δ: 7.82 (d, J = 9 Hz, 2H), 7.38 (m, 2H), 7.34 (s, 1H), 7.15 (d, J = 9 Hz, 3H), 3.25 (M, 4H), 2.96 (m, 4H), 2.90 (t, J = 8 Hz, 2H), 2 . 50 (t, J = 8 Hz, 2H).Reaction scheme 7 Ethyl 2- [4- (4- (4- (1,1-dimethylethoxycarbonyl) pipera) Zin-1-yl) phenylcarbonylamino) phenoxypropanoate (7- 2)   Phenol in 5 ml DMF2-3(381 mg; 0.993 mmol), Ethyl 2-bromopropionate (7-1129 μl; 0.99 mmol) and Cs_TwoCO_Three(807 mg; 2.5 mmol). After stirring overnight, mix the reaction The material was diluted with EtOAc and water (3 ×), 10% KHSO_Four(3x) and brie And then dehydrated (MgSO 4)_Four), Filtered and concentrated. Flash chromatog By raffy (silica; 40% EtOAc / hexane)7-2The white solid Obtained as body. TLCR_f= 0.41 (silica; 50% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 7.78 (d, J = 9 Hz, 2 H), 7.60 (s, 1H), 7.52 (d, J = 9 Hz, 2H), 6.92 ( d, J = 9 Hz, 2H), 6.89 (d, J = 9 Hz, 2H), 4.72 (q, J = 7Hz, 1H), 4.22 (q, J = 7Hz, 2H), 3.59 (m, 4H), 3.28 (m, 4H), 1.61 (d, J = 7 Hz, 3H), 1.49 (s, 9 H), 1.26 (t, J = 7 Hz, 3H). Ethyl 2- (4- (4- (piperazin-1-yl) phenylcarbonylamino) Phenoxy) propanoate (7-3) 7-2(266 mg; 0.3 mmol) and anisole (200 μl; 1.8) mmol) in 1: 1 CH_TwoCl_TwoStir for 20 minutes in 5 ml of TFA / TFA did. After concentration and azeotrope with toluene, flash chromatography (silica; 33: 1: 1 EtOH / H_TwoO / NH_FourOH)7-3Is a white solid I got it. TLCR_f= 0.37 (silica; 20: 1: 1 EtOH / H_TwoO / NH_FourO               H)¹ 1 H NMR (400 MHz; CD_ThreeOD) δ: 7.84 (d, J = 9 Hz, 2H ), 7.54 (d, J = 9 Hz, 2H), 7.01 (d, J = 9 Hz, 2H), 6.88 (d, J = 9 Hz, 2H); 4.21 (q, J = 7 Hz, 2H); 31 (m, 4H), 2.98 (m, 4H), 1.57 (d, J = 7 Hz, 3H) , 1.26 (t, J = Hz, 3H). 2- (4- (4- (piperazin-1-yl) phenylcarbonylamino) pheno Xy) propionic acid (7-4)   ester7-3(44 mg; 0.11 mmol) dissolved in 1 ml of EtOH And 1M NaOH (122 μl; 0.12 mmol) was added. 3 o'clock After a while, the reaction mixture is neutralized with 1N HCl, concentrated, and then flash chromatographed. Raffy (silica; 50: 1: 1 EtOH / H_TwoO / NH_FourOH) hand,7-4Was obtained as a white solid. TLCR_f= 0.15 (silica; 50: 1: 1 EtOH / H_TwoO / NH_FourO               H)¹ 1 H NMR (400 MHz; D_TwoO) δ: 7.69 (d, J = 9 Hz, 2H), 5.22 (d, J = 9 Hz, 2H), 7.01 (d, J = 9 Hz, 2H), 80 (d, J = 9 Hz, 2H), 4.48 (q, J = 7 Hz, 1H), 3.10 (M, 4H), 2.82 (m, 4H), 1.40 (d, J = 7 Hz, 3H).Reaction scheme 8 Ethyl 6- [4- (1,1-dimethylethoxycarbonyl) piperazine-1-i Le] nicotinate (8-2)   Ethyl 6-chloronicotinate (54 ml NMP)8-1Maybrid; ge Chemical Co. 2.0 g; 10.8 mmol) and piperazi (1.4 g; 15 mmol) was heated and heated at 50 ° C. overnight. After cooling , Boc_TwoO (2.6 g; 11.9 mmol) was added. The reaction mixture is stirred overnight. Stir, then dilute with EtOAc, water, NaHCO_ThreeWith saturated solution and brine Wash and dehydrate (MgSO 4_Four), Filtered and concentrated. Flash chromatograph By silica (silica; 25% EtOAc / hexane)8-2The white solid and I got it. TLCR_f= 0.63 (silica; 40% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 8.80 (d, J = 2 Hz, 1H ), 8.04 (dd, J = 9 Hz, 2 Hz, 1 H), 6.58 (d, J = 9 Hz) , 1H), 4.34 (q, J = 7 Hz, 2H), 3.68 (m, 4H), 3.5 4 (M, 4H), 1.49 (s, 9H), 1.37 (t, J = 7 Hz, 3H). 6- [4- (1,1-dimethylethoxycarbonyl) piperazin-1-yl] ni Cotinic acid (8-3)   ester8-2(3.0 g; 9.3 mmol) dissolved in 93 ml of EtOH. And 1M NaOH (23 ml; 23 mmol) was added thereto, and the resulting reaction was performed. The mixture was stirred overnight. After concentration, the residue was dissolved in water, washed with EtOAc, Aqueous layer 10% KHSO_FourAnd acidified. After extraction with EtOAc, the organic layer is And then dried (MgSO 4)_Four), Filter and concentrate,8-3The white Obtained as a solid.¹ 1 H NMR (400 MHz; CD_ThreeOD) δ: 8.71 (d, J = 2 Hz, 1H ), 8.08 (dd, J = 9 Hz, 2 Hz, 1H), 6.77 (d, J = 9 Hz) , 1H), 3.61 (m, 4H), 3.53 (m, 4H), 1.49 (s, 9H). ). N- (4-hydroxyphenyl) -6- (4- (1,1-dimethylethoxycal (Bonyl) piperazin-1-yl) nicotinamide (8-4)   Acid in 8 ml DMF8-3(500 mg; 1.6 mmol), NMM (72 0 μl; 6.5 mmol) and BOP reagent (793 mg; 1.8 mmol). I combined. After 1.5 hours, 4-aminophenol (260 mg; 1.8 mmol) Was added and the reaction mixture was heated to 60 ° C. overnight. Dilute the reaction mixture with EtOAc And water (5 ×), NaHCO_ThreeWashed with saturated solution and brine, dried (Mg SO_Four), Filtered and concentrated. Flash chromatography (silica; 50% → 60% EtOAc / hexane)8-4Was obtained as a brown solid. TLCR_f= 0.40 (silica; 70% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 8.66 (d, J = 2 Hz, 1H ), 7.98-7.95 (m, 2H), 7.33 (d, J = 9 Hz, 2H), 6 . 75 (d, J = 9 Hz, 2H), 6.58 (d, J = 9 Hz, 1H), 3.61 (M, 4H), 3.52 (m, 4H), 1.48 (m, 9H). t-butyl 2-((4- (2- (4- (1,1-dimethylethoxycarbonyl)) Piperazin-1-yl) pyridin-5-yl) carbonylamino) phenoxy) Acetate (8-5)   Phenol in 5 ml DMF8-4(374 mg; 0.94 mmol), T-butyl lomoacetate (151 μl; 0.94 mmol) and Cs_TwoCO_Three(761 mg; 2.3 mmol). After 90 minutes, dilute the reaction mixture with EtOAc And washed with water (4 ×) and brine, dried (MgSO 4)_Two), Filter and concentrate Was. Flash chromatography (silica; 50% EtOAc / hexane) By8-5Was obtained as a brown solid. TLCR_f= 0.53 (silica; 70% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 8.66 (d, J = 2 Hz, 1H ), 7.99 (dd, J = 9 Hz, 2 Hz, 1H), 7.56 (s, 1H), 7 . 52 (d, J = 8 Hz, 2H), 6.90 (d, J = 8 Hz, 2H), 6.65 (D, J = 9 Hz, 1H), 4.51 (s, 2H), 3.68 (m, 4H), 3 . 56 (m, 4H), 1.49 (s, 18H). 2- (4-(((2-piperazin-1-yl) pyridin-5-yl) carbonyl Amino) phenoxy) acetic acid (8-6)   ester8-5(290 mg; 0.57 mmol) in 1: 1 TFA / CH_Two Cl_Two  Dissolved in 5 ml. After 1 hour, the reaction mixture is concentrated and azeotroped with toluene. did. Flash chromatography (silica; 10: 1: 1 EtOH / H_Two O / NH_FourOH) and Et_TwoBy grinding with O,8-6As a light brown solid Was.¹ 1 H NMR (400 MHz; D_TwoO) δ: 8.42 (d, J = 2 Hz, 1H), 7.89 (dd, J = 9 Hz, 2 Hz, 1 H), 7.04 (d, J = 8 Hz, 2 H), 6.78 (d, J = 9 Hz, 2H), 6.76 (d, J = 10 Hz, 1H) ), 4.32 (s, 2H), 3.37 (m, 4H), 2.74 (m, 4H).Reaction scheme 9 Reaction scheme 9(Continued) Reaction scheme 9(Continued) Reaction scheme 9(Continued) Reaction scheme 9(Continued) Ethyl 2- (4-bromo-1-hydrazinimine) propanoate (9-1)   4-bromophenylhydrazine (Aldrich; 0.5 g; 2.2 mmol ) And ethyl acetoacetate (Aldrich; 0.24 ml; 2.2 mmol) The mixture added to pyridine (0.6 ml) was heated to reflux overnight. Cool the reaction mixture Discard, dilute with water, collect the resulting precipitate, wash with water and dry under vacuum9- 1 I got R_f= 0.86 (10% MeOH / NH_ThreeSaturated CHCl_Three)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 7.64 (s, 1H), 7.41 (D, 2H), 7.39 (d, 2H), 4.30 to 4.34 (q, 2H), 2. 10 (s, 3H), 1.36 (t, 3H). 5-bromo-2-ethoxycarbonylindole (9-2) 9-1(0.54 g; 1.9 mmol) and polyphosphoric acid (1.6 ml) The material was heated to 115 ° C. for 10 minutes, then diluted with cold water and extracted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. Combine the organic layers and combine with brine And washed with MgSO_Four, Filtered and concentrated,9-2The brown solid and I got it. R_f= 0.45 (30% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 8.95 (bs, 1H), 7.8 2 (s, 1H), 7.41 (d, 1H), 7.30 (d, 1H), 7.15 (s , 1H), 4.44 (q, 2H), 1.40 (t, 3H). 1- (cyanomethyl) -2-ethoxycarbonyl-5-bromo-indole (9 -3) 9-2(11.2 g; 44.4 mmol) in DMF (40 0 h) was dissolved in NaH (60% dispersion in oil; 3.2 g) for 0.5 h. 66.6 mmol), to which chloroacetonitrile (Aldrich; 5.6 ml; 88.8 mmol) was added and the resulting reaction mixture was stirred overnight. . The solvent was removed under vacuum and the residue was partitioned between water and EtOAc. Etch aqueous layer Extract with OAc, combine the organic layers and wash with water, brine and MgSO_Fourso Dehydrate, filter and evaporate,9-3Was obtained as a brown solid. R_f= 0.46 (30% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 7.82 to 7.83 (bs, 1H ), 7.51-7.54 (dd, 1H), 7.30-7.32 (bd, 2H), 5.60 (s, 2H), 4.41 to 4.43 (q, 2H), 1.41 to 1.43 (T, 3H). 8-bromo-2,3,4,5-tetrahydropyrazino- [12-a] indole (9-4) 9-3(12.2 g; 39.7 mmol) in diethyl ether The slurry obtained by adding the slurry to the ether (400 ml) was added to an LAH ether solution (ether ether). 1M; 79.4 ml; 79.4 mmol) in a dropping funnel. It was stirred overnight at room temperature. Slurry sodium potassium tartrate (Rochelle salt) And stirred for 15 minutes, then into a separatory funnel containing EtOAc. Transfer and separate layers. Extract the aqueous layer with EtOAc, combine the organic layers and add water , Washed with brine and MgSO_Four, Filtered and evaporated,9-4To Obtained as a brown solid. R_f= 0.42 (10% MeOH / NH_ThreeSaturated CHCl_Three)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 8.38 to 8.41 (bs, 1H) ), 7.66 (s, 1H), 7.21 to 7.22 (dd, 2H), 7.14 (d , 2H), 6.14 (s, 1H), 4.22 (s, 2H), 3.99 (t, 2H) ), 3.36-3.37 (t, 2H). 8-bromo-3- (1,1-dimethylethoxycarbonyl) -2,3,4,5- Tetrahydropyrazino- [1,2-a] yne Doll (9-5) 9-4(10 g; 40 mmol) in CH_TwoCl_Two(200ml) The solution was cooled to 0 ° C. and di-t-butyl dicarbonate (8.7 g; 40 mmol) and tri Treated with ethylamine (5.6 ml; 40 mmol). Warm the solution slowly , Concentrated after 48 hours, the residue was dissolved in EtOAc, washed with water and brine And Na_TwoSO_Four, Filtered and evaporated. The residue is chromatographed ( 30% EtOAc / hexane)9-5Was obtained as a solid. R_f= 0.22 (30% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 7.67 (d, 1H), 7.23. (D, 1H), 7.13 (d, 1H), 6.21 (s, 1H), 4.80 (s, 1H) 2H), 4.04 (t, 2H), 3.93 (t, 2H), 1.50 (s, 9H) . 8-methoxycarbonyl-3- (1,1-dimethylethoxycarbonyl) -2, 3,4,5-tetrahydropyrazino- [1. 2-a] Indole (9-6) 9-5(3.0 g; 8.5 mmol) in MeOH (60 ml) and DMSO ( 20 ml) was dissolved in triethylamine (3.55 ml; 25.5 mm). ol), 1,3-bis (diphenylphosphino) propane (1.75 g; 4.2) 5 mmol) and palladium (II) acetate (0.952 g; 4.25 mmol) Processed. Carbon monoxide was bubbled through the solution while heating the solution to reflux for 2 hours. Anti The reaction mixture was placed under balloon atmosphere (carbon monoxide). At reflux temperature overnight. Additional 1,3-bis (diphenylphosphino) pro Bread (0.8 g; 2.12 mmol) and palladium acetate (0.476 g; 2. 12 mmol) and the reaction mixture is heated at reflux temperature under balloon pressure of carbon monoxide for 4 hours. Heated for 8 hours. Cool the reaction mixture to room temperature and partition the residue between water and EtOAc did. Extract the aqueous layer with EtOAc, combine the organic layers and wash with water, brine Purified, MgSO^Four, Filtered and evaporated. Chromatography of the residue (25% EtOAc / hexane)9-6Was obtained as a yellow solid. R_f= 0.21 (30% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 8.32 (s, 1H), 7.90 (D, 1H), 7.26 (d, 1H), 6.38 (s, 1H), 4.83 (s, 1H) 2H), 4.12 (t, 2H), 3.96-3.93 (m, 5H), 1.50 ( s, 9H). 3- (1,1-dimethylethoxycarbonyl) -2,3,4,5-tetrahydro Pyrazino- [1,2-a] indole-8-carboxylic acid (9-7) 9-6(150 mg; 0454 mmol) in THF / H_TwoIn addition to O / MeOH Treating the resulting slurry with LiOH (38.2 mg; 0.91 mmol), Stir for 1 hour. No reaction occurred by TLC. LiOH (38.2m g) was added and the reaction mixture (still a slurry) was stirred for an additional hour, No beam reaction occurred. The reaction mixture was concentrated to dryness, MeOH and H_TwoSoluble in O Let it go. LiOH (114 mg) was added and the resulting reaction mixture was stirred, Time to 75 ° C Upon heating and stirring at RT for 16 hours, a complete reaction was achieved. Reaction mixing The material was diluted with EtOAc and 10% citric acid. Separate the layers and separate the organic layer with water and Washed in line, dehydrated, filtered and concentrated,9-7As a white solid Was.¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 8.40 (s, 1H), 7.95 (D, 1H), 7.32 (d, 1H), 6.41 (s, 1H), 4.84 (s, 2H), 4.14 to 4.11 (m, 2H), 3.96 (m, 2H), 1.50 ( s, 9H). Ethyl 4-((3- (1,1-dimethylethoxycarbonyl) -2,3,4,5 -Tetrahydropyrazino- [1,2-a] indol-8-yl) carbonylamido G) -3-Methylphenoxyacetate (9-8) 9-7(110 mg; 0.35 mmol) and10-4(85.7 mg; 35 mmol) in CH_TwoCl_TwoDissolved in The solution was diluted with diisopropylethylamine and PYCLU,23-5About Work up as described and chromatograph eluting with 50% EtOAc / hexane. After the fee9-8Was obtained as a white solid. R_f= 0.34 (50% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 8.12 (s, 1H), 7.8 to 7.65 (m, 2H), 7.59 (s, 1H), 7.36 (d, 1H), 6.8 4 (m, 2H), 6.39 (s, 1H), 4.85 (s, 2H), 4.62 (s , 2H), 4.29-4.27 (q, 2H), 4.15-4.13 (t, 2H). , 3.96 (t, 2H), 2.33 (s, 3H), 1.50 (s, 9H), 1. 33-1.31 (t, 3H). 4-((2,3,4,5-tetrahydropyrazino- [1,2-a] indole-8 -Yl) carbonylamino) -3-methylphenoxyacetic acid (9-9) 9-8(75 mg; 0.15 mmol) and THF / H_Two A slurry consisting of O / MeOH was treated with LiOH (13 mg; 0.30 mmol). And stirred for 1 hour. The reaction mixture was diluted with EtOAc and 10% citric acid . Separate the layers and separate the organic layer from H_TwoWashed with O and brine. Dehydrate and filter the organic layer And concentrated to give the desired acid as a white solid. This solid in EtOAc Add slurry and cool to -78 ° C, which is saturated with HCl. Reaction mixing Warm the product to 0 ° C. and stir for 15 minutes. The reaction mixture was concentrated to give a white solid, This solid was taken up in an EtOAc / hexane / ether mixture and filtered. Solid Wash with ether,9-9Was obtained as a white solid. R_f= 0.16 (10: 1: 1 EtOH / NH_FourOH / H_TwoO)¹ 1 H NMR (400 MHz; D_TwoO) δ: 8.09 (s, 1H), 7.62 to 7 . 60 (d, 1H), 7.45 (d, 1H), 7.14 to 7.12 (d, 1H) , 6.84 (d, 1H), 6.79-6.76 (dd, 1H), 6.35 (s, 1H), 4.40 (s, 2H), 4.07 to 4.02 (m, 4H), 3.23 to 3.22 (t, 2H), 2.15 (s, 3H). (±) 8-methoxycarbonyl-3- (1,1-dimethylethoxycarbonyl) -1,1a, 2,3,4,5-hexahydropyrazino- [1,2-a] indole (9-10) 9-6(30 mg; 0.091 mmol) dissolved in EtOAc and cooled to 0 ° C Rejected. NaBH_ThreeCN (28 mg; 0.45 mmol) was gradually added, and the reaction was continued. The mixture was warmed to room temperature for 15 minutes. The reaction mixture was washed with NaHCO_ThreeBase in a saturated solution of And extracted into EtOAc. The organic layer is washed with brine, dried (MgS O_Four), Filter and concentrate,9-10Was obtained as a colorless oil. R_f= 0.4 (2: 1 hexane / EtOAc)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 7.83 to 7.82 (d, 1H) , 7.73 (s, 1H), 6.40-6.38 (d, 1H), 4.15-4.0. (Bs, 2H), 3.85 (s, 3H), 3.60 to 3.56 (m, 2H), 3 . 05 to 2.65 (m, 4H), 2.60 to 2.58 (dd, 1H), 1.50 (S, 9H). (±) 3- (1,1-dimethylethoxycarbonyl) -1,1a, 2,3,4 5-hexahydropyrazino- [1,2-a] indole-8-carboxylic acid (9- 11) 9-10(300 mg; 0.90 mmol) in THF / H_TwoO / MeOH (2 (ml / 2ml / 2ml). LiOH (76 mg; 1.8 mmol) was added and the reaction mixture was heated to 50 ° C. 0.5 hours later, reaction mixture The mixture became homogeneous and the mixture was stirred at room temperature for another 2 hours. 10% reaction mixture Diluted with citric acid and EtOAc. Separate the layers and separate the organic layer from H_TwoO and brine And washed. Dehydrate (MgSO 4_Four), Filter and concentrate,9-11The yellow Obtained as a solid. R_f= 0.70 (97: 3: 1 CHCl_Three/ MeOH / HOAc)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 7.90 (d, 1H), 7.87 (S, 1H), 6.41 to 6.39 (d, 1H), 4.25 to 4.0 (bs, 2 H) 3.65-3.57 (m, 2H), 3.10-3.0 (dd, 1H), 3 . 02 to 2.98 (d, 1H), 2.98 to 2.91 (bs, 1H), 2.69 ~ 2.66 (bs, 1H), 2.62 to 2.60 (dd, 1H), 1.50 (s , 9H). (±) ethyl 4-((3- (1,1-dimethylethoxycarbonyl) -1,1a , 2,3,4,5-Hexahydropyrazino- [1,2-a] indol-8-yl ) Carbonylamino) -3-methylphenoxyacetate (9-12) 9-11(250 mg; 0.79 mmol) and10-4(193 mg; 79 mmol) CH_TwoCl_TwoSolution dissolved in diisopropylethylamine and And PYCLU,23-5Processed as described for 50% EtOAc / Chromatography after elution with hexane9-12Was obtained as a white solid . R_f= 0.35 (50% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 7.70 to 7.63 (m, 3H) , 7.36 (s, 1H), 6.82-6.76 (m, 2H), 6.45-6.4. 3 (d, 1H), 4.60 (s, 2H), 4.30 to 4.25 (q, 2H), 4 . 21 to 4.09 (bs, 2H), 3.59 to 3.57 (m, 2H), 3.10 -3.09 (m, 1H), 3.05-2.51 (m, 3H), 2.78-2.6 0 (m, 1H), 2.29 (s, 3H), 1.50 (s, 9H), 1.32 to 1.29 ( t, 3H). (±) 4-((3- (1,1-dimethylethoxycarbonyl) -1,1a, 2, 3,4,5-hexahydropyrazino- [1,2-a] indol-8-yl) cal Bonylamino) -3-methylphenoxyacetic acid (9-13) 9-12(125 mg; 0.25 mmol) and THF / H_TwoO / MeOH or The resulting slurry was treated with LiOH (21 mg; 0.50 mmol), Heated to 80 ° C. for hours. The reaction mixture was diluted with EtOAc and 10% citric acid . Separate the layers and separate the organic layer from H_TwoWashed with O and brine. Dehydrate and filter the organic layer And concentrated to give the desired acid as a white solid. This solid in EtOAc The slurry was added and cooled to −78 ° C., which was saturated with HCl. Reaction mixing Warm things to 0 ° C And stirred for 15 minutes. Concentrate the reaction mixture and remove the remaining white solid with ether. Crush,9-13Was obtained as a white solid. R_f= 0.3 (10: 1: 1 EtOH / NH_FourOH / H_TwoO)¹ 1 H NMR (400 MHz; D_TwoO) δ: 7.70 to 7.67 (d, 1H), 7 . 63 (s, 1H), 7.11 to 7.09 (d, 1H), 6.86 (d, 1H) , 6.78-6.76 (dd, 1H), 6.69-6.68 (d, 1H), 4. 57 (s, 2H), 3.93 to 3.90 (bd, 2H), 3.39 to 3.31 ( m, 3H), 3.19 to 3.07 (m, 3H), 2.74 to 2.68 (dd, 1 H).Reaction scheme 10 Reaction scheme 10(Continued) 4- (1,1-dimethylethoxycarbonyl) amino-3-methylphenol ( 10-2)   A 4 L round bottom flask equipped with a stir bar, reflux condenser and argon inlet -Amino-3-methylphenol (15.00 g; 121.79 mmol), Di-tert-butyl carbonate (27.25 g; 124.84 mmol) and CHCl_Three( 300 ml). The resulting heterogeneous mixture is heated at reflux temperature. Upon heating for 24 hours, all solids dissolved during that time. Cool the mixture to room temperature The solid product was collected by filtration. Et this substance_TwoO and hexane 1: 1 mixture, collected on frit and dried under vacuum to 21.25 g (9 2%) of 4- (1,1-dimethylethoxycarbonyl) amino-3-methylphen Knoll (10-2) (Mp: 143-144 ° C).¹ H NMR (CDCl_Three) Δ: 1.51 (s, 9H), 2.14 (s, 3H), 6.08 (br s, 1H), 6.48 (m, 2H), 6.60 (br s, 1H) H), 7.20 (d, J = 8.5 Hz, 1H).Ethyl 4- (1,1-dimethylethoxycarbonyl) amino-3-methylpheno Kisia acetate (10-3)   In a 200 ml round bottom flask equipped with a stirring rod and an argon inlet, 4- (1 , 1-Dimethylethoxycarbonyl) amino-3-methylphenol (5.00 g; 22.39 mmol), Cs_TwoC0_Three(14.59 g; 44.78 mmol) , DMF (50 ml) and ethyl bromoacetate (2.61 ml; 23.51 mmol) l) was added. The resulting mixture at ambient temperature Stir vigorously for 24 hours. Filter the mixture through a frit and remove DMF under high vacuum did. The residue was dissolved in EtOAc (300 ml) and H_TwoO (2x) and bra Washed in (1 ×). Dehydrate (MgSO 4_Four), Filter and remove the solvent under vacuum Removal gave a solid. 5% Et_TwoGrind with O / hexane and filter the solid Collected by filtration and dried in vacuo, 5.40 g (78%) of ethyl 4- (1 , 1-Dimethylethoxycarbonyl) amino-3-methylphenoxyacetate Was obtained as a white crystalline solid.¹ H NMR (CDCl_Three) Δ: 1.29 (t, J = 7.2 Hz, 3H), 1.5 1 (s, 9H), 2.22 (s, 3H), 4.26 (q, J = 7.2 Hz, 2H ), 4.57 (s, 2H), 6.08 (br s, 1H), 6.72 (m, 2H) ), 7.56 (s, 1H).Ethyl 4-amino-3-methylphenoxyacetate, hydrochloride (10-4)   In a 500 ml round bottom flask equipped with a gas dispersion tube, ethyl 4- (1,1- Dimethylethoxycarbonyl) amino-3-methylphenoxyacetate (5. 31g; 17.13mm ol) in EtOAc (200 ml). Solution in ice bath Upon cooling, dry HCl gas was vigorously dispersed in the solution for 10 minutes. The resulting blend The mixture was aged at 0 ° C. for 15 minutes. Excess HCl gas is removed with a stream of argon and dissolved. The medium was removed under vacuum. The product is triturated with 50 ml of EtOAc and placed on a frit Collected. The crystals were washed with additional EtOAc and dried in vacuo to give 4.21 g ( 100%) ethyl 4-amino-3-methylphenoxyacetate, hydrochloride Obtained as color crystals (mp: 198-200 ° C.).¹ 1 H NMR (DMSO-d₆) Δ: 1.21 (t, J = 7.1 Hz, 3H), 2 . 33 (s, 3H), 4.17 (q, J = 7.1 Hz, 2H), 4.78 (s, 3H) 2H), 6.82 (dd, J = 3 Hz, 9 Hz, 1H), 6.92 (d, J = 3 Hz, 1H), 7.39 (d, J = 9 Hz, 1H), 10.21 (brs, 3 H).Ethyl 2- (4- (4- (4- (1,1-dimethylethoxycarbonyl) pipera) Zin-1-yl) phenylcarbonylamino) -3-methylphenoxy) acete (10-5)   In a 100 ml round bottom flask equipped with a stirring rod and an argon inlet, 4- (4 -(1,1-dimethylethoxycarbonyl) Piperazinyl) benzoic acid (0.75 g; 2.45 mmol), ethyl 4-amino -3-Methylphenoxyacetate, hydrochloride (0.60 g; 2.45 mmol) Chloro-N, N, N ', N'-bis (pentamethylene) formamidinium Xafluorophosphate (0.97 g; 2.69 mmol) and CH_TwoCl_Two( 30 ml). The resulting mixture was cooled in an ice bath and diisopropylethyl The amine (1.74 ml; 10.0 mmol) was added. The ice bath melted and disappeared Afterwards, the solution was stirred at ambient temperature for 48 hours. CHCl solution_ThreeDiluted with citric acid 10% aqueous solution of NaHCO_ThreeWith saturated aqueous solution and brine. Dehydrate ( MgSO_Four), Filtered, and the solvent was removed in vacuo to give an oil. This substance On 75 g silica gel using 50% EtOAc / hexane as eluent And chromatographed. 1.22 g (100%) of ethyl 2- (4- ( 4- (4- (1,1-dimethylethoxycarbonyl) piperazin-1-yl) phenyl Phenylcarbonylamino) -3-methylphenoxy) acetate is a crystalline solid Was obtained.¹ H NMR (CDCl_Three) δ: 1.30 (t, J = 7.1 Hz, 3H), 1.49 (s, 9H), 2.27 (s, 3H), 3.27 (m, 4H), 3.59 (m, 4H), 4.26 (q, J = 7.1 Hz, 2H), 4.59 (s, 2H), 6.75 ( m, 2H), 6.90 (d, J = 8.8 Hz, 2H), 7.54 (brs, 1H) , 7.65 (m, 1H), 7.79 (d, J = 8.8 Hz, 2H).2- (4- (4- (4- (1,1-dimethylethoxycarbonyl) piperazine- 1-yl) phenylcarbonylamino) -3-methylphenoxy) acetic acid (10- 6)   Ethyl 2 was added to a 100 ml round bottom flask equipped with a stir bar and an argon inlet. -(4- (4- (4- (1,1-dimethylethoxycarbonyl) piperazine-1 -Yl) phenylcarbonylamino) -3-methylphenoxy) acetate (1 . 22g; 2.45mmol) and 20ml CH_ThreeOH was added. The resulting solution To the solution was added an aqueous solution of NaOH (1N solution; 10 ml). Mix at ambient temperature Stir for 18 hours. The mixture was neutralized with 10 ml of 1N HCl and H_TwoDiluted with O Was. The product is collected on a frit and a small amount of H_TwoWashed with O. Vacuum dry this material Dry and dry 0.953 g (83%) of 2- (4- (4- (4- (1,1-dimethyl). Ethoxycarbonyl) piperazin-1-yl) phenylcarbonylamino) -3 -Methylphenoxy) acetic acid was obtained as a white solid.¹ H NMR (CDCl_Three) δ: 1.49 (s, 9H), 2.26 (s, 3H), 3.2 7 (m, 4H), 3.58 (m, 4H), 4.57 (s, 2H), 6.74 (m, 2H) , 6.90 (d, J = 8.5 Hz, 2H), 7.60 (m, 1H), 7.65 (m, 1H), 7.79 (d, J = 8.5 Hz, 2H).2- (4- (4- (1-piperazinyl) phenylcarbonylamino) -3-methyl Rufenoxy) acetic acid dihydrochloride (10-7)   In a 200 ml round bottom flask equipped with a stirring rod and a gas dispersion tube, 2- (4- ( 4- (4- (1,1-dimethylethoxycarbonyl) piperazin-1-yl) phenyl Enylcarbonylamino) -3-methylphenoxy) acetic acid (0.95 g; 2.0 3 mmol) and 100 ml of dry EtOAc. Enough of the resulting suspension Stir and cool in an ice bath and disperse HCl gas in this suspension for 15 minutes. This The mixture was aged at 0 ° C. for 30 minutes, after which excess HCl was removed with a stream of argon. , EtOAc was removed under vacuum. Triturate the product with EtOAc and place on a frit Collect and dry under vacuum 895 mg of 2- (4- (4- (1-piperazinyl) (Phenylcarbonylamino) -3-methylphenoxy) acetic acid, dihydrochloride was obtained ( mp:> 250 ° C).¹ 1 H NMR (DMSO-d₆) δ: 2.16 (s, 3H), 3.20 (m, 4H), 3 . 54 (m, 4H), 4.66 (s, 2H), 6.72 (d, J = 3 Hz, 1H), 6 . 75 (s, 1H), 7.06 (d, J = 9.0 Hz, 2H), 7.15 (d, J = 3.0 Hz, 1H), 7.90 (d, J = 9.0 Hz, 2H), 9.43 (br s , 1H), 9.56 (s, 1H).Reaction Scheme 11 Reaction Scheme 11(Continued) Reaction Scheme 11(Continued) Reaction Scheme 11(Continued) Methyl 4-bromo-2-hydroxybenzoate (11-2)   200 ml of MeOH was cooled to 0 ° C. and thionyl chloride (30 ml; 0.4 mo 1), wherein the thionyl chloride is maintained at a reaction temperature below 15 ° C. throughout the addition It was added dropwise as possible. In the reaction mixture,11-1(R. Glannon et al., J. Med. Chem. 35, p. 732, 1992; 12.7 g ; 0.0585 mol) in 50 ml of MeOH. The resulting mixture was warmed to room temperature and stirred for 48 hours, then heated to 60 ° C. for 7 hours. Volatile components are removed under high vacuum and the residue is chromatographed (silica; pure Gradient elution from xane to 10% EtOAc / hexane)11-2To Obtained as a pale yellow oil which solidified on standing. R_f= 0.6 (5% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 10.8 (s, 1H), 7.6 8 (d, 1H), 7.19 (s, 1H), 7.03 (d, 1H), 3.95 (s, 3H) . Methyl 4-bromo-2- (ethylaceto-2-yloxy) -benzoate (1 1-3) 11-2(26.6 g; 0.115 mol) dissolved in acetone (80 ml) Chloroethyl acetate (14 g; 0.115 mol), potassium iodide (3 g; 0.018 mol) and potassium carbonate (31.7 g; 0.23 mol) 1), which was heated to 50 ° C. with vigorous stirring for 2 hours. Obtained suspension The suspension was filtered, evaporated to dryness, resuspended in ether, filtered again and concentrated. hand11-3Was obtained as a golden brown oil. R_f= 0.11 (10% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.7 (d, 1H), 7.2 (d, 1) H), 7.04 (s, 1H), 4.7 (s, 2H), 4.3 (q, 2H), 3.9 (s, 3H), 1.3 (t, 3H). 6-bromo-benzofuran-3-one (11-5)   Overhead stirrer, argon conduit, reflux cooling Sodium hydride (60% dispersion in oil) in a 3 L vessel equipped with a vessel and an addition funnel ; 5.52 g; 0.138 mol). Add toluene (215ml) The resulting solution was heated to reflux.11-3(36.3 g; 0.115 mol) Was dissolved in 100 ml of toluene over 1.5 hours. Gave an orange suspension. The reaction mixture is heated for a further 3 hours, then cooled to room temperature and filtered through a glass fiber filter. Filtered. Add 500 ml of cake to Et_TwoWash with O and vacuum dry11-4 Was obtained as an orange sandy solid (storage from baseline in 30% EtOAc / hexane). leak).11-4(5 g; 0.016 mol) in EtOH (20 ml) The turbid suspension was treated with NaOH (4 g; 0.1 mol l) is H_TwoAdded to a solution dissolved in O (35 ml). The reaction mixture was 1.25 Heated to reflux for hours and then cooled, and the volatile components were removed in vacuo. 20 residues 0 ml 6N HCl and 200 ml CHCl_ThreeSuspended for 0.5 hours Stirred well. The layers were separated and the aqueous layer was washed with CHCl_ThreeAnd washed. Combine organic layers MgSO_Four, Filtered and evaporated11-5The crimson solid and I got it. R_f= 0.61 (20% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.53 (d, 1H), 7.35 (s , 1H), 7.24 (d, 1H), 4.64 (s, 2H). (6-Bromo-benzofuran-3-yl) -acetonitrile (11-6)   Sodium hydride (0.7 g; 0.0173 mol) was washed with hexane, Was then suspended in THF (8 ml). The Ethyl cyanomethyl phosphonate (3.07 g; 0.0173 mol) was added dropwise. The mixture was stirred for 10 minutes to obtain a yellow transparent solution.11-5(3.38 g; 0.0 158 mol) in THF (20 ml) was added dropwise to obtain a solution. The solution was stirred for 0.5 hours and then heated to reflux for 0.5 hours. HCl 6N solution (3.4 ml) was added and the THF was removed under vacuum. The solution thus concentrated To Et_TwoDilute with O, wash with 4 × 30 ml of 6N HCl and dehydrate ether layer (MgSO_Four), Filtered and evaporated. The residue was chromatographed (20%   EtOAc / hexane)11-6Was obtained as an orange solid. R_f= 0.45 (20% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.7 (s, 1H), 7.65 (s, 1H) 1H), 7.45 (s, 2H), 3.75 (s, 2H). 2- (6-bromo-benzofuran-3-yl) -ethylamine (11-7) 11-6(10.9 g; 0.0462 mol) dissolved in THF (100 ml) The solution was cooled to 0 ° C._Three/ THF solution (1M; 110.8 ml; (11 mol) was added dropwise. Remove the cooling bath and mix the reaction mixture Was stirred overnight. MeOH (20 ml) was carefully added and the solvent was removed under vacuum Was. The residue was washed with 50 ml MeOH and 400 ml HCl saturated MeOH. And heated to reflux for 3 hours. Volatile components are removed under vacuum and the residue is t_TwoSuspended in O. The precipitated pale yellow solid was collected and_TwoWash with O 5 times, Then vacuum dry,11-7Was obtained as a tan solid. R_f= 0.23 (5% MeOH / NH_ThreeSaturated CHCl_Three)¹ 1 H NMR (400 MHz; CD_ThreeOD) δ: 7.72 (s, 2H), 7.6 (d, 1H), 7.45 (d, 2H), 3.25 (m, 2H), 3.06 (m, 2H). 7-bromo-2- (1,1-dimethylethoxycarbonyl) -1,2,3,4- Tetrahydro-9H-pyrido [3,4-b] benzofuran (11-10) 11-7(11.8 g; 0.043 mol) dissolved in MeOH (150 ml) CHCl_Three(400ml) and with 75ml 1N NaOH Washed. CHCl aqueous layer_ThreeAnd the organic layers are combined, evaporated and the remaining The distillate was azeotroped with toluene to remove residual water. The obtained brown oily substance was The mixture was treated with 00 ml of ethyl formate and refluxed for 1.5 hours to obtain a homogeneous solution. The solvent was removed and the residue was washed with 200 ml CHCl_ThreeAnd 30 ml of 1N HCl, brine, MgSO_Four, Filtered and evaporated11 -8 Was obtained as a solid, which was used without further purification. R_f= 0.47 (5% MeOH / NH_ThreeSaturated CHCl_Three)¹ 1 H NMR (400 MHz; CD_ThreeOD) [delta]: 8.04 (s, 1H), 7.6. 7 (s, 1H), 7.63 (s, 1H), 7.55 (d, 1H), 7.4 (d, 1H), 3.53 (m, 2H), 2.4 (m, 2H).   solid11-8Was crushed and placed in a flask equipped with an overhead stirrer. Polyphosphoric acid (20 ml) and CHCl_Three(5 ml) is added and the reaction mixture is left Heated to ° C. The reaction mixture was removed from the oil bath and 250 ml of H_TwoO, 3 0 ml of NH_FourOH and 200 ml CHCl_ThreeWas added and stirred vigorously. Get The opaque mixture was transferred to a separatory funnel, the layers were separated, and the aqueous layer was washed with CHCl_ThreeWith Extracted back. Combine the organic layers and filter through a Solka Floc pad, Na_TwoSO_Four, Filtered and evaporated to give the intermediate cyclic imine (11-9 ) Was obtained as a pale yellow foam. A 5 g (0.02 mol) sample of this material was Dissolved in 00 ml MeOH and 20 ml 1N HCl. Borohydride (1.5 g; 0.04 mol) was added slowly. After 0.5 hour, remove the solvent. And the residue is washed with NaHCO_ThreeSaturated solution of CHCl_ThreeAnd distributed. CH2 aqueous layer Cl_ThreeAnd the organic layers are combined, dehydrated (Na_TwoSO_Three) And filter A clear yellow solution was obtained. R_f(Amine) = 0.45 (5% MeOH / NH_ThreeSaturated CHCl_Three) Di-tert-butyl dicarbonate (4.5 g; 0.02 mol) and TEA (2.8 ml; 0.02 mol) was added and the solution was stirred overnight, after which 10% KHSO_FourWash with Was cleaned. Evaporate the organic layer and elute the residue with 10% EtOAc / hexane Chromatography,11-10Was obtained as a white solid. R_f= 0.60 (20% EtOAC / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.6 (s, 1H), 7.35 (d, 1H), 7.3 (d, 1H), 4.56 (bs, 2H), 3.75 (bs, 2H), 2. 7 (bs, 2H), 1.5 (s, 9H). Methyl 2- (1,1-dimethylethoxycarbonyl) -1,2,3,4-tetra Hydro-9H-pyrido [3,4-b] benzofuran-7-ylcarboxylate (11-11) 11-10(1 g; 2.84 mmol) and 1,3-bis (diphenylphosphine) Ino) propane (0.35 g; 0.852 mmol) was added to DMSO / MeOH (1 : 15 ml) was dissolved in TEA (1.5 ml; 10.7 mmol) And thoroughly purged with carbon monoxide followed by Pd (OAc)_Two(0. 191 g; 0.852 mmol) and warmed to 80 ° C. After heating overnight, The reaction mixture was cooled and additional 1,3-bis (diphenylphosphino) propane (0. . 35 g; 0.852 mmol), purge again with carbon monoxide and add additional Pd (OAc)_Two(0.191 g; 0.852 mmol). 3 days After heating, the reaction mixture was evaporated, water and CHCl_ThreeAnd the aqueous layer was separated_Threeso Washed. Combine the organic layers and add MgSO_FourAnd filtered through a glass filter. And concentrated. The residue was chromatographed (silica; 5% → 10% EtOAc) / Hexane gradient elution)11-11Was obtained as a yellow oil. R_f= 0.5 (20% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 8.13 (s, 1H), 7.96 (d , 1H), 7.48 (d, 1H), 4.6 (bs, 2H), 3.95 (s, 3H), 3.75 (bs, 2H), 2.75 (bs, 2H), 1.5 (s, 9H). 2- (1,1-dimethylethoxycarbonyl) -1,2,3,4-tetrahydro -9H-pyrido [3,4-b] benzofuran-7-ylcarboxylic acid (11-12 ) 11-11(0.79 g; 2.38 mmol) in 1: 1 THF / MeOH ( 30 ml) in 10 ml of H_TwoLiOH in O (0.95 g; 2 (3.8 mmol) and heated to 30 ° C. overnight. The solvent is removed under vacuum and the remaining H_TwoDissolved in O, 10% KHSO_FourAnd extracted with EtOAc . Organic layer_Four, Filtered and evaporated,11-12The off-ho Obtained as wight solid. R_f= 0.27 (97: 3: 1 CHCl_Three/ MeOH / HOAc)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 8.2 (s, 1H), 8.0 (d, 1) H), 7.50 (d, 1H), 4.65 (bs, 2H), 3.8 (bs, 2H), 2. 75 (bs, 2H), 1.52 (s, 9H). Ethyl 4- (2- (1,1-dimethylethoxycarbonyl) -1,2,3,4- Tetrahydro-9H-pyrido [3,4-b] benzofuran-7-yl) carbonyl Ruamino) -3-methylphenoxyacetate (11-13) 11-12(0.1 g; 0.321 mmol) in CH_TwoCl_Two(10ml) Oxalyl chloride (0.06 ml; 0.7 mmol) and 2 drops of D Treated with MF. After stirring at room temperature for 0.5 hour, the reaction mixture was diluted with benzene and evaporated. Fired. The resulting acid chloride is washed with CHCl_Three(5 ml),10-4(0 . 075 g; 0.26 mmol) and then cooled to 0 ° C. Treated with ruethylamine (0.167 ml; 0.3 mmol). The reaction mixture Warm to room temperature and stir overnight, then evaporate, EtOAc and 10% KHSO_Four And the EtOAc layer again with 10% KHSO_Four And washed. The EtOAc layer was washed with brine, washed with MgSO_Four, Filtered and And let it evaporate11-13I got R_f= 0.64 (60% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 8.0 (s, 1H), 7.73 (m, 2H), 7.62 (s, 1H), 7.53 (d, 1H), 6.85 (s, 1H), 6. 8 (m, 1H), 4.62 (d, 2H), 4.61 (s, 2H), 4.29 (q, 2H) 3.68 (bs, 2H), 2.75 (bs, 2H), 2.30 (s, 3H), 1.5 (s, 9H), 1.3 (t, 3H). 4- (2- (1,1-dimethylethoxycarbonyl) -1,2,3,4-tetra Hydro-9H-pyrido [3,4-b] benzofuran-7-yl) carbonylamido G) -3-Methylphenoxyacetic acid (11-14) 11-13(0.145 g; 0.285 mmol) in 1: 1 THF / MeO H (6 ml) was dissolved in 6 ml of H_TwoLiOH dissolved in O (0. 114g; 28.5m mol). After stirring at room temperature for 1 hour, the solvent was removed and the residue was_TwoO / E tOAc / 10% KHSO_FourAnd the layers were separated. Aqueous layer with EtOAc And combine the organic layers, dehydrate and filter to remove the intermediate acid as a yellow oil. Obtained as a solid. This material was dissolved in EtOAc (10 ml) and brought to -78 ° C. Cool and saturate the resulting solution with HCl gas, which was warmed to 0 ° C. for 0.5 h. , Then concentrated and dried under vacuum,11-14Was obtained as a fluffy solid. R_f= 0.78 (9: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; D_TwoO) δ: 7.84 (s, 1H), 7.65 (d, 1) H), 7.5 (d, 1H), 7.1 (d, 1H), 6.81 (s, 1H), 6.72 (d , 1H), 4.28 (s, 2H), 3.8 (bs, 2H), 2.96 (m, 2H), 2 . 6 (bs, 2H), 2.13 (s, 3H).Reaction Scheme 12 Reaction Scheme 12(Continued) 2-methyl-3-aminophenol (12-2)   In a 500 ml Erlenmeyer flask, sulfanilic acid (14.38 g; 83 mmol) ), Sodium carbonate (4.29 g; 40.5 mmol) and distilled water (83 ml) And the solution obtained when the sulfanilic acid is completely dissolved is brought to 0 ° C. in an ice bath. Cool and add sodium nitrite (6.16 g; 89.3 mmol) to H_TwoO (15 ml) was added all at once. Heat the ice bath to + 15 ° C and mix. The mixture was stirred at that temperature for 1 hour. The reaction mixture was washed with ice (100 g) and 12N HC (17.4 ml). Melt ice and solid diazonium salt Was collected by suction filtration on a sintered glass frit. NaOH (1.21 g 30.25 mmol) in H_TwoO-creso is added to a solution dissolved in O (100 ml). (9.10 g; 84.1 mmol) was dissolved. Cool the solution to 0 ° C The solid diazonium salt described above was added thereto all at once. Stir the resulting mixture thoroughly And maintained at + 15 ° C. for 4 hours. Raise the temperature of the mixture to + 60 ° C and add dithionous acid Sodium (35 g; 1.03 mol) was added slowly. Reaction at + 60 ° C for 1 Let go for 5 minutes. The mixture is cooled to room temperature and NaHCO_ThreeSaturated aqueous solution of And extracted with EtOAc. The EtOAc extract was dried (MgSO 4_Four), Filter and concentrate under vacuum, using 1: 3 EtOAc / hexane as eluent Chromatography on 100 g of silica gel. 2-methyl-3-amido Nophenol was obtained as a tan solid.¹ H NMR (CDCl_Three) δ: 2.18 (s, 3H), 3.35 (br s, 2H) 5.24 (brs, 1H), 6.42 (m, 1H), 6.50 (m, 1H), 6. 61 (d, J = 9 Hz, 1H).4- (1,1-dimethylethoxycarbonyl) amino-2-methylphenol ( 12-3)   Compound10-2Using the same method as described for 4- (1,1-dimethylmeth) (Rethoxyethoxy) amino-2-methylphenol was prepared.¹ H NMR (CDCl_Three) δ: 1.51 (s, 9H), 2.21 (s, 3H), 4.6. 2 (br s, 1H), 6.22 (br s, 1H), 6.62 (m, 1H), 6.9 8 (m, 1H), 7.08 (br s, 1H).Ethyl 4- (1,1-dimethylethoxycarbonyl) amino-2-methylpheno Kisia acetate (12-4)   Compound10-3Ethyl 4- (1,1- (Dimethylethoxycarbonyl) amino-2-methylphenoxyacetate did.¹ H NMR (CDCl_Three) δ: 1.29 (t, J = 7.2 Hz, 3H), 1.52 ( s, 9H), 2.28 (s, 3H), 4.25 (q, J = 7.2 Hz, 2H), 4. 58 (s, 2H), 6.25 (br s, 1H), 6.65 (d, J = 8.5 Hz, 1H), 7.08 (br d, J = 8.5 Hz, 1H), 7.17 (brs, 1H) .Ethyl 4-amino-2-methylphenoxyacetate, hydrochloride (12-5)   Compound10-4Ethyl 4-amino-2 using a method similar to that described for -Methylphenoxy acetate, hydrochloride was prepared.¹ H NMR (CD_ThreeOD) δ: 1.21 (t, J = 7.1 HZ, 3H), 2.35 ( s, 3H), 4.25 (q, J = 7.1 Hz, 2H), 4.81 (s, 2H), 6. 95 (d, J = 9 Hz, 1H), 7.21 (m, 2H).Ethyl 2- (4- (4- (4- (1,1-dimethylethoxycarbonyl) pipera) Zin-1-yl) phenylcarbonylamido G) -2-Methylphenoxy) acetate (12-6)   Compound10-5Ethyl 2- (4- (4 -(4- (1,1-dimethylethoxycarbonyl) piperazin-1-yl) fe Nylcarbonylamino) -2-methylphenoxy) acetate was prepared.¹ 1 H NMR (DMSO-d₆) δ: 1.41 (t, J = 7 Hz, 3H), 1.42 ( s, 9H), 2.20 (s, 3H), 2.50 (m, 4H), 3.29 (m, 4H), 4.29 (q, J = 7 Hz, 2H), 4.78 (s, 2H), 6.80 (d, J = 8 . 5 Hz, 1 H), 7.01 (d, J = 8.8 Hz, 2 H), 7.50 (m, 2 H) , 7.86 (d, J = 8.8 Hz, 2H), 9.68 (s, 1H).2- (4- (4- (4- (1,1-dimethylethoxycarbonyl) piperazine- 1-yl) phenylcarbonylamino) -2-methylphenoxy) acetic acid (12- 7)   Compound10-6Using a method similar to that described for 2- (4- (4- (4 -(1,1-dimethylethoxycarbonyl) piperazin-1-yl) phenylca (Rubonylamino) -2-methylphenoxy) acetic acid was prepared and purified without purification. Step.2- (4- (4- (1-piperazinyl) phenylcarbonyla) Mino) -2-methylphenoxy) acetic acid dihydrochloride (12-8)   Compound10-7Using a method similar to that described for 2- (4- (4- (1 -Piperazinyl) phenylcarbonylamino) -2-methylphenoxy) acetic acid, The dihydrochloride was prepared (mp:> 250 ° C).¹ H NMR (D_TwoO) δ: 2.15 (s, 3H), 3.29 (m, 4H), 3.48 (m , 4H), 4.65 (s, 2H), 6.76 (d, J = 8.5 Hz, 1H), 7.0 4 (d, J = 8.6 Hz, 2H), 7.17 (m, 2H), 7.69 (d, J = 8. 6 Hz, 2H).Reaction Scheme 13 Reaction Scheme 13(Continued) Reaction Scheme 13(Continued) Methyl 3-methyl-4-aminobenzoate (13-2)   In a 500 ml round bottom flask equipped with a stir bar, reflux condenser and dehydration tube, Methyl-4-aminobenzoic acid (8.00 g; 52.92 mmol) and meta anhydride Knol (300 ml) was charged. The resulting solution was saturated with anhydrous HCl gas and mixed. The mixture was stirred at ambient temperature for 26 hours. Methanol and HCl under vacuum Removed and the solid product was suspended in 400 ml of EtOAc. This mixture is NaHCO_ThreeWas made basic by careful addition of an aqueous solution of Separate the layers The organic phase was washed with brine, dried (MgSO 4)_Four), Filtered and concentrated under vacuum Reduction yielded methyl 3-methyl-4-aminobenzoate as a yellow solid.¹ H NMR (CDCl_Three) δ: 2.18 (s, 3H), 3.85 (s, 3H), 3.9 9 (br s, 2H), 6.63 (d, J = 8.3 Hz, 1H), 7.75 (m, 3 H).Methyl and n-butyl 3-methyl-4- (1-piperazinyl) benzoate (1 3-3)   Place the flask in a 1 L round bottom flask equipped with a stir bar, reflux condenser, and argon inlet. Cyl 3-methyl-4-aminobenzoate (8.74 g; 52.74 mmol) , Bis 2-chloroethylamine hydrochloride (9.81 g; 55.0 mmol) and n -BuOH (175 ml) was charged. The resulting mixture is heated at reflux for 8 days Was. The n-BuOH was removed under vacuum and the residue was taken up with EtOAc (200 ml) and 0.1 mL. 2N HCl (300ml) And distributed. Separate the layers and separate the organic phase from another 100 ml of 0.2 N HC Extracted with l. Combine the aqueous phases and add solid NaHCO_ThreeTo make it basic. this Extract the mixture with EtOAc (2 × 200 ml) and combine the combined EtOAc extracts. The effluent was washed with brine, dried (Na_TwoSO_Four), Filter and concentrate under vacuum And methyl 3-methyl-4- (1-piperazinyl) benzoate and n-butyl 3 10.39 g of a mixture with -methyl-4- (1-piperazinyl) benzoate were obtained. Was. This material was used for the next step without further purification.Methyl and n-butyl 3-methyl-4- (1- (4- (1,1-dimethylethoxy) B) carbonyl) piperazinyl) benzoate (13-4)   Methyl 3-methyl was added to a 1 L round bottom flask equipped with a stir bar and an argon inlet. 4- (1-piperazinyl) benzoate and n-butyl 3-methyl-4- (1 -Piperazinyl) benzoate (10.39 g; m of methyl ester 44.35 mmol based on w alone; see above), di-t-butyl dicarbonate (14 . 67 g; 67.22 mmol) and dry CHCl_Three(100 ml). The resulting solution is heated at reflux temperature. Heated for 19 hours. The cooled reaction mixture is concentrated under vacuum and the residue is eluent And chromatographed on silica gel (300 g) using 40% EtOAc / hexane. Chromatography gave methyl 3-methyl-4- (1- (4- (1,1-dimethyl) Ruethoxy) carbonyl) piperazinyl) benzoate and n-butyl 3-methyl -4- (1- (4- (1,1-dimethylethoxy) carbonyl) piperazinyl) 5.0 g of a mixture with benzoate were obtained. This material can be used without further purification Used for step.3-methyl-4- (1- (4- (1,1-dimethylethoxy) carbonyl) pipe (Radinyl) benzoic acid (13-5)   The methyl 3-methyl-4- (1- (4- (1,1-dimethyl) Tylethoxy) carbonyl) piperazinyl) benzoate and n-butyl 3-methyl 4- (1- (4- (1,1-dimethylethoxy) carbonyl) piperazinyl ) Dissolve the mixture with benzoate (5.0 g) in 95% EtOH (100 ml). Disrupted and NaOH (10 g; 250 mmol) was added. Reflux the resulting solution Heated at temperature for 2 hours. The mixture was cooled to room temperature and the EtOH was removed under vacuum. 300 ml of H_TwoDissolved in O. Add this solution to Et_TwoO (200m 1) and then acidified with a 10% aqueous solution of citric acid. Add this mixture to Et Extracted with OAc (2 × 250 ml). Combined EtOAc extracts were combined with H_Two Washed with O and brine. Dehydrate (MgSO 4_Four), Filter and remove the solvent under vacuum To give an oil. This material was eluted with 40% EtOAc / Chromatograph on 75 g of silica gel with xane. The black The product obtained by chromatography was added to 15 ml of 20% EtOAc / hex. After recrystallization from sun, 228 mg of 3-methyl-4- (1- (4- (1,1- Dimethylethoxy) carbonyl) piperazinyl) benzoic acid as white crystals Was.¹ H NMR (CDCl_Three) Δ: 1.49 (s, 9H), 2.35 (s, 3H), 2. 94 (m, 4H), 3.59 (m, 4H), 6.99 (d, J = 8 Hz, 1H), 7. 92 (m, 2H), 11.65 (br s, 1H).4- (1,1-dimethylethoxycarbonylamino) phenol (13-7)   500 ml round bottom flask equipped with stir bar, reflux condenser and argon inlet 4-aminophenol (10.00 g; 91.63 mmol), di-t-butyl dicarbonate (20.00 g; 91.63 mm) ol) and dry CHCl_Three(250 ml). The resulting solution is heated at reflux temperature. Heat for 6 hours. The mixture was cooled in an ice bath and the product was collected by filtration. Raw Add the product to a small amount of cold CHCl_ThreeAnd dried under vacuum to give 16.43 (86%) Of 4- (1,1-dimethylethoxycarbonylamino) phenol as white crystals (Mp: 142-143 ° C.).¹ H NMR (CDCl_Three) δ: 1.51 (s, 9H), 5.27 (br s, 1H), 6.34 (br s, 1H), 6.72 (d, J = 8 Hz, 2H), 7.16 (d, J = 8 Hz, 2H).Ethyl (4- (1,1-dimethylethoxycarbonylamino) phenoxy) ace Tate (13-8)   In a 500 ml round bottom flask equipped with a stirring rod and an argon inlet, 4- (1 , 1-Dimethylethoxycarbonylamino) phenol (8.20 g; 39.1) 9 mmol), Cs_TwoCO_Three(25.54 g; 78.38 mmol), DMF (7 5 ml) and ethyl bromoacetate (4.78 ml; 43.11 m) mol). The resulting heterogeneous mixture was stirred at ambient temperature for 3.5 hours. Mixed The compound was added to a small amount of CHCl_ThreeAnd filtered through a frit to remove salts. DMF Removed under high vacuum and the residue was suspended in 500 ml of EtOAc. This mixture H_TwoWashed with O (3x) and brine. Dehydrate (MgSO 4_Four), Filtered, The solvent was removed under vacuum to give an oil. This substance is used as eluent in 20% Chromatography on 400 g silica gel with EtOAc / hexane Hung. 11.9 g (100%) of ethyl (4- (1,1-dimethylethoxyca) Rubonylamino) phenoxy) acetate was obtained as an oil.¹ H NMR (CDCl_Three) δ: 1.29 (t, J = 6.4 Hz, 3H), 1.50 ( s, 9H), 4.25 (q, J = 6.4 Hz, 2H), 4.57 (s, 2H), 6. 36 (brs, 1H), 6.84 (d, J = 8 Hz, 2H), 7.26 (d, J = 8) Hz, 2H).Ethyl 4-aminophenoxyacetate, hydrochloride (13-9)   In a 500 ml round bottom flask equipped with a stir bar and a gas dispersion tube, ethyl (4- (1,1-dimethylethoxycarbonylamido G) phenoxy) acetate (11.9 g; 40.29 mmol) and dry Et OAc was charged. The resulting solution was cooled in an ice bath, and anhydrous HCl gas was added to the solution. Saturated for 15 minutes. The resulting suspension was aged at 0 ° C. for 30 minutes. Extra HCl was removed with a stream of argon and EtOAc was removed under vacuum. The solid product to E Triturate with tOAc, collect on frit and vacuum dry at room temperature to obtain 7.33 g (78%) of ethyl 4-aminophenoxyacetate, hydrochloride, on a white crystalline solid. Obtained as body.¹ 1 H NMR (DMSO-d₆3.) δ: 1.211 (t, J = 6.4 Hz, 3H); 16 (q, J = 6.4 Hz, 2H), 4.82 (s, 2H), 7.05 (d, J = 8 Hz, 2H), 7.34 (d, J = 8 Hz, 2H), 10.27 (brs, 3H) .Ethyl 2- (4- (4- (3-methyl-4- (1,1-dimethylethoxycarbo) Nyl) piperazin-1-yl) phenylcarbonylamino) phenoxy) acete (13-10)   acid13-5And aniline13-8Using the compound10-5With regard to Similarly, ethyl 2- (4- (4- (3-methyl-4- (1,1-dimethylethoxy) Xycarbonyl) piperazi 1-yl) phenylcarbonylamino) phenoxy) acetate was prepared. .¹ H NMR (CDCl_Three) δ: 1.29 (t, J = 7.0 Hz, 3H), 1.48 ( s, 9H), 2.37 (s, 3H), 2.95 (m, 4H), 3.59 (m, 4H), 4.25 (q, J = 7 Hz, 2H), 4.61 (s, 2H), 6.95 (d, J = 8 . 5Hz, 2H), 7.03 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8 . 5 Hz, 2H), 7.62 (m, 2H).2- (4- (4- (3-methyl-4- (1-piperazinyl) phenylcarbonyl) Amino) phenoxy) acetic acid (13-11)   In a 100 ml round bottom flask equipped with a stir bar, ethyl 2- (4- (4- (3 -Methyl-4- (1,1-dimethylethoxycarbonyl) piperazin-1-yl )) Phenylcarbonylamino) phenoxy) acetate (311 mg; 0.63) mmol), MeOH (5 ml), THF (20 ml) and 1N LiOH (2 0 ml). The resulting solution was stirred at ambient temperature for 24 hours. Solvent under vacuum And the residue was acidified with a 10% aqueous solution of citric acid. This mixture is added to EtO Extracted with Ac. The EtOAc extract was dried (MgSO 4_Four), Filtered and in an ice bath Cooled to 0 ° C. This solution was saturated with dry HCl gas, Was aged at 0 ° C. for 30 minutes. Remove excess HCl with a stream of argon and remove solvent in vacuo Removed below. The product was purified on a Waters C-18 column with H_TwoO / CH_ThreeCN concentration Purified by preparative reverse phase HPLC using a gradient. 105 mg of 2- (4- ( 4- (3-methyl-4- (1-piperazinyl) phenylcarbonylamino) fe (Noxy) acetic acid was obtained as a white solid.¹ H NMR (D_TwoO) δ: 2.28 (s, 3H), 3.17 (m, 4H), 3.35 (m , 4H), 4.55 (s, 2H), 6.49 (d, J = 7.5 Hz, 2H), 7.1 2 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 7.5 Hz, 2H), 7.6 3 (m, 2H).Reaction Scheme 14 1-nitrophenyl-4- (1,1-dimethylethoxycarbonyl) piperazine (14-2)   1-nitrophenylpiperazine (5.01; g) was placed in a 200 ml round bottom flask.   24.2 mmol), di-tert-butyl dicarbonate (5.85 g; 26.8 mmol) ), Triethylamine (3.87 ml; 27.8 mmol) and dry THF (1 00 ml). The resulting solution was heated at reflux for 18 hours. Mix room Cooled to warm and the solvent was removed under vacuum. Dissolve the residue in EtOAc and quench 10% aqueous solution of acid, H_TwoWashed with O and brine. Dehydrate (MgSO 4_Four),filtration And removing the solvent under vacuum, 7.7 g of 1-nitrophenyl-4- (1,1 1-Dimethylethoxycarbonyl) piperazine was obtained as a yellow solid.¹ H NMR (CDCl_Three) δ: 1.42 (s, 9H), 3.41 (m, 4H), 3.6 2 (m, 4H), 6.81 (d, J = 8.5 Hz, 2H), 8.16 (d, J = 8. 5 Hz, 2H).4- (4- (1,1-dimethylethoxycarbonyl) piperazin-1-yl) a Nirin (14-3)   1-Nitrophenyl-4- (1,1-dimethyl) was added to a 250 ml Parr hydrogenation bottle. Tylethoxycarbonyl) piperazine (4.5 g; 16.34 mmol), Et OAc (81 ml), MeOH (27 ml) and 5% Pd-C (01.8 g). Was put. The resulting mixture is allowed to stand at ambient temperature for 24 hours at 45 psig H_TwoUnder the water Simplification. The mixture was filtered through a pad of celite and the solvent was removed under vacuum. Residue With 250 g of silica gel using 70% EtOAc / hexane as eluent Chromatographed above. 3.43 g of 4- (4- (1,1-dimethyl Ethoxycarbonyl) piperazin-1-yl) aniline was obtained as a yellow solid. Was.¹ H NMR (CDCl_Three) δ: 1.49 (s, 9H), 2.98 (m, 4H), 3.4 9 (br s, 2H), 3.57 (m, 4H), 6.66 (d, J = 9 Hz, 2H), 6.82 (d, J = 9 Hz, 2H).N- (4- (4- (1,1-dimethylethoxycarbonyl) piperazine-1-i Phenyl) -4-hydroxybenzamide (14-4)   1 ml round bottom filter equipped with stir bar and argon inlet Lasco has 4- (4- (1,1-dimethylethoxycarbonyl) piperazine-1- Il) aniline (0.868 g; 3.13 mmol), 4-hydroxybenzoic acid (0.525 g; 3.80 mmol), chloro-N, N, N ', N'-bis (pe (Tamtamethylene) formamidinium hexafluorophosphate (1.35 g; 3.74 mmol) and CH_TwoCl_Two(45 ml). Ice the resulting mixture Cool in bath and add diisopropylethylamine (0.96 ml; 5.52 mmol ) Was added. After the ice bath melted and disappeared, the mixture was stirred at ambient temperature for 18 hours . The mixture was diluted with EtOAc and washed with a 10% aqueous solution of citric acid, water and brine. Was cleaned. Dehydrate (MgSO 4_Four), Lower limbs, and solvent under vacuum to remove oil Obtained. This material was purified by 100% using 70% EtOAc / hexane as eluent. g of silica gel and 0.57 g of N- (4- (4- (1,1-dimethylethoxycarbonyl) piperazin-1-yl) phenyl)- 4-Hydroxybenzamide was obtained as a gray solid.¹ H NMR (CDCl_Three) δ: 1.48 (s, 9H), 3.01 (m, 4H), 3.4 8 (m, 4H), 6.82 (d, J = 9 Hz, 2H), 6.85 (d, J = 9Hz, 2H), 7.58 (d, J = 8 Hz, 2H), 7.81 (d, J = 8 Hz, 2H), 9.80 (br s, 1H), 10.01 (br s, 1H).t-butyl 4- (4- (4- (1,1-dimethylethoxycarbonyl) piperazine 1-yl) phenylaminocarbonyl) phenoxyacetate (14-5)   In a 100 ml round bottom flask equipped with a stirring rod and an argon inlet, N- (4 -(4- (1,1-dimethylethoxycarbonyl) piperazin-1-yl) fe Nyl) -4-hydroxybenzamide (0.56 g; 1.41 mmol), DM F (35 ml), Cs_TwoCO_Three(0.49 g; 1.51 mmol) and bromoacetic acid t-Butyl (0.28 ml; 1.75 mmol) was charged. Circumfer the resulting mixture Stir at ambient temperature for 18 hours. The mixture was diluted with EtOAc and H_TwoO and brine And washed. Dehydrate (MgSO 4_Four), Filter and remove the solvent under vacuum. 78 g of t-butyl 4- (4- (4- (1,1-dimethylethoxycarbonyl)) Piperazin-1-yl) phenylaminocarbonyl) phenoxyacetate This was used in the next step without purification.¹ 1 H NMR (DMSO-d₆) δ: 1.48 (s, 9H), 1.49 (s, 9H), 3 . 02 (m, 4H), 3.39 (m, 4H), 4.78 (s, 2H), 6.88 (d, J = 9 Hz, 2H), 7.02 (d, J = 9 Hz, 2H), 7.62 (d, J = 8 Hz) , 2H), 7.82 (d, J = 8 Hz, 2H), 9.82 (brs, 1H).4- (4- (piperazin-1-yl) phenylaminocarbonyl) phenoxy vinegar Acid (14-6)   T-butyl 4 was added to a 100 ml round bottom flask equipped with a stir bar and a gas dispersion tube. -(4- (4- (1,1-dimethylethoxycarbonyl) piperazin-1-yl ) Phenylaminocarbonyl) phenoxyacetate (0.78 g; 1.52 m mol) and EtOAc (40 ml). Cool the resulting solution in an ice bath HCl gas was dispersed in this solution for 15 minutes. The resulting mixture is ripened for 90 minutes Was completed. Excess HCl and EtOAc are removed under vacuum and the crude product is separated by preparative reverse phase. Purified by HPLC. 0.218 g of 4- (4- (piperazin-1-yl) ) Phenylaminocarbonyl) phenoxyacetic acid was obtained as a crystalline solid.¹ 1 H NMR (0.1 N NaOD-D_TwoO) δ: 2.99 (m, 4H), 3.15 ( m, 4H), 4.59 (s, 2H), 7.03 (d, J = 9 Hz, 2H), 7.16 ( d, J = 9 Hz, 2H), 7.7.37 (d, J = 8 Hz, 2H), 7.88 (d, J = 8 Hz, 2H).Reaction Scheme 15 Reaction Scheme 15(Continued) 2- (4- (4- (1-piperazinyl) phenylcarbonylamino) -3,5- Dimethylphenoxy) acetic acid, dihydrochloride (15-8)   Compound12-8Using substantially the same procedure as described for Dimethylphenol (15-1) And starting with 2- (4- (4- (1-piperazi Nyl) phenylcarbonylamino) -3,5-dimethylphenoxy) acetic acid, disalt The acid salt was prepared (mp:> 250 ° C).¹ H NMR (D_TwoO) δ: 2.15 (s, 6H), 3.32 (m, 4H), 3.54 (m , 4H), 4.64 (s, 2H), 6.72 (s, 2H), 7.12 (d, J = 8.6). Hz, 2H), 7.17 (m, 2H), 7.83 (d, J = 8.6 Hz, 2H).Reaction scheme 16 Reaction scheme 16(Continued) 4- (4-pyridinyl) benzoic acid (16-2) 16-1(5 g; 29.6 mmol; JC Chambron, JPS) auavage, Tetrahedron 895, 1987; L. Co mins, A.M. H. Abdulah, J .; Org. Chem. 47, p. 43 15, 1982) prepared in 200 ml of H_Two The resulting slurry in addition to O was treated with 10% HCl until the solids dissolved. The solution was washed with solid KMnO_Four(11.2 g; 888 mmol) slowly added Treated with KMnO_FourWas stirred and heated to 90 ° C. for 18 hours . 2 g of KMnO_FourWas added and the reaction mixture was again heated to 90 ° C. for 2 hours . The reaction mixture was cooled to ６０60 ° C., filtered, and the solid was washed with warm water. Evaporate the filtrate And the residue is chromatographed (silica gel; 10: 1: 1 EtOH / H_Two O / NH_FourOH)16-2Was obtained as an off-white solid.¹ 1 H NMR (400 MHz; DMSO) δ: 8.61 (m, 2H), 8.0 (m, 2 H), 7.72 (m, 4H). 4- (1- (1,1-dimethylethoxycarbonyl) piperidin-4-yl) an Benzoic acid (16-3) 16-2(0.5 g; 2.5 mmol) in 20 ml of 20% HOAc / Me OH dissolved in 250 mg of PtO_TwoAnd water at 50 psi for 4 hours Simplification. The solution was filtered through Solka Flo, evaporated and azeotroped with heptane. Excess HOAc was removed. Intermediate amino acid acetate obtained as a white solid . R_f= 0.3 (10: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; CD_ThreeOD) δ: 8.96 (m, 2H), 7.35 (m , 2H), 3.5 (bd, 2H), 3.4 (m, 2H), 3.2 (m, 2H), 3.0 ( m, 2H).   The above amino acid (0.5 g; 1.9 mmol) was converted to 30% H_Two O / dioxane (12 ml) and the resulting slurry at room temperature for 6 hours with 1N   NaOH (4.8 ml) and di-tert-butyl dicarbonate (0.564 g; 2.58 mmol). The reaction mixture was diluted with 10% KHSO_FourAcidify to pH 5 with Extracted several times with EtOAc. The EtOAc layers were combined and evaporated,1 6-3 Was obtained as a white solid. R_f= 0.39 (97: 3: 1 CHCl_Three/ MeOH / HOAc)¹ 1 H NMR (400 MHz; CD_ThreeOD) δ: 7.95 (d, 2H), 7.33 (d , 2H), 4.2 (bd, 2H), 2.85 (b, 3H), 1.8 (bd, 2H), 1 . 6 (m, 2H), 1.48 (s, 9H). Ethyl 2- (4- (4- (1- (1,1-dimethylethoxycarbonyl) piperi Zin-4-yl) phenylcarbonylamino) -3-methylphenoxy) acete (16-4) 16-3(0.15 g; 0.49 mmol) and10-4 (0.12 g; 0.49 mmol) in CH_TwoCl_TwoTo the slurry. Rollo-N, N, N ', N'-bis (pentamethylene) formamidinium hexa Fluorophosphate (0.194 g; 0.54 mmol) and diisopropyl Treat with ethylamine (0.34 ml; 1.96 mmol) and stir at room temperature for 24 hours. Stirred. The resulting solution was diluted with EtOAc and H_TwoO, 10% citric acid, NaH CO_ThreeWashed with a saturated solution of_Four, Filtered and evaporated Was. The residue was chromatographed (silica gel; 50% EtOAc / hexane) ) And then crushed with ether / hexane16-4I got R_f= 0.33 (50% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.81 (2s, 2H), 7.70 ( d, 1H), 7.50 (s, 1H), 7.31 (2s, 2H), 6.8 (m, 2H), 4.6 (s, 2H), 4.28 (q, 2H), 2.8 (m, 2H), 2.72 (m, 1 H), 2.30 (s, 3H), 1.85 (bd, 2H), 1.75 (m, 2H), 1. 48 (s, 9H), 1.3 (t, 3H). 2- (4- (4- (piperidin-4-yl) phenylcarbonylamino) -3- Methylphenoxy) acetate (16-5) 16-4(0.1 g; 0.2 mmol) in 1: 1: 1 THF / MeOH / H_Two The solution dissolved in O was added with LiOH (0.084 g; 2 mmol) at room temperature. Processed. After 1 hour, the reaction mixture was washed with EtOAc and 10% KHSO_FourDiluted in And the layers were separated. Organic layer H_TwoO, washed with brine, MgSO_FourDehydrated and filtered And evaporated to give the intermediate acid as a clear oil. R_f= 0.57 (9: 1: 1 CH_TwoCl_Two/ MeOH / HOAc)¹ 1 H NMR (400 MHz; CD_ThreeOD) δ: 7.94 (2s, 2H), 7.44 ( 2s, 2H), 7.2 (d, 1H), 6.90 (m, 1H), 6.8 (m, 1H), 4 . 62 (s, 2H), 4.24 (bd, 2H), 2.9 (b, 2H), 2.83 (m, 1H), 2.28 (s, 3H), 1.86 (bd, 2H), 1.7 to 1.6 (m, 2H ), 1.5 (s, 9H).   Cool the slurry of the above acid (0.9 g; 1.19 mmol) to -78 ° C, Was saturated with HCl gas. The reaction mixture was warmed to 0 ° C. and then concentrated in vacuo. hand,16-5Was obtained as the HCl salt. R_f= 0.81 (10: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; CD_ThreeOD) δ: 7.94 (2s, 2H), 7.44 ( 2s, 2H), 7.2 (d, 1H), 6.90 (m, 1H), 6.8 (m, 1H), 4 . 65 (s, 2H), 3.52 (bd, 2H), 3.15 (bt, 2H), 3.05 ( m, 1H), 2.12 (bd, 2H), 1.97 (m, 2H). Ethyl 2- (4- (4- (pyridin-4-yl) phenylcarbonylamino)- 3-methylphenoxy) acetate (16-6) 16-2(0.5 g; 2.5 mmol) and ethyl 2-acetoxy-4-amino Benzene hydrochloride (13-90.579 g; 2.5 mmol)16-4About In the operation described Coupling and chromatography (silica gel; 5% MeOH / EtO) Ac) followed by preparative reverse phase HPLC16-6I got¹ 1 H NMR (400 MHz; CD_ThreeOD) δ: 8.82 (d, 2H), 8.30 (d , 2H), 8.15 (d, 2H), 8.05 (d, 2H), 7.60 (d, 2H), 6 . 98 (d, 2H), 4.70 (s, 2H), 4.23 (q, 2H), 1.30 (t, 3H). 2- (4- (4- (pyridin-4-yl) phenylcarbonylaminophenoxy) ) Acetic acid (16-7) 16-6With LiOH,16-5Proceed as described for Raffy (silica gel; 10: 1: 1 EtOH / H_TwoO / NH_FourOH) After preparative reverse phase HPLC16-7I got R_f= 0.76 (10: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; DMSO) δ: 8.65 (d, 2H), 8.10 (d, 2H), 7.96 (d, 2H), 7.8 (d, 2H), 7.65 (d, 2H), 6.9 0 (d, 2H), 4.58 (bs, 2H).Reaction scheme 17 Reaction scheme 17(Continued) Reaction scheme 17(Continued) 2-amino-4- (4-methylphenyl) pyridine (17-1)   NaNH_Two(142 mmol). T. Leffler, "Organic   Reactions, "Vol. I, 1942. When manufactured. This newly produced NaNH_TwoDimethylaniline (20 ml) It was added dropwise.16-1(8.0 g; 47.3 mmol) in a small amount of dimethylani Dissolved in phosphorus and added to the mixture obtained as above. slurry Was heated to 160 ° C. for 2 hours. Cool the reaction mixture and add 10% KHSO_FourAnd water To dilute. Separate the layers and add the dimethylaniline layer to 10%_FourWash with . Combine the aqueous phases and add NaHCO_ThreeBasified with a saturated solution of EtOAc and EtOAc ( 3 ×). Wash the combined organic layers with brine and concentrate to an oil To obtain a crystalline solid. This oily solid was purified by flash chromatography (5% MeO H / EtOAc)17-1Was obtained as a tan solid. R_f= 0.36 (5% MeOH / EtOAc)¹ 1 H NMR (400 MHz; DMSO-d₆) δ: 7.9 (d, 1H), 7.5 (d , 2H), 7.3 (d, 2H), 6.7 (d, 1H), 6.6 (s, 1H), 5.9 (d , 1H), 2.3 (s, 3H). 2- (1,1-dimethylethoxycarbonylamino-4- (4-methylphenyl) ) Pyridine (17-2) 17-1Is dissolved in dichloroethane (30 ml) and Boc_TwoO for dichloroe It is quickly added dropwise to a refluxing solution dissolved in tan (10 ml). After this addition, The reaction mixture is refluxed for 30 minutes and then stirred at RT overnight. Cool the reaction mixture And concentrated to give a yellow solid which was chromatographed (silica; 30% EtOAc / hexane)17-2To Obtained as a white solid. R_f= 0.73 (50% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 8.3 (d, 1H), 8.2 (s, 1) H), 7.5-7.6 (m, 4H), 7.3 (bs, 1H), 7.1 (d, 1H), 2 . 3 (s, 3H), 1.5 (s, 9H). 2- (1,1-dimethylethoxycarbonylamino-4- (4-dibromomethyl Phenyl) pyridine (17-3) 17-2(1.0 g; 3.5 mmol) in CCl_FourTo dissolve. NBS (1 . 3 g; 7.3 mmol) followed by AIBN (28.7 mg; 0.18 mmol) ) Is added. The resulting reaction mixture is heated to reflux, at which time the mixture is directly A white light is emitted to illuminate the flask. Two hours later, AIBN (28.7 mg) was added. The light is turned off and the reaction mixture is stirred overnight to complete the product. Reaction mixture Cool and filter by filtration The imide is removed and the solid is washed with CCl_FourWash with. Concentrate the filtrate17-3To Obtained as a brown solid, which is used in the next step without further purification. R_f= 0.70 (50% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 8.3 (d, 1H), 8.2 (s, 1) H), 7.7 (m, 3H), 7.2 (bs, 1H), 7.1 (d, 1H), 6.7 (s, 1H), 1.5 (s, 9H). 4- (2- (1,1-dimethylethoxycarbonylamino) pyrid-4-yl) Benzaldehyde (17-4) 17-3(1.5 g; 34 mmol) in water / THF (15 ml / 45 ml) Allow to dissolve. AgNO_Three(1.1 g; 6.8 mmol) and stirred for 1/2 hour. You. The reaction mixture is diluted with EtOAc and water. Separate the layers and filter the organic layer Remove the solid. The filtrate was washed with brine, dried (MgSO 4)_Four), Filter and concentrate to give a brown solid. This solid is placed on a silica “plug” Purified with 50% EtOAc / hexane first, then 100% EtOAc Elute with c to elute all products. Concentrate fractions,17-4The brown solid and Get it. R_f= 0.62 (50% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 10.1 (s, 1H), 8.29 (d , 1H), 8.26 (s, 1H), 8.0 (d, 2H), 7.8 (d, 2H), 7.5 ( bs, 1H), 7.2 (d, 1H), 1.5 (s, 9H). 4- (2- (1,1-dimethylethoxycarbonylamino) pyrid-4-yl) Benzoic acid (17-5) 17-4(1.0 g; 3.4 mmol) in CH_ThreeIn addition to CN (40 ml) Rally. 10% KHSO_Four(1.3 ml) and 30% H_TwoO_Two(0.9 57 ml) is added and the resulting solution is cooled in an ice bath. NaC in 50 ml of water 10_Two (770 mg; 8.5 mmol) is added dropwise over 20 minutes. The reaction mixture Stir for 16 hours. The reaction mixture was diluted with EtOAc and NaHCO_ThreeA saturated solution of Wash with (2x). Combine the aqueous layers and add 10% KHSO_FourAcidify with And CH_TwoCl_Two(2 ×) and EtOAc (2 ×),17-5The yellow Obtained as a solid.¹ 1 H NMR (400 MHz; DMSO-d₆) δ: 12.6 to 12.8 (bs, 1 H), 9.9 (s, 1H), 8.3 (d, 1H), 8.0 to 8.1 (m, 3H), 7. 9 (d, 2H), 7.3 (d, 1H), 1.5 (s, 9H). Ethyl 2- (4- (4- (2- (1,1-dimethylethoxycarbonylamino)) Pyrid-4-yl) carbonylamino) phenoxy) acetate (17-6) 17-5(300 mg; 0.956 mmol);13-9(236 mg; 0 . 956 mmol) and diisopropyl Ethylamine (0.66 ml; 3.8 mmol) and PYCLU (378 mg; 1.05 mmol) and CH_TwoCl_Two(10 ml) at RT for 16 h. Mix. The reaction mixture was diluted with EtOAc and NaHCO_ThreeSaturated solution and brie Wash with The organic layer is dehydrated (MgSO 4_Four), Filtered and concentrated to pink To obtain a solid. Trituration with hexane followed by flash chromatography (silica gel) F; 30% EtOAc / hexane)17-6As a white solid obtain. R_f= 0.24 (30% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 8.3 (d, 1H), 8.2 (s, 1) H), 7.9 (d, 2H), 7.8 (2d, 3H), 7.4 (bs, 1H), 7.6 (b s, 1H), 7.2 (d, 1H), 6.8 (s, 1H), 6.7 (d, 1H), 4.6 (d). s, 2H), 4.3 (q, 2H), 2.3 (s, 3H), 1.5 (s, 9H), 0.9 ( t, 3H). 2- (4- (4- (2- (1,1-dimethylethoxycarbonyl) Ruamino) pyrid-4-yl) carbonylamino) phenoxy) acetic acid (17-7) ) 17-6(90 mg; 0.17 mmol) and LiOH (25 mg; 0.60 mmol) and THF / H_TwoMixing with O / MeOH (1ml / 1ml / 1ml) Stir the material for 2 hours. The reaction mixture was washed with EtOAc and 10% KHSO_FourDilute with You. The aqueous layer is back-extracted with EtOAc. Combine organic layers and wash with brine And dehydrated (MgSO 4_Four), Filter and concentrate,17-7Is a white solid Get it.¹ 1 H NMR (400 MHz; CD_ThreeOD) δ: 8.3 (d, 1H), 8.1 (bd, 3H), 7.9 (d, 2H), 7.5 (bs, 1H), 7.2 (s, 1H), 6.9 (s , 1H), 6.8 (d, 1H), 4.7 (s, 2H), 2.3 (s, 3H), 1.5 (s). , 9H). 2- (4- (4- (2-aminopyrid-4-yl) carbonyl Amino) phenoxy) acetic acid (17-8) 17-7(70 mg; 0.14 mmol) dissolved in EtOAc (3 ml) , Cooled to -78 °. HCl (gas) is bubbled through the solution until it is saturated. Anti The reaction mixture is stirred at 0 ° for 3 hours and then at 35 ° for 16 hours. Concentrate the reaction mixture To give a tan solid which was purified by flash chromatography (10: 0.25 : EtOH / NH of 0.25_FourOH / H_TwoO)17-8The off-ho Obtained as wight solid. R_f= 0.86 (EtOH / NH of 10: 0.5: 0.5_FourOH / H_TwoO)¹ 1 H NMR (400 MHz; DMSO-d₆) δ: 9.8 (s, 1H), 8.0 (d , 2H), 7.9 (d, 1H), 7.7 (d, 2H), 7.2 (d, 1H), 6.9 (m , 2H), 6.8 (m, 2H), 6.0 (d, 1H), 2.2 (s, 3H).Reaction scheme 18 Reaction scheme 18(Continued) 4- (3 (R)-((N-benzyl) pyrrolidinyl) amino) phenylnitrile (18-1)   N-benzyl-3- (R) -aminopyrrolidine (TCI; 0.45 g; 2.2 7 mmol) in 1 ml of acetonitrile was added to 4-fluorophenylene. Treat with Lucyanide (Aldrich; 3 g; 25.5 mmol) and bring to 100 ° C Heated. The acetonitrile was evaporated and the resulting slurry was heated for 18 hours. Additional 4-fluorophenyl cyanide (1 g) is added and the reaction mixture is left for 18 hours Heated. The oily mixture was absorbed on silica gel and firstly 20% EtOAc / hex. Sun, then 5% MeOH / NH_ThreeSaturated CHCl_ThreeElute with18-1I got R_f= 0.55 (5% MeOH / NH_ThreeSaturated CHCl_Three)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.4 (d, 2H), 7.3 (m, 5 H), 6.5 (d, 2H), 4.45 (bd, 1H), 4.0 (m, 1) H), 3.64 (s, 2H), 2.83 (m, 1H), 2.75 (dd, 1H), 2. 6 (dd, 1H), 2.43 (m, 1H), 2.34 (m, 1H), 1.6 (m, 1H) . Methyl 4- (3 (R)-((N-benzyl) pyrrolidinyl) amino) benzoate To (18-2) 18-1(0.52 g; 1.87 mmol) in dioxane (10 ml) and 1 : 1 H_TwoO / concentrated H_TwoSO_Four(10 ml) at 100 ° C for 18 hours Heated. The solvent was removed under vacuum and the residue was dissolved in MeOH (30 ml), Stirred for 4 days. The solvent was removed and the residue was washed with NaHCO_ThreeSaturated solution and 1N N Take up in aOH to pH 10 and then extract with chloroform. Organic extract Combine and evaporate and concentrate the residue from 20% to 30% EtOAc / hexanes. Chromatography eluting with a gradient18-2With a clear oily substance I got it. R_f= 0.31 (50% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.45 (d, 2H), 7.30 (m , 5H), 4.35 (bd, 1H), 4.05 (m, 1H), 3.34 (s, 3H), 3.63 (s, 2H), 2.8 (m, 2H), 2.58 (dd, 1H), 2.45 (d d, 1H), 2.84 (m, 1H), 1.65 (m, 1H). Methyl 4- (3 (R)-(1- (1,1-dimethylethoxycarbonyl) pyrroli Dinyl) amino) benzoate (18-3) 18-2(0.29 g; 0.93 mmol) and 10% Pd / C (0.068 g; 23% by weight)_ThreeSuspension in OH (7 ml) under hydrogen atmosphere For 48 hours. The mixture was filtered over Solka Flo and the solvent was removed . CH residue_TwoCl_Two(5 ml) and Et._ThreeN (0.65 ml; 4.7 mmol) and BOC_TwoTreated with O (0.45 g; 2.1 mmol). Reaction mixture The mixture was stirred at room temperature for 1 hour, Then diluted with EtOAc and 10% KHSO_FourAnd washed with brine, dehydrated (Na_TwoSO_Four), The solvent was removed. Dissolve the residue in 1: 1 EtOAc / hexane Purification by flash chromatography on silica gel separating18- 3 Was obtained as an oil. R_f= 0.3 (silica gel; 3: 2 EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 1.47 (9H, s), 1.92 (1 H, s), 2.20 (1H, q), 3.25 (3H, s), 4.11 (1H, m), 4 . 19 (1H, m), 6.55 (2H, d), 7.87 (2H, d). Ethyl 2- (3-methyl-4- (4- (3 (R)-((1- (1,1-dimethyl Ethoxycarbonyl) pyrrolidinyl) amino) phenylcarbonylamino) fe Nyloxy) acetic acid (18-4) 18-3(0.245 g; 0.76 mmol) dissolved in dioxane (4 ml) The solution was treated with 1N NaOH (3.0 ml; 3.0 mmol) for 1 hour at room temperature. I understood. Thereafter, additional 1N NaOH (3.0 ml; 3.0 mmol) was added. And the reaction mixture was stirred for 15 hours. Then adjust the solution to pH 7 with 1N HCl And the solvent was removed. CH residue_TwoCl_Two(6 ml),10-4( 0.19 g; 0.77 mmol), diisopropylethylamine (0.53 ml) 3.0 mmol) and PYCLU (Fluka; 0.30 g; 0.83 mmol) 1). The reaction mixture was stirred at room temperature for 48 hours, after which the solvent was removed and the remaining Flash fraction on silica gel eluting the distillate with 3: 2 EtOAc / hexane Purified by chromatography,18-4Was obtained as an oil. R_f= 0.2 (silica gel; 3: 2 EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 1.30 (3H, t), 1.47 (9 H, s), 1.93 (1H, s), 2.24 (1H, m), 2.28 (3H, s), 3 . 27 (1H, m), 3.49 (2H, m), 3.73 (1H, m), 4.11 (2H , M), 4.16 (1H, m), 4.29 (2H, q), 4.60 (2H, s), 6. 62 (2H, d), 6.77 (1H, d), 6.81 (1H, s), 7.41 (1H, s), 7.68 (1H, d), 7.73 (2H, d). 2- (3-methyl-4- (4- (3 (R)-(pyrrolidinyl) amino) phenyl Carbonylamino) phenyloxy) acetic acid (18-5) 18-4(0.216 g; 0.434 mmol) in EtOAc (10 ml) The dissolved solution was cooled to −78 ° C. and treated with HCl (gas) for 1.5 minutes. Anti The reaction mixture was stirred at 0 ° C. for 1 hour, after which the solvent was removed. 1: 1: 1 residue THF / CH_ThreeOH / H_TwoO (6 ml) and LiOH.H for 2.5 hours at room temperature_Two Treated with O (0.11 g; 2.6 mmol). The solvent was removed and the residue was 1: 1 EtOH / H_TwoO / NH_FourFlash on silica gel eluting with OH Purified by chromatography,18-5Was obtained as a white solid. R_f= 0.2 (silica gel; 18: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; D_TwoO) δ: 1.57 (1H, m), 2.06 (1H, m) m), 2.08 (3H, s), 2.60 (1H, m), 2.76 (1H, m), 2.8 6 (1H, m), 3.03 (1H, m), 3.93 (1H, m), 4.38 (2H, s) , 6.71 (3H, m), 6.80 (1H, s), 7.05 (1H, d), 7.66 ( 2H, d).Reaction Scheme 19 Reaction Scheme 19(Continued) N-benzyl-3 (R)-((1,1-dimethylethoxycarbonyl) amino) Pyrrolidine (19-1)   N-benzyl-3 (R) -aminopyrrolidine (TCI; 5.00 g; 28.4) mmol) CH_TwoCl_Two(100 ml) was dissolved in Boc_TwoO (6.8 0 g; 31.2 mmol) and Et_ThreeTreated with N (7.9 ml; 57 mmol) Was. The reaction mixture was stirred at room temperature for 15 hours, after which the solvent was removed. Residue 3: Flash chromatography on silica gel, eluting with EtOAc / hexane 2 Purify by fee,19-1Was obtained as an oil. R_f= 0.4 (silica gel; 1: 1 EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 1.43 (9H, s), 1.60 (1 H, m), 2.27 (2H, m), 2.51 (1H, m), 2.62 (1H, m), 2 . 76 (1H, m), 3.58 (2H, s), 4.13 (1H, m), 4.89 (1H , M), 7.29 (5H, m). 4-((3 (R)-(1,1-dimethylethoxycarbonyl) amino) pyrrolidine 1-yl) phenylnitrile (19-2) 19-1(7.43 g; 26.9 mmol) and 10% Pd / C (2.45 g) ; 33% by weight)_ThreeThe suspension suspended in OH (150 ml) was_Two(gas) The mixture was stirred under an atmosphere for 5 hours. The reaction mixture was filtered through a Solka Floc pad And the solvent was removed. CH residue_ThreeDissolve in CN (20 ml) and Treated with 4-fluorobenzonitrile (16.1 g; 133 mmol) for hours. Then the reaction mixture was cooled to room temperature and the solvent was removed. Residue is 1: 1 EtOA by flash chromatography on silica gel eluting with c / hexane Purify,19-2Was obtained as a white solid. R_f= 0.4 (silica gel; 2: 3 EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 1.45 (9H, s), 1.9. 9 (1H, m), 2.30 (1H, m), 3.18 (1H, m), 3.46 (2H, m) 3.62 (1H, m), 4.36 (1H, b), 4.67 (1H, b), 6.52 ( 2H, d), 7.47 (2H, d). Methyl 4-((3 (R)-(1,1-dimethylethoxycarbonyl) amino) pi (Loridin-1-yl) -benzoate (19-3) 19-2(1.48 g) in dioxane (25 ml) and 1: 1 H_TwoSO_Four/ H_Two The solution dissolved in O (25 ml) was heated at 70 ° C. for 15 hours. Next, the reaction mixture The mixture was concentrated to remove dioxane and the mixture was_ThreeWith OH (100ml) Dilute, heat at 60 ° C. for 2 hours and stir at room temperature for 48 hours. Concentrate the reaction mixture CH_ThreeOH was removed and the residue was treated with 6N NaOH and NaHCO_ThreeP with a saturated solution of Adjusted to H10. CH2 aqueous mixture_TwoCl_TwoAnd extract the organic extract with oil Substance was obtained. This residue is CH_TwoCl_Two(25 ml) and Boc_TwoO (2.96 g; 13.6 mmol) and Et_ThreeN (2.2 ml; 16 mmol) Processed. The reaction mixture was stirred at room temperature for 15 hours. After that, the solvent is removed, Flash fraction on silica gel eluted with 2: 3 EtOAc / hexanes Purified by chromatography,19-3Was obtained as an oil. R_f= 0.5 (silica gel; 2: 3 EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 1.27 (9H, s), 1.99 (1 H, m), 2.30 (1H, m), 3.22 (1H, m), 3.42 (2H, m), 3 . 85 (3H, s), 4.37 (1H, b), 4.69 (1H, b), 6.51 (2H , D), 7.91 (2H, d). Ethyl 2- (4-((3 (R)-(1,1-dimethylethoxycarbonyl) amido No) pyrrolidin-1-yl) phenylcarbonylamino) -3-methylphenoki B) Acetic acid (19-4) 19-3(0.418 g; 1.30 mmol) in dioxa Solution dissolved in 10 ml of 1N NaOH (7.0 ml; 7.0 mmol). 1) and the reaction mixture was stirred at room temperature for 15 hours. Next, additional 1N Na OH (3.0 ml; 3.0 mmol) was added and the reaction mixture was stirred for another 15 hours did. The solvent was removed and the residue was_TwoTake in O, 10% KHSO_FourPH 6-7 And extracted with EtOAc. The combined organic extracts were dried (Na_Two SO_Four), The solvent was removed. CH residue_TwoCl_Two(7ml)10-4 (0.33 g; 1.3 mmol), DIPEA (0.81 ml; 4.6 mmol) ) And PYCLU (Fluka; 0.53 g; 1.5 mmol). Anti The reaction mixture was stirred at room temperature for 48 hours. Then the solvent was removed and the residue was 1: 1 Flash chromatography on silica gel, eluting with EtOAc / hexane -19-4Was obtained as a white solid. R_f= 0.3 (silica gel; 1: 1 EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 1.30 (3H, t), 1.46 (9 H, s), 2.04 (1H, m), 2.29 (3H, s), 2.31 (1H, m), 3 . 23 (1H, m), 3.45 (2H, m), 3.65 (1H, m), 4.27 (2H , Q), 4.38 (1H, b), 4.60 (2H, s), 4.72 (1H, b), 6. 57 (2H, d), 6.77 (1H, d), 7.67 (1H, s), 7.41 (1H, s), 7.72 (1H, d), 7.77 (2H, d). 2- (4-((3 (R) -amino) pyrrolidin-1-yl) phenylcarbonyl Amino) -3-methylphenoxy) acetic acid (19-5)   At -78 ° C19-4(0.306 g; 0.615 mmol) in EtOA The solution dissolved in c (15 ml) was treated with HCl (gas) for 1.5 minutes. next The reaction mixture was stirred at 0 ° C. for 1 hour and the solvent was removed. The residue is 1: 1: 1 T HF / CH_ThreeOH / H_TwoO (6 ml) and LiOH.H for 1 hour at room temperature_TwoIn O Processed. The solvent was removed and the residue was washed with 18: 1: 1 EtOH / H_TwoO / NH_FourOH Purified by flash chromatography on silica gel, eluting with1 9-5 Was obtained as a white solid. R_f= 0.4 (silica gel; 18: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; D_TwoO) δ: 1.74 (1H, m), 2.10 (3H, s), 2.12 (1H, m), 3.00 (1H, m), 3.28 (1H, m), 3.3 9 (1H, m), 3.47 (1H, m), 3.59 (1H, m), 4.39 (2H, s) , 6.61 (2H, d), 6.71 (1H, d), 6.81 (1H, s), 7.07 ( 1H, d), 7.79 (2H, d).Reaction Scheme 20 Reaction Scheme 20(Continued) 4- (piperidin-4-yl) piperidinylcarboxylic acid, acetate (20-1)   Lithium salt of N- (pyridin-4-yl) -4-piperidinecarboxylic acid (Te trehedron 44 (23), pp. 7095-7108, 1988 Manufactured as indicated; 1 g; 5.55 mmol) in 50 ml of 20% HOAc / MeOH, 10 ml of H_TwoO and suspended in 10 ml of concentrated HCl PtO suspension_Two(1.7 g) and hydrogenated at 65 psi for 24 hours. Dissolution The liquid was filtered and evaporated, the residue azeotroped with heptane,20-1The white solid and I got it. R_f= 0.39 (9: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; D_TwoO) δ: 3.6 to 3.5 (m, 4H), 3.9 (m , 1H), 3.1-3.0 (m, 4H), 2.65 (m, 1H), 2.32 (d, 2H) ), 2.25 (d, 2H), 2.0-1.7 (m, 4H). 4-((1,1-dimethylethoxycarbonyl) piperidin-4-yl) piperi Dinyl carboxylic acid (20-2) 20-1(1.7 g; 5.55 mmol) in H_TwoDissolved in O (10 ml) The solution was treated with a sufficient amount of 1N NaOH, thereby bringing the solution to pH 11. Was. No BOC dissolved in dioxane (20 ml) followed by 5 ml of dioxane Water (1.33 g; 6.2 mmol) was added. After one hour, the solvent was removed and the remaining The distillate was triturated with acetonitrile and n-butanol, filtered and the filtrate was concentrated. The residue is chromatographed (silica gel; EtOH / H 9: 1: 1)._TwoO / N H_FourOH)20-2Was obtained as a white solid. R_f= 0.70 (9: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; D_TwoO) δ: 4.12 (bd, 2H), 3.5 (bd, 2H), 3.32 (m, 1H), 2.95 (bt, 2H), 2.75 (bt, 2H), 2.9 (m, 1H), 2.15 (bd, 2H), 2.0 (bd, 2 H), 1.7 (m, 2H), 1.55 (m, 2H), 1.35 (s, 9H). Ethyl 2- (4- (4-((1,1-dimethylethoxycarbonyl) piperidine -4-yl) piperidinylcarboxamide) -3-methylphenoxy) acetic acid (2 0-3) 20-2(486 mg; 1.6 mmol) and10-4(250 mg; 1.6 mmol) CH_TwoCl_TwoWas dissolved. PYCLU (634 mg; 1.8 mmo l), followed by diisopropylethylamine (1.1 ml; 6.4 mmol). Added. The reaction mixture is stirred for 2 days. The reaction mixture was diluted with EtOAc and H_Two O, 10% KHSO_Four, NaHCO_ThreeWith saturated solution and brine. Organic Dehydrate the layer (MgSO 4_Four), Filter and concentrate to give a tan oil. H Rush chromatography (10% MeOH / NH_ThreeSaturated CHCl_ThreeBy) With the by-product bispiperidine urea Product (20-3) Got. This material is triturated with hexane, Remove most of R_f= 0.20 (10% MeOH / NH_ThreeSaturated CHCl_Three)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.55 to 7.57 (d, 1H), 6 . 88 (s, 1H), 6.74 (s, 1H), 6.71 to 6.72 (d, 1H); 6 (s, 1H), 4.27 to 4.29 (q, 2H), 4.23 to 4.25 (bs, 2 H), 2.9-3.0 (d, 2H), 2.6-2.7 (t, 2H), 2.35-2. 45 (t, 2H). 2- (4- (4-((1,1-dimethylethoxycarbonyl) piperidine-4- Il) piperidinylcarboxamide) -3-methylphenoxy) acetic acid (20-4) ) 20-3(300 mg) in THF / H_TwoO / MeOH (2ml / 2ml / 2m l). LiOH (50 mg) was added and the reaction mixture was stirred for 2 hours. Was. 1N HCl (0.50 ml) was added and the reaction mixture was concentrated,20-4 The tan As a solid. R_f= 0.16 (9: 1: 1 CH_TwoCl_Two/ MeOH / HOAc)¹ 1 H NMR (400 MHz; CD_ThreeOD) [delta]: 7.06 to 7.08 (d, 1H), 6 . 81 (s, 1H), 6.75 (d, 1H), 4.88 (s, 2H), 4.12-4. 15 (bd, 2H), 3.04 to 3.07 (bd, 2H), 2.6 to 2.8 (vbs , 2H), 2.25 to 2.45 (m, 4H), 2.17 (s, 3H), 1.46 to 1. . 56 (m, 6H), 1.45 (9H). 2- (4- (4- (piperidin-4-yl) piperidinylcarboxamide) -3 -Methylphenoxy) acetic acid (20-5) 20-4(0.08 mmol) dissolved in EtOAc and cooled to -78 ° . HCl (gas) is bubbled through the solution until it is saturated. Warm the reaction mixture to 0 ° And stir for 5 minutes. Concentrate the reaction mixture to give a tan solid. This substance 10: 1: 1 EtOH / NH as eluent_FourOH / H_TwoUse O Purified by lash chromatography20-5Is white Obtained as a solid. R_f= 0.15 (10: 1: 1 EtOH / NH_FourOH / H_TwoO)¹ 1 H NMR (400 MHz; D_TwoO) δ: 7.0 (d, 1H), 6.8 (s, 1H), 6.7 (dd, 1H), 4.7 (s, 1H), 3.4 (d, 2H), 3.1 (bd, 2) H), 2.9 (t, 2H), 2.8 (bt, 1H), 2.5 (bs, 3H), 2.10 ~ 2.13 (d, 2H), 2.06 (s, 3H), 1.96 to 1.99 (d, 2H), 1.65 to 1.75 (m, 4H).Reaction Scheme 21 Reaction Scheme 21(Continued) Reaction Scheme 21(Continued) 4-hydroxy-2-methylbenzoic acid (21-3)   4'-hydroxy-2'-methylacetophenone21-1(Aldrich; 18.0 g; 0.120 mol)21-3Was produced in two steps.   The first step is described in Merck's method patent US 852870-92031. Using the operation found in21-3And 3-iodo-4-hydroxy-6 -Methylbenzoic acid (21-2) Was obtained.   In the second step,21-2When21-3And the above mixture (7.0 g) with a balloon MeOH (200 ml) using 10% Pd / C (700 mg) under atmospheric pressure of hydrogen ) Reduced in After stirring for 16 hours, the reaction mixture was filtered through celite, The pad was washed with MeOH and the filtrate was concentrated to21-3As a tan solid I got it. R_f= 0.34 (90% ethyl acetate / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.8 (d, 1H), 6.6 (m, 2 H), 2.5 (s, 3H). Methyl 4-hydroxy-2-methylbenzoate (21-4) 21-3(5.0 g; 32.9 mmol) was again dissolved in MeOH (150 ml). Disengaged and cooled to 0 °. HCl (gas) is bubbled for several minutes, the cooling bath is removed, The reaction mixture was stirred at RT for 16 hours. Then the reaction mixture is concentrated to pure2 1-4 Was obtained as a tan solid. R_f= 0.83 (50% ethyl acetate / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.9 (d, 1H), 6.7 (m, 2 H), 3.85 (s, 3H), 2.57 (s, 3H). Ethyl 2- (3-methyl-4-methoxycarbonylphenoxy) acetate (2 1-5) 21-4(1.5 g; 9.0 mmol) was dissolved in DMF (150 ml). . Ethyl bromoacetate (1.0 ml; 9.0 mmol) followed by Cs_TwoCO_Three(2. 9 g; 9.0 mmol) was added. The resulting slurry was stirred vigorously for 16 hours. Was. The reaction mixture was diluted with EtOAc and diluted with water, 10% KHSO_FourAnd in brine Washed twice. The organic layer is dehydrated (MgSO 4_Four), Filter and concentrate21-5 I got This compound is used in the next step without any further purification. R_f= 0.40 (30% ethyl acetate / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.9 (d, 1H), 6.7-6.8. (m, 2H), 4.6 (s, 2H), 4.3-4.3 (q, 2H), 3.9 (s, 3H) , 2.6 (s, 3H), 1.3 (t, 3H). Ethyl 2- (3-bromomethyl-4-methoxycarbonylphenoxy) acetate To (21-6) 21-5(2.1 g; 8.3 mmol) in CCl_Four(40 ml) . NBS (1.9 g; 10.3 mmol) followed by dibenzoyl peroxide (400 mg; 1.66 mmol). The reaction mixture was heated at reflux for 16 hours. The reaction mixture was cooled and filtered through a pad of celite to remove excess succinimide. Was. Concentrate the filtrate21-6As a tan oil which was further purified. Used in the next step without doing. R_f= 0.52 (30% ethyl acetate / hexane) Ethyl 1- (4- (1,1-dimethylethoxycarbonylpiperazin-1-yl) )) Phenyl) -2-oxoisoindoline-5-oxy) acetate (21- 7)   In benzene (100ml)21-6(8.3 mmol), then14-3Dissolve Let it go. The resulting mixture was heated at reflux for 32 hours. Triethylamine (8. 3 mmol) was added and the reaction mixture was refluxed for another 2 days. Then reaction mixing The material was concentrated to give a brown solid, which was absorbed on silica and flash chromatographed. Purified by luffy. Small amount of product eluted with 50% EtOAC / hexane did. Next, the majority of the product was removed from 10% MeOH / NH_ThreeSaturated CHCl_ThreeIn column Rinsed from. The rinse gives a brown solid, which is used as eluent for 1 0% MeOH / CHCl_ThreeRepurified on a silica column using21-7To Obtained as a brown solid. R_f= 0.48 (50% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.8 (d, 1H), 7.7 (d, 2) H), 7.0 (m, 4H), 4.77 (s, 2H), 4.72 (s, 2H), 4.3 (q , 2H), 3.6 (m, 4H), 3.1 (m, 4H), 1.5 (s, 9H), 1.3 (t) , 3H). 1- (4- (1,1-dimethylethoxycarbonylpiperazin-1-yl) fe Nyl) -2-oxo-isoindoline-5-oxy) acetic acid (21-8) 21-7(1.3 g; 2.6 mmol) in THF / H_TwoO / MeOH (5 ml / 5ml / 5ml). LiOH (218 mg; 5.2 mmol) Was added and the resulting reaction mixture was stirred for 2 hours. 1N HCl (2.6 ml) And concentrate the reaction mixture,21-8And excess LiCl as a brown solid I got it. R_f= 0.80 (9: 1: 1 CH_TwoCH_Two/ MeOH / HOAc)¹ 1 H NMR (400 MHz; CD_ThreeOD) [delta]: 7.7 (m, 3H), 7.0 to 7.1. (m, 4H), 3.3 (bm, 4H), 3.1 (bm, 4H), 1.5 (s, 9H). 1-(((4-piperazin-1-yl) phenyl) -2-oxo-isoindori -5-oxy) acetic acid (21-9) 21-8(2.6 mmol) was dissolved in EtOAc and cooled to -78 [deg.]. The solution was bubbled until HCl was saturated. Thereafter, the reaction mixture was stirred at 0 ° for 10 minutes and concentrated to give a brown solid. Flash chromatography (10: 0.8: 0.8 EtoH / NH_FourOH / H_TwoBy O)21-9Was obtained as a brown solid. Preparative HPLC of this material Further purified by pure21-9(TFA salt) as an off-white solid Obtained. R_f= 0.72 (10: 1: 1 EtOH / NH_FourOH / H_TwoO)¹ 1 H NMR (400 MHz; DMSO-d₆) δ: 7.8 (d, 2H), 7.7 (d , 1H), 7.2 (s, 1H), 7.1 (d, 3H), 4.9 (s, 2H), 4.8 (s , 2H), 3.2-3.3 (bd, 8H).Reaction Scheme 22 Reaction Scheme 22(Continued) Reaction Scheme 22(Continued) Reaction Scheme 22(Continued) Reaction Scheme 22(Continued) Reaction Scheme 22(Continued) 1-chloro-2- (2-methyl-4-acetamidophenyl) ethanone (22- 2)   3-acetamidotoluene (Aldrich; 33.45 g; 0.224 mo l) is suspended in nitromethane (100 ml). Treated with lid (69.3 ml; 0.739 mol). The liquid became uniform. Tri-salt Aluminide (92.3 g; 0.694 mol) in 10 g portions over 40 minutes Was added. The temperature rose to 50 ° C. and the solution became dark brown. Reaction mixture for 2 hours Heat to 80 ° C., then cool to room temperature and concentrate to give a green viscous oil This material was added to the crushed ice chips and stirred with a top stirrer. The resulting tan solid is removed Collected in a sintered glass funnel, washed with water and dried,22-2The tan solid Obtained as body. R_f= 0.14 (40% EtOAc / hexane)¹ 1 H NMR (300 MHz; CDCl_Three) δ: 7.66 (d, 1H), 7.5 8 (m, 1H), 7.43 (s, 1H), 7.28 (s, 1H), 4.62 (s, 2H) , 2.55 (s, 3H), 2.2 (s, 3H). 1- (1-pyridinium) -2- (2-methyl-4-acetamidophenyl) e Tanone chloride (22-3) 22-2(21.8 g; 0.098 mol) in refluxing ethanol (110 ml) Was treated with pyridine (28 ml). Salmon pink sediment The mixture was cooled to room temperature after 2 hours at reflux, filtered and cooled (−20 ° C.) Rinse with EtOH and dry,22-3Was obtained as an off-white solid. R_f= 0.12 (9: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; D_TwoO) δ: 8.66 (d, 2H), 8.5 (m, 1H) , 8.08 (d, 2H), 7.92 (d, 1H), 7.5 (d, 1H), 7.33 (s , 1H), 2.4 (s, 3H), 2.1 (s, 3H). 2-methyl-4-amino-benzoic acid (22-4) 22-3(23.5 g; 0.077 mol) in H_TwoDissolved in O (155 ml) The temperature of the solution was adjusted to 60 ° C, and a 2.5 M solution of NaOH (160 ml) was added thereto. Added. An orange precipitate formed. The reaction mixture was heated at reflux for 2.5 hours, The homogeneous solution was cooled to room temperature, treated with 2.5 M HCl (160 ml) and stirred overnight. Stirred. The pH of the solution was adjusted to 4-5 with a solution of NaOH and the resulting yellow precipitate was removed. Wash with water and dry,22-4Was obtained as a yellow gummy solid. R_f= 0.76 (9: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (300 MHz; CD_ThreeOD) δ: 7.75 (d, 1H), 6.43 (m, 2H), 2.42 (s, 3H). n-butyl 2-methyl-4-amino-benzoate, hydrochloride (22-5) 22-4(8.8 g; 58 mmol) in n-butanol (200 ml). The cloudy suspension was cooled to O'C under argon, which was saturated with HCl gas. A precipitate of salmon pinta formed. The liquid was heated at reflux for 18 hours and then evaporated Was. The residue is taken up in EtOAc and NaHCO_ThreeDissolved in a saturated solution of and the layers were separated . The aqueous layer was washed repeatedly with EtOAc, the combined EtOAc layers were combined, and the And MgSO_Four, Filtered and evaporated. The oily residue is CHCl_ThreeDissolved in Let it evaporate,22-5Was obtained as a brown solid. R_f= 0.5 (20% EtOAc / hexane)¹ 1 H NMR (300 MHz; CDCl_Three) δ: 7.83 (d, 1H), 6.48 (m , 2H), 4.23 (t, 2H), 3.9 (bs, 2H), 3.53 (s, 3H), 1 . 7 (m, 2H), 1.48 (m, 3H), 0.95 (t, 3H). n-butyl 2-methyl-4-piperidin-1-yl-benzoate hydrochloride (22 -6) 22-5(10.7 g; 52 mmol) dissolved in n-butanol (285 ml) The dissolved solution was treated with bischloroethylamine hydrochloride (9.22 g; 52 mmol). Treated and refluxed for one week. The ethanol was removed under vacuum and the residue was taken up in EtOAc And diluted. A precipitate formed which was collected, washed with EtOAc and dried. ,22-6Was obtained as a tan solid. R^f= 0.31 (2.5% MeOH / NH_ThreeSaturated CHCl_Three)¹ 1 H NMR (400 MHz; CD_ThreeOD) δ: 7.88 (d, 1H), 6.88 (m , 2H), 4.24 (t, 2H), 3.55 (m, 4H), 3.36 (m, 4H), 2 . 56 (s, 3H), 1.73 (m, 2H), 1.5 (m, 2H), 1.0 (t, 3H) . n-butyl 2-methyl-4- (4- (1,1-dimethylethoxycarbonylpipe Lysin-1-yl) benzoate (22-7) 22-6(10.5 g; 33.3 mmol) in CH_TwoCl_Two(100ml) The thawed solution was cooled to 0 ° C. and triethylamine (18.8 ml; 0.133 m ol) and di-tert-butyl dicarbonate (14.75 g; 66 mmol). The solution was warmed to room temperature and after 1 hour 10% KHSO_Four, Washed with brine, MgS O_Four, Filtered and evaporated,22-7Was obtained as a brown oil . R_f= 0.4 (5% EtOAc / hexane)¹ 1 H NMR (300 MHz; CDCl_Three) δ: 7.9 (d, 2H), 6.68 (m, 2H), 4.23 (t, 2H), 3.55 (m, 4H), 3.38 (m, 4H), 2. 6 (s, 3H), 1.75 (m, 2H), 1.5 (m, 11H), 0.95 (t, 3H) . 2-methyl-4- (4- (1,1-dimethylethoxycarbonylpiperidine-1 -Yl) benzoic acid (22-8) 22-7(2.55 g; 6.78 mmol) in 4: 1 EtOH / H_TwoO (1 25 ml) and treated with NaOH (2.7 g; 67.8 mmol). And refluxed overnight. The solvent was removed and the residue was taken up in EtOAc and 10% KHSO_Four And distributed. The layers were separated and the aqueous layer was washed several times with EtOAc. One organic layer And washed with brine, MgSO_Four, Filtered and evaporated,22-8 Was obtained as a white solid.¹ 1 H NMR (400 MHz; CDCl_Three) δ: 8.0 (d, 1H), 6.7 (m, 2 H), 3.6 (m, 4H), 3.34 (m, 4H), 2.6 (s, 3H), 1.5 (s, 9H). N- (4-benzyloxyphenyl) -2-methyl-4- (4- (1,1-dimethyl Tylethoxycarbonyl) piperidin-1-yl) benzamide (22-9) 22-8(2.06 g; 6.43 mmol) in CH_TwoCl_Two(50ml) The solution thus obtained was treated with p-benzyloxyanaline hydrochloride (Aldrich; 1.66 g) 7.08 mmol), diisopropylamine (5.6 ml; 32 mmol) and And PYCLU (93.47 g; 9.6 mmol). After stirring for 24 hours, The volatile components were removed under vacuum, the residue was dissolved in EtOAc and 10% KHS O_Four, Water, NaHCO_ThreeWashed with saturated solution of water, water and brine, MgSO_FourDehydration with And filtered and evaporated. The residue was eluted with 20% → 50% EtOAc / hexane. Chromatography eluting with22-9Was obtained as an oil. R_f= 0.57 (50% EtOAc / hexane)¹ 1 H NMR (300 MHz; CDCl_Three) δ: 7.4 (m, 8H), 7.0 (d, 2) H), 6.76 (m, 2H), 4.08 (s, 2H), 3.6 (s, 4H), 3.22 ( bs, 4H), 2.53 (s, 3H), 1.5 (s, 9H). 1- (4-benzyloxyphenyl) -5- (4- (1,1-dimethylethoxy) Carbonyl) piperidin-1-yl) isoindoline-2-one (22.10) 22-9(0.66 g; 1.31 mmol) dissolved in THF (65 ml). The solution was cooled to -78 ° C under argon. n-butyllithium (in hexane 2.2M; 2.4ml) was added dropwise to give a deep red solution. 20 reaction mixtures And then cooled to -78 ° C in a THF solution of cyanogen bromide (in 65 ml). 2.77 g of cyanogen bromide; 26.2 mmol) Added rapidly via pore size cannula. The resulting colorless solution was stirred for 25 minutes And then quenched with methanol. Dilute the solution with water and remove volatile solvents under vacuum And the remaining aqueous layer was extracted with EtOAc. EtOAc layer with brine Washed, MgSO_Four, Filtered and evaporated. 20% to 30% residue Chromatography with a gradient elution with EtOAc / hexane,22-10 Was obtained as an oil. R_f= 0.25 (40% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.77 (s, 1H), 7.7 (d, 2H), 7.44 (m, 2H), 7.4 (m, 2H), 7.34 (m, 1H), 7.0 ( m, 3H), 6.9 (s, 1H), 5.1 (s, 2H), 4.73 (s, 2H), 3. 6 (m, 4H), 3.3 (m, 4H), 1.5 (s, 9H). 1- (4-hydroxyphenyl) -5- (4- (1,1-dimethylethoxycal Bonyl) piperidin-1-yl) isoindo Phosphorus-2-one (22-11) 22-10(0.155 g; 0.31 mmol) dissolved in 10 ml glacial acetic acid Treated solution with 10% Pd / C (0.3 g) and hydrogenate at 60 psi for 5 hours did. The solution from which the catalyst has been removed by decantation is concentrated and the residue is reduced to 60% → Chromatography eluting with 90% EtOAc / hexane gradient22-11 Was obtained as an oil. R_f= 0.19 (50% EtOAc / hexane)¹ 1 H NMR (300 MHz; CDCl_Three) δ: 7.79 (d, 1H), 7.55 (d , 2H), 7.0 (m, 1H), 6.92 (bs, 1H), 6.86 (m, 2H), 4 . 72 (s, 2H), 3.6 (m, 4H), 3.3 (m, 4H), 1.5 (s, 9H). Ethyl 4- (2-oxo-5- (4- (1,1-dimethylethoxycarbonyl) Piperidin-1-yl) isoindoline-1 -Yl) phenoxy acetate (22-12) 22-11(0.045 g; 0.11 mmol) dissolved in DMF (5 ml). Cesium carbonate (23 mg; 0.07 mmol) and ethyl bromoacetate (15 μl; 0.011 mmol). After 3 hours, remove solvent under vacuum And the residue was dissolved in EtOAc, washed with water, brine, MgSO_FourDehydration with And filtered and evaporated. The residue was concentrated with 30% → 50% EtOAc / hexane. Chromatography eluting with22-12Was obtained as an oil, R_f= 0.36 (40% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.74 (m, 3H), 7.0 (m, 3H) 2.H), 6.95 (m, 2H), 4.73 (s, 2H), 4.62 (s, 2H), 28 (q, 2H), 3.6 (m, 4H), 3.3 (m, 4H), 1.5 (s, 9H). Ethyl 4- (2-oxo-5-piperidin-1-yl) isoy Ndlin-1-yl) phenoxyacetate hydrochloride (22-13) 22-12(0.04 g; 0.08 mmol) in EtOAc (10 ml). The thawed solution was cooled to −78 ° C., saturated with HCl gas, and the resulting solution Is warmed to 0 ° C. and evaporated at ambient temperature,22-13As a white solid Was.¹ 1 H NMR (300 MHz; D_TwoO) δ: 7.54 (d, 1H), 7.4 (d, 2H) , 7.03 (m, 3H), 6.89 (d, 2H), 4.6 (s, 2H), 4.15 (q , 2H), 3.43 (m, 4H), 3.23 (m, 4H), 1.15 (t, 3H). 4- (2-oxo-5-piperidin-1-yl) isoindoline-1-yl) f Enoxyacetic acid (22-14) 22-13(0.04 g; 0.08 mmol) in 1: 1 THF / H_TwoO (6 ml) was dissolved in 1N NaOH. Treated with solution (0.4 ml). The reaction mixture is concentrated and the residue is 9: 1: 1 E tOH / H_TwoO / NH_FourChromatography eluting with OH gives22-14 Was obtained as a white solid. R_f= 0.62 (9: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; D_TwoO + deuteriotrifluoroacetic acid) δ: 7.4 9 (d, 1H), 7.44 (d, 2H), 6.95 (m, 3H), 6.74 (d, 2H) 4.33 (bs, 4H), 3.42 (bs, 4H), 3.25 (bs, 4H).Reaction Scheme 23 Reaction Scheme 23(Continued) Reaction Scheme 23(Continued) Reaction Scheme 23(Continued) 2-nitro-4- (1,1-dimethylethoxycarbonylamino) phenol ( 23-1)   2-nitro-4-aminophenol (Aldrich; 20 g; 130 mmo l) in THF (500 ml) was cooled to 0 ° C. and di-t-dicarbonate was added. Butyl (64 g; 293 mmol) and triethylamine (37 ml; 265 m) mol). After 24 hours, the solution was concentrated and the residue was dissolved in EtOAc. 10% KHSO_Four, NaHCO_ThreeWashed with a saturated solution of_Two SO_Four, Filtered and evaporated. The resulting crude bis-prot (bis-prot) edted) Substance [R_f= 0.69 (40% EtOAC / hexane)] 1 THF / H_TwoO dissolved in 400 ml, LiOH.H_TwoO (38 g; 1.3 mol). After stirring at room temperature overnight, the solvent was removed and the residue was taken up in EtOAc. Dissolve, wash with brine, Na_TwoSO_Four, Filtered and concentrated Thus, 23-1 was obtained as a reddish oily solid. R_f= 0.41 (20% EtOAC / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 10.35 (s, 1H), 8.18 ( s, 1H), 7.58 (d, 1H), 7.13 (d, 1H), 6.45 (bs, 1H) , 1.55 (s, 9H). Ethyl 2- (2-nitro-4- (1,1-dimethylethoxycarbonylamino) Phenoxy) acetic acid (23-2)   At room temperature23-1(5 g; 19.7 mol) dissolved in DMF (125 ml) The lysed solution was treated with cesium carbonate (3.17 g; 9.73 mmol), Stirred for minutes and treated with ethyl bromoacetate (2.2 ml; 19.8 mmol). After 1.5 hours, the solution was concentrated under high vacuum, the residue was absorbed on silica gel and % → 30% EtOAc / Hexanes gradient elution ,23-2The bright yellow solid As obtained. R_f= 0.26 (30% EtOAC / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.95 (s, 1H), 7.5 (d, 1H), 6.97 (d, 1H), 6.62 (bs, 1H), 4.72 (s, 2H), 4 . 25 (q, 2H), 1.5 (s, 9H), 1.28 (t, 3H). Ethyl 2- (2-methanesulfonamido-4-aminophenoxy) acetate, Hydrochloride (23-4) 23-2(2 g; 5.88 mmol) was dissolved in EtOAc (25 ml). Treat solution with 10% Pd / C (0.67 g) and hydrogenate at balloon pressure for 1.5 h did. The solution was filtered over SolkaFloc and the cake was rinsed with EtOAc. Filtrate Without concentrating methanesulfonyl chloride (3.0 ml; 39 mmol) and Treated with pyridine (5.0 ml; 62 mmol) and stirred overnight. The resulting solution And the residue is extracted with EtOA cH, 10% KHSO_Four, Na_TwoCO_ThreeWash with saturated solution and brine And Na_TwoOS_Four, Filtered and concentrated to give a yellow oil which was Is chromatographed (40% EtOAC / hexane)23-3[R_f = 0.19 (30% EtOAC / hexane)]23-3aWith Obtained in a state of being. This mixture (1.7 g) was dissolved in EtOAc (75 ml) And cooled to −78 ° C., saturated with HCl gas, and the resulting solution was cooled to 0 ° C. for 1 hour. And concentrated. CH residue_TwoCl_TwoAnd Na_TwoCO_ThreeAnd a saturated solution of Separate the layers and separate the aqueous layer with CH_TwoCl_TwoExtracted. Organic layer_TwoSO_FourDehydrated and filtered Filtered, evaporated and the residue was chromatographed (60% EtOAc / hexane). )23-4Was obtained as an off-white solid. R_f= 0.3 (60% EtOAC / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.7 (bs, 1H), 6.95 (s , 1H), 6.74 (d, 1H), 6.4 (d, 1H), 4.6 (s, 2H), 4.3 3 (q, 2H), 2.98 (s, 3H), 1.3 (t, 3H). Ethyl 2- (4- (4- (4- (1,1-dimethylethoxycarbonyl) pipera) Zin-1-yl) phenylcarbonylamino) -2-methanesulfonamide Nonoxy) acetate (23-5) 23-4(0.125 g; 0.433 mmol) and1-5(0.136 g; 0.444 mmol) in CH_TwoCl_Two(4ml) in diisopropane Ropyramine (0.3 ml; 1.7 mmol) and PYCLU (0.173 g; 0.48 mmol) and stirred at room temperature for 3 days. Concentrate the resulting solution, Absorb the residue on silica gel and gradient with 20% → 60% EtOAc / hexane Chromatography eluting,23-5Was obtained as a pale yellow oil . R_f= 0.27 (60% EtOAC / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.82 (dd, 1H), 7.79 ( s, 1H), 7.77 (s, 1H), 7.54 (bs, 1H), 7.48 (s, 1H), 6.90 (m, 3H), 4.7 (s, 2H), 4.25 (q, 2H), 3 . 6 (m, 4H), 3.3 (m, 4H), 3.03 (s, 3H), 1.5 (s, 9H), 1.3 (t, 3H). 2- (4- (4- (piperazin-1-yl) phenylcarbonylamino) -2- Methanesulfonamidophenoxy) acetic acid (23-6) 23-5(0.093 g; 0.16 mmol) dissolved in EtOAc (10 ml). The thawed solution was cooled to −78 ° C., saturated with HCl gas, and the resulting solution Was warmed to 0 ° C. for 1 hour and concentrated. The resulting white solid is 1: 1: 1 H_TwoO / T Dissolve in HF / MeOH and add LiOH.H_TwoO (0.038 g; 0.9 mmol ) And stirred at room temperature for 1 hour. Concentrate the reaction mixture and chromatograph (18: 1: 1 EtOH / H_TwoO / NH_FourOH) to remove the yellow oil Get this substance To CH_TwoCl_TwoDiluted with and evaporated23-6Was obtained as a white solid. R_f= 0.48 (9: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; D_TwoO + NaOD) [delta]: 7.74 (s, 1H), 7.7 2 (s, 1H), 7.21 (s, 1H), 7.07 (s, 1H), 7.05 (s, 1H) , 6.9 (d, 1H), 6.74 (d, 1H), 4.38 (s, 2H), 3.15 (m , 4H), 2.85 (m, 7H). Ethyl 2- (4- (4- (4- (1,1-dimethylethoxycarbonyl) pipera) Zin-1-yl) phenylcarbonylamino) -2-nitrophenoxy) acete (23-7) 23-2(0.3 g; 0.88 mmol) dissolved in EtOAc (10 ml). The cooled solution was cooled to −78 ° C., and saturated with HCl gas. Heat to 0 ° C. for hours and concentrate to give ethyl 2- (2-nitro-4-aminophenoxy). B) Acetate was obtained as a white solid. This material (0.26 g; 0.88 mmol) immediately1-5(0.29 g; 0.95 mmol);23 -5 Coupling as described for 40% EtOAc / hexane After chromatography eluting with a gradient from23-7To Obtained as a yellow solid. R_f= 0.22 (50% EtOAc / hexane) 2- (4- (4- (piperazin-1-yl) phenylcarbonylamino) -2- Nitrophenoxy) acetic acid (23-8) 23-7(0.186 g; 0.352 mmol) in EtOAc 1 gas, then LiOH.H_TwoIn O,23-6Processing as described for 18: 1: 1 EtOH / H_TwoO / NH_FourAfter chromatography eluting with OH23-8 Was obtained as a yellow solid. R_f= 0.47 (18: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; D_TwoO) δ: 8.0 (s, 1H), 7.68 (2s, 2 H), 7.52 (d, 1H), 7.0 (m, 2H), 3.12 (bs, 4H), 2.8 5 (bs, 4H). Ethyl 2- (2- (3-pyridyl) sulfonamido-4- (1,1-dimethyle Toxicarbonyl) aminophenoxy) acetate (23-9) 23-2(2 g; 5.88 mmol) was dissolved in EtOAc (25 ml). The solution was combined with 10% Pd / C and 3-pyridylsulfonyl chloride (JOC 54, pp. 389-393, 1989)23-3Process as described for After chromatography, gradient elution with 30% → 50% EtOAc / hexane To23-9Was obtained as a white solid. R_f= 0.11 (40% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 9.02 (s, 1H), 8.71 (d , 1H), 8.1 (m, 2H), 7.4 (s, 1H), 7.33 (m, 2H), 6.6. 9 (d, 1H), 6.58 (s, 1H), 4.4 (s, 2H), 4.23 (q, 2H), 1.5 (s, 9H), 1.25 (t, 3H). Ethyl 2- (4- (4- (4- (1,1-dimethylethoxycarbonyl) pipera) Zin-1-yl) phenylcarbonylamino) -2- (3-pyridylsulfone Mido) phenoxy) acetate (23-11) 23-9(0.318 g; 0.704 mmol) in EtOAc (10 ml) Dissolve the solution with HCl gas,23-4Process as described for23- 10 As a white solid, which is directly1-5When,23-5Operations mentioned for And eluting with a gradient of 20% → 40% acetone / hexane After toography23-11Was obtained as a yellow oily solid. R_f= 0.41 (50% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 2- (4- (4- (piperazin-1-yl) phenylcarbonylamino) -2- (2- (3-pyridylsulfonamido) phenoxy) acetic acid (23-12) 23-11(0.047 g; 0.087 mmol) in EtOAc Cl gas, then LiOH.H_TwoIn O,23-6Process as described for , 18: 1: 1 EtOH / H_TwoO / NH_FourAfter chromatography eluting with OH To23-12Was obtained as a yellow solid. R_f= 0.38 (18: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; D_TwoO + NaOD) [delta]: 8.76 (s, 1H), 8.5 (m, 1H), 8.13 (m, 1H), 7.7 (m, 2H), 7.45 (m, 1H) 1H), 7.12 (s, 1H), 7.08 (m, 2H), 6.84 (m, 1H), 6. 67 (d, 1H), 4.13 (s, 2H), 3.25 (m, 4H), 2.87 (m, 4 H). Ethyl 2- (2-methoxy-4-nitrophenoxy) acetate (23-13)   2-methoxy-4-nitrophenol (Aldrich; 1.0 g; 5.9 m mol) with cesium carbonate and ethyl bromoacetate,23-2As stated with respect to And after removing DMF,23-13I got This crude material is combined with water and EtOA C and the organic layer was separated with brine and MgSO_Four, Filtered and evaporated Let me23-13Was obtained as a yellow solid. R_f= 0.54 (50% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.8 (d, 1H), 7.76 (s, 1H), 6.75 (d, 1H), 4.71 (s, 2H), 4.2 (q, 2H), 3.9 ( s, 3H), 1.21 (t, 3H). Ethyl 2- (2-methoxy-4-aminophenoxy) acetate (23-14) 23-13(0.7 g; 2.7 mmol) dissolved in EtOH (10 ml) The solution was treated with 10% Pd / C (0.14 g) and hydrogenated at balloon pressure. Dissolution The liquid is filtered through Solka Flo and evaporated23-14The tan oil Obtained as a solid.¹ 1 H NMR (400 MHz; CDCl_Three) δ: 6.78 (d, 1H), 6.33 (s , 1H), 6.21 (d, 1H), 4.59 (s, 2H), 4.21 (q, 2H), 3 . 8 (s, 3H), 3.45 (bs, 2H), 1.28 (t, 3H). Ethyl 2- (4- (4- (4- (1,1-dimethylethoxycarbonyl) pipera) Zin-1-yl) phenylcarbonylamino) -2-methoxyphenoxy) ace Tate (23-15)   acid1-5And amine23-14And23-5Coupling with the operation described for And after chromatography eluting with 50% EtOAc / hexane23- Fifteen Was obtained as a brown solid. R_f= 0.13 (50% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.8 (d, 2H), 7.6 (d, 1) H), 6.92 (d, 2H), 6.86 (m, 2H), 4.64 (s, 2H), 4.2 4 (q, 2H), 3.9 (s, 3H), 3.6 (m, 4H), 3.3 (m, 4H), 1. 5 (s, 9H), 1.25 (t, 3H). 2- (4- (4- (4-piperazin-1-yl) phenylcarbonylamino)- 2-methoxyphenoxy) acetic acid (23-16)   Compound23-15With LiOH and HCl gas,23-6As stated with respect to To 10: 1: 1 EtOH / H_TwoO / NH_FourChromatog eluting with OH After ruffy23-16Was obtained as a white solid. R_f= 0.15 (10: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; D_TwoO) δ: 7.78 (d, 2H), 7.15 (s, 1) H), 7.08 (d, 2H), 6.9 (m, 1H), 6.78 (d, 1H), 4.4 ( s, 2H), 3.8 (s, 3H), 3.18 (bs, 4H), 2.88 (bs, 4H) .Reaction Scheme 24 2- (1,1-dimethylethoxycarbonyl) -7-bromo-1,2,3,4-te Trahydro-9H-pyrido [3,4-b] indole (24-2)   Rinehard et al., J. Am. Chem. Soc. 3378-3387, 1987).24-1(0.366 g; 1.4 6 mmol) in CH_TwoCl_Two(8 ml) at room temperature for 1 hour. Triethylamine (0.61 ml; 4.4 mmol) followed by di-tert-butyl dicarbonate (0.38 g; 1.7 mmol). The resulting solution is concentrated and the residue Is chromatographed (20% EtOAC / hexane).24-2To Obtained as a white solid. R_f= 0.28 (20% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 8.0 to 7.6 (m, 1H), 7 . 46 (s, 1H), 7.33 (d, 1H), 7.2 (d, 1H), 4.6 (b) s, 2H), 3.78 (bs, 2H), 2.76 (bs, 2H), 1.5 (s, 9H). 2- (1,1-dimethylethoxycarbonyl) -1,2,3,4-tetrahydro -9H-pyrido [3,4-b] indol-7-ylcarboxylic acid (24-3) 24-2(0.26 g; 0.734 mmol) dissolved in THF (10 ml). The solution was cooled to 0 ° C., and methylmagnesium chloride (3.0M THF solution 0. 29 ml; 0.87 mmol) to give a pale yellow solution. 15 minutes later, solution Was cooled to −78 ° C. and t-BuLi (4.35 ml of a 1.7 M pentane solution; 39 mmol) to give a bright yellow solution. After 10 minutes, CO_TwoGas Intensely aerated for 10 minutes. NH_FourA saturated solution of Cl, water, and a pH of 12. A sufficient amount of 6N NaOH was added and the solution was extracted with EtOAc. Back-extract the EtOAc layer with 0.5 N NaOH, combine the aqueous layers and acidify To pH 7, extract with EtOAc, dry the EtOAc layer (Na_TwoSO_Four), Filter and concentrate,24-3Was obtained as an off-white solid. R_f= 0.48 (75: 25: 1 CHCl_Three/ MeOH / HOAc)¹ 1 H NMR (400 MHz; DMSO-d₆) Δ: 12.0 (bs, 1H); 2 (s, 1H), 7.93 (s, 1H), 7.6 (d, 1H), 7.45 (d, 1H), 4.6 (s, 2H), 3.68 (m, 2H), 2.7 (m, 2H), 1.4 (s, 9H) . Ethyl 4- (2- (1,1-dimethylethoxycarbonyl) -1,2,3,4-te Trahydro-9H-pyrido [3,4-b] indol-7-yl) carbonylamido G) -3-Methylphenoxyacetate (24-4) 24-3(0.078 g; 0.25 mmol) and10-4(0.303 g; 1.23 mmol) in CH_TwoCl_TwoDissolved in Dissolve the solution with diisopropylamine and PYCLU,23-5With respect to And then gradient elution with 40% → 60% EtOAc / hexanes After matography24-4Was obtained as a white solid. R_f= 0.11 (40% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 8.5 to 8.2 (m, 1H), 8.0 (s, 1H), 7.75 (d, 1H), 7.63 (s, 1H), 7.52 (s, 2H), 6.83 (s, 1H), 6.80 (d, 1H), 4.7 (bs, 2H), 4.6 (s, 1H) 2H), 4.28 (q, 2H), 3.8 (bs, 2H), 2.83 (bs, 2H), 2. 82 (s, 3H), 1.5 (s, 9H), 1.3 (t, 3H). 3-methyl-4-((1,2,3,4-tetrahydro-9H-pyrido [3,4- b] Indol-7-yl) carbonylamino) phenoxyacetic acid (24-5) 24-4(0.082 g; 0.16 mmol) in EtOA c (10 ml) was dissolved in HCl gas, then LiOH.H_TwoIn O ,23-618: 1: 1 EtOH / H_TwoO / NH_FourAfter chromatography eluting with OH24-5Was obtained as a white solid . R_f= 0.48 (18: 1: 1 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; D_TwoO) δ: 7.9 (s, 1H), 7.54 (m, 2H) ), 7.13 (d, 1H), 6.84 (s, 1H), 6.75 (d, 1H), 4.40 (s, 2H), 3.8 (s, 2H), 3.0 (m, 2H), 2.7 (m, 2H), 2. 15 (s, 3H).Reaction scheme 25 Reaction scheme 25(Continued) Reaction scheme 25(Continued) 2,6-dibromo-3-methyl-4- (1,1-dimethylethoxycarbonyl) Aminophenol (25-1)   Under argon10-2(1.0 g; 450 mmol) in 20 ml of THF The digested solution was treated with N-bromosuccinimide (1.6 g; 9 mmol) for 2 hours. I understood. The solution was concentrated and the residue was resuspended in carbon tetrachloride and filtered. The filtrate Concentrate and chromatograph (15% EtOAC / hexane)25-1 Was obtained as a white solid. R_f= 0.56 (20% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDC1_Three) δ: 7.79 (bs, 1H), 6.08 ( bs, 1H), 5.8 (s, 1H), 2.33 (s, 3H), 1.43 (s, 9H). Ethyl 2- (2,6-dibromo-3-methyl-4- (1,1-dimethylethoxy) Carbonyl) aminophenoxy) acetate (25-2) 25-1(0.6 g; 1.57 mmol) in DMF was added to cesium carbonate and With ethyl lomoacetate,10-3Processing as described for25-2The tan As a solid. R_f= 0.56 (20% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 8.0 (bs, 1H), 6.21 (b s, 1H), 4.56 (s, 2H), 4.3 (q, 2H), 2.35 (s, 3H), 1. 5 (s, 9H), 1.33 (t, 3H). Ethyl 2- (2,6-dibromo-3-methyl-4-aminophenoxy) acetate To (25-3) 25-2(0.6 g; 1.29 mmol) dissolved in EtOAc (10 ml). HCl solution with HCl gas16-10Processing as described for25-3 Was obtained as a tan solid.¹ 1 H NMR (400 MHz; DMSO) δ: 7.0 (s, 1H), 4.8 to 4.4 ( b, 2H), 4.41 (s, 2H), 4.2 (q, 2H), 2.18 (s, 3H), 1. 2 (t, 3H). Ethyl 2- (2,6-dibromo-3-methyl-4- (4- (N- (1,1-dimethyl Tylethoxycarbonyl) piperidin-4-yl) phenylcarboxamide) f Enoxy) acetate (25-4) 25-3(0.520 g; 1.29 mmol) and1-5 (0.395 g; 1.29 mmol) in CH_TwoCl_TwoThe solution dissolved in N, N, N ', N'-bis (pentamethylene) formamidinium hexafluoro Lophosphate (0.504 g; 0.1.4 mmol) and diisopropylethyl Luamine (0.9 ml; 5.16 mmol) and stirred at room temperature for 24 hours . Dilute the solution with EtOAC and add H_TwoO, 10% KHSO_Four, NaHCO_ThreeSaturation of Wash with solution and brine_Four, Filtered and evaporated. Residue Is chromatographed (silica gel; 30% EtOAc / hexane) ,25-4When25-4aTo obtain a mixture.25-4a R_f= 0.45 (50% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 8.0 (m, 2H), 7.8 (d, 2 H), 7.5 (s, 1H), 6.93 (d, 2H), 6.85 (d, 1H), 4.6 (s) , 2H), 4.3 (q, 2H), 3.6 (bs, 8H), 3.35 (m, 8H), 2. 4 (s, 3H), 1.45 (s, 9H), 1.35 (t, 3H).25-4 Rf = 0.37 (50% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.6 (d, 2H), 6.7 (d, 2H) H), 4.6 (s, 2H), 4.3 (q, 2H), 3.55 (bs, 4 H), 3.3 (bs, 4H), 2.38 (s, 3H), 1.45 (s, 9H), 1.3 3 (t, 3H). 2- (2,6-dibromo-3-methyl-4- (4- (4- (1,1-dimethyle Toxylcarbonyl) piperidin-4-yl) phenylcarbonylamino) pheno Xy) acetic acid (25-5) 25-4as well as25-4a(0.3 g) in 1: 1: 1 THF / MeOH / H_Two The solution dissolved in O at 60 ° C. with LiOH (0.084 g; 2 mmol) Processed. After 1 hour, the reaction mixture was washed with EtOAc and 10% KHSO_FourDiluted in And the layers were separated. Organic layer H_TwoO, washed with brine, MgSO_FourDehydrated and filtered And evaporated to give 9: 0.5: 0.5 CH_TwoCl_Two/ MeOH / HOAc After chromatography to elute25-5Was obtained as a clear oil. R_f= 0.6 (9: 0.5: 0.5 CHCl_Three/ MeOH / HOAc)¹ 1 H NMR (400 MHz; CD_ThreeOD) δ: 7.90 (d, 2H), 7.6 (s , 2H), 7.05 (d, 2H), 4.55 (s, 2H), 3.6 (bs, 4H), 3 . 3 (bs, 4H), 2.35 (s, 3H), 1.5 (s, 9H). 2- (2,6-dibromo-3-methyl-4- (4-piperidin-4-yl) fe Nylcarbonylamino) phenoxy) acetic acid, hydrochloride (25-6)   A slurry obtained by adding the intermediate acid (0.4 g; 0.6 mmol) to EtOAc. The tree was cooled to -78 ° C, which was saturated with HCl gas. The resulting reaction mixture Is warmed to 0 ° C. and then concentrated in vacuo to give the HCl salt25-6I got R_f= 0.18 (10: 0.5: 0.5 EtOH / H_TwoO / NH_FourOH)¹ 1 H NMR (400 MHz; D20) δ: 7.73 (d, 2H), 7.23 (s, 1 H), 7.02 (d, 2H), 4.3 (s, 2H), 3.1 (bs, 4H), 2.82 ( bs, 4H), 2.1 (s, 3H).Reaction scheme 26 Reaction scheme 26(Continued) Reaction scheme 26(Continued) 1- (1,1-dimethylethoxycarbonyloxy) -3-nitro-4-amino Phenol (26-1)   3-nitro-4-aminophenol (Aldrich; 8 g; 52.6 mmol) l) in THF (250 ml) was cooled to 0 ° C and di-t-dicarbonate was added. Butyl (24 g; 110 mmol) and triethylamine (14 ml; 105 m mol). The solution was warmed slowly and concentrated after 24 hours and the residue was dissolved in tOAc, 10% KHSO_Four, NaHCO_ThreeSaturated solution and brine And washed with Na_TwoSO_Four, Filtered and evaporated,26-1The brown oil Obtained as a solid.¹ 1 H NMR (400 MHz; CDCl_Three) δ: 7.94 (s, 1H), 7.21 (dd , 1H), 6.8 (d, 1H), 6.04 (bs, 2H), 1.5 (s, 9H). 3-nitro-4- (1,1-dimethylethoxycarbonylamino) phenol ( 26-2)   Di-t-butyl dicarbonate (12 g; 52.6 mmol) was added to dichloroethane (10 0 ml) is refluxed, and26-1(52.6 mmol) Was dissolved in dichloroethane (150 ml), and the solution was rapidly added dropwise. The mixture was refluxed for 20 minutes, then cooled to room temperature and stirred overnight. Triethylamine (52.6 mmol) and 2,6-dimethylaminopyridine ( (1.3 g; 10.5 mmol) and the solution is refluxed for 2 hours and stirred at room temperature overnight. Stirred. The solvent was removed and the residue was washed with 1: 1: 1 THF / MeOH / H_TwoO 24 Dissolve in 0 ml, LiOH.H_TwoO (22 g; 526 mmol) for 48 hours I understood. The solution was washed with water, 10% KHSO_FourAnd diluted with EtOAc and the layers were separated. . Wash the organic layer with water and brine, and add MgSO_Four, Filtered and evaporated . Clean residue Chromatography (20% EtOAC / Hexane)26-2The yellow As a solid. R_f= 0.26 (20% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) Δ: 9.5 (bs, 1H), 8.35 (d , 1H), 7.61 (s, 1H), 7.13 (d, 1H), 5.33 (s, 1H), 1 . 55 (s, 9H). Ethyl 2- (3-nitro-4- (1,1-dimethylethoxycarbonylamino) Phenoxy) acetate (26-3)   At room temperature26-2(2 g; 7.87 mmol) dissolved in DMF (75 ml) The lysed solution was treated with cesium carbonate (1.28 g; 3.93 mmol), Stirred for minutes and treated with ethyl bromoacetate (0.8 ml; 7.92 mmol). After 1.5 hours, the solution was concentrated under high vacuum, the residue was absorbed on silica gel, and Elution with 10% EtOAc / hexane On the chromatograph,26-3Was obtained as a yellow solid. R_f= 0.18 (30% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDCl_Three) δ: 9.4 (bs, 1H), 8.44 (d, 1H), 7.65 (s, 1H), 7.26 (m, 1H), 4.63 (s, 2H), 24 (q, 2H), 1.55 (s, 9H), 1.3 (t, 3H). Ethyl 2- (3-nitro-4-aminophenoxy) acetate, hydrochloride (26- 4) 26-3(0.5 g; 0.2.5 mmol) dissolved in EtOAc (15 ml) The solution was cooled to −78 ° C., and saturated with HCl gas. Warm to 0 ° C. for 1 hour and concentrate,26-4Was obtained as an orange solid. R_f= 0.13 (10% MeOH / NH_ThreeSaturated CHCl_Three)¹ 1 H NMR (400 MHz; CD_ThreeOD) δ: 7.51 (d, 1H), 7.18 (d d, 1H), 7.0 (d, 1H), 4.68 (s, 2H), 4.24 (q, 2H), 1 . 15 (t, 3H). Ethyl 2- (3-nitro-4- (4- (4- (1,1-dimethylethoxycarbo) Nyl) piperazin-1-yl) phenylcarbonylamino) phenoxy) acete (26-5) 26-4(0.65 g; 2.46 mmol) and1-5(1.5 g; 4.9 m mol.) with PYCLU and diisopropylamine,23-5To Work up as described above and chromatograph elute with 30% EtOAc / hexane. After toography26-5as well as26-5aI got R_f= 0.16 (30% EtOAc / hexane)26-5 ¹ 1 H NMR (400 MHz; CDC1_Three) Δ: 8.95 (d, 1H), 7.9 (d, 1H) 2.H), 7.75 (s, 1H), 6.95 (d, 2H), 4.65 (s, 2H), 28 (q, 2H), 3.6 (m, 4H), 3.35 (m, 4H), 1.5 (s, 9H), 1.3 (t, 3H). Ethyl 2- (3-phenylsulfonamido-4- (4- (4- (1,1-dimethyl) Ruethoxycarbonyl) piperazin-1-yl) phenylcarbonylamino) f Enoxy) acetate (26-7) 26-5(0.4 g; 0.76 mmol) dissolved in EtOH (10 ml) The solution was treated with 10% Pd / C (0.070 g), Simplification. The solution was filtered through Solka Flo and the cake was rinsed with EtOAc . Concentrate the filtrate26-6I got R_f= 0.72 (10% MeOH / NH_ThreeSaturated CHCl_Three)   The crude amine obtained as above was dissolved in pyridine (3 ml) and Treat with Nylsulfonyl chloride (0.10 ml; 0.83 mmol) for 4 hours Stirred. Add the solution to EtO Diluted with Ac, washed with water and brine, dried over MgSO_Four, Filtered and concentrated Compressed to give a yellow oil which was chromatographed (30% EtOA). c / hexane to 100% EtOAc in gradient elution)26-7To Obtained as an oil. R_f= 0.85 (30% EtOAc / hexane)¹ 1 H NMR (400 MHz; CDC1_Three) δ: 8.04 (s, 1H), 7.7 (d, 2 H), 7.65 (d, 2H), 7.5 (s, 2H), 7.42 (d, 1H), 7.38 ( m, 2H), 6.9 (m, 2H), 6.8 (d, 1H), 6.6 (s, 1H), 4.4 6 (s, 2H), 4.25 (q, 2H), 3.6 (m, 4H), 3.3 (m, 4H), 1 . 5 (s, 9H), 1.28 (t, 3H). 2- (3-phenylsulfonamido-4- (4- (4-piperazin-1-yl)) Phenylcarbonylamino) phenoxy) acetic acid (26-8) 26-7(0.18 g; 0.28 mmol) in Li Chromatographic treatment with OH and HC1 gas as described for 23-6 Fee (10: 0.5: 0.5 EtOH / NH_FourOH / H_TwoO) and reversed-phase HPL After further purification by C26-8Was obtained as a white solid.¹ 1 H NMR (400 MHz; D_TwoO) δ: 7.6 (m, 3H), 7.48 (d, 2H) , 7.23 (m, 1H), 7.18 (m, 2H), 7.1 (d, 2H), 6.59 (s , 1H), 6.5 (d, 1H), 4.23 (s, 2H), 3.2 (m, 4H), 2.9 ( m, 4H).Reaction scheme 27 Reaction scheme 27(Continued) 4- [4- (4- (1,1-dimethylethoxycarbonyl) piperazine-1-i L) phenylcarbonylamino] -3-methylphenoxyacetic acid; N, N-diethyl Luglycolamide ester (27-2)   carboxylic acid10-6(500 mg; 1.07 mmol) and N, N-diethyl Chloroacetamide27-1(0.154 ml; 1.12 mmol) and NaI (5 mg; 0.03 mmol) and Cs_TwoCO_Three(173 mg; 0.535 mmol l) and DMF (5 ml) at 60 ° C. for 20 hours Heated. The reaction mixture was diluted with EtOAc, water, KHSO_Four10% aqueous solution And washed with brine. Dehydration (MgSO_Four), Filtration, removal of the solvent under vacuum, and Silica using EtOAC in hexane with a concentration gradient from 50% to 90% as eluent By chromatography on a gel, 4- [4- (4- (1,1-dimethyl Ethoxycarbonyl) piperazin-1-yl) phenylcarbonylamino] -3 -Methylphenoxyacetic acid N, N-diethylglycolamide ester (27-2 ) Was obtained as a white solid.¹ H NMR (CD_ThreeOD) δ: 1.23 (t, J = 7 Hz, 6H), 1.48 (s, 9 H), 2.25 (s, 3H), 3.32 (m, 8H), 3.58 (m, 2H), 4.8 3 (s, 2H), 4.92 (s, 2H), 6.83 (dd, J = 3 Hz, 9 Hz, 1H ), 6.90 (s, 1H), 7.03 (d, J = 9 Hz, 2H), 7.19 (d, J = ( Hz, 1H), 7.78 (d, J = 9 Hz, 2H).4- [4- (piperazin-1-yl) phenylcarbonylamino] -3-methyl Phenoxyacetic acid; N, N-diethylglycolamide ester, hydrochloride (27- 3)   Stir the HCl saturated solution in EtOAc (7 ml), then add EtOAc Ester suspended in (3 ml)27-2 (500 mg; 0.86 mmol) was added. The resulting mixture is heated at ambient temperature for 1 hour. Stir for 30 minutes, purge with dry argon for 30 minutes and concentrate under vacuum to give 4- [ 4- (piperazin-1-yl) phenylcarbonylamino] -3-methylpheno N, N-diethylglycolamide ester of xyacetic acid, hydrochloride (27-3) White Obtained as a colored solid.¹ H NMR (D_TwoO) δ: 1.11 (t, J = 7 Hz, 3H), 1.21 (t, J = 7 Hz, 3H), 2.23 (s, 3H), 3.37 (t, J = 7 Hz, 4H), 3.4 4 (m, 4H), 3.62 (m, 4H), 4.96 (s, 2H), 5.01 (s, 2H) , 6.92 (d, J = 9 Hz, 1H), 7.00 (s, 1H), 7.21 (m, 3H) , 7.90 (d, J = 9 Hz, 2H).4- [4- (4- (1,1-dimethylethoxycarbonyl) piperazine-1-i L) phenylcarbonylamino] -3-methylphenoxyacetic acid; N-methylglycol Choleamide ester (27-5)   carboxylic acid10-6(500 mg; 1.07 mmol) and N-methylchloro Acetamide27-4(0.121 mg; 1.12 mmol) and Nal (5 m g; 0.03 mmol) and Cs_TwoC0_Three(173 mg; 0.535 mmol) And DMF (5 ml) were heated at 60 ° C. for 20 hours. Reaction mixture Diluted with EtOAC, water, KHSO_FourWashed with 10% aqueous solution and brine . Dehydration (MgSO_Four), Filtration, solvent removal under vacuum and EtOA as eluent By chromatography on silica gel using C, 4- [4- (4- ( 1,1-dimethylethoxycarbonyl) piperazin-1-yl) phenylcarbo Nylamino] -3-methylphenoxyacetic acid N-methylglycolamide ester (27-5) Was obtained as a white solid.¹ H NMR (CD_ThreeOD) δ: 1.49 (s, 9H), 2.31 (s, 3H), 2.7 7 (d, J = 5 Hz, 3H), 3.29 (m, 4H), 3.61 (m, 4H), 4.6 7 (s, 2H), 4.75 (s, 2H), 5.85 (br s, 1H), 6.87 (m , 2H), 6.95 (d, J = (Hz, 2H), 7.47 (s, 1H), 7.78 (m, 1H), 7.79 (d, J = 9 Hz, 2H).4- [4- (piperazin-1-yl) phenylcarbonylamino] -3-methyl Phenoxyacetic acid; N-methylglycolamide ester, hydrochloride (27-6)   4- [4- (4- (1,1-dimethylethoxycarbonyl) piperazine-1- Yl) phenylcarbonylamino] -3-me N-methylglycolamide ester of tilphenoxyacetic acid (27-5325m g; 0.60 mmol) in EtOAC (30 ml) at 0 ° C. HCl gas was rapidly bubbled in for 0 minutes. The resulting mixture is aged for 40 minutes, Purge with Lugon and concentrate under vacuum. Residual solid was extracted with EtOAc and Et._TwoPowder with O Crushed to give 4- [4- (piperazin-1-yl) phenylcarbonylamino] -3 -Methylphenoxyacetic acid N-methylglycolamide ester, hydrochloride (27- 6 ) Was obtained as a white solid.¹ H NMR (D_TwoO) δ: 2.23 (s, 3H), 2.78 (s, 3H), 3.43 ( m, 4H), 3.62 (m, 4H), 4.75 (s, 2H), 4.95 (s, 2H), 6.90 (d, J = 8 Hz, 1H), 6.99 (s, 1H), 7.21 (m, 3H) , 7.90 (d, J = 9 Hz, 2H).Reaction scheme 28 Reaction scheme 28(Continued) 4- [4- (1-piperazinyl) phenylcarbonylamino] -3-methoxyphenyl Enoxyacetic acid, hydrochloride (28-8)   Compound15-8Using substantially the same procedure as described for Xyphenol (28-1)) And starting with 4- [4- (1-piperazinyl) Nylcarbonylamino] -3-methoxyphenoxyacetic acid, hydrochloride (28-8) Manufactured.¹ H NMR (D_TwoO) δ: 3.33 (d, J = 3.9 Hz, 4H), 3.51 (t, J = 3.9 Hz, 4H), 3.75 (s, 3H), 4.62 (s, 2H), 6.51 ( d, J = 8.6 Hz, 1H), 6.64 (s, 1H), 7.05 (d, J = 7.4) Hz, 2H), 7.32 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 7.4) Hz, 2H).Reaction scheme 29 Reaction scheme 29(Continued) 4-hydroxy-2-methylbenzoic acid (29-2)   Following the operation disclosed in US 92-852870 920317, 4- Hydroxy-2-methylacetophenone29-1From 4-hydroxy-2-methyl Benzoic acid was produced.¹ H NMR (CD_ThreeOD) δ: 2.52 (s, 3H), 6.64 (m, 2H), 7.8 4 (d, J = 8.4 Hz, 1H).4- [4- (1-piperazinyl) phenylaminocarbonyl] -3-methylphen Nonoxyacetic acid, hydrochloride (29-5)   Compound14-6Using substantially the same procedure as described for Roxy-3-methylbenzoic acid (29-2) And starting with 4- [4- (1-pipera Dinyl) phenylaminocarbonyl] -3-methylphenoxyacetic acid, hydrochloride (2 9-5 ) Manufactured.¹ 1 H NMR (DMSO-d₆) δ: 2.36 (s, 3H), 3.26 (d, J = 7. 3Hz, 8H), 3.80 (brs, 4H), 4.73 (s, 2H), 6.81 (d d, J = 2.4 Hz, 8.4 Hz, 2H), 6.84 (d, J = 2.4 Hz, 1H) ), 6.97 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.4 Hz, 1H) ), 7.62 (d, J = 8.7 Hz, 2H), 8.72 (brs, 1H), 9.9 9 (s, 1H).Reaction scheme 30 Reaction scheme 30(Continued) Reaction scheme 30(Continued) 4- (1,1-dimethylethoxycarbonyl) amino-3-trifluoromethyl Phenol (30-3)   Compound15-3Using a method similar to that described for 4- (1,1-dimethylethoxycarbonyl) amino-3 starting from the phenol -Trifluoromethylfe Knoll (30-3) Manufactured.¹ H NMR (CDCl_Three) δ: 1.55 (s, 9H), 4.12 (m, 2H), 6.7 2 (d, 1H), 7.12 (m, 1H), 7.26 (m, 1H).Ethyl 4- (1,1-dimethylethoxycarbonylamino-3-trifluoromethyl Tilphenoxy acetate (30-5)   In a 200 ml round bottom flask equipped with a stirring rod and an argon inlet, 4- (1 , 1-Dimethylethoxycarbonyl) amino-3-trifluorophenol (4 . 80 g; 17.3 mmol), 18-crown-6 (4.63 g; 17.5 m) mol) and THF (69 ml). The resulting mixture is brought to 0 ° C. in an ice-water bath. After cooling, a toluene solution of potassium hexamethyldisilyl azide (34.7) was added. ml; 17.4 mmol) followed by ethyl bromoacetate (1.93 ml; 17.4 ml). mmol) was added. The mixture was stirred under argon for 16 hours, during which time The cooling bath melted and disappeared. Transfer the mixture to a separatory funnel and add a 10% aqueous solution of citric acid. And extracted with EtOAC. The organic layer is washed with water and brine, dried (MgSO_Four), Filtered and concentrated in vacuo. BOC group29-9With respect to Removed. The material thus obtained is chromatographed on silica gel. And subjected to ethyl 4- (1,1-dimethylethoxycarbonylamino- 3-trifluoromethylphenoxyacetate (30-5) As an oily substance Was.¹ H NMR (CDCl_Three) δ: 1.58 (t, 3H), 3.93 (brs, 2H), 4 . 27 (q, 2H), 4.56 (s, 2H), 6.69 (d, 1H), 6.95 (dd, 1 H), 7.00 (d, 1H).4- [4- (1-piperazinyl) phenylcarbonylamino] -3-trifluoro Romethylphenoxyacetic acid (30-8)   Compound12-8A procedure similar to the one described for was used except that ethyl 4- ( 1,1-dimethylethoxycarbonylamino-3-trifluoromethylphenoxy Shea acetate (30-5)) And starting with 4- [4- (1-piperazinyl) phenyl Rucarbonylamino] -3-trifluoromethylphenoxyacetic acid (30-8) Manufactured.¹ 1 H NMR (DMSO-d₆) δ: 3.25 (s, 4H), 3.50 (s, 4H), 4 . 84 (s, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.25 (m, 2H) , 7.39 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H) , 8.82 (br s, 1H), 9.72 (s, 1H).Reaction scheme 31 Reaction scheme 31(Continued) Ethyl 4- (4-nitrophenylcarbamate) -3-methylphenoxyacete (31-1)   Ethyl 4-amino-3-methylphenoxyacetate was placed in a 50 ml flask. Hydrochloride (10-4300 mg; 1.22 mmol) in CH_TwoCl_Two(30m The solution dissolved in 1) was added. To this solution was added 4-nitrophenyl chloroformate (2 46 mg; 1.22 mmol) and pyridine (0.22 ml) were added at room temperature. . The reaction mixture was stirred at ambient temperature for 18 hours, then concentrated in vacuo to ethyl 4- (4-nitrophenyl carbamate) -3-methylphenoxyacetate (31 -1 ) Got.¹ H NMR (CDCl_Three) δ: 3.25 (s, 4H), 3.50 (s, 4H), 4.8 4 (s, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.25 (m, 2H), 7 . 39 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 8 . 82 (br s, 1H), 9.72 (s, 1H).4- (1,1-dimethylethoxycarbonyl) -4,4′-bipiperidine (31 -3)   Bipiperidine dihydrochloride (Aldrich;31-23 5 g; 0.1 mol)_TwoThe solution dissolved in O (100 ml) was Placed in bottom flask. A 6N solution of NaOH was added dropwise to adjust the pH to 8-9. Was. The solution was diluted with EtOH (1200 ml) and stirred vigorously at ambient temperature. Profit The resulting mixture was treated with di-tert-butyl dicarbonate (24 g; 0.11 mol) in EtOH. (800 ml). Add 6N NaOH periodically To maintain the pH at 8-9. After stirring for 18 hours at ambient temperature, the reaction mixture is Concentrated. Residue in 1: 1 ether: H_TwoDissolved in O (1000 ml), 6 The pH was adjusted to 12 with N NaOH. The aqueous phase was separated and extracted again with ether. Was. Combine the ether phases, combine brine, 10% citric acid and H_TwoWash with O Was. Citric acid washing solution and H_TwoCombined with the O washing solution and the pH is adjusted to 12 to 12 with 6N NaOH. The mixture was adjusted to 13 and extracted with ether (600 ml) in three portions. Athe Extract (brine), dehydrate (Na_TwoSO_Four) And concentrate under vacuum A clear oil was obtained which solidified on standing to give 4- (1,1-dimethylethoxy). (Cicarbonyl) -4,4'-bipiperidine (31-3) Got.¹ H NMR (CDCl_Three) δ: 1.25 (br m, 7H), 1.45 (s, 9H), 1.66 (br d, 4H), 2.60 (dd, 4H), 3.1 (d, J = 12 Hz, 2H), 4.21 (br s, 2H).Ethyl 4-[(4- (1,1-dimethylethoxycarbonyl) -4,4′-bipi Peridinyl-1-carbonyl) amino] -3-methylphenoxyacetate (3 1-4)   Ethyl 4- (4-nitrophenylcarbamate) -3-methylphenoxyacetate Tate (31-1457 mg; 1.22 mmol), 4- (1,1-dimethyl Ethoxycarbonyl) -4,4'-bipiperidine (31-3327 mg; 22 mmol) and triethylamine (0.34 ml; 2.44 mmol) with C H_TwoCl_Two(20 ml), the resulting solution was refluxed for 4 hours, cooled and CH_Two Cl_Two(10 ml). The reaction mixture is_TwoExtracted with O (15 ml). C H_TwoCl_TwoWash the extract (1% NaOH, H_TwoO, 10% KHSO_Four, Bly Dehydrated (Na)_TwoSO_Four), Filtered and then concentrated in vacuo to give an oil . Chromatography on silica eluting this material with 50% EtOAc / hexane Raffy And ethyl 4-[(4- (1,1-dimethylethoxycarbonyl) -4,4 '-Bipiperidinyl-1-carbonyl) amino] -3-methylphenoxyacete (31-4) Got.¹ H NMR (CDCl_Three) δ: 1.27 (br m, 7H), 1.30 (t, J = 7.0 Hz, 3H), 1.46 (s, 9H), 1.68 (d, J = 12 Hz, 2H) , 1.75 (d, J = 10 Hz, 2H), 2.22 (s, 3H), 2.65 (t, J = 12 Hz, 2H), 2.83 (t, J = 12 Hz, 2H), 4.08 (d, J = 1 2Hz, 1H), 4.25 (brs, 2H), 4.27 (q, J = 7Hz, 2H) 4.58 (s, 2H), 5.97 (s, 1H), 6.70 (dd, J = 8.3 Hz) , 2 Hz, 1H), 6.73 (d, J = 2 Hz, 1H), 7.40 (d, J = 8.3) Hz, 1H).4-[(4- (1,1-dimethylethoxycarbonyl) -4,4′-bipiperidi Nyl-1-carbonyl) amino] -3-methylphenoxyacetic acid (31-5)   4-[(4- (1,1-dimethylethoxy) placed in a 25 ml round bottom flask was used. Cicarbonyl) -4,4'-bipiperidinyl-1-carbonyl) amino] -3- Methylphenoxy acetate (31-4; 100 mg; 0.2 mmol) and 1 MLiOH (0.6 ml; 0.6 mmol) and H_TwoO (5 ml) and THF ( 5 ml) and MeOH (5 ml) The solution was stirred at ambient temperature for 3 hours. The reaction mixture is concentrated under vacuum, then CHC l_Three(20 ml). CHCl_ThreeWash the extract (1N HCl, H_Two O and brine), dehydrate (Na_TwoSO_Four), Filtered and concentrated to 4-[(4- (1,1-dimethylethoxycarbonyl) -4,4'-bipiperidinyl-1-ca Rubonyl) amino] -3-methylphenoxyacetic acid (31-5) Got.¹ H NMR (CDCl_Three) Δ: 1.22 (br m, 6H), 1.46 (s, 9H), 1.6 (br m, 4H), 2.2 (s, 3H), 2.6 (br t, 2H), 2. 79 (t, J = 11 Hz, 2H), 4.0 (br m, 5H), 4.58 (s, 2H) , 6.1 (dd, J = 9 Hz, 2 Hz, 1H), 6.75 (d, J = 2 Hz, 1H) , 7.21 (d, J = 9 Hz, 1H), 8.1 (s, 1H).4-[(4- [4,4 ′]-bipiperidinyl-1-carbonyl) amino] -3- Methylphenoxyacetic acid hydrochloride (31-6)   4-[(4- (1,1-dimethylethoxycal) in a 35 ml round bottom flask Bonyl) -4,4'-Bipiperidinyl-1-carbonyl) amino] -3-methyl Phenoxyacetic acid(31-5; 83 mg; 0.17 mmol) in CH_TwoCl_Two(10 ml) and cooled to 0 °. Anhydrous HCl is bubbled through the resulting solution for 5 minutes. Was. The reaction mixture was stirred at 0 ° for 4 hours, then concentrated in vacuo to 4-[(4- [ 4,4 ']-Bipiperidinyl-1-carbonyl) amino] -3-methylphenoxy Acetic acid, hydrochloride (31-6) Got.¹ 1 H NMR (DMSO-d₆) δ: 1.04 (br d, J = 11 Hz, 3H), 1 . 3 (brs, 3H), 1.62 (d, J = 12 Hz, 2H), 1.79 (d, J = 11 Hz, 2H), 2.07 (s, 3H), 2.67 (t, J = 12 Hz, 2H) , 2.74 (br m, 2H), 4.07 (d, J = 12 Hz, 2H), 4.59 ( s, 2H), 6.62 (dd, J = 9 Hz, 2 Hz, 1H), 6.70 (d, J = 2 Hz, 1H), 6.95 (d, J = 9 Hz, 1H), 7.87 (s, 1H), 8.2 ( br s, 1H), 8.5 (br s, 1H).Reaction scheme 32 4- (2- (4-dimethoxyethoxycarbonyl)-(4,4 ')-bipiperidi Nyl-1-carbonyl) phenol (32-2a)   In a 50 ml round bottom flask, 4- (1,1-dimethylethoxycarbonyl) ) -4,4'-Bipiperidine (31-3; 400 mg; 1.49 mmol), 4 -Hydroxybenzoic acid (32-1a; 206 mg; 1.49 mmol), chloro -N, N, N ', N'-bis (pentamethyl) formamidinium hexafluoro Lophosphate (537 mg; 1.49 mmol) and diisopropylethyl acetate A solution of min (0.52 ml; 2.98 mmol) dissolved in 25 ml of DMF Was stirred at ambient temperature for 48 hours. The reaction mixture is concentrated under vacuum and then EtOAc c and H_TwoAnd O. Wash the EtOAc extract (H_TwoO, NaHCO_ThreeTired of Sum solution, H_TwoO, 10% KHSO_FourAnd brine), dehydrate (Na_TwoSO_Four), Filtration And concentrated under vacuum. The resulting oil was purified with 5% MeOH / CHCl_ThreeAnd chromatographed on silica using 4- (2- (4- Dimethoxyethoxycarbonyl)-(4,4 ')-bipiperidinyl-1-carbo Nyl) phenol (32-2a) Got.¹ H NMR (CDCl_Three) δ: 1.2 (br m, 6H), 1.4 (s, 9H), 1. 58 (br m, 4H), 4.1 (m, 2H), 4.3 (m, 1H), 6.83 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H).4- (2- (4-dimethoxyethoxycarbonyl)-(4,4 ')-bipiperidi Nyl-1-yl-2-oxo-ethyl) phenol (32-2b)   Compound32-2aWas prepared in the same manner as in the production of 4- (2- (4-dimethoxy) Toxicarphonyl)-(4,4 ')-bipiperidinyl-1-yl-2-oxo- Ethyl) phenol (32-2b) Manufactured.¹ H NMR (CDCl_Three) δ: 0.89 (m, 1H), 1.1 (m, 3H), 1.45 (s, 9H), 1.5 (br m, 6H), 2.49 (t, J = 12 Hz, 1H), 2 . 62 (m, 2H), 2.91 (t, J = 12 Hz, 1H), 3.64 (s, 2H), 3.90 (d, J = 12 Hz, 1H), 4.1 (m, 2H), 4.68 (d, J = 1 2 Hz, 1 H), 6.12 (br m, 1 H), 6.77 (d, J = 8 Hz, 2 H) , 7.07 (d, J = 8 Hz, 2H).t-butyl 4- (2- (4-dimethoxyethoxycarbonyl) -(4,4 ')-Bipiperidinyl-1-carbonyl) phenoxyacetate (3 2-3a)   In a 50 ml round bottom flask, 4- (2- (4-dimethoxyethoxycarbo) Nil)-(4,4 ')-Bipiperidinyl-1-carbonyl) phenol (32- 2a 378 mg; 0.97 mmol), t-butyl bromoacetate (0.16 ml) ; 1.067 mmol) and cesium carbonate (348 mg; 1.067 mmol). Was added to 50 ml of DMF and the mixture was stirred at ambient temperature for 18 hours. Reaction mixture Is concentrated under vacuum, then CHCl_ThreeAnd H_TwoAnd O. CHCl_ThreeExtract Wash (10% KHSO_Four, H_TwoO, NaHCO_ThreeAnd brine), dehydrated (N a_TwoSO_Four), Filtered and concentrated in vacuo to give t-butyl 4- (2- (4-dimethoate). (Xyethoxycarbonyl)-(4,4 ')-bipiperidinyl-1-carbonyl) Phenoxy acetate (32-3a) Got.¹ H NMR (CDCl_Three) δ: 1.2 (m, 6H), 1.42 (s, 9H), 1.45 (s, 9H), 2.68 (m, 4H), 2.61 (t, 2H), 2.8 (m, 2H), 4 . 18 (m, 4H), 4.5 (s, 2H), 6.9 (d, J = 8 Hz, 2H), 7.3 5 (d, J = 8 Hz, 2H).t-butyl 4- (2- (4-dimethoxyethoxycarbonyl)-(4,4 ')- Bipiperidinyl-1-yl-2-oxo-ethyl) phenoxyacetate (32 -3b) 32-3aWas prepared in the same manner as in the production of t-butyl 4- (2- (4-dimethoxy). (Cyethoxycarbonyl)-(4,4 ')-bipiperidinyl-1-yl-2-oxo So-ethyl) phenoxyacetate (32-3b) Manufactured.¹ H NMR (CDCl_Three) δ: 0.88 (m, 1H), 1.11 (m, 5H), 1.4 5 (s, 9H), 1.48 (s, 9H), 1.61 (m, 4H), 2.48 (t, J = 12 Hz, 1 H), 2.61 (br t, 2 H), 2.88 (t, J = 13 Hz, 1 H), 3.66 (s, 2H), 3.88 (d, J = 13 Hz, 1H), 4.1 (m, 2 H), 4.49 (s, 2H), 4.68 (d, J = 13 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H).[4-([4,4 ′]-Bipiperidinyl-1-carbonyl) phenoxy] acetic acid ( 32-4a)   T-butyl 4- (2- (4-dimethoxyethoxycarbonyl) in a round bottom flask )-(4,4 ')-Bipiperidinyl-1-carbonyl) phenoxyacetate (32-3a 56 mg; 0.11 mmol) in trifluoroacetic acid (2.5 ml) and CH_TwoCl_Two(5ml ) Was added and stirred at 0 ° for 18 hours. The reaction mixture was concentrated in vacuo to give [4- ( [4,4 ']-Bipiperidinyl-1-carbonyl) phenoxy] acetic acid (32-4 a ) Got.¹ 1 H NMR (DMSO-d₆) δ: 1.11 (m, 2H), 1.32 (m, 4H), 1 . 78 (m, 2H), 1.80 (d, J = 12 Hz, 2H), 2.81 (dd, J = 11 Hz, 4H), 3.28 (d, J = 11 Hz, 2H), 4.73 (s, 2H), 6.94 (d, J = 8.5 Hz, 2H), 7.32, J = 8.5 Hz, 2H), 8 . 16 (br s, 1H), 8.47 (br s, 1H).[4- (2- [4,4 ']-Bipiperidinyl-1-yl-2-oxo-ethyl) Phenoxy] acetic acid (32-4b) 32-4a[4- (2- [4,4 ']-Bipiperi] Dinyl-1-yl-2-oxo-ethyl) phenoxy] acetic acid (32-4b) Made Built.¹ H NMR (CDCl_Three) δ: 0.81 (m, 1H), 1.07 (m, 1H), 1.3 6 (brs, 2H), 1.62 (d, J = 13 Hz, 1H), 1.74 (d, J = 12 Hz, 1H), 1.87 (brs, 2H), 2.56 (t, J = 11 Hz, 1 H), 2.94 (m, 3H), 3.36 (d, J = 12 Hz, 2H), 3.70 (m, 3H) 3H), 4.0 (d, J = 13 Hz, 1H), 4.57 (d, J = 13 Hz, 1 H), 4.64 (s, 2 H), 6.89 (d, J = 8.5 Hz, 2 H) , 7.17 (d, J = 8.5 Hz, 2H).Reaction scheme 33 Reaction scheme 33(Continued) Ethyl 4-pyridylpiperidin-4-ylcarboxylate (33-1)   Ethyl isonipecotate (6.0 g; 38.66 mmol), 4-chloropyri Gin hydrochloride (5.9 g; 38.66 mmol) and N-methylmorpholine (9. 3ml; 85.00mmol) in N-methylpyrrolidine (50ml). The resulting solution was heated at 100 ° C. for 48 hours. Solution under vacuum Concentrate and dissolve the residue in EtOAc and add water and brine (2 × 100 ml) Wash, then dehydrate (Na_TwoSO_Four), Evaporated. Flash chroma residue Torography (5% MeOH / CHCl_Three)33-1The crystal Obtained as a crystalline solid.¹ H NMR (CDCl_Three) δ: 8.21 (d, J = 6.8 Hz, 2H), 6.78 (d , J = 6.8 Hz, 2H), 4.18 (q, J = 7.0 Hz, 2H), 3.85 (m , 2H), 3.10 (m, 2H), 2.61 (m, 1H), 2.05 (m, 2H), 1 . 85 (m, 2H), 1.23 (t, J = 7.0 Hz, 3H). 4-pyridylpiperidin-4-ylcarboxylic acid (33-2) 33-1(10 g; 42.7 mmol) in THF (50 ml). Treat the solution with 1N LiOH (47 ml; 47.0 mmol) and water (50 ml) did. The resulting solution was stirred at ambient temperature for 12 hours. The solution is concentrated and the aqueous residue Was cooled to 0 ° C. and adjusted to pH 6 with 1N HCl. The resulting solid The body is recovered by filtration and dried under vacuum,33-2Was obtained as a white solid .¹ H NMR (D_TwoO) δ: 7.95 (d, J = 6.8 Hz, 2H), 6.73 (d, J = 6.8 Hz, 2H), 3.76 (d, J = 12.8 Hz, 2H), 2.81 (m , 2H), 2.20 (m, 1H), 1.85 (d, J = 12.9 Hz, 2H), 1. 55 (m, 2H). Ethyl 4- (pyridyl) (piperidin-4-yl) -carbonylamino-3-meth Tilphenoxy acetate (33-3)   Ethyl 4-amino-3-methylphenoxyacetate hydrochloride (10-40. 35 g; 1.41 mmol), 4- (pyridyl) (piperidin-4-yl) -ca Rubonic acid (0.30 g; 1.41 mmol), chloro-N, N, N ', N'-bi (Pentamethylene) formamidinium hexafluorophosphate (0.5 0 g; 1.41 mmol) and diisopro Pyrethylamine (0.25 ml; 1.41 mmol) was added to dimethylformamide (15 ml). The resulting solution was stirred at ambient temperature for 48 hours and the solvent was removed. Removal under vacuum gave an oil. This material was used as eluent in 5:95 methano Chromatography on silica gel using ammonia-saturated chloroform Over33-3Was obtained as a beige solid.¹ H NMR (CDCl_Three) δ: 8.27 (d, J = 5.6 Hz, 2H), 7.53 (d , J = 8.8 Hz, 1H), 7.03 (s, 1H), 6.78 (s, 1H), 6.7. 3 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 6.1 Hz, 2H), 4.5 9 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.97 (d, J = 13 . 2Hz, 2H), 2.95 (t, J = 11.7 Hz, 2H), 2.53 (m, 1H ), 2.06 (d, J = 10.7 Hz, 2H), 1.92 (m, 2H), 1.73 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 4- (pyridyl) (piperidin-4-yl) -carbonylamido No-3-methylphenoxyacetate (33-4)   Ethyl 4- (pyridyl) (piperidin-4-yl) -carbonylamino-3- Methylphenoxy acetate (33-3; 0.05 g; 0.126 mmol) A solution of tetrahydrofuran (10 ml) was dissolved in 1N lithium hydroxide (0. 13 ml; 0.132 mmol) and H_TwoTreated with O (10 ml). Got The solution was stirred at ambient temperature, the solvent was removed under vacuum,33-4The colorless glassy Obtained as material.¹ H NMR (CD_ThreeOD) δ: 8.09 (d, J = 6.6 Hz, 2H), 7.09 ( d, J = 8.6 Hz, 2H), 6.87 (d, J = 6.8 Hz, 1H), 6.81 ( s, 1H), 6.75 (d, J = 8.6 Hz, 1H), 4.34 (s, 2H), 4. 10 (d, J = 13.2 Hz, 2H), 3.02 (t, J = 10.0 Hz, 2H), 2.82 (m, 1H), 2.18 (s, 3H), 1.98 (d, J = 10.3 Hz, 2H), 1.83 (m, 2H).Reaction Scheme 34 Reaction Scheme 34(Continued) 3-chloro-4-aminophenol (34-2)   Compound12-2An operation similar to the one described for, except that 3-chlorophenol was used. Enol (34-1) Starting with 3-chloro-4-aminophenol (34- 2 ) Manufactured.¹ H NMR (CDCl_Three) δ: 6.57 (dd, J = 2.8 Hz, 8.6 Hz, 1 H), 6.73 (m, 2H).4- (1,1-dimethylethoxycarbonyl) amino-3-chlorophenol ( 34-3)   In a 100 ml round bottom flask equipped with a stirring rod and an argon inlet, 4- (1 , 1-Dimethylethoxycarbonyl) amino-3-chlorophenol (1.91 g; 13.3 mmol), di-t-butyl dicarbonate (3.14 g; 14.4 mmol) l) and THF (50 ml). Triethylamine (2 . 23 ml; 16.0 mmol) was added and this was stirred at room temperature for 98 hours. Dissolution The medium was removed under vacuum. The residue was acidified with a 10% aqueous solution of citric acid and EtOA Extracted with c. The EtOAc extract was washed with water and brine. Dehydration (MgSO_Four ), Filtration, solvent removal under vacuum, and EtO Oily substance by chromatography on silica gel with Ac / hexane I got This material was dissolved in THF (25 ml) and MeOH (8 ml) and 1 N LiOH (25 ml) was added. The solution was stirred at ambient temperature for 4 hours. this The mixture was acidified with 10% citric acid and extracted with EtOAc. Dehydrate the organic layer ( MgSO_Four), Filter and concentrate under vacuum34-3Was obtained as an oil. .¹ H NMR (CDCl_Three) δ: 1.53 (s, 9H), 6.69 (dd, J = 2.8) Hz, 8.9 Hz, 2H), 6.85 (d, J = 2.8 Hz, 1H), 7.80 (d , J = 8.9 Hz, 1H).Ethyl 4- (1,1-dimethylethoxycarbonyl) amino-3-chloropheno Kisia acetate (34-4)   4- (1,1) was added to a 50 ml round bottom flask equipped with a stir bar and an argon inlet. 1-dimethylethoxycarbonyl) amino-3-chlorophenol (0.831 g; 3.41 mmol) and DMF (16 ml). Ice the resulting mixture Cool in bath, then Cs_TwoCO_Three(0.552 g; 1.69 mmol) and bromide Ethyl moacetate (0.37 ml; 3.34 mm ol) was added. The mixture was stirred for 6 hours, during which time the cooling bath melted and disappeared. Lost. The mixture was filtered on a frit and DMF was removed under vacuum. Et residue Dissolved in OAc and washed with water (12 ×) and brine. Dehydration (MgSO_Four) , Filtration and removal of the solvent under vacuum gave an oil which was Purification by chromatography (EtOAc / hexane) gave ethyl 4- (1,1 -Dimethylethoxycarbonyl) amino-3-chlorophenoxyacetate (3 4-4 ) Was obtained as an oil.¹ H NMR (CDCl_Three) δ: 1.30 (m, 3H), 1.53 (s, 9H), 4.2 7 (m, 2H), 4.57 (s, 2H), 6.78 (br s, 1H), 6.83 (dd , J = 2.8 Hz, 8.8 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H) 8.02 (br d, J = 8.8 Hz, 1H).4- [4- (1-piperazinyl) phenylcarbonylamino] -3-chlorophen Nonoxyacetic acid (34-8)   Compound12-8A procedure similar to the one described for was used except that ethyl 4- ( (1,1-dimethylethoxycarbonyl) amino-3-chlorophenoxyacetate To (34-4Starting from) 4- [4- (1-piperazinyl) phenylcarbonylamino] -3-chlorophenyl Enoxyacetic acid was produced.¹ 1 H NMR (DMSO-d₆, HCl salt) δ: 3.22 (t, J = 5.0 Hz, 4H) 3.53 (t, J = 5.0 Hz, 4H), 4.75 (s, 2H), 6.94 (dd) , J = 2.9 Hz, 8.8 Hz, 1H), 7.08 (d, J = 8.9 Hz, 2H), 7.11 (d, J = 2.9 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.9 Hz, 2H), 9.12 (brs, 1H), 9.69 ( s, 1H).Reaction scheme 35 Reaction scheme 35(Continued) Reaction scheme 35(Continued) 1-hydroxymethyl-4- (4- (1,1-dimethylethoxycarbonyl) pi Perazinyl) benzene (35-1)   500 ml round bottom flask equipped with stir bar and argon inlet Dry and add acid1-5(5.00 g; 16.32 mmol) and distilled dry TH F (80 ml) was charged. The resulting solution was cooled in an ice bath and borane-THF complex Body (1M borane in THF; 125 ml; 125 mmol) via syringe And added. Keep this solution at 0 ° C. for 3.5 hours did. MeOH (50 ml) is added slowly via syringe over 5 hours. To stop the reaction. The mixture was stirred at ambient temperature for 18 hours. Dissolution The medium was removed under vacuum and the residue was dissolved in EtOAc (300 ml). This solution The solution to NaHCO_ThreeWith saturated aqueous solution and brine. Dehydration (MgSO_Four), Filtration 4.86 g of 1-hydroxymethyl-4 by filtration and solvent removal under vacuum -(4- (1,1-dimethylethoxycarbonyl) piperazinyl) benzene35 -1 Was obtained as a white solid.¹ H NMR (CDCl_Three) δ: 1.48 (s, 9H), 3.11 (m, 4H), 3.5 9 (m, 4H), 4.61 (s, 2H), 6.91 (d, J = 7 Hz, 2H), 7.2 7 (d, J = 7 Hz, 2H).4- (4- (11-dimethylethoxycarbonyl) piperazinyl) benzal Dehid (35-2)   1-Hydrohydrogen was added to a 50 ml round bottom flask equipped with a stir bar and an argon inlet. Xymethyl-4- (4- (1,1-dimethylethoxycarbonyl) piperazinyl )benzene35-1(2.15 g; 7.35 mmol), CHCl_Three(100ml) Passing And MnO_Two(12.0 g; 138 mmol). Allow the resulting mixture to ambient temperature And stirred for 24 hours. The salt was removed by filtration and the solvent was removed under vacuum. Remaining The distillate was washed with 90 g of silica using 30:70 EtOAC / hexane as eluent. Chromatography on Kagel. 4- (4- (1,1-dimethylethoxy) Cicarbonyl) piperazinyl) benzaldehyde35-2(2.10 g; 99% ) Was obtained as a crystalline solid.¹ H NMR (CDCl_Three) δ: 1.49 (s, 9H), 3.39 (m, 4H), 3.5 9 (m, 4H), 6.89 (d, J = 9 Hz, 2H), 7.75 (d, J = 9 Hz, 2H), 9.79 (s, 1H).Ethyl 2- (4-hydroxymethylphenoxy) acetate (35-4)   In a 500 ml round bottom flask equipped with a stir bar and an argon inlet, Roxybenzyl alcohol (7.50 g; 60.42 mmol), Cs_TwoCO_Three( 29.53 g; 90.63 mmol), DMF (100 ml) and bromoacetic acid Chill (11.09 g; 66.46 mmol) was charged. Allow the resulting mixture to ambient temperature And stirred for 2 hours. The mixture is filtered and the filtrate is Concentrated under vacuum. The residue was partitioned between EtOAc and water. Phase separated, organic phase Was washed twice with additional water. Dehydration (MgSO_Four), Filtration, and solvent removal under vacuum An oil was obtained by leaving. This material was eluted with 1: 1 EtOAc / hexane as eluent. Chromatograph on 250 g of silica gel with xane. ethyl 2- (4-hydroxymethylphenoxy) acetate35-4(7.47 g; 5 9%) as an oil.¹ H NMR (CDCl_Three) δ: 1.29 (t, J = 7 Hz, 3H), 2.07 (br   s, 1H), 4.26 (q, J = 7 Hz, 2H), 4.58 (s, 2H), 4.6 0 (s, 2H), 6.88 (d, J = 9 Hz, 2H), 7.27 (d, J = 9 Hz, 2H).Ethyl 2- (4-bromomethylphenoxy) acetate (35-5)   Ethyl was added to a 1 L round bottom flask equipped with a stir bar, addition funnel and argon inlet. 2- (4-hydroxymethylphenoxy) acetate35-4(7.47 g; 35.53 mmol), CBr_Four(13.26 g; 39.97 mmol) and dry Dry CH_TwoCl_Two(300 ml). The resulting solution in an ice bath Cool and add triphenylphosphine (10.48 g; 39.97 mmol ) CH_TwoCl_Two(100 ml) was added dropwise over 1 hour. The ice bath was thawed and the mixture was stirred at ambient temperature for 18 hours. Solvent under vacuum The residue was removed and the residue was dried over 200% using 15% EtOAc / hexane as eluent. g of silica gel were chromatographed directly. Ethyl 2- (4-bromo Methylphenoxy) acetate35-5(7.2 g; 74%) is a low melting solid (Mp: 44-45 [deg.] C).¹ H NMR (CDCl_Three) δ: 1.29 (t, J = 7 Hz, 3H), 4.26 (q, J = 7 Hz, 2H), 4.48 (s, 2H), 4.61 (s, 2H), 6.86 (d, J = 9 Hz, 2H), 7.32 (d, J = 9 Hz, 2H).4- (ethoxycarbonylmethoxy) benzyltriphenylphosphonium bromide Do (35-6)   100 m with stir bar and reflux condenser and with an argon inlet at the top Ethyl 2- (4-bromomethylphenoxy) acetate in a 1-volume round bottom flask3 5-5 (2.73 g; 10 mmol), triphenylphosphine (2.62 g; 10 mmol) and dry benzene (50 ml). The resulting solution is allowed Warmed to 0 ° C. The mixture was cooled to room temperature and the product was collected by filtration. White The solid was washed with a small amount of benzene and dried in vacuo to give 4- (ethoxycarbonyl). Lemethoxy) benzyltriphenylphosphonium bromide35-6The white crystals Obtained as a crystalline solid (4.79 g; 89%).¹ H NMR (CDCl_Three) δ: 1.28 (t, J = 7 Hz, 3H), 4.27 (q, J = 7 Hz, 2H), 4.53 (s, 2H), 5.38 (d, J = 14 Hz, 2H), 6.66 (d, J = 9 Hz, 2H), 7.06 (d, J = 9 Hz, 2H), 7.62 (m, 6H), 7.76 (m, 9H).(E) -ethyl 4- (2- (4- (4- (1,1-dimethylethoxycarbonyl) ) Piperazinyl) phenyl) ethenyl) phenoxyacetate (35-7)   A 100 ml round bottom flask equipped with a stir bar and an argon inlet was placed in an oven. After drying, add 4- (ethoxycarbonylmethoxy) benzyltriphenylphospho Honium bromide (1.106 g; 2.07 mmol) and dry THF (50 m l) was added. The resulting mixture was sufficiently stirred, and lithium hex was added thereto. A solution of methyldisilyl azide (1M in THF; 2.20 ml) was added. The crimson solution was stirred at ambient temperature for 1 hour and then cooled to 0 ° C. in an ice bath. this In the mixture, 4- (4- (1,1-dimethylethoxycarbonyl) piperazinyl) Dissolve benzaldehyde (0.60 g; 2.07 mmol) in 10 ml of THF The allowed solution was added. The ice bath was removed and the solution was stirred at ambient temperature for 3 hours. reaction The mixture was diluted with EtOAc and washed with water and brine. Dehydration (MgSO_Four) Filtration, and solvent removal under vacuum gave 1 g of an oil. This substance Clean on 80 g silica gel using 25% EtOAc / hexane as eluent It was chromatographed. (E) -ethyl 4- (2- (4- (4- (1,1- Dimethylethoxycarbonyl) piperazinyl) phenyl) ethenyl) phenoxy acetate35-7Was obtained as an oil.¹ H NMR (CDCl_Three) δ: 1.26 (t, J = 7HZ, 3H), 1.49 (s, 9H), 3.16 (m, 4H), 3.57 (m, 4H), 4.27 (q, J = 7 Hz, 2H), 4.60 (s, 2H), 6.90 (m, 6H), 7.40 (m, 4H) (E, Z 175 mg of a mixture of isomers).4- (2- (4- (1-piperazinyl) phenyl) ethyl) phenoxyacetic acid (3 5-8)   In a 25 ml round bottom flask equipped with a stir bar and a balloon pressure hydrogenation adapter (E, Z) -ethyl 4- (2- (4- (4- (1,1-dimethylethoxycarbo) Nil) piperazinyl) phenyl) ethenyl) phenoxyacetate (175 mg) ; 0.36 mmol), anhydrous EtOH (10 ml) and 10% Pd-C Was. The resulting mixture was hydrogenated at ambient temperature for 18 hours and 1 atmosphere. Catalyst for filtration It was then removed and the filtrate was concentrated under vacuum. The residue was purified with 20% Et as eluent. Chromatographed on 40 g of silica gel with OAc / hexane . The hydrogenated product thus purified is allowed to stand at ambient temperature for 3 hours in THF (2 ml). Hydrolyzed with 1N NaOH (1 ml). The reaction mixture was diluted with EtOAc, Washed with a 10% aqueous solution of citric acid, water and brine. Dehydration (MgSO_Four), Filtration Filtration and removal of the solvent under vacuum gave the corresponding acid as a white solid. This Material was dissolved in EtOAc (20 ml) and cooled to 0 ° C. in an ice bath. In solution Saturated dry HCl gas for 15 minutes. The resulting suspension is aged at 0 ° C. for 30 minutes. And then solvent and And excess HCl was removed under vacuum. Triturate the solid product with fresh EtOAc, Collected on frit. After drying at 60 ° C. and 0.05 Torr, 103 mg of 4 -(2- (4- (1-piperazinyl) phenyl) ethyl) phenoxyacetic acid35- 8 Was obtained as the hydrochloride salt (mp:> 250 ° C.).¹ 1 H NMR (DMSO-d₆) δ: 2.76 (s, 4H), 3.20 (m, 4H), 3 . 33 (m, 4H), 4.61 (s, 2H), 6.80 (d, J = 8 Hz, 2H), 6 . 90 (d, J = 8 Hz, 2H), 7.12 (m, 4H), 9.21 (brs, 2 H).(E) -4- (2- (4- (1-piperazinyl) phenyl) ethenyl) phenoxy Acetic acid (35-9)   (E) -E was added to a 25 ml round bottom flask equipped with a stirring rod and an argon inlet. Cyl 4- (2- (4- (4- (1,1-dimethylethoxycarbonyl) piperazine Nyl) phenyl) ethenyl) phenoxyacetate (57 mg; 0.12 mmol) l), THF (2.0 ml) and 1 N NaOH (1.00 ml). Profit The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was washed with 1N HCl (1. 00 ml) and EtOAc Extracted several times. The combined EtOAc extracts were washed with water and brine . Dehydration (MgSO_Four), Filtration and removal of the solvent under vacuum to give 45 mg of solid I got This solid was dissolved in 4N HCl-1,4-dioxane. The mixture Stirred at ambient temperature for 18 hours. The resulting milky suspension was concentrated under vacuum. The crude product was triturated with a small amount of EtOAc and collected on a frit. The material was dried in vacuo to give 24 mg of (E) -4- (2- (4- (1-piperazine Nyl) phenyl) ethenyl) phenoxyacetic acid35-9Was obtained as the hydrochloride salt (mp :> 250 ° C).¹ 1 H NMR (DMSO-d₆3.) δ: 3.2 (m, 4H), 3.45 (m, 4H), 69 (s, 2H), 6.89 (d, J = 9 Hz, 2H), 6.98 (d, J = 9 Hz) , 2H), 7.02 (s, 2H), 7.48 (m, 4H), 9.15 (brs, 2H), 13.02 (brs, 1H).Reaction Scheme 36 Reaction Scheme 36(Continued) 5-Nitrothiophene-2-carboxylic acid (36-2)   CH into a 500 ml round bottom flask equipped with a stir bar_ThreeIn CN (50 ml) 5-nitrothiophene-2-carboxaldehyde (7.86 g; 50.00 m mol), NaH in water (20 ml)_TwoPO_Four(1.86 g; 13.50 mmol ), And H_TwoO_TwoOf a 30% aqueous solution (6 ml). The resulting mixture in an ice bath Cool and add NaClO in water (70 ml)_Two(8 g; 70.80 mmol) Was added dropwise over 1 hour. The reaction mixture was stirred at room temperature for 5 hours. This mixture To Na_TwoSO_Three(500 mg) and acidified with 1 M HCl And then extracted with ethyl acetate (3 ×). Combine the combined organic layers with water (1 ×) And brine (1 ×). Dehydration (MgSO_Four), Filtration and dissolution under vacuum Removal of the medium gave 5-nitrothiophene-2-carboxylic acid as a yellow powder. Was.¹ 1 H NMR (300 MHz; CDC1_Three) δ: 7.91 (d, J = 4.4 Hz, 1 H), 7.80 (d, J = 4.4 Hz, 1H). Methyl 5-nitrothiophene-2-carboxylate (36-3)   In a 500 ml round bottom flask equipped with a stirring rod, 5-nitrothiophene-2- Carboxylic acid (4.62 g; 26.68 mmol) and MeOH (100 ml) were added. I put it. Cool the resulting solution in an ice bath and saturate the solution with dry HCl gas Until ventilated. Using a reaction vessel equipped with a condenser and a dehydration tube, the reaction mixture was allowed to stand overnight. Reflux. Then the solvent was removed under vacuum to give a yellow solid, which was Was dissolved. This solution is added to NaHCO_ThreeSaturated aqueous solution (3 ×) and brine (2 ×) and dehydrated (MgSO 4)_Four) And filtered. Solvent is removed under vacuum to form The product was dried in vacuo to remove methyl 5-nitrothiophene-2-carboxylate from yellow-brown. Obtained as a colored solid.¹ 1 H NMR (300 MHz; CDCl_Three) δ: 7.88 (d, J = 4.4 Hz, 1 H), 7.70 (d, J = 4.4 Hz, 1H), 3.96 (s, 3H). Methyl 5-aminothiophene-2-carboxylate (36-4)   In a Parr flask, add methyl 5-nitrothiophene-2-carboxylate (5 . 00g; 26.71 mmol) and MeOH (100 ml). Obtained The purged solution was purged with a stream of Ar and added to it with 5% platinum-carbon sulfide. onsulfide carbon (2.00 g) was added. Mix 6 . Hydrogenated for 5 hours on a Parr apparatus set at 50 psi. Then reaction mixing The material was filtered through celite, the solvent was removed in vacuo and methyl 5-aminothiophene -2-carboxylate was obtained as a yellow-green oil.¹ 1 H NMR (300 MHz; CDCl_Three) δ: 7.45 (d, J = 4.0 Hz, 1H ), 6.09 (d, J = 4.0 Hz, 1H), 4.31 (brs, 2H), 3.81 (s, 3H). 5- (4- (1,1-dimethylethoxycarbonyl) -piperazin-1-yl) -Thiophene-2-carboxylate (36-5)   In a 500 ml round bottom flask equipped with a condenser, stir bar and argon inlet Methyl 5-aminothiophene-2-carboxylate (4.27 g; 27.16 mmol), bis (2-chloroethyl) amine, hydrochloride (5.82 g; 32.5 9 mmol) and n-BuOH (90 ml; purged with Ar). Get The solution was refluxed under Ar for 7 days and the reaction was monitored by HPLC. Next, remove the solvent Remove under vacuum and remove the residue with EtOAc and NaHCO_ThreeAnd an aqueous solution of water Layer was extracted with EtOAc (3 ×) and the combined organic extracts were combined with brine (1 ×). ×), and dehydrated (Na_TwoSO_Four), Filtered and concentrated in vacuo. Remove the residue Azeotrope with Ruen (3x), vacuum overnight Dried.   The dried product is CH_TwoCl_Two(80 ml), and triethylamine (4 . 2 ml; 30.13 mmol), di-t-butyl pyrocarbonate (6.53 g; 29) . 90 mmol) and CH_TwoCl_Two(20 ml) was added and the reaction mixture was cooled to room temperature for 2 hours. Stirred for hours. Thereafter, the reaction mixture was concentrated under vacuum. Thereby 490 mg of n-butyl 5- (4- (1,1-dimethylethoxycarbonyl) -pipera Zin-1-yl) -thiophene-2-carboxylate and 700 mg of 5- ( 4- (1,1-dimethylethoxycarbonyl) -piperazin-1-yl) -thio Mixing phen-2-carboxylate with methyl and n-butyl esters Obtained as a product. n-butyl ester¹ 1 H NMR (300 MHz; CDCl_Three) δ: 7.55 (d, J = 4.4 Hz, 1H ), 6.06 (d, J = 4.4 Hz, 1H), 4.24 (t, 2H), 3.58 (t, 4H), 3.22 (t, 4H), 1.69 (m, 2H), 1.48 (s, 9H), 1. 42 (m, 2H), 0.95 (t, 3H). 5- (4- (1,1-dimethylethoxycarbonyl) -piperazin-1-yl) -Thiophene-2-carboxylic acid (36-6)   In a 50 ml round bottom flask equipped with a stirring rod, n-butyl 5- (4- (1,1 -Dimethylethoxycarbonyl) -piperazin-1-yl) -thiophen-2- Carboxylate (490 mg; 1.33 mmol) and NaOH in 3: 1 M OH / H_Two4.2 ml of a solution of 2.5 M in O were added. TH F (2 ml) was added to keep the reaction mixture homogeneous. Reaction mixture at room temperature Stir and follow the reaction by HPLC. After 2 days, the reaction mixture was concentrated under vacuum and Acidified with 0% citric acid and extracted with EtOAc (3x). Organic for one The extract was washed with water (1 ×), brine (1 ×), dried (Na_TwoSO_Four),filtration And the solvent was removed under vacuum. The product is azeotroped with benzene (3x) and vacuumed for 2 days Dry and dry 5- (4- (1,1-dimethylethoxycarbonyl) -piperazine- 1-yl) -thiophene-2-carboxylic acid as a dark green solid Obtained.¹ 1 H NMR (300 MHz; CD_ThreeOD) δ: 7.51 (d, J = 4.4 Hz, 1 H), 6.19 (d, J = 4.4 Hz, 1H), 3.57 (t, 4H), 3.24 (t , 4H), 1.47 (s, 9H). Ethyl 2- (4- (5- (4- (1,1-dimethylethoxycarbonyl) -pipe) Razin-1-yl) -2-thienylcarbonylamino) -3-methylphenoxy ) -Acetate (36-7)   In a 100 ml round bottom flask equipped with a stirring rod and an argon inlet, 5- (4 -(1,1-dimethylethoxycarbonyl) -piperazin-1-yl) -thiof Ene-2-carboxylic acid (428 mg; 1.370 mmol), anhydrous CH_TwoCl_Two( 10 ml), DMF (0.05 ml) and distilled oxalyl chloride (0. 180 ml; 2.6 mmol). Shake the contents of the flask at room temperature for 1.5 hours. Stirred. The acid chloride is concentrated under vacuum, azeotroped with benzene (3 ×) and under Ar atmosphere Stored.   Ethyl was added to another 100 ml round bottom flask equipped with stir bar and argon inlet. 4-amino-3-methylphenoxyacetate hydrochloride, anhydrous pyridine (7 ml) And dimethylaminopyridine (34 mg; 0.278 mmol).   The contents of the flask were cooled in an ice bath. Dissolve the above acid chloride in pyridine (3 ml) The lysed solution was added. The ice bath was removed and the reaction mixture was stirred at 80 C overnight.   The reaction mixture was concentrated in vacuo, dissolved in EtOAc and KHSO_FourAqueous solution ( 3 ×), NaHCO_ThreeWashed with an aqueous solution (2 ×), brine (1 ×), and dehydrated ( Na_TwoSO_Four), Filtered and the solvent was removed under vacuum. The residue is eluted with 18 Chromatography on silica gel using% EtOAc / hexane Ethyl 2- (4- (5- (4- (1,1-dimethylethoxycarbonyl) -pi Perazin-1-yl) -2-thienylcarbonylamino) -3-methylphenoxy C) -acetate was obtained.¹ 1 H NMR (300 MHz; DMSO-d₆) δ: 9.42 (s, 1H), 7.67 ( d, J = 4.3 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.83 ( d, J = 2.7 Hz, 1 H), 6.74 (dd, J = 8.8 Hz, 2.7 Hz, 1) H), 6.24 (d, J = 4.3 Hz, 1H), 4.76 (s, 2H), 4.17 (q , J = 7.1 Hz, 2H), 3.47 (t, 4H), 3.16 (t, 4H), 2.1 5 (s, 3H), 1.42 (s, 9H), 1.22 (t, J = 7.1 Hz, 3H). 2- (4- (5- (4- (1,1-dimethylethoxycarbonyl) -piperazine -1-yl) -2-thienylcarbonylamino) -3-methylphenoxy) -vinegar Acid (36-8)   In a 100 ml round bottom flask equipped with a stirring bar, ethyl 2- (4- (5- (4 -(1,1-dimethylethoxycarbonyl) -piperazin-1-yl) -2-thio (Enylcarbonylamino) -3-methylphenoxy) -acetate (250 mg 0. 496 mmol), MeOH (8 ml) and 1 M NaOH (1 ml). . The reaction mixture was stirred overnight at room temperature.   The reaction mixture is concentrated under vacuum and the KHSO_FourWith aqueous solution of EtOAc and EtOAc ( 2x). The organic extract was washed with brine (1 ×), dried (Na)_TwoS O_Four), Filtered and the solvent was removed under vacuum.   CH to product_TwoCl_Two(8 ml), and trifluoroacetic acid (2 ml) was added. Added. The reaction mixture was stirred at room temperature for 2 hours, then concentrated under vacuum. Residue 100% H for 40 minutes_Two50% H from O_TwoO / CH_ThreeCN (TFA HPLC on a C-18 reverse phase column, eluting with up to 0.1%). Suitable The relevant fractions were collected and lyophilized to give 2- (4- (5- (4- (1,1-dimethyl Ethoxycarbonyl) -piperazin-1-yl) -2-thienylcarbonylamido No) -3-Methylphenoxy) -acetic acid was obtained as a white fluffy solid.¹ 1 H NMR (300 MHz; CD_ThreeOD) δ: 7.62 (d, J = 4.1 Hz, 1 H), 7.16 (d, J = 8.5 Hz, 1H), 6.86 (d, J = 2.7 Hz, 1 H), 6.79 (dd, J = 8.5 Hz, 2.7 Hz, 1H), 6.34 (d, J = 4.1 Hz, 1H), 4.65 (s, 2H), 3.50 (m, 4H), 3.4 0 (m, 4H), 2.24 (s, 3H).                       Example 37 Tablet preparation   25.0 mg, 50.0 mg and 100.0 mg of the active compound 3- (4- (4 -Piperazin-1-ylphenylcarbonylamino) phenyl) -propanoic acid Tablets containing each are prepared as described below.                             table Dosage formulations containing 25-100 mg of active compound   Mix the whole amount of active compound and cellulose and part of corn starch, granulate To make 10% corn starch paste. The obtained granules are sieved and dried And mix with the rest of the corn starch and magnesium stearate. like this To get The granules are compressed to 25.0 mg, 50.0 mg and 100.0 mg per tablet. Tablets containing each mg of active ingredient are formed.                         Example 38 Formulation for intravenous administration   An intravenous dosage form of the active compound shown in Example 37 is prepared as follows.   Active compound 0.5-10.0 mg   Sodium citrate 5-50mg   Citric acid 1-15mg   Sodium chloride 1-8mg   Water for injection (USP) q. s. (For 1L total volume)   Using each component in the above amount, add sodium chloride, citric acid and sodium citrate in advance. Um for water for injection [USP; United States Pharmacope ial Convention, Inc. , Rockville, Maryla nd issued United States Pharmacopeia / Nati onal Formulary for 1995 (copyright 19 94) See page 1636 The active compound is dissolved at room temperature in the solution prepared by dissolving the active compound.                         Example 39 Formulation for intravenous administration   At room temperature, 3- (4- (4-piperazin-1-ylphenylcarbonylamido) G) activity using phenyl) propanoic acid, citrate buffer and sodium chloride A pharmaceutical composition having a component concentration of 0.25 mg / ml was prepared.   800 g of water is introduced into a standard pharmaceutical mixing container, into which 0.25 g of 4- (N-piperazine) benzoyl-N- (aminophen-4-yl) propionic acid Was dissolved. Add 2.7g sodium citrate and 0.16g citric acid Thereby, the citrate concentration at completion was 10 mM. 8 g of sodium chloride Was added. Thereafter, 200 g of water are added, whereby the desired A final concentration was achieved. The concentrations of various components of the obtained aqueous preparation were as follows.component amount   3- (4- (4-piperazin-1-ylphenyl)   Carbonylamino) phenyl) propanoic acid 0.25mg / ml   Citrate buffer 10 mM   Sodium chloride 8mg / ml   The finished concentrate is placed in a standard USP Type I borosilicate glass container. And store at 30-40 ° C. Prior to compound administration, the concentrated formulation was diluted 4: 1 The active ingredient concentration at the time of use is 0.05 mg / ml, which is transferred to an infusion bag.Therapeutic treatment   Compounds of the invention inhibit human or mammalian platelet aggregation or adhesion It can be administered to patients where it is desired.   The compounds of the present invention are useful for inhibiting platelet aggregation, i.e., treating arteries and organs, And / or the interaction between platelets and the surface of the artifact causes platelet aggregation and depletion. Useful for peripheral artery surgery (artery transplantation, carotid endarterectomy) and cardiovascular surgery Can be Aggregated platelets can form thrombi and thromboemboli. The above surgery By administering a compound of the present invention to a recipient patient, the formation of thrombi and thromboemboli can be reduced. Can be prevented.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/4409 A61K 31/4409 31/445 31/445 31/4545 31/4545 31/495 31/495 31 / 496 31/496 31/519 31/519 A61P 7/02 A61P 7/02 C07D 209/08 C07D 209/08 209/46 209/46 211/26 211/26 211/34 211/34 211/62 211 / 62 213/55 213/55 213/56 213/56 213/73 213/73 213/74 213/74 213/75 213/75 295/08 295/08 A 295/14 295/14 A 295/20 295 / 20 A 333/40 333/40 401/04 401/04 471/04 103 471/04 103A 487/04 140 487/04 140 491/048 491/048 (81) Designated country EP (AT, BE, CH, DE , DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, L, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ) , TM), AL, AM, AU, AZ, BA, BB, BG, BR, BY, CA, CN, CU, CZ, EE, GE, HU, IL, IS, JP, KG, KR, KZ, LC , LK, LR, LT, LV, MD, MG, MK, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK, SL, TJ, TM, TR, TT, UA, US, UZ, VN, YU, ZW (72) Inventor Egbertson, Melitssa S. United States, New Jersey 07065, Lowway, East Lincoln Avenue 126 (72) Inventor Hartman, Georges Day United States, New York Jersey 070 65, Lowway, East Lincoln Avenue 126 (72) Inventor Young, Stephen D. United States, New Jersey 07065, Lowway, East Lincoln Avenue 126 (72) Inventor Isle, Nathan Sea United States, New Jersey 07065, Lowway, East Lincoln Avenue 126

Claims (1)

[Claims] 1. formula                         XYZAB (In the formula X has one, two or three heteroatoms selected from N, O and S 5-, 6-, or 7-membered aromatic or non-aromatic ring, wherein this ring is unsubstituted Squid, R at carbon and nitrogen atoms¹Mono-substituted or with carbon and nitrogen R in the elementary atom¹And R^TwoWherein R is¹And R^TwoIs   hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   amino,   Amino C_{1 ~ 8}Alkyl,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Independently selected from X has one, two or three heteroatoms selected from N, O and S A 9- or 10-membered fused aromatic or non-aromatic ring, wherein the ring is unsubstituted. Squid, carbon and nitrogen atoms Then R¹Or at the carbon and nitrogen atoms¹And R^Two Wherein R is¹And R^TwoIs   hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   amino,   Amino C_{1 ~ 8}Alkyl,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Independently selected from among Y represents 0, 1, 2, or 3 heteroatoms selected from N, O and S A 5- or 6-membered aromatic or non-aromatic ring, wherein the ring is unsubstituted. Squid or R at carbon and nitrogen atoms^ThreeWith R^ThreeIs   hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   amino,   Amino C_{1 ~ 8}Alkyl,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Dialkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Selected from The structure of X and Y together Constitute Z is -CH_TwoCH_Two−, -CH = CH-, -CH_Two-O-, -O-CH_Two−, -CH_TwoNR^Four−, -NR^FourCH_Two−, Or Z is a bond, R^FourIs hydrogen, C_{1 ~Four}Alkyl, or C_{Three ~ 6}Cycloalkyl And A represents 0, 1, 2, or 3 heteroatoms selected from N, O and S A 5- or 6-membered aromatic ring, which is unsubstituted or Or R at the nitrogen atom^Five Is monosubstituted or R^FiveAnd R⁶Or disubstituted with R^Five, R⁶ And R⁷Wherein R is^Five, R⁶And R⁷Is   hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   Arylsulfonylamino,   amino,   Amino C_{1 ~ 8}Alkyl,   Nitro,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 3}Alkylsulfonylamino,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Dialkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Trihaloalkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Independently selected from A represents 0, 1, 2, or 3 heteroatoms selected from N, O and S A 9- or 10-membered fused aromatic ring, which is unsubstituted or Represents R at a carbon or nitrogen atom^FiveIs monosubstituted or R^FiveAnd R⁶In two places Has been replaced or R^Five, R⁶And R⁷Tri-substituted by R^Five, R⁶And R⁷Is   hydrogen,   halogen,   C_{1 ~Ten}Alkyl,   C_{Three ~ 8}Cycloalkyl,   Aryl,   Aryl C_{1 ~ 8}Alkyl,   amino,   Amino C_{1 ~ 8}Alkyl,   C_{1 ~ 3}Acylamino,   C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkylamino,   C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Dialkylamino,   C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl,   C_{1 ~ 6}Alkoxy,   C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl,   Aryl C_{1 ~ 6}Alkyloxy,   Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl,   Carboxy,   Carboxy C_{1 ~ 6}Alkyl,   C_{1 ~ 3}Alkoxycarbonyl,   C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl,   Carboxy C_{1 ~ 6}Alkyloxy,   Hydroxy, and   Hydroxy C_{1 ~ 6}Alkyl Independently selected from among B is -O (CH_Two)_mCO_TwoR⁹, − (CH_Two)_nCO_TwoR⁹, -OCH (R⁸) (CH_Two)_pCO_TwoR⁹ At that time m is 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3; R⁸Is hydrogen, C_{1 ~Ten}Alkyl, C_{Three ~ 8}Cycloalkyl, Aryl, Aryl C_{1 ~ 8}Alkyl, amino, Amino C_{1 ~ 8}Alkyl, C_{1 ~ 3}Acylamino, C_{1 ~ 3}Acylamino C_{1 ~ 8}Alkyl, C_{1 ~ 6}Alkylamino, C_{1 ~ 6}Alkylamino C_{1 ~ 8}Alkyl, C_{1 ~ 6}Dialkylamino, C_{1 ~ 6}Dialkylamino C_{1 ~ 8}Alkyl, C_{1 ~ 6}Alkoxy, C_{1 ~ 6}Alkoxy C_{1 ~ 6}Alkyl, Aryl C_{1 ~ 6}Alkyloxy, Aryl C_{1 ~ 6}Alkyloxy C_{1 ~ 6}Alkyl, Carboxy, Carboxy C_{1 ~ 6}Alkyl, C_{1 ~ 3}Alkoxycarbonyl, C_{1 ~ 3}Alkoxycarbonyl C_{1 ~ 6}Alkyl, Carboxy C_{1 ~ 6}Alkyloxy, Hydroxy, and Hydroxy C_{1 ~ 6}Alkyl Selected from R⁹Is hydrogen, C_{1 ~ 8}Alkyl, Aryl, Aryl C_{1 ~ 6}Alkyl, C_{1 ~ 8}Alkylcarbonyloxy C_{1 ~ 6}Alkyl, Arylcarbonyloxy C_{1 ~ 6}Alkyl, Aryl C_{1 ~ 6}Alkylcarbonyloxy C_{1 ~ 6}Alkyl, C_{1 ~ 8}Alkylaminocarbonyl C_{1 ~ 6}Alkyl, or C_{1 ~ 8}Dialkylaminocarbonyl C_{1 ~ 6}Alkyl And a pharmaceutically acceptable salt thereof. 2. formula                         XYZAB (In the formula X is a 5-, 6- or 7-membered aromatic ring having one, two or three nitrogen atoms or Is a non-aromatic ring, which is unsubstituted or NH_TwoHas been replaced by And Y is a 5- or 6-membered aromatic ring having 0, 1, 2, or 3 nitrogen atoms or Is a non-aromatic ring, which ring is unsubstituted or_{1 ~ 3}Substitute with alkyl Has been or X and Y together form a fused ring system Constitute Z is a bond, A is a 5- or 6-membered aromatic ring having 0, 1, 2, or 3 nitrogen atoms The ring is unsubstituted or at the carbon or nitrogen atom^FiveOne Substituted or identical or different R^FiveAnd R⁶Di-substituted by Or R which is the same or different from each other^Five, R⁶And R⁷Trisubstituted by In that case, R^Five, R⁶And R⁷Is   Arylsulfonylamino,   C_{1 ~ 3}Alkylsulfonylamino,   C_{1 ~ 3}Alkyl,   -CF_Three,   C_{1 ~ 3}Alkyloxy,   halogen,   Nitro Selected from or A is a 9-membered fused ring having 0, 1, 2, or 3 nitrogen atoms Is aromatic, or A is isoindolinone or indolinone, B is -OCH (R⁸) (CH_Two)_pCO_TwoR⁹, − (CH_Two)_nCO_TwoR⁹ At that time n is 0, 1, 2 or 3; p is 0, 1, 2 or 3; R⁸Is hydrogen or C_{1 ~ 3}Alkyl, R⁹Is hydrogen,-(CH_Two)_{1 ~ 3}C (O) NH (CH_Two)_{0 ~ 2}CH_ThreeOr-(CH_Two )_{1 ~ 3}C (O) N ((CH_Two)_{0 ~ 2}CH_Three)_Two). A compound according to claim 1 and a pharmaceutically acceptable salt thereof. 3. formula                         XYZAB (In the formula X is a 5- or 6-membered aromatic or non-aromatic ring having one or two nitrogen atoms The ring is unsubstituted or NH_TwoHas been replaced by Y is a 6-membered aromatic or non-aromatic ring having 0 or 1 nitrogen atom; Is unsubstituted or CH_ThreeHas been replaced by, or X and Y are fused ring systemsConstitute Z is a bond, A is unsubstituted or R^FiveIs monosubstituted or R^FiveAnd R⁶Di-substituted by Or R^Five, R⁶Or R⁷so Trisubstituted phenyl, wherein R^Five, R⁶And R⁷Is   -NHSO_TwoC₆H_Five,   -NHSO_TwoCH_Three,   -CH_Three,   -CF_Three,   -OCH_Three,   -Cl,   -NO_Two,as well as   -Br Selected from or A is a 9-membered fused aromatic ring system having one nitrogen atom, or A is isoindolino Or indolinone, B is -OCH (R⁸) CO_TwoR⁹, − (CH_Two)_nCO_TwoR⁹ At that time n is 1 or 2, R⁸Is hydrogen or C_{1 ~ 3}Alkyl, R⁹Is hydrogen,-(CH_Two)_{1 ~ 3}C (O) NH (CH_Two)_{0 ~ 2}CH_ThreeOr-(CH_Two )_{1 ~ 3}C (O) N ((CH_Two)_{0 ~ 2}CH_Three)_TwoIs characterized by having 3. A compound according to claim 2 and a pharmaceutically acceptable salt thereof. 4. formula                         XYZAB (In the formula X is And Y isOr X and Y are fused ring systems Constitute Z is a bond, A isAnd B is -OCH_TwoCO_TwoH, -OCH_TwoCO_TwoCH_TwoC (O) NHCH_Three, -OCH_TwoCO_TwoCH_TwoC (O) N (CH_TwoCH_Three)_Two, -OCH_TwoCO_TwoCH_TwoCH_Three, -CH_TwoCH_TwoCO_TwoH, -CH_TwoCOOH, -OCH (CH_Three) CO_TwoH, or -OCH (CH_Three) CO_TwoCH_TwoCH_Three The compound according to claim 3, which is pharmaceutically acceptable. Effective salt. 5. 3- (4- (4-piperazin-1-ylphenylcarbonylamino) fe Nyl) propanoic acid, 2- (4- (4-piperazinyl-1-yl) phenylcarbonylamino) pheno Xy) acetic acid, Ethyl 2- (4- (4- (1-piperazinyl) phenylcarbonylamino) Nonoxy) acetate, hydrochloride, 2- (5- (4- (1-piperazinyl) phenylcarbonyla) Mino) indol-1-yl) acetic acid, 3- (3- (4-piperazin-1-ylphenyl) carbonylamino) phenyl ) Propanoic acid, Ethyl 2- (4- (4- (piperazin-1-yl) phenylcarbonylamino) Phenoxy) propanoate, 2- (4- (4- (piperazin-1-yl) phenylcarbonylamino) pheno Xy) propionic acid, 2- (4-(((2-piperazin-1-yl) pyridin-5-yl) carbonyl Amino) phenoxy) acetic acid, 3-methyl-4-((1,2,3,4-tetrahydro-9H-pyrido [3,4- b] indol-7-yl) carbonylamino) phenoxyacetic acid, 2- (4- (5- (4- (1,1-dimethylethoxycarbonyl) -piperazine -1-yl) -2-thienylcarbonylamino) -3-methylphenoxy) -vinegar acid, 4- (2- (1,1-dimethylethoxycarbonyl) -1,2,3,4-tetra Hydro-9H-pyrido [3,4-b] benzofuran-7-yl) carbonylamido G) -3-methylphenoxyacetic acid, 4-((2,3,4,5-tetrahydropyrazino- [1,2-a] indole-8 -Yl) carbonylamino) -3-methylphenoxyacetic acid, and (±) 4-((3- (1,1-dimethylethoxycarbonyl) -1,1a, 2, 3,4,5-hexahydropyrazino- [1,2-a] indol-8-yl) cal Bonylamino) -3-methylphenoxyacetic acid 5. The compound according to claim 4, which is selected from the group consisting of: Possible salt. 6. Inhibition of fibrinogen binding to platelets, platelet aggregation in mammals Control, treatment of thrombus or embolism, or prevention of thrombus or embolism The compound according to claim 1, which is used for: 7. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. . 8. Method for inhibiting fibrinogen from binding to platelets in mammals 10. A method comprising treating a mammal with the composition of claim 7. 9. Fibrinogen causes platelet aggregation in mammals A method for inhibiting the action of a receptor site by blocking the action, A method comprising treating an animal with the composition of claim 7. 10. A composition used to inhibit platelet aggregation in mammals. And one or more drugs selected from thrombolytics, anticoagulants and antiplatelet drugs An effective amount of the compound of claim 1 in combination with a pharmaceutically acceptable carrier. And a composition comprising: 11. In mammals, platelet aggregation is induced by fibrinogen, Claims 1. A method for inhibiting the action of a mammal by blocking the action of the mammal. A method comprising treating with the composition of claim 0. 12. Binding of fibrinogen to platelets in mammals A method of inhibiting the action of a gene on its receptor site by blocking A method comprising treating a mammal with the composition of claim 10. 13. A method for inhibiting osteoclast-mediated bone resorption, wherein the mammal is described in claim 7. A method comprising treating with the described composition. 14． A method for suppressing angiogenesis in a mammal, A method comprising treating a mammal with the composition of claim 7. 15. A method for inhibiting tumor growth in a mammal, comprising the steps of: A method comprising treating with the composition of item 7. 16. Suppress platelet aggregation, prevent thrombotic thrombosis, thromboembolism in mammals 2. A compound according to claim 1 for the manufacture of a medicament for use in the prevention of relapse or the prevention of reocclusion. Use of a product or a pharmaceutically acceptable salt thereof.