TWI247008B - Heterocyclic glycyl beta-alanine derivatives - Google Patents

Abstract

The present invention relates to a class of compounds represented by the formula I, or a pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of treating conditions mediated by the alphavbeta3 integrin.

Description

1247008 V. INSTRUCTION STATEMENT α) This case is based on US 35 USC § 119(e) claiming the priority of the provisional patent application dated April 10, 1998, 6 0 / 0 8 1, 3 94. Field of the Invention The present invention relates to an agent (compound) which can be used as an αν /?3 integrin antagonist, a pharmaceutical composition, and a method for inhibiting the disease involved in αν /53 by inhibiting or enclosing an av / S3 integrin. BACKGROUND OF THE INVENTION Integrins are cell surface glycoproteins that are involved in cell attachment and are therefore useful as mediators of cell attachment interactions that occur during various biological processes. An integrins are heterodimers comprising non-covalently linked alpha and /3 polypeptide subunits. 4 It has been confirmed that there are different alpha subunits and six different point units. Various alpha subunits can be combined with various /3 subunits to form different integrins. Integrin αν /33 (also known as the vitronectin receptor) has been identified as an integrin that is involved in a variety of symptoms or diseases, including tumor metastasis, solid tumor growth (tumor formation), osteoporosis Symptoms, Péget's disease, malignant body fluids, angiogenesis, including tumor angiogenesis, retinopathy, including leukoplakia, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, and Smooth muscle cell migration (eg restenosis η sis). In addition, the agent has been found to be useful as an antiviral, antifungal, and antimicrobial agent. Therefore, compounds that selectively inhibit or antagonize αν /53 can be used. Treatment of these diseases. αν /93 integrin and other macromolecules containing 7 integrin binding to many Arg-Gly-Asp (RGD) matrices have been shown. Compounds containing RGD sequences mimic extracellular matrix ligands, binding Cell surface receptors. However,

Page 8 1247008 V. INSTRUCTIONS (2) It is also known that R G D peptides are generally non-selective for R G D - dependent integrins. For example, most of the RGD peptides that bind to av/S3 are also bound to ~call 5, ^ ^, and a llb /33. The antagonism of platelet a [lb cold 3 (also known as fibrinogen receptor) is known to block the accumulation of platelets in the human body. In the treatment of symptoms or diseases associated with integrin α V. million, in order to avoid bleeding side effects, it is advantageous to develop a selective antagonist relative to α I I b 3 as α ν /5 3 . Tumor cell invasion occurs in a three-step process: 1) tumor cells attach to the extracellular matrix, 2) proteolytic lysis of the matrix, and 3) cell movement through the barrier of dissolution. This process can occur repeatedly, causing a shift to a location away from the original tumor.

Seftor et a 1 (Proc. Natl. Acad. Sc i. USA. Vo 1. 8 9 ( 1 9 92 ) 1 5 57- 1 5 6 1 ) has shown that av / S3 integrin has a biological invasion in melanoma cells. Learning function. Montgomery et al., (Proc.

Natl. Acad·Sci· USA, Vol· 9 1 ( 1 9 94 ) 8 8 56-6 0 ) Integrin αν /S3 on human melanoma cells has been shown to initiate survival signals, protecting cells from programmed cells Death (ap 〇pt 〇sis). Modulation of the tumor cell transduction pathway is advantageous by blocking the attachment of α v / 3 3 integrin cells to the receptor to prevent tumor metastasis.

Brooks et al (Cell, VoL 79 (1994) 1157-1164) have demonstrated that the antagonist of 30,000 provides a method for the treatment of neoplasia (inhibition of solid tumor growth), since systemic administration of αν0000 antagonists causes various histologies Different human tumors are severely degraded. Attachment receptor integrin 〇: ν / 3 3 has been identified as a marker of chicken and human angiogenic blood vessels. Therefore, this receptor plays an important role in angiogenesis or neovascular growth. Blood vessel

Page 9 Less 'Restore the normal balance of bone formation and absorption activity. Therefore, it is advantageous to provide an antagonist of osteoclast αν A, which is an effective inhibitor of bone resorption, so that it can be used for the treatment or prevention of osteoporosis. The role of A integrin in smooth muscle cell migration also makes it a therapeutic target for preventing or inhibiting neovascular intimal hyperplasia, which is the main cause of restenosis after angiogenesis (Choi et al., J. Vase. Surg. 〇ι 1 9 ( 1 ) ( 1 994 ) 1 2 5-34 ). It is advantageous to prevent or inhibit new blood vessels with drugs 1247008

: It is characterized by the invasion and migration of smooth muscle and endothelial cells. Several doses are caused by selective promotion of fine blood vessel distribution in the distribution of new blood vessels, and inhibition of this process. The growth of new business, or the shape of blood vessels & also become pathological symptoms, such as diabetic retinopathy, including alopecia degeneration amis et al·Amer·J· 〇phthal·, ν〇1·118 (1994) 45-45 0 ), And rheumatoid arthritis (peac〇ck et ai·, j. Εχρ· = V〇1· 175 (1 9 9 2 ), ^35-1138). Therefore, αν/53 antagonism is a useful therapeutic agent for the treatment of symptoms associated with neovascularization (Br〇〇ks et al., Science, V〇i 264 (1994), 569-571). $$ reports that the cell surface receptor αν /?3 is the major integrin responsible for attachment to bone in osteoclasts. Osteoclasts cause bone resorption, which causes osteoporosis (skeletal loss) when bone absorption activity exceeds bone formation activity, resulting in increased number of fractures, insufficient function, and increased mortality. /53 Bactericide has been shown to be a potent inhibitor of osteoclast activity, in vitro [Sato et al., J# Cell Biol. Vol. Ill (1990) 1713-1723] and in vivo [Fishe]rd ai · Endocrinology, v〇i· 1 32 ( 1 99 3 ) 1 41 1 - 1 4 1 3 ]. Antagonism of heart palpitations leads to reduced bone absorption

Page 10 1247008 V. INSTRUCTIONS (4) Intimal hyperplasia to prevent or inhibit restenosis.

White (Current Biology, Vol. 3(9) (1993) 596-5 9 9 ) has been reported to enter the host cell using α v yS 3 . Integrins are clearly required for endocytosis of virions and are required for the penetration of viral genomes into the cytoplasm of host cells. Therefore, a compound which inhibits av / S3 can be used as an antiviral agent. SUMMARY OF THE INVENTION The present invention relates to compounds of the formula I below

Or a pharmaceutically acceptable salt thereof, wherein: ΗΕΤ: is a 5-8 membered monocyclic heterocyclic ring which is optionally unsaturated and contains 1 to 4 hetero atoms selected from 0, oxime, or S, wherein X1 is selected from CH, CH2, Ν, ΝΗ, 〇 and S base; Υ1

Page 11 1247008 V. INSTRUCTIONS (5) wherein Y1 is selected from N-R2, 0 and S; R2 is selected from the group consisting of hydrazine; alkyl; aryl; hydroxy; alkoxy; cyano; nitro; Alkenyl; alkynyl; decylamino; alkylcarbonyl; arylcarbonyl; alkoxycarbonyl; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl a mercaptooxymethoxycarbonyl group; the alkyl group is substituted with one or more substituents selected from the group consisting of: a lower alkyl group, a halogen group, a 'haloalkyl group', a cyano group, a wall group, a 'weiki' amine The base 'alkoxy' aryl, or aryl is optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, decyl, sulphur Base, fluorenyl, thiol, amine, thiol, acid, decylamine, aryl, copper φ aryl, monocyclic heterocycle, or slightly monocyclic heterocycle; aryl selective via one or Substituted by a plurality of substituents selected from the group consisting of halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, fluorenyldioxy, hypoethyldioxy, cyano, schiffyl thiol Base continued Group 'Continued acid' continued acid amine, slow derivatives,

An amine group, an aryl group, a fused aryl group, a monocyclic hetero ring, and a fused monocyclic hetero ring; a monocyclic hetero ring; and a monocyclic hetero ring optionally substituted with one or more substituents selected from the group consisting of halogen , ii alkyl group, low alkyl group, alkoxy group, amine group, base group, thiol-derivative derivative, cyano group, sulphur-based, sulphur-based, sulphur-based, sulphur-based, sulphate, aryl, Or a fused aryl group; or H R2 and R7 together form a 4- 12 member-containing dinitrogen heterocycle, optionally substituted with one or more substituents selected from the group consisting of low alkyl, sulfur alkyl, and amine a hydroxy group, a keto group, an alkoxy group, a halogen group, a phenyl group, an amine group, a carboxyl group, or a carboxy ester, and a fused phenyl group; or R2 and R7 together form a 4-12 member heterocyclic ring containing one or Multiple miscellaneous

Page 12 1247008 V. INSTRUCTIONS (6) Sub-selected from 0, N and S, selectively unsaturated; or R2 and R7 together form a 5- to 9-membered heteroaryl ring, optionally selected from one or more Substituted by the following substituents: lower alkyl, phenyl, alkoxy, and hydroxy; or R2 and R7 together form a 5-membered heteroaryl ring, slightly fused to an aryl or heteroaryl ring; R7 (when not And R8 are independently selected from the group consisting of hydrazine; alkyl; alkenyl; alkynyl; aralkyl; amine; alkylamino; hydroxy; alkoxy; arylamino; decylamino; alkylcarbonyl Arylcarbonyl; alkoxycarbonyl; aryloxy; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; mercaptooxymethoxycarbonyl Cycloalkyl; bicycloalkyl; aryl; fluorenyl; phenyl fluorenyl; alkyl-selective substituted with one or more substituents selected from the group consisting of lower alkyl, halo, hydroxy, haloalkyl, a cyano group, a nitro group, a thiol derivative, an amine group, an alkoxy group, a thio group, a thiol group, a fluorenyl group, an aryl group, an aralkyl group, an aryl group, optionally selected from the group consisting ofSubstituent substitution: halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, hypoethyldioxy, thiol, halogen thio, thio, thio, cyano, Nitro, carboxy derivative, aryloxy, decylamino, decylamino, amine 'alkylamine' dialkylamine-trifluoroanthracene tris-methyl' contig, base a Si group, a halogen group, a S-blue group, a crude acid, an acid aryl group, an aryl group, a fused aryl group, a monocyclic hetero ring, a fused monocyclic hetero ring; the aryl group is optionally selected from one or more Substituted by the following substituents: halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, hypoethyldioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano , nitro, carboxy derivative, aryloxy,

Page 13 1247008 V. INSTRUCTIONS (7) S&Aminos; S-Blue-Amino, Amine, Acryl, Di-Amino, Trifluoro-Oxo, Di-Gas-Methyl An acid group, a carboxylic acid, an aryl group, a fused aryl group, a monocyclic heterocyclic ring, or a fused monocyclic heterocyclic ring; a monocyclic heterocyclic ring; the monocyclic heterocyclic ring is optionally selected from one or more Substituted by the following substituents: halogen, halogen-based, low-alkyl, alkoxy, aryloxy, amine, acetyl, hydroxy, carboxy derivative, cyano, alkylthio, alkylsulfonyl, aryl a fused aryl group; a monocyclic and bicyclic heterocycloalkyl group, -S02R1G, wherein R1G is selected from the group consisting of an alkyl group, an aryl group, and a monocyclic heterocyclic ring, each optionally having one or more substituents selected from the group consisting of Substituted: halogen, halogen, base, alkoxy, cyano, schwitz, amine, acid amine, tri-gas, amide, anthranyl, hydrazino 'Acrylic acid amino group alkyl group amine' dialkylamino group, trifluorosulfonylthio group, trifluoroalkoxy group, trifluoromethylsulfonyl group, aryl group, aryloxy group, sulfur group , alkylthio, and monocyclic heterocycle And 〇-C-R10, wherein R1G is as defined above; or NR7 and R8 together form a 4-12 member of a monocyclic or bicyclic ring containing a nitrogen, optionally substituted by one or more substituents selected from the group consisting of a lower alkyl group, a carboxy derivative, an aryl group, or a hydroxy group, wherein the ring optionally contains a hetero atom selected from the group consisting of 0, N and S; and R5 is selected from the group consisting of an anthracene, an alkyl group, an alkenyl group, an alkynyl group, and a benzoinyl group. And phenethyl; or

R5

III Teng 11 _ ρι Page 14 1247008 V. Description of the invention (8) wherein Y2 is selected from alkyl; cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycle; alkyl selective aryl substituted, aromatic The group may also be optionally substituted by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or slightly aryl The aryl group is optionally substituted with one or more substituents selected from the group consisting of halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylene Oxy-p-ethylenedioxy, or alkyl; fast-radical; dilute; -S-R9 and _0_R9, wherein R9 is selected from the group consisting of hydrazine; alkyl; arylalkyl; aryl; alkenyl; Alkynyl; or R9 and R7 together form a 4-12 membered heterocyclic ring containing a nitrogen and a sulfur or an oxygen, optionally via a low alkyl group, a trans group, a keto group, a phenyl group, a carboxyl group or a carboxyl ester, and a thick Substituted with phenyl; or R9 and R7 together with thiazole; 卩fazole; benzoxazole; or benzothiazole; and R5 and R7 are as defined above; or Y2 (when Y2 is carbon) and R7 A 4-12 member contains a nitrogen Or a dinitrogen ring optionally substituted with an alkyl group, an aryl group, a keto group, or a hydroxy group; N-R2

Wherein R 2 and R 7 together form a 5-8 membered dinitrogen heterocycle, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, keto, phenyl, or a carboxy derivative; R8 is selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, i alkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, or Mercaptooxycarbonyloxycarbonyl

Page 15 1247008 V. INSTRUCTIONS (9) Base; and R5 are as defined above; or R2 and R7 together form a heteroaromatic ring, such as a sigma or a 17 hexamidine, R5 N-R2 or Α is - XN-R7 R8 wherein R2 and R7 together form a 5-8 membered dinitrogen heterocycle, optionally substituted by hydroxy, keto, phenyl or alkyl; and R8 is selected from alkylcarbonyl, arylcarbonyl , alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, and mercaptooxymethoxycarbonyl; Z1 is one or more substitutions The base is selected from the group consisting of hydrazine; alkyl; hydroxy; alkoxy; aryloxy; halogen; halogen; halogen alkoxy; schloss; amine; alkylamino, arylamino; ; aryl group; sulphur-based group; succinyl acid group; carboxy derivative; trihaloacetamide; acetamidine; fluorenyl; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycle a fused monocyclic heterocycle; and A, wherein Α is as defined above; V is selected from the group consisting of -N-(R6)-, wherein R6 is selected from the group consisting of hydrazine, lower alkyl, cycloalkyl; aralkyl; aryl And monocyclic heterocycles; or R6 and Υ - forming a 4-12 member containing a nitrogen ring; Υ, Υ 3, Ζ and Ζ 3 are independently selected from hydrogen; alkyl; aryl; and cycloalkyl; or Υ and Ζ to form a cycloalkyl; Υ3 and Ζ3 together form a cycloalkyl group;

Page 16 1247008 V. Description of the Invention (ίο) η is an integer of 1, 2 or 3; t is an integer of 0, 1 or 2; p is an integer of 0, 1, 2 or 3; R is X-R3, wherein X is selected from the group consisting of 0, S and NR4, wherein R3 and R4 are independently selected from nitrogen; the base; the dilute group; the fast group; the halo group; the aryl group; the aryl group; the sugar, the leaven; An alkylamino group; an alkyl N,N-diphorhylamine; a trimethylacetoxycarbonyl group; in the case of a free acid, and a pharmaceutically acceptable salt thereof; the R1 is selected from the group consisting of hydrogen; Alkyl; alkenyl; alkynyl; aryl; carboxy derivative; haloalkyl; cycloalkyl; monocyclic heterocycle; monocyclic heterocycle selective via alkyl, halo, haloalkyl, cyano, hydroxy, Aryl, fused aryl, nitro, alkoxy, aryloxy, alkylsulfonyl, arylsulfonyl, sulfonate amine, thio-thiol-based derivative 'S-amino substituted, alkyl-selective substituted with one or more of the following groups: halo, alkyl, hydroxy, oxy, aryloxy, thio, thiol, alkynyl, dilute , alkyl, arylthio, alkyl sulphide Aryl sulphate, aryl sulphate, gas-based 'tip' amine amide 'alkylamino' dialkylamino ' ketone sulfonamide, aryl sulfonamide, decyl decylamine, carboxyl derivatization , sulfonamide, sulfonic acid, phosphonic acid derivative, phosphinic acid derivative, aryl, arylthio, aryl sulfoxide, or aryl maple, all selectively substituted in the aromatic ring, alkyl, Halogenated ketone group - fluorenyl group per ke group derivative 5 oxime 'aryl oxy' amine group 'alkylamino' bis-alkylamino 'bristyl 'aryl' fused Aryl, monocyclic heterocyclic substituted; and fused monocyclic heterocyclic ring, monocyclic heterocyclic thio group, monocyclic heterocyclic yam, and monocyclic heterocyclic maple, optionally halogenated, halogenated

Page 17 1247008 V. INSTRUCTIONS (LA), mercapto group, mercapto group, alkoxy group, fused aryl group, or alkyl group; alkylcarbonyl, haloalkylcarbonyl, and arylcarbonyl; aryl selectivity Halogen at one or more positions, ii alkyl, alkyl, alkoxy, aryloxy, fluorenyldioxy, hypoethyldioxy, alkylthio, halosulfanylthio * via a base 5 gas-based 'Jingji' stearyloxy' slow-base derivative, carboxy alkoxy group, decylamino group, mercaptoamine group, amine group, alkylamino group, dialkylamino group Oxyl, trifluoromethyl schistosyl, pyridylxanthyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycle, and fused monocyclic heterocycle; and 〇/一^ 1. R$ wherein R7 and R8 are as defined above, but R7 and R8 together with nitrogen comprise an amino acid; and R11 is selected from the group consisting of anthracene, alkyl, arylalkyl, alkenyl, alkynyl, haloalkyl, Or a halogen group or R11 forms a 4-12 member containing a nitrogen ring. Another object of the invention is to provide a pharmaceutical composition comprising a compound of formula I. The compound and composition are useful for selection Sexually inhibiting or antagonizing αν /33 integrin. In another specific embodiment, the present invention relates to a method for selectively inhibiting or antagonizing av yS3 integrin. The invention further relates to treating or inhibiting pathological symptoms associated with mammals, such as bone Obesity, malignant body fluid high calcium, Paige's disease, tumor metastasis, solid tumor growth (tumor formation), angiogenesis, including tumor angiogenesis, retinopathy, including vision

Page 18 1247008

For plaque and diabetic opticitis, periodontal disease, and cowhide, the agent can be used as an omental disease, arthritis, 癣' smooth muscle cell migration antiviral agent and anti-microbial including rheumatoid joint movement, and restenosis. This agent. j sheep detail

The present invention relates to a compound of the above formula i in the main A subgroup of 卜, 十, 斗, τ & One of the present inventions $$ 4 to s μ ^ a preferred embodiment is a compound of the following formula I 〇

Wherein R32 is Η 'alkyl" alkoxyalkyl, aminoalkyl, dialkylaminoalkyl] wherein the alkyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl groups, alkoxy groups Base, amine group, alkylamino group, dialkylamino group, aryl- or alkyl-sulfonyl group, carboxyl group, and carboxyl derivative, and other variables are as described in the formula. Another preferred embodiment of the invention is a compound of the formula I I I

R

Vxl^X/ri }CH2,p^ 1247008 V. Description of invention (13)

选择性 Selective substitution, other variables are as defined in formula I above. Another preferred embodiment of the invention is a compound of the formula IV below

Ζ1

The substituents are optionally substituted, and the other variables are as defined in the above formula I. Another preferred embodiment of the invention is a compound of formula V

〇

The substituents are optionally substituted, and the other variables are as defined in the above formula I. Another preferred embodiment of the invention is a compound of formula V I

Page 20 1247008 V. Description of invention (14) Ο

The substituents are optionally substituted, and the other variables are as defined in the above formula I. The invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I-V I. The invention also relates to a method for selectively inhibiting or antagonizing αν integrin, more particularly to inhibiting bone resorption, periodontal disease, osteoporosis, malignant body fluid high #5, Paige's disease, tumor metastasis Solid tumor growth (tumor formation), angiogenesis, including tumor angiogenesis, retinopathy, including plaque and diabetic retinopathy, arthritis, including rheumatoid arthritis, smooth muscle cell movement, and restenosis, A therapeutically effective amount of a compound of formula I-VI is administered with a pharmaceutically acceptable carrier to achieve inhibition. The following are definitions of the terms used herein. The term "alkyl" or "lower alkyl" as used herein, denotes a straight or branched chain hydrocarbon radical having from about 1 to about 10 carbon atoms, more preferably from about 1 to about 6 carbon atoms. Examples of such alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl, Wait.

Page 21 1247008 V. INSTRUCTION DESCRIPTION (15) The hydrocarbyl group contained herein may have a bond which may be exemplified as ethylhexenyl, and the terms "alkenyl" or "low alkenyl" as used herein, and at least one double bond and Up to about 6 carbon atoms or trans-geometry, with respect to double-bonded carbon, alkenyl, propenyl, butenyl, isobutylene, the term "alkynyl" or "lowerkynyl", containing one or more triple bonds And 2 to about 6 carbon atoms. The radical, cycloalkynyl, pentynyl, hexynyl, and the like are used herein to mean "cycloalkyl" which means saturated or has from 3 to about 8 carbon atoms, more preferably from 4 to about 6 including cyclopropyl, cyclic. A propylene group, a cyclobutyl group, a propyne group, a cyclic carbon group, a cycloalkyl group containing a cycloalkyl group, a 2-cyclohexen-1-yl group, and the like. The system in this article. Preferred are aryl groups such as phenyl and the like. The term "aryl" as used herein includes one or more aryl groups containing 1, 2 or 3 aromatic rings (, sigma ratio, sigma, decyl, fluorenyl, unsaturated, acyclic, carbon) - a carbon disubstituted group. An example of the group, the pentylene group, and the acyclic hydrocarbon group is a partially unsaturated carbon atom of the group B. The group, the cyclopentyl group, the aromatic ring of the aromatic ring is the term Inclusion of a group, biphenyl, as used herein, the term "cyano" is represented by the formula |—CNI. The term “radian” as used herein is used as the basis of the formula |

Page 22 1247008 V. INSTRUCTIONS (16) Table 5-10 Members are selected from the zeros of 0 used in pyrimidine, indole, and imidazole, of which R2Q, ethoxylate is second. A heterozygous phenanthrene used in butoxygen, thiamidoxime, a carbon-based carbonyloxy group, a ring or a bicyclic heterocycle, optionally unsaturated, containing 1 to 3, N &amp ; S ; where X1 is CH, N, 0 or S. This base generation bites, D is more than σ, 17 bite, glutinous rice squat, squat, isoindole, thiophene, furan, pyrazole, and bicyclic heterocycles, such as benzopyridine, benzofuran, and the like. The term "lower alkyl" or "secondary alkyl" is given in Tables 1 to 6 of a straight or branched bond saturated nicotine. The term "alkoxy" is a straight or branched chain of the formula -OR2G which is an alkyl group as defined above. Examples of the alkoxy group include n-propoxy group, n-butoxy group, isopropoxy group, isobutyl group, tert-butoxy group, and the like. The term "arylalkyl" or "aralkyl" refers to the radicals of formula I-R22-R21 wherein R21 is aryl as defined above and R22 is alkyl as defined above. Examples of the aralkyl group include an anthracenyl group, a pyridinium group, a naphthylpropyl group, a phenethyl group, and the like. The term "nitro" as used herein is represented by the formula h"N〇2. The term "halo" or "halogen" as used herein refers to bromine, gas, fluorine, or angstrom. The term "haloalkyl" as used herein, is as defined above, wherein one or more of the same or different halo groups are substituted on one or more carbon atoms. Examples of the haloalkyl group include a trifluoromethyl group, a di-haloethyl group, a fluoropropyl group, and the like. The term "mercapto" is used herein to refer to the formula - C00H.

Page 23 1247008 V. INSTRUCTION DESCRIPTION (17) The term "carboxy ester" as used herein, the formula -C00R23, wherein R2.3 is selected from the group consisting of anthracene, alkyl, arylalkyl, or aryl, as described above definition. Υ6 The term "carboxy derivative" as used herein, wherein Υ6 and Υ7 are independently selected from 0, Ν or S, and R23 is selected from fluorene, alkyl, aryl, or aryl, as defined above . The term "amine group" as used herein is represented by the radical of the formula -νη2. The term "alkylsulfonyl" or "alkyl maple" as used herein, is a radical of the formula — |-s-R24, wherein R24 is alkyl as defined above. The term "alkylthio" as used herein, and the radical of the formula SR24, wherein R24 is an alkyl group as defined above. 〇 - onsno Table J Acid Sulfonic Acid Language The R25 of the text in the text is an alkyl group as defined above.

S R The term "sulfonamide" as used herein, is a radical of the formula <RTIgt;</RTI>>, wherein R7 and R8 in O R8 are as defined above. The term "fused aryl", as used herein, refers to an aromatic ring, as defined above, fused to one or more benzene rings. The term "fused aryl" includes naphthyl, and the like.

Page 24 1247008 V. INSTRUCTIONS (18) The term "monocyclic heterocyclic" form ring as used herein contains 4 to about 12 atoms, more preferably 5 to about 10 atoms, of which 1 to 3 atoms are A hetero atom, selected from the group consisting of oxygen, nitrogen, and sulfur. If two or more different heteroatoms are present, at least one of the heteroatoms must be it. The monocyclic heterocyclic ring is represented by σ rice bran, 咲 吼, bite, 曙 ,, warm ,, three. Sit, thiophene, oh oh, thiophene, thiazide, etc. The term "fused monocyclic heterocyclic ring" as used herein refers to a monocyclic heterocyclic ring as defined above fused to benzene. Examples of the fused monocyclic heterocyclic ring include benzofuran, benzopyran, benzodiazepine, benzothiazepine, benzothiophene, benzimidazole, and the like. I-〇- The term "indenyldioxy" as used herein, the table f-%, the term hypoethyldioxy", as used herein, the term r A - 1 2 member contains a di-II heterocycle" formula

The base of _, wherein m is 1 or 2, and R19 is hydrazine, alkyl, aryl, or arylalkyl. More preferably, the ring of 4 to 9 members includes a ring of 1:1 m. The term "5-membered selectively substituted heteroaryl ring" as used herein includes, for example, the basic formula of the formula Ν-Ν

Page 25 1247008 V. INSTRUCTIONS (19) AND "5-member hetero-aromatic ring condensed and stupid base" The table "5-member heteroaryl ring" is fused with a phenyl group. The 5-membered heteroaryl ring is a benzoic acid derived from a phenyl group. sit. The term "bicycloalkyl" as used herein, denotes a bicyclic hydrocarbon group of from 6 to about 12 carbon atoms which is saturated or partially unsaturated. The term "mercapto" as used herein, wherein R26 is alkyl, alkenyl, alkynyl, aryl, or arylalkyl, is optionally substituted as defined above. The base includes an ethylene base, a benzoic acid base, and the like. As used herein, the term "thio" forms |~SH. 〇 no The term "tartaric acid group" as used herein has the formula |_ s - the group of R27', wherein R27 is an alkyl group, an aryl group, or an arylalkyl group, as defined above. The term "haloalkylthio" as used herein, has the formula -S-R28, wherein R28 is haloalkyl as defined above. The term "aryloxy" as used herein has the formula |- R29, wherein R29 is an aryl group as defined above. The term "acid-based amine group" as used herein refers to the formula K3. The base of _C—NM—| wherein R3G is an alkyl group, an aryl group, or an aryl group, as defined above.

Page 26 1247008 V. INSTRUCTIONS (20) 〇 The term "ammonium" as used herein refers to the radical -Nh2. The term "alkylamino", as used herein, is a radical of the formula -NHR32, wherein R32 is alkyl as defined above. 4. The term "dialkylamino" as used herein refers to the radical -NR33R34, wherein R33 And R34 are the same or different alkyl groups as defined above. The term "trifluoromethyl" as used herein has the formula |~CF3. The term "trifluoroalkoxy" as used herein, is a radical of the formula f3c-f^ck|, wherein R35 is a bond or a sub-alkyl group as defined above. The term "alkylaminoglycol" as used herein refers to the formula R36-N-S-| Μ ,, wherein R36 is an alkyl group as defined above. 〇

The term "alkylsulfonylamino" as used herein, is a radical of the formula R36-I, wherein R36 is alkyl as defined above. The term "trifluorosulfonylthio" as used herein refers to the formula F3c-s-|.术语 The term "trifluoromethylsulfonyl" as used herein refers to the formula <base of Formula F3cd-|.术语 The term “4-12 members containing a single ring or double ring of nitrogen” is used in this article.

Page 27 1247008 V. INSTRUCTIONS (21) 4-1 2 atoms, more preferably 4-9 atoms, one of which is a saturated or partially unsaturated monocyclic or bicyclic ring. The ring may optionally contain other hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. The base is morpholine, hexahydropyridine, hexahydropyridinium, thiomorpholine, pyrrolidine, valine acid, azepanene, and the like. The term "benzyl" is used herein. The term "phenethyl" is used herein. The term "4 -1 2 member containing a nitrogen, monosulfide or monooxyheterocycle" as used herein contains 4 to 12 atoms, more preferably 4 to 9 atoms, at least one of which is nitrogen and at least one The atom is a ring of oxygen or sulfur. Rings in this definition include, for example, thioporphyrins, and the like. The term "arylsulfonyl" or "aryl maple" as used herein is used.

The base of gy 11_S R wherein R37 is an aryl group as defined above. The term "alkyl sulfoxide" or "aryl sulfame" as used herein, is a radical of the formula 3 R3d_s—, wherein R.s. 38 are respectively alkyl or aryl as defined above. The term "phosphonic acid derivative" as used herein, refers to the formula, r 〇 R40 wherein R39 and R4G are the same or different and are fluorene, alkyl, aryl, or arylalkyl.术语 The term "phosphinic acid derivative" as used herein is a formula - ^ - OR41 , Η

Page 28 1247008 V. INSTRUCTION DESCRIPTION (22) wherein R41 is fluorene, alkyl, aryl, or arylalkyl, as defined above. The term "aryl" is used herein to refer to the radical |-sr42, wherein R42 is aryl as defined above. The term "monocyclic heterocyclic thio" as used herein, is a radical of the formula SR-, wherein R43 is a monocyclic heterocyclic group as defined above. The terms "monocyclic heterocyclic yam" and "monocyclic heterocyclic maple" as used herein have the following formulae and the radical -R43, wherein R43 is as defined above for monocyclic heterocyclyl 13 〇 terms used herein. "Alkylcarbonyl" represents the formula R5. One base, of which R5. It is an alkyl group as defined above. The term "arylcarbonyl" as used herein refers to the formula R5Lg-, wherein R51 is an aryl group as defined above. The term "alkoxycarbonyl" as used herein, has the formula R52 -^, wherein R52 is an alkoxy group as defined above. The term "aryloxycarbonyl" as used herein refers to the formula R51 - which is an aryl group as defined above. 〇 The term "haloalkylcarbonyl" as used herein, is a radical of the formula R53,

Page 29 1247008 V. Description of the invention (23) wherein R53 is a haloalkyl group as defined above. 0. The term "haloalkoxycarbonyl" as used herein, is a radical of the formula r53_〇, wherein R53 is a haloalkyl group as defined above. The term "alkylthiocarbonyl" as used herein refers to the radical r5G-s - ϋ-, wherein R5G is alkyl as defined above. The term "arylthiocarbonyl" as used herein, is a radical of the formula R5LS, wherein R51 is an aryl radical as defined above. The term "mercaptooxymethoxycarbonyl" as used herein, is a radical of the formula: R54 - CH2 - 〇-C-, wherein R54 is an acid group as defined above. The term "arylamino" as used herein, refers to a radical of the formula R51-NH-, wherein R51 is aryl as defined above. The term "polyalkyl ether" as used herein refers to a diol which is generally used, such as triethylene glycol, tetraethylene glycol, polyethylene glycol, and the like. The term "alkylammonium" as used herein refers to the formula R50-NH-S-, wherein R5G is alkyl as defined above. pSO 〇 The term "N,N-dialkylammonium" as used herein, the radical n-R50, wherein R5G is the same or different alkyl radical as defined above.

Page 30 1247008 V. INSTRUCTIONS (24) The term "trimethylethyl fluorenyl fluorenyl" is used herein.

Me, brother] C-C-Ο-CH2 —

The basis of Me Λ. The term "mercaptooxy" as used herein, denotes a radical of the formula R55-0-, wherein R55 is a fluorenyl group as defined above. The term "composition" as used herein means a product produced by mixing or combining more than one element or component. The term "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which is involved in carrying or Transport a chemical agent. The term "therapeutically effective amount" means the amount of a biological or medical response that a drug or agent sought by a researcher or clinician elicits a tissue, system, or animal. The following is a shorthand for the interactive use in this article and the corresponding meaning. UMRz proton nuclear magnetic resonance

Ac〇H diacetate

Ar = argon B H3 - T H F = oleo-tetrahydrofuran complex Β η = benzyl B0C = third butoxycarbonyl

ButLiz butyl via C a t.=catalytic amount

Page 31 1247008 V. INSTRUCTIONS (25) CDMT di-2-gas- 4,6-dimethoxytriazine CH2C12 dichloromethane CH3CN=acetonitrile C H3 I diiodomethane CHN analysis = carbon/hydrogen/nitrogen element Analysis of CHNC1 analysis = carbon/hydrogen/nitrogen/gas elemental analysis CHNS analysis = carbon/hydrogen/nitrogen/sulfur elemental analysis DAST=diethylammonium trifluoride DCC = 1,3 -dicyclohexylcarbodiimide DCM Dichloromethane DIBAL: diisobutylaluminum hydride DIEA=diisopropylethylamine DI water=deionized water DMA, 』-dimercaptoacetamide DMAON, N-dimethylacetamide DMAP = 4 -(M,e-didecylamino)pyridine DMFU-dimethyl decylamine DS ruthenium disuccinate E DC 1 =Bu (3-dimethylaminopropyl)-3-ethylcarbylation Diimine hydrochloride E t =ethyl E t2 0 Diethyl E t3 N ditriethylamine EtOAc = acetic acid B for EtOH diethanol

Page 32 1247008 V. INSTRUCTIONS (26) FAB MS = fast atomic impact mass spectrometry g II free GIHA = m-mercaptopurine GIHA HC1 = m-mercaptopurine hydrochloride G 1 y = glycine citrate MPA II Hexamethyl sulphate H0BT = 1-hydroxybenzotriazole hydrate HPLO high ten lb & layer IBCF = isobutyl phthalate i -Pr = isopropyl i-Prop = isopropyl K2 C 03 = carbonic acid _ ΚΜη04 = potassium permanganate Κ 0 Η = potassium hydroxide KSC Ν = potassium thiocyanate

LiOH=Lithium hydroxide MCPBA di-chloroperoxybenzoic acid or m-chloroperbenzoic acid Me=mercaptoMe I dithiol MeOH dimethanol MEMCI dimethoxy ethoxy ethoxy group gas MesCI diterpene sulfonate Base gas mg two mg

Page 33 1247008 V. Description of invention (27) M g S 04 disulfate town m 1 =ml mL^ml MS II mass spectrometry

MTBE=methyl tert-butyl ether N2 - 5L

NaCNBH3=Cyanide hydrogenation N aH =Sodium hydride N a HC 03 =NaHCO3 NaOH=Sodium hydroxide NaOMez decyl hydride N a2 P 04 Diacid N Na 2 S 04 =Sodium sulfate NEt3 =Triethylamine N H4 HC 03 = acid ammonium hydroxide NH/HC (V = ammonium formate ΝΗ 40 Η diammonium hydroxide NMM di N-methyl morphine NMP di-methyl-2-pyrrolidone NMR = nuclear magnetic resonance

Pd/C dipalladium/carbon

Ph = phenyl

Pt/C=platinum/carbon R Ρ Η P L reversed phase high performance liquid chromatography

Page 34 1247008 V. INSTRUCTIONS (28) RT = room temperature t-BOO tert-butoxycarbonyl TFA: trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography TMEDA = tetradecyl ethylenediamine TMS = Trimethyl hydrazino Δ nd heating reaction mixture The compounds shown in formula I-VI can exist in various isomeric forms, including all such isomeric forms. Also included are tautomeric forms and pharmaceutically acceptable salts of isomers and tautomers b. In the structures and formulae shown herein, a bond can be attached to any of the possible atoms of the ring through a bond of a ring. The term "pharmaceutically acceptable salts" is a salt prepared from an acid of the formula I and an anion which is generally considered to be suitable for human consumption. Examples of pharmaceutically acceptable salts include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinic acid Salt, tartrate, etc. All pharmaceutically acceptable salts can be prepared in a conventional manner. (See Berge et al, Pharm. Sc i. 6 6(1), 1-19 (1 9 77) for other examples of pharmaceutically acceptable salts). For the selective inhibition or antagonism of av y53 integrin, the compounds of the invention may be administered orally, parenterally, or by inhalation, or topically, in a unit dosage form containing conventional pharmaceutical acceptable carriers, adjuvants, and vehicles. Formulation. The term parenteral as used herein includes, for example, subcutaneous, intravenous, and intramuscular.

Page 35 1247008 V. Inventive Note (29), through the sternum, by infusion technique, - the compound of the present invention can be any suitable in the sputum. The form of the composition, and the use of a compound which is required for the progress or treatment of a medical form suitable for the route. Prevention or prevention of medical symptoms Skilled people familiar with the use of medical skills, =, 2 doses can be easily prepared. Pre-bed and clinical methods, therefore, the present invention provides a method for treating a disease selected by a cell surface receptor to selectively inhibit or antagonize a disease selected from the formula I-V丨. Treating a compound with one or more non-toxic agents, wherein one or more of the agents and/or adjuvants (in this context, a total acceptable carrier and/or sexual ingredient, if desired, is administered as a combination of agents) Substance), and other methods of living av A cell surface receptors. This \Ming 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制, inhibition of angiogenesis, including ▲ 卩, neoplasia (solid tumor disease, including visual plaque and diabetic visual / adult, k retinal palsy, periodontal / disease, and inhibition of smooth muscle cells, =, inhibition of arthritis, leather method Also privately mobilized 'including restenosis based on well-known and well-understood procedures, and compared with known useful compounds, the second laboratory test techniques and treatment of patients with these pathological symptoms. Cooked: compounds can be used for optimal treatment The choice of compound is in the skilled artisan: it should be clear from the 'factors', including standard analysis and animal models; obtained; species page 36, 1247008

2 Therapy for patients suffering from one of the above pathological symptoms, in the form of a compound to control the symptoms or prolong the disease, and to treat the person who has not been treated with the treatment. The use of the technique in this paper is too slow to slow down the 'tf, block, or stop the symptoms, and may not necessarily show a complete = shape. The belief that prolonging the patient's survival rate beyond the original and natural manifestations also showed that the symptoms were favorably controlled to some extent. Excellent As described above, the compound of the present invention can be used for various biological and prophylactic purposes. aspect. These compounds are useful for the prevention or treatment of any condition or symptom of the treatment of the horn. The dosage of the compound and/or the composition containing the compound is determined by factors including the type, age, weight, sex of the patient, the severity of the symptoms, the use of the shuttle, and the specificity used. Hua eight and medical activity. Therefore, the dosage can vary widely. A dose of from 0. 〇ι gram to about 10,000 mg per kilogram of body weight per day can be used to treat the above symptoms. The active ingredient for injection administration is formulated into a composition in which, for example, saline, dextrose, or water is used as a suitable carrier. Suitable for two daily use, the daily type is about 〇 · 〇 1矣1 〇 gram / kg body weight, in multiple doses, according to the factors mentioned in the code. The therapeutically effective amount is administered to a mammal in need of such treatment in combination with one or more adjuvants suitable for the indicated application. Compounds ~ lactose, sucrose, starch powder, cellulose ester of siutaric acid, cellulose 舆 ’ grease 'talc, stearic acid, stearic acid k 镬 gasification magnesium, 粦 粦 acid and ' '. Base and calcium salt, gelatin, acacia gum, bathing sodium, polyethylene called sodium LL ϋ 啶 124 1247008 5, invention description (31) ketone, and / or polyvinyl alcohol mixture, and ingot or plastic For ease of application. Alternatively, the compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well known in the art of medicinal techniques. The pharmaceutical compositions useful in the present invention may be subjected to conventional medical procedures such as sterilization, and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents, buffers, and the like. A general synthetic sequence for the preparation of compounds useful in the present invention is shown in Figures 1-5. Where appropriate, the description of various aspects of the invention and the actual procedures are described. The following figures and examples are merely illustrative of the invention and are not intended to limit the scope or spirit of the invention. It will be readily apparent to those skilled in the art that the compounds of the invention can be synthesized using known variations in the conditions and methods described in the Figures and Examples. All starting materials and equipment used are commercially available unless otherwise stated.

Page 38 1247008

Page 39 1247008 V. Description of invention (33)

A culvert 2

1} DIEA DSA Δ -1 2} HCI

_

S2H • 2HCI

'C02H •2HCI j~^5 2 Page 40 1247008 V. Description of invention (34)

Δ

2) HCI

If β

S

S11J 'i

〇H

2HCI z-

{A9J

HN

N-fNH

OH

THF OH + CS2imiairo_\^ NaKBOC gf 0--H SI HN/, NH ~.

CPH • 2HCI

JT

Roool2/\f ro8 Y s OH

QBOC Page 41 1247008 V. INSTRUCTION DESCRIPTION (35) Figure 1-3 illustrates a pyridylpyridine/cyclodecylpyridinecarboxylic acid moiety useful for the preparation of the present invention (which is used to couple to glycine-/3-amino group) The method of the acid part). It can be accomplished using a skilled person known to the skilled person. The method of Figures 1-3 can be modified using conventional techniques and methods to prepare alternative compounds that can be coupled to the glycine-lu-amino acid moiety. Figure 4 H2i

NH S Η ΝΗ2 ten

OEt

1) EtOH △ -_ 2) NH4〇H

1) NaOH H20/Et0H

2) HCI

_/C〇2H 2γΝ HN NH2 NH 'HCI (A13) Figure 4 illustrates a method for preparing the mercaptothiazolecarboxylic acid moiety of the present invention for coupling to a glycine-dot-amino acid moiety . The method of Figure 4 can be modified using conventional techniques known to those skilled in the art to prepare such compounds and alternative compounds that can be coupled to the glycine-/3-amino acid moiety.

Page 42 1247008

Page 43 1247008

V. INSTRUCTIONS (37) Preparation of potassium iodide and gas amine T reaction. Conventional treatment produces a substance which is processed by hexane to produce the desired 3 - moth-5 - chlorinated water disk. Second production! Precipitate to filter... The rest of the product is recovered from the filtrate by water dilution and separation. The combined solids were dried and resigned as 3-gas-5-di- benzene-based benzoquinone. 3_Moth_5_Oxygen water is produced by the reaction of 5_^2 yang = plaque ν - 峨 醯 醯 imine in DMF and the reaction mixture is subjected to conventional treatment conditions. 3-iodo-5-bromo salicylaldehyde can be prepared from 5-bromo salicylaldehyde in acetonitrile with oxacillin. A modified perliin &

Preparation (for example, Vogel s Textbook of Practical Organic Chemistry, 5th Ed., 1 989, ρ·1 040). The halogen-substituted oxacin is converted to 3-aminohydrogenin (see J. G. RiC0, Tett· Let·1 9 9 4, 35, 6599-6602), which can be easily opened in an acidic alcohol to produce 3-amino-3-(3,5-halo-2-pyridyl)phenylpropionic acid g. 3-Amino-3-(3,5-2-di-trans)phenylpropionic acid S is converted to glycine-3-amino-3-(3,5-t--2-yl)phenylpropane Acid S, which is reacted with Boc-N-glycine_N-hydroxysuccinimide to produce Boc-N-glycine-3-amino-3-(3,5-ii-2-yl)benzene Propionate S, which is converted to N-glycine-3-amino-3-(3,5-dent-2-hydroxy)phenylpropionate, the HX salt (where X is

Cl, Br or I).

Figure 6 (A1-13)-C〇2H^HCI + CC'

1) ΝΜΜ Π 丫〆~ DMA (i〇DMF co2h

2) (C)^NMM 3> UOhVHzO 4) 7FA

Page 44 1247008 V. INSTRUCTION DESCRIPTION (38) Figure 6 illustrates a method which can be used to couple the heterocyclic acid moiety (A A A 3 3 ) of the present invention to the glycine-/3-amino moiety (C). The synthesis of Ab A13 is shown in Figure 4, and the synthesis of (C) is shown in Figure 5 (where X and Y are halogen, the same or different). The method can be modified using conventional methods known to those skilled in the art. Figure 7

Step A H02C^^C02H Ten NCHO Ten NHZch3CCV

- A

y—C〇2H R30—l H2N-^HOIL h2n

COsR3 -HCl (E)

Step B

Y BOC—N R6 C+CO2H ten CC〇2_ z,

1247008 V. INSTRUCTION DESCRIPTION (39) Figure 7 illustrates a method of preparing a glycine-cold-amino acid moiety of the molecule (F) in a general manner. The aldehyde (R' CH0) used in this method is commercially available or can be prepared from commercially available reagents by methods known in the art for preparing aldehydes. All other reagents are commercially available or can be readily synthesized by those skilled in the art. Such methods and conditions can be further modified using conventional techniques to produce similar intermediates. 1247008 V. Description of invention (40) i __ Jb co τ Ο +

1) NMS dsauiomf 2) 34 ΝΜΜ 3) LI0H/HO 4) TFA Ν {Α1-Α13) 0Λ. 〇if ICINH-η 0, .003⁄4ν·πΑ 1247008 V. Description of invention (41) Figure 8 illustrates that it can be used for coupling The cyclic acid moiety (A A A 3 3) is in the glycine-5-amino acid moiety (F) to prepare a compound of the invention. A synthesis example of A A13 is shown in Figs. 1-4, and a synthesis example of (F) is shown in Fig. 7. The method can be modified using conventional methods known to those skilled in the art. Figures 9 - 1 2 illustrate a general method for preparing the compounds of the invention.

Page 48 1247008 V. Description of invention (42)

0 2 history

» Paintings _1 Page 49 1247008 V. INSTRUCTIONS (43) Figure 9 illustrates a general method for the synthesis of heterocyclic-derived glycine-/5-amino acid coupled standard compounds. The heterocyclic carboxylic acid is reacted with glycine-/3-amino acid under peptide coupling conditions to produce an intermediate (, 2). The nitro group is reduced using catalytic hydrogenation (e.g., Pt/C, H2) to yield the amine intermediate (3). This transformation can also be carried out chemically using SnCl2. Amine groups can be used to form sulfhydryl groups or other functional groups of formula I using the methods described above.

Page 50 1247008

Page 51 1247008 V. INSTRUCTIONS (45) Alternatively, the target compound can be synthesized by coupling the left-hand portion of the molecule with glycine-cold-amino acid (Figure 10). The amino functional group of the heterocyclic amine (1) is functionalized to a thiol or other group (A, formula I) and then coupled to a glycine-/3-amino acid under standard coupling conditions.

Page 52 1247008 V. Description of invention (46)

Page 53 1247008 V. INSTRUCTIONS (47) Figure 11 shows the synthesis of one of the substituted pyridine and pyridone-derived compounds. 6 - After acidification based on acid chemistry, then chlorination to produce 6-chloro-5 - stone xiao based on acid testing. Intermediate 3 is coupled with glycine "/3-amino acid to give product 4. The chloro group of intermediate 4 can be easily replaced with various nucleophiles to produce a 0.45 reduction of nitro group and further treatment of the amine group. As discussed in Figure 9, the target compound is produced.

Page 54 1247008

Page 55 1247008 V. INSTRUCTION DESCRIPTION (49) Figure 12 shows the synthesis of the substituted pyridine and pyridone derived standard compounds starting with 2-amino-6-hydroxypyridine-4-carboxylic acid. The starting material 1 used in this figure can be prepared by reacting a commercially available 2-chloro-6-mercapto-pyridin-4-carboxylic acid with ammonium hydroxide under high pressure. The amine treatment followed by coupling to the glycine-/3-amino acid, as discussed in Figure 10, gave the subject compound.

Page 56 1247008 V. Description of invention (50)

H2N, /N, S2H

0 force

JL

COX

OR

I 云 涵一3 Η 0 force 1 'Λ,>=>-'C02R2

0 force A, /N, S2H IIO page 1247008

Page 58 1247008 V. Description of invention (52)

Page 59 1247008 V. INSTRUCTIONS (53) Heterogeneous pyridine and pyridone derived compounds can be prepared using the method illustrated in Figure 14. The main intermediate 4 can be prepared starting with 6-chloro-picolinic acid. Oxidation, then deuteration, yields 4-mercapto D to bite derivative (3). N-oxide deoxygenation, nitro reduction, and nucleophilic nucleophilic displacement produce intermediate 4. The method described in Figure 10 can be used to achieve the synthesis of the subject compounds.

Page 60 1247008 V. Description of invention (54)

1247008 V. INSTRUCTIONS (55) The method shown in Figure 10 can also be used for the synthesis of pyrimidine-derived target compounds (Figure 15). The isomeric pyrimidine derivatives 1 and 2 can be synthesized according to the literature preparation method (J. Org. Chem. 26, 2 75 5, 1 9 6 1.).

Example A Preparation of the following formula

5_ Aminonicotinic acid (4.0 g, 0.021 mol) (Helv. Chim· Acta' 47, 3 6 3 (1 9 64 ); JACS, 70, 238 1 [1 948 ]), 1H-pyrene Carboxylic acid hydrochloride (4.6 g, 0.031 mol), diisopropylethylamine (8·g, 0·062 mol), dioxane (14 ml), and ratio 0 (7) (ml) heated at reflux for 2 days. The reaction mixture was cooled to room temperature and allowed to stand; the chamber was filtered and washed with Η2〇/dioxane (50:50) and dried. The precipitate became a liquid in the crucible 20' and made acidic with 2 N H C 1 . The solvent was removed in vacuo to give the title compound as a white solid ( 750 mg). MS and 1 H-NMR were consistent with the desired structure.

Instance B

Preparation of the following formula 12470008 V. Description of the invention (56) Step 1 In 3, 4, 5, 6-tetrahydro-2-pyrimidinethiol (1 g, 0.086 mol) (Aldrich) in absolute ethanol (75 mTorr) Add Mel (12. 2 grams, 0. 0 8 6 moles). The reaction mixture was stirred at reflux for 2.5 hours. The solvent was removed under vacuum and the product dried to give 2-methylthio-3,4,5,6-tetrahydro-2-pyridinium iodide as a white solid (22 g). MS and 1H-NMR were consistent with the desired structure. Step 2 In the above step 1 product (5.3 g, 0.021 mol) and triethylamine (2. 〇7 g, 0·021 mol) in CH2C12 (25 ml), add BOC anhydride (4.5 g, 0 · 0 2 1 mol) at the ice bath temperature. The reaction mixture was then mixed for 2 days at room temperature. The CH2C12 was washed with H.sub.2 (3.sub.3), dried over <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; MS and 1 H-NMR were consistent with the desired structure. Step 3 The product of the above step 2 (3.08 g, 0· 01 34 mol), 5~ amine based on acid test (1.8 g, 0.0134 mol) in DMA (12 ml) heated at 80-85 t for 2 weeks . The reaction mixture was diluted with CH3CN, filtered, washed with EtOAc and dried. The precipitate was slurried in H20 and the pH was reduced to 1-2 with concentrated HC1. The solution was frozen and lyophilized to give the desired product as a pale brown solid (2 g). MS and 1H-NMR were consistent with the desired structure.

Example C Preparation of the following formula

1247008

Step 1 In 2-methylthio-2-imidazoline hydroiodide (2 gram, 〇·082 mol) (Aldrich) and triethylamine (8.28 g, 0.0 8 2 mol) in CH2C12 (1〇〇 Add BOC anhydride (17·9 g, 〇·〇82 mol) to the ice bath temperature. The reaction mixture was then stirred at room temperature overnight. The CH2Cl2 was washed with 4 〇 (2 χ), dried with MgS 〇 4, and removed under vacuum to obtain N-B0C-2-methylthio-2-imidazoline as a viscous oil and converted to a waxy white solid (丨5 · 9 3 grams). MS and 1H-NMR were consistent with the desired structure. Step 2 The product of the above step 1 (15.93 g, 0.0737 mol), 5-aminonicotinic acid (9.6 g, 0.07 mol), and triethylamine (7.1 g, 0.07 mol) in DMA (60 ml) was heated at 1 ° C for 2 days, then heated at 130 ° C for 1 day and heated at 150 ° C for 2 days. After the reaction mixture was cooled and diluted with CH3CN, the precipitate was filtered, washed and dried (Zwitter ion yield: 10 · 16 g). It was slurried in Η20 and made acidic with TFA (pH 1-2). The solution was frozen and lyophilized to give the desired product as a pale yellow solid (20.15 g). MS and 1H-NMR were consistent with the desired structure. Preparation of the following formula

Page 64 1247008 V. Description of invention (58)

Step 1 Preparation of the following formula

In a 2 liter round bottom flask equipped with a mechanical stirrer and a condenser, 3,5-gas hydrated water (20 〇. gram, mol, 1 equivalent), acetic anhydride (356 g, 3.49 mol) was placed. ), and triethylamine (95.0 g, 〇·94 mol, 0. 90 eq.). The reaction solution was heated under reflux overnight. The dark brown reaction mixture was cooled to 50. (:, water (1 liter) was added and stirred. After 1 hour, the mixture was filtered. The filtrate was combined with EtOH (1 liter). The mixture was heated to 45 ° C for 1 hour, cooled to room temperature, filtered, solid ( Part A) is washed with £1: 〇11 (〇·5 liters). The combined EtOH solution is concentrated by rotary evaporation to produce an oil (part. The solid of the sputum is dissolved in dichloromethane (15 liters) to form The solution was passed through a silicone pad (130 ml volume). The resulting dark brown solution was concentrated to an oil and triturated with hexane (1.3 g) to give a solid, which was separated by filtration and washed (hexane).

Page 65 1247008 V. INSTRUCTIONS (59) Essentially pure 6,8-dichlorosulphonin (1 63 g). The other 31 g of the product was obtained by treating the oil (part β) in a similar manner; the oil was dissolved in a methane (5 liters) and passed through a pad of ruthenium (0.5 liter by volume) and hexane. The total isolated yield was 194 g, or 86%, brown solid. MS and 1H-NMR were consistent with the desired product. Step 2 Preparation of the following formula

C〇2Et OH •HCI Cl

In a 3-necked 2 liter round bottom flask equipped with a mechanical stirrer, 6,8-dichlorosulphonin (160 g, 0.77 mol) prepared in step 1 and anhydrous thf (375 ml, Aldrich Sure Seal). The resulting mixture was cooled to -40 ° C (dry ice-acetone bath), bis (tridecyl decyl) guanamine lithium (〇. 8 〇 Mo Er, 800 ml 1 M in THF) was added, the temperature was maintained at one 4〇. At the time of addition and completion, the cooling bath was removed. After 5 hours, the mixture was heated to -5 °C. The reaction mixture was quenched by a solution of HCl (0.5 liters of 4 M in dioxane) in E10 Η (1 · 25 liters). The temperature was maintained below 〇 overnight. The mixture should be concentrated to about half of the original volume and distributed between Et〇H (3 liters) and reverse (2 liters). The organic layer was washed with an aqueous solution of HCl (3 X 1 liter, 〇 5 N HCl). The p Η of the combined aqueous layer was adjusted to about 10% by adding a solution of dioxane (3 X 2 liters). The combined organic layer is dried (MgS〇4),’

1247008 V. INSTRUCTIONS (60) Filtration, adding HC1 (21 ml of 4M in dioxane) and stirring. Upon completion of the precipitation, the solids were removed by filtration. The filtrate was concentrated to a small volume, and decyl tertiary butyl ether was added. The solid obtained was combined with the solid which was originally formed, and the combined product was washed with methyl t-butyl ether, separated by filtration and dried (vacuum oven over one week) to give the desired product (1 72 g, yield 74%) . MS and 1 H-NMR were consistent with the desired product. Step 3 Preparation of the following formula

Nt-Boc-glycine N-hydroxysuccinimide (Sigma, 15.0 g '0.055 mol) was added to a flame-dried round bottom flask (〇·5 liter) equipped with a mechanical stir bar. Anhydrous j) MF (Aldrich Sure Seal, 200 ml), and the product of Step 2 (21.67 g, 0.055 mol) under inert atmosphere (Ar). The reaction mixture was cooled to about 〇 (salt-ice bath), n-methylmorpholine (5.58 g, 0.056 mol) and a catalytic amount of DMAP was added. The reaction was allowed to go through the night. The reaction mixture was concentrated to a grease and partitioned between MEt0Ac (yield: 4 liters) and an aqueous alkali solution (2×0.2 liters, saturated aqueous NaHc 〇3). The organic layer was successively washed with citric acid aqueous solution (2 X 〇 · 2 liters, 1 〇 % by weight/volume), sodium hydrogencarbonate aqueous solution (2×0 · 2 liters), brine, and dried (N 7 s 4 ). The volatiles were removed under vacuum at 55 ° C to give an oil (22.5 g, yield 92%).

Page 67 1247008 V. Description of invention (61) Time-curing. MS and 1 H-NMR are consistent with the desired product. Step 4 Preparation of the following formula

C〇2Et OH • HCl Cl The product obtained in Step 3 was deprotected using the following procedure to give the amine salt. The product obtained in the step 3 (14.0 g, 0.032 mol) was added to a dry-boiled round bottom flask (0.1 liter) equipped with a stirring bar, and anhydrous dioxane (40 ml) was added. To this solution was added HCl (4.00 N in dioxane, 2 equivalents, 6.32 ml) at 0 °C. The reaction was allowed to proceed until the gas evolution ceased and the reaction was completed. The volatiles were removed in vacuo and the residue was taken ethyl ether (EtOAc). The solid was collected by filtration, washed with diethyl ether and dried to give the desired product (12.5 g). M S and 1 Η - N M R are consistent with the desired product. Example 制备 Preparation of the following formula Η

Page 68 1247008 V. Description of invention (62) Step 1 Preparation of the following formula

Add triethylamine (1 〇3. 6) to a suspension of 3-bromo-5-chloro-salicylic acid (175 g, 743.2 mmol) in acetic anhydride (280 ml, 5 ml, 3 mol). ML '7 4 3 · 2 house Moer). The reaction solution was heated under reflux for 4 · 5 hours. The solution was cooled and concentrated in vacuo. The brown residue was added to absolute ethanol (7 3 Torr). The mixture was stored at 〇 ° C for 14 hours. The brown solid was collected by filtration and washed with cold ethanol. The solid was dried in vacuo to give the desired product U2 3 g, yield 46%). 1 Η - N M R is consistent with the structure shown. Step 2 Preparation of the following formula

The suspension of the oxacin (4 〇·〇克, 154.1 mmol) produced in step 1 in THF (4003⁄4: liter) was in-76. 〇 was added dropwise, and the lithium bis(trimethyldecyl) decylamine (1 54·ml 丨M solution in THF) was disturbed. plus

Page 69 1247008 V. Description of the invention (63) The completion is completed within 10 minutes. The reaction mixture was then stirred for 5 minutes and heated to - 20 C' to stir: 15 minutes. To the solution was added acetic acid (9 25 g, 1 54·1 mmol) in THF (28 mL) for 5 min. The mixture was heated to room temperature and the volatiles were removed in vacuo. The residue was dissolved in aq. (8 mL), EtOAc (EtOAc (EtOAc m. Add HCl (4M in dioxane, 56 3 ml, 2 2 5 cfe Mo), stir the mixture for 3 〇 minutes. The suspension is filtered and the filter cake is washed thoroughly with ether. The solid is dried in vacuo. The desired product was obtained as the HCl salt, dioxane solvate (45 g). 1H-Nmr was consistent with the structure shown. Step 3 Preparation of the formula

Add HCl to the suspension of ^: 3 (; 42.2 g, 354.5 mmol) in the middle of the B, and add HCl to the distillate at room temperature. House Moer) 1 minute. The reaction mixture was removed in vacuo. The residue is dissolved in the precipitate to aid the recovery: the V" solution remains in the mash. ° 15 hours. Yellow brown | &quot; set, washed with cold ethyl acetate. The solid is dried in a vacuum

Page 70 1247008 V. INSTRUCTIONS (64) The desired product was obtained as the hydrochloride salt (100.4 g, yield 79%). 4-question 1^ is consistent with the structure shown. Step 4. Preparation of the following formula

Add N_t-Boc-glycinic acid N-base amber-bromide (Sigma, 2.72 g, 0.010 mol) in a flame-dried round bottom flask (0.1 liter) equipped with a magnetic stir bar. THF (Aldrich Sure Seal, 50 mL), and the product from Step 3 (3.10 g, 0.01 M. The reaction mixture was cooled to about 0 ° C (salt-ice bath) and triethylamine (1·0 1 g, 0·0 10 mole) was added. The reaction was allowed to go through the night. The reaction mixture was concentrated to a semi solid which was treated in a similar manner to that of Example 3 Step 3. The volatiles were removed from the organic layer <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt; M S and 1 Η - N M R are consistent with the desired product. Step 5 Preparation of the following formula

Page 71 1247008 V. INSTRUCTIONS (65) The product obtained in Knowledge 4 is deprotected using the following procedure to obtain the product obtained in Step 4 of hydrochloric acid (4.0 g, 〇·〇〇84 mol) Add a dry dioxane (2 ml) to the dry round bottom flask (〇·丨). Add HC1 to this solution (4N in dioxane, 20 ί reaction until gas release stops, reverse shore, complete (about 1 hour). Volatile matter under vacuum ^ 魇兀 魇兀 King U1 system. The mixture was collected by filtration, and the residue was purified eluting with diethyl ether (50 EtOAc) (27 g, yield: EtOAc, EtOAc, EtOAc

• HCI Step 1 3 - Preparation of Shidian-5-Gas Water Brewing

, 0· 641 Moer) Add 5-gas salicylaldehyde, page 72, 1247008 V. Description of the invention (66) (100 g, 0.638 mol) in a solution of dimethylformamide (4 ml) . The reaction mixture was stirred at room temperature for 2 days. N-iodosuccinimide (20 · 0 g) was added and stirring was continued for 2 days. The reaction mixture was diluted with ethyl acetate (1 L) with hydrochloric acid (300 mL, &lt;RTI ID=0.0&gt;&gt; 30 ml), washed, dried (MgSO.sub.4), evaporated to dryness UMR and MS are consistent with the desired product. Step 2 Preparation of 6-gas-8-ephedrine

A mixture of 3-A-5-gas hydrazine (100 g, 0.354 mol), acetic anhydride (300 ml) and diethylamine (5 4 liter) was heated under reflux for 18 hours. Upon cooling, the desired herbicide precipitates as a dark brown crystalline material. The precipitate was filtered, washed with hexane/ethyl acetate (4:1, EtOAc) and dried. [Production amount 60 g (yield 55%)]. Other desired products (10 g, 9% yield) were obtained from the storage of the filtrate. l-NMR and MS are consistent with the desired product. Step 3 Preparation of (R,S)-4-amino-3,4-dihydro-6-chloro-8-iodonium hydrochloride

Page 73 1247008 V. Description of invention (67)

Lithium hexamethyl diazepine (21·62 ml, 1 M, 21·62 mmol) was added to 6-chloro-8-iodine (6. 63 g, 21·62 mmol) to tetrahydrofuran. (1 〇〇 升) in the solution of -7 8 C. The reaction mixture was stirred at this temperature for 3 Torr and then stirred at 0 C for 1 hour. Acetic acid (1.3 g, 2 1 · 6 2 mmol) was added to the reaction mixture. The reaction mixture was poured into a solution of ethyl acetate (3 (10 mL)) and saturated sodium sulfate (200 mL). The organic layer was separated, washed with brine (2 mL) and then washed with &lt;RTI ID=0.0&gt; The reaction mixture was stirred at room temperature for 1 hour, filtered, and dried in vacuo to give the desired product as a powder (4·6 g, yield 59%) /Uphplc/, Rf for 6.8 min; concentration gradient 1% Acetonitrile-9〇% acetonitrile for 15 minutes, then to 10 0% acetonitrile for 6 minutes. Water and acetonitrile contain 〇·1% TFA. Vydac Π8 protein peptide column '2 ml/min flow rate, detected at 254 nm). UMR and MS are consistent with the desired product. Step 4

Preparation of (R,S)-3-amino-3-(5-chloro-2-hydroxy-3-iodo)phenylpropionic acid ethyl ester hydrochloride

Page 74 1247008 V. INSTRUCTIONS (68) Vaporized hydrogen bubbling into 4~amino-3,4-dihydro-6-chloro-8-iomoxanthin hydrochloride (22.0 g, 61·〇) 9 mmoles in a solution in ethanol (250 ml) 'The reaction mixture was kept at 〇~丨〇丨c until saturation. After refluxing 6 hours, most of the solvent was removed by distillation. The cooled residue was added to anhydrous ether and stirred for 2 hours. The initial gum is converted to a crystalline material. The crystallized product was filtered, &apos;dried&apos; to give the desired product as an off-white crystalline powder (2 g, yield 81%) (R f 7 · 5 2 min, conditions as in step 3). NMR and MS are consistent with the desired product. Step 5

Preparation of (1^'3)-3-(1^4〇(:117)-Amino-3-(5-chloro-2-hydroxy-3-iodo)phenylpropionic acid ethyl ester

B〇C—f &amp; (2. 16 grams, 12. 31 millimoles), Η0ΒΤ (1. 67 grams,

12·耄莫耳), a mixture of EDCI (2.36 g, 12.31 mmol), and DMF (5 ml) was stirred at 0 °C for 1 hour. 3-Amino-3_(5-chloro-2-hydroxy-3-iodo)propanoic acid ethyl ester hydrochloride (5 g, 1231 mmol) was added to the mixture, then triethylamine (3.5) ML) to join. The reaction mixture was mixed in a chamber for 18 hours. The bribe was removed in vacuo and the residue was partitioned between acetic acid (1 mL) and sodium bicarbonate (2 mL). The organic layer is washed with hydrochloric acid (1N '100 liters), brine (2 liters), dried (10), thick

Page 75 1247008 V. INSTRUCTIONS (69) Shrinkage to obtain the desired product as a solid (6 g, yield 93%). UMR and MS are consistent with the desired product. Step 6 Preparation of (R,S)-3-(N-gly)-amino-3-(5-chloro-2-yl-3-yl-phenyl)phenylpropionic acid ethyl ester hydrochloride Η

Dioxane/HC1 (4Ν, 20 ml) was added to ethyl 3-(N-BOC-gly)-amino-3-(5-aero-2-hydroxy-3-iodo)propanoate (6.0 g, 11.30 Melt in 0 t, stir at room temperature for 3 hours. The reaction mixture was concentrated and concentrated again with EtOAc (EtOAc). The residue obtained was suspended in ether, filtered and dried to give the desired product as crystal powder (5.0 g, yield: 5%). (rphplc ·· Rf 8. 3 minutes, conditions as in step 3). UMR and MS are consistent with the desired product.

Example G Preparation of the following formula

(S-isomer)

Page 76 1247008

Step 1 Preparation of R e f 〇 r m a t s k i reagent

BrZnCH2C02-t-Bu A 4 liter flask equipped with a condenser, temperature probe, and mechanical stirrer was charged with Zn metal (180.0 g, 2.76 mol, 30-1 〇〇 mesh) and THF (1 25 liter). When stirring, 1,2-dibromoethane (4·74 ml, 〇·〇6 mol) mother's syringe is added [or, TMS C1 (0" equivalent) can be substituted at room temperature plus = 1 hour] . After washing with inert gas (3 ^ / vacuum cycle), the suspension of zinc in THF was heated to reflux (65 ° 〇, maintained at this temperature for 1 hour. The mixture was cooled to 50 ° C, then the third butyl bromoacetate (488 g, 3 6 9 mA, 2 · 5 1 ear) After 5 hours of charging through a 50 ml syringe and syringe pump (transport setting to work house liters / minute). The reaction temperature is 5 〇. + / -5 t was maintained during the addition. After the addition was completed, the reaction mixture was stirred for 5 hours at 5 ° C. Then, the mixture was cooled to 25 〇c to deposit the precipitated product. The mother liquor was used to make a coarse glass filter rod and a partial vacuum transfer device. (2 〇 mmHg) was decanted in a 2 liter round bottom flask. About 65% THF was removed from the mixture. Dimethyl 2- ketone (NMP '800 liter) was added and stirred for 5 minutes. The reaction mixture was filtered. Any residual zinc was removed. Analysis showed that the desired reagent = Ϊ ί 1乂7, M ' I ear yield was 94%. Alternatively, the solid reagent could be filtered, and the μ mixture separated. The filter cake was washed with THF until a white solid was obtained. After drying, dry at ν2 to obtain the desired product as a THF solvate, pot: -20 C (drying) prolonged storage. Typical recoveries "-g⑽. /, A · Preparation of the formula

Page 77 1247〇〇8 V Description of invention (71) Η, /0 (X /〇

* Potassium carbonate (powder, dried in a vacuum oven at 100 ° C, 8.82 g, 6 〇 kHz) was added 3,5-dihydrate salicylaldehyde (11.46 g, 60 mol) in DMF (40 liters) A pale yellow slurry was obtained in the warm solution. Then MEMC1 / 99. 7. 64 grams, 61 millimoles) was added and the bath temperature was maintained at 20 °C. The mixture was mixed for 6 hours and MEMC1 (0.3 g, 2.4 mmol) was added. The mixture was further mixed for 0.5 hours, and the reaction mixture was poured into cold water (2 ml) to filter the liquid mixture on the pressure filter. The cake was washed with water (2 X 50 m). Drying under vacuum gave the product as an off-white solid (.94 g, yield 89%). 1{1_circle (CDCl3, Tms) 3 37 &amp; Η), 3.54^3.56 (m, 2H), 3.91^3.93 (m, 2H), 5.30 (s, 2H), 7.63 (d, 1H), 7.73 (d,1H)' 1 0 30 (s, !H); 13C NMR (CDC13, TMS) 5 (ppm): 59·〇3,7Q n, 99.57,1 26.60,1 29.5 7,130.81,132.07,' 135·36: « 154· 66, 188· 30, DSC: 48· 24 °C (within 90·5l; /g). ’

Microanalytical calculation of Cui^C l2〇4: C: 47. 33%; Η: 4. 33%; Cl: 25. 4〇〇^ Found: C: 47.15%; H: 4.26%; Cl: 25 16% B • Preparation of the following formula · °

Page 78 1247008

Page 79 1247008 DESCRIPTION OF THE INVENTION (73) The solution was cooled to -1 (rc' was stirred at 35 rpm. A solution of the imine (prepared in internal force: prepared) in NMP was prepared under nitrogen and then at 2 sec ec. Into the above reaction mixture 'temperature maintained at -5 °c (casing temperature -1 〇, after the completion of the addition, the mixture was stirred at _ 8 for 1.5 hours, at _ $. 〇 disturbed t hours. After cooling to _ After 1〇1, a mixture of concentrated solution (1 liter), water (1 liter), and brine (100 ml) was added; in the solution, ΜΤΒΕ (200 ml) was added, and the mixture was added. The mixture was stirred at 2 ° rpm for 15 minutes at 23 ° C. Stirring was stopped and the layers were separated. The aqueous layer was extracted with mtbe (1 mL). The two organic layers were combined, followed by a saturated solution of NH4Cl (1 〇〇) House liter) 'water (1003⁄4 liters)' and brine (1003⁄4 liters) wash. The solution is dried with MgS〇4 (30 g), filtered and concentrated to give an orange oil (6 6 · 3 g) (cured in standing) ), containing the desired product 'as a single diastereomer, measured by proton and carbon nmr. One sample was purified by Geng Xuan and then crucible The product was obtained as an off-white solid. The proton and carbon nmr and IR spectra were consistent with the desired product. [a ]D25 = + 8 · 7. (c = 1·0 57, Me0H). Microanalytical calculation of C25H33C12N06: c: 58.77%; Η: 6.47%; Ν: 2.72%; Cl: 13.78% Found: C: 58.22%; Η: 6.45%; N: 2.70%; Cl: 13.66% f3

Preparation of the following formula

Page 80 1247008 V. INSTRUCTIONS (74) A. The solution of the crude ester prepared in step 2 [1 7.40 g, 0·03 3 mol, (theoretical)] and EtOH (250 ml) 1 liter 3 neck casing reactor. The solution was cooled to 0 ° C, Pb (0Ac) 4 (.14. 63 g, 〇 · 〇 33 mol) was added once in 2 hours ^ 15% of NaOH: gluten solution (303⁄4 liters) was added, ethanol was reduced Press to remove. Another portion of 15% NaOH (1 ml) was added and the mixture was extracted with MTBE (2 x 100 mL), washed with η 2 〇 (2 χΐ〇〇 ml) and brine (5 〇 * liter), dried with NaJO4, on ceiite Filtration and concentration under reduced pressure afforded an orange oil &lt;RTI ID=0.0&gt; This oil was used without further purification.

The oil of B. A was diluted with EtOH (30 ml) and p-toluic acid (1 3 when 0.043 mol &lt;8.18 g) was added. The solution was heated to reflux for 8 hours to cool to ambient temperature and concentrated under reduced pressure. The residue is subjected to thf and heated to reflux to form a solution. Solution human /, crystal. Gengyuan (30 ml) and THF (1 ml; part to room temperature, the compound is filtered. The filter cake is vacuumed under nitrogen with THF/heptane (40 亳卩, 々 'forming a fluid slurry') Drying for 2 hours, obtaining white peony 71) Washing in a pressurized ruthenium solid (7 40 scent, proton and carbon NMR and IR spectroscopy and desired product * 凡 ” enantiomers. C18H21C12N06S, 0.25 C4H80 microanalytical calculation C: 48. 73°/〇; H: 4. 95%; N . ^ Found: C: 4 8 · 9 1 % ; Η : 4 · 9 5 % ; μ : 2 Step 4 Value: 99°/〇; 9 0 °/〇; C1 : C1 :

15. 14% 14. 95% Preparation of the following formula

1247008 Five invention description (75)

The product of step 3 (21.7 g, 〇〇65 mol), N-t_B〇c_glycine N-hydroxyl was charged in a 5 〇〇 ml round bottom flask equipped with a magnetic stir bar and a nitrogen bubbler. Amber sulphite (17.7 g, 〇〇65 mol), and MF (2 〇〇 ml). The reaction mixture was stirred at room temperature for 3.25 hours under nitrogen to give a pale color. The reaction mixture was poured into ice-cold acetic acid (1 · 2 L). Organic; the broth was washed with 1 Μ HC 1 (250 liters), then washed with brine (5 〇〇 ml), dried (MgSO*), concentrated under vacuum to near dryness to give an oil. Dry at 50 ° C to give the product as a colorless oil (2 § · 12 g, yield 99%). Seed crystals were prepared from ethyl acetate/hexane. The product (ca. 28 g) was dissolved in ethyl acetate (35 ml) and hexanes (125 ml). The solution is inoculated and the seeds are crystallized to form a precipitate. Solid filtration, in a straight space at 5 5 . After overnight, a colorless solid (1). gram was obtained, yield 95% twice at 55 CI "1 Η ~ N M R consistent with the desired product.

Preparation of the following formula

Page 82 l247〇〇8

Page 83 1247008 V. Inventions (77) Wu Er) Add 3_gas~~5 - &gt; Stinky Water (35g, 0·ΐ5m) to dmf (175 pens) t at room temperature A light yellow slurry was obtained in solution. Then ΜΕΜ (Μ (pure ' 2 5 · 0 g, 0 · 2 mol) plus eight, the bath temperature is maintained at 2 〇 ° C. Mix the mixture at 2 2 ° C for 6 hours, pour DI water (1 2 0 〇 ))) 沈 沈; 殿 product. The slurry was filtered on a pressure filter, the filter cake was washed with DI water (2 x 40 mL), dried under N2 / vacuum to give the product as an off-white solid (46 g. Yield 95%) NMR (CDC13, TMS) 3.35 (s, 3H), 3.54 to 3.56 (m, 2H), 3·91 to 3.93 (m, 2H), 5.30 (s, 2H), 7.77 ( d, 1H), 7.85 (d, 1H), 10·30 (s, 1H); 13C NMR (CDC13, TMS) (ppm) 5 9.0 5, 70.1 1, 7 1.49, 9 9.5 0, 1 1 7.93, 1 29.6 9, 1 29.78, 1 32.37, 1 38.1 4, 1 5 5.1 2, 1 88.22, DSC: 48· 24 °C (within 90· 51 J/g);

Microanalytical calculation of CuH21BrC104: C: 40·82%; Η: 3·74%; Cl: 1〇· 95%; Br: 24. 69%; Found: C: 40·64%; Η: 3.48% Cl: 1〇·99%; βΓ: 24. 67% Step 2 Preparation of the following formula

1247008 V. INSTRUCTIONS (78) The product obtained in step 1 (32.35 g, 0.1 mol) was placed in a 500 ml 3-neck round bottom flask equipped with a mechanical stirrer, then thf (1 60 ml) was added. And (3)-phenylglycolamine (13, 71 g, 〇.1 mol). At 22. (After 3 minutes, MgS〇4 (20 g) was added. The mixture was stirred at 22 ° C for 1 hour and filtered on a coarse glass filter. The filtrate was concentrated under reduced pressure to give pale yellow oil (4 8 · 0 g), containing imine. Without purification, the crude product is directly used in the coupling reaction.

Microanalytical calculation of Ci9H21BrClN04: C: 51. 54%; C1: 8· 00% Found: C: 51. 52%; c 1 ·· 7 · 6 1 % Preparation of the following formula: 4·78%; Ν : 3. Η: 5. 02%; Ν : 2· 16%; Br: 18. 04%; 82%; Br: 16. 31%;

In I set a mechanical reagent (332 g, 〇β 5 liter 3-neck round bottom flask in the 'example (} step 1 then the solution cold fine / ear absorption into the ΝΜΡ (66 〇 ml), in the nitrogen 1 0 C. The imine produced in step 2 is prepared in nitrogen under the conditions of .卩ΡN: 2.50%; βΓ. 14.29%; 1247008 5. The invention (79) (32 ml) is then prepared in nitrogen for 3 minutes. Adding to the above reaction mixture, the temperature is maintained at _5. The mixture is re-worked for a few hours, then cooled to -1 (rc. Han HQ1/NH4C1 saturated solution (3 〇ml / 72 0 house liter) mixture is added to the calendar 1 〇min.μτβε (76〇ml) was added, and the mixture was stirred at 23 ° C for 1 hour. Stirring was stopped, and the layers were separated and the aqueous layer was extracted with MTBE (320 ml). The organic layers were combined, and the saturated solution of &amp;nhci (32) 0 ml), DI water (32 0 ml), and brine (32 〇 4 ml) were washed. The solution was dried over MgS04 (60 g), filtered, and concentrated to give a color oil (228 g) containing the desired product. , is a single diastereomer. &amp; ', DSC 227. 54 °C (inside 61. 63 J / g); ~ 脰C25H33BrClN06 differential Analysis calculated: C: 53. 72 ° / 〇; H: 5. 95%; C1: 6. 33 ° / 〇 measured: C: 53.80%; Η: 6.45%; N: 2.23%; Br: 12 85%

Cl : 6. 12% 5 Step 4 Preparation of the following formula

The solution of the crude ester of step 3 (about 111 g) in ethanol (1500 ml) is in the gas.

1247008 V. INSTRUCTIONS INSTRUCTIONS (80) Installed under pressure at a pressure, mechanically, and crying, and 淳人舲,人细$ η V See the 3 liter 3颂 round bottom flask of °σ. Anti-accumulation This cold part of the mouth to 〇c, tetraacetic acid (88.67 ΐ, 〇·2 Mo) once added. The mixture should be stirred at 〇t for 3 hours, then 15 15% aqueous solution (j 5 4 liters) β is added to the reaction mixture below 5 c. The ethanol was removed under reduced pressure on a rotary evaporator. Another 15% aqueous NaOH solution (60 mL) was added to the mixture. The mixture was extracted with ethyl acetate (2×3 mL), EtOAc (2×200 mL), and ethyl acetate (2×200 mL) . The organic layers were combined, washed with DI water (2×200 mL) and brine (2·········· The solution was then filtered with EtOAc EtOAc EtOAc EtOAc. . (Intra-67.85 J/g); Microanalytical calculated value of C24H29BrClN05: C: 54.71〇/〇; η: 5.54%; N: 2.65%; Br: 15.16%; Cl: 6.72; Found: C: 52·12%; Η: 5.40%; N: 2.47%; Br: 14.77%; Cl: 6.48 Preparation of the following formula

s〇3H

Ch3

Ml

Page 87 1247008 V. INSTRUCTIONS (81) The crude product of step 4 (about 94 g) is taken up in absolute ethanol (18 ml), and the p-benzoic acid monohydrate (5 〇·〇克' 〇 · 2 6 moles to join. The reaction mixture was then heated to reflux for 8 hours. The solvent was then removed under reduced pressure. The residual solid was taken up in THF (100 mL) and then THF was evaporated and evaporated. The residue was dissolved in ethyl acetate (500 mL) and cooled to EtOAc. The resulting solid was filtered and washed with heptane (2×50 mL) to afford white solid. The solid was dried to give the product as a white solid (38 g) as a single. ^-NMR (DMSO, TMS) (ppm) 1.12 (t, 3H), 2.29 (s, 3H), 3.0 (m, 2H), 4.05 (q, 2H), 4.88 (t, 1H), 7.11 (d, 2H), 7.48 (d, 2H), 7.55 (d, 1H), 7.68 (1H, d), 8.35 (br, s, 3H); 13C NMR (DMSO, TMS) (ppm): 13.82, 2 0.75, 3 7.1 3, 45.59, 60.59, 1 1 0.53, 1 22.47, 1 25.44, 1 27.87, 1 28.0 6, 1 29.5 1, 1 3 1.95, 1 37.77, 1 45.33, 150.14, 1 68.98; DSC: 6 9.8 6 t: (inside 406·5 J/g), 1 65.72 °C (inside 62.27 J/g), 211.24 °C (outer 20.56 J/g) [a] D25 = +4·2° (c=0.960, MeOH); IR (MIR) (cm-1) 2922, 1726, 1621, 1591, 1494, 1471, 1413, 1376, 1324, 1286, 1237, 1207; Microanalytical calculation of C18H21BrClN06S: C: 43. 69°/〇; H : 27°/〇; N : 2. 83%; Br: 16. 15%; Cl : 7. 16%; S : 6. 48% Found: C: 43·40%; H: 4.24%; N : 2. 73%; Br: 16.40%; C1 : 7.20%; S: 6. 54%

Page 88 1247008 V. INSTRUCTIONS (82) STEP 6 Preparation of the following formula COsEt Ο

HCI The above compound was prepared according to the procedure shown in Steps 4 and 5 of Example G, in which the free base of the intermediate prepared in Step 5 was substituted for the step G of Example G. HMR and MS are consistent with the desired product.

Example I Preparation of the following formula

Step 1 Preparation of the following formula

Page 89 1247008 V. INSTRUCTION DESCRIPTION (83) The above compound was prepared according to the procedure of Example G, Step 2A, substituting 3,5-dichlorohydrin with 1 equivalent of 2-hydroxy-3,5-dibromophenylfurfural. aldehyde. Yield 88%; pale yellow solid, mp 46-47 ° C; Rf = 0.6 (EtOAc / hexanes 1.1 v/v), I-NMR (CDC13) 53.37 (s, 3H), 3.56 (m, 2H) ), 3.92 (m, 2H), 5.29 (s, 2H), 7.91 (d, 1H, J = 2.4 Hz), 7.94 (d, 1H, J = 2.4 Hz), 10.27 (s, 1H), FAB-MS m/z 367

(M + ) HR-MS calculated for CnH12Br2 04 3 67.90 83 Found 36 7.9 077 1 H-NMR and MS were consistent with the desired compound. Step 2

The above compounds were prepared using the procedures of Examples G, Steps 2B and 2C, substituting the compound of Step 1 in this procedure. Yield 90%; yellow solid, m.p.: 57-59 ° C; Rf = 0.46 (EtOAc / hexane 1:1 vol/vol), 4-NMR (CDC13) 51.45 (s, 9H); 2.1 (br, 1H, Exchanging), 2.51 (d, 1H, 1^9.9 Hz, J2 = 15.3 Hz), 2.66 (d, 1H, J, 4.2 Hz, J2 = 15.3 Hz), 3·02 (br, 1H, exchangable), 3.39

Page 90 1247008 V. INSTRUCTIONS (84) (s, 3H), 3.58 - 3.62 (m, 4H), 3.81 (m, 1H), 3.93 (m, 2H), 4.63 (dd, 1H, J: 4.2 Hz ), 5.15 (s, 2H), 7.17-7.25 (m, 6H), 7.49 (d, 1H); FAB-MS m/z 602 (M + H) C25H34NBr2 06 HR-MS Calculated value: 6 0 2.0 75 3 Measured: 6 02.0 749 1 Η - NMR and MS are consistent with the desired compound. Step 3 Preparation of the following formula

The above compound (p-toluenesulfonate) was prepared according to the procedure of Example G, Step 3, substituting the product of Step G in Step 2 for the product of Step G. Yield 62%; white solid; UMR (DMS〇-d6) occupies 1.09 (t, 3H, J 27.2 Hz), 2·27 (s, 3H), 2. 97 (dd, 2H, 1,= 3. 0 Hz, J2 = 7· ^ ί Hz); 4. .02 (q, 2H, J-7. 2 Hz), 4. 87 (t, 1H, J: 7. 2 Hz), 7· 08 (d, 2H, J: 4·8 Hz), 7·45 (m, 3H), 7. 57 (d, 1H J 22.4 Hz), 8.2 (br, 3H), FAB-MS m/z 365 (M+H)

HR-MS calculated for CnH14NBr2 03: 3 65.9340 Found: 365.9311

Page 91 1247008 V. INSTRUCTIONS (85) 4-NMR and MS are consistent with the desired product. Step 4 Preparation of the following formula

• HC1 is the B0C compound produced in step 3.

Preparation of the hydrochloride salt The above compound was replaced with the compound prepared by the procedure of Example G, Step 4, to produce a B0C protected intermediate protected by the procedure of Example G, step 5, &amp; p ^ HMR and MS and The compound is consistent. Place

Example J 泠-[(2-Aminoethyl)amino]pyridin-3-propionic acid B g 二2Ν&quot;^γ 〇

C〇2£t • 2HCI

Step 1 In 3-D, add the ammonium acetate (279 g) to 2-propanol (3 L) in 2-propanol: (3 ml), then add malonic acid (39 g). The reaction mixture was stirred at reflux for 5 hours. The precipitate was filtered while hot and washed with hot isopropanol (2 L). The resulting white solid is then dried to obtain DL-3-amino-3-(3-pyridyl)propionic acid.

Page 92 1247008 V. Description of invention (86) White solid (22 0 g). NMR and MS are consistent with the desired product. Step 2 Step 1 of DL-3-amino-3-(3-pyridyl)propanoic acid (220 g) was slurried in absolute EtOH (3.6 L). HC1 gas (1 demonstration bottle, lbs) was bubbled into the reaction mixture and stirred for 40 minutes. The slurry was then heated at reflux for 4 hours (solution formed after 1 to 1.5 hours). The reaction mixture was cooled to 5 C in an ice bath. After 5 · 5 hours of 5 C scramble, the resulting white sediment was filtered and washed thoroughly with ether. After drying at 50 t under vacuo to give the desired product </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> <RTIgt; NMR and MS are consistent with the desired product. Step 3 In step 2, DL-3-amino-3-(3-pyridyl)propionic acid ethyl ester dihydrochloride (22 0·6 g) 0·83 mol) in anhydrous THF (2 L) and Add trimethylamine (167. 2 g, 1.65 mol) to N-t-B〇c-glycine N-hydroxyammonium imidate (225 g, 0.826 mol) (Sigma), divided into several Share, at 5_1〇t:.

The reaction mixture was stirred overnight at room temperature. The resulting precipitate was filtered and washed with THF. The solvent was removed from the filtrate under vacuum. The residue was taken up in ethyl acetate ^^^^. The Acetate layer was washed with saturated sodium bicarbonate (1) and HO (3×900 mL), dried with MgSO 4 and dried under vacuum. Residue 4 = 10% in acid = vinegar / hexane (2.5 liters) in the middle of the incineration overnight. The sect of the temple is over ί / / / / (1 liter) wash, then burned with hexane, and then dry can' ^ ^ ^ [[2~[[(1, 卜 dimethyl ethoxy) drum base] Amino]

Step 1 1247008 V. INSTRUCTION DESCRIPTION (87) Mercapto]-amino]-acridine-3-propionic acid ethene NMR and MS are consistent with the desired product. Hey, Wang white solid (233 grams). Step 4 Cold one [[2 - [[(1,1-dimethylethyl hydrazine | XI -nth soil)] yl]amino]acetic acid]-amino" 〇3 丙3 propionate (Step 3 η α visits the tile, - dioxane (1 liter). Cooling?克, 〇 · 66 莫) 洛热热 tbri 7 After the temperature, 4MHC1 was slowly added to the dioxane (1.6 liters) (Aldrich). The chyle soil garden is formed, and then transformed into a sticky copper viscous material. Residue; ^ M rb 4 @ ,. After 2 hours, the solvent was decanted and the residue was slurried in ether, and the ether was poured into a scorpion warrior, a a sec. It is dried under vacuum and removed by hand until a white solid is formed. 〇 咬 -3- -3- propyl acetate acetate dihydrochloride, and the amino group is amine] gram). The ruthenium is white and the wettable solid (224. 2 NMR and MS are consistent with the desired product.

Example K 2-Mercapto-4-carboxythiazole hydrochloride i preparation

^CCbH ί^Λ 8γΝ HNVv^NH2 X *HC|

NH in 2 -imido~ (Aldrich) in ethyl ketoacetate (2 0 β 〇 mixed for 2 hours. Mo, internal 1 to thiourea (11.1 g, 0094 mol) oblique EtOH (100 ml) Partially added to the chlorhexate, 0.102 mol) (Aldrich). The solution was refluxed with ethyl acetate (2.0 g) and the reaction was continued at reflux.

Page 94

1247008 V. Description of invention (88) ' 2 hours. The reaction mixture was cooled to 1 〇 ° C 'concentrated NH 4 〇 H until pH = l 〇. The resulting &gt; children's material was washed and dried to obtain 2 - hydroxy-4-ethylcarboxythiazole as a yellow solid (15.1 g). MS and 1H-NMR were consistent with the desired structure. Step 2 NaOH (0.93 g, 0.023 mol) was added to a slurry of the product from step 1 (5.0 g, 0.023 m) in 1 EtOAc (EtOAc) The solution was stirred at room temperature overnight. Ethanol (20 ml) and NaOH (〇·93 g) were added to the reaction mixture, and the solution was stirred at room temperature for 1 hour. The p 降低 was reduced to 7 with 1 n H C 1 , and the resulting precipitate was filtered, washed with EtOAc and ether, and then dried to give product (4·1 g) as a zwitter. The zwitterion is slurried in hydrazine 20 and acidified with concentrated HCl until a solution is formed. The solution was frozen and lyophilized to give 2-mercapto- 4-carboxythiazole hydrochloride as a pale yellow solid (4.33 g). MS and 1H-NMR were consistent with the desired structure. Examples L and Μ were inflicted on the basis of the commercially available 2-amino-6-methyl succinyl and 2-amino-4-methyl-indole ratios, respectively.

Example L Preparation of 2-Aminopyridine-6-carboxylic acid

Page 95 1247008 V. Description of invention (89)

Step A To a solution of 2-ethyl-bromoamino-6-methyl [I-bit (10.0 g) in water (125 mL), EtOAc (21.0 g, The reaction mixture was cooled, filtered and the residue washed with hot water (2 &lt The combined aqueous filtrate and washings were washed with dioxane (3 X 40 mL) and acidified with cold 3N EtOAc. The resulting precipitate was filtered, washed with water to a neutral pH, and dried under vacuo to give 2-ethylaminoaminopyridine-6-carboxylic acid (3.8 g, yield: 8%). The dichloromethane extract was concentrated to dryness to give &lt;EMI ID=9.1&gt;&gt; lH-NMR (CD30D) 58.32 (m, 1H), 7.94 (t, 1H), 7.87 (m, 1H), 2.2 (s, 3H), FAB MS m/z 181 (M + H) 2-Ethyl A suspension of the aminopyridine-6-carboxylic acid (4.1 g) in 2.5 N NaOH (36.5 mL) was heated at 80 ° C under a nitrogen atmosphere for 1.5 hours. The resulting solution was cooled and acidified with cold 3N HC1. The obtained precipitate was filtered and washed with water and acetonitrile in that order. The resulting white solid was dried under vacuum to give 2-aminopyridine-6-carboxylic acid (2.4 g, yield 76%). 1R'NMR (DMS0~d6) 57. 57 (t, 1H, J = 8. 1 Hz), 7.14 (d, 1H&gt; J-7.2 Hz), 6.67 (1H, J = 8. 1 Hz), 6.51 ( Br, 2H); FAB MS m/z 139 (M+H).

The 2-amino ti is heated to a suspension of bite-6-rebel (2 g) in EtOH (1 〇·〇 ml) and 4n HC1/monooxin (1 〇· 〇 ml) under anhydrous conditions. The reflux period is 16 hours. The reaction mixture is then concentrated to dry 'residue in a desiccator

Page 96 1247008 V. INSTRUCTIONS (90) Drying under vacuum gave 2-amino-6-ethoxycarbonylpyridine hydrochloride as a white powder (1.6 g). ^-NMR (DMS〇-d6) 58. 3 (br), 7.94 (m, 1H), 7.37 (d, 1H, J 7.2 Hz), 7. 22 (dd, 1H, J-8. 7 Hz) , 4. 37 (q, 2H, J = 7.2 Hz), 1.32 (t, 3H, J 2 7.2 Hz); FAB MS m/z 167 (M+H).

Example M Preparation of 2-Aminopyridine-4-Ethoxycarbonylpyridine Hydrochloride

The compound (oxime) was prepared starting from 2-ethinylamino-4-mercapto-pyridine in a similar procedure to the preparation of 2-aminopyridin-6-ethoxycarbonylpyridine hydrochloride. HMR and MS are consistent with the structure shown. Example 1 Human Η Preparation of the following formula

Page 97 1247008

The product of Example A (〇·5 g, 0·0 02 mol), the product of Example E (0.83 g, 0.002 mol), triethylamine (〇·2 g, 〇〇〇 2 mol), and DMAP (24 mg) was added to an anhydrous bath DMA (5 mL) with EDC I (〇· 38 g 0·0 2 Mo) at ice bath temperature. The reaction mixture was stirred at room temperature for 2 days. The product was isolated by reverse phase preparative HPLC. Li〇H (〇·51 g, 0·012 mol) was added to the ester in 112〇 (3 ml) and CH^ (3 ml). It mixes 1 small 4 in the room. p Η is reduced to 2 with TFA, and the product is prepared as a reverse phase preparative η pl (; isolated 'obtained (after lyophilization) as a white solid (3 gram). MS and 1 H-NMR The structure is consistent. Example 2 Preparation of the following formula

The title compound was prepared according to the procedure of Example 1 to give the product of Example E. MS and iH-NMR were combined with the desired structure. Example 3 Preparation of the following formula

Page 98 1247008

V. Description of the invention (92)

The product of Example C (19. 5 g, 〇·045 Mohr) &amp; N-methylmorpholine (9 g, 〇·09 Mo) in anhydrous DMA (85 mL) in a flame-dried flask Under the ice bath temperature, isobutyl chloroformate (6 · 2 g, 0·045 m) was slowly added. The solution was stirred at ice bath temperature for 15 minutes. The product of Example D (15 g, 0.44 mol) was then added at ice bath temperature, then n-mercapto-maline (4 · 1 g, 〇 · 〇 4 mol) was slowly added. The reaction mixture was stirred overnight at room temperature. Add Li〇H (16 g, 0. 38 mol) to the ester in 1120 (50 mL) / Ch3CN (30 mL). It was stirred at room temperature for 1 hour. The pH &amp; tfa was reduced to 2 and the product was isolated by reverse phase preparative HPLC to give (after lyophilization) the desired product as a white solid (13.7 g). MS and 1H-NMR were consistent with the desired structure. Example g Preparation of the following formula

Page 99 1247008 V. INSTRUCTIONS (93) Production of an equivalent amount of Example E The above compound was substituted for the product of Example D according to the procedure of Example 3. MS and 1H-NMR were consistent with the desired structure. Example 5 Preparation of the following formula

2TFA was produced in equal amounts of Example F. The above compound was prepared according to the procedure of Example 3, substituting the product of Example D. MS and 1 Η-NMR were consistent with the desired structure. Example 6 Preparation of the following formula

The above compound was prepared according to the procedure of Example 3, substituting the product of Example C in an equivalent amount of the product of Example C.

Page 100 1247008

M S and 1 Η _ N M R are consistent with the desired structure. Example 8 Preparation of the following formula

The product of Example K (0.5 g, 0.0 022 mol)-methylmorpholine (0.23 g, 0.0022 mol) was added in anhydrous dmf (8 mL). 31 grams, 〇· 〇〇 22 moles). After mixing 5 minutes on ice bath temperature, the product of Example J (0.73 g, 0.0022 mol) and N-mercaptomorpholine (0.45 g, 0.0045 mol) in anhydrous DMF (8 ml) were once in ice. Bath temperature is added. The reaction mixture was stirred overnight at room temperature. The separation was carried out by reverse phase preparative HPLC (530 mg). To this ester (40 0 mg) was added Li 〇H (91 mg) in 1120 (1 mL). It was stirred at room temperature for 1 hour. The pH was reduced to 3 with TF A and the product was isolated by reverse phase preparative HPLC to give (after lyophilization) the desired product as a white solid (350 mg). MS and 1 H-NMR were consistent with the desired structure. Deuteration of 2-amino-6-ethoxycarbonylpyridine hydrochloride and 2-amino-4-ethoxycarbonylpyrrolidine hydrochloride using a tri-B 0 C reagent as shown in Examples N and 0 Figure (Kim·SK·Q, L., Tetrahedron Lett 34, 7677, 1 9 9 3 ).

Page 101 1247008 V. Description of invention (95)

Instance N

OEt in 2-amino-6-ethoxycarbonylpyridine hydrochloride (0.56 g, 2.8 mmol) and tri-B0C reagent (91.2 g, 2.8 mmol) in degassed DMF (7.0 mL) Mercuric chloride (0.76 g, 2.8 mmol) and triethylamine (0.79 g, 7 · 8 mmol) were added to the solution. The resulting mixture was heated at 70 ° C under nitrogen pressure for 24 hours and filtered. DMF was evaporated in vacuo and the residue was triturated with ethyl acetate and filtered. The orange filtrate was concentrated, and the resulting material was purified by flash chromatography using ethyl acetate containing 1% triethylamine as a solvent. The fractions (blue fluorescent) were combined and concentrated to dryness under reduced pressure to give a yellow powder. MS analysis [m/z 565 (M + H)] confirmed the desired three-B0C product N. Example 0 °&lt;v-OEt

BOC 〇

Page 102 1247008

Page 103 1247008 V. Description of invention (97)

Page 104 1247008 V. INSTRUCTIONS (98) Example 9 In a reagent 1 (18·68 g) in THF (1 L), sodium hydride (1 9 g, 60%) was added to a suspension of 〇t mechanically turbid. Suspension in mineral oil) kg 3 minutes. After 30 minutes, dibutyl succinate (95 g) was added and the reaction mixture was gently heated to reflux for 16 hours. The mixture was cooled to hydrazine and purged with a saturated solution of NaHC 〇3. The mixture was extracted with acetic acid. The organic extract was washed with water, dried (Naj O 4), and concentrated. The residue was flash chromatographed using a small column of EtOAc (603⁄4 m X 1803⁄4 m) to give the desired product 2 as a thick yellow liquid (68 g). NMR was consistent with the structure shown. Step 2 3-Amino-pyridine-6-carboxylic acid (25 g) in EtOAc (3 mL). The stirred suspension is saturated with gaseous hydrogen gas. The mixture was heated to 23 and heated to reflux for 2 hours. A clear solution was obtained. After cooling to 23, the mixture ''' was vacuumed; the mixture was neutralized with an aqueous solution of NaH?? The organic phase was washed with water, dried (MgSO4) The product of Step 1 (40.0 g), HgCl2 (25.0 g), triethylamine (27 m

升), and a mixture of 3-amino-pyridine-carboxylic acid ethyl ester (13 g), and DMF (2 mL) was stirred and heated to 5 5 for 3 hrs. The reaction mixture was cooled to 23 ° C, diluted with ethyl acetate (EtOAc) The filtrate was washed with water (2x), dried over MgSO 4 and concentrated in vacuo. The residue was chromatographed using ethyl acetate in hexanes to afford the desired intermediate. NMR is consistent with the desired structure. 1247008 V. INSTRUCTION OF THE INVENTION (99) Step (IV) The suspension of the product of Step 2 (13 g) in 5N HCl (100 mL) was stirred at 2 3 C for 16 h. The mixture was concentrated in vacuo. The residue was taken up in methanol and filtered with a white solid to give the desired product. NMR and MS were combined with the desired structure. </ RTI> </ RTI> </ RTI> </ RTI> The product of Step 3 (0.30 g) was suspended in DMF (10 mL) and 4-methylmorpholine (0.2 mL) was added to the suspension. The mixture was stirred at 2 3 for a few hours. After the reaction mixture was cooled to dryness, [BCF ( 〇 · 丨 2 9 mL) was added.

After 1/2 hour, the product of Example R (〇·416 g) and the solution of 4_mercaptomorpholine TDMFJ 3 ml were added. The mixture was heated to 2 generations for 2 hours. The mixture was then filtered and the filtrate was concentrated in vacuo. Purification by HPLC to obtain 5. Microanalytical data, NMR and MS were consistent with the desired structure. ° Step 5

The solution of the product of step 4 in 3.5 ΗΠ 在 is in 23 ^ 静,

Concentrate in vacuo and the residue was purified by HPLC to give the desired product. Product microanalysis

Page 106 1247008 V. Description of invention (100) C21H22BrClN6 06 · 2CF3C02H · H20 Analysis calculated value: C: 3 6.8 0; Η: 3.21; Ν: 10.30 Measured value ·· C: 36. 5.2.; Η: 2· 90; Ν: 9. 91 Example 1 0

Ci, ▽ This compound was replaced with the product of Example R Step 4 using the product prepared using the procedure described in Example 9. C21H22C12N6 06 · 2CF3C02H · Analytical calculated value of Η20 C: 38.93; Η: 3.40; Ν: Measured value: C : 3 9 · 2 7 ; Η : 3 · 1 2 ; Ν : Example 11

But use the example G 10.89 11.09 〇

COOH

TFA 〇 This compound was prepared as described in Example 9 using the product from Example 1 in the next step. Analysis of calculated values for C21H22Br2N6 06 · 2CF3C00H · Η20:

Page 107 1247008

Page 108 1247008 V. INSTRUCTIONS (102) However, to -30 ° C, a solution of 70% nitric acid (7.7 ml) (d = 1.40) in concentrated sulfuric acid (30 ml) was treated dropwise. The reaction mixture was stirred at -25 ° C for 30 minutes, then poured onto ice water and stirred for a few minutes. The precipitated solid was filtered, recrystallized from water and dried to give white powder (2.3 g). iH-NMR was consistent with the structure shown. The solution of the product of Step 2 (1·7 g) in THF (25 mL) was treated with a catalytic amount of 5% Pd/C under a pressure of 5 pSi of hydrogen at room temperature for 16 hours. The reaction mixture was filtered to concentrate. The residue was heated with EtOAc (EtOAc)EtOAc. iH-NMR was consistent with the structure shown. Step 3 The product of Step 2 (725 mg) and EtOAc (EtOAc) (EtOAc) The reaction mixture was concentrated and the residue was crystaljjjjjjjj After stirring for 1 hour, the reaction mixture was concentrated, and the residue was purified on EtOAc EtOAc EtOAc . ! H-NMR was consistent with the structure shown. Step 4 The product of Step 3 (2 75 mg) was dissolved in &lt;RTI ID=0.0&gt;&gt;&gt; The solution was stirred and cooled to 0.degree. C., and then evaporated and evaporated. The reaction mixture was stirred up in hydrazine, then the product of Example G (28 6 mg) &amp; N-decylmorpholine (knife 81)

1247008 V. INSTRUCTIONS (103) Pen gram) treated with a solution in dimethyl ethamine (2 ml). The reaction mixture was heated to room temperature and stirring was continued for 6 hours. The reaction mixture was concentrated and the residue was purified using EtOAc EtOAc. The UMR is consistent with the structure shown. The product of Step 5, Step 4, (250 mg) was dissolved in methanol (8 ml) and 1N sodium hydroxide (8 pens), and the solution was stirred at room temperature for 6 hours. The reaction is a '( 〇 · 7 liters) sweat ‘threat. The residue was purified using reverse phase HpLC, mp. iH-NMR was consistent with the structure shown. C20 H2i N5 06 C 12 S · 1 · 5 〇TFA · 〇 · 2 5 H2 0 Analysis calculated: C,39· 13; H, 3· 28; N, 9· 92; S, 4. 54; C1 , 10.04; Found: C, 38.81; H, 3.17; N, 9.90; S, 4.86; C1, 10.25 Example 1 3 N-[ [4-[(4, 5 -Dihydro-1H-imidazol-2-yl) Amino]-2-thienyl]carbonyl] ganfeyl-3-(3,5-dichloro-2-ylphenyl)-callo-alanine, trifluoroacetate

ϊΓΥ

Page 110 1247008 V. INSTRUCTION DESCRIPTION (104) The above compounds were prepared using similar reaction sequences used to prepare the compounds described in Example 12. The hydrating agent described in Example C (Step 1) was used instead of G1 in Step 3 of Example 12. Similarly, the product of Example D was used instead of the product of Example G, step 4. 1 Η - N M R is consistent with the structure shown. C19H19N5 05 C12S · 1· 50TFA · 0· 50Η2Ο Analytical calculations·· C, 38. 84; Η, 3.18; Ν, 10. 29; S, 4. 71 ; C1, 10. 42 ; Measured value: C, 38·84; Η, 3·01; Ν, 10.50; S, 5.08; C1, 11.01 €

Page 111 1247008 V. Description of invention (105)

K令j 14 赛爵^-3-(3,5-卜羚-2.潜^树^)-/?-2咐漭-^.|1众爇婶~5#

Page 112 l247〇〇8 Description of Invention (106) (5 (3) Series # Use 5-methyl-2-thiophenecarboxylic acid as described in Example 13, Step 1 1) ▲ Injury. The product was extracted with dilute hydrogen peroxide. The solution was extracted with dilute hydrochloric acid and taken into ethyl acetate. The organic extract was dried (Na 2 SO 4 ) and concentrated to give a solid color (2 2 g). [h-NMR was consistent with the structure shown. (10 I ϊ ϊ * 骤 骤 骤 骤 骤 骤 骤 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及The organic extract was washed with a saturated sodium chloride solution, and dried to a color solid (3.5 g). 1 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 25 milligrams of tin (π) dihydrate in concentrated hydrochloric acid (1 gram / 2 = = ^ solution is treated dropwise with chlorine temperature, i to a solution that seems to show complete elimination of the starting material in the chamber, aqueous solution Part of the mixture was extracted with a solution of hydrogencarbonate in a solution of hydrogen chloride in water, organic solvent (3) / 丨2, and dried (NaJOJ, concentrated, and the enthalpy of the enthalpy of the enthalpy was in gram). QiH-NMR was consistent with the structure shown. The product of the chlorochrome powder (1. 1 step 4 in the product of step 3 (3. 5 mg) and the step of step 9) in DMF (15 ml) The mixture was stirred at 95-1 Torr with water (326 g) and the mixture was cooled with ethyl acetate (3 mL) for </ RTI> hr. Reduction, two residue: 30 min, then dried with paper flash chromatography (97 · 5%

Page 113 1247008 V. INSTRUCTIONS (107) CHC13 - 2.5% CH30H elution) was purified to give a tan solid (415 g). NMR was consistent with the structure shown. Step 5 The product of Step 4 (40 mg, EtOAc) The reaction mixture was concentrated, and the residue was applied to a mixture of CHJH (1 mL) and sodium hydroxide solution (1 mL) at room temperature for 16 hours. The reaction "TFa (〇······················································································································· Analysis calculated for 50H2O: c, 39· 79; H, 3. 55; N, 9. 67; S, 4. 43; C1, 9. 79; Measured: C, 3 9.5 0; 3.24; N, 9.58; S, 4.71; C1 10.22 'Example 1 5 ) N[[4[(4,5-—hydro-1H - 11 m σ圭)-2-yl)amino]- 5-indolyl-2- phenanthrene Preparation of glycidinyl-3-(3,5-dichloro-2-hydroxyphenyl)-cold-alanine, preparation of trifluoroacetate

1247008 V. INSTRUCTION DESCRIPTION (108) The above compound was prepared using a similar reaction sequence for the preparation of the compound as described in Example 14 except that the hydrating agent described in Example C (Step 1) was used instead of the reagent used in Step 4 of Example 14. NMR was consistent with the structure shown. C20H21N5 05 C12S · 1. Analysis of calculated values for 50TFA · 0· 25H20: C, 40.04; H, 3.36; N, 10.15; S, 4. 65 ; C1, 10.28; Found: C, 39·82; H, 3.19 ; N, 10.17; S, 4.86; C1, 10. 69

Page 115 1247008 V. Description of invention (109)

Distortion 16 2丨[[5-[(4,5-b^-£-per ^-2-^)漭^-2-罗4] ^1:]4漭觳^-3-(3&gt;卜净| ♦ Page 116 1247008 V. INSTRUCTION DESCRIPTION (110) The title compound was synthesized starting from the same reaction sequence as described in Example 15 with 2-nitro-5-thiophene-carboxylic acid. For deuteration reaction, according to the example 1 7 Conditions described in Step G.. Ci9H19N5 05 Cl2S · 1. Analysis and calculation of 50TFA · C, 3 9.3 6; H, 3.08; N, 10.43; S, 4. 78 ; Found: C, 39.05; H, 2.79; N, 10·37; S, 4·90 Ο ο

Page 117 1247008 V. Description of invention (111)

Ho, /N

0 ΟΗ rooo/z\fa/ z\

, B0C tp) —T

NaOMe.MeOH°oc, 30

1 SOC 一 2- 13^二 h 2 Hunig-S^, THF.IDMA.O^^^ 0Ϊ.Ϊ1 〇H Cl Page 118 ΗΝ03- 90p4h 0^ -▼

CN/N OHIOr:?3h f

〇

OH K窆17 N-[[5-(4vJ:l (4)·lH-^i4.2-;&amp;s^-6-f |1蝌.3°1:硌;$0鸡办]4漭^蝌-3-(3,5-卜'沭蝌)ϋ^髁-Hong (WIL 髁藤) ♦ 1247008 V. Description of invention (112) Step 1: 6 - based on alkali acid (20 g) and colorless fumes The mixture of lithospermic acid (60 ml) (d = 150) was heated to 90 - 9 5 ° C for 3 hours. The reaction mixture was cooled to room temperature, poured into 1.5 liters of ice water and stirred. Filtration after 15 minutes. The precipitate was washed with water and dried to give a pale-yellow powder (9·3 g). 1 Η - NM R was consistent with the structure shown. C6H4N2 05 analytical value · · C, 39.14; H, 2.19; N, 15.22; Found: C, 3 9 · 0 8 ; Η, 2 · 1 7 ; N , 1 5. 1 9 Step 2 : Product of Step 1 (5.0 g) and Phosphorus (15) The mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature, added to ice-water mixture and stirred for 30 minutes. then ice was added to keep the mixture cooled during this period. The reaction mixture was THF-ether (1:2) The mixture is extracted, and the organic extract is washed with a saturated sodium sulphate solution, dried (N^SO4), and concentrated. Recrystallization from hydrazine: i-ether: hexane afforded a yellow powder (4.0 g). NMR is consistent with the structure shown. Step 3: The product of step 2 (1.6 g) in sulphur sulphur (5 mM) The solution was refluxed for 3 hours. The reaction mixture was cooled to room temperature and evaporated under nitrogen. The residue was dried <RTI ID=0.0></RTI> <RTI ID=0.0> Dissolved in dimethyl ethanoamine (3 mM) and N,% diisopropylethylamine (23 g). The solution was cooled in an ice bath, and the chlorobenzene (as obtained above) was dissolved in THF (2)溶液ml))

1247008 V. Description of invention (113). The reaction mixture was allowed to "heat to room temperature" and then quenched with water (25 ml). The mixture was concentrated with acetic acid, 'organic stroke, washed with saturated gasified sodium solution, dried (Na2S04). The resulting yellow solid was recrystallized from ethyl acetate to give a pale yellow powder (3.4 g). l-NMR was consistent with the structure shown. Step 4: A solution of the product from Step 3 (4.5 g) in MeOH (30 mL). The reaction mixture was stirred for 30 minutes and then quenched with acetic acid (2. 3 mL). The reaction mixture was concentrated and distributed between ethyl acetate and water. The organic extract was dried (N4), concentrated and purified eluting with EtOAc EtOAc EtOAc NMR is consistent with the structure shown. Step 5: A solution of the product from step 4 (1.07 g) in ethanol (25 mL). Handle for 4 hours. The reaction mixture was filtered and evaporated tolululululu iH-NMR was consistent with the structure shown. ^1^6 : In the solution of the product of step 5 (33 0 mg), G2 (276 g) in DMF (10 ml), triethylamine (150 mg) and vaporized mercury (258 mg), The mixture was heated at 85 ° C for 16 hours under nitrogen. The reaction mixture was cooled, dried with ethyl acetate (li. The filtrate was concentrated, and the residue was purified on a Shixi hose column, and dissolved in 98% CH2C12-2% decyl alcohol to obtain white.

Page 120 1247008 V. Description of the invention (114) Solid (325 mg). The UMR is consistent with the structure shown. Step 7 A solution of the product (114 mg), EtOAc (EtOAc) The solvent was evaporated and the residue was crystalljjjjjjjjjjjj The reaction mixture was quenched with EtOAc (1 mL). The residue was purified using reverse phase HPLC to give white solid (76 mg). The HMR is consistent with the structure shown. For C21H22N6 06 C12 · 2TFA: C, 41. 74; H, 3.88; N, 12.70; Found: C, 41. 47; H, 3· 49; N, 12. 85

Page 121 1247008 V. Description of invention (115)

HO

2 WleOH, H

〇 1. _3, OH

1. f OH.NaOH 2· SOC12 3

Ho, Ν 9Q1Ρ41&quot;03⁄4

0

0 〇se w&gt;Xuan 18 N-[[5-[(4,5-卜净-1甲丧^-2.^)漭蝌]-1,6·卜办-14^-6-烨蝌- 34硌;&amp;]难^]4漭谬^-3-(3,5-Bu^-2-激^^^)-/?-2咐烟,卜笋, although 漭藤♦ 4 Page 122 1247008 V. INSTRUCTIONS (116) Step 1 · Example 17 The suspension of the product of Step 1 (1 2·m) in decyl alcohol (2 mL) was taken up in concentrated sulfuric acid (1 mL) and refluxed. After refluxing for 16 hours, the reaction mixture became a homogeneous solution and was cooled to room temperature. About half of the solvent was removed and the product was crystallized from the solution. The mixture was cooled in an ice bath, and a dry powder was obtained to give a yellow powder (1 6 · 7 g). 1 Η - NMR is consistent with the structure shown. Step 2 · · ·, the product of step 1 (2.6 g) in 〇^^ (40 ml) in the lower part of the underarm to 0 C, sodium hydride in mineral oil 60% dispersion (6 5 5 mg) was treated. The mixture was stirred at 0 C for 45 minutes and then treated with iododecane (2 · 8 g). The reaction mixture was mixed at room temperature for 6 hours, then partitioned between acetic acid and water, and extracted with ethyl acetate for several times, and then combined; :: two saturated sodium chloride solution, dried, dried (Salmon, concentrated. Residual = = purified on column (dissolved in 2% methanol, % dimethyl gas) to obtain a ruthenium solid (1.9 g). 1H-NMR was consistent with the structure shown. 2.6 g), 曱 I I, ^rRn ^ ^ T know (6 () 3⁄4 liters), and 2N sodium hydroxide solution and (60 * liter) solution at room temperature 醅 r R 〇 ancient, t, Mix for 16 hours. The reaction mixture is arsenic with ice vinegar = 9.9 liters. The residue was dry welded under high direct air. After the absence of this substance and sulphur sulphur (100 ml), work, dry, and cool, concentrate, under high vacuum; withdraw under two reflux for 3 hours. Reaction mix n 2 grams). NMR and Structure shown - product of Example D under nitrogen (3 5 g / gram in a dry flask), gluten in N,N-dimercaptoacetamide (35

1247008 V. Inventive Note (117) Zhaisheng) and monoisopropylethylamine (2.9 ml). The solution was cooled to 0 ° C and treated with a solution of dichloromethane (1·9 g) (as obtained) in THF (35 mL). The reaction mixture was stirred for 30 minutes and then concentrated under high vacuum to remove solvent. The residue was partitioned between ethyl acetate and water, and the water portion was extracted several times with ethyl acetate. The combined organic extracts were washed with water several times, then washed with a saturated aqueous solution of sodium chloride &apos; dried (Na.sub.2) and concentrated to yield a yellow solid (1·3 g). 1 Η - N M R is consistent with the structure shown. Step 4: The product of Step 3 (5 g) in THF (10 mL) and DMF (10 mL) was treated with 5% EtOAc. The reaction mixture was filtered and concentrated. The residue is absorbed into the minimum amount of Ding, and the Fuling is crystallized at the temperature. An equal volume of ethyl acrylate was added to the crystallized mixture and shoveled for 15 minutes. The mixture was cooled, filtered and washed with cold ethyl acetate. The product was dried to give a white solid ( 730 mg). iH-NMR was consistent with the structure shown. Step 5: Add a mixture of triethylamine (3〇4 mg) and mercuric chloride (544 mg) in a solution of the product from Step 4 (72 mg) and G2 (581 mg) in DMF (25 mL) Heat at 8 ° C for 1 hour under nitrogen. The reaction mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated and purified on a silica gel column (1% hydr.) to afford a white solid (375 mg). I-NMR is not related to the structure. Free of step 6: The above compound is used in the compound prepared in step 5 (300 mg).

Page 124 1247008 _______ ___ --- ---•丨 丨· * V. Description of the Invention (118) Example 1 4 (Step 5) Preparation of the procedure described. The crude product was purified using reverse phase HPLC to afford a white solid (2 23 mg). 1H_NMR was consistent with the structure shown. C2iH22N6〇6Cl2 · 2. 5TFA · 〇· 5H20 Analysis calculated: C, 38· Π '· H,3· 14; N, 10· 26; C1, 8. 65; Found: C, 38·18; Η,3·05; N, 10.79; C1, 9.34 Example 1 j N-[[6-gas-5_[(4,5-dual-l- 1H-miso. sit-2-yl)amino]-3- 3⁄4 咬基] carbonyl]glycidyl-3-(3,5-dioxa-2~hydroxyphenyl-alanine, trifluoroacetate, monohydrate

OH OH CI Step 1: Prepare a solution of tin (11) (6 · 3 g) in concentrated hydrochloric acid (1 mL), and add the product of Step 3 in Example 17 (1·g) to THF ( Within 15 ml) of the solution. The reaction mixture was stirred for 15 minutes at which time the reaction mixture was cooled to room temperature. The organic solvent was removed to obtain a colloidal precipitate. The water was partially decanted and the colloidal precipitate was partitioned between ethyl acetate and dilute sodium bicarbonate solution. The water fraction was extracted with ethyl acetate: owed&apos; and the combined organic extracts were washed with water and saturated sodium sulphate solution and dried (N.sup.4). The residue is dried under direct air

Page 125 1247008 V. INSTRUCTIONS (119) Drying, obtaining a tan powder (375 mg). The ih_NMR was identical to the structure shown. Step 2: The compound (3 6 5 mg) described in Step 1 was deuterated using the method described in Step 5 of Example 18. The crude product was purified on a silica gel column (solvent with 2% decyl alcohol _ 9 8 %) to afford a brown thick liquid (2 〇 5 mg). 111-off 1^ is consistent with the structure shown. ^^3: The title compound was prepared using the product from step 2 (2 mg) and the procedure described in the procedure The crude product was purified using the reverse phase of the above-mentioned reversed phase to give a white solid (53 mg), eH NMR, and s.. C20H19N6 05 C13.1. 7TFA. 1. 〇h2〇 analysis: 37·9〇; H, 3. 09: μ ▼ “π~々 矸 矸 nose value: measured value r, J· Η, 3· 09; Ν, 11· 33; C1, 14· 34; , · 3, Η, 2·71; Ν, 11 · 33; C1, 15· 01 Example 2 0 Ν-[ [5_(4, ^ϋ 唾 ΤΙ ΤΙ ΤΙ ΤΙ ΤΙ 胺 胺 胺 6 6 6 6 6 6 6 6 6 6 6 ] ] ] ] ] ] ] ] Base_3 one (3,5_digas_2_pyridylphenyl)- 10,000-alanine, &gt; fluoroacetate

Page 126 1247008 V. INSTRUCTION DESCRIPTION (120) The above compound was prepared from the product of Example 1 Step 6 (3, 3 mg) in EtOAc (EtOAc)EtOAc The reaction mixture was concentrated. i-NMR was consistent with the structure shown. C2〇H2QN6 06 C12 · 1 · 25TFA Analysis calculated: C, 41.33; H, 3.28; N, 12.85 Found: C, 41. 57; H, 3· 29; N, 12· 92

I

I

Page 127 1247008 V. Description of invention (121)

Distortion j 21 Miscellaneous ^] 4 casts ^-3-(3,5-b^-2-^^^^)ϋ^^&gt; w^^gi^^^^

Page 128 1247008 V. INSTRUCTIONS (122) The starting materials used in the preparation of the title compound were synthesized using the reaction sequences described in Example 17 (Steps 1 - 3). The product of Example D was replaced with the palm intermediate of Example G for the coupling reaction described in Step 3. Step 1: (A) was prepared using the procedure shown in Step 4 of Example 17. 1 h-NMR was consistent with the structure shown. Step 2: The solution of the material from step 1 (2.7 g) in 4N anhydrous EtOAc (1 mL) was warmed to 4 5 ° C for 24 hours. The reaction mixture was concentrated to dryness to give a pale brown solid (2 6 g). l-NMR was consistent with the structure shown. Step 3: A solution of the product from Step 2 (1.85 g) in EtOAc (50 mL) The reaction mixture was filtered and concentrated. The residue was purified using reverse phase HPLC to afford white solid (507 mg) u u. Step 4:

To a solution of the product from step 3 (50 mg) and the product of step 4 of step 4 in hexane (15 ml), triethylamine (3 〇 4 mM water (40 耄g)) The mixture was heated to a temperature of 1 〇〇 〇〇. The mixture was cooled to room temperature, and then stirred with ethyl acetate (3 mL). The solution of 'Li, Li' was treated at room temperature for 1 hour. The mixture was concentrated, and the residue was identical to the structure shown.

1247008 V. INSTRUCTIONS (123) Step 5: A solution of the product from Step 4 (200 mg), 1N sodium hydroxide (8 mL) and methanol (8 mL). The reaction mixture was quenched with TFA (1 mL) and concentrated. The residue was purified by reverse phase HPLC using EtOAc (EtOAc) The UMR is consistent with the structure shown. Analysis calculated for C21H22N6 07 C12 · 1 · 5TFA: C, 40·46; H, 3.32; N, 11.80 Found: C, 40. 12; H,3· 57; N, 12. 26

Page 130 1247008 V. Description of invention (124)

Distortion 22 N-[[5-[(4,5-b^'H-^+2-ft^^]-2-f!L;&amp;.3°t^;i:s;s:;L4sf&amp;-3- (3,5-Bu Ling|2-^^柘^丫^-£咐爵,卜^锞漭_豸

Page 131 1247008 V. INSTRUCTIONS (125) Step 1 · Adding fuming nitric acid (7 · · dropwise) to a solution of 2-hydroxynicotinic acid (10.0 g, 71.9 mmol) in concentrated sulfuric acid (28.6 mL) 1 ml). The reaction mixture was heated at 55 °C for 4 hours. The cooled reaction mixture was poured into ice water. The product precipitated as a yellow solid. The precipitated solid was collected by filtration, washed with water, and then evaporated to give the desired product (7.2 g, yield 54%). NMR was consistent with the structure shown. Step 2: The product of Step 1 (5.0 g, 27.2 mmol) was refluxed in a dish of helium (13.5 g) for 4.5 hours. The cooled reaction mixture was poured into ice water (2 〇 〇 )). The resulting mixture was applied for 3 minutes and extracted with tetrahydrofuran/succinic acid (2/1). The organic layer was washed with brine, dried over Na 2 EtOAc and filtered. The filtrate was concentrated to give an oil. This oil was treated with a mixture of hexane/ether (4/1) to give the desired product as a fine yellow powder (5 gram, yield 91% σ). Step 3:

The product of step 2 (3.1 g, 15.3 mmol) is ruthenium chloride (8. 丨 t t 容! The liquid is refluxed for 4.5 hours. The residual sulphur gas is liquefied at 35 psi A light brown oil was obtained. The oil was dried under vacuum to give a sm. (2.7 g, yield: 79%). NMR and the structure shown in the step 4: 9 ml) The product dimercaptoacetamide (40 ml) and tetra-diisopropylethylamine (3.7 g. 4 · (5. 5 g '14·8 mmol) in Ν, Ν一

Page 132 1247008 V. Inventive Note (126) In a solution of South U5 ml), the reaction mixture is cooled to _5t. The force product of the bovine solution (3.1 g &lt; 14.1 mmol) was applied to the tetra-nano-block (South) (25 ml) for 15 minutes. The reaction mixture was heated to the temperature in a knife. After 3 hours, the tetrahydrofuran reaction mixture was removed. The reaction mixture was poured/over-purged, washed with water, and dried in air to obtain a product (6.2 g, yield 85%). NMR and the structure shown s color solids. Step 5: 30: Γ莫之Ear 1: (4. °g, 7.7 mmol) and sodium decoxide (U7 g, anti-bank, 'person\methanol (45 house liters) solution in which it is stirred for 4 hours. ~1 T and Jiazhi It was removed from the reaction mixture, and purified by crude acetic acid, ethyl acetate (yield 6/4) to obtain the desired compound. /, body (2.5 grams, yield 67%) 1MR and the structure shown in the day and step 6 · 2 7 7 ^ ^ ^ ^ Ο &quot; gram ' 1,9 millimoles) and 3% platinum / carbon And sterol t ^ i shift 2 2 milk at room temperature for 1 6 hours at 5 ′ 1 . The catalyst was removed with care. A. Xueli, weeping solid (“2 g, yield at bottom: △, obtained The desired product, which is yellow, should be in the middle of the structure shown. Consistently further purified for the next reverse: 2 mM), (18 g,

1247008

5. Inventive Note (127) The mixture of liters was heated at 90-95 ° C for 16 hours. The cooled reaction mixture was filtered through a short celite column with ethyl acetate (40 mL) and dichloromethane. The crude mixture was chromatographed (Shixijiao CH.2C12-CH30H-NH4 〇H, 95/5/0.5) to give the product as a yellow solid (yield: 31 g, yield 76%) The structure is consistent. : 5 milli a 2 milli 0 vinegar

The product of step 7 (0.31 g of '〇·41 mmol), trifluoroacetic acid (3 liters), and dichloromethane (7.03⁄4 liters) were stirred at room temperature for 2 hours with fluoroacetic acid and dioxins. It was removed under reduced pressure, and the crude mixture was treated with decyl alcohol (2 N &lt;RTI ID=0.0&gt; The sterol was removed to obtain a crude mixture. The compound was purified using reverse phase Η P L C to give the title compound as white ( s. 10 g, yield 36%). SOLID C21H22H6 06 C12 · 1 · 3CF3CO〇H · 〇 · 25H20 Analysis calculated: C, 41·80; H, 3· 54; N, 12· 39; C1, 10, 4β· Found: C, 42.12; Η,3·84; N, 11.87; C1, 10.99' Example 23

1[[5-(4,5-dihydro-111-imidazolyl-2-yl)amino]-1,2-dihydro, 2~-mono-3-pyridyl]amino]glycolyl- Preparation of 3-(3,5-dioxa-2-hydroxyphenyl)yl-alanine, trifluoroacetate a 曰Η . Ο

Page 134 1247008 V. INSTRUCTIONS (128) EXAMPLE 2 2 The product of Step 7 (0.21 g, 0 · 28 mmol) in dioxane (4 mL) was 6N HC1 (6) ML) was treated at room temperature for 72 hours. The solvent was removed under reduced pressure. EtOAc (EtOAc m. For C20H2()H6 06 C12 · 1 · 6CF3COOH: C, 40.17; H, 3.14; N, 12.11 ; Found: C, 40. 10; H, 3. 22; N, 11· 84

I 4

Page 135 1247008 V. Description of invention (129)

窆24窆 [【5-[(4,5-卜净-5矣异-2-;&amp;)漭;&amp;1-1--9;&amp;-11-1-^^-3 -^_;&amp;]4漭谬- π DD ♦ Page 136 1247008 V. INSTRUCTIONS (130) Steps 1 and 2 in the synthesis of the title compound are based on the literature procedure (Justus Liebigs· Ann·Chem· 512, respectively) , 97, 1934, and J·

Heterocyclic Chem· 21,73.7, 1 9 94 ). Step 3: In the solution of the product of step 2 (〇·9 g, 5.3 mmol), &amp;G2 (1.9 g, 5·9 mmol) in DMF (25 ml) Ethylamine (2. 5 ml '1 plant 6 mmol) and mercury chloride (1.6 g, 5. 9 mmol). After the mixture was heated at 80 - 85 ° C for 18 hours, the reaction mixture was cooled and filtered through a c e 1 i t e column. The residue was washed with dichloromethane and the combined portions were concentrated. The residue was redissolved in dichloromethane and washed with water and brine. After drying over sodium sulfate, the mixture was filtered and concentrated. The crude orange solid (8 g) was purified using EtOAc (EtOAc/EtOAc) Step 4: To a solution of the product from Step 3 (2.4 g, 5.5 mmol) in EtOAc (50 mL) EtOAc. The reaction mixture was stirred at room temperature for 24 hours. Acetic acid (22 ml) was added to the reaction mixture and the mixture was stirred for 15 minutes. After the solvent was removed under reduced pressure, the crude mixture was purified by reverse phase HPLC (acetonitrile/water containing trifluoroacetic acid) to give the product, and the 壬TFA salt was a thick white liquid. The residue was treated with hydrogen chloride (4M solution in EtOAc) and stirred for s. The reaction mixture was concentrated to remove the solvent. This procedure was repeated twice to give the desired product as a white solid (3·9 g). The product was used in the next step without further purification. Step 5:

1247008 V. INSTRUCTIONS (131) N-methylmorpholine (605 ml, 5) was added sequentially to the product of step 4 (0.9 g, 3.7 mmol) in DMF (15 mL) in EtOAc. 5 mM) and isobutyl chlorodecanoate (475 $. liter, 3.7 mmol). After stirring for 5 minutes, the product of Step D was poured into a reaction mixture containing a solution of fluorenyl-mercaptomorpholine (650 ml, 5 · 5 mmol) in DMF (10 ml). The mixture was stirred at 〇C for 1 hour and at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was purified to purified crystalljjjjjjjjj Step 6: To a solution of the product from Step 5 (540 mg, 1 mmol) in EtOAc (5 mL) The reaction mixture was stirred at room temperature for 24 hours. Acetic acid (305 ml) was added to the reaction mixture, and the mixture was stirred for 15 minutes. After the solvent was removed under reduced pressure, the crude mixture was purified mjjjjlilililililili Analysis of calculated values for C19H21 N7 05 C 12 · 1 · 5CF3C02Η: C, 3 9. 48; Η, 3. 39; Ν, 14. 65 Measured value·· C, 39· 29; Η, 3· 14; Ν, 14. 72 NMR and MS are consistent with the desired structure. Example 2 5 N - [[5_[(4,5-Dihydro-1H-imidazol-2-yl)amino]-1H-pyrazole-yl]carbonyl]Glycidyl-3-(3,5- Preparation of diox-2-hydroxyphenyl)-cold-alanine, trifluoroacetate

Page 138 1247008 V. Description of invention (132)

The compound was synthesized as in Example 24 using benzyl hydrazine instead of the hydrazine hydrazine in Step 2. The resulting N-phenylmercaptopyrazole compound was deprotected using a catalytic hydrogenation condition (5% Pd/C, 20 psi, room temperature, 26 hours) in the final step. This reaction was carried out using acetic acid-trifluoroacetic acid (4/1) as a solvent. C18H19N7 05 C12 · 1 · 75CF3C02H · 1 · 25H20 Analysis calculated: C, 36. 56; H, 3. 32; N, 13. 88 Found: C, 36. 35 ; H, 2. 96 ; N, 14. 28 NMR and MS are consistent with the desired structure. Example 2 6

The above compound was prepared as described in Example 9, except that the product of Example S was used instead of the product of Example R Step 4. Analysis and calculation value of C21H22Br ΙΝ6 06 · 2CF3C00H · 0· 25H20··

Page 139 1247008 V' invention description (133) C, 33. 6 0 ; H, 2. 76 ; N, 9. 40 Found: C, 34. 23; H, 2. 35; N, 9. 72 Example 27 〇^OEi 〇2 Mei Ο, /OEt X^Vr c

Cl , Eton

Cl HIM, . MeO·

O

Cl &gt;〇H hydrolysis

Me丨 o

Suihua

Cl &lt; 1 The starting material required for this preparation was synthesized using the procedure of Step 1 of Example 2 1 . Step 1 A solution of the starting material (1.4 g) in ethanol (50 ml) was treated with a catalytic amount of 5 % P t / C under 5 s i hydrogen pressure at room temperature for 5 hours. The reaction mixture was filtered, evaporated, evaporated The UMR is consistent with the structure shown. Step 2 The compound name was prepared according to the experimental procedure shown in Step 4 of Example 2. 1 Η - N M R is consistent with the structure shown. Step 3 __ Μ

Wi-page 140 1247008 V. INSTRUCTION DESCRIPTION (134) The ester group of the compound name is hydrolyzed according to the experimental procedure shown in Step 2 of Example 2 1 . 1 Η - N M R is consistent with the structure shown. Analysis of calculated values for C22H24N6 07 C12 · 1 · 50TFA · 0· 2.5fi20: C, 41.08; Η, 3.59; Ν, 11.50 Measured: C, 4 1 · 0 3 ; Η, 3. 6 9 ; Ν, 1 1 · 4 5 〇〇

Page 141 1247008 V. Description of invention (135)

Page 142 1247008 V. INSTRUCTIONS (136) The starting materials required for this preparation were prepared as described in Step 1 of Example 18. Step 1 • Compound 1 was prepared according to the procedure shown in Step 2 of Example 18. except that 2-methoxyethoxymethyl chloride was used as the alkylating agent in place of methyl iodide. The HMR is consistent with the structure shown. Step 2 The product of Step 1 (4.6 g) in MeOH (50 mL) was taken from EtOAc (EtOAc) The reaction mixture was filtered, concentrated and dried to give viscous oil (4.3 g). Step 3 A portion of the product from Step 2 (2·0 g) was purified using the reaction conditions described in Example 2 1 Step 4 to afford product 3 as a viscous golden oil (800 mg). 1 Η - N M R is consistent with the structure shown. Step 4 The ester group of product 2 was hydrolyzed using the experimental procedure shown in Example 2, Step 5. 1H-NMR was consistent with the structure shown. Step 5 The product of Step 4 was coupled to the product of Example I according to the procedure shown in Example 1 2 Step 4. 1 H-NMR was consistent with the structure shown. Step 6 The ester group of the product of Step 5 was hydrolyzed according to the procedure shown in Example 2, Step 5. 1H-NMR was consistent with the structure shown.

Page 143 1247008

Page 144 1247008 V. Description of invention (138) C, 35. 27; H, 2.93; N, 10.07 Found: C, 3 5 · 2 1 ; Η, 3 · 1 6 ; N, 1 0 · 2 7

Example S

The above compounds were prepared according to the procedure described in Example G. In step 2 A, 3-iodo-5-bromo salicylaldehyde is used in place of 3,5-dioleic salicylaldehyde.

Example T

The above compounds were prepared according to the procedure described in Example G. In step 2 A, 3-bromo-5-salicylidene is used in place of 3,5-dihydrate salicylaldehyde. Similarly, in step 2B, R-phenylglycolamine was used in place of S-phenylglycolamine.

Example U

CO^Et (The above compound was prepared according to the procedure described in Example D. The m.p.

Page 145 1247008 V. Description of invention (139)

A COsEi Τ Τ

h2N

C〇2Et Step 1 The racemic amine ester hydrochloride (50.0 g, 158.9 mmol) obtained in Example D, Step 2 was added to CH2C12 (500 mL) and water (380 mL). NaHC03 (3 8.2 g, 4 54.5 mmol). The mixture was stirred at room temperature for 10 minutes and the gas was released vigorously. A solution of benzoic acid benzoate (43. 4 g, 22 2. 8 mmol) in CH 2 C 12 (43 mL) was added over 20 min and stirred rapidly. After 40 minutes, the reaction mixture was poured into a separating funnel to collect organic

Page 146 1247008 V. Description of the invention (140) Solution. The aqueous phase was washed with CH2C12 (170 mL). The combined organic solutions were dried (MgS 4) and concentrated in vacuo. The resulting gummy solid was triturated with hexane and collected by filtration. The tan solid was dried in vacuo to give the desired product (6 2 · 9 g, yield: 6%). This material was purified by HPLC on the palm of the column to obtain the pure enantiomer Α. The column used - ^ (R, R), 10 micron particle size, using 9 〇: 1 〇 heptane: ethanol shift Optical purity using analytical HPLC with similar solvents and conditions 1 NMR is consistent with the structure shown. .

Step 2A

Enantiomer A (57·9 g '140·4 mmol) in a solution of CH2C12 (60 liters) was added to the trimethyl decane by a cannula 2 gram of '168. 5 millimoles. The mixture was stirred for 1 hour in CH2C12 (125 ml). Sterol (27. 3 ml, 6 74 · 1 寮 甘 Gan,, not warehouse

The solution was stirred for 15 minutes. The reaction solution was added dropwise under vacuum in a vacuum, and ν was condensed to obtain a pulverized oil. == methyl tert-butyl ether (67 ml), with ιμ Ηπ(4). Solid NaHCO.c was added as a mixture of MTBE (1×1·2 μL) and water (1×230 mL, 1×130 mL) and t-MTBE (130 mL). In the aqueous solution, with + stroke, (52·9 g, 63〇 mmol). Alkaline water mixture 1247008 V. Description of the invention (141) liter, 2 X 2 6 5 ml) extraction. The combined organics were washed with EtOAc (EtOAc)EtOAc. 4 NMR was consistent with the structure shown.

Step 2B C02Et Addition of trimethyldecane to the enantiomer of Step 1, the compound of Example 1 (38. 5 g, 93.4 mmol) in CH2C12 (380 mL) The iodine (25. 0 g, 12.5 mmol) was taken in CH2C12 (80 mL). 5小时。 The orange solution was stirred at room temperature for 1.5 hours. Sterol (20 ml, 5 0 0. 0 mmol) was added dropwise and the solution was stirred for 20 minutes. The reaction solution was concentrated in vacuo to give an orange oil. The residue was dissolved in EtOAc (EtOAc) (EtOAc) The aqueous extract was back washed with diethyl ether (100 mL). Solid NaHC03 (4 0 · 1 g, 4 7 8 mmol) was added in small portions in an aqueous solution. The alkalized water mixture was extracted with diethyl ether (1×1·0 L, 2×200 mL). The combined organic solution was washed with brine and concentrated in vacuo to give the desired product (20. 8 g, yield 80%). Analysis calculated for CUH13C12N03: C, 47. 50; H, 4.71; N, 5. 04 Found: C, 47. 11 ; H, 4. 66 ; N, 4· 93

Page 148 1247008 V. INSTRUCTIONS (142) The product of Step 2B is converted to the target intermediate using the reagents and conditions described in Examples G, Steps 4 and 5.

Example V

C02Et OH : ΓίΧ: The above compounds were prepared according to the procedure described in Example G. In step 2 A, 5 - bromo-3-iodophenylfurfural is used in place of 3,5 -dihydrate salicylaldehyde.

I Example 3 0

Step 1 Preparation of the following formula

H3 C ο 4-decyloxy-2-amine-based picolinic acid decyl ester (602 mg, 3. 3 mmol)

Page 149 1247008 V. INSTRUCTIONS (143) Ears (JACS, 78, 4130, 1956) Add phenylhydrazine isothiocyanate (丨 ml, Aldrich) to a stirred solution in CH2C12 (20 mL). The reaction was stirred at a temperature of 90 minutes. The mixture was diluted with ether (20 mL). The mixture was cooled in EtOAc (EtOAc)EtOAc. iH NMR·· 3 0 0 Μ Η z is consistent with the structure shown. Step 2 Preparation of the following formula

To a stirred solution of the product of Step 1 (750 mg, 2.17 mmol) in methanol (30 mL) The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with glacial acetic acid (〇·57.5 mL) and stirred at room temperature for 15 min. The solid was filtered under EtOAc (EtOAc)EtOAc. Step 3 Preparation of the following formula

Page 150 1247008 V. Description of the Invention (144) To a stirred solution of the product of Step 2 (364 mg, 1.5 mmol) in methanol (20 mL), EtOAc (EtOAc) The reaction mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature and concentrated to give the desired compound ( 650 mg). Step 4 Preparation of the following formula

HO

i Add 1,3 -diamino-2-hydroxypropane to a stirred solution of the product of Step 3 (500 mg, 1.30 mmol) in N,N-didecylacetamide (10 mL) 1 2 3 mg, 1. 3 7 millimoles). The reaction mixture was heated to 90 ° C for 2 hours. The mixture was concentrated in vacuo to give crystals crystals crystals crystals 4 NMR : 3 0 0 Μ Η 一致 is consistent with the structure shown. Step 5 Preparation of the following formula

Page 151 1247008 V. Description of the Invention (145) A solution of the product from Step 4 (200 mg) in EtOAc (3 mL) The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to give an oily gum which was taken up in water (2 ml) and neutralized with 1 N HCl (3 mL). The mixture was concentrated in vacuo to give a crystallite. iH NMR: 300 MHz is consistent with the structure shown. Step 6 Preparation of the following formula

Add 4-mercaptomorpholine (2〇2 mM) to the stirred solution of the product from step 5 (151.25 mg, 0.5 mmol) in n, n~ dimethylamine (5 mL) g '2 mmol> and hydroxybenzotriazole (67 mg, 〇·5 mmol) and the amino ester product of Example R (2 0 8. 5 mg, 〇·5 mmol). , θ person' is stirred at room temperature for 5 minutes. The reaction mixture is 1 - [ 3 - (didecylamine)

Treatment with 3-ethylcarbodiimide (96 mg, 0.55 mmol) and 4 (dihydrophenyl)pyridine (10 mg). The reaction mixture was stirred at room temperature under nitrogen for a period of 72 hours. The reaction mixture was quenched with water (1 mL) EtOAc (EtOAc) NMR: 4 0 0MHz and the structure shown in the second 42

Page 152 1247008 V. Description of invention (146) Step 7 Preparation of the following formula

A solution of 1 N N a 0 hydrazine (3 ml) was added to a stirred solution of EtOAc (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to give EtOAc (EtOAc). The mixture was concentrated in vacuo to give crystals crystals crystals crystals 4 NMR: 4000 MHz is consistent with the structure shown. For C22H24N6 07 BrCl · 2TFA · 0· 5H20 : C, 37· 22; H, 3.25; N, 10.04 Found: C, 36. 91 ; H, 3. 17; N, 10· 02 Example 3 1

HO

step 1

Page 153 1247008 V. Description of invention (147) Preparation of the following formula

To a stirred solution of the product of Example 3, Step 4 (900 mg), EtOAc (EtOAc) The reaction mixture was heated to reflux for 3 hours. The mixture was cooled to room temperature and stirred at room temperature for 18 hours. The mixture was concentrated in vacuo to give a crude material. 1H NMR: 300 MHz was consistent with the structure shown. Step 2 Preparation of the following formula

Ο Η

Add 4-mercaptomorpholine (520 mg, 5.2 mmol) to a stirred solution of the product from step 1 (720 mg, 1.7 mmol) in EtOAc (EtOAc) And 1-hydroxybenzotriazole (221 mg, 1.71 mmol), and the amino ester product of Example R (7 10 mg, 1.7 mmol). The mixture was stirred at room temperature for 5 minutes. The reaction mixture is a [3-(didecylamino)propyl group

Page 154 j2470〇8 — —_________ V. INSTRUCTIONS (148) 3-Ethylcarbodiimide (211 home grams, 1.7 millimoles) and 4-(dimethylamino) alpha ratio bite ( 1 〇 mg) treatment. The reaction mixture was stirred at room temperature under nitrogen for 7 h. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The iH NMR 300 MHz was consistent with the structure shown. Step j Preparation of the following formula

A solution of 1 N N a hydrazine (3 ml) was added to the turbid solution of the product from step 2 (1 mg) in methanol (3 ml) and THF (3 ml). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to give EtOAc (EtOAc). The mixture was concentrated in vacuo to give crystals crystals crystals crystals 1H nmR 3 0 0MHz is consistent with the structure shown. Analysis of calculated values for C21H22N6 07 Brci · 1· 5TFA · 0· 5H20 : C, 37· 64; H, 3·22; N, 10·97 Found: C, 37Hm, 1 (K Μ Example 32

Page 155 1247008

V. Description of the invention (149)

In the solution of the product of Example 9 Step 3 (86 0 mg, 2.45 mmol) and the product of the butyl hydrazine (0 g, 2.41 mmol) in dimercaptoacetamide (24 mL) °(: Add 11 (^1[(35 8 mg, 2.64 mmol), then add N-methylmorpholine (〇·6 ml, 5.15 mmol). The reaction solution is stirred for 15 minutes, EDC (470 mg) , the mixture is heated to a temperature. The mixture is concentrated in vacuo and the residue is partitioned between ethyl acetate and water.

(Na2S04), concentrated. The residue was purified by RP HPLC (90························· (Compound β) was treated with aq. EtOAc (3 mL) EtOAc (3 mL). EtOAc EtOAc EtOAc EtOAc 〇mg, two

Page 156 1247008 V. Description of the invention (150) The yield of the step is 8%). C21H22BrClN5 06 · 2. Analysis of calculated values for 4TFA: C, 36. 74; H, 2. 92,; N, 9. 96 Found: C, 36.83; H, 3. 07 ; N, 9. 88 1 Η NMR is consistent with the structure shown. Example 3 3 ! H〇~/ ypi

) Soc ^ -N-h J a -Q^* Deprotection 1) Coupling A1NII3

2) Hydrolysis

Step 1 A solution of the material from Example 18 Step 2 (5·72 g) in THF (80 mL) was applied to 5% EtOAc. The reaction mixture was filtered and the residue washed with EtOAc EtOAc The filtrate was concentrated and the residue was crystalljjjjjjjjjjjjj [H-NMR was consistent with the structure shown. step. Step 2 Substance 1 (500 mg) using the three boc described in Example 21, Step 4.

Page 157 1247008 V. INSTRUCTIONS (151) The reagents and conditions are deuterated to obtain the desired product (1 2 8 mg) in the form of a golden glass. 1H-NMR was consistent with the structure shown. Step 3 The ester group of the product of Step 2 was hydrolyzed using the experimental procedure shown in Example 2, Step 5. 1 Η - N M R is consistent with the structure shown.

CnH14N4 04 · 1. Analysis of calculated values for 5TFA: C, 38. 45 ; H, 3. 57; N, 12. 81 Found: C, 38. 32; H, 3. 77; N, 12· 80 Step 4 The desired compound was prepared by coupling the product of Step 3 to the product of Example R using the same procedure as described in Step 4, Example 2. iH-NMR was consistent with the structure shown. Step 5 The ester group of the product of Step 4 was hydrolyzed using the same procedure as described in Example 1 2, Step 5. 1 Η - N M R is consistent with the structure shown. For C21H22N6 07 BrCl · 1 · 5TFA · 0· 25Η20 Analysis calculated: C, 37. 8 6; Η, 3. 18; Ν, 11. 04; C1, 4. 66; Br, 10.50 Found: C, 37.6 0; Η, 3.26; N, 11.20; C1, 47.79;

Br, 10.19

Page 158 1247008 V. Description of invention (152) Example 34

The above compound was prepared by the method described in Example 33. In step 4, the product of Example R was used instead of the product of Example R. C21H22N6 07 BrCl · 2. 0TFA · 0· 5Η20 Analysis calculated value·· C, 36.49; Η, 3. 06; Ν, 10.21 Measured value: C, 36. 10; Η, 2. 83; Ν, 10. 29 Example 3 5 〇

The above compound was prepared by the method described in Example 33. In step 4, the product of Example V was used instead of the product of Example R. Analysis of calculated values for C21H22N6 06 Br2 · 1 · 75TFA: C, 3 5.76; H, 3. 03; N, 10.21 Actual value ·· C, 3 5. 5 8; H, 3. 07; N, 10. 61

Page 159 1247008

Page 160 1247008 V. INSTRUCTIONS (154) Step 2 The desired compound was prepared in the same manner as described in Example 1, Step 4. The product described in Step 1 was coupled to the product of Example 1. iH-NMR was consistent with the structure shown. Step 3 The ester group of the product of Step 2 was hydrolyzed using the same procedure as described in Example 1 2, Step 5. 1 Η - N M R is consistent with the structure shown. Analysis calculated for C20H20N6O6Br2 · 1 · 75TFA · 0. 25Η20: C, 35.10; Η, 2. 79; Ν, 10.45 Found: C, 34. 8 5; Η, 2. 59; Ν, 10. 62

Page 161 1247008

Page 162 1247008 V. INSTRUCTIONS (156) Step 1 2-Nitrothiophene-4 -carboxaldehyde (5.0 g) was suspended in water (1 mL) at room temperature. Sodium Hydroxide (5.2 cc) One portion of the solution in water (5 ml) was added. The black reaction mixture was stirred at room temperature for 1 hour and then filtered through a pad. The filtrate was acidified with a 1 N HCl solution and then extracted with ethyl acetate. The combined organic extracts were washed with a saturated aqueous solution of sodium sulphate, dried (v &amp; The UMR is consistent with the structure shown. Step 2 The product of Step 1 (2.5 g) was stirred with EtOAc (EtOAc) EtOAc (EtOAc) The reaction mixture was partitioned between ethyl acetate and water, and the layers were separated. The water portion was extracted with ethyl acetate, and the combined organic extracts were washed with water, a saturated sodium carbonate solution, and dried (S? 4). The dark residue was purified on a silica gel column eluted with EtOAc (EtOAc) 1H-NMR was consistent with the structure shown. Step 3 The product obtained in Step 2 (2 g) was dissolved in methanol (5 mL) and treated with a catalytic amount of 5% Pd/C under a pressure of 50 psi of hydrogen at 6 Torr for 32 hours. The reaction mixture was cooled, @filtered, and the filtrate was concentrated. The residue was purified on a column and eluted with 25% ethyl acetate - 75% hexane to afford &lt;RTIgt; 4-NMR was consistent with the structure shown. The product of Step 3 of Step 3 (9003⁄4g) is dissolved in ethyl acetate (2〇ml) to benzene 1247008 V. Inventive Note (157) A copy of formazan isothiocyanate (947 mg) The reaction mixture was stirred at room temperature. The reaction mixture was stirred for 30 min, and then filtered and evaporated to ethyl ether. The product obtained was dissolved in methanol (70 ml) and treated with sodium decoxide (1.3 g) at room temperature. The reaction mixture was stirred for 30 min 5 and then quenched with glacial acetic acid (1. 4 g). The reaction mixture was concentrated, the residue was partitioned between ethyl acetate and water. Water was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium carbonate solution, dried (Na2S04) Powder (900 mg). l-NMR was consistent with the structure shown. The product from step 5 (900 mg) was dissolved in methanol (2 mL) and treated with methyl iodide, 4.4 g. The mixture was refluxed for 2 hours, then cooled and concentrated. And air dried to yield a white solid (1 g) .l-NMR is consistent with structure shown in FIG.

The product of Step 6 (1.2 g) was heated with ι,3 -diamino-2-hydroxypropanone (469 mg) and DMA (20 mL) at 95-1 °C for 8 hours. The reaction mixture was cooled and the granules were removed under vacuum. The residue was purified by reverse phase HPLC eluting with EtOAc (EtOAc:EtOAc) 1-NMR was consistent with the structure shown. ^^8 The desired compound is used in the conditions described in Example 2 1 Step 5, using step 7

Page 164

1247008 V. Preparation of substances produced in the description of the invention (158). 1H-NMR was consistent with the structure shown. Step 9 The desired compound was prepared by coupling the product of Step 8 with the material of Example G using the same procedure as described in Example 1 2 Step 4. HMR and the structure shown ^- 〇 step. Step 1 0 The ester group of the product of Example 9 was hydrolyzed using the same procedure as described in Example 1 2, Step 5. 1 Η - N M R is consistent with the structure shown. For C.sub.3.

Page 165 1247008

Page 166 1247008 V. INSTRUCTIONS (160) Step 1 Acetic anhydride (20 ml) was treated with 70% nitric acid (4 mL) at room temperature. Then, the solution was added dropwise to the N-methyl π ratio. Each 2-hydrogenated acid (5·g) was stirred in a mixture of -3 °C in acetic anhydride (3 Torr). The reaction mixture was stirred and heated to room temperature for 30 minutes. The reaction mixture was then cooled to -25, filtered over a cold filter, washed with cold hexane and air dried to give a yellow powder (5 g). NMR was consistent with the structure shown. Step 2 The desired compound was prepared using the procedure described in Example 3, Step 2, using the product prepared in Step 1. The crude product was purified by chromatography on a silica gel column eluting with 40% ethyl acetate-hexane. 1H-NMR was consistent with the structure shown. Step 3 The product of Step 2 (1.0 g) was dissolved in methanol (25 mL), and treated with a catalyst amount of 5% Pd / C under a hydrogen pressure of 5 p s i at room temperature for 3 hours. The reaction mixture was filtered and concentrated to give crystals eluted eluted eluted 1 Η — N M R is consistent with the structure shown. Step 4 The desired compound was prepared using the procedure described in Example 3, Steps 4 - 8 using the product described in Step 3. l-NMR was consistent with the structure shown. 16 Step 5 Step 4 product (42 5 mg), 2- gas-4,6-dimethoxyoxy three tillage (201 mg), and N-mercaptomorpholine (263 mg) in DMA (10 mL) The solution was stirred under nitrogen in an ice bath. The reaction mixture was allowed to warm to room temperature and stirring was continued for 3 hours. Preparation of the product of Example G ( 386 mg) and N-methylmorpholine (105 m

Page 167 1247008 V. INSTRUCTIONS (161) g) A solution in DMA (5 ml) was added to the reaction mixture as a portion at room temperature. The reaction mixture was stirred for 15 hours, quenched with TF A (1·5 mL) and concentrated under high vacuum. Residue_purified by reverse phase HPLC eluting with water (0. 5% TFA) - acetonitrile gradient to give a white solid ( s. 1 Η - N M R is consistent with the structure shown. Step 6 The ester group of the product of Step 5 was hydrolyzed using the same procedure as described in Example 1 2, Step 5. 1 Η - N M R is consistent with the structure shown. C21H24N6 06 C12 · 1 · 5TFA · 0· 5Η20 Analysis calculated value·· C, 40. 75; Η, 3. 78; Ν, 11.88; C1, 10. 02 Measured value: C, 40.40; Η, 3.68; Ν , 12.10; C1, 10.20

Page 168 1247008 V. Description of invention (162) Example 3 9

Page 169 1247008

V. Description of the invention (163)

Step 13 - Mixture of dimethyl-4-mercaptophene (10 g) 'copper cyanide (I) (11.3 g), and HMPA (15 ml) was heated at 1 30 - 1 40 ° C for 18 hours. a. Cool, pour in sodium cyanide (1 8 · 8 g) in water (28 ml); stir well; and stir for 1 hour. The thick brown mixture is diluted with some water to make it ~. The combined ether extracts were washed with water, saturated sodium chloride solution, dried, (N S 〇 4 ) / dec. The residue was purified on a Shixi rubber column, and the pale yellow liquid (5.2 g) was obtained as g%^-(tetra)'. Step 2 Raise the 曰1 ^ Preparation of 臆 (1.5 g) and 2N sodium hydroxide solution (150 mM back /;, L 1 small pity. The reaction mixture is cooled, acidified with 2 N hydrochloric acid P] Extracted with ether. Combined ether extract dried

1247008 V. Inventive Note (164) (Na2S04), concentrated to give a white solid (1 6 · 4 g), which was used without further purification. 1 Η - N M R is consistent with the structure. Step 3 · The product of Step 2 (1 6 · 4 g) was esterified as described in Example 3, Step 2, and purified on a silica gel column after dissolving with 10% acid ethyl ester-9 0 % hexane. The desired product (13·6 g) was obtained. 1H-NMR was consistent with the structure shown. Step 4 Add a mixture of N-bromosuccinimide (6 · 3 g) and benzoyl peroxide (100 mg) in tetrachlorinated (25 ml) in 90 minutes. The product of 3 (5.0 g) and the benzhydryl peroxide (1 mg) in a cocurrent solution in CC14 (25 ml). After refluxing for 2 hours, the reaction mixture was cooled, filtered, and the residue was purified on a silica gel column eluting with 10% ethyl acetate-90% hexanes to give the desired compound (4.3 g) H-NMR Consistent to the structure shown. Step 5 A mixture of the product (4.2 g), sodium azide (2.9 g), and DMF (50 mL) was stirred at <RTIgt; The reaction mixture was cooled and partitioned between water and ethyl acetate. The layers were separated and the water portion was extracted with ethyl acetate. The combined organic extracts were washed with a saturated aqueous solution of sodium chloride, dried (N?SO?), and concentrated to give a golden oil (3.5 g) and used without further purification. 1 Η - N M R is consistent with the structure shown. A solution of the product (1.0 g), 1 EtOAc (15 mL) and EtOAc (15 mL) Reaction mix

Page 171 1247008

The compound was treated with glacial acetic acid (2 ml), g &amp; ^ 妒r". The residue is distributed between water and Sa, B from day to day. The layers are separated, the water portion and the vinegar organic extract are water, saturated with a naphthalene solution; stroked; and shrunk. The residue was dry welded at 6KC under high direct air for 2 hours: \=\), "Nong r 〇 〇 λ Hawthorn, and the work r钇 ζ ζ 蚪 蚪 蚪, get white solid 86 ( 86 0 * g). iH-NMR was consistent with the structure shown. The solution of the product (850 mg) in dioxane (1 mL) was cooled in an ice-bath, and a solution of chloroform (5 ml) in dichloromethane Treat and then treat with 2 drops of DMF. The reaction mixture was stirred for 2 hours while heating to room temperature. The solution was concentrated and dried <RTI ID=0.0> l-NMR and the indicated structure - Step 8 In a flame-dried flask, diisopropylethylamine (1.3 mL) was placed under nitrogen, the product of Example G (1 · 4 g) , and a solution of DMA (10 ml). The solution was cooled in an ice bath, and a solution of the hydrazinyl chloride (770 mg) in DMA (5 ml) was added dropwise. After the addition was completed, the reaction mixture was allowed to stand for 30 minutes and then partitioned between ethyl acetate and water. The layers were separated and the water portion was extracted with ethyl acetate. The combined organic extracts were purified on a silica gel column eluting with 50% ethyl acetate - 50% hexane to afford a white solid (1 g). The UMR is consistent with the structure shown. Step 9 The product of Step 8 (806 mg) in EtOAc (20 mL) EtOAc. Reaction mix

Page 172 1247008 V. Inventive Note (166) The compound was filtered, concentrated, and purified to purified crystals eluted eluted eluted eluted eluted The UMR is consistent with the structure shown. The product (5500 mg) obtained in Step 1 was purified and purified using EtOAc. 111-off 1^ is consistent with the structure shown. Step 1 1 Step 1 0 The ester group of the product was hydrolyzed using the same procedure as described in Example 1 2, Step 5. NMR was consistent with the structure shown. For C21H23N5 05 C12S · 1· 5TFA · 0· 5H20 : C, 3 9. 79; H, 3.55; N, 9.67; C1, 9.79; S, 4. 43 Found: C, 39.91; Η, 3 ·58; N, 9.94; C1, 10.06; 5, 4.52

Page 173 1247008 V. Description of invention (167) Example 4 0

Couple

H2n C02Et

NaOH *

N

NM

1) Coupling 2) Hydrolysis

Step 1 Example 3 The product prepared in Step 3 (1.0 g) was coupled with the ethyl glycinate hydrochloride using the procedure described in Example 3, Step 5, and after similar purification, a yellow solid was obtained. 1. 1 g). 1 Η - N M R is consistent with the structure shown. Step 2 The product of Step 1 (1.0 g) was purified using EtOAc m. The HMR is consistent with the structure shown. Step 3

Page 174 1247008

V. INSTRUCTION DESCRIPTION (168) The product of Step 2 was coupled with 3-amino-4,4,4-trifluoro-butyric acid ethyl ester hydrochloride using the procedure described in Example 3, Step 8. UMR and the structure shown. Step 4 The ester group of the product of Step 3 was hydrolyzed using the procedure described in Example 1, Step 2. iH-NMR was consistent with the structure shown.

Analysis calculated for Ci 71 N5 06 F3 ·1·5ΤΡΑ: C, 38· 01; Η, 3· 67; Ν, 11· 〇8 Measured: C, 37. 88; Ν, 3. 64; Ν, 11 . 〇 2 Example 41

Step 1 Example 33 The product of Step 3 ( 527 mg, 1-3 mmol) and EtOAc ( 244 mg, 1.4 mM) was dissolved in EtOAc (8 mL). The solution was cooled to 0 ° C for 3 hours, and ΝΜΜ (0·15 ml, 1 · 3 mmol) was added dropwise. The solution was stirred at 0 °C for 3 hours, then the product of Example U and NMM (0·15 mL) was added in DMAC (1 mL). The reaction mixture was warmed to room temperature and stirred at room temperature overnight. The reaction mixture was quenched with EtOAc (2 mL). The crude yellow solid was purified by RP-HPLC eluting using a concentration gradient of 9 〇: 1 〇 H20 / TFA.CHsCN ( λ = 254 nm). The product was isolated as a white solid ( 725 mg, yield 75%).

1247008 V. Description of invention (169) C23 H26 N6 〇7 C 12 · 1 · 5 TF A analytical calculations: C, 42.12; H, 3·74; N, 35 measured values · C, 4 2 · 2 6 ; Η,3 · 8 7 ; N,1 1 4 5 C23H27N6 07 C12 of 11· R· Μ· S. Μ +1 Calculated value: 5 6 9· 1318, measured value: 569·1323 ^ Step 2 Step 1 The product (725 mg, 0.98 mmol) was dissolved in <RTI ID=0.0># </RTI> </RTI> </RTI> </RTI> <RTIgt; The reaction mixture was stirred at room temperature overnight then 1 M EtOAc (EtOAc). After concentration in vacuo, the crude yellow solid was purified by RP-HPLC eluting with a concentration gradient of 95. 5 H20/TFA: CH3CN (λ = 254 nm). The product was isolated as a white solid (589 mg, yield 79%). C21 H22 N6 07 C12 · 1.9 TFA Analysis calculated: C, 39·30; H, 3·is; N, 11·09 Found: C, 3 9 · 2 2 ; η, 3 · 1 6 ; N, 11. 3 9 C21H23N6 07 C12 HRMS· Μ + 1 Calculated value: 54 1.1 0 0 5, measured value: 541·1000

Page 176 1247008 V. Description of invention (170) Example 4 2

Step screw 3 Step 1 2: Methoxy-6-chloropyridinecarboxylic acid (1 g, 〇·5 5 3 mol) was dissolved in an excess of aqueous ammonium hydroxide in a high pressure reactor and heated to 175. It takes 24 hours to get a pressure of 500 psi. The solution was evaporated to dryness under reduced pressure and then was taken to acid with &lt;2&gt; After 12 hours, the residual water was removed azeotrope with absolute ethanol, and the resulting residue was treated with methanol and evaporated three times under reduced pressure. The residue was dissolved in decyl alcohol (25 ml), and 4n HCl was added to the solution in dioxane (-25, ear), followed by reflux for 2.5 days. The solvent was removed under the pressure of the strip, and the crude residue was obtained by reverse phase HpLC (concentration gradient, 95/5 0.1% TFAKH2 〇 /CH3CN-6 0 /4 0 0.1 % TFAKH20 /ch3CN) =. = The product is dissolved in decyl alcohol, treated with sodium argon carbonate solid, filtered, and bathed. The resulting solid is suspended in 5 〇 / 5 〇 ethyl acetate / hexane, solid

Page 177 1247008 V. INSTRUCTIONS (171) The body is collected by filtration to obtain the desired brown solid (1.7 g, yield 2 〇 %). Step 2

The compound of Step 1 (300 mg, 1.8 mmol) was dissolved in DMF (7.1 ml), and the product of Step 9 of Example 9 (92 7 mg, 2.1 mmol) was added, then three Ethylamine (0.44 ml, 325 mg, 3.2 mM) and chlorinated (3,26 mg, 1.25 mmol) were added. The reaction mixture was stirred at 2.5 ° C for 3.5 hours and then heated to 60 ° C for 16 hours. After cooling to room temperature, ethyl acetate (7 ml) was added to the reaction mixture, and the heterogeneous solution was filtered through EtOAc. The cel ite was washed thoroughly with 9 7/3 ethyl acetate/ethanol. The solvent was removed under reduced pressure and the crude red oil was dissolved in dichloromethane (30 mL). The reaction mixture was cooled and the solvent was removed under reduced pressure to give a brown oil. The sample was purified by reverse-phase HPLC (C1 8, concentration gradient 90/10 〇·1% TFA/H20) to give an impure compound which was dissolved in methanol (2 mL) and treated with IN NaOH (0.15 mL). Lift to dry and obtain dark brown oil. This oil was purified by reverse phase HPLC (C1, EtOAc: EtOAc: EtOAc) Step 3 The compound from the above step (74 mg, 0.18 mmol) was dried in a vacuum oven overnight, dissolved in DMF (1 mL) (stored on molecular sieves) and cooled to 〇°C. Then, N-decylpiperidine (27 ml, 22 mg, 0.22 mmol) was added, then isobutyl carbamic acid ester (47 ml, 49 mg, 0.36 m) was added and stirred for 5 min. The product of Example G was added to a solution of DMF (2 mL) and the residual stone-amino ester was washed with DMF (0.2 mL). then

Page 178 1247008 V. Description of the invention (172) N-methylhexahydropyridine (22 ml, 18 mg, 0.18 mmol) was added. The reaction mixture was slowly warmed to room temperature. After stirring at 25 ° C for 12 hours, the solvent was removed under a south vacuum to obtain a red-brown oil with a reverse phase H pl C (C1 8, concentration gradient 80/2 0 0·1% TFA/H20/ Purification of CH3CN) gave the coupled product ( 224⁄4 g) and the coupled product (47 mg) with the isobutyl-branched group in the p-bite-oxygen atom. The combined products were dissolved in MeOH (2 mL). The reaction mixture was stirred at 25 ° C overnight and trifluoroacetic acid (8 4 · 7 mL). The solvent was removed under reduced pressure and purified with EtOAc EtOAc EtOAc (EtOAc: Calcd for C21 H22 N6 07 C 12 · 2 · 1 TF A · 0 · 2 H2 0: C, 38. 58; H, 3.15; N, 10.71 Found: C, 38. 12 ; H, 3. 36 ; N, 1 0. 71 Example 43

OH

The above compound was prepared according to the procedure described in Example 4, Step 3, from the product of Example 2 2 Step 2 and the product of Example R. C21 H22 Ν6〇7[1Βγ · 1. 8TFA microanalyzer nose value: C, 37. 35; Η, 3.03; Ν, 10. 62

Page 179 l247〇〇8 V.

= Description (173) Actual value: C 37.31 3.23; N, 10.65 Example 44

OEt Step 1

OEt Step 2 # 实例 Example 17 The product of Step 3 (3.0 g, 5.77 mmol) was dissolved in isopropanol. Concentrated ammonium hydroxide (45 ml) was added to this solution in 25 ml). After 3 hours at 25 C, the solution was evaporated to dryness under reduced pressure. The crude sample was oxidized in a parr apparatus in ethanol (3A) (50 mL) at 5% platinum/carbon at 5 psi K25 for 2.5 hours. The sample was filtered and the filtrate was concentrated under reduced pressure.

:!^^^〇18,30/2〇 CH3CN/H2〇,t/^)L ^The desired product (丨.5g, yield 39%). = product of step 1 (2 mg) dissolved in methanol (2 ml), sodium bicarbonate 3 = g). The solution was stirred at 25 ° C for 30 minutes, and the resulting air was dried. The resulting sample (2°5 mg, °.43 mmol) was dissolved in 0 65^)' then the product of Example 9 Step 1 (282.8 mg, 〇·14ΐί^) was added, then triethylamine (&quot;mg , 0.97 millimolar, 〇.14 pen liters), then vaporized mercury (177 mg, 〇65 mmol) plus

Page 180 1247008

V. Description of invention (174). The solution was heated to 60 V s. The reaction mixture was cooled:: clock secret: after heating to 9 (rc 12 small one, . P then diluted with ethyl acetate (1.7 ml), red ce 11 e over; heart-forming filtrate Cai hair to dry. Coarse The sample was purified by flash chromatography to remove the unreacted starting material. This material was neutralized with 5 〇 5 〇tfa / with TFA (77 mL) and then evaporated to dryness under reduced pressure. Purification of (C1 8 ' 9 5 / 5 H2 0 / C H3 CN) afforded the desired product (6 · 8 mg). Ch2ci2 affords the desired product which is obtained as a crude product. 1N gas in sodium (2 ml). At 25t: after stirring for 12 hours, the solution

C21H23N7 06 C12 · 3. Microanalytical calculation of 3TFA: C, 36· 17; H, 2· 89; N, 1〇· 70 Found: C, 36.57; H, 3.21; H, 10.37

Page 181 1247008

Page 182 1247008 V. INSTRUCTIONS (176) Methyl iodide (1 · 49 g, 1 0 · 5 mmol) was added to the compound. The reaction mixture was stirred at room temperature for EtOAc (EtOAc) (EtOAc). The organic layer was dried (MgSO.sub.4). 4 NMR was consistent with the structure shown. ^^2 : Add N to the solution of the product of step 1 (5.0 g, 32.0 mmol), benzoyl peroxide (0. 8 g), and carbon tetrachloride (20 ml). A mixture of -bromosuccinimide (6.3 g, 35.3 mmol), diphenylguanidino peroxide (〇·8 8 g) and tetra-carbonated carbon (20 ml) was refluxed for 30 minutes. The resulting reaction mixture was heated at reflux for 18 hours. The solid was filtered and washed with carbon tetrachloride (2×10 mL). The filtrate was concentrated to give a mixture of oil and solid (8.1 g, yield 80%). : a mixture of less than 2 (8.1 g '34.7 house Moules), sodium azide (5.6 g, 87 mmol), and a mixture of N,N-dimethylformamide (25 ml) at 58 Mouth heat 2 · 5 hours. The reaction mixture was diluted with ethyl acetate (8 mL) and washed (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried (MgSCU, concentrated to give a pale brown oil (yield: 85%). 4 NMR was consistent with the structure shown. The product of less 3 (6.0 g, 25.9 mmol), A solution of EtOAc (2 mL, EtOAc)

1247008

V. INSTRUCTIONS (177) The layers were dried over Na 〇 S 〇 4 and concentrated to give a yellow oil. A yellow solid (2.0 g, yield 42%) was obtained in vacuo. 1H_NMR was consistent with the structure shown. Step 5 · One step &amp; 4 product (〇·5 g, 2.7 mmol), Mo 醯 gas (2M in di-methane methane '2^7 ml, 5.4 mmol), and dichloromethane ( Mix 20 ml) at room temperature for 2 · 5 hours. The solvent was removed from the reaction mixture to give a brown oil (0. 51 g, yield: 85%). 4 NMR and the structure shown—° Step 6:

Example G product (〇·91 g, 2.43 mmol), diisopropylethylamine (0.63 g, 4.86 mmol), and hydrazine, hydrazine-dimercaptoacetamide (2 〇 ml) The solution was added to the mixture of the product of step 5 (0.46 g, 2.43 mmol) and THF (1 liter) in the Q. The reaction mixture was stirred for 丨〇 for a few minutes and heated to room temperature. After 16 hours, the solvent was removed from the reaction mixture under vacuum. The product was extracted with ethyl acetate (300 mL). The organic solution was washed with a saturated NaHC03 solution (1 mL), EtOAc (1 mL). The crude product was purified by column chromatography (on silica gel, CH 2 Cl 2 /Me 〇H/NH 4 〇H, 98/2 / 〇 2) to obtain a transparent product.

The colloidal solid (0.7 g, yield 58%) NMR was consistent with the structure shown. Step 7: The product of step 6 (〇·78 g, 1 56 ginseng, r

A mixture of 5% Pt/C, and EtOH is used to hold 9 η ί 士 ^ u at room temperature at 5 p s i for 20 hours. Catalyst filtration. The filtrate was treated with trifluoroacetic acid (0.6 mL), and the crude material was obtained from </ br>. The crude product was purified by Η P L C and was given as a “n d 士

Also Baco 4 g, yield 54%) NMR

Page 184 1247008 V. Description of invention (178) Consistent with the structure shown. Step 8: Mercury chloride (II) (〇·1 1 g, 1·87 mmol) was added to the product of Step 7 (〇·55 g, ι·25 mmol), the product of Step 1 of Example 9 (0) · 8] ί, 1.87 mmol, triethylamine (0·38 g, 3.75 mmol), and a mixture of hydrazine, hydrazine-dimercaptocaramine (15 ml) at room temperature . The reaction mixture was at 9 5 - 1 〇 〇. Heat the crucible for 6 hours. The cooled reaction mixture was filtered through a pad of EtOAc (2) and washed with ethyl acetate. The solvent is removed from the filtrate under vacuum to obtain

= ° This oil was diluted with CH2C12 / trifluoroacetic acid (10 ml / 10 ml) and allowed to stand for 1 hour in the chamber. The solid formed was collected by filtration. The filtrate was concentrated and treated with 2^/2/tris acetic acid (15 mL / 15 mL) for 1.5 hours. The solvent is falling and its =, a brown oil is obtained. This oil was purified by HpLc to obtain a desired solid (a mixture of 〇酉曰L. The compound was recrystallized from acetonitrile to give a white yield of 0.45 g). Brewed product #Na0H/ethanol (7. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 23 5〇6Cl2S · 2· 计算 Calculated value of CF3C00H: measured value C, 38· 87; H, 3·26; N, 9· 07 C, 38· 78; H, 3· 6; N, 9· 16

Page 185 1247008 V. Description of invention (179) Example 46

Page 186 1247008 V. Invention Description (180) &quot;&quot;&quot;&quot;&quot; —~ Step 1: Add benzhydryl isothiocyanate (3.34 g, 21.3 mmol), step ^1 The product (3.5 mM '20·8 mmol) and N,N-dimethylhydrazine &amp;amine (45 liter) were solution at room temperature. The reaction mixture was stirred for 2 hours in ether (300 mL). The resulting mixture was stirred for 15 minutes. The product was washed with scaly (2 X 40 mL), air dried, 3 廿 a (7) „1° heart was yellow solid (6.95 collected 'stained with scales (2×40 ml), air dried, gram yield 100%). 1}{ NMR was consistent with the structure shown. Step 2 I alcohol (2.64 g '48.9 mmol) was added in small portions at room temperature = (6.90 g, 20.8 mmol) and methanol (2 mL) When the suspension is completed, the reaction mixture is stirred for "hours." Acetic acid (2 agglomerated in the reaction mixture. The resulting mixture was stirred and the product was collected by hydrazine in methanol (2 χ 3 〇 ml) washed in the reduced account; the second J was obtained as an off-white solid (3.8 g 'yield 81%) 1 _ and steps 3 25.1 Ϊ 2 Mo's ear 1 (\90 g 丄 8.4 mmol), methyl hard (3.66 g, when, cold work and methanol (60 ml) mixture is heated at reflux 3. 5 small color oil :: Residual Ϊ. = Moved from the reaction solution under reduced pressure to obtain yellow (3' yield UmPH is consistent with the structure shown / color mouth (0. 12 ml ear; · 36 millimoles)' 2 _曱-oxyethylamine. 36 moles of molybdenum) and N,N-dimercaptoacetamide (5〇ml)

L247〇〇8 l The solution of the invention (181) was heated at 85 ° C for 2.5 hours. 2-Methoxyethylamine (012 ml, 1.36 house mole) was added. The reaction mixture was heated at 85 C for 2 hours. N,N-dimethylacetamide was removed from the cooled reaction mixture under reduced pressure to give a crude material. The crude product was purified by reverse phase HPLC to give the desired product (yield: 38 g, yield 76%). Step 5

A solution of the product from Step 1 (0.38 g, 1.42 mmol), EtOAc (1 N, 15 mL), MeOH (15 mL) . The solvent was removed from the reaction solution under reduced pressure to give a crude product. The crude product was purified by EtOAc (EtOAc) NMR was consistent with the structure shown.

N-Mercaptomorpholine (0.1 mL, 1.42 mmol) was added to the product from Step 5 (〇··········· Dissolve in the night. Isobutyl chloroformate (〇·18 g, 丨·35 mmol) was added to the reaction mixture at -5 °C for 5 minutes and stirred for 15 minutes. The product of Example g (0.396 g '1.07 mmol) and N-Mercaptomorpholine (〇〇75 mL, 1〇7)

A solution of millimolar) and N,N-dimercaptoacetamide (1 ml) was added to the reaction mixture. The resulting reaction solution was heated to room temperature and stirred for 6 hours. The solvent was removed from the reaction solution under reduced pressure to give a crude product. The crude product was purified with H.sub.3HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1 Η N M R is consistent with the structure shown.

Page 188 1247008 V. Inventive Note (182) 25 ml), and a solution of Me0H (25 ml) was stirred for 16 hours. The solvent was removed from the reaction mixture under reduced pressure to give a crude material. The crude product was purified with EtOAc EtOAc (EtOAc) Calculated for C21H24N6 07 C12 .2CF3COOH: C, 38· 93; H, 3.40; N, 10. 89 Found: C, 39. 29; H,3· 47; N, 11. 15

Page 189 1247008

Page 190 1247008 V. Description of invention (184)

To room temperature. The solid formed overnight. The product was collected by EtOAc (EtOAc) (EtOAc) 4-NMR was consistent with the structure shown. Step 2: The product of the ancient step i ( 〇·························· The solvent was removed = removed from the reaction mixture to give a crude product. The crude product was worked up in EtOAc (EtOAc) elute elute Wang 曰 color solid step g : (λ- : ίη14 g '1,41 mmol) in n, n- dimethyl ethylamine · ^ 升 ^ 中之洛液 added to the product of step 2 (0. % grams , 〇η毫莫N, _—虱—4' 6-dimethoxy three tillage (〇. 18 g, 1. 03 mmol) and, Ν'N _methylacetic acid amine hexahydrate, color solution plus敎到室卜β = in the bath of ±. Generated freshly dialed 0 94 * / stirred for 3 hours. The product of Example G (〇. 3 50 g, the solution is given at room temperature: (over; liter) The mash was added to the reaction solution, and the resulting solution was treated with anti-bank and liquid solution of acetic acid (1.0 ml) under reduced pressure. The solvent was purified to obtain crude crude product. The crude product was purified by HPLC. One of the desired products (〇·35 g, yield 54%). The product from Step 3 (0.33 g house liters), and MeOH (9 mL) at <RTIgt; , Na〇H solution (1Ν, 9; gluten solution: mix for 18 hours. The reaction mixture is rational. The solvent is transferred from the reaction solution under reduced pressure to 1247008. 5. Inventive description (185), the crude product is obtained. Purified by HPLC to obtain the desired compound as a pale yellow solid (0. 285 g, yield 84%) C23H26N6 06 C12 · 1 · 25CF3COOH · 1.· OH20 Calculated: C, 42. 90; Η, 4.13; Ν, 11. 77 Found: C, 43 03; Η, 4· 03; Ν, 11.26 Example 48 ο cVr^〇aOCH3 φ The above compound was synthesized using the method described in Example 47. In step 1, ethylenediamine was used instead of 2,2-difluorenyl. -1,3-Diaminopropanediamine. In step 3, the product of Example U was used instead of the product of Example G.

Page 192 1247008 V. Description of invention (186) C20H2〇N6O6Cl2 · 1 · 25CF3C00H · 0· 5H20 Calculated value C, 40.77; Η, 3.38; Ν, 12. 68 Measured value: C, 4 0 · 9 8 ; ,3 · 1 7 ; Ν, 1 2 · 5 7

Example X 5 - Preparation of bromo-3 -iodohydroxanal

CHO

ΟΗ I

Br

Chem The above compounds were prepared from 5-bromo-hydrazone: iodide as described in the literature (J. 0 r g. 1 99 0, 55, 5 287-5291). Example Y&amp;Z Figure A1 h2n

苯 Benzyl thiol isothiocyanate acetonitrile, reflux for 16 hours

〇 〇 S

ΟΗ

i NaOMe, MeOH R, 2.5 h 2. Mcl, CH3COOH HN

OH DMF, 90 QC R2 3 -4b Z window Ri = R2 = CH3 Y - R, = H, R2 - 〇H

Page 193 1247008 V. Description of invention (187) Step 1 Preparation of the following formula

5-aminonicotinic acid (10.0 g, 0.072 mol), phenylhydrazine isothiocyanate (11.8 g, 0.072 mol), and DMAP (catalytic amount) in anhydrous acetonitrile (250 ml) The mixture was heated to reflux overnight under anhydrous conditions and stirred vigorously (Figure A1). The resulting yellow suspension was cooled and filtered. The residue was washed with EtOAc (EtOAc)EtOAc. MS and 1H-NMR were consistent with the desired structure. Step 2 Preparation of the following formula

NaOMe (25% by weight solution in decyl alcohol, 2 1. 1 mL, 0. 0 9 2) was added to a suspension of the product from step 1 (11.1 g, 0.03 7 mol) in anhydrous MeOH (230 mL). Moore), at which point the reactants entered the solution to obtain an orange-brown solution (Figure A1). This solution was stirred at room temperature for 3 hours, cooled in an ice bath, and thiol iodine (3 · 4 5 mL, 0. 5 5 m) was added. Generated mix

Page 194 1247008 V. INSTRUCTIONS (188) The material was stirred at 10 C for 30 minutes and at room temperature for 5 hours. The reaction mixture was then quenched with EtOAc (2 mL). The solid was dried with EtOAc (EtOAc)EtOAc. MS and 1 H-NMR were combined with the desired structure. Step 3 Preparation of Example Y&amp;Z The product of Step 2 was added to a solution of 1,3 -diamino-2-hydroxypropane (11.2 g, 〇124 mol) in anhydrous DMF (80 liter). 8·7 grams, 〇·〇41 Moer). The mixture was heated at 85 ° C for 3 hours under anhydrous conditions (Figure Α丨). After heating for 1-2 hours, the solution became cloudy and the turbidity increased during heating. The reaction mixture was then cooled in an ice bath and filtered. The solid was washed with EtOAc (EtOAc)EtOAc (EtOAc) MS and 1H-NMR were consistent with the desired structure. Example Z was synthesized by the procedure described in Example Y using 4 equivalents of 2,2-dimethyl-1,3-propanediamine in place of 1,3 -diamino-2-hydroxypropane. The product of step 3 is converted to a solution of 1 hr of anhydrous THF (10 ml for 1. gram of base) and Ί7 Α (1 eq.) or 4N HCl / dioxane (2 eq.) for 1 hour. Its TFA or HCl salt.

Page 195 l247〇〇8 rr—- Example 49 Description of the Invention (189) Preparation of the following formula

Figure A2

Rj- R2 β

In the example Υ (0.40 g, 0.0 0 1 25 mol, Fig. 2), isobutyl chloroformic acid was added to the suspension of -20 c in anhydrous DMF (1 liter), (0), 0 0 0 1 2 5 m), then add n-methylmorpholine (〇·丄4 g, dropwise,

〇 · 〇 〇 1 3 7 Moh). After the mixture was stirred at _ 2 Torr for 5 minutes under argon pressure, Ν-methylmorpholine (〇·14 g, 〇·〇〇137 mol) was further added, and the product of the iron II example G (0·46) Gram, 0·0 0 1 2 5 Moer) to join. Generate ... 'stupid people Stir at -20 ° C for 15 minutes, then stir at room temperature for 2 hours. Dj^ was distilled in a straight line, and the residue was purified by reverse-phase HPLC (after lyophilization): </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; &amp;

Page 196 1247008 V. INSTRUCTIONS (190) MS and ih-NMR are consistent with the desired structure. This ester (0.2 g) was stirred with 1M LiOH (2 mL) at room temperature for 1 hour. The pH was adjusted to 2 with trifluoroacetic acid, and the product was purified by reverse phase HPLC (after lyophilization) to give the desired acid as a white solid (1·1 g). M S and 1 Η - Μ M R is consistent with the desired structure. Example 5 0 Preparation of the following formula

The above compound was prepared by substituting Example G with an equivalent amount of the procedure described in Example 49 (Fig. 2). MS and 1 H-NMR were consistent with the desired structure. This solution (0.19 g of '0.00023 mol) was stirred with 1 M Li〇H (2 mL) at room temperature for 1 hour. The pH was adjusted to 2 with trifluoroacetic acid, and the product was purified by reverse phase hplc (yield after ice/east drying) to give the desired acid as a white solid (1·3 g, yield 72%). MS and 1 H-NMR were consistent with the desired structure.

Page 197 1247008 Example 5 1 V. Description of invention (191) Preparation of the following formula

Figure B

HO ^NH2 h2 2-ONSu, NMM RT, 16 h CH2C12

liQ

^NM-Z

DMSO/EDC trifluoroacetate pyridinium

HO

.ON pTSA di-ethane, DMSO 80 ° C, 24 h o , NH-2 .^Nh-2 H〇 Pd/C (5%) £e〇H, ElOAc 16 h, 50 psj

Nm2

90 °CV 3 h Step 1 Preparation of bis-N-benzoyloxycarbonyl-2-hydroxy-1,3-diaminopropane ^NH-2

HO contains N-methylmorpholine (14 ml) in 2 - mercapto-1,3-diaminopropane (5.8 g, 0.064 mol) in dioxane (150 ml) at 10 °C Suspension

Page 198 !247〇〇8 V. INSTRUCTIONS (192) Phenyloxycarbonyl amber succinimide (32 g, 〇·129 mol) was added portionwise to the solution (Fig. B). The reaction mixture was stirred at room temperature for 16 hours, and a clear solution was obtained, which was diluted with dichlorohydrin (100 ml), successively washed with 1% citric acid (2 x liters), washed with water and dried (N S Ο*). After filtration, the solvent was removed under reduced pressure. &lt;RTI ID=0.0&gt;&gt; NMR and MS are consistent with the structure. Preparation of bis-N-benzyloxycarbonyl-1,3-diaminoprop-2-one

.NH-Z

Add the product of step 1 (21·〇克, 0.0 5 8 mol) and EDC (33.0 g) in dichlorohydrazine (120 ml) containing DMS0 (24.0 ml) in a suspension. A solution of difluoroacetic acid (33.0 g) in dichloromethane (50 ml) was stirred for 30 minutes at 1 °C. After the addition, a clear yellow solution was obtained. After stirring at room temperature for 3 hours, a white solid was separated from the reaction mixture. It was cooled&apos; filtered and the solid was washed with cold dioxane and water. The white solid obtained was dried under vacuum in a desiccator to give the desired product (15. 5 g, yield 74%). NMR and MS are consistent with the structure. Preparation of the following formula

Page 199 1247008 V. INSTRUCTIONS (193) The product of step 2 (2·5 g, 〇·〇〇7 Mo), to ~A## 克, 0·0016 mol), and DMSO (1·0 ML) in a mixture of dioxo-xanthate (0.3 liters) containing ethylene glycol (2.0 ml) in a dry atmosphere in an anhydrous gas (25 4 reflux (Fig. 。). After 24 hours, the reaction mixture is cooled, '',, under the conditions of heating to (25 ml) diluted, successively with 1% sodium bicarbonate, washed with water, with methylene chloride (NS〇4). After the solvent was removed under reduced pressure, residual, tracane Crystallization, obtaining the desired compound (2.5 g, yield - methyl chloride / hexane MS consistent with structure. Sheep δ9 / 〇. 4-NMR and step 4 Step 3 product (3. 〇克, 〇.〇 〇75 mole) soluble in ethanol 〇

+ ' ^5〇 P^^pd/C Divide, with 4 η Γ at the next *hydrogenation for 6 hours (Figure β). The catalyst was washed with 40% water in ethanol (5 〇 ml), and the liquid and water washing liquid were concentrated under reduced pressure. 妒 妒 曰 曰 曰 干 干 干 干 干 干 干 干 干 干 干. This material was dissolved in .7 liter), the product of Step 2 of Example 1 (1.0 g, 0.0 047 mol of material in: 〇. "Amine (〇. 7 ml) and DMAP (〇.05 g) were added. Mixing _ Heated under anhydrous conditions. After 3 hours, DMF was dried in vacuo, taken in water, washed with acetonitrile and dried in a dry apparatus to give Example 5 (0.4 g, 30%) as powder. This step is purified and used in step B. 丨H-NMR and MS and structure--

1247008 V. INSTRUCTIONS (194) Injury of the following formula Example 5 2 d Ο H C〇〇H 2.TFA 〇, Br Figure c -OEt cP^ C1H.H2N&quot; Ο cr

-OH 1 isobutyl chloroformate NMM, DMF, -15 °C-RT3 b 2. IM UOH, HC1 2.TFA C, COOh, 曰r Example 5 1 扑 匕 (5 〇 匕 匕 ( 〇·38 g, 0·0014 mol) suspended in anhydrous THF under the condition of 'trifluoroacetic acid (〇·1 ml) added at 10 ° C in the anhydrous bar in the true two. C). After 30 minutes, the THF was distilled under reduced pressure, and the residue was dried and dried over three hours. The resulting material was dissolved in anhydrous DMF (4.0 ml) de N-methyl. 1 5 C , isobutyl hydroxyacetic acid vinegar (〇 · 18 ml) was added to the uranium (0·17 ml). The solution was stirred under argon atmosphere for 3 Torr. The mixture was added with hydrazine monomethylmorpholine (〇·17 ml) in the example R • in DMF (3.0 ml) in a solution at 0 °C. The dissolution of amines. The resulting mixture was stirred at -15 ° C for 30 minutes, then in the chamber and then the solvent was removed by evaporation in a vacuum, and the substrate was purified by /1〇~9〇% acetonitrile/water concentration gradient (4〇 minutes). At a flow rate of μ ml / min. 1247008 V. Description of the invention (195) The solvate is combined and lyophilized to obtain the desired ester (0.4 g) as a fluffy white powder. This material was stirred at room temperature with lithium hydroxide (1 Torr, 2.0 mL). After 45 minutes, the reaction mixture was cooled, diluted with water, acidified with trifluoroacetic acid, and the desired acid (0.25 g) was separated by reverse phase HPLC using 10-90% acetonitrile / water, as described above. 1 Η - N M R and M S are consistent with the structure. Example 5 3 Preparation of the following formula

Ui 〇

OH

Figure D

DAST, pyridine CHnCU -50, C: RT 16h

EtOH, EtOAc 16 h, 50 psi H2 Pd/C (10%)

DMF, 90 C, 3 h 2 = benzoquinoneoxycarbonyl

OH

Step 1 Preparation of bis-N-benzyloxypropionyl-2-fluoro-1,3-diaminopropane

NH-Z

A^NM-Z

Page 202 1247008 V. INSTRUCTIONS (196) In bis-N-benzyloxycarbonyl-2-hydroxy-1,3-diaminopropanone (6 g, 0.017 mol) in dioxane (5 〇 ml) and pyridine (2.7 ml) were added dropwise in a stirred suspension at -5 ° C. Add dAST (2.5 ml) to a solution of dioxane (7.53⁄4 liters 'Figure D) . The reaction mixture was gradually heated to room temperature under air pressure for 16 hours. A clear yellow solution was obtained. The solution was cooled and poured into a mixture of ice water (100 mL) and dioxane (5 mL). The organic phase was washed with water (2 X 50 ml) and dried (Na2 S04). After solvent removal, the residue was purified by flash chromatography using EtOAc EtOAc EtOAc. The appropriate fractions are combined and concentrated to dryness. The product is crystallised from methylene chloride/hexane to give the desired fluoro intermediate as a white fluffy powder (2 gram). iH-NMR and MS were consistent with the structure. The bis-N-benzofluorenyloxycarbonyl-2-fluoro-1,3-diaminopropanone (3.3 g of 〇·〇〇92 mol) obtained in Step 1 in EtOAc (30 mL) and EtOH The solution in (30 ml) was hydrogenated at room temperature for 5 hours at 5 psi in the presence of pd/c (1 g/g, 2.7 g) (panel D). After filtration, the catalyst was stirred with EtOH (50 mL) containing 40% water and filtered. The filtrate was concentrated to dryness to give a syrup (yield: 7 g). The slurry was suspended in DMF (8 ml). The product of Step 2 of Example 1 (0.7 g, 0.0 033 mol), a catalytic amount of DMAP (0.01 g) was added and heated at 90 ° C for 3 hours under anhydrous conditions. The dmF was distilled in vacuo and the residue was suspended in water (25 mL) and pH was adjusted to &lt; The resulting mixture is cooled. The separated solid was filtered, washed with water, acetonitrile and dried in vacuo to give the desired compound as a brown powder (0·24 g) q1H-NMR and MS.

Page 203 1247008 V. Description of invention (197) Preparation of the following formula

COOH OH

HE

NMM. DMF, -15 °C - RT 3 h 2. IM LiOH, HC1

The compound of Example 53 (〇·22 g) obtained above was suspended in anhydrous THF (4.0 mL). Trifluoroacetic acid (0.1 ml) was added, and the solution was stirred at 1 (TC for 30 min, concentrated under reduced pressure. The residue was dried in vacuo to dryness in vacuo. Add isobutyl chloroformamide _ (0 · 12 ml), then add N-methylmorpholine (〇·1 1 ml). Stir the solution at -15 °C under argon pressure (Figure e) After 30 minutes, a solution of the amine produced in the solution of the product of Example r (〇· 37 g) in DMF (3.0 mL) was added from N-methyl morpholine (0.95 mL). The resulting mixture was stirred at ~15 ° C for 30 minutes and stirred at room temperature for 1 β hours. The residue was subjected to distillation in vacuo, and the residue was purified by reverse phase HPLC using 1 〇-90% acetonitrile/water. The fractions were combined and lyophilized to obtain the desired ester product as a pale yellow powder. 1247008 V. Inventive Note (198) End (0·35 g) ^H-NMR and MS were consistent with the structure. Product (0.3 g, Figure E) Stirred with 1 M LiOH (3.0 mL) at room temperature. After 1 hour, the solution was diluted with water, (3.0 mL), cooled and acidified with trifluoroacetic acid. The mixture was purified by reverse phase HPLC using 10 0-90% acetonitrile/water (30 min 4 Hz gradient) at a flow rate of 7 〇 ml/min. The suitable fractions were combined and lyophilized to give the desired compound. White powder (0.22 g). 1-NMR and MS were consistent with structure. Example 33 Preparation of the formula

Figure F

Page 205 1247008

Preparation of the following formula

HO

OH in 1,4 -diamino-2,3-dihydroxybutane dihydrochloride [2.21 g, 0.012 mol] [synthesized from l-dioxalate tartrate, such as j· Carbohydrate

Sodium carbonate (1.83 g, 0 · 0 1 7 mol) was added to a solution of water (6 ml) and anhydrous DM F (10 ml) in Chemistry, 5, (2), 183 - 197, 1986. . To the mixture was added the product of Step 2 of Example 1 (1 · 2 1 g &lt;RTIgt;&lt;/RTI&gt; After cooling in an ice bath, 'D M F was steamed in a vacuum, and the resulting residue was suspended in water. ρ η is adjusted to 5 · 6. The solution was lyophilized to obtain the desired product (〇 · 9 〇 7 g, yield 59%). The MS is consistent with the desired structure (Μ + Η 26 7 ). The compound obtained was converted to its salt by stirring with 4 Ν HC 1 / dioxin (2 eq.) in THF (10 mL) at 10 t: 1 hour.

Step 2: Add the isobutyl chloroantimonate in the suspension of the product of step 1 (〇 11 g, 〇〇〇〇 23 mol) in anhydrous (1 mL) in -2 0 t: 〇16 g, 0 · 0 0 0 1 2 mol), then add N-methylmorpholine (〇· 〇i 3 g, 0 · 0 0 0 1 3 Mo, Figure F) dropwise. After the mixture was stirred under argon pressure at -2 Torr for 20 minutes, N-hydrazinyl phthalocyanine (〇·013g, 〇·〇〇〇13mol) was added.

Page 206 1247008 V. INSTRUCTIONS (200) The product of the latter example R (〇·048 g, 0·0 0 1 2 mol) was added. The resulting mixture was mixed at -20 C for 15 minutes. After 2 hours of stirring at room temperature, j) MF was distilled in vacuo, and the residue was purified by reverse phase HPLC (after cold drying) to give the desired compound as a white solid (0.03 g, yield 33%) ). MS (M + H 627 M + H 629 ) and 1H-NMR were consistent with the desired structure. lH-NMR (400MHz, Cd3Od): (58.8 (s, 1H), (58 5 (s 1H), 8. 1 (s, 1H), 7. 4 (s, 1H), 7. 2 (s, 1H) ), 5. 6 (m, 1H), 4.1 (m, 4H), 3.7 (m, 2H), 3.6 (m, 2H),

3.3 (m, 2H), 2.9 (m, 2H), 1,2 (m, 3H) The resulting ester (0.03 g, 0.000035 mol) was stirred with 1M u〇H (2 mL). After stirring at room temperature for 1 hour, the pH was adjusted to 2 with trifluoroacetic acid, and the product was separated by reverse phase HPLC (after lyophilization) to give the desired acid as a white solid (0. 001 g, yield 3-5. ). MS (M + H 5 9 9 M + H 601) and iH-NMR with the desired structure. 8· 5 (s, IH), 5.6 (m, 2H), UMR (40 0MHz, CD3OD): 58·8 (s, 1H), 1H), 8.0 (s, 1H), 7.4 (s, ih), 7.2 (s, (m, 1H), 4·1 (m, 2H), 3·8 (m, 2H), 3·5 3.3 (m, 2H), 2.8 (m, 2H)

Page 207 1247008

Page 208 1247008 V. Preparation of the invention (202) 1 1 0,7 5 3 8 ). figure 2

CH3CN, reflux 16h

McOH S.TMS-C1. TMS-hN^

TMSO

^-Nh-TMS CII2Cl2-McOHCl〇%) RT, 24 h

O &gt;-NH2 wide

DMF, y〇 °c 3 -4h

Reflux, 16h 2 HCi HQ

The monoalkylated intermediate is synthesized by hydrazide, decanelation, and N-desmethylation. This monoalkylene derivative is reduced with diborane to obtain the corresponding diamine dihydrochloride. The free diamine is then condensed with a 5-amino nicotinic acid derivative of S-hydrazinoisothiourea to give the corresponding 7-membered hydrazine derivative. This hydrazine is reacted with glycine-/3-amino acid-ester, then hydrolyzed and acidified to obtain the final compound. Example 5 8 A 2-alkyl/diol substituted 7-membered cyclic oxime compound was prepared according to the reaction shown in the following scheme. Starting with a known diamine protected by a benzomethoxycarbonyl group (J.

Med. Chem. 1 9 96,3 9,2156), the corresponding 7-membered cyclic lanthanide is reacted with a free diamine precursor and a 5-amino nicotinic acid derivative of S-mercaptoisothiourea.

Page 209 1247008 V. Invention description (203) and synthesis. The resulting vein-remediation is condensed with glycine-/3-amino acid-vinegar, then hydrolyzed and acidified to obtain the final desired compound. image 3

2-MN

HO

NH-Z H2Pd/C (10%) EtOH

2 lMU〇H, HCl Bu\! Mine DMF, 90 ϋΟ 3-4h

R-CII^. CIi2〇H.CH2Ph, ..CF3. or alkyl Example 5 9 The dihydroxy compound is prepared by acid-catalyzed cleavage of a cyclic ketal precursor as shown in the following figure. 〇

COOH

COOh concentrated HC1

I R Butane Halogen Example 60 A compound containing a 7-membered diol-substituted cyclic oxime is prepared starting from D or an endo-tartaric acid ester derivative as shown in Figure F.

Page 210 1247008 V. INSTRUCTIONS (204) The activity of the compounds of the invention is tested by the following analysis. The results of the tests in the analysis are not in Table 1. The cellophane attachment analysis material human vitectin receptor (αν /33) is purified from human placenta, as described above [Pytela et al. Methods in Enzymo1ogy, 1 44: 475-489 (1 987)] . Human cyclamate is purified from fresh frozen plasma as previously described [Yat〇hg〇 et a 1 ·, Cell Structure and Function, 13:281-292 (1988)]. The biotinylated human cyclamate is prepared by coupling NHS-biotin of Pierce Chemical Company (Rockford IL) to carotenoids as previously described [Charo et al., h Biol. Chem., 2 6 6 ( 3 ) , 1 4 1 5 - 1 4 2 1 ( 1 9 9 1 )]. Analytical buffer, 〇PD matrix ingot, and RIA grade BSA were obtained from Sigma (St. Louis, MO). The avidin resistant system was obtained from Calbiochem (La Jolla, CA). Linbro microtiter plates were obtained from Flow Labs (McLean, VA). The ADP reagent was obtained from Sigma (St. Louis, MO). Method Solid phase receptor analysis This analysis is essentially identical to the previous reporter [Niiya et al., -BV〇〇d, 70: 475 -483 (1 9 87 )]. The purified human chlorophyll receptor (αν/33) contains 1.0 mM Ca++ from the raw material solution in Tris buffered saline.

Mg++, and Mn++, ΡΗ 7· 4 (TBS+++) are diluted to 1·〇 microgram/ml. The diluted receptor was immediately transferred to a Linbro microtiter plate at 1 〇〇 microliter/well (1 (10) nanograms of receptor per well). Plate sealed and incubated overnight at 4 °c to allow receptor binding

Page 211 1247008 V. Description of the invention (205) Inoue. All other steps are at room temperature. The assay plate was emptied, 2 〇〇 microliters 1% RIA grade BSA was added in TBS+” (TBS+++/BSA) to block exposure to the plastic surface. After 2 hours of incubation, the assay plate was washed with TBS+++ using a 96 well plate washer The logarithmic serial dilutions of the test compound and the control were started with the concentration of the raw material 2 and using 2 nM biotinylated botanin as a diluent in tbs+++/bsa. The labeled ligand was premixed with the test (or control) ligand. And then 5 〇 microliters were transferred into the analytical plate with the CETUS Propet te robot; the final concentration of the labeled ligand was 1 nM, and the highest concentration of the test compound was 丨.〇χ 1 0_4 Μ. Competition took place for 2 hours' then Each well was washed with a plate washer as described above. Affinity-purified horseradish peroxidase-labeled goat anti-biotin antibody was diluted 1:3 in TBS+++/BSA, and 125 μl was added to each well. After 4 minutes, 'wash plate' and 0 PD / Η2 02 substrate were incubated in 1 〇〇m Μ / liter of citrate buffer, pH 5. 0. The plate was read by a microtiter plate reader at a wavelength of 45 〇 nm. Take the record when the maximum combined control well reaches about 1 · 〇 absorption The data was analyzed using the uppercase of the EXCELj spreadsheet program. The average concentration, standard deviation, &amp;% CV of the two groups were determined. The average value was for the four largest binding controls (not included in the competition). The average normalization of (B-MAX). The normalized value is calculated for four parameter curves [Rodbard et al., Energy Agency Vienna, PP 46 9 (1 977 )], plotted on a semi-log scale, for The most tested concentration showed a compound greater than 5 q % inhibition, reported to inhibit the calculated concentration of 50% biotinylated cytochrome maximal binding (1 (^) and corresponding R2; otherwise, IQ was reported to be greater than the highest concentration tested. Cold —[[ 2 — [ [ 5 _ [(Aminoiminoindolyl)amino]-1-methoxypentyl]amino]-1-oxy

Page 212 1247008 V. INSTRUCTIONS (206) Amino]-3-pyridylpropionic acid [USSN 0 8/3 7 5,3 3 8, Example 1] is a potent antagonist (IC5G at 3-10 πΜ) Within the range), included on each plate as a positive control. Purified II b / III a receptor assay material Human fibrinogen receptor (α v々3 ) from the old (ou t da t ed) platelet system 屯 4 匕 (Pytela, R, P i er schbacher, MD, Argr a ves, S. , Suzuki, S. , and Rous 1 aht i, E. &quot;Arginine-Glycine-Aspartic acid adhesion receptors", Methods in Enz ymo 1 ogy 144 (1987): 475-489). Human glass The melamine is purified from fresh cold; East plasma, such as Y atohg ο, T., I zumi, Μ.,

Kashi wag i, H. , and Hayash i, M. , M Novel purification of vitronectin from human plasma by hepairn affinity chromatography, &quot; Cell Structure and Function 13 (1988): 281-292. Biotinylated human cyclamate was prepared by coupling NHS-Biotin from Pierce Chemical Company (Rockford, IL) to purified carotenoids as previously described (Charo, IF, Nannizzi, L., Phillips, DR, Hsu, M·A·, Scarborough, RM, &quot;Inhibition of fibrinogen binding to GP Ilb/IIIa by a GP Ilia peptide&quot;, J. Bio. Chem., 266(3) (1991), 1415-1421). Analytical buffer, 〇PD matrix ingot, and RIA grade BSA were obtained from Sigma (St. Louis, M0). The avidin-resistant system was obtained from Calbiochem (La Jolla, CA) from the QLinbro microtiter plate line.

Page 213 1247008 V. Description of invention (207)

Flow Labs (McLean, VA). The ADP reagent was obtained from Sigma (St. Lou is, MO) ° Method Solid Phase Receptor Analysis This analysis is essentially identical to Niiya, K, Hodson, E., Bader, R, Byers-Ward, V Koziol, J·A ·, Plow, Ε·F· and Ruggeri, ZM , &quot; Increased surface expression of the membrane glycoprotein Ilb/IIIa complex induced

By platelet activation: Relationships to the binding of fibrinogen and platelet aggregation&quot;, Blood, 7 0 (1 9 8 7 ) : 4 7 5 - 4 8 3 as reported. The purified human fibrinogen receptor (αν /53) is diluted from the raw material solution into Tris buffered saline containing 1. mM mM Ca++, Mg++, and Mn++, pH 7·4 (TBS&quot;+) to 1 · 〇μg/ml . The diluted receptor was immediately transferred to a Li nbro microtiter plate at 1 〇〇 microliter/well (100 ng acceptor/well). The plates were sealed and incubated overnight at 4 °C to allow the receptor to bind to the well. All other steps are at room temperature. The analysis plate was emptied, 200 μl of 1% RIA grade BSA was added in TBS+++ (TBS++VBSA) to block exposure to the plastic surface. After 2 hours of incubation, the assay plates were washed with TBS+++ using a 96 well plate washer. The logarithmic serial dilutions of the test compounds and controls were started at a stock concentration of 2 mM and using 2 nM biotinylated celloside as a diluent in TBS +++/BSA. Pre-mixing the labeled ligand with the test (or control) ligand and then moving 50 μl into the assay plate with the CETUSP r 〇pe 11 e robot; the final concentration of the labeled ligand is 1 η Μ, test The highest concentration of the compound is 1 · 0 X 1 0_4 Μ. The competition took place for 2 hours, then the wells were washed with a plate washer.

1247008 V. Description of invention (208) as above. Affinity-purified horseradish peroxidase-labeled goat anti-biotin antibody was diluted 1:3 in D.6^/^3, and 125 μl was added to each well. After 30 minutes, the plates were washed and incubated with QDD/H2〇2 matrix in 1 mM liter/liter of citrate buffer, p Η 5 · 0. The plate was taken at a wavelength of 45 〇 nm by a microtiter plate reader. When Yuan Da combined with the control well reached about 1. 〇 absorption, the record was finally analyzed. The data is capitalized using the EXCELJ extended program analysis. The average of the two groups of concentrations, the standard deviation, and the % (^. average value for the average of the four largest binding controls (not added to the competitor) (β - ΜΑχ) are normalized. The normalized value is suitable for the calculation of four parameter curves. [R〇bard et a1·,~Atomic Energy Agency Viann^, pp 469 (1 9 77 )]' is plotted on a semi-log scale, reporting a inhibition of 5〇% for compounds exhibiting greater than 50% inhibition at the highest concentration tested. The maximum binding of biotinylated chlorophyllin = the difference in concentration (I) and the corresponding R2; otherwise, the 丨Csg is reported to be greater than the highest concentration of the test ^. /3-[ [2-[ [5-[(Aminoimido) Amidino)amino-1-ylpentyl]amino]-iodoethyl]amino]_3_pyridine propionate ^ as ^ 0^/ 375, 338, Example 1] is effective ~ a Antagonists (%. in the range of 3-1 nM) were included on each plate as a positive control. Class A Chang Box ___ Platelet Plasma: Analysis of health suppliers without aspirin was selected from a group of volunteers Platelet-rich plasma acquisition and ADP-induced platelet aggregation analysis such as Zucker, Μ·B·' Platelet Aggregation Measured by the Photom Etric Method'', Me_thods_in Enzymology 169 (1 9 8 9 ) : 1 1 7 - 1 3 3. Perform the standard venipuncture technique of butterfly to extract 4 5 liters of whole blood and add 5 · 8 % of 5 ml Trisodium citrate

Page 215 1247008 V. Description of invention (209) 6 0 liters in the syringe. After thorough mixing in the syringe, the anticoagulated whole blood was transferred into a 50-liter conical polyethylene tube. The blood was centrifuged at 2 〇〇 xg for 1 2 minutes at room temperature to deposit non-platelet cells. Platelet-rich plasma is transferred to a polyethylene column&apos; when stored at room temperature until use. Very few platelets of plasma were obtained from residual blood at a second centrifugation for 2 minutes at 2000 xg. The platelet count is typically 300, 〇〇〇 to 5 每, 〇〇 0 per microliter. Platelet-rich blood aggregates (2, 45 liters) were added to the sputum tube, stirred at 37 Torr (11 rpm) for 1 minute 1 / then 50 μL of pre-diluted test compound was added. After mixing 1 minute f, 'aggregation was initiated by the addition of 50 μl of 2 〇〇 a M ADP. The maximum response (saline control) diluted with a series of test compounds was recorded in the Pay ton double tank =, i§ (Payt〇n Scientific, Buffalo, NY). The dose response curve was determined as the percent inhibition. All compounds were tested in two groups; the half-maximal inhibitory concentration (IC5G) was calculated from the dose response curve of the compound inhibited at the highest concentration of 5 %:M on the test; otherwise, I c was reported to be greater than the highest concentration tested. . 50

Page 216 1247008 V. Description of invention (210) Example number nrn) llb/IHa (ICso, nm) 1 1.58 313 2 132 272 3 0.41 298 4 0 74 581 5 0.42 884 6 0.27 1260 7 0.21 361 8 95.1 857 9 0.18 244 10 0.14 161 11 0.34 462 12 45 442 13 9,32 780 14 124 772 15 25 4 1040 16 22000 6180 17 0.46 724 18 0.43 798 19 2.96 2490 20 G 32 2020 21 0.2 551 22 6.96 1710 23 3600 10100 24 91200 15800 25 1870 3910 26 0.71 831 27 0.26 482 28 0.43 984 29 0.46 1385 30 155 29.5

__画第217页1247008 V. INSTRUCTIONS (211) 31 3942 1803 Example number ilCw nm) ilb/llla (ICso, nm) 32 • 2.1 49 33 0.2 520 34 0.34 1203 35 0.14 340 36 1.13 970 37 63.8 267 38 278 115 39 1917 2458 40 1.5 20630 41 10.2 35400 42 3.1 5954 43 6.5 7527 44 42.1 1061 45 1094 1678 46 1,97 2693 47 0.99 6709 48 4.3 27910

Ill page 218

Claims (1)

1247008 p:7 Case No. 88105718 VI. Scope of Application The compound corresponds to 1. A compound or a pharmaceutically acceptable salt thereof: The structure: ί HET ; is selected from the group consisting of 5-8 membered monocyclic heterocycles containing 1 to 4 heteroatoms selected from the group consisting of 0, Ν and S; X1 is selected from CH , CH2, Ν, ΝΗ, 0, S and a bond group; A is selected from the group consisting of: ^NH Μ: Ν-R2 'N-R7 and R5 N-R2', N-R7 And R2 together with R7 and the atom to which it is bonded form a 5-8 membered dinitrogen heterocycle which is optionally substituted with one or more substituents selected from the group consisting of C"C6 alkyl, Base, halo, thio-C "C6 alkyl, phenyl-C6 O:\57\57964-940729.ptc Page 220 1247008 _ Case No. 88105718 September 曰 Amendment _ VI. The scope of application for the patent base 'Ci-C6 alkyl base and C!-C2 extension base dioxyl; R2' and R7': R2' together with R7' and the atom to which it is bonded form a 5-8 membered diazo heterocycle, optionally substituted by a hydroxy group, or R2' and R7' are selected from hydrogen and Ci-q a group consisting of alkoxy-C "C6 alkyl; R5 and R8 are selected from the group consisting of hydrogen and 1-(:6 alkoxycarbonyl; Z1 is one or more substituents selected from ruthenium, C6 a group consisting of an alkyl group, a C6 alkoxy group 'halogen' amino group' and a Ci-C6 alkoxy C6 alkoxy group; t is selected from the group consisting of 0 and 1; and R3 is selected from hydrogen. And a group consisting of a C6 alkyl group; and R1 is selected from the group consisting of pyridyl, alkyl, optionally substituted with one or more halo groups, and phenyl, optionally by one or more a compound selected from the group consisting of a group consisting of an i group and a hydroxyl group. 2. A compound according to claim 1 or a salt thereof, wherein: t is 0; O:\57\57964-940729.ptc Page 221 1247008 _ Case No. 88105718 Year of the Amendment _ VI. Patent Application Range R32 is selected from the group consisting of bismuth, Ci-Ce alkyl and alkoxy-Ci-Ce Group. 3. A compound according to claim 2 or a salt thereof, wherein the compound is selected from the group consisting of: O:\57\57964-940729.ptc Page 222 1247008 _ Case No. 88105718 VI. Scope of Application for Patent Revision IlIHI O:\57\57964-940729.ptc Page 223 1247008 Case No. 88105718 VI. Scope of Application 曰 Amendment OH Ο Ι1Ι·11 Page 224 O:\57\57964-940729.ptc Case No. 88105718 f f July 曰 Correction 1247008 κι O:\57\57964-940729.ptc Page 225 1247008 _ Case No. 88105718 &lt;9 July of the year 曰 Amendment VI. Patent application scope O:\57\57964-940729.ptc Page 226 1247008 O:\57\57964-940729.ptc Page 227 1247008 _ Case No. 88105718 0 Amendment / VI. Patent application scope Page 228 O:\57\57964-940729.ptc O:\57\57964-940729.ptc Page 229 1247008 曰 Case No. 88105718 Amendment O:\57\57964-940729.ptc Page 230 1247008 O:\57\57964-940729.ptc Page 231 1247008 _ Case number 88105718 ? &gt; September September 曰 Amendment VI. Patent application scope O:\57\57964-940729.ptc Page 232 1247008 O:\57\57964-940729.ptc Page 233 1247008 O:\57\57964-940729.ptc Page 234 1247008 O:\57\57964-940729.ptc第235页 O:\57\57964-940729.ptc Page 236 1247008 _ Case No. 88105718 VI. Scope of Application for Patent 曰 Amendment 1 0 · A compound according to claim 1 or a salt thereof, wherein: t is 0, and A is eight. 1 1 · A compound according to claim 10 or a salt thereof, wherein the structure of the compound corresponds to the following formula: 12. A pharmaceutical composition for treating a symptom involving αν/33 integrin, wherein the composition comprises: a compound according to claim 1 of the patent application, and a pharmaceutically acceptable carrier. O:\57\57964-940729.ptc Page 237 1247008 _ Case No. 88105718 Revised on October _^ a / ...... &quot; ............... ............ VI. Patent Application Range 13. The pharmaceutical composition according to Item 12 of the patent application, wherein the disease is a tumor metastasis. The pharmaceutical composition according to claim 12, wherein the symptom is solid tumor growth. The pharmaceutical composition according to claim 12, wherein the symptom is blood vessel formation. The pharmaceutical composition according to item 12 of the patent application, wherein the symptom is osteoporosis. 17. The pharmaceutical composition according to claim 12, wherein the symptom is a malignant body fluid bureau. 18. The pharmaceutical composition according to claim 12, wherein the symptom-call is smooth muscle cell movement. The pharmaceutical composition according to claim 12, wherein the composition inhibits restenosis. The pharmaceutical composition according to claim 12, wherein the symptom is rheumatoid arthritis. The pharmaceutical composition according to claim 12, wherein the symptom is visual plaque. A compound according to claim 1 or a salt thereof, wherein: R2 together with R7 and an atom to which it is bonded form a 5-8 membered dinitrogen heterocycle, optionally selected from C i - C 6 Substituting one or more substituents of a group consisting of an alkyl group and a radical; R2' together with R7' and the atom to which it is bonded form a 5-8 membered dinitrogen-containing heterocycle, which is optionally substituted by a hydroxyl group ;and O:\57\57964-940729.ptc Page 238 1247008 Case No. 88105718 曰 Amendment VI. Patent Application Range Z1 is one or more selected from the group consisting of hydrazine, Ci-C6 alkyl, CrC6 alkoxy, halogen and amine. Substituents of the group. A compound according to claim 1 or a salt thereof, wherein the compound structure corresponds to the following formula: and A compound or a pharmaceutically acceptable salt thereof, wherein the structure of the compound corresponds to the formula: O:\57\57964-940729.ptc第239页