JP2002511462A - Heterocyclic glycyl β-alanine derivatives as vitronectin antagonists - Google Patents

Abstract

The present invention is mediated by a set of compounds of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising such a compound and an α _v β ₃ integrin. And methods for treating a condition. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

This invention claims priority to US Provisional Patent Application No. 60 / 081,394, filed on April 10, 1998 under 35 USC §119 (e). The present invention relates, alpha _v beta ₃ are useful as integrin antagonists and for the treatment of conditions mediated by alpha _v beta ₃ by such alpha _v to or antagonize inhibit beta ₃ integrin as And pharmaceutical agents (compounds) useful in the pharmaceutical compositions and methods of the present invention. BACKGROUND OF THE INVENTION Integrins are a group of cell surface glycoproteins that mediate cell adhesion and are therefore useful mediators of cell adhesion interactions that occur during various biological processes. Integrins are heterodimers composed of non-covalently linked α and β polypeptide subunits. At present, 11 different α subunits have been identified and 6 different β subunits have been identified. Different α subunits combine with different β subunits to form unique integrins.

Integrin, also known as α _v β ₃ (also known as vitronectin receptor), is known to be involved in tumor metastasis, solid tumor growth (neoplasm), osteoporosis, Paget's disease, malignant humoral hypercalcemia, tumor angiogenesis Angiogenesis, including retinopathy including macular degeneration, arthritis including rheumatoid arthritis, periodontal disease, psoriasis and smooth muscle cell migration (ie,
It has been identified as an integrin that plays an important role in a variety of conditions or disease states, including restenosis. In addition, such agents have been found to be useful as antivirals, antifungals and antibacterials. Thus, compounds that selectively inhibit or antagonize α _v β ₃ would be beneficial for treating such conditions.

[0003] The α _v β ₃ integrin and other α _v -containing integrins have been identified by numerous Arg-Gly.
-It was shown to bind to Asp (RGD) containing matrix macromolecules.
Compounds containing an RGD sequence mimic extracellular matrix ligands to bind to cell surface receptors. However, it is also known that RGD peptides are generally non-selective for RGD-dependent integrins. For example, most peptide RGDs that bind to α _v β ₃ also bind to α _v β ₅ , α _v β ₁ , and α _IIb β ₃ . Antagonism of platelet α _IIb β ₃ (also known as fibrinogen receptor) is known to block platelet aggregation in humans. Developed to avoid the side effects of bleeding, when treating conditions of the condition or disease associated with integrin alpha _v beta _3, as opposed to alpha _{II b} beta _3, the alpha _v beta ₃ selective antagonist, Compound Doing so would be beneficial.

[0004] Tumor cell invasion occurs in a three step process: 1) attachment of tumor cells to the extracellular matrix; 2) proteolytic lysis of the matrix; and 3) migration of cells through the lysed barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor.

[0005] Seftor et al. (Proc. Natl . Acad. Sci. USA, Vol. 89 (1992) 1557-1561) is, alpha _v beta ₃ integrin, revealed that it has a biological function in melanoma cell invasion I made it. Montgomery et al., (Poc. Natl. Acad. Sci. USA, Vol. 91
(1994) 8856-60), the integrin alpha _v beta ₃ appearing on human melanoma cells promotes a survival signal (survival Signal), demonstrated that protect cells from fragmentation. To prevent tumor metastasis, mediating the metastatic pathway of tumor cells by using the α _v β ₃ integrin cell adhesion receptor would be effective.

[0006] Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) demonstrated that systemic administration of α _v β ₃ antagonists can be performed in a variety of histologically distinct humans. Antagonists of α _v β ₃ offer a therapeutic approach to the treatment of neoplasms (inhibition of solid tumor growth), as they result in dramatic regression of the tumor.

[0007] The adhesion receptor integrin α _v β ₃ has been identified as a marker of vascular blood vessels in chicks and humans and thus such receptors play an important role in angiogenesis or angiogenesis. Angiogenesis is characterized by smooth muscle and endothelial cell invasion, migration and proliferation. Antagonists of α _v β ₃ inhibit this process by selectively promoting cell fragmentation in the neovasculature. The growth of new blood vessels, or angiogenesis, is also associated with diabetic retinopathy, including macular degeneration (Adamis et al., Amer. J. Ophthal., Vol 118, (1194) 445-4.
50) and rheumatoid arthritis (Peacock et al., J. Exp. Med., Vol. 175, (1992
), 1135-1138). Thus, α _v β ₃ antagonists would be useful pharmaceutical agents for the treatment of such conditions associated with angiogenesis (Brooks et al., Science, Vol. 264, (1994), 569-571). ).

[0008] The cell surface receptor α _v β ₃ has been reported to be the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption and when such bone resorption activity exceeds osteogenic activity, it causes osteoporosis (bone loss), which increases the number of bone destruction, incapacitation and increased death Bring rate. antagonists of alpha _v beta ₃ are potent inhibitors of osteoclast activity in vitro
[Sato et al., J. Cell. Biol., Vol., 111 (1990) 1713-1723] and potent inhibitors of osteoclast activity in vivo [Fisher et al., Endocrinology, Vol. 132].
(1993) 1411-1413]. Antagonism of α _v β ₃ leads to reduced bone resorption, thus restoring the normal balance of bone formation and resorption activity. Accordingly, it would be beneficial to provide an antagonist of osteoclast α _v β ₃ that is an effective inhibitor of bone resorption and is therefore effective in treating or preventing osteoporosis.

[0009] The role of α _v β ₃ integrin in smooth muscle cell migration has been further elucidated by therapies to prevent or inhibit neointimal hyperplasia, which is a major cause of post-vascular restenosis. The above goal (Choi et al., J. Vasc. Surg. Vol. 19 (1)
(1994) 125-34). It would be beneficial to prevent or suppress neointimal hyperplasia with pharmaceutical agents for preventing or controlling restenosis.

[0010] White (Current Biology, vol. 3 (9) (1993) 596-599) shows that adenovirus
The use of α _v β ₃ to enter host cells was reported. Integrins appear to require cellular uptake of viral particles and may require entry of the viral genome into the cytoplasm of the host cell. Thus, compounds that inhibit α _v β ₃ will find efficacy as antiviral agents. SUMMARY OF THE INVENTION The present invention provides a compound of formula I:

[0011]

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A compound of the class represented by or a pharmaceutically acceptable salt thereof, wherein

[0013]

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Contains 1 to 4 heteroatoms selected from the group consisting of O, N or S;
A 5- to 8-membered monocyclic heterocyclic ring which may be unsaturated; wherein X ¹ is
A is selected from the group consisting of H, CH ₂ , N, NH, O and S;

[0015]

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Wherein Y ¹ is selected from the group consisting of NR ² , O, and S; R ² is hydrogen; alkyl; aryl; hydroxy; alkoxy; cyano; nitro; amino; alkenyl; Alkynyl; amide; alkylcarbonyl; arylcarbonyl; alkoxycarbonyl; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl; Amino, alkoxy, aryl or one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydride It may be substituted with one or more substituents selected from xyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycle, or aryl optionally substituted with fused monocyclic heterocycle. Alkyl; halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, carboxyl derivative, amino, aryl, fused aryl,
Aryl optionally substituted with one or more substituents selected from monocyclic heterocycles and fused monocyclic heterocycles; monocyclic heterocycles; and halogen, haloalkyl, lower alkyl, alkoxy, amino, From the group consisting of monocyclic heterocycles optionally substituted with one or more substituents selected from nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl Or R ² together with R ⁷ is one or more selected from lower alkyl, thioalkyl, alkylamino, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fused phenyl The two 4-12 membered nitrogens which may be substituted with the above substituents are A heterocycle formed with; or R ^2, taken together with R ⁷ O, containing 1 or more heteroatoms selected from N and S, 4-12 membered may be unsaturated Or R ² together with R ⁷ is a 5-9 membered heterocyclic optionally substituted with one or more substituents selected from lower alkyl, phenyl, alkoxy and hydroxy. form an aromatic ring; or R ² forms a heteroaromatic ring 5-membered together with R ⁷ fused with aryl or heteroaryl ring; (when not together with R ²⁾ R ⁷ and R ⁸ is hydrogen; alkyl; alkenyl;
Alkynyl; aralkyl; amino; alkylamino; hydroxy; alkoxy; arylamino; amide, alkylcarbonyl, arylcarbonyl; alkoxycarbonyl; aryloxy; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; Methoxycarbonyl, cycloalkyl, bicycloalkyl, aryl, acyl, benzoyl, lower alkyl, halogen, hydroxy,
Haloalkyl, cyano, nitro, carboxyl derivative, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, Cyano, nitro, carboxyl derivative, aryloxy, amide, acylamino, amino, alkylamino,
One or more selected from dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycle, fused monocyclic heterocycle Alkyl optionally substituted with one or more substituents selected from aryl optionally substituted with the following substituents: halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio , Thio, hydroxy, cyano, nitro, carboxyl derivative, aryloxy, amide, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid Aryl optionally substituted with one or more substituents selected from sulfonamide, aryl, fused aryl, monocyclic heterocycle, or fused monocyclic heterocycle; monocyclic heterocycle; halogen, haloalkyl , Lower alkyl,
A monocyclic heterocycle optionally substituted with one or more substituents selected from alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl; Cyclic and bicyclic heterocyclic alkyls; SO ₂ R ^10, wherein R ¹⁰ is selected from the group consisting of alkyl, aryl, and monocyclic heterocycles, all halogen, haloalkyl, alkyl, alkoxy, cyano , Nitro, amino, acylamino, trifluoroalkyl, amide, alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio, trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio , Alkylthio and monocyclic heterocycles), and may be substituted with one or more substituents selected from the group consisting of:

[0017]

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Wherein R ¹⁰ has the meaning as defined above; or NR ⁷ and R ^{8 taken} together from lower alkyl, carboxyl derivative, aryl or hydroxy 4-, optionally substituted with one or more selected substituents
Forming a monocyclic or bicyclic ring having one 12-membered nitrogen and wherein said ring may contain a heterocyclic ring selected from the group consisting of O, N and S; R ⁵ Is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, benzyl, and phenethyl; or

[0019]

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Wherein Y ² is alkyl; cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycle; halo, haloalkyl, alkyl, nitro, hydroxy,
Alkyl optionally substituted with aryl optionally substituted with one or more substituents selected from alkoxy, aryloxy, aryl or fused aryl; halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl,
Aryl optionally substituted with one or more substituents selected from fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl; alkynyl; alkenyl; -SR ⁹ and -OR ⁹ ( Wherein R ⁹ is selected from the group consisting of hydrogen; alkyl; aralkyl; aryl; alkenyl; and alkynyl; or R ⁹ together with R ⁷ is lower alkyl, hydroxy, keto, phenyl, carboxyl or carboxyl. 4-, which may be substituted with an ester and a condensed phenyl
R 12 forms a heterocyclic ring containing one nitrogen and one sulfur or one oxygen containing 12 members; or R ⁹ together with R ⁷ is thiazole; oxazole; benzoxazole; or benzo And R ⁵ and R ⁷ have the meanings as defined above; or Y ² (when Y ² is carbon) together with R ⁷ is alkyl, aryl Forming a 4-12 membered 1 nitrogen or 2 nitrogen containing ring optionally substituted with keto or hydroxy; or

[0021]

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Wherein R ² and R ⁷ are taken together and are substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, keto, phenyl, or carboxyl derivatives. And R ⁸ forms an alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, R ⁵ is as defined above; or R ² and R ⁷ are taken together to form a heteroaromatic of a member such as imidazole or pyrimidone. Forming an aromatic ring; or A is

[0023]

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Wherein R ² and R ⁷ together form a 5-8 membered two nitrogen containing heterocycle optionally substituted with hydroxy, keto, phenyl, or alkyl. And R ⁸ is both selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkylalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl and acyloxymethoxycarbonyl; and Z ¹ is Hydrogen; alkyl; hydroxy; alkoxy; aryloxy; halogen; haloalkyl; haloalkoxy; nitro; amino; alkylamino; acylamino; dialkylamino; cyano; alkylthio; alkylsulfonyl; Acyl; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycle; fused monocyclic heterocycle and A wherein A is as defined above. V is —N— (R ⁶ ) —, wherein R ⁶ is hydrogen; lower alkyl; cycloalkyl; aralkyl; aryl; R ⁶ is selected from the group consisting of: Y, Y ³ , Z; and R ⁶ is taken together with Y to form a 4-12 membered single nitrogen-containing ring); And Z ³ is independently selected from the group consisting of hydrogen; alkyl; aryl; and cycloalkyl; or Y and Z together form cycloalkyl; or Y ³ and Z ³ are Together form a cycloalkyl N is an integer 1, 2 or 3; t is an integer 0, 1, or 2; p is an integer 0, 1, 2, or 3; R is XR ³ ( Where X is selected from the group consisting of O, S, and NR ⁴ ;
Wherein R ³ and R ⁴ are hydrogen; alkyl; alkenyl; alkynyl; haloalkyl; aryl; arylalkyl; sugar; steroid; polyalkyl ether; alkylamide; alkyl N, N-dialkylamide; pivaloyloxymethyl; R ¹ is hydrogen; alkyl; alkenyl; alkynyl; aryl; carboxyl derivative; haloalkyl; cycloalkyl; in the case of the free acid, all are independently selected from the group consisting of pharmaceutically acceptable salts thereof. Monocyclic heterocycle; substituted by alkyl, halogen, haloalkyl, cyano, hydroxy, aryl, fused aryl, nitro, alkoxy, aryloxy, alkylsulfonyl, arylsulfonyl, sulfonamide, thio, alkylthio, carboxyl derivative, amino, amide hand A monocyclic heterocycle; halo, haloalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl, arylthio, alkylsulfoxide, alkylsulfonyl, arylsulfoxide, arylsulfonyl, cyano, nitro, amino, alkyl Substituted with one or more of amino, dialkylamino, alkylsulfonamide, arylsulfonamide, acylamide, carboxyl derivative, sulfonamide, sulfonic acid, phosphonic acid derivative, phosphinic acid derivative, aryl, arylthio, arylsulfoxide, or arylsulfone Alkyl, halo, alkyl, haloalkyl, all on the aryl ring,
Cyano, nitro, hydroxy, carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino, amide, aryl, fused aryl, monocyclic heterocycles; and fused monocyclic heterocycles, monocyclic heterocycles. Cyclic heterocyclic thio, monocyclic heterocyclic sulfoxide, and monocyclic heterocyclic sulfones, which may be substituted with halo, haloalkyl, nitro, hydroxy, alkoxy, fused aryl or alkyl; alkylcarbonyl , Haloalkylcarbonyl, and arylcarbonyl; halo, haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, acyloxy, Hexyl derivatives,
Carboxyalkoxy, amide, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycle and fused monocyclic heterocycle Aryl optionally substituted with; and

[0025]

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Wherein R ⁷ and R ⁸ have the meaning as defined above and together with the nitrogen, R ⁷ and R ⁸ are selected from the group consisting of: ;
And R ¹¹ is selected from the group consisting of hydrogen, alkyl, aralkyl, alkenyl, alkynyl, haloalkyl, or haloalkynyl, or R ¹¹ together with Y forms one 4-12 membered nitrogen. Forms a ring containing.

It is another object of the present invention to provide a pharmaceutical composition comprising a compound of formula I. Such compounds and compositions, α _v β ₃ integrin selectively inhibit or another embodiment of the antagonizing and thus alpha _v beta ₃ integrin selectively inhibit or present invention relates to a method of antagonizing Effective in embodiments.
The invention further relates to osteoporosis, malignant humoral hypercalcemia, Paget's disease, tumor metastasis, solid tumor growth (neoplasm), angiogenesis including tumor angiogenesis, macular degeneration in mammals in need of treatment And treatment or control of pathological conditions associated therewith, such as retinopathy and diabetic retinopathy, arthritis including rheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cell migration and restenosis. In addition, such medicinal agents are effective as antivirals and antibacterials. DETAILED DESCRIPTION The present invention relates to compounds of the class represented by Formula I above.

A preferred embodiment of the present invention is a compound of formula II

[0029]

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Is a compound of the formula

[0031]

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Is

[0033]

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Wherein R ³² is hydrogen, alkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, wherein the alkyl group is hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl- Alternatively, it may be substituted with one or more substituents selected from the group consisting of alkyl-sulfonyl, carboxyl, and carboxyl derivatives, and the other symbols have the same meanings as defined above in Formula I.

Another preferred embodiment of the present invention is a compound of formula III

[0036]

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Is a compound of the formula

[0038]

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Is optionally substituted

[0040]

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And the other symbols have the same meanings as defined above in Formula I. Another preferred embodiment of the present invention is a compound of formula IV

[0042]

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Is a compound of the formula

[0044]

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Is optionally substituted

[0046]

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And other symbols have the same meanings as defined above in Formula I. Another preferred embodiment of the present invention is a compound of formula V

[0048]

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Is a compound of the formula

[0050]

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Has been optionally substituted

[0052]

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And the other symbols have the same meanings as defined above in Formula I. Another preferred embodiment of the present invention is a compound of formula VI

[0054]

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A compound of the formula wherein

[0056]

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Is optionally substituted

[0058]

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And the other symbols have the same meanings as defined above in Formula I. The present invention is further directed to pharmaceutical compositions containing a therapeutically effective amount of a compound of Formulas I-VI.

The present invention further relates to a method of selectively inhibiting or antagonizing α _v β ₃ integrin and, more particularly, to achieve such inhibition with a pharmaceutically acceptable carrier in order to achieve such inhibition. Administration of a large amount of a compound of Formula I-VI may result in bone resorption, periodontal disease, osteoporosis, malignant humoral hypercalcemia, Paget's disease, tumor metastasis, solid tumor growth (neoplasm), tumor The present invention relates to a method for inhibiting angiogenesis including angiogenesis, retinopathy and diabetic retinopathy including macular degeneration, arthritis including rheumatoid arthritis, smooth muscle cell migration and restenosis.

The following is a list of definitions of various terms used herein. As used herein, the term "alkyl" or "lower alkyl" refers to a straight or branched chain having about 1 to about 10 carbon atoms, more preferably 1 to about 6 carbon atoms. Examples of such alkyl groups are methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl and the like.

As used herein, the term “alkenyl” or “lower alkenyl”
Refers to an unsaturated acyclic hydrocarbon group containing at least one double bond and 2 to 6 carbon atoms, and the carbon-carbon double bond is substituted on the double bond carbon. Can have either a cis or trans configuration within the alkenyl moiety. Examples of such groups are ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and the like.

As used herein, the term “alkynyl” or “lower alkynyl”
Refers to an acyclic hydrocarbon group containing one or more triple bonds and 2 to about 6 carbon atoms. Examples of such groups are ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.

As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated ring containing 3 to about 8 carbon atoms, and more preferably 4 to about 6 carbon atoms. Refers to the formula carbon group. Examples of such cycloalkyl groups include cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-1-yl and the like.

As used herein, the term “aryl” refers to an aromatic ring system composed of one or more aromatic rings. Preferred aryl groups are aryl groups consisting of 1, 2 or 3 aromatic rings. The term includes aromatic groups such as phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, and the like.

As used herein, the term “cyano” has the formula

[0067]

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Is represented by the group As used herein, the terms “hydroxy” and “hydroxyl” are synonymous and have the formula

[0069]

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Is represented by the group Next formula

[0071]

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Is a 5-10 membered monocyclic or bicyclic heterocycle optionally containing unsaturation, containing 1-3 heteroatoms selected from the group consisting of O, N and S A formula ring; wherein X ¹ is CH, N, O or S. Representative examples of such groups include pyridone, pyridine, pyrimidine, imidazole, oxazole, isoxazole, thiazole, pyridazine, thiophene, furan, pyrazole and bicyclic heterocycles such as benzimidazole, imidazopyridine, benzofuran, and the like. It is.

As used herein, the term “lower alkylene” or “alkylene”
Refers to a divalent straight or branched chain saturated hydrocarbon group of 1 to about 6 carbon atoms. As used herein, the term “alkoxy” refers to a compound of the formula —OR ²⁰ where
R ²⁰ is an alkyl group as described above) or a straight-chain or branched oxy-containing group. Examples of alkoxy groups include methoxy, ethoxy, n-propyl, n-butoxy, isopropoxy, isobutoxy, sec-butoxy, t-butoxy and the like.

As used herein, the term “arylalkyl” or “aralkyl” has the formula

[0075]

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Wherein R ²¹ is aryl as defined above and R ²² is alkylene as defined above. Examples of aralkyl groups include benzyl, pyridylmethyl, naphthylpropyl, phenethyl and the like.

As used herein, the term “nitro” has the formula

[0078]

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Is represented by the group As used herein, the term “halo” or “halogen” refers to bromo,
Refers to chloro, fluoro or iodine.

As used herein, the term “haloalkyl” is as defined above which is substituted at one or more carbon atoms with one or more identical or different halo groups. A suitable alkyl group. Examples of haloalkyl groups include trifluoromethyl, dichloroethyl, fluoropropyl, and the like.

As used herein, the term “carboxyl” or “carboxy” refers to a group of formula —COOH. As used herein, the term “carboxyl ester” refers to a compound of the formula —CO 2
A group of OR ²³ , wherein R ²³ is hydrogen, alkyl as defined above,
It is selected from the group consisting of aralkyl or aryl.

As used herein, the term “carboxyl derivative” has the formula

[0083]

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Wherein Y ⁶ and Y ⁷ are independently selected from the group consisting of O, N, or S, and R ²³ is hydrogen, alkyl, aralkyl as defined above. Or selected from the group consisting of aryl.

As used herein, the term “amino” is represented by a group of formula —NH ₂ . As used herein, the term “alkylsulfonyl” or “alkylsulfone” has the formula

[0086]

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Wherein R ²⁴ is alkyl as defined above. As used herein, the term "alkylthio" refers to a group of the formula -SR ^24, in the formula, R ²⁴ is alkyl as defined above.

As used herein, the term “sulfonic acid” has the formula

[0089]

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Wherein R ²⁵ is alkyl as defined above. As used herein, the term “sulfonamide” refers to a compound of the formula

[0091]

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Wherein R ⁷ and R ⁸ have the meaning as defined above. As used herein, the term "fused aryl" refers to an aromatic ring, such as an aryl group as defined above, fused to one or more phenyl rings. The groups naphthyl and the like are encompassed by the term "fused aryl".

As used herein, the term “monocyclic heterocycle” or “monocyclic heterocyclic” refers to 4 to about 12 atoms, and more preferably 5 to about 10 atoms. Wherein the 1-3 atoms are heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, if two or more different heteroatoms are It is understood that, if present, at least one heteroatom must be nitrogen. Representative examples of such monocyclic heterocycles are imidazole, furan, pyridine, oxazole, pyran, triazole, thiophene, pyrazole, thiazole, thiadiazole and the like.

As used herein, the term “fused monocyclic heterocycle” refers to a monocyclic heterocycle as defined above having benzene fused thereto. Examples of such fused monocyclic heterocycles include benzofuran, benzopyran, benzodioxole, benzothiazole, benzothiophene, benzimidazole and the like.

[0095] As used herein, the term "methylenedioxy" refers to the group

[0096]

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And the term “ethylenedioxy” refers to the group

[0098]

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[0099] As used herein, the term "4-12 membered two nitrogen containing heterocycle" is represented by the formula

[0100]

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Wherein m is 1 or 2 and R ¹⁹ is hydrogen, alkyl, aryl, or aralkyl and more preferably refers to a 4-9 membered ring and like imidazoline Ring.

As used herein, the term “5-membered optionally substituted heteroaromatic ring” refers to, for example, a compound of the formula

[0103]

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A “5-membered heteroaromatic ring fused to phenyl” comprising such a group refers to such a “5-membered heteroaromatic ring” having phenyl fused thereto. A representative example of such a 5-membered heteroaromatic ring fused to phenyl is benzimidazole.

As used herein, the term “bicycloalkyl” refers to a saturated or partially unsaturated bicyclic hydrocarbon group containing from 6 to about 12 carbon atoms. As used herein, the term “acyl” is defined by the formula

[0106]

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Wherein R ²⁶ is alkyl, alkenyl, alkynyl, aryl or aralkyl and they are optionally substituted as defined above. The groups acetyl, benzoyl and the like are encompassed by such groups.

As used herein, the term “thio” is defined by the formula

[0109]

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The group of As used herein, the term “sulfonyl” has the formula

[0111]

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Wherein R ²⁷ is alkyl, aryl or araryl as defined above. As used herein, the term "haloalkylthio" refers to a group of the formula -S-R ^28, in the formula, R ²⁸ is haloalkyl as defined above.

As used herein, the term “aryloxy” has the formula

[0114]

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Wherein R ²⁹ is aryl as defined above. As used herein, the term “acylamino” has the formula

[0116]

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Wherein R ³⁰ is alkyl, aralkyl, or aryl as defined above. As used herein, the term “amide” refers to a compound of the formula

[0118]

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The group of As used herein, the term "alkylamino" refers to a group of the formula -NHR ^32, in the formula, R ³² is alkyl as defined above.

As used herein, the term “dialkylamino” has the formula —NR³³R ³⁴ Represents a group of the formula:³³And R³⁴Are the same as defined above or
Different alkyl groups.

As used herein, the term “trifluoromethyl” has the formula

[0122]

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The group of As used herein, the term “trifluoroalkoxy” refers to a compound of the formula

[0124]

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Wherein R ³⁵ is a bond or alkylene as defined above. As used herein, the term “alkylaminosulfonyl” has the formula

[0126]

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Wherein R ³⁶ is alkyl as defined above. As used herein, the term “alkylsulfonylamino” has the formula

[0128]

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Wherein R ³⁶ is alkyl as defined above. As used herein, the term “trifluoromethylthio” is defined by the formula

[0130]

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The group of As used herein, the term "trifluoromethylsulfonyl"
formula

[0132]

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The group of As used herein, the term “4-12 membered monocyclic or bicyclic ring containing one nitrogen” refers to a saturated or partially saturated monocyclic ring of 4-12 atoms. A ring of formula or bicyclic and more preferably a ring of 4-9 atoms, wherein one atom is nitrogen. Such rings can optionally contain additional heteroatoms selected from nitrogen, oxygen, or sulfur. This group includes morpholine, piperidine, piperazine, thiomorpholine, pyrrolidine, proline, azacycloheptene and the like.

As used herein, the term “benzyl” refers to the group

[0135]

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[0136] As used herein, the term “phenethyl” refers to the group

[0137]

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[0138] As used herein, the term "4-12 membered nitrogen-containing 1
A heterocyclic ring containing one sulfur or one oxygen "refers to a ring consisting of 4-12 atoms and more preferably 4-9 atoms, wherein at least one atom is nitrogen And at least one atom is oxygen or sulfur This definition includes rings such as thiazoline and the like.

As used herein, the term “arylsulfonyl” or “arylsulfone” has the formula

[0140]

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Wherein R ³⁷ is aryl as defined above. As used herein, the term “alkylsulfoxide” or “arylsulfoxide” has the formula

[0142]

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Wherein R ³⁸ is alkyl or aryl, respectively, as defined above. As used herein, the term "phosphonic acid derivative" refers to a compound of the formula

[0144]

Embedded image

Wherein R ³⁹ and R ⁴⁰ are the same or different and are hydrogen, alkyl, aryl or aralkyl. As used herein, the term “phosphinic acid derivative” refers to a compound of the formula

[0146]

Embedded image

Wherein R ⁴¹ is hydrogen, alkyl, aryl or aralkyl as defined above. As used herein, the term “arylthio” is defined by the formula

[0148]

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Wherein R ⁴² is aryl as defined above. As used herein, the term “monocyclic heterocyclic thio” refers to a compound of the formula

[0150]

Embedded image

Wherein R ⁴³ is a monocyclic heterocyclic group as defined above. As used herein, the terms “monocyclic heterocyclic sulfoxide” and “
Each of the monocyclic heterocyclic sulfones has the formula

[0152]

Embedded image

And

[0154]

Embedded image

Wherein R ⁴³ is a monocyclic heterocyclic group as defined above. As used herein, the term “alkylcarbonyl” refers to a compound of the formula

[0156]

Embedded image

Wherein R ⁵⁰ is alkyl as defined above. As used herein, the term "arylcarbonyl" has the formula

[0158]

Embedded image

Wherein R ⁵¹ is aryl as defined above. As used herein, the term "alkoxycarbonyl" refers to a compound of the formula

[0160]

Embedded image

Wherein R ⁵² is alkoxy as defined above. As used herein, the term "aryloxycarbonyl" has the formula

[0162]

Embedded image

Wherein R ⁵¹ is aryl as defined above. As used herein, the term “haloalkylcarbonyl” has the formula

[0164]

Embedded image

Wherein R ⁵³ is haloalkyl as defined above. As used herein, the term “haloalkoxycarbonyl” has the formula

[0166]

Embedded image

Wherein R ⁵³ is haloalkyl as defined above. As used herein, the term “alkylthiocarbonyl” has the formula

[0168]

Embedded image

Wherein R ⁵⁰ is alkyl as defined above. As used herein, the term "arylthiocarbonyl" has the formula

[0170]

Embedded image

Wherein R ⁵¹ is aryl as defined above. As used herein, the term “acyloxymethoxycarbonyl” has the formula

[0172]

Embedded image

Wherein R ⁵⁴ is acyl as defined above. As used herein, the term “arylamino” refers to a compound of the formula R ⁵¹ —NH—
Wherein R ⁵¹ is aryl as defined above.

As used herein, the term “polyalkyl ether” refers to commonly used glycols such as triethylene glycol, tetraethylene glycol, polyethylene glycol, and the like.

As used herein, the term “alkylamide” has the formula

[0176]

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Wherein R ⁵⁰ is alkyl as defined above. As used herein, the term “N, N-dialkylamide” is defined by the formula

[0178]

Embedded image

Wherein R ⁵⁰ is the same or different alkyl as defined above. As used herein, the term “pivaloyloxymethyl” has the formula

[0180]

Embedded image

Embedded image As used herein, the term “acyloxy” refers to a group of formula R ⁵⁵ —O—, wherein R ⁵⁵ is acyl as defined above.

[0182] As used herein, the term "composition" means a product obtained by mixing or combining one or more elements or components. As used herein, the term "pharmaceutically acceptable carrier" refers to a liquid or solid filler, diluent, excipient, solvent or encapsulation involved in carrying or transporting a chemical agent. A pharmaceutically acceptable substance, composition or excipient, such as an agent.

The term “therapeutically effective amount” refers to the tissue sought by a researcher or clinician,
A quantity of a pharmaceutical or pharmaceutical agent that elicits a biological or medical response in a system or animal.

The following is a list of symbols and their corresponding meanings as used interchangeably herein: ¹ H-NMR = proton nuclear magnetic resonance AcOH = acetic acid Ar = argon BF ₃ − THF = borane-tetrahydrofuran complex Bn = benzyl BOC = tert-butoxycarbonyl ButLi = butyllithium Cat. = Catalytic amount CDMT = 2-chloro-4,6-dimethoxytriazine CH ₂ Cl ₂ = dichloromethane CH ₃ CN = acetonitrile CH ₃ I = iodomethane CHN analysis = carbon / hydrogen / nitrogen elemental analysis CHNCl analysis = carbon / hydrogen / nitrogen / chlorine Elemental analysis CHNS analysis = carbon / hydrogen / nitrogen / sulfur elemental analysis DAST = diethylaminosulfur trifluoride DCC = 1,3-dicyclohexylcarbodiimide DCM = dichloromethane DIBAL = diisobutylaluminum hydride DIEA = diisopropylethylamine DI water = deionized water DMA = N, N-dimethylacetonitrile DMAC = N, N-dimethylacetamide DMAP = 4- (N, N-dimethylamino) pyridine DMF = N, N-dimethylformamide DSC = disuccinyl Ruboneto EDCl = 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Et = ethyl Et ₂ O = diethyl ether Et ₃ N = triethylamine EtOAc = ethyl acetate EtOH = ethanol FABMS = fast atom bombardment mass spectrometry g = Grams GIHA = metaganidinohippuric acid GIHA HCl = metaganidinohippurate Gly = glycine HMPA = hexamethylphosphoramide HOBT = 1-hydroxybenzotriazole hydrate HPLC = high performance liquid chromatography IBCF = isobutylchloroformate i- Pr = isopropyl i-Prop = isopropyl K ₂ CO ₃ = potassium carbonate KMnO ₄ = potassium permanganate KOH = potassium hydroxide KSCN = potassium thiocyanate L = liter IOH = lithium MCPBA = m- chloroperoxybenzoic acid or m- chloroperbenzoic acid Me = methyl MeI = methyl iodide MeOH = methanol MEMCl = methoxyethoxymethyl chloride MesCl = methanesulfonyl chloride mg = milligram MgSO ₄ = magnesium sulfate hydroxide ml = milliliter mL = milliliter MS = mass spectroscopy MTBE = methyl t- butyl ether N ₂ = nitrogen NaCNBH ₃ = sodium cyanoborohydride sodium NaH = hydride NaHCO ₃ = sodium bicarbonate NaOH = sodium hydroxide NaOMe = sodium methoxide Na ₂ PO ₄ = sodium phosphate Na ₂ SO ₄ = sodium sulfate NEt ₃ = triethylamine NH ₄ HCO ₃ = ammonium hydrogen carbonate NH ₄ ⁺ HCO ₂ ⁻ = formic acid Ammonium NH ₄ OH = ammonium hydroxide NMM = N-methylmorpholine NMP = 1-methyl-2-pyrrolidinone NMR = nuclear magnetic resonance Pd / C = palladium on carbon Ph = phenyl Pt / C = platinum RPHPLC = reverse phase on carbon High performance liquid chromatography RT = room temperature t-BOC = tert-butoxycarbonyl TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography TMEDA = tetramethylethylenediamine TMS = trimethylsilyl △ = heating the reaction mixture Formula I-VI The compounds may exist in various isomeric forms and all such isomeric forms are intended to be included. In addition to tautomeric forms, pharmaceutically acceptable salts of such isomers and tautomers are also included.

In the structures and formulas herein, bonds drawn beyond ring bonds can be to any available atom on the ring. The term "pharmaceutically acceptable salt" refers to a salt prepared by contacting a compound of Formula I with an acid whose anion is generally considered suitable for human consumption. Examples of pharmaceutically acceptable salts include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, tartrate salts and the like.
All pharmaceutically acceptable salts can be prepared by conventional methods. (For additional examples of pharmaceutically acceptable salts, see Berge et al., J Pharm. Sci., 66 (1), 1-19 (1977
)checking. ) For the selective inhibition or antagonism of α _v β ₃ integrin, the compounds of the present invention can be administered orally in a unit dosage formulation containing conventional pharmaceutically acceptable carriers, additives and excipients. It can be administered orally, or by absorption spray, or topically. As used herein, the term “parenteral” includes, for example, subcutaneous, intravenous,
Intramuscular, intrasternal, infusion, or intraperitoneally.

The compounds of the present invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and at an effective dose for the intended treatment. Medical condition (
Therapeutically effective doses of the compound required to prevent or arrest the progress of the medical condition or treat the condition thereof can be determined using preclinical and clinical methods known in the medical arts. It is easily determined by one skilled in the art.

Thus, the present invention provides a method of treating a condition mediated by selectively inhibiting or antagonizing an α _v β ₃ cell surface receptor, and the method comprises formula I-
Administering a therapeutically effective amount of a compound selected from the class of compounds represented by VI, wherein the compound of Formula I-VI is one or more non-toxic pharmaceutically acceptable compounds. It is co-administered with the resulting carrier and / or diluent and / or additive (collectively referred to herein as "carrier" materials) and optionally other active ingredients. More specifically, the present invention provides methods for inhibiting α _v β ₃ cell surface receptors. Most preferably, the invention relates to inhibiting bone resorption, treating osteoporosis, inhibiting malignant humoral hypercalcemia, treating Paget's disease, neoplasms (solid tumor growth)
Of angiogenesis including tumor angiogenesis, treatment of retinitis including macular degeneration and diabetic retinitis, suppression of arthritis, psoriasis and periodontal disease, and method of suppressing smooth muscle cell migration including restenosis I will provide a.

Based on standard laboratory procedures and procedures well known and appreciated by those skilled in the art, and comparisons with known useful compounds, the compounds of Formula I are useful for treating patients suffering from the aforementioned pathological conditions. Can be used in Those skilled in the art will recognize that the selection of the most suitable compound of the present invention is within the capabilities of those skilled in the art and includes the evaluation obtained in standard assays and animal models. It will depend on various factors.

Treatment of a patient afflicted with one of the pathological conditions modulates the patient's condition or prolongs the patient's viability beyond what would be expected in the absence of such treatment Administering to such a patient an amount of a compound of Formula I that is therapeutically effective. As used herein, the term "suppressing" a state refers to slowing, suspending, preventing or stopping the state and does not necessarily indicate a total elimination of the state. It is believed that extending the viability of a patient, on its own and beyond its own significant beneficial effects, also indicates that the condition is effectively controlled to some extent.

As mentioned above, the compounds of the present invention can be used in a variety of biological, prophylactic or therapeutic areas. These compounds are believed to be effective in preventing or treating disease states or conditions in which the α _v β ₃ integrin plays a role.

Dosage regimens for the compounds and / or compositions containing the compounds may vary with a variety of factors, including the type, age, weight, sex and condition of the patient; the extent of the condition; the route of administration; and the activity of the particular compound employed. Based. Thus, the dosage regimen can vary widely. Dosage levels on the order of about 0.01 mg / kg to about 1000 mg / kg of body weight per day are effective in treating the above conditions.

The active ingredient to be administered by injection may be formulated as a composition and in that composition, for example, saline, dextrose or water, may be used as a suitable carrier. A suitable daily dose will typically be about 0.01-10 mg / kg of body weight injected daily in multiple doses depending on the factors mentioned above.

For administration to a mammal in need of such treatment, a therapeutically effective amount of the compound is usually combined with one or more additives suitable for the indicated route of administration. Compounds include lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, acacia, sodium alginate, polyvinyl It can be mixed with pyrrolidone, and / or polyvinyl alcohol and tableted or encapsulated for convenient administration. Alternatively, the compound can be dissolved in water, polyethylene glycol, polypropylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. Other additives and modes of administration are well and widely known in the pharmaceutical art.

The pharmaceutical compositions useful in the present invention can be subjected to conventional pharmaceutical procedures such as sterilization and / or conventional pharmaceutical additives such as preservatives, stabilizers, wetting agents, emulsifiers, buffers. Agents and the like can be contained.

The general synthetic sequence for preparing compounds useful in the present invention is outlined in Schemes 1-15. Both description and actual procedures of the various aspects of the invention are described where appropriate. The following schemes and examples are intended to be merely illustrative of the present invention, but not limiting of the invention in scope and spirit. Those skilled in the art will readily understand the following; known variations of the reaction schemes and conditions described in the examples can be used to synthesize the compounds of the present invention.

[0196] Unless otherwise indicated, all starting materials and equipment used were commercially available. Reaction process formula 1

[0197]

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Reaction Scheme 2

[0199]

Embedded image

Reaction Scheme 3

[0201]

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[0202] Schemes 1-3 illustrate a method useful for preparing the guanidinopyridine / cycloguanidinopyridine carboxylic acid moieties of the present invention used to couple to gly-β-amino acids. This can be achieved using other suitable guanidating reagents known to those skilled in the art. Schemes 1-3 can be modified using conventional techniques and methods to prepare alternative compounds useful for coupling to the gly-β-amino acid moiety. Reaction process formula 4

[0203]

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[0204] Scheme 4 illustrates the method used to prepare the guanidinothiazole carboxylic acid moieties of the present invention used to couple to gly-β-amino acids. The method of Scheme 4 is modified using conventional techniques known to those skilled in the
This and alternative compounds useful for coupling to the y-β-amino acid moiety can be prepared. Reaction process formula 5

[0205]

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Scheme 5 shows the reaction of the compound of the present invention with ethyl N-gly-amino-3- (3,5
A method useful for preparing a -dihalo-2-hydroxy) phenylpropionate moiety is described. Briefly, 3,5-halo-substituted salicylaldehydes (halo-substituted-2-hydroxybenzaldehydes) were prepared by direct halogenation. For example, 5-bromosalicylaldehyde is slurried in acetic acid and an equivalent or more of chlorine is added to prepare 3-chloro-5-bromo-2-hydroxybenzaldehyde.

Some product precipitates out and is collected by filtration. The remainder is recovered by diluting the filtrate with water and isolating the precipitate. The solids are combined and dried to give 3-chloro-5-bromo-2-hydroxybenzaldehyde. D
3-Iodo-5-chlorosalicylaldehyde was prepared by reacting 5-chlorosalicylaldehyde with N-iodosuccinimide in MF and subjecting the reaction mixture to normal processing conditions. 3-Iodo-5-bromosalicylaldehyde can be prepared by reacting 5-bromosalicylaldehyde with potassium iodide and chloramine T in acetonitrile. The usual treatment gives a material which gives the desired 3-iodo-5-chlorosalicylaldehyde when treated with hexane.

[0208] Coumarins are modified by a modified Parkin reaction (eg, Vogel's Textbook of Practical
anic Chemisry, 5th edition, 1989, p. 1040). Halo-substituted coumarins are converted to 3-aminohydrocoumarins (JG Rico
, Tett. Let., 1994, 35, 6599-6602) and it readily opened in acidic alcohols to produce 3-amino-3- (3,5-halo-2-hydroxy) phenylpropanoate. .

3-Amino-3- (3,5-halo-2-hydroxy) phenylpropanoic acid ester is reacted with Boc-N-gly-N-hydroxysuccinimide to give
Boc-N-gly-3-amino-3- (3,5-halo-2-hydroxy) phenylpropanoic acid ester (this is N-gly-3-amino-3- (3,5-halo-2-hydroxy) phenylpropane HX salt of an acid ester (where X is C
l, Br or I) to produce N-gly-3-amino-3.
Converted to-(3,5-halo-2-hydroxy) phenylpropanoic acid ester. Reaction process formula 6

[0210]

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Reaction Scheme 6 shows that the heterocyclic acid moiety (A1-A13) can be substituted with the gly-β-
A useful method for coupling to the amino moiety (C) is shown. The synthesis of A1-A13 is shown in Schemes 1-4 and the synthesis of (C) is shown in Scheme 5 where X and Y were the same or different halogens.

[0212] Such methods can be improved by conventional methods known to those skilled in the art. Reaction process formula 7

[0213]

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Scheme 7 illustrates a method for preparing the gly-β-amino acid portion (F) of a molecule by a general method. The aldehyde (R'CHO) used in this method is commercially available or can be prepared from commercially available reagents using methods for the preparation of aldehydes commonly known to those skilled in the art.

All other reagents are commercially available or can be easily synthesized by one skilled in the art. Such methods and conditions are further refined using conventional methods to produce similar desired intermediates. Reaction process formula 8

[0216]

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Scheme 8 illustrates the use of the heterocyclic acid moiety (A1-
13) shows a useful method for coupling gly-β-amino acid moiety (F).

The synthesis of A1-13 is shown in Schemes 1-4 and the synthesis of (F) is shown in Scheme 7. Such methods can be modified using conventional methods known to those skilled in the art.

Schemes 9-12 illustrate general methods for the preparation of the compounds of the present invention. Reaction process formula 9

[0220]

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Scheme 9 shows a method for the synthesis of heterocyclic derived gly-β-amino acid binding target compounds. Reaction of a gly-β-amino acid with a heterocyclic carboxylic acid under peptide coupling conditions affords intermediate (2). Catalytic hydrogenation (eg, P
The nitro group is reduced using t / C, H ₂ ) to give the amino intermediate (3). This transformation can also be accomplished chemically using ScCl _2. Amino groups can be converted to guanidino or other functional groups of formula I using the methods described above. Reaction process formula 10

[0222]

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Alternatively, the target compound can be synthesized by establishing the left hand part of the molecule before coupling with the gly-β-amino acid (Scheme 10). Heterocyclic amine (
The amino functionality of 1) is functionalized to guanidine or other groups (A, Formula I) and then binds to a gly-β-amino acid under standard coupling conditions. Reaction process formula 11

[0224]

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Scheme 11 shows the general synthesis of substituted pyridine and pyridone derived target compounds. Nitration and chlorination of 6-hydroxynicotinic acid gives 6-chloro-
5-nitronicotinic acid is obtained. Combining the Gly-β-amino acid with Intermediate 3 gives the product 4. The chloro group of multipurpose intermediate 4 can be easily replaced by various nucleophiles to give 5. Reduction of the nitro group at 4 or 5 and further refinement of the amino group, as discussed in Scheme 9, yields the target compound.

[0226]

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Scheme 12 shows the synthesis of substituted pyridine and pyridone derived target compounds starting from 2-amino-6-hydroxypyridine-4-carboxylic acid.
Starting material 1 used in the scheme can be prepared by reacting commercially available 2-chloro-6-methoxy-pyridine-4-carboxylic acid with ammonium hydride under pressure. As discussed in Scheme 10, when the amino group is engineered to attach to a gly-β-amino acid, the target compound is obtained.

[0228]

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Scheme 13 shows the synthesis of isomeric pyridines and pyridones starting from 6-amino-4-methoxy-picolinic acid. Starting material 1 used in Scheme 13 is described in the literature (J. Am. Chem. Soc., 78, 4130,
1956). Functionalization and coupling reactions of one amino group and hydrolysis (as described in Scheme 10) provide the target compound.

[0230]

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Homomeric pyridine and pyridone derived compounds can be prepared using the methodology illustrated in Scheme 14. Key intermediate 4 can be prepared starting from 6-chloro-picolinic acid. Oxidation and nitration gives the 4-nitropyridine derivative 3. Deoxygenation of the N-oxide, reduction of the nitro group, and nucleophilic substitution of the chloro group gives intermediate 4. Applying the methodology discussed in Scheme 10, the target compound can be synthesized.

[0232]

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The methodology shown in Scheme 10 can be used for the synthesis of pyrimidine-derived target compounds (Scheme 15). Allogeneic pyrimidine derivatives 1 and 2
It can be synthesized according to the production method of the literature (J. Org. Chem., 26, 2755, 1961). Example A

[0234]

Production of

5-aminonicotinic acid (4.0 g, 0.021 mole) (Helv. Chi
m. Acta. , 47, 363, 1964; JACS, 70, 2381, 194.
8), ¹ H-pyrazole-1-carboxamidine hydrochloride (4.6 g, 0.03
1 mole), diisopropylethylamine (8.0 g, 0.062 mole)
, Dioxane (14 ml) and H ₂ O (7ml), ₂ days and then heated under reflux. The reaction was cooled to room temperature, the precipitate was filtered and H ₂ O / dioxane (50: 5
Washed with 0) and dried. The precipitate was slurried in H ₂ in 0, 2N
Acidified with HCl. The solvent was removed under vacuum to leave the compound as a white solid (75
0 mg). Example B

[0236]

Production of

Step 1 To 3,4,5,6-tetrahydro-2-pyrimidinethiol in absolute ethanol (75 ml) is added Mel (12.2 g, 0.086 mole). The reaction was stirred at reflux for 2.5 hours. The solvent was removed under vacuum and the product was dried to give 2-methylthio-3,4,5,6-tetrahydro-2-pyrimidine hydroiodide as a white solid (22 g).

MS and ¹ H-NMR were consistent with the desired structure. Step 2 The product from Step 1 above (5.3 g, 0.03 in CH ₂ Cl ₂ (25 ml))
21 mole) and triethylamine (2.07 g, 0.021 mole) were added with BOC anhydride (4.5 g, 0.021 mole) at ice bath temperature. The reaction was then stirred at room temperature for 2 days. If the CH ₂ Cl ₂ was washed with H ₂ O (3x), dried over MgSO _4, and removed under vacuum, N-Boc-2- methylthio-3,4
, 5,6-tetrahydro-2-pyrimidine (4.14 g) were obtained.

MS and ¹ H-NMR were consistent with the desired structure. Step 3 The product from step 3 above (3.08 g, 0.0134 mole), 5-aminonicotinic acid (1.8 g, 0.0134 mole) / DMA (12 ml) was added to 8
Heated to 0-85 ° C for 2 weeks. The reaction mixture was diluted with CH ₃ CN, the precipitate was filtered, washed with CH ₃ CN, and dried. The precipitate was slurried in H ₂ 0, was lowered to 1-2 pH with concentrated HCl. The solution was frozen, frozen and dried to give the desired product as a light brown solid (1.2 g). MS and ¹ H-NMR were consistent with the desired structure. Example C

[0240]

Production of

[0241]Step 1 2-methylthio-2-imidazoline hydroiodide (20 g, 0.082 mo
le) (Aldrich) and triethylamine (8.28 g, 0.082 m)
ole) / CH_TwoCl_Two(100 ml), BOC anhydride (17.9 g, 0.08
2 moles) at ice bath temperature. The reaction was stirred overnight at room temperature. CH_TwoCl_TwoTo H _Two Wash with O (2x) and MgSO_FourDried over and removed under vacuum, N-BO
C-2-Methylthio-2-imidazoline is a viscous oil-modified white solid containing wax (
15.93 g).

MS and¹1 H-NMR was consistent with the desired structure.Step 2 Product from Step 1 above (15.93 g, 0.0737 mole), 5-
Aminonicotinic acid (9.5 g, 0.07 mole), and triethylamine (
7.1 g, 0.07 mole) / DMA (60 ml) was added to 100 ° C for 2 days.
Heating, then to 130 ° C for one day and then to 150 ° C for two more days
Was. The reaction mixture is CH_ThreeAfter cooling and diluting with CN, the precipitate is filtered and washed with ether.
Washed and dried (zwitter ion yield is 10.16 g). This is H _Two Slurried with O and acidified (pH 1-2) with TFA. Freeze the solution and freeze
Upon drying, the desired product was obtained as a pale yellow solid (20.15 g).

MS and ¹ H-NMR were consistent with the desired structure. Example D

[0244]

Production of

Step 1

[0246]

Production of

In a 2 liter round bottom flask equipped with a mechanical stirrer and a condenser,
3,5-dichlorosalicylaldehyde (200.0 g, 1.05 mol, 1 equivalent), acetic anhydride (356 g, 3.49 mol) and triethylamine (95.0).
g, 0.94 mol, 0.90 equivalent). The reaction solution was heated under reflux overnight. The dark brown reaction mixture was cooled to 50 ° C. and water (1 liter) was added with stirring. After 1 hour, the mixture was filtered and the filtrate was combined with EtOH (1 liter). The mixture was heated to 45 ° C. for 1 hour, cooled to room temperature, filtered, and the solid (fraction A) was washed with EtOH (0.5 L). The combined EtOH solution was concentrated by rotary vacuum concentration to yield a fat (fraction B). The solid from fraction A was dissolved in methylene chloride (1.5 L) and the resulting solution was passed through a silica gel pad (1300 ml volume). The resulting dark brown solution is concentrated to a fat and triturated with hexane (1.3 liter) to give a solid which is isolated by filtration and washed (hexane) to give substantially pure 6,8- Dichlorocoumarin (163 g) was obtained. In a similar manner: dissolve the fats and oils in methylene chloride (0.5 liter), silica pad (0.5 liter volume)
And trituration with hexane: treatment of the oils and fats in (fraction B) gave an additional 31 g of product. The total yield isolated is 194 g or 86% (brown solid).

MS and ¹ H-NMR were consistent with the desired structure. Step 2

[0249]

Preparation of

A 2-liter 3-neck round bottom flask equipped with a mechanical stirrer was charged with the 6,8-dichlorocoumarin (160 g, 0.74 mol) prepared in Step 1 and dry THF (375 ml, Aldrich Sure Seal). The resulting mixture was cooled to -40 ° C (dry ice-acetone bath) and the temperature was reduced to -4 ° C.
While maintaining the temperature at 0 ° C or less, lithium bis (trimethylsilyl) amide (0.80
mol. 800 ml, 1M / THF). At the end of the addition, the cooling bath was removed. After 0.5 hour, the mixture was warmed to -5 ° C. The reaction was stopped by adding HCl (0.5 L, 4 M / dioxane) / EtOH (1.25 L). The temperature was kept below 0 ° C overnight. The reaction mixture was concentrated to about 1/2 its original volume and partitioned between EtOAc (3 L) and water (2 L). The organic layer was washed with aqueous HCl (3 × 1 L, 0.5N HCl).
The pH of the combined aqueous layers was adjusted to about 7 by adding 10% aqueous NaOH and extracted with methylene chloride (3 × 2 liters). Dry the combined organic layers (M
gSO ₄ ), filtered and HCl (210 ml, 4M / dioxane) was added with stirring. When the precipitation was complete, the solid was removed by filtration. The filtrate was concentrated to a small volume, and methyl t-butyl ether was added. The solid obtained is combined with the solid originally formed, the combined products are washed with methyl t-butyl ether, isolated by filtration and dried (over a weekend in a vacuum oven) to give the desired product. (172 g, yield 74%) was obtained.

MS and ¹ H-NMR were consistent with the desired structure. Step 3

[0252]

Production of

A flame-dried round bottom flask (0.5 liter) equipped with a magnetic stir bar was charged with N
-T-Boc-glycine N-hydroxysuccinimide ester (Sigma
, 15.0 g, 0.055 mol), dry DMF (Aldrich Sure)
Seal, 200 ml) and the product from step 2 (21.67 g, 0.0
55 mol) were added under an inert atmosphere (Ar). Bring the reaction mixture to approximately 0 ° C
(Salt ice bath) and N-methylmorpholine (5.58 g, 0.056 mol)
e) and a catalytic amount of DMAP were added. The reaction was allowed to proceed overnight. The reaction mixture was concentrated to a slush, and EtOAc (0.4 L) and a basic aqueous solution (
(2 × 0.2 liter, saturated aqueous NaHCO ₃ ). The organic layer was washed successively with aqueous citric acid (2 × 0.2 liter, 10% W / V), aqueous sodium bicarbonate (2 × 0.2 liter), brine and dried (Na _2).
SO ₄ ). Removal of the volatiles at 55 ° C. under vacuum gave a fat (22.5 g, 92% yield) which solidified on standing.

MS and ¹ H-NMR were consistent with the desired structure. Step 4

[0255]

Production of

The product from Step 3 was deprotected using the following method to give the amine hydrochloride. Flame-dried round bottom flask (0.1 liter) with stirring bar
To the product (14.0 g, 0.032 mole) obtained in Step 3 of the above was added dry dioxane (40 ml). To this solution was added HCl (4.0 N / dioxane, 2 eq, 6.32 ml) at 0 ° C. The reaction was allowed to proceed until gas evolution had ceased and the reaction was complete. Volatiles were removed under vacuum and the residue was triturated with diethyl ether (50ml). The solid was collected by filtration, washed with ether and dried to give the desired product (12.5g).

MS and ¹ H-NMR were consistent with the desired structure. Example E

[0258]

Production of

Step 1

[0260]

Production of

3-Bromo-5-chlorosalicylaldehyde (175 g, 743.2 mmol
) / Acetic acid anhydride (280.5 ml, 3 mol) was added to triethylamine (1
(03.6 ml, 743.2 mmol). The reaction solution was heated under reflux for 4.5 hours. The solution was cooled and concentrated under vacuum. The brown residue was added to absolute ethanol (730ml). The mixture was stored at 0 ° C. for 14 hours. The brown solid was collected by filtration and washed with cold ethanol. The solid is dried under vacuum to give the desired product (
123 g, yield 64%). ¹ H-NMR was consistent with the desired structure. Step 2

[0262]

Production of

Coumarin generated in Step 1 (40.0 g, 154.1 mmol) / THF
(400 ml) suspension was added dropwise with stirring at −76 ° C. with lithium bis (trimethylsilyl) amide (154.1 ml 1M solution in THF). Add 1
Completed within 0 minutes. The reaction mixture was then stirred for 5 minutes, warmed to -20 ° C and stirred for 15 minutes. Acetic acid (9.25 g, 154.1 mmol) /
THF (28 ml) was added over 5 minutes. The mixture was warmed to room temperature and volatiles were removed under vacuum. The residue was dissolved in ether (850 ml) and saturated
Washed with aHCO ₃ aqueous solution (2 × 100 ml), brine (2 × 40 ml) and dried (MgSO ₄ ). The ether solution was concentrated to about 160 ml and cooled to 0 ° C. HCl (4M / dioxane, 56.3 ml, 225 mmol) in this suspension
Was added and the mixture was stirred at 0 ° C. for 30 minutes. The suspension was filtered and the filter cake was thoroughly washed with ether. The solid is dried under vacuum and the desired product is HC
1 salt, dioxane solvate (45 g). ¹ H-NMR was consistent with the desired structure. Step 3

[0264]

Production of

To a suspension of lactone (142.2 g, 354.5 mmol) / absolute ethanol (533 ml) produced in Step 2 was added HCl (4M / dioxane, 157.8).
ml, 631.1 mmol) was added over 10 minutes. The reaction mixture was stirred at room temperature for 2.5 hours. Volatile materials were removed under vacuum. The residue was taken up in ethyl acetate (4
50 ml) and the solution was kept at 0 ° C. for 15 minutes. The tan precipitate was collected by filtration and washed with cold ethyl acetate. The solid was dried under vacuum to give the desired product as the hydrochloride salt (100.4 g, 79% yield). ¹ H-NMR was consistent with the desired structure. Step 4

[0266]

Production of

In a flame-dried round bottom flask (0.1 liter) equipped with a magnetic stir bar, add Nt
-Boc-glycine N-hydroxysuccinimide ester (Sigma, 2
. 72 g, 0.010 mol), dry THF (Aldrich Sure Se)
al, 50 ml) and the product of step 3 (3.10 g, 0.01 mole,
(Dried under reduced pressure overnight in a desiccator over P ₂ O ₅ ) was added under an inert atmosphere (Ar). The reaction mixture was cooled to approximately 0 ° C (salt ice bath) and triethylamine (1
. 01g, 0.010 mole). The reaction was allowed to proceed overnight. The reaction mixture was concentrated to a semi-solid and proceeded in a manner similar to Example A, Step 3. The volatiles were removed from the organic layer under vacuum at 55 ° C. to give a fat (4.0 g, 83% yield).
) Was obtained and solidified when standing.

MS and ¹ H-NMR were consistent with the desired structure. Step 5

[0269]

Production of

The product obtained in Step 4 was deprotected and the hydrochloride was obtained using the following method. The product (4.0 g, 0.0084 mole) obtained in Step 4 in a flame-dried round-bottomed flask (0.1 liter) containing a stirring rod was charged with dry dioxane (20 m 2).
l) was added. To this was added HCl (4N / dioxane, 20 ml) and the reaction was allowed to proceed until gas evolution ceased, completing the reaction (about 1 hour). Volatiles were removed under vacuum and the residue was triturated with diethyl ether (50ml). The solid was collected by filtration, washed with ether and dried to give a light brown solid (2.7 g,
(78% yield).

MS and ¹ H-NMR were consistent with the desired structure. Example F

[0272]

Production of

Step 1 Preparation of 3-iodo-5-chlorosalicylaldehyde

[0274]

Embedded image

N-iodosuccinimide (144.0 g, 0.641 mole) was added to a solution of 5-chlorosalicylaldehyde (100 g, 0.638 mole) / dimethylformamide (400 ml). The reaction mixture was stirred for 2 days at room temperature. Further N
-Iodosuccinimide (20.0 g) was added and stirring was continued for another 2 days. The reaction mixture was diluted with ethyl acetate (1 liter) and hydrochloric acid (100 ml, 0.1 ml).
N), water (300 ml), sodium thiosulfate (5%, 300 ml), saline (
(300 ml), dried (MgSO ₄ ) and concentrated to dryness to afford the desired aldehyde as a pale yellow solid (162 g, 90% yield).

¹ H-NMR and MS were consistent with the desired structure. Step 2 Production of 6-chloro-8-iodocoumarin

[0277]

Embedded image

3-Iodo-5-chlorosalicylaldehyde (100 g, 0.354 mole)
), Acetic anhydride (300 ml) and triethylamine (54 ml)
Heat under reflux for 18 hours. Upon cooling, the desired coumarin precipitated as dark brown crystalline material. The precipitate was filtered, washed with hexane / ethyl acetate (4: 1, 200 ml) and air-dried [60 g (55% yield)]. An additional amount of the desired product (10 g, 9% yield) is obtained by filtration on storage.

¹ H-NMR and MS indicated this was the desired product. Step 3 Preparation of (R, S) -4-amino-3,4-dihydro-6-chloro-8-iodocoumarin hydrochloride

[0280]

Embedded image

Lithium hexamethyldisilazane (21.62 ml, 1M, 21.62 mmol)
1) was treated with 6-chloro-8-iodocoumarin (6.63 g, 21.62 mmol).
/ Tetrahydrofuran (100 ml), -78 ° C. The reaction mixture was stirred at this temperature for 30 minutes and then at 0 ° C. for 1 hour. Acetic acid (1.3 g, 2
1.62 mmol) was added to the reaction mixture. The reaction mixture was treated with ethyl acetate (300 m
l) and saturated sodium carbonate solution (200 ml). Separate the organic layer and at 0 ° C. brine (200 ml), then dioxane / HCl (4N, 30 ml).
And washed. The reaction mixture was stirred at room temperature for 1 hour, filtered and dried under vacuum to give the desired product as a powder (4.6 g, 59% yield) (rphplc:
Rf 6.8 min; 15% or more with 10% acetonitrile-90% acetonitrile gradient, then another 6 minutes with 100% acetonitrile. Water and acetonitrile both contain 0.1% TFA. Vydac C18 protein peptide column, flow rate 2 ml / min, monitored at 254 nm).

¹ H-NMR and MS were consistent with the desired product. Step 4 Preparation of (R, S) -ethyl 3-amino-3- (5-chloro-2-hydroxy-3-iodo) phenylpropion hydrochloride

[0283]

Embedded image

The hydrogen chloride gas was added to 4-amino-3,4-dihydro-6-chloro-8-iodocoumarin hydrochloride (22.0 g, 61.09 mmol) / ethanol (250 ml).
The reaction mixture was bubbled until saturation while maintaining the reaction mixture at 0-10 ° C. After refluxing for 5 hours, most of the solvent was removed by distillation. The cooled residue was added to anhydrous ether and stirred for 2 hours. Initially, the gum-like material turned into crystalline material. The crystalline product is filtered and dried to give the desired product as an off-white crystalline powder (2
(0 g, yield 81%) (Rf 7.52 min, step 3 conditions).

¹ H-NMR and MS were consistent with the desired product. Step 5 Preparation of (R, S) -ethyl-3- (N-Boc-Gly) -amino-3- (5-chloro-2-hydroxy-3-iodo) phenylpropionic acid

[0286]

Embedded image

BOC-gly (2.16 g, 12.31 mmol), HOBT (1.67 g)
, 12.31 mmol), a mixture of EDCl (2.36 g, 12.31 mmol) and DMF (50 ml) was stirred at 0 ° C. for 1 hour. Ethyl 3-amino-3- (5-chloro-2-hydroxy-3-iodo) propion hydrochloride (5.
0 g, 12.31 mmol) and then triethylamine (3.5 ml) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 18 hours. DMF was removed under vacuum and the residue was partitioned between ethyl acetate (300ml) and sodium bicarbonate (200ml). The organic layer was washed with hydrochloric acid (1N, 100 ml), brine (200 ml), dried (MgSO ₄ ) and concentrated to give the desired product as a solid (6 g, 93% yield).

¹ H-NMR and MS were consistent with the desired product. Step 6 Preparation of (R, S) -ethyl 3- (N-gly) -amino-3- (5-chloro-2-hydroxy-3-iodo) phenylpropionate hydrochloride

[0289]

Embedded image

Dioxane / HCl (4N, 20 ml) was added to ethyl 3- (N-Boc-gl
y) -Amino-3- (5-chloro-2-hydroxy-3-iodo) phenylpropionic acid (6.0 g, 11.30 mmol) was added at 0 ° C and stirred at room temperature for 3 hours. The reaction mixture was concentrated and once more after addition of toluene (100 ml). The residue obtained is suspended in ether, filtered and dried,
The desired product was obtained as a crystalline powder (5.0 g, 95% yield) (rphpl
c: Rf 8.3 min, step 3 conditions).

¹ H-NMR and MS were consistent with the desired product. Example G

[0292]

Production of

Step 1 Preparation of Reformatski Reagent

[0294]

Embedded image

A 4 liter flask equipped with a condenser, temperature probe and mechanical stirrer was charged with Zn metal (180.0 g, 2.76 mol, 30-100 mesh) and THF (1.25 liter). With stirring, 1,2-dibromoethane (4.74 ml, 0.06 mol) was added via syringe [alternatively, TMS Cl (0.1 eq) could be replaced at room temperature for 1 hour]. . After pressurizing with inert gas (3N ₂ / vacuum cycle), the zinc / THF suspension was heated to reflux (65 ° C.) and maintained at this temperature for 1 hour. After cooling the mixture to 50 ° C., tert-butyl bromoacetate (488 g, 369 ml,
(2.5 mol) was charged over 1.5 hours through a 50 ml syringe and a syringe pump (set at 4.1 ml / min). During the addition, the reaction temperature was maintained at 50 ° C +/- 5 ° C. After the addition was complete, the reaction mixture was stirred at 50 ° C for 1 hour. The mixture is then cooled to 25 ° C. and the precipitated product is set aside. The THF mother liquor was decanted into a 2 liter round bottom flask using a coarse glass fritted filter stick and partial vacuum transfer (20 mmHg). This removed about 65% THF from the reaction. 1-Methyl-2-pyrrolidinone (NMP, 800 ml) is added and stirring is continued again for 5 minutes. Filtration of the reaction mixture can remove any remaining zinc. Analysis showed the desired Reformatoski reagent titer of 1.57M with a molar yield of 94%. As an alternative, the solid reagent can be isolated from the original reaction mixture by filtration. Until a white solid was obtained, the cake was washed with THF, and dried under N _2, the desired product is obtained as a mono THF solvate, be stored in long term -20 ° C (dry) it can. Typical recovery is 85-90%. Step 2 A.

[0296]

Production of

Potassium carbonate (powder, oven dried at 100 ° C. under vacuum, 8.82 g,
60 mmoles) with 3,5-dichlorosalicylaldehyde (11.46 g,
60 mols) / DMF (40 ml) at room temperature to give a light yellow slurry. Next, while maintaining the bath temperature at 20 ° C., the MEMCl (net,
7.64 g, 61 mmoles) was added. The mixture was stirred at 22 ° C. for 6 hours,
MEMCl (0.3 g, 2.4 mmoles) was added. Add 0.5 more mixture
After stirring for an hour and pouring the reaction mixture into cold water (200 ml), the product precipitated. The slurry was filtered on a pressure filter, washed with water ( ₂ × 50 ml) and dried under N ₂ / vacuum to give the product as an off-white solid (14.94 g, 8% yield).
9%).

[0298]

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Calculated for C ₁₁ H ₁₂ Cl ₂ O ₄ ; Calculated; C, 47.33%; H, 4.33%; Cl, 25.40% Found; C, 47.15 %; H, 4.26%; Cl, 25.16%

[0300]

Preparation of

The product from Step 2A (35.0 g, 0.125 mol) was charged to a 1 liter 3-neck round bottom flask equipped with a mechanical stirrer and funnel, and additional THF (200 ml) was added. The solution was stirred at 22 ° C and (S) -phenylglycinol (17.20 g, 0.125 mol) was added in one portion. 30 minutes (
After 22 ° C.), MgSO ₄ (20 g) was added. The mixture was stirred at 22 ° C. for 1 hour and filtered through a coarse glass filter. The filtrate was concentrated under reduced pressure. No further purification was performed and the crude imine was used directly in the coupling reaction (Step 2C). C.

[0302]

Production of

[0303] In a 1 liter three-necked round bottom flask equipped with a mechanical stirrer and funnel,
The solid reagent from step 1 (91.3 g, 0.275 mol) and NMP (2
00 ml) was charged under nitrogen. The solution was then cooled to -10 ° C and 350
Stirred at rpm. An imine (prepared in step B) / NMP solution was prepared under nitrogen and then added to the above reaction mixture over 20 minutes while maintaining the temperature at -5 ° C (jacket temperature -10 ° C). . After the addition is complete, the mixture is further
The mixture was stirred at 8 ° C for 1.5 hours and at -5 ° C for 1 hour. After cooling to -10 ° C,
Concentrated HCl / NH ₄ Cl saturated solution (100 ml), water (100 ml) and brine (100 ml) were added to the solution. MTBE (200 ml) was added and the mixture was added to 23
The mixture was stirred at 200 rpm for 15 minutes. The stirring was stopped and the layers were separated. The aqueous layer was extracted with MTBE (100ml). The two organic layers were combined and washed thoroughly with a saturated NH ₄ Cl solution (100 ml), water (100 ml) and brine (100 ml). The solution is dried over MgSO ₄ , filtered and concentrated to give an orange oil (66.3 g) containing the desired product, which solidifies on standing, single diastereomer by proton and carbon NMR It was determined to be an isomer. A sample was purified for analysis by recrystallization from heptane to give the product as an off-white solid. Proton and carbon NMR and IR spectra were consistent with the desired product. [Α] ^D ₂₅ = + 8.7 ° (c = 1.057,
MeOH). Microanalysis; C ₂₅ H ₃₃ was calculated as _{Cl 2 NO 6: C: 58.77} %, H: 6.4%, N: 2.72%, Cl: 13.78% Found C: 58.22 %, H: 6.54%, N: 2.70%, Cl: 13.66%
Step 3

[0304]

Production of

A. Crude ester prepared in step 2 [17.40 g, 0.033 mole
(Theoretical value)], and a solution of EtOH (250 ml) was placed in a 1-liter three-necked jacketed reactor. The solution was cooled to 0 ° C and Pb (OAc) (14.
63 g, 0.033 mole) were added all at once. After 2 hours, a 15% solution of NaOH (30 ml) was added and the ethanol was removed under reduced pressure. Further 15% NaO
A portion of H (100 ml) was added and the mixture was extracted with MTBE (2 × 100 ml), washed with H ₂ O (2 × 100 ml) and brine (50 ml), dried over NA ₂ SO ₄ , filtered over celite and reduced pressure To give an orange oil (12.46 g) which was homogeneous by TLC. The fat was used without further purification.
B. The oil from A was diluted with EtOH (30 ml) and paratoluenesulfonic acid (1.3 eq, 0.043 mole, 8.18 g) was added. The solution was heated at reflux for 8 hours, cooled to ambient temperature and concentrated under reduced pressure. Residue in THF
(20 ml) and heated under reflux to form a solution. The solution was cooled to room temperature and the compound crystallized. Heptane (30 ml) and THF (10 ml)
Was added, a fluid slurry was formed and filtered. The cake was washed with THF / heptane (
40 ml, 1/1) and dried under vacuum with a pressure filter under nitrogen for 2 hours.
A white solid (7.40 g) was obtained.

The proton and carbon NMR and IR spectra were substantially consistent with the desired product, a single enantiomer. _{Microanalysis: C 18 H 21 Cl 2 NO} 6 S, 0.25C 4 H 8 O C, 48.73%; H, 4.95%; N, 2.99%: Cl, 15.14%
Found: C, 48.91%; H, 4.95%; N, 2.90%; Cl, 14.95%.
Step 4

[0307]

Production of

Step 3 In a 500 ml flask equipped with a magnetic stir bar and nitrogen bubbler
(21.7 g, 0.065 mole) from Nt-Boc-glycine N-hydroxysuccinimide ester (17.7 g, 0.065 mole)
And DMF (200 ml) were charged. The reaction mixture was added at room temperature under nitrogen.
Upon stirring for 25 hours, a light orange solution was formed. The reaction mixture was cooled with ice-cooled ethyl acetate (
1.2 liters). The organic solution was diluted with 1M HCl (250 ml),
It is then washed with brine (500 ml), dried (MgSO ₄ ) and concentrated under vacuum to near dryness to give a fat, which is then dried at 50 ° C. to give the product as a colorless fat. (28.12 g, 99% yield). Seed crystals were prepared from ethyl acetate / hexane. The product (about 28 g) was dissolved in ethyl acetate (35 ml) and hexane (125 ml). The solution was seeded with crystals to form a precipitate. The solid was filtered and dried under vacuum at 55 ° C. overnight to yield a colorless solid (27
. 0 g, 95% yield).

¹ H-NMR was consistent with the desired product. Step 5

[0310]

Production of

The Boc-protected glycinamide prepared in Step 4 (27.0 g, 0.062
mole) was dried over P ₂ O ₅ and NaOH pellets overnight. The solid was dissolved in dioxane (40 ml) and the solution was cooled to 0 ° C. Equivalent amount of 4N HCl
/ Dioxane (0.062 mole) was added and the reaction was carried out for 2 hours. The conversion at this point was 80% as determined by rphplc. The reaction mixture was warmed to room temperature and left for more than 4 hours. The reaction mixture was concentrated at 40 ° C. until a foam formed and triturated with ether (200 ml). The white solid formed was filtered and dried over P ₂ O ₅ to give the desired glycine β-amino acid ethyl esul compound as the HCl salt (20.4%, 88.5% isolated yield). ).

¹ H-NMR and MS were consistent with the structure. Example H

[0313]

Production of

Step 1

[0315]

Production of

Potassium carbonate (powder, oven dried at 100 ° C. under vacuum, 22.1 g, 0
. 16 moles) with 3-chloro-5-bromosalicylaldehyde (35 g,
(0.15 moles) / DMF (175 ml) at room temperature to give a light yellow slurry. Then, while maintaining the bath temperature at 20 ° C., the MEMCl
(Net 25.0 g, 0.2 moles). The mixture is then brought to 22 ° C for 6 hours.
After stirring for an hour and pouring into DI water (1200 ml), the product precipitated. The slurry was filtered on a pressure filter and the cake was washed with DI water (2 × 400 ml) and dried under N ₂ / vacuum to give the product as an off-white solid (46%, 95% yield)
).

[0317]

Embedded image

Microanalysis: calculated for C ₁₁ H ₁₂ BrClO ₄ C, 40.82%; H, 3.74%; Cl, 10.95%; Br, 24.69%: found; C, 40 H, 3.48%; Cl, 10.99%; Br, 24.67%: Step 2.

[0319]

Production of

The product from Step 1 (32.35 g, 0.1 mol) was placed in a 500 ml three-necked round bottom flask with a mechanical stirrer, then THF (160
ml) and (S) -phenylglycinol (13.71 g, 0.1 mol). After 30 minutes (22 ° C.), MgSO ₄ (20 g) was added. The mixture was stirred for 1 hour at 22 ° C. and filtered on a coarse glass filter. The filtrate was concentrated under reduced pressure to obtain a light yellow oil (48.0 g) containing imine. The crude product was used directly in the coupling reaction without further purification. Microanalysis; calculated for C ₁₉ H ₂₁ BrClNO ₄ C, 51.54%; H, 4.78%; N, 3.16%; Br, 18.04%; Cl, 8.00%: found. H, 5.02%; N, 2.82%; Br, 16.31%; Cl, 7.61%: Step 3.

[0321]

Production of

The reagent from Step 1 of Example G (332 g, 0.8 mol) was placed in a 5 liter three-necked round bottom flask with a mechanical stirrer under nitrogen under NMP (660).
ml). Next, the solution was cooled to -10 ° C. The imine / NMP (320 ml) solution produced in Step 2 was prepared under nitrogen and then added to the above reaction mixture within 30 minutes, maintaining the temperature at -5 ° C. The mixture was stirred for an additional hour and then cooled to -10 ° C. Concentrated HCl / saturated NH ₄ Cl solution (30 ml / 72
0 ml) was added over 10 minutes. MTBE (760 ml) was added and the mixture was stirred for 1 hour at 23 ° C. The stirring was stopped and the layers were separated. MTBE in water layer
(320 ml). The two organic layers were collected and combined with a saturated NH ₄ Cl solution (320
ml), DI water (320 ml) and brine (320 ml). The solution was dried over MgSO ₄ (60 g), filtered and concentrated to give a yellow oil (228 g) containing the desired product as a single diastereoisomer.
DSC: 227.54 ° C (endo.61.63J / g) microanalysis; was calculated to be C ₂₅ H ₃₃ BrClNO _6.

H, 5.95%; N, 2.50%; Br, 14.29%; Cl, 6.33%: found C, 53.80%; H, 6 N, 2.23%; Br, 12.85%; C, 6.12%: Step 4.

[0324]

Preparation of

The crude ester (〜111 g) / ethanol (1500 ml) solution from Step 3 was charged to a 3 liter 3-neck round bottom flask equipped with a mechanical stirrer under a nitrogen atmosphere. The reaction mixture was cooled to 0 ° C and lead tetraacetate (88.6
7 g, 0.2 mol) were added in one portion. The reaction mixture was stirred at 0 ° C. for 3 hours, then a 15% aqueous NaOH solution (150 ml) was added to the reaction mixture at below 5 ° C. The ethanol was removed under reduced pressure with a rotary vacuum concentrator. 15% NaO
H aqueous solution (600 ml) was added and the reaction mixture was ethyl acetate (2 x 300 ml),
Extracted with MTBE (2 × 200 ml) and ethyl acetate (2 × 200 ml).
The organic layer was collected, washed with DI water (2 × 200 ml) and brine (2 × 100 ml), and dried over anhydrous MgSO ₄ (30 g). The solution was then filtered through celite and concentrated under reduced pressure to give the product as an orange oil (96 g), which was used for the next step without further purification. DSC: 233.60 ° C (endo.67.85J / g) microanalysis: was calculated to C ₂₄ H ₂₉ BrClNO _5.

H, 5.54%; N, 2.65%; Br, 15.16%; Cl, 6.72%: found C, 52.12%; H, 5. N, 2.47%; Br, 14.77%; Cl, 6.48%: Step 5.

[0327]

Production of

The crude product from Step 4 (〜94 g) was taken up in absolute ethanol (180 ml) and paratoluenesulfonic acid monohydrate (50.0 g, 0.26 mol) was added. Then, after removing the solvent under reduced pressure, the reaction mixture was heated under reflux for 8 hours. The residual solid was taken up in THF (100 ml) and then the THF was removed under reduced pressure. The residue was dissolved in ethyl acetate (500ml) and cooled to ~ 5 ° C. The resulting solid was filtered and washed with heptane (2 × 50 ml) to give a white solid. The solid was air dried to give the product as a white solid (38g), single isomer.

[0329]

Embedded image

Microanalysis: calculated for C ₁₈ H ₂₁ BrClNO ₆ S, C, 43.69%; H, 4.27%; 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%; Cl, 7.20%; 54%: Step 6

[0331]

Production of

The above compound was prepared according to the method outlined in Steps 4 and 5 of Example G, but substituting the equivalent of the intermediate prepared in Step 5 as the free base in place of Step 4 of Example G. Was.

¹ H-NMR and MS were consistent with the desired product. Example I

[0334]

Production of

Step 1

[0336]

Production of

The above compound was prepared according to the methodology of Example G, Step 2A, but with 3,5
An equivalent amount of 2-hydroxy-3,5-dibromobenzaldehyde was used in place of -dichlorosalicylaldehyde.

Yield: 88%, pale yellow solid: m.p. p. 46-47 ° C., Rf = 0.6 (EtOAc / Hexane 1: 1 v / v);

[0339]

Embedded image

[0340] (M +) HR-MS C 11 H 12 Br 2 O 4 Calculated: 367.9083 Found: 367.9077 ¹ H-NMR and MS were consistent with the desired product. Step 2

[0341]

Embedded image

The above compound was prepared using the method of Example G, steps 2B and 2C,
The equivalent amount of compound from step 1 in this example was used instead. Yield: 90%, yellow solid: m.p. p. 57-59 ° C, Rf = 0.46 (EtOAc / Hexane 1: 1 v / v)

[0343]

Embedded image

HR-MS Calculated for C ₂₅ H ₃₄ NBr ₂ O ₆ : 602.0753 Found: 602.0749 ¹ H-NMR and MS were consistent with the desired product. Step 3

[0345]

Production of

The above compound (p-toluenesulfonate) was prepared according to the methodology of Example G, Step 3, except that Step 3A of Example G was replaced with an equivalent of Step 2.

Yield: 62%, white solid,

[0348]

Embedded image

HR-MS, calculated for C ₁₁ H ₁₄ NBr ₂ O ₃ : 365.340 Found: 365.9311 ¹ H-NMR and MS were consistent with the desired product. Step 4

[0350]

Production of

The above compound was prepared using the method of Example G, Step 4, but using the compound prepared in Step 3 of this Example produced a BOC protected intermediate. The resulting protected BOC intermediate was converted to the desired compound using the method described in Example G, Step 5.

¹ H-NMR and MS were consistent with the desired product. Example J ethyl β-[(2-aminoacetyl) amino] pyridine-3-propanoate, bis hydrochloride

[0353]

Embedded image

Step 1 To 3-pyridinecarboxaldehyde (300 ml) / 2-propanol (3 liters) was added ammonium acetate (297 g) followed by malonic acid (398 g). The reaction mixture was stirred under reflux for 5 hours. The precipitate was filtered while warm and washed with warm isopropanol (2 L). Next, when the obtained white solid was dried, DL-3-amino-3- (3-pyridyl) propionic acid was converted into a white solid (220
g).

The NMR and MS were consistent with the desired product. Step 2 DL-3-amino-3- (3-pyridyl) propionic acid (2
20 g) was slurried with anhydrous EtOH (3.6 L). HCl gas (one
leture bottle-1b) bubbled into the reaction over 40 minutes with stirring. The slurry was then heated at reflux for 4 hours (a solution forms after 1-1.5 hours).
The reaction mixture was cooled to 5 ° C in an ice bath. After stirring at 5 ° C for 1.5 hours, the resulting white precipitate was filtered and washed thoroughly with ether. After drying under vacuum at 50 ° C., the desired compound, ethyl DL-3-amino-3- (3-pyridyl) propionic acid dihydrochloride, was obtained as a white solid (331.3 g).

The NMR and MS were consistent with the desired product. Step 3 Ethyl DL-3-amino-3- (3-pyridyl) propionic acid dihydrochloride from step 2 (220.6 g, 0.83 mole) in anhydrous THF (2 L)
And triethylamine (167.2 g, 1.65 mole) in Nt-BO
C-glycine N-hydroxysuccinimide ester (225 g, 0.826
Mole) (Sigma) was added in several portions at 5-10 ° C. The reaction mixture was stirred overnight at room temperature. The resulting precipitate was filtered and washed with THF. The solvent from the filtrate was removed under vacuum. The residue was taken up in ethyl acetate (2.3 l). Sodium ethyl acetate layer was washed with saturated bicarbonate (2x900ml) and H ₂ O (3x
900 ml), dried over MgSO ₄ and removed under vacuum. The residue was slurried in 10% ethyl acetate / hexane (2.5 L) overnight. The precipitate was filtered, washed with 10% ethyl acetate / hexane (1 liter), then with hexane, and then dried to give ethyl β-[[2-[[(1,1-dimethylethoxy) carbonyl] amino]. [Acetyl] -amino] -pyridine-3-propanoate was converted to a white solid (23
3g).

NMR and MS were consistent with the desired product. Step 4 Ethyl β-[[2-[[(1,1-dimethylethoxy) carbonyl] amino] acetyl] amino] -pyridine-3-propanoate (from step 3) (232 g, 0.66 mo
le) was dissolved in warm dioxane (1 liter). After cooling to room temperature, 4M HCl
/ Dioxane (1.6 L) (Aldrich) was added slowly. After a few minutes, a white precipitate formed, which then turned into a more and more viscous material. Two hours later,
The solvent was decanted off. The residue was slurried in ether and the ether was decanted off until a white solid was obtained. This is dried under vacuum to give ethyl
β-[(2-Aminoacetyl) amino] pyridine-3-propanoic acid dihydrochloride was obtained as a white hygroscopic solid (224.2 g).

The NMR and MS were consistent with the desired product. Example K Preparation of 2-guanidino-4-carboxythiazole hydrochloride

[0359]

Embedded image

Step 1 2-Imino-4-thiobiuret (11.1 g, 0.094 mole) (Al
Ethyl bromopyruvate (20.0 g, 0.102 mole) (Aldrich) was added in portions to the (drich) / absolute EtOH (100 ml) under reflux.
The solution was stirred under reflux for 2 hours. More ethyl bromopyruvate (2.0 g) was added and the reaction continued under reflux for another 2 hours. The reaction was cooled to 10 ° C and concentrated N
H ₄ OH was added until pH = 10. The resulting precipitate was filtered, washed with ether and dried to give 2-guanidino-4-carboxyethylthiazole as a yellow solid (15.1 g).

MS and ¹ H-NMR were consistent with the desired product. Step 2 To the product of Step 1 (5.0 g, 0.023 mole) slurried in H ₂ O (100 ml) and ethanol (40 ml) was added NaOH (0.93 g,
0.023 mole). The solution was stirred overnight at room temperature. Further ethanol (20 ml) and NaOH (0.93 g) were added to the reaction mixture and the solution was stirred at room temperature for another hour. The pH was lowered to 7 with 1N HCl, the resulting precipitate was filtered, washed with H ₂ O and ether, and then dried to give the product (4.1 g) as a zwitterion.

The zwitterions were slurried with H ₂ O and acidified with concentrated HCl until solution.
The solution was frozen and lyophilized to give 2-guanidino-4-carboxythiazole hydrochloride as a pale yellow solid (4.33 g).

MS and ¹ H-NMR were consistent with the desired product. Examples L and M were prepared according to the scheme shown, starting with commercially available 2-amino-6-methylpyridine and 2-amino-4-methyl-pyridine, respectively. Example L Preparation of 2-aminopyridine-6-carboxylic acid

[0364]

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Step A 2-Acetylamino-6-methylpyridine (10.0 g) / water (125 ml)
KMnO ₄ (21.0 g) was added in portions to the solution at 75 ° C. and heating was continued for 2 hours. The reaction mixture was cooled, filtered, and the residue was washed with hot water (2x25ml). The combined aqueous filtrate and washings were washed with dichloromethane (3x40ml) and acidified with cold 3N HCl. The resulting precipitate is filtered, washed with water,
The pH was neutralized and dried under vacuum to give 2-acetylaminopyridine-6-carboxylic acid (3.8 g, 48% yield). The dichloromethane extract was concentrated to dryness and unreacted 2-acetylamino-6-methylpyridine (3.5
g) was obtained.

[0366]

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Step B 2-Acetylaminopyridine-6-carboxylic acid (4.1 g) /2.5 N Na
A suspension of OH (36.5 ml) was heated to 80 ° C. under a nitrogen atmosphere for 1.5 hours. The resulting solution was cooled and acidified with cold 3N HCl. The resulting precipitate was filtered and washed thoroughly with water and acetonitrile. The obtained white solid was dried under vacuum to obtain 2-aminopyridine-6-carboxylic acid (2.4 g, yield 76%).

[0368]

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Step C : A suspension of 2-aminopyridine-6-carboxylic acid (2 g) / EtOH (10.0 ml) and 4N HCl / dioxane (10.0 ml) was added under anhydrous conditions to 16 ml.
Heated to reflux for hours. The reaction mixture was then concentrated to dryness and the residue was dried in a desiccator under vacuum to give 2-amino-6-carbethoxypyridine hydrochloride as a white powder (1.6 g).

[0370]

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Example M Preparation of 2-aminopyridine-4-carbethoxypyridine hydrochloride

[0372]

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This compound (M) was prepared by a method similar to the method for producing 2-aminopyridine-6-carbethoxypyridine hydrochloride of Example L using 2-acetylamino-4-methyl-pyridine as a starting material. did.

The ¹ H-NMR and MS were consistent with the structure. Example 1

[0375]

Preparation of

The product of Example A (0.5 g, 0.002 mole), the product of Example E (0
. 83g, 0.002mole), triethylamine (0.2g, 0.002m
ole) and DMAP (24 mg) / anhydrous DMA (5 ml) were added to EDCl (0
. 38 g, 0.002 mole) at ice bath temperature. The reaction was stirred at room temperature for 2 days. The ether product was isolated by reverse phase separation HPLC. H ₂ O (3 ml
) And CH ₃ ester in CN (3ml), LiOH (0.51g , 0.0
12 moles). This was stirred at room temperature for 1 hour. The pH was reduced to 2 with TFA and the product was isolated by reverse phase separation HPLC to give (after lyophilization) the desired product as a white solid (350 mg). ¹ H-NMR and MS were consistent with the desired product. Example 2

[0377]

Production of

The title compound was prepared according to the method of Example 1, but using the equivalent product of Example D instead of the product of Example E to give the desired product as a white solid (210 mg). .

MS and ¹ H-NMR were consistent with the desired product. Example 3

[0380]

Preparation of

The product of Example C (19.5 g, 0.04) in a flame dried flame under N ₂
5 moles) and N-methylmorpholine (9.1 g, 0.09 moles) in anhydrous DMA (85 ml) were added to isobutyl chloroformate (6.2 g, 0.045 moles).
mole) was slowly added at ice bath temperature. The solution was stirred at ice bath temperature for 15 minutes. Thereafter, the product of Example D (15 g, 0.04 mole) was added at ice bath temperature and then N 2
-Methylmorpholine (4.1 g, 0.04 mole) was added slowly. The reaction mixture was stirred overnight at room temperature. Ester / CH ₃ CN (3 in H ₂ O (50 ml)
0 ml) was added LiOH (16 g, 0.38 mole). This was stirred for 1 hour at room temperature. The pH was reduced to 2 with TFA and the product was isolated by reverse phase separation HPLC to give (after lyophilization) the desired product as a white solid (13.7 g).

MS and ¹ H-NMR were consistent with the desired product. Example 4

[0383]

Production of

The above compound was prepared according to the methodology of Example 3, except that the product of Example D was replaced by an equivalent amount of the product of Example E. MS and ¹ H-NMR were consistent with the desired product. Example 5

[0385]

Production of

The above compound was prepared according to the methodology of Example 3, except that the product of Example D was replaced with an equivalent amount of the product of Example F. MS and ¹ H-NMR were consistent with the desired product. Example 6

[0387]

Preparation of

The above compound was prepared according to the methodology of Example 3, except that the product of Example C was replaced with an equivalent amount of the product of Example B. MS and ¹ H-NMR were consistent with the desired product. Example 7

[0389]

Preparation of

Example 9 Product of Step 3 (0.6 g, 0.0019 mole) / anhydrous DM
A (4 ml) was added to isobutyl chloroformate (0.27 g, 0.002 mol)
e) at ice bath temperature and then N-methylmorpholine (0.4 g, 0.0038 mole
) Was added. The solution was stirred at ice bath temperature for 15 minutes. The product of Example H (0.71 g
, 0.0017 mole) at ice bath temperature and then N-methylmorpholine (0.17 mole).
g, 0.0017 mole). The reaction was stirred overnight at room temperature. HPLC
Analysis showed product plus significant amount of starting material. EDCl (0.38 g, 0.00
2 moles) and DMAP (15 mg) were added to the reaction mixture and the reaction was stirred at room temperature overnight. The ester product was isolated by reverse phase separation HPLC. H ₂ O (
10 ml) and the ester in CH ₃ CN (5 ml) were added to LiOH (700 mg).
, 0.017 mole). This was stirred at room temperature for 1 hour. pH to TFA
And the product was isolated by reverse phase separation HPLC to give (after lyophilization) the desired product as a white solid (270 mg).

MS and ¹ H-NMR were consistent with the desired product. Example 8

[0392]

Production of

To the product of Example K (0.5 g, 0.0022 mole) and N-methylmorpholine (0.23 g, 0.0033 mole) / anhydrous DMF (8 ml) were added isobutyl chloroformate (0.31 g, 0 .0022mol) at ice bath temperature. After stirring at ice bath temperature for 5 minutes, the product of Example J (0.73 g, 0.0022 m
ole) and N-methylmorpholine (0.45 g, 0.0045 mole) /
Anhydrous DMF (8 ml) was added in one portion at ice bath temperature. The reaction mixture was stirred overnight at room temperature. The ester was isolated by reverse phase separation HPLC (530mg). This ester (
LiOH (91 mg) was added to 400 mg) / H ₂ O (10 ml). This was stirred at room temperature for 1 hour. The pH was lowered to 3 with TFA and the product was isolated by reverse phase separation HPLC to give (after lyophilization) the desired product as a white solid (350 mg).

MS and ¹ H-NMR were consistent with the desired product. Guanidation of 2-amino-6-carboethoxypyridine hydrochloride and 2-amino-4-carboethoxypyridine hydrochloride was carried out according to Examples N and O (Kim, SK, Qian, L. et al. , Tetrahedron Lett
. , 34, 7677, 1993) according to the method described in the scheme shown in
Performed using the ris-BOC reagent. Example N

[0395]

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2-Amino-6-carbethoxypyridine hydrochloride (0.56 g, 2.8 mmol
l) and tris-BOC reagent (91.2 g, 2.8 mmol) / degasification D
To a solution of MF (7.0 ml) was added mercuric chloride (0.76 g, 2.8 mmol) and triethylamine (0.79 g, 7.8 mmol). The resulting mixture was heated to 70 ° C. under a nitrogen atmosphere for 24 hours and filtered. DMF is distilled under vacuum,
The residue was triturated with ethyl acetate and filtered. The orange filtrate was concentrated and the resulting material was purified by flash chromatography on silica gel using ethyl acetate containing 1% triethylamine as eluent. Appropriate fractions (blue fluorescence) were combined and concentrated to dryness under reduced pressure to give a yellow powder. MS analysis [m /
z565 (M + H)] confirmed the formation of the desired tris-BOC product N. Example 0

[0397]

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This compound O was prepared using a method similar to that of Example N. MS analysis [m / z 565 (M + H)] confirmed the formation of the desired tris-BOC product O.

The following compounds P and Q can be prepared according to the conditions shown in Example 9 Steps 3-5. Example P

[0400]

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Embodiment Q

[0402]

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Embodiment R

[0404]

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The above compound was prepared using the method described in Example G. Reagent 3-bromo-
5-chlorosalicylaldehyde was used in step 2 instead of 3,5-dichlorosalicylaldehyde. Example 9

[0406]

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Step 1 To a mechanically stirred suspension of Reagent 1 (18.68 g) / THF (1 liter) at 0 ° C., sodium hydride (19 g, 60% suspension in mineral oil) Was added over 30 minutes. After 30 minutes, di-tert-butyl dicarbonate (95 g) was added neatly and the reaction mixture was gently heated to reflux for 16 hours. Mix at 0 ° C
And quenched with saturated NaHCO ₃ solution. The mixture was extracted with ethyl acetate. The organic extracts were washed with water, dried (Na ₂ SO _4), and concentrated. The residue was rapidly chromatographed on a small column of silica gel (60 mm × 180 mm) to give the desired product 2 as a dark yellow liquid (68 g). NMR was consistent with the indicated structure. Step 2 3-Amino-pyridine-6-carboxylic acid (25 g) / ethanol (300 ml)
) Was saturated with hydrogen chloride gas. The mixture was warmed to 23 ° C and heated to reflux for 2 hours. A clear solution was obtained. After cooling to 23 ° C., the mixture was concentrated in vacuo, neutralized with aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO _4, and concentrated in vacuo, ethyl 3-amino - pyridine-6-carboxylate as a pale yellow solid.

The product of Step 1 (40.0 g), HgCL_Two(25.0 g), triethyl
Amine (27 ml) and ethyl 3-amino-pyridine-6-carboxylate
(13 g) and DMF (200 ml) were stirred and kept at 55 ° C for 30 minutes.
Heated for hours. The reaction mixture was cooled to 23 ° C. and diluted with ethyl acetate (500 ml).
And filtered through celite. The filtrate is washed with water (2x), MgSO _Four Dry over and concentrate under vacuum. The residue was purified on silica gel with vinegar as eluent.
Chromatography using ethyl acetate / hexane gives the desired intermediate 3.
Was done. NMR was consistent with the desired structure.Step 3 A suspension of the product of Step 2 (13 g) in 5N hydrochloric acid (100 ml) was added to 23 °
Stirred at C for 16 hours. The mixture was concentrated under vacuum. Pulverize the residue with methanol
The white solid was then filtered to provide the desired product 4. NMR and MS
, Consistent with the desired structure.Step 4 The product of Step 3 (0.308 g) was suspended in DMF (10 ml) and
Methylmorpholine (0.2 ml) was added to the suspension. Mix for 1 hour at 23 ° C
Stirred. After cooling the reaction mixture to 0 ° C., IBCF (0.129 ml) was added.
. After 時間 hour, the product of Example R (0.416 g) and 4-methylmorpholine
(0.11 ml) / DMF (3 ml) was added. Mix the mixture at 23 ° C
Warmed for more than an hour. Thereafter, the mixture was filtered and the filtrate was concentrated under vacuum. Residue
Purification by HPLC provided 5. Microanalysis data, NMR and MS
, Consistent with the desired structure.Step 5

[0409]

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A solution of the product of Step 4 / 3.5 N HCl was allowed to stand at 23 ° C. for 3 hours, concentrated under vacuum, and the residue was purified by HPLC to provide the desired product. Microanalytical data, NMR and MS were consistent with the desired product.

[0411] _{Analysis, C 21 H 22 BrClN 6 O} 6 · 2CF 3 CO 2 H · H 2 0, and was calculated. C, 36.80; H, 3.21; N, 10.30: found C, 36.52; H, 2.90; N, 9.91: Example 10

[0412]

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This compound was prepared using the method described in Example 9 and substituting the product of Example G for the product of Step 4 of Example R. From analysis, it was found that C ₂₁ H ₂₂ Cl ₂ N ₆ O ₆ .2CF ₃ CO ₂ H. It was calculated to H ₂ 0.

C, 38.93; H, 3.40; N, 10.89: found C, 39.27; H, 3.12; N, 11.09: Example 11

[0415]

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The compound was prepared according to the method described in Example 9 using the product of Example I instead of the product of Step 4 of Example R. Analysis showed that C ₂₁ H ₂₂ Br ₂ N ₆ O ₆ . 2CF ₃ COOH. It was calculated as H ₂ O.

C, 35.65; H, 2.87; N, 9.98: found C, 35.81; H, 2.79; N, 10.14: Example 12 (3S) -N-. [[4-[(1,4,5,6-tetrahydro-5-hydroxy-2-pyrimidinyl) amino] -2-thienyl] carbonyl] glycyl-3- (3,5-dichloro-2-hydroxyphenyl)- Production of β-alanine and trifluoroacetate

[0418]

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Step 1 A solution of 5-bromo-2-thiophenecarboxylic acid (5.0 g) / concentrated sulfuric acid (30 ml) was cooled to -30 ° C. and 70% nitric acid (7.7 ml) (d = 1.40) ) / Concentrated sulfuric acid (30 ml) was added dropwise. The reaction mixture was stirred for 30 minutes at -25 ° C, then poured onto ice water and the slurry was stirred for several minutes. The precipitated solid was filtered, recrystallized from water and dried to give a white powder (2.3 g). ¹ H-N
MR was consistent with the desired structure. Step 2 A solution of the product from Step 1 (1.7 g) / THF (25 ml) with 5 ps
i was treated with a catalytic amount of 5% Pb / C in a hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered and concentrated. The residue was heated with ethyl acetate and filtered to give a brown solid (
750 mg). ¹ H-NMR was consistent with the desired structure. Step 3 The product of Step 2 (725 mg) and guanylating reagent G1 / THF (15
ml) and dimethylacetamide (10 ml) were refluxed for 16 hours. The reaction mixture was concentrated, the residue was treated with a solution of TFA (5 ml) and CH ₂ Cl ₂ (5ml). After stirring at room temperature for 1 hour, the reaction mixture was concentrated and the residue was subjected to reverse phase HPL.
Purification on C, using water (0.5% TFA) and acetonitrile gradient as eluent, gave a pale yellow thick fluid (300 mg). ¹ H-NMR was consistent with the desired structure. Step 4 N ₂ under in flame dried flask, the product from Step 3 (275 mg)
Was dissolved in 8 ml of dimethylacetamide and N-methylmorpholine (81 mg). The stirred solution was cooled to 0 ° C., and isobutyl chloroformate (109
mg) / dimethylacetamide (1 ml). The reaction mixture was stirred at 0 ° C. for 45 minutes and then treated dropwise with the product of Example G (286 mg) and a solution of N-methylmorpholine (81 mg) / dimethylacetamide (2 ml). The reaction mixture was warmed to room temperature and stirring was continued for 16 hours. The reaction mixture was concentrated and the residue was purified using reverse phase HPLC according to the method described in Example 3 to give a colorless thick fluid (262 mg). ¹ H-NMR was consistent with the desired structure. Step 5 A solution of the product of Step 4 (250 mg) in methanol (8 ml) and 1N
The sodium hydroxide solution (8 ml) was stirred at room temperature for 16 hours. The reaction was performed with TFA (0
. 7 ml) and concentrated. The residue was purified using reverse phase HPLC according to the method described in Step 3 to give a white solid (144 mg). ¹ H-N
MR was consistent with the desired structure.

From the analysis, it was calculated to be C ₂₀ H ₂₁ N ₅ O ₆ Cl ₂ S.1.50 TFA.0.25H ₂ O. H, 3.28; N, 9.92; S, 4.54; Cl, 10.04: found C, 38.81; H, 3.17; N, 9.90; S, 4.86; Cl, 10.25: Example 13 N-[[4-[(4,5-dihydro-1H-imidazol-2-yl) amino] -2-thienyl]
Production of carbonyl] glycyl-3- (3,5-dichloro-2-hydroxyphenyl) -β-alanine, trifluoroacetate

[0421]

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The above compounds were prepared in a sequence similar to the reaction used to prepare the compounds described in Example 12. The guanylating reagent described in Example C (Step 1) was used in place of G1 in Step 3 of Example 12. Similarly, the product of Example D was used in place of the product of Step 4 of Example G. ¹ H-NMR was consistent with the desired structure.

From the analysis, it was calculated to be C ₁₉ H ₁₉ N ₅ O ₅ Cl ₂ S.1.50 TFA.0.50 H ₂ O. H, 3.18; N, 10.29; S, 4.71; Cl, 10.42: found C, 38.84; H, 3.01; N, 10.50; S, 5.08; Cl, 11.101 Example 14 (3S) -N-[[5-methyl-4-[(1,4,5,6-tetrahydro-5-hydroxy-2-
Pyrimidinyl) amino] -2-thienyl] carbonyl] glycyl-3- (3,5-dichloro
Production of (-2-hydroxyphenyl) -β-alanine and trifluoroacetate

[0424]

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[0425]Step 1 (A) was prepared according to the method described in Step 1 of Example 13 by using 5-methyl-2-
Manufactured using thiophene carboxylic acid (5.2 g). Sodium hydroxide
Purified by extraction with dilute solution of um, acidification with dilute hydrochloric acid, and extraction with ethyl acetate
did. Dry the organic extract (Na_TwoSO_Four) And concentrate to a yellowish orange solid
A body (2.2 g) was obtained.¹1 H-NMR was consistent with the desired structure.Step 2 (B) uses the product of Step 1 (2.2 g) and then proceeds to Step 12 of Example 12.
Prepared under the coupling conditions described in Step 4. The reaction was concentrated and the residue was
Partitioned between chill and water. The organic extracts are washed with saturated sodium chloride solution and dried.
Dry (Na_TwoSO_Four) And concentrated. Recrystallization of the residue from ethyl acetate gave a tan
A solid (3.5 g) was obtained.¹1 H-NMR was consistent with the desired structure.Step 3 A solution of the product from step 2 (2.8 g) in THF (25 ml) was added at room temperature
, A solution of tin (II) chloride dihydrate / concentrated hydrochloric acid (1.0 g / 2 ml) was added dropwise, and TLC
Until complete disappearance of starting material was indicated. Remove the organic solvent and remove the aqueous
Neutralized with sodium bicarbonate solution. Aqueous part CH_TwoCl_TwoAnd dried (Na _Two SO_Four) And concentrated to give a yellow powder (1.1 g).¹H-
NMR was consistent with the desired structure.Step 4 The product described in Example 3 (375 mg) and the product from Step 1 of Example 9 (5
19 mg) / DMF (15 ml) was added to mercuric chloride (326 mg) and
Ethylamine (182 mg) was added. Heat mixture to 95-100 ° C for 3 hours
did. The reaction mixture was cooled, treated with ethyl acetate (30 ml) and stirred for 30 minutes
And then filtered through a pad of celite. Concentrate the filtrate and flush the residue
Chromatography (97.5% CHCl_Three-2.5% CH_ThreeElute with OH
) To give a yellowish-brown solid (415 mg).¹H
-NMR was consistent with the desired structure.Step 5 Product from step 4 (400 mg) / CH_TwoCl_Two(7.5 ml) and T
A solution of FA (7.5 ml) was stirred at room temperature for 1 hour. The reaction was concentrated and the residue
To CH_ThreeOH (10 ml) solution and 1N sodium hydroxide solution (10 ml)
The mixture was stirred at room temperature for 16 hours. The reaction was quenched with TFA (0.8 ml) and concentrated
did. The residue was purified using reverse phase HPLC according to the method described above to give a white solid.
(80 mg) was obtained.¹1 H-NMR was consistent with the desired structure. From the analysis, C_{twenty one}H_{twenty three}N_FiveO₆Cl_Two・ 1.50TFA ・ 0.50H_TwoCalculated as O
. C, 39.79; H, 3.55; N, 9.67; S, 4.43; Cl, 9.79: found C, 39.50; H, 3.24; N, 9.58; S, 4.71; Cl, 10.22:Example 15 (3S) -N-[[4- (4,5-dihydro-1H-imidazol-2-yl) amino] -5-methyl-2-thiie
Nyl] carbonyl] glycyl-3- (3,5-dichloro-2-hydroxyphenyl) -β-alani
Of trifluoroacetate

[0426]

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The reagents used in Example 4, Step 4 were replaced with the reagents described in Example C (Step 1).
Except that an anilating agent was used, it was used in the preparation of the compound described in Example 14.
The above compound was prepared in a reaction sequence similar to¹1 H-NMR was consistent with the expected structure. C₂₀H _{twenty one} N_FiveO_FiveCl_TwoS ・ 1.50TFA ・ 0.25H_TwoAnalysis of O: Calculated: C, 40.04; H, 3.36; N, 10.15; S, 4.65; Cl, 10.28. Found: C, 39.82; H, 3.19; N, 10.17; S, 4.86; Cl, 10.69.Example 16 N-[[5- (4,5-dihydro-1H-imidazol-2-yl) amino] -2-thienyl] carbonyl
] Glycyl-3- (3,5-dichloro-2-hydroxyphenyl) -β-alanine, trifluoro
Roacetate

[0428]

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Using the same reaction sequence as described in Example 15, the title compound was prepared starting from 2-nitro-5-thiophene-carboxylic acid. The conditions described in Example 17, Step G, were followed for the guanylation reaction. _{C 19 H 19 N 5 O 5} Cl 2 S · 1.50TFA Analysis: Calculated:. C, 39.36; H, 3.08; N, 10.43; S, 4.78 Found: C, 39.05; H, 2.79 ; N, 10.37 S, 4.90. Example 17 N-[[5- (4,5-dihydro-1H-imidazol-2-yl) amino] -6-methoxy-3-pyridinyl] carbonyl] glycyl-3- (3,5 -Dichloro-2-hydroxyphenyl) -β-alanine, bis (trifluoroacetic acid) salt

[0430]

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[0431]Stage 1 A mixture of 6-hydroxynicotinic acid (20 g) and colorless fuming nitric acid (60 ml) (d = 1.50) is mixed with 90
Heated to 9595 ° C. for 3 hours. Cool the reaction to room temperature and add 1.5 liter ice-water slurry
Poured over with stirring and then filtered after 15 minutes. Wash and dry the precipitate
And a pale yellow powder (9.3 g) were obtained.¹1 H-NMR was consistent with the expected structure. C₆H_FourN_TwoO_FiveAnalysis: Calculated: C, 39.14; H, 2.19; N, 15.22. Found: C, 39.08; H, 2.17; N, 15.19.Stage 2 A mixture of the product of Step 1 (5.0 g) and phosphorus oxychloride (15 ml) was refluxed for 3 hours.
The reaction mixture was cooled to room temperature, added to an ice-water mixture and stirred for 30 minutes. During this time,
More ice was added to keep the mixture cold. The reaction mixture is THF-ether
(1: 2) extract with the mixture, wash the organic extract with saturated sodium chloride solution and dry (Na _Two SO_Four) And concentrated. The residue was recrystallized from 1: 1 ether-hexane to give a yellow powder (
4.0 g) were obtained.¹1 H-NMR was consistent with the expected structure.Stage 3 A solution of the product of Step 2 (1.6 g) in thionyl chloride (5.0 ml) was refluxed for 3 hours. Anti
The reaction was cooled to room temperature and evaporated under a stream of nitrogen. The residue is dried under vacuum and
Used without production. Preparation of Example D in a flame dried flask under nitrogen
Product (3.0 g) in dimethylacetamide (30 ml) and N, N-diisopropylethylamine (2.3
g). The solution was cooled in an ice bath and the acid (obtained above) in THF (20 ml)
A solution of chloride was added dropwise. The reaction was stirred and allowed to warm to room temperature, then
Quenched with water (25 ml). The mixture was extracted with ethyl acetate and the organic extract was saturated
Wash with sodium solution and dry (Na_TwoSO_Four) And concentrated. Vinegar obtained yellow solid
Recrystallization from ethyl acid gave a pale yellow powder (3.4 g).¹H-NMR is planned
Matched with the structure.Stage 4 : To a suspension of sodium methoxide (2.2 g) in methanol (30 ml) was added methanol (3
A solution of the product of Step 3 (4.5 g) in 0 ml) was added dropwise at 0 ° C. Stir the reaction for 30 minutes
Stir and quench with acetic acid (2.3 ml). Concentrate the reaction and add ethyl acetate and water
Distributed. Dry the organic extract (Na_TwoSO_Four), Concentrate and concentrate on a silica gel column (80%
Purification with chill-20% hexane) yielded a pale yellow solid (3.5 g).¹H-NMR is
It matched the planned structure.Stage 5 A solution of the product described in step 4 (1.07 g) in ethanol (25 ml) is added at room temperature to water
In a 5 psi atmosphere, the catalyst was treated with a catalyst amount of 3% Pt / C contaminated with sulfur for 4 hours. reaction
The mixture was filtered and concentrated to give a white solid (930mg), which was further purified
Used without.¹1 H-NMR was consistent with the expected structure.Stage 6 : Step 5 (330 mg) in DMF (10 mL), G_Two(276 mg) in a solution of the product
(150 mg) and mercuric chloride (258 mg) were added and the mixture was heated at 85 ° C. under nitrogen for 16 hours.
. The reaction was cooled, treated with ethyl acetate (25ml) and filtered. The filtrate is concentrated and the residue
The 98% CH_TwoCl_TwoPurification on a silica gel column eluted with -2% methanol gives a white solid.
Body (325 mg) was obtained.¹1 H-NMR was consistent with the expected structure.Stage 7 A solution of the product from step 6 (114 mg), TFA (8 ml) and methylene chloride (8 ml) at room temperature
Stir for 90 minutes. The solvent was evaporated and the residue was washed with 1N sodium hydroxide (8 mL) and methanol.
(8 mL) at room temperature for 16 hours. Quench the reaction with TFA (1 mL) and concentrate
did. The residue was purified using reverse phase HPLC as previously described to give a white solid (76 mg).
Was.¹1 H-NMR was consistent with the expected structure. C_{twenty one}H_{twenty two}N₆O₆Cl_TwoAnalysis of 2TFA: Calculated: C, 41.74; H, 3.88; N, 12.70. Found: C, 41.47; H, 3.49; N, 12.85.Example 18 N-[[5- (4,5-dihydro-1H-imidazol-2-yl) amino] -1,6-dihydro-1-methyl
-6-Oxo-3-pyridinyl] carbonyl] glycyl-3- (3,5-dichloro-2-hydroxy
(Phenyl) -β-alanine, (trifluoroacetic acid) salt

[0432]

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Step 1 : A suspension of the product from Example 17, Step 1 (12.0 g) in methanol (200 ml) was treated with concentrated sulfuric acid (1 ml) and refluxed. After refluxing for 16 hours, the reaction mixture became a homogeneous solution, which was allowed to cool to room temperature. About half of the solvent was removed, at which point the product crystallized from solution. The mixture was cooled in an ice bath, filtered and dried to a yellow powder (1
6.7 g) were obtained. ¹ H-NMR was consistent with the expected structure. Step 2 : A solution of the product from step 1 (2.6 g) in DMF (40 ml) was cooled to 0 ° C. under N ₂ and treated with a 60% dispersion of sodium hydride (655 mg) in mineral oil. The mixture was stirred at 0 ° C. for 45 minutes and then treated in one portion with iodomethane (2.8 g). The reaction was stirred at room temperature for 16 hours, then partitioned between ethyl acetate and water. The aqueous portion was further extracted several times with ethyl acetate, then the combined organic extracts were washed with saturated sodium chloride solution and dried (N
a ₂ SO ₄ ) and concentrated. The residue was purified on a silica gel column (eluted with 2% methanol-98% methylene chloride) to give a yellow solid (1.9 g). ¹ H-NMR was consistent with the expected structure. Step 3 : The product from step 2 (2.6 g), methanol (60 ml) and 2N sodium hydroxide solution (6
(0 ml) was stirred at room temperature for 16 hours. The reaction was quenched with glacial acetic acid (6.9 ml) and concentrated. The residue was dried under high vacuum. This material is then converted to thionyl chloride under nitrogen.
(100 ml) and refluxed for 3 hours. The reaction was cooled, concentrated and dried completely under high vacuum to give a brown solid (2.2g). ¹ H-NMR was consistent with the expected structure. In a flask that was flame dried under nitrogen, the product of Example D (3.5 g) was dissolved in N, N-dimethylacetamide (35 ml) and diisopropylethylamine (2.9 ml). The solution was cooled to 0 ° C. and treated with a solution of acid chloride (obtained above) (1.9 g) in THF (35 ml).
The reaction was stirred for 30 minutes and then concentrated under high vacuum to remove the solvent. The residue was partitioned between ethyl acetate and water, and the aqueous portion was extracted several more times with ethyl acetate. The combined organic extracts were washed several times with water, then with a saturated sodium chloride solution, dried (Na ₂ SO ₄ ) and concentrated to give a yellow solid (1.3 g). ¹ H-NMR was consistent with the expected structure. Step 4 : A solution of the product of Step 3 (1.0 g) in THF (10 ml) and DMF (10 ml) under a 5 psi hydrogen atmosphere
It was treated with a catalytic amount of 5% Pt / C at room temperature for 4 hours. The reaction mixture was filtered and concentrated.
The residue was taken up in a minimum amount of THF and left to crystallize slowly at room temperature. An equal volume of ethyl acetate was added to the crystallization mixture and digested for 15 minutes. The mixture was cooled, filtered and washed with cold ethyl acetate. The product was dried to give a white solid (730mg). ¹ H-NMR was consistent with the expected structure. Step 5 : To a solution of the product of Step 4 (720 mg) and G ₂ (581 mg) in DMF (25 ml) was added triethylamine (304 mg) and mercury chloride (544 mg) and the mixture was heated at 85 ° C. under nitrogen for 1 hour. Heated for hours. The reaction mixture was cooled and filtered through a pad of celite. The filtrate was concentrated and purified on a silica gel column (eluted with 10% methanol-90% chloroform) to give a white solid (375mg). ¹ H-NMR was consistent with the expected structure. Step 6 : The compound prepared in Step 5 (360) using the method described in Example 14 (Step 5).
mg) to produce the above compound. The crude product is subjected to reverse phase HPLC as outlined previously.
Purification using gave a white solid (223 mg). ¹ H-NMR was consistent with the expected structure. _{C 21 H 22 N 6 O 6} Cl 2 · 2.5TFA · 0.5H 2 O Analysis: Calculated:. C, 38.11; H, 3.14; N, 10.26; Cl, 8.65 Found: C, 38.18; H, 3.05 N, 10.79; Cl, 9.34. Example 19 N-[[6-Chloro-5-[(4,5-dihydro-1H-imidazol-2-yl) amino] -3-pyridinyl] carbonyl] -glycyl- 3- (3,5-dichloro-2-hydroxyphenyl) -β-alanine, (trifluoroacetic acid) salt, monohydrate

[0434]

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Step 1 : A solution of tin (II) chloride (6.3 g) in concentrated hydrochloric acid (10 ml) was prepared and Example 1 in THF (15 ml).
7, was added dropwise to a solution of the product from Step 3 (1.0 g). The reaction was stirred for 15 minutes,
The reaction was then cooled back to room temperature. Removal of the organic phase resulted in a gummy precipitate. The aqueous portion was decanted and the gummy precipitate was partitioned between ethyl acetate and dilute sodium bicarbonate solution. Extracted several times and the aqueous portion with additional ethyl acetate, the combined organic phases were washed with water and saturated sodium chloride solution, dried (Na ₂ SO _4), and concentrated. The residue was dried in vacuo to give a brown powder (375mg). ¹ H-NMR was consistent with the expected structure. Step 2 : The compound described in Step 1 (365 mg) was guanylated using the method described in Example 18, Step 5. The crude product was purified on a silica gel column (eluted with 2% methanol-98% chloroform) to give a brownish viscous liquid (205mg). ¹ HN
MR was consistent with the planned structure. Step 3 : The title compound was prepared according to the method described in Example 17, Step 7 using the product of Step 2 (200 mg). The crude product was purified using reverse phase HPLC as previously described to give a white solid (53 mg). ¹ H-NMR was consistent with the expected structure. _{C 20 H 19 N 6 O 5} Cl 3 · 1.7TFA · 1.0H 2 O Analysis: Calculated:. C, 37.90; H, 3.09; N, 11.33; Cl, 14.34 Found: C, 37.53; H, 2.71 N, 11.33; Cl, 15.01. Example 20 N-[[5-[(4,5-dihydro-1H-imidazol-2-yl) amino] -1,6-dihydro-6-oxo-3-pyridinyl ] -Carbonyl] glycyl-3- (3,5-dichloro-2-hydroxyphenyl) -β-alanine, (trifluoroacetic acid) salt

[0436]

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The above compound was prepared by dissolving the product from Example 17, Step 6 (353 mg) in a 6N solution of hydrochloric acid (50 ml) at room temperature for 48 hours. The reaction was concentrated and the residue was purified using reverse-phase HPLC as described above to give a white solid (115 mg). ¹ H-NMR was consistent with the expected structure. _{C 20 H 20 N 6 O 6} Cl 2 · 1.25TFA Analysis: Calculated:. C, 41.33; H, 3.28; N, 12.85 Found:. C, 41.57; H, 3.29; N, 12.92 Example 21 ( 3S) -N-[[1,6-dihydro-6-oxo-5-[(1,4,5,6-tetrahydro-5-hydroxy-2-
Pyrimidinyl) amino] -3-pyridinyl] carbonyl] glycyl-3- (3,5-dichloro-2-
Production of hydroxyphenyl-β-alanine and trifluoroacetate

[0438]

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The starting materials used in the preparation of the title compound were synthesized using the reaction sequence described in Example 17 (Steps 1-3). Instead of the product of Example D, the chiral intermediate of Example G was used in the coupling reaction detailed in Step 3. Step 1 : (A) was prepared using the method described in Example 17, Step 4. ¹ H-NMR was consistent with the expected structure. Step 2 : A solution of the material from step 1 (2.7 g) in 4N anhydrous HCl / dioxane (100 ml) under N ₂ under 72
Warmed to 45 ° C. for hours. The reaction was concentrated to dryness to give a light brown solid (2.6g). ¹ H-NMR was consistent with the expected structure. Step 3 : A solution of the product from Step 2 (1.85 g) in ethanol (50 ml) was treated with a catalytic amount of 5% Pt / C under a 5 psi hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered, concentrated and the residue was purified using reverse phase HPLC to yield a white solid (507mg). ¹ H-NMR was consistent with the expected structure. Step 4 : The product from Step 3 (500 mg) and the product of Step 1 of Example 4 (650 mg) in DMF (15 ml).
mg), triethylamine (304 mg) and mercuric chloride (408 mg) were added and the mixture was heated to 100 ° C. under nitrogen for 2 hours. The reaction mixture was cooled to room temperature and ethyl acetate (30
ml) for 15 minutes and then filtered. The filtrate was concentrated and the residue was treated with TFA (7 ml) and CH ₂ C
A solution of l ₂ (7 ml) was treated at room temperature for 1 hour. Concentrate the mixture and reverse phase HP as described above.
Purification of the residue using LC yielded a white solid (400 mg). ¹ H-NMR was consistent with the expected structure. Step 5 : A solution of the product of Step 4 (200 mg), 1N sodium hydroxide (8 ml) and methanol (8 ml) was stirred at room temperature for 16 hours. The reaction was quenched with TFA (1 ml) and concentrated. The residue was purified using reverse phase HPLC as previously described to yield a white solid (79 mg). ¹ H-NMR
Matched the expected structure. _{C 21 H 22 N 6 O 7} Cl 2 · 1.5TFA Analysis: Calculated:. C, 40.46; H, 3.32; N, 11.80 Found:. C, 40.12; H, 3.57; N, 12.26 Example 22 N -[[5-[(4,5-Dihydro-1H-imidazol-2-yl) amino] -2-methoxy-3-pyridinyl] carbonyl] glycyl-3- (3,5-dichloro-2-hydroxyphenyl) of β-alanine, (trifluoroacetic acid) salt

[0440]

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Step 1 : To a solution of 2-hydroxynicotinic acid (10.0 g, 71.9 mmol) in concentrated sulfuric acid (28.6 ml) was added dropwise fuming nitric acid (7.1 ml). The reaction mixture was heated at 55 ° C. for 4 hours. The cooled reaction mixture was poured on ice-water. The product precipitated as a yellow solid. The precipitated solid was collected by filtration, washed with water, and air-dried to yield the desired product (7.2 g, 54% yield). NMR was consistent with the expected structure. Step 2 : A solution of the product of Step 1 (5.0 g, 27.2 mmol) in phosphorus oxychloride (13.5 g) was refluxed for 4.5 hours. The cooled reaction mixture was poured on ice water (200g). The resulting mixture was stirred for 30 minutes and extracted with tetrahydrofuran / ethyl acetate (2/1). The organic phase was washed with brine, dried over Na ₂ SO _4, and filtered. The filtrate was concentrated to an oil. Treatment of the oil with a mixture of hexane / ether (4/1) gave the desired product as a fine yellow powder (5.0 g, 91% yield). NMR was consistent with the expected structure. Step 3 : A solution of the product of Step 2 (3.1 g, 15.3 mmol) in thionyl chloride (8.1 ml) was refluxed for 4.5 hours. The remaining thionyl chloride was removed from the reaction mixture under reduced pressure to give a light brown oil. The oil was dried under vacuum to give a yellow solid (2.7 g, 79% yield)
The product was obtained as NMR was consistent with the expected structure. Step 4 : To a solution of the product of Example D (5.5 g, 14.8 mmol) in N, N-dimethylacetamide (40 ml) and tetrahydrofuran (15 ml) was added diisopropylethylamine (3.7 g, 4.9 ml) and the reaction mixture was added. Was cooled to -5 ° C. A solution of the product of Step 3 (3.1 g, 14.1 mmol) in tetrahydrofuran (25 ml) was added to the reaction over 15 minutes. Bring the reaction to
Stirred for 0 min and allowed to warm to room temperature. After 3 hours, tetrahydrofuran was removed from the reaction mixture under reduced pressure. The reaction mixture was poured over ice-water. The precipitated solid was collected by filtration, washed with water, and air-dried to give the product as a yellow solid (6.2g, 85% yield). NMR was consistent with the expected structure. Step 5 : A solution of the product of Step 4 (4.0 g, 7.7 mmol) and sodium methoxide (1.67 g, 30.8 mmol) in methanol (45 ml) was stirred at 0 ° C. for 4 hours. The reaction was neutralized with acetic acid. The methanol was removed from the reaction mixture and the crude mixture was purified by chromatography (silica gel, ethyl acetate-toluene, 6/4) to give the desired product as a yellow solid (2.5 g, 67% yield). NMR was consistent with the expected structure. Step 6: The product of Step 5 (0.99g, 1.9mmol), 3 % on carbon platinum, and a mixture of methanol and treated at room temperature for 16 h, at 5psi under H ₂ gas. The platinum catalyst was removed by filtration. Removal of the methanol under reduced pressure afforded the desired product as a yellow solid (0.62 g, 70% yield). This was used in the next reaction without further purification. NMR was consistent with the expected structure. Step 7 : Step 6 product (0.26 g, 0.54 mmol), G ₂ (0.18 g, 0.59 mmol), triethylamine (0
.25 g, 1.78 mmol), mercury (II) chloride (0.16 g, 0.59 mmol) and N, N-dimethylformamide
(15 ml) 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 then dichloromethane (30 ml). The crude mixture was purified by chromatography (silica _{gel, CH 2 Cl 2 -CH 3 OH} -NH 4 OH, 95/5/0
.5) gave a yellow solid (0.31 g, 76% yield). NMR was consistent with the expected structure. Step 8 : A solution of the product of step 7 (0.31 g, 0.41 mmol), trifluoroacetic acid (3.5 ml), and dichloromethane (7.0 ml) was stirred at room temperature for 2 hours. The trifluoroacetic acid and dichloromethane were removed under reduced pressure, and the crude mixture was treated with methanol (5 ml) and sodium hydroxide solution (
2N, 2.5 ml) for 18 hours at room temperature. Acetic acid was added to neutralize the sodium hydroxide. The methanol was removed to give a crude mixture. The crude mixture was purified using reverse phase HPLC to give the compound as a white solid (0.10 g, 36% yield). Analysis for C ₂₁ H ₂₂ N ₆ O ₆ Cl ₂ · 1.3CF ₃ COOH · 0.25H ₂ O: Calculated: C, 41.80; H, 3.54; N, 12.39; Cl, 10.46. Found: C, 42.12; H N, 11.84; N, 11.87; Cl, 10.99. Example 23 N-[[5-[(4,5-dihydro-1H-imidazol-2-yl) amino]
-1,2-dihydro-2-oxo-3-pyridinyl] -carbonyl] glycyl-
Production of 3- (3,5-dichloro-2-hydroxyphenyl) -β-alanine, (trifluoroacetic acid) salt

[0442]

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A solution of the product of Example 22, Step 7 (0.21 g, 0.28 mmol) in dioxane (4 ml) was treated with 6N HCl (6 ml) for 72 hours at room temperature. The solvent was distilled off under reduced pressure, and the crude mixture was subjected to reverse-phase H
Purification by PLC gave the desired compound as a slightly off-white solid (0.052 g, 27% yield). As Elemental Analysis _{C 20 H 20 N 6 O 6} Cl 2 · 1.6CF 3 COOH: Calculated: C, 40.17; H, 3.14 ; N, 12.11; Found: C, 40.10; H, 3.22; N, 11.84. Example 24 N-[[5-[(4,5-dihydro-1H-imidazol-2-yl) amino]
-1-methyl-1H-pyrazol-3-yl] carbonyl] glycyl-3- (3
Of 5,5-dichloro-2-hydroxyphenyl) -β-alanine, (trifluoroacetic acid) salt

[0444]

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Steps 1 and 2 in the synthesis of the target compound were performed according to literature methods (
Each of Justus Liebigs. Ann. Chem, 512, 96, 193
4 and J.I. Heterocyclic Chem. 21,737,1994)
. Step 3 : The product of Step 2 (0.9 g, 5.3 mmol) and G2 (1.9 g, 5.9)
Mmol) in DMF (25 ml).
6 mmol) mercuric chloride (1.6 g, 5.9 mmol) was added. Mix 8
After heating at 0-85 ° C. for 18 hours, the reaction mixture was cooled and filtered through a celite column. The residue was washed with methylene chloride, and the combined fractions were concentrated. The residue was redissolved in methylene chloride and washed with water and brine. After drying over sodium sulfate,
The mixture was filtered and concentrated. Purification of the crude orange solid (1.8 g) using silica gel chromatography (hexane / ethyl acetate 1/1) yielded NB
The oc-protected compound was obtained as a slightly off-white solid (1.4 g).
. Step 4 : To a solution of the product of Step 3 (2.4 g, 5.5 mmol) in ethanol (50 ml) was added an aqueous lithium hydroxide solution (526 mg in 5 ml of water). The reaction mixture was stirred at room temperature for 24 hours. Acetic acid (22 ml) was added to the reaction and the mixture was stirred for 15 minutes. After removing the solvent under reduced pressure, the crude mixture was purified by reverse phase HPLC (acetonitrile / water containing trifluoroacetic acid) to give the product as a TFA salt as a thick white liquid. The residue was treated with hydrogen chloride (4M dioxane solution)
Stirred for minutes. The reaction was concentrated to remove the solvent and this process 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 : To a solution of the product of Step 4 (0.9 g, 3.7 mmol) in DMF (15 ml)
At 0 ° C., N-methylmorpholine (605 ml, 5.5 mmol) and isobutyl chloroformate (475 ml, 3.7 mmol) were added successively. After stirring for 5 minutes, the DMF of the product of Step D (10 ml, N-methylmorpholine (605 ml, 5 ml
. 5 mmol) was injected into the reaction. The mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 36 hours. After removal of the solvent under reduced pressure, the residue was separated on reverse phase HP
Purification by LC (acetonitrile / water containing trifluoroacetic acid) yields TFA
Obtained as a salt (525 mg). Step 6 : To a solution of the product of Step 5 (540 mg, 1 mmol) in ethanol (50 ml) was added an aqueous lithium hydroxide solution (144 mg in 10 ml of water). The reaction mixture was stirred at room temperature for 24 hours. Acetic acid (305 ml) was added to the reaction and the mixture was stirred for 15 minutes. After removing the solvent under reduced pressure, the crude mixture was purified by reverse phase HPLC (acetonitrile / water containing trifluoroacetic acid) to give the desired compound as a TFA salt (486 mg, 75% yield). Elemental analysis As C ₁₉ H ₂₁ N ₇ O ₅ Cl ₂ .1.5CF ₃ CO ₂ H: Calculated: C, 39.48; H, 3.39; N, 14.65; Found: C, 39. 29; H, 3.14; N, 14.72.

NMR and MS were consistent with the desired structure. Example 25 N-[[5-[(4,5-dihydro-1H-imidazol-2-yl) amino]
1H-Pyrazol-3-yl] carbonyl] -glycyl-3- (3,5-dichloro-2-hydroxyphenyl) -β-alanine, (trifluoroacetic acid) salt

[0447]

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This compound was synthesized as in Example 24 using benzylhydrazine instead of methylhydrazine in step 2. The resulting N-benzylpyrazole compound was deprotected in the last step using catalytic hydrogenation conditions (5% Pd / C, 20 psi, room temperature, 26 hours). This reaction was performed using acetic acid-trifluoroacetic acid as a solvent. Elemental analysis As C ₁₈ H ₁₉ N ₇ O ₅ Cl ₂ 1.75 CF ₃ CO ₂ H.1.25 H ₂ O: Calculated: C, 36.56; H, 3.32; N, 13.88; Values: C, 36.35; H, 2.96; N, 14.28.

NMR and MS were consistent with the desired structure. Example 26

[0450]

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The above compound was prepared as described in Example 9 except that Step R of Example R
The product of Example S was used in place of the product of Example S. Elemental analysis: C ₂₁ H ₂₂ BrIN ₆ O ₆ .2CF ₃ COOH.0.25H ₂ O: Calculated: C, 33.60; H, 2.76; N, 9.40; Found: C, 34. 23; H, 2.35; N, 9.72. Example 27

[0452]

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The starting materials required for this example were synthesized using the method of Example 21, Step 1. Step 1 A solution of the starting material (1.4 g) in ethanol (50 ml) under 5 psi hydrogen pressure
The mixture was treated with a catalytic amount of 5% Pd / C at room temperature for 5 hours. The reaction mixture was filtered, concentrated and dried to give a white solid (1.1 g). ¹ H-NMR was consistent with the proposed structure. Step 2 Compound 2 was prepared according to the experimental procedure shown in Step 4 of Example 21. ¹ H-
NMR was consistent with the proposed structure. Step 3 The ester group of compound 2 was hydrolyzed according to the experimental procedure shown in Step 5 of Example 21. ¹ H-NMR was consistent with the proposed structure. As Elemental Analysis _{C 22 H 24 N 6 O 7} Cl 2 · 1.50TFA · 0.25H 2 O: Calculated: C, 41.08; H, 3.59 ; N, 11.50; Found: C, 41.03; H, 3.69; N, 11.45. Example 28

[0454]

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The starting materials required for this Preparation Example were prepared using the method of Example 18, Step 1.
Was done.Step 1 Compound 1 was prepared according to the procedure shown in Step 2 of Example 18, except that
2-methoxyethoxymethyl chloride as an alkylating agent in place of iodomethane
Was used.¹1 H-NMR was consistent with the proposed structure.Step 2 A solution of the product described in Step 1 (4.6 g) in methanol (50 ml) was added in 5 ps.
The mixture was treated with a catalytic amount of 5% Pd / C at room temperature for 5 hours under a hydrogen pressure of i. Reaction mixture
The mixture was filtered, concentrated and dried to give a viscous oil (4.3 g).¹
1 H-NMR was consistent with the proposed structure.Step 3 A part (2.0 g) of the product of Step 2 was subjected to the reaction conditions described in Step 4 of Example 21.
Guanylation with afforded product 3 as a viscous oil (890 mg). ¹ 1 H-NMR was consistent with the proposed structure.Step 4 The ester group of product 3 was hydrolyzed according to the experimental procedure set forth in step 5 of Example 21.
It was solved.¹1 H-NMR was consistent with the proposed structure.Step 5 The product of Step I is converted to the product of Example I according to the method set forth in Step 4 of Example 12.
And coupled.¹1 H-NMR was consistent with the proposed structure.Step 6 The ester group of the product of Step 5 was prepared according to the experimental method shown in Step 5 of Example 21.
Hydrolyzed.¹1 H-NMR was consistent with the proposed structure. Elemental analysis C_{twenty five}H₃₁N₆O₉Br_Two・ 1.75 TFA ・ 0.25H_TwoAs O: Calculated: C, 37.07; H, 3.63; N, 9.10; Found: C, 36.86; H, 3.66; N, 9.39.Example 29

[0456]

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The product of Step 5 of Example 28 was used as starting material for this example. Step 1 A portion of the starting material (425 mg) was treated with anhydrous saturated HCl-ethanol (10 ml) at room temperature for 4 hours. The reaction mixture was concentrated to dryness and the product was used for the next step without further purification. Step 2 The ester group of the crude product of Step 1 was hydrolyzed according to the experimental method described in Step 5 of Example 21. ¹ H-NMR was consistent with the proposed structure. Elemental analysis As C ₂₁ H ₂₂ N ₆ O ₇ Br ₂ · 1.75 TFA · 0.25H ₂ O: Calculated: C, 35.27; H, 2.93; N, 10.07; 35.21; H, 3.16; N, 10.27. Example S

[0458]

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The above compound was prepared according to the method described in Example G. In Step 2A, 3-iodo-5-bromosalicylaldehyde was used instead of 3,5-dichlorosalicylaldehyde. Example T

[0460]

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The above compound was prepared according to the method described in Example G. In step 2A, 3-bromo-5-chlorosalicylaldehyde was used instead of 3,5-dichlorosalicylaldehyde. Similarly, in step 2B, R-phenylglycinol was used instead of S-phenylglycinol. Example U

[0462]

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The above compound was prepared according to the method described in Example D. The racemic compound obtained in Step 2 was resolved as follows.

[0464]

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Step 1 : Racemic aminoester hydrochloride obtained from Example D, Step 2 (50.0 g,
158.9 mmol of CH ₂ Cl ₂₎ (500 mL) and water (380 mL) NaHCO ₃ solution (38.2 g, was added 454.5 mmol). The mixture is stirred at room temperature for 10 minutes with vigorous gas evolution. Benzyl chloroformate (43
. 4g, was added with stirring rapidly over 222.8 mmol of CH ₂ Cl ₂₎ (435 mL) solution over 20 minutes. After 40 minutes, the reaction mixture was placed in a separatory funnel and the organic solution was collected. The aqueous phase was washed with CH ₂ Cl ₂ (170mL). The combined organic solution was dried (MgSO ₄ ) and concentrated in vacuo. The resulting rubbery solid was triturated with hexane and collected by filtration. The tan solid was dried under vacuum to give the desired racemic product (62.9 g, 96% yield). This material was subjected to reverse phase HPLC using a chiral column to give each pure enantiomer, A and B. The column used was Welk-O (R, R), 10 micron particle size, using 90:10 heptane: ethanol as mobile phase. Using analytical HPLC with similar solvents and conditions, the optical purity was determined to be> 98%. ¹ H-NMR was consistent with the proposed structure. Step 2A

[0466]

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A solution of enantiomer A of step 1 (57.9 g, 140.4 mmol) in CH ₂ Cl ₂ (600 mL) was cannulated through a cannula into iodotrimethylsilane (33.7 g).
, 168.5 mmol) in CH ₂ Cl ₂ (125 mL) was added. The orange solution was stirred at room temperature for 1 hour. Methanol (27.3 mL, 674.1 mmol) was added dropwise and the solution was stirred for another 15 minutes. The reaction solution was concentrated under vacuum to give an orange oil. The residue was treated with methyl t-butyl ether (670 m
L) and dissolved in 1M HCl (420 mL) and water (1 × 230 mL, 1 × 1
30 mL). The aqueous extract was backwashed with MTBE (130 mL). To the aqueous solution was added solid NaHCO ₃ (52.9 g, 630 mmol) in portions.
The basified aqueous mixture was extracted with MTBE (1 × 1.2 L, 2 × 265 mL). The combined organic solution was washed with brine and concentrated under vacuum to give the desired product (28.6 g, 73% yield). ¹ H-NMR was consistent with the proposed structure. Step 2B

[0468]

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A solution of the compound of Example 1, enantiomer B of Step 1 (38.5 g, 93.4 mmol) in CH ₂ Cl ₂ (380 mL) was added via cannula to a solution of iodotrimethylsilane (25.0 g, 125.0 mmol). A CH ₂ Cl ₂ (80 mL) solution was added. The orange solution was stirred at room temperature for 1.5 hours. Methanol (20.0 mL
, 500.0 mmol) was added dropwise and the solution was stirred for a further 20 minutes. The reaction solution was concentrated under vacuum to give an orange oil. The residue is treated with diethyl ether (
450 mL) and 1M HCl (320 mL) and water (1 × 200 mL)
, 1x100 mL). The aqueous extract is diethyl ether (100 mL)
Backwash. To the aqueous solution was added solid NaHCO ₃ (40.1 g, 478 mmol) in portions. The basified aqueous mixture was diluted with diethyl ether (1 × 1.0 L,
2 × 200 mL). The combined organic solution was washed with brine and concentrated under vacuum to give the desired product (20.8 g, 80% yield). Elemental analysis for C ₁₁ H ₁₃ Cl ₂ NO ₃ : Calculated: C, 47.50; H, 4.71; N, 5.04; Found: C, 47.11; H, 4.66; N, 4.93.

The product of Step 2B was converted to the target intermediate by using the reagents and conditions described in Steps 4 and 5 of Example G. Example V

[0471]

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The above compound was prepared according to the method described in Example G. In Step 2A, 5-bromo-3-iodobenzaldehyde was used instead of 3,5-dichlorosalicylaldehyde. Example 30

[0473]

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Step 1

[0475]

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Preparation of methyl 4-methoxy-2-aminopicolinate (602 mg, 3.3 mmol)
(JACS, 78, 4130, 1956) CH_TwoCl_Two(20mL) stir solution
While adding benzoyl isothiocyanate (1 ml, Aldrich)
The reaction mixture was stirred at room temperature for 90 minutes. The mixture is then diluted with ether (20 ml)
Was. The mixture was cooled on an ice bath, the solid was filtered, washed with ether and dried.
The desired compound was obtained as a white solid (828 mg, 73.27% yield): ¹ 1 H-NMR: 300 MHz was consistent with the proposed structure.Step 2

[0477]

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Preparation of Step 1 (750 mg, 2.17 mmol) in methanol (30 ml)
To the stirring solution was added NaOMe (538 mg) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with glacial acetic acid (0.575 ml),
Stir for 5 minutes. The solid was filtered under reduced pressure, washed with cold methanol and dried to give the desired compound as a white solid (385 mg, 73% yield): ¹ H.
-NMR: 300 MHz was consistent with the proposed structure. Step 3

[0479]

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Preparation of A To a stirred solution of the product of Step 2 (364 mg, 1.5 mmol) in methanol (20 ml) was added iodomethane (0.25 ml). The reaction mixture was heated at reflux for 2 hours. The mixture was cooled to room temperature and concentrated to give the desired compound as a white solid (560 mg): ¹ H-NMR: 300 MHz consistent with the proposed structure. Step 4

[0481]

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Preparation of Step 3 A solution of the product of Step 3 (500 mg, 1.30 mmol) in N, N-dimethylacetamide (10 ml) was stirred in 1,3-diamino-2-hydroxypropane (1
23 mg, 1.37 mmol). The reaction mixture was heated to 90 C for 2 hours. Mixture of crude product and concentrated in vacuo to obtain a, it was obtained the desired compound is purified by reverse phase HPLC as a white solid ^{(228mg): 1 H-NMR} :
300 MHz was consistent with the proposed structure. Step 5

[0483]

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Preparation of Step 4 (200 mg) in methanol (3 ml) and THF (3 ml)
)) The solution was stirred and a 1N NaOH solution (3 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum to give an oily gum which was dissolved in water (2 ml) and neutralized with 1N HCl (3 ml). The mixture was concentrated in vacuo to give the crude product, which was purified by reverse phase HPLC to give the desired compound as a white solid (228 mg): ¹ H-NMR: 300 MHz with the proposed structure Matched. Step 6

[0485]

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Preparation of 4-Methylmorpholine (202 mg, 2 mmol), 1-hydroxybenzotriazole in a stirred solution of the product of Step 5 (151.25 mg, 0.5 mmol) in N, N-dimethylacetamide (5 ml) (67 mg, 0.5 mmol) and the amino ester product of Example R (208.5 mg, 0.5 mmol). The mixture was stirred at room temperature for 5 minutes. The reaction mixture was then treated with 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (96 mg, 0.5 mmol) and 4- (dimethylamino) pyridine (10 mg). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 72 hours. The reaction mixture was quenched with water (1 ml) and concentrated in vacuo to give the crude product, which was purified by reverse phase HPLC to give the desired compound as a white solid (42 mg): ¹ H. -NMR: 400
MHz was consistent with the proposed structure. Step 7

[0487]

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Preparation of The product of Step 6 (35 mg) in methanol (3 ml) and THF (3 ml)
A 1N NaOH solution (3 ml) was added to the stirring solution. The reaction mixture was stirred at room temperature for 1 hour. The mixture is concentrated under vacuum to give an oily rubber, which is then treated with water (2 m
1) and neutralized with 1N HCl (3 ml). The mixture was concentrated under vacuum to give the crude product, which was purified by reverse-phase HPLC to give the desired compound as a white solid (22 mg): ¹ H-NMR: 400 MHz with the proposed structure Matched. As Elemental Analysis _{C 22 H 24 N 6 O 7} BrCl · 2TFA · 0.5H 2 O: Calculated: C, 37.22; H, 3.25 ; N, 10.04; Found: C, 36.91 H, 3.17; N, 10.02. Example 31

[0489]

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Step 1

[0490]

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Preparation of To a stirred solution of the product of Step 4 of Example 30 (900 mg) in glacial acetic acid (10 ml) was added 48% HBr (10 ml). The reaction mixture was heated at reflux for 3 hours. The mixture was cooled to room temperature and stirred at room temperature for 18 hours. The mixture was concentrated under vacuum to give the crude product, which was purified by reverse phase HPLC to give the desired compound as an oily gum (720 mg): ¹ H-NMR: 300 MHz with the proposed structure Matched. Step 2

[0493]

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Preparation of 4-Methylmorpholine (520 mg, 5.2 mmol), 1-hydroxybenzotriazole in a stirred solution of the product of Step 1 (720 mg, 1.7 mmol) in N, N-dimethylacetamide (10 ml) (221 mg, 1.71 mmol)
And the aminoester product of Example R (710 mg, 1.71 mmol) was added. The mixture was stirred at room temperature for 5 minutes. The reaction mixture was then treated with 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (211 mg, 1.7 mmol) and 4- (dimethylamino) pyridine (10 mg). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 72 hours. The reaction mixture was quenched with water (1 ml) and concentrated in vacuo to give the crude product, which was purified by reverse phase HPLC to give the desired compound as a white solid (182 mg): ¹ H. -NMR:
300 MHz was consistent with the proposed structure. Step 3

[0495]

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Preparation of The product of Step 2 (100 mg) in methanol (3 ml) and THF (3 ml)
) 1N NaOH solution (3 ml) was added to the stirred solution. The reaction mixture was stirred at room temperature for 1 hour. Concentration of the mixture under vacuum yields an oily gum, which is treated with water (2
ml) and neutralized with 1N HCl (3 ml). The mixture was concentrated under vacuum to give the crude product, which was purified by reverse phase HPLC to give the desired compound as a white solid (42 mg): ¹ H-NMR: 300 MHz with the proposed structure Matched. Elemental analysis As C ₂₁ H ₂₂ N ₆ O ₇ BrCl.1.5 TFA.0.5H ₂ O: Calculated: C, 37.64; H, 3.22; N, 10.97; Found: C, 37 .56; H, 3.05; N, 10.99. Example 32

[0497]

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Example 9, Step 3 Product (860 mg, 2.45 mmol) and Example T
(1.0 g, 2.41 mmol) of dimethylacetamide (24 mL)
To the solution at 0 ° C. was added HOBT (358 mg, 2.64 mmol) followed by N-methylmorpholine (0.6 mL, 5.15 mmol). The reaction solution was stirred for 15 minutes and EDC (470 g, 2.45 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate and water. The aqueous solution was extracted with ethyl acetate, combined organic layers were dried (Na ₂ SO ₄₎ and concentrated. The residue was purified by RP HPLC (starting with a gradient of 90:10 water / TFA: MeCN, retention time 22.5 minutes) to give the desired coupled product with the recovered compound B (480 mg). . 1M of this substance
The solution was added to an aqueous NaOH solution (6 mL) and stirred for 3 hours. The solution was acidified to pH 4 with TFA. The mixture was purified by RP HPLC (initiating a gradient with 95: 5 water / TFA: MeCN, retention time 24.5 minutes) to give the desired product (16).
0 mg, 8% yield over two steps). Elemental analysis as C ₂₁ H ₂₂ BrClN ₅ O ₆ +2.4 TFA: Calculated: C, 36.74; H, 2.92; N, 9.96; Found: C, 36.83; H, 3.07 N, 9.88. ¹ H-NMR was consistent with the proposed structure. Example 33

[0499]

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Step 1 A solution of the product of Example 18, Step 2 (5.72 g) in THF (80 ml) was added to 5 p.
It was treated with a catalytic amount of 5% Pd / C at room temperature under a hydrogen pressure of si for 2 hours. The reaction mixture was filtered and the residue was washed with DMF (250ml). The filtrate was concentrated, the residue was filtered with ether and air dried to give a brown powder (4.9 g), which was used directly in the next step without further purification. ¹ H-NMR was consistent with the proposed structure. Step 2 The material from Step 1 (500 mg) was guanylated using the Tris Boc reagent and the conditions described in Step 4 of Example 21 to give the desired compound as a golden vitreous (128 mg). ¹ H-NMR was consistent with the proposed structure. Step 3 The ester group of the product of Step 2 was hydrolyzed using the experimental conditions set forth in Step 5 of Example 21. ¹ H-NMR was consistent with the proposed structure. Elemental analysis for C ₁₁ H ₁₄ N ₄ O ₄ 1.5 TFA: Calculated: C, 38.45; H, 3.57; N, 12.81; Found: C, 38.32; 77; N, 12.80. Step 4 The desired compound is prepared using the methodology described in Example 12, Step 4, Step 3
Prepared by coupling the product of Example R with the product described in Example R. ¹ H-NMR was consistent with the proposed structure. Step 5 The ester group of the product of Step 4 was hydrolyzed using the experimental conditions set forth in Step 5 of Example 12. ¹ H-NMR was consistent with the proposed structure. Elemental analysis As C ₂₁ H ₂₂ N ₆ O ₇ BrCl.1.5 TFA.0.25H ₂ O: Calculated: C, 37.86; H, 3.18; N, 11.04; Cl, 4.66;
Br, 10.50 Found: C, 37.60; H, 3.26; N, 11.20; Cl, 4.79;
Br, 10.19. Example 34

[0501]

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The above compound was prepared utilizing the methodology described in Example 33. In Step 4, the product of Example H was used instead of the product of Example R. Elemental analysis As C ₂₁ H ₂₂ N ₆ O ₇ BrCl · 2.0 TFA · 0.5H ₂ O: Calculated: C, 36.49; H, 3.06; N, 10.21 Found: C, 36. 10; H, 2.83; N, 10.29. Example 35

[0503]

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The above compound was prepared utilizing the methodology described in Example 33. In step 4, the product of Example V was used instead of the product of Example R. Elemental analysis for C ₂₁ H ₂₂ N ₆ O ₆ Br ₂ .1.75 TFA: Calculated: C, 35.76; H, 3.03; N, 10.21 Found: C, 35.58; H, 3 .07; N, 10.61. Example 36

[0505]

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[0506]Step 1 The product from Step 1 of Example 33 (261 mg) was converted to bis-Boc reagent G_TwoAnd
Guanylation using the conditions described in Step 5 of Example 18 and Example 18 gave a white product
Obtained as a solid (207 mg). This material is then described in Example 21, Step 5.
Saponification was performed using the experimental conditions specified.¹1 H-NMR is consistent with the proposed structure
Was.Step 2 The desired compound was prepared using the same methodology as described in Example 12, Step 4.
Was built. The product described in step 1 was coupled with the product of Example I. ¹ 1 H-NMR was consistent with the proposed structure.Step 3 The ester group of the product of Step 2 was prepared using the method described in Step 5 of Example 12.
Hydrolyzed.¹1 H-NMR was consistent with the proposed structure. Elemental analysis C₂₀H₂₀N₆O₆Br_Two・ 1.75TFA ・ 0.25H_TwoAs O: Calc: C, 35.10; H, 2.79; N, 10.45 Found: C, 34.85; H, 2.59; N, 10.62.Example 37

[0507]

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[0508]Step 1 2-Nitrothiophene-4-carboxaldehyde (5.0 g) was added at room temperature to water (
100 ml), and an aqueous solution (50 ml) of sodium hydroxide (5.2 g) was added.
Added at once. The black reaction mixture was stirred at room temperature for 1 hour before the celite pad was removed.
And filtered through. The filtrate was acidified with 1N HCl and extracted with ethyl acetate. merger
The organic extract was washed with saturated sodium chloride solution, dried (Na_TwoSO_Four) Dark
Shrinking gave a pale yellow solid (5.0 g), which was used without further purification.
Was used.¹1 H-NMR was consistent with the proposed structure.Step 2 The product from step 1 (2.5 g) was treated with potassium carbonate (2 ml) in DMF (16 ml).
. 0g) and methyl iodide (2.2g) at room temperature for 16 hours. Reaction mixing
The material was partitioned between ethyl acetate and water and the layers were separated. The aqueous phase is further extracted with ethyl acetate.
The combined organic extracts were washed with water, saturated sodium chloride solution, dried and dried (
Na_TwoSO_Four) Concentrated. Elute the dark residue with 15% ethyl acetate-85% hexane
Purification on a silica gel column yielded a yellow solid (950 mg). ¹ 1 H-NMR was consistent with the proposed structure.Step 3 The product obtained in step 2 (2.0 g) was dissolved in methanol (50 ml),
Treated at 60 ° C. for 32 hours with a catalytic amount of 5% Pd / C under 0 psi hydrogen pressure
. The reaction was cooled, filtered and the filtrate was concentrated. The residue was 25% ethyl acetate-75%
Purification on a silica gel column eluted with hexane gave a yellow solid (
920 mg).¹1 H-NMR was consistent with the proposed structure.Step 4 Dissolve the product of Step 3 (900 mg) in ethyl acetate (20 ml) and add
Treated with luisothiocyanate (947 mg) in one portion at room temperature. The reaction solution is
Stir for 30 minutes, filter the precipitate, wash with ethyl acetate and air dry to give a pale yellow solid.
Was obtained (1.51 g).¹1 H-NMR was consistent with the proposed structure.Step 5 The product obtained in Step 4 of Example 35 was dissolved in methanol (70 ml).
Thorium methoxide (1.3 g) was added in portions at room temperature. Reaction solution is 3
Stirred for 0 min and quenched with glacial acetic acid (1.4 g). Concentrate the reaction mixture to a residue
Was partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate and combined
The organic extract is washed with saturated sodium chloride solution, dried (Na_TwoSO_Four) Concentrate
This gave a pale yellow solid (900 mg).¹H-NMR shows the proposed structure and
Matched.Step 6 Dissolve the product of Step 5 (900 mg) in methanol (20 ml) and add
Treated with chill (1.4 g). The reaction was refluxed for 2 hours, then cooled and concentrated.
Was. The residue was treated with ether, filtered and air dried to give a white solid (1
. 27g).¹1 H-NMR was consistent with the proposed structure.Step 7 The product of Step 6 (1.2 g) was treated with 1,3-diamino-2-hydroxypropane (
469 mg) and DMA (20 ml) for 8 hours at 95-100 ° C. Anti
The reaction was cooled and the solvent was removed under high vacuum. The residue was washed with water (0.5% TFA) -acetate.
Purification by reverse phase HPLC eluting with a tonitrile gradient yields the desired product.
(255 mg).¹1 H-NMR was consistent with the proposed structure.Step 8 The desired compound was formed in Step 7 using the conditions described in Example 21, Step 5.
Manufactured from material.¹1 H-NMR was consistent with the proposed structure.Step 9 The desired compound utilizes the same methodology as Step 4 of Example 12 and combines the product of Step 8 with the product of Step 8.
Prepared by coupling the material of Example G.¹H-NMR is eye
Consistent with the structure discussed.Step 10 The ester group of the product of Step 9 was prepared using the method described in Step 5 of Example 12.
Hydrolyzed.¹1 H-NMR was consistent with the proposed structure. Elemental analysis C₂₀H_{twenty one}N_FiveO₆Cl_TwoAs S · 1.75 TFA: Calculated: C, 38.43; H, 3.19; N, 9.54; S, 4.37 Found: C, 38.43; H, 3.39; N, 9.73; S, 4.27.Example 38

[0509]

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Step 1 Acetic anhydride (20 ml) was treated with 70% nitric acid (4 ml) at room temperature. This solution was added dropwise to a stirred mixture of N-methylpyrrole-2-carboxylic acid (5.0 g) and acetic anhydride (30 ml) at -30 ° C. The reaction was mixed and warmed to room temperature in 30 minutes.
The reaction was cooled again to −25 ° C., filtered through a chilled filter, washed with cold hexane and air-dried to give a yellow powder (1.5 g). ¹ H-NMR was consistent with the proposed structure. Step 2 The desired compound was prepared using the purified product prepared in Step 1 and by the method described in Example 37, Step 2. The crude product was purified by silica gel column chromatography eluting with 40% ethyl acetate-hexane. ¹ H-NMR was consistent with the proposed structure. Step 3 The product (1.0 g) obtained in Step 2 was dissolved in methanol (25 ml),
Treatment was performed at room temperature for 3 hours using a catalytic amount of 5% Pd / C under hydrogen pressure of psi. The reaction was filtered and concentrated to give a deep red liquid (1.0 g), which was used without further purification. ¹ H-NMR was consistent with the proposed structure. Step 4 The desired compound was prepared using the product described in Step 3 and utilizing the sequence of Steps 4-8 described in Example 37. ¹ H-NMR was consistent with the proposed structure. Step 5 The product from Step 4 (425 mg), 2-chloro-4,6-dimethoxytriazine (201 mg) and N-methylmorpholine (263 mg) in DMA (10 mg)
ml) The solution was stirred in an ice bath under a nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirring continued for another 3 hours. The product of Example G (385 mg) and N-methylmorpholine (105 mg) were dissolved in DMA (5 ml) and added in one portion to the previous reaction at room temperature. After stirring the reaction solution for 15 hours, the reaction was stopped with TFA (1.5 ml) and concentrated under high vacuum. The residue was purified by reverse phase HPLC, eluting with a water (0.5% TFA) -acetonitrile gradient to give a white solid (706m).
g). ¹ H-NMR was consistent with the proposed structure. Step 6 The ester group of the product of Step 5 was hydrolyzed using the method described in Step 5 of Example 12. ¹ H-NMR was consistent with the proposed structure. Elemental analysis As C ₂₁ H ₂₄ N ₆ O ₆ Cl ₂ .1.5 TFA.0.5 H ₂ O: Calculated: C, 40.75; H, 3.78; N, 11.88; Cl, 10.02 Found: C, 40.40; H, 3.68; N, 12.10; Cl, 10.20.
. Example 39

[0511]

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[0512]

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Step 1 3-Bromo-4-methylthiophene (10 g), copper (I) cyanide (11.3)
g) and HMPA (15 ml) was heated to 130-140 ° C for 18 hours. The mixture was cooled and stirred with an aqueous solution of sodium cyanide (18.8 g) (28.8 g).
8 ml) and stirred for 1 hour. The thick brown mixture was diluted with some additional water and extracted with ether. The combined ether extracts were washed with water, saturated sodium chloride solution, dried (Na ₂ SO ₄ ) and concentrated. 90% hexane-1
Purification on a silica gel column eluted with 0% ethyl acetate gave a pale yellow liquid (5.2 g). ¹ H-NMR was consistent with the proposed structure. Step 2 A mixture of the nitrile (1.5 g) produced in Step 1 and a 2N aqueous sodium hydroxide solution (150 ml) was heated to reflux for 1 hour. Cool the reaction solution and add 2N hydrochloric acid.
Extracted with ether as H-2 acid. Dry the combined ether extract (
When Na ₂ SO ₄₎ and concentrated white solid was obtained (16.4 g), which was used without further purification. ¹ H-NMR was consistent with the proposed structure. Step 3 Esterify the product of Step 2 (16.4 g) as described in Step 2 of Example 37 to give the desired product after purification on a silica gel column eluted with 10% ethyl acetate-90% hexane. Obtained (13.6 g). ¹ H-NMR was consistent with the proposed structure. Step 4 A mixture of N-bromosuccinimide (6.3 g) and dibenzoyl peroxide (100 mg) dissolved in carbon tetrachloride (25 ml) was added to the product of Step 3 (5
. 0 g) and dibenzoyl peroxide (100 mg) in CCl ₄ (25 ml
) Added to the refluxing solution over 90 minutes. After refluxing for 2 hours, the reaction mixture was cooled,
Filtration and concentration, and purification of the residue on a silica gel column eluted with 10% ethyl acetate-90% hexane gave the desired compound (4.3 g). ¹ H-N
MR was consistent with the proposed structure. Step 5 A mixture of the product described in Step 4 (4.2 g), sodium azide (2.6 g) and DMF (50 ml) was heated to 55 ° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled and partitioned between water and ethyl acetate. The layers were separated and the aqueous phase was further extracted with fresh ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried (Na ₂ SO ₄ ) and concentrated to give a golden oil (3.5 g),
It was used without further purification. ¹ H-NMR was consistent with the proposed structure. Step 6 A mixed solution of the product described in Step 5 (1.0 g) in 1N sodium hydroxide (15 ml) and methanol (15 ml) was stirred at room temperature for 16 hours. Glacial acetic acid (2 ml) was added to the reaction solution and concentrated. The residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous phase was further extracted with fresh ethyl acetate. The combined organic extracts were washed with water, saturated sodium chloride solution, dried (Na ₂ SO ₄ ) and concentrated. The residue was dried under high vacuum at 61 ° C. for 2 hours to give a white solid (860 mg). ¹ H
-NMR was consistent with the proposed structure. Step 7 A solution of the product described in Step 6 (850 mg) in methylene chloride (10 ml) was cooled in an ice bath and a 2N solution of oxalyl chloride in methylene chloride (5 ml) was added at once, followed by 2 drops of DMF. The reaction was stirred for 2 hours while warming to room temperature. The solution was concentrated and dried under high vacuum at room temperature for 16 hours to give a tan solid (
785 mg). ¹ H-NMR was consistent with the proposed structure. Step 8 Under a nitrogen atmosphere, diisopropylethylamine (1.
A solution of the product of Example G (1.4 g) in DMA (10 ml) was added.
The solution was cooled in an ice bath and the acid chloride from step 7 (770 mg) in DMA (5 ml
) The solution was added dropwise. After the addition was complete, the reaction was stirred for 30 minutes and partitioned between ethyl acetate and water. The layers were separated and the aqueous phase was further extracted with fresh ethyl acetate. The combined organic extracts were purified on a silica gel column eluted with 50% ethyl acetate-50% hexane to give a white solid (1.0 g). ¹ H-NMR was consistent with the proposed structure. Step 9 A solution of the product from Step 8 (806 mg) in ethanol (20 ml) was added with 5 ps
Under hydrogen pressure of i, the mixture was treated with a catalytic amount of 5% Pd / C at room temperature for 21 hours. The reaction was filtered and concentrated, and the residue was purified by reverse phase HPLC, eluting with a water (0.5% TFA) -acetonitrile gradient to give a white solid (480 mg). ¹
1 H-NMR was consistent with the proposed structure. Step 10 The product described in Step 9 (550 mg) was guanylated and purified using the conditions described in Step 4 of Example 21 to give a white solid (206 mg). ¹
1 H-NMR was consistent with the proposed structure. Step 11 The ester group of the product of Step 10 was hydrolyzed using the same method as shown in Step 5 of Example 12. ¹ H-NMR was consistent with the proposed structure. Elemental analysis As C ₂₁ H ₂₃ N ₅ O ₅ Cl ₂ S.1.5 TFA.0.5H ₂ O: Calculated: C, 39.79; H, 3.55; N, 9.67; Cl, 9. 79; S
, 4.43 found: C, 39.91; H, 3.58; N, 9.94; Cl, 10.06;
S, 4.52. Example 40

[0514]

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Step 1 The product prepared in Step 3 of Example 33 (1.0 g) is coupled with glycine ethyl ester hydrochloride using the method described in Step 5 of Example 38 to give a similar product. After the purification process, a yellow solid was obtained (1.1 g). ¹ H-NMR was consistent with the proposed structure. Step 2 The product described in Step 1 (1.0 g) was hydrolyzed using the method described in Step 5 of Example 12 to give a white solid (910 mg). ¹ H-NMR was consistent with the proposed structure. Step 3 The product from Step 2 was coupled with 3-amino-4,4,4-trifluorobutyric acid ethyl ester hydrochloride using the protocol described in Step 5 of Example 38. ¹ H-NMR was consistent with the proposed structure. Step 4 The ester group of the product of Step 3 was hydrolyzed using the method described in Step 5 of Example 12. ¹ H-NMR was consistent with the proposed structure. Elemental analysis for C ₁₇ H ₂₀ N ₅ O ₆ F ₃ .1.5 TFA: Calculated: C, 38.01; H, 3.67; N, 11.08 Found: C, 37.88; H, 3 .64; N, 11.02. Example 41

[0516]

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[0517]Step 1 Example 33, Step 3 product (527 mg, 1.3 mmol) and CDMT
(244 mg, 1.4 mmol) was dissolved in DMAC (8 ml) under an argon atmosphere.
I understand. The solution was cooled at 0 ° C. for 3 hours and NMM (0.15 ml, 1.3 mmol)
Was added dropwise. The reaction solution was stirred at 0 ° C. for 3 hours before the product of Example U and NM
A solution of M (0.15 ml) in DMAC (10 ml) was added. Leave the reaction solution in the room
Warm to warm and stir at room temperature overnight. The reaction was quenched with TFA (2 ml) and placed under vacuum
And concentrated. 90:10 H for crude yellow solid_TwoO / TFA: CH_ThreeCN concentration gradient
Purified by RP-HPLC using elution (λ = 254 nm). Elemental analysis C_{twenty three}H₂₆N₆O₇Cl_TwoAs 1.5 TFA: Calculated: C, 42.12; H, 3.74; N, 11.35 Found: C, 42.26; H, 3.87; N, 11.45. H. R. M. S. M + 1 C_{twenty three}H₂₇N₆O₇Cl_TwoCalculated as 569.13
18; found 569.1323.Step 2 The product of Step 1 (725 mg, 0.98 mmol) was added in THF (5 ml) / CH _Three Dissolved in OH and added 1M NaOH (6.5 ml). Reaction at room temperature overnight
Stir then 1M HCl (6.5 ml) was added. After concentration under vacuum, the crude yellow solid
95: 5 H_TwoO / TFA: CH_ThreeRP-H using gradient elution of CN
Purified by PLC (λ = 254 nm). The product was isolated as a white solid (
589 mg, 79% yield). Elemental analysis C_{twenty one}H_{twenty two}N₆O₇Cl_Two-As 1.9 TFA: Calculated: C, 39.30; H, 3.18; N, 11.09 Found: C, 39.22; H, 3.16; N, 11.39. H. R. M. S. M + 1 C_{twenty one}H_{twenty three}N₆O₇Cl_TwoCalculated as 541.10
05; found 5411,000.Example 42

[0518]

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Step 1 2-Methoxy-6-chloropyridinecarboxylic acid (10 g, 0.053 mol) is dissolved in an excess of aqueous ammonium hydroxide in a high pressure reactor and heated to 175 ° C. for 24 hours to give a pressure of 500 psi. Become. The solution was evaporated to dryness under reduced pressure and 2N H
It was converted to the acid by treatment with Cl at 25 ° C. for 2 days and evaporated to dryness under high vacuum while heating to 60 ° C. After 12 hours, the remaining water was azeotropically removed with absolute ethanol, methanol was added to the resulting residue and evaporated under reduced pressure (3 times). The obtained residue was dissolved in methanol (250 ml), and 4N HCl in dioxane (25 ml).
Mol) and refluxed for 2.5 days. The solvent was removed by evaporation under reduced pressure and the resulting crude residue is purified by reverse phase HPLC (gradient, 95/5 0.1% TFA-containing _{H 2 O / CH 3 CN-} 60/40 0.1% TFA H ₂ O / CH ₃ CN). The desired product is dissolved in methanol, treated with solid sodium bicarbonate,
Filter and evaporate the solvent. The resulting solid was suspended in 50/50 ethyl acetate / hexane and the solid was collected by filtration to give the desired brown solid (1.7 g,
Yield 20%). Step 2 The compound from Step 1 (300 mg, 1.8 mmol) was added to DMF (7.1 ml)
And the product of Example 9, Step 1 (927 mg, 2.1 mmol) was added followed by triethylamine (0.44 ml, 325 mg, 3.2 mmol) and mercuric chloride (326 mg, 1.2 mmol). added. The reaction mixture was stirred at 25 ° 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 and the heterogeneous solution was filtered through celite. Celite was thoroughly washed with 97/3 ethyl acetate / ethanol. Removing the solvent under reduced pressure,
The obtained crude red oil was dissolved in methylene chloride (30 ml), trifluoroacetic acid (2.77 ml) was added, and the mixture was refluxed for 1 hour. The reaction was cooled and the solvent was removed under reduced pressure to give a brown oil. This sample was subjected to reverse phase HPLC (C18, concentration gradient,
Purification with 99/1 0.1% TFA / H ₂ O) gave an impure compound, which was dissolved in methanol (2 ml) and treated with 1N NaOH (0.15 ml),
Upon drying, a dark brown oil was obtained. The oil was purified by reverse phase HPLC (C18, gradient, 99/1 0.1% TFA / H ₂ O / CH ₃ CN) to give a tan solid (36 mg). Step 3 The compounds of the previous step (74 mg, 0.18 mmol) was dried overnight in a vacuum oven, was dissolved in DMF (1 ml) (molecular sieve and those stored), 0
Cooled to ° C. N-Methylpiperidine (27 ml; 22 mg; 0.22 mmol) was added, followed by isobutyl chloroformate (47 ml; 49 mg; 0.36 mmol) and stirred for 5 minutes. A solution of the product of Example G in DMF was added and the remaining β-aminoester was washed with additional DMF (0.2 ml). Next, N-methylpiperidine (22 ml; 18 mg; 0.18 mmol) was added. The reaction mixture was allowed to gradually warm to room temperature. After stirring at 25 ° C. for 12 hours, the solvent was removed under high vacuum to give a red-brown oil, which was subjected to reverse phase HPLC (C18, gradient, 80/2).
Purification with 0.1% TFA / H ₂ O / CH ₃ CN) gave the coupled product (22 mg) and the coupled product with the isobutylformyl group incorporated into the pyridone oxygen atom (47 mg). These products were combined and dissolved in methanol (82 ml), and a 1N aqueous sodium hydroxide solution (240 ml) was added thereto. The reaction solution was stirred at 25 ° C. overnight, and trifluoroacetic acid (84.7 ml) was added. The solvent was removed under reduced pressure and reversed phase HPLC (C18, gradient, 95/5 0.
The desired product is purified by _{1% TFA / H 2 O /} CH 3 CN) was obtained (37m
g). Trace element analysis As C ₂₁ H ₂₂ N ₆ O ₇ Cl ₂ · 2.1 TFA · 0.2H ₂ O: Calculated: C, 38.58; H, 3.15; N, 10.71 Found: C, 38.12; H, 3.36; N, 10.71. Example 43

[0520]

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The above compound was prepared according to the procedure described in Example 42, Step 3, Example 42, Step 2.
By reacting the product of Example R with the product of Example R. Trace Element Analysis As C ₂₁ H ₂₂ N ₆ O ₇ ClBr · 1.8 TFA: Calculated: C, 37.35; H, 3.03; N, 10.62 Found: C, 37.31; H, 3 .23; N, 10.65. Example 44

[0522]

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Step 1 The product of Example 17, Step 3 (3.0 g, 5.77 mmol) was dissolved in isopropanol (25 ml) and concentrated ammonium hydroxide (45 ml) was added. 25
After stirring at C for 3 hours, the solution was evaporated to dryness under reduced pressure. The crude sample was placed in a pearl shaker.
1. Dissolve in ethanol (3A) (50 ml) and over 5% platinum-carbon at 5 psi.
Hydrogenated for 5 hours at room temperature. The sample was filtered and the filtrate was concentrated to dryness under reduced pressure. Compound reverse phase desired product is purified by chromatography _{(C18,80 / 20 CH 3 CN /} H 2 O) was obtained (1.5 g, 39% yield). Step 2 The product of Step 1 (200 mg) was dissolved in methanol (2 ml) and sodium hydrogen carbonate (133 mg) was added. The solution was stirred at 25 ° C. for 30 minutes and the resulting solution was evaporated to dryness. The obtained sample (205 mg; 0.43 mmol) was added to DMF (1
. 72 ml) and the product of Example 9, Step 1 (282.8 mg; 0.65).
Mmol), followed by triethylamine (99 mg; 0.97 mmol; 0.14
ml), followed by mercuric chloride (177 mg; 0.65 mmol). The solution was heated to 60 ° C. for 30 minutes followed by 90 ° C. for 12 hours. The reaction mixture was cooled, diluted with ethyl acetate (1.7 ml) and filtered through celite. The filtrate obtained was evaporated to dryness. The crude sample was purified by flash chromatography to remove unreacted starting material. When this material was treated with 50/50 TFA / CH ₂ Cl ₂ impure desired product was obtained. This material was dissolved in methanol (2 ml) and 1 N sodium hydroxide (2 ml). After stirring at 25 ° C. for 12 hours, the solution was washed with TFA (
(77 ml) and evaporated to dryness under reduced pressure. The desired product is purified the crude product was purified by reverse-phase chromatography _{(C18,95 / 5 H 2 O /} CH 3 CN) was obtained (6.8 mg). Trace Element Analysis As C ₂₁ H ₂₃ N ₇ O ₆ Cl ₂ .3.3 TFA: Calculated: C, 36.17; H, 2.89; N, 10.70 Found: C, 36.57; H, 3.21; N, 10.37. Example 45

[0524]

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[0525]Step 1 3-methyl-2-thiophenecarboxylic acid (1.0 g, 7.0 mmol), N,
N-dimethylformamide (4.0 ml) and potassium carbonate (1.93 g, 1
4 mmol) of iodomethane (1.49 g, 10.5 mmol).
Was. The reaction was stirred at room temperature for 80 hours, diluted with ethyl acetate (150 ml),_Two
Washed with O (100 ml) and brine (100 ml). Dry the organic layer (
MgSO_Four) Concentration gave a clean product as a light brown oil (0.8
7 g, 81% yield).¹1 H-NMR was consistent with the proposed structure.Step 2 Step 1 product (5.0 g, 32.0 mmol), dibenzoyl peroxide
(0.08 g) and carbon tetrachloride (20 ml) at reflux.
Cinimide (6.3 g, 35.3 mmol), dibenzoyl peroxide (0.
08g) and carbon tetrachloride (20 ml) were added over 30 minutes. Profit
The resulting reaction mixture was heated at reflux for 18 hours. The solid is filtered and carbon tetrachloride (2 ×
10 ml). The filtrate was concentrated to give a mixture of oil and solid (
8.1 g, 80% yield).¹1 H-NMR was consistent with the proposed structure.Step 3 Step 2 product (8.1 g, 34.7 mmol), sodium azide (5.6
g, 87 mmol) and N, N-dimethylformamide (25 ml)
Was heated to 58 ° C. for 2.5 hours. Dilute the reaction with ethyl acetate (800 ml),
H_TwoWashed with O (500 ml). The aqueous layer was extracted with ethyl acetate (100ml)
. Dry the combined organic layers (MgSO 4_Four) Concentration gave a pale brown oil
(6.0 g, 85% yield).¹1 H-NMR was consistent with the proposed structure.Step 4 Step 3 product (6.0 g, 25.9 mmol), NaOH (1N, 50 ml)
) And MeOH (50 ml) were stirred overnight. Acetic acid (2.5m
l) was added. The product was extracted with ethyl acetate (300ml). Organic layer N
a_TwoSO_FourAnd concentrated to a yellow oil. A yellow solid is obtained under vacuum
(2.0 g, 42% yield).¹1 H-NMR was consistent with the proposed structure.Step 5 Step 4 product (0.5 g, 2.7 mmol), oxalyl chloride (2M dichloromethane)
Dichloromethane solution (2.7 ml, 5.4 mmol) and dichloromethane (20 ml)
) Was stirred at room temperature for 2.5 hours. When the solvent is removed from the reaction solution, the product
Obtained as a brown oil (0.15 g, 85% yield).¹H-NMR
With the structure that was obtained.Step 6 Example G product (0.91 g, 2.43 mmol), diisopropylethyl
Amine (0.63 g, 4.86 mmol) and N, N-dimethylacetamide
(20 ml) to a solution of the product of step 5 (0.46 g, 2.43 mmol) at 0 ° C.
) And THF (10 ml) was added. The reaction mixture was stirred at 0 ° C for 10 minutes.
Stir and leave to warm to room temperature. After 16 hours, the solvent was removed from the reaction solution under reduced pressure.
Was. The product was extracted with ethyl acetate (300ml). Organic solution is saturated NaHCO _Three Solution (100 ml), H_TwoWash with O (100 ml), Na_TwoSO_FourAnd dry
A crude product was obtained upon shrinking. The crude product is purified by column chromatography (silica gel).
Le, CH_TwoCl_Two/ MeOH / NH_FourOH, 98/2 / 0.2)
The product was obtained as a rubbery solid (0.7 g, 58% yield).¹H-
NMR was consistent with the proposed structure.Step 7 Step 6 product (0.78 g, 1.56 mmol), 5% Pt / C and Et
The OH mixture was stirred at room temperature under a pressure of 5 psi for 20 hours. The catalyst was filtered off
. Add trifluoroacetic acid (0.6 ml) to the filtrate and concentrate to give the crude product.
Was. The crude product was purified by HPLC to give a white solid (0.4 g, yield
Rate 54%).¹1 H-NMR was consistent with the proposed structure.Step 8 Mercury (II) chloride (0.51 g, 1.87 mmol) was added to the product of Step 7 (0.
55 g, 1.25 mmol), Example 9, Step 1 product (0.81 g, 1.8)
7 mmol), triethylamine (0.38 g, 3.75 mmol) and N,
To a mixture of N-dimethylformamide (15 ml) was added at room temperature. The reaction solution is 95
Heated to -100 ° C for 16 hours. The cooled reaction solution passes through a layer of Celite (2 ")
And filtered and washed with ethyl acetate. Removal of the solvent from the filtrate under vacuum leaves an oil
Obtained. This oil is converted to CH_TwoCl_Two/ Trifluoroacetic acid (10ml / 10ml)
And stirred at room temperature for 1 hour. The solid formed was collected by filtration. The filtrate
Concentrate and CH_TwoCl_Two/ Trifluoroacetic acid (15ml / 15ml) for 1.5 hours
I understood. Removal of the solvent under reduced pressure gave a brown oil. This oil is converted to HPL
Purification by C gave the desired product and its ethyl ester. Desired
The compound was recrystallized from acetonitrile to give a white solid (0.068
g). The ester product was treated with NaOH / ethanol (7 ml / 7 ml) for 18 hours.
And purified by HPLC to give additional product (0.055 g). Elemental analysis C_{twenty one}H_{twenty three}N_FiveO₆Cl_TwoS ・ 2.0CF_ThreeAs COOH: Calculated: C, 38.87; H, 3.26; N, 9.07; Found: C, 38.78; H, 3.6; N, 9.16.Example 46

[0526]

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Step 1 Benzoyl isothiocyanate (3.34 g, 21.3 mmol) was obtained from Example 33, the product of Step 1 (3.5 g, 20.8 mmol) in N, N-dimethylformamide (45 ml). The solution was added at room temperature. The reaction was stirred for 2 hours and the ether (
300 ml). The resulting mixture was stirred for 15 minutes. The product was collected by filtration, washed with ether (2 × 40 ml) and air dried to give a yellow solid (6
. 95 g, 100% yield). ¹ H-NMR was consistent with the proposed structure. Step 2 The product of Step 2 (6.90 g, 20.8 mmol) and methanol (200 ml)
To a suspension of was added sodium methoxide (2.64 g, 48.9 mmol) in small portions at room temperature. After the addition was completed, the reaction solution was stirred for 1 hour. Acetic acid (2.8 ml, 4
8.9 mmol) was added to the reaction. The resulting mixture was stirred for 15 minutes. The product was collected by filtration, washed with methanol (2 × 30 ml) and air-dried to give a slightly off-white solid (3.8 g, 81% yield). ¹ H-NMR was consistent with the proposed structure. Step 3 The product of Step 2 (1.90 g, 8.4 mmol), methyl iodide (3.56 g)
, 25.1 mmol) and methanol (60 ml) were heated at reflux for 3.5 hours and cooled to room temperature. Removal of the solvent from the reaction solution under reduced pressure gave a yellow oil. Treatment of the oil with ether provided a clean product as a yellow solid (3.1 g, 100% yield). ¹ H-NMR was consistent with the proposed structure. Step 4 The product of Step 3 (0.5 g, 1.36 mmol), 2-methoxyethylamine (0.12 ml, 1.36 mmol) and N, N-dimethylacetamide (5
. (0 ml) was heated to 85 ° C. for 2.5 hours. Additional 2-methoxyethylamine (0.12 ml, 1.36 mmol) was added. The reaction was heated to 85 ° C. for 2 hours. The N, N-dimethylacetamide was removed from the cooled reaction solution under reduced pressure to obtain a crude product. The crude product was purified by reverse phase HPLC to give the desired clean product (0.38 g, 76% yield). ¹ H-NMR was consistent with the proposed structure. Step 5 N-methylmorpholine (0.1 ml, 1.42 mmol) was added to the product of step 5 (
0.54 g, 1.42 mmol) N, N-dimethylacetamide (16 ml)
Added to the solution. To the reaction solution was added isobutyl chloroformate (0.18 g, 1.35 mmol) at -5 ° C over 5 minutes and stirred for 15 minutes. The product of Example G (0.
396 g, 1.07 mmol) and N-methylmorpholine (0.075 ml,
1.07 mmol) in N, N-dimethylacetamide (10 ml) was added to the reaction. The resulting reaction solution was allowed to warm to room temperature and stirred for 16 hours. Removal of the solvent from the reaction solution under reduced pressure gave a crude product. The crude product was purified by HPLC to give the desired product as a white solid (0.145g, 14% yield). ¹ H-NMR was consistent with the proposed structure. Step 7 The product of Step 6 (0.145 g, 0.20 mmol), NaOH (1 N, 25
ml) and MeOH (25 ml) was stirred for 16 hours. Removal of the solvent from the reaction mixture under reduced pressure gave a crude product. The crude product was treated with trifluoroacetic acid (
2ml) and purified by HPLC to give the desired product as a slightly off-white solid (0.11 g, 70% yield). Elemental analysis for C ₂₁ H ₂₄ N ₆ O ₇ Cl ₂ .2CF ₃ COOH: Calculated: C, 38.93; H, 3.40; N, 10.89; Found: C, 39.29; 3.47; N, 11.15. Example 47

[0528]

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Step 1 The product of Example 46, Step 3 (1.56 g, 4.22 mmol), 2,2-dimethyl-1,3-propanediamine (0.45 g, 4.40 mmol) and N
, N-dimethylacetamide (15 ml) was heated to 92 ° C-95 ° C for 6.5 hours and allowed to cool to room temperature. A solid formed overnight. The product was collected by filtration, N, N-dimethylacetamide (5 ml) and ether (5 ml)
) To give a clean product as a white solid (0.50 g, 43% yield). ¹ H-NMR was consistent with the proposed structure. Step 2 The product of Step 1 (0.48 g, 1.7 mmol), NaOH (1N, 10 ml)
) And MeOH (10 ml) were stirred overnight at room temperature. Removal of the solvent from the reaction mixture under reduced pressure gave a crude product. The crude product was treated with trifluoroacetic acid (2
ml) and purified by HPLC to give the desired product as a white solid (0.38 g, 58% yield). Step 3 A solution of 4-methylmorpholine (0.14 g, 1.41 mmol) in N, N-dimethylacetamide (15 ml) was added to the product of Step 2 (0.36 g, 0.94 mmol), 2-chloro-4 , 6-Dimethoxytriazine (0.18 g, 1.03 mmol) and N, N-dimethylacetamide (10 ml) at 0 ° C. The resulting bright orange solution was allowed to warm to room temperature and stirred for 3 hours. The product of Example G (0.350 g, 0.94 mmol), 4-methylmorpholine (
0.93 g, 0.94 mmol) and N, N-dimethylacetamide (4 ml
) Was added to the reaction solution. The resulting solution was stirred overnight at room temperature and treated with trifluoroacetic acid (1.0ml). Removal of the solvent from the reaction mixture under reduced pressure gave a crude product. The crude product was purified by HPLC to give the desired product as a yellow solid (0.35 g, 54% yield). Step 4 The product of Step 3 (0.33 g, 0.47 mmol), NaOH (1N, 9 ml)
) And MeOH (9 ml) were stirred for 18 hours. The reaction was treated with trifluoroacetic acid (1.0 ml). Removal of the solvent from the reaction solution under reduced pressure gave a crude product. Desired product and the crude product was purified by HPLC as a pale yellow solid (0.285 g, 84% yield) Elemental analysis _{C 23 H 26 N 6 O 6} Cl 2 · 1.25CF 3 COOH · As 1.0 H ₂ O: Calculated: C, 42.90; H, 4.13; N, 11.77; Found: C, 43.03; H, 4.03; N, 11.26. Example 48

[0530]

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The above compound was synthesized using the methodology described in Example 47. In step 1, ethylenediamine was used instead of 2,2-dimethyl-1,3-propanediamine. In step 3, the product of Example U was used instead of the product of Example G. As Elemental Analysis _{C 20 H 20 N 6 O 6} Cl 2 · 1.25CF 3 COOH · 0.5H 2 O: Calculated: C, 40.77; H, 3.38 ; N, 12.68; Found: C, 40.98; H, 3.17; N, 12.57. Example X

[0532]

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The above compounds are described in the literature (J. Org. Chem. 1990).
, 55, 5287-5291) prepared by iodination of 5-bromosalicylaldehyde. Example Y & Z

[0534]

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Step 1

[0536]

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Preparation of 5-aminonicotinic acid (10.0 g, 0.072 mol), benzoyl isothiocyanate (11.8 g, 0.072 mol) and DMAP (catalytic amount) were added to anhydrous acetonitrile (250 ml). The mixture was heated to reflux overnight under vigorous stirring under anhydrous conditions (Scheme A1). The resulting yellow suspension was cooled and filtered. The residue was washed with water followed by acetonitrile and dried under vacuum overnight to give the desired product as a pale yellow solid (21.4 g, 98% yield).

MS and ¹ H-NMR were consistent with the desired structure. Step 2

[0539]

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Preparation of The product from step 1 (11.1 g, 0.037 mol) was treated with anhydrous MeOH (230
mL of NaOMe (25% by weight methanol solution, 21.1 mL, 0.1 mL).
(092 mol) at which point the reaction goes into solution and an orange-brown solution is obtained (Scheme A1). The solution was stirred at room temperature for 3 hours, then cooled in an ice bath and methyl iodide (3.45 mL, 0.055 mol) was added. The resulting mixture was stirred at 10 ° C. for 30 minutes and at room temperature for 1.5 hours. The reaction mixture was then treated with acetic acid (2
mL), cooled in an ice bath and filtered. The solid was washed with cold MeOH and dried under vacuum to give the desired product as a beige solid (
2.66 g, 37% yield).

MS and ¹ H-NMR were consistent with the desired structure. Step 3 Preparation of Example Y & Z 1,3-Diamino-2-hydroxypropane (11.2 g, 0.124 mol)
To a solution of in anhydrous DMF (80 mL) was added the product of Step 2 (8.7 g, 0.041 mol). The mixture was heated to 85 ° C. for 3 hours under anhydrous conditions (Scheme A1)
). After 1-2 hours of heating, the solution began to become turbid, and the turbidity increased during the heating process. Then the reaction mixture was cooled in an ice bath and filtered. The solid was washed with acetonitrile, water, acetonitrile and dried under vacuum to give the desired product (Example Y) as a beige solid (3.7 g, 38% yield).

MS and ¹ H-NMR were consistent with the desired structure. The product of Example Z was prepared using the methodology described in Example Y, using 1,3-diamino-
It was synthesized by replacing 2-hydroxypropane with 4 equivalents of 2,2-dimethyl-1,3-propanediamine.

Each product from step 3 was added to each anhydrous THF solution (1 to 1.0 substrate)
0 mL) and TFA (1 equivalent) or 4N HCl / dioxane (2 equivalents) were converted to the respective TFA or HCl salts by stirring at 10 ° C. for 1 hour. Example 49

[0544]

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Production scheme A2 of

[0546]

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The product of Example Y (0.40 g, 0.00125 mol, Scheme A2) was suspended in anhydrous DMF (10 mL) and isobutyl chloroformate (0.17 g,
0.00125 mol), followed by N-methylmorpholine (0.14 g, 0.1 g).
[00137 mol) was added dropwise. After stirring the mixture at −20 ° C. for 20 minutes under an argon atmosphere, additional N-methylmorpholine (0.14 g, 0.00137 mol) was added, followed by the product of Example G (0.46 g, 0.00125 g). Mol) was added. The resulting mixture was stirred at -20 <0> C for 15 minutes, then at room temperature for 2 hours. The DMF was distilled under vacuum and the residue was purified by reverse phase HPLC to give the desired ester as a white solid (after lyophilization) (0.20 g, 21% yield).

MS and ¹ H-NMR were consistent with the desired structure. This ester (0.2 g) was stirred with 1 M 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 (0.11 g).

MS and ¹ H-NMR were consistent with the desired structure. Example 50

[0550]

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Preparation of The above compound was prepared using the method described in Example 49 and substituting the product of Example G with an equivalent amount of the product of Example R (Scheme A2).

MS and ¹ H-NMR were consistent with the desired structure. This ester (0.19 g, 0.00023 mol) was in 1 M LiOH (2 mL
) And 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 (
0.13 g, yield 72%).

MS and ¹ H-NMR were consistent with the desired structure. Example 51

[0554]

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Production Scheme B of

[0556]

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Step 1 Preparation of Bis-N-benzyloxycarbonyl-2-hydroxy-1,3-diaminopropane

[0558]

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2-Hydroxy-1,3-diaminopropane (5.8 g, 0.064 mol) in N-methylmorpholine (14 mL) in dichloromethane (150 mL)
In benzyloxycarbonylsuccinimide (32 g, 0.1 g).
29 mol) were added all at once (Scheme B). The reaction mixture was stirred at room temperature for 16 hours, the resulting clear solution was diluted with dichloromethane (100 mL), washed successively with 10% aqueous citric acid (2 × 50 mL) and dried (Na ₂ SO ₄ ). After filtration,
The solvent was removed under reduced pressure and the resulting white solid was crystallized from dichloromethane to give the desired compound (20.0 g, 87%). ¹ H-NMR and MS were consistent with the structure. Step 2 Preparation of bis-N-benzyloxycarbonyl-1,3-diaminopropan-2-one

[0560]

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The product from Step 1 (21.0 g, 0.058 mol) and EDC (33.0
g) was suspended in dichloromethane (120 mL) containing DMSO (24.0 mL) and stirred at 10 ° C. with pyridinium trifluoroacetate (33.0).
g) in dichloromethane (50 mL) was added dropwise over 30 minutes. After the addition was complete, a clear yellow liquid was obtained. After stirring at room temperature for 3 hours, a white solid separated from the reaction mixture. The reaction was cooled and filtered, and the solid was washed with cold dichloromethane and water. The resulting white solid was dried under vacuum in a desiccator to give the desired compound (15.5 g, 74% yield). ¹ H-NMR and MS were consistent with the structure. Step 3

[0562]

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Preparation of The product from step 2 (2.5 g, 0.007 mol), p-toluenesulfonic acid (0.3 g, 0.0016 mol) and DMSO (1.0 mL) were added to ethylene glycol (2. 0 mL) in dichloroethane (25 mL) was heated to reflux under anhydrous conditions (Scheme B). After 24 hours, the reaction mixture was cooled, diluted with dichloromethane (25 mL), washed successively with 10% sodium bicarbonate, water and dried (Na ₂ SO ₄ ). After removing the solvent under reduced pressure, the residue was crystallized from dichloromethane / hexane to give the desired compound (2.5 g, 89 yield).
%). ¹ H-NMR and MS were consistent with the structure. Step 4 The product from Step 3 (3.0 g, 0.0075 mol) was added to ethanol (50.0
dissolved in a mixed solvent of ethyl acetate (50.0 mL) and Pd / C (5%
, 1.5 g) at a pressure of 50 psi for 16 hours at room temperature (Scheme B). The catalyst was removed by filtration and washed with 40% water-containing ethanol (50 mL). The combined filtrate and aqueous wash were concentrated to dryness under reduced pressure to give a syrup. This material was dissolved in DMF (10.0 mL) and the product from Step 2 of Example 1 (1.0 g, 0.0047 mol) was added to triethylamine (0.7 mL).
mL) and DMAP (0.05 g). The resulting mixture was heated to 90 ° C under anhydrous conditions. After 3 hours, the DMF was distilled under vacuum and the residue was triturated with water and filtered. Washing with water, acetonitrile and drying in a desiccator under vacuum gave the compound of Example 51 (0.4 g, 30%). This material was used in Step B without further purification. ¹ H-NMR and MS were consistent with the structure. Example 52

[0564]

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Production Scheme C of

[0566]

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The compound of Example 51 (0.38 g, 0.0014 mol) was dried in dry THF (5.0
trifluoroacetic acid (0.1 mL) while stirring at 10 ° C. under anhydrous conditions.
mL) was added (Scheme C). After 30 minutes, the THF was distilled off under reduced pressure and the residue was dried under vacuum for 3 hours. The resulting material was dissolved in dry DMF (4.0 mL),
Upon cooling to −15 ° C., isobutyl chloroformate (0.18 mL) was added, followed by N-methylmorpholine (0.17 mL). The solution was stirred under an argon atmosphere for 30 minutes. To this mixture was added at 0 ° C. an amine solution generated by the addition of N-methylmorpholine (0.17 mL) to a solution of the product of Example R (0.51 g) in DMF (3.0 mL). The resulting mixture was stirred at −15 ° C. for 30 minutes, then at room temperature for 16 hours. The solvent was removed by distillation under vacuum and the residue was washed at a flow rate of 70 mL / min, 10-9
Purified by reverse phase HPLC using a 0% acetonitrile / water gradient (40 min).

The appropriate fractions were combined and lyophilized to give the desired ester as a fluffy white powder. This material was stirred at room temperature with lithium hydroxide solution (1M, 2.0 mL). After 45 minutes, the reaction mixture was cooled, diluted with water, acidified with trifluoroacetic acid and the desired acid was isolated by purification by reverse phase HPLC using 10-90% acetonitrile / water as described above ( 0.25 g). ¹ H-NMR and MS were consistent with the structure. Example 53

[0569]

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Production Scheme D of

[0571]

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Step 1 Preparation of Bis-N-benzyloxycarbonyl-2-fluoro-1,3-diaminopropane

[0573]

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Bis-N-benzyloxycarbonyl-2-hydroxy-1,3-diaminopropane (6.0 g, 0.017 mol) was suspended in dichloromethane (50 mL) and pyridine (2.7 mL), and was suspended at −50 ° C. While stirring with DAST (2.5 mL)
Of dichloromethane (7.5 mL) was added dropwise (Scheme D). The reaction mixture was gradually warmed to room temperature over 16 hours under an argon atmosphere. A clear yellow solution was obtained. The solution was cooled and ice, water (100 mL) and dichloromethane (50
mL) of the mixture. The organic phase was washed with water (2 × 50 mL) and dried (Na ₂ SO ₄ ). After removal of the solvent, the residue was purified by flash chromatography on silica gel using hexane containing 30% ethyl acetate. The appropriate fractions were combined, concentrated to dryness and crystallized from dichloromethane / hexane to give the desired fluoro intermediate as a fluffy white powder (2.0 g). ¹ H-NMR and MS were consistent with the structure. Step 2 Bis-N-benzyloxycarbonyl-2-fluoro-1, obtained in Step 1,
3-Diaminopropane (3.3 g, 0.0092 mol) was added to EtOAc (30 mL).
) And EtOH (30 mL) and hydrogenated in the presence of Pd / C (10%, 2.7 g) at a pressure of 50 psi for 16 hours at room temperature (Scheme D). After filtration, the catalyst was stirred with EtOH containing 50% water (50 mL) and filtered again. The filtrate was concentrated to dryness to give a syrup (0.7 g). This syrup is DM
F (8.0 mL). The product from Step 2 of Example 1 (0.7 g, 0.
0033 mol) and a catalytic amount of DMAP (0.01 g) at 90 ° C. under anhydrous conditions.
For 3 hours. Distill DMF under vacuum, suspend the residue in water (25 mL),
The pH was adjusted to 4.5 by adding 1N HCl. The resulting mixture was cooled. The separated solid was filtered, washed well with water, acetonitrile and dried in a desiccator under vacuum to give the desired compound as a brown powder (0.2
4g). ¹ H-NMR and MS were consistent with the structure. Example 54

[0575]

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Production Scheme E of

[0577]

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The compound of Example 53 (0.22 g) obtained as above was suspended in dry THF. Trifluoroacetic acid (0.1 mL) was added and the solution was stirred at 10 ° C. for 30 minutes,
Concentrated under reduced pressure. The residue was dried in a desiccator under vacuum. The obtained substance was suspended in dry DMF (5 mL). Isobutyl chloroformate (0.12 mL) was added, followed by N-methylmorpholine (0.11 mL). The solution was stirred at −15 ° C. under an argon atmosphere (Scheme E). After 30 minutes, the product of Example R (
N-methylmorpholine (0.09 g) in a solution of 0.37 g) in DMF (3.0 mL).
(5 mL) was added. The resulting mixture is -15
Stirred at C for 30 min then at room temperature for 16 h. Distill DMF under vacuum and remove residue
Purified by reverse phase HPLC using 0-90% acetonitrile / water. The appropriate fractions were combined and lyophilized to give the desired ester as a pale yellow powder (0.
35 g). ¹ H-NMR and MS were consistent with the structure.

The resulting product (0.3 g, Scheme E) was stirred at room temperature with 1 M LiOH (3.0 mL). After 1 hour, the solution was diluted with water (3.0 mL) and acidified with trifluoroacetic acid. The resulting mixture was purified by reverse phase HPLC using a flow rate of 70 mL / min, 10-90% acetonitrile / water (concentration gradient of 30 min). The appropriate fractions were combined and lyophilized to give the desired compound as a white powder (0.2
2g). ¹ H-NMR and MS were consistent with the structure. Example 55

[0580]

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Production Scheme F of

[0582]

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Step 1

[0584]

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Production of J. Carbohydrate Chemistry, 5, (2), 183-
197 (1986), 1,4-diamino-2,3-dihydroxybutane dihydrochloride synthesized from L-dimethyl tartrate (2.21 g, 0.2 g).
(012 mol) in water (6 mL) and anhydrous DMF (10 mL) was added sodium carbonate (1.83 g, 0.017 mol). This mixture was added to Step 2 of Example 1.
(1.21 g, 0.006 mol) was added and the mixture was heated to 85 ° C. for 3 hours. After cooling in an ice bath, DMF was distilled under vacuum and the resulting residue was suspended in water. The pH was adjusted to 5.6. Lyophilization of the solution gave the desired product (
0.907 g, 59% yield).

MS was consistent with the desired structure (M + H 267). The obtained compound was dissolved in THF (10 mL), and 4N
Converted to HCl salt by stirring with Cl / dioxane (2 eq). Step 2 At -20 ° C, the product from Step 1 (0.11 g, 0.00023 mol) was
Suspended in MF (10 mL) and isobutyl chloroformate (0.016 g, 0.000 g).
12 mol), followed by N-methylmorpholine (0.013 g, 0.0001 g).
37 mol) was added dropwise (Scheme F). After stirring the mixture at −20 ° C. for 20 minutes under an argon atmosphere, additional N-methylmorpholine (0.013 g, 0.000 g
137 mol), followed by the product of Example R (0.048 g, 0.00012).
Mol) was added. The resulting mixture was stirred at -20 C for 15 minutes. After stirring at room temperature for 2 hours, DMF was distilled under vacuum and the residue was purified by reverse phase HPLC to give the desired ester as a white solid (after lyophilization) (0.03 g, 33% yield)
).

MS (M + H 627 M + H 629) and ¹ H-NMR were consistent with the desired structure. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.8 (s, 1 H) 8.5 (
s, 1H), 8.1 (s, 1H), 7.4 (s, 1H), 7.2 (s, 1H),
5.6 (m, 1H), 4.1 (m, 1H), 3.7 (m, 2H), 3.6 (m, 1H)
2H) 3.3 (m, 2H), 2.9 (m, 2H), 1.2 (m, 3H) The resulting ester (0.03 g, 0.000035 mol) was 1 M LiOH (
2 mL). After stirring at room temperature for 1 hour, the pH was adjusted to 2 with trifluoroacetic acid and the product was isolated by reverse-phase HPLC to give the desired acid as a white solid (after lyophilization) (0.001 g, Yield 3.5%).

MS (M + H 599 M + H 601) and ¹ H-NMR were consistent with the desired structure. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.8 (s, 1 H) 8.5 (
s, 1H), 8.0 (s, 1H), 7.4 (s, 1H), 7.2 (s, 1H),
5.6 (m, 1H), 4.1 (m, 1H), 3.8 (m, 2H), 3.5 (m, 1H)
2H) 3.3 (m, 2H), 2.8 (m, 2H) Example 56 The difluoro analog was prepared according to the synthetic sequence outlined in Scheme 1 below.

[0589]

Embedded image

The carbobenzoxy protected ketone is converted to the corresponding difluoro intermediate using DAST diethylaminosulfur trifluoride. Subsequent removal of the carbobenzoxy group (Z) by catalytic hydrogenation and coupling of the resulting diamine with the S-methylisothiourea derivative of a 5-aminonicotinic acid derivative is corresponding to the corresponding reaction involving the nicotinic acid precursor. A difluoro-substituted guanidine. This compound is reacted with glycine-beta amino acid-ester, followed by hydrolysis and acidification to yield the final desired compound. Example 57 Compounds containing a 7-membered fluoro / hydroxy-substituted guanidine are known L-
Diisopropyl tartrate ( J. Am. Chem , Soc. 1988 , 110 , 75)
Prepared according to the following scheme starting from 38). Scheme 2

[0591]

Embedded image

The monosilylated intermediate is synthesized by amidation, silylation, and N-desilylation. Diborane reduction of this monosilyl derivative gives the corresponding diamine dihydrochloride. Subsequent condensation of the free diamine with the S-methylisothiourea 5-aminonicotinic acid derivative provides the corresponding 7-membered guanidine derivative. Further reaction of this guanidine with glycine-beta amino acid-ester, followed by hydrolysis and acidification, yields the final desired compound. Example 58 A dialkyl / diol substituted 7 membered cyclic guanidine compound is prepared according to the reaction outlined in the scheme below. Starting from a known carbobenzoxy-protected diamine ( JM Med. Chem. 1996, 39, 2156), the corresponding 7-membered cyclic guanidine reacts the free diamine precursor with an S-methylisothiourea 5-aminonicotinic acid derivative And synthesized. Condensation of the resulting guanidine-carboxylic acid with glycine-beta amino acid-ester, followed by hydrolysis and acidification, yields the final desired compound. Scheme 3

[0593]

Embedded image

Example 59 A dihydroxy compound is prepared by acid catalyzed cleavage of a cyclic ketal precursor as shown in the scheme below. Scheme 4

[0595]

Embedded image

[0596]Example 60 7-membered cyclic diol-substituted guanidines starting from D or meso-tartaric acid derivatives
The compounds involved are prepared as outlined in Scheme F. The activity of the compounds of the invention was tested in the following assays. Test of the assay
The results are shown in Table 1.Vitronectin adhesion assay material Human vitronectin receptor (α_vβ_Three) Is [P
ytela et al. ,Methods in Enzymology, 1
44: 475-489 (1987)], and purified from human placenta. Human vitron
Kuching has been described previously [Yatohgo et al. ,Cel l Structure and Function , 13: 281-292 (
1988)], purified from fresh frozen plasma. Biotinylated human vitronectin
Is Pierce Chemical Company (Rockford, IL)
)) From purified vitronectin as previously described [
Charo et al. ,J. Biol. Chem. 266 (3): 1415
-1421 (1991)]. Assay buffer, OPD substrate
Tablets and BSA for RIA from Sigma (St. Louis, MO)
obtained. Anti-biotin antibody is available from Calbiochem (La Jolla, CA)
Obtained from. Limbro microtiter plates are available from Flow Labs (Mc
(Lean, VA). The ADP reagent is Sigma (St. Louis,
MO).Method Solid phase receptor assay This assay is based on a previously reported assay [Niiya et al. , Blood , 70: 475-483 (1987)]. Purification
Human vitronectin receptor (α_vβ_Three) Indicates the stock solution is 1.0 mM C
a⁺⁺, Mg⁺⁺And Mn⁺⁺Containing Tris buffer (pH 7.4) (TBS^{++ +} ) To 1.0 μg / mL. 100 μL of diluted receptor immediately
Microtiter plate / well (100 ng receptor / well)
Moved to Seal the plate and incubate overnight at 4 ° C.
Was bound to the wells. All remaining steps were performed at room temperature. Assay pre
1% RIA B to empty plate and block exposed plastic surface
TBS including SA⁺⁺⁺(TBS⁺⁺⁺/ BSA) was added. 2 hours ink
After incubation, the assay plate was washed with TBS using a 96-well washer.⁺⁺⁺so
Washed. TBS containing 2 nM biotinylated vitronectin⁺⁺⁺/ Dilute BSA
A series of logarithmic dilutions of test compound and control were used as stock solutions at 2 mM stock concentration
I went from starting. The label ligand and test compound (or control) are
Mixing and subsequent transfer of 50 μL to the assay plate was performed using CETUS P
carried out on a robot robot; final concentration of labeled ligand was 1 nM
, The highest concentration of test compound is 1.0 × 10^-FourM. Two hours of competition
All wells were then washed in a plate washer as before. Affinity
Purified horseradish peroxidase-labeled goat anti-biotin antibody^{++ +} / BSA diluted 1: 3000 and 125 μL was added to each well. 30
After one minute, the plate is washed and dissolved in 100 mM / L citrate buffer (pH 5.0).
OPD / H_TwoO_TwoIncubated with substrate. Plate at a wavelength of 450nm
Read on a microtiter reader and find that the maximum binding control wells
When the brightness is reached, the final A₄₅₀Was recorded for analysis. The data is EXCELJ
Analyzed using macros written for use in spreadsheet programs
Was. Mean, standard deviation and% CV were determined at duplicate concentrations. Average A₄₅₀Value is 4
It was normalized to the mean of the maximum binding control (no competitor added) (B-MAX). standard
The quantified values were calculated using a four-parameter curve fitting algorithm [Rodbard et al. , Int. Atomic Energy Agency, Vienna , Pp46
9 (1977)], plotted on a semi-log scale, and the highest tested
For compounds showing greater than 50% inhibition at concentrations, biotinylated vitro
The calculated concentration corresponding to 50% inhibition of maximal binding of Nectin (IC₅₀) And corresponding
R^TwoWas reported; or IC₅₀Is higher than the highest concentration tested
It has been reported. Powerful α_vβ_ThreeIs an antagonist (IC in the range of 3-10 nM)₅₀ ) Β-[[2-[[5-[(aminoiminomethyl) amino] -1-oxopentene)
[Amino] -1-oxoethyl] amino] 3-pyridinepropanoic acid (USSN
 08 / 375,338, Example 1) was included in each plate as a positive control.
I wasPurified IIb / IIIa receptor assay material Human fibrinogen receptor (α_vβ_Three) Is purified from expired platelets
Was. (Pytela, R., Pierschbacher, MD, Argr
aves, S.A. Suzuki, S .; , And Rouslahti, E .; "A
Luginin-glycine-aspartate adhesion receptor ",Methods in Enzymology 144 (1987): 475-489. ) Hitovitro
Nectin is described in Yatohgo, T .; , Izumi, M .; , Kashiwagi, H
. , And Hayashi, M .; , "Heparin Affinity Chromatography
A novel purification of vitronectin from human plasma by fee "Cell Struc cure and function , 13: 281-292 (1988).
Purified from fresh frozen plasma as indicated. Biotinylated human vitronect
Chin is from Pierce Chemical Company (Rockford,
ILS) from a purified vitronectin as described previously.
Prepared by binding to (Charo IF, Nannizzi, L.,
Phillips, D .; R. Hsu, M .; A. , Scarborough, R
. M. Fibri to GP IIb / IIIa with GP IIIa peptide
Inhibition of noogen binding ”,J. Biol. Chem. 266 (3) (1991):
1415-1421. ) Assay buffer, for OPD substrate tablets and RIA
BSA was obtained from Sigma (St. Louis, MO). Anti-biotin antibody
Was obtained from Calbiochem (La Jolla, CA). Limbroma
Microtiter plates are available from Flow Labs (McLean, VA)
did. ADP reagent was obtained from Sigma (St. Louis, MO).Method Solid phase receptor assay This assay is described in Niiya, K .; Hodson, E .; , Bader, R .; ,
Byers-Ward, V .; Koziol, J .; A. , Plow, E .; F. an
d Ruggeri, Z .; M. Membrane glycoprotein induced by platelet activation
Surface expression of the quality IIb / IIIa complex: fibrinogen binding and blood
Relationship with platelet aggregation ",Blood, 70: 475-483 (1987).
It is essentially the same as the assay used. Purified human fibrinogen resin
Puter (α_vβ_Three) Indicates that the stock solution is 1.0 mM Ca⁺⁺, Mg⁺⁺And Mn⁺⁺Including
Tris buffer (pH 7.4) (TBS⁺⁺⁺) Diluted to 1.0μg / mL
did. The diluted receptor was immediately added to 100 μL / well (100 ng receptor).
-/ Well) to a Limbro microtiter plate. Sea plate
And incubated overnight at 4 ° C. to allow the receptor to bind to the wells. Remaining
All steps were performed at room temperature. Empty the assay plate and expose the
TBS with 1% RIA BSA to block tic surface⁺⁺⁺(TBS^{+ ++} / BSA) was added. After 2 hours incubation, assay
The plate was washed with TBS using a 96-well washer.⁺⁺⁺And washed. 2 nM biotinylation
TBS containing vitronectin⁺⁺⁺/ BSA as diluent, test compound and
And a series of logarithmic dilutions of controls were performed starting from a stock concentration of 2 mM. This sign
Premixing of the ligand with the test compound (or control) and subsequent assay
50 μL transfer to the plate is performed with a CETUS Propette robot
The final concentration of labeled ligand was 1 nM and the highest concentration of test compound was
1.0x10^-FourM. Let the competition occur for 2 hours and then all wells
And washed with a plate washer as described above. Affinity purified horseradish pelvis
Oxidase-labeled goat anti-biotin antibody with TBS⁺⁺⁺/ BSA: 1: 3000 rare
And 125 μL was added to each well. After 30 minutes, wash the plate and
OPD / H dissolved in 0 mM / L citrate buffer (pH 5.0)_TwoO_TwoSubstrates and Inns
Cubbed. Plates are read on a microtiter reader at a wavelength of 450 nm
The final A was read when the maximum binding control well reached an absorbance of about 1.0.₄₅₀But
Recorded for analysis. Data is in EXCELJ spreadsheet program
Analyzed using macros written for use. Mean, standard deviation and% C
V was determined at duplicate concentrations. Average A₄₅₀Values are 4 maximum binding controls (without competitor addition).
And (B-MAX). Normalized value fits a 4-parameter curve
Algorithm [Rodbard et al. ,Int. Atomic Energy rgy Agency, Vienna , Pp 469 (1977)],
Plotted on a semilog scale, showing greater than 50% inhibition at the highest concentration tested
50% inhibition of maximal binding of biotinylated vitronectin to the indicated compounds
Calculated concentration corresponding to harm (IC₅₀) And the corresponding R^TwoWas reported; or
IC₅₀Is reported as higher than the highest concentration tested. Powerful α_vβ_Three Is an antagonist (IC in the range of 3-10 nM)₅₀) Β-[[2-[[5-[(amino
Iminomethyl) amino] -1-oxopentyl] amino] -1-oxoethyl]
Amino] 3-pyridinepropanoic acid (USSN 08 / 375,338, Example 1
) Was included in each plate as a positive control.Human platelet-rich plasma assay Healthy, non-aspirin donors were selected from a group of volunteers
. Platelet-rich plasma and subsequent ADP-induced platelet aggregation assays are described in Zucke
r, M. B. , "Platelet aggregation measured by spectrophotometry",Methods in Enzymology 169 (1989): 117-133.
It was implemented as such. The standard venipuncture technique using a butterfly is 5 mL
45 mL into a 60 mL syringe containing 3.8% trisodium citrate
Enabled the removal of whole blood. After mixing in the syringe, the anticoagulated blood
Transferred to a conical polyethylene tube. Blood at 200 xg for 12 minutes at room temperature
Non-platelet cells were sedimented by centrifugation. Platelet-rich plasma
And stored at room temperature until use. Platelet poor plasma removes remaining blood
Obtained by a second centrifugation at 2000 × g for 15 minutes. Platelet count is typically
Was from 300,000 to 500,000 per microliter. platelet
Rich plasma (0.45 mL) was split into siliconized cuvettes and 50 μL
Stirred at 37 ° C. for 1 minute prior to addition of prediluted test compound (11
00 rpm). One minute after mixing, aggregation was added by adding 50 μL of 200 μM ADP.
Started. Aggregation is performed using a Payton dual channel aggregometer (Payton S
scientific, Buffalo, NY) for 3 minutes. A series of tests
Percent inhibition of maximal response to compound dilution (saline control)
Used to determine. All test compounds were tested in duplicate and tested
The dose response curve for compounds showing 50% or greater inhibition at the highest concentration
Roughly half-maximal inhibition (IC₅₀) Was calculated; or IC₅₀Is tested
Higher than the highest concentration reported.

[0597]

[Table 1]

[0598]

[Table 2]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/527 A61K 31/527 4H045 31/551 31/551 A61P 3/14 A61P 3/14 9/00 9 / 00 9/10 9/10 19/02 19/02 19/10 19/10 27/02 27/02 29/00 101 29/00 101 35/00 35/00 35/04 35/04 43/00 111 43/00 111 C07D 333/38 C07D 333/38 401/12 401/12 403/12 403/12 409/12 409/12 417/12 417/12 491/113 491/113 C07K 5/023 C07K 5/023 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH , GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT , AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ , PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW Devadas, Barrexdure 63017 Missouri, United States Chesterfield, Umbrellas Drive 2175 (72) Inventor Huff, Lenny 60068, Illinois, USA, Park Ridge, North Lincoln Avenue 837 (72) Inventor, Canna, Ish Cay 60061, Illinois, United States of America, Vernon Hills, Brandywine・ Coat 149 (72) Inventor Lao, Shasidhar N. 60060, Illinois, United States, Mundelein, Windsor Place 43 (72) Inventor Rico, Joseph G. 63201, Missouri, United States of America, Ballwin, Weatherby Terrace Drive 524 (72) Inventor Rogers, Thomas E. 63201, Missouri, USA, Ballwin, Trago Creek Drive 755 (72) Inventor Luminsky, Peter G. 63366, Missouri, USA, Dardenne Prairie, Pierside Dry Bu 7687 (72) Inventor Russell, Mark Andrew 60031, Illinois, USA, Garni, Cross Road 475 (72) Inventor U, E 60077, Illinois, United States of America, Skokie, Gross Point Road 9065, Apartment Number GR (72) Inventor Gashieki, Alan Frank 60061, Illinois, United States of America, Alexandria Drive, Vernon Hills 105 Miyashiro, Julie M. 60076, Illinois, USA, Skokie, West Kearney 4654, Number 3W F-term (reference) 4C023 HA03 4C050 AA04 BB08 CC17 EE02 FF01 GG04 HH04 4C055 AA01 BA02 BA15 CA03 CA54 CA58 CB10A013 BB09 CC23 CC29 CC92 DD12 DD23 DD29 EE01 4C086 AA01 AA03 BB02 BC17 BC38 BC82 CA01 GA06 MA04 NA14 ZA36 ZA94 ZA96 ZA97 ZB21 ZB26 ZC21 4H045 AA10 AA30 BA51 EA22 EA23 EA27 EA28 FA44 GA01 GA22 GA25 HA02

Claims (22)

[Claims] 1. A compound of the following formula or a pharmaceutically acceptable salt thereof: [In the above formula, Contains 1-4 heteroatoms selected from the group consisting of O, N or S;
A 5- to 8-membered monocyclic heterocyclic ring which may be unsaturated; wherein X ¹ is
A is selected from the group consisting of H, CH ₂ , N, NH, O and S; Wherein Y ¹ is selected from the group consisting of NR ² , O, and S; R ² is hydrogen; alkyl; aryl; hydroxy; alkoxy; cyano; nitro; amino; alkenyl; Alkylcarbonyl; arylcarbonyl; alkoxycarbonyl; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl; lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy. , Aryl or one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, Alkyl optionally substituted with one or more substituents selected from sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycle, or aryl optionally substituted with fused monocyclic heterocycle; Halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, carboxyl derivative, amino, aryl, fused aryl,
Aryl optionally substituted with one or more substituents selected from monocyclic heterocycles and fused monocyclic heterocycles; monocyclic heterocycles; and halogen, haloalkyl, lower alkyl, alkoxy, amino, From the group consisting of monocyclic heterocycles optionally substituted with one or more substituents selected from nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl Or R ² together with R ⁷ is selected from lower alkyl, thioalkyl, alkylamino, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, spirodioxolane, and fused phenyl 4- which may be substituted with one or more substituents Form a heterocyclic ring containing two nitrogen of 2 members; or R ² contains one or more heteroatoms selected together with R ⁷ O, N and S, unsaturated R ⁴ together with R ⁷ is substituted with one or more substituents selected from lower alkyl, phenyl, alkoxy and hydroxy. also form a heterocyclic aromatic ring may 5-9 membered; or R ² forms a heteroaromatic ring 5-membered fused with aryl or heteroaryl ring together with R ^7; (R ² R ⁷ and R ⁸ are hydrogen; alkyl; alkenyl;
Alkynyl; aralkyl; amino; alkylamino; hydroxy; alkoxy; arylamino; amide, alkylcarbonyl, arylcarbonyl; alkoxycarbonyl; aryloxy; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; Methoxycarbonyl, cycloalkyl, bicycloalkyl, aryl, acyl, benzoyl, lower alkyl, halogen, hydroxy,
Haloalkyl, cyano, nitro, carboxyl derivative, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, Cyano, nitro, carboxyl derivative, aryloxy, amide, acylamino, amino, alkylamino,
One or more selected from dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycle, fused monocyclic heterocycle Alkyl optionally substituted with one or more substituents selected from aryl optionally substituted with the following substituents: halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio , Thio, hydroxy, cyano, nitro, carboxyl derivative, aryloxy, amide, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid Aryl optionally substituted with one or more substituents selected from sulfonamide, aryl, fused aryl, monocyclic heterocycle, or fused monocyclic heterocycle; monocyclic heterocycle; halogen, haloalkyl , Lower alkyl,
A monocyclic heterocycle optionally substituted with one or more substituents selected from alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl; Cyclic and bicyclic heterocyclic alkyls; —SO ₂ R ^10, wherein R ¹⁰ is selected from the group consisting of alkyl, aryl, and monocyclic heterocycles, all halogen, haloalkyl, alkyl, alkoxy, Cyano, nitro, amino, acylamino, trifluoroalkyl, amide, alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio, trifluoroalkoxy, trifluoromethylsulfonyl, aryl,
And optionally substituted with one or more substituents selected from the group consisting of aryloxy, thio, alkylthio and monocyclic heterocycles); and Wherein R ¹⁰ is as defined above; or NR ⁷ and R ^{8 taken} together are selected from lower alkyl, carboxyl derivative, aryl or hydroxy 4- which may be substituted with one or more substituents
Forming a monocyclic or bicyclic ring having one 12-membered nitrogen and wherein said ring may contain a heteroatom selected from the group consisting of O, N and S; R ⁵ Is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, benzyl, and phenethyl; or A is Wherein Y ² is alkyl; cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycle; halo, haloalkyl, alkyl, nitro, hydroxy,
Alkyl optionally substituted with aryl optionally substituted with one or more substituents selected from alkoxy, aryloxy, aryl or fused aryl; halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl,
Aryl optionally substituted with one or more substituents selected from fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl; alkynyl; alkenyl; -SR ⁹ and -OR ⁹ ( Wherein R ⁹ is selected from the group consisting of hydrogen; alkyl; aralkyl; aryl; alkenyl; and alkynyl; or R ⁹ together with R ⁷ is lower alkyl, hydroxy, keto, phenyl, carboxyl or carboxyl. 4-, which may be substituted with an ester and a condensed phenyl
R 12 forms a heterocyclic ring containing one nitrogen and one sulfur or one oxygen containing 12 members; or R ⁹ together with R ⁷ is thiazole; oxazole; benzoxazole; or benzo And R ⁵ and R ⁷ have the meanings as defined above; or Y ² (when Y ² is carbon) together with R ⁷ is alkyl, aryl Forms a 4-12 membered one nitrogen or two nitrogen containing ring optionally substituted with keto or hydroxy; or A is Wherein R ² and R ⁷ are together substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, keto, phenyl, or carboxyl derivatives. form a heterocyclic ring containing two nitrogen of good 5-8 members; and R ⁸ is, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl Or R ⁵ is as defined above; or R ² and R ⁷ are taken together to form a membered heteroaromatic ring such as imidazole or pyrimidone. Or A is: Wherein R ² and R ⁷ together form a 5-8 membered two nitrogen containing heterocycle optionally substituted by hydroxy, keto, phenyl, or alkyl; and R ⁸ is both selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl and acyloxymethoxycarbonyl; Z ¹ is hydrogen; alkyl; Hydroxy, alkoxy, aryloxy, halogen, haloalkyl, haloalkoxy, nitro, amino, alkylamino, acylamino, dialkylamino, cyano, alkylthio, alkylsulfonyl, carboxyl derivative, trihaloacetamide; Aryl; cycloalkyl; thio; monocyclic heterocycle; fused monocyclic heterocycle and A, wherein A is as defined above. V is -N- (R ⁶ )-(where R ⁶ is hydrogen; lower alkyl; cycloalkyl; aralkyl; aryl; and a monocyclic heterocycle. Or R ⁶ is selected from the group consisting of: 4-12 members forming a nitrogen-containing ring together with 4-12 members; Y, Y ³ , Z and Z ³ Is independently selected from the group consisting of hydrogen; alkyl; aryl; and cycloalkyl; or Y and Z together form cycloalkyl; or Y ³ and Z ³ together N is an integer 1, 2 Or t is an integer 0, 1, or 2; p is an integer 0, 1, 2, or 3; R is XR ³ (where X is O, S , And NR ⁴ are selected from the group consisting of:
Wherein R ³ and R ⁴ are hydrogen; alkyl; alkenyl; alkynyl; haloalkyl; aryl; arylalkyl; sugar; steroid; polyalkyl ether; alkylamide; alkyl N, N-dialkylamide; pivaloyloxymethyl; R ¹ is hydrogen; alkyl; alkenyl; alkynyl; aryl; carboxyl derivative; haloalkyl; cycloalkyl; in the case of the free acid, all are independently selected from the group consisting of pharmaceutically acceptable salts thereof. Monocyclic heterocycle; substituted by alkyl, halogen, haloalkyl, cyano, hydroxy, aryl, fused aryl, nitro, alkoxy, aryloxy, alkylsulfonyl, arylsulfonyl, sulfonamide, thio, alkylthio, carboxyl derivative, amino, amide hand A monocyclic heterocycle; halo, haloalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl, arylthio, alkylsulfoxide, alkylsulfonyl, arylsulfoxide, arylsulfonyl, cyano, nitro, amino, alkyl Substituted with one or more of amino, dialkylamino, alkylsulfonamide, arylsulfonamide, acylamide, carboxyl derivative, sulfonamide, sulfonic acid, phosphonic acid derivative, phosphinic acid derivative, aryl, arylthio, arylsulfoxide, or arylsulfone Alkyl, halo, alkyl, haloalkyl, all on the aryl ring,
Cyano, nitro, hydroxy, carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino, amide, aryl, fused aryl, monocyclic heterocycles; and fused monocyclic heterocycles, monocyclic heterocycles. Cyclic heterocyclic thio, monocyclic heterocyclic sulfoxide, and monocyclic heterocyclic sulfones, which may be substituted with halo, haloalkyl, nitro, hydroxy, alkoxy, fused aryl or alkyl; alkylcarbonyl , Haloalkylcarbonyl, and arylcarbonyl; halo, haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, acyloxy, Hexyl derivatives,
Carboxyalkoxy, amide, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycle and fused monocyclic heterocycle Aryl optionally substituted with; and Wherein R ⁷ and R ⁸ have the meaning defined above and are combined with nitrogen, wherein R ⁷ and R ⁸ comprise an amino acid;
And R ¹¹ is selected from the group consisting of hydrogen, alkyl, aralkyl, alkenyl, alkynyl, haloalkyl, or haloalkynyl, or R ¹¹ together with Y forms one 4-12 membered nitrogen. To form a ring containing). 2. The following formula: (In the above formula, Is Wherein R ³² is hydrogen, alkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, wherein the alkyl group is hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl- or alkyl-sulfonyl, (Can be substituted with one or more substituents selected from the group consisting of carboxyl and carboxyl derivatives). 3. The compound according to claim 1, wherein Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image And 3. The compound according to claim 2, wherein the compound is selected from the group consisting of: 4. The following formula: (In the above formula, Is The compound according to claim 1, wherein 5. The compound according to claim 1, wherein the compound is Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image 5. The compound according to claim 4, wherein the compound is selected from the group consisting of: 6. The following formula: (In the above formula, Is The compound according to claim 1, wherein 7. The following compound: Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image 7. The compound of claim 6, wherein the compound is selected from the group consisting of: 8. The compound of the formula: (In the above formula, Is The compound of claim 1, wherein 9. The following formula: Embedded image The compound according to claim 8, wherein 10. The following formula: (In the above formula, Is The compound according to claim 1, wherein 11. The following formula: embedded image The compound according to claim 10. 12. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 1.
A pharmaceutical composition comprising a therapeutically effective amount of one compound and a pharmaceutically acceptable carrier. 13. A method of treating a condition mediated by α _v β ₃ integrin in a mammal in need thereof, comprising the steps of claim 1, 2, 3, 4, 5, 6, 7,
The method comprising administering a therapeutically effective α _v β ₃ inhibitory amount of a compound of 8, 9, 10 or 11. 14. The method of claim 13, wherein the condition to be treated is a tumor metastasis. 15. The method of claim 13, wherein the condition to be treated is the growth of a solid tumor. 16. The method of claim 13, wherein the condition to be treated is angiogenesis. 17. The method of claim 13, wherein the condition to be treated is osteoporosis. 18. The condition to be treated is malignant humoral hypercalcemia.
The method according to claim 13. 19. The method of claim 13, wherein the condition to be treated is smooth muscle cell migration. 20. The method of claim 13, wherein restenosis is suppressed. 21. The condition to be treated is rheumatoid arthritis.
3. The method according to 3. 22. The method of claim 13, wherein the condition to be treated is macular degeneration.