WO2011025565A1 - Morpholinone compounds as factor ixa inhibitors - Google Patents

Morpholinone compounds as factor ixa inhibitors Download PDF

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Publication number
WO2011025565A1
WO2011025565A1 PCT/US2010/036853 US2010036853W WO2011025565A1 WO 2011025565 A1 WO2011025565 A1 WO 2011025565A1 US 2010036853 W US2010036853 W US 2010036853W WO 2011025565 A1 WO2011025565 A1 WO 2011025565A1
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Prior art keywords
hydroxy
oxo
oxomorpholin
compound
acetamide
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PCT/US2010/036853
Other languages
French (fr)
Inventor
Hidemitsu Nishida
Fumihiko Saitoh
Tomokazu Hirabayashi
Samuel Chackalamannil
Tin-Yau Chan
Mariappan V. Chelliah
Martin C. Clasby
Michael P. Dwyer
William J. Greenlee
Yan Xia
Santhosh Neelamkavil
Unmesh G. Shah
Original Assignee
Mochida Pharmaceutical Co., Ltd.
Schering Corporation
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Publication date
Priority claimed from PCT/US2009/066548 external-priority patent/WO2010065717A1/en
Application filed by Mochida Pharmaceutical Co., Ltd., Schering Corporation filed Critical Mochida Pharmaceutical Co., Ltd.
Priority to AU2010286933A priority Critical patent/AU2010286933A1/en
Priority to EP10722268.9A priority patent/EP2473491B1/en
Priority to JP2012526744A priority patent/JP2013503163A/en
Priority to CA2771601A priority patent/CA2771601A1/en
Publication of WO2011025565A1 publication Critical patent/WO2011025565A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to novel compounds of the Formula (I) having antithrombotic activity which, in particular, inhibit blood clotting factor IXa, to processes for their preparation and to use thereof as medicaments.
  • Factor IXa is a plasma serine protease involved in the regulation of blood coagulation. While blood coagulation is a necessary and important part of the regulation of an organism's homeostasis, abnormal blood coagulation can also have deleterious effects. For instance, thrombosis is the formation or presence of a blood clot inside a blood vessel or cavity of the heart. Such a blood clot can lodge in a blood vessel blocking circulation and inducing a heart attack or stroke. Thromboembolic disorders are the largest cause of mortality and disability in the industrialized world.
  • Blood clotting is a process of control of the blood stream essential for the survival of mammals.
  • the process of clotting, as shown in the Patent Document 1, and the subsequent dissolution of the clot after wound healing has taken place commences after vascular damage and can be divided into four phases:
  • the next phase is platelet activation by thrombin.
  • the platelets attach to the site of the vessel wall damage and form a platelet aggregate.
  • the protein fibrinogen is responsible here for the crosslinkage of the platelets by means of appropriate surface receptors.
  • Platelets also bind to exposed collagen of the extracellular matrix of the damaged vessel wall and are activated by this means.
  • a number of messenger substances are secreted, which induce the activation of further platelets.
  • a membrane lipid, phosphatidylserine is transported from the inside of the membrane of the platelets to the outside, on which complexes of clotting factors can accumulate.
  • the platelets accelerate blood clotting by means of this mechanism.
  • clotting factor X is activated.
  • the activated factor X is responsible for the formation of thrombin from the inactive precursor prothrombin circulating in the blood.
  • the formation of a thrombus on the bottom of a vessel wall abnormality without a wound is the result of the intrinsic pathway.
  • Fibrin clot formation as a response to tissue damage or an injury is the result of the extrinsic pathway. Both pathways comprise a relatively large number of proteins, which are known as clotting factors.
  • the intrinsic pathway requires the clotting factors V, VIII, IX, X, XI and XII and also prekallikrein, high molecular weight kininogen, calcium ions and
  • the intrinsic pathway is initiated when prekallikrein, high molecular weight kininogen factor XI and XII bind to a negatively charged surface. This point in time is designated as the contact phase. Exposure to vessel wall collagen is the primary stimulus of the contact phase. The result of the processes of the contact phase is the conversion of prekallikrein to kallikrein, which in turn activates factor XII. Factor XIIa hydrolyzes further prekallikrein to kallikrein, such that activation is the result. With increasing activation of factor XII, activation of factor XI occurs, which leads to a release of bradykinin, a vasodilator.
  • factor IXIa activates factor IX.
  • Factor IX is a proenzyme, which contains vitamin K-dependent, ⁇ -carboxyglutamic acid (GLA) residues. The serine protease activity becomes noticeable after binding of Ca *+ to these GLA residues.
  • GLA ⁇ -carboxyglutamic acid
  • a number of the serine proteases of the blood clotting cascade (factors II, VII, IX and X) contain such vitamin K-dependent GLA residues.
  • Factor IXa cleaves factor X and leads to activation to factor Xa.
  • factor IXa The prerequisite for the formation of factor IXa is the formation of a tenase complex from Ca 2+ and the factors Villa, IXa and X on the surface of activated platelets.
  • One of the reactions of activated platelets is the presentation of phosphatidylserine and phosphatidylinositol along the surfaces. The exposure of these phospholipids first makes the formation of the tenase complex possible.
  • Factor VIII in this process has the function of a receptor for the factors IXa and X. Factor VIII is therefore a cofactor in the clotting cascade.
  • factor Villa With increase in the concentration of thrombin, factor Villa is finally cleaved further and inactivated by thrombin.
  • This dual activity of thrombin in relation to factor VIII leads to a self-restriction of tenase complex formation and thus to a limitation of blood clotting.
  • the extrinsic pathway requires a tissue factor (TF) and clotting factors V, VII, VIII, IX and X.
  • tissue factor TF
  • clotting factors V, VII, VIII, IX and X clotting factors V, VII, VIII, IX and X.
  • Clotting factor IX can be activated by means of the intrinsic pathway and the extrinsic pathway.
  • the activation of factor IXa is thus a central point of intersection between the two pathways of activation of clotting.
  • Factor IXa has an important role in blood clotting. Defects in factor IXa lead to hemophilia B, while increased concentrations of factor IXa in the blood lead to a significantly increased risk of thrombosis formation ( Weltermann A, et al., J Thromb Haemost. 2003; 1 : 28-32). The regulation of factor IXa activity can reduce thrombus formation in animal models (Feuerstein GZ, et al., Thromb Haemost. 1999; 82:
  • Factor IXa antagonists include problems in terms of usefulness and safety.
  • these compounds may have low absorption, and oral administration of these compounds may be difficult; these compounds also may exhibit inhibitory activity of the human ether-a-go-go related gene (hERG) channel, which may cause arrhythmia, and pharmacokinetics of these compounds might not satisfactory.
  • hERG human ether-a-go-go related gene
  • the present invention provides a novel class of cyclic morpholine compounds or its analogue, pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing a thromboses, embolisms, hypercoagulability or fibrotic changes.
  • the compounds of the Formula (I) according to the invention are suitable for prophylactic and for therapeutic administration to humans who suffer from diseases which accompany thromboses, embolisms, hypercoagulability or fibrotic changes. They can be employed for secondary prevention and are suitable both for acute and for long-term therapy.
  • the invention therefore relates to a compound of Formula (I)
  • compounds of the Formula (I), or a pharmaceutical acceptable salt or a solvate thereof can be useful for treating or preventing a disorder or disease mediated by factor IXa, or a thromboembolic disorder (each disorder being a "Condition").
  • the present invention provides pharmaceutical compositions comprising at least one compound of the Formula (I) or a pharmaceutically acceptable carrier.
  • the composition can be useful for treating or preventing a Condition.
  • the present invention provides a method for treating a Condition, the method comprising administering to a patient an effective amount of at least one compound of Formula (I) or a pharmaceutically acceptable salt or a solvate thereof.
  • the present invention provides compounds of Formula (I) and/or pharmaceutically acceptable salts, solvates and prodrugs thereof.
  • the compounds of Formula (I) can be useful for treating or preventing a Condition in a patient.
  • the invention provides compounds of Formula (I)
  • -(C j -C 6 )-alkyl part of 2) and 6) of said Y is unsubstituted or substituted independently with the substituents selected from the group consisting of -(C 3 -C 8 )-cycloalkyl, -C(O)OH, and -C(O)-(C 1 -C 6 )-alkyl,
  • the compounds are of the formula
  • the compounds are of the absolute configuration of Formula (I) is
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the invention is also the compound
  • (C d -C b )-alkyl' ⁇ in which a and b is each independently integers representing 1 to 6, is understood as meaning hydrocarbon radicals whose carbon chain are each straight-chain or branched and contains a to b carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary-butyl, pentyl, isopentyl, neopentyl, hexyl, 2,3-dimethylbutyl or neohexyl.
  • -(C 0 -C 4 )-alkylene is understood as meaning a bond or hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 4 carbon atoms, for example methylene, ethylene, propylene, isopropylene, isobutylene, butylene or tertiary-butylene.
  • "-C 0 -alkylene” is a covalent bond.
  • -(C 1 -C 4 )-alkylene is understood as meaning hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 4 carbon atoms, for example methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), (-CH 2 ( CH 3 )-), propylene (-CH 2 -CH 2 -CH 1 -), isopropylene, isobutylene, butylene or tertiary-butylene.
  • -(C 3 -C 1 , )-cycloalkyl is understood as meaning rings of 3 to 12 carbon atoms such as compounds which partially have monocycles having 3 to 8 carbon atoms in the ring such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane, which are derived from the bicycles bicyclo[4.2.0]octane, octahydroindene, decahydronaphthalene, decahydroazulene,
  • -(C ⁇ -C 8 )-cycloalkyl is understood as meaning radicals which are derived from monocycles having 3 to 8 carbon atoms in the ring such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclo-heptane or cyclooctane.
  • -(C 6 -C ]4 )-aryl is understood as meaning aromatic hydrocarbon radicals having 6 to 14 carbon atoms in the ring.
  • -(C,-C 14 )-aryl radicals are, for example, phenyl, 1-naphthyl, 2-naphthyl, anthryl or fluorenyl. Naphthyl radicals and in particular phenyl radicals are preferred aryl radicals.
  • three- to fifteen-membered heterocyclic ring is understood as meaning ring systems having 3 to 15 carbon atoms, which are present in one, two or three ring systems connected to one another and in which one, two, three or four identical or different heteroatoms from the group consisting of oxygen, nitrogen or sulfur can replace the respective carbon atoms.
  • bicyclic ring system represented by Formula (a) is a bicyclic ring system represented by Formula (a).
  • Formula (a) is a bicyclic ring system represented by Formula (a).
  • Formula (a) is unsubstituted or substituted independently with one to four Y; and wherein:
  • o and p are independently selected from 0 or 1 ;
  • J, K, L and M are independently selected from the group consisting of CH2, C(O), NH, O and S(O)q, wherein q is 0, 1 or 2;
  • D, E and F are independently selected from the group consisting of carbon atom, nitrogen atom, oxygen atom and sulfur atom.
  • Examples of three- to fifteen-membered heterocyclic ring are the radicals acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazolinyl, benzimidazolyl, benzisoxazole, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4H-carbazolyl, carbolinyl, beta-carbolinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran
  • -(C j -C ⁇ -haloalkyl is understood as meaning a partially or completely fluorinated or chlorinated alkyl radical which is selected, for example, from the following radical -CF 3 , -CHF 2 , -CH 2 F, -CHF-CF,, -CHF-CHF 2 , -CHF-CH 2 F, -CH 2 -CF 1 , -CH 2 -CHF 2 , -CH 2 -CH 2 F, -CF 2 -CF 3 , -CF 2 -CHF 2 , -CF 2 -CH 2 F, -CH 2 -CHF-CF 3 , -CH 2 -CHF-CHF 2 , -CH 2 -CHF-CH 2 F, -CH 2 -CH 2 -CF 3 , -CH 2 -CHF-CHF 2 , -CH 2 -CHF-CH 2 F, -CH 2 -CH 2 -CF 3 , -CH
  • halogen is understood as meaning fluorine, chlorine, bromine or iodine; fluorine, chlorine or bromine is preferred, in particular fluorine or chlorine is preferred.
  • Suitable protective groups for amino functions are, for example, para methoxy benzyl, benzyl, t-butoxycarbonyl, benzyloxycarbonyl, phthalolyl, trityl or tosyl protective group.
  • Suitable protective groups for the carboxyl function are, for example, alkyl, aryl or arylalkyl esters.
  • Protective groups can be introduced and removed by techniques which are well-known or described here (see Greene, T. W., et. al., Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups ( 1994), Thieme).
  • the term protective group can also include polymer-bound protective groups.
  • Such masked compounds according to Formula (I), in which the functional groups can optionally also be masked can, although optionally themselves not pharmacologically active, optionally be converted after administration to mammals by metabolization to the pharmacologically active compounds according to the invention.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Compounds having Factor IXa antagonistic activity are preferably used.
  • a measurement of fluorescence value using microtiter plate reader, ARVO 1420 Multilabel Counter of 30 ⁇ M or less, preferably 1 ⁇ M or less, more preferably 100 nM or less, and the most preferably 50 nM or less in terms of an IC50 value are preferably used.
  • agent or “drug” means a material which is used for improvement of disease or symptom, not only for treatment of disease or symptom.
  • the term “compound” when used, the term also refers to pharmaceutically acceptable salts thereof.
  • the compounds of the present invention have asymmetric carbon atoms. Accordingly, the compounds of the present invention include mixtures of various stereoisomers, such as geometrical isomers, tautorners, such as keto- and enol- tautomers, or amidino- and imidino- tautomers, and optical isomers, and isolated isomers, for example, (R, R), (S, S), (R, S) and (S, R) isomers. (R, R) isomer is preferred.
  • the isolation and the purification of such stereoisomers can be performed by those skilled in the art with a known technique such as optical resolution using preferential crystallization or column chromatography, or asymmetric synthesis.
  • the compounds represented by Formula (I) of the present invention may form acid addition salts.
  • these compounds may form salts with a base according to the type of substituent.
  • These salts are not particularly limited as long as the salts are pharmaceutically acceptable salts.
  • Specific examples of the salts include acid addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid; an organic carboxylic acid such as an aliphatic monocarboxylic acid, e.g., formic acid, acetic acid, trifluoroacetic acid (TFA), propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, or mandelic acid, an aromatic monocarboxylic acid, e.g., benzoic acid or salicylic acid, an aliphatic dicarboxylic acid,
  • These salts can be obtained by a known method, for example, by mixing a compound of the present invention with an equivalent amount and a solution containing a desired acid, base, or the like, and then collecting the desired salt by filtering the salt or distilling off the solvent.
  • the compounds of the present invention and salts thereof can form solvates with a solvent such as water, ethanol, or glycerol.
  • the salts of a compound of the present invention include monosalts and di-salts.
  • the compounds of the present invention can form an acid addition salt and a salt with a base at the same time according to the type of substituent of the side chain.
  • the present invention includes hydrates, pharmaceutically acceptable various solvates, and crystal polymorphism of the compounds represented by Formula (I) of the present invention.
  • the present invention is not limited to the compounds described in examples below and includes all compounds represented by Formula (I) of the present invention and pharmaceutically acceptable salts thereof.
  • prodrugs means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or a solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Nobel Delivery Systems.” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Associatiion and
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci ⁇ C 6 )alkanoyloxymethyl,
  • each ⁇ -aminoacyl group is independently selected from the naturally occurring L-anino acids, -P(O)(OH) 2 , -P(O)(O(C r C 6 )alky I) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal from of a carbohydrate), and the like.
  • Rl is selected from the group consisting of:
  • -(C,-C p )-cycloalkyl independently are unsubstituted or substituted independently with one to four Y;
  • each of said -(three- to fifteen-membered heterocyclic ring)- is independently unsubstituted or substituted independently with one to four Y;
  • R2 is selected from the group consisting of hydrogen atom, -C(O)-R6, -C(O)-O-R6,
  • each R6 independently is selected from the group consisting of hydrogen atom
  • R3 is absent, or selected from the group consisting of hydrogen atom and
  • R4 is selected from the group consisting of:
  • fifteen-membered heterocyclic ring is independently unsubstituted or additionally substituted independently with one to four Y;
  • each of said (three- to fifteen-membered heterocyclic ring) is independently unsubstituted or substituted independently with one to four Y;
  • each R5 independently is selected from the group consisting of;
  • each of R7 and R8 is independently selected from the group consisting of hydrogen atom, -(C 6 -C 14 )-aryl, -(C 3 -C 8 )-cycloalkyI, and -(C 1 -C 6 )-alkyl, wherein said -(C 1 -C 6 )-alkyl is unsubstituted or substituted with at least one substituent selected from the group consisting of OH, -O-(C 1 -C 4 )-alkyl, -(C 1 -C 3 )-fluoroalky, -O-(C 1 -C 3 )-haloalkyl, C(O)OH, and C(O)O-(C 1 -C 6 )-alkyl;
  • each U independently is selected from the group consisting of a covalent bond
  • -(C 1 -C 4 )-aIkylene -NH-, -N((C 1 -C 4 )-alkyl)-, -O-, -SO,- or -S-, wherein said -(C 1 -C 4 )-aIkylene or -(C 1 -C 4 )-alkyl is unsubstituted or substituted independently with one to four T,
  • each V independently is selected from the group consisting of -(C 1 -C 4 )-alkylene, -SO--, -C(O)-, -C(O)-NH- and -SO 1 -NH-,
  • -SO 1 -NH- is connected to a nitrogen atom of the morpholinone ring, and wherein said -(C -C 4 )-alkylene is unsubstituted or substituted independently with one to four T,
  • each T independently is selected from the group consisting of:
  • each of R7 and R8 independently is selected from the group consisting of a hydrogen atom, -(C -C )-cycloalkyl, halogen and -(C j -Cy-alkyl, wherein said -(C j -C 6 )-alkyl is optionally substituted with at least one substituent selected from the group consisting of OH, -O-(C 1 -C 4 )-alkyl, -(C 1 -C 3 )-fluoroalky, and -O-(C r C 3 )-haloalkyl;
  • G is selected from the group consisting of oxygen atom, imino, sulfur atom, sulfoxide, sulfone and methylene;
  • W is selected from the group consisting of oxygen atom, nitrogen atom and carbon atom;
  • X is selected from the group consisting of nitrogen atm, carbon atom and oxygen atom;
  • Y is selected from the group consisting of:
  • Y independently is selected from the group consisting of hydrogen atom, -(C 3 -C 8 )-cycloalkyl, and -(C 1 -C 6 )-alkyl, wherein said -(C 1 -C 6 )-alkyl is optionally substituted with OH, -O-(C 1 -C 4 )-alkyl, -(C 1 -C 1 )-fluoroalky, -O-(C 1 -C,)-haloalkyI, -C(O)OH, or
  • n O or 1
  • n O, 1, 2, 3 or 4,
  • Formula (I) comprises one to four carbon atoms to form alkylene chain, wherein said alkylene chain or G (imino or methylene) is unsubstituted or substituted independently with one to four R5: the dotted linkage between W and R4 of the substructure (III)
  • substructure (III) is a (three- to fifteen-membered
  • heterocyclic ring)-Z wherein said Z is a basic nitrogen-containing group and wherein said (three- to fifteen-membered heterocyclic ring) is unsubstituted or additionally substituted independently with one to four Y;
  • substructure (III) is a (three- to fifteen-membered
  • heterocyclic ring U-( three- to fifteen-membered heterocyclic ring) -Z, wherein said Z is a basic nitrogen-containing group and wherein each of said (three- to fifteen-membered heterocyclic ring) is independently unsubstituted or additionally substituted independently with one to four Y;
  • substructure (III) is a (three- to fifteen-membered
  • heterocyclic ring wherein said (three- to fifteen-membered heterocyclic ring) is unsubstituted or substituted independently with one to four Y;
  • substructure (III) is a (three- to fifteen-membered
  • heterocyclic ring -U-(three- to fifteen-membered heterocyclic ring), wherein each of said (three- to fifteen-membered heterocyclic ring) is independently unsubstituted or substituted independently with one to four
  • the compounds represented by Formula (I) and salts thereof, which are the compounds of the present invention can be readily produced from known compounds or commercially available compounds by, for example, known processes described in published documents, and produced by production processes described below.
  • the present invention is not limited to the production processes described below.
  • Rl, R2, R3, R4, R5, G, W, X, m, and n in the formulae shown in the description of the production method are as defined above for the Formula (I).
  • the alkyiene group in the side chain or ring of the compound may be substituted with the substituents defined for the Formula (I).
  • R4' and R in the formulae shown in the description of the production method are defined in the corresponding part.
  • each of P 1 , P 2 , P 3 , P 4 or P 5 in the production method independently designate protecting group, and exemplary appropriate protecting groups include typical an arylmethyl group such as benzyl group, para methoxy benzyl group or triphenylmethyl group; acyl protecting groups, namely, an alkanoyl group such as acetyl group; an alkoxycarbonyl group such as methoxycarbonyl group,
  • ethoxycarbonyl group ethoxycarbonyl group, or t-butoxycarbonyl group; an arylmethoxycarbonyl group such as benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, or
  • the method used for deprotecting such protecting group differs depending on the chemical nature of the protecting group employed, and in the case of an arylmethyl group such as para methoxy benzyl group or benzyl group, the deprotection can be accomplished by hydrogenation using a palladium-carbon catalyst for conversion into nitrogen-hydrogen bond, or alternatively, by Birch reduction using metal sodium in liquid ammonia, or by oxidative condition using such as CAN (eerie ammonium nitrate) or DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone).
  • CAN eerie ammonium nitrate
  • DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone
  • the triphenylmethyl group can be removed by using an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluorometlianesulfonic acid, or a combination thereof, or alternatively, or by Birch reduction using metal sodium in liquid ammonia.
  • an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluorometlianesulfonic acid, or a combination thereof, or alternatively, or by Birch reduction using metal sodium in liquid ammonia.
  • an acyl protecting group such as an alkanoyl group, an alkoxycarbonyl group, or aroyl group
  • the deprotection can be accomplished by the hydrolysis using an appropriate base such as an alkaline metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide.
  • the substituted methoxycarbonyl protecting group such as t-butoxycarbonyl group or paramethoxybenzyloxycarbonyi group can be removed by an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or a combination thereof.
  • an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or a combination thereof.
  • the ary I methoxycarbonyl group such as benzyloxycarbonyl group,
  • paramethoxybenzyloxycarbonyi group, or para(ortho)nitrobenzyloxycarbonyl group can be removed by the hydrolysis using a palladium-carbon catalyst.
  • the protecting groups P 1 , P 2 , P 3 , P 4 or P 5 Of the imino group (-NH-) can be independently or simultaneously deprotected by adequately selecting the type of the protecting group and deprotection conditions, and if desired, the protecting group can be re-introduced.
  • each of Li , L 2 , L 3 , L 4 , L 5 , Lg , L 7 or Lg in the production method designates a leaving group such as a halogen atom (for example, fluorine, chlorine, bromine, or iodine), methanesulfonyloxy group, or p-toluenesulfonyloxy group, or a replaceable substituent such as hydroxy group or an alkoxy group.
  • a leaving group such as a halogen atom (for example, fluorine, chlorine, bromine, or iodine), methanesulfonyloxy group, or p-toluenesulfonyloxy group, or a replaceable substituent such as hydroxy group or an alkoxy group.
  • the derivative of the Formula (I) of the present invention synthesized has a reactive group such as hydroxy group, amino group, carboxyl group, or thiol group as its substituent such group may be adequately protected with a protective group in each reaction step and the protective group may be removed at an adequate stage.
  • the process of such introduction and removal of the protective group may be adequately determined depending on the group to be protected and the type of the protective group, and such introduction and removal are conducted, for example, by the process described in the review section of Greene, T. W., et. al., "Protective Groups in Organic Synthesis", 2007, 4th Ed., Wiley, New York, or Kocienski, P., "Protecting Groups ' " 1994, Thieme.
  • the required starting materials such as (i-a), (i-b), (i-c), (i-d), (i-e), (i-f), (i-g), ( ⁇ -a), (iii-a), (iii-b), (v-b), (viii-a), (viii-b), (viii-c), (viii-d), (viii-e), (ix-a), (xvi-a), or (xvii-a) are either commercially available, or capable of being readily synthesized by the method commonly used in the organic chemistry from commercially available products. Unless otherwise noted, the reaction conditions employed in the production method are as described below:
  • Reaction temperature is in the range of -78°C to the solvent-reflux temperature, and reaction time is the time sufficient for required progress of the reaction.
  • Solvent which is not involved in the reaction may be any of the aromatic hydrocarbon solvents such as toluene and benzene; polar solvents such as water, methanol, DMF, and DMSO; basic solvents such as triethylamine and pyridine; halogen solvents such as chloroform, methylene chloride, and 1,2-dichloroethane; ethereal solvent such as diethylether, tetrahydrofuran, and dioxane; and mixed solvents thereof; and the solvent used may be adequately selected depending on the reaction conditions.
  • Base may be any of inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and sodium hydride; and organic bases such as triethylamine, pyridine, N,N-dialkylaniline, lithium diisopropylamide and lithium hexamethyldisilazide; and acid may be any of mineral acids such as hydrochloric acid, and sulfuric acid; and organic acids such as methanesulfonic acid, trifluoroacetic acid and p-toluenesulfonic acid.
  • the base and the acid are not necessarily limited to those mentioned above.
  • a compound represented by formula (ii-a) can be produced by allowing a compound represented by formula (i-a) to react with a commercially available aminoalcohol or aminothiol (i-g), readily prepared aminoalcohol or aminothiol from known compounds by a process similar to that described in published documents, for example, Organic Synthesis, Collective Vol.5, pp.88 1973, in the presence of a base such as potassium tert-buthoxide, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate using a solvent which is inactive to the reaction, such as methanol, ethanol, acetone, N,N-dimethylformamide, dioxane or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
  • a base such as potassium tert-buthoxide, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydrox
  • a compound represented by formula (ii-a) can be produced by conducting a reaction using a compound represented by formula (i-b) by a process of reductive animation. After a compound represented by formula (i-b) is converted to an imine with a suitable aminoalcohol (i-g), an aminothiol (i-g) using a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran,
  • a solvent which is inactive to the reaction such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran,
  • a compound represented by formula (ii-a) can be produced by a process similar to that described in published documents, for example, Journal of Medical Chemistry, 23( 12), pp.
  • a reductive reagent such as sodium borohydride using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature.
  • a solvent which is inactive to the reaction such as an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, or an aromatic hydrocarbon solvent,
  • hydrogen gas can be used to an imine with a suitable process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Organic synthesis VIII, Asymmetric synthesis, reduction, sugar, and labeled compound, pp.
  • a catalyst such as palladium-carbon (Pd-C), Raney-Ni, or platinum oxide (Pt ⁇ 2) in a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or
  • a polar solvent e.g., ethyl acetate or acetonitrile
  • an aromatic hydrocarbon solvent e.g., toluene or benzene
  • an acid solvent e.g., acetic acid at a temperature in the range of room temperature to the solvent-reflux temperature, thereby producing a compound represented by formula (ii-a).
  • a compound represented by formula (ii-a) can be produced by conducting a reaction using a compound represented by formula (i-c) by a process similar to that of ⁇ step 1- 1> with a suitable alcohol or thiol in the presence of copper iodide and cesium carbonate using a solvent which is inactive to the reaction, such as acetonitrile.
  • a compound represented by formula (ii-b) can be produced by conducting a reaction using a compound represented by formula (ii-c) and a compound represented by formula (i-c) (for example, a known amine) as follows.
  • a compound represented by formula (ii-c) is a carboxylic acid
  • a compound represented by formula (ii-b) can be produced by allowing a compound represented by formula (ii-c) to react with a compound represented by formula (i-c) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 191-309. 1992.
  • a condensing agent such as 1 ⁇ -dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSC-HCl), benzotriazol- l-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), 2-chloro- l ,3-dimethylimidazolinium hexafluorophosphate (CIP), or
  • a condensing agent such as 1 ⁇ -dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSC-HCl), benzotriazol- l-yloxy tri
  • a solvent which is inactive to the reaction such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, a polar solvent, e.g.,
  • N,N-dimethylformamide or an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, in the presence or absence of a base such as triethylamine or pyridine at a temperature in the range of O°C to the solvent-reflux temperature.
  • a compound represented by formula (ii-c) is an acid halide
  • a compound represented by formula (ii-b) can be similarly produced by conducting a reaction with a compound represented by formula (i-c) by a process similar to that described in, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp.
  • a base such as triethylamine or pyridine
  • a solvent which is inactive to the reaction such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a polar solvent, e.g., N,N-dimethylformamide at a temperature in the range of 0°C to the solvent-reflux temperature.
  • a halogenated solvent e.g., dichloromethane or chloroform
  • an ethereal solvent e.g., diethyl ether or tetrahydrofuran
  • an aromatic hydrocarbon solvent e.g., toluene or benzene
  • polar solvent e.g., N,N-dimethylformamide
  • a compound represented by formula (ii-c) can be produced by the same process as that used in ⁇ Step 1- 1> of (Reaction Scheme 1) using a compound represented by formula (i-d) and compound represented by formula (i-e).
  • a compound represented by formula (ii-c) can be produced from a compound represented by formula (i-f) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp.
  • step 2-l in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate using water and a solvent which is inactive to the reaction, such as methanol, ethanol, 2-propanol, N,N-dimethylformamide, dioxane, or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature.
  • a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate
  • a solvent which is inactive to the reaction such as methanol, ethanol, 2-propanol, N,N-dimethylformamide, dioxane, or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature.
  • a compound represented by formula (iii-a) can be produced by a process similar to that described in published documents, for example, Zhurnal Organicheskoi Khimii, (6), 1305-8, 1970, or by a similar process as that used in ⁇ Step l-4> and ⁇ step l-5> of (Reaction Scheme 1) using a compound represented by formula (i-e) as an acid halide, and compound represented by formula (ii-a) as a suitable aminoalcohol or aminothiol.
  • cyclization process of producing a compound represented by formula (iii-a) can be also conducted step by step process using different base or different solvent system.
  • a compound represented by formula (iii-a) can be produced by the same process as that used in ⁇ Step 2-l> of (Reaction Scheme 1) using a compound represented by formula (ii-b).
  • Protective groups of a compound represented by formula (iii-a) can be introduced and removed between (iii-a) and (iii-b) by techniques which are well-known or described here (see Greene, T. W., et. al., Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups ( 1994), Thieme).
  • G represents O, S, NH, or CH 2 in the Scheme 2 (v-d)
  • a compound represented by formula (iv-a) can be produced by allowing a compound represented by formula (iii-a) or (iii-b), which was produced in the Reaction scheme 1 or commercially available, to react with alkyl glyoxylate, such as ethyl glyoxylate by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 31(1), pp.
  • a base such as lithium hexamethyldisiladide, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate
  • a solvent which is inactive to the reaction such as tetrahydrofuran, N,N-dimethylformamide, dioxane, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
  • a compound represented by formula (v-a) can be produced by the same process as that used in ⁇ Step l-6> of (Reaction Scheme 1) using a compound represented by formula (iv-a) or (iv-c).
  • a compound represented by formula (v-c) can be produced by allowing a compound represented by formula (iv-a) to react with a compound represented by formula (v-b) by a process similar to that described in published documents, for example, Organic synthesis IV, Acids, amino acids, and peptides, pp. 191-309, 1992, Maruzen Co., Ltd., in the presence of a condensing agent, in a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, in the presence or absence of a base such as triethylamine or pyridine at a temperature in the range of 0°C to the solvent-reflux temperature.
  • a condensing agent in a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol
  • a base such as triethylamine or pyridine
  • a compound represented by formula (iv-c) can be produced by a process similar to that described in published documents, for example, Organic synthesis, Collective Vol. 7, pp.221, 1990, Organic synthesis , Collective Vol. 7, pp.530, 1990, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Reduction by borane, hydrazine or diimide pp 237-248, using a compound represented by formula (iv-a) in the presence of borane-THF complex, borane -diethyl ether complex, borane-dimethyl sulfide complex, hydradine or hydroxylamine using a solvent such as an ethereal solvent, e.g., diethyl ether or tetrahydrofuran at a temperature in the range of -78°C to the solvent-reflux temperature.
  • a solvent such as an ethereal solvent, e.g., diethyl ether or tetrahydrofur
  • a compound represented by formula (v-c) can be produced by allowing a compound represented by formula (v-a) to react with a compound represented by formula (v-b) by a process similar to that described in published documents, for example, Organic synthesis IV, Acids, amino acids, and peptides, pp. 191-309, 1992, Maruzen Co., Ltd., in the presence of a condensing agent such as
  • a solvent which is inactive to the reaction such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, a polar solvent, e.g.,
  • N,N-dimethylformamide or an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, in the presence or absence of a base such as triethylamine or pyridine at a temperature in the range of 0°C to the solvent-reflux temperature.
  • a compound represented by formula (v-a) is converted to an acid halide
  • a compound represented by formula (v-c) can be similarly produced by conducting a reaction by a process similar to that described in, for example, Organic synthesis IV, Acids, amino acids, and peptides, pp.
  • a base such as triethylamine or pyridine
  • a solvent which is inactive to the reaction such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a polar solvent, e.g., N,N-dimethylformamide at a temperature in the range of 0°C to the solvent-reflux temperature.
  • a halogenated solvent e.g., dichloromethane or chloroform
  • an ethereal solvent e.g., diethyl ether or tetrahydrofuran
  • an aromatic hydrocarbon solvent e.g., toluene or benzene
  • polar solvent e.g., N,N-dimethylformamide
  • a compound represented by formula (v-c) can be produced by using triphosgene by a process similar to that described in published documents, for example, Letters in Organic Chemistry, 4, 20-22, 2007, in the presence of a base such as triethyl amine using a solvent which is inactive to the reaction, such as
  • step 5-2> Protective groups of a compound represented by formula (v-c) can be introduced and removed between (v-c) and (v-d) by techniques which are well-known or described here (see Greene, T. W., et. al., Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups (1994), Thieme).
  • G represents O, S, NH, or CH 2 in the Scheme 3 (Reaction scheme 3)
  • a compound represented by formula (vi-d) can be produced by the similar process as that used in ⁇ Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (v-a).
  • a compound represented by formula (vii-a) can be produced by allowing a compound represented by formula (vi-a) to react with by a process similar to that described in published documents, for example, Synthetic Communications, 37(24), 2007, in the presence of an acid such as acetic acid, trifluoroacetic acid or
  • p-toluenesulfonic acid using a solvent such as acetic acid, trifluoroacetic acid, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
  • a solvent such as acetic acid, trifluoroacetic acid, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
  • a compound represented by formula (vii-a) can be produced by the similar process as that used in ⁇ Step 3-l> of (Reaction Scheme 2) using a compound represented by formula (iii-a) and a compound represented by formula (vi-b).
  • a compound represented by formula (vii-a) can be produced by a process similar to that described in published documents, for example, Bioorganic & Medicinal Chemistry Letters, 17(14), 2007, 3860 using a compound represented by formula (vi-d) and a compound represented by formula (vi-c), wherein Ra represents a suitable substituent.
  • a compound represented by formula (viii-a) can be produced by allowing a compound represented by formula (iv-a) to react with by a process similar to that described in published documents, for example, Organic synthesis , Collective VoI 1, pp.238, 1941, Maruzen Co., Ltd, in the presence of a base such as sodium ethoxide using a solvent such as ethanol at a temperature in the range of room temperature to the solvent-reflux temperature.
  • Ra of the formula (vi-c) represents a suitable substituent or leaving group of Ll to L4 described above.
  • a compound represented by formula (vii-a) can be produced by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 48, 14, pp4541 , 2005, using a compound represented by formula (viii-a) in the presence of hydradine or hydroxylamine using a solvent such as ethanol at a temperature in the range of room temperature to the solvent-reflux temperature.
  • a compound represented by formula (viii-b) can be produced from (viii-a) by conducting a reaction using the compound represented by formula (viii-a) by a process similar to that described in published documents, for example, Jikken Kagaku Koza ⁇ Experimental Chemistry Series), 4th edition, 26, Organic synthesis VIII, Asymmetric synthesis, reduction, sugar, and labeled compound, pp.
  • a catalyst such as palladium-carbon (Pd-C), Raney-Ni, platinum oxide (PtO2), or dichloro triphenyl phosphine ruthenium, under hydrogen atmosphere, using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, an ethereal solvent, e.g., diethyl ether or
  • tetrahydrofuran 1 ,2-dimethoxyethane, or 1,4-dioxane
  • a polar solvent e.g., ethyl acetate or methyl acetate, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
  • a compound represented by formula (viii-b) can be produced from (viii-a) by using Fe, or Sn, in hydrochloric acid or acetic acid, at a temperature in the range of O°C to the solvent-reflux temperature.
  • a compound represented by formula (viii-b) can also be produced from (viii-a) by using sodium borohydride in the presence of Lewis Acid, e.g., Nickel(II)chloride (NiCh), Tin(Il)chloride (SnCh) using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, an ethereal solvent, e.g., diethyl ether or
  • tetrahydrofuran 1 ,2-dimethoxyethane, or 1,4-dioxane, or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature.
  • a compound represented by formula (viii-d) can be produced by conducting a reaction using a compound represented by formula (viii-b) by a process of reductive amination. After a compound represented by formula (viii-c) is converted to an imine with a suitable amine (viii-b) using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature, a compound represented by formula (viii-d) can be produced
  • a reductive reagent such as sodium borohydride or sodium triacetoxy borohydride in the presence of acid such as acetyl alcohol
  • a solvent which is inactive to the reaction such as an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene or a mixed solvent thereof at a
  • an alcoholic solvent e.g., methanol, ethanol, 2-propanol
  • an ethereal solvent e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane
  • aromatic hydrocarbon solvent e.g., toluene or benzene or
  • hydrogen gas can be used to hydrogenate an imine with a suitable process similar to that described in published documents, for example, Jikken Kagaku Koza ⁇ Experimental Chemistry Series), 4th edition, 26, Asymmetric synthesis, reduction, sugar, and labeled compound, pp.
  • a catalyst such as palladium-carbon (Pd-C), Raney-Ni, or platinum oxide (PtO>) in a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, a polar solvent, e.g., ethyl acetate or acetonitrile, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or an acid solvent, e.g., acetic acid at a temperature in the range of room temperature to the solvent-reflux temperature, thereby producing a compound represented by formula (viii-d).
  • alcoholic solvent e.g., methanol, ethanol, or 2-propanol
  • a compound represented by formula (viii-f) can be produced by the similar process as that used in ⁇ Step 5- 1 > of (Reaction Scheme 2) using a compound represented by formula (viii-e).
  • a compound represented by formula (viii-d) can be produced by a process similar to that described in published documents, for example, Jikken Kagaku Koza ⁇ Experimental Chemistry Series), 4th edition, 26, Reduction by borane, hydrazine or diimide pp 237-248, using a compound represented by formula (viii-f) in the presence of hydradine or hydroxylamine using a solvent such as ethanol at a temperature in the range of room temperature to the solvent-reflux temperature.
  • a solvent such as ethanol
  • a compound represented by formula (ix-b) can be produced by conducting a reaction using (2R, J/?j-2,3-diacetoxysuccinic anhydride represented by formula (ix-a) in the presence of amine (v-b) by a process similar to that described in published documents, for example, Organic Synthesis, Collective Vol.3, pp.169 1955, using a solvent which is inactive to the reaction, such as tetrahy drofuran, N,
  • a compound represented by formula (x-a) can be produced by allowing a compound represented by formula (ix-b) to react with a compound represented by formula (viii-d) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Acids, amino acids, and peptides, pp. 193-309, 1992, Maruzen Co., Ltd., in the presence of a condensing agent such as 1,3-dicyclohexylcarbodiimide (DCC),
  • DCC 1,3-dicyclohexylcarbodiimide
  • a solvent which is inactive to the reaction such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, a polar solvent, e.g.,
  • N,N-dimethylfor ⁇ namide or an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, in the presence or absence of a base such as triethylarnine or pyridine at a temperature in the range of -78°C to the solvent-reflux temperature.
  • a compound represented by formula (ix-b) is converted to an acid halide, a compound represented by formula (x-a) can be similarly produced by conducting a reaction by a process similar to that described in, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Acids, amino acids, and peptides, pp.
  • a base such as triethylamine or pyridine
  • a solvent which is inactive to the reaction such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g.. diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a polar solvent, e.g., N,N-dimethylformamide at a temperature in the range of -IS 0 C to the solvent-reflux temperature.
  • a halogenated solvent e.g., dichloromethane or chloroform
  • an ethereal solvent e.g... diethyl ether or tetrahydrofuran
  • an aromatic hydrocarbon solvent e.g., toluene or benzene
  • polar solvent e.g., N,N-dimethylformamide at a temperature in the range
  • a compound represented by formula (x-a) can be produced by using triphosgene with (ix-b) by a process similar to that described in published documents, for example, Letters in Organic Chemistry, 4, 20-22, 2007, in the presence of a base such as triethyl amine using a solvent which is inactive to the reaction, such as tetrahydrofuran, N,N-dimethylformamide, dioxane, CH2C12 or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
  • a base such as triethyl amine
  • a solvent which is inactive to the reaction such as tetrahydrofuran, N,N-dimethylformamide, dioxane, CH2C12 or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
  • a compound represented by formula (ix-c) wherein R represents hydrogen or Cl -6 alkyl group, can be produced by conducting a reaction using
  • an alcoholic solvent e.g., benzyl alcohol, tert-buthyl alcohol, methanol, ethanol, 2-propanol, or tetrahydrofuran, N, N-dimethylformamide, dioxane, CH2C12 or a mixed solvent thereof
  • a compound represented by formula (ix-d) can be produced by the same process as that used in ⁇ Step 9-2> of (Reaction Scheme 5) using a compound represented by formula (ix-c).
  • a compound represented by formula (ix-d) wherein R represents hydrogen atom can be produced by allowing (2R, Ji?)-2,3-diacetoxysuccinic anhydride
  • a solvent such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, a polar solvent, e.g., DMF, ethyl acetate or acetonitrile, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or an acid solvent, e.g., acetic acid or a mixed solvent thereof in the presence of DMAP, Pyridine or sulfuric acid as a catalyst if needed at a temperature in the range of O°C to the solvent-reflux temperature.
  • a solvent such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichloromethane or chloroform
  • a compound represented by formula (x-a) can also be produced by the same process as that used in ⁇ Step 4-3> of (Reaction Scheme 2) using a compound represented by formula (ix-d) wherein R represents C 1-6 alkyl group in the presence of amine (v-b), and also be produced by the same process as that used in ⁇ step 5- 1> of (Reaction scheme 2) or ⁇ step 13-3> and ⁇ step 13-4> of (Reaction scheme 11) using a compound represented by formula (ix-d) wherein R represents hydrogen atom, in the presence of amine (v-b).
  • Protective groups of a compound in the process of producing a compound represented by formula (x-a) can be introduced and removed by techniques which are well-known or described here (see Greene, T. W., et. al., Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups (1994), Thieme).
  • a compound represented by formula (ix-e) can be produced by allowing a compound represented by formula (ix-d) to react with a compound represented by formula (ix-g) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp.
  • an acidic reagent such as hydrochloric acid, sulfuric acid, thionyl chloride, or acetyl chloride
  • a solvent which is inactive to the reaction such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, dioxane, or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of -78°C to the room temperature.
  • a compound represented by formula (ix-d) can be produced by conducting a reaction using a compound represented by formula (ix-e) by a process similar to that described in published documents, for example, Can. J. Chem., 49, 493 (1971) or Greene, T. W., et. al..
  • a solvent which is inactive to the reaction such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, dioxane, or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of -78°C to the room temperature.
  • a compound represented by formula (x-b) can be produced by the similar process as that used in ⁇ Step 9-8> of (Reaction Scheme 6) using a compound represented by formula (x-a).
  • Protective groups of a compound in the process of producing a compound represented by formula (x-b) can be introduced and removed by techniques which are well-known or described here (see Greene, T. W., et. ah, Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups (1994), Thieme).
  • a compound represented by formula (x-c) can be produced by allowing a compound represented by formula (x-b) by a process similar to that described in published documents, for example, Organic Synthesis, Collective Vol.6, pp.301, 395, 1988, or Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 20, alcohol and amine, pp.
  • a base such as potassium tert-buthoxide, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, tert-buthanol, or a polar solvent, e.g., DMF, DMSO, ethyl acetate, or acetonitril, or an aromatic hydrocarbon solvent, e.g., toluene or benzene, or acetone, dioxane or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature.
  • a solvent which is inactive to the reaction such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, tert-buthanol, or
  • R4' When R4' is used as a precursor for R4 representing 4-amidino-phenyl group or its analogue, R4' represents 4-cyano-phenyl group or 1,2,4-oxadiazol-5-one-3-yl phenyl group or their analogues, which can be converted to 4-amidino-phenyl group R4 or its analogue by techniques which are well-known or described:
  • G represents O, S, NH, or CH 2 , and
  • M represents independently CH or N, and n represents 1 to 4 in the Scheme 7
  • R4' of a compound represented by formula (x-c) of Scheme 6 represents 4-cyano-(aryl or heteroaryl) group or its analogue wherein 4-cyano-(aryl or heteroaryl) ring is optionally substituted with one to four Y
  • a compound represented by formula (xi-a) which corresponds to a compound (x-c) can be converted to a compound represented by formula (xi-b) via its imidate compound.
  • 4-cyano-(aryl or heteroaryl) group or, R4' of a compound represented by formula (xi-a), can be converted to its imidate by allowing a compound represented by formula (xi-a) to acidic condition such as HCl gas solution of, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g.,
  • dichloromethane or chloroform or a mixed solvent thereof at a temperature in the range of O°C to the room temperature.
  • Resulting imidate compound is converted to 4-amidino-(aryl or heteroaryl) compound (xi-b) or its analogue by conducting an imidate compound to ammonium or ammonium carbonate alcoholic solvent, e.g. methanol, ethanol, tert-buthanol or in a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature in a sealed tube.
  • ammonium or ammonium carbonate alcoholic solvent e.g. methanol, ethanol, tert-buthanol or in a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature in a sealed tube.
  • R4' represents 4-cyano-(aryl or heteroaryl) group or its analogue wherein 4-cyano-(aryl or heteroaryl) is optionally substituted with one to four Y
  • a compound represented by formula (xi-a) can be converted to 4-amidino-(aryl or heteroaryl) group R4 via its N-hydroxy amidine compound.
  • R4' of a compound represented by formula (xi-a) can be converted to its N-hydroxy amidino group by allowing a compound (xi-a) in the presence of a base such as triethyl amine, hunig base, potassium ferr-buthoxide, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate using a solvent which is inactive to the reaction, such as water, methanol, ethanol, acetone, N,N-dimethylformarnide, dioxane or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of O°C to the solvent-reflux temperature in a sealed tube.
  • a base such as triethyl amine, hunig base, potassium ferr-buthoxide, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate
  • N-hydroxy amidino group can be converted to its amidine compound represented by formula (xi-b) by a suitable process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Asymmetric synthesis, reduction, sugar, and labeled compound, pp. 251-266, 1992, Maruzen Co., Ltd., in the presence of a catalyst such as
  • a solvent which is inactive to the reaction such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichlorome thane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, a polar solvent, e.g., ethyl acetate or acetonitrile, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or an acid solvent, e.g., acetic acid or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
  • an alcoholic solvent e.g., methanol, ethanol, or 2-propanol
  • a halogenated solvent e.g., dichlorome thane or chloroform
  • an ethereal solvent e.g., diethyl ether or te
  • G represents O, S, NH, or CH 2 , and
  • M represents independently CH or N, and n represents 1 to 4 in the Scheme 8
  • step 10-4b When R4' is used as a precursor for R4 representing 4-amidino-(aryl or heteroaryl) group or its analogue wherein 4-amidino-(aryl or heteroaryl) group is optionally substituted with one to four Y, R4' also represents 1,2,4-oxadiazol-5-one-3-yl (aryl or heteroaryl) group or its analogues wherein phenyl group is optionally
  • a compound represented by formula (xi-d) can be produced by the same process as that used in ⁇ Step 8-l> of (Reaction Scheme 4) using a compound represented by formula (xi-c).
  • G in the formula (xi-c) represents sulfur atom
  • sulfur can be oxidized to its sulfone or sulfoxide with Oxone ® by a process similar to that described in published documents, for example, Shin-Jikken Kagaku Kouza, Vol. 14- 111, pi 759, R. J. Kennedy, J. Org. Chem., 25, 1901 (1960), BM. Trost, Tetrahedron Lett., 22, 1287(1981), in the presence of Oxone ® using a solvent which is inactive to the reaction, such as water, or
  • an alcoholic solvent e.g., methanol, ethanol, or 2-propanol
  • a halogenated solvent e.g., dichloromethane or chloroform
  • an ethereal solvent e.g., diethyl ether, dioxane, or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature.
  • step 1 1 - 1 When Rl in the Formula (I) represents biaryl groups optionally substituted with one to four Y, such as, for example, 4-thienyl phenyl group or 4-phenyl phenyl group, a compound represented by formula (xi-f) can be produced by conducting a reaction using a compound represented by formula (xi-e) by a process of
  • R4 represents l-imino-2,3-dihydroisoindoi-5-yl group, or its heteroaryl analogue wherein M represents nitrogen atom, are optionally substituted with one to four Y, which is shown as a partial structure of a compound represented by formula (xii-b) in Scheme 10 or its analogue
  • a compound represented by formula (xii-b) can be produced from a compound represented by formula (xii-a) which is identical to the comound represented by formula (ix-d) in the Scheme 5, wherein its R is hydrogen atom, and from a compound 39-2 (N-[(5-Amino-2-cyanophenyl)-methyl]-N- [(2-methylpropan-2-yl) oxycarbonyl] carbamate) which is described in Experimental section 39.
  • a compound represented by formula (ix-d) is converted to its analogous compound of 39-3 in the Example 39 procedure similar to that used in ⁇ Step 5-l> of (Reaction Scheme 2), which is followed by the conversion to compounds analogous to compounds 39-4, 39-5 and 39-6 by a process similar to that used in ⁇ Step 10-l> of (Reaction Scheme 5), ⁇ Step 10-2> of (Reaction Scheme 6) and deprotection of Boc group by a process similar to that used in the Experimental section Example 38-6 or by techniques which are well-known or described here (see Greene, T. W., et. al.,
  • a compound represented by formula (xii-b) can be produced with resulting amine compound analogous to the compound 39-6 by a process similar to that described in the Experimental section 39 [step 39-7] using alcoholic solvent, other solvent or a mixed solvent thereof at a temperature in the range of room temperature to the sol vent- reflux temperature.
  • a compound represented by formula (ix-d) can be produced by the similar process as that used in ⁇ Step 5-l> of (Reaction Scheme 2) using compounds represented by formula (viii-d) and represented by formula (ix-c).
  • R represents ferz-butyl group
  • a compound represented by formula (ix-c) could be prepared by a similar process that described in published document, for example, Tetrahedron, 45, 3071 -3080, 1989.
  • a compound represented by formula (xiii-a) can be produced by the similar process as that used in ⁇ Step 10- 1> of (Reaction Scheme 5) using a compound represented by formula (ix-d), and followed by the similar process as that used in ⁇ step 10- 2> of (Reaction Scheme 6) using the resulting alcoholic compound from a compound represented by formula (ix-d).
  • a compound represented by formula (xiii-b) can be produced from a compound represented by formula (xiii-a) by a well-known or similar process that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp.
  • inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, hemisulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4-bromobenzenesulfonic, cyciohexylarnidosulfonic, trifluoromethylsulfonic, 2-hydroxyethanesulfonic, acetic, oxalic, tartaric, succinic, glycerol phosphoric, lactic, malic, adipic, citric, fumaric, maleic, gluconic, glucuronic, palmitic or trifluoroacetic acid using water and a solvent which is inactive to the reaction, such as methanol, ethanol, 2-propanol,
  • a compound represented by formula (xiii-d) can be produced by the similar process as that used in ⁇ Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (xiii-b) via its intermediate represented by formula (xiii-c), with a compound represented by formula (v-b).
  • Protective groups of a compound represented by formula (xiii-d) can be introduced and removed between (xiii-d) and (xiii-e) by techniques which are well-known or described here (see Greene, T. W., et. aL, Protective Groups in Organic Synthesis (2007), 4th Ed.. Wiley, New York, or Kocienski, P., Protecting Groups ( 1994), Thieme).
  • a compound represented by formula (x ⁇ -f), which is identical to the compound represented by formula (x-e) in Scheme 6 wherein m is 1 and R is hydrogen atom, can be produced by a similar process as that used in ⁇ Step 10-4> of (Reaction Scheme 6) using a compound represented by formula (xiii-d).
  • a compound represented by formula (xiv-b) can be produced by the similar process as that used in ⁇ Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (xiv-a).
  • a compound represented by formula (xiv-c) can be produced by the similar process as that used in ⁇ Step 10-4> of (Reaction Scheme 6) using a compound represented by formula (xiv-b).
  • a compound represented by formula (xiv-d) can be produced by the similar process as that used in ⁇ Step 5- 1 > of (Reaction Scheme 2) using a compound represented by formula (xiv-a) and corresponding sulfonyl halide such as sulfonyl chloride reagent.
  • a compound represented by formula (xiv-e) can be produced by the similar process as that used in ⁇ Step 10-4> of (Reaction Scheme 6) using a compound represented by formula (xiv-d).
  • a compound represented by formula (xiv-f) wherein each M represents independently oxygen atom, nitrogen atom or carbon atom, can be produced with step by step cyclization process as that used in ⁇ Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (xiv-a) and a compound represented by formula
  • a compound represented by formula (xiv-g) can be produced by the similar process as that used in ⁇ Step 10-4> of (Reaction Scheme 6) using a compound represented by formula (xiv-f).
  • a compound represented by formula (xv-a) can be produced by the similar process as that used in ⁇ Step 10-2> of (Reaction Scheme 6) using a compound represented by formula (ix-f) in the Scheme 5.
  • a compound represented by formula (xv-b), a key intermediate to produce compounds represented by formula (xv-f) which corresponds to the compounds represented by Formula (I), can be produced by deprotection of the compound represented by formula (xv-a) using CAN (eerie ammonium nitrate) using a solvent which is inactive to the reaction, such as a polar solvent, e.g., DMF, DMSO, ethyl acetate, water, or acetonitril, or an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 1,4-dioxane, or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature, or by techniques which are well-known or described here (see Greene, T. W., et. al., Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York
  • a compound represented by formula (xv-c) can be produced by allowing a key intermediate compound represented by formula (xv-b) to react with a compound represented by R 1 -X (aryl halide or heteroaryl halide, wherein X represents halogen atom) by a process known as Goldberg reaction which are similar to that described in published documents, for example, JACS, 2002, 124, 7421 in the presence of a base such as potassium phosphate, cesium carbonate, potassium ter ⁇ -buthoxide, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate in the presence of 1,2-diamine ligand such as trans- 1 ,2-cyclohexanediamine, trans-N,N'-dimethylcyclohexane- 1,2-diamine, or ethylene diamine, and in the presence of catalytic amount of cupper iodide using a solvent which is inactive to the reaction, such as an e
  • a compound represented by formula (xv-c) can be produced by allowing a compound represented by formula (xv-b) to react with acetic anhydride by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 191-309, 1992, Maruzen Co., Ltd., and resulting acetylated alcohol comound can be hydrolyzed by the similar process as that used in ⁇ Step 4-2> of (Reaction Scheme 2).
  • a compound represented by formula (xv-e) can be produced by the similar process as that used in ⁇ Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (xv-d) in the Scheme 13 and a compound represented by formula (v-b).
  • a compound represented by formula (xv-f) can be produced by a similar process as that used in ⁇ Step 10-4> of (Reaction Scheme 6) using a compound represented by formula (xv-e).
  • a compound represented by formula (xvi-a) are commercially available, or capable of being readily synthesized by the method as identical to the route descrived in Scheme 1 to synthesize a compound represented by formula (ii-b), or commonly used in the organic chemistry from commercially available products.
  • a compound represented by formula (xvi-b) can be produced by the similar process as that used in ⁇ Step 2-3> of (Reaction Scheme 1 ) using a compound represented by formula (xvi-a) in the Scheme 14.
  • a compound represented by formula (xvi-c) can be produced by a similar process as that used in ⁇ Step 2-2> of (Reaction Scheme 1 ) using a compound represented by formula (xvi-b) in the Scheme 14.
  • a compound represented by formula (xvi-d) can be produced by the similar 5 process as that used in ⁇ Step 3-l> of (Reaction Scheme 2) using a compound
  • a compound represented by formula (xvi-e) can be produced by a similar process as that used in ⁇ Step 2-2> of (Reaction Scheme 1 ) using a compound 10 represented by formula (xvi-d) in the Scheme 14.
  • a compound represented by formula (xvi-f) can be produced by the similar process as that used in ⁇ Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (xvi-e) in the Scheme 14 when R5 represents acyl group such 15 as, for example, acetyl group or benzyl group.
  • a compound represented by formula (xvi-g) can be produced by a similar process as that used in ⁇ Step l-6> of (Reaction Scheme 1) using a compound represented by formula (xvi-f) in the Scheme 14.
  • a compound represented by formula (xvi-h) can be produced by a similar process as that used in ⁇ Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (xvi-g) in the Scheme 14.
  • a compound represented by formula (xvi-i) can be produced by a similar process as that used in ⁇ Step 5-2> of (Reaction Scheme 2) using a compound represented by formula (xvi-h) in the Scheme 14.
  • a compound represented by formula (xvii-b) can be produced by allowing a compound represented by formula (xvii-a) to react with TMSCN(trimethylsilyl cyanide) by a process similar to that described in published documents, for example, Organic synthesis Collective Vol. 1, pp.336 (1941), Collective Vol. 2, pp.7 (1943), Colletive Vol. 7, pp.521 ( 1990) using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, or a mixed solvent thereof at a temperature in the range of -78 °C to the solvent-reflux temperature.
  • a solvent which is inactive to the reaction such as an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, or a mixed solvent thereof at a temperature in the range of -78 °C to the solvent-reflux temperature.
  • Pi - 3 represents typically a benzyl group and deprotection
  • a compound represented by formula (xvii-c) can be produced by allowing a compound represented by formula (xvii-b) by a process similar to that described in published documents, for example, Organic synthesis Collective Vol. 1, pp.270 (1941),
  • a compound represented by formula (xvii-e) can be produced by the same process as that used in ⁇ Step 4-3> of (Reaction Scheme 2) using a compound represented by formula (xvii-c) and a compound represented by formula (v-b).
  • a compound represented by formula (xvii-g) can be produced by a similar process as that used in ⁇ Step 1 -6> of (Reaction Scheme 1 ) using a compound represented by formula (xvii-c) in the Scheme 15.
  • a compound represented by formula (xvii-e) can be produced by the same process as that used in ⁇ Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (xvii-g) and a compound represented by formula (v-b).
  • a compound represented by formula (xvii-f) can be produced by the same process as that used in ⁇ step 14-1> or ⁇ step 14-3> of (Reaction Scheme 12), or ⁇ step 15-3> of (Reaction Scheme 13) using a compound represented by formula (xvii-f)- ⁇ step 17-8>
  • a compound represented by formula (xvii-h) can be produced by a similar process as that used in ⁇ Step 10-4> of (Reaction Scheme 6) using a compound represented by formula (xvii-g).
  • (5, S), (R,S) and (S, R) forms of compounds represented by Formula (I) can also be made from corresponding starting materials.
  • the required starting materials for the synthesis of (S, S), (R,S) and (S,R) isoforms of compound (ix-a) are either commercially available, or capable of being readily synthesized by the method commonly used in the organic chemistry from commercially available products.
  • Acidic or basic products of the compound of the Formula (I) can be present in the form of their salts or in free form.
  • Pharmacologically acceptable salts are preferred, for example alkali metal or alkaline earth metal salts such as hydrochlorides, hydrobromides, sulfates, hemisulfates, all possible phosphates, and salts of the amino acids, natural bases or carboxylic acids.
  • the preparation of pharmacologically acceptable salts from compounds of the Formula (I) capable of salt formation, including their stereoisomeric forms is carried out in a manner known per se.
  • basic reagents such as hydroxides, carbonates, hydrogencarbonates alkoxides and ammonia or organic bases for example trimethyl- or tr mol or alternatively basic amino acids, for example lysine, ornithine or arginine
  • the compounds of the Formula (I) form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts.
  • stable acid addition salts can also be prepared using strong acids.
  • inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, hemisulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic,
  • 2-hydroxyethanesulfonic, acetic, oxalic, tartaric, succinic, glycerolphosphoric, lactic, malic, adipic, citric, fumaric, maleic, gluconic, glucuronic, palmitic or trifluoroacetic acid are suitable.
  • Step 1-1 Synthesis of ethyl 2-hydroxy-2-(3-oxo-4-p-tolylrnorpholin-2-yl)acetate (compound 1-1 (LP) and compound 1-1 (MP))
  • Step 1-3 Synthesis of N-[N,N-bis(tert-butoxylcarbonyl)- 1 -aminoisoquinolin-6-yl]-2- hydroxy-2-(3-oxo-4-p-tolylmorpholin-2-yl)acetamide (compound 1 -3) activated-charcoal (4.5 mg) and triphosgene (403 mg) at 0 °C. The reaction mixture was stirred at room temperature for 15 hours. Then activated-charcoal was removed by filtration and the filtrate was concentrated in vacuo. The resulting residue was resolved in CH 2 CI 2 (2 ml).
  • 6-Amino-1-bis(tert-butoxyl carbonyl)aminoisoquinoline (146 mg) was added into the CFLoCh solution at O°C.
  • the reaction mixture was stirred at room temperature for 4 hours.
  • the reaction mixture was concentrated in vacuo and a half volume of the resulting residue was purified by LC/MS to obtain compound 1 -3 (30.6 mg) as a colorless amorphous solid.
  • Oxalyl chloride (0.55 mL) in CH 2 CI 2 (1.7 mL) was added dropwise into the reaction mixture. After stirring for 1 hour, pyridine (1.99 mL) was added dropwise thereto and stirred for 15 min. Then 7-1 (0.99 g) in CH 2 CI 2 (6 mL) was added dropwise into the reaction mixture. The mixture was stirred below -60 °C for 20 min, then it was stirred at -30 °C for 15 hours.
  • Step 7-3 in synthetic method for EXAMPLE 7 compound 20-2 (0.8 g) was used instead of compound 7-2 to obtain compound 20-3 (1.6 g) as a colorless amorphous solid.
  • Step 7-4 in synthetic method for EXAMPLE 7 compound 20-3 (1.6 g) was used instead of compound 7-3 to obtain crude 20-4.
  • the crude 20-4 was used in the next step without further purification.
  • Step 7-5 in synthetic method for EXAMPLE 7 crude 20-4 was used instead of compound 7-4 to obtain compound 20-5 (100 mg) as a brown amorphous solid.
  • Step 7-6 in synthetic method for EXAMPLE 7 compound 20-5 (50 mg) was used instead of compound 7-5 to obtain EXAMPLE 20 (8 mg) as a pale yellow amorphous solid.
  • Step 7-5 in synthetic method for EXAMPLE 7 crude 26-3 was used instead of compound 7-4 to obtain compound 26-4 ( 1.68 g) as a colorless amor
  • Step 26-5 Synthesis of (2R)-2-[(2R)-4-(4-aminophenyl)-3-oxomorpholin-2-yl]- N-(4-cyanophenyl)-2-hydroxyacetamide (compound 26-5)
  • Step 7-6 in synthetic method for EXAMPLE 7 compound 26-6 (50mg) was used instead of compound 7-5 to obtain EXAMPLE 26 (2 mg) as a colorless amorphous solid.
  • Step 7-5 in synthetic method for EXAMPLE 7 compound 26- 11 (2.8 g) was used instead of compound 7-4 to obtain compound 26- 12 ( 1.24 g) as an ivory whight amorphous solid.
  • Step 38-1 Synthesis of N-[4-(2-chloroethylamino)phenyl]acetamide (compound 38-1) According to the Step 7-1 in synthetic method for EXAMPLE 7,
  • N-(4-aminophenyl)acetamide (10 g) was used instead of 4-methylaniline to obtain compound 38-1 (7.9 g) as a pale yellow amorphous solid.
  • Step 7-4 in synthetic method for EXAMPLE 7 compound 38-3 (0.5 g) was used instead of 7-3 to obtain compound 38-4 (0.42 g) as a yellow amorphous solid.
  • Step 7-4 in synthetic method for EXAMPLE 7 compound 52-1 (15.5 g) was used instead of 7-3 to obtain compound 52-2 (13 g) as a brown oil.
  • Step 52-3 Synthesis of tert-butyl (2R)-2-[(2R)-4-(4-tert-butylphenyl)-3- oxomorpholin-2-yl]-2-hydroxyacetate (compound 52-3)
  • Step 7-5 in synthetic method for EXAMPLE 7 compound 52-2 (12.8 g) was used instead of 7-4 to obtain compound 52-3 (4.85 g) as a pale yellow amorphous solid.
  • Step 54-2 Synthesis of N-(2-chloroethyl)-4-(trifluoromethyI)aniIine (compound 54-2) According to the Step 20-2 in synthetic method for EXAMPLE 20, compound 54-2)
  • Step 54-7 Synthesis of (2R)-N-[N,N-bis(tert-butoxycarbonyl)-l ⁇ aminoisoqumolin- 6-yl]-2-hydroxy-2-[(2R)-3-oxo-4-[4-(trifluoromethyl)phenyl]morpholin-2-yl]acetamide (com According to the Step 1 -3 in synthetic method for EXAMPLE 1 , compound 54-6 (128 mg) was used instead of 1-2 to obtain compound 54-7 (107 mg) as a beige amorphous solid.
  • Step 1-3 in synthetic method for EXAMPLE 1 a cyclic carbonate analogue (0.15 g) derived from compound 55-6 and 39-2 (0.14 g) were used instead of 1 -2 and 6-amino- l-bis(tert-butoxycarbonyl)aminoisoquinoline to obtain compound 57-1 ( 147 mg) as a pale yellow amorphous solid.
  • Step 38-6 in synthetic method for EXAMPLE 38 57-1 (0.14 g) was used instead of 38-5 to obtain compound 57-2 (93 mg) as a pale yellow amorphous solid.
  • Step 39-7 in synthetic method for EXAMPLE 39 57-3 (89 mg) was used instead of 39-6 to obtain EXAMPLE 57 (66.4 mg) as a pale yellow 10 amorphous solid.
  • the batch was cooled to 0-5 °C and sodium borohydride (1050 g, 27.8 mol, Aldrich lot # 10106TC) was added portionwise over 2.8 hours while maintaining the temperature of the batch between 0 and 10 °C. Once the addition was complete, the batch was allowed to gradually warm to 20-25 °C
  • the batch was cooled to 10-15 °C and the pH was adjusted to 1-2 using concentrated hydrochloric acid (2.2 L).
  • the batch was washed with tert-huty ⁇ methyl ether (MTBE, 3 x 10.3 L), cooled to 10-15 °C and the pH was adjusted to 13-14 using 6 M aqueous sodium hydroxide (6.0 L).
  • the batch was extracted with CH 2 CI 2 (2 x
  • step 68-2 Synthesis of compound 68-2.
  • the batch was cooled to 20-25 °C and concentrated using a rotavap at 40-45 °C until distillation ceased.
  • the concentrate was swapped once with MTBE (22.0 L), slurried in MTBE (21.7 L) and filtered to afford 68-2 » HCl (5420 g, 96%) as white solids after drying in a vacuum oven at 20-30 °C for 17 hours.
  • a 50-L glass-jacketed reactor was charged with di-O-acetyl-L-tartaric anhydride (1775 g, 8.2 mol, Alfa Aesar lot # El 3UO33) and tetrahydrofuran (17.5 L, THF).
  • the batch was cooled to 0-5 °C and a solution of compound 68-2 ( 1720 g) in THF (2.0 L) was added over 1.3 hours while maintaining the temperature of the batch between 0 and 10 °C.
  • a 50-L glass-jacketed reactor was charged with compound 68-3 (3520 g, assuming theoretical yield for step 3, 8.5 mol) and THF (35.0 L), and the batch was heated to 50-60 °C.
  • Two portions of O-terr-butyl-N,N-diisopropylurea (2115 g, 10.6 mol, and 1700 g, 8.9 mol) were each added dropwise over 30 minutes while maintaining the temperature of the batch between 50 and 60 °C.
  • This material was purified by silica-gel column chromatography (Four 1.1 to 1.3-kg batches using 5.5 kg of silica gel each, 20 to 60% EtOAc in heptane) to afford compound 68-4 [1915 g, 48%, 96.7-97.1% (AUC) by HPLC] as well as mixed fractions that were combined with other lots for further purification.
  • a 50-L glass-jacketed reactor was charged with compound compound 68-4 (1 100 g, 2.3 mol) and methanol (10.2 L), and the batch was cooled to -10 to 0 °C.
  • a slurry of potassium cyanide (80 g, 1.2 mol, Aldrich lot # 14614KA) in methanol (800 mL) was added over 5 minutes while maintaining the temperature of the batch between -10 and 0 °C.
  • the batch was held at -10 to 0 °C for 3.3 hours until the reaction was deemed complete by HPLC analysis [5.3% (AUC) of compound 68-4 remaining].
  • Solid sodium bicarbonate 200 g, 2.4 mol, Natrium Products lot # 01096A was added and the batch was concentrated on a rotary evaporator at 20-25 °C until distillation ceased.
  • MTBE 1 1.0 L
  • DI water 11.0 L
  • a 50-L glass-jacketed reactor was charged with compound 68-6 (490 g, 1.4 mol), acetonitrile ( 10.1 L) and DI water (2.0 L).
  • the batch was cooled to 0-5 °C and a slurry of cerium (IV) ammonium nitrate (3060 g, 5.6 mol, Alfa Aesar lot # H22T016) in acetonitrile (8.0 L) was added while maintaining the temperature of the batch between 0 and 5 °C.
  • the batch was held at 0-5 °C for 30 minutes, warmed to 20-25 °C and held at this temperature for 3 5 hours until the reaction was deemed comp L) was added until the pH of the reaction mixture reached 4.5 to 5.
  • This material was purified by silica-gel column chromatography [4 kg of silica gel, 1 to 5% methanol in dichloromethane]. The pure fractions were slurried in 1 :4 CH 2 C1 2 /MTBE to yield compound 68-7 [Two lots: 189 g, 59%] as white to off-white solids.
  • frans-NJV-Dimethylcyclohexane-l ⁇ -diamine 37 ⁇ L was added dropwise and the mixture was affixed with a condenser.
  • the mixture was degassed under vacuum ( ⁇ 20 mm), filled with N 2 , and heated to 80 °C. The mixture stirred for 2.5 h at 80 °C, cooled to rt, and was diluted with EtOAc. The mixture was then sequentially washed with cone NH 4 OH, water, and brine. The organic layer was dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to afford a yellow oil.
  • the crude product was purified by flash chromatography using a gradient of 100% CH 2 CI 2 to 60%
  • Step 70-3 Synthesis of (i?)-tert-butyl 2-acetoxy-2-((R)-4-(2-methyl-3-oxoisoindolin-5- yl)-3
  • pyridine 26 ⁇ L
  • AC 2 O 30 ⁇ l
  • DMAP 4 mg
  • the mixture was stirred for 1 hour at 0°C, warmed to rt, and stirred for an additional 12 h.
  • the mixture was diluted with EtOAc and the organic layer was washed sequentially with sat. aq. CuSO 4 solution, water, and brine.
  • the organic layer was dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to afford compound 70-3 (85 mg) as a light yellow semisolid.
  • LC-MS: M+H 419. This material was used without further purification.
  • Step 70-5 Synthesis of ( ⁇ )-l -(( ⁇ )-4-(2-methyl-3-oxoisoindolin-5-yl)-3- oxomorpholin-2-yl)-2-oxo-2-(4-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)phenylamino) ethyl acetate (compound 70-5)
  • Step 70-61 Synthesis of ammonium 3-(4-((R)-2-hydroxy-2-((R)-4-(2-methyl-3- oxoisoindolin-5-yl)-3-oxomorpholin-2 ⁇ yl)acetamido)phenyl)-1,2,4-oxadiazol-5-olate (compound 70-6)
  • Step 73- 1 Synthesis of (R)-tert-butyl 2-((R)-4-(3,5-bis(trifluoromethyl)phenyl)-3- oxom According to the Step 70-2 in the synthetic method for Example 70,
  • Step 70-3 in the synthetic method for EXAMPLE 70 73-1 (0.13 g) was used instead of compound 70-2 to obtain compound 73-2 (0.14 g) as a yellow semisolid that was used without further purification.
  • Step 70-4 in the synthetic method for EXAMPLE 70 compound 73-2 (0.14 g) was used instead of compound 70-3 to afford compound 73-3 (0.12 g) as a light yellow solid that was used without further purification.
  • Step 70-5 in the synthetic method for EXAMPLE 70 compound 73-3 (65 mg) was used instead of compound 70-4 to obtain compound 73-4 (69 mg) as a white solid after reverse-phase (C 18) HPLC purification.
  • Step 70-6 in the synthetic method for EXAMPLE 70 compound 73-4 (69 mg) was used instead of compound compound 70-5 to obtain com cation.
  • Step 73-6 Synthesis of (R)-2-((R)-4-(3,5-bis(trifluoromethyl)phenyl)-3- oxomorpholin-2-yl)-N-(4-carbamimidoylphenyl)-2-hydroxyacetamide hydrochloride (EXAMPLE 73)
  • Step 70-7 in the synthetic method for EXAMPLE 70 compound 73-5 (53 mg) was used instead of compound 70-6 to obtain EXAMPLE 73 (37 mg) as a maize solid.
  • Step 98-4 Synthesis of tert-buty ⁇ 7-aminoquinazolin-4-ylcarbamate (compound 98-4)
  • a mixture of 600 mg of tert-butyl 7-nitroquinazolin-4-ylcarbamate and 150 mg of 10% Pd-C in 15 ml each of THF and MeOH was stirred overnight under a hydrogen ballo tography eluting with 5% methanol in dichloromethane to provide 385 mg of tert-butyl 7-aminoquinazolin-4-ylcarbamate (compound 98-4).
  • MS m/e 261.1 (MH + )
  • Compound 98-5 was prepared using a procedure similar to the preparation of compound 93-3.
  • Liquid chromatography-mass spectrometry (LC-MS, Table 2) was performed using a Waters FractionLynx MS system (manufactured by Waters Corporation) from the Example 1 to Example 38.
  • a SunFire columnTM (4.6 mm x 5 cm, 5 ⁇ m)
  • acetoxyborohydride NaBH(OAc) 3 ; 14.2 g was added into the reaction mixture at one portion and the mixture was stirred for 15 minutes.
  • reaction mixture was diluted with water and was extracted with
  • Oxalyl chloride ( 1.0 mL) in CH 2 Cl 2 (3 mL) was added dropwise into the reaction mixture. After stirring for 1 hour, pyridine (3.67 mL) was added dropwise thereto and stirred for 15 min. Then compound aal-1 (2.28 g) in CH 2 Cl 2 (13.7 mL) was added dropwise into the reaction mixture. The mixture was stirred below -70 °C for 12 hours.
  • the crude aal-4 was dissolved in t-BuOH (4.5 mL)-DMS0 (3 mL), and t-BuOK (191 mg) was added portionwise into the reaction mixture at 0 °C. The mixture was stirred for 5 minutes in the same temperature.
  • Step 2- 1 Synthesis of 2-[tert-butyl(diphenyl)silyl

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Abstract

The present invention provides compounds having the formula (I) or a pharmaceutically acceptable salt or a solvate thereof, pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing thromboses, embolisms, hypercoagulability or fibrotic changes.

Description

MORPHOLINONE COMPOUNDS AS FACTOR IXA INHIBITORS CTELD OF THE INVENTION
The invention relates to novel compounds of the Formula (I) having antithrombotic activity which, in particular, inhibit blood clotting factor IXa, to processes for their preparation and to use thereof as medicaments.
BACKGROUND OF THE INVENTION
Factor IXa is a plasma serine protease involved in the regulation of blood coagulation. While blood coagulation is a necessary and important part of the regulation of an organism's homeostasis, abnormal blood coagulation can also have deleterious effects. For instance, thrombosis is the formation or presence of a blood clot inside a blood vessel or cavity of the heart. Such a blood clot can lodge in a blood vessel blocking circulation and inducing a heart attack or stroke. Thromboembolic disorders are the largest cause of mortality and disability in the industrialized world.
Blood clotting is a process of control of the blood stream essential for the survival of mammals. The process of clotting, as shown in the Patent Document 1, and the subsequent dissolution of the clot after wound healing has taken place commences after vascular damage and can be divided into four phases:
1. The phase of vasoconstriction or vasocontraction: By means of this the blood loss in the damaged area is decreased.
2. The next phase is platelet activation by thrombin. The platelets attach to the site of the vessel wall damage and form a platelet aggregate. The protein fibrinogen is responsible here for the crosslinkage of the platelets by means of appropriate surface receptors. Platelets also bind to exposed collagen of the extracellular matrix of the damaged vessel wall and are activated by this means. After activation of the platelets, a number of messenger substances are secreted, which induce the activation of further platelets. At the same time, a membrane lipid, phosphatidylserine, is transported from the inside of the membrane of the platelets to the outside, on which complexes of clotting factors can accumulate. The platelets accelerate blood clotting by means of this mechanism.
3. The formation of these clotting complexes leads to the massive formation of thrombin, which converts soluble fibrinogen to fibrin by cleavage of two small peptides. Fibrin monomers spontaneously form threadlike strands, from which, after crosslinkage by clotting factor XIII, a stable protein network forms. The initially even looser platelet aggregate is stabilized by this fibrin network; platelet aggregates and fibrin network are the two essential constituents of a thrombus.
4. After wound healing, the thrombus is dissolved by the action of the key enzyme of the endogenous fibrinolysis system, plasmin.
Two alternative pathways can lead to the formation of a fibrin clot, the intrinsic and the extrinsic pathway. These pathways are initiated by different
mechanisms, but in the later phase they converge to give a common final path of the clotting cascade. In this final path of clotting, clotting factor X is activated. The activated factor X is responsible for the formation of thrombin from the inactive precursor prothrombin circulating in the blood. The formation of a thrombus on the bottom of a vessel wall abnormality without a wound is the result of the intrinsic pathway. Fibrin clot formation as a response to tissue damage or an injury is the result of the extrinsic pathway. Both pathways comprise a relatively large number of proteins, which are known as clotting factors.
The intrinsic pathway requires the clotting factors V, VIII, IX, X, XI and XII and also prekallikrein, high molecular weight kininogen, calcium ions and
phospholipids from platelets. The intrinsic pathway is initiated when prekallikrein, high molecular weight kininogen factor XI and XII bind to a negatively charged surface. This point in time is designated as the contact phase. Exposure to vessel wall collagen is the primary stimulus of the contact phase. The result of the processes of the contact phase is the conversion of prekallikrein to kallikrein, which in turn activates factor XII. Factor XIIa hydrolyzes further prekallikrein to kallikrein, such that activation is the result. With increasing activation of factor XII, activation of factor XI occurs, which leads to a release of bradykinin, a vasodilator. As a result, the ending of the initial phase of vasoconstriction occurs. Bradykinin is formed from high molecular weight kininogen. In the presence of Ca + ions, factor XIa activates factor IX. Factor IX is a proenzyme, which contains vitamin K-dependent, γ-carboxyglutamic acid (GLA) residues. The serine protease activity becomes noticeable after binding of Ca*+ to these GLA residues. A number of the serine proteases of the blood clotting cascade (factors II, VII, IX and X) contain such vitamin K-dependent GLA residues. Factor IXa cleaves factor X and leads to activation to factor Xa. The prerequisite for the formation of factor IXa is the formation of a tenase complex from Ca2+ and the factors Villa, IXa and X on the surface of activated platelets. One of the reactions of activated platelets is the presentation of phosphatidylserine and phosphatidylinositol along the surfaces. The exposure of these phospholipids first makes the formation of the tenase complex possible. Factor VIII in this process has the function of a receptor for the factors IXa and X. Factor VIII is therefore a cofactor in the clotting cascade. The activation of factor VIII with formation of factor Villa, the actual receptor, needs only a minimal amount of thrombin. With increase in the concentration of thrombin, factor Villa is finally cleaved further and inactivated by thrombin. This dual activity of thrombin in relation to factor VIII leads to a self-restriction of tenase complex formation and thus to a limitation of blood clotting.
The extrinsic pathway requires a tissue factor (TF) and clotting factors V, VII, VIII, IX and X. In the case of a vessel injury, the tissue factor (TF) accumulates with the clotting factor VII and the latter is activated. The complex of TF and clotting factor VII has two substrates, clotting factors X and IX.
Clotting factor IX can be activated by means of the intrinsic pathway and the extrinsic pathway. The activation of factor IXa is thus a central point of intersection between the two pathways of activation of clotting.
Factor IXa has an important role in blood clotting. Defects in factor IXa lead to hemophilia B, while increased concentrations of factor IXa in the blood lead to a significantly increased risk of thrombosis formation ( Weltermann A, et al., J Thromb Haemost. 2003; 1 : 28-32). The regulation of factor IXa activity can reduce thrombus formation in animal models (Feuerstein GZ, et al., Thromb Haemost. 1999; 82:
1443-1445).
Recently, compounds having a Factor IXa antagonism are being studied.
Known compounds each having an amide bond are disclosed in, for example, PCT Publication No. 08/031508, and PCT Publication No. 08/031509. However, these patent documents do not disclose cyclic morpholinone derivatives.
In the development of pharmaceuticals, it is required to satisfy strict criteria for not only target pharmacological activity but also absorption, distribution, metabolism, excretion, and the like. With respect to drug interactions, desensitization or tolerance, digestive absorption in oral administration, the rate of transfer to a small intestine, the rate of absorption and first-pass effect, an organ barrier, protein binding, induction of a drug-metabolizing enzyme, an excretion pathway and body clearance, a method of administration (an application site, a method, and purpose), and the like, various agenda are required. However, a drug that satisfies these requirements is seldom discovered.
These comprehensive problems in drug development might also exist for Factor IXa antagonists, and Factor IXa antagonists have not yet been released onto the market. More specifically, known compounds having a Factor IXa antagonism may also include problems in terms of usefulness and safety. For example, these compounds may have low absorption, and oral administration of these compounds may be difficult; these compounds also may exhibit inhibitory activity of the human ether-a-go-go related gene (hERG) channel, which may cause arrhythmia, and pharmacokinetics of these compounds might not satisfactory.
Accordingly, a compound in which these problems are solved and which has high activity has been desired.
SUMMARY OF THE INVENTION
In its many embodiments, the present invention provides a novel class of cyclic morpholine compounds or its analogue, pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing a thromboses, embolisms, hypercoagulability or fibrotic changes.
The compounds of the Formula (I) according to the invention are suitable for prophylactic and for therapeutic administration to humans who suffer from diseases which accompany thromboses, embolisms, hypercoagulability or fibrotic changes. They can be employed for secondary prevention and are suitable both for acute and for long-term therapy.
The invention therefore relates to a compound of Formula (I)
In another aspect, compounds of the Formula (I), or a pharmaceutical acceptable salt or a solvate thereof can be useful for treating or preventing a disorder or disease mediated by factor IXa, or a thromboembolic disorder (each disorder being a "Condition").
In another aspect, the present invention provides pharmaceutical compositions comprising at least one compound of the Formula (I) or a pharmaceutically acceptable carrier. The composition can be useful for treating or preventing a Condition.
In another aspect, the present invention provides a method for treating a Condition, the method comprising administering to a patient an effective amount of at least one compound of Formula (I) or a pharmaceutically acceptable salt or a solvate thereof.
DETAILED DESCRIPTION OF THE INVENTION
In an embodiment, the present invention provides compounds of Formula (I) and/or pharmaceutically acceptable salts, solvates and prodrugs thereof. The compounds of Formula (I) can be useful for treating or preventing a Condition in a patient.
The invention provides compounds of Formula (I)
Figure imgf000007_0001
or a pharmaceutically acceptable salt or a solvate thereof, wherein
A is
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0003
Figure imgf000008_0004
Figure imgf000008_0005
Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000009_0003
Figure imgf000009_0004
Figure imgf000010_0001
Figure imgf000010_0002
Figure imgf000010_0003
Figure imgf000010_0004
Figure imgf000010_0005
Figure imgf000010_0006
Figure imgf000011_0001
Figure imgf000011_0002
Figure imgf000011_0003
Figure imgf000011_0004
Figure imgf000011_0006
Figure imgf000011_0005
Figure imgf000011_0007
Figure imgf000012_0001
Y, attached to a carbon or nitrogen ring atom, is
D halogen,
2) -(CrC6)-alkyl,
3) -(C1-C,)-haloalkyl,
4) -(C3-C8)-cycloalkyl,
5) -OH,
6) -Q-(C -C J-alkyl,
7) -O-(C1-C3)-haloalkyl,
8) =O (oxo),
wherein said -(Cj-C6)-alkyl part of 2) and 6) of said Y is unsubstituted or substituted independently with the substituents selected from the group consisting of -(C3-C8)-cycloalkyl, -C(O)OH, and -C(O)-(C1 -C6)-alkyl,
B is
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0003
rovided that
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0003
and
Figure imgf000015_0004
In one aspect of the invention, the compounds are of the formula
Figure imgf000015_0005
or a pharmaceutically acceptable salt or a solvate thereof, wherein A is
Figure imgf000016_0001
Figure imgf000016_0002
Figure imgf000016_0003
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0003
Figure imgf000017_0004
Figure imgf000017_0005
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0003
Figure imgf000018_0004
Figure imgf000018_0005
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000019_0003
Figure imgf000019_0004
Figure imgf000019_0006
Figure imgf000019_0005
Figure imgf000019_0007
Figure imgf000019_0008
Figure imgf000020_0001
Figure imgf000020_0003
Figure imgf000020_0002
Bis
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0003
r rovided that
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000022_0003
and
Figure imgf000022_0004
In another aspect of the invention, the compounds are of the absolute configuration of Formula (I) is
Figure imgf000022_0005
In another aspect of the invention, the compound is
(2R)-2-f(2R)-4-(4-tert-butylphenyl)-3-oxomorpholin-2-yl]-2-hydroxy-N-[4-(N- methylearbamimidoyl)phenyl]acetamide,
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-l(2R)-3-oxo-4-(l-oxo-2,3- dihydroisoindol-5-yl)morpholin-2-yl)acetamide, (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-oxo-1H- quinolin-6-yl)morpholin-2-yl]acetamide,
(2R)-2-[(2R)-4-l7-(difluoromethoxy)-2-oxo-1H-quinolin-6-yl]-3-oxomorpholin-2-yl]-2
-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)acetamide,
(2R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl
)morpholin-2-ylJacetamide,
(2R)-N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1H- quinolin-6-yl)morpholin-2-ylJacetamide,
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-oxo-1H- quinolin-7-yl)morpholin-2-yl]acetamide, (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-( 1 -methyl-2- oxoquinolin-7-yl)-3-oxomorpholin-2-yl]acetamide, (2R)-2-[(2R)-4-l 1 -(cyclopropylmethyl)-2-oxoquinolin-7-yl l-3-oxonwpholin-2-yl]-2- hydroxy-N-( 1 -imino-2,3-dihydroisøindol-5-yl)acetamide,
2-t7-[(2R)-2-t(lR)-1-hydroxy-2-[( l-imino-2,3-dihydroisoindol-5-yl)amino]-2- oxoethyl]-3-oxomorphoIin-4-yl]-2-oxoquinolin- l-yl]acetate,
2-[7-[(2R)-2-[(lR)-1-hydroxy-2-f( l-imino-2,3-dihydroisoindol-5-yl)amino]-2- oxoethylJ-3-oxomorpholin-4-yl]-2-oxoquinolin- l-yl]acetic acid, (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-(8-methyt-2-oxo- tH- quinolin-7-yl)-3-oxomorpholin-2-yl]acetamide,
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-(2-methoxyquinolin-7
-yl)-3-oxomorpholin-2-yl]acetamide,
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-quinolin-7- ylraorpholin-2-yl]acetamide,
(2R)-N-(3-amino-1,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3- oxo-4-quinolin-7-ylmorpholin-2-yl]acetamide,
(2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2-l(2R)-3-oxo-4-(2-oxo- 1H- quinolin-5-yl)morpholin-2-yl]acetamide, (2R)-2-hydroxy-N-( l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-( l-oxo-3,4- dihydro-2H-isoquinolin-6-yl)morpholin-2-yl]acetamide,
(2R)-2-hydroxy-N-( l-imino-2.3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-oxo-3,4- dihydro- 1 H-quinolin-7-y l)morpholin-2-yl ]acetamide,
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-(l-methyl-2-oxo-3,4- dihydroquinolin-7-yl)-3-oxomorpholin-2-yl]acetamide,
(2R)-2-[(2R)-4-[ l-(cyclopropylmethyl)-2-oxo-3,4-dihydroquinolin-7-yl]-3- oxomorpholin-2-yll-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)acetamide, methyl 2-l7-[(2R)-2-f( lR)-1-hydroxy-2-[( l-imino-2,3-dihydroisoindol-5-yl)amino]-2- oxoethyl]-3-oxomorpholin-4-yl]-2-oxo-3,4-dihydroquinolin-1-yl]acetate,
2-[7-[(2R)-2-[(lR)-1-hydroxy-2-[(l-imino-2,3-dihydroisoindol-5-yl)amino]-2-oxoethyl ]-3-oxomorpholin-4-yl]-2-oxo-3,4-dihydroquinolin-1-yl]acetic acid, (2R)-N-(4-carbamimidoy l-3-fluorophenyl)-2-hy droxy-2- [(2R)-3-oxo-4-(2-oxo-3 ,4- dihydro- 1 H-quinolin-7-yl)morpholin-2-yllacetamide,
(2R)-N-(3-amino-l ,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-
4-(2-oxo-3,4-dihydro- 1 H-quinolin-7-yl)raorpholin-2-yllacetamide
(2R)-N-( 1 -aminoisoquinolin-6-yl)-2-hydroxy-2-f(2R)-3-oxo-4-(2-oxo-3,4-dihydro- 1 H- quinolin-7-yl)morpholin-2-yl]acetamide,
(2R)-N-(4-aminoquinazolin-7-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro-1H- quinolin-7-yl)morpholin-2-yl]acetamide,
(2R)-2-hydroxy-N-( l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-oxo-3,4- dihy dro- 1 H-quinol in-5-y 1 )morphol in-2-y 1 ] acetamide, (2R)-2-hydroxy-2-[(2R)-4-[2-(3-hydroxy-3-methylbutoxy)phenyl]-3-oxomorpholin-2- yl]-N-(l-imino-2,3-dihydroisoindol-5-yl)acetamide,
5 (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-y l)-2-[(2R)-4-[2-(3-methoxy-3- methylbutoxy)phenyl]-3-oxomorpholin-2-yl)acetamide,
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-[2-(2- oxopiperidin-1-yl)phenyl]morpholin-2-yl1acetamide,
10
(2R)-2-[(2R)-4-[2-(difluoromethoxy)-5-fluorophenylJ-3-oxomorpholin-2-yll-2-hydroxy
-N-( 1 -imino-2,3-dihydroisoindol-5-yl)acetamide, methyl 2-(difluoromethoxy)-3-f(2R)-2-[( IR)-I -hydroxy-2-f(l -imino-2,3-dihydro- 15 isoindol-5-yl)amino)-2-oxoethyl]-3-oxomorpholin-4-yl]benzoate,
2-(difluoromethoxy)-3-[(2R)-2-f( 1 R)- 1 -hydroxy-2-[( 1 -imino-2,3-dihydroisoindol-5-yl) amino]-2-oxoethyl]-3-oxomorpholin-4-ylJbenzoic acid,
20 2-(difluoromethoxy)-3-f(2R)-2-[(lR)- l-hydroxy-2-[(l-imino-2,3-dihydroisoindol-5-yl) amino]-2-oxoethyl]-3-oxomorpholin-4-yl]-N,N-dimethylbenzamide,
2-(difluoromethoxy)-3-r2-[(l-hydroxy-2-[(l-imino-2,3-dihydroisoindol-5-yl)amino]-2- oxoethyl]-3-oxomorpholin-4-yl]benzamide,
•>.n
methyl 2-[(2R)-2-[( 1 R)- 1 -hydroxy-2-[( 1 -imino-2,3-dihydroisoindol-5-yl)amino J-2- oxoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)benzoate, 2-[(2R)-2-[(lR)-1-hydroxy-2-[( l-imino-2,3-dihydroisoindol-5-yl)amino]-2-oxoethylj-3 -oxomorpholin-4-yl]-5-(trilluoromethoxy)benzoic acid,
2-[(2R)-2-[( 1 R)- 1 -hydroxy-2-[( 1 -imino-2,3-dihydroisoindol-5-yI)amino]-2-oxoethyl J-3 -oxomorpholin-4-yl]-5-(trifluoromethoxy)benzarnide,
(2R)-N-(3-amino- l ,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinol in-6-yl)morpholin-2-yl]acetamide, (2R)-N-(3-amino- 1 ,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo- 1H-quinol in-7-yl)morpholin-2-yl]acetamide, or
(2R)-N-(3-amino-1,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinol in-5-yl)rnorpholin-2-yl]acetamide, or a pharmaceutically acceptable salt or a solvate thereof.
In another embodiment, the compound is
(2R)-2-[(2R)-4-(4-tert-butylphenyl)-3-oxomorpholin-2-ylJ-2-hydroxy-N-[4-(N-methylc arbamimidoyl)phenyl]acetamide hydrochloride (Example aal),
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(l-oxo-2,3-dih ydroisoindol-5-yl)morpholin-2-yl]acetamide hydrochloride (Example aa2),
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-oxo-1H-qui nolin-6-yl)morpholin-2-yl]acetamide hydrochloride (Example aa3), (2R)-2-[(2R)-4-[7-(difluoromethoxy)-2-oxo- 1H-quinolin-6-yl]-3-oxomorpholin-2-yl]-2 -hydroxy-N-( l-imino-2,3-dihydroisoindol-5-yl)acetamide hydrochloride (Example aa4),
(2R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-L(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl
)morpholin-2-yl]acetamide hydrochloride (Example aa5),
(2R)-N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quin olin-6-yl)morpholin-2-yl]acetamide hydrochloride (Example aa6),
(2R)-2-hydroxy-N-( l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-oxo-1H-qui nolin-7-yl)morpholin-2-yl]acetamide hydrochloride (Example aa7), (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-(l-methyl-2-oxoquino lin-7-yl)-3-oxomorpholin-2-yl]acetamide hydrochloride (Example aa8),
(2R)-2-f(2R)-4-[ l-(cyclopropylmethyl)-2-oxoquinolin-7-yll-3-oxomorpholin-2-yl1-2-h ydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)acetamide hydrochloride (Example aa9),
2-[7-[(2R)-2-[( lR)- l-hydroxy-2-[( l-imino-2,3-dihydroisoindol-5-yl)amino]-2-oxoethyl l-3-oxomorpholin-4-yl]-2-oxoquinolin-1-yl]acetate hydrochloride (Example aalO),
2-l7-[(2R)-2-[(lR)- l-hydroxy-2-L( l-imino-2,3-dihydroisoindol-5-yl)aminol-2-oxoethyl )-3-oxomorpholm-4-yl]-2-oxoquinolin-1-yl]acetic acid hydrochloride (Example aal 1),
(2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2-L(2R)-4-(8-methyl-2-oxo- 1H- quinolin-7-yl)-3-oxomorpholin-2-yl]acetamide hydrochloride (Example aal2), (2R)-2-hydroxy-N-( l -imino-2,3-dihydroisoindol-5-yl)-2-l(2R)-4-(2-methoxyquinolin-7 -yl)-3-oxomorpholin-2-yl]acetamide hydrochloride (Example aal3), (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-quinolin-7-ylm orpholin-2-yi]acetamide dihydrochloride (Example aal4),
(2R)-N-(3-amino- 1 ,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3- oxo-4-quinolin-7-ylmorpholin-2-yl]acetamide hydrochloride (Example aal5),
(2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2-f(2R)-3-oxo-4-(2-oxo- 1H-qui nolin-5-yl)morpholin-2-yl]acetamide hydrochloride (Example aalβ),
(2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-( 1 -oxo-3,4-dih ydro-2H-isoquinolin-6-yl)morpholin-2-yl]acetamide hydrochloride (Example aal7),
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-oxo-3,4-dih ydro-1H-quinolin-7-yl)morpholin-2-yl]acetamide hydrochloride (Example aal8), (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-( l-methyl-2-oxo-3,4- dihydroquinolin-7-yl)-3-oxomorpholin-2-yl]acetamide hydrochloride (Example aal9),
(2R)-2-[(2R)-4-[ l-(cyclopropylmethyl)-2-oxo-3,4-dihydroquinolin-7-yll-3-oxomorphol in-2-yl]-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)acetamide hydrochloride (Example aa20), methyl 2-[7-[(2R)-2-[( lR)-1-hydroxy-2-[(l-imino-2,3-dihydroisoindol-5-yl)amino]- 2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxo-3,4-dihydroquinolin- l-yl]acetate hydrochloride (Example aa21 ),
2-[7-f(2R)-2-f( lR)-1-hydroxy-2-[(l-imino-2,3-dihydroisoindol-5-yl)amino]-2-oxoethyl ]-3-oxomorphoIin-4-yl)-2-oxo-3,4-dihydroquinolin-1-yl]acetic acid hydrochloride (Example aa22),
(2R)-N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4-dihy dro-1H-quinolin-7-yl)morpholin-2-yl]acetamide hydrochloride (Example aa23), (2R)-N-(3 -amino- 1 ,2-benzoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro -1H-quinolin-7-yl)morpholin-2-yl]acetamide (Example aa24),
(2R)-N-(l-aminoisoquinolin-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro-1H- quinolin-7-yl)morpholin-2-yl]acetamide hydrochloride (Example aa25),
(2R)-N-(4-aminoquinazolin-7-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro-1H-q uinolin-7-yl)morpholin-2-yl]acetamide (Example aa26),
(2R)-2-hydroxy-N-( l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-oxo-3,4-dih ydro- 1H-quinolin-5-yl)morpholin-2-yl]acetamide hydrochloride (Example aa27),
(2R)-2-hydroxy-2-[(2R)-4-r2-(3-hydroxy-3-methylbutoxy)phenyl]-3-oxomorpholin-2-y I]-N-(I -imino-2,3-dihydroisoindol-5-yl)acetamide hydrochloride (Example aa28), (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-[2-(3-methoxy-3-met hylbutoxy)phenyl]-3-oxomorpholin-2-yl]acetamide hydrochloride (Example aa29),
(2R)-2-hydroxy-N-( l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-f2-(2-oxopiperi din-1-yl)phenyl]morpholin-2-yl]acetamide hydrochloride (Example aa30),
(2R)-2-[(2R)-4-[2-(difluoromethoxy)-5-fluorophenylJ-3-oxomorpholin-2-yl]-2-hydroxy
-N-(l-imino-2,3-dihydroisoindol-5-yl)acetamide hydrochloride (Example aa31 ), methyl 2-(difluoromethoxy)-3-[(2R)-2-[(lR)-1-hydroxy-2-[(l-imino-2,3- dihydroisoindol-5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]benzoate hydrochloride (Example aa32), 2-(difluoromethoxy)-3-[(2R)-2-[( lR)-1-hydroxy-2-[(l-imino-2,3-dihydroisoindol-5-yl) aminol-2-oxoethyll-3-oxomorpholin-4-yl]benzoic acid hydrochloride (Example aa33),
2-(difluoromethoxy)-3-[(2R)-2-f( lR)-1-hydroxy-2-t(l-imino-2,3-dihydroisoindol-5-yl) amino]-2-oxoethyl]-3-oxomorpholin-4-yl]-N,N-dimethylbenzamide hydrochloride (Example aa34),
2-(difluoromethoxy)-3-[2-r(l-hydroxy-2-r(l-imino-2,3-dihydroisoindol-5-yl)amino]-2- oxoethyl)-3-oxomorpholin-4-ylJbenzamide hydrochloride (Example aa35), methyl 2-[(2R)-2-[( 1 R)- 1 -hydroxy-2-[( 1 -imino-2,3-dihydroisoindol-5-y l)amino 1- 2-oxoethyl]-3-oxomorpholin-4-yi]-5-(trifluoromethoxy)benzoate hydrochloride (Example aa36),
2-f (2R)-2-f( 1 R)- 1 -hydroxy-2-[( 1 -imino-2,3-dihydroisoindol-5-y l)amino]-2-oxoethyl]-3 -oxomorpholin-4-yl]-5-(trifluoromethoxy)benzoic acid hydrochloride (Example aa37), or
2-[(2R)-2-[( lR)-1-hydroxy-2-[(l-imino-2,3-dihydroisoindol-5-yl)aminoJ-2-oxoethyll-3 -oxomorphoIin-4-yl]-5-(trifluoromethoxy)benzamide hydrochloride (Example aa38), or a solvate thereof.
In another embodiment, the compound is
2-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)- 1 -hydroxy-2-oxoethyl)-3-oxomorp holino)phenyl)acetate (Example aa40),
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(3-methyl-5-(pyrrolidine-1-carbo nyl)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aa53),
(R)-2-hydroxy-N-( l-iminoisoindolin-5-yl)-2-((R)-4-(3-methyl-5-(pyrrolidine-l -carbon yi)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aa54),
2-(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)-N-methylbenzamido)acetic acid (Example aa50),
2-(3-((R)-2-((R)- l-hydroxy-2-(l-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)-N-methylbenzamido)acetate (Example aa51 ), (S)- 1 -(3-((R)-2-((R)-2-(4-carbamimidoylpheny lamino)- 1 -hydroxy-2-oxoethyl)-3-oxom orpholino)benzoyl)pyrrolidine-2-carboxylic acid (Example aa58),
1 -(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)- 1 -hydroxy-2-oxoethyl)-3-oxomoφ holino)benzoyl)pyrrolidine-2-carboxylate (Example aa52),
3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-oxomorpholi no)-N-methyl-N-(2-oxo-2-(pyrroIidin-1-yl)ethyl)benzamide (Example aa56),
3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-y lamino)-2-oxoethy l)-3-oxomorpholin o)-N-methyl-N-(2-oxo-2-(pyrrolidin- 1 -yl)ethyl)benzamide (Example aa59),
(R)-N-(4-carbamimidoyIphenyl)-2-hydroxy-2-((R)-4-(3-methyl-5-(morpholine-4-carbo nyI)phenyl)-3-oxomorpholin-2-yI)acetamide (Example aa60), (R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(3-methyl-5-(morpholine-4-carbon yl)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aaόl),
(R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(3-((R)-3-methoxypyrrolidine- 1 -ca rbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aa63),
(R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(3-((S)-3-methoxypyiτolidine- 1 -ca rbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aa64),
(R)-2-((R)-4-(3-chloro-4-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hyd roxy-N-(l-iminoisoindolin-5-yl)acetamide (Example aa66),
(R)-2-hydroxy-N-(l-iminoisoindolin-5-yl)-2-((R)-4-(3-(2-morphoIino-2-oxoethyl)phen yl)-3-oxomorphoIin-2-yl)acetamide (Example aa68), (S)- 1 -(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomo rpholino)benzoyl)pyrrolidine-2-carboxylic acid (Example aa55),
1 -(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)benzoyl)pyrrolidine-2-carboxylate (Example aa57),
2-(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)phenyl)acetate (Example aa65),
2-(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)phenyl)acetic acid (Example aa67),
2-(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)-N-methylbenzamido)acetate (Example aa62), 2-(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)phenyl)-2-methylpropanoate (Example aa70),
(R)-2-hydroxy-N-(l-iminoisoindolin-5-yl)-2-((R)-4-(3-(morpholine-4-carbonyl)phenyl) -3-oxomorpholin-2-yI)acetamide (Example aa69),
3-((R)-2-((R)-1-hydroxy-2-( l-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorpholin o)-N-methyl-N-(2-morpholino-2-oxoethyl)benzamide (Example aa71 ), (R)-2-hydroxy-N-( 1 -iminoisoindolin-5-y l)-2-((R)-4-(3-(2-((R)-3-methoxypyrrolidin- 1 - yl)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yI)acetamide (Example aa72), (R)-2-hydroxy-N-( l -iminoisoindolin-5-yl)-2-((R)-4-(3-(2-((S)-3-methoxypyπ-olidin-1- yl)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aa73),
2-(3-((R)- 2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph o!ino)phenyl)-2-methylpropanoate (Example aa74),
2-(3-((R)-2-((R)- l-hydroxy-2-(l-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)phenyl)acetate (Example aa75),
(R)-2-hydroxy-N-(l-iminoisoindolin-5-yl)-2-((R)-4-(3-(4-methyl-3-oxopiperazine-1-ca rbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aa76),
2-(3-((R)-2-((R)-1-hydroxy-2-( l-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)phenyl)-2-methylpropanoate (Example aa77), (R)-2-hydroxy-N-(l -iminoisoindolin-5-yl)-2-((R)-4-(3-(2-(4-methyl-3-oxopiperazin- l- yl)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aa79),
(R)-2-((R)-4-(3-(2-(dimethylamino)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)-2-hydro xy-N-( l -iminoisoindolin-5-yl)acetamide (Example aa82),
1 -(3-((R)-2-((R)- 1 -hydro xy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)benzoyl)piperidine-4-carboxylic acid (Example aa83),
1 -(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)benzoyl)piperidine-4-carboxylate (Example aa84),
2-(3-((R)-2-((R)- 1 -acetoxy-2-( 1 -imino-3-oxoisoindolin-5-y lamino)-2-oxoethy l)-3-oxo morpholino)-N-methyIbenzamido)acetic acid (Example aa85), (R)-N-( 1 ,3-diiminoisoindolin-5-yl)-2-((R)-4-(3-(2-(dimethylamino)-2-oxoethyl)phenyl) -3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aa86), (R)-2-( l-imino-3-oxoisoindolin-5-ylamino)-1-((R)-4-(3-(methyl(2-oxo-2-(pyrrolidin- l- yl)ethyl)carbamoyl)phenyl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate (Example aa87),
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)p henyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide ((Example aa95),
(R)-N-(3-aminobenzofd]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-((4,4-difluoropiperidin-1-y l)methyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aa97), (R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorpholin o)phenyl)morpholin-2-yl)acetamide (Example aa98),
(R)-N-(3-aminobenzo[d)isoxazol-6-yl)-2-((R)-4-(2-(difluoromethoxy)phenyl)-3-oxomo rpholin-2-yl)-2-hydroxyacetamide (Example aa99),
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-4-(2-isopropoxyphenyl)-3-ox omorpholin-2-yl)acetamide (Example aalOO),
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(3-cyanophenyl)-3-oxomorpholin-2-yl )-2-hydroxyacetamide (Example aalOl),
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-(morpholine-4-carbonyl)p henyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aalO3), (R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-4-(4-methyl-3-(morpholine-4 -carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aalO4),
(R)-N-(3-aminobenzo[dlisoxazol-6-yl)-2-hydroxy-2-((R)-3-oxo-4-(3-(trifluoromethoxy )phenyl)morpholin-2-yl)acetamide (Example aalO5),
(R)-N-(3-aminobenzo[dlisoxazol-6-yl)-2-hydroxy-2-((R)-3-oxo-4-(3-(trifluoromethyl)p henyl)morpholin-2-yl)acetamide (Example aalO6),
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-( 1,2,3,4-tetrahydroisoquin oline-2-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aalO7),
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-(4,4-difluoropiperidine-1- caτbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aal08),
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(3-fluoro-4-(trifluoromethyl)phenyl)-3 -oxomorpholin-2-yl)-2-hydroxyacetamide (Example aal09),
(R)-N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorphol iπo)phenyl)morpholin-2-yl)acetamide (Example aal l4),
(R)-2-hydroxy-N-(l-imino-7-(trifluoromethyI)isoindolin-5-yl)-2-((R)-3-oxo-4-(3-(3-ox omorpholino)phenyl)morpholin-2-yl)acetamide (Example aal 16),
(R)-2-Hydroxy-N-(l-iminoisoindolin-5-yl)-2-((R)-3-oxo-4-(3-(trifluoromethoxy)pheny l)morpholin-2-yl)acetamide (Example aal l7), Ethyl
2-(3-((R)-2-((R)-1-hydroxy-2-(l-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)phenoxy)acetate (Example aal20),
(R)-2-Hydroxy-N-(l-iminoisoindolin-5-yl)-2-((R)-4-(4-methoxybenzyl)-3-oxomorphol in-2-yl)acetamide (Example aal 21),
(R)-2-((R)-4-(3-(Benzyloxy)phenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N-(l-iminoisoin dolin-5-yl)acetamide (Example aal 23), (R)-N-( 1 - Aminoisoquinolin-6-yl)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbony l)phenyl )-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aal 32),
N-(2,3-Dihydro-1-imino- lh-isoindol-5-yl)-4-[2-f(dimethylamino)carbonyl]phenyl]-alp ha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide ((Example aal40),
N-(2,3-Dihydro-1-imino- 1H-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo-4-[2-(l-pyrrolidin ylcarbonyl)phenylJ-2(R)-morpholineacetamide ((Example aal41 ),
4-(2-Cyanophenyl)-N-(2,3-dihydro- 1 -imino- 1 h-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo -2(R)-morpholineacetamide ((Example aal 42),
N-(2,3-Dihydro- 1 -imino- 1 h-isoindol-5-yl)-4-[4-fluoro-3-(4-morpholinyIcarbonyI)phen yl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide (Example aal44),
N-(2.3-Dihydro- l-imino- lh-isoindol-5-yl)-4-f4-fluoro-3-f(3(R)-methyl-4-morpholinyl) carbonyl)phenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide(Example aal45),
N-(2,3-Dihydro- 1 -imino- 1 h-isoindol-5-yl)-4-[4-fluoro-3-[(3(S)-methyl-4-morpholinyl) carbonyl|phenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide (Example aal46),
N-[4-(Aminoiminomethyl)phenyl]-4-(2-cyanophenyl)-alpha(R)-hydroxy-3-oxo-2(R)-m orpholineacetamide (Example aal47),
N-(4-Amino-7-quinazolinyl)-4-[4-fluoro-3-(4-morpholinylcarbonyl)phenyl]-alpha(R)-h ydroxy-3-oxo-2(R)-morpholineacetamide (Example aal48),
[3-[2(R)-f2-|(3-Amino-l ,2-benzisoxazol-6-yl)amino]-l(R)-hydroxy-2-oxoethyl]-3-oxo- 4-morpholinyl]phenyl]pentafluorosulfur (Example aal50), f4-l2(R)-[2-[(3-Amino-l ,2-benzisoxazol-6-yl)amino]- 1 (R)-hydroxy-2-oxoethyl]-3-oxo- 4-morphoiinyl]phenyl]pentafluorosulfur (Example aal51),
N-(3-Amino-5-fluoro-1,2-benzisoxazol-6-yl)-4-[4-fluoro-3-(4-morphoIinylcarbonyl)ph enyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide (Example aal52),
N-(2-Amino-6-quinazoliπyl)-4-[4-fluoro-3-(4-morpholinylcarbonyl)phenyl]-alpha(R)-h ydroxy-3-oxo-2(R)-morpholineacetamide ((Example aal53),
(R)-2-((R)-4-(5-fluoro-2-isopropoxyphenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N-(l-imi noisoindolin-5-yl)acetamide (Example aal54),
(R)-2-hydroxy-N-(l-iminoisoindolin-5-yl)-2-((R)-3-oxo-4-(2-(trifluoromethyl)phenyl) morpholin-2-yl)acetamide (Example aal55), (R)-2-((R)-4-(2-(difluoromethoxy)phenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N-(l-imin oisoindolin-5-yl)acetamide (Example aal56),
(R)-2-hydroxy-N-( l-iminoisoindolin-5-yl)-2-((R)-4-(2-isopropoxyphenyl)-3-oxomorph olin-2-yI)acetamide (Example aal57),
(R)-2-hydroxy-N-( l-iminoisoindolin-5-yl)-2-((R)-3-oxo-4-(2-(trifluoromethoxy)phenyl )morpholin-2-yl)acetamide ((Example aal59),
N-(3-Amino-1,2-benzisoxazol-6-yl)-4-[4-fluoro-3-[(tetrahydro-2H-pyran-4-yl)oxy]phe nyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide ((Example aalόO),
N-(3-Amino- l ,2-benzisoxazol-6-yl)-4-f3-[(3,3-difluoro-1-azetidinyl)carbonyl]-4-fluoro phenyl ]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide ((Example aal62), N-(3-Amino-l ,2-benzisoxazol-6-yl)-4-[3-[(4,4-difluoro- l-piperidinyl)carbonyl]-4-fluor ophenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide (Example aal63),
N-(3-amino- 1 ,2-benzisoxazol-6-yl)-4-[4-chloro-3-[3-( 1 , 1-dimethylethyl)- 1 ,2,4-oxadiaz ol-5-yllphenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide (Example aal64),
N-(3-amino-l ,2-benzisoxazol-6-yl)-4-[2-fluoro-5-(trifluoromethyl)phenyl]-alpha(R)-hy droxy-3-oxo-2(R)-morpholineacetamide ((Example aal65), or a solvate thereof.
In another embodiment, the compound is
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(3-((S)-2-methylpyrrolidine-1-car bonyl)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aa39),
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-3-(morpholine-4-carbo nyl)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aa41),
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-3-(pyrrolidine- l-carbo nyl)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aa42), (R)-2-((R)-4-(3-(azetidine-1-carbonyl)-5-fluorophenyl)-3-oxomorpholin-2-yl)-N-(4-caτ bamimidoylphenyl)-2-hydroxyacetamide (Example aa43), (R)-2-((R)-4-(3-(azetidine- 1 -carbony !)-2~methy lphenyl)~3-oxomorpholin-2-y l)-N-(4-ca rbamirnidoylphenyl)-2-hydroxyacetamide (Example aa44),
(R)-2-((R)-4-(5-(azetidine-1-carbonyl)-2-methylphenyl)-3-oxomorpholin-2-yl)-N-(4-ca rbamimidoylphenyl)-2-hydroxyacetamide (Example a45),
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-3-oxo-4-(6-(trifluoromethyl)pyridin -2-yl)morpholin-2-yl)acetamide (Example aa46),
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-5-(pyrrolidine- l-carbo nyl)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aa47),
(R)-2-((R)-4-(3-(azetidine- l-carbonyl)-5-methylphenyl)-3-oxomorpholin-2-yl)-N-(4-ca rbamimidoylphenyl)-2-hydroxyacetamide (Example aa48), (R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-5-(morpholine-4-carbo nyl)phenyl)-3-oxomorpholm-2-yi)acetamide (Example aa49),
(S)- l-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)- 1 -hydroxy-2-oxoethyl)-3-oxom orpholino)-5-fluorobenzoyl)pyrrolidine-2-carboxylic acid (Example aa78), l-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-oxomoφ holino)-5-fluorobenzoyl)pyrrolidine-2-carboxylate (Example aa80), 1 -(3-((R)-2-((R)-2-(4-carbamimidoy Iphenylamino)- 1 -hydroxy-2-oxoethyl)-3-oxomoφ holino)-5-fluorobenzoyl)pyrrolidine-2-carboxylate (Example aa81),
2-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-oxomoφ holino)-5-fluoro-N-methylbenzamido)acetic acid (Example aa88),
2-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-oxomoφ holino)-5-fluoro-N-methylbenzamido)acetate (Example aa89), 3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-oxomorpholi no)-N-(2-(dimethylamino)-2-oxoethyl)-5-fluoro-N-methylbenzamide (Example aa90), (R)-N-( 1 ,3-diiminoisoindolin-5-yl)-2-hydroxy-2-((R)-4-(3-(2-(4-methyl-3-oxopiperazin - l -yl)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aa91),
N-(2-(dimethylamino)-2-oxoethyl)-3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-yla mino)-2-oxoethyl)-3-oxomorpholino)-N-methylbenzamide (Example aa92),
(R)-N-(3-aminobenzofd]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-(morpholinomethyl)pheny l)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aa96),
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-4-(3-(morpholine-4-carbonyl) phenyl)-3-oxomorpholin-2-yl)acetamide (Example aalO2),
3-((R)-2-((R)-2-(4-carbamimidoyl-3-fluorophenylamino)-1-hydroxy-2-oxoethyl)-3-oxo morpholino)benzoic acid (Example aal lO), (R)-N-(4-carbamimidoyl-3,5-difluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomor pholino)phenyl)morpholin-2-yl)acetamide (Example aall l),
(R)-N-(4-carbamimidoyl-2,3-difluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomor pholino)phenyl)morpholin-2-yl)acetamide (Example aal l2),
(R)-N-(4-carbamimidoyl-2,5-difluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomor pholino)phenyl)morpholin-2-yl)acetamide (Example aal l3),
(R)-N-(3-(aminomethyl)-4-cyano-5-(trifluoromethyl)phenyl)-2-hydroxy-2-((R)-3-oxo- 4-(3-(3-oxomorpholino)phenyl)morpholin-2-yl)acetamide (Example aal l5),
(R)-2-Hydroxy-N-( l-iminoisoindolin-5-yl)-2-((R)-4-(2-methyl-1-oxoisoindolin-5-yl)-3 -oxomorpholin-2-yl)acetamide (Example aal l δ), (R)-2-Hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(2-methyl-3-oxoisoindolin-5-yl)-3 -oxomorpholin-2-yl)acetamide hydrochloride (Example aal l9), (R)-2-((R)-4-(2-(Cyclopropylmethyl)-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)-2-hy droxy-N-(l-iminoisoindolin-5-yl)acetamide (Example aa! 24),
(R)-N-(4-(Aminomethyl)-3-fluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorphol ino)phenyl)morpholin-2-yl)acetamide (Example aa 125),
(R)-N-(4-Guanidinophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorpholino)phenyl)m orpholin-2-yl)acetamide (Example aal26), (R)-N-(4-(Aminomethyl)phenyl)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl) -3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aal27),
(R)-2-(4-Carbamoylphenylamino)- l-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl )-3-oxomorpholin-2-yl)-2-oxoethyl acetate (Example aal28),
(R)-2-((R)-4-(4-Fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hyd roxy-N-(1,2,3,4-tetrahydroisoquinolin-6-yl)acetamide (Example aa!29),
(R)-N-(4-(Aminomethyl)-3-fluorophenyl)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl )phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aal30),
(R)-N-(4-((R)- l -Aminoethyl)phenyl)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phe nyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aal31), (R)-N-((R)- 1 -amino-2,3-dihydro- 1 H-inden-5-y l)-2-((R)-4-(4-fluoro-3-(morpholine-4-c arbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aal33),
(R)-N-((S)- l -Amino-2,3-dihydro-1H-inden-5-yl)-2-((R)-4-(4-fluoro-3-(morpholine-4-c arbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aal34), (R)-N-(2-Aminoquinolin-6-yl)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3 -oxomorpholin-2-yl)-2-hydroxyacetamide (Example aal35),
N-(7-fluoro-2,3-dihydro- l -imino-1H-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo-4-[3-(3-o xo-4-morpholinyl)phenyl]-2(R)-morpholineacetamide (Example aal36),
N-(4-chloro-2,3-dihydro- 1 -imino- 1 H-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo-4-[3-(3-o xo-4-morpholinyl)phenyl]-2(R)-morpholineacetamide (Example aal37),
3-(2(R)-l2-[(2,3-Dihydro-l -irnino-lh-isoindol-5-yl)aminoJ-l (R)-hydroxy-2-oxoethyl]- 3-oxo-4-morpholinyl]benzoic acid (Example aal38),
Methyl 3-[2(R)-[2-[(2,3-dihydro- l -imino-1H-isoindol-5-yl)amino]- 1(R)- hydroxy-2-oxoethyl]-3-oxo-4-morpholinyl]benzoate (Example aal39),
Methyl 2-l2(R)-[2-[(2,3-dihydro- 1 -imino- lh-isoindol-5-yl)amino]- 1 (R)- hydroxy-2-oxoethyl]-3-oxo-4-morpholinyl]benzoate (Example aal43),
N-(3-Amino-1,2-benzisoxazol-6-yl)-4-[4-fluoro-3-l2,2,2-trifluoro-1-(4-morpholinyl)eth ylJphenyll-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide (Example aaI49), (R)-2-((R)-4-(5-chloro-2-isopropoxyphenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N-(l-im inoisoindolin-5-yl)acetamide (Example aal58),
N-(3-Amino-1,243enzisoxazol-6-yl)-4-[3-(difluoromethoxy)-4-fluorophenyll-alpha(R)- hydroxy-3-oxo-2(R)-morpholineacetamide (Example aalόl),
(2R)-N-(3-amino- 1 ,2-benzoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo- 1 H-quinolin -6-yl)morpholin-2-yl]acetamide,
(2R)-N-(3-amino-1,2-benzoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-l H-quinolin -7-yl)morpholin-2-yl]acetamide,
(2R)-N-(3-amino-1,2-benzoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-l H-quinolin -5-yl)morpholin-2-yl]acetamide, or a solvate thereof.
The invention is also the compound
2-((S)-hydroxy((R)-3-oxo-4-p-tolylmorpholin-2-yl)methyl)-4-oxo-l ,4- dihydroquinazoline-6-carboximidamide (Example aa93), or l , l-dioxo-3-((S)-hydroxy((R)-3-oxo-4-p-tolylmorpholin-2-yl)methyl)-4H-benzole][ l ,2,
4]thiadiazine-7-carboximidamide (Example aa94)
or a pharmaceutically acceptable salt or a solvate thereof.
As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
The term "(Cd-Cb)-alkyl'\ in which a and b is each independently integers representing 1 to 6, is understood as meaning hydrocarbon radicals whose carbon chain are each straight-chain or branched and contains a to b carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary-butyl, pentyl, isopentyl, neopentyl, hexyl, 2,3-dimethylbutyl or neohexyl.
The term "-(C0-C4)-alkylene" is understood as meaning a bond or hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 4 carbon atoms, for example methylene, ethylene, propylene, isopropylene, isobutylene, butylene or tertiary-butylene. "-C0-alkylene" is a covalent bond. The term
"-(C1-C4)-alkylene" is understood as meaning hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 4 carbon atoms, for example methylene (-CH2-), ethylene (-CH2-CH2-), (-CH2( CH3)-), propylene (-CH2-CH2-CH1-), isopropylene, isobutylene, butylene or tertiary-butylene.
The term "-(C3-C1, )-cycloalkyl" is understood as meaning rings of 3 to 12 carbon atoms such as compounds which partially have monocycles having 3 to 8 carbon atoms in the ring such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane, which are derived from the bicycles bicyclo[4.2.0]octane, octahydroindene, decahydronaphthalene, decahydroazulene,
decahydrobenzocycloheptene or dodecahydroheptalene or from the bridged cycles such as spiral 2.51octane, spiro|3.4]octane, spiro[3.5]nonane, bicyclo[3, l . l ]heptane, bicyclo[2.2.1 Jheptane or bicyclo[2.2.2]octane.
The term "-(C^-C8)-cycloalkyl" is understood as meaning radicals which are derived from monocycles having 3 to 8 carbon atoms in the ring such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclo-heptane or cyclooctane.
The term "-(C6-C]4)-aryl" is understood as meaning aromatic hydrocarbon radicals having 6 to 14 carbon atoms in the ring. -(C,-C14)-aryl radicals are, for example, phenyl, 1-naphthyl, 2-naphthyl, anthryl or fluorenyl. Naphthyl radicals and in particular phenyl radicals are preferred aryl radicals.
The term "three- to fifteen-membered heterocyclic ring" is understood as meaning ring systems having 3 to 15 carbon atoms, which are present in one, two or three ring systems connected to one another and in which one, two, three or four identical or different heteroatoms from the group consisting of oxygen, nitrogen or sulfur can replace the respective carbon atoms.
One of the examples of "three- to fifteen-membered heterocyclic ring" is a bicyclic ring system represented by Formula (a). In the bicyclic ring system represented by Formula (a);
Figure imgf000044_0001
wherein Formula (a) is unsubstituted or substituted independently with one to four Y; and wherein:
o and p are independently selected from 0 or 1 ;
J, K, L and M are independently selected from the group consisting of CH2, C(O), NH, O and S(O)q, wherein q is 0, 1 or 2;
D, E and F are independently selected from the group consisting of carbon atom, nitrogen atom, oxygen atom and sulfur atom. Examples of three- to fifteen-membered heterocyclic ring are the radicals acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazolinyl, benzimidazolyl, benzisoxazole, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4H-carbazolyl, carbolinyl, beta-carbolinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran [2,3-b]-tetrahydrofuranyl, dihydrofuranyl, 1 , l-dioxido-2H-l ,2,4-benzothiadiazinyl, dioxolyl, dioxanyl, dioxolenyl, 2H, 6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isoquinolinyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxiranyl, oxothiolanyl, phenanthridinyl, phenanthrenyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,
tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, tetrazolyl, 6H-l ,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1 ,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazinyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl, thienopyridinyl, thienopyrrolyl, thienothiazolyl, thienothiophenyl, thiomorpholinyl, thiopyranyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl. 1 ,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl, oxindolyl, benzimidazolinyl, benzoxalonyl, 1,3-dihydro- benzisothiazolyl, 3,4-dihydro-2,3-benzothiazinyl, 2,3-dihydro-isoindolyl, 1 ,4-dihydro-isoquinolinonyl, 3,4-dihydro-quinolinonyl or
3,4-dihydro-benzothiadiazinyl.
The term "-(Cj-C^-haloalkyl" is understood as meaning a partially or completely fluorinated or chlorinated alkyl radical which is selected, for example, from the following radical -CF3, -CHF2, -CH2F, -CHF-CF,, -CHF-CHF2, -CHF-CH2F, -CH2-CF1, -CH2-CHF2, -CH2-CH2F, -CF2-CF3, -CF2-CHF2, -CF2-CH2F, -CH2-CHF-CF3, -CH2-CHF-CHF2, -CH2-CHF-CH2F, -CH2-CH2-CF3, -CH2-CH2-CHF2, -CH2-CH2-CH2F, -CH2-CF2-CF3, -CH2-CF2-CHF2, -CH2-CF2-CH2F, -CHF-CHF-CF3, -CHF-CHF-CHF2, -CHF-CHF-CH2F, -CHF-CH2-CF3, -CHF-CH2-CHF2, -CHF-CH2-CH2F, -CHF-CF2-CF3, -CHF-CF2-CHF2, -CHF-CF2-CH2F, -CF2-CHF-CF3, -CF2-CHF-CHF2, -CF2-CHF-CH2F, -CF2-CH2-CF3, -CF2-CH2-CHF2, -CF2-CH2-CH2F, -CF2-CF2-CF3, -CF2-CF2-CHF2 or -CF2-CF2-CH2F.
The term or "halogen" is understood as meaning fluorine, chlorine, bromine or iodine; fluorine, chlorine or bromine is preferred, in particular fluorine or chlorine is preferred.
Functional groups of the intermediates used, for example amino or carboxyl groups, can be masked here by suitable protective groups. Suitable protective groups for amino functions are, for example, para methoxy benzyl, benzyl, t-butoxycarbonyl, benzyloxycarbonyl, phthalolyl, trityl or tosyl protective group. Suitable protective groups for the carboxyl function are, for example, alkyl, aryl or arylalkyl esters.
Protective groups can be introduced and removed by techniques which are well-known or described here (see Greene, T. W., et. al., Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups ( 1994), Thieme). The term protective group can also include polymer-bound protective groups. Such masked compounds according to Formula (I), in which the functional groups can optionally also be masked, can, although optionally themselves not pharmacologically active, optionally be converted after administration to mammals by metabolization to the pharmacologically active compounds according to the invention.
When any variable occurs more than one time in any constituent or in Formula
(I), its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Compounds having Factor IXa antagonistic activity (determined by, for example, pharmacological examples described below: a measurement of fluorescence value using microtiter plate reader, ARVO 1420 Multilabel Counter) of 30 μM or less, preferably 1 μM or less, more preferably 100 nM or less, and the most preferably 50 nM or less in terms of an IC50 value are preferably used.
In the embodiments described in this description, "agent" or "drug" means a material which is used for improvement of disease or symptom, not only for treatment of disease or symptom.
In all the above embodiments, when the term "compound" is used, the term also refers to pharmaceutically acceptable salts thereof. The compounds of the present invention have asymmetric carbon atoms. Accordingly, the compounds of the present invention include mixtures of various stereoisomers, such as geometrical isomers, tautorners, such as keto- and enol- tautomers, or amidino- and imidino- tautomers, and optical isomers, and isolated isomers, for example, (R, R), (S, S), (R, S) and (S, R) isomers. (R, R) isomer is preferred. The isolation and the purification of such stereoisomers can be performed by those skilled in the art with a known technique such as optical resolution using preferential crystallization or column chromatography, or asymmetric synthesis.
The compounds represented by Formula (I) of the present invention may form acid addition salts. Alternatively, these compounds may form salts with a base according to the type of substituent. These salts are not particularly limited as long as the salts are pharmaceutically acceptable salts. Specific examples of the salts include acid addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid; an organic carboxylic acid such as an aliphatic monocarboxylic acid, e.g., formic acid, acetic acid, trifluoroacetic acid (TFA), propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, or mandelic acid, an aromatic monocarboxylic acid, e.g., benzoic acid or salicylic acid, an aliphatic dicarboxylic acid, e.g., oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, or tartaric acid, and an aliphatic tricarboxylic acid e.g., citric acid; an organic sulfonic acid such as an aliphatic sulfonic acid, e.g., methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, or 2-hydroxyethanesulfonic acid, or an aromatic sulfonic acid, e.g., benzenesulfonic acid or p-toluenesulfonic acid; or an acidic amino acid, e.g., aspartic acid or glutamic acid; salts with a metal such as an alkali metal, e.g., sodium or potassium, or an alkaline earth metal, e.g., magnesium or calcium; salts with an organic base such as methylamine, ethylamine, ethanolamine, pyridine, lysine, arginine, or ornithine; and ammonium salts.
These salts can be obtained by a known method, for example, by mixing a compound of the present invention with an equivalent amount and a solution containing a desired acid, base, or the like, and then collecting the desired salt by filtering the salt or distilling off the solvent.
The compounds of the present invention and salts thereof can form solvates with a solvent such as water, ethanol, or glycerol.
The salts of a compound of the present invention include monosalts and di-salts. The compounds of the present invention can form an acid addition salt and a salt with a base at the same time according to the type of substituent of the side chain.
Furthermore, the present invention includes hydrates, pharmaceutically acceptable various solvates, and crystal polymorphism of the compounds represented by Formula (I) of the present invention. The present invention is not limited to the compounds described in examples below and includes all compounds represented by Formula (I) of the present invention and pharmaceutically acceptable salts thereof.
Prodrugs and solvates of the compounds of the invention are also
contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, 14, 1987, of the A.C1S. Symposium Series, and in Bioreversible Carriers in Drug Design, 1987, Edward B. Roche, ed., American Pharmaceutical Assosiation and Pergamon Press. The term "prodrug" means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or a solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Nobel Delivery Systems." Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Associatiion and
Pergamon Press, 1987. For example, if a compound of Formula (1) or a pharmaceutically acceptable salt, hydrate or a solvate of the compound contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci~C6)alkanoyloxymethyl,
l -((Ct-C6)alkanoyloxy)ethyl, l-methyl-1-((C1-C6)alkanoyloxy)ethyl,
(CrCή)alkoxycarbonyloxymethyl, N-( Ci-C6)alkoxycarbonylaminomethyl, succinoyl, (Ci-Q,)alkanoyl, α-amino(Ci-C4)alkanyl, arylacyl and α-aminoacyl, or
α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-anino acids, -P(O)(OH)2, -P(O)(O(C rC6)alky I)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal from of a carbohydrate), and the like.
Methods for Making Morpholinone Compounds of the Invention
Compounds of the invention can be prepared by procedures described below. Variables used in the described procedures correspond to compounds of the invention included within the scope of Formula (I),
Figure imgf000050_0001
and have the following meanings:
Rl is selected from the group consisting of:
1 ) -(Cfi-Cj4)-aryl, which is unsubstituted or substituted independently with one to four Y;
2) -(three- to fifteen-membered heterocyclic ring), which is unsubstituted or substituted independently with one to four Y;
3) -(C6-C)4)-aryl-U-(C6-C14)-aryl, wherein each of said -(C6-C14)-aryl- independently is unsubstituted or substituted independently with one to four
Y;
4) -(C6-CI4)-aryl-U-(C3-CI2)-cycloalkyl, wherein said -(C6-Cj4)-aryl and
-(C,-Cp)-cycloalkyl independently are unsubstituted or substituted independently with one to four Y;
5) -(C6-C14)-aryl-U-(three- to fifteen-membered heterocyclic ring), wherein said -(C6-C(4)-aryl and said (three- to fifteen-membered heterocyclic ring) are independently unsubstituted or substituted independently with one to four Y;
6) -(three- to fifteen-membered heterocyclic ring)-U-(C6-C14)-aryl, wherein said -(C6-C)4)-aryI and said (three- to fifteen-membered heterocyclic ring) are independently unsubstituted or substituted independently with one to four Y;
7) -(three- to fifteen-membered heterocyclic ring)-U-(three- to
fifteen-membered heterocyclic ring), wherein each of said -(three- to fifteen-membered heterocyclic ring)- is independently unsubstituted or substituted independently with one to four Y;
8) -(three- to fifteen-membered heterocyclic ring)-U-(C3-Cp)-cycloalkyl, wherein said -(C3-Cp)-cycloalkyl, and said -(three- to fifteen-membered heterocyclic ring)- are independently unsubstituted or substituted independently with one to four Y; 9) -V-(C6-C)4)-aryl, which is unsubstituted or substituted independently with one to four Y; and
10) -V-(three~ to fifteen-membered heterocyclic ring), which is unsubstituted or substituted independently with one to four Y;
R2 is selected from the group consisting of hydrogen atom, -C(O)-R6, -C(O)-O-R6,
-C(O)-NH-Ro , -C(O)-N(Ro) ,, -P(O)(OR6), and
-(Cj-C6)-alkyl, wherein
each R6 independently is selected from the group consisting of hydrogen atom,
-(CrC6)-alkyl, -(C3-C8)-cycloalkyl, -(C6-C14)-aryl and a three- to fifteen-membered heterocyclic ring;
R3 is absent, or selected from the group consisting of hydrogen atom and
-(C1-C4)-alkyI,
R4 is selected from the group consisting of:
1 ) -(C6-C 14)-aryl-Z, wherein said Z is a basic nitrogen-containing group and wherein said -(C6-C14)-aryl is unsubstituted or substituted independently with one to four Y;
2) -(C3-Cp)-cycloalkyl-Z, wherein said Z is a basic nitrogen-containing group and wherein said -(C1-C p)-cycloalkyl is unsubstituted or substituted independently with one to four Y;
3) -(three- to fifteen-membered heterocyclic ring)-Z, wherein said Z is a basic nitrogen-containing group and wherein said (three- to fifteen-membered heterocyclic ring) is unsubstituted or additionally substituted independently with one to four Y;
4) -(three- to fifteen-membered heterocyclic ring)-U-(three- to
fifteen-membered heterocyclic ring) -Z, wherein said Z is a basic nitrogen-containing group and wherein each of said (three- to
fifteen-membered heterocyclic ring) is independently unsubstituted or additionally substituted independently with one to four Y;
5) -(C -C14)-aryl, which is unsubstituted or substituted independently with one to four Y;
6) -(C3-Cp)-cycloalkyl, which is unsubstituted or substituted independently with one to four Y;
7) -(three- to fifteen-membered heterocyclic ring), which is unsubstituted or substituted independently with one to four Y;,
8) -(three- to fifteen-membered heterocyclic ring)-U-(three- to
fifteen-membered heterocyclic ring), wherein each of said (three- to fifteen-membered heterocyclic ring) is independently unsubstituted or substituted independently with one to four Y;
each R5 independently is selected from the group consisting of;
1 ) halogen;
2) -(C1-C )-alkyl, which is unsubstituted or substituted independently with one to four -(C1-C3)-haloaIkyl, -N-C(O)-OH, -N-C(O)-(C1-C4)-alkyl, or -C(O)OR7;
3) -(CfC3)-haloalkyl;
4) -(C,-C8)-cycloaIkyI;
5) -OH;
6) -O-(CrC4)-alkyl;
7) -O-(C1-C3)-haloalkyl;,
8) -NO.;
9) -CN; 1O) -N(R7)(R8);
1 1 ) -C(O)-N(R7)(R8);,
12) -N(R8)-C(O)-R7;
13) -N(R8)-SO,-R7;
14) -SO2-(C1-C4)-alkyl;
15) -SO,-N(R7)(R8);
16) -SO1-(C1-C3)-haloalkyl;
17) -S-(C1 -C4)-alkyl;
18) -S-(C1-C3)-haloalkyl;
19) =O (oxo);
20) -C(O)OR7; and
21) -C(O)R7
wherein each of R7 and R8 is independently selected from the group consisting of hydrogen atom, -(C6-C14)-aryl, -(C3-C8)-cycloalkyI, and -(C1-C6)-alkyl, wherein said -(C1-C6)-alkyl is unsubstituted or substituted with at least one substituent selected from the group consisting of OH, -O-(C1-C4)-alkyl, -(C1-C3)-fluoroalky, -O-(C1-C3)-haloalkyl, C(O)OH, and C(O)O-(C1-C6)-alkyl;
each U independently is selected from the group consisting of a covalent bond,
-(C1-C4)-aIkylene, -NH-, -N((C1-C4)-alkyl)-, -O-, -SO,- or -S-, wherein said -(C1-C4)-aIkylene or -(C1-C4)-alkyl is unsubstituted or substituted independently with one to four T,
or wherein geminal hydrogens in said -(C1-C4)-aIkyiene or -(C1-C4)-alkyl can be replaced by a (C3-C8)-cycloalkyl to form a spiro cyclic ring; each V independently is selected from the group consisting of -(C1-C4)-alkylene, -SO--, -C(O)-, -C(O)-NH- and -SO1-NH-,
wherein the carbon atom of said -C(O)-NH- or the sulfur atom of said
-SO1-NH- is connected to a nitrogen atom of the morpholinone ring, and wherein said -(C -C4)-alkylene is unsubstituted or substituted independently with one to four T,
or wherein geminal hydrogens in said -(C1-C,)-alkylene can be replaced by a
(C3-C )-cycloalkyl to form a spiro cyclic ring;
each T independently is selected from the group consisting of:
1 ) halogen;
2) -(Cj-C6)-alkyl, which is unsubstituted or substituted independently with one to four substituents selected from the group consisting of OH,
-O-(C1-C4)-alkyl, -(C1-C3)-haloalkyl, -O-(CrC3)-haloalkyl, -N-C(O)-OH and -N-C(O)-(C1 -C4)-alkyl;
3) -(C1-C3)-haloalkyl;
4) -(C3-C8)-cycloalkyl;
5) -OH;
6) -O-(C1-C4)-alkyl, which is unsubstituted or mono substituted with OH, -O-(C1-C4)-alkyl, -(C1-C3)-haloalkyi, -O-(C1-C,)-haloalkyl, -N-C(O)-OH or -N-C(O)-(C1-C4)-alkyl;
7) -O-(C1-C3)-haIoaIkyl;
8) -NO2;
9) -CN;
10) -N(R7)(R8);
1 1 ) -C(O)- N(R7)(R8);
I 2) -N(R8)-C(O)-R7; I S) -N(RS)-SO1-R?;
14) -SO,-(C1-C4)-alkyl;
15) -SO,-N(R7)(R8);
16) -SO,-(C1-C3)-haloalkyl;
17) -S-(C1-C4)-alkyl;
18) -S-(C1-C1)-haloalkyI;
19) -(CrC6)-alkyl-N(R7)(R8);
20) -NH-C(O)-N(R7)(R8);
2I) =O (OXo); and
22) -C(O)OR7;
23) -C(O)OR7;
24) -N-C(O)-OR7
wherein each of R7 and R8 independently is selected from the group consisting of a hydrogen atom, -(C -C )-cycloalkyl, halogen and -(Cj-Cy-alkyl, wherein said -(Cj-C6)-alkyl is optionally substituted with at least one substituent selected from the group consisting of OH, -O-(C1-C4)-alkyl, -(C1-C3)-fluoroalky, and -O-(CrC3)-haloalkyl; G is selected from the group consisting of oxygen atom, imino, sulfur atom, sulfoxide, sulfone and methylene;
W is selected from the group consisting of oxygen atom, nitrogen atom and carbon atom;
X is selected from the group consisting of nitrogen atm, carbon atom and oxygen atom; Y is selected from the group consisting of:
1 ) halogen; 2) -(C1-C6)-alkyI;
3) -(C1-C3)-haloalkyl;
4) -(C3-C8)-cycloalkyl;
5) -OH;
6) -0-(C1-C6)-alkyI;
7) -O-(C1-C3)-haloalkyl;
8) -NO2;
9) -CN;
10) -N(R7)(R8);
11 ) -C(O)-N(R7)(R8);
12) -N(R8)-C(O)-R7;
13) -N(R8)-SO,-R7;
14) -SO2-(C1-C4)-alkyl;
15) -SO2-N(R7)(R8);
16) -SO2-(C1 -C3-haloalkyl;
17) -S-(C1-C4)-aIkyl;
18) -S-(C1-C3)-haloalkyl;
19) -(C1-C6)-alkyl-N(R7)(R8);
20) -N(R8)-C(O)-N(R7)(R8);
21) =O (oxo);
22) -SF5;
23) -C(O)OR7;
24) -N-C(O)-OR7
25) -N(R8)-C(O)-(C1-C4)-alkyl-O-(C1-C4)-alkyl-(C6-C14)-aryl, wherein said -(C6-C(4)-aryl is unsubstituted or substituted independently with one to four
Y selected from ( 1) to (24) as set forth above;
26) -N(R8)-C(O)-(C1-C4)-alkyl-O-(C1-C4)-alkyl-(three- to fifteen-mernbered heterocyclic ring), wherein said -(three- to fifteen-membered heterocyclic ring) is unsubstituted or substituted independently with one to four
Yselected from ( 1 ) to (24) as set forth above;
wherein said -(C1-C4)-alkyl part or -(C1-C6)-alkyl part of 2), 6), 14), 17), 19),
25) or 26) of said Y is unsubstituted or substituted independently with one to four T;
wherein each of R7 and R8 of 10), 11), 12), 13), 15), 19), 20), 23), 24), 25) or
26) of said Y independently is selected from the group consisting of hydrogen atom, -(C3-C8)-cycloalkyl, and -(C1-C6)-alkyl, wherein said -(C1-C6)-alkyl is optionally substituted with OH, -O-(C1-C4)-alkyl, -(C1-C1)-fluoroalky, -O-(C1-C,)-haloalkyI, -C(O)OH, or
C(O)O-(C1 -C6)-alkyl;
m is O or 1 ,
n is O, 1, 2, 3 or 4,
the linkage between G atom and Nitrogen atom of the substructure (II)
Figure imgf000058_0001
in Formula (I) comprises one to four carbon atoms to form alkylene chain, wherein said alkylene chain or G (imino or methylene) is unsubstituted or substituted independently with one to four R5: the dotted linkage between W and R4 of the substructure (III)
Figure imgf000059_0001
in Formula (I) is
1 ) absent,
2) present such that substructure (III) is a (three- to fifteen-membered
heterocyclic ring)-Z, wherein said Z is a basic nitrogen-containing group and wherein said (three- to fifteen-membered heterocyclic ring) is unsubstituted or additionally substituted independently with one to four Y;
3) present such that substructure (III) is a (three- to fifteen-membered
heterocyclic ring)-U-( three- to fifteen-membered heterocyclic ring) -Z, wherein said Z is a basic nitrogen-containing group and wherein each of said (three- to fifteen-membered heterocyclic ring) is independently unsubstituted or additionally substituted independently with one to four Y;
4) present such that substructure (III) is a (three- to fifteen-membered
heterocyclic ring), wherein said (three- to fifteen-membered heterocyclic ring) is unsubstituted or substituted independently with one to four Y;
5) present such that substructure (III) is a (three- to fifteen-membered
heterocyclic ring)-U-(three- to fifteen-membered heterocyclic ring), wherein each of said (three- to fifteen-membered heterocyclic ring) is independently unsubstituted or substituted independently with one to four
Y.
General Methods
The compounds represented by Formula (I) and salts thereof, which are the compounds of the present invention can be readily produced from known compounds or commercially available compounds by, for example, known processes described in published documents, and produced by production processes described below. The present invention is not limited to the production processes described below.
Unless otherwise noted, Rl, R2, R3, R4, R5, G, W, X, m, and n in the formulae shown in the description of the production method are as defined above for the Formula (I). The alkyiene group in the side chain or ring of the compound may be substituted with the substituents defined for the Formula (I). R4' and R in the formulae shown in the description of the production method are defined in the corresponding part.
Unless otherwise noted, each of P1, P2, P3, P4 or P5 in the production method independently designate protecting group, and exemplary appropriate protecting groups include typical an arylmethyl group such as benzyl group, para methoxy benzyl group or triphenylmethyl group; acyl protecting groups, namely, an alkanoyl group such as acetyl group; an alkoxycarbonyl group such as methoxycarbonyl group,
ethoxycarbonyl group, or t-butoxycarbonyl group; an arylmethoxycarbonyl group such as benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, or
para(ortho)nitrobenzyloxycarbonyl group; or an aroyl group such as benzoyl group. The method used for deprotecting such protecting group differs depending on the chemical nature of the protecting group employed, and in the case of an arylmethyl group such as para methoxy benzyl group or benzyl group, the deprotection can be accomplished by hydrogenation using a palladium-carbon catalyst for conversion into nitrogen-hydrogen bond, or alternatively, by Birch reduction using metal sodium in liquid ammonia, or by oxidative condition using such as CAN (eerie ammonium nitrate) or DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone). The triphenylmethyl group can be removed by using an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluorometlianesulfonic acid, or a combination thereof, or alternatively, or by Birch reduction using metal sodium in liquid ammonia.
In the case of an acyl protecting group such as an alkanoyl group, an alkoxycarbonyl group, or aroyl group, the deprotection can be accomplished by the hydrolysis using an appropriate base such as an alkaline metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide.
The substituted methoxycarbonyl protecting group such as t-butoxycarbonyl group or paramethoxybenzyloxycarbonyi group can be removed by an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or a combination thereof.
The ary I methoxycarbonyl group such as benzyloxycarbonyl group,
paramethoxybenzyloxycarbonyi group, or para(ortho)nitrobenzyloxycarbonyl group can be removed by the hydrolysis using a palladium-carbon catalyst. The protecting groups P1, P2, P3, P4or P5 Of the imino group (-NH-) can be independently or simultaneously deprotected by adequately selecting the type of the protecting group and deprotection conditions, and if desired, the protecting group can be re-introduced.
Unless otherwise noted, each of Li , L2, L3, L4, L5, Lg , L7 or Lg in the production method designates a leaving group such as a halogen atom (for example, fluorine, chlorine, bromine, or iodine), methanesulfonyloxy group, or p-toluenesulfonyloxy group, or a replaceable substituent such as hydroxy group or an alkoxy group.
It should be noted that, when the derivative of the Formula (I) of the present invention synthesized has a reactive group such as hydroxy group, amino group, carboxyl group, or thiol group as its substituent such group may be adequately protected with a protective group in each reaction step and the protective group may be removed at an adequate stage. The process of such introduction and removal of the protective group may be adequately determined depending on the group to be protected and the type of the protective group, and such introduction and removal are conducted, for example, by the process described in the review section of Greene, T. W., et. al., "Protective Groups in Organic Synthesis", 2007, 4th Ed., Wiley, New York, or Kocienski, P., "Protecting Groups'" 1994, Thieme. The required starting materials, such as (i-a), (i-b), (i-c), (i-d), (i-e), (i-f), (i-g), (ϋ-a), (iii-a), (iii-b), (v-b), (viii-a), (viii-b), (viii-c), (viii-d), (viii-e), (ix-a), (xvi-a), or (xvii-a) are either commercially available, or capable of being readily synthesized by the method commonly used in the organic chemistry from commercially available products. Unless otherwise noted, the reaction conditions employed in the production method are as described below:
Reaction temperature is in the range of -78°C to the solvent-reflux temperature, and reaction time is the time sufficient for required progress of the reaction. Solvent which is not involved in the reaction may be any of the aromatic hydrocarbon solvents such as toluene and benzene; polar solvents such as water, methanol, DMF, and DMSO; basic solvents such as triethylamine and pyridine; halogen solvents such as chloroform, methylene chloride, and 1,2-dichloroethane; ethereal solvent such as diethylether, tetrahydrofuran, and dioxane; and mixed solvents thereof; and the solvent used may be adequately selected depending on the reaction conditions. Base may be any of inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and sodium hydride; and organic bases such as triethylamine, pyridine, N,N-dialkylaniline, lithium diisopropylamide and lithium hexamethyldisilazide; and acid may be any of mineral acids such as hydrochloric acid, and sulfuric acid; and organic acids such as methanesulfonic acid, trifluoroacetic acid and p-toluenesulfonic acid. The base and the acid are not necessarily limited to those mentioned above. The production processes will now be described in detail. Scheme 1 Synthetic route of the key intermediate (iii-a)
Figure imgf000064_0001
(Reaction scheme 1 )
<step 1-1>
A compound represented by formula (ii-a) can be produced by allowing a compound represented by formula (i-a) to react with a commercially available aminoalcohol or aminothiol (i-g), readily prepared aminoalcohol or aminothiol from known compounds by a process similar to that described in published documents, for example, Organic Synthesis, Collective Vol.5, pp.88 1973, in the presence of a base such as potassium tert-buthoxide, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate using a solvent which is inactive to the reaction, such as methanol, ethanol, acetone, N,N-dimethylformamide, dioxane or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
<step l-2>
Alternatively, a compound represented by formula (ii-a) can be produced by conducting a reaction using a compound represented by formula (i-b) by a process of reductive animation. After a compound represented by formula (i-b) is converted to an imine with a suitable aminoalcohol (i-g), an aminothiol (i-g) using a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran,
1 ,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature, a compound represented by formula (ii-a) can be produced by a process similar to that described in published documents, for example, Journal of Medical Chemistry, 23( 12), pp. 1405-1410, 1980 in the presence of a reductive reagent such as sodium borohydride using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature.
Alternatively, hydrogen gas can be used to an imine with a suitable process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Organic synthesis VIII, Asymmetric synthesis, reduction, sugar, and labeled compound, pp. 251 -266, 1992, Maruzen Co., Ltd., in the presence of a catalyst such as palladium-carbon (Pd-C), Raney-Ni, or platinum oxide (Ptθ2) in a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or
tetrahydrofuran, a polar solvent, e.g., ethyl acetate or acetonitrile, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or an acid solvent, e.g., acetic acid at a temperature in the range of room temperature to the solvent-reflux temperature, thereby producing a compound represented by formula (ii-a).
<step l-3>
Alternatively, a compound represented by formula (ii-a) can be produced by conducting a reaction using a compound represented by formula (i-c) by a process similar to that of <step 1- 1> with a suitable alcohol or thiol in the presence of copper iodide and cesium carbonate using a solvent which is inactive to the reaction, such as acetonitrile.
<step l-4>
A compound represented by formula (ii-b) can be produced by conducting a reaction using a compound represented by formula (ii-c) and a compound represented by formula (i-c) (for example, a known amine) as follows. When a compound represented by formula (ii-c) is a carboxylic acid, a compound represented by formula (ii-b) can be produced by allowing a compound represented by formula (ii-c) to react with a compound represented by formula (i-c) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 191-309. 1992. Maruzen Co., Ltd., in the presence of a condensing agent such as 1 ^-dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSC-HCl), benzotriazol- l-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), 2-chloro- l ,3-dimethylimidazolinium hexafluorophosphate (CIP), or
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, in a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, a polar solvent, e.g.,
N,N-dimethylformamide, or an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, in the presence or absence of a base such as triethylamine or pyridine at a temperature in the range of O°C to the solvent-reflux temperature. When a compound represented by formula (ii-c) is an acid halide, a compound represented by formula (ii-b) can be similarly produced by conducting a reaction with a compound represented by formula (i-c) by a process similar to that described in, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 144-146, 1992, Maruzen Co., Ltd., in the presence of a base such as triethylamine or pyridine in a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a polar solvent, e.g., N,N-dimethylformamide at a temperature in the range of 0°C to the solvent-reflux temperature.
<step l -5>
A compound represented by formula (ii-c) can be produced by the same process as that used in <Step 1- 1> of (Reaction Scheme 1) using a compound represented by formula (i-d) and compound represented by formula (i-e). <step l-6>
A compound represented by formula (ii-c) can be produced from a compound represented by formula (i-f) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 1-43, 1992, Maruzen Co., Ltd., in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate using water and a solvent which is inactive to the reaction, such as methanol, ethanol, 2-propanol, N,N-dimethylformamide, dioxane, or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature. <step 2-l>
A compound represented by formula (iii-a) can be produced by a process similar to that described in published documents, for example, Zhurnal Organicheskoi Khimii, (6), 1305-8, 1970, or by a similar process as that used in <Step l-4> and <step l-5> of (Reaction Scheme 1) using a compound represented by formula (i-e) as an acid halide, and compound represented by formula (ii-a) as a suitable aminoalcohol or aminothiol. When aminothiol (ii-a) was used, cyclization process of producing a compound represented by formula (iii-a) can be also conducted step by step process using different base or different solvent system.
<step 2-2>
Alternatively, a compound represented by formula (iii-a) can be produced by the same process as that used in <Step 2-l> of (Reaction Scheme 1) using a compound represented by formula (ii-b).
<step 2-3>
Protective groups of a compound represented by formula (iii-a) can be introduced and removed between (iii-a) and (iii-b) by techniques which are well-known or described here (see Greene, T. W., et. al., Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups ( 1994), Thieme).
Scheme 2 Synthetic route of Example compounds and combination compounds.
(v-a)
Figure imgf000069_0001
G represents O, S, NH, or CH2 in the Scheme 2 (v-d)
(Reaction scheme 2)
<step 3-l>
A compound represented by formula (iv-a) can be produced by allowing a compound represented by formula (iii-a) or (iii-b), which was produced in the Reaction scheme 1 or commercially available, to react with alkyl glyoxylate, such as ethyl glyoxylate by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 31(1), pp. 230-243, 1988, in the presence of a base such as lithium hexamethyldisiladide, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate using a solvent which is inactive to the reaction, such as tetrahydrofuran, N,N-dimethylformamide, dioxane, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature. The resulting alcoholic compound (iv-a) wherein R2 represents hydrogen can be protected in any step described hereafter by techniques which are well-known or described here (see Greene, T. W., et. al.. Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups ( 1994), Thieme), to be, for example, alcoxy groups or ester groups.
<step 4- 1 >
Protective groups of a compound represented by formula (iv-a) can be introduced and removed between (iv-a) and (iv-b) by techniques which are well-known or described here (see Greene, T. W., et. al., Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups ( 1994), Thieme). <step 4-2>
A compound represented by formula (v-a) can be produced by the same process as that used in <Step l-6> of (Reaction Scheme 1) using a compound represented by formula (iv-a) or (iv-c).
<step 4-3>
A compound represented by formula (v-c) can be produced by allowing a compound represented by formula (iv-a) to react with a compound represented by formula (v-b) by a process similar to that described in published documents, for example, Organic synthesis IV, Acids, amino acids, and peptides, pp. 191-309, 1992, Maruzen Co., Ltd., in the presence of a condensing agent, in a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, in the presence or absence of a base such as triethylamine or pyridine at a temperature in the range of 0°C to the solvent-reflux temperature.
<step 4-4>
A compound represented by formula (iv-c) can be produced by a process similar to that described in published documents, for example, Organic synthesis, Collective Vol. 7, pp.221, 1990, Organic synthesis , Collective Vol. 7, pp.530, 1990, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Reduction by borane, hydrazine or diimide pp 237-248, using a compound represented by formula (iv-a) in the presence of borane-THF complex, borane -diethyl ether complex, borane-dimethyl sulfide complex, hydradine or hydroxylamine using a solvent such as an ethereal solvent, e.g., diethyl ether or tetrahydrofuran at a temperature in the range of -78°C to the solvent-reflux temperature.
<step 5-l>
A compound represented by formula (v-c) can be produced by allowing a compound represented by formula (v-a) to react with a compound represented by formula (v-b) by a process similar to that described in published documents, for example, Organic synthesis IV, Acids, amino acids, and peptides, pp. 191-309, 1992, Maruzen Co., Ltd., in the presence of a condensing agent such as
1 ,3-dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3'-dimethylaminopropyl)carbodiirnide hydrochloride (WSC-HCl), benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), 2-chloro- l ,3-dimethylimidazolinium hexafluorophosphate (CIP), or
4-(4,6-dimethoxy- 1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, in a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, a polar solvent, e.g.,
N,N-dimethylformamide, or an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, in the presence or absence of a base such as triethylamine or pyridine at a temperature in the range of 0°C to the solvent-reflux temperature. When a compound represented by formula (v-a) is converted to an acid halide, a compound represented by formula (v-c) can be similarly produced by conducting a reaction by a process similar to that described in, for example, Organic synthesis IV, Acids, amino acids, and peptides, pp. 144-146, 1992, Maruzen Co., Ltd., in the presence of a base such as triethylamine or pyridine in a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a polar solvent, e.g., N,N-dimethylformamide at a temperature in the range of 0°C to the solvent-reflux temperature.
Alternatively, a compound represented by formula (v-c) can be produced by using triphosgene by a process similar to that described in published documents, for example, Letters in Organic Chemistry, 4, 20-22, 2007, in the presence of a base such as triethyl amine using a solvent which is inactive to the reaction, such as
tetrahydrofuran, N,N-dimethylformamide, dioxane, CH2C12 or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
<step 5-2> Protective groups of a compound represented by formula (v-c) can be introduced and removed between (v-c) and (v-d) by techniques which are well-known or described here (see Greene, T. W., et. al., Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups (1994), Thieme).
Scheme 3 Synthetic route of Example compounds and combination compounds.
(iv-a) (viii-a) (vιi-a)
Figure imgf000073_0001
G represents O, S, NH, or CH2 in the Scheme 3 (Reaction scheme 3)
<step 6- l>
A compound represented by formula (vi-d) can be produced by the similar process as that used in <Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (v-a). <step 6-2>
A compound represented by formula (vii-a) can be produced by allowing a compound represented by formula (vi-a) to react with by a process similar to that described in published documents, for example, Synthetic Communications, 37(24), 2007, in the presence of an acid such as acetic acid, trifluoroacetic acid or
p-toluenesulfonic acid using a solvent such as acetic acid, trifluoroacetic acid, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
<step 6-3>
Alternately, a compound represented by formula (vii-a) can be produced by the similar process as that used in <Step 3-l> of (Reaction Scheme 2) using a compound represented by formula (iii-a) and a compound represented by formula (vi-b).
<step 6-4>
Alternatively, a compound represented by formula (vii-a) can be produced by a process similar to that described in published documents, for example, Bioorganic & Medicinal Chemistry Letters, 17(14), 2007, 3860 using a compound represented by formula (vi-d) and a compound represented by formula (vi-c), wherein Ra represents a suitable substituent..
<step 6-5>
Protective groups of a compound represented by formula (vi-a) can be introduced and removed between (vii-a) and (vii-b) by techniques which are
well-known or described here (see Greene, T.W., et. al., Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups (1994), Thieme).
<step 7-l > A compound represented by formula (viii-a) can be produced by allowing a compound represented by formula (iv-a) to react with by a process similar to that described in published documents, for example, Organic synthesis , Collective VoI 1, pp.238, 1941, Maruzen Co., Ltd, in the presence of a base such as sodium ethoxide using a solvent such as ethanol at a temperature in the range of room temperature to the solvent-reflux temperature.
Ra of the formula (vi-c) represents a suitable substituent or leaving group of Ll to L4 described above.
<step 7-2>
A compound represented by formula (vii-a) can be produced by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 48, 14, pp4541 , 2005, using a compound represented by formula (viii-a) in the presence of hydradine or hydroxylamine using a solvent such as ethanol at a temperature in the range of room temperature to the solvent-reflux temperature.
Furthermore, in the case of some of the compounds according to the invention the possibility arises of employing diastereomerically or enantiomerically pure starting products for the preparation of the ring structures. By this means, other or simplified processes can be employed for the purification of the final products. These starting products were prepared beforehand in enantiomerically or diastereomerically pure form according to processes known from the literature. This can mean, in particular, that in the synthesis of the scaffold structures either enantioselective processes are used, or else an enantiomeric (or diastereomeric) separation is carried out at an earlier stage of the synthesis and not only at the stage of the final products. Likewise, a simplification of the separations can be achieved by proceeding in two or more stages. Scheme 4 Synthetic route of intermediate compounds (viii-d)
Figure imgf000076_0001
(Reaction scheme 4)
<steρ 8- 1 >
A compound represented by formula (viii-b) can be produced from (viii-a) by conducting a reaction using the compound represented by formula (viii-a) by a process similar to that described in published documents, for example, Jikken Kagaku Koza {Experimental Chemistry Series), 4th edition, 26, Organic synthesis VIII, Asymmetric synthesis, reduction, sugar, and labeled compound, pp. 159-266, 1992, Maruzen Co., Ltd., in the presence of a catalyst such as palladium-carbon (Pd-C), Raney-Ni, platinum oxide (PtO2), or dichloro triphenyl phosphine ruthenium, under hydrogen atmosphere, using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, an ethereal solvent, e.g., diethyl ether or
tetrahydrofuran, 1 ,2-dimethoxyethane, or 1,4-dioxane, a polar solvent, e.g., ethyl acetate or methyl acetate, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
Alternatively, a compound represented by formula (viii-b) can be produced from (viii-a) by using Fe, or Sn, in hydrochloric acid or acetic acid, at a temperature in the range of O°C to the solvent-reflux temperature. Furthermore, a compound represented by formula (viii-b) can also be produced from (viii-a) by using sodium borohydride in the presence of Lewis Acid, e.g., Nickel(II)chloride (NiCh), Tin(Il)chloride (SnCh) using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, an ethereal solvent, e.g., diethyl ether or
tetrahydrofuran, 1 ,2-dimethoxyethane, or 1,4-dioxane, or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature.
<step 8-2>
A compound represented by formula (viii-d) can be produced by conducting a reaction using a compound represented by formula (viii-b) by a process of reductive amination. After a compound represented by formula (viii-c) is converted to an imine with a suitable amine (viii-b) using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature, a compound represented by formula (viii-d) can be produced by a process similar to that described in published documents, for example, Journal of Medical Chemistry, 23(12), pp. 1405-1410, 1980 in the presence of a reductive reagent such as sodium borohydride or sodium triacetoxy borohydride in the presence of acid such as acetyl alcohol, using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene or a mixed solvent thereof at a
temperature in the range of 0°C to the solvent-reflux temperature.
Alternatively, hydrogen gas can be used to hydrogenate an imine with a suitable process similar to that described in published documents, for example, Jikken Kagaku Koza {Experimental Chemistry Series), 4th edition, 26, Asymmetric synthesis, reduction, sugar, and labeled compound, pp. 25 i -266, 1992, Maruzen Co., Ltd., in the presence of a catalyst such as palladium-carbon (Pd-C), Raney-Ni, or platinum oxide (PtO>) in a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, a polar solvent, e.g., ethyl acetate or acetonitrile, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or an acid solvent, e.g., acetic acid at a temperature in the range of room temperature to the solvent-reflux temperature, thereby producing a compound represented by formula (viii-d).
<step 8-3>
A compound represented by formula (viii-f) can be produced by the similar process as that used in <Step 5- 1 > of (Reaction Scheme 2) using a compound represented by formula (viii-e).
<step 8-4>
A compound represented by formula (viii-d) can be produced by a process similar to that described in published documents, for example, Jikken Kagaku Koza {Experimental Chemistry Series), 4th edition, 26, Reduction by borane, hydrazine or diimide pp 237-248, using a compound represented by formula (viii-f) in the presence of hydradine or hydroxylamine using a solvent such as ethanol at a temperature in the range of room temperature to the solvent-reflux temperature.
Scheme 5 Synthetic route of optically active compounds (x-b)
Figure imgf000079_0001
Figure imgf000079_0002
(Reaction scheme 5)
<step 9- 1 >
A compound represented by formula (ix-b) can be produced by conducting a reaction using (2R, J/?j-2,3-diacetoxysuccinic anhydride represented by formula (ix-a) in the presence of amine (v-b) by a process similar to that described in published documents, for example, Organic Synthesis, Collective Vol.3, pp.169 1955, using a solvent which is inactive to the reaction, such as tetrahy drofuran, N,
N-dimethylformarnide, dioxane, CH2C12 or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
<step 9-2>
A compound represented by formula (x-a) can be produced by allowing a compound represented by formula (ix-b) to react with a compound represented by formula (viii-d) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Acids, amino acids, and peptides, pp. 193-309, 1992, Maruzen Co., Ltd., in the presence of a condensing agent such as 1,3-dicyclohexylcarbodiimide (DCC),
1 -ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSC HCl), benzotriazol- 1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl),
2-chloro- 1,3-dimethyIimidazolinium hexafluorophosphate (CIP), or
4-(4,6-dimethoxy- 1 ,3,5-triazin-2-yl)-4-methylmorpholiniurn chloride, in a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, a polar solvent, e.g.,
N,N-dimethylforτnamide, or an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, in the presence or absence of a base such as triethylarnine or pyridine at a temperature in the range of -78°C to the solvent-reflux temperature. When a compound represented by formula (ix-b) is converted to an acid halide, a compound represented by formula (x-a) can be similarly produced by conducting a reaction by a process similar to that described in, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Acids, amino acids, and peptides, pp. 144-146, 1992, Maruzen Co., Ltd., in the presence of a base such as triethylamine or pyridine in a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g.. diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a polar solvent, e.g., N,N-dimethylformamide at a temperature in the range of -IS0C to the solvent-reflux temperature. Alternatively, a compound represented by formula (x-a) can be produced by using triphosgene with (ix-b) by a process similar to that described in published documents, for example, Letters in Organic Chemistry, 4, 20-22, 2007, in the presence of a base such as triethyl amine using a solvent which is inactive to the reaction, such as tetrahydrofuran, N,N-dimethylformamide, dioxane, CH2C12 or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
<step 9-3>
A compound represented by formula (ix-c) , wherein R represents hydrogen or Cl -6 alkyl group, can be produced by conducting a reaction using
(2R, 3i?)-2,3-diacetoxysuccinie anhydride represented by formula (ix-a) in the presence of suitable alcoholic solvent by a process similar to that described in published documents, for example, Organic Synthesis, Collective Vol.3, pp.169 1955, using a solvent, such as an alcoholic solvent, e.g., benzyl alcohol, tert-buthyl alcohol, methanol, ethanol, 2-propanol, or tetrahydrofuran, N, N-dimethylformamide, dioxane, CH2C12 or a mixed solvent thereof in the presence of DMAP at a temperature in the range of 0°C to the solvent-reflux temperature.
<step 9-4>
A compound represented by formula (ix-d) can be produced by the same process as that used in <Step 9-2> of (Reaction Scheme 5) using a compound represented by formula (ix-c).
<step 9-5>
A compound represented by formula (ix-d) wherein R represents hydrogen atom can be produced by allowing (2R, Ji?)-2,3-diacetoxysuccinic anhydride
represented by formula (ix-a) to react with a compound represented by formula (viii-d) by a process similar to that described in published documents, for example, Organic Synthesis, Collective Vol.3, pp.169 1955, Organic Synthesis, Collective Vol.5, pp.944, 1973, VoIAl, 93, 1961, or J 'ikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Acids, amino acids, and peptides, pp. 146-148, 1992, Maruzen Co., Ltd., using a solvent, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, a polar solvent, e.g., DMF, ethyl acetate or acetonitrile, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or an acid solvent, e.g., acetic acid or a mixed solvent thereof in the presence of DMAP, Pyridine or sulfuric acid as a catalyst if needed at a temperature in the range of O°C to the solvent-reflux temperature.
<step 9-6>
A compound represented by formula (x-a) can also be produced by the same process as that used in <Step 4-3> of (Reaction Scheme 2) using a compound represented by formula (ix-d) wherein R represents C 1-6 alkyl group in the presence of amine (v-b), and also be produced by the same process as that used in <step 5- 1> of (Reaction scheme 2) or <step 13-3> and <step 13-4> of (Reaction scheme 11) using a compound represented by formula (ix-d) wherein R represents hydrogen atom, in the presence of amine (v-b).
Protective groups of a compound in the process of producing a compound represented by formula (x-a) can be introduced and removed by techniques which are well-known or described here (see Greene, T. W., et. al., Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups (1994), Thieme).
<step 9-1 > A compound represented by formula (ix-e) can be produced by allowing a compound represented by formula (ix-d) to react with a compound represented by formula (ix-g) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 1-82, 1992, Maruzen Co., Ltd., in the presence of an acidic reagent such as hydrochloric acid, sulfuric acid, thionyl chloride, or acetyl chloride, using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, dioxane, or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of -78°C to the room temperature.
<step 9-8>
A compound represented by formula (ix-d) can be produced by conducting a reaction using a compound represented by formula (ix-e) by a process similar to that described in published documents, for example, Can. J. Chem., 49, 493 (1971) or Greene, T. W., et. al.. Protective Groups in Organic Synthesis (2007), 4th Ed., in the presence of ammonia, using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, dioxane, or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of -78°C to the room temperature.
<step 10- l>
A compound represented by formula (x-b) can be produced by the similar process as that used in <Step 9-8> of (Reaction Scheme 6) using a compound represented by formula (x-a). Protective groups of a compound in the process of producing a compound represented by formula (x-b) can be introduced and removed by techniques which are well-known or described here (see Greene, T. W., et. ah, Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups (1994), Thieme).
Scheme 6 Synthetic route of optically active compounds (x-c) and (x-e) lW
Figure imgf000084_0001
(Reaction scheme 6)
<step 10-2>
A compound represented by formula (x-c) can be produced by allowing a compound represented by formula (x-b) by a process similar to that described in published documents, for example, Organic Synthesis, Collective Vol.6, pp.301, 395, 1988, or Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 20, alcohol and amine, pp. 187- 194, 1992, Maruzen Co., Ltd., in the presence of a base such as potassium tert-buthoxide, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, tert-buthanol, or a polar solvent, e.g., DMF, DMSO, ethyl acetate, or acetonitril, or an aromatic hydrocarbon solvent, e.g., toluene or benzene, or acetone, dioxane or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature.
<step 10-3>
Protective groups of a compound represented by formula (x-c) can be introduced and removed by techniques which are well-known or described here (see Greene, T. W., et. al., Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups (1994), Thieme).
<step 10-4>
When R4' is used as a precursor for R4 representing 4-amidino-phenyl group or its analogue, R4' represents 4-cyano-phenyl group or 1,2,4-oxadiazol-5-one-3-yl phenyl group or their analogues, which can be converted to 4-amidino-phenyl group R4 or its analogue by techniques which are well-known or described:
Scheme 7
Figure imgf000085_0001
(xι-a) (xι-b)
G represents O, S, NH, or CH2 , and
M represents independently CH or N, and n represents 1 to 4 in the Scheme 7
(Reaction scheme 7) <step 10-4a>
When R4' of a compound represented by formula (x-c) of Scheme 6 represents 4-cyano-(aryl or heteroaryl) group or its analogue wherein 4-cyano-(aryl or heteroaryl) ring is optionally substituted with one to four Y, a compound represented by formula (xi-a) which corresponds to a compound (x-c) can be converted to a compound represented by formula (xi-b) via its imidate compound.
4-cyano-(aryl or heteroaryl) group or, R4' of a compound represented by formula (xi-a), can be converted to its imidate by allowing a compound represented by formula (xi-a) to acidic condition such as HCl gas solution of, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g.,
dichloromethane or chloroform, or a mixed solvent thereof at a temperature in the range of O°C to the room temperature.
Resulting imidate compound is converted to 4-amidino-(aryl or heteroaryl) compound (xi-b) or its analogue by conducting an imidate compound to ammonium or ammonium carbonate alcoholic solvent, e.g. methanol, ethanol, tert-buthanol or in a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature in a sealed tube.
Alternatively, when R4' represents 4-cyano-(aryl or heteroaryl) group or its analogue wherein 4-cyano-(aryl or heteroaryl) is optionally substituted with one to four Y, a compound represented by formula (xi-a) can be converted to 4-amidino-(aryl or heteroaryl) group R4 via its N-hydroxy amidine compound.
4-cyano group, R4' of a compound represented by formula (xi-a), can be converted to its N-hydroxy amidino group by allowing a compound (xi-a) in the presence of a base such as triethyl amine, hunig base, potassium ferr-buthoxide, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate using a solvent which is inactive to the reaction, such as water, methanol, ethanol, acetone, N,N-dimethylformarnide, dioxane or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of O°C to the solvent-reflux temperature in a sealed tube.
Resulting N-hydroxy amidino group can be converted to its amidine compound represented by formula (xi-b) by a suitable process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Asymmetric synthesis, reduction, sugar, and labeled compound, pp. 251-266, 1992, Maruzen Co., Ltd., in the presence of a catalyst such as
palladium-carbon (Pd-C), Raney-Ni, or platinum oxide (Ptθ2) in a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichlorome thane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, a polar solvent, e.g., ethyl acetate or acetonitrile, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or an acid solvent, e.g., acetic acid or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
Scheme 8
Figure imgf000087_0001
(Xi-C) (xi-d)
G represents O, S, NH, or CH2 , and
M represents independently CH or N, and n represents 1 to 4 in the Scheme 8
(Reaction scheme 8)
<step 10-4b> When R4' is used as a precursor for R4 representing 4-amidino-(aryl or heteroaryl) group or its analogue wherein 4-amidino-(aryl or heteroaryl) group is optionally substituted with one to four Y, R4' also represents 1,2,4-oxadiazol-5-one-3-yl (aryl or heteroaryl) group or its analogues wherein phenyl group is optionally
5 substituted with one to four Y, which can be converted to 4-amidino-(aryl or heteroaryl) group R4 by techniques which are well-known or described here.
A compound represented by formula (xi-d) can be produced by the same process as that used in <Step 8-l> of (Reaction Scheme 4) using a compound represented by formula (xi-c).
10 When G in the formula (xi-c) represents sulfur atom, sulfur can be oxidized to its sulfone or sulfoxide with Oxone® by a process similar to that described in published documents, for example, Shin-Jikken Kagaku Kouza, Vol. 14- 111, pi 759, R. J. Kennedy, J. Org. Chem., 25, 1901 (1960), BM. Trost, Tetrahedron Lett., 22, 1287(1981), in the presence of Oxone® using a solvent which is inactive to the reaction, such as water, or
15 an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, dioxane, or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature.
Scheme 9
Figure imgf000088_0001
(xi-e) (xi-f)
,,Q G represents O, S, NH, or CH2 in the Scheme 9
(Reaction scheme 9)
<step 1 1 - 1 > When Rl in the Formula (I) represents biaryl groups optionally substituted with one to four Y, such as, for example, 4-thienyl phenyl group or 4-phenyl phenyl group, a compound represented by formula (xi-f) can be produced by conducting a reaction using a compound represented by formula (xi-e) by a process of
Suzuki-Miyaura coupling similar to that described in published documents, for example, Miyaura, N, et.al., Tetrahedron Lett, 1979, 3437, J. Chetn. Soc. Chem. Commun., 1979, 866, Chem. Rev. 1995, 95, 2457, in the presence of catalyst such as palladium-carbon (Pd-C), Raney-Ni, or platinum oxide (Ptθ2), and in the presence of a base such as potassium ferr-buthoxide, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate with a corresponding arylboronic acid using a solvent which is inactive to the reaction, such as water, acetone, toluene, dioxane or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature. Scheme 10
Figure imgf000089_0001
(Reaction scheme 10)
<step 12-1>
When R4 represents l-imino-2,3-dihydroisoindoi-5-yl group, or its heteroaryl analogue wherein M represents nitrogen atom, are optionally substituted with one to four Y, which is shown as a partial structure of a compound represented by formula (xii-b) in Scheme 10 or its analogue, a compound represented by formula (xii-b) can be produced from a compound represented by formula (xii-a) which is identical to the comound represented by formula (ix-d) in the Scheme 5, wherein its R is hydrogen atom, and from a compound 39-2 (N-[(5-Amino-2-cyanophenyl)-methyl]-N- [(2-methylpropan-2-yl) oxycarbonyl] carbamate) which is described in Experimental section 39. A compound represented by formula (ix-d) is converted to its analogous compound of 39-3 in the Example 39 procedure similar to that used in <Step 5-l> of (Reaction Scheme 2), which is followed by the conversion to compounds analogous to compounds 39-4, 39-5 and 39-6 by a process similar to that used in <Step 10-l> of (Reaction Scheme 5), <Step 10-2> of (Reaction Scheme 6) and deprotection of Boc group by a process similar to that used in the Experimental section Example 38-6 or by techniques which are well-known or described here (see Greene, T. W., et. al.,
Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups ( 1994), Thieme). A compound represented by formula (xii-b) can be produced with resulting amine compound analogous to the compound 39-6 by a process similar to that described in the Experimental section 39 [step 39-7] using alcoholic solvent, other solvent or a mixed solvent thereof at a temperature in the range of room temperature to the sol vent- reflux temperature.
Scheme 1 1 Alternative synthetic route of optically active compounds (xiii-f) subset of compounds (x-e)
Figure imgf000091_0001
(Reaction scheme 11 )
<step 13-1>
A compound represented by formula (ix-d) can be produced by the similar process as that used in <Step 5-l> of (Reaction Scheme 2) using compounds represented by formula (viii-d) and represented by formula (ix-c). When R represents ferz-butyl group, a compound represented by formula (ix-c) could be prepared by a similar process that described in published document, for example, Tetrahedron, 45, 3071 -3080, 1989.
<step 13-2>
A compound represented by formula (xiii-a) can be produced by the similar process as that used in <Step 10- 1> of (Reaction Scheme 5) using a compound represented by formula (ix-d), and followed by the similar process as that used in <step 10- 2> of (Reaction Scheme 6) using the resulting alcoholic compound from a compound represented by formula (ix-d).
<step 13-3>
A compound represented by formula (xiii-b) can be produced from a compound represented by formula (xiii-a) by a well-known or similar process that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 1-43, 1992, Maruzen Co., Ltd., in the presence of inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, hemisulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4-bromobenzenesulfonic, cyciohexylarnidosulfonic, trifluoromethylsulfonic, 2-hydroxyethanesulfonic, acetic, oxalic, tartaric, succinic, glycerol phosphoric, lactic, malic, adipic, citric, fumaric, maleic, gluconic, glucuronic, palmitic or trifluoroacetic acid using water and a solvent which is inactive to the reaction, such as methanol, ethanol, 2-propanol,
N.N-dimethylformamide, dioxane, or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of O°C to the solvent-reflux temperature.
<step 13-4> and <step 13-5>
A compound represented by formula (xiii-d) can be produced by the similar process as that used in <Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (xiii-b) via its intermediate represented by formula (xiii-c), with a compound represented by formula (v-b).
<step 13-6>
Protective groups of a compound represented by formula (xiii-d) can be introduced and removed between (xiii-d) and (xiii-e) by techniques which are well-known or described here (see Greene, T. W., et. aL, Protective Groups in Organic Synthesis (2007), 4th Ed.. Wiley, New York, or Kocienski, P., Protecting Groups ( 1994), Thieme).
<step 13-7>
A compound represented by formula (xϊή-f), which is identical to the compound represented by formula (x-e) in Scheme 6 wherein m is 1 and R is hydrogen atom, can be produced by a similar process as that used in <Step 10-4> of (Reaction Scheme 6) using a compound represented by formula (xiii-d).
Scheme 12 Synthetic route of Rl aniline derivative compounds (xiv-b), (xiv-c). and (xiv-d) from aniline analogue compound represented by formula (xiv-a)
Figure imgf000093_0001
( Reaction scheme 12) <step 14- 1>
A compound represented by formula (xiv-b) can be produced by the similar process as that used in <Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (xiv-a).
<step 14-2>
A compound represented by formula (xiv-c) can be produced by the similar process as that used in <Step 10-4> of (Reaction Scheme 6) using a compound represented by formula (xiv-b).
<step 14-3>
A compound represented by formula (xiv-d) can be produced by the similar process as that used in <Step 5- 1 > of (Reaction Scheme 2) using a compound represented by formula (xiv-a) and corresponding sulfonyl halide such as sulfonyl chloride reagent.
<step 14-4>
A compound represented by formula (xiv-e) can be produced by the similar process as that used in <Step 10-4> of (Reaction Scheme 6) using a compound represented by formula (xiv-d).
<steρ 14-5>
A compound represented by formula (xiv-f) wherein each M represents independently oxygen atom, nitrogen atom or carbon atom, can be produced with step by step cyclization process as that used in <Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (xiv-a) and a compound represented by formula
(xiv-i) denoting acid halide or acid reagent wherein X represents halogen or hydroxyl group, such as 2-chloroethoxy acetic acid.
<step l4-6> The resulting compound represented by formula (xiv-f) can be cyclized to produce a compound represented by formula (xiv-g) by the same prosess as that used in <Step tO-2> of (Reaction Scheme 6).
<step 14~7>
A compound represented by formula (xiv-g) can be produced by the similar process as that used in <Step 10-4> of (Reaction Scheme 6) using a compound represented by formula (xiv-f).
Scheme 13 Alternative synthetic route of optically active compounds represented by a formula (xv-f) which is a subset of compounds represented by a formula (x-e) via key intermediate compound represented by formula (xv-b).
(xv
Figure imgf000095_0001
(Reaction scheme 13) <step 15- 1 >
A compound represented by formula (xv-a) can be produced by the similar process as that used in <Step 10-2> of (Reaction Scheme 6) using a compound represented by formula (ix-f) in the Scheme 5.
<step 15-2>
A compound represented by formula (xv-b), a key intermediate to produce compounds represented by formula (xv-f) which corresponds to the compounds represented by Formula (I), can be produced by deprotection of the compound represented by formula (xv-a) using CAN (eerie ammonium nitrate) using a solvent which is inactive to the reaction, such as a polar solvent, e.g., DMF, DMSO, ethyl acetate, water, or acetonitril, or an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 1,4-dioxane, or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature, or by techniques which are well-known or described here (see Greene, T. W., et. al., Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups ( 1994), Thieme). <step 15-3>
A compound represented by formula (xv-c) can be produced by allowing a key intermediate compound represented by formula (xv-b) to react with a compound represented by R 1 -X (aryl halide or heteroaryl halide, wherein X represents halogen atom) by a process known as Goldberg reaction which are similar to that described in published documents, for example, JACS, 2002, 124, 7421 in the presence of a base such as potassium phosphate, cesium carbonate, potassium terϊ-buthoxide, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate in the presence of 1,2-diamine ligand such as trans- 1 ,2-cyclohexanediamine, trans-N,N'-dimethylcyclohexane- 1,2-diamine, or ethylene diamine, and in the presence of catalytic amount of cupper iodide using a solvent which is inactive to the reaction, such as an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, polar solvents such as DMF, and DMSO; or an aromatic hydrocarbon solvent, e.g., toluene or benzene or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
<step 15-4>
A compound represented by formula (xv-c) can be produced by allowing a compound represented by formula (xv-b) to react with acetic anhydride by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 191-309, 1992, Maruzen Co., Ltd., and resulting acetylated alcohol comound can be hydrolyzed by the similar process as that used in <Step 4-2> of (Reaction Scheme 2).
<step 15-5>
A compound represented by formula (xv-e) can be produced by the similar process as that used in <Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (xv-d) in the Scheme 13 and a compound represented by formula (v-b).
<step 15-6>
A compound represented by formula (xv-f) can be produced by a similar process as that used in <Step 10-4> of (Reaction Scheme 6) using a compound represented by formula (xv-e).
Scheme 14 Alternative synthetic route of compounds (xvi-h) identical to the compound represented Formula (I) wherein G represents nitrogen group.
Figure imgf000098_0001
(Reaction scheme 14)
<step 16-1>
A compound represented by formula (xvi-a) are commercially available, or capable of being readily synthesized by the method as identical to the route descrived in Scheme 1 to synthesize a compound represented by formula (ii-b), or commonly used in the organic chemistry from commercially available products.
A compound represented by formula (xvi-b) can be produced by the similar process as that used in <Step 2-3> of (Reaction Scheme 1 ) using a compound represented by formula (xvi-a) in the Scheme 14.
<step 16-2>
A compound represented by formula (xvi-c) can be produced by a similar process as that used in <Step 2-2> of (Reaction Scheme 1 ) using a compound represented by formula (xvi-b) in the Scheme 14.
<step 16-3>
A compound represented by formula (xvi-d) can be produced by the similar 5 process as that used in <Step 3-l> of (Reaction Scheme 2) using a compound
represented by formula (xvi-c) in the Scheme 14.
<step 16-4>
A compound represented by formula (xvi-e) can be produced by a similar process as that used in <Step 2-2> of (Reaction Scheme 1 ) using a compound 10 represented by formula (xvi-d) in the Scheme 14.
<step 16-5>
A compound represented by formula (xvi-f) can be produced by the similar process as that used in <Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (xvi-e) in the Scheme 14 when R5 represents acyl group such 15 as, for example, acetyl group or benzyl group.
<step 16-6>
A compound represented by formula (xvi-g) can be produced by a similar process as that used in <Step l-6> of (Reaction Scheme 1) using a compound represented by formula (xvi-f) in the Scheme 14.
20 <step 16-7>
A compound represented by formula (xvi-h) can be produced by a similar process as that used in <Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (xvi-g) in the Scheme 14.
<step 16-8>
ZX) A compound represented by formula (xvi-i) can be produced by a similar process as that used in <Step 5-2> of (Reaction Scheme 2) using a compound represented by formula (xvi-h) in the Scheme 14.
Scheme 15 Alternative synthetic route of morpholine compounds.
(XV! (XVIl-C)
<step 17-3>
I ♦
Figure imgf000100_0001
<step IT-I >
A compound represented by formula (xvii-b) can be produced by allowing a compound represented by formula (xvii-a) to react with TMSCN(trimethylsilyl cyanide) by a process similar to that described in published documents, for example, Organic synthesis Collective Vol. 1, pp.336 (1941), Collective Vol. 2, pp.7 (1943), Colletive Vol. 7, pp.521 ( 1990) using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, or a mixed solvent thereof at a temperature in the range of -78 °C to the solvent-reflux temperature. Pi- 3 represents typically a benzyl group and deprotection of benzyl group can be reductive deprotection by a similar process of <step 8- 1>.
<step 17-2>
A compound represented by formula (xvii-c) can be produced by allowing a compound represented by formula (xvii-b) by a process similar to that described in published documents, for example, Organic synthesis Collective Vol. 1, pp.270 (1941),
Collective Vol. 2, pp.310 (1943) in the presence of concentrated HCl using a solvent such as an alcoholic solvent containing hydrogen chloride, e.g., methanol-HCl, ethanol-HCl, or a mixed solvent thereof at a temperature in the range of 0°C to the solvent-reflux temperature.
<step 17-3>
Protective groups of a compound represented by formula (xvii-c) can be introduced and removed by techniques which are well-known or described here (see
Greene, T. W., et. al., Protective Groups in Organic Synthesis (2007), 4th Ed., Wiley, New York, or Kocienski, P., Protecting Groups ( 1994), Thieme).
<step 17-4>
A compound represented by formula (xvii-e) can be produced by the same process as that used in <Step 4-3> of (Reaction Scheme 2) using a compound represented by formula (xvii-c) and a compound represented by formula (v-b).
<step 17-5>
A compound represented by formula (xvii-g) can be produced by a similar process as that used in <Step 1 -6> of (Reaction Scheme 1 ) using a compound represented by formula (xvii-c) in the Scheme 15.
<step l7-6>
A compound represented by formula (xvii-e) can be produced by the same process as that used in <Step 5-l> of (Reaction Scheme 2) using a compound represented by formula (xvii-g) and a compound represented by formula (v-b).
<step 17-7>
A compound represented by formula (xvii-f) can be produced by the same process as that used in <step 14-1> or <step 14-3> of (Reaction Scheme 12), or <step 15-3> of (Reaction Scheme 13) using a compound represented by formula (xvii-f)- <step 17-8>
A compound represented by formula (xvii-h) can be produced by a similar process as that used in <Step 10-4> of (Reaction Scheme 6) using a compound represented by formula (xvii-g).
(5, S), (R,S) and (S, R) forms of compounds represented by Formula (I) can also be made from corresponding starting materials. The required starting materials for the synthesis of (S, S), (R,S) and (S,R) isoforms of compound (ix-a) are either commercially available, or capable of being readily synthesized by the method commonly used in the organic chemistry from commercially available products.
Acidic or basic products of the compound of the Formula (I) can be present in the form of their salts or in free form. Pharmacologically acceptable salts are preferred, for example alkali metal or alkaline earth metal salts such as hydrochlorides, hydrobromides, sulfates, hemisulfates, all possible phosphates, and salts of the amino acids, natural bases or carboxylic acids.
The preparation of pharmacologically acceptable salts from compounds of the Formula (I) capable of salt formation, including their stereoisomeric forms is carried out in a manner known per se. With basic reagents such as hydroxides, carbonates, hydrogencarbonates alkoxides and ammonia or organic bases for example trimethyl- or tr mol or alternatively basic amino acids, for example lysine, ornithine or arginine, the compounds of the Formula (I) form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts. If the compounds of the Formula (I) have basic groups, stable acid addition salts can also be prepared using strong acids. For this, inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, hemisulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic,
4-bromobenzenesulfonic, cyclohexylamidosulfonic, trifluoromethylsulfonic,
2-hydroxyethanesulfonic, acetic, oxalic, tartaric, succinic, glycerolphosphoric, lactic, malic, adipic, citric, fumaric, maleic, gluconic, glucuronic, palmitic or trifluoroacetic acid are suitable.
REFERENCE EXAMPLES
(EXAMPLE 1)
Synthesis of N-( 1 -aminoisoquinolm-6-yl)-2-hydroxy-2-(3-oxo-4-p-tolylmorpholin- 2-yl)acetamide trifluoroacetate
Figure imgf000103_0001
[Step 1-1] Synthesis of ethyl 2-hydroxy-2-(3-oxo-4-p-tolylrnorpholin-2-yl)acetate (compound 1-1 (LP) and compound 1-1 (MP))
nicheskoi Khimii, 6(6), 1305-8, 7970) (1.08 g) in THF (21.6 ml), was added 1 M lithium hexamethyldisilazide solution (7.34 ml) in THF at -78 C. The mixture was stirred at -78 °C for 15 minutes then 0 °C for 1 hour. Then the reaction mixture was cooled down at -78 °C and ethyl glyoxylate solution (1.84 ml) in toluene was added into the reaction mixture. The reaction mixture was stirred at 0 °C overnight. At the end of the reaction, saturated NH4Cl aqueous solution was added into the reaction mixture. The mixture was concentrated in vacuo and the resulting mixture was extracted with AcOEt. The organic layer was washed with brine and dried with anhydrous Na^SOφ The solvent was removed under reduced pressure and the resulting residue was purified by silica gel flash column chromatography (eluent: n-Hex/ AcOEt = 50/50 - 0/100) to obtain two diastereomers, compound 1-1 (LP) (405 mg; Rf value = 0.36 on TLC
(n-Hex/AcOEt=l/2)) as a pale yellow amorphous solid and 1 -1 (MP) (287 mg; Rf value = 0.27 on TLC (n-Hex/AcOEt=l/2)) as yellow oil. LP indicates a less polar spot on TLC, MP indicates a more polar spot on TLC.
[Step 1-2] Synthesis of 2-hydroxy-2-(3-oxo-4-p-tolylmorpholin-2-yl)acetic acid (compound 1-2)
To a solution of compound 1 -1 (LP) (100 mg) in EtOH (1 mL), was added 1 N NaOH aqueous solution (1 mL) at 0 "C. The reaction mixture was stirred at room temperature for 1 hour. Then DowEx®-50Wx8-200 was added into the reaction mixture, then the mixture was filtered to remove DowEx®-50Wx8-200. The filtrate was concentrated in vacuo to obtain compound 1-2 (90 mg) as a colorless amorphous solid. Compound 1-2 was used in the next step without further purification.
[Step 1-3] Synthesis of N-[N,N-bis(tert-butoxylcarbonyl)- 1 -aminoisoquinolin-6-yl]-2- hydroxy-2-(3-oxo-4-p-tolylmorpholin-2-yl)acetamide (compound 1 -3) activated-charcoal (4.5 mg) and triphosgene (403 mg) at 0 °C. The reaction mixture was stirred at room temperature for 15 hours. Then activated-charcoal was removed by filtration and the filtrate was concentrated in vacuo. The resulting residue was resolved in CH2CI2 (2 ml). 6-Amino-1-bis(tert-butoxyl carbonyl)aminoisoquinoline (146 mg) was added into the CFLoCh solution at O°C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and a half volume of the resulting residue was purified by LC/MS to obtain compound 1 -3 (30.6 mg) as a colorless amorphous solid.
[Step l-4]Synthesis of N-(l-aminoisoquinolin-6-yl)-2-hydroxy-2-(3-oxo-4-p- tolylmorpholin-2-yl)acetamide trifluoroacetate (EXAMPLE 1)
To a solution of compound 1-3 (30.6 mg) in CH2CI2 (1.5 ml), was added trifluoroacetic acid (0.5 ml) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour and the mixture was concentrated in vacuo. To the resulting residue, Et2<~) was added and the residue was triturated. Then the precipitate was collected by filtration to obtain EXAMPLE 1 (19.3 mg) as a colorless amorphous solid.
(EXAMPLE 7)
Synthesis of (2R)-N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-p-tolylmorpholin- 2-yl]acetamide hydrochloride (EXAMPLE 7)
7-5
Figure imgf000106_0001
[Step 7- 1 J Synthesis of N-(2-chloroethyl)-4-methylaniline (compound 7-1)
To a solution of 4-methylaniline (100 mg) in MeOH (2.0 mL) was added 40% chroloacetaldehyde solution in water (0.17 mL) at O °C. The mixture was stirred for 45 minutes at the same temperature, sodium borohydride (NaBHU ; 70.6 mg) was added into the reaction mixture at one portion and the mixture was stirred for 1 hour.
The reaction mixture was diluted with water and was extracted with EtOAc. The extract was washed with water, sat.NaHC03 and brine. The organic layer was dried with anhyd. NaaSOφ It was filtrated to remove insoluble matters and it was concentrated in vacuo. The residue was purified by silica gel flush chromatography (elue n oil. [Step 7-2] Synthesis of (2R,3R)-2,3-diacetyloxy-4-(4-cyanoanilino)-4-oxobutanoic acid (compound 7-2)
To a solution of (+)-Diacetyl-L-tartaric anhydride (9.15 g) in dry DMF (100 mL), was added 4-aminobenzonitrile (5 g,) under ice cooling and the reaction mixture was stirred to obtain compound 7-2 at room temperature overnight. The solution of compound 7-2 was used in the next step without any treatment.
[Step 7-3] Synthesis of [(2R,3R)-3-acetyloxy-1-[N-(2-chloroethyl)-4-methylanilino]-4- (4-cyanoanilino)- 1 ,4-dioxobutan-2-ylJ acetate (compound 7-3)
The above DMF solution of 7-2 (13.8 mL) was diluted with CH2Cl2 (13.8 mL). The internal temperature of the mixture was kept below -60 °C over all additions with dry ice bath.
Oxalyl chloride (0.55 mL) in CH2CI2 (1.7 mL) was added dropwise into the reaction mixture. After stirring for 1 hour, pyridine (1.99 mL) was added dropwise thereto and stirred for 15 min. Then 7-1 (0.99 g) in CH2CI2 (6 mL) was added dropwise into the reaction mixture. The mixture was stirred below -60 °C for 20 min, then it was stirred at -30 °C for 15 hours.
The reaction mixture was quenched with water and was extracted with EtOAc. The extract was washed with water, IN HCl, sat.NaHCO.3 and brine. The organic layer was dried with anhyd. Na2SO4. It was filtrated and was concentrated in vacuo. The residue was purified by silica gel flush chromatography (eluent : Hexane : EtOAc = 75 : 25 ~ 25 : 75) to obtain 7-3 (1.70 g) as a light brown solid.
[Step 7-4] Synthesis of (2R,3R)-N-(2-chloroethyl)-N'-(4-cyanophenyl)-2,3-dihydroxy- N-p-tolylbutanediamide (compound 7-4)
To a solution of 7-3 (0.20 g) in MeOH (4 mL), was added 8N NH3 / MeOH (0.26 perature. The mixture was concentrated and was dried in vacuo to obtain crude 7-4. The crude
7-4 was used in the next step without further purification.
[Step 7-5]Synthesis of (2R)-N-(4-cyanophenyl)-2-hydroxy-2-[(2R)-3-oxo-4- p-tolylmorpholin-2-ylJacetarnide (compound 7-5)
The crude 7-4 was dissolved in t-BuOH ( 12 mL)-DMSO (8 mL), and t-BuOK
(554 mg) was added portionwise into the reaction mixture at 0 °C. The mixture was stirred for 10 minutes in the same temperature.
To the reaction mixture was added IN HCl and EtiO to obtain precipitate. Then the precipitate was collected by filtration, was rinsed with water, was washed with EtiO and was dried in vacuo to obtain 7-5 (603 mg) as a white solid.
[Step 7-6] Synthesis of (2R)-N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4- p-tolylmorpholin-2-yl]acetamide hydrochloride (EXAMPLE 7)
Compound 7-5 (27 mg) was suspended in MeOH(15 mL)-CH2θ2(7 mL). The suspension was saturated with HCl gas by bubbling at 0 °C for 0.5 hours. Then the mixture was stood to form the imidate at the same temperature overnight. The reaction mixture was concentrated and was dried in vacuo to obtain crude imidate. The crude imidate was dissolved in MeOH (10 mL), then 8N NHs-MeOH (2 mL) was added into the above MeOH solution. The reaction mixture was stirred in sealed tube at 80 C for
3 hours to convert EXAMPLE 7. The reaction mixture was stirred for 1 day at room temperature then it was concentrated in vacuo. The resulting residue was dissolved in
IN HCl-MeOH, then the mixture was purified by preparative LC/MS to obtain
EXAMPLE 7 (7 mg) as a colorless amorphous solid. (EXAMPLE 20)
(2R)-N-(4-Amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1,3-dihydrobenzimidaz ol-5-yl)morpholin-2-yl]acetamide hydrochloride (EXAMPLE 20)
Figure imgf000109_0001
δ [Step 20- 1 ] Synthesis of 2-chloro-N-(2-oxo- 1 ,3-dihydrobenzimidazol-5-yl)acetamide
20- 1
To a suspension of 5-amino-1,3-dihydro-2H-benzimidazol-2-one (1 g) and
K2CO3 ( 1.02 g) in DMF (20 mL), was added dropwise a solution of
chloroacetylchloride (0,59 mL) in DMF (10 mL) at 0 °C. The reaction mixture was 10 stirred at room temperature for 3 hours. Then the mixture was diluted with water to precipitate. The precipitate was collected by filtration, rinsed with Η?O to obtain compound 20-1 (1.2 g) as a colorless amorphous solid.
[Step 20-2] Synthesis of 5-(2-chloroethylamino)-1,3-dihydrobenzimidazol-2-one
(compound 20-2)
lδ To a suspension of compound 20-1 (1 g) in THF (10 mL), was added dropwise
IM BH3-THF complex at 0 °C. The reaction mixture was stirred at room temperature for 3 hours to complete the reaction. Then MeOH was carefully added to decompose an excess of BH3 and then cone. HCl was added at 0 °C. After stirring under reflux condition for 20 minutes, the mixture was diluted with water. It was extracted with 0 EtOAc and the organic layer was washed with brine and dried with anhyd. Na2SO4. The solvent was removed under reduced pressure to obtain compound 20-2 (0.85 g) as a colorless amorphous solid.
[Step dihydrobenzimidazol-5-yl)amino]- 1 -(4-cyanoanilino)- 1 ,4-dioxobutan-2-yl] acetate (compound 20-3)
According to the Step 7-3 in synthetic method for EXAMPLE 7, compound 20-2 (0.8 g) was used instead of compound 7-2 to obtain compound 20-3 (1.6 g) as a colorless amorphous solid.
[Step 20-4] Synthesis of (2R,3R)-N-(2-chloroethyl)-N'-(4-cyanophenyl)-2,3-dihydroxy- N-(2-oxo- 1 ,3-dihydrobenzimidazol-5-yl)butanediamide (compound 20-4)
According to the Step 7-4 in synthetic method for EXAMPLE 7, compound 20-3 (1.6 g) was used instead of compound 7-3 to obtain crude 20-4. The crude 20-4 was used in the next step without further purification.
[Step 20-5] Synthesis of (2R)-N-(4-cyanophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo- 1 ,3-dihydrobenzimidazol-5-yl)morpholin-2-yl]acetamide (compound 20-5)
According to the Step 7-5 in synthetic method for EXAMPLE 7, crude 20-4 was used instead of compound 7-4 to obtain compound 20-5 (100 mg) as a brown amorphous solid.
[Step 20-6] Synthesis of (2R)-N-(4-amidinophenyl)-2-hydroxy-2-[(2R)- 3-oxo-4-(2-oxo- l ,3-dihydrobenzimidazol-5-yl)morpholin-2-yl]acetamide
hydrochloride (EXAMPLE 20)
According to the Step 7-6 in synthetic method for EXAMPLE 7, compound 20-5 (50 mg) was used instead of compound 7-5 to obtain EXAMPLE 20 (8 mg) as a pale yellow amorphous solid.
(EXAMPLE 26)
Synthesis of (2R)-2-[(2R)-4-(4-acetamidophenyl)-3-oxomorpholin-2-yl]- N-(4
Figure imgf000111_0001
[Method A)
[Step 26-1 ] Synthesis of tert-butyl N-[4-(2-chloroethylamino)phenyl]carbamate
(compound 26- 1 )
According to the Step 7-1 in synthetic method for EXAMPLE 7,
4-(tert-butoxycarbonylamino)aniline (11.6 g) was used instead of 4-methylaniline to obtain compound 26-1 (3.2 g) as a yellow brown amorphous solid.
[Step 26-2] Synthesis of [(2R,3R)-3-acetyloxy-1-[N-(2-chloroethyl)-4-[(2- methylpropan-2-yl)oxycarbonylamino]anilino]-4-(4-cyanoanilino)-l ,4-dioxobutan-2-yl ] acetate (compound 26-2)
According to the Step 7-3 in synthetic method for EXAMPLE 7, compound
26- 1 (3.2 g) was used instead of compound 7-1 to obtain compound 26-2 (3.2 g) as colorless amorphous solid.
[Step 26-3] Synthesis of tert-butyl N-[4-[2-chloroethyl-[(2R,3R)-4-(4-cyanoanilino)- 2,3-dihydroxy-4-oxobutanoyl]amino]phenyl]carbarnate (compound 26-3)
According to the Step 7-4 in synthetic method for EXAMPLE 7, compound
26-2 (3.2 g) was used instead of compound 7-3 to obtain crude 26-3. The crude 26-3 was used in the next step without further purification.
[Step 26-4] Synthesis of tert-butyl N-[4-[(2R)-2-[(lR)-2-(4-cyanoanilino)-1-hydroxy- 2-oxoethyl]-3-oxomorpholin-4-yl]phenyl]carbamate (compound 26-4)
According to the Step 7-5 in synthetic method for EXAMPLE 7, crude 26-3 was used instead of compound 7-4 to obtain compound 26-4 ( 1.68 g) as a colorless amor [Step 26-5] Synthesis of (2R)-2-[(2R)-4-(4-aminophenyl)-3-oxomorpholin-2-yl]- N-(4-cyanophenyl)-2-hydroxyacetamide (compound 26-5)
To compound 26-4 (1.65 g), was added trifluoroacetic acid (10 mL) with anisole (0.2 mL) at 0 "C. The reaction mixture was stirred at 0 °C for 1 hour then EtiO was added into the mixture to precipitate. The precipitate was collected by filtration and washed with EtiO. Then the precipitate was solved in water and the solution was basified with sat. NaHCOs aq. The precipitate was collected by filtration and washed with H2O to obtain compound 26-5 ( 1.2 g) as a pale brown amorphous solid.
[Step 26-61 Synthesis of [(lR)-1-[(2R)-4-(4-acetamidophenyl)-3-oxomorpholin-2-yl]- 2-(4-cyanoanilino)-2-oxoethyl] acetate (compound 26-6)
To a suspension of compound 26-5 (70 mg) in pyridine ( 1 mL), was added AC2O (43.4 microL). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water to precipitate. The precipitate was collected by filtration and rinsed with water to obtain compound 26-6 (85 mg) as a colorless amorphous solid.
[Step 26-Al Synthesis of (2R)-2-[(2R)-4-(4-acetamidophenyl)-3-oxomorpholin-2-yl]- N-(4-amidinophenyl)-2-hydroxyacetamide hydrochloride (EXAMPLE 26)
According to the Step 7-6 in synthetic method for EXAMPLE 7, compound 26-6 (50mg) was used instead of compound 7-5 to obtain EXAMPLE 26 (2 mg) as a colorless amorphous solid.
[Method B]
[Step 26-7] Synthesis of tert-butyl N-[4-[(2-chloroacetyl)amino]phenyl]carbamate (compound 26-7)
According to the Step 20-1 in synthetic method for EXAMPLE 20
4-(te 5-amino-l ,3-dihydro-2H-benzimidazol-2-one to obtain compound 26-7 (19.5 g) as a gray amorphous solid.
[Step 26-8] Synthesis of tert-butyl N-[4-(2-chloroethylamino)phenyl]carbamate (compound 26- 1 )
According to the Step 20-2 in synthetic method for EXAMPLE 20, compound
26-7 (4 g) was used instead of compound 20- 1 to obtain compound 26-1 (3.84 g). [Step 26-9] Synthesis of (2R,3R)-2,3-diacetyloxy-4-[N-(2-chloroethyl)-4-[(2- methylpropan-2-yl)oxycarbonylamino]anilino]-4-oxobutanoic acid (compound 26-9) To a solution of (+)-diacetyl-L-tartaric anhydride (3.01 g) in CH2Cl2 (40 mL), was added compound 26-1 (3.77 g) at 0 °C. The mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to obtain compound 26-9 (7.4Ig) as a gray amorphous solid.
[Step 26-10] Synthesis of l(2R,3R)-3-acetyloxy-4-[N-(2-chloroethyl)-4-[(2- methylpropan-2~yl)oxycarbonylamino]anilinoj- 1 ,4-dioxo- 1 -[4-(5-oxo-4H- 1 ,2,4-oxadia zol-3-yl)anilino]butan-2-yl] acetate (compound 26-10)
To a solution of compound 26-9 (4 g) in CH2CI2 (40 mL), were added 3-(4-aminophenyl)-1,2,4-oxadiazol-5(2H)-one (1.46 g; EPl 574516 Al),
1 -hydroxybenzotriazole hydrate (HOBt-H2O; 0.13g), and WSC-HCl (1.73 g). The reaction mixture was stirred at room temperature for 1.5 hours and it was concentrated in vacuo. The resulting residue was solved in EtOAc, the organic layer was washed with brine and dried with anhyd. Na2SO4. The solvent was removed under reduced pressure and the resulting residue was suspended in HeX-Et2O = 1 - 1. The precipitate was collected by filtration and rinsed with the above solvent to obtain compound 26-10 (4.45 g) as a pale brown amorphous solid
[Step oxy-4- oxo-4-[4-(5-oxo-4H-1,2,4-oxadiazol-3-yl)anilino]butanoyl]amino]phenyllcarbamate ammonium salt (compound 26- 1 1 )
According to the Step 7-4 in synthetic method for EXAMPLE 7, compound
26-10 (3.5 g) was used instead of compound 7-3 to obtain compound 26-11 (3.04 g) as a pale brown amorphous solid.
[Step 26-12] Synthesis of tert-butyl N-[4-f(2R)-2-[( IR)-I -Hydroxy-2-oxo-2-[4-(5-oxo-
4H-1,2,4-oxadiazol-3-yI)anilino]ethylJ-3-oxomorpholin-4-ylJphenylJcarbamate
(compound 26-12)
According to the Step 7-5 in synthetic method for EXAMPLE 7, compound 26- 11 (2.8 g) was used instead of compound 7-4 to obtain compound 26- 12 ( 1.24 g) as an ivory whight amorphous solid.
[Step 26-13] Synthesis of (2R)-2-[(2R)-4-(4-aminophenyI)-3-oxomorpholin-2-yl]-2- hydroxy-N-[4-(5-oxo-4H- 1 ,2,4-oxadiazol-3-yl)phenyl]acetamide hydrochloride
(compound 26-13)
According to the Step 26-5 in synthetic method for EXAMPLE 26, compound
26-12 (1 g) was used instead of compound 26-4 to obtain compound 26-13 (830 mg) as a pale brown amorphous solid.
[Step 26-14J Synthesis of (2R)-2-[(2R)-4-(4-acetamidophenyl)-3-oxomorpholin-2-ylJ-
2-hydroxy-N-[4-(5-oxo-4H-l ,2,4-oxadiazol-3-yl)phenyI]acetamide (compound 26-14) According to the Step 26-6 in synthetic method for EXAMPLE 26, compound
26-13 (0.1 g) was used instead of compound 26-5 to obtain compound 26-14 (83 mg) as a colorless amorphous solid.
[Step 26-BJ Synthesis of (2R)-2-[(2R)-4-(4-acetamidophenyl)-3-oxomorpholin-2-yl]-
N-(4-amidinophenyl)-2-hydroxyacetamide hydrochloride (EXAMPLE 26)
mL - 8 mL), was added 10% Pd-C (80 mg) at room temperature. The reaction mixture was stirred under H2 gas atmosphere at room temperature overnight. The reaction mixture was filtered with Celite® pad. The Celite® pad was washed with DMF and the filtrate was concentrated in vacuo. The resulting residue was suspended in MeOH and the precipitate was collected by filtration to obtain EXAMPLE 26 (38 mg) as a colorless amorphous solid.
(EXAMPLE 38)
Synthesis of (2R)-2-[(2R)-4-(4-acetamidophenyl)-3-oxomorpholin-2-yl]-N- (l-aminoisoquinolin-6-yl)-2-hydroxyacetamide hydrochloride (EXAMPLE 38)
Figure imgf000115_0001
[Step 38-1] Synthesis of N-[4-(2-chloroethylamino)phenyl]acetamide (compound 38-1) According to the Step 7-1 in synthetic method for EXAMPLE 7,
N-(4-aminophenyl)acetamide (10 g) was used instead of 4-methylaniline to obtain compound 38-1 (7.9 g) as a pale yellow amorphous solid.
[Step 38-21 Synthesis of (2R,3R)-4-[4-acetamido-N-(2-chloroethyl)anilino]-2,3- diacetyloxy-4-oxobutanoic acid (compound 38-2)
According to the Step 26-9 in synthetic method for EXAMPLE 26, compound
38-1 (7.5 g) was used instead of compound 26-1 to obtain compound 38-2 (15.1 g) as a beige amorphous solid.
[Step 38-3J Synthesis of [(2R,3R)- l-[4-acetamido-N-(2-chloroethyl)anilino]-3- acety -ylJamino] - 1,4-dioxobutan-2-yl] acetate (compound 38-3)
To a solution of compound 38-2 (0.7 g) in CH2Cl2-DMF (30 - 2 mL), was added oxalyl chloride (0.25 mL) at 0 °C. The reaction mixture was stirred for 1 hour in the same temperature. Then the mixture was concentrated in vacuo to remove excess oxalyl chloride. The resulting residue was resolved in CH2Cl2 (20 mL) and pyridine (0.19 mL) was added to the above solution at 0 °C. The mixture was stirred for 10 minutes at the same temperature and then a solution of 6-amino-1-bis(tert-butoxy
carbonyl)aminoisoquinoline (0.52 g) in CH2Cl2 (10 mL) was added to the mixture at 0 °C. The reaction mixture was stirred for 1 hour at 0 °C, then for 2 days at room temperature. MeOH was added to the reaction mixture and the mixture was
concentrated in vacuo. Then sat. NaHCCh aq. was added to residue and the mixture was extracted with EtOAc. The organic layer was washed with water, brine and dried with anhyd. Na2SO4. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel flash chromatography (eluent : Hexane/EtOAc = 1/4) to obtain compound 38-3 (0.52 g) as a pale yellow amorphous solid.
[Step 38-4] Synthesis of tert-butyl N-[6-[[(2R,3R)-4-[4-acetamido-N-(2- chloroethyl)anilino]-2,3-dihydroxy-4-oxobutanoylJaminoJisoquinolin-1-ylJ-N-[(2-meth ylpropan-2-yl)oxycarbonyl1carbamate (compound 38-4)
According to the Step 7-4 in synthetic method for EXAMPLE 7, compound 38-3 (0.5 g) was used instead of 7-3 to obtain compound 38-4 (0.42 g) as a yellow amorphous solid.
[Step 38-51 Synthesis of (2R)-2-[(2R)-4-(4-acetamidophenyl)-3-oxomorpholin-2- yl]-N-[N,N-bis(tert-butoxycarbonyl)-1-aminoisoquinolin-6-yl]-2-hydroxyacetamide (compound 38-5)
pound 38-4 (0.4 g) and DMF were used instead of 7-4 and t-BuOH-DMSO to obtain compound 38-5 (0.13 g) as a yellow amorphous solid.
[Step 38-6] Synthesis of (2R)-2-[(2R)-4-(4-acetamidophenyl)-3-oxomorpholin-2-yl]- N-(l-aminoisoquinolin-6-yl)-2-hydroxyacetamide hydrochloride (EXAMPLE 38)
To a solution of compound 38-5 (40 mg) in MeOH (0.4 mL), was added
4N-HClZEtOAc (1 mL) at 0 °C. The reaction mixture was stirred for 21 hours at room temperature. After the reaction, the precipitate was collected by filtration to obtain EXAMPLE 38 (22 mg) as a pale yellow amorphous solid. (EXAMPLE 52)
Synthesis of (2R)-N-(I -aminoisoquinolin-6-yl)-2-[(2R)-4-(4-tert-butylphenyl)- 3-oxomorpholin~2-yl]-2-hydroxyacetamide hydrochloride (EXAMPLE 52)
Figure imgf000117_0001
[Step 52-1] Synthesis of tert-butyl (2R,3R)-2,3-diacetyloxy-4-[4-tert-butyl-N-(2- chloroethyl)anilino]-4-oxobutanoate (compound 52- 1)
To a solution of (R, R)-2,3-bis(acetyloxy)-butanedioic acid mono tert-butyl ester (9 g: Tetrahedron, 45, 3071-3080, 1989) in CH2Cl2 (90 mL), were added compound 11-1 (6.6 g) and l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride at 0 °C. The reaction mixture was stirred for 5 hours at room temperature. Then water was added into the mixture and it was extracted with CH2Cl2. The organic layer was washed with brine, dried with anhyd. Na2SO4. The solvent was removed unde hous solid. [Step 52-2] Synthesis of tert-butyl (2R,3R)-4-[4-tert-butyl-N-(2-chloroethyl)anilinol- 2,3-dihydroxy-4-oxobutanoate (compound 52-2)
According to the Step 7-4 in synthetic method for EXAMPLE 7, compound 52-1 (15.5 g) was used instead of 7-3 to obtain compound 52-2 (13 g) as a brown oil. [Step 52-3] Synthesis of tert-butyl (2R)-2-[(2R)-4-(4-tert-butylphenyl)-3- oxomorpholin-2-yl]-2-hydroxyacetate (compound 52-3)
According to the Step 7-5 in synthetic method for EXAMPLE 7, compound 52-2 (12.8 g) was used instead of 7-4 to obtain compound 52-3 (4.85 g) as a pale yellow amorphous solid.
LStep 52-4] Synthesis of (2R)-2-[(2R)-4-(4-tert-butylphenyl)-3-oxomorpholin- 2-yl]-2-hydroxyacetic acid (compound 52-4)
Compound 52-3 (1.5 g) was resolved in 4N HCl-dioxane (30 mL). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to obtain compound 52-4 ( 1.44 g) as a beige amorphous hygroscopic solid. [Step 52-5] Synthesis of (2R)-N-[N,N-bis(tert-butoxycarbonyl)- 1 -aminoisoquinolin- 6-yl]-2-[(2R)-4-(4-tert-butylphenyl)-3-oxomorpholin-2-yl]-2-hydroxyacetamide (compound 52-5)
According to the Step 1-3 in synthetic method for EXAMPLE 1, 52-4 (0.38 g) was used instead of 1-2 to obtain compound 52-5 (92 mg) as a colorless amorphous solid.
[Step52-6] Synthesis of (2R)-N-(I ~aminoisoquinolin-6-yl)-2-[(2R)-4-(4- tert-butylphenyl)-3-oxomorpholin-2-yl]-2-hydroxyacetamide hydrochloride
(EXAMPLE 52)
According to the Step 38-6 in synthetic method for EXAMPLE 38 52-5 (91 mg) amorphous solid.
(EXAMPLE 54)
Synthesis of (2R)-N-(I -aminoisoquinolin-6-yl)-2-hydroxy-2-[(2R)- 3-oxo-4-[4-(trifluoromethyl)phenyl]morpholin-2-yl]acetamide hydrochloride
(EXAMPLE 54)
Figure imgf000119_0001
EXAMPLE 54
[Step 54-1] Synthesis of N-(2 -chloro-N-[4-(trifluoromethyl)phenyl]acetamide
(compound 54- 1 )
According to the Step 20- 1 in synthetic method for EXAMPLE 20,
4-trifluoromethyl aniline (5 g) was used instead of
5-amino-l ,3-dihydro-2H-benzirnidazoi-2-one to obtain compound 54-1 (6.94 g) as a brown amorphous solid.
[Step 54-2] Synthesis of N-(2-chloroethyl)-4-(trifluoromethyI)aniIine (compound 54-2) According to the Step 20-2 in synthetic method for EXAMPLE 20, compound
54-1 (3.5 g) was used instead of 20-1 to obtain compound 54-2 (3.36 g) as brown oil.
[Step 54-3] Synthesis of tert-butyl (2R,3R)-2,3-diacetyIoxy-4-[N-(2-chloroethyI)-4-
(trifluoromethyl)anilino]-4-oxobutanoate (compound 54-3)
To a solution of (R, R)-2,3-bis(acety!oxy)-butanedioic acid mono tert-butyl ester (3.25 g: Tetrahedron, 45, 3071 -3080, 1989) in CH2Cl2 (65 niL), were added oxalyi chloride (1.06 mL) and DMF (50 microL) at 0 °C. The reaction mixture was stirred at
0 °C e same temperature. The reaction mixture was stirred at the same temperature for 5 minutes. To the mixture, was added a solution of compound 54-2 (2.5 g) in CH2CI2 (12.5 mL) at 0 °C. The mixture was stirred for 1 hour at the same temperature. Then the mixture was concentrated in vacuo and the resulting residue was suspended in water. The mixture was extracted with EtOAc and the organic layer was washed with IN HCl aq., sat. NaHCOa aq., brine, and it was dried with anhyd. Na2SOφ The solvent was removed under reduced pressure to obtain compound 54-3 (5.7 g) as brown oil.
[Step 54-41 Synthesis of tert-butyl (2R,3R)-4-[N-(2-chloroethyl)-4- (trifluoromethyl)anilino]-2,3-dihydroxy-4-oxobutanoate (compound 54-4)
According to the Step 7-4 in synthetic method for EXAMPLE 7, compound
54-3 (5.5 g) was used instead of 7-3 to obtain compound 54-4 (4.57 g) as a brown amorphous solid.
[Step 54-51 Synthesis of tert-butyl (2R)-2-hydroxy-2-[(2R)-3-oxo-4-[4- (trifluoromethyl)phenyllmorpholin-2-yl]aeetate (compound 54-5)
According to the Step 7-5 in synthetic method for EXAMPLE 7, compound
54-4 (3 g) was used instead of 7-4 to obtain compound 54-5 (220 mg) as a pale yellow amorphous solid.
[Step 54-6] Synthesis of (2R)-2-hydroxy-2-[(2R)-3-oxo-4-[4- (trifluoromethyl)phenyl]morpholin-2-yl]acetic acid (compound 54-6)
According to the Step 52-4 in synthetic method for EXAMPLE 52, compound
54-5 (0.2 g) was used instead of 52-3 to obtain compound 54-6 (128 mg) as a colorless amorphous solid.
[Step 54-7] Synthesis of (2R)-N-[N,N-bis(tert-butoxycarbonyl)-l ~aminoisoqumolin- 6-yl]-2-hydroxy-2-[(2R)-3-oxo-4-[4-(trifluoromethyl)phenyl]morpholin-2-yl]acetamide (com According to the Step 1 -3 in synthetic method for EXAMPLE 1 , compound 54-6 (128 mg) was used instead of 1-2 to obtain compound 54-7 (107 mg) as a beige amorphous solid.
[Step 54-8] Synthesis of (2R)-N-(I -aminoisoquinolin-6-yl)-2-hydroxy-2-[(2R)-3-oxo- 4-[4-(trifluoromethyl)phenyl]morpholin-2-yl]acetamide hydrochloride (EXAMPLE 54)
According to the Step 38-6 in synthetic method for EXAMPLE 38, 54-7 (50 mg) was used instead of 38-5 to obtain EXAMPLE 54 (28.3 mg) as a leaf green amorphous solid. (EXAMPLE 57)
Synthesis of (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3- oxo-4-f4-(trifluoromethoxy)phenyl]morpholin-2-yl]acetamide hydrochloride
(EXAMPLE 57)
Figure imgf000121_0001
[Step 57-1 ] Synthesis of N-[[2-cyano-5-[[(2R)-2-hydroxy-2-[(2R)-3-oxo-4-[4-
(trifluoromethoxy)phenyl]morpholin-2-yl]acetyl]amino]phenyl]methyl]-N-[(2-methylp ropan-2-yl)oxycarbonyl]carbamate (compound 56-1)
According to the Step 1-3 in synthetic method for EXAMPLE 1, a cyclic carbonate analogue (0.15 g) derived from compound 55-6 and 39-2 (0.14 g) were used instead of 1 -2 and 6-amino- l-bis(tert-butoxycarbonyl)aminoisoquinoline to obtain compound 57-1 ( 147 mg) as a pale yellow amorphous solid.
[Step 57-2] Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyl]-2-hydroxy-2- [(2R chloride (compound 57-2)
According to the Step 38-6 in synthetic method for EXAMPLE 38, 57-1 (0.14 g) was used instead of 38-5 to obtain compound 57-2 (93 mg) as a pale yellow amorphous solid.
δ [Step 57-3] Synthesis of (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2- L(2R)-3-oxo-4-[4-(trifluoromethoxy)phenyl]morpholin-2-yllacetarnide hydrochloride (EXAMPLE 57)
According to the Step 39-7 in synthetic method for EXAMPLE 39, 57-3 (89 mg) was used instead of 39-6 to obtain EXAMPLE 57 (66.4 mg) as a pale yellow 10 amorphous solid.
(EXAMPLE 68)
Synthesis of (R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-3-oxo-4-(3- oxo-2-propylisoindolin-5-yl)morpholin-2-yl)acetamide hydrochloride (EXAMPLE 68)
Figure imgf000122_0001
Λ K Example 68
Figure imgf000123_0001
[Step 68- 1 ] Synthesis of compound 68- 1.
A 100-L glass-jacketed reactor was charged with 4-methoxybenzaldehyde (3440 g, 25.3 mol, Aldrich lot # 05826MH and 20098PJ) and absolute ethanol (34.4 L). 2-Aminoethanol ( 1840 mL, 30.0 mol, Aldrich lot # 06201 PE) was added over 30 minutes while maintaining the temperature of the batch between 20 and 30 °C. After the addition was complete, the batch was held at 20-25 °C for 2 hours until formation of the imine intermediate was deemed complete by 1H NMR analysis (DMSO-de, aldehyde peak at 9.8 ppm not observed). The batch was cooled to 0-5 °C and sodium borohydride (1050 g, 27.8 mol, Aldrich lot # 10106TC) was added portionwise over 2.8 hours while maintaining the temperature of the batch between 0 and 10 °C. Once the addition was complete, the batch was allowed to gradually warm to 20-25 °C
(20 °C/hour) and was held at this temperature for 16 hours until the reduction of the imine intermediate was deemed complete by HPLC analysis [<1.0% (AUC) of imine by HPLC]. The reaction mixture was quenched by carefully adding 1 M aqueous sodium hydroxide (25.0 L) to the batch. This process led to the formation of insoluble masses of solid. These solids were dissolved by adding DI water (25.0 L) and the quen H2CI2, 3 x 17.2 L). The combined organic extracts were concentrated on a rotary evaporator at 40-45 °C until distillation ceased and then the concentrate was slurried in DI water ( 17.2 L). The batch was cooled to 10-15 °C and the pH was adjusted to 1-2 using concentrated hydrochloric acid (2.2 L). The batch was washed with tert-huty\ methyl ether (MTBE, 3 x 10.3 L), cooled to 10-15 °C and the pH was adjusted to 13-14 using 6 M aqueous sodium hydroxide (6.0 L). The batch was extracted with CH2CI2 (2 x
10.3 L). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the filter cake was washed with CH2CI2 (6.0 L). The filtrate was concentrated on a rotary evaporator at 30-35 °C until distillation ceased to afford compouond 68-1 (4325 g, 94%).
[step 68-2] Synthesis of compound 68-2.
A 100-L glass-jacketed reactor was charged with compound 68-1 (4325 g, 23.9 mol) and 1 ,2-dichloroethane (86.5 L). Thionyl chloride (1900 mL, 26.1 mol, Aldrich lot # 05497DJ) was added over 50 minutes while maintaining the temperature of the batch between 20 and 30 °C. Once the addition was complete, the batch was heated to 55-60 °C and held at this temperature for 5.5 hours until the reaction was deemed complete by 1H NMR analysis (DMSO-de, doublets at 7.3 ppm and 6.9 ppm shifted to 7.5 ppm and 7.0 ppm respectively, and doublets at 9.2 min and multiplet at 4.4 ppm disappeared). The batch was cooled to 20-25 °C and concentrated using a rotavap at 40-45 °C until distillation ceased. The concentrate was swapped once with MTBE (22.0 L), slurried in MTBE (21.7 L) and filtered to afford 68-2»HCl (5420 g, 96%) as white solids after drying in a vacuum oven at 20-30 °C for 17 hours.
[Step 68-3] Synthesis of compound 68-3.
A 50-L glass-jacketed reactor was charged with compound 68-2ΗC1 ( 1940 g, 8.2 m yer was adjusted to 11-12 using 1 M aqueous sodium hydroxide (10.5 L) and maintaining the temperature of the batch between 15 and 30 °C. The phases were separated and the aqueous layer was extracted with MTBE (2 x 9.7 L). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, washed with MTBE (8.0 L) and the filtrate was concentrated on a rotary evaporator at 20-25 °C until distillation ceased, affording free amine 68-2 (1720 g, containing 6.8 wt % of MTBE by 1H NMR
(DMSOd6), corrected weight: 1604 g, 98%)
A 50-L glass-jacketed reactor was charged with di-O-acetyl-L-tartaric anhydride (1775 g, 8.2 mol, Alfa Aesar lot # El 3UO33) and tetrahydrofuran (17.5 L, THF). The batch was cooled to 0-5 °C and a solution of compound 68-2 ( 1720 g) in THF (2.0 L) was added over 1.3 hours while maintaining the temperature of the batch between 0 and 10 °C. The batch was held at 0-5 °C for 18 hours until the reaction was deemed complete by HPLC analysis L2.8% (AUC) of compound 68-2 remaining] and then it was concentrated on a rotary evaporator at 20-25 °C until distillation ceased to afford compound 68-3 [4485 g, containing 22.7 wt % of THF by 1H NMR (DMSO-d6), corrected weight: 3467 g, 102%, 86.9 % (AUC) by HPLC].
[Step 68-4] Synthesis of compound 68-4.
A 50-L glass-jacketed reactor was charged with compound 68-3 (3520 g, assuming theoretical yield for step 3, 8.5 mol) and THF (35.0 L), and the batch was heated to 50-60 °C. Two portions of O-terr-butyl-N,N-diisopropylurea (2115 g, 10.6 mol, and 1700 g, 8.9 mol) were each added dropwise over 30 minutes while maintaining the temperature of the batch between 50 and 60 °C. In-process assay by HPLC analysis after these additions were complete indicated that 19.5% (AUC) of compound 68-3 remained and that 70.9% (AUC) of compound 68-4 had formed.
Addi to the batch until the reaction was deemed complete by HPLC analysis [4.4% (AUC) of compound 68-3 remaining). The batch was cooled to 15-25 °C and MTBE (19.4 L) was added. The batch was filtered over Celite® and washed with MTBE (15.0 L). The combined filtrate and washes were concentrated on a rotary evaporator at 40-45 °C until distillation ceased to afford crude compound 68-4 [4675 g, containing 10.6 wt % of THF by 1H NMR (DMSOd6), corrected weight 4180 g, 105%, 55.7% (AUC) by HPLC]. This material was purified by silica-gel column chromatography (Four 1.1 to 1.3-kg batches using 5.5 kg of silica gel each, 20 to 60% EtOAc in heptane) to afford compound 68-4 [1915 g, 48%, 96.7-97.1% (AUC) by HPLC] as well as mixed fractions that were combined with other lots for further purification.
[Step 68-5] Synthesis of compound 68-5.
A 50-L glass-jacketed reactor was charged with compound compound 68-4 (1 100 g, 2.3 mol) and methanol (10.2 L), and the batch was cooled to -10 to 0 °C. A slurry of potassium cyanide (80 g, 1.2 mol, Aldrich lot # 14614KA) in methanol (800 mL) was added over 5 minutes while maintaining the temperature of the batch between -10 and 0 °C. The batch was held at -10 to 0 °C for 3.3 hours until the reaction was deemed complete by HPLC analysis [5.3% (AUC) of compound 68-4 remaining]. Solid sodium bicarbonate (200 g, 2.4 mol, Natrium Products lot # 01096A) was added and the batch was concentrated on a rotary evaporator at 20-25 °C until distillation ceased. MTBE ( 1 1.0 L) and DI water ( 11.0 L) were added to the concentrate, and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate (6.0 L), dried over anhydrous sodium sulfate, filtered, washed with MTBE (7.0 L) and concentrated on a rotary evaporator at 20-25 °C until distillation ceased to yield compound 68-5 [910 g, containing 10.2 wt % of MTBE by 1H NMR (CDCl3), corre tored in the freezer.
[Step 68-6J Synthesis of compound 68-6.
A 50-L glass-jacketed reactor was charged with compound 68-5 (817 g, 2.1 mol), CH2CI2 (8.2 L) and deionized water ( 1.9 L). Benzyltrimethylammonium hydroxide (1912 mL, 40 wt % in methanol, 4.2 mol, Aldrich lot # 10896HJ) was added to the batch over 10 minutes while maintaining the temperature between 20 and 25 °C. The batch was held at 20-25 °C for 1.5 hours until the reaction was deemed complete by HPLC analysis [<1.0% (AUC) of compound 68-5 remaining]. At completion of the reaction, DI water (6.5 L) was added and the layers were separated. The aqueous layer was extracted with CH2CI2 (8.2 L). The combined organic extracts were washed with brine (8.2 L), dried over anhydrous sodium sulfate, filtered and washed with CH2CI2 (2.5 L). The combined filtrate and washes were concentrated on a rotary evaporator at 30-35 °C until distillation ceased to afford crude compound 68-6 f625 g, 84%, 82.5% (AUC) by HPLC]. This material was purified by silica-gel column chromatography L5 kg of silica gel, 20 to 60% EtOAc in heptane] and the pure fractions were slurried in 1 :4 MTBE/heptane to yield compound 68-6 [Two lots: 155 g, 21%, >99% (AUC) by HPLC, and 335 g, 45%, >99% (AUC) by HPLC] as white solids. [Step 68-7] Synthesis of compound 68-7.
A 50-L glass-jacketed reactor was charged with compound 68-6 (490 g, 1.4 mol), acetonitrile ( 10.1 L) and DI water (2.0 L). The batch was cooled to 0-5 °C and a slurry of cerium (IV) ammonium nitrate (3060 g, 5.6 mol, Alfa Aesar lot # H22T016) in acetonitrile (8.0 L) was added while maintaining the temperature of the batch between 0 and 5 °C. The batch was held at 0-5 °C for 30 minutes, warmed to 20-25 °C and held at this temperature for 3 5 hours until the reaction was deemed comp L) was added until the pH of the reaction mixture reached 4.5 to 5. The resulting suspension was filtered over Celite" and the filter cake was washed with CH2CI2 (2 x 10.0 L) followed by 5% methanol in CH2CI2 (10.0 L). The combined filtrate and washes were transferred to a 50-L, glass-jacketed reactor and the phases were separated. The aqueous layer was extracted with CH2Cb (15.0 L). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and the filter cake was washed with CH2CI2 (10.0 L). The combined filtrate and washes were concentrated on a rotary evaporator at 30-35 °C until distillation ceased to give crude compound 68-7 [700 g, >100%]. This material was purified by silica-gel column chromatography [4 kg of silica gel, 1 to 5% methanol in dichloromethane]. The pure fractions were slurried in 1 :4 CH2C12/MTBE to yield compound 68-7 [Two lots: 189 g, 59%] as white to off-white solids.
,2-diamine
Figure imgf000129_0001
[Step 68-8] Synthesis of compound 68-8.
To a 50 mL round bottom flask was added 5-iodo-3-oxo-isoindolin (1.00 g, 3.86 mmol) in DMF (10.0 mL) and the reaction mixture was stirred at 0-5 °C. NaH (60% in oil, 186 mg, 4.65 mmol) was added, and the reaction mixture was allowed to warm to room temperature. After 20 min, the reaction obtained a green color, and a solution of ra-propyl bromide (706 mg 5 78 mmol) in DMF (2 00 mL) was added drop t at room temperature, then diluted with EtOAc (100 mL), washed with saturated aqueous NH4CI (2 x 25 mL), saturated aqueous LiCl (25 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by CombiFlash (80 g, Hex/EtOAc, 100:0 to 30:70 over 30 min) to provide compound 68-8 (700 mg, 60%) as a white solid.
[Step 68-9] Synthesis of compound 68-9.
A mixture of compound 68-7 (100 mg, 0.432 mmol), aryl iodide compound 68-8 (156 mg, 0.518 mmol), CuI (8.1 mg, 43 μmol), K3PO4 (183 mg, 0.861 mmol), DMSO (1.5 mL), and ?ra«s-N,N'-dimethylcyclohexane-1,2-diamine (13.6 μL, 86.1 μmol) were stirred at room temperature under nitrogen in the dark. After 14 h, additional CuI (8.1 mg, 43 μmol) and ?rαns-N,N'-dimethylcyclohexane-1,2-diamine (13.6 μL, 86.1 μmol) were added and the mixture was stirred for an additional 2.5 h. The mixture was diluted with EtOAc (100 mL), washed with water (3 x 25 mL), brine (25mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified on CombiFlash (12 g SiO2, Hex/EtOAc, 100:0 to 0: 100 over 45 min) to provide pure product compound 68-9 (120 mg, 69%) as a yellow solid. [Step 68-10]
Synthesis of compound 68-10.
To a 50 mL round bottom flask was added compound 68-9 (114 mg, 0.281 mmol), DMAP (3.4 mg, 28 μmol), pyridine (45 μL, 0.56 mmol) and CH2Cl2 (5.00 mL). The reaction mixture was cooled to 0-5 °C, Ac2O (53 μL, 0.56 mmol) was added, stirred at 0-5 °C for 2 h, and then diluted with EtOAc (40 mL), washed with saturated aqueous CuSO4 (2 x 25 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide crude compound 68-10 (125 mg, quant) as a y her purification.
[Step 68- 1 11 Synthesis of compound 68- 1 1.
In a 50 mL round bottom flask containing compound 68-10 (125 mg, 0.281 mmol) was added CH2CI2 (1.00 mL) and TFA (2.00 mL). The reaction mixture was stirred at room temperature for 2 h, then TFA and CH2CI2 were removed under reduced pressure. The crude product was triturated with ether to provide pure 68-11 (110 mg, quant.) as a yellow solid.
[Step 68-12] Synthesis of compound 68-12.
To a 100 mL round bottom flask was added compound 68-11 (110 mg, 0.281 mmol), DMAP (3.4 mg, 28 μmol), and 3-(4-aminophenyl)-1,2,4-oxadiazol-5(2H)-one 1 (53.1 mg, 0.299 mmol) in CH3CN (3.00 mL). The reaction mixture was cooled to 0-5 °C, then EDCI-HCl (57.5 mg, 0.299 mmol) was added and the reaction mixture was warmed to room temperature. After 30 min DMF (1.00 mL) was added to dissolve the precipitate and stirring was continued for an additional 3 h. The solvents were removed under reduced pressure and the residue was triturated with ether (20.0 mL) then decanted. The undissolved material was washed with water (2 x 5 mL) and acetonitrile (2 x 5 mL) then dried on under vacuum to provide pure product 68-12 (95 mg, 62%) as off-white solid.
[Step 68-13] Synthesis of compound 68-13.
To a 50 mL round bottom flask was added compound 68- 12 (95 mg, 0.17 mmol), CH3OH (2.00 mL) and 7 N NH3 in CH3OH (6.00 mL). The reaction mixture was stirred at room temperature for 1 h then the volatiles were removed under reduced pressure. Additional CH3OH (2 x 50 mL) was used to strip off excess NH3. The crude product was redissolved in CH3OH (50 mL) and the solvent degassed with N2 to remo compound 68-13 (85 mg, 99%) as off-white solid.
[Step 68-14] Synthesis of (R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-3- oxo-4-(3-oxo-2-propylisoindolin-5-yl)morpholin-2-yl)acetamide hydrochloride (EXAMPLE 68)
To a 250 mL round bottom flask was added compound 68- 13 (84 mg, 0.17 mmol) in CH3OH (6.00 mL) and 1 M HCl (6.00 mL). The solvent was degassed for 10 min with N2, then 10% Pd/C (84 mg, 39 μmol) was added and the reaction mixture was hydrogenated at 1 atm overnight. The mixture was diluted with hot CH3OH (250 mL), filtered and the filtrate was concentrated under reduced pressure. The residue was triturated with CH3OH (5.00 mL) and filtered to provide pure product compound 68 (51 mg, 64%) as off-white solid.
(EXAMPLE 70)
Synthesis of (R)-N-(4-Carbamimidoylphenyl)-2-hydroxy-2-((R)-4- (2-methyl-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)acetamide hydrochloride (EXAMPLE 70)
Figure imgf000133_0001
Figure imgf000133_0002
EXAMPLE 70
[Step 70- I J Synthesis of compound 70-1.
To a mixture of 2 3-dihydro-6-iodo-1H-isoindol- l-one (1 0 g) in DMF (20 mL) at 0 ° s stirred for 30 min at 0 °C whereupon MeI (0.25 mL) was added dropwise. The mixture was allowed to warm to rt and was stirred for 72 h. The mixture was quenched by addition of sat. aq. NH4CI (~ 3 mL) and was diluted with EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined and washed sequentially with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified The crude product was purified by flash chromatography (ISCO, 120 g) using a gradient of 100% hexanes to 80:20 hexanes/EtOAc to afford compound 70-1 (0.84 g) as a yellow solid. LC-MS: M+H = 274.
LStep 70-2] Synthesis of (i?)-tert-butyl 2-hydroxy-2-((i?)-4-(2-methyl-3-oxoisoindolin- 5-yl)-3-oxomorpholin-2-yl)acetate (compound 70-2)
To a round bottom flask charged with a stir bar was added morpholinone compound 68-7 (0.28 g) and compound 70-1 (0.40 g) in DMSO (8 mL) at rt was added K3PO4 (0.51 g), and CuI (23 mg) under N2.
frans-NJV-Dimethylcyclohexane-l^-diamine (37 μL) was added dropwise and the mixture was affixed with a condenser. The mixture was degassed under vacuum (~ 20 mm), filled with N2, and heated to 80 °C. The mixture stirred for 2.5 h at 80 °C, cooled to rt, and was diluted with EtOAc. The mixture was then sequentially washed with cone NH4OH, water, and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford a yellow oil. The crude product was purified by flash chromatography using a gradient of 100% CH2CI2 to 60%
CH2C12/4O% MeOH to afford compound 70-2 (0.23 g) of a yellow solid. LC-MS: M+H = 377.
[Step 70-3] Synthesis of (i?)-tert-butyl 2-acetoxy-2-((R)-4-(2-methyl-3-oxoisoindolin-5- yl)-3 To a solution of compound 70-2 (80 mg) in CH2Cl2 (2 ml) at 0°C was added pyridine (26 μL), AC2O (30 μl), and DMAP (4 mg). The mixture was stirred for 1 hour at 0°C, warmed to rt, and stirred for an additional 12 h. The mixture was diluted with EtOAc and the organic layer was washed sequentially with sat. aq. CuSO4 solution, water, and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford compound 70-3 (85 mg) as a light yellow semisolid. LC-MS: M+H = 419. This material was used without further purification.
[Step 70-41 Synthesis of (i?)-2-acetoxy-2-((R)-4-(2-methyl-3-oxoisoindolin-5-yl)- 3-oxornorpholin-2-yl)acetic acid (compound 70-4)
To a solution of compound 70-3 (85 mg) in CH2Cl2 (2.5 mL) at 0°C was added
TEA (0.5 mL) dropwise. The mixture was stirred for Ih at 0°C and at rt for 30 min whereupon an additional portion of TFA (0.5 mL) was added. After an additional 1 h at rt, the mixture was diluted with CH2Cl2 and concentrated to dryness under reduced pressure. The crude mixture was redissolved in CH2Cl2 and concentrated and this protocol was repeated 5 times with to afford compound 70-4 (65 mg) as a light semisolid. LC-MS: M+H = 363. This material was used without further purification. [Step 70-5] Synthesis of (Λ)-l -((Λ)-4-(2-methyl-3-oxoisoindolin-5-yl)-3- oxomorpholin-2-yl)-2-oxo-2-(4-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)phenylamino) ethyl acetate (compound 70-5)
To a solution of compound 70-4 (40 mg) in CH3CN ( 1 mL) at 0 °C was added
4-(5-oxo-4,5-dihydro-[ l ,2,4]oxadiazol-3-yl)-phenyl amide (21 mg) followed by EDCI (25 mg). The reaction mixture was warmed to rt and stirred for 72 h. The mixture was concentrated under reduced pressure and placed under high vacuum. The crude material was purified by reverse phase HPLC using a C 18 column and a gradient of
(89.9 to afford compound 70-5 (30 mg) as a white solid. LC-MS: M+H = 522.
[Step 70-61 Synthesis of ammonium 3-(4-((R)-2-hydroxy-2-((R)-4-(2-methyl-3- oxoisoindolin-5-yl)-3-oxomorpholin-2~yl)acetamido)phenyl)-1,2,4-oxadiazol-5-olate (compound 70-6)
To a solution of the compound 70-5 (30 mg) in MeOH (2 mL) at 0 °C was added 7M NH3/MeOH (0.3 mL) dropwise. The mixture was stirred for Ih at 0 °C and an additional hour at rt. The mixture was concentrated under reduced pressure and placed under high vacuum to afford compound 70-6 (27 mg) as a clear glass. LC-MS: M+H = 480 (free base).
[Step 70-7] Synthesis of (R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4- (2-methyl-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)acetamide hydrochloride (EXAMPLE 70)
To a solution of the compound 70-6 (27 mg) in MeOH (2 mL) was added IN HCl (2 mL) followed by 10% Pd/C (50 mg). The mixture was stirred under a H2 balloon for 3 h and was filtered through a pad of Celite®. The Celite® pad was washed with MeOH and the resultant filtrate was concentrated under reduced pressure. The crude residue was treated with MeOH followed by dilution with Et2θ and the resultant solid was collected by filtration and dried under vacuum to afford 17 mg of Example 70 as a maize solid. LC-MS: M+H = 438 (free base).
(EXAMPLE 73)
Synthesis of (R)-2-((R)-4-(3,5-bis(trifluoromethyl)phenyl)-3-oxomorpholin-2- yl)-N-(4~carbamimidoylphenyl)-2-hydroxyacetamide hydrochloride (EXAMPLE 73)
Figure imgf000137_0001
[Step 73- 1 ] Synthesis of (R)-tert-butyl 2-((R)-4-(3,5-bis(trifluoromethyl)phenyl)-3- oxom According to the Step 70-2 in the synthetic method for Example 70,
3,5-(bistrifluoromethyl)iodobenzene (0.11 mL) was used instead of compound 70-1 to obtain compound 73- 1 (0.13 g) as a white solid after reverse-phase (C 18) purification. I Step 73-21 Synthesis of (R)-tert-butyl 2-acetoxy-2-((R)-4-(3,5- bis(trifluoromethyl)phenyl)-3-oxomorpholin-2-yl)acetate (compound 73-2)
According to the Step 70-3 in the synthetic method for EXAMPLE 70, 73-1 (0.13 g) was used instead of compound 70-2 to obtain compound 73-2 (0.14 g) as a yellow semisolid that was used without further purification.
[Step 73-31 Synthesis of (R)-2-acetoxy-2-((R)-4-(3,5-bis(trifluoromethyl)phenyl)- 3-oxomorpholin-2-yl)acetic acid (compound 73-3)
According to the Step 70-4 in the synthetic method for EXAMPLE 70, compound 73-2 (0.14 g) was used instead of compound 70-3 to afford compound 73-3 (0.12 g) as a light yellow solid that was used without further purification.
[Step 73-4] Synthesis of (R)-1-((R)-4-(3,5-bis(trifluoromethyl)phenyl)-3- oxomorpholin-2-yl)-2-oxo-2-(4-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)phenylamino) ethyl acetate (compound 73-4)
According to the Step 70-5 in the synthetic method for EXAMPLE 70, compound 73-3 (65 mg) was used instead of compound 70-4 to obtain compound 73-4 (69 mg) as a white solid after reverse-phase (C 18) HPLC purification.
[Step 73-51 Synthesis of ammonium 3-(4-((R)-2-((R)-4-(3,5-bis(trifluoromethyl)- phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamido)phenyl)-1,2,4-oxadiazol-5-olate (compound 73-5)
According to the Step 70-6 in the synthetic method for EXAMPLE 70, compound 73-4 (69 mg) was used instead of compound compound 70-5 to obtain com cation. [Step 73-6] Synthesis of (R)-2-((R)-4-(3,5-bis(trifluoromethyl)phenyl)-3- oxomorpholin-2-yl)-N-(4-carbamimidoylphenyl)-2-hydroxyacetamide hydrochloride (EXAMPLE 73)
According to the Step 70-7 in the synthetic method for EXAMPLE 70, compound 73-5 (53 mg) was used instead of compound 70-6 to obtain EXAMPLE 73 (37 mg) as a maize solid.
(EXAMPLE 98)
Synthesis of N-(4~Amino-7-quinazolinyl)-alpha(R)-hydroxy-3-oxo-4- [4-(trifluoromethyl)phenyl]-2(R)-morpholineacetamide (Example 98)
Figure imgf000139_0001
98-5 98-6
Figure imgf000139_0002
EXAMPLE 98
[Step A mixture of 2-amino-4-nitrobenzoic acid (5.0g, 27.5 mmol) and formamide (8.0 ml, 201.5 mmol) in a microwave reaction vessel was heated in a microwave reactor at 150 °C for 1 hr. The slurry was cooled to rt, stirred with aq. NaHCθ3, filtered, washed with water followed by ether and dried in vacuum oven to provide 3.7 g of 7-nitroquinazolin-4(3H)-one (compound 98-1).
[Step 98-2] Synthesis of 7-Nitroquinazolin-4-amine (compound 98-2)
To a solution of 7-nitroquinazolin-4(3H)-one (2.0 g, 10.5 mmol) in 40 ml thionyl chloride was added 0.8 ml of DMF and the mixture was heated at reflux overnight then evaporated to dryness to provide crude 4-chloro-7-nitroquinazoline.
A mixture of 1.6 g of 4-chloro-7-nitroquinazoline in 50 ml 7N ammonia in methanol was stirred overnight at rt and concentrated to dryness. The solid was suspended in water, filtered, rinsed with water followed by ether and dried overnight in vacuum oven to provide 0.98 g of 7-nitroquinazolin-4-amine (compound 98-2).
[Step 98-3] Synthesis of tert-Butyl 7-nitroquinazolin-4-ylcarbamate (compound 98-3) To a suspension of 7-nitroquinazolin-4-amine (0.98 g, 5.2 mmol) in 20 ml THF at rt was added a IM solution of di-tert-butyldicarbonate in THF (10.3 ml, 10.3 mmol, 2 eq.) followed by a IM solution of LHMDS in THF (8.8 mmol, 1.7 eq.). The resultant clear solution was stirred for 10 min. quenched with aq. NH4Cl, extracted 3x with ethyl acetate, the combined organic layers washed with brine, dried over MgSO4, filtered, concentrated and purified by chromatography eluting with 30% ethyl acetate in hexanes to provide 713 mg of tert-butyl 7-nitroquinazolin-4-ylcarbamate (compound 98-3). [Step 98-4] Synthesis of tert-buty\ 7-aminoquinazolin-4-ylcarbamate (compound 98-4) A mixture of 600 mg of tert-butyl 7-nitroquinazolin-4-ylcarbamate and 150 mg of 10% Pd-C in 15 ml each of THF and MeOH was stirred overnight under a hydrogen ballo tography eluting with 5% methanol in dichloromethane to provide 385 mg of tert-butyl 7-aminoquinazolin-4-ylcarbamate (compound 98-4). MS m/e = 261.1 (MH+)
(Step 98-5 J
Synthesis of compound 98-5.
Compound 98-5 was prepared using a procedure similar to the preparation of compound 93-3.
[Step 98-61 Synthesis of (R)-2-chloro-2-oxo-l -((R)-3-oxo-4-(4-(trifluoromethyl)- phenyl)morpholin-2-yl)ethyl acetate (compound 98-6)
To a solution of compound 98-5 (0.30 mmol) in 4 ml of dichloromethane was added oxalylchloride (75 μl, 0.886 mmol, 3 eq.) followed by 1 drop of DMF. Stirred at rt for 1 hr, added toluene and evaporated to dryness to provide crude compound 98-6 which was used as such for the next step.
[Step 98-7] Synthesis of N-(4-Amino-7-quinazolinyl)~alpha(R)-hydroxy-3-oxo- 4-[4-(trifluoromethyl)phenylJ-2(R)-morpholineacetamide (EXAMPLE 98)
To a solution of compound 98-6 (-0.15 mmol) in 2 ml dichloromethane at 0 °C was added tert-butyl 7-aminoquinazolin-4-ylcarbamate (compound 98-4) (77 mg, 0.30 mmol, 2 eq.) followed by pyridine (24 μl, 0.30 mmol, 2 eq.) and DMAP (2 mg, 0.016 mmol, 0.1 eq.). To the mixture was added 1 ml of acetonitrile and stirred overnight while warming to rt. It was diluted with ethyl acetate, washed with aq. NaHCC>3, water and brine, dried over MgSO4, filtered, concentrated to dryness. The residue was stirred overnight with 5 ml of 7N ammonia in methanol. The methanol was evaporated and the residue was stirred with 2 ml each of dichloromethane and trifluoroacetic acid for about 75 min. The mixture was evaporated to dryness and the residue was purified by
RPHPLC to provide 14 mg of EXAMPLE 98 EXAMPLES
The present invention will now be described in more detail using examples, but the present invention is not limited to the examples.
The measurement of nuclear magnetic resonance (NMR) spectrum (Table 1 ) was performed using a JEOL JNM-ECX300 FT-NMR (manufactured by JEOL Ltd.) or a JEOL JNM-ECX400 FT-NMR (manufactured by JEOL Ltd.).
Liquid chromatography-mass spectrometry (LC-MS, Table 2) was performed using a Waters FractionLynx MS system (manufactured by Waters Corporation) from the Example 1 to Example 38. A SunFire column™ (4.6 mm x 5 cm, 5 μm)
(manufactured by Waters Corporation) was used as an analytical column. A SunFire column™ (19 mm x 5 cm, 5 μm) (manufactured by Waters Corporation) was used as a preparative column. Methanol and 0.05% aqueous acetic acid solution or 0.05% aqueous trifluoroacetic acid solution were used as the mobile phase. Acetonitrile and 0.05% aqueous acetic acid solution or 0.05% aqueous trifluoroacetic acid solution were also used as the mobile phase. The analysis was performed under the following gradient conditions: Methanol: 0.05% aqueous acetic acid solution or 0.05% aqueous trifluoroacetic acid solution = 1 :9 (0 minutes), 10:0 (5 minutes), and 10:0 (7 minutes). Acetonitrile: 0.05% aqueous acetic acid solution or 0.05% aqueous trifluoroacetic acid solution = 1 :9 (0 minutes), 9: 1 (5 minutes), and 9:1 (7 minutes). The solvent systems are described as the followings: A indicates MeOH-AcOH, B indicates MeOH-TFA, C indicates MeCN-AcOH, and D indicates MeCN-TFA.
Examples aal - aa38
EXAMPLE aal
Synt droxy- N-[4-(N-methylcarbamimidoyl)phenyl]acetamide hydrochloride (EXAMPLE aal)
Figure imgf000143_0001
[Step 1-1] Synthesis of 4-tert~butyl-N-(2-chloroethyl)aniline (compound aal- 1)
To a solution of 4-tert-butylaniline (5.00 g) in MeOH (100 mL) was added
40% chroloacetaldehyde solution in water (8.24 mL) and AcOH (3.84 mL) at 0 °C. The mixture was stirred for 15 minutes at the same temperature, sodium
acetoxyborohydride (NaBH(OAc)3 ; 14.2 g) was added into the reaction mixture at one portion and the mixture was stirred for 15 minutes.
The reaction mixture was diluted with water and was extracted with
EtOAc. The extract was washed with water, sat.NaHCO3 and brine. The organic layer was dried with anhyd. Na2SO4. It was filtrated to remove insoluble matters and it was concentrated in vacuo. The residue was purified by silica gel flush chromatography (NH-type, eluent : Hexane) to obtain aal-1 (4.8 g) as pale yellow oil.
[Step 1-2] Synthesis of (2R,3R)-2,3-diacetyloxy-4-(4-cyanoanilino)-4-oxobutanoic acid (compound aal -2)
To a solution of (+)-Diacetyl-L -tartaric anhydride (9.15 g) in dry DMF (100 mL), was added 4-aminobenzonitrile (5 g,) under ice cooling and the reaction mixture was stirred at room temperature overnight to obtain compound aal -2. The solution of compound aal -2 was used in the next step without any treatment. [Step 1-3]
Synthesis of [(2R,3R)-3-acetyloxy- l-[4-tert-butyl-N-(2-chloroethyl)anilino]-4-
(4-cyanoanilmo)- 1 ,4-dioxobutan-2-yl] acetate (compound aal-3)
The above DMF solution of aal-2 (25.4 mL) was diluted with CH2Cl2 (25.4 mL). The internal temperature of the mixture was kept below -70 °C over all additions with dry ice bath.
Oxalyl chloride ( 1.0 mL) in CH2Cl2 (3 mL) was added dropwise into the reaction mixture. After stirring for 1 hour, pyridine (3.67 mL) was added dropwise thereto and stirred for 15 min. Then compound aal-1 (2.28 g) in CH2Cl2 (13.7 mL) was added dropwise into the reaction mixture. The mixture was stirred below -70 °C for 12 hours.
The reaction mixture was quenched with water and was extracted with EtOAc. The extract was washed with water, 1 N HCl, SaLNaHCO3 and brine. The organic layer was dried with anhyd. Na2SO4. It was filtrated and was concentrated in vacuo. The residue was purified by silica gel flush chromatography (eluent : Hexane : EtOAc = 90 : 10 ~ 25 : 75) to obtain 1-3 (1.19 g) as a white amorphous solid.
[Step 1-4] Synthesis of (2R,3R)-N-(4-tert-butylphenyl)-N-(2-chloroethyl)-N'-(4- cyanophenyl)-2,3-dihydroxybutanediamide (compound aal-4)
To a solution of aal-3 (0.3 g) in MeOH (6 mL), was added 8N NH3 /
MeOH (0.36 mL) at 0 °C and the mixture was stirred for 10 minutes in the same temperature. The mixture was concentrated and was dried in vacuo to obtain crude aal-4. The crude aal -4 was used in the next step without further purification. [Step Synthesis of (2R)-2-[(2R)-4-(4-tert-butylphenyl)-3-oxomorphoIin-2-yl]-N-(4- cyanophenyl)-2-hydroxyacetamide (compound aal-5)
The crude aal-4 was dissolved in t-BuOH (4.5 mL)-DMS0 (3 mL), and t-BuOK (191 mg) was added portionwise into the reaction mixture at 0 °C. The mixture was stirred for 5 minutes in the same temperature.
To the reaction mixture was added IN HCl and Et2O to obtain precipitate. Then the precipitate was collected by filtration, was rinsed with water, was washed with Et2θ and was dried in vacuo to obtain aa 1 -5 ( 115 mg) as a white amorphous solid. [Step 1 -6] Synthesis of (2R)-2-[(2R)-4-(4-tert-butylphenyl)-3-oxomorpholin-2-yl]-2- hydroxy-N-[4-(N-methylcarbamimidoyl)phenyl]acetamide hydrochloride (EXAMPLE aal)
A mixture of compound aal-5 (0.15 g) in CH2Cl2-MeOH (10-50 mL) was bubbled with HCl gas at 0 °C for Ih. Then the mixture was left at room
temperature overnight. The mixture was concentrated in vauo. Then the resulting mixture was solved in MeOH (10 mL) and 2M MeNH2 in THF (0.74 mL) were added into the mixture at 0 °C. The solution was stirred at room temperature overnight. The solvent was removed and the resulting residue was purified by preparative LC/MS to obtain EXAMPLE aal (15 mg) as a beige amorphous solid.
EXAMPLE aa2
Synthesis of (2R)-2-hydroxy-N-( 1 -imino-2.3-dihydroisoindol-5-yl)-2- [(2R)-3-oxo-4-(l-oxo-2,3-dihydroisoindol-5-yl)morpholin-2-yl]acetamide
hydrochloride (EXAMPLE aa2)
Figure imgf000146_0001
[Step 2- 1] Synthesis of 2-[tert-butyl(diphenyl)silyl|-5-iodo-3H-isoindol-1-one (compound aa2-l )
To a suspension of 5-iodo-2,3-dihydroisoindol-1-one (3 g) in DMF (60 niL), were added N,N-dimthylaminopyridine (DMAP: 14 mg), Et3N (4.84 mL) and tert-butyl-diphenylsilyl chloride (9.0 mL). The mixture was stirred at 50 °C for 2 h. After cooling, saturated NaHCO3 aq. was added into the reaction mixture. Then it was extracted with EtOAc. The organic layer was washed with water and brine, then was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The tritulation with Et^O followed by filtration gave compound aa2-l (2.78 g) as a yellow amorphous solid.
[Step 2-2] Synthesis of tert-butyl (2R)-2-[(2R)-4-[2-[tert-butyl(diphenyl)silyl]-
1 -oxo-3H-isoindol-5-yl]-3-oxomorpholin-2-yl]-2-hydroxyacetate (compound aa2-2)
The mixture of (R)-tert-butyl (2-hydroxy-2-(R)-3-oxomorpholin-
2-yl)acetate (1.2 g) and compound 2-1 (2.71 g) were solved in degassed DMSO (17 mL). Then crushed K3PO4 (2.2 g) and CuI (0.2 g) were added into the mixture. Then trans-N,N-dimethyl cyclohexanediamine (0.49 mL) was immediately added into the mixture. The mixture was stirred at room temperature for 3 h, then CuI (0.1 g) and trans-N,N-dimethyl cyclohexanediamine (0.29 mL) were added to complete the reaction The reaction mixture was stirred at room temperature for more 2 h Then, 1 N HCl solvent was washed with water and brine. It was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (Hexane/EtOAc =100/0 - 50/50) to obtain compound aa2-2 (1.40 g) as a pale yellow amorphous solid.
[Step 2-3] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-4-[2- ftert-butyl(diphenyl)silyll-1-oxo-3H-isoindol-5-yll-3-oxomorpholin-2-yl]acetate (compound aa2-3)
To the solution of compound aa2-2 (0.1 g) and DMAP (2.0 mg) in CH2Cl2 ( 1.7 mL), were added pyridine (27 uL) and Ac2O (31 uL) at 0°C. The mixture was stirred at 0 °C for 75 min. Then the mixture was diluted with EtOAc, the organic layer was washed with 5% CuSO4 aq., water and brine. It was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain compound aa2-3 (101 mg) as a white amorophous solid. It was used to the next step without further purification.
[Step 2-4] Synthesis of (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(l -oxo-2,3- dihydroisoindol-5-yl)morpholin-2-yl]acetic acid (compound aa2-4)
To a solution of compound aa2-3 (91 mg) in CH2Cl2 (0.6 mL), was added trifluoroacetic acid (TFA: 2.4 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo. The resulting residue was co-evaporated with CH2Cl2, several times. Then trituration with Et2O gave compound aa2-4 (46 mg) as a white amorphous solid. [Step amino]- methyl]-4-cyanoanilino]-2-oxo-1-[(2R)-3-oxo-4-(l-oxo-2,3-dihydroisoindol-5-yl)moφ holin-2-yl]ethyl] acetate (compound aa2-5)
To the suspension of compound aa2-4 (40 mg),
N-[(5-amino-2-cyanophenyl)methylJ-N-f(2-methylpropan-2-yl)oxycarbonyl]carbamate (39.9 mg) and DMAP ( 1.4 mg) in CH2Cl2 (1.1 mL), were added WSC-HCl (28.6 mg) at 0°C. The reaction mixture was stirred at 0 °C for 4 h. The mixture was diluted with EtOAc and the organic layer was washed with IN HCl and brine. It was dried over anhydrous Na^SO4 and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (EtOAc /MeOH= 100/0 - 90/10) to obtain compound aa2-5 (26 mg) as a colorless amorphous solid.
[Step 2-6] Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-hydroxy-2-[(2R)-3-oxo- 4-(l-oxo-2,3-dihydroisoindol-5-yl)morpholin-2-yl]acetyl]amino]phenyl]methyl]-N-[(2- methylpropan-2-yl)oxycarbonyl]carbamate (compound aa2-6)
A solution of compound aa2-5 (25.9 mg) in 8N NH3-MeOH (1 mL) was stirred at room temperature for 2 h. Then the solvent was removed in vacuo.
Acetonitrile was added to the resulting residue and the mixture was concentrated in vacuo to obtain compound aa2-6 (23 mg) as a white amorphous solid. [Step 2-7] Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyl]-2- hydroxy-2-[(2R)-3-oxo-4-(l-oxo-2,3-dihydroisoindol-5-yl)morpholin-2-yl]acetamide hydrochloride (compound aa2-7)
Compound aa2-6 (23 mg) was suspended in 4N HCl-dioxane (2 mL). The reaction mixture was stirred at room temperature for 2 h and evaporated. The resid (17 mg) as a colorless amorphous solid.
[Step 2-81 Synthesis of (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)- 2-[(2R)-3-oxo-4-(l-oxo-2,3-dihydroisoindol-5-yl)morpholin-2-yl]acetamide hydrochloride (EXAMPLE aa2)
A solution of compound aa2-7 ( 15 mg) in EtOH (3 mL) was refluxed for 7 h 30 m. After cooling, the mixture was concentrated in vacuo and trituration with Et2θ followed by filtration gave EXAMPLE aa2 (14.8 mg) as a colorless amorphous solid.
EXAMPLE aa3
Synthesis of (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2- [(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]acetarnide hydrochloride (EXAMPLE aa3)
Figure imgf000149_0001
[Step 3- 1 ] Synthesis of tert-butyl (2R)-2~hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1H- quinolin-6-yl)morpholin-2-yl]acetate (compound aa3- l)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, 6-iodo- 1H-quinolin-2-one (2.00 g) was used instead of aa2-l to obtain compound aa3-l ( 1.13 g) as a colorless amorphous solid.
[Step 3 2] Synthesis of tert butyl (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo- 1H- According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa3-l (1.00 g) was used instead of aa2-2 to obtain compound aa3-2 (0.85 g) as a colorless amorphous solid. [Step 3-31 Synthesis of (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo-1H- quinolin-6-yl)morpholin-2-yl]acetic acid (compound aa3-3)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aa3-2 (0.80 g) was used instead of aa2-3 to obtain compound aa3-3 (0.56 g) as a pale brown amorphous solid.
[Step 3-4] Synthesis of [(lR)-2-[3-[[bis[(2-methylpropan-2-yl)oxycarbonyl]- amino]methyl]-4-cyanoanilino]-2-oxo-1-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl)morp holin-2-yl]ethyll acetate (compound aa3-4)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aa3-3 (0.10 g) was used instead of aa2-4 to obtain compound aa3-4 (47 mg) as a colorless amorphous solid.
[Step 3-5] Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-hydroxy-2-[(2R)-3- oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]acetyl]amino]phenyl]methyl]-N-[(2-me thylpropan-2-yl)oxycarbonyl]carbamate (compound aa3-5)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aa3-4 (45 mg) was used instead of aa2-5 to obtain compound aa3-5 (35 mg) as a colorless amorphous solid. [Step Synthesis of methyl (2R)-2-hydroxy-2-[(2R)-4-(4-iodophenyl)-3- oxomorpholin-2-yl]acetate hydrochloride (compound aa3-6)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa3-5 (35 mg) was used instead of aa2-6 to obtain compound aa3-6 (25 mg) as a colorless amorphous solid.
[Step 3-7] Synthesis of (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisomdol- 5-yl)-2-[(2R)-3-oxo-4-(2-oxo- 1H-quinolin-6-yl)morpholin-2-yl]acetamide
hydrochloride (EXAMPLE aa3)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa3-6 (25 mg) was used instead of aa2-7 to obtain EXAMPLE aa3 (20 mg) as a pale brown amorphous solid.
EXAMPLE aa4
Synthesis of (2R)-2-[(2R)-4-[7-(difluoromethoxy)-2-oxo- 1H-quinolin-6-yl]-3- oxomorpholin-2-yl]-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)acetamide hydrochloride (EXAMPLE aa4)
Figure imgf000151_0001
[Step 4-1] Synthesis of 2-(difluoromethoxy)-1-iodo-4-nitrobenzene (compound aa4-l)
A mixture of 2-iodo-5-nitrophenol (8.98 g), K2CO3 ( 18.7 g) and
2-ch L) was stirred at 110 °C for 3.5 h and at room temperature for 12 h. The mixture was diluted with EtOAc and washed with 1H HCl, saturated NaHCCH aq., water and brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (Hexane/EtOAc = 9/1 ) to obtain compound aa4- 1 (9.17 g) as a brown amorphous solid.
[Step 4-21 Synthesis of 3-(difluoromethoxy)-4-iodoaniline (compound aa4-2)
A mixture of compound aa4-l (8 g) and Na2S2C>4 in THF-EtOH-^O (150-75-225 mL) was stirred at 0 °C for Ih and at room temperature for 6 h.The mixture was extracted with EtOAc and the organic layer was washed with H2O, brine. It was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain compound aa4-2 (2.36 g) as brown oil. It was used to the next step without further purification. [Step 4-31 Synthesis of (E)-N-[3-(difluoromethoxy)-4-iodophenyl]-3-ethoxyprop-
2-enamide (compound aa4-3)
To a solution of compound aa4-2 (2.35 g) and pyridine (1.33 mL) in
CH2CI2 (60 mL), was added dropwise 3-ethoxy-2-propenoyl chloride (1.33 g) at 0°C.
The reaction mixture was stirred at 0°C for 5 min and at room temperature for 20 min. The mixture was concentrated in vacuo, and the resulting residue was solved in EtOAt and the organic layer was washed with IN HCl, saturated NaHCO3 aq., water and brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain compound aa4-3 (3.2 g) as brown oil. It was used to the next step without further purifi tio [Step 4-4] Synthesis of 7-(difluoromethoxy)-6-iodo-1H-quinolin-2-one (compound aa4-4)
To compound aa4-3 (3.15 g), cone. H2SO4 was added dropwise at 0 °C. The mixture was stirred at 0 °C for 10 min then it was poured into crashed ice. The mixture was diluted with water and it was extracted with EtOAc. The organic layer was washed with saturated NaHCO3 aq., water and brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain compound aa4-4 (2.06 g) as a pale brown amorphous solid. It was used to the next step without further purification. [Step 4-5] Synthesis of tert-butyl (2R)-2-[(2R)-4-[7-(difluoromethoxy)-2- oxo-1H-quinolin- 6-yl]-3-oxomorpholin-2-yl]-2-hydroxyacetate (compound aa4-5)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, compound aa4-4 (1.91 g) was used instead of aa2-l to obtain compound aa4-5 (0.6 g) as a brown amorphous solid.
[Step 4-6] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-4-[7-(difluoromethoxy)- 2-oxo- 1H-quinolin-6-yl]-3-oxomorpholin-2-yl]acetate (compound aa4-6)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa4-5 (0.59 g) was used instead of aa2-2 to obtain compound aa4-6 (0.58 g) as a brown amorphous solid.
[Step 4-7] Synthesis of (2R)-2-acetyloxy-2-[(2R)-4-[7-(difluoromethoxy)-2- oxo-1H-quinolin-6-yl]-3-oxomorpholin-2-yl]acetic acid (compound aa4-7)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, comp 7 (0.53 g) as a brown amorphous solid.
[Step 4-81 Synthesis of [(lR)-2-[3-[[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]- methyl]-4-cyanoanilino]- 1 -[(2R)-4-[7-(difluoromethoxy)-2-oxo- 1 H-quinolin-6-yl]-3-ox omorpholin-2-yl]-2-oxoethyl] acetate (compound aa4-8)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aa4-7 (0.35 g) was used instead of aa2-4 to obtain compound aa4-8 (97 mg) as a pale yellow amorphous solid. [Step 4-9] Synthesis of tert-butyl N-L[2-cyano-5-[[(2R)-2-[(2R)-4-[7-
(difluoromethoxy)-2-oxo- 1H-quinolin-6-yl]-3-oxomorpholin-2-ylJ-2-hydroxyacetylJam ino]phenyl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (compound aa4-9)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aa4-8 (96 mg) was used instead of aa2-5 to obtain compound aa4-9 (88 mg) as a white amorphous solid.
[Step 4- 10] Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyl]-2-[(2R)-4-[7- (difluoromethoxy)-2-oxo-1H-quinolin-6-yl]-3-oxomorpholin-2-yl]-2-hydroxyacetamid e hydrochloride (compound aa4- 10)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa4-9 (82 mg) was used instead of aa2-6 to obtain compound aa4-10 (59 mg) as a white amorphous solid. [Step nolin- 6-yl]-3-oxomorpholin-2-yll-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)acetamide hydrochloride (EXAMPLE aa4)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa4-10 (57 mg) was used instead of aa2-7 to obtain EXAMPLE aa4 (39 mg) as a white amorphous solid.
EXAMPLE aa5
Synthesis of (2R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-[(2R)- 3-oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]acetamide hydrochloride
(EXAMPLE aa5)
Figure imgf000155_0001
[Step 5-11 Synthesis of [(lR)-2-oxo-2-[4-(5-oxo-2H-1,2,4-oxadiazol-3-yl)anilinoJ- l-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]ethyl] acetate (compound aa5-l)
To a solution of compound aa3-3 (100 mg) in DMF (2.5 mL), was added oxalyl chrolide (48 uL) at 0 °C. The reaction mixture was stirred at 0°C for 0.5 h, then CH2CI2 (2.5 mL) and pyridine (95.5 uL) were added into the reaction mixture at 0°C. The mixture was stirred at 0 °C for 0.5h, then 3-(4-aminophenyl)-l ,2,4-oxadiazol- 5(2H)-one (60.2 mg) was added into the mixture at 0 °C. The mixture was stirred at room temperature for 3 days. Then water and IN HCl were added into the reaction mixture and the mixture was extracted with EtOAc. The organic layer was washed with water oved under reduced pressure to obtain compound aa5-l (77 mg) as a beige amorphous solid. It was used to the next step without further purification.
[Step 5-2] Synthesis of (2R)-2-hydroxy-N-[4-(5-oxo-2H-1,2,4-oxadiazol-3- yl)phenylJ-2-L(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]acetamide ammonium salt (compound aa5-2)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aa5- 1 (75 mg) was used instead of aa2-5 to obtain compound aa5-2 (44 mg) as a beige amorphous solid.
[Step 5-3] Synthesis of (2R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-[(2R)- 3-oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]acetamide hydrochloride
(EXAMPLE aa5)
To the solution of compound aa5-2 (40 mg) in IN HCl-dioxane/MeOH - MeOH (= 0.34 - 40 mL), was added 10 % palladium charcoal (Pd/C: 40 mg). The reaction mixture was stirred under hydrogen gas atmosphere for 1 h. MeOH (20 mL) was added into the reaction mixture and the mixture was stirred for more 1.5 h to complete the reaction. Then Pd/C was removed by filtration with Celite® pad and rinsed with MeOH. The filtrate was concentrated in vacuo and trituration with MeOH/Et2θ followed by filtration gave EXAMPLE aa5 (30 mg) as a beige amorphous solid.
EXAMPLE aaό
Synthesis of (2R)-N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy-2- [(2R) 3 oxo 4 (2 oxo 1H quinolin 6 yl)morpholin 2 yl]acetamide hydrochloride (EX
Figure imgf000157_0001
LStep 6-11 Synthesis of [(lR)-2-[3-fluoro-4-(5-oxo-2H-1,2,4-oxadiazol-3-yl)anilino]- 2-oxo- l -[(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]ethyl] acetate (compound aa6- 1 )
According to the Step 5-1 in synthetic method for EXAMPLE aa5,
3-fluoro-4-(5-oxo-2H-1,2,4-oxadiazol-3-yl)aniline (55 mg) was used instead of 4-(5-oxo-2H-1,2,4-oxadiazol-3-yl)aniline to obtain compound aa6-l (31 mg) as a colorless amorphous solid. [Step 6-2] Synthesis of (2R)-N-[3-fluoro-4-(5-oxo-2H-l ,2,4-oxadiazol-3-yl)phenylJ- 2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]acetamide ammonium salt (compound aa6-2)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aa6- 1 (30 mg) was used instead of aa2-5 to obtain compound aa6-2 (28 mg) as a beige amorphous solid.
[Step 6-3J Synthesis of (2R)-N-(4-carbamirnidoyl-3-fluorophenyl)-2-hydroxy-2- [(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-ylJacetamide hydrochloride (EXAMPLE aa6)
According to the Step 5-3 in synthetic method for EXAMPLE aa5, compound aa6 2 (22 mg) was used instead of aa5 2 to obtain EXAMPLE aaό (19 mg) as a EXAMPLE aa7
Synthesis of (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-y l)-2- f(2R)-3-oxo-4-(2-oxo-1H-quinolin-7-yl)morpholin-2-yl]acetamide hydrochloride (EXAMPLE aa7)
Figure imgf000158_0001
EXAMPLE aa7
[Step 7- 1 ] Synthesis of 7-iodo-1H-quinolin-2-one (compound aa7-l)
According to the Step 4-4 in synthetic method for EXAMPLE aa4, (E)-N-(3-iodophenyl)-3-ethoxyprop-2-enamide (13.00 g) was used instead of aa4-3 to obtain compound aa7- 1 ( 1 1.2 g) as a colorless powder.
[Step 7-2] Synthesis of tert-butyl (2R)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo- 1H-quinolin- 7-yl)morpholin-2-yl] acetate (compound aa7-2)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, compound aa7-l (4.00 g) was used instead of aa2-l to obtain compound aa7-2 (1.76 g) as a yellow amorphous solid.
[Step 7-3] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo- 1H- quinolin-7-yl)morpholin-2-yl]acetate (compound aa7-3)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa7 2 (0 83 g) was used instead of aa2 2 to obtain compound aa7-3 (0.64 g) as a [Step 7-41 Synthesis of (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo- 1H-quinolin- 7-yl)morpholin-2-yl]acetic acid (compound aa7-4)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aa7-3 (0.63 g) was used instead of aa2-3 to obtain compound aa7-4 (0.50 g) as a pale yellow amorphous solid.
LStep 7-51 Synthesis of N-[[2~cyano-5-[[(2R)-2-hydroxy-2-[(2R)~3-oxo-4- (2-oxo-1H-quinolin-7-yl)morpholin-2-yllacetyllamino]phenyl]methyl]-N-[(2-methylpr opan-2-yl)oxycarbonyl]carbamate (compound aa7-5)
According to the Step 2-5 and 2-6 in synthetic method for EXAMPLE aa2, compound aa7-4 ( 1.0 g) was used instead of aa2-4 to obtain compound aa7-5 (0.39 g) as a pale yellow amorphous solid. [Step 7-6] Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyl]-2-hydroxy-2- [(2R)-3-oxo-4-(2-oxo-1H-quinolin-7-yl)morpholin-2-yl]acetamide hydrochloride (compound aa7-6)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa7-5 (0.38 g) was used instead of aa2-6 to obtain compound aa7-6 (0.27 g) as a yellow amorphous solid.
[Step 7-71 Synthesis of (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2- [(2R)-3-oxo-4-(2-oxo-1H-quinolin-7-yI)morpholin-2-yl]acetamide hydrochloride (EXAMPLE aa7)
E aa2, compound aa7-6 (0.27 g) was used instead of aa2-7 to obtain EXAMPLE aa7 (0.27 g) as a yellow amorphous solid.
EXAMPLE aa8
Synthesis of (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2-
[(2R)-4-(l-methyl-2-oxoquinolin-7-yl)-3-oxomorpholin-2-yl]acetamide hydrochloride (EXAMPLE aa8)
Figure imgf000160_0001
EXAMPLE aaδ
[Step 8-1] Synthesis of 7-iodo-l -methylquinolin-2-one (compound aa8-l)
To a solution of compound aa7-l (1 g) in DMF (18 mL), was added 60%
NaH (0.22 g) at 0°C and the mixture was stirred at 0°C for 15 min. Then MeI (0.46 mL) was added into the reaction mixture at 0°C and the mixture was stirred at room temperature for 3 h. After the reaction, water and IN HCl were added into the reaction mixture at 0 °C. The mixture was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 aq. and brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain the crude product. Trituration with hexane followed by filtration gave compound aa8- 1 (0.73 g) as a yellow amorphous solid. [Step 8-21 Synthesis of tert-butyl (2R)-2-hydroxy-2-[(2R)-4-( 1 -methyl-2-oxoquinolin- 7-yl) 3-oxomorpholin-2-yl]acetate (compound aa8-2)
E aa2, compound aa8-l (0.71 g) was used instead of aa2-l to obtain compound aa8-2 (0.43 g) as a yellow amorphous solid.
[Step 8-3] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-4-( l-methyl-2-oxoquinolin- 7-yl)-3-oxomorpholin-2-yI]acetate (compound aa8-3)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa8-2 (0.45 g) was used instead of aa2-2 to obtain compound aa8-3 (0.46 g) as a yellow amorphous solid. [Step 8-41 Synthesis of (2R)-2-acetyloxy-2-[(2R)-4-( 1 -methyl-2-oxoquinolin-
7-yl)-3-oxomorpholin-2-yl]acetic acid (compound aa8-4)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aa8-3 (0.45 g) was used instead of aa2-3 to obtain compound aa8-4 (0.48 g) as a pale brown amorphous solid.
[Step 8-5] Synthesis of [(lR)-2-[3-[[bis[(2-methylpropan-2-yl)oxycarbonyl] amino]methyl]-4-cyanoanilino]- l-[(2R)-4-(l-methyl-2-oxoquinolin-7-yl)-3-oxomorpho lin-2-yl]-2-oxoethyl] acetate (compound aa8-5)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aa8-4 (0.47 g) was used instead of aa2-4 to obtain compound aa8-5 (0.52 g) as a yellow amorphous.
[Step 8-6] Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-hydroxy-2-[(2R)-4-(l- methyl 2 oxoquinolin-7 yl) 3-oxomorpholin 2 yl]acetyl]amino]phenyl]methyl]-N-[(2- meth According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aa8-5 (0.51 g) was used instead of aa2-5 to obtain compound aa8-6 (0.47 g) as a yellow amorphous solid. LStep 8-7] Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyl]-2- hydroxy-2-[(2R)-4-( l-methyl-2-oxoquinolin-7-yl)-3-oxomorpholin-2-yl]acetamide hydrochloride (compound aa8-7)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa8-6 (0.46 g) was used instead of aa2-6 to obtain compound aa8-7 (0.35 g) as a pale yellow amorphous solid.
[Step 8-8] Synthesis of (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol- 5-yl)-2-[(2R)-4-( l-meftyl-2-oxoquinolin-7-yl)-3-oxomorpholin-2-yl]acetamide hydrochloride (EXAMPLE aa8)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa8-7 (0.34 g) was used instead of aa2-7 to obtain EXAMPLE aa8 (0.33 g) as a pale yellow amorphous solid.
EXAMPLE aa9
Synthesis of (2R)-2-[(2R)-4-[ 1 -(cyclopropylmethyl)-2-oxoquinolin-
7-yl]-3-oxomorpholin-2-ylJ-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)acetamide hydrochloride (EXAMPLE aa9)
Figure imgf000163_0001
EXAMPLE aa9
[Step 9- IJ Synthesis of l-(cyclopropylmethyl)-7-iodoquinolin-2-one (compound aa9-l)
According to the Step 8-1 in synthetic method for EXAMPLE aa8, (bromomethyl)cycloprolane ( 1.00 g) was used instead of iodomethane to obtain compound aa9-l (0.48 g) as a colorless amorphous solid.
[Step 9-21 Synthesis of tert-butyl (2R)-2-[(2R)-4-[l-(cyclopropylmethyl)-2- oxoquinolin-7-yll-3-oxomorpholin-2-yl]-2-hydroxyacetate (compound aa9-2)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, compound aa9-l (0.47 g) was used instead of aa2-l to obtain compound aa9-2 (0.34 g) as a colorless amorphous solid.
[Step 9-3] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-4-[l-(cyclopropylmethyl)- 2-oxoquinolin-7-yl]-3-oxomorpholin-2-yl]acetate (compound aa9-3)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa9-2 (0.34 g) was used instead of aa2-2 to obtain compound aa9-3 (0.37 g) as a colorless amorphous solid.
[Step 9-4] Synthesis of (2R)-2-acetyloxy-2-[(2R)-4-[l-(cyclopropylmethyl)- 2-oxoquinolin-7-yl]-3-oxomorpholin-2-yl]acetic acid (compound aa9-4)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, com -4 (0.32 g) as a colorless amorphous solid.
[Step 9-51 Synthesis of [(lR)-2-[3-[[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]- methyl]-4-cyanoanilino]- 1 -[(2R)-4-[ 1 -(cyclopropylmethyl)-2-oxoquinolin-7-yl]-3-oxo morpholin-2-ylJ-2-oxoethyl] acetate (compound aa9-5)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aa9-4 (0.32 g) was used instead of aa2-4 to obtain compound aa9-5 (0.42 g) as a colorless amorphous solid. [Step 9-61 Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-[(2R)-4-[ 1 -
(cyclopropylmethyl)-2-oxoquinolin-7-yl]-3-oxomorpholin-2-yl]-2-hydroxyacetyl]amin o]phenyl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (compound aa9-6)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aa9-5 (0.41 g) was used instead of aa2-5 to obtain compound aa9-6 (0.38 g) as a colorless amorphous solid.
LStep 9-7] Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyll-2-[(2R)-4- [l-(cyclopropylmethyl)-2-oxoquinolin-7-yl]-3-oxomorpholin-2-yl]-2-hydroxyacetamid e hydrochloride (compound aa9-7)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa9-6 (0.39 g) was used instead of aa2-6 to obtain compound aa9-7 (0.30 g) as a colorless amorphous solid.
[Step 9-81 Synthesis of (2R)-2-[(2R)-4-[l-(cyclopropylmethyl)-2-oxoquinolin- 7-yll )acetamide hydrochloride (EXAMPLE aa9)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa9-7 (0.30 g) was used instead of aa2-7 to obtain EXAMPLE aa9 (0.24 g) as a yellow amorphous solid.
EXAMPLE aalO
Synthesis of methyl 2-|7-[(2R)-2-[( IR)-I -hydroxy-2-L(l -imino-2,3-dihydroisoindol- 5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxoquinolin-1-yl]acetate hydrochloride (EXAMPLE aalO)
Figure imgf000165_0001
EXAMPLE aa10
[Step 10-1 ] Synthesis of methyl 2-(7-iodo-2-oxoquinolin-1-yl)acetate (compound aalO-1)
According to the Step 8- 1 in synthetic method for EXAMPLE aa8, methyl bromoacetate (1.75 ml) was used instead of iodomethane to obtain compound aalO-1 (1.76 g) as a pale yellow amorphous solid.
[Step 10-2] Synthesis of tert-butyl (2R)-2-hydroxy-2-[(2R)-4-[l-(2-methoxy-2- oxoethy l)-2-oxoquinolin-7-y 1] -3-oxomorphol in-2-yl] acetate (compound aa 10-2)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, compound aa 10-1 (1.69 g) was used instead of aa2-l to obtain compound aal 0-2 (1.52 g) as a yellow amorphous solid [Step 10-3] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-4-[l-(2- methoxy-2-oxoethyl)-2- oxoquinolin-7-yl]-3-oxomorpholin-2-yl]acetate (compound aalO-3)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aalO-2 ( 1.50 g) was used instead of aa2-2 to obtain compound aal 0-3 ( 1.77 g) as a pale yellow amorphous.
[Step 10-4] Synthesis of (2R)-2-acetyloxy-2-[(2R)-4-[ l -(2-methoxy-2-oxoethyl)-2- oxoquinolin-7-yl]-3-oxomorpholin-2-yl]acetic acid (compound aalO-4)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aal 0-3 (1.63 g) was used instead of aa2-3 to obtain compound aalO-4 (1.69 g) as a pale yellow amorphous.
[Step 10-5] Synthesis of methyl 2-[7-[(2R)-2-[( IR)-I -acetyloxy-2-[3-[[bis[(2- methylpropan-2-yl)oxycarbonyl]aminoJmethyl]-4-cyanoanilino]-2-oxoethyl]-3-oxomor pholin-4-y]J-2-oxoquinolin-1-ylJacetate (compound aal0-5)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aalO-4 ( 1.00 g) was used instead of aa2-4 to obtain compound aal0-5 (1.13 g) as a pale yellow amorphous.
[Step 10-61 Synthesis of methyl 2-[7-[(2R)-2-[(lR)-2-[3-[[bis[(2-methylpropan-2- yl)oxycarbonyl]amino]methyl]-4-cyanoanilino]- l-hydroxy-2-oxoethyl]-3-oxomorpholi n-4-yl]-2-oxoquinolin-1-yl]acetate (compound aalO-6)
To a solution of compound aal0-5 (04 g) in MeOH (5 3 mL) was added 28% at 0 °C for 15 min. Then water was added into the mixture and it was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain compound aalO-6 (0.34 g) as a pale yellow amorphous solid. It was used to the next step without further purification.
[Step 10-7] Synthesis of methyl 2-[7-[(2R)-2-[(lR)-2-[3-(aminomethyl)-4- cyanoanilino]-1-hydroxy-2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxoquinolin-1-yl]acetate hydrochloride (compound aalO-7)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aalO-6 (0.32 g) was used instead of aa2-6 to obtain compound aalO-7 (0.22 g) as a pale yellow amorphous solid.
[Step 10-8] Synthesis of methyl 2-[7-[(2R)-2-[( lR)-1-hydroxy-2-[(l -imino-2,3- dihydroisoindol-5-yl)aminol-2-oxoethyl]-3-oxomorpholin-4-yll-2-oxoquinolin-1-yl]ace tate hydrochloride (EXAMPLE aa 10)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aalO-7 (0.21 g) was used instead of aa2-7 to obtain EXAMPLE aalO (0.20 g) as a pale yellow amorphous solid. EXAMPLE aa 11
Synthesis of 2-[7-[(2R)-2-[( IR)-I -hydroxy-2-[(l -immo-2,3-dihydroisoindol- 5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxoquinolin-1-yl]acetic acid hydrochloride (EXAMPLE aal 1 )
Figure imgf000168_0001
EXAMPLE aa11
[Step 11-1] Synthesis of 2-[7-[(2R)-2-[(lR)-2-[3-[[bis[(2-methylpropan-2- yl)oxycarbonyl]amino]methyl]-4-cyanoanilino]-1-hydroxy-2-oxoethylJ-3-oxomorpholi n-4-yl]-2-oxoquinolin-1-yl]acetic acid (compound aal 1- 1)
To a solution of compound aal 0-5 (0.4 g) in MeOH (5 mL), was added
IN NaOH (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 35 min. Then water and IN HCl were added into the mixture and it was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous NaISO4. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (CH?Cl2/MeOH = 95/5) to obtain compound aal 1 - 1 (0.18 g) as a white amorphous solid.
[Step 11 -2] Synthesis of 2-[7-[(2R)-2-[(lR)-2-[3-(aminomethyl)-4-cyanoanilino]- 1 -hydroxy-2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxoquinolin- 1 -yl]acetic acid hydrochloride (compound aal 1-2)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aal 1-1 (0.18 g) was used instead of aa2-6 to obtain compound aal 1-2 (0.13 g) as a white amorphous solid. [Step 11 -3] Synthesis of 2-[7-[(2R)-2-[( IR)-I -hydroxy-2-[(l -imino-2.3- dihydroisoindol-5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxoquinolin-1-yl]ace tic ac According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aal 1 -2 (0.13 g) was used instead of aa2-7 to obtain EXAMPLE aal 1 (0.11 g) as a white amorphous solid. EXAMPLE aal 2
Synthesis of (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2-[(2R)- 4-(8-methyl-2-oxo-1H-quinolin-7-yl)-3-oxomorpholin-2-yl]acetarnide hydrochloride (EXAMPLE aal 2)
Figure imgf000169_0001
EXAMPLE aal 2
[Step 12-1] Synthesis of (E)-3-ethoxy-N-(3-iodo-2-methylphenyl)prop-2-enamide (compound aa 12- 1 )
According to the Step 4-3 in synthetic method for EXAMPLE aa4, 3-Iodo-2-methylaniline (0.50 g) was used instead of aa4-2 to obtain compound aal 2-1 (0.68 g) as a brown amorphous solid.
LStep 12-2] Synthesis of 7-iodo-8-methyl-1H-quinolin-2-one (compound aal2-2)
According to the Step 4-4 in synthetic method for EXAMPLE aa4, compound aal2-l (0.68 g) was used instead of aa4-3 to obtain compound aal2-2 (0.47 g) as a pale yellow amorphous solid.
[Step 12 3] Synthesis of tert butyl (2R) 2 hydroxy 2 [(2R) 4 (8 methyl 2 oxo-1H- quin According to the Step 2-2 in synthetic method for EXAMPLE aa2, compound aal2-2 (0.20 g) was used instead of aa2-l to obtain compound aal2-3 (89 mg) as a pale yellow amorphous solid. LStep 12-4] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-4-(8-methyl-2-oxo- 1 H- quinolin-7-yl)-3-oxomorpholin-2-yl]acetate (compound aal2-4)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa 12-3 ( 1.11 g) was used instead of aa2-2 to obtain compound aa 12-4 ( 1.23 g) as a yellow amorphous solid.
LStep 12-5] Synthesis of (2R)-2-acetyloxy-2-[(2R)-4-(8-methyl-2-oxo- 1H-quinolin- 7-yl)-3-oxomorpholin-2-yl]acetic acid (compound aal2-5)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aal2-4 (1.22 g) was used instead of aa2-3 to obtain compound aal2-5 ( 1.39 g) as a colorless amorphous solid.
[Step 12-6] Synthesis of L( lR)-2-L3-L[bis[(2-methylpropan-2-yl)oxycarbonyl]- amino]methyl]-4-cyanoanilino]-1-L(2R)-4-(8-methyl-2-oxo- 1H-quinolin-7-yl)-3-oxomo rpholin-2-yl]-2-oxoethyl] acetate (compound aal2-6)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aal2-5 (1.38 g) was used instead of aa2-4 to obtain compound aal2-6 (0.89 g) as a pale yellow amorphous solid.
[Step 12-7] Synthesis of tert-butyl N-LL2-cyano-5-l[(2R)-2-hydroxy-2-L(2R)-4-(8- meth methyl]-N- [(2-methylpropan-2-yl)oxycarbonyl]carbamate (compound aal2-7)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aal2-6 (0.88 g) was used instead of aa2-5 to obtain compound aal2-7 (0.80 g) as a pale yellow amorphous solid.
[Step 12-8] Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyl]-2-hydroxy-
2-f(2R)-4-(8-methyl-2-oxo-1H-quinolin-7-yl)-3-oxomorpholin-2-yl]acetamide hydrochloride (compound aal2-8)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aal2-7 (0.78 g) was used instead of aa2-6 to obtain compound aal2-8 (0.57 g) as a pale yellow amorphous solid.
[Step 12-9J Synthesis of (2R)-2-hydroxy-N-(l -imino-2,3-dihydroisoindol- 5-yl)-2-[(2R)-4-(8-methyl-2-oxo-1H-quinolin-7-yl)-3-oxomorpholin-2-yllacetamide hydrochloride (EXAMPLE aa 12)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aal2-8 (0.56 g) was used instead of aa2-7 to obtain EXAMPLE aal2 (0.55 g) as a pale yellow amorphous solid. EXAMPLE aa 13
Synthesis of (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)- 2-[(2R)-4-(2-methoxyquinolin-7-yl)-3-oxomorpholin-2-yl]acetamide hydrochloride (EXAMPLE aa 13)
Figure imgf000172_0001
EXAMPLE aa13
[Step 13- IJ Synthesis of 7-iodo-2-methoxyquinoline (compound aal3-l)
To a solution of compound aa7-l ( 1.00 g) in CH2CI2 (100 mL), was added trimethyloxonium tetrafluoroborate (1.09 g) at 0 °C. The reaction mixture was stirred at room temperature for 4 days. The mixture was concentrated in vacuo, then water was added to the resulting residue. The mixture was extracted with EtOAc and the organic layer was washed with brine and was dried over anhydrous NaiSCλt. The solvent was removed under reduced pressure to obtain compound aal3-l (0.95 g) as a colorless amorphous solid. It was used to the next step without further purification. fStep 13-2] Synthesis of tert-butyl (2R)-2-hydroxy-2-[(2R)-4-(2-methoxyquinolin-7- yl)-3-oxomorpholin-2-yll acetate (compound aal3-2)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, compound aal3-l (0.93 g) was used instead of aa2-l to obtain compound aal 3-2 (0.28 g) as a colorless amorphous solid.
[Step 13-3] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-4-(2-methoxyquinolin- 7-yl)-3-oxomorpholin-2-yl]acetate (compound aal3-3)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aal3-2 (0.28 g) was used instead of aa2-2 to obtain compound aal3-3 (0.32 g) as a colorless amorphous solid [Step 13-4] Synthesis of (2R)-2-acetyloxy-2-[(2R)-4-(2-methoxyquinolin-7-yI)- 3-oxomorpholin-2-yl]acetic acid (compound aal3-4)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aal3-3 (0.31 g) was used instead of aa2-3 to obtain compound aal3-4 (0.27 g) as a colorless amorphous solid.
[Step 13-51 Synthesis of [OR)-2-[3-[[bis[(2-methylpropan-2-yI)oxycarbonyl]- amino]methyl]-4-cyanoanilino]-1-[(2R)-4-(2-methoxyquinolin-7-yl)-3-oxomorpholin-2 -yl]-2-oxoethylJ acetate (compound aal3-5)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aal3-4 (0.27 g) was used instead of aa2-4 to obtain compound aal 3-5 (0.33 g) as a colorless amorphous solid.
[Step 13-6] Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-hydroxy-2-[(2R)-4- (2-methoxyquinolin-7-yl)-3-oxomorpholin-2-yl]acetyl]aminoJphenyl]methylJ-N-[(2-m ethylpropan-2-yl)oxycarbonyl]carbamate (compound aal3-6)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aal3-5 (0.32 g) was used instead of aa2-5 to obtain compound aal3-6 (0.28 g) as a colorless amorphous solid.
[Step 13-7] Synthesis of (2R)-N-[3-(ammomethyl)-4-cyanophenyl]-2-hydroxy-
2-[(2R)-4-(2-methoxyquinolin-7-yl)-3-oxomorpholin-2-yl]acetamide hydrochloride
(compound aal3-7)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, com l3-7 (0.23 g) as a colorless amorphous solid.
[Step 13-8] Synthesis of (2R)-2-hydroxy-N-(l -imino-2,3-dihydroisoindol-5-yl)- 2-[(2R)-4-(2-methoxyquinolin-7-yl)-3-oxomorpholin-2-yl]acetamide hydrochloride (EXAMPLE aa 13)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aal3-7 (0.22 g) was used instead of aa2-7 to obtain EXAMPLE aal3 (45 mg) as a yellow amorphous solid. EXAMPLE aa!4
Synthesis of (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)- 3-oxo-4-quinolin-7-ylmorpholin-2-yl]acetamide dihydrochloride (EXAMPLE aal4)
Figure imgf000174_0001
EXAMPLE aa14
[Step 14-1 ] Synthesis of tert-butyl (2R)-2-hydroxy-2-[(2R)-3-oxo-4-quinolin-7- ylmorpholin-2-yl]acetate (compound aal4-l)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, 7-ϊodoquinoline (2.76 g) was used instead of aa2-l to obtain compound aa!4-l (2.50 g) as a colorless amorphous solid.
[Step 14-2] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-quinolin-7- ylmo According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aal4- l (1.25 g) was used instead of aa2-2 to obtain compound aal4-2 (1.32 g) as a colorless amorphous solid. [Step 14-3 J Synthesis of (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-quinolin-7- ylmorpholin-2-yl] acetic acid trifluoroacetic acid salt (compound aal4-3)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aa 14-2 ( 1.3 g) was used instead of aa2-3 to obtain compound aa 14-3 ( 1.4 g) as a colorless amorphous solid.
[Step 14-4] Synthesis of l(lR)-2-[3-[[bis[(2-methylpropan-2-yl)oxycarbonyl] aminojmethyl ]-4-cyanoanilino]-2-oxo- 1 -[(2R)-3-oxo-4-quinolin-7-ylmorpholin-2-yl]et hyl] acetate (compound aal4-4)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aal4-3 (0.5 g) was used instead of aa2-4 to obtain compound aal4-4 (0.64 g) as a colorless amorphous solid.
[Step 14-5] Synthesis of tert-butyl N-fl2-cyano-5-[[(2R)-2-hydroxy-2-[(2R)-3-oxo-4- quinolin-7-ylmorpholin-2-ylJacetyl]amino]phenyl]methyl]-N-[(2-methylpropan-2-yl)ox ycarbonyl]carbamate (compound aal4-5)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aal4-4 (0.63 g) was used instead of aa2-5 to obtain compound aal4-5 (0.59 g) as a colorless amorphous solid. [Ste xy- 2-[(2R)-3-oxo-4-quinolin-7-ylmorpholin-2-yl]acetamide dihydrochloride (compound aal4-6)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aal4-5 (0.58 g) was used instead of aa2-6 to obtain compound aal4-6 (0.46 5 K g) as a colorless amorphous solid.
[Step 14-7] Synthesis of (2R)-2-hydroxy-N-(l -imino-2,3-dihydroisoindol- 5-yl)-2-f(2R)-3-oxo-4-quinolin-7-ylrnorpholin-2-yl]acetamide dihydrochloride (EXAMPLE aa 14)
0 According to the Step 2-8 in synthetic method for EXAMPLE aa2. compound aal4-6 (0.45 g) was used instead of aa2-7 to obtain EXAMPLE aal4 (0.31 g) as a yellow amorphous solid.
EXAMPLE aa 15
5 Synthesis of (2R)-N-(3-amino-1,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3- oxo-4-quinolin-7-ylmorpholin-2-yl]acetamide hydrochloride (EXAMPLE aa!5)
Figure imgf000176_0001
EXAMPLE aa15
[Step 15-1 ] Synthesis of [(lR)-2-[[3-(l ,3-dioxoisoindol-2-yl)-1,2-benzisoxazol-6- yl]amino]-2-oxo-1-[(2R)-3-oxo-4-quinolin-7-ylmorpholin-2-yl]ethyl] acetate
(compound aa 15-1)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, comp oxazole (0.61 g) were used instead of aa2-4 and tert-butyl
N-(2-cyano-5-aminophenyl)methyl-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate to obtain compound 15-1 (0.42 g) as a colorless amorphous solid. [Step 15-2J Synthesis of (2R)-N-(3-amino- 1 ,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)- 3-oxo-4-quinolin-7-ylrnorpholin-2~yl]acetamide hydrochloride (EXAMPLE aal5)
To a solution of compound aal5-l (400 mg) in CH2Cl2-MeOH (14-14 mL), was added NH2NH2-H2O (0.32 niL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The precipitate was appeared. The precipitate was collected by filtration and the filtrate was concentrated in vacuo. The resulting residue was suspended in CH2Cl2-MeOH, then the precipitate was collected by filtration and combined the first crops. Then the precipitate was solved in 10% HCl-MeOH then the solvent was removed in vacuo to obtain EXAMPLE aal5 (240 mg) as a pale yellow amorphous solid.
EXAMPLE aa 16
Synthesis of (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2- f(2R)-3-oxo-4-(2-oxo-1H-quinolin-5-yl)morpholin-2-yl]acetamide hydrochloride (EXAMPLE aal6)
Figure imgf000177_0001
EXAMPLE aa16
[Step 16- 1] Synthesis of 5-iodo-1H-quinolin-2-one (compound aal6-l)
H-H2O (0.73 - 0.3 mL), was added dropwise cone. H2SO4 (66 uL) at 0 °C. Then a solution of NaNOi (86 mg) in water (0.38 mL) was added dropwise into the reaction mixture at 0 °C. The mixture was stirred at 0 °C for 30 min, then a solution of KI (0.31 g) in water (0.25 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 4 h. Water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3 aq. and brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure.
Trituration with Et2θ followed by filtration gave al6-l (0.14 g) as a brown amorphous solid. It was used to the next step without further purification.
[Step 16-2] Synthesis of tert-butyl (2R)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo- 1H-quinolin-5-yl)morpholin-2-yl] acetate (compound aal6-2)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, compound aal6- l (1.20 g) was used instead of aa2-l to obtain compound aal6-2 (0.48 g) as an orange amorphous solid.
[Step 16-3] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo-1H- quinolin-5-yl)morpholin-2-yl]acetate (compound aal6-3)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aal6-2 (0.47 g) was used instead of aa2-2 to obtain compound aal6-3 (0.55 g) as a brown amorphous solid.
[Step 16-4] Synthesis of (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinolin- 5-yl)morpholin-2-yl]acetic acid (compound aal6-4)
aa2, compound aal6-3 (0.51 g) was used instead of aa2-3 to obtain compound aal6-4 (0.38 g) as an orange amorphous solid.
[Step 16-5] Synthesis of [(lR)-2-[3-[[bis[(2-methylpropan-2-yl)oxycarbonyl]- amino]methylJ-4-cyanoanilinol-2-oxo-l -[(2R)-3-oxo-4-(2-oxo-1H-quinolin-5-yl)moφ holin-2-yl]ethyl] acetate (compound aal6-5)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aal6-4 (0.37 g) was used instead of aa2-4 to obtain compound aal6-5 (0.19 g) as an orange amorphous solid.
[Step 16-6] Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-hydroxy-2-[(2R)-3-oxo- 4-(2-oxo-1H-quinolin-5-yl)morpholin-2-yl]acetyl]aminoJphenyl]methyl]-N-[(2-methyl propan-2-yl)oxycarbonyl]carbamate (compound aal6-6)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aal6-5 (0.18 g) was used instead of aa2-5 to obtain compound aal6-6 (0.16 g) as an orange amorphous solid.
[Step 16-7] Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyl]-2- hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-5-yl)morpholin-2-yl]acetamide hydrochloride (compound aa 16-7)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aal6-6 (0.15 g) was used instead of aa2-6 to obtain compound aal6-7 (0.13 g) as a pale yellow amorphous solid. [Step 5-yl)-2-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-5-yl)morpholin-2-yl]acetamide hydrochloride (EXAMPLE aalό)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aal6-7 (0.12 g) was used instead of aa2-7 to obtain EXAMPLE aa 16 (0.10 g) as a pale yellow amorphous solid.
EXAMPLE aa!7
Synthesis of (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2- l(2R)-3-oxo-4-( l-oxo-3,4-dihydro-2H-isoquinolin-6-yl)morpholin-2-yl]acetamide hydrochloride (EXAMPLE aa 17)
Figure imgf000180_0001
EXAMPLE aa17
[Step 17-1 ] Synthesis of tert-butyl (2R)-2-hydroxy-2-[(2R)-3-oxo-4-(l-oxo-3,4- dihydro-2H-isoquinolin-6-yl)morpholin-2-yl]acetate (compound aal7-l)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, 6-bromo-3,4-dihydroisoquinolin-l(2H)-one (500 mg) was used instead of aa2- l to obtain compound aal7-l (288 mg) as a yellow amorphous solid (contained diastereomer).
[Step 17-2] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-( l-oxo- 3,4-dihydro-2H-isoquinolin-6-yl)morpholin-2-yl]acetate (compound aal7-2)
aa2, compound aal7-l (231 mg) was used instead of aa2-2 to obtain compound aal7-2 (313 g) as a white amorphous solid (contained diastereomer).
[Step 17-3] Synthesis of (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(l-oxo-3,4- dihydro-2H-isoquinolin-6-yl)morpholin-2-yl]acetic acid (compound aal7-3)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aal7-2 (270 mg) was used instead of aa2-3 to obtain compound aal7-3 (254 mg) as a white amorphous solid (contained diastereomer). [Step 17-41 Synthesis of [(lR)-2-[3-[[bis[(2-methylpropan-2-yl)oxycarbonyl]- amino]methyll-4-cyanoanilino]-2-oxo-1-[(2R)-3-oxo-4-(l-oxo-3,4-dihydro-2H-isoquin olin-6-yl)morpholin-2-yl]ethyl] acetate (compound aal7-4)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aal7-3 (250 mg) was used instead of aa2-4 to obtain compound aal7-4 (120 mg) as a white amorphous solid.
[Step 17-5] Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-hydroxy-2-[(2R)-3-oxo- 4-(l-oxo-3,4-dihydro-2H-isoquinolin-6-yl)morpholin-2-yl]acetyl]amino]phenyl]methyl ]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (compound aal7-5)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aal7-4 (98 mg) was used instead of aa2-5 to obtain compound aal7-5 (83 mg) as a white amorpous solid.
[Step 17-6]
Synt (2R)-N-I3-(aminomethyl)-4-cyanophenyl]-2-hydroxy-2-[(2R)-3-oxo-4-(l-oxo-3,4-dihy dro-2H-isoquinolin-6-yI)morpholin-2-yl]acetamide hydrochloride (compound aal7-6)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aal7-5 (79 mg) was used instead of aa2-6 to obtain compound aal7-6 (75 mg) as a white amorphous solid.
[Step 17-71 Synthesis of (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol- 5_yl)_2-f(2R)-3-oxo-4-(l-oxo-3,4-dihydro-2H-isoquinolin-6-yl)morpholin-2-yl]acetami de hydrochloride (EXAMPLE aal7)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aal7-6 (55 mg) was used instead of aa2-7 to obtain EXAMPLE aal7 (47 mg) as a white amorphous solid.
EXAMPLE aa 18
Synthesis of (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-
5-yl)-2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro- 1H-quinolin-7-yl)morpholin-2-yl]acetamide hydrochloride (EXAMPLE aal8)
Figure imgf000182_0001
EXAMPLE aa18
[Step 18- 1 ] Synthesis of tert-butyl (2R)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4- dihydro-1H-quinolin-7-yl)morpholin-2-yl]acetate (compound aal 8-l)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, 3,4-d obtain compound aal8-l (0.59 g) as a brown amorphous solid.
[Step 18-2] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo-3,4- dihydro- 1 H-quinolin-7-yl)morpholin-2-yl] acetate (compound aal 8-2)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aal8- i (0.57 g) was used instead of aa2-2 to obtain compound aal8-2 (0.59 g) as a white amorphous solid.
[Step 18-3] Synthesis of (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo-3,4- dihydro-1H-quinolin-7-yl)morpholin-2-yl]acetic acid (compound aal 8-3)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aal 8-2 (0.28 g) was used instead of aa2-3 to obtain compound aal 8-3 (0.21 g) as a white amorphous solid. [Step 18-4] Synthesis of [(lR)-2-[3-[[bis[(2-methylpropan-2-yl)oxycarbonyl]- amino]methyl]-4-cyanoanilino]-2-oxo-l -[(2R)-3-oxo-4-(2-oxo-3,4-dihydro-1H-quinoli n-7-yl)morpholm-2-yl]ethylj acetate (compound aal 8-4)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aal 8-3 (75 mg) was used instead of aa2-4 to obtain compound aal 8-4 (62 mg) as a white amorphous solid.
[Step 18-5] Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-hydroxy-2-[(2R)- 3-oxo-4-(2-oxo-3,4-dihydro-1H-quinolin-7-yl)morpholin-2-yl]acetyl]amino]phenyl]me thyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (compound aal 8-5)
aa2, compound aal 8-4 (52 mg) was used instead of aa2-5 to obtain compound aal8-5 (47 mg) as a white amorphous solid.
[Step 18-6] Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyl]-2- hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro- 1H-quinolin-7-yl)morpholin-2-ylJacetam ide hydrochloride (compound aal 8-6)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aal 8-5 (44 mg) was used instead of aa2-6 to obtain compound aal 8-6 (33 mg) as a white amorphous solid.
[Step 18-7]
Synthesis of
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-oxo-3,4-dih ydro-1H-quinolin-7-yl)rnorpholin-2-yl]acetarnide hydrochloride (EXAMPLE aal8)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aal 8-6 (31 g) was used instead of aa2-7 to obtain EXAMPLE aal 8 (26 g) as a white amorphous solid.
EXAMPLE aal 9
Synthesis of (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-
2-[(2R)-4-(l-methyl-2-oxo-3,4-dihydroquinolin-7-yl)-3-oxomorpholin-2-yl]acetamide hydrochloride (EXAMPLE aal 9)
Figure imgf000185_0001
[Step 19-1 ] Synthesis of 7-iodo-1-methyl-3,4-dihydroquinolin-2-one (compound aal9-l)
According to the Step 8-1 in synthetic method for EXAMPLE aa8, 3,4-dihydro-7-iodo-2( 1 H)-quinolinone ( 1.50 g) was used instead of aa7- 1 to obtain compound aal9-l (1.23 g) as a pale yellow amorphous solid.
[Step 19-2] Synthesis of tert-butyl (2R)-2-hydroxy-2-[(2R)-4-(l-methyl-2-oxo-3,4- dihydroquinolin-7-yl)-3-oxomorpholin-2-yl]acetate (compound aal9-2)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, compound aal9-l (1.22 g) was used instead of aa2-l to obtain compound aal9-2 (0.95 g) as a pale yellow amorphous solid.
[Step 19-3] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-4-(l-methyl-2-oxo- 3,4-dihydroquinolin-7-yl)-3-oxomorpholin-2-yl]acetate (compound aal9-3)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aal9-2 (0.60 g) was used instead of aa2-2 to obtain compound aal9-3 (0.68 g) as a pale yellow amorphous solid. [Step 19-4] Synthesis of (2R)-2-acetyloxy-2-[(2R)-4-( 1 -methyl-2-oxo-
3,4-dihydroquinolin 7 yl) 3 oxomorpholin 2 yl]acetic acid (compound aal9-4)
E aa2, compound aal9-3 (0.65 g) was used instead of aa2-3 to obtain compound aal9-4 (0.74 g) as a pale brown amorphous solid.
[Step 19-5] Synthesis of [(lR)-2-[3-[[bis[(2-methylpropan-2-yl)oxycarbonyll- aminoJmethyl]-4-cyanoanilino]-1-[(2R)-4-(l-methyl-2-oxo-3,4-dihydroquinolin-7-yl)-3 -oxomorpholin-2-yl]-2-oxoethyl] acetate (compound aal9-5)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aal9-4 (0.56 g) was used instead of aa2-4 to obtain compound aal9-5 (0.78 g) as a white amorphous solid.
[Step 19-61 Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-hydroxy-2-[(2R)-4- (l-methyl-2-oxo-3.4-dihydroquinolin-7-yl)-3-oxomorpholin-2-yl]acetyl]aminoJphenyl] methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (compound aa 19-6)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aal9-5 (0.75 g) was used instead of aa2-5 to obtain compound aal9-6 (0.69 g) as a white amorphous solid.
[Step 19-71 Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenylJ-2- hydroxy-2-[(2R)-4-(l-methyl-2-oxo-3,4-dihydroquinolin-7-yl)-3-oxomorpholin-2-yl]ac etamide hydrochloride (compound aal9-7)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aal9-6 (0.67 g) was used instead of aa2-6 to obtain compound aal9-7 (0.50 g) as a white amorphous solid. [Step yI)-2-[(2R)-4-(l-methyl-2-oxo-3,4-dihydroquinolin-7-yl)-3-oxomorpholin-2-yl]acetami de hydrochloride (EXAMPLE aal9)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aal9-7 (0.49 g) was used instead of aa2-7 to obtain EXAMPLE aal9 (0.35 g) as a white amorphous solid.
EXAMPLE aa20
Synthesis of (2R)-2-[(2R)-4-[ l-(cycIopropylmethyl)-2-oxo-3,4-dihydroquinolin- 7-ylJ-3-oxomorpholin-2-ylJ-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)acetamide hydrochloride (EXAMPLE aa20)
Figure imgf000187_0001
EXAMPLE aa20
[Step 20- 1] Synthesis of l-(cyclopropylmethyI)-7-iodo-3,4-dihydroquinolin-2-one (compound aa20- 1 )
According to the Step 8-1 in synthetic method for EXAMPLE aa8, 3,4-dihydro-7-iodo-2(1H)-quinolinone (1.50 g) and cyclopropylmethyl bromide (0.80 mL) were used instead of a7-l and MeI to obtain compound aa20-l (1.23 g) as a pale red amorphous solid.
[Step 20-2] Synthesis of tert-butyl (2R)-2-[(2R)-4-[l-(cyclopropyImethyl)-2-oxo- 3,4-dihydroquinolin-7-yl]-3-oxomorpholin-2-yI]-2-hydroxyacetate (compound aa20-2)
According to the Step 2 2 in synthetic method for EXAMPLE aa2, com 20-2 (1.16 g) as a pale brown amorphous solid.
[Step 20-3] Synthesis of tert-butyl (2R)-2-acetyIoxy-2-[(2R)-4-[ 1 -(cyclopropylmethyl)- 2-oxo-3,4-dihydroquinolin-7-yl]-3-oxomorpholin-2-yl]acetate (compound aa20-3)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa20-2 (0.60 g) was used instead of aa2-2 to obtain compound aa20-3 (0.65 g) as a pale yellow amorphous solid.
[Step 20-41 Synthesis of (2R)-2-acetyloxy-2-[(2R)-4-[l-(cyclopropylmethyl)- 2-oxo-3,4-dihydroquinolin-7-yl]-3-oxomorpholin-2-yllacetic acid (compound aa20-4)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aa20-3 (0.64 g) was used instead of aa2-3 to obtain compound aa20-4 (0.70 g) as a pale brown amorphous solid. [Step 20-5] Synthesis of f(lR)-2-[3-[[bis[(2-methylpropan-2-yl)oxycarbonyl] amino]methyl]-4-cyanoanilino]-1-[(2R)-4-[l-(cyclopropylmethyl)-2-oxo-3,4-dihydroqu inolin-7-yl]-3-oxomorpholin-2-yl]-2-oxoethyl] acetate (compound aa20-5)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aa20-4 (0.55 g) was used instead of aa2-4 to obtain compound aa20-5 (0.67 g) as a white amorphous solid.
[Step 20-6] Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-[(2R)-4-[l- (cyclopropylmethyl)-2-oxo-3,4-dihydroquinolin-7-yl]-3-oxomorpholin-2-yl]-2-hydroxy acetyl]amino]phenyl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (com According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aa20-5 (0.66 g) was used instead of aa2-5 to obtain compound aa20-6 (0.62 g) as a white amorphous solid. [Step 20-71 Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyll-2-[(2R)-4-
[l-(cyclopropylmethyl)-2-oxo-3,4-dihydroquinolin-7-yl]-3-oxomorpholin-2-yl]-2-hydr oxyacetamide hydrochloride (compound aa20-7)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa20-6 (0.61 g) was used instead of aa2-6 to obtain compound aa20-7 (0.47 g) as a white amorphous solid.
[Step 20-8] Synthesis of (2R)-2-[(2R)-4-[l-(cyclopropylmethyl)-2-oxo-3,4- dihydroquinolin-7-yl]-3-oxomorpholin-2-yl]-2-hydroxy-N-(l-imino-2,3-dihydroisoindo l-5-yl)acetamide hydrochloride (EXAMPLE aa20)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa20-7 (0.46 g) was used instead of aa2-7 to obtain EXAMPLE aa20 (0.43 g) as a white amorphous solid.
EXAMPLE aa21
Synthesis of methyl 2-f7-[(2R)-2-[(lR)-1-hydroxy-2-[(l-imino-2,3- dihydroisoindol-5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxo-3,4-dihydroquin olin-1-yl]acetate hydrochloride (EXAMPLE a21)
Figure imgf000190_0001
EXAMPLE aa21
[Step 21- 1] Synthesis of methyl 2-(7-iodo-2-oxo-3,4-dihydroquinolin- l-yl)acetate (compound aa21-l)
According to the Step 8- 1 in synthetic method for EXAMPLE aa8, 3,4-dihydro-7-iodo-2(1H)-quinolinone (2.12 g) and bromoacetic acid methyl ester (1.10 mL) were used instead of aa7- 1 and MeI to obtain compound aa21 - 1 (2.24 g) as a white amorphous solid.
[Step 21-2] Synthesis of tert-butyl (2R)-2-hydroxy-2-[(2R)-4-[l-(2-methoxy-2- oxoethyl)-2-oxo-3,4-dihydroquinolin-7-yl]-3-oxomorpholin-2-yl]acetate (compound aa21-2)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, compound aa21- 1 (2.23 g) was used instead of aa2-l to obtain compound aa21-2 (2.27 g) as a pale brown amorphous solid.
[Step 21-3] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-4-[l-(2-methoxy-2- oxoethyl)-2-oxo-3,4-dihydroquinolin-7-yl]-3-oxomorpholin-2-yl]acetate (compound aa21-3)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa21-2 (2.27 g) was used instead of aa2-2 to obtain compound aa21-3 (2.17 g) as a pale yellow amorphous solid. [Step 21-4] Synthesis of (2R)-2-acetyloxy-2-[(2R)-4-[l -(2-methoxy-2-oxoethyl)- 2-oxo-3,4-dihydroquinolin-7-yl]-3-oxomorpholin-2-yl]acetic acid (compound aa21-4)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aa21 -3 (2.15 g) was used instead of aa2-3 to obtain compound aa21 -4 (2.1 1 g) as a white amorphous.
[Step 21-5] Synthesis of methyl 2-[7-[(2R)-2-[( IR)-I -acetyloxy-2-[3-[ [bis[(2- methy lpropan-2-y 1 )oxycarbony 1] aminojmethy 1] -4-cyanoanilino] -2-oxoethy 1] -3-oxomor pholin-4-yl]-2-oxo-3,4-dihydroquinolin-1-yl]acetate (compound aa21-5)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aa21 -4 (1.90 g) was used instead of aa2-4 to obtain compound aa21-5 (2.44 g) as a white amorphous solid.
[Step 21 -61 Synthesis of methyl 2-[7-[(2R)-2-[(lR)-2-[3-[[bis[(2-methylpropan-2- yl)oxycarbonylJamino]methylJ-4-cyanoanilinoJ-1-hydroxy-2-oxoethyl]-3-oxomorpholi n-4-yl]-2-oxo-3,4-dihydroquinolin-l -yl]acetate (compound a21-6)
According to the Step 10-6 in synthetic method for EXAMPLE aalO, compound aa21 -5 (0.54 g) was used instead of aa 10-5 to obtain compound aa21 -6 (0.50 g) as a white amorphous solid.
[Step 21-7] Synthesis of methyl 2-[7-[(2R)-2-[(lR)-2-[3-(aminomethyl)-4- cyanoanilinol-1-hydroxy-2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxo-3,4-dihydroquinolin
-1-yl]acetate hydrochloride (compound aa21-7)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, comp 21-7 (0.29 g) as a white amorphous solid.
[Step 21 -81 Synthesis of methyl 2-[7-[(2R)-2-[( IR)-I -hydroxy-2-[(l -imino-2,3- dihydroisoindol-5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-ylj-2-oxo-3,4-dihydroquin olin- 1 -y 1] acetate hydrochloride (EXAMPLE aa21 )
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa21-7 (0.28 g) was used instead of aa2-7 to obtain EXAMPLE aa21 (0.12 g) as a white amorphous solid. EXAMPLE aa22
Synthesis of 2-[7-[(2R)-2-[( IR)-I -hydroxy-2-[( l -imino-2,3-dihydroisoindol- 5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxo-3,4-dihydroquinolin-1-yl]acetic acid hydrochloride (EXAMPLE aa22)
Figure imgf000192_0001
EXAMPLE aa22
[Step 22- 1 ] Synthesis of 2-f 7-f (2R)-2-[( 1 R)-2-[3-[fbis[(2-methylpropan-2- yl)oxycarbonyl]amino]methyl]-4-cyanoanilino]-1-hydroxy-2-oxoethyl]-3-oxomorpholi n-4-yl]-2-oxo-3,4-dihydroquinolin-1-yl]acetic acid (compound aa22-l)
According to the Step 11-1 in synthetic method for EXAMPLE aal 1, compound aa21-5 ( 1.20 g) was used instead of aal0-5 to obtain compound aa22-l (0.99 g) as a pale yellow amorphous solid.
[Step no]- l -hydroxy-2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxo-3,4-dihydroquinolin-1-yl]acetic acid hydrochloride (compound aa22-2)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa22-l (0.40 g) was used instead of aa2-6 to obtain compound aa22-2 (0.30 g) as a white amorphous solid.
[Step 22-3] Synthesis of 2-[7-[(2R)-2-[( IR)-I -hydroxy-2-[( 1 -imino-2,3- dihydroisoindol-5-yl)aminoJ-2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxo-3,4-dihydroquin olin-1-yl]acetic acid hydrochloride (EXAMPLE aa22)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa22-2 (0.29 g) was used instead of aa2-7 to obtain EXAMPLE aa22 (0.19 g) as a white amorphous solid.
EXAMPLE aa23
Synthesis of (2R)-N-(4-carbamimidoyl-3-fluorophenyl)-2- hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro-1H-quinolin-7-yl)morpholin-2-yl]acetam ide hydrochloride (EXAMPLE aa23)
Figure imgf000193_0001
EXAMPLE aa23
[Step 23-1] Synthesis of [(lR)-2-[3-fluoro-4-(5-oxo-2H- 1,2,4-oxadiazol-3- yl)anilino]-2-oxo- 1 -[(2R)-3-oxo-4-(2-oxo- 1 H-quinolin-7-yl)morpholin-2-yl]ethyl] acetate (compound aa23-l)
aa5, aa7-4 (0.20 g) was used instead of aa3-3 to obtain compound aa23-l (0.12 g) as a beige amorphous solid.
[Step 23-2] Synthesis of (2R)-N-[3-fluoro-4-(5-oxo-2H-1,2,4-oxadiazol-3- yl)phenyl]-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-7-yl)morpholin-2-yl]aceta mide ammonium salt (compound aa23-2)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aa23- 1 (0.18 g) was used instead of aa2-5 to obtain compound aa23-2 (0.12 g) as a beige amorphous solid.
[Step 23-31 Synthesis of (2R)-N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy- 2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro- 1H-quinolin-7-yl)morpholin-2-yl]acetamide hydrochloride (EXAMPLE aa23)
According to the Step 5-3 in synthetic method for EXAMPLE aa5, compound aa23-2 (0.12 g) was used instead of aa5-2 to obtain EXAMPLE aa23 (88 mg) as a beige amorphous solid.
EXAMPLE aa24
Synthesis of (2R)-N-(3-amino-1,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo- 4-(2-oxo-3,4-dihydro-1H-quinolin-7-yl)morpholin-2-yllacetamide (EXAMPLE aa24)
Figure imgf000194_0001
EXAMPLE aa24
[Step ol-6-yl]- amino]-2-oxo-1-f(2R)-3-oxo-4-(2-oxo-3,4-dihydro-1H-quinolin-7-yl)morpholin-2-yl]et hyl ] acetate (compound aa24- 1 )
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aal8-3 (0.50 g) and 6-amino-3-(l ,3-dioxoisoindol-2-yl)-1,2-benzisoxazole (0.50 g) were used instead of aa2-4 and tert-butyl
N-(2-cyano-5-aminophenyl)methyl-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate to obtain compound aa24-l (0.40 g) as a pale yellow amorphous solid.
[Step 24-2] Synthesis of (2R)-N-(3 -amino- l ,2-benzisoxazol-6-yl)-2-hydroxy-2- r(2R)-3-oxo-4-(2-oxo-3,4-dihydro-1H-quinolm-7-yl)morpholin-2-ylJacetamide
(EXAMPLE aa24)
According to the Step 15-2 in synthetic method for EXAMPLE aal5, compound aa24-l (0.35 g) was used instead of aal5-l to obtain EXAMPLE aa24 (0.27 g) as a colorless amorphous solid.
EXAMPLE aa25
Synthesis of (2R)-N-( 1 -aminoisoquinolin-6-yl)-2-hydroxy-2-[(2R)-3-oxo-
4-(2-oxo-3,4-dihydro- 1H-quinolin-7-yl)morpholin-2-yl]acetamide hydrochloride
(EXAMPLE aa25)
Figure imgf000195_0001
EXAMPLE aa25
[Step 25-1 ] Synthesis of [(lR)-2-[[l-[bis[(2-methylpropan-2-yl)oxycarbonylJ- amin H-quinolin -7-yl)morpholin-2-yl]ethyl] acetate (compound aa25-l)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aal 8-3 (0.50 g), 6-amino- 1 -bis(tert-butoxycarbonyl)aminoisoquinoline (0.5 g), ( 1 -cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU: 1.18 g) and diisopropylethylamine (0.96 mL) were used instead of 2-4, N-[(5-Amino-2-cyanophenyl)methyl]-N-[(2-methylpropan-2- yl)oxycarbonyl]carbamate, WSC-HCl, and DMAP to obtain compound aa25-l (0.49 g) as a brown amorphous solid. [Step 25-2] Synthesis of tert-butyl N-[6-[[(2R)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4- dihydro- 1H-quinolin-7-yl)morpholin-2-ylJacetyl]amino]isoquinolin-1-yl]-N-[(2-methyl propan-2-yl)oxycarbonyl]carbamate (compound aa25-2)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aa25- 1 (0.47 g) was used instead of aa2-5 to obtain compound aa25-2 (0.43 g) as a pale yellow amorphous solid.
[Step 25-3 J Synthesis of (2R)-N-(I -aminoisoquinolin-6-yl)-2-hydroxy-2-[(2R)- 3-oxo-4-(2-oxo-3,4-dihydro-1H-quinolin-7-yl)morpholin-2-yl]acetamide hydrochloride (EXAMPLE aa25)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa25-2 (0.41 g) was used instead of aa2-6 to obtain EXAMPLE aa25 (0.25 g) as a pale brown amorphous solid.
EXAMPLE aa26
Synt 3-oxo-4-(2-oxo-3,4-dihydro-1H-quinolin-7-yl)morpholin-2-yl]acetamide (EXAMPLE aa26)
Figure imgf000197_0001
EXAMPLE aa26
[Step 26-1 ] Synthesis of [(lR)-2-[[4-[(2-methylpropan-2-yl)oxycarbonylamino]- quinazolin-7-yl]amino]-2-oxo-l -[(2R)-3-oxo-4-(2-oxo-3,4-dihydro-1H-quinolin-7-yl)m orpholin-2-yl]ethyl] acetate (compound aa26-l)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aal8-3 (0.50 g), 7-amino-4-(tert-butoxycarbonyl)aminoquinazoline (0.36 g), O-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU: 1.05 g) and diisopropylethylamine (0.96 mL) were used instead of 2-4,
N-[(5-amino-2-cyanophenyl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate , WSC-HCl, and DMAP to obtain compound aa26-l (0.21 g) as a pale yellow amorphous solid. [Step 26-2] Synthesis of tert-butyl N-[7-[[(2R)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-
3,4-dihydro-1H-quinolin-7-yl)morpholm-2-ylJacetyl]amino]quinazolin-4-yl]carbamate (compound aa26-2)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aa26-l (0.21 g) was used instead of aa2-5 to obtain compound aa26-2 (0.19 g) as a white amorphous solid.
[Step [(2R)-3-oxo-4-(2-oxo-3,4-dihydro- 1H-quinolin-7-yl)morpholin-2-yl]acetamide (EXAMPLE aa26)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa26-2 (0.18 g) was used instead of aa2-6 to obtain EXAMPLE aa26 (20 mg) as a pale brown amorphous solid.
EXAMPLE aa27
Synthesis of
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-oxo-3,4-dih ydro-1H-quinolin-5-yl)morpholin-2-yl]acetamide hydrochloride (EXAMPLE aa27)
Figure imgf000198_0001
EXAMPLE aa27
[Step 27-1 ] Synthesis of tert-butyl (2R)-2-hydroxy-2-[3-oxo-4-(2-oxo-3,4-dihydro-1H- quinolin-5-yl)morpholin-2-ylJacetate (compound aa27-l)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, 5-bromo-3,4-dihydroquinolin-2(1H)-one (2.0 g) was used instead of aa2-l to obtain compound aa27-l (0.34 g) as a white amorphous solid (contained diastereomer).
[Step 27-2] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[3-oxo-4-(2-oxo-3,4-dihydro- 1H-quinolin-5-yl)morpholin-2-yl]acetate (compound aa27-2)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa27-l (0.30 g) was used instead of aa2-2 to obtain compound aa27-2 (0.32 g) as [Step 27-3J Synthesis of (2R)-2-acetyloxy-2-[3-oxo-4-(2-oxo-3.4-dihydro-1H- quinolin-5-yl)morpholin-2-yl]acetic acid (compound aa27-3)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aa27-2 (0.30 g) was used instead of aa2-3 to obtain compound aa27-3 (0.24 g) as a white amorphous solid (contained diastereomer).
[Step 27-4] Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-hydroxy-2-[(2R)-3-oxo- 4-(2-oxo-3,4-dihydro-1H-quinolin-5-yl)morpholin-2-yl]acetyl]amino]phenyl]methyl]- N-[(2-methylpropan-2-yl)oxycarbonyllcarbamate (compound aa27-4)
According to the Step 2-5 and 2-6 in synthetic method for EXAMPLE aa2, compound aa27-3 (0.24 g) was used instead of aa2-4 to obtain compound aa27-4 (38 mg) as a white amorphous solid. [Step 27-51 Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyl1-2-hydroxy- 2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro-1H-quinolin-5-yl)morpholin-2-yl]acetamide hydrochloride (compound aa27-5)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa27-4 (36 mg) was used instead of aa2-6 to obtain compound aa27-5 (33 mg) as a white amorphous solid.
[Step 27-6] Synthesis of (2R)-2-hydroxy-N-(l -imino-2,3-dihydroisoindol-5- yl)-2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro-1H-quinolin-5-yl)morpholin-2-yl]acetamide hydrochloride (EXAMPLE aa27)
aa2, compound aa27-5 (30 mg) was used instead of aa2-7 to obtain EXAMPLE aa27 (22 mg) as a white amorphous solid.
EXAMPLE aa28
Synthesis of (2R)-2-hydroxy-2-[(2R)-4-[2-(3-hydroxy-3- methylbutoxy)phenyl]-3-oxomorpholin-2-yl]-N-(l -imino-2,3-dihydroisoindol-5-yl)acet amide hydrochloride (EXAMPLE aa28)
Figure imgf000200_0001
EXAMPLE aa28
fStep 28-1 ] Synthesis of 4-(2-iodophenoxy)-2-methylbutan-2-ol (compound aa28-l)
A mixture of 2-iodophenol (6 g) , 3-hydroxy-3-methylbutyl tosylate (7.4 g) and Cs2CO3 (13.3 g) in DMF (120 mL) was stirred at 0 °C for 2 h and at room temperature for 10 h. The mixture was diluted with EtOAc and washed with IN HCl, saturated NaHCO3 aq., H2O, and brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (Hexane/EtOAc = 7/3) to obtain compound aa28-l (8.02 g) as pale yellow oil.
[Step 28-2] Synthesis of tert-butyl (2R)-2-hydroxy-2-[(2R)-4-[2-(3-hydroxy- 3-methylbutoxy)phenyl]-3-oxomorpholin-2-yl]acetate (compound aa28-2)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, compound aa28 1 (2 20 g) was used instead of aa2 1 to obtain compound aa28-2 ( 1.69 g) as [Step 28-3] Synthesis of tert-butyl (2R)-2-acetyloxy-2-|(2R)-4-[2-(3-hydroxy-3- methylbutoxy)phenylJ-3-oxomorpholin-2-yl]acetate (compound aa28-3)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa28-2 ( 1.60 g) was used instead of aa2-2 to obtain compound aa28-3 (1.72 g) as a white amorphous solid.
[Step 28-4] Synthesis of (2R)-2-acetyloxy-2-[(2R)-4-[2-(3-hydroxy-3- methylbutoxy)phenyl]-3-oxomorpholin-2-yl]acetic acid (compound aa28-4)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aa28-3 (0.85 g) was used instead of aa2-3 to obtain compound aa28-4 (0.85 g) as a white amorphous solid.
[Step 28-5] Synthesis of [(lR)-2-[3-[[bis[(2-methylpropan-2-yl)oxycarbonyl]- amino]methyl]-4-cyanoanilino]-1-[(2R)-4-[2-(3-hydroxy-3-methylbutoxy)phenyl]-3-ox omorpholin-2-yl]-2-oxoethyl] acetate (compound aa28-5)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aa28-4 (0.40 g) was used instead of aa2-4 to obtain compound aa28-5 (0.33 g) as a white amorphous solid.
[Step 28-6] Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-hydroxy-2-[(2R)-4-[2-
(3-hydroxy-3-methylbutoxy)phenyl]-3-oxomorpholin-2-yl]acetyl]amino]phenyl]methyl
]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (compound aa28-6)
A di h S 2 6 i h i h d f EXAMP E aa2, com 28-6 (87 mg) as a white amorphous solid.
[Step 28-7] Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyl]-2-hydroxy- 2-[(2R)-4-[2-(3-hydroxy-3-methylbutoxy)phenyl]-3-oxomorpholin-2-yl]acetamide hydrochloride (compound aa28-7)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa28-6 (83 mg) was used instead of aa2-6 to obtain compound aa28-7 (63 mg) as a white amorphous solid. [Step 28-81 Synthesis of (2R)-2-hydroxy-2-[(2R)-4-[2-(3-hydroxy-3- methylbutoxy)phenylJ-3-oxomorpholin-2-yl]-N-(l-imino-2,3-dihydroisoindol-5-yl)acet amide hydrochloride (EXAMPLE aa28)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa28-7 (61 mg) was used instead of aa2-7 to obtain EXAMPLE aa28 (24 mg) as a white amorphous solid.
EXAMPLE aa29
Synthesis of (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2- [(2R)-4-[2-(3-methoxy-3-methylbutoxy)phenyl]-3-oxomorpholin-2-yl]acetamide hydrochloride (EXAMPLE aa29)
Figure imgf000202_0001
EXAMPLE aa29
[Step mpound aa29-l)
According to the Step 28-1 in synthetic method for EXAMPLE aa28, 3-methoxy-3-methylbutyl p-toluenesulfonate (6.50 g) was used instead of
3-hydroxy-3-methylbutyl p-toluenesulfonate to obtain compound aa29-l (5.77 g) as colorless oil.
(Step 29-2] Synthesis of tert-butyl (2R)-2-hydroxy-2-[(2R)-4-[2-(3-methoxy-3- methylbutoxy)phenyl]-3-oxornorpholin-2-yl]acetate (compound aa29-2)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, compound aa29-l (4.00 g) was used instead of aa2-l to obtain compound aa29-2 (2.43 g) as pale yellow oil.
LStep 29-31 Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-4-[2-(3-methoxy-3- methylbutoxy)phenyl]-3-oxomorpholin-2-yl]acetate (compound aa29-3)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa29-2 (2.42 g) was used instead of aa2-2 to obtain compound aa29-3 (2.61 g) as a white amorphous solid.
[Step 29-4] Synthesis of (2R)-2-acetyloxy-2-[(2R)-4-[2-(3-methoxy-3- methylbutoxy)phenyl]-3-oxomorpholin-2-yl]acetic acid (compound aa29-4)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aa29-3 (2.50 g) was used instead of aa2-3 to obtain compound aa29-4 (2.78 g) as pale brown oil. LStep amino]methyll-4-cyanoanilino]- l-f(2R)-4-[2-(3-methoxy-3-methylbutoxy)phenyl]-3-o xomorpholin-2-yl]-2-oxoethyl] acetate (compound aa29-5)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aa29-4 (1.00 g) was used instead of aa2-4 to obtain compound aa29-5 (0.96 g) as a white amorphous solid.
[Step 29-6] Synthesis of tert-butyl N-[[2-cyano-5-f[(2R)-2-hydroxy-2-[(2R)-4- [2-(3-methoxy-3-methylbutoxy)phenyl]-3-oxomorpholin-2-yl]acetyl]aminolphenyl]met hyll-N-[(2-methylpropan-2-yl)oxycarbonyl]carbarnate (compound aa29-6)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aa29-5 (0.70 g) was used instead of aa2-5 to obtain compound aa29-6 (0.64 g) as a white amorphous solid.
[Step 29-7] Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyl]-2-hydroxy- 2-[(2R)-4-[2-(3-methoxy-3-methylbutoxy)phenyl]-3-oxomorpholin-2-yl]acetamide hydrochloride (compound aa29-7)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa29-6 (0.62 g) was used instead of aa2-6 to obtain compound aa29-7 (0.45 g) as a cream amorphous solid.
[Step 29-8] Synthesis of (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5- yl)-2-[(2R)-4-[2-(3-methoxy-3-methylbutoxy)phenyl]-3-oxomorpholin-2-yl]acetamide hydrochloride (EXAMPLE aa29)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, com a29 (0.21 g) as a white amorphous solid.
EXAMPLE aa30
Synthesis of (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5- yl)-2-[(2R)-3-oxo-4-[2-(2-oxopiperidin- 1 -yl)phenyl]morpholin-2-yl]acetamide hydrochloride (EXAMPLE aa30)
Figure imgf000205_0001
EXAMPLE aa30
IStep 30-1 ] Synthesis of tert-butyl (2R)-2-hydroxy-2-[(2R)-3-oxo-4-[2-(2-oxopiperidin- l-yl)phenyl]morpholin-2-ylJacetate (compound aa30-l)
According to the Step 2-2 in synthetic method for EXAMPLE aa2,
1 -(2-iodophenyl)-2-piperidinone (2.73 g) was used instead of aa2- 1 to obtain compound aa30- l (0.85 g) as a brown amorphous solid.
[Step 30-2] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-[2-(2- oxopiperidin-1-yl)phenyl]morpholin-2-yl]acetate (compound aa30-2)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa30-l (0.85 g) was used instead of aa2-2 to obtain compound aa30-2 (0.80 g) as a pale yellow amorphous solid. [Step 30-3] Synthesis of (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-[2-(2-oxopiperidin- l-yl)phenyl]morpholin-2-yl]acetic acid (compound aa30-3)
aa2, compound aa30-2 (0.79 g) was used instead of aa2-3 to obtain compound aa3O-3 (0.58 g) as a colorless amorphous solid.
[Step 30-4J Synthesis of [(lR)-2-[3-[[bis[(2-methylpropan-2-yl)oxycarbonylJ- amino]methyl]-4-cyanoanilino]-2-oxo- l-[(2R)-3-oxo-4-[2-(2-oxopiperidin-l -yl)phenyl ]morpholin-2-yl]ethyl] acetate (compound aa30-4)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aa30-3 (0.30 g) was used instead of aa2-4 to obtain compound aa30-4 (0.16 g) as a pale yellow amorphous solid.
[Step 30-51 Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-hydroxy-2-[(2R)-3-oxo-4- [2-(2-oxopiperidin-l -yl)phenyl]morpholin-2-yl]acetyl]amino]phenyl]methyl]-N-[(2-me thylpropan-2-yl)oxycarbonyl]carbamate (compound aa30-5)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aa30-4 (0.15 g) was used instead of aa2-5 to obtain compound aa3O-5 (0.14 g) as pale yellow oil.
[Step 30-6] Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyl]-2-hydroxy- 2-[(2R)-3-oxo-4-[2-(2-oxopiperidin-l -yl)phenyl]morpholin-2-yl]acetamide
hydrochloride (compound aa30-6)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa3O-5 (0.14 g) was used instead of aa2-6 to obtain compound aa30-6 (78 mg) as a colorless amorphous solid. [Step yl)-2-[(2R)-3-oxo-4-f2-(2-oxopiperidin-1-yl)phenylJmorpholin-2-ylJacetamide hydrochloride (EXAMPLE aa30)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa30-6 (78 mg) was used instead of aa2-7 to obtain EXAMPLE aa30 (72 mg) as a colorless amorphous solid.
EXAMPLE aa31
Synthesis of (2R)-2-[(2R)-4-[2-(difluoromethoxy)-5-fluorophenyl]-3- oxomorpholin-2-yl]-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)acetamide hydrochloride (EXAMPLE aa31 )
Figure imgf000207_0001
[Step 31-1] Synthesis of 2-bromo-1-(difluoromethoxy)-4-fluorobenzene (compound aa31-l )
According to the Step 4- 1 in synthetic method for EXAMPLE aa4, 2-bromo-4-fluorophenol (5.0 g) was used instead of 2-iodo-5-nitrophenol to obtain compound aa31-l (5.25 g) as a red amorphous solid.
[Step 31-2] Synthesis of tert-butyl (2R)-2-[(2R)-4-[2-(difluoromethoxy)-5- fluorophenyl]-3-oxomorpholin-2-yll-2-hydroxyacetate (compound aa31-2)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, compound aa31-l (2.08 g) was used instead of aa2-l to obtain compound aa31-2 (0.75 g) as [Step 31-3] Synthesis of tert-butyl (2R)-2-acetyloxy-2-[(2R)-4-[2-(difluoromethoxy)- 5-fluorophenyl]-3-oxomorpholin-2-yl]acetate (compound aa31-3)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa31 -2 (0.74 g) was used instead of aa2-2 to obtain compound aa31 -3 (0.82 g) as pale yellow oil.
[Step 31-4J Synthesis of (2R)-2-acetyloxy-2-[(2R)-4-[2-(difluoromethoxy)- 5-fluorophenyl]-3-oxomorpholin-2-yllacetic acid (compound aa31-4)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aa31 -3 (0.80 g) was used instead of aa2-3 to obtain compound aa31-4 (0.56 g) as a colorless amorphous solid.
[Step 31 -5] Synthesis of [(lR)-2-[3-[[bis[(2-methylpropan-2-yl)oxycarbonyl]- amino]methyl]-4-cyanoanilino]- 1 -[(2R)-4-[2-(difluoromethoxy)-5-fluorophenyl]-3-oxo morpholin-2-yl]-2-oxoethyl] acetate (compound aa31-5)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aa31 -4 (0.20 g) was used instead of aa2-4 to obtain compound aa31-5 (0.19 g) as a colorless amorphous solid.
[Step 31 -61 Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-[(2R)-4-[2-
(difluoromethoxy)-5-fluorophenyl]-3-oxomorpholin-2-yl]-2-hydroxyacetyl]amino]phen ylJmethyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (compound aa31 -6)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, comp 1 -6 (0.11 g) as colorless oil.
[Step 31-71 Synthesis of (2R)-N-[3-(aminomethyl)-4-cyanophenyl]-2- [(2R)-4-[2-(difluoromethoxy)-5-fluorophenyl]-3-oxomorpholin-2-yl]-2-hydroxyacetam ide hydrochloride (compound aa31-7)
According to the Step 2-7 in synthetic method for EXAMPLE a2, compound aa31 -6 (95 mg) was used instead of aa2-6 to obtain compound aa31 -7 (70 mg) as a pale yellow amorphous solid. [Step 31-8] Synthesis of (2R)-2-[(2R)-4-[2-(diftuoromethoxy)-5-fluorophenylJ- 3-oxomorpholin-2-ylJ-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)acetamide hydrochloride (EXAMPLE aa31)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa31 -7 (70 mg) was used instead of aa2-7 to obtain EXAMPLE aa31 (57 mg) as a pale yellow amorphous solid.
EXAMPLE aa32
Synthesis of methyl 2-(difluoromethoxy )-3-[(2R)-2-[(lR)-l -hydroxy-2- [(l-imino-2,3-dihydroisoindol-5-yl)aminoj-2-oxoethyl]-3-oxomorpholin-4-yllbenzoate hydrochloride (EXAMPLE aa32)
Figure imgf000209_0001
EXAMPLE aa32
[Step ound aa32-l)
According to the Step 4-1 in synthetic method for EXAMPLE aa4, 2-hydroxy-3-nitrobenzoic acid methyl ester ( 18.3g) was used instead of
2-iodo-5-nitrophenol to obtain compound aa32-l (3.70 g) as a colorless amorphous solid.
[Step 32-2] Synthesis of methyl 3-amino-2-(difluoromethoxy)benzoate (compound aa32-2)
According to the Step 5-3 in synthetic method for EXAMPLE aa5, compound aa32-l (3.75 g) was used instead of aa5-2 to obtain compound aa32-2 (3.17 g) as colorless amorphous solid.
[Step 32-3] Synthesis of methyl 2-(difluoromethoxy)-3-iodobenzoate (compound aa32-3)
According to the Step 16-1 in synthetic method for EXAMPLE aalό, compound aa32-2 (2.87 g) was used instead of 5-Aminoquinolin-2(1H)-one to obtain compound aa32-3 (3.99 g) as a yellow amorphous solid.
[Step 32-41 Synthesis of methyl 2-(difluoromethoxy)-3-[(2R)-2-[( IR)-I -hydroxy- 2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-3-oxomorpholin-4-yl]benzoate (compound aa32-4)
According to the Step 2-2 in synthetic method for EXAMPLE aa2, compound aa32-3 (3.98 g) was used instead of aa2-l to obtain compound aa32-4 (1.21 g) as a yellow amorphous solid [Step 32-5] Synthesis of methyl 3-[(2R)-2-[( IR)-I -acetyloxy-2-[(2-methylpropan- 2-yl)oxyJ-2-oxoethyl]-3-oxornorpholin-4-yl]-2-(difluoromethoxy)benzoate (compound aa32-5)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa32-4 ( 1.20 g) was used instead of aa2-2 to obtain compound aa32-5 (1.32 g) as a yellow amorphous solid.
[Step 32-6] Synthesis of (2R)-2-acetyloxy-2-[(2R)-4-[2-(difluoromethoxy)- 3-methoxycarbonylphenyl]-3-oxomorpholin-2-yl [acetic acid (compound aa32-6)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aa32-5 ( 1.32 g) was used instead of aa2-3 to obtain compound aa32-6 ( 1.16 g) as a pink amorphous solid.
[Step 32-7] Synthesis of methyl 3-[(2R)-2-[( IR)-I -acetyloxy-2-[3-[[bis[(2- methylpropan-2-yl)oxycarbonyl]amino]methyl]-4-cyanoanilino]-2-oxoethyl]-3-oxomor pholin-4-yl]-2-(difluoromethoxy)benzoate (compound aa32-7)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aa32-6 (0.93 g) was used instead of aa2-4 to obtain compound aa32-7 (0.60 g) as a colorless amorphous solid.
[Step 32-8] Synthesis of methyl 3-[(2R)-2-[(l R)-2-[3-[[bis[(2-methylpropan-
2-yl)oxycarbonyl]amino]methyl]-4-cyanoanilino]-1-hydroxy-2-oxoethyl]-3-oxomorpho lin-4-yl]-2-(difluoromethoxy)benzoate (compound aa32-8)
According to the Step 10-6 in synthetic method for EXAMPLE aalO, comp a32-8 (0.1 1 g) as a colorless amorphous solid.
LStep 32-9] Synthesis of methyl 3-[(2R)-2-[(lR)-2-[3-(aminomethyl)-4-cyanoanilino]- l-hydroxy-2-oxoethylJ-3-oxomorpholin-4-yl]-2-(difluoromethoxy)benzoate hydrochloride (compound aa32-9)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa32-8 (0.10 g) was used instead of aa2-6 to obtain compound aa32-9 (70 mg) as a yellow amorphous solid. [Step 32-10] Synthesis of methyl 2-(difluoromethoxy)-3-[(2R)-2-[( IR)-I -hydroxy-2- r(l-imino-2,3-dihydroisoindol-5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]benzoate hydrochloride (EXAMPLE aa32)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa32-9 (70 mg) was used instead of aa2-7 to obtain EXAMPLE aa32 (57 mg) as a yellow amorphous solid.
EXAMPLE aa33
Synthesis of 2-(difluoromethoxy)-3-[(2R)-2-[( IR)-I -hydroxy-2- [(l-imino-2,3-dihydroisoindol-5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]benzoic acid hydrochloride (EXAMPLE aa33)
Figure imgf000212_0001
EXAMPLE aa33
[Step yl)oxycarbonyl]amino]methyl]-4-cyanoanilino]-l -hydroxy-2-oxoethyl]-3-oxomorpholi n-4-yl]-2-(difluoromethoxy)benzoic acid (compound aa33-l)
According to the Step 11 -1 in synthetic method for EXAMPLE aal 1 , compound aa32-7 (0.30 g) was used instead of aal0-5 to obtain compound aa33-l (0.26 g) as a colorless amorphous solid.
[Step 33-2] Synthesis of 3-[(2R)-2-[(lR)-2-[3-(aminomethyl)-4-cyanoanilino]- 1 -hydro xy-2-oxoethyl]-3-oxomorpholin-4-ylJ-2-(difluoromethoxy)benzoic acid hydrochloride (compound aa33-2)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa33-l (0.10 g) was used instead of aa2-6 to obtain compound aa33-2 (76 mg) as a colorless amorphous solid.
[Step 33-3 ] Synthesis of 2-(difluoromethoxy)-3-[(2R)-2-[( IR)-I -hydroxy-2- [( I -imino-2,3-dihydroisoindol-5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]benzoic acid hydrochloride (EXAMPLE aa33)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa33-2 (76 mg) was used instead of aa2-7 to obtain EXAMPLE aa33 (60 mg) as a colorless amorphous solid.
EXAMPLE aa34
Synthesis of 2-(difluoromethoxy)-3-[(2R)-2-[( IR)-I -hydroxy-2-
[(l-imino-2,3-dihydroisoindol-5-yl)aminoJ-2-oxoethyl]-3-oxomorpholin-4-yl]-N,N-di methylbenzamide hydrochloride (EXAMPLE aa34)
Figure imgf000214_0001
[Step 34-1] Synthesis of tert-butyl N-[[2-cyano-5-[[(2R)-2-[(2R)-4-[2- (difluoromethoxy)-3-(dimethylcarbamoyl)phenylJ-3-oxomorpholin-2-yl]-2-hydroxyace tylJamino]phenyl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate
(compound aa34- 1 )
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aa33-l (0.12 g), dimethylamine (2M in THF, 174 μl), and HOBt (3 mg) were used instead of 2-4, tert-butyl
N-(5-amino-2-cyanophenyl)methyl-N-[(2-methylpropan-2-yl)oxycarbonylJcarbamate, and DMAP to obtain compound aa34-l (24 mg) as a colorless amorphous solid.
[Step 34-2] Synthesis of 3-[(2R)-2-[(lR)-2-[3-(aminomethyl)-4-cyanoanilino]- l -hydroxy-2-oxoethyl]-3-oxomorpholin-4-yl]-2-(difluoromethoxy)-N,N-dimethylbenza mide hydrochloride (compound aa34-2)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa34- 1 (24 mg) was used instead of aa2-6 to obtain compound aa34-2 ( 18 mg) as a colorless amorphous solid.
[Step 34-31 Synthesis of 2-(difluoromethoxy)-3-[(2R)-2-l( IR)-I -hydroxy-2- l(l-imino-2,3-dihydroisoindol-5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]-N,N-di methylbenzamide hydrochloride (EXAMPLE aa34)
E aa2, compound aa34-2 ( 18 mg) was used instead of aa2-7 to obtain EXAMPLE aa34 ( 15 mg) as a colorless amorphous solid.
EXAMPLE aa35
Synthesis of 2-(difluoromethoxy)-3-[2-[(l-hydroxy-2-[(l-imino-
2,3-dihydroisoindol-5-yl)aminoJ-2-oxoethyl]-3-oxomorpholin-4-ylJbenzamide hydrochloride (EXAMPLE aa35)
Figure imgf000215_0001
[Step 35-1] Synthesis of tert-butyl N-[[5-[[2-|4-[3-carbamoyl-2- (difluoromethoxy)phenylJ-3-oxomorpholin-2-ylJ-2-hydroxyacetyl]amino]-2-cyanophen yl]methyl]-N-f(2-methylpropan-2-yl)oxycarbonyl]carbamate (compound aa35- 1)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aa32-7 (0.12 g) was used instead of aa2-5 to obtain compound aa35-l (40 mg) as a colorless amorphous solid (diastereomer mixture).
[Step 35-2] Synthesis of 3-[2-[2-[3-(aminomethyl)-4-cyanoanilino]-l -hydroxy-
2-oxoethyl]-3-oxomorpholin-4-yl]-2-(difluoromethoxy)benzamide hydrochloride
(compound aa35-2)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa35-l (39 mg) was used instead of aa2-6 to obtain compound aa35-2 (30 mg) as a colorless amorphous solid (diastereomer mixture) LStep 35-3 ) Synthesis of 2-(difluoromethoxy)-3-|>[( IR)-I -hydroxy-2-[(l -imino- 2,3-dihydroisoindol-5-yl)aminoJ-2-oxoethyl]-3-oxomorpholin-4-ylJbenzamide hydrochloride (EXAMPLE aa35)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa35-2 (54 mg) was used instead of aa2-7 to obtain EXAMPLE aa35 (49 mg) as a pale yellow amorphous solid (diastereomer mixture).
EXAMPLE aa36
Synthesis of methyl 2-L(2R)-2-L(lR)-1-hydroxy-2-L( l-imino-2,3- dihydroisoindol-5-yl)aminoJ-2-oxoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)be nzoate hydrochloride (EXAMPLE aa36)
Figure imgf000216_0001
EXAMPLE aa36
[Step 36-1 ] Synthesis of methyl 2-iodo-5-(trifluoromethoxy)benzoate (compound aa36-l)
According to the Step 16-1 in synthetic method for EXAMPLE aal6, methyl 2-amino-5-trifluoromethoxybenzoate (4.0 g) was used instead of
5-Aminoquinolin-2(1H)-one to obtain compound aa36-l (4.73 g) as pale yellow oil.
[Step 36-2] Synthesis of methyl 2-[(2R)-2-[( IR)-I -hydroxy-2-L(2-methylpropan- 2-yl)oxyJ-2-oxoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)benzoate (compound aa36 2)
aa2, compound aa36-l (2.35 g) was used instead of aa2-l to obtain compound aa36-2 (0.74 g) as a white amorphous solid.
[Step 36-3] Synthesis of methyl 2-[(2R)-2-[( IR)-I -acetyloxy-2-[(2-methylpropan- 2-yl)oxy]-2-oxoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)benzoate (compound aa36-3)
According to the Step 2-3 in synthetic method for EXAMPLE aa2, compound aa36-2 (0.74 g) was used instead of aa2-2 to obtain compound aa36-3 (0.86 g) as colorless oil.
[Step 36-4] Synthesis of (2R)-2-acetyloxy-2-[(2R)-4-[2-methoxycarbonyl- 4-(trifluoromethoxy)phenyl]-3-oxornorpholin-2-yl]acetic acid (compound a36-4)
According to the Step 2-4 in synthetic method for EXAMPLE aa2, compound aa36-3 (0.86 g) was used instead of aa2-3 to obtain compound aa36-4 (0.74 g) as a white amorphous solid.
[Step 36-5] Synthesis of methyl 2-[(2R)-2-[( IR)-I -acetyloxy-2-[3-[[bis[(2- methylpropan-2-yl)oxycarbonyl]amino]methyl]-4-cyanoanilino]-2-oxoethyl]-3-oxomor pholin-4-yl]-5-(trifluoromethoxy)benzoate (compound aa36-5)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aa36-4 (0.35 g) was used instead of aa2-4 to obtain compound aa36-5 (0.43 g) as a white amorphous solid.
[Ste 36 6] S th i f th l 2 [(2R) 2 [(lR) 2 [3 [[bi [(2 th l -2- yl)o xomorpholi n-4-yl]-5-(trifluoromethoxy)benzoate (compound aa36-6)
According to the Step 2-6 in synthetic method for EXAMPLE aa2, compound aa36-5 (70 mg) was used instead of aa2-5 to obtain compound aa36-6 (63 mg) as a white amorphous solid.
[Step 36-7] Synthesis of methyl 2-[(2R)-2-[(lR)-2-[3-(aminomethyl)-4- cyanoanilino]-1-hydroxy-2-oxoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)benzo ate hydrochloride (compound aa36-7)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa36-6 (59 mg) was used instead of aa2-6 to obtain compound aa36-7 (45 mg) as a white solid.
[Step 36-8] Synthesis of methyl 2-[(2R)-2-[( IR)-I -hydroxy-2-[(l -imino-2,3- dihydroisoindol-5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)be nzoate hydrochloride (EXAMPLE aa36)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa36-7 (43 mg) was used instead of aa2-7 to obtain EXAMPLE aa36 (32 mg) as a white amorphous solid. EXAMPLE aa37
Synthesis of 2-[(2R)-2-[( 1 R)- 1 -hydroxy-2-[( 1 -imino-2,3-dihydroisoindol- 5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)benzoic acid hydrochloride (EXAMPLE aa37)
Figure imgf000219_0001
[Step 37-11 Synthesis of 2-[(2R)-2-[(lR)-2-[3-[[bis[(2-methylpropan-2- yl)oxycarbonyl ] amino ]methyl] -4-cyanoanilino] - 1 -hydroxy-2-oxoethy 1] -3-oxomorpholi n-4-yl]-5-(trifluoromethoxy)benzoic acid (compound aa37-l)
According to the Step 11-1 in synthetic method for EXAMPLE aal 1, compound aa36-5 (0.35 g) was used instead of aal 0-5 to obtain compound aa37-l (0.33 g) as a white amorphous solid.
[Step 37-2J Synthesis of 2-[(2R)-2-[(lR)-2-[3-(aminomethyl)-4-cyanoanilino]- l-hydroxy-2-oxoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)benzoic acid hydrochloride (compound aa37-2)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa37-l (33 mg) was used instead of aa2-6 to obtain compound aa37-2 (26 mg) as a white amorphous solid.
[Step 37-3] Synthesis of 2-[(2R)-2-[( IR)-I -hydroxy-2-[(l -imino-2,3- dihydroisoindol-5-yl)aminol-2-oxoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)be nzoic acid hydrochloride (EXAMPLE aa37)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa37-2 (24 mg) was used instead of aa2-7 to obtain EXAMPLE aa37 (16 mg) EXAMPLE aa38
Synthesis of 2-f(2R)-2-[( lR)-1-hydroxy-2-[(l-imino-2,3-dihydroisoindol- 5-yl)aminoJ-2-oxoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)benzamide hydrochloride (EXAMPLE aa38)
Figure imgf000220_0001
EXAMPLE aa38
[Step 38- 1 ] Synthesis of tert-butyl N-[[5-[f(2R)-2-[(2R)-4-[2-carbamoyl-4- (trifluoromethoxy)phenyl]-3-oxomorpholin-2-yl]-2-hydroxyacetyl]aminoJ-2-cyanophe nyl)methylj-N-[(2-raethylpropan-2-yl)oxycarbonyl]carbamate (compound aa38- 1)
According to the Step 2-5 in synthetic method for EXAMPLE aa2, compound aa37-l (88 mg), NH4Cl (33 mg), HOBt (30 mg), and diisopropylethylamine (0.1 1 ml) were used instead of compound aa37- l, tert-butyl
N-(5-amino-2-cyanophenyl)methyl-N-[(2-methylpropan-2-yl)oxycarbonylJcarbamate, and DMAP to obtain compound aa38-l (9.8 mg) as a white amorphous solid. [Step 38-2J Synthesis of 2-[(2R)-2-[(lR)-2-[3-(aminomethyl)-4-cyanoanilino]- l-hydroxy-2-oxoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)benzamide hydrochloride (compound aa38-2)
According to the Step 2-7 in synthetic method for EXAMPLE aa2, compound aa38-l (9 mg) was used instead of aa2-6 to obtain compound aa38-2 (9 mg) as a white amorphous solid.
[Step dihydroisoindol-5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)be nzamide hydrochloride (EXAMPLE aa38)
According to the Step 2-8 in synthetic method for EXAMPLE aa2, compound aa38-2 (8 mg) was used instead of aa2-7 to obtain EXAMPLE aa38 (5 mg) as a white amorphous solid.
Table 1
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Table 2
Figure imgf000226_0002
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
EXAMPLE apt
Synthesis of (2R)-N-(3-amino-l ,2-benzisoxazol-ό-yl)-2-hydroxy-2-[(2R)-3-oxo-
4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]acetamide (EXAMPLE apl)
Figure imgf000232_0001
EXAMPLE apl
According to the Step 15-1 in the synthetic method for Example aal5,
(2R)-2-acetyloxy-2-r(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]acetic acid (compound aa3-3) and 6-amino-3-(l ,3~dioxoisoindol-2-yl)-1,2-benzisoxazole can be used to obtain [(lR)-2-[[3-(1,3-dioxoisoindol-2-yl)~1,2-benzisoxazoI-6- yllaminoJ-2-oxo-1-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]ethyJJacetat e (compound apl -I), then further treatment can be achieved according to the Step 15-2 to obtain the title compound apl.
EXAMPLE ap2
Synthesis of (2R)-N-(3-amino- 1 ,2-benzisoxazol-6-yI)-2-hydroxy-2-[(2R)-3-oxo- 4-(2-oxo-1H-quinolin-7~yl)morpholin-2-yl]acetamide (EXAMPLE ap2)
Figure imgf000232_0002
EXAMPLE ap2
According to the Step 15-1 in the synthetic method for Example aal5,
(2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo- 1 H~quinolin~7-yl)morpholin-2-yl Jacetic acid (com e can be used to obtain [( lR)-2-[L3-( l ,3-dioxoisoindol-2-yl)-l ,2-benzisoxazol-6- yl]amino]-2-oxo- l-[(2R)-3-oxo-4-(2-oxo- 1H-quinolin-7-yl)morpholin-2-yl]ethyl]acetat e (compound ap2-l), then further treatment can be achieved according to the Step 15-2 to obtain the title compound ap2.
EXAMPLE ap3
Synthesis of (2R)-N-(3-amino-l ,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)- 3-oxo~4-(2-oxo- 1H-quinolin-5-yl)morpholin-2-yl]acetamide (EXAMPLE ap3)
Figure imgf000233_0001
EXAMPLE ap3
According to the Step 15- 1 in the synthetic method for Example aal5,
(2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-5-yl)morpholin-2-yl]acetic acid (compound aal6-4) and 6-amino-3-( l ,3-dioxoisoindol-2-yl)-1,2-benzisoxazole can be used to obtain [( lR)-2-[[3-( 1 ,3-dioxoisoindol-2-yl)- 1 ,2-benzisoxazol-
6-yl]amino]-2-oxo-1-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-5-yl)morpholin-2-yl]ethyl]acet ate (compound ap3-l), then further treatment can be achieved according to the Step 15-2 to obtain the title compound ap3.
EXAMPLES aa39 - aa94
Figure imgf000233_0002
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000241_0002
Figure imgf000242_0001
(EXAMPLE aa39)
Preparation of
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(3-((S)-2-methylpyrrolidine-1-car bonyl)phenyl)-3-oxomorpholin-2-yl)acetamide EXAlVIPLE aa39
aa aa39-l
Step 39-2s
aa39-2
Figure imgf000243_0001
EXAMPLE aa39
[Step 39- IsJ
To a solution of aa39a (150 mg, 0.65 mmol) in anhydrous DMSO (8 niL) under a nitrogen atmosphere was added aa39b (225 mg, 0.71 mmol), potassium phosphate (275 mg, 1.30 mmol), copper (I) iodide (12 mg, 0.063 mmol) and trans-N,N'-dimethylcyclohexane- 1 ,2-diamine ( 18 mg, 0.13 mmol). The reaction mixture was heated at 80 °C for 2 hours. Ethyl acetate (100 rnL) was added and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to afford the d [Step 39-2s]
To a solution of aa39-l (170 mg, 0.41 mmol) in anhydrous dichloromethane (6 niL) under a nitrogen atmosphere was added acetic anhydride (84 mg, 0.82 mmol), DMAP (5.0 mg, 0.041 mmol) and triethylamine (124 mg, 1.23 mmol). The reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate ( 100 mL) was added and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to afford the desired aa39-2 (179 mg, 0.39 mmol).
(Step 39-2s]
To aa39-2 (179 mg, 0.39 mmol) was added a 50% solution of trifluoroacetic acid in dichloromethane (8 mL). The reaction mixture was stirred at room
temperature for 16 hours. The organic solvent was evaporated under reduced pressure to afford the desired aa39-3 (0.39 mmol) which was used in the next step without further purification.
[Step 39-4s]
To a solution of aa39-3 (0.39 mmol) in acetonitrile (8 mL) was added aa39c (1 14 mg. 0.64 mmol). EDCI (107 mg, 0.56 mmol) and DMAP (5 mg, 0.041 mmol). The reaction mixture was stirred at room temperature for 2 hour. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to afford the desired aa39-4 (208 mg, 0.37 mmol). [Step 39-5s]
To aa39-4 (208 mg, 0.37 mmol) was added a solution of 7 N ammonia in methanol (8 mL). The reaction mixture was stirred at room temperature for 40 minutes. The organic solvent was evaporated under reduced pressure to afford the desired aa39-5 (0.37 mmol) which was used in the next step without further
purification.
LStep 39-6s]
To a solution of aa39-5 (0.37 mmol) in a 50% solution of 1 N hydrochloric acid in methanol (5 mL) was added palladium-charcoal (10%, 200 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours.
The ed pressure. The LE aa39 (171 mg, 0.36 mmol) as a white amorphous solid.
(EXAMPLE aa40)
Preparation of methyl
2-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyI)-3-oxomorp holino)phenyl)acetate EXAMPLE aa40.
Figure imgf000245_0001
EXAMPLE aa40
[Step 40- Is]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa40a (420 mg, 1.52 mmol) was used instead of compound aa39b to obtain com [Step 40-2sl
According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa40-l (468 mg, 1.23 mmol) was used instead of compound aa39-l to obtain compound aa40-2 (484 mg, 1.15 mmol).
[Step 40-3 s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa40-2 (332 mg, 0.79 mmol) was used instead of compound aa39-2 to obtain compound aa40-3 (0.79 mmol) which was used in the next step without further purification.
[Step 40-4s]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa40-3 (0.79 mmol) was used instead of compound aa39-3 to obtain compound aa40-4 (381 mg, 0.73 mmol).
[Step 40-5sj
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa40-4 (190 mg, 0.36 mmol) was used instead of compound aa39-4 to obtain compound aa40-5 (93 mg, 0.19 mmol) which was used in the next step without further purification.
[Step 40-6s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa40-5 (93 mg, 0.19 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa40 (65 mg, 0. 15 mmol) as a white amorphous solid.
(EXAMPLE aa41)
Preparation of
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-3-(morpholine-4-carbo nyl)phenyl)-3-oxomorpholin-2-yl)acetamide EXAMPLE aa41
Figure imgf000247_0001
[Step 41 -I s]
According to Step 39- I s in the synthetic method for EXAMPLE aa39, compound aa41a (236 mg, 0.71 mmol) was used instead of compound aa39b to obtain compound aa41-l (81 mg, 0.19 mmol).
[Step
39, compound aa41-l (81 mg, 0.19 mmol) was used instead of compound aa39-l to obtain compound aa40-2 (82 mg, 0.17 mmol).
[Step 41 -3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa41-2 (82 mg, 0.17 mmol) was used instead of compound aa39-2 to obtain compound aa41-3 (0.17 mmol) which was used in the next step without further purification. LStep 41-4s]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa41-3 (0.17 mmol) was used instead of compound aa39-3 to obtain compound aa41-4 (50 mg, 0.086 mmol). [Step 41 -5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa41-4 (50 mg, 0.086 mmol) was used instead of compound aa39-4 to obtain compound aa41-5 (0.086 mmol) which was used in the next step without further purification.
[Step 41 -6s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa41-5 (0.086 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa41 (21 mg, 0.042 mmol) as a white amorphous solid.
(EXAlVtPLE aa42)
Preparation of
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-3-(pyrrolidine-1-carbo nyl)phenyl)-3-oxomorphoIin-2-yl)acetamide EXAMPLE aa42
a aa42-l
Step 42-2s
aa42-2
Figure imgf000249_0001
EXAMPLE aa42
[Step 42- Is]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa42a (225 mg, 0.71 mmol) was used instead of compound aa39b to obtain compound aa42-l (92 mg, 0.22 mmol).
[Step
39, compound aa42-l (92 mg, 0.22 mmol) was used instead of compound aa39-l to obtain compound aa42-2 (88 mg, 0.19 mmol).
[Step 42-3sl
According to Step 39-3 s in the synthetic method for EXAMPLE aa39, compound aa42-2 (88 mg, 0.19 mmol) was used instead of compound aa39-2 to obtain compound aa42-3 (0.19 mmol) which was used in the next step without further purification. (Step 42-4sl
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa42-3 (0.19 mmol) was used instead of compound aa39-3 to obtain compound aa42-4 (70 mg, 0.12 mmol). [Step 42-5 s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa42-4 (70 mg, 0.12 mmol) was used instead of compound aa39-4 to obtain compound aa42-5 (0.12 mmol) which was used in the next step without further purification.
[Step 42-6s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa42-5 (0.12 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa42 (28 mg, 0.058 mmol) as a white amorphous solid.
(EXAMPLE aa43)
Preparation of
(R)-2-((R)-4-(3-(azetidine-1-carbonyl)-5-fluorophenyl)-3-oxomorpholin-2-yl)-N-(4-car bamimidoylphenyl)-2-hydroxyacetamide EXAMPLE aa43 I s
Figure imgf000251_0001
EXAMPLE aa43
[Step 43- Is]
According to Step 39- 1 s in the synthetic method for EXAMPLE aa39, compound aa42a (290 mg, 0.95 mrnol) was used instead of compound aa39b to obtain compound aa43-l (243 mg, 0.60 mmol).
[Step 43-2sl
According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa43-l (243 mg, 0.60 mmol) was used instead of compound aa39-l to obta LStep 43-3s]
According to Step 39-3 s in the synthetic method for EXAMPLE aa39, compound aa43-2 (0.60 mmol) was used instead of compound aa39-2 to obtain compound aa43-3 (0.60 mmol) which was used in the next step without further purification.
[Step 43-4s]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa43-3 (0.60 mmol) was used instead of compound aa39-3 to obtain compound aa43-4 (316 mg, 0.57 mmol).
[Step 43-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa43-4 (316 mg, 0.57 mmol) was used instead of compound aa39-4 to obtain compound aa43-5 (0.57 mmol) which was used in the next step without further purification.
[Step 43-6s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa43-5 (0.57 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa43 (237 mg, 0.51 mmol) as a white amorphous solid.
(EXAMPLE aa44)
Preparation of (R)-2-((R)-4-(3-(azetidine- 1 -carbonyl)-2-methylphenyl)-3- oxomorpholin-2-yl)-N-(4-carbamimidoylphenyl)-2-hydroxyacetamide EXAMPLE aa44
aa39a aa44-l
Step 44-2s
aa44-3 aa44-2
Figure imgf000253_0001
EXAMPLE aa44
[Step 44- I s]
According to Step 39- 1 s in the synthetic method for EXAMPLE aa39, compound aa44a (300 mg, 1.00 mmol) was used instead of compound aa39b to obtain compound aa44-l (129 mg, 0.32 mmol).
[Step According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa44-l (129 mg, 0.32 mmol) was used instead of compound aa39-l to obtain compound aa44-2 (144 mg, 0.32 mmol). [Step 44-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa44-2 (144 mg, 0.32 mmol) was used instead of compound aa39-2 to obtain compound aa44-3 (0.32 mmol) which was used in the next step without further purification.
[Step 44-4s]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa44-3 (0.32 mmol) was used instead of compound aa39-3 to obtain compound aa44-4 (48 mg, 0.087 mmol).
[Step 44-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa44-4 (48 mg, 0.087 mmol) was used instead of compound aa39-4 to obtain compound aa44-5 (0.087 mmol) which was used in the next step without further purification.
[Step 44-6s)
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa44-5 (0.087 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa44 (33 mg, 0.071 mmol) as a white amorphous solid.
(EXAMPLE aa45)
Preparation of (R)-2-((R)-4-(5-(azetidine- 1 -carbonyl)-2-methylphenyl)-3- oxomorpholin-2-yl)-N-(4-carbamimidoylphenyl)-2-hydroxyacetamide EXAMPLE aa45
aa
Figure imgf000255_0001
[Step 45- I s]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa45a (282 mg, 0.94 mmol) was used instead of compound aa39b to obtain compound aa45-l (186 mg, 0.46 mmol).
[Ste According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa45-l (186 mg, 0.46 mmol) was used instead of compound aa39-l to obtain compound aa45-2 (96 mg, 0.22 mmol). [Step 45-3sJ
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa45-2 (96 mg, 0.22 mmol) was used instead of compound aa39-2 to obtain compound aa45-3 (0.22 mmol) which was used in the next step without further purification.
[Step 45-4s]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa45-3 (0.22 mmol) was used instead of compound aa39-3 to obtain compound aa45-4 (117 mg, 0.21 mmol).
[Step 45-5sJ
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa45-4 ( 117 mg, 0.21 mmol) was used instead of compound aa39-4 to obtain compound aa45-5 (0.21 mmol) which was used in the next step without further purification.
[Step 45-6s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa45-5 (0.21 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa45 (48 mg, 0.10 mmol) as a white amorphous solid.
(EXAMPLE aa46)
Preparation of (R)-N-(4-carbamimidoylphenyI)-2-hydroxy-2-((R)-3-oxo-4-(6-
(trifluoromethyl)pyridin-2-yl)morpholin-2-yl)acetamide EXAMPLE aa46
Figure imgf000257_0001
[Step 46- Is]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa46a (500 mg, 1.83 mmol) was used instead of compound aa39b to obtain comp [Step 46-2s]
According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa46-l (380 mg, 1.01 mmol) was used instead of compound aa39-l to obtain compound aa46-2 (1.01 mmol).
[Step 46-3sJ
According to Step 39-3 s in the synthetic method for EXAMPLE aa39, compound aa46-2 (222 mg, 0.53 mmol) was used instead of compound aa39-2 to obtain compound aa46-3 (0.53 mmol) which was used in the next step without further purification.
[Step 46-4s]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa46-3 (0.53 mmol) was used instead of compound aa39-3 to obtain compound aa46-4 ( 155 mg, 0.30 mmol).
[Step 46-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa46-4 (155 mg, 0.30 mmol) was used instead of compound aa39-4 to obtain compound aa46-5 (0.30 mmol) which was used in the next step without further purification.
[Step 46-6s[
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa46-5 (0.30 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa46 (59 mg, 0.14 mmol) as a white amorphous solid.
(EXAMPLE aa47)
Preparation of (R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-5- (pyrrolidine- 1 -carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide EXAMPLE aa47
Figure imgf000259_0001
EXAMPLE aa47
[Step 47- I s]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa47a (300 mg, 0.95 mmol) was used instead of compound aa39b to obtain compound aa47-l (338 mg, 0.81 mmol).
[Step 47-2s]
According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa47-l (338 mg, 0.81 mmol) was used instead of compound aa39-l to obta [Step 47-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa47-2 (146 mg, 0.32 mmol) was used instead of compound aa39-2 to obtain compound aa47-3 (0.32 mmol) which was used in the next step without further purification.
[Step 47-4sJ
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa47-3 (0.32 mmol) was used instead of compound aa39-3 to obtain compound aa47-4 (163 mg, 0.29 mmol).
[Step 47-5s)
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa47-4 ( 163 mg, 0.29 mmol) was used instead of compound aa39-4 to obtain compound aa47-5 (0.29 mmol) which was used in the next step without further purification.
[Step 47-6s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa47-5 (0.29 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa47 (115 mg, 0.24 mmol) as a white amorphous solid.
(EXAMPLE aa48)
Preparation of (R)-2-((R)-4-(3-(azetidine- l-carbonyl)-5-methylphenyl)-3- oxomorpholin-2-yl)-N-(4-carbamimidoylphenyl)-2-hydroxyacetamide EXAMPLE aa48
Step 48-2s
Figure imgf000261_0001
EXAMPLE aa48
[Step 48- I s]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa48a (205 mg, 0.68 mmol) was used instead of compound aa39b to obtain compound aa48-l (222 mg, 0.55 mmol).
[Step According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa48-l (222 mg, 0.55 mmol) was used instead of compound aa39-l to obtain compound aa48-2 (219 mg, 0.49 mmol). [Step 48-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa48-2 (219 mg, 0.49 mmol) was used instead of compound aa39-2 to obtain compound aa48-3 (0.49 mmol) which was used in the next step without further purification.
[Step 48-4sJ
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa48-3 (0.49 mmol) was used instead of compound aa39-3 to obtain compound aa48-4 (182 mg, 0.33 mmol).
IStep 48-5sJ
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa48-4 (182 mg, 0.33 mmol) was used instead of compound aa39-4 to obtain compound aa48-5 (0.33 mmol) which was used in the next step without further purification.
[Step 48-6s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa48-5 (0.33 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa48 (1 18 mg, 0.25 mmol) as a white amorphous solid.
(EXAMPLE aa49)
Preparation of
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-5-(morpholine-4-carbo nyl)phenyl)-3-oxomorpholin-2-yl)acetamide EXAMPLE aa49
aa39a aa49-l
Step 49-2s
aa49-
Figure imgf000263_0001
EXAMPLE aa49
[Step 49- Is]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa49a (315 mg, 0.95 mmol) was used instead of compound aa39b to obtain compound aa49-l (177 mg, 0.41 mmol).
[Step According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa49-l (177 mg, 0.41 mmol) was used instead of compound aa39-l to obtain compound aa49-2 (160 mg, 0.34 mmol). [Step 49-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa49-2 (160 mg, 0.34 mmol) was used instead of compound aa39-2 to obtain compound aa49-3 (0.34 mmol) which was used in the next step without further purification.
[Step 49-4s]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa49-3 (0.34 mmol) was used instead of compound aa39-3 to obtain compound aa49-4 (90 mg, 0.16 mmol).
[Step 49-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa49-4 (90 mg, 0.16 mmol) was used instead of compound aa39-4 to obtain compound aa49-5 (0.16 mmol) which was used in the next step without further purification.
[Step 49-6s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa49-5 (0.16 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa49 (60 mg, 0.12 mmol) as a white amorphous solid.
(EXAMPLE aa53)
Preparation of
(R)-N-(4-carbamimidoylpheny])-2-hydroxy-2-((R)-4-(3-methyl-5-(pyrrolidine-1-carbo nyl)phenyl)-3-oxomorpholin-2-yl)acetamide EXAMPLE aa53
Figure imgf000265_0001
LStep 53- ls]
According to Step 39- 1 s in the synthetic method for EXAMPLE aa39, compound aa53a (225 mg, 0.71 mmol) was used instead of compound aa39b to obtain compound aa53-l (222 mg, 0.53 mmol).
[Step According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa53-l (222 mg, 0.53 mmol) was used instead of compound aa39-l to obtain compound aa53-2 (207 mg, 0.45 mmol). [Step 53-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa53-2 (207 mg, 0.45 mmol) was used instead of compound aa39-2 to obtain compound aa53-3 (0.45 mmol) which was used in the next step without further purification.
[Step 53-4s]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa53-3 (106 mg, 0.26 mmol) was used instead of compound aa39-3 to obtain compound aa53-4 (147 mg, 0.26 mmol).
[Step 53-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa53-4 (147 mg, 0.26 mmol) was used instead of compound aa39-4 to obtain compound aa53-5 (0.26 mmol) which was used in the next step without further purification.
[Step 53-6s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa53-5 (0.26 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa53 (83 mg, 0.17 mmol) as a white amorphous solid.
(EXAMPLE aa54)
Preparation of (R)-2-hydroxy-N-(l -iminoisoindolin-5-yl)-2-((R)-4-(3-methyl-5-
(pyrrolidine- 1 -carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide EXAMPLE aa54
Figure imgf000267_0001
[Step 54- Is]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa54a (225 mg, 0.71 mmol) was used instead of compound aa39b to obtain compound aa54-l (222 mg, 0.53 mmol).
[Step According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa54-l (222 mg, 0.53 mmol) was used instead of compound aa39-l to obtain compound aa54-2 (207 mg, 0.45 mmol). [Step 54-3sl
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa54-2 (207 mg, 0.45 mmol) was used instead of compound aa39-2 to obtain compound aa54-3 (0.45 mmol) which was used in the next step without further purification.
[Step 54-4s]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa53-3 (109 mg, 0.27 mmol) was used instead of compound aa39-3 and compound aa54b (140 mg, 0.40 mmol) was instead of compound aa39c to obtain compound aa54-4 (116 mg, 0.16 mmol).
[Step 54-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa54-4 (116 mg, 0.16 mmol) was used instead of compound aa39-4 to obtain compound aa54-5 (0.16 mmol) which was used in the next step without further purification.
[Step 54-6s]
To a solution of compound aa54-5 (0.16 mmol) was added a 4 N solution of hydrogen chloride in dioxane (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The organic solvent was evaporated under reduced pressure.
Anhydrous ethanol ( 12 mL) was added and the reaction mixture was heated under reflux for 16 hours. The organic solvent was evaporated under reduced pressure.
The crude product was purified by RP-HPLC to afford the desired EXAMPLE aa54 (55 mg, 0.11 mmol) as a white amorphous solid. (EXAMPLE aa50)
Preparation of
2-(3-((R)-2-((R)- 1 -hydro xy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)-N-methylbenzamido)acetic acid EXAMPLE aa50
aa39a
EXAMPLE aa5
Figure imgf000269_0001
[Step 50-1 sl
According to Step 39- 1 s in the synthetic method for EXAMPLE aa39, compound aa50a (1.24 g, 3.03 mmol) was used instead of compound aa39b to obtain compound aa50-l (1.16 g, 2.27 mmol).
[Step 5O-2s]
39, comp to obtain compound aa50-2 (1.16 g, 2.09 mmol).
LStep 5O-3s]
According to Step 39-3 s in the synthetic method for EXAMPLE aa39, compound aa50-2 (250 mg, 0.50 mmol) was used instead of compound aa39-2 to obtain compound aa50-3 (0.50 mmol) which was used in the next step without further purification.
[Step 50-4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa50-3 (0.50 mmol) was used instead of compound aa54-3 to obtain compound aa50-4 (255 mg, 0.31 mmol).
[Step 5O-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa50-4 (255 mg, 0.31 mmol) was used instead of compound aa39-4 to obtain compound aa40-5 (0.31 mmol) which was used in the next step without further purification. [Step 50-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa50-5 (0.31 mmol) was used instead of compound aa54-5 to obtain compound aa50-6 (0.31 mmol) which was used in the next step without further purification.
[Step 5O-7s]
To a solution of compound aa50-6 (0.31 mmol) in methanol (2 mL) and water
(2 mL) was added triethylamine (0.43 mL). The reaction mixture was stirred at room temperature for 16 hours. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to afford the desired EXAMPLE aa50
(153 mg, 0.31 mmol) as a white amorphous solid. (EXAMPLE aa51)
Preparation of methyl 2-(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-
2-oxoethyl)-3-oxomorpholino)-N-methylbenzamido)acetate EXAMPLE aa51
Figure imgf000271_0001
aaSO EXAMPLE aa51
[Step 51- I s]
To a solution of compound aa50 (90 mg, 0.18 mmol) in methanol (4 mL) was added 1 N hydrochloric acid (1 mL). The reaction mixture was stirred at room temperature for 3 days. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to afford the desired EXAMPLE aa51 (48 mg, 0.094 mmol) as a white amorphous solid.
(EXAMPLE aa58)
Preparation of (S)-I -(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-l -hydroxy-
2-oxoethyl)-3-oxomorpholino)benzoyl)pyrrolidine-2-carboxylic acid EXAMPLE aa58
aa39a aa58 aa58-l
Step 58-2s
aa58-3
Figure imgf000272_0001
EXAMPLE aa58
[Step 58- IsI
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa58a (616 mg, 1.42 mmol) was used instead of compound aa39B to obtain compound aa58-l (710 mg, 1.32 mmol). [Step 58-2s]
39, comp l to obtain compound aa58-2 (707 mg, 1.22 mmol).
[Step 58-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa58-2 (0.66 mmol) was used instead of compound aa39-2 to obtain compound aa58-3 (0.66 mmol) which was used in the next step without further purification.
[Step 58-4s]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa58-3 (0.66 mmol) was used instead of compound aa39-3 to obtain compound aa58-4 (445 mg, 0.65 mmol).
[Step 58-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa58-4 (445 mg, 0.65 mmol) was used instead of compound aa39-4 to obtain compound aa58-5 (0.65 mmol) which was used in the next step without further purification. [Step 58-6s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa58-5 (0.65 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa58 (42 mg, 0.083 mmol) as a white amorphous solid.
(EXAMPLE aa52)
Preparation of (S)-methyl l-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1- hydroxy-2-oxoethyl)-3-oxomorpholino)benzoyl)pyrrolidine-2-carboxylate EXAMPLE aa52
Figure imgf000274_0001
aa5 XAMPLE aa52
[Step 52- Is]
According to Step 51 -1 s in the synthetic method for EXAMPLE aa51, compound aa58 (24 mg, 0.047 mmol) was used instead of compound aaSO to obtain EXAMPLE aa52 (24 mg, 0.046 mmol) as a white amorphous solid.
(EXAMPLE aa56)
Preparation of 3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)- 1 -hydroxy-2-oxoethyl)-
3-oxomorpholino)-N-methyl-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)benzamide
EXAMPLE aa56
^56"1
Step 56-2s
aa56-2
Figure imgf000275_0001
EXAMPLE aa56
[Step 56-1 sl
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa56a (886 mg, 2.38 mmol) was used instead of compound aa39b to obtain compound aa56-l (669 mg, 1.41 mmol).
[Step 56-2s]
According to Step 39-2s in the synthetic method for EXAMPLE aa39, com d aa39-l to obta [Step 56-3s)
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa56-2 (477 mg, 0.92 mmol) was used instead of compound aa39-2 to obtain compound aa40-3 (0.92 mmol) which was used in the next step without further purification.
[Step 56-4sl
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa40-3 (235 mg, 0.51 mmol) was used instead of compound aa39-3 to obtain compound aa56-4 (244 mg, 0.39 mmol).
[Step 56-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa56-4 (244 mg, 0.39 mmol) was used instead of compound aa39-4 to obtain compound aa56-5 (0.39 mmol) which was used in the next step without further purification.
[Step 56-6s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa56-5 (0.39 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa56 (160 mg, 0.30 mmol) as a white amorphous solid.
(EXAMPLE aa59)
Preparation of 3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-
3-oxomorpholino)-N-methyl-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)benzamide
EXAMPLE aa59
Figure imgf000277_0001
aa39a aa56a aa59-l
Step 59-2s
Figure imgf000277_0002
Figure imgf000277_0004
Figure imgf000277_0003
EXAMPLE aa59
[Step 59- Is]
According to Step 39-1 s in the synthetic method for EXAMPLE aa39, compound aa56a (886 mg, 2.38 mmol) was used instead of compound aa39b to obtain compound aa59-l (669 mg, 1.41 mmol).
[Step 59-2sl
According to Step 39-2s in the synthetic method for EXAMPLE aa39, com -l to obta [Step 59-3s]
According to Step 39-3 s in the synthetic method for EXAMPLE aa39, compound aa59-2 (477 mg, 0.92 mmol) was used instead of compound aa39-2 to obtain compound aa59-3 (0.92 mmol) which was used in the next step without further purification.
[Step 59-4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa54b (235 mg, 0.51 mmol) was used instead of compound aa54-3 to obtain compound aa59-4 (224 mg, 0.28 mmol).
[Step 59-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa59-4 (224 mg, 0.28 mmol) was used instead of compound aa39-4 to obtain compound aa59-5 (0.28 mmol) which was used in the next step without further purification.
[Step 59-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa59-5 (0.28 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aa59 (57 mg, 0.10 mmol) as a white amorphous solid.
(EXAMPLE aa60)
Preparation of (R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(3-methyl-5-
(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide EXAMPLE aa60
Figure imgf000279_0001
EXAMPLE aa60
[Step 60- I s]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa60a (315 mg, 0.95 mmol) was used instead of compound aa39b to obtain compound aa60-l (218 mg, 0.50 mmol). [Ste
a39, compound aa60-l (218 mg, 0.50 mmol) was used instead of compound aa39-l to obtain compound aa60-2 (226 mg, 0.47 mmol).
[Step 60-3s]
According to Step 39- 3 s in the synthetic method for EXAMPLE aa39, compound aa60-2 (226 mg, 0.47 mmol) was used instead of compound aa39-2 to obtain compound aa60-3 (0.47 mmol) which was used in the next step without further purification. [Step 60-4sl
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa60-3 (100 mg, 0.24 mmol) was used instead of compound aa39-3 to obtain compound aa60-4 (87 mg, 0.15 mmol). [Step 6O-5sl
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa60-4 (87 mg, 0.15 mmol) was used instead of compound aa39-4 to obtain compound aa60-5 (0.15 mmol) which was used in the next step without further purification.
[Step 60-6sj
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa60-5 (0.15 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa60 (71 mg, 0.14 mmol) as a white amorphous solid.
(EXAMPLE aa61)
Preparation of (R)-2-hydroxy-N-(l -iminoisoindolin-5-yl)-2-((R)-4-(3-methyl-5-
(morpholine-4-carbonyl)ph'enyl)-3-oxomorpholin-2-yl)acetamide EXAMPLE aaόl
S
Figure imgf000281_0001
[Step 61-lsl
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa60a (315 mg, 0.95 mmol) was used instead of compound aa39b to obtain compound aa61-l (218 mg, 0.50 mmol). [Step 61-2sl
According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa61-l (218 mg, 0.50 mmol) was used instead of compound aa39-l to obtain compound aa61-2 (226 mg, 0.47 mmol). [Step According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa61-2 (226 rng, 0.47 mmol) was used instead of compound aa39-2 to obtain compound aa61-3 (0.47 mmol) which was used in the next step without further purification.
[Step 61 -4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa61-3 ( 124 mg, 0.30 mmol) was used instead of compound aa54-3 to obtain compound aa61-4 (118 mg, 0.16 mmol).
[Step 61 -5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa61-4 (1 18 mg, 0.16 mmol) was used instead of compound aa39-4 to obtain compound aa61-5 (0.16 mmol) which was used in the next step without further purification.
[Step 61 -6s J
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa61-5 (0.16 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aaόl (71 mg, 0.14 mmol) as a white amorphous solid.
(EXAMPLE aa63)
Preparation of (R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(3 -((R)-3- methoxypyrrolidine- l-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide EXAMPLE aa63
Figure imgf000283_0001
EXAMPLE aa63
[Step 63- I s]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa63a (158 mg, 0.48 mmol) was used instead of compound aa39b to obtain compound aa63-l (124 mg, 0.29 mmol).
[Step According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa63-l (124 mg, 0.29 mmol) was used instead of compound aa39-l to obtain compound aa63-2 (132 mg, 0.28 mmol). [Step 63-3sl
According to Step 39-3 in the synthetic method for EXAMPLE aa39, compound aa63-2 (132 mg, 0.28 mmol) was used instead of compound aa39-2 to obtain compound aa63-3 (0.28 mmol) which was used in the next step without further purification.
[Step 63-4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa63-3 (0.28 mmol) was used instead of compound aa54-3 to obtain compound aa63-4 (88 mg, 0.12 mmol).
[Step 63-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa63-4 (88 mg, 0.12 mmol) was used instead of compound aa39-4 to obtain compound 63-5 (0.12 mmol) which was used in the next step without further purification.
[Step 63-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa63-5 (0.12 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aa63 (26 mg, 0.051 mmol) as a white amorphous solid.
(EXAMPLE aa64)
Preparation of (R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(3-((S)-3- methoxypyrrolidine-1-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide EXAMPLE aa64
Step
64-6s
Figure imgf000285_0001
EXAMPLE aa64
[Step 64- IsI
According to Step 39- I s in the synthetic method for EXAMPLE aa39, compound aa64a (158 mg, 0.48 mmol) was used instead of compound aa39b to obtain compound aa64-l (125 mg, 0.29 mmol).
[Ste According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa64-l (125 mg, 0.29 mmol) was used instead of compound aa39-l to obtain compound aa64-2 (136 mg, 0.29 mmol). [Step 64-3sl
According to Step 39-3 s in the synthetic method for EXAMPLE aa39, compound aa64-2 (136 mg, 0.29 mmol) was used instead of compound aa39-2 to obtain compound aa64-3 (0.29 mmol) which was used in the next step without further purification.
[Step 64-4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa64-3 (0.29 mmol) was used instead of compound aa54-3 to obtain compound aa64-4 (109 mg, 0.15 mmol).
[Step 64-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa64-4 (109 mg, 0.15 mmol) was used instead of compound aa39-4 to obtain compound aa64-5 (0.15 mmol) which was used in the next step without further purification.
[Step 64-6sl
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa64-5 (0.15 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aa64 (70 mg, 0.14 mmol) as a white amorphous solid.
(EXAMPLE aa66)
Preparation of (R)-2-((R)-4-(3-chloro-4-(morpholine-4-carbonyl)phenyl)-3- oxomorpholin-2-yl)-2-hydroxy-N-(l-iminoisoindolin-5-yl)acetamide EXAMPLE aa66
Figure imgf000287_0001
[Step 66- IsJ
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa66a (334 mg, 0.95 mmol) was used instead of compound aa39B to obtain compound aa66-l (276 mg, 0.61 mmol). LStep 6 2
39, compound aa66-l (276 mg, 0.61 mmol) was used instead of compound aa39-l to obtain compound aa66-2 (0.61 mmol).
!Step 66-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa66-2 (0.61 mmol) was used instead of compound aa39-2 to obtain compound aa66-3 (0.61 mmol) which was used in the next step without further purification. [Step 66-4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa66-3 (213 mg, 0.48 mmol) was used instead of compound aa54-3 to obtain compound aa66-4 (310 mg, 0.40 mmol). [Step 66-5s1
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa66-4 (310 mg, 0.40 mmol) was used instead of compound aa39-4 to obtain compound aa66-5 (0.40 mmol) which was used in the next step without further purification.
[Step 66-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa66-5 (0.40 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aa66 (208 mg, 0.39 mmol) as a white amorphous solid.
(EXAMPLE aa68)
Preparation of (R)-2-hydroxy-N-(l-iminoisoindolin-5-yl)-2-((R)-4-(3-(2-morpholino-
2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide EXAMPLE aa68
Step 68-2s
Step 68~4s
Bo
Figure imgf000289_0001
EXAMPLE aa68
[Step 68- Is]
According to Step 39- 1 s in the synthetic method for EXAMPLE aa39, compound aa68a (923 mg, 2.38 mmol) was used instead of compound aa39b to obtain compound aa68-l (701 mg, 1.43 mmol). [Step 68-2sl
39, com -l to obtain compound aa68-2 (477 mg, 0.89 mmol).
[Step 68-3sl
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa68-2 (477 mg, 0.89 mmol) was used instead of compound aa39-2 to obtain compound aa68-3 (0.89 mmol) which was used in the next step without further purification.
[Step 68-4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa68-3 (0.89 mmol) was used instead of compound aa54-3 to obtain compound aa68-4 (536 mg, 0.67 mmol).
[Step 68-5sl
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa68-4 (536 mg, 0.67 mmol) was used instead of compound aa39-4 to obtain compound aa68-5 (0.67 mmol) which was used in the next step without further purification. [Step 68-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa68-5 (0.67 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aa68 (291 mg, 0.36 mmol) as a white amorphous solid.
(EXAMPLE aa55)
Preparation of (S)- 1 -(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-
2-oxoethyl)-3-oxomorpholino)benzoyl)pyrrolidine-2-carboxylic acid EXAMPLE aa55 5-l
Step 55-2s
5-2
St
Figure imgf000291_0001
5-6
[Step 55-1 s]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa55a (616 mg, 1.42 mmol) was used instead of compound aa39b to obtain compound aa55-l (710 mg, 1.32 mmol). [Step 55-2sl
According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa55-l (710 mg, 1.32 mmol) was used instead of compound aa39-l to obta [Step 55-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa55-2 (707 mg, 1.22 mmol) was used instead of compound aa39-2 to obtain compound aa55-3 (1.22 mmol) which was used in the next step without further purification.
[Step 55-4s]
According to Step 54-4 in the synthetic method for EXAMPLE aa54, compound aa55-3 (1.22 mmol) was used instead of compound aa54-3 to obtain compound aa55-4 (409 mg, 0.48 mmol).
[Step 55-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa55-4 (409 mg, 0.48 mmol) was used instead of compound aa39-4 to obtain compound aa55-5 (0.48 mmol) which was used in the next step without further purification.
[Step 55-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa55-5 (0.48 mmol) was used instead of compound aa54-5 to obtain compound aa55-6 (0.48 mmol) which was used in the next step without further purification.
[Step 55-7s]
According to Step 5O-7s in the synthetic method for EXAMPLE aa50, compound aa55-6 (0.48 mmol) was used instead of compound aa50-6 to obtain EXAMPLE aa55 (80 mg, 0.15 mmol) as a white amorphous solid.
(EXAMPLE aa57)
Preparation of (S)-methyl
1 -(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2- oxoethyl)-3-oxomorpholino)benzoyl)pyrrolidine-2-carboxylate EXAMPLE aa57 Is
Figure imgf000293_0001
Figure imgf000293_0002
EXAxMPLE aa57
[Step 57- Is]
According to Step 50-7s in the synthetic method for EXAMPLE aa50, compound aa55-6 (0.48 mmol) was used instead of compound aa50-6 to obtain EXAMPLE aa57 (31 mg, 0.058 mmol) as a white amorphous solid.
(EXAMPLE aa65)
Preparation of ethyl 2-(3~((R)-2-((R)-l-hydroxy-2-(l-iminoisoindolin-5-ylamino)-
2-oxoethyl)-3-oxomorpholino)phenyl)acetate EXAMPLE aa65
Figure imgf000294_0001
[Step 65- I s]
According to Step 39- I s in the synthetic method for EXAMPLE aa39, compound aa65a (636 mg, 1.81 mmol) was used instead of compound aa39b to obtain compound aa65-l (694 mg, 1.53 mmol). [Step 65-2s)
According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa65-l (694 mg, 1.53 mmol) was used instead of compound aa39-l to
293 obtain compound aa65-2 (723 mg, 1.45 mmol).
[Step 65-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa65-2 (723 mg, 1.45 mmol) was used instead of compound aa39-2 to obtain compound aa65-3 (1.45 mmol) which was used in the next step without further purification.
[Step 65-4sJ
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa65-3 (1.45 mmol) was used instead of compound aa54-3 to obtain compound aa65-4 (715 mg, 0.93 mmol).
[Step 65-5sl
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa65-4 (715 mg, 0.93 mmol) was used instead of compound aa39-4 to obtain compound aa65-5 (0.93 mmol) which was used in the next step without further purification. [Step 65-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa65-5 (0.93 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aa65 (261 mg, 0.56 mmol) as a white amorphous solid.
(EXAMPLE aa67)
Preparation of 2-(3-((R)-2-((R)-l -hydroxy-2-(l-iminoisoindolin-5-ylamino)-2- oxoethyl)-3-oxomorpholino)phenyl)acetic acid EXAMPLE aa67
Figure imgf000296_0001
[Step 67- Is]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa65-5 (715 mg, 0.93 mmol) was used instead of compound aa54-5 to obtain aa67-l (64 mg, 0.12 mmol). [Step 67-2sl
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa67-l (64 mg, 0.12 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa67 (30 mg, 0.068 mmol) as a white amorphous solid.
(EXAMPLE aa62)
Preparation of ethyl 2-(3-((R)-2-((R)- l-hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2- oxoethyI)-3-oxomorpholino)-N-methylbenzamido)acetate EXAMPLE aa62
EXAMPLE aa62
Figure imgf000297_0001
[Step 62-1 J
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa50-5 (276 mg, 0.35 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aa62 (65 mg, 0.12 mmol) as a white amorphous solid.
(EXAMPLE aa70)
Preparation of benzyl 2-(3-((R)-2-((R)-1-hydroxy-2-(l-immoisoindolin-5-ylamino)-2- oxoethyl)-3-oxomorpholino)phenyl)-2-methylpropanoate EXAMPLE aa70
Figure imgf000298_0001
E aa70-6
[Step 70- Is]
According to Step 39- 1 s in the synthetic method for EXAMPLE aa39, compound aa70a (559 mg, 1.47 mmol) was used instead of compound aa39b to obtain compound aa70-l (524 mg, 1.08 mmol). [Step 70-2s]
According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa70-l (524 mg, 1.08 mmol) was used instead of compound aa39-l to obtain compound aa70-2 (558 mg, 1.06 mmol). [Step 7O-3s]
A ording to Step 39 3s in the synthetic method for EXAMPLE aa39, comp -2 to obtain compound aa70-3 (1.06 mmol) which was used in the next step without further purification.
[Step 70-4sJ
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa70-3 (1.06 mmol) was used instead of compound aa54-3 to obtain compound aa70-4 (415 mg, 0.54 mmol).
[Step 7O-5sJ
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa70-4 (415 mg, 0.54 mmol) was used instead of compound aa39-4 to obtain compound aa70-5 (0.54 mmol) which was used in the next step without further purification. [Step 7O-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa70-5 (0.54 mmol) was used instead of compound aa54-5 to obtain aa70-6 (0.54 mmol). [Step 7O-7s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa70-6 (0.54 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa70 (83 mg, 0.18 mmol) as a white amorphous solid.
(EXAMPLE aa69)
Preparation of (R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(3-(morpholine-4- carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide EXA]VIPLE aa69
Figure imgf000300_0001
[Step 69- Is]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa69a (296 mg, 0.93 mmol) was used instead of compound aa39b to obtain compound aa69-l (345 mg, 0.82 mmol). [Ste
a39, compound aa69-l (345 mg, 0.82 mmol) was used instead of compound aa39-l to obtain compound aa69-2 (372 mg, 0.81 mmol).
[Step 69-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa69-2 (372 mg, 0.81 mmol) was used instead of compound aa39-2 to obtain compound aa69-3 (0.81 mmol) which was used in the next step without further purification. [Step 69-4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa69-3 (0.81 mmol) was used instead of compound aa54-3 to obtain compound aa69-4 (523 mg, 0.71 mmol). [Step 69-5sJ
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa69-4 (523 mg, 0.71 mmol) was used instead of compound aa39-4 to obtain compound aa69-5 (0.71 mmol) which was used in the next step without further purification.
[Step 69-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa69-5 (0.71 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aa69 (274 mg, 0.56 mmol) as a white amorphous solid.
(EXAMPLE aa71)
Preparation of 3-((R)-2-((R)-1-hydroxy-2-(l-iminoisoindolin-5-ylamino)-2- oxoethyl)-3-oxomorpholino)-N-methyl-N-(2-morpholino-2-oxoethyl)benzamide
EXAlVIPLE aa71
Figure imgf000302_0001
[Step 71 -Is]
According to Step 39- 1 s in the synthetic method for EXAMPLE aa39, compound aa71a (923 mg, 2.38 mmol) was used instead of compound aa39b to obtain compound aa71-l (701mg, 1.43 mmol).
[Step 71 -2s]
According to Step 39-2s in the synthetic method for EXAMPLE aa39, comp d 71 l (485 099 l) d i t d f d 39l to obtai [Step 71-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa71-2 (477 mg, 0.89 mmol) was used instead of compound aa39-2 to obtain compound aa71-3 (0.89 mmol) which was used in the next step without further purification.
[Step 71 -4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa71-3 (345 mg, 0.85 mmol) was used instead of compound aa54-3 to obtain compound aa71-4 (523 mg, 0.71 mmol).
[Step 71-5sJ
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa71-4 (523 mg, 0.71 mmol) was used instead of compound aa39-4 to obtain compound aa71-5 (0.71 mmol) which was used in the next step without further purification.
[Step 71 -6s J
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa71-5 (0.71 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aa71 (274 mg, 0.56 mmol) as a white amorphous solid.
(EXAMPLE aa72)
Preparation of (R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(3-(2-((R)-3- methoxypyrrolidin-l-yl)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide
EXAMPLE aa72
Figure imgf000304_0001
[Step 72- IsJ
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa72a (356 mg, 1.03 mmol) was used instead of compound aa39b to obtain compound aa72-l (358 mg, 0.80 mmol).
[Step 72-2s]
di 2 i h h i h d f EX E 39, comp -l to obtain compound aa72-2 (391 mg, 0.80 mmol).
[Step 72-3 s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa72-2 (391 mg, 0.80 mmol) was used instead of compound aa39-2 to obtain compound aa72-3 (0.80 mmol) which was used in the next step without further purification.
[Step 72-4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa72-3 (0.80 mmol) was used instead of compound aa54-3 to obtain compound aa72-4 (534 mg, 0.70 mmol).
[Step 72-5sl
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa72-4 (534 mg, 0.70 mmol) was used instead of compound aa39-4 to obtain compound aa72-5 (0.70 mmol) which was used in the next step without further purification. [Step 72-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa72-5 (0.70 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aa72 (283 mg, 0.56 mmol) as a white amorphous solid.
(EXAMPLE aa73)
Preparation of (R)-2-hydroxy-N-(l -iminoisoindolin-5-yl)-2-((R)-4-(3-(2-((S)-3- methoxypyrrolidin-1-yl)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide
EXAMPLE aa73
aa39a aa73-l
Step 73-2s
aa7 aa73-2
Figure imgf000306_0001
EXAiMPLE aa73
[Step 73- I s]
According to Step 39- I s in the synthetic method for EXAMPLE aa39, compound aa73a (724 mg, 2.10 mmol) was used instead of compound aa39b to obtain compound aa73-l (331 mg, 0.74 mmol).
[Step 73-2s]
A di t St 39 2 i th th ti th d f EXAMPLE 39, comp l to obtain compound aa73-2 (359 mg, 0.73 mmol).
LStep 73-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa73-2 (359 mg, 0.73 mmol) was used instead of compound aa39-2 to obtain compound aa73-3 (0.73 mmol) which was used in the next step without further purification.
[Step 73-4s]
According to Step 54~4s in the synthetic method for EXAMPLE aa54. compound aa73-3 (0.73 mmol) was used instead of compound aa54-3 to obtain compound aa73-4 (395 mg, 0.52 mmol).
[Step 73-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa73-4 (395 mg, 0.52 mmol) was used instead of compound aa39-4 to obtain compound aa73-5 (0.52 mmol) which was used in the next step without further purification. [Step 73-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa73-5 (0.52 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aa73 (222 mg, 0.43 mmol) as a white amorphous solid.
(EXAMPLE aa74)
Preparation of methyl 2-(3-((R)-2-((R)-1-hydroxy-2-( l-iminoisoindolin-5-ylamino)-
2-oxoethyl)-3-oxomorpholino)phenyl)-2-methylpropanoate EXAMPLE aa74
Figure imgf000308_0001
[Step 74- I s]
To a solution of compound aa70 (44 mg, 0.094 mmol) in methanol (4 mL) was concentrated sulfuric acid (0.08 mL). The reaction mixture was heated at 80 °C for 16 hours. Triethylamine (0.5 mL) was added. The organic solvent was evaporated under reduced pressure. The crude product was purified RP-HPLC to afford the desired EXAMPLE aa74 (20 mg, 0.042 mmol) as a white amorphous solid.
(EXAMPLE aa75)
Preparation of methyl 2-(3-((R)-2-((R)-1-hydroxy-2-(l-iminoisoindolin-5-ylamino)-
2-oxoethyl)-3-oxomorpholino)phenyl)acetate EXAMPLE aa75
Figure imgf000308_0002
[Step 75- Is]
To a solution of compound aa65 (237 mg, 0.51 mmol) in methanol (5 mL) and water (5 mL) was added triethylamine (0.5 mL). The reaction mixture was stirred at room temperature for 3 days. The organic solvent was evaporated under reduced pressure. The residue was dissolved in methanol (5 mL) and concentrated sulfuric acid (0.1 mL) was added. The reaction mixture was heated at 80 °C for 16 hours. Triethylamine (1 mL) was added. The organic solvent was evaporated under reduced pressure. The crude product was purified RP-HPLC to afford the desired EXAMPLE aa75 (20 mg, 0.042 mmol) as a white amorphous solid. (EXAMPLE aa76)
Preparation of
(R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(3-(4-methyl-3-oxopiperazine- 1 -ca rbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide EXAMPLE aa76
Ste
Figure imgf000309_0001
[Step 76- Is]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa76a (328 mg, 0.95 mmol) was used instead of compound aa39b to obtain compound aa76-l (347 mg, 0.71 mmol).
[Step 76-2s]
A di S 392 i h h i h d f EXAMPLE 39, comp -l to obtain compound aa76-2 (265 mg, 0.54 mmol).
[Step 76-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa76-2 (265 mg, 0.54 mmol) was used instead of compound aa39-2 to obtain compound aa76-3 (0.54 mmol) which was used in the next step without further purification.
[Step 76-4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa76-3 (0.54 mmol) was used instead of compound aa54-3 to obtain compound aa76-4 (282 mg, 0.37 mmol).
[Step 76-5 si
According to Step 39-5 s in the synthetic method for EXAMPLE aa39, compound aa76-4 (282 mg, 0.37 mmol) was used instead of compound aa39-4 to obtain compound aa76-5 (0.37 mmol) which was used in the next step without further purification. [Step 76-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa76-5 (0.37 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aa76 (135 mg, 0.26 mmol) as a white amorphous solid.
(EXAMPLE aa77)
Preparation of ethyl
2-(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)phenyl)-2-methylpropanoate EXAMPLE aa77
Figure imgf000311_0001
aa70 EXAMPLE aa77
[Step 77- Is]
To a solution of compound aa70 (55 mg, 0, 12 mmol) in absolute ethanol (4 πiL) was added concentrated sulfuric acid (0.05 mL). The reaction mixture was heated at 80 °C for 16 hours. Triethylamine (0.5 mL) was added. The organic solvent was evaporated under reduced pressure. The crude product was purified RP-HPLC to afford the desired EXAMPLE aa77 (24 mg, 0.049 mmol) as a white amorphous solid.
(EXAMPLE aa78)
Preparation of
(S)- l-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-l -hydroxy-2-oxoethyl)-3-oxom orpholino)-5-fluorobenzoyl)pyrrolidine-2-carboxylic acid EXAMPLE aa78
aa39a
Figure imgf000312_0001
[Step 78- I s]
According to Step 39- 1 s in the synthetic method for EXAMPLE aa39, compound aa78a (1.59 g, 3.51 mmol) was used instead of compound aa39b to obtain compound aa78-l (895 mg, 1.61 mmol).
[Step 78 2 ]
39, compound aa78-l (895 mg, 1.61 mmol) was used instead of compound aa39-l to obtain compound aa78-2 (854 mg, 1.43 mmol).
[Step 78-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa78-2 (854 mg, 1.43 mmol) was used instead of compound aa39-2 to obtain compound aa78-3 (1.43 mmol) which was used in the next step without further purification. [Step 78-4s]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aaa78-3 (1.43 mmol) was used instead of compound aa39-3 to obtain compound aa78-4 (968 mg, 1.38 mmol). [Step 78-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa78-4 (968 mg, 1.38 mmol) was used instead of compound aa39-4 to obtain compound aa78-5 (1.38 mmol) which was used in the next step without further purification.
[Step 78-6s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa78-5 (1.38 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa78 (542 mg, 1.03 mmol) as a white amorphous solid.
(EXAMPLE aa79)
Preparation of (R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(3-(2-(4-methyl-3- oxopiperazin-1-y[)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide EXAMPLE aa79
Figure imgf000314_0001
[Step 79- Is]
According to Step 39- 1 s in the synthetic method for EXAMPLE aa39, compound aa79a (341 mg, 0.95 mmol) was used instead of compound aa39b to obtain compound aa79-l (214 mg, 0.46 mmol).
[Step 2
39, compound aa79-l (214 mg, 0.46 mmol) was used instead of compound aa39-l to obtain compound aa79-2 (207 mg, 0.41 mmol).
[Step 79-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa79-2 (207 mg, 0.41 mmol) was used instead of compound aa39-2 to obtain compound aa79-3 (0.41 mmol) which was used in the next step without further purification. [Step 79-4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa79-3 (0.41 mmol) was used instead of compound aa54-3 to obtain compound aa79-4 (277 mg, 0.36 mmol).
[Step 79-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa79-4 (277 mg, 0.36 mmol) was used instead of compound aa39-4 to obtain compound aa79-5 (0.36 mmol) which was used in the next step without further purification.
[Step 79-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa79-5 (0.36 mmol) was used instead of compound aa54-5 to obtain
EXAMPLE aa79 (147 mg, 0.28 mmol) as a white amorphous solid.
(EXAMPLE aa80)
Preparation of (S)-ethyl l-(3-((R)-2-((R)-2-(4-carbamimidoyIphenylamino)-1- hydroxy-2-oxoethyl)-3-oxomorpholino)-5-fluorobenzoyl)pyrrolidine-2-carboxylate EXAMPLE aa80
Figure imgf000315_0001
EXAMPLE aa80
According to Step 77- I s in the synthetic method for EXAMPLE aa77, comp obtain EXA (EXAMPLE aa81)
Preparation of (S)-methyl 1 -(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)~ 1 - hydroxy-2-oxoethyl)-3-oxomorpholino)-5-fluorobenzoyl)pyrrolidine-2-carboxylate
EXAMPLE aa81
Figure imgf000316_0001
EXAMPLE aa81
[Step 81-1 sj
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa78-4 (968 mg, 1.38 mmol) was used instead of compound aa39-4 to obtain compound aa81-l which was used in the next step without further purification.
[Step 81 -2s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa81-l was used instead of compound aa39-5 to obtain EXAMPLE aa81 (50 mg, 0.092 mmol) as a white amorphous solid.
(EXAMPLE aa82)
Preparation of (R)-2-((R)-4-(3-(2-(dimethylamino)-2-oxoethyl)phenyl)-3- oxomorpholin-2-yl)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)acetamide EXAMPLE aa82
Step 82-4s
Figure imgf000317_0001
[Step 82- IsJ
According to Step 39- 1 s in the synthetic method for EXAMPLE aa39, compound aa82a (275 mg, 0.95 mmol) was used instead of compound aa39b to obtain compound aa82-l (304 mg, 0.78 mmol). [Step 82-2sJ
According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa82-l (304 mg, 0.78 mmol) was used instead of compound aa39-l to obtain compound aa82-2 (302 mg, 0.70 mmol). [Step According to Step 39-3 s in the synthetic method for EXAMPLE aa39, compound aa82-2 (302 mg, 0.70 mmol) was used instead of compound aa39-2 to obtain compound aa82-3 (0.70 mmol) which was used in the next step without further purification.
[Step 82-4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa82-3 (104 mg, 0.28 mmol) was used instead of compound aa54-3 to obtain compound aa82-4 (143 mg, 0.20 mmol).
[Step 82-5s]
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa82-4 (143 mg, 0.20 mmol) was used instead of compound aa39-4 to obtain compound aa82-5 (0.20 mmol) which was used in the next step without further purification.
[Step 82-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa82-5 (0.20 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aa82 (61 mg, 0.13 mmol) as a white amorphous solid.
(EXAMPLE aa83)
Preparation of 1 -(3-((R)- 2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-
2-oxoethyl)-3-oxomorpholino)benzoyl)piperidine-4-carboxylic acid EXAMPLE aa83
-2s
Figure imgf000319_0001
[Step 83- I s]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa83a (616 mg, 1.37 mmol) was used instead of compound aa39b to obtain compound aa83-l (592 mg, 1.07 mmol). [Step 83-2sJ
According to Step 39-2s in the synthetic method for EXAMPLE aa39, compound aa83-l (592 mg, 1.07 mmol) was used instead of compound aa39-l to obtain compound aa83-2 (608 mg, 1.02 mmol). [Step According to Step 39-3 s in the synthetic method for EXAMPLE aa39, compound aa83-2 (608 mg, 1.02 mmol) was used instead of compound aa39-2 to obtain compound aa83-3 ( 1.02 mmol) which was used in the next step without further purification.
[Step 83-4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa83-3 ( 1.02 mmol) was used instead of compound aa54-3 to obtain compound aa83-4 (612 mg, 0.71 mmol).
[Step 83-5sJ
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa83-4 (612 mg, 0.71 mmol) was used instead of compound aa39-4 to obtain compound aa83-5 (0.71 mmol) which was used in the next step without further purification.
[Step 83-6s]
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa83-5 (0.71 mmol) was used instead of compound aa54-5 to obtain compound aa83-6 (0.71 mmol) which was used in the next step without further purification.
[Step 83-7s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa83-6 (0.71 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa83 (124 mg, 0.23 mmol) as a white amorphous solid.
(EXAMPLE aa84)
Preparation of ethyl
l-(3-((R)-2-((R)- l-hydroxy-2-(l-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)benzoyl)piperidine-4-carboxylate EXAMPLE aa84
EXAMPLE aa84
Figure imgf000321_0001
[Step 84- Is]
According to Step 77- 1 s in the synthetic method for EXAMPLE aa77, compound aa83 (90 mg, 0.17 mmol) was used instead of compound aa70 to obtain EXAMPLE aa84 (92 mg, 0.16 mmol) as a white amorphous solid.
(EXAMPLE aa85)
Preparation of
2-(3-((R)-2-((R)- 1 -acetoxy-2-( 1 -imino-3-oxoisoindolin-5-ylamino)-2-oxoethyl)-3-oxo morpholino)-N-methylbenzamido)acetic acid EXAMPLE aa85
Figure imgf000321_0002
aa85-2
[Step 85- IsJ
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa50-3 (250 mg, 0.50 mmol) was used instead of compound aa39-3 and compound aa85a (105 mg, 0.60 mmol) was used instead of compound aa39c to obtain compound aa85-l (254 mg, 0.39 mmol).
[Step 85-2s]
To a solution of aa85-l (254 mg, 0.39 mmol) in methanol (8 mL) was added palladium-charcoal (10%, 26 mg). The reaction mixture was stirred at room temp 6 i ure was filter ound aa85-2 (0.39 mmol) which was used in the next step without further purification.
[Step 85-3s]
To compound aa85-2 (0.39 mmol) was added a 7 N solution of ammonia in methanol (2 mL). The reaction mixture was stirred at room temperature for 5 days. The organic solvent was evaporated under reduced pressure. The crude product was purified by high pH RP-HPLC to afford the desired EXAMPLE aa85 (4 mg, 0.0073 mmol) as a white amorphous solid. (EXAMPLE aa86)
Preparation of (R)-N-( 1 ,3-diiminoisoindolin-5-yl)-2-((R)-4-(3-(2-(dimethylamino)- 2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide EXAMPLE a86
s
Figure imgf000322_0001
[Step 86- Is]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa82-3 (175 mg, 0.46 mmol) was used instead of compound aa39-3 and compound aa86a (100 mg, 0.70 mmol) was used instead of compound aa39c to obtain compound aa86-l (81 mg, 0.16 mmol). [Step 86-2sl
To compound aa86-l (81 mg, 0.16 mmol) was added a 7 N solution of ammonia in methanol (10 mL). The reaction mixture was stirred at room temperature for 4 days. The organic solvent was evaporated under reduced pressure. The crude product was purified by high pH RP-HPLC to afford the desired EXAMPLE aa86 (45 mg, 0 (EXAMPLE aa87)
Preparation of (R)-2-(l -imino-S-oxoisoindolin-S-ylamino)- l-((R)-4-(3-
(methyl(2-oxo-2-(pyrrolidin-1-yl)ethyl)carbamoyl)phenyl)-3-oxomorpholin-2-yl)-2-ox oethyl acetate EXAMPLE aa87
Figure imgf000323_0001
7
[Step 87- I s]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa59-3 (179 mg, 0.44 mmol) was used instead of compound aa39-3 and compound aa87a ( 117 mg, 0.66 mmol) was used instead of compound aa39c to obtain compound aa87-l (163 mg, 0.29 mmol).
LStep 87-2s]
To compound aa87-l (163 mg, 0.29 mmol) was added a 7 N solution of ammonia in methanol (20 niL). The reaction mixture was stirred at room temperature for 3 days. The organic solvent was evaporated under reduced pressure to afford the desired EXAMPLE aa87 (144 mg, 0.29 mmol) as a white amorphous solid.
(EXAMPLE aa88)
Preparation of 2-(3-((R)-2-((R)-2-(4-carbarnimidoylphenylamino)- 1 -hydroxy-
2-oxoethyl)-3-oxomorpholino)-5-fIuoro-N-methylbenzamido)acetic acid EXAMPLE aa88
Figure imgf000324_0001
[Step 88- LsJ
According to Step 39- 1 s in the synthetic method for EXAMPLE aa39, compound aa88a (760 mg, 1.78 mmol) was used instead of compound aa39b to obtain compound aa88-l (618 mg, 1.17 mmol).
[Step 88-2s]
39, com -l to obtain compound aa88-2 (550 mg, 0.99 mmol).
[Step 88-3s]
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa88-2 (550 mg, 0.99 mmol) was used instead of compound aa39-2 to obtain compound aa88-3 (0.99 mmol) which was used in the next step without further purification.
[Step 88-4s]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa88-3 (0.99 mmol) was used instead of compound aa39-3 to obtain compound aa88-4 (649 mg, 0.96 mmol).
[Step 88-5sl
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa88-4 (649 mg, 0.96 mmol) was used instead of compound aa39-4 to obtain compound aa88-5 (0.96 mmol) which was used in the next step without further purification. [Step 88-6s]
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa88-5 (0.96 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa88 (156 mg, 0.31 mmol) as a white amorphous solid.
(EXAMPLE aa89)
Preparation of ethyl 2-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-
2-oxoethyl)-3-oxornorpholino)-5-fluoro-N-methylbenzamido)acetate EXAMPLE aa89
Figure imgf000326_0001
[Step 89- Is]
According to Step 77- 1 s in the synthetic method for EXAMPLE aa77, compound aa88 (150 mg, 0.30 mmol) was used instead of compound aa70 to obtain EXAMPLE aa89 (136 mg, 0.28 mmol) as a white amorphous solid.
(EXAMPLE aa90)
Preparation of 3-((R)-2-((R)-2-(4-carbamimidoylphenylarnmo)- l-hydroxy-2-oxoethyl)-
3-oxomorpholino)-N-(2-(dimethylamino)-2-oxoethyl)-5-fluoro-N-raethylbenzamide
EXAMPLE aa90 Is
Figure imgf000327_0002
2s
Figure imgf000327_0003
aa90-3
Figure imgf000327_0001
Figure imgf000327_0004
EXAMPLE aa90
[Step 90- I s]
According to Step 39- I s in the synthetic method for EXAMPLE aa39, compound aa90a (293 mg, 0.80 mmol) was used instead of compound aa39b to obtain compound aa90-l (347 mg, 0.74 mmol).
[Step 90-2s]
39, comp -l to obtain compound aa90-2 (282 mg, 0.55 mmol).
[Step 9O-3s)
According to Step 39-3s in the synthetic method for EXAMPLE aa39, compound aa90-2 (282 mg, 0.55 mmol) was used instead of compound aa39-2 to obtain compound aa90-3 (0.55 mmol) which was used in the next step without further purification.
[Step 90-4s]
According to Step 39-4s in the synthetic method for EXAMPLE aa39, compound aa90-3 (0.55 mmol) was used instead of compound aa39-3 to obtain compound aa90-4 (219 mg, 0.36 mmol).
[Step 90-5s]
According to Step 39-5 s in the synthetic method for EXAMPLE aa39, compound aa90-4 (219 mg, 0.36 mmol) was used instead of compound aa39-4 to obtain compound aa90-5 (0.36 mmol) which was used in the next step without further purification. [Step 90-6sl
According to Step 39-6s in the synthetic method for EXAMPLE aa39, compound aa90-5 (0.36 mmol) was used instead of compound aa39-5 to obtain EXAMPLE aa90 (156 mg, 0.30 mmol) as a white amorphous solid.
(EXAMPLE aa91)
Preparation of (R)-N-( 1 ,3-diiminoisoindolin-5-yl)-2-hydroxy-2-((R)-4-(3-(2-(4-methyl-
3-oxopiperazin- 1 -yl)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide EXAMPLE aa91
Figure imgf000329_0001
EXAMPLE 91
[Step 91 -Is)
According to Step 86- Is in the synthetic method for EXAMPLE aa86, compound aa79-3 (176 mg, 0.35 mmol) was used instead of compound aa82-3 to obtain compound aa91-l (50 mg, 0.079 mmol).
[Step 91 -2s]
According to Step 86-2s in the synthetic method for EXAMPLE aa86, compound aa91-l (50 mg, 0.079 mmol) was used instead of compound aa86-l to obtain EXAMPLE aa91 (29 mg, 0.048 mmol).
(EXAMPLE aa92)
Preparation of N-(2-(dimethylamino)-2-oxoethyl)-3-((R)-2-((R)- 1 -hydroxy-2-( 1 - iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorpholino)-N-methylbenzamide
EXAMPLE aa92
aa39a
Step 92-4
Figure imgf000330_0001
[Step 92- Is]
According to Step 39- Is in the synthetic method for EXAMPLE aa39, compound aa92a (330 mg, 0.95 mmol) was used instead of compound aa39b to obtain compound aa92-l (223 mg, 0.45 mmol).
[Step 92-2sl
39, comp l to obtain compound aa92-2 (234 mg, 0.48 mmol).
[Step 92-3sl
According to Step 39-3 s in the synthetic method for EXAMPLE aa39, compound aa92-2 (210 mg, 0.48 mmol) was used instead of compound aa39-2 to obtain compound aa92-3 (0.48 mmol) which was used in the next step without further purification.
[Step 92-4s]
According to Step 54-4s in the synthetic method for EXAMPLE aa54, compound aa92-3 (0.48 mmol) was used instead of compound aa54-3 to obtain compound aa92-4 (292 mg, 0.38 mmol).
[Step 92-5sl
According to Step 39-5s in the synthetic method for EXAMPLE aa39, compound aa92-4 (292 mg, 0.38 mmol) was used instead of compound aa39-4 to obtain compound aa92-5 (0.38 mmol) which was used in the next step without further purification. [Step 92-6sl
According to Step 54-6s in the synthetic method for EXAMPLE aa54, compound aa92-5 (0.38 mmol) was used instead of compound aa54-5 to obtain EXAMPLE aa92 (160 mg, 0.0.31 mmol) as a white amorphous solid.
(EXAMPLE aa93)
Preparation of 2-((S)-hydroxy((R)-3-oxo-4-p-tolylmorpholin-2-yl)methyl)-4-oxo- 1 ^-dihydroquinazoline-β-carboximidamide EXAMPLE aa93
Figure imgf000332_0001
lStep 93-ls]
To a solution of imidazole (258 mg, 3.79 mmol) in anhydrous DCM (4 mL) cooled at -10 °C was added thionyl chloride (113 mg, 0.95 mmol). The reaction mixture was stirred at room temperature for 10 minutes and was added to a solution of compound 93b (304 mg, 1.89 mmol) in anhydrous DCM (3 mL) cooled at -40 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered. The filtrate was added to a solution of compound aa93a (100 mg, 0.38 mmol) and 1,2,4-triazole (39 mg, 0.57 mmol) in anhydrous DCM (3 mL) cooled at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. Ethyl acetate (100 mL) was added and the organic layer was washed with 2 N hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to afford the desired aa93-l (15 mg, 0.037 mmol). [Step 93-2s]
ed a 1 N sodiu oom temperature for 2 hours. Ethyl acetate (50 mL) was added and the organic layer was washed with 1 N hydrochloric acid, water and brine. The organic solvent was evaporated under reduced pressure to afford the desired aa93-2 (0.012 mmol). The crude product was used in the next step without further purification.
[Step 93-3s]
Acetyl chloride (3 mL) was added to absolute ethanol ( 1 mL) cooled at 0 °C to generate a hydrogen chloride solution. To the hydrogen chloride solution was added a solution of aa93-2 (0.012 mmol) in absolute ethanol (2 mL). The reaction mixture was stirred at room temperature for 2 days. The organic solvent was evaporated under reduced pressure. To the residue was added a 7 N solution of ammonia in methanol (5 mL). The reaction mixture was stirred at room temperature for 16 hours. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to afford the desired EXAMPLE aa93 (1 mg, 0.0023 mmol).
(EXAMPLE aa94)
Preparation of 1, l-dioxo-3-((S)-hydroxy((R)-3-oxo-4-p-tolylmorpholin-2-yl)methyl)- 4H-benzo[e][ L2,4Jthiadiazine-7-carboximidamide EXAMPLE aa94
Figure imgf000333_0001
EXAMPLE aa94
[Step
93, compound aa94a (606 mg, 3.08 mmol) was used instead of compound aa93b to obtain compound aa94-l (86 mg, 0.19 mmol).
[Step 94-2s] To compound aa94-l (86 mg, 0.19 mmol) was added saturated ammonium hydroxide solution (8 rnL). The reaction mixture was heated under reflux for 2 days. The solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to afford the desired compound aa94-2 (8.5 mg, 0.020 mmol).
[Step 94-3sl According to Step 93-3s in the synthetic method for EXAMPLE aa93, compound aa94-2 (8.5 mg, 0.020 mmol) was used instead of compound aa93-2 to obtain EXAMPLE aa94 (7.2 mg, 0.016 mmol).
EXAMPLES aa95 - aal 16
EXAMPLE aa95
Figure imgf000334_0001
Figure imgf000335_0001
Synthesis of tert-butyl 4-cyano-3-fluorophenylcarbamate (compound Ml-Ia) and (compound M 1 - 1 b)
4-amino-2-fluorobenzonitrile (1Og, 0.0735mol) was dissolved in THF (50ml), NaH (2.94g of a 60% dispersion, leq) was added. After 30 minutes the resulting mixture was added to a mixture of BOC2O (16g, leq) and DMAP (0.897g, 10%) in THF ( 100ml). This mixture was stirred for 2 hours and was diluted with EtOAc. The mixture was washed with NH4Cl(S31). dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc in hexane) to give, in order of elution, 7.7g (31 %) of M-I-Ib and 4.4g (25%) of Ml-Ia.
Synthesis of tert-butyl 3-aminobenzo[dJisoxazoI-6-ylcarbamate (compound M 1-2) Compound Ml-I a or Ml-Ib (0.0229mol) was dissolved in 10: 1 DMF/H20 (114ml). Acetohydroxamic acid (10.3g, 6eq) and K2CO3 (38g, 12eq) were added and the mixture heated at 55°C overnight. After cooling to room temperature the mixture was diluted with EtOAc, washed with NH4Cl(SaO and dried (MgSO4) The residue was purified by silica gel chromatography (0-70% EtOAc in hexane) to give 5g (87%) of Ml-2.
Synthesis of tert-butyl 3-(l ,3-dioxoisoindolin-2-yl)benzo[dlisoxazol-6-ylcarbamate (compound Ml -3)
C d 2 5 3 0 0213 l di l d i CH Cl 06 l) and coole y Et^N (7.18ml, 2.4eq), The mixture was stirred overnight. The mixture was diluted with EtOAc, washed with NH4Cl(S31) and dried (MgSO4). The residue was purified by silica gel chromatography (0-100% EtOAc in hexane) to give 5.6g of Ml-3. Synthesis of 2-(6-aminobenzo[d]isoxazol-3-yl)isoindoline-1,3-dione (compound M 1-4) Compound Ml-3 (1.37g, 0.00363mol) was dissolved in 1,4-dioxane (18ml), 4N HCl in 1 ,4-dioxane ( 18ml) was added and the mixture stirred overnight. The mixture was concentrated and the residue suspended in EtOAc. NaHCθ3(sat) was added and stirred until a clear organic layer persisted. The organic layer was dried (MgSO4), and concentrated to give 1 g of Ml -4 (98%).
Synthesis of (2-fluoro-5-iodophenyl)(morpholino)methanone (compound M 1-5)
2-Fluoro-5-iodobenzoic acid (2g, 0.0088mol) was dissolved in MeCN (44ml) and the mixture cooled to 0°C. Morpholine (0.929ml, 1.2eq) followed by EDCI.C1 (2.03 g, 1.2eq) and DMAP ( 108mg, 0. leq) were added and the mixture stirred overnight. The mixture was diluted with EtOAc, washed with NHtC^sat), dried (MgSO4), and concentrated. The resulting residue was then purified by silica gel chromatography (0-30% EtOAc in hexane) gave 2g of Ml -5. LCMS MH+ = 336. Synthesis of (R)-tert-butyl
2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxy acetate (compound Ml -6).
Compound Ml -5a (1.37g, 0.0059mol) and compound Ml-I (1.99g, leq) were dissolved in 1,4-dioxane (60ml), to this mixture were added CuI (339 mg, 0.2eq), CS2CO3 (3.87g, 2eq), and frαns-N,N-dimethylcyclohexane-1,2-diamine (0.281ml,
0.3eq). The resulting solution was degassed and heated at 90°C for 6.5 hours. The mixture was cooled to rt, NH4Cl(SaI) was added and the mixture extracted with EtOAc.
The extracts were washed with NH4Cl(sat), dried (MgSO4), and concentrated. The resulting residue was then purified by silica gel chromatography (0-100% EtOAc in hexane) gave 1.6g of M 1-6.
Synthesis of (R)-tert-butyl
2-acetoxy-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl) acetate (compound M 1 -7)
M 1-6 (1.6g, 0.00365mol) was dissolved in CH2Cl2 (18.25ml) and cooled to 0°C,
Ac2O added.
The 4 solution, water, dried, and concentrated to give 1.75g of M 1-7.
Synthesis of
(R)-2-acetoxy-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2 -yl)acetic acid (compound M 1-8)
M 1-7 ( 1.75g, 0.00364mol) was dissolved in 1: 1 CH2C12/TFA (40ml) and stirred for 30 minutes. The mixture was concentrated to give 1.6g of M 1-8.
Synthesis of
(R)-2-(3-(l ,3-dioxoisoindolin-2-yl)benzo[dJisoxazol-6-ylamino)-1-((R)-4-(4-fluoro-3-( morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate (compound
M 1 -9)
Compound M 1-8 (Ig, 0.00235mol) and compound M 1-4 (724mg, 1.1 eq) were dissolved in MeCN (4.71 ml, 0.5M) and the mixture cooled to 0°C. EDCI.C1 (0.542g, 1. leq) and DMAP (29mg, 10%) were added and the mixture stirred overnight. The mixture was diluted with EtOAc, washed with NH4Cl(SaO. dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in
CH2Cl2) to give Ig (63%) of M 1-9. Synthesis of
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)p henyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (example aa95)
Compound Ml-9 (I g, 0.00146mol) was dissolved in a 1 : 1 mixture of
CH2Cl2ZMeOH (58ml), NH2NH2 (0.458ml, 10eq) was added and the mixture stirred for 2 hours. The mixture was concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give 0.5g (67%) of Example aa95.
EXAMPLE aa96
Figure imgf000338_0001
Synthesis of 2-chloro-5-iodobenzaldehyde (compound M2- 1)
M2- 1 was synthesized using the procedure described in WO 2008/077009, page 39, example 27, steps (a) to (b).
Synthesis of 4-(2-chloro-5-iodobenzyl)morpholine (compound M2-2)
M2-1 (0.875g, O.0033mol) was dissolved in DCE (8.2ml), morpholine (0.373ml, 1.3eq) and AcOH (0.94ml, 5eq) were added and the mixture stirred for 30 minutes. Na(OAc)3BH ( 1.392g, 2eq) was added and the mixture stirred overnight. The mixture was diluted with EtOAc and washed with NaHCO3(Sat). dried (MgSO4), and concentrated. The residue was dissolved in ether and acidified with 1 M HCl in ether. The resulting precipitate was collected, suspended in EtOAc, and neutralized with NaHCθ3(Sat), The organic layer was dried (MgSO4) and concentrated to give 305mg of M2-2.
Synthesis of (R)-tert-butyl
2-((R)-4-(4-chloro-3-(morpholinomethyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacet ate (compound M2-3).
Compound M2-2a (0.23g, O.OOlmol) and compound M2-2 (O.3O5g, leq) were dissolved in DMSO (10ml), to this mixture were added CuI (57 mg, 0.2eq), K3PO4 (422mg, 2eq), and Zrα«s-N,N-dimethylcyclohexane-l ,2-diamine (0.047ml, 0.3eq). The °C mixture was c. The extracts were washed with NILjCKsat), dried (MgSO4), and concentrated. The resulting residue was then purified by silica gel chromatography (0-100% EtOAc in hexane) gave 266mg of M2-3. Synthesis of (R)-tert-butyl
2-acetoxy-2-((R)-4-(4-chloro-3-(morpholinomethyl)phenyl)-3-oxomorpholin-2-yl)aceta te (compound M2-4).
Compound M2-4 was synthesized using a procedure similar to the synthesis of compound M 1-7.
Synthesis of
(R)-2-acetoxy-2-((R)-4-(4-chloro-3-(morpholinomethyl)phenyl)-3-oxomorpholin-2-yl) acetic acid (compound M2-5).
M2-4 (230mg, 0.000476) was treated with 4M HCl in dioxane for 16 hours. The mixture was then concentrated to give M2-5 as a hydrochloride salt.
Synthesis of
(R)-1-((R)-4-(4-chloro-3-(morpholinomethyl)phenyl)-3-oxomorpholin-2-yl)-2-(3-(1,3- dioxoisoindolin-2-yl)benzo[d|isoxazol-6-ylamino)-2-oxoethyl acetate (compound M2-6)
M2-5.C1 ( lOOmg, 0.000216) and M 1-4 (66mg, 1.1 eq) were dissolved in MeCN and cooled to 0°C. DMAP (3 mg, 0. leq), pyridine (0.017ml, leq), and EDCI.C1 (50 mg, 1.2eq) were added and the mixture stirred for 2 hours. The mixture was diluted with EtOAc, washed with NH4Cl(SaD. dried (MgSO4). and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give 40mg of M2-6.
Synthesis of
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-(morpholinomethyl)pheny l)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aa96)
Example aa96 was synthesized using a procedure similar to the synthesis of compound aa95. Additionally an ether solution of aa96 was converted to the hydrochloride salt by treatment with IM HCl in ether and isolated by filtration. EXAMPLE aa97
Figure imgf000340_0001
(R)-N-(3-aminobenzofd]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-((4,4-difluoropiperidin-1-y l)methyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aa97) was synthesized in a similar manner to example aa96 using previously described procedures.
EXAMPLE aa98
Figure imgf000340_0002
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorpholin o)phenyl)morpholin-2-yl)acetamide (Example aa98) was synthesized in a similar manner to example aa95 using previously described procedures.
EXAMPLE aa99
Figure imgf000340_0003
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(2-(difluoromethoxy)phenyl)-3-oxomo rpholin-2-yl)-2-hydroxyacetamide (Example aa99) was synthesized in a similar manner to example aa95 using previously described procedures.
EXA
Figure imgf000341_0001
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-4-(2-isopropoxyphenyl)-3-ox omorpholin-2-yl)acetamide (Example aalOO) was synthesized in a similar manner to example aa95 using previously described procedures.
EXAMPLE aa 101
Figure imgf000341_0002
(R)-N-(3-aminobenzofdlisoxazol-6-yl)-2-((R)-4-(3-cyanophenyl)-3-oxomorpholin-2-yl )-2-hydroxyacetamide (Example aalOl) was synthesized in a similar manner to example aa95 using previously described procedures.
EXAMPLE
Figure imgf000341_0003
(R)-N-(3-aminobenzord]isoxazol-6-yl)-2-hydroxy-2-((R)-4-(3-(morpholine-4-carbonyl) phenyl)-3-oxomorpholin-2-yl)acetamide (Example aalO2) was synthesized in a similar manner to example aa95 using previously described procedures.
EXAMPLE aalO3
Figure imgf000342_0001
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-(morpholine-4-carbonyl)p henyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aal03) was synthesized in a similar manner to example aa95 using previously described procedures.
EXAMPLE aalO4
Figure imgf000342_0002
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-4-(4-methyl-3-(morpholine-4 -carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide (Example aalO4) was synthesized in a similar manner to example aa95 using previously described procedures. EXAMPLE aa 105
Figure imgf000342_0003
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-3-oxo-4-(3-(trifluoromethoxy )phenyl)morpholin-2-yl)acetamide (Example aalO5) was synthesized in a similar manner to example aa95 using previously described procedures.
EXAMPLE aa 106
Figure imgf000343_0001
(R)-N-(3-aminobenzo[dJisoxazol-6-yl)-2-hydroxy-2-((R)-3-oxo-4-(3-(trifluoromethyl)p henyl)morpholin-2-yl)acetamide (Example aalO6) was synthesized in a similar manner 5 to example aa95 using previously described procedures.
EXAMPLE aa 107
Figure imgf000343_0002
10
(R)-N-(3-aminobenzo[dJisoxazol-6-yl)-2-((R)-4-(4-chloro-3-(l ,2,3,4-tetrahydroisoquin oline-2-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aalO7) was synthesized in a similar manner to example aa95 using previously described procedures.
lδ
EXAMPLE aa 108
Figure imgf000343_0003
0 (R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-(4,4-difluoropiperidine-1- carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide (Example aalO8) was synthesized in a similar manner to example a95 using previously described procedures.
EXAMPLE aa 109
5
Figure imgf000344_0001
(R)-N-(3-aminobenzo[dlisoxazol-6-yl)-2-((R)-4-(3-fluoro-4-(trifluoromethyl)phenyl)-3 -oxomorpholin-2-yl)-2-hydroxyacetamide (Example aalO9) was synthesized in a similar manner to example a95 using previously described procedures.
EXAMPLE aal lO
Figure imgf000344_0002
Figure imgf000344_0003
Synthesis of 4-amino-2-fluoro-N'-hydroxybenzimidamide (compound M 16-1)
4-cyano-3-fluoroaniline (1Og, 0.073mol) dissolved in EtOH (36ml). Water (7.3m of the mixt ded slowly, and the mixture heated at 60°C overnight. The mixture was cooled to rt, the solid was collected by filtration, washed with, water (7ml), EtOH (7ml), ether (20ml), and dried to give 7.5g of M 16-1. Synthesis of 3-(4-aminophenyl)- 1,2,4-oxadiazol-5(4H)-one (compound M16-2)
M 16-1 (7.5g, 0.044mol) was suspended in EtOH (26ml), diethyl carbonate (5.34ml, 1 eq) was added and the mixture warmed to 65°C. NaOEt ( 16.5g of a 21 % wt solution in EtOH, 1.15eq) added slowly and the temperature of the mixture raised to 70°C for 2 hours. The mixture was cooled to rt, concentrated and dissolved in water (25 ml) at 70°C, HCl(c) added to bring the PH to 2, the mixture was cooled to 0°C. The solid was collected by filtration and washed with water (20ml), EtOH (7 ml), and ether (20 ml) to give 6.4g of M16-2.
Synthesis of l-(3-iodophenyl)-2-phenylethanone (compound M16-3)
m-Iodobenzoic acid ( 1 g, 0.004mol) was dissolved in MeCN (20ml), Cs2CO3
(2.63g, 2eq) and benzyl bromide (0.528ml, 1. leq) added. The mixture was heated at reflux overnight. The mixture was concentrated, taken up in EtOAc, washed with water, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc in hexane) to give 1.6g of M 16-3.
Synthesis of benzyl
3-((R)-2-((R)- 1 -acetoxy-2-(3-fluoro-4-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)pheny 1 amino)-2-oxoethyl)-3-oxomorpholino)benzoate (compound M 16-7)
Compound M 16-3 was converted to compound M 16-7 using previously described procedures.
Synthesis of
3-((R)-2-((R)-2-(4-carbamimidoyl-3-fluorophenylamino)-1-hydroxy-2-oxoethyl)-3-oxo morpholino)benzoic acid (Example aal 10)
Compound M 16-7 (200mg, 0.00033mol) was dissolved in MeOH (5.5ml), 7N
NH3 (0.284ml, 6eq) was added, and the mixture stirred for 1 hour. The mixture was concentrated, taken up in MeOH (5ml). IM HCl (0.662ml, 2eq) was added followed by 10% Pd(C) ( 1 OOmg). The mixture was put under H2 ( 1 atm) for 1 hour. The solids were removed by filtration, the mixture was concentrated. The residue was triturated with ether/MeOH, and solid collected to give 143 mg of Example aal 10.
EXA
Figure imgf000346_0001
Figure imgf000346_0002
(R)-N-(4-carbamimidoyl-3,5-difluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomor phoIino)phenyl)morphoIin-2-y])acetamide (Example aal 1 1) was synthesized in a similar manner to previously described examples.
EXAMPLE aal 12
Figure imgf000347_0001
Figure imgf000347_0002
(R)-N-(4-carbamimidoyl-2,3-difluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomor pholino)phenyl)morpholin-2-yl)acetamide (Example aal 12) was synthesized in a similar manner to previously described examples.
EXAMPLE aal 13
Figure imgf000348_0001
Figure imgf000348_0002
(R)-N-(4-carbamimidoyl-2,5-difluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomor pholino)phenyl)morpholin-2-yl)acetamide (Example aal 13) was synthesized in a similar manner to previously described examples.
EXAMPLE aal 14
Figure imgf000349_0001
(R)-N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorphol ino)phenyl)morpholin-2-yl)acetamide (Example aal 14) as synthesized in a similar manner to previously described examples.
EXAMPLES aa 1 15 and aa 1 16
Figure imgf000350_0001
Synthesis of 4-bromo-3-methyl-5-(trifluoromethyl)aniline (Compound M21-1)
3-methyl-5-(trifluoromethyl)aniline (4.84g, 0.01 lmol) was dissolved in CH2CI2 and cooled to O°C. NBS (4.92g, leq) was added and the mixture stirred over 0-20% EtOA Synthesis of 4-amino-2-methyl-6-(trifluoromethyl)benzonitrile (Compound M21-2)
M21- 1 (2.3g, 0.009053mol) was dissolved in NMP (45ml). Pd(Ph3P)4 (0.937mg, 0. leq), Zn(CN)2 (1.27g, 1.2eq), and Zn powder (0.592g, leq) were added. 5 The mixture was degassed and heated at 1 10°C overnight. After cooling to rt the mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution. The extracts were dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc in hexane) to give l.5g of M21-2
10 Synthesis of 4-( 1 ,3-dioxoisoindolin-2-yl)-2-methyl-6-(trifluoromethyl)benzonitrile (Compound M21-3)
M21-2 (1.5g, 0.00614mol), was dissolved in AcOH (30ml), phthalic anhydride (Ig, 1.leq) was added and the mixture heated at 130°C for 2 hours. The mixture was cooled to rt and concentrated. The residue was purified by silica gel chromatography lδ (0-30% EtOAc in hexane) to give 2.Og of M21-3.
Synthesis of
2-(bromomethyl)-4-(1,3-dioxoisoindolin-2-yl)-6-(trifluoromethyl)benzonitrile
(Compound M21 -4)
20 M21 -3 (2.6g, 0.0078mol) was dissolved in CCl4 (39ml), AIBN (0.259g,
0.2eq) and NBS ( 1.822g, 1.3 eq) was added and the mixture heated at reflux while being irradiated with a 250W lamp for 2 days. The mixture was concentrated and the residue was purified by silica gel chromatography (0-30% EtOAc in hexane) to give
2.15g of M21-4.
5
Synthesis of Compound M21 -5
M21-4 (2.15g, 0.00525mol) was dissolved in DMF (52ml), K2CO3 (1.45g,
2eq) and (Boc)2NH (2.28g, 2eq) was added and the mixture stirred overnight. The mixture was diluted with EtOAc and washed with NH4CIfSaD- The organic layers were 0 dried (MgSO4) concentrated and the residue was purified by silica gel chromatography
(0-30% EtOAc in hexane) to give 1.4g of M21-5.
Synthesis of Compound M21-6
M21-5 (1.4g, 0.00257) was dissolved in 1 : 1 MeOH/CH2Cl2 (25ml) and cooled 5 to 0°C. Hydrazine ( 1.6ml, 20eq) was added, after 15 minutes the mixture was allowed to wa d h i d f i l pension was filtered and the filtrate purified by silica gel chromatography (0-40% EtOAc in hexane) to give 0.583g of M21-6.
Synthesis of Compound M20-7
M21 -6 (0.538g, 0.0013mol) and M21 -x (disclosed previously in this filing)
(0.66 Ig, 1.3eq) were dissolved in MeCN (2.6ml) and cooled to 0°C.
EDCI .HCl(0.372g, 1.5eq) and DMAP (16mg, O. leq) were added and the mixture stirred overnight. The mixture was diluted with EtOAc, washed with NH4Cl(Sat), the extracts were dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexane) to give 167mg of M21-7.
Synthesis of Compound M21-8
M21 -7 (167mg, 0.0002 lmol) was treated with 7N NH3 in MeOH for lhour. The mixture was concentrated and the residue was purified by silica gel
chromatography (0-5% MeOH in CH2Cl2) to give 60mg of M21 -8.
EXAMPLE aal 15
Compound M21-8 (60 mg) was treated with 4M HCl in dioxane for 1 hour. The mixture was concentrated to give 60mg of
(R)-N-(3-(aminomethyl)-4-cyano-5-(trifluoromethyl)phenyl)-2-hydroxy-2-((R)-3-oxo- 4-(3-(3-oxomorpholino)phenyl)morpholin-2-yl)acetamide (Example aal 15).
EXAMPLE aal 16
Example aal 15 (5mg) was dissolved in EtOH and heated at 90°C for 2 hours. After cooling to rt the mixture was concentrated to give 4 mg of
(R)-2-hydroxy-N-(l -imino-7-(trifluoromethyl)isoindolin-5-yl)-2-((R)-3-oxo-4-(3-(3-ox omorpholino)phenyl)morpholin-2-yl)acetamide (example aal 16).
Figure imgf000353_0001
* except when noted.
Solvent A: Column: Agilent SBC (3.0x50 mm, 1.8u); Flow: 1.0 ml/min; solvent A: H2O-0.1 % TFA: Solvent B: ACN-0.1% TFA; Gradient Table : 0.1 min: 5%B, 2.3 min: 99%B, 2.90 min: 99%B, 3.0 min: 5%B stop time 3.50 min.
Solvent B: Column: Agilent SBC (3.0x50 mm, 1.8u); Flow: 1.0 ml/min; solvent A: H2O-0.1% TFA: Solvent B: ACN-0.1 % TFA; Gradient Table : 0 min: 10%B, 1.5 min: 95%B, 2.76 min: 10%B, stop time 3.60 min, Post Time 0.70 min.
Figure imgf000354_0001
Figure imgf000355_0001
Figure imgf000356_0001
EXAMPLES aal 17 -aal 35 (EX (R)-2-Hydroxy-N-(l -iminoisoindolin-5-yl)-2-((R)-3-oxo-4-(3-(trifluoromethoxy)phenyl )morpholin-2-yl)acetamide EXAMPLE aal l 7
Figure imgf000357_0001
Figure imgf000357_0002
Figure imgf000357_0003
Figure imgf000357_0004
[Step MD 1-1 ]
(R)-tert-Butyl
2-hydroxy-2-((i?)-3-oxo-4-(3-(trifluoromethoxy)phenyl)morpholin-2-yl)acetate MD 1-1
To a round bottom flask charged with a stir bar was added morpholinone (0.15 g) AMRI 1 - 1 and 3-trifluoromethoxyiodobenzene (0.12 mL) in dioxane (4 mL) at rt was added Cs2CO3 (0.42 g), and CuI (37 mg) under N2.
trans-N,N'-Dimethylcyclohexane-1,2-diamine (31 L) was added dropwise and the mixture was affixed with a condenser. The mixture was degassed under vacuum (~ 20 mm), filled with N2, and heated to 90 °C. The mixture stirred for 3 h at 90 °C, cooled to rt, and was diluted with cone NH4OH and water, EtOAc. The mixture was extracted with EtOAc three times and the organic layers were combined. The organic layer was washed with brine, dried (Na2Sθ4), filtered, and concentrated under reduced pressure to afford a yellow oil. The crude product was purified by flash
chromatography using a 95% CH2Cl2/5% MeOH mixture to afford MD 1 - 1 (0.21 g) as a white solid. [Step MD 1 -2]
OR)-tert-butyl
2-acetoxy-2-((i?)-3-oxo-4-(3-(trifluoromethoxy)phenyl)morpholin-2-yl)acetate MD 1-2
To a solution of MD 1-1 (0.21 g) in CH2Cl2 (2.5 ml) at 0°C was added pyridine (63 μL), Ac2O (74 μl), and DMAP (5 mg). The mixture was stirred for 1 hour at 0°C, warmed to rt, and stirred for an additional 12 h. The mixture was diluted with EtOAc and the organic layer was washed sequentially with sat. aq. CuSO4 solution, water, and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford MD 1-2 (0.22 g) as a light yellow semisolid. This material was used without further purification.
[Step MD 1-3]
(R)-2-acetoxy-2-((^)-3-oxo-4-(3-(trifluoromethoxy)phenyl)morpholin-2-yl)acetic acid MD 1-3
To a solution of MD 1 -2 (0.22 g) in CH2Cl2 (2 mL) at 0°C was added TEA (0.6 mL) dropwise. The mixture was stirred for 1h at 0°C and at rt for 30 min whereupon an additional portion of TFA (0.4 mL) was added. After an additional 1 h at rt, the mixture was diluted with CH2CI2 and concentrated to dryness under reduced pressure. The crude mixture was redissolved in a 10: 1 mixture of toluene/CH2Cl2 and concentrated and this protocol was repeated 5 times with to afford MD 1-3 (0.18 g) as a light yellow solid. This material was used without further purification.
[Step MD 1-4]
(i?)-2-(3-((Bis(tert-butoxycarbonyl)amino)methyl)-4-cyanophenylamino)-2-oxo-1-((i?)- 3-oxo-4-(3-(trifluoromethoxy)phenyl)morpholin-2-yl)ethyl acetate MD 1-4
To a solution of MD 1-3 (0.41 g) in CH2Cl2 (5 mL) at 0 °C was added
3-bis(tert-butoxycarbonylaminomethyl)-4-cyanophenylamine XX (0.42 g) followed by EDCI (0.27 g) and DMAP (13 mg). The reaction mixture was warmed to rt and stirred for 12 h. The mixture was diluted with EtOAc (15 mL) and the organic layer was washed with IN HCl (2 x 3 mL) and brine (1 x 2 mL). The organic layer was dried (Na2SC^), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (ISCO, 20 g) using a gradient of 100% CH2Cl2 to 90: 10 CH2Cl2 /MeOH to afford MD 1 -4 (0.35 g) as a white solid.
[Step MD 1-5 J
(i?)-2-(3-((Bis(tert-butoxycarbonyl)amino)methyl)-4-cyanophenylamino)-2-oxo-1-((-R)-
3-oxo-4-(3-(trifluoromethoxy)phenyl)morpholin-2-yl)ethyl MD 1-5
To a solution of the MD 1-4 (0.35 g) in MeOH (0.5 mL) at rt was added 7M
NH^/MeOH (2.5 mL) dropwise. The mixture was stirred for 45 min at rt and the mixture was concentrated under reduced pressure and placed under high vacuum. The crude product was purified by flash chromatography (ISCO, 12 g) using a gradient of
100% CH2Cl2 to 90: 10 CH2Cl2 /MeOH to afford MD 1-5 (0.26 g) as a white solid.
[Step MD 1-6]
(R)-2-Hydroxy-N-(l-iminoisoindolin-5-yl)-2-((R)-3-oxo-4-(3-(trifluoromethoxy)phenyl )morpholin-2-y l)acetamide EXAMPLE aa 117
To a flask containing MD 1-5 (0.26 g) and a stir bar was added 4N HCl in dioxane (4 mL) at rt. The mixture was stirred for 1.5 h and was concentrated to ~ 2 mL. Toluene (8 mL) was added and the mixture was concentrated under reduced pressure. The crude material was treated with toluene (2 x 8 mL) and concentrated und and was heat reduced pressure, and placed under high vacuum. The crude residue was treated with MeOH followed by dilution with EtiO and the resultant solid was collected by filtration and dried under vacuum to afford Example aal 17 (106 mg) hydrochloride as a white solid. (EXAMPLE aal 18)
(i?)-2-Hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(2-methyl- 1 -oxoisoindolin-5-yl)-3- oxomorpholin-2-yl)acetamide EXAMPLE aa 118
Figure imgf000361_0001
[Step MD 2-1]
5-lodo-2-methylisoindolin-1-one MD 2-1
To a mixture of 2,3-dihydro-5-iodo-1H-isoindol-1-one ( 1.0 g) in DMF (20 mL) at 0 °C was added NaH (97 mg) in a single portion. The resulting mixture was stirred for 30 min at 0 °C whereupon MeI (0.25 mL) was added dropwise. The mixture was allowed to warm to rt and was stirred for 72 h. The mixture was quenched by addition of sat. aq. NH4CI (~ 3 mL) and was diluted with EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined and washed sequentially with water and brine. The organic layer was dried (NaISO4), filtered, and concentrated under reduced pressure. The crude material was purified The crude product was purified by flash chromatography (ISCO, 120 g) using a gradient of 100% hexanes to 80:20 hexanes/EtOAc to afford MD 2-1 (0.78 g) as a light yellow solid. [Step MD 2-2]
(R)-tert-Buty\
2-hydroxy-2-((i?)-4-(2-methyl-1-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)acetate MD 2-2
According to the Step MD 1- 1 in the synthetic method for EXAMPLE aal l7, compound MD 2- 1 (0.20 g) was used instead of MD 1 - 1 to obtain MD 2-2 (0.29 g) as an off-white solid.
[Step MD 2-3]
(Λ)-tert-butyl
2-acetoxy-2-((R)-4-(2 -methyl- 1 -oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)acetate MD 2-3
According to the Step MD 1-2 in the synthetic method for EXAMPLE aal 17, compound MD 2-2 (0.29 g) was used instead of MD 1-1 to obtain MD 2-3 (0.31 g) as an off-white solid which was used without further purification.
[Step MD 2-4J
(i?)-2-Acetoxy-2-((R)-4~(2-methyl-1-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)acetic acid MD 2-4
According to the Step MD 1-3 in the synthetic method for EXAMPLE aal 17, compound MD 2-3 (0.31 g) was used instead of MD 1 -2 to obtain MD 2-4 (0.27 g) as a whit [Step MD 2-5]
(^)-2-(3-((Bis(tert-butoxycarbonyl)amino)methyl)-4-cyanophenylamino)-l -((R)-4-(2-im ethyl- l-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate MD 2-5 According to the Step MD 1 -4 in the synthetic method for EXAMPLE aal l7, compound MD 2-4 (0.11 g) was used instead of MD 1-3 to obtain MD 2-5 (0.14 g) as an off-white solid after reverse phase HPLC purification using a C18 column and a gradient of 89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O: MeCN: HCO2H.
[Step MD 2-6J
(i?)-2-(3-((Bis(tert-butoxycarbonyl)amino)methyl)-4-cyanophenylamino)-
1 -((R)-4-(2-methyl- 1 -oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)-2-oxoethyl MD 2-6 According to the Step MD 1-5 in the synthetic method for EXAMPLE aal l7, compound MD 2-5 (0.14 g) was used instead of MD 1-4 to obtain MD 2-6 (0.13 mg) as a off-white solid which was used without further purification.
[Step MD 2-7]
(/f)-2-Hydroxy-N-( 1 -imiπoisomdolin-5-yl)-2-((i?)-4-(2-methyl- 1 -oxoisoindolin-5-yl)-3- oxomorpholin-2-yl)acetamide EXAMPLE aa 118
According to the Step MD 1-6 in the synthetic method for EXAMPLE aall7, compound MD 2-5 (0.13 g) was used instead of MD 1-5 to obtain EXAMPLE aal lδ
(25 mg) as a pale white solid as the hydrochloride salt after reverse phase HPLC purification using a C18 column and a gradient of 89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O: MeCN: HCO2H and treatment with HCl. (EXAMPLE aa 119)
(i?)-2-Hydroxy-N-(l-iminoisoindolin-5-yl)-2-((R)-4-(2-methyl-3-oxoisoindolin-5-yl)-3- oxomorpholin-2-yl)acetamide hydrochloride EXAMPLE aal 19
Figure imgf000364_0001
K3PO4, DMSO
Figure imgf000364_0002
MD 3-2 MD 3-3
Figure imgf000364_0003
[Step MD 3-1 ]
6-Iodo-2-methylisoindolin- 1 -one MD 3- 1
To a mixture of 2,3-dihydro-6-iodo-1H-isoindol-1-one (1.0 g) in DMF (20 mL) at 0 °C was added NaH (97 mg) in a single portion. The resulting mixture was stirred for 30 min at 0 °C whereupon MeI (0.25 mL) was added dropwise. The mixture was allowed to warm to rt and was stirred for 72 h. The mixture was quenched by addition of sat. aq. NH4CI (~ 3 mL) and was diluted with EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined and washed sequentially with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified The crude product was purified by flash chromatography (ISCO, 120 g) using a gradient of 100% hexanes to 80:20 hexanes/EtOAc to afford MD 3-1 (0.84 g) as a yellow solid.
[Step MD 3-21
(R)-tert-Butyl
2-hydroxy-2-((R)-4-(2-memyl-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)acetate MD 3-2
To a round bottom flask charged with a stir bar was added AMRI 1-1 (0.28 g) and MD 11-1 (0.40 g) in DMSO (8 mL) at rt was added K3PO4 (0.51 g), and CuI (23 mg) under N2. /rans-N,N'-Dimethylcyclohexane-1,2-diamine (37 μL) was added dropwise and the mixture was affixed with a condenser. The mixture was degassed under vacuum (~ 20 mm), filled with N2, and heated to 80 °C. The mixture stirred for 2.5 h at 80 °C, cooled to rt, and was diluted with EtOAc. The mixture was then sequentially washed with cone NH4OH, water, and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford a yellow oil. The crude product was purified by flash chromatography using a gradient of 100% CH2Cl2 to 60% CH2C12/4O% MeOH to afford MD3-2 (0.23 g) as a yellow solid. fSte
(Λ) 2-acetoxy-2-((R)-4-(2-methyl-3-oxoisoindolin-5-yl)-3-oxomorpholin~2-yl)acetate MD 3-3
According to the Step MD 1-2 in the synthetic method for EXAMPLE aal l7, compound MD 3-2 (80 mg) was used instead of MD 1-1 to obtain MD 3-3 (85 mg) as an off-white solid which was used without further purification.
(Step MD 3-4]
(R)-2-Acetoxy-2-((R)-4-(2-methyl-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)acetic acid MD 3-4
According to the Step MD 1-3 in the synthetic method for EXAMPLE aal l7, compound MD 3-3 (85 mg) was used instead of MD 1-2 to obtain MD 3-4 (65 mg) as a light yellow semisolid solid which was used without further purification.
[Step MD 3-5J
(R)-2-(3-((Bis(tert-butoxycarbonyl)amino)methyl)-4-cyanophenylamino)-1-((R)-4-(2-m ethyl-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate MD 3-5
According to the Step MD 1-4 in the synthetic method for EXAMPLE aal l7, compound MD 3-4 (0.25 g) was used instead of MD 1-3 to in the presence of aniline XX (0.29 g) obtain MD 3-5 (0.23 g) as a pale yellow solid after reverse phase HPLC purification using a Cl 8 column and a gradient of 89.95:9.95:0.1 H2O: MeCN: HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 3-6]
(^)-2-(3-((Bis(tert-butoxycarbonyl)amino)methyl)-4-cyanophenylamino)- l-((i?)-4-(2-m ethyl-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)-2-oxoethyl MD 3-6
According to the Step MD 1-5 in the synthetic method for EXAMPLE aal l7, compound MD 3-5 (0.23 g) was used instead of MD 1-4 to obtain MD 3-6 (0.16 g) as a white solid after reverse phase HPLC purification using a C18 column and a gradient of 89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
IStep MD 3-7]
(R)-N-(4-Carbamimidoyl-2-ethylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-3-oxoisoindoli n-5-y l)-3-oxomorpholin-2-yl)acetamide hydrochloride EXAMPLE aa 119
According to the Step MD 1-6 in the synthetic method for EXAMPLE aal 17, comp PLE aal 19 (0.1 1 (EXAMPLE aa 120)
Ethyl
2-(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorpho lino)phenoxy )acetate EXAMPLE aa 120
Figure imgf000368_0001
LStep MD 4-l ]
(R)-tert-Butyl
2-((i?)-4-(3-(2-ethoxy-2-oxoethoxy)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetate MD 4-1
According to the Step MD 1- 1 in the synthetic method for EXAMPLE aal 17, AMRI 1-1 (0.35 g) was treated with ethyl 2-(3-iodophenoxy)acetate (0.56 g) from Eur. J. Org. Chem. 2008, 337 to obtain MD 4-1 (0.54 g) as an yellow solid after flash chromatography with 40: 1 CHaCWMeOH as eluent.
LStep MD 4-21
(R)-tert-Buty\
2-acetoxy-2-((R)-4-(3-(2-ethoxy-2-oxoethoxy)phenyl)-3-oxomorpholin-2-yl)acetate MD 4-2
According to the Step MD 1-2 in the synthetic method for EXAMPLE aal 17, compound MD 4-1 (0.54 g) was used instead of MD 1- 1 to obtain MD 4-2 (0.56 g) as a yellow oil which was used without further purification.
[Step MD 4-3]
(R)-2-Acetoxy-2-((R)-4-(3-(2-ethoxy-2-oxoethoxy)phenyl)-3-oxomorpholin-2-yl)acetic acid MD 4-3
According to the Step MD 1-3 in the synthetic method for EXAMPLE aal 17, compound MD 9-2 (0.55 g) was used instead of MD 1-2 to obtain MD 4-3 (0.45 g) as a yellow solid which was used without further purification.
[Step MD 4-4]
Ethyl
2-(3-((i?)-2-((R)- l-acetoxy-2-(3-((bis(tert-butoxycarbonyl)amino)methyl)-4-cyanophen ylamino)-2-oxoethyl)-3-oxomorpholino)phenoxy)acetate MD 4-4
According to the Step MD 1 -4 in the synthetic method for EXAMPLE aal 17, compound MD 4-3 (0.38 g) was used instead of MD 1-3 to obtain MD 3-4 (0.26 g) after flash chromatography using a gradient of 100% hexanes to 100% EtOAc.
[Step MD 4-5]
Ethy
2-(3 thyl)-3-oxo morpholino)phenoxy)acetate MD 4-5
According to the Step MD 1-5 in the synthetic method for EXAMPLE aal 17 except using 2M NH3 in EtOH, compound MD 4-4 (0.26 g) was used instead of MD 1-4 to obtain MD 5-5 (0.21 g) as an off-white solid after reverse phase HPLC purification using a C18 column and a gradient of 89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 4-6]
Ethyl
2-(3-((Λ)-2-((i?)-1-hydroxy-2-(l -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorpho lino)phenoxy)acetate EXAMPLE aal 20
According to the Step MD 1-6 in the synthetic method for EXAMPLE aal 17 except substituting EtOH for MeOH as solvent, compound MD 4-5 (0.20 g) was used instead of MD 1-5 to obtain EXAMPLE aal 20 (81 mg) as the hydrochloride salt after reverse phase HPLC purification using a Cl 8 column and a gradient of 89.95:9.95:0.1
H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O: MeCN: HCO2H and subsequent treatment with HCl.
(EXAMPLE aal21)
(R)-2-Hydroxy-N~(l -iminoisoindolin-5-yl)-2-((R)-4-(4-methoxybenzyl)-3-oxomorpholi n-2-y Oacetamide EXAMPLE aa 121
Figure imgf000371_0001
Figure imgf000371_0002
Figure imgf000371_0003
EXAMPLEaa121
[Step MD 5- 1]
(R)-tert-Butyl 2-acetoxy-2-((i?)-4-(4-methoxybenzyl)-3-oxomorpholin-2-yl)acetate MD 5-1
According to the Step MD 1-2 in the synthetic method for EXAMPLE aal l 7, compound AMRI 2-1 (0.35 g) was used instead of MD 1-1 to obtain MD 5-1 (0.37 g) as a yellow oil which was used without further purification. [Ste
(i?) cid MD 5-2
According to the Step MD 1-3 in the synthetic method for EXAMPLE aal l7, compound MD 5- 1 (0.37 g) was used instead of MD 1-2 to obtain MD 5-2 (0.32 g) as a δ yellow solid which was used without further purification.
[Step MD 5-3]
(R)-2-(3-((bis(terϊ-Butoxycarbonyl)amino)methyl)-4-cyanophenylamino)-1-((R)-4-(4- methoxybenzyl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate MD 5-3
0 According to the Step MD 1-4 in the synthetic method for EXAMPLE aal l7, compound MD 5-2 (0.25 g) was used instead of MD 1-3 to obtain MD 5-3 (0.24 g) of a white solid after reverse phase HPLC purification using a C18 column and a gradient of 89.95:9.95:0.1 H2O: MeCN: HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H. 5 [Step MD 5-4]
(i?)-2-(3-((bis(fer?-Butoxycarbonyl)amino)methyl)-4-cyanophenylamino)- l-((i?)-4-(4- methoxybenzyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide MD 5-4
According to the Step MD 1-5 in the synthetic method for EXAMPLE aal l7, compound MD 5-3 (0.24 g) was used instead of MD 1 -4 to obtain MD 5-4 (0.23 g) as0 an off-white solid which was used without further purification.
[Step MD 5-51
(i?)-2-Hydroxy-N-(l-iminoisoindolin-5-yl)-2-((/0-4-(4-methoxybenzyl)-3-oxomorphoIi n-2-yl)acetamide EXAMPLE aa 121
5 According to the Step MD 1-6 in the synthetic method for EXAMPLE aal l7, compound MD 5-4 (0.23 g) was used instead of MD 1-5 to obtain EXAMPLE aal21 (0.15 g) as a pale yellow solid as the hydrochloride salt.
(EXAMPLE aa 122)
This Example number is intentionally left blank.
(EXAMPLE aa 123)
(R)- iminoisoin dolin
Figure imgf000373_0001
[Step MD 7-1 ]
(R)-tert-Butyl 2-((i?)-4-(3-(benzyloxy)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetate MD 7-1
According to the Step MD 1-1 in the synthetic method for EXAMPLE aal l 7, AMRI 1-1 (0.50 g) was treated with l-benzyloxy-3-iodobenzene (0.81 g) to obtain MD 7-1 (0.71 g) as a clear oil after flash chromatography with 50: 1 CH2Cl2/MeOH as eluent.
LStep MD 7-2]
(R)-tert-Euty[ 2-acetoxy-2-((R)-4-(3-(benzyloxy)phenyl)-3-oxomorpholin-2-yl)acetate MD 7-2
According to the Step MD 1 -2 in the synthetic method for EXAMPLE aal l7, compound MD 7-1 (0.71 g) was used instead of MD 1-1 to obtain MD 7-2 (0.78 g) as a yellow oil which was used without further purification. [Step MD 7-3]
(i?)-2-Acetoxy-2-((R)-4-(3-(benzyloxy)phenyl)-3-oxomorpholin-2-yl)acetic acid MD
7-3
According to the Step MD 1-3 in the synthetic method for EXAMPLE aal l7, compound MD 7-2 (0.78 g) was used instead of MD 1-2 to obtain MD 7-3 (0.68 g) as a yellow solid which was used without further purification.
[Step MD 7-4]
(^)-1-((R)-4-(3-(Benzyloxy)phenyl)-3-oxomorpholin-2-yl)-2-(3-((bis(ferr-butoxycarbo nyl)amino)methyl)-4-cyanophenylamino)-2-oxoethyl acetate MD 7-4
According to the Step MD 1-4 in the synthetic method for EXAMPLE aal 17, compound MD 7-3 (0.68 g) was used instead of MD 1-3 to obtain MD 7-4 (0.20 g) of an off-white solid after flash chromatography with a gradient of 100% hexanes to 50:50 hexanes/EtOAc. [Step MD 7-5]
i?)- l- oxycarbon yl)am According to the Step MD 1-5 in the synthetic method for EXAMPLE aal l7, compound MD 7-4 (0.20 g) was used instead of MD 1-4 to obtain MD 7-5 (0.16 g) as an off-white solid after reverse phase HPLC purification using a C18 column and a gradient of 89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 7-6]
(i?)-2-((R)-4-(3-(BenzyIoxy)phenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N-(l-iminoisoin dolin-5-yl)acetamide EXAMPLE aal23
According to the Step MD 1-6 in the synthetic method for EXAMPLE aal l7, compound MD 7-5 (0.16 g) was used instead of MD 1-5 to obtain EXAMPLE aal23 (86 mg) as the hydrochloride salt.
(EXAMPLE aa 124)
(Λ)-2-((i?)-4-(2-(Cyclopropylmethyl)-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)-2-hy droxy-N-( 1 -iminoisoindolin-5-yl)acetamide EXAMPLE aal24
Figure imgf000376_0001
Cs2CO3, dioxane
Figure imgf000376_0002
Figure imgf000376_0003
[Step MD 8- IJ
2-(Cyclopropylmethyl)-6-iodoisoindolin-l -one MD 8-1
According to the Step MD 3-1 in the synthetic method for EXAMPLE 3,
2,3-dihydro-6-iodo-1H-isoindol-1-one (0.50 g) was treated with cyclopropyl bromide
(0.20 mL) to afford MD 8-1 (0.22 g) of a yellow solid after purification by flash chromatography (ISCO, 120 g) using a gradient of 100% hexanes to 40:60 hexanes/EtOAc.
[Step MD 8-2J
(R)-tert-Butyl
2-((R)-4-(2-(cyclopropylmemyl)-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)-2-hydrox yacetate MD 8-2
According to the Step MD 1- 1 in the synthetic method for EXAMPLE aal l7,
AMRI 1-1 (0.14 g) was treated with MD 8-1 (0.22 g) to obtain MD 8-2 (0.22 g) as a white solid after flash chromatography with 50: 1 CH^C^/MeOH as eluent.
[Step MD 8-3]
(R)-tert-Butyl
2-acetoxy-2-((i?)-4-(2-(cyclopropylmethyl)-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl
)acetate MD 8-3
According to the Step MD 1-2 in the synthetic method for EXAMPLE aal l7, compound MD 8-2 (0.22 g) was used instead of MD 1 -1 to obtain MD 8-3 (0.24 g) as an off-white solid which was used without further purification.
[Step MD 8-4]
(R)-2-Acetoxy-2-((R)-4-(2-(cyclopropylmethyl)-3-oxoisoindolin-5-yl)-3-oxomorpholin
-2-yl)acetic acid MD 8-4
According to the Step MD 1-3 in the synthetic method for EXAMPLE aal l7, compound MD 8-3 (0.24 g) was used instead of MD 1-2 to obtain MD 8-4 (0.22 g) as a light yellow semisolid solid which was used without further purification.
[Ste
(R)- ((i?)-4-(2-( cyclopropylmethyl)-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate MD 8-5
According to the Step MD 1-4 in the synthetic method for EXAMPLE aal l7, compound MD 8-4 (0.22 g) was used instead of MD 1-3 to in the presence of aniline XX (0.22 g) obtain MD 8-5 (0.25 g) as a pale yellow solid after reverse phase HPLC purification using a Cl 8 column and a gradient of 89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 8-6]
(R)-2-(3-((bis(tert-Butoxycarbonyl)amino)methyl)-4-cyanophenylamino)-1-((i?)-4-(2-( cyclopropylmethyl)-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide
MD 8-6
According to the Step MD 1-5 in the synthetic method for EXAMPLE aal l7, compound MD 8-5 (0.25 g) was used instead of MD 1-4 to obtain MD 8-6 (0.18 g) as a white solid after reverse phase HPLC purification using a Cl 8 column and a gradient of
89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 8-7]
(i?)-2-((^)-4-(2-(Cyclopropylmethyl)-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)-2-hy droxy-N-(l -iminoisoindolin-5-yl)acetamide EXAMPLE aal24
According to the Step MD 1-6 in the synthetic method for EXAMPLE aal 17, compound MD 8-6 (0.18 g) was used instead of MD 1 -5 to obtain EXAMPLE aal 24
(78 mg) as a white solid as the hydrochloride salt after HCl treatment.
EXAMPLE aal 25
(R)-N-(4-(Aminomethyl)-3-fluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorphol ino)phenyl)morpholin-2-yl)acetamide EXAMPLE aa 125
Figure imgf000379_0001
Figure imgf000379_0002
MD 9-3 MD 9-4
Figure imgf000379_0003
[Step MD 9-2]
4-(3-Iodophenyl)morpholin-3-one MD 9-2
To a solution of r-BuOK ( 1.3 g) in THF ( 15 mL) at it was added
2-(3-iodophenylamino)ethanol MD 9-1 (3.0 g) prepared from US 2004/0167188 followed by ethyl chloroacetate (1.1 mL). The resulting mixture was stirred for 12 h at rt whereupon an additional portion of ?-BuOK (0.6 g) and ethyl chloroacetate (0.5 mL) was added. The mixture was heated to 55 °C, stirred for 12 h, and was cooled to rt. The mixture was treated with sat. aq NaHCCb and water and was extracted with EtOAc. The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography using a gradient of 100% hexanes to 20% hexanes/80% EtOAc to afford MD 9-2 ( 1.5 g) of the title compound as a light yellow solid.
[Step MD 9-3]
(R)-tert-butyl
2-hydroxy-2-((i?)-3-oxo-4-(3-(3-oxomorpholino)phenyl)morpholin-2-yl)acetate MD
9-3
According to the Step MD 1-1 in the synthetic method for EXAMPLE aal 17, compound MD 9-2 (0.72 g) was used in the presence of AMRI 1-1 (0.50 g) to obtain
MD 9-3 (0.65 g) as yellow crystalline solid after flash chromatography using a 20: 1 mixture of CH2Cl2ZMeOH.
[Step MD 9-4]
(R)-tert-buty\
2-acetoxy-2-((i?)-3-oxo-4-(3-(3-oxomorpholino)phenyl)morpholin~2-yl)acetate MD
9-4
According to the Step MD 1-2 in the synthetic method for EXAMPLE aal 17, compound MD 9-3 (0.65 g) was used instead of MD 1 -1 to obtain MD 9-4 (0.72 g) as an off-white solid which was used without further purification.
[Step
(i?)-2 acetic acid MD 9-5
According to the Step MD 1-3 in the synthetic method for EXAMPLE aal 17, compound MD 9-4 (0.72 g) was used instead of MD 1-2 to obtain MD 9-5 (0.60 g) as a light yellow solid which was used without further purification.
[Step MD 9-6]
(^)-2-(4-((tert-Butoxycarbonylamino)methyl)-3-fluorophenylamino)-2-oxo-1-((Λ)-3-ox o-4-(3-(3-oxomorpholino)phenyl)morpholin-2-yl)ethyl acetate MD 9-6
According to the Step MD 1-4 in the synthetic method for EXAMPLE aal 17, MD 4-5 (70 mg) was treated with tert-butyl-4-amino-2-fluorobenzylcarbamate (65 mg) to afford MD 9-6 (0.10 g) as a pale yellow solid after reverse phase HPLC purification using a C18 column and a gradient of 89.95:9.95:0.1 H2O: MeCN: HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H. [Step MD 9-7]
ter/-Butyl
2-fluoro-4-((R)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorpholino)phenyl)morpholin-2-y l)acetamido)benzylcarbamate MD 9-7
According to the Step MD 1-5 in the synthetic method for EXAMPLE aal 17 , MD 9-6 (0.10 g) was used instead of compound MD 1-4 to obtain MD 9-7 (90 mg) as a white solid. Crude MD 9-7 was used without further purification in the next step.
[Step MD 9-81
(i?)-N-(4-(Aminomethyl)-3-fluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorphol ino)phenyl)morpholin-2-yl)acetamide EXAMPLE aal25
To a solution of MD 9-7 (90 mg) in CH2Cl2 (5 mL) at 0°C was added TEA (1.5 mL) dropwise. The mixture was stirred for 3h at 0°C and concentrated to dryness and this protocol was repeated 5 times. The crude mixture was taken up in MeOH and treated with IM HCl in Et2O to afford after filtration EXAMPLE aal 25 (45 mg) as a pale yellow solid.
EXAMPLE aal 26
(R)-iV-(4-Guanidinophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorpholino)phenyl)m orpholin-2-yl)acetamide EXAMPLE aal 26
Figure imgf000382_0001
Figure imgf000382_0002
MD 10-1
Figure imgf000382_0003
EXAMPLE aa126
[Step MD 10- 1 ]
(i?)-2-(4-Guanidinophenylamino)-2-oxo-1-((i?)-3-oxo-4-(3-(3-oxomorpholino)phenyl) morpholin-2-yl)ethyl acetate MD 10- 1
According to the Step MD 1 -4 in the synthetic method for EXAMPLE aal 17,
MD 9-5 (70 rng) was treated with N-(4-aminophenyl)guanidine (41 mg) to afford MD
10- 1 (65 mg) as a pale yellow solid after reverse phase HPLC purification using a C18 column and a gradient of 89.95:9.95:0.1 H2O:MeCΝ:HCO2H to 9.95:89.95:0.1
H2O:MeCN:HCO2H.
[Step MD 10-2]
(R)-N-(4-Guanidinophenyl)-2-hydroxy-2-((i?)-3-oxo-4-(3-(3-oxomorpholino)phenyl)m orpholin-2-yl)acetamide EXAMPLE aal 26
According to the Step MD 1-5 in the synthetic method for EXAMPLE aal 17 , MD 10- 1 (60 mg) was used instead of compound MD 1 -4 to obtain EXAMPLE aal 26
(35 mg) as a yellow solid after reverse phase HPLC purification using a Cl 8 column and 95:89.95:0.1
H2O EXAMPLE aa 127
(R)-N-(4-(Aminomethyl)phenyl)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)- 3-oxornorpholin-2-yl)-2-hydroxyacetamide EXAMPLE aal27
1-1
ioxane, 90 °C
Figure imgf000384_0001
[Step MD l l-l ]
(2-Fluoro-5-iodophenyl)(morpholino)methanone MD l l -l
To a solution of 3-iodo-6-fluorobenzoic acid (5.0 g) in DMF (50 mL) at rt was added morpholine (1.8 mL), HATU (8.6 g), and DIPEA (9.8 mL). The mixture was stirre The organic layer c layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography using a gradient of 100% CH2CI2 to 97.5% CH2O2/2.5 % MeOH to afford MD 11-1 (5.2 g) of the title compound as a brown solid. [Step MD 11-2]
(R)-tert-Butyl
2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxy acetate MD 11-2
According to the Step MD 1 -1 in the synthetic method for EXAMPLE aal l7, compound MD 1 1-1 (0.87 g) was used in the presence of AMRI 1-1 (0.50 g) to obtain MD 11 -2 (0.64 g) as yellow semisolid after flash chromatography using a 50: 1 mixture of CH2Cl2MeOH.
[Step MD 11-31
(R)-te rt-Butyl
2-acetoxy-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl) acetate MD 1 1 -3
According to the Step MD 1-2 in the synthetic method for EXAMPLE aal l7, compound MD 1 1 -2 (0.64 g) was used instead of MD 1 - 1 to obtain MD 11 -3 (0.71 g) as an light yellow oil which was used without further purification.
[Step MD 11 -4]
(i?)-2-Acetoxy-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin- 2-yl)acetic acid MD 1 1-4
According to the Step MD 1-3 in the synthetic method for EXAMPLE aal l7, compound MD 11 -3 (0.71 g) was used instead of MD 1-2 to obtain MD 11-4 (0.60 g) as a light yellow solid which was used without further purification. [Step MD 11-51
(R)-2-(4-((tert-Butoxycarbonylamino)methyl)phenylamino)-1-((Λ)-4-(4-fluoro-3-(morp holine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate MD 1 1 -5
According to the Step MD 1-4 in the synthetic method for EXAMPLE aal l7,
MD 11 -4 (0.62 g) was treated with ten -butyl-4-aminobenzylcarbamate (0.48 g) to afford MD 11 -5 (0.71 g) as a pale yellow solid after flash chromatography using a 50: 1 mixt I Step MD 1 1 -6]
tert-Eutyl
4-((R)-2-((i?)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-h ydroxyacetamido)benzylcarbamate MD 1 1 -6
According to the Step MD 1-5 in the synthetic method for EXAMPLE aal l7
, MD 11-5 (0.71 g) was used instead of compound MD 1-4 to obtain MD 11-6 (0.66 g) as a white solid. Crude MD 9-7 was used without further purification in the next step.
LStep MD 11-71
(R)-iV-(4-(Aminomethyl)phenyl)-2-((i?)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-
3-oxomorpholin-2-yl)-2-hydroxyacetamide EXAMPLE aal27
According to the Step MD 9-8 in the synthetic method for EXAMPLE aal25,
MD 11-6 (0.66 g) was used instead of compound MD 9-7 to obtain EXAMPLE aal27
(0.21 g) as a pale yellow hydrochloride salt upon treatment with HCl.
EXAMPLE aa 128
(^)-2-(4-Carbamoylphenylamino)-l -((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl )-3-oxomorpholin-2-yl)-2-oxoethyl acetate EXAMPLE aa 128
Figure imgf000387_0001
Figure imgf000387_0002
[Step MD 12- 1]
(i?)-2-(4-carbamoylphenylammo)-l -((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl) -3-oxomorpholin-2-yl)-2-oxoethyl acetate MD 12- 1
According to the Step MD 1-4 in the synthetic method for EXAMPLE aal l7, MD 11-4 (0.10 g) was treated with 4-aminobenzamide (49 mg) to afford MD 12-1 (60 mg) as a yellow solid after reverse phase HPLC purification using a C18 column and a gradient of 89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step 12-2]
(i?)-2-(4-Carbamoylphenylamino)-l -((^)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl )-3-oxomorpholin-2-yl)-2-oxoethyl acetate EXAMPLE aa 128 i LE aal 17 , MD PLE aal 28 (31 mg) as a pale white solid after reverse phase HPLC purification using a Cl 8 column and a gradient of 89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H. EXAMPLE aa 129
(R)-2-((Λ)-4-(4-Fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholm-2-yl)-2-hyd roxy-N-(l ,2,3,4-tetrahydroisoquinolin-6-yl)acetamide EXAMPLE aal29
Figure imgf000388_0001
Figure imgf000388_0002
Figure imgf000388_0003
Figure imgf000388_0004
EXAMPLE aa129
[Ste tert-Butyl
6-((JR)-2-acetoxy-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholi n-2-yl)acetamido)-3,4-dihydroisoquinoline-2( 1 H)-carboxylate MD 13- 1
According to the Step MD 1 -4 in the synthetic method for EXAMPLE aal 17, MD 11 -4 (0.10 g) was treated with tert-butyl
6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (89 mg) to afford MD 13-1 (0.10 g) as a yellow solid after reverse phase ΗPLC purification using a C 18 column and a gradient of 89.95:9.95:0.1 Η2O:MeCN:ΗCO2Η to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 13-2] tert-Butyl
6-((i?)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-h ydroxyacetamido)-3,4-dihydroisoquinoline-2( 1 H)-carboxylate MD 13-2
According to the Step MD 1-5 in the synthetic method for EXAMPLE aal 17 , MD 13-1 (0.10 g) was used instead of compound MD 1-4 to obtain MD 13-2 (94 mg) as a pale yellow solid after reverse phase HPLC purification using a C18 column and a gradient of 89.95:9.95:0.1 H2O :MeCN: HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 13-3] (i?)-2-((i?)-4-(4-Fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hyd roxy-N-( 1 ,2,3,4-tetrahydroisoquinolin-6-yl)acetamide EXAMPLE aa 129
According to the Step MD 9-8 in the synthetic method for EXAMPLE aal 25, MD 13-2 (94 mg) was used instead of compound MD 9-7 to obtain EXAMPLE aal 29 (90 mg) as a pale yellow solid after treatment with HCl.
EXAMPLE aal 30 (i?)-N-(4-(Aminomethyl)-3-fluorophenyl)-2-((i?)-4-(4-fluoro-3-(morpholine-4-carbonyl )phen l) 3 h li 2 l) 2 h d id EXAMPLE l 30
Figure imgf000390_0001
Figure imgf000390_0002
EXAMPLE aa130
[Step MD 14- 1 ]
(i?)-2-(4-((tert-Butoxycarbonylamino)methyl)-3-fluorophenylamino)-1-((i?)-4-(4-fluoro -3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate MD 14-1
According to the Step MD 1-4 in the synthetic method for EXAMPLE aal l7, MD 11-4 (0.10 g) was treated with rerr-butyl-4-amino-2-fluorobenzylcarbamate (86 mg) to afford MD 14-1 (0.13 g) as an off-white solid after reverse phase HPLC purif d di f CN:HCO2H to 9. [Step MD 14-21 tert-Biityl
2-fluoro-4-((R)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin- 2-yl)-2-hydroxyacetamido)benzylcarbamate MD 14-2
According to the Step MD 1-5 in the synthetic method for EXAMPLE aal 17 , MD 14-1 (0.13 g) was used instead of compound MD 1-4 to obtain MD 14-2 (90 mg) as a pale yellow solid after reverse phase HPLC purification using a Cl 8 column and a gradient of 89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 14-3] (R)-N-(4-(Aminomethyl)-3-fluorophenyl)-2-((i?)-4-(4-fluoro-3-(morpholine-4-carbonyl )phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide EXAMPLE aal 30
According to the Step MD 9-8 in the synthetic method for EXAMPLE aal 25. MD 14-2 (90 mg) was used instead of compound MD 9-7 to obtain EXAMPLE aal 30 (95 mg) as a pale yellow solid after treatment with HCl.
EXAMPLE aal 31 (R)-N-(4-((R)- 1 -Aminoethyl)phenyl)-2-((^)-4-(4-fluoro-3-(morpholine-4-carbonyl)phe nyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide EXAMPLE aal 31
Figure imgf000392_0001
Figure imgf000392_0002
EXAMPLE aa131
[Step MD 15-1]
(R)-2-(4-((R)- 1 -(tert-Butoxycarbonylamino)ethyl)phenylamino)- 1 -((R)-4-(4-fluoro-3-( morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate MD 15-1
According to the Step MD 1-4 in the synthetic method for EXAMPLE aal 17, MD 11-4 (0.10 g) was treated with (R)-[ l-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (85 mg) to afford MD 15-1 (0.12 g) as an off-white solid after reverse phase HPLC purification using a C18 column and a gradient of 89.95:9.95:0.1 H2O [Step MD 15-21 tert-Butyl
(R)- l-(4-((R)-2-((^)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2- yI)-2-hydroxyacetamido)phenyl)ethylcarbamate MD 15-2
According to the Step MD 1-5 in the synthetic method for EXAMPLE aal 17 , MD 15-1 (0.12 g) was used instead of compound MD 1-4 to obtain MD 15-2 (80 mg) as a pale yellow solid after reverse phase HPLC purification using a C 18 column and a gradient of 89.95:9.95:0.1 H2O: MeCN: HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 15-3]
(R)-N-(4-((i?)-1-Aminoethyl)phenyl)-2-((i?)-4-(4-fluoro-3-(morpholine-4-carbonyl)phe nyl)-3-oxornorpholin-2-yl)-2-hydroxyacetamide EXAMPLE aal31
According to the Step MD 9-8 in the synthetic method for EXAMPLE aal 25, MD 15-3 (90 mg) was used instead of compound MD 9-7 to obtain EXAMPLE aal 31 (80 mg) as a pale yellow solid after treatment with HCl.
EXAMPLE aal 32
(R)-N-(I -Aminoisoquinolin-6-yl)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl) -3-oxomorpholin-2-y])-2-hydroxyacetamide EXAMPLE aal 32
Figure imgf000394_0001
Figure imgf000394_0002
[Step MD 16-1]
(R)-2-( 1 -(bis(tert-Butoxycarbonyl)amino)isoquinolin-6-ylamino)- 1 -((i?)-4-(4-fiuoro-3-( morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate MD 16-1
According to the Step MD 1-4 in the synthetic method for EXAMPLE aal 17, MD 11 -4 (0.23 g) was treated with
di-tert-butyl(6-aminoisoquinolin-l -yl)imidocarbonate (0.25 g) from WO 2006/062972 to afford MD 16-1 (0.29 g) as an yellow solid after reverse phase HPLC purification usin 8 l d di f 89 9 95 0 C
9.95 [Step MD 16-2]
(i?)-2-(l-(bis(?erϊ-Butoxycarbonyl)amino)isoquinolin-6-ylamino)-1-((i?)-4-(4-fluoro-3-( morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2- hydroxyacetamide MD 16-2
According to the Step MD 1-5 in the synthetic method for EXAMPLE aal 17 , MD 16-1 (0.29 g) was used instead of compound MD 1-4 to obtain MD 16-2 (0.27 g) as maize solid which was used without further purification.
[Step MD 16-3]
(R)-N-(I -Aminoisoquinolin-6-yl)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl) -3-oxomorpholin-2-yl)-2-hydroxyacetamide EXAMPLE aal 32
According to the Step MD 9-8 in the synthetic method for EXAMPLE aal 25,
MD 16-3 (0.27 g) was used instead of compound MD 9-7 to obtain EXAMPLE aal 32
(0.11 g) as a pale yellow solid after reverse phase HPLC purification using a Cl 8 column and a gradient of 89.95:9.95:0.1 H2O:MeCN:TFA to 9.95:89.95:0.1
H2θ:MeCN:TFA to afford the trifluoroacetate salt.
EXAMPLE aal 33
(i?)-N-((R)-1-amino-2,3-dihydro-1H-inden-5-yl)-2-((i?)-4-(4-fluoro-3-(morpholine-4-ca rbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetarnide EXAMPLE aal 33
Figure imgf000396_0001
[Step MD 17-1]
(R)-tert-Butyl 5-amino-2,3-dihydro-lH-inden-1-ylcarbamate MD 17-1
To a solution of (l/?)-indane-1,5-amine hydrochloride (0.60 g) in CΗ2CI2 (16 mL) at 0 °C was added Et3N (1.4 mL) followed by BoC2O (0.85 g). The mixture was allowed to warm to rt and was stirred for 12 h. The mixture was diluted with CH2CI2 (5 mL) and sat. aq. NaHCO3 (3 mL) and the layers were separated. The aqueous layer was d ih CHCI (2 5 L) d h i l bined. The organ d pressure. The crude material was purified by flash chromatography using a gradient of 100% hexanes to 20% hexanes/80% EtOAc to afford MD 17-1 (0.26 g) as a yellow/orange semisolid. [Step MD 17-2]
(R)-2-((R)- 1 -(rm-Butoxycarbonylamino)-2,3-dihydro- 1 H-inden-5-ylamino)- 1 -((Z?)-4-( 4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate MD 17-2
According to the Step MD 1-4 in the synthetic method for EXAMPLE aal l7, MD 17-1 (0.11 g) was treated with MD 11-4 (0.15 g) to afford MD 17-2 (0.21 g) as a white solid afterreverse phase HPLC purification using a Cl 8 column and a gradient of 89.95:9.95:0.1 H2O: MeCN: HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 17-3J tert-Butyl
(Λ)-5-((i?)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl) -2-hydroxyacetamido)-2,3-dihydro-1H-inden-l -ylcarbamate MD 17-3
According to the Step MD 1 -5 in the synthetic method for EXAMPLE aa 117 , MD 17-2 (0.21 g) was used instead of compound MD 1-4 to obtain MD 17-2 (0.14 g) as a white solid after reverse phase HPLC purification using a C18 column and a gradient of 89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 17-41
(R)-N-((R)- 1 -amino-2,3-dihydro- 1 H-inden-5-yl)-2-((i?)-4-(4-fluoro-3-(morpholine-4-ca rbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide EXAMPLE aal33
According to the Step MD 9-8 in the synthetic method for EXAMPLE aal25,
MD 17-3 (0.14 g) was used instead of compound MD 9-7 to obtain EXAMPLE aal33
(38 mg) as a clear glass after reverse phase HPLC purification using a C 18 column and a gradient of 89.95:9.95:0.1 H2O:MeCN:TFA to 9.95:89.95:0.1 H2O:MeCN:TFA to afford h ifl l EXAMPLE aa 134
(R)-N-I(S)- 1 -Amino-2,3-dihydro- 1H-inden-5-yl)-2-((R)-4-(4-fluoro-3-(morpholine-4-ca rbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide EXAMPLE aal34
H
Figure imgf000398_0001
[Step MD 18-1 ]
(S)-t According to the Step MD 17- 1 in the synthetic method for EXAMPLE aal33, (lS)-indane- l ,5-amine hydrochloride (0.72 g) was used to produce MD 18-1 (0.4Og) as a yellow semisolid.
[Step MD 18-2]
(R)-2-((S)- 1 -(rm-Butoxycarbonylamino)-2,3-dihydro- 1 H-inden-5-y lamino)- 1 -((R)-A-(A -fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate MD 18-2
According to the Step MD 1-4 in the synthetic method for EXAMPLE aal l7, MD 18-1 (0.11 g) was treated with MD 11 -4 (0.15 g) to afford MD 17-2 (0.24 g) as a white solid afterreverse phase ΗPLC purification using a C18 column and a gradient of 89.95:9.95:0.1 Η2O:MeCN:ΗCO2Η to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 18-3] tert-Butyl
(5)-5-((R)-2-((i?)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)- 2-hydroxyacetamido)-2,3-dihydro-lH-inden-l -ylcarbamate MD 18-3
According to the Step MD 1-5 in the synthetic method for EXAMPLE aal 17 , MD 18-2 (0.24 g) was used instead of compound MD 1-4 to obtain MD 18-3 (0.18 g) as a white solid after reverse phase ΗPLC purification using a Cl 8 column and a gradient of 89.95:9.95:0.1 Η2O:MeCN:ΗCO2Η to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 18-4] (R)-N-((S)-1-Amino-2,3-dihydro- lH-inden-5-yl)-2-((R)-4-(4-fluoro-3-(morpholine-4-ca rbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide EXAMPLE aa 134
According to the Step MD 9-8 in the synthetic method for EXAMPLE aal 25,
MD 18-3 (0.14 g) was used instead of compound MD 9-7 to obtain EXAMPLE aal 34 (56 mg) as a clear glass after reverse phase ΗPLC purification using a Cl 8 column and a gr di f 89 95 9 95 0 1 Η O M CΝ TFA 9 95 89 95 0 1 H O M CN:TFA to affor EXAMPLE aa 135
(R)-N-(2-Aminoquinolin-6-yl)-2-((i?)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3- oxomorpholin-2~yl)-2-hydroxyacetamide EXAMPLE aa 135
Figure imgf000400_0001
[Step MD 19-1 ]
2-bis To a solution of 6-nitroquinoline-2-amine (1.0 g) in THF (30 mL) was added
BocoO (2.9 g) and DMAP (32 mg). The mixture was heated at refux for 12 h whereupon an additional portion of BOC2O (0.7 g) and DMAP (60 mg) were added. The mixture was stirred at reflux for an additional 12 h whereupon the mixture was cooled and concentrated under reduced pressure. The resultant solid was dissolved in
CH2Cl2 (50 mL) and was washed with sat. aq. NH4Cl (1 x 15 mL) and sat. aq. NaHCO3
(1 x 15 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography using a gradient of 100% hexanes to 50% hexanes/50% EtOAc to afford MD 19-1 (2.1 g) as a white solid.
[Step MD 19-21 2-(bis(terr-Butoxycarbonyl)amino)quinolin-6-ylamine MD 19-2
To a heterogenous mixture of MD 19-1 (2.0 g) in MeOH/THF ( 12 mL/12 mL) was added 10% Pd/C (100 mg). The mixture was stirred under a H2 balloon for 12 h whereupon the mixture was purged to N2. The mixture was filtered thru a pad of Celite and the pad was generously washed with MeOH (5 x 10 mL). The filtrate was concentrated under reduced pressure and placed under high vacuum to afford MD 19-2 (1.7 g) as a light yellow solid.
[Step MD 19-3]
(i?)-2-(2-(bis(tert-Butoxycarbonyl)amino)quinolin-6-ylamino)-1-((R)-4-(4-fluoro-3-(m orpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate MD 19-3
According to the Step MD 1-4 in the synthetic method for EXAMPLE aal l7, MD 1 1-4 (0.15 g) was treated with MD 19-2 (0.17 g) to afford MD 19-3 (0.13 g) as an yellow solid after reverse phase HPLC purification using a C 18 column and a gradient of 89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 19-4]
(R)-2 uoro-3-(m orph D 19-4 According to the Step MD 1-5 in the synthetic method for EXAMPLE aal 17, MD 19-3 (0.13 g) was used instead of compound MD 1-4 to obtain MD 19-4 (0.10 g) as white solid after reverse phase HPLC purification using a C18 column and a gradient of 89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H.
[Step MD 19-5]
(R)-N-(2-Aminoquinolin-6-yl)-2-((^)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3- oxomorpholin-2-yl)-2-hydroxyacetamide EXAMPLE aal 35
According to the Step MD 9-8 in the synthetic method for EXAMPLE aa 125, MD 19-4 (0.10 g) was used instead of compound MD 9-7 using 4Ν HCl in dioxane obtain EXAMPLE aal 35 (85 mg) as a yellow solid after treatment with HCl.
Figure imgf000402_0001
Figure imgf000403_0001
Figure imgf000404_0001
Figure imgf000405_0001
Method A:
Electro Spray Ionization Liquid Chromatography-Mass Spectrometry
(ESI-LCVMS)
Column: Phenomenex Gemini C 18, 50 x 4.6 mm, 5 micron
Mobile Phase: A: 0.05% Trifluoroacetic acid in water
B: 0.05% Trifluoroacetic acid in acetonitrile
Gradient: 90% A and 10% B to 5% A and 95% B over 5 minutes
Flow rate: 1.0 ml/min
UV detection: 254 nM
Spectrometer: PE SCIEX API- 150EX, single quadrupole mass spectrometer
Method B:
Column: Zorbax SB-C- 18; 1.8 micron
Mobile Phase: A: 0.1 % Trifluoroacetic acid in water
B: 0.1% Trifluoroacetic acid in acetonitrile
Gradient: 0 min = 10 % B
1.3 min = 55 % B
2.7 min = 95 % B
2.8 min = 10 % B
Flow rate: 1.0 ml/min
UV detection: 254 nM
Spectrometer: Agilent 6140 Quadrapole LC-MS, single quadrupole mass spectrometer
Figure imgf000405_0002
Figure imgf000406_0001
Figure imgf000407_0001
Figure imgf000408_0001
[Step I] Synthesis of
Methyl 2-cyano-3-fluoro-5-nitrobenzoate (compound MCHl-2)
A mixture of MCHl-I (3.9 g, 14.03 mmol (prepared according to the procedure described in WO 2006/021457 A2 )), CuCN (6.3 g, 70.34 mmol, 5 eq.) in 40 mL DMF was degassed under vacuum, filled with argon atmosphere and heated in an oil bath at ~ 160 °C (bath temp.) for 20 min. It was removed from the bath, cooled to rt then diluted with ethyl acetate while being stirred vigorously. The mixture was filtered through a pad of CELITE, rinsed with ethyl acetate and the filtrate was washed with water and brine. It was dried over MgSO/j, filtered and evaporated to dryness to give 3.02 g of MCHl-2 as solid.
[Step Methyl 5-(benzyloxycarbonylamino)-2-cyano-3-fluorobenzoate (compound MCHl-3) A suspension of 3 (500 mg) and 10% Pd/C (50 mg) in 10 mL of 1 : 1 THF-EtOH was under overnight under a hydrogen balloon. It was filtered through a CELlTE pad and evaporated to dryness to give 435 mg of aniline.
To a solution of the above aniline (430 mg, 2.22 mmol) and NaHCO3 (930 mg, 11.07 mmol, 5 eq.) in 10 mL THF at it was added benzylchloroformate (0.95 mL, 0.66 mmol, 3 eq.). The mixture was stirred overnight at rt, diluted with water and extracted 3x with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to a small volume to give a suspension. The suspension was diluted with ether and the solid was filtered, washed with ether and dried to give 485 mg MCHl-3.
[Step 31 Synthesis of
Benzyl 3-((di-tert-butoxycarbonyl)aminomethyl)-4-cyano-5-fluorophenylcarbamate (compound MCHl-5)
To a solution of MCHl-3 (650 mg, 1.98 mmol), LiORH2O (330 mg, 5.96 mmol, 3 eq.) in 10 mL THF and 2 mL water was stirred at rt for 45 min. and diluted with water. The solution was acidified with IN HCl to ~pH 1 and extracted 3x with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness to give 62Og of the acid. To a solution of the above acid (620 mg, 1.97 mmol) and triethyl amine (0.55 mL, 3.95 mmol, 2 eq.) in 10 mL THF at—20 °C was added a IM solution of
isopropylchlroformate in toluene (2.4 mL, 2.4 mmol, 1.2 eq.). The mixture was stirred for about 10 min and filtered through a fritted funnel and the precipitate rinsed with 10 mL THF. The filtrate was cooled to— 20°C and a solution of sodium borohydride (375 mmol, 9.91 mmol, 5 eq.) in 2 mL water was added. After being stirred for 10 min. at -20°C, the reaction mixture was diluted with water and extrated 3x with ethyl acetate. The combined organic layers was washed aq. NH4Cl solution followed by brine, dried over MgSθ4, filtered and evaporated to dryness to provide the crude alcohol. The above alcohol was dissolved in 10 mL of dichloromethane and cooled to 0°C. To this ane sulfo r 1 hr, diluted with ethyl acetate, washed with IN HCl, 2x with aq. NaHCC^ and brine. It was dried over MgSO4, filtered and concentrated to provide the crude mesylate which was used for the subsequent step.
A solution of the above mesylate, di-tert-buty] iminodicarboxylate (560 mg, 2.58 mmol, 1.3 eq.), K2CO3 (540 mg, 3.97 mmol). and tetrabutyl ammonium iodide (973 mg, 0.198 mmol, 0.1 eq) in 10 mL DMF was stirred overnight at rt. The mixture was diluted with water, extracted 3x with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered, concentrated and purified by chromatography eluting with 0% to 20% ethyl acetate in hexane to provide 49 mg of MCHl-5.
[Step 4] Synthesis of
4-Amino-2-((di-tert-butoxycarbonyl)aminomethyl)-6-fluorobenzonitrile (compound MCHl-6)
A suspension of 5 ( 180 mg), 10% Pd-C (30 mg) in 2 mL THF and 2 mL ethanol was stirred under a hydrogen balloon for 6 hr. filtered through a CELITE pad, concentrated and purified by chromatography eluting with 100% hexane to 1 : 1 :3 ethyl
acetate/dichloromethane/hexane to provide 50 mg of MCHl-6.
[Step 5] Synthesis of
N-(7-fluoro-2,3-dihydro-1-imino-1H-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo-4-[3-(3-o xo-4-morpholinyl)phenyl]-2(R)-morpholineacetamide (Example aal36)
Compound MCHl-6 was converted to example aal36 using a procedure similar to the preparation of Example 57.
Figure imgf000410_0001
EXA
Figure imgf000411_0001
[Stepl] Synthesis of
4-Amino-2-((di-tert-butoxycarbonyl)aminomethyl)-3-chlorobenzonitrile (compound
MCH 2-2)
To a solution of MCH2-1 (950 mg, 2.73 mmol) in 10 ml isopropanol at 60°C was added N-chlorosuccinimide (400 mg, 2.99 mmol, 1.1 eq). The mixture was heated at reflux for 1.5 hr, left overnight at rt, concentrated and diluted with ethyl acetate. The solution was washed 2x with water, brine, dried over MgSθ4, filtered, concentrated and purified by flash chromatography using 40% ethyl acetate in hexanes to provide 288 mg of MCH2-2. [Step 2] Synthesis of
N-(4-chloro-2,3-dihydro- l-imino-1H-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo-4-[3-(3-o xo-4-morpholinyl)phenyl]-2(R)-morpholineacetamide (Example aal37)
Compound MCH2-2 was converted to example aal37 using procedure similar to the preparation of Example 57.
The following analogs were prepared using analogous procedure:
Figure imgf000411_0002
Figure imgf000412_0001
Figure imgf000413_0001
EXAMPLE aal47 N-[4-(Aminoiminomethyl)phenylJ-4-(2-cyanophenyl)-alpha(R)-hydroxy-3-oxo-2(R)-m orpholineacetamide (Example aal47)
Example aal47 was prepared using procedures similar to the preparation of Example
73.
Figure imgf000414_0001
aa147
EXAMPLE aal48 N-(4-Amino-7-quinazolinyl)-4-[4-fluoro-3-(4-morpholinylcarbonyl)phenylJ-alpha(R)-h ydroxy-3-oxo-2(R)-morpholineacetamide (Example aal48)
Example aal48 was prepared using procedures similar to the preparation of example 98.
Figure imgf000414_0002
EXAMPLE aal49
Figure imgf000414_0003
[Step 11 Synthesis of
4-(2,2,2-trifluoro- 1 -(2-fluoro-5-iodophenyl)ethyl)morpholine (compound MCH14-1)
To a solution of commercially available
2,2,2-trifluoro- l -(2-fluoro-5-iodophenyl)ethanone (2 g, 6.29 mmol) in 20 rnL dichloromethane at rt was added N,N-diisopropylethylamine (3.3 mL, 18.95 mmol, 3 eq.) followed by IM solution of TiCU in dichloromethane (6.3 mL, 6.3 mmol, 1 eq.). The mixture was stirred at rt for 3 days, added 10 mL of methanol followed by
NaCNBH3 (3.2 g) and trifluoroacetic acid (4.7 mL). The mixture was stirred overnight at at rt, poured into aq. NaHCO^ and extracted 3x with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered, concentrated and purified by chromatography eluting with 0% to 20% ethyl acetate in hexane to provide 1.16 g of MCH14-l.
[Step 2] Synthesis of
N-(3-Amino- 1,2-benzisoxazol-6-yl)-4-[4-fluoro-3-[2,2,2-trifluoro- l-(4-morpholinyl)eth yl]phenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide (example aal49)
Compound MCH14-1 was converted to example aal49 using experimental procedure similar to the one described for the preparation of aa95 The following examples were prepared using analogous procedure:
Figure imgf000415_0001
]
Figure imgf000416_0001
EXAMPLE aal52 e
Figure imgf000416_0002
[Step 1] Synthesis of
tert-Butyl 3-amino-5-fluorobenzo[d]isoxazol-6-ylcarbamate (compound MCH17-1)
To a solution of 4-amino-2,5-difluorobenzonitrile (10 g, 64.88 mmol,)
di-tert-butyldicarbonate (43 g, 197 mmol, 3 eq.) in dichloromethane at rt was added DMAP (1.6 g, 13.10 mmol, 0. 2eq.) and triethyl amine (28 mL, 200 mmol, 3 eq.). The mixture was stirred overnight at rt and poured into 1 N HCl. The organic layer separated and the aqueous phase extracted twice with dichloromethane. The combined organic layer was washed with brined, dried over MgSO4, filtered and evaporated to dryness to obtain 22.6 g of the protected aniline.
To a solution of the above aniline (12.6 g, 36 mmol) acetohydroxamic acid (16 g, 213 mmol, 6 eq.) and K2CO3 (58 g, 0.426 mmol, 12 eq.) in 150 mL of 9: 1 DMF-water was heated overnight in an oil bath kept ~60°C. It was poured into water, extracted 3x with ethyl acetate, the combined organic layer was washed with brine, dried over MgSO4, filter % ethyl aceta own byproduct.
[Step 2] Synthesis of
2-(6-Amino-5-fluorobenzo[dJisoxazol-3-yl)isoindoline-1,3-dione (compound
MCH17-2)
To a solution of MCH17-1 (520 mg), triethyl amine (0.82 mL) and DMAP (24 mg) in 10 mL dichloromethane at 0°C was added phthaloyl chloride (0.36 mL). The mixture was stirred overnight at rt, diluted with ethyl acetate and washed with IN HCl, aq. NaHCCh and brine. It was dried over anhydrous MgSO4, filtered, concentrated and purified by chromatography eluting with 0% to 50% ethyl acetate in hexane to provide 338 mg of phthalimide protected intermediate which was stirred with 5 mL of trifluoroacetic acid at rt for 40 min. The reaction mixture was evaporated to dryness, the residue was suspended in aq. NaHCCλ? and extracted 3x with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness to obtain 220 mg MCH 17-2.
[Step 3] Preparation of
N-(3-Amino-5-fluoro-l ,2-benzisoxazol-6-yl)-4-[4-fluoro-3-(4-morpholinylcarbonyl)ph enyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide (example aal52)
Compound MCH17-2 was converted to aal52 using a procedure similar to the preparation of aal49
EXAMPLE aal53
Figure imgf000418_0001
MCH18-1
Figure imgf000418_0002
[Stepl ] Preparation of
(compound MCH18-1)
To 1.7g of 6-nitroquinazolin-2-amine (prepared according the procedure described in WO 2006/039718) in 45mL of dry dichloromethane at room temperature was added 6.2 mL of triethylamine, 5.85g of di-tert-butyldicarbonate, and 110 mg of DMAP and the mixture was stirred under nitrogen overnight. The reaction mixture was washed with water, aq. sodium bicarbonate and brine then dried with magnesium sulfate, filtered and evaporated to dryness. Purification by flash chromatography yielded 3.04g of the protected aniline.
To 0.5g of the above product in 2OmL of methanol was added 50mg of 10% palladium on carbon and the mixture was shaken under 40 psi of hydrogen for 45 minutes. The mixture was filtered and evaporated to dryness. Recrystallization from ethyl acetate/he xanes yielded 220mg of MCH18-1.
[Step 2J Synthesis of
N-(2-Amino-6-quinazolinyl)-4-[4-fluoro-3-(4-morpholinylcarbonyl)phenyl]-alpha(R)-h ydroxy-3-oxo-2(R)-morpholineacetamide (example aal53).
Compound MCHl 8-1 was converted to aal53 using a procedure similar to the preparation of Example 98.
Analytical Data:
Mass
Figure imgf000419_0001
Figure imgf000419_0002
Figure imgf000420_0001
Figure imgf000421_0001
Examples aa 154 - aa!59
EXAMPLE aal54
(R)-2-((R)-4-(5-fluoro-2-isopropoxyphenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N-(l-imi noisoindolin-5-yl)acetamide
aa154-1
Figure imgf000422_0001
[Step l ]
To a mixture of 2-bromo-4-fluorophenol (1.3 g. 7.0 mmol) and potassium carbonate (2.0 g, 14 mmol) in DMF (15 mL), 2-iodopropane (1.8 g, 10.5 mmol) was adde n mixture was cooled to room temperature and diluted with diethyl ether. The organics were washed with saturated aqueous ammonium chloride, water, and dried with Na^SO4. The organics were evaporated to dryness to give Compound aal54-2 (1.4 g, 86%) which was used without further purification in the next step.
[Step 2]
To a nitrogen purged vessel, a solution of compound aal54-2 (1.4 g, 6.0 mmol) in 1,4-dioxane (6 mL), sodium iodide (1.8 g, 12.0 mmol), copper iodide (0.057 g, 0.3 mmol), and trans-N, N'-dimethylcyclohexane- l, 2-diamine (0.085 g, 0.6 mmol) were added. The vessel was sealed and heated to 110 °C for 16 h. The reaction mixture was cooled to room temperature, washed with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organics were dried with Νa2SC>4 and evaporated to dryness to give Compound aal54-3 (1.4 g, 83%) which was used without further purification in the next step.
[Step 3]
To a nitrogen purged vessel, a solution of compound aal54-3 (1.4 g, 5.0 mmol) in DMSO (40 mL), (i?)-tert-butyl 2-hydroxy-2-((R)-3-oxomorpholin~
2-yl)acetate (0.96 g, 4.1 mmol), potassium phosphate (1.75 g, 8.2 mmol), copper iodide (0.157 g, 0.82 mmol), and rrα«.s-N,N'-dimethylcyclohexane- l.2-diamine (0.116 g, 0.82 mmol) were added. The vessel was sealed and heated to 85 °C for 3 h. The reaction mixture was cooled to room temperature, washed with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organics were dried with Νa?Sθ4 and evap d d Th d i l ifi d b ili l h atography (ethy [Step 4]
To a solution of compound aal54-4 (1.2 g, 3.1 mmol) in DCM (30 mL) that was chilled to 0 °C was added DMAP (0.038 g, 0.31 mmol), pyridine (0.49 g, 6.2 mmol), and acetic anhydride (0.64 g, 6.2 mmol). The reaction was stirred at 0 °C for
3 h. The reaction was diluted with ethyl acetate, washed with aqueous Cu2SO4 and
H2O (X3). The organics were dried with NaISO4 and evaporated to dryness. The crude material was purified by silica gel chromatography (ethyl acetate/Hexanes 0 to
45%) to give Compound aal54-5 (0.9 g, 68%).
[Step 5]
Compound aal54-5 was dissolved in DCM (20 mL), TFA (10 mL) and H2O
(0.1 mL). The reaction was stirred at room temperature for 2 h. The reaction was evaporated to dryness. The residue was dissolved in 50 mL of toluene and evaporated to dryness (X3). The residue was dissolved in 50 mL of hexanes and evaporated to dryness (X2) to give Compound aal54-6 (0.8 g, 100%) which was used without further purification in the next step.
[Step 6]
According to the step 70-5 in the synthetic method for EXAMPLE 70, compound aal54-6 (0.6 g, 1.6 mmol) was used instead of compound 70-4 to couple to compound aal54a (0.55 g, 1.6 mmol) instead of compound 68-12 to obtain compound aal54-7 (0.16 g, 14%) after chromatography purification on silica gel eluting with DCM
[Step According to the step 70-6 in the synthetic method for EXAMPLE 70, compound aal54-7 (0.16 g, 0.23 mmol) was used instead of compound 70-5. The crude reaction mixture was evaporated to dryness and dissolved in 4N HCl in dioxane (3 mL). The reaction was stirred at ambient temperature for two h. The reaction mixture was evaporated to dryness to give compound aal54-8 (0.1 g, 95%) which was used without further purification in the next step.
[Step 8]
Compound aal54-8 was dissolved in ethanol (5 mL) and heated to 85 °C for 16 h. The reaction was cooled to ambient temperature, evaporated to dryness, and purified by HPLC. The resulting fraction was purified by silica gel chromatography and eluted with DCM/(7N NH3 in MeOH) (90/10) to obtain compound aal54
((R)-2-((R)-4-(5-fluoro-2-isopropoxyphenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N-(l -i minoisoindolin-5-yl)acetamide) (0.002 g, 2%).
EXAMPLE aa 155
(R)-2-hydroxy-N-(l-iminoisoindolin-5-yl)-2-((R)-3-oxo-4-(2-(trifluoromethyl)phenyl) morpholin-2-yl)acetamide
Figure imgf000425_0001
Compound was obtained using the synthetic method for EXAMPLE aal54 beginning from Step 3 using l-iodo-2-(trifluoromethyl)benzene instead of compound aal5 EXAMPLE aa 156
(R)-2-((R)-4-(2-(difluoromethoxy)phenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N-(l-imin oisoindolin-5-yl)acetamide
Figure imgf000426_0001
Compound was obtained using the synthetic method for EXAMPLE aal54 beginning from Step 3 using 1 -(difluoromethoxy)-2-iodobenzene instead of compound aal54-3. EXAMPLE aa 157
(R)-2-hydroxy-N-(l -iminoisoindolin-5-yl)-2-((R)-4-(2-isopropoxyphenyl)-3-oxomorph olin-2-yl)acetamide
Figure imgf000426_0002
Compound was obtained using the synthetic method for EXAMPLE aal54 using with 2-iodophenol instead of 2-bromo-4-fluorophenol in Step 1. Step 2 was skipped.
EXAMPLE aa 158
(R)-2-((R)-4-(5-chloro-2-isopropoxyphenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N-(l-im inoi
Figure imgf000427_0001
Compound was obtained using the synthetic method for EXAMPLE aal54 using 2-bromo-4-chlorophenol instead of 2-bromo-4-fluorophenol in Step 1. EXAMPLE aa 159
(R)-2-hydroxy-N-(l-iminoisoindolin-5-yl)-2-((R)-3-oxo-4-(2-(trifluoromethoxy)phenyl )morpholin-2-yl)acetamide
Figure imgf000427_0002
Compound was obtained using the synthetic method for EXAMPLE aal54 beginning from Step 3 using 1 -iodo-2-(trifluoromethoxy)benzene instead of compound aa!54-3.
Figure imgf000427_0003
Figure imgf000428_0001
Figure imgf000428_0002
Figure imgf000429_0002
EXAMPLES aa 160 - aa 163
EXAMPLE aa 160
Figure imgf000429_0001
[Step I -2]
Synthesis of SN 1-2:
To a cooled solution of 2-fluoro-5-iodophenylboronic acid (5.Og, 18.81 mmol) in THF (200 mL) at 0 °C was added an aqueous solution of 30% H2O2 ( 1.73 mL, 18.0 mmol) dropwise and stirred for 10 min. This was followed by the addition of an aqueous solution of 4N NaOH (0.3 mL, 1.2 mmol). The reaction was then warmed to rt and stirred overnight MnO (40 0 mg) was then added to the reaction mixture and stirred for 9 tioned between diethyl ether (150 mL) and water (150 mL). Separated the organics and washed further with brine and dried. The product was purified by eluting with silica-gel from 100:0 to 70:30 hexanes to ethyl acetate to give the product SNl-2(3.4g, 76%). [Step 1-4]
Synthesis of SN1-4:
To a sealed tube was added SN 1-2 (218 mg, 0.92 mmol), commercially available tetrahydro-2H-pyran-4-yl methanesulfonate (0.2g, 1.1 mmol), potassium carbonate
(0.384g, 2.78 mmol) in DMF (4.0 mL) and heated at 70 °C overnight. The reaction mixture was then cooled and extracted with ethyl acetate. The organics were washed multiple times with water and brine and this was followed by washing with IM NaOH.
The organic fractions were concentrated and purified over column chromatography using 25% acetone/hexanes to give product SN1-4(12O mg, 41 %). The yield of this reaction was greatly improved by heating at 100 °C for a similar substrate.
[Step 1-61
Synthesis of SN1-6:
A mixture of aryl iodide SN1-4(0.120g, 0.37 mmol), previously described SN1-5
(0.064g, 0.28 mmol), CuI (l lmg, 0.056 mmol), K3PO4 (119 mg, 0.56 mmol) and trans-N, JV'-dimethylcyclohexane-l^-diamine (9 μL, 0.056 mmol) were stirred in
DMSO (4.0 mL). The degassed reaction mixture was then heated at 100 °C for 5.0h.
The reaction was then cooled, quenched with water, extracted with EtOAc and washed with brine. The organic fractions were concentrated and purified with 50-60%
EtOAc/hexanes to give the product SΝ1-6 (0.084 mg, 71%).
Synthesis of aal60:
N-(3-Amino-1,2-benzisoxazol-6-yl)-4-[4-fluoro-3-[(tetrahydro-2H-pyran-4-yl)oxyJphe nyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide The iodide SN1-6 was converted to aal60 using experimental procedure described for the preparation of aa95.
EXAMPLE aal 61
Figure imgf000431_0001
[Step 2- 11
Synthesis of 2-1:
A mixture of aryl iodide SN1-2 (l .Og, 4.2 mmol), potassium carbonate (21.Og, 151.9 mmol), 2-chloro-2,2-difluoro-1-phenylethanone (3.9g, 20.5 mmol) were stirred in acetonitrile/water (1 : 1, 50 mL) and heated in a sealed tube at 85 °C for 5.0h. The reaction mixture was cooled and the organics were extracted thrice with ether. The ether fractions were washed with IM NaOH and concentrated. The product was purified by column chromatography with 10-20% EtO Ac/he xanes to give the product SN2-l(0.5g, 42%).
Synthesis of aalόl:
N-(3-Amino-1,2-benzisoxazol-6-yl)-4-[3-(difluoromethoxy)-4-fluorophenyl]-alpha(R)- hydroxy-3-oxo-2(R)-morpholineacetamide
The iodide SΝ2-1 was converted to aal61 using experimental procedure similar to the preparation of aa95. EXAMPLE aa 162
Figure imgf000431_0002
[Step 3-2]
Synthesis of SN3-2:
To commercially available SN3-1 (0.5g, 1.88 mmol) was added 3,3-difluoroazetidine hydrochloride (0.244g, 1.88 mmol), HATU ( 1.17g, 3.1 mmol), NMM ( 1.2 mL, 11 mmol) in DMF (4.0 mL) and stirred at 0 °C. The reaction was quenched with NH4CI and e ntrated and p he product SN3-2 (0.45g, 70%).
Synthesis of aa 162:
N-(3-Amino- 1 ,2-benzisoxazol-6-yl)-4-[3-[(3,3-difluoro- l-azetidinyl)carbonyl]-4-fluoro phenyl]-aIpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide
The iodide SN3-2 was converted to aal62 using experimental procedure described for the preparation of aa95. EXAMPLE aal63:
Figure imgf000432_0001
[Step 4-21
Synthesis of SN4-2:
2-fluoro-5-iodobenzoic acid ( 1.1 g, 4.14 mmol) was dissolved in CH3CN (20 mL) and cooled to O0C. 4,4-Difluoropiperidine (0.6g, 4.96 mmol) was added to the mixture followed by EDCI (0.95g, 4.96 mmol) and DMAP (0.05g, 0.41 mmol) and the resulting mixture was stirred overnight at room temperature. Reaction mixture was diluted with ethyl acetate and washed with saturated NH4CI, water and brine respectively. Organic layer was dried over anhydrous MgSO4, filtered, concentrated, purified by silica gel column chromatography using (0-70)% ethyl acetate - hexanes as mobile phase and the product SNl-I (1.15g, 75.65%) was obtained.
Synthesis of aal63:
N-(3-Amino-1,2-benzisoxazol-6-yl)-4-[3-f(4,4-difluoro-1-piperidinyl)carbonylJ-4-fluor ophenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide
The iodide SN4-2 was converted to aal63 using experimental procedure similar to the preparation of aa95.
Analytical Data:
Mass Spectra:
Figure imgf000432_0002
Figure imgf000433_0001
Figure imgf000433_0002
EXAMPLE aa 164 - aa 165
EXAMPLE aa 164
Figure imgf000434_0001
Figure imgf000434_0002
Example aa164
Synthesis of intermediate US 1-2
(3-tert-butyl-5-(2-chloro-5-iodophenyl)- 1 ,2,4-oxadiazole)
To a solution of 2-chloro-5-iodobenzoic acid ( 1.0 g, 3.54 mmol) in 40 rnL DMF was added diisopropylethyl amine ( 1.23 mL, 7.08 mmol) followed by HATU (2.02 g, 5.31 mmol). After stirring the reaction at room temperature for 10 min,
N-hydroxy-2,2-dimethylpropanimidamide (0.82 g, 7.08 mmol) was added. The resulting reaction mixture was stirred at room temperature for Ih and then at 110 °C for 16h. After cooling to room temperature the reaction was quenched with water and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography (2-5% EtOAc in hexanes) to yield 660 mg of intermediate US 1 -2.
Synthesis of Example aal64
N-(3-amino-l ,2-benzisoxazol-6-yl)-4-[4-chloro-3-[3-(l , l-dimethylethyl)-1,2,4-oxadiaz ol-5-yl]phenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide
Intermediate US 1-2 was converted to Example aal64 using previously described procedures. EXAMPLE aa 165
N-(3-amino- l ,2-benzisoxazol-6-yl)-4-[2-fluoro-5-(trifluoromethyl)phenylJ-alpha(R)-hy droxy-3-oxo-2(R)-morpholineacetamide
Figure imgf000435_0001
Example aa165
Example aal65 was prepared starting from l-fluoro-2-iodo-4-(trifluoromethyl)benzene using previously described procedures. Analytical Data:
Mass S ectra:
Figure imgf000435_0002
1H-NMR Data:
Figure imgf000435_0003
Utility
The invention also relates to medicaments which contain an efficacious amount of at least one compound of the Formula (I) and/or of a pharmaceutically acceptable salt of the compound of the Formula (I) and/or an optionally stereoisomeric form of the compound of the Formula (I), together with a pharmaceutically suitable and pharm and auxiliaries.
On account of their pharmacological properties, the compounds according to the invention are suitable, for example, for the prophylaxis, secondary prevention and therapy of all those diseases which are treatable by inhibition of blood clotting factor IXa. Thus, the compounds according to the invention are suitable as inhibitors both for prophylactic and for therapeutic administration to humans. They are suitable both for acute treatment and for long-term therapy. The compounds of the Formula (I) can be employed in patients who are suffering from disorders of well-being or diseases which accompany thromboses, embolisms, hypercoagulability or fibrotic changes.
These include myocardial infarct, angina pectoris and all other forms of acute coronary syndrome, stroke, peripheral vascular diseases, deep vein thrombosis, pulmonary embolism, embolic or thrombotic events caused by cardiac arrhythmias, cardiovascular events such as restenosis after revascularization, angioplasty and similar interventions such as stent implantations and bypass operations. Furthermore, the compounds of the Formula (I) can be employed in all interventions which lead to contact of the blood with foreign surfaces, as in dialysis patients and patients with indwelling catheters. Compounds of the Formula (I) can also be employed in order to reduce the risk of thrombosis after surgical interventions such as in knee and hip joint operations.
Compounds of the Formula (I) are suitable for the treatment of patients with disseminated intravascular coagulation, sepsis and other intravascular events which accompany inflammation. Furthermore, compounds of the Formula (I) are suitable for the prophylaxis and treatment of patients with atherosclerosis, diabetes and the metab i d d h i l Di d f h h i (for exam umor growth and tumor metastasis, and in the inflammatory and degenerative joint diseases such as rheumatoid arthritis and arthrosis. Compounds of the Formula (I) are suitable for the retardation or prevention of such processes.
Further indications for the use of the compounds of the Formula (I) are fibrotic changes of the lungs such as chronic obstructive pulmonary disease, adult respiratory distress syndrome (ARDS) and of the eye, such as fibrin deposits after eye operations. Compounds of the Formula (1) are also suitable for the prevention and/or treatment of scar formation.
The medicaments according to the invention can be administered by oral, inhalative, rectal or transdermal administration or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Oral administration is preferred. Coating of stents with compounds of the Formula (I) and other surfaces which come into contact with blood in the body is possible.
The invention also relates to a process for the production of a medicament, which comprises bringing at least one compound of the Formula (I) into a suitable administration form using a pharmaceutically suitable and pharmaceutically acceptable carrier and optionally further suitable active substances, additives or auxiliaries.
Suitable solid or galenical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro )capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and preparations having prolonged release of active substance, in whose preparation customary excipients such as vehicles, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used. Frequently used auxiliaries whic , mannitol and o imal and plant oils such as cod liver oil. sunflower, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.
Preferably, the pharmaceutical preparations are prepared and administered in dose units, where each unit contains as active constituent a certain dose of the compound of the Formula (I) according to the invention. In the case of solid dose units such as tablets, capsules, coated tablets or suppositories, this dose can be approximately 1000 rng, but preferably approximately 50 to 300 mg and in the case of injection solutions in ampoule form approximately 300 mg, but preferably approximately 10 to 100 mg.
For the treatment of an adult patient weighing approximately 70 kg, depending on the efficacy of the compound according to Formula (I), daily doses of approximately 2 mg to 1000 mg of active substance, preferably approximately 50 mg to 500 mg, are indicated. Under certain circumstances, however, higher or lower daily doses may also be appropriate. The daily dose can be administered both by single administration in the form of an individual dose unit or else of a number of smaller dose units and by multiple administration of subdivided doses at certain intervals.
Compounds of the Formula (I) can be administered both as a monotherapy and in combination or together with all antithrombotics (anticoagulants and platelet aggregation inhibitors), thrombolytics (plasminogen activators of any type), other profibrinolytically active substances, hypotensives, blood sugar regulators,
lipid-lowering agents and antiarrhythmics.
The inhibitatory effectiveness of compounds of the present invention to the coag l i f
deter ropriate synthetic substrate.
Pharmacological examples
Determination of inhibitory activity against factor IXa
Inhibitory activity against factor IXa was tested using the substrate
SPECTROFLUOR FIXa (american diagnostica inc.; 500 West Avenue, Stamford, CT 06902 USA; Pr. No. 299F) and human factor IXa (american diagnostica inc.; Pr. No. 449b). Test substances dissolved in buffer A (50 niM α,α,α-tris (hydroxymethyl) methylamine (Tris), 100 mM NaCl, 5 mM CaCl,, 15 %(v/v) ethylene glycol, pH 8.0) were mixed with factor IXa (2.0 μg/ml final concentration). The enzyme reaction was started by addition of SPECTROFLUOR FIXa (100 μM final concentration). After incubation for 60 minutes at room temperature, the reaction was stopped by the addition of 20 %(v/v) acetic acid solution, and then measured the fluorescence value (Excitation Wavelength:355nm, Emission Wavelength;460nm) in a microtiter plate reader (ARVO 1420 Multilabel Counter; PerkinElmer).
The IC-0 was calculated from a dilution series of the test substance with the aid of the software. Symix Assay Explorer (Symyx Technologies, Inc.). All examples have IC10 of 30 μM or less. Table 5 shows the results specific results.
Table 5:
Figure imgf000439_0001
Figure imgf000440_0001
In one embodiment, the compounds of the present invention were selective factor IXa inhibitors, i.e., selective for factor IXa over other coagulation factors, such as factor Xa. Determination of inhibitory activity against factor Xa
This measuring was performed as well as Factor IXa method excluding the following conditions. As substrate and enzyme, SPECTROFLUOR FXa (american diagnostica inc.; Pr. No. 222F, 100 μM final concentration) and human factor Xa (american diagnostica inc.; Pr. No. 526, 44 ng/ml final concentration) were used respectively. Test substances dissolved in buffer B (20 mM Tris, 200 mM NaCl, 2.5 mM CaCl2, pH 8.0).
Selectivity calculation
Selectivity for Factor IXa activity over Factor Xa activity can be determined by the following calculation.: (IC50 Factor Xa) / (IC50 Factor IXa). Similar calculations can be made for selectivity of compounds for Factor IXa compared to other coagulation factors.
These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.
The present invention is not to be limited in scope by the specific
embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are with ntion in addition to those shown and described herein will become apparent to those skilled in the relevant art and are intended to fall within the scope of the appended claim.
A number of references have been cited, the entire disclosures of which have been incorporated herein in their entirety.
The compounds of the present invention may also be useful as inhibitors of additional serine protease, notably human thrombin, human plasma kallikrein and human plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, as it were "Conditions" including thromboembolic disorder (arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, thromboembolic disorders in the chambers of the heart, unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis), blood coagulation, fibrinolysis, blood pressure regulation and inflammation, and wound healing catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity of the aforementioned serine proteases, such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to p
or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents anti-platelet or platelet inhibitory agents, anti-inflammatory agents, thrombin inhibitors, thrombolytic or fibrinolytic agents, thrombin receptor (PAR-I ) antagonist, a factor Vila inhibitor, factor Villa inhibitor, a factor IXa inhibitor different from the compound of claim 1, a factor Xa inhibitor, a factor XIa inhibitor, TAFI, and fibrinogen inhibitors.
The compounds are administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" it is meant an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat (i.e. prevent, inhibit or ameliorate) the thromboembolic and/or inflammatory disease condition or treat the progression of the disease in a host.
The compounds of the invention are preferably administered alone to a mammal in a therapeutically effective amount. However, the compounds of the invention can also be administered in combination with an additional therapeutic agent, as define below, to a mammal in a therapeutically effective amount. When administered in a combination, the combination of compounds in preferably, but not necessarily, a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55, occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased anticoagulant effec individual com By "administered in combination" or "combination therapy" it is meant that the compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
Compounds which can be administered in combination with the compounds of the present invention include, but are not limited to, anticoagulants, anti-thrombin agents, anti-platelet agents, fibrinolytics, hypolipidemic agents, antihypertensive agents, and anti-ischemic agents.
Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin, heparin (either unfractionated heparin or any commercially available low molecular weight heparin, for example LOVANO), aprotinin, synthetic pentasaccharide, direct acting thrombin inhibitors including hirudin and argatroban, as well as other factor Vila inhibior, Villa inhibior, IXa inhibior, Xa inhibior, XIa inhibior, thrombin inhibior, fibrinogen inhibitors, TAFI, and known in the art. Factor IXa inhibitors different from the compounds of Formula (I) include synthetic active-site blocked competitive inhibitors, oral inhibitors and RNA aptamers. These are described in the previously cited Howard et al. reference (Howard, EL, Becker KC, Rusconi, CP, Becker RC. Factor IXa
Inhibitors as Novel Anticoagulents. Arterioscler Thromb Vase Biol. 2007; 27:
722-727.).
The term anti-platelet agents (or platelet inhibitory agents), as used herein, deno h i hibi l l f i f l b i hibi i h gregation, adhe mited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicylic acid or ASA), and piroxicam are preferred. Other suitable platelet inhibitory agents include Ilb/1Ha antagonists (e.g., tirofiban, eptifibatide, and abciximab), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors, phosphodiesterase-III (PDE-III) inhibitors (e.g., dipyridamole, cilostazol), and PDE V inhibitors (such as sildenafil), and pharmaceutically acceptable solts or prodrugs thereof.
The term anti-platelet agents (or platelet inhibitory agents), as used herein, is also intended to include ADP (adenosine diphosphate) receptor antagonists, preferable antagonists of the purinergic receptors P2Y 1 and P2Y 12 with P2Y 12 being even more preferred. Preferred P2Y12 receptor antagonists include ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrel are also preferred compounds since they are known to be gentle on the gastro-intestinal tract in use. The compounds of the present invention may also be dosed in combination with aprotinin.
The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-I and/or serotonin), endothelial cell activation, inflammatory reactions, and/or fibrin formation are disrupted. A number of thrombin inhibitors are know f kill i h d h i hibi l d b ed in comb ot limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptiders include N-acetyl and peptide derivatives of boronic acid, such as C-terminal alpha-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin.
The term "thrombin receptor antagonists", also known as protease activated receptor (PAR) antagonists or PAR-I antagonists, are useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role.
Thrombin receptor antagonist peptides have been identified based on structure-activity studies involving substitutions of amino acids on thrombin receptors. In Bematowicz et al, J. Med. Chem., vol. 39, pp. 4879-4887 (1996), tetra-and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH2 and
N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg-Nffi. Peptide thrombin receptor antagonists are also disclosed in WO 94/03479, published Feb. 17, 1994.
Substituted tricyclic thrombin receptor antagonists are disclosed in U.S. Pat.
Nos. 6,063,847, 6,326,380 and WO 01/96330 and 10/271,715.
Other thrombin receptor antagonists include those disclosed in U.S. Pat. Nos. 71304,078; 7,235,567; 7,037,920; 6,645,987; and EP Patent Nos. EP1495018 and EP 1294714 fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator (TPA, natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor Vila inhibitors, PAI-I inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), alpha-2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complexs, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator comples, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
Examples of suitable anti-arrythmic agents for use in combination with the present compounds include: Class I agents (such as propafenone); Class II agents (such as carvedilol and propranolol); Class III agents (such as sotalol, dofetilide,
aminodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); K+ cannel openers such as IAch inhibitors, and IKur inhibitors (e.g., compounds such as those disclosed in WOO 1/40231).
The term antihypertensive agents, as used herein, include: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil nifedipine, amlodipine and mybefradil); diuretics (e.g., chlorothiazide,
hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amil e (ACE) inhib ril, delapril, pentopril, quinapril, ramipril, Lisinopril); angiotensin-II-receptor antagnonists (e.g., irbestatin, Losartan, valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265); Dual ET/A11 antagonist (e.g., compounds disclosed in WO 00/01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual CCE/NEP inhibitors, e.g., omapatrilat, gemopatrilat, nitrates); and β-blockers (e.g., propranolol, nadolol, or carvedilol).
Examples of suitable cardiac glycosides for use in combination with compounds of the present invention include digitalis and ouabain.
Examples of suitable mineralocorticoid receptor antagonists for use in combination with the compounds of the present invention include spironolactone and eplirinone.
Examples of suitable cholesterol/lipid lowering agents and lipid profile therapies for use in combination with the compounds of the present invention include: HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatin, atrbastatin, simvastatin, fluvastatin, NK- 104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin)); squalene synthetase inhibitors; fibrates; bile acid sequestrants (such as questran); ACAT inhibitors; MTP inhibitors; lipooxygenase inhibitors; cholesterol absorption inhibitors; and cholesterol ester transfer protein inhibitors (e.g., CP-529414).
Examples of suitable anti-diabetic agents for use in combination with the compounds of the present invention include: biguanides (e.g., metformin); glucosidase inhibitors (e.g., acarbose); insulins (including insulin secretagogues or insulin sensitizers); meglitinides (e.g., repaglinide); sulfonylureas (e.g., glimepiride, glyburide and li i id bi id / l b id bi i ( l ) hi lidinediones (e.g. AR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein (aP2) such as those disclosed in WOOO/59506, glucagons-like peptide- 1 (GLP- 1 ), and dipeptidyl peptidase IV (DP4) inhibitors.
Examples of suitable anti-depressant agents for use in combination with the compounds of the present invention include nefazodone and sertraline.
Examples of suitable anti- inflammatory agents for use in combination with the compounds of the present invention include: prednisone; dexamethasone; enbrel;
protein tyrosine kinase (PTK) inhibitors; cyclooxygenase inhibitors (including NSAIDs, and COX-I and/or COX-2 inhibitors); aspirin; indomethacin; ibuprofen; piroxicam; naproxen; celecoxib; and/or rofecoxib.
Examples of suitable anti-osteoporosis agents for use in combination with the compounds of the present invention include alendronate and raloxifene.
Examples of suitable hormone replacement therapies for use in combination with the compounds of the present invention include estrogen (e.g., conjugated estrogens) and estradiol.
Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include orlistat and aP2 inhibirotr (such as those disclosed in WOOO/59506).
Examples of suitable anti-anxiety agents for use in combination with the compounds of the present invention include diazepam, lorazepam. buspirone, and hydroxyzine pamoate.
Examples of suitable anti-proliferative agents for use in combination with the compounds of the present invention include cyclosporine A, paclitaxel, adriamycin; epith
agents for use in combination with the compounds of the present invention include famotidine, ranitidine, and omeprazole.

Claims

What is claimed is:
1. A compound of the Formula (I)
Figure imgf000450_0001
or a pharmaceutically acceptable salt or a solvate thereof, wherein A is
Figure imgf000450_0002
Figure imgf000450_0003
Figure imgf000450_0004
Figure imgf000450_0005
Figure imgf000450_0006
Figure imgf000451_0001
Figure imgf000451_0002
Figure imgf000451_0003
Figure imgf000451_0004
Figure imgf000451_0005
Figure imgf000452_0001
Figure imgf000452_0002
Figure imgf000452_0003
Figure imgf000452_0004
Figure imgf000452_0005
Figure imgf000452_0006
Figure imgf000453_0001
Figure imgf000453_0002
Figure imgf000453_0003
Figure imgf000453_0004
Figure imgf000453_0006
Figure imgf000453_0005
Figure imgf000453_0007
Figure imgf000453_0008
Figure imgf000454_0001
Figure imgf000454_0002
Y, attached to a carbon or nitrogen ring atom, is
1 ) halogen,
2) -(q-φ-alkyl,
3) -(CrC3)-haloalkyl,
4) -(C3-C8)-cycloalkyl,
5) -OH,
6) -O-(C1-C6)-alkyl,
7) -O-(C1-C3)-haloalkyl,
8) =O (oxo),
wherein said -(C.-C,)-alkyl part of 2) and 6) of said Y is unsubstituted or substituted independently with the substituents selected from the group consisting of -(C3-C8)-cycloalkyl, -C(O)OH, and -C(O)-(C1 -C6)-alkyl,
Bis
Figure imgf000456_0001
p
Figure imgf000456_0002
Figure imgf000456_0003
provided that
Figure imgf000457_0001
Figure imgf000457_0002
Figure imgf000457_0003
and
Figure imgf000457_0004
2. A compound of the Formula (I)
Figure imgf000458_0001
or a pharmaceutically acceptable salt or a solvate thereof, wherein
A is
Figure imgf000459_0001
Figure imgf000459_0003
Figure imgf000460_0001
Figure imgf000460_0002
Figure imgf000460_0003
Figure imgf000460_0004
Figure imgf000460_0005
Figure imgf000461_0001
Figure imgf000461_0002
Figure imgf000461_0003
Figure imgf000461_0004
Figure imgf000461_0005
Figure imgf000462_0001
Figure imgf000462_0002
Figure imgf000462_0003
Figure imgf000462_0004
Figure imgf000462_0005
Figure imgf000462_0006
Figure imgf000462_0007
Figure imgf000462_0008
Figure imgf000463_0001
Figure imgf000463_0002
Bis
Figure imgf000464_0001
Figure imgf000464_0002
Figure imgf000464_0003
provided that
Figure imgf000465_0001
Figure imgf000465_0002
Figure imgf000465_0003
and
Figure imgf000465_0004
A compound of claim 1 or 2 wherein the absolute configuration of Formula (I) is
Figure imgf000465_0005
4. (2R)-2-l(2R)-4-(4-tert-butylphenyl)-3-oxomorpholin-2-yll-2-hydroxy-N-[4-(N- methylcarbamimidoyl)phenyljacetamide, (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(l-oxo-2,3- dihydroisoindol-5-yl)morpholin-2-yl]acetamide,
(2R)-2-hydτoxy-N-(l -imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-oxo-1H- quinolin-6-yl)morpholin-2-yllacetamide,
(2R)-2-r(2R)-4-[7-(difluoromethoxy)-2-oxo-1H-quinolin-6-yl]-3-oxomorpholin-2-yl]-2
-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)acetamide,
(2R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl )morpholin-2-ylJacetamide,
(2R)-N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1H- quinolin-6-yl)morpholin-2-yl]acetamide, (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-oxo- 1 H- quinolin-7-yl)morpholin-2-yl]acetamide,
(2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-( 1 -methyl-2- oxoquinolin-7-y l)-3 -oxomorpholin-2-yl] acetamide,
(2R)-2-[(2R)-4-[l -(cyclopropylmethyl)-2-oxoquinolin-7-yl]-3-oxomorpholin-2-yl]-2- hydro 2-[7-[(2R)-2-[(lR)-1-hydroxy-2-f(l-imino-2,3-dihydroisoindol-5-yl)amino]-2- oxoethyl J -3-oxomorpholin-4-y 1 ] -2-oxoquinol in- 1 -y 1] acetate, 2-[7-[(2R)-2-[( IR)-I -hydroxy-2-[(l -imino-2,3-dihydroisoindol-5-yl)amino]-2- oxoethyl]-3-oxomorpholin-4-ylj-2-oxoquinolin- 1 -yl Jacetic acid,
(2R)-2-hydroxy-N-(l -imino-2,3-dihydroisoindol-5-yI)-2-[(2R)-4-(8-methyl-2-oxo-1H- qumolin-7-yl)-3-oxomorpholin-2-yl]acetamide,
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-(2-methoxyquinolin-7
-yl)-3-oxomorpholin-2-yI]acetamide,
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-quinolin-7- ylmorpholin-2-yI]acetamide,
(2R)-N-(3-amino- 1 ,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3- oxo-4-quinolin-7-ylmorpholin-2-yllacetamide, (2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-oxo-1H- quinolin-5-yl)morphoIin-2-yl]acetamide,
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(l-oxo-3,4- dihydro-2H-isoquinolin-6-yl)morpholin-2-yl]acetamide,
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-oxo-3,4- dihyd 1 H quinoIin 7 I) orpholin 2 yl]acetamide (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-( 1 -methyl-2-oxo-3,4- dihydroquinolin-7-yl)-3-oxomorpholin-2-yl]acetamide,
(2R)-2-[(2R)-4-[l-(cyclopropylmethyl)-2-oxo-3,4-dihydroquinolin-7-yl]-3- oxomorpholin-2-yl]-2~hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)acetamide, methyl 2-[7-f(2R)-2-[( 1 R)- 1 -hydroxy-2- [( 1 -imino-2,3-dihydroisoindol-5-yl)amino] -2- oxoethyl]-3-oxomorpholin-4-yl]-2-oxo-3,4-dihydroquinolin-1-yl]acetate, 2-[7-l(2R)-2-[(lR)-l -hydroxy-2-[(l-imino-2,3-dihydroisoindol-5-yl)amino]-2-oxoethyl l-3-oxomorpholin-4-yl]-2-oxo-3,4-dihydroquinolin-1-ylJacetic acid,
(2R)-N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4- dihydro-1H-quinolin-7-yl)morpholin-2-yl]acetamide,
(2R)-N-(3-amino- 1,2-benzoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro
- 1H-quinolin-7-yl)morpholin-2-yl]acetamide,
(2R)-N-( 1 -aminoisoquinolin-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro- 1 H- quinolin-7-yl)morpholin-2-yl]acetamide,
(2R)-N-(4-aminoquinazolin-7-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro-1H- quinolin-7-yl)morpholin-2-yl]acetamide, (2R)-2-hydroxy-N-( 1 -imino-2,3-dihydroisoindol-5-yl)-2-f(2R)-3-oxo-4-(2-oxo-3,4- dihydro- 1 H-quinolin-5-yl)morpholin-2-yl]acetamide,
(2R) rpholin-2- yll-N-(l -imino-2,3-dihydroisoindol-5-yl)acetamide,
(2R)-2-hydroxy-N-(l-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-[2-(3-methoxy-3- methylbutoxy)phenyl]-3-oxomorpholin-2-yl]acetamide,
(2R)-2-hydroxy-N-(l -imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-[2-(2- oxopiperidin- 1 -y l)pheny 1 ] morpholin-2-yl ] acetamide,
(2R)-2-[(2R)-4-[2-(difluoromethoxy)-5-fluorophenyll-3-oxomorpholin-2-yl]-2-hydroxy -N-( 1 -imino-2,3-dihydroisoindol-5-y l)acetamide, methyl 2-(difluoromethoxy)-3-[(2R>2-[( IR)- 1 -hydroxy-2-[( 1 -imino-2,3-dihydro- isoindol-5~yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]benzoate, 2-(difluoromethoxy)-3-[(2R)-2-[(lR)-1-hydroxy-2-f(l -imino-2,3-dihydroisoindol-5-yl) amino]-2-oxoethyll-3-oxomorpholin-4-yl]benzoic acid,
2-(difluoromethoxy)-3-[(2R)-2-[(lR)-1-hydroxy-2-[(l-imino-2,3-dihydroisoindol-5-yl) aminoJ-2-oxoethyl]-3-oxomorpholin-4-yl]-N,N-dimethylbenzamide,
2-(difluoromethoxy)-3-[2-[( 1 -hydroxy-2-f( 1 -imino-2,3-dihydroisoindol-5-yl)amino]-2- oxoethyl]-3-oxomorpholin-4-yl]benzamide, methyl 2-[(2R)-2-[(lR)-1-hydroxy-2-[(l-imino-2,3-dihydroisoindol-5-yl)amino]-2- oxoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)benzoate,
2- [(2R) 2 [( 1 R) 1 hydroxy 2 [( 1 imino 2 3 dihydroisoindol 5 yl)amino] 2 oxoethyl] -3 -oxo 2-[(2R)-2-[(lR)-1-hydroxy-2-[( l -imino-2,3-dihydroisoindol-5-yl)aminoI-2-oxoethyl]-3 -oxomorpholin-4-ylJ-5-(trifluoromethoxy)benzamide, (2R)-N-(3 -amino- 1 ,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo- 1H-quinol in-6-yl)morpholin-2-yl]acetamide,
(2R)-N-(3-amino- 1 ,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo- 1 H-quinol in-7-yl)morpholin-2-yl]acetamide, or
(2R)-N-(3-amino- 1,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinol in-5-yl)morpholin-2-yl]acetamide,
or a pharmaceutically acceptable salt or a solvate thereof.
5. A compound of claim 1 , which is
2-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-oxomoφ holino)phenyl)acetate, (R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(3-methyl-5-(pyrrolidine- 1 -carbo nyl)phenyl)-3-oxomorpholin-2-yl)acetamide,
(R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(3-methyl-5-(pyrrolidine- 1 -carbon yl)phenyl)-3-oxomorpholin-2-yl)acetamide,
2-(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)-N-methylbenzamido)acetic acid,
2-(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino (S)- 1 -(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)- 1 -hydroxy-2-oxoethyl)-3-oxom orpholino)benzoyl)pyrrolidine-2-carboxylic acid,
1 -(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)- 1 -hydroxy-2-oxoethyl)-3-oxomoφ holino)benzoyl)pyrrolidine-2-carboxylate,
3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)- l-hydroxy-2-oxoethyl)-3-oxomorpholi no)-N-methyl-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)benzamide( 3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorpholin o)-N-methy l-N-(2-oxo-2-(pyrrol idin- 1 -y 1 )ethy l)benzamide,
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(3-methyl-5-(morpholine-4-carbo nyl)phenyl)-3-oxomorpholin-2-yl)acetamide,
(R)-2-hydroxy-N-(l -iminoisoindolin-5-yl)-2-((R)-4-(3-methyl-5-(morpholine-4-carbon yl)phenyl)-3-oxomorpholin-2-yl)acetamide,
(R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(3-((R)-3-methoxypyrrolidine- 1 -ca rbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide,
(R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(3-((S)-3-methoxypyrrolidine- 1 -ca rbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)-2-((R)-4-(3-chloro-4-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hyd roxy-N-( 1 -iminoisoindolin-5-yl)acetamide,
(R)-2-hydroxy-N-(l -iminoisoindolin-5-yl)-2-((R)-4-(3-(2-morpholino-2-oxoethyl)phen yl)-3-oxomorpholin-2-yl)acetamide,
(S)- 1 -(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-y lamino)-2-oxoethyl)-3-oxomo rpholino)benzoyl)pyrrolidine-2-carboxylic acid,
1 -(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)benzoyl)pyrrolidine-2-carboxylate,
2-(3 oxomorph olino)phenyl)acetate,
2-(3-((R)-2-((R)-1-hydroxy-2-(l-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)phenyl)acetic acid,
2-(3-((R)-2-((R)-1-hydroxy-2-(l-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)-N-methylbenzamido)acetate,
2-(3-((R)-2-((R)- 1 -hydro xy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)phenyl)-2-methylpropanoate,
(R)-2-hydroxy-N-( l -iminoisoindolin-5-yl)-2-((R)-4-(3-(morpholine-4-carbonyl)phenyl) -3-oxomorpholin-2-yl)acetamide, 3-((R)-2-((R)-1-hydroxy-2-(l-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorpholin o)-N-methyl-N-(2-morpholino-2-oxoethyl)benzamide,
(R)-2-hydroxy-N-( l-iminoisoindolin-5-yl)-2-((R)-4-(3-(2-((R)-3-methoxypyrrolidin-1- yl)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide,
(R)-2-hydroxy-N-( l-iminoisoindolin-5-yl)-2-((R)-4-(3-(2-((S)-3-methoxypyrrolidin- l- yl)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide,
2-(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)phenyl)-2-methy[propanoate,
2-(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-y lamino)-2-oxoethy l)-3-oxomorph olino)phenyl)acetate, (R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-4-(3-(4-methyl-3-oxopiperazine- 1 -ca rbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide,
2-(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)phenyl)-2-methy[propanoate,
(R)- perazin- 1 - yl)-2 (R)-2-((R)-4-(3-(2-(dimethylamino)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)-2-hydro xy-N-( 1 -iminoisoindolin-5-yl)acetamide,
1 -(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)benzoyl)piperidine-4-carboxylic acid,
1 -(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorph olino)benzoyl)piperidine-4-carboxylate,
2-(3-((R)-2-((R)-1-acetoxy-2-(l-imino-3-oxoisoindolin-5-ylamino)-2-oxoethyl)-3-oxo morpholino)-N-methylbenzamido)acetic acid, (R)-N-( 1 ,3-diiminoisoindolin-5-yl)-2-((R)-4-(3-(2-(dimethylamino)-2-oxoethyl)phenyl) -3-oxomorpholin-2-yl)-2-hydroxyacetamide,
(R)-2-( 1 -imino-3-oxoisoindolin-5-ylamino)- 1 -((R)-4-(3-(methyl(2-oxo-2-(pyrrolidin- 1 - yl)ethyl)carbamoyl)phenyl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate,
(R)-N-(3-aminobenzofd]isoxazol-6-yl)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl)p henyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide,
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-((4,4-difluoropiperidin-1-y l)methyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide),
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorpholin o)phenyl)morpholin-2-yl)acetamide, (R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(2-(difluoromethoxy)phenyl)-3-oxomo rpholin-2-yl)-2-hydroxyacetamide,
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-4-(2-isopropoxyphenyl)-3-ox omorpholin-2-yl)acetamide,
(R)- pholin-2-yl )-2- (R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-(morpholine-4-carbonyl)p henyO-S-oxomorpholin-1-yO-Z-hydroxyacetamide, (R)-N-(3-aminobenzofd]isoxazol-6-yl)-2-hydroxy-2-((R)-4-(4-methyl-3-(morpholine-4 -carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide,
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-3-oxo-4-(3-(trifluoromethoxy )phenyl)rnorpholin-2-yl)acetamide,
(R)-N-(3 -aminobenzo f d] isoxazol-6-y l)-2-hydroxy-2-((R)-3 -oxo-4-(3 -(trifluoromethy l)p henyl)morpholin-2-yl)acetamide,
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-(1,2,3,4-tetrahydroisoquin oline-2-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide,
(R)-N-(3-aminobenzord]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-(4,4-difluoropiperidine-1- carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, (R)-N-(3-aminobenzord]isoxazol-6-yl)-2-((R)-4-(3-fluoro-4-(trifluoromethyl)phenyl)-3 -oxomorpholin-2-yl)-2-hydroxyacetamide,
(R)-N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorphol ino)phenyl)morpholin-2-yl)acetamide,
(R)-2-hydroxy-N-(l-imino-7-(trifluoromethyl)isoindolin-5-yl)-2-((R)-3-oxo-4-(3-(3-ox omorpholino)phenyl)morpholin-2-yl)acetamide,
(i?)-2-Hydroxy-N-(l-iminoisoindolin-5-yl)-2-((i?)-3-oxo-4-(3-(trifluoromethoxy)phenyl )morpholin-2-yl)acetamide,
Ethyl
2-(3-((R)-2-((R)- 1 -hydroxy-2-( 1 -iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxomorpho lino)phenoxy)acetate,
(i?)-2 omorpholi n-2-y (i?)-2-((Λ)-4-(3-(Benzyloxy)phenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N-(l-iminoisoin dolin-5-yl)acetamide, (R)-N-( 1 -Aminoisoquinolin-6-yl)-2-((i?)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl) -3-oxomorpholin-2-yl)-2-hydroxyacetarnide,
N-(2,3-Dihydro-1-imino- lh-isoindol-5-yl)-4-[2-[(dimethylamino)carbonyl]phenyl]-alp ha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide,
N-(2,3-Dihydro- 1 -imino- 1 H-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo-4-[2-( 1 -pyrrolidin ylcarbonyl)phenyl]-2(R)-morpholineacetamide,
4-(2-Cyanophenyl)-N-(2,3-dihydro- 1 -imino- 1 h-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo -2(R)-morpholineacetamide,
N-(2,3-Dihydro- l-iraino-lh-isoindol-5-yl)-4-l4-fluoro-3-(4-morpholinylcarbonyl)phen yl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide, N-(2,3-Dihydro-l -imino- lh-isoindol-5-yl)-4-[4-fluoro-3-t(3(R)-methyl-4-morpholinyl) carbonyl]phenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide,
N-(2,3-Dihydro-l -imino- lh-isoindol-5-yl)-4-[4-fluoro-3-r(3(S)-methyl-4-morpholinyl) carbonyl]phenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide,
N-[4-(Aminoiminomethyl)phenyl]-4-(2-cyanophenyl)-alpha(R)-hydroxy-3-oxo-2(R)-m Orpholineacetamide,
N-(4-Amino-7-quinazolinyl)-4-[4-fluoro-3-(4-morpholinylcarbonyl)phenyl]-alpha(R)-h ydroxy-3-oxo-2(R)-morpholineacetamide,
[3-[2(R)-[2-[(3-Amino-l ,2-benzisoxazol-6-yl)amino]- l(R)-hydroxy-2-oxoethyl]-3-oxo- 4-morpholinyl]phenyl]pentafluorosulfur, [4-[2(R)-[2-[(3-Amino- l ,2-benzisoxazol-6-yl)amino]- l(R)-hydroxy-2-oxoethyl]-3-oxo- 4-m N-(3-Amino-5-fluoro-l ,2-benzisoxazol-6-yl)-4-[4-fluoro-3-(4-morpholinylcarbonyl)ph enyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide,
N-(2-Amino-6-quinazolinyl)-4-[4-fluoro-3-(4-morpholinylcarbonyl)phenyl]-alpha(R)-h ydroxy-3-oxo-2(R)-morpholineacetamide,
(R)-2-((R)-4-(5-fluoro-2-isopropoxyphenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N-(l-imi noisoindolin-5-yl)acetamide, (R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-3-oxo-4-(2-(trifluoromethyl)phenyl) morpholin-2-yl)acetamide,
(R)-2-((R)-4-(2-(difluoromethoxy)phenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N-(l-imin oisoindolin-5-yl)acetamide,
(R)-2-hydroxy-N-(l -iminoisoindolin-5-yl)-2-((R)-4-(2-isopropoxyphenyl)-3-oxomorph olin-2-yl)acetamide,
(R)-2-hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((R)-3-oxo-4-(2-(trifluoromethoxy)phenyl )morpholin-2-yl)acetamide,
N-(3-Amino-l ,2-benzisoxazol-6-yl)-4-[4-fluoro-3-[(tetrahydro-2H-pyran-4-yl)oxyJphe nyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide,
N-(3-Amino-1,2-benzisoxazol-6-yl)-4-[3-[(3,3-difluoro- l -azetidinyl)carbonyl]-4-fluoro phenyll-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide,
N-(3-Amino-1,2-benzisoxazol-6-yl)-4-[3-[(4,4-difluoro- l -piperidinyl)carbonyl]-4-fluor ophenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide, N-(3-amino- 1 ,2-benzisoxazol-6-yl)-4-[4-chloro-3-f 3-( 1 , 1 -dimethyl ethyl)- 1 ,2,4-oxadiaz ol-5-yl]phenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide,
N-(3-amino-l ,2-benzisoxazol-6-yl)-4-[2-fluoro-5-(trifluororaethyl)phenyl]-alpha(R)-hy droxy-3-oxo-2(R)-morpholineacetamide, or a pharmaceutically acceptable salt or a solvate thereof.
6. A compound of claim 1 , which is
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(3-((S)-2-methylpyrτolidme-1-car bonyl)phenyl)-3-oxomorpholin-2-yl)acetamide,
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-3-(morpholine-4-carbo nyl)phenyl)-3-oxomorpholin-2-yl)acetamide,
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-3-(pyrrolidine-1-carbo nyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)-2-((R)-4-(3-(azetidine- 1 -carbonyl)-5-fluorophenyl)-3-oxomorpholin-2-yl)-N-(4-car bamimidoyIphenyl)-2-hydroxyacetamide,
(R)-2-((R)-4-(3-(azetidine-1-carbonyl)-2-methylphenyl)-3-oxomorpholin-2-yl)-N-(4-ca rbamimidoylphenyl)-2-hydroxyacetamide,
(R)-2-((R)-4-(5-(azetidine-1-carbonyl)-2-methylphenyl)-3-oxomorpholin-2-yl)-N-(4-ca rbamimidoylphenyl)-2-hydroxyacetamide,
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-3-oxo-4-(6-(trifluoromethyl)pyridin -2-yl)morpholin-2-yl)acetamide,
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-5-(pyrrolidine-1-carbo nyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)-2 yl)-N-(4-ca rbamimidoylphenyl)-2-hydroxyacetamide,
(R)-N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-5-(morpholine-4-carbo nyl)phenyl)-3-oxomorpholin-2-yl)acetarnide,
(S)-1-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-oxom orpholino)-5-fluorobenzoyl)pyrrolidine-2-carboxylic acid, 1 -(3-((R)-2-((R)-2-(4-carbamimidoylphenylaraino)- 1 -hydroxy-2-oxoethyl)-3-oxomorp holino)-5-fluorobenzoyl)pyrrolidine-2-carboxylate,
1 -(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)- 1 -hydroxy-2-oxoethyl)-3-oxomorp holino)-5-fluorobenzoyl)pyrrolidine-2-carboxylate,
2-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-oxomoφ holino)-5-fluoro-N-methylbenzamido)acetic acid,
2-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-oxomoφ holino)-5-fluoro-N-methylbenzamido)acetate,
3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-oxomorpholi no)-N-(2-(dimethylamino)-2-oxoethyl)-5-fluoro-N-methylbenzamide, (R)-N-( 1,3-diiminoisoindolin-5-yl)-2-hydroxy-2-((R)-4-(3-(2-(4-methyl-3-oxopiperazin - 1 -yl)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide,
N-(2-(dimethylamino)-2-oxoethyl)-3-((R)-2-((R)-1-hydroxy-2-(l-iminoisoindolin-5-yla mino)-2-oxoethyl)-3-oxomorpholino)-N-methylbenzamide,
2-((S)-hydroxy((R)-3-oxo-4-p-tolylmorpholin-2-yl)methyl)-4-oxo-1,4-dihydroquinazoli ne-6-carboximidamide, l. l-dioxo-3-((S)-hydroxy((R)-3-oxo-4-p-tol(Example
ylmorpholin-2-yl)methyl)-4H-benzo[eJ[1,2,4]thiadiazine-7-carboximidamide,
(R)-N hyl)pheny l)-3-oxomorpholin-2-yl)-2-hydroxyacetamide,
(R)-N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-4-(3-(morpholine-4-carbonyl) phenyl)-3-oxomorpholin-2-yl)acetamide,
3-((R)-2-((R)-2-(4-carbamimidoyl-3-fluorophenylamino)-l -hydroxy-2-oxoethyl)-3-oxo morpholino)benzoic acid,
(R)-N-(4-carbamimidoyl-3,5-difluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomor pholino)phenyl)morpholin-2-yl)acetamide,
(R)-N-(4-carbamimidoyl-2,3-difluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomor pholino)phenyl)morpholin-2-yl)acetamide, (R)-N-(4-carbamimidoyl-2,5-difluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomor pholino)phenyl)morpholin-2-yl)acetamide,
(R)-N-(3-(aminomethyl)-4-cyano-5-(trifluoromethyl)phenyl)-2-hydroxy-2-((R)-3-oxo- 4-(3-(3-oxomorpholino)phenyl)morpholin-2-yl)acetamide,
(i?)-2-Hydroxy-N-( 1 -iminoisoindolin-5-yl)-2-((i?)-4-(2-methyl- 1 -oxoisoindolin-5-yl)-3- oxomorpholin-2-yl)acetamide,
(R)-2-Hydroxy-N-(l-iminoisoindolin-5-yl)-2-((Λ)-4-(2-methyl-3-oxoisoindolin-5-yl)-3- oxomorpholin-2-yl)acetamide hydrochloride,
(i?)-2-((Λ)-4-(2-(Cyclopropylmethyl)-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-yl)-2-hy droxy-Ν-( 1 -iminoisoindolin-5-yl)acetamide, (Λ)-N-(4-(Aminomethyl)-3-fluorophenyl)-2-hydroxy-2-((i?)-3-oxo-4-(3-(3-oxomorphol ino)phenyl)morpholin-2-yl)acetamide,
(Λ)-N-(4-Guanidinophenyl)-2-hydroxy-2-((i?)-3-oxo-4-(3-(3-oxomorpholino)phenyl)m orpholin-2-yl)acetamide,
(i?)-N yl)phenyl)- 3-ox (R)-2-(4-Carbamoylphenylaniino)- l-((Λ)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl )-3-oxomorpholin-2-yl)-2-oxoethyl acetate, (^)-2-((i?)-4-(4-Fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hyd roxy-N-( 1 ,2,3,4-tetrahydroisoquinolin-6-yl)acetamide,
(Λ)-iV-(4-(Aminomethyl)-3-fluorophenyl)-2-((i?)-4-(4-fluoro-3-(morpholine-4-carbonyl )phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide,
(R)-N-(4-((Λ)-1-Aminoethyl)phenyl)-2-((^)-4-(4-fluoro-3-(πiorpholine-4-carbonyl)phe nyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide,
(R)-N-((R)- 1 -amino-2,3-dihydro- 1 H-inden-5-yl)-2-((i?)-4-(4~fluoro-3-(morpholine-4-ca rbonyl)phenyI)-3-oxomorpholin-2-yl)-2-hydroxyacetamide,
(R)-iV-((S)- 1 -Amino-2.3-dihydro- 1H-inden-5-yl)-2-((Λ)-4-(4-fluoro-3-(morpholine-4-ca rbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, (^)-N-(2-Aminoquinolin-6-yl)-2-((Λ)-4-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)-3- oxomorpholin-2-yl)-2-hydroxyacetamide,
Ν-(7-fluoro-2,3-dihydro-1-imino-lΗ-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo-4-[3-(3-o xo-4-morpholinyl)phenyl]-2(R)-morpholineacetamide,
N-(4-chloro-2,3-dihydro- 1-imino- 1 H-isoindoI-5-yl)-alpha(R)-hydroxy-3-oxo-4-[3-(3-o xo-4-morpholinyl)phenyI]-2(R)-morpholineacetamide,
3-[2(R)-[2-f(2,3-Dihydro- 1-imino- lh-isoindol-5-yl)aminol-l(R)-hydroxy-2-oxoethylJ- 3-oxo-4-morpholinyllbenzoic acid,
Methyl
3-[2(R)-[2-[(2,3-dihydro- l-irnino-1H-isoindol-5-yl)aminol-l(R)-hydroxy-2-oxoethyl]- 3-oxo-4-morpholinylJbenzoate,
Met 2-[2(R)-[2-[ (2,3-dihydro- 1 -imino- 1 h-isoindol-5-yl)aminol- 1 (R)-hydroxy-2-oxoethyl] -3 -oxo-4-morpholinyl]benzoate,
N-(3-Amino-1,2-benzisoxazol-6-yl)-4-[4-fluoro-3-[2,2,2-trifluoro-l -(4-raorpholinyl)eth yllphenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetaraide,
(R)-2-((R)-4-(5-chloro-2-isopropoxyphenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N-(l-im inoisoindolin-5-yl)acetaraide, N-(3-Amino- 1 ,2-benzisoxazol-6-yl)-4-[3-(difluoromethoxy)-4-fluorophenyl]-alpha(R)- hydroxy-3-oxo-2(R)-morpholineacetamide, or a pharmaceutically acceptable salt or a solvate thereof.
7. A compound which is 2-((S)-hydroxy((R)-3-oxo-4-p-tolylmorpholin-2- yl)methyl)-4-oxo-l ,4- dihydroquinazoline-6-carboximidamide, or l,l-dioxo-3-((S)- hydroxy((R)-3-oxo-4-p-tolylmorpholin-2-yl)methyl)-4H-benzofeJ[1,2,4]thiadiazine-7-c arboximidamide, or a pharmaceutically acceptable salt or a solvate thereof.
8. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt or a solvate thereof and at least one pharmaceutically acceptable carrier.
9. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt or a solvate thereof and at least one pharmaceutical ingredient having other pharmacokinetics and at least one pharmaceutically acceptable carrier.
10. A method of treating a disorder or disease mediated by factor IXa, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt or a solv
1 1. The method of claim 10, wherein said disorder or disease is a thromboembolic disorder.
12. The method of claim 1 1, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart.
13. The method of claim 11, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, .ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
14. The method of claim 1 1, further comprising administering to said patient at least one anticoagulant agent selected from the group consisting of a thrombin inhibitor, a thrombin receptor (PAR-I) antagonist, a factor Vila inhibitor, factor Villa inhibitor, a factor IXa inhibitor different from the compound of claims 1-7, a factor Xa inhibitor, a factor XIa inhibitor, TAFI and fibrinogen inhibitors.
15. The method of claim 13, wherein said factor IXa inhibitor is selected from the group consisting of monoclonal antibodies, synthetic active siteblocked competitive inhibitors oral inhibitors and RNA aptamers
16. a therapeutically effective amount of at least one compound of any one of claims 1-7 or a pharmaceutically acceptable salt or a solvate thereof, and at least one
pharmaceutically acceptable carrier, and an effective amount of at least one agent selected from the group sonsisiting of : (a) anticoagulants, (b) anti-thrombin agents, (c) anti-platelet agents, (d) fibrinolytics, (e) hypolipidemic agents, (f) antihypertensive agents, and (g) anti-ischemic agents.
17. A pharmaceutical composition comprising:
a therapeutically effective amount of at least one compound of any one of claims 1 -7 or a pharmaceutically acceptable salt or a solvate thereof, and at least one
pharmaceutically acceptable carrier, and an effective amount of at least one agent selected from the group sonsisiting of(a-l) warfarin, (a-2) heparin, (a-3) aprotinin, (a-4) synthetic pentasaccharide, (a-5) direct acting thrombin inhibitors including hirudin and argatroban, (a-6) a factor Vila inhibitor, (a-7) a factor Villa inhibitor, (a-8) a factor IXa inhbitor different from the compounds of Formula (I), (a-9) a factor Xa inhibitor, (a- 10) a factor XIa inhibitor, (a-1 1) a thrombin inhibitor, (a-12) a TAFI, (a-13) a fibrinogen inhibitor, (b-1) a boroarginine derivative, (b-2) a boropeptide, (b-3) heparin, (b-4) hirudin, (b-5) argatroban, (c-1) a NSAID, (c-2) a Ilb/IIIa antagonist, (c-3) a
thromboxane-A2-receptor antagonist, (c-4) a thromboxane- A2-synthetase inhibitor, (c-5) a PDE-III inhibitor, (c-6) a PDE V inhibitor, (c-7) a ADP receptor antagonist, (c-8) an antagonist of the purinergic receptor P2Y1, (c-9) an antagonist of the purinergic receptor P2Y12, (d-1) tissue plasminogen activator (TPA, natural or recombinant) and modified forms thereof, (d-2) anistreplase, (d-3) urokinase, (d-4) streptokinase, (d-5) tenecteplase (TNK), (d-6) lanoteplase (nPA), (d-7) a factor Vila inhibitor (d 8) a PAI I inhibitor (d 9) an alpha 2 antiplasmin inhibitor (d 10) an aniso A reductase inhibitor, (e-2) a squalene synthetase inhibitor, (e-3) a fibrate, (e-4) a bile acid sequestrant, (e-5) an ACAT inhibitor, (e-6) a MTP inhibitor, (e-7) a lipooxygenase inhibitor, (e-8) a cholesterol absorption inhibitor, (e-9) a cholesterol ester transfer protein inhibitor, (f-1) an alpha adrenergic blocker, (f-2) a beta adrenergic blocker, (f-3) a calcium channel blocker, (f-4)a diuretics, (f-5) a rennin inhibitor, (f-6) an
angiotensin-converting enzyme inhibitor, (f-7) an angiotensin-ll-receptor antagnonist, (f-8) an ET receptor antagonist, (f-9) a Dual ET/AI1 antagonist, (f-10) a neutral endopeptidase inhibitors, (f- 11 ) a vasopepsidase inhibitor, (g- 1 ) a Class I agent, (g-2) a Class II agent, (g-3) a Class OI agent, a (g-4) Class IV agent, (g-5) a K+ cannel opener, (g-6) an IKur inhibitor and (g-7) a cardiac glycoside.
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