HK1206013B - Novel bicyclic pyridinones - Google Patents

Description

Novel bicyclic pyridinones

Technical Field

The present invention relates to the treatment of alzheimer's disease and other neurodegenerative and/or neurological disorders in mammals, including humans. The invention also relates to modulating the production of a- β peptides that contribute to the formation of amyloid nerve deposits in mammals, including humans. More particularly, the present invention relates to novel bicyclic pyridone compounds useful in the treatment of neurodegenerative and/or neurological disorders, such as alzheimer's disease and down's syndrome.

Background

Dementia can result from a variety of different pathological processes. The most common pathological processes that cause dementia are Alzheimer's Disease (AD), cerebral amyloid angiopathy (CM) and prion-mediated diseases (see, e.g., Haan et al, Clin. neuron. neurosurg.1990,92(4): 305-. AD affects nearly half of all people over the age of 85, the fastest growing segment of the us population. Thus, the number of us AD patients is expected to increase from about four million to about one thousand four million by year 2050.

The present invention relates to a group of gamma-secretase modulators useful in the treatment of neurodegenerative and/or neurological disorders such as alzheimer's disease and down's syndrome (see ann. rep. med. chem.2007, Olsen et al, 42: 27-47).

Disclosure of Invention

The present invention relates to gamma-secretase modulators of formula I, or a pharmaceutically acceptable salt thereof, as shown below:

wherein:

x is a 5-14 membered heteroaryl group containing 1-3 heteroatoms;

R¹is hydrogen, halogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl or C₂-C₆An alkenyl group; wherein said alkyl, cycloalkyl or alkenyl is optionally substituted with one to three substituents each independently selected from fluoro, hydroxy and C₁-C₆Substituent substitution of alkoxy;

a is C₃-C₆Cycloalkyl or 4-to 10-membered heterocycloalkyl; wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three substituents each independently selected from halogen and C₁-C₆Alkyl substituent substitution;

R^2aand R^2bIndependently at each occurrence is hydrogen, fluoro, cyano, -CF₃、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₆Cycloalkyl radical, C₄-C₈Bicycloalkyl radical, C₂-C₆Alkynyl or phenyl; wherein said alkyl, alkenyl, cycloalkyl, bicycloalkyl, alkynyl or phenyl is optionally substituted with one to three substituents each independently selected from cyano, C₁-C₃Alkyl and fluoro; or R^2aAnd R^2bTogether with the carbon to which they are bonded to form an optionally substituted one to three R⁸Substituted 3-5 membered cycloalkyl;

R³is hydrogen, halogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl, - (C (R)¹⁰)₂)_t-(C₃-C₆Cycloalkyl), - (C (R)¹⁰)₂)_t- (4-to 10-membered heterocycloalkyl), - (C (R)¹⁰)₂)_t-(C₆-C₁₀Aryl), - (C (R)¹⁰)₂)_t- (5-to 10-membered heteroaryl) or- (C (R)¹⁰)₂)_t-OR¹²(ii) a Wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one to five R¹¹Substitution;

R^4aand R^4bEach independently is hydrogen, -CF₃Or C_1-C₆Alkyl, wherein said alkyl is optionally substituted with one to three substituents each independently selected from-CF₃Cyano, and fluoro; or R^4aAnd R^4bTogether with the carbon to which they are bonded form a 3-5 membered cycloalkyl group, wherein said cycloalkyl group is optionally substituted with one to three substituents each independently selected from-CF₃Cyano, fluorine and C_1-C₆Alkyl substituent substitution;

R^5aand R^5bEach occurrence is independently hydrogen, -CF₃Or C₁-C₆An alkyl group; wherein said alkyl is optionally substituted with one to three substituents each independently selected from-CF₃Cyano, and fluoro;or R^5aAnd R^5bTogether with the carbon to which they are bonded form a 3-5 membered cycloalkyl group, wherein said cycloalkyl group is optionally substituted with one to three substituents each independently selected from-CF₃Cyano, fluorine and C_1-C₆Alkyl substituent substitution;

R⁶、R⁷and R⁸Each independently is hydrogen, -CF₃Cyano, halogen, C_1-C₆Alkyl OR-OR⁹(ii) a Provided that R is⁶And R⁷Cannot all be-OH;

R⁹is hydrogen, C_1-C₆Alkyl or-CF₃(ii) a Wherein said alkyl is optionally substituted with one to three substituents each independently selected from cyano and fluoro;

each R¹⁰Independently hydrogen, halogen, cyano, -CF₃、C_1-C₆Alkyl or-SF₅(ii) a Wherein said alkyl is optionally substituted with one to three fluoro;

each R¹¹Independently hydrogen, halogen, -CF₃、-SF₅、-Si(CH₃)₃、-OR¹²、C_1-C₆Alkyl radical, C_2-C₆Alkenyl radical, C_2-C₆Alkynyl, - (C (R)¹⁰)₂)_t-(C_3-C₆Cycloalkyl), - (C (R)¹⁰)₂)_t-(C_6-C₁₀Aryl) or- (C (R)¹⁰)₂)_t- (5-to 10-membered heteroaryl), wherein the-Si (CH)₃)₃Alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl optionally substituted with one to five substituents each independently selected from halogen and-CF₃Substituted with the substituent(s);

each R¹²Is hydrogen, C_1-C₆Alkyl, - (C (R)¹³)₂)_n-(C_3-C₆Cycloalkyl), - (C (R)¹³)₂)_n- (4-to 10-membered heterocycloalkyl), - (C (R)¹³)₂)_n-(C_6-C₁₀Aryl) or- (C (R)¹³)₂)_n- (5-to 10-membered heteroaryl); wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to five R¹⁴Substitution;

each R¹³Independently of one another is hydrogen, C_1-C₆Alkyl radical, C_2-C₆Alkenyl radical, C_2-C₆Alkynyl, halogen, cyano, -CF₃or-OCF₃；

R¹⁴Independently hydrogen, -CF₃Cyano, halogen or C_1-6An alkyl group; wherein said alkyl is optionally substituted with one to three substituents each independently selected from hydroxy, -CF₃Cyano, and fluoro; and is

Each t or n is an integer independently selected from 0,1, 2 or 3;

each z is an integer independently selected from 1 or 2;

each y is an integer independently selected from 0,1, 2,3, or 4.

The compounds of the present invention include examples 1-73 as described herein or a pharmaceutically acceptable salt thereof.

Also provided herein are compositions comprising a pharmaceutically effective amount of one or more compounds described herein and a pharmaceutically acceptable vehicle, carrier, or excipient.

The compounds of formula I are gamma-secretase modulators. Gamma-secretase enzymes play a role in the production of amyloid beta protein (a β) plaques associated with alzheimer's disease. Accordingly, the compounds of formula I are useful for treating a variety of neurodegenerative and/or neurological disorders related to a β production.

Other features and advantages of the invention will be apparent from the description and the appended claims, which describe the invention.

Detailed Description

The headings in this document are only used to speed up reader browsing. It should not be construed as limiting the invention or the claims in any way.

Definition and example

As used throughout this application (including the claims), the following terms have the meanings defined below, unless otherwise explicitly indicated. The plural and singular are to be considered interchangeable, except to indicate the number:

the term "C_1-C₆Alkyl "refers to a straight or branched chain saturated hydrocarbon substituent containing 1 to 6 carbon atoms (i.e., a substituent derived from a hydrocarbon by removal of hydrogen). Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl and hexyl.

The term "C_1-C₃Alkyl "refers to a straight or branched chain saturated hydrocarbon substituent containing 1 to 3 carbon atoms (i.e., a substituent derived from a hydrocarbon by removal of hydrogen). Examples of such substituents include methyl, ethyl and propyl (including n-propyl and isopropyl).

The term "C_2-C₆Alkenyl "refers to aliphatic hydrocarbons containing 1 to 6 carbon atoms and having at least one carbon-carbon double bond, including straight or branched chain groups having at least one carbon-carbon double bond. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl. When the compound of the present invention contains C_2-C₆When alkenyl groups, the compounds may be present as pure e (entgegen), pure z (zusammen), or any mixture thereof.

The term "C_2-C₆Alkynyl "refers to aliphatic hydrocarbons containing 2 to 6 carbon atoms and having at least one carbon-carbon triple bond, including straight or branched chain groups having at least one carbon-carbon triple bond. Representative examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term "C₃-C₆Cycloalkyl "refers to a carbocyclic substituent having 3 to 6 carbon atoms obtained by removal of hydrogen from a saturated carbocyclic ring molecule. Cycloalkyl groups may be monocyclic, typically containing from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl groups may contain one or more double or triple bonds depending on the number of carbon atoms contained in the ring (e.g., cyclohexene has one carbon-carbon double bond, or cyclohexyne (cyclohexyne) has one carbon-carbon triple bond). Alternatively, the cycloalkyl group may be bicyclic such as bicycloalkyl, e.g. C₄-C₈A bicycloalkyl group. The term "C₄-C₈Bicycloalkyl "is a bicycle containing 4 to 8 carbon atoms. Bicycloalkyl radicals may be fused together, e.g. bicyclo [1.1.0]Butane, bicyclo [2.1.0 ]]Pentane, bicyclo [2.2.0]Hexane, bicyclo [3.1.0]]Hexane, bicyclo [3.2.0 ]]Heptane and octahydropentalene (octohydropentalene). The term "bicycloalkyl" also includes bridged bicycloalkyl systems such as, but not limited to, bicyclo [2.2.1]Heptane and bicyclo [1.1.1]Pentane.

The term "C₆-C₁₀Aryl "means an aromatic substituent containing 6 to 10 carbon atoms, including one ring or two fused rings. Examples of such aryl substituents include, but are not limited to, phenyl, naphthyl, and indanyl.

The term "hydrogen" refers to a hydrogen substituent and may be represented as — H.

The term "hydroxy" refers to-OH. When used in conjunction with another term, the prefix "hydroxy" means that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents. Compounds having one or more hydroxy substituents attached to the carbon include, for example, alcohols, enols, and phenols.

The term "cyano" (also known as "nitrile") refers to-CN, which may also be denoted as

The term "halogen" refers to fluorine (which may be represented by-F), chlorine (which may be represented by-Cl), bromine (which may be represented by-Br), or iodine (which may be represented by-I). In one embodiment, the halogen is chlorine. In another embodiment, the halogen is fluorine. In another embodiment, the halogen is bromine.

The term "(C) as used herein₁-C₆) Alkoxy "means (C) as defined herein₁-C₆) The alkyl group is attached to the parent molecular moiety through an oxygen atom. Examples include, but are not limited to, methoxy, ethoxy, and n-propoxy.

The term "4-10 membered heterocycloalkyl" refers to a substituent obtained by removing hydrogen from a saturated or partially saturated ring structure containing a total of 4 to 10 ring atoms, wherein at least one of the ring atoms is a heteroatom selected from oxygen, nitrogen or sulfur. Examples of 4-10 membered heterocycloalkyl groups include, but are not limited to, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrothienyl, and tetrahydrothienyl. The heterocycloalkyl group can optionally contain 2 or 3 rings fused together, with at least one such ring containing a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur). In a group having a heterocycloalkyl substituent, the ring atom of the heterocycloalkyl substituent to which the group is bound can be the at least one heteroatom when the heteroatom is nitrogen, or it can be a ring carbon atom, where the ring carbon atom can be in the same ring as the at least one heteroatom, or where the ring carbon atom can be in a different ring from the at least one heteroatom. Similarly, if the heterocycloalkyl substituent is in turn substituted with a group or substituent, that group or substituent may be bound to the at least one heteroatom when said heteroatom is nitrogen, or it may be bound to a ring carbon atom, wherein the ring carbon atom may be in the same ring as the at least one heteroatom, or wherein the ring carbon atom may be in a different ring from the at least one heteroatom.

The term "5-14 membered heteroaryl" refers to an aromatic ring structure containing 5-14 ring atoms, wherein at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen, and sulfur. Heteroaryl groups can be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include, but are not limited to: 6-membered ring substituents such as pyridyl, pyrazolyl, pyrimidinyl and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl or 1,3, 4-oxadiazolyl and isothiazolyl; 6/5 membered fused ring substituents such as benzothienyl, isobenzothienyl, benzisoxazolyl, benzoxazolyl, purinyl and anthranoyl (anthraciliyl); and 6/6 membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1, 4-benzoxazinyl. In a heteroaryl substituent-containing group, the ring atom of the heteroaryl substituent to which the group is bound may be the at least one heteroatom when the heteroatom is nitrogen, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom, or where the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if the heteroaryl substituent is further substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom when said heteroatom is nitrogen, or it may be bound to a ring carbon atom, wherein the ring carbon atom may be in the same ring as the at least one heteroatom, or wherein the ring carbon atom may be in a different ring from the at least one heteroatom. The term "heteroaryl" also includes pyridyl N-oxides and groups containing a pyridine N-oxide ring.

If a substituent is described as "substituted," then the non-hydrogen substituent is at the position of a hydrogen substituent on a carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is one in which at least one non-hydrogen substituent is at the position of a hydrogen substituent on the alkyl substituent. To illustrate, a monofluoroalkyl is an alkyl substituted with a fluorine substituent, and a difluoroalkyl is an alkyl substituted with two fluorine substituents. It will be appreciated that if there is more than one substitution on a substituent, each non-hydrogen substituent may be the same or different (unless otherwise specified).

If a substituent is described as "optionally substituted," that substituent may be (1) unsubstituted, or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more hydrogens on that carbon (to the extent any hydrogen is present) may be replaced individually and/or together with an independently selected optional substituent. If a substituent nitrogen is described as being optionally substituted with one or more of a list of substituents, then one or more hydrogens on that nitrogen (to the extent any hydrogen is present) may each be replaced with an independently selected optional substituent.

The present specification uses the terms "substituent", "group" and "group" interchangeably.

If a substituent is described as being optionally substituted with up to the specified number of non-hydrogen substituents, then that substituent may be (1) unsubstituted; or (2) substituted with up to the specified number of non-hydrogen substituents or with up to the maximum number of substitutable positions on the substituent, whichever is smaller. Thus, for example, if a substituent is described as a heteroaryl group optionally substituted with up to 3 non-hydrogen substituents, any heteroaryl group having less than 3 substitutable positions will be optionally substituted with up to only as many non-hydrogen substituents as the heteroaryl group has substitutable positions. To illustrate, a tetrazolyl group (which has only one substitutable position) will be optionally substituted with up to one non-hydrogen substituent. To further illustrate, if an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen substituents, then the nitrogen will be optionally substituted with up to 2 non-hydrogen substituents if the amino nitrogen is a primary nitrogen, and the amino nitrogen will be optionally substituted with up to only 1 non-hydrogen substituent if the amino nitrogen is a secondary nitrogen.

If a substituent is described as "independently selected from" a group, then each substituent is selected independently of the others. Each substituent may thus be the same or different from the other substituents.

It is understood that for any one substituent (e.g., R)¹Described) may be substituted with any other substituent (e.g., R)²Description of (b) are combined so that various combinations of first substituent and second substituent are provided herein, as if each combination were specifically listed individually. For example, in one variation, R¹And R²Together provide an embodiment wherein R¹Is methyl and R²Is a halogen.

As used herein, the terms "formula I", "formula Ia", "formula Ib", and "formula Ic" may be referred to hereinafter as "compounds of the invention". Such terms are also defined to include all forms of the compounds of formulae I, Ia, Ib, and Ic, including hydrates, solvates, isomers, crystalline and non-crystalline forms, polymorphs, and metabolites thereof. For example, the compounds of formulae I, Ia, Ib, and Ic, or pharmaceutically acceptable salts thereof, can exist in unsolvated as well as solvated forms. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound, as in channel solvates (channelsolvates) and hygroscopic compounds, the water/solvent content will depend on the humidity and drying conditions. In such cases, the non-stoichiometry will become the norm.

The compounds of the invention may be present as clathrates or other complexes. Included within the scope of the present invention are complexes (e.g., clathrates), drug-host inclusion complexes, wherein the drug and host are present in stoichiometric or non-stoichiometric amounts, as opposed to the solvates described above. Also included are complexes of formulae I, Ia, Ib and Ic containing two or more organic and/or inorganic components, which may be present in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized, or non-ionized. For a review of such complexes see j.pharm.sci.,64(8),1269-1288 by Haleblian(August 1975)。

the compounds of the present invention may have asymmetric carbon atoms. The carbon-carbon bond of the compounds of the invention may be used herein as a solid lineSolid wedge shapeOr a dotted wedgeTo be depicted. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate the inclusion of a possible stereoisomer (e.g., a particular enantiomer, a racemic mixture, etc.) at that carbon atom. The use of a solid or dashed wedge to depict bonds to asymmetric carbon atoms is intended to indicate the presence of the indicated stereoisomer. When present in a racemic compound, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Racemic compounds with the relative stereochemistry so represented are labeled (+/-). For example, unless otherwise specified, it is contemplated that the compounds of the present invention may exist as stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, and conformers. The compounds of the present invention may exhibit more than one type of isomerization; and mixtures thereof (e.g., racemates and diastereomer pairs). Also included are acid addition salts or base addition salts in which the counterion is optically active, such as D-lactate or L-lysine, or racemic, such as DL-tartrate or DL-arginine.

When any racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound (true racemate) described above, in which crystals are produced in a homogeneous form containing equimolar amounts of the two enantiomers. The second type is a racemic mixture or an agglomerate, where equimolar amounts of the two forms of the crystal, each containing a single enantiomer, are produced.

The invention also includes isotopically-labelled compounds, which are identical to those recited in formulae I, Ia, Ib and Ic, but for the fact that one or more atoms are different in atomic mass or mass number from those recited in natureAtomic substitution of atomic mass or mass number is commonly found. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to²H,³H,¹³C,¹⁴C,¹⁵N,¹⁸O,¹⁷O,³²P,³⁵S,¹⁸F and³⁶and (4) Cl. Certain isotopically-labeled compounds of the present invention, for example, those into which a radioactive isotope (such as³H and¹⁴C) can be used in drug and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation)³H) And carbon-14 (i.e.¹⁴C) Isotopes are particularly preferred for their ease of preparation and detectability. In addition, heavier isotopes (such as deuterium) are employed²H) Substitutions may be made which may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and may therefore be preferred in some circumstances. Isotopically-labeled compounds of the present invention can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples and preparations below by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

The compounds of the invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, salts of the compound may be advantageous due to one or more physical properties of the salt, such as enhanced pharmaceutical stability at different temperatures and humidities, or desired water or oil solubility. In some cases, salts of compounds may also be used as an aid in the isolation, purification, and/or resolution of the compounds.

When the salt is intended for administration to a patient (as opposed to, for example, being used in vitro), the salt is preferably pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt prepared by combining a compound of formula I with an acid (the anion of which is generally considered suitable for human consumption) or a base (the cation of which is generally considered suitable for human consumption). Pharmaceutically acceptable salts are particularly useful as the products of the process of the invention because of their greater water solubility relative to the parent compound.

Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, boric acid, fluoroboric acid, phosphoric acid, metaphosphoric acid, nitric acid, carbonic acid, sulfonic acid and sulfuric acid, and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid (isothionic), lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, succinic acid, toluenesulfonic acid, tartaric acid and trifluoroacetic acid, where possible. Suitable organic acids generally include, but are not limited to, aliphatic, cycloaliphatic, aromatic, araliphatic (araliphatic), heterocyclic, carboxylic and sulfonic classes of organic acids, for example.

Specific examples of suitable organic acids include, but are not limited to, acetic acid, trifluoroacetic acid, formic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, digluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclamic acid, alginic acid (algenic acid), beta-hydroxybutyric acid, galactaric acid (galactarate), galacturonic acid, adipic acid, alginic acid, butyric acid, camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid, dodecylsulfuric acid, glucoheptanoic acid (glycoheptanedioate), glycerophosphoric acid, Heptanoic acid, hexanoic acid, nicotinic acid (nicotinate), 2-naphthalenesulfonic acid, oxalic acid, palmoate, pectic acid, 3-phenylpropionic acid, picric acid, pivalic acid, thiocyanic acid, and undecanoic acid.

Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e. sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts with suitable organic ligands, for example, quaternary ammonium salts. In another embodiment, the base salt is formed from a base that forms non-toxic salts, including aluminum, arginine, benzathine (benzathine), choline, diethylamine, diethanolamine, glycinate, lysine, meglumine, ethanolamine, tromethamine salts, and zinc salts.

The organic salts may be prepared from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Basic nitrogen-containing groups can be quaternary bases using agents such as: lower alkyl (C)₁-C₆) Halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (i.e., decyl, dodecyl, tetradecyl, and octadecyl chlorides, bromides, and iodides), arylalkyl halides (i.e., benzyl and phenethyl bromides), and others.

In one embodiment, hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed.

Typically, the compounds of the invention are administered in an amount effective to treat the conditions as described herein. The compounds of the invention are administered by any suitable route, in the form of pharmaceutical compositions adapted to such route, and in dosages that are effective for the intended treatment. The therapeutically effective dose of the compound required to treat the progression of a medical condition is readily determined by one of ordinary skill in the art using preclinical and clinical methods well known in the medical arts. The term "therapeutically effective amount" as used herein refers to an amount of a compound administered that will alleviate one or more symptoms of the disorder being treated to some extent.

As used herein, the term "treating," unless otherwise indicated, means reversing, slowing, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. As used herein, the term "treatment", unless otherwise indicated, refers to the act of treating, and the verb "treat" is defined as above. The term "treatment" also includes both adjuvant and neoadjuvant treatment of a subject.

Compound (I)

To further illustrate the compounds of the present invention, the following subgenera are described below.

Formula Ia depicted below is a subgroup of formula I as depicted, wherein z is 1, and R^5a,R^5b,R⁶And R⁷Each is hydrogen. In formula Ia, X is a 5-membered heteroaryl selected from imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl or pyridyl; r¹Selected from hydrogen, halogen or C₁-C₃An alkyl group; y is 0 or 1; r^2aAnd R^2bEach independently is hydrogen or C₁-C₃An alkyl group; r^4aAnd R^4bEach independently is hydrogen or C₁-C₃An alkyl group; a is C selected from cyclobutyl, cyclopentyl or cyclohexyl₃-C₆Cycloalkyl, or A is a 5-6 membered heterocycloalkyl selected from tetrahydrofuranyl, tetrahydropyranyl or dihydroisoxazolyl, wherein said cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or dihydroisoxazolyl is optionally substituted with one to three substituents each independently selected from halogen or C₁-C₃Alkyl substituent substitution; and R is³Is- (C (R)¹⁰)₂)_t-(C₆-C₁₀Aryl), - (C (R)¹⁰)₂)_t- (5-to 10-membered heteroaryl) or- (C (R)¹⁰)₂)_t-OR¹²(ii) a Wherein said aryl is optionally substituted with one to five substituents each independently selected from the group consisting of fluorine, chlorine, -CF₃,-SF₅,-OCF₃,-OCHF₂,-OCH₃,-CF₂CF₃,-CF₂CH₃Substituted with the substituent(s); each R¹²Independently is C_6-C₁₀Aryl or 5-10 membered heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one to five fluoro, chloro, CF₃Methyl or isopropyl; and t is 0 or 1.

In certain embodiments of the invention, in formula Ia as depicted above, x is imidazolyl; r¹Is methyl; y is 0; r^2aAnd R^2bEach independently is hydrogen; r^4aAnd R^4bEach independently is hydrogen; a is cyclobutyl; and R is³Is (6, 7-difluoronaphthalen-1-yl) oxy.

In certain embodiments of the invention, in formula Ia as depicted above, x is imidazolyl; r¹Is methyl; y is 1; r^2aAnd R^2bOne is hydrogen and the other is methyl; r^4aAnd R^4bEach independently is hydrogen; a is tetrahydrofuranyl; and R is³Is 5-trifluoromethylthiophen-2-yl.

Formula Ib, depicted below, is a subgroup of formula I as depicted, wherein x is imidazolyl, R³Is phenyl, z is 1, and R^5a,R^5b,R⁶And R⁷Each is hydrogen. In formula Ib, R is as depicted below¹Selected from hydrogen, halogen or C₁-C₃An alkyl group; y is 0 or 1; r^2aAnd R^2bIndependently is hydrogen or C₁-C₃An alkyl group; r^4aAnd R^4bEach independently is hydrogen or C₁-C₃An alkyl group; a is C selected from cyclopentyl or cyclohexyl₃-C₆Cycloalkyl, or A is a 5-6 membered heterocycloalkyl selected from tetrahydrofuranyl, tetrahydropyranyl or dihydroisoxazolyl, wherein said cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or dihydroisoxazolyl is optionally substituted with one to three substituents each independently selected from halogen or C₁-C₃Alkyl substituent substitution; m is 1,2 or 3; and each R¹¹Independently selected from hydrogen, fluorine, chlorine, -CF₃,-SF₅,-OCF₃,-OCHF₂,-OCH₃,-CF₂CF₃,-CF₂CH₃Or a cyclopropyl group.

In certain embodiments of the invention, in formula Ib as depicted above, R¹Is methyl; y is 1; r^2aAnd R^2bIndependently is hydrogen; r^4aAnd R^4bEach independently is hydrogen; a is tetrahydropyranyl; m is 1; and R is¹¹Is CF₃. In certain embodiments, CF₃The substituent is attached to the benzene ring at the para position.

In certain embodiments of the invention, in formula Ib as depicted above, R¹Is methyl; y is 1; r^2aAnd R^2bIndependently is hydrogen; r^4aAnd R^4bEach independently is hydrogen; a is cyclohexyl; m is 1 and R¹¹Is chlorine. In certain embodiments, the chlorine substituent is attached to the phenyl ring at the para position.

Formula Ic, depicted below, is a subgroup of formula I as depicted, wherein x is imidazolyl, R³Is phenyl, A is tetrahydrofuranyl, z is 1, and R^5a,R^5b,R⁶And R⁷Each independently hydrogen. In formula Ic, R is depicted below¹Selected from hydrogen, halogen or C₁-C₃An alkyl group; r^2aAnd R^2bIndependently hydrogen or methyl; r^4aAnd R^4bEach independently is hydrogen or C₁-C₃An alkyl group; the tetrahydrofuranyl moiety is optionally substituted with one to three substituents each independently selected from halogen or C₁-C₃Alkyl substituent substitution; and R is¹¹Selected from hydrogen, fluorine, chlorine, -CF₃,-SF₅,-OCF₃,-OCHF₂,-OCH₃,-CF₂CF₃,-CF₂CH₃Or a cyclopropyl group.

In some of the present inventionIn embodiments, in formula Ic as depicted above, R¹Is methyl; r^2aAnd R^2bAre all hydrogen; r^4aAnd R^4bOne is hydrogen and the other is methyl; and R is¹¹is-CF₃. In certain embodiments, -CF on the phenyl ring₃The substituents are attached in the para position.

In certain embodiments of the invention, in formula Ic as depicted above, R is¹Is methyl; r^2aAnd R^2bAre all hydrogen; r^4aAnd R^4bAre all hydrogen; the tetrahydrofuranyl moiety is substituted with a single fluoro or methyl substituent; and R is¹¹is-CF₃. In certain embodiments, -CF on the phenyl ring₃The substituents are attached in the para position.

In certain embodiments of the invention, in formula Ic as depicted above, R is¹Is methyl; r^2aAnd R^2bAre all hydrogen; r^4aAnd R^4bAre all hydrogen; and R is¹¹Is fluorine, chlorine, -CF₃,-SF₅or-OCH₃。

In certain embodiments of the invention, in formula Ic as depicted above, R is¹Is methyl; r^2aAnd R^2bOne is hydrogen and the other is methyl; r²Is hydrogen; r^4aAnd R^4bAre all hydrogen; and R is¹¹Is fluorine, chlorine, -CF₃,-OCF₃,-OCHF₂or-OCH₃。

Formula Id, depicted below, is a subgroup of formula I as depicted, wherein x is imidazolyl, A is tetrahydrofuranyl, z is 1, and R is^5a,R^5b,R⁶And R⁷Each independently hydrogen. In the formula Id depicted below, R²Is hydrogen or methyl; r³Is C₆-C₁₀Aryl or 5-6 membered heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one to three R¹¹Substituted, wherein each R¹¹Independently selected from fluorine, chlorine, -CF₃,-SF₅,-OCH₃,-OCF₃and-OCHF₂。

In certain embodiments of formula Id as depicted above, R³Is optionally substituted with one to three substituents independently selected from fluorine, chlorine, -CF₃,-SF₅,-OCH₃,-OCF₃and-OCHF₂R of (A) to (B)¹¹Phenyl substituted with a substituent.

In certain embodiments of formula Id as depicted above, R³Is optionally substituted with one to three substituents independently selected from fluorine, chlorine, -CF₃,-SF₅,-OCH₃,-OCF₃and-OCHF₂R of (A) to (B)¹¹Thienyl substituted with a substituent.

Pharmacology of

Alzheimer's Disease (AD) studies have shown that the disease is associated with the accumulation of plaques of variable shape and size in the brain. The major plaques associated with AD are amyloid beta protein (a β). A β is produced when Amyloid Precursor Protein (APP) undergoes continuous proteolysis by β -and γ -secretases (Haas, et al, "Trafficking and proteolytic processing of APP," Cold Spring Harbor Perspect Med., 2011). Gamma-Secretase is a large complex of four different integral proteins, one of which was identified as a catalytic component containing unusual membrane-embedded components (De Strooper, Bart, et al, "Presenilins and Gamma-Secretase: Structure, Function, and Role in Alzheimer's disease" Cold spring Harb Perspectrum Med 2012; 2: a 006304). The catalytic component known as presenilins was first discovered as the site responsible for missense mutations in early-onset Alzheimer's Disease (AD). The encoded multichannel membrane proteins were subsequently found to be the catalytic component of γ -secretase, with the membrane-embedded aspartyl protease complex responsible for the production of the carboxy-terminus of amyloid b-protein (a β) from amyloid precursor (APP) (De Strooper, Bart, et al, 2012). Accordingly, targeting gamma-secretase proteins as potential targets for drug discovery in the treatment of alzheimer's disease has been the major focus of alzheimer's disease research.

The compounds of the invention are gamma-secretase modulators and are useful in the treatment of central nervous system disorders or diseases identified as having enhanced gamma secretase activity, such as niemann pick disease type C; neurological disorders (such as migraine; epilepsy; Alzheimer's disease; Parkinson's disease; brain injury; stroke; cerebrovascular diseases (including cerebral arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage and cerebral hypoxia-ischemia), cognitive disorders (including amnesia, senile dementia, HIV-related dementia, Alzheimer's disease, Huntington's disease, Lewy body dementia, vascular dementia, drug-related dementia, tardive dyskinesia, myoclonus, dystonia, delirium, pick's disease, Creutzfeldt-Jakob disease, HIV disease, Tourette syndrome, epilepsy, myospasm and disorders associated with myotonia or weakness including tremor and mild cognitive disorders), intellectual impairment (including ankylosis, Down's syndrome and fragile x syndrome), sleep disorders (including hypersomnia, circadian rhythm sleep disorders, Parkinson's disease, cerebral ischemia, stroke, cerebral vascular dementia, cerebral ischemia, Insomnia, abnormal sleep and sleep deprivation) and psychiatric disorders such as anxiety (including acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, agoraphobia, and obsessive compulsive disorder); artificial disorders (including acute hallucinogenic mania); impulse control disorders (including compulsive gambling and intermittent mania); mood disorders (including bipolar I disorder, bipolar II disorder, mania, mixed affective state, major depression, chronic depression, seasonal depression, psychotic depression, seasonal depression, premenstrual syndrome (PMS), Premenstrual Dysphoric Disorder (PDD), and postpartum depression); psychogenic motor disease; psychotic disorders (including schizophrenia, schizoaffective disorder, schizophreniform disorder and delusional disorder); drug dependence (including narcotic dependence, alcoholism, amphetamine dependence, cocaine addiction, nicotine dependence, and drug withdrawal syndrome); eating disorders (including anorexia, bulimia, binge eating, hyperphagia, obesity, compulsive eating, and binge eating); sexual dysfunction, urinary incontinence; neuronal damage disorders (including eye injury, retinopathy or macular degeneration of the eye, tinnitus, hearing disorders and loss, and cerebral edema) and childhood psychiatric disorders (including attention deficit disorder, attention deficit hyperactivity disorder, behavioral disorders, and autism) comprising administering to the mammal a therapeutically effective amount of a compound of formula I, formula Ia, formula Ib, and formula Ic, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compounds of the present invention are useful for treating neurological disorders (such as migraine, epilepsy, alzheimer's disease, parkinson's disease, niemann pick disease type C, brain injury, stroke, cerebrovascular disease, cognitive disorders, sleep disorders) or psychiatric disorders (such as anxiety, human disorders, impulse control disorders, mood disorders, psychomotor disorders, psychiatric disorders, drug dependence, eating disorders, and childhood mental disorders) in a mammal (preferably a human) comprising administering to the mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

The compounds of the invention are also useful for improving memory (both short term and long term) and learning.

The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington D.C.) fourth edition text revision provides a Diagnostic tool to identify many of the Disorders described herein. Those skilled in the art will recognize that there are alternative nomenclatures, nosologies, and taxonomies for the disorders described herein, including those described in DMS-IV, and that the terms and taxonomies evolve with medical progress.

Preparation

The compounds of the invention may be administered orally. Oral administration may involve swallowing, thereby allowing the compound to enter the gastrointestinal tract, or buccal or sublingual administration may be employed, whereby the compound enters the blood stream directly from the oral cavity.

In another embodiment, the compounds of the invention may also be administered directly into the bloodstream, into muscles or into internal organs. Suitable parenteral administration means include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable parenteral administration devices include needle (including microneedle) syringes, needle-free syringes, and infusion techniques.

In another embodiment, the compounds of the present invention may also be administered topically to the skin or mucosa, i.e., dermally or transdermally. In another embodiment, the compounds of the invention may also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention may be administered rectally or vaginally. In another embodiment, the compounds of the invention may also be administered directly to the eye or ear.

The dosage regimen of the compound and/or the composition containing the compound is based on a variety of factors including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound used. Thus, the dosage regimen may vary widely. Dosage levels on the order of about 0.01mg to about 100mg/kg body weight/day may be useful in the treatment of the above-mentioned conditions. In one embodiment, the total daily dose of the compounds of the invention (administered as a single dose or in divided doses) is typically from about 0.01 to about 100 mg/kg. In another embodiment, the total daily dose of a compound of the invention is from about 0.1 to about 50mg/kg, and in another embodiment, from about 0.5 to about 30mg/kg (i.e., mg of a compound of the invention per kg of body weight). In one embodiment, the dose administered is from 0.01 to 10 mg/kg/day. In another embodiment, the dose administered is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions may contain these amounts or submultiples thereof to make up the daily dose. In many cases, administration of the compound will be repeated multiple times (usually no more than 4 times) throughout the day. Multiple daily doses are generally used to increase the total daily dose, if desired.

For oral administration, the compositions may be provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500mg of the active ingredient, to provide symptomatic dose adjustment to the patient. The medicament typically contains from about 0.01mg to about 500mg of the active ingredient, or in another embodiment, from about 1mg to about 100mg of the active ingredient. For intravenous administration, the dosage may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.

Suitable subjects according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodent, lagomorph, primate, and the like and include mammals in utero. In one embodiment, a human is a suitable subject. The human subject may be of either gender and may be at any stage of development.

In another embodiment, the invention includes the use of one or more compounds of the invention for the manufacture of a medicament for the treatment of the conditions described herein.

For the treatment of the conditions described above, the compounds of the invention may be administered as the compound itself. Or alternatively, a pharmaceutically acceptable salt is suitable for medical use due to its greater water solubility relative to the parent compound.

In another embodiment, the invention encompasses pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the invention presented with a pharmaceutically acceptable carrier. The carrier may be a solid, a liquid, or both, and may be formulated with the compound as a unit dosage composition, e.g., a tablet, which may contain from 0.05% to 95% by weight of the active compound. The compounds of the invention may be coupled to suitable polymers as targetable drug carriers. Other pharmacologically active substances may also be present.

The compounds of the invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such route and in a dose effective for the intended treatment. The active compounds and compositions may be administered, for example, orally, rectally, parenterally or topically.

Oral administration of solid dosage forms may be presented, for example, as discrete units such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention. In another embodiment, oral administration may be in powder or granular form. In another embodiment, the oral dosage form is sublingual, such as a lozenge. In such solid dosage forms, the compounds of formula I are typically combined with one or more adjuvants. Such capsules or tablets may contain a controlled release formulation. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents or may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art (i.e., water). Such compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweetening agents), and/or perfuming agents.

In another embodiment, the invention encompasses parenteral dosage forms. "parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing, wetting and/or suspending agents.

In another embodiment, the present invention includes a topical dosage form. "topical administration" includes, for example, transdermal administration (such as via a transdermal patch or iontophoresis device), intraocular administration, or intranasal or inhalational administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of the present invention are administered by transdermal means, administration may be accomplished using a reservoir (reservoir) and a patch of the porous membrane type or a patch of the solid matrix type. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated-see for example Finnin and Morgan, J.Pharm.Sci., 88(10), 955-958 (1999).

Formulations suitable for topical administration to the eye include, for example, eye drops wherein a compound of the invention is dissolved or suspended in a suitable carrier. A typical formulation suitable for ocular or otic administration may be in the form of drops of a micronized suspension or solution in isotonic, pH adjusted sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and particulate or vesicular systems such as vesicles or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers (e.g., hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose), or heteropolysaccharide polymers (e.g., agarose gel) may be blended with preservatives such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container which is squeezed or pumped by the patient, or as an aerosol spray from a pressurised container or spray device using a suitable propellant. Formulations suitable for intranasal administration are generally administered from dry powder inhalers (alone; as a mixture, e.g. in dry blend with lactose; or as particles of a mixing component, e.g. in admixture with a phospholipid such as phosphatidylcholine) or as aerosol sprays from pressurised containers, pumps, nebulisers (preferably nebulisers which utilise electro-hydrodynamic generation of a fine mist) or nebulisers, with or without the use of a suitable propellant, such as 1,1, 1, 2-tetrafluoroethane or 1,1, 1,2, 3,3, 3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive, such as chitosan or cyclodextrin.

In another embodiment, the invention encompasses rectal dosage forms. Such rectal dosage forms may be in the form of, for example, suppositories. Cocoa butter is a traditional suppository base, but a variety of alternatives may be suitably used.

Other carrier materials and modes of administration known in the pharmaceutical art may also be employed. The pharmaceutical compositions of the invention may be prepared by any of the well-known techniques in pharmacy such as efficient formulation and administration procedures. The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard texts. The formulation of drugs is described, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; liberman et al eds, Pharmaceutical Dosage Forms, marcedecker, New York, n.y., 1980; and Kibbe et al, eds., Handbook of pharmaceutical excipients (3)^rdEd.), discussed in American Pharmaceutical Association, Washington, 1999.

The compounds of the present invention may be used alone or in combination with other therapeutic agents to treat a variety of conditions or disease states. The compound of the invention and the other therapeutic agent may be administered simultaneously (in the same dosage form or in separate dosage forms) or sequentially. An exemplary therapeutic agent can be, for example, a metabotropic glutamate receptor agonist.

By "co-administered" two or more compounds is meant that the two compounds are administered close enough in time that the presence of one compound affects the biological effect of the other. Two or more compounds may be administered simultaneously, concurrently or sequentially. In addition, simultaneous administration can be carried out by mixing the compounds prior to administration, or by at the same time point but at different anatomical sites or using different routes of administration.

The phrases "concurrently administering," "co-administering," "simultaneously administering," and "simultaneously administering" refer to the compounds being administered in combination.

The present invention includes the use of a gamma-secretase modulator compound as provided in formula I in combination with one or more additional pharmaceutically active agents. If a combination of active agents is used, they may be administered sequentially or simultaneously, in separate dosage forms or combined in a single dosage form. Accordingly, the present invention also includes a pharmaceutical composition comprising an amount of (a) a first agent comprising a compound of formula I or a pharmaceutically acceptable salt of the compound; (b) a second pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier, vehicle or diluent.

Depending on the disease, disorder or condition to be treated, a variety of pharmaceutically active agents may be selected for use in combination with the compounds of formula I. Pharmaceutically active agents that may be used in combination with the compositions of the present invention include, but are not limited to:

(i) acetylcholinesterase inhibitors such as donepezil hydrochloride (ARICEPT, MEMAC), physostigmine salicylate (ANTILIRIUM), physostigmine sulfate (ESERINE), metribuzin, neostigmine, dostigmine, bistein (MESTINON), amberlite (MYTELASE), demacaranium, Debio9902 (also known as ZT-1; Debiopharm), rivastigmine (EXELON), ladostigil (ladostigil), NP-0361, galantamine hydrobromide (RAZADYNE, RIMINYL, VANILIN), tacrine (COGNEX), tolserine, dactinoid, memoquin, huperzine A (HUP-A; NeuroHitech), phenyalanine, tenulone (ENILLON, TENSON), and INM-176;

(ii) amyloid- β (or fragments thereof), such as A β conjugated to a pan HLA DR-binding epitope (PADRE)_1-15ACC-001(Elan/Wyeth), ACI-01, ACI-24, AN-1792, Affiniope AD-01, CAD106 and V-950;

(iii) antibodies to amyloid-beta (or fragments thereof), such as ponezumab, desmorezumab (solarezumab), Bapineuzumab (Bapineuzumab) (also known as AAB-001), AAB-002(Wyeth/Elan), ACI-01-Ab7, BAN-2401, intravenous ig (gammagard), LY2062430 (humanized m 266; Lilly), R-1450(Roche), ACU-5a5, huC091, and those disclosed in international patent publications WO04/032868, WO05/025616, WO06/036291, WO06/069081, WO06/118959, US patent publications US2003/0073655, US2004/0192898, US2005/0048049, US2005/0019328, european patent publications EP0994728 and 1257584 and US 5,750,349;

(iv) amyloid reducing or inhibiting agents (including those that reduce amyloid production, accumulation and fibrillar shape), such as dimopone (dimebon), davunetide (davunetide), eprodil (epiodiate), leuprorelin, SK-PC-B70M, celecoxib, lovastatin, anapsos, oxiracetam, pramitan, valneman, nicergoline, colostrin, bisorcymperiod (also known as BNC), 5-15(Humanetics), E-2012(Eisai), pioglitazone, clioquinol (also known as PBT1), PBT2(Prana Biotechnology), flurbiprofen (pro, FROBEN) and its R-enantiomer talflurbipel (tarenflurbipil) (flurbiprofen), nitroflurbiprofen, fenoprofen (fenolnfen), ibuprofen (pro, naln), ibuprofen (trin, sodium chloride), ibuprofen (sodium chloride, ibuprofen (sodium chloride), ibuprofen (sodium chloride, sodium chloride, Diclofenac potassium, sulindac (CLINORIL), sulindac sulfide (sulindac sulfate), diflunisal (DOLOBID), naproxen (NAPOLOSYN), naproxen sodium (ANAPROX, ALEVE), ARC031(Archer Pharmaceuticals), CAD-106(Cytos), LY450139(Lilly), insulin degrading enzyme (also known as insulinolytic enzyme), gingko biloba extract EGb-761(ROKAN, TEBONIN), homotaurine (tramiprosate, JNREBRIL, ALZHEMD), iselodiligen (FIBRILEX, KIACTA), compound W (3, 5-bis (4-nitrophenoxy) benzoic acid), NGX-96992, neprilysin (also known as Neutral Endopeptidase (NEP)), inositol (also known as scyllo-inositol), atorvastatin (CORZO), Evone (VFF) (SKEEF) (VFF-3, SKEEF) (SKEEF-3683, KLASP), AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, E2609 and TTP-854; gamma-secretase modulators such as ELND-007; and RAGE (receptor for advanced glycation end products) inhibitors such as TTP488(Transtech) and TTP4000(Transtech), as well as those disclosed in us patent 7,285,293, including PTI-777;

(v) alpha-adrenergic receptor agonists such as guanfacine (INTUNIV, TENEX), Clonidine (CATEPRS), metahydroxylamine (ARAMINE), methyldopa (ALDOMET, DOPAMET, NOVOMEDOPA), tizanidine (ZANAFLEX), phenylephrine (also known as phenylephrine), methoxyamine, cilazazoline, guanfacine (INTUNIV), lofexidine, xylazine, modafinil (PROVIGIL), efenil and armodafinil (NUVIGIL);

(vi) beta-adrenergic receptor blockers (beta blockers), such as carteolol, esmolol (breviboc), labetalol (norodyne, TRANDATE), oxprenolol (LARACOR, TRASACOR), pindolol (VISKEN), propranolol (INDERAL), sotalol (BETAPACE, sotalox, SOTACOR), timolol (BLOCADREN, timoteic), acebutolol (SECTRAL, PRENT), nadolol (CORGARD), metoprolol tartrate (lossor), metoprolol succinate (topol-XL), atenolol (TENORMIN), butoxylamine, and SR59230A (Sanofi);

(vii) anticholinergics such as amitriptyline (ELAVIL, ENDEP), butiline, benzalkonium mesylate (COGENTIN), diphenhydramine (artiane), diphenhydramine (BENADRYL), oxyphennarwedine (NORFLEX), hyoscyamine, Atropine (ATROPEN), scopolamine (TRANSDERM-SCOP), scopolamine methylbromide (paramine), bicycloprolin (BENTYL, cyclomine, dibert, diamomine), tolterodine (rol), oxybutynin (DITROPAN, lyrinxl, OXYTROL), pentiazamide, propantheline (PRO-BANTHINE), benethazine, imipramine hydrochloride (tonil), imipramine maleate (surimil), lofepramine (rponin), doxylamine (suppl), and thiamethoxam (nurazine) and hydramine (nurolol);

(viii) anticonvulsants such as carbamazepine (TEGRETOL, carbyrol), oxcarbazepine (TRILEPTAL), phenytoin sodium (PHENYTEK), phenytoin (CEREBYX, PRODILANTIN), divalproex sodium (DEPAKOTE), gabapentin (nerontin), pregabalin (LYRICA), Topiramate (TOPAMAX), valproic acid (DEPAKENE), sodium valproate (depalon), 1-benzyl-5-bromouracil, pregabab, benzylchloropropanamide, zonisamide (TRERIEF, EXCEGRAN), CP-465022, retigabine, tarampanel, and primidone (mysolae);

(ix) antipsychotics, such as lurasidone (LATUDA, also known as SM-13496; Dainippon Sumitomo), Aripiprazole (ABILIFY), chlorpromazine (THORAZINE), Haloperidol (HALDOL), iloperidone (FANAPTA), thiothixene decanoate (DEPIXOL, FLUANXOL), reserpine (SERPLAN), piperacillin (ORAP), fluphenazine decanoate, fluphenazine hydrochloride, prochlorperazine (COMPRO), asenapine (SAPHRIS), Loxapine (LOXITANE), Molindone (MOBAN), perphenazine, methidazine, thioridazine, trifluoperazine (STELAZINE), ramelteon, Clozapine (CLOZARIL), desmethylclozapine (ACP-104), risperidone (RISPERDAL), paliperidone (INVAGA), melphalan, olanzapine (Zhia), quetiapine (LOBENTIAN), thioprine (LOADE), ketoprofen (GEAPEN), and ketoprofen (GEL ), L-103);

(x) Calcium channel blockers such as lomerizine, ziconotide, nilvadipine (ESCOR, NIVADIL), diperdipine, amlodipine (norvascc, ISTIN, AMLODIN), felodipine (plenidil), nicardipine (CARDENE), nifedipine (adalate, procadia), MEM1003 and its parent compound Nimodipine (NIMOTOP), nisoldipine (SULAR), nitrendipine, lacidipine (larcipil, MOTENS), lercanidipine (zanipip), lifarizine, diltiazem (dicarm), verapamil (an, VERELAN), cal-R18565 (AstraZeneca) and enecapin (enecapin);

(xi) Catechol O-methyltransferase enzyme (COMT) inhibitors such as nitecapone, Tolcapone (TASMAR), entacapone (COMTAN) and tropolone;

(xii) Central nervous system stimulants such as atomoxetine, reboxetine, yohimbine, caffeine, phenmetrazine, phendimetrazine, pimoline, fencanfamine (gluconergan, REACTIVAN), phendimethine (captain), Methylphenidate (MERETRAN), danol (also known as dimethylaminoethanol), methylphenidate (DAYTRANA), methylphenidate hydrochloride (RITALIN), dexmethylphenidate (FOCALIN), amphetamine (alone or in combination with other CNS stimulants such as ADDERALL (amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate and dextroamphetamine sulfate), dextroamphetamine sulfate (DEXEDRINE, dexrostratostat), methamine tosylamine (DESOXYN), amphetamine (vvansee) and benzphemine (diex);

(xiii) Corticosteroids such as prednisone (STERAPRED, DELTASONE), Prednisolone (PRELONE), prednisolone acetate (OMNIPRED, PRED mld, PRED FORTE), prednisolone sodium phosphate (ORAPREDODT), Methylprednisolone (MEDROL), methylprednisolone acetate (DEPO-MEDROL), and methylprednisolone sodium succinate (a-METHAPRED, SOLU-MEDROL);

(xiv) Dopamine receptor agonists such as Apomorphine (APOKYN), bromocriptine (PARLODEL), cabergoline (dosteine), Dihydrexidine, dihydroergocriptine, fenoldopam (coropam), lisuride (DOPERGIN), terguride, pergolide (pergolide, PERMAX), piribedil (TRIVASTAL, TRASTAL), pramipexole (MIRAPEX), quinpirole, Ropinirole (REQUIP), rotigotine (neuprodo), SKF-82958(GlaxoSmithKline), carisopiperazine (cariprazine), papuono, and soriztan;

(xv) Dopamine receptor antagonists such as chloroppramumazine, fluphenazine, haloperidol, loxapine, risperidone, thiamethoxam, thiothixene, trifluoperazine, tetrabenazine (NITOMAN, xene), 7-hydroxyamoxapine, droperidol (inadsine, DRIDOL, dropletin), domperidone (MOTILIUM), L-741742, L-745870, lorapride, SB-277011A, SCH-23390, ecopipam, SKF-83566, and metoclopramide (regan);

(xvi) Dopamine reuptake inhibitors such as bupropion, safinamide, nomifensine Maleate (MERITAL), vanoxerine (also known as GBR-12909) and its decanoate DBL-583 and amiheptanoic acid;

(xvii) Gamma-aminobutyric acid (GABA) receptor agonists such as baclofen (LIORESAL, KEMSTRO), siclofen, pentobarbital (NEMBUTAL), proparabine (GABRENE), and clomeprazole;

(xviii) Histamine 3(H3) antagonists, such as ciprofloxacin, ticarcinol (tiprolisant), S-38093, irdabisant, ticarcinol (pitolisant), GSK-239512, GSK-207040, JNJ-5207852, JNJ-17216498, HPP-404, SAR-110894, trans-3-fluoro-3- (3-fluoro-4-pyrrolidin-1-ylmethyl-phenyl) -cyclobutanecarboxylic acid acetamide (PF-3654746 and those disclosed in US patent publication US2005-0043354, US2005-0267095, US2005-0256135, US2008-0096955, US2007-1079175 and US 2008-0176925; International patent publication WO2006/136924, WO2007/063385, WO2007/069053, WO2007/088450, WO2007/099423, WO2007/105053, WO2007/138431 and WO 2007/088462; and US patent 7,115,600);

(xix) Immunomodulators such as glatiramer acetate (also known as copolymer-1; COPAXONE), MBP-8298 (synthetic myelin basic protein peptide), dimethyl fumarate, fingolimod (also known as FTY720), roquinacre (linolide), laquinimod (also known as ABR-215062 and SAIK-MS), ABT-874 (human anti-IL-12 antibody; Abbott), rituximab (rixan), alemtuzumab (CAMPATH), daclizumab (ZENAPAX), and natalizumab (TYSABRI);

(xx) Immunosuppressants such as methotrexate (trexal, rhetomatrix), mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT), sodium Mycophenolate (MYFORTIC), azathioprine (AZASAN, IMURAN), mercaptopurine (PURI-NETHOL), cyclophosphamide (NEOSAR, cycloxan), chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX), alpha fetoprotein, Yisencept (ENBREL), and 4-benzyloxy-5- ((5-undecyl-2H-pyrrol-2-ylidene) methyl) -2,2' -di-1H-pyrrole (also known as PNU-156804);

(xxi) Interferons, including interferon beta-1 a (AVONEX, REBIF) and interferon beta-1 b (BETASERON, betafenon);

(xxii) Levodopa (or its methyl or ethyl ester), alone or in combination with a dopa decarboxylase inhibitor (such as carbidopa (SINEMET, CARBILEV, PARCOPA), benserazide (MADOPAR), alpha-methyldopa, monofluoromethyldopa, difluoromethyldopa, bromocline, or m-hydroxybenzylhydrazine);

(xxiii) N-methyl-D aspartate (NMDA) receptor antagonists such as memantine (NAMENDA, AXURA, EBIXA), amantadine (SYMMETREL), acamprosate (campal), besoprodil, ketamine (kelar), delucemin (delucemin), dexefaroxan (dexfaroxan), dextromethorphan, dextrorphan, troxolodine, CP-283097, himantane, idantadol, ipaxazone, L-701252(Merck), lanicimine, levorphanol (DROMORAN), LY-233536 and LY-235959 (all from Lilly), methadone (DOLOPHINE), neramexane, pervyne, pervylfotel (perzinfotel), phencyclidine, tenectermin (blon), desipramine (blazepine (also known as tatxipine-318), vaveb-801), spinach (e), luteine (wrightine, meglumine), tequiline (tene), texadine (tene), tebuclizine (tamarine), texadine (texate;

(xxiv) Monoamine oxidase (MAO) inhibitors such as selegiline (EMSAM), selegiline hydrochloride (I-alkynylamine, ELDEPRYL, ZELAPAR), dimethylselegiline, bromofamine, phenelzine (NARDIL), tranylcypromine (para), moclobemide (AURORIX, MANERIX), befloxatone, safinamide, isoxazole (MARPLAN), Niacinamide (NIAMID), rasagiline (azteril), isopropylisoniazide (marsiiid, IPROZID, IPRONID), CHF-3381 (chiesifaraciticiti), isopropylchlorhydrazine, toloxanone (humoriyl, peenum), diphenylmelem, harmine (also known as nanamesite or baneserine), dihydroharmine, ranelate (ZYVOX, zyxid) and voilin (eudyl );

(xxv) Muscarinic receptor (particularly subtype M1) agonists such as cevimeline, levetiracetam, uracil hydrochloride (DUVOID, URECHOLINE), itameprine, pilocarpine (SALAGEN), NGX267, arecoline, L-687306(Merck), L-689660(Merck), fursulobium (FURAMON, FURANOL), fursulobium besylate, fursulobium paratoluene sulfonate, MCN-A-343, oxotremorine, sabcomeline, AC-90222(AcadiA Pharmaceuticals) and carbaco (CARBATAT, MIOSTAT, CARBOPTIC);

(xxvi) Neuroprotective agents such as bosutinib, condolilase, airoclomol, lamotrigine, birampanel, aniracetam, minapirme, viluzole 2,3, 4, 9-tetrahydro-1H-carbazol-3-one oxime, deazapine, anatabint, astaxanthin, neuropeptides NAP (e.g. AL-108 and AL-208; both from Allon Therapeutics), neurostrol, peramptel, eprinoclin, bis (4-beta-D-glucopyranosyloxybenzyl) -2-beta-D-glucopyranosyl-2-isobutyltartrate (also known as dactylorhin B or DHB), formobactin, Xazaron (XAPRILA), lactein, dimebonine hydrochloride (DIMEBON), disofeon (CEROVE), virodicine (6, prol-2506), dihydrocholine (also known as acetylcholine) (also known as irinotect), and intracellular dicapryline (III) (also known as irin-5' -acetylcholine) (also known as irinotect), and so-D-vopholine (E) salts thereof, AEOL-10113 and AEOL-10150 (both from Aeolus Pharmaceuticals), AGY-94806 (also known as SA-450 and Msc-1), granulocyte colony stimulating factor (also known as AX-200), BAY-38-7271 (also known as KN-387271; Bayer AG), snake venom defibrase (VIPRINEX, ARWIN), DP-b99(D-Pharm Ltd), HF-0220 (17-. beta. -hydroxyepiandrosterone; Newron Pharmaceuticals), HF-0420 (also known as oligotropin), pyridoxal 5' -phosphate (also known as MC-1), microfibrillar lysozyme, S-18986, piclotan, NP 112, tacrolimus, L-seryl-L-methionyl-L-alanyl-L-glutamyl-glycyl-L-valine, L-seryl-L-methionyl-L-alanyl-L-alanyl-valyl-L-valyl, AC-184897(acadia pharmaceuticals), ADNF-14(National Institute of Health), stilbazulenyl nitrate, SUN-N8075(Daiichi Suntory biological Research), and Azole Perbinant;

(xxvii) Nicotinic receptor agonists such as epibatidine, bupropion, CP-601927, Vannikland, ABT-089(Abbott), ABT-594, AZD-0328(AstraZeneca), EVP-6124, R3487 (also known as MEM 3454; Roche/Memory Pharmaceuticals), R4996 (also known as MEM 63908; Roche/Memory Pharmaceuticals), TC-4959 and TC-5619 (both from Targacept) and RJR-2403;

(xxviii) Norepinephrine reuptake inhibitors such as atomoxetine (Strattera), doxepin (APONAL, ADAPIN, sinoquinan), nortriptyline (AVENTYL, pametor, nortriptyline), amoxapine (asedin, DEMOLOX, MOXIDIL), reboxetine (EDRONAX, VESTRA), viloxazine (VIVALAN), maprotiline (DEPRILEPT, LUDIOMIL, PSYMION), bupropion (WELLBUTRIN), and radaxafine;

(xxix) Phosphodiesterase (PDE) inhibitors including (a) PDE1 inhibitors (e.g., vinpocetine (CAVINTON, CERACTIN, INTELECTOL) and those disclosed in U.S. Pat. No. 6,235,742, (b) PDE2 inhibitors (e.g., erythro-9- (2-hydroxy-3-nonyl) adenine (EHNA), BAY 60-7550 and those described in U.S. Pat. No. 6,174,884), (c) PDE3 inhibitors (e.g., anagrelide, cilostazol, milrinone, olprinone, paroxetine and pimobendan), (d) PDE4 inhibitors (e.g., apremilast, ibundaflutriat, rolipram, Ro20-1724, ibudilast (KETAS), piracetamide (also known as 73401), CDP840, cilomilast (ARIFLO), roflumilast, olamide (also known as GRC3886), tea trefitide (also known as PHYLLOST), PHYLLORITE (ORL) and PHELLACTAST (e), THEOLAIR), arophylline (also known as LAS-31025), doxofylline, RPR-122818, or echinacea; and (E) PDE5 inhibitors (e.g., sildenafil (VIAGRA, REVATIO), tadalafil (CIALIS), vardenafil (LEVITRA VIVANZA), udenafil, avanafil, dipyridamole (PERSANTINE), E-4010, E-4021, E-8010, zaprinast, iodenafil, milonafil, DA-8159, and those disclosed in International patent application WO2002/020521, WO2005/049616, WO2006/120552, WO2006/126081, WO2006/126082, WO2006/126083, and WO 2007/122466), (f) PDE9 inhibitors (e.g., BAY73-6691(Bayer AG) and those disclosed in US patent publication US2003/0195205, US2004/0220186, US2006/0111372, US2006/0106035, and US SN 12/118,062 (on day 2008/9), and PDE inhibitors (e.g., PDE 2006-3-H-394-pyridyl) such as those disclosed in US2003/0195205, US2004/0220186, and those disclosed in US 2006/2008 (2008) and (G) and (P1-3-H-4-H-3-p.3) Methyl ] quinoline (PF-2545920) and SCH-1518291;

(xxx) Quinolines, such as quinine (including its hydrochloride, dihydrochloride, sulfate, bisulfate, and gluconate), chloroquine, methylchloroquine, hydroxychloroquine (PLAQUENIL), mefloquine (LARIAM), and amodiaquine (CAMOQUIN, FLAVOQUINE);

(xxxi) β -secretase inhibitors, such as ASP-1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, LY-2886721, E-2609, HPP-854, (+) -phenylalanine tartaric acidSalt (POSIPHEN), LSN-2434074 (also known as LY-2434074), KMI-574, SCH-745966, Ac-rER (N)²-acetyl-D-arginyl-L-arginine), allositagliptin (also known as E64D) and CA074 Me;

(xxxii) Gamma-secretase inhibitors and modulators, such as BMS-708163(Avagacest), WO20060430064(Merck), DSP8658(Dainippon), ITI-009, L-685458(Merck), ELAN-G, ELAN-Z, 4-chloro-N- [ 2-ethyl-1 (S) - (hydroxymethyl) butyl ] benzenesulfonamide;

(xxxiii) Serotonin (5-hydroxytryptamine) 1A (5-HT)_1A) Receptor antagonists such as spiperone, levorotatory pindole, BMY7378, NAD-299, S (-) -UH-301, NAN 190, lecozotan;

(xxxiv) Serotonin (5-hydroxytryptamine) 2C (5-HT)_2C) Receptor agonists such as pentachromycin and zilonapine (zicronapine);

(xxxv) Serotonin (5-hydroxytryptamine) 4(5-HT₄) Receptor agonists such as PRX-03140 (Epix);

(xxxvi) Serotonin (5-hydroxytryptamine) 6(5-HT₆) Receptor antagonists such as A-964324, AVI-101, AVN-211, mianserin (TORVOL, BOLVIDON, NORVAL), mecapine (also known as methpine), ritanserine, ALX-1161, ALX-1175, MS-245, LY-483518 (also known as SGS 518; lilly), MS-245, Ro 04-6790, RO 43-68544, Ro63-0563, Ro 65-7199, Ro 65-7674, SB-399885, SB-214111, SB-258510, SB-271046, SB-357134, SB-699929, SB-271046, SB-742457(GlaxoSmithKline), Lu AE58054(Lundbeck A/S) and PRX-07034 (Epix);

(xxxvii) Serotonin (5-HT) reuptake inhibitors such as alapropyl ester, citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX), clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (malexl), fenfluramine (pandimin), desfenfluramine, fluoxetine (proac), fluvoxamine (LUVOX), indapamide, milnacipran (IXEL), paroxetine (PAXIL, SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (deslorel, molaxin), venlafaxine (EFFEXOR), zimelimerine (normailud, zernid), bicifadine, desvenlafaxine (PRISTIQ), bucfenfenadine (brefangine), vilazone, carazine, carisoprex and neresofen;

(xxxviii) Trophic factors such as Nerve Growth Factor (NGF), basic fibroblast growth factor (bFGF; ERSOFERMIN), neurotrophic factor-3 (NT-3), cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neublastin, nickel insin, and glial cell-derived neurotrophic factor (GDNF), and agents that stimulate trophic factor production such as propentofylline, idebenone, PYM50028 (COGANE; Phytopharm), and AIT-082 (NEOTROFIN);

(xxxix) Glycine transporter-1 inhibitors such as paliflutine, ORG-25935, JNJ-17305600, and ORG-26041;

(xl) AMPA-type glutamate receptor modulators, such as pirampanel, mibamcator, selurampanel, GSK-729327, and N- ((3S,4S) -4- (4- (5-cyanothiophen-2-yl) phenoxy) tetrahydrofuran-3-yl) propane-2-sulfonamide; and so on.

The invention also includes kits suitable for use in performing the above-described methods of treatment. In one embodiment, the kit contains a first dosage form comprising one or more compounds of the invention and a dosage container, the dosage amount being sufficient to carry out the method of the invention.

In another embodiment, a kit of the invention comprises one or more compounds of the invention.

The compounds of formula I, formula Ia, formula Ib and formula Ic or pharmaceutically acceptable salts thereof may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry or modifications and derivations familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or may be prepared by conventional METHODS known in the art (such as those disclosed in standard references, such as the composition OF ORGANIC synthtic METHODS, vol.i-XII (Wiley-lnterscience). Preferred methods include, but are not limited to, those described below.

During any of the synthetic sequences described below, it may be necessary and/or desirable to protect sensitive or reactive groups on any molecule of interest. This can be achieved by conventional protecting groups such as those described in t.w. greene, protective groups in Organic Chemistry, John Wiley & Sons, 1981; T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991; and T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999 (which is hereby incorporated by reference).

The compounds of formula I, formula Ia, formula Ib, formula Ic and formula Id, or pharmaceutically acceptable salts thereof, may be prepared according to the reaction schemes discussed herein below. Unless otherwise indicated, substituents in the schemes are as defined above. Isolation and purification of the product is accomplished by standard procedures known to the ordinarily skilled chemist.

Those skilled in the art will appreciate that the various symbols, superscripts, and subscripts used in the schemes, methods, and embodiments are used for convenience in indicating and/or reflecting the order in which they are introduced in the schemes, and are not intended to necessarily correspond to the symbols, superscripts, or subscripts in the appended claims. These schemes represent methods for synthesizing the compounds of the present invention. They are not intended to limit the scope of the invention in any way.

Scheme 1

Scheme 1 illustrates a method for preparing compounds of formula I. Heating the compound of formula 1.1 in the presence of an aqueous acid (e.g., hydrochloric acid) to provide the corresponding pyridonic acid of formula 1.2. Using coupling agents such as HATU [ O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylHexafluorophosphates]Reacting an intermediate of formula 1.2An amide coupling and in situ cyclization reaction with an amino alcohol of formula 1.3 is carried out. The reaction is carried out in the presence of a suitable base such as diisopropylethylamine and in a solvent such as dichloromethane or N, N' -dimethylformamide.

Scheme 2

Scheme 2 illustrates a method for preparing compounds of formula I. The process begins with the reaction of a chloral formula 2.1 with an amine of formula 2.2 using one of many reductive amination protocols known to those skilled in the art. For example, the reaction can be carried out by using a reducing agent such as sodium triacetoxyborohydride in a suitable solvent such as methanol. After purification, the resulting chloroalkylamine of formula 2.3 can be isolated and stored as its HCl salt. The final compound of formula I can then be prepared by treating a mixture of chloroalkylamine formula 2.3, acid form 1.2, and base (e.g., diisopropylethylamine) with a suitable amide coupling agent such as BOP-Cl [ (bis (2-oxo-3-oxazolidinyl) phosphonic acid chloride ], T3P [ propylphosphonic anhydride ], or HATU (preferably HATU) in a solvent (e.g., dichloromethane).

Scheme 3

The amino alcohol coupling partners of formula 1.3 can be prepared via a variety of synthetic methods, which can be readily envisioned and developed by those skilled in the art. These include, but are not limited to, those methods exemplified in scheme 3. For example, the amino alcohol of formula 1.3 can be prepared by performing a reductive amination reaction of the ketone of formula 3.1 with the amine of formula 2.2 using one of many procedures well known to those skilled in the art. Another method involves the reductive amination of an aldehyde of formula 3.2 with an amine of formula 2.2, followed by removal of the TBS protecting group by using a suitable procedure, including treatment with HCl in methanol or tetrabutylammonium fluoride. Another method for synthesizing the amino alcohol of formula 1.3 involves halogenation with the amino alcohol of formula 3.4The amine of formula 3.3 is alkylated with a mesylate. Yet another method involves alkylating an amine of formula 2.2 with a bromohydrin of formula 3.5. Various synthetic methods of amine formula 2.2 and alternative methods of preparing amino alcohols formula 1.3 are illustrated in the experimental section. Those skilled in the art, using this disclosure in conjunction with common general knowledge in the art, can further generalize those syntheses to yield a variety of amine formula 2.2 and amino alcohol formula 1.3, including but not limited to R^2a,R^2bVariations of y, alternative cycloalkyl and heterocycloalkyl groups A, and various substituted aryl and heteroaryl groups R³。

Scheme 4

Scheme 4 illustrates a process for preparing compounds of formula 1.1 wherein R¹-X ═ 4-methylimidazol-1-yl. The 3-aminopyridine compound of formula 4.1 is brominated with N-bromosuccinimide in a solvent such as a mixture of DMSO and water. The resulting intermediate of formula 4.2 is then heated with sodium methoxide in a suitable solvent (e.g., 1, 4-dioxane) to provide the compound of formula 4.3. The intermediate of formula 4.3 is then treated with a mixture of acetic anhydride and formic acid to provide the formamide of formula 4.4, which is treated with chloroacetone in potassium iodide and a base (e.g., Cs)₂CO₃) Alkylation in a suitable solvent such as DMF in the presence of a catalyst. The resulting intermediate of formula 4.5 is then reacted in NH₄Heating in acetic acid in the presence of OAc provides the imidazole derivative formula 4.6. Finally, the compound of formula 1.1 can be prepared by subjecting the intermediate of formula 4.6 to a carbonylation reaction. This conversion can be carried out over a suitable palladium catalyst such as Pd (dppf)₂Cl₂DCM [ [1, 1' -bis (diphenylphosphino) ferrocene [ ]]Palladium (II) dichloride, dichloromethane complexes]Heating a solution of 4.6 and a base (e.g. triethylamine) in an alcoholic solvent (e.g. MeOH) in the presence of CO atmosphere.

Scheme 5

Scheme 5 depicts a method of preparing a compound of formula 1.1. The pyridyl derivative of formula 5.1 is treated with an oxidizing agent such as mCPBA [ 3-chloroperoxybenzoic acid]Oxidation in a suitable solvent (e.g., dichloromethane) provides the corresponding N-oxide of formula 5.2. The intermediate of formula 5.2 is then reacted in TMSCN [ trimethylsilyl cyanide ]]And a base (e.g., triethylamine) in a solvent (e.g., acetonitrile) to provide an intermediate of formula 5.3. The corresponding ester can then be prepared in two steps from formula 5.3: formula 5.3 is contacted with sodium methoxide in a solvent such as THF, followed by treatment with an alcohol and an acid such as HCl. The esters of formula 5.5 are versatile intermediates that allow the introduction of a variety of heterocyclic rings R¹And (4) X. For example, formula 5.5 can be subjected to Suzuki coupling with a heteroaryl boronic acid using methods well known to those skilled in the art [ see Tetrahedron2002,58,9633-]. Alternatively, compounds of formula 5.5 can be coupled to heterocyclic ring X using direct arylation methods [ see D.Lapointe et al, J.org.chem.2011,76, 749-one 759 and references therein]. For example, by reacting a suitable palladium catalyst (e.g., allylpalladium chloride dimer) with a base (e.g., K)₂CO₃) Heating in a solvent (such as 1, 4-dioxane) in the presence of a solvent, formula 5.5 can be reacted with 2-methyl-1, 3-oxazole [ formula 5.7, wherein R is¹＝Me]Coupling to provide an intermediate of formula 1.1, wherein R¹X is 2-methyl-1, 3-oxazol-5-yl.

Alternatively, compounds of formula 5.5 can be converted to the corresponding borates of formula 5.6 using potassium acetate and palladium catalysts (e.g., Pd (dppf)₂Cl₂DCM) in the presence of a solvent (e.g. 1, 4-dioxane) with a palladium-catalyzed cross-coupling with a diboron reagent (e.g. 5,5,5',5' -tetramethyl-2, 2' -bis-1, 3, 2-dioxaborolan). The resulting borate intermediate of formula 5.6 can then be subjected to Suzuki coupling with a heteroaryl halide to provide the final compound of formula 1.1. Another method for introducing heterocyclic ring X involves the use of Chan-Lam coupling [ see Tetrahedron Lett.2003,44,3863-3865, and Synthesis2008,5,795-799]. For example, formula 5.6 can be coupled with a substituted imidazole of formula 5.8 by heating with a suitable copper source such as copper oxide or copper acetate in a solvent (e.g., methanol) in the presence of air to provide an intermediate of formula 1.1, which isWherein X is imidazol-1-yl.

Scheme 6

Scheme 6 illustrates a method of synthesizing the compound of formula I. The process begins by heating a 6.1 compound in an acid (e.g., hydrochloric acid) to provide a pyridonic acid intermediate of formula 6.2. Using the chemistry described in scheme 1, an acid of formula 6.2 can be subjected to a coupling/cyclization reaction with an amino alcohol of formula 1.3 to provide an intermediate of formula 6.3. The final compound formula I can then be formed directly from formula 6.3, or via the borate salt formula 6.4 using the strategy discussed in scheme 5. Alternatively, compounds of formula I wherein the heterocyclic ring X is attached to the pyridone ring via a C-N bond may be formed by nucleophilic aromatic substitution. For example, triazoles of formula 6.5 can be prepared by reaction in the presence of a base (e.g., K)₂CO₃) And a solvent (e.g. DMSO) to provide a compound of formula I wherein X is triazol-1-yl.

Scheme 7

Scheme 7 illustrates a method of synthesizing a compound of formula I, wherein z ═ 1 and R^4a＝R^4b＝R^5a＝R^5bH. The process involves heating a 1.2 compound, dibromoethane and a base (e.g., Cs)₂CO₃) In a solvent such as DMF to provide the lactone intermediate of formula 7.1. The lactone of formula 7.1 can then be reacted with an amine of formula 2.2 in a reagent such as DIBAL (diisobutylaluminum hydride) or bis (trimethylaluminum) -1, 4-diazabicyclo [2.2.2]In the presence of an octane adduct in a solvent such as THF to provide the amide alcohol of formula 7.2. This intermediate can then be reacted with methanesulfonyl chloride in the presence of a base (e.g., triethylamine) in a solvent (e.g., THF), followed by a base such as 1,3,4,6,7, 8-hexahydro-2H-pyrimido [1,2-a ]]Pyrimidine treatment to provide compounds of formula I wherein z ═1 and R^4a＝R^4b＝R^5a＝R^5bH. Alternatively, the closed loop may be completed in a step-wise manner: the alcohol of formula 7.2 is first converted to the corresponding chloride by treatment with thionyl chloride and then the amide NH is deprotonated with a suitable base such as lithium bis (trimethylsilyl) amide to provide the final compound of formula I.

Scheme 8

Scheme 8 illustrates a method for synthesizing an amine of formula 8.7, which represents a subset of the general structure of formula 2.2. The synthesis starts with deprotonating ethynyl (trimethyl) silane with a suitable base such as n-butyllithium in a solvent such as THF. This mixture is then added to a solution of an epoxide of formula 8.1 (see J.Barluenga et al, J.org.chem.1995,60,6696-6699) in a solvent such as THF. The resulting alkyne of formula 8.3 can then be subjected to Sonogashira coupling with an aryl or heteroaryl halide of formula 8.4, wherein hal ═ bromine or iodine, using standard conditions known to those skilled in the art (see r. chinchialla et al, chem. soc. rev.2011,40, 5084-. This intermediate is then subjected to a reaction in a solvent (e.g., CH)₂Cl₂) To a cyclization reaction mediated by a platinum catalyst, such as di-mu-chlorodichlorobis (ethylene) diplatin (II), and an acid, such as trifluoroacetic acid, to provide the dihydrofuran intermediate of formula 8.6. Finally, transfer hydrogenation using ammonium formate and a suitable catalyst (e.g., palladium hydroxide on carbon) in a solvent (e.g., methanol) provides amines of formula 8.7, a subgroup of formula 2.2 where y ═ 1, R^2a＝CH₃,R^2bH, A is tetrahydrofuranyl, and R³Aryl or heteroaryl.

Scheme 9

Scheme 9 illustrationAn alternative method for synthesizing the amine of formula 8.7, which is a subset of the general structure of formula 2.2. reacting the methyl ester of formula 9.1 with a dianion resulting from deprotonation of chloroacetic acid (formula 9.2) with a suitable base (e.g., LDA) in a solvent (e.g., THF). The resulting α -chloroketone of formula 9.3 is then treated with a suitable reducing agent (e.g., lithium tri-tert-butoxyaluminum hydride) in a solvent (e.g., diethyl ether) to provide the chlorohydrin formula 9.4, which in turn can be prepared by reaction in DMAP [4- (dimethylamino) pyridine]And acylation with p-nitrobenzoyl chloride (formula 9.5) in a solvent (such as dichloromethane) in the presence of a base (such as triethylamine) to convert to the p-nitrobenzoate ester of formula 9.6. The intermediate of formula 9.6 is then treated with a base (e.g., potassium hydroxide) resulting in the formation of the epoxide of formula 9.7. In analogy to scheme 8, the epoxide of formula 9.7 can undergo ring opening using the acetylide obtained by deprotonating formula 8.2 with a base (such as n-butyllithium) in the presence of dimethylaluminum chloride in a solvent (such as toluene) to provide the alkyne of formula 9.8. The intermediate is then subsequently freed of the trimethylsilyl group by exposure to a protic solvent (e.g., methanol) and a base (e.g., potassium carbonate) to give the deprotected alkyne of formula 9.9. This intermediate is then subjected to Sonogashira coupling with an aryl halide formula 8.4 as described in scheme 8 to provide an intermediate of formula 9.10. This intermediate is then subjected to a cyclization reaction mediated by a platinum catalyst such as di- μ -chlorodichlorobis (ethylene) diplatin (II), an acid such as p-toluenesulfonic acid, and trimethyl orthoformate in a solvent such as MeOH to provide the compound of formula 9.11. Treatment of formula 9.11 with boron trifluoride diethyl ether and a reducing agent (e.g., triethylsilane) in a suitable solvent (e.g., dichloromethane) affords tetrahydrofuran of formula 9.12. Finally, removal of the Boc protecting group by exposure to an acid (e.g., trifluoroacetic acid or hydrochloric acid) in a solvent (e.g., dichloromethane or 1, 4-dioxane) provides an amine of formula 8.7, a subgroup of formula 2.2, where y ═ 1, R^2a＝CH₃,R^2bH, A is tetrahydrofuranyl, and R³Aryl or heteroaryl.

When intermediates used in the synthesis of the compounds of the invention introduce a basic center, suitable acid addition salts thereof may be employed in the synthetic route. Such suitable addition salts include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, boric acid, fluoroboric acid, phosphoric acid, nitric acid, carbonic acid, and sulfuric acid, and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, fumaric acid, lactic acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, succinic acid, toluenesulfonic acid, and trifluoroacetic acid. Suitable organic acids generally include, but are not limited to, organic acids of the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes.

Specific examples of suitable organic acids include, but are not limited to, acetic acid, trifluoroacetic acid, formic acid, propionic acid, succinic acid, lactic acid, maleic acid, fumaric acid, benzoic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, adipic acid, butyric acid, camphoric acid, cyclopentanepropionic acid, dodecylsulfuric acid, heptanoic acid, hexanoic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, 3-phenylpropionic acid, pivalic acid, and undecanoic acid.

In addition, where the intermediates used to prepare the compounds of the present invention carry an acidic moiety, suitable salts thereof are useful in the synthesis. Such salts include alkali metal salts, i.e., lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts with suitable organic ligands such as amines or quaternary ammonium cations. Organic salts of such acidic intermediates can be prepared from primary, secondary or tertiary amines (e.g., methylamine, diethylamine, ethylenediamine or trimethylamine). The quaternary amine may be reacted with a reagent such as lower alkyl (C) through a tertiary amine₁-C₆) Halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), arylalkyl halides (i.e., benzyl and phenethyl bromides), and others.

Experimental procedures and working examples

The following illustrates the synthesis of various compounds of the invention. Other compounds within the scope of the invention may be prepared using the methods exemplified in these examples alone or in combination with techniques well known in the art.

It is to be understood that the intermediate compounds of the present invention delineated above are not limited to the particular enantiomers as shown, but also include all stereoisomers and mixtures thereof.

Experimental procedures

Experiments are generally carried out under an inert atmosphere (nitrogen or argon), especially when reagents or intermediates sensitive to oxygen or moisture are employed. Commercial solvents and reagents are generally used without further purification, including anhydrous solvents as appropriate (typically Sure-Seal from Aldrich Chemical Company, Milwaukee, Wisconsin^TMProduct). The product is usually dried under vacuum before further reaction or submission for biological testing. Mass spectral data were reported from liquid chromatography-mass spectrometry (LCMS), Atmospheric Pressure Chemical Ionization (APCI), or gas chromatography-mass spectrometry (GCMS) instruments. Chemical shifts of Nuclear Magnetic Resonance (NMR) data are expressed in parts per million (ppm) referenced to residual peaks from the deuterated solvents used.

For synthetic reference operations in other examples or methods, the reaction conditions (reaction length and temperature) may vary. Generally, the reaction is followed by thin layer chromatography or mass spectrometry, and examination is performed at the appropriate time (work-up). Purification was variable between experiments: in general, the solvent and solvent ratio for the eluent/gradient are selected to provide the appropriate R_fs or retention time.

Preparation of

Preparation of P1:5- (4-methyl-1H-imidazol-1-yl) -6-oxo-1, 6-dihydropyridine-2-carboxylic acid, hydrobromide (P1)

Step 1. Synthesis of methyl 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxylate (C2).

To a solution of known 6-bromo-2-methoxy-3- (4-methyl-1H-imidazol-1-yl) pyridine (C1, t.kimura et al, u.s.pat.appl.pub.2009, US 20090062529 a1) (44.2g,165mmol) in methanol (165mL) was added triethylamine (46mL,330mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II), dichloromethane complex (6.7g,8.2 mmol). The mixture was degassed several times with nitrogen. The reaction was heated to 70 ℃ in a Parr apparatus under a CO atmosphere (3 bar). After 30 minutes, the pressure was reduced to 0.5 bar; additional CO was added until the pressure remained constant for 30 minutes. The mixture was cooled to room temperature and filtered through a pad of celite. The celite pad was washed twice with methanol, and the combined filtrates were concentrated under reduced pressure. The residue (88g) was dissolved in ethyl acetate (1L) and water (700 mL); the organic layer was washed with water (200mL), and the aqueous layer was extracted with ethyl acetate (500 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to provide the title compound. Yield 42.6g, quantitative.

Step 2. Synthesis of 5- (4-methyl-1H-imidazol-1-yl) -6-oxo-1, 6-dihydropyridine-2-carboxylic acid, hydrobromide (P1).

A solution of compound C2(3.82g,15.9mmol) in acetic acid (30mL) and aqueous hydrobromic acid (48%, 30mL) was heated at reflux for 4 h. The reaction was cooled to room temperature and then cooled in an ice bath; the resulting precipitate was collected by filtration and washed with ice water (30 mL). Recrystallization from ethanol (20mL) afforded the title compound as a pale yellow solid. Yield 3.79g,12.6mmol, 79%. LCMS M/z 220.1(M +1).¹H NMR(400MHz,DMSO-d₆)12.6(v br s,1H),9.58-9.60(m,1H),8.07(d,J＝7.6Hz,1H),7.88-7.91(m,1H),7.09(d,J＝7.4Hz,1H),2.34(br s,3H).

Preparation of P2- (4-methyl-1H-imidazol-1-yl) -6-oxo-1, 6-dihydropyridine-2-carboxylic acid, hydrochloride (P2)

A mixture of compound C2(12.8g,51.8mmol) and 37% hydrochloric acid (25mL) was heated at reflux for 18 h. After the reaction mixture was cooled to room temperature, the solid was collected by filtration; stir with 1, 4-dioxane (2 × 20mL) and filter again to give the product as a yellow solid. Yield 13g,51mmol, 98%.¹H NMR(400MHz,CD₃OD)9.52(br s,1H),8.07(d,J＝7.5Hz,1H),7.78(br s,1H),7.21(d,J＝7.5Hz,1H),2.44(s,3H).

Preparation of P3:7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydropyrido [2,1-c ]][1,4]Oxazine-1, 6-bis Ketones (P3)

Compound P2(65g,250mmol), 1, 2-dibromoethane (52.5g,280mmol) and cesium carbonate (124g,381mmol) were combined in N, N-dimethylformamide (850mL) and heated at 90 ℃ for 6 h. The reaction mixture was then cooled and filtered through celite. After concentrating the filtrate in vacuo, the residue was dissolved in dichloromethane (500mL), washed with saturated aqueous sodium chloride (100mL), washed with water (50mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was washed with acetonitrile to afford the product. Yield 46.5g,190mmol, 76%.¹H NMR(400MHz,CDCl₃)8.33(d, J ═ 1.4Hz,1H),7.43(AB quartet, J)_AB＝7.7Hz,Δν_AB＝33.4Hz,2H),7.15-7.17(m,1H),4.66-4.70(m,2H),4.38-4.42(m,2H),2.30(d,J＝0.8Hz,3H).

Preparation of P4:2- ({ cis-2- [2- (trifluoromethyl) phenoxy)]Cyclobutyl } amino) ethanol (P4)

Step 1. Synthesis of 2-bromocyclobutanone (C3).

A solution of cyclobutanone (1.28mL,17.1mmol) in chloroform (20mL) at 0 deg.C was treated dropwise with bromine (0.88mL,17mmol) over 25 minutes, warmed to room temperature and stirred for 16 hours. Dichloromethane (100mL) was added and the solution was washed with aqueous sodium thiosulfate (50mL) and saturated aqueous sodium chloride (50 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a colorless oil. Yield 2.45g,16.4mmol, 96%.¹H NMR(400MHz,CDCl₃)4.97-5.04(m,1H),3.16-3.24(m,2H),2.69-2.80(m,1H),2.18-2.30(m,1H).

Step 2, synthesizing 2- [2- (trifluoromethyl) phenoxy ] cyclobutanone (C4).

A solution of 2- (trifluoromethyl) phenol (2.72g,16.8mmol) in acetone (147mL) at 0 deg.C was treated with cesium carbonate (5.47g,16.8mmol) and then Compound C3(2.5g,16.8mmol) was added dropwise. The mixture was stirred at 0 ℃ for 1.5 h, filtered through celite, and concentrated in vacuo to give the title compound as a colorless oil. Yield 3.5g,15mmol, 89%.¹H NMR(400MHz,CDCl₃)7.56(br d,J＝7.7Hz,1H),7.45-7.50(m,1H),7.14(d,J＝8.3Hz,1H),7.07(br dd,J＝7.6,7.6Hz,1H),5.31-5.37(m,1H),2.92-3.00(m,2H),2.55-2.66(m,1H),2.19-2.30(m,1H).

Step 3. Synthesis of 2- ({ cis-2- [2- (trifluoromethyl) phenoxy ] cyclobutyl } amino) ethanol (P4).

A solution of compound C4(3.5g,15mmol) and 2-aminoethanol (1.03g,16.8mmol) in 1, 2-dichloroethane (100mL) was treated with sodium triacetoxyborohydride (5.62g,25.2mmol) and stirred at room temperature for 2 h. The reaction was treated with acetic acid (4mL) and stirred at room temperature for 16 h. Aqueous sodium hydroxide (1N,100mL) was added and the mixture was extracted with dichloromethane (2 × 100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0% -70% [ 10% 2N methanolic ammonia solution/90% ethyl acetate)]In ethyl acetate) to give the title compound as a light amber oil. Yield 2.1g,7.6mmol, 51%. the indicated cis stereochemistry is tentatively assigned based on the NOE (nuclear Overhauser enhancement).¹H NMR(400MHz,CDCl₃)7.57(br dd,J＝7.7,1.3Hz,1H),7.41-7.47(m,1H),6.99(br dd,J＝7.6,7.6Hz,1H),6.80(d,J＝8.2Hz,1H),4.88-4.93(m,1H),3.54-3.66(m,3H),2.81-2.88(m,1H),2.63-2.70(m,1H),2.22-2.31(m,1H),1.97-2.16(m,2H),1.86-1.94(m,1H).

Preparation of P5:2- ({ [3- (4-chlorophenyl) cyclohexyl]Methyl } amino) ethanol (P5)

Step 1, synthesizing 1-chloro-4- [3- (methoxymethylene) cyclohexyl ] benzene (C5).

To a solution of-78 deg.C (methoxymethyl) trimethylsilane (694mg,5.75mmol) in tetrahydrofuran (6.8mL) was added sec-butyllithium (1.4M,4.45mL,6.23mmol) dropwise. The solution was warmed to-25 ℃, held at this temperature for 30 minutes, and then cooled to-78 ℃. To the reaction was added dropwise 3- (4-chlorophenyl) cyclohexanone (prepared according to the method of G.A. Whitlock et al, bioorg.Med.chem.Lett.2009,19, 3118-Buchner 3121) (1.0g,4.8 mmol). The reaction was warmed to-25 ℃ and stirred for 30 minutes, then allowed to warm slowly to room temperature and stirred for 48 hours. The reaction was diluted with tetrahydrofuran (10mL), quenched with saturated aqueous ammonium chloride solution, and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford the crude title compound as a pale yellow oil. Yield 1.25 g. This material was used directly in the following step. GCMS M/z236 (M)⁺).

And step 2, synthesizing 3- (4-chlorphenyl) cyclohexane formaldehyde (C6).

Crude compound C5 (1.25g,. ltoreq.4.8 mmol from the previous step) was dissolved in aqueous formic acid (3M,2.0mL) and the mixture was refluxed for 2 hours. The solution was cooled to room temperature, diluted with water and extracted twice with ethyl acetate; the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Silica gel chromatography (gradient: 0% -100% ethyl acetate in heptane) afforded the title compound as an oil¹H NMR speculated to be about 4 of the two isomers: 1 of a mixture. Yield 338mg,1.52mmol, two steps 32%. GCMS M/z 222 (M)⁺).¹H NMR(400MHz,CDCl₃) [9.65(d, J ═ 1.4Hz) and 9.79(br s), total 1H],7.25-7.30(m,2H),7.12-7.18(m,2H),1.21-2.66(m,10H).

And 3, synthesizing 2- ({ [3- (4-chlorphenyl) cyclohexyl ] methyl } amino) ethanol (P5).

To a solution of compound C6(338mg,1.52mmol) in methanol (5mL) was added 2-aminoethanol (139mg,2.28mmol) andthen acetic acid (89. mu.L, 1.55mmol) was added. The reaction was stirred at reflux for 2 hours and then cooled to 0 ℃. Sodium borohydride (115mg,3.04mmol) was added and the mixture was allowed to warm to room temperature. The reaction was diluted with ethyl acetate, quenched with water, and then extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide the crude title compound as a liquid. Yield 362mg,1.35mmol, 89%. This is presumably a mixture of stereoisomers. LCMS M/z 268.3(M +1).¹H NMR(400MHz,CDCl₃) Characteristic peaks are 7.22-7.28(m,2H),7.10-7.16(m,2H),3.63(dd, J ═ 5.3,5.1Hz,2H),2.75(dd, J ═ 5.3,5.1Hz,2H).

Examples

Example 1

7- (4-methyl-1H-imidazol-1-yl) -2- { trans-2- [2- (trifluoromethyl) phenoxy]Cyclobutyl } -3, 4-di hydro-2H-pyrido [1,2-a ]]Pyrazine-1, 6-dione, trifluoroacetate (1)

Step 1, synthesizing cis-2- [2- (trifluoromethyl) phenoxy ] cyclobutanol (C7).

Compound C4(3.00g,13.0mmol) was dissolved in methanol (100mL) and cooled to-78 ℃. Sodium borohydride (1.48g,39.1mmol) was added portionwise over 10 min and the mixture was stirred at-78 ℃ for a further 30 min, then allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with saturated aqueous sodium bicarbonate (100mL) and extracted with dichloromethane (2 × 150 mL). The organic layers were combined, washed with saturated aqueous sodium chloride (100mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification was performed twice via silica gel chromatography [ gradient: 1) 0% -50% ethyl acetate in heptane; 2) 0% -50% dichloromethane in heptane]The title compound was provided as a colorless oil. The product was tentatively assigned to cis-stereotaxic based on NOE studiesAnd (5) studying. Yield 650mg,2.80mmol, 22%.¹H NMR(400MHz,CDCl₃)7.60(br dd,J＝7.8,1.2Hz,1H),7.47(br ddd,J＝8.2,7.8,1.2Hz,1H),7.04(br dd,J＝7.6,7.6Hz,1H),6.87(br d,J＝8.4Hz,1H),4.86-4.91(m,1H),4.45-4.53(m,1H),2.75(d,J＝9.2Hz,1H),2.27-2.36(m,1H),2.02-2.22(m,3H).

Step 2, synthesizing cis-2- [2- (trifluoromethyl) phenoxy ] cyclobutylmethanesulfonate (C8).

A mixture of compound C7(484mg,2.08mmol), triethylamine (0.87mL,6.3mmol) and dichloromethane (30mL) was cooled to 0 deg.C and methanesulfonyl chloride (0.32mL,4.2mmol) was added dropwise over 15 minutes. After an additional 30 minutes at 0 ℃, the reaction was quenched with saturated aqueous sodium bicarbonate (50mL) and the mixture was extracted with dichloromethane (2 × 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (50mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a colorless oil. The yield was 640mg,2.06mmol, 99%.¹H NMR(400MHz,CDCl₃)7.60(br dd,J＝7.8,1.2Hz,1H),7.45-7.51(m,1H),7.06(br dd,J＝7.7,7.6Hz,1H),6.88(br d,J＝8.4Hz,1H),5.26-5.32(m,1H),5.01-5.06(m,1H),2.95(s,3H),2.53-2.63(m,1H),2.37-2.46(m,1H),2.18-2.30(m,2H).

Step 3. Synthesis of 2- ({ trans-2- [2- (trifluoromethyl) phenoxy ] cyclobutyl } amino) ethanol (C9).

A mixture of compound C8(500mg,1.61mmol) and 2-aminoethanol (5mL) was heated at 90 ℃ for 18 h and then at 100 ℃ for a further 24 h. The reaction was cooled, diluted with ethyl acetate (100mL) and washed with aqueous sodium hydroxide (1M,5 × 50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by HPLC (column: Phenomenex Luna C18(2),5 μm; mobile phase A: 0.1% formic acid in water; mobile phase B: 0.1% formic acid in methanol; gradient: 5% to 100% B) gave the title compound as a solid. Yield 191mg,0.694mmol, 43%. LCMS M/z 276.3(M +1).¹H NMR(400MHz,CDCl₃)8.49(br s,1H),7.56(br d,J＝7.6Hz,1H),7.44-7.50(m,1H),7.04(br dd,J＝7.6,7.6Hz,1H),6.92(br d,J＝8.4Hz,1H),4.90-4.97(m,1H),3.75-3.90(m,3H),2.99-3.15(m,2H),2.46-2.56(m,1H),2.21-2.31(m,1H),1.90-2.02(m,1H),1.77-1.89(m,1H).

Step 4. Synthesis of 7- (4-methyl-1H-imidazol-1-yl) -2- { trans-2- [2- (trifluoromethyl) phenoxy ] cyclobutyl } -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione, trifluoroacetate (1).

A reaction mixture of compound P1(35mg,0.13mmol), C9(39mg,0.14mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylA mixture of hexafluorophosphate (HATU,149mg,0.392mmol) and N, N-diisopropylethylamine (0.89mL,0.51mmol) in dichloromethane (2.3mL) was stirred for 20 h. Water (5mL) was added and the mixture was extracted with dichloromethane (3 × 5 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification was performed using reverse phase HPLC (column: Waters Sunfire C18,5 μm; mobile phase A: 0.05% trifluoroacetic acid in water (v/v); mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); gradient: 10% -100% B). Yield 50mg,0.11mmol, 85%. LCMS M/z459.1(M +1). Retention time: 2.53 min (column: Waters Atlantis dC18,4.6X 50mm,5 μm; mobile phase A: 0.05% trifluoroacetic acid in water (v/v); mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); gradient: 5% -95% B linear over 4.0 min; flow rate 2 mL/min).

Example 2

7- (4-methyl-1H-imidazol-1-yl) -2- { trans-2- [2- (trifluoromethyl) phenoxy]Cyclopentyl } -3, 4-bis hydro-2H-pyrido [1,2-a ]]Pyrazine-1, 6-dione (2)

Step 1. Synthesis of trans-2- (dibenzylamino) cyclopentanol (C10).

Trans-2-aminocyclopentanesTo a solution of the alkoxide (385mg,2.82mmol) in 1, 2-dichloroethane were added benzaldehyde (748mg,7.04mmol) and triethylamine (0.51mL,3.7 mmol). The mixture was heated to reflux for 2 hours, cooled to room temperature, and sodium triacetoxyborohydride was added. The reaction mixture was heated under reflux for a further 18 hours, cooled to room temperature and taken up in dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate and with water, then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 25% -50% ethyl acetate in heptane) gave the title compound as a gold oil. Yield 734mg,2.61mmol, 93%. LCMS M/z 282.2(M +1).¹H NMR(400MHz,CDCl₃)7.35-7.39(m,4H),7.32(br dd,J＝7.8,7.2Hz,4H),7.21-7.26(m,2H),4.05-4.12(m,1H),3.79(d,J＝13.9Hz,2H),3.52(d,J＝13.9Hz,2H),2.90-2.99(m,1H),1.74-1.95(m,2H),1.52-1.71(m,3H),1.39-1.49(m,1H).

Step 2, synthesizing trans-N, N-dibenzyl-2- [2- (trifluoromethyl) phenoxy ] cyclopentylamine (C11).

To a solution of compound C10(820mg,2.91mmol) in tetrahydrofuran (20mL) in high pressure tubing was added sodium hydride (60% in oil, 175mg,4.37 mmol). After 15 minutes, 1-fluoro-2- (trifluoromethyl) benzene (1.43g,8.74mmol) was introduced, the tube sealed and the mixture heated to 70 ℃ for 18 hours whereupon it was cooled to room temperature. The mixture was taken up in ethyl acetate and then washed with water and with saturated aqueous sodium chloride; the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 20% -40% ethyl acetate in heptane) gave the title compound as a gold oil. Yield 212mg,0.498mmol, 17%. LCMS M/z 426.2(M +1).¹H NMR(400MHz,CDCl₃)7.55(d, J ═ 7.8Hz,1H),7.41(dd, J ═ 8.0,7.8Hz,1H),7.34-7.39(m,4H),7.24-7.30(m,4H),7.17-7.23(m,2H),7.03(d, J ═ 8.4Hz,1H),6.95(dd, J ═ 7.6,7.6Hz,1H),4.76-4.82(m,1H),3.68(AB quartet, J ═ 7.8Hz,1H), 3.68(AB quartet, J ═ 8.6Hz, 7.6Hz,1H)_AB＝14.0Hz,Δν_AB＝41.1Hz,4H),3.50-3.57(m,1H),1.85-2.00(m,2H),1.62-1.84(m,4H).

Step 3, synthesizing trans-2- [2- (trifluoromethyl) phenoxy ] cyclopentylamine, hydrochloride (C12).

A solution of compound C11(212mg,0.498mmol), hydrogen chloride (4N in 1, 4-dioxane, 2mL) and 10% Pd/C (100mg) in methanol (5mL) was hydrogenated at 50psi in a Parr shaker at 50 ℃. After 3 hours, the reaction was filtered through celite and concentrated in vacuo to provide a dark residue of the title compound. Yield 156mg, quant.LCMS M/z 246.2(M +1).

Step 4, synthesizing trans-N- (2-chloroethyl) -2- [2- (trifluoromethyl) phenoxy ] cyclopentylamine, hydrochloride (C13).

To a solution of compound C12(130mg,0.463mmol), triethylamine (0.097mL,0.695mmol) and sodium triacetoxyborohydride (238mg,1.06mmol) in methanol (5mL) was added chloroacetaldehyde (55% in water, 0.071mL,0.60 mmol). After three hours, the reaction mixture was concentrated in vacuo. The residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution and with water. The organic layer was dried over magnesium sulfate and filtered. To the filtrate was added hydrogen chloride (2N in diethyl ether, 2mL) and the mixture was concentrated in vacuo to give the title compound as a light brown solid. This material was used in the next step without further purification. Yield 111mg,0.323mmol, 70%. LCMS M/z308.1 (M +1).

Step 5. Synthesis of 7- (4-methyl-1H-imidazol-1-yl) -2- { trans-2- [2- (trifluoromethyl) phenoxy ] cyclopentyl } -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (2).

To a solution of compound P1(80mg,0.27mmol) and C13(110mg,0.32mmol) in dichloromethane (5mL) were added N, N-diisopropylethylamine (0.19mL,1.07mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylHexafluorophosphate (HATU, 97%, 124mg,0.32 mmol). The reaction was stirred for 5 days, then taken up in additional dichloromethane and washed with saturated aqueous sodium bicarbonate and with water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by reverse phase HPLC (column: Waters Xbridge C18,5 μm; mobile phase A: 0.03% aqueous ammonium hydroxide solution (v/v); mobile phase B: 0.03% acetonitrile in ammonium hydroxideSolution (v/v); gradient: 30% -70% B) to give the title compound as an oil. Yield 3.6mg, 7.6. mu. mol, 3%. LCMS M/z 473.3(M +1). Retention time: 2.62 min (column: Waters Atlantis dC18,4.6X 50mm,5 μm; mobile phase A: 0.05% aqueous trifluoroacetic acid (v/v); mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); gradient: 5% -95% B over 4.0 min, linear; flow rate: 2 mL/min).

Example 3

2- { trans-2- [ (6, 7-difluoronaphthalen-1-yl) oxy]Cyclobutyl } -7- (4-methyl-1H-imidazol-1-yl) -3,4- dihydro-2H-pyrido [1,2-a ]]Pyrazine-1, 6-dione (3)

Step 1 Synthesis of 2- { [ cis-2- (benzyloxy) cyclobutyl ] amino } ethanol (C14).

A solution of 2- (benzyloxy) cyclobutanone (prepared according to the method of P.Bisel et al, Eur.J.org.chem.1998,4, 729-733; 2.35g,13.3mmol) and 2-aminoethanol (1.63g,26.7mmol) in dichloromethane (47mL) was treated with acetic acid (0.76mL,13.3mmol) and sodium triacetoxyborohydride (5.95g,26.7mmol) and stirred at room temperature for 16 h. Aqueous sodium hydroxide (1N,100mL) was added and the mixture was extracted with dichloromethane (2 × 100 mL). The combined organic layers were washed with aqueous sodium hydroxide (1N,100mL), dried over magnesium sulfate and concentrated in vacuo to afford the product as a colorless oil. Yield 2.9g,13mmol, 98%.¹H NMR(400MHz,CDCl₃)7.28-7.39(m,5H),4.51(AB quartet, J)_AB＝11.7Hz,Δν_AB＝61.1Hz,2H),4.13-4.18(m,1H),3.54-3.58(m,2H),3.32-3.39(m,1H),2.72-2.78(m,2H),2.5(v br s,2H),2.05-2.14(m,1H),1.83-1.98(m,3H).

Step 2 Synthesis of 2- [ cis-2- (benzyloxy) cyclobutyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (C15).

Compound P1(2.40g,8.00mmol) and C14(2.00g,9.04mmol) were combined in dichloromethane (160mL) and treated with N, N-diisopropylethylamine (6.06mL,34.8mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylHexafluorophosphate (HATU, 97%, 7.84g,20.0 mmol). The reaction was stirred at room temperature for 55 hours. Water (200mL) was added and the mixture was extracted with dichloromethane (3 × 150 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (gradient: 50% -100% [ 10% 2N methanolic ammonia solution/90% ethyl acetate)]In ethyl acetate) to give the title compound as a pale yellow solid. Yield 2.95g,7.29mmol, 91%.¹H NMR(400MHz,CDCl₃) Characteristic peaks of 8.35(d, J-1.4 Hz,1H),7.52(d, J-7.8 Hz,1H),7.23-7.35(m,6H),7.18-7.20(m,1H),5.22-5.29(m,1H),4.45(AB quartet, J)_AB＝11.7Hz,Δν_AB＝52.2Hz,2H),4.06-4.18(m,2H),3.68-3.79(m,2H),2.46-2.58(m,1H),2.31(d,J＝0.8Hz,3H).

Step 3 Synthesis of 2- [ cis-2-hydroxycyclobutyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (C16).

Compound C15(2.50g,6.18mmol) was combined with dichloromethane (110mL), treated with methanesulfonic acid (27mL) and stirred at room temperature for 1.5 h. Aqueous sodium hydroxide (6N) was added until the pH reached 12, then the mixture was extracted with dichloromethane (3x 150mL, then 5x 50 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography (gradient: 50% -100% [ 20% 2N methanolic ammonia/80% ethyl acetate)]In ethyl acetate) afforded the title compound as a white solid. Yield 1.40g,4.45mmol, 72%.¹H NMR(400MHz,CDCl₃)8.24(d,J＝1.2Hz,1H),7.36(d,J＝7.6Hz,1H),7.15(d,J＝7.8Hz,1H),7.03-7.05(m,1H),4.70-4.78(m,2H),4.26-4.40(m,2H),3.99(ddd,J＝13.4,6.9,4.3Hz,1H),3.68(ddd,J＝13.3,7.8,4.3Hz,1H),2.54-2.65(m,1H),2.26(d,J＝0.8Hz,3H),2.20-2.34(m,2H),1.89-1.99(m,1H).

Step 4, synthesizing cis-2- [7- (4-methyl-1H-imidazol-1-yl) -1, 6-dioxo-1, 3,4, 6-tetrahydro-2H-pyrido [1,2-a ] pyrazin-2-yl ] cyclobutylmethanesulfonate (C17).

Methanesulfonyl chloride (148. mu.L, 1.91mmol) was added dropwise to a solution of 0 ℃ C16(150mg,0.47mmol) and triethylamine (530. mu.L, 3.82mmol) in dichloromethane (15mL) and the mixture was stirred for 20 min. Water (50mL) was added and the mixture was extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a pale yellow solid. Yield 175mg,0.45mmol, 94%. LCMS M/z 393.4(M +1).¹H NMR(400MHz,CDCl₃)8.24(d, J ═ 1.2Hz,1H),7.44(d, J ═ 7.8Hz,1H),7.24(d, J ═ 7.6Hz,1H),7.13-7.15(m,1H),5.30-5.35(m,1H),5.13-5.20(m,1H),4.47(ddd, half ABXY pattern, J ═ 14.3,7.6,4.1Hz,1H),4.37(ddd, half ABXY pattern, J ═ 14.4,7.4,4.0Hz,1H),3.96(ddd, J ═ 13.3,7.4,4.1Hz,1H),3.74(ddd, J ═ 13.2,7.6,4.0Hz,1H),2.99(s, 2.66, 2, 3.1H), 3.50H (m, 3.3H, 3.3.3, 3, 3.2, 3, 3.3.2, 3,3.3, 3.

Step 5 Synthesis of 2- { trans-2- [ (6, 7-difluoronaphthalen-1-yl) oxy ] cyclobutyl } -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (3).

A mixture of compound C17(20mg, 51. mu. mol),6, 7-difluoronaphthalen-1-ol (9.2mg, 51. mu. mol) and potassium carbonate (35.6mg, 255. mu. mol) in dimethylsulfoxide (1.0mL) was heated to 100 ℃ for 3 hours, filtered, and purified by reverse phase HPLC (column: Waters XBridge C18, 5. mu.m; mobile phase A: 0.03% aqueous ammonium hydroxide solution (v/v); mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v); gradient: 20% -70% B). LCMS M/z477.0(M +1). retention time: 2.58 min (column: Waters Atlantis dC18,4.6X 50mm,5 μm; mobile phase A: 0.05% trifluoroacetic acid in water (v/v); mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); gradient: 5% -95% B over 4.0 min, linear; flow rate: 2 mL/min).

Example 4

2- ({3- [ 4-chloro-3- (trifluoromethyl) phenyl]-4, 5-dihydro-1, 2-oxazol-5-yl } methyl) -7- (4-methyl- 1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a]Pyrazine-1, 6-dione (4)

Step 1 Synthesis of 7- (4-methyl-1H-imidazol-1-yl) -2- (prop-2-en-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (C18).

Compound P1(2.02g,6.73mmol) and 2- (prop-2-en-1-ylamino) ethanol (prepared according to the method of m.matteucci et al, u.s.pat.appl.pub.2007, US 20070060534 a 120070315) (681mg,6.73mmol) were combined in dichloromethane (40mL) and N, N-diisopropylethylamine (5.86mL,33.7mmol) and the mixture was stirred until it became homogeneous. Adding O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylHexafluorophosphate (HATU, 97%, 7.92g,20.2mmol) and the reaction stirred at room temperature for 48 h. Aqueous sodium hydroxide (1N) was added and the mixture was extracted three times with 20% isopropanol in chloroform. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification was carried out using silica gel chromatography (gradient: 0% -20% [2M NH ]₃In methanol solution of]In dichloromethane) and then triturated with ethyl acetate. Yield 718mg,2.52mmol, 38%. the second yield was obtained from the filtrate via double trituration. Yield 221mg,0.77mmol, 11%.¹H NMR(400MHz,CDCl₃)8.28(d,J＝1.2Hz,1H),7.47(d,J＝7.8Hz,1H),7.29(d,J＝7.6Hz,1H),7.13-7.15(m,1H),5.83(ddt,J＝16.8,10.5,6.1Hz,1H),5.28-5.35(m,2H),4.34-4.38(m,2H),4.21(ddd,J＝6.0,1.4,1.2Hz,2H),3.63-3.67(m,2H),2.30(d,J＝1.0Hz,3H).

Step 2, (E) -1- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N-hydroxymethanimine (methanimine) (C19) is synthesized.

To a solution of 4-chloro-3- (trifluoromethyl) benzaldehyde (93.9mg,0.45mmol) in tetrahydrofuran (0.9mL) and ethanol (0.9mL) was added hydroxylamine (50% aqueous solution, 0.20mL) and the reaction was maintained at room temperature for 36 hours. Methanol (3.0mL) was added, the solvent removed in vacuo, and the residue triturated with toluene (2 × 1mL) to give the title compound as a solid. Yield 101mg,0.45mmol, 100%.

Step 3 Synthesis of 4-chloro-N-hydroxy-3- (trifluoromethyl) benzimidoyl chloride (C20).

To a solution of compound C19(101mg,0.45mmol) in N, N-dimethylformamide (1.05mL) was added N-chlorosuccinimide (0.45M in N, N-dimethylformamide, 1.05mL,0.47 mmol). The reaction mixture was heated to 60 ℃ for 3 hours, then cooled to room temperature and used directly in the following step.

Step 4 Synthesis of 2- ({3- [ 4-chloro-3- (trifluoromethyl) phenyl ] -4, 5-dihydro-1, 2-oxazol-5-yl } methyl) -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (4).

A solution of compound C18 (0.4M in dichloromethane, 0.375mL,0.15mmol) was added to the crude reaction mixture from the previous step, followed by N-methylmorpholine (1.0M in N, N-dimethylformamide, 0.60mL,0.60mmol) and the reaction mixture was left at room temperature for 66 hours. After removal of the solvent in vacuo, the residue was dissolved in 1, 2-dichloroethane (5.0mL) and treated with 50% saturated aqueous sodium bicarbonate solution (4.0 mL). The aqueous layer was extracted with 1, 2-dichloroethane (4.0ml) and the combined organic layers were concentrated in vacuo. Purification via reverse phase High Pressure Liquid Chromatography (HPLC) (column: Phenomenex Gemini C18,5 μm; mobile phase A: 0.1% aqueous ammonium hydroxide solution (v/v); mobile phase B: 0.1% aqueous ammonium hydroxide in methanol (v/v); gradient: 5% to 100% B) yielded the material designated as the designated 3, 5-disubstituted dihydro-1, 2-oxazole isomer (based on 2-dimensional NMR experiments). This was concentrated three times from ethyl acetate to afford the title compound as a yellow solid. Yield 5.7mg,0.011mmol,7％.LCMS m/z505.9(M+1).¹H NMR(400MHz,CDCl₃)8.24(d, J ═ 1.2Hz,1H),7.87(d, J ═ 2.2Hz,1H),7.54-7.64(m,2H),7.45(d, J ═ 7.8Hz,1H),7.26(d, J ═ 8Hz,1H, assumed; partially obscured by solvent peaks), 7.13-7.16(m,1H),5.11-5.20(m,1H),4.45(ddd, J ═ 14.3,7.0,4.1Hz,1H),4.31(ddd, J ═ 14.3,7.6,4.3Hz,1H),3.87-4.04(m,3H),3.74(dd, J ═ 14.4,6.7Hz,1H),3.63(dd, one-half ABX mode, J ═ 17.5,10.7Hz,1H),3.47(dd, one-half ABX mode, J ═ 17.6,7.2Hz,1H),2.28 (brs, 3H).

Example 5

2- { cis-2- [ 4-fluoro-2- (trifluoromethyl) phenoxy]Cyclopentyl } -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ]]Pyrazine-1, 6-dione (5)

Step 1. Synthesis of trans-2- [ (2-hydroxyethyl) amino ] cyclopentanol (C21).

Reacting 6-oxabicyclo [3.1.0]]A mixture of hexane (3.00g,35.7mmol) and 2-aminoethanol (2.18g,35.7mmol) in ethanol (15mL) was stirred in a sealed tube at 80 ℃ for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by silica gel chromatography (eluent methanol in dichloromethane) gave the title compound. Yield 1.6g,11mmol, 31%.¹H NMR(400MHz,DMSO-d₆)4.43-4.64(br m,2H),3.68-3.75(m,1H),3.44(t,J＝5.6Hz,2H),2.71-2.77(m,1H),2.58-2.63(m,2H),1.73-1.89(m,2H),1.47-1.64(m,2H),1.34-1.44(m,1H),1.17-1.28(m,1H).

Step 2. Synthesis of 2- [ trans-2-hydroxycyclopentyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (C22).

The reaction of compound C21 with P1 was carried out according to the general procedure for synthesis 1 in example 1. When the reaction was assessed to be complete by thin layer chromatography,the reaction mixture was diluted with water. The aqueous layer was extracted three times with 5% methanol in dichloromethane and the combined organic layers were dried over sodium sulfate and dried in vacuo. Chromatography on silica gel (eluent: methanol in dichloromethane) and trituration with ethyl acetate afforded the title compound as an off-white solid. Yield 340mg,1.04mmol, 22%. LCMS M/z 329.0(M +1).¹HNMR(300MHz,DMSO-d₆)8.27(s,1H),7.80(d,J＝7.3Hz,1H),7.42(s,1H),7.08(d,J＝7.3Hz,1H),4.85-4.98(br m,1H),4.44-4.60(m,1H),4.03-4.36(m,3H),3.59-3.68(m,2H),2.15(s,3H),1.42-1.96(m,6H).

Step 3. Synthesis of 2- { cis-2- [ 4-fluoro-2- (trifluoromethyl) phenoxy ] cyclopentyl } -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (5).

Triphenylphosphine (12.2mg,0.046mmol) was added to a solution of C22(11mg,0.033mmol) and 4-fluoro-2- (trifluoromethyl) phenol (7.4mg,0.041mmol) in tetrahydrofuran (0.5 mL). The reaction mixture was treated with a solution of diisopropyl azodicarboxylate (94%, 0.015mL,0.071mmol) in tetrahydrofuran and heated at 50 ℃ for 18 hours and then at 90 ℃ for 4 hours. The same amounts of triphenylphosphine and diisopropyl azodicarboxylate were added again and continued at 90 ℃ for an additional 4 days. The mixture was concentrated in vacuo. Purification by reverse phase HPLC (column: Waters Xbridge C18,5 μm; mobile phase A: 0.03% aqueous ammonium hydroxide solution (v/v); mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v); gradient: 40% -100% B) gave the title compound. Yield 2.8mg, 5.7. mu. mol, 17%. LCMS M/z 491.1(M +1). Retention time: 2.32 min (column: Waters Atlantis dC18,4.6X 50mm,5 μm; mobile phase A: 0.05% trifluoroacetic acid in water (v/v); mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); gradient: 5% -95% B over 4.0 min, linear; flow rate: 2 mL/min).

Example 6

7- (4-methyl-1H-imidazol-1-yl) -2- ({ (2S,3S,5R) -3-methyl-5- [4- (trifluoromethyl) phenyl]Fourthly Hydrofuran-2-yl } methyl) -3, 4-dihydro-2H-pyridineAnd [1,2-a ]]Pyrazine-1, 6-dione (6)

Step 1. Synthesis of (5S) -5- ({ [ tert-butyl (diphenyl) silyl ] oxy } methyl) furan-2 (5H) -one (C23).

Imidazole (1.22g,17.6mmol) and tert-butyl (diphenyl) silyl chloride (3.95mL,15.4mmol) were added to a solution of (5S) -5- (hydroxymethyl) furan-2 (5H) -one (1.60g,14.0mmol) in N, N-dimethylformamide (50mL) and the reaction mixture was stirred at room temperature for 18H. It was then partitioned between tert-butyl methyl ether and water; the organic layer was washed twice with water, dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 5% -30% ethyl acetate in heptane) afforded the product as a white solid. Yield 5.20g, quantitative.¹H NMR(400MHz,CDCl₃)7.63-7.66(m,4H),7.38-7.49(m,7H),6.19(dd, J ═ 5.7,2.0Hz,1H),5.06-5.10(m,1H),3.93(dd, half ABX pattern, J ═ 10.9,4.5Hz,1H),3.88(dd, half ABX pattern, J ═ 10.8,5.0Hz,1H),1.05(s,9H).

Step 2. Synthesis of (4S,5S) -5- ({ [ tert-butyl (diphenyl) silyl ] oxy } methyl) -4-methyldihydrofuran-2 (3H) -one (C24).

Copper (I) bromide-dimethyl sulfide complex (99%, 3.65g,17.6mmol) was suspended in diethyl ether (25mL) and cooled to 0 ℃. After dropwise addition of methyllithium (1.6M solution in diethyl ether, 22.0mL,35.2mmol), the reaction mixture was cooled to-25 ℃. A solution of compound C23(3.10g,8.79mmol) in diethyl ether (20mL) was added at such a rate that the reaction temperature was maintained below-20 ℃. After 30 min, the reaction was quenched with saturated aqueous ammonium chloride (50mL) and warmed to room temperature. Extracting the mixture with diethyl ether, combining the organic layers, drying over magnesium sulfate, and filteringFiltered and concentrated under reduced pressure to give the product as a thick oil which was used in the next step without additional purification. Yield 3.20g,8.68mmol, 99%.¹H NMR(400MHz,CDCl₃)7.65-7.69(m,4H),7.38-7.48(m,6H),4.09-4.13(m,1H),3.87(dd, half ABX pattern, J ═ 11.5,3.3Hz,1H),3.73(dd, half ABX pattern, J ═ 11.5,3.5Hz,1H),2.83(dd, J ═ 17.6,8.8Hz,1H),2.53-2.64(m,1H),2.18(dd, J ═ 17.4,7.0Hz,1H),1.14(d, J ═ 7.0Hz,3H),1.06(s,9H).

Step 3. Synthesis of (4S,5S) -5- ({ [ tert-butyl (diphenyl) silyl ] oxy } methyl) -4-methyl-2- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-ol (C25).

Finely ground cerium chloride (95%, 6.98g,26.9mmol) was heated at 135 ℃ under high vacuum for 2 hours and then cooled to room temperature. To this material was added a solution of compound C24(3.20g,8.68mmol) in tetrahydrofuran (40 mL); the resulting mixture was stirred for 1 hour and then cooled to an internal temperature of-45 ℃. [4- (trifluoromethyl) phenyl ] magnesium bromide (0.48M solution in tetrahydrofuran, 54.3mL,26.1mmol) was added at a rate to maintain the reaction temperature below-40 ℃ and stirring was continued for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (30mL) and filtered through celite. The filtrate was extracted with tert-butyl methyl ether and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The oily product obtained was used without additional purification. Yield 4.4g,8.6mmol, 99%.

Step 4. Synthesis of tert-butyl ({ (2S,3S,5R) -3-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methoxy) diphenylsilane (C26).

Compound C25(4.4g,8.6mmol) was dissolved in dichloromethane (50mL) and cooled to-78 ℃. Triethylsilane (98%, 6.97mL,42.8mmol) was added, followed by dropwise addition of boron trifluoride etherate (98%, 5.50mL,42.7 mmol). After 1 hour at-78 ℃, the reaction was quenched with saturated aqueous sodium bicarbonate, warmed to room temperature, and extracted with tert-butyl methyl ether. The combined organic layers were dried over magnesium sulfate, filtered, combined with the product of the same reaction on 2.5g (4.9mmol) of C25, and concentrated in vacuo. On silica gelSub-chromatographic purification [1) gradient: 0% -2.5% ethyl acetate in heptane; 2) eluent 1% ethyl acetate in heptane]The product was obtained as an oil (second eluting isomer from the column). Yield 1.19g,2.39mmol, 18%. the relative stereochemistry indicated is based on the product of the following step¹H NMR studies. The products of the relevant reactions (see below) are assigned the corresponding stereochemistry.¹H NMR(400MHz,CDCl₃)7.70-7.75(m,4H),7.51(s,4H),7.36-7.48(m,6H),5.10(dd, J ═ 7.0,6.8Hz,1H),3.91(dd, half ABX mode, J ═ 10.9,4.1Hz,1H),3.80(dd, half ABX mode, J ═ 10.9,4.3Hz,1H),3.72(ddd, J ═ 7.1,4.1,4.0Hz,1H),2.29-2.41(m,1H),1.97-2.09(m,2H),1.09(s,9H),1.07(d, J ═ 6.8Hz,3H).

Step 5. Synthesis of { (2S,3S,5R) -3-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methanol (C27).

Tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 2.62mL,2.62mmol) was added to a solution of Compound C26(1.19g,2.39mmol) in tetrahydrofuran (15 mL). After 1 hour at room temperature, tert-butyl methyl ether was added and the mixture was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 10% -50% ethyl acetate in heptane) afforded the product as a colorless oil. Yield 530mg,2.04mmol, 85%. the relative stereochemistry indicated is supported by the NOE study of C27 and its aryl stereoisomer (which was obtained in the same way from the first eluting isomer of the previous step).¹H NMR(400MHz,CDCl₃)7.60(br d,J＝8.0Hz,2H),7.44-7.49(m,2H),5.09(dd,J＝7.2,7.0Hz,1H),3.84-3.91(m,1H),3.67-3.75(m,2H),2.16-2.27(m,1H),2.05-2.10(m,2H),1.90(br s,1H),1.13(d,J＝6.8Hz,3H).

Step 6, synthesizing { (2S,3S,5R) -3-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl methanesulfonate (C28).

The product was prepared as an oil from compound C27 following the general procedure for the synthesis of compound C8 in example 1. Yield 689mg,2.04mmol, 100%.¹H NMR(400MHz,CDCl₃)7.61(br d,J＝8.1Hz,2H),7.45-7.49(m,2H),5.13 (brdd, J ═ 7.1,6.9Hz,1H),4.43(dd, half of the ABX pattern, J ═ 11.0,3.4Hz,1H),4.37(dd, half of the ABX pattern, J ═ 11.0,5.6Hz,1H),3.90(ddd, J ═ 7.2,5.6,3.3Hz,1H),3.07(s,3H),2.18-2.30(m,1H),2.07-2.12(m,2H),1.17(d, J ═ 6.8Hz,3H).

Step 7. Synthesis of 2- [ ({ (2S,3S,5R) -3-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl) amino ] ethanol (C29).

Compound C28(689mg,2.04mmol) was combined with 2-aminoethanol (96%, 2mL,30mmol) and heated to 85 ℃ for 2 h. After cooling to room temperature, the reaction mixture was partitioned between tert-butyl methyl ether and water (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the product as a thick oil. Yield 618mg,2.04mmol, 100%. LCMSM/z 304.2[ M + H ]⁺].¹H NMR(400MHz,CDCl₃)7.59(br d,J＝8Hz,2H),7.42-7.47(m,2H),5.05(br dd,J＝6.8,6.6Hz,1H),3.69-3.75(m,1H),3.67(t,J＝5.3Hz,2H),2.79-2.94(m,4H),2.01-2.12(m,3H),1.11(d,J＝6.2Hz,3H).

Step 8. Synthesis of 7- (4-methyl-1H-imidazol-1-yl) -2- ({ (2S,3S,5R) -3-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (6).

To a solution of compound P2(514mg,2.01mmol) and C29(610mg,2.01mmol) in dichloromethane (20mL) were added N, N-diisopropylethylamine (1.23mL,7.06mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylHexafluorophosphate (HATU, 99%, 1.78g,4.63 mmol). The reaction mixture was heated at reflux for 2 hours, then diluted with additional dichloromethane and washed with saturated aqueous sodium bicarbonate, water and with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient: 0% -5% [ -0.7M ammonia in methanol solution)]In ethyl acetate). The off-white foam from the column was treated with ethyl acetate; a precipitate formed after standing. Separating by filtration and using lessThe amount of ethyl acetate and t-butyl methyl ether washed to give the product as a white solid. Yield 243mg,0.499mmol, 25%. LCMS M/z 487.3[ M + H ]⁺].¹H NMR(400MHz,CDCl₃)8.33(d, J ═ 1.3Hz,1H),7.62(br d, J ═ 8.1Hz,2H),7.49(d, J ═ 7.7Hz,1H),7.43(br d, J ═ 8Hz,2H),7.29(d, J ═ 7.7Hz,1H),7.15-7.17(m,1H),5.04(br dd, J ═ 7,7Hz,1H),4.40(ddd, half ABXY mode, J ═ 14.2,7.2,4.2Hz,1H),4.30(ddd, half ABXY mode, J ═ 14.2,7.7,4.2Hz,1H),4.22(dd, J ═ 14.0,2.5, 1H, 3.99, J ═ 14.2,7.2, 3.9H, 3.9, 3.19H, 3.3H, 3.9, 3.7, 3H, 3.19H, 3.9, 3.3H, 3H, 3.3.7, 3H, 3.7, 3H, 1H, 3H, 1H, 3H.

Example 7

2- ({ (2S,4R,5S) -4-fluoro-5- [4- (trifluoromethyl) phenyl]Tetrahydrofuran-2-yl } methyl) -7- (4-methyl 1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a]Pyrazine-1, 6-dione (7)

Step 1. Synthesis of (5S) -5- ({ [ tert-butyl (diphenyl) silyl ] oxy } methyl) dihydrofuran-2 (3H) -one (C30).

Following the general procedure for the synthesis of compound C23 in example 6, (5S) -5- (hydroxymethyl) dihydrofuran-2 (3H) -one was converted into the product. In this example, the crude product was recrystallized from hexane and the product was obtained as a white solid. Yield 10.6g,29.9mmol, 56%.¹H NMR(400MHz,CDCl₃)7.65-7.69(m,4H),7.38-7.48(m,6H),4.58-4.64(m,1H),3.89(dd, half ABX pattern, J ═ 11.3,3.3Hz,1H),3.70(dd, half ABX pattern, J ═ 11.3,3.3Hz,1H),2.69(ddd, half ABXY pattern, J ═ 17.7,10.2,7.1Hz,1H),2.52(ddd, half ABXY pattern, J ═ 17.8,10.0,6.6Hz,1H),2.18-2.35(m,2H),1.07(s,9H).

Step 2. Synthesis of (3R,5S) -5- ({ [ tert-butyl (diphenyl) silyl ] oxy } methyl) -3-fluorodihydrofuran-2 (3H) -one (C31).

A solution of C30(5.00g,14.1mmol) and N-fluoro-N- (phenylsulfonyl) benzenesulfonamide (4.45g,14.1mmol) in tetrahydrofuran (50mL) was cooled to-78 ℃. Lithium bis (trimethylsilyl) amide (1.0M solution in tetrahydrofuran, 14.1mL,14.1mmol) was added dropwise over 15 minutes and the reaction mixture was stirred at-78 ℃ for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (15mL), warmed to room temperature, and partitioned between tert-butyl methyl ether and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and with saturated aqueous sodium chloride, then dried over magnesium sulfate, filtered and concentrated in vacuo. After purification by silica gel chromatography (gradient: 5% -30% ethyl acetate in heptane), recrystallization from hexane gave the product as a white solid. Yield 1.64g,4.40mmol, 31%.¹H NMR(400MHz,CDCl₃)7.61-7.66(m,4H),7.39-7.50(m,6H),5.50(ddd,J＝52.7,8.6,7.6Hz,1H),4.69-4.74(m,1H),3.93(ddd,J＝11.6,2.2,2.2Hz,1H),3.62(dd,J＝11.5,2.0Hz,1H),2.71(dddd,J＝13.6,9.4,8.6,2.4Hz,1H),2.55(dddd,J＝27.7,13.6,8.8,7.7Hz,1H),1.06(s,9H).

Step 3. Synthesis of (3R,5S) -5- ({ [ tert-butyl (diphenyl) silyl ] oxy } methyl) -3-fluoro-2- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-ol (C32).

Compound C31 was converted to the product following the general procedure for the synthesis of compound C25 in example 6. The product was obtained as an oil which was used directly in the following step. Yield 2.20g,4.24mmol, 99%.

Step 4. Synthesis of tert-butyl ({ (2S,4R,5S) -4-fluoro-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methoxy) diphenylsilane (C33).

Using the general procedure for the synthesis of compound C26 in example 6, a product was prepared from C32. In this example, purification was performed using silica gel chromatography (gradient: 0% -5% ethyl acetate in heptane). Yield 890mg,1.77mmol, 42%. the relative stereochemistry indicated is consistent with the NOE study performed on the product.¹H NMR(400MHz,CDCl₃)7.69-7.74(m,4H),7.58-7.62(m,2H),7.53(br d, half of br AB quartet, J ═ 8Hz,2H),7.37-7.49(m,6H),5.22(br d, J ═ 26.6Hz,1H),4.93-5.11(m,1H),4.43-4.50(m,1H),4.10(dd, J ═ 11.4,3.2Hz,1H),3.84(dd, J ═ 11.3,3.5Hz,1H),2.08-2.32(m,2H),1.11(s,9H).

Step 5. Synthesis of { (2S,4R,5S) -4-fluoro-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methanol (C34).

According to the general procedure for the synthesis of compound C27 in example 6, a product was prepared from compound C33, which was obtained as a thick oil which slowly solidified. Yield 392mg,1.48mmol, 84%. the relative stereochemistry indicated is consistent with the NOE study performed on this sample.¹H NMR(400MHz,CDCl₃)7.64(br d,J＝8Hz,2H),7.52(br d,J＝8Hz,2H),5.19(br d,J＝26.8Hz,1H),5.04(dddd,J＝55.0,5.1,1.8,1.6Hz,1H),4.44-4.51(m,1H),4.03(dd,J＝12.0,2.8Hz,1H),3.77(dd,J＝12.0,4.8Hz,1H),2.00-2.25(m,2H),1.81(br s,1H).

Step 6, synthesizing { (2S,4R,5S) -4-fluoro-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl methanesulfonate (C35).

According to the general procedure for the synthesis of compound C8 in example 1, a product was prepared from compound C34, which was obtained as a thick oil which slowly solidified. Yield 505mg,1.48mmol, 100%.¹H NMR(400MHz,CDCl₃)7.65(br d, J ═ 8Hz,2H),7.52(br d, J ═ 8Hz,2H),5.25(br d, J ═ 26.6Hz,1H),4.98-5.15(m,1H),4.60-4.67(m,1H),4.57(dd, half ABX mode, J ═ 11.3,2.9Hz,1H),4.45(dd, half ABX mode, J ═ 11.3,4.9Hz,1H),3.10(s,3H),2.30(dd, J ═ 19.9,14.1,5.2,1.2Hz,1H),2.04(dd, J ═ 36.8,14.1,10.7,5.0Hz,1H).

Step 7. Synthesis of 2- [ ({ (2S,4R,5S) -4-fluoro-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl) amino ] ethanol (C36).

The product was prepared as an oil from compound C35 following the general procedure for the synthesis of compound C29 in example 6. Yield 454mg,1.48mmol, 100%. LCMS M/z308.1[ M + H ]⁺].¹H NMR(400MHz,CDCl₃)7.63(brd,J＝8Hz,2H),7.49(br d,J＝8Hz,2H),5.16(br d,J＝273Hz,1H),4.93-5.10(m,1H),4.44-4.52(m,1H),3.69(dd, J ═ 5.7,4.9Hz,2H),3.01(dd, half ABX mode, J ═ 12.5,3.5Hz,1H),2.84-2.96(m,3H),2.24(dddd, J ═ 21.1,14.1,5.0,1.2Hz,1H),1.90(dddd, J ═ 37.1,14.0,10.8,5.3Hz,1H).

Step 8. Synthesis of 2- ({ (2S,4R,5S) -4-fluoro-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl) -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (7).

Compound C36 was converted to the product according to the general procedure described for the synthesis of compound 6 in example 6. The product was obtained as a solid. Yield 50mg,0.10mmol, 7%. LCMS M/z 491.3[ M + H ]⁺].¹H NMR(400MHz,CDCl₃)8.39(br s,1H),7.67(br d,J＝8Hz,2H),7.51(d,J＝7.8Hz,1H),7.48(br d,J＝8Hz,2H),7.31(d,J＝7.6Hz,1H),7.16-7.18(m,1H),5.17(br d,J＝27.3Hz,1H),5.04(br dd,J＝55,5Hz,1H),4.57-4.65(m,1H),4.32-4.47(m,2H),4.30(dd,J＝14.2,2.7Hz,1H),4.02(ddd,J＝13.5,7.6,4.1Hz,1H),3.85(ddd,J＝13.5,7.2,4.1Hz,1H),3.53(dd,J＝14.1,8.2Hz,1H),2.33(d,J＝1.0Hz,3H),2.32-2.43(m,1H),1.77-1.95(m,1H).

Example 8

7- (4-methyl-1H-imidazol-1-yl) -2- [ (1S) -1- { (2S,5R) -5- [4- (trifluoromethyl) phenyl]Tetrahydrofuran derivatives Pyran-2-yl } ethyl]-3, 4-dihydro-2H-pyrido [1,2-a]Pyrazine-1, 6-diones (8)

Step 1. Synthesis of (2S,3S) -2- (dibenzylamino) hex-5-yn-3-ol (C38).

N-butyllithium (2.5M in hexane)Solution, 131mL,328mmol) was added dropwise over about 9 minutes to a solution of-70 ℃ ethynyl (trimethyl) silane (46.3mL,328mmol) in tetrahydrofuran (1L) and the reaction mixture was then stirred at-70 ℃ for 30 minutes. Adding (1S) -N, N-dibenzyl-1- [ (2R) -oxirane-2-yl]A solution of ethylamine (C37, see J.Barluenga et al, J.org.chem.1995,60,6696-6699) (79.6g,298mmol) in tetrahydrofuran (250 mL); the reaction mixture, which had warmed up as a result of the addition, was cooled again to about-65 ℃ and boron trifluoride etherate (37.6mL,298mmol) was added. The reaction mixture was stirred at-70 ℃ for 1.5 hours. Saturated aqueous ammonium chloride (200mL) was added and the mixture was allowed to warm to room temperature. The organic layer was washed with saturated aqueous sodium chloride solution, and the aqueous layer from the quenching reaction was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methanol (500mL), treated with potassium carbonate (206g,1.49mol) and stirred at room temperature for 18 h. After filtration through celite and washing with ethyl acetate, the crude product solution was concentrated in vacuo, dissolved in diethyl ether (1L), washed with water (250mL) and with saturated aqueous sodium chloride (75mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. After inoculation with a small sample of the solid product, heptane (60mL) was added and the mixture was stirred vigorously for 5 minutes and then filtered; the isolated solid was washed with heptane (50mL) to give the product as a light orange solid. Yield 37.3g,127mmol, 43%.¹H NMR(400MHz,CDCl₃)7.22-7.36(m,10H),4.53(s,1H),3.84(d, J ═ 13.1Hz,2H),3.63(ddd, J ═ 9.5,5.8,4.0Hz,1H),3.34(d, J ═ 13.3Hz,2H),2.80(dq, J ═ 9.4,6.6Hz,1H),2.46(ddd, half ABXY mode, J ═ 17.0,4.0,2.6Hz,1H),2.21(ddd, half ABXY mode, J ═ 17.0,6.0,2.6Hz,1H),1.86(dd, J ═ 2.7,2.5Hz,1H),1.07(d, J ═ 6.8, 3H).

Step 2, (2S,3S) -2- (dibenzylamino) -6- [4- (trifluoromethyl) phenyl ] hex-5-yn-3-ol (C39) is synthesized.

Compound C38(25.6g,87.2mmol) was added to a mixture of 1-bromo-4- (trifluoromethyl) benzene (12.2mL,87.1mmol), tetrakis (triphenylphosphine) palladium (0) (5.04g,4.36mmol) and copper (I) iodide (997mg,5.24mmol) in triethylamine (degassed with nitrogen for 20 min, 250mL via a dispersion tube beforehand) and the reaction mixture was taken at 75 deg.CStir for 1.75 hours. After cooling to room temperature, the reaction mixture was filtered through celite, and the filter pad was washed with diethyl ether (300 mL). The filtrate was poured into saturated aqueous ammonium chloride (250 mL); the aqueous layer was extracted with diethyl ether (250mL), and the combined organic layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. Heptane (150mL) was added to the residue and the mixture was again concentrated under reduced pressure. This material was combined with the corresponding solid from a similar reaction to C38(25.0g,85.2mmol) and purified by silica gel chromatography (eluent: 25% ethyl acetate in heptane). The isolated solid (-60 g) was recrystallized from heptane (250mL) to give the product as a red-brown solid. Yield 47.2g,108mmol, 63%.¹H NMR(400MHz,CDCl₃)7.49(br d, J ═ 8Hz,2H),7.20-7.33(m,12H),4.55(br s,1H),3.87(d, J ═ 13.1Hz,2H),3.70-3.76(m,1H),3.36(d, J ═ 13.3Hz,2H),2.93(dq, J ═ 9.4,6.7Hz,1H),2.76(dd Hz, half ABX mode, J ═ 17.4,3.9, 1H),2.48(dd, half ABX mode, J ═ 17.3,5.0Hz,1H),1.12(d, J ═ 6.7Hz,3H).

Step 3 Synthesis of (1S) -N, N-dibenzyl-1- { (2S) -5- [4- (trifluoromethyl) phenyl ] -2, 3-dihydrofuran-2-yl } ethanamine (C40).

Trifluoroacetic acid (18mL,230mmol) and bis- μ -chlorodichlorobis (vinyl) diplatin (II) (97%, 3.76g,6.20mmol) were added to a solution of compound C39(49.4g,113mmol) in dichloromethane (80 mL). After 1.5 h at room temperature, the reaction mixture was poured into aqueous sodium hydroxide (0.5M,500mL) and the aqueous layer was extracted with dichloromethane (250 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was combined with the crude product of a similar reaction performed on compound C39(10.0g,22.9mmol) and rapidly purified by silica gel chromatography over a short column (eluent: 2% ethyl acetate in heptane) to afford the product as a pale yellow-orange solid. Yield 46.5g,106mmol, 78%.¹H NMR(400MHz,CDCl₃)7.65(br AB quartet, J)_AB＝8.2Hz,Δν_AB＝40.1Hz,4H),7.40(br d,J＝8Hz,4H),7.23-7.28(m,4H),7.16-7.22(m,2H),5.46(dd,J＝2.9,2.7Hz,1H),4.80(ddd,J＝9.8,9.6,7.2Hz,1H),3.95(d,J＝13.8Hz,2H),3.63(d,J＝13.8Hz,2H),2.96-3.04(m,1H),2.73(br dd,J＝9.8,2.5Hz,2H),1.18(d,J＝6.8Hz,3H).

Step 4 Synthesis of (1S) -1- { (2S,5R) -5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethanamine (C41).

Palladium hydroxide on carbon (. about.50% water, 10 wt% palladium, 7.1g,5mmol) was added to a slurry of C40(22.0g,50.3mmol) and ammonium formate (80.2g,1.27mol) in methanol (500mL) and the reaction mixture was stirred at room temperature for 2.5 hours, then combined with a similar reaction to C41(24.5g,56.0mmol) and filtered through celite, rinsing with methanol (1L). The filtrate was concentrated in vacuo and treated with aqueous sodium hydroxide (0.2M, approximately 800mL) while maintaining the pH at about 9. It was extracted three times with ethyl acetate (0.5L,1L and 0.5L), and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to give the product as a pale yellow oil. It is presumed that hydrogenation occurred on the less hindered face; the stereochemistry specified also gives the IC obtained for the end product 8₅₀Support of (a), which indicates that the tetrahydrofuran moiety carries substituents in cis-direction (see table 1). Yield 26.3g,101mmol, 95%.¹H NMR(400MHz,CDCl₃)7.53(br AB quartet, J)_AB＝8Hz,Δν_AB＝50Hz,4H),4.96(dd,J＝7.4,7.0Hz,1H),3.70-3.77(m,1H),2.93-3.01(m,1H),2.33-2.43(m,1H),2.00-2.10(m,1H),1.66-1.85(m,2H),1.12(d,J＝6.4Hz,3H).

Step 5 Synthesis of 1- (2-hydroxyethyl) -5- (4-methyl-1H-imidazol-1-yl) -6-oxo-N- [ (1S) -1- { (2S,5R) -5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -1, 6-dihydropyridine-2-carboxamide (C42).

Bis (trimethylaluminum) -1, 4-diazabicyclo [2.2.2]Octane adduct (97%, 27.8g,105mmol) was added to a solution of compound C41(21.0g,81.0mmol) in tetrahydrofuran (800mL) and the mixture was heated to 40 ℃ for 45 min. Compound P3(28g,110mmol) was added and the reaction mixture was heated at reflux for 2 hours and then cooled to about 5 ℃ in an ice bath. With vigorous stirring, aqueous hydrochloric acid (1N,75mL) was slowly added dropwise { caution: gas evolution does not start immediately! And bringing the pH to 7-8. Aqueous sodium hydroxide (1M,75mL) was added and the mixture was filteredCelite was filtered and washed with ethyl acetate (3 × 500 mL). The organic layer from the filtrate was washed with aqueous sodium hydroxide (1M,150mL), with water (250mL), and with saturated aqueous sodium chloride (100mL), then dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting pasty solid was dried under vacuum at 50 ℃, then cooled, stirred with diethyl ether (300mL) for 20 minutes, and filtered to provide a cream-colored solid product, still containing approximately 13% by weight diethyl ether (via filtration)¹H NMR analysis). Corrected yield 31.0g,61.4mmol, 76% the material was used in the following step.¹H NMR(400MHz,CDCl₃)8.19(br d, J ═ 8.8Hz,1H),7.99(d, J ═ 1.2Hz,1H),7.58(br AB quartet, J)_AB＝8.2Hz,Δν_AB＝28.5Hz,4H),7.17(d,J＝7.6Hz,1H),6.98-7.00(m,1H),6.34(d,J＝7.6Hz,1H),5.00(dd,J＝7.4,6.6Hz,1H),4.34-4.41(m,1H),4.28-4.33(m,2H),4.06-4.14(m,1H),3.96-4.03(m,1H),3.71-3.78(m,1H),2.38-2.47(m,1H),2.15-2.23(m,1H),2.12(d,J＝1.0Hz,3H),1.80-1.95(m,2H),1.35(d,J＝6.6Hz,3H).

Step 6. Synthesis of 7- (4-methyl-1H-imidazol-1-yl) -2- [ (1S) -1- { (2S,5R) -5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (8).

Compound C42 (from previous step; corrected weight: 30.9g,61.2mmol) and triethylamine (16mL,110mmol) were combined in tetrahydrofuran (1L) and cooled in an ice bath. Methanesulfonyl chloride (98%, 8.5mL,110mmol) was added dropwise over 3-5 minutes, whereupon the cooling bath was removed. The reaction mixture was stirred at room temperature for 40 minutes, then cooled again in an ice bath and quenched with 1,3,4,6,7, 8-hexahydro-2H-pyrimido [1,2-a ]]Pyrimidine (97%, 30.2g,210mmol) was treated and stirred for 2.5 hours. To the cold reaction mixture was added ethyl acetate (500mL), which was then washed with water (2 × 500 mL). The aqueous layer was extracted with ethyl acetate (500mL), and the combined organic layers were washed with saturated aqueous sodium chloride (250mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (eluent: ethyl acetate, then 5% methanol in ethyl acetate) afforded the product-containing fractions; these were concentrated to a volume of approximately 500mL and the resulting slurry was stirred under nitrogen for 18 hours. After cooling to 7 ℃, the slurry was filtered to provide a white colorSolid (22 g). The filtrate was concentrated under reduced pressure, and the resulting solid was slurried with diethyl ether (70mL) and isolated by filtration; the material was recrystallized from ethyl acetate (60mL), cooled in ice, filtered, and washed with ice-cold ethyl acetate to give a cream solid (5.5 g). The two batches were combined and recrystallized from ethyl acetate (330mL) to give the product as a white solid. Yield 24.3g,49.9mmol, 82%. LCMS M/z 487.3[ M + H ]⁺].¹H NMR(400MHz,CDCl₃)8.25(d, J ═ 1.2Hz,1H),7.58(br d, J ═ 8Hz,2H),7.47(d, J ═ 7.6Hz,1H),7.42(br d, J ═ 8Hz,2H),7.30(d, J ═ 7.6Hz,1H),7.12-7.14(m,1H),4.92(dd, J ═ 7.4,6.8Hz,1H),4.82-4.90(m,1H),4.26-4.39(m,2H),4.09-4.16(m,1H),3.79(ddd, half ABXY mode, J ═ 13.3,7.3,4.3Hz,1H),3.67(ddd, half ABXY, 3,3.3, 3, 1H, 7.3H, 1H, 7.7.7, 7.3H, 1H, 15 (1H, 7.7.7H, 1H, 15H, 1H, 7.7.7.7.7.7.7.7, 1H, and.

Example 9

2- [ (1S) -1- { (2S,5R) -5- [ 4-chloro-2- (trifluoromethyl) phenyl]Tetrahydrofuran-2-yl } ethyl]-7-(4- methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a]Pyrazine-1, 6-dione (9)

Step 1. Synthesis of tert-butyl [ (2S) -4-chloro-3-oxobutan-2-yl ] carbamate (C43).

A solution of chloroacetic acid (23.2g,246mmol) in tetrahydrofuran (100mL) was added over 35 minutes to a-78 deg.C solution of lithium diisopropylamide in tetrahydrofuran (2.05M,240mL,492mmol) at a rate that maintained the internal temperature below-65 deg.C. After 30 minutes, the reaction mixture was quickly transferred to a (dry ice) -jacketed addition funnelDockel and add a solution of methyl N- (tert-butoxycarbonyl) -L-alanine (10.0g,49.2mmol) in tetrahydrofuran (120mL) over 5 min. Mechanical stirring was used for the reaction. The mixture was stirred for 30 minutes during which time the reaction mixture was warmed to 0 ℃. It was cooled to-78 ℃ and treated with a solution of acetic acid (41mL,720mmol) in tetrahydrofuran (41mL) over 10 minutes. At this point, the flask was immersed in an ice bath and stirring was continued for 1.5 hours while the reaction was warmed to 5 ℃. Water (250mL) was added followed by diethyl ether (400 mL); the organic layer was washed with saturated aqueous sodium bicarbonate (150mL) and with saturated aqueous sodium chloride (50mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford the product as a waxy pale yellow solid. Yield 9.47g,42.7mmol, 87%.¹H NMR(400MHz,CDCl₃)5.11(br d, J ═ 6Hz,1H),4.48-4.58(m,1H),4.28(AB quartet, J)_AB＝15.9Hz,Δν_AB＝8.3Hz,2H),1.44(s,9H),1.38(d,J＝7.1Hz,3H).

Step 2. Synthesis of tert-butyl [ (2S,3R) -4-chloro-3-hydroxybutan-2-yl ] carbamate (C44).

A solution of compound C43(16.0g,72.2mmol) in diethyl ether (100mL) was added to a mixture of lithium tri-tert-butoxide aluminum hydride (97%, 28.4g,108mmol) in diethyl ether (500 mL). After 3 hours at room temperature, the reaction mixture was cooled to 0 ℃, quenched with aqueous hydrochloric acid (1M,150mL), and extracted with tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a thick oil, which was stirred with methylcyclohexane (45 mL). The resulting solid was isolated by filtration and washed with methylcyclohexane to give the product (3.1 g). The filtrate was concentrated, mixed with pentane (25mL), heated to reflux, cooled with stirring, and inoculated with the solid product. The resulting material was filtered and washed with pentane to provide a solid product (8.1 g). Total yield 11.2g,50.1mmol, 69%.¹H NMR(400MHz,CDCl₃)4.76(br s,1H),3.77-3.87(m,1H),3.69-3.76(m,1H),3.65(dd, half ABX pattern, J ═ 11.3,3.9Hz,1H),3.53(dd, half ABX pattern, J ═ 11.3,8.0Hz,1H),2.95(br s,1H),1.45(s,9H),1.27(d, J ═ 6.8Hz,3H).

Alternative step 2. Synthesis of tert-butyl [ (2S,3R) -4-chloro-3-hydroxybutan-2-yl ] carbamate (C44).

0.1M potassium phosphate buffer, 2.0mM magnesium chloride was prepared as follows: combine potassium dihydrogen phosphate (9.86g,72.4mmol), potassium hydrogen phosphate (22.2g,127mmol) and magnesium chloride hexahydrate (0.812g,4.0mmol) in water (2L); the pH of the resulting solution was 7.05. To the phosphate buffer (1.8L) were added nicotinamide adenine dinucleotide phosphate, disodium salt trihydrate (1.9g,2.4mmol) and ketoreductase (Codexis, KRED-P1-E05) (8g), and the mixture was stirred at 22 ℃ for 45 minutes to dissolve the ketoreductase. Adding [ (2S) -4-chloro-3-oxobutan-2-yl]A solution of tert-butyl carbamate (C43) (50.0g,226mmol) in 2-propanol (200mL) and the resulting suspension was stirred at 30 ℃ for 46 h under a stream of nitrogen (10 mL/min) from the sparge inlet containing 2-propanol and water (1:1,300 mL). At this point, tert-butyl methyl ether (1L) was added to the reaction mixture, which was swirled for 20 minutes. The resulting emulsion was filtered through celite (200g), the filter cake was broken and washed with tert-butyl methyl ether (3 × 400 mL). The combined organic layers from the filtrate were dried over sodium sulfate (625g), filtered, and concentrated in vacuo to give the crude product as a red oil (50 g). The material was mixed with ethyl acetate (80mL) and treated with decolorizing charcoal (5g) over 10 minutes while gently heating. After filtration through celite, the solution was concentrated in vacuo and mixed with warm hexane (40mL) with stirring. After 18 hours, the resulting solid was collected by filtration and washed with pentane to provide the product as a white powder (14.14 g). The mother liquor was concentrated under reduced pressure to give an oil (32g), which was crystallized in the same manner with warm hexane (30mL) to obtain additional white powder product (13.65 g). Total yield 27.79g,124mmol, 55%.¹H NMR(400MHz,CDCl₃)4.77(br s,1H),3.77-3.87(m,1H),3.69-3.76(m,1H),3.65(dd, half ABX pattern, J ═ 11.1,3.9Hz,1H),3.53(dd, half ABX pattern, J ═ 11.3,8.0Hz,1H),3.00(br s,1H),1.45(s,9H),1.26(d, J ═ 6.8Hz,3H).

Step 3. Synthesis of (2R,3S) -3- [ (tert-butoxycarbonyl) amino ] -1-chlorobutan-2-yl 4-nitrobenzoate (C45).

A solution of Compound C44(15g,67mmol) in dichloromethane (400mL) was cooled to 0 deg.C and treated with TrisEthylamine (11.7mL,83.9mmol) and 4- (dimethylamino) pyridine (99%, 827mg,6.70 mmol). A solution of 4-nitrobenzoyl chloride (15.6g,84.1mmol) in dichloromethane (100mL) was then added and the reaction mixture was allowed to warm slowly to room temperature over 18 hours. Dichloromethane (500mL) was added and the solution was washed with brine in water (1M,250mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0% to 3% ethyl acetate in dichloromethane) gave the product as a pale yellow solid. Yield 23g,62mmol, 92%.¹H NMR(400MHz,CDCl₃)8.24-8.34(m,4H),5.28-5.33(m,1H),4.55(br d,J＝9Hz,1H),4.19-4.30(br m,1H),3.71-3.87(m,2H),1.38(br s,9H),1.25(d,J＝6.8Hz,3H).

Step 4. Synthesis of tert-butyl { (1S) -1- [ (2R) -oxiran-2-yl ] ethyl } carbamate (C46).

Aqueous potassium hydroxide (23.9g of 85% purity, 362mmol in 160mL water) was added dropwise to a0 ℃ solution of C45(27g,72mmol) in ethanol (1L) and the reaction mixture was stirred at 0 ℃ for 1 hour. At this point, it was diluted with water (1L) and extracted with tert-butyl methyl ether (2 × 500 mL). The combined organic layers were washed with aqueous sodium hydroxide (1M,2 × 250mL), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 5% -30% ethyl acetate in heptane) afforded the product as a colorless oil. Yield 11.9g,63.6mmol, 88%.¹H NMR(400MHz,CDCl₃)4.41(br s,1H),3.93-4.06(br m,1H),2.99(ddd,J＝3.9,2.5,2.5Hz,1H),2.74(dd,J＝4.7,4.0Hz,1H),2.61(br dd,J＝4.7,2.7Hz,1H),1.44(s,9H),1.27(d,J＝6.9Hz,3H).

Step 5. Synthesis of tert-butyl [ (2S,3S) -3-hydroxy-6- (trimethylsilyl) hex-5-yn-2-yl ] carbamate (C47).

N-butyllithium (2.5M in hexanes, 39.7mL,99mmol) was added dropwise to a solution of-20 ℃ ethynyl (trimethyl) silane (15mL,110mmol) in toluene (100mL) at a rate that maintained the reaction temperature below-15 ℃. The reaction mixture was stirred at this temperature for 15 minutes. Dimethylaluminum chloride (97%, 1.0M solution in hexane, 96mL,96mmol) was added and the reaction flask was immersed in an ice bath for 1 hour, thenThen warmed to room temperature for 30 minutes. After cooling the reaction mixture to 0 ℃, a solution of C46(6.2g,33mmol) in toluene (50mL) was added and stirring was continued at 0 ℃ for 1 hour, at which time the reaction mixture was allowed to warm to room temperature for 1 hour and then cooled to 0 ℃. A mixture of saturated aqueous citric acid (100mL) and water (100mL) was added and the ice bath was removed. Tert-butyl methyl ether (500mL) was added and the mixture was stirred for 15 min; the organic layer was then washed with water (100mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the product as a thick oil. Yield 7.2g,25mmol, 76%.¹H NMR(400MHz,CDCl₃)4.79(br s,1H),3.64-3.74(m,2H),2.48(dd, half ABX pattern, J ═ 16.9,7.4Hz,1H),2.43(dd, half ABX pattern, J ═ 16.9,5.3Hz,1H),2.36(br s,1H),1.45(s,9H),1.24(d, J ═ 6.6Hz,3H),0.17(s,9H).

Step 6. Synthesis of tert-butyl [ (2S,3S) -3-hydroxyhex-5-yn-2-yl ] carbamate (C48).

Potassium carbonate (6.97g,50.4mmol) was added to a solution of C47(7.2g,25mmol) in methanol (50 mL). After stirring at room temperature for 1.5 h, the reaction mixture was partitioned between water (50mL) and tert-butyl methyl ether (400 mL). The aqueous layer was extracted with tert-butyl methyl ether (100 mL); the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the product as a thick oil. Yield 5.0g,23mmol, 92%.¹H NMR(400MHz,CDCl₃)4.76(br s,1H),3.67-3.80(m,2H),2.74(br s,1H),2.41-2.44(m,2H),2.06(dd,J＝2.7,2.6Hz,1H),1.45(s,9H),1.23(d,J＝6.8Hz,3H).

Step 7. Synthesis of tert-butyl { (2S,3S) -6- [ 4-chloro-2- (trifluoromethyl) phenyl ] -3-hydroxyhex-5-yn-2-yl } carbamate (C49).

Compound C48 was reacted with 4-chloro-1-iodo-2- (trifluoromethyl) benzene using the general procedure described for the synthesis of compound C39 in example 8, except that in this example tert-butyl methyl ether was used instead of diethyl ether and no recrystallization was performed. The product was obtained as thick oil. Yield 19.2g,49.0mmol, 100%.¹H NMR(400MHz,CDCl₃)7.63(br d,J＝2.0Hz,1H),7.44-7.52(m,2H),4.80(br s,1H),3.73-3.84(m,2H),2.63-2.75(m,2H),1.45(s,9H),1.27(br d,J＝6.6Hz,3H).

Step 8 Synthesis of tert-butyl [ (1S) -1- { (2S) -5- [ 4-chloro-2- (trifluoromethyl) phenyl ] -5-methoxytetrahydrofuran-2-yl } ethyl ] carbamate (C50).

P-toluenesulfonic acid monohydrate (96%, 1.55g,7.82mmol) and di- μ -chlorodichlorobis (vinyl) diplatin (II) (97%, 545mg,0.900mmol) were added to a solution of C49(33g,84mmol) and trimethyl orthoformate (40mL,360mmol) in methanol (400mL), and the reaction mixture was stirred at room temperature for 3 hours. Additional di- μ -chlorodichlorobis (vinyl) diplatin (II) (97%, 500mg,0.82mmol) was introduced and stirring was continued for 3 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (400mL) and extracted with tert-butyl methyl ether; the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the product as a thick oil, which was directly subjected to the following reaction.

Step 9 Synthesis of tert-butyl [ (1S) -1- { (2S,5R) -5- [ 4-chloro-2- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] carbamate (C51).

Compound C50 from the previous step was converted to the product using the general procedure for the synthesis of compound C26 in example 6. In this case, the reaction was quenched by extraction with dichloromethane; the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 0% -10% ethyl acetate in heptane) gave a solid (41.8g), which was dissolved in methanol (50mL) and treated with water (. about.7 mL) until the solution became cloudy. After stirring for 2 hours, the mixture was filtered and the isolated solid was washed with a 3:7 mixture of methanol and water to provide a solid product (6.9 g). Concentrating the filtrate until a precipitate forms; it was isolated by filtration to give 15g of solid which was treated in the same manner to give additional solid product (9.5 g). Overall yield in two steps: 16.4g,41.6mmol, 50%.¹H NMR(400MHz,CDCl₃)7.77(br d,J＝8.4Hz,1H),7.61(br d,J＝2.2Hz,1H),7.53(br dd,J＝8.6,2.2Hz,1H),5.13(br dd,J＝8,7Hz,1H),4.67(br s,1H),3.84-3.94(m,2H),2.32-2.42(m,1H),2.01-2.11(m,1H),1.78-1.89(m,1H),1.58-1.68(m,1H),1.47(s,9H),1.26(d,J＝6.5Hz,3H).

Step 10 Synthesis of (1S) -1- { (2S,5R) -5- [ 4-chloro-2- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethanamine (C52).

Trifluoroacetic acid (25mL,340mmol) was added to a solution of C51(16.4g,41.6mmol) in dichloromethane (250 mL). The reaction mixture was stirred at room temperature for 18 hours, then poured into aqueous sodium hydroxide (1M,350 mL). Additional dichloromethane (500mL) was added and the aqueous layer was extracted with dichloromethane (2x 200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the product as a brown oil. Yield 12g,41mmol, 98%.¹H NMR(400MHz,CDCl₃)7.73(br d,J＝8.4Hz,1H),7.60(br d,J＝2.2Hz,1H),7.50-7.54(m,1H),5.17-5.23(m,1H),3.67-3.74(m,1H),3.01-3.09(m,1H),2.35-2.46(m,1H),1.98-2.09(m,1H),1.59-1.74(m,2H),1.14(d,J＝6.5Hz,3H).

Step 11 Synthesis of N- [ (1S) -1- { (2S,5R) -5- [ 4-chloro-2- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -1- (2-hydroxyethyl) -5- (4-methyl-1H-imidazol-1-yl) -6-oxo-1, 6-dihydropyridine-2-carboxamide (C53).

Compound C52 was converted to the product using the general procedure employed for the synthesis of compound C42 in example 8, except that C53 was not stirred with diethyl ether. The product was obtained as an off-white solid. Yield 21g,39mmol, 95%. LCMS M/z 539.3[ M + H ]⁺].¹H NMR(400MHz,CDCl₃)8.12(br d,J＝9Hz,1H),8.00-8.02(m,1H),7.89(br d,J＝8.5Hz,1H),7.62(d,J＝2.2Hz,1H),7.56(br dd,J＝8.5,2Hz,1H),7.22(d,J＝7.5Hz,1H),7.00-7.02(m,1H),6.39(d,J＝7.6Hz,1H),5.22(br dd,J＝8,7Hz,1H),4.36-4.46(m,1H),4.27-4.31(m,2H),3.93-4.07(m,2H),3.72-3.78(m,1H),2.40-2.49(m,1H),2.16-2.26(m,1H),2.14(d,J＝0.9Hz,3H),1.7-1.9(m,2H),1.36(d,J＝6.7Hz,3H).

Step 12. Synthesis of 2- [ (1S) -1- { (2S,5R) -5- [ 4-chloro-2- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (9).

Compound C53 was converted to the product using the general procedure described for the synthesis of Compound 8 in example 8. In this example, after silica gel chromatography (gradient: 0% -5% methanol in dichloromethane), the material from the chromatography was recrystallized from ethyl acetate to provide the product. The filtrate from the recrystallization was concentrated, triturated with diethyl ether, and recrystallized from ethyl acetate to provide additional product. The two batches were combined (25g), slurried in t-butyl methyl ether (50mL) and warmed to 50 ℃ for 15 minutes. Cooling and isolation by filtration gave the product as an off-white solid. Yield 24.7g,47.4mmol, 72%. LCMS M/z 521.3[ M + H ]⁺].¹HNMR(400MHz,CDCl₃)8.30 (brs,1H), 7.70 (brd, J, 8.4Hz,1H),7.57 (brd, J, 2.2Hz,1H),7.52(dd, J, 8.3,2.1Hz,1H),7.48(d, J, 7.8Hz,1H),7.30(d, J, 7.8Hz,1H),7.12-7.14(m,1H),5.14-5.20(m,1H),4.93(dq, J, 9.4,6.8Hz,1H),4.43(ddd, half ABXY mode, J, 14.1,7.0,3.9Hz,1H),4.26(ddd, half ABXY mode, J, 14.1,8.0, 4.0, 4.1H), 4.6.6H, 3.13H, 3.9H), 4.26(ddd, half ABXY mode, 1,8.0, 4.0, 3.3.3.6.6H, 3.6H, 3H, 2.17-2.27(m,1H),1.70-1.88(m,2H),1.31(d, J ═ 6.8Hz,3H).

Example 10

2- [ (1S) -1- { (2S,5R) -5- [3, 5-difluoro-4- (trifluoromethyl) phenyl]Tetrahydrofuran-2-yl } ethyl]- 7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a]Pyrazine-1, 6-diones (10)

Step 1. Synthesis of (2S,3S) -2- (dibenzylamino) -6- [3, 5-difluoro-4- (trifluoromethyl) phenyl ] hex-5-yn-3-ol (C54).

Compound C38 was converted to the product via reaction with 5-bromo-1, 3-difluoro-2- (trifluoromethyl) benzene using the method described for the synthesis of compound C49 in example 9. The product was obtained as a solid. Yield 3.10g,6.55mmol, 96%. LCMSM/z 474.2[ M + H ]⁺].¹H NMR(400MHz,CDCl₃)7.22-7.35(m,10H),6.74(d,J＝10.2Hz,2H),4.56(s,1H),3.86(d,J＝13.3Hz,2H),3.68-3.76(m,1H),3.34(d,J＝13.3Hz,2H),2.85-2.96(m,1H),2.79(dd,J＝17.4,3.7Hz,1H),2.47(dd,J＝17.4,4.3Hz,1H),1.11(d,J＝6.6Hz,3H).

Step 2 Synthesis of (1S) -N, N-dibenzyl-1- { (2S) -5- [3, 5-difluoro-4- (trifluoromethyl) phenyl ] -2, 3-dihydrofuran-2-yl } ethanamine (C55).

Compound C54 was converted to the product using the general procedure described for the synthesis of compound C40 in example 8. In this example, the reaction was quenched with saturated aqueous sodium bicarbonate instead of aqueous sodium hydroxide. The product was isolated as thick oil. Yield 1.96g,4.14mmol, 78%. LCMS M/z474.2[ M + H ]⁺].¹H NMR(400MHz,CDCl₃)7.38(br d, half of AB quartet, J ═ 7.4Hz,4H),7.25-7.30(m,4H),7.15-7.23(m,4H),5.50-5.53(m,1H),4.78(ddd, J ═ 9.8,9.8,7.0Hz,1H),3.91(d, J ═ 14.0Hz,2H),3.58(d, J ═ 13.7Hz,2H),2.92-3.01(m,1H),2.68-2.83(m,2H),1.19(d, J ═ 7.0Hz,3H).

Step 3 Synthesis of (1S) -1- { (2S,5R) -5- [3, 5-difluoro-4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethanamine (C56).

The product was prepared from C55 following the general procedure for the synthesis of compound C41 in example 8, except that t-butyl methyl ether was used instead of ethyl acetate in the work-up. The product obtained was an oil. Yield 629mg,2.10mmol, 90%.¹HNMR(400MHz,CDCl₃)7.00(d,J＝10.2Hz,2H),4.91(dd,J＝7.2,6.8Hz,1H),3.70-3.77(m,1H),2.93-3.01(m,1H),2.34-2.44(m,1H),1.99-2.09(m,1H),1.73-1.87(m,3H),1.61-1.71(m,1H),1.11(d,J＝6.6Hz,3H).

Step 4 Synthesis of N- [ (1S) -1- { (2S,5R) -5- [3, 5-difluoro-4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -1- (2-hydroxyethyl) -5- (4-methyl-1H-imidazol-1-yl) -6-oxo-1, 6-dihydropyridine-2-carboxamide (C57).

The conversion of C56 to product used the overall procedure described in example 8 for the synthesis of compound C42. In this case, the cooled reaction mixture is treated with sodium hydroxideThe solution (1M,25mL) was quenched and then extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with tert-butyl methyl ether to give the product as a white solid. Yield 730mg,1.35mmol, 65%.¹H NMR(400MHz,CDCl₃)8.61(br d,J＝9Hz,1H),7.96(br s,1H),7.17(d,J＝7.6Hz,1H),7.11(br d,J＝10.3Hz,2H),6.98-7.00(m,1H),6.41(d,J＝7.4Hz,1H),4.95(dd,J＝7.2,6.6Hz,1H),4.30-4.46(m,3H),4.07-4.18(m,2H),3.94-4.02(m,1H),2.41-2.50(m,1H),2.12-2.22(m,1H),2.08(br s,3H),1.74-1.93(m,2H),1.35(d,J＝6.6Hz,3H).

Step 5 Synthesis of 1- (2-chloroethyl) -N- [ (1S) -1- { (2S,5R) -5- [3, 5-difluoro-4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -5- (4-methyl-1H-imidazol-1-yl) -6-oxo-1, 6-dihydropyridine-2-carboxamide (C58).

Thionyl chloride (1.0mL,14mmol) was added to a0 ℃ mixture of compound C57(1.00g,1.85mmol) in dichloromethane (20 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours, then cooled to 0 ℃ and quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the product as a viscous yellow foam which was directly subjected to the following procedure. Yield 1.00g,1.79mmol, 97%. LCMSM/z 559.1[ M + H ]⁺].

Step 6. Synthesis of 2- [ (1S) -1- { (2S,5R) -5- [3, 5-difluoro-4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (10).

Lithium bis (trimethylsilyl) amide (1M solution in THF, 2.24mL,2.24mmol) was added dropwise to a0 ℃ solution of compound C58 (from the previous step, 1.00g,1.79mmol) in tetrahydrofuran (20mL) and the reaction mixture was stirred at 0 ℃ for 15 min. The ice bath was removed and stirring was continued for 1 hour. After cooling to 0 ℃, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 0% -20% methanol in ethanol)Ethyl acetate) afforded a pale yellow foam (709mg) which was recrystallized from tert-butyl methyl ether to give the product as a white solid. Yield (two batches) 404mg,0.773mmol, 43%. LCMS M/z 523.3[ M + H [, M + ]⁺].¹HNMR(400MHz,CDCl₃)8.30(br s,1H),7.49(d,J＝7.8Hz,1H),7.34(d,J＝7.8Hz,1H),7.13-7.15(m,1H),6.98(br d,J＝10.3Hz,2H),4.81-4.89(m,2H),4.51(ddd,J＝14.2,6.2,4.1Hz,1H),4.21(ddd,J＝14.2,8.2,4.1Hz,1H),4.07-4.14(m,1H),3.63-3.77(m,2H),2.38-2.47(m,1H),2.31(s,3H),2.17-2.26(m,1H),1.76-1.92(m,2H),1.31(d,J＝6.8Hz,3H).

Examples 11 and 12

7- (4-methyl-1H-imidazol-1-yl) -2- ({ (2S,5R) -5-methyl-5- [4- (trifluoromethyl) phenyl]Tetrahydrofuran derivatives Pyran-2-yl } methyl) -3, 4-dihydro-2H-pyrido [1,2-a]Pyrazine-1, 6-dione (11) and 7- (4-methyl-1H-imidazole-) 1-yl) -2- ({ (2R,5S) -5-methyl-5- [4- (trifluoromethyl) phenyl]Tetrahydrofuran-2-yl } methyl) -3, 4-dihydro-2H- Pyrido [1,2-a ]]Pyrazine-1, 6-dione (12)

Step 1. Synthesis of 2- [4- (trifluoromethyl) phenyl ] hex-5-en-2-ol (C59).

A solution of hex-5-en-2-one (1.00g,10.2mmol) in tetrahydrofuran (3mL) was added to [4- (trifluoromethyl) phenyl at 0 deg.C]Magnesium bromide (0.26M solution in tetrahydrofuran, 50mL,13 mmol). After 15 minutes at 0 ℃ the reaction mixture was heated to 70 ℃ for 18 hours, then cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, water and with saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 10% -30% ethyl acetate in heptane) gave the product as a dark gold colored oil. Yield 1.86g,7.61mmol, 75%. of crude product¹H NMR(400MHz,CDCl₃) Characteristic peak 7.59(br AB quartet, J)_AB＝8Hz,Δν_AB＝19Hz,4H),5.74-5.85(m,1H),4.93-5.01(m,2H),1.59(s,3H).

Step 2. Synthesis of { 5-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methanol (C60).

3-Chloroperoxybenzoic acid (70%, 3.73g,15.1mmol) was added to a solution of C59(1.85g,7.57mmol) in dichloromethane (50 mL). After 3 hours, the reaction mixture was washed with 10% aqueous sodium sulfite solution, with saturated aqueous sodium bicarbonate solution and with water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. According to¹H NMR, this crude product contained a small amount of intermediate epoxide [ characteristic epoxide peak at 400MHz in CDCl₃2.87-2.92(m,1H),2.75(dd, J ═ 4.7,4.1Hz,1H),2.45(dd, J ═ 4.9,2.7Hz,1H)]. The crude product was therefore dissolved in dichloromethane (30mL), treated with p-toluenesulfonic acid monohydrate (142mg,0.746mmol) and allowed to stir at room temperature for 18 h. The reaction mixture was then washed with saturated aqueous sodium bicarbonate and with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (gradient: 20% -40% ethyl acetate in heptane) afforded the product as a yellow oil¹H NMR analysis consisted of an approximately 1:1 mixture of diastereomers. Yield 1.65g,6.34mmol, 84%.¹H NMR(400MHz,CDCl₃) Characteristic peaks of 7.49-7.61(m,4H), [4.29-4.37(m) and 4.13-4.20(m), total 1H]3.78(br dd, J11.6, 2.4Hz) and 3.71(br dd, J11.4, 2.8Hz), total 1H]3.54-3.64(m,1H),2.03-2.28(m,3H),1.55 and 1.53(2s, total 3H).

Step 3. Synthesis of { cis-5-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl 4-methylbenzenesulfonate (C61).

4-Methylbenzenesulfonyl chloride (98%, 1.60g,8.22mmol) was added to a solution of C60(1.65g,6.34mmol) and triethylamine (1.32mL,9.47mmol) in dichloromethane (25mL) at 0 deg.C and the reaction mixture was allowed to slowly warm to room temperature as the ice bath melted. After 18 hours, the solution was washed with saturated aqueous sodium bicarbonate and with water. The organic layer was concentrated in vacuo and purified by silica gel chromatography (gradient: 10% -40% ethyl acetate in heptane). To obtainWhite solid product, which is the more polar isomer. Yield 830mg,2.00mmol, 32%.¹H NMR(400MHz,CDCl₃)7.79(br d, J ═ 8.4Hz,2H),7.44(br AB quartet, J)_AB＝8.2Hz,Δν_AB31.0Hz,4H),7.34(br d, J ═ 8Hz,2H),4.37-4.44(m,1H),4.05(dd, half ABX pattern, J ═ 10.1,4.4Hz,1H),4.00(dd, half ABX pattern, J ═ 10.1,5.8Hz,1H),2.47(s,3H),2.08-2.22(m,3H),1.62-1.71(m,1H),1.48(s,3H), the less polar isomer { trans-5-methyl-5- [4- (trifluoromethyl) phenyl]Tetrahydrofuran-2-yl } methyl 4-methylbenzenesulfonate (C62) as a thick colorless gum (878mg).¹H NMR(400MHz,CDCl₃) The relative stereochemistry of C61 and C62 indicated are specified based on the NOE study, 7.84(br d, J ═ 8.4Hz,2H),7.56(br d, J ═ 8.5Hz,2H),7.44(br d, J ═ 8.5Hz,2H),7.35-7.39(m,2H),4.19-4.26(m,1H),4.06-4.14(m,2H),2.46(s,3H),2.16-2.24(m,1H),2.04-2.12(m,1H),1.82-1.89(m,2H),1.47(s,3H).

Step 4. Synthesis of 2- [ ({ cis-5-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl) amino ] ethanol (C63).

A mixture of 2-aminoethanol (856mg,14.0mmol) and C61(830mg,2.00mmol) in acetonitrile (10mL) was heated at 90 ℃ for 18 h, then cooled to room temperature, diluted with ethyl acetate and washed with water and with saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the product as a pale yellow oil. Yield 559mg,1.84mmol, 92%. LCMS M/z 304.1[ M + H ]⁺].¹H NMR(400MHz,CDCl₃)7.56(br AB quartet, J)_AB＝8.4Hz,Δν_AB＝15.9Hz,4H),4.29-4.37(m,1H),3.65(t,J＝5.3Hz,2H),2.79-2.91(m,2H),2.74(d,J＝5.9Hz,2H),2.06-2.25(m,3H),1.54-1.64(m,1H),1.52(s,3H).

Step 5 Synthesis of 7- (4-methyl-1H-imidazol-1-yl) -2- ({ (2S,5R) -5-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (11) and 7- (4-methyl-1H-imidazol-1-yl) -2- ({ (2R,5S) -5-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (12).

Compound C63 was converted to the product using the general procedure described for the synthesis of compound 6 in example 6. In this example, silica gel chromatography was performed using a gradient of 0% to 20% methanol in ethyl acetate. The racemic product was resolved into its enantiomers via supercritical fluid chromatography (column: Chiralcel OJ-H,5 μm; eluent: 4:1 carbon dioxide/methanol, containing 0.2% isopropylamine). The first elution peak was example 11, which was obtained as a solid. Yield 47mg, 97. mu. mol, 5%. LCMS M/z 487.2[ M + H ]⁺].¹H NMR(400MHz,CDCl₃)8.23(d, J ═ 1.4Hz,1H),7.57(br AB quartet, J)_AB＝8.2Hz,Δν_AB36.4Hz,4H),7.46(d, J ═ 7.6Hz,1H),7.28(d, J ═ 7.6Hz,1H, presumably; partial occlusion by solvent peaks), 7.14-7.15(m,1H),4.39-4.51(m,2H),4.28(ddd, half ABXY pattern, J ═ 14.3,8.0,4.1Hz,1H),4.10(dd, J ═ 13.9,3.1Hz,1H),4.01(ddd, J ═ 13.5,8.0,4.1Hz,1H),3.80(ddd, J ═ 13.5,7.2,4.1Hz,1H),3.34(dd, J ═ 14.0,8.1Hz,1H),2.30(d, J ═ 1.0Hz,3H),2.17-2.25(m,3H),1.63-1.73(m,1H),1.50(s,3H), the second example obtained solid elution. Yield 39mg, 80. mu. mol, 4%. LCMS M/z 487.2[ M + H ]⁺].¹H NMR(400MHz,CDCl₃)8.22(d, J ═ 1.2Hz,1H),7.59-7.63(m,2H),7.50-7.54(m,2H),7.46(d, J ═ 7.6Hz,1H),7.28(d, J ═ 7Hz,1H, presumably; partially obscured by solvent peaks), 7.13-7.15(m,1H),4.39-4.50(m,2H),4.28(ddd, half ABXY pattern, J ═ 14.2,7.9,4.0Hz,1H),4.10(dd, J ═ 13.9,3.1Hz,1H),4.01(ddd, J ═ 13.5,7.9,4.0Hz,1H),3.80(ddd, J ═ 13.5,7.2,4.1Hz,1H),3.33(dd, J ═ 14.0,8.1Hz,1H),2.29(d, J ═ 1.0Hz,3H),2.17-2.25(m,3H),1.63-1.73(m,1H),1.50(s,3H), absolute chemical compounds based on stereochemistry₅₀Differences in values (see table 1); compounds having the (2S,5R) configuration around the tetrahydrofuran ring are generally more potent than their (2R,5S) enantiomer.

Examples 13 and 14

7- (4-methyl-1H-imidazol-1-yl) -2- ({ cis-2-methyl-5- [4- (trifluoromethyl) phenyl]Tetrahydrofuran- 2-yl } methyl) -3 (a) is,4-dihydro-2H-pyrido [1,2-a ]]Pyrazine-1, 6-dione, formate (13) and 7- (4-methyl-1H-imidazole) Azol-1-yl) -2- ({ trans-2-methyl-5- [4- (trifluoromethyl) phenyl]Tetrahydrofuran-2-yl } methyl) -3, 4-dihydro-2H- Pyrido [1,2-a ]]Pyrazine-1, 6-dione, formate (14)

Step 1. Synthesis of methyl 5- [4- (trifluoromethyl) phenyl ] furan-2-carbamate (C64).

Methyl 5-bromofuran-2-carboxylate (497mg,2.42mmol) and 4- (trifluoromethyl) phenyl]Boronic acid (472mg,2.48mmol) was combined in 1, 4-dioxane (5 mL). Saturated aqueous sodium bicarbonate (5.0mL) was added followed by tetrakis (triphenylphosphine) palladium (0) (140mg,0.121mmol) and the reaction mixture was heated in a microwave reactor at 150 ℃ for 20 min. After dilution with dichloromethane (20mL) and water (20mL), the layers were separated and the aqueous layer was extracted with dichloromethane (10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0% to 50% ethyl acetate in heptane) gave the product as a pale off-white solid. Yield 298mg,1.10mmol, 45%. LCMS M/z 271.0[ M + H ]⁺].¹H NMR(500MHz,CDCl₃)7.90(br d,J＝8.3Hz,2H),7.68(br d,J＝8.4Hz,2H),7.28(d,J＝3.7Hz,1H),6.86(d,J＝3.7Hz,1H),3.94(s,3H).

Step 2. Synthesis of methyl 5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-carboxylate (C65).

Palladium hydroxide on carbon (. about.50% water, 10 wt% palladium, 650mg,0.46mmol) was added to a solution of C64(6.5g,32mmol) in ethanol (170mL) and the reaction mixture was hydrogenated at room temperature for 3 h. Filtering to remove the catalyst; the filtrate was concentrated in vacuo and purified by supercritical fluid chromatography (column: Chiralpak AD-H,5 μm; eluent: 9:1 carbon dioxide/methanol) to afford the product as an oil. The starting compound C64 was also recovered (2 g). Yield 3.0g,11mmol, 34% (44% based on recovered starting material).¹H NMR(400MHz,CDCl₃)7.63(br AB quartet, J)_AB＝8.5Hz,Δν_AB＝15Hz,4H),5.09(dd,J＝8.9,5.8Hz,1H),4.65-4.69(m,1H),3.81(s,3H),2.33-2.45(m,2H),2.18-2.27(m,1H),1.84-1.95(m,1H).

Step 3. Synthesis of methyl 2-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-carboxylate (C66).

Potassium bis (trimethylsilyl) amide (1M in tetrahydrofuran, 9.1mL,9.1mmol) at-100 ℃ was added to a solution of compound C65(1.25g,4.56mmol) and iodomethane (98%, 2.90mL,45.6mmol) in diethyl ether (5mL) at-100 ℃ and the reaction mixture was gradually warmed to room temperature. After completion of the reaction, aqueous citric acid (1M,5mL) was added. The aqueous layer was extracted with diethyl ether (2 × 10mL) and the combined organic layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (eluent: 4:1 heptane/ethyl acetate) afforded the product. According to¹H NMR, the material showed an approximate 1:1 mixture presumably consisting of cis and trans isomers of the product. Yield 560mg,1.94mmol, 42%.¹H NMR(400MHz,CDCl₃) {7.60(s) & [7.60(br d, J ═ 8Hz) and 7.45-7.49(m)]Total 4H }, [5.20(dd, J ═ 7.0,7.0Hz), and 5.14(dd, J ═ 9.4,5.8Hz), total 1H }, and]3.80 and 3.79(2s, total 3H),2.34-2.58(m,2H),1.82-2.07(m,2H),1.65 and 1.60(2s, total 3H).

Step 4. Synthesis of { 2-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methanol (C67).

Lithium aluminum hydride (2M solution in tetrahydrofuran, 0.26mL,0.52mmol) was added to a solution of C66(125mg,0.434mmol) in diethyl ether (2mL) and the reaction mixture was stirred at room temperature for 1 hour. After acidification with aqueous hydrochloric acid, the mixture was extracted with ethyl acetate, the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give an oily product, presumably a-1: 1 mixture of stereoisomers. Yield 85mg,0.33mmol, 76%.¹H NMR(400MHz,CDCl₃)7.59(br d, J ═ 8.2Hz,2H),7.43-7.49(m,2H),4.97-5.08(m,1H),3.51-3.63(m,2H),2.32-2.44(m,1H),2.08-2.19(m,1H),1.76-1.95(m,2H),1.34 and 1.33(2s, total 3H).

Step 5 Synthesis of { 2-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl methanesulfonate (C68).

Compound C67 was converted to the product using the general procedure described for the synthesis of compound C17 in example 3. The product isolated as a roughly 1:1 mixture of stereoisomers was used without additional purification.¹H NMR(400MHz,CDCl₃) Characteristic peaks 7.60(br d, J ═ 8.6Hz,2H),7.44-7.50(m,2H),5.04-5.10(m,1H) and [4.21(AB quartet, J)_AB＝10.4Hz,Δν_AB17.5Hz) and 4.19(s), total 2H]3.08 and 3.03(2s, total 3H),1.44 and 1.41(2s, total 3H).

Step 6. Synthesis of 2- [ ({ 2-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl) amino ] ethanol (C69).

The product was prepared from C68 using the general method described for the synthesis of compound C9 in example 1. In this case, the product was used in the next step without HPLC purification. The yield was 295mg,0.973mmol, 94%.

Step 7. Synthesis of 7- (4-methyl-1H-imidazol-1-yl) -2- ({ cis-2-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione, formate (13) and 7- (4-methyl-1H-imidazol-1-yl) -2- ({ trans-2-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione, formate (14).

Compound C69 was reacted with P2 according to the procedure described for the synthesis of compound 1 in example 1. In this example, only the crude reaction mixture was concentrated in vacuo and the isomers separated by HPLC (column: Phenomenex Luna C-18(2),5 μm; mobile phase A: 0.1% aqueous formic acid solution; mobile phase B: 0.1% methanolic formic acid solution; gradient: 5% -95% B). Example 13 is the first eluting isomer, isolated as a glass sample. Yield 38mg, 71. mu. mol, 7%. LCMS M/z 487.3[ M + H ]⁺].¹HNMR(400MHz,CDCl₃)8.39(s,1H),8.23(br s,1H),7.62(br d,J＝8Hz,2H),7.51(d,J＝7.8Hz,1H),7.43(br d,J＝8Hz,2H),7.29(d,J＝7.7Hz,1H),7.14-7.18(m,1H),5.07(dd,J＝7.6,7.2Hz,1H),4.20-4.35(m,2H),4.11(d,J＝14.0Hz,1H),3.97 to 4.05(m,1H),3.78 to 3.86(m,1H),3.50(d, J ═ 14.0Hz,1H),2.44 to 2.53(m,1H),2.30(s,3H),2.04 to 2.13(m,1H),1.92 to 2.01(m,1H),1.80 to 1.91(m,1H),1.36(s,3H). the second eluting isomer was example 14, which was obtained as a glass sample. Yield 26mg, 49. mu. mol, 5%. LCMS M/z 487.3[ M + H ]⁺].¹H NMR(400MHz,CDCl₃)8.46(s,1H),8.23(br s,1H),7.61(br d, J ═ 8Hz,2H),7.55(d J ═ 7.6Hz,1H),7.44(br d, J ═ 8Hz,2H),7.32(d, J ═ 7.8Hz,1H),7.16-7.20(m,1H),5.02(dd, J ═ 9.4,5.8Hz,1H),4.28-4.43(m,2H),4.03(ddd, half of the ABXY pattern, J ═ 13.7,7.3,4.2Hz,1H),3.94(d, J ═ 14.2Hz,1H),3.85-3.93(m,1H),3.62(d, J ═ 14.1H, 1H), 3.35 (m,2H), 3.85-3.93(m,1H),3.62(d, J ═ 14.2H, 2H), 2H, 3.35 (m,2H), 3.32H, 2H), 3.85 (m,2H), 3.32H, 2H), and two stereoisomers are shown in the study.

Examples 15 and 16

7- (4-methyl-1H-imidazol-1-yl) -2- ({ trans-6- [4- (trifluoromethyl) phenyl]tetrahydro-2H-pyran-2- Methyl group) -3, 4-dihydro-2H-pyrido [1,2-a]Pyrazine-1, 6-dione, formate (15) and 7- (4-methyl-1H-imidazole) Azol-1-yl) -2- ({ cis-6- [4- (trifluoromethyl) phenyl]tetrahydro-2H-pyran-2-yl } methyl) -3, 4-dihydro-2H-pyri-dine Pyrido [1,2-a ]]Pyrazine-1, 6-dione, formate (16)

Step 1. Synthesis of 1- [4- (trifluoromethyl) phenyl ] hex-5-en-1-ol (C70).

A mixture of 5-bromopent-1-ene (6.0g,40mmol) and magnesium (1.44g,59.2mmol) in tetrahydrofuran (40mL) was stirred at 0 ℃ for 30 min. 4- (trifluoromethyl) benzaldehyde (4.6g,26mmol) was added dropwise and the reaction mixture was cooled to room temperatureStir for 4 hours, then quench by adding water (30 mL). After extraction with ethyl acetate (3 × 15mL), the combined organic layers were washed with saturated aqueous sodium chloride (10mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the product as a yellow oil. It was used without additional purification. Yield 2.6g,11mmol, 42%.¹H NMR(400MHz,CDCl₃)7.58-7.64(m,2H),7.44-7.50(m,2H),5.72-5.84(m,1H),4.93-5.04(m,2H),4.73-4.79(m,1H),2.05-2.13(m,2H),1.64-1.85(m,2H),1.47-1.60(m,1H),1.34-1.47(m,1H).

Step 2, synthesizing 2- (iodomethyl) -6- [4- (trifluoromethyl) phenyl ] tetrahydro-2H-pyran (C71).

To a solution of compound C70(2.3g,9.4mmol) in acetonitrile (25mL) was added N-iodosuccinimide (95%, 5.0g,21mmol) and the reaction mixture was stirred at room temperature for 18 h. After quenching with water (15mL), the mixture was extracted with ethyl acetate (3 × 15mL), and the combined organic layers were washed with saturated aqueous sodium chloride (15mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 1% -10% ethyl acetate in petroleum ether) afforded the product as a yellow oil. According to¹H NMR, which consisted of an approximately 2:1 mixture of isomers. Yield 1.8g,4.9mmol, 52%.¹H NMR(400MHz,CDCl₃) Characteristic peaks [7.51(d, J ═ 8.5Hz) and 7.56-7.67(m), total 4H]4.51(br d, J ═ 11Hz) and 4.93(br dd, J ═ 5,5Hz), total 1H][3.48-3.57(m) and 3.78-3.86(m), total 1H],3.26-2.42(m,2H).

Step 3. Synthesis of 2- [ ({6- [4- (trifluoromethyl) phenyl ] tetrahydro-2H-pyran-2-yl } methyl) amino ] ethanol (C72).

Compound C71 was converted to the product using the procedure described for the synthesis of compound C29 in example 6. The product is obtained as a yellow oil according to¹H NMR estimated it to be an approximately 3:1 mixture of isomers. Yield 1.1g,3.6mmol, 73%.¹H NMR(400MHz,CDCl₃) Characteristic peaks 7.41-7.66(m,4H), [4.43(br d, J ═ 10.5Hz) and 4.88(br dd, J ═ 5,5Hz), total 1H].

Step 4. Synthesis of 7- (4-methyl-1H-imidazol-1-yl) -2- ({ trans-6- [4- (trifluoromethyl) phenyl ] tetrahydro-2H-pyran-2-yl } methyl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione, formate (15) and 7- (4-methyl-1H-imidazol-1-yl) -2- ({ cis-6- [4- (trifluoromethyl) phenyl ] tetrahydro-2H-pyran-2-yl } methyl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione, formate (16).

Compound C72 was reacted with P2 using the procedure described for synthesis of compound 1 in example 1. In this example, the separation of stereoisomers is done via reverse phase HPLC (column: Boston analytes, Boston symmetry ODS-H,5 μm; mobile phase A: 0.225% formic acid in water; mobile phase B: 0.225% formic acid in acetonitrile; gradient: 24% -44% B). Example 16 was taken from the column before example 15; both were obtained as white solids. The relative stereochemistry indicated is based on the NOE study assignment. Example 15 yield, 4.7mg, 8.8. mu. mol, 1.3%. LCMS M/z 487.0[ M + H⁺].¹H NMR(400MHz,CD₃OD)8.57(br s,1H),7.82(d, J ═ 8.0Hz,1H),7.57(br AB quartet, J)_AB＝8Hz,Δν_AB21Hz,4H),7.39-7.42(m,1H),7.23(d, J ═ 8.0Hz,1H),5.01-5.06(m,1H),4.30-4.36(m,2H),4.17-4.27(m,2H),3.83-3.88(m,2H),3.48-3.57(m,1H),2.28(br s,3H),1.70-2.0(m,5H),1.56-1.66(m,1H). example 16:32.8mg,61.6 μmol, 9%.¹H NMR(400MHz,CD₃OD)9.05(brs,1H),7.93(d, J ═ 7.5Hz,1H),7.58(br AB quartet, J)_AB＝8.5Hz,Δν_AB＝31Hz,4H),7.58(brs,1H),7.28(d,J＝7.5Hz,1H),4.52(br d,J＝10.5Hz,1H),4.30-4.38(m,1H),4.21-4.29(m,1H),3.85-3.98(m,4H),3.62(dd,J＝13.8,8.3Hz,1H),2.36(s,3H),1.97-2.05(m,1H),1.72-1.93(m,3H),1.34-1.52(m,2H).

Example 17

7- (4-methyl-1H-imidazol-1-yl) -2- ({ (2S,4S,5R) -4-methyl-5- [4- (trifluoromethyl) phenyl]Fourthly Hydrofuran-2-yl } methyl) -3, 4-dihydro-2H-pyrido [1,2-a]Pyrazine-1, 6-dione, trifluoroacetate (17)

Step 1 Synthesis of (3S,5S) -5- ({ [ tert-butyl (diphenyl) silyl ] oxy } methyl) -3-methyldihydrofuran-2 (3H) -one (C73).

A solution of C30(1.02g,2.88mmol) in tetrahydrofuran (15mL) was added dropwise to a solution of lithium bis (trimethylsilyl) amide (1.0M in heptane, 3.45mL,3.45mmol) in tetrahydrofuran (12mL) at-78 deg.C; after 30 minutes, methyl iodide (0.215mL,3.45mmol) was added to the cold solution, which was then stirred at-78 ℃ for 30 minutes, warmed to-50 ℃ and stirred at that temperature for 3 hours. After quenching with aqueous ammonium chloride (50% saturation, 20mL), diethyl ether (20mL) was added and the aqueous layer was extracted with diethyl ether (2X20 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil (1.27g) was dissolved in tetrahydrofuran (15mL) and added dropwise to a-78 deg.C solution of lithium bis (trimethylsilyl) amide (1.0M in heptane, 5.0mL,5.0mmol) in tetrahydrofuran (10 mL). After stirring the reaction mixture at-78 ℃ for 1 hour, it was briefly warmed to-50 ℃ and then cooled back to-78 ℃. Saturated aqueous sodium sulfate (10mL) was added and the mixture was slowly thawed. Water (10mL) and diethyl ether (20mL) were added and the aqueous layer was extracted with diethyl ether (2X20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0% -50% ethyl acetate in heptane) gave the product as a colorless oil which subsequently solidified. The indicated stereochemistry was specified according to the work of S.F. Martin et al, J.org.chem.2000,65, 1305-1318. Yield 558mg,1.51mmol, 52%.¹H NMR(400MHz,CDCl₃)7.66-7.70(m,4H),7.38-7.48(m,6H),4.44-4.51(m,1H),3.87(dd, half ABX pattern, J ═ 11.3,3.7Hz,1H),3.74(dd, half ABX pattern, J ═ 11.5,4.3Hz,1H),2.71(ddq, J ═ 11.6,9.1,7.1Hz,1H),2.39(ddd, J ═ 12.5,9.2,6.2Hz,1H),1.86(ddd, J ═ 12.5,11.7,10.0Hz,1H),1.30(d, J ═ 7.2Hz,3H),1.07(s,9H).

Step 2. Synthesis of (3S,5S) -5- ({ [ tert-butyl (diphenyl) silyl ] oxy } methyl) -3-methyl-2- (4- (trifluoromethyl) phenyl) tetrahydrofuran-2-ol (C74).

Compound C73 was converted to the product using the procedure for the synthesis of compound C25 in example 6. The product was obtained as an orange oil and was directly subjected to the following procedure.

Step 3. Synthesis of tert-butyl ({ (2S,4S,5R) -4-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methoxy) diphenylsilane (C75).

Compound C74 (. ltoreq.1.51 mmol) was converted to the product using the method described for the synthesis of C26 in example 6 to give an oil. The yield was 336mg,0.674mmol, 45% over 2 steps.¹H NMR(400MHz,CDCl₃)7.73-7.78(m,4H),7.53(br d, J ═ 8.2Hz,2H),7.37-7.48(m,8H),5.06(d, J ═ 7.4Hz,1H),4.14-4.21(m,1H),3.95(dd, half ABX mode, J ═ 10.9,4.1Hz,1H),3.86(dd, half ABX mode, J ═ 10.9,4.7Hz,1H),2.59-2.71(m,1H),2.17(ddd, J ═ 12.4,7,7Hz,1H),1.66(ddd, J ═ 12.4,8.8,7.5Hz,1H),1.11(s,9H),0.58(d, J ═ 7.0, 3H).

Step 4. Synthesis of { (2S,4S,5R) -4-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methanol (C76).

Deprotection of C75 was carried out using the method described for the synthesis of compound C27 in example 6. The product obtained is an oil. The stereochemistry indicated for aryl groups is specified based on the NOE test. Yield 139mg,0.534mmol, 81%. GCMS M/z 260[ M ]⁺].¹H NMR(400MHz,CDCl₃)7.60 (brd, J ═ 8.2Hz,2H),7.39-7.43(m,2H),5.06(d, J ═ 7.0Hz,1H),4.14-4.21(m,1H),3.90(dd, half ABX mode, J ═ 11.7,3.3Hz,1H),3.77(dd, half ABX mode, J ═ 11.7,6.2Hz,1H),2.62-2.73(m,1H),2.24(ddd, J ═ 12.5,7.6,7.0Hz,1H),1.49(ddd, J ═ 12.5,8.6,6.6Hz,1H),0.60(d, J ═ 7.0Hz,3H).

Step 5. Synthesis of { (2S,4S,5R) -4-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl methanesulfonate (C77).

Compound C76 was converted to the product using the procedure described for the synthesis of compound C8 in example 1; the product obtained was an oil. Yield 176mg,0.520mmol, 100%.¹H NMR(400MHz,CDCl₃)7.61(br d,J＝8Hz,2H),7.38-7.42(m,2H),5.09(d,J＝7.2Hz,1H),4.41-4.49(m,2H),4.30-4.37(m,1H),3.11(s,3H),2.63-2.75(m,1H),2.34(ddd,J＝12.7,7.4,7.4Hz,1H),1.53(ddd,J＝12.7,8.4,6.6Hz,1H),0.62(d,J＝7.0Hz,3H).

Step 6. Synthesis of 2- [ ({ (2S,4S,5R) -4-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl) amino ] ethanol (C78).

The product was prepared as oil from C77 using the procedure used for the synthesis of compound C29 in example 6. Yield 132mg,0.435mmol, 86%. LCMS M/z 304.4[ M + H ]⁺].¹HNMR(400MHz,CDCl₃)7.59(br d,J＝8Hz,2H),7.36-7.41(m,2H),5.03(d,J＝7.4Hz,1H),4.15-4.23(m,1H),3.67-3.71(m,2H),2.82-3.00(m,4H),2.59-2.71(m,1H),2.29(ddd,J＝12.3,7.6,6.8Hz,1H),1.38(ddd,J＝12.5,8.6,7.0Hz,1H),0.59(d,J＝7.0Hz,3H).

Step 7. Synthesis of 7- (4-methyl-1H-imidazol-1-yl) -2- ({ (2S,4S,5R) -4-methyl-5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione, trifluoroacetate (17).

The conversion of C78 to product was performed using the method described for synthesis of compound 6 in example 6. After chromatography on silica gel, the product was purified by reverse phase HPLC (column: Waters Sunfire C18,5 μm; mobile phase A: 0.05% trifluoroacetic acid in water (v/v); mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); gradient: 5% -100% B) to give the solid product. Yield 12mg, 20. mu. mol, 4%. LCMS M/z 487.3[ M + H ]⁺].¹H NMR(600MHz,DMSO-d₆)9.37(br s,1H),8.05(br d,J＝7.5Hz,1H),7.81(br s,1H),7.70(br d,J＝7.9Hz,2H),7.52(br d,J＝7.9Hz,2H),7.20(d,J＝7.5Hz,1H),5.04(d,J＝7.0Hz,1H),4.21-4.31(m,3H),3.83-3.96(m,3H),3.70(dd,J＝13.8,8.1Hz,1H),2.62-2.68(m,1H),2.31(s,3H),2.28-2.36(m,1H),1.36-1.42(m,1H),0.52(d,J＝7.0Hz,3H).

Example 18

2- ({ (2S,5R) -5- [3, 5-difluoro-4- (trifluoromethyl)Radical) phenyl]Tetrahydrofuran-2-yl } methyl) -7- (4-methyl 1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a]Pyrazine-1, 6-diones (18)

Step 1 Synthesis of (2S) -1- [ (2-hydroxyethyl) amino ] -5- (trimethylsilyl) pent-4-yn-2-ol (C79).

A mixture of (2S) -1-chloro-5- (trimethylsilyl) pent-4-yn-2-ol (80g,420mmol) and 2-aminoethanol (110g,1.8mol) was stirred at 80 ℃ for 18 h. Silica gel chromatography (gradient: 1% -10% methanol in dichloromethane) afforded the product as a yellow oil. Yield 30g,140mmol, 33%.¹H NMR(400MHz,CD₃OD)3.80-3.88(m,1H),3.61-3.72(m,2H),2.84(dd, J ═ 12.3,3.3Hz,1H),2.69-2.81(m,2H),2.64(dd, J ═ 12.0,8.5Hz,1H),2.45(dd, half ABX mode, J ═ 16.6,5.5Hz,1H),2.37(dd, half ABX mode, J ═ 16.6,7.0Hz,1H),0.12(s,9H).

Step 2 Synthesis of N- (2-hydroxyethyl) -N- [ (2S) -2-hydroxy-5- (trimethylsilyl) pent-4-yn-1-yl ] -5- (4-methyl-1H-imidazol-1-yl) -6-oxo-1, 6-dihydropyridine-2-carboxamide (C80).

Compound C79 was converted to the product using the general procedure described for the preparation of compound 1 in example 1. In this synthesis, slightly less than 1 equivalent of HATU was employed, the reaction was carried out in acetonitrile, and the extraction was done with ethyl acetate. In this case the crude product solution was dried over sodium sulfate and the crude product was directly subjected to the following steps.

Step 3. Synthesis of 2- [ (2S) -2-hydroxy-5- (trimethylsilyl) pent-4-yn-1-yl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (C81).

Diisopropyl azodicarboxylate (14g,69mmol) was added dropwise to a mixture of 0 ℃ crude compound C80 (. ltoreq.60 mmol) and triphenylphosphine (18.9g,72.0mmol) in tetrahydrofuran (500 mL). After stirring at 0 ℃ for 2.5 hours, the reaction mixture was concentrated in vacuo; purification by silica gel chromatography (gradient: 1% -6% methanol in dichloromethane) afforded the product as a yellow solid. Yield 7.0g,18mmol, 30% over two steps.

Step 4. Synthesis of 2- [ (2S) -2-hydroxypent-4-yn-1-yl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (C82).

A mixture of compound C81(6.5g,16mmol) and potassium carbonate (2.25g,16.3mmol) in methanol (150mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (gradient: 1% -2.5% methanol in dichloromethane) to afford the product as a yellow solid. Yield 2.5g,7.7mmol, 48%.¹H NMR(400MHz,CD₃OD)8.31(d,J＝1.2Hz,1H),7.78(d,J＝7.8Hz,1H),7.31-7.33(m,1H),7.25(d,J＝7.8Hz,1H),4.33-4.39(m,2H),4.04-4.12(m,1H),3.82-3.96(m,3H),3.50(dd,J＝13.7,8.4Hz,1H),2.41-2.46(m,2H),2.37(t,J＝2.8Hz,1H),2.24(d,J＝1.0Hz,3H).

Step 5. Synthesis of 2- { (2S) -5- [3, 5-difluoro-4- (trifluoromethyl) phenyl ] -2-hydroxypent-4-yn-1-yl } -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (C83).

Compound C82 was reacted with 5-bromo-1, 3-difluoro-2- (trifluoromethyl) benzene using the general procedure described for the synthesis of compound C39 in example 8. In this example, the reaction solvent was a 1.6:1 mixture of N, N-dimethylformamide and triethylamine, and the catalyst used was dichlorobis (triphenylphosphine) palladium (II). The extraction was carried out with ethyl acetate and the product obtained as a pale orange solid was purified by silica gel chromatography (gradient: 0% -100% [ 10% (2M ammonia in methanol) in ethyl acetate)]In ethyl acetate). Yield 505mg,0.997mmol, 65%.¹H NMR(400MHz,CDCl₃)8.28(d, J ═ 1.2Hz,1H),7.40(d, J ═ 7.8Hz,1H),7.22(d, J ═ 7.6Hz,1H),7.06-7.08(m,1H),7.04(d, J ═ 9.8Hz,2H),4.41(ddd, half ABXY pattern, J ═ 14.3,7.2,4.2Hz,1H),4.26-4.36(m,2H),3.92-4.00(m,2H),3.83(ddd, half ABXY pattern, J ═ 13.5,7.3,4.2Hz,1H),3.55(dd, J ═ 14.0,8.3Hz,1H),2.68-2.80(m,2H),2.28(br, 3H).

Step 6. Synthesis of 2- ({ (2S,5R) -5- [3, 5-difluoro-4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl) -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione (18).

Di- μ -chlorodichlorobis (vinyl) diplatin (II) (97%, 60mg,99 μmol), trifluoroacetic acid (380 μ L,5.0mmol) and water (89 μ L,5.0mmol) were added to a solution of C83(250mg,0.494mmol) in dichloromethane (5mL) and the reaction mixture was stirred at room temperature until thin layer chromatography analysis indicated that the starting material was consumed. The reaction mixture was cooled to-20 ℃ and treated with trifluoroacetic acid (0.958mL,12.4mmol), then triethylsilane (99%, 1.19mL,7.39mmol) was added dropwise over 5 minutes. After warming slowly to room temperature, the reaction was allowed to proceed for 1.5 h, followed by addition of dichloromethane (50mL), and the mixture was washed with water (25mL) and with saturated aqueous sodium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo; chromatography on silica gel (gradient: 0% -70% [ 10% (2M ammonia in methanol) ] in ethyl acetate]In ethyl acetate) followed by HPLC (column: phenomenex Lux Cellulose-1,5 μm; gradient: 70% -100% ethanol in heptane) to provide a solid product. Yield 40mg,79 μmol, 16%. LCMS M/z 509.0[ M + H [ ]⁺].¹H NMR(400MHz,CDCl₃)8.35(br s,1H),7.49(d,J＝7.6Hz,1H),7.29(d,J＝7.6Hz,1H),7.16(br s,1H),6.98(d,J＝10.4Hz,2H),4.86-4.92(m,1H),4.31-4.41(m,3H),4.14(dd,J＝13.9,2.7Hz,1H),3.92-4.01(m,1H),3.78-3.86(m,1H),3.47(dd,J＝14.0,8.5Hz,1H),2.37-2.48(m,1H),2.31(s,3H),2.16-2.26(m,1H),1.69-1.87(m,2H).

Method A

Preparation of 2-substituted 7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pir-ines via initial reductive amination Pyrido [1,2-a ]]Pyrazine-1, 6-diones M1

Step 1 Synthesis of N-substituted 2- { [ tert-butyl (dimethyl) silyl ] oxy } ethylamine C84.

A solution of primary amine (300. mu. mol) in methanol (1mL) was treated with { [ tert-butyl (dimethyl) silyl ] oxy } acetaldehyde (28. mu.L, 150. mu. mol) and shaken at 30 ℃ for 40 min. The reaction vial was cooled to 0 ℃, sodium borohydride (17mg,450 μmol) was added, and the reaction was shaken at 30 ℃ for 100 minutes. The solvent was removed in vacuo, water (1mL) was added and the mixture was extracted with ethyl acetate (3 × 1 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo, and purified via preparative thin layer chromatography.

And 2, synthesizing N-substituted 2-aminoethanol C85.

A solution of Compound C84 in methanol (500. mu.L) was treated with a solution of acetyl chloride (188. mu.L) in methanol (312. mu.L) at 30 ℃ for 16 h. The solvent was removed in vacuo.

Step 3. Synthesis of 2-substituted 7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione M1.

Compound C85 was purified using compound P1(34.4mg, 125. mu. mol), dichloromethane (2mL), diisopropylethylamine (217. mu.L, 1.25mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylHexafluorophosphate (HATU, 97%, 122mg, 320. mu. mol) treatment, followed by shaking at 30 ℃ for 16 hours. The solvent was removed in vacuo, and the residue was treated with saturated aqueous sodium bicarbonate (2mL) and extracted with ethyl acetate (3 × 1 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo, and purified by reverse phase HPLC. Purification was carried out using a Phenomenex Gemini C18 column (8-10 μm), the non-aqueous mobile phase consisting of ammonium hydroxide in acetonitrile (pH 10) and using a suitable gradient.

TABLE 1

3, 4-difluoro-N-hydroxybenzeneamidochloride (M.R.Barbachyn et al, J.Med.Chem.2003,46,284-302) is subjected to cycloaddition with ethylene and the product is acylated according to the method of A.Corsaro et al, J.heterocyclic Chem.1989,26,1691-9 to give methyl 3- (3, 4-difluorophenyl) -4, 5-dihydro-1, 2-oxazole-4-carboxylate. After aminolysis, the resulting primary amine is converted to a tert-butoxycarbonyl protected amine via a hofmann rearrangement. Deprotection and resolution with (-) -anilyphos [ (4S) -2-hydroxy-4- (2-methoxyphenyl) -5, 5-dimethyl-1, 3, 2-dioxaphosphorinane-2-oxide ] gives (4R) -3- (3, 4-difluorophenyl) -4, 5-dihydro-1, 2-oxazol-4-amine. This was converted to the desired 2-aminoethanol using the general procedure described in method a.

HPLC conditions. Column: waters Atlantis dC18,4.6 × 50mm,5 μm; mobile phase A: 0.05% trifluoroacetic acid in water (v/v); mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); gradient: linear at 4.0 min 5% -95% B; flow rate: 2 mL/min.

Reaction of tert-butyl [ cis-3-hydroxycyclopentyl ] carbamate (see M.Pineschi et al, org.Lett.2005,7,3605-3607) with 3- (trifluoromethyl) phenol under Mitsunobu conditions affords tert-butyl { trans-3- [3- (trifluoromethyl) phenoxy ] cyclopentyl } carbamate. Deprotection using acidic conditions gives trans-3- [3- (trifluoromethyl) phenoxy ] cyclopentylamine. This was converted to the desired 2-aminoethanol using the general procedure described in method a.

[ (2-Hydroxycyclopentyl) methyl ] carbamic acid tert-butyl ester was subjected to a Mitsunobu reaction and deprotected as described in footnote 3 to give 1- {2- [3- (trifluoromethyl) phenoxy ] cyclopentyl } methylamine. This was converted to the desired 2-aminoethanol using the overall process described in method a. The final product was subjected to supercritical fluid chromatography (column: Chiralpak AD-H; eluent: 7:3 carbon dioxide/propanol) and the second eluted enantiomer was collected. The absolute and relative configuration of the compound was not determined.

Tert-butyl (trans-3-hydroxycyclobutyl) carbamate (p.liu, PCT int.appl.2007, WO2007062332 a2) is treated with carbon tetrabromide and triphenylphosphine to produce tert-butyl (cis-3-bromocyclobutyl) carbamate, which is subjected to the reaction of 2- (trifluoromethyl) phenol and then deprotected with an acid to give trans-3- [2- (trifluoromethyl) phenoxy ] cyclobutylamine. This was converted to the desired 2-aminoethanol using the overall process described in method a.

6. The desired amine can be prepared according to T.A. shepherd et al, J.Med.chem.2002,45, 2101-.

HPLC conditions. Column: waters XBridge C18,2.1 × 50mm,5 μm; mobile phase A: 0.0375% trifluoroacetic acid in water (v/v); mobile phase B: 0.01875% trifluoroacetic acid in acetonitrile (v/v); gradient: 1% -5% B after 0.6 min, then 5% -100% B after 3.4 min; the flow rate was 0.8 mL/min.

8. Cyclobutanecarbonitrile is alkylated with 1- (bromomethyl) -4-fluorobenzene and the product is reduced with lithium aluminum hydride to give 1- [1- (4-fluorobenzyl) cyclobutyl ] methylamine.

9. Reaction of Grignard reagent prepared from 1- (bromomethyl) -3, 5-difluorobenzene with 6-oxabicyclo [3.1.0] hexane affords trans-2- (3, 5-difluorobenzyl) cyclopentanol. Conversion to the mesylate followed by displacement with sodium azide (displacement) and reduction with triphenylphosphine gave cis-2- (3, 5-difluorobenzyl) cyclopentylamine.

[ trans-3- (hydroxymethyl) cyclobutyl ] carbamic acid tert-butyl ester and 4-fluoro-2- (trifluoromethyl) phenol were used for preparation similar to footnote 3.

11. Commercially available amines are converted to the desired 2-aminoethanol using the overall process as described in Process A.

2-Chlorocyclohexanone is reacted with 4-chlorophenol followed by reductive amination with 2-aminoethanol to provide the desired 2-aminoethanol derivative.

13. The final product was subjected to supercritical fluid chromatography (column: Chiralpak OJ-H; eluent: 7:3 carbon dioxide/methanol) and the first eluted enantiomer was collected. NOE studies indicate cis stereochemistry. The absolute stereochemistry indicated is arbitrary.

Directed metalation of 2-chloro-1-fluoro-4-methoxybenzene with n-butyllithium and tetramethylethylenediamine allowed the regiospecific introduction of methyl groups. Followed by cleavage with methyl ether with boron tribromide to afford 3-chloro-4-fluoro-2-methylphenol.

Chlorination of 3- (propan-2-yl) phenol with ozone (oxone) and potassium chloride gave the desired phenol.

16. The required naphthols are prepared as described in J.T.Repline et al Tetrahedron Lett.2007,48, 5539-.

Methyl 2-fluoro-6-hydroxybenzoate was treated with methylmagnesium bromide to give a tertiary alcohol, which was hydrogenated over palladium on carbon to give the desired phenol.

5- (3, 4-dichlorophenyl) dihydrofuran-2 (3H) -one (see G.J.Quallich et al, J.org.chem.1990,55,4971-4973) was reduced with diisobutylaluminum hydride, treated with acetic anhydride and converted to 5- (3, 4-dichlorophenyl) tetrahydrofuran-2-carbonitrile by treatment with trimethylsilyl cyanide and boron trifluoride diethyl ether complex. Reduction with diisobutylaluminum hydride gave 1- [5- (3, 4-dichlorophenyl) tetrahydrofuran-2-yl ] methylamine, which was converted to the desired 2-aminoethanol using the overall strategy described in method A.

19. The desired [ cis-5- (4-chlorophenyl) tetrahydrofuran-2-yl ] methanol was prepared by hydrogenating 5- (4-chlorophenyl) furan-2-carbaldehyde in the presence of ruthenium (IV) oxide hydrate.

20. Example 46 was separated from the racemic mixture by supercritical fluid chromatography (column: Chiralcel OJ-H,5 μm; eluent: 4:1 carbon dioxide/methanol, containing 0.2% isopropylamine) and was the second of the enantiomers to be eluted from the column. The first material eluted was the enantiomer of example 46 and exhibited an IC of 511nM₅₀. The absolute stereochemistry of example 46 is based on its lower IC₅₀(see table 1) similar to other compounds described herein.

21. Required { cis-5- [4- (pentafluoro- λ)⁶-sulfanyl) phenyl]Tetrahydrofuran-2-yl } methanol with (5-formylfuran-2-yl) boronic acid and 1-bromo-4- (pentafluoro-lambda)⁶-sulfanyl) benzene, followed by hydrogenation in the presence of ruthenium (IV) oxide hydrate.

22. Example 47 separation from racemic mixture by supercritical fluid chromatography (column: Chiralcel OJ-H,5 μm; eluent: 65:35 carbon dioxide/propanol, containing 0.2% isopropylamine) and from columnThe second of the eluted enantiomers. The first material eluted was the enantiomer of example 47 and exhibited an IC of 329nM₅₀. The absolute stereochemistry of example 47 is based on its lower IC₅₀(see table 1) similar to other compounds described herein.

{ cis-5- [4- (trifluoromethoxy) phenyl ] tetrahydrofuran-2-yl } methanol was prepared from 5-bromofuran-2-carbaldehyde and [4- (trifluoromethoxy) phenyl ] boronic acid using a method analogous to that described in footnote 21.

24. Example 48 was separated from the racemic mixture by supercritical fluid chromatography (column: Chiralcel OJ-H,5 μm; eluent: 3:1 carbon dioxide/methanol, containing 0.2% isopropylamine) and was the second of the enantiomers to be eluted from the column. The first material eluted was the enantiomer of example 48 and exhibited an IC of 1230nM₅₀. The absolute stereochemistry of example 48 is based on its lower IC₅₀(see table 1) similar to other compounds described herein.

25. Tert-butyl { [ (2S,5R) -5- (4-chloro-2-methoxyphenyl) tetrahydrofuran-2-yl ] methoxy } diphenylsilane was prepared from (2S) -1- { [ tert-butyl (diphenyl) silyl ] oxy } -5- (4-chloro-2-methoxyphenyl) pent-4-yn-2-ol using the general procedure of T.X.M. Nguyen et al, Letters in Organic Chemistry2009,6, 630-. The alkyne is prepared via the reaction of tert-butyl [ (2S) -oxiran-2-ylmethoxy ] diphenylsilane with 4-chloro-1-ethynyl-2-methoxybenzene using n-butyllithium and boron trifluoride etherate.

26. In this example, reaction with bis- μ -chlorodichlorobis (vinyl) diplatin (II) produced (4S,5S) -5- (dibenzylamino) -1- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -4-hydroxyhex-1-one instead of the corresponding 2, 3-dihydrofuran. Reaction with p-toluenesulfonic acid and trimethyl orthoformate followed by triethylsilane and boron trifluoride etherate gave (1S) -N, N-dibenzyl-1- { (2S) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -2, 3-dihydrofuran-2-yl } ethylamine.

27. The final ring closure was performed via a Mitsunobu reaction using diisopropyl azodicarboxylate.

The Sonogashira product was converted to the next intermediate in this example using an aqueous solution of platinum (II) chloride.

29. The final ring closure was done with cesium carbonate in N, N-dimethylformamide instead of lithium bis (trimethylsilyl) amide.

30. The desired (1S) -1- [ (2S,5R) -5-aryltetrahydrofuran-2-yl ] ethylamine was prepared from C48 according to example 9 except that the Sonogashira product was converted in this example to the intermediate tert-butyl { (1S) -1- [ (2S) -5-hydroxy-5-aryltetrahydrofuran-2-yl ] ethyl } carbamate or tert-butyl { (1S) -1- [ (2S) -5-methoxy-5-aryltetrahydrofuran-2-yl ] ethyl } carbamate using aqueous platinum (II) chloride or platinum (II) chloride and trimethyl orthoformate, respectively.

2- [ ({ cis-5- [3- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methyl) amino ] ethanol was prepared via reaction of cis-2- (bromomethyl) -5- [3- (trifluoromethyl) phenyl ] tetrahydrofuran (see H.Ebel et al, PCT int. appl.,2010070032, June 24,2010) with 2-aminoethanol.

32. Example 58 separation from a racemic mixture by supercritical fluid chromatography (column: Chiralcel OJ-H,5 μm; eluent: 4:1 carbon dioxide/methanol, containing 0.2% isopropylamine) and is the second of the enantiomers to elute from the column. The first eluted material was the enantiomer of example 58 and exhibited an IC of 1040nM₅₀. The absolute stereochemistry of example 58 is based on its lower IC₅₀(see table 1) similar to other compounds described herein.

33.1-chloro-2-fluoro-4-iodo-5-methoxybenzene as starting material; see j.m. blaney et al, pctint.appl.,2008150914, Dec 11,2008.

Sandmeyer reaction of 4-chloro-2- (trifluoromethoxy) aniline gave the desired 5-chloro-2-iodophenyl trifluoromethyl ether.

35. The required { cis-5- [4- (pentafluoroethyl) phenyl ] tetrahydrofuran-2-yl } methanol was prepared via a Suzuki reaction of (5-formylfuran-2-yl) boronic acid with 1-bromo-4- (pentafluoroethyl) benzene, followed by hydrogenation over palladium on carbon. 1-bromo-4- (pentafluoroethyl) benzene was prepared according to the procedure of W.Lambert et al, PCT Int.appl.,2011017513, Feb 10,2011.

36. The desired { cis-5- [4- (1, 1-difluoroethyl) phenyl ] tetrahydrofuran-2-yl } methanol is prepared via a Suzuki reaction of 5-bromofuran-2-carbaldehyde with 2- [4- (1, 1-difluoroethyl) phenyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan, followed by hydrogenation in the presence of ruthenium (IV) oxide hydrate.

37. Example 62 was separated from the racemic mixture by HPLC (column: Phenomenex Lux Cellulose-3,5 μm; gradient: 50% -100% ethanol in heptane) and was the second of the enantiomers to elute from the column. The first material eluted was the enantiomer of example 62 and exhibited an IC of 723nM₅₀. The absolute stereochemistry of example 62 is based on its lower IC₅₀(see table 1) similar to other compounds described herein.

1-bromo-4-chloro-2- (difluoromethoxy) benzene was prepared according to m.ge et al, u.s.pat.appl.pub., 20070265332, Nov 15,2007.

39. In this example, the reaction was run with bis- μ -chlorodichlorobis (vinyl) diplatin (II) and water to yield the intermediate tert-butyl [ (1S) -1- { (2S) -5- [ 4-chloro-2- (difluoromethoxy) phenyl ] -5-hydroxytetrahydrofuran-2-yl } ethyl ] carbamate.

40. Example 64 trans isomer (2- { [ (2S,5S) -5- (4-chloro-3, 5-difluorophenyl) tetrahydrofuran-2-yl]Methyl } -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a]Pyrazine-1, 6-dione) was also isolated from the final step. The compound has an IC of 184nM₅₀。

Conversion of (2S) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -5- [2- (trifluoromethyl) phenyl ] pent-4-yn-2-ol (prepared in a similar manner to the alkyne described in footnote 26) to { (2S,5R) -5- [2- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } methanol using boron trifluoride etherate and triethylsilane.

42. Example 66 is the minor diastereomer isolated during the purification of example 17, presumably with the stereochemistry shown.

43. The desired aryl starting material is prepared from the appropriate fluorinated aniline via halogenation with N-halosuccinimide followed by Sandmeyer reaction.

TABLE 2

1. Suitable homochiral 2-aminopropan-1-ols are used instead of 2-aminoethanol.

HPLC conditions. Column: waters Atlantis dC18,4.6 × 50mm,5 μm; mobile phase A: 0.05% trifluoroacetic acid in water (v/v); mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); gradient: linear at 4.0 min 5% -95% B; flow rate: 2 mL/min.

Cell-based gamma-secretase assay using ELISA readout

The ability of compounds to modulate the production of amyloid β protein A β (1-42) was determined using CHO cells overexpressing human WT-APP cells were seeded at 22,000 cells/100 μ L well in DMEM/F12 medium in 96-well tissue culture-treated transparent plates (Falcon) and incubated at 37 ℃ for 24 hours₅₀And (4) measuring. Compounds were added to fresh medium to reach 1% final DMSO. Appropriate vehicle or inhibitor controls were added separately to the control wells to obtain minimum or maximum inhibition values, respectively, for the assay signal window, and the plates were then incubated at 37 ℃ for 24 hours. This operation produces conditioned medium in each well, for whichThe A β (1-42) levels were determined in the ELISA assay procedure described next the cell cultures remaining in each well were also tested for cytotoxicity as described below.

Coating of the ELISA assay plate was initiated as follows: 50 μ L/well (3 μ g/mL) in 0.1M NaHCO₃(pH9.0) the self-made A β (1-42) -specific antibody was added to the black 384-wellPlate (Nunc) and incubation at 4 ℃ overnight then capture antibody is aspirated from ELISA Assay plate and plate is washed (2X 100. mu.L to 4X 100. mu.L) with Wash Buffer (Dulbecco's PBS, 0.05% Tween 20.) then 90. mu.L/well Blocking Buffer (Dulbecco's PBS, 1.0% BSA (Sigma A7030)) is added to the plate. Normal temperature incubation is allowed to proceed for a minimum of 2 hours then Blocking Buffer is removed, followed by 20. mu.L/well Assay Buffer (Dulbecco's PBS, 1.0% BSA (Sigma A7030), 0.05% Tween 20). at this point, 40. mu.L (in duplicate) of Assay condition medium (described above) is transferred to wells of blocked ELISA plate containing antibody, followed by overnight colorimetric cell proliferation Assay (CellL) after removal of condition medium at 4 ℃ for A β (1-42) Assay, also after removal of the condition medium at 4 ℃ overnightAQ_ueousOne Solution Cell promotion Assay, Promega) cytotoxicity was measured in the corresponding remaining cells according to the manufacturer's instructions.

ELISA Assay plates were incubated at 4 ℃ overnight, unbound A β peptide was removed by washing with Wash Buffer (2X 100. mu.L to 4X 100. mu.L) europium (Eu) -labeled (custom-labeled, Perkin Elmer) A β (1-16)6e10 monoclonal antibody (Covance # SIG-39320), (50. mu.L/well Eu-6e10@1:10,000,20uM EDTA) was added in Assay Buffer, incubated at ambient temperature for a minimum of 2 hours, then washed with Wash Buffer (2X 100. mu.L to 4X 100. mu.L), followed by 30. mu.L/well Delfia Enhancement Solution (Perkin Elmer). after incubation at ambient temperature for 1 hour, plate reading was performed on an EnVision plate reader (Perkin Elmer) using standard DELFIA TRF set-up plate reader₅₀Analysis of data including assay using non-lineSexual regression fit analysis (homemade software) and plate means appropriate for maximum and minimum inhibition controls.

TABLE 3 biological data for examples 1-73

a. Reported IC₅₀The values are the geometric means of 2-4 determinations.

b.IC₅₀Values were from a single assay.

c. Reported IC₅₀The value is the geometric mean of ≧ 5 determinations.

d. And (4) not measuring.

Claims (17)

1. A compound having the structure of formula I, or a pharmaceutically acceptable salt thereof:

wherein:

x is imidazole;

R¹is C₁-C₆An alkyl group;

a is C₃-C₆Cycloalkyl or 4-to 10-membered heterocycloalkyl, ring-atom of said heterocycloalkylAt least one of the atoms is a heteroatom selected from oxygen, nitrogen or sulfur;

R^2aand R^2bEach occurrence independently is hydrogen, or C₁-C₆An alkyl group;

R³is C₆-C₁₀Aryl OR OR¹²(ii) a Wherein said aryl is optionally substituted with one to five R¹¹Substitution;

R^4aand R^4bEach is hydrogen;

R^5aand R^5bEach is hydrogen;

R⁶and R⁷Each is hydrogen;

each R¹¹Independently hydrogen, halogen, -CF₃、-SF₅、-Si(CH₃)₃、C_1-C₆Alkyl, wherein said-Si (CH)₃)₃Or alkyl is optionally substituted with one to five substituents each independently selected from halogen and-CF₃Substituted with the substituent(s);

each R¹²Is C₆-C₁₀An aryl group; wherein said aryl is optionally substituted with one to five R¹⁴Substitution;

R¹⁴independently hydrogen, -CF₃Cyano, halogen or C_1-6An alkyl group; wherein said alkyl is optionally substituted with one to three substituents each independently selected from hydroxy, -CF₃Cyano, and fluoro; and is

z is 1;

y is 0 or 1.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹Is methyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a is cyclobutyl, cyclopentyl, or cyclohexyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a is dihydroisoxazolyl, tetrahydrofuranyl, or tetrahydropyranyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a is tetrahydrofuranyl.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a is tetrahydropyranyl.

7. A compound of formula Id, or a pharmaceutically acceptable salt thereof:

wherein:

R²is hydrogen or methyl;

R³is C₆-C₁₀Aryl, wherein said aryl is optionally substituted with one to three substituents independently selected from the group consisting of fluoro, chloro, -CF₃,-SF₅,-OCH₃,-OCF₃and-OCHF₂R of (A) to (B)¹¹And (4) substitution.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R³Is optionally substituted by one to three R¹¹A substituted phenyl group.

9. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein the compound is:

7- (4-methyl-1H-imidazol-1-yl) -2- [ (1S) -1- { (2S,5R) -5- [4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione;

2- [ (1S) -1- { (2S,5R) -5- [ 4-chloro-2- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione;

2- [ (1S) -1- { (2S,5R) -5- [3, 5-difluoro-4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione;

2- { (1S) -1- [ (2S,5R) -5- (4-chloro-3, 5-difluorophenyl) tetrahydrofuran-2-yl ] ethyl } -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione;

2- [ (1S) -1- { (2S,5R) -5- [4, 5-difluoro-2- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione;

2- [ (1S) -1- { (2S,5R) -5- [ 4-fluoro-2- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione;

2- [ (1S) -1- { (2S,5R) -5- [ 4-chloro-5-fluoro-2- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione;

2- [ (1S) -1- { (2S,5R) -5- [ 4-chloro-3-fluoro-2- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione.

10. The compound 2- [ (1S) -1- { (2S,5R) -5- [ 4-chloro-5-fluoro-2- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione, or a pharmaceutically acceptable salt thereof.

11. The compound 2- [ (1S) -1- { (2S,5R) -5- [ 4-chloro-2- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione, or a pharmaceutically acceptable salt thereof.

12. The compound 2- { (1S) -1- [ (2S,5R) -5- (4-chloro-3, 5-difluorophenyl) tetrahydrofuran-2-yl ] ethyl } -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione, or a pharmaceutically acceptable salt thereof.

13. The compound 2- [ (1S) -1- { (2S,5R) -5- [3, 5-difluoro-4- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione, or a pharmaceutically acceptable salt thereof.

14. The compound 2- [ (1S) -1- { (2S,5R) -5- [ 4-fluoro-2- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione, or a pharmaceutically acceptable salt thereof.

15. The compound 2- [ (1S) -1- { (2S,5R) -5- [4, 5-difluoro-2- (trifluoromethyl) phenyl ] tetrahydrofuran-2-yl } ethyl ] -7- (4-methyl-1H-imidazol-1-yl) -3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione, or a pharmaceutically acceptable salt thereof.

16. Use of a compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of neurodegenerative and psychiatric disorders including alzheimer's disease and niemann pick disease type C.

17. A pharmaceutical composition comprising a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.