KR20090090385A - 2-quinolinone and 2-quinoxalinone-derivatives, and their use as antibacterial agents - Google Patents

Abstract

The present invention relates to compounds of the formula (I) and pharmaceutically acceptable salts thereof, their use in the treatment of bacterial infections, and methods for their preparation.

<Formula I>

Description

2-quinolinone and 2-quinoxalinone-derivatives, and their use as antibacterial agents {2-QUINOLINONE AND 2-QUINOXALINONE-DERIVATIVES AND THEIR USE AS ANTIBACTERIAL AGENTS}

The present invention relates to novel piperidine, pharmaceutical compositions thereof and methods of use. The invention also relates to therapeutic methods for the treatment of bacterial infections.

The International Health Organization continues to express the serious importance of creating strains in which the development of antimicrobial resistance makes the currently available antimicrobial agents invalid. For example, methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant coagulase-negative staphylococcus (MRCNS), penicillin resistant Streptococcus pneumoniae and Resistant strains of Gram-positive pathogens, such as multiple resistant Enterococcus faecium , are difficult to treat and hard to eradicate. As a result, there is a continuing need for the development of new antibiotics, particularly novel antibiotics with new mechanisms of action and / or containing new drug action groups, in order to overcome the threat of a wide range of multi-drug resistant microorganisms. .

Summary of the Invention

In accordance with the present invention, Applicant has found herein a compound having the ability to act as an antimicrobial agent. Accordingly, the present invention relates to a compound exhibiting antimicrobial activity, a method for preparing the same, a pharmaceutical composition containing the same as an active ingredient, its use as a medicament, and its use in the manufacture of a medicament for use in treating a bacterial infection in a warm blooded animal such as a human. It is about.

Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Where

A is selected from CH and N;

D is selected from CR ⁷ and N;

Wherein at least one of A and D is carbon;

E is selected from O, NH, and S,

here,

i) when R ⁸ and R ⁹ together form ═O, E is NH;

ii) when R ⁸ and R ⁹ are each H, E is O or S;

G is selected from O and S;

J is selected from CR ⁴ and N;

R ¹ is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, OR ^1a , and —N (R ^1a ) ₂ , wherein said C _{1 -6} alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ¹⁰ ;

R ^1a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ²⁰ ;

R ² is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ^2a , and —N (R ^2a ) ₂ , wherein the C _{1 -6} alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ²⁰ ;

R ^2a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ²⁰ ;

R ³ is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, —OR ^3a , and —N (R ^3a ) ₂ , wherein C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ³⁰ ;

R ^3a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ³⁰ ;

R ⁴ is selected from H, halo, —CO ₂ H, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein the C _1-6 alkyl, C _{2- 6} alkenyl, and C _2-6 alkynyl, are optionally substituted with one or more R ⁴⁰ ;

R ⁶ is selected from fluoro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ^6a , wherein the C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl is optionally substituted with one or more R ⁶⁰ ;

R ^6a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ⁶⁰ ;

R ⁷ is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein the C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl is optionally substituted with one or more R ⁷⁰ ;

R ⁸ and R ⁹ are each hydrogen or R ⁸ and R ⁹ together form ═O;

R ¹⁰ , R ²⁰ , R ³⁰ , R ⁴⁰ , R ⁶⁰ , and R ⁷⁰ are independently at each occurrence halo, hydroxy, cyano, -CO ₂ H, C _1-6 alkyl, C _2-6 alkenyl , And C _2-6 alkynyl,

The compounds of formula (I) are substantially free of cis (±) mixtures of their enantiomers.

In another aspect, the present invention provides a compound of formula II, or a pharmaceutically acceptable salt thereof.

Where

A is selected from CH and N;

D is selected from CR ⁷ and N;

Wherein at least one of A and D is carbon;

E is selected from O, NH, and S,

here,

i) when R ⁸ and R ⁹ together form ═O, E is NH;

ii) when R ⁸ and R ⁹ are each H, E is O or S;

G is selected from O and S;

J is selected from CR ⁴ and N;

R ¹ is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, OR ^1a , and —N (R ^1a ) ₂ , wherein said C _{1 -6} alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ¹⁰ ;

R ^1a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ²⁰ ;

R ² is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ^2a , and —N (R ^2a ) ₂ , wherein the C _{1 -6} alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ²⁰ ;

R ^2a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ²⁰ ;

R ³ is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, —OR ^3a , and —N (R ^3a ) ₂ , wherein C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ³⁰ ;

R ^3a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ³⁰ ;

R ⁴ is selected from H, halo, —CO ₂ H, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein the C _1-6 alkyl, C _{2- 6} alkenyl, and C _2-6 alkynyl, are optionally substituted with one or more R ⁴⁰ ;

R ⁶ is selected from fluoro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ^6a , wherein the C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl is optionally substituted with one or more R ⁶⁰ ;

R ^6a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ⁶⁰ ;

R ⁷ is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein the C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl is optionally substituted with one or more R ⁷⁰ ;

R ⁸ and R ⁹ are each hydrogen or R ⁸ and R ⁹ together form ═O;

R ¹⁰ , R ²⁰ , R ³⁰ , R ⁴⁰ , R ⁶⁰ , and R ⁷⁰ are independently at each occurrence halo, hydroxy, cyano, -CO ₂ H, C _1-6 alkyl, C _2-6 alkenyl , And C _2-6 alkynyl,

Here, the R ⁶ groups on carbon "a" and the -NH- groups on carbon "b" are in trans relationship with each other.

Compounds of formulas (I) and (II) and their pharmaceutically acceptable salts are believed to be effective in treating bacterial infections. Accordingly, the present invention provides compounds of formulas (I) and (II) exhibiting antimicrobial activity, methods for their preparation, pharmaceutical compositions containing them as active ingredients, methods for their use in the treatment of bacterial infections, and their medicaments for the treatment of bacterial infections. Use and their use in the manufacture of such a medicament.

As used herein, the prefix C _xy as used in the term C _xy alkyl and the like, where x and y are integers, refers to the numerical range of carbon atoms present in the group; For example C _1-4 alkyl is C ₁ alkyl (methyl), C ₂ alkyl (ethyl), C ₃ alkyl (propyl and isopropyl) and C ₄ alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and t-butyl).

The term "alkyl" as used herein refers to straight and branched chain saturated hydrocarbon radicals having a certain number of carbon atoms. Reference to an individual alkyl group such as "propyl" only specifies a straight chain version, and reference to an individual branched alkyl group such as "isopropyl" only specifies a branched version.

The term "alkenyl" refers to straight and branched chain hydrocarbon radicals having a certain number of carbon atoms and containing one or more carbon-carbon double bonds. For example, "C _2-8 alkenyl" includes C _2-6 alkenyl, C _2-4 alkenyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, Groups such as 4-pentenyl, 5-hexenyl, 2-heptenyl, and 2-methyl-1-heptenyl, and the like.

The term "alkynyl" refers to straight and branched chain hydrocarbon radicals having a certain number of carbon atoms and containing one or more carbon-carbon triple bonds. For example, "C _2-8 alkynyl" includes C _2-6 alkynyl, C _2-4 alkynyl, ethynyl, 2-propynyl, 2-methyl-2-propynyl, 3-butynyl, Groups such as 4-pentynyl, 5-hexynyl, 2-heptinyl, and 4-methyl-5-heptinyl, and the like.

The term "halo" refers to fluoro, chloro, and bromo. In one aspect, “halo” may refer to fluoro.

When any substituent is selected from "one or more" groups, it is to be understood that this definition includes both substituents selected from one specified group or substituents selected from two or more specified groups.

The term “carbocyclyl” refers to a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring containing 3 to 12 ring atoms, wherein at least one —CH ₂ — group is a corresponding number of —C Optionally substituted with an (O)-group. In one aspect, the term “carbocyclyl” may refer to a monocyclic ring containing 3 to 6 ring atoms or a bicyclic ring containing 9 or 10 atoms. In another aspect, the term “carbocyclyl” may refer to a monocyclic ring containing 5 or 6 atoms. Examples of "carbocyclyl" are adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1-oxocyclopentyl, phenyl, naphthyl, tetralinyl, indanyl Or 1-oxoindanyl, but is not limited thereto. Particular example of a "carbocyclyl" group is phenyl.

The term “heterocyclyl” is saturated, partially saturated or unsaturated, containing 4 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen and can be carbon or nitrogen linked unless otherwise specified, Refers to a mono or bicyclic ring, wherein the —CH ₂ — group may be optionally substituted with —C (O) —. Ring sulfur atoms may be optionally oxidized to form S-oxides. Ring nitrogen atoms may be optionally oxidized to form N-oxides. Examples of the term “heterocyclyl” include 1,3-benzodioxolyl, 3,5-dioxopiperidinyl, imidazolyl, indolyl, isoquinolone, isothiazolyl, isoxazolyl, morpholino, 2-oxopyrrolidinyl, 2-oxo-1,3-thiazolidinyl, piperazinyl, piperidyl, pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, pyrimidyl, Pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridone, quinolyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thienyl, thiomorpholino, thiophenyl, pyridine-N-oxide And quinoline-N-oxides. In one aspect of the invention, the term “heterocyclyl” is saturated, partially saturated, containing 5 or 6 atoms, wherein one or more atoms are selected from nitrogen, sulfur, and oxygen and can be carbon or nitrogen linked unless otherwise specified. Or unsaturated, monocyclic rings, and ring nitrogen atoms may be optionally oxidized to form N-oxides.

The symbol "(±)" denotes a racemic mixture; Ie an optically inert mixture having the same amount of the (+) and (-) enantiomers of the designated compound. When a compound or mixture is shown to be "cis (±)" or "trans (±)", the cis or trans relationship specified herein is the relationship between the group on carbon "a" and the -NH- group on carbon "b". It is about.

Where more than one particular R group is present in a compound of formula (I) or (II), each choice for this R group is intended to be independent in each case.

Unless stated otherwise, the bonding atoms of a group can be any suitable atom of the group; For example, propyl includes prop-1-yl and prop-2-yl.

The term “substantially free” indicates that the specified monomer is present in an amount of less than 10%, more particularly less than 5%, especially less than 2%, more particularly less than 1%, especially less than 0.5%, especially less than 0.2%. It is intended to be.

As used herein, the term "optionally substituted" indicates that the substitution is optional and that the designated group can be substituted or unsubstituted. If substitution is desired, any number of hydrogens on the designated group may be substituted with a group selected from the specified substituents provided that a stable compound exhibiting an antimicrobial effect is provided, provided that the normal valence of the atoms on the particular substituent is not exceeded On the condition that

As used herein, the term “pharmaceutically acceptable” refers to contacting tissues of humans and animals without excessive toxicity, irritation, allergic reactions, or other problems or difficulties, within the scope of safety medical assessment, in accordance with moderate benefit / hazard ratios. Refers to compounds, materials, compositions, and / or formulations suitable for use.

As used herein, the phrase “effective amount” means an amount of a compound or composition that is sufficient to significantly and positively alleviate (eg, provide a positive clinical response) the condition and / or disease being treated. An effective amount of the active ingredient for use in the pharmaceutical composition may be determined by the specific disease being treated, the severity of the disease, the duration of treatment, the nature of the concurrent therapy, the specific active ingredient (s) used, the specific pharmaceutically acceptable excipient (s) / used / Carrier (s), and other factors within the knowledge and skills of the attending physician.

Compounds and substituent definitions of the invention are named by ACD / Name by ACD / Labs®.

The compounds of formulas (I) and (II) and their pharmaceutically acceptable salts may form pharmaceutically acceptable stable acid or base salts, in which case administration of the compound as a salt may be appropriate, and the pharmaceutically acceptable salts may be It can be prepared by conventional methods known in the art.

Suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, acid-addition salts of sufficiently basic compounds of the invention, for example inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoro Acid-addition salts with roacetic acid, citric acid or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the invention that are sufficiently acidic provide alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts or physiologically acceptable cations. Salts with organic bases such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.

Compounds of formulas (I) and (II) have two chiral carbons, carbon “a” and carbon “b” on the central piperidine ring. In addition, the compounds of formulas (I) and (II) may have other chiral centers and / or geometric isomeric centers (E- and Z-isomers). It is to be understood that the present invention includes all such optical, diastereomers and geometric isomers having antimicrobial activity. The invention further relates to any and all tautomeric forms of the compounds of formulas (I) and (II) having antimicrobial activity and pharmaceutically acceptable salts thereof.

It is also to be understood that certain compounds of Formulas (I) and (II) may exist in solvated and unsolvated forms, such as hydrated forms. It is to be understood that the present invention encompasses all such solvated forms having antimicrobial activity.

Further embodiments of the invention are as follows. Unless otherwise indicated, these additional embodiments relate to both compounds of Formulas (I) and (II), and pharmaceutically acceptable salts thereof. Where appropriate, certain substituents and stereochemical relationships may be utilized with any of the definitions, claims or embodiments defined above or below.

Carbon "a" and carbon "b"

In one aspect, the R ⁶ group on carbon "a" and the -NH- group on carbon "b" of the compound of Formula I are in cis (+) relationship with each other, where the compound of Formula I is a cis (±) mixture of its enantiomers It does not include substantially.

In another aspect, the R ⁶ groups on carbon "a" and the -NH- groups on carbon "b" of the compound of Formula I are in a cis (-) relationship with each other, where the compound of Formula I is the cis (±) of its enantiomer. ) Is substantially free of mixtures.

In another aspect, the R ⁶ groups on carbon "a" and the -NH- groups on carbon "b" of the compound of Formula I are in trans (+) relationship with each other.

In another aspect, the R ⁶ groups on carbon "a" and the -NH- groups on carbon "b" of the compound of Formula I are in trans (-) relationship with each other.

A

In one aspect, A is N.

In another aspect, A is CH.

D

In one aspect, D is N.

In another aspect, D is CH.

In another aspect, D is selected from N and CH.

A and D

In one aspect, A is N;

D is CH.

In another aspect, A is CH;

D is N.

E, G, R ⁸ , And R ⁹

In one aspect, E and G are each O;

R ⁸ and R ⁹ are each H.

In another aspect, E is NH; G is selected from O and S;

R ⁸ and R ⁹ together form ═O.

In another aspect, E is NH; G is S;

R ⁸ and R ⁹ together form ═O.

In another aspect, E is NH; G is O;

R ⁸ and R ⁹ together form ═O.

J

In one aspect, J is N.

In another aspect, J is CH.

In another aspect, J is selected from N and CH.

In another aspect, J is selected from N and CR ⁴ ;

R ⁴ is selected from H and C _1-6 alkyl.

In further aspects, J is selected from N and CR ⁴ ;

R ⁴ is selected from H and methyl.

And in further aspects, J is selected from CR ⁴ ;

R ⁴ is selected from H and methyl.

A, D, E, G, R ⁸ , And R ⁹

In one aspect, A, D, E, G, R ⁸ , and R ⁹ together with the ring atom to which they are attached

To form a group selected from.

In another aspect, A, D, E, G, R ⁸ , and R ⁹ together with the ring atom to which they are attached

To form.

In another aspect, A, D, E, G, R ⁸ , and R ⁹ together with the ring atom to which they are attached

To form.

In another aspect, A, D, E, G, R ⁸ , and R ⁹ together with the ring atom to which they are attached

To form.

In a further aspect, A, D, E, G, R ⁸ , and R ⁹ together with the ring atom to which they are attached

To form a group selected from.

R ^One

In one aspect, R ¹ is H.

R ²

In one aspect, R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl.

In another aspect, R ² is selected from cyano and methoxy.

In another aspect, R ² is cyano.

In another aspect, R ² is —OR ^2a ;

R ^2a is C _1-6 alkyl.

In a further aspect, R ² is methoxy.

R ³

In one aspect, R ³ is H.

R ⁶

In one aspect, R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

In another aspect, R ⁶ is selected from fluoro, hydroxy, and methoxy.

In another aspect, R ⁶ is fluoro.

In another aspect, R ⁶ is hydroxy.

In a further aspect, R ⁶ is methoxy.

R ^One , R ² , R ³ , R ⁶ , R ⁸ , R ⁹ , A, D, E, G, and J

Formula I

1) In one aspect, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof.

<Formula Ia>

Wherein R ¹ , R ² , R ³ , R ⁶ , G and J are as defined above and the compound of formula (Ia) is substantially free of a cis (±) mixture of its enantiomers.

1.1) In one aspect of the compound of formula (Ia), or a pharmaceutically acceptable salt thereof,

G is selected from O and S;

J is selected from N and CH;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

1.2) In another aspect of a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof,

G is selected from O and S;

J is selected from N and CH;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁶ is selected from fluoro, hydroxy, and methoxy.

1.3) In another aspect of the compound of formula (Ia), or a pharmaceutically acceptable salt thereof,

G is selected from O and S;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

1.4) In another aspect of a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof,

G is selected from O and S;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is methyl;

R ³ is H;

R ⁴ is selected from H and methyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and methyl.

2) In another aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be a compound of formula (Ib), or a pharmaceutically acceptable salt thereof.

<Formula Ib>

Wherein R ¹ , R ² , R ³ , R ⁶ , and J are as defined above, and the compound of Formula Ib is substantially free of a cis (±) mixture of its enantiomers.

2.1) In one aspect of the compound of formula (lb),

J is selected from N and CH;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

2.2) In another aspect of the compound of formula (lb),

J is selected from N and CH;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁶ is selected from fluoro, hydroxy, and methoxy.

2.3) In another aspect of a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof,

J is selected from N and CH;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

2.4) In another aspect of a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof,

J is selected from N and CH;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁶ is selected from fluoro, hydroxy, and methoxy.

3) In another aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be a compound of formula (Ic), or a pharmaceutically acceptable salt thereof.

<Formula Ic>

Wherein R ¹ , R ² , R ³ , R ⁶ , R ⁸ , R ⁹ , A, D, E, G, and J are as defined above, wherein the compound of Formula Ic is the cis of its enantiomer (±) substantially free of mixtures

3.1) In one aspect of the compound of formula (Ic), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

3.2) In another aspect of a compound of Formula (Ic), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

3.3) In another aspect of a compound of Formula (Ic), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is methyl;

R ³ is H;

R ⁴ is selected from H and methyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and methyl.

3.4) In another aspect of a compound of Formula (Ic), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is methyl;

R ³ is H;

R ⁴ is selected from H and methyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and methyl.

4) In a further aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be a compound of formula (Id), or a pharmaceutically acceptable salt thereof.

<Formula Id>

Wherein R ¹ , R ² , R ³ , R ⁶ , R ⁸ , R ⁹ , A, D, E, G, and J are as defined above, wherein the compound of Formula Id is a cis of its enantiomer (±) substantially free of mixtures

4.1) In one aspect of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

4.2) In another aspect of a compound of Formula (Id), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

4.3) In another aspect of a compound of Formula (Id), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is methyl;

R ³ is H;

R ⁴ is selected from H and methyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and methyl.

4.4) In another aspect of a compound of Formula (Id), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is methyl;

R ³ is H;

R ⁴ is selected from H and methyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and methyl.

5) Also in a further aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be a compound of formula (Ie), or a pharmaceutically acceptable salt thereof.

<Formula Ie>

Wherein R ¹ , R ² , R ³ , R ⁶ , R ⁸ , R ⁹ , A, D, E, G, and J are as defined above, wherein the compound of Formula Ie is a cis of its enantiomer (±) substantially free of mixtures

5.1) In one aspect of the compound of formula (Ie), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

5.2) In another aspect of a compound of Formula (Ie), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

5.3) In another aspect of the compound of Formula (Ie), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is selected from H and methyl.

5.4) In another aspect of the compound of formula (Ie), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is selected from H and methyl.

6) Also in a further aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be a compound of formula (If), or a pharmaceutically acceptable salt thereof.

<Formula If>

Wherein R ¹ , R ² , R ³ , R ⁸ , R ⁹ , A, D, E, G, and J are as defined above, and the fluoro group on carbon "a" and on carbon "b" The -NH-groups are in cis relation to one another and the compound of formula If is substantially free of a cis (±) mixture of its enantiomers.

6.1) In one aspect of the compound of Formula If, or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

6.2) In another aspect of a compound of Formula If, or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

6.3) In another aspect of a compound of Formula If, or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is selected from H and methyl.

6.4) In another aspect of a compound of Formula If, or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is selected from H and methyl.

7) In one aspect, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (Ig), or a pharmaceutically acceptable salt thereof.

<Formula Ig>

Wherein R ¹ , R ² , R ³ , R ⁸ , R ⁹ , A, D, E, G, and J are as defined above and the compound of Formula Ig is the cis (±) of its enantiomer It is substantially free of mixtures.

7.1) In one aspect of the compound of formula (Ig), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

7.2) In another aspect of a compound of Formula (Ig), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

7.3) In another aspect of the compound of formula (Ig), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is selected from H and methyl.

7.4) In another aspect of a compound of Formula (Ig), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is selected from H and methyl.

8) In another aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be a compound of formula (Ih), or a pharmaceutically acceptable salt thereof.

<Formula Ih>

Wherein R ¹ , R ² , R ³ , R ⁸ , R ⁹ , A, D, E, G, and J are as defined above, wherein the compound of Formula Ih is the cis (±) of its enantiomer It is substantially free of mixtures.

8.1) In one aspect of the compound of formula (Ih), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

8.2) In another aspect of a compound of Formula (Ih), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

8.3) In another aspect of a compound of Formula (Ih), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is selected from H and methyl.

8.4) In another aspect of a compound of Formula (Ih), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is selected from H and methyl.

Formula II

1.1 In one aspect of the compound of Formula II, or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

1.2) In another aspect of a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

1.3) In another aspect of the compound of Formula II, or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is methyl;

R ³ is H;

R ⁴ is selected from H and methyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and methyl.

1.4) In another aspect of the compound of Formula II, or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is methyl;

R ³ is H;

R ⁴ is H;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and methyl.

1.5) In a further aspect of the compound of formula (II), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is methyl;

R ³ is H;

R ⁴ is selected from H and methyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and methyl.

2) In one aspect, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (IIa), or a pharmaceutically acceptable salt thereof.

<Formula IIa>

Wherein R ¹ , R ² , R ³ , R ⁶ , R ⁸ , R ⁹ , A, D, E, G, and J are as defined above.

2.1) In one aspect of the compound of Formula (IIa), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

2.2) In another aspect of a compound of Formula (IIa), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

2.3) In another aspect of a compound of Formula (IIa), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is H;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

2.4) In another aspect of a compound of Formula (IIa), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is methyl;

R ³ is H;

R ⁴ is selected from H and methyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and methyl.

2.5) in further aspects of the compound of formula (IIa), or a pharmaceutically acceptable salt thereof

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is methyl;

R ³ is H;

R ⁴ is H;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and methyl.

3) In another aspect, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (IIb), or a pharmaceutically acceptable salt thereof.

<Formula IIb>

Wherein R ¹ , R ² , R ³ , R ⁶ , R ⁸ , R ⁹ , A, D, E, G, and J are as defined above.

3.1) In one aspect of the compound of Formula (IIb), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

3.2) In another aspect of a compound of Formula (IIb), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

3.3) In another aspect of the compound of Formula (IIb), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and C _1-6 alkyl.

3.4) In another aspect of a compound of Formula (IIb), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is methyl;

R ³ is H;

R ⁴ is selected from H and methyl;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and methyl.

3.5) in a further aspect of the compound of formula (IIb), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is methyl;

R ³ is H;

R ⁴ is H;

R ⁶ is selected from fluoro and —OR ^6a ;

R ^6a is selected from H and methyl.

4) In another aspect, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (IIc), or a pharmaceutically acceptable salt thereof.

<Formula IIc>

Wherein R ¹ , R ² , R ³ , R ⁸ , R ⁹ , A, D, E, G, and J are as defined above and are on fluoro group on carbon "a" and on carbon "b" The -NH- groups are in trans relation to each other.

4.1) In one aspect of the compound of Formula (IIc), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

4.2) In another aspect of a compound of Formula (IIc), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

4.3) In another aspect of a compound of Formula (IIc), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is H.

4.4) In another aspect of a compound of Formula (IIc), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is selected from H and methyl.

4.5) In a further aspect of the compound of formula (IIc), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is H.

5) In another aspect, the compound of Formula II, or a pharmaceutically acceptable salt thereof, may be a compound of Formula IId, or a pharmaceutically acceptable salt thereof.

<Formula IId>

Wherein R ¹ , R ² , R ³ , R ⁸ , R ⁹ , A, D, E, G, and J are as defined above.

5.1) In one aspect of the compound of Formula (IId), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

5.2) In another aspect of a compound of Formula (IId), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

5.3) In another aspect of a compound of Formula (IId), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is H.

5.4) In another aspect of the compound of formula (IId), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is selected from H and methyl.

5.5) In a further aspect of the compound of formula (IId), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is H.

6) In a further aspect, the compound of formula (II), or a pharmaceutically acceptable salt thereof, may be a compound of formula (IIe), or a pharmaceutically acceptable salt thereof.

<Formula IIe>

Wherein R ¹ , R ² , R ³ , R ⁸ , R ⁹ , A, D, E, G, and J are as defined above.

6.1) In one aspect of the compound of Formula (IIe), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

6.2) In another aspect of a compound of Formula (IIe), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

6.3) In another aspect of the compound of formula (IIe), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is H.

6.4) In another aspect of a compound of Formula (IIe), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is selected from H and methyl.

6.5) In a further aspect of the compound of formula (IIe), or a pharmaceutically acceptable salt thereof,

A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from;

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is methyl.

7) Also in a further aspect, the compound of formula (II), or a pharmaceutically acceptable salt thereof, may be a compound of formula (IIf), or a pharmaceutically acceptable salt thereof.

<Formula IIf>

Wherein R ¹ , R ² , R ³ , and J are as defined above and the fluoro group on carbon "a" and the -NH- group on carbon "b" are in trans relationship with each other.

7.1) In one aspect of the compound of formula (IIf), or a pharmaceutically acceptable salt thereof,

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

7.2) In another aspect of a compound of Formula (IIf), or a pharmaceutically acceptable salt thereof,

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is H.

7.3) In another aspect of a compound of Formula (IIf), or a pharmaceutically acceptable salt thereof,

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is selected from H and methyl.

7.4) In another aspect of a compound of Formula (IIf), or a pharmaceutically acceptable salt thereof,

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is H.

8) Also in a further aspect, the compound of formula (II), or a pharmaceutically acceptable salt thereof, may be a compound of formula (IIg), or a pharmaceutically acceptable salt thereof.

<Formula IIg>

Wherein R ¹ , R ² , R ³ , and J are as defined above and the fluoro group on carbon "a" and the -NH- group on carbon "b" are in trans relationship with each other.

8.1) In one aspect of the compound of formula (IIg), or a pharmaceutically acceptable salt thereof,

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is selected from H and C _1-6 alkyl.

8.2) In another aspect of a compound of Formula (IIg), or a pharmaceutically acceptable salt thereof,

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and -OR ^2a ;

R ^2a is C _1-6 alkyl;

R ³ is H;

R ⁴ is H.

8.3) In another aspect of a compound of Formula (IIg), or a pharmaceutically acceptable salt thereof,

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is selected from H and methyl.

8.4) In another aspect of a compound of Formula (IIg), or a pharmaceutically acceptable salt thereof,

J is selected from N and CR ⁴ ;

R ¹ is H;

R ² is selected from cyano and methoxy;

R ³ is H;

R ⁴ is H.

In another aspect, the present invention provides compounds of Formulas I and II and pharmaceutically acceptable salts thereof, as exemplified in the Examples, each of which provides a further independent aspect of the present invention.

Biological activity

Compounds of formulas (I) and (II) and their pharmaceutically acceptable salts are of importance because of their antimicrobial effects. The ability of the compounds of the invention disclosed herein to achieve antimicrobial effects can be demonstrated by the following test.

Bacterial Susceptibility Testing Method 1

Compounds can be tested for antimicrobial activity by sensitivity test in liquid medium in 96 well format. Compounds can be dissolved in dimethylsulfoxide and tested in ten 2-fold dilutions in susceptibility assays. The microorganisms used in the assay can be grown overnight in a suitable agar medium and then suspended in liquid medium suitable for microbial growth. The suspension can be adjusted to be equal to 0.5 McFarland, and additional 1:10 dilutions can be made in the same liquid medium to prepare the final microbial suspension in 100 μl. The plates can be read after incubating at 37 ° C. for 24 hours under appropriate conditions. The minimum inhibitory concentration (MIC) was determined, which is the lowest drug concentration that can reduce growth by at least 80%.

Compounds were evaluated on a panel of Gram-positive species, including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes , and Enterococcus paesium. Compounds were also evaluated on a panel of Gram-negative species, including Haemophilus influenzae , Escherichia coli , and Moraxella catarrhalis . Compounds of the present invention and pharmaceutically acceptable salts thereof are generally believed to have a MIC of 8 μg / mL or less for one or more of the aforementioned microorganisms.

The compound of Example 2 had a MIC of 0.25 (mg / L) for Staphylococcus aureus and a MIC of 0.5 (mg / L) for E. coli.

Bacterial Susceptibility Testing Method 2

Compounds can be tested for antimicrobial activity by susceptibility testing using the microbroth dilution method presented by CSLI. Compounds can be dissolved in dimethylsulfoxide and tested in ten 2-fold dilutions in sensitivity assays to give a final dimethylsulfoxide concentration of 2% (v / v) in the assay. Staphylococcus aureus (516) cells used in the assay can be grown overnight in appropriate agar medium and then suspended in NCCLS-presented liquid susceptibility-test medium. The turbidity of each suspension can be adjusted to be equivalent to a 0.5 McFarland standard, and an additional 1: 200 dilution can be made in the same liquid medium to prepare the final microbial suspension, and 100 μl of this suspension is added to dimethylsulfoxide 2 It can be added to each well of the microtiter plate containing the compound dissolved in [mu] l. The plates can be read for a time according to the NCCLS standard method and also after incubation under appropriate atmospheric and temperature conditions. As used in Table 1 below, the term “inhibition rate” refers to the percentage of Staphylococcus aureus 516 cell growth inhibited by the compounds of the indicated Example No. compared to the untreated sample.

When tested in the in vitro assay, the compounds and salts of Example No. listed below were tested at the indicated concentrations, from which the indicated inhibition rates were provided. In most cases, the highest concentration at which the compound was tested was 8 μg / mL. However, in some instances, compounds were tested at concentrations greater than 8 μg / mL (typically, concentrations were first measured in μM and then converted to μg / mL). When compounds were tested at more than one concentration above 8 μg / mL, the concentration closest to 8 μg / mL is shown below.

^{* The} inhibition rate for the compound of Example 43 at 8 μg / mL concentration was 12%, but the 12% value is considered to be an error.

Thus, in one aspect, there is provided a compound of Formula I or II, or a pharmaceutically acceptable salt thereof, for use as a medicament.

In another aspect, there is provided a use of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a bacterial infection in a warm blooded animal such as a human.

In another aspect, Acinetobacter baumanii , Aeromis Hydrophila , Bacillus, of a warm blooded animal, such as a human, of a compound of Formula I or II, or a pharmaceutically acceptable salt thereof Anthracis ( Bacillus anthracis ), Bacteroides fragilis , Bordatella pertussis , Burkholderia cepacia , Chlamyida pneumoniae , Citrobacter freundii , Clostridium difficile , Enterobacter cloacae , Enterococcus faecalis , Enterococcus paesium , Enterobacter a erotic jeneseu, E. coli, Fu simple teryum necromancer Forum a brush loose parainfluenza under (Fusobacterium necrophorum), a brush under the loose influenza, The writing brush loose cotton Augustine (Haemophilus somnus), Klebsiella oxy cytokines (Klebsiella oxytoca), Klebsiella pneumoniae in (Klebsiella pneumoniae), Legionella pneumophila (Legionella pneumophila), L. monocytogenes Cistercian jeneseu (Listeria monocytogenes) , Moraxella catarrhalis, Morganella morganii , Mycoplasma pneumoniae , Neisseria gonorrhoeae , Neisseria meningitidis , Paz Chateau Relais water Toshi is (Pasteurella multocida), Proteus Mira Billy's (Proteus mirabilis), Proteus vulgaris (Proteus vulgaris), Pseudomonas ah rugi labor (Pseudomonas aeruginosa), Salmonella typhimurium (Salmonella typhi), Salmonella typhimurium (Salmonella typhimurium ), Serratia Marseille sense (Serratia marcesens), Shigella flex neriah (Shigella flexneria), Shigella disen Leah on (Shigella dysenteriae), Staphylococcus Hancock Syracuse aureus, Staphylococcus Hancock Syracuse epi der US display (Staphylococcus epidermidis), Staphylococcus Molly Tee Coos under Kok Syracuse (Staphylococcus haemolyticus), Staphylococcus Hancock Syracuse Inter Medi-house (Staphylococcus intermedius ), Staphylococcus saprophyticus , Stenotrophomonas maltophila , Streptococcus agalactiae , Streptococcus mutans , Streptococcus mutans Use is provided in the manufacture of a medicament for use in the treatment of bacterial infections caused by one or more pathogens such as Streptococcus pneumoniae and Streptococcus pyrogenes .

In a further aspect, bronchitis of a warm blooded animal such as human, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation anthrax, abdominal cavity, of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof Use is provided in the manufacture of a medicament for use in the treatment of infections such as internal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, sepsis, sinusitis, skin and soft tissue infections, and urinary tract infections.

In the further aspect of, Pseudomonas (Aeromonas), Acinetobacter (Acinetobacter), teroyi Bacillus (Bacillus), night by the O of a warm-blooded animal such as a formula I or compounds of II, or a pharmaceutically acceptable salt thereof that is human des (Bacteroides), Bordetella (Bordetella), Burkholderia (Burkholderia), Cloud shown pillar (Chlamydophila), bakteo (Citrobacter), Clostridium (Clostridium), Enterobacter bakteo (Enterobacter) into a sheet, Enterobacter cock kusu ( Enterococcus), Escher Escherichia (Escherichia), Playa bobak teryum (Flavobacterium), Fu earthy teryum (Fusobacterium), under a brush Ruth (Haemophilus), Klebsiella (Klebsiella), Legionella (Legionella), Listeria monocytogenes (Listeria), do not know the Nella (Morganella), morak Cellar (Moraxella), Miko plasma (Mycoplasma), nose, ceria (Neisseria), Paz Chateau Pasteurella (Pasteurella), Pep tokok when (Peptococci), streptomycin pepto cock when (Peptostreptococci), pre boaters La (Prevotella), Proteus (Proteus), Salmonella (Salmonella), Pseudomonas (Pseudomonas), Serratia marcescens (Serratia), Shigella (Shigella), a stacking notes Pomona's (Stenotrophomonas), streptomycin cock kusu (Streptococcus), and star Use is provided in the manufacture of a medicament for use in the treatment of bacterial infections of the genus selected from Staphylococcus .

In another aspect, there is provided a method of treating bacterial infection in an animal comprising administering to a warm blooded animal, such as a human, an effective amount of a compound of Formula I or II, or a pharmaceutically acceptable salt thereof.

In another aspect, Acinetobacter Baumani, Aeromis hydrophila, comprising administering to a warm blooded animal such as a human an effective amount of a compound of Formula I or II, or a pharmaceutically acceptable salt thereof , Bacillus anthracis, Bacteroides pragillis, Bordatelella pertussis, Burgholderia sepasia, Chlamydia pneumoniae, Citrobacter preundi, Clostridium difficile, Enterobacter cloacae, Enterococcus paecalis, Enterococcus paesium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsi Ella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morgani , Mycoplasma pneumoniae, Neisseria gonorhoea, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhimurium , Serratia Marsense, Shigella Flexneria, Shigella Decenteria, Staphylococcus aureus, Staphylococcus epiderimides, Staphylococcus haemolyticus, Staphylococcus intermedy Usus, Staphylococcus sapropiticus, Stenotropomonas maltopila, Streptococcus agalactiae, Streptococcus mutanz, Streptococcus pneumoniae, and Streptococcus pyogenes Provided are methods for treating bacterial infections caused by the above pathogens.

In another aspect, bronchitis, C. difficile colitis, cervicitis, endocarditis in an animal comprising administering to a warm blooded animal such as a human an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof Methods for treating bacterial infections include gonococcal urethritis, inhalation anthrax, intraperitoneal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, sepsis, sinusitis, skin and soft tissue infections, and urinary tract infections.

In a further aspect, aeromonas, acinetobacter, bacillus, gourd of an animal comprising administering to a warm blooded animal such as a human an effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof Terroides, Bordetella, Burkholderia, Chlamidophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella , Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prebotella, Proteus, Salmonella, Pseudomonas, Ceratia, Shigella, Stenotro Provided are methods for treating bacterial infections of the genus selected from Pomonas, Streptococcus, and Staphylococcus.

In a further aspect, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection in a warm blooded animal such as a human.

In another aspect, acetobacter baumani, aeromis hydrophila, bacillus anthracis, bacteroides pragilis, bordella pertussis, burkholderia sepacia, clah, Mida pneumoniae, Citrobacter Freundy, Clostridium difficile, Enterobacter Chloeca, Enterococcus paecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necro Forum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis , Morganella morgany, mycoplasma pneumoniae, neisseria gonorhoea, neisseria meningitidis, pasteurella water Roteus Mirabilis, Proteus Bulgari, Pseudomonas aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marsense, Shigella flexneria, Shigella decenteriae, Staphylococcus aureus, Staphylococcus Cuz epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus sapropiticus, Stenotropomonas maltopila, Streptococcus agalactiae, Streptococcus Compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, for use in the treatment of bacterial infections caused by one or more pathogens, such as Kusu mutanz, Streptococcus pneumoniae, and Streptococcus pyrogenes. This is provided.

In another aspect, bronchitis in warm-blooded animals such as humans, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation anthrax, intraperitoneal infection, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, sepsis, sinusitis Provided are compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, for use in treating infections, such as skin and soft tissue infections, and urinary tract infections.

In another aspect, of a warm-blooded animal such as human, Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamidophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Formula I, for use in the treatment of bacterial infections of the genus selected from peptostreptococci, prebotella, proteus, salmonella, pseudomonas, serratia, shigella, stenotropomonas, streptococcus, and staphylococcus. Compounds of II, or pharmaceutically acceptable salts thereof, are provided.

In one aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Acinetobacter Baumani. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by Aeromis hydrophila. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Bacillus anthracis. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Bacteroides pragillis. In further aspects, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Bordella pertussis. Also in further aspects, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Burkholderia Sephacia. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by chlamydia pneumoniae. In one aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Citrobacter prepundy. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Clostridium difficile. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Enterobacter cloacae. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Enterococcus paecalis. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by enterococcus faesium. In further aspects, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Enterobacter aerogenes. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by E. coli. In one aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Fusobacterium necrophorum. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Haemophilus influenzae. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Haemophilus parainfluenza. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Haemophilus somnus. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by Klebsiella oxytoca. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by Klebsiella pneumoniae. Also in further aspects, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Legionella pneumophila. In one aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Listeria monocytogenes. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Moraxella catarrhalis. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Morganella morgani. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Mycoplasma pneumoniae. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by Neisseria gonorhoea. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by Neisseria meningitidis. Also in further aspects, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Pasteurella multocida. In one aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Proteus mirabilis. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Proteus vulgaris. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Pseudomonas aeruginosa. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Salmonella typhi. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by Salmonella typhimurium. In further aspects, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Serratia marsense. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by Shigella flexneria. In one aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Shigella descenteria. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Staphylococcus aureus. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Staphylococcus epidermidis. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Staphylococcus spp. In further aspects, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Staphylococcus intermedius. Also in further aspects, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Staphylococcus saprophyticus. Also in further aspects, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Stenotropomonas maltopila. In one aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Streptococcus agalactiae. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Streptococcus mutanz. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Streptococcus pneumoniae. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Streptococcus pyrogenes.

In one aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Aeromonas. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria in the genus Acinetobacter. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Bacillus. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Bacteroides. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Bordetella. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria in the genus Burkholderia. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Chlamydophila. In one aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria in the genus Citrobacter. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Clostridium. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria in the enterobacter. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Enterococcus. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Escherichia. Also in further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Flavobacterium. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Fusobacterium. In one aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Haemophilus. In one aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Klebsiella. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Legionella. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the Listeria genus. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Morganella. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Moraxella. Also in further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Mycoplasma. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Neisseria. In one aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Pasteurella. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the peptococcus genus. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the peptostreptococci. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Prebotella. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Proteus. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Pseudomonas. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Salmonella. In further aspects, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Serratia. In one aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Shigella. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Staphylococcus. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Stenotropomonas. In another aspect, the terms “infection” and “bacterial infection” may refer to bacterial infections caused by bacteria of the genus Streptococcus.

In one aspect, the terms “infection” and “bacterial infection” may refer to a gynecological infection. In another aspect, the terms “infection” and “bacterial infection” may refer to respiratory tract infections (RTI). In another aspect, the terms “infection” and “bacterial infection” may refer to sexually transmitted diseases. In another aspect, the terms “infection” and “bacterial infection” may refer to a urinary tract infection. In further aspects, the terms “infection” and “bacterial infection” may refer to acute exacerbation of chronic bronchitis (ACEB). In further aspects, the terms “infection” and “bacterial infection” may refer to acute otitis media. In one aspect, the terms “infection” and “bacterial infection” may refer to acute sinusitis. In another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by drug resistant bacteria. In another aspect, the terms “infection” and “bacterial infection” may refer to catheter related sepsis. In another aspect, the terms “infection” and “bacterial infection” may refer to a soft ulcer. In further aspects, the terms “infection” and “bacterial infection” may refer to chlamydia. In further aspects, the terms “infection” and “bacterial infection” may refer to regional acquired pneumonia (CAP). Also in further aspects, the terms “infection” and “bacterial infection” may refer to combined skin and skin structure infections. In one aspect, the terms “infection” and “bacterial infection” may refer to simple skin and skin structure infections. In another aspect, the terms “infection” and “bacterial infection” may refer to endocarditis. In another aspect, the terms “infection” and “bacterial infection” may refer to febrile neutropenia. In another aspect, the terms “infection” and “bacterial infection” may refer to gonococcal cervicitis. In further aspects, the terms “infection” and “bacterial infection” may refer to gonococcal urethritis. In further aspects, the terms “infection” and “bacterial infection” may refer to hospital acquired pneumonia (HAP). In another aspect, the terms “infection” and “bacterial infection” may refer to osteomyelitis. In further aspects, the terms “infection” and “bacterial infection” may refer to sepsis. In further aspects, the terms “infection” and “bacterial infection” may refer to syphilis.

In a further aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In a further aspect, there is provided a pharmaceutical composition comprising a compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In a further aspect, there is provided a pharmaceutical composition comprising a compound of Formula Id, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (Ie), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula If, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (Ig), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula Ih, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula IIa, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (IIb), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula IIc, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula IIe, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (IIf), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula IIg, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

Compositions of the present invention may be in orally suitable forms (e.g. tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), forms suitable for topical use (e.g. Creams, ointments, gels, or aqueous or oily solutions or suspensions), forms suitable for inhalation administration (e.g., finely divided powders or liquid aerosols), forms suitable for aeration administration (e.g., finely divided powders) Or in a form suitable for parenteral administration (eg, sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intramuscular administration, or suppositories for rectal administration).

The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients known in the art. Thus, a composition intended for oral use may contain, for example, one or more colorants, sweeteners, flavors and / or preservatives.

Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; Granulation and disintegrating agents such as corn starch or alginic acid; Binders such as starch; Lubricants such as magnesium stearate, stearic acid or talc; Preservatives such as ethyl or propyl p-hydroxybenzoate; And antioxidants such as ascorbic acid. Uncoated or coated tablet formulations can modify their disintegration and subsequent absorption in the gastrointestinal tract, or improve their stability and / or appearance, in each of these cases being conventionally known in the art. Coatings and procedures are used.

Oral compositions are in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient is mixed with water or oils such as peanut oil, liquid paraffin, or olive oil. In the form of soft gelatin capsules.

Aqueous suspensions generally include one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; Condensation products of dispersing or wetting agents such as lecithin or alkylene oxides with fatty acids (eg polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, Or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, or Condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbate Finely divided powder with non-elastic monooleate It contains a tag or a nano or micro particles of the active ingredient form. Aqueous suspensions also include one or more preservatives such as ethyl or propyl p-hydroxybenzoate; Antioxidants such as ascorbic acid); coloring agent; Flavoring agents; And / or sweetening agents such as sucrose, saccharin or aspartame.

Oil suspensions can be formulated by suspending the active ingredient in vegetable oils such as arachis oil, olive oil, sesame oil or coconut oil or mineral oil such as liquid paraffin. The oil suspension may also contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents as described above, and flavoring agents may be added to provide a tasty oral preparation. These compositions can be preserved by the addition of antioxidants such as ascorbic acid.

Dispersible powders and granules suitable for the preparation of aqueous suspensions by addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those mentioned above. Additional excipients may also be present, such as sweetening, flavoring and coloring agents.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or any mixture thereof. Suitable emulsifiers are, for example, esters or partial esters derived from natural gums such as gum acacia or gum tragacanth, natural phosphatides such as soybean, lecithin, fatty acids and hexitol anhydrides (eg sorbitan mono Oleate) and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may contain sweetening, flavoring and preservatives.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, which may contain a thickener, preservative, flavoring agent and / or coloring agent.

The pharmaceutical compositions may also be in the form of sterile injectable aqueous or oily suspensions, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents mentioned above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in nontoxic parenterally-acceptable diluents or solvents, for example solutions in 1,3-butanediol.

Compositions for inhalation administration can be in the form of conventional pressurized aerosols arranged to dispense the active ingredient as an aerosol containing the active ingredient in liquid droplets or finely divided solids. Conventional aerosol propellants can be used, such as volatile fluorinated hydrocarbons or hydrocarbons, and the aerosol device is conveniently arranged to dispense a metered amount of active ingredient.

For further information on formulation, the reader sees Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Volume 5, Chapter 25.2, Pergamon Press 1990.

The amount of active ingredient combined with one or more excipients to form a single formulation essentially depends on the host treated and the particular route of administration. For example, formulations intended for oral administration to humans generally range from 0.5 mg to 4 g of activity in combination with an appropriate and convenient amount of excipient, which may vary, for example, from about 5 to about 98 weight percent of the total composition. It contains a formulation. Unit dosage forms generally contain about 1 mg to about 500 mg of active ingredient. For further information on the mode of administration and dosing regimen, the reader sees Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Volume 5, Chapter 25.3, Pergamon Press 1990.

In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may also contain other clinically useful classes of antibacterial agents (eg, macrolides, quinolones, ß-lactams or aminoglycosides) and / or other anti-infective agents. One or more known drugs selected from (eg, antifungal triazole or amphotericin) may be contained or co-administered with them (simultaneously, sequentially or separately). These may include carbapenems such as meropenem or imipenem to broaden the therapeutic effect. Compounds of the present invention may also contain or co-administer with bactericidal / permeability-promoting protein (BPI) products or effluent pump inhibitors to enhance activity against gram negative bacteria and bacteria that are resistant to antimicrobial agents. .

As noted above, the dosage size required for therapeutic or prophylactic treatment of a particular disease state depends essentially on the host being treated, the route of administration and the severity of the disease being treated. Preferably a daily dosage in the range of 1 to 50 mg / kg is used. Thus, the optimal dosage can be determined by the practitioner treating any particular patient.

Compounds of formula (I) and their pharmaceutically acceptable salts, in addition to their use in therapeutics, are part of the search for novel therapeutic agents, which evaluate the antimicrobial effect in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice. It is also useful as a pharmacological means in the development and standardization of in vitro and in vivo test systems.

In any of the pharmaceutical compositions, processes, methods, uses, medicaments, and manufacturing features of the invention described above, any alternative embodiments of the compounds of the invention described herein also apply.

Way

Essential starting materials for procedures such as those described herein, if not commercially available, are similar to standard organic chemistry techniques, techniques similar to the synthesis of structurally similar known compounds, or procedures (s) described in the Examples. It may be prepared by a procedure selected from the art.

Most of the starting materials for the synthetic methods described herein are commercially available and / or widely reported in the scientific literature, or can be prepared from commercially available compounds using modifications of the methods reported in the scientific literature. Be aware. For general guidance on reaction conditions and reagents, readers are further referred to Advanced Organic Chemistry, 5 ^th Edition, Jerry March and Michael Smith, published by John Wiley & Sons 2001.

It will also be appreciated that in some of the reactions mentioned herein, it may be necessary / desirable to protect any reactive groups in the compound. Where protection is essential or desirable, those skilled in the art are known and suitable methods for such protection are also known. Conventional protecting groups can be used in accordance with standard practice (see, eg, T.W. Greene, Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1991).

Examples of suitable protecting groups for hydroxy groups are, for example, acyl groups such as alkanoyl groups such as acetyl, aroyl groups such as benzoyl, silyl groups such as trimethylsilyl or arylmethyl groups such as benzyl. The deprotection conditions for the protecting group essentially depend on the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or aroyl groups can be removed, for example, by hydrolysis with suitable bases such as alkali metal hydroxides such as lithium hydroxide or sodium hydroxide. Alternatively, silyl groups such as trimethylsilyl can be removed, for example by fluoride or by aqueous acid; Or arylmethyl groups such as benzyl groups can be removed, for example, by hydrogenation in the presence of a catalyst such as palladium on carbon.

Suitable protecting groups for the amino group are, for example, acyl groups, for example alkanoyl groups such as acetyl, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl groups, arylmethoxycarbonyl groups, For example benzyloxycarbonyl, or aroyl groups such as benzoyl. The deprotection conditions for the protecting group essentially depend on the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or alkoxycarbonyl groups or aroyl groups can be removed, for example, by hydrolysis with suitable bases such as alkali metal hydroxides such as lithium hydroxide or sodium hydroxide. Alternatively acyl groups such as t-butoxycarbonyl groups can be removed by treatment with a suitable acid such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups, for example For example, it can be removed by hydrogenation on a catalyst such as palladium on carbon or by treatment with a Lewis acid such as boron tris (trifluoroacetate). Alternative protecting groups suitable for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with alkylamines, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine. Another protecting group suitable for amines is, for example, cyclic ethers such as tetrahydrofuran, which can be removed by treatment with a suitable acid such as trifluoroacetic acid.

The protecting groups can be removed at any convenient step in the synthesis using conventional techniques known in the chemical art, or they can be removed during the later reaction step or work-up.

In one aspect, the present invention is directed to reacting a compound of formula AA with a compound of formula AB in the presence of a suitable reducing agent,

<Formula AA>

<Formula AB>

After that, if necessary

i) converting the compound of formula I or II to another compound of formula I or II;

ii) removing any protecting group;

iii) a process for preparing a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, comprising forming a pharmaceutically acceptable salt.

Compounds of formula AA can be reacted with compounds of formula AB under typical reducing amination conditions. In the first stage of the reaction, imine-forming is typically carried out in the presence of a dehydrating agent such as molecular sieve (MS 3 ′), but the reaction generally proceeds without the dehydrating agent. Suitable solvents are methanol or methanol / chloroform mixtures. Typically the imine intermediates are not isolated; Rather, a reducing agent is generally added to the reaction mixture after imine formation. Suitable reducing agents in the second (reduction) step of the process include boron reducing agents such as NaB (OAc) ₃ H or NaBH ₃ CN.

In another aspect, the invention provides a process for reacting a compound of formula AC with a compound of formula AB in the presence of a suitable reducing agent,

<Formula AC>

<Formula AB>

After that, if necessary

i) converting the compound of formula I or II to another compound of formula I or II;

ii) removing any protecting group;

iii) a process for preparing a compound of formula (I) or (II) wherein R ⁶ is F, or a pharmaceutically acceptable salt thereof, comprising forming a pharmaceutically acceptable salt.

The reaction conditions for the reaction of the compound of formula AC with the compound of formula AB are as described above for the reaction of the compound of formula AA with the compound of formula AB.

In another aspect, the invention provides a process for reacting a compound of formula BI with a suitable reducing agent,

<Formula BI>

After that, if necessary

i. Converting the compound of formula I or II to another compound of formula I or II;

ii. Remove any protecting group;

iii. Provided are methods for preparing a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, comprising forming a pharmaceutically acceptable salt.

Suitable reducing agents for the reduction of compounds of formula BI include boron reducing agents such as NaB (OAc) ₃ H or NaBH ₃ CN. Suitable solvents are methanol or methanol / chloroform mixtures.

Compounds of formula AA can be prepared as shown in Scheme 1 below.

The reaction of the compound of formula AD with the compound of formula AE in the presence of a base such as sodium hydride can be used to obtain the compound of formula AF. Compounds of formula AA are provided from deprotection. Suitable leaving groups include leaving groups such as mesylate, chloro, bromo, and iodo. Suitable protecting groups include alkoxycarbonyl groups, such as t-butoxycarbonyl, which can be deprotected using an acid such as HCl.

Another method that can be used to prepare the compound of formula AA is shown in Scheme 2 below.

The reaction of the compound of formula AD with the compound of formula AG can be obtained under Mitsunobu conditions to obtain the compound of formula AF. Compounds of formula AA are provided from deprotection. Suitable protecting groups include alkoxycarbonyl groups such as t-butoxycarbonyl, which can be removed using an acid such as HCl.

Another method for preparing the compound of formula AA is shown in Scheme 3 below.

The compound of formula AD is reacted with a base such as NaH, followed by bromo- or chloroethanol or bromo- or chloroacetaldehyde, or a protected derivative thereof (in the case of alcohol derivatives, then deprotection and Oxidation), to give a compound of formula AH. Compounds of formula AH can be reacted with compounds of formula AI under typical reducing amination conditions. As described above for the reaction of a compound of formula AA with a compound of formula AB, imine-forming is typically carried out in the presence of a dehydrating agent, such as a molecular sieve (MS 3 ′), but the reaction generally proceeds without dehydrating agent. Suitable solvents are tetrahydrofuran, dichloromethane or chloroform / methanol mixtures. Typically the imine intermediates are not isolated; Rather, a reducing agent is generally added to the reaction mixture after imine formation. Suitable reducing agents for the second stage (reduction) of the reaction include boron reducing agents such as NaB (OAc) ₃ H or NaBH ₃ CN. Compounds of formula AA are provided from deprotection of compounds of formula AF. Suitable protecting groups for amino group substituents on the piperidine ring of the compound of formula AI include alkoxycarbonyls such as t-butoxycarbonyl (which can be removed using an acid such as HCl); And azides, which can be converted reductively to amines by triphenyl phosphine (Staudinger reaction) or by hydrogenation.

Compounds of formula AL wherein the leaving group is a compound of formula AE wherein the leaving group is a mesylate leaving group can be prepared according to Scheme 4 below.

Compounds of formula AL can be prepared by reacting a compound of formula AI with bromoethanol or a derivative thereof in the presence of a base such as triethylamine to obtain a compound of formula AG. The compound of formula AG can be reacted with mesyl chloride in the presence of a base such as trialkyl amine, or a fixed variant thereof on the resin to obtain a compound of formula AL. Compounds of formula AL are potentially unstable and may exist as part of a mixture with the corresponding chloride (formed from the attack of chloride on the mesyl group), which needs to be prepared fresh under carefully controlled conditions.

Compounds of Formula AO, wherein J is CH, is a compound of Formula AD, can be prepared according to Scheme 5 below.

As shown in Scheme 5, a compound of formula AO is reacted with a cinnamoylchloride from a commercially available compound of formula AM in the presence of a suitable base such as 2,6-lutidine and then cyclized to aluminum trichloride. It can manufacture.

In a similar manner, cinnamoyl chloride can be replaced with E-ethoxyacryloyl chloride, and sulfuric acid can be used to cyclize the intermediate E-ethoxyacryloylamide instead of aluminum trichloride (E. Baston et al. , European Journal of Medicinal Chemistry 35 (2000) 931]. Asymmetric substituted anilines generally produce regioisomeric quinoline-2 (1H) -one derivatives which may be difficult to separate by chromatography due to limited solubility. This mixture can be separated by crystallization or can be converted to the corresponding 2-chloroquinoline derivative (eg by phosphorus oxychloride), which can be separated by chromatography or by crystallization. It may then be hydrolyzed again by hydrochloric acid reflux to form a single regioisomer of the compound of formula AO.

Compounds of formula AO can also be prepared according to Scheme 6 below.

Compounds of formula AO can be prepared from compounds of formula AP by carbon-carbon bond formation followed by intramolecular amide bond formation of a suitably configured cis unsaturated system. Isomerization of trans double bonds can be carried out photochemically or thermally under UV light. Alternatively, carbon-carbon bond formation can be performed as sonogashira coupling to the alkyne intermediate, which carbon-carbon bonds can be partially hydrogenated to cis double bonds under Lindla conditions.

Compounds of formula AO can also be prepared according to the following Scheme 7.

Compounds of formula AO can be prepared from compounds of formula BE by deprotonation with a base such as sodium ethoxide and then reacted with diethyl oxalate to form compounds of formula BF. The intermediate can then be reduced with a suitable reducing agent such as sodium borohydride to afford the compound of formula BG. The compound of formula BG can then be cyclized to the compound of formula BH after reduction of the nitro group with a suitable reducing agent such as iron or tin dichloride in acetic acid. Finally, the compound of formula AO is obtained by the removal reaction with a base such as DBU.

The compound of formula AU, which is a compound of formula AD wherein J is N, can be prepared according to Scheme 8 below.

Regioisomeric mixtures of compounds of Formula (AU) may be separated by the method described above for Scheme 5.

Scheme 9 shows another method for preparing a compound of formula AU.

The compound of formula AU can be obtained by oxidizing the compound of formula AX with an oxidizing agent such as hydrogen peroxide. Compounds of formula AX can be obtained by reacting a compound of formula AV with bromoacetic acid ester, or ethylglyoxylate, followed by reduction and spontaneous cyclization of the nitro group. Suitable reducing agents include Pd / C and H ₂ , iron in acetic acid, and tin chloride.

Compounds of formula AZ wherein the protecting group is a compound of formula AG wherein t-butoxycarbonyl can be prepared according to Scheme 10 below.

Compounds of formula BA can be reacted with compounds of formula BB in the presence of a base to afford compounds of formula BC. Examples are Cs ₂ CO ₃ , NaH, K ₂ CO ₃ or Na ₂ CO ₃ . Suitable leaving groups for this reaction include mesylates and halo groups such as chloro and bromo. Suitable protecting groups for this reaction include silyl protecting groups such as t-butyl-dimethylsilyl. The protecting group of the compound of formula BC can be removed using t-butylammonium fluoride to afford the compound of formula BD. Compounds of formula BD can be deprotected by hydrogenation. Examples of suitable catalysts for this _half include Pd (OH) ₂ , platinum black, and PtO ₂ , which are then reacted with di-t-butylcarbonate to give the compound of formula AZ.

If optically active forms of the compounds of the invention are desired, they can be obtained by performing one of the above procedures using pure enantiomers as starting materials, or by using standard procedures to enantiomers or diastereomers of the final product or chiral intermediates. It can be obtained by separating the mixture. Separation of the enantiomers can be accomplished by chromatography on a chiral stationary phase, such as a Chiralpak AD column. Resolution as well as solubility should also be considered. Alternatively, degradation can be achieved by the preparation and selective crystallization of diastereomeric salts of chiral acids, such as camphorsulfonic acid and chiral intermediates or chiral products. Alternatively, stereoselective synthesis methods can be employed, for example by using chiral modifications of the protecting groups, chiral catalysts or chiral reagents as appropriate in the reaction sequence.

Enzyme techniques may also be useful for the preparation of optically active compounds and / or intermediates.

Similarly, where pure regioisomers of the compounds of the present invention are desired, they are obtained by performing one of the above procedures using pure regioisomers as starting materials, or by separating mixtures of regioisomers or intermediates using standard procedures. Can be.

The skilled organic chemist can use and adapt the information contained in and referred to in the above references, and the examples attached thereto, and also the examples herein, to obtain the necessary starting materials and products.

Now, the present invention is illustrated by the following examples, but the present invention is not limited thereto and unless stated otherwise,

(i) Evaporation was carried out by rotary evaporation in vacuo, and the workup procedure was carried out after the removal of residual solids by filtration.

(ii) the temperature is referred to as ° C; The operation was carried out at room temperature, ie typically in the range of 18 to 26 ° C., unless otherwise stated, or unless the skilled person worked otherwise in an inert atmosphere, without air blocking.

(iii) The compounds were purified using column chromatography (by flash method) and performed on Merck Kieselgel silica (Art. 9385) unless otherwise noted.

(iv) In general, TLC, HPLC, or LC / MS was carried out after the reaction procedure, and the reaction time is given by way of example only; Yields are given by way of example only and are not necessarily the maximum attainable.

(v) The structure of the final product of the present invention was generally confirmed by NMR and mass spectral techniques. Proton magnetic resonance spectra are generally used in either of DMSO-d ₆ , either Bruker DRX-300 spectrometer or Bruker DRX-400 spectrometer (operated at a magnetic field intensity of 300 MHz or 400 MHz, respectively). It measured using. In the case of complex NMR spectra, only characteristic signals were recorded. Chemical displacements are reported in parts per million in low field from tetramethylsilane as internal standard (δ scale), in which case the peak multiplicity is expressed as: s, singlet; d, doublet; dd, doublet of doublets; dt, doublet of triplets; dm, doublet of multiplets; t, triplet; m, multiplet; br, broad. Fast atom bombardment (FAB) mass spectral data is generally obtained by using a platform spectrometer (supplied by Micromass) which is run by electrospray, collecting positive ion data or negative ion data as appropriate, or cedex Agilent 1100 Series LC / MSD with (Sedex) 75ELSD was used and, where appropriate, positive or negative ion data were collected. If multiple mass spectral peaks were formed in the isotope split (eg, chlorine is present), the lowest mass macro ions were recorded for the molecule. Reverse phase HPLC was performed using a YMC Pack ODS-AQ (100 × 20 mmID, S-5μ particle size, 12 nm pore size) on an Agilent instrument.

(vi) each intermediate was purified to the standards required in subsequent steps, which were characterized in sufficient detail to confirm that the structure imparted was correct; Purity was assessed by HPLC, TLC, or NMR and compound identity was determined by infrared spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate.

(vii) The following abbreviations can be used.

TLC is thin layer chromatography; HPLC is high pressure liquid chromatography; MPLC is medium pressure liquid chromatography; NMR is nuclear magnetic resonance spectroscopy; DMSO is dimethyl sulfoxide; CDCl ₃ is deuterated chloroform; MeOD is deuterated methanol, ie D ₃ COD; MS is mass spectroscopy; ESP (or ES) is electrospray; EI is an electron impact; APCI is atmospheric pressure chemical ionization; THF is tetrahydrofuran; DCM is dichloromethane; MeOH is methanol; DMF is dimethylformamide; EtOAc is ethyl acetate; LC / MS is liquid chromatography / mass spectrometry; h is time (s); min is minute (s); d is day (s); MTBD is N-methyl-1,5,7-triazabicyclo [4.4.0] dec-5-ene; TFA is trifluoroacetic acid; v / v is the ratio of volume / volume; Boc represents t-butoxycarbonyl; Cbz represents benzyloxycarbonyl; Bz represents benzoyl; atm represents atmospheric pressure; rt represents room temperature; mg represents milligrams; g represents gram; Μl represents microliters; mL represents milliliters; L represents liter; μM represents micromolar; mM represents millimoles; M represents mole; N represents normal; nm represents nanometers.

Intermediate 1

1- {2-[(3R, 4S) -4-amino-3-hydroxypiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline-7-carbonitrile

And

Intermediate 2

1- {2-[(3S, 4R) -4-amino-3-hydroxypiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline-7-carbonitrile

1- [2-cis (±) (4-azido-3-hydroxypiperidin-1-yl) ethyl] -2-oxo-1,2 in acetonitrile / water (9: 1, 50 mL) A mixture of dihydroquinoline-7-carbonitrile (intermediate 3) (0.545 g, 1.61 mmol) and triphenylphosphine (0.507 g, 1.93 mmol) was stirred for 6 days at room temperature. The reaction mixture was concentrated to dryness under reduced pressure. Chromatography on silica gel with dichloromethane / methanol (6: 1 with 0.2% ammonium hydroxide) gave a racemic mixture of intermediates 1 and 2 as colorless hard foam (0.452 g (90%)).

The racemic mixture was separated on a Chiralpak AD column (250 × 20 mm, 10 μm) using 60% hexane and 40% ethanol / methanol (1: 1) (containing 0.1% diethyl amine). Intermediate 2 eluted first ([α] _D = +45.5), then intermediate 1 eluted ([α] _D = -45.9) (c = 1 in methanol / chloroform 1: 1).

Intermediate 3

1- [2-cis (±) (4-azido-3-hydroxypiperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile

1- [2-cis ± (4-azido-3-{[tert-butyl (dimethyl) silyl] oxy} piperidin-1-yl) ethyl] -2-oxo-1 in THF (5 mL), A solution of 2-dihydroquinoline-7-carbonitrile (intermediate 4) (0.724 g, 1.6 mmol) was treated dropwise with a solution of tetrabutyl ammonium fluoride (1 M, 2.2 mL) in THF at room temperature. After 1 h, saturated aqueous sodium hydrogen carbonate solution (10 mL) was added and THF was removed under reduced pressure. It was extracted with dichloromethane / ether (1: 1, about 200 mL). The organic phase containing some insoluble product is separated, the aqueous phase is extracted again with dichloromethane (100 mL) and the combined organic phases are concentrated to dryness under reduced pressure and dried under high vacuum to give the product as a colorless solid (0.545). g (quantitative)).

Intermediate 4

1- [2-cis (±) (4-azido-3-{[tert-butyl (dimethyl) silyl] oxy} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydro Quinoline-7-carbonitrile

A suspension of 2-oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 5) (0.51 g, 3.0 mmol) in DMF (15 mL) was added sodium hydride (60% in oil, 132 mg in 0 ° C.). ). It is stirred for 2 hours and then 2-cis ± (4-azido-3-{[tert-butyl (dimethyl) silyl] oxy} piperidin-1-yl) ethyl methanesulfonate in DMF (7 mL) (Intermediate 6) A solution of (3 mmol) was added by syringe. Cooling was stopped and it was stirred overnight at room temperature. DMF was removed under reduced pressure and the residue was collected in dichloromethane (about 200 mL) and saturated aqueous sodium hydrogen carbonate solution (20 mL, pH adjusted to pH 10 with 1 M NaOH solution). The aqueous phase was back extracted twice with dichloromethane (2 × 100 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel using hexanes / acetone (4: 1) gave the product as a rigid foam (0.724 g (53%)).

Intermediate 5

2-oxo-1,2-dihydroquinoline-7-carbonitrile

7-bromoquinolin-2 (1H) -one (intermediate 46) (9.21 g, 41 mmol) and copper cyanide (I) (4.05 g) in N-methylpyrrolidone (50 mL) for 16 h at 160 ° C. Heated. It was cooled to rt, an aqueous solution of ethylenediamine tetraacetate (2 M, pH 8.3, 100 mL) was added and the mixture was stirred at rt and air opened for 5 days. The precipitate was collected by filtration into 0.45 μm membrane, washed with water and ethyl acetate and recrystallized from DMF / water to give the product as a brown solid in 90% purity which was used without further purification (4.72 g). (60%)).

Alternative procedure for the synthesis of intermediate 5

3-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline-7-carbonitrile (intermediate 66, 15.51 g, 82.42 mmol) and 1,8-diazabicycle in acetonitrile (155 mL) The mixture of rho [5.4.0] undes-7-ene (DBU) was heated at 75 ° C. for 2.5 h. The reaction mixture was cooled to room temperature and the precipitate collected by filtration, washed with water (77 mL) and methanol (77 mL) and dried under reduced pressure to give the product as an off-white solid (9.71 g (68%)). ).

Mp> 250 ℃

Intermediate 6

2- (cis (±))-(4-azido-3-{[tert-butyl (dimethyl) silyl] oxy} piperidin-1-yl) ethyl methanesulfonate

2- (cis ±)-(4-azido-3-{[tert-butyl (dimethyl) silyl] oxy} piperidin-1-yl) ethanol in anhydrous dichloromethane (20 mL) (intermediate 7, 1.8 g , 6 mmol) and triethyl amine (1.18 mL, 8.4 mmol) were treated with methanesulfonyl chloride (0.556 mL, 7.2 mmol) at 0 ° C. After 90 minutes, the reaction was complete by TLC (chloroform / methanol 6: 1, rf about 0.9). Potassium phosphate buffer (pH 7, 1 M, 15 mL) was added and dichloromethane was removed under reduced pressure, which was extracted with ice cold ether (100 mL). The aqueous phase was back extracted once with ether (50 mL) and the combined organic phases were dried over sodium sulfate. Solvent was removed under reduced pressure and the residue was collected in DMF (10 mL). The crude formulation of this mesylate was used in the next step without delay.

Intermediate 7

2- (cis (±))-(4-azido-3-{[tert-butyl (dimethyl) silyl] oxy} piperidin-1-yl) ethanol

(Cis ±) -4-azido-3-{[tert-butyl (dimethyl) silyl] oxy} piperidine (intermediate 8) in anhydrous acetonitrile (17 mL) (1.625 g, 6.34 mmol), N, N A mixture of diisopropylethylamine (1.65 mL, 9.5 mmol) and 2-bromoethanol (0.584 mL, 8.25 mmol) was heated in microwave at 70 ° C. for 2 hours. The solvent was removed under reduced pressure and the residue was collected in ethyl acetate (about 150 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (about 25 mL). The aqueous phase was back extracted once with ethyl acetate (100 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane / methanol (20: 1) gave 1.80 g (95%) of the product as a colorless oil.

Intermediate 8

(Cis (±))-4-azido-3-{[tert-butyl (dimethyl) silyl] oxy} piperidine

Tert-butyl (cis ±) -4-azido-3-{[tert-butyl (dimethyl) silyl] oxy} piperidine-1-carboxylate (Intermediate 9) in dichloromethane (50 mL) (2.3 g, 6.45 mmol) was treated with trifluoroacetic acid (5 mL) at 0 ° C. After 3 h, the mixture was concentrated under reduced pressure and the residue was codistillated twice with dichloromethane. The residue was collected in dichloromethane (100 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (30 mL). The aqueous phase was back extracted once with dichloromethane (100 mL) and the combined organic phases were dried over sodium sulphate to give the product as a slightly yellow oil (1.625 g (98%)).

Intermediate 9

tert-butyl (cis (±))-4-azido-3-{[tert-butyl (dimethyl) silyl] oxy} piperidine-1-carboxylate

Tert-butyl (cis ±) -4-azido-3-hydroxypiperidine-1-carboxylate (Intermediate 10) (1.76 g, 7.25 mmol) and imidazole (0.74 g, in DMF (7 mL) 10.9 mmol) was treated with tert-butyl dimethylsilyl chloride (1.3 g, 8.7 mmol) at 0 ° C. Cooling was stopped and the mixture was stirred at rt overnight. It was cooled to 0 ° C. and quenched with phosphate buffer (1 M, pH 7, 20 mL). After 15 minutes, the mixture was diluted with ethyl acetate (100 mL) and the organic phase was washed with water (2 x 50 mL) and dried over sodium sulfate. Chromatography on silica gel using hexanes / ethyl acetate (9: 1) gave the product as a colorless oil (2.3 g (89%)).

Intermediate 10

tert-butyl (cis (±))-4-azido-3-hydroxypiperidine-1-carboxylate

(Cis ±) -4-azidopiperidin-3-ol (prepared according to the procedure described in WO 2005/066176 for chiral materials) in isopropanol (20 mL) and dichloromethane (25 mL) at 0 ° C. (2.1 g, 14.8 mmol) and potassium hydroxide (2.5 g, 44 mmol) were added a solution of di-tert-butyl dicarbonate (3.9 g, 17.7 mmol) in dichloromethane (10 mL). Cooling was stopped and it was stirred for 2 hours at room temperature. It was quenched with water (50 mL) and isopropanol and dichloromethane were removed under reduced pressure. It was neutralized with potassium phosphate buffer (1 M, pH 7, 100 mL), extracted twice with ethyl acetate (2 x 300 mL) and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated from hexane (about 20 mL) to give 0.966 g of product as a colorless solid. The mother liquor was chromatographed with hexane / ethyl acetate (5: 1) to afford 0.353 g (35%) of product.

Intermediate 11

1- {2-[(3R, 4S) -4-amino-3-hydroxypiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one

And

Intermediate 12

1- {2-[(3S, 4R) -4-amino-3-hydroxypiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one

1- [2-{(cis ±)-(4-azido-3-hydroxypiperidin-1-yl)} ethyl] -7-methoxy in acetonitrile / water (9: 1, 20 mL) A mixture of quinoxaline-2 (1H) -one (intermediate 13) (0.507 g, 1.47 mmol) and triphenylphosphine (0.463 g, 1.77 mmol) was stirred at room temperature for 5 days. The reaction mixture was concentrated to dryness under reduced pressure. The residue was collected in dichloromethane (5 mL) and chromatographed on silica gel with dichloromethane / methanol (6: 1, containing 0.2% ammonium hydroxide) to give the racemic mixture of intermediates 11 and 12 a colorless hard foam. Obtained as (0.422 g, 90%).

MS (ESP) : 319 (MH ⁺ ) for C ₁₆ H ₂₂ N ₄ O ₃

The racemic mixture was separated on a Chiralpak AD column (250 × 20 mm, 10 μm) using ethanol / methanol (1: 1) (containing 0.1% diethyl amine). Intermediate 12 eluted first ([a] _D = +45.5), then intermediate 11 eluted ([a] _D = -44.7) (c = 1 in methanol / chloroform 1: 1).

Intermediate 13

1- [2-{(cis (±))-(4-azido-3-hydroxypiperidin-1-yl)} ethyl] -7-methoxyquinoxalin-2 (1H) -one

1- [2- (cis ±) -4-azido-3-{[tert-butyl (dimethyl) silyl] oxy} piperidin-1-yl) ethyl] -7-methoxy in THF (5 mL) A solution of quinoxaline-2 (1H) -one (intermediate 14, 0.721 g, 1.57 mmol) was treated dropwise with a solution of tetrabutyl ammonium fluoride (1 M, 2.2 mL) in THF at room temperature. After 1 h, saturated aqueous sodium hydrogen carbonate solution (10 mL) was added and THF was removed under reduced pressure. It was extracted with dichloromethane / ether (1: 1, about 200 mL). The aqueous phase was back extracted with dichloromethane (100 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel using hexanes / acetone (1: 1) gave the product as a colorless hard foam (0.507 g (94%)).

Intermediate 14

1- [2- (cis (±))-4-azido-3-{[tert-butyl (dimethyl) silyl] oxy} piperidin-1-yl) ethyl] -7-methoxyquinoxaline-2 (1H) -on

Using a procedure similar to that described for the synthesis of intermediate 4, 7-methoxyquinoxalin-2 (1H) -one (intermediate 15, 0.528 g, 3.0 mmol) was added sodium hydride (60% in oil, 132 mg). And 2-cis ± (4-azido-3-{[tert-butyl (dimethyl) silyl] oxy} piperidin-1-yl) ethyl methanesulfonate (Intermediate 6, 3 mmol) to give the product hard Obtained as a foam (0.721 g (52%)).

Intermediate 15

7-methoxyquinoxalin-2 (1H) -one

To a solution of 8% aqueous sodium hydroxide (1.32 L) 7-methoxy-3,4-dihydroquinoxalin-2 (1H) -one (intermediate 16, 100 g), then 3 weights in water (1.17 L) A solution of% hydrogen peroxide was added. The reaction mixture was slowly heated to 80 ° C. and maintained at this temperature for 4 hours. The heat source was then removed and acetic acid (150 mL) was added dropwise. The suspension was stirred at rt overnight and the precipitated solid was collected by filtration to give the product as a tan solid (90 g).

Intermediate 16

7-methoxy-3,4-dihydroquinoxalin-2 (1H) -one

In an 18-L Parr apparatus, a suspension of ethyl [(4-methoxy-2-nitrophenyl) imino] acetate (Intermediate 17) was added to 20% by weight Pd / C (100) until no hydrogen was consumed. g, containing about 50% water by weight) at 55 psi. (Note: The reaction is strongly exothermic, so the temperature must be adjusted to about 60 ° C. by adjusting the hydrogen recharge rate and also by the cooling system.) The reaction mixture is discharged, filtered through a celite cake and evaporated under reduced pressure. , A crude solid was obtained, which was triturated with MTBE (6 L) to give the product as a tan solid (400 g).

Alternative Procedure for Intermediate 16

Ethyl N- (4-methoxy-2-nitrophenyl) glycinate (intermediate 18, 15.8 g of crude) was collected in 200 mL of 1: 1 methanol / acetic acid and palladium on carbon (10%, 2 g ) And stirred overnight in hydrogen atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated to dryness to give 10.6 g of crude product as a tan solid. It was used without further purification.

Intermediate 17

Ethyl [(4-methoxy-2-nitrophenyl) imino] acetate

A solution of 4-methoxy-2-nitroaniline (1 kg, 5.95 mol) and ethyl glyoxylate (1180 mL, 50 wt.% In toluene, 5.95 mol) in toluene (10 L) was Dean-Stark. Reflux in the apparatus for 48 hours and evaporate under reduced pressure to give the crude product as dark brown oil, which was used without further purification.

Intermediate 18

Ethyl N- (4-methoxy-2-nitrophenyl) glycinate

A mixture of 4-methoxy-2-nitroaniline (25.0 g, 0.15 mol), ethyl bromoacetate (200 mL, 1.8 mol) and potassium carbonate (31.1 g, 0.23 mol) was heated at 150 ° C. for 4.5 hours. After cooling to room temperature, aqueous sodium hydroxide solution (1 M, 600 mL) was added. This mixture was extracted with ethyl acetate (2 x 500 mL). The combined organic phases were dried over magnesium sulphate and concentrated to dryness. Chromatography on silica gel with 25-50% acetone in hexanes gave 22.1 g of crude product as a red solid. ¹ H NMR showed about 20% dialkylation product present. This material was used without further purification.

Intermediate 19

Cis (±) 1- [2- (4-amino-3-fluoropiperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile

Cis (±) tert-butyl {1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl] -3-fluoropiperidin-4- in chloroform (8 mL) A solution of monocarbamate (intermediate 20, 397 mg, 0.95 mmol) was treated with 30% trifluoroacetic acid in chloroform (5 mL) at 0 ° C. After 5 hours at room temperature, the solvent was removed under reduced pressure to give the trifluoroacetate salt of the product, which was used in the next step without further purification.

Intermediate 20

Cis (±) tert-butyl {1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl] -3-fluoropiperidin-4-yl} carbamate

As described for intermediate 4, a suspension of 2-oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 5, 0.3 g, 1.7 mmol) in DMF (10 mL) was prepared at room temperature with sodium hydride and cis ( ±) 2- {4-[(tert-butoxycarbonyl) amino] -3-fluoropiperidin-1-yl} ethyl methanesulfonate (Intermediate 21, about 1.7 mmol). Chromatography on silica gel using hexanes / ethyl acetate (2: 3) gave the product as a solid (397 mg (73%)).

Intermediate 21

Cis (±) 2- {4-[(tert-butoxycarbonyl) amino] -3-fluoropiperidin-1-yl} ethyl methanesulfonate

Cis (±) tert-butyl [3-fluoro-1- (2-hydroxyethyl) piperidin-4-yl] carbamate (Intermediate 22) using a procedure similar to that described for the synthesis of intermediate 6 , 314 mg, 1.2 mmol) were reacted with mesyl chloride in the presence of triethyl amine. Crude mesylate was used in the next step without delay.

Intermediate 22

Cis (±) tert-butyl [3-fluoro-1- (2-hydroxyethyl) piperidin-4-yl] carbamate

Cis (±) tert-butyl [1- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -3-fluoropiperidin-4-yl in tetrahydrofuran (10 mL) at 0 ° C. ] To a solution of carbamate (intermediate 23, 530 mg, 1.4 mmol) was added tetrabutylammonium fluoride (1M in THF, 2.8 mL). After 30 minutes, the reaction was quenched with saturated sodium bicarbonate, extracted twice with ethyl acetate, dried over magnesium sulfate and concentrated. Silica gel chromatography with 2.5% methanol in ethyl acetate gave the product as a colorless solid (314 mg (85%)).

Intermediate 23

Cis (±) tert-butyl [1- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -3-fluoropiperidin-4-yl] carbamate

Cis (±) 1- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -3-fluoropiperidin-4-amine (intermediate 24, 2.8 g, 10.4 mmol) and di-tert- Butyl dicarbonate (3.4 g, 15.6 mmol) was combined in tetrahydrofuran (50 mL) at room temperature. After 90 minutes, the reaction mixture was concentrated under reduced pressure. Silica gel chromatography using hexanes / ethyl acetate (3: 2) gave the product as a colorless oil (3.2 g (82%)).

Intermediate 24

Cis (±) 1- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -3-fluoropiperidin-4-amine

Cis (±) benzyl benzyl [1- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -3-fluoropiperidin-4-yl] carbamate (intermediate 25, 5.2 g, 10.4 mmol) was hydrogenated over anhydrous methanol (15 mL) on palladium hydroxide on carbon (20 wt.%, 31 mg) for 24 h, then filtered through celite and concentrated under reduced pressure to give the product as a colorless oil (2.8). g).

Intermediate 25

Cis (±) benzyl benzyl [1- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -3-fluoropiperidin-4-yl] carbamate

Cis (±) benzyl benzyl (3-fluoropiperidin-4-yl) carbamate hydrochloride (intermediate 26, 4.3 g, 6.1 mmol), (2-bromoethoxy) -tert in acetonitrile (150 mL) A mixture of -butyldimethylsilane (9.8 mL, 45.7 mmol) and cesium carbonate (9.9 g, 30.4 mmol) was heated at 60 ° C. overnight. The reaction mixture was filtered and concentrated under reduced pressure. Silica gel chromatography using hexanes / ethyl acetate (3: 2) gave the product as a colorless oil (5.2 g (91%)).

　　　

　　　

Intermediate 26

Cis (±) benzyl benzyl (3-fluoropiperidin-4-yl) carbamate

Cis (±) tert-butyl 4- {benzyl [(benzyloxy) carbonyl] amino} -3-fluoropiperidine-1-carboxylate (intermediate 27, 6) in dichloromethane (50 mL) at 0 ° C. g, 13.5 mmol) was added 4N HCl in dioxane (6.8 mL). The reaction mixture was stirred at rt overnight. The precipitate was collected by filtration to give the product as a colorless solid (4.4 g (86%)).

Intermediate 27

Cis (±) tert-butyl 4- {benzyl [(benzyloxy) carbonyl] amino} -3-fluoropiperidine-1-carboxylate

Cis (±) tert-butyl 4- (benzylamino) -3-fluoropiperidine-1-carboxylate (intermediate 28, 1.1 g, 3.6 mmol) in dioxane (20 mL) at 0 ° C. and saturated sodium carbonate Benzyl chloroformate (0.76 mL, 5.4 mmol) was added dropwise to the mixture of (10 mL) and the reaction mixture was stirred at 0 ° C. for 1 h. Ethyl acetate (about 20 mL) and brine (about 20 mL) were added and the layers separated. The aqueous phase was extracted once with ethyl acetate and the combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure to give the product as a colorless solid (1.4 g (89%)).

Intermediate 28

Cis (±) tert-butyl 4- (benzylamino) -3-fluoropiperidine-1-carboxylate

Tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (intermediate 29, 8.1 g, 37.3 mmol) in dichloromethane (150 mL), benzylamine (4.5 mL, 41 mmol) and 3 ′ molecules The mixture of sieves was treated in portions with sodium triacetoxyborohydride (11.8 g, 56 mmol) at 0 ° C. The reaction mixture was stirred at rt for 30 min and then filtered. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was extracted once with dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. Silica gel chromatography using hexanes / ethyl acetate (3: 2) gave the product as an off-white solid (6.9 g (60%)).

Intermediate 29

tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate

A solution of tert-butyl 4-[(trimethylsilyl) oxy] -3,6-dihydropyridine-1 (2H) -carboxylate (intermediate 30, 14 g, 51 mmol) in acetonitrile (200 mL) was zero Partial treatment with SELECTFLUOR ^™ (20 g, 57 mmol) at &lt; RTI ID = 0.0 &gt; The reaction mixture was stirred at 0 ° C. for 30 minutes, then diluted with ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate and concentrated. Silica gel chromatography using hexanes / ethyl acetate (3: 2) gave the product as a colorless oil (8.1 g (72%)).

Intermediate 30

tert-butyl 4-[(trimethylsilyl) oxy] -3,6-dihydropyridine-1 (2H) -carboxylate

A mixture of tert-butyl 4-oxo-1-piperidinecarboxylate (11 g, 55 mmol) and triethylamine (18.5 mL, 132 mmol) in DMF (40 mL) was added to chlorotrimethylsilane (8.4) at 0 ° C. mL, 66 mmol) was added dropwise. The reaction mixture was heated at 80 ° C. overnight, then cooled to room temperature. Saturated sodium bicarbonate was added and the product was extracted twice with hexane. The combined organic extracts were dried over magnesium sulfate and concentrated to give 14 g (93%) of the product as a yellow oil.

Intermediate 31

1- {2-[(3S, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one

Tert-butyl {(3S, 4R) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperi in dichloromethane (50 mL) A solution of din-4-yl} carbamate (intermediate 32, 420 mg, 0.97 mmol) was treated with trifluoroacetic acid (10 mL). After 1 hour, the reaction was concentrated to dryness. The residue was collected in 15% methanol (30 mL) in chloroform and washed with saturated sodium bicarbonate solution. The aqueous layer was reextracted with 15% methanol / chloroform (4 × 30 mL). The combined organic phases were dried over magnesium sulfate and concentrated to dryness to afford 310 mg (97%) of crude product as an oil.

Intermediate 32

tert-butyl {(3S, 4R) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} cart Barmate

A solution of 7-methoxyquinoxalin-2 (1H) -one (intermediate 15, 320 mg, 1.79 mmol) in anhydrous DMF (10 mL) was cooled in an ice bath under nitrogen and sodium hydride (60% in oil, 86 mg) , 2.15 mmol). The reaction was stirred at room temperature for about 90 minutes. The reaction was again cooled in an ice bath and of 2-{(3S, 4R) -4-[(tert-butoxycarbonyl) amino] -3-methoxypiperidin-1-yl} ethyl methanesulfonate in anhydrous DMF. Solution (intermediate 33, about 0.20 mmol / mL, 1.97 mmol). The reaction was stirred overnight at room temperature and then concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was reextracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate. Chromatography on silica gel using a gradient of 15-25% acetone in hexanes gave 420 mg (55%) of the product as a colorless solid.

Intermediate 33

2-{(3S, 4R) -4-[(tert-butoxycarbonyl) amino] -3-methoxypiperidin-1-yl} ethyl methanesulfonate

Tert-butyl [(3S, 4R) -1- (2-hydroxyethyl) -3-methoxypiperidin-4-yl] carbamate (intermediate 34, 540 mg, 1.97 in anhydrous dichloromethane (20 mL) mmol) was treated with triethylamine (0.38 mL, 2.76 mmol) at 0 ° C. and then with methanesulfonyl chloride (0.18 mL, 2.36 mmol). After 15 minutes, TLC showed complete loss of starting material. The reaction was quenched with potassium phosphate buffer (1 M, pH 7). The aqueous phase was reextracted with dichloromethane (1x). Ethyl acetate was added to the combined organic phases. Dichloromethane was removed under reduced pressure leaving the product as a solution in ethyl acetate. This organic phase was washed with water to remove any residual salts. The aqueous phase was reextracted with ethyl acetate (1x). The combined organic phases were dried over sodium sulphate and filtered. Anhydrous DMF (10 mL) was added to the filtrate. Ethyl acetate was removed under reduced pressure to leave the product in DMF, which was used directly in the next step without further purification.

Intermediate 34

tert-butyl [(3S, 4R) -1- (2-hydroxyethyl) -3-methoxypiperidin-4-yl] carbamate

2-[(3S, 4R) -4- (dibenzylamino) -3-methoxypiperidin-1-yl] ethanol (intermediate 35, 940 mg, 2.66 mmol) and di-tert- in methanol (100 mL) A solution of butyl dicarbonate (0.67 mL, 2.92 mmol) was hydrogenated over palladium hydroxide on carbon (20%, 240 mg) overnight. The reaction mixture was filtered through celite and concentrated to dryness under reduced pressure. Chromatography on silica gel with 2-10% methanol in chloroform gave 540 mg (74%) of the product as a colorless oil.

Intermediate 35

2-[(3S, 4R) -4- (dibenzylamino) -3-methoxypiperidin-1-yl] ethanol

And

Intermediate 36

2-[(3R, 4S) -4- (dibenzylamino) -3-methoxypiperidin-1-yl] ethanol

Cis (±) N, N-dibenzyl-3-methoxypiperidin-4-amine (1.7 g, 5.5 mmol) (WO 2005/068461), bromoethanol (0.5 mL, 7.1 mmol), and N, N The mixture of diisopropylethylamine (1.4 mL, 8.3 mmol) was reacted as described for intermediate 7 except that it was heated at 70 ° C. for 1 hour. Chromatography on silica gel with 5% methanol in dichloromethane (containing 0.25% ammonium hydroxide) gave 1.3 g (68%) of cis-racemic product as a colorless solid.

Enantiomers were separated by chiral chromatography on a chiral cell OJ column (250 × 20 mm, 10 μm) eluting with 1: 1 methanol / ethanol and 0.1% diethylamine at a flow rate of 10 mL / min. The (-) isomer (intermediate 36) first eluted, then the (+) isomer (intermediate 35).

Intermediate 37

1- {2-[(3R, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one

Tert-butyl {(3R, 4S) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxaline-1 (2H), using a procedure similar to that described for the synthesis of intermediate 31 -Yl) ethyl] piperidin-4-yl} carbamate (intermediate 38, 100 mg, 0.23 mmol) was reacted with trifluoroacetic acid to give 70 mg (91%) of crude product as an oil.

Intermediate 38

tert-butyl {(3R, 4S) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} cart Barmate

Using a procedure similar to that described for the synthesis of intermediate 32, 7-methoxyquinoxalin-2 (1H) -one (intermediate 15, 530 mg, 3.00 mmol), 2-{(3R, 4S) -4- [ (tert-butoxycarbonyl) amino] -3-methoxypiperidin-1-yl} ethyl methanesulfonate (intermediate 39, about 0.33 mmol / mL, 3.30 mmol), and sodium hydride (60% in oil, 140 mg, 3.60 mmol) was reacted. The crude product was eluted with 25% acetone in hexanes and purified by flash chromatography to give 540 mg (42%) of the product as off white solid.

Intermediate 39

2-{(3R, 4S) -4-[(tert-butoxycarbonyl) amino] -3-methoxypiperidin-1-yl} ethyl methanesulfonate

As described for intermediate 33, tert-butyl [(3R, 4S) -1- (2-hydroxyethyl) -3-methoxypiperidin-4-yl] carbamate (intermediate 40, 0.91 g, 3.3 mmol), triethylamine (0.64 mL, 4.62 mmol), and methanesulfonyl chloride (0.31 mL, 3.99 mmol). The crude product was used directly in the next step without further purification.

Intermediate 40

tert-butyl [(3R, 4S) -1- (2-hydroxyethyl) -3-methoxypiperidin-4-yl] carbamate

Using a procedure similar to that described for the synthesis of intermediate 34, 2-[(3R, 4S) -4- (dibenzylamino) -3-methoxypiperidin-1-yl] ethanol (intermediate 36, 3.2 g, 9.0 mmol) was reacted to give 1.7 g (68%) of the product as a colorless oil.

Intermediate 41

1- {2-[(3S, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl} -2-oxo-1,2-dihydro quinoline-7-carbonitrile

Tert-butyl {(3S, 4R) -1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl]-using a procedure similar to that described for the synthesis of intermediate 31 3-methoxypiperidin-4-yl} carbamate (intermediate 42, 370 mg, 0.87 mmol) was reacted with trifluoroacetic acid in dichloromethane to give 300 mg (quant) of crude product as an oil.

MS (ESP): 327 (MH ⁺ ) for C ₁₈ H ₂₂ N ₄ O ₂

Intermediate 42

tert-butyl {(3S, 4R) -1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl] -3-methoxypiperidin-4-yl} carbamate

Using a procedure similar to that described for the synthesis of intermediate 32, 2-oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 5, 370 mg, 2.20 mmol), 2-{(3S, 4R)- 4-[(tert-butoxycarbonyl) amino] -3-methoxypiperidin-1-yl} ethyl methanesulfonate (Intermediate 33, about 0.24 mmol / mL, 2.40 mmol), and sodium hydride (60 in oil) %, 110 mg, 2.60 mmol) was reacted. Chromatography on silica gel using 25-35% acetone in hexanes gave 370 mg (39%) of the product as an off-white solid.

Intermediate 43

1- {2-[(3R, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline-7-carbonitrile

Using a procedure similar to that described for the synthesis of intermediate 31, tert-butyl {(3R, 4S) -1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl]- 3-methoxypiperidin-4-yl} carbamate (intermediate 44, 320 mg, 0.75 mmol) was reacted with trifluoroacetic acid to give 250 mg (quantity) of crude product as an oil.

Intermediate 44

tert-butyl {(3R, 4S) -1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl] -3-methoxypiperidin-4-yl} carbamate

Tert-butyl {(3R, 4S) -1- [2- (7-bromo-2-oxoquinolin-1 (2H) -yl) ethyl] -3-methoxypiperidine- in acetonitrile (10 mL) A mixture of 4-yl} carbamate (intermediate 45, 460 mg, 0.98 mmol) and potassium cyanide (96 mg, 1.5 mmol) was degassed and purged with nitrogen (3 hours). Solution of tributyl tin chloride (14 μl / mL in heptane, 0.90 μl, 0.003 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (3 mg, 0.005 mmol), and tris (Dibenzylideneacetone) dipalladium (0) (5 mg, 0.005 mmol) was added. The mixture was degassed (3 ×) and stirred at rt for 30 min. The mixture was degassed once more and then heated to 80 ° C. overnight. Incomplete conversion from LC / MS to product was shown. Additional tributyl tin chloride (14 μl / mL in heptane, 0.90 μl, 0.003 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (3 mg, 0.005 mmol), and tri S (dibenzylideneacetone) dipalladium (0) (5 mg, 0.005 mmol) was added. The reaction was stirred again overnight to achieve complete conversion to the product. The reaction was diluted with dichloromethane. The organic phase was washed with water. The aqueous phase was reextracted with dichloromethane (4x). The combined organic phases were dried over sodium sulphate and concentrated. Chromatography on silica gel using 25-35% acetone in hexanes gave 320 mg (76%) of the product as a yellow solid.

Intermediate 45

tert-butyl {(3R, 4S) -1- [2- (7-bromo-2-oxoquinolin-1 (2H) -yl) ethyl] -3-methoxypiperidin-4-yl} carbamate

Using a procedure similar to that described for the synthesis of intermediate 32, 7-bromoquinolin-2 (1H) -one (intermediate 46, 450 mg, 2.00 mmol), 2-{(3R, 4S) -4-[( tert-butoxycarbonyl) amino] -3-methoxypiperidin-1-yl} ethyl methanesulfonate (intermediate 39, about 0.23 mmol / mL, 2.30 mmol), and sodium hydride (60% in oil, 100 mg , 2.61 mmol) were reacted. The crude product was eluted with a gradient of 15-30% acetone in hexanes and purified by flash chromatography to give 460 mg (48%) of the product as an off-white solid.

Intermediate 46

7-bromoquinolin-2 (1H) -one

(2E) -N- (3-bromophenyl) -3-phenylacrylamide (intermediate 47, 16 g, 53 mmol) and aluminum trichloride (31.8 g, 238 mmol) were bathed in 90 ° C. in chlorobenzene (100 mL) Heat at temperature for 1 hour. The reaction mixture was cooled to rt and poured onto ice. It was stirred until the ice completely melted. The mixture was filtered and washed with water and ethyl acetate to afford the crude product as a slightly brown solid in a mixture with a small amount of product 5-bromoquinolin-2 (1H) -one (about 3: 2) (8.8 g (70%)). This mixture could not be separated. The mixture was heated in phosphoroxychloride (50 mL) at 65 ° C. for 1 h. The reaction mixture was cooled to rt and poured onto ice. It is carefully neutralized with sodium carbonate at 0 ° C., extracted with ethyl acetate (300 mL), washed with brine, dried over sodium sulfate and concentrated to give 7-bromo-2-chloroquinoline and 5-bromo-2 A crude mixture of chloroquinoline was obtained. The mixture was collected in dichloromethane (100 mL), treated with silica gel (about 20 g), filtered and the filter cake washed with dichloromethane. The filtrate and washes were combined and concentrated. The residue was crystallized from toluene / hexanes (about 70 mL, 1: 1) to give 3.74 g of pure 7-bromo-2-chloroquinoline as a colorless solid (mp 113 ° C.).

This chloride was heated at reflux for 1 h in 5 M HCl (100 mL) and dioxane (10 mL). It was cooled, filtered and washed with water to give 2.89 g of the title compound as a colorless solid (mp 295 ° C.).

Intermediate 47

(2E) -N- (3-bromophenyl) -3-phenylacrylamide

Cinnamoylchloride in dichloromethane (50 mL) to a solution of 3-bromoaniline (13.1 mL, 120 mmol) and 2,6-lutidine (21 mL, 180 mmol) in dichloromethane (100 mL) at 0 ° C. 20 g, 120 mmol) was added dropwise. The reaction mixture was allowed to reach room temperature and stirred for 2 hours. It was quenched with potassium phosphate buffer (100 mL, 1 M, pH 7) and stirred for 15 minutes. Dichloromethane was removed under reduced pressure, which was extracted with ethyl acetate. The organic phase was washed with phosphate buffer (as above, 200 mL), dried over sodium sulphate and concentrated to dryness. The residue was crystallized from toluene / hexanes to give the product as a colorless solid (33.4 g, 92%).

Intermediate 48

1- {2-[(3S, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one

As described for intermediate 31, tert-butyl {(3S, 4S) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] pi Ferridin-4-yl} carbamate, (-) trans enantiomer (intermediate 49, 190 mg, 0.44 mmol) was reacted with trifluoroacetic acid to give 140 mg (93%) of crude product as an oil.

Intermediate 49

tert-butyl {(3S, 4S) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} cart Bamate, (-) trans enantiomer

And

Intermediate 50

tert-butyl {(3R, 4R) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} cart Bamate, (+) trans enantiomer

Using a procedure similar to that described for the synthesis of intermediate 32. 7-methoxyquinoxalin-2 (1H) -one (intermediate 15, 430 mg, 2.45 mmol), 2- {trans (±) -4-[(tert-butoxycarbonyl) amino] -3-methoxypy Ferridin-1-yl} ethyl methanesulfonate (intermediate 51, about 0.27 mmol / mL, 2.70 mmol), and sodium hydride (60% in oil, 110 mg, 2.70 mmol) were reacted. The crude product was eluted with a gradient of 15-35% acetone / hexane and purified by flash chromatography to give 490 mg (45%) of racemic mixture of the product as off-white solid.

Supercritical fluid on a Chiralpak AD-H column (250 x 21 mm, 5 μm) eluting the mixture of enantiomers with an isocratic gradient of 20% isopropanol / 0.1% dimethylethylamine at a flow rate of 60 mL / min Isolate by chromatography. Thus, tert-butyl {(3S, 4S) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidine-4 -Yl} carbamate (intermediate 49) (first eluting compound, (-) trans enantiomer) 190 mg and tert-butyl {(3R, 4R) -3-methoxy-1- [2- (7- 190 mg of methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} carbamate (intermediate 50) (second eluting compound, (+) trans enantiomer) Obtained.

Intermediate 51

2- {trans (±) -4-[(tert-butoxycarbonyl) amino] -3-methoxypiperidin-1-yl} ethyl methanesulfonate

Tert-butyl [trans (±) -1- (2-hydroxyethyl) -3-methoxypiperidin-4-yl] carbamate (Intermediate 52) using a procedure similar to that described for the synthesis of intermediate 33 , 0.74 g, 2.7 mmol), triethylamine (0.53 mL, 3.78 mmol), and methanesulfonyl chloride (0.25 mL, 3.24 mmol) were reacted. The crude product was used directly in the next step without further purification.

Intermediate 52

tert-butyl [trans (±) -1- (2-hydroxyethyl) -3-methoxypiperidin-4-yl] carbamate

Tert-butyl [trans (±) -3-methoxypiperidin-4-yl] carbamate (intermediate 53, 1.1 g, 4.8 mmol), 2- using a procedure similar to that described for the synthesis of intermediate 7 Bromoethanol (0.44 mL, 6.2 mmol), and ethyl (diisopropyl) amine (1.25 mL, 7.2 mmol) were reacted to give 0.74 g (57%) of the product as a colorless oil.

Intermediate 53

tert-butyl [trans (±) -3-methoxypiperidin-4-yl] carbamate

Benzyl trans (±) -4-[(tert-butoxycarbonyl) amino] -3-methoxypiperidine-1-carboxylate (intermediate 54, 0.98 g, 2.69 mmol) is normal in methanol (50 mL) Hydrogenated on 10% Pd / C (400 mg) at pressure. After 1 hour, the reaction mixture was filtered through celite. The filtrate was concentrated to dryness to give 0.61 g (98%) of the product as a colorless oil.

Intermediate 54

Benzyl trans (±) -4-[(tert-butoxycarbonyl) amino] -3-methoxypiperidine-1-carboxylate

Benzyl trans (±) -4-[(tert-butoxycarbonyl) amino] -3-hydroxypiperidine-1-carboxylate (intermediate 55, 1.0 g, 2.86 mmol) is suspended in 10 mL of toluene and , 50% by weight solution of aqueous sodium hydroxide (6 mL), then treated with dimethylsulfate (0.33 mL, 3.43 mmol) and benzyl triethylammonium chloride (catalyst amount). The reaction was stirred vigorously for 1 hour. The reaction was quenched with ice. The phases were separated. The aqueous phase was reextracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated to dryness. Chromatography on silica gel using 25-50% acetone in hexanes gave 0.78 g (78%) of the product as a colorless oil.

Intermediate 55

Benzyl trans (±) -4-[(tert-butoxycarbonyl) amino] -3-hydroxypiperidine-1-carboxylate

Benzyl trans (±) -4-amino-3-hydroxypiperidine-1-carboxylate (WO 2005/066176, 3.0 g, 12.0 mmol) in ethyl acetate / water (1: 1, 100 mL), di A mixture of -tert-butyl dicarbonate (2.9 g, 13.2 mmol) and sodium bicarbonate (3.0 g, 36.0 mmol) was stirred vigorously overnight. The biphasic mixture was separated. The aqueous phase was reextracted with ethyl acetate (1x). The combined organic phases were dried over sodium sulphate and concentrated to dryness to give 4.2 g of product as a colorless solid. This material was used without further purification.

Intermediate 56

1- {2-[(3R, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one

Tert-butyl {(3R, 4R) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxaline-1 (2H), using a procedure similar to that described for the synthesis of intermediate 31 -Yl) ethyl] piperidin-4-yl} carbamate, (+) trans enantiomer (intermediate 50, 190 mg, 0.44 mmol) was reacted with trifluoroacetic acid to give 150 mg (quant) of crude product as an oil. Obtained as

Intermediate 57

1- {2-[(4-amino-3-hydroxypiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer A

As described for intermediate 31, tert-butyl {(3-hydroxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidine-4- Il carbamate, trans enantiomer A (intermediate 58, 130 mg, 0.31 mmol) was reacted with trifluoroacetic acid to give 78 mg (79%) of crude product as an oil.

Intermediate 58

tert-butyl {3-hydroxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} carbamate, trans enantiomer A

And

Intermediate 59

tert-butyl {3-hydroxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} carbamate, trans enantiomer B

Tert-butyl {trans (±) -3-{[tert-butyl (dimethyl) silyl] oxy} -1- [2- (7-methoxy-2-oxoquinoxaline-1 (2H) in THF (20 mL) ) -Yl) ethyl] piperidin-4-yl} carbamate (intermediate 60, 0.60 g, 1.13 mmol) with a solution of tetrabutylammonium fluoride in THF (1 M, 2.2 mL) at 0 ° C. Treated. The reaction was stirred at rt for 2 h and then concentrated to dryness under reduced pressure. The crude residue was collected in ethyl acetate. The organic phase was washed with water. The aqueous phase was reextracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. Chromatography on silica gel with 0-5% methanol in dichloromethane gave 0.27 g of the desired product and 0.12 g of O-acetylated byproduct. By-products were collected in methanol and treated with a catalytic amount of potassium carbonate. It was stirred for 1 hour at room temperature to achieve complete conversion to alcohol. The reaction mixture was concentrated to dryness. The residue was partitioned between aqueous potassium phosphate buffer (pH = 7) and ethyl acetate. The aqueous phase was reextracted with ethyl acetate (2x). The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness to give 100 mg (79% total) of additional desired product.

The mixture of enantiomers was eluted with an isocratic gradient of 25% isopropanol / 0.1% dimethylethylamine at a flow rate of 60 mL / min and subjected to supercritical fluid chromatography on a Chiralpak AD-H column (250 x 21 mm, 5 μm). Separated by. Thus, tert-butyl {3-hydroxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} carbamate , 130 mg of trans enantiomer A (Intermediate 58, first eluting enantiomer) and tert-butyl {(3-hydroxy-1- [2- (7-methoxy-2-oxoquinoxaline-1 (2H) 130 mg of -yl) ethyl] piperidin-4-yl} carbamate, trans enantiomer B (intermediate 59, second eluting enantiomer) were obtained.

Intermediate 60

tert-butyl {trans (±) -3-{[tert-butyl (dimethyl) silyl] oxy} -1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] Piperidin-4-yl} carbamate

Using a procedure similar to that described for the synthesis of intermediate 32, 7-methoxyquinoxalin-2 (1H) -one (intermediate 15, 430 mg, 2.43 mmol), 2- (trans (±) -4-[( tert-butoxycarbonyl) amino] -3-{[tert-butyl (dimethyl) silyl] oxy} piperidin-1-yl) ethyl methanesulfonate (intermediate 61, about 0.27 mmol / mL, 2.70 mmol), And sodium hydride (60% in oil, 110 mg, 2.70 mmol). The crude product was eluted with a gradient of 10-25% acetone / hexane and purified by flash chromatography to yield 600 mg (46%) of the product as an off-white solid.

Intermediate 61

2- (trans (±) -4-[(tert-butoxycarbonyl) amino] -3-{[tert-butyl (dimethyl) silyl] oxy} piperidin-1-yl) ethyl methanesulfonate

Using a procedure similar to that described for the synthesis of intermediate 33, tert-butyl [trans (±) -3-{[tert-butyl (dimethyl) silyl] oxy} -1- (2-hydroxyethyl) piperidine 4-yl] carbamate (Intermediate 62, 1.0 g, 2.7 mmol), triethylamine (0.52 mL, 3.74 mmol), and methanesulfonyl chloride (0.25 mL, 3.21 mmol) were reacted. The crude product was used directly in the next step without further purification.

Intermediate 62

tert-butyl [trans (±) -3-{[tert-butyl (dimethyl) silyl] oxy} -1- (2-hydroxyethyl) piperidin-4-yl] carbamate

Tert-butyl (trans (±) -3-{[tert-butyl (dimethyl) silyl] oxy} piperidin-4-yl) carbamate (intermediate) using a procedure similar to that described for the synthesis of intermediate 7 63, 1.3 g, 3.9 mmol), 2-bromoethanol (0.36 mL, 5.1 mmol), and ethyl (diisopropyl) amine (1.0 mL, 5.9 mmol) reacted to give 1.0 g (67%) of the desired product. Obtained.

Intermediate 63

tert-butyl (trans (±) -3-{[tert-butyl (dimethyl) silyl] oxy} piperidin-4-yl) carbamate

Benzyl trans (±) -4-[(tert-butoxycarbonyl) amino] -3-{[tert-butyl (dimethyl) silyl] oxy} piperidine-1-carboxylate (intermediate 64, 1.8 g, 3.9 mmol) was hydrogenated over palladium on carbon (10%, about 400 mg) at normal pressure for 1 h in methanol (50 mL). The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give 1.3 g (quant) of product as a colorless solid.

Intermediate 64

Benzyl trans (±) -4-[(tert-butoxycarbonyl) amino] -3-{[tert-butyl (dimethyl) silyl] oxy} piperidine-1-carboxylate

Benzyl trans (±) -4-[(tert-butoxycarbonyl) amino] -3-hydroxypiperidine-1-carboxylate (intermediate 55, 2.0 g, 5.7 mmol) in DMF (15 mL), A mixture of imidazole (0.58 g, 8.6 mmol) and tert-butyl (chloro) dimethylsilane (1.0 g, 6.9 mmol) was stirred overnight at room temperature under nitrogen. Water (50 mL) was added to the reaction and the mixture was extracted with ether (2 ×). The combined organic phases were dried over sodium sulphate and concentrated to dryness. Chromatography on silica gel with 10-25% acetone in hexanes gave 1.8 g (69%) of the product as a colorless solid.

Intermediate 65

1- {2- [4-amino-3-hydroxypiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer B

Tert-butyl {3-hydroxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] blood] using a procedure similar to that described for the synthesis of intermediate 31 Ferridin-4-yl} carbamate trans enantiomer B (intermediate 59, 130 mg, 0.31 mmol) was reacted with trifluoroacetic acid to give 84 mg (85%) of crude product as off-white foam.

Intermediate 66

3-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline-7-carbonitrile

Ethyl 3- (4-cyano-2-nitrophenyl) -2-oxopropanoate (6.5 kg, 24.8 mol) and acetonitrile (21 L) were stirred at 22 ° C. and sodium borohydride (0.30 kg, 7.9 mol) was added in portions, and the mixture was then stirred at 24 ° C. for 1 hour. The solution was charged with acetic acid (65 L) and the internal temperature was raised to 65 ° C. To the solution was added iron (3.3 kg) in portions (6 × 0.5 kg) for 1 hour. After an additional 1 hour, the product was isolated by filtration, washed sequentially with water (3 x 25 L) and ethanol (29 L) and dried under reduced pressure to give the product as a beige solid (3.07 kg ( 66%)).

Intermediate 67

1- {2-[-4-amino-3-fluoropiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer A

Tert-butyl {1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl] -3-fluoropiperidin-4-yl} carbohydrate in dichloromethane (20 mL) To a solution of barmate, trans enantiomer A (intermediate 68, 0.30 g, 0.72 mmol), trifluoroacetic acid (4 mL) was added while cooling in an ice bath. The reaction mixture was allowed to warm to room temperature. TLC showed clear but incomplete conversion after about 30 minutes (using 15% methanol / dichloromethane with 0.5% ammonium hydroxide as eluent). Additional 4 mL of trifluoroacetic acid was added. After 30 minutes, the reaction was concentrated to dryness. The crude residue was partitioned between 15% methanol / dichloromethane and saturated sodium bicarbonate. The aqueous phase was adjusted to pH about 10 with saturated sodium carbonate solution. The layers were separated. The aqueous phase was reextracted with 15% methanol / dichloromethane (2x). The combined organic phases were dried over sodium sulphate, filtered and concentrated to dryness to afford 0.30 g of crude product as an oil.

Intermediate 68

tert-butyl {1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl] -3-fluoropiperidin-4-yl} carbamate, trans enantiomer A

A solution of 2-oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 5, 500 mg, 2.94 mmol) in anhydrous DMF (10 mL) was added sodium hydride (60% in oil, 153 mg, 3.82 mmol). Cooling was stopped and the reaction stirred at room temperature for 90 minutes. The reaction was again cooled in an ice bath and 2-{(3R, 4R) -4-[(tert-butoxycarbonyl) amino] -3-fluoropiperidin-1-yl} ethyl methanesulfonate in anhydrous DMF , Trans enantiomer A (intermediate 69, about 0.38 mmol / mL, 3.82 mmol). The reaction was stirred at rt overnight. It was quenched with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel using a gradient of 10-50% acetone in hexanes gave 680 mg (56%) of the product as an off-white solid.

Intermediate 69

2- {4-[(tert-butoxycarbonyl) amino] -3-fluoropiperidin-1-yl} ethyl methanesulfonate, trans enantiomer A

Tert-butyl [3-fluoro-1- (2-hydroxyethyl) piperidin-4-yl] carbamate, trans enantiomer A (intermediate 70, 2.0 g, 7.62) in anhydrous dichloromethane (50 mL) mmol) was treated with triethylamine (1.5 mL, 10.7 mmol) at 0 ° C. followed by methanesulfonyl chloride (0.71 mL, 9.15 mmol). After 15 minutes, the reaction was quenched with potassium phosphate buffer (1 M, pH 7). The aqueous phase was extracted once with dichloromethane. Ethyl acetate was added to the combined organic phases. Dichloromethane was removed under reduced pressure leaving the product as a solution in ethyl acetate. This organic phase was washed with water to remove any residual salts. The aqueous phase was reextracted with ethyl acetate (1x). The combined organic phases were dried over sodium sulphate and filtered. To the filtrate was added dry DMF (20 mL). Ethyl acetate was removed under reduced pressure to leave the product in DMF, which was used without delay in the next step without further purification.

Intermediate 70

tert-butyl [3-fluoro-1- (2-hydroxyethyl) piperidin-4-yl] carbamate, trans enantiomer A

Of benzyl benzyl [3-fluoro-1- (2-hydroxyethyl) piperidin-4-yl] carbamate, trans enantiomer A (intermediate 71, 5.6 g, 14.5 mmol) in ethanol (100 mL) To the solution was added palladium hydroxide on carbon (20%, 1.5 g). The reaction was stirred overnight under hydrogen atmosphere. TLC showed complete loss of starting material (using 15% methanol / dichloromethane containing 0.5% ammonium hydroxide as eluent). The reaction mixture was then treated with di-tert-butyl dicarbonate (4.0 mL, 17.4 mmol) and stirred under nitrogen for 1 hour. TLC showed complete loss of starting material. The reaction mixture was filtered through celite. The filtrate was concentrated to dryness and chromatographed on silica gel, eluting with a gradient of 0-5% methanol / dichloromethane, then with an isocratic gradient of 5% methanol / dichloromethane containing 0.25% ammonium hydroxide. 2.86 g (75%) of product was obtained as a yellow oil.

Intermediate 71

Benzyl benzyl- [3-fluoro-1- (2-hydroxyethyl) piperidin-4-yl] carbamate, trans enantiomer A

And

Intermediate 72

Benzyl benzyl- [3-fluoro-1- (2-hydroxyethyl) piperidin-4-yl] carbamate, trans enantiomer B

A solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 21.3 mL, 21.3 mmol) was added trans (±) benzyl benzyl [1- (2-{[tert-butyl) in tetrahydrofuran (20 mL) at 0 ° C. To (dimethyl) silyl] oxy} ethyl) -3-fluoropiperidin-4-yl] carbamate (intermediate 73, 8.9 g, 17.8 mmol). The solution was allowed to warm to rt and stirred for 1 h. The mixture was then cooled to 0 ° C. and quenched with water. The mixture was extracted with ethyl acetate and washed with brine. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. Chromatography on silica with 40% acetone in hexanes gave the product as an oil (5.1 g, 74%).

The racemic mixture was separated on a Chiralpak AD column (500 × 20 mm, 20 μm) using ethanol / methanol (1: 1) (containing 0.1% diethyl amine). Trans Enantiomer A (Intermediate 71) eluted first, followed by Trans Enantiomer B (Intermediate 72). Chiral purity (using analytical methods equivalent to the above preparation method) was determined to be> 98% e.e. for both enantiomers.

Intermediate 73

Trans (±) benzyl benzyl-1- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -3-fluoropiperidin-4-yl] carbamate

Trans (±) benzyl benzyl (3-fluoropiperidin-4-yl) carbamate hydrochloride (intermediate 74, 7.98 g, 21.1 mmol), (2-bromoethoxy) -tert in acetonitrile (60 mL) A mixture of -butyldimethylsilane (6.85 g, 27.5 mmol) and cesium carbonate (17.9 g, 55.0 mmol) was heated at 60 ° C. for 12 h. The reaction mixture was cooled to room temperature and concentrated to almost dryness under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. Chromatography on silica with 10% acetone in hexanes gave the product as an oil (8.9 g, 84%).

Intermediate 74

Trans (±) benzyl benzyl (3-fluoropiperidin-4-yl) carbamate hydrochloride

Trans (±) tert-butyl 4- {benzyl [(benzyloxy) carbonyl] amino} -3-fluoropiperidine-1-carboxylate in dichloromethane (50 mL) at 0 ° C. (Intermediate 75, 12.05 g, 28.2 mmol), was added hydrogen chloride (1M in diethyl ether, 56.5 mL, 56.5 mmol). The solution was stirred for 1 hour. The solid was filtered off and the filter cake was washed with diethyl ether to give the monohydrochloride of the product (10.1 g, 95%).

Intermediate 75

Trans (±) tert-butyl-4- {benzyl [(benzyloxy) carbonyl] amino} -3-fluoropiperidine-1-carboxylate

Trans (±) tert-butyl (4-benzylamino) -3-fluoropiperidine-1-carboxylate in intermediate 1,4-dioxane (100 mL) (Intermediate 76, 10.3 g, 33.4 mmol ) And a solution of sodium carbonate (5.31 g, 50.1 mmol) in water (20 mL) was added dropwise. The mixture was allowed to warm to rt and stirred for 2 h. The reaction mixture was then concentrated almost to dryness and diluted with ethyl acetate. The organic phase was washed with water and brine and then dried over sodium sulfate. Chromatography on silica with 20% ethyl acetate in hexanes gave the product as a solid (12.5 g, 94%).

Intermediate 76

Trans (±) tert-butyl (4-benzylamino) -3-fluoropiperidine-1-carboxylate

Monique B. van Neil et al, J. Med. Chem., 1999, 42, 2087-2104, and references therein, to prepare the title compound.

Intermediate 77

1- {2- [4-amino-3-fluoropiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer A

Tert-butyl {3-fluoro-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] py] using a procedure similar to that described for the synthesis of intermediate 67 Ferridin-4-yl} carbamate, trans enantiomer A (intermediate 78, 0.30 g, 0.71 mmol) was reacted with trifluoroacetic acid to give 0.25 g of crude product as an oil.

Intermediate 78

tert-butyl {3-fluoro-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} carbamate, trans enantiomer A

Using a procedure similar to that described for the synthesis of intermediate 68, 7-methoxyquinoxalin-2 (1H) -one (intermediate 15, 0.52 g, 2.95 mmol), 2- {4-[(tert-butoxycar Carbonyl) amino] -3-fluoropiperidin-1-yl} ethyl methanesulfonate, trans enantiomer A (intermediate 69, about 0.38 mmol / mL, 3.82 mmol), and sodium hydride (60% in oil, 153 mg, 3.82 mmol) was reacted. Chromatography on silica gel using a gradient of 10-50% acetone in hexane gave 0.83 g (67%) of the product as an off-white solid.

Intermediate 79

1- {2- [4-amino-3-fluoropiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer B

Tert-butyl {1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl] -3-fluoropiperi using a procedure similar to that described for the synthesis of intermediate 67 Din-4-yl} carbamate, trans enantiomer B (intermediate 80, 0.30 g, 0.72 mmol) was reacted with trifluoroacetic acid to give 0.25 g of crude product as an oil.

Intermediate 80

tert-butyl {1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl] -3-fluoropiperidin-4-yl} carbamate, trans enantiomer B

Using a procedure similar to that described for the synthesis of intermediate 68, 2-oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 5, 0.50 g, 2.94 mmol), 2- {4-[(tert- Butoxycarbonyl) amino] -3-fluoropiperidin-1-yl} ethyl methanesulfonate, trans enantiomer B (intermediate 81, about 0.38 mmol / mL, 3.82 mmol), and sodium hydride (60 in oil) %, 153 mg, 3.82 mmol) were reacted. Chromatography on silica gel using a gradient of 10-50% acetone in hexanes gave 0.64 g (53%) of the product as an off-white solid.

Intermediate 81

2- {4-[(tert-butoxycarbonyl) amino] -3-fluoropiperidin-1-yl} ethyl methanesulfonate, trans enantiomer B

Tert-butyl [3-fluoro-1- (2-hydroxyethyl) piperidin-4-yl] carbamate, trans enantiomer B (intermediate), using procedures similar to those described for the synthesis of intermediate 69 82, 2.0 g, 7.62 mmol), triethylamine (1.5 mL, 10.7 mmol), and methanesulfonyl chloride (0.71 mL, 9.15 mmol) were reacted. The crude product was used directly in the next step without further purification.

Intermediate 82

tert-butyl [3-fluoro-1- (2-hydroxyethyl) piperidin-4-yl] carbamate, trans enantiomer B

Benzyl benzyl [3-fluoro-1- (2-hydroxyethyl) piperidin-4-yl] carbamate, trans enantiomer B (Intermediate 72), using procedures similar to those described for the synthesis of intermediate 70 , 5.6 g, 14.4 mmol), palladium hydroxide on carbon (20%, 0.5 g), and di-tert-butyl dicarbonate (3.5 g, 15.8 mmol) were reacted. Chromatography on silica gel eluting with 10% methanol (0.1% ammonium hydroxide) in ethyl acetate gave 2.9 g (76%) of the product as an oil.

Intermediate 83

1- {2- [4-amino-3-fluoropiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer B

Tert-butyl {3-fluoro-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] py] using a procedure similar to that described for the synthesis of intermediate 67 Ferridin-4-yl} carbamate, trans enantiomer B (intermediate 84, 0.33 g, 0.78 mmol) was reacted with trifluoroacetic acid to give 0.27 g of crude product as an oil.

Intermediate 84

tert-butyl {3-fluoro-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} carbamate, trans enantiomer B

Using a procedure similar to that described for the synthesis of intermediate 68, 7-methoxyquinoxalin-2 (1H) -one (intermediate 15, 0.52 g, 2.95 mmol), 2- {4-[(tert-butoxycar Carbonyl) amino] -3-fluoropiperidin-1-yl} ethyl methanesulfonate, trans enantiomer B (intermediate 81, about 0.38 mmol / mL, 3.82 mmol), and sodium hydride (60% in oil, 153 mg, 3.82 mmol) was reacted. Chromatography on silica gel using a gradient of 10-50% acetone in hexanes gave 0.93 g (78%) of the product as an off-white solid.

Intermediate 85

1- {2-[(3R, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline-7-carbonitrile

Tert-butyl {(3R, 4R) -1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl] -3-methoxypiperidine- in dichloromethane (30 mL) A solution of 4-yl} carbamate (intermediate 86, 280 mg, 0.66 mmol) was treated with trifluoroacetic acid (10 mL). After 1 hour, the reaction was concentrated to dryness. The residue was collected in 15% methanol in chloroform (30 mL) and washed with saturated sodium bicarbonate solution. The aqueous layer was adjusted to pH about 10 with saturated sodium carbonate solution and reextracted with 15% methanol / chloroform (3 × 30 mL). The combined organic phases were dried over sodium sulphate and concentrated to dryness to give 240 mg of crude product as an oil.

Intermediate 86

tert-butyl {(3R, 4R) -1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl] -3-methoxypiperidin-4-yl} carbamate

And

Intermediate 87

tert-butyl {(3S, 4S) -1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl] -3-methoxypiperidin-4-yl} carbamate

Tert-butyl [trans (±) -3-methoxypiperidin-4-yl] carbamate (intermediate 53, 0.63 g, 2.7 mmol) and 2-oxo- in 1: 1 anhydrous methanol / chloroform (30 mL) A mixture of 1- (2-oxoethyl) -1,2-dihydroquinoline-7-carbonitrile (intermediate 88, 0.57 g, 2.7 mmol) was heated to 70 ° C. for 2 hours. The reaction was cooled to rt, treated with sodium triacetoxy borohydride (1.7 g, 8.1 mmol) and stirred at rt for 2 h. The reaction was filtered through celite and the filtrate was concentrated in vacuo. The crude residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous phase was reextracted once with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo. Chromatography on silica gel with 25-50% acetone in hexanes gave 0.74 g (62%) of a racemic mixture of the product.

The mixture of enantiomers was subjected to a Chiralpak AD column (20 × 250 mm, 10 μm) using an isocratic gradient of 80% hexane, 20% 1: 1 ethanol / methanol and 0.1% diethylamine at a flow rate of 20 mL / min. Phase separated by HPLC. Thus, tert-butyl {(3R, 4R) -1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl] -3-methoxypiperidin-4-yl } 0.28 g of carbamate (intermediate 86, second eluting peak, (+) isomer) and tert-butyl {(3S, 4S) -1- [2- (7-cyano-2-oxoquinoline-1 ( 0.32 g of 2H) -yl) ethyl] -3-methoxypiperidin-4-yl} carbamate (intermediate 87, first eluting peak, (-) isomer) were obtained.

Intermediate 88

2-oxo-1- (2-oxoethyl) -1,2-dihydroquinoline-7-carbonitrile

Concentrated hydrochloric acid in a solution of 1- (2,2-diethoxyethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 89, 21.5 g, 75.1 mmol) in acetonitrile (230 mL) (2 equiv, 12.5 mL) was added. After 1 hour, the resulting precipitate was collected by filtration. This gave 16 g (100%) of product as a colorless solid after drying, which was used without further purification.

Intermediate 89

1- (2,2-diethoxyethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile

2-oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 5, 35.0 g, 201 mmol) in anhydrous NMP (200 mL), 2-bromo-1,1-diethoxyethane (44.1 mL, 281 mmol) and cesium carbonate (78.5 g, 241 mmol) were stirred at 70 ° C. overnight. The reaction mixture was diluted with water (350 mL) and extracted with butyl acetate (2 x 350 mL). The combined organic phases were filtered through celite and washed with water (1 x 175 mL). The butyl acetate solution was concentrated to 140 mL and diluted with 525 mL of iso-hexane. The precipitate was isolated by filtration and washed with 70 mL of iso-hexane. This gave 34 g (60%) of product as a colorless solid after drying, which was used without further purification.

Intermediate 90

1- {2-[(3S, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline-7-carbonitrile

Using a procedure similar to that described for the synthesis of intermediate 85, tert-butyl {(3S, 4S) -1- [2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl]- 3-methoxypiperidin-4-yl} carbamate (intermediate 87, 0.32 g, 0.75 mmol) was reacted with trifluoroacetic acid to give 0.24 g of crude product as an oil.

Intermediate 91

Cis (±) 1- [2- (4-amino-3-fluoropiperidin-1-yl) ethyl] -7-methoxyquinoxalin-2 (1H) -one, trifluoroacetic acid salt

Cis (±) tert-butyl {3-fluoro-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperi in chloroform (10 mL) at 0 ° C. To a solution of din-4-yl} carbamate (intermediate 92, 222 mg, 0.53 mmol) was added 30% trifluoroacetic acid in chloroform (6 mL). After 3 h at rt, the solvent was removed under reduced pressure to afford the title compound which was used in the next step without purification. The title compound may exist in the form of the bis-trifluoroacetic acid salt.

Intermediate 92

Cis (±) tert-butyl {3-fluoro-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} carbamate

Using a procedure similar to that described for the synthesis of intermediate 20, 7-methoxyquinoxalin-2 (1H) -one (intermediate 15, 181 mg, 1 mmol) and cis (±) 2- {4-[(tert -Butoxycarbonyl) amino] -3-fluoropiperidin-1-yl} ethyl methanesulfonate (intermediate 21, about 1 mmol) was reacted. Chromatography on silica gel using hexanes / ethyl acetate (2: 3) gave 222 mg (51%) of the product as a solid.

Intermediate 93

1- {2-[(3R, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl} -4-methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile , Trifluoroacetic acid salt

Tert-butyl {(3R, 4S) -1- [2- (7-cyano-4-methyl-2-oxoquinolin-1 (2H) -yl, using a procedure similar to that described for the synthesis of intermediate 91 ) Ethyl] -3-methoxypiperidin-4-yl} carbamate (intermediate 94, 360 mg, 0.81 mmol) was reacted with trifluoroacetic acid to afford the title compound. The title compound may exist in the form of the bis-trifluoroacetic acid salt.

Intermediate 94

tert-butyl {(3R, 4S) -1- [2- (7-cyano-4-methyl-2-oxoquinolin-1 (2H) -yl) ethyl] -3-methoxypiperidin-4-yl } Carbamate

4-Methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile in dry DMF (20 mL) (VN Gogte, SB Kulkarni and BD Tilak, Indian Journal of Chemistry, 15B, 769-773) 1977)]) (368 mg, 2 mmol) was added sodium hydride (120 mg, 60% in oil, 3 mmol). The mixture was stirred at rt for 1 h. Subsequently, 2-{(3R, 4S) -4-[(tert-butoxycarbonyl) amino] -3-methoxypiperidin-1-yl} ethyl methanesulfonate in DMF at 0 ° C. (Intermediate 39, about 2 mmol) solution was added. The reaction mixture was stirred at rt overnight, then diluted with water and extracted three times with dichloromethane. The organic extract was dried over magnesium sulfate and concentrated. Silica gel chromatography using hexanes / ethyl acetate (3: 2) gave 360 mg of a 3: 1 mixture of the title compound and O-alkylated product.

Intermediate 95

Cis (±) 1- [2- (4-amino-3-fluoropiperidin-1-yl) ethyl] -4-methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile, Trifluoroacetic acid salt

Cis (±) tert-butyl {1- [2- (7-cyano-4-methyl-2-oxoquinolin-1 (2H) -yl) ethyl, using a procedure similar to that described for the synthesis of intermediate 91 ] -3-fluoropiperidin-4-yl} carbamate (intermediate 96, 269 mg, 0.63 mmol) was reacted with trifluoroacetic acid to give the crude product (200 mg). The title compound may exist in the form of the bis-trifluoroacetic acid salt.

Intermediate 96

Cis (±) tert-butyl {1- [2- (7-cyano-4-methyl-2-oxoquinolin-1 (2H) -yl) ethyl] -3-fluoropiperidin-4-yl} Carbamate

4-Methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile in dry DMF (20 mL) (VN Gogte, SB Kulkarni and BD Tilak, Indian Journal of Chemistry, 15B, 769-773) 1977)]) (350 mg, 1.9 mmol) was added sodium hydride (90 mg, 60% in oil, 2.2 mmol). The mixture was stirred at rt for 1 h. Then cis (±) 2- {4-[(tert-butoxycarbonyl) amino] -3-fluoropiperidin-1-yl} ethyl methanesulfonate in DMF at 0 ° C. (Intermediate 21, about 1.9 mmol) was added. The reaction mixture was stirred at rt overnight, then diluted with water and extracted three times with dichloromethane. The organic extract was dried over magnesium sulfate and concentrated. Silica gel chromatography using hexanes / ethyl acetate (1: 1) gave 269 mg (33%) of the product as a tan solid.

Intermediate 97

1- (2-((3S, 4R) -4-amino-3-fluoropiperidin-1-yl) ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, trifluor Roacetic acid salt

Tert-butyl (3S, 4R) -1- (2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl) -3 using a similar procedure as described for the synthesis of intermediate 91 -Fluoropiperidin-4-ylcarbamate (intermediate 98, 0.5 g, 1.21 mmol) was reacted with trifluoroacetic acid to give the crude product in quantitative yield, which was used directly in the next step. The title compound may exist in the form of the bis-trifluoroacetic acid salt.

Intermediate 98

tert-butyl (3S, 4R) -1- (2- (7-cyano-2-oxoquinolin-1 (2H) -yl) ethyl) -3-fluoropiperidin-4-ylcarbamate

A mixture of 2-oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 5, 0.5 g, 2.94 mmol) and 60% by weight sodium hydride (0.176 g, 4.41 mmol) in DMF (50 mL) was added. Stir at room temperature under nitrogen for 1 hour. The solution was cooled to 0 ° C. and 2-((3S, 4R) -4- (tert-butoxycarbonylamino) -3-fluoropiperidin-1-yl) ethylmethanesulfo in DMF (10 mL) A solution of Nate (Intermediate 99, 1 g, 2.94 mmol) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulphate, filtered and evaporated. Silica gel chromatography (0% to 75% ethyl acetate in hexanes) gave the title compound as a tan solid (0.55 g (45%)). [a] _D = +0.063 (c = 0.2, DMSO).

Intermediate 99

2-((3S, 4R) -4- (tert-butoxycarbonylamino) -3-fluoropiperidin-1-yl) ethylmethanesulfonate

Using a procedure similar to that described for the synthesis of intermediate 21 from intermediate 24, (3S, 4R) -1- (2- (tert-butyldimethylsilyloxy) ethyl) -3-fluoropiperidine-4- The title compound was prepared from amine (intermediate 100).

Intermediate 100

(3S, 4R) -1- (2-tert-butyldimethylsilyloxy) ethyl) -3-fluoropiperidin-4-amine

Benzyl (3S, 4R) -1- (2- (tert-butyldimethylsilyloxy) ethyl) -3-fluoropiperidin-4-ylcarbamate (intermediate 101, 8 g, in ethanol (100 mL) 19.48 mmol) was hydrogenated over palladium on carbon (10%, activation, 1.037 g) overnight at room temperature under normal pressure. The reaction mixture was filtered through 0.45 μm membrane and the solvent was evaporated under reduced pressure to give the title compound as an oil (5 g, 93%).

Intermediate 101

Benzyl (3S, 4R) -1- (2-tert-butyldimethylsilyloxy) ethyl) -3-fluoropiperidin-4-ylcarbamate

Benzyl (3S, 4R) -3-fluoropiperidin-4-ylcarbamate hydrochloride (intermediate 102, 5.9 g, 20.43 mmol) and cesium carbonate (33.3 g, 102.17 mmol) in acetonitrile (300 mL) at room temperature To the stirred mixture of was added (2-bromoethoxy) (tert-butyl) dimethylsilane (21.92 mL, 102.17 mmol). The reaction was stirred at 60 ° C. overnight. The reaction mixture was filtered through a sinter funnel and concentrated. Silica gel chromatography (0% to 50% ethyl acetate in hexanes) gave the title compound as a yellow oil (8 g (95%)).

Intermediate 102

Benzyl (3S, 4R) -3-fluoropiperidin-4-ylcarbamate, hydrochloride

(3S, 4R) -tert-butyl 4- (benzyloxycarbonylamino) -3-fluoropiperidine-1-carboxylate (intermediate 103, 8 g, 22.7 in dichloromethane (200 mL) at 0 ° C) mmol) was added 4 M hydrogen chloride (11.35 mL, 45.4 mmol) in dioxane. The reaction mixture was allowed to warm up to room temperature and stirred overnight. An additional equivalent amount of 4 M hydrogen chloride in dioxane was added and the reaction stirred for an additional 4 hours. The resulting white precipitate was collected by filtration and dried under reduced pressure to give the title compound (5.9 g, 90%).

Intermediate 103

(3S, 4R) -tert-butyl 4- (benzyloxycarbonylamino) -3-fluoropiperidine-1-carboxylate

(3S, 4R) -tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate in dioxane (150 mL) (described in PCT Publication WO 2006087543 and WO 2007071965). To be prepared using the procedure) (5.1 g, 23.37 mmol) and saturated sodium carbonate (50 mL) was added benzyl chloroformate (5.00 mL, 35.05 mmol). After 15 minutes, the reaction mixture was diluted with ethyl acetate and saturated sodium chloride. The layers were separated and the organic extract was dried over magnesium sulphate, filtered and evaporated. Silica gel chromatography (0% to 50% ethyl acetate in hexanes) gave the title compound as an off-white solid (8 g (97%)).

Intermediate 104

1- {2-[(3S, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl} -4-methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile , Trifluoroacetic acid salt

Tert-butyl {(3S, 4R) -1- [2- (7-cyano-4-methyl-2-oxoquinolin-1 (2H) -yl, using a procedure similar to that described for the synthesis of intermediate 91 ) Ethyl] -3-methoxypiperidin-4-yl} carbamate (intermediate 105, 191 mg, 0.43 mmol) was reacted with trifluoroacetic acid to give the crude title compound in quantitative yield, which was obtained in the next step. Used directly. The title compound may be present in the form of a bis-trifluoroacetic acid salt.

Intermediate 105

tert-butyl {(3S, 4R) -1- [2- (7-cyano-4-methyl-2-oxoquinolin-1 (2H) -yl) ethyl] -3-methoxypiperidin-4-yl } Carbamate

4-Methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile in dry DMF (20 mL) (VN Gogte, SB Kulkarni and BD Tilak, Indian Journal of Chemistry, 15B, 769-773) 1977)]) (435 mg, 2.36 mmol) was added sodium hydride (142 mg, 60% in oil, 3.54 mmol). The mixture was stirred at rt for 1 h. Subsequently, 2-{(3S, 4R) -4-[(tert-butoxycarbonyl) amino] -3-methoxypiperidin-1-yl} ethyl methanesulfonate in DMF at 0 ° C. (Intermediate 33, about 2.8 mmol) was added. The reaction mixture was stirred at rt overnight, then diluted with water and extracted three times with dichloromethane. The organic extract was dried over magnesium sulfate and concentrated. Reverse phase chromatography with acetonitrile / water / ammonium acetate gave the title compound as a pale yellow solid after lyophilization (191 mg, 18%)).

Intermediate 106

1- (2-((3R, 4S) -4-amino-3-fluoropiperidin-1-yl) ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile trifluoro acetate

The title compound was converted to tert-butyl (3R, 4S) -4- (benzylamino) -3 by a method analogous to the procedure described for racemic material (Intermediate 19), except for the following modifications in the final step. Prepared from -fluoropiperidine-1-carboxylate (WO 2007071965 and WO 2006087543): The crude trifluoroacetic acid salt of the title compound was collected in dichloromethane (100 mL) and saturated sodium bicarbonate (20 mL) Wash once). The aqueous wash was adjusted to pH = 10 with 20% sodium hydroxide and extracted three times with dichloromethane (100 mL). The combined organic extracts were dried over magnesium sulphate, filtered and concentrated to dryness to afford the title compound as an off-white solid (352 mg (81%)).

Example 1

1- (2-{(3R, 4S) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-hydrate Roxypiperidin-1-yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

1- {2-[(3R, 4S) -4-amino-3-hydroxypiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 1 , 74 mg, 0.24 mmol) and 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (WO 2004/058144) (39 mg, 0.24 mmol) The mixture was heated on an activated 3mm molecular sieve directly at 70 ° C. for 3 hours. The reaction mixture was cooled to room temperature and sodium triacetoxy borohydride (150 mg, 0.75 mmol) was added. The resulting reaction mixture was stirred for 30 minutes at room temperature, then filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. Chromatography on silica gel using dichloromethane / methanol (8: 1 to 4: 1). Fractions containing product were combined and concentrated to dryness. The residue was collected in dichloromethane / diethyl ether (1: 2, 10 mL) and HCl (2 M, about 0.15 mL) in diethyl ether was added. The mixture was concentrated to dryness under reduced pressure, twice (2 × 15 mL) co-distilled with dichloromethane and triturated from ether to give the title composition as a colorless solid (91 mg (72%), mp> 210 ° C.). ).

Example 2

1- [2-((3R, 4S) -3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Picture-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbaldehyde, using a procedure similar to that described for the synthesis of Example 1 (WO 2004/058144) and Intermediate 1 were reacted to yield the title composition.

Example 3

1- [2-((3R, 4S) -3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thia Jin-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbaldehyde, using a procedure similar to that described for the synthesis of Example 1 (WO 2004/058144) and Intermediate 1 were reacted to yield the title composition.

Example 4

1- (2-{(3S, 4R) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-hydrate Roxypiperidin-1-yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

Using a procedure similar to that described for the synthesis of Example 1, 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde and intermediate 2 were reacted to give the title A composition was obtained.

Example 5

1- [2-((3S, 4R) -3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Picture-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbaldehyde, using a procedure similar to that described for the synthesis of Example 1 And Intermediate 2 were reacted to give the title composition.

Example 6

1- [2-((3S, 4R) -3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thia Jin-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbaldehyde, using a procedure similar to that described for the synthesis of Example 1 And Intermediate 2 were reacted to give the title composition.

Example 7

1- (2-{(3R, 4S) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-hydrate Roxypiperidin-1-yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, dihydrochloride

Using a procedure similar to that described for the synthesis of Example 1, 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde and intermediate 11 were reacted to give the title A composition was obtained.

Example 8

6-[({(3R, 4S) -3-hydroxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} Amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, dihydrochloride

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbaldehyde, using a procedure similar to that described for the synthesis of Example 1 And intermediate 11 to yield the title composition.

Example 9

6-[({(3R, 4S) -3-hydroxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} Amino) methyl] -2H-pyrido [3,2-b] [1,4] thiazine-3 (4H) -one, dihydrochloride

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbaldehyde, using a procedure similar to that described for the synthesis of Example 1 And intermediate 11 to yield the title composition.

Example 10

1- (2-{(3S, 4R) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-hydrate Roxypiperidin-1-yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, dihydrochloride

Using a procedure similar to that described for the synthesis of Example 1, 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde and intermediate 12 were reacted to give the title A composition was obtained.

Example 11

6-[({(3S, 4R) -3-hydroxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} Amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, dihydrochloride

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbaldehyde, using a procedure similar to that described for the synthesis of Example 1 And Intermediate 12 were reacted to yield the title composition.

Example 12

1- (2-{(3S, 4R) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-fluoro Ropiperidin-1-yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, monoacetic acid salt

And

Example 13

1- (2-{(3R, 4S) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-fluoro Ropiperidin-1-yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, monoacetic acid salt

Cis (±) 1- [2- (4-amino-3-fluoropiperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile (Intermediate 19, 0.95 mmol) was suspended in chloroform / methanol (1: 1, 20 mL) and free basified by the dropwise addition of N, N-diisopropylethylamine until all material was solubilized. Then, using a procedure similar to that described for the synthesis of Example 1, this was followed by 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (160 mg, 0.95 mmol) and sodium triacetoxyborohydride (600 mg, 2.8 mmol). The residue obtained after filtration was collected in dichloromethane and saturated sodium bicarbonate. The pH of the aqueous phase was adjusted to pH about 10 with 1 M sodium hydroxide solution. The aqueous phase was back extracted with dichloromethane and the combined organic phases were dried over sodium sulphate and concentrated. Reverse phase chromatography with water / acetonitrile / ammonium acetate gave the product as a tan foam (276 mg (62%)).

The racemic mixture was separated on a Chiralpak AD, 250 × 20 mm, 10 μ column (50% methanol, 50% ethanol, 0.1% diethylamine). Example 12 eluted first ([α] _D = +14.3 (c = 0.3, methanol)) (89 mg), then Example 13 eluted ([α] _D = -11.6 (c = 0.328, methanol) )) (80 mg).

Example 14

1- (2-{(3S, 4R) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-methok Cipiperidin-1-yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, dihydrochloride

1- {2-[(3S, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl} -7-methoxyquinoxaline- in anhydrous methanol / chloroform (1: 1, 10 mL) 2 (1H) -one (intermediate 31, 160 g of crude compound, 0.48 mmol) and 2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-carbaldehyde (80 mg, 0.48 mmol) was heated under nitrogen on 3 cc molecular sieve at 70 ° C. for 1 h. The reaction was cooled to room temperature and sodium triacetoxy borohydride (310 mg, 1.44 mmol) was added. After 30 minutes, the reaction was filtered through celite. The filtrate was concentrated to dryness, collected in 15% methanol in chloroform and washed with saturated sodium bicarbonate solution. The aqueous phase was reextracted twice with 15% methanol / chloroform. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. Chromatography on silica gel using a gradient of 2-5% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 160 mg (70%) of the free base of the title composition as an oil. It was collected in dichloromethane / diethyl ether (1: 1, 5 mL) and treated with 2.0 M HCl (about 2 equiv) in ether. The resulting precipitate was collected by filtration, reconstituted in water and lyophilized to give 148 mg of the title composition as a solid.

Example 15

6-[({(3S, 4R) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} Amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one

As described for Example 14 (excluding hydrochloride preparation), 1- {2-[(3S, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl} -7-methoxyquinoxaline -2 (1H) -one (Intermediate 31, 160 mg crude compound, 0.48 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine -6-carbaldehyde (WO 2004/058144) (85 mg, 0.48 mmol) and sodium triacetoxy borohydride (310 mg, 1.44 mmol) were reacted to give 139 mg (58%) of the title composition.

Example 16

1- (2-{(3R, 4S) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-methok Cipiperidin-1-yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, dihydrochloride

As described according to Example 14, 1- {2-[(3R, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -One (intermediate 37, 37 mg, 0.11 mmol), 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (WO 2004/058144) (18 mg , 0.11 mmol) and sodium triacetoxy borohydride (70 mg, 0.33 mmol) gave 29 mg of the title composition as a colorless solid.

Example 17

6-[({(3R, 4S) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} Amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one

As described for Example 14 (except for hydrochloride preparation), 1- {2-[(3R, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl} -7-methoxyquinoxaline -2 (1H) -one (intermediate 37, 37 mg crude compound, 0.11 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine -6-carbaldehyde (WO 2004/058144) (20 mg, 0.11 mmol) and sodium triacetoxy borohydride (70 mg, 0.33 mmol) were reacted to give 34 mg (63%) of the title composition.

Example 18

6-[({(3R, 4S) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} Amino) methyl] -2H-pyrido [3,2-b] [1,4] thiazine-3 (4H) -one, dihydrochloride

Using a procedure similar to that described for the synthesis of Example 14, 1- {2-[(3R, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl} -7-methoxyquinoxy Saline-2 (1H) -one (intermediate 37, 70 mg crude compound, 0.21 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thia Gene-6-carbaldehyde (WO 2004/058144) (40 mg, 0.21 mmol) and sodium triacetoxy borohydride (130 mg, 0.63 mmol) were reacted to give 73 mg of the title composition as off-white solid.

Example 19

1- (2-{(3S, 4R) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-methok Sipiperidin-1-yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

Using a procedure similar to that described for the synthesis of Example 14, 1- {2- [(3S, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl} -2-oxo-1 , 2-dihydroquinoline-7-carbonitrile (intermediate 41, 93 mg, 0.29 mmol), 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (WO 2004/058144) (47 mg, 0.29 mmol) and sodium triacetoxy borohydride (180 mg, 0.86 mmol) were reacted to give 95 mg of the title composition as a colorless solid.

Example 20

1- [2-((3S, 4R) -3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Photo-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile

Using a procedure similar to that described for the synthesis of Example 14 (except for hydrochloride preparation), 1- {2-[(3S, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl}- 2-oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 41, 93 mg, 0.29 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [ 1,4] oxazine-6-carbaldehyde (WO 2004/058144) (51 mg, 0.29 mmol) and sodium triacetoxy borohydride (180 mg, 0.86 mmol) were reacted to give 80 mg (57%) of the title compound. ) Was obtained as an off-white solid.

Example 21

1- [2-((3S, 4R) -3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thia Jin-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

Using a procedure similar to that described for the synthesis of Example 14, 1- {2-[(3S, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl} -2-oxo-1 , 2-dihydroquinoline-7-carbonitrile (intermediate 41, 93 mg, 0.29 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thia Gene-6-carbaldehyde (WO 2004/058144) (55 mg, 0.29 mmol) and sodium triacetoxy borohydride (180 mg, 0.86 mmol) were reacted to give 68 mg of the title composition as a yellow solid.

Example 22

1- (2-{(3R, 4S) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-methok Sipiperidin-1-yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

Using a procedure similar to that described for the synthesis of Example 14, 1- {2-[(3R, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl} -2-oxo-1 , 2-dihydroquinoline-7-carbonitrile (intermediate 43, 80 mg, 0.25 mmol), 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (WO 2004/058144) (41 mg, 0.25 mmol) and sodium triacetoxy borohydride (160 mg, 0.74 mmol) were reacted to give 69 mg of the title composition as off-white solid.

Example 23

1- [2-((3R, 4S) -3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Photo-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile

Using a procedure similar to that described for the synthesis of Example 14 (except for hydrochloride preparation), 1- {2-[(3R, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl}- 2-oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 43, 80 mg, 0.25 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [ 1,4] oxazine-6-carbaldehyde (WO 2004/058144) (45 mg, 0.25 mmol) and sodium triacetoxy borohydride (160 mg, 0.74 mmol) were reacted to give 62 mg of the title compound (yield 55). %) Was obtained as off-white solid.

Example 24

1- [2-((3R, 4S) -3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thia Jin-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

As described for Example 14, 1- {2-[(3R, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline -7-carbonitrile (intermediate 43, 80 mg, 0.25 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carb Aldehyde (WO 2004/058144) (48 mg, 0.25 mmol) and sodium triacetoxy borohydride (160 mg, 0.74 mmol) were reacted to give 56 mg of the title composition as off-white solid.

Example 25

1- (2-{(3S, 4S) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-methok Cipiperidin-1-yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, dihydrochloride

Using a procedure similar to that described for the synthesis of Example 14, 1- {2-[(3S, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl} -7-methoxyquinox Saline-2 (1H) -one (intermediate 48, 70 mg, 0.21 mmol), 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (WO 2004 (35 mg, 0.21 mmol) and sodium triacetoxy borohydride (130 mg, 0.63 mmol) gave 61 mg of the title composition as a yellow solid.

Example 26

6-[({(3S, 4S) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} Amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one

As described for Example 14 (excluding hydrochloride preparation), 1- {2-[(3S, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl} -7-methoxyquinoxaline -2 (1H) -one (intermediate 48, 70 mg, 0.21 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6- Carbaldehyde (WO 2004/058144) (37 mg, 0.21 mmol) and sodium triacetoxy borohydride (130 mg, 0.63 mmol) were reacted. The crude product was eluted with a gradient of 0-10% methanol / dichloromethane and flash chromatography gave 62 mg (62%) of the title compound ([α] _D = -19.5 (methanol, c = 0.58)).

Example 27

1- (2-{(3R, 4R) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-methok Cipiperidin-1-yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, dihydrochloride

As described for Example 14, 1- {2-[(3R, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -One (intermediate 56, 75 mg, 0.23 mmol), 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (WO 2004/058144) (37 mg , 0.23 mmol) and sodium triacetoxy borohydride (150 mg, 0.69 mmol) gave the title composition (63 mg) as a yellow solid.

Example 28

6-[({(3R, 4R) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} Amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one

As described for Example 14 (except for hydrochloride preparation), 1- {2-[(3R, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl} -7-methoxyquinoxaline -2 (1H) -one (intermediate 56, 75 mg, 0.23 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6- Carbaldehyde (WO 2004/058144) (40 mg, 0.23 mmol) and sodium triacetoxy borohydride (150 mg, 0.69 mmol) were reacted to give 73 mg (66%) of the title compound ([α] _D = +17.5 (methanol, c = 0.56)).

Example 29

1- (2- {4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-hydroxypiperidine-1 -Yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer A, dihydrochloride

As described for Example 14, 1- {2- [4-amino-3-hydroxypiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one, trans mirror image Isomer A (Intermediate 57, 39 mg, 0.12 mmol), 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (WO 2004/058144) (20 mg , 0.12 mmol) and sodium triacetoxy borohydride (76 mg, 0.36 mmol) gave the title composition as a yellow solid (39 mg).

Example 30

6-[({3-hydroxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} amino) methyl] -2H -Pyrido [3,2-b] [1,4] oxazine-3 (4H) -one, trans enantiomer A

As described for Example 14 (excluding hydrochloride preparation), 1- {2- [4-amino-3-hydroxypiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -One, trans enantiomer A (intermediate 57, 39 mg, 0.12 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6- Carbaldehyde (WO 2004/058144) (21 mg, 0.12 mmol) and sodium triacetoxy borohydride (76 mg, 0.36 mmol) were reacted to give 49 mg (84%) of the title compound.

Example 31

1- (2- {4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-hydroxypiperidine-1 -Yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer B, dihydrochloride

As described for Example 14, 1- {2- [4-amino-3-hydroxypiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one, trans mirror image Isomers (intermediate 65, 42 mg, 0.13 mmol), 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (WO 2004/058144) (22 mg, 0.13 mmol) and sodium triacetoxy borohydride (83 mg, 0.39 mmol) gave 45 mg of the title composition as a yellow solid.

Example 32

6-[({3-hydroxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} amino) methyl] -2H -Pyrido [3,2-b] [1,4] oxazine-3 (4H) -one, trans enantiomer B

As described for Example 14 (excluding hydrochloride preparation), 1- {2- [4-amino-3-hydroxypiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -One, trans enantiomer (intermediate 65, 42 mg, 0.13 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carr Broaldehyde (WO 2004/058144) (24 mg, 0.13 mmol) and sodium triacetoxy borohydride (83 mg, 0.39 mmol) were reacted to give 42 mg (yield 68%) of the title compound.

Example 33

1- (2- {4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-fluoropiperidine-1 -Yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer A, dihydrochloride

1- {2- [4-amino-3-fluoropiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline-7 in anhydrous methanol / chloroform (1: 1, 20 mL) -Carbonitrile, trans enantiomer A (intermediate 67, crude compound, 150 mg, 0.48 mmol) and 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (WO 2004/058144) (80 mg, 0.48 mmol) was heated under nitrogen on 3 mm molecular sieve at 70 ° C. for 1 h. The reaction was cooled to rt and sodium triacetoxy borohydride (300 mg, 1.43 mmol) was added. The reaction was stirred at rt overnight. The reaction mixture was filtered through celite. The filtrate was concentrated to dryness. The crude product was collected in 15% methanol / chloroform and washed with saturated sodium bicarbonate solution. The aqueous phase was reextracted once with 15% methanol / chloroform. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. Chromatography on silica gel using a gradient of 0-5% methanol in dichloromethane gave 66 mg (26%) of the free base of the title composition as an oil. It was collected in 1: 1 dichloromethane / diethyl ether (5 mL) and treated with 1.0 M HCl (about 2 equiv) in ether to give a precipitate. This mixture was concentrated to dryness. The resulting solid was reconstituted in water and lyophilized to give 66 mg of the title composition.

Example 34

1- [2-((3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl ) Methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer A

As described in Example 33 (excluding hydrochloride preparation), 1- {2- [4-amino-3-fluoropiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline- 7-carbonitrile, trans enantiomer A (intermediate 67, 150 mg, 0.48 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine- 6-carbaldehyde (WO 2004/058144) (85 mg, 0.48 mmol), and sodium triacetoxyborohydride (300 mg, 1.43 mmol) were reacted to give 70 mg (30%) of the title composition ([ α] _D = -12.4 (methanol, c = 0.5)).

Examples 35-40 were eluted with 5-50% water / acetonitrile containing ammonium acetate buffer (pH = 8) and purified by reverse phase HPLC on a Waters XBridge C-18 column.

Example 35

1- (2- {4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-fluoropiperidine-1 -Yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer A, dihydrochloride

Using a procedure similar to that described for the synthesis of Example 33, 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde and 1- {2- [4-Amino-3-fluoropiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer A (Intermediate 77) was reacted to give the title composition. .

Example 36

6-[({3-fluoro-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} amino) methyl] -2H -Pyrido [3,2-b] [1,4] oxazine-3 (4H) -one, trans enantiomer A

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine- using a procedure similar to that described for the synthesis of Example 33 (except for hydrochloride preparation) 6-carbaldehyde and 1- {2- [4-amino-3-fluoropiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer A ( Intermediate 77) was reacted to afford the title compound.

Example 37

1- (2- {4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-fluoropiperidine-1 -Yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer B, dihydrochloride

Using a procedure similar to that described for the synthesis of Example 33, 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde and 1- {2- [ 4-amino-3-fluoropiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer B (Intermediate 79) to react the title composition Obtained.

Example 38

1- [2- (3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) Methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer B

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine- using a procedure similar to that described for the synthesis of Example 33 (except for hydrochloride preparation) 6-carbaldehyde and 1- {2- [4-amino-3-fluoropiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans mirror image Isomer B (Intermediate 79) was reacted to give the title compound.

Example 39

1- (2- {4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-fluoropiperidine-1 -Yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer B, dihydrochloride

Using a procedure similar to that described for the synthesis of Example 33, 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde and 1- {2- [ 4-amino-3-fluoropiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer B (Intermediate 83) was reacted to give the title composition.

Example 40

6-[({3-fluoro-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} amino) methyl] -2H -Pyrido [3,2-b] [1,4] oxazine-3 (4H) -one, trans enantiomer B

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine- using a procedure similar to that described for the synthesis of Example 33 (except for hydrochloride preparation) 6-carbaldehyde and 1- {2- [4-amino-3-fluoropiperidin-1-yl] ethyl} -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer B ( Intermediate 83) was reacted to give the title compound.

Example 41

1- (2-{(3R, 4R) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-methok Sipiperidin-1-yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

1- {2-[(3R, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl} -2-oxo-1,2 in anhydrous methanol / chloroform (1: 1, 10 mL) -Dihydroquinoline-7-carbonitrile (intermediate 85, 105 mg crude compound, 0.32 mmol) and 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carb A mixture of aldehyde (WO 2004/058144) (53 mg, 0.32 mmol) was heated at 70 ° C. for 3 hours under 3 atmosphere molecular sieve under nitrogen atmosphere. The reaction was cooled to room temperature and sodium triacetoxy borohydride (205 mg, 0.97 mmol) was added. The reaction was stirred at rt overnight and then filtered through celite. The filtrate was concentrated to dryness, collected in 15% methanol in chloroform and washed with saturated sodium bicarbonate solution. The aqueous phase was reextracted twice with 15% methanol / chloroform. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. Chromatography on silica gel using a gradient of 2-10% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 61 mg (40%) of the free base of the title composition as an oil. It was collected in 1: 1 dichloromethane / diethyl ether (5 mL) and treated with 1.0 M HCl (about 2 equivalents) in ether. The resulting precipitate was collected by filtration, reconstituted in water and lyophilized to give 63 mg of the title composition as a solid.

Example 42

1- [2-((3R, 4R) -3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Photo-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile

Using a procedure similar to that described for the synthesis of Example 41 (except for hydrochloride preparation), 1- {2-[(3R, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl}- 2-oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 85, 105 mg, 0.32 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [ 1,4] oxazine-6-carbaldehyde (WO 2004/058144) (57 mg, 0.32 mmol) and sodium triacetoxy borohydride (205 mg, 0.97 mmol) were reacted. Chromatography on silica gel using a gradient of 2-10% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 88 mg (56%) of the title compound as an off-white solid.

Example 43

1- (2-{(3S, 4S) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-methok Sipiperidin-1-yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

Using a procedure similar to that described for the synthesis of Example 41, 1- {2-[(3S, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl} -2-oxo-1 , 2-dihydroquinoline-7-carbonitrile (intermediate 90, 120 mg, 0.37 mmol), 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (WO 2004/058144) (61 mg, 0.37 mmol) and sodium triacetoxy borohydride (234 mg, 1.10 mmol) were reacted to give the title composition (54 mg).

Example 44

1- [2-((3S, 4S) -3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Photo-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile

Using a procedure similar to that described for the synthesis of Example 41 (except for hydrochloride preparation), 1- {2-[(3S, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl}- 2-oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 90, 120 mg, 0.37 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [ 1,4] oxazine-6-carbaldehyde (WO 2004/058144) (61 mg, 0.37 mmol) and sodium triacetoxy borohydride (234 mg, 1.10 mmol) were reacted to afford the title compound.

Example 45

6-[({(3S, 4R) -3-fluoro-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} Amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, dihydrochloride

And

Example 46

6-[({(3R, 4S) -3-fluoro-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} Amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, dihydrochloride

Cis (±) 1- [2- (4-amino-3-fluoropiperidin-1-yl) ethyl] -7-methoxyquinoxaline-2 in dichloroethane / methanol (1: 1, 20 mL) A solution of (1H) -one, trifluoroacetic acid salt (intermediate 91, about 0.53 mmol) was neutralized with N, N-diisopropylethylamine. 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbaldehyde (WO 2004/058144) (113 mg, 0.63 mmol) was added The reaction was stirred over night at 3 μg molecular sieve at reflux. The reaction mixture was cooled to 0 ° C. and sodium cyanoborohydride (40 mg, 0.63 mmol) was added. The reaction mixture was stirred at rt for 2 h, then filtered through a sinter funnel and concentrated. The residue was collected in ethyl acetate and washed with saturated sodium bicarbonate and then saturated sodium chloride. The organic extract was dried over magnesium sulfate and concentrated. Reverse phase chromatography with water / methanol / trifluoroacetic acid gave the product as a trifluoroacetic acid salt. The salt was dissolved in water and chloroform and basified with saturated sodium carbonate. The layers were separated and the aqueous layer was extracted with chloroform. The organic extract was dried over magnesium sulfate and concentrated to give a racemic mixture of the free base of the title composition as a solid (26 mg (10%)).

The racemic mixture was separated by chiral chromatography (HPLC, chiralcel OJ, 250 × 20 mm, 10 μ mobile phase: 50% hexane, 25% ethanol, 25% methanol, 0.1% diethylamine). The free base of Example 45 eluted first, followed by the free base of Example 46. The free base was dissolved in dichloromethane (2 mL) and hydrochloride was prepared by adding 2.2 N of 4 N HCl in dioxane. The resulting colorless precipitate was collected by filtration to give 48 mg and 46 mg of Examples 45 and 46, respectively.

Example 47

1- [2-((3R, 4S) -3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Picture-6-yl) methyl] amino} piperidin-1-yl) ethyl] -4-methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

1- {2-[(3R, 4S) -4-amino-3-methoxypiperidin-1-yl] ethyl} -4-methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile (Intermediate 93, about 0.81 mmol) was suspended in chloroform / methanol (1: 1, 20 mL) and N, N-diisopropylethylamine was added dropwise until the solid became a solution. 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbaldehyde (WO 2004/058144) (210 mg, 1.2 mmol) was added The reaction was refluxed on a 3mm molecular sieve for 5 hours. Sodium triacetoxyborohydride (340 mg, 1.6 mmol) was added at 0 ° C. The reaction mixture was stirred at rt for 2 h, then filtered through a 0.45 μm membrane and concentrated. The residue was collected in dichloromethane and saturated sodium bicarbonate. The pH of the aqueous phase was adjusted to pH about 10 with 1 M sodium hydroxide solution. The aqueous phase was back extracted with dichloromethane and the combined organic phases were dried over sodium sulphate and concentrated. Reverse phase chromatography with water / acetonitrile / ammonium acetate gave the free base of the title composition as a tan foam (144 mg (36%)). Dihydrochloride was prepared using a procedure similar to that described for the synthesis of Example 45.

Example 48

1- [2-((3S, 4R) -3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Picture-6-yl) methyl] amino} piperidin-1-yl) ethyl] -4-methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

And

Example 49

1- [2-((3R, 4S) -3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Picture-6-yl) methyl] amino} piperidin-1-yl) ethyl] -4-methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

Using a procedure similar to that described for the synthesis of Example 47, cis (±) 1- [2- (4-amino-3-fluoropiperidin-1-yl) ethyl] -4-methyl-2- Oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 95, 200 mg, 0.63 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1, 4] oxazine-6-carbaldehyde (WO 2004/058144) (170 mg, 0.94 mmol) and sodium triacetoxyborohydride (260 mg, 1.26 mmol) were reacted. Reversed phase chromatography with water / acetonitrile / TFA gave a racemic mixture of the title compound as a dry film (80 mg).

The racemic mixture was separated by chiral chromatography (SFC, Chiralpak AD-H, 250 x 21 mm, 5μ; 50% methanol, 0.1% dimethylethylamine). The free base of Example 48 eluted first, followed by the free base of Example 49. Dihydrochloride was prepared using a procedure similar to that described for the synthesis of Example 45 to give the title compound as a colorless solid (6 mg and 4 mg, respectively).

Example 50

1- [2-((3S, 4R) -3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Picture-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

1- {2-[(3S, 4R) -4-amino-3-fluoropiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline-7-carbonitrile trifluoro Acetate (intermediate 97, 1.2 mmol) was suspended in chloroform / methanol (1: 2, 30 mL) and neutralized by the dropwise addition of N, N-diisopropylethylamine. 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbaldehyde (WO 2004/058144) (258 mg, 1.45 mmol) was added The reaction was refluxed on a 3mm molecular sieve for 5 hours. Sodium triacetoxyborohydride (512 mg, 2.42 mmol) was added at 0 ° C. The reaction mixture was stirred at rt for 30 min, then filtered through a sinter funnel and concentrated. The residue was collected in dichloromethane and washed with saturated sodium bicarbonate and saturated sodium chloride. The organic phase was dried over magnesium sulphate and concentrated. Reversed phase chromatography with water / acetonitrile / ammonium acetate gave the product as an off-white solid after freeze drying. The lyophilized product was dissolved in dichloromethane (5 mL) and hydrochloride was prepared by adding 2.2 equivalents of 4 N HCl in dioxane to give the title composition as a colorless solid (154 mg (26%)).

Example 51

1- [2-((3S, 4R) -3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Photo-6-yl) methyl] amino} piperidin-1-yl) ethyl] -4-methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile, bis-trifluoroacetic acid salt

1- {2-[(3S, 4R) -4-amino-3-methoxypiperidin-1-yl] ethyl} -4-methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile Trifluoroacetate (intermediate 104, about 0.52 mmol) was suspended in chloroform / methanol (1: 2, 15 mL) and neutralized by the dropwise addition of N, N-diisopropylethylamine. 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbaldehyde (WO 2004/058144) (93 mg, 0.52 mmol) is added And the reaction was refluxed on a 3mm molecular sieve overnight. Sodium triacetoxyborohydride (138 mg, 0.65 mmol) was added at 0 ° C. The reaction mixture was stirred at rt for 5 h, then filtered through a sinter funnel and concentrated. The residue was collected in dichloromethane and washed with saturated sodium bicarbonate and saturated sodium chloride. The organic phase was dried over magnesium sulphate and concentrated. Reverse phase chromatography using water / acetonitrile / trifluoroacetic acid gave the title composition as a white solid after lyophilization (108 mg (34%)).

Example 52

1- [2-((3R, 4S) -3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Picture-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride

1- {2-[(3R, 4S) -4-amino-3-fluoropiperidin-1-yl] ethyl} -2-oxo-1,2-dihydroquinoline-7-carbonitrile (intermediate 106 , 352 mg, 1.12 mmol) was suspended in chloroform / methanol (1: 1, 30 mL). 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbaldehyde (WO 2004/058144) (299 mg, 1.68 mmol) was added And the reaction was refluxed on a 3mm molecular sieve overnight. Sodium triacetoxyborohydride (356 mg, 1.68 mmol) was added at 0 ° C. The reaction mixture was stirred at rt for 5 h, then filtered through a sinter funnel and concentrated. The residue was collected in dichloromethane and washed with saturated sodium bicarbonate and brine. The organic phase was dried over magnesium sulphate and concentrated. Reverse phase chromatography using water / acetonitrile / ammonium acetate gave the acetic acid salt of the title compound as an off-white solid after lyophilization. From a solution of acetic acid salt in dichloromethane (5 mL), a bis-HCl salt was prepared by adding thereto an equivalent of 4 N HCl in dioxane. Filtration and drying in vacuo gave the desired compound as a colorless solid (154 mg (26%)).

Claims (32)

A compound of formula (I), or a pharmaceutically acceptable salt thereof. <Formula I>

Where A is selected from CH and N; D is selected from CR ⁷ and N; Wherein at least one of A and D is carbon; E is selected from O, NH, and S, here, i) when R ⁸ and R ⁹ together form ═O, E is NH; ii) when R ⁸ and R ⁹ are each H, E is O or S; G is selected from O and S; J is selected from CR ⁴ and N; R ¹ is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, OR ^1a , and —N (R ^1a ) ₂ , wherein said C _{1 -6} alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ¹⁰ ; R ^1a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ²⁰ ; R ² is selected from halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ^2a , and —N (R ^2a ) ₂ , wherein said C _1-6 Alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ²⁰ ; R ^2a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ²⁰ ; R ³ is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, —OR ^3a , and —N (R ^3a ) ₂ , wherein C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ³⁰ ; R ^3a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ³⁰ ; R ⁴ is selected from H, halo, cyano, —CO ₂ H, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein the C _1-6 alkyl, C _{2- 6} alkenyl, and C _2-6 alkynyl, are optionally substituted with one or more R ⁴⁰ ; R ⁶ is selected from fluoro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ^6a , wherein the C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl is optionally substituted with one or more R ⁶⁰ ; R ^6a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ⁶⁰ ; R ⁷ is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein the C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl is optionally substituted with one or more R ⁷⁰ ; R ⁸ and R ⁹ are each hydrogen or R ⁸ and R ⁹ together form ═O; R ¹⁰ , R ²⁰ , R ³⁰ , R ⁴⁰ , R ⁶⁰ , and R ⁷⁰ are independently at each occurrence halo, hydroxy, cyano, -CO ₂ H, C _1-6 alkyl, C _2-6 alkenyl , And C _2-6 alkynyl, The compounds of formula (I) are substantially free of cis (±) mixtures of their enantiomers. The compound of formula (I) according to claim ¹ , or a pharmaceutically acceptable salt thereof, wherein R ¹ is H. 3. The method according to claim 1 or 2, R ² is selected from cyano and -OR ^2a ; R ^2a is selected from C _1-6 alkyl A compound of formula (I), or a pharmaceutically acceptable salt thereof. The compound of formula (I) according to any one of claims 1 to ³ , or a pharmaceutically acceptable salt thereof, wherein R ³ is H. The method according to any one of claims 1 to 4, R ⁶ is selected from fluoro and —OR ^6a ; R ^6a is selected from H and C _1-6 alkyl A compound of formula (I), or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1 to 5, J is selected from CR ⁴ and N; R ⁴ is selected from H and C _1-6 alkyl A compound of formula (I), or a pharmaceutically acceptable salt thereof. 7. The compound of claim 1, wherein A, D, E, G, R ⁸ , and R ⁹ together with the ring atom to which they are attached

A compound of formula (I), or a pharmaceutically acceptable salt thereof, forming a group selected from. The method of claim 1, J is selected from N and CR ⁴ ; A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from; R ¹ is H; R ² is selected from cyano and methoxy; R ³ is H; R ⁴ is selected from H and methyl; R ⁶ is selected from fluoro, hydroxy, and methoxy A compound of formula (I), or a pharmaceutically acceptable salt thereof. The compound of formula I according to any one of claims 1 to 8, wherein the R ⁶ group on carbon "a" and the -NH- group on carbon "b" of the compound of formula I are cis (+) in relation to each other. , Or pharmaceutically acceptable salts thereof. The compound of formula I according to any one of claims 1 to 8, wherein the R ⁶ group on carbon "a" and the -NH- group on carbon "b" of the compound of formula I are in a cis (-) relationship with each other, Or pharmaceutically acceptable salts thereof. The method of claim 1, 1- [2-((3R, 4S) -3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Photo-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride; 6-[({(3R, 4S) -3-hydroxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} Amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, dihydrochloride; 1- (2-{(3R, 4S) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-fluoro Lopiperidin-1-yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, monoacetic acid salt; 1- (2-{(3S, 4R) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-methok Sipiperidin-1-yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride; 1- (2-{(3R, 4R) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3- Methoxypiperidin-1-yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, dihydrochloride; 1- [2-((3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl ) Methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer A; 1- [2-((3R, 4R) -3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Photo-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile; 1- [2-((3S, 4R) -3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Photo-6-yl) methyl] amino} piperidin-1-yl) ethyl] -4-methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride; And 1- [2-((3R, 4S) -3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Picture-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride A compound of formula (I), or a pharmaceutically acceptable salt thereof, selected from Reacting a compound of formula AA with a compound of formula AB in the presence of a suitable reducing agent, <Formula AA>

<Formula AB>

After that, if necessary i. Converting the compound of formula I to another compound of formula I; ii. Remove any protecting group; iii. A process for preparing a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, comprising forming a pharmaceutically acceptable salt. Reacting a compound of formula BI with a suitable reducing agent, <Formula BI>

After that, if necessary i. Converting the compound of formula I to another compound of formula I; ii. Remove any protecting group; iii. A process for preparing a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, comprising forming a pharmaceutically acceptable salt. Use of a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a bacterial infection in a warm blooded animal such as a human. A method of treating bacterial infection in an animal comprising administering to a warm blooded animal, such as a human, an effective amount of a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection in a warm blooded animal such as a human. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. A compound of formula II, or a pharmaceutically acceptable salt thereof. <Formula II>

Where A is selected from CH and N; D is selected from CR ⁷ and N; Wherein at least one of A and D is carbon; E is selected from O, NH, and S, here, i) when R ⁸ and R ⁹ together form ═O, E is NH; ii) when R ⁸ and R ⁹ are each H, E is O or S; G is selected from O and S; J is selected from CR ⁴ and N; R ¹ is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, OR ^1a , and —N (R ^1a ) ₂ , wherein said C _{1 -6} alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ¹⁰ ; R ^1a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ²⁰ ; R ² is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ^2a , and —N (R ^2a ) ₂ , wherein the C _{1 -6} alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ²⁰ ; R ^2a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ²⁰ ; R ³ is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, —OR ^3a , and —N (R ^3a ) ₂ , wherein C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ³⁰ ; R ^3a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ³⁰ ; R ⁴ is selected from H, halo, —CO ₂ H, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein the C _1-6 alkyl, C _{2- 6} alkenyl, and C _2-6 alkynyl, are optionally substituted with one or more R ⁴⁰ ; R ⁶ is selected from fluoro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ^6a , wherein the C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl is optionally substituted with one or more R ⁶⁰ ; R ^6a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more R ⁶⁰ ; R ⁷ is selected from H, halo, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein the C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl is optionally substituted with one or more R ⁷⁰ ; R ⁸ and R ⁹ are each hydrogen or R ⁸ and R ⁹ together form ═O; R ¹⁰ , R ²⁰ , R ³⁰ , R ⁴⁰ , R ⁶⁰ , and R ⁷⁰ are independently at each occurrence halo, hydroxy, cyano, -CO ₂ H, C _1-6 alkyl, C _2-6 alkenyl , And C _2-6 alkynyl, Here, the R ⁶ groups on carbon "a" and the -NH- groups on carbon "b" are in trans relationship with each other. ^19. A compound of formula II, or a pharmaceutically acceptable salt thereof, according to claim 18, wherein R ¹ is H. The method of claim 18 or 19, R ² is selected from cyano and -OR ^2a ; R ^2a is selected from C _1-6 alkyl A compound of Formula (II), or a pharmaceutically acceptable salt thereof. The compound of formula (II) according to any one of claims 18 to 20, or a pharmaceutically acceptable salt thereof, wherein R ³ is H. The method according to any one of claims 18 to 21, R ⁶ is selected from fluoro and —OR ^6a ; R ^6a is selected from H and C _1-6 alkyl A compound of Formula (II), or a pharmaceutically acceptable salt thereof. The method according to any one of claims 18 to 22, J is selected from CR ⁴ and N; R ⁴ is selected from H and C _1-6 alkyl A compound of Formula (II), or a pharmaceutically acceptable salt thereof. 24. The compound of any one of claims 18 to 23, wherein A, D, E, G, R ⁸ , and R ⁹ together with the ring atom to which they are attached

A compound of formula (II), or a pharmaceutically acceptable salt thereof, forming a group selected from. The method of claim 18, J is selected from CR ⁴ and N; A, D, E, G, R ⁸ , and R ⁹ together with the ring atoms to which they are attached

To form a group selected from; R ¹ is H; R ² is selected from cyano and -OR ^2a ; R ^2a is selected from methyl; R ³ is H; R ⁴ is selected from H and methyl A compound of Formula (II), or a pharmaceutically acceptable salt thereof. The method of claim 18, 1- (2-{(3S, 4S) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3- Methoxypiperidin-1-yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, dihydrochloride; 6-[({(3S, 4S) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} Amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one; 1- (2-{(3R, 4R) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-methok Sipiperidin-1-yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, dihydrochloride; 6-[({(3R, 4R) -3-methoxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} Amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one; 1- (2- {4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-hydroxypiperidine-1 -Yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer A, dihydrochloride; 6-[({3-hydroxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} amino) methyl] -2H -Pyrido [3,2-b] [1,4] oxazine-3 (4H) -one, trans enantiomer A; 1- (2- {4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-hydroxypiperidine-1 -Yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer B, dihydrochloride; 6-[({3-hydroxy-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} amino) methyl] -2H -Pyrido [3,2-b] [1,4] oxazine-3 (4H) -one, trans enantiomer B; 1- (2- {4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-fluoropiperidine- 1-yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer A, dihydrochloride; 1- [2-((3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl ) Methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer A; 1- (2- {4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-fluoropiperidine-1 -Yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer A, dihydrochloride; 6-[({3-fluoro-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} amino) methyl] -2H -Pyrido [3,2-b] [1,4] oxazine-3 (4H) -one, trans enantiomer A; 1- (2- {4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-fluoropiperidine-1 -Yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer B, dihydrochloride; 1- [2- (3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) Methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer B; 1- (2- {4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-fluoropiperidine-1 -Yl} ethyl) -7-methoxyquinoxalin-2 (1H) -one, trans enantiomer B, dihydrochloride; 6-[({3-fluoro-1- [2- (7-methoxy-2-oxoquinoxalin-1 (2H) -yl) ethyl] piperidin-4-yl} amino) methyl] -2H -Pyrido [3,2-b] [1,4] oxazine-3 (4H) -one, trans enantiomer B; 1- (2-{(3R, 4R) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-methok Sipiperidin-1-yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride; 1- [2-((3R, 4R) -3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Photo-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile; 1- (2-{(3S, 4S) -4-[(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-methok Sipiperidin-1-yl} ethyl) -2-oxo-1,2-dihydroquinoline-7-carbonitrile, dihydrochloride; And 1- [2-((3S, 4S) -3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Photo-6-yl) methyl] amino} piperidin-1-yl) ethyl] -2-oxo-1,2-dihydroquinoline-7-carbonitrile A compound of formula (II) selected from: or a pharmaceutically acceptable salt thereof. Reacting a compound of formula AA with a compound of formula AB in the presence of a suitable reducing agent, <Formula AA>

<Formula AB>

After that, if necessary i. Converting the compound of formula II to another compound of formula II; ii. Remove any protecting group; iii. 27. A process for the preparation of a compound of formula (II) as claimed in any one of claims 18 to 26, or a pharmaceutically acceptable salt thereof, comprising forming a pharmaceutically acceptable salt. Reacting a compound of formula BI with a suitable reducing agent, <Formula BI>

After that, if necessary i. Converting the compound of formula II to another compound of formula II; ii. Remove any protecting group; iii. 27. A process for the preparation of a compound of formula (II) as claimed in any one of claims 18 to 26, or a pharmaceutically acceptable salt thereof, comprising forming a pharmaceutically acceptable salt. Use of a compound of formula (II) claimed in any one of claims 18-26, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a bacterial infection in a warm blooded animal such as a human. A method of treating bacterial infection in an animal comprising administering to a warm blooded animal such as a human an effective amount of a compound of Formula (II) as claimed in any one of claims 18 to 26, or a pharmaceutically acceptable salt thereof. A compound of formula (II) as claimed in any one of claims 18-26, or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection in a warm blooded animal such as a human. A pharmaceutical composition comprising a compound of Formula (II) as claimed in any one of claims 18 to 26, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.