PHENYLETHYLPYRIDINE DERIVATIVES AS PDE4-INHIBITORS AND MUSCARINIC RECEPTOR ANTAGONISTS

FIELD OF THE INVENTION

The present invention relates to novel compounds which are both inhibitors of the phosphodiesterase 4 (PDE4) enzyme and muscarinic M3 receptor antagonists. More particularly, the invention relates to compounds of formula (I) as below described, methods of preparing such compounds, compositions containing them and therapeutic use thereof.

BACKGROUND OF THE INVENTION

Chronic obstructive pulmonary disease (COPD) is a respiratory disorder characterized by progressive, not fully reversible, airflow limitation associated with an abnormal pulmonary inflammatory response to noxious particles or gases.

For this reason, bronchial relaxation and inflammatory response suppression represent a mechanistic approach to the treatment of COPD that might improve symptoms such as dyspnea, wheezing, chest tightness, cough and mucus secretion, improve health status and reduce exacerbations.

Nowadays, the drug therapy options for COPD fall into 2 general classes: bronchodilators, (β2-adrenoceptor agonists, antimuscarinic agents and methylxanthines) and antiinflammatory agents (glucocorticosteroids and selective phosphodiesterase-4 (PDE4) inhibitors).

Bronchodilator drugs are the current mainstay of treatment for symptoms' relief.

As anticholinergic bronchodilators, the efficacy of muscarinic M3 antagonists is based on the fact that the major reversible component of airflow narrowing in COPD patients is the increase of acetylcholine (ACh) released to airway smooth muscle, by the bronchial postganglionic vagal efferent in some pathological conditions. Therefore, compounds that antagonize the action of ACh at muscarinic receptors are able to counteract the bronchoconstriction and thus improve lung function in these patients.

Muscarinic antagonists block the effects of ACh at muscarinic receptors. Currently, there are five known muscarinic receptor subtypes (M1 - M5); human airway smooth muscle contains M1, M2 and M3 receptors. M1 receptors facilitate neurotransmission through parasympathetic ganglia and are weakly expressed on submucosal glands in human airways. The M2 receptors are located on the smooth-muscle fibers. Some studies have suggested a small role of M2 mediating the inhibition of airway smooth-muscle relaxation caused by adenylyl cyclase activation by compounds such as beta agonists. In addition, presynaptic M2 receptors are found on postganglionic parasympathetic nerves that project to airway smooth muscle and mucus-producing cells. These presynaptic M2 autoreceptors provide a negative feedback mechanism, which, when stimulated, inhibit further release of ACh. Postsynaptic M3 receptors are known to mediate both contraction of smooth muscle in the respiratory tract and mucus secretion, making them a major target for symptomatic relief of COPD. Consequently, in the airways, the major effects of muscarinic antagonists are bronchodilation and reduction of mucus secretion via blockage of ACh-induced effects in the parasympathetic nervous system.

Given the distribution of muscarinic receptors, systemically available agents that bind to muscarinic receptors outside of the respiratory tract have the potential to produce unwanted side effects such as tachycardia, dry mouth, urinary retention and constipation. Whereas dry mouth is the most common systemic anticholinergic side effect associated with the use of antimuscarinic antagonists as a result of the systemic blockade of M1 and M3 receptors the most potentially serious systemic effect is tachycardia, which results from the blockade of cardiac M2 receptors.

Inhaled anticholinergic antimuscarinic drugs approved for the treatment of COPD include ipratropium bromide (Atrovent®), oxitropium bromide (Oxivent®) and tiotropium bromide (Spiriva®). Both ipratropium and oxitropium are short-acting agents. In contrast, tiotropium bromide is the only long-acting antimuscarinic agent (LAMA) currently marketed for COPD, proved to be suitable for one-daily administration as a dry powder. Several others newer LAMAs are newly registered for the treatment of COPD, including aclidinium bromide and glycopyrrolate bromide, or are currently in phase III development, including umeclidinium.

Although bronchodilators are quite effective to improve symptoms, they do not address the underlying chronic inflammation or the changes in airway structure.

Standard treatment with glucocorticosteroids as antiinflammatory agents has demonstrated limited efficacy. However, among the antiinflammatory agents currently being developed, PDE4 inhibitors proved to be effective in attenuating the responses of various inflammatory cells, through their ability to elevate cAMP levels.

PDE4 is the predominant PDE expressed in neutrophils and T cells, suggesting that PDE4 inhibitors would be effective in controlling inflammation in COPD. Inhibition of PDE4 in inflammatory cells influences various specific responses, such as the production and/or release of pro-inflammatory mediators including cytokines and reactive oxygen species, with a well-documented efficacy in animal models mimicking certain aspects of asthma and COPD, as well as inflammatory bowel disease, atopic dermatitis, psoriasis and rheumatoid arthritis.

The selective PDE4 inhibitor, roflumilast (Daxas®) is an approved phosphodiesterase-4 inhibitor for the treatment of COPD associated with chronic bronchitis and a history of exacerbations. Roflumilast inhibits lung inflammation and emphysema in a smoking model of COPD in mice. In COPD patients, oral roflumilast given over 4 weeks significantly reduces the numbers of neutrophils (by 36%) and CXCL8 concentrations in sputum. In clinical trials roflumilast (500 mg once daily) given over 12 months improved lung function in COPD patients to a small extent but had little effect in reducing exacerbations or improving quality of life. More recently roflumilast has been shown to significantly improve FEV 1 (by approximately 50 ml) and reduce exacerbation (by about 15%) in patients with severe disease who have frequent exacerbations and mucus hypersecretion. Roflumilast provides clinical benefit when added to salmeterol or tiotropium and so may be used as an additional treatment in patients with severe disease.

Other structurally related PDE4 inhibitors are disclosed in documents such as EP 2 022 783 A1 and EP 2 216 327 A1.

However, the clinical utility of PDE4 inhibitors has so far been compromised by the occurrence of mechanism-associated side effects, including headache, nausea and emesis, which often limited the maximally tolerated dose. This problem could be overcome by inhaled delivery and designing compounds with a potentially more advantageous therapeutic window.

Since bronchial relaxation and inflammatory response suppression represent a mechanistic approach to the treatment of COPD, the combination of muscarinic M3 antagonism with selective PDE4 inhibition may lead to a new class of drugs, combining both bronchodilating and antiinflammatory properties in one molecule, which may open new perspectives in the management of COPD.

The present invention addresses the above mentioned need by providing the compounds of the invention.

SUMMARY OF THE INVENTION

The invention is directed to compounds acting as inhibitors of the phosphodiesterase 4 (PDE4) enzyme and as muscarinic M3 receptor antagonists, methods of preparing said compounds, compositions containing them and therapeutic use thereof.

In particular the invention is directed to compounds of formula (I),

wherein

• W is selected from an aryl and a heteroaryl;
• R₁ is hydrogen or is selected in the group consisting of: halogen, (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, hydroxy, -SO₂NR₆R₇, -CN, -NR₈SO₂R₉, -NR₆R₇, -CONR₆R₇ and -NR₈COR₉ and wherein (C₁-C₄) alkyl is optionally substituted by one or more groups selected from (C₃-C₇) cycloalkyl, hydroxy and -NR₆R₇ and wherein (C₁-C₄) alkoxy is optionally substituted by one or more halogens or groups (C₃-C₇) cycloalkyl wherein,

  • R₆ is hydrogen or (C₁-C₆) alkyl;
  • R₇ is hydrogen or (C₁-C₆) alkyl;
  • R₈ is hydrogen or (C₁-C₆) alkyl;
  • R₉ is hydrogen or (C₁-C₆) alkyl;

• n is an integer ranging from 1 to 3;
• R₂ is hydrogen or is selected in the group consisting of: halogen, (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkyl, hydroxy, -SO₂NR₁₀R₁₁, -CN and -NR₁₂SO₂R₁₃ and wherein (C₁-C₄) alkyl and (C₁-C₄) alkoxy are optionally substituted by one group (C₃-C₇) cycloalkyl,

  • R₁₀ is hydrogen or (C₁-C₆) alkyl;
  • R₁₁ is hydrogen or (C₁-C₆) alkyl;
  • R₁₂ is hydrogen or (C₁-C₆) alkyl;
  • R₁₃ is hydrogen or (C₁-C₆) alkyl;

• m is an integer ranging from 1 to 3;
• p is zero or 1;
• L₁ is a group (CH₂)_t wherein t is 0 or an integer ranging from 1 to 3
• L₂ is a group selected from (CH₂)_q wherein q is an integer ranging from 1 to 3, ortho-, meta-, para-benzyl, ortho-, meta- and para-methylenoxy-benzyl wherein the carbon chain atom of the benzyl group is linked to the nitrogen atom;
• R₃ and R₄ are different or the same and are independently selected from the group consisting of:

  • H;
  • (C₃-C₇) cycloalkylcarbonyl;
  • (C₁-C₆) alkyl, optionally substituted by one or more substituents selected from (C₃-C₇) cycloalkyl or (C₅-C₇) cycloalkenyl;
  • (C₁-C₆) haloalkyl;
  • (C₃-C₇) cycloalkyl;
  • (C₅-C₇) cycloalkenyl;
  • (C₂-C₆) alkenyl; and
  • (C₂-C₆) alkynyl;

• or R₃ and R₄, together with the interconnecting atoms, form a 2,2-difluoro-1,3-dioxolane ring of formula (r) fused to the phenyl moiety which bears groups -OR₃ and -OR₄, wherein asterisks indicate carbon atoms shared with such phenyl ring:

• R₅ is selected from the group consisting of: CN, NO₂, CF₃ and halogen atoms;
• k is an integer ranging from 1 to 3; and
• A is a nitrogen containing group which may be:

  • group (a) which is -(CH₂)_s-NR₁₄R₁₅ wherein s is an integer ranging from 1 to 4 and R₁₄ and R₁₅ are independently hydrogen or (C₁-C₄) alkyl; or
  • a group (b) which is a saturated monocyclic, bicyclic or tricyclic heterocyclic ring system optionally substituted by one or two groups R₁₆ which are at each occurrence independently (C₁-C₄) alkyl or benzyl;

  their N-oxides on the pyridine ring, deuterated derivatives, and pharmaceutically acceptable salts, and solvates thereof.

The invention further involves the corresponding N-oxides on the pyridine ring of compounds of formula (I).

The invention further involves the corresponding deuterated derivatives of compounds of formula (I) wherein at least one hydrogen atom is substituted by corresponding atoms of deuterium.

The invention also encompasses the pharmaceutically acceptable salts and/or solvates thereof.

The term "Pharmaceutically acceptable salts", as used herein, refers to derivatives of compounds of formula (I) or of their corresponding N-oxides on the pyridine ring wherein the parent compound is suitably modified by converting any of the free acid or basic group, if present, into the corresponding addition salt with any base or acid conventionally intended as being pharmaceutically acceptable.

Suitable examples of said salts may thus include mineral or organic acid addition salts of basic residues such as amino groups, as well as mineral or organic acid residues such as carboxylic groups.

Cations of inorganic bases which can be suitably used to prepare salts within the invention comprise ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium.

Those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt comprise, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". Pharmaceutically acceptable solvates of compound of the invention are within the scope of the invention.

Included within the scope of the present invention are also polymorphs and crystalline forms of compounds of formula (I), of their N-oxides on the pyridine ring, or of pharmaceutically acceptable salts, or solvates thereof.

Hereinafter, compounds of formula (I), (IA), (IB), (IC), (ID), (Ia), (Ib), (Ic), (Id) and (I)', corresponding N- Oxides on the pyridine ring, enantiomers, diastereoisomers thereof, their pharmaceutically acceptable salts and solvates, and polymorphs or crystalline forms thereof defined in any aspect of the invention (except intermediate compounds described in the chemical processes) are referred to as "compounds of the invention".

The invention further comprises a process for the preparation of compounds of the invention.

The present invention also provides pharmaceutical compositions of compounds of the invention either alone or in combination with another active ingredient, in admixture with one or more pharmaceutically acceptable carriers.

In a further aspect the present invention provides the use of the compounds of the invention as a medicament.

In one aspect the present invention provides the use of the compounds of the invention for the manufacture of a medicament.

In particular the present invention provides the use of the compounds of the invention for the prevention and/or treatment of any disease wherein an inhibition of PDE4 activity along with muscarinic M3 receptor antagonism is desirable.

In particular the compounds of the invention alone or combined with other active ingredients may be administered for the prevention and/or treatment of a disease of the respiratory tract characterized by airway obstruction such as asthma and COPD. In one embodiment, the compounds of the invention may be administered for the prevention and/or treatment of COPD.

In a further aspect the present invention provides the use of compounds of the invention for the preparation of a medicament for the prevention and/or treatment of any disease wherein an inhibition of PDE4 activity along with muscarinic M3 receptor antagonism is desirable.

Moreover disclosed herein is a method for prevention and/or treatment of any disease wherein an inhibition of PDE4 activity along with muscarinic M3 receptor antagonism is desirable, said method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of the invention.

A further aspect of the invention provides a suitable inhalation device, comprising a pharmaceutical composition of a compound of the invention, which may be respectively selected from a single- or multi-dose dry powder inhaler, a pressurized metered dosed inhaler or a nebulizer and in particular a soft mist nebulizer.

A further aspect of the invention provides a kit comprising the pharmaceutical compositions of a compound of the invention either alone or in combination with one or more active ingredient and a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler or a nebulizer.

DEFINITIONS

The term "halogen atoms" as used herein includes fluorine, chlorine, bromine, and iodine, preferably chlorine.

As used herein, the term "(C₁-C_x) alkyl" where x is an integer greater than 1, refers to straight-chained and branched alkyl groups wherein the number of constituent carbon atoms is in the range 1 to x. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl.

By analogy, the term "(C₁-C_x)alkylene", refers to a divalent (C₁-C_x)alkyl radical, wherein (C₁-C_x)alkyl is as above defined.

The term "(C₁-C_x) alkoxy" where x is an integer greater than 1, refers to straight-chained and branched alkoxy groups wherein the number of constituent carbon atoms is in the range 1 to x. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy and t-butoxy.

The expressions "(C₁-C_x)haloalkyl" refer to the above defined "(C₁-C_x)alkyl" groups wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which can be the same or different from each other.

Not limiting examples of said (C₁-C₆)haloalkyl groups may thus include halogenated, poly-halogenated and fully halogenated alkyl groups wherein all of the hydrogen atoms are replaced by halogen atoms, e.g. trifluoromethyl or difluoro methyl groups.

The term "(C₃-C_y) cycloalkyl", where y is an integer greater than or equal to 3, refers to saturated cyclic hydrocarbon groups containing from 3 to y ring carbon atoms. Not limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The derived expression "(C₃-C_y)heterocycloalkyl" refers to monocyclic (C₃-C_y)cycloalkyl groups, in which at least one ring carbon atom is replaced by a heteroatom (e.g. N, NH, S or O). Not limiting examples of (C₃-C_y)heterocycloalkyl are represented by: pyrrolidinyl, thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, azetidinyl.

By analogy, the term "(C₃-C_y)heterocycloalkyl-ene", refers to a divalent (C₃-C_y)heterocycloalkyl radical, wherein (C₃-C_y)heterocycloalkyl is as above defined.

The expression "(C₃-C_y)cycloalkylcarbonyl" refers to (C₃-C_y)cycloalkylCO-groups wherein the group "(C₃-C_y)cycloalkyl" has the meaning above defined.

The term "(C₂-C₆)alkenyl" refers to straight or branched, conjugated or not conjugated, carbon chains with one or more double bonds, in cis or trans configuration, wherein the number atoms is in the range 2 to 6.

The term "(C₅-C_z) cycloalkenyl", where z is an integer greater than or equal to 5, refers to cyclic hydrocarbon groups containing from 5 to z ring carbon atoms and one or more double bonds.

The term "(C₂-C₆)alkynyl" refers to straight or branched carbon chains with one or more triple bonds wherein the number atoms is in the range 2 to 6.

The term "aryl" refers to mono or bi-cyclic systems which have 6 to 10 ring atoms, wherein at least one ring is aromatic.

The expression "heteroaryl" refers to mono or bi-cyclic systems with 5 to 11 ring atoms, in which at least one ring is aromatic and in which at least one ring atom is a heteroatom (e.g. N, NH, S or O).

Not limiting examples of suitable aryl or 5,6-membered heteroaryl monocyclic systems include, for instance, benzene, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, isothiazole, thiazole, pyridine, furan derived radicals and the like.

Not limiting examples of suitable aryl or heteroaryl bicyclic systems include naphthalene, biphenylene, purine, pteridine, benzimidazole, benzotriazole, quinoline, isoquinoline, indole, isoindole, indazole, benzothiophene, dihydrobenzo dioxin, dihydrobenzo dioxepin, benzo oxazin radicals and the like.

As used herein, the expression "heterocyclic ring system" refers to optionally substituted mono- bi- or tri-cyclic ring systems which may be saturated, partially unsaturated or unsaturated, such as (C₃-C₇) heterocycloalkyl or heteroaryl, having 5 to 11 ring atoms in which at least one ring atom is a heteroatom (e.g. N, S or O). Not limiting examples of "heterocyclic ring system" are represented by: pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, quinuclidinyl, 8-azabicyclo[3.2.1]octanyl or dehydroxylate scopine radical all optionally substituted by (C₁-C₄) alkyl or benzyl on a nitrogen atom.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a class of compounds acting both as inhibitors of the phosphodiesterase 4 (PDE4) enzyme and as muscarinic M3 receptor antagonists.

The present invention relates to derivatives of general formula (I), N-oxides on the pyridine ring, deuterated derivatives and pharmaceutically acceptable salts and solvates thereof,

wherein R₁, R₂, R₃, R₄, R₅, A, W, L₁, L₂, m, n, p, and k are as above defined.

It will be apparent to those skilled in the art that compounds of general formula (I) at least contain one stereogenic center, namely represented by the carbon atom (1) and therefore exist as optical stereoisomers:

Where the compounds according to the invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more stereogenic centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.

In a preferred embodiment, the present invention is directed to compounds of formula (I)', which are compounds of formula (I) as above defined where the absolute configuration of carbon (1) is that shown herebelow:

The absolute configuration for carbon (1) is assigned on the basis of Cahn-Ingold-Prelog nomenclature based on groups'priorities.

In one preferred embodiment, for compounds of formula (I), absolute configuration at carbon (1) is (S).

Where the compounds of formula (I) possess a second stereogenic center, they exist as at least four diastereoisomers; the four diastereoisomers thereof are comprised within the scope of the present invention.

In one embodiment, when A is a group of formula (i), as below defined, compounds of formula (I) may exist as at least four diastereoisomers (Ia), (Ib), (Ic) and (Id) herebelow reported, which are comprised within the scope of the present invention:

In one embodiment, compounds of formula (Ic) are provided as above reported.

It is to be understood that all preferred groups or embodiments described herebelow and hereabove for compounds of formula (I) may be combined among each other and apply to compounds of formula (IA), (IB), (IC), (ID), (Ia), (Ib), (Ic), (Id) and (I)' as well mutatis mutandis.

In one embodiment, the invention provides compounds of formula (IA), which are N-oxides on the pyridine ring of compounds of formula (I), deuterated derivatives and pharmaceutically acceptable salts and solvate thereof:

wherein R₁, R₂, R₃, R₄, R₅, A, W, L₁, L₂, m, n, p, and k are as defined above.

In one embodiment, 4-pyridinyl ring has two R₅ substituents which are halogen atom. In a further preferred embodiment, such R₅ substituents are two chlorine atoms at positions 3 and 5 of the pyridine ring.

In one embodiment, R₄ is selected from (C₁-C₆) haloalkyl and (C₁-C₆) alkyl.

In one embodiment, R₃ is selected from (C₃-C₇) cycloalkyl and (C₁-C₆) alkyl optionally substituted by (C₃-C₇) cycloalkyl.

In another embodiment, R₃ and R₄, together with the interconnecting atoms, form a 2,2-difluoro-1,3-dioxolane ring of formula (r) fused to the phenyl moiety which bears groups -OR₃ and -OR₄, wherein asterisks indicate carbon atoms shared with such phenyl ring:

In a further embodiment, R₄ is (C₁-C₆) haloalkyl and R₃ is (C₁-C₆) alkyl which is substituted by (C₃-C₇) cycloalkyl.

In a still further embodiment, R₃ is (C₁-C₆) alkyl and R₄ is (C₁-C₆) alkyl.

In one embodiment, compounds of general formula (I) are provided wherein the 4-pyridinyl ring is substituted in 3 and 5 with two atoms of chlorine, according to formula (IB)

wherein R₁, R₂, R₃, R₄, A, W, L₁, L₂, m, n, and p are as above defined; and the corresponding N-oxides on the pyridine ring, deuterated derivatives, and pharmaceutically acceptable salts and solvates thereof.

In one embodiment, another group of compounds of formula (I) is provided which is that shown below according to formula (IC):

wherein R₁, R₂, R₅, A, W, L₁, L₂, m, n, p, and k are as above defined; and the corresponding N-oxides on the pyridine ring, and pharmaceutically acceptable salts and solvates thereof.

In a still further embodiment, a group of compounds of formula (I) is provided which is that shown below according to formula (ID):

wherein R₁, R₂, R₅, A, W, L₁, L₂, m, n, p, and k are as above defined; and the corresponding N-oxides on the pyridine ring, and pharmaceutically acceptable salts and solvates thereof.

In a still further embodiment, a group of compounds of formula (I) is provided which is that shown below according to formula (IE):

• wherein L₂ and L₁ are located in the ortho, meta or para position on the phenyl ring they are linked to,
• L₁ is selected from a group (CH₂)_t wherein t is 0 or an integer ranging from 1 to 3;
• L₂ is a group selected from (CH₂)_q wherein q is an integer ranging from 1 to 3, meta-, para-benzyl, meta- and para-methylenoxy-benzyl wherein the carbon chain atom of the benzyl group is linked to the nitrogen atom while the respective aromatic carbon atom or the methylene carbon atom are linked to the phenyl group;
• and wherein R₁, R₂, R₅, A, W, m, n, p, and k are as above defined; and the corresponding N-oxides on the pyridine ring, and pharmaceutically acceptable salts and solvates thereof.

In one embodiment, A is a group (b) represented by a group of formula (i), (ii), (iii) or (iv):

wherein

• f=1, 2 or 3;
• g =1, 2 or 3.

In another embodiment, A is a group (b) represented by a group of formula (i):

According to one embodiment, the present invention provides a compound selected in the list consisting of:

• (1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(4-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(3-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(4-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(4-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(3-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-methyl-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]benzoate;
• [(1R)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1R)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1 -(3,4-dimethoxyphenyl)ethyl] 4-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(4-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1R)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(4-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-bromo-5-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 2-[4-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenyl]acetate;
• [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl]2-[4-[(N-[(3R)-quinuclidyl]oxycarbonylanilino)-methyl]phenyl] acetate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 2-[4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl]acetate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(3-chloro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2,3-difluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2,5-difluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(3-methyl-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[N-[(3R)-quinuclidin-3-yl]oxycarbonyl-3-(trifluoromethyl)anilino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-methyl-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(3-cyano-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-methoxyphenyl]ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-isopropoxyphenyl]ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-ethoxyphenyl]ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-methoxyphenyl]ethyl] 3-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-isopropoxyphenyl]ethyl] 3-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-ethoxyphenyl]ethyl] 3-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-methoxyphenyl]ethyl] 4-[(2-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-isopropoxyphenyl]ethyl] 4-[(2-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-ethoxyphenyl]ethyl] 4-[(2-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2,3-difluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2,4-difluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2,5-difluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(3-methyl-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(3-cyano-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 2-fluoro-4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1 -ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 2-fluoro-4-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-fluoro-5-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-fluoro-4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-(trideuteriomethoxy)phenyl]ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate ;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-(trideuteriomethoxy)phenyl]ethyl] 3-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-(trideuteriomethoxy)phenyl]ethyl] 4-[(2-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl]4-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-1-[3-(cyclopentoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-1-[3-(cyclopentoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[4-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[4-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoate;
• [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-isopropoxyphenyl]ethyl] 4-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-(trideuteriomethoxy)phenyl]ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-methoxyphenyl]ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-ethoxyphenyl]ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-isopropoxyphenyl]ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 2-fluoro-5-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[2-(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)ethyl]benzoate;
• [2-(3,5-dichloro-4-pyridyl)-1-(3,4-dimethoxyphenyl)ethyl]4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [2-(3,5-dichloro-4-pyridyl)-1-(3,4-dimethoxyphenyl)ethyl]3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-5-methyl-benzoate;
• [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 2-[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]-phenyl]acetate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 2-[3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl]acetate;
• [(1R)-1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1R)-1-[3,4-bis(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-1-[3,4-bis(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1R)-1-[3,4-bis(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-1-[3,4-bis(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1R)-1-[3-(cyclopentoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-1-[3-(cyclopentoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1R)-1-[3-(cyclopentoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1R)-1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1R)-1-[3-(cyclopentoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-1-[3-(cyclopentoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-1-[3-(cyclopentoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1R)-1-[3-(cyclopentoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[3 -pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]-benzoate;
• [(1R)-1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]-benzoate;
• [(1S)-1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]-benzoate;
• [(1R)-1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-chloro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2,4-difluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-fluoro-3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-fluoro-3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1 -oxido-pyridin-1 -ium-4-yl)-1 -(3,4-dimethoxyphenyl)ethyl] 4-[(2-fluoro-4-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[2-(difluoromethoxy)-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-fluoro-6-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(3-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[(5-fluoro-3-pyridyl)-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[(4-fluoro-2-pyridyl)-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[3-(dimethylcarbamoyl)-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[(2-methoxy-3 -pyridyl)- [(3 R)-quinuclidin-3 -yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[(5-methoxy-3 -pyridyl)- [(3 R)-quinuclidin-3 -yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[(6-hydroxy-3-pyridyl)-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-cyano-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-isopropoxyphenyl] ethyl] 4-[[3-pyridyl- [(3R)-quinuclidin-3 -yl] oxycarbonyl-amino]methyl]benzoate;
• [1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [1-[3-(cyclopentoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[[(3R)-quinuclidin-3-yl]oxycarbonyl-thiazol-2-yl-amino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1 -oxido-pyridin-1 -ium-4-yl)-1 -(3,4-dimethoxyphenyl)ethyl] 4-[[1H-indazol-7-yl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[1H-indol-7-yl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(2-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[3-(difluoromethyl)-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(3-fluoro-5-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-methoxy-3-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-methyl-3-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-chloro-5-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-fluoro-5-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(5-hydroxy-2-methyl-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-chloro-3-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-Dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(3-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2,6-difluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-chloro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2,6-difluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-fluoro-4-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(4-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[4-(methanesulfonamido)-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(3-tert-butyl-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-propoxyphenyl]ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-propoxyphenyl]ethyl] 4-[(3-pyridyl-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[3-(methanesulfonamido)-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[4-(methanesulfonamido)-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[2-(cyclopropylmethoxy)-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-fluoro-6-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[3-(hydroxymethyl)-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino]methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-carbamoyl-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2,3-dihydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[[(3R)-quinuclidin-3-yl]oxycarbonyl-(1H-tetrazol-5-yl)amino]methyl]benzoate;
• [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
• [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-benzoate;
• [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 2-hydroxy-3-[(2-hydroxy-N-[(3R)-quinuclidin-3-yl] oxycarbonyl-anilino)methyl]benzoate

and pharmaceutically acceptable salts and solvates thereof.

In one aspect of the present invention, processes for the preparation of compounds of the invention are provided.

Compounds of formula (I) can be obtained according to general synthetic routes reported in Scheme A or Scheme B or following the procedures of Scheme A and Scheme B starting from slightly modified reagents, easily identifiable by the skilled person and/or following slightly modified procedures that the skilled person can easily apply.

In Scheme A reference is made to specific synthetic schemes (S1/A to S7/A), and in Scheme B reference is made to specific synthetic schemes (S1/B to S3/B) which are better detailed in the following paragraphs.

Processes which can be used and are described in Scheme A should not be viewed as limiting the scope of the synthetic methods available for the preparation of the compounds of the invention.

In the following Schemes, for compounds of formula (II) to (XIII), unless otherwise indicated, groups R₁, R₂, R₃, R₄, R₅, A, m, n and k have the same meanings as described for compounds of formula (I) above.

Compounds of formula (Ie), i.e. compounds of formula (I) which are in the form of N-oxide on the pyridine ring and wherein L1 is absent (i.e. L₁ is (CH₂)_t and t is 0) and L₂ is CH₂, may be prepared according to Scheme S1/A (S1/A) below reported by reaction of a compound of formula (III) with an appropriate compound of formula (II) as below reported.

Typical reaction conditions comprise reacting a compound of formula (III) with a compound of formula (II) in a suitable solvent, such as DMF, in the presence of a coupling agent, such as EDC/DMAP or HATU, at an appropriate temperature such as room (or ambient) temperature or 40°C.

Compounds of formula (III) may be prepared according to Scheme 2/A (S2/A) below by reaction of a compound of formula (IV) as below reported.

Typical reaction conditions comprise hydrolysis of a compound of formula (IV) in a suitable solvent mixture, such as THF/MeOH/water, in the presence of a suitable base, e.g. lithium hydroxide, at an appropriate temperature such as room temperature or 40°C.

Compounds of formula (IV) may be prepared according to Scheme 3/A(S3/A) below by reaction of a compound of formula (VIII) with an appropriate compound of formula (V) as below reported.

Typical reaction conditions comprise reacting a compound of formula (VIII) with a compound of formula (V) in a suitable solvent, such as THF or pyridine, in the presence of a base, such as LHMDS or pyridine, and an optional catalyst, such as DMAP, at an appropriate temperature such as room (or ambient) temperature or 0°C or 40°C or 50°C.

Compounds of formula (VIII) may be prepared according to Scheme 4/A (S4/A) by reaction of a compound of formula (X) with an appropriate compound of formula (IX) as below reported.

Typical reaction conditions comprise reacting a compound of formula (X) with a compound of formula (IX) in a suitable solvent, such as DCM, in the presence of an acid, such as acetic acid, under reducing conditions, for example with sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or by catalytic hydrogenation, and an optional catalyst, such as DMAP, at an appropriate temperature such as room (or ambient) temperature or 0°C or 40°C or 50°C.

Compounds of formula (II) may be prepared according to Scheme 5 (S5) by reaction of a compound of formula (XI) as below reported.

Typical reaction conditions comprise reacting a compound of formula (XI) with a suitable oxidizing agent, such as mCPBA or hydrogen peroxide or perbenzoic acid or peracetic acid, in a suitable solvent, such as DCM or chloroform, at an appropriate temperature, such as room (or ambient) temperature.

Compounds of formula (XI) may be prepared according to Scheme 6 (S6) by reaction of a compound of formula (XIII) with an appropriate compound of formula (XII) as below reported.

Typical reaction conditions comprise reacting a compound of formula (XIII) with a compound of formula (XII) in a suitable solvent, such as THF or other aprotic solvents, in the presence of a base, such as LHMDS or a similar strong base, at an appropriate temperature, such as -78°C.

Compounds of formula (V) may be prepared according to Scheme 7 (S7) by reaction of a compound of formula (VI) with a compound of formula (VII) as below reported.

Typical reaction conditions comprise reacting a compound of formula (VI) with a compound of formula (VII) in a suitable solvent, such as MeCN, at an appropriate temperature, such as 0°C.

Processes which can be used and are described in Scheme B should not be viewed as limiting the scope of the synthetic methods available for the preparation of the compounds of the invention.

In the following Schemes, for compounds of formula (II), (V), (IX), (XV), (XVI), (XVII), unless otherwise indicated, groups R₁, R₂, R₃, R₄, R₅, A, m, n and k have the same meanings as described for compounds of formula (I) above.

Compounds of formula (Ie), i.e. compounds of formula (I) which are in the form of N-oxide on the pyridine ring and wherein L₁ is absent (i.e. L₁ is (CH₂)_t and t is 0) and L₂ is CH₂, may be prepared according to Scheme S1/B (S1/B) below reported by reaction of a compound of formula (XV) with an appropriate compound of formula (V) as below reported.

Typical reaction conditions comprise reacting a compound of formula (XV) with a compound of formula (V) in a suitable solvent, such as THF or pyridine or CH₃CN, at high temperatures, typically between 70°C and 150°C.

Compounds of formula (XV) may be prepared according to Scheme 2/B(S2/B) by reaction of a compound of formula (XVI) with an appropriate compound of formula (IX) as below reported.

Typical reaction conditions comprise reacting a compound of formula (XVI) with a compound of formula (IX) in a suitable solvent, such as an alcoholic solvent or DCM or THF, in the presence of an acid, such as acetic acid, under reducing conditions, for example with sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or by catalytic hydrogenation, and an optional catalyst, such as DMAP, at an appropriate temperature such as room (or ambient) temperature or 0°C or 40°C or 50°C.

Compounds of formula (XVI) may be prepared according to Scheme 3/B(S3/B) below by reaction of a compound of formula (XVII) with a compound of formula (II) as below reported.

Typical reaction conditions comprise reacting a compound of formula (XVIII) with a compound of formula (II) in a suitable solvent, such as DMF, in the presence of a coupling agent, such as EDC/DMAP or HATU, at an appropriate temperature such as room (or ambient) temperature or 40°C.

The processes described are particularly advantageous as they are susceptible of being properly modulated, through any proper variant known to the skilled person, so as to obtain any of the desired compounds of the invention. Such variants are comprised within the scope of the present invention.

From all of the above, it should be clear to the skilled person that any of the described groups may be present as such or in any properly protected form.

In particular, functional groups present in the compounds of formula (II), to (XVII) and which could generate unwanted side reaction and by-products, need to be properly protected before the alkylation, acylation, coupling, oxidation or sulfonylation takes place. Likewise, subsequent deprotection of those same protected groups may follow upon completion of the said reactions.

In the present invention, unless otherwise indicated, the term "protecting group" designates a protective group adapted to preserve the function of the group it is bound to. Typically, protective groups are used to preserve amino, hydroxy, or carboxyl functions. Appropriate protecting groups may thus include, for example, benzyl, benzyloxycarbonyl, t-butoxycarbonyl, alkyl or benzyl esters or the like, which are well known to those skilled in the art [see, for a general reference, T.W. Green; Protective Groups in Organic Synthesis (Wiley, N.Y. 1999)].

Likewise, selective protection and deprotection of any of the said groups, for instance including carbonyl, hydroxy or amino groups, may be accomplished according to very well known methods commonly employed in organic synthetic chemistry.

The N-oxides on the 4-pyridinyl ring of the compounds of general formula (I) and embodiments thereof may be prepared according to methods available in the literature and well known to the skilled person. For instance they may be prepared by dissolving the compound of general formula (I) or embodiments thereof in CH₂Cl₂ or CHCl₃, then adding an oxidizing agent such as m-chloro perbenzoic acid (mCPBA) to the resulting solution. Other oxidizing agents which may be used are hydrogen peroxide, perbenzoic acid and peracetic acid.

Alternatively, in particular for those compounds comprising functional groups sensitive to oxidation, the corresponding N-oxides are prepared by carrying out the oxidation step before further functional groups are introduced, for example on compounds of formula (IX) as above reported.

In a preferred embodiment, the process for preparation of compounds of formula (I) or embodiments thereof is performed starting from N-oxide on the pyridine ring of compound of formula (II), thus allowing the preparation of compound of formula (I) or embodiments thereof in the form of N-oxides on the pyridine ring.

Optional salification of the compounds of formula (I) or N-oxides on the pyridine ring thereof may be carried out by properly converting any of the free acidic or amino groups into the corresponding pharmaceutically acceptable salts. In this case too, the operative conditions being employed for the optional salification of the compounds of the invention are all within the ordinary knowledge of the skilled person.

From all of the above, it should be clear to the skilled person that the above process, comprehensive of any variant thereof for the preparation of suitable compounds of the invention, may be conveniently modified so that to adapt the reaction conditions to the specific needs, for instance by choosing appropriate condensing agents, solvents and protective groups, as the case may be.

With an analogous synthetic approach to that reported above in Scheme 1 the following compounds may be obtained:

The present invention also provides pharmaceutical compositions of compounds of the invention in admixture with one or more pharmaceutically acceptable carriers, for example those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.

Administration of the compounds of the present invention may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and by ocular administration. Various solid oral dosage forms may be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The compounds of the present invention may be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.

Various liquid oral dosage forms may also be used for administering compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms can also contain suitable inert diluents known in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention. The compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.

Suppositories for rectal administration of the compounds of the present invention may be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.

Formulations for vaginal administration may be in the form of cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such suitable carriers as are known in the art.

For topical administration the pharmaceutical composition may be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches.

For the treatment of the diseases of the respiratory tract, the compounds according to the invention are preferably administered by inhalation.

Inhalable preparations include inhalable powders, propellant-containing metered aerosols or propellant-free inhalable formulations and may be administered through a suitable inhalation device which may be respectively selected from dry powder inhaler, pressurized metered dosed inhaler, or a nebulizer.

For administration as a dry powder, single- or multi-dose inhalers known from the prior art may be utilized. In that case the powder may be filled in gelatine, plastic or other capsules, cartridges or blister packs or in a reservoir.

A diluent or carrier, generally non-toxic and chemically inert to the compounds of the invention, e.g. lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention.

Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form. The propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.

The propellant-free inhalable formulations comprising the compounds of the invention may be in form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers such as Respimat®.

The compounds of the invention may be administered as the sole active agent or in combination with other pharmaceutical active ingredients including those currently used in the treatment of respiratory disorders, e.g. beta2-agonists, antimuscarinic agents, corticosteroids, mitogen-activated protein kinases (P38 MAP kinase) inhibitors, nuclear factor kappa-B kinase subunit beta (IKK2) inhibitors, human neutrophil elastase (HNE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, leukotriene modulators, non-steroidal anti-inflammatory agents (NSAIDs) and mucus regulators.

The present invention also provides combinations of a compound of the invention, with a β2-agonist selected from the group consisting of carmoterol, vilanterol (GSK-642444), indacaterol, milveterol, arformoterol, formoterol, salbutamol, levalbuterol, terbutaline, AZD-3199, olodaterol (BI-1744-CL), abediterol (LAS-100977), bambuterol, isoproterenol, procaterol, clenbuterol, reproterol, fenoterol and ASF-1020 and salts thereof.

The present invention also provides combinations of a compound of the invention, with a corticosteroid selected from the group consisting of fluticasone propionate, fluticasone furoate, mometasone furoate, beclometasone dipropionate, ciclesonide, budesonide, GSK 685698, GSK 870086.

The present invention also provides combinations of a compound of the invention, with an antimuscarinic agent selected from the group consisting of aclidinium, tiotropium, ipratropium, trospium, glycopyrronium and oxitropium salts.

The present invention also provides combinations of a compound of the invention, with a PDE4 inhibitor selected from the group consisting of AN-2728, AN-2898, CBS-3595, apremilast, ELB-353, KF-66490, K-34, LAS-37779, IBFB-211913, AWD-12-281, cipamfylline, cilomilast, roflumilast, BAY19-8004 and SCH-351591, AN-6415, indus-82010, TPI-PD3, ELB-353, CC-11050, GSK-256066, oglemilast, OX-914, tetomilast, MEM-1414 and RPL-554.

The present invention also provides combinations of a compound of the invention, with a P38 MAP kinase inhibitor selected from the group consisting of semapimod, talmapimod, pirfenidone, PH-797804, GSK-725, minokine and losmapimod and salts thereof.

In a preferred embodiment, the present invention provides combinations of a compound of the invention with an IKK2 inhibitor.

The invention also provides combinations of a compound of the invention with a HNE inhibitor selected from the group consisting of AAT, ADC-7828, Aeriva, TAPI, AE-3763, KRP-109, AX-9657, POL-6014, AER-002, AGTC-0106, respriva, AZD-9668, zemaira, AAT IV, PGX-100, elafin, SPHD-400, prolastin C and prolastin inhaled.

The invention also provides combinations of a compound of the invention with a leukotriene modulator selected from the group consisting of montelukast, zafirlukast and pranlukast.

The invention also provides combinations of a compound of the invention with a NSAID selected from the group consisting of ibuprofen and ketoprofen.

The invention also provides combinations of a compound of the invention with a mucus regulator selected from the group consisting of INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-333, MSI-1956 and gefitinib.

The dosages of the compounds of the present invention depend upon a variety of factors including the particular disease to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, and pharmacokinetic profile of the compound.

Advantageously, the compounds of the invention may be administered for example, at a dosage comprised between 0.001 and 1000 mg/day, preferably between 0.1 and 500 mg/day.

When they are administered by inhalation route, the dosage of the compounds of the invention is advantageously comprised between 0.01 and 20 mg/day, preferably between 0.1 and 10 mg/day.

Preferably, the compounds of the invention alone or combined with other active ingredients may be administered for the prevention and/or treatment of any obstructive respiratory disease such as asthma, chronic bronchitis and chronic obstructive pulmonary disease (COPD).

However the compounds of the invention may be administered for the prevention and/or treatment of any disease wherein PDE4 inhibition or M3 antagonism is required. Said disease include: allergic disease states such as atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, cystic fibrosis, arterial restenosis, artherosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, systemic lupus erythematosus, follicular and wide-area pyodermias, endogenous and exogenous acne, acne rosacea, Behçet's disease, anaphylactoid purpura nephritis, inflammatory bowel disease, leukemia, multiple sclerosis, gastrointestinal diseases, autoimmune diseases and the like.

They also include neurological and psychiatric disorders such as Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS), multiple systems atrophy (MSA), schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, depression, stroke, and spinal cord injury.

The present invention will now be further described by way of the following nonlimiting examples.

EXAMPLES

Abbreviations

EDC = 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide) hydrochloride; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; EtOAc = Ethyl acetate; RT = room temperature; THF = tetrahydrofuran; DCM = dichloromethane; MeOH = methyl alcohol; EtOH = ethylic alcohol; LHMDS = Lithium bis(trimethylsilyl)amide; m-CPBA = meta-Chloroperoxybenzoic acid; LC-MS = Liquid Chromatography/Mass Spectrometry; HPLC = high pressure liquid chromatography; MPLC = medium pressure liquid chromatography; SFC = Supercritical Fluid Chromatography; HATU = (Dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate.

General Experimental details

Analytical Methods

Liquid Chromatography-Mass Spectrometry

Method 1

LC-MS was performed on a Waters 2795 Alliance HT HPLC with Waters 2996 Diode Array Detector coupled to a Micromass ZQ, single quadrapole mass spectrometer using a Phenomenex Luna C18 (2) column (5 µm, 100 x 4.6 mm plus guard cartridge) with a linear gradient of 5-95% acetonitrile/water (with 0.1% formic acid in each mobile phase) within 3.5 minutes and held at 95% for 2.0 minutes.

Method 2

LC-MS was performed on a Waters 2795 Alliance HT HPLC with Waters 2996 Diode Array Detector coupled to a Micromass ZQ, single quadrapole mass spectrometer using a Waters Xterra MS C18 column (5 µm, 100 x 4.6mm plus guard cartridge) being initially held at 5% acetonitrile/water (with 10mM ammonium bicarbonate in the aqueous mobile phase) for 0.5 minutes, followed by a linear gradient of 5-95% within 3.5 minutes and then held at 95% for 1.5 minutes.

NMR

¹H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker instrument operating at 400 MHz using the stated solvent at around room temperature unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad.

Preparative reverse-phase HPLC conditions

Preparative HPLC - Method 1

• Waters Micromass ZQ/Sample manager 2767
• Photodiode array detector 2996;
• Column: XTerra Prep MS C18 Column (5 µm, 19 x 150 mm, Waters)
• Flow rate: 20 ml/min with MS detection
• UV wavelength: 254 nm.
• Mobile phase: Solvent A (water:MeCN:HCOOH 95:5:0.05); Solvent B (water:MeCN:HCOOH 5:95:0.05)

Time (min)

%A

%B

0.00

100.0

0.00

1.00

100

0.00

10.00

0.00

100.0

11.00

0.00

100.0

12.00

100.0

0.00

The above method, or slightly modifications known to the skilled in the art, were used.

Compound preparation

Where the preparation of starting materials is not described, these are commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. Where it is stated that compounds were prepared "analogously" or "similarly" to earlier examples or intermediates, it will be appreciated by the skilled person that the reaction time, number of equivalents of reagents and temperature can be modified for each specific reaction and that it may be necessary or desirable to employ different work-up or purification techniques.

Flash chromatography refers to silica gel chromatography and is carried out using an Isolera MPLC system (manufactured by Biotage); pre-packed silica gel cartridges (supplied by Biotage); or using conventional glass column chromatography.

In the procedures that follow, after each starting material, reference to a compound number is made is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to.

Many of the Compounds described in the following Examples have been prepared from stereochemically pure starting materials, for example 95% ee.

The stereochemistry of the compounds in the Examples, where indicated, has been assigned on the assumption that absolute configuration at resolved stereogenic centers of staring materials in maintained throughout any subsequent reaction conditions.

Intermediate 1

(R)-Quinuclidin-3-yl carbonochloridate hydrochloride (I-1)

To a stirred solution of (R)-3-quinuclidinol (2.5 g, 19.66 mmol) in acetonitrile (200 mL) was added trichloromethyl chloroformate (3.06 mL, 25.57 mmol) dropwise at 0°C and the mixture was allowed to stir at 0°C for 1 hour. The reaction mixture was then stirred at RT for 16 hours and then the solvent was removed in vacuo to afford the title compound as a white solid (4.39 g, 98%).

¹H NMR (400 MHz, DMSO-d₆): δ 10.29 (s, 1 H), 4.05-3.95 (m, 1 H), 3.43 (t, J = 10.8 Hz, 1 H), 3.12 (m, 3 H), 3.10-2.95 (m, 1 H), 2.79 (d, J = 13.3 Hz, 1 H), 2.12-2.02 (m, 1 H), 1.98 (m, J = 3.4 Hz, 1 H), 1.89-1.78 (m, 1 H), 1.75-1.59 (m, 2 H).

Intermediate 2

Methyl 3-(((4-fluorophenyl)amino)methyl)benzoate (1-2)

To a stirred solution of methyl 3-formylbenzoate (0.5 g, 3.046 mmol) in anhydrous DCM (15 mL) was added 4-fluoroaniline (0.303 mL, 3.198 mmol) followed by glacial acetic acid (0.174 mL, 3.046 mmol). The reaction was stirred at room temperature for 64 hours. Sodium triacetoxyborohydride (1.614 g, 7.615 mmol) was added and the reaction was stirred at room temperature for 2 hours. Water was added to quench the reaction and the mixture was diluted with DCM. The organic layer was washed with brine, passed through a hydrophobic frit and the solvent was removed in vacuo to afford the title compound as a red oil (0.805 g, quantitative yield).

¹H NMR (400 MHz, CDCl₃): δ 8.04 (s, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 7.56 (d, J = 7.7 Hz, 1 H), 7.42 (t, J = 7.7 Hz, 1 H), 6.91-6.82 (m, 2 H), 6.58-6.51 (m, 2 H), 4.35 (s, 2 H), 4.06-3.94 (br s, 1 H), 3.91 (s, 3 H). LCMS (Method 2): [MH+] = 260 at 3.56 min.

The following intermediates were synthesised via a similar method as that described for intermediate 2:

Structure

Intermediate number

Analytical Data

Intermediate 3

¹H NMR (400 MHz, CDCl₃): δ 8.06 (s, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 7.58 (d, J = 7.7 Hz, 1 H), 7.45-7.36 (m, 1 H), 7.20-7.13 (m, 2 H), 6.78-6.65 (m, 1 H), 6.63 (dd, J = 7.5, 1.4 Hz, 2 H), 4.39 (s, 2 H), 4.16 (bs, 1 H), 3.91 (s, 3 H).

Intermediate 4

¹H NMR (400 MHz, CDCl₃): δ 8.06 (s, 1 H), 7.96 (d, J = 7.8 Hz, 1 H), 7.58 (d, J = 7.7 Hz, 1 H), 7.43 (t, J = 7.7 Hz, 1 H), 7.02-6.90 (m, 2 H), 6.67-6.59 (m, 2 H), 4.45-4.41 (m, 2 H), 4.36 (bs, 1 H), 3.92 (s, 3 H).

LCMS (Method 1): [MH+] = 260 at 4.33 min.

Intermediate 5

¹H NMR (400 MHz, CDCl₃): δ 8.06-8.02 (m, 1 H), 7.98-7.93 (m, 1 H), 7.58-7.53 (m, 1 H), 7.42 (t, J = 7.7 Hz, 1 H), 7.12-7.04 (m, 1 H), 6.46-6.35 (m, 2 H), 6.33-6.27 (m, 1 H), 4.37 (s, 2 H), 3.92 (s, 3 H). LCMS (Method 1): [MH+] = 260 at 4.26 min.

Intermediate 6

¹H NMR (400 MHz, CDCl₃): δ 8.06 (s, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.58 (d, J = 7.7 Hz, 1 H), 7.40 (t, J = 7.7 Hz, 1 H), 6.84-6.77 (m, 2 H), 6.75-6.65 (m, 1 H), 6.56-6.52 (m, 1 H), 4.41 (s, 2 H), 3.91 (s, 3 H), 3.86 (s, 3 H).

LCMS (Method 2): [MH+] = 272 at 3.69 min.

Intermediate 7

¹H NMR (400 MHz, CDCl₃): δ 8.05 (s, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.41 (t, J = 7.7 Hz, 1 H), 7.07 (t, J = 8.1 Hz, 1 H), 6.32-6.23 (m, 2 H), 6.18 (t, J = 2.3 Hz, 1 H), 4.37 (s, 2 H), 4.15 (bs, 1 H), 3.91 (s, 3 H), 3.74 (s, 3 H).

LCMS (Method 2): [MH+] = 272 at 3.50 min.

Intermediate 8

¹H NMR (400 MHz, CDCl₃): δ 8.05 (s, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.58 (d, J = 7.7 Hz, 1 H), 7.41 (t, J = 7.7 Hz, 1 H), 6.79-6.74 (m, 2 H), 6.62-6.56 (m, 2 H), 4.34 (s, 2 H), 3.91 (s, 3 H), 3.74 (s, 3 H).

LCMS (Method 2): [MH+] = 272 at 3.40 min.

Intermediate 9

¹H NMR (400 MHz, DMSO): δ 7.95 (d, J = 8.0 Hz, 2 H), 7.52 (d, J = 7.9 Hz, 2 H), 7.10-7.01 (m, 2 H), 6.61-6.50 (m, 3 H), 6.36 (t, J = 7.9 Hz, 1 H), 4.38 (d, J = 8.1 Hz, 2 H), 3.87 (s, 3 H).

LCMS (Method 2): [MH+] = 242 at 4.04 min.

Intermediate 10

Purified by chromatography using EtOAc/isohexane (1:9) as eluent.

¹H NMR (400 MHz, CDCl₃): δ 8.04-7.99 (m, 2 H), 7.44 (d, J = 8.1 Hz, 2 H), 7.02-6.96 (m, 1 H), 6.93 (t, J = 7.9 Hz, 1 H), 6.72-6.61 (m, 1 H), 6.61-6.54 (m, 1 H), 4.45 (s, 2 H), 3.91 (s, 3 H), 3.71 (bs, 1 H).

LCMS (Method 1): [MH+] = 260 at 4.34 min.

Intermediate 11

¹H NMR (400 MHz, CDCl₃): δ 8.05-7.99 (m, 2 H), 7.46-7.40 (m, 2 H), 7.13-7.05 (m, 1 H), 6.45-6.35 (m, 2 H), 6.32-6.25 (m, 1 H), 4.39 (s, 2 H), 3.91 (s, 3 H).

LCMS (Method 2): [MH+] = 260 at 3.60 min.

Intermediate 12

¹H NMR (400 MHz, CDCl₃): δ 8.03-7.99 (m, 2 H), 7.45-7.41 (m, 2 H), 6.91-6.83 (m, 2 H), 6.56-6.49 (m, 2 H), 4.37 (s, 2 H), 4.07 (bs, 1 H), 3.91 (s, 3 H).

LCMS (Method 2): [MH+] = 260 at 3.55 min

Intermediate 13

¹H NMR (400 MHz, CDCl₃): δ 8.02-7.98 (m, 2 H), 7.47-7.42 (m, 2 H), 6.82-6.65 (m, 3 H), 6.51-6.48 (m, 1 H), 4.43 (s, 2 H), 3.91 (s, 3 H), 3.87 (s, 3 H).

LCMS (Method 2): [MH+] = 272 at 3.68 min.

Intermediate 14

¹H NMR (400 MHz, CDCl₃): δ 8.03-7.98 (m, 2 H), 7.46-7.41 (m, 2 H), 7.07 (t, J = 8.1 Hz, 1 H), 6.29 (dd, J = 8.2, 2.3 Hz, 1 H), 6.23 (dd, J = 8.1, 2.2 Hz, 1 H), 6.16 (t, J = 2.3 Hz, 1 H), 4.40 (s, 2 H), 3.91 (s, 3 H), 3.74 (s, 3 H).

Intermediate 15

Purified by chromatography using EtOAc/isohexane (3:7) as eluent.

¹H NMR (400 MHz, CDCl₃): δ 8.03-7.97 (m, 2 H), 7.44 (d, J = 8.1 Hz, 2 H), 6.79-6.74 (m, 2 H), 6.60-6.55 (m, 2 H), 4.36 (s, 2 H), 3.91 (s, 3 H), 3.74 (s, 3 H).

LCMS (Method 2): [MH+] = 272 at 3.40 min.

Intermediate 16

¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, J = 8.1 Hz, 2 H), 7.45 (d, J = 7.9 Hz, 2 H), 7.11-7.01 (m, 2 H), 6.73-6.65 (m, 1 H), 6.51 (d, J = 8.0 Hz, 1 H), 4.46 (s, 2 H), 3.91 (s, 3 H), 2.20 (s, 3 H). LCMS (Method 2): [MH+] = 256 at 3.76 min.

Intermediate 17

(R)-methyl-3-(((4-fluorophenyl)((quinuclidin-3-yloxy)carbonyl)amino)-methyl)benzoate (1-17)

A stirred solution of methyl 3-(((4-fluorophenyl)amino)methyl)benzoate (0.3 g, 1.157 mmol) in anhydrous pyridine (6 mL) at 0°C under N₂ was added with (R)-quinuclidin-3-yl carbonochloridate hydrochloride (0.314 g, 1.39 mmol) in one portion. After stirring at 0°C for 1 hour the reaction was allowed to warm to room temperature. After 25 minutes, further (R)-quinuclidin-3-yl carbonochloridate (0.314 g, 1.39 mmol) was added and the reaction was stirred at room temperature for 18 hours. The reaction was quenched by addition of 10% aqueous potassium carbonate solution and extracted with ethyl acetate (× 3). The combined organic extracts were washed with brine and dried (sodium sulfate), filtered and the solvent was removed in vacuo to afford a red oil. The crude material was purified by silica gel column chromatography eluting sequentially with ethyl acetate, 10% methanol in ethyl acetate, 5% 7N methanolic ammonia in ethyl acetate and 10% 7N methanolic ammonia in ethyl acetate to afford the title compound as a yellow oil (0.471 g, 98%).

¹H NMR (400 MHz, CDCl₃): δ 7.96-7.88 (m, 2 H), 7.46-7.36 (m, 2 H), 7.12-6.94 (m, 4 H), 4.87 (s, 2 H), 4.81-4.75 (m, 1 H), 3.90 (s, 3 H), 3.25-3.16 (m, 1 H), 2.80-2.54 (m, 5 H), 1.99-1.92 (m, 1 H), 1.68-1.32 (m, 4 H).

The following intermediates were synthesised via a similar method as that described for intermediate 17:

Structure

Intermediate number

Precursor

Analytical Data

Intermediate 18

Intermediate 3

¹H NMR (400 MHz, CDCl₃): δ 7.96-7.90 (m, 2 H), 7.46 (d, J = 7.7 Hz, 1 H), 7.38 (t, J = 7.9 Hz, 1 H), 7.30 (t, J = 7.6 Hz, 2 H), 7.21 (t, J = 7.4 Hz, 1 H), 7.14 (bs, 2 H), 4.97-4.86 (m, 2 H), 4.82-4.76 (m, 1 H), 3.90 (s, 3 H), 3.19 (ddd, J = 14.7, 8.2, 2.2 Hz, 1 H), 2.78-2.52 (m, 5 H), 1.96 (bs, 1 H), 1.67-1.58 (m, 1 H), 1.56-1.46 (m, 1 H), 1.45-1.35 (m, 1 H), 1.29-1.16 (m, 1 H).

Intermediate 19

Intermediate 5

¹H NMR (400 MHz, CDCl₃): δ 7.97-7.90 (m, 2 H), 7.47-7.37 (m, 2 H), 7.29-7.22 (m, 1 H), 6.98-6.88 (m, 3 H), 4.97-4.87 (m, 2 H), 4.83-4.77 (m, 1 H), 3.90 (s, 3 H), 3.25-3.17 (m, 1 H), 2.81-2.54 (m, 5 H), 2.00-1.95 (m, 1 H), 1.69-1.47 (m, 2 H), 1.46-1.36 (m, 1 H), 1.30-1.20 (m, 1 H).

Intermediate 20

Intermediate 7

¹H NMR (400 MHz, CDCl₃): δ 7.95-7.91 (m, 2 H), 7.49-7.44 (m, 1 H), 7.41-7.36 (m, 1 H), 7.20 (t, J = 8.1 Hz, 1 H), 6.78-6.67 (m, 3 H), 4.95-4.85 (m, 2 H), 4.82-4.76 (m, 1 H), 3.90 (s, 3 H), 3.74 (s, 3 H), 3.24-3.16 (m, 1 H), 2.82-2.55 (m, 5 H), 1.99-1.93 (m, 1 H), 1.67-1.37 (m, 3 H), 1.29-1.19 (m, 1 H).

Intermediate 21

Intermediate 8

¹H NMR (400 MHz, CDCl₃): δ 7.96-7.88 (m, 2 H), 7.48-7.42 (m, 1 H), 7.38 (t, J = 7.7 Hz, 1 H), 7.10-6.90 (m, 2 H), 6.88-6.75 (m, 2 H), 4.91-4.81 (m, 2 H), 4.80-4.74 (m, 1 H), 3.90 (s, 3 H), 3.78 (s, 3 H), 3.25-3.13 (m, 1 H), 2.78-2.53 (m, 5 H), 2.00-1.92 (m, 1 H), 1.69-1.33 (m, 3 H), 1.30-1.17 (m, 1 H).

Intermediate 22

Intermediate 9

¹H NMR (400MHz, MeOD): δ 8.00 (d, J = 8.0 Hz, 2 H), 7.43-7.34 (m, 4 H), 7.30-7.20 (m, 3 H), 5.00 (s, 2 H), 4.85-4.80 (m, 1 H), 3.92 (s, 3 H), 3.21 (ddd, J = 14.7, 8.2, 2.4 Hz, 1 H), 2.82-2.66 (m, 3 H), 2.61 (dt, J = 14.7, 2.3 Hz, 1 H), 2.61-2.48 (m, 1 H), 2.00-1.95 (m, 1 H), 1.78-1.68 (m, 1 H), 1.66-1.56 (m, 1 H), 1.52-1.41 (m, 1 H), 1.40-1.29 (m, 1 H). LCMS (Method 2): [MH+] = 395 at 3.57 min.

Intermediate 23

Intermediate 10

¹H NMR (400 MHz, CDCl₃): δ 7.96 (d, J = 7.8 Hz, 2 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.28-7.19 (m, 1 H), 7.15-6.95 (m, 3 H), 4.89-4.74 (m, 3 H), 3.90 (s, 3 H), 3.23-3.14 (m, 1 H), 2.80-2.52 (m, 5 H), 1.96-1.83 (m, 1 H), 1.76-1.35 (m, 3 H), 1.30-1.13 (m, 1 H).

Intermediate 24

Intermediate 11

¹H NMR (400 MHz, CDCl₃): δ 7.99 (d, J = 8.1 Hz, 2 H), 7.34-7.22 (m, 3 H), 6.99-6.88 (m, 3 H), 4.98-4.87 (m, 2 H), 4.82-4.77 (m, 1 H), 3.91 (s, 3 H), 3.24-3.16 (m, 1 H), 2.79-2.50 (m, 5 H), 1.98-1.93 (m, 1 H), 1.68-1.57 (m, 1 H), 1.56-1.46 (m, 1 H), 1.44-1.33 (m, 1 H), 1.29-1.19 (m, 1 H).

Intermediate 25

Intermediate 12

¹H NMR (400 MHz, CDCl₃): δ 7.98 (d, J = 8.0 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.12-6.94 (m, 4 H), 4.93-4.82 (m, 2 H), 4.81-4.75 (m, 1 H), 3.91 (s, 3 H), 3.23-3.15 (m, 1 H), 2.82-2.51 (m, 5 H), 1.97-1.91 (m, 1 H), 1.68-1.19 (m, 4 H).

Intermediate 26

Intermediate 14

¹H NMR (400 MHz, CDCl₃): δ 7.98 (d, J = 8.1 Hz, 2 H), 7.33 (d, J = 8.1 Hz, 2 H), 7.20 (t, J = 8.1 Hz, 1 H), 6.78-6.66 (m, 3 H), 4.96-4.85 (m, 2 H), 4.81-4.75 (m, 1 H), 3.91 (s, 3 H), 3.73 (s, 3 H), 3.23-3.15 (m, 1 H), 2.82-2.52 (m, 5 H), 1.98-1.92 (m, 1 H), 1.68-1.35 (m, 3 H), 1.29-1.18 (m, 1 H). LCMS (Method 2): [MH+] = 425 at 3.62 min.

Intermediate 27

Intermediate 15

¹H NMR (400 MHz, CDCl₃): δ 7.97 (d, J = 7.8 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 6.95 (bs, 2 H), 6.80 (d, J = 8.2 Hz, 2 H), 4.85 (bs, 2 H), 4.77 (bs, 1 H), 3.91 (s, 3 H), 3.78 (s, 3 H), 3.18 (dd, J = 14.6, 8.2 Hz, 1 H), 2.74-2.66 (m, 3 H), 2.65-2.53 (m, 2 H), 1.94 (bs, 1 H), 1.67-1.57 (m, 1 H), 1.56-1.45 (m, 1 H), 1.45-1.30 (m, 1 H), 1.29-1.15 (m, 1 H).

Intermediate 28

(R)-methyl 3-(((2-fluorophenyl)((quinuclidin-3-yloxy)carbonyl)amino)-methyl)benzoate (1-28)

A stirred solution of methyl 3-(((2-fluorophenyl)amino)methyl)benzoate (0.3 g, 1.157 mmol) in anhydrous pyridine (6 mL) at 0°C under N₂ was added with 4-(dimethylamino)pyridine (0.014 g, 0.116 mmol) followed by (R)-quinuclidin-3-yl carbonochloridate hydrochloride (0.314 g, 1.39 mmol) in one portion. After stirring at 0°C for 1 hour the reaction was allowed to warm to room temperature. After 2.5 hours, further (R)-quinuclidin-3-yl carbonochloridate (0.628 g, 2.777 mmol) was added and the reaction was stirred at room temperature for 65 hours. The reaction was quenched by addition of 10% aqueous potassium carbonate solution and extracted with ethyl acetate (× 3). The combined organic extracts were washed with brine and dried (sodium sulfate), filtered and the solvent was removed in vacuo to afford a brown oil. The crude material was purified by silica gel column chromatography eluting sequentially with ethyl acetate, 5% methanol in ethyl acetate, 5% 7N methanolic ammonia in ethyl acetate and 10% 7N methanolic ammonia in ethyl acetate to afford the title compound as a yellow oil (0.349 g, 73%).

¹H NMR (400 MHz, CDCl₃): δ 7.97-7.86 (m, 2 H), 7.53-7.45 (m, 1 H), 7.37 (t, J = 7.7 Hz, 1 H), 7.27-7.19 (m, 1 H), 7.16-6.96 (m, 3 H), 4.90-4.74 (m, 3 H), 3.89 (s, 3 H), 3.24-3.14 (m, 1 H), 2.84-2.53 (m, 5 H), 1.96-1.83 (m, 1 H), 1.66-1.36 (m, 3 H), 1.33-1.13 (m, 1 H).

The following intermediates were synthesised via a similar method as that described for intermediate 28:

Structure

Intermediate number

Precursor

Analytical Data

Intermediate 29

Intermediate 6

¹H NMR (400 MHz, CDCl₃): δ 7.94-7.88 (m, 2 H), 7.52-7.42 (m, 1 H), 7.39-7.31 (m, 1 H), 7.28-7.17 (m, 1 H), 6.94-6.78 (m, 3 H), 5.12-4.45 (m, 3 H), 3.89 (s, 3 H), 3.83-3.69 (m, 3 H), 3.21-3.09 (m, 1 H), 2.83-2.43 (m, 5 H), 1.95-1.79 (m, 1 H), 1.76-1.36 (m, 3 H), 1.21-1.06 (m, 1 H).

Intermediate 30

Intermediate 13

¹H NMR (400 MHz, CDCl₃): δ 7.94 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.25-7.18 (m, 1 H), 6.93-6.78 (m, 3 H), 5.13-4.41 (m, 3 H), 3.90 (s, 3 H), 3.84-3.69 (m, 3 H), 3.21-3.09 (m, 1 H), 2.85-2.43 (m, 5 H), 1.93-1.80 (m, 1 H), 1.66-1.37 (m, 3 H), 1.28-1.06 (m, 1 H).

Intermediate 31

Intermediate 16

¹H NMR (400 MHz, CDCl₃): δ 7.96 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 7.9 Hz, 2 H), 7.23-7.14 (m, 2 H), 7.13-7.04 (m, 1 H), 6.82 (dd, J = 13.5, 7.8 Hz, 1 H), 5.01 (d, J = 14.6 Hz, 1 H), 4.79-4.70 (m, 1 H), 4.53 (d, J = 14.7 Hz, 1 H), 3.93-3.88 (m, 3 H), 3.29-3.10 (m, 1 H), 2.95-2.40 (m, 5 H), 2.15-1.99 (m, 3 H), 1.90-1.81 (m, 1 H), 1.75-1.45 (m, 2 H), 1.21-1.07 (s, 2 H).

Intermediate 32/A (I-32/A)

(S)-3,5-Dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide

Step 1: Preparation of (R,S)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (I-32/Aa)

3,5-Dichloro-4-methylpyridine (54 g, 331 mmol) was dissolved in dry THF (480 mL) under Argon atmosphere and cooled at -78°C in dry-ice/acetone bath. LHMDS IN THF solution (331 mL, 331 mmol) was added drop-wise keeping the temperature at -78°. The mixture was stirred at -78° for 1 h. Thereafter, a solution of 3,4-dimethoxybenzaldehyde (50 g, 301 mmol) in dry THF (120 mL) was added drop-wise keeping the temperature at -78°C. When the addition was completed, the mixture was allowed to warm at RT.

The reaction was poured into ice and water (1L) and the mixture was stirred until a copious precipitate formed. The solid was filtered, and dissolved in Ethyl Acetate (500 mL), dried over Na₂SO₄ and the solvent evaporated under vacuum. The crude was crystallized in CHCl₃/Hexane. The precipitate was filtered, washed with hexane and dried under vacuum at 40°C for 8 h to give 55 g of the title compound (45% yield). The mother liquor solution was evaporated under vacuum at 40°C, dissolved in ethyl acetate (200 mL) and extracted with 200 mL of water. The organic solution was dried over Na₂SO₄ and the solvent evaporated under vacuum at 40°C. The crude was crystallized in CHCl₃/Hexane, and additional 15 g of the title product were obtained (70% overall yield).

Step 2: Preparation of (R,S)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethyl) (R)-2-(6-methoxynaphthalen-2-yl)propanoate (I-32/Ab)

(R,S)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (50 g, 152 mmol), (R)-2-(6-methoxynaphthalen-2-yl)propanoic acid (38.6 g, 168 mmol), DMAP (20.5 g, 168 mmol) and EDC (43.8 g, 229 mmol) were dissolved in DMF (300 mL) and the reaction mixture was stirred at RT for 2 h. Thereafter, water (500 mL) was added, and the solution stirred till complete precipitation occurs. The solid was filtered and dissolved in DCM (500 mL). The organic solution was washed with aqueous HCl 1N (2x500 mL), saturated aqueous NaHCO₃ solution (500 mL) and dried over Na₂SO₄. The solvent was evaporated under vacuum and the solid residue sonicated in EtOH (300 mL) and triturated for 1 h. The resulting precipitate was collected by filtration and dried under vacuum at 40°C for 4 h to give 79 g (99% yield) of the title compound, as diastereoisomeric mixture.

Step 3: Preparation of (S)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethyl) (R)-(2-(6-methoxynaphthalen-2-yl)propanoate (I-32/Ac)

(R,S)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethyl) (R)-(6-methoxynaphthalen-2-yl)propanoate (diastereoisomeric mixture, 79 g, 146 mmol) was dissolved in CHCl₃ (100 mL) and MeOH (30 mL) was slowly added up to persistent opalescence and the mixture left at RT for 2 h. The solid formed was collected by filtration and re-crystallized by CHCl₃/MeOH (70 mL/20 mL) solvent system to obtain 35 g of the desired compound (yield 88%, ee 98%). Chiral HPLC analysis: Chiralcel OD column, 10 µm, 250 x 4.6 mm; Flow= 0.8 ml/min; eluent= hexane:isopropanol 97/3; Rt= 42.33 min; ¹H NMR (600 MHz, chloroform-d) δ ppm 8.04 (s, 2 H), 7.67 (d, J=8.79 Hz, 1 H), 7.58 (d, J=8.52 Hz, 1 H), 7.53 (m, 1 H), 7.12 - 7.20 (m, 3 H), 6.95 (dd, J=8.24, 1.92 Hz, 1 H), 6.78 - 6.88 (m, 2 H), 6.14 (dd, J=10.44, 4.12 Hz, 1 H), 3.95 (s, 3 H), 3.88 (s, 3 H), 3.78 - 3.81 (m, 4 H), 3.55 (dd, J=13.73, 10.44 Hz, 1 H), 3.14 (dd, J=13.60, 4.26 Hz, 1 H), 1.44 (d, J=7.14 Hz, 3 H).

Step 4: Preparation of (S)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethanol, (I-32/Ad)

(S)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethyl) (R)-2-(6-methoxynaphthalen-2-yl)propanoate (30 g, 56 mmol) was dissolved in MeOH, and toluene was slowly added. Potassium tert-butoxide was slowly added to the suspension. The mixture was stirred for 24 h at RT. The reaction was diluted with water (500 mL) and the aqueous mixture was extracted with CHCl₃ (500 mL). The organic layer was dried over Na₂SO₄ and the solvent was evaporated under vacuum. The residue was crystallized from CHCl₃ (100 mL) and Hexane (20 mL). The mother liquor was concentrated and recrystallized with an analogous procedure giving a second crop of desired compound. In total, 16 g of the title compound (87% yield) were obtained. Chiral HPLC analysis; Chiralcel OD column, 10 µm, 250 x 4.6 mm; flow= 0.8 ml/min; eluent= hexane:isopropanol 95/5; Rt= 58.03 min; ${\left[\alpha \right]}_D^{20}=+10.21\mathrm{}\left(\mathrm{c}=\mathrm{0.506,}\mathrm{Methanol}\right);$ ¹H NMR (400 MHz, acetone) δ ppm 8.47 (s, 2 H), 6.96 - 7.15 (m, 1 H), 6.87 (m, 2 H), 4.93 - 5.21 (m, 1 H), 4.50 (d, J=3.97 Hz, 1 H), 3.78 (s, 6 H), 3.44 (dd, J=12.79, 8.38 Hz, 1 H), 3.22 (dd, J=13.01, 5.51 Hz, 1 H). MS/ESI⁺ [MH]⁺: 328.19

Step 5: Preparation of (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (I-32/A)

(S)-2-(3,5-Dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (4 g, 12 mmol) was dissolved in Ethyl Acetate, and m-CPBA was added to the solution. The mixture was stirred at RT for 5 h. The formed solid was collected by filtration, washed with ethyl acetate and dried under vacuum to give 1.72 g of (S)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (41% yield). Chiral HPLC analysis: Chiralcel OD column, 10 µm, 250 x 4.6 mm; Flow= 0.8 ml/min; eluent= hexane:isopropanol 60/40; Rt= 22.16 min; ${\left[\alpha \right]}_D^{20}=+68.91\mathrm{}\left(\mathrm{c}=\mathrm{0.253,}\mathrm{Methanol}/\mathrm{CHCl}3\mathrm{}1:1\right);$ 1H NMR (400 MHz, chloroform-d) δ ppm 8.15 (s, 2 H), 6.99 (m, 1 H), 6.79 - 6.88 (m, 2 H), 5.03 (dd, J=8.50, 5.32 Hz, 1 H), 3.75 - 3.98 (m, 6 H), 3.42 (dd, J=13.57, 8.56 Hz, 1 H), 3.19 (dd, J=13.51, 5.32 Hz, 1 H), 2.06 - 2.15 (m, 1 H); MS/ESI⁺ [MH]⁺: 344

Intermediates I-32/B, I-32/C, I-32/D, I-32/E, I-32/F

The racemic alcohol intermediates reported in table below are described in patent application WO2009/018909 or may be obtained following the above procedure (only step 1 followed by step 5) substituting 3,4-dimethoxybenzaldehyde with the suitable 3,4-dialkoxybenzaldehyde:

Structure

Name

Intermediate

Analytical data

(R,S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)-pyridine 1-oxide

I-32/B

¹H NMR (400 MHz, (CDCl₃) δ ppm 8.15 (s, 2 H), 6.99 (m, 1 H), 6.79 - 6.88 (m, 2 H), 5.03 (dd, J=8.50, 5.32 Hz, 1 H), 3.75 - 3.98 (m, 6 H), 3.42 (dd, J=13.57, 8.56 Hz, 1 H), 3.19 (dd, J=13.51, 5.32 Hz, 1 H), 2.06 - 2.15 (m, 1 H); MS/ESI+ [MH]⁺: 344

(R,S)-3,5-dichloro-4-(2-(3-ethoxy-4-methoxyphenyl)-2-hydroxyethyl)-pyridine 1-oxide

I-/32/C

MS/ESI+ [MH]⁺:358

(R,S)-3,5-dichloro-4-(2-(3-cyclopropyl-methoxy-4-methoxyphenyl)-2-hydroxyethyl)-pyridine 1-oxide

I/32D

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 6.97 (s, 1 H), 6.83-6.81 (m, 2 H), 5.00-4.97 (m, 1 H), 3.87-3.84 (m, 5 H), 3.41-3.13 (m, 1 H), 3.18-3.13 (m, 1 H), 2.13-2.11 (br s, 1 H), 1.35-1.31 (m, 1 H), 0.68-0.63 (m, 2 H), 0.37-0.35 (m, 2 H).

LCMS (Method 1): [MH+]= 384 at 3.21 min.

(R,S)-3,5-dichloro-4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-hydroxyethyl)-pyridine 1-oxide

I/32E

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 6.94 (s, 1 H), 6.82-6.81 (m , 2 H), 5.01-4.80 (m, 1 H), 4.79-4.76 (m, 1 H), 3.42 (s, 3 H), 3.41-3.36 (m, 1 H), 3.19-3.14 (m, 1 H), 1.95-1.79 (m, 6 H), 1.65-1.57 (m, 3 H).

LCMS (Method 2): [MH+]= 398 at 3.13 min.

(R,S)-4-(2-(3,4-bis(difluoro-methoxy)phenyl)-2-hydroxyethyl)-3,5-dichloropyridine 1-oxide

I/32F

¹H NMR (400 MHz, CDCl₃): δ 8.15 (s, 2 H), 7.33 (s, 1 H), 7.28-7.19 (m, 2 H), 6.55 (t, J = 73.4 Hz, 1 H), 6.53 (t, J = 73.4 Hz, 1 H), 5.08 (app t, J = 6.4 Hz, 1 H), 3.38 (dd, J = 13.6, 8.7 Hz, 1 H), 3.17 (dd, J = 13.6, 5.2 Hz, 1 H), 2.29 (s, 1 H).

LCMS (Method 1): [MH+]= 416 at 3.54 min.

Intermediate 32/G (I-32/G)

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide

The intermediate I-32/G may be obtained following the procedure described in patent application WO2010/089107.

Intermediate 32/H (I-32/H)

(S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-methoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide

Step 1: (S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-hydroxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (I-32/I)

(S)-3,5-Dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (5 g, 11.90 mmol) was added to 100 mL of 37% HCl and stirred at room temperature for about 3 min., obtaining a yellow solution.

After stirring for further 3 min. the solution was poured into a solution of NaOH (48 g) in water (500 mL).

The red solution was added with 1 M HCl to pH 1. The brown solid was filtered, washed with water and triturated with hot EtOH (50 mL). After stirring at r.t. for 1 h the solid was filtered, washed with EtOH and dried under vacuum at 40 C yielding 2.4 of the title compound. MS/ESI+ [MH]⁺ : 366

Step 2: (S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-methoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (I-32/H)

(S)-3,5-Dichloro-4-(2-(4-(difluoromethoxy)-3-hydroxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (2 g, 5.46 mmol) was dissolved in DMF (16 mL) then K₂CO₃ (2 g, 14.47 mmol) and iodomethane (1.72 g, 12.12 mmol) were added and the mixture was stirred at r.t,. for 4 h. The mixture was poured into 200 mL of water, filtered, washed with water and dried under vacuum at 40°C.

1.98 g of whitish solid was obtained.

¹H NMR (400 MHz, DMSO-d6): δ ppm 8.53 (s, 2 H), 7.08 - 7.13 (m, 2 H), 7.01 (t, J=75.00 Hz, 1 H), 6.88 (dd, J=7.94, 1.76 Hz, 1 H), 5.64 (d, J=4.41 Hz, 1 H), 4.77 - 4.94 (m, 1 H), 3.81 (s, 3 H), 3.17 (d, J=8.38 Hz, 1 H), 3.05 (d, J=5.73 Hz, 1 H)

MS/ESI+ [MH]⁺:380

Intermediates I-32/J, I-32/K, I-32/L, I-32/M, I-32/N

The intermediates reported in table below, I-32/J, I-32/K, I-32/L, I-32/M, I-32/N, may be obtained following the procedure described above for intermediate 32/H, by reacting intermediate I-32/I with a suitable alkylating agent.

Structure

Name

Intermediate

Analytical data

(S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-trideuteromethoxy-phenyl)-2-hydroxyethyl)-pyridine 1-oxide

I-32/J

¹H NMR (400 MHz, DMSO-d6): δ ppm 8.53 (s, 2 H), 7.06 - 7.13 (m, 2 H), 7.01 (t, J=75.00 Hz, 1 H), 6.88 (dd, J=8.38, 1.76 Hz, 1 H), 5.63 (d, J=4.41 Hz, 1 H), 4.64 - 4.91 (m, 1 H), 3.19 (dd, J=13.23, 8.38 Hz, 1 H), 3.05 (d, J=5.73 Hz, 1 H)

MS/ESI+ [MH]⁺:383

(S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-ethoxyphenyl)-2-hydroxyethyl)-pyridine 1-oxide

I-32/K

¹H NMR (400 MHz, DMSO-d6): δ ppm 8.53 (s, 2 H), 7.06 - 7.13 (m, 2 H), 7.01 (t, J=75.00 Hz, 1 H), 6.86 (dd, J=8.16, 1.54 Hz, 1 H), 5.62 (d, J=3.97 Hz, 1 H), 4.72 - 4.97 (m, 1 H), 3.91 - 4.19 (m, 2 H), 3.18 (dd, J=13.23, 8.38 Hz, 1 H), 3.02 (dd, J=13.23, 5.29 Hz, 1 H), 1.33 (t, J=7.06 Hz, 3 H)

MS/ESI+ [MH]⁺:394

(S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-hydroxyethyl)-pyridine 1-oxide

I-32/L

¹H NMR (400 MHz, DMSO-d6): δ ppm 8.52 (s, 2 H), 7.04 - 7.13 (m, 2 H), 6.97 (t, J=75.00 Hz, 1 H), 6.86 (dd, J=7.94, 1.76 Hz, 1 H), 5.63 (d, J=3.53 Hz, 1 H), 4.81 - 4.90 (m, 1 H), 4.46 - 4.65 (m, 1 H), 3.16 (d, J=7.94 Hz, 1 H), 3.04 (d, J=6.17 Hz, 1 H), 1.26 (dd, J=13.67, 6.17 Hz, 6 H)

MS/ESI+ [MH]⁺ :408

(S)-3,5-dichloro-4-(2-(4-(difluoro-methoxy)-3-hydroxyethyl)-pyridine 1-oxide

I-32/M

MS/ESI+ [MH]⁺ :408

(S)-3,5-dichloro-4-(2-(3-(cyclopentyloxy)-4-(difluoromethoxy)-hydroxyethyl)-pyridine 1-oxide

I-32/N

MS/ESI+ [MH]⁺ :434

Similarly to Intermediate 2 were also prepared the following intermediates 1-33 to I-52:

Structure

Intermediate number

Analytical Data

Intermediate 33

¹H NMR (400 MHz, CDCl₃): δ 8.03 (s, 1 H), 7.96 (d, J = 7.8 Hz, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.42 (t, J = 7.7 Hz, 1 H), 7.06 (t, J = 8.0 Hz, 1 H), 6.72-6.66 (m, 1 H), 6.60 (t, J = 2.1 Hz, 1 H), 6.48 (dd, J = 8.2, 2.3 Hz, 1 H), 4.37 (s, 2 H), 3.92 (s, 3 H). LCMS (Method 1): [MH+] = 276 at 4.42 min.

Intermediate 34

¹H NMR (400 MHz, CDCl₃): δ 8.04 (s, 1 H), 7.97 (d, J = 7.8 Hz, 1 H), 7.56 (d, J = 7.7 Hz, 1 H), 7.43 (t, J = 7.7 Hz, 1 H), 6.88-6.80 (m, 1 H), 6.55-6.45 (m, 1 H), 6.37 (t, J = 7.9 Hz, 1 H), 4.50-4.41 (m, 3 H), 3.92 (s, 3 H). LCMS (Method 1): [MH+] = 278 at 4.33 min.

Intermediate 35

¹H NMR (400 MHz, CDCl₃): δ 8.04 (s, 1 H), 7.97 (d, J = 7.8 Hz, 1 H), 7.56 (d, J = 7.7 Hz, 1 H), 7.44 (t, J = 7.7 Hz, 1 H), 6.94-6.85 (m, 1 H), 6.39-6.25 (m, 2 H), 4.39 (d, J = 5.7 Hz, 2 H), 3.92 (s, 3 H), 3.81 (br s, 1 H). LCMS (Method 6): [MH+] = 278 at 3.69 min.

Intermediate 36

¹H NMR (400 MHz, CDCl₃): δ 8.05 (s, 1 H), 7.94 (d, J = 7.6 Hz, 1 H), 7.57 (d, J = 7.7 Hz, 1 H), 7.41 (t, J = 7.7 Hz, 1 H), 7.06 (t, J = 7.7 Hz, 1 H), 6.55 (d, J = 7.5 Hz, 1 H), 6.47-6.40 (m, 2 H), 4.37 (s, 2 H), 4.12 (br s, 1 H), 3.91 (s, 3 H), 2.26 (s, 3 H). LCMS (Method 1): [MH+] = 256 at 4.31 min.

Intermediate 37

¹H NMR (400 MHz, CDCl₃): δ 8.05 (s, 1 H), 7.97 (d, J = 7.8 Hz, 1 H), 7.56 (d, J = 7.7 Hz, 1 H), 7.46-7.40 (m, 1 H), 7.27-7.21 (m, 1 H), 6.95 (d, J = 7.7 Hz, 1 H), 6.84 (s, 1 H), 6.74 (dd, J = 8.2, 2.3 Hz, 1 H), 4.41 (s, 2 H), 4.35 (br s, 1 H), 3.92 (s, 3 H). LCMS (Method 1): [MH+] = 310 at 4.47 min.

Intermediate 38

¹H NMR (400 MHz, CDCl₃): δ 8.07 (s, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 7.59 (d, J = 7.7 Hz, 1 H), 7.42 (t, J = 7.7 Hz, 1 H), 7.10-7.05 (m, 2 H), 6.68 (t, J = 7.4 Hz, 1 H), 6.56 (d, J = 8.3 Hz, 1 H), 4.43 (s, 2 H), 3.96 (br s, 1 H), 3.92 (s, 3 H), 2.19 (s, 3 H). LCMS (Method 1): [MH+] = 256 at 4.37 min.

Intermediate 39

¹H NMR (400 MHz, CDCl₃): δ 8.03 (s, 1 H), 7.97 (d, J = 7.8 Hz, 1 H), 7.54 (d, J = 7.7 Hz, 1 H), 7.47-7.41 (m, 1 H), 7.25-7.19 (m, 1 H), 6.98 (dt, J = 7.6, 1.2 Hz, 1 H), 6.83-6.77 (m, 2 H), 4.39 (s, 2 H), 4.30 (br s, 1 H), 3.92 (s, 3 H). LCMS (Method 1): [MH+] = 267 at 4.05 min.

Intermediate 40

¹H NMR (400 MHz, CDCl₃): δ 8.02 (d, J = 7.6 Hz, 2 H), 7.43 (d, J = 7.6 Hz, 2 H), 6.86-6.79 (m, 1 H), 6.49 (dd, J = 17.1, 8.5 Hz, 1 H), 6.33 (t, J = 7.8 Hz, 1 H), 4.78 (d, J = 5.6 Hz, 1 H), 4.46 (d, J = 5.6 Hz, 2 H), 3.91 (s, 3 H). LCMS (Method 1): [MH+] = 278 at 4.32 min.

Intermediate 41

¹H NMR (400 MHz, CDCl₃): δ8.02 (d, J = 8.0 Hz, 2 H), 7.43 (d, J = 8.0 Hz, 2 H), 6.84-6.76 (m, 1 H), 6.71-6.64 (m, 1 H), 6.49 (td, J = 9.3, 5.3 Hz, 1 H), 4.42 (s, 2 H), 3.91 (s, 3 H). Note: NH not visible. LCMS (Method 6): [MH+] = 278 at 3.71 min.

Intermediate 42

¹H NMR (400 MHz, CDCl₃): δ 7.93 (dd, J = 6.8, 2.4 Hz, 1 H), 7.51 (ddd, J = 8.5, 4.6, 2.5 Hz, 1 H), 7.09 (dd, J = 10.5, 8.5 Hz, 1 H), 6.97 (ddd, J = 11.9, 8.0, 1.4 Hz, 1 H), 6.93 (t, J = 7.8 Hz, 1 H), 6.63 (tdd, J = 7.8, 4.9, 1.6 Hz, 1 H), 6.58 (dt, J = 7.9, 1.4 Hz, 1 H), 4.72-4.01 (m, 3 H), 3.91 (s, 3 H). LCMS (Method 6) [M+H] =278 at 4.07 min.

Intermediate 43

¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, J = 8.1 Hz, 2 H), 7.40 (d, J = 8.1 Hz, 2 H), 6.93-6.81 (m, 1 H), 6.31-6.22 (m, 2 H), 4.57 (br s, 1 H), 4.38 (d, J = 5.9 Hz, 2 H), 3.90 (s, 3 H). LCMS (Method 6): [MH+] = 278 at 3.68 min.

Intermediate 44

¹H NMR (400 MHz, CDCl₃): 8.02 (d, J = 8.1 Hz, 2 H), 7.42 (d, J = 8.1 Hz, 2 H), 7.06 (t, J = 8.0 Hz, 1 H), 6.68 (d, J = 8.6 Hz, 1 H), 6.59 (t, J = 2.2 Hz, 1 H), 6.47 (dd, J = 8.2, 2.4 Hz, 1 H), 4.39 (s, 2 H), 4.22 (s, 1 H), 3.91 (s, 3 H). LCMS (Method 1): [MH+] = 276 at 4.42 min.

Intermediate 45

¹H NMR (400 MHz, CDCl₃): δ 8.00 (d, J = 8.0 Hz, 2 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.05 (t, J = 7.7 Hz, 1 H), 6.55 (d, J = 7.7 Hz, 1 H), 6.46-6.40 (m, 2 H), 4.40 (s, 2 H), 3.91 (s, 3 H), 2.26 (s, 3 H). LCMS (Method 6): [MH+] = 256 at 3.73 min.

Intermediate 46

¹H NMR (400 MHz, CDCl₃): δ 8.02 (d, J = 8.1 Hz, 2 H), 7.43 (d, J = 8.1 Hz, 2 H), 7.29-7.21 (m, 1 H), 6.96 (d, J = 7.8 Hz, 1 H), 6.83 (s, 1 H), 6.72 (d, J = 8.4 Hz, 1 H), 4.43 (s, 2 H), 4.24 (br s, 1 H), 3.92 (s, 3 H). LCMS (Method 1): [MH+] = 310 at 4.43 min.

Intermediate 47

¹H NMR (400 MHz, CDCl₃): δ 8.03 (d, J = 8.0 Hz, 2 H), 7.41 (d, J = 8.1 Hz, 2 H), 7.22 (t, J = 7.8 Hz, 1 H), 6.99 (d, J = 7.5 Hz, 1 H), 6.82-6.77 (m, 2 H), 4.42 (s, 2 H), 3.92 (s, 3 H). LCMS (Method 6): [MH+] = 267 at 3.41 min.

Intermediate 48

¹H NMR (400 MHz, CDCl₃): δ 8.11 (d, J = 5.1 Hz, 1 H), 8.00 (d, J = 8.1 Hz, 2 H), 7.44-7.41 (m, 3 H), 6.61 (dd, J = 7.1, 5.1 Hz, 1 H), 6.36 (d, J = 8.4 Hz, 1 H), 4.95 (br s, 1 H), 4.59 (d, J = 6.0 Hz, 2 H), 3.91 (s, 3 H). LCMS (Method 6): [MH+] = 243 at 3.02 min.

Intermediate 49

¹H NMR (400 MHz, CDCl₃): δ 8.30 (s, 1 H), 8.02 (d, J = 8.0 Hz, 2 H), 7.93 (d, J = 5.0 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.18 (dd, J = 8.4, 4.9 Hz, 1 H), 6.94 (dd, J = 8.5, 2.7 Hz, 1 H), 4.46 (s, 2 H), 3.91 (s, 3 H). LCMS (Method 6): [MH+] = 243 at 2.61 min.

Intermediate 50

¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.48-7.44 (m, 1 H), 7.30-7.25 (m, 2 H), 7.19-7.15 (m, 2 H), 6.96-6.93 (m, 2 H), 6.73-6.69 (m, 1 H), 6.64-6.62 (m, 2 H), 5.10 (s, 2 H), 4.31 (s, 2 H), 4.25 (brs, 1 H), 3.92 (s, 3 H). LCMS (Method 1): [MNa+] = 370 at 4.60 min.

Intermediate 51

¹H NMR (400 MHz, CDCl₃): δ 8.06-8.04 (m, 2 H), 7.51-7.49 (m, 2 H), 7.30-7.26 (m, 2 H), 7.19-7.15 (m, 2 H), 6.94-6.92 (m, 2 H), 6.73-6.69 (m, 1 H), 6.64-6.62 (m, 2 H), 5.12 (s, 2 H), 4.25 (s, 2 H), 3.94 (brs, 1 H), 3.90 (s, 3 H).

Intermediate 52

¹H NMR (400 MHz, CDCl₃): δ 8.00-7.98 (m, 2 H), 7.30-7.25 (m, 2 H), 7.02-6.93 (m, 2 H), 6.75-6.71 (m, 1 H), 6.66-6.60 (m, 1 H), 3.91-3.89 (m, 4 H), 3.51-3.43 (m, 2 H), 3.00-2.97 (m, 2 H). LCMS (Method 1): [MH+] = 274 at 4.45 min.

Intermediate 53

Methyl 3-bromo-5-formylbenzoate (I-53)

A mixture of methyl 3-formylbenzoate (5.0 g, 30.5 mmol) in concentrated sulfuric acid (50 mL) was added with N-bromosuccinimide (5.4 g, 30.5 mmol) in one portion at 0°C. After warming to room temperature, the reaction mixture was stirred for 2 days before being poured into 400 mL of ice/water. Once the ice had melted, the aqueous phase was extracted with DCM (2 × 400 mL). The combined organic phases were passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was purified via silica gel chromatography, eluting with 0-10% EtOAc in isohexane, to give the title compound as an oil that solidified upon standing (4.6 g, 63%). ¹H NMR (400 MHz, CDCl₃): δ 10.02 (s, 1 H), 8.45 (t, J = 1.5 Hz, 1 H), 8.41 (t, J = 1.7 Hz, 1 H), 8.20 (t, J = 1.7 Hz, 1 H), 3.98 (s, 3 H).

Intermediate 54

Ethyl 2-(4-formylphenyl)acetate (I-54)

A screw cap tube was loaded with (4-formylphenyl)boronic acid (450 mg, 3 mmol), ethylbromoacetate (0.22 mL, 2 mmol), potassium carbonate (830 mg, 6 mmol), Pd₂(dba)₃ (46 mg, 0.05 mmol), tri-1-naphtylphosphine (62 mg, 0.15 mmol), H₂O (0.5 mL) and THF (4.5 mL). The mixture was degassed with nitrogen for 5 min and then heated to 65 °C for 18 h. The reaction was cooled to room temperature and diluted with ethyl acetate (50 mL) and washed with water (2 × 50 mL). The organic phase was filtered through a phase separator and the solvent was removed in vacuo. The residue was purified by silica gel chromatography, eluting with 0-20% EtOAc in isohexane, to yield ethyl 2-(4-formylphenyl)acetate as colourless oil (327 mg, 57%).

¹H NMR (400 MHz, CDCl₃): δ 9.99 (s, 1 H), 7.83 (d, J = 8.0 Hz, 2 H), 7.45 (d, J = 8.0 Hz, 2 H), 4.19-4.12 (m, 2 H), 3.70 (s, 2 H), 1.28-1.20 (m, 3 H). LCMS (Method 1): [MH+] = 193 at 3.58 min.

Intermediate 55

Methyl 4-((4-formylphenoxy)methyl)benzoate (I-55)

A suspension of 4-hydroxybenzaldehyde (244.2 mg, 2 mmol) and cesium carbonate (445 mg, 1.36 mmol) in anhydrous DMF (8 mL) was added with methyl-4-(bromomethyl)benzoate (481 mg, 2.1 mmol). The resulting mixture was stirred for 24 h at room temperature, after which time the mixture was concentrated under reduced pressure. The resulting crude was partitioned between dichloromethane (30 mL) and water (10 mL). The mixture was filtered through a phase separator, washed with dichloromethane and the solvent was removed in vacuo to yield the title compound as an off-white solid (520 mg, 96%).

¹H NMR (400 MHz, CDCl₃): δ 9.89 (s, 1 H), 8.08-8.06 (m, 2 H), 7.86-7.83 (m, 2 H), 7.51-7.49 (m, 2 H), 7.07-6.98 (m, 2 H), 5.23 (s, 2 H), 3.93 (s, 3 H). LCMS (Method 1): [MH+] = 271 at 4.12 min.

The following intermediate was synthesised via the same method as that of 1-55:

Structure

Intermediate number

Analytical Data

Intermediate 56

¹H NMR (400 MHz, CDCl₃): δ 9.89 (s, 1 H), 8.12 (s, 1 H), 8.04-8.02 (m, 1 H), 7.87-7.84 (m, 2 H), 7.64-7.63 (m, 1 H), 7.50-7.47 (m, 1 H), 7.10-7.06 (m, 2 H), 5.19 (s, 2 H), 3.93 (s, 3 H).

The following intermediates (I-57 to 1-61) were synthesised via procedure as used for intermediate 2

Structure

Intermediate number

Precursor

Analytical Data

Intermediate 57

Intermediate 53

¹H NMR (400 MHz, CDCl₃): δ 8.08 (t, J = 1.7 Hz, 1 H), 7.97 (s, 1 H), 7.72 (t, J = 1.7 Hz, 1 H), 7.00 (ddd, J = 11.8, 8.0, 1.4 Hz, 1 H), 6.93 (t, J = 7.8 Hz, 1 H), 6.65 (tdd, J = 7.8, 4.9, 1.6 Hz, 1 H), 6.55 (td, J = 8.4, 1.5 Hz, 1 H), 4.40 (s, 3 H), 3.91 (s, 3 H). HPLC (Method 1): [MH+] = 338 at 4.62 min.

Intermediate 58

Intermediate 54

¹H NMR (400 MHz, CDCl₃): δ 7.49-7.09 (m, 6 H), 6.80-6.66 (m, 3 H), 5.92-5.63 (brs, 1 H), 4.29 (s, 2 H), 4.16-4.11 (m, 2 H), 3.58 (s, 2 H), 1.26-1.22 (m, 3 H). LCMS (Method 1): [MH+] = 270 at 4.20 min.

Intermediate 59

Intermediate 54

¹H NMR (400 MHz, CDCl₃): δ 7.41-7.12 (m, 5 H), 6.71-6.59 (m, 3 H), 5.90-5.64 (brs, 1 H), 4.31 (s, 2 H), 4.16-4.10 (m, 2 H), 3.59 (s, 2 H), 1.26-1.21 (m, 3 H).

Intermediate 60

Intermediate 55

¹H NMR (400 MHz, CDCl₃): δ 8.06-8.04 (m, 2 H), 7.51-7.49 (m, 2 H), 7.30-7.26 (m, 2 H), 7.19-7.15 (m, 2 H), 6.94-6.92 (m, 2 H), 6.73-6.69 (m, 1 H), 6.64-6.62 (m, 2 H), 5.12 (s, 2 H), 4.25 (s, 2 H), 3.94 (brs, 1 H), 3.90 (s, 3 H).

Intermediate 61

Intermediate 56

¹H NMR (400 MHz CDCl₃): δ 8.11 (s, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.48-7.44 (m, 1 H), 7.30-7.25 (m, 2 H), 7.19-7.15 (m, 2 H), 6.96-6.93 (m, 2 H), 6.73-6.69 (m, 1 H), 6.64-6.62 (m, 2 H), 5.10 (s, 2 H), 4.31 (s, 2 H), 4.25 (brs, 1 H), 3.92 (s, 3 H).

LCMS (Method 1): [MNa+] = 370 at 4.60 min.

Intermediate 62

Methyl 4-((3-((phenylamino)methyl)phenoxy)methyl)benzoate (1-62)

Step 1: Preparation of 3-((phenylamino)methyl)phenol (I-62a)

To a solution of 3-hydroxybenzaldehyde (1.05 g, 8.6 mmol) and aniline (821 µL, 9.0 mmol) in dichloromethane (35 mL) was added acetic acid (516 µL, 9.0 mmol). The reaction mixture was stirred at room temperature for 24 h. Sodium triacetoxyborohydride (4.55 g, 21.5 mmol) was added and the reaction was stirred at room temperature for 24 h. Water was added to quench the reaction and the mixture was diluted with dichloromethane. The organic layer was washed with brine, passed through a hydrophobic frit and the solvent was removed in vacuo to afford the title compound as a brown oil (1.7 g, quantitative yield).

¹H NMR (400 MHz, CDCl₃): δ 7.25-7.15 (m, 3 H), 6.94-6.92 (m, 1 H), 6.85 (s, 1 H), 6.74-6.69 (m, 2 H), 6.63-6.60 (m, 2 H), 4.71 (brs, 1 H), 4.29 (s, 2 H), 4.11 (brs, 1 H). LCMS (Method 1): [MH+] = 200 at 3.48 min.

Step 2: Preparation of methyl 4-((3-((phenylamino)methyl)phenoxy)-methyl)benzoate (I-62b)

A suspension of 3-((phenylamino)methyl)phenol (398 mg, 2 mmol) and cesium carbonate (651 mg, 2 mmol) in anhydrous DMF (8 mL) was added with methyl-4-(bromomethyl)benzoate (481 mg, 2.1 mmol). The resulting mixture was stirred for 22 h at room temperature, after which time the solvent was removed in vacuo. The residue was partitioned between dichloromethane (30 mL) and water (10 mL). The mixture was passed through a phase separator, washed with dichloromethane and solvent was removed in vacuo to afford a brown oil. The crude material was purified by silica gel chromatography eluting with 25% ethyl acetate in iso-hexane to afford the title compound as a yellow oil (133 mg, 19%).

¹H NMR (400 MHz, CDCl₃): δ 8.04-8.02 (m, 2 H), 7.48 (d, J = 8.0 Hz, 2 H), 7.27-7.14 (m, 3 H), 7.00-6.97 (m, 2 H), 6.88-6.85 (m, 1 H), 6.73-6.69 (m, 1 H), 6.63-6.60 (m, 2 H), 5.10 (s, 2 H), 4.30 (s, 2 H), 4.03 (brs, 1 H), 3.90 (s, 3 H).

The following intermediate was synthesised via the same method as that of I-62:

Structure

Intermediate number

Analytical Data

Intermediate 63

¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.47-7.43 (m, 1 H), 7.28-7.24 (m, 1 H), 7.18-7.14 (m, 2 H), 7.01-6.97 (m, 2 H), 6.89-6.86 (m, 1 H), 6.73-6.69 (m, 1 H), 6.63-6.61 (m, 2 H), 5.08 (s, 2 H), 4.31 (s, 2 H), 4.03 (brs, 1 H), 3.92 (s, 3 H).

Intermediate 64

Methyl 3-fluoro-5-(((2-fluorophenyl)amino)methyl)benzoate (1-64)

A mixture of methyl 3-fluoro-5-methylbenzoate (1.0 g, 5.95 mmol), N-bromosuccinimide (1.27 g, 7.14 mmol), and dibenzoylperoxide (145 mg, 0.60 mmol) in CHCl₃ (50 mL) was heated to reflux for 6 h. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous NaHCO₃ (50 mL) and the layers were separated. The organic phase was washed with saturated aqueous NaHCO₃ (50 mL) and then passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was used directly in the next step without any further purification. To the residue was added 2-fluoroaniline (0.23 mL, 2.41 mmol) and potassium carbonate (454 mg, 3.29 mL) in DMF (5.5 mL). The mixture was stirred at room temperature for 18 h and then partitioned between EtOAc (30 mL) and water (20 mL). The layers were separated and the aqueous phase extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (20 mL) and dried over Na₂SO₄. The mixture was filtered and the solvent was removed in vacuo. The residue was purified on an SCX cartridge washing with MeOH and eluting with 3 to 10% NH₃ in DCM. Further purification via silica gel chromatography, eluting with 0-20% EtOAc in isohexane, gave methyl 3-fluoro-5-(((2-fluorophenyl)amino)methyl)benzoate (CD6) as a yellow oil (133 mg, 8.1% over two steps).

¹H NMR (400 MHz, CDCl₃): δ 7.85 (s, 1 H), 7.63-7.59 (m, 1 H), 7.30 (d, J = 9.2 Hz, 1 H), 7.00 ddd, J = 11.8, 8.0, 1.4 Hz, 1 H), 6.93 (t, J = 7.8 Hz, 1 H), 6.68-6.61 (m, 1 H), 6.59-6.51 (m, 1 H), 4.43 (s, 2 H), 3.92 (s, 3 H). LCMS (Method 1): [MH+] = 278 at 4.37 min.

The following compound was synthesised using the above procedure used for I-64.

Structure

Intermediate number

Analytical Data

Intermediate 65

¹H NMR (400 MHz, CDCl₃): δ 7.77 (dd, J = 8.0, 1.5 Hz, 1 H), 7.72 (dd, J = 10.5, 1.6 Hz, 1 H), 7.48-7.39 (m, 1 H), 7.03-6.94 (m, 1 H), 6.96-6.90 (m, 1 H), 6.67-6.60 (m, 1 H), 6.61-6.56 (m, 1 H), 4.49 (d, J = 5.9 Hz, 2 H), 4.43 (s, 1 H), 3.90 (s, 3 H).

Intermediate 66

Methyl 2-fluoro-4-[(2-fluoroanilino)methyl]benzoate (I-66)

To a mixture of 2-fluoroaniline (0.12 mL, 1.2 mmol) and potassium carbonate (207 mg, 1.5 mL) in DMF (5 mL) was added methyl 4-(bromomethyl)-2-fluoro-benzoate (247 mg, 1 mmol). The mixture was heated to 60 °C for 18 h. The solvent was removed in vacuo. The mixture was partitioned between DCM (15 mL) and water (15 mL), the layers were separated and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was used directly in the next step without any further purification. LCMS (Method 2): [MH+] = 278 at 3.60 min.

The following intermediate was synthesised via a similar method as that for 1-66:

Structure

Intermediate number

Analytical Data

Intermediate 67

LCMS (Method 2): [MH+] = 260 at 3.51 min.

Intermediate 68

Methyl 3-fluoro-5- [(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate (1-68)

A suspension of methyl 3-fluoro-5-(((2-fluorophenyl)amino)methyl)benzoate (133 mg, 0.48 mmol) and (R)-quinuclidin-3-yl carbonochloridate hydrochloride (163 mg, 0.72 mmol) in anhydrous CH₃CN (6 mL) was heated to 100 °C for 30 min under microwave irradiation. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL) and saturated aqueous NaHCO₃ (20 mL). The layers were separated and the organic phase was dried over Na₂SO₄. The mixture was filtered and the solvent was removed in vacuo to yield the title compound which was used directly in the next step without any further purification.

¹H NMR (400 MHz, CDCl₃): δ 7.75-7.65 (m, 1 H), 7.61 (d, J = 9.0 Hz, 1 H), 7.29-7.20 (m, 2 H), 7.14-7.03 (m, 3 H), 4.85 (s, 2 H), 4.82-4.74 (m, 1 H), 3.90 (s, 3 H), 3.28-3.11 (m, 1 H), 2.83-2.46 (m, 5 H), 2.03-1.96 (m, 1 H), 1.69-1.57 (m, 1 H), 1.56-1.45 (m, 1 H), 1.37-1.25 (m, 1 H), 1.25-1.13 (m, 1 H). LCMS (Method 2) [MH+] = 431 at 3.36 min

The following compounds (I-69 to I-92) were synthesised using the above procedure used for I-68.

Structure

Intermediate number

Precursor

Analytical Data

Intermediate 69

Intermediate 65

¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J = 8.0 Hz, 1 H), 7.63 (d, J = 10.3 Hz, 1 H), 7.53-7.46 (m, 1 H), 7.27-7.21 (m, 1 H), 7.14-7.02 (m, 3 H), 4.94 (s, 2 H), 4.79 (bs, 1 H), 3.91 (s, 3 H), 3.27-3.14 (m, 1 H), 2.83-2.52 (m, 4 H), 1.97-1.90 (m, 1 H), 1.78-1.67 (m, 2 H), 1.56-1.47 (m, 1 H), 1.36-1.27 (m, 1 H), 1.24-1.15 (m, 1 H). HPLC (Method 1): [MH+] = 431 at 2.65 min

Intermediate 70

Intermediate 57

¹H NMR (400 MHz, CDCl₃): δ 8.06 (s, 1 H), 7.84 (s, 1 H), 7.63 (s, 1 H), 7.32-7.20 (m, 1 H), 7.14-7.05 (m, 3 H), 4.83 (s, 2 H), 3.90 (s, 3 H), 3.28-3.16 (m, 1 H), 2.79-2.59 (m, 5 H), 2.03-1.93 (m, 1 H), 1.71-1.59 (m, 1 H), 1.59-1.47 (m, 1 H), 1.39-1.28 (m, 1 H), 1.28-1.16 (m, 1 H). LCMS (Method 1): [MH+] = 491 at 2.78 min.

Intermediate 71

Intermediate 58

LCMS (Method 2): [MH+] = 423 at 3.73 min.

Intermediate 72

Intermediate 59

¹H NMR (400 MHz, CDCl₃): δ 7.23-6.99 (m, 8 H), 4.84-4.82 (m, 3 H), 4.16-4.11 (m, 2 H), 3.57 (s, 2 H), 3.11-3.47 (m, 1 H), 2.87-2.52 (m, 4 H), 2.09-2.07 (m, 1 H), 1.72-1.71 (m, 1 H), 1.69-1.48 (m, 4 H), 1.23-1.21 (m, 3 H).

Intermediate 73

Intermediate 33

¹H NMR (400 MHz, CDCl₃): δ 7.97-7.90 (m, 2 H), 7.47-7.37 (m, 2 H), 7.26-7.16 (m, 3 H), 7.04 (br s, 1 H), 4.91 (d, J = 3.2 Hz, 2 H), 4.82-4.77 (m, 1 H), 3.90 (s, 3 H), 3.21 (ddd, J = 14.8, 8.2, 2.3 Hz, 1 H), 2.81-2.55 (m, 5 H), 2.00-1.95 (m, 1 H), 1.69-1.59 (m, 1 H), 1.57-1.47 (m, 1 H), 1.47-1.37 (m, 1 H), 1.32-1.21 (m, 1 H).

Intermediate 74

Intermediate 42

¹H NMR (400MHz, CD₃CN): δ 7.82 (br s, 1 H), 7.53-7.46 (m, 1 H), 7.37-7.21 (m, 2 H), 7.20-7.09 (m, 3 H), 4.87 (t, J = 16.1 Hz, 2 H), 4.77-4.68 (m, 1 H), 3.87 (s, 3 H), 3.13 (dd, J = 14.8, 8.1 Hz, 1 H), 2.79-2.42 (m, 5 H), 1.95-1.73 (m, 1 H), 1.72-1.58 (m, 1 H), 1.58-1.42 (m, 1 H), 1.39-1.07 (m, 2 H). LCMS (Method 2): [MH+] = 431 at 3.60 min.

Intermediate 75

Intermediate 34

¹H NMR (400 MHz, CDCl₃): δ 7.97-7.87 (m, 2 H), 7.48 (d, J = 7.7 Hz, 1 H), 7.39 (t, J = 7.7 Hz, 1 H), 7.12-7.04 (m, 1 H), 7.04-6.96 (m, 1 H), 6.90-6.80 (m, 1 H), 4.88 (s, 2 H), 4.81 (br s, 1 H), 3.90 (s, 3 H), 3.27-3.15 (m, 1 H), 2.80-2.55 (m, 5 H), 2.02-1.92 (m, 1 H), 1.71-1.58 (m, 1H), 1.58-1.46 (m, 1 H), 1.45-1.17 (m, 2 H). LCMS (Method 2): [MH+] = 431 at 3.73 min.

Intermediate 76

Intermediate 35

¹H NMR (400 MHz, CDCl₃): δ 7.94 (d, J = 7.9 Hz, 1 H), 7.78 (d, J = 8.6 Hz, 1 H), 7.50-7.45 (m, 1 H), 7.39 (t, J = 7.7 Hz, 1 H), 7.12-7.00 (m, 1 H), 6.99-6.90 (m, 1 H), 6.81-6.74 (m, 1 H), 4.87 (s, 2 H), 4.84-4.77 (m, 1 H), 3.90 (s, 3 H), 3.29-3.16 (m, 1 H), 2.95-2.60 (m, 5 H), 2.00-1.91 (m, 1 H), 1.72-1.59 (m, 1 H), 1.59-1.49 (m, 1 H) 1.45-1.15 (m, 2 H).

Intermediate 77

Intermediate 36

¹H NMR (400 MHz, CDCl₃): δ 7.94 (d, J = 5.8 Hz, 2 H), 7.47 (d, J = 7.7 Hz, 1 H), 7.39 (t, J = 7.8 Hz, 1 H), 7.18 (t, J = 7.7 Hz, 1 H), 7.05-6.89 (m, 3 H), 4.90 (d, J = 4.0 Hz, 2 H), 4.81-4.76 (m, 1 H), 3.90 (s, 3 H), 3.20 (dd, J = 14.8, 8.2 Hz, 1 H), 2.79-2.68 (m, 3 H), 2.68-2.54 (m, 2 H), 2.30 (s, 3 H), 2.00-1.94 (m, 1 H), 1.68-1.58 (m, 1 H), 1.57-1.46 (m, 1 H), 1.46-1.37 (m, 1 H), 1.29-1.21 (m, 1 H).

Intermediate 78

Intermediate 37

¹H NMR (400 MHz, CDCl₃): δ 7.96 (d, J = 7.4 Hz, 1 H), 7.92 (s, 1 H), 7.51-7.38 (m, 5 H), 7.38-7.28 (m, 1 H), 4.95 (d, J = 3.6 Hz, 2 H), 4.84-4.79 (m, 1 H), 3.90 (s, 3 H), 3.22 (ddd, J = 14.8, 8.2, 2.2 Hz, 1 H), 2.81-2.68 (m, 3 H), 2.68-2.53 (m, 2 H), 2.00-1.94 (m, 1 H), 1.70-1.60 (m, 1 H), 1.58-1.47 (m, 1 H), 1.44-1.33 (m, 1 H), 1.31-1.21 (m, 1 H).

Intermediate 79

Intermediate 38

¹H NMR (400 MHz, CDCl₃): δ 7.95 (d, J = 7.7 Hz, 1 H), 7.89 (s, 1 H), 7.51-7.45 (m, 1 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.23-7.14 (m, 2 H), 7.09 (d, J = 8.0 Hz, 1 H), 6.83 (dd, J = 12.4, 7.8 Hz, 1 H), 5.02 (d, J = 14.6 Hz, 1 H), 4.80-4.70 (m, 1 H), 4.53 (d, J = 14.6 Hz, 1 H), 3.89 (s, 3 H), 3.22-3.12 (m, 1 H), 2.82-2.42 (m, 5 H), 2.13-2.02 (m, 3 H), 1.86 (br s, 1 H), 1.63-1.54 (m, 1 H), 1.54-1.45 (m, 1 H), 1.21-1.09 (m, 2 H).

Intermediate 80

Intermediate 39

¹H NMR (400 MHz, CDCl₃): δ 7.99-7.94 (m, 1 H), 7.90 (s, 1 H), 7.53-7.47 (m, 2 H), 7.45-7.40 (m, 4 H), 4.94 (d, J = 4.9 Hz, 2 H), 4.85-4.80 (m, 1 H), 3.91 (s, 3 H), 3.23 (ddd, J = 14.8, 8.2, 2.3 Hz, 1 H), 2.80-2.68 (m, 3 H), 2.68-2.52 (m, 2 H), 2.01-1.95 (m, 1 H), 1.70-1.59 (m, 1 H), 1.59-1.47 (m, 1 H), 1.45-1.33 (m, 1 H), 1.33-1.23 (m, 1 H).

Intermediate 81

Intermediate 40

LCMS (Method 2): [MH+] = 431 at 3.35 min.

Intermediate 82

Intermediate 41

LCMS (Method 2): [MH+] = 431 at 3.34 min.

Intermediate 83

Intermediate 43

LCMS (Method 2): [MH+] = 431 at 3.34 min.

Intermediate 84

Intermediate 44

LCMS (Method 2): [MH+] = 429 at 3.49 min.

Intermediate 85

Intermediate 45

LCMS (Method 2): [MH+] = 409 at 3.38 min.

Intermediate 86

Intermediate 46

LCMS (Method 2): [MH+] = 463 at 3.57 min.

Intermediate 87

Intermediate 47

LCMS (Method 2): [MH+] = 420 at 3.08 min.

Intermediate 88

Intermediate 66

LCMS (Method 2): [MH+] = 431 at 3.40 min.

Intermediate 89

Intermediate 67

LCMS (Method 2): [MH+] = 413 at 3.38 min.

Intermediate 90

Intermediate 48

¹H NMR (400 MHz, CDCl₃): δ 8.41-8.40 (m, 1 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.74-7.67 (m, 2 H), 7.28 (d, J = 8.0 Hz, 2 H), 7.12-7.10 (m, 1 H), 5.24-5.20 (m, 2 H), 5.05-5.04 (m, 1 H), 3.90 (s, 3 H), 3.58-3.47 (m, 1 H), 3.30-3.10 (m, 4 H), 2.82-2.77 (m, 1 H), 2.28-2.26 (m, 1 H), 2.01-1.76 (m, 4 H). LCMS (Method 1): [MH+] = 396 at 2.47 min.

Intermediate 91

Intermediate 49

LCMS (Method 2): [MH+] = 396 at 2.64 min.

Intermediate 92

Intermediate 52

¹H NMR (400 MHz, CDCl₃): δ 7.94 (d, J = 8.4 Hz, 2 H), 7.32-7.23 (m, 3 H), 7.15-7.05 (m, 3 H), 4.79-4.78 (m, 1 H), 3.90 (s, 3 H), 3.86-3.84 (m, 2 H), 3.25-3.21 (m, 1 H), 2.97-2.93 (m, 2 H), 2.81-2.66 (m, 5 H), 2.04-1.98 (m, 1 H), 1.69-1.66 (m, 1 H), 1.59-1.55 (m, 1 H), 1.36-1.21 (m, 2 H). LCMS (Method 1): [MH+] = 427 at 2.69 min.

Example 1

(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)-ethyl] 3-[(4-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

A stirred solution of (R)-methyl 3-(((4-fluorophenyl)((quinuclidin-3-yloxy)carbonyl)amino)methyl)benzoate (0.471 g, 1.144 mmol) in tetrahydrofuran (5.8 mL) and methanol (5.8 mL) was added with a solution of lithium hydroxide monohydrate (0.096 g, 2.29 mmol) in water (2.3 mL). The reaction was stirred rapidly at room temperature for 18 hours. The mixture was cooled using an ice bath and acidified by addition of concentrated hydrochloric acid (0.46 mL, 5.52 mmol) dropwise. The mixture was allowed to warm to room temperature and then the solvent was removed in vacuo (3 × toluene azeotrope followed by 2 × acetonitrile azeotrope) and dried in the vacuum oven at 40°C to afford a pale yellow solid. This crude material was dissolved in dimethylformamide (5 mL) and added to a stirred suspension of (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (0.394 g, 1.144 mmol) in dimethylformamide (12 mL). To the resultant solution was added 4-(dimethylamino)pyridine (0.0699 g, 0.572 mmol) followed by N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.439 g, 2.288 mmol) and the reaction was stirred at room temperature for 18 hours. The majority of the dimethylformamide was removed in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine (× 2) and the solvent was removed in vacuo to afford an off white solid. The crude material was partially purified using an SCX-2 cartridge eluting sequentially with 1:1:1 methanol:acetonitrile:water, methanol and 2.3 M methanolic ammonia. Final purification was achieved by preparative HPLC to afford the title compound as a pale yellow solid (0.199 g, 24%).

¹H NMR (400 MHz, CDCl₃): δ 8.42 (s, 1 H), 8.13 (s, 2 H), 7.97-7.91 (m, 1 H), 7.87 (s, 1 H), 7.46-7.35 (m, 2 H), 7.03-6.95 (m, 6 H), 6.86 (d, J = 8.4 Hz, 1 H), 6.27 (dd, J = 9.9, 4.5 Hz, 1 H), 4.94-4.78 (m, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.69 (dd, J = 14.0, 9.7 Hz, 1 H), 3.38-3.26 (m, 2 H), 2.93-2.61 (m, 5 H), 2.12-2.06 (m, 1 H), 1.82-1.72 (m, 1 H), 1.71-1.59 (m, 1 H), 1.58-1.31 (m, 2 H). LCMS (Method 1): [MH+] = 724 at 2.81 min.

The following compounds (Ex. 2 to 12) were synthesized via the same method as that used for compound of Ex. 1:

Structure

Example number

Precursor

Analytical Data

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 2

Intermediate 28

¹H NMR (400 MHz, CDCl₃): δ 8.42 (s, 1 H), 8.12 (s, 2 H), 7.96-7.87 (m, 2 H), 7.46 (d, J = 7.6 Hz, 1 H), 7.41-7.33 (m, 1 H), 7.32-7.23 (m, 1 H), 7.14-6.95 (m, 5 H), 6.85 (d, J = 8.1 Hz, 1 H), 6.29-6.23 (m, 1 H), 4.98-4.93 (m, 1 H), 4.91-4.77 (m, 2 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.69 (dd, J = 14.0, 9.7 Hz, 1 H), 3.40-3.29 (m, 2 H), 3.01-2.61 (m, 5 H), 2.17 (s, 1 H), 1.85-1.75 (m, 1 H), 1.74-1.60 (m, 1 H), 1.59-1.47 (m, 1 H), 1.46-1.36 (m, 1 H).

LCMS (Method 1): [MH+] = 724 at 2.77 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 3

Intermediate 19

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 2 H), 7.96-7.92 (m, 1 H), 7.88 (s, 1 H), 7.47-7.37 (m, 2 H), 7.32-7.24 (m, 1 H), 7.02-6.83 (m, 6 H), 6.27 (dd, J = 9.7, 4.5 Hz, 1 H), 4.96-4.84 (m, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.69 (dd, J = 14.0, 9.7 Hz, 1 H), 3.37-3.25 (m, 2 H), 2.90-2.61 (m, 5 H), 2.11-2.05 (m, 1 H), 1.79-1.69 (m, 1 H), 1.68-1.58 (m, 1 H), 1.53-1.43 (m, 1 H), 1.41-1.31 (m, 1 H).

LCMS (Method 1): [MH+] = 724 at 2.77 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 4

Intermediate 29

¹H NMR (400 MHz, DMSO @ 85°C): δ 8.39 (s, 2 H), 8.15 (s, 1 H), 7.90 (s, 1 H), 7.85 (d, J = 7.7 Hz, 1 H), 7.51 (d, J = 7.7 Hz, 1 H), 7.46-7.40 (m, 1 H), 7.28-7.21 (m, 1 H), 7.06-6.95 (m, 5 H), 6.90-6.83 (m, 1 H), 6.26 (dd, J = 9.2, 4.7 Hz, 1 H), 4.77 (s, 2 H), 4.67-4.62 (m, 1 H), 3.79 (s, 3 H), 3.79 (s, 3 H), 3.70 (s, 3 H), 3.63 (dd, J = 14.4, 9.1 Hz, 1 H), 3.38 (dd, J = 14.0, 4.7 Hz, 1 H), 3.13-3.03 (m, 1 H), 2.65-2.58 (m, 3 H), 2.51-2.39 (m, 2 H), 1.85-1.79 (m, 1 H), 1.61-1.52 (m, 1 H), 1.51-1.42 (m, 1 H), 1.35-1.21 (m, 1 H), 1.20-1.10 (m, 1 H).

LCMS (Method 1): [MH+] = 736 at 2.79 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(3-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 5

Intermediate 20

¹H NMR (400 MHz, CDCl₃): δ 8.44 (s, 1 H), 8.12 (s, 2 H), 7.95-7.89 (m, 2 H), 7.46 (d, J = 7.7 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.21 (t, J = 8.1 Hz, 1 H), 7.01-6.96 (m, 2 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.79 (dd, J = 8.3, 2.4 Hz, 1 H), 6.67 (s, 2 H), 6.27 (dd, J = 9.7, 4.5 Hz, 1 H), 4.93-4.84 (m, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.74 (s, 3 H), 3.69 (dd, J = 14.0, 9.7 Hz, 1 H), 3.36-3.24 (m, 2 H), 2.92-2.82 (m, 3 H), 2.77 (d, J = 14.8 Hz, 1 H), 2.71-2.60 (m, 1 H), 2.13-2.06 (m, 1 H), 1.79-1.69 (m, 1 H), 1.69-1.58 (m, 1 H), 1.56-1.46 (m, 1 H), 1.41-1.31 (m, 1 H).

LCMS (Method 2): [MH+] = 736 at 3.65 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(4-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 6

Intermediate 21

¹H NMR (400 MHz, CDCl₃): δ 8.44 (s, 1 H), 8.13 (s, 2 H), 7.96-7.86 (m, 2 H), 7.46-7.33 (m, 2 H), 7.05-6.78 (m, 7 H), 6.27 (dd, J = 9.6, 4.4 Hz, 1 H), 4.95-4.90 (m, 1 H), 4.81 (s, 2 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.79 (s, 3 H), 3.69 (dd, J = 14.1, 9.7 Hz, 1 H), 3.37-3.29 (m, 2 H), 3.00-2.61 (m, 5 H), 2.20-2.10 (m, 1 H), 1.84-1.74 (m, 1 H), 1.73-1.63 (m, 1 H), 1.62-1.47 (m, 1 H), 1.46-1.35 (m, 1 H). LCMS (Method 1): [MH+] = 736 at 2.80 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]benzoate

Example 7

Intermediate 22

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.35-7.21 (m, 5 H), 7.10 (br s, 2 H), 7.04-6.95 (m, 2 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.30 (dd, J = 9.7, 4.6 Hz, 1 H), 4.95-4.89 (m, 1 H), 4.89 (s, 2 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.71 (dd, J = 14.0, 9.7 Hz, 1 H), 3.40-3.28 (m, 2 H), 2.90 (t, J = 9.1 Hz, 2 H), 2.81 (d, J = 18.1 Hz, 2 H), 2.73-2.59 (m, 1 H), 2.16-2.10 (m, 1 H), 1.84-1.73 (m, 1 H), 1.72-1.60 (m, 1 H), 1.55-1.45 (m, 1 H), 1.44-1.33 (m, 1 H).

LCMS (Method 1): [MH+] = 706 at 2.49 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 8

Intermediate 23

¹H NMR (400 MHz, CDCl₃): δ 8.44 (s, 1 H), 8.12 (s, 2 H), 7.95 (d, J = 7.8 Hz, 2 H), 7.32 (d, J = 7.9 Hz, 2 H), 7.25-7.22 (m, 1 H), 7.12-6.96 (m, 5 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.29 (dd, J = 9.5, 4.1 Hz, 1 H), 4.95-4.79 (m, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.74-3.65 (m, 1 H), 3.38-3.27 (m, 2 H), 2.99-2.63 (m, 5 H), 2.11 (s, 1 H), 1.82-1.72 (m, 1 H), 1.70-1.58 (m, 1 H), 1.52-1.32 (m, 2 H).

LCMS (Method 1): [MH+] = 724 at 2.81 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(4-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 9

Intermediate 25

¹H NMR (400 MHz, CDCl₃): δ 8.43 (s, 1 H), 8.13 (s, 2 H), 7.97 (d, J = 7.9 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2 H), 7.03-6.97 (m, 6 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.30 (dd, J = 9.7, 4.6 Hz, 1 H), 4.94-4.84 (m, 3 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.71 (dd, J = 14.0, 9.7 Hz, 1 H), 3.38-3.25 (m, 2 H), 2.90-2.60 (m, 5 H), 2.14-2.04 (m, 1 H), 1.82-1.72 (m, 1 H), 1.69-1.59 (m, 1 H), 1.54-1.34 (m, 2 H).

LCMS (Method 1): [MH+] = 724 at 2.84 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 10

Intermediate 30

¹H NMR (400 MHz, DMSO @ 85°C): δ 8.40 (s, 2 H), 7.91 (d, J = 8.1 Hz, 2 H), 7.40 (d, J = 8.1 Hz, 2 H), 7.29-7.23 (m, 1 H), 7.12-6.95 (m, 5 H), 6.90-6.85 (m, 1 H), 6.26 (dd, J = 9.2, 4.7 Hz, 1 H), 4.78 (s, 2 H), 4.73-4.68 (m, 1 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.75 (s, 3 H), 3.64 (dd, J = 14.2, 9.2 Hz, 1 H), 3.38 (dd, J = 14.3, 5.4 Hz, 1 H), 3.23-3.15 (m, 1 H), 2.76-2.65 (m, 3 H), 2.59-2.46 (m, 2 H), 1.93-1.86 (m, 1 H), 1.69-1.49 (m, 2 H), 1.37-1.18 (m, 2 H).

LCMS (Method 1): [MH+] = 736 at 2.84 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(3-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 11

Intermediate 26

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.21 (t, J = 8.1 Hz, 1 H), 7.04-6.97 (m, 2 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.78 (dd, J = 8.4, 2.4 Hz, 1 H), 6.68 (br s, 2 H), 6.30 (dd, J = 9.7, 4.6 Hz, 1 H), 4.96-4.90 (m, 1 H), 4.88 (s, 2 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.75 (s, 3 H), 3.71 (dd, J = 14.0, 9.7 Hz, 1 H), 3.39-3.29 (m, 2 H), 2.91 (t, J = 9.2 Hz, 2 H), 2.83 (d, J = 15.0 Hz, 2 H), 2.75-2.64 (m, 1 H), 2.17-2.11 (m, 1 H), 1.84-1.74 (m, 1 H), 1.72-1.62 (m, 1 H), 1.59-1.49 (m, 1 H), 1.48-1.38 (m, 1 H). LCMS (Method 1): [MH+] = 736 at 2.50 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-methyl-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 12

Intermediate 31

¹H NMR (400 MHz, DMSO): δ 8.56 (s, 2 H), 7.97 (d, J = 8.1 Hz, 2 H), 7.50-7.37 (m, 2 H), 7.31-7.25 (m, 1 H), 7.25-7.12 (m, 2 H), 7.10-6.94 (m, 4 H), 6.24 (dd, J = 9.4, 4.4 Hz, 1 H), 5.05-4.95 (m, 1 H), 4.73-4.55 (m, 2 H), 3.81 (s, 3 H), 3.78 (s, 3 H), 3.66 (dd, J = 14.2, 9.6 Hz, 1 H), 3.40-3.32 (m, 1 H), 3.16-3.04 (m, 1 H), 2.67-2.55 (m, 3 H), 2.46-2.27 (m, 2 H), 2.14-2.02 (m, 3 H), 1.81-1.40 (m, 3 H), 1.35-1.00 (m, 2 H). LCMS (Method 2): [MH+] = 720 at 3.34 min.

The following compounds were synthesised in a similar manner substituting (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide with (R,S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide. Purification was achieved by preparative HPLC to afford a 1:1 mixture of diastereoisomers. Single diastereoisomers were obtained by SFC purification.

Structure

Example number

Precursors

Analytical Data

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino) methyl]benzoate

Example 13

Intermediate 18

¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 2H), 7.93-7.91 (m, 2H), 7.48-7.46 (m, 1H), 7.40-7.36 (m, 1H), 7.32-7.22 (m, 3H), 7.14-7.12 (m, 2H), 7.00-6.96 (m, 2H), 6.86-6.84 (m, 1H), 6.27 (dd, J = 9.6, 4.4 Hz, 1H), 4.89 (s, 2H), 4.82-4.81 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.68 (dd, J = 14.0, 9.6 Hz, 1H), 3.33 (dd, J = 14.0, 4.4 Hz, 1H), 3.22-3.18 (m, 1H), 2.76-2.62 (m, 5H), 1.97-1.96 (m, 1H), 1.65-1.62 (m, 1H), 1.55-1.54 (m, 1H), 1.40-1.39 (m, 1H), 1.25-1.21 (m, 1H).

LCMS (Method 1): [MH+] = 706 at 2.79 min.

[(1R)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyhenyl)ethyl] 3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)ethyl]benzoate

Example 14

Intermediate 18

¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, 2H), 7.92-7.90 (m, 2H), 7.48-7.46 (m, 1H), 7.39-7.36 (m, 1H), 7.32-7.20 (m, 3H), 7.11-7.10 (m, 2H), 7.00-6.96 (m, 2H), 6.86-6.84 (m, 1H), 6.26 (dd, J = 9.6, 4.4 Hz, 1H), 4.95-4.78 (m, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.68 (dd, J = 14.0, 10.0 Hz, 1H), 3.32 (dd, J = 14.0, 4.4 Hz, 1H), 3.22-3.16 (m, 1H), 2.72-2.55 (m, 5H), 1.95-1.94 (m, 1H), 1.64-1.61 (m, 1H), 1.53-1.51 (m, 1H), 1.39-1.37 (m, 1H), 1.25-1.21 (m, 1H).

LCMS (Method 1): [MH+] = 706 at 2.79 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 15

Intermediate 24

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2H), 7.98 (d, J = 8.0 Hz, 2H), 7.32-7.23 (m, 3H), 7.02-6.90 (m, 4H),6.85 (d, J = 8.0 Hz, 2H), 6.30 (dd, J = 9.6, 4.8 Hz, 1H), 4.92-4.79 (m, 3H), 3.90 (s, 3H), 3.87 (s, 3H),

3.70 (dd, J = 14.0, 9.6 Hz, 1H), 3.34 (dd, J = 14.0, 4.4 Hz, 1H), 3.23-3.19 (m, 1H), 2.76-2.60 (m, 5H), 2.00-1.97 (m, 1H), 1.66-1.62 (m, 1H), 1.54-1.52 (m, 1H), 1.41-1.39 (m, 1H), 1.25-1.20 (m, 1H).

LCMS (Method 2): [MH+] = 724 at 3.20 min.

[(1R)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 16

Intermediate 24

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 2H), 7.97 (d, J = 8.0 Hz, 2H), 7.32-7.23 (m, 3H), 7.02-6.84 (m, 6H), 6.28 (dd, J = 9.6, 4.8 Hz, 1H), 4.90 (s, 2H), 4.83-4.82 (m, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.71 (dd, J = 14.0, 9.6 Hz, 1H), 3.34 (dd, J = 14.0, 4.4 Hz, 1H), 3.24-3.23 (m, 1H), 2.76-2.60 (m, 5H), 2.02-1.99 (m, 1H), 1.68-1.65 (m, 1H), 1.58-1.57 (m, 1H), 1.41-1.39 (m, 1H), 1.29-1.20 (m, 1H).

LCMS (Method 2): [MH+] = 724 at 3.20 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(4-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 17

Intermediate 27

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.96 (d, J = 7.9 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.03-6.89 (m, 4 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.83-6.77 (m, 2 H), 6.30 (dd, J = 9.6, 4.5 Hz, 1 H), 4.84 (br s, 2 H), 4.81-4.75 (m, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.78 (s, 3 H), 3.70 (dd, J = 13.9, 9.7 Hz, 1 H), 3.35 (dd, J = 13.9, 4.6 Hz, 1 H), 3.25-3.15 (m, 1 H), 2.79-2.69 (m, 3 H), 2.67-2.52 (m, 2 H), 1.97 (br s, 1 H), 1.70-1.60 (m, 1 H), 1.60-1.50 (m, 1 H), 1.48-1.35 (m, 1 H), 1.33-1.24 (m, 1 H).

LCMS (Method 1): [MH+] = 736 at 2.76 min

[(1R)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(4-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 18

Intermediate 27

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.96 (d, J = 7.8 Hz, 2 H), 7.31 (d, J = 7.9 Hz, 2 H), 7.03-6.89 (m, 4 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.84-6.76 (m, 2 H), 6.29 (dd, J = 9.7, 4.6 Hz, 1 H), 4.87-4.77 (m, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.78 (s, 3 H), 3.71 (dd, J = 13.9, 9.7 Hz, 1 H), 3.35 (dd, J = 13.9, 4.6 Hz, 1 H), 3.22 (dd, J = 14.6, 8.2 Hz, 1 H), 2.78-2.71 (m, 3 H), 2.70-2.58 (m, 2 H), 1.99 (br s, 1 H), 1.70-1.60 (m, 1 H), 1.60-1.50 (m, 1 H), 1.48-1.35 (m, 1 H), 1.33-1.24 (m, 1 H).

LCMS (Method 1): [MH+] = 736 at 2.74 min

The following compounds were synthesised via the same method as that used in Example 1

Structure

Example number

Precursors

Analytical Data

[2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]benzoate

Example 19

Intermediate 18

1H NMR (300 MHz, DMSO-d6) δ ppm 8.50 and 8.51 (s, 2 H), 7.80 - 7.92 (m, 2 H), 7.51 - 7.59 (m, 1 H), 7.47 (t, 1 H), 7.30 - 7.40 (m, 2 H), 7.16 - 7.30 (m, 3 H), 6.88 - 7.06 (m, 3 H), 6.21 (dd, 1 H), 4.96 (s, 2 H), 4.71 (br. s., 1H), 3.77 (s, 3 H), 3.76 (s, 3 H), 3.60 (dd, 1 H), 3.32 (dd, 1 H), 2.96 - 3.22 (m, 1 H), 2.56 - 2.77 (m, 5 H), 1.87(br. s., 1 H), 1.39 - 1.69 (m, 2 H), 1.02 - 1.39 (m, 2 H)

LCMS (Method 1): [MH+] = 706 at 2.80 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-bromo-5-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-formate salt

Example 20

Intermediate 70

¹H NMR (400 MHz, CDCl₃): δ 8.14 (s, 2 H), 8.06 (s, 1 H), 7.81 (s, 1 H), 7.59 (s, 1 H), 7.34-7.26 (m, 1 H), 7.16-7.07 (m, 2 H), 7.06-6.93 (m, 3 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.22 (dd, J = 9.7, 4.4 Hz, 1 H), 5.03-4.98 (m, 1 H), 4.82-4.75 (m, 2 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.70 (dd, J = 14.1, 9.8 Hz, 1 H), 3.45-3.35 (m, 1 H), 3.34 (dd, J = 14.0, 4.4 Hz, 1 H), 3.08-2.93 (m, 3 H), 2.86 (d, J = 14.9 Hz, 1 H), 2.80-2.65 (m, 1 H), 2.24 (bs, 1 H), 1.89-1.81 (m, 1 H), 1.80-1.70 (m, 1 H), 1.59-1.47 (m, 2 H). LCMS (Method 2): [MH+] = 802 at 3.27 min.

anilino)methyl]benzoate

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 2-[4-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)-methyl]phenyl]acetate

Example 21

Intermediate 71

¹H NMR (400 MHz, DMSO): δ 8.54 (s, 2 H), 8.31 (s, 1 H), 7.34-7.30 (m, 2 H), 7.26-7.21 (m, 2 H), 7.20-7.12 (m, 4 H), 6.93-6.90 (m, 1 H), 6.83-6.81 (m, 2 H), 5.95 (dd, J = 9.6, 4.8 Hz, 1 H), 4.87 (s, 2 H), 4.67-4.64 (m, 1 H), 3.74 (s, 3 H), 3.70 (s, 3 H), 3.64-3.54 (m, 2 H),3.49-3.35 (m, 2 H), 3.11-3.05 (m, 1 H), 2.67-2.47 (m, 5 H), 1.88-1.83 (m, 1 H), 1.58-1.52 (m, 1 H), 1.50-1.39 (m, 1 H), 1.37-1.22 (m, 1 H), 1.19-1.12 (m, 1 H). LCMS (Method 1): [MH+] = 720 at 2.73 min.

[(1S)-1-[3-(cyclopropyl-methoxy)-4-(difluoro-methoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 2-[4-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)-methyl]phenyl]acetate

Example 22

Intermediate 71

1H NMR (400 MHz, DMSO): δ 8.47 (s, 2 H), 8.24 (s, 1 H), 7.34-7.19 (m, 4 H), 7.17-7.01 (m, 7 H), 6.91-6.87 (m, 1 H), 5.95 (dd, J = 4.4, 9.6 Hz, 1 H), 4.88 (brs, 2 H), 4.73-4.71 (m, 1 H), 3.85-3.83 (m, 2 H), 3.66-3.56 (m, 2 H), 3.38 (dd, J = 9.6, 14.0 Hz, 1 H), 3.21-3.16 (m, 2 H), 2.73-2.56 (m, 5 H), 1.91-1.89 (m, 1 H), 1.65-1.48 (m, 2 H), 1.28-1.14 (m, 3 H), 0.59-0.55 (m, 2 H), 0.36-0.34 (m, 2 H). LCMS (Method 1): [MH+] = 713 at 2.52 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 2-[4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl] acetate

Example 23

Intermediate 72

1H NMR (400 MHz, CDCl₃): δ 8.01 (s, 2 H), 7.28-7.18 (m, 3 H), 7.10-7.05 (m, 5 H), 6.84-6.78 (m, 3 H), 6.04 (dd, J = 9.6, 4.8 Hz, 1 H), 4.82-4.79 (m, 3 H), 3.86 (s, 3 H), 3.81 (s, 3 H), 3.59-3.47 (m, 3 H), 3.20-3.15 (m, 2 H), 2.71-2.62 (m, 5 H), 1.97-1.87 (m, 1 H), 1.68-1.56 (m, 1 H), 1.55-1.44 (m, 1 H), 1.38-1.24 (m, 1 H), 1.24-1.13 (m, 1 H). LCMS (Method 1): [MH+] = 738 at 2.73 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(3-chloro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 24

Intermediate 73

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 2 H), 7.97-7.92 (m, 1 H), 7.88 (s, 1 H), 7.46-7.38 (m, 2 H), 7.28-7.22 (m, 2 H), 7.17 (br s, 1 H), 7.02-6.96 (m, 3 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.27 (dd, J = 9.7, 4.5 Hz, 1 H), 4.93-4.86 (m, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.70 (dd, J = 14.0, 9.8 Hz, 1 H), 3.37-3.27 (m, 2 H), 2.92-2.83 (m, 3 H), 2.76 (d, J = 15.0 Hz, 1 H), 2.72-2.60 (m, 1 H), 2.11-2.06 (s, 1 H), 1.81-1.70 (m, 1 H), 1.70-1.58 (m, 1 H), 1.54-1.43 (m, 1 H), 1.43-1.33 (m, 1 H). LCMS (Method 2): [MH+] = 742 at 3.45 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2,3-difluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 25

Intermediate 75

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.96-7.88 (m, 2 H), 7.47 (d, J = 7.7 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.15-7.08 (m, 1 H) 7.06-6.96 (m, 3 H), 6.86 (d, J = 8.2 Hz, 2 H), 6.29-6.23 (m, 1 H), 4.93-4.88 (m, 1 H), 4.88-4.84 (m, 2 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.70 (dd, J = 13.9, 9.8 Hz, 1 H), 3.37-3.27 (m, 2 H), 2.92-2.81 (m, 3 H), 2.81-2.65 (m, 2 H), 2.10 (br s, 1 H), 1.81-1.70 (m, 1 H), 1.69-1.58 (m, 1 H), 1.52-1.42 (m, 1 H), 1.42-1.32 (m, 1 H).

LCMS (Method 2): [MH+] = 742 at 3.29 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-[(2,5-difluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 26

Intermediate 76

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 2 H), 7.95-7.89 (m, 2 H), 7.48 (d, J = 7.7 Hz, 1 H), 7.39 (t, J = 7.7 Hz, 1 H), 7.09-6.90 (m, 4 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.84-6.75 (m, 1 H), 6.27 (dd, J = 9.7, 4.5 Hz, 1 H), 4.85 (s, 2 H), 4.82-4.76 (m, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.69 (dd, J = 14.0, 9.7 Hz, 1 H), 3.34 (dd, J = 14.0, 4.6 Hz, 1 H), 3.25-3.16 (m, 1 H), 2.78-2.68 (m, 3 H), 2.68-2.58 (m, 2 H), 1.95 (br s, 1 H), 1.67-1.57 (m, 1 H), 1,57-1.46 (m, 1 H), 1.40-1.29 (m, 1 H), 1.29-1.18 (m, 1 H).LCMS (Method 1): [MH+] = 742 at 2.75 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(3-methyl-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 27

Intermediate 77

¹H NMR (400 MHz, CDCl3): δ 8.11 (s, 2 H), 7.94-7.89 (m, 2 H), 7.48 (d, J = 7.7 Hz, 1 H), 7.39 (t, J = 7.9 Hz, 1 H), 7.22-7.15 (m, 1 H), 7.05-6.87 (m, 5 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.27 (dd, J = 9.7, 4.6 Hz, 1 H), 4.89 (s, 2 H), 4.80-4.75 (m, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.68 (dd, J = 14.0, 9.7 Hz, 1 H), 3.33 (dd, J = 14.0, 4.6 Hz, 1 H), 3.18 (dd, J = 14.8, 8.2 Hz, 1 H), 2.76-2.66 (m, 3 H), 2.65-2.55 (m, 2 H), 2.30 (s, 3 H), 1.96-1.91 (m, 1 H), 1.66-1.56 (m, 1 H), 1.55-1.45 (m, 1 H), 1.44-1.33 (m, 1 H), 1.26-1.15 (m, 1 H). LCMS (Method 1): [MH+] = 720 at 2.80 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[N-[(3R)-quinuclidin-3-yl]oxycarbonyl-3-(trifluoromethyl)anilino] methyl]benzoate

Example 28

Intermediate 78

¹H NMR (400 MHz, CDCl3): δ 8.11 (s, 2 H), 7.94 (d, J = 7.5 Hz, 1 H), 7.90 (s, 1 H), 7.50-7.38 (m, 6 H), 7.01-6.94 (m, 2 H), 6.85 (d, J = 8.1 Hz, 1 H), 6.30-6.24 (m, 1 H), 4.94 (s, 2 H), 4.83-4.77 (m, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.72-3.64 (m, 1 H), 3.37-3.30 (m, 1H), 3.24-3.15 (m, 1 H), 2.76-2.65 (m, 3 H), 2.63-2.50 (m, 2 H), 1.96-1.90 (m, 1 H), 1.65-1.50 (m, 2 H), 1.40-1.30 (m, 1 H), 1.27-1.18 (m, 1 H). LCMS (Method 1): [MH+] = 774 at 2.85 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-[(2-methyl-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 29

Intermediate 79

¹H NMR (400 MHz, DMSO at 125 °C): δ 8.23 (s, 2 H), 7.83-7.76 (m, 2 H), 7.41 (d, J = 7.6 Hz, 1 H), 7.36 (t, J = 7.5 Hz, 1 H), 7.17-7.03 (m, 3 H), 6.97-6.88 (m, 4 H), 6.21 (dd, J = 9.0, 4.9 Hz, 1 H), 4.73 (br s, 2 H), 4.64-4.58 (m, 1 H), 3.72 (s, 6 H), 3.55 (dd, J = 14.2, 9.0 Hz, 1 H), 3.32 (dd, J = 14.2, 4.9 Hz, 1 H), 3.01 (ddd, J = 14.5, 8.1, 2.3 Hz, 1 H), 2.56-2.35 (m, 5 H), 1.99 (s, 3 H), 1.78-1.73 (m, 1 H), 1.55-1.45 (m, 1 H), 1.45-1.34 (m, 1 H), 1.27-1.17 (m, 1 H), 1.14-1.04 (m, 1 H). LCMS (Method 1): [MH+] = 720 at 2.76 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-[(3-cyano-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 30

Intermediate 80

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 2 H), 7.98-7.94 (m, 1 H), 7.87 (s, 1 H), 7.54-7.48 (m, 2 H), 7.46-7.39 (m, 4 H), 7.02-6.95 (m, 2 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.28 (dd, J = 9.7, 4.6 Hz, 1 H), 4.93 (s, 2 H), 4.84-4.78 (m, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.70 (dd, J = 14.0, 9.8 Hz, 1 H), 3.35 (dd, J = 14.0, 4.6 Hz, 1 H), 3.21 (ddd, J = 14.8, 8.2, 2.2 Hz, 1 H), 2.78-2.67 (m, 3 H), 2.63-2.50 (m, 2 H), 1.98-1.92 (m, 1 H), 1.70-1.60 (m, 1 H), 1.57-1.46 (m, 1 H), 1.40-1.30 (m, 1 H), 1.30-1.20 (m, 1 H). LCMS (Method 1): [MH+] = 731 at 2.71 min.

(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-methoxy-phenyl]ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 31

Intermediate 28

¹H NMR (400 MHz, CDCl₃): δ 8.14 (s, 2 H), 7.96-7.88 (m, 2 H), 7.47 (d, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.7 Hz, 1 H), 7.30-7.23 (m, 1 H) 7.20-7.15 (m, 1 H) 7.13-6.98 (m, 5 H), 6.55 (t, J = 75.0 Hz, 1 H), 6.26 (dd, J = 9.8, 4.1 Hz, 1 H), 4.94-4.78 (m, 3 H), 3.90 (s, 3 H), 3.67 (dd, J = 14.1, 10.0 Hz, 1 H), 3.36-3.26 (m, 2 H), 2.94-2.61 (m, 5 H), 2.14-2.06 (m, 1 H), 1.81-1.56 (m, 2 H), 1.53-1.30 (m, 2 H). LCMS (Method 2): [MH+] = 760 at 3.56 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridm-1-ium-4-yl)-1-[4-(difluoro-methoxy)-3 -isopropoxy-phenyl] ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 32

Intermediate 28

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.94-7.88 (m, 2 H), 7.48 (d, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.29-7.23 (m, 1 H) 7.19-7.14 (m, 1 H), 7.13-6.99 (m, 5 H), 6.55 (t, J = 75.3 Hz, 1 H), 6.23 (dd, J = 9.7, 4.2 Hz, 1 H), 4.92-4.78 (m, 3 H), 4.62-4.51 (m, 1 H), 3.65 (dd, J = 14.1, 9.9 Hz, 1 H), 3.35-3.24 (m, 2 H), 2.91-2.59 (m, 5 H), 2.11-2.05 (m, 1 H), 1.78-1.57 (m, 2 H), 1.50-1.26 (m, 8 H). LCMS (Method 2): [MH+] = 788 at 3.88 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-ethoxy-phenyl]ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 33

Intermediate 28

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.94-7.88 (m, 2 H), 7.48 (d, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.7 Hz, 1 H), 7.29-7.22 (m, 1 H), 7.19-7.14 (m, 1 H), 7.13-6.98 (m, 5 H), 6.56 (t, J = 75.2 Hz, 1 H), 6.24 (dd, J = 9.7, 4.2 Hz, 1 H), 4.91-4.79 (m, 3 H), 4.17-4.04 (m, 2 H), 3.66 (dd, J = 14.1, 9.9 Hz, 1 H), 3.35-3.23 (m, 2 H), 2.89-2.59 (m, 5 H), 2.10-2.03 (m, 1 H), 1.77-1.56 (m, 2 H), 1.49-1.26 (m, 5 H). LCMS (Method 2): [MH+] = 774 at 3.75 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-methoxy-phenyl]ethyl] 3-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 34

Intermediate 19

¹H NMR (400 MHz, CDCl₃): δ 8.14 (s, 2 H), 7.97-7.87 (m, 2 H), 7.48-7.38 (m, 2 H), 7.32-7.24 (m, 1 H), 7.20-7.15 (m, 1 H), 7.06-6.82 (m, 5 H), 6.54 (t, J = 74.9 Hz, 1 H), 6.27 (dd, J = 10.0, 4.2 Hz, 1 H), 4.95-4.83 (m, 3 H), 3.90 (s, 3 H), 3.68 (dd, J = 14.1, 10.1 Hz, 1 H), 3.36-3.24 (m, 2 H), 2.90-2.59 (m, 5 H), 2.10-2.04 (m, 1 H), 1.79-1.57 (m, 2 H), 1.52-1.30 (m, 2 H). LCMS (Method 2): [MH+] = 760 at 3.59 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoro-methoxy)-3-isopropoxy-phenyl]ethyl] 3-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 35

Intermediate 19

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.96-7.86 (m, 2 H), 7.49-7.38 (m, 2 H), 7.32-7.24 (m, 1 H), 7.19-7.15 (m, 1 H), 7.05-6.82 (m, 5 H), 6.55 (t, J = 75.3 Hz, 1 H), 6.24 (dd, J = 9.9, 4.3 Hz, 1 H), 4.94-4.84 (m, 3 H), 4.62-4.51 (m, 1 H), 3.66 (dd, J = 14.1, 9.9 Hz, 1 H), 3.35-3.23 (m, 2 H), 2.87-2.58 (m, 5 H), 2.08-2.03 (m, 1 H), 1.77-1.54 (m, 2 H), 1.51-1.40 (m, 1 H), 1.39-1.28 (m, 7 H). LCMS (Method 1): [MH+] = 788 at 3.13 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoro-methoxy)-3-ethoxy-phenyl]ethyl] 3-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 36

Intermediate 19

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.96-7.87 (m, 2 H), 7.48-7.38 (m, 2 H), 7.32-7.24 (m, 1 H), 7.19-7.14 (m, 1 H), 7.05-6.83 (m, 5 H), 6.57 (t, J = 75.2 Hz, 1 H), 6.25 (dd, J = 9.9, 4.2 Hz, 1 H), 4.95-4.84 (m, 3 H), 4.17-4.04 (m, 2 H), 3.67 (dd, J = 14.1, 10.0 Hz, 1 H), 3.35-3.24 (m, 2 H), 2.90-2.59 (m, 5 H), 2.10-2.04 (m, 1 H), 1.79-1.57 (m, 2 H), 1.52-1.29 (m, 5 H). LCMS (Method 2): [MH+] = 774 at 3.77 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-methoxy-phenyl]ethyl]4-[(2-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 37

Intermediate 30

¹H NMR (400 MHz, DMSO@85°C): δ 8.41 (s, 2 H), 7.95 (d, J = 8.1 Hz, 2 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.31-7.20 (m, 3 H), 7.14-7.06 (m, 3 H), 7.00 (t, J = 74.8 Hz, 1 H), 6.93-6.88 (m, 1 H), 6.32 (dd, J = 9.1, 4.8 Hz, 1 H), 4.80 (s, 2 H), 4.69-4.64 (m, 1 H), 3.89 (s, 3 H), 3.78 (s, 3 H), 3.67 (dd, J = 14.2, 9.1 Hz, 1 H), 3.44 (dd, J = 14.3, 5.0 Hz, 1 H), 3.12-3.05 (m, 1 H), 2.71-2.55 (m, 3 H), 2.50-2.41 (m, 2 H), 1.87-1.81 (m, 1 H), 1.64-1.54 (m, 1 H), 1.54-1.43 (m, 1 H), 1.36-1.24 (m, 1 H), 1.23-1.13 (m, 1 H). LCMS (Method 2): [MH+] = 772 at 3.51 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-isopropoxy-phenyl]ethyl]4-[(2-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 38

Intermediate 30

¹H NMR (400 MHz, DMSO@85°C): δ 8.41 (s, 2 H), 7.94 (d, J = 8.1 Hz, 2 H), 7.44 (d, J = 8.1 Hz, 2 H), 7.31-7.19 (m, 3 H), 7.13-7.05 (m, 3 H), 6.97 (t, J = 74.9 Hz, 1 H), 6.93-6.87 (m, 1 H), 6.29 (dd, J = 8.9, 5.0 Hz, 1 H), 4.80 (s, 2 H), 4.70-4.60 (m, 2 H), 3.78 (s, 3 H), 3.66 (dd, J = 14.2, 8.9 Hz, 1 H), 3.44 (dd, J = 14.2, 5.1 Hz, 1 H), 3.12-3.04 (m, 1 H), 2.68-2.57 (m, 3 H), 2.50-2.40 (m, 2 H), 1.87-1.81 (m, 1 H), 1.64-1.55 (m, 1 H), 1.53-1.44 (m, 1 H), 1.36-1.25 (m, 7 H), 1.23-1.13 (m, 1 H). LCMS (Method 1): [MH+] = 800 at 3.04 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-ethoxy-phenyl]ethyl] 4-[(2-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 39

Intermediate 30

¹H NMR (400 MHz, DMSO@85°C): δ 8.41 (s, 2 H), 7.95 (d, J = 8.1 Hz, 2 H), 7.44 (d, J = 8.1 Hz, 2 H), 7.31-7.19 (m, 3 H), 7.14-7.05 (m, 3 H), 6.99 (t, J = 74.9 Hz, 1 H), 6.94-6.87 (m, 1 H), 6.30 (dd, J = 9.0, 4.9 Hz, 1 H), 4.80 (s, 2 H), 4.70-4.63 (m, 1 H), 4.23-4.11 (m, 2 H), 3.78 (s, 3 H), 3.66 (dd, J = 14.2, 9.1 Hz, 1 H), 3.43 (dd, J = 14.3, 5.0 Hz, 1 H), 3.12-3.04 (m, 1 H), 2.72-2.56 (m, 3 H), 2.50-2.39 (m, 2 H), 1.87-1.80 (m, 1 H), 1.65-1.54 (m, 1 H), 1.54-1.43 (m, 1 H), 1.37 (t, J = 6.9 Hz, 3 H), 1.34-1.24 (m, 1 H), 1.23-1.12 (m, 1 H). LCMS (Method 1): [MH+] = 786 at 2.98 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2,3-difluoro-N-[(3R)-quinuclidin-3-ylloxycarbonyl-anilino)methyl]benzoate

Example 40

Intermediate 81

¹H NMR (400 MHz, CD3CN): δ 8.20 (s, 2 H), 8.00 (d, J = 7.9 Hz, 2 H), 7.41 (s, 2 H), 7.28-7.04 (m, 5 H), 6.94 (d, J = 8.2 Hz, 1 H), 6.23 (dd, J = 9.6, 4.5 Hz, 1 H), 4.98-4.79 (m, 3 H), 3.83 (s, 3 H), 3.81 (s, 3 H), 3.71 (dd, J = 14.1, 9.6 Hz, 1 H), 3.36 (dd, J = 14.1, 4.5 Hz, 1 H), 3.23 (ddd, J = 14.7, 8.2, 2.4 Hz, 1 H), 2.87-2.54 (m, 5 H), 2.00-1.80* (m, 1H), 1.76-1.64 (m, 1 H), 1.64-1.53 (m, 1 H), 1.41-1.28 (m, 2 H). LCMS (Method 1): [MH+] = 742 at 2.79 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2,4-difluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate formate salt

Example 41

Intermediate 82

¹H NMR (400 MHz, CDCl₃): δ 8.33 (s, 1 H), 8.13 (s, 2 H), 7.95 (d, J = 7.9 Hz, 2 H), 7.34-7.24 (m, 2 H), 7.04-6.95 (m, 3 H), 6.89-6.78 (m, 3 H), 6.30 (dd, J = 9.7, 4.6 Hz, 1 H), 5.01-4.93 (m, 1 H), 4.89-4.74 (m, 2 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.71 (dd, J = 14.0, 9.7 Hz, 1 H), 3.44-3.31 (m, 2 H), 3.05-2.69 (m, 5 H), 2.25-2.13 (m, 1 H), 1.86-1.73 (m, 1 H), 1.83-1.63 (m, 1 H), 1.60-1.44 (m, 2 H). LCMS (Method 1): [MH+] = 742 at 2.78 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2,5-difluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate Formate salt

Example 42

Intermediate 83

¹H NMR (400 MHz, CD3CN): δ 8.33 (s, 1 H), 8.17 (s, 2 H), 7.96 (d, J = 7.9 Hz, 2 H), 7.38 (d, J = 7.8 Hz, 2 H), 7.19-6.98 (m, 5 H), 6.91 (d, J = 8.2 Hz, 1 H), 6.20 (dd, J = 9.6, 4.5 Hz, 1 H), 4.95-4.80 (m, 3 H), 3.80 (s, 3 H), 3.78 (s, 3 H), 3.68 (dd, J = 14.1, 9.6 Hz, 1 H), 3.38-3.28 (m, 2 H), 2.95-2.77 (m, 4 H), 2.75-2.64 (m, 1 H), 2.12-1.99 (m, 1 H), 1.83-1.73 (m, 1 H), 1.72-1.60 (m, 1 H), 1.53-1.38 (m, 2 H). LCMS (Method 1): [MH+] = 742 at 2.77 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxy-phenyl)ethyl] 4-[(3-chloro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate Formate salt

Example 43

Intermediate 84

¹H NMR (400 MHz, CDCl₃): δ 8.29 (s, 1 H), 8.14 (s, 2 H), 7.99 (d, J = 8.0 Hz, 2 H), 7.32-7.23 (m, 5 H), 7.04-6.96 (m, 3 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.30 (dd, J = 9.7, 4.6 Hz, 1 H), 5.02-4.97 (m, 1 H), 4.88 (s, 2 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.71 (dd, J = 13.9, 9.7 Hz, 1 H), 3.46-3.31 (m, 2 H), 3.08-2.90 (m, 4 H), 2.84-2.73 (m, 1 H), 2.23-2.16 (m, 1 H), 1.94-1.81 (m, 1 H), 1.80-1.68 (m, 1 H), 1.60-1.48 (m, 2 H). LCMS (Method 1): [MH+] = 740 at 2.82 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(3-methyl-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate Formate salt

Example 44

Intermediate 85

¹H NMR (400 MHz, CDCl₃): δ 8.33 (s, 1 H), 8.14 (s, 2 H), 7.97 (d, J = 7.9 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.19 (t, J = 8.0 Hz 1 H) 7.09-6.96 (m, 3 H) 6.95-6.76 (m, 2 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.30 (dd, J = 9.6, 4.6 Hz, 1 H), 5.03-4.96 (m, 1 H), 4.86 (s, 2 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.71 (dd, J = 13.9, 9.7 Hz, 1 H), 3.45-3.31 (m, 2 H), 3.10-2.90 (m, 4 H), 2.83-2.71 (m, 1 H), 2.31 (s, 3 H), 2.27-2.21 (m, 1 H), 1.93-1.82 (m, 1 H), 1.81-1.69 (m, 1 H), 1.62-1.46 (m, 2 H). LCMS (Method 1): [MH+] = 720 at 2.80 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxy-phenyl)ethyl]4-[[N-[(3R)-quinuclidin-3-yl]oxycarbonyl-3-(trifluoromethyl)anilino]-methyllbenzoate Formate salt

Example 45

Intermediate 86

¹H NMR (400 MHz, CDCl₃): δ 8.33 (s, 1 H), 8.14 (s, 2 H), 7.99 (d, J = 8.0 Hz, 2 H), 7.55-7.34 (m, 4 H), 7.30 (d, J = 8.1 Hz, 2 H), 7.04-6.95 (m, 2 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.30 (dd, J = 9.7, 4.6 Hz, 1 H), 5.05-4.96 (m, 1 H), 4.92 (s, 2 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.71 (dd, J = 14.0, 9.8 Hz, 1 H), 3.47-3.31 (m, 2 H), 3.08-2.87 (m, 4 H), 2.84-2.70 (m, 1 H), 2.24-2.18 (m, 1 H), 1.93-1.82 (m, 1 H), 1.81-1.68 (m, 1 H), 1.58-1.46 (m, 2 H). LCMS (Method 1): [MH+] = 774 at 2.86 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(3-cyano-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 46

Intermediate 87

¹H NMR (400 MHz, CDCl₃): δ 8.14 (s, 2 H), 8.00 (d, J = 8.1 Hz, 2 H), 7.56-7.39 (m, 4 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.04-6.96 (m, 2 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.30 (dd, J = 9.7, 4.6 Hz, 1 H), 5.01-4.87 (m, 2 H), 4.84-4.78 (m, 1 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.71 (dd, J = 14.0, 9.8 Hz, 1 H), 3.35 (dd, J = 14.0, 4.6 Hz, 1 H), 3.22 (ddd, J = 14.8, 8.2, 2.2 Hz, 1 H), 2.80-2.65 (m, 3 H), 2.59 (dt, J = 14.9, 2.6 Hz, 1 H), 2.55-2.45 (m, 1 H), 1.99-1.92 (m, 1 H), 1.71-1.58 (m, 1 H), 1.57-1.47 (m, 1 H), 1.40-1.21 (m, 2 H). LCMS (Method 1): [MH+] = 751 at 2.72 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 2-fluoro-4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 47

Intermediate 88

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 2 H), 7.83 (t, J = 7.3 Hz, 1 H), 7.16-6.90 (m, 8 H), 6.84 (d, J = 8.2 Hz, 1 H), 6.32 (dd, J = 9.1, 5.1 Hz, 1 H), 4.84 (s, 2 H), 4.82-4.74 (m, 1 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.67 (dd, J = 14.0, 9.2 Hz, 1 H), 3.35 (dd, J = 13.9, 5.1 Hz, 1 H), 3.28-3.13 (m, 1 H), 2.83-2.53 (m, 5 H), 1.96-1.88 (m, 1 H), 1.68-1.45 (m, 2 H), 1.37-1.24 (m, 1 H), 1.24-1.13 (m, 1 H). LCMS (Method 1): [MH+] = 742 at 2.77 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridm-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 2-fluoro-4-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)-methyl]benzoate

Example 48

Intermediate 89

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.85 (t, J = 7.7 Hz, 1 H), 7.33 (t, J = 7.6 Hz, 2 H), 7.28-6.93 (m, 6 H) 6.84 (d, J = 8.3 Hz, 1 H) 6.33 (dd, J = 9.1, 5.1 Hz, 1 H), 4.94-4.88 (m, 1 H), 4.86 (d, J = 6.8 Hz, 2 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.67 (dd, J = 13.9, 9.1 Hz, 1 H), 3.35 (dd, J = 13.9, 5.0 Hz, 1 H), 3.30 (ddd, J = 14.8, 8.2, 2.2 Hz, 1 H), 2.87 (t, J = 7.8 Hz, 3 H), 2.78 (d, J = 14.8 Hz, 1 H), 2.71-2.62 (m, 1 H), 2.13-2.08 (m, 1 H), 2.05-1.71 (m, 2 H), 1.69-1.58 (m, 1 H), 1.54-1.44 (m, 1 H), 1.44-1.33 (m, 1 H). LCMS (Method 1): [MH+] = 724 at 2.78 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-fluoro-5-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 49

Intermediate 68

¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 2 H), 7.71 (s, 1 H), 7.59 (d, J = 8.0 Hz, 1 H), 7.26-7.22 (m, 2 H), 7.09-7.00 (m, 3 H), 6.98-6.95 (m, 2 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.25 (dd, J = 4.4, 9.6 Hz, 1 H), 4.84 (s, 2 H), 4.83-4.81 (m, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.68 (dd, J = 9.6, 14.0 Hz, 1 H), 3.33 (dd, J = 4.4, 14.0 Hz, 1 H), 3.19-3.16 (m, 1 H), 2.71-2.61 (m, 5 H), 1.99-1.92 (m, 1 H), 1.62-1.59 (m, 1 H), 1.54-1.49 (m, 1 H), 1.36-1.24 (m, 1 H), 1.23-1.13 (m, 1 H).). LCMS (Method 1): [MH+]=742 at 2.77 min

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-fluoro-4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 50

Intermediate 69

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 2 H), 7.76 (dd, J = 1.2, 8.0 Hz, 1 H), 7.62-7.60 (m, 1 H), 7.52-7.50 (m, 1 H), 7.25-7.22 (m, 1 H), 7.15-7.09 (m, 3 H), 7.06-6.95 (m, 2 H), 6.85 (d, J = 8.0 Hz, 1 H), 6.26 (dd, J = 4.4, 9.6 Hz, 1 H), 4.93-4.91 (m, 2 H), 4.85-4.83 (m, 1 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.69 (dd, J = 9.6, 14.0 Hz, 1 H), 3.35 (dd, J = 4.4, 14.0 Hz, 1 H), 3.26-3.21 (m, 1 H), 2.80-2.55 (m, 5 H), 1.97-1.89 (m, 1 H), 1.67-1.57 (m, 1 H), 1.56-1.44 (m, 1 H), 1.37-1.25 (m, 1 H), 1.24-1.13 (m, 1 H). LCMS (Method 1): [MH+] = 742 at 2.80 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-(trideuteriomethoxy)phenyl]ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 51

Intermediate 28

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.94-7.88 (m, 2 H), 7.48 (d, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.7 Hz, 1 H), 7.30-7.23 (m, 1 H) 7.20-7.15 (m, 1 H), 7.13-6.99 (m, 5 H), 6.54 (t, J = 75.0 Hz, 1 H), 6.26 (dd, J = 9.8, 4.2 Hz, 1 H), 4.93-4.78 (m, 3 H), 3.67 (dd, J = 14.1, 10.0 Hz, 1 H), 3.36-3.25 (m, 2 H), 2.92-2.60 (m, 5 H), 2.12-2.05 (m, 1 H), 1.79-1.57 (m, 2 H), 1.50-1.28 (m, 2 H). LCMS (Method 1): [MH+] = 763 at 2.99 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3 -(trideuteriomethoxy)phenyl] ethyl] 3 - [(3 -fluoro-N- [(3R)-quinuclidin-3 -yl] oxycarbonyl-anilino)methyl]benzoate

Example 52

Intermediate 19

¹H NMR (400 MHz, CDCl₃): δ 8.14 (s, 2 H), 7.97-7.88 (m, 2 H), 7.48-7.38 (m, 2 H), 7.32-7.25 (m, 1 H), 7.20-7.16 (m, 1 H), 7.06-6.83 (m, 5 H), 6.54 (t, J = 74.9 Hz, 1 H), 6.27 (dd, J = 10.0, 4.2 Hz, 1 H), 4.95-4.84 (m, 3 H), 3.68 (dd, J = 14.1, 10.1 Hz, 1 H), 3.35-3.24 (m, 2 H), 2.89-2.58 (m, 5 H), 2.09-2.03 (m, 1 H), 1.78-1.56 (m, 2 H), 1.51-1.29 (m, 2 H). LCMS (Method 2): [MH+] = 763 at 3.57 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-(trideuteriomethoxy)phenyl]ethyl] 4-[(2-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 53

Intermediate 30

¹H NMR (400 MHz, DMSO@85°C): δ 8.41 (s, 2 H), 7.95 (d, J = 8.1 Hz, 2 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.31-7.20 (m, 3 H), 7.14-7.05 (m, 3 H), 7.00 (t, J = 74.9 Hz, 1 H), 6.93-6.87 (m, 1 H), 6.32 (dd, J = 9.1, 4.8 Hz, 1 H), 4.80 (s, 2 H), 4.70-4.64 (m, 1 H), 3.78 (s, 3 H), 3.67 (dd, J = 14.2, 9.1 Hz, 1 H), 3.44 (dd, J = 14.2, 4.9 Hz, 1 H), 3.13-3.04 (m, 1 H), 2.71-2.55 (m, 3 H), 2.51-2.39 (m, 2 H), 1.87-1.81 (m, 1 H), 1.65-1.54 (m, 1 H), 1.54-1.43 (m, 1 H), 1.36-1.25 (m, 1 H), 1.23-1.12 (m, 1 H). LCMS (Method 2): [MH+] = 775 at 3.51 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 54

Intermediate 90

¹H NMR (400 MHz, CD3CN): δ 8.37 (dd, J = 4.9, 1.8 Hz, 1 H), 8.14 (s, 2 H), 7.95 (d, J = 8.1 Hz, 2 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.69 (ddd, J = 8.4, 7.2, 2.0 Hz, 1 H), 7.36 (d, J = 8.1 Hz, 2 H), 7.06 (dd, J = 7.2, 4.9 Hz, 1 H), 7.02-6.96 (m, 2 H), 6.84 (d, J = 8.2 Hz, 1 H), 6.29 (dd, J = 9.7, 4.5 Hz, 1 H), 5.30 (dd, J = 37.3, 16.2 Hz, 2 H), 4.83-4.77 (m, 1 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.69 (dd, J = 13.9, 9.7 Hz, 1 H), 3.33 (dd, J = 13.9, 4.5 Hz, 1 H), 3.19 (ddd, J = 14.8, 8.2, 2.2 Hz, 1 H), 2.79-2.62 (m, 3 H), 2.55 (dt, J = 14.7, 2.4 Hz, 1 H), 2.48-2.34 (m, 1 H), 1.97-1.91 (m, 1 H), 1.69-1.59 (m, 1 H), 1.56-1.46 (m, 1 H), 1.45-1.35 (m, 1 H), 1.30-1.20 (m, 1 H). LCMS (Method 1): [MH+] = 707 at 2.66 min.

[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 55

Intermediate 90

¹H NMR (400 MHz, CDCl₃): δ 8.38 (d, J = 4.9 Hz, 1 H), 8.17-8.12 (m, 2 H), 7.95 (d, J = 8.1 Hz, 2 H), 7.76-7.63 (m, 2 H), 7.37 (d, J = 8.1 Hz, 2 H), 7.17 (d, J = 8.1 Hz, 1 H), 7.10-7.00 (m, 3 H), 6.61 (t, J = 75.3 Hz, 1 H), 6.26 (dd, J = 10.0, 4.2 Hz, 1 H), 5.29 (dd, J = 26.7, 16.3 Hz, 2 H), 4.88-4.83 (m, 1 H), 3.88 (d, J = 6.9 Hz, 2 H), 3.67 (dd, J = 14.1, 10.0 Hz, 1 H), 3.33-3.20 (m, 2 H), 2.84-2.71 (m, 3 H), 2.70-2.61 (m, 1 H), 2.61-2.37 (m, 1 H), 2.03-2.00 (m, 1 H), 1.74-1.66 (m, 1 H), 1.67-1.41 (m, 2 H), 1.35-1.22 (m, 2 H), 0.68-0.62 (m, 2 H), 0.38-0.33 (m, 2 H). LCMS (Method 1): [MH+] = 783 at 2.99 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate Formate salt

Example 56

Intermediate 91

¹H NMR (400 MHz, CDCl₃): δ 8.48 (d, J = 4.9 Hz, 1 H), 8.44 (s, 1 H), 8.35 (s, 1 H), 8.14 (s, 2 H), 7.98 (d, J = 8.0 Hz, 2 H), 7.33-7.23 (m, 4 H), 7.04-6.96 (m, 2 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.30 (dd, J = 9.7, 4.6 Hz, 1 H), 4.96-4.90 (m, 1 H), 4.92 (s, 2 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.71 (dd, J = 14.0, 9.7 Hz, 1 H), 3.38-3.29 (m, 2 H), 2.88 (t, J = 8.1 Hz, 3 H), 2.80 (d, J = 15.0 Hz, 1 H), 2.73-2.62 (m, 1 H), 2.14-2.09 (m, 1 H), 1.83-1.73 (m, 1 H), 1.72-1.60 (m, 1 H), 1.53-1.34 (m, 2 H). LCMS (Method 1): [MH+] = 707 at 2.57 min.

[(1S)-1-[3-(cyclopentoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate formate salt

Example 57

Intermediate 28

¹H NMR (400 MHz, CDCl₃): δ 8.44 (s, 1 H), 8.13 (s, 2 H), 7.95-7.88 (m, 2 H), 7.49 (d, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.7 Hz, 1 H), 7.32-7.19 (m, 2 H), 7.15 (d, J = 8.0 Hz, 1 H), 7.12-7.04 (m, 2 H), 7.02-6.95 (m, 2 H), 6.52 (t, J = 75.4 Hz, 1 H), 6.23 (dd, J = 9.5, 4.2 Hz, 1 H), 4.94-4.87 (m, 1 H), 4.89-4.77 (m, 3 H), 3.66 (dd, J = 14.0, 9.9 Hz, 1 H), 3.36-3.26 (m, 2 H), 3.01-2.70 (m, 3 H), 2.75 (d, J = 15.9 Hz, 1 H), 2.71-2.61 (m, 1 H), 2.14-2.05 (m, 1 H), 1.96-1.88 (m, 2 H), 1.87-1.70 (m, 5 H), 1.70-1.57 (m, 3 H), 1.50-1.40 (m, 1 H), 1.40-1.30 (m, 1 H). LCMS (Method 1): [MH+] = 814 at 3.11 min.

[(1S)-1-[3-(cyclopentoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 58

Intermediate 23

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.95 (d, J = 7.8 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.25-7.20 (m, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 7.13-7.03 (m, 3 H), 7.04-6.95 (m, 2 H), 6.51 (t, J = 75.4 Hz, 1 H), 6.27 (dd, J = 9.6, 4.5 Hz, 1 H), 4.89-4.77 (m, 4 H), 3.67 (dd, J = 14.0, 9.7 Hz, 1 H), 3.33 (dd, J = 14.0, 4.6 Hz, 1 H), 3.25 (dd, J = 14.7, 8.3 Hz, 1 H), 2.82-2.73 (m, 3 H), 2.70 (d, J = 16.5 Hz, 1 H), 2.66-2.57 (m, 1 H), 2.05-1.97 (m, 1 H), 1.92-1.88 (m, 2 H), 1.89-1.74 (m, 4 H), 1.73-1.51 (m, 4 H), 1.43-1.32 (m, 1 H), 1.32-1.22 (m, 1 H). LCMS (Method 1): [MH+] = 814 at 3.14 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoate

Example 59

Intermediate 63

¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 2 H), 8.08 (s, 1 H), 7.98 (d, J = 7.8 Hz, 1 H), 7.61 (d, J = 7.7 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 1 H), 7.32-7.24 (m, 2 H), 7.24-7.10 (m, 4 H), 7.04-6.97 (m, 2 H), 6.90-6.83 (m, 4 H), 6.30 (dd, J = 9.7, 4.6 Hz, 1 H), 5.05 (s, 2 H), 4.86-4.82 (m, 2 H), 4.81-4.75 (m, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.71 (dd, J = 14.0, 9.7 Hz, 1 H), 3.35 (dd, J = 14.0, 4.6 Hz, 1 H), 3.21-3.14 (m, 1 H), 2.76-2.66 (m, 3 H), 2.65-2.51 (m, 2 H), 1.94 (br s, 1 H), 1.66-1.55 (m, 1 H), 1.55-1.45 (m, 1 H), 1.45-1.33 (m, 1 H), 1.27-1.15 (m, 1 H). LCMS (Method 1): [MH+] = 812 at 2.99 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoate

Example 60

Intermediate 62

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 8.03 (d, J = 8.2 Hz, 2 H), 7.47 (d, J = 8.1 Hz, 2 H), 7.31-7.25 (m, 2 H), 7.25-7.09 (m, 4 H), 7.04-6.98 (m, 2 H), 6.89-6.82 (m, 4 H), 6.31 (dd, J = 9.6, 4.6 Hz, 1 H), 5.07 (s, 2 H), 4.86-4.82 (m, 2 H), 4.80-4.75 (m, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.71 (dd, J = 14.0, 9.7 Hz, 1 H), 3.36 (dd, J = 13.9, 4.6 Hz, 1 H), 3.18 (ddd, J = 14.8, 8.2, 2.2 Hz, 1 H), 2.76-2.66 (m, 3 H), 2.65-2.50 (m, 2 H), 1.93 (br s, 1 H), 1.66-1.55 (m, 1H), 1.55-1.45 (m, 1 H), 1.45-1.34 (m, 1 H), 1.27-1.15 (m, 1 H). LCMS (Method 1): [MH+] = 812 at 2.98 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[4-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoate

Example 61

Intermediate 61

¹H NMR (400 MHz, CDCl₃): δ 8.13-8.08 (m, 3 H), 7.98 (d, J = 7.8 Hz, 1 H), 7.63 (d, J = 7.7 Hz, 1 H), 7.46 (t, J = 7.7 Hz, 1 H), 7.34-7.20 (m, 3 H), 7.15 (d, J = 8.3 Hz, 2 H), 7.13-6.97 (m, 4 H), 6.92-6.84 (m, 3 H), 6.30 (dd, J = 9.7, 4.5 Hz, 1 H), 5.07 (s, 2 H), 4.96-4.90 (m, 1 H), 4.82-4.75 (m, 2 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.72 (dd, J = 13.9, 9.8 Hz, 1 H), 3.39-3.28 (m, 2 H), 2.96-2.86 (m, 3 H), 2.86-2.78 (m, 1 H), 2.74-2.62 (m, 1 H), 2.14 (br s, 1 H), 1.83-1.73 (m, 1 H), 1.72-1.61 (m, 1 H), 1.60-1.46 (m, 1 H), 1.45-1.35 (m, 1 H). LCMS (Method 1): [MH+] = 812 at 3.01 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[4-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoate formate salt

Example 62

Intermediate 60

¹H NMR (400 MHz, CDCl₃): δ 8.49 (s, 1 H), 8.13 (s, 2 H), 8.04 (d, J = 8.1 Hz, 2 H), 7.49 (d, J = 8.1 Hz, 2 H), 7.34-7.28 (m, 2 H), 7.22 (t, J = 7.3 Hz, 1 H), 7.15 (d, J = 8.3 Hz, 2 H), 7.12-6.97 (m, 4 H), 6.91-6.84 (m, 3 H), 6.30 (dd, J = 9.7, 4.5 Hz, 1 H), 5.10 (s, 2 H), 4.91-4.85 (m, 1 H), 4.78 (s, 2 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.72 (dd, J = 14.0, 9.8 Hz, 1 H), 3.35 (dd, J = 14.0, 4.6 Hz, 1 H), 3.32-3.24 (m, 1 H), 2.91-2.81 (m, 3 H), 2.76 (d, J = 14.9 Hz, 1 H), 2.70-2.59 (m, 1 H), 2.08 (br s, 1 H), 1.79-1.69 (m, 1 H), 1.67-1.57 (m, 1 H), 1.55-1.41 (m, 1 H), 1.41-1.30 (m, 1 H).

LCMS (Method 1): [MH+] = 812 at 2.97 min.

[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate formate salt

Example 63

Intermediate 23

¹H NMR (400 MHz, CDCl₃): δ 8.37 (s, 1 H), 8.14 (s, 2 H), 7.94 (d, J = 7.9 Hz, 2 H), 7.36-7.23 (m, 3 H), 7.17 (d, J = 8.1 Hz, 1 H), 7.13-6.99 (m, 5 H), 6.61 (t, J = 75.3 Hz, 1 H), 6.26 (dd, J = 9.8, 4.3 Hz, 1 H), 5.04-4.97 (m, 1 H), 4.92-4.77 (m, 2 H), 3.88 (d, J = 6.9 Hz, 2 H), 3.68 (dd, J = 14.0, 9.9 Hz, 1 H), 3.47-3.37 (m, 1 H), 3.31 (dd, J = 14.0, 4.4 Hz, 1 H), 3.10-2.70 (m, 5 H), 2.28-2.20 (m, 1 H), 1.91-1.81 (m, 1 H), 1.80-1.69 (m, 1 H), 1.62-1.44 (m, 2 H), 1.33-1.21 (m, 1 H), 0.68-0.61 (m, 2 H), 0.40-0.33 (m, 2 H). LCMS (Method 1): [MH+] = 800 at 3.10 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-isopropoxy-phenyl]ethyl] 4-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 64

Intermediate 90

¹H NMR (400 MHz, CDCl₃): δ 8.40-8.36 (m, 1 H), 8.17-8.12 (m, 2 H), 7.95 (d, J = 8.1 Hz, 2 H), 7.77-7.65 (m, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.16 (d, J = 8.0 Hz, 1 H), 7.10-7.00 (m, 3 H), 6.55 (t, J = 75.3 Hz, 1 H), 6.26 (dd, J = 9.9, 4.3 Hz, 1 H), 5.29 (dd, J = 12.5, 1.0 Hz, 2 H), 4.87-4.82 (m, 1 H), 4.60-4.53 (m, 1 H), 3.66 (dd, J = 14.0, 9.9 Hz, 1 H), 3.34-3.19 (m, 2 H), 2.82-2.71 (m, 3 H), 2.68-2.60 (m, 2 H), 2.53-2.41 (m, 1 H), 2.01 (s, 1 H), 1.76-1.49 (m, 2 H), 1.41-1.25 (m, 7 H). LCMS (Method 1): [MH+] = 771 at 2.97 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-(trideuteriomethoxy)phenyl]ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 65

Intermediate 23

¹H NMR (400 MHz, CDCl₃): δ 8.20 (s, 2 H), 7.95-7.93 (m, 2 H), 7.35-7.33 (m, 2 H), 7.25-6.99 (m, 7 H), 6.53 (t, J = 74.8 Hz, 1 H), 6.29 (dd, J = 4.4, 10.0 Hz, 1 H), 4.86-4.82 (m, 2 H), 4.79-4.78 (m, 1 H), 3.67 (dd, J = 10.0, 14.0 Hz, 1 H), 3.32 (dd, J = 4.4, 14.0 Hz, 1 H), 3.22-3.17 (m, 1 H), 2.78-2.56 (m, 4 H), 1.93-1.89 (m, 1 H), 1.53-1.44 (m, 3 H), 1.35-1.13 (m, 2 H). LCMS (Method 2): [MH+] = 763 at 3.44 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-methoxy-phenyl]ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 66

Intermediate 23

¹H NMR (400 MHz, CDCl₃): δ 8.16 (s, 2 H), 7.95-7.93 (m, 2 H), 7.33-7.31 (m, 2 H), 7.25-6.95 (m, 7 H), 6.53 (t, J = 74.8 Hz, 1 H), 6.28 (dd, J = 4.4, 10.0 Hz, 1 H), 4.86-4.76 (m, 3 H), 3.89 (s, 3 H), 3.37-3.65 (m, 1 H), 3.32 (dd, J = 4.4, 14.0 Hz, 1 H), 3.25-3.15 (m, 1 H), 2.75-2.50 (m, 4 H), 1.92-1.89 (m, 1 H), 1.51-1.45 (m, 3 H), 1.37-1.07 (m, 2 H). LCMS (Method 2): [MH+] = 760 at 3.44 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-ethoxy-phenyl]ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 67

Intermediate 23

1H N MR (400 MHz, CD₃CN): δ 8.20 (s, 2 H), 7.99 (d, J = 7.9 Hz, 2 H), 7.49-7.25 (m, 4 H), 7.23-7.12 (m, 4 H), 7.11-7.04 (m, 1 H), 6.75 (t, J = 75.3 Hz, 1 H), 6.23-6.21 (m, 1 H), 5.10-4.81 (m, 3 H), 4.20-4.06 (m, 2 H), 3.75-3.53 (m, 2 H), 3.45-3.33 (m, 1 H), 3.27-3.03 (m, 4 H), 2.98-2.83 (m, 1 H), 2.24-2.13 (m, 1 H), 1.95-1.79 (m, 2 H), 1.72-1.47 (m, 2 H), 1.39 (t, J = 6.9 Hz, 3 H). LCMS (Method 1): [MH+] = 774 at 2.99 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-isopropoxy-phenyl]ethyl]4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate formate salt

Example 68

Intermediate 23

NMR (400MHz, DMSO): δ 8.54 (s, 2 H), 8.29 (s, 1 H), 7.95 (d, J = 7.8 Hz, 2 H), 7.46-7.12 (m, 8 H), 7.07 (dd, J = 8.3, 1.9 Hz, 1 H), 7.02 (t, J = 74.6 Hz, 1 H), 6.19 (dd, J = 9.0, 4.7 Hz, 1 H), 4.90 (s, 2 H), 4.72-4.63 (m, 2 H), 3.60 (dd, J = 14.4, 9.1 Hz, 1 H), 3.35 (dd, J = 14.1, 4.8 Hz, 1 H), 3.07 (ddd, J = 14.7, 8.0, 2.2 Hz, 1 H), 2.65-2.34 (m, 5 H), 1.85-1.75 (m, 1 H), 1.61-1.49 (m, 1 H), 1.49-1.37 (m, 1 H), 1.29 (d, J = 6.0 Hz, 3 H), 1.22 (d, J = 6.0 Hz, 3 H), 1.19-1.09 (m, 2 H). LCMS (Method 1): [MH+] = 788 at 3.07 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 2-fluoro-5-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate formate salt

Example 69

Intermediate 74

NMR (400MHz, CDCl₃): δ 8.28 (s, 1 H), 8.14 (s, 2 H), 7.73 (d, J = 6.6 Hz, 1 H), 7.46-7.39 (m, 1 H), 7.33-7.24 (m, 2 H), 7.15-6.99 (m, 4 H), 6.95 (dd, J = 8.2, 2.0 Hz, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 6.29 (dd, J = 9.2, 4.9 Hz, 1 H), 5.06-4.99 (m, 1 H), 4.78 (dd, J = 29.8, 15.0 Hz, 2 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.66 (dd, J = 14.0, 9.2 Hz, 1 H), 3.50-3.39 (m, 1 H), 3.34 (dd, J = 14.1, 5.2 Hz, 1 H), 3.14-2.99 (m, 3 H), 2.92 (d, J = 14.3 Hz, 1 H), 2.83-2.72 (m, 1 H), 2.30-2.22 (m, 1 H), 1.94-1.84 (m, 1 H), 1.84-1.73 (m, 1 H), 1.64-1.48 (m, 2 H). LCMS (Method 2): [MH+] = 742 at 3.24 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[2-(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)ethyl]benzoate

Example 70

Intermediate 92

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.92 (d, J = 7.9 Hz, 2 H), 7.38-7.16 (m, 3 H), 7.17-7.08 (m, 3 H), 7.03-6.97 (m, 2 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.29 (dd, J = 9.6, 4.6 Hz, 1 H), 4.69 (s, 1 H), 3.92-3.79 (m, 7 H), 3.70 (dd, J = 14.0, 9.7 Hz, 1 H), 3.34 (dd, J = 14.0, 4.6 Hz, 1 H), 3.24-3.22 (m, 1 H), 2.96 (t, J = 7.8 Hz, 2 H), 2.73-2.65 (m, 6 H), 2.05-1.98 (m, 1 H), 1.78-1.52 (m, 2 H), 1.49-1.18 (m, 2 H). LCMS (Method 1): [MH+] = 738 at 2.81 min.

Example 71

Intermediate 23

¹H NMR (400MHz, CDCl₃): δ 8.43 (s, 2 H), 8.39 (s, 1 H), 7.96 (d, J = 7.9 Hz, 2 H), 7.32-7.23 (m, 2 H), 7.13-6.98 (m, 5 H), 6.97 (d, J = 2.0 Hz, 1 H), 6.85 (dd, J = 8.3, 2.2 Hz, 1 H), 6.36-6.30 (m, 1 H), 5.01-4.95 (m, 1 H), 4.92-4.75 (m, 2 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.79 (ddd, J = 13.6, 9.8, 1.8 Hz, 1 H), 3.44-3.34 (m, 2 H), 3.07-2.91 (m, 3 H), 2.87 (d, J = 14.8 Hz, 1 H), 2.80-2.69 (m, 1 H), 2.26-2.16 (m, 1 H), 1.90-1.79 (m, 1 H), 1.78-1.66 (m, 1 H), 1.64-1.42 (m, 2 H). LCMS (Method 1): [MH+] = 708 at 3.01 min.

[2-(3,5-dichloro-4-pyridyl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl] oxycarbonyl-anilino)methyl]benzoateformate salt

Example 72

Intermediate 28

¹H NMR (400MHz, CDCl₃): δ 8.41 (s, 2 H), 8.39 (s, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.87 (s, 1 H), 7.47 (d, J = 7.7 Hz, 1 H), 7.37 (t, J = 7.5 Hz, 1 H), 7.13-6.92 (m, 6 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.30 (dd, J = 9.7, 4.2 Hz, 1 H), 5.02-4.92 (m, 1 H), 4.84 (s, 2 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.77 (ddd, J = 13.6, 10.0, 2.4 Hz, 1 H), 3.43-3.33 (m, 2 H), 3.04-2.90 (m, 3 H), 2.85 (d, J = 16.6 Hz, 1 H), 2.79-2.54 (m, 1 H), 2.24-2.17 (m, 1 H), 1.89-1.77 (m, 1 H), 1.77-1.64 (m, 1 H), 1.60-1.40 (m, 2 H). LCMS (Method 1): [MH+] = 708 at 2.98 min.

[2-(3,5-dichloro-4-pyridyl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl] oxycarbonyl-anilino)methyl]benzoate formate salt

Example 73

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-5-methyl-benzoate formate salt

A mixture of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-bromo-5-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate formate salt (98 mg, 0.20 mmol), methylboroxine (0.03 mL, 0.20 mmol) and Pd(PPh₃)₄ (23 mg, 0.02 mmol) in 10% dioxane in water (2.5 mL) was heated to 160 °C under microwave irradiation for 5 min. After cooling to room temperature, the reaction mixture was neutralized with 0.30 mL of 2 N HCl and filtered through celite, washed with EtOAc (50 mL). the solvent was removed in vacuo and the residue was azeotroped with toluene to yield a white foam that was redissolved in DMF (2 mL). (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (76 mg, 0.22 mmol) followed by 4-(dimethylamino)-pyridine (12 mg, 0.10 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (77 mg, 0.40 mmol) were then added and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over Na₂SO₄, filtered and the solvent was removed in vacuo. The residue was purified by preparative HPLC to provide [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-5-methyl-benzoate (19 mg) as white solid.

¹H NMR (400 MHz, CDCl₃): δ 8.42 (s, 1 H), 8.11 (s, 2 H), 7.71 (d, J = 9.9 Hz, 2 H), 7.32-7.20 (m, 3 H), 7.13-7.03 (m, 2 H), 7.01-6.95 (m, 2 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.24 (dd, J = 9.6, 4.4 Hz, 1 H), 4.92-4.86 (m, 1 H), 4.81 (s, 2 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.68 (dd, J = 13.9, 9.8 Hz, 1 H), 3.33 (dd, J = 13.4, 4.3 Hz, 1 H), 3.28 (dt, J = 8.5, 3.3 Hz, 1 H), 2.88-2.80 (m, 3 H), 2.75 (d, J = 15.2 Hz, 1 H), 2.70-2.63 (m, 1 H), 2.35 (s, 3 H), 2.08 (s, 1 H), 1.80-1.68 (m, 1 H), 1.68-1.56 (m, 1 H), 1.49-1.38 (m, 1 H), 1.38-1.28 (m, 1 H). LCMS (Method 1): [MH+] = 738 at 2.8 min.

Example 74

[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 2-[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenyl]acetate formate salt

Step 1: Preparation of ethyl 2-[3-(bromomethyl)phenyl]acetate (E/74a)

Acetonitrile (30 mL) was degassed with nitrogen for 5 min and then ethyl-m-tolylacetate (2 mL, 2 mmol), NBS (1.9 g, 10.7 mmol) and benzoyl peroxide (266 mg, 1.1 mmol) were added. The resulting mixture was heated to 70 °C for 18 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by silica gel chromatography, eluting with 0-50% DCM in isohexane, to provide ethyl 2-[3-(bromomethyl)phenyl]acetate (2.23 g, 77%).

¹H NMR (400 MHz, CDCl₃): δ 7.32-7.22 (m, 4 H), 4.47 (s, 2 H), 4.18-4.09 (m, 2 H), 3.63 (s, 2 H), 1.58-1.23 (m, 3 H).

Step 2: Preparation of ethyl 2-[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl] phenyl] acetate (E/74b)

A mixture of ethyl 2-[3-(bromomethyl)phenyl]acetate (600 mg, 2.33 mmol), aniline (202 mg, 2.21 mmol) and potassium carbonate (420 mg, 3.04 mmol) in N,N-dimethylformamide (15 mL) was heated to 90 °C for 18 h. After cooling to room temperature, the reaction was filtered and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with brine (3 × 20 mL). The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. The crude material was dissolved in acetonitrile (5 mL) and (R)-quinuclidin-3-yl carbonochloridate hydrochloride (530 mg, 2.35 mmol) was added. The resulting mixture was heated to 100 °C for 30 min under microwave irradiation. The solvent was removed in vacuo, then the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluting sequentially with ethyl acetate, 10% methanol in ethyl acetate and 10% 7N methanolic ammonia in ethyl acetate to afford the title compound as a yellow solid (331 mg, 35%).

¹H NMR (400 MHz, CDCl₃): δ 7.31-7.23 (m, 4 H), 7.21-7.14 (m, 5 H), 4.85 (s, 2 H), 4.81-4.77 (m, 1 H), 4.15-4.09 (m, 2 H), 3.56 (s, 2 H), 3.22-3.16 (m, 1 H), 2.74-2.68 (m, 5 H), 2.04-1.95 (m, 1 H), 1.63-1.62 (m, 1 H), 1.61-1.60 (m, 1 H), 1.53-1.50 (m, 1 H), 1.27-1.20 (m, 4 H).

Step 3: Preparation of [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 2-[3-[(N- [(3R)-quinuclidin-3-yl] oxycarbonylanilino)methyl] phenyl] acetate formate salt (Example 74)

A solution of ethyl 2-[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenyl]acetate (150 mg, 0.35 mmol) in THF (2.5 mL) and methanol (2.5 mL) was added with 1M lithium hydroxide aqueous solution (0.8 mL). The mixture was stirred at room temperature for 18 h then acidified with concentrated HCl until pH = 2. The solvent was removed in vacuo and the residue was azeotroped with toluene and acetonitrile successively and then dried in a vacuum oven. The carboxylic acid previously obtained was then dissolved in N,N-dimethylformamide (3 mL) and (1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethanol (148 mg, 0.35 mmol) followed by 4-(dimethylamino)-pyridine (21 mg, 0.175 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (136 mg, 0.70 mmol). The resulting mixture was stirred at room temperature for 18 h. The solvent was removed in vacuo then the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was dissolved in DMSO (1.5 mL) and purified by preparative HPLC to provide [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 2- [3 - [(N- [(3 R)-quinuclidin-3 -yl]oxycarbonylanilino)methyl]phenyl] - acetate formic acid (10 mg) as white solid.

¹H NMR (400 MHz, CDCl₃): δ 8.38 (s, 1 H), 8.04 (s, 2 H), 7.31-7.21 (m, 5 H), 7.15-7.05 (m, 5 H), 6.89-6.86 (m, 2 H), 6.61 (t, J = 75.6 Hz, 1 H), 6.02 (dd, J = 4.4, 10.0 Hz, 1 H), 5.00-4.98 (m, 1 H), 4.85-4.80 (m, 2 H), 3.82-3.74 (m, 2 H), 3.59-3.50 (m, 2 H), 3.48-3.38 (m, 2 H), 3.15 (dd, J = 4.4, 14.0 Hz, 1 H), 3.08-2.93 (m, 4 H), 2.71 (dd, J = 10.0, 14.0 Hz, 1 H), 2.23-2.21 (m, 1 H), 1.90-1.83 (m, 1 H), 1.82-1.73 (m, 1 H), 1.58-1.46 (m, 2 H), 1.28-1.21 (m, 1 H), 0.68-0.63 (m, 2 H), 0.37-0.33 (m, 2 H). LCMS (Method 1): [MH+] = 796 at 3.07 min.

Example 75

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 2-[3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl]acetate

The compound was prepared similarly to Example 74, using as intermediates ethyl 2-[3-[(2-fluoro N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenyl]acetate and (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide

¹H N MR (400 MHz, CDCl₃): δ 8.03 (s, 2 H), 7.25-6.99 (m, 8 H), 6.83-6.78 (m, 3 H), 6.03 (dd, J = 9.6, 4.8 Hz, 1 H), 4.82-4.79 (m, 3 H), 3.86 (s, 3 H), 3.80 (s, 3 H), 3.57-3.49 (m, 2 H), 3.48-3.44 (m, 1 H), 3.20-3.16 (m, 2 H), 2.72-2.61 (m, 5 H), 1.98-1.86 (m, 1 H), 1.68-1.53 (m, 1 H), 1.57-1.44 (m, 1 H), 1.37-1.22 (m, 1 H), 1.21-1.13 (m, 1 H). LCMS (Method 1): [MH+] = 738 at 2.74 min.

The following compounds were synthesised in a similar manner by reacting the appropriate racemic alcoholic intermediate (intermediates 32/D, 32/E, 32/F) with the suitable acid obtained in situ from the corresponding methyl ester (intermediates 23, 28, 90, 91).

The compounds were purified by HPLC and the single diastereoisomers were obtained by SFC purification

Structure

Example number

Precursors

Analytical Data

[(1R)-1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 76

Intermediate 23 and Intermediate 32/D

¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 2 H), 7.94 (d, J = 7.9 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.28-7.19 (m, 1 H), 7.13-6.97 (m, 5 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.26 (dd, J = 9.7, 4.6 Hz, 1 H), 4.86 (s, 2 H), 4.82-4.74 (m, 1 H), 3.89-3.84 (m, 5 H), 3.68 (dd, J = 13.9, 9.7 Hz, 1 H), 3.32 (dd, J = 13.9, 4.6 Hz, 1 H), 3.24-3.14 (m, 1 H), 2.79-2.53 (m, 5 H), 1.96-1.88 (m, 1 H), 1.70-1.44 (m, 2 H), 1.37-1.13 (m, 3 H), 0.67-0.60 (m, 2 H), 0.39-0.33 (m, 2 H). LCMS (Method 1): [MH+] = 764 at 2.92 min.

[(1S)-1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 77

Intermediate 23 and Intermediate 32/D

¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 2 H), 7.94 (d, J = 7.8 Hz, 2 H), 7.32 (d, J = 7.8 Hz, 2 H), 7.29-7.22 (m, 1 H), 7.15-6.97 (m, 5 H), 6.86 (d, J = 8.1 Hz, 1 H), 6.27 (dd, J = 9.5, 4.7 Hz, 1 H), 4.92-4.82 (m, 3 H), 3.91-3.83 (m, 5 H), 3.68 (dd, J = 14.0, 9.6 Hz, 1 H), 3.37-3.23 (m, 2 H), 2.90-2.60 (m, 5 H), 2.11-2.03 (m, 1 H), 1.78-1.67 (m, 1 H), 1.66-1.54 (m, 1 H), 1.48-1.25 (m, 3 H), 0.68-0.60 (m, 2 H), 0.41-0.33 (m, 2 H). LCMS (Method 1): [MH+] = 764 at 2.92 min.

[(1R)-1-[3,4-bis(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 78

Intermediate 28 and Intermediate 32/F

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 2 H), 7.95-7.88 (m, 2 H), 7.54-7.49 (m, 1 H), 7.42-7.21 (m, 5 H), 7.14-7.00 (m, 3 H), 6.55 (t, J = 73.4 Hz, 1 H), 6.53 (t, J = 73.2 Hz, 1 H), 6.27 (dd, J = 9.5, 4.6 Hz, 1 H), 4.87 (s, 2 H), 4.82-4.75 (m, 1 H), 3.64 (dd, J = 14.0, 9.6 Hz, 1 H), 3.32 (dd, J = 14.0, 4.7 Hz, 1 H), 3.23-3.14 (m, 1 H), 2.78-2.52 (m, 5 H), 1.98-1.89 (m, 1 H), 1.66-1.56 (m, 1 H), 1.56-1.45 (m, 1 H), 1.37-1.13 (m, 2 H). LCMS (Method 2): [MH+] = 796 at 3.73 min.

[(1S)-1-[3,4-bis(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 79

Intermediate 28 and Intermediate 32/F

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 2 H), 7.96-7.88 (m, 2 H), 7.53-7.47 (m, 1 H), 7.41-7.21 (m, 5 H), 7.13-7.00 (m, 3 H), 6.56 (t, J = 73.39 Hz, 1 H), 6.53 (t, J = 73.2 Hz, 1 H), 6.26 (dd, J = 9.6, 4.5 Hz, 1 H), 4.94-4.76 (m, 3 H), 3.65 (dd, J = 14.0, 9.7 Hz, 1 H), 3.32 (dd, J = 14.0, 4.6 Hz, 1 H), 3.25-3.17 (m, 1 H), 2.78-2.54 (m, 5 H), 2.02-1.76 (m, 1 H), 1.69-1.57 (m, 1 H), 1.57-1.46 (m, 1 H), 1.36-1.14 (m, 2 H). LCMS (Method 1): [MH+] = 796 at 2.98 min.

[(1R)-1-[3,4-bis(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 80

Intermediate 23 and Intermediate 32/F

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.95 (d, J = 7.7 Hz, 2 H), 7.39-7.20 (m, 6 H), 7.13-7.00 (m, 3 H), 6.54 (t, J = 73.3 Hz, 1 H), 6.52 (t, J = 73.2 Hz, 1 H), 6.28 (dd, J = 9.4, 4.7 Hz, 1 H), 4.87 (s, 2 H), 4.82-4.74 (m, 1 H), 3.66 (dd, J = 14.0, 9.5 Hz, 1 H), 3.33 (dd, J = 14.0, 4.8 Hz, 1 H), 3.25-3.15 (m, 1 H), 2.79-2.53 (m, 5 H), 1.96-1.88 (m, 1 H), 1.78-1.44 (m, 2 H), 1.37-1.13 (m, 2 H). LCMS (Method 2): [MH+] = 796 at 4.08 min.

[(1S)-1-[3,4-bis(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 81

Intermediate 23 and Intermediate 32/F

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.96-7.94 (m, 2 H), 7.36-7.21 (m, 7 H), 7.11-7.06 (m, 2 H), 6.53 (t, J = 73.2 Hz, 1 H), 6.51 (t, J = 73.2 Hz, 1 H), 6.28 (dd, J = 4.4, 9.6 Hz, 1 H), 4.86 (brs, 2 H), 4.79 (brs, 1 H), 3.64 (dd, J = 9.6, 14.0 Hz, 1 H), 3.20 (dd, J = 4.4, 14.0 Hz, 1 H), 3.22-3.17 (m, 1 H), 2.73-2.59 (m, 5 H), 2.00-1.94 (m, 1 H), 1.64-1.61 (m, 1 H), 1.52-1.50 (m, 1 H), 1.32-1.30 (m, 1 H), 1.21-1.19 (m, 1 H). LCMS (Method 1): [MH+] = 796 at 2.99 min.

[(1R)-1-[3-(cyclopentoxy)-4-methoxyphenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 82

Intermediate 23 and Intermediate 32/E

¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 2 H), 7.95 (d, J = 7.9 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.27-7.20 (m, 1 H), 7.12-6.95 (m, 5 H), 6.85-6.82 (m, 1 H), 6.27 (dd, J = 9.4, 4.8 Hz, 1 H), 4.86 (s, 2 H), 4.81-4.74 (m, 2 H), 3.83 (s, 3 H), 3.67 (dd, J = 13.9, 9.5 Hz, 1 H), 3.34 (dd, J = 13.9, 4.8 Hz, 1 H), 3.24-3.14 (m, 1 H), 2.78-2.53 (m, 5 H), 1.97-1.76 (m, 7 H), 1.69-1.45 (m, 4 H), 1.35-1.13 (m, 2 H). LCMS (Method 1): [MH+] = 778 at 3.04 min.

[(1S)-1-[3-(cyclopentoxy)-4-methoxyphenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 83

Intermediate 23 and Intermediate 32/E

¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 2 H), 7.95 (d, J = 7.8 Hz, 2 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.28-7.20 (m, 1 H), 7.14-6.93 (m, 5 H), 6.83 (d, J = 8.5 Hz, 1 H), 6.27 (dd, J = 9.4, 4.8 Hz, 1 H), 4.86 (s, 2 H), 4.83-4.74 (m, 2 H), 3.83 (s, 3 H), 3.67 (dd, J = 13.9, 9.5 Hz, 1 H), 3.33 (dd, J = 13.9, 4.8 Hz, 1 H), 3.27-3.16 (m, 1 H), 2.82-2.55 (m, 5 H), 2.03-1.75 (m, 7 H), 1.70-1.47 (m, 4 H), 1.40-1.16 (m, 2 H). LCMS (Method 1): [MH+] = 778 at 3.03 min.

[(1R)-1-[3-(cyclopentoxy)-4-methoxyphenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 84

Intermediate 28 and Intermediate 32/E

¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 2 H), 7.94-7.88 (m, 2 H), 7.48 (d, J = 7.7 Hz, 1 H), 7.37 (t, J = 7.7 Hz, 1 H), 7.28-7.21 (m, 1 H), 7.13-6.94 (m, 5 H), 6.87-6.82 (m, 1 H), 6.24 (dd, J = 9.5, 4.5 Hz, 1 H), 4.91-4.82 (m, 3 H), 4.82-4.75 (m, 1 H), 3.84 (s, 3 H), 3.67 (dd, J = 13.9, 9.6 Hz, 1 H), 3.36-3.22 (m, 2 H), 2.85-2.58 (m, 5 H), 2.06-1.99 (m, 1 H), 1.97-1.76 (m, 6 H), 1.74-1.53 (m, 4 H), 1.44-1.23 (m, 2 H). LCMS (Method 2): [MH+] = 778 at 4.28 min.

[(1R)-1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 85

Intermediate 28 and Intermediate 32/D

¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 2 H), 7.93-7.88 (m, 2 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.36 (t, J = 7.7 Hz, 1 H), 7.28-7.21 (m, 1 H), 7.12-6.96 (m, 5 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.23 (dd, J = 9.7, 4.3 Hz, 1 H), 4.90-4.80 (m, 3 H), 3.89-3.84 (m, 5 H), 3.68 (dd, J = 14.0, 9.9 Hz, 1 H), 3.34-3.22 (m, 2 H), 2.85-2.58 (m, 5 H), 2.05-1.98 (m, 1 H), 1.74-1.64 (m, 1 H), 1.63-1.52 (m, 1 H), 1.44-1.22 (m, 3 H), 0.67-0.60 (m, 2 H), 0.39-0.33 (m, 2 H). LCMS (Method 2): [MH+] = 764 at 4.02 min.

[(1R)-1-[3-(cyclopentoxy)-4-methoxyphenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 86

Intermediate 90 and Intermediate 32/E

¹H NMR (400 MHz, CD₃CN): δ 8.35-8.33 (m, 1 H), 8.17 (s, 2 H), 7.99 (d, J = 8.3 Hz, 2 H), 7.84-7.75 (m, 2 H), 7.42 (d, J = 8.3 Hz, 2 H), 7.15-7.12 (m, 1 H), 7.02-7.00 (m, 2 H), 6.94-6.92 (m, 1 H), 6.22 (dd, J = 4.7, 9.3 Hz, 1 H), 5.36-5.20 (m, 2 H), 4.86-4.73 (m, 2 H), 3.79 (s, 3 H), 3.66 (dd, J = 9.3, 14.0 Hz, 1 H), 3.35 (dd, J = 4.7, 14.0 Hz, 1 H), 3.17-3.04 (m, 1 H), 2.75-2.59 (m, 3 H), 2.58-2.56 (m, 1 H), 2.49-2.35 (m, 1 H), 2.01-1.80 (m, 7 H), 1.78-1.44 (m, 4 H), 1.39-1.33 (m, 1 H), 1.31-1.18 (m, 1 H). LCMS (Method 1): [MH+] = 761 at 2.92 min.

[(1S)-1-[3-(cyclopentoxy)-4-methoxyphenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 87

Intermediate 90 and Intermediate 32/E

1H NMR (400 MHz, CD₃CN): δ 8.36-8.34 (m, 1 H), 8.19 (s, 2 H), 7.99 (d, J = 8.3 Hz, 2 H), 7.86-7.75 (m, 2 H), 7.42 (d, J = 8.3 Hz, 2 H), 7.15-7.12 (m, 1 H), 7.03-7.01 (m, 2 H), 6.94-6.92 (m, 1 H), 6.22 (dd, J = 4.7, 9.3 Hz, 1 H), 5.36-5.23 (m, 2 H), 4.84-4.75 (m, 2 H), 3.79 (s, 3 H), 3.66 (dd, J = 9.3, 14.0 Hz, 1 H), 3.35 (dd, J = 4.7, 14.0 Hz, 1 H), 3.15-3.08 (m, 1 H), 2.75-2.58 (m, 3 H), 2.56-2.55 (m, 1 H), 2.35-2.26 (m, 1 H), 2.03-1.82 (m, 7 H), 1.79-1.47 (m, 4 H), 1.43-1.33 (m, 1 H), 1.31-1.14 (m, 1 H). LCMS (Method 1): [MH+] = 761 at 2.91 min.

[(1S)-1-[3-(cyclopentoxy)-4-methoxyphenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 88

Intermediate 91 and Intermediate 32/E

¹H NMR (400 MHz, CDCl₃): δ 8.46 (d, J = 5.0 Hz, 2 H), 8.14 (s, 2 H), 7.98 (d, J = 7.9 Hz, 2 H), 7.45 (brs, 1 H), 7.34-7.21 (m, 3 H), 6.99-6.96 (m, 2 H), 6.86-6.81 (m, 1 H), 6.27 (dd, J = 9.5, 4.7 Hz, 1 H), 4.94 (s, 2 H), 4.86-4.73 (m, 2 H), 3.84 (s, 3 H), 3.69 (dd, J = 13.9, 9.5 Hz, 1 H), 3.34 (dd, J = 13.9, 4.8 Hz, 1 H), 3.25-3.18 (m, 1 H), 2.66-2.58 (m, 2 H), 2.01-1.81 (m, 9 H), 1.72-1.58 (m, 4 H), 1.39-1.21 (m, 3 H). LCMS (Method 2): [MH+] = 761 at 9.72 min.

[(1R)-1-[3-(cyclopentoxy)-4-methoxyphenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl] oxycarbonyl-amino]methyl]benzoate

Example 89

Intermediate 91 and Intermediate 32/E

¹H NMR (400 MHz, CDCl₃): δ 8.47-8.44 (m, 2 H), 8.13 (s, 2 H), 7.98 (d, J = 8.0 Hz, 2 H), 7.54-7.35 (brs, 1 H), 7.01-6.95 (m, 2 H), 6.84 (d, J = 8.4 Hz, 1 H), 6.29-6.24 (m, 1 H), 4.93 (s, 2 H), 4.85-4.73 (m, 2 H), 3.84 (s, 3 H), 3.69 (dd, J = 13.9, 9.6 Hz, 1 H), 3.34 (dd, J = 14.0, 4.7 Hz, 1 H), 3.26-3.18 (m, 1 H), 2.77-2.68 (m, 4 H), 2.67-2.57 (m, 2 H), 2.00-1.79 (m, 7 H), 1.72-1.50 (m, 5 H), 1.32-1.21 (m, 3 H). LCMS (Method 1): [MH+] = 761 at 2.77 min.

[(1S)-1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 90

Intermediate 91 and Intermediate 32/D

¹H NMR (400 MHz, CDCl₃): δ 8.49-8.45 (m, 2 H), 8.14 (s, 2 H), 7.97 (d, J = 7.9 Hz, 2 H), 7.57-7.34 (brs, 1 H) 7.29 (m, 3 H), 7.05-6.96 (m, 2 H), 6.86 (d, J = 8.4 Hz, 1 H), 6.27 (dd, J = 9.6, 4.3 Hz, 1 H), 4.96-4.85 (m, 3 H), 3.87 (m, 5 H), 3.70 (dd, J = 14.0, 9.8 Hz, 1 H), 3.33 (m, 2 H), 2.86 (m, 3 H), 2.77 (m, 1 H), 2.65 (s, 1 H) 2.08 (s, 1 H), 1.75-1.49 (m, 1 H), 1.57-1.23 (m, 2 H), 1.39-1.25 (m, 2 H), 0.67-0.61 (m, 2 H), 0.38-0.33 (m, 2 H). LCMS (Method 2): [MH+] = 747 at 3.48 min.

[(1R)-1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 91

Intermediate 91 and Intermediate 32/D

¹H NMR (400 MHz, CDCl₃): δ 8.48-8.44 (m, 2 H), 8.13 (s, 2 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.57-7.35 (brs, 1 H), 7.31 (d, J = 7.9 Hz, 2 H), 7.28-7.23 (m, 1 H), 7.03-6.96 (m, 2 H), 6.86 (d, J = 8.3 Hz, 1 H), 6.26 (dd, J = 9.8, 4.5 Hz, 1 H), 4.93 (s, 2 H), 4.84-4.78 (m, 1 H), 3.91-3.85 (m, 5 H), 3.70 (dd, J = 14.0, 9.8 Hz, 1 H), 3.33 (dd, J = 14.0, 4.6 Hz, 1 H), 3.21 (m, 1 H), 2.76-2.68 (m, 4 H), 2.65-2.55 (m, 2 H), 1.97 (s, 1 H), 1.39-1.21 (m, 4 H), 0.67-0.61 (m, 2 H), 0.38-0.33 (m, 2 H).

LCMS (Method 2): [MH+] = 747 at 3.25 min.

[(1S)-1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 92

Intermediate 90 and Intermediate 32/D

¹H NMR (400 MHz, CD₃CN): δ 8.25-8.23 (m, 1 H), 8.07 (s, 2 H), 7.87 (d, J = 8.2 Hz, 2 H), 7.73-7.67 (m, 2 H), 7.31 (d, J = 8.2 Hz, 2 H), 7.04-7.01 (m, 1 H), 6.94-6.92 (m, 2 H), 6.84-6.82 (m, 1 H), 6.11 (dd, J = 4.4, 9.6 Hz, 1 H), 5.22-5.13 (m, 2 H), 4.68-4.66 (m, 1 H), 3.73-3.62 (m, 5 H), 3.55 (dd, J = 9.6, 14.0 Hz, 1 H), 3.21 (dd, J = 4.4, 14.0 Hz, 1 H), 3.05-2.98 (m, 1 H), 2.64-2.25 (m, 5 H), 1.86-1.78 (m, 1 H), 1.61-1.47 (m, 1 H), 1.46-1.37 (m, 1 H), 1.35-1.34 (m, 1 H), 1.23-1.21 (m, 2 H), 0.51-0.47 (m, 2 H), 0.23-0.19 (m, 2 H). LCMS (Method 1): [MH+] = 747 at 2.82 min.

[(1R)-1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[2-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 93

Intermediate 90 and Intermediate 32/D

¹H NMR (400 MHz, CD₃CN): δ 8.24-8.23 (m, 1 H), 8.05 (s, 2 H), 7.87 (d, J = 8.2 Hz, 2 H), 7.73-7.64 (m, 2 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.04-7.01 (m, 1 H), 6.93-6.91 (m, 2 H), 6.83-6.81 (m, 1 H), 6.09 (dd, J = 4.4, 9.6 Hz, 1 H), 5.24-5.11 (m, 2 H), 4.68-4.66 (m, 1 H), 3.75-3.67 (m, 5 H), 3.55 (dd, J = 9.6, 14.0 Hz, 1 H), 3.22 (dd, J = 4.4, 14.0 Hz, 1 H), 3.05-2.98 (m, 1 H), 2.63-2.26 (m, 5 H), 1.84-1.76 (m, 1 H), 1.60-1.48 (m, 1 H), 1.47-1.36 (m, 1 H), 1.35-1.34 (m, 1 H), 1.23-1.21 (m, 2 H), 0.52-0.45 (m, 2 H), 0.25-0.17 (m, 2 H). LCMS (Method 1): [MH+] = 747 at 2.81 min.

Intermediate 93

[(1S)-2-(3,5-Dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-formylbenzoate

A solution of (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (0.688 g, 2 mmol), 3-formylbenzoic acid (0.300 g, 2 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.767 g, 4 mmol) and 4-(dimethylamino)pyridine (0.122 g, 1 mmol) in anhydrous DCM (30 mL) was stirred at RT for 21 h. The reaction mixture was partitioned between saturated aqueous NaHCO₃ (20 mL) and DCM (10 mL) and filtered through a phase separator. The solvent was removed in vacuo and the crude material was purified by silica gel column chromatography eluting with 1:1 DCM:EtOAc to afford the title compound as an off-white solid (0.863 g, 91%).

¹H NMR (400 MHz, CDCl₃): δ 10.08 (s, 1 H), 8.54 (t, J = 1.7 Hz, 1 H), 8.27 (dt, J = 7.8, 1.5 Hz, 1 H), 8.14 (s, 2 H), 8.09 (dt, J = 7.7, 1.5 Hz, 1 H), 7.63 (t, J = 7.7 Hz, 1 H), 7.05 (dd, J = 8.2, 2.1 Hz, 1 H), 7.00 (d, J = 2.1 Hz, 1 H), 6.87 (d, J = 8.3 Hz, 1 H), 6.33 (dd, J = 9.7, 4.6 Hz, 1 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.76 (dd, J = 14.0, 9.8 Hz, 1 H), 3.39 (dd, J = 14.0, 4.6 Hz, 1 H). LCMS (Method 1): [MH+] = 476 at 3.55 min.

The following intermediates were synthesised similarly to the method of the intermediate 93 by reacting the suitable alcoholic intermediate 1-32 (I-32/A to I-32/N) with the suitable formylbenzoic acid:

Structure

Intermediate number

Analytical Data

Intermediate 94

¹H NMR (400 MHz, CDCl₃): δ 10.10 (s, 1 H), 8.18 (d, J = 8.0 Hz, 2 H), 8.13 (s, 2 H), 7.95 (d, J = 8.0 Hz, 2 H), 7.05-6.99 (m, 2 H), 6.87 (d, J = 8.4 Hz, 1 H), 6.33 (dd, J = 4.4, 9.6 Hz, 1 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.75 (dd, J = 9.6, 14.0 Hz, 1 H), 3.38 (dd, J = 4.4, 14.0 Hz, 1 H). LCMS (method 1): [MH+]=476 at 3.65 min.

Intermediate 95

¹H NMR (400 MHz, CDCl₃): δ 10.37 (s, 1 H), 8.59 (dd, J = 6.7, 2.3 Hz, 1 H), 8.25 (ddd, J = 8.7, 5.0, 2.4 Hz, 1 H), 8.15 (s, 2 H), 7.06-6.99 (m, 2 H), 6.88 (d, J = 8.3 Hz, 1 H), 6.29 (dd, J = 9.1, 4.5 Hz, 1 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.75 (dd, J = 14.1, 9.8 Hz, 1 H), 3.38 (dd, J = 14.4, 4.4 Hz, 1 H). LCMS (Method 1): [MH+] = 494 at 3.64 min.

Intermediate 96

¹H NMR (400 MHz, CDCl₃): δ 10.10 (s, 1 H), 8.18-8.13 (m, 2 H), 8.12 (s, 2 H), 7.96-7.94 (m, 2 H), 7.20-7.18 (m, 1 H), 7.08-7.03 (m, 2 H), 6.43 (t, J = 75.2 Hz, 1 H), 6.29 (dd, J = 4.4, 9.6 Hz, 1 H), 3.90-3.88 (m, 2 H), 3.72 (dd, J = 9.6, 14.0 Hz, 1 H), 3.33 (dd, J = 4.4, 14.0 Hz, 1 H), 1.30-1.24 (m, 1 H), 0.67-0.64 (m, 2 H), 0.38-0.35 (m, 2 H). LCMS (Method 2): [MH+] = 552 at 3.97 min.

Intermediate 97

¹H NMR (400MHz, CDCl₃): δ 10.08 (s, 1 H), 8.53 (s, 1 H), 8.26 (d, J = 7.8 Hz, 1 H), 8.15 (s, 2 H), 8.10 (d, J = 7.6 Hz, 1 H), 7.64 (t, J = 7.7 Hz, 1 H), 7.19 (d, J = 8.1 Hz, 1 H), 7.10-7.03 (m, 2 H), 6.62 (t, J = 75.3 Hz, 1 H), 6.30 (dd, J = 10.0, 4.3 Hz, 1 H), 3.91 (d, J = 6.9 Hz, 2 H), 3.73 (dd, J = 14.1, 10.0 Hz, 1 H), 3.35 (dd,J= 14.1, 4.3 Hz, 1 H), 1.32-1.23 (m, 1 H), 0.69-0.63 (m, 2 H), 0.40-0.35 (m, 2 H). LCMS (Method 2): [MH+] = 552 at 4.00 min.

Intermediate 98

¹H NMR (400 MHz, CDCl₃): δ 10.10 (s, 1 H), 8.18-8.14 (m, 2 H), 8.12 (s, 2 H), 7.97-7.95 (m, 2 H), 7.19-7.17 (m, 1 H), 7.07-7.04 (m, 2 H), 6.55 (t, J = 75.2 Hz, 1 H), 6.29 (dd, J = 4.4, 9.6 Hz, 1 H), 4.60-4.54 (m, 1 H), 3.70 (dd, J = 9.6, 14.0 Hz, 1 H), 3.34 (dd, J = 4.4, 14.0 Hz, 1 H), 1.38-1.27 (m, 6 H). LCMS (Method 2): [MH+] = 540 at 4.02 min.

Intermediate 99

¹H NMR (400 MHz, CDCl₃): δ 10.10 (s, 1 H), 8.15 (d, J = 8.0 Hz, 2 H), 8.12 (s, 2 H), 7.94 (d, J = 8.0 Hz, 2 H), 7.04-6.99 (m, 2 H), 6.88-6.86 (m, 1 H), 6.29 (dd, J = 4.4, 9.6 Hz, 1 H), 3.88 (s, 2 H), 3.87 (s, 3 H), 3.69 (dd, J = 9.6, 14.0 Hz, 1 H), 3.35 (dd, J = 4.4, 14.0 Hz, 1 H), 1.33-1.30 9m, 1 H), 0.66-0.62 (m, 2 H), 0.38-0.35 (m, 2 H). LCMS (Method 1): [MH+] = 516 at 3.97 min.

Intermediate 100

¹H NMR (400 MHz, CDCl₃): δ 10.10 (s, 1 H), 8.18 (d, J = 8.4 Hz, 2 H), 8.12 (s, 2 H), 7.95 (d, J = 8.4 Hz, 2 H), 7.00-6.98 (m, 2 H), 6.86-6.84 (m, 1 H), 6.30 (dd, J = 4.4, 9.6 Hz, 1 H), 4.79-4.77 (m, 1 H), 3.84 (s, 3 H), 3.71 (dd, J = 9.6, 14.0 Hz, 1 H), 3.35 (dd, J = 4.4, 14.0 Hz, 1 H), 2.04-1.83 (m, 6 H), 1.61-1.56 (m, 2 H). LCMS (Method 1): [MH+] = 530 at 4.21 min.

Intermediate 101

¹H NMR (400 MHz, CDCl₃): δ 10.1 (s, 1 H), 8.14-8.11 (m, 4 H), 7.99-7.97 (m, 2 H), 7.78-7.70 (m, 2 H), 7.69-7.68 (m, 2 H), 7.06-6.99 (m, 2 H), 6.88-6.85 (m, 1 H), 6.33 (dd, J = 4.4, 9.6 Hz, 1 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.74 (dd, J = 9.6, 14.0 Hz, 1 H), 3.37 (dd, J = 4.4, 14.0 Hz, 1 H). LCMS (Method 2): [MH+] = 552 at 3.51 min.

Intermediate 102

LCMS (Method 2): [MH+] = 552 at 3.54 min.

Intermediate 103

¹H NMR (400 MHz, CDCl₃): δ 10.10 (s, 1 H), 8.29-8.28 (m, 1 H), 8.17 (s, 2 H), 8.13-8.12 (m, 1 H), 8.06-8.04 (m, 1 H), 7.90-7.81 (m, 3 H), 7.67-7.63 (m, 1 H), 7.57-7.53 (m, 1 H), 7.06-7.02 (m, 2 H), 6.88-6.86 (m, 1 H), 6.33 (dd, J = 4.4,9.6 Hz, 1 H), 3.91 (s, 3 H), 3.87 (s, 3 H), 3.75 (dd, J = 9.6, 14.0 Hz, 1 H), 3.37 (dd, J = 4.4, 14.0 Hz, 1 H). LCMS (Method 2): [MH+] = 552 at 3.54 min.

Intermediate 104

¹H NMR (400 MHz, CDCl₃): δ 10.07 (s, 1 H), 8.29-8.28 (m, 1 H), 8.14 (s, 2 H), 8.08-8.06 (m, 1 H), 7.99-7.97 (m, 2 H), 7.84-7.82 (m, 1 H), 7.75 (d, J = 8.2 Hz, 2 H), 7.58-7.54 (m, 1 H), 7.07-7.01 (m, 2 H), 6.88-6.86 (m, 1 H), 6.34 (dd, J = 4.4, 9.6 Hz, 1 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.74 (dd, J = 9.6, 14.0 Hz, 1 H), 3.37 (dd, J = 4.4, 14.0 Hz, 1 H). LCMS (Method 2): [MH+] = 552 at 3.49 min

Intermediate 105

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-chloroanilino)methyl]benzoate

To a solution of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-formylbenzoate (332 mg, 0.697 mmol) and 2-chloroaniline (0.077 mL, 0.732 mmol) in anhydrous DCM (3.5 mL) was added acetic acid (0.042 mL, 0.732 mmol). The mixture was stirred at room temperature for 24 hours. NaBH(OAc)₃ (369 mg, 1.74 mmol) was added and the mixture was stirred at room temperature for 24 h. After addition of water (2.5 mL) the mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a phase separator and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography eluting with 1:1 DCM:EtOAc to afford the title compound as a white solid (274 mg, 67%).

¹H NMR (400 MHz, CDCl₃): δ 8.08 (s, 2 H), 8.04 (s, 1 H), 7.93 (d, J = 7.8 Hz, 1 H), 7.56 (d, J = 7.7 Hz, 1 H), 7.42 (t, J = 7.7 Hz, 1 H), 7.29 (dd, J = 7.9, 1.5 Hz, 1 H), 7.11-7.05 (m, 1 H), 7.01 (dd, J = 8.2, 1.9 Hz, 1 H), 6.97 (d, J = 2.0 Hz, 1 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.67 (td, J = 7.6, 1.4 Hz, 1 H), 6.54 (dd, J = 8.2, 1.4 Hz, 1 H), 6.29 (dd, J = 10.0, 4.4 Hz, 1 H), 4.86-4.81 (m, 1 H), 4.47 (d, J = 5.6 Hz, 2 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.70 (dd, J = 13.9, 10.0 Hz, 1 H), 3.32 (dd, J = 14.0, 4.4 Hz, 1 H).

The following intermediates were synthesised: similarly to the method of the intermediate 105 by using the suitable amine:

Structure

Intermediate number

Precursor

Analytical Data

Intermediate 106

Intermediate 93

¹H NMR (400 MHz, CDCl₃): δ 8.14 (s, 2 H), 8.02 (s, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.56 (d, J = 7.7 Hz, 1 H), 7.42 (t, J = 7.7 Hz, 1 H), 7.02-6.96 (m, 2 H), 6.88-6.76 (m, 2 H), 6.74-6.66 (m, 1 H), 6.50 (td, J = 9.3, 5.4 Hz, 1 H), 6.29 (dd, J = 9.9, 4.5 Hz, 1 H), 4.40 (s, 2 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.71 (dd, J = 14.0, 9.9 Hz, 1 H), 3.34 (dd, J = 14.0, 4.5 Hz, 1 H).

Intermediate 107

Intermediate 94

¹H NMR (400 MHz, DMSO): δ 8.54 (s, 2 H), 7.93 (d, J = 7.8 Hz, 2 H), 7.48 (d, J = 7.8 Hz, 2 H), 7.05-6.95 (m, 3 H), 6.76-6.72 (m, 1 H), 6.49-6.45 (m, 2 H), 6.20 (dd, J = 9.6, 4.4 Hz, 1 H), 5.82-5.81 (m, 1 H), 4.37-4.35 (m, 2 H), 3.77 (s, 3 H), 3.75 (s, 3 H), 3.65-3.61 (m, 4 H), 3.35-3.29 (m, 1 H). LCMS (Method 2): [MH+] = 601 at 3.22 min.

Intermediate 108

Intermediate 94

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 2 H), 7.99 (d, J = 8.4 Hz, 2 H), 7.41 (d, J = 8.4 Hz, 2 H), 7.04-6.98 (m, 4 H), 6.86-6.83 (m, 1 H), 6.68-6.66 (m, 1 H), 6.55-6.53 (m, 1 H), 6.50 (d, J = 74.4 Hz, 1 H), 6.28 (dd, J = 4.8, 9.6 Hz, 1 H), 4.74-4.72 (m, 1 H), 4.45-4.44 (m, 2 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.70 (dd, J = 9.6, 14.0 Hz, 1 H), 3.33 (dd, J = 4.8, 14.0 Hz, 1 H). LCMS (Method 1): [MH+] = 619 at 4.22 min.

Intermediate 109

Intermediate 94

¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 2 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H), 7.01-6.97 (m, 2 H), 6.71-6.69 (m, 1 H), 6.67-6.58 (m, 3 H), 6.28 (dd, J = 4.4, 9.6 Hz, 1 H), 4.52 (s, 2 H), 4.29 (brs, 1 H), 3.91 (s, 3 H), 3.89 (s, 3 H), 3.86 (s, 3 H), 3.72 (dd, J = 9.6, 14.0 Hz, 1 H), 3.32 (dd, J = 4.4, 14.0 Hz, 1 H). LCMS (Method 2): [MH+] = 601 at 3.41 min.

Intermediate 110

Intermediate 94

¹H N MR (400 MHz, DMSO): δ 9.63 (brs, 1 H), 8.54 (s, 2 H), 7.92 (d, J =8.0 Hz, 2 H), 7.47 (d, J = 8.0 Hz, 2 H), 7.04-6.94 (m, 3 H), 6.65-6.64 (m, 1 H), 6.51-6.49 (m, 1 H), 6.40-6.36 (m, 1 H), 6.29-6.27 (m, 1 H), 6.19 (dd, J = 4.4, 9.6 Hz, 1 H), 5.43 (t, J = 6.2 Hz, 1 H), 4.38 (d, J = 6.2 Hz, 2 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.61 (dd, J = 9.6, 14.0 Hz, 1 H), 3.34-3.31 (m, 1 H). LCMS (Method 1): [MH+] = 569 at 3.64 min.

Intermediate 111

Intermediate 94

¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 2 H), 7.94 (d, J = 8.4 Hz, 2 H), 7.40 (d, J = 8.4 Hz, 2 H), 7.05-6.97 (m, 3 H), 6.86-6.82 (m, 2 H), 6.34-6.29 (m, 1 H), 6.28-6.16 (m, 1 H), 6.15-6.03 (m, 1 H), 4.39 (s, 2 H), 3.94 (s, 3 H), 3.89 (s, 3 H), 3.71 (dd, J = 9.6, 14.0 Hz, 1 H), 3.32 (dd, J = 4.8, 14.0 Hz, 1 H). NH and OH not observed. LCMS (Method 1): [MH+] = 569 at 3.58 min.

Intermediate 112

Intermediate 94

¹H NMR (400 MHz, DMSO): δ 8.55 (s, 2 H), 7.96-7.94 (m, 2 H), 7.50-7.45 (m, 3 H), 7.15-7.11 (m, 1 H), 7.05-6.95 (m, 3 H), 6.87-6.84 (m, 1 H), 6.54 (t, J = 6.4 Hz, 1 H), 6.20 (dd, J = 4.4,9.6 Hz, 1 H), 4.36 (d, J = 6.4 Hz, 2 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.61 (dd, J = 9.6, 14.0, 1 H), 3.32 (dd, J = 4.4, 14.0 Hz, 1 H). LCMS (Method 1): [MH+] = 572 at 3.75 min

Intermediate 113

Intermediate 94

1H NMR (400 MHz, DMSO): δ 8.55 (s, 2 H), 7.99-7.94 (m, 4 H), 7.62-7.58 (m, 1 H), 7.48-7.45 (m, 2 H), 7.06-6.95 (m, 3 H), 6.78-6.75 (m, 1 H), 6.20 (dd, J = 4.4, 9.6 Hz, 1 H), 4.58 (brs, 2 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 3.62 (dd, J = 9.6, 14.0 Hz, 1 H), 3.33 (dd, J = 4.4, 14.0 Hz, 1 H). LCMS (Method 1): [MH+] = 572 at 3.48 min

Intermediate 114

Intermediate 94

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 2 H), 7.98 (d, J = 8.4 Hz, 2 H), 7.41 (d, J = 8.4 Hz, 2 H), 7.15 (t. J = 8.0 Hz, 1 H), 7.02-6.98 (m, 2 H), 6.85 (d, J = 8.0 Hz, 1 H), 6.72-6.71 (m, 1 H), 6.63-6.58 (m, 2 H), 6.29 (dd, J = 4.4, 9.6 Hz, 1 H), 4.42-4.41 (brs, 2 H), 4.25-4.24 (brs, 1 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.70 (dd, J = 9.6, 14.0 Hz, 1 H), 3.34 (dd, J = 4.4, 14.0 Hz, 1 H), 3.10-3.06 (brs, 3 H), 2.99-2.92 (brs, 3 H). LCMS (Method 1): [MH+] = 624 at 2.98 min.

Intermediate 115

Intermediate 94

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 2 H), 7.99 (d, J = 8.4 Hz, 2 H), 7.50-7.49 (m, 1 H), 7.41 (d, J = 8.4 Hz, 2 H), 7.02-6.99 (m, 2 H), 6.86-6.84 (m, 1 H), 6.71-6.68 (m, 1 H), 6.57-6.55 (m, 1 H), 6.29 (dd, J = 4.4, 9.6 Hz, 1 H), 4.71-4.68 (m, 1 H), 4.42-4.41 (m, 2 H), 4.00 (s, 3 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.70 (dd, J = 9.6, 14.0 Hz, 1 H), 3.32 (dd, J = 4.4, 14.0 Hz, 1 H). LCMS (Method 1): [MH+] = 584 at 3.92 min.

Intermediate 116

Intermediate 94

¹H NMR (400 MHz, CDCl₃): δ 8.19 (d, J = 2.0 Hz, 1 H), 8.12 (s, 2 H), 7.99 (d, J = 8.4 Hz, 2 H), 7.55 (d, J = 2.0 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 2 H), 7.02-6.97 (m, 2 H), 6.86-6.84 (m, 1 H), 6.51-6.50 (m, 1 H), 6.31-6.27 (m, 2 H), 4.47-4.45 (m, 2 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.79 (s, 3 H), 3.70 (dd, J = 9.6, 14.0 Hz, 1 H), 3.32 (dd, J = 4.4, 14.0 Hz, 1 H). LCMS (Method 1): [MH+] = 584 at 2.67 min.

Intermediate 117

Intermediate 94

LCMS (Method 2): [MH+] = 584 at 2.67 min.

Intermediate 118

Intermediate 94

LCMS (Method 1): [MH+] = 578 at 4.04 min.

Intermediate 119

Intermediate 96

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 8.06-8.00 (m, 1 H), 7.98-7.97 (m, 3 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.18-7.16 (m, 1 H), 7.07-7.02 (m, 3 H), 6.83-6.81 (m, 1 H), 6.42 (t, J = 75.2 Hz, 1 H), 6.26 (dd, J = 4.4, 9.6 Hz, 1 H), 4.43-4.42 (m, 2 H), 4.32-4.31 (m, 1 H), 4.03-4.00 (m, 2 H), 3.68 (dd, J = 9.6, 14.0 Hz, 1 H), 3.31 (dd, J = 4.4, 14.0 Hz, 1 H), 1.28-1.25 (m, 1 H), 0.66-0.62 (m, 2 H), 0.37-0.34 (m, 2 H).

Intermediate 120

Intermediate 98

¹H NMR (400 MHz, CDCl₃): δ 8.13-8.10 (m, 3 H), 8.00-7.97 (m, 3 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.17-7.15 (m, 1 H), 7.10-7.02 (m, 3 H), 6.86-6.83 (m, 1 H), 6.54 (t, J = 75.2 Hz, 1 H), 6.27 (dd, J = 4.4, 9.6 Hz, 1 H), 4.59-4.53 (m, 1 H), 4.43-4.41 (m, 3 H), 3.67 (dd, J = 9.6, 14.0 Hz, 1 H), 3.31 (dd, J = 4.4, 14.0 Hz, 1 H), 1.37-1.32 (m, 6 H).

Intermediate 121

Intermediate 99

¹H NMR (400 MHz, CDCl₃): δ 8.35-8.31 (m, 1 H), 8.11 (s, 2 H), 8.00 (d, J = 8.0 Hz, 2 H), 7.98-7.93 (m, 1 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.19-7.16 (m, 1 H), 7.02-6.91 (m, 3 H), 6.86-6.84 (m, 1 H), 6.28 (dd, J = 4.4, 9.6 Hz, 1 H), 5.34 (brs, 1 H), 4.47-4.45 (m, 2 H), 3.87 (s, 2 H), 3.86 (s, 3 H), 3.66 (dd, J = 9.6, 14.0 Hz, 1 H), 3.33 (dd, J = 4.4, 14.0 Hz, 1 H), 1.32-1.24 (m, 1 H), 0.64-0.61 (m, 2 H), 0.37-0.34 (m, 2 H). LCMS (Method 1): [MH+] = 594 at 2.73 min.

Intermediate 122

Intermediate 100

¹H NMR (400 MHz, CDCl₃): δ 8.16 (s, 2 H), 8.11-8.06 (m, 1 H), 8.01-7.98 (m, 3 H), 7.43-7.41 (m, 2 H), 7.21-7.19 (m, 1 H), 7.07-6.96 (m, 2 H), 6.85-6.81 (m, 2 H), 6.28 (dd, J = 4.4, 9.6 Hz, 1 H), 4.78-4.76 (m, 1 H), 4.43-4.42 (m, 2 H), 4.13-4.11 (m, 1 H), 3.83 (s, 3 H), 3.69 (dd, J = 9.6, 14.0 Hz, 1 H), 3.33 (dd, J = 4.4, 14.0 Hz, 1 H), 1.92-1.82 (m, 6 H), 1.27-1.24 (m, 2 H). LCMS (Method 1): [MH+] = 608 at 2.81 min.

Intermediate 123

Intermediate 95

¹H NMR (400 MHz, CDCl₃): δ 8.10 (dd, J = 7.2, 2.2 Hz, 1 H), 8.05 (s, 2 H), 7.95-7.90 (m, 1 H), 7.12 (t, J = 9.0 Hz, 1 H), 7.02 (ddd, J = 11.9, 8.0, 1.4 Hz, 1 H), 6.98-6.92 (m, 3 H), 6.84 (d, J = 8.2 Hz, 1 H), 6.71-6.64 (m, 1 H), 6.63-6.55 (m, 1 H), 6.24 (dd, J = 10.1, 4.3 Hz, 1 H), 4.52-4.39 (m, 3 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.65 (dd, J = 14.0, 10.1 Hz, 1 H), 3.28 (dd, J = 14.0, 4.3 Hz, 1 H). HPLC (Method 1): [MH+] = 589 at 4.24 min

Intermediate 124

Intermediate 95

¹H NMR (400 MHz, CDCl₃): δ 8.10 (dd, J = 7.2, 2.0 Hz, 1 H), 8.06 (s, 2 H), 7.93 (ddd, J = 8.6, 5.1, 2.3 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.35-7.28 (m, 1 H), 7.18 (dd, J = 8.4, 7.2 Hz, 2 H), 7.11 (t, J = 8.9 Hz, 2 H), 6.95 (dd, J = 7.9, 1.8 Hz, 1 H), 6.93 (dd, J = 10.0, 2.0 Hz, 1 H), 6.83 (d, J = 8.2 Hz, 1 H), 6.24 (dd, J = 10.0, 4.3 Hz, 1 H), 4.44 (d, J = 5.3 Hz, 2 H), 4.13 (d, J = 6.7 Hz, 1 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.65 (dd, J = 14.0, 10.0 Hz, 1 H), 3.29 (dd, J = 14.0, 4.3 Hz, 1 H). LCMS (Method 1) [MH+] =571 at 4.23 min

Intermediate 125

Intermediate 101

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 8.06 (d, J = 8.4 Hz, 2 H), 7.64 (d, J = 8.4 Hz, 2 H), 7.60 (d, J = 8.4 Hz, 2 H), 7.47 (d, J = 8.4 Hz, 2 H), 7.05-6.94 (m, 4 H), 6.87-6.85 (m, 1 H), 6.69-6.63 (m, 2 H), 6.32 (dd, J = 4.4, 9.6 Hz, 1 H), 4.45-4.43 (m, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.73 (dd, J = 9.6, 14.0 Hz, 1 H), 3.38 (dd, J = 4.4, 14.0 Hz, 1 H). LCMS (Method 1): [MH+] = 647 at 4.58 min.

Intermediate 126

Intermediate 102

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 8.09-8.07 (m, 2 H), 7.65-7.62 (m, 3 H), 7.54-7.51 (m, 1 H), 7.46-7.39 (m, 2 H), 7.05-6.93 (m, 4 H), 6.86 (d, J = 8.4 Hz, 1 H), 6.70-6.61 (m, 2 H), 6.32 (dd, J = 4.4, 9.6 Hz, 1 H), 4.43-4.40 (m, 3 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.73 (dd, J = 9.6, 14.0 Hz, 1 H), 3.35 (dd, J = 4.4, 14.0 Hz, 1 H). LCMS (Method 1): [MH+] = 647 at 4.59 min.

Intermediate 127

Intermediate 103

¹H NMR (400 MHz, CDCl₃): δ 8.25 (s, 1 H), 8.12 (s, 2 H), 8.00-7.99 (m, 1 H), 7.78-7.76 (m, 1 H), 7.61 (s, 1 H), 7.52-7.39 (m, 4 H), 7.05-6.94 (m, 4 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.71-6.60 (m, 2 H), 6.31 (dd, J = 4.4, 9.6 Hz, 1 H), 4.45-4.44 (m, 3 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.73 (dd, J = 9.6, 14.0 Hz, 1 H), 3.35 (dd, J = 4.4, 14.0 Hz, 1 H). LCMS (Method 1): [MH+] = 647 at 4.60 min.

Intermediate 128

Intermediate 104

¹H NMR (400 MHz, CDCl₃): δ 8.26 (s, 1 H), 8.12 (s, 2 H), 8.00-7.98 (m, 1 H), 7.77-7.75 (m, 1 H), 7.58-7.56 (m, 2 H), 7.51-7.45 (m, 3 H), 7.05-6.93 (m, 4 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.69-6.60 (m, 2 H), 6.32 (dd, J = 4.4, 9.6 Hz, 1 H), 4.44-4.42 (m, 3 H), 3.89 (s, 3 H), 3.86 (s, 3 H), 3.72 (dd, J = 9.6, 14.0 Hz, 1 H), 3.36 (dd, J = 4.4, 14.0 Hz, 1 H). LCMS (Method 1): [MH+] = 647 at 4.61 min.

Intermediate 129

Intermediate 94

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 2 H), 8.00 (d, J = 8.1 Hz, 2 H), 7.44 (d, J = 8.1 Hz, 2 H), 7.08 (d, J = 3.6 Hz, 1 H), 7.04 (d, J = 3.6 Hz, 1 H), 7.02 (dd, J = 8.3, 2.5 Hz, 1 H), 6.98 (d, J = 2.1 Hz, 1 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.30 (dd, J = 9.6, 4.5 Hz, 1 H), 5.12-5.01 (bs, 1H), 4.56 (s, 2 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.70 (dd, J = 14.7, 9.7 Hz, 1 H), 3.35 (dd, J = 14.7, 4.3 Hz, 1 H). LCMS (Method 1) [MH+]=560 at 2.74 min

Intermediate 130

Intermediate 94

¹H NMR (400 MHz, CDCl₃): δ 8.07 (s, 2 H), 8.02 (s, 1 H), 7.96 (d, J = 8.03 Hz, 2 H), 7.46 (d, J = 8.01 Hz, 2 H), 7.16 (d, J = 8.12 Hz, 1 H), 7.03-6.96 (m, 3 H), 6.85 (d, J = 8.16 Hz, 1 H), 6.44 (d, J = 7.34 Hz, 1 H), 6.31 (dd, J = 9.73, 4.62 Hz, 1 H), 4.52 (s, 2 H), 3.88 (d, J = 9.08 Hz, 6 H), 3.71 (dd, J = 13.97, 9.70 Hz, 1 H), 3.34 (dd, J = 14.00, 4.70 Hz, 1 H). LCMS (Method 1): [MH+] = 593 at 3.83 min

Intermediate 131

Intermediate 93

¹H NMR (400 MHz, CDCl₃): δ 8.07-8.00 (m, 3 H), 7.93 (s, 1 H), 7.88 (d, J = 7.84 Hz, 1 H), 7.60 (d, J = 7.74 Hz, 1 H), 7.40 (t, J = 7.79 Hz, 1 H), 7.17 (d, J = 8.09 Hz, 1 H), 7.04-6.95 (m, 3 H), 6.86 (d, J = 8.24 Hz, 1 H), 6.47 (d, J = 7.38 Hz, 1 H), 6.35 (dd, J = 9.99, 4.77 Hz, 1 H), 5.10 (s, 1 H), 4.49 (d, J = 5.85 Hz, 2 H), 3.88 (t, J = 10.44 Hz, 7 H), 3.66 (dd, J = 13.94, 9.98 Hz, 1 H), 3.36 (dd, J = 13.95, 4.75 Hz, 1 H). LCMS (Method 1): [MH+] = 593 at 3.84 min

Intermediate 132

Intermediate 94

¹H NMR (400 MHz, CDCl₃): δ 8.42 (s, 1 H), 8.08 (t, J = 9.97 Hz, 2 H), 7.96 (t, J = 8.10 Hz, 2 H), 7.45 (dd, J = 16.60, 8.05 Hz, 2 H), 7.18-7.13 (m, 2 H), 7.03-6.95 (m, 3 H), 6.85 (d, J = 8.21 Hz, 1 H), 6.54 (dd, J = 3.18, 1.96 Hz, 1 H), 6.45 (d, J = 7.50 Hz, 1 H), 6.30 (dd, J = 9.81, 4.62 Hz, 1 H), 4.50 (s, 2 H), 4.13 (s, 1 H), 3.88 (d, J = 8.13 Hz, 6 H), 3.75-3.65 (m, 1 H), 3.34 (dd, J = 13.98, 4.65 Hz, 1 H), LCMS (Method 1): [MH+] = 592 at 4.05 min.

Intermediate 133

Intermediate 96

¹H NMR (400 MHz, CDCl₃): δ 8.14 (s, 2 H), 7.97 (d, J = 8.09 Hz, 2 H), 7.44 (d, J = 8.06 Hz, 2 H), 7.17 (d, J = 8.12 Hz, 1 H), 7.07-6.97 (m, 3 H), 6.81-6.72 (m, 2 H), 6.65-6.59 (m, 1 H), 6.55-6.52 (m, 1 H), 6.27 (dd, J = 10.06, 4.19 Hz, 1 H), 5.17 (s, 1 H), 4.43 (s, 2 H), 3.88 (d, J = 6.89 Hz, 2 H), 3.68 (dd, J = 14.06, 10.09 Hz, 1 H), 3.31 (dd, J = 14.07, 4.23 Hz, 1 H), 2.28 (s, 1 H), 1.30-1.24 (m, 1 H), 0.67-0.61 (m, 2 H), 0.38-0.33 (m, 2 H).LCMS (Method 2): [MH+] = 645 at 3.66 min.

Intermediate 134

Intermediate 97

LCMS (Method 2): [MH+] = 645 at 3.71 min.

Intermediate 135

Intermediate 94

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 2 H), 8.00 (d, J = 8.1 Hz, 2 H), 7.42 (d, J = 8.1 Hz, 2 H), 7.22 (t, J = 7.9 Hz, 1 H), 7.04-6.98 (m, 2 H), 6.88-6.81 (m, 2 H), 6.73 (s, 1 H), 6.71-6.40 (m, 2 H), 6.30 (dd, J = 9.8, 4.5 Hz, 1 H), 4.43 (d, J = 5.7 Hz, 2 H), 4.30 (t, J = 5.7 Hz, 1 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.71 (dd, J = 14.0, 9.8 Hz, 1 H), 3.35 (dd, J = 14.0, 4.6 Hz, 1 H).

LCMS (Method 1): [MH+] = 603 at 4.17 min.

Intermediate 136

Intermediate 94

LCMS (Method 1): [MH+] = 583 at 3.70 min.

Intermediate 137

Intermediate 94

LCMS (Method 1): [MH+] = 587 at 3.56 min.

Intermediate 138

Intermediate 94

LCMS (Method 1): [MH+] = 599 at 3.69 min.

Intermediate 139

Intermediate 94

LCMS (Method 2): [MH+] = 603 at 3.71 min.

Intermediate 140

Intermediate 94

LCMS (Method 1): [MH+] = 587 at 3.70 min.

Intermediate 141

Intermediate 94

LCMS (Method 2): [MH+] = 583 at 3.58 min.

Intermediate 142

Intermediate 94

LCMS (Method 2): [MH+] = 603 at 3.63 min

Example 94

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3- [(2-chloro-N- [(3R)-quinuclidin-3-yl] oxycarbonyl-anilino)methyl] benzoate

A suspension of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-chloroanilino)methyl]benzoate (72 mg, 0.123 mmol) and (R)-quinuclidin-3-yl carbonochloridate hydrochloride (138 mg, 0.612 mmol) in anhydrous CH₃CN (1 mL) was heated at 80°C for 3 min under microwave irradiation. After cooling to room temperature, the solvent was removed in vacuo. Purification of the crude material by preparative HPLC afforded the title compound as a yellow solid (47.8 mg, 53%). ¹H NMR (400 MHz, DMSO at 125 °C): δ 8.23 (s, 2 H), 7.84 (br s, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 7.46-7.39 (m, 2 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.26-7.17 (m, 2 H), 7.10-7.06 (m, 1 H), 6.96 (d, J = 2.0 Hz, 1 H), 6.95-6.88 (m, 2 H), 6.21 (dd, J = 8.9, 4.8 Hz, 1 H), 4.76 (br s, 2 H), 4.65-4.60 (m, 1 H), 3.72 (s, 6 H), 3.56 (dd, J = 14.2, 9.1 Hz, 1 H), 3.32 (dd, J= 14.2, 4.9 Hz, 1 H), 3.05-2.97 (m, 1 H), 2.61-2.45 (m, 5 H), 1.80-1.74 (m, 1 H), 1.55-1.45 (m, 1 H), 1.45-1.35 (m, 1 H), 1.28-1.17 (m, 1 H), 1.15-1.04 (m, 1 H). LCMS (Method 1): [MH+] = 742 at 2.77 min.

The following compounds were synthesised similarly to the method of the example 94:

Structure

Example number

Precursor

Analytical Data

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2,4-difluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 95

Intermediate 106

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 7.93 (d, J = 7.7 Hz, 1 H), 7.88 (s, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.7 Hz, 1 H), 7.02-6.94 (m, 3 H), 6.89-6.77 (m, 3 H), 6.30-6.24 (m, 1 H), 4.91-4.74 (m, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.69 (dd, J = 14.0, 9.7 Hz, 1 H), 3.38-3.24 (m, 2 H), 2.90-2.80 (m, 3 H), 2.76-2.60 (m, 2 H), 2.08-2.02 (m, 1H), 1.78-1.68 (m, 1 H), 1.67-1.56 (m, 1 H), 1.46-1.29 (s, 2 H). LCMS (Method 1): [MH+] = 742 at 2.85 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-fluoro-3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 96

Intermediate 123

¹H NMR (400 MHz, CDCl₃): δ 8.13-8.11 (m, 3 H), 7.93-7.90 (m, 1 H), 7.24-7.22 (m, 1 H), 7.18-6.98 (m, 6 H), 6.86 (d, J = 8.0 Hz, 1 H), 6.25 (dd, J = 4.4, 9.6 Hz, 1 H), 4.92 (s, 2 H), 4.81-4.78 (m, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.68 (dd, J = 9.6, 14.0 Hz, 1 H), 3.33 (dd, J = 4.4, 14.0 Hz, 1 H), 3.20-3.15 (m, 1 H), 2.70-2.59 (m, 5 H), 1.99-1.93 (m, 1 H), 1.62-1.57 (m, 1 H), 1.53-1.47 (m, 1 H), 1.36-1.24 (m, 1 H), 1.22-1.14 (m, 1 H). LCMS (Method 1): [MH+] = 742 at 2.75 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-fluoro-3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]benzoate

Example 97

Intermediate 124

¹H NMR (400 MHz, CDCl₃): δ 8.10-8.06 (m, 3 H), 7.95-7.91 (m, 1 H), 7.33-7.29 (m, 2 H), 7.24-7.18 (m, 3 H), 7.05 (t, J = 8.9 Hz, 1 H), 6.99-6.95 (m, 2 H), 6.85 (d, J = 8.0 Hz, 1 H), 6.25 (dd, J = 4.4, 9.6 Hz, 1 H), 4.97 (s, 2 H), 4.79-4.77 (m, 1 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.66 (dd, J = 9.6, 14.0 Hz, 1 H), 3.33 (dd, J = 4.4, 14.0 Hz, 1 H), 3.17-3.15 (m, 1 H), 2.72-2.59 (m, 5 H), 2.00-1.92 (m, 1 H), 1.60-1.57 (m, 1 H), 1.52-1.47 (m, 1 H), 1.42-1.31 (m, 1 H), 1.24-1.17 (m, 1 H). LCMS (Method 2): [MH+]=724 at 3.48 min

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-fluoro-4-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 98

Intermediate 107

¹H NMR (400 MHz, DMSO): δ 8.53 (s, 2 H), 7.99-7.88 (m, 2 H), 7.48-7.32 (m, 2 H), 7.29-7.14 (m, 1 H), 7.07-6.93 (m, 3 H), 6.91-6.81 (m, 1 H), 6.78-6.65 (m, 1 H), 6.21 (dd, J = 9.6, 4.4 Hz, 1 H), 4.91-4.69 (m, 2 H), 4.69-4.58 (m, 1 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.61 (dd, J = 14.0, 4.4 Hz, 1 H), 3.47-3.45 (m, 1 H), 3.11-3.01 (m, 1 H), 2.67-2.53 (m, 3 H), 2.46-2.33 (m, 2 H), 1.93-1.73 (m, 1 H), 1.59-1.36 (m, 2 H), 1.28-1.09 (m, 2 H). LCMS (Method 1): [MH+] = 754 at 2.78 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[2-(difluoromethoxy)-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino]methyl]benzoate

Example 99

Intermediate 108

¹H NMR (400 MHz, DMSO@110 °C): δ 8.32 (s, 2 H), 7.91-7.88 (m, 2 H), 7.40-7.30 (m, 3 H), 7.25-7.14 (m, 3 H), 7.04-6.94 (m, 4 H), 6.26 (dd, J = 4.8, 9.1 Hz, 1 H), 4.81-4.80 (m, 2 H), 4.67-4.63 (m, 1 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 3.62 (dd, J = 9.1, 14.1 Hz, 1 H), 3.37 (dd, J = 4.8, 14.1 Hz, 1 H), 3.08-3.04 (m, 1 H), 2.65-2.50 (m, 5 H), 1.82-1.80 (m, 1 H), 1.58-1.52 (m, 1 H), 1.49-1.41 (m, 1 H), 1.34-1.27 (m, 1 H), 1.20-1.17 (m, 1 H). LCMS (Method 2): [MH+] = 772 at 3.58 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-fluoro-6-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate formate salt

Example 100

Intermediate 109

¹H N MR (400 MHz, DMSO @ 125 °C): δ 8.31 (s, 2 H), 8.20 (s, 1 H), 7.89 (d, J = 8.4 Hz, 2 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.30-7.24 (m, 1 H), 7.06-6.97 (m, 3 H), 7.06-7.04 (m, 1 H), 6.89-6.74 (m, 1 H), 6.28 (dd, J = 4.8, 9.2 Hz, 1 H), 4.81-4.66 (m, 3 H), 3.80 (s, 3 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.64 (dd, J = 9.2, 14.0 Hz, 1 H), 3.40 (dd, J = 4.8, 14.0 Hz, 1 H), 3.10-3.04 (m, 1 H), 2.66-2.54 (m, 5 H), 1.84-1.81 (m, 1 H), 1.58-1.56 (m, 1 H), 1.55-1.47 (m, 1 H), 1.43-1.31 (m, 1 H), 1.30-1.18 (m, 1 H). LCMS (Method 1): [MH+] = 754 at 2.76 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate

Example 101

Intermediate 110

1H NMR (400 MHz, CD₃CN): δ 8.22 (brs, 1 H), 8.09 (s, 2 H), 7.85 (d, J = 7.8 Hz, 2 H), 7.32-7.30 (m, 2 H), 7.02-6.92 (m, 3 H), 6.86-6.78 (m, 3 H), 6.69-6.59 (m, 1 H), 6.13 (dd. J = 4.6, 9.6 Hz, 1 H), 4.93-4.70 (m, 2 H), 4.63-4.50 (m, 1 H), 3.78 (s, 3 H), 3.75 (s, 3 H), 3.59 (dd, J = 9.6, 14.0 Hz, 1 H), 3.25 (dd, J = 4.6, 14.0 Hz, 1 H), 3.22-3.13 (m, 1 H), 2.92-2.72 (m, 5 H), 2.02-1.92 (m, 1 H), 1.66-1.53 (m, 1 H), 1.52-1.39 (m, 1 H), 1.28-1.13 (m, 2 H). LCMS (Method 1): [MH+] = 722 at 2.68 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(3-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate trifluoroacetic acid salt

Example 102

Intermediate 111

¹H NMR (400 MHz, CD₃CN): δ 8.21 (s, 2 H), 7.99 (d, J = 8.4 Hz, 2 H), 7.40 (d, J = 8.4 Hz, 2 H), 7.19-7.15 (m, 1 H), 7.09-7.05 (m, 2 H), 6.95-6.93 (m, 1 H), 6.77-6.70 (m, 3 H), 6.24 (dd, J = 4.4, 9.6 Hz, 1 H), 5.02-5.01 (m, 1 H), 4.94-4.92 (m, 2 H), 3.83 (s, 3 H), 3.81 (s, 3 H), 3.73 (dd, J = 9.6, 14.0 Hz, 1 H), 3.59-3.55 (m, 1 H), 3.39 (dd, J = 4.4, 14.0 Hz, 1 H), 3.22-3.13 (m, 4 H), 2.99-2.94 (m, 1 H), 2.24-2.21 (m, 1 H), 1.89-1.74 (m, 2 H), 1.70-1.69 (m, 2 H). OH not observed. LCMS (Method 1): [MH+] = 722 at 2.64 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[(5-fluoro-3-pyridyl)-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate formate salt

Example 103

Intermediate 112

¹H NMR (400 MHz, CDCl₃): δ 8.38 (s, 1 H), 8.14 (s, 2 H), 7.99-7.97 (m, 3 H), 7.49 (brs, 1 H), 7.29-7.26 (m, 2 H), 7.03-6.97 (m, 2 H), 6.92-6.89 (m, 1 H), 6.86 (d, J = 8.4 Hz, 1 H), 6.30 (dd, J = 4.8, 10.0 Hz, 1 H), 4.99-4.96 (m, 1 H), 4.91-4.88 (m, 2 H), 3.93 (s, 3 H), 3.90 (s, 3 H), 3.71 (dd, J = 10.0, 14.0 Hz, 1 H), 3.42-3.36 (m, 2 H), 3.01-2.89 (m, 4 H), 2.80-2.77 (m, 1 H), 2.19-2.17 (m, 1 H), 1.87-1.86 (m, 1 H), 1.84-1.82 (m, 1 H), 1.61-1.49 (m, 2 H). LCMS (Method 1): [MH+] = 725 at 2.72 min

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[(4-fluoro-2-pyridyl)-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate formate salt

Example 104

Intermediate 113

1H NMR (400 MHz, DMSO): δ 8.55 (s, 2 H), 8.40 (s, 1 H), 8.38-8.37 (m, 1 H), 7.94-7.92 (m, 2 H), 7.85-7.77 (m, 2 H), 7.45-7.40 (m, 2 H), 7.05-6.95 (m, 3 H), 6.21 (dd, J = 9.6, 4.4 Hz, 1 H), 5.24-5.13 (m, 2 H), 4.76-4.73 (m, 1 H), 3.78 (s, 3 H), 3.74 (s, 3 H), 3.59 (dd, J = 9.6, 14.0 Hz, 1 H), 3.30 (dd, J = 4.4, 14.0 Hz, 1 H), 3.16-3.10 (m, 1 H), 2.70-2.51 (m, 4 H), 2.33-2.32 (m, 1 H), 1.89-1.88 (m, 1 H), 1.58-1.55 (m, 1 H), 1.53-1.47 (m, 1 H), 1.32-1.19 (m, 2 H). LCMS (Method 2): [MH+] = 725 at 3.63 min

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[3-(dimethylcarbamoyl)-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino]methyl]benzoate formate salt

Example 105

Intermediate 114

¹H NMR (400 MHz, DMSO): δ 8.53 (s, 2 H), 8.21 (s, 1 H), 7.94 (d, J = 8.4 Hz, 2 H), 7.42-7.35 (m, 4 H), 7.31-7.29 (m, 1 H), 7.22-7.20 (m, 1 H), 7.04-6.95 (m, 3 H), 6.20 (dd, J = 4.4, 9.6 Hz, 1 H), 4.99 (brs, 2H), 4.70-4.68 (m, 1 H), 3.77 (s, 3 H), 3.75 (s, 3 H), 3.66-3.57 (m, 1 H), 3.36-3.29 (m, 1 H), 3.16-3.06 (m, 1 H), 2.98 (brs, 3 H), 2.77 (brs, 3 H), 2.69-2.54 (m, 3 H), 2.47-2.30 (m, 2 H), 1.89-1.82 (m, 1 H), 1.63-1.52 (m, 1 H), 1.51-1.41 (m, 1 H), 1.33-1.24 (m, 1 H), 1.23-1.13 (m, 1 H). LCMS (Method 1): [MH+] = 777 at 2.65 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[(2-methoxy-3-pyridyl)-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate formate salt

Example 106

Intermediate 115

¹H NMR (400 MHz, CDCl₃): δ 8.40 (s, 1 H), 8.13 (s, 2 H), 8.10-8.06 (m, 1 H), 7.94 (d, J = 7.8 Hz, 2 H), 7.31 (d, J = 7.9 Hz, 2 H), 7.14 (d, J = 7.5 Hz, 1 H), 7.03-6.96 (m, 2 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.83-6.76 (m, 1 H), 6.29 (dd, J = 9.6, 4.5 Hz, 1 H), 4.88 (br s, 2 H), 4.85-4.75 (m, 1 H), 3.92 (s, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.71 (dd, J = 14.0, 9.7 Hz, 1 H), 3.38-3.27 (m, 2 H), 2.94-2.84 (m, 3 H), 2.83-2.73 (m, 1 H), 2.70-2.59 (m, 1 H), 2.10-2.02 (m, 1 H), 1.82-1.71 (m, 1 H), 1.70-1.58 (m, 1 H), 1.45-1.28 (m, 2 H). LCMS (Method 1): [MH+] = 737 at 2.71 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[(5-methoxy-3-pyridyl)-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 107

Intermediate 116

¹H NMR (400 MHz, CDCl₃): δ 8.24-8.19 (m, 4 H), 8.01 (d, J = 8.0 Hz, 2 H), 7.34-7.28 (m, 3 H), 7.04-6.97 (m, 2 H), 6.86 (d, J = 8.3 Hz, 1 H), 6.31 (dd, J = 9.7, 4.5 Hz, 1 H), 5.13-5.07 (m, 1 H), 4.95 (s, 2 H), 3.91 (s, 3 H), 3.88 (s, 6 H), 3.74 (dd, J = 13.9, 9.7 Hz, 1 H), 3.60 (dd, J = 14.8, 8.6 Hz, 1 H), 3.38 (dd, J = 14.0, 4.7 Hz, 1 H), 3.34-3.15 (m, 4 H), 3.08-2.96 (m, 1 H), 2.39 (br s, 1 H), 2.09-1.98 (m, 1 H), 1.94-1.83 (m, 1 H), 1.73-1.65 (m, 2 H). LCMS (Method 2): [MH+] = 737 at 3.25 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[(6-hydroxy-3-pyridyl)-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 108

Intermediate 117

¹H NMR (400 MHz, DMSO): δ 11.40 (brs, 1 H), 8.55 (s, 2 H), 7.92 (d, J = 8.0 Hz, 2 H), 7.60 (br s, 2 H), 7.50-7.42 (m, 2 H), 7.07-6.95 (m, 3 H), 6.27-6.18 (m, 2 H), 4.85-4.62 (m, 2 H), 4.58 (br s, 1 H), 3.78 (s, 3 H), 3.75 (s, 3 H), 3.63 (dd, J = 14.1, 9.6 Hz, 1 H), 3.40-3.30 (m, 1 H), 3.06-2.97 (m, 1 H), 2.66-2.48 (m, 5 H), 1.81 (br s, 1 H), 1.59-1.50 (m, 1 H), 1.50-1.38 (m, 1 H), 1.38-1.28 (m, 1 H), 1.22-1.10 (m, 1 H). LCMS (Method 1): [MH+] = 723 at 2.44 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[(2-cyano-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate formate salt

Example 109

Intermediate 118

¹H NMR (400 MHz, CDCl₃): δ 8.41 (s, 1 H), 8.13 (s, 2 H), 7.96 (d, J = 7.8 Hz, 2 H), 7.66 (d, J = 7.6 Hz, 1 H), 7.57 (t, J = 7.9 Hz, 1 H), 7.39 (t, J = 7.7 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.17-7.10 (m, 1 H), 7.04-6.96 (m, 2 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.29 (dd, J = 9.2, 4.3 Hz, 1 H), 5.04-4.85 (m, 3 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.71 (dd, J = 13.8, 9.8 Hz, 1 H), 3.42-3.31 (m, 2 H), 2.98-2.87 (m, 3 H), 2.87-2.68 (m, 2 H), 2.20-2.10 (m, 1 H), 1.86-1.75 (m, 1 H), 1.75-1.64 (m, 1 H), 1.57-1.37 (m, 1 H). LCMS (Method 1): [MH+] = 731 at 2.71 min.

[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 110

Intermediate 119

¹H NMR (400 MHz, CDCl₃): δ 8.46 (dd, J = 4.7, 1.6 Hz, 2 H), 8.14 (s, 2 H), 8.00-7.93 (m, 2 H), 7.47 (s, 1 H), 7.35-7.29 (m, 2 H), 7.26 (m, 1 H), 7.18 (d, J = 8.1 Hz, 1 H), 7.06-7.01 (m, 2 H), 6.61 (t, J = 75.3 Hz, 1 H), 6.27 (dd, J = 9.9, 4.2 Hz, 1 H), 4.97-4.89 (m, 2 H), 4.84-4.79 (m, 1 H), 3.89 (d, J = 6.9 Hz, 2 H), 3.68 (dd, J = 14.1, 10.0 Hz, 1 H), 3.31 (dd, J = 14.1, 4.3 Hz, 1 H), 3.26-3.18 (m, 1 H), 2.78-2.68 (m, 3 H), 2.66-2.50 (m, 2 H), 1.97-1.94 (m, 1 H), 1.70-1.60 (m, 1 H), 1.56-1.47 (m, 1 H), 1.30-1.21 (m, 3 H), 0.68-0.62 (m, 2 H), 0.39-0.34 (m, 2 H). LCMS (Method 1): [MH+] = 783 at 2.86 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[4-(difluoromethoxy)-3-isopropoxy-phenyl]ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 111

Intermediate 120

¹H NMR (400 MHz, CDCl₃): δ 8.48-8.44 (m, 2 H), 8.15 (s, 2 H), 7.98 (d, J = 8.0 Hz, 2 H), 7.53-7.45 (m, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.17 (d, J = 8.2 Hz, 1 H), 7.05-7.00 (m, 2 H), 6.55 (t, J = 75.3 Hz, 1 H), 6.27 (dd, J = 9.8, 4.4 Hz, 1 H), 4.96-4.88 (m, 2 H), 4.83-4.78 (m, 1 H), 4.60-4.53 (m, 1 H), 3.68 (dd, J = 14.0, 9.8 Hz, 1 H), 3.33 (dd, J = 14.1, 4.4 Hz, 1 H), 3.24-3.16 (m, 1 H), 2.79-2.51 (m, 6 H), 2.01-1.91 (m, 1 H), 1.68-1.60 (m, 1 H), 1.52 (m, 1 H), 1.39-1.30 (m, 8 H). LCMS (Method 1): [MH+] = 771 at 2.85 min.

[1-[3-(cyclopropylmethoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 112

Intermediate 121

¹H NMR (400 MHz, CDCl₃): δ 8.47-8.44 (m, 2 H), 8.14 (d, J = 3.0 Hz, 2 H), 8.00-7.94 (m, 2 H), 7.46 (s, 1 H), 7.34-7.27 (m, 3 H), 7.04-6.97 (m, 2 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.28-6.23 (m, 1 H), 4.93 (s, 2 H), 4.83-4.78 (m, 1 H), 3.89-3.85 (m, 5 H), 3.70 (dd, J = 14.0, 9.8 Hz, 1 H), 3.33 (dd, J = 14.0, 4.6 Hz, 1 H), 3.25-3.17 (m, 1 H), 2.76-2.68 (m, 3 H), 2.64-2.56 (m, 2 H), 1.96 (m, 1 H), 1.68-1.60 (m, 1 H), 1.56-1.48 (m, 1 H), 1.38-1.21 (m, 3 H), 0.67-0.61 (m, 2 H), 0.39-0.34 (m, 2 H). LCMS (Method 1): [MH+] = 747 at 2.73 min.

[1-[3-(cyclopentoxy)-4-methoxy-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[[3-pyridyl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 113

Intermediate 122

¹H NMR (400 MHz, CDCl₃): δ 8.55-8.50 (m, 2 H), 8.20 (d, J = 5.1 Hz, 2 H), 8.00 (d, J = 7.9 Hz, 2 H), 7.58-7.41 (m, 2 H), 7.29 (d, J = 8.1 Hz, 2 H), 7.02-6.95 (m, 2 H), 6.88-6.81 (m, 1 H), 6.33-6.24 (m, 1 H), 5.23-5.01 (m, 1 H), 4.97 (s, 2 H), 4.85-4.73 (m, 1 H), 3.84 (s, 3 H), 3.76-3.67 (m, 1 H), 3.74-3.47 (m, 1 H), 3.43-3.10 (m, 5 H), 3.15-2.90 (m, 1 H), 2.44-2.33 (m, 1 H), 2.08-1.83 (m, 9 H), 1.70-1.57 (m, 3 H). LCMS (Method 1): [MH+] = 761 at 2.81 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl]benzoate

Example 114

Intermediate 126

¹H NMR (400 MHz, CDCl₃): δ 8.14 (s, 2 H), 8.07 (d, J = 8.4 Hz, 2 H), 7.59-7.57 (d, J = 8.4 Hz, 2 H), 7.51-7.48 (m, 2 H), 7.40-7.36 (m, 1 H), 7.28-7.22 (m, 2 H), 7.11-7.00 (m, 5 H), 6.88 (d, J = 8.4 Hz, 1 H), 6.32 (dd, J = 4.4, 9.6 Hz, 1 H), 4.89-4.85 (m, 3 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.73 (dd, J = 9.6, 14.0 Hz, 1 H), 3.36 (dd, J = 4.4, 14.0 Hz, 1 H), 3.31-3.25 (m, 1 H), 2.85-2.61 (m, 5 H), 2.10-2.05 (m, 1 H), 1.78-1.68 (m, 1 H), 1.65-1.54 (m, 1 H), 1.50-1.38 (m, 1 H), 1.37-1.26 (m, 1 H). LCMS (Method 1): [MH+] = 800 at 2.98 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl]benzoate

Example 115

Intermediate 127

¹H NMR (400 MHz, CDCl₃): δ 8.19 (s, 1 H), 8.16 (s, 2 H), 7.99 (d, J = 7.6 Hz, 1 H), 7.72-7.70 (m, 1 H), 7.51-7.47 (m, 3 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.26-7.21 (m, 2 H), 7.11-6.99 (m, 5 H), 6.86 (d, J = 8.4 Hz, 1 H), 6.32 (dd, J = 4.4, 9.6 Hz, 1 H), 4.93-4.87 (m, 3 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.74 (dd, J = 9.6, 14.0 Hz, 1 H), 3.36 (dd, J = 4.4, 14.0 Hz, 1 H), 3.29-3.24 (m, 1 H), 2.82-2.63 (m, 5 H), 2.06-2.00 (m, 1 H), 1.72-1.68 (m, 1 H), 1.65-1.52 (m, 1 H), 1.50-1.37 (m, 1 H), 1.36-1.25 (m, 1 H). LCMS (Method 1): [MH+] = 800 at 2.97 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl]benzoate

Example 116

Intermediate 125

¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 2 H), 8.08-8.06 (m, 2 H), 7.64-7.61 (m, 2 H), 7.55-7.53 (m, 2 H), 7.35-7.33 (m, 2 H), 7.26-7.23 (m, 1 H), 7.07-7.00 (m, 5 H), 6.86 (d, J = 8.4 Hz, 1 H), 6.32 (dd, J = 4.4, 9.6 Hz, 1 H), 4.92-4.86 (m, 3 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.72 (dd, J = 9.6, 14.0 Hz, 1 H), 3.36 (dd, J = 4.4, 14.0 Hz, 1 H), 3.28-3.25 (m, 1 H), 2.84-2.72 (m, 5 H), 2.05-2.00 (m, 1 H), 1.72-1.69 (m, 1 H), 1.61-1.57 (m, 1 H), 1.49-1.37 (m, 1 H), 1.36-1.22 (m, 1 H). LCMS (Method 1): [MH+] = 800 at 2.95 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl]benzoate

Example 117

Intermediate 128

¹H NMR (400 MHz, CDCl₃): δ 8.22 (s, 1 H), 8.13 (s, 2 H),7.98 (d, J = 8.0 Hz, 1 H), 7.77-7.75 (m, 1 H), 7.53-7.47 (m, 3 H), 7.35-7.33 (m, 2 H), 7.26-7.22 (m, 1 H), 7.12-6.99 (m, 5 H), 6.86 (d, J = 8.4 Hz, 1 H), 6.31 (dd, J = 4.4, 9.6 Hz, 1 H), 4.91-4.87 (m, 3 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.73 (dd, J = 9.6, 14.0 Hz, 1 H), 3.36 (dd, J = 4.4, 14.0 Hz, 1 H), 3.29-3.26 (m, 1 H), 2.86-2.78 (m, 5 H), 2.08-2.00 (m, 1 H), 1.74-1.71 (m, 1 H), 1.63-1.60 (m, 1H), 1.51-1.38 (m, 1H), 1.37-1.28 (m, 1 H). LCMS (Method 1): [MH+] = 800 at 2.97 min

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[[(3R)-quinuclidin-3-yl]oxycarbonyl-thiazol-2-yl-amino]methyl]benzoate formate salt

Example 118

Intermediate 129

¹H NMR (400 MHz, CDCl₃): δ 8.36 (s, 1 H), 8.14 (s, 2 H), 7.97 (d, J = 8.2 Hz, 2 H), 7.43 (d, J = 3.6 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 2 H), 7.02-6.95 (m, 3 H), 6.84 (d, J = 8.2 Hz, 1 H), 6.29 (dd, J = 9.7, 4.6 Hz, 1 H), 5.50 (d, J = 16.5 Hz, 1 H), 5.43 (d, J = 17.0 Hz, 1 H), 4.99 (s, 1 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.69 (dd, J = 13.9, 9.8 Hz, 1 H), 3.34 (dd, J = 13.9, 4.5 Hz, 1 H), 3.34-3.29 (m, 1 H), 2.92-2.75 (m, 4 H), 2.13-2.03 (m, 1 H), 1.83-1.71 (m, 2 H), 1.68-1.57 (m, 1 H), 1.54-1.31 (m, 2 H). LCMS (Method 2): [MH+] = 713 at 3.59 min.

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[1H-indazol-7-yl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate formate salt

Example 119

Intermediate 130

¹H NMR (400 MHz, DMSO at 105°C): δ 8.35 (s, 2 H), 8.17 (s, 1 H), 8.06 (s, 1 H), 7.90-7.85 (m, 2 H), 7.64 (dd, J = 7.90, 1.05 Hz, 1 H), 7.45 (d, J = 8.07 Hz, 2 H), 7.10-6.96 (m, 5 H), 6.26 (dd, J = 9.04, 4.84 Hz, 1 H), 5.01 (s, 2 H), 4.74-4.70 (m, 1 H), 3.81- 3.76 (m, 7 H), 3.63 (dd, J = 14.15, 9.12 Hz, 1 H), 3.38 (dd, J = 14.18, 4.95 Hz, 2 H), 3.10-3.00 (m, 2H), 2.32 (d, J = 11.73 Hz, 1 H), 2.04 (s, 1 H), 1.81 (s, 1 H), 1.57-1.46 (m, 2 H), 1.04 (s, 2 H). LCMS (Method 1): [MH+] = 746 at 2.75 min

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[1H-indazol-7-yl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate formate salt

Example 120

Intermediate 131

¹H NMR (400 MHz, DMSO- at 105°C): δ 8.34 (t, J = 2.51 Hz, 2 H), 8.20 (s, 1 H), 8.07 (s, 1 H), 7.89 (s, 1 H), 7.84 (d, J = 7.76 Hz, 1 H), 7.67-7.62 (m, 1 H), 7.57 (d, J = 7.69 Hz, 1 H), 7.42 (t, J = 7.68 Hz, 1 H), 7.03-6.94 (m, 5 H), 6.25 (dd, J = 9.10, 4.86 Hz, 1 H), 5.00 (s, 2 H), 4.74-4.69 (m, 1 H), 3.79 (s, 6 H), 3.65-3.57 (m, 1 H), 3.38 (dd, J = 14.19, 5.07 Hz, 2 H), 2.60-2.52 (m, 3 H), 2.36-2.28 (m, 1 H), 1.80 (d, J = 4.36 Hz, 1 H), 1.58-1.43 (m, 3 H), 1.04 (s, 2 H).

LCMS (Method 1): [MH+] = 746 at 2.74 min

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[1H-indol-7-yl-[(3R)-quinuclidin-3-yl]oxycarbonyl-amino]methyl]benzoate

Example 121

Intermediate 132

¹H NMR (400 MHz, DMSO@110°C): δ 10.85 (s, 1 H), 8.35 (s, 2 H), 7.89 (d, J = 8.13 Hz, 2 H), 7.46 (dd, J = 13.89, 7.99 Hz, 3 H), 7.30 (t, J = 2.81 Hz, 1 H), 7.07-6.91 (m, 4 H), 6.85 (d, J = 7.45 Hz, 1 H), 6.49 (dd, J = 3.09, 1.89 Hz, 1 H), 6.27 (dd, J = 9.12, 4.88 Hz, 1 H), 5.00 (br s, 3 H), 3.84-3.77 (m, 6 H), 3.69-3.59 (m, 2 H), 3.39 (dd, J = 14.33, 5.45 Hz, 2 H), 2.68 (dd, J = 5.34, 3.35 Hz, 1 H), 2.11 (s, 1 H), 1.88-1.78 (m, 3 H), 1.49 (br s, 1 H), 1.20 (br s, 1 H). LCMS (Method 1): [MH+] = 745 at 2.83 min.

[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 4-[(2-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate formate salt

Example 122

Intermediate 133

¹H NMR (400 MHz, DMSO D₂O): δ 8.22 (s, 2 H), 8.08 (s, 1 H), 7.99 (s, 1 H), 7.64 (d, J = 8.21 Hz, 2 H), 7.19 (dd, J = 24.61, 7.95 Hz, 2 H), 6.95-6.39 (m, 8 H), 5.92 (dd, J = 9.16, 4.53 Hz, 1 H), 4.85-4.20 (br m, 4 H), 3.63 (d, 2 H), 3.36 (dd, J = 14.17, 9.58 Hz, 1 H), 3.13-3.05 (m, 2 H), 2.61 (s, 4 H), 2.45-2.35 (m, 1 H), 1.69 (s, 1 H), 1.56-0.85 (m, 5 H), 0.32-0.24 (m, 2 H), 0.07-0.02 (m, 2 H).

LCMS (Method 1): [MH+] = 798 at 2.98 min.

[(1S)-1-[3-(cyclopropylinethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-[(2-hydroxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate formate salt

Example 123

Intermediate 134

¹H NMR (400 MHz, DMSOD2O): δ 8.41 (s, 2 H), 8.33 (s, 1 H), 8.22 (s, 1 H), 7.90-7.76 (t, 2 H), 7.52-7.38 (m, 2 H), 7.19-6.64 (m, 6 H), 6.15 (s, 1 H), 5.10 ( br m, 3 H), 3.85 (d, J = 6.78 Hz, 2 H), 3.60 (t, J = 10.46 Hz, 1 H), 3.33 (d, J = 13.75 Hz, 2 H), 2.88-2.53 (m, 4 H), 1.99 (s, 1 H), 1.65 (d, J = 35.98 Hz, 2 H), 1.40-1.10 (m, 3 H), 0.50 (d, J = 7.43 Hz, 2 H), 0.26 (s, 2 H).