WO2010126953A1 - Corticosteroid linked beta-agonist compounds for use in therapy - Google Patents

Abstract

New chemical entities which comprise corticosteroids and phosphorylated β- agonists for use in therapy and compositions comprising and processes for preparing the same are provided.

Description

CORTICOSTEROID LINKED BETA-AGONIST COMPOUNDS FOR USE IN THERAPY

Field of the Invention

The instant invention relates to new chemical entities which comprise corticosteroids and phosphorylated β-agonists for use in therapy and compositions comprising and processes for preparing the same.

Background of the Invention

Asthma is a chronic inflammatory disease of the airways produced by the infiltration of pro-inflammatory cells, mostly eosinophils and activated T- lymphocytes (Poston, Am. Rev. Respir. Dis._t 145 (4 Pt 1), 918-921 , 1992; Walker, J. Allergy Clin. Immunol., 88 (6), 935-42, 1991) into the bronchial mucosa and submucosa. The secretion of potent chemical mediators, including cytokines, by these proinflammatory cells alters mucosal permeability, mucus production, and causes smooth muscle contraction. Ail of these factors lead to an increased reactivity of the airways to a wide variety of irritant stimuli (Kaliner, "Bronchial asthma, Immunologic diseases" E. M. Samter, Boston, Little, Brown and Company: 1 17-118. 1988).

Glucocorticoids, which were first introduced as an asthma therapy in 1950 (Carryer, Journal of Allergy, 21 , 282-287, 1950), remain the most potent and consistently effective therapy for this disease, although their mechanism of action is not yet fully understood (Morris, J. Allergy CHn. Immunol., 75 (1 Pt) 1 - 13, 1985). Unfortunately, oral glucocorticoid therapies are associated with profound undesirable side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, acceleration of cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Giiman, 10^th edition, 2001 ). A solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to mitigate the severe adverse effects of oral steroids. While ICS are very effective in controlling inflammation in asthma, they too are not precisely delivered to the optimal site of action in the lungs and produce unwanted side effects in the mouth and pharynx (candidiasis, sore throat, dysphonia).

Combinations of inhaled β₂-adrenoreceptor agonist bronchodilators such as formoterol or salmeterol with ICS's are also used to treat both the bronchoconstriction and the inflammation associated with asthma and COPD (Symbicort^® and Advair^®, respectively). However, these combinations have the side effects of both the ICS's and the β2-adrenoreceptor agonist because of systemic absorption (tachycardia, ventricular dysrhythmias, hypokalemia) primarily because neither agent is delivered exclusively to the optimal sites of action in the lungs. In consideration of all problems and disadvantages connected with the adverse side effect profile of ICS and of β-agonists it would be highly advantageous to provide a drug which masks the pharmacological properties of both steroids and β-agonists until such a drug reaches the optimal site of action.

Phenylphosphate based mutual prodrugs of corticosteroids and β₂-agonists have been described by Baker (WO/2006/138212) wherein the component drugs are released at the site of action in the lungs.

Summary of the Invention

In one aspect, the present invention provides compounds of Formula I:

and pharmaceutically acceptable salts thereof, wherein:

R¹⁵ is a side chain radical of a β-agonist;

R¹⁶ is H₁ methyl or ethyl;

R¹⁹ is H₁ F₁ OH or methyl;

L is a bond Or -(CH₂O)-;

Q is selected from

wherein each W¹ is the same or different and is O or S; W² is O, S or N(R¹);

Ph is phenyl optionally substituted on any available carbon with a substituent selected from halo,

OH, C_1-4alkoxy[, NH₂, N(H)C_1-4aikyl, and N(C_1-4aikyl)₂; each R¹ is the same or different and is independently H or C-i_-4alkyl; a is 0-6; b is 0 and c is 1-4, or b is 1 and c is 2-4; each W³ is the same or different and is independently -O- or -N(R¹)-; x and y are both 0 and z is 1 or x is 1 , y is 0 or 1 and z is 0-6; Ring A is phenyl, pyridyl or pyrimidyl each optionally substituted on any available carbon with a substituent selected from halo, Ci_-4alkyl, OH₁ C_1-4alkoxyl, NH₂, N(H)C_Malkyi, and N(C_1-4a!kyl)₂; d is 0 or 1 ; each R², R³, R⁴, and R⁵ are independently H, C_1-4 alkyl or halo; one of R⁶ and R⁷ is H and the other is OH; or R⁶ and R⁷ taken together with the carbon to which they are attached form a >C=O group;

R⁸ is H₁ OH, 0(CO)R⁹, or 0(CO)OR⁹; each R⁹ is independently Ci_-4 alkyl; each R¹⁰ and R¹¹ is independently H or C_1-4 alkyl;

R¹² is H, OH, or C_1-4 alkyl; or

R¹¹ and R¹² taken together with the carbon to which they are attached form a >=CH₂ group; or

R¹² and R⁸ taken together with the carbons to which they are attached form a 1 ,3-dioxoiane ring represented by formula B:

wherein one of R¹³ and R¹⁴ is H, methyl or ethyl and the other is H, C_1-10 alkyi, C2-10 alkenyl, C_2-io alkynyl, optionally substituted C3-1G carbocycle or optionally substituted 5-6 ring atom heterocycle wherein one or two ring atoms are selected from N, O and S, and wherein said carbocycle and said heterocycle are each optionally substituted 1 , 2 or 3 times with a substituent selected from halo, C-|.₄alkyl, and O-C^alkyl.

According to one embodiment, the compounds of Formula I are defined wherein R¹⁵ is: C_1-6alkyl;

C_6-iocarbocyde optionally substituted 1 or 2 times with halo, C^alkyl, O-C_1-4alkyl, O-(CH₂)₄-NH₂, O-(CH₂)₄-N(H)C_1-4alkyl, O-(CH₂)₄-N(C_1-4alkyl)₂, O-C_1-4afkyl-C(O)-NH₂, O-C^alkyl-CtOJ-N^C^alkyl, O-C^alkyl-C^-NfC^alkyl^_, or a group represented by formula i, ii, iii, iv, v, vi, vii, viii, or ix: i: C₆alkylene-O-R²¹-Ph⁴; ii: C_2-3alkylene-Ph¹-O-R²¹-Ph⁴; iii: C_2-3alkylene-Ph¹-N(H)-R²²-Ph²; iv: C_2-3alkylene-Het-(R²³)-Ph³; v: C2-₃alkylene-Ph¹-Co_-2alkylene-C(O)N(H)-C_1-4alkylene-Ph³; vi; C_2-3alkylene-Ph³; vii: C_2-3alkylene-S{O)2-C2-4aIkylene-O-C_2-4alkylene-Ph³; viii: C3-6a!kylene-Ph¹-Co-2aikylene-C(0)N(H)-Cio-i2 bicyclic carbocycle; ix: C_3-6alkylene-Het-Ph⁴; wherein:

R²¹ is C2- ecilkylene wherein one carbon of said alkylene is optionally replaced by O; Ph⁴ is phenyl optionally substituted 1 or 2 times by halo,

N(H)C(O)NH₂, SO₂NH₂ or S-cyctopentyl, Ph¹ is phenyϊene;

R²² is a bond or C_1-2alkylene optionally substituted once by OH or NH₂;

Ph² is phenyl optionally substituted 1 or 2 times by O-methyl, -OCH₂CH(CHS)₂CH₂NH₂, unsubstituted phenyl,

-SO₂-NH-(C₆H₃)(CH₃)(C₇H₁₅) Or

Het is 4-10 ring atom heterocyclene wherein 1 , 2 or 3 ring atoms is/are N, O or S optionally substituted once by methyl; R²³ is a C_2-4aikylene wherein one carbon of said alkylene is optionally replaced by O or -C₀-₂alky!ene-C(O)N(H)-C₂-4alkylene; and Ph³ is phenyl optionally substituted 1 or 2 times by halo or O-methyi.

In another aspect, the invention provides compounds of Formula II:

and pharmaceutically acceptable salts thereof, wherein all variables are as defined above. In another aspect, the invention provides compounds of Formula

and pharmaceuticaily acceptable salts thereof, wherein all variables are as defined above.

In another aspect, the invention provides compounds of Formula SV:

R³ and pharmaceutically acceptable salts thereof, wherein ail variables are as defined above.

In another aspect, the invention provides compounds of Formula V:

R³ and pharmaceutically acceptable salts thereof, wherein all variables are as defined above.

in another aspect, the invention provides compounds of Formula Vl:

and pharmaceutically acceptable salts thereof, wherein all variables are as defined above.

In another aspect, the invention provides a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient, diluent or carrier. In one embodiment, the composition further comprises a therapeutically active agent selected from anti-inflammatory agents, anticholinergic agents, β-agonists, antiinfective agents and antihistamines. in another aspect, the invention provides a method comprising administering to a human, an effective amount of a compound of Formula i, or a pharmaceuticaliy acceptable sait thereof.

In another aspect, the invention provides a method for the treatment of pulmonary inflammation or bronchoconstriction in a human in need thereof, comprising administering to said human an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method for the treatment of a disease associated with reversible airway obstruction, asthma, COPD, bronchiectasis or emphysema in a human in need thereof, comprising administering to the human an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method for delivering an effective amount of a steroid and a β-agonist to the iung of a human. The method comprises delivering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to the lung of the human, wherein a phosphate group of the compound is cleaved by an endogenous enzyme and an ester group of the compound is cleaved by an endogenous esterase or chemically by hydrolysis to deliver the steroid and the β-agonist.

in another aspect, the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use as a medicament.

In another aspect, the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of pulmonary inflammation or bronchoconstriction in a human.

In another aspect, the invention provides a compound of Formula i or a pharmaceutically acceptable salt thereof for use in the treatment of a disease associated with reversible airway obstruction, asthma, COPD, bronchiectasis, or emphysema in a human. In another aspect, the invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of puimonary inflammation or bronchoconstriction in a human.

In another aspect, the invention provides the use of a compound of Formula i or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease associated with reversible airway obstruction, asthma, COPD, bronchiectasis, or emphysema in a human.

In another aspect, the invention provides a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for the treatment of pulmonary inflammation or bronchoconstriction in a human.

In another aspect, the invention provides a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for the treatment of reversible airway obstruction, asthma, COPD, bronchiectasis, or emphysema in a human.

In another aspect, the invention provides a pharmaceutical composition for treating pulmonary inflammation or bronchoconstriction in a human comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a pharmaceutical composition for treating reversible airway obstruction, asthma, COPD, bronchiectasis, or emphysema in a human comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides processes and novel intermediates which are useful for preparing the compounds of Formula 1 and pharmaceutically acceptable salts thereof. In another aspect, the present invention includes compounds of Formula I and pharmaceutically acceptable salts thereof and all racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs and amorphous forms thereof.

Detailed Description of the Invention

Headings are employed throughout the disclosure solely for ease of reference and are in no way to be construed as indicating that al! subject matter in the passages below a particular heading constitute the sole disclosure relevant to the topic.

DEFINITIONS

When trade names are used herein, applicants intend to independently include the trade name product and the active pharmaceutical ingredient(s) of the trade name product.

Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:

"a compound of the invention" means a compound of Formula i, which includes compounds of formula II, III, IV, V, and Vl, or a salt, particularly a pharmaceutically acceptable salt thereof.

"a compound of Formula I" means a compound having the structural formula designated herein as Formula I₁ including compounds of Formulas II, IH₁ IV, V, and Vl. Compounds of Formula I include solvates and hydrates as well as any amorphous and crystalline (polymorphic) forms thereof.

In those embodiments wherein a compound of Formula I includes one or more chiral centers, the phrase is intended to encompass each individual stereoisomer including optical isomers (enantiomers and diastereomers) and geometric isomers (cis~/trans-isomerism) and mixtures of stereoisomers. Similarly, with respect to other compounds referred to herein, such as compounds of Formula II, III, IV, V, and Vl, and isolatabie intermediates, the phrase "a compound of Formula (number)" means a compound of that formula and solvates and hydrates as well as amorphous and crystalline (polymorphic) forms thereof, and stereoisomers (where compounds include a chira! center) thereof, "alkyl" as used herein refers to linear or branched hydrocarbon chains containing from 1 to 8 carbon atoms (i.e., Ci_-8 alkyl), unless a different number of atoms is specified. Examples of "alkyl as used herein include but are not limited to methyl (Me), ethyl (Et), n-propyS (1-Pr₁ 1-propyl), isopropyl (i-Pr, 2-propyl), n-butyl (n-Bu, 1 -butyl), isobutyi, (i-Bu, 2-methyl-1 -propyl), sec-butyl (s-Bu, 2-butyl), tert-butyl (t-butyl, t-Bu, 2- methyl-2-propyl), n-pentyl (1-pentyl), 2-pentyi, 3-pentyl (-CH(CH₂CH₃)₂), 2-methyI-2-butyl (-C(CHs)₂CH₂CH₃), 3-methyl-2-butyl

(-CH(CH₃)CH(CH₃)2), 3-methyl-1 -butyl (-CH₂CH₂CH(CHs)₂), 2-methyl-1- butyl (-CH₂CH(CH₃)CH₂CH₃), 1-hexyl, 2-hexyl, 3-hexyl (-CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (-C(CHa)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (-CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyi-2-pentyl (-CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyf (-C(CH₃)(CH₂CHs)₂),

2-methyϊ-3-pentyl (-CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (-C(CHs)₂CH(CHs)₂), 3,3-dimethyl-2-butyl (-CH(CH₃)C(CH₃)₃, and octy! (-(CH₂J₇CH₃), When the compound of Formula i includes more than one alkyl, the alkyls may be the same or different. "alkylene" refers to a linear or branched divalent hydrocarbon chain having from 1 to 8 carbon atoms (i.e., Ci_β alkylene), unless a different number of carbon atoms is specified. Examples of "alkylene" as used herein include but are not limited to methylene, 1 ,1 -ethyl (-CH(CH₃))-, ethylene, propylene (1 ,3- propyl (-CH₂CH₂CH₂-)); 1 ,1 -propyl (-CH(CH₂CH₃)-), or 1 ,2-propyl (-CH₂CH(CH₃)-)) and butyiene (1 ,4-butyl (-CH₂CH₂CH₂CH₂-)), and the like.

When the compound of Formula I includes more than one alkylene, the alkylenes may be the same or different.

"alkenyl" " as used herein refers to linear or branched hydrocarbon chains containing from 2 to 8 carbon atoms (i.e., C_2-e alkenyl), unless a different number of atoms is specified, and at least one carbon-carbon double bond. Examples of suitable alkenyl groups include, but are not limited to, ethenyl or vinyl (-CH=CH₂), propenyl or ally! (-CH₂CH=CH₂), and 5-hexenyl (-CH₂CH₂CH₂CH₂CH=CH₂). When the compound of Formula I includes more than one alkenyl, the alkenyls may be the same or different.

"alkynyl" as used herein refers to linear or branched hydrocarbon chains containing from 2 to 8 carbon atoms (i.e., C₂-s alkyny!), unless a different number of atoms is specified, and at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH₂C=CH)₁ and the like. When the compound of Formula I includes more than one alkynyl, the alkynyls may be the same or different. "halo" or "halogen" are synonymous and refer to fluoro, chloro, bromo, and iodo. "oxo" as used herein refers to the group =0 attached directly to a carbon atom of a hydrocarbon ring or a C, N or S of a heterocyclic ring to result in oxides, - N-oxides, sulfones and sulfoxides, "alkoxyi" as used herein refers to linear or branched hydrocarbon chains containing from 1 to 8 carbon atoms (i.e., Ci_-8 afkyi), unless a different number of carbon atoms is specified, and an oxygen atom, i.e., -O-Ci_ 8alkyl or alkyl-O-alkyϊ wherein the total number of carbon atoms is from 2 to 8. "carbocycle" or "carbocyclyl" refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic (i.e., aryl ring) hydrocarbon rings having 3 to 7 carbon atoms as a monocycle, or 7 to 12 carbon atoms as a bicycle, including spiro-fused rings, unless a different number of carbon atoms is specified. Monocyclic carbocycles typically have 3 to 6 ring atoms ("C-₃.₆ carbocycle"), and in one embodiment, 5 or 6 ring atoms ("C_5-6 carbocycle"). Bicyclic carbocycles typically have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicycio [5,6] or [6,6] system, or spiro-fused rings. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1 -cyclopent-1- enyl, i-cyclopent-2-enyl, 1-cyclopent-3-enyi, cyclohexyl, 1-cyclohex-1- enyl, 1-cyclohex-2-enyi, 1-cyclohex-3-enyl, and phenyl. Non-limiting examples of bicyclo carbocycles includes naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, and indanyl. In those embodiments wherein the compound of Formula I inciudes more than one carbocycie, the carbocycles may be the same or different, "aryi" refers to a subset of carbocycies, namely those mono- and bi-cyclic aromatic hydrocarbon rings having 6 to 12 carbon atoms. Typical aryl groups include, but are not limited to phenyl, naphthyi, biphenyl, and the like, in those embodiments wherein the compound of Formula I includes more than one aryl, the aryls may be the same or different. In one embodiment, aryl refers to phenyl or naphthyi. In one particular embodiment, aryl is phenyl. "heterocycle" or "heterocyclyl" are synonymous and refer to monocyclic saturated, partially saturated or aromatic rings having 3 to 7 ring atoms wherein 1 , 2, 3 or 4 ring atoms is/are a heteroatom independently selected from N, O and S, and fused or bridged bicyclic saturated, partially saturated, aromatic, or aromatic and non-aromatic (i.e., mixed functionality) rings having 7 to 12 ring atoms wherein 1 , 2, 3 or 4 ring atoms is/are a heteroatom independently selected from N, O and S. in all embodiments therein the heterocycle includes 2 or more heteroatoms (N, O and S) the heteroatoms may be the same or different. In one particular embodiment, "heterocycle" or "heterocyciyl" refers to saturated, partially unsaturated or aromatic monocyclic ring having 4, 5 or 6 ring atoms wherein 1 , 2 or 3 of the ring atoms is/are a heteroatom independently selected from N, O and S, and saturated, partially unsaturated, aromatic or mixed functionality bicyclic ring system of 9 or 10 ring atoms wherein 1 , 2, 3 or 4 of the ring atoms is/are a heteroatom independently selected from N, O and S. In ail embodiments wherein the compound of Formula I includes 2 or more heterocycles, the heterocycles may be the same or different. Examples of heterocycles include but are not limited to pyridyl, dihydropyridyl, piperidyl, thiazoiyi, tetrahydrothtophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazoiyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indoiyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyi, 2-pyrroiidonyl, pyrrolinyl, tetrahydrofuranyi, tetrahydroquinolinyl, tetrahydroisoquinolinyi, decahydroquinoiinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1 ,2,5- thiadiazinyl, 2H,6H-1₁5,2-dithiazinyl, thienyl, pyranyl, isobenzofuranyi, chromenyl, 2H-pyrro!yl, isothiazolyl, isoxazolyi, pyrazinyl, pyridazinyi, indoϋzinyi, isoindolyl, 3H-indolyl, I H-indazoiy, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyi, quinoxalinyl, quinazolinyl, cinnoliny!, pteridinyl, 4aH- phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazoiidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholiny!, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and bis- tetrahydrofuranyl:

"heteroaryl" refers to a subset of heterocycles, namely monocyclic and bicyclic fused aromatic rings having 5 to 7 ring atoms wherein 1 , 2 or 3 ring atoms is/are a heteroatom independently selected from N, O and S, and fused or bridged bicyclic aromatic, or mixed functionality) rings having 7 to 12 ring atoms wherein 1 , 2, 3 or 4 ring atoms is/are a heteroatom independently selected from N₁ O and S. Non-limiting examples of heteroaryls include all of aromatic heterocycles listed above, and particularly pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyi, pyrazolyl, isothiazoly!, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc. In those embodiments wherein the compounds of Formula I include more than one heteroaryl, the heteroaryls may be the same or different.

"heterocyclene" refers to a bivalent heterocycle as defined herein. For example, heterocyclenes include:

In those embodiments wherein the compounds of Formula I, include more than one heterocyclene, the heterocyclenes may be the same or different.

COMPOUNDS

One skilled in the art will recognize that substituents and other moieties of the compounds of Formula I should be selected in order to avoid embodiments which would be recognized by one of ordinary skill in the art as obviously inoperative.

In some chemical structure representations where carbon atoms do not have a sufficient number of variables attached to produce a valence of four, the remaining carbon substituents needed to provide a valence of four should be

assumed to be hydrogen. For example,

has the same meaning

Similarly, in some chemical structures where a bond is drawn without specifying the terminal group, such bond is indicative of a methy! group, as is conventional in the art. Thus,

is the same as For ease of reference, the constituent moieties of the compounds of Formuia I may be referred to herein from time to time as follows:

"corticosteroid moiety" "β-agonist moiety"

In one aspect, the invention comprises a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹⁵ is a side chain radical of a β-agonist; R¹⁶ is H, methyl or ethyl; R¹⁹ is H, F, OH or methyl; L is a bond or -(CH₂O)-; Q is selected from

and

wherein each W¹ is the same or different and is O or S; W² is O, S or N(R¹); Ph is phenyl optionally substituted on any available carbon with a substituent selected from halo, Ci_-4alkyl, OH, d^alkoxyl, NH₂, N(H)C_1-4alkyi, and N(C_1-4alkyl)₂; each R¹ is the same or different and is independently H or Ci_-4alkyl; a is 0-6; b is 0 and c is 1-4 or b is 1 and c is 2-4; each W³ is the same or different and is independently -O- or -N(R¹)-; x and y are both 0 and z is 1 or x is 1 , y is 0 or 1 and z is 0-6;

Ring A is phenyl, pyridyl or pyrimidyl each optionally substituted on any available carbon with a substituent selected from halo, Ci_-4a!kyl,

OH, Ci_-4alkoxyl, NH₂, N(H)C_1-4alkyl, and N(C_1-4alkyl)₂; d is 0 or 1 ; each R², R³, R⁴, and R⁵ are independently H, Ci_-4 alkyl or halo; one of R⁶ and R⁷ is H and the other is OH; or R⁶ and R⁷ taken together with the carbon to which they are attached form a >C=O group;

R⁸ is H₁ OH₁ O(CO)R⁹ _S or 0(CO)OR⁹; each R⁹ is independently C-₁.₄ alkyl; each R¹⁰ and R¹¹ is independently H or Ci_-4 alkyl; R¹² is H, OH, or C_1-4 alkyl; or R¹¹ and R¹² taken together with the carbon to which they are attached form a

>=CH₂ group; or R¹² and R⁸ taken together with the carbons to which they are attached form a

1 ,3-dioxolane ring represented by formula B:

formula B; wherein one of R¹³ and R¹⁴ is H, methyl or ethyl and the other is H, C_1-10 alkyl, C-2--I0 alkenyi, C_2-io alkynyi, optionally substituted C_3-10 carbocycle or optionally substituted 5-6 ring atom heterocycle wherein one or two ring atoms are selected from N, O and S, and wherein said carbocycle and said heterocycle are each optionally substituted 1 , 2 or 3 times with a substituent selected from halo, C_1-4alkyi, and O-C_1-4alkyi.

For the sake of brevity, the description of embodiments below may reference "compounds of Formula I". It should be understood that the definitions of variables and embodiments thereof apply equally to the same variable in compounds of Formula !l, III, IV, V₁ and Vl as if the disclosure referenced all of the foregoing as well, since such compounds are also compounds of Formula I.

Specific examples of known β-agonists from which the side chain radical R¹⁵ may be derived include but are not limited to the following compounds:

, wherein R^15a is t-butyl; isopropyl; -(CH₂)₆O(CH₂)₄-phenyl;

or any subset thereof.

in a particular embodiment, R¹⁵ is Ci-ealkyl;

C₅-iocarbocycle optionally substituted 1 or 2 times with halo, C-i^alkyS, O-C_{1 -4}aϊkyI, O-(CH₂)₄-NH₂, O-(CH₂)₄-N(H)C_1-4alkyl, O-(CH₂)4-N(C_1-4alky!)₂, O-C_1-4aikyl-C(O)-NH₂, O-C_1-4alkyl-C(O)-N(H)C_1-4alkyi, O-C_1-4alkyϊ-C(O)-N(C_1-4alkyl)₂, or a group represented by formula i, it, iii, iv, v, vi, vii, viii or ix: i: C₆alkyiene-O-R²¹-Ph⁴; ii: C₂.₃alky!ene-Ph¹-O-R²¹-Ph⁴; iii: C_2-3a!ky!ene-Ph¹-N(H)-R²²-Ph²; iv: C₂.₃alkylene-Het-{R²³)-Ph³; v: C_2-3alkylene-Ph¹-Co-₂aIkylene-C(0)N(H)-C_1-4alkylene-Ph³; vi: C_2-3alkylene-Ph³; vii: C₂-3aikytene-S(O)₂-C_2-4alkylene-O-C_2-4alkylene-Ph³; viii: C3-6alkylene-Ph¹-Co_-2alkylene-C(0)N(H)-Cio-i2 bicyciic carbocycie; ix: C₃-₆alkyiene-Het~Ph⁴; wherein: R²¹ is C₂-₆alkylene wherein one carbon of said alkylene is optionally replaced by O;

Ph⁴ is phenyl optionally substituted 1 or 2 times by halo, N(H)C(O)NH₂, SO₂NH₂Or S-cyclopentyl,

Ph¹ is phenyiene;

R²² is a bond or Ci_-2alkylene optionally substituted once by OH or NH₂; Ph² is phenyl optionally substituted 1 or 2 times by O-methyl, -OCH₂CH(CH_S)₂CH₂NH₂, unsubstituted phenyl,

-SO₂-NH(C₆H₃)(CH₃)(C₇H₁₅), or

_; Het is 4-10 ring atom heterocyclene wherein 1 , 2 or 3 ring atoms is/are N, O or S (e.g., indolene or benzodioxolene);

R²³ is a C₂-C₄alkylene wherein one carbon of said alkylene is optionally replaced by O or -C_0-2alkylene-C(O)N(H)-C₂-₄alkylene; and Ph³ is phenyl optionally substituted 1 or 2 times by halo or O-methyl.

in one embodiment, R¹⁵ is C_halky!. More particularly R¹⁵ is C_3-4alkyl. In one particular embodiment, R¹⁵ is isopropyl or t-butyl.

In one embodiment, R¹⁵ is C_6-io carbocycle optionally substituted 1 or 2 times with C_halky!,

or O-Ci_-4alkyl-C(O)-NH₂, or any subset thereof. In one embodiment, R¹⁵ is Cg-iocarbocycle optionally substituted 1 or 2 times with C_1-4alkyl, O-Ci_-4alkyl, or O~Ci_-4alky!-C(O)-NH₂, or any subset thereof. In one embodiment, R¹⁵ is

In one embodiment, R¹⁵ is a group represented by formula i: C₆alkylene-O-R²¹-Ph⁴. In one embodiment R¹⁵ is a group represented by formula i and R²¹ is C₄alkylene. in one particular embodiment, R¹⁵ is a group represented by formula i and R²¹ is C₄alkylene and Ph⁴ is phenyl, particularly unsubstituted phenyl. According to one preferred embodiment, R¹⁵ is -(CH₂)β0(CH₂)4-phenyl, i.e.,

In one embodiment R¹⁵ is a group represented by formula i and R²¹ is C₄alkyiene wherein one C is replaced by O; more particularly, R²¹ is -(CH₂J₂-O- CH₂-. In one particular embodiment R²¹ is -(CH₂J₂-O-CH₂- and Ph⁴ is phenyl optionally substituted 1 or 2 times with halo, particularly Cl, or 1 time with - N(H)-C(O)-NH₂.

In one embodiment R¹⁵ is a group represented by formula ii: C_2-3alkylene-Ph¹-O-R²¹-Ph⁴. in one embodiment R¹⁵ is a group represented by formula ii and R²¹ is C₄a!kylene wherein one C is optionally replaced by O and Ph⁴ is unsubstituted phenyl. In one particular embodiment R¹⁵ is a group represented by formula it and R²¹ is -(CH₂J₄- or -(CH₂^-O-CH₂- and Ph⁴ is unsubstituted phenyl.

In one embodiment R¹⁵ is a group represented by formula iii:

C_2-3alkylene-Ph¹-N(H)-R²²-Ph². In one embodiment R¹⁵ is a group represented by formula iii and R²² is a bond or C₂alkylene substituted once by OH or NH. In one embodiment R¹⁵ is a group represented by formula iii, R²² is a bond and Ph² is phenyl substituted by O-methyl and unsubstituted phenyl or Ph² is phenyl substituted by -OCH₂CH(CH_S)₂CH₂NH₂. In one embodiment R¹⁵ is a group represented by formula iii, R²² is C₂ alkylene substituted once by OH or NH, and Ph² is unsubstituted phenyl.

In one embodiment R¹⁵ is a group represented by formula iv: C₂.₃alkylene-Het-(R²³)-Ph³. In one embodiment R¹⁵ is a group represented by formula iv and Het is a 9 or 10 ring atom heterocyclene wherein 1 or 2 ring atoms is N, O or S. In one embodiment, R¹⁵ is a group represented by formula iv and Het is indolene or benzodioxolene. In one embodiment, R¹⁵ is a group represented by formula iv and R²³ is -CH₂-O-CH₂- or -C(O)N(H)-CH₂-. In one embodiment, R¹⁵ is a group represented by formula iv and Ph³ is unsubstituted phenyl, phenyl substituted twice by halo (particularly Cl) or O-methyl, or any subset thereof.

In one embodiment R¹⁵ is a group represented by formula v: C_2-3alkylene-Ph¹-Co-C₂alkylene-C(O)N(H)-C_1-4alkylene-Ph³. In one embodiment, R¹⁵ is a group represented by formula v and Ph³ is phenyl substituted twice by halo (particularly Ci) or O-methyl. in one embodiment, R¹⁵ is C_2-3aikylene-Ph¹-CH₂-C(O)N(H)-CH₂"Ph³.

In one embodiment R¹⁵ is a group represented by formula vi: C₂-₃alkylene-Ph³. In one embodiment, R¹⁵ is a group represented by formula vi and Ph³ is phenyl substituted once by O-methyl.

In one embodiment, R¹⁵ is a group represented by formula vii: C₂-₃alkylene-S(O)₂~C₂~₄alkylene-O-C_2-4alkylene-Ph³. in one embodiment, R¹⁵ is a group represented by formula vii and Ph³ is unsubstituted phenyl.

In one embodiment, R¹⁵ is a group represented by formula viii: C_3-6alkylene~Ph¹-Co_-2aϊkylene-C(O)N(H)-Cio-i₂ bicyclic carbocycle. In one embodiment, R¹⁵ is a group represented by formula viii-a: (branched) C₃aikylene-Ph¹-CH₂C(O)N(H)-adamantyl.

In one embodiment, R¹⁵ is a group represented by formula ix: C₃-₆alkylene-Het-Ph⁴. in one embodiment, R¹⁵ is a group represented by formula ix wherein Het is a 5 or 6 ring atom heterocyclene wherein 1 , 2 or 3 atoms are N and the remaining atoms are C, wherein said heterocyciene is optionally substituted once by methyl and Ph⁴ is halo-substituted, particularly Cl-su bstituted phenyl. In one particular embodiment, R¹⁵ is selected from:

wherein the wavy bond indicates

the point of attachment.

In one preferred embodiment, R¹⁵ is selected from t-butyl, isopropyl,

or any subset thereof.

In one preferred embodiment, R 15 is

In one preferred embodiment, R 1 5 ^■ is

OCH₃

In one preferred embodiment, R

in one preferred embodiment, R

In one preferred embodiment, R

In one preferred embodiment, R

In one preferred embodiment, R

In one preferred embodiment, R

In one embodiment R¹⁶ is H or methyl. In one preferred embodiment, R¹⁶ is H.

in one preferred embodiment, R¹⁹ is OH.

In one preferred embodiment L is a bond. When L is a bond, it is intended that the aryl oxygen is directly attached to the P atom. In another embodiment L is - -CH₂O-. In addition to the β-agonist moiety, the compounds of Formula I also include a corticosteroid moiety:

wherein each R², R³, R⁴, and R⁵ are independently H, Ci_-4 alkyl or halo; one of R⁶ and R⁷ is H and the other is OH; or R⁶ and R⁷ taken together with the carbon to which they are attached form a >C=O group; R⁸ is H, OH, 0(CO)R⁹, or 0(CO)OR⁹; each R⁹ is independently Ci_-4 alkyl; each R¹⁰ and R¹¹ is independently H or Ci_-4 aikyl; R¹² is H, OH, or C₁^₄ alkyl; or R¹¹ and R¹² taken together with the carbon to which they are attached form a

>=CH₂ group; or

R¹² and R^δ taken together with the carbons to which they are attached form a 1 ,3-dioxoiane ring represented by formula B:

formula B; wherein one of R¹³ and R¹⁴ is H, methyl or ethyl and the other is H, Ci-io alkyl, C2-10 alkenyl, C-2.10 afkyny!, optionally substituted C₃.1₀ carbocycle or optionally substituted 5-6 ring atom heterocycle wherein one or two ring atoms are selected from N, O and S, and wherein said carbocycle and said heterocycie are each optionally substituted 1 , 2 or 3 times with a substituent selected from halo, Ci_-4alkyl, and O-Ci_-4alkyl. In one embodiment each of R², R³, R⁴, and R⁵ are independently H, methyl, F or Cl, or any subset thereof. In one preferred embodiment R², R³, R⁴, and R⁵ are H. In one embodiment R⁴ and R⁵ are H and R² and R³ are H, F, Cl or methyl, in one embodiment R⁴ and R⁵ are H, R² is H, F or Ci and R³ is H, F or methyl. In one particular embodiment R⁴ and R⁵ are H and R² and R³ are H or F. In one particular embodiment R⁴ and R⁵ are H and R² and R³ are F. In one particular embodiment R⁴ and R⁵ are H, R² is H and R³ is F or R² is F and R³ is H.

In one particular embodiment R⁶ and R⁷ taken together with the carbon to which they are attached form a >C~O group. In one preferred embodiment R⁶ is H and R⁷ is OH.

In one embodiment R⁸ is H, OH, 0(CO)CH₂CH₃₁ 0(CO)OCH₃, or 0(CO)OCH₂CH₃, or any subset thereof.

In one embodiment R¹⁰ is H. In one particular embodiment R¹⁰ and R¹¹ are H. In one embodiment R¹⁰ is H and R¹¹ is methyl.

In one embodiment R¹² is H, OH, or methyl. In one particular embodiment R¹² is H or methyl, more particularly H.

In one embodiment R¹¹ and R¹² taken together with the carbon to which they are attached form a >=CH₂ group.

In one preferred embodiment R¹² and R⁸ taken together with the carbons to which they are attached form a 1 ,3-dioxolane ring represented by formula B:

formula B.

In one embodiment wherein R¹² and R⁸ form a ring represented by formula B, one of R¹³ and R¹⁴ is H, methyl or ethyl and the other is H, C-_{M O} aikyl, C_2-io alkeny!, C_2-io alkynyl, optionally substituted C_3-io carbocycle or optionafly substituted 5-6 ring atom heterocycle wherein one or two ring atoms are selected from N₁ O and S, or any subset thereof, wherein the carbocycle and heterocycle are each optionally substituted 1 , 2 or 3 times with a substituent selected from halo, Ci_-4alkyl, and

In one embodiment wherein R¹² and R⁸ form a ring represented by formula B, one of R¹³ and R¹⁴ is H, methyl or ethyl and the other is H, C_1-I₀ alkyl, C_2-Io alkenyl, C_2-10 alkynyl, or optionally substituted C_3--I₀ carbocycle, wherein the carbocycfe is optionally substituted 1 , 2 or 3 times with a substituent selected from halo, C_1-4alky!, and O-C_1-4alkyl. In one embodiment one of R¹³ and R¹⁴ is H, methyl or ethyl and the other is H, C_{1- 10} alkyl, or C_3-10 carbocycle, or any subset thereof. In one embodiment one of R¹³ and R¹⁴ is H, methyl or ethyl and the other is H, C_1-4 aikyl, or C_3-6 cycloalkyl, or any subset thereof, more particularly cyclohexyi. In one embodiment one of R¹³ and R¹⁴ is H or methyl, more particularly H, and the other is H, C_1-4 alkyl, or C_3-6 cycioalkyl, or any subset thereof, more particularly cyclohexyi. !n one embodiment R¹³ and R¹⁴ are each methyl. In one embodiment R¹³ is H and R¹⁴ is propyl. In one preferred embodiment R¹³ is H and R¹⁴ is cyciohexyl.

In a particular embodiment the corticosteroid moiety is

In one preferred embodiment the corticosteroid moiety is

The corticosteroid moiety and the aforementioned β-agontst moiety are joined by a linker "Q". Q in Formula I is selected from

|— C—(W³)_b (CH₂)_C— N-C-W¹ 1 , and

wherein each W¹ is the same or different and is O or S;

W² is O₁ S or N(R¹); Ph is phenyl optionally substituted on any available carbon with a substituent selected from halo, Ci_-4alkyl, OH, Ci_-4aikoxyl, NH₂, N(H)C_1-4alkyl, and N(C_1-4alkyl)₂; each R¹ is the same or different and is independently H or C_halky!; a is 0-6; b is 0 and c is 1-4 or b is 1 and c is 2-4; each W³ is the same or different and is independently -O- or -N(R¹)-; x and y are both 0 and z is 1 or x is 1 , y is 0 or 1 and z is 0-6; Ring A is phenyl, pyridyi or pyrimidyl each optionally substituted on any available carbon with a substituent selected from halo, Ci_-4alkyl, OH₁ C_1-4alkoxy[, NH₂, N(H)Ci_-4aikyl, and N(C_1-4alkyi)₂; and d is O or 1.

in one embodiment, Q is

. in one embodiment, W¹ is O. In one embodiment, W² is O or N(R¹). in one embodiment, W² is O. In another embodiment, W² is N(H).

In another embodiment, Q is

. In one particular embodiment

R¹ is H.

In another embodiment, Q is

, wherein each W¹ is the same or different and is O or S; a is 0-6; and Ph is phenyl optionally substituted on any available carbon with a substituent selected from halo, C_1-4alkyl, OH, C_1-4alkoxyl, NH₂, N(H)C_1-4alkyI, and N(Ci_-4alkyl)₂. In one embodiment, each W¹ is O. In one embodiment, a is 1-4, particularly 1-2. In one particular embodiment, a is 1. In one embodiment, Ph is optionally substituted 1 ,2- or 1 ,4-phenyl. In one particular embodiment Ph is optionally substituted 1 ,4-phenyl. In one embodiment, Ph is unsubstituted phenyl or phenyl substituted with halo or methyl. In one particular embodiment, Ph is unsubstituted 1 ,4-phenyl.

In one particular embodiment, Q is

wherein each R is independently halo, Chalky!, OH, Ci_-4alkoxyl, NH₂, N(H)Ci _-4alkyl, and N(Ci_-4alkyl)₂, and al! other variables are as defined above. In one embodiment, each R is H, halo or methyl, more particularly H.

In one embodiment, Q is

wherein each W¹ is the same or different and is O or S; b is 0 and c is 1-4 or b is 1 and c is 2-4; and W³ is -O- or -N(R¹)-.

In one embodiment, each W¹ is O. In one embodiment, b is O and c is 1-3. In one embodiment b is 1 and W³ is N(H) and c is 2-3.

In one embodiment, Q is

herein each W¹ is the same or different and is O or S; a is 0-6; each W³ is the same or different and is independently -O- or -N(R¹)-, wherein each R¹ is the same or different and is independently H or Ci_-4alkyl; x and y are both 0 and z is 1 or x is 1 , y is 0 or 1 and z is 0-6;

Ring A is phenyl, pyridyl or pyrimidyl each optionally substituted on any available carbon with a substituent selected from halo, C_halky!, OH, C_1-4alkoxyl, NH₂, N(H)C_1-4alkyl, and N(C_1-4alkyl)₂; and d is O or l

in the above group is referred to herein as "Ring A". In one embodiment, Ring A is optionally substituted pyridyl. In another embodiment, Ring A is optionally substituted phenyl. In one embodiment, Ring A is unsubstituted phenyl or phenyl substituted once with a halo or methyl or twice with the same or different substituents selected from halo and methyl, in one particular embodiment, Ring A is unsubstituted 1 ,4-phenyl. In one embodiment, Ring A is unsubstituted pyridyl or pyridyl substituted once with halo or methyl or twice with the same or different substituents selected from halo and methyl. In one embodiment, Ring A is unsubstituted pyridyl.

In one embodiment, x and y are both 0 and z is 1. In one embodiment, x is 1 , y is 0 and z is 0-6, particularly z is 0-3. in one embodiment, x is 1 , y is 1 and z is 0-6, particularly z is 0-3. In one embodiment, x is 1 , y is 0 and z is 1.

In one embodiment, a is 0-4, particularly 0-2. in one particular embodiment, a is 0. In one embodiment, d is 0. In one embodiment, x and y are both 0, z is 1 , d is 1 and (W³)_d is -N(R¹)-, more particularly, (W³)_d is -N(H)-. In one embodiment, , x is 1 , y is 1 , z is 0-6, d is 1 and (W³)_d is O or -N(R¹)-, more particularly, (W³)_d is O or -N(H)-.

In one embodiment, all W¹ are O.

In one embodiment, the invention provides compounds of Formula II, III, IV, V, or Vi:

and pharmaceutically acceptable salts thereof, or any subset thereof, wherein all variables are as defined above, including all embodiments of each variable as described hereinabove. Specific embodiments, including particular and preferred embodiments of R², R³, R¹³, R¹⁴, R¹⁵, Q and L are as described above for compounds of Formula I. For the sake of brevity, the disclosure of those embodiments, including particular and preferred embodiments is not repeated. Any of the previously disclosed embodiments, particular embodiments and preferred embodiments of R², R³, R¹³, R¹⁴, R¹⁵, Q and L are contemplated for combination in any of the foregoing Formulas.

It is to be understood that the present invention includes all combinations and subsets of the particular variable definitions defined hereinabove in the compounds of the invention. Specific examples of compounds of the invention include the compounds set forth in the examples below (and free base and pharmaceutically acceptable salt forms thereof).

The compounds of Formula !, may be in the form of a salt, particularly a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts of the compounds of the Formula I include salts derived from an appropriate base, such as an alkali metal or an aikaline earth (for example,

Na⁺, Li⁺, K⁺. Ca²⁺ and Mg²⁺), ammonium and N(C_1-4alkyl)₄ ⁺. Pharmaceutically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maletc acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, iactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, naphthalene-1 ,5-disulfonic acid, poiygalacturonic acid, malonic acid, sulfosalicyϋc acid, glycolic acid, 2-hydroxy-3-naphthoate, 1-hydroxy-2- naphthoate pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like; and (c) salts formed from elemental anions for example, chlorine, bromine, and iodine.

For therapeutic use, salts of active ingredients of the compounds of Formula I will be pharmaceutically acceptable, i.e. they will be salts derived from a pharmaceuticaliy acceptable acid or base. However, salts of acids or bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether or not derived from a pharmaceutically acceptable acid or base, are within the scope of the present invention. Finaliy, it is to be understood that the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.

The term "chiral" refers to molecules which have the property of non- superimposability of the mirror image partner, while the term "achiral" refers to molecules which are supertmposable on their mirror image partner.

The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

"Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.

"Enantiomers" refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., MCGRAW-HILL DICTIONARY OF CHEMICAL TERMS (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., STEREOCHEMISTRY OF ORGANIC COMPOUNDS (1994) John Wiley & Sons, Inc., New York.

Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light, in describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimoiar mixture of two enantiomeric species.

It is to be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopolymorphs of compounds within the scope of Formula I and pharmaceutically acceptable salts thereof are embraced by the present invention. All mixtures of such enantiomers and diastereomers, including enantiomerically enriched mixtures and diastereomerically enriched mixtures are within the scope of the present invention. Enantionmerically enriched mixtures are mixtures of enantiomers wherein the ratio of the specified enantiomer to the alternative enantiomer is greater than 50:50. More particularly, an enantiomerically enriched mixture comprises at least about 75% of the specified enantiomer, and preferably at least about 85% of the specified enantiomer. in one embodiment, the enantiomericaily enriched mixture is substantially free of the other enantiomer. Similarly, diastereomerically enriched mixtures are mixtures of diastereomers wherein amount of the specified diastereomer is greater than the amount of each alternative diastereomer. More particularly, a diastereomerically enriched mixture comprises at least about 75% of the specified diastereomer, and preferably at least about 85% of the specified diastereomer. In one embodiment, the diastereomericaily enriched mixture is substantially free of all other diastereomers.

For illustrative purposes, specific examples of enantiomers within the scope of the present invention include:

In one embodiment, the present invention provides an enantiomerically enriched mixture comprising

acceptable salt thereof, as the predominant isomer.

A compound of Formula 1 and pharmaceutically acceptable salts thereof may exist as different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures. The crystalline polymorphism may result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism also includes the ability of a hydrate or solvate of a compound to exist in different crystal structures. The pseudopoiymorphs of the instant invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformers of the same molecule (conformational pseudopolymorphism). The instant invention comprises all polymorphs and pseudopolymorphs of the compounds of Formula I and pharmaceutically acceptable salts thereof.

A compound of Formula I and pharmaceutically acceptable salts thereof may also exist as an amorphous solid. As used herein, an amorphous solid is a solid in which there is no long-range order of the positions of the atoms in the solid. This definition applies as well when the crystal size is two nanometers or less. Additives, including solvents, may be used to create the amorphous forms of the instant invention. The instant invention comprises all amorphous forms of the compounds of Formula I and pharmaceutically acceptable salts thereof.

The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity).

USES

The compounds of the invention are useful as a medicament and more particularly, are useful for the treatment of ciinical conditions for which a corticosteroid and/or selective β-agonists, and particularly β₂-agonists, are indicated. Such conditions may involve pulmonary inflammation and/or bronchoconstriction, and include diseases associated with reversible or irreversible airway obstruction. More particularly, such conditions include asthma, chronic obstructive pulmonary diseases (COPD), chronic bronchitis, bronchiectasis, emphysema, respiratory tract infection and upper respiratory tract diseases (e.g., rhinitis, including seasonal and allergic rhinitis).

Accordingly, in one aspect, the present invention provides a method for the treatment of a condition in a mammal, such as a human, for which a corticosteroid and/or β-agonist is indicated.

The terms "treating" and "treatment", as used herein refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition or one or more symptoms of such disorder or condition.

All therapeutic methods described herein are carried out by administering an effective amount of a compound of the invention, i.e., a compound of Formula I or a pharmaceutically acceptable salt thereof, to a subject (typically mammal and preferably human) in need of treatment.

In one embodiment the invention provides a method for the treatment of pulmonary inflammation and bronchoconstriction in a mammal, particularly a human, in need thereof. In one particular embodiment the present invention provides a method for the treatment of a condition associated with reversible airway obstruction in a mammal, particularly a human in need thereof. In one embodiment the invention provides a method for the treatment of asthma in a mammal, particularly a human, in need thereof. In one embodiment the invention provides a method for the treatment of chronic obstructive pulmonary disease in a mammal, particularly a human, in need thereof. In one embodiment the invention provides a method for the treatment of bronchitis, including chronic bronchitis in a mammal, particularly a human, in need thereof. in one embodiment the invention provides a method for the treatment of bronchiectasis in a mammal, particularly a human, in need thereof. In one embodiment the invention provides a method for the treatment of emphysema in a mammal, particularly a human in need thereof, in one embodiment the invention provides a method for the treatment of a respiratory tract infection or upper respiratory tract disease in a mammal, particularly a human in need thereof.

There is also provided a compound of the invention for use in medical therapy, particularly for use in the treatment of condition in a mammal, such as a human, for which a corticosteroid and/or β-agonist is indicated. All therapeutic uses described herein are carried out by administering an effective amount of a compound of the invention to the subject in need of treatment. In one embodiment there is provided a compound of the invention for use in the treatment of pulmonary inflammation and bronchoconstriction in a mammal, particularly a human, in need thereof. In one particular embodiment there is provided a compound of the invention for use in the treatment of a condition associated with reversible airway obstruction in a mammal, particularly a human in need thereof. In one embodiment, there is provided a compound of the invention for use in the treatment of asthma in a mammal, particularly a human, in need thereof. In one embodiment there is provided a compound of the invention for use in the treatment of chronic obstructive pulmonary disease in a mammal, particularly a human, in need thereof. In one embodiment there is provided a compound for use in the treatment of bronchitis, including chronic bronchitis in a mammal, particuiariy a human, in need thereof. In one embodiment there is provided a compound for use in the treatment of bronchiectasis in a mammal, particularly a human, in need thereof. In one embodiment there is provided a compound for use in the treatment of emphysema in a mammal, particularly a human in need thereof. In one embodiment there is provided a compound of the invention for use in the treatment of a respiratory tract infection or upper respiratory tract disease in a mamma!, particuiariy a human, in need thereof.

The present invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a condition in a mammal, such as a human, for which a corticosteroid and/or β-agonist is indicated. In one embodiment is provided the use of a compound of the invention in the manufacture of a medicament for the treatment of pulmonary inflammation and bronchoconstriction in a mammal, particularly a human, in need thereof. In one particular embodiment is provided the use of a compound of the invention in the manufacture of a medicament for the treatment of a condition associated with reversible airway obstruction in a mammal, particuiariy a human in need thereof. !n one embodiment is provided a compound of the invention in the manufacture of a medicament for the treatment of asthma in a mammal, particularly a human, in need thereof. In one embodiment is provided the use of a compound of the invention in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease in a mammal, particularly a human, in need thereof. In one embodiment is provided the use of a compound of the invention in the manufacture of a medicament for the treatment of bronchitis, including chronic bronchitis in a mammal, particularly a human, in need thereof. In one embodiment is provided the use of a compound of the invention in the manufacture of a medicament for the treatment of bronchiectasis in a mammal, particularly a human, in need thereof. In one embodiment is provided the use of a compound of the invention for the manufacture of a medicament for the treatment of emphysema in a mammal, particularly a human in need thereof. In one embodiment is provided the use of a compound of the invention for the manufacture of a medicament for the treatment of a respiratory tract infection or upper respiratory tract disease in a mammal, particularly a human in need thereof.

The term "effective amount", as used herein, is an amount of compound of the invention which is sufficient in the subject to which it is administered, to elicit the biological or medical response of a cell culture, tissue, system, mammal (including human) that is being sought, for instance by a researcher or clinician. The term also includes within its scope, amounts effective to enhance normal physio!ogica! function. In one embodiment, the effective amount is the amount needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a composition is administered by inhalation. For example an effective amount of a compound of the invention for the treatment of a condition for which a corticosteroid and/or β-agonist is indicated is sufficient in the subject to which it is administered to treat the particular condition. In one embodiment an effective amount is an amount of a compound of the invention which is sufficient for the treatment of asthma, or COPD in a human.

The precise effective amount of the compounds of the invention will depend on a number of factors including but not limited to the species, age and weight of the subject being treated, the precise condition requiring treatment and its severity, the bioavailability, potency, and other properties of the specific compound being administered, the nature of the formulation, the route of administration, and the delivery device, and wil! ultimately be at the discretion of the attendant physician or veterinarian.

An estimated dose (for inhalation) of a compound of the invention for treatment of a 70 kg human may be in the range of from about 10 to about 5000μg. The selection of the specific dose for a patient will be determined by the attendant physician, clinician or veterinarian of ordinary skill in the art based upon a number of factors including those noted above. In one particular embodiment, the dose of a compound of the invention for the treatment of a 70 kg human will be in the range of from about 50 to about 2500 μg. In one preferred embodiment the dose of a compound of the invention for the treatment of a 70 kg human will be in the range of from about 100 to about 1000 μg. Doses may be adjusted if the compound is administered via a different route. Determination of an appropriate dose for administration by other routes is within the skill of those in the art in light of the foregoing description and the general knowledge in the art.

Delivery of an effective amount of a compound of the invention may entail delivery of a single dosage form or multiple unit doses which may be delivered contemporaneously or separate in time over a designated period, such as 24 hours. Typically, a compound of the invention (alone or in the form of a composition comprising the same) wilt be administered four, three, two, or most preferably once per day (24 hours).

COMPOSITIONS

While it is possible for a compound of the invention to be administered alone, it is preferable to present it in the form of a composition, particularly a pharmaceutical composition (formulation). Thus, in another aspect, the invention provides compositions, and particularly pharmaceutical compositions (such as an inhalable pharmaceutical composition) comprising a compound of the invention as an active ingredient and a pharmaceutically acceptable excipient, diluent or carrier. The term "active ingredient" as employed herein refers to any of a compound of Formula i or a pharmaceutically acceptable salt thereof. !n a particular embodiment, the composition is a novel, efficacious, safe, nonirritating and physiologically compatible inhalable composition comprising the active ingredient. The composition is preferably suitable for treating asthma, bronchitis, or COPD.

Pharmaceutical compositions according to the invention include those suitable for oral administration; parenteral administration, including subcutaneous, intradermal, intramuscular, intravenous and intraarticular; and administration to the respiratory tract, including the nasal cavities and sinuses, oral and extrathoracic airways, and the lungs, including by use of aerosols which may be delivered by means of various types of dry powder inhalers, pressurized metered dose inhalers, softmist inhalers, nebulizers, or insufflators. The most suitable route of administration may depend upon, several factors including the patient and the condition or disorder being treated.

The formulations may be presented in unit dosage form or in bulk form as for example in the case of formulations to be metered by an inhaler and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier, diluent or excipient and optionally one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with one or more liquid carriers, diluents or excipients or finely divided solid carriers, diluents or excipients, or both, and then, if necessary, shaping the product into the desired formulation.

In one preferred embodiment, the composition is an inhalable pharmaceutical composition which is suitable for inhalation and delivery to the endobronchial space. Typically, such composition is in the form of an aerosol comprising particles for delivery using a nebulizer, pressurized metered dose inhaler (pMDI), softmist inhaler, or dry powder inhaler (DPI).

Aerosols used to administer medicaments to the respiratory tract are typically polydisperse, that is they are comprised of particles of many different sizes. The particle size distribution is typically described by the Mass Median

Aerodynamic Diameter (IvIMAD) and the Geometric Standard Deviation (GSD). For optimum drug delivery to the endobronchial space the MMAD is in the range from about 1 to about 10 μm and preferably from about 1 to about 5μm, and the GSD is less than 3, and preferably less than about 2. Aerosols having a MMAD above 10 μm are generally too large when inhaled to reach the lungs. Aerosols with a GSD greater than about 3 are not preferred for lung delivery as they deliver a high percentage of the medicament to the oral cavity. To achieve these particle sizes the particles of the active ingredient as produced may be size reduced using conventional techniques such as micronisation or spray drying. The desired fraction may be separated out by air classification or sieving. Preferably, the particles will be crystalline.

Aerosol particle size distributions are determined using devices well known in the art. For example a multi-stage Anderson cascade impactor or other suitable method such as those specifically cited within the US Pharmacopoeia Chapter 601 as characterizing devices for aerosols emitted from metered-dose and dry powder inhalers.

Dry powder compositions for topical delivery to the lung by inhalation generally contain a mix of the active ingredient and a suitable powder base (carher/diluent/exciptent substance) such as mono-, di- or polysaccharides (e.g., lactose or starch). Lactose is typically preferred. When a solid excipient such as lactose is employed, generally the particle size of the excipient will be much greater than the active ingredient to aid the dispersion of the formulation in the inhaler.

Non-limiting examples of dry powder inhalers include reservoir multi-dose inhalers and pre-metered multi-dose inhalers. A reservoir inhaler contains a large number of doses (e.g. 60) in one container. Prior to inhalation, the patient actuates the inhaler which causes the inhaler to meter one dose of medicament from the reservoir and prepare it for inhalation. In a pre-metered multi-dose inhaler, each individual dose has been manufactured in a separate container, and actuation of the inhaler prior to inhalation causes a new dose of drug to be released from its container and prepared for inhalation. During inhalation, the inspiratory flow of the patient accelerates the powder out of the device and into the oral cavity. Turbulent flow characteristics of the powder path cause the excipient-drug aggregates to disperse, and the particles of active ingredient are deposited deep in the lungs. In preferred embodiments, a compound of the invention is delivered as a dry powder using a dry powder inhaler wherein the particles emitted from the inhaler have an MMAD in the range of about 1 μrn to about 5 μm and a GSD about less than 2. Examples of suitable dry powder inhalers and dry powder dispersion devices for use in the delivery of compounds and compositions according to the present invention include but are not limited to those disclosed in US7520278; US7322354; US7246617; US7231920; US7219665; US7207330; US6880555; US5,522,385; US6845772; US6637431 ; US6329034; US5,458,135; US4.805.811.

In one embodiment, the pharmaceutical formulation according to the invention is a dry powder for inhalation which is formuiated for delivery by a Diskus®-type device. The Diskus® device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing a predetermined amount active ingredient either alone or in admixture with one or more carriers or excipeints (e.g., lactose) and/or other therapeutically active agents. Preferably, the strip is sufficiently flexible to be wound into a roll. The iid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the leading end portions is constructed to be attached to a winding means. Also, preferably the hermetic seal between the base and lid sheets extends over their whole width. To prepare the dose for inhalation, the lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the base sheet.

Spray compositions for topical delivery to the endobronchial space or iung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurized packs, such as metered dose inhalers, with the use of suitable liquefied propeilants, softmist inhalers, or nebulizers. Such aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the active ingredient together with a pharmaceutically acceptable carrier or diluent (e.g., water, saline, or ethanoi) and optionally one or more therapeutically active agents.

Aerosol compositions for delivery by pressurized metered dose inhalers typically further comprise a pharmaceutically acceptable propellant. Examples of such propellants include fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, especially 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3,-heptafiuoro-n-propane or a mixture thereof. The aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants e.g., oleic acid or lecithin and cosolvents e.g., ethanol. Pressurized formulations will generally be retained in a canister (e.g., an aiuminum canister) closed with a valve (e.g., a metering valve) and fitted into an actuator provided with a mouthpiece.

In another embodiment, a pharmaceutical composition according to the invention is delivered as a dry powder using a metered dose inhaler. Non- iimiting examples of metered dose inhalers and devices include those disclosed in US5,261 ,538; US5,544,647; US5,622,163; US4.955.371 ; US3,565,070; US3.361306 and US6, 116,234. In a preferred embodiment, a compound of the invention is delivered as a dry powder using a metered dose inhaler wherein the emitted particles have an MMAD that is in the range of about 1 μm to about 5 μm and a GSD that is less than about 2.

In one embodiment is provided a pharmaceutical composition comprising an effective amount of a compound of the invention in a dosage form suitable for delivery via a nebulizer, metered dose inhaler, or dry powder inhaler. In one particular embodiment is provided a pharmaceutical composition comprising an effective amount of a compound of the invention in a dosage form suitable for aerosofization by metered-dose inhaler; or jet, ultrasonic, or vibrating porous plate nebulizer.

Such liquid inhalable solutions for nebulization may be generated by solubilizing or reconstituting a solid particle formulation or may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, and isotonicity adjusting agents. They may be sterilized by in process techniques such as filtration, or terminal processes such as heating in an autoclave or gamma irradiation. They may also be presented in non-sterile form.

Such formulations may be administered using commercialiy available nebulizers or other atomizer that can break the formulation into particles or droplets suitable for deposition in the nasal cavities or respiratory tract. Non- limiting examples of nebulizers which may be employed for the aerosol delivery of a composition of the invention include pneumatic jet nebulizers, vented or breath enhanced jet nebulizers, or ultrasonic nebulizers including static or vibrating porous plate nebulizers. A jet nebulizer utilizes a high velocity stream of air blasting up through a column of water to generate droplets. Particles unsuitable for inhalation impact on walls or aerodynamic baffles. A vented or breath enhanced nebulizer works the same as a jet nebulizer except that inhaled air passes through the primary droplet generation area to increase the output rate of the nebulizer while the patient inhales. In an ultrasonic nebulizer, vibration of a piezoelectric crystal creates surface instabilities in the drug reservoir that cause droplets to be formed. In porous plate nebulizers pressure fields generated by sonic energy force liquid through the mesh pores where it breaks into droplets by Rayleigh breakup. The sonic energy may be supplied by a vibrating horn or plate driven by a piezoelectric crystal, or by the mesh itself vibrating. Non-limiting examples of atomizers include any single or twin fluid atomizer or nozzle that produces droplets of an appropriate size. A single fluid atomizer works by forcing a liquid through one or more holes, where the jet of liquid breaks up into droplets. Twin fluid atomizers work by either forcing both a gas and liquid through one or more holes, or by impinging a jet of liquid against another jet of either liquid or gas.

The nebulizer which aerosolizes the formulation of the active ingredient is important in the administration of the active ingredient. Different nebulizers have differing efficiencies based their design and operation principle and are sensitive to the physical and chemical properties of the formulation. For example, two formulations with different surface tensions may have different particle size distributions. Additionally, formulation properties such as pH, osmolality, and perrneant ion content can affect tolerability of the medication, so preferred embodiments conform to certain ranges of these properties, in a preferred embodiment, the formulation for nebulization is delivered to the endobronchial space as an aerosol having an MMAD between about 1 μm and about 5 μrη and a GSD less than 2 using an appropriate nebulizer. To be optimally effective and to avoid upper respiratory and systemic side effects, the aerosol should not have a MMAD greater than about 5 μm and should not have a GSD greater than about 2. Jf an aerosol has an MMAD larger than about 5 μm or a GSD greater than about 2 a large percentage of the dose may be deposited in the upper airways decreasing the amount of drug delivered to the site of inflammation and bronchoconstriction in the lower respiratory tract. If the MMAD of the aerosol is smaller than about 1 μm then the particles may remain suspended in the inhaled air and may then be exhaled during expiration.

Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oii-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a sachet, bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binders, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.

Formulations for topical administration in the mouth, for example buccally or sublinguaily, include lozenges, comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a base such as gelatin and glycerin or sucrose and acacia.

Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or muiti-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (iyophilized) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for- injection, immediately prior to use.

Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. in another aspect of the invention, the aerosolizable formulation of a compound of the invention delivers an effective amount of the compound ranging from about 1 to about 5000 μg to the lungs wherein the composition produces plasma concentrations of the β-agonist and/or corticosteroid of less than about 10 nanograms/mL one hour after administration of said composition, in a preferred embodiment of the invention, the plasma concentrations of the β- agonist and/or corticosteroid produced are less than about 5 nanograms /mL one hour after administration of the composition. In a particularly preferred embodiment of the invention, the plasma concentrations of the β-agonist and/or corticosteroid produced are less than about 2 nanograms /mL one hour after administration of the composition.

In another aspect, the invention provides a method of treating pulmonary inflammation and bronchoconstriction comprising treating a subject in need thereof with an effective amount of an inhalable pharmaceutical composition of a compound of the invention wherein the inhalable pharmaceutica! composition produces plasma concentrations of the β-agonist and/or corticosteroid comprising the compound of the invention of less than 10 nanograms/mL one hour after administration of said composition. In a preferred embodiment of the method, the plasma concentrations of the β-agonist and/or corticosteroid produced are less than about 5 nanograms /ml_ one hour after administration of said formulation. In a particularly preferred embodiment of the method, the plasma concentrations of the β-agonist and/or corticosteroid produced are less than about 2 nanograms /ml one hour after administration of said formulation.

in another aspect, the invention provides a method of treating asthma, COPD, bronchitis, bronchiectasis, emphysema or rhinitis in a human subject comprising treating the subject with an effective amount of a inhaiable pharmaceutical composition of a compound of the invention wherein the inhaiable pharmaceutical composition produces plasma concentrations of the β-agonist and/or corticosteroid of less than 10 nanograms/mL one hour after administration of said composition. In a preferred embodiment of the method, the plasma concentrations of the β-agonist and/or corticosteroid produced are less than about 5 nanograms /mL one hour after administration of said formulation. In a particularly preferred embodiment of the method, the plasma concentrations of the β-agonist and/or corticosteroid produced are less than about 2 nanograms /mL one hour after administration of said formulation.

Preferred unit dosage formulations for the compounds of the invention are those containing an effective amount of the active ingredient or an appropriate fraction thereof.

It should be understood that in addition to the ingredients particularfy mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question for example those suitable for oral administration may include flavoring agents.

As noted above, the compounds of the invention may be formulated and/or used in combination with other therapeutically active agents. Examples of other therapeutically active agents which may be formulated or used in combination with the compounds of the invention include but are not limited to antiinflammatory agents, anticholinergic agents, β-agonists (including selective β₂- agonists), peroxisome proliferator-activated receptor (PPAR) gamma agonists, PPAR delta agonists, epithelial sodium channel blockers (ENaC receptor blockers), kinase inhibitors, antiinfective agents and antihistamines. The present invention thus provides, as another aspect, a composition comprising an effective amount of compound of the invention and another therapeutically active agent selected from anti-inflammatory agents, anticholinergic agents, β- agonists (including selective β₂-agonists), PPAR gamma agonists, PPAR delta agonists, ENaC receptor blockers, kinase inhibitors, antiinfective agents and antihistamines.

Suitable anti-inflammatory agents for use in combination with the compounds of the invention include corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs), particularly phosphodiesterase (PDE) inhibitors. Examples of corticosteroids for use in the present invention include oral or inhaled corticosteroids or prodrugs thereof. Specific examples include but are not limited to ciclesonide, desisobutyryl-ciciesonide, budesonide, flunisolide, mometasone and esters thereof (e.g., mometasone furoate), fluticasone propionate, fluticasone furoate, beclomethasone, methyl prednisolone, prednisolone, dexamethasone, 6α,9α-difiuoro-17a-[(2-furanylcarbonyl)oxy]- 11β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α- propionyioxy-androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro- furan-3S-yl) ester, beclomethasone esters (e.g., the 17-propionate ester or the 17,21-dipropionate ester, fluoromethyi ester, triamcinolone acetonide, rofleponide, or any combination or subset thereof. Preferred corticosteroids for formulation or use in combination with the compounds of the invention are selected from ciclesonide, desisobutyryl-ciciesonide, budesonide, mometasone, fluticasone propionate, and fluticasone furoate, or any combination or subset thereof.

NSAIDs for use in the present invention include but are not limited to sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g., theophylline, PDE4 inhibitors, mixed PDE3/PDE4 inhibitors or mixed PDE4/PDE7 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (e.g., 5 LO and FLAP inhibitors), nitric oxide synthase (iNOS) inhibitors, protease inhibitors (e.g., tryptase inhibitors, neutrophil elastase inhibitors, and metailoprotease inhibitors) β2-integrin antagonists and adenosine receptor agonists or antagonists (e.g., adenosine 2a agonists), cytokine antagonists (e.g., chemokine antagonists) or inhibitors of cytokine synthesis (e.g., prostaglandin D2 (CRTh2) receptor antagonists).

The PDE4 inhibitor, mixed PDE3/PDE4 inhibitor or mixed PDE4/PDE7 inhibitor may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are selective PDE4 inhibitors (i.e., compounds which do not appreciably inhibit other members of the PDE famiiy). Examples of specific PDE4 inhibitors for formulation and use in combination with the compounds of the present invention include but are not limited to roflumilast, pumafentrine, arofylline, cslomilast, tofimilast, oglemiiast, tolafentrine, piclamiiast, ibudilast, apremilast, 2-[4-[6,7-diethoxy-2,3- bis(hydroxymethyl)-1 -naphthaleny!]-2-pyridinyϊ]-4-(3-pyridinyl)-1 (2H)- phthalazinone (T2585), N-(3,5-dichloro-4-pyridinyl)-1-[(4-fluorophenyl)methy!]-5- hydroxy-α-oxo-1 H-indoie-3-acetamide (AWD-12-281 ), 4-[(2R)-2-[3- (cyclopentyloxy)-4-methoxypheny!]-2-phenylethy[]-pyridine (CDP-840), 2-[4- [[[[2-(1 ,3-benzodioxol-5-yloxy)-3-pyridinyl3carbonyl]amino]methyl]-3- fluorophenoxy]-(2R)-propanoic acid (CP-671305), N-(4,6-dtmethyl-2- pyrimidiny!)-4-[4,5,6,7-tetrahydro-2-(4-methoxy-3-methyiphenyl)-5-(4-methyl-1- piperazinyl)-1 H-indol-1-yl]- benzenesulfonamide, (2E)-2-butenedioate (YM- 393059), 9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-purin-6- amine (NCS-613), N-(2,5-dichloro-3-pyridinyl)-8-methoxy-5- quinolinecarboxamide (D-4418), N-[(3R)-9-amino-3,4,6,7-tetrahydro-4-oxo-1- phenylpyrrolo[3,2,1-][1 ,4]benzodiazepin-3-yl]-3H-purin-6-amine (PD-168787), 3- p-tcyclopentyloxyH-methoxyphenyljmethyπ-N-ethyi-δ-ti-methylethyO-SH- purin-6-amine hydrochloride (V-11294A), N-(3,5-dichloro-1-oxido-4-pyhdinyl)-8- methoxy-2-(trifluoromethyi)-5-quinolinecarboxamide (Sch351591 ), 5-[3- (cydopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl]-(3S,5S)- 2- piperidinone ( HT-0712), 5-(2-((1r,4r)-4-amino-1-(3-(cyc!opentyloxy)-4- methyoxyphenyl)cyclohexyl)ethynyl)-pyrimidine-2-amine, cis-[4-cyano~4-(3- cyciopropylmethoxy^-difluoromethoxyphenyOcyciohexan-i -ol], and 4~[6,7- diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-2(1 H)- pyridinone (T-440), and any combination or subset thereof.

Leukotriene antagonists and inhibitors of leukotriene synthesis include zafirlukast, montelukast sodium, zileuton, and pranlukast.

Anticholinergic agents for formulation or use in combination with the compounds of the invention include but are not limited to muscarinic receptor antagonists, particularly including pan antagonists and antagonists of the M₃ receptors. Exemplary compounds include the alkaloids of the belladonna plants, such as atropine, scopolamine, homatropine, hyoscyamine, and the various forms including salts thereof (e.g., anhydrous atropine atropine sulfate, atropine oxide or HCI, methylatropine nitrate, homatropine hydrobromide, homatropine methyl bromide, hyoscyamine hydrobromide, hyoscyamine sulfate, scopolamine hydrobromide, scopolamine methyl bromide) tolterodine, revatropate, solifenacine, darifenacin, or any combination or subset thereof.

Additionai anticholinergics for formulation and use in combination with the methantheline, propantheline bromide, anisotropine methyl bromide or Vaipin 50, aclidinium bromide, glycopyrrolate (Robinul), isopropamide iodide, mepenzoiate bromide, tridihexethyl chloride, hexocyclium methyl sulfate, cyciopentoiate HCI, tropicamide, trihexyphenidyl CCi, pirenzepine, telenzepine, and methoctramine, or any combination or subset thereof.

Preferred anticholinergics for formulation and use in combination with the compounds of the invention include ipratropium (bromide), oxitropium (bromide) and tiotropium (bromide), or any combination or subset thereof.

Examples of β-agonists for formulation and use in combination with the compounds of the invention include but are not limited to salmeterol, R- salmeterol, and xinafoate salts thereof, albuterol or R-albuterol (free base or sulfate), formoterol (fumarate), indacaterol, fenoteroi, terbutaline and salts thereof, and any combination or subset thereof. Examples of PPAR gamma agonists for formulation and use in combination with the compounds of the invention include but are not limited to thiazolidinediones, rosiglitazone, piogiitazone, and troglitazone.

Examples of ENaC receptor blockers for formulation and use in combination with the compounds of the invention include but are not limited to amiloride and derivatives thereof such as those compounds described in US Patent Nos. 6858615 to Parion Sciences, Inc.

Exampies of kinase inhibitors include inhibitors of NFkB, PI3K (phosphatidylinositol 3-kinase), p38-MAP kinase and Rho kinase.

Antiinfective agents for formulation and use in combination with the compounds of the invention include antivirais and antibiotics. Examples of suitable antivirals include Tamiflu® and Relenza®. Examples of suitable antibiotics include but are not limited to aztreonam (arginine or lysine), fosfomycin, and tobramycin, or any combination or subset thereof.

Antihistamines (i.e., H1 -receptor antagonists) for formuiation and use in combination with the compounds of the invention include but are not limited to: ethanolamines, ethylenediamines, alkylamines, pyridines, piperazines, piperidines, tri- and tetracyclics and combinations thereof. Specific examples of antihistamines for formulation and use in combination with the compounds of the invention include but are not limited to diphenhydramine HC!, carbinoxamine maleate, doxylamine, clemastine fumarate, diphenylhydramine HCI, dimenhydrinate, pyrilamine maieate (metpyramine), tripelennamine HCI, tripelennamine citrate, antazoiine pheniramine, chloropheniramine, bromopheniramine, dexchlorpheniramine, triproiidine, acrivastine methapyrilene, hydroxyzine HCI, hydroxyzine pamoate, cycliztne HCI, cyclizine lactate, meclizine HCI, cetirizine HCl astemisole, levocabastine HCI, loratadine, descarboethoxy loratadine, terfenadine, fexofenadine HCI, promethazine, chlorpromethazine, trimeprazine, azatadine, and azelastine HCI, or any combination or subset thereof. In one aspect, the present invention provides a composition comprising a compound of the invention and an anti-inflammatory agent. In one embodiment, the composition comprises a compound of the invention and a corticosteroid, in one particular embodiment, the composition comprises a compound of the invention and a corticosteroid selected from ciciesonide, desisobutyryl-ciclesonide, budesonide mometasone, fluticasone propionate, and fluticasone furoate. In one particular embodiment, the composition comprises a compound of the invention and ciciesonide or desisobutyryl- ciclesonide.

In one aspect, the present invention provides a composition comprising a compound of the invention and a PDE4 inhibitor. In one embodiment the PDE4 inhibitor is roflumilast or cilomilast.

In one aspect, the present invention provides a composition comprising a compound of the invention and a β2-agontst. In one embodiment, the composition comprises a compound of the invention and salmeteroi, R- salmeterol, formoterol, or indacaterol. In one particular embodiment, the composition comprises a compound of the invention and salmeteroi or R- salmeteroi.

In one aspect, the present invention provides a composition comprising a compound of the invention and an anticholinergic agent. In one embodiment, the composition comprises a compound of the invention and tiotropium.

In one aspect, the present invention provides a composition comprising a compound of the invention and anti-histamine.

In the above-described methods of treatment and uses, a compound of the invention may be employed alone, or in combination with one or more other therapeutically active agents. Typically, any therapeutically active agent that has a therapeutic effect in the disease or condition being treated with the compound of the invention may be utilized in combination with the compounds of the invention, provided that the particular therapeutically active agent is compatible with therapy employing a compound of the invention. Typical therapeutically active agents which are suitable for use in combination with the compounds of the invention include the anti-inflammatory agents, anticholinergic agents, β-agonists, antiinfective agents and antihistamines described above.

In another aspect, the invention provides methods for treatment and uses as described above, which comprise administering an effective amount of a compound of the invention and at least one other therapeutically active agent. The compounds of the invention and at least one additional therapeutically active agent may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination. The administration of a compound of the invention with one or more other therapeutically active agents may be by administration concomitantly in 1 ) a unitary pharmaceutical composition, such as the compositions described above, or 2) separate pharmaceutical compositions each including one or more of the component active ingredients. The components of the combination may be administered separately in a sequential manner wherein the compound of the invention is administered first and the other therapeutically active agent is administered second or vice versa.

When a compound of the invention is used in combination with another therapeutically active agent, the dose of each compound may differ from that when the compound of the invention is used alone. Appropriate doses will be readily determined by one of ordinary skill in the art. The appropriate dose of the compound of the invention, the other therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect, and are within the expertise and discretion of the attendant physician, clinician or veterinarian.

In another aspect, the present invention provides methods for treating any of the conditions enumerated above, comprising administering an effective amount of a compound of the invention and an anti-inflammatory agent. In one embodiment, the method comprises administering an effective amount of a compound of the invention and a corticosteroid. !n one particular embodiment, the method comprises administering an effective amount of a compound of the invention and a corticosteroid selected from cidesonide, desisobutyryl- ciclesonide, budesonide mometasone, fluticasone propionate, and fluticasone furoate. In one particular embodiment, the method comprises administering an effective amount of a compound of the invention and ciciesonide or desisobutyryl-ciclesonide.

In one embodiment the present invention provides a method for treating any of the conditions enumerated above comprising administering an effective amount of a compound of the invention and a PDE4 inhibitor, particularly roflumilast or cilomiiast.

In one embodiment the present invention provides a method for treating any of the conditions enumerated above comprising administering an effective amount of a compound of the invention and a β-agonist, particularly a selective β₂- agonist. In one embodiment, the method comprises administering an effective amount of a compound of the invention and salmeterol, R-salmeterol, formoterol, or indacaterol. In one particular embodiment, the method comprises administering an effective amount of a compound of the invention and salmeteroi or R-salmeterol.

In one embodiment the present invention provides a method for treating any of the conditions enumerated above by administering an effective amount of a compound of the invention and an anticholinergic agent. In one embodiment, the method comprises administering an effective amount of a compound of the invention and tiotropium.

In one embodiment the present invention provides a method for treating any of the conditions enumerated above by administering an effective amount of a compound of the invention and anti-histamine. In another aspect the present invention provides a combination comprising a compound of the invention and an anti-inflammatory agent for the treatment of any condition enumerated above; and a!so the use of such combination for the manufacture of a medicament for the treatment of any of the conditions enumerated above. In one embodiment, the combination comprises a compound of the invention and a corticosteroid selected from ciclesonide, desisobutyryl-ciclesonide, budesonide mometasone, fluticasone propionate, and fluticasone furoate. in one particular embodiment, the combination comprises a compound of the invention and cidesonide or desisobutyryl- ciclesonide.

In another aspect the present invention provides a combination comprising a compound of the invention and a PDE4 inhibitor for the treatment of any condition enumerated above; and a!so the use of such combination for the manufacture of a medicament for the treatment of any of the conditions enumerated above.

In another aspect the present invention provides a combination comprising a compound of the invention and a β-agonist for the treatment of any condition enumerated above; and also the use of such combination for the manufacture of a medicament for the treatment of any of the conditions enumerated above. In one embodiment the combination comprises a compound of the invention and salmeterol, R-salmeterol, formoterol, or indacaterol. In one particular embodiment, the combination comprises a compound of the invention and saimeterol or R-salmeterol.

In another aspect the present invention provides a combination comprising a compound of the invention and an anticholinergic agent for the treatment of any condition enumerated above; and also the use of such combination for the manufacture of a medicament for the treatment of any of the conditions enumerated above. In one embodiment the combination comprises a compound of the invention and tiotropium. In another aspect the present invention provides a combination comprising a compound of the invention and an antihistamine for the treatment of any condition enumerated above; and also the use of such combination for the manufacture of a medicament for the treatment of any of the conditions enumerated above.

The present invention also provides processes for preparing the compounds of the invention and to the synthetic intermediates useful in such processes, as described in detail below.

Having generally described this invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be iimiting unless otherwise specified.

Certain abbreviations and acronyms are used in describing the experimental details. Although most of these would be understood by one skilled in the art, the following table contains a list of many of these abbreviations and acronyms.

Compounds of Formula I wherein Q

(i.e., a compound of

Formula I-B) may be prepared according to the process illustrated in Scheme 1. Scheme 1

wherein:

X¹ is halo, particularly Cl;

R²⁵ is OH or NH₂; each PG¹ is a phosphonic acid protecting group such as methyl, ethyl, benzyl or t-butyl; each PG² is H or Boc; and all other variables are as defined herein. Generally, the process comprises the steps of a) coupling a compound of formula 11 with a compound of formula 12 to prepare a compound of formula 13 or a pharmaceutically acceptable salt thereof; and b) deprotecting the compound of formula 13 to prepare a compound of

Formula I-B, or a pharmaceutically acceptable salt thereof.

More particularly, a compound of formula 11 may be reacted with the compound of formula 12 in the presence of a base such as 1 ,2,2,6,6- pentamethyipiperidine, N,N-diisopropylethyiamine, triethylamine or other amine base. The reaction may be carried out at an appropriate temperature based the definition of R²⁵. Suitable solvents include acetonitrile and methylene chloride. Deprotection of a compound of formula 13 may be carried out using conventional techniques, including acidic conditions, either by brief treatment with HCi in dioxane or by fow-temperature treatment with trifluoroacetic acid in dichloromethane at about 0^°C. The optimal method for removing the protecting groups may be based upon the definition of L. For example, in those embodiments wherein L is a bond, deprotection with HCI is preferred whereas in those embodiments wherein L is CH₂O, deprotection via trifluoroacetic acid may be preferred.

As will be apparent to those skilled in the art, the choice of protecting groups on the compound of formula 13 will be based at least in part on the steric bulk of the particular β-agonist side chain (R¹⁵) selected. For protecting groups other than Boc, deprotection may be accomplished using conventional techniques including reaction with TMS-Br or TMS-i in a solvent such as acetonitrile or methylene chloride at a temperature from room temperature to 7O⁰C.

The compound of formula 11 may be prepared by reacting the corresponding compound of formula 1 :

R³ wherein a!l other variables are as defined herein, with phosgene at room temperature. Compounds of formula 1 are commercially available or may be prepared using conventional techniques and commercially available reagents.

The compounds of formula 12 wherein R²⁵ is OH may be prepared by the processes described below for the preparation of intermediate compounds of formula 7 wherein R³⁵ is H.

Useful Intermediate compounds may be prepared according to process illustrated in Scheme 2 below.

Scheme 2

wherein: each PG¹ is a phosphonic acid protecting group such as methyl, ethyl, benzyl or t-butyi;

LG is a suitable leaving group, such as mesylate, triflate or iodide; each PG² is H or Boc;

R³⁵ is H or an alcohol protecting group such as tert-butyldimethylsilyl; and all other variables are as defined herein, in one embodiment, the process comprises the steps of: a) oxidizing a compound of formula 4 to prepare a compound of formula 5; b) phosphoryiating the compound of formula 5 to prepare a compound of formula 6; c) reducing the compound of formula 6 to prepare a compound of formula 7; and d) installing a leaving group on the compound of formula 7 to prepare the compound of formula 2.

More particularly, the starting material compounds of formula 4 are either commercially available or may be prepared using conventional techniques. See, PCT Publication No. 2006/138212 to Baker et al., published 28 Dec 2006. The compounds of formula 4 may be oxidized using conventional oxidation techniques and oxidizing agents to prepare compounds of formula 5. Suitable oxidation techniques include, for example, manganese(IV) oxide in chloroform. As will be apparent to those skilled in the art, it is desirable to install amine and/or alcohol protecting groups prior to oxidation. Suitable protecting groups include carboaikoxy protecting groups such as Boc, Methods are well known in the art for installing and removing such protecting groups and such conventional techniques may be employed in the instant reaction as well.

The compound of formula 5 may be phosphorylated using conventional techniques and phosphoryiating agents. Examples of suitable phosphorylation techniques include but are not limited to reacting with ds-t-butyl- phosphobromidate synthesized in situ in a one-pot procedure and alkylating at 5OO with di-tert-butyl chloromethyl phosphate (Krise et al., J Med Chem (1999) 42:3094-3100).

The aldehyde moiety of the thus produced compound of formula 6 may be reduced using conventional techniques and reagents such as sodium borohydride at O⁰C.

If desired, additional secondary hydroxyl protection can be introduced by reaction with excess di-t-butyi-dicarbonate. The foregoing reduction may then be employed to prepare the primary alcohol analog of formula 7. The installation of the leaving group on the compound of formula 7 may be accomplished using conventional techniques. For installation of the methanesulfonate leaving group, the foregoing protection strategy advantageously allows for quantitative sulfonylation carried out at room temperature, using methanesulfonyl chloride (MsCI) in the presence of 1 ,2,2,6, 6-pentamethylpiperidine (PMP) to give the compound of formula 2 wherein LG is mesylate. In case of triflate leaving group the reaction may be carried out at -78^°C in order to minimize the formation of byproducts.

In another embodiment, the process comprises the steps of a) phosphoryiating and reducing 5-bromosalicyiaidehyde to prepare a compound of formula 8; b) reacting the compound of formula 8 under Suzuki reaction conditions to prepare a compound of formuia 9; c) reacting the compound of formula 9 with an epoxidation agent to prepare a compound of formula 10; d) reacting the compound of formula 10 with an amine of formula H₂N-R¹⁵ to prepare a compound of formula 7; and e) instaliing a leaving group on the compound of formula 7 to prepare the compound of formula 2. in the preparation of compounds of Formuia I wherein R¹⁵ is t-butyl, the steric bulk around the aminoalcohof moiety leads to a preference for the indirect synthetic approach.

The syntheses starts with 5-bromosaiicylaldehyde, which is phosphorylated using the techniques and reagents described above and reduced to form the alcohol. An alcohol protecting group is typically installed, such as by treatment with tert-butyidimethylsϋyl chloride in the presence of imidazole, to prepare the compound of formuia 8. Suzuki reaction conditions including the trivinylboroxine-pyridine complex in the presence of catalytic amounts of tricyclohexylphosphine and palladium (il) acetate may be used to introduce the vinyl substituent, thereby preparing the compound of formula 9. The compound of formula 9 then undergoes epoxidation and the epoxide is then opened through nucleophtiic substitution by treatment with an appropriate amine of formula NH₂-R¹⁵, in the presence of a Lewis acid such as lithium perchlorate. The epoxidation reaction may be accomplished by conventional means, including treatment with 2,2-dimethyidioxirane (DMDO) which may be conveniently generated in situ in a mixture of oxone and acetone. The nucleophiiic substitution results in compounds of formula 7. Depending upon the definition of PG₁ the compounds of formula 7 may be acylated with, for example, di-tert-butyf dicarbonate, to install the Boc protecting group. The removal of R³⁵ {if not H) and installation of the leaving group LG₁ in the compounds of formula 7 results in the compounds of formula 2, as described above.

Compounds of formula 12 wherein R²⁵ is NH₂ may be prepared by the process illustrated below.

wherein R >35 ; i„s I HJ₁ D R25 is NH₂, and all other variables are as defined above.

A compound of formula 7 is reacted with diphenyl azidophosphate to give the azide compound of formula 14, which may be reduced by reaction with a conventional reducing agent, such as triphenyl phosphine, using standard techniques, to yield the compound of formula 12, wherein R²⁵ is NH₂.

The foregoing process may be utilized to prepare the corresponding R-isomer of a compound of Formula I-B by substituting the R-enantiomer of the N-Boc- protected compound of formula 12 starting material for the racemate. Similarly the corresponding S-isomer of a compound of Formula I-B may be made by using the S-enantiomer of the N-Boc-protected compound of formula 12. This same approach may be utilized to prepare enantiomerically enriched mixtures of any of the compounds of Formula I which contain a chiral center, and pharmaceutically acceptable salts thereof via any of the processes which follow.

Compounds of Formula I wherein Q is

(i.e., compounds of Formula I-C) may be prepared according to the process illustrated in Scheme 3.

wherein:

R³⁰ is _C(=O)-(CH₂)a- and W² is O or S₁ wherein a is 0-6; each PG¹ is a phosphonic acid protecting group such as methyl, ethyl benzyl or t-butyl;

LG is a suitable leaving group, such as mesylate, triflate or iodide; each PG² is H or Boc; and all other variables are as defined herein. Generally, the process comprises the steps of a) coupling a compound of formula 15 with a compound of formula 2 to prepare a compound of formula 16 or a pharmaceutically acceptable salt thereof; and b) deprotecting the compound of formula 16 to prepare a compound of

Formula I-C, or a pharmaceutically acceptable salt thereof.

More particularly, a compound of formula 15 may be reacted with the compound of formula 2 in an analogous manner to that described above for the coupling of a compound of formula 1 to a compound of formula 2. Deprotection of a compound of formula 16 may be carried out using conventional techniques including those described above for the deprotection of a compound of formula 13.

Compounds of formula 15 may be prepared from compounds of formula 1 as illustrated below

R³ wherein

R²⁷ is halo, particularly Cl₁ or OH;

PG³ is a silyl, acetate, or benzyl protecting group optionally substituted by methoxy or nitro; R³⁰ is -C(=O)-(CH₂)_a- and W² is O or S, wherein a is 1-6; and all other variables are as defined above.

The compound of formula 15 may be prepared by reacting a compound of formula 1 with a compound of formula 18 with or without an activating agent such as HATU₁ and a general amine base such as triethyiamine, DIEA, or the like, in acetonitrile or dimethylformamide at appropriate temperature. Compounds of formula 18 are commercially available or may be prepared using commercially available reagents and conventional techniques.

Compounds of Formula I wherein Q is , i.e., compounds of

Formula I-D, may be prepared according to the process illustrated in Scheme 4.

Scheme 4

wherein: each PG¹ is a phosphonic acid protecting group such as methyl, ethyl, benzyl or t-butyl; each PG² is H or Boc; and all other variables are as defined herein.

Advantageously, the reaction may be carried out as a one-pot reaction. Generally, the process comprises the steps of a) reacting a compound of formuia T with a compound of formula 20 and a compound of formula 1, in the presence of an activator, followed by phosphite oxidation to prepare a compound of formuia 22 or a pharmaceutically acceptable salt thereof; and c) deprotecting the compound of formula 22 to prepare a compound of Formula I-D, or a pharmaceutically acceptable salt thereof.

More specifically, the process comprises reacting a compound of formula T with a compound of formula 20 in solution in a suitable solvent such as tetrahydrofuran at an appropriate temperature, followed by addition of an activator that includes tetrazole or 5-(ethy!thio)tetrazole). Advantageously the reaction may be continued in the same vessel without isolation or purification of intermediates. The compound of formula 1 is added and reacted, preferably in the presence of the activator, followed by phosphite oxidation. Phosphite oxidation may be accomplished with conventional means including reaction with tert-butyl hydrogen peroxide, iodine, 3-chioroperoxybenzoic acid or oxone. The compound of formula 22, thus produced may be deprotected using conventional techniques including those described above for the deprotection of a compound of formula 3 (Meier et al., J.Mθd Chem 2008 50(6):1335-1346).

The compounds of formula T may be prepared as described above. The compounds of formula 20 are commercially available or may be prepared using commercially available reagents using conventional techniques.

Compounds of Formuia I wherein Q is

, i.e., compounds of Formula I-E may be prepared according to the process illustrated in Scheme 5.

wherein:

X ¹ is halo, particularly Cl;

b is 1; each PG¹ is a phosphonic acid protecting group such as methyl, ethyi, benzyl or t-butyt; each PG² is H or Boc; PG³ is benzyl or Boc; and al! other variables are as defined herein.

A compound of formula 24 may be obtained by reacting a compound of a formula 11 with a compound of formula 23 with triethyiamine at appropriate temperature in CH₂CI₂ follow by deprotection using conventional methods including hydrogenation in acid such as acetic acid or acid hydrolysis with HCI or TFA. A compound of formula 25 may be prepared by the same process as compound of formula 11 by substituting the compound of formula 1 with the compound of formula 7. A compound of formula 24 is coupled with a compound of formula 25 in presence of base such as triethyiamine at appropriate temperature to prepare a compound of formula 26 in a manner analogous to the process described in H. W. Scheeren and et al. J. Org. Chem. 2001 , 8815. The resulting compound of formula 26 may be deprotected using acid as previously described.

Compounds of Formula I wherein Q is

, i.e., compounds of Formula I-F may be prepared according to the process illustrated in Scheme 6.

Scheme 6

wherein

LG¹ is a leaving group such as halo, preferably chloro or an activated carboxylic acid using HATU;

each PG¹ is the same or different and is an alcohol protecting group such as methyl, ethyl, benzy! or t-butyl; each PG² is H or Boc; and all other variables are as defined herein. Generally, the process comprises the steps of a) coupling a compound of formula 1 with a compound of formula 12 in the presence of a compound of formula 27, to prepare a compound of formula 28 or a pharmaceutically acceptable salt thereof; and b) deprotecting the compound of formula 28 to prepare a compound of Formula l-F, or a pharmaceutically acceptable salt thereof.

More particularly, a compound of formula 1 may be reacted with a compound of formula 2 in the presence of a compound of formula 27, in a manner analogous to the process described above for the reaction of a compound of formula 11 with a compound of formula 12. Suitable solvents include acetonitrile and methylene chloride. Deprotection of a compound of formula 28 may be carried out using conventional techniques including those described above for the deprotection of a compound of formula 13.

Compounds of Formula I wherein Q is

particularly -N(H)-, i.e., compounds of Formula i-G may be prepared according to the process illustrated in Scheme 7.

Scheme

wherein:

LG¹ is a leaving group such as a halo, particularly chioro, or an activated carboxyltc acid using HATU; Y³ is -(CH₂)_Z— Ring A— (CH₂)_a— (W³)_d— and (W³)_d is N(R¹)-, particularly

-N(H)s

LG is a suitable leaving group, such as mesylate, triflate or iodide; each PG¹ is the same or different and is an phosphate protecting group such as methyl, ethyl, benzyl or t-butyl; each PG² is H or Boc; and al! other variables are as defined herein.

Generally, the process comprises the steps of a) coupling a compound of formula 30 with a compound of formula 12 to prepare a compound of formula 31 or a pharmaceutically acceptable salt thereof; and b) deprotecting the compound of formula 31 to prepare a compound of Formula I-G, or a pharmaceutically acceptable salt thereof.

More particularly, a compound of formula 30 may be reacted with a compound of formula 12 in the same manner as the reaction of a compound of formula 11 with a compound of formula 12. Suitable solvents include acetonitrile and methylene chloride. Deprotection of a compound of formula 31 may be carried out using conventional techniques including those described above for the deprotection of a compound of formula 13. Compounds of formula 30 may be prepared by reaction of a compound of formula 1 with a compound of formula 32 to prepare a compound of formula 33 which is reacted with phosgene in a manner analogous to the methods described above for the preparation of compounds of formula 11 and 15.

L_Gi

wherein:

LG is a leaving group such as halo (e.g., Ci); Y³ is -(CH₂)z— Ring A^(CH₂)_a— (W³)_d— ;

PG³ is a silyl, acetate or benzyl protecting group optionally substituted by methoxy or nitro; and

LG¹ is a leaving group such as halo, particularly Cl or activated carboxyiic acid using HATU.

Examples The foregoing may be better understood from the following examples, which are presented for the purposes of illustration and are not intended to limit the scope of the inventive concepts. The invention is defined solely by the claims which follow.

In the following examples, compounds are named using standard IUPAC naming principles where possible. The naming convention employed for the novel compounds are exemplified by the following name , Carbonic acid [5- [1(R)-hydroxy-2-[[6-(4-phenylbutoxy)hexyl]amino]ethyl]-2-(2- phosphonooxy)benzyl] ester [[11 β,16α]-[16_f17-{(R)- cyclohexylmethylene)bis(oxy)]-11-hydroxypregna-1 ,4-diene-3,20-dion-21-yl] ester.

Intermediate 1 : U 11 β,16α1-f 16.17-((R)-cvclohexyimethylene)bisfoxyϊl-11 - hvdroxypregna-1 ,4-diene-3,20-dion-21-vπ chloroformate.

Phosgene (20% in toluene, 56 mL, 106 mmo!) was added to a stirred solution of des-isobutyryi-ciclesonide (5 g, 10.6 mmol) in THF (100 mL) at rt. The resulting mixture was stirred for 2 h then concentrated to give a yellow solid (6.77 g). Recrystallization (EtOAc/hexanes) afforded the title compound (3.7 g, 65 %) as an off white solid.

Intermediate 2: Carbonic acid [5-f1fRVr(t-butoxycarbonyl)oxy1-2-[t- butoxycarbonvi[6-(4-phenylbutoxy)hexyilamino]ethyll-2-(di-tert- butoxyphosphoryloxy)benzyll ester rf11 β,16α1-F16,17-((R)- cyclohexyimethylene)bis(oxy)1-11 -hydroxypregna-1 ,4-diene-3,20-dion-21 -yl^" ester .

Intermediate 1 (1 g, 1.88 mmol), Et₃N (0.261 mL, 1.88 mmol) and DMAP (0.23 g, 1.88 mmol) were added to a stirring solution of carbonic acid (R)-[2-[tert- butoxycarbonyl[6-(4-phenylbutoxy)hexyl]amino]-1-[4-(di-tert- butoxyphosphoryioxy)-3-hydroxymethylphenyljethyl]ester tert-buty! ester (0.5 g, 0.619 mmol) in CH₂CI₂ (6 mL) at rt. The resulting suspension was stirred for 4 days then quenched with 10 % (w/v) citric acid (10 mL). The aqueous layer was extracted with CH₂CI₂ (3 x 10 mL) and the combined organic layers were washed with satd. NaHCO₃ (20 ml_), H₂O (20 mL), brine (20 mL), dried over Na₂SO₄, and concentrated to give a yellow oil (1.54 g). Chromatography (1 :1 , hexanes/EtOAc) afforded the title compound (0.226 g, 30 %) as clear oil. ¹H NMR (400 MHz, CDCf₃) d 7.48-7.22 (m, 7H)₁ 7.17 (m, 2H), 6.27 (dd, 1 H₁ J = 1.5, 10.1 Hz), 6.02 (m, 1 H)₁ 5.86 (m, 1 H), 5.74 (m, 1 H), 5.28 (s, 2H), 5.17 (m, 1 H), 4.86 (m, 3H), 4.47 (m, 1 H), 4.32 (m, 1 H), 3.58-3.31 (m, 6H), 3.14 (m, 4H), 2.62 (t, 2H, J = 7.4 Hz), 2.53 (q, 3H, J = 7.2 Hz), 2.32 (m, 1 H)₁ 2.24-0.81 (m, 69H); ³¹P NMR (400 MHz, CDCI₃) d -15.91. Intermediate 3: Carbonic acid 1-f3-azidomethv!-4-(di-tert- butoxyphosphoryloxy)phenvπ-2-f(tert-butoxycarbonyi)[6-(4-phenylbutoxy)hexyn- aminoiethyl ester tert-butyl ester

Diphenyl azidophosphate (0.363 mL, 1.68 mmol) and DBU (0.251 mL, 1.68 mmoi) were added to a stirring solution of carbonic acid [2-[tert- butoxycarbonyl[6-(4-phenylbutoxy)hexyl]amino]-1-[4-(di-tert- butoxyphosphoryloxy)-3-hydroxymethyiphenyl]ethyI] ester tert-butyl ester (0.97 g, 1.2 mmo!) in THF (10 mL) at rt. The reaction mixture was stirred for 4h then quenched with H₂O. The aqueous layer was extracted with EtOAc (3 x 10 mL) and the combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give a brown oil (1.2 g). Chromatography (1 :1 , hexanes/EtOAc) afforded the title compound (0.186 g, 18 %). ¹H NMR (400 MHz, CDCi₃) d 7.47 (d, 1 H, J = 8.5 Hz), 7.35-7.13 (m, 7H), 5.83 (ddd, 1H₁ J = 4.3, 7.8, 37.7 Hz), 4.48 (s, 2H), 3.61-3.31 (m, 5H), 3.27-2.99 (m, 2H), 2.64 (t, 2H₁ J = 7.5 Hz)₁ 1.49 (m, 49H).

Intermediate 4: Carbonic acid 1-[3-aminomethyl-4-(di-tert- butoxyphosphoryloxy)phenyl1-2-r(tert-butoxycarbonyl)g^'6-(4-phenylbutoxy)hexyll- aminolethyl ester tert-butyf ester

PPh₃ (0.113 g, 0.432 mmol) and H₂O (0.077 ml_, 4.32 mmoi) were added to a stirring solution of Intermediate 3 (0.18 g, 0.216 mmol) in THF (2 mL) at rt. The resulting solution was stirred for 2 days then diluted with EtOAc (10 mL). The organic layer was washed with satd. NaHCO₃ (10 mL) and brine (10 mL), dried over Na₂SO₄, and concentrated to a semi-white solid (0.36 g). Chromatography (9:1 , CH₂C!₂/MeOH) afforded the title compound (0.154 g, 88 %) as a clear oil. ¹H NMR (400 MHz₁ CDCI₃) d 7.89-7.13 (m, 8H), 5.81 (ddd, 1 H₁ J - 3.7, 7.8, 12.1 Hz), 3.87 (s, 2H), 3.61-3.30 (m, 5H), 3.21-3.12 (m, 2H), 2.62 (t, 2H, J = 7.5 Hz)₁ 1.49 (m, 51 H).

Intermediate 5: r5-ri-[(tert-butoxycarbonyπoxy1-2-[(t-butoxycarbonyl)-6-(4- phenylbutoxy)hexylaminolethyl1-2-di-tert-butoxyphosphonooxybenzvncarbamic acid fTPI 1 β,16α1-π6 J 7-((R)-cyclohexylmethylene)bis(oxyyi-11-hydroxypreqna-

1.4-diene-3.20-dion-21-vn ester

Intermediate 1 (0.149 g, 0.279 mmol) and PMP (0.067 mL, 0.372 mmol) were added to a stirring solution of intermediate 4 (0.15 g, 0.186 mmoi) in ACN (2 mL) at rt. The resulting suspension was stirred over night then quenched with 10 % (w/v) citric acid (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL) and the combined organic layers were washed with satd. NaHCO₃ (20 m!_), H2O (20 mL), and brine (20 mL), dried over Na₂SO₄, and concentrated to give a clear oil (0.308 g). Chromatography (1 1 hexanes/EtOAc) afforded the title compound (0.118, 32 %) ¹H NMR (400 MHz, CDCI₃) d 7 41-7 11 (m, 9H), 6 39 (m, 1 H), 6.26 (dd, 1 H, J = 1.3, 10.1 Hz)₁ 6.02 (s, 1 H), 5 79 (m, 2H)₁ 4.94- 4 25 (m, 9H)₁ 3 65-0.79 (m, 84H); ³¹P NMR (400 MHz₁ CDCI₃) d -14.95.

Intermediate 6: Pyπdιne-3,5-dicarboxylic acid [5-[1(R)-[(tert- butoxycarbonyl)oxy1-2-}^'(tert-butoxycarbonyi)[6-(4- phenylbϋtoxy)hexyl1amιno1ethvn-2-(dι-tert-butoxyphosphoryloxy)benzyil ester |T11 β, 16αH 16, 17-((R)-cvclohexylmethylene)bis(oxy)1-11 -hydroxypregna-1 A- dιene-3,20-dιon-21-vH ester .

HATU (0.227 g, 0.598 mmol), DIEA (0.142 mL, 0.742 mmoi), pyridtne-3,5- dicarboxylic acid (0.045 g, 0 272 mmol), and des-isobutyryi-ciclesomde (0.128 g, 0 272 mmol) were added to a stirring solution of carbonic acid [2-[tert- butoxycarbonyl[6-(4-phenylbutoxy)hexyl]amιno]-1-[4-(dι-tert- butoxyphosphoryloxy)-3~hydroxymethylphenyl]ethyl] ester tert-butyl ester (0 22 g, 0 272 mmol) in DMF (3 mL) at it The reaction mixture was stirred over night and quenched with H₂O (20 mL) and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with H₂O (2 x 30 mL) and brine (30 mL), dried over Na₂SO₄, and concentrated to give a brown solid (0 39 g). Chromatography (1 3_r hexanes/EtOAc) afforded the title compound (0 087 g, 23 %) ¹H NMR (400 MHz, CDCi₃) d 9 40 (s, 2H)₁ 8.89 (m, 1 H), 7.55-7.15 (m, 8H), 6.30 (dd, 1 H₁ J = 1.8, 10.1 H), 6.04 (s, 1 H), 5.80 (m, 1 H), 5.49 (s, 2H), 5.09 (q, 2H, J = 8, 17.5 Hz)₁ 4.84 (d, 1 H, J = 4.9 Hz), 4.54 (m, 1 H), 4.42 (d, 1 H₁ J = 4.6 Hz), 3.55 (m, 1 H), 3.38 (m, 3H), 3.15 (m, 2H), 2.62 (t, 2H, J = 7.4 Hz), 2.56 (dd, 1 H, J = 5.7, 13.5 Hz), 2.35 (m, 1 H), 2.23-2.03 (m, 3H), 1.44 (m, 75H); ³¹P NMR (400 MHz, CDCI₃) d -15.73.

Intermediate 7: Carbonic acid [5-[1(R)-r(t-butoxycarbonyl)oxyl-2-rt- butoxycarbonyl[6-(4-phenylbutoxy)hexyllaminolethyl1-2-fdi-tert- butoxyphosphoryloxy)benzyll ester rf 11 β.16oc1-π 6, 17-((R)- cvclohexylmethylene)bis(oxy)1-11-hvdroxypregna-1.4-diene-3,20-dion-21-yl1 ester

The title compound was prepared in a manner similar to intermediate 2. ¹H NMR (400 MHz, CDCI₃) d 7.48-7.22 (m, 7H), 7.17 (m, 2H), 6.27 (dd, 1 H₁ J = 1.5, 10.1 Hz), 6.02 (m, 1 H), 5.86 (m, 1 H), 5.74 (m, 1 H), 5.28 (s, 2H), 5.17 (m, 1H)₁ 4.86 (m, 3H), 4.47 <m, 1H), 4.32 (m, 1 H)₁ 3.58-3.31 (m, 6H), 3.14 (m, 4H)₁ 2.62 (t, 2H, J = 7.4 Hz)₁ 2.53 (q, 3H, J = 7.2 Hz)₁ 2.32 (m, 1 H)₁ 2.24-0.81 (m, 69H); ³¹ P NMR (400 MHz₁ CDCI₃) d -15.91.

Example 1 : Carbonic acid rM 1 β.16αH16,17-f(R)- cvdohexyimethylene)bis(oxy)l-11-hydroxypreqna-1₁4-diene-3,20-dion-21-yl1 ester f5-[1fR)~hvdroxy-2-rr6-(4-ρhenylbutoxy)hexynamino1ethyll-2-f2- phosphonooxy)benzyll ester

Neat TFA (2 mL) was added to a stirring solution of intermediate 2 (0.19 g,

0.146 mmoi) in CH₂CI₂ (2 mL) at 0⁰C. The resulting mixture was allowed to warm to rt, stirred for 2h, then concentrated. The residue was redissolved in a minimum amount of CH₂Cb and passed through Dowex Cl^" resin (prewashed with 2 CV 5N HCI, 3 CV H₂O, 2 CV 1 :1 ACN/H₂O). The resin was washed with 1 :1 ACN/H₂O (3 CV) and the eiuant was lyophilized to give the title compound (134 mg, 90 %) as an off-white amorphous solid. ¹H NMR (400 MHz, DMSO-d₆) d 9.04 (brs, 1 H), 8.71 (brs, 1 H), 7.41-7.23 (m, 7H), 7.18 (m, 2H), 6.16 (dd, 1 H, J = 1.5, 10.0 Hz)₁ 5.92 (s, 1 H), 5.26 (dd, 2H₁ J = I 3.0, 22.4 Hz), 5.15-4.80 (m, 4H), 4.72 (d, 1 H, J = 3.9 Hz), 4.39 (<_, 1 H₁ J = 3.9 Hz), 4.31 (m, 1 H), 3.32 (m, 4H), 3.04 (m, 2H), 2.89 (m, 3H)₁ 2.57 (t, 2H, J = 7.5 Hz), 2.29 (m, 1 H), 2.04 (m, 3H), 1.93-0.79 (m, 37H); ³¹P NMR (400 MHz, DMSO-d₆) d -5.404; ES/MS calcd. for C₅₄H₇₅NO₁₄P 992.5, found mlz = 992.5 (MH⁺).

Example 2: Carbonic acid rn i β,16α1-M6.17-f(R)- cvclohexyimethylene)bis(oxy)1-11-hvdroxypregna-1 ,4-diene-3,20-dion-21-vπ ester [5-[1-hvdroxy-24f6-(4-phenylbutoxy)hexyllamino1ethvπ-2-(2- phosphonooxy)benzyi1 ester

The title compound was synthesized in a manner analogous to that described in Example 1 , using 4N HCI in dioxane instead of TFA. ¹H NMR (400 MHz, DMSO-de) d 8.92 (brs, 1 H), 8.64 (brs, 1 H), 7.49-7.12 (m, 9H)₁ 6.17 (d, 1 H, J = 9.9 Hz)₁ 5.90 (m, 1 H), 5.25 (m, 1 H), 5.17-4.65 (m, 4H), 4.54 (s, 2H), 4.33 (m, 1H), 3.33 (m, 4H), 3.08 (m, 2H), 2.87 (m, 4H), 2.57 (t, 2H, J = 7.4 Hz), 2.39- 0.81 (m, 41 H); ³¹P NMR (400 MHz, DMSOd₆) d -5.316; ES/MS calcd. for C₅₄H₇₅NOi₄P 992.5, found m/z = 992.4 (MH⁺).

Example 3: f5-[1 -Hvdroxy-2-r6-(4-phenylbutoxy)hexyiamino1ethyl|~2~ phosphonooxybenzyl^"|carbamic acid πT11β,16αH16,17-((R)- cvclohexylmethylene^isCoxy^-H -hydroxypregna-i ^-diene-S^O-dion^i-vIl ester.

Anhydrous HCl (g) was bubbled through a stirring solution of intermediate 5 (0.118 g, 0.0905 mmol) in CH₂CI₂ (2 ml_) at rt for 1 min. The resulting solution was stirred for 4 h then anhydrous ether (50 mL) was added. The resulting precipitate was filtered. The filter cake was washed with ether and dried to give title compound (73 mg, 79 %) as an off-white solid. ¹H NMR (400 MHz, DMSO- d₆) d 8.67 (m, 2H)₁ 7.91 (brs, 1 H), 7.36-7.24 (m, 7H), 7.17 (m, 2H), 6.18 (m, 2H), 5.92 (m, 1 H), 4.89 (m, 3H), 4.72 (m, 2H), 4.38 (d, 1 H, J = 4.1 Hz), 4.30 (m, 2H), 3.33 (m, 4H), 3.14-2.88 (m, 5H), 2.59-2.44 (m, 2H), 2.30 (m, 1 H)₁ 2.15- 1.95 (m, 3H), 1.94-0.70 (m, 37H); ³¹P NMR (400 MHz, DMSO-d₆) d -5.62; ES/MS calcd for C₅₄H₇₆N₂O₁₃P 991.5, found mlz = 991.5 (MH⁺).

Example 4: Pyridine-3,5-dicarboxylic acid [^"5-[^"1(R)-hydroxy-2-lT6-(4- phenylbutoxy)hexynamino1ethyi]-2-(phosphonooxy)benzyl1 ester IT11 β,16α]- π 6,17-((R)-cvciohexylmethylene)bis(oxy)l-11-hvdroxypregna-1 ,4-diene-3,20- dion-21-γl] ester

The title compound was synthesized in a manner analogous to that described in Example 1 using Intermediate 6 (50 mg, 0.035 mmol) in place of Intermediate 2, ¹H NMR (400 MHz, DMSO-d₆) d 9.35 (dd, 2H, J = 1.9, 17.7 Hz), 8.83 (brs, 1 H), 8.72 (m, 1 H), 8.63 (brs, 1 H), 7.48-7.13 (m, 9H)₁ 6.18 (dd, 1 H₁ J = 1.9, 9.9 Hz), 5.93 (m, 1 H)₁ 5.48 (m, 2H), 5.21 (dd, 2H, J = 17.6, 70.1 Hz), 4.82 (m, 1 H), 4.71 <d, 1 H₁ J = 3.4 Hz)₁ 4.48 (d, 1 H₁ J = 4.3 Hz)₁ 4.35 (m, 1 H), 3.46-3.2 (m, 4H), 3.00 (m, 2H), 2.87 (m, 3H), 2.56 (t, 2H, J = 7.3 Hz₁), 2.30 <m, 1 H), 2.19-1.82 (m, 5H), 1.78-0.82 (m, 36H); ³¹P NMR (400 MHz, DMSO-d₆) d - 5.174; ES/MS calcd. for C₆₀H₇₈N₂Oi₅P 1097.5, found mlz = 1097.5 (MH⁺). Examples 5-12

The foilowing compounds may be made using the general techniques described herein and methods analogous to those employed for making Examples 1-4 and Intermediates therefore.

Example 5: Phosphonic acid [5-[1-hydroxy-2-[[6-{4- phenylbutoxy)hexyl]amino]ethyl]-2-(2-phosphonooxy)benzyl] ester

[[11 β, 16α]-[16,17-{(R)-cyciohexylmethylene)bis(oxy)]-11 -hydroxypregna-1 A-

diene-3,20-dion-21-yl] ester

Example 6: [5-[1-Hydroxy-2-[6-(4-phenylbutoxy)hexy!amino]ethyl]-2- phosphonooxybenzyloxy]benzoic acid [[11 β,16αH16,17-((R)- cyclohexy!methylene)bis(oxy)]-11 -hydroxypregna-1 ,4-diene-3,20-dion-21-yl] ester

Example 10: Method for Evaiuating Stability of Compounds of the Invention in Rat Lung Homogenate Preparation of rat lung homogenate Lungs from Fischer 344 rats are obtainable fresh by overnight delivery at 4°C from BioReciamation Inc. (Hicksville, NY). Lungs are weighed and homogenized in a 1 :3 w/v ratio with sterile phosphate buffered saline (PBS, 1OmIvI, pH 7.4) in glass vials on ice. After centrifugation at 3,000 x g for 10 min at 4°C the supernatant is decanted into sterile conical tubes and placed on ice. The total protein content of the supernatant is determined by the bicinchoninic acid (BCA) method (Pierce Biotechnology, Rockford, IL), using bovine serum albumin (BSA) as the standard. Lung homogenates are prepared to a final concentration of 1 mg total protein/mL in 1OmM PBS, pH 7.4.

In vitro metabolism of compounds of the invention in rat lung homogenate Compounds are incubated with active or heat-inactivated rat lung homogenate in 1 OmM PBS (pH 7.4). Heat-inactivation is achieved by incubation at 8O⁰C for 30 min, after which the homogenate is allowed to cool to rt, stored overnight at 4°C. The homogenate is used for the assay and standard curve preparations. Before use, each homogenate preparation is equilibrated for 15 min in a 37⁰C water bath. The metabolism reactions are initiated by the addition of stock solutions of 21-derivatized steroids ciclesonide and des-isobutyryl ciclesonide in 1 mM dimethyl sulfoxide (DMSO) to a final concentration of 900 nM. DMSO (2.7 μL) added to 3 mL of temperature-equilibrated homogenate serves as a control. Aliquots (100 μL) of homogenate + compound are added to 400 μL quenching solution consisting of 100% HPLC-grade acetonitrile + 500 ng/mL glyburide for the zero time point (n = 3 for each time point). The glybuhde serves as an internal LC/MS/MS standard. The remainder of each drug + homogenate solution is aliquoted into a 96-well tissue culture plates. After an additional 30min and 120 min incubation at 37°C, 100 μL aliquots are added to 400 μL quenching solution. Denatured proteins in the quenching solution are separated by centrifugation at 3000 x g for 2 min at 4°C, and 160 μL of the supernatants are transferred to new 96-wel! plate for analysis by LC/MS/MS. Collection plates are covered with plastic film and kept on ice. For storage, covered plates are kept stored at -80⁰C until further use.

Liquid chromatography and mass spectrometry analysis (LC/MS/MS) An aliquot (50 μL) of each sample is diluted with 50 μL of water containing internal standard at 4⁰C. The diluted samples are then centrifuged for 20 min at 3000 rpm at 4 ⁰C. An aliquot of 20 μL of the solution is injected into the TSQ Ultra Quantum LC/MS/MS system. The compounds are separated by HPLC using a HyPurity C18 HPLC column (30 X 2.1 mm, 5 μ) from ThermoHypersil. A Multiplex LX-2 HPLC system (Cohesive Technologies, Franklin, MA) with two identical Agilent 1100 series binary pumps (P/N G1312A) are used for eiution and separation. Samples are maintained at 4°C in an HTS Pal autosampler (LEAP Technologies, Carrboro, NC) in order to reduce any potential spontaneous hydrolysis of the compounds before injection onto the HPLC. The analytes are eluted using the following mobile phases: Mobile phase A contains 1 % acetonitrile in 10 mM ammonium formate aqueous solution with 1 % formic acid. Mobile phase B contains 80% acetonitrile in 10 mM ammonium formate with 1 % formic acid. The HPLC eiution program used to elute the analytes is as follows:

Time (sec) Step Flow Rate Mobile Phase Mobile Phase

Comments (mL/min) A (%) B (%)

90 Sample 0.50 100 0

Loading

150 Ramp 0.50 50 50

180 Eiution 0.50 0 100

120 Re-equilibrium 0.50 100 0

The samples are further analyzed by tandem mass spectrometry using a TSQ Quantum Ultra triple quadrupole mass spectrometer (Thermo Finnigan, San Jose, CA) using a selective reaction monitoring (SRM) scan type. The mass spectrometry parameters used are as follows: ~n source C!D Spray Sheath gas Aux gas Capiliary

_{Λ A} ,. _{A A} pressure pressure temperature

Source (V) voltage (V) ^ P^ _røP

ESi + 10 4000 40 15 350

Date analysis

Nine-point standard curves for each test compound are prepared and analyzed in heat-inactivated lung homogenate. The concentration range is from 1 nM to 10 μM. The calibration curves of the steroid linkers, ciclesonide (CIC) and des- isobutyryl ciclesonide (des-CIC) are evaluated by linear regression analysis. The data represent the mean percent remaining compound in both types of homogenate at 2 hours, 37⁰C and the value for mean concentration remaining of the parent compound and des-CIC at 2 hours, 37⁰C.

Example 11 : Pharmacokinetic Analysis of Drug Levels of Saimeterol, Des- isobutyryl Ciclesonide ("des-ciclesonide") and Compounds of the Invention Conducted in Lung, Bronchoalveoiar Lavage Fluid and Plasma After IT Administration in the Rat Dosing

Compounds of the invention are formulated for intratracheal (!T) dosing in 10%EtOH, 90% Sterile Water, and are dosed in male Sprague-Dawley rats at 3 mg/kg or 1 mg/kg. Each dosing group consists of 3 male, naϊve purebred Sprague-Dawiey rats. At dosing, the animals are weighed. The animals are fasted overnight prior to dose administration and up to 2 hr after dosing. The compounds are administered IT using a Penn Century Microsprayer (Model 1A- 1B).

Sample Collection and Analysis A. Plasma

Blood samples are collected at 0.5, 2, and 4 hours post-dose. Each blood sample (0.5-0.6 mL per sample) is collected via the orbital sinus (following anesthesia for BAL procedure) into tubes containing EDTA anti-coagulant in containers surrounded by dry ice at 0.5, 2 and 4 hr (mean, n=6). Blood samples are stored at -20 ± 5 ⁰C unti! shipped for anaiysis.

B. BALF The animals are anesthetized with an intramuscular (IM) injection of a ketamine/xylazine/acepromazine (80/10/2 mg/kg) cocktail at a dose volume of 1.1 mL/kg. A cannula (modified Bard® infant feeding tube) is inserted into the trachea. Warmed sterile saline is injected into the lungs. The lungs are gently massaged by palpation of the chest for approximately 45 seconds. The fluid (BALF) is recovered and placed on ice. The procedure is repeated two more times, and all three BALF samples are pooled. The fluid is centrifuged under refrigerated conditions at 350 g for 10 min. The supernatant and ceil pellet are collected and stored at approximately -70⁰C until shipped for analysis.

C. Lung tissue Collection

Immediately following each BAL procedure, the lungs from each animal are removed, blotted dry, weighed, and stored frozen at -70°C until shipped for analysis.

D. Assay Methods

An LC/MS/MS method is used to measure the concentration of compound in plasma.

Bioanalytical Method 1. Lung homogenate

A 3x w/v of IxPBS buffer (90:10-PBS:ACN) is added to each lung tissue. The sample is homogenized with Polytron (PT1200) and a 5OuL supernatant sample is injected to an LC/MSMS.

2. Sample Processing

An aliquot of 50 μL of each plasma sample is treated with 100 μL of acetonitrile (ACN) containing interna! standard. After the protein precipitation, an aliquot of 100 μ L of water. An aliquot of 30 μ L of the above solution is injected to the TSQ Ultra Quantum LC/MS/MS system.

3. HPLC Condition

A HyPurity C18 HPLC column (30 X 2.1 mm, 5 μ) from ThermoHypersil (Part #: 22105-032130) is used. Mobile phase A contains 1 % acetonitrile in 10 mM ammonium formate aqueous solution with 1 % formic acid. Mobile phase B contains 80% acetonitrile in 10 mM ammonium formate with 1 % formic acid. An Agilent 1100 series binary pump (P/N G1312A Bin Pump) is used for elution and separation, HTS Pal autosampler from LEAP Technologies, Carrboro, NC is used.

HPLC elution program:

4. Mass Spectrometry

TSQ Quantum Ultra triple quadrupole mass spectrometer from Thermo Finnigan, San Jose, CA is used in selective reaction monitoring (SRM) operation mode, Tune fife: ESI_tune112807_BL.

Mass spectrometry parameters:

Results

100 The results will demonstrate whether the compounds of the invention are metabolized to salmeterol and des-isobutyryl ciciesonide in the lung following IT administration. Based upon the structure of the compounds of the invention, it is believed that the results will demonstrate that the compounds of the invention are metabolized to salmeterol and des-isobutyryf ciciesonide.

Example 12: Drug Metaboiism Studies Using Airway Epithelial Ceils Cultured at an Air-Liquid Interface

Cryopreserved passage 1 cells are cultured in bronchial epithelial growth medium (Fulcher, M. L., et a!., Well-differentiated human airway epithelial cell cultures. Methods MoI Med, 2005. 107: p. 183-206) on 100 mm Type I collagen-coated plastic dishes. At 70% confluence, passage 2 ceils are transferred to type IV collagen-coated Millicell membranes (Miliipore, Bedford, MA) in medium that supports growth at an air-liquid-interface (AL!) (Fuicher et a/., 2005). Ceils are maintained at an ALl and allowed to differentiate fully for approximately 28 days. Approximately 24 hrs prior to the start of the experiment, the apical surfaces of the cells are washed with sterile phosphate buffered saline (PBS₁ 1OmM, pH 7.4) and the basolaterat media is replaced with fresh ALI media. Approximately 1 hour prior to the start of the experiment, the apical surfaces of the cells are washed once again with PBS and the basolateral media replaced with fresh ALI media. At time = 0 hrs, the test article is diluted from a 10 mM stock solution in DMSO to a 40 μM solution in ALI media/PBS/10% EtOH/water (v/v). 50 μ! of the resulting 40 μM solution is immediately added to the apical surface of the cells. 200 μl of the dosing solution is also added to 800 μl of 100% ACN and frozen immediately on dry ice. The remaining dosing solution is placed in the incubator with the cells. The dosing solution and cells are allowed to incubate for 10, 120 and 240 min at which points the apical surfaces of cells from 4 miliicell cell culture inserts (n = 4) are washed with 3 x 100 μl of PBS or 10% EtOH/water (v/v) per millicell. The three washes from each millicell ceil culture insert are pooled. The entire basolateral medium from each millicel! cell culture insert is also collected as are the airway epithelial cells which are excised from each miliicell cell culture insert and added to 300 μl of 90% ACN/0.1 % formic acid/9.9% water and immediately frozen on dry ice. The cells are thawed and lysed for 2 mins with a sonicator (Misonix, Farmingdale, NY) set at 30 Amp. The ceii suspension is then centrifuged at 18,000 g for 2 min and 50 μi of the supernatant is added to 200 μl of acetonitrile containing 100 ng ml^"1 glyburide. 50 μl of the pooled apical washes and basoiateral medium is also added to 200 μl of ACN containing 100 ng ml^"1 glyburide. These samples are then frozen on dry ice and kept at -80 ⁰C for their analysis by LC/MS/MS. At the same 10, 120 and 240 min time points, 200 μl of the dosing solution is added to 800 μl of ACN and immediately frozen on dry ice. These dosing solution samples are also kept at -80 ⁰C for analysis by LC/MS/MS. Untreated control cells dosed at the apical surface with 50 μl of test article vehicle (ALI media/PBS/10% EtOH/water (v/v) are also included to provide apical, basoiateral and cellular matrices for LC/MS/MS analytical standards.

The above samples are thawed prior to centrifugation for 10 minutes at 3000 rpm at 4⁰C. An aliquot of 150 μL of the above solution is mixed with 150 μL of water. 10 μL of the acetonitrile/water mix are injected into the Applied Biosystems/ Sciex API 5000 LC/MS/MS system. The compounds are separated by HPLC using a Zorbax Extend C18 HPLC column (50 X 2.1 mm, 3.5 μ) from Agiient Technologies. An Aria Transcend duplexed HPLC system (Thermo Fisher, Franklin, MA) with two identical Agilent 1100 series binary pumps {P/N G1312B) are used for elution and separation. Samples are maintained at 4°C in an HTS Pal autosampier (LEAP Technologies, Carrboro, NC) in order to reduce any potential spontaneous hydrolysis of the compounds before injection onto the HPLC. The analytes are eluted using the following mobile phases: Mobile phase A contains 1 % acetonitrile in 10 mM ammonium formate aqueous solution with 1 % formic acid. Mobile phase B contains 80% acetonitrile in 10 mM ammonium formate with 1 % formic acid. The HPLC elution program used to elute the analytes is as follows: Time Step Flow Rate Mobile Phase Mobile Phase

(sec) Comments (mL/min) A (%) B (%)

30 Sample 0.50 90 10 Loading

150 Ramp 0.50 50 50

180 Elution 0.50 0 100

90 Re-equiiib. 0.50 90 10

The samples are further analyzed by tandem mass spectrometry using an ABI/Sciex APi 5000 triple quadrupole mass spectrometer (Applied Biosystems, Foster City, CA) using a selective reaction monitoring (SRM) scan type. The mass spectrometry parameters are as follows:

CAD Curtain GS21 gas

Ion Spray GS1 gas Capillary gas gas pressure voltage pressure temperature source pressure pressure (Arb)

(Arb)

(arb) (V) (Arb) (⁰C)

ESI + 6 5000 25 40 60 350

Eleven-point standard curves for each test compound are prepared and analyzed in heat-inactivated iung homogenate, the concentration ranged from 1 nM to 10 μM. The calibration curves of the steroid linkers, ciclesonide (CIC) and des-isobutyryl ciclesonide (des-CIC) are prepared by quadratic regression analysis.

The results indicate the amount of each of 1 ) the parent compound of the invention, 2) salmeterol and 3) des-isobutyryl ciciesonide in the apical and cellular compartments and whether the amount in each compartment increases or decreases over time. It is expected that the amount of the compound of the invention will decrease over time in both the apical and cellular compartments while the amount of salmeterol and des-isobutyry! ciciesonide will increase in the cellular compartment. The compound of Example 1 demonstrated the desired breakdown in this model. Exampfe 13: in vivo Efficacy of Compound of the Invention in the Mouse Ovalbumin Model of Lung inflammation

Mice (Baib/c) are immunized by intraperitoneal injection of ovalbumin (10 μg OVA suspended in 2 mg aluminum hydroxide) on day 0 and 7. One group is sensitized and treated with vehicle (NSV). One group is immunized with sterile water only and treated with vehicle, e.g. to serve as a nonsensitized (negative) control (Vehicie). Ciclesonide (positive control treatment; 1X per day (day 14 and 15; 3 mg/kg), Compound of the invention at 1 , 3, and 6 mg/kg) or vehicle is delivered by intratracheal (IT) instillation 1X/day (day 14 and 15), 1 hour prior to OVA inhalation challenge. On days 14 and 15, the animals are exposed to OVA by inhalation (3 h; 5 mg/m³). Forty eight hours following the last OVA challenge (day 17) mice are sacrificed. Bronchoalveolar lavage (BAL) is taken from each animal to collect ceils and fluid. Cell numbers and differentials were calculated from BAL.

Example 14: LPS-tnduced Airway Inflammation in Rats

Compound of the invention is evaluated in an LPS-induced airway inflammation model in rats. Male Fischer 344 rats (n = 8/group) are treated with either vehicle or test article by intratracheal instillation in 400 μl volume 1 hour prior to LPS challenge. Animals are then exposed to LPS by nose-only inhalation exposure for 10 minutes at 5 mg/m³, resulting in an estimated 5 μg lung deposition. Animals are sacrificed 4 hours after LPS exposure. Lungs are lavaged for bronchoalveoiar lavage cell differentials and cytokine analysis by Luminex multiplex immunoassay. It is believed that compounds of the invention and ciclesonide will inhibit LPS-induced airway inflammation measured as neutrophil influx and TNFα production at doses tested (p<-0.05 versus vehicie control).

Example 15: Tobacco Smoke Model of Airway Inflammation in Mice Compounds of the invention may be evaluated in a tobacco-smoke-induced airway inflammation model in female C3H mice. Vehicle and test compounds are delivered by intratracheal instillation in 10% ethanohwater to animals anesthetized with 3-5% isoflurane (n=8 animals per test article group). All compounds will be delivered on a daily (5 days per week) schedule for 3 weeks during the smoke exposures. Mice are exposed to cigarette smoke for 6 hours per day, 5 days per week for 3 weeks, in H1000 or H2000 chambers. Type 2R4F research cigarettes (Kentucky Tobacco Research and Development Center) are used in the study. Total particulate material (TPM) exposure is kept at 100 TPM/m³for the first week to allow animals to reduce adverse effects during adaptation to smoke exposure. TPM exposure is maintained between 100 and 250 mg TPM/m³ during the remainder of the study. After 3 weeks, animals are euthanized and bronchoalveolar lavage fluid is obtained for cell differentials and cytokine analysis by Luminex multiplex immunoassay.

Inhibition of neutrophil influx is not expected in other treatment groups, including ciclesonide, salmetero! xinafoate, and is not expected to be as high in the ciclesonide + salmeterol xinafoate combination. In a 20-plex Luminex assay for cytokines and growth factors, it is expected that the compounds of the invention will exhibit inhibition of tobacco-smoke-induced IL-1 α and MiP-Ia production (p<0.05 versus vehicle control at 1.0 and 0.6 mg/kg doses).

Example 16: Ragweed-Induced Bronchoconstriction in Dogs The compound of the invention may be assesed for bronchodilator activity in a ragweed-induced bronchoconstriction model in beagle dogs. Dogs are mechanically ventilated during each experiment. Airflow and tidai volume are measured using a differential pressure transducer located in front of the endotracheal tube. An esophageal balloon catheter placed in the esophagus is used to determine transpulmonary pressure. Pulmonary resistance and dynamic lung compliance are calculated from the simultaneous measurement of transpulmonary pressure and respiratory flow. The canine exposure system is designed to expose an anesthetized animal via an intubation tube. Dogs are administered vehicle or test article by inhalation 30 minutes before ragweed antigen exposure (n=4). Dogs are challenged with ragweed antigen (ragweed short, Ambrosia artemisifolia, Greer, Lenoir, NC) by inhalation (5 breaths), immediately following ragweed challenge, changes in pulmonary resistance and compliance are measured for up to 30 min. At doses of 20 mg/kg of the compound of the invention, an inhibition of ragweed-induced increases in puimonary resistance (p<0.05 versus vehicle control) is expected. An inhibition of increased pulmonary resistance change following antigen challenge (p<0.05 versus vehicle control) may also be observed at 10 mg/kg of salmeterol xinafoate (10 mg/kg).

Example 17: Ascaris sui/m-induced Pulmonary Responses in Sheep The compound of the invention is assessed for inhibition of early and late phase bronchoconstriction and development of airway hyperreactivity in sheep sensitized to Ascaris suum antigen as previously described (Abraham, W. M., A. Ahmed, I Serebrlakov, IT. Lauredo, J. Bassuk, J.A. Adams, and M.A. Sackner. Am. J. Respir. Crit. Care. Med. 2006; 174:743-752). Early and late phase responses are measured as a function of increased pulmonary resistance during the 8 hour period following antigen. Airway hyperreactivity is evaluated as a function of PC400, the number of carbachol breath units required to induce a four-fold increase in bronchoconstriction measured 24 hours after antigen challenge. One breath unit is defined as one breath of a 1 % w/v carbachol solution. Test compound is administered either by a pre-dosing or duration of action protocol. In the pre-dosing regimen, animals are dosed once daily for four days, with the last dose administered 1 hr before antigen. In the duration of action regimen, animais are dosed once daily for four days, with the last dose administered 24 hours before antigen. Test compound, Ascaris antigen, and carbachol are administered by nebulized aerosol to intubated sheep.

Using the predosing regimen, inhibition of late phase bronchoconstriction and development of airway hyperreactivity is expected with both compounds of the invention and ciclesonide.

In the duration of action regimen a reduction of early phase bronchoconstriction and complete inhibition of late phase bronchoconstriction and development of airway hyperreactivity is expected with compounds of the invention. An inhibition of late phase bronchoconstriction and development of airway hyperreactivity is also expected with a combination of ciciesonide + salmeterol. In contrast, reduced efficacy is expected with ciciesonide and saimeterol individually.

Example 18: Carbachol-induced bronchoconstriction in sheep

The compounds of the invention may be assessed for inhibition of carbachol- induced bronchoconstriction as previously described (Abraham, VJM., A. Ahmed, I Serebrtakov, A.N. Carmillo, J. Ferrant, A.R. de Fougerolles, E.A. Garber, P. J. Gowals, V.E. Koteilansky, F. Taylor, R. R. Lobb. Am, J. Respir. Crtt. Care. Med. 2004; 169:97-104). Bronchoconstriction is evaluated as a function of increased pulmonary resistance following carbachol challenge. Measurements of R_L are repeated immediately after inhalation of buffer and after each administration of 10 breaths of increasing concentrations of carbachol solution (0.25%, 0.5%, 1.0%, and 2.0% w/v). Test compound is administered either by a pre-dosing or duration of action protocol. In the pre- dosing regimen, animals are dosed once daily for four days, with the last dose administered 1 hr before carbachol challenge. In the duration of action regimen, animals are dosed once daily for four days, with the last dose administered 24 hours before carbachol challenge. Test article and carbachoS are administered by nebulized aerosol to intubated sheep.

Using the predosing regimen, inhibition of carbachol-induced bronchoconstriction may be observed with the compounds of the Invention and salmeterol xinafoate. Inhibition (p<0.05) of carbachol-induced bronchoconstriction may also be observed with the compounds of the invention in the duration of action regimen.

Example 19: Pharmaceuticai Formulations:

A. DPI Formulation for Multidose Blister Strip or Capsule Based Inhaler Target Unit Dose:

500 meg micronized compound of Formula I ("API") 15 mg lactose monohydrate for inhalation. Micronize the API using a mill (e.g. jet mill) to a mass median aerodynamic diameter (MMAD) from about 1 to about 10 μm, and preferably a MMAD from about 1 to about 5μm.

The lactose may be milled or sieved. Suitable commercial sources of lactose include DMV-Fonterra Excipients (Lactohaie®) and Friesiandfoods Domo (Respotise®).

500 mg of API is blended with 15 g of lactose using an appropriate mixer (e.g. Turbula® Powder Blender). Additional fine lactose particles of less than 10 μm may be added. The blended product is filled into capsules or blister strips.

B. pMDI Liquid Suspension or Liquid Solution Formulation

Target Unit Dose: 250 meg of micronized API

150 μl of propeliant (e.g., HFA 134a or 227)

Each canister is to contain 120 dose equivalents of API and propeliant + 10% overage. Each canister is filled with 33 mg of AP! and sealed with a metering valve. The canister is then pressurized with 19.8 mL of propeliant.

Claims

Claims:That Which Is Claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹⁵ is a side chain radical of a β-agontst; R¹⁶ is H, methyl or ethyl; R¹⁹ is H, F₁ OH or methyl; L is a bond or -(CH₂O)-; Q is selected from

and

wherein each W¹ is the same or different and is O or S; W² is O₁ S or N(R¹);

Ph is phenyl optionally substituted on any available carbon with a substituent selected from halo, Ci_-4aikyl, OH, Ci_-4alkoxyi, NH₂,

N(H)C_1-4alkyl, and N(C_1-4alkyi)₂; each R¹ is the same or different and is independently H or Ci_-4aikyl; a is 0-6; b is 0 and c is 1-4 or b is 1 and c is 2-4; each W³ is the same or different and is independently -O- or -N(R¹)-; x and y are both 0 and z is 1 or x is 1 , y is 0 or 1 and z is 0-6;

Ring A is phenyl, pyridyl or pyrimidy! each optionally substituted on any available carbon with a substituent selected from halo, Ci_-4alkyl, OH, C_1-4aikoxyl, NH₂, N(H)C_1-4alkyl, and N(C₁-₄alkyl)₂; d is O oM ; each R², R³, R⁴, and R⁵ is independently H, Ci_-4 alkyl or halo; one of R⁶ and R⁷ is H and the other is OH; or R⁶ and R⁷ taken together with the carbon to which they are attached form a >C=O group; R⁸ is H₁ OH, O(CO)R⁹, or 0(CO)OR⁸; each R⁹ is independently Ci_-4 alkyl; each R¹⁰ and R¹¹ is independently H or C-₁.₄ alkyl;

R¹² is H, OH, or Ci_-4 alky!; or

R¹¹ and R¹² taken together with the carbon to which they are attached form a

>=CH₂ group; or R¹² and R⁸ taken together with the carbons to which they are attached form a 1 ,3-dioxolane ring represented by formula B:

formula B; wherein one of R¹³ and R¹⁴ is H, methyl or ethyl and the other is H, Ci_io alkyl,

C2-10 alkenyi, C_2-io alkynyi, optionally substituted C3.10 carbocycie or optionally substituted 5-6 ring atom heterocycie wherein one or two ring atoms are selected from N, O and S₁ and wherein said carbocycie and said heterocycie are each optionally substituted 1 , 2 or 3 times with a substituent selected from halo, C^alkyl, and O-Ci_-4alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R¹⁵ is Ci_-6alky!;

C_6-iocarbocycle optionally substituted 1 or 2 times with halo, d.₄alkyl, O-C^alkyl, O-(CH₂)₄-NH₂, O-(CH₂)₄~N(H)C_1-4alkyl, O-(CH₂)₄-N(C_1-4alkyl)₂, O-Ci_-4alkyi-C(O)-NH_2> O-d_~4aikyl-C(O)-N(H)d-4alkyl, O-d.₄alkyl-C(O)-N(C_1-4alkyl)_2i or a group represented by formula i, ii, iii, iv, v, vi, vii, viii, or ix: i: C₆alkylene-O-R²¹-Ph⁴; ii: C_2-3alkylene-Ph¹-O-R²¹-Ph⁴; iii: C₂.₃alkyiene-Ph¹-N(H)-R²²-Ph²; iv: C_2-3a!kylene-Het-(R²³)-Ph³; v: C_2-3alkylene-Ph¹-Co-2alky!ene-C{O)N(H)-C_1-4alkylene-Ph³; vi: C_2-3alkylene-Ph³; vii: C₂.3alkylene-S(O)2-C_2-4alkylene-O-C₂-₄aikyiene-Ph³; viii: C_3-6alkylene-Ph¹-Co_-2alkylene-C(0)N(H)-Cio-i2 bicyclic carbocycle; ix: C_3-6alkylene-Het-Ph⁴; wherein: R²¹ is C_{2- 6}aIkylene wherein one carbon of said alkylene is optionally replaced by O;

Ph⁴ is phenyl optionally substituted 1 or 2 times by halo, N(H)C(O)NH₂, SO₂NH₂Or S-cyclopenty!,

Ph¹ is phenylene; R²² is a bond or d.₂alkylene optionally substituted once by OH or

NH₂;

Ph² is phenyl optionally substituted 1 or 2 times by O-methyl, -OCH₂CH(CHS)₂CH₂NH₂, unsubstituted phenyl,

-SO₂-NH-(C₆H₃)(CH₃)(C₇H₁₅) Or

_;

Het is 4-10 ring atom heterocydene wherein 1 , 2 or 3 ring atoms is/are N, O or S optionally substituted once by methyl; R²³ is a C₂-4alkylene wherein one carbon of said alkylene is optionally replaced by O or -C_0-2aikyiene-C(O)N(H)-C₂-₄alkylene; and

Ph³ is phenyl optionally substituted 1 or 2 times by halo or O-methyl.

I l l

3. The compound according to Claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is C_halky!.

4. The compound according to Claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a Ce-io carbocycle optionally substituted 1 or 2 times with C_1-4alkyl, O-C_1-4alkyl, or O-C_1-4a!kyϊ-C(O)-NH₂.

5. The compound according to Ciaim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a group represented by formula i: C₆alkylene-O-R²¹-Ph⁴, wherein R²¹ is C₄a!kylene and Ph⁴ is unsubstituted phenyl.

6. The compound according to Ciaim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a group represented by formula ii: C₂-₃alkylene-Ph¹-O-R²¹-Ph⁴, wherein R²¹ is C₄alkylene wherein one C is optionally replaced by O and Ph⁴ is unsubstituted phenyl.

7. The compound according to Claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a group represented by formula iii: C_2-3alkyIene-Ph¹-N(H)-R²²-Ph², wherein R²² is a bond or C₂ alkylene substituted once by OH or NH₂, Ph² is phenyl optionally substituted once by O-methyi or -OCH₂CH(CH₃)₂CH₂NH₂.

8. The compound according to Claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a group represented by formula iv: C_2-3alkylene-Het-(R²³)-Ph³, wherein Het is a 9 or 10 ring atom heterocyclene wherein 1 or 2 ring atoms is N, O or S₁ R²³ is -CH₂-O-CH₂- or -C(O)N(H)-CH₂-, and Ph³ is unsubstituted phenyl, or phenyl substituted twice by halo or O- methyl.

9. The compound according to Claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a group represented by formula v: C₂.₃alkylene-Ph¹-C₀-₂alkylene-C(O)N(H)-C_1-4alkylene-Ph³, wherein Ph³ is phenyl substituted twice by halo or 0-methyl.

10. The compound according to Claim 1 or 2 or a pharmaceuticaliy acceptable salt thereof, wherein R¹⁵ is a group represented by formulε ₃alkylene-Ph³, wherein Ph³ is phenyl substituted once by O-methyl.

11. The compound according to Claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a group selected from

wherein the wavy bond indicates the point of attachment.

12, The compound according to any of Claims 1-11 or a pharmaceutically acceptable salt thereof wherein R¹⁶ is H.

13. The compound according to any of Claims 1 -12 or a pharmaceutically acceptable salt thereof wherein R¹⁹ is OH.

14. The compound according to any of Claims 1-13 or a pharmaceutically acceptable salt thereof wherein L is a bond.

15. The compound according to any of Claims 1-14 or a pharmaceutically

acceptable salt thereof wherein Q is

16. The compound according to any of Claims 1 -14 or a pharmaceutically

acceptable salt thereof wherein Q is

17. The compound according to any of Claims 1-14 or a pharmaceutically

acceptable salt thereof wherein Q is

wherein each R is independently halo, C-ι_-4alkyi, OH, C_1-4alkoxyl, NH₂, N(H)Ci- ₄alkyl, and N(Ci_-4alkyl)₂.

18. The compound according to any of Claims 1-14 or a pharmaceutically acceptable salt thereof wherein Q is

19. The compound according to any of Claims 1-14 or a pharmaceutically acceptable salt thereof wherein Q is

20. The compound according to any of Claims 1 -19 or a pharmaceutically acceptable salt thereof, wherein R², R³, R⁴, and R⁵ are independently H, methyl, F or Cl.

21. The compound according to any of Claims 1-20 or a pharmaceutically acceptable salt thereof, wherein R², R³, R⁴, and R⁵ are H.

22. The compound according to any of Claims 1-21 or a pharmaceutically acceptable salt thereof, wherein R⁶ is H and R⁷ is OH.

23. The compound according to any of Claims 1-22 or a pharmaceutically acceptable salt thereof, wherein R¹⁰ and R¹¹ are H.

24. The compound according to any of Claims 1-23 or a pharmaceutically acceptable salt thereof, wherein R¹² and R⁸ taken together with the carbons to which they are attached form a 1 ,3-dioxolaπe ring represented by formula B:

formula B.

25. The compound according to any of Claims 1-24 or a pharmaceutically acceptable salt thereof, wherein R¹² and R⁸ taken together with the carbons to which they are attached form a 1 ,3-dioxolane ring represented by formula B, and one of R¹³ and R¹⁴ is H, methyl or ethyl and the other is H, C-_MG alkyl, or C₃-1₀ carbocycle.

26. The compound according to any of Claims 1-25 or a pharmaceutically acceptable salt thereof, wherein R², R³, R⁴ _: R⁶, R⁶, R⁷, R¹⁰, R¹¹, R¹², R⁸, R¹³, and R¹⁴ are defined as

27. The compound according to any of Claims 1-26 or a pharmaceutically acceptable salt thereof, which is a compound of Formula ϋ, III, IV, V, or Vl, :

R³

R³

R³

; wherein all variables are defined as in any of Claims 1-26.

28. A composition comprising a compound according to any one of claims 1- 27 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent or carrier.

29. The composition according to Claim 28, wherein said composition is suitable for inhalation.

30. The composition according to any of Claims 28-29, wherein said excipient, diluent or carrier is water, saline or lactose.

31. The composition according to any of claims 28-30, wherein said composition is a solution for aerosol ization and administration by nebulizer.

32. The composition according to any of claims 28-31 , wherein said composition has a pH between about 4.5 to about 7.5.

33. The composition according to any of claims 28-32, wherein said composition has an osmolality of about 50 to about 1200 mθsm/kg.

34. The composition according to any of claims 28-33 wherein said composition further comprises chloride, bromide, iodide, or bicarbonate ions.

35. The composition according to any of claims 28-30 wherein said composition is a dry powder.

36. The composition according to any of claims 28-35 further comprising a therapeutically active agent selected from anti-inflammatory agents, anticholinergic agents, β-agonists, peroxisome proliferator-activated receptor agonists, epithelial sodium channel blockers, kinase inhibitors, antiinfective agents and antihistamines

37. The composition according to Claim 36, wherein said therapeutically active agent is a corticosteroid.

38. A method comprising administering to a human, an effective amount of a compound according to any of Claims 1-27 or a pharmaceutically acceptable salt thereof.

39. A method for the treatment of pulmonary inflammation or bronchoconstriction in a human in need thereof, comprising administering to said human an effective amount of a compound according to any of Claims 1- 27 or a pharmaceutically acceptable salt thereof.

40. A method for the treatment of a disease associated with reversible airway obstruction in a human in need thereof, comprising administering to said human an effective amount of a compound according to any of Claims 1-27 or a pharmaceutically acceptable salt thereof.

41. A method for the treatment of asthma in a human in need thereof, comprising administering to said human an effective amount of a compound according to any of Claims 1-27 or a pharmaceutically acceptable salt thereof.

42. A method for the treatment of COPD in a human in need thereof, comprising administering to said human an effective amount of a compound according to any of Claims 1-27 or a pharmaceutically acceptable salt thereof.

43. A method for the treatment of bronchiectasis in a human in need thereof, comprising administering to said human an effective amount of a compound according to any of Claims 1-27 or a pharmaceutically acceptable salt thereof.

44. A method for the treatment of emphysema in a human in need thereof, comprising administering to said human an effective amount of a compound according to any of Claims 1-27 or a pharmaceutically acceptable salt thereof.

45. A compound according to any of claims 1-27 for use as a medicament.

46. A compound according to any of claims 1-27 for use in the treatment of pulmonary inflammation or bronchoconstriction in a human.

47. A compound according to any of claims 1-27 for use in the treatment of a disease associated with reversible airway obstruction, asthma, COPD, bronchiectasis, or emphysema in a human.

48. The use of a compound according to any one of claims 1 -27 for the manufacture of a medicament for the treatment of pulmonary inflammation or bronchoconstriction in a human.

49. The use of a compound according to any one of claims 1-27 for the manufacture of a medicament for the treatment of a disease associated with reversible airway obstruction, asthma, COPD, bronchiectasis, or emphysema in a human.

50. A composition comprising a compound according to any one of claims 1- 27 for use in the treatment of pulmonary inflammation or bronchoconstriction in a human.

51. A composition comprising a compound according to any one of claims 1 - 27 for use in the treatment of reversible airway obstruction, asthma, COPD, bronchiectasis, or emphysema in a human.

52. A pharmaceutical composition for treating pulmonary inflammation or bronchoconstriction in a human comprising a compound according to any one of claims 1-27.

53. A pharmaceutical composition for treating reversible airway obstruction, asthma, COPD, bronchiectasis, or emphysema in a human comprising a compound according to any one of claims 1-27.