WO2010132743A1

WO2010132743A1 - Corticosteroid beta-agonist compounds for use in therapy

Info

Publication number: WO2010132743A1
Application number: PCT/US2010/034861
Authority: WO
Inventors: William R. Baker; Alexander Rudolph
Original assignee: Gilead Sciences Inc
Current assignee: Gilead Sciences Inc
Priority date: 2009-05-15
Filing date: 2010-05-14
Publication date: 2010-11-18
Anticipated expiration: 2011-11-15

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 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. , 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. All 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: 117-1 18. 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 fuliy 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 Gilman, 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, indacaterol, or salmeterol with ICS's are also used to treat both the bronchoconstriction and the inflammation associated with asthma and COPD (Symbtcort^® 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. !n 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 et a!. (WO/2006/138212) wherein the component drugs are released at the site of action in the iungs.

Summary of the Invention

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

or a pharmaceutically acceptable salt thereof, wherein: R¹ is

and one of R⁶ and R⁷ is OH and the other is H; or R⁶ and R⁷ taken together with the carbon to which they are attached form a >C=O group; or

R⁶ is H, and R¹ is CH₂-OH, CH₂-CI,

CH₂-O-C(O)C_{1 -4}alkyl, S-C^alkyl, S-haioC_1-4alkyl, or CH₂-O-PO₃H₂; wherein,

R¹⁰ is H or C_1-4alkyl;

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

R¹⁶ is H, methyl or ethyl;

R¹⁹ is H₁ F, OH or methyl; each R², R³, R⁴, and R⁵ are independently H₁ C_halky! or halo; R⁸ is H₁ OH₁ 0(CO)R⁹, or 0(CO)OR⁹; each R⁹ is independently

R¹¹ is H or C_halky!; R¹² is H₁ OH, or C_1-4alkyl; 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:

B; wherein one of R¹³ and R¹⁴ is H, methyl or ethyl and the other is H, C-i.-ioalkyl, C_2-iøalkenyl, C_2--_IOa I kynyl, optionally substituted Ca.-iocarbocyclyl or optionally substituted 5-6 ring atom heterocycie wherein one or two ring atoms are selected from N, O and S, and wherein said carbocyclyl and said heterocyclyl are each optionally substituted 1 , 2 or 3 times with a substituent selected from halo, Ci-₄alkyl, and O-Ci_-4alkyl.

In one embodiment, the compounds of Formula I is defined wherein R¹ is

and either one of R⁶ and R⁷ is OH and the other is H; or R⁶ and R⁷ taken together with the carbon to which they are attached form a >C=O group.

In another embodiment, the compounds of Formula I is defined wherein R⁷ is

R⁶ is H, and R¹ is CH₂-OH, CH₂-CI, CH₂-O-C(O)Ci_-4a!kyl, S-C^alkyl, S-haloC_1-4alkyi, or CH₂-O-PO₃H₂.

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

C_6-i₀carbocycle optionaily substituted 1 or 2 times with halo, Ci_-4alkyl, O-C_1-4alkyl, O-(CH₂)₄-NH₂, O~(CH₂)₄-N(H)C_1-4aIkyl,

O-(CH₂)4-N(Ci_-4aikyl)₂, O-C_1-4alkyl-C(O)-NH₂, O-C_1-4alkyl-C(O)-N(H)C_1-4alkyl, O-C_1-4alkyl-C(O)-N(C_1-4alkyl)_2, or a group represented by formula i, ii, Ni, iv, v, vi, vii, viii, or ix: i: C₆alkylene-O-R²¹-Ph⁴; ii: C₂,₃aikylene-Ph¹-O-R²¹-Ph⁴; iii: C₂.₃aIkyiene-Ph¹-N(H)-R²²-Ph²; iv; C_2-3aikyiene-Het-(R²³)-Ph³; v: C₂-3alkylene-Ph¹-Co.2alkylene-C(0)N(H)-Ci_-4alkylene-Ph³; vi: C_2-3aikyIene-Ph³; vii: C_2-3alkylene-S{O)₂-C₂-₄alkylene-O-C₂.₄aikylene-Ph³; viii: C3_-6alkylene-Ph¹-Co_-2alkylene-C(0)N(H)-Cio-i₂ bicyciic carbocycle; ix: C₃.₆alkyiene-Het-Ph⁴; wherein:

R²¹ is C₂- ealkyiene 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-cyclopentyl, Ph¹ is phenylene;

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, -SO₂-NH-(C₆H₃XCH₃)(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_2-4alkylene wherein one carbon of said alkylene is optionally replaced by O or -C_0-2alkylene-C(O)N(H)- C_2-4alkylene; and

Ph³ is phenyl optionally substituted 1 or 2 times by halo or O-methyi. As another aspect, the present invention provides compounds of Formula M:

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

As another aspect, the present invention provides compounds of Formula III:

and pharmaceutically acceptable saits thereof wherein all variables are defined above.

In another aspect, the present invention provides a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent or carrier, in one embodiment, the composition is suitable for inhalation.

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

As another aspect, the present invention provides a method for the treatment of a disease associated with reversible airway obstruction in a human in need thereof. The method comprises administering to the human an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

As another aspect, the present invention provides a method for the treatment of asthma in a human in need thereof. The method comprises administering to the human an effective amount of a compound of Formula i or a pharmaceutically acceptable salt thereof.

As another aspect, the present invention provides a method for the treatment of COPD in a human in need thereof. The method comprises administering to the human an effective amount of a compound of Formula t or a pharmaceutically acceptable salt thereof.

As another aspect, the present invention provides a method for the treatment of bronchiectasis in a human in need thereof. The method comprises administering to the human an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

As another aspect, the present invention provides a method for the treatment of emphysema in a human in need thereof. The method comprises administering to the human an effective amount of a compound of Formula ! or a pharmaceutically acceptable salt thereof.

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

As another aspect, the present invention provides a compound of Formula ! 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.

As another aspect, the present 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 pulmonary inflammation or bronchoconstriction in a human,

As another aspect, the present 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.

As another aspect, the present 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.

As another aspect, the present invention provides a composition comprising a compound of Formula ! 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.

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 all 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 foiiowing 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, and III, 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 I, including compounds of Formulas II, and 111. 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 chira! 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, 111, and isolatable 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 chiral center) thereof, "alky!" as used herein refers to linear or branched hydrocarbon chains containing from 1 to 8 carbon atoms (i.e., C_halky!), unless a different number of atoms is specified. Examples of "alkyl as used herein include but are not limited to methy! (Me), ethyl (Et), n-propyl (1 -Pr, 1-propyl), isopropyl Q-Pr, 2-propyi), n-butyl (n-Bu, 1 -buty!), isobuty!, (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-pentyl, 3-pentyl (-CH(CH₂CHs)₂), 2-methyl-2-butyl (-C(CH₃J₂CH₂CH₃), 3-methyl-2-butyl (-CH(CH₃)CH(CH₃)₂), 3-methyM -butyl (-CH₂CH₂CH(CHs)₂), 2-methyl-1- butyl (-CH₂CH(CH₃)CH₂CH₃), 1-hβxyl, 2-hexyl, 3-hexyl (-CH(CH₂CH_SXCH₂CH₂CH₃)), 2-methyl-2-pentyl (-C(CHa)₂CH₂CH₂CH₃),

3-methyl-2-penty! (-CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (-CH(CH₃)CH₂CH(CH₃)₂), 3-methy!-3-pentyl (-C(CH₃)(CH₂CHs)₂), 2~methyl-3-pentyl (-CH(CH₂CH₃)CH(CHs)₂), 2,3-dimethyi-2-butyl (-C(CHs)₂CH(CHs)₂), 3,3-dimethy!-2-butyl (-CH(CH₃)C(CH₃)_3! and octyl (-(CH₂J₇CH₃). When the compound of Formula I includes more than one alkyl, the aikyis may be the same or different.

"alkyiene" refers to a linear or branched divalent hydrocarbon chain having from 1 to 8 carbon atoms (i.e., C-ι_-8alkyiene), unless a different number of carbon atoms is specified. Examples of "alkyiene" as used herein include but are not limited to methylene, 1 ,1 -ethyi (-CH(CH₃)-), ethylene, propylene (1 ,3- propyl (-CH₂CH₂CH₂-); 1 ,1 -propyl (-CH(CH₂CH₃)-), or 1 ,2-propyl (-CH₂CH(CH₃)-)) and butyfene (1 ,4-butyl (-CH₂CH₂CH₂CH₂-)), and the like. When the compound of Formula I includes more than one alkyiene, 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., C₂.₈aikenyl), 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), 2-propenyl or ally! (-CH₂CH=CH₂), and 5- hexeny! (-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., C₂-₈a'kynyi), unless a different number of atoms is specified, and at least one carbon-carbon triple bond. Examples of aikynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH₂C≡CH), 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. "haloalkyi" as used herein refers to a linear or branched hydrocarbon chain containing from 1 to 8 carbon atoms, unless a different number of carbon atoms is specified, wherein at least one carbon atom is substituted by 1 , 2 or 3 halogen atoms which may be the same or different and are selected from fluoro, chloro, bromo and iodo. In those instances where the alkyl group does not contain from 1 to 8 carbon atoms, the number of carbon atoms in the haloalkyi is expressed as, for example "haloC_1-4a!kyr.

"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, "carbocycle" or "carbocyclyl" refers to a saturated (i.e., cycioalkyl), partially unsaturated (e.g., cycioalkeny!, cycloalkadienyi, etc.) or aromatic (i.e., aryl ring) hydrocarbon rings having 3 to 7 carbon atoms as a monocycie, 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_3-6carbocycle"), and in one embodiment, 5 or 6 ring atoms ("Cs-gcarbocycle"). 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 bicyclo [5,6] or [6,6] system, or spiro-fused rings. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyi, 1-cyclopent-1- enyl, i-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1- enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and phenyl. Non-limiting examples of bicycio carbocycles includes naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, and indanyl. In those embodiments wherein the compound of Formula I includes more than one carbocycle, the carbocycles may be the same or different.

"aryl" refers to a subset of carbocycles, 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, naphthyl, 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, aryi refers to phenyl or naphthyl. In one particular embodiment, ary! is phenyl. "heterocycie" or "heterocycly!" 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 N₁ 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 heterocycie includes 2 or more heteroatoms (N, O and S) the heteroatoms may be the same or different. In one particular embodiment, "heterocycie" or "heterocycly!" 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 all embodiments wherein the compound of Formula ! includes 2 or more heterocycles, the heterocycies may be the same or different. Examples of heterocycles include but are not limited to pyridyl, dihydropyridyl, piperidyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imϊdazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimϊdazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyi, octahydroisoquinolinyi, azocinyl, triazinyl, 6H-1 ,2,5- thiadiazinyl, 2H,6H-1 ,5,2-dithiazinyI, thienyl, pyranyl, isobenzofuranyl, chromenyl, 2H-pyrroiyl, isothiazoiyl, isoxazolyl, pyrazinyl, pyridazinyl, indoiizinyl, isoindolyl, 3H-indolyl, 1 H-indazoly, purinyi, 4H-quinolizinyl, phthalazinyi, naphthyridiny!, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4H-phenanthridinyl, acridinyi, pyrimidinyl, phenanthrolinyl, furazanyl, isochromanyl, chromanyl, imidazolidinyi, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indoliπyl, isoindoiinyl, quinuclidinyl, morpholinyi, oxazolidinyi, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and bis-tetrahydrofuranyl:

"heteroaryl" refers to a subset of heterocycles, namely monocyclic 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 N, O and S. Non-limiting examples of heteroaryls include all of aromatic heterocycles listed above, and particularly pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindoiyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, imidazoly!, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyπmidyl, 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 1, include more than one heterocyclene, the heterocyclenes may be the same or different. COMPOUNDS

One skilled in the art wii! 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 skilf 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.

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

is the same as

For ease of reference, the constituent moieties of the compounds of Formula may be referred to herein from time to time as follows: "corticosteroid moiety" "β-agonist moiety"

In one aspect, the invention comprises compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ JS

R⁷ is

R⁶ is H₁ and R¹ is CH₂-OH, CH₂-CI,

CH₂-O-C(O )C_{1 -4}alkyl, S-C_1-4aikyl, S-haloC_1-4alkyl, or CH₂-O-PO₃H₂; wherein,

R¹⁰ is H or C_1-4alkyl;

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

R¹⁶ Js H, methyl or ethyl;

R¹⁹ is H, F, OH or methyl; each R², R³, R⁴, and R⁵ are independently H, Ci_-4alkyl or halo; R⁸ is H, OH, 0(CO)R⁹, or 0(CO)OR⁹; each R⁹ is independently C^alkyl; R¹¹ is H or C_1-4aikyl; R¹² is H, OH, or Ci_₄alkyl; or R¹¹ and R¹² taken together with the carbon 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-_Moalkyl, C-2-ioalkenyl, C₂-ioalkynyl, optionally substituted C_3-iocarbocyclyl or optionally substituted 5-6 ring atom heterocycle wherein one or two ring atoms are selected from N, O and S, and wherein said carbocyclyl and said heterocyclyl are each optionally substituted 1 , 2 or 3 times with a substituent selected from halo, Ci-₄alkyl, and O-Ci_-4alkyl.

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 I! and III, as if the disclosure referenced all, since such compounds are also compounds of Formula I.

The β-agonist moiety of the compound of Formula I may be bound at the 11- or 21-oxy of the corticosteroid moiety. Thus, compounds of the invention include compounds of Formula I wherein

R¹ is

and either one of R⁶ and R⁷ is OH and the other is H; or R⁶ and R⁷ taken together with the carbon to which they are attached form a >C=O group. Such compounds may be referred to as compounds of Formula I-A, and are illustrated as follows:

In one preferred embodiment, the compounds of Formula ! are compounds of Formula I-A, wherein one of R⁶ and R⁷ is OH and the other is H; or R⁶ and R⁷ taken together with the carbon to which they are attached form a >C=O group, 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.

The compounds of the invention also include compounds of Formula I wherein

R⁷ is

R⁶ is H, and R¹ is CH₂-OH, CH₂-Ci,

CH₂-O-C(O)C_1-4alkyl, S-Ci_-4alkyi, S-haloC^alkyl, Or CH₂-O-PO₃H₂, or any subset thereof. Such compounds may be referred to as compounds of Formula I-B, and are iliustrated as follows:

In one embodiment, R¹ is S-Ci_-4alkyl or S-haioC-Malkyl, or any subset thereof. In one particular embodiment, R¹ is S-haloCi_-4alkyl, more particularly S-f!uoroCi-₄alkyI. In one preferred embodiment, R¹ is -S-CH₂F.

In one embodiment the compounds of the invention are defined wherein 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, CI or methyl. In one embodiment R⁴ and R⁵ are H, R² is H, F or Cl 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 embodiment R⁸ is H, OH₁ 0(CO)CH₂CH₃, 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 methyi.

in one embodiment R j12 is H, OH, or methyl. In one particular embodiment R 12 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

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, d-ioalkyl, C_2- -soaikenyi, C^-ioaikynyl, optionally substituted C₃^ocarbocycle or optionally substituted 5-6 ring atom heterocycle wherein one or two ring atoms are selected from N, 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 O-C₁.₄alk.yl. in one embodiment wherein R¹² and R⁸ form a ring represented by formula B, one of R¹³ and R¹⁴ is H, methyl or ethy! and the other is H, Ci_i_Oa!kyl, C_2-ioaIkenyl, C₂-ioaIkynyl, or optionally substituted C_3-10carbocycle, wherein the carbocycle is optionally substituted 1 , 2 or 3 times with a substituent selected from halo, C_halky!, and

In one embodiment one of R¹³ and R¹⁴ is H, methyl or ethyl and the other is H, Ci- _loalkyt, or C_3-iocarbocycle, or any subset thereof. In one embodiment one of R¹³ and R¹⁴ is H, methy! or ethyl and the other is H, C_1-4alkyl, or C_3-6cycloalkyl, or any subset thereof, more particularly cyclohexyl. In one embodiment one of R¹³ and R¹⁴ is H or methyl, more particularly H, and the other is H, C^aikyi, or Cs-ecycloalkyl, or any subset thereof, more particularly cyclohexyl. In 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 cyclohexyl.

In a particular embodiment the corticosteroid moiety is

or , or any subset thereof.

In one preferred embodiment the corticosteroid moiety is

In one preferred embodiment the corticosteroid moiety is

In one particular embodiment, the corticosteroid moiety is

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)6θ(CH₂)4-phenyl;

or any subset thereof. rticular embodiment, R¹⁵ is d-Cealkyl;

C₆~C_tocarbocycle optionally substituted 1 or 2 times with halo, C₁- C₄alkyl, O-CrC₄alkyl, O-(CH₂)₄-NH₂, 0-{CH₂)₄-N(H)C_1-4alkyl_! O-(CH₂)4-N(C₁.₄aikyl)₂, O-C_1-4afkyl-C(O)-NH₂,

O-Ci_-4aikyl-C(O)-N(H)Ci_-4alkyl, O-C_1-4alkyl-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: C₂.₃alkylene-Ph¹-O-R²¹-Ph⁴; iii: C_2-3alkylene-Ph¹-N(H)-R²²-Ph²; iv: C_2-3aikylene-Het-(R²³)-Ph³; v: C_2-3alkylene-Ph¹-Co-₂aϊkylene-C(O)N(H)-C_1-4alkyiene-Ph³; vi: C_2-3alkylene-Ph³; vii: C₂-₃alkylene-S(0)₂-C₂.₄alkylene-O-C_2-4alkylene-Ph³; viii: Ca-ealkylene-Ph^Co^aikylene-C^NfHJ-C-io--^ bicyclic carbocycle; ix: C_3-6alkyiene-Het-Ph⁴; wherein:

R²¹ is C_{2- 6}alkylene 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-cyclopentyl, Ph¹ is phenylene;

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,

-OCH_ZCH(CH₃)₂CH₂NH₂, -SO₂-NH(C₆H₃XCH₃XC₇H₁₅), 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 C-₂-C₄alkylene wherein one carbon of said alkylene is optionally replaced by O or -C₀-₂aikyiene-C(O)N(H)-C_2-4alkylene; and Ph³ is phenyl optionally substituted 1 or 2 times by halo or O- rnethyl.

in one embodiment, R¹⁵ is Ci_-6alkyl. More particularly R¹⁵ is C^alkyl. In one preferred embodiment, R¹⁵ is isopropyl or t-butyl.

in one embodiment, R¹⁵ is Cg--I ocarbocycle optionally substituted 1 or 2 times with C_1-4alkyl, O-C_1-4alkyl, or O-Ci_-4alkyl-C(O)-NH₂, or any subset thereof. In one embodiment, R¹⁵ is Cg.-iøcarbocycle optionally substituted 1 or 2 times with C_1-4alkyl, O-Ci»₄alkyl, or O-Ci.₄aikyl-C(O)-NH_2> or any subset thereof. In one embodiment, R¹⁵ is

In one embodiment, R¹⁵ is a group represented by formula i:

C₆alky!ene-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 C₄afkylene and Ph⁴ is phenyl, particularly unsubstituted phenyl. According to one preferred embodiment, R¹⁵ is -<CH₂)₆θ(CH₂)₄-pheny!, i.e.,

In one embodiment R is a group represented by formula i and R is C₄alkylene 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 C₄alkylene wherein one C is optionally replaced by O and Ph⁴ is unsubstituted phenyl. In one particular embodiment R¹⁵ is a group represented by formula ii 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(CH₃)₂CH₂NH_2. in one embodiment R¹⁵ is a group represented by formula iii, R²² is C_2aι_kylene substituted once by OH or NH, and Ph² is unsubstituted phenyl.

In one embodiment R¹⁵ is a group represented by formula iv: C_2-3alkylene-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, R¹⁶ 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 CI) or O-methyl, or any subset thereof.

In one embodiment R¹⁵ is a group represented by formula v: C_2-3a!kylene-Ph¹-C₀-C₂alky!ene-C(O)N(H)-C_1-4alky!ene-Ph³. in one embodiment, R¹⁵ is a group represented by formula v and Ph³ is phenyl substituted twice by halo (particularly Cl) 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 formuia vii: C₂-₃alkylene-S(O)₂-C₂-₄alkylene~O^»C2-₄alkylene-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_3-6alky!ene-Ph¹-Co_-2a[kylene-C(0)N(H)-Cio-i2 bicyclic carbocycle. In one embodiment, R¹⁵ is a group represented by formuia viii-a: (branched) C₃alky!ene-Ph¹-CH₂C(O)N(H)-adamanty!.

In one embodiment, R¹⁵ is a group represented by formula ix: C_3-6alkylene-Het-Ph⁴. In one embodiment, R¹⁵ is a group represented by formula ix wherein Het is a 5 or 6 ring atom heterocyciene 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:

or any subset thereof, wherein the wavy bond indicates the point of attachment. in one preferred embodiment, R 15 is selected from t-butyl, isopropyl,

or any subset thereof.

In one preferred embodiment, R¹⁵ is

In one preferred embodiment, R¹⁵ is In one preferred embodiment, R¹⁵ is

In one preferred embodiment, R

In one preferred embodiment, R 15 is

In one preferred embodiment, R¹⁵ is

in one preferred embodiment, R¹⁵ is

In one embodiment R )16 is H or methyl. In one preferred embodiment, R 16 is H

In one preferred embodiment, R¹⁹ is OH.

In one embodiment, the invention provides compounds of Formula II:

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, and R¹⁵ 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, and R¹⁵ are contemplated for combination in any of the foregoing Formula.

In one embodiment, the invention provides compounds of Formula III:

and pharmaceutically acceptable salts thereof, or any subset thereof, wherein R²⁰ is ethyl or furanyl and all other variables are as defined above, including all embodiments of each variable as described hereinabove. Specific embodiments, including particular and preferred embodiments of R¹⁵ 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 R¹⁵ are contemplated for combination in any of the foregoing Formula.

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 I, may be in the form of a sait, 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 alkaiine earth (for example,

Na⁺, Li⁺, K⁺. Ca²⁺ and Mg2⁺), ammonium and N(C₁^aIKyI)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, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polygiutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, naphthalene-1 ,5-disulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, 1-hydroxy-2- naphthoate pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ctnnamic 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 pharmaceutically 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.

Finally, 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 superimposable 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 Elief, 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 chira! 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 equimolar mixture of two enantiomeric species. It is to be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopoiymorphs 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 diastereomericaliy 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 enantiomerically enriched mixture is substantially free of the other enantiomer. Similariy, diastereomericaliy enriched mixtures are mixtures of diastereomers wherein amount of the specified diastereomer is greater than the amount of each alternative diastereomer. More particularly, a diastereomericaliy 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 diastereomericaliy 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 enantiomericaily enriched mixture comprising

a pharmaceutically acceptable salt thereof, as the predominant isomer. In one embodiment, the present invention provides an enantiomerically enriched mixture comprising

or a pharmaceutically acceptable salt thereof, as the predominant isomer.

A compound of Formula I 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 pseudopolymorphs 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 clinical 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. Ail 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, particularly 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 mammal, particularly 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 mamma!, 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, particularly a human in need thereof, In 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 ceil 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 physiological 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 will 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) will 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, II, or II! or a pharmaceutically acceptable salt of any of the foregoing. In 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 (MMAD) 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. Non limiting examples of other processes or techniques that can be used to produce respirabie particles include spray drying, precipitation, supercritical fluid, and freeze drying. The desired fraction may be separated out by air classification or sieving. In one embodiment, the particles will be crystalline.

Aerosoi 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 generaliy contain a mix of the active ingredient and a suitable powder base (carrier/diluent/excipient substance) such as mono-, di- or poly-saccharides (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 inhaier 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 μrη 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 formulated for delivery by a Diskus®-type device. The Diskus® device comprises an eiongate 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 excipients (e.g., lactose) and/or other therapeutically active agents. Preferably, the strip is sufficiently flexible to be wound into a roll. The Nd 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.

in another embodiment, the pharmaceutical formulation according to the invention is a dry powder for inhalation wherein the dry powder is formulated into microparticles as described in PCT Publication No. WO2009/015286 or WO2007/114881 , both to NexBio. Such microparticles are generally formed by adding a counterion to a solution containing a compound of the invention in a solvent, adding an antisolvent to the solution; and gradually cooling the solution to a temperature below about 25⁰C, to form a composition containing microparticles comprising the compound. The microparticles comprising the compound may then be separated from the solution by any suitable means such as sedimentation, filtration or lyophilization. Suitable counterions, solvents and antisolvents for preparing microparticles of the compounds of the invention are described in WO2009/015286.

Spray compositions for topical delivery to the endobronchial space or lung 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 propellants, 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 ethanol) 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 chforofluorocarbon or mixtures thereof, particularly hydroffuoroalkanes, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichJorotetrafluoroethane, especially 1 ,1 ,1 ,2-tetraf!uoroethane, 1 ,1 ,1 ,2,3,3,3,-heptafluoro-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 aluminum 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- limiting 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 aerosolization 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 formuiated 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 commercially 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 nebuiizers 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-iimiting 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 phi, osmolality, and permeant 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 μm 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. If an aerosol has an MIvIAD 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 oil-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 sublingually, 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 multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for- injection, immediateiy 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 iess 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 inhaiable pharmaceutical composition of a compound of the invention wherein the inhaiable pharmaceutical 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 asthma, bronchitis or COPD comprising treating a 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-agontst 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 iess 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 formuiations 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 particularly mentioned above, the formuiations 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 proiiferator-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-ciclesonide, budesonide, flunisolide, mometasone and esters thereof (e.g., mometasone furoate), fluticasone propionate, fluticasone furoate, beciomethasone, methyl prednisolone, prednisolone, dexamethasone, 6α,9α-difluoro-17a-[(2-furanylcarbonyl)oxy]- 11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethy! ester, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo-1 Ia- propionyloxy-androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro- furan-3S-yi) ester, beclomethasone esters (e.g., the 17-propionate ester or the 17,21-dipropionate ester, fluoromethy! 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 ciciesonide, desisobutyryl-ciclesonide, budesonide, mometasone, fluticasone propionate, and fluticasone furoate, or any combination or subset thereof.

NSAlDs 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 (ΪNOS) inhibitors, protease inhibitors (e.g., tryptase inhibitors, neutrophil elastase inhibitors, and metalloprotease 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 family). 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, cilomilast, tofimilast, oglemiiast, tolafentrine, piclamilast, ibudiiast, apremilast, 2-[4-[6,7-diethoxy~2,3~ bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4-(3-pyridiny!)-1(2H)- phthalazinone (T2585), N-(3,5-dichioro-4-pyπdinyi)-1-[(4-fluorophenyl)methyl]-5- hydroxy-α-oxo-1 H-indo!e-3-acetamide (AWD- 12-281 , 4-[(2R)-2-[3- (cyclopentyloxy)-4-methoxyphenyl]-2-pheπyiethyl]-pyridiπe (CDP-840), 2-[4- [[[^-(I .S-benzodioxol-δ-yloxyJ-S-pyridiny^carbonyljaminolmethyll-S- fiuorophenoxy]-(2R)-propanoic acid (CP-671305), N-(4,6-dimethyl-2- pyrimidinyl)-4-[4,5,6,7-tetrahydro-2-(4-methoxy-3-methy!phenyl)-5-(4-methyl-1- piperazinyl)-1 H-indol-1-yl]- benzenesulfonamide, (2E)-2-butenedioate (YM- 393059), 9-[(2-fluorophenyl)methyl]-N-methyI-2-(trifluoromethyl)-9H-purin-6- amine (NCS-613), !Ni-(2,5-d!chloro-3-pyridinyl)-8-methoxy-5- quinolinecarboxamide (D-4418), N-[(3R)-9-amino-3,4,6,7-tetrahydro-4-oxo-1 - phenylpyrroio[3,2,1-][1 ,4]benzodiazepin-3-yl]-3H-purin-6-amine (PD-168787), 3- [^-(cyclopentyloxy^-methoxyphenyllmethyQ-N-ethyf-δ-ti-methyiethylJ-SH- purin-6-amine hydrochloride (V-11294A), N-(3,5-dich!oro-1-oxido-4-pyridiny!)-8~ methoxy-2-(trifiuoromethyl)-5-quinoliriecarboxamide (Sch351591 ), 5-[3- (cyclopentyloxy)-4-methoxypheny!]-3-[{3-methylpheny!)methyl]-(3S,5S)- 2- piperidinone ( HT-0712), 5-(2-((1 R,4R)-4-amino-1-(3-(cyclopentyloxy)-4- methyoxyphenyt)cyclo-hexyl)ethynyl)pyrimidine-2-amine, 6-[3- (dimethylcarbamoyi)pheny!sulfonyl]-4-(3-methoxyphenylamino)-8- methylquinolirιe-3-carboxamide {GSK-256066),ciε-[4-cyano-4-(3- cyclopropylmethoxy-4-difiuoromethoxyphenyi)cyclohexan-1 -ol], and 4-[6,7- diethoxy-2,3-bis(hydroxymethyl)-1 -naphthalenyi]»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, ziieuton, 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 saits 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. Additional anticholinergics for formulation and use in combination with the methantheline, propantheline bromide, anisotropine methyl bromide or Valpin 50, aclidinium bromide, glycopyrrolate (Robinul), isopropamide iodide, mepenzolate bromide, tridihexethyl chloride, hexocyclium methylsulfate, cyclopentolate HCf, 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), indacaterol, formoterol (fumarate), fenoterol, 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, pioglitazone, and troglitazone.

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

Examples 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 formulation and use in combination with the compounds of the invention include but are not limited to: Ethanolamines, ethylenediamines, alkyiamines, 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 HCI₁ carbinoxamine maleate, doxylamine, clemastine fumarate, diphenylhydramine HCI, dimenhydrinate, pyrilamine maleate (metpyramine), tripeiennamine HCI, tripelennamine citrate, antazoline pheniramine, chloropheniramine, bromopheniramine, dexchlorpheniramine, triprolidine, acrivastine methapyhlene, hydroxyzine HCI, hydroxyzine pamoate, cyclizine HCI, cyclizine lactate, meclizine HCl, cetirizine HCI astemisole, levocabastine HCI, loratadine, descarboethoxy loratadine, terfenadine, fexofenadine HCl, 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-ciciesonide, budesonide mometasone, fluticasone propionate, and fluticasone furoate. In one particular embodiment, the composition comprises a compound of the invention and cidesonide or desisobutyryl- ciciesonide.

In one aspect, the present invention provides a composition comprising a compound of the invention and a PDE4 inhibitor. In one aspect, the present invention provides a composition comprising a compound of the invention and a β2-agonist. in one embodiment, the composition comprises a compound of the invention and salmeterol, R- salmeterol, indacaterol, or formoterol. In one particular embodiment, the composition comprises a compound of the invention and salmeterol or R- salmeterol.

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 skili 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. In one particular embodiment, the method comprises administering an effective amount of 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 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. 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 (J₂- agonist. In one embodiment, the method comprises administering an effective amount of a compound of the invention and salmeteroi, R-salmeterol, indacaterol, or formoterol. 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 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 a corticosteroid selected from ciciesonide, desisobutyryl-ciclesonide, budesonide mometasone, fluticasone propionate, and fluticasone furoate. In one particular embodiment, the combination comprises a compound of the invention and ciciesonide 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 also 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, indacaterof, or formoterol. In one particular embodiment, the combination comprises a compound of the invention and salmeterol 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 limiting 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 may be prepared according to the processes illustrated in Scheme 1. Scheme 1

wherein

R^1a is selected from CHR¹⁰-OH,CH₂-OH, CH₂-Cl, CH₂-O-C(O)C_1-4alkyl,

S-Ci_-4alky!, S-haloC_1-4alkyl, or CH₂-O-PO₃H₂ R^7a is H or OH, each PG is H or Boc, and all other variables are as defined herein.

In general, the process comprises the steps of: a) reacting a compound of formula 1 with phosphorous trichloride followed by a base, adding to a compound of formula 2 and base and then oxidizing in a one-pot reaction to prepare a compound of formula 3-A or 3-B or a pharmaceutically acceptable salt thereof; and b) deprotecting the compound of formula 3-A or 3-B to prepare a compound of Formula I or a pharmaceutically acceptable salt thereof.

The first step is carried out in a manner analogous to that described in C. Meter et al., J. Med. Chem., 2007, 50(6), 1335-1346. More specifically, the process comprises reacting the alcohol of formula 1 with phosphorous trichloride then a base, such as triethylamine, or DIPEA in a suitable solvent. Suitable solvents include but are not limited to diethyl ether, tetrahydrofuran, and dichloromethane. The reaction is typically carried out at reduced temperature, from about -20 to about -80°C, particularly at about -78⁰C₁ then warmed to ambient temperature if required. The reaction is then added to a solution at, from about -20 to about -8O⁰C, particularly at about -78⁰C, of the compound of formula 2 and additional base and then the solution is allowed to warm to room temperature. A suitable oxidizing agent such as terf-butyl hydroperoxide, iodine, MCPBA or oxone is then added to prepare a compound of formula 3-A or 3-B or a pharmaceutically acceptable salt thereof.

Whether the substitution on the steroid occurs on the 11 or 21 position is dependent upon the steric hindrance around the 11 and 21 position. The substitution may be driven toward one over the other through the use of protecting groups on the steroid. The selection, installation and removal of protecting groups on the steroid is within the ordinary skill of those in the art. The resulting compound of formula 3-A or 3-B may be deprotected using conventional processes, including acidic conditions, either by brief treatment with HCI in dioxane or by low-temperature treatment with trifluoroacetic acid in dichloromethane at about 0^°C. As will be apparent to those skilled in the art, the choice of protecting groups on the compound of formula 3-A or 3-B will be based at least in part on the steric bulk of the particular β-agonist side chain (R¹⁵) selected. The foregoing process may be utilized to prepare the corresponding R-isomer of a compound of Formula I-A by substituting the R-enantiomer of the N-Boc- protected compound of formuia 2 starting material for the racemate. Similarly the corresponding S-isomer of a compound of Formuia I-A may be made by using the S-enantiomer of the N-Boc-protected compound of formula 2. This same approach may be utilized to prepare enantiomericaify enriched mixtures of any of the compounds of Formula I which contain a chiral center, and pharmaceuticaliy acceptable salts thereof.

Compounds of formulas 1 and 2 are commercially available or may be prepared using conventional techniques and commercially available reagents, including conventional techniques for the installation of protecting groups.

EXAMPLES The foregoing may be better understood from the following exam pies, 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, [[11 β,16α]-[16,17- ((R)-cyclohexyimethy!ene)bis(oxy)]-11 -hydroxy-21 -[[2-oxido-7-[2-[6-(4~ phenylbutyoxy)hexyl]amino]-1 (R)-hydroxyethyl]-4H-1 ,3,2- benzodioxaphosphorin-2-yl]oxy]pregna-1 ,4-diene-3,20-dione.

Example 1 : π i β,16αH16,17-(fR)-cvclohexylmethylene)bisfoxy)1-11-hvdroxy-

21-rr2-oxido-7-[2-f6-(4-ρhenylbutvoxy)hexyl1amino1-1(RVhvdroxvethy]1-4H-

1 ,3,2-benzodioxaphosphorin-2-vπoxy1pregna-1 ,4-diene-3,20-dione

To a stirred, cooled (dry ice/acetone bath) solution of ctes-/so-butyry! ciclesonide (100 mg, 0.212 mmo!) in DCM (2 mL) was added PCI₃ (19.5 μL, 0.223 mmol) in DCM (1 mL) and TEA (31.1 μL, 0.223 mmol) in DCM (1 mL). The solution was added to a stirring cooled (dry ice/acetone bath) solution of (R)-2-(3-hydroxymethyl-4-hydroxyphenyl)-2-hydroxyethyi][6-(4- phenylbutoxy)hexyl]carbamic acid tert-butyl ester (99 mg, 0.193 mmol) and TEA (147.7 μL, 1.060 mmoi) in DCM (3 mL). . After 10 min, the bath was removed and allowed to warm to ambient temperature while stirring continued for 1 h, then ferf-butyl hydrogen peroxide (1 mL, 5.5 M in nonanes) was added and stirred. After 10 minutes, the solution was washed with water (20 mL x 3), brine (20 mL), dried (MgSO₄) and concentrated to provide the crude material (266 mg). Chromatography [C18 column (16 gram), H₂O/ACN (both with 0.1 % AcOH) gradient 5:95 to 0:1] fractions were dried (MgSO₄) to afford the protected analog (52 mg, 26 % yield) as a white foam. ES/MS calcd. for C₅₈H₈₀NOi₃P 1029.5, found mlz = 1052.5 (M+Na).

To a solution of the protected analog (120 mg, 0.116 mmol) in DCM (2 mL) was added HCi (1 mL, 4 M in dioxane). The solution was stirred for 2 h then concentrated. The oil was dissolved in DCM (1 mL) then Et₂O (20 mL) was added and the suspension was vigorously stirred and sonicated, then filtered to provide crude solid (85 mg). To a solution of the crude solid in DCM (10 mL), activated carbon was added, stirred 5 min, filtered, and concentrated to provide the title compound (55 mg, 51 % yield) as a white solid. ES/MS calcd. for C₅₃H₇₂NO₁₁P 929.5, found m/z - 930.5 <M+H).

Example 2: (6α,113,16α,17α) 6₁9-difluoro-16-methyi-11-rr2-oxido-7-r2-[f6-(4- phenylbutyoxy)hexynamino1-1 (R)-hydroxyethvπ-4H-1 ,3,2- benzodioxaphosphorin-2-yl1oxy1-3-oxo-17-(1-oxopropoxy)androsta-1 ,4-diene- 17-carbothioic acid, S-(fluoromethyi) ester

A solution of (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl~3~oxo-17-(1- oxopropoxy)-androsta-1 ,4-diene-17-carbothioic acid, S-(fluoromethyl) ester

(fluticasone propionate) (500 mg, 0.999 mmol) in DCM (10 ml_) was cooled (dry ice/acetone bath) while stirring, then PCI₃ (91.5 μl_, 1.049 mmol) in DCM (2 ml_) and TEA (146 μL, 1.049 mmol) in DCM (2 ml_) were added sequentially and stirred 5 min. The bath was removed and the reaction was allowed to warm to ambient temperature while stirring 2 h. To a cooled solution (dry ice/acetone bath) of (R)-2-(3-hydroxymethyl-4-hydroxyphenyi)-2-hydroxyethylj[6-(4- phenylbutoxy)hexy!]carbamic acid tert-butyl ester (464 mg, 0.899 mmol) and TEA (696 μL, 4.995 mmol) in DCM (5 ml_), the steroid solution was added dropwise with stirring. After 10 min, the bath was removed and the reaction was allowed to warm to ambient temperature while stirring continued 1 h. tert- Butyl hydrogen peroxide (3 ml_, 5.5 M in nonanes) was added and stirred for 10 minutes. The solution was washed with water (20 ml_ x 3), brine (20 ml_), dried (MgSO₄) and concentrated to provide the crude phosphate (1064 mg). Chromatography [C18 column (16 gram), H₂O/ACN eluant with 0.1 % AcOH (gradient 1 :1 to 0:1 )] fractions were repeatedly extracted with DCM. Combined extractions were dried (MgSO,*), treated with activated carbon, filtered and concentrated to afford the product (357 mg, 37 % yield) as a white foam. ES/MS calcd for C₅₅H₇₃F₃NOi₂PS 1059.5, found m/z = 1082.5 (M+Na)

To a solution of the product (177 mg, 0 167 mmol) in DCM (3 mL), HCI (1 mL, 4 M in dioxane) was added and stirred 2 h then concentrated The oil was triturated with Et₂O (20 mL) then filtered to provide the title compound (147 mg, 92 % yield) as a white solid ES/MS calcd for C_5OH_6SF₃NO₁₀PS 959 4, found m/z = 960 4 (M+H)

Example 3 2-Methylpropanoιc acid, M 1 β,16αH16,17-ffR)- cyclohexylmethylene)bιs(oxy)1-11 -[f2-oxιdo-7-|^"2-[6-(4- phenylbutvoxy)hexyflamιnoH (R)~hydroxyethyl1~4H~1 ,3,2- benzodipxaphosphorιn-2-yπoxy]-21-(2-methvl-1-oxopropoxv)-preqna-1 ,4-diene- 3,20-dιone ester

Example 3 was prepared in a manner similar to example 2 ES/MS caicd for C₅₇H₇₈NO₁₂P 999 5, found m/z = 1000 5 (M+H)

Examples 4-6

The following compounds may be made using the general techniques described herein and methods analogous to those employed for making Examples 1 and 2.

Example 7: Method for Evaluating Stability of Compounds of the Invention and Metabolites thereof 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. (Hicksvilie, NY). Lungs are weighed and homogenized in a 1 :3 w/v ratio with sterile phosphate buffered saline (PBS, 1OmM, 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 and Metabolites thereof in rat lung homogenate

Compounds are incubated with active or heat-inactivated rat lung homogenate in 1OmM PBS (pH 7.4). Heat-inactivation is achieved by incubation at 80°C 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 37°C water bath. The metabolism reactions are initiated by the addition of stock solutions of compounds of the invention and their metabolites 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 glyburide 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 30 min and 120 min incubation at 37⁰C, 100 μL aliquots are added to 400 μL quenching solution. Denatured proteins in the quenching solution are separated by centrifugation at 3000 x gravity for 2 min at 4°C, and 160 μL of the supematants are transferred to new 96-weil piate 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 4⁰C. 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 elution and separation. Samples are maintained at 4⁰C 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 eiuted 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% acetonitriie in 10 mM ammonium formate with 1 % formic acid. The HPLC elution program used to elute the analytes is as follows:

Time Step Comments Flow Rate Mobile Mobile

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

90 Sample Loading 0.50 100 0

150 Ramp 0.50 50 50

180 Elution 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 foϋows: Capillary

Ion Source Spray Sheath gas Aux gas temperature

Source CID (V) voltage (V) pressure (Arb) pressure (Arb)

(⁰C)

ESI + 10 4000 40 15 350

Data 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 compounds of the invention and their metabolites are evaluated by linear regression analysis. The data represent the mean percent remaining compound in both types of homogenate at 2 hours, 37°C and the value for mean concentration remaining of the parent compound and steroid at 2 h, 37⁰C.

Example 8: Pharmacokinetic Analysis of Drug Levels of Beta-agonist, Steroid and Compounds of the Invention Conducted in Lung, Bronchoalveolar Lavage

Fluid and Plasma After IT Administration in the Rat

Dosing

Compounds of the invention are formulated for intratracheal (IT) 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-Dawley rats. At dosing, the animals are weighed. The animals are fasted overnight prior to dose administration and up to 2 h after dosing. The compounds are administered IT using a Penn Century Microsprayer (Model 1A-

1 B).

Sample Collection and Analysis A. Plasma Blood samples are collected at 0.5, 2, and 4 h 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 until shipped for analysis. 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 cell 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 -70⁰C 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 internal standard. After the protein precipitation, an aliquot of 100 μL of the supernatant is transferred to a clean 96-well plate and mixed with 100 μL of water. An aliquot of 30 μL 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 ThermoHypersiS (Part #: 22105-032130) is used. Mobile phase A contains 1 % ACN in 10 mM ammonium formate aqueous solution with 1 % formic acid. Mobile phase B contains 80% ACN 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 Pa! autosampler from LEAP Technologies, Carrboro, NC is used.

HPLC elution program:

Time (sec) Step Comments Flow Rate Mobile Phase Mobile Phase

(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

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 file: ESI_tune112807_BL.

Mass spectrometry parameters:

Results

The results will demonstrate whether the compounds of the invention are metabolized to beta-agonist and steroid 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 beta-agonist and steroid. Example 9: Drug Metabolism Studies Using Airway Epithelial Cells Cultured at an Air-Liquid interface

Cryopreserved passage 1 ceils are cultured in bronchial epithelial growth medium (Fulcher, M. L., et al., 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 (Millipore, Bedford, MA) in medium that supports growth at an air-liquid-interface (ALi) (Fulcher et al., 2005). Cells are maintained at an AL! 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 (PBS, 1OmM, pH 7.4) and the basolatera! 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 μl of the resulting 40 μM solution is immediately added to the apicai 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 millicell 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 cell culture insert are pooled. The entire basolateral medium from each milliceli cell culture insert is also collected as are the airway epithelial cells which are excised from each millicell 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 cell suspension is then centrifuged at 18,000 g for 2 min and 50 μl of the supernatant is added to 200 μl of acetonitrile containing 100 ng ml^"1 glyburide. 50 μl of the pooled apical washes and basoiatera! medium is also added to 200 μl of ACN containing 100 ng ml^"1 giyburide. These samples are then frozen on dry ice and kept at -80 ⁰C for their analysts 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, basolateral 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 Agilent 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 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 % ACN in 10 mM ammonium formate aqueous solution with 1 % formic acid. Mobile phase B contains 80% ACN in 10 mM ammonium formate with 1 % formic acid. The HPLC elution program used to elute the analytes is as follows:

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

Eleven-point standard curves for each test compound are prepared and analyzed in heat-inactivated lung homogenate, the concentration ranged from 1 nM to 10 μM. The calibration curves of the compounds of the invention and their metabolites are prepared by quadratic regression analysis.

The results indicate the amount of each of 1 ) the parent compound of the invention, 2) beta-agonist and 3) steroid in the apicai 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 beta-agonist and steroid will increase in the cellular compartment. Example 1 gives the expected breakdown

Example 10: In vivo Efficacy of Compound of the Invention in the Mouse Ovalbumin Model of Lung inflammation

Mice (Balb/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 (Vehicle). Steroid (positive contro! 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. Bronchoalveoiar lavage (BAL) is taken from each animal to collect cells and fluid. Cell numbers and differentials were calculated from BAL.

Example 11 : LPS-lnduced Airway Inflammation in Rats

Compound of the invention is evaluated in an LPS-induced airway inflammation mode! 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 min at 5 mg/m³, resulting in an estimated 5 μg lung deposition. Animals are sacrificed 4 h 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 will inhibit LPS-induced airway inflammation measured as neutrophil influx and TNFα production at doses tested (p<-0.05 versus vehicle control).

Example 12: Tobacco Smoke Model of Airway inflammation in Mice Compounds of the invention may be evaluated in a tobacco-smoke-induced airway inflammation mode! in female C3H mice. Vehicle and test compounds are delivered by intratracheal instiliation in 10% ethanoi:water 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 H 1000 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 bronchoalveoiar lavage fluid is obtained for cell differentials and cytokine analysis by Luminex multiplex immunoassay. 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-1α and IVlIP-I α production (p<0.05 versus vehicle controi at 1.0 and 0.6 mg/kg doses).

Example 13: 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 tidal volume are measured using a differential pressure transducer located in front of the endotracheal tube. An esophageal bailoon catheter placed in the esophagus is used to determine transpulmonary pressure. Pulmonary resistance and dynamic Sung compliance are calculated from the simultaneous measurement of transpuimonary 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 min 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 pulmonary 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 14: Ascaris suum-mάuceά 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 Serebriakov, 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 h 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 h 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 h before antigen. In the duration of action regimen, animals are dosed once daily for four days, with the last dose administered 24 h 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 steroid.

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.

Example 15: Carbachol-induced bronchoconstriction in sheep The compounds of the invention may be assessed for inhibition of carbachol- induced bronchoconstriction as previously described (Abraham, W. M., A. Ahmed, I Serebrlakov, A.N. Carmillo, J. Ferrant, A.R. de Fougerolies, E.A. Garber, P. J. Gowals, V.E. Koteliansky, F. Taylor, R. R. Lobb. Am. J. Respir. Crit. 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 carbachoi are administered by nebulized aerosol to intubated sheep.

Using the predosing regimen, inhibition of carbachof-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.

Exampie 16: Pharmaceutical Formulations:

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

500 μg 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 Frieslandfoods 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. pMD! Liquid Suspension or Liquid Solution Formulation Target Unit Dose: 250 μg of micronized API

150 μl of propellant (e.g., HFA 134a or 227) Each canister is to contain 120 dose equivalents of API and propellant + 10% overage. Each canister is filled with 33 mg of API and sealed with a metering valve. The canister is then pressurized with 19.8 mi_ of propellant.

Claims

That Which Is Claimed Is:

1. A compound of Formula !:

or £ 3 pharmaceutically acceptable salt thereof, wherein:

_R15 j

R¹ I i« R¹⁰ a anndd

r of R⁶ and R⁷ is OH and the other is H; or R⁶ and R⁷ taken together with the carbon to which they are attached form a >C=O group; or

R⁷ is

R⁶ is H, and R¹ is CH₂-OH, CH₂-Ci,

CH2-O-C(O)C_1-4a!kyl, S-C_1-4alkyi, S-haloC_1-4alkyl, or CH₂-O-PO₃H₂; wherein,

R¹⁰ is H or Ci_-4alkyl;

R¹⁵ is a side chain radical of a β-agonist; R¹⁶ Ss H, methyl or ethyl;

R¹⁹ is H, F, OH or methyl; each R², R³, R⁴, and R⁵ are independently H, C-^alkyl or halo; R⁸ is H, OH, 0(CO)R⁹, or 0(CO)OR⁹; each R⁹ is independently C-i_-4alkyi; R¹¹ is H or d.₄alkyl; R¹² is H, OH, or C_1-4alkyl; 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 formuia B:

wherein one of R¹³ and R¹⁴ is H, methyl or ethyl and the other is H, C-_Moalky!, C₂-ioalkenyl, C_2-ioalkynyl, optionally substituted C_3-iocarbocyc!yi or optionally substituted 5-6 ring atom heterocycle wherein one or two ring atoms are selected from N, O and S, and wherein said carbocyclyl and said heterocyclyl are each optionally substituted 1 , 2 or 3 times with a substituent selected from halo, Ci_-4alkyl, and O~Ci-₄alkyl.

2. The compound according to Claim 1 or a pharmaceutically acceptable

salt thereof wherein R¹ is

and one of R⁶ and R⁷ is

OH and the other is H; or R⁶ and R⁷ taken together with the carbon to which they are attached form a >C=O group.

3. The compound according to any Claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R⁶ is H and R⁷ is OH.

4. The compound according to Claim 1 or a pharmaceutically acceptable

salt thereof wherein R⁷ is

R⁶ j_s H, and R¹ is CH₂-

OH, CH₂-Ci, CH₂-O-C(O)C₁.₄alkyl, S-C_1-4a!kyl, S-haloC_1-4a!kyi, or CH₂-O- PO₃H₂.

5. The compound according to any of Claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R², R³, R⁴, and R⁵ are independently H, methyl, F or CL

6. The compound according to any of Claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R², R³, R⁴, and R⁵ are H.

7. The compound according to any of Claims 1-6 or a pharmaceutically acceptable salt thereof, wherein R¹⁰ and R¹¹ are H.

8. The compound according to any of Claims 1-7 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:

9. The compound according to any of Claims 1-8 or a pharmaceutically acceptable sait 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, CrC-joalkyi, or C₃-C-_I ocarbocycie.

10. The compound according to any of Ciaims 1 -9 or a pharmaceutically acceptable salt thereof, wherein R², R³, R⁴, R⁵, R⁶, R⁸, R¹¹, R¹², R¹³, and R¹⁴ are defined as

1 1. The compound according to claim any of claims 1 -10 or a pharmaceuticaily acceptable salt thereof wherein R¹⁵ is d-βalkyl;

Ce-iocarbocycle optionally substituted 1 or 2 times with halo, C_halky!, O-d^alkyl, O-(CH₂)₄-NH_2J O-(CH₂)₄-N(H)C_{1 -4}alkyl,

0-{CH₂)₄-N(C_1-4alkyl)2, O-C_1-4alkyl-C(O)-NH₂, O-d.₄alkyl-C(O)-N(H)C_1-4alkyl, O-d.₄alkyl-C(O)-N(Ci_-4alkyl)₂, or a group represented by formula i, ii, iii, iv, v, vi, vii, viii, or ix: i: C₆alkylene-O-R²¹-Ph⁴; ii: C₂.₃aikylene-Ph¹-O-R²¹-Ph⁴; iii: C_2-3alkylene-Ph¹-N(H)-R²²-Ph²; iv: C_2-3alkylene-Het-(R²³)-Ph³; v: C_2-3aikylene-Ph¹-C₀-2alkyiene-C(O)N(H)-C_1-4alky[ene-Ph³; vi: C^alkylene-Ph³; vii: C2-₃alkylene-S(O)₂-C₂.₄alkyiene-O-C_2-4alkylene-Ph³; viii: C_3-6alkylene-Ph¹-Co-2aikylene-C(0)N(H)-C₁o_-12 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, SO₂NH₂ or S-cyciopentyi, Ph¹ is phenyiene; R²² is a bond or Ci_-2alkylene optionaliy substituted once by OH or NH₂;

Ph² is phenyl optionaliy substituted 1 or 2 times by O-methyl, -OCH₂CH(CHa)₂CH₂NH₂, -SO₂-NH-(C₆H₃)(CH₃)(C₇H₁₅) or

Het is 4-10 ring atom heterocyclene wherein 1 , 2 or 3 ring atoms is/are N₁ O or S optionally substituted once by methyl;

R²³ is a C_2-4alkylene 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- methyi.

12. The compound according to any of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is C_halky!.

13. The compound according to any of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a Ce-iocarbocycle optionally substituted 1 or 2 times with C_halky!, O-C^alkyl, or O-Ci_-4alkyi-C(O)-NH₂.

14. The compound according to any of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a group represented by formuia i: Cealkylene-O-R^-Ph⁴, wherein R²¹ is C₄alkylene and Ph⁴ is unsubstituted phenyl.

15. The compound according to any of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a group represented by formula ii: C_2-3alkylene-Ph¹-O-R²¹-Ph⁴, wherein R²¹ is C₄alkylene wherein one C is optionally replaced by O and Ph⁴ is unsubstituted phenyl.

16. The compound according to any of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a group represented by formula iii: C₂-₃alkylene-Ph¹-N(H)-R²²-Ph², wherein R²² is a bond or C₂alkylene substituted once by OH or NH, Ph² is pheny! optionally substituted once by O-methy! or -OCH₂CH(CHa)₂CH₂NH₂.

17. The compound according to any of claims 1-11 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 S, 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.

18. The compound according to any of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a group represented by formula v: C^alkylene-Ph^Co^alkylene-CfOJNtHJ-d^alkylene-Ph³, wherein Ph³ is phenyl substituted twice by halo or O-methyl.

19. The compound according to any of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a group represented by formula vi: C₂.

₃a!kylene-Ph³, wherein Ph³ is phenyl substituted once by O-methyi.

20. The compound according to any of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a group selected from

wherein the wavy bond indicates the point of attachment.

21. The compound according to any of Claims 1 -20 or a pharmaceutically acceptable salt thereof wherein R¹⁶ is H.

22. The compound according to any of Claims 1-21 or a pharmaceutically acceptable salt thereof wherein R¹⁹ is OH.

23. The compound according to any of Claims 1-22 or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ii;

wherein all variables are defined as in any of Claims 1-22.

24, The compound according to any of claims 1-22 or a pharmaceutically acceptable salt thereof, which is a compound of Formula HI:

wherein all variables are defined as in any of Claims 1-22.

25. A composition comprising a compound according to any one of claims 1- 24 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent or carrier.

26. The composition according to Claim 25, wherein said composition is suitable for inhalation,

27. The composition according to any of Claims 25-26, wherein said excipient, diluent or carrier is water, saline or lactose.

28. The composition according to any of claims 25-27, wherein said composition is a solution for aerosolization and administration by nebulizer.

29. The composition according to any of claims 25-27, wherein said composition is suitable for administration by metered dose inhaler.

30. The composition according to any of claims 25-27 wherein said composition is a dry powder.

31. The composition according to any of claims 25-32 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

32. The composition according to Claim 33, wherein said therapeutically active agent is a corticosteroid.

33. A method comprising administering to a human, an effective amount of a compound according to any of Claims 1-24 or a pharmaceutically acceptable salt thereof.

34. 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 Ciaims 1- 24 or a pharmaceutically acceptable salt thereof.

35. 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 1-24 or a pharmaceutically acceptable salt thereof.

36. 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 1-24 or a pharmaceutically acceptable salt thereof.

37. 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 1-24 or a pharmaceutically acceptable salt thereof,

38. 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 1-24 or a pharmaceutically acceptable salt thereof.

39. 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 Ciaims 1-24 or a pharmaceutically acceptable sait thereof.

40. A compound according to any of claims 1-24 for use as a medicament.

41. A compound according to any of claims 1-24 for use in the treatment of pulmonary inflammation or bronchoconstriction in a human.

42. A compound according to any of claims 1-24 for use in the treatment of a disease associated with reversible airway obstruction, asthma, COPD, bronchiectasis, or emphysema in a human.

43. A compound according to any of claims 1-24 for use in the treatment of asthma or COPD in a human.

44. The use of a compound according to any one of claims 1-24 for the manufacture of a medicament for the treatment of pulmonary inflammation or bronchoconstriction in a human.

45. The use of a compound according to any one of claims 1-24 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.

46. A composition comprising a compound according to any one of claims 1 - 24 for use in the preparation of a medicament for the treatment of pulmonary inflammation or bronchoconstriction in a human.

47. A composition comprising a compound according to any one of claims 1- 24 for use in the preparation of a medicament for the treatment of reversible airway obstruction, asthma, COPD, bronchiectasis, or emphysema in a human.