WO2010059836A1 - Substituted aza-bridged bicyclics for cardiovascular and cns disease - Google Patents

Abstract

The invention relates to substituted imidazopyridines, pyrazolotriazinones, triazolopyridines, pyrazolopyridines and pyrazolopyrimidines that are useful for treating stroke, myocardial infarct, and cardiovascular inflammatory conditions, to pharmaceutical compositions comprising these compounds, and to methods for the treatment of stroke, myocardial infarct, and cardiovascular inflammatory conditions in a mammal. The compounds have general formula I (I) or II (II) in which Cy¹ and Cy² are carbocycles or heterocycles.

Description

SUBSTITUTED AZA-BRIDGED BICYCLICS FOR CARDIOVASCULAR AND CNS

DISEASE

Cross-Reference to Related Applications

[0001] This application claims the priority of US provisional application 61/116,569, filed

November 20, 2008, the entire contents of which are incorporated herein by reference.

Field of the Invention

[0002] The invention relates to substituted imidazopyridines, pyrazolotriazinones, triazolopyridines, pyrazolopyridines and pyrazolopyrimidines that are useful for treating stroke, myocardial infarct, and cardiovascular inflammatory conditions, to pharmaceutical compositions comprising these compounds, and to methods for the treatment of stroke, myocardial infarct, and cardiovascular inflammatory conditions in a mammal.

Background of the Invention

[0003] PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells. PDE4 inhibitors have proven potential as anti-inflammatory drugs, especially in inflammatory pulmonary diseases such as asthma, COPD and rhinitis. They suppress the release of cytokines and other inflammatory signals and inhibit the production of reactive oxygen species. A large number of PDE4 inhibitors have been developed for a variety of clinical indications (Torphy and Page. 2000. TIPS 21, 157-159; Burnouf and Pruniaux. 2002. Curr. Pharm. Design 8, 1255-1296; Lipworth. 2005. Lancet 365, 167-175). To quote from a recent article in the British Journal of Pharmacology, "PDE4 inhibitors have been in development as a novel anti- inflammatory therapy since the 1980s with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, none have yet reached the market. In most cases, the development of PDE4 inhibitors of various structural classes, including cilomilast, filaminast, lirimilast, piclamilast, tofimilast has been discontinued due to lack of efficacy. A primary problem is the low therapeutic ratio of these compounds, which severely limits the dose that can be given. Indeed, for many of these compounds it is likely that the maximum tolerated dose is either sub-therapeutic or at the very bottom of the efficacy dose-response curve. Therefore, the challenge is to overcome this limitation." [Giembycz, Brit.J.Pharmacol. 155, 288-290 (2008)]. Many of the PDE4 inhibitors of the prior art have not reached the market because of the adverse side effect of emesis (Giembycz 2005. Curr. Opin. Pharm. 5, 238-244). Analysis of all known PDE4 inhibitors suggests that they are competitive with cAMP and bind within the active site (Houslay et al. 2005. DDT 10, 1503-1519); this may explain their narrow therapeutic ratio. The compounds of the present invention are non-competitive inhibitors of cAMP while being gene- specific inhibitors (PDE4D), and, based on the target rationale and in vitro potency, a person of skill in the art would expect the compounds to be useful as anti- inflammatory agents for the treatment, amelioration or prevention of inflammatory diseases and of complications arising therefrom.

Description of the Invention

[0004] There is provided, in accordance with an embodiment of the invention, a compound of formula I or formula II:

wherein

P is chosen from nitrogen and carbon;

Q is chosen from nitrogen and carbon, with the provisos that one of P or Q must be nitrogen, but P and Q cannot both be nitrogen;

R¹ is selected from hydrogen, (Ci-C₆) alkyl, haloalkyl, -CONHR⁵, lower alkoxy, alkylamino, dialkylamino, amino, -NHCOOR₂ and -OCONH₂;

W is nitrogen or CR²; R² is selected from hydrogen, (Ci-C₆) alkyl, haloalkyl and optionally substituted heterocyclyl;

Y is CR³ or nitrogen;

R³ is selected from hydrogen, fluoro, hydroxyl and -OR¹⁰;

R¹⁰ is selected from (Ci-C₆) alkyl optionally substituted with fluoro;

X is selected from CR⁴, nitrogen and N⁺ O^";

R⁴ is selected from hydrogen, (Ci-C₆) alkyl, halogen, amino, alkoxy and hydroxyl;

R⁵ is selected from hydrogen and (Ci-C₆) alkyl;

R⁸ and R⁹ are independently selected from hydrogen, (Ci-C₆) alkyl, (Ci-C₆) hydroxyalkyl, (Cs-C₆) carbocyclyl and a 3- to 6-membered heterocyclyl; or R⁸ and R⁹ together form a 4-6 membered ring which optionally contains a heteroatom selected from -O-, -NR⁵ and S(O)_0-2; or R⁸ and R⁹ together form an oxo group;

Z is selected from -O-, -S(O)_0-2, -NH-, -CH₂- and a direct bond;

Cy¹ is selected from optionally substituted (Cs-C₆) carbocyclyl and optionally substituted heterocyclyl;

Cy² is selected from optionally substituted aryl and optionally substituted heteroaryl; and

M is chosen from -CH₂-, -CH₂CH₂-, -O-, -S(O)_0-2, -OCH₂, -CH₂O, -CONH, -CONHCH₂, -NHCO and -NHSO₂.

[0005] There is also provided, in accordance with embodiments of the invention, a pharmaceutical composition comprising a compound as described herein, and a pharmaceutically acceptable carrier, excipient or diluent therefore.

[0006] In a third aspect, the invention relates to methods for the treatment or prophylaxis of a disease or condition mediated by phosphodiesterase-4. The methods comprise administering to a mammal a therapeutically effective amount of a compound having the general formula of formula I or II above. The disease or condition may be related to allergic, acute or chronic inflammation. The disease may be, for example, atherosclerosis, thrombosis, stroke, acute coronary syndrome, stable angina, peripheral vascular disease, critical leg ischemia, intermittent claudication, abdominal aortic aneurysm or myocardial infarction. [0007] Selective PDE4 inhibitors of the invention are useful in improving cognition and thus useful for treating learning disorders, memory loss and other cognitive dysfunctions. Selective PDE4 inhibitors of the invention are also useful for treating asthma and Chronic Obstructive Pulmonary Disease (COPD). Compounds of the invention, which inhibit tumor growth and metastases, also find utility in the treatment and prevention of cancer, including esophageal cancer, brain cancer, pancreatic cancer, and colon cancer.

[0008] Selective PDE4 inhibitors of the invention are also thought to be useful for treating or preventing schizophrenia or Huntington's disease, bone loss, depression, anxiety, bladder inflammation, bladder pain and bladder overactivity.

[0009] These and other embodiments of the present invention will become apparent in conjunction with the description and claims that follow.

Detailed Description of the Invention

[0010] The invention relates to compounds of formula I or formula II

as described above.

[0011] In accordance with some embodiments of the invention, P is nitrogen and Q is carbon. In accordance with other embodiments, Y is CR³. In further embodiments, X is CR⁴. In other embodiments, X is nitrogen. In still other embodiments, W is CR². In yet other embodiments, W is nitrogen. [0012] In accordance with some embodiments of the invention, P is carbon and Q is nitrogen. In accordance with other embodiments, W is CR². In further embodiments, X is CR⁴. In other embodiments, X is nitrogen. In still other embodiments, Y is CR . In yet other embodiments, Y is nitrogen.

[0013] In accordance with some embodiments of the invention, in compounds of formula II, P is carbon and Q is nitrogen. In further embodiments, W can be nitrogen. In still other embodiments, W is CR². Examples of "cores" include imidazolopyridines, triazolopyridines, pyrazolotriazinones and imidazolopyrazines:

. Other examples include pyrazolopyridines and pyrazolopyrimidines:

and

[0014] In accordance with some embodiments, R² is selected from hydrogen and (Ci-C₆) alkyl, and in some embodiments, R² is hydrogen. In further embodiments, X is CR⁴. In other embodiments, X is nitrogen. In further embodiments, R¹ is selected from hydrogen and (Ci-C₆) alkyl. In some embodiments, R¹ is methyl. In other embodiments Z is a direct bond. In yet other embodiments, Z is selected from -O- and -S(O)_0-2. In further embodiments, Z is -CH₂-. In still other embodiments, Cy ^l is selected from optionally substituted aryl and heteroaryl. In further embodiments, Cy² is selected from optionally substituted aryl and heteroaryl. In yet other embodiments, Cy¹ and Cy² are both optionally substituted phenyl. In accordance with other embodiments, R⁸ and R⁹ are each independently selected from hydrogen and (Ci-C₆) alkyl. In further embodiments, R⁸ and R⁹ together form an oxo group. In still other embodiments, R⁸ and R⁹ together form a 4-6 membered ring, and this ring may optionally contain a heteroatom. In one embodiment, this heteroatom may be oxygen. In another embodiment, the heteroatom may be NR⁵. In still other embodiments, the heteroatom may be -S-, -S(O)- or -S(O)₂-.

[0015] In accordance with some embodiments of the invention, Z is a direct bond. In other embodiments, M is -CH₂-. In still other embodiments, M is -CONH-. In yet other embodiments, Cy¹ is selected from optionally substituted aryl and an optionally substituted 5- or 6-membered ring nitrogen heterocycle. In accordance with some embodiments, Cy¹ is selected from optionally substituted phenyl and an optionally substituted 5- or 6-membered ring nitrogen heterocycle. In still other embodiments, Cy¹ is selected from optionally substituted phenyl, pyridinyl, morpholin-4-yl, piperazin-1-yl, piperidiny-1-yl, imidazol-1-yl, pyrazol-1-yl, and pyrazol-5-yl. In further embodiments, Cy² is selected from optionally substituted phenyl and an optionally substituted 5- or 6-membered ring nitrogen heterocycle. Yet other embodiments include compounds in which Cy² is selected from phenyl, 3-chlorophenyl, 3-nitrophenyl, 3- bromophenyl, 3-acetylphenyl, 3-trichloromethylphenyl and 3-methylthiophenyl. In some embodiments, Cy² is selected from phenyl and 3-chlorophenyl.

[0016] Yet other embodiments include compounds in which Cy¹ is selected from phenyl and pyridinyl, each of which is optionally substituted with a substituent chosen from (1) hydrogen, halogen, halo alky 1, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxy alky It hio, alkoxycarbonylaminoalkyl, carboxy alky lcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, amino carbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylamino alkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, -NHC(=O)NHalkyl, -NHC(=O)NH-heterocyclyl, -alkyl-NHC(=O)N(alkyl)2, heterocyclylalkylcarbonylamino, benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid amides, protected residues of aminoacids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides and (2) phenyl and monocyclic heterocycle substituted with any of the foregoing.

[0017] In accordance with some embodiments of the invention, Cy¹ is selected from phenyl and pyridinyl, each of which is optionally substituted with a substituent chosen from -CH₃, -CH₂CF₃, -CF₃, -CHO, -COOH, -CN, halogen, -OH, , -OEt, -C(K))NH₂, -C(K))NHEt, -C(K))NMe₂ -COOCH3, -COOEt, -CH₂NHC(K))NH₂, -CH(CH₃)NHC(K))NH₂, -CH₂NHC(K))H, -CH₂NHC(K))CH₃, -CH₂C(K))NH₂, -CH₂COOH, -CH₂COOEt, -CH₂NHC(K))OEt, -CH₂NHC(K))O-C₆H₅, -CH₂NHC(O)C(O)NH₂, -CH₂NHC(O)NHEt, -C(CH₃)₂OH, -CH₂NHC(O)N(CHs)₂, -CH₂NHC(O)NHCH₃, -CH₂NH₂, -CH(CH₃)NH₂, -C(CH₃)₂NH₂, -CH₂OH, -CH₂CH₂OH, -CH₂NHSO₂CH₃, -CH₂OC(O)NHEt, -OCH₃, -OC(O)NH₂, -OCH₂CH₂N(CH₃)₂, -OCH₂CH₂OCH₃, -OCH(CH₃)COOH, -SCH₂COOH, -NHC(O)NH₂, -NHC(=O)NHEt, -NHCH₃, -NHEt, -NH(tBoc), -NHCH₂COOH, -N(CH₃)CH₂COOH, -NHC(=O)NHCH₂CH₂C1, -NHSO₂NH₂, -NHEt, -N(CH₃)₂, -NH₂, , -NH(CH₃)C(=O)NH₂, - NHSO₂CH₃, -N(SO₂CH₃)₂, -NHC(=0)0CH₃, -NHC(=O)OtBu, -NHC(=O)CH₃, -SO₂NH₂, -NHC(=O)CH₂CH₂COOH, -NHC(=0)NHCH₂C00H, -CH₂NHCHO, -NHC(=O)NHCH₂COOEt, -NHC(=O)NH(CH₂)₃COOEt, -NHC(=O)NH(CH₂)₂COOEt, -N(CH₃)CH₂CH₂OH, -NHC(=O)OEt, -N(Et)C(=O)OEt, -NHC(=O)NH(CH₂)₂COOH, -NHC(=O)CH₂N(CH₃)₂, -NHC(=O)NH(CH₂)₃COOH, -NHC(=O)CH₂NH₂, -NHC(=O)CH₂CH₂NH₂,

, and . In some embodiments, Cy¹ is selected from phenyl and pyridinyl, each of which is substituted with a monocyclic heterocycle, and the monocyclic heterocycle is optionally substituted with a substituent chosen from the foregoing list. An example of the embodiment in which Cy¹ is a pyridinyl substituted with a monocyclic heterocycle substituted with a carboxylic acid is found in example D-25 below:

. Exemplary carboxyalkoxy and carboxyalkylthio are lactic acid and thioglycollic acid respectively. Exemplary amino acids are glycine, alanine and proline. [0018] In accordance with some embodiments of the invention, W is CR and R is selected from

H₃C

hydrogen, methyl, -∞JΛW and

. In other embodiments, R > 2 is

J is selected from O, S, S(O), SO₂, NH and NCH₃ and L is C or N. In some of these embodiments, R² is hydrogen.

[0019] In accordance with some embodiments of the invention, R⁴ is hydrogen. In other embodiments, R³ is hydrogen.

[0020] In some embodiments of the invention, R¹ is selected from hydrogen and (Ci-C₆) alkyl. In some of these compounds, R¹ is methyl. In other embodiments, X is CH. In yet other embodiments, X is CF. Still other embodiments include compounds in which Cy ^l is selected from optionally substituted phenyl, pyridinyl, morpholin-4-yl, piperazin-1-yl, piperidiny-1-yl, imidazol-1-yl, pyrazol-1-yl, and pyrazol-5-yl. In other embodiments of the invention, Cy¹ is phenyl optionally substituted with a substituent selected from amino, urea, alkylurea, -

NHCO₂(C i-C₆)alkyl, azeditine acid, azeditine amide,

_and J_n further embodiments, Cy² is optionally substituted phenyl. In yet other embodiments, Z is a direct bond. In some embodiments, M is -CH₂-.

[0021] In accordance with some embodiments of the invention, R¹ is selected from hydrogen and (Ci-C₆) alkyl; X is CH; Cy ¹ is selected from optionally substituted phenyl, pyridinyl, morpholin- 4-yl, piperazin-1-yl, piperidiny-1-yl, imidazol-1-yl, pyrazol-1-yl, and pyrazol-5-yl; Cy² is optionally substituted phenyl; Z is a direct bond; and M is -CH₂-. [0022] In accordance with some embodiments of the invention, the compounds are of formula (A)

wherein

Cy¹ is selected from optionally substituted (Cs-C₆) carbocyclyl and optionally substituted heterocyclyl;

Cy² is selected from optionally substituted aryl and optionally substituted heteroaryl;

R¹ is selected from hydrogen, (Ci-C₆) alkyl, haloalkyl, -CONHR⁵, lower alkoxy, alkylamino, dialkylamino, amino, -NHCOOR₂ and -OCONH₂;

R² is selected from hydrogen, (Ci-C₆) alkyl, haloalkyl and optionally substituted heterocyclyl;

R³ is selected from hydrogen, fluoro, hydroxyl and -OR¹⁰;

R¹⁰ is selected from (Ci-C₆) alkyl optionally substituted with fluoro;

R⁴ is selected from hydrogen, (Ci-C₆) alkyl, halogen, amino, alkoxy and hydroxyl; and

M is chosen from -CH₂-, -CH₂CH₂-, -O-, -S(O)_0-2, -OCH₂, -CH₂O, -CONH, -CONHCH₂, -

NHCO and -NHSO₂.

[0023] In some embodiments, Cy ^l is selected from optionally substituted phenyl, pyridinyl, morpholinyl, piperazinyl, piperidinyl, imidazolyl, pyrazolyl, oxazolidinyl, pyrrolidinyl, thiazolyl and benzo[c][l,2,5]oxadiazolyl.

[0024] In further embodiments of the invention, the compounds are of formula (A) wherein

Cy¹ is selected from optionally substituted aryl and an optionally substituted 5- or 6-membered ring nitrogen heterocycle;

Cy² is selected from optionally substituted phenyl and an optionally substituted 5- or 6- membered ring nitrogen heterocycle;

R¹ is selected from hydrogen and (Ci-C₆) alkyl; R² is selected from hydrogen, methyl,

and wherein J is selected from O, S(0)o-2, NH and NCH₃ and L is selected from C and N; R³ is hydrogen; R⁴ is hydrogen; and M is -CH₂-.

[0025] In yet other embodiments of the invention, the compounds are of formula (A) wherein Cy¹ is selected from phenyl and pyridinyl, each of which is optionally substituted with a substituent chosen from halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, carboxy alky lcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfϊnyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, amino sulfonyl, trityl, amidino, guanidino, ureido, -NHC(=O)NHalkyl, -NHC(=O)NH-heterocyclyl, -alkyl-NHC(=O)N(alkyl)₂, heterocyclylalkylcarbonylamino, benzyloxyphenyl, benzyloxy, azetidine acid, azedtidine amide, the residues of amino acids, amino acid amides, protected residues of aminoacids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides.

[0026] In still other embodiments, Cy¹ is selected from phenyl and pyridinyl, each of which is optionally substituted with a substituent chosen from -CH₃, -CH₂CF₃, -CF₃, -CHO, -COOH, -CN, halogen, -OH, , -OEt, -C(K))NH₂, -C(K))NHEt, -C(O)NMe₂ -COOCH₃, -COOEt, -CH₂NHC(=O)NH₂, -CH(CH₃)NHC(=O)NH₂, -CH₂NHC(=O)H, -CH₂NHC(=O)CH₃, -CH₂C(=O)NH₂, -CH₂COOH, -CH₂COOEt, -CH₂NHC(=O)OEt, -CH₂NHC(=O)O-C₆H₅, -CH₂NHC(=O)C(=O)NH₂, -CH₂NHC(=O)NHEt, -C(CH₃)₂OH, -CH₂NHC(=O)N(CH₃)₂, -CH₂NHC(=O)NHCH₃, -CH₂NH₂, -CH(CH₃)NH₂, -C(CH₃)₂NH₂, -CH₂OH, -CH₂CH₂OH, -CH₂NHSO₂CH₃, -CH₂0C(=0)NHEt, -OCH₃, -0C(=0)NH₂, -OCH₂CH₂N(CH₃)₂, -OCH₂CH₂OCH₃, -OCH(CH₃)COOH, -SCH₂COOH, -NHC(=0)NH₂, -NHC(=0)NHEt, -NHCH₃, -NHEt, -NH(tBoc), -NHCH₂COOH, -N(CH₃)CH₂COOH, -NHC(=O)NHCH₂CH₂C1, -NHSO₂NH₂, -NHEt, -N(CH₃)₂, -NH₂, , -NH(CH₃)C(=O)NH₂, -NHSO₂CH₃, -N(SO₂CH₃)₂, -NHC(=0)0CH₃, -NHC(=O)OtBu, -NHC(=O)CH₃, -SO₂NH₂, -NHC(=O)CH₂CH₂COOH, -NHC(=0)NHCH₂C00H, -CH₂NHCHO, -NHC(=O)NHCH₂COOEt, -NHC(=O)NH(CH₂)₃COOEt, -NHC(=O)NH(CH₂)₂COOEt, -N(CH₃)CH₂CH₂OH, -NHC(=O)OEt, -N(Et)C(=O)OEt, -NHC(=O)NH(CH₂)₂COOH, -NHC(=O)CH₂N(CH₃)₂, -NHC(=O)NH(CH₂)₃COOH, -NHC(=O)CH₂NH₂, -NHC(=O)CH₂CH₂NH₂,

-NHC(=O)CH₂NH(tBoc),

[0027] In further embodiments of the invention, Cy² is selected from phenyl and 3-chlorophenyl.

[0028] In some embodiments of the invention, the compound is selected from the following (Table 1): [0029] Table 1.

[0030] In other embodiments of the invention, the compound is represented by the following (Table 2): [0031] Table 2.

[0032] All of the compounds falling within the foregoing parent genus I and its subgenera are useful as PDE4 inhibitors. It may be found upon examination that species and genera not presently excluded are not patentable to the inventors in this application because of prior art. In this case, the exclusion of species and genera in applicants' claims are to be considered artifacts of patent prosecution and not reflective of the inventors' concept or description of their invention. The invention, in a composition aspect, is all active compounds of formula I and formula II except those that are in the public's possession.

[0033] PDE4 inhibitors have been shown to be effective therapeutic agents in clinical studies. For example, administration of cilomilast and roflumilast (PDE4 inhibitors) to patients suffering from asthma and COPD showed initially excellent results, although the effect of cilomilast disappeared on long-term trial [Lipworth, Lancet 365. 167-175 (2005)]. L- 454,560, a selective PDE4 inhibitor has been shown to improve learning in a rat model in vivo [Huang et al. Biochemical Pharmacology 73, 1971-1981 (2007)]. This suggests that selective PDE4 inhibitors will be useful in treating learning disorders, memory loss (e.g. Alzheimer's disease) and other cognitive dysfunctions. Selective PDE4 inhibitors (e.g. rolipram) are also useful for treating bone loss [Yao et al., J.Musculoskelet.Neuronal Interact. 7, 119-130 (2007)]. Additionally, a PDE4 inhibitor, YM976, was shown to ameliorate the effects of experimentally- induced interstitial cystitis in rats, resulting in a decrease in the frequency of urination and an increase in the volume of urine at each time of urination [Kitta et al., BJU Int. 102. 1472-1476 (2008)]. Another PDE4 inhibitor, IC485, was shown to be equally efficacious as tolteradine tartrate, a marketed drug for treating overactive bladder, in a rodent model of obstructive bladder [Kaiho et al. BJU Int. 101, 615-20 (2008)]. These findings suggest that PDE4 inhibitors will be useful in treating symptoms of bladder inflammation, such as overactivity and pain. [0034] Furthermore, the compounds, compositions and methods of the present invention are useful in treating cancer. Phosphodiesterase activity has been shown to be associated with hematological malignancies [Lerner et al., BiochemJ. 393, 21-41 (2006); Ogawa et al, Blood 99, 3390-3397 (2002)].

[0035] Throughout this specification the terms and substituents retain their definitions.

[0036] Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. A combination would be, for example, cyclopropylmethyl. When not otherwise restricted, the term refers to alkyl of 20 or fewer carbons. Lower alkyl refers to alkyl groups of 1, 2, 3, 4, 5 and 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like. Preferred alkyl and alkylene groups are those of Ci₀ or below (e.g. Ci, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, Ci₀); most preferred are lower alkyl. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of 3, 4, 5, 6, 7, and 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.

[0037] C₁ to C₂₀ Hydrocarbon (e.g. C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀) includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. The term "phenylene" refers to ortho, meta or para residues of the formulae:

Hydrocarbon refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.

[0038] Unless otherwise specified, the term "carbocycle" (or "carbocyclyl") is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state. Thus (C₃-C₁₀) carbocycle refers to such systems as cyclopropane, benzene and cyclohexene; (C₈- Ci₂) carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene. Carbocycle, not otherwise limited, refers to monocycles, bicycles and polycycles.

[0039] Alkoxy or alkoxyl refers to groups of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purposes of the present patent application alkoxy also includes methylenedioxy and ethylenedioxy in which each oxygen atom is bonded to the atom, chain or ring from which the methylenedioxy or ethylenedioxy group is pendant so as to form a ring. Thus, for example, phenyl substituted by alkoxy may be, for example,

Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9- trioxadecyl and the like. The term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 1196, but without the restriction of Tfl27(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds). It does not refer to doubly bonded oxygen, as would be found in carbonyl groups. Similarly, thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.

[0040] Acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched or cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, propionyl, isobutyryl, ϊ-butoxycarbonyl, benzoyl, benzyloxycarbonyl and the like. Lower- acyl refers to groups containing one to four carbons. The double bonded oxygen, when referred to as a substituent itself, is called "oxo". [0041] Aryl and heteroaryl refer to aromatic or heteroaromatic rings, respectively, as substituents. Aryl and heteroaryl mean (i) a phenyl group (or benzene) or a monocyclic 5- or 6-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N, or S; (ii) a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-4 heteroatoms selected from O, N, or S; or (iii) a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-5 heteroatoms selected from O, N, or S. Aromatic 6, 7, 8, 9, 10, 11, 12, 13 and 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5, 6, 7, 8, 9 and 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole. As used herein aryl refers to residues in which one or more rings are aromatic, but not all need be.

[0042] Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure through alkyl. Examples are benzyl, phenethyl and the like. This is in contradistinction to alkylaryl, in which an aryl residue is attached to the parent structure through alkyl (e.g. a p-tolyl residue). Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like. Heterocyclylalkyl refers to a substituent in which a heterocyclyl residue is attached to the parent structure through alkyl. Examples include morpholinoethyl and pyrrolidinylmethyl.

[0043] The term "heterocycle" (or "heterocyclyl") means a monocyclic, bicyclic or tricyclic residue with 1 to 13 carbon atoms and 1 to 4 heteroatoms chosen from the group consisting of nitrogen, oxygen and sulfur. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Unless otherwise specified, a heterocycle may be non-aromatic or aromatic. The heterocycle may be fused to an aromatic hydrocarbon radical. Suitable examples include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3- triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, quinolinyl, and the like. A nitrogen heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms. Examples include piperidine, piperazine, morpholine, pyrrolidine and thiomorpholine. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic; examples include pyridine, pyrrole and thiazole. Examples of heterocyclyl residues additionally include piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl and tetrahydroquinolinyl. For the purpose of the present disclosure, heteroaryl includes the corresponding oxo compounds, e.g. pyridinone, imidazolone, pyridazinone, pyrimidinone etc.

[0044] An oxygen heterocycle is a heterocycle containing at least one oxygen in the ring; it may contain additional oxygens, as well as other heteroatoms. A sulphur heterocycle is a heterocycle containing at least one sulphur in the ring; it may contain additional sulphurs, as well as other heteroatoms. A nitrogen heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms.

[0045] As used herein, the term "optionally substituted" may be used interchangeably with "unsubstituted or substituted". Substituted alkyl, aryl, cycloalkyl, heterocyclyl, etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with a specified radical. For example, substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, alkyl, haloalkyl, haloalkoxy, hydroxy, loweralkoxy (which for the purpose of the present disclosure includes methylene dioxy and ethylene dioxy), oxaalkyl, carboxy, carboalkoxy (also referred to as alkoxycarbonyl[-C(=O)O-alkyl]), carboxamido (i.e. [-C(=O)NH₂]), alkylaminocarbonyl (i.e. [-C(=O)NH-alkyl]), alkylaminocarbonylamino (i.e. [-NHC(=O)NH-alkyl]),alkoxycarbonylamino (i.e. [-NHC(=O)O-alkyl]), acyl, alkoxyalkyl, benzenesulfonyl, cyano, carbonyl, nitro, amino, hydroxyalkyl, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl (including cycloalkylaminoalkyl), dialkylaminoalkyl, dialkylaminoalkoxy, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfinyl, alkylsulfonyl, acylamino, diacylamino, acylaminoalkyl, acylaminoalkoxy, amidino, alkoxycarbonylamino, acetoxy, sulfoxide, sulfone, sulfonylamino, aryl, phenyl, heterocyclyl, hydroxyimino, alkoxyimino, aminosulfonyl, trityl, amidino, guanidino, ureido (i.e. [-NHC(=O)NH₂]), benzyloxyphenyl, benzyl, heteroaryl, heterocyclylalkyl, phenoxy, benzyloxy, or heteroaryloxy. Haloakyl refers to an alkyl group in which one or more hydrogens are replaced by halogen, for example, trifluoromethyl, trifluoromethoxy, trichloroethyl, and difluoromethyl. "Oxo" is also included among the substituents referred to in "optionally substituted"; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl). In one embodiment, 1, 2 or 3 hydrogen atoms are replaced with a specified radical. Additional substituents that are considered within the scope of the term are the are the residues of amino acids, amino acid amides, protected residues of aminoacids and their amides, and N-methylated (mono- or di-, as appropriate) amino acids and amino acid amides.

[0046] The term "a residue of an amino acid, amino acid amide", etc. refers to an amino acid etc. minus the functional groups that are considered part of the bond to the parent structure. For example, in Fragment A illustrated below:

after one subtracts the hydrogen that connects (BOC)glycinamide to the phenyl ring, the structure of A that remains is:

This is not sensu stricto a protected amino acid amide, since it lacks the hydrogen on the C-terminal amide. This and similar structures that lack atoms at the points of attachment (e.g. the OH of COOH or the H OfNH₂) are referred to herein as "residues" of their respective parents.

[0047] The term "halogen" means fluorine, chlorine, bromine or iodine. [0048] The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy, respectively, substituted with one or more halogen atoms. The terms "alkylcarbonyl" and "alkoxycarbonyl" mean -C(=O)alkyl or -C(O)alkoxy, respectively.

[0049] Substituents Rⁿ are generally defined when introduced and retain that definition throughout the specification and in all independent claims.

[0050] In the characterization of some of the substituents, it is recited that certain substituents may combine to form rings. Unless stated otherwise, it is intended that such rings may exhibit various degrees of unsaturation (from fully saturated to fully unsaturated), may include heteroatoms and may be substituted with lower alkyl or alkoxy.

[0051] The term "prodrug" refers to a compound that is made more active in vivo. Commonly the conversion of prodrug to drug occurs by enzymatic processes in the liver or blood of the mammal. Many of the compounds of the invention may be chemically modified without absorption into the systemic circulation, and in those cases, activation in vivo may come about by chemical action (as in the acid-catalyzed cleavage in the stomach) or through the intermediacy of enzymes and microflora in the gastrointestinal GI tract.

[0052] It will be recognized that the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine, iodine and chlorine include ³H, ¹⁴C, ³⁵S, ¹⁸F, ³²P, ³³P, ¹²⁵I, and ³⁶Cl, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Radiolabeled compounds described herein and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radio labeled reagent.

[0053] PDE4 inhibitors have been shown to be effective therapeutic agents in clinical studies. For example, administration of cilomilast and roflumilast (PDE4 inhibitors) to patients suffering from asthma and COPD showed initially excellent results, although the effect of cilomilast disappeared on long-term trial [Lipworth, Lancet 365, 167-175 (2005)]. L-454,560, a selective PDE4 inhibitor has been shown to improve learning in a rat model in vivo [Huang et al. Biochemical Pharmacology 73. 1971-1981 (2007)]. This suggests that selective PDE4 inhibitors will be useful in treating learning disorders, memory loss (e.g. Alzheimer's disease) and other cognitive dysfunctions. Rolipram, a selective PDE4 inhibitor has been shown to improve the outcome in two separate studies in mice in vivo in models accepted by persons of skill in the art as predictive of utility in schizophrenia [Kanes et al., Neuroscience 144. 239-246 (2007); Davis and Gould, Behav.Neurosci. 119. 595-602 (2005)]. Rolipram has also been shown to exhibit a neuroprotective effect in a rat model of Huntington's disease [DeMarch et al. Neurobiol.Dis. 25, 266-273 (2007)]. Selective PDE4 inhibitors (e.g. rolipram) are also useful for treating bone loss [Yao et al., J.Musculoskelet.Neuronal Interact. 7. 119-130 (2007)].

[0054] In addition to the foregoing studies demonstrating utility in in vivo models, a number of authors have suggested connections between PDE4 inhibition and putative utilities as antidepressants [Houslay et al., Drug Discov Today 10, 1503-1519 (2005); Polesskaya et al., BioLPsychiatr. 61, 56-64 (2007); anon. Current Opin.Invetig. Drugs 5. 34-39 (2004)] and as anxiolytics [Zhang et al., Neuropsychopharmacology Aug 15, 2007 Epub; Cherry et al., Biochim.Biophys.Acta 1518. 27-35 (2001)]. Other possible utilities may include Pick's disease and epilepsy.

[0055] Furthermore, the compounds, compositions and methods of the present invention are useful in treating cancer. Phosphodiesterase activity has been shown to be associated with hematological malignancies [Lerner et al., BiochemJ. 393. 21-41 (2006); Ogawa et al., Blood 99. 3390-3397 (2002)]. The compounds may also be administered to overcome cognitive impairment induced by one or more of the following agents, alcohol, amphetamine, antipsychotic medication, anti-retroviral therapy, MDMA ( 3,4-methylenedioxy-N- methylamphetamine, cannabis, cocaine, delta-9 tetrahydrocannabinol, dexamphetamine, haloperidol, heroin and other opiates, ketamine and metamphetamine.

[0056] Furthermore, the compounds, compositions and methods of the present invention, particularly when radiolabeled as described above or labeled by methods well-known in the art with florescent and spin labels, may be employed as imaging agents and in other ways for diagnosis and/or treatment. Moreover, immobilization of compounds of the invention on solid support could be of utility for affinity purification and modification of compounds of the invention with chemically active groups may be used for protein labeling.

[0057] For many of the utilities outlined above, it may be advantageous to administer compounds of the general formula I or formula II together with cholinesterase inhibitors (e.g. tacrine, huperzine, donepezil); NMDA antagonists (e.g. lanicemine, remacemide, neramexane, memantine); calpain inhibitors (e.g. CEP-3122); antioxidants (e.g. vitamin E, coenzyme QlO) and agents that have shown clinical efficacy but whose mechanism is unclear (e.g. dimebon). Compounds of formula I or formula II may also be administered together with one or more of the following agents to improve cognition: amisulpride, atomoxetine, bromocryptine, buspirone, caffeine, chlorpromazine, clonidine, clozapine, diazepam, flumazenil, fluoxetine, galantamine, guanfacine, methylphenidate, idazoxan, modafinil, olanzapine, paroxetine, pergolide, phenserine, quetiapine, risperidone, rivastigmine, SGS742 and sulpiride.

[0058] The terms "methods of treating or preventing" mean amelioration, prevention or relief from the symptoms and/or effects associated with lipid disorders. The term "preventing" as used herein refers to administering a medicament beforehand to forestall or obtund an acute episode or, in the case of a chronic condition to diminish the likelihood or seriousness of the condition. The person of ordinary skill in the medical art (to which the present method claims are directed) recognizes that the term "prevent" is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, and this is the sense intended in applicants' claims. As used herein, reference to "treatment" of a patient is intended to include prophylaxis.

[0059] The term "mammal" is used in its dictionary sense. The term "mammal" includes, for example, mice, hamsters, rats, cows, sheep, pigs, goats, and horses, monkeys, dogs (e.g., Canis familiaris), cats, rabbits, guinea pigs, and primates, including humans.

[0060] The cognitive impairment to be treated may arise from one or more of the following disorders, which may not in themselves be necessarily associated with PDE4 abnormality: acute pain, AD/HD - Attention deficit hyperactivity disorder, AIDS dementia complex, alcoholism, amphetamine addiction, amygdalo-hippocampectomy, anorexia nervosa, anterior parietal damage, antisocial behavior, antisocial personality disorder, anxiety, autism, basal ganglia lesions, bipolar disorder, borderline personality disorder, camptocormia, capgras syndrome, carcinoid syndrome, carotid endarterectomy surgery, chronic drug misuse, chronic fatigue syndrome, chronic occupational solvent encephalopathy, chronic pain, brain ischemia, coronary artery bypass surgery, critical illness requiring intensive care, dementia Alzheimer- type (DAT), dementia Lewy Body type, dementia of frontal type, dementia caused by ischemia, dental pain, developmental dyslexia, diabetes, dorsolateral frontal cortical compression, Down's Syndrome, drug abuse, dysexecutive syndrome, fibromyalgia, frontal lobe damage, frontal lobe excision, frontal variant frontotemporal dementia, gluten ataxia, hallucinosis, head injury, hearing loss, heart disease, heart failure, heavy social drinking, hepatic encephalopathy, heroin addiction, herpes encephalitis, hippocampal atrophy, HIV/AIDS, Huntington's disease, hydrocephalus, hypercortisolemia, hyperostosis frontalis interna, hypertension, idiopathic pain, insomnia, Korsakoff syndrome, late paraphrenia, lead exposure, left ventricular systolic dysfunction, orbitofrontal cortex lesion, liver failure, long term health effects of diving, Machado-Joseph disease, mad hatter's disease, manic depression, melancholia, mercury poisoning, mild cognitive impairment (MCI), mild cognitive impairment (MCI) of aging, motor neuron disease, multiple sclerosis, multiple system atrophy, narcolepsy, neuronal migration disorders, normal pressure hydrocephalus, obsessive compulsive disorder, organophosphate pesticide exposure, panic disorder, paraphrenia, Parkinson's disease, periventricular brain insult, personality disorder, gasoline sniffing, phenylketonuria, post-concussion syndrome, premature birth needing intensive care, premenstrual dysphoric disorder, progressive supranuclear palsy, psychopathy, psychosis, questionable dementia, renal cancer, Roifman syndrome, schizoaffective disorder, schizophrenia, seasonal affective disorder, self harm, semantic dementia, specific language impairment, social withdrawal in schizophrenia, solvent encephalopathy, spina bifida, Steele- Richardson-Olzsewski syndrome, stiff person syndrome, striatocapsular infarct, subarachnoid hemorrhage, substance abuse, tardive dyskinesia, temporal lobe excision, temporal lobe lesion, tinnitus, Tourette's syndrome, transient cerebral ischemia, traumatic brain injury, trichotillomania, tuberous sclerosis, and white matter lesions.

[0061] Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0062] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114- 120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines and single thin lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration.

[0063] As used herein, and as would be understood by the person of skill in the art, the recitation of "a compound" is intended to include salts, solvates and inclusion complexes of that compound as well as any stereoisomeric form, or a mixture of any such forms of that compound in any ratio. Thus, in accordance with some embodiments of the invention, a compound as described herein, including in the contexts of pharmaceutical compositions, methods of treatment, and compounds per se, is provided as the salt form. In accordance with some embodiments of the invention, the salt is a hydrochloride salt.

[0064] The term "solvate" refers to a compound in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19^th Ed. (1995) volume 1, page 176-177. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, with or without added additives and polymer(s), such as described in US Patents 5,324,718 and 5,472,954, are specifically encompassed within the claims. [0065] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, pamoic, pantothenic, phosphoric, polygalacturonic, salicylic, stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic, p- toluenesulfonic, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

[0066] The term "enantiomeric excess" is well known in the art and is defined for a resolution of ab into a + b as

_ J cone, of a - cone, of b \ ee_a 100 yconc. of a + cone, of b

[0067] The term "enantiomeric excess" is related to the older term "optical purity" in that both are measures of the same phenomenon. The value of ee will be a number from 0 to 100, zero being racemic and 100 being pure, single enantiomer. A compound which in the past might have been called 98% optically pure is now more precisely described as 96% ee; in other words, a 90% ee reflects the presence of 95% of one enantiomer and 5% of the other in the material in question.

[0068] The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; thus a carbon- carbon double bond depicted arbitrarily herein as E may be Z, E, or a mixture of the two in any proportion.

[0069] Terminology related to "protecting", "deprotecting" and "protected" functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes which involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection" occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as "protecting groups". Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W.Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference. Particular attention is drawn to the chapters entitled "Protection for the Hydroxyl Group, Including 1,2- and 1,3- Diols" (pages 10-86).

[0070] The abbreviations Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, toluenesulfonyl and methanesulfonyl respectively. A comprehensive list of abbreviations utilized by organic chemists (i.e. persons of ordinary skill in the art) appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations" is incorporated herein by reference.

[0071] While it may be possible for compounds of formula I and formula II to be administered as the raw chemical, it will often be preferable to present them as part of a pharmaceutical composition. In accordance with an embodiment of the present invention there is provided a pharmaceutical composition comprising a compound of formula I or formula II or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Furthermore, when reference is made in an independent claim to a compound or a pharmaceutically acceptable salt thereof, it will be understood that claims which depend from that independent claim which refer to such a compound also include pharmaceutically acceptable salts of the compound, even if explicit reference is not made to the salts in the dependent claim.

[0072] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association a compound of formula I or formula II or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0073] 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 a 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 bolus, electuary or paste.

[0074] 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 binder, lubricant, inert diluent, lubricating, 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 sustained, delayed or controlled release of the active ingredient therein. The pharmaceutical compositions may include a "pharmaceutically acceptable inert carrier", and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques, "Pharmaceutically acceptable carrier" also encompasses controlled release means.

[0075] Pharmaceutical compositions may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient must be compatible with the compound of formula I or formula II to insure the stability of the formulation. The composition may contain other additives as needed, including for example lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino acids, for example alanine, glycine and betaine, and peptides and proteins, for example albumen.

[0076] Examples of excipients for use as the pharmaceutically acceptable carriers and the pharmaceutically acceptable inert carriers and the aforementioned additional ingredients include, but are not limited to binders, fillers, disintegrants, lubricants, anti-microbial agents, and coating agents.

[0077] The dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of formula I or formula II which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity.

[0078] A dosage unit (e.g. an oral dosage unit) can include from, for example, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to 500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g. 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg) of a compound described herein. [0079] For additional information about pharmaceutical compositions and their formulation, see, for example, Remington: The Science and Practice of Pharmacy, 20^th Edition, 2000. The agents can be administered, e.g., by intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, topical, sublingual, intraarticular (in the joints), intradermal, buccal, ophthalmic (including intraocular), intranasaly (including using a cannula), or by other routes. The agents can be administered orally, e.g., as a tablet or cachet containing a predetermined amount of the active ingredient, gel, pellet, paste, syrup, bolus, electuary, slurry, capsule, powder, granules, as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, via a micellar formulation (see, e.g. WO 97/11682) via a liposomal formulation (see, e.g., EP 736299,WO 99/59550 and WO 97/13500), via formulations described in WO 03/094886 or in some other form. The agents can also be administered transdermally (i.e. via reservoir-type or matrix-type patches, microneedles, thermal poration, hypodermic needles, iontophoresis, electroporation, ultrasound or other forms of sonophoresis, jet injection, or a combination of any of the preceding methods (Prausnitz et al. 2004, Nature Reviews Drug Discovery 3: 115)). The agents can be administered locally, for example, at the site of injury to an injured blood vessel. The agents can be coated on a stent. The agents can be administered using high-velocity transdermal particle injection techniques using the hydrogel particle formulation described in U.S. 20020061336. Additional particle formulations are described in WO 00/45792, WO 00/53160, and WO 02/19989. An example of a transdermal formulation containing plaster and the absorption promoter dimethylisosorbide can be found in WO 89/04179. WO 96/11705 provides formulations suitable for transdermal administration. The agents can be administered in the form a suppository or by other vaginal or rectal means. The agents can be administered in a transmembrane formulation as described in WO 90/07923. The agents can be administered non-invasively via the dehydrated particles described in U.S. 6,485,706. The agent can be administered in an enteric-coated drug formulation as described in WO 02/49621. The agents can be administered intranasaly using the formulation described in U.S. 5,179,079. Formulations suitable for parenteral injection are described in WO 00/62759. The agents can be administered using the casein formulation described in U.S. 20030206939 and WO 00/06108. The agents can be administered using the particulate formulations described in U.S. 20020034536. [0080] The agents, alone or in combination with other suitable components, can be administered by pulmonary route utilizing several techniques including but not limited to intratracheal instillation (delivery of solution into the lungs by syringe), intratracheal delivery of liposomes, insufflation (administration of powder formulation by syringe or any other similar device into the lungs) and aerosol inhalation. Aerosols (e.g., jet or ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry-Powder inhalers (DPIs)) can also be used in intranasal applications. Aerosol formulations are stable dispersions or suspensions of solid material and liquid droplets in a gaseous medium and can be placed into pressurized acceptable propellants, such as hydrofluoroalkanes (HFAs, i.e. HFA-134a and HFA-227, or a mixture thereof), dichlorodifluoromethane (or other chlorofluorocarbon propellants such as a mixture of Propellants 11, 12, and/or 114), propane, nitrogen, and the like. Pulmonary formulations may include permeation enhancers such as fatty acids, and saccharides, chelating agents, enzyme inhibitors (e.g., protease inhibitors), adjuvants (e.g., glycocholate, surfactin, span 85, and nafamostat), preservatives (e.g., benzalkonium chloride or chlorobutanol), and ethanol (normally up to 5% but possibly up to 20%, by weight). Ethanol is commonly included in aerosol compositions as it can improve the function of the metering valve and in some cases also improve the stability of the dispersion. Pulmonary formulations may also include surfactants which include but are not limited to bile salts and those described in U.S. 6,524,557 and references therein. The surfactants described in U.S. 6,524,557, e.g., a C₈-Ci₆ fatty acid salt, a bile salt, a phospholipid, or alkyl saccharide are advantageous in that some of them also reportedly enhance absorption of the compound in the formulation. Also suitable in the invention are dry powder formulations comprising a therapeutically effective amount of active compound blended with an appropriate carrier and adapted for use in connection with a dry-Powder inhaler. Absorption enhancers which can be added to dry powder formulations of the present invention include those described in U.S. 6,632,456. WO 02/080884 describes new methods for the surface modification of powders. Aerosol formulations may include U.S. 5,230,884, U.S. 5,292,499, WO 017/8694, WO 01/78696, U.S. 2003019437, U. S. 20030165436, and WO 96/40089 (which includes vegetable oil). Sustained release formulations suitable for inhalation are described in U.S. 20010036481A1, 20030232019A1, and U.S. 20040018243A1 as well as in WO 01/13891, WO 02/067902, WO 03/072080, and WO 03/079885. Pulmonary formulations containing microparticles are described in WO 03/015750, U.S. 20030008013, and WO 00/00176. Pulmonary formulations containing stable glassy state powder are described in U.S. 20020141945 and U.S. 6,309,671. Other aerosol formulations are described in EP 1338272A1 WO 90/09781, U. S. 5,348,730, U.S. 6,436,367, WO 91/04011, and U.S. 6,294,153 and U.S. 6,290,987 describes a liposomal based formulation that can be administered via aerosol or other means. Powder formulations for inhalation are described in U.S. 20030053960 and WO 01/60341. The agents can be administered intranasally as described in U.S. 20010038824.

[0081] Solutions of medicament in buffered saline and similar vehicles are commonly employed to generate an aerosol in a nebulizer. Simple nebulizers operate on Bernoulli's principle and employ a stream of air or oxygen to generate the spray particles. More complex nebulizers employ ultrasound to create the spray particles. Both types are well known in the art and are described in standard textbooks of pharmacy such as Sprowls' American Pharmacy and Remington's The Science and Practice of Pharmacy. Other devices for generating aerosols employ compressed gases, usually hydrofluorocarbons and chlorofluorocarbons, which are mixed with the medicament and any necessary excipients in a pressurized container, these devices are likewise described in standard textbooks such as Sprowls and Remington.

[0082] The agent can be incorporated into a liposome to improve half-life. The agent can also be conjugated to polyethylene glycol (PEG) chains. Methods for pegylation and additional formulations containing PEG-conjugates (i.e. PEG-based hydrogels, PEG modified liposomes) can be found in Harris and Chess, Nature Reviews Drug Discovery 2:214-221 and the references therein. The agent can be administered via a nanocochleate or cochleate delivery vehicle (BioDelivery Sciences International). The agents can be delivered transmucosally (i.e. across a mucosal surface such as the vagina, eye or nose) using formulations such as that described in U.S. 5,204,108. The agents can be formulated in microcapsules as described in WO 88/01165. The agent can be administered intra-orally using the formulations described in U.S. 20020055496, WO 00/47203, and U.S. 6,495,120. The agent can be delivered using nanoemulsion formulations described in WO 01/91728A2.

[0083] In general, compounds of formula I or formula II may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here. [0084] Tables 1 and 2 above list compounds representative of embodiments of the invention. Processes for obtaining compounds of formula I or formula II are presented below. Other compounds of formula I or formula II may be prepared in analogous fashion to those whose synthesis is exemplified herein. The procedures below illustrate such methods. Furthermore, although the syntheses depicted herein may result in the preparation of enantiomers having a particular stereochemistry, included within the scope of the present invention are compounds of formula I and formula II in any stereoisomeric form, and preparation of compounds of formula I and formula II in stereoisomeric forms other than those depicted herein would be obvious to one of ordinary skill in the chemical arts based on the procedures presented herein.

[0085] General Synthetic Methods

3 3 RI R₂

1 ⁸ L ^{1 8}ArZHeI

Cy₂

General formula I ₌> QJ Q2 QJ Q4 Q^ General formula Il => Qg

[0086] Scheme 1.

S2 S 4 S6

Compounds of the Formula Gl can be prepared by reaction of the 2-aminopryridies or 2- aminopyrazine with an α-haloketone (or α-halo aldehyde) to provide the imidazo[l,2- a]pyridine (X=CH or CF)/imidazo[l,2-a]pyrazine (X=N) (S4/S5). The substituent at C8 can be introduced either before formation of the bicyclic core (S2) by Suzuki/Stille reaction allowing C-C bond formatting chemistries. Alternatively, the intermediate S3 could be reacted by Buchwald or Cu mediated chemistries to for ether/amine linked C 8 substituent (S7). The substituent at the C-6 position can be introduced by a wide variety of approaches. When Y is an alkyl, ester, nitrile, following standard function group inter-conversion intermediates S6/S7 containing alcohol, alkyl halide (W) could be generated. The subsequent chemistries employed depends on the 1 -carbon functionality (Y = CH3, CHO, COOR', CN etc.) present as C6. For example, the function group alcohol may be coveted to a carbonate (W= CH-OCO2R'). The carbonate or -CH2-Br (W, S6/S7) upon reaction via organometallic coupling protocols (e.g. Suzuki, Stille reaction) allows C-C liked substituents or displacement of a halogen or tosylate (W) with a cyclic or heterocyclic -NH2, -OH, or -SH containing reagents allow formation of a C-N, C-O, or C-S bond linked substituent at C6. Alternatively, addition of a Grignard or organolithium reagent to Y=ester, allows formation of the ketone/secondary alcohol linked substituents (M = CO, C(OH)H or C(OH)R). S6/S7 intermediates (W= CH2Br or CH20H) could be derivatized to produce ether / amine linked C6 substituents. The alcohol can be converted to a primary or secondary amine. The W as acid or amine thus allows formation of amide, reverse amide, sulfonamide from acylation /sulfonation chemistries or diverse amine via reductive amine chemistry approaches. The substituents containing additional functions groups allow subsequent elaboration by standard chemistries outlines above depending upon the functional groups introduced at C6. These strategies allow incorporation of acyclic, heterocyclic or heteroaryl derived substituents at the C6 / C8 position of the imidazo[l,2-a]pyridine/ imidazo[l,2-a]pyrazine core.

[0087] Scheme 2.

Formation of the [l,2,4]triazolo[l,5-a]pyridine (SlO, X=CH,CF)/ [l,2,4]triazolo[l,5- ajpyrazine (SlO, X=N) can be obtained from the 2-aminopryridies (S8, X=CH, CF) or 2- aminopyrazine (S8, X=N) starting material via reaction with dimethylformamide dimethyl acetal (R2= H) or dimethyl acetamide dimethyl acetal (R2= CH3) to provide intermediate S9, which following the ring closing reaction with dehydrating reagents (such as: TFAA, PPA, Ts-Cl or Ms-Cl) can provide the key triazolo-pyridine/pyrazine cores (SlO). Subsequent elaboration at C6/C8, analogous to approaches described above for Gl would provide analogs represented by G2.

[0088] Scheme 3.

V ^KJ H₂N V ^H*C00CH3 <VY H2SO4 <YY

SH S15

Formation of pyrozolo[l,5-a]pyridine (S14) can be obtained from 2,4-substituted pyridine (S12) via S13. N-amination of 2,4-disubstituted pyridine (S12) by O-2-mesitylenesulfonyl hydroxyamine provides intermediate (S13). Subsequent 1,3-dipolar cycloaddition with methyl propiolate furnish the pyrozolo[l,5-a]pyridine (S 14), which can subsequently be transformed into the decarboxylated product (S 15) under acidic conditions. The 3 -ester in pyrozolo[l,5-a]pyridine (S 14) could also be converted to other group (S 16) by standard functional group transformations. Subsequent elaboration at C6/C8 in pyrozolo[l,5- a]pyridine (S 15 or S 16), analogous to approaches described above for Gl would provide analogs represented by G3.

[0089] Scheme 4. ,COOMe

S17 S18 S19 S20 S21

G4 a

R3

\ R3

R3 R3

R2 — ( ~^ » _^/^^CH₂Ra

^" R2- N ^NH -*" R2-

N ^{N H} R2^ I I K^^_N NH O N NH NH₂

S18 S23 S24 325

S26 G4 b

Formation of the key intermediate pyrazolo[l,5-a]pyrimidine (S21) can be obtained from the pyrazole starting material (S 18). Reaction of pyrazole (S 18) with methyl chloroformate and subsequent bromination with NBS give intermediate bromomethyl pyrazole (S20). Nucleophilic substitution of tosylmethyl isocyanide (TosMIC) on the bromomethyl pyrazole (S20) followed by intramolecular transfer of the methoxycarbonyl group followed by cyclization and 1 ,2-elimination of p-toluenesulfinic acid to afford the pyrazolo[l,5-a] pyrimidine intermediate (S21) analogous to Mendiola, J. et.al. JOC 2004, 69, 4974-83. The substitution at C-6 position can be obtained via the ester group at C-6 position by similar approaches described above for Gl analogs. The introduction of the substitutions at C-8 position to form a C-C bond can be accomplished by metal assisted cross coupling reactions.

The key intermediate pyrazolo[l,5-a]pyrimidine (S26) can be also obtained from S25. The intermediate S25 in turn can be obtained from S18 via bromination and subsequent conversion to the ketone S24. Reaction of S25 with an orthoformate would then provide S26. When Ra =h (for S26) elaboration to final product can be achieved as described above. Alternatively, the final substituent can be introduced as part of formation of S24; in such case cyclization of S25 to S26 directly would yield the desired analogs. [0090] Scheme 5.

S30 G5 (Z = bone ieteroatom

Formation of the key intermediate pyrazolo[l,5-a]pyrimidine (S28) can be obtained via cyclization reaction of the pyrazole starting material (S27) with acetoacetic acid ethyl ester (or β-keto esters). A large number of starting materials of the general structure S27 are commercial available or can be prepared by published procedures. The -OH group in S28 can convert to chloride or bromide (S29) which can form C-C link substitutions in S30 via organometallic coupling protocols (e.g. Suzuki, Stille reaction). The introduction of C-6 substitution in G5 can be obtained via the methyl (R' =H) at C-6 position by similar approaches described above for Gl analogs.

[0091] Scheme 6.

Compounds of the Formula G6-a, can be obtained from the intermediate 5H-pyrazolo[l,5- d][l,2,4]triazin-4-one (S26). By coupling of 2-ester pyrazole (S24) with hydrazine give an intermediate S25, which can be subsequently cyclized to key intermediate S26. Pyrazole starting material, S24, with varying R2/R3 groups are either commercial available or can be prepared by literature procedures. The introduction of substitutions at N-5 position (G6-a) can be obtained via N-alkylation with Ari/Heti-CH2-halide (-Br or Cl).

[0092] Alternatively, compounds of the formula G6-b, can be prepared from the intermediate 2,3-disubstituted-5,6-dihydro-pyrazolo[l,5-d][l,2,4]triazine-4,7-dione (S27). Cyclization of S25 with coupling reagents (such as CDI, triphosgene etc) afford S27, which can subsequently N-alkylation with Hetl/Arl/Rl-halide at N-5 position to provide (S28). The substitutions at C-7 position in compounds G6-b can be obtained by displacement of halogen (Cl or F) of S29 with hydroxyl, amine or thiol containing heterocyclic/aryls.

Examples

[0093] Example 1. D-Ol

[0094] Stepl. 6-Amino-5-(3-chloro-phenyl)-nicotinic acid methyl ester (2). To a 100 ml INRBF were added methyl 6-amino-5-bromonicotinate (Ig, 4.33 mmole), 40 ml toluene, 10 ml ethanol, 20 ml water, 1.37g, 13 mmole sodium carbonate and 3-chlorophenyl boronic acid (740mg, 4.73 mmole). The solution was degassed for 10 min. under argon, then the palladium tetrakis (500mg, 10%) was added. Reaction mixture was heated at 100⁰C for 6 hours. TLC (20%EA/hexane) shows no SM. The reaction mixture was concentrated down to half, diluted with 20 ml water and extracted 3x 80 ml ethylacetate. Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give about 1.5 g crude. Trituration with 5% methanol in ether gave 700 mg solid (2). Mother liquor was concentrated to a solid and trituration was repeated to get a second crop of 230 mg (2). IH- NMR confirmed the structure.

[0095] Step 2. 8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridine-6-carboxylic acid methyl ester (3). A 50 ml INRB flask equipped with condenser and Dean Stark trap was loaded with 6- Amino-5-(3-chloro-phenyl)-nicotinic acid methyl ester (680 mg, 2.6 mmole) 20 ml, toluene and 1.2 g chloroacetaldehyde (50% solution in water). The mixture was heated to reflux and water was colected in the trap. After 4 hrs, TLC (EA/ hexane= 1;1) shows a new spot, Rf closer to starting material. Mixture was concentrated down, diluted with 10 ml water, neutralized to pH= 7 using saturated aq. Solution of NaHCO3 and extracted 3X 50 ml methylene chloride. Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford 500 mg product as brown solid (3), pure by IH-NMR. This material was used for the next step.

[0096] Step 3. [8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridin-6-yl]-methanol (4). To a solution of 8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridine-6-carboxylic acid methyl ester 3 (200 mg, 0.698 mmole) in 10 ml anhydrous THF was added at 0⁰C LiBH4 (2M in THF, 2 ml). Reaction mixture was stirred at RT for 3 days. Mixture was quenched with saturated solution of NH4C1, then extracted several times with ethylacetate. Combined organic layers were washed with water, brine, dried over Na2SO4, filtered, concentrated to afford 230 mg crude. This was purified by a preparative silicagel plate (1.5 mm) using 5%MeOH/ CH2C12 to afford 150 mg product (4), pure by IH-NMR.

[0097] Step 4. Carbonic acid 8-(3-chloro-phenyl)-imidazo[l,2-a]pyridin-6-ylmethyl ester (5). To a solution of [8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridin-6-yl]-methanol (4) (100 mg, 0.387 mmole) in 2 ml anhydrous THF was added pyridine (80 ul, 0.96 mmole). The mixture was cooled to 0⁰C and methylchloro formate was added slowly (65uL, 0.81 mmole). Reaction mixture was stirred at room temperature for 3 days. Water was added and the aqueous portion was extracted with ethyl acetate(2 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by silicagel preparative TLC plate 50%ethylacetate/ hexane as the eluent to give 80 mg of product (5) in 65 % yield.

[0098] Step 5. 4-[8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridin-6-ylmethyl]-phenylamine (D- 01). A reaction mixture of compound 5 (80 mg, 0.25 mmol), 2-aminopyridine-5-boronic acid pinacol ester 5 (62 mg, 0.27 mmol), l,5-bis(diphenylphosphino) pentane (33 mg, 0.075 mmole), allylpalladium chloride dimer (14 mg, 0.0375 mmol), K2CO3 (104 mg, 0.75 mmole) in DMF (2 ml)) was stirred at 85 ⁰C for 8 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(2 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by silicagel preparative TLC plate 60%ethylacetate/ hexane as the eluent to give 22 mg of product D-Ol in 28 % yield.

[0099] IH-NMR, MS, LCMS. [00100] Example 2. D-02

[00101] Synthesis of 8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridine-6- carboxylic acid methyl ester and 8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridine-6- carboxylic acid ethyl ester (6 and 7): In a microwave vial, was place 2 (990 mg, 3.76 mmole), chloroacetone (1.74 g, 19 mmole) and ethanol (15 ml). The reaction mixture was stirred at 160 oC for 3 hrs on a microwave synthesizer and then cooled to room temperature. After removal of solvent under vacuum, the residue was dissolved in water and the pH was adjusted to 8-9 by addition of NaHCO3 aq. The aqueous portion was extracted with ethyl acetate (3 x 50 ml), the organic portions were combined, washed with sat. NaHCO3 aq., brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing EtOAc/hexanes as the eluent to give 1.18 g of a mixture of 6 and 7 (-1.8: 1.5) in 53% yield. ¹H-NMR (400 MHz, CDCl₃).

[00102] Synthesis of [8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6-yl]- methanol (8): To a mixture of compound 6 and 7 (-1.8: 1.5) (1.18 g, 2.2 mmol) in THF (anhydrous, 60 ml), was added DIBAL-H (IM in hexane, 24 ml) dropwise at -78 oC under N2. The reaction mixture was stirred at -78 oC to r.t. and r.t. for 3 hrs. The reaction mixture was diluted with ice/water, adjusted pH to acidic and then stirred at r.t for about 20 min. After pH adjusted to 8-9 by addition of NaOH aq (6N), the aqueous portion was extracted with ethyl acetate (3x 100 ml). Organic layer was washed with sat. NaHCO3 aq., brine, and dried over Na2SO4. After removal of solvent, the solid was washed with ether to give 800 mg of product 8 in 75 % yield. ¹H-NMR (400 MHz, DMSO-d6) [00103] Synthesis of 6-Bromomethyl-8-(3-chloro-phenyl)-2-methyl-imidazo[l,2- a]pyridine (9): To a mixture of compound 8 (27 mg, 0.1 mmol) in DCM (2 ml) was added PBr3 (14 mg, 0.05 mmole) at -10 oC under N2. The reaction mixture was stirred at -10 oC to r.t. and r.t for 1 hr. The reaction mixture was diluted with DCM (4 ml) and washed with diluted NaHCO3 aq., water, brine, and dried over Na2SO4. After removal of solvent, crude product 9 obtained. Crude 9 directly used in next step without further purification.

[00104] Synthesis of {4-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl] -phenyl} -urea (D-02): A reaction mixture of compound 9 (~0.1 mmol), A- ureidophenylboronic acid pinacol ester (26 mg, 0.1 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), K3PO4 (42 mg, 0.2 mmole) in DME (4 ml), ethanol (1 ml) and water (1 ml) was stirred at 65 ⁰C for 2 hours and then cooled to room temperature. Water (5 ml) was added and the aqueous portion was extracted with ethyl acetate(2 x 10 mL), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 4 mg of D-02 in 10% yield for two step. ¹H-NMR (400 MHz, Acetone-d₆): 2.37 (3H, s), 3.97 (2H, s), 5.35 (2H, br), 7.20 (2H, d, J=8 Hz), 7.36 - 7.48 (5H, m), 7.64 (IH, m), 7.97 (IH, br), 8.07 (IH, m), 8.23 (IH, m), 8.33 (IH, m). MS(ESI+): 391.5 (M+l). LC-MS: 90 %.

[00105] Example 3. D-03

10 D-03

[00106] Synthesis of 4-[8-(3-Chloro-phenyl)-6-methoxycarbonyloxymethyl-2-methyl- imidazo[l,2-a]pyridin-3-yl]-4H-pyridine-l-carboxylic acid methyl ester (10): To a mixture of compound 8 (480 mg, 1.76 mmol) and pyridine (362 mg, 4.6 mmole) in THF (15 ml), was added methyl chloroformate (376 mg, 3.96 mmole) dropwise at -10 oC under N2. The reaction mixture was stirred at r.t over night. The reaction mixture was diluted with water, pH adjusted to 8-9 by addition of NaHCO3 aq and then extracted with ethyl acetate (2x 5 ml). The organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing ethyl acetate/hexane as the eluent to give 520 mg of 10 in 63% yield. ¹H-NMR (400 MHz, CDCl₃)

[00107] Synthesis of {(Z)-3-[6-(6-Amino-pyridin-3-ylmethyl)-8-(3-chloro-phenyl)-2- methyl-imidazo[l,2-a]pyridin-3-yl]-but-l-enyl}-vinyl-carbamic acid methyl ester (D-03): A reaction mixture of compound 10 (100 mg, 0.3 mmol), 2-aminopyridine-5-boronic acid pinacol ester (73 mg, 0.33 mmol), l,5-bis(diphenylphosphino) pentane (44 mg, 0.1 mmole), allylpalladium chloride dimer (14 mg, 0.045 mmol), K2CO3 (124 mg, 0.9 mmole) in DMF (2 ml)) was stirred at 90 ⁰C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(3 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 20 mg of D-03 in 14 % yield. ¹H-NMR (400 MHz, DMSO-d₆): 2.32 (3H, s), 3.76 (2H, s), 3.84 (3H, s), 4.90 (3H, br), 5.72 (2H, s), 6.36 (IH, d, J = 8 Hz), 6.94 (2H, br), 7.27 (IH, dd, J = 8 and 2.4 Hz), 7.36 (IH, d, J=I.6 Hz), 7.45 (IH, m), 7.50 (IH, dd, J = 8 and 8 Hz), 7.86 (IH, d, J=2.4 Hz), 7.99 (IH, m), 8.18 (IH, m), 8.21 (IH, s). MS(ESI+): 486.6 (M+ 1). LC-MS: 99 %.

[00108] Example 4. D-04.

5 D-04

[00109] Synthesis of S-CS-Chloro-pheny^-ό-Cό-fluoro-pyridin-S-ylmethyl)- imidazo[l,2-a]pyridine (D-04): A suspension of 5 (80 mg, 0.253 mmol), 2-fluoro-5- pyridine boronic acid (35.7 mg, 0.253 mmol), and solid potassium carbonate (104 mg, 0.759 mmol) was degassed with a nitrogen stream for 20 min. To the suspension was added palladium allyl chloride dimer (13.9 mg, 0.0380 mmol) and bis(diphenylphosphino)pentane (33.4 mg, 0.0759 mmol) and the reaction was stirred at 100 ⁰C under nitrogen overnight. The reaction was diluted with ethyl acetate (10 mL), washed with saturated ammonium chloride (10 mL), the aqueous wash back extracted with ethyl acetate (2 x 10 mL), and the organic extracts were combined. The organic solution was washed with brine (15 mL) and the solvent removed under vacuum. The crude material was purified by silica gel thin layer preparatory chromatography eluting with 7.5 % acetone in dichloromethanes to give D-04 PR231 (15.1 mg, 18% yield) as a yellow gum. IH NMR (400 MHz CDC13) d: 8.163 (d, J = 2.40 Hz, IH), 7.934-7.865 (m, 3H), 7.689-7.610 (m, 3H), 7.429-7.357 (m, 2H), 7.066 (d, J = 1.60 Hz, IH), 6.166 (dd, J = 608.40 Hz, 602.80 Hz, IH), 4.008 (s, 3H). LCMS = 96.7%. MS(APCI+) = 338.1 (M+l).

[00110] Example 5. D-05

to r t

12 13

[00111] Synthesis of 8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2-a]pyridine-6- carboxylic acid methyl ester and 8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2- a]pyridine-6-carboxylic acid ethyl ester (11 and 12): In a microwave vial, was place 2 (1052 mg, 4 mmole), 3-bromo-2-butanone (2820 mg, 18.6 mmole) and ethanol (15 ml). The reaction mixture was stirred at 160 oC for 2 hrs on a microwave synthesizer and then cooled to room temperature. After removal of solvent under vacuum, the residue was dissolved in water and the pH was adjusted to 8-9 by addition of NaHCO3 aq. The aqueous portion was extracted with ethyl acetate (3 x 50 mL), the organic portions were combined, washed with sat. NaHCO3 aq., brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing EtOAc/hexanes as the eluent to gave 600 mg of a mixture of 11 and 12 (-1:6) in 46% yield. ¹H-NMR (400 MHz, CDCl₃)

[00112] Synthesis of [8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2-a]pyridin-6- yl]-methanol (13): To a mixture of compound 11 and 12 (~6: 1) (600 mg, 1.8 mmol) in THF (anhydrous, 30 ml), was added DIBAL-H (IM in Toluene, 12 ml) dropwise at -78 oC under N2. The reaction mixture was stirred at -78 oC to r.t. and r.t over night. The reaction mixture was diluted with ice/water, adjusted pH to acidic and then stirred at r.t for about 20 min. After pH adjusted to 8-9 by addition of NaOH aq (6N), the aqueous portion was extracted with ethyl acetate (3x100 ml). Organic layer was washed with sat. NaHCO3 aq., brine, and dried over Na2SO4. After removal of solvent, the solid was washed with ether to give 428 mg of product 13. Yield: 82 %. ¹H-NMR (400 MHz, DMOS-d₆)

[00113] Synthesis of 6-Bromomethyl-8-(3-chloro-phenyl)-2,3-dimethyl- imidazo[l,2-a]pyridine (14): To a mixture of compound 13 (57 mg, 0.2 mmol) in DCM (4 ml) and DMF (0.2 ml), was added PBr3 (57 mg, 0.2 mmole) at -10 oC under N2. The reaction mixture was stirred at -10 oC to r.t. and r.t for 1 hr. The reaction mixture was diluted with DCM (4 ml) and washed with diluted NaHCO3 aq., water, brine, and dried over Na2SO4. After removal of solvent, 60 mg of crude product 14 obtained. Crude 14 directly used in next step without further purification.

[00114] Synthesis of {4-[8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2-a]pyridin-

6-ylmethyl]-phenyl}-urea (D-05): A reaction mixture of compound 14 (60 mg crude, 0.2 mmol), 4-ureidophenylboronic acid pinacol ester (52 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (46 mg, 0.04 mmol), K3PO4 (84 mg, 0.4 mmole) in DME (6 mL), ethanol (1.5 mL) and water (1.5 ml) was stirred at 65 ⁰C for 2 hours and then cooled to room temperature. Water (10 mL) was added and the aqueous portion was extracted with ethyl acetate(2 x 15 mL), the organic portions were combined, washed with brine (75 mL), dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to gave 6 mg of D-05 as a solid in 7% yield for two step. ¹H-NMR (400 MHz, Acetone-d₆): 2.36 (3H, s), 2.45 (3H, s), 4.01 (2H, s), 5.35 (2H, br), 7.21 (2H, d, J= 8 Hz), 7.34 (IH, d, J = 2 Hz), 7.38 (IH, m), 7.42 (2H, d, J = 8 Hz), 7.45 (IH, dd, J = 8 and 8 Hz), 7.95 (IH, br), 8.04 (IH, m), 8.06 (IH, m), 8.34 (IH, m). MS(APCI+): 405.1 (M+ 1). LC-MS: 99 %.

[00115] Example 6. D-06

13

14 D-06

[00116] Synthesis of 6-Bromomethyl-8-(3-chloro-phenyl)-2,3-dimethyl- imidazo[l,2-a]pyridine (14): To a mixture of compound 13 (57 mg, 0.2 mmol) in DCM (4 ml) and DMF (0.2 ml), was added PBr3 (57 mg, 0.2 mmole) at -10 oC under N2. The reaction mixture was stirred at - 10 oC to r.t. and r.t for 1 hr. The reaction mixture was diluted with DCM (4 ml) and washed with diluted NaHCCβ aq., water, brine, and dried over Na2SO4. After removal of solvent, crude product 14 obtained. Crude 14 directly used in next step without further purification.

[00117] Synthesis of l-[8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyrrolidin-2-one (D-06): To a mixture of NaH (60 % in oil, 16 mg, 0.4 mmole) in DMF (2 ml), was added 2-pyrrolidone (34 mg, 0.4 mmole) at -10 oC. After reaction mixture stirring at r.t. for 10 min, compound 14 (crude, 0.2 mmol) dissolved in DMF (3 ml) was added at -10 oC under N2. The reaction mixture was stirred at -10 oC to r.t. and r.t over night. After removal of solvent under vacuum, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 10 ml), the organic portions were combined, washed with brine (75 mL), dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing ethyl acetate/hexane as the eluent gave 50 mg of D-06 as an oil in 70% yield for two step. To a solution of D-06 (50 mg) in DCM (4 ml), was added HCl in Et2O (2N, 0.2 ml), after removal of solvent, solid was washed with ether to give 37 mg of D-06 HCl salt as solid. ¹H-NMR (400 MHz, CD3OD): 2.07 (2H, m), 2.45 (2H, t, J=8 Hz), 2.50 (3H, s), 2.60 (3H, s), 3.48 (2H, m), 4.67 (2H, s), 7.58 - 7.64 (3H, m), 7.74 (IH, m), 7.78 (IH, m), 8.58 (IH, m). MS(APCI+): 354 (M+ 1). LC-MS: 98 %. [00118] Example 7. D-07

[00119] Synthesis of Carbonic acid 8-(3-chloro-phenyl)-2,3-dimethyl-imidazo[l,2- a]pyridin-6-ylmethyl ester methyl ester (15): To a mixture of compound 13 (57 mg, 0.2 mmol) and pyridine (79 mg, 1 mmole) in THF (2 ml), was added methyl chloroformate (76 mg, 0.8 mmole) dropwise at r.t. under N2. The reaction mixture was stirred at r.t over night. The reaction mixture was diluted with water, pH adjusted to 8-9 by addition of NaHCO3 aq and then extracted with ethyl acetate (2x 5 ml). The organic portions were combined, washed with brine, dried over Na2SO4. After removal of solvent, 60 mg of crude product 15 obtained. Crude 15 directly used in next step without further purification.

[00120] Synthesis of 5-[8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-ylamine (D-07): A reaction mixture of compound 15 (crude, 0.15 mmol), 2-aminopyridine-5-boronic acid pinacol ester (33 mg, 0.15 mmol), 1,5- bis(diphenylphosphino) pentane (20 mg, 0.045 mmole), allylpalladium chloride dimer (7 mg, 0.023 mmol), K2CO3 (62 mg, 0.45 mmole) in DMF (1 ml)) was stirred at 90 ⁰C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(3 x 15 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 18 mg of D-07 in 33 % yield for two step. ¹H-NMR (400 MHz, Acetone-d₆): 2.36 (3H, s), 2.45 (3H, s), 3.92 (2H, s), 5.22 (2H, br), 6.48 (IH, d, J = 8), 7.34 - 7.42 (3H, m), 7.46, (IH, dd, J = 8 and 8 Hz), 7.99, IH, d, J = 1.6 Hz), 8.05 (IH, s), 8.08 (IH, m), 8.35 (IH, m). MS(APCI+): 363.1 (M+l). LC-MS: 99 %. [00121] Example 8. D-08

OH

[00122] Synthesis of S-CS-Chloro-pheny^-ό-Cό-fluoro-pyridin-S-ylmethyl)^^- dimethyl-imidazo[l,2-a]pyridine (D-08): A reaction mixture of compound 15 (crude, 0.15 mmol), 2-fluoro-5-pyridine-boronic acid (21 mg, 0.15 mmol), l,5-bis(diphenylphosphino) pentane (20 mg, 0.045 mmole), allylpalladium chloride dimer (7 mg, 0.023 mmol), K2CO3 (62 mg, 0.45 mmole) in DMF (1 ml)) was stirred at 90 ⁰C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(4 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing ethyl acetate/hexane as the eluent to give 28 mg of D-08 in 51 % yield. To a solution of D-08 (28 mg) in Et20 (4 ml), was added HCl in Et20 (2N, 0.1 ml), solid was washed with ether to give 26 mg of D-08 HCl salt as solid. ¹H-NMR (400 MHz, DMSO- d₆): 2.44 (3H, s), 2.55 (3H, s), 4.19 (2H, s), 7.15 (IH, dd, J = 8 and 3Hz), 7.60 - 7.68 (3H, m), 7.76 (IH, m), 7.92 (IH, m), 8.01 (IH, m), 8.31 (IH, m), 8.79 (IH, s). MS(APCI+): 366.1 (M+l). LC-MS: 98 %.

[00123] Example 9. D-09

[00124] Synthesis of 4-[8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2-a]pyridin-6- ylmethylj-phenylamine (D-09): A reaction mixture of compound 15 (crude, 0.15 mmol), A- aminophenyl boronic acid pinacol ester (33 mg, 0.15 mmol), l,5-bis(diphenylphosphino) pentane (20 mg, 0.045 mmole), allylpalladium chloride dimer (7 mg, 0.023 mmol), K2CO3 (62 mg, 0.45 mmole) in DMF (1 ml)) was stirred at 90 ⁰C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(4 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing ethyl acetate/hexane as the eluent to give D-09. To a solution of D-09 in DCM (3 ml), was added HCl in Et20 (2N, 0.1 ml), solid was washed with ether to give 19 mg of D-09 HCl salt as solid. ¹H-NMR (400 MHz, DMSO- d₆): 2.44 (3H, s), 2.55 (3H, s), 4.13 (2H, s), 7.11 (2H, m), 7.40 (2H, m), 7.60 - 7.68 (3H, m), 7.74 (IH, m), 7.83 (IH, m), 8.75 (IH, m). MS(APCI+): 362.1 (M+l). LC-MS: 96 %.

[00125] Example 10. D-10

D-07 D-10

[00126] Synthesis of l-{5-[8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2- a]pyridin-6-ylmethyl]-pyridin-2-yl}-3-ethyl-urea (D-10): To a mixture of compound D-07 (7 mg, 0.02 mmol) in pyridine (1 ml), was added ethyl isocyanate (20 mg, 0.25 mmole). The reaction mixture was stirred at r.t. for 5 days and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 6 mg of D-10 in 69 % yield. ¹H-NMR (400 MHz, CD3OD): 1.18 (3H, t, J= 7.2 Hz), 2.51 (3H, s), 2.61 (3H, s), 3.20 (2H, q, J =7.2 Hz), 4.30 (2H, s), 7.28 (IH, d, J= 8Hz), 7.60 (3H, m), 7.71 (IH, m), 7.80 (IH, m), 8.22 (IH, m), 8.25 (IH, m), 8.66 (IH, s). MS(APCI+): 434.1 (M+l). LC-MS: 97 %.

[00127] Example 11. D-Il

[00128] Synthesis of Carbonic acid 8-(3-chloro-phenyl)-2-methyl-imidazo[l,2- a]pyridin-6-ylmethyl ester methyl ester (16): To a mixture of compound 8 (136 mg, 0.5 mmol) in THF (10 ml), was added NaH (60 % in oil, 50 mg, 1.25 mmole) at -10 oC and stirred at r.t. for 20 min. Methyl chloro formate (105 mg, 1.1 mmole) was added dropwise at - 20 oC under N2. The reaction mixture was stirred at r.t over night. The reaction mixture was diluted with water and extracted with ethyl acetate (2x 20 ml). The organic portions were combined, washed with brine, dried over Na2SO4. After removal of solvent, 180 mg of crude product 16 obtained. Crude 16 directly used in next step without further purification. ¹H-NMR (400 MHz, CDC13)

[00129] Synthesis of 4-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethylj-phenylamine (D-Il): A reaction mixture of compound 16 (70 mg crude, 0.25 mmol), 4-aminophenyl boronic acid pinacol ester (55 mg, 0.25 mmol), 1,5- bis(diphenylphosphino) pentane (33 mg, 0.075 mmole), allylpalladium chloride dimer (14 mg, 0.038 mmol), K2CO3 (104 mg, 0.75 mmole) in DMF (2 ml)) was stirred at 90 ⁰C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(4 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing ethyl acetate/hexane as the eluent to give 11 mg of D-Il in 13 % yield for two steps. To a solution of D-Il (11 mg) in ether (3 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 11 mg of D-Il HCl salt as solid. ¹H-NMR (400 MHz, DMSO-d6): 2.45 (3H, s), 4.11 (2H, s), 6.85 (IH, m), 7.18 (3H, m), 7.38 (2H, d, J = 8Hz), 7.64 (3H, m), 7.78 (IH, s), 7.86 (IH, s), 8.14 (IH, s), 8.77 (IH, s), 9.70-10.0 (2H, br). MS(APCI+): 348.1 (M+l) LC-MS: 95 %.

[00130] Example 12. D- 12 [00131] Example 13. D-13

[00132] Synthesis of 5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-ylamine (D-12): A reaction mixture of compound 16 (70 mg crude, 0.25 mmol), 2-aminopyridine-5-boronic acid pinacol este (55 mg, 0.25 mmol), 1,5- bis(diphenylphosphino) pentane (33 mg, 0.075 mmole), allylpalladium chloride dimer (14 mg, 0.038 mmol), K2CO3 (104 mg, 0.75 mmole) in DMF (2 ml)) was stirred at 90 ⁰C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(4 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 35 mg of D-12 in 40 % yield for two step. To a solution of D-12 (35 mg) in DCM (3 ml), was added HCl in Et20 (2N, 0.1 ml), solid was washed with ether to give 35 mg of D-12 HCl salt as solid. ¹H-NMR (400 MHz, DMSO-d6): 2.46 (3H, s), 4.02 (2H, s), 6.98 (IH, d, J=8 Hz), 7.60 - 7.70 (3H, m), 7.82 (IH, br), 7.87 (IH, br), 7.90 (IH, m), 7.96 (IH, m), 8.04 (IH, br), 8.11 (IH, br), 8.75 (IH, br). MS(APCI+): 349.1 (M+ 1). LC-MS: 99 %.

[00133] Synthesis of l-{5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-3-ethyl-urea (D-13): To a mixture of compound D-12 (30 mg, 0.08 mmol) in pyridine (1 ml), was added ethyl isocyanate (57 mg, 0.8 mmole). The reaction mixture was stirred at r.t. for 5 days and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 25 mg of D-13 in 75 % yield. To a solution of D-13 (25 mg) in DCM (3 ml), was added HCl in Et20 (2N, 0.1 ml), solid was washed with ether to give 25 mg of D-13 HCl salt as solid. ¹H-NMR (400 MHz, DMSO-d6): 1.09 (3H, m), 2.46 (3H, s), 3.18 (2H, m), 4.10 (2H, s), 7.37 (IH, d, J= 8 Hz), 7.65 (3H, m), 7.78 (IH, br), 7.80 - 7.88 (2H, br), 7.90 (IH, m), 8.14 (IH, m), 8.23 (IH, m), 8.77 (IH, s), 9.8 - 10.4 (IH, br). MS(APCI+): 420.1 (M+l). LC-MS: 99 %.

[00134] Example 14. D- 14

[00135] Example 15. D- 15

2-bromopropanal (17) was prepared according to reference (Aleem Gangjee, et al. J. Medi. Chem. 2005, 48, 7215-7222).

[00136] Synthesis of 8-(3-Chloro-phenyl)-3-methyl-imidazo[l,2-a]pyridine-6- carboxylic acid methyl ester and 8-(3-Chloro-phenyl)-3-methyl-imidazo[l,2-a]pyridine- 6-carboxylic acid ethyl ester (18 and 19): In a microwave vial, was place 2 (570 mg, 2.1 mmole), 2-bromopropanal (17) (1.3 g, 10 mmole) and ethanol (10 ml). The reaction mixture was stirred at 150 oC for 2 hrs on a microwave synthesizer and then cooled to room temperature. After removal of solvent under vacuum, the residue was dissolved in water and the pH was adjusted to 8-9 by addition of NaHCO3 aq. The aqueous portion was extracted with ethyl acetate (3 x 30 ml), the organic portions were combined, washed with sat. NaHCO3 aq., brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing EtOAc/hexanes as the eluent to give 400 mg of a mixture of 18 and 19 (-1 :2) in 63% yield. ¹H-NMR (400 MHz, CDCl₃) [00137] Synthesis of [8-(3-Chloro-phenyl)-3-methyl-imidazo[l,2-a]pyridin-6-yl]- methanol (20): To a mixture of compound 18 and 19 (-1 :2) (700 mg, 2.2 mmol) in THF (anhydrous, 30 ml), was added DIBAL-H (IM in Toluene, 14 ml) dropwise at -78 oC under N2. The reaction mixture was stirred at -78 oC to r.t. and r.t. for 3 hrs. The reaction mixture was diluted with ice/water, adjusted pH to acidic and then stirred at r.t for about 20 min. After pH adjusted to 8-9 by addition of NaOH aq (6N), the aqueous portion was extracted with ethyl acetate (4x 80 ml). Organic layer was washed with sat. NaHCO3 aq., brine, and dried over Na2SO4. After removal of solvent, the residue was purified by column chromatography utilizing MeOH/DCM as the eluent to give 145 mg of product 20 in 24 % yield. ¹H-NMR (400 MHz, CDCl₃)

[00138] Synthesis of Carbonic acid 8-(3-chloro-phenyl)-3-methyl-imidazo[l,2- a]pyridin-6-ylmethyl ester methyl ester (21): To a mixture of compound 20 (110 mg, 0.4 mmol) in THF (8 ml), was added NaH (60 % in oil, 40 mg, 1 mmole) at -10 oC and stirred at r.t. for 20 min. Methyl chloroformate (86 mg, 0.9 mmole) was added dropwise at -20 oC under N2. The reaction mixture was stirred at r.t over night. The reaction mixture was diluted with water and extracted with ethyl acetate (3x 8 ml). The organic portions were combined, washed with brine, dried over Na2SO4. After removal of solvent, 130 mg of crude product 21 obtained. Crude 21 directly used in next step without further purification.

[00139] Synthesis of 5-[8-(3-Chloro-phenyl)-3-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-ylamine (D-14): A reaction mixture of compound 21 (65 mg crude, 0.2 mmol), 2-aminopyridine-5-boronic acid pinacol ester (44 mg, 0.2 mmol), 1,5- bis(diphenylphosphino) pentane (26 mg, 0.06 mmole), allylpalladium chloride dimer (11 mg, 0.03 mmol), K2CO3 (83 mg, 0.6 mmole) in DMF (2 ml)) was stirred at 90 ⁰C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(2 x 30 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 32 mg of D-14 in 45 % yield for two steps. To a solution of D-14 (16 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 17 mg of D-14 HCl salt as solid. ¹H-NMR (400 MHz, CD3OD): 2.70 (3H, s), 4.16 (2H, s), 7.01 (IH, d, J= 8 Hz), 7.58 - 7.64 (3H, m), 7.71 (IH, m), 7.83 (IH, m), 7.86 (IH, m), 7.88 (IH, m), 7.94 (IH, m), 8.71 (IH, s). MS(APCI+): 349.1 (M+ 1). LC- MS: 99 %. [00140] Synthesis of l-{5-[8-(3-Chloro-phenyl)-3-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-3-ethyl-urea (D-15): To a mixture of compound D-14 (16 mg, 0.046 mmol) in pyridine (1 ml), was added ethyl isocyanate (36 mg, 0.5 mmole). The reaction mixture was stirred at r.t. for 2 days and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 16 mg of D- 15 in 83 % yield. To a solution of D-15 (16 mg) in DCM (3 ml), was added HCl in Et20 (2N, 0.1 ml), solid was washed with ether to give 16 mg of D-15 HCl salt as solid. ¹H-NMR (400 MHz, CD3OD): 1.18 (3H, t, J= 7.2 Hz), 2.70 (3H, s), 3.13 (2H, q, J=7.2 Hz), 4.32 (2H, s), 7.28 (IH, d, J = 8Hz), 7.58 - 7.64 (3H, m), 7.72 (IH, m), 7.84 (IH, m), 7.88 (IH, m), 8.23 - 8.25 (2H, m), 8.74 (IH, m). MS(APCI+): 420.1 (M+l). LC-MS: 97 %.

[00141] Example 16. D- 16

[00142] Example 17. D- 17

[00143] Synthesis of 4-[8-(3-Chloro-phenyl)-3-methyl-imidazo[l,2-a]pyridin-6- ylmethylj-phenylamine (D-16): A reaction mixture of compound 21 (65 mg crude, 0.2 mmol), 4-aminophenyl boronic acid pinacol ester (44 mg, 0.2 mmol), 1,5- bis(diphenylphosphino) pentane (26 mg, 0.06 mmole), allylpalladium chloride dimer (11 mg, 0.03 mmol), K2CO3 (83 mg, 0.6 mmole) in DMF (2 ml)) was stirred at 90 ⁰C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(3 x 30 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 21 mg of D-16 in 30 % yield. To a solution of D- 16 (14 mg) in DCM (3 ml), was added HCl in Et20 (2N, 0.1 ml), solid was washed with ether to give 14 mg of D-16 HCl salt as solid. ¹H-NMR (400 MHz, CD3OD): 2.68 (3H, s), 4.31 (2H, s), 7.37 (2H, d, J=7.2 Hz), 7.54 - 7.60 (5H, m), 7.67 (IH, m), 7.78 (IH, m), 7.81 (IH, m), 8.69 (IH, s). MS(APCI+): 348.1 (M+ 1). LC-MS: 99 %.

[00144] Synthesis of l-{4-[8-(3-Chloro-phenyl)-3-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-phenyl}-3-ethyl-urea (D-17): To a mixture of compound D-16 (12 mg, 0.034 mmol) in pyridine (1 ml), was added ethyl isocyanate (36 mg, 0.5 mmole). The reaction mixture was stirred at r.t. for 2 days and concentrated. The crude material was purified by column chromatography utilizing ethyl acetate/hexane as the eluent to give 12 mg of D-17 in 84 % yield. To a solution of D-17 (12 mg) in DCM (3 ml), was added HCl in Et20 (2N, 0.1 ml), solid was washed with ether to give 12 mg of D-17 HCl salt as solid. ¹H-NMR (400 MHz, CD3OD): 1.13 (3H, t, J=7.2 Hz), 2.66 (3H, s), 3.20 (2H, q, J=7.2 Hz), 4.16 (2H, s), 7.24 (2H, d, J=8 Hz), 7.33 (2H, d, J= 8 Hz), 7.50 - 7.60 (3H, m), 7.68 (IH, m), 7.77 (2H, m), 8.55 (IH, m). MS(APCI+): 419.1 (M+ 1). LC-MS: 98 %.

[00145] Example 18. D- 18

[00146] Example 19. D- 19

[00147] Example 20. D-20

MeMgBr

THF

D-19 D-20

[00148] Synthesis of 5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridine-2-carboxylic acid methyl ester (D-18): A reaction mixture of compound 16 (200 mg crude, 0.55 mmol), 2-(methylcarboxy) pyridine-5-boronic acid pinacol este (145 mg, 0.55 mmol), l,5-bis(diphenylphosphino) pentane (73 mg, 0.165 mmole), allylpalladium chloride dimer (30 mg, 0.082 mmol), K2CO3 (228 mg, 1.65 mmole) in DMF (3 ml)) was stirred at 90 ⁰C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate (3 x 8 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 72 mg of D-18 in 33 % yield for two step. To a solution of D-18 (11 mg) in DCM (3 ml), was added HCl in Et20 (2N, 0.1 ml), solid was washed with ether to give 11 mg of D-18 HCl salt as solid. ¹H-NMR (400 MHz, CD3OD): 2.52 (3H, s), 4.01 (2H, s), 4.39 (2H, s), 7.57 - 7.63 (3H, m), 7.72 (IH, m), 7.84 (IH, m), 8.00 (IH, m), 8.20 (IH, m), 8.26 (IH, d, J=8 Hz), 8.69, IH, m), 8.78 (IH, m). MS(APCI+): 392.0 (M+ 1). LC-MS: 98 %.

[00149] Synthesis of 2-{5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-propan-2-ol (D-19) and l-{5-[8-(3-Chloro-phenyl)-2-methyl- imidazo[l,2-a]pyridin-6-ylmethyl]-pyridin-2-yl}-ethanone (D-20): To a mixture of compound D-18 (60 mg, 0.15 mmol) in THF (3 ml), was added MeMgBr (3 M in ether, 0.26 ml, 0.78 mmole) dropwise at -10 oC. The reaction mixture was stirred at r.t. over night. Water was added and the aqueous portion was extracted with ethyl acetate (4 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 22 mg of D-19 in 37 % yield and 9 mg of D-20 in 16 % yield. To a solution of D-19 (22 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 22 mg of D-19 HCl salt as solid. For D-19 HCl salt: ¹H-NMR (400 MHz, DMSO-d6): 1.52 (6H, s), 2.46 (3H, s), 4.27 (2H, s), 7.65 (3H, m), 7.79 (IH, br), 7.94 (IH, br), 7.98 (IH, br), 8.14-8.20 (2H, m), 8.70 (IH, m), 8.88 (IH, br). MS(APCI+): 392.1 (M+l). LC-MS: 94 %.

[00150] To a solution of D-20 (9 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 9 mg of D-20 HCl salt as solid. For D-20 HCl salt:

¹H-NMR (400 MHz, DMSO-d6): 2.46 (3H, s), 2.61 (3H, s), 4.27 (2H, s), 7.65 (3H, m), 7.78 (IH, br), 7.90 - 7.98 (3H, m), 8.14 (IH, m), 8.77 (IH, m), 8.84 (IH, br). MS(APCI+): 376.1 (M+l). LC-MS: 84 %. [00151] Example 21. D-21

D-12 D-21

[00152] Synthesis of N-{5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-2-dimethylamino-acetamide (D-21): To a mixture of compound D-12 (20 mg, 0.057 mmol) and dimethylamino acetyl chloride hydrochloride (23 mg, 0.14 mmole) in DCM (2 ml), was added diisopropylethylamine (37 mg, 0.3 mmole). The reaction mixture was stirred at 40 oC for 3 days and diluted with DCM (5 ml) and sat. NaHCO3 aq. The aqueous portion was extracted with DCM (3 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 13 mg of D- 21 in 53 % yield. To a solution of D-21 (13 mg) in DCM (3 ml), was added HCl in Et20 (2N, 0.1 ml), solid was washed with ether to give 13 mg of D-21 HCl salt as solid. ¹H-NMR (400 MHz, DMSO-d6): 2.47 (3H, s), 2.85 (3H, s), 2.87 (3H, s), 4.14 (2H, s), 4.18 (2H, br), 7.65 (3H, m), 7.78 (IH, br), 7.84 (IH, dd, J= 8 and 2.4 Hz), 7.90 (IH, br), 8.00 (IH, br), 8.16 (IH, br), 8.40 (IH, d, J=2.4 Hz), 8.82 (IH, br, 10.0 (IH, br), 11.15 (IH, s), 14.0 (IH, br). MS(APCI+): 434.1 (M+l). LC-MS: 99 %.

[00153] Example 22. D-22

[00154] Example 23. D-23

D-12 D-22 D-23

[00155] Synthesis of (D-22): To a mixture of compound D-12 (40 mg, 0.115 mmol) and diisopropylethylamine (74 mg, 0.57 mmole) in DCM (3 ml), was added ethyl chloroformate (31 mg, 0.29 mmole). The reaction mixture was stirred at r.t. over night and diluted with DCM (5 ml) and sat. NaHCO3 aq. The aqueous portion was extracted with DCM (2 x 8 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 49 mg of D-22 in 87 % yield. To a solution of D-22 (40 mg) in ether (8 ml), was added HCl in Et20 (2N, 0.15 ml), solid was washed with ether to give 50 mg of D-22 HCl salt as solid. ¹H-NMR (400 MHz, DMSO-d6): 1.11 (6H, m), 2.46 (3H, s), 4.14 (4H, q, J=7.2 Hz), 4.20 (2H, s), 7.43 (IH, d, J=8 Hz), 7.64 (3H, m), 7.77 (IH, br), 7.89 (IH, dd, J=8 and 2.4 Hz), 7.95 (IH, s), 8.17 (IH, s), 8.50 (IH, d, J=2.4 Hz), 8.90 (IH, s), 14.0 (IH, br). MS(APCI+): 493.1 (M+ 1). LC-MS: 99 %.

[00156] Synthesis of {5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-carbamic acid ethyl ester (D-23): A reaction mixture of compound D-22 (20 mg, 0.04 mmol) in EtOH (3 ml) and NaOH aq. (2N, 1 ml) was stirred at r.t. for 4 hrs and diluted with water (5 ml). The aqueous portion was extracted with ethyl acetate (2 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 16 mg of D-23 in 95 % yield. To a solution of D- 23 (16 mg) in ether (5 ml), was added HCl in Et20 (2N, 0.1 ml), solid was washed with ether to give 17 mg of D-23 HCl salt as solid. ¹H-NMR (400 MHz, DMSO-d6): 1.23 (3 H, t, J=7.2 Hz), 2.46 (3H, s), 4.10 (2H, s), 4.14 (2H, q, J=7.2 Hz), 7.65 (3H, m), 7.78 (3H, m), 7.91 (IH, m), 8.14 (IH, s), 8.30 (IH, br), 8.78 (IH, s), 10.25 (IH, br). MS(APCI+): 421.1 (M+l). LC- MS: 99 %.

[00157] Example 24. D-24

[00158] Example 25. D-25

OH

[00159] Synthesis of S-CS-Chloro-pheny^-ό-Cό-fluoro-pyridin-S-ylmethyl)-!- methyl-imidazo[l,2-a]pyridine (D-24): A reaction mixture of compound 16 (220 mg crude, 0.55 mmol), 2-fluoro-5-pyridine boronic acid (78 mg, 0.55 mmol), 1,5- bis(diphenylphosphino) pentane (73 mg, 0.165 mmole), allylpalladium chloride dimer (30 mg, 0.082 mmol), K2CO3 (228 mg, 1.65 mmole) in DMF (3 ml)) was stirred at 90 ⁰C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate (5 x 8 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 120 mg of D-24 in 62 % yield. To a solution of D-24 (70 mg) in DCM (3 ml), was added HCl in Et20 (2N, 0.2 ml), solid was washed with ether to give 70 mg of D-24 HCl salt as solid. ¹H-NMR (400 MHz, DMSO- d6): 2.46 93H, s), 4.17 (2H, s), 7.17 (IH, dd, J= 8 and 2.4 Hz), 7.64 (3H, m), 7.78 (IH, br), 7.93 (IH, d, J=1.6 Hz), 7.98 (IH, m), 8.14 (IH, s), 8.28 (IH, d, J = 2.8 Hz), 8.80 (IH, s). MS(APCI+): 352.0 (M+l). LC-MS: 99 %.

[00160] Synthesis of ({5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-methyl-amino)-acetic acid (D-25): A mixture of compound D-24 (50 mg, 0.13 mmol), sacosine (23 mg, 0.26 mmole) and DBU (120 mg, 0.78 mmole) was stirred at 150 oC for 1 hr. and cooled to r.t.,. A sat. NH4C1 aq. was added and the aqueous portion was extracted with DCM (5 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 38 mg of D-25 in 70 % yield. To a solution of D-25 (38 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.15 ml), solid was washed with ether to give 38 mg of D-25 HCl salt as solid. ¹H-NMR (400 MHz, DMSO-d6): 2.46 (3H, s), 3.17 (3H, s), 4.08 (2H, s), 4.46 (2H, s), 4.40 - 4.70 (2H, br), 7.10 (IH, br), 7.65 (3H, m), 7.78 (IH, br), 7.94 (2H, m), 8.11 (IH, m), 8.16 (IH, br), 8.83 (IH, br). MS(APCI+): 421.1 (M+l). LC-MS: 99 %. [00161] Example 26. D-26

D-24 D-26

[00162] Synthesis of l-{5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-azetidine-2-carboxylic acid (D-26): A mixture of compound D-24 (65 mg, 0.17 mmol), D,L-Azetidine-2-carboxylic acid (34 mg, 0.34 mmole) and DBU (304 mg, 2 mmole) was stirred at 150 oC for 1 hr. and cooled to r.t.,. A saturated NH4C1 aq. was added and the aqueous portion was extracted with DCM (5 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 35 mg of D-26 in 48 % yield. To a solution of D-26 (35 mg) in DCM (3 ml), was added HCl in Et20 (2N, 0.15 ml), solid was washed with ether to give 35 mg of D-26 HCl salt as solid. ¹H- NMR (400 MHz, DMSO-d6): 2.40 (IH, m), 2.46 (3H, s), 2.77 (IH, m), 4.08 (2H, s), 4.12 (IH, m), 4.21 (IH, m), 5.10 (IH, m), 6.90 (IH, br), 7.65 (3H, m), 7.78 (IH, s), 7.94 (IH, s), 7.96 (IH, m), 8.11 (IH, m), 8.17 (IH, s), 8.85 (IH, s). MS(APCI+): 433.1 (M+l). LC-MS: 97 %.

[00163] Example 27. D-27

[00164] 5-Methyl-2H-pyrazole-3-carboxylic acid hydrazide (23): To a 20 mL vial with stir bar was added, Ethyl 3-methylpyrazole-5-carboxylate (1.56 g, 10.1 mmol), EtOH (4 mL), and hydrazine hydrate (2.46 mL, 50.6 mmol). The reaction was heated at 78 ⁰C for 18 hours. The reaction was concentrated to afford 23 as a white solid (1.35 g, 95%), 23 was used as is in the next reaction.

[00165] 2-Methyl-7-phenyl-5H-pyrazolo[l,5-d] [l,2,4]triazin-4-one (24): Into a 50 mL round bottom flask equipped with a stir bar was added 23 (1.35 g, 9.63 mmol), DMF (25 mL), and phenyl orthoformate (2.48 mL, 14.5 mmol). The reaction was refluxed for 24 hours. The DMF was removed by blowing a stream of N₂ into the hot flask. Ethyl acetate (5 mL) was added to the flask followed by H₂O (5 mL). The flask was shaken and the aqueous portion discarded. This was repeated once more. The EA was concentrated. EtOH (2 mL) was added to the viscous oil, the flask was capped, and allowed to sit overnight at RT. The mixture was filtered to obtain the off- white solid that had formed overnight. The solid was washed with EtOH, collected, and dried under vacuum to give 0.37 g (17%) of off-white solid, 24. ¹H-NMR (500 MHz, CDCl₃) δ 13.35 (s, IH), 8.07 (dd, 2H, J= 7.5, 1.5 Hz), 7.66- 7.61 (m, 3H), 6.72 (s, IH), 2.34 (s, 3H).

[00166] 5-(4-Fluoro-benzyl)-2-methyl-7-phenyl-5H-pyrazolo[l,5-d] [l,2,4]triazin-

4-one, (D-27): To a 25 mL round bottom flask equipped with a stir bar was added 24 (50.6 mg) and dry THF (2 mL). The 24 remained insoluble so dry DMF (2 mL) was added to obatin a homogeneuos solution which was cooled to 0 ⁰C and NaH (6.4 mg) was added. The reaction was stirred at 0 ⁰C for 15 min. then RT for 15 min. The mixture was then cooled to 0 ⁰C and 4-Fluorobenzyl bromide (0.028 ml, 0.22 mmole) was added. The reaction was allowed to slowly come to RT and stir for 16 hours. 5 drops Of H₂O were added and the reaction concentrated. Purification by flash column chromatography (15 g SiO₂, wet-pack with hexane) using 15% EA/Hexanes afforded 40.4 mg (54%) of D-27 as a off- white solid. ¹H-NMR (500 MHz, CDCl₃) δ 8.12 - 8.09 (m, 2H), 7.55 - 7.49 (m, 5H), 7.04 - 6.98 (m, 3H), 5.28 (s, 2H), 2.47 (s, 3H). ¹³C-NMR (125 MHz, CDCl₃) δ 163.7, 161.8, 154.2, 153.3, 138.6, 135.5, 132.3, 131.1, 131.0, 129.8, 129.3, 128.5, 115.8, 115.6, 106.7, 52.8, 14.2; LC/MS = 96.6%, 335.6 (ESI+). [00167] In similar fashion the following were synthesized:

[00168] Methods of the invention parallel the compositions and formulations. The methods comprise administering to a patient in need of treatment a therapeutically effective amount of a compound according to the invention. The present invention also provides a method for inhibiting phosphodiesterase 4.

[00169] In-vitro assay for PDE4 enzymes. The in-vitro activity of PDE4 enzymes and the in-vitro potency of therapeutic agents described in the present invention was measured using a real-time, enzyme-coupled spectrophotometric assay. By using three different coupling enzymes, the product of the PDE4 reaction is coupled to the oxidation of the reduced form β -nicotinamide adenine dinucleotide (NADH), which dissipation can be monitored spectrophotmetrically at 340 nM.

[00170] Assay description. Buffer A containing 50 mM Tris, pH 8.0, 16 mM MgCl₂ and 80 mM KCl is prepared and stored at room temperature. Buffer B containing 50 mM Tris, pH 8.0 is prepared and stored at toom temperature. Stock solutions of the following reagents are prepared in Buffer B and stored at -20⁰C: Adenosine-5 '-triphosphate (ATP), cyclic adenosine-5 '-monophosphate (cAMP), phosphoenolpyruvate (PEP) and NADH. An assay mix is prepared by mixing Buffer A, trichloroethylphosphine (TCEP), ATP, PEP, NADH, myokinase (MK), pyruvate kinase (PK), lactate dehydroganese (LDH) and PDE4 to a final volume of 20 mL, which is enough for a single 96-well assay plate. Assay mix (180 μL) and test article (10 μL ) in 1 : 1 DMSO/H₂O mixture is pre-incubated at room temperature for 10 min. The enzymatic reaction is initiated by addition of c AMP (10 μL). Final concentration of all components in the assay (200 μL/well) are as follows: 10 mM MgCl₂, 50 mM KCl, 5 mM TCEP, 2.5% DMSO, 0.4 mM NADH, 1 mM PEP, 0.04 mM ATP, 5 units MK, 1 unit PK, 1 unit LDH and appropriate amount of PDE4. Reaction progress curves are monitored in a plate reader capable of measuring light absorbance at 340 nM. A decrease in light absorbance at 340 nm is due to oxidation of NADH. Positive controls containing no test article and negative controls containing no test article and no cAMP are included on every assay plate. Reaction rates are determined from the slopes of the linear portions of the progress curves. All data is percent normalized with respect to controls and presented as percent inhibition.

[00171] The results of testing of representative species are shown below. The values

A-E are based on IC₅₀ in the assay described above.

[00172] Table 3.

[00174] It should be noted that compounds D-28 and D-49 are 50 to 70-fold selective for inhibiting the B isoform over the D isoform, whereas D-29, D-30 and D-31 are slightly (3 to 6-fold) more selective for the D isoform over the B.

[00175] The activity of PDE4 inhibitors decribed in the present invention was also measured using in an ex- vivo assay measuring leukotriene E4 (LTE4) in human whole blood after Sephadex stimulation. The anti- inflammatory activity of therapeutic agents of the present invention is demonstrated by the inhibition of eosinophil activation as measured by sephadex bead stimulated LTE4 production in whole human blood. For each sample, 356 μl of heparinized human whole blood (Vacutainer tube #6480) is added to wells of a 96 well plate. Then, 4 μl of a series of compound dilutions (in DMSO) are added in triplicates, suspension mixed and allowed to incubate at 37⁰C for 15 min with gentle shaking. After that, blood samples are stimulated by adding 40 μL of Sephadex G-15 beads (Sigma-Aldrich, Sweden). The beads are predissolved in PBS (0.16 g/ mL PBS). After mixing, the suspension is incubated at 37 ⁰C for 90 min. Then, 8 μL of 15% EDTA/PBS is added to each sample, mixed and plate centrifuged for 5 min at 115 x g at 21⁰C and supernatants taken. In each plate, 10 positive controls and 10 negative controls are used, containing DMSO instead of compound solution. The positive controls are stimulated with Sephadex as described for the samples, and in the negative controls (unstimulated), Sephadex solution is replaced by PBS. LTE₄ levels in the resulting plasma samples are determined using a commercial enzyme- linked immunoassay (Cayman Chemical Company, Ann Arbor, MI) according to the manufacturer's instructions. Table 5 provides data for some representative examples:

[00176] Table 5.

[00177] Persons of skill in the art accept that positive results in PDE4 models are predictive of therapeutic utility as discussed above.

Claims

CLAIMS We claim: 1. A compound of formula I or formula II

wherein

P is chosen from nitrogen and carbon;

Q is chosen from nitrogen and carbon, with the provisos that one of P or Q must be nitrogen, but P and Q cannot both be nitrogen;

R¹ is selected from hydrogen, (Ci-C₆) alkyl, haloalkyl, -CONHR⁵, lower alkoxy, alkylamino, dialkylamino, amino, -NHCOOR₂ and -OCONH₂;

W is nitrogen or CR ;

R² is selected from hydrogen, (Ci-C₆) alkyl, haloalkyl and optionally substituted heterocyclyl;

Y is CR³ or nitrogen;

R³ is selected from hydrogen, fluoro, hydroxyl and -OR¹⁰;

R¹⁰ is selected from (Ci-C₆) alkyl optionally substituted with fluoro;

X is selected from CR⁴, nitrogen and N⁺ O^";

R⁴ is selected from hydrogen, (Ci-C₆) alkyl, halogen, amino, alkoxy and hydroxyl;

R⁵ is selected from hydrogen and (Ci-C₆) alkyl;

R⁸ and R⁹ are independently selected from hydrogen, (Ci-C₆) alkyl, (Ci-C₆) hydroxyalkyl, (C3-C₆) carbocyclyl and a 3- to 6-membered heterocyclyl; or R⁸ and R⁹ together form a 4-6 membered ring which optionally contains a heteroatom selected from -O- , -NR⁵ and S(Oy₂; or R⁸ and R⁹ together form an oxo group;

Z is selected from -0-, -S(0)o-₂, -NH-, -CH₂- and a direct bond;

Cy¹ is selected from optionally substituted (C₃-C₆) carbocyclyl and optionally substituted heterocyclyl; Cy² is selected from optionally substituted aryl and optionally substituted heteroaryl; and

M is chosen from -CH₂-, -CH₂CH₂-, -O-, -S(O)_0-2-, -OCH₂-, -CH₂O-, -CONH-, -CONHCH₂-, -NHCO- and -NHSO₂-, with the proviso that when M is -NH- or -CONH-, Q is not nitrogen; and with the proviso that 4'-[(7-phenylpyrazolo[l,5-a]pyrimidin-5-yl)methyl]-[l,r- Biphenyl]-2-carbonitrile, 7-[3-(acetylethylamino)phenyl]-3-cyanopyrazolo[ 1 ,5-a]pyrimidin- 5-yl-β-D-Glucopyranosiduronic acid and 7-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-5- (phenylmethyl)-[l,2,4]Triazolo[l,5-a]pyrimidine are excluded compounds.

2. A compound according to claim 1 wherein P is nitrogen;

Q is carbon; W is CR²;

Y is CR³; and

X is selected from CR⁴ and N.

3. A compound according to claim 1 wherein P is nitrogen;

Q is carbon; W is nitrogen;

Y is CR³; and

X is selected from CR⁴ and N.

4. A compound according to claim 1 wherein P is carbon;

Q is nitrogen; W is CR²;

Y is CR³;

X is selected from CR⁴ and N; and

Z is selected from -0-, -S(0)o_-2, -CH₂- and a direct bond.

5. A compound according to claim 1 wherein P is carbon;

Q is nitrogen;

W is CR²;

Y is nitrogen;

X is CR⁴; and

Z is selected from -O-, -S(0)o_-2, -CH₂- and a direct bond.

6. A compound according to claim 1 of formula II wherein P is carbon;

Q is nitrogen;

W is nitrogen or CR²; and

X is nitrogen.

7. A compound according to any of claims 1-6 wherein Z is a direct bond;

M is -CH₂- or -CONH-;

Cy¹ is selected from optionally substituted aryl and an optionally substituted 5- or 6- membered ring nitrogen heterocycle; and

Cy² is selected from optionally substituted phenyl and an optionally substituted 5- or 6- membered ring nitrogen heterocycle.

8. A compound according to claim 7 wherein

Cy¹ is selected from optionally substituted phenyl and an optionally substituted 5- or 6- membered ring nitrogen heterocycle; and

Cy² is selected from phenyl, 3-chlorophenyl, 3-nitrophenyl, 3-bromophenyl, 3-acetylphenyl, 3-trichloromethylphenyl and 3-methylthiophenyl.

9. A compound according to claim 8 wherein

Cy¹ is selected from optionally substituted phenyl, pyridinyl, morpholin-4-yl, piperazin-1-yl, piperidiny-1-yl, imidazol-1-yl, pyrazol-1-yl, and pyrazol-5-yl; and Cy² is selected from phenyl and 3-chlorophenyl.

10. A compound according to claim 9 wherein Cy¹ is selected from phenyl and pyridinyl, each of which is optionally substituted with a substituent chosen from halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylamino alkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, -NHC(=O)NHalkyl, -NHC(=O)NH-heterocyclyl, -alkyl-NHC(=O)N(alkyl)₂, heterocyclylalkylcarbonylamino, benzyloxyphenyl, benzyloxy, azetidine acid, azedtidine amide, the residues of amino acids, amino acid amides, protected residues of aminoacids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides.

11. A compound according to claim 9 wherein Cy¹ is selected from phenyl and pyridinyl, each of which is optionally substituted with a substituent chosen from -CH₃, -CH₂CF₃, -CF₃, -CHO, -COOH, -CN, halogen, -OH, , -OEt, -C(=0)NH₂, -C(=O)NHEt, -C(=0)NMe₂ -COOCH₃, -COOEt, -CH₂NHC(=O)NH₂, -CH(CH₃)NHC(=O)NH₂, -CH₂NHC(=0)H, -CH₂NHC(=O)CH₃, -CH₂C(=O)NH₂, -CH₂COOH, -CH₂COOEt, -CH₂NHC(=O)OEt, -CH₂NHCC=O)O-C₆H₅, -CH₂NHC(=O)C(=O)NH₂, -CH₂NHC(=O)NHEt, -C(CH₃)₂OH, -CH₂NHC(=O)N(CH₃)₂, -CH₂NHC(=O)NHCH₃, -CH₂NH₂, -CH(CH₃)NH₂, -C(CH₃)₂NH₂, -CH₂OH, -CH₂CH₂OH, -CH₂NHSO₂CH₃, -CH₂OC(=O)NHEt, -OCH₃, -0C(=0)NH₂, -OCH₂CH₂N(CH₃)₂, -OCH₂CH₂OCH₃, -NHC(=0)NH₂, -NHC(=O)NHEt, -NHCH₃, -NHEt, -NH(tBoc), -NHCH₂COOH, -N(CH₃)CH₂COOH, -NHC(=O)NHCH₂CH₂C1, -NHSO₂NH₂, -NHEt, -N(CH₃)₂, -NH₂, , -NH(CH₃)C(=O)NH₂, -NHSO₂CH₃, -N(SO₂CH₃)₂, -NHC(=O)OCH₃, -NHC(=O)OtBu, -NHC(=O)CH₃, -SO₂NH₂, -NHC(=O)CH₂CH₂COOH, -NHC(=O)NHCH₂COOH, -CH₂NHCHO, -NHC(=O)NHCH₂COOEt, -NHC(=O)NH(CH₂)₃COOEt, -NHC(=O)NH(CH₂)₂COOEt, -N(CH₃)CH₂CH₂OH, -NHC(O)OEt, -N(Et)C(O)OEt, -NHC(=O)NH(CH₂)₂COOH, -NHC(=O)CH₂N(CH₃)₂, -NHC(=O)NH(CH₂)₃COOH, -NHC(=O)CH₂NH₂, -NHC(=O)CH₂CH₂NH₂,

12. A compound according to any of claims 1, 2, 4, 5 or 6 wherein W is CR ; and

R² is selected from hydrogen, methyl,

and ΛΛΛXWV _; wherein J is selected from O, S(O)_0-2, NH and NCH₃; and L is selected from C and N.

13. A compound according to claim 12 wherein R is hydrogen.

14. A compound according to any of claims 1-5 wherein R⁴ is hydrogen.

15. A compound according to any of claims 1-4 wherein R³ is hydrogen.

16. A compound according to any of claims 1-5 wherein R¹ is selected from hydrogen and (Ci-Cβ) alkyl; X is selected from CH and CF;

Cy ¹ is selected from optionally substituted phenyl, pyridinyl, morpholinyl, piperazinyl, piperidinyl, imidazolyl, pyrazolyl, oxazolidinyl, pyrrolidinyl, thiazolyl, benzo[c] [ 1 ,2,5]oxadiazolyl;

Cy² is optionally substituted phenyl;

Z is a direct bond; and

M is -CH₂- or -CONH-.

17. A compound according to claim 16 wherein R¹ is methyl; and Cy ¹ is phenyl optionally substituted with a substituent selected from amino, urea,

alkylurea, -NHCO₂(Ci-C₆)alkyl, azeditine acid, azeditine amide,

and

18. A compound according to claim 6 wherein R¹ is selected from hydrogen and (Ci-C₆) alkyl; R² is selected from hydrogen and (Ci-C₆) alkyl;

Cy ¹ is selected from optionally substituted aryl and heteroaryl; and Cy² is selected from optionally substituted aryl and heteroaryl.

19. A compound according to claim 18 wherein R¹ is methyl;

R² is hydrogen;

R⁸ and R⁹ together form an oxo group; Cy * is optionally substituted phenyl; and Cy² is optionally substituted phenyl.

20. A compound according to claim 18 wherein R¹ is methyl;

R² is hydrogen;

R⁸ and R⁹ are each independently selected from hydrogen and (Ci-Cβ) alkyl;

Cy * is optionally substituted phenyl; and

Cy² is optionally substituted phenyl.

21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any of claims 1-20.

22. A method for the treatment or prophylaxis of a disease or condition mediated by phosphodiesterase-4 comprising administering to a mammal a therapeutically effective amount of a compound according to any of claims 1-20.

23. A method according to claim 22 wherein said disease or condition is chosen from stroke, myocardial infarct, cardiovascular inflammatory conditions, atherosclerosis, thrombosis, acute coronary syndrome, stable angina, peripheral vascular disease, critical leg ischemia, intermittent claudication and abdominal aortic aneurysm.

24. A method according to claim 22 wherein said disease or condition is cancer.

25. A method according to claim 22 wherein said disease or condition is chosen from asthma and COPD.

26. A method for improving cognitive function comprising administering to a mammal a therapeutically effective amount of a compound according to any of claims 1-20.

27. A method according to claim 26 wherein said cognitive function is memory or cognition.

28. A method according to claim 26 for treating learning disorders.

29. A method for treating schizophrenia or Huntington's disease comprising administering to a mammal a therapeutically effective amount of a compound according to any of claims 1-20.

30. A method for treating or preventing bone loss comprising administering to a mammal a therapeutically effective amount of a compound according to any of claims 1-20.

31. A method for treating depression or anxiety comprising administering to a mammal a therapeutically effective amount of a compound according to any of claims 1-20.

32. A method for treating or preventing bladder inflammation, bladder pain or bladder overactivity comprising administering to a mammal a therapeutically effective amount of a compound according to any of claims 1-20.

33. A pharmaceutical composition comprising

(a) a pharmaceutically acceptable carrier;

(b) a compound according to any of claims 1-20; and

(c) a second agent chosen from cholinesterase inhibitors, NMDA antagonists, calpain inhibitors and antioxidants.

34. A pharmaceutical composition according to claim 33 wherein said second agent is chosen from tacrine, huperzine, donepezil, lanicemine, remacemide, neramexane, memantine, vitamin E and coenzyme QlO.

35. Use of a compound according to any of claims 1-20 for the treatment or prophylaxis of a disease or condition mediated by phosphodiesterase-4 comprising administering to a mammal a therapeutically effective amount of said compound.

36. Use according to claim 35 wherein said disease or condition is selected from stroke, myocardial infarct, cardiovascular inflammatory conditions, atherosclerosis, thrombosis, acute coronary syndrome, stable angina, peripheral vascular disease, critical leg ischemia, intermittent claudication and abdominal aortic aneurysm.

37. Use according to claim 35 wherein said disease or condition is cancer.

38. Use according to claim 35 wherein said disease or condition is chosen from asthma and COPD.

39. Use of a compound according to any of claims 1-20 for improving cognitive function comprising administering to a mammal a therapeutically effective amount of said compound.

40. Use according to claim 39 wherein said cognitive function is memory or cognition.

41. Use according to claim 39 for treating learning disorders.

42. Use of a compound according to any of claims 1-20 for treating schizophrenia or Huntington's disease comprising administering to a mammal a therapeutically effective amount of said compound.

43. Use of a compound according to any of claims 1-20 for treating or preventing bone loss comprising administering to a mammal a therapeutically effective amount of said compound.

44. Use of a compound according to any of claims 1-20 for treating depression or anxiety comprising administering to a mammal a therapeutically effective amount of said compound.

45. Use of a compound according to any of claims 1-20 for treating or preventing bladder inflammation, bladder pain or bladder overactivity comprising administering to a mammal a therapeutically effective amount of said compound.

46. A salt of a compound of any of claims 1-20 wherein said salt is pharmaceutically acceptable.