INHIBITORS OF PHOSPHODIESTERASE
Field of the Invention
The present invention relates to catechol derivatives, which can be used as inhibitors of phosphodiesterase (PDE) type 4 or type 7
Compounds disclosed herein can be useful in the treatment of CNS disorders, inflammatory diseases such as, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans
Processes for the preparation of disclosed compounds are provided, as well as pharmaceutical compositions containing the disclosed compounds, and their use as phosphodiesterase (PDE) type 4 or type 7 inhibitors
Background of the Invention
It is known that cyclic adenosine-3',5'-monophosphate (cAMP) exhibits an important role of acting as an intracellular secondary messenger (Sutherland and Roll, Pharmacol 7?ev(1960),12 265) Its intracellular hydrolysis to adenosine 5'-monophosphate (AMP) causes number of inflammatory conditions which are not limited to psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis The most important role in the control of cAMP (as well as of cGMP) levels is played by cyclic nucleotide phosphodiesterases (PDE) which represent a biochemically and functionally, highly variable superfamily of the enzyme Eleven distinct families of phosphodiesterases with more than 25 gene products are currently recognized Although PDE1, PDE2, PDE3, PDE4, and PDE7 all use cAMP as a substrate, only the PDE4 and PDE7 types are highly selective for hydrolysis of cAMP Inhibitors of PDE, particularly the PDE4 inhibitors, such as rolipram or Ro-1724 are therefore known as cAMP-enhancers Immune cells contain type 4 and type 3 PDE, the PDE4 type being prevalent in human mononuclear cells Thus the inhibition of phosphodiesterase type 4 has been a target for modulation and, accordingly, for therapeutic intervention in a range of disease processes Studies have shown that administering PDE4 inhibitors can have a restorative effect on memory loss in animal models, including those of Alzheimer's disease {Expert Opin Ther Targets (2005) 9 (6) 1283-1305, Drug Discovery Today, (2005), 10 (22) 1503-19) The potential importance of subtypes of PDE4 in terms of development of new inhibitors of PDE4 has recently emerged In PDE4B-deficient mice, but not those lacking PDE4D, there is a profound reduction in the ability of LPS to generate TNFcc from stimulated peripheral blood leukocytes (Jin and Conti, Proc Natl Acad Sci (2002), 99 (11) 7628-33) It would appear that
development of more specific PDE4B inhibitors may be useful, since the PDE4B knock-out mice showed reduced duration of xylazine/ketamine-tnggered anaesthesia which is used as a surrogate marker for emesis in mice, which do not usually demonstrate vomiting (Robichaud et al, 2002, J Clin Invest 110 1045)
Of the other cAMP family of proteins discovered so far, PDE7A also offers itself as a promising candidate for inhibitor development because of its cellular distribution in almost all pro inflammatory and immune cells (Curr Pharm Des (2006), 12 (25) 3207-20) Additionally, it has been shown to be a prime modulator of human T cell function {Science (1999) Feb 5, 283 (5403) 848-51)
The initial observation that xanthine derivatives, theophylline and caffeine inhibit the hydrolysis of cAMP led to the discovery of the required hydrolytic activity in the cyclic nucleotide phosphodiesterase (PDE) enzymes More recently, distinct classes of PDEs have been recognized (Beavo and Reifsnyder, Trends Pharmacol Sci, (1990), 11 150), and their selective inhibition has led to improved drug therapy (Nicholus, Chalhss and Shahid, Trends Pharmacol Sci, (1991), 12 19) Thus it was recognized that inhibition of PDE 4 could lead to inhibition of inflammatory mediator release (Verghese et al, J Mol Cell Cardiol, (1989), 12 (Suppl II) S
61)
WO 2004046095 discloses certain arylthiourea derivatives and related compounds, which possess antiviral activity WO 00/35891 discloses certain morphohnone and morphohne derivative, which are selective antagonists for human α1a receptor WO 2004050024 discloses 3-aminopyrrohdine derivatives and their use as modulators of chemokine receptors WO 2005/21515 relates to isoxazoline derivatives, which can be used as selective inhibitors of phosphodiesterase (PDE) type IV WO2005/051931 discloses phosphodiesterase inhibitors
Summary of Invention
The present invention provides catechol derivatives, which can be used for the treatment of CNS disorders, inflammatory diseases such as, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans, and the processes for the synthesis of these compounds
Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides of these compounds having the same type of activity are also provided
Pharmaceutical compositions containing the compounds, which may also contain pharmaceutically acceptable carriers or diluents, can be used for CNS disorders, inflammatory
diseases such as, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans
The present invention encompasses a compound having the structure of Formula I,
(Formula Removed)
its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides wherein when X is oxygen,
Ri can be hydrogen, alkyl, heterocyclyl, -(CH2)1-4OR', provided that R2 is also (CH2)1-4 OR' (wherein R' can be hydrogen, alkyl, alkenyl, alkynyl, (un)saturated cycloalkyl, aryl, heterocyclyl or heteroaryl), -C(=O)NRxRy provided that R2 is also -C(=O)NRxRy [wherein RX and Ry can be hydrogen, alkyl, alkenyl of three to six carbon atoms, alkynyl of three to six carbon atoms, cycloalkyl, -SO2R5 (wherein R5 can be hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl), aryl, alkaryl, heteroaryl, 1heterocyclyl, heteroarylalkyl, and heterocyclylalkyl], -(CH2)m-C(=O)R3 (wherein m can be an integer in the range of 0-2 and R3 can be cycloalkyl, aryl, optionally substituted Rp or Rq, wherein Rp can be heterocyclyl or heteroaryl ring wherein the said rings can be attached to (CH2)mC(:=O) through N, and Rq can be heterocyclyl or heteroaryl ring wherein the said rings can be attached to -(CH2)mC(=O) through C),
R2 can be -(CH2)mC(=O)R3 (wherein m and R3 are the same as defined earlier), -(CH2)1-4OR', provided R1 is also (CH2)1-4OR' (wherein R' is same as defined earlier), -C(=O)NRxRy provided R1 is also -C(=O)NRxRy (wherein RX and Ry are same as defined earlier), or R1 and R2 may together form optionally substituted cycloalkyl or heterocyclyl ring wherein the substituents of such a joint R1-R2 nng(s) can be oxo, alkyl, alkenyl, alkynyl, halogen (F, CI, Br, I), nitro, -NH2,
=NOH, -C(=O)NRxRy, -COORx, -COONRxRy (wherein RX and Ry are the same as defined
earlier), -NHCOOR6 (wherein R6 can be alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl,
heteroarylalkyl or heterocyclylalkyl), cyano, hydroxy, alkoxy, or substituted amino,
R4 can be hydrogen, alkyl, -OR5 (wherein R5 is the same as defined earlier), halogen (F, CI, Br,
I), -NH2, substituted amino, cyano, carboxy, or -C(=O)NRxRy (wherein RX and Ry are the same as
defined above), or R2 and R4 may together form optionally substituted 4-12 membered
(un)saturated monocyclic or bicyclic ring system fused to ring B having 0-4 heteroatom(s)
selected from N, O and S with the proviso that R2 and R4 together does not form -CH2-O-CH2-
O-CH2-, wherein the substituents can be one or more of alkyl, halogen (F, CI, Br, I), hydroxy,
alkoxy, -NH2 or substituted ammo,
R7 can be hydrogen, alkyl, alkenyl, alkynyl, -OR5 (wherein R5 is the same as defined earlier),
halogen (F, CI, Br, I), cyano, -NH2 or substituted amino,
X1 and X2 can be hydrogen, alkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, aryl,
heteroarylalkyl or heterocyclylalkyl, -(CH2)mCOR3, -(CH2)gC(=O)NRxRy or -(CH2)g1C(=O)OR3
(wherein g and g1 can be an integer from 0-3, m, RX, Ry and R3 are the same as defined earlier),
Y can be an oxygen atom, a sulphur atom, or -NR (wherein R can be hydrogen, acyl, aryl, or
alkyl),
Y1 and Y2 can be independently selected from hydrogen, alkyl, -OR (wherein R is the same as
defined earlier), -SR (wherein R is the same as defined earlier, and -NHR (wherein R is the
same as defined earlier),
Any of Y1 and X2 & X1 and Y2 may together form a cyclic ring fused with the ring A shown in
Formula I, the ring containing 3-5 carbon atoms within the ring and having 1-3 heteroatoms
such as N, O and S
X1 and X2 may together form a cyclic ring fused with the ring A shown in Formula I, the ring
containing 3-5 carbon atoms within the ring and having 2-3 heteroatoms such as N, O and S
When X is NR7 or S, wherein R7 is hydrogen or lower alkyl (C1-C6)
R1 and R2 can be independently alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, cyano, nitro, halogen
(F, CI, Br, I), heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, -NH2, substituted
amino, carboxy, -(CH2)m(C=O)R3 (wherein m and R3 are the same as defined earlier), -
C(=O)NRxRy (wherein Rx and Ryare the same as defined above), or -(CH2)1-4OR' (wherein R' is
same as defined earlier) or Ri and R2 may together form optionally substituted cycloalkyl or
heterocyclyl ring wherein the substituents of such a joint R1-R2 nng(s) can be oxo, alkyl,
alkenyl, alkynyl, halogen (F, CI, Br, I), nitro, -NH2, =NOH, -C(=O)NRxRy, -COORx, -
COONRxRy (wherein Rx and Ry are the same as defined earlier), -NHCOOR6 (wherein R6 can
be alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl or heterocyclylalkyl), cyano,
hydroxy, alkoxy or substituted ammo,
R4 can be hydrogen, alkyl, halogen (F, CI, Br, I), -OR5 (wherein R5 is the same as defined
earlier), cyano, carboxy, -NH2, substituted ammo, or -C(=O)NRxRy (wherein RxandRy are the
same as defined above), or R2 and R4 may together form optionally substituted 4-12 membered
(un)saturated monocyclic or bicyclic ring system fused to ring B having 0-4 heteroatom(s) such
as N, 0 and S, with the proviso that R2 and R4 together does not form -CH2-O-CH2-O-CH2-,
wherein the substituents can be one or more of alkyl, halogen (F, CI, Br, I), hydroxy, alkoxy, or
amino,
R7 can be hydrogen, alkyl, alkenyl, alkynyl, -OR5 (wherein R5 is the same as defined earlier),
halogen (F, CI, Br, I), cyano, -NH2 or substituted amino,
X1 and X2 can be alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl or
heterocyclylalkyl, -(CH2)gC(=O)NRxRy or -(CH2)g1C(=O)OR3 (wherein g and g1 can be an
integer from 0-3, R3, Rx and Ryare the same as defined earlier),
Y can be an oxygen atom, a sulphur atom, or -NR (wherein R can be hydrogen, acyl, aryl or
alkyl),
Y1 and Y2 can be independently hydrogen, alkyl, -OR (wherein R is the same as defined earlier),
-SR (wherein R is the same as defined earlier), or -NHR (wherein R is the same as defined
earlier),
Any of Y1 and X2 & X1 and Y2 may together form a cyclic ring fused with the ring A shown in
Formula I, the ring containing 3-5 carbon atoms within the ring and having 1-3 heteroatoms
such as N, O and S,
X1 and X2 may together form a cyclic ring fused with the ring A shown in Formula I, the ring
containing 3-5 carbon atoms within the ring and having 2-3 heteroatoms such as N, O and S
The following definitions apply to terms as used herein
The term "alkyl," unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon having from 1 to about 20 carbon atoms This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like The alkyl groups may further be substituted with one or more substituents such as alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryloxy, aminosulfonyl, aminocarbonylamino, hydroxyamino, alkoxyamino, nitro, -S(O)nR5 (wherein n is 0, 1 or 2 and R5 is the same as defined earlier), heterocyclyl or heteroaryl Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 -3 substituents chosen from alkyl, carboxy, aminocarbonyl,
hydroxy, alkoxy, halogen, -CF3, amino, substituted amino, cyano, and -S(O)nRs (wherein R5 and n are same as defined earlier) or an alkyl group as defined above that is interrupted by 1-5 atoms or groups independently chosen from oxygen, sulfur and -NRa- (where Ra is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl) Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O)nR5 (wherein n and R5 are the same as defined earlier), or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1 -5 atoms or groups as defined above
The term "alkenyl" unless otherwise specified, refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms with cis or trans geometry Preferred alkenyl groups include ethenyl or vinyl (CH=CH2), 1-propylene or allyl (-CH2CH=CH2), iso-propylene (-C(CH3)=CH2), bicyclo[2 2 l]heptene, and the like In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom The alkenyl group may further be substituted with one or more substituents such as alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylammo, acyloxy, ammo, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aryloxy, aminosulfonyl, aminocarbonylamino, hydroxyammo, alkoxyamino, mtro, -S(O)nRs (wherein n and R5 are the same as defined earlier), heterocyclyl or heteroaryl Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, aminocarbonyl, hydroxy, alkoxy, halogen, -CF3, amino, substituted amino, cyano, and -S(O)nRs (wherein R5 and n are the same as defined earlier)
The term "alkynyl" unless otherwise specified, refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms Preferred alkynyl groups include ethynyl (-C=CH), propargyl (or propynyl, -CH2C=CH), and the like
In the event that alkynyl is attached to a heteroatom, the triple bond cannot be alpha to the heteroatom The alkynyl group may further be substituted with one or more substituents such as alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aryloxy, aminosulfonyl, aminocarbonylamino, hydroxyammo, alkoxyamino, mtro, -S(O)nRs (wherein R5 and n are the same as defined earlier) Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 -3 substituents chosen from alkyl, carboxy, aminocarbonyl, hydroxy, alkoxy,
halogen, CF3, amino, substituted amino, cyano, and -S(O)nR5 (wherein R5 and n are the same as defined earlier)
The term "cycloalkyl" refers to saturated or unsaturated cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which contains an optional olefinic bond Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclopropylene, cyclobutylene and the like, or multiple ring structures such as adamantanyl, and bicyclo [2 2 ljheptane, l,4-dioxa-spiro[4,5] decane or cyclic alkyl groups to which is fused an aryl group, for example indane, and the like The cycloalkyl may further be substituted with one or more substituents such as alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylammo, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aryloxy, aminosulfonyl, aminocarbonylamino, hydroxyamino, alkoxyamino, nitro, -S(O)nR.5 (wherein R5 and n are the same as defined earlier), heteroaryl or heterocyclyl Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, -NH2, substituted ammo, cyano, and -S(O)nR5 (wherein R5 and n are the same as defined earlier)
The term "alkoxy" denotes the group O-alkyl, wherein alkyl is the same as defined above
The term "alkaryl" refers to alkyl-aryl linked through alkyl (wherein alkyl is the same as defined earlier) portion and the said alkyl portion contains carbon atoms from 1 -6 and aryl is same as defined below
The term "aryl" herein refers to phenyl, naphthyl, 2,3-dihydro-l#-mdenyl or indanyl ring and the like optionally substituted with 1 to 3 substituents selected from the group consisting of halogen (F, CI, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, oxo, -S(O)nR5 (wherein R5 is the same as defined earlier), cyano, nitro, carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, amino, -NHCOalkyl, -NHCOOalkyl, -NHS02alkyl, heteroarylalkyl, acyl or (CH2)o-3C(=O)NRxRy (wherein Rx and Ry are same as defined earlier)
The term "carboxy" as defined herein refers to -C(=O)0-R6 wherein R6 can be for example, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl or heterocyclylalkyl
The term "heteroaryl" unless otherwise specified, refers to an aromatic ring structure containing 5 or 6 carbon atoms, or a bicychc aromatic group having 8 to 10 carbon atoms, with one or more heteroatom(s) independently selected from the group consisting of N, O and S, optionally substituted with 1 to 3 substituent(s) such as halogen (F, CI, Br, I), hydroxy, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, -S(O)nRs (wherein n and R5 are the same as defined earlier), alkoxy, alkaryl, cyano, nitro, acyl or C(=O)NRxRy (wherein RX and Ry are the same as defined earlier) Examples of heteroaryl groups are pyndinyl, pyndazmyl, pynmidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, tnazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like such as analogous oxygen, sulphur, and mixed hetero atom containing groups
The term 'heterocyclyl" unless otherwise specified refers to a saturated or unsaturated monocyclic or polycychc ring having 3 to 10 atoms, in which 1 to 3 carbon atoms in a ring are replaced by heteroatoms selected from the group comprising of 0, S, SO, SO2, N or N-oxide, and are optionally benzofused or fused heteroaryl of 5-6 ring members and are optionally substituted wherein the substituents can be halogen (F, CI, Br, I), hydroxy, alkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl, carboxy, aryl, alkoxy, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, oxo, alkoxyalkyl or -S(O)nRs (wherein n and R5 are the same as defined earlier), cyano, nitro, -NH2, substituted amino, acyl or -C(=O)NRxRy (wherein RX and Ry are the same as defined earlier) Examples of heterocyclyl groups are tetrahydrofuranyl, dihydrofuranyl, azabicyclohexane, dihydropyndinyl, pipendinyl, isoxazolme, piperazinyl, dihydrobenzofuryl, morphohnyl, pyrrohdinyl, oxetane, tetrahydropyranyl, thietane,
(Formula Removed)
and the like
"Heteroarylalkyl" refers to alkyl-heteroaryl group, wherein the alkyl and heteroaryl are the same as defined earlier
"Heterocyclylalkyl" refers to alkyl-heterocyclyl group, wherein the alkyl and heterocyclyl are the same as defined earlier
The term "acyl" as defined herein refers to -C(=O)R" wherein R" is the hydrogen, alkyl, alkaryl, cycloalkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl
"Substituted amino" unless and otherwise specified refers to a group -N(R02 wherein each Rkis independently selected from the group consisting of hydrogen [provided that both Rk groups are not hydrogen (defined as "-NH2")], alkyl, alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, acyl, -S(O)mR5 wherein m and R5 is the same as defined above, -C(=O)NRxRy, -C(=O)ORx (wherein RX and Ry are the same as defined earlier) or -NHC(=O)NRyRx (wherein Ry and RX are the same as defined earlier)
Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 -3 substituents chosen from alkyl, alkaryl, cycloalkyl, aryl, heteroaryl, heterocyclyl, carboxy, hydroxy, alkoxy, halogen, -CF3, cyano, -C(=O)NRxRy, -0(C=O)NRxRy (wherein Rx and Ry are the same as defined earlier) and -OC(=O)NRxRyi, -S(O)mRs (where R5 is the same as defined above and m is 0,1 or 2)
The compounds of the present invention can be used for treating CNS disorders, inflammatory diseases such as, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans
In accordance with yet another aspect, there are provided processes for the preparation of the compounds as described herein
Detailed Description of the Invention
The compounds of the present invention may be prepared by techniques well known in the art In addition, the compounds of the present invention may be prepared following a reaction sequence as depicted below
(Scheme Removed)
The compounds of Formulae II, IV, V, VI, VII, IX, XI and XIII can be prepared by following the procedure as depicted in Scheme I The reaction comprises deprotecting a compound of Formula la [wherein * refers to chiral centre (racemic or R or S isomer), V is alkyl
and V1 is cycloalkyl] to give a compound of Formula II, which can be reacted with a compound of Formula III (wherein hal is Br, CI or I, Ryy can be alkyl, aryl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, -(CH2)g1COOR3, -(CH2)mCOR3 or-(CH2)gC(=O)NRxRy) (wherein R3, g, m, Rx, Ry and gi are the same as defined earlier) to give a compound of Formula IV, which can be deprotected to give a compound of Formula V, which can be reacted with a compound of Formula Ilia to give a compound of Formula VI (wherein hal is Br, CI or I, Rxy can be alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl), which can be deprotected (when Ryy attached meta to the phenyl ring is benzyl) to give a compound of Formula VII, which can be reacted with a compound of Formula VIII (wherein Rff can be alkyl, cycloalkyl, alkaryl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl and hal is Br, CI or I)) to give a compound of Formula IX The compound of Formula VII can be reacted with a compound of Formula X (wherein R3y can be -(CH2)giC(=O)OR3, -(CH2)mCOR3, alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl or -(CH2)gC(=O)NRxRy) to give a compound of Formula XI, which can be reacted with a compound of Formula XII (wherein P is selected from alkyl, aralkyl, cycloalkyl, -C(O)0aralkyl, -C(=O)OC(CH3)3, -C(=O)OC(CH3)2CHBr2 or -C(=O)0C(CH3)2CC13) to give a compound of Formula XIII
The deprotection of a compound of Formula la to give a compound of Formula II can be carried out in an organic solvent selected from dichloromethane, dichloroethane, chloroform or carbon tetrachloride in the presence of Lewis acid as a catalyst selected from aluminium trichloride, aluminium tnbromide, zirconium tetrachloride, tin chloride or trichlorobismuthine
The reaction of a compound of Formula II with a compound of Formula III to give a compound of Formula IV can be carried out in an organic solvent selected from dimethylformamide, tetrahydrofuran, diethylether or dioxane in the presence of a base selected from potassium carbonate, sodium carbonate or sodium bicarbonate
The deprotection of a compound of Formula IV to give a compound of Formula V can be carried with an agent selected from sodium ethane thiolate, sodium decane thiolate, sodium dodecane thiolate, sodium thiocresolate in an organic solvent selected from N,N-dimethylacetamide, hexamethyl phosphoramide or dimethylformamide
The reaction of a compound of Formula V with a compound of Formula Ilia to give a compound of Formula VI can be carried out in an organic solvent selected from dimethylformamide, tetrahydrofuran, diethylether or dioxane in the presence of a base selected from potassium carbonate, sodium carbonate or sodium bicarbonate
The deprotection of a compound of Formula VI to give a compound of Formula VII can be carried out in an organic solvent selected from methanol, ethanol, propanol or
isopropylalcohol in the presence of palladium on carbon, palladium on carbon with ammonium formate or palladium hydroxide
The reaction of a compound of VII with a compound of Formula VIII to give a compound of Formula IX can be carried out in an organic solvent selected from dimethylformamide, tetrahydrofuran, diethylether or dioxane in the presence of a base selected from sodium hydride, potassium hydride, tnethyl amine, potassium carbonate or sodium bicarbonate
The reaction of a compound of Formula VII with a compound of Formula X to give a compound of Formula XI can be carried out in an organic solvent selected from dimethylformamide, tetrahydrofuran, diethylether or dioxane in the presence of a base selected from potassium carbonate, sodium carbonate or sodium bicarbonate
The compound of Formula XI can be reacted with a compound of Formula XII to give a compound of Formula XIII Particular compounds are listed below
3-[2-(Difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]propan-l -ol (Compound No 2),
[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetonitnle (Compound No 3),
4-[(5S or 5R)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (Compound No 4),
4-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (Compound No 5),
5-[(5S or 5R)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (Compound No 6),
(5S or 5R)-3-(3,4-Dimethoxyphenyl)-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 7),
(5R or 5S)-3-(3,4-Dimethoxyphenyl)-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 8),
2-(Benzyloxy)-4-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenol (Compound No 9), 2-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]ethanol (Compound No 10),
3-[4-(Difluoromethoxy)-3-ethoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 11),
3-[3-(Cyclohexyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 12),
(5R or 5S)-3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 13),
(5S or 5R)-3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 14),
Ethyl [2-(difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetate
(Compound No 15),
2-(Cyclopropylmethoxy)-4-[(5R or 5S)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (Compound No 65),
4-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-isopropoxyphenol
(Compound No 66),
(5Ror 5S)-3-[3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 67),
(5R or 5S)-3-[4-(difluoromethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 68)
3 - [4-(Difluoromethoxy)-3 -(2-morphohn-4-ylethoxy)phenyl] -1,7-dioxa-2-azaspiro [4 4]non-2-ene
(Compound No 16),
2-(Difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenyl cyclohexanecarboxylate
(Compound No 17),
5-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]pentanoic acid
(Compound No 18),
3-[3-(2,2,2-Tnfluoroethoxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 19),
3-[3-(Cyclopentylmethoxy)-4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 20),
N-cyclopropyl-2-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-
yl)phenoxy]acetamide (Compound No 21),
2-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetamide
(Compound No 22),
2-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]-JV-
methylacetamide (Compound No 23),
3-[3-(Cyclopentyloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 24),
2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenyl
cyclopropanecarboxylate (Compound No 25),
2-(Difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenyl morphohne-4-
carboxylate (Compound No 26),
2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenyl benzoate (Compound
No 27),
5-[2-(Difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy] pentanamide
(Compound No 28),
3-[3-Propoxy-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 29),
3-[3-Isopropoxy-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 30),
3-[3-(Cyclopropylmethoxy)-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-
ene (Compound No 31),
3-[3-(2,3-Dihydro-lH-mden-2-yloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 32),
5-(l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy)phenol (Compound No
33),
3-[3-Methoxy-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound
No 34),
3-[3-Ethoxy-4-(2,2,2-trifluoroethoxy)phenyl]-l ,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound
No 35),
3-[3-Butoxy-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound
No 36),
3-[3-(Cyclohexylmethoxy)-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 37),
3-{[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]methyl}
benzonitnle (Compound No 38),
2-{2-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]ethyl}-l//-
ISOindole-1,3(2//)-dione (Compound No 39),
3-[3-(Cyclohexyloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 40),
Ethyl [5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy) phenoxy]acetate
(Compound No 41),
3-[3-(Cyclohexylmethoxy)-4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 42),
Tert-butyl [2-(difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetate
(Compound No 43),
N-cyclopropyl-2-[5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy)
phenoxyjacetamide (Compound No 44),
N-benzyl-2-[5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy)
phenoxyjacetamide (Compound No 47),
N-Cyclopentyl-2-[5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy)
phenoxyjacetamide (Compound No 48),
(5S or 5R)-3-(3-isopropoxy-4-methoxyphenyl)-l,7-dioxa-2-azaspiro[4 4Jnon-2-ene (Compound
No 57),
(5S or 5R)-3-[3-(Cyclopropylmethoxy)-4-methoxyphenylJ-l,7-dioxa-2-azaspiro[4 4Jnon-2-ene
(Compound No 58),
2-(Cyclopropylmethoxy)-4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4Jnon-2-en-3-ylJphenol
(Compound No 59),
4-[(5S or 5R)-l,7-Dioxa-2-azaspiro[4 4Jnon-2-en-3-ylJ-2-isopropoxyphenol
(Compound No 60),
(5S or 5R)-3-[3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenylJ-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 62),
(5S or 5R)-3-[4-(difluoromethoxy)-3-isopropoxyphenylJ-l,7-dioxa-2-azaspiro[4 4Jnon-2-ene
(Compound No 63),
(5R or 5S)-3-[4-(difluoromethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4 4Jnon-2-ene
(Compound No 64),
(5S or 5R)-3-[3-(Benzyloxy)- 4-(difluoromethoxy)phenylJ-l,7-dioxa-2-azaspiro[4 4Jnon-2-ene
(Compound No 76),
2-(Benzyloxy)-4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4Jnon-2-en-3-yl]phenol
(Compound No 77),
(5S or 5R)-3-[3-(Benzyloxy)-4-methoxyphenylJ-l,7-dioxa-2-azaspiro[4 4Jnon-2-ene
(Compound No 78),
3-[3-(Benzyloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4Jnon-2-ene
(Compound No 90),
2-(Difluoromethoxy)-5-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4Jnon-2-en-3-ylJphenol (Compound
No 91),
5-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol
(Compound No 92),
(5R or 5S)-3-[3-(benzyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound
No 126),
2-(Benzyloxy)-4-[(5R or 5S)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol
(Compound No 127),
(5R or 5S)-3-[3-(Benzyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 128),
2-(Difluoromethoxy)-5-[(5R or 5S)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (Compound
No 130),
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides thereof
(Scheme Removed)
The compounds of Formulae Ha and IVa can be prepared by following the procedure as depicted m Scheme II Thus the reaction comprises deprotectmg a compound of Formula la (wherein V and Vi are the same as defined earlier) [wherein * represents chiral centre (racemic or optically active)] to give a compound of Formula Ha which can be reacted with a compound of Formula III (wherein hal is Br, CI or I, Ryy can be alkyl, aryl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl, -(CH2)gC(=O)NRxRy, -(CH2)mCOR3 or -(CH2)giC(=O)OR3 (wherein m, R3, g, gi, Rx and Ry are the same as defined earlier) to give a compound of Formula IVa
The deprotection of a compound of Formula la to give a compound of Formula Ila can be carried out with an agent selected from sodium ethane thiolate, sodium decane thiolate, sodium dodecane thiolate, sodium thiocresolate m an organic solvent selected from N,N-dimethylacetamide, hexamethyl phosphoramide or dimethylformamide
The reaction of a compound of Formula Ila with a compound of Formula HI to give a compound of Formula IVa can be carried out m an organic solvent selected from dimethylformamide, tetrahydrofuran, diethylether or dioxane in the presence of a base selected from potassium carbonate, sodium carbonate or sodium bicarbonate
Particular compounds are described below 2-(Cyclopentyloxy)-4-[(5R or 5S)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (Compound No 45),
2-(Cyclopentyloxy)-4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (Compound
No 46),
(5R or 5S)-3-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-
ene (Compound No 56),
(5S or 5R)-3-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-
ene (Compound No 61),
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides thereof
(Scheme Removed)
The compounds of Formula XVII and XIX can be prepared by following the procedure as depicted in Scheme III Thus the reaction comprises reacting a compound of Formula XIV (wherein X\ and Y are the same as defined earlier) with a compound of Formula XV (wherein P is the same as defined earlier and L is a leaving group selected from hal (Br, CI or I), -Omesyl, -Otosyl or -Otriflyl) to give a compound of Formula XVI (wherein n is an integer from 0-2), which can be deprotected to give a compound of Formula XVII, which can be reacted with a compound of Formula XVIII (wherein G is -CO or -S02 and Rff is the same as defined earlier) to give a compound of Formula XIX
The reaction of a compound of Formula XIV with a compound of Formula XV to give a compound of Formula XVI can be carried out in an organic solvent selected from
dimethylformamide, tetrahydrofuran, diethylether or dioxane in the presence of a base selected from potassium carbonate, sodium carbonate or sodium bicarbonate
The deprotection of a compound of Formula XVI (when P is -C(=O)OC(CH3)3 or -C(=O)OC(CH3)2CHBr2) to give a compound of Formula XVII can be carried out in, for example, hydrochloric acid solution of methanol, ethanol, propanol, isopropylalcohol, tetrahydrofuran or ether
Alternatively, the deprotection of a compound of Formula XVI (when P is -C(=O)OC(CH3)3 or -C(=O)OC(CH3)2CHBr2) to give a compound of Formula XVII can be carried with trifluoroacetic acid in dichloromethane
The deprotection of a compound of Formula XVI (when P is -C(=O)OC(CH3)2CCl3) to give a compound of Formula XVII can be carried out by a supernucleophile (for example, lithium cobalt (I) phthalocyanine, zinc and acetic acid or cobalt phthalocyanine)
The deprotection of a compound of Formula XVI (when P is aralkyl) to give a compound of Formula XVII can be carried out in an organic solvent selected from methanol, ethanol, propanol or isopropylalcohol in the presence of palladium on carbon in presence of hydrogen gas or palladium on carbon with a source of hydrogen gas selected from ammonium formate solution, cyclohexene or formic acid
The reaction of a compound of Formula XVII with a compound of Formula XVIII to give a compound of Formula XIX can be carried out in an organic solvent selected from dimethylformamide, tetrahydrofuran, diethylether or dioxane m the presence of a base selected from potassium carbonate, sodium carbonate or sodium bicarbonate Particular compounds are described below
3-[3-{[(35)-l-Benzylpyrrolidin-3-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 1),
Tert-butyl 4-[2-(difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy] pipendine-1-carboxylate (Compound No 49),
Hydrochloride salt of 3-[4-(difluoromethoxy)-3-(pipendin-4-yloxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 50),
3-{3-[(l -Acetylpipendin-4-yl)oxy]-4-(difluoromethoxy)phenyl}-l ,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 51),
Tert-butyl (3S)-3-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]pyrrohdine-l-carboxylate (Compound No 52), Tert-butyl (3R)-3-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]pyrrohdme-l-carboxylate (Compound No 53),
Tert-butyl 3-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-
yl)phenoxy]pipendine-l-carboxylate (Compound No 54),
rert-butyl(2S)-2-{[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-
yl)phenoxy]methyl}pyrrohdine-l-carboxylate (Compound No 55),
Hydrochloride salt of 3-{4-(Difluoromethoxy)-3-[(3S)-pyrrohdin-3-yloxy]phenyl}-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 69),
Hydrochloride salt of 3-{4-(difluoromethoxy)-3-[(2S)-pyrrohdin-2-ylmethoxy]phenyl}-l,7-
dioxa-2-azaspiro[4 4]non-2-ene (Compound No 70),
Hydrochloride salt of 3- {4-(difluoromethoxy)-3-[(2/?)-pyrrohdin-2-ylmethoxy]phenyl}-1,7-
dioxa-2-azaspiro[4 4]non-2-ene (Compound No 71),
3-[4-(Difluoromethoxy)-3-{[(2i?)-l-propionylpyrrolidin-2-yl]methoxy}phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 72),
3-[3-{ [(25)-1 -acetylpyrrohdin-2-yl]methoxy} -4-(difluoromethoxy)phenyl]-1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 73),
3-[3- {[(3 S)-1 -benzoylpyrrohdin-3-yl]oxy} -4-(difluoromethoxy)phenyl]-1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 74),
3-[4-(Difluoromethoxy)-3-{[(3S)-l-propionylpyrrolidin-3-yl]oxy}phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 75),
3-{4-(Difluoromethoxy)-3-[(l-propionylpipendin-4-yl)oxy]phenyl}-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 79),
3 -[4-(Difluoromethoxy)-3 - {[ 1 -(4-fluorobenzoyl)pipendin-4-yl] oxy} phenyl] -1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 80),
3-[3-{[l-(Cyclopropylcarbonyl)pipendin-4-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 81),
3-[3-{[l-(Cyclopentylcarbonyl)pipendin-4-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 82),
3-[4-(Difluoromethoxy)-3-({l-[(trifluoromethyl)sulfonyl]piperidin-4-yl}oxy)phenyl]-l,7-dioxa-
2-azaspiro[4 4]non-2-ene (Compound No 83),
3 - {3 - [(1 - Acetylpipendin-3 -yl)oxy]-4-(difluoromethoxy)phenyl} -1,7-dioxa-2-azaspiro[4 4]non-
2-ene (Compound No 84),
3 - {4-(Difluoromethoxy)-3 - [(1 -propionylpipendin-3 -yl)oxy]phenyl} -1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 85),
3-[4-(Difluoromethoxy)-3-{[l-(4-fluorobenzoyl)piperidin-3-yl]oxy}phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 86),
3-[3-{[l-(Cyclopropylcarbonyl)pipendin-3-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 87),
3-[3-{[l-(Cyclopentylcarbonyl)pipendin-3-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 88),
3-[4-(Difluoromethoxy)-3-{[l-(ethylsulfonyl)pipendin-3-yl]oxy}phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 89),
3 - [3 - {[(35)-1 -acetylpyrrolidin-3 -yl]oxy} -4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 93),
Hydrochloride salt of 3-[4-(Difluoromethoxy)-3-(pipendin-3-yloxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 94),
3-[4-(Difluoromethoxy)-3-{[l-(phenylcarbonyl)pipendin-4-yl]oxy}phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 95),
3-[4-(Difluoromethoxy)-3- {[ 1 -(morpholin-4-ylcarbonyl)pipendin-4-yl]oxy} phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 96),
3-[4-(Difluoromethoxy)-3- {[1 -(phenylcarbonyl)piperidm-3-yl]oxy} phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 97),
3-[4-(Difluoromethoxy)-3- {[ 1 -(morphohn-4-ylcarbonyl)pipendm-3-yl]oxy jphenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 98),
3 -[4-(Difluoromethoxy)-3 -({1 -[(trifluoromethyl)sulfonyl]pipendin-3 -yl} oxy)phenyl] -1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 99),
3-[4-(Difluoromethoxy)-3-{[(2i?)-l-(phenylcarbonyl)pyrrohdin-2-yl]methoxy}phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 100),
3 - [3 - {[(2R)-1 -acetylpyrrohdin-2-yl]methoxy} -4-(difluoromethoxy)phenyl] -1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 101),
3-[4-(Difluoromethoxy)-3-{[(2i?)-l-propanoylpyrrohdin-2-yl]methoxy}phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 102),
3 - [3 - {[(2R)-1 -(cyclopropylcarbonyl)pyrrolidin-2-yl]methoxy} -4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 103),
3-[3 - {[(35)-1 -(cyclopropylcarbonyl)pyrrohdin-3-yl]oxy} -4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 104),
3-[3-{[(35)-l-(cyclopentylcarbonyl)pyrrolidm-3-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 105),
3 - [4-(Difiuoromethoxy)-3 -({(3i?)-1 -[(4-fluorophenyl)carbonyl]pyrrohdin-3 -yl} oxy)phenyl] -1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 106),
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides thereof
(Scheme Removed)

The compounds of Formula XXIV can be prepared by following the procedure as depicted in Scheme IV Thus a compound of Formula XX (wherein X1 and X2 are the same as defined earlier) can be reacted with a compound of Formula XXa (wherein Q is a chiral resolving agent selected from L-Ephednne, D-Ephednne, (+)-Brussian, (-)-Brussian, (IS, 2R) (-)-cis-l-amino-2-indanol, (1R2S) (+)-cis-l-amino-2-indanol, (1R, 2R)-(-)-l,2-diamino cyclohexane or (IS, 2S)-(+)-l,2-diamino cyclohexane, a-methylbenzylamine or (3-methylbenzylamine) to give a compound of Formula XXI [wherein * refers to chiral centre (racermc or optically active)], which undergoes protection with a compound of Formula P'-OH to give a compound of Formula XXII (wherein P' can be alkyl or aralkyl), which undergoes reduction to give a compound of Formula XXIII, which undergoes cychsation to give a compound of Formula XXIV
The compound of Formula XX can be reacted with a compound of Formula XXa to give a compound of Formula XXI in an organic solvent, for example, acetone, ethanol, isopropyl alcohol, methanol, acetonitnle, ter/-butyl alcohol, ethyl acetate, dioxane, dichloromethane or chloroform
The protection of a compound of Formula XXI with a compound of Formula P'-OH to give a compound of Formula XXII can be carried out with halogenating agents, for example, thionyl chloride, oxalyl chloride, phosphorous pentachlonde or phosphorous trichloride
The compound of Formula XXII undergoes reduction to give a compound of Formula XXIII in an organic solvent, for example, tetrahydrofuran, dimethylformamide, diethyl ether or dioxane with a reducing agent selected from lithium aluminium hydride, sodium borohydnde, borane dimethyl sulphide or lithium borohydnde
Alternatively, the compound of Formula XXIII can also be prepared by reducing free acid form of compound of Formula XXII
The compound of Formula XXIII undergoes cychsation to give a compound of Formula XXIV in an organic solvent, for example, tetrahydrofuran, dimethylformamide, dioxane or diethyl ether in the presence of a redox couple The oxidizing part of the redox couple is selected from the group consisting of dnsopropylazodicarboxylate (DIAD), diethylazodicarboxylate (DEAD), N,N,N',N'-tetramethylazodicarboxylate (TMAD), l,l'-(azodicarbonyl) dipipendine (ADDP), cyanomethylenetnbutylphosphorane (CMBP), 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione (DHTD) or N,N,N',N,'-tetraisopropylazodicarboxamide (TIPA) The reduction part of the redox couple is phosphine selected from the group consisting of tnalkylphosphine (such as tnbutylphosphine), triarylphosphine (for example, tnphenylphosphine), tncycloalkylphosphine (for example, tnscyclohexylphosphine) or tetraheteroarylphosphine The phosphine reagents with a combination of aryl, alkyl or heteroaryl substituents may also be used (for example, diphenylpyndylphosphine)
Particular compounds, which can be prepared following scheme IV, are disclosed below 4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (Compound No 4),
4-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (Compound No 5),
5-[(5S or 5R)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (Compound No 6),
(5S or 5i?)-3-(3,4-Dimethoxyphenyl)-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 7),
(5R or 5S)-3-(3,4-Dimethoxyphenyl)-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 8),
(5R or 55)-3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 13),
(5S or 5R)-3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l ,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 14),
(5R or 5S)-3-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 56),
(5S or 5R)-3-(3-isopropoxy-4-methoxyphenyl)-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 57),
(5S or 5R)-3-[3-(Cyclopropylmethoxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 58),
2-(Cyclopropylmethoxy)-4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol
(Compound No 59),
4-[(5S or 5R)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-isopropoxyphenol
(Compound No 60),
(5S or 5R)-3-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-
ene (Compound No 61),
(5S or 5R)-3-[4-(difluoromethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 63),
(5R or 5S)-3-[4-(difluoromethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 64),
2-(Cyclopropylmethoxy)-4-[(5R or 5S)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (Compound No 65),
4-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-isopropoxyphenol (Compound No 66),
(5R or 5S)-3-[3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 67),
(5R or 5S)-3-[4-(difluoromethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 68),
(5S or 5R)-3-[3-(Benzyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 76),
2-(Benzyloxy)-4-[(55' or 5/?)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (Compound No 77),
(5S or 5R)-3-[3-(Benzyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 78),
2-(Difluoromethoxy)-5-[(5S' or 5i?)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (Compound No 91),
5-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (CompoundNo 92), pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides thereof
(Scheme Removed)

The compounds of Formula XXV b can be prepared by following the procedure as depicted in Scheme V The reaction comprises reacting a compound of Formula XXV with a compound of Formula XXV a to give a compound of Formula XXV b
The reaction of a compound of Formula XXV with a compound of Formula XXV a to give a compound of Formula XXV b can be carried out in the presence of one or more of reagents, for example, sodium hypochlorite, N-bromosuccimmide, N-chlorosuccinimide or mixtures thereof in an organic solvent, for example, tetrahydrofuran, dimethylformamide or dimethylsulphoxide
Particular compounds prepared by this scheme are
{3-[4-(Difluoromethoxy)-3-methoxyphenyl]-4,5-dihydroisoxazole-5,5-diyl}dimethanol (Compound No 107), 3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l,8-dioxa-2-azaspiro[4 5]dec-2-ene (CompoundNo
HI),
7-[4-(Difluoromethoxy)-3-methoxyphenyl]-5-oxa-6-azaspiro[3 4]oct-6-ene
(Compound No 115),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l-oxa-2-azaspiro[4 4]non-2-ene
(Compound No 116),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-1 -oxa-2-azaspiro[4 5]dec-2-ene
(Compound No 117),
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides thereof
(Scheme Removed)

The compounds of Formulae XXVIII, XXIX and XXX can be prepared by following the procedure as depicted in Scheme VI The reaction comprises the mesylation of a compound of
Formula XXVI (wherein X1 and X2 are the same as defined earlier and n is an integer from 0-2) to give a compound of Formula XXVII, which can be cychzed to give a compound of Formula XXVIII, which can be oxidized to give compounds of Formulae XXIX and XXX
The mesylation of a compound of Formula XXVI to give a compound of Formula
XXVII can be carried out in the presence of one or more of mesylating agents, for example,
methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfomc anhydrides-
toluene sulphonyl chloride or mixtures thereof m the presence of one or more of bases, for
example, tnethylamme, pyridine, 2,6-lutidene, dnsopropyl ethylamine or mixtures thereof in a
solvent, for example, dichloromethane, chloroform, tetrahydrofuran or acetonitnle
The cychzation of a compound of Formula XXVII to give a compound of Formula
XXVIII can be earned out in the presence of one or more of hydrated or anhydrous alkali metal
sulphides, for example, sodium sulphide in a solvent, for example, tetrahydrofuran,
dimethylformamide, dimethylsulfoxide or dichloromethane
The oxidation of a compound of Formula XXVIII to give compounds of Formulae XXIX and XXX can be earned out in the presence of one or more of oxidizing agents, for example, sodium penodate, m-chloroperoxybenzoic acid, tert-butyl hydroperoxide or mixtures thereof in a solvent, for example, methanol, dichloromethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, water or mixtures thereof Particular compounds prepared by this scheme are listed below
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-1 -oxa-7-thia-2-azaspiro[4 4]non-2-ene (Compound No 108),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l -oxa-7-thia-2-azaspiro[4 4]non-2-ene 7-oxide (Compound No 109),
7-[4-(Difluoromethoxy)-3-methoxyphenyl]-5-oxa-2-thia-6-azaspiro[3 4]oct-6-ene (Compound No 110),
7-[4-(Difluoromethoxy)-3-methoxyphenyl]-5-oxa-2-thia-6-azaspiro[3 4]oct-6-ene 2-oxide (Compound No 113),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-1 -oxa-7-thia-2-azaspiro[4 4]non-2-ene 7,7-dioxide (Compound No 114),
7-[4-(Difluoromethoxy)-3-methoxyphenyl]-5-oxa-2-thia-6-azaspiro[3 4]oct-6-ene 2,2-dioxide (Compound No 120),
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides thereof
(Scheme Removed)

The compounds of Formula XXXIV can be prepared by following the procedure as depicted in Scheme VII Accordingly, a compound of Formula XXV (wherein X1 and X2 are the same as defined earlier) can be reacted with a compound of Formula XXXI (wherein R1a can be alkyl and hal is the same as defined earlier) to give a compound of Formula XXXII, which can be reduced to give a compound of Formula XXXIII, which can be cychzed to give a compound of Formula XXXIV
The reaction of a compound of Formula XXV with a compound of Formula XXXI to give a compound of Formula XXXII can be carried out, for example, by 1,3-dipolar cycloaddition reaction in the presence of one or more of reagents, for example, sodium hypochlorite, N-bromosuccimmide, N-chlorosuccinimide or mixtures thereof in a solvent, for example, dichloromethane, chloroform or mixtures thereof
The reduction of a compound of Formula XXXII to give a compound of Formula
XXXIII can be carried out in the presence of one or more of reducing agents, for example,
sodium borohydnde, lithium aluminium hydride, borane dimethyl sulphide or mixtures thereof
m a solvent, for example, methanol, ethanol, tetrahydrofuran, ethyl acetate or mixtures thereof
The cychzation of a compound of Formula XXXIII to give a compound of Formula
XXXIV can be carried out in the presence of one or more of alkali metal hydroxides, for
example, sodium hydroxide, potassium hydroxide or lithium hydroxide, alkali metal carbonates,
for example, sodium carbonate or potassium carbonate, alkali metal alkoxides, for example,
potassium /-butoxide, alkali metal hydrides, for example, sodium hydride or mixtures thereof in
a solvent, for example, methanol, ethanol, tetrahydrofuran, dimethylformamide, water or
mixtures thereof
Particular compound prepared by this scheme is listed below
7-[4-(Difluoromethoxy)-3-methoxyphenyl]-2,5-dioxa-6-azaspiro[3 4]oct-6-ene (Compound No
123)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides thereof
(Scheme Removed)

The compounds of Formula XXXVII can be prepared by following the procedure as depicted in Scheme VIII Accordingly, a compound of Formula XXXV (wherein X1 is same as defined earlier) can be reacted with a compound of Formula XXXV a to give a compound of Formula XXXVI (wherein Pr can be a protecting group, for example, tert-butyl dimethyl silyl) which can be deprotected to give a compound of Formula XXXVII
The reaction of a compound of Formula XXXV with a compound of Formula XXXV a to give a compound of Formula XXXVI can be carried out in a solvent, for example, tetrahydrofuran, dimethylformamide, dimethoxy ethane, dioxane or diethyl ether in the presence of a redox couple The oxidizing part of the redox couple is selected from the group consisting of dnsopropyl azodicarboxylate (DIAD), diethylazodicarboxylate (DEAD), N,N,N',N'-tetramethylazodicarboxylate (TMAD), l,l'-(azodicarbonyl) dipiperidme (ADDP), cyanomethylenetnbutylphosphorane (CMBP), 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione (DHTD) or N,N,N',N,'-tetraisopropylazodicarboxamide (TIPA) The reduction part of the redox couple is phosphme selected from the group consisting of tnalkylphosphme (such as tnbutylphosphine), tnarylphosphine (for example, triphenylphosphine), tncycloalkylphosphine (for example, tnscyclohexylphosphine) or tetraheteroarylphosphme The phosphme reagents with a combination of aryl, alkyl or heteroaryl substituents may also be used (for example, diphenylpyndylphosphme)
The deprotection of a compound of Formula XXXVI to give a compound of Formula XXXVII can be carried out in a solvent, for example, methanol or ethanol in the presence of a acid, for example, hydrochloric acid Particular compound prepared by this scheme is listed below
3-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]cyclopentanol (Compound No 129)

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides thereof
(Scheme Removed)

The compounds of Formulae XXXIX, XL, XLI and XLII can be prepared by following the procedure as depicted in Scheme IX Accordingly, a compound of Formula XXXV (wherein X1 is the same as defined earlier) can be reacted with a compound of Formula XXXVIII (wherein T can be halogen, alkoxy, alkyl or -NHCOOalkyl) to give a compound of Formula XXXIX, which (when T is -NHCOOalkyl) can be deprotected to give a compound of Formula XL, which can be
(a) mesylated to give a compound of Formula XLI
(b) acylated to give a compound of Formula XLII
The reaction of a compound of Formula XXXV with a compound of Formula XXXVIII to give a compound of Formula XXXIX can be carried out in the presence of a transition metal source, for example, copper acetate or elemental copper, in a solvent, for example, dichloromethane, acetomtnle or toluene
The reaction of a compound of Formula XXXV with a compound of Formula XXXVIII to give a compound of Formula XXXIX can be carried out in the presence of a base, for example, tnethyl amine, tnmethyl amine, pyridine or Hunig's base
The reaction of a compound of Formula XXXV with a compound of Formula XXXVIII to give a compound of Formula XXXIX can be carried out in the presence of, for example, 4 A molecular sieves
The deprotection of a compound of Formula XXXIX to give a compound of Formula XL can be carried out in a solvent, for example, methanol or ethanol in the presence of a acid, for example, hydrochloric acid
The mesylation of a compound of Formula XL to give a compound of Formula XLI can be carried out in the presence of one or more of mesylating agents, for example, methanesulfonyl chloride, methanesulfomc anhydride, trifluoromethanesulfomc anhydrides-toluene sulphonyl chloride or mixtures thereof in the presence of a base, for example, pyridine, tnethyl amine, dnsopropyl ethyl amine or potassium carbonate in a solvent, for example, pyridine, dichloromethane, dichloroethane, dimethylformamide or dimethylacetamide
The acylation of a compound of Formula XL to give a compound of Formula XLII can be carried out using acetic anhydride in a solvent, for example, pyridine, dichloromethane, dichloroethane, chloroform, dimethylformamide or dimethylacetamide
The acylation of a compound of Formula XL to give a compound of Formula XLII can be carried out in the presence of a base, for example, pyridine, tnethyl amine, dnsopropyl ethyl amine or potassium carbonate
Particular compounds prepared by this scheme are listed below Hydrochloride salt of 4-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy] aniline (Compound No 124),
tert-Butyl {4-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]phenyl}carbamate (Compound No 125),
3-[4-(Difluoromethoxy)-3-(4-fluorophenoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 131),
3-[3-(4-Chlorophenoxy)-4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 132),
3- {4-(Difluoromethoxy)-3-[4-(trifluoromethoxy)phenoxy]phenyl} -1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 133),
3-{4-(Difluoromethoxy)-3-[4-(trifluoromethyl)phenoxy]phenyl}-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 134),
N-{4-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl) phenoxy] phenyl} acetamide (Compound No 135),
N-{4-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl) phenoxy] phenyl} methane sulfonamide (Compound No 136),
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides thereof
(Scheme Removed)

The compounds of Formulae XLIV and XLVI can be prepared by following the procedure as depicted in Scheme X Accordingly, a compound of Formula XXXV (wherein X1 is the same as defined earlier) can be reacted
(a) with a compound of Formula XLIII (wherein hal is the same as defined earlier) to give a compound of formula XLIV
(b) with a compound of Formula XLV (wherein hal is the same as defined earlier) to give a compound Formula XLVI
The reaction of a compound of Formula XXXV with a compound of Formula XLIII to give a compound of Formula XLIV can be earned out under ullmann coupling conditions, for example, in the presence of copper powder in a solvent, for example, pyridine
The reaction of a compound of Formula XXXV with a compound of Formula XLIII to give a compound of Formula XLIV can be carried out in the presence of a base, for example, potassium carbonate or cesium carbonate
The reaction of a compound of Formula XXXV with a compound of Formula XLV to give a compound of Formula XLVI can be carried out in the presence of a base, for example, potassium fluoride or cesium carbonate in a solvent, for example, dimethyl sulphoxide, dimethyl formamide or dimethyl acetamide
Particular compounds prepared by this scheme are listed below
3-[4-(Difluoromethoxy)-3-phenoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 112)
3-[4-(Difluoromethoxy)-3-(pyridm-4-yloxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 137)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides thereof
(Scheme Removed)

The compounds of Formulae XLVIII, XLIX, L and LI can be prepared by following the procedure as depicted in Scheme XI Accordingly, a compound of Formula XXV (wherein X1 and X2 are the same as defined earlier) can be reacted with a compound of Formula XLVII to give a compound of Formula XLVIII, which can be deprotected to give a compound of Formula XLIX, which can be
(a) reduced to give a compound of Formula L
(b) reacted with hydroxylamme hydrochlonde to give a compound of Formula LI The reaction of a compound of Formula XXV with a compound of Formula XLVII to
give a compound of Formula XLVIII can be earned out in the presence of one or more of reagents, for example, sodium hypochlorite, N-bromosuccimmide, N-chlorosuccimmide or mixtures thereof in a solvent, for example, dichloromethane, tetrahydrofuran, dimethylformamide or dimethylsulphoxide
The deprotection of a compound of Formula XLVIII to give a compound of Formula XLIX can be carried out in the presence of one or more of acids, for example, trifluroacetic acid, jc-toluene sulphonic acid or mixtures thereof in a solvent, for example, dichloromethane, water or mixtures thereof
The reduction of a compound of Formula XLIX to give a compound of Formula L can be earned out in the presence of a reducing agent, for example, sodium borohydnde, lithium aluminium hydride, sodium triacetoxy borohydnde or L-selectnde in a solvent, for example, tetrahydrofuran, diethyl ether, methanol, ethanol or mixtures thereof
The reaction of a compound of Formula XLIX with hydroxylamme hydrochloride to give a compound of Formula LI can be carried out in the presence of one or more of bases, for example, alkali metal carbonates, for example, potassium carbonate or sodium carbonate, alkali
metal acetates, for example, sodium acetate or mixtures thereof in a solvent, for example, dichloromethane, tetrahydrofuran, acetomtnle, dimethylformamide or mixtures thereof
Particular compounds prepared by this scheme are listed below 3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l,9,12-tnoxa-2-azadispiro[4 2 4 2]tetradec-2-ene (Compound No 118),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-1 -oxa-2-azaspiro[4 5]dec-2-en-8-one (Compound No 119),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-1 -oxa-2-azaspiro[4 5]dec-2-en-8-one oxime (Compound No 121),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l-oxa-2-azaspiro[4 5]dec-2-en-8-ol (Compound No 122),
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides
Where desired, the compounds of Formula I and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides may be advantageously used in combination with one or more other therapeutic agents Examples of other therapeutic agents, which may be used in combination with compounds of Formula I of this invention and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides include, but are not limited to, corticosteroids, B2- agonists, muscarinic receptor antagonists, anticholinergics, antiallergic agents, PAF antagonists, EGFR kinase inhibitors, p38 MAP Kinase inhibitors, additional PDE-IV inhibitors, kinase inhibitors, dopamine receptor antagonists, histamines, antitussives, leukotnene antagonists, 5-hpoxygenase inhibitors, chemokine inhibitors or combinations thereof
The one or more 132- agonist as described herein may be chosen from those described in the art The 132-agomsts may include one or more compounds described in U S Patent Nos 3,705,233, 3,644,353, 3,642,896, 3,700,681, 4,579,985, 3,994,974, 3,937,838, 4,419,364, 5,126,375, 5,243,076, 4,992,474, and 4,011,258
Suitable 132-agonists include, for example, one or more of albuterol, salbutamol, biltolterol, pirbuterol, levosalbutamol, tulobuterol, terbutahne, bambuterol, metaproterenol, fenoterol, salmeterol, carmoterol, arformoterol, formoterol, and their pharmaceutically acceptable salts or solvates thereof
Corticosteroids as described herein may be chosen from those described in the art Suitable corticosteroids may be include one or more compounds described in U S Patent Nos 3,312,590, 3,983,233, 3,929,768, 3,721,687, 3,436,389, 3,506,694, 3,639,434, 3,992,534,
3,928,326, 3,980,778, 3,780,177, 3,652,554, 3,947,478,4,076,708,4,124,707, 4,158,055, 4,298,604, 4,335,121, 4,081,541,4,226,862, 4,290,962, 4,587,236, 4,472,392, 4,472,393, 4,242,334, 4,014,909, 4,098,803, 4,619,921, 5,482,934, 5,837,699, 5,889,015, 5,278,156, 5,015,746, 5,976,573, 6,337,324, 6,057,307, 6,723,713, 6,127,353, and 6,180,781 The disclosures of these patents are incorporated herein by reference in their entireties
Suitable corticosteroids may include, for example, one or more of alclometasone, amcinonide, amelometasone, beclometasone, betamethasone, budesonide, ciclesomde, clobetasol, cloticasone, cyclomethasone, deflazacort, deprodone, dexbudesomde, diflorasone, difluprednate, fluticasone, flunisohde, halometasone, halopredone, hydrocortisone, methylprednisolone, mometasone, prednicarbate, prednisolone, nmexolone, tixocortol, triamcinolone, tolterodine, oxybutynin, ulobetasol, roflepomde, GW 215864, KSR 592, ST-126, dexamethasone and pharmaceutically acceptable salts, solvates thereof Preferred corticosteroids include, for example, flunisohde, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesomde, and dexamethasone Examples of possible salts or derivatives include sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates, or furoates In some cases, the corticosteroids may also occur in the form of their hydrates
Suitable muscarinic receptor antagonists include substances that directly or indirectly block activation of muscarinic cholinergic receptors Examples include, but are not limited to, the compounds disclosed in WO04/004629, WO04/005252, WO04/089900, WO04/89364, quaternary amines (e g, methanthehne, ipratropium, propantheline), tertiary amines (e g, dicyclomine, scopolamine) and tricyclic amines (e g, telenzepine) Other suitable muscarinic receptor antagonists include benztropme (commercially available as COGENTIN from Merck), hexahydro-sila-difenidol hydrochloride (HHSID hydrochloride disclosed in Lambrecht et al, Trends in Pharmacol Sci, lO(Suppl) 60 (1989), (+/-)-3-quinuchdmyl xanthene-9-carboxylate hemioxalate (QNX-hemioxalate, Birdsall et al, Trends in Pharmacol Sci, 4 459 (1983), telenzepine dihydrochlonde (Coruzzi et al, Arch Int Pharmacodyn Ther, 302 232 (1989), and Kawashima et al, Gen Pharmacol ,2117 (1990)), and atropine
Suitable anticholinergics include, for example, tiotropium salts, ipratropium salts, oxitropium salts, salts of the compounds known from WO 02/32899 tropenol N-methyl-2,2-diphenylpropionate, scopine N-methyl-2,2-diphenylpropionate, scopine N-methyl-2-fluoro-2,2-diphenylacetate and tropenol N-methyl-2-fluoro-2,2-diphenylacetate, as well as salts of the compounds known from WO 02/32898 tropenol N-methyl-3,3',4,4'-tetrafluorobenzilate, scopine N-methyl-3,3',4,4'-tetrafluorobenzilate, scopine N-methyl-4,4'-dichlorobenzilate, scopine N-methyl-4,4'-difluorobenzilate, tropenol N-methyl-3,3'-difluorobenzilate, scopine N-
methyl-3,3'-difluorobenzilate, and tropenol N-ethyl-4,4'-difluorobenzilate, optionally in the form of their hydrates and solvates By salts are meant those compounds which contain, in addition to the above mentioned cations, as counter-ion, an anion with a single negative charge selected from among the chloride, bromide, and methanesulfonate
Preferred anticholinergics include, for example, tiotropium bromide, ipratropium bromide, oxitropium bromide, tropenol 2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionate methobromide, scopine 2-fluoro-2,2-diphenylacetate methobromide, tropenol 2-fluoro-2,2-diphenylacetate methobromide, tropenol 3,3',4,4'-tetrafluorobenzilate methobromide, scopine 3,3',4,4'-tetrafluorobenzilate methobromide, scopine 4,4'-dichlorobenzilate methobromide, scopine 4,4'-difluorobenzilate methobromide, tropenol 3,3'-difluorobenzilate methobromide, scopine 3,3'-difluorobenzilate methobromide, and tropenol 4,4'-difiuorobenzilateethylbromide
Suitable antiallergic agents include, for example, epinastine, cetinzine, azelastine, fexofenadine, levocabastme, loratadine, mizolastine, ketotifene, emedastme, dimetindene, clemastine, bamipine, hexachloropheniramine, phemramine, doxylamine, chlorophenoxamine, dimenhydnnate, diphenhydramine, promethazine, ebastine, desloratadine, and meclizine Preferred antiallergic agents include, for example, epinastine, cetinzine, azelastine, fexofenadine, levocabastme, loratadine, ebastine, desloratadine, and mizolastine Any reference to the above-mentioned antiallergic agents also includes any pharmacologically acceptable acid addition salts thereof, which may exist
Suitable PAF antagonists include, for example, 4-(2-chlorophenyl)-9-methyl-2-[3-(4-morphohnyl)-3 -propanon-1 -yl] -6H-thieno [3,2-fj [ 1,2,4]tnazolo[4,3 -a] [ 1,4]diazepine and 6-(2-chlorophenyl)-8,9-dihydro-l-methyl-8-[(4-morphohnyl)carbonyl]-4H,7H-cyclopenta[4 5]thieno[3,2-fJ[l,2,4]tnazolo[4,3-a][l,4]diazepine
Suitable EGFR kinase inhibitors include, for example, 4-[(3-chloro-4-fluorophenyl)amino] -7-(2- {4- [(S)-(2-oxotetrahydrofuran-5-yl)carbonyl]piperazin-1 -yl} -ethoxy)-6-[(vinylcarbonyl)amino]quinazohne, 4-[(3-chloro4-fluorophenyl)amino]-7-[4-((S)-6-methyl-2-oxomorphohn-4-yl)butyloxy]-6-[(vinylcarbonyl)amino]quinazoline, 4-[(3-chloro4-fluorophenyl)amino]-7-[4-((R)-6-methyl-2-oxomorpholin-4-yl)butyloxy]-6-[(vinylcarbonyl)amino]qumazohne, 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-((S)-6-methyl-2-oxomorpholin-4-yl)ethoxy]-6-[(vinylcarbonyl)amino]quinazohne, 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)ethyl]-N-[(ethoxycarbonyl)methyl]-ammo}-l-oxo-2-buten-l-yl)amino]-7-cyclopropylmethoxyquinazohne, 4-[(R)-(l-phenylethyl)amino]-6-{[4-(morphohn-4-yl)-1 -oxo-2-buten-1 -yl]ammo} -7-cyclopropyl-methoxyquinazohne, and 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(morpholin-4-yl)propyloxy]-7-methoxyquinazohne Any
reference to the above-mentioned EGFR kinase inhibitors also includes any pharmacologically acceptable acid addition salts thereof which may exist By the physiologically or pharmacologically acceptable acid addition salts thereof which may be formed by the EGFR kinase inhibitors are meant, according to the invention, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumanc acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid The salts of the EGFR kinase inhibitors selected from among the salts of acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid are preferred according to the invention
Suitable p38 kinase inhibitors include, for example, l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morphohn-4-ylethoxy)naphthalen-l -yl]urea, 1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(l-oxothiomorphohn-4-yl)ethoxy)naphthalen-l-yl]urea, l-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyndin-4-ylethoxy)naphthalen-l-yl]urea, l-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morphohn-4-ylethoxy)naphthalen-l-yl]urea, and l-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholm-4-ylethoxy)naphthalen-l-yl]urea disclosed in our co-pending US patent application no 60/605,344, 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyndo[2,3-d]pynmidin-2-ylamino]-piperidme-l-carboxyhc acid tert-butyl ester, Hydrochloride salt of 2-(Pipendin-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyndo[2,3-d]pynmidin-7-one, 2-(l-Methanesulfonyl-pipendin-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyndo[2,3-d]pynmidin-7-one, 2-(l-Benzyl-pipendin-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyrido[2,3-d]pynmidin-7-one, 2-(l-Methyl-pipendin-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyndo[2,3-d]pynmidin-7-one, 2-(4-Methyl-piperazin-l-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyndo[2,3-d]pyrimidin-7-one, 4-[6-(2-Chloro-phenyl)-7-oxo-8-(tetrahydro-pyran-4-yl)-7,8-dihydro-pyndo[2,3-d]pyrimidin-2-ylamino]-pipendine-1 -carboxyhc acid tert-butyl ester, 2-(Pipendin-1 -ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyndo[2,3-d]pynmidin-7-one, 2-Cyclobutylamino-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyndo[2,3-d]pynmidm-7-one, 2-( 1 -Acetyl-pipendm-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyndo[2,3-d]pynmidin-7-one, 2-(l-Benzoyl-pipendin-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyndo[2,3-d]pynmidin-7-one, 2-(l-Benzoyl-pipendin-4-yIamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyndo[2,3-d]pynmidin-7-one, 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyrido[2,3-d]pyrimidm-2-ylamino]-piperidine-l-carboxylic acid (4-fluoro-phenyl)-amide, 2-( 1 -Ethanesulfonyl-pipendm-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyndo[2,3-d]pynmidin-7-one, 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyndo[2,3-d]pynmidin-2-ylamino]-piperidine-l-carbothioic acid (4-fluoro-phenyl)-amide, 4-[7-
Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyrido[2,3-d]pynmidin-2-ylamino]-piperidine-1-carboxyhc acid (4-trifluoromethyl-phenyl)-amide, 2-[4-(Propane-2-sulfonyl)-piperazin-1-ylamino]-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyrido[2,3-d]pynmidin-7-one, 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyndo[2,3-d]pynmidin-2-ylamino]-piperazine-1-carboxyhc acid propylamide, 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyrido[2,3-d]pynmidin-2-ylamino]-piperazine-1 -carboxyhc acid ((R)-1,2-dimethyl-propyl)-amide, 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyndo[2,3-d]pynmidin-2-ylamino]-piperazine-l -carboxyhc acid cyclohexylamide, 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyrido[2,3-d]pynmidin-2-ylamino]-piperazine-l-carboxyhc acid (4-fluoro-phenyl)-amide, 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyrido[2,3-d]pynmidin-2-ylamino]-piperazine-l-carboxyhc acid cyclopentyl methyl-amide, and the compounds which are disclosed in our co-pending US patent application no 60/598621, 60/630,517, and Indian patent application no 1098/DEL/2005 and 21 l/DEL/2005 Any reference to the above mentioned p38 kinase inhibitors also includes any pharmacologically acceptable acid addition salts thereof According to the invention, physiologically or pharmacologically acceptable acid addition salts thereof of the p38 kinase inhibitors are include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfomc acid, acetic acid, fumanc acid, succinic acid, lactic acid, citric acid, tartaric acid, and maleic acid
The leukotnene antagonist can be selected from compounds not limited to those described in US 5,565,473, US 5,583,152, US 4,859,692 or US 4,780,469
Examples of leukotnene antagonist include, but are not limited to, montelukast, zafirlukast, pranlukast and pharmaceutically acceptable salts thereof
5-Lipoxygenase inhibitors can be selected from the compounds disclosed in U S 4,826,868,4,873,259, EP 419049, EP 542356 or EP 542355 Examples may include but are not limited to atreleuton, zyflo (zileuton), ABT-761, fenleuton or tepoxahn
Chemokme inhibitors can be selected from the compounds disclosed in EP 287436, EP 389359, EP 988292, WO 02/26723 or WO 01/90106
Examples of chemokine inhibitors include, but are not limited to AMD3100, AZD 8309, BX-471, GW-766994, UK-427857, CP-481715, UK-107543, UK-382055 or UK-395859
Because of their valuable pharmacological properties, the compounds described herein may be administered to an animal for treatment orally, by inhalation, by intranasal route, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally, intratracheally, intravaginally, intraperitoneally or topically
The pharmaceutical compositions described herein can be produced and administered in dosage units, each unit containing a certain amount of at least one compound described herein and at least one physiologically acceptable addition salt thereof The dosage may be varied over extremely wide limits, as the compounds are effective at low dosage levels and relatively free of toxicity The compounds may be administered in the low micromolar concentration, which is therapeutically effective, and the dosage may be increased as desired up to the maximum dosage tolerated by the patient
The compounds described herein can be produced and formulated as their racemic mixtures, enantiomers, diastereomers, rotamers, N-oxides, polymorphs, solvates and pharmaceutically acceptable salts, as well as the active metabolites Pharmaceutical compositions comprising the molecules of Formula I or metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable carrier and optionally included excipient can also be produced
The examples mentioned below demonstrate general synthetic procedures, as well as specific preparations of particular compounds The examples are provided to illustrate the details of the invention and should not be constrained to limit the scope of the present invention
EXPERIMENTAL General Procedure; Synthesis of a compound of Formula VI
Step a Formula II
To a solution of the compound (S or R)-3-[3-(cycloalkyloxy)-4-alkoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (2 g) (prepared by following the procedure described in WO 2006/085212) in dichloromethane was added aluminium trichloride (1 68 g) at 0°C and stirred the reaction mixture at room temperature for 2 hours The reaction mixture was subsequently poured into ice-cold water and extracted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound
The following compounds were prepared by following the above procedure 5-[(5S or 5R)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (Compound No 6) Mass (m/z) 250 03 (M++l)
5-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (Compound No 92) Mass 250 27(M+1) Stepb Formula IV
To a solution of the compound obtained from step a above (2 5 g) in dimethyl formamide was added the compound of Formula III (1 8 mL) and potassium carbonate (2 77 g) The reaction mixture was stirred at 50-60°C overnight To the resulting reaction mixture was added water and extracted with ethyl acetate The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound
The following compounds were prepared by following the above procedure (5S or 5R)-3-(3,4-Dimethoxyphenyl)-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 7), Mass(m/z) 263 97(M++1)
(5Ror 5S)-3-(3,4-Dimethoxyphenyl)-l,7-dioxa-2-azaspiro[4 4]non-2-ene (CompoundNo 8), (5S or 5R)-3-(3-isopropoxy-4-methoxyphenyl)-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 57),
Mass(m/z) 292(M++1)
(5S or 5R)-3-[3-(Cyclopropylmethoxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 58), Mass(m/z) 304 (M++l)
(5S or 5R)-3-[3-(Benzyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 78), Mass(m/z) 340 30(M++1)
(5R or 5S)-3-[3-(benzyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 126),
Mass(nVz) 340 05(M++1) Step c Formula V
To a solution of the compound obtained from step b above (500 mg) in dimethyl acetamide under nitrogen atmosphere was added sodium ethane thiolate (505 mg) and stirred the reaction mixture at 110-120°C for about 3 hours Excess of dimethyl acetamide was evaporated under reduced pressure and the reaction mixture was acidified with ammonium chloride solution The mixture was extracted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure The residue thus obtained was purified by column chromatography to furnish the title compound
The following compounds were prepared by following the above procedure 2-(Benzyloxy)-4-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenol (Compound No 9), Mass(m/z) 325 94 (M++l)
4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (CompoundNo 4), Mass(m/z) 250 02(M++1)
4-[(5R or 5S)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (Compound No 5),
Mass(m/z) 250 02(M++1)
2-(Cyclopropylmethoxy)-4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol
(Compound No 59),
Mass(m/z) 290(M++1)
4-[(5S or 5R)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-isopropoxyphenol (Compound No
60),
Mass(m/z) 278 (M++l)
2-(Cyclopropylmethoxy)-4-[(5R or 5S)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol
(Compound No 65),
4-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-isopropoxyphenol (Compound No
66),
2-(Benzyloxy)-4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (CompoundNo
77),
2-(Benzyloxy)-4-[(5R or 5S)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (Compound No
127),
Mass(m/z) 325 99 (M++l)
Stepd Formula VI
To a mixture of the compound obtained from step c above (370 mg) and potassium carbonate (369 mg) in dimethyl formamide was added the compound of Formula Ilia and stirred the reaction mixture overnight To the resulting mixture water was added, extracted with ethyl acetate, washed with water and brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure The residue thus obtained was purified by column chromatography to furnish the title compound
The following compounds were prepared by following the above procedure (5R or 5S)-3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 13), Mass(m/z) 300(M++1)
(5S or 5R)-3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 14), Mass(m/z) 299 98(M++1)
(5S or 5R)-3-[3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 62), Mass(nVz) 340(M++1)
(5S or 5R)-3-[4-(difluoromethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 63),
Mass(m/z) 328 (M++l)
(5R or 5S)-3-[4-(difluoromethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 64)
Mass(m/z) 292(M++1)
(5R or 5S)-3-[3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-l ,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 67),
Mass(m/z) 340 24 (M++l)
(5R or 5S)-3-[4-(difluoromethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 68),
Mass(m/z) 328 26(M++1)
(5S or 5R)-3-[3-(Benzyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 76),
Mass(m/z) 376(M++1)
3-[3-(Benzyloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 90),
Mass (m/z) 408 8 (M++l)
(5R or 5S)-3-[3-(Benzyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 128),
Mass (m/z) 376 02(M++1)
Synthesis of a compound of Formula XI
Step a Formula VII
To a solution of the compound of Formula VI (1 0 eq) in methanol was added palladium on carbon (10 % by weight) and hydrogen gas was purged through baloon in the reaction mixture The reaction mixture was stirred overnight The mixture was filtered through cehte pad The filtrate was concentrated under reduced pressure The residue thus obtained was purified by column chromatography to furnish the title compound
The following compounds were prepared by following the above procedure 5-(l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy)phenol (Compound No 33),
Mass (m/z) 318 11 (M++l)
2-(Difluoromethoxy)-5-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (Compound No 91), Mass (m/z) 286 1 (M++l)
2-(Difluoromethoxy)-5-[(5R or 5S)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (Compound
No 130),
Mass(nVz) 286 09 (M++l)
Step b Formula XI
The title compound was prepared following the procedure as described for the preparation of Formula IV by reacting the compound of Formula VII with a compound of Formula X
The following compounds were prepared by following the above procedure 3 - [2-(Difluoromethoxy> 5-( 1,7-dioxa-2-azaspiro [4 4]non-2-en-3 -yl)phenoxy]propan-1 -ol (Compound No 2), Mass(m/z) 344 10(M++1)
[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetomtnle (Compound No 3), Mass(m/z) 347 01(M++23)
2-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]ethanol (Compound No 10), Mass(nVz) 330 11 (M++l) 3-[4-(Difluoromethoxy)-3-ethoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No
11),
Mass(m/z) 314 06(M++1)
3-[3-(Cyclohexyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 12),
Ethyl [2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetate
(Compound No 15),
Mass(m/z) 372 04(M++1)
3-[4-(Difluoromethoxy)-3-(2-morphohn-4-ylethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 16),
Mass(nVz) 399 06(M++1)
5-[2-(Difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]pentanoic acid
(Compound No 18),
Mass(nVz) 386 09(M++1)
3-[3-(2,2,2-Tnfluoroethoxy)-4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 19),
Mass(m/z) 368 04 (M++l)
nm3-[3-(Cyclopentylmethoxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 20),
3-[3-(cyclopentyloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 24),
Mass(m/z) 386(M++1)
3-[3-Propoxy-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 29),
Mass (m/z) 360 (M++l)
3-[3-Isopropoxy-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 30),
Mass(m/z) 360(M++1)
3-[3-(Cyclopropylmethoxy)-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-
ene (Compound No 31),
Mass(m/z) 372 (M++l)
3-[3-(2,3-Dihydro-lH-inden-2-yloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 32),
Mass(m/z) 434 (M++l)
3-[3-Methoxy-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 34),
Mass(m/z) 332(M++1)
3-[3-Ethoxy-4-(2,2,2-trifluoroethoxy)phenyl]-l ,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound
No 35),
Mass (m/z) 346(M++1)
3-[3-Butoxy-4-(2,2,2-trifluoroethoxy)phenyl]-l ,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound
No 36),
3-[3-(Cyclohexylmethoxy)-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 37),
Mass (m/z) 414(M++1)
3-{[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]methyl}
benzonitnle (Compound No 38),
Mass (m/z) 401 (M++l)
2-{2-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]ethyl}-lH-
isomdole-l,3(2H)-dione (CompoundNo 39),
Mass (m/z) 459(M++1)
3-[3-(Cyclohexyloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 40),
Mass(nVz) 400 (M++l)
Ethyl [5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy) phenoxy]acetate
(Compound No 41),
Mass(m/z) 404(M++1)
3-[3-(Cyclohexylmethoxy)-4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 42),
Mass(nVz) 382 (M++l)
Tert-butyl [2-(difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetate
(Compound No 43),
Mass(m/z) 400(M++1)
Synthesis of a compound of Formula IX
To a solution of a compound of Formula VII (50 mg) in dimethylformamide (5 mL) was added sodium hydride (16 mg) at 0°C and stirred the reaction mixture for 1 hour followed by the addition of the compound of Formula VIII (0 02 mL) The reaction mixture was stirred at room temperature for 4 hours followed by the addition of water The compound was extracted with ethyl acetate, washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound
The following compounds were prepared by following the above procedure 2-(Difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenyl cyclohexanecarboxylate (Compound No 17) Mass(m/z) 396 08 (M++l)
2-(Difluoromethoxy)-5-( 1,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenyl cyclopropanecarboxylate (Compound No 25), Mass(m/z) 354 09(M++1)
2-(Difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenyl morphohne-4-carboxylate (Compound No 26), Mass(m/z) 399 15 (M++l)
2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenyl benzoate (Compound No 27),
Mass(m/z) 390 13 (M++l) Synthesis of a compound of Formula XIII Step a Formula XI
The title compound was prepared following the procedure as described for the preparation compound of Formula IV, by reacting the compound of Formula VII with a compound of Formula X Stepb Formula XIII
To a solution of the compound of Formula XI (wherein R3y is -(CH2)g1C(=O)OR3) (0 060 g) in dichloromethane (4 mL) was added the compound of Formula XII (2 mL) and stirred the reaction mixture for 3 to 4 hours at 50-60°C The reaction mixture was washed with dilute hydrochloric acid and water The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound The following compounds were prepared by following the above procedure Ar-cyclopropyl-2-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetamide (Compound No 21), Mass(m/z) 383 08 (M++l)
2-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetamide (Compound No 22), Mass(m/z) 343 09 (M++l)
2-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]-A^-methylacetamide (Compound No 23), Mass(m/z) 357 06(M++1)
5-[2-(Difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy] pentanamide (Compound No 28), Mass(nVz) 385 20(M++1)
N-cyclopropyl-2-[5-( 1,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy)phenoxy] acetamide (Compound No 44), Mass(nVz) 415(M++1)
N-benzyl-2-[5-( 1,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy)phenoxy] acetamide (Compound No 47), Mass(m/z) 465(M++1)
N-cyclopentyl-2-[5-( 1,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy)phenoxy] acetamide (Compound No 48), Mass(m/z) 443 (M++l) Scheme II: General Procedure:
Synthesis of a compound of Formula IVa Step a Formula Ha
To a solution of the compound (S or R)-3-[3-(cycloalkyloxy)-4-alkoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (510 mg) (prepared by following the procedure described in WO 2006/085212) under nitrogen atmosphere m dimethylacetamide was added sodium ethane thiolate (473 mg) and stirred the reaction mixture at 110-120°C for 5-6 hours Excess of dimethyl acetamide was evaporated under reduced pressure and the residue thus obtained was acidified by ammonium chloride solution The mixture was extracted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure The residue thus obtained was purified by column chromatography to furnish the title compound Step b Formula IVa
To a solution of the compound obtained from step a above (400 mg) in dimethyl formamide was added potassium carbonate (364 mg) and a compound of Formula III over a period of 10 minutes The reaction mixture was stirred overnight which was thereafter diluted with water and extracted with ethyl acetate The organic layer was washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure The residue thus obtained was purified by column chromatography to furnish the title compound
The following compounds were prepared by following the above procedure 2-(Cyclopentyloxy)-4-[(5R or 5S)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (Compound No 45),
Mass(m/z) 304 (M++l)
2-(Cyclopentyloxy)-4-[(55' or Ji?)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (Compound No 46),
Mass(m/z) 304(M++1)
(5R or 5S)-3-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 56), Mass(m/z) 354 (M++l)
(5S or 5R)-3-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 61), Mass(m/z) 354(M++1)
Scheme III:
General procedure:
Synthesis of a compound of Formula XVI
To a solution of the compound of Formula XIV (450 mg) in dimethylformamide was added a compound of Formula XV (728 mg) and potassium carbonate (653 mg) The reaction
mixture was stirred for 4 hours at 60-70°C The reaction mixture was diluted with water and was extracted with ethyl acetate The organic layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure The residue thus obtained was purified by preparative thin layer chromatography to furnish the title compound
The following compounds were prepared by following the above procedure 3-[3- {[(35)-1 -Benzylpyrrohdin-3-yl]oxy} -4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 1), Mass (m/z) 445 (M++l)
Tert-butyl (3S)-3-[2-(difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]pyrrohdine-1 -carboxylate (Compound No 52), Mass (m/z) 455 (M++l)
Tert-butyl 4-[2-(difluoromethoxy)-5-(l,7-dioxa-2- azaspiro[4 4]non-2-en-3-yl)phenoxy] pipendine-1-carboxylate (Compound No 49), Mass (m/z) 369 (M++l-Boc)
7ert-butyl (3R)-3-[2-(difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]pyrrohdine-l-carboxylate (Compound No 53), Mass (m/z) 455 (M++l)
Tert-butyl 3-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]pipendme-1 -carboxylate (Compound No 54), Mass (m/z) 469(M++1)
rert-butyl(2S)-2-{[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]methyl}pyrrohdine-l-carboxylate (Compound No 55), Mass (m/z) 469 34 (M++l) Synthesis of a compound of Formula XVII
A solution of the compound of Formula XVI (150 mg) in methanohc HC1 (3 0 mL) was stirred at room temperature for 3 hours The solvent was evaporated under reduced pressure and dried under high vacuum to furnish the title compound
The following compounds were prepared by following the above procedure Hydrochloride salt of 3-[4-(difluoromethoxy)-3-(pipendin-4-yloxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 50), Mass (m/z) 369(M++1)
Hydrochloride salt of 3-{4-(Difluoromethoxy)-3-[(3S)-pyrrohdin-3-yloxy]phenyl}-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 69), Mass (m/z) 355 (M++l)
Hydrochloride salt of 3-{4-(difluoromethoxy)-3-[(2S)-pyrrohdm-2-ylmethoxy]phenyl}-l ,7-
dioxa-2-azaspiro[4 4]non-2-ene (Compound No 70),
Mass(m/z) 369 (M++l)
Hydrochloride salt of 3-{4-(difluoromethoxy)-3-[(2R)-pyrrohdin-2-ylmethoxy]phenyl}-l,7-
dioxa-2-azaspiro[4 4]non-2-ene (Compound No 71),
Mass(m/z) 369(M++1)
Hydrochloride salt of 3-[4-(difluoromethoxy)-3-(piperidin-3-yloxy)phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 94),
Mass(m/z) 369 34(M++1)
Synthesis of a compound of Formula XIX
To a solution of the compound of Formula XVII (50 mg) in dimethylformamide was added potassium carbonate (75 mg) and a compound of Formula XVIII (21 mg) The reaction mixture was stirred overnight The mixture was diluted with water and extracted with ethyl acetate The organic layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure The residue thus obtained was purified by preparative thin layer chromatography to furnish the title compound
The following compounds were prepared by following the above procedure 3-{3-[(l-Acetylpipendin-4-yl)oxy]-4-(difluoromethoxy)phenyl}-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 51), Mass(m/z) 411(M++1)
3 - [4-(Difluoromethoxy)-3 - {[(2R)-1 -propionylpyrrohdin-2-yl]methoxy} phenyl] -1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 72), Mass(m/z) 425 (M++l)
3-[3-{[(25)-l-Acetylpyrrohdin-2-yl]methoxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 73), Mass(m/z) 411(M++1)
3-[3-{[(3S)-l-Benzoylpyrrohdin-3-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 74), Mass(m/z) 459(M++1)
3-[4-(Difluoromethoxy)-3-{[(3S)-l-propionylpyrrohdin-3-yI]oxy}phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 75), Mass(m/z) 410(M++1)
3 - {4-(Difluoromethoxy)-3 - [(1 -propionylpipendin-4-yl)oxy]phenyl} -1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 79), Mass (m/z) 425 (M++l)
3-[4-(Difluoromethoxy)-3-{[l-(4-fluorobenzoyl)piperidin-4-yl]oxy}phenylJ-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 80),
Mass (m/z) 491 (M++l)
3 - [3 - {[ 1 -(Cyclopropylcarbonyl)pipendin-4-yl]oxy} -4-(difluoromethoxy)phenyl]-1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 81),
Mass (m/z) 437(M++1)
3-[3-{[l-(Cyclopentylcarbonyl)pipendin-4-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 82),
Mass (m/z) 465 (M++l)
3-[4-(Difluoromethoxy)-3-({l-[(trifluoromethyl)sulfonyl]pipendin-4-yl}oxy)phenyl]-l,7-dioxa-
2-azaspiro[4 4]non-2-ene (Compound No 83),
Mass (m/z) 501 (M++l)
3-{3-[(l-Acetylpipendin-3-yl)oxy]-4-(difluoromethoxy)phenyl}-l,7-dioxa-2-azaspiro[4 4]non-
2-ene (Compound No 84),
Mass (m/z) 411 (M++l)
3 - {4-(Difluoromethoxy)-3 - [(1 -propionylpipendin-3 -yl)oxy]phenyl} -1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 85),
Mass (m/z) 425 (M++l)
3-[4-(Difluoromethoxy)-3-{[l-(4-fluorobenzoyl)pipendm-3-yl]oxy}phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 86),
Mass (m/z) 491 (M++l)
3-[3-{[l-(Cyclopropylcarbonyl)pipendin-3-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 87),
Mass (m/z) 437(M++1)
3-[3-{[l-(Cyclopentylcarbonyl)pipendm-3-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 88),
Mass (m/z) 465 (M++l)
3-[4-(Difluoromethoxy)-3-{[l-(ethylsulfonyl)pipendin-3-yl]oxy}phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 89),
Mass (m/z) 461 (M++l)
3-[3-{ [(3iS)-l -acetylpyrrohdin-3-yl]oxy}-4-(difluoromethoxy)phenyl]-1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 93),
Mass (m/z) 397 1
3-[4-(Difluoromethoxy)-3-{[l-(phenylcarbonyl)pipendm-4-yl]oxy}phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 95),
Mass(m/z) 473 (M++l)
3-[4-(Difluoromethoxy)-3- {[ 1 -(morpholin-4-ylcarbonyl)pipendin-4-yl]oxy}phenyl]-l ,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 96), Mass(m/z) 482(M++1)
3-[4-(Difluoromethoxy)-3-{[l-(phenylcarbonyl)pipendin-3-yl]oxy}phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 97), Mass (m/z) 473 (M++l)
3-[4-(Difluoromethoxy)-3-{ [1 -(morpholin-4-ylcarbonyl)piperidin-3-yl]oxy} phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 98), Mass (m/z) 482 (M++l)
3-[4-(Difluoromethoxy)-3-({l-[(trifluoromethyl)sulfonyl]piperidin-3-yl}oxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 99), Mass (m/z) 501 (M++l)
3-[4-(Difluoromethoxy)-3-{[(2i?)-l-(phenylcarbonyl)pyrrolidin-2-yl]methoxy}phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 100), Mass (m/z) 473 14(M++1)
3 - [3 - {[(2R)-1 -acetylpyrrohdin-2-yl]methoxy} -4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 101), Mass (m/z) 41125(M++1)
3-[4-(Difluoromethoxy)-3-{[(2i?)-l-propanoylpyrrolidin-2-yl]methoxy}phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 102), Mass (m/z) 425 27(M++1)
3-[3-{[(2i?)-l-(cyclopropylcarbonyl)pyrrohdin-2-yl]methoxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 103), Mass (m/z) 437 28(M++1)
3-[3-{[(35)-l-(cyclopropylcarbonyl)pyrrolidm-3-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 104), Mass (m/z) 423 27 (M++l)
3 -[3 - {[(35)-1 -(cyclopentylcarbonyl)pyrrohdin-3 -yl]oxy} -4-(difluoromethoxy)phenyl] -1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 105), Mass (m/z) 451 30(M++1)
3 -[4-(Difluoromethoxy)-3 -({(3i?)-1 - [(4-fluorophenyl)carbonyl]pyrrohdin-3 -yl} oxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 106), Mass (m/z) 491 29 (M++l)
Scheme V
The following compounds of Formula XXV b were prepared by following the procedures described in WO 2005/021515
{3-[4-(Difluoromethoxy)-3-methoxyphenyl]-4,5-dihydroisoxazole-5,5-diyl}dimethanol (Compound No 107), Mass(m/z) 304 31(M++1) 3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l,8-dioxa-2-azaspiro[4 5]dec-2-ene (Compound No
111),
Mass(m/z) 314 26(M++1)
7-[4-(Difluoromethoxy)-3-methoxyphenyl]-5-oxa-6-azaspiro[3 4]oct-6-ene (Compound No
115),
Mass(m/z) 284 03(M++1)
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l-oxa-2-azaspiro[4 4]non-2-ene (Compound No
116),
Mass(m/z) 298 08 (M++l)
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l-oxa-2-azaspiro[4 5]dec-2-ene (Compound No
117),
Mass(m/z) 312 06(M++1)
Scheme VI
Synthesis of a compound of Formula XXVIII
Step a Formula XXVII
To a solution of a compound of Formula XXVI (0 00078 mole) in dichloromethane (10 mL), tnethylamme (0 003 mole) was added and the reaction mixture was cooled to 0°C Methane sulphonyl chloride (0 0023 mole) was added drop wise and the reaction mixture was stirred at 0°C to room temperature for about 2 hours The reaction mixture was then diluted with dichloromethane and washed with sodium bicarbonate solution Organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the crude title compound Stepb Formula XXVIII
To a solution of a compound of Formula XXVII (0 00076 mole) in dimethylformamide (5 mL), sodium sulphide 9 H2O (0 0019 mole) was added and the reaction mixture was refluxed at 90 - 100°C for about 14-16 hours Excess of the solvent was evaporated, water was added to the residue and the solution was extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the pure title compound
The following compounds were prepared by following the above procedure 3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l-oxa-7-thia-2-azaspiro[4 4]non-2-ene (Compound No 108), Mass(m/z) 316 24(M++1)
7-[4-(Difluoromethoxy)-3-methoxyphenyl]-5-oxa-2-thia-6-azaspiro[3 4]oct-6-ene (Compound No 110), Mass(m/z) 302 17(M++1) Synthesis of a compound of Formula XXIX
A compound of Formula XXVIII (0 00015 mole) was dissolved in methanol (5 mL), sodium penodate (0 00015 mole) was added at 0°C and the reaction mixture was stirred at room temperature for about 5 hours The residue was filtered and the organic solvent was removed under reduced pressure to furnish solid compound, which was further purified by preparative TLC using 50% ethyl acetate in hexane
The following compounds were prepared by following the above procedure 3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l-oxa-7-thia-2-azaspiro[4 4]non-2-ene7-oxide (Compound No 109), Mass(m/z) 332 24(M++1)
7-[4-(Difluoromethoxy)-3-methoxyphenyl]-5-oxa-2-thia-6-azaspiro[3 4]oct-6-ene 2-oxide (Compound No 113), Mass(m/z) 317 98(M++1) Synthesis of a compound of Formula XXX
To a solution of a compound of Formula XXVIII (0 00022 mole) in dichloromethane (5 mL), m-chloroperoxy benzoic acid (0 00033 mole) was added at 0°C and the reaction mixture was stirred at room temperature over-mght The reaction mixture was extracted with water Organic layer was washed with IN sodium hydroxide solution and then with water, dried over sodium sulphate and concentrated under reduced pressure to furnish the crude title compound, which was further purified by preparative TLC using ethyl acetate as eluent
The following compounds were prepared by following the above procedure 3-[4-(Difluoromethoxy)-3-methoxyphenyl]-1 -oxa-7-thia-2-azaspiro[4 4]non-2-ene 7,7-dioxide (Compound No 114) Mass(m/z) 347 92(M++1)
7-[4-(Difluoromethoxy)-3-methoxyphenyl]-5-oxa-2-thia-6-azaspiro[3 4]oct-6-ene 2,2-dioxide (Compound No 120) Mass(m/z) 333 92(M++1)
Scheme VII
Synthesis of a compound of Formula XXXIV
Step a Formula XXXII
The compounds of Formula XXXII were prepared by following the procedures described in WO 2005/021515 Step b Formula XXXIII
A compound of Formula XXXII (0 00071 mole) was taken in tetrahydrofuran (15 mL) Methanol (5 mL) was added to it Sodium borohydnde (0 0014 mole) was added and the reaction mixture was stirred at room temperature over-night The reaction was quenched with saturated ammonium chloride and the solvent was removed under reduced pressure Water was added to the residue and extraction was done with ethyl acetate, the residue was dried over sodium sulphate and concentrated under reduced pressure to furnish the crude title compound, which was further purified by column chromatography using silica gel (100-200) Step c Formula XXXIV
A compound of Formula XXXIII (0 00027 mole) was dissolved in a mixture of ethanol water (10 2 mL), potassium hydroxide (0 0005 mole) was added and the reaction mixture was stirred at refluxing temperature over-night Excess solvent was removed under reduced pressure Water was added to the residue and it was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure The compound was purified by column chromatography
The following compound was prepared by following the above procedure 7-[4-(Difluoromethoxy)-3-methoxyphenyl]-2,5-dioxa-6-azaspiro[3 4]oct-6-ene (Compound No 123)
Mass(m/z) 286 02(M++1) Scheme VIII
Synthesis of a compound of Formula XXXVII Step a Formula XXXV a
Cyclopentane 1,3-diol (0 0014 mole) and tert-butyl dimethyl silyl chloride (0 0008 mole) in dichloromethane (5 mL) were treated dropwise with 1,8-diaza bicyclo [5 4 0]undec-7-ene (0 0008 mole) at room temperature and the reaction mixture was stirred for about 14 hours The reaction mixture was then diluted with dichloromethane, washed with 1 N HC1 solution, followed by saturated sodium bicarbonate solution and brine solution It was dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound Step b Formula XXXV
It was prepared by following Scheme I Stepc Formula XXXVI
A compound of Formula XXXV (0 00035 mole), a compound of Formula XXXV a (0 00035 mole) and tnphenyl phosphine (0 00052 mole) were taken together in tetrahydrofuran (10 mL) and the reaction mixture was stirred for about 10 minutes, followed by dropwise addition of dnsopropyl azodicarboxylate (0 00052 mole) The reaction mixture was stirred overnight, solvent was then removed under reduced pressure and the residue purified by column chromatography Step d Formula XXXVII
A compound of Formula XXXVI (70 mg) was taken m ethanohc HC1 (10 mL) and stirred over-night Ethanol was removed under reduced pressure, water was added and the solution was extracted with ethyl acetate It was washed with saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure Purification was done by preparative TLC using ethyl acetate hexane (1 1) to get the pure title compound
The following compound was prepared by following the above procedure 3-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]cyclopentanol (Compound No 129), Mass(m/z) 370 13 (M++l) Scheme IX Synthesis of a compound of Formula XXXIX
A compound of Formula XXXV (0 701 mmole), copper II acetate (0 701 mmole), 4-(«-butoxycarbonyl) aminophenyl boromc acid (1 4 mmole), 4 A0 molecular sieves were taken together in dichloromethane Tn ethyl amine (3 505 mmole) was added to the reaction mixture and stirred together at room temperature over-night The reaction mixture was then filtered through celite pad The organic solvent was evaporated under reduced pressure, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure The crude mixture was purified by column chromatography
The following compounds were prepared by following the above procedure tert-butyl {4-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl) phenoxy] phenyl} carbamate (Compound No 125), Mass(m/z) 477 07(M++1)
3-[4-(Difluoromethoxy)-3-(4-fluorophenoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 131), Mass(m/z) 380 09 (M++l)
3-[3-(4-Chlorophenoxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 132),
Mass(m/z) 396 11(M++1)
3 - {4-(Difluoromethoxy)-3 -[4-(trifluoromethoxy)phenoxy]phenyl} -1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 133),
Mass(m/z) 446 14(M++1)
3-{4-(Difluoromethoxy)-3-[4-(trifluoromethyl)phenoxy]phenyl}-l,7-dioxa-2-azaspiro[4 4]non-
2-ene (Compound No 134),
Mass(m/z) 430 18(M++1)
Synthesis of a compound of Formula XL
7er/-butyl {4-[2-(difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]phenyl}carbamate (Compound No 125) (50 mg) was dissolved in ethereal HC1 and the mixture was stirred at room temperature over-night The solvent was evaporated under reduced pressure to obtain a solid, which was washed with hexane and dried
The following compound was prepared by following the above procedure Hydrochloride salt of 4-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy] aniline (Compound No 124), Mass(m/z) 377 0(M++1) Synthesis of a compound of Formula XLI
Hydrochloride salt of 4-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]anihne (Compound No 124) (80 mg, 0 212 mmole) and methane sulphonyl chloride (0 424 mmole) were taken in pyridine (1 mL) and the reaction mixture was stirred at room temperature over-night The solvent was evaporated under reduced pressure Water was added to the residue and extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the compound, which was further purified by preparative TLC
The following compound was prepared by following the above procedure A^-{4-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl) phenoxy] phenyl} methane sulfonamide (Compound No 136), Mass(m/z) 455 10(M++1) Synthesis of a compound of Formula XLII
To the solution of hydrochloride salt of 4-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]amhne (Compound No 124) (80 mg, 0 212 mmole) in dichloromethane (2 mL) tnethyl amine ( 0 425 mmole) and acetic anhydride ( 0 425 mmole)
were added and the reaction mixture was stirred at room temperature over-night Water was added to the reaction mixture and extracted with dichloromethane, washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish crude title compound with was purified by preparative TLC
The following compound was prepared by following the above procedure N-{4-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl) phenoxy] phenyl} acetamide (Compound No 135), Mass(m/z) 419 13 (M++l) Scheme X Synthesis of a compound of Formula XLIV
A compound of Formula XXXV (0 350 mmole) and bromo benzene (0 636 mmole) were taken in pyridine (2 5 mL), potassium carbonate (0 507 mmole) was added and the reaction mixture was stirred at 150°C temperature for about 5 minutes Cu powder (0 314 mmole) was added and the mixture was stirred again at 150°C temperature for about 24 hours, It was neutralized with HC1, water was added, extraction was done with ethyl acetate, washings were done with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish a crude mixture which was purified by preparative TLC using 30% ethyl acetate m hexane as solvent
The following compound was prepared by following the above procedure 3-[4-(Difluoromethoxy)-3-phenoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 112),
Mass(m/z) 36196(M++1) Synthesis of a compound of Formula XLVI
To a solution of a compound of Formula XXXV (0 526 mmole) in dimethyl sulphoxide (3 mL), suspension of potassium fluoride in dimethyl sulphoxide (1 052 mmole) was added, followed by cesium carbonate (2 104 mmole) and stirred for about 10 minutes 4-Bromo pyridine (0 784 mmole) was added and the reaction mixture was refluxed at 140°C for about 6 hours Water was added and the mixture was extracted with ethyl acetate, washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure The crude compound was purified by column chromatography
The following compound was prepared by following the above procedure 3-[4-(Difluoromethoxy)-3-(pyndin-4-yloxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 137), Mass(m/z) 362 92 (M++l)
Scheme XI
Synthesis of a compound of Formula XLVIII
The following compound of Formula XLVIII was prepared by following the procedures described in WO 2005/021515
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l,9,12-tnoxa-2-azadispiro[4 2 4 2]tetradec-2-ene (Compound No 118), Mass(m/z) 369 99 (M++l) Synthesis of a compound of Formula XLIX
To the solution of a compound of Formula XLVIII (0 271 mmole) in dichloromethane (2 rnL), trifluoroacetic acid (1 355 mmole) was added drop wise in about 1 hour Water (0 1 mL) was added and the reaction mixture was stirred vigorously for about 6 hours The reaction mixture was diluted with dichloromethane, washed with sodium bicarbonate solution, the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure The crude compound was purified by preparative TLC
The following compound was prepared by following the above procedure 3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l-oxa-2-azaspiro[4 5]dec-2-en-8-one (Compound No 119), Mass(m/z) 326 0(M++1) Synthesis of a compound of Formula L
To the solution of 3-[4-(difluoromethoxy)-3-methoxyphenyl]-l-oxa-2-azaspiro[4 5]dec-2-en-8-one (Compound No 119) (200 mg, 0 615 mmole) in methanol tetrahydrofuran (0250 mL), sodium borohynde (46 mg, 1 230 mmole) was added The reaction mixture was stirred for about 3 hours and quenched with ammonium chloride solution Excess of solvent was removed and the mixture was extracted with ethyl acetate, washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure The crude compound obtained was purified by preparative TLC
The following compound was prepared by following the above procedure 3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l-oxa-2-azaspiro[4 5]dec-2-en-8-ol (Compound No 122),
Mass(m/z) 327 98(M++1) Synthesis of a compound of Formula LI
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-1 -oxa-2-azaspiro[4 5]dec-2-en-8-one (Compound No 119) (250 mg, 0 769 mmole), hydroxylamine hydrochloride (106 mg, 1 538 mmole) and potassium carbonate (530 mg, 3 845 mmole) were taken together in acetomtnle (3 mL) The reaction mixture was stirred for about 6 hours at room temperature Excess of solvent
was removed under reduced pressure and water was added to the residue Solid, which separated out was filtered and dried under vacuo
The following compound was prepared by following the above procedure 3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l-oxa-2-azaspiro[4 5]dec-2-en-8-one oxime (Compound No 121), Mass(m/z) 340 99 (M++l)
Example 1: Biological Assay PDE Enzyme Assay
The efficacy of compounds was determined by an enzyme assay using cell lysate of HEK293 cells transfected with PDE4B2 or PDE7A1 plasmids as PDE4B or PDE7A source Some compounds were screened against PDE7A enzyme The enzyme reaction was carried out in the presence of cAMP (1 uM) at 30 °C m the presence or absence of test compound for 45 -60 min An aliquot of this reaction mixture was taken further for the ELISA assay and the protocol of the kit followed to determine level of c AMP in the sample The concentration of the cAMP in the sample directly correlates with the degree of PDE-4 or PDE-7 enzyme inhibition Results were expressed as percent control and the IC50 values of test compounds were reported IC50 values of test compounds were found to be in the range from about 10 uM to about 1 nM concentration
Cell based Assay for TNF-a release Method of isolation of Human Peripheral Blood Mononuclear Cells
Human whole blood was collected in vacutainer tubes containing heparin or EDTA as an anti coagulant The blood was diluted (1 1) in sterile phosphate buffered saline and 10 mL was carefully layered over 5 mL Ficoll Hypaque gradient (density 1 077 g/mL) in a 15 mL conical centrifuge tube The sample was centnfuged at 3000 rpm for 25 minutes in a swing-out rotor at room temperature After centnfugation, interface of cells were collected, diluted at least 1 5 with PBS (phosphate buffered saline) and washed three times by centnfugation at 2500 rpm for 10 minutes at room temperature The cells were resuspended in serum free RPMI1640 medium at a concentration of 2 million cells/mL LPS stimulation of Human PBMNC 's
PBMN cells (0 1 mL, 2 rmlhon/mL) were co-incubated with 20 mL of compound (final DMSO concentration of 0 2 %) for 10 min m a flat bottom 96 well microtiter plate Compounds were dissolved in DMSO initially and diluted in medium for a final concentration of 0 2 % DMSO LPS (1 mg/mL, final concentration) was then added at a volume of 10 ul per well After 30 min, 20 µl of fetal calf serum (final concentration of 10 %) was added to each well Cultures
were incubated overnight at 37 °C in an atmosphere of 5 % CO2 and 95 % air Supernatant were
then removed and tested by ELISA for TNF-a release using a commercial kit (e g BD
Biosciences) The level of TNF-a in treated wells was compared with the vehicle treated D
controls and inhibitory potency of a compound was expressed as IC50 values calculated by using
Graph pad prism IC50 values of some of the compounds was found to be in the range from about
10 uM to about 100 nM concentration
(Formula Removed)
In-vitro assay to evaluate efficacy of PDE4 inhibitors in combination with p38 MAP Kinase inhibitors or corticosteroids
The procedure was same as above except that the test compounds were added either singly or in combination with other therapeutic agents at sub-optimal doses A synergistic effect was seen with the combination of PDE4 inhibitor with corticosteroid or PDE4 inhibitor with p38 MAP kinase inhibitor as compared to the individual compounds when used singly In-vitro assay to evaluate efficacy of PDE4 inhibitors in combination with B2-agonists Measurement of Intracellular cAMP Elevation in U937 Cells
U937 cells (human promonocyte cell line) are grown in endotoxin-free RPMI1640 +
HEPES medium containing 10% (v/v) heat-inactivated foetal bovine serum and 1% (v/v) of an
antibiotic solution (5000 IU/mL penicillin, 5000 ng/mL streptomycin) Cells (0 25 x 106/200 ul)
are resuspended in Krebs' buffer solution and incubated at 37°C for 15 mm in the presence of
test compounds or vehicle (20ul) cAMP generation is initiated by adding 50 ul of 10 uM
prostaglandin (PGE2) Reaction is stopped after 15 mm, by adding 1 N HC1 (50 ul) and assay
mixture placed on ice for 30 mm Sample is centnfuged (450g, 3 mm), and levels of cAMP
measured in the supernatant using cAMP enzyme-linked immunosorbent assay kit (Assay
Designs) Percent inhibition is calculated by the following formula and IC50 value determined
using Graph pad prism
(Formula Removed)
In-vitro functional assay to evaluate efficacy of PDE4 inhibitors in combination with Muscarinic Receptor Antagonists Animals and anaesthesia
Procure Guinea Pig (400-600gm) from expenmental animal facility at Ranbaxy Research laboratories Remove trachea under anesthesia (sodium pentobarbital, 300 mg/kg 1 p) and immediately keep it in ice-cold Krebs Henseleit buffer Indomethacm (lOuM) is present throughout the KH buffer to prevent the formation of bronchoactive prostanoids Trachea experiments
Clean the tissue off adherent fascia and cut it into strips of equal size (with approx 4-5 tracheal rings in each strip) Remove the epithelium by careful rubbing, minimizing damage to the smooth muscle Open the trachea along the mid-dorsal surface with the smooth muscle band intact and make a series of transverse cuts from alternate sides so that they do not transect the preparation completely Tie opposite end of the cut rings with the help of a thread Mount the tissue m isolated tissue baths containing lOmL Krebs Henseleit buffer maintained at 37°C and bubbled with carbogen, at a basal tension of 1 gm Change the buffer 4-5 times for about an hour Equilibrate the tissue for 1 hr for stabilization After 1 hr, challenge the tissue with luM carbachol Repeat this after every 2-3 washes till two similar consequetive responses are obtained At the end of stabilization, wash the tissues for 30 minutes followed by incubation with suboptimal dose of MRA/ Vehicle for 20 minutes prior to contraction of the tissues with lµM carbachol and subsequently assess the relaxant activity of the PDE4 inhibitor [10-9M to 10-4M ] on the stabilized developed tension/response Record the contractile response of tissues either on Powerlab data acquisition system or on Grass polygraph (Model 7) Express the relaxation as percentage of maximum carbachol response Express the data as mean ± s e mean for n observations Calculate the EC50 as the concentration producing 50% of the maximum relaxation to 1 uM carbachol Compare percent relaxation between the treated and control tissues using non-parametric unpaired t-test A p value of < 0 05 is considered to be statistically significant
In-vitro functional assay to evaluate efficacy of PDE4 inhibitors in combination with beta-agonists Experimental Procedure"
Experimental Procedure and data analysis was the same as above except that tissues were stabilized with lµM carbachol or 10 µM histamine, washed for 30 minutes followed by a precontraction with histamine (10 µM) or carbachol (lµM) Tension was allowed to develop to stabilize for 15-20 minutes followed by the cumulative addition of beta-agonists prior to
incubation with suboptimal dose of PDE4 inhibitor A potentiation of the relaxant activity of a beta agonist was seen with the addition of a PDE4 inhibitor
In-vivo assay to evaluate efficacy of PDE4 inhibitors in combination with MRA compounds
LPS induced Airway hyper-reactivity in rats
Drug treatment
PDE-4 inhibitor and muscarinic receptor antagonist were instilled intratracheally under anesthesia at different doses, either alone or in combination Method
Wistar rats (250-350gm) were placed in body box of a whole body plethysmograph
(Buxco Electronics , USA) to induce bronchoconstriction Animals were allowed to acclimatize
in the body box and were given successive challenges, each of 2 mm duration, with PBS
(vehicle for acetylcholine) or acetylcholine (1 e 24, 48, 96,144, 384, and 768 mg/mL) The
respiratory parameters were recorded online using Biosystem XA software, (Buxco Electronics,
USA) for 3 mm A gap of 2 mm was allowed for the animals to recover and then challenged
with the next higher dose of acetylcholine (ACh) This step was repeated until Penh of rats
attained 2 times the value (PC-100) seen with PBS challenge Following PBS/ACh challenge,
Penh values (index of airway resistance) in each rat was obtained in the presence of PBS and
different doses of ACh Penh, at any chosen dose of Ach, was expressed as percent of PBS
response The Penh values thus calculated were fed into Graph Pad Prism software (Graphpad
Software Inc ,USA) and using a nonlinear regression analysis PCI 00 (2 folds of PBS value)
values computed Percent inhibition was computed using the following formula
(Formula Removed)
where,
PC 1 OOCON = PC 100 m vehicle treated group
PCIOOTEST = PC 100 in group treated with a given dose of test compound
768 = is the maximum amount of acetylcholine used
A synergistic effect was seen with the combination of selected PDE4 inhibitors with a
MRA compound as compared to the individual compounds when used singly
In-vivo assay to evaluate efficacy of PDE4 inhibitors in combination with corticosteroids LPS induced rat neutrophilia model
Drug treatment
PDE-4 inhibitor and corticosteroids were instilled intratracheally under anesthesia at
different doses, either alone or in combination
LPS challenge One hour after drug instillation, (LPS 20 µg/200 µl of PBS) was instilled
intratracheally One group of vehicle treated rats were instilled with 200 ul of phosphate
buffered saline (PBS) and served as negative control
Bronchoalveolar lavage (BALI Two hours after LPS challenge, bronchoalveolar lavage was
performed, the animals were sacrificed using thiopentone sodium (150 mg/kg/i p) Trachea was
cannulated and BAL was performed using Hank's Buffer salt solution (HBSS) (5 mL x 10
times) The bronchoalveolar lavage fluid was centrifuged at 800 g for 5 min, at 4°C and the
pellet was resuspended in 1 mL HBSS Total leukocyte count was performed in the resuspended
sample by using hemocytometer A cytocentnfuge preparation was made using the resuspended
bronchoalveolar lavage fluid on a glass slide, stained with Leishmann's stain and then
differential leukocyte counts were performed for computation of neutrophil Statistical
significance of each parameter in different treatment groups was determined with respect to
vehicle control group using one-way analysis of variance followed by Dunnett's 't' test for
multiple comparison A p level of < 0 05 was considered to be statistically significant ED50
value was obtained by regression analysis of concentration and percent inhibition data using
GraphPad Prism software v4 2
Percent inhibition was computed using the following formula

(Formula Removed)

where,
NeuLPS = Neutrophil count in vehicle treated LPS challenged group
NeuTEST - Neutrophil count in group treated with a given dose of test compound
NeuPBS = Percentage of Neutrophil in group challenged with PBS
A synergistic effect was seen with the combination of selected PDE4 inhibitors with a
corticosteroid as compared to the individual compounds when used singly.

WE CLAIMS :-
1 A compound having the structure of Formula I
(Formula Removed)
Formula I its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides wherein when X is oxygen,
R1 is hydrogen, alkyl, heterocyclyl, -(CH2)1-4OR', provided that R2 is also (CH2)1-4 OR' (wherein R' is hydrogen, alkyl, alkenyl, alkynyl, (un)saturated cycloalkyl, aryl, heterocyclyl or heteroaryl), -C(=O)NRxRy provided that R2 is also -C(=O)NRxRy [wherein RX and Ry are hydrogen, alkyl, alkenyl of three to six carbon atoms, alkynyl of three to six carbon atoms, cycloalkyl, -SO2R5 (wherein R5 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl), aryl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl], -(CH2)m-C(=O)R3 (wherein m is an integer in the range of 0-2 and R3 is cycloalkyl, aryl, optionally substituted Rp or Rq, wherein Rp is heterocyclyl or heteroaryl ring wherein the said rings are attached to (CH2)mC(=O) through N, and Rq is heterocyclyl or heteroaryl ring wherein the said rings are attached to -(CH2)mC(=O) through C),
R2 is -(CH2)mC(=O)R3 (wherein m and R3 are the same as defined earlier), -(CH2)1-4OR', provided R1 is also (CH2)1-4OR' (wherein R' is same as defined earlier), -C(=O)NRxRy provided R1 is also -C(=O)NRxRy (wherein RX and Ry are same as defined earlier), or R1 and R2 may together form optionally substituted cycloalkyl or heterocyclyl ring wherein the substituents of such a joint RpR2 nng(s) can be oxo, alkyl, alkenyl, alkynyl, halogen (F, CI, Br, I), nitro, -NH2, =NOH, -C(=O)NRxRy, -COORx, -COONRxRy (wherein RX and Ry are the
same as defined earlier), -NHC00R6 (wherein R6 is alkyl, alkenyl, alkynyl, cycloalkyl,
alkaryl, heteroarylalkyl or heterocyclylalkyl), cyano, hydroxy, alkoxy, or substituted amino,
R4 is hydrogen, alkyl, -OR5 (wherein R5 is the same as defined earlier), halogen (F, CI, Br, I),
-NH2, substituted amino, cyano, carboxy, or -C(=O)NRxRy (wherein RxandRyare the same
as defined above), or R2 and R4 may together form optionally substituted 4-12 membered
(unsaturated monocyclic or bicychc ring system fused to ring B having 0-4 heteroatom(s)
selected from N, O and S with the proviso that R2 and R4 together does not form -CH2-O-
CH2-O-CH2-, wherein the substituents can be one or more of alkyl, halogen (F, CI, Br, I),
hydroxy, alkoxy, -NH2 or substituted amino,
R7 is hydrogen, alkyl, alkenyl, alkynyl, -OR5 (wherein R5 is the same as defined earlier),
halogen (F, CI, Br, I), cyano, -NH2 or substituted amino,
X1 and X2 are hydrogen, alkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, aryl, heteroarylalkyl
or heterocyclylalkyl, -(CH2)mCOR3, -(CH2)gC(=O)NRxRy or -(CH2)g1C(=O)OR3 (wherein g and
gi are an integer from 0-3, m, Rx, Ry and R3 are same as defined earlier),
Y is an oxygen atom, a sulphur atom, or -NR (wherein R is hydrogen, acyl, aryl, or alkyl),
Y1 and Y2 are independently selected from hydrogen, alkyl, -OR (wherein R is the same as
defined earlier), -SR (wherein R is the same as defined earlier, and -NHR (wherein R is the
same as defined earlier),
Any of Y1 and X2 & X1 and Y2 may together form a cyclic nng fused with the nng A shown
in Formula I, the ring containing 3-5 carbon atoms within the ring and having 1-3
heteroatoms such as N, 0 and S
X1 and X2 may together form a cyclic ring fused with the nng A shown in Formula I, the ring
containing 3-5 carbon atoms within the ring and having 2-3 heteroatoms such as N, O and S
When X is NR7 or S. wherein R7 is hydrogen or lower alkyl (C1-C6)
R1 and R2 are independently alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, cyano, nitro, halogen
(F, CI, Br, I), heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, -NH2, substituted
ammo, carboxy, -(CH2)m(C=O)R3 (wherein m and R3 are the same as defined earlier), -
C(=O)NRxRy (wherein RxandRyare the same as defined above), or -(CH2)1-4OR' (wherein R'
is same as defined earlier) or R1 and R2 may together form optionally substituted cycloalkyl
or heterocyclyl ring wherein the substituents of such a joint R1-R2 nng(s) can be oxo, alkyl,
alkenyl, alkynyl, halogen (F, CI, Br, I), nitro, -NH2, =NOH, -C(=O)NRxRy, -COORx, -
COONRxRy (wherein Rx and Ry are the same as defined earlier), -NHCOOR6 (wherein R6 is
alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl or heterocyclylalkyl), cyano,
hydroxy, alkoxy or substituted amino,
R4 is hydrogen, alkyl, halogen (F, CI, Br, I), -OR5 (wherein R5 is the same as defined earlier),
cyano, carboxy, -NH2, substituted amino, or -C(=O)NRxRy (wherein RX and Ry are the same
as defined above), or R2 and R4 may together form optionally substituted 4-12 membered
(un)saturated monocyclic or bicychc ring system fused to ring B having 0-4 heteroatom(s)
such as N, 0 and S, with the proviso that R2 and R4 together does not form -CH2-0-CH2-0-
CH2-, wherein the substituents can be one or more of alkyl, halogen (F, CI, Br, I), hydroxy,
alkoxy, or amino,
R7 is hydrogen, alkyl, alkenyl, alkynyl, -OR5 (wherein R5 is the same as defined earlier),
halogen (F, CI, Br, I), cyano, -NH2 or substituted ammo,
X1 and X2 are alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl or
heterocyclylalkyl, -(CH2)gC(=O)NRxRy or -(CH2)giC(=O)OR3 (wherein g, RX, Ry, R3 and g1
are an integer from 0-3),
Y is an oxygen atom, a sulphur atom, or -NR (wherein R is hydrogen, acyl, aryl or alkyl),
Y1 and Y2 are independently hydrogen, alkyl, -OR (wherein R is the same as defined earlier),
-SR (wherein R is the same as defined earlier), or -NHR (wherein R is the same as defined
earlier),
Any of Y1 and X2 & X1 and Y2 may together form a cyclic ring fused with the ring A shown
in Formula I, the ring containing 3-5 carbon atoms within the ring and having 1-3
heteroatoms such as N, 0 and S,
X1 and X2 may together form a cyclic ring fused with the ring A shown in Formula I, the ring
containing 3-5 carbon atoms within the ring and having 2-3 heteroatoms such as N, O and S
2 A compound which is selected from
3-[3-{ [(3S)-1 -Benzylpyrrohdin-3-yl]oxy}-4-(difluoromethoxy)phenyl]-l ,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 1),
3-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]propan-l-ol
(Compound No 2),
[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetonitnle
(Compound No 3),
4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (CompoundNo 4),
4-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (CompoundNo 5),
5-[(5S or 5R)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (CompoundNo 6),
alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl or heterocyclylalkyl), cyano,
hydroxy, alkoxy or substituted amino,
R4 is hydrogen, alkyl, halogen (F, CI, Br, I), -OR5 (wherein R5 is the same as defined earlier),
cyano, carboxy, -NH2, substituted amino, or -C(=O)NRxRy (wherein RX and Ry are the same
as defined above), or R2 and R4 may together form optionally substituted 4-12 membered
(un)saturated monocyclic or bicychc ring system fused to ring B having 0-4 heteroatom(s)
such as N, 0 and S, with the proviso that R2 and R4 together does not form -CH2-O-CH2-O-
CH2-, wherein the substituents can be one or more of alkyl, halogen (F, CI, Br, I), hydroxy,
alkoxy, or amino,
R7 is hydrogen, alkyl, alkenyl, alkynyl, -OR5 (wherein R5 is the same as defined earlier),
halogen (F, CI, Br, I), cyano, -NH2 or substituted amino,
X1 and X2 are alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl or
heterocyclylalkyl, -(CH2)gC(=O)NRxRy or -(CH2)g1C(=O)OR3 (wherein g, RX, Ry, R3 and gi
are an integer from 0-3),
Y is an oxygen atom, a sulphur atom, or -NR (wherein R is hydrogen, acyl, aryl or alkyl),
Y1 and Y2 are independently hydrogen, alkyl, -OR (wherein R is the same as defined earlier),
-SR (wherein R is the same as defined earlier), or -NHR (wherein R is the same as defined
earlier),
Any of Y1 and X2 & X1 and Y2 may together form a cyclic ring fused with the ring A shown
in Formula I, the ring containing 3-5 carbon atoms within the ring and having 1-3
heteroatoms such as N, O and S,
X1 and X2 may together form a cyclic ring fused with the ring A shown in Formula I, the ring
containing 3-5 carbon atoms within the ring and having 2-3 heteroatoms such as N, O and S
2 A compound which is selected from
3-[3- {[(35)-1 -Benzylpyrrohdin-3-yl]oxy} -4-(difluoromethoxy)phenyl]-l ,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 1),
3-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]propan-l-ol
(Compound No 2),
[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetonitnle
(Compound No 3),
4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (Compound No 4),
4-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (Compound No 5),
5-[(5S or 5R)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (Compound No 6),
(5S or 5R)-3-(3,4-Dimethoxyphenyl)-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 7), (5R or 5S)-3-(3,4-Dimethoxyphenyl)-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 8), 2-(Benzyloxy)-4-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenol (Compound No 9), 2-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]ethanol (Compound No 10),
3-[4-(Difluoromethoxy)-3-ethoxyphenyl]-l ,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 11),
3 - [3 -(Cyclohexyloxy)-4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro [4 4]non-2-ene (Compound No 12),
(5R or 5S)-3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 13),
(5S or 5R)-3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 14),
Ethyl [2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetate (Compound No 15),
3-[4-(Difluoromethoxy)-3-(2-morpholin-4-ylethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 16),
2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenyl cyclohexanecarboxylate (Compound No 17),
5-[2-(Difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]pentanoic acid (Compound No 18),
3-[3-(2,2,2-Trifluoroethoxy)-4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 19),
3-[3-(Cyclopentylmethoxy)-4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 20),
N-cyclopropyl-2-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetamide (Compound No 21),
2-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetamide (Compound No 22),
2-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]-A^-methylacetamide (Compound No 23),
3-[3-(Cyclopentyloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 24),
2-(Difluoromethoxy)-5 -(1,7-dioxa-2-azaspiro [4 4]non-2-en-3 -yl)phenyl cyclopropanecarboxylate (Compound No 25),
2-(Difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenyl morphohne-4-carboxylate (Compound No 26),
2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenyl benzoate (Compound No 27),
5-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy] pentanamide (Compound No 28),
3-[3-Propoxy-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 29),
3-[3-Isopropoxy-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 30),
3-[3-(Cyclopropylmethoxy)-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 31),
3-[3-(2,3-Dihydro-lH-inden-2-yloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 32),
5-(l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy)phenol (Compound No 33),
3-[3-Methoxy-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 34),
3-[3-Ethoxy-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 35),
3-[3-Butoxy-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 36),
3-[3-(Cyclohexylmethoxy)-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 37),
3-{[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]methyl} benzomtnle (Compound No 38),
2-{2-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]ethyl}-l//-isoindole-l,3(2/f)-dione (Compound No 39),
3-[3-(Cyclohexyloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 40),
Ethyl [5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy) phenoxy]acetate (Compound No 41),
3-[3-(Cyclohexylmethoxy)-4-(difluoromethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 42),
7ert-butyl [2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]acetate
(Compound No 43),
N-cyclopropyl-2-[5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy)
phenoxy]acetamide (Compound No 44),
2-(Cyclopentyloxy)-4-[(5R or 5S)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol
(Compound No 45),
2-(Cyclopentyloxy)-4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol
(Compound No 46),
N-benzyl-2-[5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy)
phenoxyjacetamide (Compound No 47),
N-Cyclopentyl-2-[5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy)
phenoxy]acetamide (Compound No 48),
7ert-butyl 4-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]
pipendine-1-carboxylate (Compound No 49),
Hydrochloride salt of 3-[4-(difluoromethoxy)-3-(pipendm-4-yloxy)phenyl]-l ,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 50),
3-{3-[(l-Acetylpipendm-4-yl)oxy]-4-(difluoromethoxy)phenyl}-l,7-dioxa-2-azaspiro
[4 4]non-2-ene (Compound No 51),
7ert-butyl (3S)-3-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-
yl)phenoxy]pyrrohdme-l-carboxylate (Compound No 52),
Tert-butyl (3R)-3-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-
yl)phenoxy]pyrrohdine-l-carboxylate (Compound No 53),
Tert-butyl 3-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-
yl)phenoxy]pipendine-l-carboxylate (Compound No 54),
Tert-butyl (2S)-2- {[2-(difluoromethoxy)-5-( 1,7-dioxa-2-azaspiro[4 4]non-2-en-3-
yl)phenoxy]methyl}pyrrolidine-1-carboxylate (Compound No 55),
(5R or 5S)-3-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-
2-ene (Compound No 56),
(5S or 5R)-3-(3-isopropoxy-4-methoxyphenyl)-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 57),
(5S or 5R)-3-[3-(Cyclopropylmethoxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-
ene (Compound No 58),
2-(Cyclopropylmethoxy)-4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol
(Compound No 59),
4-[(5S or 5R)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-isopropoxyphenol (CompoundNo
60),
(5S or 5R)-3-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-
2-ene (Compound No 61),
(5S or 5R)-3-[3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 62),
(5S or 5R)-3-[4-(difluoromethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 63),
(5R or 5S)-3-[4-(difluoromethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 64),
2-(Cyclopropylmethoxy)-4-[(5R or 5S)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol
(Compound No 65),
4-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-isopropoxyphenol (Compound No
66),
(5R or 5S)-3-[3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-l ,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 67),
(5R or 5S)-3-[4-(difluoromethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 68),
Hydrochloride saltof3-{4-(difluoromethoxy)-3-[(3S)-pyrrolidm-3-yloxy]phenyl}-l,7-dioxa-
2-azaspiro[4 4]non-2-ene (Compound No 69),
Hydrochloride salt of 3-{4-(difluoromethoxy)-3-[(2S)-pyrrohdin-2-ylmethoxy]phenyl}-l,7-
dioxa-2-azaspiro[4 4]non-2-ene (Compound No 70),
Hydrochloride salt of 3-{4-(difluoromethoxy)-3-[(2i?)-pyrrolidin-2-ylmethoxy]phenyl}-1,7-
dioxa-2-azaspiro[4 4]non-2-ene (Compound No 71),
3 - [4-(Difluoromethoxy)- 3 - {[(2R)-1 -propionylpyrrohdin-2-y l]methoxy} phenyl] -1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 72),
3-[3- {[(2S)-1 -acetylpyrrolidm-2-yl]methoxy} -4-(difluoromethoxy)phenyi]-l ,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 73),
3-[3-{[(3S)-l-benzoylpyrrohdin-3-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 74),
3 - [4-(Difluoromethoxy)-3 - {[(3 S)-1 -propionylpyrrohdin-3 -yl]oxy} phenyl] -1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 75),
(5S or 5R)-3-[3-(Benzyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-
ene (Compound No 76),
2-(Benzyloxy)-4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (Compound No
77),
(5S or 5R)-3-[3-(Benzyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 78),
3 - {4-(Difluoromethoxy)-3 -[(1 -propionylpipendin-4-yl)oxy]phenyl} -1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 79),
3-[4-(Difluoromethoxy)-3-{[l-(4-fluorobenzoyl)pipendin-4-yl]oxy}phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 80),
3-[3- {[1 -(Cyclopropylcarbonyl)pipendin-4-yl]oxy} -4-(difluoromethoxy)phenyl]-1,7-dioxa-2-
azaspiro [4 4]non-2-ene (Compound No 81),
3 - [3 - {[ 1 -(Cyclopentylcarbonyl)pipendm-4-yl] oxy} -4-(difluoromethoxy)phenyl]-1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 82),
3 - [4-(Difluoromethoxy)-3 -({1 -[(trifluoromethyl)sulfonyl]pipendin-4-yl} oxy)phenyl]-1,7-
dioxa-2-azaspiro[4 4]non-2-ene (Compound No 83),
3 - {3 - [(1 - Acetylpipendin-3 -yl)oxy]-4-(difluoromethoxy)phenyl} -1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 84),
3-{4-(Difluoromethoxy)-3-[(l-propionylpipendin-3-yl)oxy]phenyl}-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 85),
3-[4-(Difluoromethoxy)-3-{[l-(4-fluorobenzoyl)pipendin-3-yl]oxy}phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 86),
3 - [3 - {[ 1 -(Cyclopropy lcarbony l)pipendin-3 -y 1] oxy} -4-(difluoromethoxy)phenyl] -1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 87),
3-[3-{[l-(Cyclopentylcarbonyl)pipendin-3-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 88),
3-[4-(Difluoromethoxy)-3-{[l-(ethylsulfonyl)pipendin-3-yl]oxy}phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 89),
3-[3-(Benzyloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 90),
2-(Difluoromethoxy)-5-[(5S' or 5i?)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol
(Compound No 91),
5-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4 4]non-2-en-3-yl]-2-methoxyphenol (Compound No
92),
3 - [3 - {[(35)-1 -acetylpyrrohdin-3 -yl] oxy} -4-(difluoromethoxy)phenyl]-1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 93),
Hydrochloride salt of 3-[4-(Difluoromethoxy)-3-(piperidin-3-yloxy)phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 94),
3-[4-(Difluoromethoxy)-3-{[l-(phenylcarbonyl)pipendin-4-yl]oxy}phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 95),
3-[4-(Difluoromethoxy)-3-{[l-(morpholin-4-ylcarbonyl)pipendin-4-yl]oxy}phenyl]-l,7-
dioxa-2-azaspiro[4 4]non-2-ene (Compound No 96),
3-[4-(Difluoromethoxy)-3-{[l-(phenylcarbonyl)pipendin-3-yl]oxy}phenyl]-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 97),
3-[4-(Difluoromethoxy)-3-{[l-(morpholin-4-ylcarbonyl)pipendin-3-yl]oxy}phenyl]-l,7-
dioxa-2-azaspiro[4 4]non-2-ene (Compound No 98),
3-[4-(Difluoromethoxy)-3-({l-[(trifluoromethyl)sulfonyl]pipendin-3-yl}oxy)phenyl]-l,7-
dioxa-2-azaspiro[4 4]non-2-ene (Compound No 99),
3-[4-(Difluoromethoxy)-3-{[(2/?)-l-(phenylcarbonyl)pyrrohdin-2-yl]methoxy}phenyl]-l,7-
dioxa-2-azaspiro[4 4]non-2-ene (Compound No 100),
3 -[3 - {[(2R)-1 -acetylpyrrolidin-2-yl]methoxy} -4-(difluoromethoxy)phenyl] -1,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 101),
3-[4-(Difluoromethoxy)-3- {[(2R)-1 -propanoylpyrrohdin-2-yl]methoxy}phenyl]-l ,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 102),
3 - [3 - {[(2R)-1 -(cyclopropylcarbonyl)pyrrohdin-2-yl]methoxy} -4-(difluoromethoxy)phenyl] -
1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 103),
3-[3-{[(3iS)-l-(cyclopropylcarbonyl)pyrrohdin-3-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-
dioxa-2-azaspiro[4 4]non-2-ene (Compound No 104),
3-[3-{[(35)-l-(cyclopentylcarbonyl)pyrrohdin-3-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-
dioxa-2-azaspiro[4 4]non-2-ene (Compound No 105),
3 - [4-(Difluoromethoxy)-3 -({(3R)-1 -[(4-fluorophenyl)carbonyl]pyrrohdin-3-yl} oxy)phenyl] -
1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 106),
{3-[4-(Difluoromethoxy)-3-methoxyphenyl]-4,5-dihydroisoxazole-5,5-diyl}dimethanol
(Compound No 107),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-1 -oxa-7-thia-2-azaspiro[4 4]non-2-ene
(Compound No 108),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-1 -oxa-7-thia-2-azaspiro[4 4]non-2-ene 7-oxide
(Compound No 109),
7-[4-(Difluoromethoxy)-3-methoxyphenyl]-5-oxa-2-thia-6-azaspiro[3 4]oct-6-ene (Compound No 110),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l ,8-dioxa-2-azaspiro[4 5]dec-2-ene (Compound No 111),
3-[4-(Difluoromethoxy)-3-phenoxyphenyl]-1,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 112),
7-[4-(Difluoromethoxy)-3-methoxyphenyl]-5-oxa-2-thia-6-azaspiro[3 4]oct-6-ene 2-oxide (Compound No 113),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-1 -oxa-7-thia-2-azaspiro[4 4]non-2-ene 7,7-dioxide (Compound No 114),
7-[4-(Difluoromethoxy)-3-methoxyphenyl]-5-oxa-6-azaspiro[3 4]oct-6-ene (Compound No 115),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l-oxa-2-azaspiro[4 4]non-2-ene (Compound No 116),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l-oxa-2-azaspiro[4 5]dec-2-ene (Compound No 117),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l,9,12-tnoxa-2-azadispiro[4 2 4 2]tetradec-2-ene (Compound No 118),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l-oxa-2-azaspiro[4 5]dec-2-en-8-one (Compound No 119),
7-[4-(Difluoromethoxy)-3-methoxyphenyl]-5-oxa-2-thia-6-azaspiro[3 4]oct-6-ene 2,2-dioxide (Compound No 120),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-1 -oxa-2-azaspiro[4 5]dec-2-en-8-one oxime (Compound No 121),
3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l-oxa-2-azaspiro[4 5]dec-2-en-8-ol (Compound No 122),
7-[4-(Difluoromethoxy)-3-methoxyphenyl]-2,5-dioxa-6-azaspiro[3 4]oct-6-ene (Compound No 123),
Hydrochloride salt of 4-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]amlme (Compound No 124),
ter/-Butyl {4-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]phenyl}carbamate (Compound No 125),
(5R or 5S)-3-[3-(benzyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene (Compound No 126),
2-(Benzyloxy)-4-[(5R or 5S)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol (CompoundNo
127),
(5R or 5S)-3-[3-(Benzyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-
ene (Compound No 128),
3-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl)phenoxy]cyclopentanol
(Compound No 129),
2-(Difluoromethoxy)-5-[(5i? or 55)-l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl]phenol
(Compound No 130),
3-[4-(Difluoromethoxy)-3-(4-fluorophenoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 131),
3-[3-(4-Chlorophenoxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 132),
3-{4-(Difluoromethoxy)-3-[4-(trifluoromethoxy)phenoxy]phenyl}-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 133),
3-{4-(Difluoromethoxy)-3-[4-(trifluoromethyl)phenoxy]phenyl}-l,7-dioxa-2-
azaspiro[4 4]non-2-ene (Compound No 134),
A^-{4-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl) phenoxy] phenyl}
acetamide (Compound No 135),
jV-{4-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4 4]non-2-en-3-yl) phenoxy] phenyl}
methane sulfonamide (Compound No 136),
3-[4-(Difluoromethoxy)-3-(pyndm-4-yloxy)phenyl]-l,7-dioxa-2-azaspiro[4 4]non-2-ene
(Compound No 137),
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides thereof
3 A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1 or 2 together with one or more of pharmaceutically acceptable carriers, excipients or diluents
4 A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or 2 and at least one other active ingredient selected from corticosteroids, B2- agonists, muscarinic receptor antagonists, anticholinergics, antiallergic agents, PAF antagonists, EGFR kinase inhibitors, p38 MAP Kinase inhibitors, additional PDE-IV inhibitors, kinase inhibitors, dopamine receptor
antagonists, histamines, antitussives, leukotnene antagonists, 5-hpoxygenase inhibitors, chemokme inhibitors or combinations thereof
5 A compound of claim 1 or 2 for treating, preventing, inhibiting or suppressing an inflammatory condition or disease or CNS diseases, in a patient
6 A pharmaceutical composition of claim 3 or 4 for treating, preventing, inhibiting or suppressing an inflammatory condition or disease or CNS diseases, in a patient
7 A compound of claim 1 or 2 for the treatment, prevention, inhibition or suppression of CNS diseases, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases in a patient
8 A pharmaceutical composition of claim 3 or 4 for the treatment, prevention, inhibition or suppression of CNS diseases, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases in a patient
9 The compound and phramaceutical composition according to claim 5, 6, 7 or 8 wherein, the disease or disorder is mediated through phosphodiesterase type 4 or 7 10 A method for the preparation of a compound of Formula II, and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides, wherein the method comprises, a deprotecting a compound of Formula la
(Formula Removed)
wherein * refers to chiral centre (racemic or R or S isomer),
V is alkyl,
V1 is cycloalkyl
11. A method for the preparation of a compound of Formula IV, and its pharmaceutical^ acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides, wherein the method comprises, a deprotecting a compound of Formula la
(Formula Removed)
b reacting a compound of Formula II with a compound of Formula III
(Formula Removed)
to give a compound of Formula IV
(Formula Removed)
wherein
* refers to chiral centre (racemic or R or S isomer),
V is alkyl,
V1 is cycloalkyl,
hal is Br, CI or I,
Ryy is alkyl, aryl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl,
heterocyclylalkyl, -(CH2)g1COOR3, -(CH2)mCOR3 or-(CH2)gC(=O)NRxRy
wherein R3, g, m, Rx, Ry and gi are the same as defined in claim 1
12 A method for the preparation of a compound of Formula V, and its pharmaceutically
acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers,
polymorphs or N-oxides, wherein the method comprises,
a deprotecting a compound of Formula la
(Formula Removed)
b reacting a compound of Formula II with a compound of Formula III
(Formula Removed)
to give a compound of Formula IV
(Formula Removed)

c deprotecting a compound of Formula IV to give a compound of Formula V
(Formula Removed)
wherein
* refers to chiral centre (racemic or R or S isomer), V is alkyl, V1 is cycloalkyl, hal is Br, CI or I,
Ryy is alkyl, aryl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, -(CH2)g1COOR3, -(CH2)mCOR3 or-CH2)gC(=O)NRxRy, wherein R3, g, m, Rx, Ry and gi are the same as defined in claim 1
13 A method for the preparation of a compound of Formula VI, and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides, wherein the method comprises, a deprotecting a compound of Formula la
(Formula Removed)
Formula II b reacting a compound of Formula II with a compound of Formula III
(Formula Removed)
Formula III to give a compound of Formula IV
(Formula Removed)
c deprotecting a compound of Formula IV to give a compound of Formula V
(Formula Removed)
d reacting a compound of Formula V with a compound of Formula Ilia
(Formula Removed)
Formula Ilia to give a compound of Formula VI
(Formula Removed)
wherein
* refers to chiral centre (racemic or R or S isomer), V is alkyl, V1 is cycloalkyl, hal is Br, CI or I,
Ryy is alkyl, aryl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, -(CH2)g1COOR3, -(CH2)mCOR3 or-(CH2)gC(=O)NRxRy, wherein R3, g, m, Rx, Ry and gi are the same as defined in claim 1,
Rxy is alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl 14 A method for the preparation of a compound of Formula VII, and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides, wherein the method comprises, a deprotecting a compound of Formula la
(Formula Removed)
Formula II b reacting a compound of Formula II with a compound of Formula III
(Formula Removed)
to give a compound of Formula IV
(Formula Removed)
c deprotecting a compound of Formula IV to give a compound of Formula V
(Formula Removed)
d reacting a compound of Formula V with a compound of Formula Ilia
Rxy-hal Formula Ilia

to give a compound of Formula VI
(Formula Removed)
e deprotecting a compound of Formula VI to give a compound of Formula VII
(Formula Removed)
wherein
* refers to chiral centre (racemic or R or S isomer), V is alkyl, V1 is cycloalkyl, hal is Br, CI or I,
Ryy is alkyl, aryl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, -(CH2)giCOOR3, -(CH2)mCOR3 or-(CH2)gC(=O)NRxRy, wherein R3, g, m, Rx, Ry and gi are the same as defined in claim 1,
Rxy is alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl 15 A method for the preparation of a compound of Formula IX, and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides, wherein the method comprises a deprotecting a compound of Formula la
(Formula Removed)
Formula la to give a compound of Formula II
(Formula Removed)
Formula II b reacting a compound of Formula II with a compound of Formula III
(Formula Removed)
to give a compound of Formula IV
(Formula Removed)
c deprotecting a compound of Formula IV to give a compound of Formula V
(Formula Removed)
d reacting a compound of Formula V with a compound of Formula Ilia
Rxy-hal Formula Ilia
to give a compound of Formula VI
(Formula Removed)
e deprotecting a compound of Formula VI to give a compound of Formula VII
(Formula Removed)
f reacting a compound of Formula VII with a compound of Formula VIII
(Formula Removed)
to give a compound of Formula IX
(Formula Removed)
wherein * refers to chiral centre (racemic or R or S isomer),
V is alkyl,
Vi is cycloalkyl,
hal is Br, CI or I,
Ryy is alkyl, aryl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl,
heterocyclylalkyl, -(CH2)g1COOR3, -(CH2)mCOR3 or-(CH2)gC(=O)NRxRy,
wherein R3, g, m, Rx, Ry and gi are the same as defined in claim 1,
Rxy is alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl,
Rff is alkyl, cycloalkyl, alkaryl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or
heterocyclylalkyl
16 A method for the preparation of a compound of Formula XI, and its pharmaceutically
acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers,
polymorphs or N-oxides, wherein the method comprises,
a deprotecting a compound of Formula la
(Formula Removed)
b reacting a compound of Formula II with a compound of Formula III
Ryy-hal Formula III
to give a compound of Formula IV
(Formula Removed)
c deprotecting a compound of Formula IV to give a compound of Formula V
(Formula Removed)
d reacting a compound of Formula V with a compound of Formula IIIa
(Formula Removed)
e deprotectmg a compound of Formula VI to give a compound of Formula VII
(Formula Removed)
f reacting a compound of Formula VII with a compound of Formula X
R3y-hal Formula X
to give a compound of Formula XI
(Formula Removed)
wherein
V is alkyl,
V1 is cycloalkyl,
hal is Br, CI or I,
Ryy is alkyl, aryl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl,
heterocyclylalkyl, -(CH2)g1COOR3, -(CH2)mCOR3 or-(CH2)gC(=O)NRxRy,
Rxy is alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl,
Rff is alkyl, cycloalkyl, alkaryl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl,
R3y is -(CH2)g1C(=O)OR3, -(CH2)mCOR3, alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl or -(CH2)gC(=O)NRxRy, R3, g, m, Rx, Ry and gi are the same as defined in claim 1 17 A method for the preparation of a compound of Formula XIII, and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides, wherein the method comprises a deprotecting a compound of Formula la
(Formula Removed)
b reacting a compound of Formula II with a compound of Formula III
(Formula Removed)
c deprotecting a compound of Formula IV to give a compound of Formula V HO—d (Formula Removed)

d reacting a compound of Formula V with a compound of Formula IIIa
(Formula Removed)
e deprotectmg a compound of Formula VI to give a compound of Formula VII
(Formula Removed)
f reacting a compound of Formula VII with a compound of Formula X
(Formula Removed)
g reacting a compound of Formula XI with a compound of Formula XII
(Formula Removed)
wherein * refers to chiral centre (racemic or R or S isomer),
V is alkyl,
V1 is cycloalkyl,
hal is Br, CI or I,
Ryy is alkyl, aryl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl,
heterocyclylalkyl, -(CH2)g1COOR3, -(CH2)mCOR3 or -(CH2)gC(=O)NRxRy,
Rxy is alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl,
Rff is alkyl, cycloalkyl, alkaryl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or
heterocyclylalkyl,
R3y is -(CH2)g1C(=O)OR3, -(CH2)mCOR3, alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl,
heteroarylalkyl, heterocyclylalkyl or -(CH2)gC(=O)NRxRy,
P is alkyl, aralkyl, cycloalkyl, -C(=O)Oaralkyl, -C(=O)OC(CH3)3, -C(=O)OC(CH3)2CHBr2
or -C(=O)0C(CH3)2CC13
R3, g, m, Rx, Ry and gi are the same as defined in claim 1
18 A method for the preparation of a compound of Formula IIa, and its pharmaceutically
acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers,
polymorphs or N-oxides, wherein the method comprises
deprotecting a compound of Formula la
(Formula Removed)
wherein
V is alkyl,
V1 is cycloalkyl,
* refers to chiral centre (racemic or R or S isomer)
19 A method for the preparation of a compound of Formula IVa, and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides, wherein the method comprises
a deprotecting a compound of Formula la
(Formula Removed)
b reacting a compound of Formula IIa with a compound of Formula III
(Formula Removed)
wherein
V is alkyl,
V1 is cycloalkyl,
hal is Br, CI or I,
Ryy is alkyl, aryl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl or
heterocyclylalkyl, -(CH2)gC(=O)NRxRy, -(CH2)mCOR3 or ~(CH2)giC(=O)OR3,
wherein R3, g, m, Rx, Ry and gi are the same as defined in claim 1,
* refers to chiral centre (racemic or R or S isomer)
20 A method for the preparation of a compound of Formula XVII, and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides wherein the method comprises
a reacting a compound of Formula XIV with a compound of Formula XV
(Formula Removed)
to give a compound of Formula XVI
(Formula Removed)
Formula XVI b deprotecting a compound of Formula XVI to give a compound of Formula XVII
(Formula Removed)
wherein Y and X1 are the same as defined in claim 1,
P is alkyl, aralkyl, cycloalkyl, -C(=O)Oaralkyl, -C(=O)OC(CH3)3, -C(=O)OC(CH3)2CHBr2
or -C(=O)0C(CH3)2CC13,
L is a leaving group selected from hal (Br, CI or I), -Omesyl, -Otosyl or -Otriflyl,
n is an integer from 0-2
21 A method for the preparation of a compound of Formula XIX, and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides wherein the method comprises
a reacting a compound of Formula XIV with a compound of Formula XV
H(Formula Removed)

to give a compound of Formula XVI
(Formula Removed)
Formula XVI b deprotecting a compound of Formula XVI to give a compound of Formula XVII
(Formula Removed)
c reacting a compound of Formula XVII with a compound of Formula XVIII
Rff-G-hal
Formula XVIII
to give a compound of Formula XIX
(Formula Removed)
wherein Y and X1 are the same as defined in claim 1,
P is alkyl, aralkyl, cycloalkyl, -C(=O)Oaralkyl, -C(=O)OC(CH3)3, -C(=O)OC(CH3)2CHBr2
or -C(=O)OC(CH3)2CC13
Rff is alkyl, cycloalkyl, alkaryl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or
heterocyclylalkyl,
hal is Br, CI or I,
L is a leaving group selected from hal (Br, CI or I), -Omesyl, -Otosyl or -Otriflyl,
n is an integer from 0-2,
G is -CO or -S02
22 A method for the preparation of a compound of Formula XXIV, and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides, wherein the method comprises
a reacting a compound of Formula XX
(Formula Removed)
b reacting a compound of Formula XXI with a compound of Formula P-OH to give a compound of Formula XXII
(Formula Removed)
c reducing a compound of Formula XXII to give a compound of Formula XXIII
(Formula Removed)
wherein
X1 and X2 are the same as defined in claim 1,
Q is a chiral resolving agent selected from L-Ephednne, D-Ephednne, (+)-Brussian, (-)-
Brussian, (IS, 2R) (-)-cis-l-ammo-2-indanol, (1R 2S) (+)-cis-l-amino-2-indanol, (1R, 2R)-(-)-
1,2-diamino cyclohexane or (IS, 2S)-(+)-l,2-diamino cyclohexane, a-methylbenzylamine or ß-
methylbenzylamine,
* refers to chiral centre (racemic or R or S isomer),
P' is alkyl or aralkyl
23 A method for the preparation of a compound of Formula XXV b, and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides, wherein the method comprises
reacting a compound of Formula XXV with a compound of Formula XXV a
(Formula Removed)
wherein X1, X2, Ri and R2 are the same as defined in claim 1
24 A method for the preparation of a compound of Formula XXVIII, and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides, wherein the method comprises
a mesylating a compound of Formula XXVI
(Formula Removed)
b cychzing a compound of Formula XXVII to give a compound of Formula XXVIII
(Formula Removed)
wherein
X1 and X2 are the same as defined in claim 1, n is an integer from 0-2
25 A method for the preparation of a compound of Formula XXIX, and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides, wherein the method comprises
a mesylating a compound of Formula XXVI
(Formula Removed)
b cychzing a compound of Formula XXVII to give a compound of Formula XXVIII
(Formula Removed)
c oxidizing a compound of Formula XXVIII to give a compound of Formula XXIX
(Formula Removed)
wherein
X1 and X2 are the same as defined m claim 1, n is an integer from 0-2
26 A method for the preparation of a compound of Formula XXX, and its
pharmaceutical^ acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides, wherein the method comprises
a mesylating a compound of Formula XXVI
(Formula Removed)
b cychzing a compound of Formula XXVII to give a compound of Formula XXVIII
(Formula Removed)
c oxidizing a compound of Formula XXVIII to give a compound of Formulae XXX
(Formula Removed)
wherein
X1 and X2 are the same as defined in claim 1, n is an integer from 0-2
27 A method for the preparation of a compound of Formula XXXIV, and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides, wherein the method comprises
a reacting a compound of Formula XXV with a compound of Formula XXXI
(Formula Removed)
b performing reduction of a compound of Formula XXXII to give a compound of
Formula XXXIII
(Formula Removed)
c cychzing a compound of Formula XXXIII to give a compound of Formula XXXIV
(Formula Removed)
wherein X1 and X2 are the same as defined in claim 1, hal is Br, CI or I, Ria is alkyl
28 A method for the preparation of a compound of Formula XXXVII, and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides, wherein the method comprises
a reacting a compound of Formula XXXV with a compound of Formula XXXV a
(Formula Removed)
b deprotectmg a compound of Formula XXXVI to give a compound of Formula
XXXVII
(Formula Removed)
wherein
X1 is the same as defined in claim 1, Pr is a protecting group
29 A method for the preparation of a compound of Formula XXXIX, and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides, wherein the method comprises
reacting a compound of Formula XXXV with a compound of Formula XXXVIII
(Formula Removed)
wherein
X1 is the same as defined m claim 1, T is halogen, alkoxy, alkyl or -NHCOOalkyl
30 A method for the preparation of a compound of Formula XL, and its pharmaceutically
acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers,
polymorphs or N-oxides, wherein the method comprises

a reacting a compound of Formula XXXV with a compound of Formula XXXVIII
(Formula Removed)
b deprotecting a compound of Formula XXXIX (when T is -NHCOOalkyl) to give a
compound of Formula XL NH2
(Formula Removed)
wherein
X1 is the same as defined in claim 1,
T is halogen, alkoxy, alkyl or -NHCOOalkyl
31 A method for the preparation of a compound of Formula XLI, and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides, wherein the method comprises
a reacting a compound of Formula XXXV with a compound of Formula XXXVIII
(Formula Removed)
b deprotecting a compound of Formula XXXIX (when T is -NHCOOalkyl) to give a
compound of Formula XL
(Formula Removed)
c mesylating a compound of Formula XL to give a compound of Formula XLI
(Formula Removed)
wherein
X1 is the same as defined in claim 1, T is halogen, alkoxy, alkyl or -NHCOOalkyl
32 A method for the preparation of a compound of Formula XLII, and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides, wherein the method comprises
a reacting a compound of Formula XXXV with a compound of Formula XXXVIII
(Formula Removed)
b deprotecting a compound of Formula XXXIX (when T is -NHCOOalkyl) to give a
compound of Formula XL
(Formula Removed)
c acylating a compound of Formula XL to give a compound of Formula XLII
(Formula Removed)
wherein
X1 is the same as defined in claim 1, T is halogen, alkoxy, alkyl or -NHCOOalkyl
33 A method for the preparation of a compound of Formula XLIV, and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides, wherein the method comprises
reacting a compound of Formula XXXV with a compound of Formula XLIII
(Formula Removed)
wherein
hal is Br, CI or I, X1 is the same as defined in claim 1
34 A method for the preparation of a compound of Formula XLVI, and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides, wherein the method comprises
reacting a compound of Formula XXXV with a compound of Formula XLV
(Formula Removed)
wherein
hal is Br, CI or I, X1 is the same as defined in claim 1
35 A method for the preparation of a compound of Formula XL VIII, and its

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides, wherein the method comprises
reacting a compound of Formula XXV with a compound of Formula XLVII
(Formula Removed)
wherein X1 and X2 are the same as defined in claim 1
36 A method for the preparation of a compound of Formula XLIX, and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides, wherein the method comprises
a reacting a compound of Formula XXV with a compound of Formula XLVII
(Formula Removed)
b deprotecting a compound of Formula XLVIII to give a compound of Formula XLIX
(Formula Removed)
wherein X1 and X2 are the same as defined m claim 1
37 A method for the preparation of a compound of Formula L, and its pharmaceutically
acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers,
polymorphs or N-oxides, wherein the method comprises
a reacting a compound of Formula XXV with a compound of Formula XLVII
(Formula Removed)
b deprotecting a compound of Formula XLVIII to give a compound of Formula XLIX
(Formula Removed)
c performing the reduction of a compound of Formula XLIX to give a compound of
Formula L
(Formula Removed)
wherein X1 and X2 are the same as defined in claim 1
38 A method for the preparation of a compound of Formula LI, and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides, wherein the method comprises
a reacting a compound of Formula XXV with a compound of Formula XLVII
(Formula Removed)
b deprotecting a compound of Formula XLVIII to give a compound of Formula XLIX
(Formula Removed)
c reacting a compound of Formula XLIX with hydroxylamme hydrochloride to give a
compound of Formula LI
(Formula Removed)
wherein X1 and X2 are the same as defined in claim 1.