Field of the Invention
Provided herein are pharmaceutical compositions comprising one or more phosphodiesterase inhibitors of type IV ("PDE-IV"), and at least one other active ingredient such as muscarinic receptor antagonists (MRA), p2-agonists, p38 MAP Kinase inhibitors, or corticosteroids and optionally one or more pharmaceutically acceptable excipients. In addition, methods of treating autoimmune, inflammatory or allergic diseases or disorders are provided.
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. The intracellular hydrolysis of cAMP to adenosine 5'-monophosphate (AMP) causes a number of inflammatory conditions, which include, but are not limited to, psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, and ulcerative colitis. Cyclic nucleotide phosphodiesterases (PDE), a biochemically and functionally, highly variable superfamily of the enzyme, is the most important factor in the control of cAMP (as well as of cGMP) levels. Eight distinct families with more than 15 gene products are currently recognized. Although PDE I, PDE II, PDE III, PDE IV, and PDE VII all use cAMP as a substrate, only the PDE IV and PDE VII types are highly selective for hydrolysis of cAMP. Accordingly, inhibitors of PDE, particularly the PDE IV inhibitors, such as rolipram or Ro-1724, are known as cAMP-enhancers. Immune cells contain PDE IV and PDE III, of which PDE IV is prevalent in human mononuclear cells. Thus, the inhibition of phosphodiesterase type IV has been a target for modulation and, accordingly, for therapeutic intervention in a range of disease processes. 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 PDE have been recognized, and their selective inhibition has led to improved drug therapy. Thus, it was recognized that inhibition of PDE IV could lead to inhibition of inflammatory mediator release and airway smooth muscle relaxation.
Particular 3-aryl-2-isoxazoline compounds are known as anti-inflammatory agents and particular isoxazoline compounds are known as inhibitors of TNF release. However, there remains a need for new selective inhibitors of phosphodiesterase (PDE) type IV, as well as compositions thereof in combination with one or more other therapeutic agents.
Summary of the Invention
In one aspect, provided are pharmaceutical compositions comprising one or more phosphodiesterase inhibitors of type IV ("PDE-IV"), and at least one other active ingredient such as muscarinic receptor antagonists (MRA), p2-agonists, p38 MAP Kinase inhibitors, or

corticosteroids and optionally one or more pharmaceutically acceptable excipients, wherein the
PDE-IV inhibitor is one or more compounds having the structure of Formula la or Formula lb,
wherein:
a. Formula la is:
(Formula Removed)
FORMULA la and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-o1des, wherein When X is oxygen,
R1 can be hydrogen, alkyl, heterocyclyl, -(CH2)mC(=O)R3, or (CH2)1-40R', (wherein m is an integer 0-2, R 3 can be alkyl, cycloalkyl, heterocyclyl, or optionally substituted Rp or Rq, wherein Rp can be heterocyclyl or heteroaryl ring, wherein the rings are attached to (CH2)mC(=O) through N, and Rq can be heterocyclyl or heteroaryl ring wherein the rings are attached to -(CH2)mC(=O) through C, and wherein R' can be alkyl, alkenyl, alkynyl, saturated or unsaturated cycloalkyl, aryl, heterocyclyl or heteroaryl);
R2 can be (CH2)mC(=O)R3, -(CH2)MOR', or C(=O)NRxRy {where m, R 3 and R' are as defined above, and wherein Rx and Ry each independently can be hydrogen, alkyl, C3-C6 alkenyl, C3-C6 alkynyl, cycloalkyl, carboxy, -S(O)mRs (wherein R5 can be hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl), aryl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl}, or R1 and R2 together form an optionally substituted cycloalkyl or heterocyclyl ring wherein the optional substituent is oxo, alkyl, alkenyl, alkynyl, halogen, nitro, -NH2, -NHC(=O)OR6, -C(=O)NRxRy, cyano, hydroxy, alkoxy, or substituted amino (wherein R$ can be alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl or heterocyclylalkyl), with the proviso that if R1 is -(CH2)1-40R', then R2 is also -(CH2)1-4OR', and with the proviso that if Rt is C(=O)NRxRy, then R2 is also C(=O)NRxRy;
R4 can be hydrogen; alkyl; -OR5; halogen; -NH2, substituted amino; cyano; carboxy; or -C(=O)NRxRy (wherein R5, Rx and Ry are as defined above); or R2 and R4 forms an optionally substituted 4-12 membered saturated or unsaturated monocyclic or bicyclic ring system fused to ring B having 0-4 heteroatom(s) selected from the group consisting of N, O and S, wherein the substituents can be one or more of alkyl, halogen, hydroxy, alkoxy, -NH2 or substituted amino (wherein R 3 and Rx and Ry are as defined above), with the proviso that R2 and R4 together does not form -CH2-O-CH2-O-CH2-;
R7 can be hydrogen, alkyl, alkenyl, alkynyl, -OR5, halogen, cyano,-NH2, or substituted
amino;
1 and X2 each independently can be hydrogen, alkyl, alkaryl, cycloalkyl, alkaryl, alkenyl, cycloalkylalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, -(CH2)gC(=O)NRxRy, -
(CH2)g1C(=O)OR3 or heteroarylalkyl; whereing1can be an integer from 1-3 (wherein Rx, Ry, g and R 3 are as defined above);
Y can each independently be an oxygen atom; a sulphur atom; or -NR (wherein R can be
hydrogen, acyl, aryl, or alkyl);
Yi and Y2 each independently can be hydrogen; alkyl; -OR; -SR; or -NHR (wherein R is as defined above);
wherein any of Yi and X2 & X1 and Y2 together optionally form a ring fused with the ring A, the ring containing 3-5 carbon atoms within the ring and having 1-3 heteroatoms such as N, O and S, andX1and X2 can together optionally form a ring fused with ring A, the ring containing 3-5 carbon atoms within the ring and having 2-3 heteroatoms such as N, O or S, and
When X is NR7' or S (wherein R7' can be hydrogen, or C 1-6 alkyl)
R1 and R2 can each independently be alkyl, alkenyl, alkynyl, alkoxy, hydroxy, cyano, nitro, halogen, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, NH2, substituted amino, carboxy, -(CH2)mC(=O)R3, -C(=O)NRxRy, or (CH2)1-4OR', {wherein rn is an integer 0-2, R 3 can be alkyl, cycloalkyl, heterocyclyl, or optionally substituted Rp or Rq (wherein Rp can be heterocyclyl or heteroaryl ring, wherein the rings are attached to (CH2)mC(=O) through N, and Rq can be heterocyclyl or heteroaryl ring wherein the rings are attached to -(CH2)mC(=O) through C), wherein R' can be alkyl, alkenyl, alkynyl, saturated or unsaturated cycloalkyl, aryl, heterocyclyl or heteroaryl, and wherein Rx and Ry each independently can be hydrogen, alkyl, C3-C6 alkenyl, C3-C6 alkynyl, cycloalkyl, carboxy, -S(O)mR5 (wherein R5 can be hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl), aryl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl}, or R1 and R2 together can form an optionally substituted cycloalkyl or heterocyclyl ring wherein the optional substituent is oxo, alkyl, alkenyl, alkynyl, halogen, nitro, -NH2, -NHC(=O)0R6 (wherein R6 can be alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl or heterocyclylalkyl), -C(=O)NRxRy, cyano, hydroxy, alkoxy, or substituted amino;
R4 can be hydrogen; alkyl; -OR5; halogen; -NH2, substituted amino; cyano; carboxy; or -C(=O)NRxRy (wherein R5, RX and Ry are as defined above); or R2 and R4 forms an optionally substituted 4-12 membered saturated or unsaturated monocyclic or bicyclic ring system fused to ring B having 0-4 heteroatom(s) selected from the group consisting of N, O and S, wherein the substituents can be one or more of alkyl, halogen, hydroxy, alkoxy or substituted amino (wherein R 3 and Rx and Ry are as defined above), with the proviso that R2 and R4 together does not form -CH2-O-CH2-O-CH2-;
R7 can be hydrogen, alkyl, alkenyl, alkynyl, -OR5, halogen, cyano,-NH2, or substituted amino;
X1 and X2 each independently can be alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl;
Y can each independently be an oxygen atom; a sulphur atom; or -NR (wherein R can be
hydrogen, acyl, aryl, or alkyl);
Yi and Y2 each independently can be hydrogen, alkyl, -OR, -SR, or -NHR (wherein R is as defined above); wherein any of Y1 and X2 &X1and Y2 together optionally form a ring fused with the ring
A, the ring containing 3-5 carbon atoms within the ring and having 1-3 heteroatoms such
as N, O and S;
X1 and X2 can together optionally forms a cyclic ring fused with the ring A, the ring
containing 3-5 carbon atoms within the ring and having 2-3 heteroatoms such as N, O or
S.
b. Formula lb is:
(Formula Removed)
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-o1des, wherein
R1 and R2 together forms an optionally substituted cycloalkyl or heterocyclyl ring wherein one or more optional substituent are oxo, alkyl, alkaryl, alkenyl, alkynes, heterocyclylalkyl, cycloalkylalkyl, -SO2NRxRy, halogen, -NH2, -(CH2)gC(=O)NRxRy, -NHC(=O)0R6, -NHC(=O)NRxRy, -C(=O)OR3, -NHC(=O)Rx, -SO2R3, cyano, hydroxy, alkoxy, substituted amino, or -C(=O)R3 (wherein Rx, Ry, g, R6 and R 3 are as defined above);
R4 can be hydrogen; alkyl, hydroxyl, halogen, or carboxy;
R7 can be hydrogen, or alkyl;
R1 can be independently hydrogen or alkyl and R2 and R4 forms an optionally substituted 4-12 membered saturated or unsaturated monocyclic or bicyclic ring system fused to ring B having 0-4 heteroatom(s) selected from the group consisting of N, O and S, wherein the substituents is one or more of oxo, alkyl, -C(=O)OR3, -SO2R3, halogen, hydroxy, alkoxy, -NH2 or substituted amino (wherein R 3 is as defined below), with the proviso that R2 and R4 together does not form -CH2-O-CH2-O-CH2-;
1 and X2 can be hydrogen, alkyl, cycloalkyl, alkaryl, alkenyl, cycloalkylalkyl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, -(CH2)gC(=O)NRxRy or - (CH2)glC(=O)OR3 (wherein g can be an integer from 0-3 and g1 can be an integer from 1-3, and Rx, Ry and R 3 are as defined below);
1 and X2 together can optionally 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 N, O or S;
wherein R 3 can be alkyl, cycloalkyl or heterocyclyl;
wherein the halogen can be F, CI, Br, or I; Rx and Ry each independently can be hydrogen, alkyl, C3-C6 alkenyl, C3-C6 alkynyl, carboxy, cycloalkyl, -S(O)mR5, aryl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl; m can be an integer between 0-2; R6 can be alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl or heterocyclylalkyl;
wherein R5 can be hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl.
In another aspect, provided are pharmaceutical compositions comprising one or more phosphodiesterase inhibitors of type IV ("PDE-IV"), and at least one other active ingredient such as muscarinic receptor antagonists (MRA), p2-agonists, p38 MAP Kinase inhibitors, and corticosteroids and one or more pharmaceutically acceptable excipients, wherein the PDE-IV inhibitor is one or more compounds having the structure of Formula la and Formula lb, as described herein.
The pharmaceutical compositions of each of the above aspects can include one or more of
the following embodiments. For example, the one or more compounds of Formula la and
Formula lb may be:
3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-en-6-ol (Compound No. 1),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-N-(4-fluorophenyl)-l-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxamide (Compound No. 2),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-7-(tetrahydrofuran-3-ylcarbonyl)-l-oxa-2,7-diazaspiro[4.4]non-2-ene (Compound No. 3),
3-[3-(cyclopentyIoxy)-4-methoxyphenyl]-N-dimethyI-l-oxa-2,7-diazaspiro[4.4]non-2-ene-7-sulfonamide (Compound No. 4),
jV-butyl-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxamide (Compound
No. 5),
2-{3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,7-diazaspiro[4.4]non-2-en-7-yl}acetamide (Compound No. 6),
Hydrochloride salt of 3-[3-(cyclopentyloxy)-4-methoxyphenyl]-8-prolyl-l-oxa-2,8-diazaspiro[4.5]dec-2-ene (Compound No. 7),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-8-(2-morpholin-4-yl-ethyl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene (Compound No. 8),
N-butyl-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxamide (Compound
No. 9),
3-[3-(cyclopentyloxy)-4-methoxyphenyl]-8-(methylsulfonyl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene (Comp No. 10), 3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2-azaspiro[4.4]non-2-ene (Compound No. 11), 3-[3,4-bis(2-morpholin-4-ylethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Comp No. 12), 3-(3.4-diisopropoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 13), 3-[3-methoxy-4-(2-morpholin-4-ylethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 14), 3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-en-8-one (Compound No. 15), 3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-en-8-ol (Compound No. 16), 3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-7-isopropyl-l-oxa-2, 7-diazaspiro [4.4] non-2-ene (Compound No. 17),
3-[3-(cyclopentyloxy)-4-methoxyphenyl]-7-(cyclopropylcarbonyl)-l-oxa-2,7-diazaspiro[4.4]non-2-ene (Compound
No. 18),
/V-benzyl-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxamide (Compound No. 19),
7-acetyl-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,7-diazaspiro[4.4]non-2-ene (Compound No. 20),
Tert-/-butyl 3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,7-diazaspiro[4.5]dec-2-ene-7-carboxylate (Compound
No. 21),
N-butyl-N'-{3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-yl}urea (Compound No. 22),
N-{3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-yl}-N-(2-methoxyphenyl)urea (Compound No. 23),
3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 24),
Hydrochloride salt of 3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,7-diazaspiro[4.5]dec-2-ene (Comp No. 25),
3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-one (Compound No. 26),
3-[3,4-bis(cyclopentyloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 27),
3-[3,4-Bis(cyclopropylmethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 28),
3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-en-4-ol (Compound No. 29),
(R)-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 30),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-8-(cyclopropylmethyl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene (Compound
No. 31),
/V-Benzyl-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxamide (Compound
No. 32),
3-[3,4-Bis(benzyloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 33),
4-(l,7-Dioxa-2-azaspiro[4.4]non-2-en-3-yl)benzene-l,2-diol (Compound No. 34),
7-Amino-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,7-diazaspiro[4.4]non-2-en-6-one (Compound No. 35),
Ethyl 8-benzyl-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-4-carboxylate (Compound No. 36),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2-azaspiro[4.5]dec-2-ene-4-carboxylic acid (Compound No. 37),
8-Benzyl-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,8-diazaspiro[4.5]dec-2-ene (Compound No. 38),
Ethyl 3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2-azaspiro[4.5]dec-2-ene-4-carboxylate (Compound No. 39),
3-[3-(Difluoromethoxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 40),
2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenol (Compound No. 41),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1 -oxa-2,7-diazaspiro[4.4]non-2-en-6-one (Compound No. 42),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3a,6a-dimethyl-3aH-cyclopenta[d]isoxazole-4,6(5H,6aH)-dione (Compound No. 43),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3a,4,6,6a-tetrahydrofuro[3,4-H]isoxazole (Compound No. 44),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-6,6a-dihydrofuro[3,4-d]isoxazol-4(3aH)-one (Compound No. 45),
Tert-buty\ [({3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-yl}amino)carbonyl]carbamate (Compound No. 46),
N-{3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-yl}cyclopentanecarboxamide (Compound No. 47),
8-Acetyl-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,8-diazaspiro[4.5]dec-2-ene (Compound No. 48),
8-(Cyclopentylcarbonyl)-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,8-diazaspiro[4.5]dec-2-ene (Compound
No. 49),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-8-(2-piperidin-l-ylethyl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene (Compound
No. 50),
3-(2,3-Dihydro-l,4-benzodio1n-6-yl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 51), 3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-l,8-dioxa-2-azaspiro[4.5]dec-2-ene (Compound No. 52), 3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3aH-cyclopenta[d]isoxazole-4,6(5H,6aH)-dione (Compound No. 53), 3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-8-ethyl-1 -oxa-2,8-diazaspiro[4.5]dec-2-ene (Compound No. 54), 3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-8-vinyl-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 55), 3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3a,4,5,6,7,7a-hexahydro-l,2-benzisoxazole (Compound No. 56), 3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole (Compound No. 57),
N-{3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-yl}methariesulfonamide(Compound No. 58),
3-(Cyclopentyloxy)-4-methoxyphenyl]-8-methyl-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 59), 3-(Allyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 60), 3-(2-Chloroethoxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 61), Cyclopentyloxy)-4-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenol (Compound No. 62), 4-Butoxy-3-isobutoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 63), 3-Isobutoxy-4-propoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 64), 3-Butoxy-4-(cyclopropylmethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 65), 3-Butoxy-4-ethoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 66), 3-Butoxy-4-(cyclohexyloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 67), 3-(Cyclohexylmethoxy)-4-ethoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 68), 3-(Cyclohexylmethoxy)-4-isopropoxyphenyl]-1,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 69), 4-Butoxy-3-(cyclohexylmethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 70), 4-Isobutoxy-3-isopropoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 71), 4-Butoxy-3-isopropoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 72), 4-(Cyclohexylmethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 73), 3-lsopropoxy-4-(2-morpholin-4-ylethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 74), 3-(Cyclopropylmethoxy)-4-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 75), 3-(Cyclopropylmethoxy)-4-(2-morpholin-4-ylethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene(Compd No. 76), 4-Butoxy-3-(cyclopropylmethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 77), 3-(Cyclopropylmethoxy)-4-isopropoxyphenyl]-1,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 78), 3-Isobutoxy-4-isopropoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 79), 4-(Cyclopropylmethoxy)-3-isobutoxyphenyl]-l ,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 80), 4-(cyclohexyloxy)-3-(cyclopentyloxy)phenyl]-1,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 81), 4-(Cyclohexylmethoxy)-3-(cyclopentyloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 82), 4-(Cyclopropylmethoxy)-3-(cyclopentyloxy)phenyl]-1,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 83), 3-(Cyclopentyloxy)-4-isobutoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 84), 3-(Cyclopentyloxy)-4-ethoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 85), 3-(CycIopropylmethoxy)-4-ethoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 86), 4-(Cyclopentyloxy)-3-isobutoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 87), 3-lsopropoxy-4-(2-morpholin-4-ylethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 88), 4-Ethoxy-3-isobutoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 89), 3-(Cyclopentyloxy)-4-propoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 90), 4-Butoxy-3-(cyclopentyloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 91), 3-(Cyclopentyloxy)-4-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 92), 3-(Cyclopentyloxy)-4-(cycloheptyloxy)pheny 1]-1,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 93), 3-(Cyclopentyloxy)-4-(2-morpholin-4-ylethoxy)phenyl]-1,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 94), 4-(Cyclohexylmethoxy)-3-isobutoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 95), 4-(Cyclohexylmethoxy)-3-(cyclopropylmethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Comp No. 96), 3-(Cyclopropylmethoxy)-4-propoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 97), 4-(Cyclopentyloxy)-3-(cyclopropylmethoxy)phenyl]-1,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 98),
3-[4-(Cyclopropylmethoxy)-3-isopropoxyphenyl]-1,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 99), 3-[4-(Cyclopentyloxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 100), 3-(3-Isopropoxy-4-propoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 101), 3-(4-Ethoxy-3-isopropoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 102),
3-Butoxy-4-(2-morpholin-4-ylethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 103), 3-|3-Butoxy-4-(cyclopentyloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 104), 3-(3-Butoxy-4-propoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 105), 3-Butoxy-4-isopropoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 106), 3-(Cyclohexylmethoxy)-4-propoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 107), 3-(Cyclohexylmethoxy)-4-isobutoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compoun No. 108), 3-[3-(Cyclohexylmethoxy)-4-(cyclopentyloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 109), 3-[3-(Cyclohexylmethoxy)-4-(cyclopropylmethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Comp No. 110), 4-(Cyclohexylmethoxy)-3-propoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. Ill), 4-(Cyclopropylmethoxy)-3-propoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 112), 3-|4-(Cyclopentyloxy)-3-propoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 113), 3-l4-(3-lsobutoxy)-3-propoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 114), 3-f3-(Cycloheptyloxy)-4-(cyclopropylmethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 115), 3-[3-(Cycloheptyloxy)-4-propoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 116), 4-Butoxy-3-(cycloheptyloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 117), 3-(Cycloheptyloxy)-4-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 118), 3-(Cycloheptyloxy)-4-(cyclopentyloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 119), 3-Ethoxy-4-propoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 120), 4-(Cycloheptyloxy)-3-ethoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 121), 4-(Cyclopropylmethoxy)-3-ethoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 122), 4-(Cyclohexylmethoxy)-3-ethoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 123), (S)-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 124), 3-Butoxy-4-isobutoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 125), 3-Ethoxy-4-isopropoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 126), 4-(Cyclopentyloxy)-3-ethoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 127), 4-Butoxy-3-ethoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 128), 3-(3-Ethoxy-4-isobutoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 129), 3-r3-(Cycloheptyloxy)-4-isobutoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 130), 3-[3-(Cycloheptyloxy)-4-(cyclopentyloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 131), 3-[3-(Cycloheptyloxy)-4-ethoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 132), 4-Butoxy-3-propoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 133), 4-Ethoxy-3-propoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 134), 3-|4-(Morpholin-4-ylethoxy)-3-propoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 135), 3-(4-lsopropoxy-3-propoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 136), 2-[5-( 1,7-Dioxa-2-azaspiro[4.4]non-2-en-3-yl)-2-methoxyphenoxy]cyclopentanol (Compound No. 137),
N-{3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-yl}-2-fluorobenzamide (Compound
No. 138),
N-{3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-yl}benzamide (Compound No. 139),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]isoxazoIe (Compound No. 140),
7-(Cyclopentylcarbonyl)-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,7-diazaspiro[4.5]dec-2-ene (Compound
No. 141),
Tert-butyl 3-[3-(cyclopentyloxy)-4-methoxyphenyl]-3a,4,6,6a-tetrahydro-5H-pyrrolo[3,4d]isoxazole-5-carboxylate (Compound No. 142),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxamide (Compound No. 143),
N-5utyl-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,7-diazaspiro[4.5]dec-2-ene-7-carboxamide (Compound
No. 144),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-7-(methylsulfonyl)-l-oxa-2,7-diazaspiro[4.5]dec-2-ene (Comp No. 145),
3-[4-Methoxy-3-(pyridin-3-yImethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 146),
5-Acetyl-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]isoxazole (Comp No. 147),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-5-(methylsulfonyl)-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-i/]isoxazole (Compound No. 148),
4-Bromo-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 149),
3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3a,5,6,7a-tetrahydro-l,2-benzisoxazol-7(4H)-one (Compound No. 150),
3-[4-(Difluoromethoxy)-3-(2,3-dihydro-lH-inden-2-yloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound
No. 151),
3-[4-(Cyclopentyloxy)-3-(2,3-dihydro-lH-inden-2-yloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound
No. 152),
3-[4-Butoxy-3-(2,3-dihydro-lH-inden-2-yloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 153),
3-(3-{[3-(Benzyloxy)cyclopentyl]oxy}-4-methoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 154),
7-Acetyl-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxa-2,7-diazaspiro[4.5]dec-2-ene (Compound No. 155),
3-[4-Methoxy-3-(pyridin-2-ylmethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 156),
3-[3-(2,3-Dihydro-lH-inden-2-yloxy)-4-ethoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 157),
3-[3-(2,3-Dihydro-lH-inden-2-yloxy)-4-propoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 158),
3-[4-(Cyclopropylmethoxy)-3-(2,3-dihydro-lH-inden-2-yloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 159),
3-[3-(2,3-Dihydro-lH-inden-2-yloxy)-4-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Comp No. 160),
2-(2,3-Dihydro-1 H-inden-2-yloxy)-4-( 1,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenol (Compound No. 161),
/V-cyclopropyl-2-[5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-2-memoxyphenoxy]acetamide (Compound No. 162),
Hydrochloride salt of 3-[4-methoxy-3-(piperidin-3-yloxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound
No. 163),
2-[5-(l,7-Dioxa-2-azaspiro[4.4]non-2-en-3-yl)-2-methoxyphenoxy]acetarnide (Compound No. 164),
Ethyl [5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-2-methoxyphenoxy]acetate (Compound No. 165),
[5-(l,7-Dioxa-2-azaspiro[4.4]non-2-en-3-yl)-2-methoxyphenoxy]acetonitrile (Compound No. 166),
3-{3-[(2,6-Dichloropyridin-4-yl)methoxy]-4-methoxyphenyl}-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Comp No. 167),
[3-(3-Cyclopentyloxy-4-methoxy phenyl)-5-(4-carboxylic acid tert butylester-piperazin-l-yl-carbonyl)-4,5-dihydroisoxazol-5-yl)-({4-carboxylic-acid- tert butyl ester piperazine-1-yl) ethanone (Compound No. 168),
l-{l-[5-(4-Acetyl-4-phenyl-piperidine-l-carbonyl)-3-(3-cyclopentyloxy-4-methoxy-phenyl)-4,5-dihydro-isoxazole-5-yl]-4-acetyl-4-phenyl-piperidin-4-yl]-ethanone (Compound No. 169),
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-(pyrrolidine-l-carbonyl)-4,5-dihydro-isoxazol-5-yl]-pyrrolidin-l-yl-ethanone (Compound No. 170),
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-(piperidine-l-carbonyl)-4,5-dihydro-isoxazol-5-yl]-piperidin-l-yl-ethanone (Compound No. 171),
3-(3-Cyclopentyloxy-4-methoxy phenyl)-5-(pyrrolidin-2-carboxylic acid methyl ester-l-carbonyl)-4,5-dihydro-isoxazol-5-yl)-[{pyrrolidine-2-carboxylic acid methyl ester-5-yl] ethanone ( Compound No. 172),
[5-[4-(4-Chlorophenyl)-4-hydroxy-piperidine-l-carbonyl]-3-(3-cyclopentyloxy-4-methoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-[4-(4-chlorophenyl)-4-hydroxy-piperidin-l-yl]-ethanone ( Compound No. 173),
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-(hydroxymethyl-piperidine-l-carbonyl)-4,5-dihydro-isoxazol-5-yl]-(4-hydroxymethyl-piperidin-l-yl)-ethanone (Compound No. 174),
[5-(5-Benzyl-2,5-diazabicyclo[2.2.1]heptane-2-(carbonyl)-3-(3-cyclopentyloxy-4-methoxy-phenyl]-4,5-dihydro-isoxozol-5-yl]-5-benzyl-2,5-diazabicylo-[2.2.1]hept-2-yl-ethanone (Compound No. 175),
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-piperdin-l-yl-methanone (Compound
No. 176),
4-[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazole-5-carbonyl]-piperazine-l-carboxylic acid tert-butyl ester (Compound No. 177),
l-[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazole-carbonyl]-pyrrolidin-2-carboxylic acid (Compound No. 178),
l-[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-carbonyl]-pyrrolidine-2-carboxylic acid methyl ester (Compound No. 179),
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazole-5-yl]-pyrrolidin-l-yl-methanone (Compound No. 180),
[l-4]-Bipiperidinyl-l-yl-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4-,5-dihydro-isoxazol-5-yl]-methanone (Compound No. 181),
l-[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazole-5-carbonyl]-4-phenyl-piperidine-4-yl}-ethanone (Compound No. 182),
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-methyl-piperazin-l-yl)-methanone (Compound No. 183),
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]- piperazin-1-yl-methanone (Compound No. 184),
[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-l-yl]-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydroisoxazol-5-yl]-methanone (Compound No. 185),
{4-[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazole-5-carbonyl]-[l,4]diazepan-l-yl}-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-methanone (Compound No. 186),
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-cyclopropylmethyl-piperazin-l-yl)-methanone (Compound No. 187),
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-isobutyl-l-piperazin-l-yl)-methanone (Compound No. 188),
[3-Hydroxymethyl-piperidin-l-yl]-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-methanone (Compound No. 189),
[3-(3-Cyclopentyloxy-4-methoxy-phenyI)-5-methyl-4, 5-dihydro-isoxazol-5-yl]-(4-hydroxy-piperidin-l-yl)-methanone (Compound No. 190),
(4-Benzyl-piperidin-l-yl)-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4, 5-dihydro-isoxazol-5-yl]-methanone (Compound No. 191),
l-[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4, 5-dihydro-isoxazole-5-carbonyl]-piperidin-4-one (Compound No. 192),
[4-(4-Bromophenyl)-4-hydroxy-piperidin-l-yl]-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyI-4, 5-dihydro-isoxazoI-5-yl]-methanone (Compound No. 193),
(5-Benzyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl- [3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4, 5-dihydro-isoxazol-5-yl]-methanone (Compound No. 194),
(4-Benzyl-piperazin-l-yl)-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyI-4, 5-dihydro-isoxazol-5-yl)-methanone (Compound No. 195),
l-[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4, 5-dihydro-isoxazole-5-carbonyl]-pyrrolidin-2-carboxylic acid methyl amide (Compound No. 196),
l-[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazole-5-carbonyl]-pyrrolidine-2-carboxylic acid diethyl amide (Compound No. 197),
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-(2-hydroxymethyl-pyrrolidin-l-yl)-methanone (Compound No. 198),
l-[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydroisoxazole-5-carbonyl]-piperidine-2-carboxylic acid methyl ester (Compound No. 199),
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxozole-5-carboxyl]-pyrrolidine-2-carboxylic acid amide (Compound No. 200),
3-[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazole-5-carbonyl]-bicyclo[2.2.1]heptan-2-one (Compound No. 201),
3-[3-Cyclopentyloxy-4-methoxy-phenyl)-1,7-dioxa-2-aza-spiro[4.4]non-2-en-6-one (Compound No. 202),
3-[3-Cyclopentyloxy-4-methoxy-phenyl)-7-methyl-1 -oxa-2,7-diaza-spiro[4.4]non-2-ene-6,9-dione (Comp No. 203),
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl-(2-methoxymethyl-pyrrolidin-l-yl)-methanone (Compound No. 204),
3-(3-Cyclopentyloxy-4-methoxy-phenyl)-l,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 205),
3-(3-Cyclopropylmethoxy-4-methoxy-phenyl)-1,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 206),
3-(4-Difluoromethoxy-3-propoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 207),
3-(4-Difluoro-3-butoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 208),
3-(4-Difluoromethoxy-3-isobutoxy-phenyl)-l,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 209),
3-(3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 210),
3-(3-Benzyloxy-4-difluoromethoxy-phenyl)-l,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 211),
3-(4-Difluoromethoxy-3-cyclopentyloxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 212),
3-(3,4-Bis-difluoromethoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 213),
3-(3-Butoxy-4-difluoromethoxy-phenyl)-l,7-dioxa-2-aza-spiro [4,4] non-2-ene (Compound No. 214),
3-[3-(Bicyclo[2.2.1]hept-2-yloxy)-4-difluoromethoxy-phenyl]-l,7-dioxo-2-aza-spiro[4.4]non-2-ene (CompNo. 215),
3-(4-Difluoromethoxy-3-methoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 216),
3-(4-Benzyloxy-3-methoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 217),
3-(3-Cycloheptyloxy-4-difluoromethoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 218),
4-(l,7-Dioxa-2-aza-spiro[4.4]non-2-en-3-yl)-2-methoxy-phenol (Compound No. 219),
3-[3-(indan-2-yloxy)-4-methoxy-phenyl]-l,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 220),
3-(4-Ethoxy-3-methoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 221),
3-(3-Methoxy-4-propoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 222),
3-(4-lsopropoxy-3-methoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 223),
3-(4-Butoxy-3-methoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 224),
3-(4-Cyclopentyloxy-3-methoxy-phenyl)-l,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 225),
3-(4-(Isobutoxy-3-methoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 226),
3-(4-Cyclohexyloxy-3-methoxy-phenyl)-l,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 227),
3-(4-Cyclopropylmethoxy-3-methoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 228),
3-(3,4-Dimethoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 229),
3-(3-Ethoxy-4-methoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 230),
3-(4-Methoxy-3-propoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 231),
3-(3-Isopropoxy-4-methoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 232),
3-(3-Butoxy-4-methoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 233),
3-(3-Isobutoxy-4-methoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 234),
3-[4-Methoxy-3-(3-methyl-butoxy)-phenyl-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 235),
3-(3-Cyclohexyloxy-4-methoxy-phenyl)-l,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 236),
3-(3-Cycloheptyloxy-4-methoxy-phenyl)-l,7-dioxa-2-aza-spiro [4.4] non-2-ene (Compound No. 237),
3-[4-Methoxy-3-(2-morpholin-4-yl-ethoxy)-phenyl]-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 238),
3-(3-Benzyloxy-4-methoxy-phenyl)-l,7-dioxa-2-aza-spiro[4.4]non-2-ene (Compound No. 239),
5-(l,7-Dioxa-2-aza-spiro[4.4]non-2-en-3-yl)-2-methoxy-phenol (Compound No. 240),
3-(3-Cyclopentyloxy-4-methoxy-phenyl)-l-oxa-2,8-diaza-spiro[4.5]dec-2-ene-8-carboxylic acid isopropyl ester (Compound No. 241),
Hydrochloride salt of 3-(3-cyclopentyloxy-4-methoxy-phenyl)-l-oxa-2,8-diaza-spiro[4.5]dec-2-ene (Comp No. 242),
4-Chloro-N-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-l-oxa-2,8-diaza-spiro[4.5]dec-2-ene-8-carbonyl]-benzene sulfonamide (Compound No. 243),
3-(3-Cyclopentyloxy-4-methoxy-phenyl)-l-oxa-2, 8-diaza-spiro [4.5] dec-2-ene-8-carboxylic acid-(2,6-difluoro-phenyl)-amide (Compound No. 244),
3-(3-Cyclopentyloxy-4-methoxy-phenyl)-l-oxa-2,8-diaza-spiro[4.5]dec-2-ene-8-carboxylic acid-(2,4-dichloro-phenyl)-amide (Compound No. 245),
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-l-oxa-2-aza-spiro[4.5]dec-2-en-8-yl]-carbamic acid isopropyl ester (Compound No. 246),
Hydrochloride salt of 3-(3-cyclopentyloxy-4-methoxy-phenyl)-l-oxa-2-aza-spiro[4.5]dec-2-en-8-ylamine (Compound
No. 247),
2-[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-l-oxa-2-aza-spiro[4.5]dec-2-en-8-yl]-isoindole-l,3-dione (Compound
No. 248),
7-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-oxa-6-aza-spiro[3.4]oct-6-ene (Compound No. 249),
3-(3-Cyclopentyloxy-4-methoxy-phenyl)-l-oxa-2-aza-spiro[4.5]dec-2-ene (Compound No. 250),
3-(3-Cyclopentyloxy-4-methoxy-phenyl)-l-oxa-2,7-diaza-spiro[4.4]non-2-ene-7-carboxylic acid tert-butyl ester (Compound No. 251),
Hydrochloride salt of 3-(3-cyclopentyloxy-4-methoxy-phenyl)-l-oxa-2,7-diaza-spiro[4.4]non-2-ene (Comp No. 252),
3-[3-{[(35)-l-Benzylpyrrolidin[2,3-d]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 253),
3-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy]propan-l-ol
(Compound No. 254),
[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy]acetonitrile
(Compound No. 255),
4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4.4]non-2-en[2,3-d]-2-methoxyphenol (Compound No. 256),
4-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4.4]non-2-en[2,3-d]-2-methoxyphenol (Compound No. 257),
5-[(5S or 5R)-l,7-Dioxa-2-azaspiro[4.4]non-2-en[2,3-d]-2-methoxyphenol (Compound No. 258),
(5S or 5R)-3-(3,4-Dimethoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 259),
(5R or 5S)-3-(3.4-Dimethoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 260),
2-(Benzyloxy)-4-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenol (Compound No. 261),
2-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy]ethanol (Compound No. 262),
3-[4-(Difluorornethoxy)-3-ethoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 263),
3-[3-(Cyclohexyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 264),
(5R or 5S)-3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 265),
(5S or 5R)-3-[4-(Difluoromethoxy)-3-methoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 266),
Ethyl [2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy]acetate (Compound No. 267),
3-[4-(Difluoromethoxy)-3-(2-morpholin-4-ylethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Comp No. 268),
2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenyl cyclohexanecarboxylate (Comp No. 269),
5-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy]pentanoic acid (Compound No. 270), 3-[3-(2,2,2-Trifluoroethoxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 271), 3-[3-(Cyclopentylmethoxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 272),
N-cyclopropyl-2-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy]acetamide (Compound
No. 273),
2-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy]acetamide (Compound No. 274),
2-[2-(Difluoromethoxy)-5-(l ,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy]-jV-methylacetamide (Comp No. 275),
3-[3-(Cyclopentyloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 276),
2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenyl cyclopropanecarboxylate (Comp No. 277),
2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenyl morpholine-4-carboxylate (Comp No. 278),
2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenyl benzoate (Compound No. 279),
5-[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy] pentanamide (Compound No. 280),
3-[3-Propoxy-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 281),
3-[3-Isopropoxy-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 282),
3-[3-(Cyclopropylmethoxy)-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Comp No. 283),
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. 284),
5-(l,7-Dioxa-2-azaspiro[4.4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy)phenol (Compound No. 285),
3-[3-Methoxy-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 286),
3-[3-Ethoxy-4-(2,2,2-trifluoroethoxy)phenyl]-l ,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 287),
3-[3-Butoxy-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 288),
3-[3-(CyclohexyImethoxy)-4-(2,2,2-trifluoroethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Comp No. 289),
3-{[2-(Difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy]methyl} benzonitrile (Comp No. 290),
2-{2-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy]ethyl}-lH-isoindole-l,3(2H)-dione (Compound No. 291),
3-[3-(Cyclohexyloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-] j-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 292),
Ethyl [5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy) phenoxy]acetate (Compound No. 293),
3-[3-(Cyclohexylmethoxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 294),
7ert-butyl [2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy]acetate (Compound No. 295),
N-cyclopropyl-2-[5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy) phenoxyjacetamide (Compound No. 296),
2-(Cyclopentyloxy)-4-[(5R or 5S)-l,7-dioxa-2-azaspiro[4.4]non-2-en[2,3-d]phenol (Compound No. 297),
2-(Cyclopentyloxy)-4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4.4]non-2-en[2,3-d]phenol (Compound No. 298),
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. 299),
N-Cyclopentyl-2-[5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-2-(2,2,2-trifluoroethoxy) phenoxyjacetamide (Compound No. 300),
7ert-butyl 4-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy] piperidine-1-carboxylate (Compound No. 301),
Hydrochloride salt of 3-[4-(difluoromethoxy)-3-(piperidin-4-yloxy)phenyl]-1,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 302),
3-{3-[(l-Acetylpiperidin-4-yl)oxy]-4-(difluoromethoxy)phenyl}-l,7-dioxa-2-azaspiro [4.4]non-2-ene (Compound
No. 303),
7ert-butyl (3S)-3-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy]pyrrolidine-l-carboxylate (Compound No. 304),
Tert-butyl (3R)-3-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yI)phenoxy]pyrrolidine-l-carboxylate (Compound No. 305),
7ert-butyl 3-[2-(difluoromethoxy)-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)phenoxy]piperidine-l-carboxylate (Compound No. 306),
7ert-buty 1 (2S)-2- {[2-(difluoromethoxy)-5-( 1,7-dioxa-2-azaspirof4.4]non-2-en-3-yl)phenoxy]methyI} pyrrolidine-1 -carboxylate (Compound No. 307),
(5R or 5S)-3-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Comp No. 308),
(5S or 5R)-3-(3-isopropoxy-4-methoxyphenyl)-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 309),
(5S or 5R)-3-[3-(Cyclopropylmethoxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 310),
2-(Cyclopropylmethoxy)-4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4.4]non-2-en[2,3-d]phenol (Compound No. 311),
4-[(5S or 5R)-l,7-Dioxa-2-azaspiro[4.4]non-2-en[2,3-d]-2-isopropoxyphenol (Compound No. 312),
(5S or 5R)-3-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No.
313),
(5S or 5R)-3-[3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 314),
(5S or 5R)-3-[4-(difluoromethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 315),
(5R or 5S)-3-[4-(difluoromethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 316),
2-(Cyclopropylmethoxy)-4-[(5R or 5S)-l,7-dioxa-2-azaspiro[4.4]non-2-en[2,3-d]phenol (Compound No. 317),
4-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4.4]non-2-en[2,3-d]-2-isopropoxyphenol (Compound No. 318),
(5R or 5S)-3-[3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound
No. 319),
(5R or 5S)-3-[4-(difluoromethoxy)-3-isopropoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 320),
Hydrochloride salt of 3-{4-(difluoromethoxy)-3-[(3S)-pyrrolidin-3-yloxy]phenyl}-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 321),
Hydrochloride salt of 3-{4-(difluoromethoxy)-3-[(2S)-pyrrolidin-2-ylmethoxy]phenyl}-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 322),
Hydrochloride salt of 3-{4-(difluoromethoxy)-3-[(2^)-pyrrolidin-2-ylmethoxy]phenyl}-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 323),
3-[4-(Difluoromethoxy)-3-{ [(2R)- l-propionylpyrrolidin-2-yl]methoxy} phenyl]- l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 324),
3-[3-{[(2,S)-l-acetylpyrrolidin-2-yl]methoxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 325),
3-[3-{[(3S)-l-benzoylpyrrolidin[2,3-d]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 326),
3-[4-(Difluoromethoxy)-3-{[(3S)-l-propionylpyrrolidin[2,3-d]oxy}phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 327),
(5S or 5R)-3-[3-(Benzyloxy)-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 328),
2-(Benzyloxy)-4-[(5S or 5R)-l,7-dioxa-2-azaspiro[4.4]non-2-en[2,3-d]phenol (Compound No. 329),
(5S or 5R)-3-[3-(Benzyloxy)-4-methoxyphenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 330),
3-{4-(Difluoromethoxy)-3-[(l-propionylpiperidin-4-yl)oxy]phenyl}-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound
No. 331),
3-[4-(Difluoromethoxy)-3-{[l-(4-fluorobenzoyl)piperidin-4-yl]oxy}phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 332),
3-[3-{[l-(Cyclopropylcarbonyl)piperidin-4-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 333),
3-[3-{[l-(Cyclopentylcarbonyl)piperidin-4-yl]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 334),
3-[4-(Difluoromethoxy)-3-({l-[(trifluoromethyl)sulfonyl]piperidin-4-yl}oxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 335),
3-{3-[(l-Acetylpiperidin-3-yl)oxy]-4-(difluoromethoxy)phenyl}-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No.
336),
3-{4-(Difluoromethoxy)-3-[(l-propionylpiperidin-3-yl)oxy]phenyl}-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound
No. 337),
3-[4-(Difluoromethoxy)-3-{[l-(4-fluorobenzoyl)piperidin[2,3-d]oxy}phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 338),
3-[3-{[l-(Cyclopropylcarbonyl)piperidin[2,3-d]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 339),
3-[3-{[l-(Cyclopentylcarbonyl)piperidin[2,3-d]oxy}-4-(difluoromethoxy)phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 340),
3-[4-(Difluoromethoxy)-3-{[l-(ethylsulfonyl)piperidin[2,3-d]oxy}phenyl]-l,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 341),
3-[3-(Benzyloxy)-4-(2,2,2-trifluoroethoxy)phenyl]-1,7-dioxa-2-azaspiro[4.4]non-2-ene (Compound No. 342),
2-(Difluoromethoxy)-5-[(5S' or 5R)-1,7-dioxa-2-azaspiro[4.4]non-2-en[2,3-d]phenol (Compound No. 343), or
5-[(5R or 5S)-l,7-Dioxa-2-azaspiro[4.4]non-2-en[2,3-d]-2-methoxyphenol (Compound No. 344).
In another embodiment, p2-agonists can be selected from albuterol, salbutamol, biltolterol, pirbuterol, levosalbutamol, tulobuterol, terbutaline, bambuterol, metaproterenol, fenoterol, salmeterol, carmoterol, arformoterol, formoterol, or their pharmaceutically acceptable salts or solvates thereof.
In yet another embodiment, corticosteroids can be selected from alclometasone,
amcinonide, amelometasone, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol,
cloticasone, cyclomethasone, deflazacort, deprodone, dexbudesonide, diflorasone, difluprednate,
fluticasone, flunisolide, halometasone, halopredone, hydrocortisone, hydrocortisone,
methylprednisolone, mometasone, prednicarbate, prednisolone, rimexolone, tixocortol,
triamcinolone, ulobetasol, or pharmaceutically acceptable salts or solvates thereof.
In another embodiment, p38 kinase inhibitors can be selected from l-[5-tert-butyl-2-p-
tolyl-2H-pyrazol[2,3-d]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-l-yl]urea; l-[5-tert-butyl-2-p-
tolyl-2H-pyrazol[2,3-d]-3-[4-(2-(l-oxothiomorpholin-4-yl)ethoxy)naphthalen-l-yl]urea; l-[5-tert-
butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol[2,3-d]-3-[4-(2-pyridin-4-ylethoxy)naphthalen-l-
yljurea; l-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol[2,3-d]-3-[4-(2-morpholin-4-
ylethoxy)naphthalen-l-yl]urea; and l-[5-tert-butyl-2-methyl-2H-pyrazol[2,3-d]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-l-yl]urea disclosed in our co-pending United States Patent Application No. 60/605,344; Other p38 kinase inhibitors can be selected from for example:
tov-Butyl 4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-l-carboxylate (Compound No. la),
Hydrochloride salt of 6-(2-methylphenyl)-2-(piperidin-4-ylamino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-