WO 2006/065686 PCT/US2005/044768
SPIRO DERIVATIVES AS LIPOXYGENASE INHIBITORS
Cross-Reference To Related Applications
[0001] This application claims the benefit under 35 U.S.C. 119(e) to co-pending provisional
applications U.S. Serial No. 60/635,581 filed on December 13, 2004, U.S. Serial No. 60/656,709 filed
on February 25, 2005, U.S. Serial No. 60/656,710 filed on February 25, 2005, U.S. Serial No.
60/675,386 filed on April 27, 2005, and U.S. Serial No. 60/702,580 filed on July 26, 2005, each of
which is incorporated herein by reference in their entirety.
Background Information
[0002] The present invention relates to certain novel spiro derivatives of Formula I, IA, IB, II,
IIA, III, or IIIA as depicted below, pharmaceutical formulations containing them, and their uses as
therapeutic agents, and syntheses therefore. Their uses as therapeutic agents that may act as
lipoxygenase inhibitors include, but are not limited to, prevention or treatment of diseases involving
apoptosis in cancer cells; diseases involving hypcxia or anoxia; diseases involving inflammation;
disorders of the airways; diseases involving central nervous system (CNS) disorders,
neurodegeneration and neuroinflammation; and diseases involving the autoimmune system.
[0003] The use of compounds having a chroman moiety as iipoxygenase inhibitors has
been disclosed, for example, in US Patents 5,059,609; US 4,950,684; US 5,015,661; US 4,780,469;
US 5,591,772; US 5,925,673; US 5,250,547; US 5,393,775; US 4,814,346; US 5,939,452, US
6,051,601; US 6,117,874; and US 6,133,286.
[0004] Arachidonic acid is an essential fatty acid that exists within the cell membrane and
can be released from phospholipids by the action of phosphoiipase. The released arachidonic acid is
metabolized through three major enzymatic pathways, i.e. the lipoxygenase pathway, to form
substances such as prostaglandins which are associated with inflammatory responses, and
thromboxanes which are associated with the formation of thrombus, or leukotrienes which induce
allergic reactions.
[0005] Lipoxygenases are non-heme iron-containing enzymes that catalyze the oxidation of
polyunsaturated fatty acids and esters thereof. They were originally classified based on their
substrate specificity for insertion of molecular oxygen into arachidonic acid at carbon positions 5, 12
and 15, but more recently a phylogenetic classification is being used. This separates the mammalian
enzymes in four main subtypes, 5-Lipoxygenase, 12/15-Upoxygenases, platelet 12-Lipoxygenases
and epidermis-type lipoxygenases. The 12/15 family of lipoxygenases includes two sub-families with
a high degree of sequence homology, the reticulocyte 15-Lipoxygenases (found in rabbit and
humans) and the leukocyte
[0006] 12-Lipoxygenases (found in mouse, pig, rat, and rabbit). This type of lipoxygenase
shares more homology to reticulocyte 15-Lipoxygenase and leukocyte 12-Lipoxygenase, than to
platelet 12-Lipoxygenases.
[0007] It is believed that oxidative metabolites of the 12/15-Lipoxygenase or the 15-
Lipoxygenase cascade have been implicated in the potentiation of thrombin induced platelet

WO 2006/065686 PCT/US2005/044768
activation (Setty et al. Blood, (1992), 2765-2773); in the progression of various cancers (Kelavkar et
al, Curr. Urol. Rep. Vol. 3 no. 3 (2002) pp. 207-214) and related pathologies (Tisdaie et al., Science
Vol. 289 no. 5488 (2000) pp. 2293-4). It has also been shown that treatment with a 15-Lipoxygenase
inhibitor suppresses atherogenesis in rabbits fed a high-fat diet (Bocan et al., Atherosclerosis, Vol.
136 (1998) pp. 203-16). There is increasing evidence that certain lipoxygenase enzymes are
involved in the pathogenesis and acceleration of atherosclerosis by inducing oxidation of LDL to its
atherogenic form (Sparrow, C. P., et al., J. Lipid Res. Vol. 29 (1988) pp. 745-753. and Steinberg, D.,
New Eng. J. Med, Vol. 320(1989) pp. 915-924). It has also been reported that 12-Lipoxygenase
enzyme plays a role in mediating angiotensin II induced vascular and adrenal actions (Natarajan, R.t
etal., Endocrinology Vol. 131 (1992) pp. 1174-1180). Recent studies (Klein, R. et al., Science Vol.
303 no. 5655 (2004) 329-332) have also shown the role of 15-Lipoxygenase enzyme in the
regulation of bone density.
[0008] The enzyme 5-Lipoxygenase converts arachidonic acid to 5-
hydroperoxyeicosatetraenoic acid (5-HPETE). This is the first step in the metabolic pathway yielding
5-hydroxyeicosatetraenoic acid (5-HETE) and the important class of mediators, the leukotrienes.
Evidence of the role of leukotrienes in the pathology of certain diseases has been described, for
example in Cloud et aL, J. Allergy Clin. Immunol., Vol. 79 (1987) pp. 256 (asthma); Turnbull et al.,
Lancet II, (1977) pp. 526-9 (chronic bronchitis); Cromwell et al., Lancet II, (1981) pp. 164-5 (cystic
fibrosis); Davidson et al., J. Pharm. Pharmacol. Vol. 34 no. 61(982) pp. 410 (rheumatoid arthritis);
Rae et al., Lancet. Vol. 2 no. 8308 (1982) pp. 1122-4. Cook et al., J. Pharmacol. Exp. Ther., 235,
(1985) pp. 470-474 (cardiovascular conditions); Tsuji et al., Biochem. Pharmacol. Vol. 55 no. 3;
(1998); pp. 297-304 (dermatitis such as psoriasis;.
[0009] It has also been shown in co-owned US application Serial No. 11/251,423 filed
October 13, 2005, titled Methods for Treating Diabetes, herein incorporated by reference in its
entirety, that dual 5-Lipoxygenase and 12/15-Lipoxygenase inhibitors or 5-Lipoxygenase and 15-
Lipoxygenase inhibitors are superior in the prevention of treatment of subjects susceptible to
diabetes, are able to improve glucose control in animal models of diabetes, and have demonstrated a
significant lowering of the baseline serum glucose levels compared to selective 5-Lipoxygenase, 15-
Lipoxygenase and 12/15-Lipoxygenase inhibitors.
[0010] The compositions, formulations and methods of this invention are particularly
applicable in preventing and/or treating diseases or disorders mediated, at least in part, by one or
more lipoxygenase enzymes, such as 5-Lipoxygenase enzyme and/or 12/15-Lipoxygenase enzyme.
SUMMARY OF THE INVENTION
[0011] The present invention is concerned with certain novel spiro derivatives of Formula I,
IA, IB, II, MA, III, or IIIA which may be useful in the manufacture of pharmaceutical compositions for
treating disorders mediated, at least in part, by lipoxygenases.

WO 2006/065686 PCT/US2005/044768
[0012] In a first aspect, the present invention concerns the compounds represented by
Formula I:

wherein,
X is O or S(O)0.2,
R1, R3, and R4 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl,
halogen, nitro, cyano, amino, aminosulfonyl, sulfonylamino, sulfanyl, aryl, heterocyclyl,
hydroxy, acyl, alkoxy, carboxy, alkoxycarbonyl, amido, alkenyl, and alkynyl, with the proviso
that said alkenyl and alkynyl are not substituted with aryl or heteroaryl;
or R3 and R4 together with the carbon atoms attached thereto join to form a cycloalkyl, aryl, or
heterocyclyl ring;
R2 is selected from the group consisting of hydroxy, amino, carbonylamino, alkoxy, -0-C(O)-0-alkyl, -
O-alkenyl, -O-acyl, O-alkylene-amino, -0-C(O)-alkylene-C00R'\ -O-C(O)-amino, -O-C(O)-
alkylene-amino, -0-C(0)-0-alkylene-amino, -O-C(O)-heterocyclyl, -O-C(O)-alkylene-
heterocyclyl, -O-glucoside, -O-phosphoryl, -O-alkylene-phosphoryl, and -O-C(O)-AA,
wherein AA is amino acid or a di-, tri- or tetra-peptide;
R5 and R6 are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl,
hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkylcarbonyl, amino, aminosulfonyl,
sulfonylamino, sulfanyl, nitro, cyano, halogen, -OC(O)NRbRc, -NRC(O)Rd,-NRORa,
and -NR-NRbRc, or
together with the carbon atom to which they are attached, form C=O; C=NORa, C=N-NRbRc,
or an optionally substituted (C3-C4)cycloalkyl ring;
R7 and R8 are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy,
alkoxy, carboxy, alkoxycarbonyl, alkylcarbonyl, amino, aminosulfonyl, sulfonylamino,
sulfanyl, nitro, cyano, halogen, aryl, heterocyclyl, -OC(O)NRbRc, -NRC{O)Rd, -NR0R3,
and -NR-NRbRc; or
together with the carbon atom to which they are attached, form OO; C=NORa, C=N-NRbRc,
or an optionally substituted (C3-C4)cycloalkyl ring;
R9 and R10 are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy,
alkoxy, carboxy, alkoxycarbonyl, alkylcarbonyl, amino, aminosulfonyl, sulfonylamino,
sulfanyl, nitro, cyano, halogen, -0C(O)NRbRc,-NRC(O)Rd, -NRORa, and -NR-NRbRc; or
-4-

WO 2006/065686 PCT/US2005/044768
together with the carbon atom to which they are attached, form C=O; C=NORa, C=N-NRbRc,
or an optionally substituted (C3-C4)cycloalkyl ring;
R is hydrogen or alkyl,
Rd is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, heterocyclyl, and aryl,
Rb and Rc are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, acyl,
aminocarbonyl, heterocyclyl and aryl; or
together with the nitrogen atom to which they are attached form an optionally substituted,
saturated or unsaturated 3-8 membered ring optionally incorporating 1 to 3 -N-, -O- or -S-
atoms;
R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkoxy, heterocyclyl,
and aryl,
and n is 0 or 1;
with the following provisos:
a. at least one of -CR5R6, -CR7R8 or -CR9R10 is a (C3-C<)cycloalkyl ring;
b. no more than one of R1, R3 and R4 is hydrogen, and
c if n is 0, R5 and R6 independently cannot be hydrogen or together with the carbon
atom to which they are attached do not form C=O;
or single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
[0013] In one embodiment of Formula I, R2 is hydroxy, and in another embodiment R2 is
hydroxy and R1, R3, and R4 are independently of each other hydrogen, halogen, or alkyl. In yet
another embodiment, R2 is hydroxy, R1, R3, and R4 are independently of each other hydrogen,
halogen, or alkyl, and -CR5R6 is optionally substituted (C3-C4)cycloalkyl ring. In another embodiment,
R2 is hydroxy, R1, R3, and R4 are independently of each other hydrogen, halogen, or alkyl, and n=1, -
CR7R8 is optionally substituted (C3-C4)cycloalkyl ring. In another embodiment, R2 is hydroxy, R1, R3,
and R4 are independently of each other hydrogen, halogen, or alkyl, and -CR9R10 is optionally
substituted cyclopropyl or cyclobutyl. In another embodiment, R5 is -NRORa, R6 is hydrogen,
and -CR9R10 is an optionally substituted (C3-C4)cyjloalkyl ring, exemplified by-CR9R10 forming an
optionally substituted cyclobutyl ring. In another embodiment RJ is -NRORa and -CR9R10 is
optionally substituted cyclobutyl ring. In yet another embodiment R^ is hydroxy and RG is hydrogen,
and -CR9R10 is an optionally substituted (C3-C4)cycloalkyl ring, exemplified by -CR9R10 forming an
optionally substituted cyclobutyl ring. One embodiment includes R5 is hydroxy, R6 is hydrogen, and
R1, R3, and R4 are independently selected from hydrogen, halogen, and alkyl.
[0014] In other embodiments, R: is hydroxy, R1, RJ, and R4 are indepdendently hydrogen,
halogen or alkyl and R5 and R6 are hydrogen.
[0015] In some embodiments n is 0 and in other embodiments n is 1.
[0016] In one embodiment, when any of R1, R3, and R4 are halo, then halo is chloro.
[0017] In one embodiment, when any of R1, R3, and R4 are alkyl, then alkyl is optionally
substituted and is selected from methyl, ethyl, isopropyl, propyl, t-butyl, S.f-dimethyloctyl,
hydroxymethyl, hydroxyaminornethyl, methoxymethyl, methoxyaminomethyl, ethoxyaminomethyl, 2-

WO 2006/065686 PCT/US2005/044768
quinolin-2-ylethyl, aminomethyl, N-morpholinomethyl, N-methylacetamidomethyl, and
acetamidomethyl,
[0018] In one embodiment, when any of R1, R3 and R4 are alkenyl, then alkenyl is optionally
substituted and is selected from vinyl and 3,7-dimethylocta-2,6-dieny!.
[0019] In one embodiment, when any of R1, R3, and R4 are heterocyclyl, then heterocyclyl is
optionally substituted and is selected from is 5-methoxycarbonyl-4,5-dihydroisoxazol-3-yl, 5-
butylisoxazol-3-yl, oxazol-5-yl, 4,5-dimethylimidazol-2-yl, benzofuran-2-yl, and 5,6-
dimethylbenzoimidazol-2-yl.
[0020] In another embodiment, the invention is directed to compounds of Formula IA:

wherein
X is O or S(O)0-2,
R41, R43, and R44 are independently selected from the group consisting of hydrogen, halo, acyl,
alkenyl, heterocyclyl, and alkyl optionally substituted with amino, hydroxy, alkoxy,
heterocyclyl, carbonylamino;
R42 is selected from the group consisting of hydroxy, alkoxy, -O-C(O)-O-alkyl, -O-acyl, -O-alkylene-
amino, -0-C(0)-alkylene-amino, -0-C(0)-0-alkylene-amino, -O-C(O)-heterocyclyl, -O-C(O)-
alkylene-heterocyclyl, and -0-C(0)-carbonylamino;
R45 and R46 are
independently selected from the group consisting of hydrogen, alkyl, heterocyclyl, hydroxy,
alkoxy, amino, aminosulfonyl, sulfonylamino, sulfanyl, cyano, -OC(O)NRbRc, -NRC(O)Rd,
-NROR3, or
together with the carbon atom to which they are attached, form C=O; C=NORa, or an
optionally substituted (C3-C4)cycloalkyl ring;
R47 and R48 are
independently selected from the group consisting of hydrogen, alkyl, hydroxy, and alkoxy,
and heterocyclyl, or
together with the carbon atom to which they are attached, form an optionally substituted
(C3-C4)cycloalkyl ring;
R49 and R410 are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy, and
alkoxy, or
together with the carbon atom to which they are attached, form an optionally substituted
(C3-C4)cycloalkyl ring;
Ra is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, heterocyclyl, and aryl;

WO 2006/065686 PCT/US2005/044768
Rb and Rc are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, acyl,
aminocarbonyl, heterocyclyl and aryl; or
together with the nitrogen atom to which they are attached form an optionally substituted,
saturated or unsaturated 3-8 membered ring optionally incorporating 1 to 3 -N-, -O- or -S-
atoms,
with the following provisos:
a. at least one of -CR45R46, -CR47R48 or -CR49R410 is a (C3-C4)cycloalkyl ring, and
b. no more than one of R41, R43 and R44 is hydrogen;
or single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
[0021] In another embodiment, the invention is directed to compounds of Formula IB:

Formula IB
wherein R41, R43, R44, R45, R4b, R47, R48, R49, and R410 are as defined above.
[0022] In another aspect, the invention relates to a pharmaceutical composition containing a
therapeutically effective amount of a compound of Formula I, (A, or IB, or a pharmaceutically
acceptable salt thereof admixed with at least one pharmaceutically acceptable excipient. In some
examples, the pharmaceutical compositions comprise a compound of Formula I, IA, or IB, and a
pharmaceutically acceptable excipient; and the compound is selected from the illustrative
compounds and stereoisomers, mixture of stereoisomers or pharmaceutically acceptable salts
thereof.
[0023] In another aspect, the present invention concerns the compounds represented by
Formula II:

wherein,
X is O,S(O)0.2i or NR20D;
R21, R23, and R24 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl,
halogen, nitro, cyano, amino, aminosulfonyl, sulfonylamino, sulfanyl, aryl, heterocyclyl,
hydroxy, alkoxy, carboxy, alkoxycarbonyl, amido, alkenyl, and alkynyl, with the proviso that
said alkenyl and alkynyl are not substituted with aryl or heteroaryl;
7

WO 2006/065686 PCT/US2005/044768
or R23 and R24 together with the carbon atoms attached thereto join to form a cycloalkyl, aryl, or
heterocyclyl ring;
R22 is selected from the group consisting of hydroxy, amino, carbonyiamino, alkoxy, -O-alkenyl, -
O-acyl, -O-alkylene-amino, -O-C(O)-alkylene-COOR2a, -O-C(O)-amino, -O-C(O)-alkylene-
amino, -O-C(O)-heterocyclyl, -0-C(0)-alkylene-heterocyc!yl, -O-glucoside, -O-
phosphoryl, -O-alkylene-phosphoryl, and -O-C(O)-AA, wherein AA is amino acid or a di-, tri-
or tetra-peptide;
R26 and R27 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl,
hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkylcarbonyl, amino, aminosulfonyl,
sulfonylamino, sulfanyl, nitro, cyano, halogen, aryl, heterocyclyl, -C=N-
OR20, -OC(O)NR2bR2c, -NR2OC(O)R2d, -NR20OR2a, and -NR20-IMR2bRZc;
R29 and R210 together with the carbon atom to which they are attached form an optionally substituted
(C3-C4)cycloalkyl ring;
R20 is hydrogen or alkyl;
R200 is selected from the group consisting of hydrogen, alkyl, aralkyl, cycloalkyl, alkenyl, alkynyl, acyl,
aminocarbonyl, heterocyclyl and aryl;
R2a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyi, heterocyclyl, and
aryl;
R2b and R2c are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, acyl,
aminocarbonyl, heterocyclyl and aryl; or
together with the nitrogen atom to which they are attached form an optionally substituted,
saturated or unsaturated 3-8 membered rir:g optionally incorporating 1 to 3 -N-, -O-or-S-
atoms; and
R2d is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, amino, alkoxy,
heterocyclyl, and aryl;
with the proviso that when R26 or R27 is -NR20C(O)R2d; -NHOR2a or -NH-NR2bR2c, then no more than
one of R21, R22, R23 and R24 is hydrogen;
or single stereoisomers, mixtures of stereoisomers, pharmaceutically acceptable salts, tautomers or
prodrugs thereof.
[0024] In some embodiments, R22 is hydroxy, and in another embodiment R22 is hydroxy
and R21, R23, and R24 are independently of each other hydrogen, halogen, or alkyl.
[0025] In one embodiment, when any of R21, R23, and R24 are alkyl, then alkyl is optionally
substituted and is selected from methyl, ethyl, and isopropyl.
[0026] In still another aspect, the invention relates to compounds of Formula IIA:

WO 2006/065686 PCT/US2005/044768

wherein,
R51, R53, and R54 are independently selected from the group consisting of hydrogen, alkyl, and
hydroxy;
R55 and R57 are independently selected from the group consisting of hydrogen, alkyl, hydroxy, cyano,
and heterocyclyl,
R59 and R510 together with the carbon atom to which they are attached form an optionally substituted
(C3-C4)cycloalkyl ring;
or single stereoisomers, mixtures of stereoisomers, pharmaceutically acceptable salts, or prodrugs
thereof.
[0027] In another aspect, the invention relates to a pharmaceutical composition containing a
therapeutically effective amount of a compound of Formula II or HA, or a pharmaceutically acceptable
salt thereof admixed with at least one pharmaceutically acceptable excipient. In some examples, the
pharmaceutical compositions comprise a compound of Formula II or IIA and a pharmaceutically
acceptable excipient; and the compound is selected from the illustrative compounds and
stereoisomers, mixture of stereoisomers or pharmaceutically acceptable salts thereof.
[0028] In another aspect, the present invention concerns the compounds represented by
Formula III:

wherein,
R30 is selected from the group consisting of hydrogen, alkyl, aralkyl, cycloalkyl, alkenyl, alkynyl, acyl,
aminocarbonyl, heterocyclyl and aryl,
R31, R33, and R34 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl,
halogen, nitro, cyano, amino, aminosulfonyl, sulfonylamino, sulfanyl, aryl, heterocyclyl,
hydroxy, alkoxy, carboxy, alkoxycarbonyl, amido, alkenyl, and alkynyl, with the proviso that
said alkenyl and alkynyl are not substituted with an aryl or heteroaryl group;
or R33 and R34 together with the carbon atoms attached thereto join to form a cycloalkyl, aryl, or
heterocyciyl ring;

WO 2006/065686 PCT/US2005/044768
R32 is selected from the group consisting of hydroxy, alkoxy, -O-alkenyl, -O-acyl, -O-glucoside; -O-
phosphoryl, -O-C(O)-AA, wherein AA is amino acid, or a di-, tri- or tetra-peptide;
R35 and R36 are
independently selected from the group consisting of hydrogen, alkyl, hydroxy,
cycloalkyl, -OC(O)NR3bR3c,-NR3dOR3a and -NR^-NR^R30; or
together with the carbon atom to which they are attached form C=O, C=NOR3a, C=N-
NR3bR3c, optionally substituted (C3-C4)cycloalkyl ring;
R37 and R38 are
independently selected from the group consisting of hydrogen, hydroxy, alkyl,
cycloalkyl, -OC(O)NR3bR3c,-NR3dOR3a and -NR3d-NR3bR3c; or
together with the carbon atom to which they are attached form C=O, C=NOR3a, C=N-
NR3bR3c, optionally substituted (C3-C4)cycloalkyl ring;
R39 and R310 are
independently selected from the group consisting of hydrogen, alkyl, or cycloalkyl; or
together with the carbon atom to which they are attached form an optionally substituted
(C3-C4)cycloalkyl ring;
R3a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, acyl, heterocyclyl,
and aryl;
R3b and R3c are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, acyl,
aminocarbonyl, heterocyclyl and aryl; or
together with the nitrogen atom to which they are attached form an optionally substituted,
saturated or unsaturated 3-8 membered ring optionally incorporating 1 to 3 N, O, or S atoms;
R3d is hydrogen or alkyl; and
m is 0 or 1;
with the followings provisos:
a. at least one of -CR35R36, -CR37R38, and -CR39R310 is a (C3-C4)cycloalkyl ring;
b. no more than one of R31, R33 and R3" is hydrogen;
c. if m is 0, then -CR35R36 is not C=O; and
d. if m is 1 and -CR39R310 is a (C3-C4)cycloalkyl ring, then R30 is not hydrogen or aminocarbonyl;
or single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
[0029] In one embodiment of Formula III, m is 0 and R32 is hydroxy, and in another
embodiment m is 0; R32 is hydroxy; and R31, R33, and R34 are independently of each other hydrogen,
halogen, or alkyl. In yet another embodiment, m is 0, R32 is hydroxy; R31, R33, and R34 are
independently of each other hydrogen, halogen, or alkyl, and -CR35R36 is optionally substituted
(C3-C4)cycloalkyl ring. In another embodiment, m is 0; R32 is hydroxy; R31, R33, and R34 are
independently of each other hydrogen, halogen, or alkyl; and -CR39RJ10 is optionally substituted
(C3-C4)cycloalkyl ring.
[0030] In another embodiment, m is 1 and R32 is hydroxy and in another embodiment m is
1; R32 is hydroxy and R31, R33, and R34 are independently of each other hydrogen, halogen, or alkyl.

WO 2006/065686 PCT/US2005/044768
In yet another embodiment, m is 1; R32 is hydroxy; R31, R33, and R34 are independently of each other
hydrogen, halogen, or alkyl; and -CR3'R38 is optionally substituted (C:rC4)cycloalkyl ring In another
embodiment, m is 1; R32 is hydroxy; R31, R33, and R34 are independently of each other hydrogen,
halogen, or alkyl; and -CR39R3'0 is optionally substituted (C3-C)cycloalkyl ring. In another
embodiment, m is 1; R32 is hydroxy; R31, R:!J, and R34 are independently of each other hydrogen,
halogen, or alkyl; and -CR35R36 is optionally substituted (C3-C,)cycloalkyl ring.
[0031] In another embodiment, m is 1, R32 is hydroxy, R31, R33, and R34are independently
of each other hydrogen, halogen, or alkyl, and R35 and R36are both hydrogen.
[0032] In another embodiment, -CR35R35 is OO; and in another embodiment, -CR37R38 is
C=O.
[0033] In another embodiment R30 is alkyl substituted with an amido, a sulfonylamino or an
aminosulfonyl group and in another embodiment R30 is -(CH2)2-6~NHS(O)2~aryl, -(CH2)2.6-S(O)2NH-
aryl; -(CH2)2-6NHC(O)-aryl or -{CH2)2^C(O)NH-aryl; illustrated by alkylbenzenesulfonaminoethyl, or
alkylbenzenesulfonaminopropyl.
[0034] In one embodiment, when any of R31, R33 or R34 are alkyl, then alkyl is selected from
methyl and t-butyl.
[0035] In one embodiment, when any of R31, R33 or R34 are alkenyl, then alkenyl is 3,7-
dimethylocta-2,6-dienyl.
[0036] In another embodiment, the invention contemplates compounds of Formula IIIA:

R60 is selected from the group consisting of hydrogen, alkyl, aralkyl, acyl, heterocydyl and aryl;
R61, R63, and RG4 are independently selected from the group consisting of hydrogen, alkyl, halogen,
alkenyl, with the proviso that alkenyl is not substituted with an aryl or heteroaryl group;
R65 and R66 are
independently selected from the group consisting of hydrogen, alkyl, and hydroxy, or
together with the carbon atom to which they are attached form C=O or optionally substituted
(C3-C4)cycloalkyl ring;
R67 and R68 are
independently selected from the group consisting of hydrogen, hydroxy, and alkyl, or
together with the carbon atom to which they are attached form an optionally substituted
(C3-C4)cycloalkyl ring;
R69 and R610 are
independently selected from the group consisting of hydrogen, alkyl, or cycloalkyl; or

WO 2006/065686 PCT/US2005/044768
together with the carbon atom to which they are attached form an optionally substituted
(C3-C4)cycloalkyl ring;
with the followings provisos:
a. at least one of -CR05R6B, -CR67R68, and -CRG9R610 is a (C3-C4)cycloalkyl ring;
b. no more than one of RR1, R63 and R64 is hydrogen;
c. if -CR69R610 is a (C3-C4)cycloalkyl ring, then RG0 is not hydrogen or aminocarbonyl;
or single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
[0037] In another aspect, the invention relates to a pharmaceutical composition containing a
therapeutically effective amount of a compound of Formula III or IIIA, or a pharmaceutically
acceptable salt thereof admixed with at least one pharmaceutically acceptable excipient. In some
examples, the pharmaceutical compositions comprise a compound of Formula III or IIIA and a
pharmaceutically acceptable excipient; and the compound is selected from the illustrative
compounds and stereoisomers, mixture of stereoisomers or pharmaceutically acceptable salts
thereof.
[0038] It is contemplated that in embodiments where R2, R22, and R32 are not hydroxy,
alkoxy, O-alkenyl, amino or carbonylamino, then the substituent will hydrolyze in vivo to form the
active hydroxy substituent. It is further contemplated that in embodiments where R42 is not hydroxy,
then R42 will hydrolyze in vivo to form hydroxy.
[0039] In another aspect, the invention relates to a method of inhibiting a lipoxygenase,
comprising contacting a cell with an effective amount of one or more compounds of Formula I:

wherein,
X is O or S(O)0-2;
R1, R3, and R4 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl,
halogen, nitro, cyano, amino, aminosulfonyl, sulfonylamino, sulfanyl, aryl, heterocyclyl,
hydroxy, alkoxy, acyl, carboxy, alkoxycarbonyl, amido, alkenyl, and alkynyl, with the proviso
that said alkenyl and alkynyl are not substituted with aryl or heteroaryl;
or R3 and R4 together with the carbon atoms attached thereto join to form a cycloalkyl, aryl, or
heterocyclyl ring;
R2 is selected from the group consisting of hydroxy, amino, carbonylamino, alkoxy, -O-C(O)-O-alkyl, -
O-alkenyl, -O-acyl, -O-alkylene-amino, -G-C(0)-alkylene-COORd, -O-C(O)-amino, -O-C(O)-
alkylene-amino, -0-C(0)-0-alkylene-amino, -O-C(O)-heterocyclyl, -O-C(O)-alkylene-
heterocyclyl, -O-glucoside, -O-phosphoryl, -O-alkylene-phosphoryl, or -O-C(O)-AA, wherein
AA is an amino acid or a di-, tri- or tetra-peptide;
R5 and R6 are

WO 2006/065686 PCT/US2005/044768
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl,
hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkylcarbonyl, amino, aminosulfonyl,
sulfonylamino, sulfanyl, nitro, cyano, halogen, -OC(O)NRbRc, -NRC(O)Rd, -NROR3,
and -NR-NRbRc; or
together with the carbon atom to which they are attached, form C=O; C=NORa, C=N-NRbRc,
or an optionally substituted (C3-C4)cycloalkyl ring;
R7 and R8 are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy,
alkoxy, carboxy, alkoxycarbonyl, alkylcarbonyl, amino, aminosulfonyl, sulfonylamino,
sulfanyl, nitro, cyano, halogen, aryl, heterocyclyl, -OC(O)NRbRG, -NRC(O)Rd, -NRORa,
and -NR-NRbRc; or
together with the carbon atom to which they are attached, form C=O; C=NORa, C=N-NRbRc,
or an optionally substituted (C3-C4)cycloalkyl ring;
R9 and R10 are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy,
alkoxy, carboxy, alkoxycarbonyl, alkylcarbonyl, amino, aminosulfonyl, sulfonylamino,
sulfanyl, nitro, cyano, halogen, -OC(O)NRbRc, -NRC(O)Rd, NRORa, and -NR-NRbRc; or
together with the carbon atom to which they are attached, form C=O; C=NORa, C=N-NRbRc,
or an optionally substituted (C3-C4)cycloalkyl ring;
R is hydrogen or alkyl;
Ra is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, heterocyclyl, or aryl;
Rb and Rc are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, acyl,
aminocarbonyl, heterocyclyl and aryl; or
together with the nitrogen atom to which they are attached form an optionally substituted,
saturated or unsaturated 3-8 membered ring optionally incorporating 1 to 3 -N-, -O- or —S-
atoms;
Rd is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkoxy, heterocyclyl,
and aryl;
and n is 0 or 1;
with the following provisos:
a. at least one of -CR5R6, -CR7R8, and -CR9R10 is a (C3-C4)cycloalkyl ring; and
b. no more than one of R1, R3 and R4 is hydrogen; or single stereoisomers, mixtures of
stereoisomers, pharmaceutically acceptable salts or thereof.
[0040] In another aspect, the invention relates to a method of inhibiting a lipoxygenase,
comprising contacting a cell with an effective amount of one or more compounds of Formula II:

WO 2006/065686 PCT/US2005/044768

wherein,
XisO, S(O)0-2orNR200;
R21, R23, and R24 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl,
halogen, nitro, cyano, amino, aminosulfonyl, sulfonylamino, sulfanyl, aryl, heterocyclyl,
hydroxy, alkoxy, carboxy, alkoxycarbonyl, amido, alkenyl, and alkynyl, with the proviso that
said alkenyl and alkynyl are not substituted with aryl or heteroaryl;
or R23 and R24 together with the carbon atoms attached thereto join to form a cycloalkyl, aryl, or
heterocyclyl ring;
R22 is selected from the group consisting of hydroxy, amino, carbonylamino, alkoxy, -O-
alkenyl,-O-acyl, -O-alkylene-amino, -O-ClOValkylene-COOR^, -O-C(O)-amino, -O-C(O)-
alkylene-ammo, -O-C(O)-heterocyclyl, -O-C(O)-alkylene-heterocyclyl, -O-glucoside, -O-
phosphoryl, -O-alkylene-phosphoryl and -0-C(O)-AA, wherein AA is amino acid or a di-, tri-
or tetra-peptide;
R26 and R27 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl,
hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkylcarbonyl, amino, aminosulfonyl,
sulfonylamino, sulfanyl, nitro, cyano, halogen, aryl, heterocyclyl, -C=N-OR20, -
OC(O)NR2bR2c, -OC(O)NR2bR2c,
-NR20C(O)R2d, -NR20S(O)2R2d, -NR20OR2a, and -NRz0-NR2bR2c;
R29 and R21G together with the carbon atom to which they are attached form an optionally substituted
(C3-C4)cycloalkyl ring;
R20 is hydrogen or alkyl;
R700 is selected from the group consisting of hydrogen, alkyl, aralkyl, cycloalkyl, alkenyl, alkynyl, acyl,
ammocarbonyl, heterocyclyl and aryl;
R2a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, heterocyclyl, and
aryl;
R2b and R2c are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, acyl,
aminocarbonyl, heterocyclyl and aryl; or
together with the nitrogen atom to which they are attached form an optionally substituted,
saturated or unsaturated 3-8 membered ring optionally incorporating 1 to 3 -N-, -O- or — S-
atoms; and
R2d is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, amino, alkoxy,
heterocyclyl, and aryl;

WO 2006/065686 PCT/US2005/044768
or single stereoisomers, mixtures of stereoisomers, pharmaceutically acceptable salts, tautomers or
prodrugs thereof.
[0041] In another aspect, the invention relates to a method of inhibiting a lipoxygenase,
comprising contacting a cell with an effective amount of one or more compounds of Formula III:

wherein,
R30 is selected from the group consisting of hydrogen, alkyl, aralkyl, cycloalkyl, alkenyl, alkynyl, acyl,
aminocarbonyl, heterocyclyl and aryl;
R31, R33, and R34 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl,
halogen, nitro, cyano, amino, aminosulfonyl, sulfonylamino, sulfanyl, aryl, heterocyclyl,
hydroxy, alkoxy, carboxy, alkoxycarbonyl, amido, alkenyl, and alkynyl, with the proviso that
said alkenyl and alkynyl are not substituted with an aryl or heteroaryl group;
or R33 and R34 together with the carbon atoms attached thereto join to form a cycloalkyl, aryl, or
heterocyclyl ring;
R32 is selected from the group consisting of hydrcxy, alkoxy, -O-alkenyl, -O-acyl, -O-glucoside; -O-
phosphoryl, -O-C(O)-AA, wherein AA is amino acid, or a di-, tri- or tetra-peptide,
R35 and R36 are
independently selected from the group consisting of hydrogen, alkyl, hydroxy,
cycloalkyl, -OC(O)NR3bR3c,-NR3dOR3a and -NR^-NR^R30; or
together with the carbon atom to which they are attached form C=O, C=NOR3a, C=N-
NR3bR3c, optionally substituted (C3-C4)cycloalkyl ring;
R37 and R38 are
independently selected from the group consisting of hydrogen, hydroxy, alkyl,
cycloalkyl, -OC(O)NR3bR3c, -NR3dOR3a and -NR3d-NR3bR3c; or
together with the carbon atom to which they are attached form C=O, C=NOR3a, C=N-
NR3bR3c, optionally substituted (C3-C4)cycloalkyl ring;
R39 and R310 are
independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl; or
together with the carbon atom to which they are attached form an optionally substituted
(C3-C4)cycloalkyl ring;
R3a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, acyl, heterocyclyl,
and aryl;
R3b and R3c are
15

WO 2006/065686 PCT/US2005/044768
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, acyl,
aminocarbonyl, heterocyclyl and aryl; or
together with the nitrogen atom to which they are attached form an optionally substituted,
saturated or unsaturated 3-8 membered ring optionally incorporating 1 to 3 N, O, or S atoms;
R3d is hydrogen or alkyl; and
is 0 or 1;
with the following provisos:
a. at least one of -CR35R36, -CR37R38, and -CR39R310 is a (C3-C,)cycloalkyl ring;
b. no more than one of R31, R33 and R34 is hydrogen;
c. if m is 0, then -CR35R36 is not C=O; and
d. if m is 1 and -CR39R310 is a (C3-C4)cycloalkyl ring, then R30 is not hydrogen or
aminocarbonyl;
or single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
[0042] In another aspect, the invention relates to a method of inhibiting a lipoxygenase,
comprising contacting a cell with an effective amount of one or more compounds of Formula IA, IB,
IIA and/or IMA
[0043] In some embodiments, the compound inhibits one or more lipoxygenase enzymes
selected from 5-Lipoxygenase, 15-Lipoxygenase, 12/15-Lipoxygenase enzymes and combinations
thereof. In other embodiments, the compound inhibits 5-Lipoxygenase enzyme. In other
embodiments, the compound inhibits both a 5-Lipoxygenase enzyme and a 15-Lipoxygenase
enzyme.
[0044] In another aspect the invention relates to treating a subject with a lipoxygenase
mediated condition with one or more compounds of Formula I:

wherein,
X is O or S(O)0-2;
R1, R3, and R4 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl,
halogen, nitro, cyano, amino, aminosulfonyl, sulfonylamino, sulfanyl, aryl, heterocyclyl,
hydroxy, alkoxy, acyl, carboxy, alkoxycarbonyl, amido, alkenyl, and alkynyl, with the proviso
that said alkenyl and alkynyl are not substituted with aryl or heteroaryl;
or R3 and R4 together with the carbon atoms attached thereto join to form a cycloalkyl, aryl, or
heterocyclyl ring;
R2 is selected from the group consisting of hydroxy, amino, carbonylamino,
alkoxy, -O-C(O)-O-alkyl, -O-alkenyl, -O-acyl, -O-alkylene-amino, O-C(O)-alkylene-COORa, -
O-C{O)-amino, -O-C(O)-alkylene-amino, -O-C(O)-O-alkylene-amino, -O-C{O)-heterocyclyl, -

WO 2006/065686 PCT/US2005/044768
O-C(O)-alkylene-heterocyclyl, -O-glucoside, -O-phosphoryl, -O-alkylene-phosphoryl,
or -O-C(O)-AA, wherein AA is amino acid or a di-, tri- or tetra-peptide;
R5 and Rc are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl,
hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkylcarbonyl, amino, aminosulfonyl,
sulfonylamino, sulfanyl, nitro, cyano, halogen, -OC(O)NRbRc, -NRC(O)Rd, -NRORa,
and -NR-NRbRc; or
together with the carbon atom to which they are attached, form C=O; C=NORa, C=N-NRbRc,
or an optionally substituted (C3-C4)cycloalkyl ring;
R7 and R8 are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy,
alkoxy, carboxy, alkoxycarbonyl, alkylcarbonyl, amino, aminosulfonyl, sulfonylamino,
sulfanyl, nitro, cyano, halogen, aryl, heterocyclyl, -OC(O)NRbRc, -NRC(O)Rd, -NRORa,
and -NR-NRbRc; or
together with the carbon atom to which they are attached, form C=O; C=NORa, C=N-NRbRc,
or an optionally substituted (C3-C()cycloalkyl ring;
R9 and R10 are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy,
alkoxy, carboxy, alkoxycarbonyl, alkylcarbonyl, amino, aminosulfonyl, sulfonylamino,
sulfanyl, nitro, cyano, halogen, -OC(0)NRbRc, -NRC(O)Rd, -NRORa, and -NR-NRbRc; or
together with the carbon atom to which they are attached, form C=O; C=NORa, C=N-NRbRc,
or an optionally substituted (C3-C4)cycloalkyl ring;
R is hydrogen or alkyl;
Ra is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, heterocyclyl, or aryl;
Rb and Rc are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, acyl,
aminocarbonyl, heterocyclyl and aryl; or
together with the nitrogen atom to which they are attached form an optionally substituted,
saturated or unsaturated 3-8 membered ring optionally incorporating 1 to 3 -N-, -O- or-S-
atoms;
Rd is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkoxy, heterocyclyl,
and aryl;
and n is 0 or 1;
with the following provisos:
a. at least one of -CR5R6, -CR7R8, and -CR9R10 is a (C3-C4)cycloalkyl ring; and
b. no more than one of R1, R3 and R4 is hydrogen; or single stereoisomers, mixtures of
stereoisomers, pharmaceutically acceptable salts or thereof.
[0045] In another aspect the invention relates to treating a subject with a lipoxygenase
mediated condition with one or more compounds of Formula II:
l7

WO 2006/065686 PCT/US2005/044768

wherein,
XisO, S(O)0-2.orNR200;
R21, R23, and R24 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl,
halogen, nitro, cyano, amino, aminosulfonyl, sulfonylamino, sulfanyl, aryl, heterocyclyl,
hydroxy, alkoxy, carboxy, alkoxycarbonyl, amido, alkenyl, and alkynyl, with the proviso that
said alkenyi and alkynyl are not substituted with aryl or heteroaryl;
or R23 and R24 together with the carbon atoms attached thereto join to form a cycloalkyl, aryl, or
heterocyclyl ring;
R22 is selected from the group consisting of hydroxy, amino, carbonylamino, alkoxy, -O-alkenyl, -
O-acyl, -O-alkylene-amino, -O-C(O)-alkylene-COOR2a, -0-C(0)-amino, -O-C(O)-alkylene-
amino, -O-C(O)-heterocyclyl, -O-C(O)-alkylene-heterocyc!yl, -O-glucoside, -O-
phosphoryi, -O-alky!ene-phosphoryl and -O-C(O)-AA, wherein AA is an amino acid or a di-,
tri- or tetra-peptide;
R26 and R27 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl,
hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkylcarbonyl, amino, aminosulfonyl,
sulfonylamino, sulfanyl, nitro, cyano, halogen, aryl, heterocyclyl, -ON-OR20, -OC(O)NR2bR2c,
-NR20C(O)R2d,
-NR20S(O)2R2d, -NR20OR2a, and -NR20-NR2bR2c;
R29 and R210 together with the carbon atom to which they are attached form an optionally substituted
(C3-C4)cycloalkyl ring;
R2D is hydrogen or alkyl;
R200 is selected from the group consisting of hydrogen, alkyl, aralkyl, cycloalkyl, alkenyl, alkynyl, acyl,
aminocarbonyl, heterocyclyl and aryl;
R2a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, heterocyclyl, and
aryl;
R2b and R2c are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, acyl,
aminocarbonyl, heterocyclyl and aryl; or
together with the nitrogen atom to which they are attached form an optionally substituted,
saturated or unsaturated 3-8 membered ring optionally incorporating 1 to 3 -N—, -O- or -S-
atoms; and
R2d is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, amino, alkoxy,
heterocyclyl, and aryl,
18

WO 2006/065686 PCT/US2005/044768
or single stereoisomers, mixtures of stereoisomers, pharmaceutically acceptable salts, or prodrugs
thereof.
[0046] In another aspect the invention relates to treating a subject with a lipoxygenase
mediated condition with one or more compounds of Formula III:

wherein,
R30 is selected from the group consisting of hydrogen, alkyl, aralkyl, cycloalkyl, alkenyl, alkynyl, acyl,
aminocarbonyl, heterocyclyl and aryl;
R31, R33, and R34 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl,
halogen, nitro, cyano, amino, aminosulfonyl, sulfonylamino, sulfanyl, aryl, heterocyclyi,
hydroxy, alkoxy, carboxy, alkoxycarbonyl, amido, alkenyl, and alkynyl, with the proviso that
said alkenyl and alkynyl are not substituted with an aryl or heteroaryl group;
or R33 and R34 together with the carbon atoms attached thereto join to form a cycloalkyl, aryl, or
heterocyclyl ring;
R32 is selected from the group consisting of hydroxy, alkoxy, -O-alkenyl, -O-acyl, -O-glucoside; -O-
phosphoryl, -O-C(O)-AA, wherein AA is amino acid, or a di-, tri- or tetra-peptide;
R35 and R36 are
independently selected from the group consisting of hydrogen, alkyl, hydroxy,
cycloalkyl, -OC(O)NR36R30,-NR3dOR3a and -NR3d-NR3bR3c; or
together with the carbon atom to which they are attached form C=O, C=NOR3a, C=N-
NR3bR3c optionally substituted (C3-C4)cycloalkyl ring;
R37 and R38 are
independently selected from the group consisting of hydrogen, hydroxy, alkyl,
cycloalkyl, -OC(O)NR3bR3c, -NR3dOR3a and -NR3d-NR3bR3c; or
together with the carbon atom to which they are attached form C=O, C=NOR3d, C=N-
NR3bR30, optionally substituted (C3-C4)cycloalkyl ring;
R39 and R310 are
independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl; or
together with the carbon atom to which they are attached form an optionally substituted
(C3-C4)cycloalkyl ring;
R3a is selected from the group consisting of hydrogen, alkyl, cycloalkyi, alkenyl, acyl, heterocyclyl,
and aryl;
R3b and R30 are
19

WO 2006/065686 PCT/US2005/044768
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, acyl,
aminocarbonyl, heterocyclyl and aryl; or
together with the nitrogen atom to which they are attached form an optionally substituted,
saturated or unsaturated 3-8 membered ring optionally incorporating 1 to 3 N, O, or S atoms;
R is hydrogen or alkyl, and
m is 0 or 1;
with the following provisos:
a. at least one of -CR35R36, -CR37R38, and -CR39R310 is a (C3-C4)cycloalkyl ring;
b. no more than one of R31, R33 and R34 is hydrogen;
c. if m is 0, then -CR35R36 is not C=O; and
d. if m is 1 and -CR39R310 is a (C3-C4)cycloalkyl ring, then R30 is not hydrogen or
aminocarbonyl;
or single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
[0047] In another aspect the invention relates to treating a subject with a lipoxygenase
mediated condition with one or more compounds of Formula IA, IB, HA and/or IIIA.
[0048] In some embodiments, the invention relates to a method of treating a subject with a
lipoxygenase mediated disorder such as but not limited to apoptosis in cancer cells including
prostatic cancer, gastric cancer, breast cancer, pancreatic cancer, colorectal or esophageal cancer
and airways carcinoma; diseases involving hypoxia or anoxia including atherosclerosis, myocardial
infarction, cardiovascular disease, heart failure (including chronic and congestive heart failure),
cerebral ischemia, retinal ischemia, myocardial ischemia, post surgical cognitive dysfunction and
other ischemias; diseases involving inflammation, including diabetes, arterial inflammation,
inflammatory bowel disease, Crohn's disease, renal disease, pre-menstrual syndrome, asthma,
allergic rhinitis, gout, cardiopulmonary inflammation, rheumatoid arthritis, osteoarthntis, muscle
fatigue and inflammatory disorders of the skin including acne, dermatitis and psoriasis; disorders of
the airways including asthma, chronic bronchitis, human airway carcinomas, mucus hypersecretion,
chronic obstructive pulmonary disease (COPD) pulmonary fibrosis caused by chemotherapy or other
drugs, idiopathic pulmonary fibrosis, cystic fibrosis and adult respiratory distress syndrome; diseases
involving central nervous system (CNS) disorders including psychiatric disorders including anxiety
and depression; neurodegeneration and neuroinfiammation including Alzheimer's, dementia and
Parkinson's disease; peripheral neuropathy including spinal chord injury, head injury and surgical
trauma, and allograft tissue and organ transplant rejection; diseases involving the autoimmune
system including psoriasis, eczema, rheumatoid arthritis, and diabetes; and disorders involving bone
loss or bone formation. In an illustrative example, the invention relates to a method of treating a
subject with a lipoxygenase mediated disorder, such as but not limited to diabetes, arthritis,
rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis, Crohn's
disease, and/or atherosclerosis.
[0049] In some of the embodiments, the compositions, methods of treatment and uses in
the manufacture of pharmaceutical compositions therefor, relate to compounds selected from:
5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,i'-cyclobutan]-6-ol;

WO 2006/065686 PCT/US2005/044768
5-chloro-7,8-dimethyl-3,4-dihydrospiro[chrorr.ene-2,1'-cyclobutan]-6-ol;
5',7',8'-trimethyl-2',3'-dihydrospiro[cyclobutane, 1,4'-thiochromen]-6'-ol;
7-chloro-5,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
5,7,8-trimethyl-3,4-d(hydrospiro[chromene-2,1'-cyclopropan]-6-ol,
5',7',8'-trimethyl-2',3'-dihydrospiro[cyclobutane-1,4'-thiochromen}-6'-ol 1 '-oxide;
5',7',8'-trimethyl-2',3'-dihydrospiro[cyclobutane-1,4'-thiochromen]-6'-ol V,1 '-dioxide,
5-chloro-8-methyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol,
5,8-dimethyI-7-(3-methylbutyl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
5',7',8'-trimethyl-2',3'-dihydrospiro[cyclobutane-1,4'-thiochromen]-6'-yl (dimethylamino)acetate;
2',2l,5',7',8'-pentamethyl-2',3'-dihydrospiro[cyclobutane-1,4'-thiochromen]-6'-ol;
5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
8-chloro-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
8-chloro-5-methyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
8-isopropyl-5-methyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
6-hydroxy-7,8-dimethylspiro[chroman-2,1'-cyclopropan]-4(3/-/)one;
7,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclopropane]-4,6-diol;
7-chloro-5,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-yl (dimethylamino)acetate;
5-isopropyl-8-methyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutan)-6-ol,
7,8-dimethylspiro(chroman-3,1'-cyclopropan]-6-ol;
6-hydroxy-7,8-dimethylspiro[chroman-3,1'-cydopropan]-4-one O-methyl oxirne;
6'-hydroxy-5',7',8'-trimethylspiro[cyclobutane-1,2'-thiochromen]-4'(3'H)-one;
5',7',8'-trimethyl-3',4'-dihydrospiro[cyclobutane-1,2'-thiochromen]-6'-ol;
6-hydroxy-5,7,8-trimethylspiro[chroman-3,1'-cyclobutan]-4-one;
5,7,8-trimethylspiro[chroman-3,1'-cyclobutane]-4,6-diol;
6'-hydroxy-5',7',8'-trimethylspiro[cyclobutane-1,2'-thiochroman]-4'(3'H)-one O-methyloxime;
4' (methoxyamino)-5',7',8'-trimethyl-3',4'-dihydrospiro[cyclobutane-1,2'-thiochromen]-6'-ol;
7-chloro-5,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-yl nicotinate;
5,7,8-tnmethylspiro[chroman-3,1'-cyclobutan]-6-ol;
4-methoxy-5,7,8-tnmethylspiro[chroman-3,1'-^yclobutan]-6-ol;
5',7',8'-trimethyl-3',4'-dihydrospiro[cyclobutane-1,2'-thiochromen]-6'-yl (dimethylamino)acetate;
5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-yl (dimethylamino)acetate;
6-hydroxy-5,7,8-trimethylthiochroman-4-yl phenylcarbamate;
5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-yl-2-(4-methylpiperazin-1-
yl)acetate;
7,8-dimethyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutan]-6-yl phenylcarbamate;
5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-yl
phenyl(phenylcarbamoyl)carbamate;
4-ethoxy-5,7,8-trimethylspiro[chroman-3,1'-cyclobutan]-6-ol;
2-(7-chloro-5,8-dimethylspiro[chroman-2,r-cyclobutane]-6-yloxy)-/V,N-d(methylethanamine;
4-(methoxyamino)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-yl acetate;
21

WO 2006/065686 PCT/US2005/044768
4-(methoxyamino)-5,7l8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
2-(dimethylamino)ethyl 5,7,8-trimethylspiro[chroman-2,1'-cyciobutane]-6-yl carbonate;
5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-yl 1/-/-imidazole-1-carboxylate;
2-(7-chloro-5,8-dimethylspirotchroman-2,1'-cyclobutane]-6-yloxy)-A/,A/-dimethylpropan-1-amine;
4-amino5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutanj-6-yl acetate;
4-(hexylamino)-5,7,8-trimethylspiro[chroman-3,1'-cyclobutan]-6-ol;
1-(dimethylamino)-3-[(5,7,8-trimethyl-3,4-dihydro-2/-/-spiro-[chromen-2,1'-cyclobutan]-6-
yl)oxy]propan-2-ol;
1-{pyrrolindinyl)-3-[(5,7,8-trimethyl-3,4-dihydro-2/-/-spiro-[chromen-2,1'-cyclobutan]-6-
yl)oxy]propan-2-ol;
5,7,8-trimethyl-4-pyrrolidin~1-yl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4-{aminomethyl)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutane]-4,6-diol;
5l7,8-trimethyl-4-morpholin-4-yl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4-{1H-imidazol-1-yl)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutane]-3,6-diol;
4-(cyclopropylamino)-5,7,8-trimethylspiro[chroman-3,1'-cyclobutan]-6-ol;
5,7,8-trimethylspiro[chroman-3,1'-cyclobutane]-6-yl 2-(dimethylamino)acetate;
3-methoxy-5,7,8-trimethyl-3,4-dihydrospiro[chiromene-2,1'-cyclobutan]-6-ol;
4-(aminomethyl)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
N-[(6-hydroxy-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,r-cyclobutan]-4-yl)methyl]acetamide;
4-[(ethylamino)methyl]-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
3-(hydroxymethyl)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
2-{[(5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-y])oxy]methyl}pyridine;
2-{[(5,7,8-trimethyl-3,4-dihydrospiro[chronnene-2,1'-cyclobutan]-6-yl)oxy]methyl}quinoline;
6-hydroxy-3l5,7,8-tetramethylspiro[chroman-2,1'-cyclobutan]-4(3H)-one;
3-(morpholinomethyl)-5,7,8-trimethyl-4-oxo-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-yl
acetate;
3-(morpholinomethyl)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutane]-4,6-diol;
4-[(diethylamino)methyl]-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4-methoxy-3,5,7,8-tetramethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
3,5,7,8-tetramethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutane]-4,6-diol;
4-methoxy-3,5,7,8-tetramethyl-3,4-dihydrospiro[chrornene-2,1 '-cyclobutan]-6-ol;
6-hydroxy-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutane]-4-carbonitrile;
methyl {[(6-hydroxy-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutan]-3-
yl)methyl]thio}acetate;
4-ethoxy-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
7,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
7,8-dimethylspiro[chroman-3,1 '-cyclobutan]-6-ol;
4-methoxy-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4-ethoxy-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;

WO 2006/065686 PCT/US2005/044768
4-(methoxyamino)-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4-isopropoxy-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
5,7-dimethylspiro[chroman-3,1 '-cyclobutanJ-6-ol;
5 ,7-dimethyl-4H-spiro[chromene-3,1'-cyclobutane]-4,6-diol;
5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutane]-4,6-diol,
5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutane]-4,6-diol;
7,8-dimethyl-4H-spiro[chromene-3,1'-cyclobutane]-4,6-diol;
4-(methoxyamino)-7,8-dimethyl-4/-/-spiro[chromene-3,1'-cyclobutan]-6-ol;
4-(ethoxyamino)-7,8-dimethyl-4/-/-spiro[chroman-3,1'-cyclobutan]-6-ol;
8-(hydroxymethyl)-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
8-(methoxymethyl)-5,7-dimethyl-3,4-dihydrospiro[chromene-2I1'-cyclobutan]-6-ol;
4-(cyclopentyloxy)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutane]- 6-diol;
4-(ethoxyamino)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4-(isopropylthio)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
7,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutane]-4,6-diol;
7,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-^yclobutan]-6-yl (dimethylamino)acetate;
4-{methoxyamino)-7,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4'-{ethoxyamino)-5',7',8'-tnmethyl-3',4'-dihydrospiro[cyclobutane-1,2'-thiochromen]-6'-ol;
4'-{ethoxyamino)-5',7'-dimethyl-3',4'-dihydrospiro[cyclobutane-1,2'-thiochromen]-6'-ol;
4-(ethoxyamino)-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutan]-6-ol;
5-[1-(ethoxyamino)ethyl]-7,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4-(methoxyamino)-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutan]-6-yl acetate;
4'-(methoxyamino)-5',7'-dimethyl-3',4'-dihydrospiro[cyclobutane-1,2'-thiochromen]-6'-ol;
4-(ethoxyamino)-7,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4-[methoxy(methyl)amino]-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
6-hydroxy-5,7,8-trimethylspiro[chromene-2,1 '-cyclobutan]-4(3H) -one oxime;
4-(hydroxyamino)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
8-[(methoxyamino)methyl]-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
5,7-dimethyi-8-vinyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4-[hydroxy(methyl)amino]-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-oi;
6-hydroxy-5,7-dimethylspiro[chromene-2,1 '-cyclobutan]-4(3/-/)-one oxime;
4-(hydroxyamino)-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4-[hydroxy(methyl)amino]-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
8-[(ethoxyamino)methyl]-5,7-dimethyl-3,4-dihydrospiro[chromene-2,r-cyclobutan]-6-ol;
4-[methoxy(methyl)amino]-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4-[ethyl(methoxy)amino]-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
5,7-dimethy!-4-methoxyamino-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-yl (dimethylamino)-
acetate;
ethyl 4-(methoxyamino)-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-yl carbonate;
6-hydroxy-5,7-dimethylspiro[chromene-2,1 '-cyclobutan]-4(3/-/)-one O-methyloxime
23

WO 2006/065686 PCT/US2005/044768
(4E)-6-hydroxy-5)7-dimethylspiro[chromene-2,1'-cyclobutan]-4(3H)-one O-ethyloxime;
4Z)-6-hydroxy-5,7-dimethylspiro[chromene-2,1 '-cyclobutan]-4(3H)-one O-ethyloxime;
5-ethyl-4-(methoxyamino)-7,8-dimethyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutan]-6-ol;
4-(ethoxyamino)-5-ethyl-7,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
5-ethyl-6-hydroxy-7,8-dimethylspiro[chromene-2,1'-cyclobutan]-4(3H)-one O-methyloxime;
5-ethyl-6-hydroxy-7,8-dimethylspiro[chromene-2,1 '-cyclobutan]-4(3/-/)-one O-ethyloxime;
6'-hydroxy-5',7',8'-trimethylspiro[cyclobutane-1,2'-thiochromen]-4'(3'H)-one O-methyloxime;
6'-hydroxy-5',7',8'-trimethylspiro[cyclobutane-1,2'-thiochromen]-4'(3'H)-one O-ethyloxime;
6'-hydroxy-5',7'-dimethylspiro[cyclobutane-1,2'-thiochromen]-4'(3'H)-one O-methyloxime;
3-[(methoxyamino)methyl]-5,7-dimethylspiro[chromene-2,1'-cyclobutan]-6-yl pivalate;
methyl 3-(6-hydroxy-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutan]-8-yl)-4,5-
dihydroisoxazole-5-carboxylate;
6'-hydroxy-5',7'-dimethylspiro[cyclobutane-1,2'-thiochromen]-4'(3'H)-one O-ethyloxime;
5,7-diethyl-6-hydroxyspiro[chromene-2,1 '-cyc;obutan]-4(3/-/)-one 0-methyloxime;
5,7-diethyl-6-hydroxyspiro[chromene-2,1'-cyclobutan]-4(3/-/)-one O-ethyloxime;
5,7-diethyl-6-hydroxyspiro[chromene-2,1'-cyclobutan]-4(3H)-one oxime;
(4S)-4-(methoxyamino)-5,7-dimethyl-3,4-dihydrospiro[chrornene-2,1'-cyclobutan]-6-ol;
(4R)-4-(methoxyamino)-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1-cyclobutan]-6-ol;
5,7-dimethyl-8-(5-butyl-isoxazol-3-yl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4-(ethoxyamino)-5,7-diethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4-(methoxyamino)-5,7-diethyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutan]-6-ol;
N-(6-hydroxy-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)methanesulfonamide;
7-tert-butyl-5-methyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutan]-6-ol;
5,7-dimethyl-8-(1,3-oxazol-5-yl)-3,4-dihydrospiro[chromene-2,1 -cyclobutan]-6-ol;
N-(6-hydroxy-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)benzenesulfonamide;
5,7-diisopropyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutan]-6-ol;
6-hydroxy-5,7-diisopropyl-3,4-dihydrospiro[chromene-2,1'-cyclobutane]-8-carbaldehyde;
4-(methoxyamino)-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-yl isobutyrate;
3-[(ethoxyamino)methyl]-5,7-dimethyl-3,4-dihydrospiro-[chromene-2,1'-cyclobutan]-6-ol;
3-[(methoxyamino)methyl]-5,7-dimethyl-3,4-dihydrospiro-[chromene-2,1'-cyclobutan]-6-ol;
7,8-dimethyl-5-(2-quinolin-2-ylethyl)) 3,4-dihydrospiro-[chromene-2,1'-cyclobutan]-6-ol;
5,7-diisopropyl-8-[(methoxyamino)methyl] 3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
5-(3,7-dimethylocta-2,6-dienyl)-7,8-dimethylspiro[chroman-2,1'-cyclobutan]-6-ol;
5,7-diethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ot;
7-isopropyl-4-(methoxyamino)-5-methyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
7-(3,7-dimethylocta-2,6-dienyl)-5,8-dimethylspiro[chroman-2,1'-cyclobutan]-6-ol;
8-(4,5-dimethyI-1/-/-imidazol-2-yl)-5,7-diethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
7-(4,5-dimethyl-1/-/-imidazol-2-yl)-5,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
7-ethyl-4-(metboxyamino)-5-methyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutan]-6-ol;
5-ethyl-4-(methoxyamino)-7-methyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;

WO 2006/065686 PCT/US2005/044768
(Z)-5,7-diethyl-8-(hydroxymethyl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
5,7-diethyl-8-(hydroxymethyl)-3,4-dihydrospiro[chrornene-2,1'-cyclobutan]-6-oi;
7-isopropyl-5-methyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
7-(1 -benzofuran-2-yl)-2,2,5,8-tetramethylchroman-6-ol;
7-(3,7-dimethyloctyl)-5,8-dimethylspiro[chroman-2,1'-cyclobutan]-6-ol,
8-(hydroxymethyi)-7-isopropyl-5-methylspiro[chroman-2,1'-cyclobutan]-6-ol;
5,7-dimethyl-3-{oxa2ol-5-yl)spiro[chroman-2,1'-cyclobutan]-6-ol;
7-isopropyl-5-methylspiro[chroman-2,1'-cyclobutane]-4r6-diol;
7-isopropyl-4-methoxy-5-methylspiro[chroman-2,1'-cyclobutan]-6-ol;
7-(5,6-dimethyi-1 H-benzo[d]imidazol-2~yl)-5,8-dimethylspiro[chroman-2,1 '-cyclobutan]-6-ol;
7-fert-butyl-5-(morpholinomethyl)spiro[chroman-2,1'-cyclobutan]-6-ol;
8-(hydroxymethyl)-5,7-diisopropylspiro[chroman-2,1'-cyclobutan]-6-ol,
8-((hydroxyarnino)methyl)-5,7-diisopropylspiro[chroman-2,1 '-cyclobutan]-6-ol;
5,8-dimethyl-7-(2-(quinolin-2-yl)ethyl)spiro[chroman-2,1'-cyclobutanj-6-ol;
A/-((6-hydroxy-5,7-diisopropylspiro[chroman-2,1'-cyclobutane]-8-yl)methyl)-A/-methylacetamide;
5,7-dnsopropyl-8-(methoxymethyl)spiro[chroman-2,1 '-cyclobutan]-6-ol;
5,7-diethyl-3-(hydroxymethyl)spiro[chroman-2,1'-cyclobutan]-6-ol;
8-(acetamidomethyl)-5,7-diisopropylspiro[chroman-2,1 '-cyclobutan]-6-ol;
methyl 2-((5,7-diethyl-6-hydroxyspiro[chroman-2,1 '-cyclobutane]-3-yl)methylthio)acetate;
(5,7-diethyl-6-hydroxyspiro[chroman-2,1 '-cyclobutane]-3-yl)methyl carbamate;
7-tert-butyl-5-methylspiro[chroman-2,1 '-cyclobutane]-4,6-diol;
7-tert-butyl-4-hydroxy-5-methylspiro[chroman-2,1 '-cyclobutane]-6-yl acetate;
5,7-diisopropylspiro[chroman-2,1'-cyclobutane]-6-yl 2-amino-2-oxoacetate;
2-hydroxy-2-(6-hydroxy-5,7-diisopropylspiro[chroman-2,1'-cyc!obutane]-8-yl)acetonitrile;
7-isopropyl-5-methylspiro[chroman-3,1'-cyclobutane]-4,6-diol;
5-ethyl-7-isopropylspiro[chroman-2,1 '-cyclobutane]-4,6-diol;
(S)-5,7-diethylspiro[chroman-2,1'-cyclobutane]-4,6-diol;
(R)-5,7-diethylspiro[chroman-2,1'-cyclobutane]-4,6-diol;
(S)-7-isopropyl-5-methylspiro[chroman-2,1'-cyclobutane]-4,6-diol;
(R)-7-isopropyl-5-methylspiro[chroman-2,1'-cyclobutane]-4,6-diol;
5,7-diethylspiro[chroman-3,1 '-cyclobutane]-4,6-diol;
and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
[0050] In some particular embodiments, the compositions, methods of treatment and uses
in the manufacture of pharmaceutical compositions therefor, relate to compounds of Formula I, IA,
and IB selected from:
■ 5,7,8-trimethylspiro[chrornan-3,1'-cyclobutane]-4,6-diol;
■ 5,7-dimethyl-4H-spiro[chromene-3,1 '-cyclobutane]-4,6-diol;
■ 5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutane]-4,6-diol;
■ 5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutane]-4,6-diol;

WO 2006/065686 PCT/US2005/044768
■ 7,8-climethylspiro[chroman-3,1'-cyclobutane]-4,6-diol;
■ 5,7-diethyl-8-(hydroxymethyl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
■ 7-isopropyl-5-methylspiro[chroman-2,1'-cyclobutane]-4,6"diol;
■ 7-tert-butyl-5-methylspiro[chroman-2,1'-cyclobutaneH,6-diol;
■ 7-isopropyl-5-methylspiro[chroman-3,1'-cyclobutane]-4,6-diol; and
? 5-ethyl-7-isopropylspiro[chroman-2,1'-cyclobutane]-4,6-diol;
? (S)-5,7-diethylspiro[chroman-2,1'-cyclobutane]-4,6-diol;
? (R)-5,7-diethylspiro[chroman-2,1'-cyclobutane]-4,6-diol;
■ (S)-7-isopropyl-5-methylspiro[chroman-2,1'-cyclobutane]-4,6-diol;
■ (R)-7-isopropyl-5-methylspiro[chroman-2,1 '-cyclobutane]-4,6-diol;
■ 5,7-diethylspiro[chroman-3,1'-cyclobutane]-<,6-diol;
and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
[0051] In another embodiment, the compositions, methods of treatment and uses in the
manufacture of a pharmaceutical composition relate to compounds selected from the group
consisting of:
4' (methoxyamino)-5',7',8'-trimethyl-3',4'-dihydrospiro[cyclobutane-1,2'-thiochromen]-6'-ol,
4-(methoxyamino)-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol,
4-(methoxyamino)-7,8-dimethyl-4/-/-spiro[chromene-3,1'-cyclobutan]-6-ol;
4-(ethoxyamino)-7,8-dimethyl-4/-/-spiro[chromene-3,1'-cyclobutan]-6-ol;
4-(ethoxyamino)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4'-(ethoxyamino)-5'l7',8'-trimethyl-3',4'-dihydrospiro[cyclobutane-1,2'-thiochromen]-6'-ol;
4'-(ethoxyamino)-5',7'-dimethyl-3',4'-dihydrospiro[cyclobutane-1,2'-thiochromen]-6'-ol;
4-(ethoxyamino)-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4'-(methoxyamino)-5',7'-dimethyl-3',4'-dihydrospiro[cyclobutane-1,2'-thiochromen]-6'-ol;
4-[ethyl(methoxy)amino]-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
5-ethyl-4-(methoxyamino)-7,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
4-(ethoxyamino)-5-ethyl-7,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
(4S)-4-(methoxyamino)-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6~ol;
(4R)-4-(methoxyamino)-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutan]-6-ol;
4-(methoxyamino)-5,7-diethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
3-[(methoxyamino)methyl]-5,7-dimethyl-3,4-dihydrospiro-[chromene-2,1'-cyclobutan]-6-ol;
7-isopropyl-4-(methoxyamino)-5-methyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
7-ethyl-4-(methoxyamino)-5-methyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
5-ethyl-4-(methoxyamino)-7-methyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
[0052] In another embodiment, the compositions, methods of treatment and uses in the
manufacture of a pharmaceutical composition relate to compounds selected from the group
consisting of:
26

WO 2006/065686 PCT/US2005/044768
7-isopropyl-5-methyl-3,4-dihydrospiro|chromene-2,1'-cyclobutan]-6-ol;
5,7-diethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
7-tert-butyl-5-methyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol,
5,7-dimethyl-8-vinyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol,
5,7-dimethylspiro[chroman-3,1'-cyclobutan]-6-ol;
7,8-dimethylspiro[chroman-3,1'-cyclobutan]-6-ol;
7,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol;
5,7,8-trimethylspiro[chroman-3,1 '-cyc!obutan]-6-ol;
7,8-dimethylspiro[chroman-311 '-cyclopropan]-6-ol;
8-chloro-5,7-dimethyl-3,4-dihydrospiro[chrorrsne-2,1-cyclobutan]-6-ol,
5,7-dimethyl-3,4-dihydrospirolchromene-2,1'-cyclobutan]-6-ol,
5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,T-cyclopropan]-6-ol;
and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
[0053] In other embodiment, the compositions, methods of treatment and uses in the
manufacture of a pharmaceutical composition relate to compounds of Formula I selected from:
? N-(6-hydroxy-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'cyclobutan]-4-yl)acetamide,
? N-(6-hydroxy-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)acetarnide;
? W-(6-hydroxy-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)butanamide;
? N-(5,7-diethyl-6-hydroxyspiro[chroman-2,1'-cyclobutaneH-yI)acetamide;
and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
[0054] In some of the embodiments, the compositions, methods of treatment and uses in
the manufacture of pharmaceutical compositions therefor, relate to compounds of Formula II and IIA
selected from:
5',7',8'-trimethylspiro[cyclobutane-1,2'-thiochromen]-6'-ol;
3-(hydroxymethyl)-5,7,8-trimethylspiro[chromene-2,1'-cyclobutan]-6-ol;
4-(aminomethyl)-5,7,8-tnmethylspiro[chromene-2,1'-cyclobutan]-6-ol;
N-{(6-hydroxy-5,7,8-trimethylspiro[chromene-2,1 '-cyclobutan]-4-yl)methyl]acetamide;
3-(methoxymethyl)-5,7,8-trimethylspiro[chromene-2,1'-cyclobutan]-6-ol;
3,5,7,8-tetramethylspiro[chromene-2,1'-cyclobutan]-6-ol;
6-hydroxy-5,7,8-trimethylspiro[chromene-2,1'-cyclobutane]-4-carbonitrile;
6-hydroxy-5,7-dimethylspiro[chromene-2,r-cyclobutane]-3-carbaldehyde O-methyloxime;
3-[(methoxyamino)methyl]--5,7-dimethylspiro[chromene-2,1'-cyclobutan]-6-ol;
-(1-methoxyethyl)-5,7,8-trimethylspiro[chromene-2,1'-cyclobutan]-6-ol;
3-(1-hydroxyethyl)-5,7,8-trimethylspiro[chromene-2,1'-cyclobutan]-6-ol;
5,7-dimethylspiro[chromene-2,1'-cyclobutan]-6-ol;
6-hydroxy-5,7-dimethylspiro[chromene-2,1'-cyclobutane]-3-carbaldehyde O-ethyloxime;
3-[(ethoxyamino)methyl]-5,7-dimethylspiro[chromene-2,1'-cyclobutan]-6-ol;
27

WO 2006/065686 PCT/US2005/044768
5,7-dimethyl-3-(1,3-oxa2ol-5-yl)spiro[chromene-2,1'-cyclobutan]-6-ol;
5,7-dimethyl-3-(-(4,5-dimethyl-1H-imidazol-2-yl)spiro[chromene-2,1'-cyclobutan]-6-ol;
7-isopropyl-5-methylspiro[chromene-2,1 '-cyclobutan]-6-ol;
5,7-diethylspiro[chromene-2,1'-cycIobutan]-6-ol;
5,7-diisopropylspiro[chromene-2,1'-cyclobutan]-6-ol,
and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
[0055] In some of the embodiments, the compositions, methods of treatment and uses in
the manufacture of pharmaceutical compositions therefor, relate to compounds of Formula III and IIIA
selected from:
■ 1'-(4-chlorophenyl)-5',7',8'-trimethyl-2',4'-dihydro-1'H-spiro[cyclobutane-1,3'-quinolin]-6'-ol;
■ 1'-(4-chlorophenyl)-5',7',8'-trimethyl-2',4'-dihydro-1'/-/-spiro[cyclobutane-1,3'-quinoline]-4',6'-diol;
? 1'-(4-chlorophenyl)-6'-hydroxy-5',7',8'-trimethyl-1'H-spiro[cyclobutane-1,3'-quinolin]-4'(2'H)-one;
? 1 '-(4-chlorophenyl)-7',8'-dimethyl-2',4'-dihydro-1 'H-spiro[cyclobutane-1,3'-quinolin]-6'-ol;
? 1'-ethyl-7',8'-dimethyl-2',4'-dihydro-1'H-spiro[cyclobutane-1,3'-quinolin]-6'-ol;
? 1'-(4-chlorophenyl)-6'-hydroxy-7',8'-dimethyl-1'H-spiro[cyclobutane-1,3'-quinolin]-4'(2IH)-one;
? 7',8'-dimethyl-1 '~(pyridin-2-yl)-2',4'-dihydro-1 '/-/-spiro[cyclobutaru;-1,3'-quinolin]-6'-ol;
■ 1 '-{4-hydroxyphenyl)-7',8'-dimethyl-2',4'-dihyJro-1 'W-spiro[cyclobutane-1,3'-quinolin]-6'-ol;
? 1 '-(4-chlorophenyl)-7',8'-dimethyl-2',4'-dihydro-1 'H-spiro[cyclobutane-1,3'-quinoline]-4',6'-diol;
? 1'-(4-fluorophenyl)-7',8'-dimethyl-2',4'-dihydro-1'/-/-spiro[cyclobutane-1,3'-quinolin]-6'-ol;

? 1'-(4-methoxyphenyl)-7',8'-dimethyl-2',4'-dihydro-1'/-/-spiro[cyclobutane-1,3'-quinolin]-6r-ol;
? 6'-hydroxy-7',8'-dimethyl-2',4'-dihydro-1'H-spiro[cyclobutane-1.3'-quinoline]-V-carbaldehyde;
? 4-(6'-methoxy-7',8'-dimethyl-2',4'-dihydro-1'/-/-spiro[cyclobutane-1,3'-quinoline]-1'-yl)phenol;
? 7',8'-dimethyl-1 '-p-tolyl-2',4'-dihydro-1 '/-/-spiro[cyclobutane-1,3'-quinolin]-6'-ol;
? 1'-(3-hydroxyphenyl)-7',8'-dimethyl-2',4'-dihydro-1'/-/-spiro[cyclobutane-1,3'-quinolin]-6'-ol;

? 7',8'-dimethyl-1 '-(4-(methylsulfonyl)phenyl)-2',4'-dihydro-1 '/-/-spiro[cyclobutane-1,3'-quinolin]-6'-
ol;
? methyl 4-(6'-hydroxy-7',8'-dimethyl-2',4'-dihydro-1 'H-spiro[cyclobutane-1,3'-quinoline]-1 '-
yl)benzoate;
? 7',8'-dimethyl-2',4'-dihydro-1'/-/-spiro[cyclopropane-1,3'-quinolin]-6'-ol;
■ 1 ',7\8'-trimethyl-2',4'-dihydro-1 'H-spiro[cyclopropane-1,3'-quinolm]-6'-ol;
? 3-(6'-methoxy-7',8'-dimethyl-2',4'-dihydro-1'H-spiro[cyclobutane-1,3'-quinoline]-1'-yl)benzoic acid;
? 4-(6'-hydroxy-7',8'-dimethyl-2',4'-dihydro-1'/-/-spiro[cyclobutane-1,3'-quinoline]-1'-yl)benzoic acid;
? 7',8'-dimethyl-1 '-(6-(piperazin-1 -yl)pyridin-3-yl)-2',4'-dihydro-1 'H-spiro[cyclobutane-1,3'-quinolin]-
6'-ol;
■ 1'-(4-chlorobenzyl)-5',7'-dimethyl-3',4'-dihydro-1'/-/-spiro[cyclobutano-1,2'-quinolin]-6'-ol;
■ 1'-(4-hydroxyphenyl)-7',8'-dimethyl-3',4'-dihydro-1'/-/-spiro[cyclopropane-1,2'-quinolin]-6'-ol;
■ 1',7',8'-trimethyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinolin]-6'-ol;
■ methyl 2-(6'-hydroxy-7',8'-dimethyl-2',4'-dihydro-1 '/-/-spiro[cyclopropane-1,3'-quinoline]-1 '-
yl)acetate;
28

WO 2006/065686 PCT/US2005/044768
? 3-(6'-hydroxy-7',8'-dimethyl-2',4'-dihydro-1 '/-/-spiro[cyclobutane-1,3'-quinoline]-1 '-yl)benzoic acid;
? 4-((6'-hydroxy-5',7'-dimethyl-3',4'-dihydro-1 'H-spiro[cyclobutane-1,2'-quinoline]-1 '-
yl)methyl)benzoic acid;
? methyl 4-((6'-hydroxy-5',7'-dimethyl-3',4'-dihydro-1 'H-spirofcyclobutane-1,2'-quinoline]-1 '-
yl)methyl)benzoate;
? I'-benzotdJthiazol-2-yl-y.S'-dimethyl-2,4'-dihydro-1'H-spirotcyclobutane-1.3'-quinolin]-6'-ol;
? 7',8'-dimethyl-1 '-(pyridin-3-yl)-2',4'-dihydro-1 'H-spiro[cyclobutane-1,3'-quinolin]-6'-ol;
? 1 '-(6-(dimethylamino)pyridin-3-yl)-7',8'-dimethyl-2',4'-dihydro-1 'H-spiro[cyclobutane-1,3'-quinolin]-
6'-ol;
? 5',7'-dimethyl-1'-(quinolin-2-ylmethyl)-3>,4'-dihydro-1'/-/-spiro[cyclobutane-1,2'-quinolin]-6'-ol;
? 7',8'-dimethyl-1'-(4-phenylthiazol-2-yl)-2',4'-dihydro-1l/-/-spiro[cyclobutane-1,3'-quinolin]-6'-ol;
? 5'-(3,7-dimethylocta-2,6-dienyl)-1 '-(4-methoxyphenyl)-7',8'-dimethyl-2',4'-dihydro-1 'H-
spiro[cycIobutane-1,3'-quinolin]-6'-ol;
? 7',8'-dimethyl-1 '-(4-methylthiazol-2-yl)-2',4'-dihydro-1 'H-spiro[cyclobutane-1,3'-quinolin]-6'-ol;
? 7',8'-dimethyl-1 '-(thiazol-2-yl)-2',4'-dihydro-1 '/-/-spiro[cyclobutane-1,3'-quinolin]-6'-ol;
1'-(1-(2-bromophenyl)-1/-/-tetrazol-5-yl)-7',8'-dimethyl-2',4'-dihydro-1'/-/-spiro[cydobutane-1,3'-
quinolin]-6'-ol,
7',8'-dimethyl-1 '-(4-(trifluoromethyl)oxazol-2-yl)-2',4'-dihydro-1 'H-spiro[cyclobutane-1,3'-quinolin]-
6'-ol;
? 2-(3-(6'-hydroxy-7',8'-dimethyl-2',4'-dihydro-1 'H-spiro[cyclopropane-1,3'-quinoline]-1 '-
yl)propyl)isoindoline-1,3-dione;
? 7',8'-dimethyl-1'-(quinolin-2-ylmethyl)-2',3'-dihydro-1'/-/-spiro[cyclobutane-1,4'-quinolin]-6'-ol;
? 2-tert-butoxy-6-(6'-methoxy~7',8'-dimethyl-2",4'-dihydro-1 '/-/-spiro[cyclobutane-1,3'-quinoline]-1 '-
yl)pyridm-3-ol;
? N-{2-(6'-hydroxy-7',8'-dimethyl-2',4'-dihydro-1'H-spiro[cyclobutane-1,3'-quinoline)-1'-yl)ethyl)-4-
propylbenzenesulfonamide;
? N-(2-(6'-hydroxy-7',8'-dimethyl-2',4'-dihydro-1'H-spiro[cyclobutane-1,3'-quinoline]-1'-yl)ethyl)-4-
methylbenzenesulfonamide,
■ 1'(5-hydroxypyridin-2-yl)-7',8'-dimethyl-2',4'-dihydro-1'H-spirolcyclobutane-1,3l-quinolin]-6'-ol;
■ N-(3-(6'-hydroxy-7',8'-dimethyl-2',4'-dihydro-1lH-spiro[cyclobutane-1,3'-quinoline]-1'-yl)propyl)-4-
propylbenzenesulfonamide;
■ N-(3-(6'-hydroxy-7',8'-dimethyl-2',4'-dihydro-1 'H-spiro[cyclobutane-1,3'-quinoline]-1 '-yl)propyl)-4-
methylbenzenesulfonamide;
? N-(3-(6'-hydroxy-7',8'-dimethyl-2',4'-dihydro-'i'/-/-spiro[cyclobutane-1,3'-quinoline]-1'-
yl)propyl)methanesulfonamide;
? N-(3-(6'-hydroxy-7',8'-dimethyl-2',4'-dihydro-1 'f/-spiro[cyclobutane-1,3'-quinoline]-1 '-
yl )propyl)benzam ide;
■ N-(2-(6'-methoxy-7',8'-dimethyl-2',4'-dihydro-1'H-spiro[cyclobutane-1,3'-quinoline]-1'-yl)ethyl)-4-
propylbenzenesulfonamide;

WO 2006/065686 PCT/US2005/044768
? 7'-terf-butyl-1 '-(5-hydroxypyridin-2-yl)-6'-methoxy-5'-methyl-1 'H-spiro[cyclobutane-1,3'-quinolin]-
4'(2'H)-one;
? 6-(7'-terf-butyl-6'-methoxy-5'-methyl-2',4'-dihydro-1'H-spiro[cyclobutane-1,3'-quinoline]-r-
yl)pyridin-3-ol;
? 7'-tert-butyl-1 '-(5-hydroxypyridin-2-yl)-5'-methyl-2',4'-dihydro-1 'H-spiro[cyclobutane-1,3'-quinolin]-
6"-ol;
and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
[0056] Compounds also contemplated by this invention are those selected from the
following:
? 4-(/V-methoxyacetamido)-5,7-dimethylspiro[chroman-2,1 '-cyclobutane]-6-yl acetate;
? ethyl 6-(ethoxycarbonyloxy)-5,7-dimethylspiro[chroman-2,1 '-cyclobutane]-4-
yl(methoxy)carbamate;
? benzyl 6-(benzyIoxycarbonyloxy)-5,7-dimethylspiro[chrornan-2,1 '-cyclobutane]-4-
yl(methoxy)carbamate;
? A/-(6-hydroxy-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)-/V-
methoxyformamide;
? N(6-hydroxy-5,7-dimethyl-3,4-dihydrospirofchromene-2,1'-cyclobutan]-yl)-N-
methoxyacetamide;
? ethyl (6-hydroxy-5,7-dimethyl-3,4-dihydrospiro[chrornene-2,1 '-cyclobutan]-4-yl)-N-
methoxycarbamate;
? benzyl-methoxy(6-hydroxy-5,7-dimethyl-3,4- dihydrospiro[chromene-2,1 '-cyclobutan]-4-
yl)carbamate;
? (Z)-5,8-dimethyl-7-(2-(quinolin-2-yl)vinyl)spirotchroman-2,1'-cyclobutan]-6-ol;
? 7-tert-butyl-3,4-dihydrospiro[chromene-2,1 '-cyclobutan]-6-ol;
■ 7,8-dimethyl-5-[(Z)-2-quinolin-2-ylvinyl] 3,4-dihydrospiro-[chromene-2,1'-cyclobutan]-6-ol,
■ (E)-5,8-dimethyl-7-(2-(quinolin-2-yl)vinyl)spiro[chroman-2,1 '-cyclobutan]-6-ol;
■ 8-tert-butylspiro[chroman-2,1 '-cyclobutan]-6-ol;
? 3,4-dihydrospiro[chromene-2,1 '-cyclobutan]-6-ol;
? spiro[chroman-3,1 '-cyclobutan]-6-ol;

? spiro[chroman-3,1'-cyclobutan]-8-ol;
? 7-methylspiro[chroman-3,1 '-cyclobutan]-8-ol;
■ 7',8'-dimethyl-4'H-spiro[cyclobutane-1,3'-quirulin]-6'-ol;
? 7'-tert-butyl-6'-hydroxy-1 '-(5-hydroxypyridin-2-yl)-5'-methyl-1 'H-spiro[cyclobutane-1,3'-quinolin]-
4'(2'H)-one;
? 6-(7'-tert-butyl-6l-methoxy-5'-methyl-2',4I-dihydro-1lH-spiro[cyclobutane-1,3'-quinoline]-1'-
yl)pyridin-3-ol;
? 7'-terf-butyl-1l-(5-hydroxypyridin-2-yl)-5'-methyl-2',4l-dihydro-1'H-spiro[cyclobutane-1,3l-quinolin]-
6'-ol;
and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

WO 2006/065686 PCT/US2005/044768
[0057] Another aspect of this invention is the processes for preparing compounds of the
invention and is set forth in "Detailed Description of the Invention."
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0058] As used in the present specification, the following words and phrases are generally
intended to have the meanings as set forth below, except to the extent that the context in which they
are used indicates otherwise.
[0059] The term "optional" or "optionally" means that the subsequently described event or
circumstance may or may not occur, and that the description includes instances where said event or
circumstance occurs and instances in which it does not.
[0060] It will be understood by those skilled in the art with respect to any group containing
one or more substituents that such groups are not intended to introduce any substitution or
substitution patterns that are sterically impractical and/or physically non-feasible.
[0061] The term "acyl" refers to the groups -C(O)-H, -C(O)-(alkyl), -C(O)-(cycloalkyl), -C(O)-
(alkenyl), -C(O)-(cycloalkenyl), -C(O)-(aryi), and -C(0)-(heterocyclyl).
[0062] The term "acyloxy" refers to the moiety -O-acyl, including, for
example, -O-C(O)-alkyl.
[0063] The term "alkenyl" refers to a monoradicai branched or unbranched, unsaturated or
polyunsaturated hydrocarbon chain, having from about 2 to 20 carbon atoms, for example 2 to 10
carbon atoms. This term is exemplified by groups such as ethenyl, but-2-enyl, 3-methyl-but-2-enyl
(also referred to as "prenyl", octa-2,6-dienyl, 3,7-dimethyl-octa-2,6-dienyl (also referred to as
"geranyl"), and the like. The term also includes substituted alkenyl groups, and refers to an alkenyl
group in which 1 or more, for example, 1 to 3 hydrogen atoms is replaced by a substituent
independently selected from the group: =0, =S, acyl, acyloxy, alkoxy, amino (wherein the amino
group may be a cyclic amine), aryl, heterocyclyl, carboxyl, carbonyl, amido, cyano, cycloalkyl,
cycloalkenyl, halogen, hydroxyl, nitro, sulfamoyl (-SO2NH2), sulfanyl, sulfinyl (-S(O)H), sulfonyl (-
SO2H), and sulfonic acid (-SO2OH). One of the optional substituents for alkenyl may be heterocyclyl,
exemplified by 2-quinolyl-2-vinyl.
[0064] The term "alkenylene" refers to a diradical derived from the above defined
monoradicai, alkenyl.
[0065] The term "alkoxy" refers to the groups: -O-alkyl, -O-alkenyl, -O-cycloalkyl, -O-
cycloalkenyl, and -O-alkynyl. Alkoxy groups that are -O-alkyl include, by way of example, methoxy,
ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,
1,2-dimethylbutoxy, and the like. The term "alkoxy" also includes substituted alkoxy groups and
refers to the groups -O-(substituted alkyl), -O-(substituted alkenyl), -©-(substituted
cycloalkyl), -©-(substituted cycloalkenyl), -O-(substituted alkynyl) and -O-(optionally substituted
alkylene)-alkoxy.
3 I

WO 2006/065686 PCT/US2005/044768
[0066] The term "alkyl" refers to a monoradical branched or unbranched saturated
hydrocarbon chain having from about 1 to 20 carbon atoms. The term "alkyl" also means a
combination of linear or branched and cyclic saturated hydrocarbon radical consisting solely of
carbon and hydrogen atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-
propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl, and the like. The term " alkyl" also includes
substituted alkyl and refers to an alkyl group in which 1 or more, such as 1 to 5, hydrogen atoms is
replaced by a substituent independently selected from the group: -O, =S, acyl, acyloxy, alkoxy,
alkoxyamino, hydroxyamino, amino (wherein the amino group may be a cyclic amine), aryl,
heterocyclyl, azido, carboxyi, alkoxycarbonyl, amido, cyano, cycloalkyl, cycloalkenyl, halogen,
hydroxyl, nitro, sulfonylamino, aminosulfonyl, sui'anyl, sulfinyl, sulfonyl, and sulfonic acid. One of the
optional substituents for alkyl may be hydroxy or amino, exemplified by hydroxyalkyl groups, such as
2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, and the like; dihydroxyalkyl groups
(glycols), such as 2,3-dihydroxypropyl, 3,4-dihydroxybutyl, 2,4-dihydroxybutyl, and those compounds
known as polyethylene glycols, polypropylene glycols and polybutylene glycols, and the like; or
aminoalkyl groups exemplified by groups such as aminomethyl, dimethylaminomethyl,
diethylaminomethyl, ethylaminomethyl, piperidinylmethyl, morpholinylmethyl, and the like. Another
substituent for alkyl may be halogen, such as trifluoromethyl. Another substituent may be
hydroxyamino or alkoxyamino, exemplified by groups such as hydroxyaminomethyl,
methoxyaminomethyl or ethoxyaminomethyl. Another substituent may be sulfanyl, exemplified by
groups such as methyl (2-methylthioacetate). Another substituent may be aryl or heterocyclyl
exemplified by methylbenzoate, propylisoindoline-1,3-dione, quinoline-rnethyl or 2-c)uinolyl-2-ethyl.
Another substituent may be amido, aminosulfonyl or sulfonylamino, exemplified by 4-
propylbenzensulfonamide-2-ethyl; 4-methylbenzene-sulfonamide-2-ethyl, 4-
propylbenzensulfonamide-3-propyl; 4-methylbenzenesulfonamide-3-propyl, or methyl-W-
methylacetamide. Another substituent may be aminocarbonyloxy (-OC(O)amino), such
as -OC(O)NH2 or -OC(O)-substituted amino.
[0067] The term "alkylene" refers to a diradical alkyl group, whereby alkyl is as defined
above.
[0068] The term "alkynyl" refers to a monoradical branched or unbranched, unsaturated or
polyunsaturated hydrocarbon chain, having from about 2 to 20 carbon atoms, for example 2 to 10
carbon atoms and comprising at least one triple bond, and preferably 1 to 3. The term also includes
substituted alkynyl groups, and refers to an alkynyl group in which 1 or more hydrogen atoms is
replaced by a substituent independently selected from the group: acyl, acyloxy, alkoxy, amino
(wherein the amino group may be a cyclic amine), aryl, heterocyclyl, carboxyi, carbonyl, amido,
cyano, cycloalkyl, cycloalkenyl, halogen, hydroxyl, nitro, sulfamoyl, sulfanyl, sulfinyl, sulfonyl, and
sulfonic acid.
[0069] The term "amido" refers to the moieties -C(O)-NR10DR101 and -NR100C(O)R101,
wherein R100 and R101 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl, provided
that R100 and R101 are not aryl or heteroaryl.
32

WO 2006/065686 PCT/US2005/044768
[0070] The term "ammo" refers to the group -NH2 as well as to the substituted amines such
as -NHRX or -NRXRX where each Rx is independently selected from the group: alky), cycloalkyl,
alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, acyl, optionally substituted alkoxy, carboxy and
alkoxycarbonyl, and where -NRXR* may also be a cyclic saturated or unsaturated amine, optionally
incorporating one or more, for example 1 to 3, additional atoms chosen form N, O or S, and
optionally substituted with a substituent selected from the group consisting of =O, =S, alkyl, hydroxy,
acyloxy, halo, cyano, nitro, sulfanyl, alkoxy, and phenyl. This term is exemplified by such groups as
amino, cyclopropylamino, dimethylamino, diethylamino, hexyiamino. The term "cyclic amine" or
"cyclic ammo" is exemplified by the group morpholinyl. The term "alkoxyamino" refers to
embodiments wherein at least one of Rx is alkoxy. The term "hydroxyamino" refers to embodiments
wherein at least one of Rx is hydroxy
[0071] "Amino acid" refers to any of the naturally occurring amino acids, as well as synthetic
analogs (e.g., D-stereoisomers of the naturally occurring amino acids, such as D-threonine) and
derivatives thereof. a-Amino acids comprise a carbon atom to which is bonded an amino group, a
carboxyl group, a hydrogen atom, and a distinctive group referred to as a "side chain". The side
chains of naturally occurring amino acids are well known in the art and include, for example,
hydrogen (e.g., as in glycine), alkyl (e.g., as in alanine, valine, leucine, isoleucine, proline),
substituted alkyl (e.g., as in threonine, senne, methionine, cysteine, aspartic acid, asparagine,
glutamic acid, glutamine, arginine, and lysine), arylalkyl or aralkyl (e.g., as in phenylalanine and
tryptophan), substituted arylalkyl (e.g., as in tyrosine), and heteroarylalkyl (e.g., as in histidine). The
term "naturally occurring amino acids" refers to these amino acids.
[0072] Unnatural amino acids are also known in the art, as set forth in, for example,
Williams (ed.), Synthesis of Optically Active a-Amino Acids, Pergamon Press (1989); Evans et al., J.
Amer. Chem. Soc, 112:4011-4030 (1990); Pu et al., J. Org Chem., 56:1280-1283 (1991); Williams et
al., J. Amer. Chem. Soc, 113:9276-9286 (1991); and all references cited therein.
[0073] The term "peptide" refers to any of various natural or synthetic compounds
containing two or more amino acids linked by the carboxyl group of one amino acid to the amino
group of another. A "dipeptide" refers to a peptide that contains 2 amino acids. A "tripeptide" refers
to a peptide that contains 3 amino acids. A "tetrapeptide" refers to a peptide that contains 4 amino
acids.
[0074] The term "aromatic" refers to a cyclic or polycyclic moiety having a conjugated
unsaturated (4n + 2) n electron system (where n is a positive integer), sometimes referred to as a
delocalized n electron system.
[0075] The term "aryl" refers to an aromatic cyclic hydrocarbon group of from 6 to 20 carbon
atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g , naphthyl or
anthryl). Aryls include phenyl, naphthyl and the like. The term "aryl" also includes substituted aryl
rings and refers to an aryl group as defined above, which unless otherwise constrained by the
definition for the aryl substituent, is substituted with one or more, such as 1 to 5, substituents,
independently selected from the group consisting of: hydroxy, acyl, acyloxy, alkenyl, alkoxy, alkyl,
33

WO 2006/065686 PCT/US2005/044768
alkynyl, amino, aryl, aryloxy, azido, carboxyl, alkoxycarbonyl, amido, cyano, cycloalkyl, cycloalkenyl,
halogen, heterocyclyl, heterocyclyloxy, nitro, sulfonylamino, aminosulfonyl, sulfanyl, sulfinyl, sulfonyl,
and sulfonic acid.
[0076] The term "aryloxy" refers to the group -O-aryl.
[0077] The term "aralkyl" refers to the group -alkylene-aryl, wherein alkylene and aryl are
defined herein.
[0078] The term "carbonyl" refers to the di-radical "C=O", which is also illustrated as
"-C(O)-". This moiety is also referred as "keto."
[0079] The term "alkylcarbonyl" refers to the
groups: -C(O) -(alkyl), -C(O) -(cycloalkyl), -C(O) -(alkenyl), and -C(O) -(alkynyl).
[0080] The term "alkoxycarbonyl" refers to the
groups: -C(O)O-(alkyl), -C(O)O-(cycloalkyl), -C(O)O-(alkenyl), and -C(O)O-(alkynyl). These moieties
may also be referred to as esters.
[0081] The term "aminosulfonyl" refers to the group -S(O)2-(amino). The term
"sulfonylamino" refers to the group -(amino) -S(0)2-Ry, wherein Ry is alkyl, cycloalkyl, alkenyl, aryl or
heterocyclyl.
[0082] The term "aminocarbonyl" refers to the group -C(O)-( amino) and the term
"cabonylamino" refers to the group -amino-C(O)-Ry, wherein Ry is alkyl, cycloalkyl, alkenyl, aryl or
heterocyclyl and the term amino is as described herein.
[0083] The term "carboxy" or "carboxyl" refers to the moiety "-C(O)OH," which is also
illustrated as "-COOH " The salts of-COOH are also included.
[0084] The term "cycloalkyl" refers to non-aromatic cyclic hydrocarbon groups having about
3 to 12 carbon atoms having a single ring or multiple condensed or bridged rings. Such cycloalkyl
groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, and the like, or multiple rhg structures such as adamantyl, and the like. The
term "cycloalkyl" additionally encompasses spiro systems wherein the cycloalkyl ring has a carbon
ring atom in common with another ring. The term "cycloalkyl" also includes substituted cycloalkyl
rings and refers to a cycloalkyl group substituted with one or more, such as 1 to 5, substituents,
independently selected from the group consisting of: =O, =S, acyl, acyloxy, alkenyl, alkoxy, alkyl,
alkynyl, amino, aryl, aryloxy, azido, carboxyl, alkoxycarbonyl, amido, cyano, cycloalkyl, cycloalkenyl,
halogen, heterocyclyl, heterocyclyloxy, hydroxyl, nitro, sulfonylamino, aminosulfonyl, sulfanyl, sulfinyl,
sulfonyl, and sulfonic acid. A cycloalkyl ring substituted with an alkyl group is also referred as
"alkyicycloalkyl."
[0085] The term "cycloalkenyl" refers to cyclic alkenyl groups of from 3 to 10 carbon atoms
having single or multiple cyclic rings. This also includes substituted cycloalkenyl which includes
substituents as those listed with cycloalkyl.
[0086] The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
[0087] The term "heteroaryl" refers to an aromatic carbocyclic radical having one or more,
such as 1 to 3, rings incorporating one or more, such as 1 to 4, heteroatoms within the ring (chosen
from nitrogen, oxygen, and/or sulfur). This term excludes saturated carbocyclic radical having one or

WO 2006/065686 PCT/US2005/044768
more rings incorporating one or more heteroatoms within the ring (chosen from nitrogen, oxygen,
and/or sulfur).
[0088] The terms "heterocycle," "heterocyclic," "heterocyclo," and "heterocyclyl" refer to a
monovalent, saturated, partially unsaturated or fully unsaturated (aromatic) carbocyclic radical having
one or more, such as 1 to 3, rings incorporating one or more, such as 1 to 4, heteroatoms within the
ring (chosen from nitrogen, oxygen, and/or sulfur). Heterocycles include morpholine, piperidine,
piperazine, thiazole, thiazolidine, isothiazole, oxazole, isoxazole, pyrazole, pyrazolidine, pyrazoline,
imidazole, imidazolidine, benzothiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole,
pyrrolidine, quinoline, quinazoline, purine, carbazole, benzimidazole, thiophene, benzothiophene,
pyran, tetrahydropyran, benzopyran, furan, tetrahydrofuran, indole, indoline, indazole, xanthene,
thioxanthene, acridine, quinuclidine, and the like. The terms "heterocycle," "heterocyclic,"
"heterocyclo," and "heterocyclyl" also include substituted rings and refer to a heterocycle group as
defined above, which unless otherwise constrained by the definition for the heterocycle, is substituted
with one or more, such as 1 to 5, substituents, independently selected from the group consisting of'
hydroxy, acyl, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryloxy, azido, carboxyl,
alkoxycarbonyl, amido, cyano, cycloalkyl, cycloalkenyl, halogen, heterocyclyl, heterocyclo-oxy, nitro,
sulfonylamino, aminosulfonyl, sulfanyl, sulfinyl, sulfonyl, and sulfonic acid. This term is exemplified
by 4,5-dihydroisoxazole-5-methylcarboxylate, 5-butyhsoxazol, pyrrolidmyl, morpholinyl, imidazolyl, 5-
hydroxypyridin-2-yl, dimethylaminopyridin-3-yl, isoindolinedione, trifluoromethyloxazolyl, 2-
bromophenyl-1H-tetrazol-5-yl, methylthiazolyl, phenylthiazolyl, and benzothiazolyl.
[0089] The term "heterocyclyloxy" refers to the moiety —O-heterocyclyl.
[0090] The term "inflammation," "inflammatory conditions," or "inflammation conditions"
includes but is not limited to muscle fatigue, osteoarthritis, rheumatoid arthritis, inflammatory bowel
syndrome or disorder, Crohn's disease, skin inflammation, such as atopic dermatitis, contact
dermatitis, allergic dermatitis, xerosis, eczema, rosacea, seborrhea, psoriasis, atherosclerosis,
thermal and radiation burns, acne, oily skin, wrinkles, excessive cellulite, excessive pore size,
intrinsic skin aging, photo aging, photo damage, harmful UV damage, keratinization abnormalities,
irritation including retinoid induced irritation, hirsutism, alopecia, dyspigmentation, inflammation due
to wounds, scarring or stretch marks, loss of elasticity, skin atrophy, and gingivitis.
[0091] The term "ischemia" refers to deficiency of blood to an organ or tissue due to
functional constriction or actual obstruction of a blood vessel.
[0092] The term "isomers" or "stereoisomers" relates to compounds that have identical
molecular formulae but that differ in the arrangement of their atoms in space. Stereoisomers that are
not mirror images of one another are termed "diastereoisomers" and stereoisomers that are non-
superimposable mirror images are termed "enantiomers," or sometimes optical isomers. A mixture of
equal amounts of stereoisomers of a molecule is termed a "racemate" or a "racemic mixture." A
carbon atom bonded to four non-identical substituents is termed a "chiral center." Certain
compounds of the present invention have one or more chiral centers and therefore may exist as
either individual stereoisomers or as a mixture of stereoisomers. Configurations of stereoisomers
that owe their existence to hindered rotation about double bonds are differentiated by their prefixes
35

WO 2006/065686 PCT/US2005/044768
cis and trans, (or Z and E), which indicate that the groups are on the same side (cis or Z) or on
opposite sides (trans or E) of the double bond in the molecule according to the Cahn-lngold-Prelog
rules. This invention includes all possible stereo'somers as individual stereoisomers, racemates, or
mixtures of stereoisomers.
[0093] A "hpoxygenase-mediated condition" or a "disorder mediated by lipoxygenases"
means any condition, disorder or disease mediated, at least in part, by a lipoxygenase enzyme. This
includes disorders related to or otherwise associated with a lipoxygenase enzyme or the inhibition
thereof, including, by way of example and without limitation, diseases involving apoptosis in cancer
cells such as prostatic cancer, gastric cancer, breast cancer, pancreatic cancer, colorectal or
esophageal cancer and airways carcinoma; diseases involving hypoxia, or anoxia such as
atherosclerosis, myocardial infarction, cardiovascular disease, heart failure (including chronic and
congestive heart failure), cerebral ischemia, retinal ischemia, myocardial ischemia, post surgical
cognitive dysfunction and other ischemias; diseases involving inflammation, including diabetes,
arterial inflammation, inflammatory bowel disease, Crohn's disease, renal disease, pre-menstrual
syndrome, asthma, allergic rhinitis, gout; cardiopulmonary inflammation, rheumatoid arthritis,
osteoarthritis, muscle fatigue and inflammatory disorders of the skin including acne, dermatitis and
psoriasis; disorders of the airways such as asthma, chronic bronchitis, human airway carcinomas,
mucus hypersecretion, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis caused by
chemotherapy or other drugs, idiopathic pulmonary fibrosis, cystic fibrosis, and adult respiratory
distress syndrome; diseases involving central nervous system (CNS) disorders including psychiatric
disorders including anxiety and depression; neurodegeneration and neuroinflammation including
Alzheimer's, dementia and Parkinson's disease; peripheral neuropathy including spinal chord injury,
head injury and surgical trauma, and allograft tissue and organ transplant rejection; diseases
involving the autoimmune system such as psoriasis, eczema, rheumatoid arthritis, and diabetes; and
disorders involving bone loss or bone formation.
[0094] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable
excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal
agents, isotonic and absorption delaying agents and the like. The use of such media and agents for
pharmaceutically active substances is well known in the art. Except insofar as any conventional
media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is
contemplated. Supplementary active ingredient can also be incorporated into the compositions.
[0095] The term "pharmaceutically acceptable salt" refers to salts which retain the biological
effectiveness and properties of the compounds of this invention and which are not biologically or
otherwise undesirable. In some cases, the compounds of this invention are capable of forming acid
and/or base salts by virtue of the presence of phenolic, amino and/or carboxyl groups or groups
similar thereto. Pharmaceutically acceptable base addition salts can be prepared from inorganic and
organic bases. Salts derived from inorganic bases, include by way of example only, sodium,
potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases
include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines,
dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted
36

WO 2006/065686 PCT/US2005/044768
alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,
di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl)
amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine,
tnsubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl)
amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl am me, trisubstituted cycloalkenyl
amines, aryl amines, diaryl amines, triaryl amines, heterocychc amines, diheterocyclic amines,
triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine
are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic,
and the like. Also included are amines where the two or three substituents, together with the amino
nitrogen, form a heterocyclic group.
[0096] Specific examples of suitable amines include, by way of example only,
isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine,
ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine, ethylenediamine, glucosamine, A/-alkylglucamines, theobromine,
purines, piperazine, piperidine, morpholine, A/-ethylpiperidine, and the like.
[0097] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and
organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic
acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid,
maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
[0098] It should be understood that for the purpose of this invention, all references to
acceptable salts also include solvent addition forms (solvates) or polymorphs (crystal forms).
"Solvate" means solvent addition form that contains either stoichiometnc or non-stoichiometric
amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent
molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate
formed is a "hydrate," when the solvent is alcohol, the solvate formed is an "alcoholate."
"Polymorphs" (or "crystal forms") means crystal structures in which a compound can crystallize in
different crystal packing arrangements, all oi which have the same elemental composition. Different
crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points,
density, hardness, crystal shape, optical and electrical properties, stability and solubility.
Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause
one crystal form to dominate.
[0099] The term "prodrug" refers to an inactive form of a compound which must be
metabolized in vivo, e.g., by biological fluids or enzymes, by a subject after administration into an
active form of the parent compound in order to produce the desired pharmacological effect. The
prodrug can be metabolized before absorption, during absorption, after absorption, or at a specific
site. Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve
subject acceptability such as masking or reducing unpleasant characteristics such as a bitter taste,
37

WO 2006/065686 PCT/US2005/044768
odor, or gastrointestinal irritability, alter solubility, provide for prolonged or sustained release or
delivery, improve ease of formulation, or provide site-specific delivery of the compound.
[0100] Prodrugs of a compound of this invention are prepared by modifying one or more
functional group(s) present in the compound in such a way that the modification(s) may be cleaved in
vivo to release the parent compound. Prodrugs include compounds wherein a hydroxyl group in a
compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free
hydroxyl, amino. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate,
and benzoate derivatives), carbamates (e.g., /V,/V-dimethylaminocarbonyl) of hydroxy functional
groups in compounds of the invention, see Bund^-gaard, H. Design of Prodrugs. New York-Oxford:
Elsevier, 1985, pp. 1-92., and the like. Reference to a compound herein includes prodrug forms of
said compound.
[0101] The term "subject" includes, but is not limited to, humans and animals, such as farm
animals (cattle, horses, sheep, goats, and swine) and domestic animals (rabbits, dogs, cats, rats,
mice and guinea pigs. The term "subject" does not denote a particular age or sex.
[0102] The term "sulfanyl" or "thio" refers to the groups: -S-H, -S-(alkyl), -S-(aryl),
or -S-(heterocyclyl). The term is exemplified by groups such as isopropylthio and methyl thioacetate.
[0103] It will also be apparent to those skilled in the art that the compounds of the invention,
including the compounds of Formula II, may be subject to tautomerization and may therefore exist in
various tautomeric forms wherein a proton of one atom of a molecule shifts to another atom and the
chemical bonds between the atoms of the molecules are consequently rearranged. See, e.g., March,
Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley &
Sons, pages 69-74 (1992). As used herein, the term "tautomer" refers to the compounds produced
by the proton shift, and it should be understood that the all tautomeric forms, insofar as they may
exist, are included within the invention.
[0104] The term "therapeutically effective amount" refers to that amount of a compound of
this invention that is sufficient to effect treatment, as defined below, when administered to a subject
in need of such treatment. The therapeutically effective amount will vary depending upon the subject
and disease condition being treated, the weight and age of the subject, the severity of the disease
condition, the particular compound chosen, the dosing regimen to be followed, timing of
administration, the manner of administration and the like, all of which can readily be determined by
one of ordinary skill in the art.
[0105] The term "treatment" or "treating" means any treatment of a disease or disorder in a
subject, including:
• preventing or protecting against the disease or disorder, that is, causing the clinical
symptoms not to develop;
• inhibiting the disease or disorder, that is, arresting or suppressing the development of clinical
symptoms; and/or
• relieving the disease or disorder that is, causing the regression of clinical symptoms.
[0106] It will be understood by those skilled in the art that in human medicine, it is not

WO 2006/065686 PCT/US2005/044768
always possible to distinguish between "preventing" and "suppressing" since the ultimate inductive
event or events may be unknown, latent, or the patient is not ascertained until well after the
occurrence of the event or events. Therefore, as used herein the term "prophylaxis" is intended as
an element of "treatment" to encompass both "preventing" and "suppressing" as defined herein. The
term "protection," as used herein, is meant to include "prophylaxis."
Nomenclature
[0107] In general, the nomenclature used in this Application was generated using or with
the help of version 2.2 of the AUTONOM™ naming package within the ChemOffice® version 7.0.3
suite of programs by CambndgeSoft Corp (Cambridge, MA) or by Chemsketch Freeware version
5.12.
A compound of Formula I , wherein R1 is chloro, R2 is hydroxy, R3 and R4 are methyl, R5 to R8 are
hydrogen, and R9 and R10 together with the carbon to which they are attached form a cyclobutane
ring, may be named: 5-chloro-7,8-dimethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-6-ol.
A compound of Formula I, wherein R1, R3, and R4 are methyl, R2 is hydroxy, R7 to R10 are hydrogen,
and R5 and R6 together with the carbon to which they are attached form a cyclobutane ring may be
named 5',7',8'-tnmethyl-2',3'-dihydrospiro[cyclobutane, 1,4'-thiochromen]-6'-oi.
Synthesis of the Compounds of the Invention
Synthetic Reaction Parameters
[0108] The terms "solvent," "inert organic solvent," or "inert solvent" mean a solvent inert
under the conditions of the reaction being described in conjunction therewith. Solvents employed in
synthesis of the compounds of the invention include, for example, methanol ("MeOH"), acetone,
water, acetonitrile, 1,4-dioxane, dimethylformamide ("DMF"), benzene, toluene, tetrahydrofuran
("THF"), chloroform, methylene chloride (also named dichloromethane ("DCM")), diethyl ether, ethyl
acetate ("EtOAc"), pyridine and the like, as well as mixtures thereof. Unless specified to the
contrary, the solvents used in the reactions of the present invention are inert organic solvents.
[0109] The term "q.s." means adding a quantity sufficient to achieve a stated function, e.g.,
to bring a solution to the desired volume (i.e., 100%).
[0110] Unless specified to the contrary, the reactions described herein take place at
atmospheric pressure within a temperature range from -10°C to 110"C and in some cases at "room"
or "ambient" temperature, e.g., 20cC. Further, unless otherwise specified, the reaction times and
conditions are intended to be approximate.
[0111] Isolation and purification of the compounds and intermediates described herein can
be effected, if desired, by any suitable separation or purification procedure such as, for example,
filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer
chromatography, or a combination of these procedures. Specific illustrations of suitable separation
and isolation procedures can be had by reference to the examples herein below. However, other
equivalent separation or isolation procedures can also be used.
[0112] A synthesis of certain spiro-chromanones has been described by H.J. Kabbe.
Synthesis, Vol. 12 (1978), pp. 886-7. A synthesis of certain spiro-dihydroquinolines has been
39

WO 2006/065686 PCT/US2005/044768
described in US 3,331,846. Synthesis of certain spiro tetrahydroquinolines has been also described
in Dorey, G. et al. Biorg. & Med.Chem. Lett., Vol. 10, no. 9 (2000), pp. 935-939.
[0113] Unless otherwise indicated, the variables used in the reactions schemes below have
the same meanings as described in the Summary of the Invention.

[0114] Compounds of Formula I of the present invention wherein X is S(O)0-2, R2 is hydroxy
or alkoxy, n is 1, -CR5R6 form a cyclobutyl ring, R7 to R10 are independently of each other hydrogen
or alkyl, and R1, R3 and R4 are as described above, can be prepared following Scheme 1.
[0115] The vinyl alcohol of formula 101, wherein A is a cyclobutyl ring can be prepared by
Grignard reaction of a vinyl magnesium bromide of formula -CR9R10=CR7MgBr with a cyclobutyl
ketone of Formula A(O), wherein A is a cyclobuty! ring, under inert conditions in a solvent such as
tetrahydrofuran. Certain vinyl alcohols of formula 101 such as 1-vinylcyclohexanol may be available
from Sigma-Aldrich, at www.siqma-aldrich.com. Reaction of the vinyl alcohol of formula 101 with the
mercaptophenol of formula 102 in the presence of a Lewis acid such as BF3-ether, methane sulfonic
acid, p-toluene sulfonic acid, or aluminum chloride, can give the desired thiochroman of formula 103,
wherein A is a cyclobutyl ring . Oxidation with one equivalent of a mild oxidant such as m-chloro-
perbenzoic acid (MCPBA) may give the thio-chroman1 -oxide derivative of formula 104, which can be
further oxidized with another equivalent of oxidant to the disulfoxide of formula 105. Alternatively the
disulfoxide can be synthesized from the thiochroman of formula 103 with an excess of mild oxidant.
40


WO 2006/065686 PCT/US2005/044768
[0116] Scheme 2 describes an alternate synthesis for compounds of formula I of the
present invention, wherein X is S(O)0-2, R5 and R6 form a cyclopropyl ring, R9 and R10 are
independently of each other hydrogen or alkyl or together with the carbon atom to which they are
attached form a cycloalkyl ring, n is 1, R7 is hydrogen, and R1 to R* and R8 are as defined above.
Under Michael addition conditions, the mercaptophenol of formula 201 is alkylated with an acrylate of
formula 202, wherein Alk is an alkyl group, in an anhydrous solvent such as methanol, to give the
ester of formula 203, which can further, in the presence of a base such as sodium hydroxide,
undergo hydrolysis of the ester group to give the acid of formula 204. Cyclization under acidic
condition can give the thio-chromanone of formula 205, which may undergo protection of its
substituent R2 under conditions well known in the art to give the compound of formula 206, wherein
Pro is a protective group. If the substituent R2 of formula 205 is hydroxy, said substituent may be
protected with, for example, triisopropylsilyl chloride or t-butyldimethylsilyl chloride. Methylenation of
the ketone of formula 206, may be achieved with the titanium carbene complex {Tebbe) reagent
(available from Sigma-Aldrich) or with methyl phosphonium (Wittig reaction) under basic conditions,
see i.e. Pine, S.H. & Shen, G.S. & Hoang, H. "Ketone Methylenation using the Tebbe and Wittig
Reagents." Synthesis (1991), p. 165; followed by cyclopropylation with diiodomethane/diethyl zinc,

WO 2006/065686 PCT/US2005/044768
to yield a compound of Formula 208, wherein Pro is a protective group. Deprotection with, for
example, tetrabutylammonium fluoride may yield the thiochroman of formula 209, which can further
be oxidized as in Scheme 1 into the sulfoxide or the disulfoxide derivatives thereof.
[0117] Alternatively, compound of formula 206 can undergo reduction of the carbonyl group
as is well known in the art, for example using the method of the Clemmensen reduction with
zinc/mercury amalgam in aqueous hydrochloric acid or any other modifications to give a compound
of formula 210.

[0118] Scheme 3 describes a synthesis for compounds of Formula I, wherein X is S(O)0.z,
R2 is hydroxy, R9 and R10 form a cyclopropyl ring, R7 and R8 are hydrogen, n is 1 and R1, R3 to R6
are as defined above. Treatment of a 4-mercaptophenol of formula 301 with acryloyl chloride of
formula 302 in a solvent such as toluene or benzene may give a compound of Formula 303, which
may undergo cyclization to give compound of formula 304. Following the methylenation of the
carbonyl group as described in Scheme 2 and deprotection may give compound of formula 305,
which may be further oxidized as described in Scheme 1 to give the sulfoxide or the disulfoxide
derivative thereof.
Compounds of Formula I, wherein R2 is amino or alkoxy may also be synthesized following this
scheme.

[0119] Scheme 4 describes a synthesis for compounds of Formula I, wherein X is O, R9 and
R10 form a cyclobutyl ring, R8 is hydrogen, n is 1 and R1 to R4, and R5 to R7 are as defined above.
The vinyl-cycloalcohol of formula 402, which may be prepared as described in Scheme 1 or which
may be available commercially, may react with the phenol of formula 401 in the presence of a Lewis
acid, such as BF3-ether, methane sulfonic acid, p-toluene sulfonic acid, or aluminum chloride, to give
the compound of formula 403, wherein A is a cyclobutyl ring.

WO 2006/065686 PCT7US2005/044768

[0120] Scheme 4A describes a synthesis for compounds of Formula I, wherein X is O, R9
and R10 form a cyclobutyl ring, R5and R6 are hydrogen, n is 0, R2 is OH, and R1, R3, R4 are as
defined above. The dimethoxy compound of formula 404 is treated with paraformaldehyde, followed
with acid bromide in the presence of acetic acid to give the bromide of Formula 405. Treatment with
magnesium will give the Gngnard reagent of formula 406 which may be reacted with cyclobutanone
in a solvent such as THF, to give the compound of formula 407. Internal cychzation in the presence
of a Lewis Acid such as boron trifluoride may give compound of formula 408.

[0121] Scheme 4B describes a synthesis for compounds of Formula I, wherein X is O, R9
and R10 form a C(3-4) cycloalkyl ring, n is 0, R2 is OH, and R1, R3, R4, are as defined above, and R5
and R6 are hydrogen, hydroxy, oxime or alkoxyamine.
[0122] The protected hydroquinone of formula 410, wherein Pro is a protective group, is
treated with sodium hydride and alkylated with alkylbromoacetate to give, after hydrolysis of the ester
group, a compound of formula 411. Internal cychzation with a Lewis acid such as methanesulfonic
acid in an inert solvent such as benzene or toluene, may give compound of formula 412. Alkylation
43

WO 2006/065686 PCT/US2005/044768
with dihalo alkyl such as dibromoalkyl in the presence of a base may give the spiro compound 413,
which can be reduced with for example sodium borohydride in a solvent such as methanol, to give
the hydroxy spiro compound of formula 414. Further reduction of compound 414 under acidic
comditions, followed by deprotection may give compound of formula 417.
[0123] Alternatively, the compound of formula 413 may be treated with hydroxyamine or
alkoxyamine to give an oxime of formula 415, which may be reduced to give the hydroxyamine or
alkoxyamine compound of formula 416. Alkylation of the compound of formula 416 wherein R is
hydrogen may give compounds of formula 416 wnerein R is different than hydrogen, for example
wherein R is alkyl. Deprotection of these compounds can be done by ways well known in the art.

[0124] Scheme 4C describes a synthesis for compounds of Formula I, wherein X is O, R9
and R10 with the atom to which they are attached form a cyclobutyl ring, R7 and R8 are hydrogen, n is
1, R2 is OH, R5 is hydrogen, R6 is either OH or alkoxyamine, and R1, R3, R4, and Raare defined as
above. Acetylation of a hydroquinone of formula 418, followed by a Fries rearrangement reaction
catalyzed by BF3 gives an intermediate of formula 420. This intermediate may be further reacted
with cyclobutanone in the presence of pyrrolidine and subsequently hydrolyzed with an aqueous
base, to yield a chromanone of formula 421. Reduction of this chrornanone with sodium borohydride
may lead to a hydroxy derivative compound of formula 422. Alternatively, a condensation reaction of
the chromanone of formula 421 with an alkoxyamine may give an O-alkyl oxime of formula 423,
which after treatment with reducing reagent BH3-pyrindine complex may give a compound of formula
424.
44

WO 2006/065686 PCT/US2005/044768

[0125] Scheme 5 describes an alternate synthesis for compounds of Formula I, wherein X is
O, n is 1, R9 and R10 form a cyclopropyl ring, R8 is hydrogen, and R1 to R4, and R5 to R7 are as
defined above. The phenol of formula 501 may react with an acrylic acid derivative of formula 502
under acidic conditions to give after ring cyclization a compound of formula 503. The substituent R2
is subsequently protected with, for example, triiscpropylsilyl or t-butyldimethylsilyl, and the protected
compound of formula 504, wherein Pro is a protective group, is methylenated followed by ring
formation as described in Scheme 2, to give compound of formula 506 . Deprotection with, for
example, t-butyl ammonium fluoride, may give a compound of formula 507.

[0126] Scheme 6 describes a synthesis for compounds of Formula I, wherein X is S, n is 1,
R7 and R8 form a cyclopropyl ring and R5 and R6 form a carbonyl group. The phenol of formula 601
is treated with sodium or potassium thiocyanate and bromine, in the presence of a sodium halide,
such as sodium bromide, that may give the para substituted thiocyanate of formula 602, which may
undergo reduction in the presence of Lithium Aluminum Hydride to give the thiol of formula 603.
45

WO 2006/065686 PCT/US2005/044768
Michael addition with methyl acrylate, followed by hydrolysis to the acid and cyclization, as described
herein, may yield the chromanone of formula 606. The phenolic hydroxyl group is protected with, for
example, methoxymethoxychloride and the resulting compound of formula 607 is reacted with a
dihaloethane, such as 1,4-dichloroethane of 1,4-dibromoethane, in the presence of sodium hydride in
a solvent such as THF or DMF to yield the protected 3-cyclopropylchroman-4-one of formula 608.
Deprotection by means well known in the art may lead to the desired compound of formula 609.

[0127] Scheme 6A describes a synthesis for compounds of Formula I, wherein X is S, n is
1, R9 and R10 form a cyclobutyl ring and R5 and RJ form a carbonyl group. The thiol of formula 603,
prepared as described in Reaction Scheme 6, may undergo a Michael addition with a 2-
cyclobutylideneacetate of formula 610 wherein Alk is alkyl, such as methylcyclobutylidene acetate to
give a compound of formula 611 which may undergo hydrolysis and cyclization go give compound of
formula 612.

[0128] Scheme 7 describes a synthesis for compounds of Formula I, wherein X is O, n is 1,
R7 and R8 form a (C3-C4)cycloalkyl spiro ring and R5 and R6 together form a carbonyl group, or R5 is
hydroxy or hydrogen and R6 is hydrogen, and R1, R3, R4, R9 and R10 are as defined above. One of
the hydroxyl groups of the hydroquinone of formula 701 is protected with, for example, a benzyl
group, by reaction with one equivalent of, for example, benzyl bromide. Addition of 1-

WO 2006/065686 PCT/US2005/044768
methanesulfonyloxymethyl-cyclopropanecarboxylic acid ester to the protected hydroquinone in a
solvent such as dimethylformamide in the presence of a base, such as cesium carbonate, may yield
a compound of formula 702, wherein R101 is alkyl, which after hydrolysis and cyclization may yield the
3-spiro-4-chromanone derivative of formula 704. Reduction of the carbonyl group with a metallic
hydride such as, for example, lithium aluminum hydride or sodium borohydnde, may yield the 4-
hydroxy derivative of formula 705, which can be further reduced to compound of formula 706 with
additional reducing agent. This scheme may also be used for the preparation of thiochromans of this
invention by substituting the hydroquinone of formula 701 with the correspondent 4-mercaptophenol.

[0129] Oxime and hydrazone analogues of compounds of Formula I may be prepared as known in
the art by addition of hydroxylamine, alkoxyamine or hydrazine as described in Examples. The oxime
and hydrazone analogues may be further reduced with, for example, sodium cyanoborohydride or
borane/pyridine to give alkoxyamines or hydrazines. Addition of an alkylhalide or alkylaldehyde to
the alkoxyamines or hydrazines may yield compounds of Formula I wherein RJ or R7 may be -
NRORa or -NR-NRbRc, wherein R is alkyl and Ra, Rb, Rc are as defined herein.
[0130] Scheme 8 describes a synthesis for compounds of Formula III of the present
invention wherein q is 1 or 2, -CR9R10 form a cyclopropyl ring; R5, R6, are hydrogen; R is -CR'R"
wherein R' and R" are alkyl, alkenyl and together may form a ring optionally including an additional
heteroatom such as N, O or S; and R1, R3, R4 are as defined above . Nitration of compound of
formula 801 can be effected, for example, by nitric acid or with esters of nitric acid such as ethyl
nitrate, or other nitration reagents well known in the art. The hydroxy group of compound of formula
802 is protected with a group such as triisopropylsilyl chloride or butyldimethysilyl chloride, and the
protected compound of formula 803, wherein Pro is a protective group, is reduced with, for example,

WO 2006/065686 PCT/US2005/044768
iron or hydrogen/palladium to give the amino compound of formula 804. Reductive alkylation may be
effected with reducing agents such as sodium cyanoborohydride or sodium borohydride in the
presence of an acid such as formic acid or acetic acid, or with Zn and hydrochloric acid to give a
compound of formula 805. Acylation of the amino group with an acyl halide of formula 806 wherein q
is 1 or 2 and Hal is a halogen group, may give compound of formula 807, which can undergo
cyclization and deprotection under Friedel-Crafts conditions with for example AICI3 to give a
compound of formula 808. Methylenation of the carbonyl group may be effected with the titanium
carbene complex (Tebbe) reagent available from Sigma-Aldrich or with methyl phosphonium (Wittig
reaction) under basic conditions, followed by cyclopropylation with dihalomethane and dihalo zinc or
diethyl zinc. Deprotection with, for example, tetrabutyl ammonium fluoride may yield a compound of
formula 810.

[0131] Scheme 9A describes a synthesis for compounds of Formula III of the present
invention wherein -CR35R36 form a cyclopropyl or a cyclobutyl ring; R37, R38, R39, R310 are hydrogen,
R30 is hydrogen. Compound 901 that may be synthesized similarly to the compound of formula 105
in scheme 1, can be treated with an allyl halide of formula 902, wherein L is a leaving group such as
a halide for example a chloride, a bromide or an iodide, and p is 0 or 1, to give a compound of
formula 903 wherein Pro is a protective group. Internal cyclization with a Lewis acid such as boron
trifluoride, followed by deprotection may yield a compound of formula 904 wherein p is 0 or 1.
Coupling of a compound of formula 904 with a compound R30L wherein R30 is as described herein
but not hydrogen, and L is a leaving group such as an halide for example a chloride, a bromide or an
iodide may yield a derivative of Formula III with R30 substitution on the nitrogen atom.

[0132] Similarly, Scheme 9B describes the synthesis for compounds of Formula III wherein
R39 and R310 form a cyclopropyl or a cyclobutyl ring; R35, R36, R37, R38 are hydrogen, and R30 is
hydrogen, starting from compound of formula 901, wherein Pro is a protective group, and treating it
with a cycloalkylidene carboxytate of formula 905, wherein Alk is alkyl to give a compound of formula
906. Internal cyclization with a Lewis acid, followed by reduction and deprotection may yield
compound of formula 907. Coupling of compound of formula 907 with a compound R30L wherein R30

WO 2006/065686 PCT/US2005/044768
is as described herein but not hydrogen, and L is a leaving group such as an halide for example a
chloride, a bromide or an iodide may yield a derivative of Formula III with R30 substitution on the
nitrogen atom.

[0133] Similarly Scheme 9C describes the synthesis for compounds of Formula III wherein
R37 and R38 form a cyclobutyl or a cyclopropyl ring, R35, R3G, R39, R310 are hydrogen, and R30 is
hydrogen, starting from compound of formula 901, wherein Pro is a protective group, and treating it
with an aldehyde of formula 908, wherein Alk is alkyl and p is 0 -1, to give a compound of formula
909. Internal cychzation with a Lewis acid, followed by reduction and deprotection may yield
compound of formula 910 Coupling of compound of formula 910 with an halide of Formula R30L
wherein R30 is as described herein but not hydrogen, and L is a leaving group such as an halide for
example a chloride, a bromide or an iodide, may yield a derivative of Formula III with R30 substitution
on the nitrogen atom.
[0134] The reaction scheme examples given herein should not be considered as limiting the scope
of the invention, but merely as being illustrative and representative thereof. The features of the
invention will become more fully apparent when the schemes are considered in conjunction with the
Examples.
Preferred Compounds
[0135] The compounds of Formula I, IA, IB, II, HA, III, and MIA encompass the spiro
derivatives of the invention as disclosed, and/or the pharmaceutically acceptable salts, solvates, or
polymorphs of such compounds. In addition, the compounds of this invention include the individual
stereochemical isomers and mixtures thereof, arising from the selection of substituent groups.
Certain compounds of this invention may exist in isomeric forms. The invention contemplates all such
stereoisomers both in pure form and in admixture, as well as racemic mixtures.
[0136] Examples of compounds of the invention include, but are not limited to those shown
in the tables below:


WO 2006/065686 PCT/US2005/044768


WO 2006/065686 PCT/US2005/044768


WO 2006/065686 PCT/US2005/044768


WO 2006/065686 PCT/US2005/044768


WO 2006/065686 PCT/US2005/044768


WO 2006/065686 PCT/US2005/044768


WO 2006/065686 PCT/US2005/044768

[0137] It will be understood by those skilled in the art with respect to any group containing
one or more substituents that such groups are not intended to introduce any substitution or
substitution patterns that are sterically impractical and/or synthetically non-feasible.
Utility, Testing and Administration
General Utility
[0138] Without subscribing to a particular theory or mechanism of action, compounds of the
invention may target certain enzymes known as "oxidoreductases" that function widely across a
variety of physiological processes, for example, certain compounds of the present invention may

WO 2006/065686 PCT/US2005/044768
target lipoxygenases such as 5-Lipoxygenase, 12-Lipoxygenase, 15-Lipoxygenase, and/or 12/15-
Lipoxygenase. In particular, oxidoreductases catalyze reactions in which two molecules interact so
that one molecule is oxidized and the other is reduced. Alterations in oxidoreductases are thought to
account for as many as 3% of all known human genetic diseases. Abnormalities in oxidoreductase
activity may underlie such disorders as congestive heart failure, respiratory chain defects (e.g.,
abnormalities associated with enzymes of the respiratory chain, acute respiratory distress syndrome
(ARDS)), glycogen storage disease, end-stage renal disease, and rheumatoid arthritis. Inhibitors of
lipoxygenases are known to be useful in the prevention or treatment of, for example, disorders
selected from apoptosis in cancer cells including prostatic cancer, gastric cancer, breast cancer,
pancreatic cancer, colorectal or esophageal cancer and airways carcinoma; diseases involving
hypoxia or anoxia, including atherosclerosis, myocardial infarction, cardiovascular disease, heart
failure (including chronic and congestive heart failure), cerebral ischemia, retinal ischemia,
myocardial ischemia, post surgical cognitive dysfunction and other ischemias; diseases involving
inflammation, including diabetes, arterial inflammation, inflammatory bowel disease, Crohn's disease,
renal disease, pre-menstrual syndrome, asthma, allergic rhinitis, gout, cardiopulmonary inflammation,
rheumatoid arthritis, osteoarthntis, muscle fatigue and inflammatory disorders of the skin including
acne, dermatitis and psoriasis; disorders of the airways including asthma, chronic bronchitis, human
airway carcinomas, mucus hypersecretion, chronic obstructive pulmonary disease (COPD),
pulmonary fibrosis caused by chemotherapy or other drugs, idiopathic pulmonary fibrosis, cystic
fibrosis, and adult respiratory distress syndrome; diseases involving central nervous system (CNS)
disorders including psychiatric disorders including anxiety and depression; neurodegeneration and
neuroinflammation including Alzheimer's, dementia and Parkinson's disease; peripheral neuropathy
including spinal chord injury, head injury and surgical trauma, and allograft tissue and organ
transplant rejection; diseases involving the autoimmune system including psoriasis, eczema,
rheumatoid arthritis, and diabetes; and disorders involving bone loss or bone formation
[0139] Certain compounds of the present invention are also useful in treating conditions
falling with the group of dermatologic conditions, such as prevention and protection of skin tissue
against age-related damage or damage resulting from insults such as harmful ultraviolet (UV)
radiation, use of retinoids, wearing diapers, stress and fatigue, and in the treatment of contact
dermatitis, skin irritation, skin pigmentation, psoriasis, or acne.
Testing
[0140] This section describes how compositions incorporating compositions of the present
invention are selected, using in vitro and/or in vivo models, and used as therapeutic interventions in
the exemplary indications in support of the present invention.
[0141] The 5-Lipoxygenase pathway is a major synthetic pathway relevant to human
inflammatory disease. The enzyme 5-Lipoxygenase catalyses the two first steps in the oxygenation
of arachidonic acid (a polyunsaturated 20-carbon fatty acid) to leukotnenes. Leukotrienes are known
to be important mediators of inflammatory and allergic reactions. The first step in the synthesis of
leukotrienes, which is catalyzed by 5-Lipoxygenase, is the formation of 5-HPETE. The
rearrangement of 5-HPETE to form the unstable LTA^, the rate-limiting step in the synthesis of the
57

WO 2006/065686 PCT/US2005/044768
leukotrienes, is also catalyzed by 5-Lipoxygenase. LTA4 is then converted to either LTB4 or LTC4.
LTC4 is rapidly metabolized to LTD4 and then to LTE4. LTC4, LTD4and LTE4 are collectively referred
to as the cysteinyl (Cys) leukotrienes.
[0142] Biosynthesis of LTB4, LTC4, LTD4 and LTE4 occurs predominantly in leukocytes, in
response to a variety of immunological stimuli. The primary target of LTB4 is the leukocyte where it
elicits enzyme release, chemotaxis, adherence, and aggregation in nM concentrations. LTB4
modulates immune responses and participates in the host-defense against infections. Hence, LTB4 is
an important chemical mediator in the development and maintenance of inflammatory reactions and
disease states.
[0143] Endogenous lipoxygenase metabolites may also be involved in enhanced cytokine
tumor necrosis factor a (TNF-cr) production following certain stimuli such as silica, asbestos and
lipopolysaccharides (Rola-Pleszczynski, M et al. Mediators of Inflammation 1 : 5-8 (1992)).
Consistent with selective lipoxygenase inhibitory effect, certain compounds of the present invention
have also shown to have an inhibitory effect on TNF-o. synthesis and/or release. The TNF-c" has a
broad spectrum of biological activities, plays an important role in coordinating the body's response to
infection, and serves as an important mediator of inflammation. It is known that inflammatory
cytokines have been shown to be pathogenic in several diseases including, but not limited to asthma
(N. M. Cembrzynska et al., Am. Rev. Respir. Dis., 147, 291 (1993)), Adult Respiratory Distress
Syndrome (ARDS). (Miller et al., Lancet 2 (8665); 712-714 (1989) and Ferrai-Baliviera et al., Arch.
Surg. 124 (12): 1400-1405 (1989)), lung fibrosis (Piguet et al., Nature, 344:245-247 (1990) and
Bissonnette et al., Inflammation 13 (3): 329-339 (1989)), bone resorption diseases (Bertolini et al.,
Nature 319: 516-518 (1986) and Johnson et al., Endocrinology 124 (3): 1424-1427 (1989)), auto-
immune diseases (W. Fiers, FEBS Lett., 1991, 285, p. 199). It will be therefore appreciated that
compounds of the present invention showing an inhibitory effect on both 5-Lipoxygenase and TNF-a
should be superior in the treatment or amelioration of for example diseases such as respiratory
disorders, antiprolilferative disorders or autoimmune disorders.
[0144] In vitro evaluation of the ability of a composition to inhibit the enzymes 5-
Lipoxygenase, 15-Lipoxygenase, or 12/15-Lipoxygenase as described in Walidge, N.B. et al. Anal.
Biochem., Vol. 231 (1995), pp. 354-358 using a high throughput colorimetric method; as well as in
vitro evaluation of inhibiting LTB4 is described in Examples.
[0145] In vitro cell-based assays for inflammation are well known in the art, for example, e-
selectin (also named Endothelial Leukocyte Adhesion Molecule or ELAM) or C-reactive protein
(CRP). The ELAM assay measures in vitro activity of the test compounds in reducing expression of
ELAM in activated endothelial cells. Briefly, endothelial cells are created by adding known activators
such as lipopolysaccharides, TNF or IL-1/7, alone or in some combination. Activated cells produce
ELAM, which can be measured using, for example, an E-selectin monoclonal antibody-based ELISA
assay.
[0146] In vivo evaluation of anti-inflammatory activity can be determined by well
characterized assays measuring Carrageenan-lnduced Paw Edema, by Mouse Ear Inflammatory
Response to Topical Arachidonic Acid (Gabor, M. Mouse Ear Inflammation Models and their
58

WO 2006/065686 PCT/US2005/044768
Pharmacological Applications (2000)), or by the in vivo murine Zymosan peritonitis assay.
Carrageenan-lnduced Paw Edema is a model of inflammation, which causes time-dependent edema
formation following carrageenan administration into the intraplantar surface of a rat paw. The
application of arachidonic acid (AA) to the ears of mice produces immediate vasodilation and
erythema, followed by the abrupt development of edema, which is maximal at 40 to 60 min. The
onset of edema coincides with the extravasations of protein and leukocytes. After one hour the
edema wanes rapidly and the inflammatory cells leave the tissue so that at 6 hours the ears have
returned to near normal.
[0147] Administration of Zymosan-A, a purified polysaccharide fraction of yeast cell wall has
been used since the 1980s to induce acute inflammatory response in rodents. The inflammatory
response is characterized by marked induction of pro-inflammatory cytokines, influx of inflammatory
cells and biosynthesis of arachidonic acid metabolites as early as five minutes after the Zymosan
injection. The purpose of this model is to evaluate the ability of compounds to reduce inflammatory
response induced by administration of Zymosan-A and assessed by the levei of inflammatory
cytokines and arachidonic metabolites in the fluid exudates.
[0148] These assays, as described in the Examples, measure a test compound's ability to
treat these inflammatory processes via systemic and topical routes of administration.
[0149] Protection against redox stress can be evaluated in cell culture using high glutamate
induced oxidative stress (HGOS) in mouse dopaminergic cell lines. The cytotoxic effect of glutamate
is not due to excitotoxicity, as this cell line is devoid of inotropic glutamate receptors. Rather, the
glutamate-induced toxicity of dopaminergic cells is associated with an inhibition of cystine transport
which subsequently leads to depletion of intracellular glutathione (GSH) levels (Murphy T. H., et al.
Neuron, Vol. 2 (1989), pp. 1547-1558), activation of neuronal 12-Lipoxygenase (Li, Y. et al. Neuron,
Vol. 19 (1997), pp. 453-463), increased ROS production (Tan S. et al. J. Cell Biol., Vol. 141 (1998),
pp. 1423-1432) and elevated intracellular Ca2+ (Li, Y. et al. see supra). Some molecules were
measured for their ability to protect cells against glutamate-induced stress and the assay is detailed
in Examples.
[0150] Further validation of neuroantnnriammatory activity of compounds can be assessed
in vitro by the inhibition of IL-1 .beta, release from a microglial cell line
[0151] lnterleukin-1 (IL-1) is a pro-inflammatory cytokine that exists in two separate forms
that share 30% sequence homology (alpha and beta). Constitutive expression of IL-1 is low in the
brain but levels of both forms of this cytokine increase dramatically after injury. There is substantial
evidence that IL-1 is an important mediator of neurodegeneration induced by cerebral ischemia
(Touzani, O. et al. J. Neuroimmunol., Vol. 100 (1999), pp. 203-215). Both IL-1 forms are rapidly
induced in experimental models of stroke and administration of recombinant IL-1/? enhances
ischemic injury (see Hill J.K., et al. Brain Res., Vol. 820 (1999), pp. 45-54); Hillhouse E.W. et al.
Neurosci. Lett. Vol. 249 (1998), pp. 177-179; Loddick S.A. et al. J. Cereb. Blood Flow Metab. Vol. 16
(1996), pp. :932-940; Stroemer R.P. etal. J. Cereb. Blood Flow Metab. Vol. 18 (1998), pp. 833-839).
Conversely, blocking IL-1 actions with a receptor antagonist or a neutralizing antibody markedly
reduces neuronal death and inflammation in models of ischemic damage (see Betz, A.L., J. Cereb.
59

WO 2006/065686 PCT/US2005/044768
Blood FlowMetab. Vol. 15 (1995), pp. 547-551; Relton, J.K., Brain Res. Bull. Vol. 29 (1992), pp. 243-
246; Yamasaki, Y. et al. Stroke, Vol. 26 (1995), pp. 676-680). Furthermore, mice with decreased IL-
1/? production (caspase-1 knockouts) are significantly protected from ischemic injury (Schielke, G.P.
et al. J. Cereb. Blood Flow Metab. Vol. 18 (1998), pp. 180-185) and IL-1" and P double knockouts
exhibit dramatically reduced ischemic infarct volumes compared with wild-type mice (87% reduction
in cortex) (Boutin, H. et al. J. Neurosci. Vol. 21 (2001), pp. 5528-5534).
[0152] In addition to a role in ischemic damage, IL-1 elevation has been associated with
many neurodegenerative diseases. There is increasing evidence for a role of IL-1 in Alzheimer's
disease (AD) (Mrak, R.E. et al. Neurobiol. Aging, Vol. 22, no. 6 (2001), pp. 903-908). Elevated levels
of IL-1/? have been shown to surround amyloid plaques in the disease and recent genetic studies
have indicated that a polymorphism in IL-1" is linked to an increased risk of AD (3-6 fold increase)
(Griffin, W.S. et al. J. Leukoc. Biol. Vol. 72, no. 2 (2002), pp. 233-238). This polymorphism has also
been correlated with rate of cognitive decline in AD patients (Murphy, G.M. et al. Neurology, Vol. 56,
no. 11 (2001), pp. 1595-1597). The risk of AD is increased even further when the polymorphism in IL-
1 .alpha, is found in combination with another polymorphism in IL-1/? (see Griffin, W.S., supra),
providing convincing evidence that these cytokines play an important role in the pathology of the
disease.
[0153] This assay measures the release of IL-1/? from a mouse microglial cell line following
an inflammatory challenge with LPS and interferon-gamma. The ability of test articles to inhibit
microglial cell activation and IL-1 release is determined by co-incubation of the test article with the
inflammatory challenge.
[0154] Cerebral ischemic insults are modeled in animals by occluding vessels to, or within,
the cranium (Molinan, G.F. in: Barnett, H.J.M. et al. (Eds.), Stroke: Pathophysiology, Diagnosis and
Management, Vol. 1 (New York, Churchill Livingstone, 1986). The rat middle cerebral artery
occlusion (MCAO) model is one of the most widely used techniques to induce transient focal cerebral
ischemia approximating cerebral ischemic damane in humans, e.g., those who suffer from a stroke.
The middle cerebral artery used as the ischemic trigger in this model is the most affected vessel in
human stroke. The model also entails a period of reperfusion, which typically occurs in human stroke
victims. MCAO involving a two-hour occlusion has been found to produce the maximum size of
cortical infarction obtainable without increased mortality at twenty-four hours.
Administration
[0155] The compounds of the invention are administered at a therapeutically effective
dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described.
Administration of the compounds of the invention or the pharmaceutically acceptable salts thereof
can be via any of the accepted modes of administration for agents that serve similar utilities.
[0156] While human dosage levels have yet to be optimized for the compounds of the
invention, a dose may be from about 1 mg to 1 g, preferably 10 mg to 500 mg and most preferably
10 mg to 100 mg per administration. The amount of active compound administered will, of course,
be dependent on the subject and disease state being treated, the severity of the affliction, the
manner and schedule of administration, and the judgment of the prescribing physician.
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WO 2006/065686 PCT/US2005/044768
[0157] In employing the compounds of this invention for treatment of the above conditions,
any pharmaceutically acceptable mode of administration can be used. The compounds of this
invention can be administered either alone or in combination with other pharmaceutically acceptable
excipients, including solid, semi-solid, liquid or aerosol dosage forms, such as, for example, tablets,
capsules, powders, liquids, suspensions, suppositories, aerosols or the like. The compounds of this
invention can also be administered in sustained or controlled release dosage forms, including depot
injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for the
prolonged administration of the compound at a predetermined rate, for example, in unit dosage forms
suitable for single administration of precise dosages. The compositions will typically include a
conventional pharmaceutical carrier or excipient and a compound of this invention or a
pharmaceutically acceptable salt thereof. In addition, these compositions may include other
medicinal agents, pharmaceutical agents, carriers, adjuvants, and the like, including, but not limited
to, anticoagulants, blood clot dissolvers, permeability enhancers, and slow release formulations.
[0158] Generally, depending on the intended mode of administration, the pharmaceutically
acceptable composition will contain about 0.1% tr 90%, for example about 0.5% to 50%, by weight of
a compound or salt of this invention, the remainder being suitable pharmaceutical excipients,
earners, etc.
[0159] One manner of administration for the conditions detailed above is oral, using a
convenient daily dosage regimen which can be adjusted according to the degree of affliction. For
such oral administration, a pharmaceutically acceptable, non-toxic composition is formed by the
incorporation of any of the normally employed excipients, such as, for example, mannitol, lactose,
starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose,
gelatin, sucrose, magnesium carbonate, and the like. Such compositions take the form of solutions,
suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations,
and the like.
[0160] Certain compositions will take the form of a pill or tablet and thus the composition will
contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or
the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum
acacia, polyvmylpyrrolidine, gelatin, cellulose and derivatives thereof, and the like.
[0161] Liquid pharmaceutically administrable compositions can, for example, be prepared
by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical
adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols,
ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical
composition to be administered may also contain minor amounts of nontoxic auxiliary substances
such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like, for
example, sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate,
triethanolamine acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms
are known, or will be apparent, to those skilled in this art; for example, see Remington's
Pharmaceutical Sciences, 15th Edition, Easton, PA, Mack Publishing Company, 1975. The
composition or formulation to be administered will, in any event, contain a quantity of the active
61


Formula IIA
wherein,
R51, R53, and R54 are independently selected from hydrogen, C1-C10 alkyl, and hydroxy;
R56 and R57 are independently selected from hydrogen, C1-C10 alkyl, hydroxy, cyano, and 5-10
membered heterocyclyl having from 1 to 4 heteroatoms selected from O, N, and S,
R59 and R510 together with the carbon atom to which they are attached form an optionally
substituted (C3-C4)cycloalkyl ring;
R50 is hydrogen or C1-C10 alkyl;
or single stereoisomers, mixtures of stereoisomers, pharmaceutically acceptable salts, or
prodrugs thereof.
30 The compound of Claim 32, wherein R22 is hydroxy.
31. The compound of Claim 34, wherein R21, R23, and R24 are independently selected from
hydrogen, halogen, and C1-C10 alkyl
32 The compound of Claim 35, wherein R27 is -NR20OR2a or -NR20-NR2bR2c.
33 The compound of Claim 35, wherein R27 is 5-10 membered heterocyclyl having from 1 to
4 heteroatoms selected from O, N, and S.
34 The compound of Claim 32, selected from'
5',7',8'-trimethylspiro[cyclobutane-1,2'-thiochromen]-6'-ol;
? 3-(hydroxymethyl)-5,7,8-trimethylspiro[chromene-2,1 '-cyclobutan]-6-ol;
? 4-(aminomethyl)-5,7,8-trimethylspiro[chromene-2,1'-cyclobutan]-6-ol;
? N-[(6-hydroxy-5,7,8-trimethylspiro[chromene-2,1 '-cyclobutan]-4-yl)methyl]acetamide;
? 3-(methoxymethyl)-5,7,8-trimethylspiro[chromene-2,1 '-cyclobutan]-6-ol;
? 3,5,7,8-tetramethylspiro[chromene-2,1'-cyclobutan]-6-ol;
■ 6-hydroxy-5,7,8-trimethylspiro[chromene-2,1'-cyclobutane]-4-carbonitrile;
■ 6-hydroxy-5,7-dimethylspiro[chromene-2,1'-cyclobutane]-3-carbaldehyde O-methyloxime,
■ 3-[(methoxyamino)methyl]-5,7-dimethylspiro[chromene-2,1 '-cyclobutan]-6-ol;
■ 3-(1-methoxyethyl)-5,7,8-trimethylspiro[chromene-2,1'-cyclobutan]-6-ol,

The present invention is concerned with certain novel spiro substituted heterocyclic ring
derivatives. These compounds may be useful in the manufacture of pharmaceutical
compositions for treating disorders mediated by lipoxygenase. They may also be useful in
the manufacture of pharmaceutical formulations for the treatment of lipoxygenase-mediated disorders.